Neuromodulation

Academic Press is an imprint of Elsevier 32 Jamestown Road, London NW1 7BY, UK 30 Corporate Drive, Suite 400, Burlington, MA 01803, USA 525 B Street, Suite 1900, San Diego, CA 92101-4495, USA First edition 2009 Copyright © 2009, Elsevier Ltd. All rights reserved No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the publisher Permissions may be sought directly from Elsevier’s Science & Technology Rights Department in Oxford, UK: phone (44) (0) 1865 843830; fax (44) (0) 1865 853333; email: [email protected]. Alternatively visit the Science and Technology Books website at www.elsevierdirect.com/rights for further information Notice No responsibility is assumed by the publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN: 978-0-12-374248-3 (Set) ISBN: 978-0-12-374967-3 (Volume 1) ISBN: 978-0-12-374968-0 (Volume 2) For information on all Academic Press publications visit our website at elsevierdirect.com Typeset by Macmillan Publishing Solutions www.macmillansolutions.com Printed and bound in China 09 10 11 12 13 11 10 9 8 7 6 5 4 3 2 1

List of Contributors

Mary Pat Aardrup Senior Vice President, National Pain Foundation, Englewood, Colorado, USA

Guy Amit, MD, MSc Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio, USA

David Abejón, MD, FIPP Pain Unit, Puerta de Hierro University Hospital, Madrid, Spain

Michael L.J. Apuzzo, MD Edwin M. Todd/Trent H. Wells, Jr Professor of Neurological Surgery and Professor of Radiation Oncology, Biology, and Physics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA

Farag Aboelsaad, MD Assistant Professor, Physical Medical & Rehabilitation, Albany Medical Center, New York, USA Daniel J. Abrams, MD Departments of Psychiatry and Neurosurgery, University of Colorado at Denver and Health Sciences Center, Denver, Colorado, USA

Jeffrey L. Ardell, PhD Department of Pharmacology, East Tennessee State University, Johnson City, Tennessee, USA

D. Michael Ackermann, Jr Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, USA

Tipu Z. Aziz, FRCS, MD, DMedSci Oxford Functional Neurosurgery, Department of Neurological Surgery, The John Radcliffe Hospital, Oxford, UK

Linda Ackermans, MD Department of Neurosurgery, University Hospital Maastricht, Maastricht, The Netherlands

Roy A.E. Bakay, MD Department of Neurosurgery, Rush University, Chicago, Illinois, USA

Adnan A. Al-Kaisy, MB ChB, FRCA Consultant in Pain Medicine, Pain Management and Neuromodulation Centre, Guy’s and St Thomas’ NHS Foundation Trust, London, UK

Gordon H. Baltuch, MD, PhD, FRCSC Department of Neurosurgery, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA

Kenneth M. Alo’, MD President, Kenneth Alo’ MDPA, Houston Texas Pain Management PA, TOPS Surgical Specialty Hospital, Palladium for Surgery–Houston, Houston, Texas, USA

Giancarlo Barolat, MD Director, The Barolat Institute, Lone Tree, Colorado, USA Allan I. Basbaum, PhD, FRS Department of Anatomy and W.M. Keck Foundation Center for Integrative Neuroscience, University of California San Francisco, California, USA

Ron L. Alterman, MD Department of Neurosurgery, Mount Sinai School of Medicine, New York, USA Arun Paul Amar, MD Department of Neurosurgery, Permanente Medical Group, and Stanford University School of Medicine, Stanford, California, USA

Marshall D. Bedder, MD, FRCP(C) Coastal Pain Management and Rehabilitation, Florida, USA

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List of contributors

Narendra Bhadra, MD, PhD Neural Engineering Center, Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, USA Sharon Bishop, BNurs, MHSci Department of Neurosurgery, Regina General Hospital, Regina, Canada Charles D. Blaha, PhD Department of Psychology, University of Memphis, Tennessee, USA Jonathan M. Bledsoe, MD Department of Neurosurgery, Mayo Clinic, Rochester, Minnesota, USA Nicholas Boulis, MD Department of Neurosurgery, Emory University School of Medicine, Atlanta, Georgia, USA Joao Braz, PhD Department of Anatomy and W.M. Keck Foundation Center for Integrative Neuroscience, University of California San Francisco, California, USA Giovanni Broggi, MD Division of Neurosurgery, Istituto Nazionale Neurologico “Carlo Besta”, Milan, Italy Adam P. Burdick, MD Department of Neurosurgery, University of Florida, Gainesville, Florida, USA Gennaro Bussone, MD Division of Neurology, Istituto Nazionale Neurologico “Carlo Besta”, Milan, Italy Linda L. Carpenter, MD Mood Disorders Research Clinic, Department of Psychiatry and Human Behavior, Butler Hospital, Brown University Medical School, Providence, Rhode Island, USA Daniel B. Carr, MD, DABPM Javelin Pharmaceuticals CEO; Saltonstall Professor of Pain Research, Departments of Anesthesiology and Internal Medicine, Tufts-New England Medical Center, Boston, Massachusetts, USA

John Chae, MD Cleveland Functional Electrical Stimulation Center, and Departments of Physical Medicine and Rehabili­ tation, and Biomedical Engineering, Case Western Reserve University, Cleveland; MetroHealth Rehabili­ tation Institute of Ohio, MetroHealth Medical Center, Cleveland, Ohio, USA Jin Woo Chang, MD, PhD Department of Neurosurgery, Brain Research Institute, Yonsei University College of Medicine, Seoul, Korea Jiande D.Z. Chen, PhD Division of Gastroenterology, Department of Internal Medicine, University of Texas Medical Branch at Galveston, Texas, USA David B. Cohen, MD Drexel University College of Medicine, Division of Neuromodulation, Department of Neurosurgery, Allegheny General Hospital, Pittsburgh, Pennsylvania, USA Jeffrey W. Cozzens, MD, FACS Associate Professor of Neurosurgery, Northwestern University Feinberg School of Medicine, NorthShore University HealthSystem, Evanston, Illinois, USA Firouz Daneshgari, MD Department of Urology & Female Pelvic Surgery, Upstate Medical University, Syracuse, New York, USA Ross Davis, MD Neurosurgeon, Neural Engineering Clinic, Melbourne, Florida, USA Timothy R. Deer, MD President and CEO, Center for Pain Relief, Department of Anesthesiology, University of West Virginia, Charleston, West Virginia, USA Mike J.L. DeJongste, MD, PhD, FESC Department of Cardiology, Thoraxcenter, Groningen University Hospital and University of Groningen, Groningen, The Netherlands Daniel M. Doleys, PhD Director, Pain and Rehabilitation Institute, Birmingham, Alabama, USA

James Cavuoto Editor and Publisher, Neurotech Reports, San Francisco, California, USA

John P. Donoghue, PhD Director, Brown Institute for Brain Science, and Depart­ment of Neuroscience, Brown University, Providence, Rhode Island, USA

Amanda Celii, BS Department of Neurosurgery, Jefferson Medical College, Philadelphia, Pennsylvania, USA

Michael F. Dorman, PhD Department of Speech and Hearing Science, Arizona State University, Tempe, Arizona, USA



List of contributors

Thomas Dresing, MD Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio, USA Dominique M. Durand, PhD Neural Engineering Center, Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, USA Allen R. Dyer, MD, PhD Professor of Psychiatry and Behavioral Sciences, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA Anthony Eidelman, MD Instructor Anesthesiology, Division of Pain Medicine, Washington University School of Medicine, Saint Louis, Missouri, USA Rosana Esteller, PhD NeuroPace, Inc., Mountain View, California, USA Steven Falowski, MD Department of Neurosurgery, Jefferson Medical College, Philadelphia, Pennsylvania, USA Thais Federici, PhD Department of Neurosciences and Center for Neurological Restoration, Cleveland Clinic, Cleveland, Ohio, USA Joseph J. Fins, MD, FACP Chief, Division of Medical Ethics, Professor of Medicine, Professor Public Health, Professor of Medicine in Psychiatry, Weill Medical College of Cornell University, New York; Member, Adjunct Faculty, The Rockefeller University, New York, USA Kelly D. Foote, MD Department of Neurosurgery, University of Florida, Gainesville, Florida, USA Robert D. Foreman, PhD Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA Kostas Fountas, MD, PhD Department of Neurosurgery, University of Larissa School of Medicine, Larissa, Greece Angelo Franzini, MD Division of Neurosurgery, Istituto Nazionale Neurologico “Carlo Besta”, Milan, Italy David Friedland, MD, PhD Department of Otolaryngology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA

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Gerhard M. Friehs, MD Department of Clinical Neurosciences (Neurosurgery Division), Brown University Medical School, Providence, Rhode Island, USA Loes Gabriëls, MD Department of Psychiatry, Katholieke Universiteit Leuven, Belgium Rollin M. Gallagher, MD, MPH Clinical Professor of Psychiatry and of Anesthesiology and Critical Care, University of Pennsylvania School of Medicine; Director of Pain Medicine, Philadelphia Veterans Medical Center; Pain Medicine Service, Philadelphia VA Medical Center, University and Woodland, Philadelphia, Pennsylvania, USA Philip L. Gildenberg, MD, PhD, FACS Adjunct Professor of Neurosurgery, Baylor Medical College; Houston Stereotactic Concepts, Inc., Houston, Texas, USA Teodor Goroszeniuk, FCA, RCSI, DA Pain Management and Neuromodulation Centre, Guy’s and St Thomas’ NHS Foundation Trust, London, UK Alexander L. Green, MB BS, MRCS Oxford Functional Neurosurgery, Department of Neurological Surgery, The John Radcliffe Hospital, Oxford, UK Benjamin D. Greenberg, MD Department of Psychiatry and Human Behavior, Warren Alpert Medical School at Brown University, Butler Hospital, Providence, Rhode Island, USA Roy K. Greenberg, MD, FACS Departments of Vascular & Cardiac Surgery and Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio, USA David A. Greene, BS NeuroPace, Inc., Mountain View, California, USA Beverley Greenwood-Van Meerveld, PhD, FACG VA Medical Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma Warren M. Grill, PhD Department of Biomedical Engineering, Duke University, Durham, North Carolina, USA William C. de Groat, PhD Department of Pharmacology and Chemical Biology, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania, USA

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List of contributors

Katherine E. Groothuis Departments of Neurological Surgery and Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA

Michael W. Keith, MD MetroHealth Medical Center, Case Western Reserve University, Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, USA

Shivani Gupta, MD Department of Neurosurgery, Regina General Hospital, Regina, Canada

Yves Keravel, MD Service de neurochirurgie, Hôpital Henri Mondor, Créteil, France

Casey H. Halpern, MD Department of Neurosurgery, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA

K. Riaz Khan, MB BS, DO, MD, FRCA Clinical Fellow in Pain Medicine, Guy’s and St Thomas’ NHS Foundation Trust, London, UK

Mouchir Harb, MD Neurologist and Pain Practice Physician, Las Vegas, Nevada, USA

Kevin L. Kilgore, PhD MetroHealth Medical Center, Louis Stokes Cleveland VA Medical Center, Case Western Reserve University, Cleveland, Ohio, USA

Bradley C. Hiner, MD Department of Neurology, Medical College of Wisconsin, and Clement J. Zablocki VA Medical Center, Milwaukee, Wisconsin, USA Leigh R. Hochberg, MD, PhD Rehabilitation Research and Development Service, Providence VA Medical Center; Department of Neuroscience, Brown University, Providence, Rhode Island, USA Svante Horsch, MD, PhD Department of Vascular Surgery, Hospital Porz am Rhein, Academic Teaching Hospital of the University of Cologne, Cologne, Germany Joseph C. Hsieh, MD, MBA, MPH, MS Section of Neurosurgery, University of Chicago, Chicago, Illinois, USA Jurg L. Jaggi, PhD Department of Neurosurgery, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA Patrick D. Jenkins, PhD Department of Neurosurgery, Medical College of Georgia, Augusta, Georgia, USA Hyun Ho Jung, MD Department of Neurosurgery, Brain Research Institute, Yonsei University College of Medicine, Seoul, Korea Leonardo Kapural, MD, PhD Clinical Research Director, Department of Pain Management, Cleveland Clinic; Associate Professor of Anesthesiology, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, Ohio, USA

David King-Stephens, MD Department of Neurosciences, California Pacific Medical Center, San Francisco, California, USA Jayme Knutson, PhD Cleveland Functional Electrical Stimulation Center, and Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, USA Brian Harris Kopell, MD Departments of Neurosurgery and Psychiatry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA Sandesha Kothari, FRCA, DA, DNB, MNAMS Pain Management and Neuromodulation Centre, Guy’s and St Thomas’ NHS Foundation Trust, London, UK Elliot S. Krames, MD, DABPM Medical Director, Pacific Pain Treatment Centers, San Francisco, California, USA; President, International Neuromodulation Society; Editor-in-Chief, Neuromodulation: Technology at the Neural Interface (The Journal of the International Neuromodulation Society) Krishna Kumar, MB, MS, FRCSC, FACS Department of Neurosurgery, Regina General Hospital, Regina, Canada Kris van Kuyck, PhD Department of Neurosciences, Laboratory for Experimental Functional Neurosurgery, Katholieke Universiteit Leuven, Belgium Kendall H. Lee, MD, PhD Department of Neurosurgery, Mayo Clinic, Rochester, Minnesota, USA



List of contributors

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Kwangdeok Lee, PhD Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, Ohio, USA

Tara M. Mastracci, MD, MSc, FRCSC Department of Vascular Surgery, Cleveland Clinic, Cleveland, Ohio, USA

Jean Pascal Lefaucheur, MD, PhD Département des explorations fonctionnelles, Hôpital Henri Mondor, Créteil, France

Paolo Mazzone, MD Operative Unit of Stereotactic and Functional Neuro­ surgery, Ospedale CTO “A. Alesini”, Rome, Italy

Massimo Leone, MD Division of Neurology, Istituto Nazionale Neurologico “Carlo Besta”, Milan, Italy

Sarah McAchran, MD Formerly Glickman Urological Institute, Cleveland Clinic, Cleveland, Ohio; Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA

Michael L. Levy, MD Division of Neurosurgery, Children’s Hospital of San Diego and University of California San Diego School of Medicine, San Diego, California, USA Robert M. Levy, MD, PhD Departments of Neurological Surgery and Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA Dianyou Li, MD Center for Functional Neurosurgery, Shanghai Jiaotong University Rui Jin Hospital, Shanghai, China Goran Lind, MD Department of Neurosurgery, Karolinska University Hospital, Stockholm, Sweden Bengt Linderoth, MD, PhD Department of Neurosurgery, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden; Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA Brian Litt, MD Department of Neurology, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA Charles Y. Liu, MD, PhD Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California, USA Andre G. Machado, MD, PhD Center for Neurological Restoration, Departments of Neurosurgery and of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio, USA Sandra Machado, MD Bakken Heart–Brain Institute; Anesthesiology Institute, Cleveland Clinic, Cleveland, Ohio, USA Carlo Marras, MD Division of Neurosurgery, Istituto Nazionale Neurologico “Carlo Besta”, Milan, Italy

Cameron C. McIntyre, MS Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio, USA Paul Meadows, MS Vice President of R&D, ImThera Medical, Inc., Glendale, California, USA Muhammad Memon, MD Former Research Fellow, Department of NeuroOphthalmology, Massachusetts Eye and Ear Infirmary, Harvard University, Boston, Massachusetts, USA; PhD student, Department of Neurosciences, Imperial College, London, UK Giuseppe Messina, MD Division of Neurosurgery, Istituto Nazionale Neurologico “Carlo Besta”, Milan, Italy Björn A. Meyerson, MD, PhD Department of Neurosurgery, Karolinska Institutet and Karolinska University Hospital Stockholm, Sweden Alon Y. Mogilner, MD, PhD Chief, Section of Functional and Restorative Surgery, North Shore-LIJ Health System, Manhasset, New York, USA Liz Moir, RGN Oxford Functional Neurosurgery, Department of Neurological Surgery, The John Radcliffe Hospital, Oxford, UK Gregory F. Molnar, PhD Senior Research Manager, Medtronic Neuromodulation, Minneapolis, Minnesota, USA J. Thomas Mortimer, PhD Neural Engineering Center, Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, USA

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List of contributors

Anthony M. Murro, MD Department of Neurology, Medical College of Georgia, Augusta, Georgia, USA

Marc S. Penn, MD, PhD, FACC Director, Bakken Heart–Brain Institute, Cleveland Clinic, Cleveland, Ohio, USA

Jean Paul Nguyen, MD Service de neurochirurgie, Hôpital Henri Mondor, Créteil; Service de neurochirurgie, Hôpital Laennec, Nantes, France

Richard D. Penn, MD Section of Neurosurgery, University of Chicago, Chicago, Illinois, USA

Richard B. North, MD Director, Neuromodulation, Surgical Pain Management & Surgical Spine Pain Program; LifeBridge Health Brain & Spine Institute, Baltimore; Professor of Neurosurgery, Anesthesiology and Critical Care Medicine (ret.), Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Bart Nuttin, MD, PhD Department of Neurosciences, Laboratory for Experimental Functional Neurosurgery, Katholieke Universiteit Leuven, Belgium Michael Y. Oh, MD Drexel University College of Medicine, Division of Neuromodulation, Department of Neurosurgery, Allegheny General Hospital, Pittsburgh, Pennsylvania, USA Michael S. Okun, MD Department of Neurology, University of Florida, Gainesville, Florida, USA John P. O’Reardon, MD Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, USA Michael H. Ossipov, PhD Department of Pharmacology, University of Arizona, Tucson, Arizona, USA Joseph J. Pancrazio, PhD Neural Engineering Program Director, The National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA Yong D. Park, MD Department of Neurology, Medical College of Georgia, Augusta, Georgia, USA P. Hunter Peckham, PhD Donnell Institute Professor, Department of Biomedical Engineering, Case Western Reserve University, Cleveland; Director, Functional Electrical Stimulation Center, Louis Stokes Cleveland VA Medical Center, and MetroHealth Medical Center, Cleveland, Ohio, USA; Editor of Neuromodulation: Technology at the Neural Interface (The Journal of the International Neuromodulation Society)

Erlick A.C. Pereira, MA, MRCS(Eng) Oxford Functional Neurosurgery, Department of Neurological Surgery, The John Radcliffe Hospital, Oxford, UK Yann Péréon, MD, PhD Département des explorations fonctionnelles, Hôpital Laennec, Nantes, France Julie G. Pilitsis, MD, PhD Department of Neurosurgery, Rush University, Chicago, Illinois, USA Katharine H. Polasek, PhD Investigator, Functional Electrical Stimulation Center of Excellence, Cleveland VA Medical Center, Cleveland, Ohio, USA Dejan Popovic, Dipl. Eng., PhD, Dr Techn. Professor, Aalborg University, Center for Sensory Motor Interaction, Aalborg, Denmark; and Faculty of Electrical Engineering, University of Belgrade, Serbia Frank Porreca, PhD Department of Pharmacology, University of Arizona, Tucson, Arizona, USA Joshua P. Prager, MD, MS Director, Center for the Rehabilitation of Pain Syndromes (CRPS), Departments of Internal Medicine and Anesthesiology, David Geffer School of Medicine at UCLA, Los Angeles, California, USA; Immediate Past President, North American Neuromodulation Society (NANS) Kara J. Quan, MD Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio, USA Raymond Rackley, MD Glickman Urological Institute, Cleveland Clinic, Cleveland, Ohio, USA Matthew T. Ranson, MD Center for Pain Relief, Department of Anesthesiology, University of West Virginia, Charleston, West Virginia, USA Sylvie Raoul, MD, PhD Service de neurochirurgie, Hôpital Laennec, Nantes, France



List of contributors

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Richard L. Rauck, MD Pain Fellowship Director, Wake Forest University Health Sciences, Winston Salem, North Carolina, USA

Ashwini D. Sharan, MD Department of Neurosurgery, Jefferson Medical College, Philadelphia, Pennsylvania, USA

Enrique Reig, MD, PhD, FIPP Clínica del Dolor de Madrid, Madrid, Spain

Lynne R. Sheffler, MD Cleveland Functional Electrical Stimulation Center, and Departments of Physical Medicine and Rehabilitation, and Biomedical Engineering, Case Western Reserve University, Cleveland; MetroHealth Rehabilitation Institute of Ohio, MetroHealth Medical Center, Cleveland, Ohio, USA

Ali R. Rezai, MD Director, Center for Neurological Restoration, Neurological Institute, and Jane and Lee Seidman Chair in Functional Neurosurgery, Department of Neurosurgery, Cleveland Clinic, Cleveland, Ohio, USA; Editor of Neuromodulation: Technology at the Neural Interface (The Journal of the International Neuromodulation Society) Jonathan Riley, BSE Department of Neurosciences and Center for Neurological Restoration, Cleveland Clinic, Cleveland, Ohio, USA Joseph F. Rizzo III, MD Director of Neuro-Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard University, Boston, Massachusetts, USA Joshua M. Rosenow, MD, FACS Director, Functional Neurosurgery Northwestern Memorial Hospital; Assistant Professor of Neurosurgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA Vincent Roualdes, MD Service de neurochirurgie, Hôpital Laennec, Nantes, France Uzma Samadani, MD, PhD Department of Neurosurgery, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA Eugenio Scarnati, PhD Department of Biomedical Sciences and Technologies, University of L’Aquila, Italy Nicholas D. Schiff, MD Director, Laboratory of Cognitive Neuromodulation; Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, USA

Frank G. Shellock, PhD, FACC, FACSM Founder, Institute for Magnetic Resonance Safety, Education, and Research; Departments of Radiology and Medicine, Keck School of Medicine, Los Angeles, California, USA Jane Shipley, BA Executive Director, The Neuromodulation Foundation, Inc., Baltimore, Maryland, USA Karl A. Sillay, MD Department of Neurological Surgery, University of Wisconsin, Madison, Wisconsin, USA Janna L. Silverstein, BA Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA Kathleen A. Sluka, PT, PhD Professor, Graduate Program in Physical Therapy and Rehabilitation Science, Pain Research Program, Neuroscience Graduate Program, University of Iowa, Iowa City, Iowa, USA Howard S. Smith, MD Associate Professor and Director of Pain Management, Department of Anesthesiology, Albany Medical College, Albany, New York, USA Joseph R. Smith, MD Department of Neurosurgery, Medical College of Georgia, Augusta, Georgia, USA Michael Stanton-Hicks, MD Department of Pain Management, Anesthesiology Institute, Cleveland Clinic, Cleveland, Ohio, USA

Stefan Schulte, MD, PhD Center for Vascular Medicine and Vascular Surgery, MediaPark Clinic, Cologne, Germany

Philip A. Starr, MD, PhD Department of Neurosurgey, University of California San Francisco, California, USA

Cristian Sevcencu, PhD Center for Sensory-Motor Interaction (SMI), Department of Health Science and Technology, Aalborg University, Denmark

Douglas Stewart, PA-C, MBA Center for Pain Relief, Department of Anesthesiology, University of West Virginia, Charleston, West Virginia, USA

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List of contributors

Bomin Sun, MD Center for Functional Neurosurgery, Shanghai Jiaotong University Rui Jin Hospital, Shanghai, China Michele Tagliati, MD Department of Neurology, Mount Sinai School of Medicine, New York, USA Rod S. Taylor, PhD Peninsula Medical School, Universities of Exeter & Plymouth, Exeter, UK Yasin Temel, MD, PhD Department of Neurosurgery, University Hospital Maastricht, Maastricht, The Netherlands Giovenni Tringali, MD Division of Neurosurgery, Istituto Nazionale Neurologico “Carlo Besta”, Milan, Italy Dustin J. Tyler, PhD Nord Distinguished Assistant Professor, Case Western Reserve University, Department of Biomedical Engineering; Associate Director, Advanced Platform Technology Center of Excellence, and Principal Investigator, Functional Electrical Stimulation Center of Excellence, Cleveland VA Medical Center, Cleveland, Ohio, USA Sandip Vasavada, MD Glickman Urological Institute, Cleveland Clinic, Cleveland, Ohio, USA Veerle Visser-Vandewalle, MD, PhD Department of Neurosurgery, University Hospital Maastricht, Maastricht, The Netherlands Deirdre M. Walsh, PT, PhD Professor of Rehabilitation Research, Health and Rehabilitation Sciences Research Institute, University of Ulster, Newtownabbey, Co. Antrim, Northern Ireland, UK

Richard L. Weiner, MD Chair, Department of Neurosurgery, Presbyterian Hospital of Dallas; Clinical Associate Professor of Neurosurgery, University of Texas Southwestern Medical School, Dallas, Texas, USA Donald Weisz, PhD Department of Neurosurgery, Mount Sinai School of Medicine, New York, USA Donald M. Whiting, MD Drexel University College of Medicine, Division of Neuromodulation, Department of Neurosurgery, Allegheny General Hospital, Pittsburgh, Pennsylvania, USA Blake S. Wilson, BSEE Department of Surgery, Division of Otolaryngology, Head & Neck Surgery, Duke University Medical Center, Durham, North Carolina, USA; MED-EL GmbH, Innsbruck, Austria Jaleh Winter, RN Department of Neurosurgery, Karolinska University Hospital, Stockholm, Sweden Margaret C. Wyche, BS Mood Disorders Research Clinic, Department of Psychiatry and Human Behavior, Butler Hospital, Warren Alpert Medical School at Brown University, Providence, Rhode Island, USA Hemmings Wu, MD Center for Functional Neurosurgery, Shanghai Jiaotong University Rui Jin Hospital, Shanghai, China Jieyun Yin, MD Division of Gastroenterology, Department of Internal Medicine, University of Texas Medical Branch at Galveston, Texas, USA Shikun Zhan, MD Center for Functional Neurosurgery, Shanghai Jiaotong University Rui Jin Hospital, Shanghai, China

Foreword Joseph J. Pancrazio, PhD

The National Institute of Neurological Disorders and Stroke

It is indeed an honor to provide a foreword for Neuromodulation. Without a doubt, this book bears the burden of being the first of its kind, and may well set the standard for efforts that follow. In the broadest sense, neuromodulation involves the use of technology to alter, adjust or modify neural activity. By its multidisciplinary nature, the research and development underlying neuromodulation draws upon the talents and experience of scientists, engineers, and clinicians, often working most productively as teams. In addition, the emergence of neuromodulation in several cases from the proof-of-concept stage to a clinical standard of care has also brought individuals with business experience to the field. This reference work is not an exception to this team science endeavor; it too is the product of a diverse group of multidisciplinary individuals who share the vision of relieving the burden of neurological diseases and injuries through the judicious use of devices. The charge for the contributors is consequently and necessarily ambitious: to convey the basic, translational, and clinical science underlying neuromodulation while providing insight into the ethical, corporate, and historical bases for such devices. Therefore, the scope of the book is wide, encompassing theoretical, applied, and logistical issues. For readers with interests in basic science, there is information concerning the fundamentals of the nervous system with emphasis on neurobiology, neuroanatomy, and the basis for electrical stimulation/recording. For readers with clinical interests, there are chapters that address the physiology and pathophysiology of regions of the nervous system relevant to movement disorders, pain, epilepsy, and psychiatric illnesses such as depression and obsessive–compulsive disorder. For clinical practitioners, the book surveys neuromodulation

approaches, primarily through electrical stimulation and drug delivery, to treat a range of neurological disorders. Of no less importance is the chapter concerned with ethical issues – a significant challenge since neuromodulation can affect the capacity of patient to provide consent. In addition, the chapter entitled “ Whom Do We Serve?” reminds the reader that this book is about treating patients. While the notion of implanted devices that interact with the nervous system may inspire the fantasies of enhancement among science fiction enthusiasts, the goal of neuromodulation is to relieve the burden of neurological disease. Insights into the future of neuromodulation require reflection on what has driven its success. While studies in basic neuroscience have been essential, neuromodulation is also indebted to advances in engineering and physics. Implanted devices of ever increasing sophistication have been enabled by the age of the integrated circuit, microfabrication methodologies, and higher density power storage systems. Physics has provided non-invasive real-time imaging technologies that allow an unprecedented view of the anatomy and functionality of the nervous system in health and disease. Indeed, hypothesis-driven applications of implanted systems are emerging where seemingly simple block diagram representations of neural network pathways important to neurological disease drive the choice of implantation targets. It is expected that this trend towards modeling will continue and become more sophisticated and the device capabilities will grow such that the activity of dysfunctional networks or even neurons will be selectively and precisely modulated in patients. Undoubtedly, to fully embrace this potential, neuromodulation will continue to be a multidisciplinary pursuit capitalizing on the strength of diverse teams.

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Preface

Neuromodulation is the first comprehensive reference work encompassing all aspects of the field of neuromodulation – a field that involves individuals with many different backgrounds and interests. We, the Editors, have chosen our contributors for this project because they are the leading experts in their field with significant contributions to neuromodulation. We believe that this book will be a reference for neuromodulation practitioners and clinicians, scientists, biomedical engineers, and members of industry for years to come. This reference work is divided into 11 major sections that represent the entire scope of neuromodulation. These sections include an introduction, the fundamentals of neuromodulation, biomedical engineering considerations, neuromodulation for chronic pain, neuromodulation for movement disorders, neuromodulation for epilepsy, neuromodulation for psychiatric disorders, neuromodulation for functional restoration, neuromodulation for specific body organs, emerging new applications for neuromodulation, implantation techniques, and finally the appendices. Each section has an introductory overview by a prominent section editor. The information presented includes the latest updates for each specific topic, including a review of the current literature. When applicable, a historical perspective of the use of neuromodulation for the specific topic is

included as well as an anatomical review, and technical considerations are provided along with a look into the future of neuromodulation for the specific condition. The purpose of this book is to provide our readers with an improved awareness and understanding and provide a comprehensive reference pertaining to the ever-growing field of neuromodulation. Fundamental principles as well as current and emerging applications are included in this book. In light of the fact that neuromodulation of the nervous system is capable of modulating all nervous system elements (brain, cranial nerves, peripheral nerves, spinal cord, and the autonomic nervous system), body organs and the corresponding functions of the human body, the potential of this field is enormous. In this regard, education, research, device development, and maturing clinical applications are crucial to further advance this field and realize its enormous impact for helping patients. We dedicate this book to our patients, neuromodulation practitioners, scientists, biomedical engineers, entrepreneurs, the medical device industry, and others working in the exciting world of neuromodulation. E.S.K. P.H.P. A.R.R.

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C H A P T E R

1

What Is Neuromodulation? Elliot S. Krames, P. Hunter Peckham, Ali R. Rezai, and Farag Aboelsaad

o u t line Defining Neuromodulation Other Definitions and Terms

3 5

The Field of Neuromodulation

5

Neuromodulation for Chronic Pain Brain Neuromodulation 

5 6

Neuromodulation for Spasticity Functional Electrical Stimulation (FES) Neuromodulation and GI Disorders Neuromodulation for Urological Disorders Neuromodulation for Cardiac Disorders References

Defining neuromodulation

7

the science of how electrical, chemical, and mechanical interventions can modulate the nervous system function. Neuromodulation is inherently non-destructive, reversible, and adjustable. The INS (the International Neuromodulation Society) (Sakas et al., 2007) defines neuromodulation as a field of science, medicine, and bioengineering that encompasses implantable and non-implantable technologies, electrical or chemical, for the purpose of improving quality of life and functioning of humans. At the present time, neuromodulation implantable devices are either neural stimulators or micro­infusion pumps. These devices are being utilized for the management of chronic pain, movement dis­orders, psychiatric disorders, epilepsy, dismotility disorders, disorders of pacing, spasticity, and others (Figure 1.2). Neuroprostheses such as cochlear implants and sacral root stimulators are also commonly included within the definition of neuromodulation.

Neuromodulation is among the fastest-growing areas of medicine, involving many diverse specialties and impacting hundreds of thousands of patients with numerous disorders worldwide. In the past decade, neuromodulation has witnessed significant advances with regard to the science, mechanisms, clinical applications, and technology development. These advances have been coupled with the rapid growth of the neuromodulation device industry and improvements in current devices and development of next generation neuromodulation systems (Figure 1.1). Neuromodulation is “technology impacting on the neural interface.” It is the process of inhibition, stimulation, modification, regulation or therapeutic alteration of activity, electrically or chemically, in the central, peripheral or autonomic nervous systems. It is

Neuromodulation

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© 2008, 2009 Elsevier Ltd.



1.  what is neuromodulation?

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Vagus nerve stimulators

Gastric electric stimulators

Figure 1.1  The growing neuromodulation market between 2004 and 2010. By the year 2010, the market is expected to reach $3bn (Source: Millennium Research Group, 2006)

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Figure 1.2  Some of the disorders and the numbers of persons affected by these disorders available to being treated by neurostimulation, a form of neuromodulation (Source: US qualitative research with referrers and potential implanters, literature search, internal discussions, and data analysis)

Jan Holsheimer (2003) suggests that for a therapy to be considered neuromodulation, the therapy must consist of the following:

3. The clinical effect is continuously controllable by varying one or more stimulation parameters to satisfy a patient’s need.

1. The therapy must be dynamic, ongoing (continuous or intermittent) intervention, and not a short and non-recurring procedure. 2. The activity of specific neural networks is affected by the ongoing electrical stimulation or by ongoing neuropharmacological stimulation.

Neuromodulation therefore is either electrical or chemical. Electrical neuromodulation is electrical stimulation of the brain, spinal cord, peripheral nerves, plexuses of nerves, the autonomic system, and functional electrical stimulation of the muscles, while chemical neuromodulation uses direct placement of

I. an introduction to neuromodulation

neuromodulation for chronic pain

chemical agents to neural tissues through utilization of technology of implantation such as epidural or intrathecal delivery systems.

Other Definitions and Terms The term neuromodulation can be defined as a technology that impacts upon neural interfaces and is the science of how electrical, chemical, and mechanical interventions can modulate or change central and peripheral nervous system functioning. It is a form of therapy in which neurophysiological signals are initiated or influenced with the intention of achieving therapeutic effects by altering the function and performance of the nervous system. The term neuromodulation, in the opinion of these authors, should replace other terms that are relevant to the field and are being used, including neuroaugmentation, neuro­ stimulation, neuroprosthetics, functional electrical stimulation, assistive technologies, and neural engineering (Sakas et al., 2007). These terms have much overlap and tend to confuse the uninitiated. Neuroaugmentation is defined by the OnLine Medical Dictionary as the use of electrical stimulation to supplement the activity of the nervous system. Neurostimulation is the process or technology that applies electrical currents, in varying parameters, by means of implanted electrodes to achieve functional activation or inhibition of specific neuronal groups, pathways, or networks. Functional electrical stimulation, also known as FES, is defined as a technique that uses electrical currents to activate nerves innervating extremities affected by paralysis resulting from spinal cord injury (SCI), head injury, stroke, or other neurological disorders, restoring function in people with disabilities (Wikipedia: Functional Electrical Stimulation). FES is electrical stimulation of a muscle to provide normal control in order to produce a functional useful contraction, therefore, electrical stimulation that produces only sensory response generally would not be termed as FES and electrical stimulation that reduces pain is also not FES. Neuroprosthetics “is a discipline related to neuroscience and biomedical engineering concerned with developing neural prostheses, artificial devices to replace or improve the function of an impaired nervous system. The neuroprosthetic that has the most widespread use today is the cochlear implant with approximately 100 000 in worldwide use as of 2006” (Wikipedia: Neuroprosthetics). Neural engineering is an emerging interdisciplinary field of research that uses engineering techniques to investigate the function and manipulate the behavior of the central or peripheral nervous systems. The field draws heavily on the fields of computational neuroscience, experimental



neuroscience, clinical neurobiology, electrical engineering and signal processing of living neural tissue, and encompasses elements from robotics, computer engineering, neural tissue engineering, materials science and nanotechnology (Answers.Com.).

The field of neuromodulation Neuromodulation, paraphrasing Jan Holsheimer (2003), should be concerned with long-term treatment of chronic conditions. It is a rapidly evolving multidisciplinary biomedical and technical field and is among the fastest-growing fields of medicine today. Multiple specialties are now utilizing neuromodulatory techniques to benefit their patients. The field of neuromodulation covers a wide and heterogeneous range of conditions that include disorders of cardiac pacing, eyesight, gastric motility, epilepsy, headaches, hearing , limb and organ ischemia, movement disorders, occipital neuralgia, chronic pain, peripheral neuralgias, psychiatric and neurobehavioral disorders, spasticity, stroke, traumatic brain injury, urinary frequency, urinary urgency, urinary and fecal incontinence, and more (see Figure 1.3). Because the nervous system controls body functions and because disorders of body functions are ubiquitous, many clinical specialists, including anesthesiologists, cardiologists, gastroenterologists, neurologists, neurosurgeons, ophthalmologists, otolaryngologists, pain physicians, psychiatrists, physical medicine and rehabilitation specialists, and urologists use the therapies of neuromodulation. The goal of this book was to provide a comprehensive review and discussion pertaining to all aspects of the field of neuromodulation. Specific chapters will address the fundamentals of neuromodulation, including mechanisms of neuromodulation, neural networks, neuroscience, basics of device design, impact of technology at the neural interface, computational science, modeling, and others. This essential information benefits all those involved with neuromodulation. In addition to the fundamentals and general background topics, specific clinical applications of neuromodulation for various conditions will be provided with chapters pertaining to the following topics.

Neuromodulation for chronic pain An extensive and detailed discussion of neuromodulation for pain management will be provided in

I. an introduction to neuromodulation



1.  what is neuromodulation?

Figure 1.3  Uses of neuromodulatory devices, both electrical and chemical, to treat a myriad of disorders of the human body (Reproduced with permission of Advanced Neuromodulation Systems, Plano, TX)

multiple chapters. Chronic pain is estimated to be the third largest healthcare problem in the world, afflicting around 30% of the worldwide population (Latham and Davis, 1994). Chapters on micro-infusion therapy, spinal cord, peripheral nerve and brain stimulation will review the various methods and approaches used to treat chronic pain conditions. This includes chronic regional pain syndrome (CRPS), headaches, occipital neuralgia, failed back pain, neck pain, extremity pain, degenerative spinal disease pain, central pain, cancer pain, visceral pain, and other pain conditions.

neuromodulation implants. In this context, the emerging use of brain stimulation for the treatment of neurobehavioral disorders such as obsessive–compulsive disorder and depression as well as epilepsy will be discussed. Additional applications of brain stimulation for eating disorders, addiction, obesity, tinnitus, blood pressure control, and traumatic brain injury will be discussed in the emerging application section. Additional brain neuromodulation chapters pertain to novel uses of brain infusion and neuromodulation approaches for Alzheimer’s and other neurodegenerative disorders.

Brain Neuromodulation Brain neuromodulation involving cortical and sub-cortical neurostimulation has been growing significantly, with a number of emerging applications involving multiple disorders. The most visible among these has been the use of deep brain stimulation (DBS) for treatment of movement disorders (Parkinson’s disease, dystonia, essential tremor). The success of DBS for movement disorders in over 55 000 patients worldwide has provided a platform for acceptance of the concept of a brain stimulator or a brain pacemaker. The use of DBS in Parkinson’s disease and other movement disorders has ushered in a new ear of brain

Neuromodulation for Spasticity The use of intrathecal baclofen infusion pumps has provided significant relief for patients suffering from spasticity secondary to multiple sclerosis, stroke, and other conditions. This is one of the most common and successful uses of neuromodulation infusion devices.

Functional Electrical Stimulation (FES) FES encompasses the control of movements that are compromised because of impairment. It enhances

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neuromodulation for chronic pain

exercise of paralyzed extremities, and augments activity of afferent neural pathways (Popovic et al., 2002). Applications to improve functional ability of patients include enhancing upper and lower extremity functions as well as increasing range of motion of affected joints. FES devices serve as neuro-orthoses or external controls for motor function. Other benefits of FES include increasing muscle mass, reducing venous pooling, increasing stroke volume and cardiac output, and improvement of cardiovascular fitness, especially for paralyzed patients, as in patients with spinal cord injury. Neuroprosthetics that employ FES are effective in providing functional enhancement in patients with severe neurological impairment as in patients with spinal cord injury or stroke. The goals of these devices are to provide independence of functions of daily living such as standing, walking, breathing, micturition, and defecation (Grill and Kirsch, 2000; Troyk and Donaldson, 2001; Chae et al., 2002).

Neuromodulation and GI Disorders The use of electrical gastric stimulation for the management of gastroparesis (Forster et al., 2001) has proven to be an effective therapy for the problem. Gastric stimulation normalizes gastric dysrhythmias, entrains gastric slow waves, accelerates gastric emptying, and significantly reduces symptoms of nausea and vomiting in gastroparetic patients (Zhiyue et al., 2003). A number of approaches using neurostimulation are being explored for the management of obesity (Cigaina, 2002, 2004). Additional stimulation of the enteric plexii and the endothelium, itself, has been used for motility disorders of the small and large intestines (Kenefick and Christiansen, 2004; Baeten, 2007; Dinning et al., 2007; Sevcencu, 2007). We have provided chapters on gastric stimulation for obesity, dysmotility disorders and intestinal electrical stimulation are presented.



bladder (and bowel) is a complication of many common neurological disorders as in multiple sclerosis and spinal cord injury (Brookoff, 2000). Treatment of refractory overactive bladder was first successfully performed using an implanted percutan­ eous tibial nerve stimulator (van der Pal et al., 2006). Neurally augmented sexual function can be achieved by the application of electrical stimulation to spinal cord or peripheral nerves, including the sacral nerves (Meloy and Southern, 2006). Sacral nerve stimulation for IC, for overactive bladder, and urinary incontinence is mainstream therapy, today. These various neuromodulation approaches for treating urological disorders are covered in this specific section.

Neuromodulation for Cardiac Disorders Cardiovascular diseases impose a heavy socioeconomic burden on any healthcare system. Today, pacemakers and defibrillators are common therapeutic tools for cardiac disorders which have improved and saved the lives of millions of patients worldwide. Cardiac pacing devices and neurostimulators have many similarities in evolution and development and significant knowledge can be learned from the story of cardiac pacemakers and defibrillators as applied to the future of neurostimulation. In addition, a number of neurostimulation approaches are being explored for treating cardiovascular disorders and these will be discussed in specific chapters. In light of the fact that neuromodulation of the nervous system is capable of modulating all nervous system elements (brain, cranial nerves, peripheral nerves, spinal cord, and the autonomic nervous system), as well as body organs and the corresponding functions of the human body, the potential of this field is indeed enormous.

References Neuromodulation for Urological Disorders Sacral neuromodulation (Ganio and Masin, 2000; Hohenfellner et al., 2001) has become a valid therapeutic option for patients with urological painful and dysmotility conditions such as interstitial cystitis, neurogenic bladder, and overactive bladder. There is an estimated 6% prevalence of classic interstitial cystitis (IC) in American women while an overactive bladder syndrome affects approximately 17% of the adult population of the USA with an estimated worldwide prevalence of 50 million. Additionally, neurogenic

Answers.Com. http://www.answers.com/topic/neural-engineering (accessed October 2008). Baeten, C.G.M.I. (2007) Sacral nerve stimulation for fecal incontinence: current worldwide results. Neuromodulation 10 (1): 185–6. Brookoff, D. (2000) Chronic pelvic pain. In: S.E. Abram and J.D. Haddox (eds), The Pain Clinic Manual. Philadelphia, PA: Lippincott, Williams & Wilkins, pp. 239–47. Chae, J., Triolo, R., Kilgore, K.L., Creasey, G. and DeMarco, A. (2002) Neuromuscular electrical stimulation in spinal cord injury. In: S. Kirshblum, D. Campagnola and J. DeLisa (eds), Spinal Cord Injury Medicine. Philadelphia, PA: Lippincott, Williams & Wilkins, pp. 360–88. Cigaina, V. (2002) Gastric pacing as therapy for morbid obesity: preliminary results. Obesity Surgery 12 (S1): S12–S16.

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1.  what is neuromodulation?

Cigaina, V. (2004) Long-term follow-up of gastric stimulation for obesity: the Mestre 8-year experience. Obes. Surg. 14 (S1): S14–S22. Dinning, P.G., Fuentealba, S.E., Kennedy, M.L., Lubowski, D.Z. and Cook, I.J. (2007) Sacral nerve stimulation induces pan-colonic propagating pressure waves and increases defecation frequency in patients with slow-transit constipation. Colorectal Dis. 9 (2): 123–32. Forster, J., Sarosiek, I., Delcore, R., Lin, Z. et al. (2001) Gastric pacing is a new surgical treatment for gastroparesis. Am. J. Surg. 182: 676–81. Ganio, E. and Masin, A. (2000) Short-term sacral nerve stimulation for functional anorectal and urinary disturbances: results in 49 patients. Dis. Colon Rectum, 43: A17. Grill, W.M. and Kirsch, R.F. (2000) Neuroprosthetic applications of electrical stimulation. Assist. Technol. 12: 6–20. Hohenfellner, M., Humke, J., Hampel, C. et al. (2001) Chronic sacral neuromodulation for treatment of neurogenic bladder dysfunction: long-term results with unilateral implants. Urology 58: 887–92. Holsheimer, J. (2003) Letters to the editor. Neuromodulation 6 (4): 270–3. Kenefick, N.J. and Christiansen, J. (2004) A review of sacral nerve stimulation for the treatment of faecal incontinence. Colorectal Dis. 6 (2): 75–80. Latham, J. and Davis, B.D. (1994) The socioeconomic impact of chronic pain. Disability Rehab. 16: 39–44. Meloy, T.S. and Southern, J.P. (2006) Neurally augmented sexual function in human females: a preliminary investigation. Neuromodulation 9 (1): 34–40.

OnLine Medical Dictionary. http://cancerweb.ncl.ac.uk/cgibin/ omd?neuroaugmentation (accessed October 2008). Popovic, D.B., Popovic, M.B. and Sinkjær, T. (2002) Neuro­ rehabilitation of upper extremities in humans with sensorymotor impairment. Neuromodulation 5 (1): 54–66. Sakas, D.E., Panourias, I.G., Simpson, B.A. and Krames, E.S. (2007) An introduction to operative neuromodulation and functional neuroprosthetics, the new frontiers of clinical neuroscience and biotechnology. In: D.E. Sakas, B.A. Simpson and E.S. Krames (eds), Operative Neuromodulation, Vol. 1. Vienna: Springer Verlag, pp. 3–10. Sevcencu, C. (2007) A review of electrical stimulation to treat motility dysfunctions in the digestive tract: effects and stimulation patterns. Neuromodulation 10 (1): 85–99. Troyk, P.R. and Donaldson, N.D. (2001) Implantable FES stimulation systems: what is needed? Neuromodulation 4: 196–204. van der Pal, F., van Balken, M.R., Heesakkers, J.P.F.A., Debruyne, F.M.J. and Bemelmans, B.L.H. (2006) Implant-driven tibial nerve stimulation in the treatment of refractory overactive bladder syndrome: 12-month follow-up. Neuromodulation 9 (2): 163–71. Wikipedia. http://en.wikipedia.org/wiki/Functional_electrical_stim‑ ulation (accessed October 2008). Wikipedia. http://en.wikipedia.org/wiki/Neuroprosthetics (accessed October 2008). Zhiyue, L., Forster, J., Sarosiek, I. and McCallum, R.W. (2003) Review: treatment of gastroparesis with electrical stimulation. Digest. Dis. Sci. 48 (5): 837–48.

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C H A P T E R

2

Neuromodulation: A Historical Perspective Philip L. Gildenberg

scientific side, he amused his friends and admirers at his home by literally shocking them as they touched a contact charged by a static electricity generator. The remarkable breadth of his contributions is all the more impressive if one recognizes that this report antedated the demonstration of electrical contraction of frog muscle by Galvani in 1780 (De viribus electricitatis in motu musculari. Commentarius. Pars prima. Bolonien Scientiarium Art Inst Adad 1791; 7: 363–418, cited in Pruel, 1997). The popular curiosity about electricity was intensified in 1818 by Mary Shelley (1818). In the introduction to her novel Frankenstein, she cited the observation of Dr Erasmus Darwin (Charles Darwin’s grandfather) that electricity might have caused reanimation of a rehydrated worm “vorticellae” (which she incorrectly quoted as vermicelli). She speculated that “perhaps a corpse would be reanimated; galvanism had given token of such things; perhaps the component parts of a creature might be manufactured, brought together, and imbued with vital warmth.” Galvanic current is direct current, which stimulates as the current is suddenly applied or suddenly discontinued. As early as 1804, Aldini (1804) stimulated the facial nerve in fresh cadavers with galvanic current and noted contraction of the facial muscles. Faradic or alternating current applies a continuous stimulation to nerve or muscle. When faradic current generators were developed early in the nineteenth century, they were soon used in the experimental animal laboratory. As early as 1824, Flourens reported on stimulation of the exposed cortex. He erroneously concluded that the cortex was homogenously non-responsive to stimulation. He was able to elicit muscle contraction on stimulating the brain stem, and concluded that was the site of motor control (P. Flourens: Recherches expérimentales sur

We are presently in a time of growth of neuromodulation. All of the information that makes for a successful technology has come together, and progress is rapid. But what is that information and where did it come from? From the standpoint of this review, we will consider neuromodulation to be chronic therapeutic electrical stimulation of the central nervous system or special nerves with an implanted stimulating device. This term does not apply to naturally occurring electrical stimulation, primitive electrical devices, cutan­eous stimulation, acute or intraoperative stimulation, or sensory stimulation of peripheral nerves. Motor stimulation via peripheral nerves, as in functional electrical stimulation (FES), is a subject beyond this chapter. We take electricity for granted today, but it was unknown until the middle of the eighteenth century. It was recognized that contact with an eel or torpedo fish was acutely painful, and it was observed that lightning made noise and even caused fires, but those two things seemed unrelated. Even so, the first use of therapeutic electrical stimulation occurred in about 15 AD. As the story is reported (Stillings, 1971), a freed slave of Emperor Tiberius was suffering from painful gout. He accidentally stepped on an electric torpedo fish and suffered a sudden severe shock. Afterward, he had much less gout pain. The Emperor’s physician, Scribonius, wrote that thereafter he recommended the torpedo fish treatment for chronically persistent pain. This apocryphal story represents the beginning of neuromodulation, although nothing further happened for more than 1700 years. By the end of the eighteenth century, electricity was identified as a form of energy. Its ability to cause sudden shock and muscle contraction was recognized. One of the first to report that phenomenon in 1774 was Benjamin Franklin (Isaacson, 2003). In addition to his

Neuromodulation



© 2008, 2009 Elsevier Ltd.

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2.  neuromodulation: a historical perspective

Figure 2.2  Sir Victor Horsley (Source:  http://cache.viewimages.com)

Figure 2.1  Roberts Bartholow (Source:  http://www.nlm.nih.gov)

les propriétés et les fonctions du système nerveux, dans les animaux vertébrés, Paris, 1824, cited in Morgan, 1982). It was not until 45 years later, in 1870, that Fritsch and Hitzig (1870) demonstrated limb movement on stimulating the motor cortex of the dog, proving that the cere­bral cortex was excitable by electricity. The first documented electrical stimulation of the living human brain occurred in 1874. A patient with a purulent ulcer of the scalp with skull osteomyelitis was admitted to Good Samaritan Hospital in Cincinnati by Dr Roberts Bartholow (see Figure 2.1). The parietal area of the brain became exposed when debridement was done. Bartholow made a faradic stimulation device to stimulate the exposed brain, since there was no such device to be purchased. When mechanical stimulation was done, there was no response, but when electrical stimulation was applied, contralateral muscle spasm was seen, documenting that the cortex was responsive to electricity (Experimental investigations into the function of the human brain. Am. J. Med. Sci. 1874; 67: 305–13, cited in Morgan, 1982). Ten years later, in 1884, the first intraoperative cortical electrical stimulation was performed by Sir Victor Horsley, the father of functional neurosurgery (see Figure 2.2). He applied faradic electrical stimulation to the tissue within an occipital encephalocele, and he demonstrated conjugate eye movements that he concluded were due to stimulation of the corpora quadrigemina. Two years after that, in 1886, after a

tumor resection, he identified the thumb area of the motor cortex that had been involved in localized seizures and resected it, the first time intraoperative stimulation was used to guide a resection (Horsley, 1909; Vilensky and Gilman, 2002). In 1909, Cushing stimulated the post-central gyrus in an awake patient and demonstrated contralateral motor movement. The twentieth century began with a widespread fascination of everything electrical. Electric lights had become a reality. Electric power was just being supplied to residences and businesses. Electric motors were used in industry. Electric batteries made electricity available everywhere. Electrical stimulation was touted as the cure to all ills, and improbable treatments were offered in stores, street corners, and carnivals. One such battery-powered device was the Electreat – Relieves Pain, sold for $1.00 by the Electreat Manufacturing Company of Peoria, Illinois, “to improve vitality and health in every organ” (see Figure 2.3). It was arguably the first TENS unit. To digress, in 1968 when Shealy began to use dorsal column spinal cord stimulation for pain management, he used the Electreat to screen patients. When it was modified to a more modern, safer, and convenient device, it was used for treatment as well as screening, and transcutaneous stimulation was born (Shealy et al., 1967). Let us return to the early twentieth century. Animal stereotaxic surgery began when Horsley and Clarke (1908) introduced the first animal stereotaxic apparatus in 1908. Their classic paper should be read by anyone with a deep appreciation of science history. The paper reported a study of cerebellar physiology in the

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Figure 2.3  The Electreat – Relieves Pain (Source: http://www.thebakken.org/artifacts/database/imagebase/ 082-135.jpg)

laboratory. It is divided into five sections. After a brief introduction, the “Material and Methods” section describes their apparatus, which used a Cartesian coordinate system. The first stereotaxic atlas was consulted to identify the location of the desired structure in relation to the landmarks on the skull. Registration of the position of the animal head to both the atlas and the stereotaxic apparatus involved bony landmarks of the skull, that is, the external auditory canals, the inf­erior orbital ridges, and the midline. They applied electrical stimulation to the cerebellar cortex and subcortex and observed the effects. They produced electrolytic lesions in the cerebellar nuclei with a direct current, which they describe in a detail that has never been matched. During the first half of the twentieth century, intraoperative stimulation was performed in patients to localize functional areas by Cushing (1909), as well as others. Detailed mapping of primarily cortical functional areas was performed in conjunction with epilepsy surgery by Penfield and Jasper (1954). In 1947, Spiegel and Wycis introduced human stereotactic surgery1 (Spiegel et al., 1947) (see Figure 2.4). From the very first case, electrical stimulation of subcortical structures was used to identify electrode placement, as well as to take the opportunity to study human neurophysiology. The first patient had Huntington’s chorea. A lesion was made in the globus

1 

 The original spelling was “stereotaxic,” and that is still the spelling for the technique used in the animal laboratory. When the technique was applied to human patients in 1947, Spiegel and Wycis used the term “stereoencephalotomy,” which never caught on, since it involved the use of brain or encephalic landmarks to register the atlas and the apparatus to the same Cartesian space as the head. Other clinicians, particularly in Europe, began to use the spelling “stereotactic.” When the World Society for Stereotactic and Functional Neurosurgery was founded in 1973, it was necessary to agree on a spelling. A vote was taken and “stereotactic” was adopted as the proper spelling for such surgery performed in the human (Gildenberg, 1993).

Figure 2.4  Spiegel and Wycis in the operating room in 1948. Spiegel is second from left and Wycis is sitting. Note the Model I device as it appeared in Science and faraday cage so recording can be done in the operating room

pallidus, in order to interrupt the extrapyramidal pathway, and a second lesion was made in the dorsomedian nucleus of the thalamus, a psychosurgical target, since the patient had magnification of symptoms when he became stressed or upset. Originally, they made the lesion by injection of alcohol, in hopes of sparing fibres en passage, but that was soon replaced by the use of electrolytic lesions, similar to what Horsley and Clarke had described (Spiegel et al., 1952). As the technology developed, they as well as other stereotacticians adopted the use of radiofrequency lesions (Cosman et al., 1983). This author had the great fortune of having difficulty finding a neurophysiologist to sponsor a newly designed summer research program when I was a freshman student at Temple Medical School in 1953. The Professor of Physiology referred me to his old teacher, Ernest Spiegel, Professor of Experimental Neurology, whose laboratory was down the hall. That was six years after the introduction of stereotactic surgery, and I continued to work with him throughout my residency and graduate school over the next 13 years, a front row seat as the field was in its most rapid stage of development.

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2.  neuromodulation: a historical perspective

Electrical stimulation was used in almost every stereotactic case. It was used to verify the placement of the electrode, since imaging technology at that time did not allow direct visualization of the target structure. Many targets had no response to stimulation, in which case stimulation was used to assure that the electrode was not in an exquisite structure, especially the pyramidal tract. Reports from that era rarely reported effects of stimulation that were only casually observed. Effects of stimulation on symptoms were recorded only subjectively, since there were few means to quantitate the severity of the symptoms in the operating room. The patients were often under considerable stress so symptoms were not consistent or typical, procedures were frequently of long duration, and the use of the stimulation was primarily for localization. Electrical recordings during the early years of stereotactic surgery required shielding in a faraday or grounded cage around the head. Localization was done by selecting the landmarks from which measurements would be made, which by the end of the 1950s were most often the anterior and posterior commissure and the intervening intercommissural line, consulting an atlas to determine the relationship of the intended target to that line and noting the three coordinates that indicate that localization, identifying the commissural landmarks during surgery, calculating the settings of the stereotactic frame to achieve the intended three coordinate settings, introducing the electrode to those coordinates, and then making physiologic observations to fine tune the electrode placement prior to making the lesion. Such physiologic observations might include change in movement disorder on insertion of the electrode into the target (mechanical effect), noting any change in physiologic signs on low and high frequency stimulation, making a mini-lesion (presumably reversible) at a modest temperature to note the effect, and making the lesion, which was irreversible. Since intraoperative stimulation was an almost universal adjunct to electrode localization, it was reported only casually without sufficient detail to reconstruct just what had been done. In 1950, Spiegel, Wycis and Umlauf used stimulation to localize thalamotomy, and then noted electroencephalographic changes after the lesion was made. In 1964, Spiegel, Wycis et al. (1964) used intraoperative stimulation prior to making lesions in Forel’s field for Parkinson’s disease. Not only was an improvement in symptoms noted on stimulation after satisfactory electrode placement, but the dramatic abrupt monocular eye movements indicated when the electrode had been lowered just below the target to involve the oculomotor fibers just below that structure. In 1966,

Alberts et al. reported improvement in dystonia on stimulation in awake patients. It was soon recognized that stimulation might either enhance the symptom, especially with tremor or other involuntary movement disorder, or it might subdue it – either effect was evidence of proper electrode placement. The effects were sometimes correlated to stimulation frequency, but often stimulation was not done with a variety of frequencies to make that distinction. In general, it was felt that higher frequency stimulation tended to subdue the symptoms and lower frequency stimulation might enhance them. There was no general agreement, however, on what constituted high verses low frequency. Low frequency might be between 6 and 60 Hz, and high frequency between 50 and 100 Hz. The picture was complicated when Riechert (1980) reported a patient who suffered a seizure following 50 Hz stimulation, which he attributed to kindling, so he discouraged colleagues from stimulating at higher than that frequency. Hassler et al. (1960) reported that stimulation within VL thalamus (later refined to Vim) might cause cessation of parkinsonian or essential tremor, and that has remained the target of choice for tremor. He had had extensive experience with chronic stimulation as a graduate researcher with Rudolph Hess in Switzerland during the 1940s, where chronic stimulation was routinely administered to cats. Although Hess had spoken encouragingly about using similar techniques in patients, the technology of his day did not permit the application of stimulation over a long period. Intraoperative stimulation was also used for physiological and anatomical studies on the human brain. Ronald Tasker produced a detained physiologic atlas of the human thalamus based on mapping of responses to stimulation in several hundred patients in and around the thalamus (Tasker et al., 1982). He had worked with Clinton Woolsey as a graduate student from 1961 to 1963, who had used similar point-by-point mapping in experimental animals (Woolsey, 1964). Tasker kept detailed records of intraoperative stimulation responses over 40 years to produce a data base reflecting the orientation of targets of interest to the stereotactic surgeon. Although the benefits of stimulation were known, there was no practical way through the 1960s to apply chronic stimulation as a permanent therapy. Nevertheless, reports appeared that touted the potential benefits of stimulation, but required intermittent connection to electrodes through the scalp. One of the earliest was Pool (1954), who, as early as 1948, stimulated the frontal projection tracts as a form of nondestructive psychosurgery. Starting in the early 1950s, Heath (1955) implanted electrodes and stimulated intermittently over long periods to study the physiology

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Neuromodulation: A Historical Perspective

of mentation and to manage psychiatric disorders. (One of his junior associates was Donald Richardson, who extended these techniques when implantable stimulators became available more than a decade later.) In Russia, Bechtereva (1969) used chronic stimulation to study the physiology of human higher mental activity and to treat movement disorders. Even after implantable stimulators became available in the West, it was necessary for her to stimulate intermittently in 1972 for the first therapy of motor disorders by chronic stimulation via electrodes emerging through the scalp (Bechtereva et al., 1972). Meanwhile, chronic stimulation in laboratory animals directly connected to stimulators was permitting interesting observations. In 1954, Olds and Milner reported intense stimulation-seeking behavior in rats with septal electrodes implanted. That observation was used by Heath (1958, 1996) to manage cancer pain. He hypothesized that pleasure is the opposite of pain, so that stimulating the septal pleasure center might alleviate cancer pain. Stimulation at intervals of one day to one week provided pain relief throughout the final seven months of a cancer patient’s life. This procedure was repeated by Gol in 1967, when implantable stimulator technology was on the brink of full implementation. The concept that led directly to the commercial introduction of implantable stimulators for pain relief by neuromodulation was provided in Melzack and Wall’s “gate theory” presented in 1965 (see Figure 2.5). Their concept involved a gate at each spinal segment which opened to allow pain transmission and closed to inhibit pain perception. Whether the gate was open or closed depended on the balance of firing of large touch peripheral nerves versus small pain nerves. That is why pain feels better when you rub it, stimulating the large pain-inhibiting nerves to close the gate, and why weak stimulation of skin or peripheral nerve may inhibit pain. By anatomical coincidence, the large nonpain fibers also ascend in the dorsal columns of the spinal cord, which consists almost entirely of large C Fibers

�

� �

Inhibitory interneuron �

2° neuron To forebrain

A�/A� Fibers

Figure 2.5  The gate control theory of Melzack and Wall

13

nerve fibers. This offers the possibility of stimulating the dorsal columns to promote firing of the large nerve fibers with retrograde transmission down to each segment to close the gate and inhibit pain. The first TENS (transcutaneous electrical nerve stimulation, an inaccurate description) unit had been introduced a half century previously as the Electreat, but for the first time its efficacy to help pain was explained. In the late 1960s a wide variety of TENS units for pain management were introduced, each consisting of a battery-operated stimulator connected to tape-on or paste-on skin electrodes. (See Chapter 24 for a full description of TENS units.) Localized anesthesia produced by stimulation of peripheral nerve was demonstrated in 1967 by Wall and Sweet, who inserted needle electrodes into their own infraorbital nerves to produce analgesia throughout the distribution of those nerves. By definition, if the stimulation has low enough voltage so it is not painful, the large fibers are being stimulated. If pain occurs on increasing the voltage, the small pain fibers are also being stimulated. Thus, the subject can adjust the voltage according to the sensation produced, and anticipate decreased pain sensation if the electrical stimulation does not stimulate pain fibers. Bill Sweet recruited Roger Avery, an engineer, to make an implantable peripheral nerve stimulator, consisting of an entirely implantable electrode connected to an induction coil and an external battery operated control unit (which, in turn led to the formation of the Avery Company that made a variety of implantable stimulators; when Roger Avery retired 20 years later he sold the company to Bill Dobelle, who developed the phrenic nerve stimulator that is still in use to treat prolonged respiratory paralysis). At just about the same time, Norm Shealy at Western Reserve Medical School (now Case Western Reserve) had the idea of stimulating the dorsal columns of the spinal cord to take advantage of the Melzack–Wall gate to inhibit pain anywhere in the body below the level of stimulation. In 1964 he recruited Tom Mortimer, a graduate student at Case Institute of Technology, to design an implantable device to apply such stimulation. The first model was not fully implantable. The electrode behind the spinal cord was attached to subcutaneous contacts that could be addressed through hypodermic needles that were attached to an external stimulator. Coincidentally, Mortimer had met Norm Hagfors, Chief Technical Officer of Medtronic, Inc., when he interviewed for a job at the company, which was making cardiac and cardiac nerve stimulators. Hagfors provided Mortimer with a circuit diagram for a radio­ frequency coupled stimulator, and Mortimer made the first fully implantable spinal cord stimulator with

I. an introduction to neuromodulation

14

2.  neuromodulation: a historical perspective

an external radiofrequency control and power supply. In October, 1967, Shealy, who had in the meantime moved to LaCrosse, Wisconsin, implanted that first dorsal column stimulator for cancer pain. The patient had good pain relief for the last few months of his life. The second patient reported by Shealy in 1967 had pain relief for four years, although Shealy commented that she required an occasional “tune up,” especially at holiday time (Shealy et al., 1967). Since Mortimer had since left to study in Sweden, Shealy contacted Medtronic directly to provide more stimulators. Medronic had a line of implantable stimulators that were used for cardiovascular disease. The model supplied to Shealy was a modified version of a carotid sinus nerve stimulator. Their Barostat, released in 1963, was designed to stimulate the carotid sinus nerve for hypertension. In 1965, they released the Angiostat to stimulate the carotid sinus nerve for the treatment of angina. Soon thereafter, in 1968, Medtronic made such radiofrequency coupled spinal cord stimulators commercially available as the Myelostat. The availability of that device, more than any other single event, signaled the birth of neuromodulation. That was coincidentally the year that functional neurosurgeons were most receptive to new techniques since levodopa had just come on the market and there was little call for stereotactic surgical treatment of Parkinson’s disease. The earliest stimulators consisted of two parts. The implantable part contained the electrodes placed behind the spinal cord, connected to an antenna located subcutaneously. There was no implanted power source. The external part contained the battery, and transmitted both power and control to the implanted part.2 In 1968, this author was at the Cleveland Clinic, just down the road from where Shealy and Mortimer had worked, so I was aware of their work very early. I soon began to use the spinal cord stimulator for pain management. In the meantime, I had a large series of spasmodic torticollis patients I had treated surgically, a series which had begun when I was still working with Wycis (Wycis and Gildenberg, 1969). It seemed that these patients might benefit from spinal cord stimulation, especially if one were able to disrupt the cervical proprioceptive reflex arc, which I thought might require very high frequency stimulation. In order to test that hypothesis, I inserted electrodes into the epidural space at the C2 level and stimulated with an external stimulator. Many patients had significant improvement, but only at frequencies between 800 2 

 In 1981, Medtronic released a totally implantable stimulator, containing the electrodes, battery, and a control unit that was programmed by radiofrequency coupling to an outside programmer.

and 1200 Hz (Gildenberg, 1977a). Medtronic and later Avery supplied spinal cord stimulators modified to provide those frequencies over the following 10 years, and 50% of patients implanted during that time had significant, but not always permanent relief, which may have constituted the first use of implanted stimulators specifically for a motor disorder. When the modified stimulators were no longer available, I could no longer provide this procedure.3 The use of dorsal column stimulation for pain became widespread over the next decade. It was felt that the effect was not only from stimulation of the dorsal columns, so the preferred nomenclature was changed to spinal cord stimulation (SCS) (Bantli et al., 1975; Hoppenstein, 1975; Larson et al., 1975). In 1976, both Cook and Dooley (Dooley and Sharkey, 1977) noted an improvement in spasticity in several patients with multiple sclerosis who were being treated with SCS for muscle pain. That same year, Ross Davis, in concert with Dooley, convinced Bill Murphy at Cordis Cardiac Pacemaker Company to make the first implantable SCS device specifically intended for motor disorders (Davis and Gray, 1981). A modification of that stimulator from Medtronic was used also by Cooper (Davis et al., 1976) to stimulate the anterior lobe of the cerebellum for cerebral palsy and spasticity, as well as epilepsy, since that area had been recognized to have an inhibitory influence on the motor system (Cooper et al., 1974). There were concerns about the safety of cerebellar stimulation which were eventually allayed (Davis et al., 1985). Efficacy in epilepsy was uncertain, but in 1985 Davis et al. (1983) reported satisfactory results on long-term follow-up. In 1976, Dooley and Kasprak documented by measurement an improvement in blood flow to the extremities when patients turned on their spinal cord stimulators. However, it was not until 1986 that SCS was advocated in Europe for peripheral vascular insufficiency (Augustinsson et al., 1985), and only more recently in the USA. With the rapid growth of neuromodulation, a symposium on Safety and Efficacy of Neuroaugmentive Devices was held in March, 1977 (Gildenberg, 1977b). Reports on stimulation for pain, epilepsy, spasticity, cerebral palsy, and bladder control were presented. The symposium was sponsored by the Food and Drug Administration in conjunction with the Association for the Advancement of Medical Instrumentation, 3 

 As an interesting aside, in 1970, I asked Medtronic to provide percutaneous electrodes to test patients without the need for surgery, but they saw no market for percutaneous electrodes for spinal cord stimulation at that time. However, we made percutaneous electrodes by hand, which worked well for temporary screening.

I. an introduction to neuromodulation



Neuromodulation: A Historical Perspective

the American Association of Neurological Surgeons, the Congress of Neurological Surgeons, and the Joint Committee on Materials and Devices. The unanimous opinion was that neuroaugmentation, now called neuromodulation, for the relief of pain by SCS had been demonstrated to be both safe and effective and should be regarded as standard for neurosurgical practice (Gildenberg, 1977c),4 but there was insufficient evidence for similar designation of neuroaugmentation for the other considered indications. In order to review deep brain stimulation (DBS), we must back up a few years. In 1973, several years after SCS for pain management had been introduced, Yoshio Hosobuchi et al. initiated DBS for pain management when he stimulated the somatosensory thal­ amus for the management of intractable denervation pain, based on the observation that this artificial input of non-painful sensation inhibited anesthesia dolorosa. About the same time, Mazars (1975) applied intermittent stimulation to the same areas for pain following amputation or stroke. Meanwhile, new concepts of pain physiology were emerging. In 1969, Reynolds observed, on stimulation of the periventricular area in rats, profound anal­ gesia intense enough to perform surgery with no sign of pain. Meyer and Price (1976) related that effect to endorphin release. Those observations led Richardson and Akil (1977a, 1977b) to implant DBS electrodes in the periventricular area of patients for the management of pain, and they verified that pain relief was correlated with endorphin release. As the use of brain stimulation became more widespread, regulatory forces began to intervene. In the late 1970s the FDA decided that all implantable devices were to be regulated and require pre-approval. At that time, there were three companies that made implantable deep brain stimulators – Medtronic, Avery, and Neuromed. They were given time to provide documentation of safety and efficacy, but two of the companies felt that such a complex study in patients who were particularly difficult to evaluate would be too expensive for the number of units to be sold, so they did not submit such a report. The only company that successfully complied was Avery, but shortly after approval in 1983, Roger Avery retired and sold the company to Bill Dobelle as stated above. At that time, Dobelle was concentrating on cortex stimulation for blindness and phrenic nerve stimulation for respiratory paralysis, so his company did not make stimulators for pain. Consequently, DBS for pain management was deapproved and has not since been reestablished.5 4 

 And much later for pain medicine practice.  The use of DBS for movement disorders was approved in 2002.

5 

15

Stimulation was a routine part of stereotactic surgery for movement disorders, so there had been a great deal of relatively informal information acquired about its effects. Generally, high frequency stimulation mimics the effect of making a lesion (Toth and Tomka, 1968), which provided a great deal of information about potential targets for DBS to treat movement disorders. In addition, as early as 1980, improvement in movement disorders was sometimes seen in patients who had DBS for pain management by Mazars et al. (1980). Even so, the mechanism for that observation has not been well defined (Anderson et al., 2004; Lee et al., 2004). The first report of patients without pain who had DBS implanted to treat a motor disorder was presented in 1980 by Brice and McLellan. They had several multiple sclerosis patients with intention tremor who were significantly improved by stimulation of the ventrolateral (VL) area of the thalamus. In 1986, Siegfried (1986) observed improvement in dyskinesia in a patient who had a stimulator inserted to treat the pain of Dejerine–Roussy syndrome,6 and advocated the use of stimulation for motor disorders. It was not until 1987, however, that Benebid et al. reported on the use of ventrointermedius nuclei (Vim) stimulation for parkinsonian tremor (see Figure 2.6). Since the response was incomplete with maximum frequency of 130 Hz, he also made a lesion to obtain a satisfactory result. Both Benabid and Siegfried had made observations over the prior few years concerning patients who had improvement in motor symptoms on implantation of a DBS for pain, but I have been unable to determine in talking with them who had made the observation first. In the 1980s, the stage had been set for the development of DBS for movement disorders. Targets were available from experiences with lesion production. Stimulators had been produced that made chronic stimulation feasible. However, the main population of patients for surgery for movement disorder was still the large group of Parkinson’s disease patients, but there remained a feeling that they could be managed indefinitely with levodopa, even though the evidence 6 

 Thalamic syndrome (Dejerine–Roussy) is a rare neurological disorder in which the body becomes hypersensitive to pain as a result of damage to the thalamus, a part of the brain that affects sensation. The thalamus has been described as the brain’s sensory relay station. Primary symptoms are pain and loss of sensation, usually in the face, arms, and/or legs. Pain or discomfort may be felt after being mildly touched or even in the absence of a stimulus. The pain associated with thalamic syndrome may be made worse by exposure to heat or cold and by emotional distress. Sometimes, this may include even such emotions as those brought on by listening to music (http://www.peacehealth.org/kbase/nord/nord796.htm).

I. an introduction to neuromodulation

16

2.  neuromodulation: a historical perspective

Figure 2.6  Professor Alim Benebid of Grenoble, France

was accumulating that this was not so. There were few neurosurgeons who still remained expert in stereotactic surgery, since there had been so little activity in the field. That changed in 1992, when Laitinen resurrected Leksell’s old observations about successful treatment of bradykinesia and dyskinesia of Parkinson’s disease by ventral posterior pallidotomy (Laitinen et al., 1992a, 1992b). Neurosurgeons returned to pallidotomy with enthusiasm, especially since there were so many Parkinson patients who had significant medicationinduced dyskinesia that might respond to surgery. During the next decade, stereotactic surgery for Parkinson’s disease grew significantly. Vim thala­ motomy was indicated for tremor (Gildenberg and Tasker, 1998) and pallidotomy was generally used for bradykinesia or dyskinesia (Lozano and Lang, 1998). Stereotactic lesions were made for a variety of other movement disorders (Parrent, 1998) and pain (Gybels and Sweet, 1989). Neurologists, the gatekeepers for referring patients for surgery, had become interested in intraoperative microelectrode recording, which was used to improve final placement of the lesion (Kelly, 1980). Imaging had improved significantly, so it was now possible to identify the target structure anatomically (Giller et al., 1998). Interest grew in techniques to replace the deficient neurotransmitters in Parkinson’s disease by implantation of adrenal medulla (Lindvall et al., 1987; Bakay, 1993; Watts et al., 1997) and embryonic tissue (Hitchcock, 1994). Additionally, during this time, surgery for epilepsy had increased dramatically, to a large extent because of

the availability of long-term monitoring with both scalp and implanted electrodes, as well as the identification of anatomic lesions by the vastly improved imaging modalities (Ojemann, 1983). Stimulators, however, offered a distinct advantage over lesions, in that the risk of implanting electrodes was low, and any adverse effect from stimulation was not permanent, so there remained great interest in DBS for epilepsy. Although the technology was available for implanted stimulators, their use had been de-approved by the FDA, so their re-incorporation into stereotactic surgery came only gradually. Nevertheless, a number of centers were set up in the USA, Canada, and overseas to study the effects of deep brain stimulators on movement disorders, so that by the time DBS obtained FDA approval in 2002, the procedure was well documented and well established (Lozano et al., 1996; Rezai et al., 1999; Benabid et al., 2000). After pallidotomy was reintroduced, that same target was used for DBS by Siegfried for the treatment of Parkinson’s disease (Siegfried and Lippitz, 1994a), as had later Lozano (2001) and Ashby et al. (1998), as well as many others. Siegfried (Siegfried and Lippitz, 1994b) and Benabid et al. (1991) stimulated Vim targets that had been the site of lesion production for tremor in Parkinson’s disease. The subthalamic nucleus, as a target for DBS, warrants special note. In 1964, Forel’s field in the subthal­ amic area was used as a lesion target by Spiegel, Wycis et al. in a procedure they called campotomy (campus Forelli) (Wycis and Gildenberg, 1965). As early as 1965, the potential beneficial effects of acute stimulation during surgery in the subthalamic area were documented (Johansson and Laitinen, 1965). Although most neuro­ surgeons were concerned about potential hemi­ballism7 if lesions were made in the subthalamic nucleus, Story (Story et al., 1965) and Houdart et al. (1965) found beneficial effects by making lesions in the subthalamic nuclei in Parkinson’s patients. When DBS became available, its risk was felt to be less than the risks presented by lesioning, so bilateral subthalamic nuclei stimulation

7

 Hemiballism is a neurological sign, a movement disorder, characterized by unilateral wild, large amplitude flinging movements of the arm and leg, normally causing falls and preventing postural maintenance. It is caused by a lesion or infarction in the contralateral subthalamic nucleus or its connections, usually in patients with a history of hypertension or diabetes, or following TB meningitis. The subthalamic nucleus normally regulates the globus pallidus by exciting the GPi, which in turn normally inhibits the ventral anter­ior nucleus, ventral lateral nucleus and lateral dorsal nucleus of the thalamus. The reduced discharge in both causes disinhibition of the thalamus and consequent involuntary stimulation of the motor cortex. Altered dopaminergic feedback mechanisms may also be involved.

I. an introduction to neuromodulation



Neuromodulation: A Historical Perspective

was an attractive target, particularly for patients with significant bradykinesia and dyskinesia (Benabid et al., 1994). Benabid has been a particular advocate of that target since 1991, and has been a moving force in the elucidation of the mechanism of DBS (Benabid et al., 2002). Although Forel’s field itself has not been claimed as a target, reports of pre-lemniscal, pre-rubral or zona inserta stimulation suggest that the same pathways are being stimulated (Velasco et al., 2001). In addition, DBS has been used for a variety of other movement disorders such as dystonia (Kumar et al., 1999; Loher et al., 2000; Tronnier and Fogel, 2000). It is noteworthy that stereotactic dorsomedian thalamotomy was used for psychosurgery as early as 1947 (Spiegel et al., 1947), and pallidotomy was performed for epilepsy in 1956 (Baird et al., 1956; Spiegel et al., 1958), so the precedent for stereotactic treatment of these disorders has long been founded, leading to the use of DBS for psychosurgery (Nuttin et al., 2003) and epilepsy (Theodore and Fisher, 2004). Velasco stimulated both the centromedian nucleus (Velasco et al., 1993) and the hippocampus (Velasco et al., 2000) for seizures. One use of DBS that is still unproved is its use in prolonged coma (Tsubokawa et al., 1990). Undoubtedly, additional indications that were not managed by lesions will be discovered for DBS. Several other types of stimulation outside of the central or peripheral nervous system are noteworthy, especially since the indications are similar to those discussed above. Chief among these is vagal nerve stimulation (VNS) for intractable epilepsy not amenable to surgical resection (Finesmith et al., 1999). Curiously, in the 1880s, Corning performed cutaneous stimulation in the area of the vagal nerve and observed a decrease in seizures (Lanska, 2002). In 1972, Zabara demonstrated that VNS could control emesis in the dog, a not unexpected finding (Zabara et al., 1972). In 1985, he demonstrated a decrease in strychnine seizure potentials, again in the dog, but he did not offer evidence in that paper about why he should perform such an experiment. Nevertheless, this led Terry et al. (1991) to design and produce a vagal nerve stimulator that has been approved for use in clinical epilepsy. Despite its long history, the mechanism for vagal nerve stimulation remains to this day obscure (Zabara, 1992). More recently, based on the observation of mood improvement in some of the patients who had VNS for epilepsy, there has been evidence that VNS may also be of benefit for severe depression (Shafique and Dalsing, 2006), although it has not been approved, as of this writing. Other indications for electrical stimulation of the central nervous system include stimulation of the conus of the spinal cord for bladder control, which was advocated by Nashold et al. as early as 1972. About a

17

decade later, Brindley developed a technique for stimulating sacral nerves for micturition (Brindley et al., 1982; Brindley, 1988), which has evolved as the preferred technique (Creasey et al., 2004). (For a complete review of sacral nerve stimulation, see Chapter 77.) The design of implantable stimulators has progressed to the point where any desired stimulation can be applied to almost any neural structure. At the meeting of the World Society for Stereotactic and Functional Neurosurgery in São Paulo in 1977, I remarked, “The engineers can give us any stimulation parameters we need. We just have to know what to ask for and where to put the electrode.” That has still not changed.

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references

Lozano, A. (2001) Deep brain stimulation: challenges to integrating stimulation technology with human neurobiology, neuroplasticity, and neural repair. J. Rehabil. Res. Dev. 38: x–xix. Lozano, A. and Lang, A.E. (1998) Pallidotomy for Parkinson’s disease. Part II: The Toronto Hospital experience. In: P.L. Gildenberg and R.R. Tasker (eds), Textbook of Stereotactic and Functional Neurosurgery. New York: McGraw–Hill, pp. 1161–6. Lozano, A., Hutchison, W., Kiss, Z., Tasker, R., Davis, K. and Dostrovsky, J. (1996) Methods for microelectrode-guided posteroventral pallidotomy. J. Neurosurg. 84: 194–202. Mazars, G.J. (1975) Intermittent stimulation of nucleus ventralis posterolateralis for intractable pain. Surg. Neurol. 4: 93–5. Mazars, G., Merienne, L. and Cioloca, C. (1980) Control of dyskinesias due to sensory deafferentation by means of thalamic stimulation. Acta Neurochir. Suppl. (Wien) 30: 239–43. Melzack, R. and Wall, P.D. (1965) Pain mechanisms: a new theory. Science 150: 971–9. Meyer, D.J. and Price, D.D. (1976) Central nervous system mechanisms of analgesia. Pain 2: 379–404. Morgan, J.P. (1982) The first reported case of electrical stimulation of the human brain. J. Hist. Med. Allied Sci. 37: 51–64. Nashold, B.S.J., Friedman, H., Glenn, J.F., Grimes, J.H., Barry, W.F. and Avery, R. (1972) Electromicturition in paraplegia. Implantation of a spinal neuroprosthesis. Arch. Surg. 104: 195–202. Nuttin, B., Gybels, J., Cosyns, P., Gabriels, L., Meyerson, B., Andreewitch, S. et al. (2003) Deep brain stimulation for psychiatric disorders. Neurosurg. Clin. North Am. 14: 15–16. Ojemann, G.A. (1983) Neurosurgical management of epilepsy: a personal perspective in 1983. Appl. Neurophysiol. 46: 11–18. Olds, J. and Milner, P. (1954) Positive reinforcement produced by electrical stimulation of the septal area and other regions of the rat brain. J. Comp. Physiol. Psychol 47: 419–27. Parrent, A.G. (1998) Overview of the surgical treatment of movement disorders. In: P.L. Gildenberg and R.R. Tasker (eds), Textbook of Stereotactic and Functional Neurosurgery. New York: McGraw–Hill, pp. 995–1004. Penfield, W. and Jasper, H. (1954) Epilepsy and the Functional Anatomy of the Human Brain. Boston, MA: Little, Brown. Pool, J.L. (1954) Psychosurgery in older people. J. Am. Geriatr. Soc. 2: 456–65. Pruel, M.C. (1997) A history of neuroscience from Galen to Gall. In: S.H. Greenblatt, T.F. Dagi and M.H. Epstein (eds), A History of Neurosurgery. Park Ridge, IL: American Association of Neurological Surgeons, pp. 99–130. Reynolds, D.V. (1969) Surgery in the rat during electrical analgesia induced by focal brain stimulation. Science 164: 444–5. Rezai, A.R., Lozano, A.M., Crawley, A.P., Joy, M.L., Davis, K.D., Kwan, C.L. et al. (1999) Thalamic stimulation and functional magnetic resonance imaging: localization of cortical and subcortical activation with implanted electrodes. Technical note. J. Neurosurg. 90: 583–90. Richardson, D.E. and Akil, H. (1977a) Pain reduction by electrical brain stimulation in man. Part 1: Acute administration in periaqueductal and periventricular sites. J. Neurosurg. 47: 178–83. Richardson, D.E. and Akil, H. (1977b) Pain reduction by electrical brain stimulation in man. Part 2: Chronic self-administration in the periventricular gray matter. J. Neurosurg. 47: 184–94. Riechert, T. (1980) Stereotactic Brain Operations. Methods, Clinical Aspects, Indications. Berne: Hans Huber. Shafique, S. and Dalsing, M.C. (2006) Vagus nerve stimulation therapy for treatment of drug-resistant epilepsy and depression. Perspect. Vasc. Surg. Endovasc. Ther. 18: 323–7.

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Shealy, C.N., Mortimer, J.T. and Reswick, J.B. (1967) Electrical inhibition of pain by stimulation of the dorsal columns. Preliminary clinical report. Anesth. Analg. (Cleve.) 46: 489–91. Shelley, M. (1818) Frankenstein. Oxford: Oxford University Press. Siegfried, J. (1986) Effect of stimulation of the sensory nucleus of the thalamus on dyskinesia and spasticity. Rev. Neurol. (Paris) 142: 380–3. Siegfried, J. and Lippitz, B. (1994a) Bilateral chronic electro­ stimulation of ventroposterolateral pallidum: a new therapeutic approach for alleviating all parkinsonian symptoms. Neurosurgery 35: 1126–9. Siegfried, J. and Lippitz, B. (1994b) Chronic electrical stimulation of the VL-VPL complex and of the pallidum in the treatment of movement disorders: personal experience since 1982. Stereotact. Funct. Neurosurg. 62: 71–5. Spiegel, E.A., Wycis, H.T. and Baird, H.W. (1952) Studies in stereoencephalotomy. I. Topical relationships of subcortical structures to the posterior commissure. Confin. Neurol. 12: 121–33. Spiegel, E.A., Wycis, H.T. and Baird, H.W., III (1958) Pallidotomy and pallidoamygdalotomy in certain types of convulsive disorders. AMA Arch. Neurol. Psychiatry 80: 714–28. Spiegel, E.A., Wycis, H.T., Marks, M. and Lee, A.S. (1947) Stereotaxic apparatus for operations on the human brain. Science 106: 349–50. Spiegel, E.A., Wycis, H.T. and Umlauf, C.W. (1950) Electro­ encephalographic studies before and after thalamotomy. Monatsschr. Psychiatr. Neurol. 120: 398–411. Spiegel, E.A., Wycis, H.T., Szekely, E.G., Soloff, L., Adams, J., Gildenberg, P. et al. (1964) Stimulation of Forel’s field during stereotaxic operations in the human brain. Electroencephalogr. Clin. Neurophysiol. 16: 537–48. Stillings, D. (1971) The first use of electricity for pain treatment. Medtronic Archive on Electro-Stimulation. Story, J.L., French, L.A., Chou, S.N. and Meier, M.J. (1965) Experiences with subthalamic lesions in patients with movement disorders. Confin. Neurol. 26: 218–21. Tasker, R.R., Organ, L.W. and Hawrylshyn, P.A. (1982) The Thalamus and Midbrain of Man. A Physiological Atlas Using Electrical Stimulation. Springfield, IL: C.C Thomas. Terry, R.S., Tarver, W.B. and Zabara, J. (1991) The implantable neurocybernetic prosthesis system. Pacing Clin. Electrophysiol. 14: 86–93. Theodore, W.H. and Fisher, R.S. (2004) Brain stimulation for epilepsy. Lancet Neurol. 3: 111–18. Tronnier, V.M. and Fogel, W. (2000) Pallidal stimulation for generalized dystonia. Report of three cases. J. Neurosurg. 92: 453–6. Toth, S. and Tomka, I. (1968) Responses of the human thalamus and pallidum to high frequency stimulations. Confin. Neurol. 30: 17–40. Tsubokawa, T., Yamamoto, T., Katayama, Y., Hirayama, T., Maejima, S. and Moriya, T. (1990) Deep-brain stimulation in a persistent vegetative state: follow-up results and criteria for selection of candidates. Brain Inj. 4: 315–27. Velasco, A.L., Velasco, M., Velasco, F., Menes, D., Gordon, F., Rocha, L. et al. (2000) Subacute and chronic electrical stimulation of the hippocampus on intractable temporal lobe seizures: preliminary report. Arch. Med. Res. 31: 316–28. Velasco, F., Jimenez, F., Perez, M.L., Carrillo-Ruiz, J.D., Velasco, A.L., Ceballos, J. et al. (2001) Electrical stimulation of the prelemniscal radiation in the treatment of Parkinson’s disease: an old target revised with new techniques. Neurosurgery 49: 293–306. Velasco, M., Velasco, F., Velasco, A.L., Velasco, G. and Jimenez, F. (1993) Effect of chronic electrical stimulation of the centromedian thalamic nuclei on various intractable seizure patterns: II. Psychological performance and background EEG activity. Epilepsia 34: 1065–74.

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2.  neuromodulation: a historical perspective

Vilensky, J.A. and Gilman, S. (2002) Horsley was the first to use electrical stimulation of the human cerebral cortex intraoperatively. Surg. Neurol. 58: 425–6. Wall, P.D. and Sweet, W.H. (1967) Temporary abolition of pain in man. Science 155: 108–9. Watts, R.L., Subramanian, T., Freeman, A., Goetz, C.G., Penn, R.D., Stebbins, G.T. et al. (1997) Effect of stereotaxic intrastriatal cografts of autologous adrenal medulla and peripheral nerve in Parkinson’s disease: two-year follow-up study. Exp. Neurol. 147: 510–17. Woolsey, C.N. (1964) Cortical localization as defined by evoked potential and electrical stimulation studies. In: G. Schaltenbrand and C.N. Woolsey (eds), Cerebral Localization and Organization. Madison, WI: University of Wisconsin Press, pp. 17–26.

Wycis, H.T. and Gildenberg, P.L. (1965) Further observations on campotomy in various extrapyramidal disorders. In: A. Barbeau, L. J. Doshay and E.A. Spiegel (eds), Parkinson’s Disease. Trends in Research and Treatment. New York: Grune and Stratton, pp. 134–48. Wycis, H.T. and Gildenberg, P.L. (1969) Long-range evaluation of the surgical treatment of spasmodic torticollis. Excerpta Med. Int. Congr. Ser. 193: 97. Zabara, J. (1985) Peripheral control of hypersynchronous discharge in epilepsy. EEG Clin. Neurophysiol. 61: 162. Zabara, J. (1992) Inhibition of experimental seizures in canines by repetitive vagal stimulation. Epilepsia 33: 1005–12. Zabara, J., Chaffee, R.B., Jr and Tansy, M.F. (1972) Neuroinhibition in the regulation of emesis. Space Life Sci. 3: 282–92.

I. an introduction to neuromodulation

C H A P T E R

3

Neuromodulation Technologies: Whom Do We Serve? Allen R. Dyer and Mary Pat Aardrup

o u tl i ne Introduction

21

Pain as Paradigm

23

Pain and Dependency

23

Psychiatric Overlay

24

24

How Do We Serve Whom We Serve?

26

The Healer’s Art

26

References

27

The American Heritage Dictionary (2000) confirms our historical orientation of patienthood:

In our quest to help patients, let us not forget the fundamental elements. John C. Oakley, MD*

patient — 1. adjective Capable of bearing affliction with calmness. 2. Tolerant; understanding. 3. Persevering; constant. 4. Capable of bearing delay and waiting for the right moment. –noun One under medical treatment. [from Latin patiens, to suffer]

Introduction

(Copyright © 2000 by Houghton Mifflin Company)

The answer to the question, “Whom do we serve?” is as simple as “We serve those who could benefit from the technology” and as complex as “We serve those who suffer from the afflictions which neuromodulation technologies might address.” The question, “Whom do we serve?” touches on scientific, technological, humanistic, ethical, and economic aspects of medicine.

Someone who is patient is capable of bearing affliction with calmness. One becomes a patient, that is comes under medical treatment, in order to bear affliction with calmness. The doctor’s role is defined by the patient. That is to say, the doctor or the healer in society exists in order to help people bear affliction with calmness. Technology, specifically neuromodulation technology, is one of the tools physicians use to help patients be patient. This chapter will address those patients whom we (the broad field of neuromodulation) serve as well as those whom we do not serve. Neuromodulation is the field of science, medicine, and bioengineering that encompasses implantable and

* 

 John Oakley (1945–2006) was a neurosurgeon neuroscientist, a pioneer in pain medicine. The fundamental elements he refers to in the above quote, which was an inscription on a photomicrograph of the brain, are nerve cells. This chapter is dedicated to Dr Oakley, colleague and friend, and is inspired by his scientific humanism.

Neuromodulation

Ethical and Economic Considerations: Whom Do We Not Serve?

21

2009 Elsevier Ltd. © 2008,

22

3.  Neuromodulation Technologies: Whom Do We Serve?

non-implantable technologies, electrical and chemical, that improve life for humanity. Neuromodulation is technology that impacts upon the neural interface (see International Neuromodulation Society website, www. neuromodulation.com). Among the technologies that neuromodulation encompasses are the following: l l l l l l l

Neurostimulation Neuroaugmentation Neural prosthetics Functional electrical stimulation (FES) Assistive technologies Neural engineering Brain–machine interface

Neuromodulatory devices are used for a growing number of indications including: l l l l l l



l l



l



l

Pain (ischemic, visceral, and neurogenic) Angina pectoris Peripheral vascular disease Epilepsy Urinary disorders Spasticity from spinal cord injury, cerebral palsy, or multiple sclerosis Diabetes Abdominal disorders such as irritable bowel syndrome or dysmotility syndromes Psychiatric disorders such as depression, obsessive– compulsive disorder and Tourette’s syndrome Movement disorders such as dystonia

Neuromodulation therapies serve a broad array of problems, as indicated by Table 3.1. Neurostimulation and other neuromodulation technologies have emerged as effective means of controlling and/or improving many bodily functions. Today, the original neuromodulation technology from

pacemaker technology is being successfully applied to the nervous system to treat diseases as diverse as Parkinson’s disease (Green et al., 2006), disorders of cardiac pacing (Sutton et al., 1980) and epilepsy (Kuba et al., 2003), and a myriad of other disabling conditions that are expected to significantly increase due to the aging population. These conditions include Alzheimer’s disease (Eriksdotter Jönhagen et al., 1998), chronic pain syndrome (Leveque et al., 2001), treatment-resistant depression (www.wireheading. com, 2007), severe migraine (Oh et al., 2004), obesity management (Liu et al., 2005) and many others. More impressive than a tabulation of the technologies used for neuromodulation therapies are the personal stories of people who have benefited from these technologies, such as the following: One of my biggest regrets is that the chronic pain and medication stole the opportunity to be actively involved in my children’s lives. Prior to the spinal cord stimulation (SCS) surgery, the last meaningful involvement I can remember having with my 14-year-old son is when he was three years old. With the help of the SCS system, I have been given the opportunity to reclaim what I lost and can live a fulfilling and productive life again. (Mike, phantom limb pain; www.advancedbionics.com/2007) It’s amazing how many simple things you give up when you’re in pain, and don’t even realize it until you get them back. For example, picking up a pen and not having it hurt. Just having the day to day things change and not needing to think about if it’s going to hurt – that’s a great deal of freedom. (Jessica, RSD hands, shoulders and back; www.advancedbionics.com/2007) My family has been extremely supportive of me, though I know they were frustrated over the years with my inability to hear. Increasingly, my family became my telephone communicator, social communicator as well as moral supporter.

Table 3.1  Populations served by neuromodulation therapies Indication

US prevalence

Source

Pain

105 000 000 (35%)

American Pain Society

Interstitial cystitis

847 000–1 000 000

National Kidney and Urologic Diseases Clearing House

Migraine

29 500 000

Population Division, US Census Bureau NCEST 2005-01

Traumatic brain injury

1 500 000

Brain Injury Association of America

Tinnitus

12 000 000

National Institutes on Deafness

Parkinson’s disease

1 500 000

National Parkinson Foundation

Essential tremor

5 000 000

Neurology Channel

Depression

14 200 000–28 000 000

NIMH

Morbid obesity

10 000 000

American Obesity Association

Angina

6 000 000

National Heart, Lung, and Blood Institute, NIH

Source: Marketing data from Advanced Neuromodulation Systems/St. Jude Medical

I.  An introduction to neuromodulation



23

Pain and dependency

The cochlear implant has been a true miracle for me, my family, my friends, my colleagues and my students. (Neina, progressive hearing loss over 30 years; www.advancedbionics.com/2007) After a diagnosis of Parkinson’s disease in 1986, Gary endured growing difficulty walking, freezing episodes and slowness of movement. Of his life now after receiving deep brain stimulation, he says “Every day when I get up it is like a new life. I can go out to dinner with friends and not embarrass them or myself by twitching all over the place.” (Gary, Parkinson’s disease; www.medtronic.com/2007) I could see the difference immediately. Within a day or two, I was amazed how easy things were like writing a check and signing my name. (Bryan, essential tremor; www.medtronic.com/2007) Spinal cord stimulation is not a universal remedy. But chronic pain sufferers whose conditions cannot be improved with surgery owe it to themselves to investigate the treatment, particularly if they are told like I was, that drugs are the only options. (Pat, failed back surgery; www.ans-medical.com/2007)

Pain as paradigm Chronic pain is not the only disability for which neuromodulation technologies are employed, but all disabilities share in some ways the issues that pain and suffering impose on people’s lives. Disabilities are subjective experiences; they involve biological, psychological, social, and even spiritual components. They may be excruciating to the individual and imperceptible to others except through the vehicles of language such as verbal language or possibly, but not necessarily, “body language,” such as the flinch or grimace. For these reasons, pain may serve as a paradigm of a number of related disorders and disabilities. The American Heritage Dictionary (2000) defines pain as follows: pain — n. 1. An unpleasant sensation, occurring in varying degrees of severity as a consequence of injury, disease, or emotional disorder. 2. Suffering or distress. 3. Plural. The pangs of childbirth. 4. Plural. Great care or effort: take pains with one’s work. 5. Informal A nuisance. [Middle English paine, from Old French peine, from Latin poena, penalty, from Greek poine, penalty.] (Copyright © 2000 by Houghton Mifflin Company)

Medically, pain is now considered to be the fifth vital sign (American Pain Society, 1995; Phillips, 2000) which should be monitored along with temperature, heart rate, respiratory rate, and blood pressure. Pain is a subjective perception, not able to be objectified, and can only be monitored by a patient’s report and, as such, is the only vital sign for which there is not an

objective measure. Properly speaking, the fifth vital sign is the perception of pain. For our purposes we use the definition of pain from the International Association for the Study of Pain: “pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” (IASP, 1994). As such, it is the paradigmatic symptom of medicine. All medicine is ultimately about pain in its myriad manifestations, in varying degrees of severity and consequence. Physical pain is seldom isolated from emotional pain and, over time, pain interferes with one’s life to the extent that mood, as a result of this “ongoing pain,” is altered in a way that we often call “depression.” Conversely, a lifetime of distress may also contribute to depression, complicating the perception of pain caused by injury or disease. pain→depression→emotional pain All medicine attempts to relieve the suffering and impatience that disrupts the lives of human beings. In the case of specialized interventions such as pharmacological treatments (modern derivatives of ancient herbal remedies) and the newer neuromodulation technologies, treatment is directed at a particular anatomical and physiological aspect of what is clearly understood to be a complex phenomenon, the bio-psycho-social experience of distress. For the physician’s purposes, the available technologies serve the larger goal of relief of suffering; they are tools of the physician’s trade. And suffering, understood as pain, is appreciated as a consequence of injury, disease, or emotional disorder. This circularity locates the physician’s work at the heart of human experience.

Pain and dependency

Case example Paul occasionally experienced back pain at times of stress in his late twenties and early thirties. Though this could be excruciating and incapacitating for a few days, it usually resolved with rest and his use of over-the-counter analgesics. His doctor prescribed diazepam for muscle relaxation, but did not perform any particular diagnostic work-up. When he was 32, his back pain became chronic after what at first seemed like a relatively minor injury (lifting boxes at work). X-rays showed degenerative disc disease and a ruptured intervertebral disc. His

I.  An introduction to neuromodulation

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3.  Neuromodulation Technologies: Whom Do We Serve?

doctor prescribed non-steroidal anti-inflammatory analgesics, renewed the diazepam, and recommended a period of rest, which helped but did not relieve the symptoms. He returned to work, but his performance suffered; his boss was unsympathetic, at times hostile. His analgesic use escalated. He became physically dependent and ultimately psychologically dependent (addicted) to the pills his doctor prescribed, then to drugs he received from his friends. He was now unable to do his job, and was fired. He became depressed and irritable. He isolated himself from family and friends and from his own feelings of anger and rage. He felt hopeless and considered suicide. Pain became his constant companion and the center of his existence. His doctor refused to see him because he was “non-compliant,” and without a job, he was without insurance. Eventually, he was granted disability. He was given a dorsal column stimulator and, for several months, it provided some intermittent relief.

account of disorders with a life of their own and must be considered when comprehensively assessing whom do we serve: l l l l l l

Anxiety Depression Psychosis Somatoform disorders Factitious disorders Axis II disorders (DSM–IV, Developmental and Personality Disorders)

The physician must deal with his or her own reactions to the feelings that these “difficult” patients bring to the table. It may be more useful to conceptualize these disorders as defenses, the characteristic way people deal with unpleasant affects and emotions, fear, anger, loss, sorrow. Such patients may have difficulty expressing their feelings directly or even recognizing them. If the physician can respond to the underlying feelings, it may be easier than responding to the behavior itself. Recognizing and responding to these disorders can significantly impact the success of the procedure and open receptivity to the healing mindset (Table 3.2).

Psychiatric overlay The ideal patient in the biomedical perspective is someone who has demonstrable organic dysfunction and no psychiatric overlay. In the real world, such a creature rarely exists. Practically speaking, the nonorganic aspects of symptom presentation complicate diagnostic evaluation and may frustrate physicians’ attempts to help the patient, both at a professional and personal level. Often such frustration may limit the care a patient receives from a healthcare giver, either from anger or misunderstanding. It may be useful to reconceptualize medicine to account for not only the anatomical and physiological aspects of disease in a reductionistic sense, but also the inter-relationships of the biological, the psychological, and the social. Philosophers of medicine call this new direction “complexity science,” acknowledging the multiplicity of variables that must be addressed in every clinical situation. Interdisciplinary teams are a practical and more or less efficient way of making sure that each aspect of a person’s problem gets the attention of a specialist prepared to consider each facet of such complex symptoms. Often in the busy clinical world, each specialist does his or her own thing. It is important that the teams be integrated at a working level and conceptually. The following list of symptoms commonly associated with disease states is intended to illustrate the complex nuance of conceptualizing human feelings and experiences as much as it is to be an exhaustive

Ethical and economic considerations: whom do we not serve? The complexities of the question “Whom do we serve?” can be appreciated by asking the question in the negative, “Whom do we NOT serve?” The answer to this form of the question opens consideration of a number of ethical and economic considerations of how we value health and how we fund health. It is obvious to all that we do not serve those whose symptoms do not indicate treatment with our technologies. We do not use neuromodulation technologies for those whose symptoms respond to less complex treatments. Similarly we do not employ these complex technologies for those who are unlikely to bene­ fit from them. Careful research, particularly outcome studies, will be needed to best predict and delineate those most likely to benefit. We do not serve those who choose not to receive surgery/treatment. In one survey of 212 implanting physicians, 40% of patients offered neurostimulation declined treatment (Table 3.3). There are many reasons for this relatively high number of refusals. Fear of the procedure itself and fear of having a foreign object implanted in one’s body top these reasons. For example, patients have concerns about paralysis due to the leads connecting

I.  An introduction to neuromodulation



25

Ethical and economic considerations: whom do we not serve?

Table 3.2  Neurostimulation applications Condition [Treatment]

Prevalence/incidence

FDA Regulatory status

Estimated implants to date/per year

Chronic pain spinal cord stimulation [Peripheral nerve stimulation]

50 000 000/5 000 000

Cleared

110 000/16 000

Parkinson’s disease/essential tremor [Deep brain stimulation]

1 500 000/250 000

Cleared

30 000/5850

Epilepsy [Vagal nerve stimulation]

2 700 000/500 000

Cleared

22 500/1250

Chronic depression [Vagal nerve stimulation]

15 000 000/4 000 000

Cleared

22 500/1250

Urge urinary incontinence [Sacral nerve stimulation]

12 000 000/150 000

Cleared

25 000/3000

Pelvic pain [Sacral nerve stimulation]

N/A

In trials

N/A

Chronic intractable pain [Spinal cord stimulation]

N/A

In trials

N/A

Peripheral vascular disease [Spinal cord stimulation]

N/A

In trials

N/A

Obesity vagal nerve stimulation [Direct gastric stimulation]

5 000 000/250 000

In development

N/A

Pain, dystonia, epilepsy, OCD, depression, motor dysfunction, brain injury [Deep brain stimulation]

N/A

In trials

N/A

Source: Medtech Insights

Table 3.3  Patients recommended for a spinal column stimulator but not receiving surgery Approximate percentage agreeing to implant

Approximate percentage declining the implant?

No.

212

212

Mean

61.9

38.1

Median

60.0

40.0

Source: Medtronic, Inc data on file, January 2007

with the spinal column and therefore may not choose the therapy that might help their pain and disability. Hope is another significant barrier to receiving implantable technologies. Many of these individuals have been defined by their illness on average for 7–12 years. How will their lives change when they are no longer defined by their malady? Many are unready to give up the symptoms. The level of enthusiasm on the part of the physician will also dictate the patient’s receptivity to the procedure as will negative word of mouth regarding the procedure. Other possible issues may involve lack of information on outcomes measurements, misperceptions about what the treatment entails, and cosmetic considerations. More work needs to be done to better understand why people do and do not choose to receive these technologies and how best to match those wanting and needing the treatments with those most likely to benefit. The next group of people that we do NOT serve that must be considered is the uninsured. One in

six Americans are uninsured – all Americans are underinsured (National Health Interview Survey, 2006). According to the National Health Interview Survey, 43.6 million Americans are uninsured. This includes 19.8% of working-age adults and 9.3% of children. Ideally everyone who could benefit from these or other treatments should have access to them. Unfortunately, the uninsured or underinsured population has very limited opportunity for benefiting from expensive neuromodulation techniques. Individuals who are at the end stage of their lives who could potentially benefit from neuromodulation are often passed over as undeserving of this opportunity for relief because of the costs incurred for little time left. Like so many ethical issues, value is often calculated as a cost–benefit analysis. What is the greatest good for the greatest number? Many people who might benefit are denied opportunity for service because of cost. The limitations of resources for treatments of proven medical benefit are ethical and economic issues. It is a matter of distributive justice. Its resolution is ultimately a matter of science and a matter of politics. The scientific contribution must rest on good evidence and sound analysis of the benefits in relation to the cost. Increasingly questions of justice are receiving more attention. What does the principle of justice – understood as fairness – require of a just and equitable society? These considerations have led many to conclude that it isn’t right that healthcare isn’t a right. It isn’t right that people should suffer from disorders that are treatable. Our moral and ethical responsibilities will be greatly challenged as the field of neuromodulation expands to address additional disease states.

I.  An introduction to neuromodulation

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3.  Neuromodulation Technologies: Whom Do We Serve?

Reimbursement issues are an ongoing challenge that requires everyone in the field of neuromodulation to be vigilant in participating in the process of educating insurers about the advances in the technology and clearly articulating success stories. Neuromodulation is a ground-breaking yet costly technique. It is difficult to receive reimbursement at the present time for those that are fully insured. Reimbursement and efficacy challenges have weighed down the field of neuromodulation since the beginning of the technology. Double blind studies are difficult to do, which makes it challenging to appreciate the true value of this technology. The most common reasons for the denial of coverage for neuromodulation procedures include: The therapy is investigational/experimental l There is a paucity of type A evidence for their efficacy l The therapy is not medically necessary l The therapy is not a standard of care

Often people with invisible illnesses blame themselves. However, irrational such blame may seem, it is understandable. It reflects a culture of individualism and self-reliance. It may reflect guilt from many unresolved sources. Many people think of illness as a burden of sin that is deserved. This perception of pain as penalty is reflected in the ancient Greek definition and is particularly prominent in people who consider themselves religious. In this sense even physicians must minister to the sick. Science and technology may come to aid, but not always to the rescue.

The healer’s art

l

Patients have a right to appeal these decisions. Coverage is often denied because the carrier does not have a clear understanding of the therapy and providing them with information about the success of neuromodulation therapy and the other therapies that have been tried with the patient in the past can be helpful.

How do we serve whom we serve? Chronic illness involves much more than the patient’s body. It involves the patient, the patient’s family, and the patient’s community. Unlike, say, an acute appendix, which can be removed and forgotten, chronic illness, by definition, is ongoing; it endures throughout time. It becomes and remains a focus of attention and consciousness. Chronic illnesses, whether they are understood to be physical illnesses or mental illnesses, become bio-psycho-social and spiritual illnesses. Serving a person with a complex chronic illness involves serving the person as a whole and serving the family-community system affected by the illness. It involves at the least, caring and acknowledging the reality the person confronts. Often people with invisible illnesses, diseases and illness that are not outwardly apparent, such as chronic pain will say, “It is important to be believed.” In a series of focus groups conducted in 1999 by the National Pain Foundation (NPF; www.NationalPainFoundation .org), lack of validation (belief that the patient was suffering what the patient said they were suffering) was identified as the most significant challenge faced by people in pain.

With impressive new technologies such as neuromodulation technologies, the physician is able to bring unprecedented interventions to patients who suffer some of the most excruciating disabilities. But treatment of human beings by human beings involves more than just applying technology. Listening to patients’ stories and validating their experience can be very important even when the problem can or can’t be fixed. This is especially true for patents whose symptoms have been minimized or doubted. Furthermore, just as illness entails a loss, loss of the healthy self, healing also involves a life change. Patients need to communicate their experiences to other human beings, and this too is an important aspect of the healer’s role and the healer’s art. Individuals considering neuromodulation may have exhausted pharmacologic, complementary, and manipulative therapies. Interventionalists hold open the door of hope for those seeking refuge from their life of suffering. It is a privilege to change the direction of an individual’s life. This privilege must be treated with great respect. Professionals, family, and friends may help people struggling with disease give voice to their experience and to focus on a life beyond the suffering. They partner with patients to make life better. Often they succeed. Always they must try. The ripple effect of health concerns on an individual’s life are far-reaching. Illness takes a toll on careers, family, friends, and finances. A person’s life can be forever changed because someone took the time hear their “story,” explored options, and determined the proper treatment. Neuromodulation is but one of those options. Sir William Osler, whose remarks have long reminded physicians of the complexities of their duties, may have had something like this in mind when he observed. “It is not nearly as important what disease the patient has as what patient has the disease.”

I.  An introduction to neuromodulation

references

References American Heritage Dictionary of the English Language (2000) Fourth edn. Boston, MA: Houghton Mifflin. American Pain Society (1995) Pain: The fifth vital sign. www. ampainsoc.org/advocacy/fifth (accessed 22 April 2004). Eriksdotter Jönhagen, M., Nordberg, A., Amberla, K., Bäckman, L., Ebendal, T., Meyerson, B. et al. (1998) Intracerebroventricular infusion of nerve growth factor in three patients with Alzheimer’s disease. Dement. Geriatr. Cogn. Disord. 9 (5): 246–57. Green, A.L., Bittar, R.G., Bain, P., Scott, R.B., Joint, C. et al. (2006) STN vs. pallidal stimulation in Parkinson Disease: improvement with experience and better patient selection. Neuromodulation 9 (1): 21–7. IASP Task Force on Taxonomy (1994) Classification of Chronic Pain, 2nd edn (edited by H. Merskey and N. Bogduk). Seattle: IASP Press, pp. 209–14. Kuba, R., Brázdil, M., Novák, Z., Chrastina, J. and Rektor, I. (2003) Effect of vagal nerve stimulation on patients with bitemporal epilepsy. Eur. J. Neurol. 10 (1): 91–4.

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Leveque, J.-C., Villavicencio, A.T., Bulsara, K.R., Rubin, L. and Gorecki, J.P. (2001) Spinal cord stimulation for failed back surgery syndrome. Neuromodulation 4 (1): 1–9. Liu, S., Hou, X. and Chen, J.D.Z. (2005) Therapeutic potential of duodenal electrical stimulation for obesity: acute effects on gastric emptying and water intake. Am. J. Gastroenterol. 100 (4): 792–6. Oh, M.Y., Ortega, J., Bellotte, J.B., Whiting, D.M. and Alo’, K. (2004) Peripheral nerve stimulation for the treatment of occipital neuralgia and transformed migraine using a C1-2-3 subcutaneous paddle style electrode: a technical report. Neuromodulation 7 (2): 103–12. Phillips, D.M. (2000) JCAHO pain management standards are unveiled. JAMA 284 (4): 428. Sutton, R., Perrins, J. and Citron, P. (1980) Physiological cardiac pacing. Pacing Clin. Electrophysiol. 3 (2): 207–19. www.wireheading.com/brainstim/antidepressant.htm  (accessed 7 April 2008).

I.  An introduction to neuromodulation

C H A P T E R

4

Challenges in Moving Toward Product Development Paul Meadows

o u tli n e Introduction

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The Neurostimulation Market Patient Population Available Technology Proposed Technology – Intellectual Property Reimbursement

30 30 31 32 33

The Implantable Medical Device  Development Process Planning Phase Product Identification and Market   Analysis Marketing Requirements Feasibility Study Product Definition Design Phase

33 33

A Modern Day Success Story – Advanced  Bionics and Alfred E. Mann The Spinal Cord Stimulation Market in 2000 The Design Approach Taken by Advanced   Bionics Corp. The Impact Upon the Market and Lessons Learned

34 34 34 34 35

References

Introduction

36 37 38 39 40

and progressing through the applications of suppression of chronic pain, restoration of hearing, control of urinary incontinence , and suppression of the symptoms of Parkinson’s disease and other movement disorders such as cerebral palsy, dystonia, and epilepsy. Emerging applications to treat the problems associated with spinal cord injury, stroke, and vision are just beginning to make an impact on the lives of patients suffering from these debilitating conditions. While some neurostimulation methods and devices have been around since the early 1960s, there have only

Implanted neuromodulation systems have advanced greatly over the decades, but have greatly accelerated in their complexity and capabilities in the most recent years. Implantable stimulators are used for a variety of applications, beginning initially with cardiac pacing, Editors’ note: The views on products given within this chapter are the author’s opinions only and do not necessarily reflect the opinions of the Editors or other contributors of this book.

Neuromodulation

35 35 35 35 35 36 36 36

Module Design Design Verification and Validation System Integration Process Development Process Validation Manufacturing Acceptance Clinical Study Transfer/Acceptance Phase

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© 2008, 2009 Elsevier Ltd.

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4.  Challenges in Moving Toward Product Development

been a small number of devices which have been introduced into the commercial marketplace and survived the test of time. The reasons for this limited presence of devices compared to the numerous potential applications are many, but primarily fall into a very few key categories: Market, Resources, and lastly, Technology. One might think that technology would be first in this list, but in fact it is, by itself, a rather small impediment to the introduction of new medical implants. It should be noted that our discussion of the field of implanted neurostimulation devices covers both commercially and academically produced devices. The latter have focused on some of the most difficult applications and have rarely been able to make the transition into the commercial arena. For the purposes of this discussion these academic institutional efforts will be discussed only briefly. The Market for an implanted neuromodulation system is perhaps one of the least appreciated elements in the development of a newly developed neurostimulation system. The implanted neurostimulation market consists of the following key participants: patients who will receive the new system physicians: – who determine that the conditions which can be addressed by the system exist in the patient – will refer the patient to an implanting surgeon – who can and will implant the system – who can program and maintain the system for the patient l third party payers who can pay for the system. l l

Factors that will affect the size of the market include the following key elements: alternative technologies, substitutes and treatment methods l scope of the application l acceptance by the patient l acceptance by the physician. l

A newly introduced product must provide a cost and risk effective result compared to alternative technologies and must use common sense regarding its outlook in addressing a clinical need. A 500 horsepower sports car with a joy-stick control may look appealing to someone with a mobility problem, but a motorized wheelchair may in fact be the best fit of technology for the application. The system developer must take careful stock of the needs of the patient and the limitations imposed upon the product by the marketplace and design their products accordingly. In this chapter I will briefly describe the product development process for implantable neurostimulation devices and describe the introduction of the most

advanced spinal cord stimulation system to date, and I will provide some guidance and process descriptions to be utilized in the development of a neuromodulation product.1

The Neurostimulation Market Patient Population The neurostimulation market can best be described by the patient population that can benefit from neurostimulation devices. In Figure 4.1 below it can be seen that neurostimulation may address both sensory and motor nerve dysfunctions, and that the sites of stimulation are literally every region of the body. In the sensory neurostimulation market one of the first commercial successes was the cochlear implant. In the USA there are roughly 1.2 million people who meet cochlear implant candidacy criteria with approximately 350 000 accessible candidates. Globally there are roughly 75 000 accessible candidates who will enter the market yearly, yet only 16 500 cochlear implants were sold in 2006 and the market penetration is at about 20%, while growing at 12–14% annually. Three major companies compete for this market: Cochlear Corporation of Australia, Advanced Bionics Corporation of the USA, and Medel of Austria. At this time Cochlear Corp. has approximately 120 000 patients implanted and Advanced Bionics has more than 28 000 patients implanted with their devices. The benefits of a cochlear implant to the patient are dramatic, but the benefits to society are also now widely appreciated. In a recent study (Mohr et al., 2000) it was determined that the lifetime costs for those with prelingual onset of profound deafness exceed $1 million, with the chances of gaining entrance into a college at 3% and a poor outlook for vocational opportunities. A child under the age of 12 months who receives a cochlear implant, however, at a cost of approximately $50 000, will very often be able to be mainstreamed into traditional educational environments with chances of college and vocation equal to their peers. Thus the cost savings to society and the chance for the child to lead a normal and productive life are greatly enhanced through cochlear implant technology. 1

 Implanted neuromodulation should rightfully include electrical stimulation and pharmacological stimulation, as well as any future modalities that affect the operation or state of the nervous system. This chapter will constrain the discussion to electrical stimulation, but the general conditions and environment of product devel­ opment described here are common to both forms of implanted neuromodulation devices.

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The Neurostimulation Market

Brain Disorders: Epilepsy Parkinson’s Cerebral palsy

Blindness Deafness

Pain: Peripheral neuropathy Angina pain Chronic low back pain

Respiratory: Sleep apnea Respiratory failure

Incontinence Paralysis: Stroke Spinal cord injury

Figure 4.1  Stimulation applications

Sensory neurostimulation for the restoration of sight is in its earliest stages. While investigated for many years in academic centers around the world using optic nerve multipolar cuff electrodes (Veraart et al., 1999), visual cortex (Brindley and Lewin, 1968), and retinal multicontact arrays and microelectrodes (Humayun et al., 2003), retinal stimulation is now being commercially developed by Second Sight in Sylmar, California. This newly developed system has been in clinical trials for two years using a cochlear implant stimulator with 16 current sources driven by an external video processing system. Next generation devices will increase the number of contacts and will reduce the size of the implanted components. Peripheral motor nerve stimulation, like visual prostheses, has been of academic interest for over 40 years. One of the first applications of peripheral nerve stimulation was the demonstration by Liberson (1961) in which he stimulated the peroneal nerve to dorsiflex the ankle of stroke patients. This early neuromodulation system was commercialized by Medtronic (Minneapolis, MN) as the Neuromuscular Assist and was implanted in thousands of patients in the USA. The device consisted of a radio frequency (RF) power­ed single channel voltage source and utilized a cuff electrode placed at the post-tibial branch of the peron­eal nerve. A foot switch triggered when the heel left the floor at the initiation of the swing phase of gait. This caused a small shoe-worn transmitter to tele­meter a signal to a waist-worn receiver which then transferred energy using a coil placed over the implanted stimulator, usually implanted into the medial thigh.

Stimulation of the peroneal nerve would then cause dorsiflexion of the ankle so that the foot could clear the floor more effectively than without the benefit of stimulation. Stimulation terminated when the heel switch again came into contact with the floor at the terminus of the swing phase removing the trigger and causing stimulation to cease. Spinal cord stimulation was one of the greatest field-changing technologies in the history of neuromodulation and was introduced by Medtronic in the late 1960s and early 1970s after the pioneering work of Shealy (Shealy et al., 1967). RF and battery-powered pulse generators were first employed to treat intractable pain and then were utilized for the treatment of peripheral nerve disorders and eventually for deep brain stimulation for Parkinson’s disease and other movement disorders. With the expansion of these products the neuromodulation market has grown to encompass many of the potential neurostimulation sites available with the opportunity to treat and correct an ever-increasing number of medical conditions.

Available Technology The development of implanted medical devices must carefully balance the desire to utilize the latest and most advanced electronic components, materials, and mechanical technologies while at the same time provide products that are both safe and reliable. Often new microelectronics are made available to the designers of consumer and other non-medical products and greatly

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4.  Challenges in Moving Toward Product Development

tempt the designer of medical devices to incorporate them into their new products. However, the risks of unproven technology having bugs or failure modes that have not yet been identified would place the products using those devices at risk of erratic behavior and potential explant before their intended useful service life is exhausted and so very often implanted technology utilizes the most conservative of technologies with, perhaps, reduced functionality, but with greater confidence in the reliability and function of the product. The risks associated with using the latest electronic devices are also similar to those pertaining to the use of new fabrication technologies. Traditional implanted electronic devices have gained much from the highreliability world of military electronics which have employed thick and thin film ceramic hybrid assemblies in which bare dice are epoxy attached to the substrate and gold wirebonded from die to substrate. Passive components such as resistors and capacitors are often conductive epoxy attached as well and the entire assembly is placed in a hermetically welded metal enclosure. This fabrication technology limits the types and varieties of components available to the designer but is a well understood and conservative method of device manufacture. When ball grid arrays and flip chip technologies were introduced to the electronics industry it heralded unprecedented opportunities to reduce circuit footprint and volume. However it has taken many years for the implanted medical device community to adopt and embrace these new technologies as the long-term reliability of these packaging methods were not well proven until only recently. The selection of components to be utilized in an implanted device requires not only conservatism on the type of technology but extraordinary levels of testing and screening. Failures in medical implants are rare, because of good design and meticulous manufacturing practices. Components are selected from suppliers who understand the requirements of high reliability (hi-rel), often from their experience in supplying components to the military and space programs. In fact, it is traditional for medical device companies to depend upon the military and space standards and performance guidelines in the testing and building of products. Few standards for neuromodulation devices exist outside of those originally developed for the cardiac pacing industry. The adherence to the military hi-rel methods adds tremendous expense to the production cost of an implanted device but ensures that the components selected and their fabrication into finished goods will result in devices that in some instances may last the life of the patient. This is especially critical in devices that are life-supporting, such as cardiac pacemakers and automatic defibrillators. Devices that

are not life-supporting must also be highly reliable, because premature device failure could mean significant harm or discomfort to the patient.

Proposed Technology – Intellectual Property Key to the introduction of new or improved medical devices is securing the rights to the intellectual property upon which it is based. Either new technology must be developed and patented, or licensing rights must be acquired to enable the legal and noninfringing introduction of products into the marketplace. This also ensures that the products introduced enjoy the fruits of their efforts for the maximum allowed period under law before they may be freely copied or utilized by others. Developers of new products would be well advised to conduct an exhaustive patent search performed by experts in the technology field of the product and applicable patent databases. A product that infringes upon the patents of others, no matter what improvements and performance enhancements might be provided, can nonetheless be prevented from entering the marketplace. Considering the monetary cost of bringing new products to market, this represents a significant risk to investors. Intellectual property (IP) can be broken down into four types: patent, trademark, copyright, and trade secret. The patent is the most visible form of IP, and (in the USA) is the grant of a property right to the inventor for a term of 20 years from the date of filing. The patent “confers the right to exclude others from making, using, offering for sale, or selling the invention in the US.” Of course, foreign patents must be considered for foreign product distribution as well. The trademark is a “word, name, symbol, or device which is used to indicate the source of the goods and to distinguish them from the goods of others” and in the medical device arena would most commonly be used in product labeling and sales materials. A copyright is “a form of protection provided to the authors of original works of authorship, both published and unpublished, giving the owner the exclusive right to reproduce or distribute copies of the original work” and has its relevance to software, labeling, and literature associated with neuromodulation products. Trade secrets are those pieces of information that are not generally known beyond the confines of the holder and have no legal protection but give the owner a competitive advantage, and which may be patentable or otherwise protected, but which it is in the best interests of the holder not to divulge to the public. The most appropriate course of action to protect the IP assets of the company is a difficult decision and one that cannot be taken lightly or after the fact.

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The Implantable Medical Device Development Process

Reimbursement Reimbursement is a key element in the sales of new implanted medical technology that must be considered early in the development of a new product. Governmental regulation or insurance industry guidelines for billing and reimbursement for durable medical goods must fall into specific categories in order that they may be reimbursed by federal agencies or private insurers. Technologies that change the methods of reimbursement may need to address or seek changes in the reimbursement structure to be successful in the marketplace. An example of this can be seen by observing the manner in which spinal cord stimulators for chronic pain are delivered. In this application a patient typically receives an electrode lead, placed percutaneously, and which is attached externally to a trial stimulation device to test for several days to a week or more to determine if the stimulation ultimately provided by an implanted version of the trial stimulator can significantly relieve pain. This trial process is reimbursed separately from the permanent implant of a pulse generator, but the latter only occurs if the trial demonstrated significant pain relief for the patient. It is foreseeable that in the future technology could be developed that could be either so effective that the trial would not be required, or that the methods employed could demonstrate efficacy so quickly that a patient could go from testing to permanent implant in a single procedure. The reimbursement methods and codes might have to be modified to support this change and it would be expected that this could take a significant amount of time and effort to work with federal regulators and third party payers to make this happen.

The Implantable Medical Device Development Process The development of a new implanted medical device is a well-understood and highly regulated process. Only a few companies have the resources to embark on such a development and be able to provide the regulatory bodies with sufficient evidence of a safe and effective product. The development process may be broken into a series of phases during which initial product exploration occurs, product and manufacturing process designs are initiated, the transition to the manufacturing phase along with formal clinical trials, and finally the product launch and monitoring phase. The strict adherence to a consistent and logical development plan for an implanted product will not only help in the smooth submission of data to the regulatory

33

bodies and introduction to the market, but, more importantly, will result in the most safe and effective device possible with the available resources. Several books have been written on the development of medical products and are well worth the time to review for anyone contemplating the development of a new medical device. An excellent example of such a reference is by Elaine Whitmore as she writes from a quality design-in perspective and presents a very wellbalanced introduction to this topic (Whitmore, 2004). The development of implanted medical devices is governed by several internationally recognized standards. Two of these standards are tremendously important to product development in the USA: ISO 13485:2003 Medical Devices – Quality Management and the US FDA Quality System Regulation of 1996: 21CFR 820.30. As described by the International Organization of Standards (ISO), “ISO 13485:2003 specifies requirements for a quality management system where an organization needs to demonstrate its ability to provide medical devices and related services that consistently meet customer requirements and regulatory requirements applicable to medical devices and related services.” The primary objective of ISO 13485:2003 is to “facilitate harmonized medical device regulatory requirements for quality management systems.” This standard forms the basis of product development documentation and is the backbone for regulatory investigation guidance during FDA reviews. The 21CFR 820.30 regulations provide the structure for the development process and provide a means to both internally and externally review the product design, evaluation, and manufacturing procedures. The development process description that follows owes its structure to these two foundation standards, and its description, while admittedly somewhat dry, highlights the effort and documentation required to bring a new medical implant product to market. Implanted medical device development is not for the faint of heart and requires extreme diligence to detail lest the wrath of the regulatory agencies descend upon you and your hapless peers. Milton Friedman perhaps said it best: “Hell hath no fury like a bureaucrat scorned.”

Planning Phase The planning phase is the first phase of product development. It is during this phase that an idea for a new product is first examined; plans are made and executed to verify that a market exists for the product, and a proof of concept is developed and verified. Following the successful completion of these initial steps, the formal product definition is made.

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Product Identification and Market Analysis Product identification and market analysis are extremely important activities in that they ultimately determine whether you have a product to sell. A careful review of the market can determine whether an existing market is being underserved, or if a nonexisting market may be developed. In most instances, the former is the easier market to enter as many of the clinical application and reimbursement issues have already been developed by your competitors allowing your company to bring improvements in function, cost, and implementation. Developing a new market requires the development of an education plan, establishment of new or modified reimbursement structures and a strong sales effort to convince the clinical and reimbursement structure that a change from existing practices will be beneficial and practical. These efforts become the design input for the development team and are consistent with the quality systems described above. In the initial product identification process the business benefits should be identified, a milestone schedule prepared, staffing and resource requirements determined and risk areas (business, technical, clinical) considered. It is important to acquire as many outside opinions as possible without jeopardizing the security of the development program to ensure that valid assumptions are being made about the ultimate clinical application. Sometimes a very small detail such as the impact upon other medical procedures can be a tremendous impediment to adoption by the market. Non-disclosure agreements are executed with key outside opinion leaders to help prevent the leakage of sensitive information to competitors. While these safeguards do help to prevent this leakage it may still occur so the amount of information dispensed should be just adequate enough to answer the internal questions about the market analysis and product requirements.

manufacturing, shipping, transfer from field representative to clinician, and explantation and return to the manufacturer. All of these conditions and environments must be considered for a complete understanding of the useful life of the product and its design requirements. Feasibility Study A feasibility study can be a very important step in the product development, as it can determine if any unresolved risks may or may not be mitigated by design changes. Feasibility studies will often require that a limited functional version of the product be developed and tested in a clinical environment or that adequate simulations and bench testing of product elements be conducted to reduce the risk of the product development process. If a feasibility study requires clinical input that involves direct patient involvement, then a very carefully prepared study with appropriate reviews and oversight is required to protect the interests of the patients and to produce valid and useful data. Product Definition Functional Specification The functional specification is the top level technical product requirements document and is drawn directly from the marketing requirements. Every feature of the product should have a traceable requirement and function so that the development of the product can be tracked and all features and functions realized in the final form of the system. Many software tools now exist for the tracking of these features, including software to track system requirements and the review process. The functional specification should be considered to be the primary design input document – all other documents refer back to this document and it should be used for all verification and validation testing of the product.

Marketing Requirements

Architectural Description

The result of the product identification and market analysis should lead directly to the development of a list of marketing requirements, the product specifications and functions that are directly tied to customer needs and the intended uses. Use cases should be defined for all of the users of the product – the surgeon, the patient, and the support clinicians who will all have to be convinced of the utility of the proposed product. The use of field clinical engineers and a medical advisory board are key to developing and identifying the important elements of product requirements. Often overlooked in the use models are the environments of

The architectural description is a document that describes all of the elements of the system and how they interact. Basic functional diagrams for each element may be defined with the interfaces to other elements so that project partition and team building may occur and be monitored. This document is typically prepared by a systems engineer who understands the inter-relationships and dependencies of the various sub-systems and the engineering teams that will be needed to create them. Further breakdown with milestones and program goals may be derived from this document.

I.  AN INTRODUCTION TO NEUROMODULATION



The Implantable Medical Device Development Process

Risk Management Risk management is composed of the activities that are required to identify, analyze, and mitigate risks associated with the development of the product, its components, and the impact from the manufacture, shipping, implantation, daily use by the patient, and, if necessary, explantation and return to the company. This includes the evaluation and testing of components, as well as the detailed analysis of how they are utilized in the implanted system. This is one of the most often overlooked and least appreciated areas in implanted device development and contributes tremendous cost to the manufacture of an implanted device, but without adequate attention can lead to far greater costs downstream if its implications are not sufficiently appreciated.

Design Phase

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conditions. Module testing is limited in scope in the absence of other modules or a complete system but is guided by the functional specification, architectural description and module specification for the element being tested, and should be sufficient to elucidate deficiencies in the design for proof of function. Failure of any module test would require re-design, review, and re-testing before the next phase of development may occur. Verification testing will utilize the functional specification primarily as the guideline while validation testing will utilize the marketing requirements specification. Often there is confusion about the difference between verification and validation testing. Put simply, verification determines if the product is made right, while validation determines whether you have made the right product. System Integration

Module Design The design phase occurs only after the successful completion of the previous phases. Every phase along the way is a gating and prerequisite phase for the next, and must not be skipped or left incomplete or the success of the final product in the marketplace would be jeopardized. In the design phase the essential design of the product development is carried out, using the information gathered in the feasibility studies and the marketing specification, functional specification, and architectural description, and the sub-modules are designed. Design reviews are extremely important during this phase and should include all persons involved in the design of the module as well as a sufficient representation of other groups involved in the program so that interface issues between modules may be adequately considered. The use of outside experts in the technology of the module is extremely helpful, because an outsider will invariably see issues and relationships that may not be apparent to those close to the project. This may require the use of paid consultants or representatives from other divisions, but is well worth the cost.

When the various modules have been designed and tested it is time to integrate all of the elements into a finished system and test it as a whole. This process should be extensively reviewed before and at the completion of testing to verify that all of the tests to be performed speak to the functional specifications of the product. All modes of operation must be tested and in all environments required and warranted. Failure of any element of the system test would necessitate a review to see what portions of the system test should be repeated once the failure is analyzed and mitigated. Process Development Prior to the start of manufacturing, the R&D staff must help to develop the processes that will be utilized in manufacturing the final product. While it is best that these processes be considered during the early stages of product development, it is imperative at the latter stages to ensure that the successful designs of R&D efforts translate to products that can be efficiently produced with high yields, low costs, and high reliability expectations.

Design Verification and Validation

Process Validation

As each module of the design is completed, both hardware and software, it is tested in a design verification and validation process. This process involves testing the module not just in the well-defined use cases and norms of operation, but at all possible extremes of use and preferably to the limits of operation to the point of failure. This will expose many of the design weaknesses and issues that should be considered to ensure that the product can survive and serve the patient in the presence of all foreseeable obstacles and

Process validation is the step that occurs after all of the product assembly procedures and manufacturing documentation have been created. The validation effort and report demonstrates that each process in the manufacture of the completed product will consistently produce devices that meet the marketing requirements and quality requirements of the company. All processes used in the fabrication of product must undergo this effort and reports for each process tested must be created and reviewed.

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A product-specific validation plan is a master listing of all processes and required validations for a product. This along with a process map identifies all of the processes that must be validated and identifies each step that must be examined. It also helps to guide the process failure mode and effects analysis, which evaluates the risk involved in each process step. Each failure mode must be evaluated for the probability of occurrence, the likelihood that it could be detected, and its severity, or what its ultimate effect would be. These factors lead directly to statistical methods to be utilized in the testing of the processes and the assignment of a risk index. If a risk index is high then additional process controls need to be added to mitigate the risk or the processes modified or replaced until the resulting risk index is reduced to acceptable levels. Manufacturing Acceptance The manufacturing acceptance phase is controlled by a manufacturing acceptance plan, which defines the deliverables, tests, and activities that are necessary to confirm that a product, meeting all of the specification and quality requirements, can be manufactured. All of the processes, materials, documentation (both engineering and manufacturing), and training mater­ ials must be in their production release revision, operators must be trained and certified, and vendors qualified to complete this phase. The measures of manufacturing must demonstrate to the business review staff that build rate, yield, and capacity are all within expectations, as this will determine the amount of product available to sell and at what cost. This will provide key determinants of the return on investment and the timeline to profitability. Clinical Study The product should undergo a field clinical trial to collect product data that verify device function in a clinical setting. The study will obtain information associated with the proposed product (or change in the product) and is conducted independently by the clinical research, marketing, and R&D teams along with clinical partners identified early on in the development of the marketing requirements for the product. Studies must be conducted in FDA approved trials with institutional review board (IRB) approval and monitoring for both the protection of patient interests and the proper and useful collection of data. This is not to be confused with the final product clinical trial, which is the gating element in FDA approval prior to product release and distribution.

Transfer/Acceptance Phase The final phase prior to product release to the market is the transfer and acceptance phase. This phase focuses on transferring the developed production processes to the manufacturing division, generating production prototypes, executing process validation and design validation protocols and running pilot production to gather performance metrics in support of manufacturing acceptance. It is during this phase that formal regulatory submissions are made and final patient testing is performed. The elements of this phase are the fabrication of production prototypes, the validation of all final manufacturing processes, a complete design validation, a systematic review of risk and its management, the production and review of all market literature, manuals and labeling, pilot production, and culminating in a formal clinical study and the first human use review. Regulatory submission and approval would then occur and, if successful, product launch and the monitoring phase of the product. Market preference testing is conducted early in the life of the product to verify product performance and to uncover any unanticipated design deficiencies or improvements that could be made to the product.

A Modern Day Success Story –  Advanced Bionics and  Alfred E. Mann Alfred Mann is the founder of Advanced Bionics Corp. and arguably one of the greatest medical technology entrepreneurs of our time. Born in 1925 in Portland, Oregon, Mr Mann moved to Los Angeles in 1946 where he earned his Bachelor of Science and Master of Science degrees in physics from the University of California. Mr Mann’s business interests began with government contracts which eventually led to his development of two companies, Spectrolab and Heliotek, both major suppliers of high technology products for the aerospace industry. In 1960 he sold both companies to Textron but continued to manage them. Alfred Mann developed many relationships with universities during this time, but one in particular led to his interest in medical products. In his work with the Johns Hopkins Applied Physics Laboratory he became interested in power supply issues for cardiac pacemakers. This interest led to the development of PaceSetter Systems, which focused on rechargeable pacemakers and the development of the first such product on the market. This breakthrough device was also the first hermetic pacemaker on the market and

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A Modern Day Success Story – Advanced Bionics and Alfred E. Mann

the first with bidirectional telemetry. There are still patients using these devices after more than 30 years of implanted service. PaceSetter was sold in 1985 and is now part of St. Jude Medical. The second medical device company developed by Alfred Mann was MiniMed Technologies, which developed the first implanted programmable rate insulin pump, as well as the most advanced external insulin pump to treat Type I diabetes. Medical Research Group, formed from the Alfred E. Mann Foundation for Scientific Research (AEMF), developed the artificial pancreas utilizing a long-term catheterbased implanted continuous glucose monitoring system and implanted programmable-rate insulin pump with a primary battery lasting up to seven years before requiring replacement. MiniMed and Medical Research Group were both later sold to Medtronic. Alfred Mann went on to found Advanced Bionics Corp., Second Sight, which is developing a visual prosthesis to restore sight to the blind, Implantable Acoustics, which is developing implantable hearing aids, NeuroSystec, which is exploring drug therapies to treat tinnitus, Bioness, which is developing prosthetics for neurostimulation to treat neurological dysfunctions, Quallion, which develops, manufactures, and markets advanced batteries for medical, aerospace, and military applications, and Stellar Microelectronics, which produces micro-circuit assemblies. Advanced Bionics Corp. was formed from members of both the AEMF and MiniMed Technologies and led to the first multichannel independent current source cochlear implant in 1994, the Clarion Implantable Cochlear Stimulator. The technology that Advanced Bionics brought to the market was revolutionary. To improve power transfer to the implanted electronics the electronics assembly was housed in a radio frequency transparent ceramic enclosure. This replaced the traditional metallic enclosure used by other companies and tremendously reduced the losses of energy due to eddy currents in the metal components of the implanted device. More important was the introduction of eight independent bipolar current sources that were directly controllable at very high speed allowing the simultan­ eous generation of either continuous analog, pulsatile or combinational approaches to auditory nerve stimulation. Other devices on the market at that time and continuing today were fabricated using a single pulse generator that was time multiplexed to the various output contacts that then would deliver stimulation current to the auditory nerve. Today Advanced Bionics Corp. sells the Harmony HiResolution Bionic Ear System, shown in Figure 4.2, which contains 16 independent current sources with 128 virtual channels of stimulation allowing unprecedented sound fidelity to our patients.

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Figure 4.2  The Advanced Bionics (Valencia, CA) Harmony HiResolution Bionic Ear System. Left: Behind-the-ear processor with headpiece; right: implantable stimulator and electrode

Alfred Mann elucidated the basic tenets for his “Model for Success” as follows: l l l l l

Select a target market Identify underserved needs Evaluate barriers to entry Establish product specifications Create a business model Allocate development resources Organize market, sales, reimbursement, and support infrastructure l Validate, qualify, and transfer to manufacturing l Pursue clinical trials and regulatory approval l Unleash sales, marketing, and service. l l

Most important in the list above is resources. The availability of capital to commit to the program early on will dramatically affect the ability of the organization to deliver a product that changes the market. PaceSetter, MiniMed, and Advanced Bionics all radically changed the technology foundation of the markets they entered because sufficient resources were provided to develop truly groundbreaking technology. Had products been introduced that were merely equivalent or modest improvements in existing technology it is likely that these companies would never have seen the market share that they ultimately acquired.

The Spinal Cord Stimulation Market in 2000 In the year 2000 Advanced Bionics started the development of the world’s most advanced spinal cord

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stimulation system. After reviewing the devices on the market, the intellectual property of competitors, and discussing with clinicians in the field the limitations of existing technology and their wishes for improvements in that technology, Advanced Bionics determined what technology was already in their existing products and what needed to be developed to advance the state of the art in this growing market. After four years of development and many millions of dollars expended, Advanced Bionics introduced the Precision Spinal Cord Stimulation System in 2004, and in less than two years on the market it displaced the number two company in the market and is quickly gaining market share. The market in 2000 was dominated by Medtronic followed by Advanced Neuromodulation Systems. Medtronic had two principal products on the market, the Itrel and the Extrel. The Itrel was a primary batterybased implantable pulse generator (IPG) product while the Extrel was an externally powered radio frequency (RF) product. Both devices used a single voltage source which was time multiplexed to four electrical contacts on a lead and the metallic case of the IPG. A batterypowered IPG was, of course, most desirable because it simplified the life of the patient – the device could be commanded to stimulate the spinal cord nerves and no external equipment would then be required. In some instances, however, where large amounts of energy were required because of poor electrode coupling with target nerves or other factors that increased the energy demand of the system, the battery-powered IPG would quickly be depleted, sometimes requiring surgical replacement in as few as three to six months. This obviously would not be desirable to the patient because of cost, pain, and the risk of infection due to additional surgery. To address this issue the RF powered Extrel was developed which supplied power to the IPG using a coil attached to the skin of the patient over the IPG and powered by a belt-worn external controller. This external controller had replaceable batteries thus extending the operation of the implanted IPG almost indefinitely. A serious drawback of both the Itrel and Extrel devices was the fact that they utilized a voltage source for their stimulation pulse generator, and second, that they multiplexed the stimulation pulses to the electrical contacts of the implanted lead. In the electrical excitation of nervous tissue it is current and not voltage that determines the population of neurons excited. Long expected was that the implanted envir­onment presented a constant electrode/tissue impedance model and that as such the current delivered to the tissue would be consistent over time. This model was not accurate, however, as electrode movement, tissue growth, and electrode degradation over time would change the impedance seen by the pulse generator and thus

the current delivered to the tissue would change, thus changing the resultant clinical effect of the implanted system. Added to this was the design deficiency of utilizing a single stimulation generator and multiplexing it to multiple contacts and the case of the stimulator. When multiple contacts were connected in parallel with the single voltage source, their individual electrode/tissue impedances determined the distribution of current to the nearby neurons, thus therapy could not easily be predicted from the simple assumption that current would be divided equally amongst the connected electrodes. If it was desirous to distribute current in a nonuniform manner to each of the electrodes this was of course not controllable with this design. Advanced Neuromodulation Systems products offered to the market the introduction of the first current source stimulation system and increased the number of stimulation contacts, but like Medtronic, used the multiplexed connection of this pulse generator source to the lead electrodes. So, while it was possible to exactly control the current delivered to a nerve using a single contact, when multiple contacts were connected together using the multiplexer the distribution of current was actually controlled by the electrode/tissue impedance, so again, there was a severe limitation in the technology delivered to the clinical environment.

The Design Approach Taken by Advanced Bionics Corp. The design team at Advanced Bionics looked first at the science of neural excitation and using its experience in the cochlear implant design determined that what was truly needed in the field of spinal cord stimulation was a design utilizing multiple independent current sources. Only in this manner could the amount of current delivered to each contact be precisely controlled. This had the added benefit that now non-uniform current distributions could be obtained, uniquely delivering the required stimulation energy to each population of nerves adjacent to the electrode contacts. This meant that multiple regions of the spinal cord could be stimulated with their own unique stimulation parameters, and that no longer would produce compromised stimulation patterns that non-optimally treated them together with the same stimulation parameters. This advanced technology came at a price. First, the delivery of current control of stimulation is more difficult than voltage control – added circuitry is required and energy is lost due to the regulation of current in addition to the current delivered to the tissue. Second, in the Advanced Bionics design there were 16 independent current sources, thus dramatically increasing the complexity

I.  AN INTRODUCTION TO NEUROMODULATION



A Modern Day Success Story – Advanced Bionics and Alfred E. Mann

of the implanted circuitry, its development cost, and cost to goods sold in the final product.  Advanced Bionics also looked at the size of the implanted device and was determined to deliver the smallest IPG but still have 16 times the number of current sources. The dilemma that this complex design presented was that of providing sufficient power while still providing a device that was still smaller than the competition. The solution chosen was to develop a rechargeable device which could power the IPG for a reasonable period of time and yet be recharged easily through the skin and have a reasonable cycle life such that the product would provide many years of service before replacement. The Precision SCS system uses a unique secondary lithium ion battery designed and supplied by Quallion of Sylmar, California that can withstand complete depletion of its voltage and yet have negligible loss of cycle life when abused in such a manner. The Advanced Bionics Precision IPG was the first rechargeable device introduced into the SCS market, although both Medtronic and ANS now offer rechargeable IPGs. For those applications where a small neurostimulation device is desired or where a larger device and leads are simply not an option, a groundbreaking device was developed by Advanced Bionics Corp. called the Bion (bionic neuron). This device measures a mere 3 mm in diameter and 20 mm in length, contains a full custom

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integrated circuit, a rechargeable lithium battery and a bidirectional telemetry system allowing programming and rechargeable stimulation in a package that is extremely small and weighing about a gram. 

The Impact Upon the Market and Lessons Learned The impact of the introduction of the Precision and Bion products on the neuromodulation market

Figure 4.4  The Boston Scientific Neuromodulation/Advanced Bionics (Valencia, CA) RF Bion microstimulator

Figure 4.3  The Boston Scientific Neuromodulation/Advanced Bionics (Valencia, CA) Precision SCS system. On the left is the remote control, in the center is the cordless charger, and on the right is the implantable pulse generator with two 8-contact epidural leads

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has been tremendous. Medtronic and ANS have been producing devices for spinal cord stimulation for close to 40 years, and in less than two years’ time the Precision system became the number two player in the market and before its third year on the market has already over 13 000 patients implanted and at the time of this chapter’s writing enjoys greater than 30% market share. Advanced Bionics has realized tremendous growth in sales, corporate structure, manufacturing capability, and has expanded the possibilities for treatment of patients utilizing this extremely capable technology. The introduction of the Precision system sparked the release by both Medtronic and ANS of their own rechargeable pulse generators, albeit larger and similar in electronic design to their previous products, but improvements nonetheless. It has proven, again, that the significant introduction of advanced technology in a well-designed and ambitious yet highquality manner can result in rapid market acceptance and improvement in the treatment of patients.

References 21CFR 820.30, Title 21: Food and Drugs, Chapter I – Food and Drug Administration, Department of Health and Human Services,

Subchapter H: Medical Devices. Rockville, MD: US Food and Drug Administration. Brindley, G.S. and Lewin, W.S. (1968) The sensations produced by electrical stimulation of the visual cortex. J. Physiol. (Lond.), 196 (2): 479. Humayun, M.S., Weiland, J., Fujii, G., Greenberg, R.J., Williamson, R., Little, J. et al. (2003) Visual perception in a blind subject with a chronic microelectronic retinal prosthesis. Vis. Res. 43 (24): 2573. ISO 13584 (2003) Medical devices – Quality management systems – Requirements for Regulatory Purposes. Geneva: International Organization for Standardization. Liberson, W.T. et al. (1961) Functional electrotherapy: stimulation of the peroneal nerve synchronized with the swing phase of the gait of hemiplegic patients. Arch. Phys. Med. Rehab. 42: 101–5. Mohr, P.E., Feldman, J.J., Dunbar, J.L., McConkey-Robbins, A., Niparko, J.K., Rittenhouse, R.K. et al. (2000) The societal costs of severe to profound hearing loss in the United States. Int. J. Technol. Assess. Health Care 16 (4): 1120–35. Shealy, C.N., Mortimer, J.T. and Reswick, J.B. (1967) Electrical Inhibition of pain by stimulation of the dorsal columns: Preliminary Clinical Report. Anesth. Analg. 46: 489–91. Veraart, C., Delbeke, J., Wanet-Defalque, M.C., Vanlierde, A., Michaux, G., Parrini, S. et al. (1999) Selective Stimulation of the Human Optic Nerve; 4th Conference of the International Functional Electrical Stimulation Society, August 1999. Japan: Sendai, pp. 57–9. Whitmore, E. (2004) Development of FDA-Regulated Medical Products – Prescription Drugs, Biologics, and Medical Devices. Milwaukee, WI: ASQ Quality Press.

I.  AN INTRODUCTION TO NEUROMODULATION

C H A P T E R

5

The Birth of an Industry James Cavuoto

o u tli n e Early Neuromodulation Devices

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The 21st Century Neuromodulation Industry 2001 2002 2003 2004 2005 2006 2007

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Commonality with Cardiac Devices

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New Product categories

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Future Outlook

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References

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This chapter is devoted to the birth and growth of the neuromodulation industry and the maturation of commercial products that accompanied the industry’s development. We will first take a look at some of the key events that highlighted the early years of the industry. Next we will examine how the industry matured in the first eight years of the 21st century. Then we will examine some of the business and marketing factors affecting the industry. The chapter will conclude with a look forward on what lies ahead for the neuromodulation industry.

addressed by today’s neuromodulation industry are quite distinct from those of the cardiac device industry, much of the basic technology, including electrodes, batteries, leads, and packaging, is common to both industries. The first implantation of a cardiac pacemaker in a human patient took place in 1958, but the first long-term successful implant took place in 1960, when William Chardack, Andrew Gage, and Wilson Greatbatch implanted a device that remained in operation for a year. In 1957, Earl Bakken (Figure 5.1), the founder of Medtronic, Inc. (Minneapolis, MN), had invented a functional battery-powered pacemaker and Bakken and Greatbatch would later collaborate on the manufacture of a commercial device. The earliest implanted pacemakers were simple two-transistor circuits powered by mercury-zinc cells. Later, Greatbatch switched to a lithium iodide cell, which provided much longer lifetimes.

Early neuromodulation devices In many ways, the neuromodulation industry traces its roots to the birth of the cardiac pacing industry. Although many of the indications and clinical specialties

Neuromodulation

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Figure 5.2  Thomas Mortimer, PhD, developed the first dorsal column stimulator that Dr Norman Shealy used

Figure 5.1  Earl Baaken, the founder of Medtronic, Inc.

Medtronic remained the dominant player in the cardiac pacemaker for the next four decades, and leveraged its expertise in cardiac pacemakers to emerging applications in neurological diseases and disorders. The company’s first forays into neuromodulation in the 1960s involved early deep brain stimulation (DBS) systems and spinal cord stimulation (SCS) systems. The first clinical use of SCS for treatment of pain took place in 1967, when C. Norman Shealy implanted an SCS (at that time, called dorsal column stimulation or DCS) system in a 70-year-old man (Shealy et al., 1967) based on the gate control theory of Melzack and Wall (1965) and the pioneering clinical work of Wall and Sweet (1967). J. Thomas Mortimer (Figure 5.2), from Case Western Reserve University, constructed the first device for Shealy. The external stimulator was connected to the electrodes via a subcutaneous jack. SCS systems went through a series of enhancements over the next four decades, including the development of single-electrode radio-frequency controlled systems in 1972 by Avery Labs (Avery Laboratories, Inc., Comack, NY) and Medtronic, and the development of epidural electrodes in 1978. In 1981, Cordis (Miami Lakes, FL), now a Johnson & Johnson company, introduced the first totally implantable SCS system. It was powered by a lithium battery. The IPG was packaged in a hermetically sealed titan­ ium case and allowed control of stimulation parameters. In 1984, Medtronic introduced its Itrel IPG for spinal cord stimulation. Originally, SCS systems used unipolar electrodes. Later more complex electrode systems were ­developed, starting with a four-contact electrode, the

Quad electrode, introduced by Neuromed in 1981. In 1986, Neuromed, which later became Advanced Neuromodulation Systems, Inc. (Plano, TX) and is now part of St. Jude Medical (St Paul, Minnesota, MN), introduced an eight-contact radio frequency controlled SCS system. In 1999, ANS introduced its 16-contact Renew RF system and Medtronic introduced its Synergy IPG, which featured eight contacts with two channels of stimulation. Outside of SCS, one of the first commercial neuro­ modulation devices to reach the market was the breathing pacemaker system from Avery Labs, which received FDA approval in 1986. The company’s founder, Roger Avery, had built several prototypes in the 1970s based on the work of William Glenn from Yale University. Medtronic has been the only manufacturer to market a DBS device for neuromodulation, though other vendors are expected to enter the market shortly. The first implantation of a DBS system took place in Grenoble, France in 1987 and Medtronic received approval to market its system in Europe in 1995. The US Food and Drug Administration (FDA) approved thalamic DBS for treatment of tremor in 1997. In 2001, the FDA approved DBS in the subthalamic nucleus and in 2002 the FDA approved Medtronic’s Activa therapy for bilateral treatment of Parkinson’s disease.

The 21st century neuromodulation industry After the year 2000, the neuromodulation industry was marked by increased competition, the development of new forms of stimulation, and a wide expansion

I. an introduction to neuromodulation

the 21st century neuromodulation industry

in the number of neurological diseases and disorders treated. The first seven years of the 21st century produced a number of key milestones for the neuromodulation industry. A look back at some of the articles published in Neurotech Business Report since its inception yields an enlightening overview of important developments, which are summarized below.

2001 One of the key industry events in 2001 was the sixth annual conference of the International Functional Electrical Stimulation Society (IFESS) meeting in Cleveland. The five-day event, themed “Envisioning a New Century of Breakthroughs,” highlighted six “millennium” papers on key areas of neurotechnology, a truly international assembly of presenters, a small but solid core of manufacturers and sponsors, and several unique attributes not often found at a scientific or engineering meeting. These “millennium papers” were published in Neuromodulation: Technology at the Neural Interface, Journal of the International Neuromodulation Society (INS) and IFESS. Exhibitors and sponsors at the event included several of the early manufacturers of neuromodulation products and systems. NeuroControl Corp. (Valley View, OH) showed its FreeHand hand grasp prosthesis, the VoCare bladder stimulation system, and a new miniaturized multichannel programmable stimulator call StIM. The device was targeted at stroke patients suffering from shoulder pain caused by the separation of the shoulder joint and weak muscles after stroke. Medtronic, the largest corporation in the business, promoted its InterStim urinary control system and DBS product line. Cleveland Medical Devices (Cleveland, OH) showed its BioRadio 110, a compact and wireless brain monitoring device. EIC Laboratories in Norwood, Massachusetts, exhibited its range of electrode coating products and services, which work with gold, platinum, silicon, iridium, and other materials. Empi (Empi, Inc., St Paul, MN) showed its line of stimulators for pain treatment and neuromuscular rehab­ ilitation. NeuroStream Technologies (Anmore, British Columbia, Canada), a Canadian manufacturer that would later be acquired by Victhom Human Bionics (Saint-Augustin-de-Desmaures, Quebec, Canada), showed its line of implantable NeuroCuff interfaces, which accommodate electrodes as well as catheters for fluid infusion. Neopraxis Pty Ltd, an Australian firm (Sydney, New South Wales, Australia), promoted its 22-channel Praxis stimulator, targeted at paraplegic patients. Advanced Bionics Corp. (Valencia, CA), one of the leaders of the cochlear implant business, promoted its line of Bion leadless stimulators.

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2002 As 2002 came to a close, the neuromodulation industry looked back on a paradoxical year, a year filled with exceptional triumphs in technology developments and depressing financial and economic news from the commercial enterprises in the field. For example, the latter months of 2002 witnessed staff reductions at Aspect Medical Systems, Inc. (Norwood, MA) and Axon (Newton, MA), flat sales at Bio-logic Systems (Mudelein, IL), and the demise of Symphonix (San Jose, CA). Other examples of bad news in the industry were microHelix’ (Tualatin, OR) decreased revenues and 4-D Neuroimaging’s (San Diego, CA) failed merger with Neuromag (Helsinki, Finland). And the functional electrical stimulation field was still reeling from NeuroControl Corp.’s decision to discontinue marketing its FreeHand hand-grasp stimulator. But 2002 was not without bits and pieces of good economic news. Several start-up neuromodulation firms received first- or second-round infusions of venture capital at a time when other technology industries were hard-pressed to get attention from VCs. The most noteworthy examples: Vertis Neuroscience, now Northstar Neuroscience (Seattle, WA), received $37 million in funding, Optobionics Corp. (Wheaton, IL) received $20 million, Sleep Solutions, Inc. (Palo Alto, CA) received $7 million, and Cyberkinetics, Inc. (Foxborough, MA) received $5 million. Several public companies also showed improving financial results – some with record performance – including Advanced Neuromodulation Systems, Cyberonics, Cochlear Ltd (Lane Cove, New South Wales, Australia), and Integra NeuroSciences (Plainsboro, NJ). Merger and acquisition activity during the year included Compumedics’ (Abbotsford, Australia) purchase of Neuroscan Labs (Sterling, VA), Bionic Technologies’ (Salt Lake City, UT) merger with Cyberkinetics, and Encore Medical Corp.’s (Austin, TX) purchase of Chattanooga Group (Hixson, TN). Significant FDA product approvals reported during the year were Vertis Neuroscience’s percutaneous stimulation system, Medtronic’s Activa deep brain stimulation therapy for Parkinson’s, and ANS’ Genesis implantable pulse generator. Some good news also came on the reimbursement front, including favorable Medicare decisions or recommendations on magnetoencephalography, functional electrical stimulation, and implanted stimulators. Still, the overall financial picture for the neuromodulation industry in 2002 was not as favorable as was the technology development outlook. Significant progress was made in a number of early-stage and

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more mature product categories, including micro­ stimulation systems, electrode development, cortical control systems, visual prostheses, and stroke rehabilitation devices.

2003 In 2003, the editors of Neurotech Business Report chose to single out a few individuals and organizations for special recognition. The result was the somewhat impromptu “Gold Electrode” Awards, which were intended to add some profile to the industry. Synapse Biomedical’s (Oberlin, OH) diaphragm pacing system was selected as the best new product of the year, and Afferent Corp. (Providence, RI) was named the most promising start-up firm. There were several events in 2003 that stood out as significant developments for the neuromodulation industry. The first was the implantation of a diaphragm stimulation system in actor/activist Christopher Reeve in February. Reeve was just one user, and the potential market for the device was not huge. But the fact that he was willing to undergo the procedure, and became a vocal proponent of the device, is significant if for no other reason than that he had previously not been a major proponent of functional electrical stimulation devices as a treatment for paralysis. Another key event of 2003 was Medicare’s decision to cover deep brain stimulation for treatment of tremor and Parkinson’s disease. Reimbursement continued to be a major hurdle confronting the neuromodulation industry, but the relative speed with which this decision followed FDA approval of DBS treatment for Parkinson’s disease was a positive sign. Still another major development in 2003 was the progress Cyberonics made in obtaining FDA approval of its VNS therapy for treatment of drug-resistant depression. Though, as later years would reveal, the process was far from over, the positive research results and the indication from the FDA that a timely decision was forthcoming were encouraging signs. Aside from the sheer market size of this application, it was significant because in penetrating even a portion of the mood disorder market, Cyberonics may well have proven to other neuromodulation device manufacturers that they can compete in markets where the pharmaceutical industry appears to have a firm grip. While venture capital investment was not rampant in 2003, there were enough deals done to give hope to start-up firms. Perhaps more significant was the fact that major medical device manufacturers, including Boston Scientific (Natick, MA), Medtronic, Guidant (St Paul, MN), and Johnson & Johnson (New Brunswick,

NJ), showed signs that they were looking closely at this market.

2004 As years go, 2004 was better in many respects than the three that preceded it. From a financial standpoint, the biggest news was undoubtedly Boston Scientific Corp.’s purchase of Advanced Bionics Corp., a deal that would prove to be worth more than $2 billion. This valuation profoundly affected the venture cap­ital community’s perception of the neuromodulation industry. Probably the biggest disappointment of the year was the FDA’s decision to ignore its own neurological devices panel recommendation and deny Cyberonics’ PMASupplement for VNS treatment for resistant depression. But between these two extremes, there were a number of significant developments in 2004 that ­ continued to highlight the maturation of the industry. The establishment of the National Science Foundation Engineering Research Center for Biomimetic Micro­electronic Systems (Los Angeles, CA) was one such development, as was the announcement of a new advanced prosthetics program at DARPA’s Defense Sciences Office. The National Institutes of Health’s first Neural Interfaces Workshop, which merged the Neural Prosthesis Workshop with the DBS Consortium, was another highlight. On the technology front, there was significant progress in areas such as EEG interpretation, brain– computer interfaces, cortical stimulation for stroke rehabilitation, deep brain stimulation, magnetic stimulation, neural-silicon hybrids, retinal implants, neurorobotics, and controlling neural growth. New product categories that emerged in 2004 included occipital nerve stimulation systems, rechargeable spinal cord stimulation systems, and navigated brain stimulation. New entrants in the industry were prosthetics vendor Innovative Neurotronics, Inc. (Bethesda, MD), implantable probe supplier NeuroNexus Technologies (Ann Arbor, MI), cortical plasticity firm Restorative Therapies, Inc. (Baltimore, MD), and neurorehabilita­ tion firm Bioness, Inc. (Valencia, CA). Initial public offerings included NeuroMetrix (Waltham, MA), which brought in $24 million, and Stereotaxis (St Louis, MO), which fetched $40 million.

2005 The year 2005 was a banner year for the neuromodulation industry in many respects. Overall, financial performance of both public and private companies trended in the direction of black ink. There were a large number of new products receiving FDA approval during the year. Plus there were several healthy mergers

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the 21st century neuromodulation industry

and acquisitions, and several start-ups in the space obtained venture-capital funding during the year. Certainly the most significant financial development of 2005 was the acquisition of Advanced Neuro­ modulation Systems by St. Jude Medical in a $1.3 billion deal. Though perhaps overshadowed by that merger, other noteworthy deals were Medtronic’s purchase of Transneuronix (Mt Arlington, NJ) and Natus Medical’s (San Carlos, CA) merger with Biologic Systems. Though the multi-billion dollar deals like the ANS acquisition dominated the landscape, the smaller ones are important too, if for no other reason than demonstrating to investors a path to liquidity for start-ups in this space. And the numerous cooperative agreements and collaborations that neuromodulation firms enter into were a sign for all observers of the industry’s vitality. Another notable trend in 2005 was the continued forays of orthopedic industry players into the neuromodulation space. Encore Medical, with its purchase of Compex Technologies (New Brighton, MN) complementing its prior acquisitions of Empi and Chattanooga Group, was one example, as was Otto Bock’s (Duderstadt, Germany) purchase of Neurodan (Aalborg, Denmark). These two firms joined Hanger Orthopedic (Bethesda, MD), which set up a neuromodulation unit called Innovative Neurotronics (Bethesda, MD), and Ossur (Reykjavik, Iceland), which is developing neural prostheses with Victhom Human Bionics. Notable start-ups of 2005 included Andara Life Science Inc. (Indianapolis, IN), which began developing a spinal cord regeneration stimulator, Medtrode, Inc. (London, Ontario, Canada), which developed novel DBS electrodes, NeuroSystec Corp. (Valencia, CA), which developed a device to treat tinnitus, and BioNeuronics, Inc. (now NeuroVista Corp., Seattle, WA), which began developing a series of implantable neuromodulation devices for treatment of neurological disorders. The latter firm secured $6 million in funding. On the new product front, the FDA’s long-awaited approval of Cyberonics’ VNS system for treating treatment-resistant depression stands out as significant, as does the heightened competition in the DBS and spinal cord stimulation markets.

2006 The year 2006 was neither the watershed year that 2005 was for the neuromodulation industry, nor was it the depressing time seen in the early years of the decade. The business experienced a number of promising technology and market developments, and a few disappointments. But overall, the industry appeared to be on a stronger footing than it was the previous year.

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From a financial standpoint, there were no multibillion dollar mergers in 2006, or anything even coming close. But the deals that were consummated, including Cyberkinetics’ purchase of Andara, Encore Medical’s purchase of Compex, and Bioness’ purchase of NESS Ltd (Ra’anana, Israel), point out the continuing viability of the $100-million-and-under segment of the industry. And while the only significant IPO activity of 2006 was Northstar Neuroscience, which fetched more than $100 million, at least two public neurotech companies, VSM MedTech (Vancouver, British Columbia, Canada) and Encore Medical went private during the year. Venture capital investment in neurotech start-ups continued to be robust in 2006. VC firms were particularly generous to firms in the obesity stimulation market segment, with EnteroMedics (St Paul, MN), IntraPace (Menlo Park, CA), and GI Dynamics (Watertown, MA) securing $87 million total. Other noteworthy fundings during the year included Intelect Medical’s (Cleveland, OH) $3 million seed round, NBI Development’s (now Nevro Corp., Palo Alto, CA) $5.5 million round, Intelligent Medical Implants’ (Zug, Switzerland) €15 million round, and Posit Science’s (San Francisco, CA) $24 million round. On the technology front, one of the most exciting developments was a dramatic increase in understanding of the mechanisms of action of deep brain stimulation, not just for treating movement disorders, but psychiatric disorders as well. Transcranial magnetic stimulation got a considerable bit of attention during the year, particularly after Neuronetics (Malvern, PA) presented promising clinical trial data at the American Psychiatric association meeting in Toronto. The year was also a good one for neurorehabilitation, with several new devices from Bioness, Innovative Neurotronics, Victhom, and Otto Bock achieving some form of regulatory approval, and with new government initiatives such as the DARPA Advanced Prosthetics Program. But challenges remained for the industry, and probably the biggest one pertains to reimbursement. Slowness and difficulty in getting CMS coverage decisions is affecting nearly every segment of the neuromodulation industry. Cyberonics, which otherwise would have been riding high from its 2005 FDA approval of VNS for treatment-resistant depression, saw limited growth in this market, and the problem was a factor in the management shake-up that afflicted that company in 2006.

2007 In 2007, a number of technological and financial developments helped move the neuromodulation industry forward. On the technology front, Northstar

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Neuroscience was awarded a patent for its cortical stimulation technology, and Aculight Corp. (Bothell, WA) signed a licensing agreement with Vanderbilt University for optical stimulation technology. On the financial side, Synapse Biomedical raised $4 million in venture capital funding, Apnex Medical Inc. (Minneapolis, MN) completed a $16 million funding round, Intelect Medical closed a $7 million round, and Afferent Corp. received an investment from orthopedic manufacturer Stryker Corp. (Kalamazoo, MI). Also in 2007, Greatbatch, Inc. (Clarence, NY), a manufacturer of batteries for implanted devices, acquired Enpath, Inc. (Minneapolis, MN) for $102 million, a few months after acquiring the assets of Biomec, Inc. (Cleveland, OH).

Competitive landscape Today, the competitive landscape of the neuromodulation industry is marked by the presence of a small number of large medical device firms, and a large number of smaller, upstart companies. Undoubtedly, the market leader at this point is Medtronic. The company’s neuromodulation group, which incorpor­ ates offerings in spinal cord stimulation, deep brain stimulation, sacral nerve stimulation, and a number of related applications, still represents a minority of overall annual revenues of $12 billion. But neuromodulation represents one of the fastest-growing segments of the company’s business. Boston Scientific is another major player in the neuromodulation industry of today. Boston Scientific’s initial venture into neuromodulation was in 2002, when it formed a strategic alliance with Advanced Neuromodulation Systems, Inc. The agreement called for Boston Scientific to market ANS’s neuromodulation products in Japan. That year Boston Scientific also signed a strategic alliance agreement with Aspect Medical Systems that included purchasing 1.4 million shares and providing $5 million in revolving credit. In 2003, Boston Scientific purchased 14.7% Cyberonics, Inc. for $50 million. In June 2004, Boston Scientific made its biggest move yet into neuromodulation by acquiring Advanced Bionics for $740 million in cash plus future payments based on performance milestones. Over a 72-month period, the performance payments could have reached a maximum of about $1.3 billion. However, in 2007, Boston Scientific amended its merger agreement with Advanced Bionics, eliminating shared management provisions and modifying the schedule of earnout payments. The amendment granted Boston Scientific sole management and control of the pain management

business, including the emerging indications program. The company agreed to sell the auditory business and drug pump development program to principals of Advanced Bionics, thereby heading off pending litigation between Boston Scientific and former Advanced Bionics shareholders. The pain management business Boston Scientific retains includes spinal cord stimulation technologies, as well as emerging technologies such as the Bion microstimulator. St. Jude Medical, Inc. entered the neuromodulation market in 2005 as a major player with the $1.35 billion cash purchase of Advanced Neuromodulation Systems. St. Jude, well-established in the multibillion dollar cardiovascular medical device market, regards the field of neuromodulation as a segment of the medical device industry with “enormous long-term growth potential.” In a report to investors, St. Jude noted that “the technologies used in pacemakers and in neuro­stimulation systems are extremely complementary. The ANS technologies complement our cardiac rhythm management expertise in microelectronics, batteries, leads, and programmers, which should benefit the flow of new products in both organizations.” The acquisition of ANS was completed as a merger, and the ANS subsidiary now operates as one of St. Jude’s six divisions. St. Jude was founded in 1976 as a heart valve company by Manuel Villafana, who named the company after the patron saint of desperate cases as a thank you for the successful corrective surgery at Mayo Clinic on his newborn son, who was named Jude. The first St. Jude mechanical heart valve was implanted in 1977 and its continuing success over the years made it the gold standard in the industry. In 1994, St. Jude acquired Pacesetter, Inc. from Siemens AG, which marked the company’s entry into the cardiac rhythm management market. The acquisition doubled St. Jude’s salesforce and tripled its workforce. Today, cardiac therapies are shifting from mechanical heart valves to tissue valve and repair products, which St. Jude also markets.

Commonality with cardiac devices Since the inception of the neuromodulation industry, many market observers, analysts, and investors have compared the emerging market for implanted neuro devices to the growth of cardiac devices 20 years earlier. One of the most prominent individuals to make that comparison is Alan Levy, founder of Northstar Neuroscience. Levy is in a position to know. Prior to founding Northstar, he was CEO of Heartstream, a manufacturer

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future outlook

of automatic external defibrillators that was eventually sold to Hewlett–Packard. Before that, he was president of Heart Technology, a manufacturer of coronary devices that was sold to Boston Scientific. Many of Northstar’s venture capital investors were no doubt betting that Levy could turn that trick again. Any doubt that investors may have had about the long-term viability of the neuromodulation market should have been put to rest with St. Jude’s purchase of ANS in 2005. Coming on the heels of Boston Scientific’s purchase of Advanced Bionics in 2004, the stage was set for a showdown in neuromodulation devices among three medical device giants, Medtronic, Boston Scientific, and St. Jude, who just happen to be competitors in the cardiac device market. The comparison of neuromodulation devices to cardiac devices is certainly a flattering one. A research report published by Neurotech Reports, The Market for Neurotechnology: 2008–2012, projects the worldwide neurotech device market will exceed $3.8 billion in 2008; the cardiac market will likely be 10 times that. Still, the comparison may be limiting in the long run, given the much larger number of clinical applications, medical specialties, and patient populations that can be served with neuro devices.

New product categories With all the attention given to the big three’s competition in neuromodulation devices, there are several other very promising categories of neurotech devices that have yet to gain the same level of investor and analyst interest. Neurorehabilitation devices, such as muscle stimulators, neurorobotic systems, and neural regeneration stimulators, are poised for dramatic growth. And new types of neural prostheses, including motor prostheses and new FES devices, have already attracted the attention of device makers such as Otto Bock, Hanger, and Ossur. And although most individuals in the neuromodulation industry would consider cardiac pacing outside

its borders, even though these devices control excitable tissue, the industry has much to gain by studying, and perhaps annexing, concepts from the cardiac device industry. Recent journal articles about neural stimulation as a potential treatment for cardiovascular disorders remind us that the nervous system and the circulatory system are connected – literally. Stimulation of the vagus nerve or the greater splanchnic nerve can elicit response in cardiac muscle, much as stimulation of the phrenic nerve or the ulnar nerve produces response in the lungs or skeletal muscle. Surely it would be narrow-minded to exclude such neuromodulatory applications just because the end organ is the heart. Given the industry’s background and success at fine-tuning stimulation parameters, the cardiovascular market may well represent a ready and lucrative opportunity for neuromodulation companies.

Future outlook The neuromodulation industry is poised for considerable growth in coming years. There will also likely be continued consolidation as large medical device and biotechnology firms acquire smaller companies and make investment in start-up firms. New technology areas such as optical stimulation, magnetic stimulation, and nanotechnology will no doubt produce more new companies competing in the neuromodulation device industry. And there will be numerous opportunities for neuromodulation firms to partner with other life sciences companies, such as pharmaceutical firms.

References Melzack, R. and Wall, P. (1965) Pain mechanisms: a new theory. Science 150: 971–8. Shealy, C., Mortimer, J. and Reswick, J. (1967) Electrical inhibition of pain by stimulation of the dorsal columns: preliminary report. Anesth. Analg. 46: 489–91. Wall, P.D. and Sweet, W.H. (1967) Temporary abolition of pain in man. Science 155: 108–9.

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Beginnings of the Societies Ross Davis, Philip L. Gildenberg, Giancarlo Barolat, Elliot S. Krames, Dejan Popovic, and Paul Meadows

o u t l i n e A: History of the Societies of Stereotactic and Functional Neurosurgery

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FES History

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References

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Advances in External Control of Humans Extremities (ECHE) Meetings

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Rehabilitation Engineering Society of North America (RESNA)

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Vienna International Workshop on Functional Electrical Stimulation

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Mission Statement of the INS

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The Development of IFESS

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References

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A: History of the Societies of Stereotactic and Functional Neurosurgery

In the animal, the apparatus was secured to the animal by ear plugs and tabs that held it to the inferior orbital rim which also served to localize the head to stereotactic (stereotaxic, as it was spelled then) space. Although this provided reasonable accuracy in animals, it was not accurate enough for patients. It was not until 40 years later that Ernest Spiegel and Henry Wycis (Spiegel et al., 1947) used intraoperative X-ray to identify landmarks around the third ventricle that stereotactic guidance could be used safely in patients. Their report drew immediate worldwide attention. Soon neurosurgeons from throughout the world visited them at Temple Medical School in Philadelphia to learn their technique. Since, at that time, there was

Philip L. Gildenberg The technique of stereotaxic surgery began in 1908 when Horsley and Clarke (1908) published a detailed description of their apparatus and technique, along with the first stereotaxic atlas and the results of investigating cerebellar physiology in the monkey. Their system was based on a Cartesian principle that defines a target by three coordinates: AP, lateral, and vertical.

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6.  beginnings of the societies

Figure 6.1  Henry T. Wycis and Ernst A. Spiegel with Model V 1959 stereoencephalotome, which they used for the duration of their practice

no commercially available stereotactic apparatus, each neurosurgeon designed their own version or copied by hand one that had already been developed. This event resulted in a flurry of information exchange and by the early 1950s meetings were called at many stereotactic centers. Most of these meetings were relatively informal. These early pioneers of stereotaxis had sufficient comradeship to speak freely and frankly and the field blossomed. I (Philip Gildenberg) was a medical student when I began to work with Spiegel and Wycis in 1956 while the field was in its infancy and returned to their service when I was a neurosurgical resident from 1962 to 1967. My meeting these early stereotacticians as they visited Temple provided to me a unique opportunity to learn of this exciting new field. In 1961, at one of those informal meetings, the decision was made to form a professional society through which meetings could be better organized. The Inter­ national Society for Research in Stereoencephalotomy was chartered in Philadelphia in that year. The term “stereoencephalotomy” was coined by Spiegel to acknowledge that the target was defined in three dimensions, using the landmarks within the encephalon from which to measure the target. At this early juncture there existed an American Branch and a European Branch. The first meeting of the International Society for Research in Stereoencephalotomy was held in Philadelphia in 1963, and was designated as the First International Symposium on Stereoencephalotomy.

The Second International Symposium on Stereo­en­cephalotomy was held in 1965. Part of the meeting was held in Copenhagen and part in Vienna to coincide with the location of the Meeting of the World Federation of Neurosurgical Societies (WFNS). To this day, the meeting every four years of the World Society for Stereotactic and Functional Neurosurgery (WSSFN) is held just before the meeting of the WFNS in a location selected to facilitate traveling from one meeting to the next. The Third International Symposium on Stereoencephalotomy was held in Madrid in 1967. Meanwhile, the continental societies began to have their own meetings. The American Branch of the Inter­national Society for Research in Stereoencephalotomy was founded in 1968 and held its first formal meeting in Atlantic City in that year. The main topic at the meeting was Parkinson’s disease, but, because L-DOPA was introduced at approximately the same time (Cotzias et al., 1967), there was a sudden disappearance of patients with Parkinson’s disease being referred to neurosurgeons. Meetings of the societies, however, were still held, but the emphasis at these meetings changed to pain management, epilepsy, and non-Parkinson movement disorders. Because of this introduction of L-DOPA, many neurosurgeons left the field and only a cadre of academically oriented neurosurgeons remained. The Societies, however, continued to function. The Fourth International Symposium on Stereoen­ cephalotomy was held in 1969 in New York, just before the meeting of the WFNS. The Fifth International Symposium, hosted by Tragott Riechert in Freiburg, Germany, was held the next year in 1970 and coincided with the founding of the European Branch of the Society for Research in Stereoencephalotomy, the precursor of the European Society for Stereotactic and Functional Neurosurgery, which will be discussed below. A significant turning point occurred at the Sixth International Symposium on Stereoencephalotomy hosted by Hirotoro Narabayashi that was held in Tokyo in 1973. The society was reorganized into more distinct components. The word “Stereoencephalotomy” had never caught on and was not used except in the name of the organization and it was decided to adopt a more recognizable name. The International Society for Research in Stereoencephalotomy was renamed the World Society for Stereotactic and Functional Neurosurgery (WSSFN) in 1973. A discussion and vote were held to decide how to spell “stereotactic” in the name of the organization. Sometime, in the late 1950s and early 1960s, human “stereotaxic” surgery became named by some neurosurgeons, particularly in Europe, as “stereotactic.” The origin of that spelling is unknown at present. Nevertheless, enough neurosurgeons used

I. an introduction to neuromodulation



A: History of the Societies of Stereotactic and Functional Neurosurgery

that spelling, so a vote was taken as to how to spell the name of the Society (Gildenberg, 1993). In 1973, Spiegel passed on to me the editorship of the journal affiliated with the stereotactic societies, Confinia Neurologica. In subsequent years the name of the journal was changed to Applied Neurophysiology, which more closely stated the purpose of functional neurosurgery in English. Several years later when the introduction of image guided surgery came about, the name of the journal was again changed to Journal of Stereotactic and Functional Neurosurgery. The proceedings of the meetings of the WSSFN and ASSFN continued to be published in that journal until the editorship changed to David W. Roberts, in 2002. The atmosphere at the meetings was always cordial and informal with members freely exchanging information. The International 1973 Tokyo meeting also forced a name change in the continental branches from the American Branch to the American Society for Stereotactic and Functional Neurosurgery (ASSFN) and the European branch to the European Society for Stereotactic and Functional Neurosurgery (ESSFN). A four-year cycle was established, whereby the WSSFN would meet one year, the ESSFN the following year, the ASSFN the next, and then the ESSFN, once again, to complete the cycle. This pattern continued with a few exceptions until 2002 when the ASSFN felt the need to meet every two years. The next quadrennial meeting of the WSSFN was held in 1977 in Saõ Paulo and hosted by Raul Marino (Gildenberg and Marino, 1978). Although still affiliated with the WSSFN, the ASSFN was declared an independent society in 1973 and it was not until 1980 that the first separate meeting was held in Houston with myself (P.L. Gildenberg) as the host. Although this meeting was held during the time that stereotactic surgery was relatively quiescent, it was attended by stereotacticians from throughout the world. Twenty-seven papers were presented on basic neurophysiology, movement disorders, epilepsy and pain. Interestingly, although the use of computers in surgery was still in its infancy, 11 papers were presented on that topic, a true reflection of the influence of this small group of surgeons on subsequent developments, which has led us to image guided surgery. The 1981 meeting held in Zurich and hosted by Jean Siegfried (Gildenberg et al., 1982) was declared by the ESSFN to be a joint meeting between the WSSFN and the ESSFN and furthermore that the ESSFN was no longer a component society of the WSSFN, but an independent society. As interest in frameless stereo­ tactic surgery grew, it became a major topic in the 1983 Meeting of the ASSFN, held in Durham, North Carolina and hosted by Blaine Nashold. The Ninth Meeting of the WSSFN, hosted by Ronald Tasker, was held in Toronto in 1985 (Tasker

51

et al., 1985), the Tenth Meeting, hosted by Chihiro Ohye, was held in Maebashi, Japan (Ohye et al., 1990), and the Eleventh Meeting, hosted by this author, was held in Ixtapa, Mexico (Gildenberg et al., 1994). In 1995, the ASSFN Meeting was held in Los Angeles and hosted by Michael Apuzzo and David Roberts (Roberts et al., 1996). At this meeting there was a resurgence of reports about pallidotomy for Parkinson’s disease and other functional neurosurgery, which constituted half of the program, an indication of the resurgence of that field. There were also reports of stereotactic radiosurgery, imaging, and computer guidance. In 1997, the WSSFN Meeting was held in Lyons, France, with Marc Sindou as host (Sindou et al., 1997). It was outstanding in several ways. It was by far the largest meeting held to date. The meeting included a large number of French scientists working in functional neurosurgery. Neuromodulation had become a particularly active field, and several of its most active proponents were amongst the French colleagues in attendance. Deep brain stimulation (DBS) was particularly well represented in this program. The Thirteenth Meeting (perhaps a prophetic number) of the WSSFN, hosted by Brian Brophy, was held in Adelaide, Australia, in September, 2001. During that meeting, the attack on the World Trade Center occurred in New York. All flights to the USA were canceled, so many of the speakers scheduled to appear at the meeting of the WFNS in Sydney the following week could not attend, nor could the WSSFN members return home. The ASSFN Meeting in 2003 was held shortly after the FDA approved the use of DBS for movement disorders. Patrick Kelly was the host of that meeting, held in New York. At this meeting there was a rush of early papers on experience with DBS, which was certainly the topic of discussion throughout the meeting hall. Many of the papers were on the intraoperative use of computers and image guidance. The most recent meeting of the WSSFN, hosted by Mario Meglio, was held in 2005 in Rome and was held to coincide with the meeting of the International Neuromodulation Society (INS). The next meeting of the WSSFN is scheduled for 2009 in Toronto, hosted by Andres Lozano, who is the current President. The 2006 meeting of the ASSFN, hosted by G. Rees Cosgrove, was held in Boston. DBS and epilepsy surgery were the most active topics. The last meeting of the Society, before the writing of this chapter, was held in 2008, in Vancouver, Canada, and was hosted by Chris Honey of Vancouver. In July, 2006, the WSSFN sponsored and organized, for the first time, an interim meeting that was held

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Figure 6.2  A gathering of the present and past presidents of the WSSFN on 30 October 2000. Left to right: Marc Sindou, Chihiro Ohye, Brian Brophy, Philip Gildenberg, and Sang Sup Chung

in Shanghai, China concerning movement disorders, pain, psychiatric disease, and epilepsy. There was great interest in neuromodulation and DBS. It was hosted by Bomin Sun from the Shanghai Jiao Tong University, Rui Jin Hospital, and Andres M. Lozano was the meeting chairman. As the need to accommodate non-English-speaking and junior colleagues has grown, several other national stereotactic societies have been formed including the Japanese, the Korean, the Argentinian, and more recently the Chinese Societies for Stereotactic and Functional Neurosurgery. Regional Societies have also been formed and include the Sociedad Latinoamericana de Neurocirugia Funcional y Estarerotaxia (SLANFE) and the Asian Society for Stereotactic, Functional and Computer Assisted Neurosurgery (ASSFCN). Acknowledgment The author wishes to thank Prof. Joachim Krauss, Hanover, Germany, for providing much of the information about the ESSFN.

Society for Stereotactic and Functional Neurosurgery. Stereotac. Funct. Neurosurg. 63: 1–301. Gildenberg, P.L., Siegfried, J., Gybels, J. and Franklin, P.O. (eds) (1982) Eighth Meeting of the World Society and the Fifth Meeting of the European Society for Stereotactic and Functional Neurosurgery. Appl. Neurophysiol. 45: 1–554. Horsley, V. and Clarke, R.H. (1908) The structure and functions of the cerebellum examined by a new method. Brain 31: 45–124. Ohye, C., Gildenberg, P.L. and Franklin, P.O. (eds) (1990) Proceedings of the Tenth Meeting of the World Society for Stereotactic and Functional Neurosurgery. Stereotac. Funct. Neurosurg. 54–55: 1–564. Roberts, D.W., Apuzzo, M.L.J., Gildenberg, P.L. and Franklin, P.O. (1996) Proceedings of the Meeting of the American Society for Stereotactic and Functional Neurosurgery, Part II. Stereotac. Funct. Neurosurg. 66: 1–156. Sindou, M., Martens, F., Gildenberg, P.L. and Franklin, P.O. (eds) (1997) Proceedings of the Twelfth Meeting of the World Society for Stereotactic and Functional Neurosurgery. Stereotac. Funct. Neurosurg. 68: 1–318. Spiegel, E.A., Wycis, H.T., Marks, M. and Lee, A.J. (1947) Stereotaxic apparatus for operations on the human brain. Science 106: 349–50. Tasker, R.R., Turnbull, I.M., Gildenberg, P.L. and Franklin, P.O. (eds) (1985) Proceedings of the Ninth Meeting of the World Society for Stereotactic and Functional Neurosurgery. Appl. Neurophysiol. 48: 1–498.

References www.assfn.org. www.essfn.org. www.wssfn.org. Cotzias, G.C., VanWoert, M.H. and Schiffer, L.M. (1967) Aromatic amino acids and modification of parkinsonism. N. Engl. J. Med. 276: 374–9. Gildenberg, P.L. (1993) “Stereotaxic” versus “stereotactic.” Neurosurgery 32: 965–6. Gildenberg, P.L. and Marino, R. Jr (eds) (1978) Seventh Symposium of the International Society for Research in Stereoencephalotomy. Conf. Neurol. 41: 1–250. Gildenberg, P.L., Franklin, P.O., Escobedo, F.R. and Garcia Flores, E. (eds) (1994) Proceedings of the Eleventh Meeting of the World

B: History of the International Neuromodulation Society Giancarlo Barolat and Elliot S. Krames Neuromodulation is defined by the International Neuromodulation Society (INS) as a field of science, medicine, and bioengineering that encompasses implantable and non-implantable technologies, electrical

I. an introduction to neuromodulation

Formation of international chapters

or chemical, that impact upon neural interfaces to improve life for humanity. Currently, the involved clinical specialists come from anesthesiology, neurosurgery, neurology, neurophysiology, cardiology, physical medicine and rehabilitation, gastroenterology, urology and orthopedics; however, this relatively new discipline of medicine will most likely encompass or influence most medical specialties. The INS was founded in 1990, because of the increasing frustration of neurosurgeons involved with “Functional Neurosurgery.” Until the mid-1980s, most of the neuro-implantation procedures were for pain management and were performed by neurosurgeons with anesthesiologists making some inroads. These implantation procedures included epidural dorsal column stimulation (DCS), peripheral nerve stimulation (PNS), and stereotactic deep brain stimulation (DBS). In the 1970s and 1980s, the use of medications helped control Parkinson’s symptoms, which resulted in a marked decrease in the use of stereotactic procedures. In the mid-1980s on, there was a radical shift for the utilization of stereotactic surgery for brain biopsy and irradiation brain lesions for the neuro-oncologists. As a result, by the late 80s most of the meetings and publications of the Stereotactic and Functional Neurosurgery Societies were dedicated to reporting the success of stereotactic brain biopsies and treatments, with functional neurosurgery being relegated to a minor part of these meetings and activities. However, in 1990 an active group of neurosurgeons, specializing in therapeutic stimulation, decided, in Paris, to create a new society inclusive of other disciplines that were related to neuromodulation. The founding members of the new International Neuromodulation Society (INS) were: l l l l l l

Lee Illis (Neurology, UK, President 1990–94) Mario Meglio (Neurosurgery, Italy) Daniel Galley (Cardiology, France) J.U. Krainick (Neurosurgery, Germany) J.C. Sier (Vascular Surgery, The Netherlands) Michiel J. Staal (Neurosurgery , The Netherlands)

The first official meeting of the Society, organized by Mario Meglio, a neurosurgeon from Rome, was held in Rome in 1992. Further successful meetings, held every two years, were as follows: 1994, Gotenburg, Sweden, hosted by Lars Augustinsson l 1996, Orlando, Florida, USA, hosted by Giancarlo Barolat l 1998, Lucerne, Switzerland, co-hosted by Claus Naumann and Ross Davis for the first combined l



l

l l l

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meeting of INS with the International Functional Electrical Stimulation Society (IFESS) 2000, San Francisco, California, hosted by Elliot Krames, combined three different world societies into one comprehensive multidisciplinary symposium 2003, Madrid, Spain, hosted by Enrique Reig 2005, Rome, Italy, hosted by Mario Meglio 2007, Acapulco, Mexico, co-hosted by Elliot Krames, President of the INS, and Joshua Prager, President of the North American Neuromodulation Society (NANS), the INS’s largest country/regional chapter

Initially, the Society encountered difficulties in asserting its role to speak for its members involved with implantable and non-implantable technologies at the “neural interface” because of competition with the various pain societies, both internationally and nationally, within each country. Because the INS membership was, by its very nature, multidisciplinary, there was difficulty in bringing its members of disparate interests together. However, the use of neurostimulation for peripheral vascular disease and angina, in Europe, helped the Society attract a substantial number of vascular specialists and cardiologists.  While Giancarlo Barolat was President of the Society from 1994 to 2000, Elliot Krames was brought onto the INS Board and undertook the task of creating the journal Neuromodulation. The journal’s first issue was published in January 1998, and has become the authoritative publication in this area. Tia Sofatzis was brought into the Society in 1998 as Managing Editor of Neuromodulation, and in 2001, she was elected Executive Director of the INS, a position she has held since. In 1999, the International Society for Functional Electrical Stimulation (IFESS) started publishing their scientific papers in Neuromodulation, in a special section devoted to Functional Electrical Stimulation (FES). In 2001, the IFESS agreed to adopt Neuromodulation as their official publication. This collaboration between Societies has fostered a healthy relationship between clinicians, engineers and scientists involved in the restoration of neurological function through implanted devices. In January 2007 the journal was renamed as Neuromodulation: Technology at the Neural Interface.

Formation of international chapters In 1994 a group of implantation specialists with interest in pain control from the USA and Canada convened in Atlanta, Georgia to form the American

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Figure 6.3  INS Board of Directors in March 1993. On the left: Mike DeJongste, Sherri Kae Calkins, Bengt Linderoth, John Oakley. On the right: Richard North, Robert Foreman, Giancarlo Barolat, Elliot Krames

Table 6.1  International Societies and formation dates Australian Neuromodulation Society – 2004 Benelux Neuromodulation Society – 2002 Brazilian Neuromodulation Society – 2007 Canadian Neuromodulation Society – 2007 German Neuromodulation Society – 2005 Italian Neuromodulation Society – 1999 Japanese Neuromodulation Society – 2005 Korean Neuromodulation Society – 2007 North American Neuromodulation Society – 1995 Neuromodulation Society of the United Kingdom and Ireland – 2005 South Eastern Europe Neuromodulation Society – 2007 Spanish Neuromodulation Society – 2007

Neuromodulation Society. While originating as an independent Society, it, in 1995, became the first chapter of the INS under the name of the North American Neuromodulation Society (NANS). Under the tutelage of the INS Presidencies of Giancarlo Barolat, Brian Simpson, Mario Meglio, and Elliot Krames, 11 more international chapters have been created (Table 6.1). Chapters currently under differing stages of development include the Argentine Neuromodulation Society, the Chinese Neuromodulation Society, the French Neuromodulation Society and the South African Neuromodulation Society. 

accounts for about 50% of the total membership of the INS and other countries outside of the USA, accounts for 50%. The INS has grown about 300 new members each year since 2005. The largest interest group is of members from the medical, scientific and industry world who are primarily interested in the specialty of pain medicine (anesthesia background), followed by neurosurgery. Other members include neuroscientists, neurologists, engineers, nurses and members of industry. In the year 2008, Daryl Kipke, Professor and Chairman of the Department of Bioengineering, University of Michigan, USA and Hunter Peckham, Professor and Chairman of the Department of Biomedical Engineering, Case Western Reserve University, Cleveland, USA will start a biomedical engineering special interest group (SIG) for the INS. 

Mission statement of the INS The INS exists to “promote, disseminate and advocate for the science, education, best practice and accessibility of all aspects of neuromodulation. Our multidisciplinary Society is established to be inclusive of all scientists, physicians, bioengineers, members of industry and other professionals who have a primary interest in the field of neuromodulation.” To accomplish this mission the INS will: Expand the community by bringing together, on a national level, practitioners and other interested stakeholders of neuromodulation into national chapters of the INS. l Protect the community by partnering with industry to expand present technologies, by advocating for l

Membership Currently the INS has approximatley 1200 members. The North American Neuromodulation Society

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Figure 6.4  INS Board of Directors Meeting in Acapulco, Mexico, December 2007: Back row: Simon Thomson, UK, INS Secretary and President-Elect; Jon Valentine, UK, President NS of UK & Ireland; Eduardo Barretto, Brazil, President Brazilian NS; Ross Davis, USA, INS Director-at-Large; Athanasios Koulousakis, Germany, Past-President German NS; Francisco Robaina, Spain, President Spanish NS; Brian Simpson, UK, former INS President, Liaison Officer for IFESS; Jung-Kyo Lee, South Korea, President Korean NS; Bart Nuttin, Belgium, President Benelux Chapter. Middle row: Takamitsu Yamamoto, Japan, representative of Japanese NS; Luan Guoming, China, President Chinese NS; Damianos Sakas, Greece, President South-Eastern European NS; Mario Meglio, Italy, INS Immediate Past President; Giancarlo Barolat, USA, INS Director-at-Large, and former INS President; Paolo Poli, Italy, President Italian NS; Krishna Kumar, Canada, President Canadian NS; Joshua Prager, USA, Past-President of NANS; Liong Liem, The Netherlands, Treasurer-INS Executive Board. Front row: Tia Sofatzis, USA, INS Executive Director; Elliot Krames, USA, INS President

Table 6.2  The INS Executive Officers Presidents 1989–1994 Lee S. Illis, UK 1994–2000 Giancarlo Barolat, USA 2000–2003 Brian Simpson, UK 2003–2006 Mario Meglio, Italy 2006–2009 Elliot Krames, USA Secretaries 1989–1994 J.C. Sier, The Netherlands 1994–2000 Claus Naumann, Switzerland 2000–2003 Michael J.L. DeJongste, The Netherlands 2003–2008 *Simon J. Thomson, UK

government acknowledgement of the technologies used by the field, and for advocating for reasonable remuneration to practitioners of the clinical science of neuromodulation and reasonable reimbursement to industry for the research and development of the devices used by the field. l Disseminate the knowledge base of the field of neuromodulation through national and international scientific meetings and the journal of the INS, Neuromodulation: Technology at the Neural Interface. l Expand the knowledge base through fostering education and research germane to the field of neuromodulation and encouraging scientific discourse.

Treasurers 1989–1994 Michiel J. Staal, The Netherlands 1994–2000 Michael J.L. DeJongste, The Netherlands 2000–2006 Robert D. Foreman, USA 2006–2009 Liong Liem, The Netherlands

C: History of the International Functional Electrical Stimulation Society

Editor-in-Chief of Neuromodulation 1998– Elliot S. Krames, USA IFESS liaison 2004– Brian Simpson, UK Executive Directors 1994–2001 Sherri Kae Calkins, USA 2001– Tia Sofatzis, USA *

President Elect 2008–2009

Dejan Popovic and Paul Meadows The International Functional Electrical Stimulation Society (IFESS) was first conceived in 1993 and founded in 1995 at the 5th Vienna International Workshop on Functional Electrostimulation, in Vienna, Austria. To fully appreciate the inspirations for this society, the history of IFESS must first be preceded with a brief history

I. an introduction to neuromodulation

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6.  beginnings of the societies Neurostimulation addressable population (000s patients) 16 000 14 000 12 000 10 000 8000 6000 4000 2000 0

2300 3069 1635

645

401

123

657

768 13850

850

200

2625

ta l To

tit is D

ep

re s

gi na

re a

nc

An

pa ic hr on C

si Er o Ep n ec Irr t i le ile ita ps bl dy y e sf bo un w ct el sy ion M nd ov ro em m e en M td ig ra is in or e de rs (P D N ) ec k pa O in ve O ra b es ct iv ity e bl Pe ad rip de he r ra lp ai Pe n lv ic pa in

118

460

Figure 6.5  Diseases amenable to neuromodulation therapies and prevalence of the disease in the USA alone (Source: US qualitative research with referrers and potential implanters, literature search, internal discussions, and data analysis) Table 6.3  FES Societies, Workshops and Conferences, starting 1963 Advances in External Control of Humans Extremities

Meetings every 3 years, 1963–1990

Society of Neuroscience Meetings

1970 on

US National Institute of Health   NINDS Neural Prosthesis   Workshops   Neural Interfaces   Workshops Engineering Foundation: Neural Prostheses; Motor Systems Meetings

1972–2003 2004–2006, 2008 on Every 3 years, 1985–2000

Case Western Reserve University Biomedical Engineering Department   Applied Neuro-Control   Research Day   Neuro Engineering   Research Lecture

1986–2002

Japanese FES Society

1989 on

Vienna International Workshop on FES

Every 3 years from 1983

International Functional Electrical Stimulation Society (FESS) formed 1993–4

Meetings yearly from 1996

2003 on

of functional electrical stimulation (FES) research and the contributions of other societies and various conferences/workshop series (Table 6.3).

FES history Since the original work of Luigi Galvani (1780), who discovered animal electricity, through to the

magnificent work of Guillaume B.A. Duchenne de Boulogne (1872) who was the first to describe the controlled use of faradizing current electricity in the human nervous system, scientists have sought ways to treat human diseases with electrical stimulation. In 1875, it was reported that Duchenne applied electrical stimulation to the lower extremities of a paraplegic subject as reported in a Paris newspaper: “Who does not recollect the astonishment exhibited in the clinic at that experiment of Duchenne of drawing from his bed a patient regarded as absolutely paraplegic, and loading him with the weight of a man of ordinary size, without him ever flinching under it?” Since then, the goal of many researchers has been to assist the disabled individual through the use of electrical stimulation. It was not until the advent of the heart pacemaker that the world began to appreciate what technology could provide to individuals with disabilities on a broader scale. The early work of the Canadian engineer John A. Hopps in 1950, with simple technology by today’s standards, nonetheless opened a completely new page in the treatment of people with heart disease. The development of small electronic devices, especially the transistor and followed later by the computer in the 1950s, enabled many researchers to investigate the effects of controlled bursts of electrical charge to the sensory-motor system and the applications in the domain of what is today called “neuromodulation.” However, early foundation technology came from the work at the Case Institute of Technology, Cleveland, Ohio, where a group of very enthusiastic young people led by James Reswick and Thomas Mortimer in the early 1960s started suggesting that it might be possible to tap into the nervous system and provide the connection between the higher and lower neural substrates that were interrupted due to the

I. an introduction to neuromodulation



Advances in external control of humans extremities (ECHE) meetings

57

Figure 6.6  (A) Rajko Tomovic; (B) Jim Reswick; (C) Dejan Popovic; (D) Tadej Bajd; (E) ECHE Conference in Dubrovnik (1975): Lojze Vodovnik, W.T. Liberson, Alojz Kralj, Primoz Strojnik, Uros Stanic

injury or disease. This coincided with the patent and publication of W.T. Liberson (Liberson et al., 1961) and his application of a simple device to treat drop-foot during gait in hemiplegic individuals. FES has been applied to the lower extremities of paraplegic persons since 1963, when A. Kantrowitz raised a paraplegic subject into a standing position using surface applied electrodes. In parallel, much interest was paid to the development of powered artificial prosthetics that would help amputees to walk, reach and grasp by using control signals that are coming from the muscles volitionally controlled by the amputee.

Advances in external control of humans extremities (ECHE) meetings In 1962, Rajko Tomovic started a unique series of triennial meetings called Advances in External Control of Humans Extremities (ECHE). The first meeting took place in the beautiful summer resort of Opatija, Yugoslavia (now Croatia). The meeting was a fantastic and rare opportunity for scientists from East and West to meet at one place and spend one week of productive and pleasant time together to present their novel and promising ideas. The first meeting attracted, among others, Norbert Wiener, who gave an interesting overview of what computers could do in the future in the domain of controlling extremities, and how cybernetics would resolve the man–machine

interface problem. The first meeting was also the occasion where the great mind of Lojze Vodovnik (University of Ljubljana, Slovenia) met Jim Reswick and decided to spend some time at Case (became Case Western Reserve University).  The success of the first meeting motivated the new group of scientists who dedicated their time, knowhow and intelligence to the development of electrical stimulation principles and applications. Tomovic decided to move the location for the ECHE Symposium to Dubrovnik on the Adriatic coast. During the last week of August, every third year from 1966, Dubrovnik became home to about 100 hot minds willing to share in what they had accomplished in the domain of new systems for rehabilitation of individuals with disability. The discussions and presentations shifted from the symposium room to the round tables at the beach, long debates in the restaurants and under the clear sky and stars. The Dubrovnik meeting became synonymous with the latest technology introductions in the field of electrical stimulation. The efforts of the Ljubljana group, led by engineers Lojze Vodovnik, Alojz Kralj, Tadej Bajd, Uros Stanic and physicians Milan Dimitrijevic and Franjo Gracanin, resulted in bringing excellent scientists and many young people with great ideas together. The Dubrovnik meeting was the best forum to place seeds for excellent collaborations between North American, Japanese, Russian, Polish, Austrian, German, French, English, Scottish, Dutch, Yugoslav and other researchers and clinicians and indeed many future collaborations can trace their roots to this international gathering of renowned scientists

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6.  beginnings of the societies

and clinicians. Dejan Popovic, one of the organizers of the ECHE meetings since 1978, followed the idea of Tomovic of providing information to many generations of researchers to come by collecting all ten proceedings of the ECHE Meeting and ­ publishing them on a CDROM that is available today. This CDROM brings important information that could help provide a better understanding of the foundation of the field of modern prosthetics and neural prostheses, especially applied to sensory-motor systems, and provides easy access to information that is not available through the Internet regarding this pioneering work.

Rehabilitation engineering society of north america (RESNA) Jim Reswick, along with Douglas Hobson, Colin McLaurin, Anthony Staros and Joseph Traub, organized a conference in Rehabilitation Engineering, and initiated the development of the RESNA, which held its first meeting in Toronto in 1980. Since that time, RESNA has changed its name to the Association for the Advancement of Rehabilitation Technology; and in 1995 it changed its name, once again, to the Rehabilitation Engineering and Assistive Technology Society of North America – RESNA. RESNA is an interdisciplinary organization dedicated to promoting the transfer of science, engineering and technology to meet the needs of individuals with disabilities, and its members include a broad range of disciplines. Key to the development of this organization was the Special Interest Groups (SIGs), one of which was dedicated to Electrical Stimulation. The SIGs solicited papers for presentation in conference sessions and held ad hoc meetings to discuss and promote their specialties. Comprised of engineers, physical therapists, and other interested parties, the group successfully integrated disparate interest groups into this single session topic. Over time, however, the electrical stimulation special interest group was unable to maintain itself and is now inactive.

Vienna international workshop on functional electrical stimulation An international tri-annual conference organized by the Department of Biomedical Engineering and

Physics of the Medical University of Vienna, Vienna Medical School, and associated with the International Federation for Artificial Organs (IFAO), which emerged and originated from the International Society for Artificial Organs (ISAO), has for many years addressed the medical application of electrical stimulation. The first of these meetings was held in 1984 in Vienna and has been held in or around Vienna every three years since. The participants at this meeting were not required to be members of the ISAO or IFAO, and the meeting has attracted engineers, medical researchers, and manufacturers. The Vienna Workshop continues on to this day and is one of the greatest contributors to the ongoing development and presentation of research in electrical stimulation.

The development of IFESS The last in the series of ten ECHE meetings took place in 1990. The tragic events in the Balkans prevented the continuation of this great tradition. Many among the original organizers of the Dubrovnik meetings strongly believed that the tradition and achievements of this great series of meetings should be remembered and continued. The need to continue this activity was recognized by Slovenian researchers and they suggested that a new Society should be organized that would have the major task of contributing to better use of electrical stimulation. In 1993, at a meeting devoted solely to electrical stimulation, in Ljubljana, which was organized by the Institute Josef Stefan and the Faculty of Engineering at the University of Ljubljana, with a follow-up meeting that was held in the seaside village of Portoroz, the formation of a new society was discussed. At this meeting the participants met to determine how the field of electrical stimulation could best be advanced. In brief, it was decided that existing meetings and professional societies were not sufficiently focused on functional electrical stimulation, and that only with the formation of a new international society that was solely focused on this topic could the field be properly represented, promoted, and clinical development accelerated. This then was the impetus behind the formation of the International Functional Electrical Stimulation Society (IFESS). An organizing team consisting of Uros Stanic, Ross Davis, Peter Veltink, Robert Jaeger, and Thomas Sinkjaer was formed, and the team of Bob Jaeger, Thomas Sinkjaer, and Peter Veltink were assigned to draft the first Bylaws of the Society. At the following

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The development of IFESS

Vienna FES Workshop in 1995, the Bylaws were presented and the Foundation Meeting of the Society was held. At this meeting elections were held and the first IFESS Executive Board and Board of Directors were elected. Elected to the Executive Board for three-year terms were: Uros Stanic, President; Ross Davis, VicePresident; Paul Meadows, Secretary; and Peter Veltink, Treasurer. Elected to the Board of Directors were Helena Benko, Gudrun Sigurjonsdottir, and Moshe Solomonow (each to hold office for one year), Stanley Salmons, Byron Marsolais, and Nick Donaldson (each to hold office for two years), Bob Jaeger, Alojz Kralj, and Dejan Popovic (each to hold office for three years). Thereafter, on a yearly basis, three new Directors would be elected and three would retire, and on a triennial basis a new Executive Board would be elected. The first Annual Conference of IFESS was organized by Hunter Peckham and held at Case Western Reserve University in Cleveland, Ohio, in 1996. The conference was well attended and served as a template for future meetings. In 1995 there were 138 members world-wide who joined IFESS as Founding Members. The 2nd through 12th conferences are described briefly in Table 6.4. In 1998 a key event in the history of IFESS occurred. At a joint conference held in Lucerne, Switzerland, with the International Neuromodulation Society (INS), a meeting was held between the Executive Boards of the two societies. At this meeting, it was agreed that, due to the mutual benefits that each Society would derive from the other, the IFESS and INS should become officially related, they should share a common official journal, and they should endeavor to have representation at each other’s Annual Conferences. As a result of this meeting, there have been official combined sessions at each of the INS and IFESS Annual Conferences, where key representatives from the complementary

Table 6.4  IFESS Conference venues and chairmen, 1996 through 2011 Year

Location

Chairmen

1996

Cleveland, Ohio, USA

Hunter Peckham

1997

Vancouver, British Columbia, Canada

Andy Hoffer, Dejan Popovic

1998

Lucerne, Switzerland

Claus Naumann (INS), Ross Davis

1999

Sendai, Japan

Yasunobu Handa, Nozomu Hoshimiya, Kouzou Satou, J. Thomas Mortimer

2000

Aalborg, Denmark

Thomas Sinkjær, Dejan Popovic, Johannes J. Struijk

2001

Cleveland, Ohio, USA

Ronald J. Triolo, Primoz Strojnik, Peter Veltink

2002

Ljubljana, Slovenia

Uros Stanic, Tadej Bajd

2003

Brisbane, Australia

Glen Davis, James Middleton

2004

Bournemouth, UK

Ian Swain, Paul Taylor

2005

Vancouver, Canada

Mohamed Sawan

2006

Mount Zao, Japan

Itaru Kimura, Nozomu Hoshimiya, Yasunobu Handa, Takashi Imai, Kazunori Seki

2007

Philadelphia, Pennsylvania, USA

Randy Betz, Brian Smith

2008

Freiburg, Germany

Thomas Stieglitz, Martin Schuettler, Thomas Becks

2009

Seoul, Korea

Gon Khang, Younghee Lee

2010

Vienna, Austria

Manfred Bijak, Winfried Mayr

2011

São Paulo, Brazil

Alberto Cliquet

Table 6.5  Executive Board of IFESS, 1996 to 2010 Term

President

Vice-President

Secretary

Treasurer

1996–1998

Uros Stanic

Ross Davis

Paul Meadows

Peter Veltink

1999–2001

Ross Davis

Thomas Sinkjaer

Aleks Kostov/ Paul Meadows

Peter Veltink

2002–2004

Thomas Sinkjaer

Paul Meadows

Manfred Bijak

Jimmy Abbas

2005–2007

Paul Meadows

Manfred Bijak

Nico Rijkhoff/ Andy Hoffer

Milos Popovic

2008–2010

Manfred Bijak

Jane Burridge

Glen Davis

Thierry Keller

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6.  beginnings of the societies

Figure 6.7  IFESS Past Presidents: Paul Meadows, Ross Davis, and Uros Stanic

Society would present scientific oral presentations to the entire assembly. It was also agreed that the journal Neuromodulation would be adopted as the official journal of IFESS, with the IFESS logo placed on the journal, and an Editorial Board was established for IFESS member submissions. Ross Davis has served as the Head of the Editorial Board since its inception, and is a key proponent of the relationship between IFESS and INS.  

IFESS continues to have successful Annual Conferences, attended by a broad mix of engineers, physical therapists, doctors of physical medicine and rehabilitation, orthopedic surgeons, neurosurgeons, and many other representatives of medical specialties. The collective works of all of these Conferences were compiled by Paul Meadows and were made available through the IFESS website and on a DVDROM which contains all of the proceedings of all of the IFESS meetings from 1996 to the present, along with proceedings of the Vienna FES Workshops and abstracts and papers from the INS and World Stereotactic and Functional Neurosurgery Society conferences. FES and IFESS’s future is bright and in good hands and promises to provide the world with many more developments in electrical stimulation as we partner with our sister organization, the INS.

References Liberson, W.T., Holmquest, H.J., Scott, D. and Dow, M. (1961) Functional electrotherapy: stimulation of the peroneal nerve synchronized with the swing phase of the gait of hemiplegic patients. Arch. Phys. Med. Rehab. 42: 101–5. www.ifess.org.

I. an introduction to neuromodulation

C H A P T E R

7

Clinical Study Design Daniel B. Carr and Anthony Eidelman

o u t l i n e Introduction

61

Quality of the Current Literature

65

Hierarchy of Clinical Study Design

61

Future Clinical Trials of Neuromodulation

65

Clinical Objective

62

Future Areas of Research

66

Study Design

63

Conclusion

66

Study Population, Intervention, and Setting

63

Summary Points

67

Assessment of Outcomes

64

References

67

Analysis of Results

64

Hierarchy of clinical study design

Introduction An understanding of clinical trial design is necessary for physicians or scientists who conduct clinical research on neuromodulation. It is also essential that practitioners who will ultimately translate clinical evidence into clinical practice understand how to critically appraise the evidence. Moreover, the language of evidence-based medicine (EBM) is increasingly used by regulators, insurers and other policy-makers to restrict payment for many medical interventions. The present chapter surveys clinical trial design, with a particular focus on investigations of neuromodulation. We review the attributes of methodologically sound clinical studies that reduce both investigator bias and confounding variables.

Neuromodulation

Proponents of EBM grade the quality of literature based on the type and quality of research study design (Carr et al., 1992; Wittink et al., 2003). An example of the hierarchy of study designs is displayed in Box 7.1. Each category of trials is considered methodologically superior to those found below it. In practice, most expert opinions may be countered by an equally vehement opinion from an equally qualified expert. Therefore, while anecdotal evidence certainly influences our medical practice, it cannot replace systematic scientific study. The next higher tier of evidence includes uncontrolled, descriptive trials, including case reports and series. Such trials are

61

© 2008, 2009 Elsevier Ltd.

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7.  clinical study design

Box 7.1 

Hierarchy of individual study types Systematic reviews of RCTs One or more well designed RCTs Observational controlled trials Uncontrolled trials (case reports or series) Expert opinion Source: Carr et al., 1992; Wittink et al., 2003

necessary when a treatment is initially introduced in order to establish its effectiveness, practicality, and safety. However, observational studies with control groups, including cohort and case–control studies, are superior to those that lack controls because the former allow estimates of therapeutic effect that may be differentiated from placebo effects, which have long been observed to have potential importance in trials with subjective outcomes such as pain relief and satis­ faction with care. A prospective cohort study involving neuromodulation would consist of a longitudinal trial that compares patients with a specified condition who were assigned to either the therapeutic arm or a matched control group. However, observational studies have inherent limitations, most notably the possibility of factors that influence the distribution of patients between the active treatment (e.g., neuromodulation) or control groups (Miller et al., 1989a, b). Accordingly, randomized controlled trials (RCT) are considered the least biased method of study design to determine the efficacy of medical interventions. Through the process of randomization, the allocation of subjects between the neurostimulation arm and control group is theoretically accomplished without bias, particularly when allocation is concealed and outcome assessment is conducted by third parties blinded to the intervention each patient received. However, it is common to find that RCTs of the same intervention yield disparate conclusions (LeLorier et al., 1997). The specific study design, patients enrolled, disease severity, concurrent treatments or particular therapeutic intervention may be heterogeneous between RCTs. Moreover, a single RCT cannot be expected to be generalizable to all clinical situations. Therefore, systematic reviews of multiple RCTs are considered to offer the highest level of medical evidence. A systematic review is a summary of the evidence that answers a specific clinical question using an explicit method­ ology to select, appraise and consolidate the literature

(Cook et al., 1997). When the trials that address a specific clinical question employ sufficiently similar methods and outcome measurements, their results may be synthesized quantitatively into a meta-analysis. One of the most extensive evidence-based collections is The Cochrane Database of Systematic Reviews, a nonprofit effort in which the results of systematic reviews performed by dozens of collaborative review groups around the world are coordinated through a central office in Oxford, England. As of February 2007 the Cochrane Library contains almost 3000 systemic reviews and 1700 protocols. For the reasons just mentioned, the hierarchy of clinical study design should be considered a “general framework” rather then an absolute ranking system and clinicians should consider the results of the best available evidence (that may comprise trials other than RCTs, if such trials provide strong, consistent evidence) when making evidence-based decisions. For instance, a well-constructed, large-scale observational study may be of greater clinical value than a poorly designed, small-scale RCT. Further, the historically accepted notion that observational studies overestimate the magnitude of treatment effects (Sacks et al., 1982; Colditz et al., 1989; Miller et al., 1989a, 1989b) has recently been challenged (McKee et al., 1999; Benson and Hartz, 2000; Concato et al., 2000). Observational studies conducted in the past 20 years likely have superior methodological design, enhanced data set selection and improved statistical analysis compared to earlier trials (Benson and Hartz, 2000). Therefore, in situations where RCTs are not practical or feasible, observational trials that are rigorously designed may be an appropriate alternative to RCTs for determining therapeutic efficacy (McKee et al., 1999).

Clinical objective The clinical objective is perhaps the most critical aspect of a research trial. The recent Nobel Prize winner in literature, Naguib Mahfouz, stated “you can tell whether a man is clever by his answers, you can tell whether a man is wise by his questions.” Likewise, every clinical study should explicitly frame a well-defined research question. An appropriately constructed objective should describe characteristics of the study population, disease condition, intervention and outcome measures. For example, it is not sufficient to pose the general question “Is spinal cord stimulation (SCS) effective for complex regional pain syndrome (CRPS)?” A more meaningful objective was presented by Kemler and associates: “In adult patients

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study population, intervention, and setting

with CRPS, are SCS with physical therapy superior to treatment with physical therapy alone after six months, with regard to pain relief, patient rated global perceived effect and functional status?” (Kemler et al., 2000). The latter study question astutely includes most of the important elements for a well-framed clinical question.

Study design Biased studies can lead to over-, or, more commonly, underestimation of the effect of a therapeutic intervention. Methodologically sound studies are less likely to be flawed by bias or confounding variables. A critical component of any trial is the method by which participants are assigned to either the intervention or control group. Selection bias may occur when one or more influencing variables are unevenly distributed among the study groups, whether or not these influencing variables are explicitly documented. For example, co-morbid depression is recognized to increase the likelihood of a poor response to any treatment for chronic pain (Bair et al., 2003). Hypothetically, if patients allocated to receive SCS had a greater incidence and severity of depression than those receiving medical management alone, then the observed benefit of SCS could be falsely underestimated. An advantage of the RCT design compared to observational and uncontrolled studies is its ability to minimize selection bias through the processes of randomization and allocation concealment. Random allocation in a 1:1 paradigm means that study participants have an equal and arbitrary chance of being assigned to the treatment or control groups. This paradigm reduces the likelihood of a disproportionate distribution of factors between study groups that could influence the clinical outcome. Appropriate methods of random allocation include computer-generated assignment or use of a table of random numbers. Allocation concealment means that investigators and participants are unaware of study assignments. Trials that lack allocation concealment overestimate treatment effect by as much as 41% (Schulz et al., 1995). Double-blinded, placebo-controlled trials are the most appropriate method of analgesic study design because suggestibility, patient or investigator expectation, and other contributors to placebo effects may introduce significant bias. However, in trials evaluating interventional therapies, including neuromodulation, blinding is more challenging to accomplish and often impractical. Double-blinding during SCS is impossible because of the associated paresthesiae.

63

However, blinding of other types of neuromodulation, including deep brain stimulation (DBS), may not produce conscious sensations and therefore concealment of treatment is feasible. For instance, Kupsch and associates (2006) conducted a double-blinded RCT evaluating the efficacy of bilateral pallidal neuro­ stimulation for 3 months for primary generalized or segmental dystonia. Permanent quadripolar electrodes were implanted bilaterally in the internal globus pallidus under general anesthesia. Postoperatively, the patients were randomized to receive either neurostimulation or sham stimulation. Both the patients and study investigators who assessed the outcome measures were unaware of the treatment allocations. The study concluded that bilateral pallidal stimulation was more effective then sham stimulation.

Study population, intervention, and setting The trial outcome may be influenced by subject selection. The characteristics of the study participants should be representative of the target general population that is eligible to receive neuromodulation. The study should have clear inclusion and exclusion criteria with well-defined demographics including age, gender, ethnicity, co-morbidities, functional status, current medications, and previous therapeutic intervention. As described above, prognostic factors between the study and control groups should be similar, to minimize confounding variables that could alter the apparent efficacy of the therapeutic intervention. Furthermore, it is essential to examine the methods by which prospective trials participants are recruited for the study. If the recruitment techniques result in only certain subsets of eligible patients being enrolled there may be selection bias, especially if participants with characteristics associated with poor clinical outcomes are selectively included or excluded. A well-designed and well-reported study should include a description of the prospective patients who were considered for the trial, but did not meet inclusion criteria. General aspects of patient screening and patient flow within the study are typically provided in a flow diagram according to the recommendations of the QUORUM statement (Altman et al., 2001). The report of the trial should provide a detailed description of the intervention, so that the study can be precisely duplicated. In studies of SCS, the trialing procedure and criteria for implantation should be reported. Additional relevant details include the

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7.  clinical study design

device model, description of the leads (type, number, and location), implantation technique, and stimulation settings. For studies involving neuromodulation, it is important that study clinicians have adequate exper­ ience with surgical and implantation techniques. In multicenter trials, there should be consensus among the site concerning the trial and implant methods. Despite having a similar protocol, consensus centerand investigator-specific effects are possible, that may potentially cause bias. Also, concurrent therapies that may influence outcome measures should be described, including medical management, physical therapy or cognitive-behavioral therapy.

Assessment of outcomes The primary and secondary outcome measures should be clearly defined, reliable, and previously validated. Both the methods of how outcomes will be determined and the timeframe of when endpoints will be determined should be explicitly reported. For studies evaluating therapies for chronic pain, recommended outcomes include pain intensity, physical and emotional function, patient self-reported ratings of global improvement and satisfaction with treatment, adverse effects, and participant recruitment process through the trial (Dworkin et al., 2005). Rogers et al. have emphasized that generic quality of life instruments such as the SF-36 are likely to be insensitive to detect clinically meaningful outcomes of interventions for chronic pain, unless such generic instruments are augmented by specific, validated questions that are relevant to the population with chronic pain (Rogers, Wittink, Ashburn et al., 2000; Rogers, Wittink, Wagner et al., 2000). Klomp and associates (1999) randomized patients with critical peripheral vascular disease, who were not candidates for revascularization surgery, to receive either SCS with maximum medical management or the latter therapy alone. The primary endpoint was limb survival at two years, and mortality was also documented. Mannheimer et al. (1998) compared electrical stimulation versus coronary artery bypass surgery in patients with severe angina pectoris despite optimal medical management (ESBY study). The primary outcomes were (1) effect on symptoms (frequency of angina, consumption of short-acting nitrates, self-estimated symptoms relief) and (2) myocardial ischemia (exercise stress test prior and 6 months post surgery). In the Klomp and Mannheimer studies the endpoints were clearly specified, but if the outcomes are vague, then the paper may selectively report the outcomes with the greatest

magnitude of response, which could lead to overestimating the effects of the therapeutic intervention studied.

Analysis of results Data analysis and statistical testing are essential components of any clinical trial. Although a comprehensive description of statistical calculations is beyond the scope of the present chapter, we provide brief discussion of this topic. A priori statistical power calculation should be performed to determine appropriate study sample size. The statistical power, which is usually specified at 0.80 or greater, is the probability that there will not be a false-negative (type II) error. In the study of SCS for CRPS by Kemler and associates (2000), statistical power was set at 90% to detect a 2.3 cm difference in visual analogue scale assessment of pain intensity between the two groups. A power of 90% (0.9) means that there is a 10% chance of concluding that there is no difference between the groups, when in fact a difference does exist. Not only should the outcome measures be carefully selected and well defined, but it is essential that the results are appropriately analyzed. Before enrolling patients into a trial, the investigators should provide detailed description of the statistical methods used to assess the results. It is possible to perform multiple stat­ istical tests until one uncovers a “significant” P-value. Therefore, estimation of the size of outcome effects is often more important then whether the effects are statistically significant. Therefore, outcomes of anal­ gesic trials are most appropriately reported by providing both mean results and measures of variability, such as standard deviations or confidence intervals. The value of potentially insensitive outcome measures, such as the number needed to treat (NNT), has been questioned (Cepeda et al., 2005; Gray et al., 2005). In the context of pain therapies, NNT refers to the number of patients required to receive the therapy in order to detect a single patient who met criteria for improvement (e.g., 50% reduction in pain intensity) who would not have shown such improvement if treated with a placebo. Furthermore, the reported results should document the incidence and nature of adverse events. Complications that occurred during the neurostimulation trial, surgical implant procedure and after permanent implantation should be described in detail. A clinical trial should account for participants who were non-compliant with follow-up or were withdrawn. Typically, dropouts are associated with poor outcomes, up to and including death. There are strategies to reduce the bias associated with withdrawals.

I. an introduction to neuromodulation



future clinical trials of neuromodulation

An “intent to treat” analysis means that all patients are included in their original assignment groups regardless of whether they completed the study or not. A “worst case scenario” principle is then applied, which assigns the worst possible outcomes to missing patient data.

Quality of the current literature Although there is abundant literature evaluating the efficacy of neurostimulation, there is a paucity of high-quality studies. The clear majority of such trials are retrospective, underpowered and methodologically flawed. This is especially true for the literature evaluating neuromodulation for chronic pain (Turner et al., 1995; Grabow et al., 2003; Cameron, 2004; MailisGagnon et al., 2004; Turner et al., 2004; Taylor et al., 2006). In 1995 Turner and associates published a systematic review of SCS for failed back surgery syndrome. At that time the world’s evidence was limited to 39 published case series, most of which were retro­ spective. Few of these papers included data on functional capacity, employment status, and adjuvant analgesic consumption. Nine years later Turner and colleagues published another systematic review of the efficacy of SCS in providing analgesia and increasing functional capacity for both failed back surgery syndrome and complex regional pain syndrome (CRPS). Although the aggregated literature suggests benefit with SCS, the article identified only a single well-designed RCT that met the inclusion criteria for the review. Several evidence-based reviews have assessed the utility of SCS for CRPS (Grabow et al., 2003; Cameron, 2004; Turner et al., 2004; Taylor et al., 2006). In 2003 Grabow and colleagues performed a critical review of the literature that identified 15 relevant trials, including one RCT and 14 observational studies (2 prospective and 12 retrospective). Although the evidence supports the use of SCS for CRPS, the authors acknowledged the limited quantity and quality of the literature. Similarly a Cochrane Review, most recently updated in 2004, identified only two RCTs that assessed SCS for chronic pain (Mailis-Gagnon et al., 2004). The authors of this Cochrane Review concluded that although there is limited high-quality evidence evaluating the effectiveness of SCS for chronic pain, it remains a viable treatment option in appropriately selected patients for neuropathic pain involving the trunk or extremities. High-quality evidence does support the use of neuromodulation for other pathological conditions.

65

A systematic review of multiple well-designed RCTs is available for SCS for inoperable critical peripheral vascular disease (Ubbink and Vermeulen, 2005). At least two high-quality RCTs have evaluated the efficacy of vagal nerve stimulation for partial seizures (Privitera et al., 2002). Moreover, well-designed, multicenter randomized trials have recently been published in the New England Journal of Medicine that demonstrated efficacy of pallidal neurostimulation for dystonia (Kupsch et al., 2006) and deep brain stimulation for Parkinson’s disease (Deuschl et al., 2006). EBM is a valuable tool, and there is no denying that the literature on pain treatments has not historically been a high-quality one. However, the recent disturbing trend to deny payment on the basis of an absence of statistically significant differences between group means in generally underpowered trials, particularly of invasive pain therapies, is a misapplication of EBM. Such misapplication may well lead to denial of care for individuals or subgroups whose beneficial responses are not evident, when pooled data alone are used as a criterion for payment (Carr, 2008).

Future clinical trials of neuromodulation It is essential that the neuromodulation community, especially those involved with chronic pain management, develop innovative studies with improved methodological quality in order to determine the value of this therapy. Unquestionably additional RCTs are necessary. Ideally, placebo or sham-stimulator controlled trials should be conducted. However, it seems clear that certain types of neurostimulation therapy are impossible to conceal from the patient or investigator. Therefore, creative strategies should be developed to reduce bias caused by lack of blinding. If RCTs are not feasible then well-designed observational trials, including rigorous case-controlled trials or prospective cohort studies, are an appropriate alternative (Benson and Hartz, 2000; Concato et al., 2000). Collaborative multicenter trials are generally necessary to accrue sufficient sample sizes. We describe additional recommendations for prospective neuro­ stimulation trials in Box 7.2. Furthermore, Turner and associates recently made several astute suggestions for future clinical studies of implantable intrathecal delivery systems and many of their recommendations are also applicable to neuromodulation (Turner et al., 2007). The article suggested that the published RCTs comparing lumbar back surgery with non-surgical treatment of chronic back pain

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7.  clinical study design

Box 7.2 

Suggestions for future clinical trials

Study design

l

Additional RCTs, if possible with placebo or sham stimulator controlled trials l Rigorous observational trials (case-controlled trials or prospective cohort studies)

Outcomes

l

Adequate experience with trial and surgical technique

Well-defined, validated, reliable endpoints Outcomes explicitly reported prior to start of study l Outcomes measurements over interval time points with sufficient duration of follow-up l If possible the treatment allocation could be undisclosed to the outcome assessors l Report mean results and standard deviations or confidence intervals l Description of adverse effects and complications l l

Study participants Adequately powered trials Well defined inclusion and exclusion criteria l Similar baseline demographics between study groups l Details of recruitment process l Description of subject flow through each stage of study, including withdrawals and dropouts l l

Intervention Details of trial and implant proceedings Description of implanted device

l l

could be used as models to guide the development of RCTs to evaluate the efficacy of intrathecal delivery systems. Moreover, they recommended additional well-designed non-randomized comparisons of intra­ thecal delivery systems with either alternative therapy or “treatment as usual.”

Future areas of research Future clinical trials of neurostimulation will no doubt focus on emerging therapeutic applications, including SCS for treatment of cerebrovascular disease (Isono et al., 1995), occipital nerve stimulators for chronic headaches (Schwedt et al., 2007) and deep brain stimulation for psychiatric disorders (Giacobbe and Kennedy, 2006). Interestingly, significant interindividual variability has been observed in the efficacy of neuromodulation, even in patients with apparently similar pathology and demographics. Certainly psychological morbidity, including personality disorders or intractable depression, is associated with poor outcome. However, insufficient attention has been given to the possibility that genetic determinants influence individual responses to neuromodulation. Recently,

much attention has been focused on pharmacogenetics as an explanation for inter-individual (Mogil, 1996) and inter-ethnic (Cepeda et al., 2001) differences in drug response. It is conceivable that, in the future, genetic profiling may lead to modifications in neurostimulation treatment planning and provide prognostic information on long-term outcome. Innovative research could be directed towards the identification of possible genetic determinants of clinical response to neuromodulation.

Conclusion Neuromodulation is a relatively novel field that incorporates clinical medicine and scientific technology. As knowledge of neuromodulation becomes more refined, its effectiveness will likely improve and the indications for this intervention will undoubtedly continue to expand. Over the past several decades we have seen electrical stimulation progress from an experimental concept to a widely practiced medical therapy. However, the available evidence to guide use of the therapy remains limited. We therefore must strive to improve the quality of clinical studies, not only to advance this technology, but also to better

I. an introduction to neuromodulation

summary points

inform the translation of technology to benefit individual patients according to tomorrow’s evidencebased practice paradigms.

Summary points The current consensus hierarchy of clinical study design stratifies the scientific literature based upon its type and quality. l Randomized, double-blinded, controlled trials (RCT) are historically considered the least biased method of study design for assessing the efficacy of medical interventions. l However, in trials evaluating the efficacy of interventional therapies, including neuromodulation, blinding is more challenging to accomplish. In fact, double-blinded trials of spinal cord stimulation are not feasible because of the paresthesiae normally present during such treatment. Therefore, creative strategies are required to reduce bias caused by the inability to conceal treatment in this setting. l Although the available evidence generally supports the use of neurostimulation, there is a paucity of high quality literature. l Misapplication of EBM (i.e. to deny payment for invasive therapies on the basis of absence of significant differences in groups means, in generally underpowered studies) may well lead to denial of care for certain individuals. l It is essential that those involved with neuromodulation, especially for chronic pain management, develop innovative studies with improved methodological quality, in order to determine the value of this emerging therapy. l

References Altman, D.G., Schulz, K.F., Moher, D. et al. (2001) The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials. Ann. Intern. Med. 134: 657–62. Bair, M.J., Robinson, R.L., Kayton, W. et al. (2003) Depression and pain comorbidity: a literature review. Arch. Intern. Med. 163: 2433–45. Benson, K. and Hartz, A. (2000) A comparison of observational studies and randomized, controlled trials. N. Engl. J. Med. 242: 1878–86. Cameron, T. (2004) Safety and efficacy of spinal cord stimulation for the treatment of chronic pain: a 20-year literature review. J. Neurosurg. 100: 254–67. Carr, D.B. (2008) When bad evidence happens to good treatments. Reg. Anesth. Pain Med. 33: 229–40. Carr, D.B., Jacox, A.K., Chapman, C.R. et al. (1992) Acute Pain Management: Operative or Medical Procedures and Trauma. Clinical

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Practice Guideline. Rockville, MD: Agency for Health Care Policy and Research, Public Health Service, US Department of Health & Human Services, AHCPR Pub No. 92-0032. Cepeda, M.S., Carr, D.B., Miranda, N. et al. (2005) Comparison of morphine, ketorolac, and their combination for postoperative pain: results from a large, randomized, double blind trial. Anesthesiology 103: 1225–32. Cepeda, M.S., Farrar, J.T., Roa, J.H. et al. (2001) Ethnicity influences opioid pharmacokinetics and pharmacodynamics. Clin. Pharmacol. Ther. 70: 351–61. Colditz, G., Miller, J. and Mosteller, F. (1989) How study design affects outcomes in comparisons of therapy. II. Medical. Stat. Med. 8: 455–66. Concato, J., Shah, N. and Horwitz, R. (2000) Randomized, controlled trials, observational studies, and the hierarchy of research designs. N. Engl. J. Med. 342: 1887–92. Cook, D., Mulrow, C. and Haynes, B. (1997) Systematic Review: synthesis of best evidence for clinical decisions. Ann. Intern. Med. 126: 376–80. Deuschl, G., Schade-Brittinger, C., Krack, P. et al. (2006) A randomized trial of deep-brain stimulation for parkinson’s disease. N. Engl. J. Med. 355: 896–908. Dworkin, R., Turk, D., Farrar, J. et al. (2005) Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain 113: 9–19. Giacobbe, P. and Kennedy, S. (2006) Deep brain stimulation for treatment-resistant depression: a psychiatric perspective. Curr. Psychiatry Rep. 8: 437–44. Grabow, T.S., Tella, P.K. and Raja, S.N. (2003) Spinal cord stimulation for complex regional pain syndrome: an evidence-based medicine review of the literature. Clin. J. Pain 19: 371–84. Gray, A., Kehlet, H., Bonnet, F. et al. (2005) Predicting postoperative analgesia outcomes: NNT league tables or procedure-specific evidence? Br. J. Anaesth. 94: 710–14. Isono, M., Kaga, A., Fujiki, M. et al. (1995) Effect of spinal cord stimulation on cerebral blood flow in cats. Stereotact. Funct. Neurosurg. 64: 40–6. Kemler, M.A., Barendse, G.A., Van Kleef, M. et al. (2000) Spinal cord stimulation in patients with chronic reflex sympathetic dystrophy. N. Engl. J. Med. 343: 618–24. Klomp, H.M., Spincemaille, G.H., Steyerberg, E.W. et al. (1999) Spinal-cord stimulation in critical limb ischaemia: a randomised trial. ESES Study Group. Lancet 353: 1040–4. Kupsch, A., Benecke, R., Müller, J. et al. (2006) Pallidal deep-brain stimulation in primary generalized or segmental dystonia. N. Engl. J. Med. 355: 1978–90. LeLorier, J., Grégoire, G., Benhaddad, A. et al. (1997) Discrepancies between meta-analyses and subsequent large randomized, controlled trials. N. Engl. J. Med. 337: 536–42. Mailis-Gagnon, A., Furlon, A., Sandoval, J. et al. (2004) Spinal cord stimulation for chronic pain. Cochrane Database of Systematic Reviews, Issue 3. Art. No. CD003783. DOI: 10.1002/14651858. CD003783.pub2. Mannheimer, C., Eliasson, T., Augustinsson, L. et al. (1998) Electrical stimulation versus coronary artery bypass surgery in severe angina pectoris: the ESBY study. Circulation 97: 1157–63. McKee, M., Britton, A., Black, N. et al. (1999) Methods in health services research: interpreting the evidence: choosing between randomised and non-randomised studies. BMJ 319: 312–15. Miller, J., Colditz, G. and Mosteller, F. (1989a) How study design affects outcomes in comparisons of therapy. I. Medical. Stat. Med. 8: 441–54. Miller, J., Colditz, G. and Mosteller, F. (1989b) How study design affects outcomes in comparisons of therapy. II: Surgical. Stat. Med. 8: 455–66.

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Mogil, J.S. (1996) The genetic mediation of individual differences in sensitivity to pain and its inhibition. Proc. Natl Acad. Sci. 93: 3048–55. Privitera, M., Welty, T., Ficker, D. and Welge, J. (2002) Vagus nerve stimulation for partial seizures. Cochrane Database of Systematic Review, Issue 1, Art. No. CD002896. DOI: 10.1002/14651858. CD002896. Rogers, W.H., Wittink, H.M., Ashburn, M.A. et al. (2000) Using the “TOPS”, an outcomes instrument for multidisciplinary out­ patient pain treatment. Pain Medicine 1: 55–67. Rogers, W.H., Wittink, H.M., Wagner, A. et al. (2000) Assessing individual outcomes during outpatient, multidisciplinary chronic pain treatment by means of an augmented SF-36. Pain Med. 1: 44–54. Sacks, H., Chalmers, T.C. and Smith, H., Jr. (1982) Randomized versus historical controls for clinical trials. Am. J. Med. 72: 233–40. Schulz, K.F., Chalmers, I., Hayes, R. et al. (1995) Empirical evidence of bias: dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 273: 408–12. Schwedt, T.J., Dodick, D.W., Hentz, J. et al. (2007) Occipital nerve stimulation for chronic headache – long-term safety and efficacy. Cephalalgia 27: 153–7. Taylor, R.S., Van Buyten, J.P. and Buchser, E. (2006) Spinal cord stimulation for complex regional pain syndrome: a systematic

review of the clinical and cost-effectiveness literature and assessment of prognostic factors. Eur. J. Pain 10: 91–101. Turner, J., Sears, J. and Loeser, J. (2007) Programmable intrathecal opioid delivery systems for chronic noncancer pain: a systematic review of effectiveness and complications. Clin. J. Pain 23: 180–95. Turner, J.A., Loeser, J.D. and Bell, K.G. (1995) Spinal cord stimulation for chronic low back pain: a systematic literature synthesis. Neurosurgery 37: 1088–95. Turner, J.A., Loeser, J.D., Deyo, R.A. et al. (2004) Spinal cord stimulation for patients with failed back surgery syndrome or complex regional pain syndrome: a systematic review of effectiveness and complications. Pain 108: 137–47. Ubbink, D. and Vermeulen, H. (2005) Spinal cord stimulation for non-reconstructable chronic critical leg ischaemia. Cochrane Database of Systematic Reviews, Issue 3. Art. No. CD004001. DOI: 10.1002/14651858.CD004001.pub2. Wittink, H., Wiffen, P. and Carr, D.B. (2003) Evidence-based medicine in pain management. Chapter 2. In: S. Berman (ed.), Approaches to Pain Management: An Essential Guide for Clinical Leaders. Oakbrook Terrace, IL: Joint Commission on Accreditation of Healthcare Organizations, pp. 21–33.

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C H A P T E R

8

Psychological Issues and Evaluation for Patients Undergoing Implantable Technology Daniel M. Doleys

o utli n e Background

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Psychological Test(s) and the Evaluation Process

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Brief Review of Psychological Variables

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How to Make What Works Work Better

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When are Psychological Factors Most Likely to Influence Outcomes?

Summary

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References

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Relevant Psychological Factors

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Shealy and his colleagues (Shealy et al., 1967) intro­ duced spinal cord stimulation (SCS) for the treat­ ment of chronic pain based on Melzack and Wall’s Gate Control Theory (Melzack and Wall, 1965). Shealy reportedly recommended emotional stability, no ele­ vations on the Minnesota Multiphasic Personality Inventory (MMPI: Keller and Butcher, 1991) except for the depression scale, and involvement with a rehab­ ilitation program, as selection criteria. Indeed, Long (1980) noted the psychological status of the patient to be the most common reason for the failure of stimula­ tion techniques. A number of studies since then have attempted to identify the relevant psychological fac­ tors and the most appropriate evaluation (see Doleys, 2006 for a review). Although a variety of psychologi­ cal variables have emerged, there is yet to be a con­ sensus as to which variables have the most reliable and predictable impact.

Only 20% of healing involves technology. Earl Bakken, founder Medtronic (personal communication, 2006) Pain cannot be reduced simply to neurophysiology or phar­ macogenomics. Pain is at the other end, the whole human being. It is a conscious experience that emerges from our very complex brains. People suffer in complicated ways. C. Richard Chapman, 2005

Background Neuromodulation in the form of electrical stimula­ tion of the brain for intractable pain was reported in the 1950s (Leone, 2006). The potential for psychologi­ cal variables to impact the outcome of neuromodula­ tion therapies was recognized as early as 1967 when

Neuromodulation

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© 2008, 2009 Elsevier Ltd.

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8.  psychological issues and evaluation for patients undergoing implantable technology

Although there is a general agreement that a psy­ chological evaluation should be undertaken, what it means to “clear” a patient psychologically for a trial or internalization remains somewhat ill-defined. A recent summary of the literature on intrathecal therapy (IT) for pain summarizing studies from 1990 to 2005 con­ cluded that a psychosocial evaluation should explore patient expectations, quality and “meaning” of the patient’s pain, presence of psychological disease, and barriers to patient and family compliance with the treatment (Raffaeli et al., 2006).

Brief review of psychological variables The following is a review of some of the stud­ ies that have examined psychological factors in neuromodulation. Most studies involved SCS ther­ apy. A more detailed account can be found elsewhere (Doleys and Klapow, 1997; Doleys, 2000a, 2006). In 1981, Long et al. reported a 33% success rate in “unscreened” patients and a 70% rate in “screened” patients. Daniel et al. (1985) stated that “electrode placement can serve as the initial step in a treatment plan followed by psychotherapy (to address psy­ chological factors influencing pain)” (p. 776). North et al. (1996) found that certain psychological vari­ ables tended to be associated with pain relief dur­ ing the trial and post-implant, but not at a 3 month follow-up. Studies utilizing the MMPI have revealed a number of findings. Shealy (1975) felt that elevations of up to two standard deviations on scales 1 (hypochon­ driasis), 2 (depression), and 3 (hysteria) should not be considered as a contraindication for treatment. However, elevations in four or more of the ten MMPI clinical scales was thought to reflect a seriously dis­ turbed patient. Long et al. (1981) stated that elevations in scales 2 (depression) and 7 (anxiety) should not be considered as criteria for exclusion. High scores on scales 1 (hypochondriasis) and 2 (depression) have been associated with negative outcomes (Blumetti and Modesti, 1976; Brandwin and Newman, 1982). Patients with high scores on scales 1 (hypochondria­ sis) and 3 (hysteria) frequently have a successful trail and proceed to internalization, but scale 3 (hysteria) was correlated with diminished therapeutic effect at a 3 month follow-up (North et al., 1991). Contrary to conventional wisdom, Brandwin and Newman (1982) reported positive outcomes with patients demonstrating a “conversion V” profile wherein scales 1 (hypochondriasis) and 3 (hysteria) are elevated

relative to scale 2 (depression). Several others (Burchiel et al., 1996; North et al., 1996; Olson et al., 1998) also noted such patients tended to have a successful trial. Olson et al. (1998) reported that lower elevations on depression (scale 2) and mania (scale 9) were associ­ ated with a positive response to SCS. Doleys and Brown (2001) found that patients with mildly elevated scores on scales 1 (hypochondriasis), 2 (depression), 3 (hyste­ ria), 7 (anxiety), and 8 (schizophrenia) reported greater pain relief at 4 year follow-up compared to those with “normal” levels in a group of patients treated with intrathecal therapy (IT). While Meilman et al. (1989) failed to find a correlation between MMPI scores and outcomes, they did note the accuracy of prediction was greater than 71% in “simple mononeuropathies” versus 32% in the more complicated arachnoiditis. This finding suggests an interaction between the complexity of the physical pathology, psychological factors, and psycho­ logical test scores. Depression and anxiety or common psychologi­ cal co-morbidities are associated with pain and dis­ ability (Covington et al., 2005). Olson et al. (1998) found patients scores approximating 12/63 on the Beck Depression Inventory (BDI; Beck et al., 1988) to be successful while those with a score of 16/63 were not. He also reported that patients proceed­ ing to SCS trial had State Trait Anxiety Inventory scores (STAI; Spielberger et al., 1997) of 23/80 and 19/80, respectively, while those that did not pass the trial had scores of 25/80 and 21/80. Long et al. (1996) noted scores exceeding 37/80 on STAI in his population, and Doleys (2000a) 46/80 and higher. The higher STAI scores in these latter two popu­ lations appear to reflect a different and more dis­ tressed group of pain patients than those of Olsen et al. Higher scores on the Affective scale of the McGill Pain Questionnaire (MPQ; Melzack, 1975), 3.7 versus 1.9, tended to predict unsuccessful SCS trials (Olsen et al., 1998). Of interest is the reporting of a greater reduction in affective compared to sensory scores on the MPQ in patients successfully treated with IT ther­ apy (Winkelmuller and Winkelmuller, 1996). Block et al. (2003) have developed a somewhat com­ prehensive model for pre-surgical evaluation of patients in pain undergoing corrective spinal surgery. They have created an algorithm incorporating a variety of “risk factors.” These risk factors are assigned a value of 0, 1, or 2 based upon the strength of the association with sur­ gical outcomes in the literature and identified through a clinical interview and psychological testing. Scores are combined with the number of “adverse clinical features,” i.e. deception, personality disorder, medica­ tion seeking etc. and patients rated as having a “good,” “fair” or “poor” prognosis. This pre-surgical behavioral

I.  AN introduction to neuromodulation



When are psychological factors most likely to influence outcomes?

medicine evaluation (PBME) has only recently been applied to implantable therapies (Schocket et al., in press). It will be interesting to note its relative applica­ bility to implantable versus surgical therapies. Most of the studies reviewed above were con­ ducted on patients with chronic low back and/or extremity pain utilizing SCS or IT therapy. The role of psychological variables in other areas such angina (DeVries et al., 2006) and deep brain stimulation (DBS) for movement disorders (Yamada et al., 2006) has received some attention. One would expect that any disorder likely to be affected by “stress,” i.e. headache, angina, gastrointestinal and genitourinary dysfunc­ tion, would rely heavily on multidisciplinary assess­ ments and concomitant treatments. The next section reviews some of the work concerning movement dis­ orders, primarily deep brain stimulation (DBS) for Parkinson’s disease (PD). Stereotactic ablative neurosurgery was used in the 1960s for various neuropsychiatric conditions and movement disorders. After being abandoned in the 1970s because of the improvement in medication man­ agement for these disorders, it has returned to some prominence (Wichman and Delong, 2006). The relative success of DBS for Parkinson’s disease (PD) has also reawakened an interest in its application for obses­ sive–compulsive disorders (OCD), Tourette’s syn­ drome, depression and pain (Skidmore et al., 2006). Randomized controlled and sham controlled studies (Kupsch et al., 2006; Wojtecki et al., 2006) have docu­ mented the efficacy of DBS and that the effects can be “dose related,” i.e. 10 Hz versus 130 Hz versus no stim­ ulation. The treatment is not, however, without adverse effects or complications. These may include hardware, physiological and psychological/cognitive adverse effects or complications (Bergamasco and Lopiano, 2006; Paluzzi et al., 2006). Because of these adverse effects/complications, there has been a call for more stringent evidentiary standards (Prehn et al., 2006). Primary outcome measure(s) for DBS often involve a reduction in observable motor activity. Quality of life (QoL) studies have employed the Parkinson’s Disability Questionnaire (PDQ-36; Bushnell and Martin, 1999; Damian et al., 2000). Deuschi et al. (2006) reported improvement in mobility, ADLs (activities of daily living), emotional well-being, stigma, and bodily discomfort. Although positive changes have also been found in depression and anxiety, these occurred in the absence of any changes in “personality traits” or social adjustment (Houeto et al., 2006). Interestingly, in one study (Gronchi-Perrin et al., 2006), patients tended to overestimate their preoperative level of function­ ing, when asked to rate it retrospectively, compared to their responses on a pre-treatment questionnaire.

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Negative psychological sequelae have been noted despite positive changes in motor behavior. Schupbach et al. (2006) reported the absence of change in cognitive status but noted improvement in ADLs, 18–24 months post implant. In addition, social adjust­ ment failed to improve, highlighted by problems affecting patients’ perception of themselves and their body, marital situation, and professional life. Indeed, 71% (17/24) of couples had marital problems and only 56% (9/16) working preoperatively returned to work. Likewise, Castelli et al. (1999) noted a “small” improvement in mood as measured by the Beck Depression Inventory (BDI; Beck et al., 1988), OCD and paranoid personality traits, but worsening of thought disorders, with no change in suicidal idea­ tion, anxiety, and apathy scores. Some 20% (15/65) of patients reported a decline in cognitive function or an increase in depression and anxiety, while another 20% of patients reported improvement in mood and 12% in anxiety. These types of negative changes have also been documented in patients with cancer pain despite a decrease in pain (Cahana, 2002). The data would seem to emphasize not only the need for proper patient selection, but pre-trial preparation and postimplant follow-up as well. Even the best preparation cannot mimic the actual experience. Nonetheless, a multidisciplinary approach would seem to be advan­ tageous (Schupbach et al., 2006).

When are psychological factors most likely to influence outcomes? Table 8.1 illustrates the conditions under which psychological factors are most likely to exert more or less influence on outcomes. These areas include pain, etiology of target symptom, patient, practice, proce­ dure, and outcomes. The table outlines the various aspects of pain and pain therapies and shows the con­ ditions under which psychological factors are more or less likely to impact the outcome of therapy. Regarding pain, the influence of psycho/social factors may be related to the degree to which the “pain” can be shown to be well localized and spec­i­ fic versus generalized and nonspecific. For example, Wallis et al. (1997) selected patients to undergo radio­ frequency neurotomy (RF) of cervical facets on the basis of response to double-blinded placebo control injections of a local anesthetic. Furthermore, the “pain generator” had to be very specific and well localized. Psychological co-morbidities, as measured by the Symptom Checklist-90 (SCL-90; Derogatis, 1983),

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8.  psychological issues and evaluation for patients undergoing implantable technology

Table 8.1  Influence of psychological factors Probably less

Probably more

Pain

Specific; well localized

Generalized; multifactorial

Etiology

Well defined

Multifactorial

Patient

Psychologically “intact”; concordant symptoms; acceptance high

Axis I/II Dx; psychological symptoms disproportionate; dependent, deferring

Procedure

Free from medical system; non-interactive; no sensation

Dependent on medical system; patient interactive; detectable sensation

Practice

Multidisciplinary/ modality; psychological support; physician attitude

Single discipline; interventional; disease/ “pain generator” oriented

Outcomes

Functional, objective, QoL; functionally related (dose/response) i.e. spasticity

Perceptual; experiential

resolved when the pain dissipated after RF therapy and returned along with the pain. The authors concluded that, in this situation, psychological factors were sec­ ondary to the pain and played no role in its develop­ ment or maintenance. This observation, however, has not been replicated in other studies, especially those involving less specific and more generalized pain, such as low back pain (Sator-Katzenschlager et al., 2003; Doleys et al., 2006). It appears that the more gen­ eralized and nonspecific the “pain” or other symptom, i.e. headache, tremor etc., and the less responsive the symptom to a targeted treatment, the more likely it will be that psychosocial factors are involved. Likewise, the more specific and physiologic the etiology, such as in urinary disorders (Craggs and McFarlane, 1999) or spasticity from spinal cord damage, the less influential psych/social factors may be. Obviously, this is a “gen­ eral” rule and may vary from case to case. In some instances resolution or improvement in the primary symptom may result in exacerbation of other problems. Cahana (2002) observed increased depres­ sion and marital conflicts in cancer patients follow­ ing improvement in pain and cognitive functioning using IT. Likewise, Schupbach et al. (2006) reported worsening of relationships with family, spouses, and social-professional environment in PD patients ben­ efiting from DBS. Seemingly, some patients and their support systems adapt to certain circumstances and may not be prepared or able to cope with change, no matter how positive or desirable these changes may appear. This may be akin to the patient with low back pain who comes to prefer freedom from work and responsibilities. Patients thus motivated may be more

likely to have a “false-positive” trial. That is, the pain improves enough to warrant implantation but not enough for increased activity or return to work. The above observation raises the question as to what constitutes an appropriate trial and criteria for internalization. Pain relief, reduction in medication(s), improvement in function, and patient satisfac­ tion have been used individually or in combination (Follett and Doleys, 2002). Ultimately, of course, these cri­teria may have to be individualized. We have come to prefer a “functionally oriented” trial preceded by a reduction in opioid medications in those cases where increased function and medication reduction are treat­ ment goals for the patient (Doleys and Kraus, 2007). The mere presence of a negative mood state (depression or anxiety) or specific personality disor­ der does not imply that it is functionally related to the problem to be treated. Indeed, an underlying mood state or personality disorder may have been camou­ flaged by adaptive coping, i.e. highly structured life and job, only to be revealed when the patient’s life is altered by pain or disease. Deuschi et al. (2006), in fact, reported the absences of change in personality traits in PD patients successfully treated with DBS. Verdolin et al. (2007) found that the presence of post-traumatic stress disorder (PTSD) in Iraq and Afghanistan war veterans did not negatively impact the treatment of neuropathic pain secondary to war related injuries with SCS. In addition, there was no change in PTSD symptoms despite the improvement in pain. The emergence of pathological states, including schizophrenia and conversion disorder, has been reported following the introduction of neuromodula­ tion therapies (Zdanowicz et al., 1999; Loughrey and Nedeljkovic, 2002; Ferrante et al., 2004). Without a thor­ ough psychological evaluation, it is difficult to deter­ mine whether such psychological conditions somehow emerged as a result of neuromodulation therapy or “pre-existed” in some form and made manifest by changes in the targeted symptom. These types of nega­ tive or maladaptive outcomes may be observed in the minority of patients. However, in the absence of pre– post psychological testing, especially of the treatment “failures,” many such cases could be inadvertently assumed under the “lost to follow-up” or technical failure categories. The attitude and expectations of the physician may also impact outcomes (Graz et al., 2005). The evidence of this is no more apparent than in the remarkable out­ comes from various “sham” surgeries (Flum, 2006). The involvement of different practitioners in patient selection, pre-implant trial, and post-implant management reduces the opportunity to take full advantage of any positive “placebo” effect. Patient satisfaction is determined in

I.  AN introduction to neuromodulation



Relevant psychological factors

part by the perceived interest and participation of the “attending” physician (Yamshita et al., 2006). The more dependent, obsessive, and suggestible the patient, the greater effect expectations are likely to have. Others may be more influenced by information on the Internet, patient testimonials, or information in the public media. The degree to which the patient, support persons, physician and his/her practice adopt a multifactor­ ial and multidisciplinary approach to the problem and therapy, can mitigate the effects of psychologi­ cal factors (Schupbach et al., 2006). As pointed out by Doleys (2002), psychological assessments/interven­ tions can and may need to be carried out during pretreatment patient selection/preparation, pre-implant trialing, and post implant management. The emphasis on “prognostication” has diverted our attention away from identifying therapeutic algorithms that consider a detailed description of the patient and disease vari­ ables which may need to be addressed post implan­ tation to obtain the maximum treatment effect and minimize “relapse” (Turk and Rudy, 1991). We should also be aware of the potential additive and synergistic effects of psychological and medical interventions (Holroyd et al., 2001; Molloy et al., 2006). This is particularly true in the area of “pain,” wherein the search for the “pain generator” can result in over­ looking crucial psycho-social factors that could impact long-term outcomes. This philosophy may or may not be responsible for the reported loss of clinical efficacy 18–24 months post implantation of SCS for pain (see Doleys, 2006). Two final considerations of importance are those of the procedure carried out and outcome measure(s) selected. Some treatments result in a perceptible par­ esthesia, i.e. SCS, others do not (DBS for PD). The abil­ ity of the patient to tolerate these sensations or other treatment adverse effects, such as opioid-induced con­ stipation, long term is likely to vary. Those who tend toward somatic preoccupation and/or emotional reac­ tivity may be most vulnerable and more likely to yield a “false-positive” trial (North et al., 1996). Over time the paresthesiae, especially if combined with posi­ tional sensitivity, may become more annoying then the baseline problem. Although the response to transcutaneous electrical nerve stimulation (TENS) does not necessarily corre­ late with SCS outcomes, we have found the procedure useful. When TENS is applied for a month prior to the SCS trial, we have identified patients who could not tolerate the stimulation over time. This seems to be particularly true for those with high scores on meas­ ures of somatic preoccupation, hysteria, obsessive– compulsive tendencies, irritability, and/or anxiety upon psychological testing. In addition, though some

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therapies such as SCS are favored because they may “free” the patient from the medical system, regular intermittent office visits could provide an opportun­ ity to assess for the absence of desirable concomitant changes, i.e. medication reduction, increased func­ tion, and the introduction of appropriate treatments. This more comprehensive approach imparts greater responsibility to the patients rather then success or failure being determined solely by the implant. It is much like reinforcing the importance of diet, weight control and exercise to the diabetic or hypertensive patient as opposed to an over-reliance on medication. The significance of the outcome measure(s) chosen has been demonstrated by Doleys et al. (2006). They reported on disease-specific and generic outcomes in a retrospective study comparing intrathecal therapy (IT), behavioral-functional restoration, and oral opioids in chronic low back pain patients. The treatment judged to be the most effective after four years was determined in large part by the particular outcome emphasized, i.e. pain, mood, function, satisfaction, opioid level, etc. A consensus panel (Turk et al., 2003) suggested using patient-reported outcomes (PROs), clinician-reported outcomes (CROs), and “third party” outcome, i.e. medical utilization, as sources to evaluate clinical pain trials. The desirable domains included pain, physical/ emotional functioning, participant ratings of improve­ ment/satisfaction, symptoms and adverse events, and participant disposition. Deyo et al. (1998) have recom­ mended assessing pain, mood, function, and personal­ ity pre and post intervention in treatments for painful disorders. Obviously, the more subjective, perceptual and experiential the outcome measure, i.e. “pain” (Price, 1999), satisfaction, mood etc., the more influen­ tial psychosocial variables are likely to be.

Relevant psychological factors Evaluating the role of psychological factors can be complicated. First, their presence or absence needs to be identified. The majority of patients are likely to show one or more indicators of psychological distress, i.e. anxiety, depression, emotional reactivity, somatic preoccupation. Some of these will be preexisting and perhaps causally related (Rome and Rome, 2000), others will be a consequence of the disorder. Second, it is difficult but necessary to establish a functional rela­ tionship between the target symptom(s) and existing psychological state(s) whenever possible. Not all psy­ chological tests have equal sensitivity or specificity in their ability to identify psychopathology (Doleys and

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8.  psychological issues and evaluation for patients undergoing implantable technology

Doherty, 2000). Furthermore, there appears to be an association between the complexity of the disorder and the magnitude of psychological factors. Dworkin et al. (1990), for example, noted the more widespread the pain the greater the degree of psychological dis­ tress. Third, psychological factors may be mediators, modulators or maintainers of symptoms (Doleys, 2000b). As noted above, when the pain was very speci­ fic, psychological states tended to be a consequence and not a cause of the pain. Early histories of physical and/or sexual abuse and victimization have been found to be relevant in pain­ ful disorders (Schofferman et al., 1992; McMahon et al., 1997; Rome and Rome, 2000). However, their influence is not always apparent during “acute” procedures or brief trialing periods but can make the “pain” more recalcitrant to long term change. Mood disorders such as depression and anxiety are among the most commonly cited psychologi­ cal co-morbidities associated with disabling medical conditions and illnesses. (Covington et al., 2005). These are particularly relevant to “pain” disorders given the complexity of “pain processing,” which includes sen­ sory/discriminative, affective/motivational, and cog­ nitive/evaluative mechanisms (Melzack and Casey, 1968). Use of a single numerical pain rating (NPR) on a 0–10 scale may obscure the differences between “pain intensity” and “pain unpleasantness” (Price, 1999). Numerical ratings of pain tend to be associated with the sensory component, i.e. its severity or perceived intensity. Unpleasantness focuses more on the patients “affective” response to the pain. That is, how much does the pain “bother him/her.” Most of us can prob­ ably recall patients reporting that a particular treatment did not change the pain intensity very much but made it such that the pain was “less bothersome” and easier to cope with. Personality disturbances (PerD; elaborated below) have been relatively overlooked. These patients, espe­ cially those with a borderline personality disorder, may pose significant management problems. Patients with more somatic or histrionic personalities often need frequent reassurance and monitoring. The abuse of alcohol and/or illicit drugs can undermine an oth­ erwise successful trial and implant. In such cases the primary symptom may be the “excuse” for substance abuse. The potential impact of family and social sup­ port cannot be underestimated. Symptoms may serve to modulate marital/family discord. In some cases the “medical system” becomes the convenient scapegoat for misdirected hostility. Patient and family expecta­ tions clearly contribute to long-term outcomes. All too often, significant others are not intimately involved

in the evaluation and therapeutic process, yet they can exert significant positive or negative influence by being overly solicitous or non-reinforcing of desirable behavior (Flor et al., 1995). The correlation between patient expectations and outcomes is a main factor in determining patient sat­ isfaction (Yamashita et al., 2006). For this reason, it may behoove the physician to be conservative and encourage expectations which can be supported by the evidence-based literature rather than personal experience or treatment “outliers.” The patient’s goals and motivation are obviously crucial but not always easily quantified. This of course relates to quality of life (QoL) measures. Patient and physician goals may not be in concert and should, as much as possible, become part of the pre-implant trial discussion. For example, if a goal is to be independent in activities of daily living (ADLs), or able to shop for two hours, or sit through a religious service or dinner, these can be directly assessed in a functionally oriented trial.

Psychological test(s) and the evaluation process There is a plethora of psychological tests and assess­ ment tools/questionnaires (Doleys and Doherty, 2000). Some are general measures of personality (MMPI) and others assess general psychological status (SCL90). There are specific measures of mood such as the Beck Depression Inventory (BDI, Beck et al., 1988) and State–Trait Anxiety scales (Spielberger et al., 1997). Those patients exhibiting high levels of depression or anxiety might benefit from cognitive behavioral ther­ apy, relaxation or other stress management treatments pre-trial. A certain amount of anxiety or depression is to be expected and should be considered as nor­ mal. Some tests can evaluate perceived “readiness for change” (Kerns and Habib, 2004) and level of chronic pain acceptance (McCracken et al., 2004). There are any number of “disease-specific” ques­ tionnaires such as the Seattle Angina Questionnaire (SAQ, Spertus et al., 1995), Migraine Disability Assess­ ment (MIDAS, Stewart et al., 2001), Parkinson’s Disease Questionnaire (PDQ-39, Bushnell and Martin, 1999), and Fecal Incontinence Quality of Life Scale (FILC, Rockwood et al., 2000). The Oswestry Disability Index (ODI; Fairbank et al., 1980) and Roland Morris (Roland and Morris, 1983) are common measures of perceived function/disability The SF-36 assesses a variety of domains relating to physical and psycho­ logical well-being (Ware et al., 1993). This assessment

I.  AN introduction to neuromodulation



Psychological test(s) and the evaluation process

tool has been widely used both pre and post treatment but may not be as sensitive or specific as first thought (Baron et al., 2006). It is important to remember that many of these scales are self-administered and rep­ resent the patient’s perception, which may or may not reflect reality. Indeed, Gronchi-Perrin et al. (2006) noted a discrepancy when PD patients were asked to rate their pre-DBS therapy functional status following treatment. Obtaining information on psychological and functional status prior to implantation can pro­ vide a baseline against which to evaluate outcomes. Patients manifesting manipulative or strongly mal­ adaptive personality disorders should be approached with caution. Personality disorders (PerD) make up a large part of the Axis II diagnoses in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) (1994) scheme and are marked by “behav­ ior that deviates markedly from the expectations of the individual’s culture” (p. 287) and leads to distress and impairment. (Diagnostic Criteria from DSM-IVTR; 2005). A personality “trait” represents a pattern of perceiving, or relating, to one’s environment and presents as less pathological compared to PerDs. The incidence of PerDs in chronic pain populations has been estimated to be as high as 50% (Fishbain et al., 1986; Polatin et al., 1993). The PerDs have been con­ veniently ordered into three clusters. Cluster A, i.e. Paranoid, Schizotypal, are characterized by individu­ als with odd or eccentric behavior. Cluster B include the more dramatic, emotional and manipulative per­ sonality disorders such as borderline, histrionic, nar­ cissistic and antisocial PerD. The anxious, fearful and depressive PerD, i.e. dependent, avoidant and obsessive–compulsive, make up cluster C. The cluster A patients (Paranoid, Schizotypal, char­ acterized by individuals with odd or eccentric behav­ ior) are prone to unusual somatic experiences. They may perceive the hardware or stimulation as produc­ ing psychological or somatic distortions. In extreme cases, there may be associated hallucinations or somatic delusions. Cluster B type patients (dramatic, emotional and manipulative personality disorders such as borderline, histrionic, narcissistic, and anti­ social PerD) often present as the greatest management problem. They tend to be noncompliant, challenging of authority, and demanding. They may have “hidden agendas.” Cluster C patients (the anxious, fearful and depressive PerD, i.e. dependent, avoidant and obsessive–compulsive) are likely to benefit from behavioral therapies to address their fears, anxieties, and depression; any of which can influence their per­ ception of pain and degree of disability. In our experi­ ence, they are more likely to have a better short-term

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versus long-term result and pose a risk of a “falsepositive trial” – that is, they have good response to the trial but report decreased effect over time. A significant percentage of patients will report the negative impact of psychological stresses on the pain or primary symptom. While this technically defines a somatoform disorder, it does not necessarily exclude the patient as an appropriate candidate for neuromod­ ulation therapies. The greater concern is those patients who meet the DSM-IV-R (1994) criteria for somatiza­ tion disorder, indicating a life-long pattern likely to be unaltered by an intervention. Psychological tests and questionnaires should be administered and interpreted in the context of structured clinical interview. Whenever possible, the interview should include a significant-other as their interpretation of treatment effectiveness does not always match that of the patient (Willis and Doleys, 1999). The patient’s goal and expectations, current means of coping with their problem, level of readi­ ness for change and degree of acceptance of the reali­ ties of their situation can be measured informally via the interview. The evaluation should be conducted prior to the final determination being made regarding a temporary trial. Ideally, agreed-upon therapeutic goals can be addressed during the trial and used as a means to determine the desirability of proceeding to implantation. Logically, the more closely the trial cir­ cumstances mimic the final outcome the less chance there is of a “false-positive” trial. Allowing the patient to examine samples of the neuromodulation device to be utilized and viewing of audiovisual materials may help to elicit questions and allay patient anxiety. Patients should be instructed that there may be a “hierarchy” of symptom improve­ ment. For example, improved functioning and QoL does not always accompany a reduction in pain but may need to be addressed as separately targeted problems. Similarly, the author has recently encoun­ tered several patients with sacral stimulators wherein improvement in bladder functioning preceded sig­ nificant reduction in “pelvic pain.” The information presented to the patient, level of understanding and comprehension of the patient and significant-other, degree of discussion/agreement and the acknowl­ edgement of awareness of complications and adverse effects should be documented in the chart note. The ill-prepared or uncertain patient and significant-other may benefit from additional education/orientation therapy sessions. There are a variety of “pain” measures ranging from a single numerical pain rating (NPR) to a more comprehensive assessment of qualitative, quantitative,

I.  AN introduction to neuromodulation

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8.  psychological issues and evaluation for patients undergoing implantable technology

suffering, affective, and pain unpleasantness. Appreciating “pain” as an experiential, multifac­ torial symptom whose components (sensory, affec­ tive, cognitive) interact in a dynamic fashion, at times rendering pain intensity and pain unpleasantness (affect) somewhat independent but related aspects, should influence the assessment. Instruments empha­ sizing this multidimensionality, i.e. McGill Pain Questionnaire (MPQ), approach should be favored. Upon reviewing the literature regarding psycho­ logical testing in SCS therapy, Doleys et al. (2001) were unable to identify any one or group of psychological tests or profiles that reliably predicted SCS outcomes. However, the grouping of patients based on diseaserelated variables such as pain, as opposed to psycho­ logical variables, may have obscured the influence of certain psychological factors/profiles (Doleys, 2003). The proposed “positive” and “negative” (Nelson et al., 1996; Doleys, 2003) psychological variables remain hypothetical, albeit theory-driven. There is some evidence that a “normal” psychological pro­ file may not predict a good outcome, at least as it relates to pain reduction (Doleys and Brown, 2001). It is important for the patient’s complaints, whether physical or psychological, to match the findings from examination and testing. Although there has been a tendency to derive some type of cutoff score for “predicting” outcomes, the development of a thera­ peutic algorithm considering the complexity of the targeted problem, psychosocial variables and pos­ sible need for adjunctive therapies during the trial and post implant would seem more in keeping with existing data. Consistent with the recommendations of Deyo et al. (1998) regarding the assessment of pain, the author has relied upon the MPQ, BDI, MMPI, ODI, and clinical interview for pain-related therapies as measures of pain, mood, personality and function, respectively. The total patient/family time required for the evaluation approximates 3–4 hours at a cost of about $500 dollars US or less depending upon insur­ ance coverage. One or more additional preparation/ educational sessions (Doleys, 2002) may be involved. Modification of this protocol would be required for disorders wherein the primary symptom is other than pain, i.e. bladder function, dystonia, etc. Each clinician is likely to have his/her favorite tests. For the field to move forward there needs to be some standardization of the process, if not the particu­ lars. The following are “process” suggestions: 1. Well known and validated tests should be used 2. Ideally, the test(s) should have validity scale(s), or some mechanism for detecting dissimilation

3. Tests should be used in the context of an overall evaluation including clinical interview 4. The assessment should be done by a knowledgeable and experienced, preferably doctoral level, provider 5. The evaluator should have contact with the patient, or at least the outcome data, from the preimplant trial and follow-up so as to determine the correlation between the evaluation and outcome 6. “Screening” tests should be re-administered on follow-up 7. Both disease-specific and generic measures should be obtained.

How to make what works work better There can be little doubt that neuromodulation is effective in the treatment of a number of disorders. The issue in part is how to maximize this effect of the therapy. “Relapse” rates are not always reported but there is a well-documented loss of benefit with time, especially in the area of chronic pain (Cameron, 2004; Mailis-Gagnon et al., 2004; May et al., 2005; Taylor et al., 2005). The addition of a psychological evalua­ tion and therapies may help to identify the presence of co-existing psychological disorders and reduce their negative impact on outcomes. For example, operant/ behavioral therapies have proven effective in a number of areas; cognitive behavior therapy with depression (Dodson, 1989), biofeedback with anal-rectal dysfunc­ tion (Byrne et al., 2007), relaxation techniques with headache (Holroyd et al., 2001), stress management with angina (van Dixhoom and White, 2005), and oper­ ant shaping of successive approximations and reinforce­ ment in function rehabilitation with neuromuscular, musculoskeletal, and “pain” disorders (Fordyce, 1976), to name a few. A recent study by Molloy et al. (2006) demonstrated that the combination of cognitive behav­ ioral/rehabilitation therapy before or after SCS or IT implantation resulted in increased improvement in affect distress, disability, self-efficacy and catastro­ phizing. Pain intensity, however, was not influenced. Indeed, Earl Bakken, the founder of Medtronic, Inc. (Minneapolis, Minnesota, USA) and holder of numer­ ous medical technology patents, advocates a holis­ tic approach in his “10 Points Related to Putting the Body Back Together” (personal communication). This approach includes “mind related medicine,” address­ ing relationships, stress, caring, compassion, attitude, belief(s) etc., and the role of “energy medicine,” e.g. guided imagery, massage, prayer.

I.  AN introduction to neuromodulation

Summary

Summary The breadth and depth of neuromodulation as an acceptable medical treatment has expanded expo­ nentially. Advancements in medical treatments can take place in a least three areas: science, technology, and clinical application. Ideally, but not always, these areas should build on one another. Often, improved technology can enhance scientific discovery through clarification of processes and mechanisms. Initially, clinical application is hypothesis-driven based on sci­ entific principles, i.e. mechanism of nociceptive versus neuropathic pain, concordant paresthesiae, action of different pharmacological agents etc. However, with time and familiarity, clinical application can become a “trial-and-error” process. The availability of multi­ ple outlets for “scientific” reports can dilute scientific rigor in favor of information dissemination. Once pub­ lished, particularly if the p value is less than 0.05, the findings of scientific exploration are often heralded as evidentiary without critical comparison and scru­ tiny. This eventually begs the question of statistical versus clinical significance. In an effort to expand the treatment’s availability, other practitioners, some less technically skillful, are “trained” and incorporate the treatment into their clinical practice. The development of best practice guidelines is thus, unfortunately, built as much on clinical failures as successes and may or may not penetrate general practice, in part because of concerns over credentialing and/or limitation of access to the therapy. It is here that a preoccupation with the therapy and technology may betray sound sense in its application. A reliable change in the tar­ geted symptom may result in overlooking psychologi­ cal co-variants. Appreciating the social and economic context in which therapies are developed might be a justifiable argument for the establishment of a worldwide net­ work of “centers of excellence” from academic and private sectors for the purpose of collaborative, multi­ center, scientifically sound studies. These studies would then form the basis of treatment guidelines as well as encourage innovative exploration ensuring that ethical considerations (Ford and Henderson, 2006) are adhered to. The role of psychological factors in neuromodula­ tion is gaining increased attention. However, studies involving new technology/hardware, electrophysi­ ological properties and clinical applications still domi­ nate the literature. The reasons for this discrepancy are many and varied including: 1. Too few psychologists involved/ interested 2. The complexity of psycho/social issues

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3. The lack of “standardized” outcomes including psycho/social factors 4. A general lack of understanding/acceptance of the bio-psycho-social model as it relates to neuromodulation 5. Cost of psychological evaluation/treatment 6. Little to be gained financially by technology/ pharmaceutical companies 7. Negative psychosocial profile may impact on the “bottom line” of the implanting physician. Hopefully, as the area of neuromodulation con­ tinues to unfold, additional attention will be given to the role of psychological variables. This will be best achieved by implanting physicians recognizing the potential impact of these variables, technologi­ cal manufactures providing support for clinical/out­ comes research, and psychologists increasing their involvement.

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I.  AN introduction to neuromodulation

C H A P T E R

9

Deep Brain Stimulation: Ethical Issues in Clinical Practice and Neurosurgical Research Joseph J. Fins

o u t line Regulation: From Research to Therapy

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Informed Consent: Theoretical and Operational Issues In the Setting of Decisional Capacity In the Setting of Decisional Incapacity Neuroethics, Consent, and Exceptionalism

83 83 84 86

As an emerging therapy that also is the subject of active clinical investigation, deep brain stimulation (DBS) can be easily misunderstood. It can be lion­ ized because of powers it does not possess or feared because of speculative applications that remain in the realm of science fiction (Fins, 2002). Such dichotomous views of neuromodulation can distort ethical analysis, either by accelerating inappropriate dissemination or impeding necessary research. In this chapter we will consider the ethics of both clinical application and research in order to more carefully articulate a norma­ tive framework for neuromodulation (Fins, 2004a).

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Historical Determinants Neurosurgical Antecedents Psychosurgery

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References

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first must determine whether a procedure constitutes established therapy or remains investigational. Deter­ mining this distinction is critical lest the investigator or clinician inadvertently mislead a potential research participant or patient about the safety and efficacy of an intervention. The most extreme example of such misrepresenta­ tions has been called the “therapeutic misconception,” where research is misunderstood as being therapeutic (Applebaum et al., 2004). A therapeutic misconception can have its origins in the hopes and desperation of a patient eager for cure or in the manner within which consent is obtained for enrollment in a clinical trial. Usually, these misperceptions stem from both a com­ bination of hope and hype, which may or may not be intended on the part of the investigator. The therapeu­ tic misconception is more than a theoretical concern; empirical studies have demonstrated a high degree of its prevalence in clinical research, although it has yet to be studied in deep brain stimulation (Glannon, 2006).

Regulation: from research to therapy To apply the proper ethical frame against which to evaluate the risks and benefits of neuromodulation we

Neuromodulation

Conflicts of Interest: Disclosure and Justification

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© 2008, 2009 Elsevier Ltd.

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9.  Deep Brain Stimulation: Ethical Issues in Clinical Practice and Neurosurgical Research

To ensure that consent is representative of the actual state of affairs it is absolutely critical that those engaged in neuromodulation have a precise stereotaxy about where their work is located in time and space, its stage and location on the research to clinical con­ tinuum. A failure to be clear about these coordinates will confuse the articulation (and understanding) of risks and benefits. Whereas established therapies have demonstrated a requisite degree of safety and efficacy, both questions remain open for investigative interventions. Moreover, questions about safety and efficacy change as a trial evolves from initial stages into maturation. At the out­ set, when a device like DBS is being piloted, the oper­ ative question is one of safety. Although investigators may have a therapeutic hypothesis that lead to an ini­ tial trial, phase I trials are not primarily about demon­ strating effect. Instead they are about demonstrating safety or an acceptable degree of toxicity. In such phase I clinical trials, the goal is to deter­ mine safety parameters and ascertain the incidence and prevalence of adverse effects (AEs) ascribed to the device or intervention. AEs are categorized as minor or major depending upon criteria established in the clinical trial. Although the details of what con­ stitutes a minor or major AE will differ depending upon the circumstances, the distinction generally hinges on reversibility and severity. Because it is dif­ ficult to always know whether adverse occurrences may be causally related to the device or the trial, sens­ itivity in reporting events is more appropriate than specificity. This is especially true when trials are blinded and investigators are unaware of all the cir­ cumstances of a particular subject’s response or when there are multi-institutional data and patterns can only be discerned by pooling information from multi­ple sources. AEs or toxicity data must be reported to regulatory bodies such as the local Institutional Review Board (IRB), which is responsible for approval of protocols within the investigator’s institution, and to the Food and Drug Administration (FDA), which allows such research to proceed with an Investigational Device Exemption (IDE). The IDE process regulates devices that pose significant risk such as the deep brain stim­ ulator and supplement the statutory oversight of the IRB (Pritchard et al., 1999). To assess data in such circumstances and to assess the overall success of the trial as it progresses, the FDA and/or IRB may require the additional estab­ lishment of a disinterested Data Safety Monitoring Board (DSMB). A DSMB is composed of experts who can make such assessments and who do not have a

conflict of interest that might distort their analyses of the data. A DSMB can halt a trial if it is unsafe, or con­ versely if the results demonstrate a degree of success that makes additional recruitment of subjects unnec­ essary from a statistical standpoint. FDA procedures are required by law and seek to establish safety and efficacy for new devices as well as when devices approved for one indication are used for another purpose such as targeting a new ana­ tomic locale. An example of this would be the use of an approved deep brain stimulator for Parkinson’s disease and utilizing it for another disorder or the tar­ geting of it to different nuclei. These circumstances would not be therapeutic but rather investigational and would require a new IDE as well as review by an Institutional Review Board. Although this point may seem obvious to the reader, it bears emphasis. Some investigators may try to assert that the use of an established device is therapeutic in order to avoid the additional regula­ tory oversight of a new IDE process. Alternately, they may view borderline uses as therapeutic (Miller et al., 1998). In either case, clinical-investigators should seek IRB guidance to avoid the appearance of impropriety and potential conflicts of interest. Returning to the evolution of a clinical protocol, a successful phase I trial will show an acceptable degree of safety and a promising degree of efficacy. If we analogize to drug trials, a 5% response is considered enough to warrant the progression into subsequent stages geared at determining whether an intervention is efficacious. Phase II trials seek to demonstrate effi­ cacy and phase III, at least in the context of pharma­ cological studies, are meant to compare efficacy of the new intervention against established therapeutic ones. This later comparison can compare the overall benefit of the proposed therapy along dual axes of both intended and unintended (side) effects. A device is deemed therapeutic when its safety and efficacy have been demonstrated in prospec­ tive trials. The evidence for approval needs to be methodologically rigorous and ideally involve dou­ ble-blinded and randomized trials. Studies can be done following implantation of electrodes with sub­ jects and evaluators being blinded to whether or not stimulation is taking place. Such blinded studies have been conducted in the evaluation of DBS and are important because there is documented poten­ tial for a placebo effect, which can confound evi­ dence regarding efficacy. For example, it has been shown in Parkinson’s disease that motor performance improved when subjects believed they were being stim­ ulated, when in fact they were not (Pollo et al., 2002).

I.  AN INTRODUCTION TO NEUROMODULATION



Informed consent: theoretical and operational issues

It has also been shown that patient expectation plays a role in functional neurosurgery (Mercado et al., 2006). The demarcation line between research and ther­ apy changes from year to year given the dynamism of neuromodulation, and this, in part, explains why there is some confusion about discerning established therapy from the investigational. At time of writing DBS is recognized as therapeutic for the management of chronic pain (Gildenberg, 2006), the evaluation and management of epilepsy (Kopell and Rezai, 2000), and the treatment of Parkinson’s disease and other move­ ment disorders. The Food and Drug Administration approved use of the deep brain stimulator for refrac­ tory Parkinson’s disease and essential tremor in 1997 (Blank, 1999). Subsequent to approval DBS has been found effective in prospective, double-blind studies (Kumar et al., 1998; Deep-Brain Stimulation for Parkinson’s Disease Study Group, 2001). DBS also has an established diagnostic niche in intraoperative corti­ cal mapping prior to tumor resection and ablations for movement disorders, like the pallidotomy for move­ ment disorders. This technique was pioneered by the great neurosurgeon Wilder Penfield in the localiza­ tion of seizure foci in epilepsy prior to surgical resec­ tion of the causative areas (Penfield, 1977; Feindel, 1982, 1998). Investigative work in neuromodulation of the brain is on-going in a wide range of neuropsychiatric con­ ditions (Roth et al., 2001). Clinical investigators are conducting trials for use in obsessive–compulsive disorders which awaits FDA approval (Rapoport and Inoff-Germain, 1997; Greenberg et al., 2006), depres­ sion (Doughert and Rauch, 2007), and traumatic brain injury (Schiff et al., 2007). Ultimately, the boundary between experimental work and therapeutic deploy­ ment rests on FDA approval of the device and the consensus of the medical community that the putative treatment is effective and safe and that the intended beneficial outcome will appear without adverse longor short-term effects. Because late effects may occur after an intervention has been approved as therapy, regulatory bodies like the FDA also engage in post-marketing surveillance of adverse events or the tracking of unexpected com­ plications. Post-marketing surveillance is especially important when considering the safety of prosthetic devices, whose engineering might fail after success­ ful insertion and a clinically fruitful deployment. Moreover, in the context of the device, there may be in vivo material failures or complications related to the capacitance of batteries which may need to replaced at a shorter than expected interval.

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Informed consent: theoretical and operational issues In the Setting of Decisional Capacity It is a tenet of modern medical ethics that com­ petent patients and subjects have a right to selfdetermination (Schloendorff v Society of New York Hospital, 1914), that is, autonomous dominion over themselves and their bodies (Fins, 2001). Legally competent patients or subjects are those who possess decision-making capacity and who have reached the age of majority (or depending upon local jurisdic­ tion are emancipated minors). Individuals with deci­ sion-making capacity have the ability to understand risks and benefits and utilize a “rational standard” when considering their options (Zaubler et al., 1996). Assessment of this capacity, and its implications for consent, should involve an interdisciplinary team including psychiatrists, psychologists and ethicists (Nuttin et al., 2002, 2003; Fins, Rezai et al., 2006; Ford and Kubu, 2006; Kubu and Ford, 2007). The ability to make such choices depends, in great part, upon the quality of information that is shared with the patient or subject through the process of informed consent. This process can be undermined if there is a fundamental misconstrual of whether the process pertains to therapy or research. It could well be asserted that distinguishing research from therapy is most critical in the context of informed consent (Applebaum and Lidz, 2006). An unproven interven­ tion, by definition, is ethically more disproportionate than an established therapy. By that, I mean that the ratio of real and potential risks relative to the bene­ fits is greater. If an investigative intervention is mis­ understood as being therapeutic it influences how these relative risks and benefits are understood, both dimensions of the informed consent process. The ethical concept of equipoise is another way of understanding this relationship of risks and benefits as they relate to the question of research versus ther­ apy. Equipoise, or standing between two positions, is generally defined as the investigator’s uncertainty about a scientific hypothesis regarding the efficacy of a proposed therapy (Freedman, 1987). It is that uncertainty, in the face of a credible hypothesis, that defines the work as investigational. Once data resolve the uncertainty, equipoise is lost and the on-going viability of the therapeutic speculation is either con­ firmed or denied. If the former occurs, the trial tends towards the therapeutic, e.g. advances towards mat­ uration. If the latter occurs, it may be halted at an early stage.

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9.  Deep Brain Stimulation: Ethical Issues in Clinical Practice and Neurosurgical Research

Investigators and clinicians should use these heur­ istics to determine whether a proposed intervention constitutes established therapy or research and explic­ itly clarify this issue with the patient or research par­ ticipant. If the consent addresses research, then the investigator must be clear that direct medical benefit cannot be promised in early phase I trials. In that case, the expectation for a “successful” trial will be that others will benefit from knowledge gleaned from the subject’s participation. Later stages may offer a proba­ bilistically greater chance of benefit, although not one equivalent to a vetted therapy. Following this contextualization, specific risks and benefits need to be addressed. Success rates for estab­ lished therapies should be shared with patients. It is important to unambiguously communicate bene­ fits (when they are known) (Kim, 2006) and provide appropriate reassurance, in the case of DBS, about the capability of stereotactic techniques, coupled with neuroimaging, to precisely target specific brain sites or nuclei. This means that the insertion of electrodes can be done without damage to adjacent tissue. In order to foster transparency, and keep patients fully informed, data should also be supplied about how local outcomes compare with national ones. This point bears special emphasis because there may be more significant regional variation in functional and stereotactic neurosurgery than other areas of neuro­ surgical practice because it is a new area of surgical expertise and without its own sub-specialty board. This makes it especially critical to define outcomes and establish criteria about what constitutes a DBS failure (Hariz, 2005). Beyond questions of relative operative compe­ tence, complication rates should also be shared related to hemorrhage; infection; seizures and hardwarerelated malfunctions that might necessitate revision or removal of the device. Informed consent discussions should also address psychiatric and neuropsychiatric adverse events that may be associated with DBS. Metaanalyses of published data suggest very low rates of adverse effects such as affective changes (depression (2–4%), mania (0.9–1.7%), emotional changes (0.1– 0.2%), and suicidal ideation or attempt (0.3–0.7%) with a completion rate of 0.16–0.32% (Appleby et al., 2007). Some of these complications may be mitigated by the putative reversibility of DBS via the removal of electrodes or the deactivation of devices. This point also needs to be part of the informed consent discussion. Unlike ablative surgery that results in irreversible dam­ age of brain tissue from the intentional destruction of targeted areas, it is important to note that the effects of DBS are generally felt to be reversible. Most believe that stimulators can be turned off and electrodes removed

without sequelae in most circumstances, although some emerging data suggest that DBS may induce changes in gene expression (Shirvalkar et al., 2006). Alternative therapies should also be discussed in order to assure that patients are aware of other options that might exist to address their problem. Provision of this additional information, for example, discussion of remaining pharmacologic agents for Parkinson’s dis­ ease, helps to maintain the patient’s ability to make an informed choice about DBS. Trust is instilled in the doctor–patient relationship by sharing information about a less invasive modality that might yet be suc­ cessful with less morbidity. Perhaps, most critically, the sharing of such infor­ mation demonstrates a willingness to allow the patient to freely choose their course of therapy. If a patient felt that the only alternative was agreeing to the insertion of a deep brain stimulator he or she would feel con­ strained in the choices available to them. Desperation may lead a patient to consent to any treatment that offers the possibility of symptomatic relief. Providing information about alternatives helps to foster volun­ tary choice, in line with the important ethical concept of voluntariness. Voluntariness comes out of the Nuremberg Trial and the subsequent Nuremberg Code of 1947 which addressed human subjects research in the wake of the abuses by Nazi doctors during the Holocaust (Trials of War Criminals, 1949). Respect for voluntariness requires that the informed consent process provides the requisite knowledge of risks and benefits while protecting the right to refuse participation. It has long been my view that the doctrine of informed consent is only tested when a patient or subject decides counter to the recommendation of a doctor or investigator. It is only in such circumstances that the power structure is challenged, true voluntariness is expressed, and patient self-determination sustained. Such refusals may also occur after consent has been given; a competent patient retains the right to with­ draw him- or herself from treatment. The standard for such withdrawals should be high when there are con­ comitant risks, such as the interruption of an operative procedure or the premature removal of a device. One commentator has suggested a standard of “informed revocation of consent” under which the individual fully understands the risks and benefits associated with a change of heart (Ford, 2007).

In the Setting of Decisional Incapacity Individuals with severe psychiatric illness or head trauma, who may be treated with DBS or enrolled in

I.  AN INTRODUCTION TO NEUROMODULATION



Informed consent: theoretical and operational issues

related research, may be at risk for decisional incapac­ ity. When these individuals are unable to engage in the informed consent process, they are considered a vul­ nerable population and in need of special protections because they are unable to autonomously defend their interests. Authorization for treatment or research in the setting of decisional incapacity poses special chal­ lenges because surrogate decision-makers are called upon to make choices for patients or subjects who are no longer able to represent their own interests. Surrogates are generally asked to make decisions based on hierarchical standards of decision-making (Sachs and Siegler, 1991). If they are known, surro­ gates should be directed by the expressed wishes of the now-incapacitated individual. Absent that, surro­ gates should invoke substituted judgment, what they believe the patient would decide if they were able to communicate. If prior wishes, or inferential know­ ledge are not available, then surrogates are meant to invoke what is called a best interests standard, what a “generic” person would decide if confronted with the question requiring a decision. As precise as these cat­ egories appear, surrogates never can know the prefer­ ences of the incapacitated individual with certainty, and thus inevitably bring an element of discretion and judgment when authorizing treatment or enrolling a subject in research (Fins et al., 2005). These surrogate judgment calls are ethically less complex when the question at hand involves a deci­ sion to pursue an established therapy. As we have seen, therapeutic interventions, by definition, have a favorable risk–benefit profile. Because of this, surro­ gates may legally authorize treatment given the ethical proportionality of therapy. It is a normative decision; when given a choice, most capacitated patients would choose to receive an established therapy to ameliorate illness. It is quite another matter when the question is whether to enroll a decisionally incapacitated indi­ vidual in a clinical trial. While surrogates are gener­ ally allowed to consent to therapeutic procedures, their authority is more constrained when permission is sought for enrollment for research, unless they have been authorized prospectively with an advance directive for research. Beyond that unlikely occur­ rence (only a minority of Americans have an advance directive that would direct medical care in the event of incapacity), there remains debate within ethical and legal circles about how much authority can be vested in surrogate decision-makers when research involves the decisionally incapacitated. At the federal level, the National Bioethics Advisory Commission (NBAC), in its report “Research involv­ ing persons with Mental Disorders that may affect

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Decisionmaking Capacity,” proposed guidelines to regulate the conduct of research on individuals who are unable to provide consent (National Bioethics Advisory Commission, 1998). Although these recom­ mendations were never enacted into statutes or prom­ ulgated as regulations, they are worth considering in some detail because they delineate this problem space. NBAC recommended three regulatory categories: research presenting minimal risk; research present­ ing greater than minimal risk that offers the prospect of direct medical benefit to subjects; and research pre­ senting greater than minimal risk without offering the prospect of direct medical benefit. For research involv­ ing minimal risk, a legally authorized representative could consent to enrollment in research of a decision­ ally incapacitated subject with or without the sub­ ject’s “prospective authorization” for research. Legally authorized representatives could also authorize enroll­ ment in research with or without prospective authori­ zation when there was the prospect of direct medical benefit. Prospective authorization would be required for legally authorized representatives to provide authorization for protocols that involved greater than minimal risk without the prospect of direct medical benefit. When prospective authorization is not avail­ able such research could only go forward with the permission of the legally authorized representative and the additional regulatory approval of a Special Standing Panel (SSP) convened by the Secretary of Health and Human Services or possibly the local IRB pursuant operating under guidance from HHS. Although the NBAC recommendations were criti­ cized for their potential adverse impact on worthy research (Michels, 1999; Miller and Fins, 1999; Fins and Miller, 2000), they do point to the ethical com­ plexity of neuromodulation research when (i) subjects lack decision-making capacity, (ii) the research has yet to demonstrate the prospect of direct medical benefit, and (iii) it poses more than minimal risk, all charac­ teristics of phase I trials. To address the challenge of research with this population, I proposed a consensus model of authorization with my colleague Franklin G. Miller (Fins and Miller, 2000). For IRB approved trials, we suggested the need for agreement amongst the subject’s legally authorized representative (LAR), physician, clinical investigator and a lay volunteer subject advocate with pertinent experience. We argued that the achievement of consensus from such a quartet would lead to ethically sound deci­ sions for potentially vulnerable subjects who could be harmed by either inappropriate inclusion or exclusion from the research enterprise. Although all involved in research have a duty to protect the incapacitated

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9.  Deep Brain Stimulation: Ethical Issues in Clinical Practice and Neurosurgical Research

subject from harm, the principles of respect for per­ sons, beneficence and justice can also be invoked to assert a fiduciary obligation to design and execute well-considered, scientifically sound clinical trials for this historically marginalized population (Fins and Miller, 2000; Fins and Schiff, 2000; Fins, Giacino et al., 2006). This perspective, in support of surrogate con­ sent-based research, has been shown to be consistent with the views of some subjects at risk for decisional incapacity (Kim et al., 2005).

Neuroethics, Consent, and Exceptionalism A final issue that has bearing on informed consent is whether DBS is ethically different because the object of its effect is the brain. And, if a salient difference is demonstrated, its application or study should be mor­ ally proscribed. No other organ is so closely involved with concepts of mind and self than the brain. Earlier commentators have written of the folk belief that to interfere with the brain “surgically carries a peculiar penumbra of sacrilege” (Editorial, 1972). While it is true that DBS may alter cognition, mem­ ory or affect and thus alter one’s personality, this capa­ bility is not unique to neuromodulation of the brain. Conventional neurosurgery, psychoactive drugs, gen­ eral anesthesia and cognitive rehabilitation all have this capability, as does naturally occurring injury, dis­ ease or spontaneous recovery. This shared capability suggests that there should be no prima facie prohibi­ tion for DBS. Having made this argument, it would be a mistake to assume that DBS does not pose special challenges about discerning risks and benefits because the brain is the target organ. The work of my colleagues and I in a clinical trial seeking to use DBS as a potential agent of cognitive rehabilitation following traumatic brain injury (TBI) raised the question of whether fostering additional self-awareness is always an ethical good (Cohadon et al., 1985; Fins, 2000; Schiff et al., 2007). Partial cognitive recovery could theoretically lead to greater awareness of one’s impairment and lead to suf­ fering. Again, this theoretical possibility is not unique to the application of DBS to TBI. A similar phenom­ ena is seen in the incidence of substance abuse several years after the incident injury, suggesting that recov­ ery is sometimes accompanied by a degree of mourn­ ing and melancholia associated with the realization of what has been lost and what challenges remain (Jorge et al., 2005). This realization is shared by patients who progress spontaneously or who are helped in con­ ventional rehabilitation. Whatever the etiology, the proper ethical response is the timely identification

of distress and its proper treatment with appropriate counseling and psychopharmacologic agents, when indicated. Finally, should an intervention be ego-dystonic, the patient or surrogate may ask for device deactiva­ tion. Moreover, consistent with the design of our trial of thalamic stimulation in the minimally conscious state, protocol design should include the provision for longitudinal assessment of decision-making capacity to ensure that subjects who regain this capability can participate in decisions about the on-going risks and benefits of continued study enrollment (Schiff and Fins, 2007; Schiff et al., 2007; Schiff et al., in press).

Conflicts of interest: disclosure and justification Because neuromodulation of the brain is such a young discipline and still undergoing rapid techno­ logical change and innovation, there is a good chance that the use of this technology may involve some degree of conflict of interest between clinicians, clinicalinvestigators and industrial suppliers and/or sponsors. Conflicts of interest are not inherently wrong. In fact sometimes they are essential to complete research that otherwise may not be funded under current modes of governmental support and statutory means to engage in technology transfer, namely the Bayh–Dole Patent and Trademark Laws Amendment (Fins and Schachter, 2001) (35 U.S.C. §§ 200–12, 1994). Conflicts become problematic when they are not adequately disclosed during the informed consent process or in published papers. They also become problematic when economic motivations impede access to care or the responsible promotion of clinical research. It is my view that prac­ titioners and investigators have an affirmative obliga­ tion to work to promote improved access to care and responsibly manage any necessary conflicts of inter­ est in order to maintain patient and public trust. If a novel device can only be developed through an indus­ trial partnership it seems justified and investigators who work with industry should not be viewed preju­ dicially by their colleagues, journal editors, regulators or society at large. They should be lauded for their frank disclosure of a potential conflict. In contrast, it is a deviation from professional norms and expectations when personal gain is the primary motivation. The American Association of Academic Medical Centers (AAMC) has promulgated stringent guidelines to direct behavior when there are conflicts of interests in research. They suggest the need for investigators to

I.  AN INTRODUCTION TO NEUROMODULATION



Historical determinants

overcome what they describe as a “rebuttable presump­ tion” – investigators with financial conflicts of interest should not be allowed to conduct clinical trials until they overcome the presumption that they should not be involved in the research (AAMC Task Force, 2003). Although I am sympathetic to the AAMC’s intent, I would prefer to support a prospective doctrine of “disclose and justify” which does not presume an investiga­ tor’s ineligibility but rather assumes that researchers will act in good faith guided by the dual ethical princi­ ples of beneficence and justice (Fins, 2007). This is a more constructive stance that can allow neurosurgeons, engineers and scientists to leverage their expertise, on the patient’s behalf, when work­ ing with corporate sponsors. They can help ensure that the exclusivity granted by patents does not make products so prohibitively expensive and support efforts to direct a percentage of royalties to the care of the underserved who may need a neuroprosthetic device or the support of translational research. Such altruism will help maintain public trust and safeguard ethical propriety of innovators and of their corporate sponsors.

Historical determinants No discussion of the ethics of DBS would be com­ plete without addressing historical determinants that so shape public perception about this work. In this next section we will trace the history of electrical stim­ ulation of the brain from the latter part of the nine­ teenth century through to the twentieth and consider the contentious issues surrounding the psychosurgery debate. This history is complex and only a part of it can be told here. But it is a dimension of the work that needs to be understood in order to proceed responsi­ bly and responsively.

Neurosurgical Antecedents Despite the frequent focus of contemporary head­ lines, neuromodulation of the brain has its roots in the work of neurophysiologists and neuroanatomists in the latter half of the nineteenth century when, as in our own time, there was a fascination with the interac­ tion of electricity and the brain. During that time Broca localized speech in the left hemisphere and Hughlings Jackson formulated his hypothesis that generalized seizures, which now bear his name, resulted from aberrant electrical activity in the cortex (Penfield, 1972). Early neurophysiolo­ gists also engaged in animal experimentation using

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electrical stimulation of the brain (Zimmerman, 1982). In 1870, Eduard Hitzig and Gustav Fritsch demon­ strated motor activity in a dog following stimula­ tion and David Ferrier, in 1873, induced seizures in a dog following contralateral stimulation (Thomas and Young, 1993). The first reported case of electrical stimulation of the brain in a human being was performed in 1874 by Roberts Bartholow, a Cincinnati physician (Thomas and Young, 1993). In what today could only be described as an ethical breach in a highly vulnerable patient, Bartholow stimulated the brain of a patient laid bare by invasive basal cell carcinoma that had locally exposed brain. An historical account reported that the patient was dying and grateful for the care she had received from Dr Bartholow and agreed to be studied. Bartholow demonstrated the insensate nature of dura mater and reproduced the findings of Ferrier that motor activity could be elicited by stimulation of the contralateral hemisphere.1 But in demonstrat­ ing that he could induce seizures from electrical stimulation and unconsciousness, Bartholow caused the patient’s death from refractory seizure activity, an outcome that led to contemporary ethical critique from his colleagues who questioned the authenticity of her willingness to be studied and the distress that had been induced (Morgan, 1982). Bartholow’s study, disproportionate in its degree of danger and its lack of any intended patient benefit, was in stark contrast with the work of later practitioners who utilized elec­ trical stimulation of the brain to map cortical function under local anesthesia. The pioneering neurosurgeon Harvey Cushing used electrical stimulation to optimize tumor resec­ tions and minimize postoperative functional loss (Cushing, 1909). His student, Wilder Penfield, extended this approach to study epilepsy and plan resections of scar tissue causing seizure activity (Fins, 2008). A by-product of his therapeutic efforts was the description of the human homunculus (Penfield, 1977; Feindel, 1982). The development of stereotactic surgery in 1947 was a major advance that would be critical to the precise three-dimensional localization of nuclei in the brain and the insertion of electrodes without full craniotomy (Gildenberg, 1990; al-Rodhan and Kelly, 1992). 1

 Ever since the ethical breaches of the Holocaust (see above), schol­ ars have debated whether it is appropriate to cite studies that have serious ethical flaws and disregarded human subjects’ protections (see S.G. Post, The echo of Nuremberg: Nazi data and ethics. J. Med. Ethics 1991; 17 (1): 42–4). I believe this report of Bartholow’s work and observations – as reported by Thomas and Young (1993) – is justified because it is recounted so as to foster ethical practice and research.

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9.  Deep Brain Stimulation: Ethical Issues in Clinical Practice and Neurosurgical Research

Electrical stimulation of the brain has also been employed in the service of analgesia and anesthe­ sia. The first use of electrical stimulation of the brain for the control of chronic pain was demonstrated by Robert G. Heath in 1954, and in 1969 David Reynolds described the production of analgesia produced by stimulation of midbrain gray matter. Deep stimulation of other selected targets was demonstrated to relieve pain in the 1970s (Young, 1990). As has been recounted, the most important cur­ rent application of DBS has been in the treatment of movement disorders. The history of this work is more recent. Siegfried noted in 1985 that thalamic stimu­ lation for pain control could improve tremor in a patient with Parkinson’s disease (Gildenberg, 1998), although the modern era of neuromodulation began in 1987 when the French neurosurgeon Alim Benabid noted improvements of Parkinsonian tremor follow­ ing stimulation of the thalamus during brain mapping prior to ablative surgery (Speelman and Bosch, 1998). Benabid’s singular contribution was in translating basic science work and clinical observations into the development of the field of which this text is such an exemplar (Fins and Schachter, 2001).

Psychosurgery While these developments in localization, pain management and treatment of motor disorders were generally accepted without controversy, electrical stimulation of the brain was also being investigated for the treatment of psychiatric disorders.2 This was a far more contentious part of the story because the pro­ cedure was contextualized within the broader societal debate over psychosurgery in the 1960s and 1970s (Gaylin et al., 1975; Fins, 2003). This discordance is evident in the definition used by The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, which studied the question of psychosurgery and issued a report in 1977 (The National Commission, 1977). The Commission, established by an Act of Congress (The National Research Act, 1974), adopted a Cartesian view of both the brain and the ways it might 2

 For the purposes of this chapter, my discussion of psychosurgery is limited to electrical stimulation of the brain and work done in the 1960s and 1970s. I am not considering the ethics of ablative proce­ dures, which for the most part characterized the era of psychosur­ gery before the advent of neuroleptic drugs in the early 1950s. For a discussion of that period and the relevant ethical issues, the reader is advised to consult J.D. Pressman, Last Resort, Psychosurgery and the Limits of Medicine. New York: Cambridge University Press, 1998.

be electrically stimulated (Fins, 2004b). Although, the Commission opined that “psychosurgery includes the implantation of electrodes, destruction or direct stimulation of the brain by any means,” not all electri­ cal stimulation constituted psychosurgery. It was only included when its primary purpose was to “control, change, or affect any behavioral or emotional distur­ bance.” It excluded brain surgery for the treatment of somatic disorders such as Parkinson’s disease, epilepsy or pain management from the definition of psychosurgery. Commentators from that era worried about the psychiatric use of electrical stimulation, especially as they might be employed to assert social control and remediate turbulent times marked by crime and civic unrest. These concerns were prompted, in part, by the controversial work of the Spanish physiologist Jose M.R. Delgado who worked at Yale during that era. He advanced the idea of psychocivilizing society using an implantable brain implant that could be oper­ ated by remote control (Delgado and Anshen, 1969). Delgado gained international fame when he allegedly stopped a charging bull in a Cordoba bullring using a radio controlled electrode called a “stimoceiver” (Osmundsen, 1965). The possibility of controlling aggression was picked up in popular culture and exemplified by Michael Crichton’s Terminal Man, whose main character under­ went electrical stimulation of the brain to treat violent behavior (Crichton, 1977), and the notion of mind control remains a lingering leitmotif (Anon., 2002; Horgan, 2004). Lay reports describing a remotely controlled “cyborg” rat with a brain implant (Talwar et al., 2002) alluded to Delgado’s work (Boyce, 2002; Onion, 2002). This error of omission leads to the misrepresenta­ tion of the past and fosters a misuse of historical anal­ ogy which has the potential to distort current policy regarding the regulation of this novel technology (Fins, 2002). Such media accounts fail to paint a full picture of the modern psychosurgery era and rarely, if ever, mention the deliberations of the National Commission or other contemporaneous deliberative bodies. Although the Commission was predicted to con­ demn psychosurgery writ large and find evidence of social control, this was not the case. In a remark­ able rebuke to popular expectations, the Commission chose not to recommend an outright ban on psycho­ surgery. Instead, it concluded that there was enough demonstrated potential for some procedures in spe­ cifically selected subjects. This led the Commission to recommend continued experimentation so long

I.  AN INTRODUCTION TO NEUROMODULATION

references

as it was limited in scope, clearly distinguished from “accepted practice”, and accompanied by strict regu­ latory guidelines. Moreover, none of the National Commission, the American Psychiatric Association Task Force on Psychosurgery (Donnelly, 1978) or the Behavioral Control Research Group of the Hastings Institute (Blatte, 1974) (a bioethics think-tank study­ ing the issue) has concluded that psychosurgery had been used for social control, an instrument of political or racial repression. The importance of psychosurgery to public percep­ tion of neuromodulation cannot be overstated. The actions of our era will be understood against the real and mythic excesses of the psychosurgery period. For this reason, investigators and practitioners need to familiarize themselves with this history. A failure to do this will lead to avoidable errors of judgment while engagement of the past will promote responsible and responsive inquiry (Fins, Rezai et al., 2006).

Acknowledgments Dr Fins is the recipient of an Investigator Award in Health Policy Research (Minds Apart: Severe Brain Injury and Health Policy) from The Robert Wood Johnson Foundation. He also gratefully acknowledges grant support from the Charles A. Dana Foundation (Mending the Brain, Minding our Ethics II), the Buster Foundation (Neuroethics and Disorders of Consciousness), and the editorial assistance of Jennifer Hersh, MBE.

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Morgan, J.P. (1982) The first reported case of electrical stimulation of the human brain. J. Hist. Med. 37 (1): 51–64. National Bioethics Advisory Commission (1998) Research Involving Persons With Mental Disorders That May Affect Decisionmaking Capacity. Rockville, MD. Nuttin, B., Gybels, J., Cosyns, P., Gabriels, L., Meyerson, B., Andreewitch, S. et al. (2002, 2003) Deep brain stimulation for psychiatric disorders. Neurosurgery 51 (2): 519, Reprinted in: Neurosurg. Clin. North Am. 14 (2): xv–xvi. Onion, A. (2002) Rat robots, scientists develop remote-controlled rats. ABCnews.com, May 1. www.abcnews.go.com/sections/scitech/ DailyNews/rats020501.html (accessed 28 November 2007). Osmundsen, J.A. (1965) “Matador” with a radio stops wired bull: modified behavior in animals subject of brain study. New York Times, May 17. Penfield, W. (1972) The electrode, the brain and the mind. Z. Neurol. 201 (4): 297–309. Penfield, W. (1977) No Man Alone: A Neurosurgeon’s Life. Boston, MA: Little Brown. Pollo, A., Torre, E., Lopiano, L., Rizzone, M., Lanotte, M., Cavanna, A. et al. (2002) Expectation modulates the response to subthalamic nucleus stimulation in Parkinsonian patients. Neuroreport 13 (11): 1383–6. Pritchard, W.F., Abel, D.B. and Karanian, J.W. (1999) The US food and drug administration, investigational device exemptions and clinical investigation of cardiovascular devices: information for the investigator. J. Vasc. Interv. Radiol. 10 (2 Pt.1): 115–22. Rapoport, J.L. and Inoff-Germain, G. (1997) Medical and surgical treatment of obsessive–compulsive disorder. Neurol. Clin. 15 (2): 421–8. Reynolds, D.V. (1969) Surgery in the rat during electrical analgesia induced by focal brain stimulation. Science 164 (878): 444–5. Roth, R.M., Flashman, L.A., Saykin, A.J. and Roberts, D.W. (2001) Deep brain stimulation in neuropsychiatric disorders. Curr. Psychiatry Rep. 3: 366–72. Sachs, G.A. and Siegler, M. (1991) Guidelines for decision making when the patient is incompetent. J. Crit. Illness 6: 348–59. Schiff, N.D. and Fins, J.J. (2007) Deep brain stimulation and cogni­ tion: moving from animal to patient. Curr. Opin. Neurol. 20 (6): 638–42. Schiff, N.D., Giacino, J.T., Fins, J.J. (in press) Deep brain stimulation, neuroethics and the minimally conscious state: moving beyond proof of principle. Arch. Neurol. Schiff, N.D., Giacino, J.T., Kalmar, K., Victor, J.D., Baker, K., Gerber, M. et al. (2007) Behavioral improvements with thalamic stimulation after severe traumatic brain injury. Nature 448 (7153): 600–3. Shirvalkar, P., Seth, M., Schiff, N.D. and Herrera, D.G. (2006) Cognitive enhancement with central thalamic electrical stimula­ tion. Proc. Natl Acad. Sci. U S A 103 (45): 17007–12. Speelman, J.D. and Bosch, D.A. (1998) Resurgence of functional neurosurgery for Parkinson’s disease: a historical perspective. Mov. Disord. 13 (3): 582–8. Talwar, S.K., Xu, S., Hawley, E.S., Weiss, S.A., Moxon, K.A. and Chapin, J.K. (2002) Rat navigation guided by mind control. Nature 417 (6884): 37–8. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (1977) Use of psycho­ surgery in practice and research: report and recommendations of National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. Federal Register 42 (99 (May 23): 26318–32. Thomas, R.K. and Young, C.D. (1993) A note on the early history of electrical stimulation of the human brain. J. Gen Psychol. 120 (1): 73–81.

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S E C T I O N   II

Fundamentals of neuromodulation Introduction Narendra Bhadra, J. Thomas Mortimer, P. Hunter Peckham, and Elliot S. Krames Neuromodulation and neurostimulation therapies and interventions are built upon a foundation of an understanding of neural structures and the behavior of the neural circuits of the nervous system. As this understanding has increased, so have our capabilities to intervene with increasing efficiency and efficacy with neuromodulatory interventions. These interventions may be electronic, as many of the devices deployed today are, but they may also be pharmacologic or cellular in nature. The first four chapters in this section discuss the fundamental features of the nervous system that underlie our ability to deploy successful technologies: “Anatomy of the Nervous System”, by Joshua Rosenow, MD, of the Department of Neurosurgey, Northwestern University Feinberg School of Medicine; “Fundamentals of Electrical Stimulation” by J. Thomas Mortimer, PhD and Narendra Bhadra, MD, PhD, from the Neural Engineering Center, Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio; “Neuromodulation and Neuronal Plasticity” by Alon Y. Mogilner, MD, PhD, Section of Functional and Restorative Neurosurgery,

Neuromodulation

North Shore-LIJ Health System, Manhasset, New York; and “Gene-Based Neuromodulation” by Thais Federici, PhD, Jonathan Riley, BSE, and Nicholas Boulis, MD, of the Cleveland Clinic Department of Neurosciences and Center for Neurological Restoration, Cleveland, Ohio. These chapters are followed by a subsection on mechanisms (Section A). The term “mechanism” has many meanings. In biology a mechanism explains how a feature is created. In chemistry it explains a reaction pathway. In the context of this section on mechanisms we intend to mean its “mechanism of action” or the means by which a drug or device exerts its biologic effects. Although mechanisms will be discussed in other sections of this work, Section IIA is intended to give an overview of some of the problems when focusing on the effects of stimulation at the neural interface. In this section, Dr Warren Grill, PhD, Associate Professor of the Department of Biomedical Eng­ineering at Duke University, Durham, North Carolina, will discuss “Electrical Field Generation for Excitation and Inhibition,” Kendal Lee, MD, of the Department

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of Neurosurgery at the Mayo Clinic of Rochester, Minnesota, Charles Blaha, PhD, of the Department of Psychology at the University of Memphis, Memphis, Tennessee, and Jonathan Bledsoe, MD, of the Depart­ ment of Neurosurgery at the Mayo Clinic, Rochester, Minnesota, will review what is known regarding the mechanisms of action of deep brain stimulation (DBS), and Dr Cameron McIntyre, of the Cleveland Clinic, Cleveland, Ohio, will discuss the “Use of Computational Models in Neurostimulation.” Dr Grill in his chapter summarizes the quantitative principles describing the generation of potentials in the central nervous system by delivery of electrical stimulation and finds that potentials generated are dependent on the electrical properties of the tissue, which in the CNS are both inhomogeneous and anisotropic, and electrode geometry. In their chapter on mechanisms of DBS, Drs Lee, Blaha, and Bledsoe describe the evidence from the literature for five possible mechanisms of action/actions for DBS which include: (1) inactivation of action potential generation in efferent outputs (depolarization block), (2) activation of neuronal terminals that inhibit and/or excite efferent outputs (synaptic modulation), (3) depletion of neurotransmitter in

terminals of efferent outputs (synaptic depression), (4) anti-oscillatory action on basal ganglion circuitry (network jamming or modulation), and (5) sustained enhancement of neurotransmitter release (synaptic facilitation). Dr McIntyre discusses computational models for the action of stimulation in brain nuclei. Dr McIntyre states that “DBS is an effective clinical treatment for several medically refractory neurological disorders, however, the clinical successes of DBS are tempered by the limited understanding of the response of neurons to applied electric fields, and scientific definition of the therapeutic mechanisms of DBS remains elusive … In addition, it is presently unclear which electrode designs and stimulation parameters are optimal for maximum therapeutic benefit and minimal side effects. Detailed computer modeling of DBS has recently emerged as a powerful technique to enhance our understanding of the effects of DBS and to create a virtual testing ground for new stimulation paradigms.” Dr McIntyre’s chapter summarizes the fundamentals of neurostimulation modeling, presents some scientific contributions of computer models to the field of DBS, and demonstrates the application of DBS modeling tools to augment the clinical utility of DBS.

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C H A P T E R

10

Anatomy of the Nervous System Joshua M. Rosenow

o u t l i ne Gross Structures Brain Spinal Cord Autonomic Nervous System

95 95 98 98

Sensory System Pyramidal Motor System References

Gross structures

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The parietal lobe serves both primary and complex sensory functions (graphesthesia) as well as corti­ cal regions for speech comprehension (Wernicke’s area) and association. The occipital lobes are prim­ arily involved in vision, containing both the primary and secondary visual regions. The hemispheres are connected by the fibers of the corpus callosum (see Figure 10.1). The primary motor and sensory cortices are organized in a homuncular pattern with the foot located in the interhemispheric fissure, the hip area medially, with the medial-to-lateral organization of arm–hand–face–mouth (see Figure 10.2). The basal ganglia are located deep within the hemi­ spheres and are comprised of the c-shaped caudate nucleus, the putamen, and the globus pallidus (see Figure 10.3). Some also include the amygdala in the temporal lobe in this group of structures. The caudate and puta­ men are connected by thin gray matter bridges and together are termed the lentiform nucleus. The anterior limb of the internal capsule passes between these bridges. The connection between these structures is more robust ventromedially. The caudate follows the curve of the ventricular system, with the tail ending

Brain The nervous system is divided into central and peripheral divisions, along with the separate autonomic system. The central nervous system consists of the brain and spinal cord while the peripheral nervous sys­ tem consists of the nerves to the trunk and extremities. The brain is composed of the hemispheres, the brain stem and the cerebellum. The hemispheres are divided into the frontal, temporal, parietal, and occip­ ital lobes. The frontal lobe houses higher personality and executive functions. The central sulcus marks the dividing line between the frontal and parietal lobes, with the primary motor cortex on the anterior aspect of this sulcus and the primary sensory cortex on the posterior border. The opercular cortex on the ­ frontal side of the sylvian fissure in the dominant hemisphere houses the motor speech area (Broca’s area). The tem­ poral lobe contains areas subserving memory (hip­ pocampus), emotion and primitive urges (amygdala), hearing (primary auditory cortex, Heschel’s gyrus) and speech (dominant posterior temporal region).

Neuromodulation

99 106

95

2009 Elsevier Ltd. © 2008,

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10.  Anatomy of the nervous system

in the anterior temporal lobe near the amygdala. The globus pallidus is divided into internal and external segments, the globus pallidus interna and externa, respectively. The posterior limb of the internal cap­ sule lies at the medial border of the globus pallidus. The basal ganglia are involved in the control of both cognitive and motor function. They form a network of deep nuclei connected with both one another and the cortex via both direct and indirect pathways through the thalamus. The nuclei of the basal ganglia form the basis of the extrapyramidal motor control system that modulates motor function.

Cleft for internal capsule

Caudate Body nucleus Head

Thalamus

Pulvinar Medial geniculate body Lateral geniculate body Tail of caudate nucleus

Lentiform nucleus (globus pallidus medial to putamen) Amygdaloid body

Fornix

Frontal lobe

Lateral ventricle

Parietal lobe

Caudate nucleus Internal capsui Putamen Claustrum Globus pallidus

Occipital lobe

Thalamus Amygdala Optic tract

Temporal lobe

Uncus

ganglia

Ne

Toes Hip

ck

ng Fi

e Ankle

Th

p

Hi

Kne

X

er s um b

of the major cerebral lobes

Trunk

Figure 10.3  Schema of the anatomic organization of the basal

Shoulder Elb ow W ris t

Figure 10.1  A schematic diagram of the general organization

ow id Br yel s E are N s Lip Tongue

Trunk Hand Face

Larynx

Lateral sulcus X�

Figure 10.2  The primary motor and sensory cortices are arranged somatotopi­ cally with fibers serving the lower body more medially located and those serving the face more laterally located

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Gross structures

The brain stem is further divided into the dien­ cephalon (thalamic complex), the mesencephalon (mid­ brain), metencephalon (pons), and ­ myelencephalon (medulla). The diencephalon includes the thalamus, which functions as a relay center for most motor and sensory tracts, the epithalamus (pineal, habenular nuclei, stria medullaris), which functions to control the diurnal cycle, the hypothalamus, which regulates mul­ tiple pituitary hormones via releasing factors as well as producing its own hormones (ADH, vasopressin),

and the subthalamic nucleus, which participates in the extrapyramidal motor system along with the basal ganglia. The thalamus is bounded laterally by the pos­ terior limb of the internal capsule and caudally by the midbrain. The midbrain contains the nuclei for cranial nerves III and IV as well as the corticobulbar and corticospi­ nal tracts carrying motor fibers from the cortex to the brain stem and spinal cord, respectively. (See Figure 10.4 in the cerebral peduncles.)

Cerebral aqueduct Trochlear nucleus (iv) Periaqueductal gray Nucleus of the inferior colliculus Medial longitudinal fasciculus Lateral lemniscus Ventral and lateral spinothalamic tracts and spinotectal tract Reticular formation Central tegmental tract Decussation of the superior cerebellar peduncle Substantia nigra Trigeminothalamic tract Parieto-temporo-occipito-pontine fibers of crus cerebri Medial lemniscus Corticospinal and corticobulbar fibers of crus cerebri Rubrospinal tract Frontopontine fibers of crus cerebri

Edinger-westphal nucleus Periaqueductal gray Stratum opticum of superior colliculus Superior colliculus

Cerebral aqueduct

Spinotectal tract Brachium of inferior colliculus Ventral and lateral spinothalamic tracts Medial geniculate nucleus Reticular formation Trigeminothalamic tract Medial lemniscus Parieto-temporo-occipito-pontine fibers of crus cerebri Corticospinal and corticobulbar fibers of crus cerebri Substantia nigra Red nucleus Medial longitudinal fasciculus Frontopontine fibers of crus cerebri Oculomotor nucleus Dorsal and ventral tegmental decussations Oculomotor nerve (iii)

Figure 10.4  The major nuclei and tracts of the midbrain at the levels of the inferior colliculus (top) and superior colliculus (bottom)

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10.  Anatomy of the nervous system Cerebellar vermis Forth ventricle Superior cerebellar peduncle Medial longitudinal fasciculus Tectospinal tract Abducens nucleus (vi) Medial vestibular nucleus Superior vestibular nucleus Lateral vestibular nucleus Facial nerve root (vii) Middle cerebellar peduncle Spinal tract and nucleus of trigeminal nerve Facial nucleus (vii) Central tegmental tract Lateral lemniscus Lateral and ventral spinothalamic tracts and spinotectal tract Superior olivary nucleus Pontine fibers Abducens nerve root (vi) Corticospinal and corticobulbar fibers Pontine nuclei Medial lemniscus

Figure 10.5  The major nuclei and tracts of the pons at the level of the middle cerebellar peduncle

The fibers of the dentatorubrothalamic tract decus­ sate in the midbrain after emerging from the superior cerebellar peduncle on their way to the red nucleus in the midbrain tegmentum and then on to the thalamus. The dorsal aspect (tectum) of the midbrain consists of the paired superior and inferior colliculi subserving coordination of vision and hearing, respectively. The pedunculopontine nucleus is also located here. This nucleus functions as part of the extrapyramidal motor system as part of the “locomotor center.” It has con­ nections to the pallidum, cortex, and substantia nigra. The pons is dominated by the crossing fibers of the middle cerebellar peduncles (see Figure 10.5). The pons contains the nuclei of cranial nerves V, VI, VII, and VIII. The facial colliculus is the bulge in the roof of the midbrain formed by the fibers of cranial nerve VII looping over the nucleus of cranial nerve VI. The brain stem anatomy of cranial nerve V is described in more detail below. The IVth ventricle lies between the roof of the pons and the ventral cerebellum. Cranial nerves III, IV, and VI control extraocular movement. Cranial nerve V controls facial sensation as well as mas­ seter muscle function. Cranial nerve VII controls the muscles of facial expression as well as carrying some of the parasympathetic fibers for salivation and tearing. The medulla houses the nuclei of cranial nerves IX, X, XI, and XII. The pyramidal tracts decussate here. The nuclei cuneatus and gracilis for the spinal sen­ sory tracts are located here as well. The caudal end of the medulla is continuous with the spinal cord (see Figure 10.6).

Spinal Cord The spinal cord extends from the caudal medulla to the conus medullaris, which usually lies approxi­ mately at the level of L1–L2 in adults. There are 31 pairs of spinal roots: 8 cervical, 12 thoracic, 5 lumbar, 5 sacral and 1 coccygeal (see Figure 10.7). The spinal gray matter is located more centrally within the cord. The cord may be divided into right and left halves, as well as dorsal and ventral halves. The dorsal paramedian region is occupied by the dorsal sen­ sory tracts, the fasciculus gracilis (for the lower extremi­ ties) and fasciculus cuneatus (for the upper extremities). Further laterally the dorsal horn of gray matter sepa­ rates these pathways from the lateral corticospinal tract, which are the fibers from the primary motor cortex. Just ventral to the dentate ligament are the rubrospinal and spinothalamic tracts, which transmit secondary motor and sensory information, respectively. The ventrome­ dial aspect contains the vestibulospinal and anterior corticospinal tracts, which function to transmit vestibu­ lar and position information. Figure 10.8 shows the gen­ eral arrangement of ascending and descending tracts in the spinal cord. The gray matter organization will be discussed in more detail below.

Autonomic Nervous System The autonomic nervous system innervates the glands, viscera, heart, and smooth muscle. This sys­ tem is divided into parasympathetic and sympathetic

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99

Gross structures Dorsal motor nucleus of vagus (x) Tectospinal tract

Fourth ventricle

Hypoglossal nucleus Medial longitudinal fasciculus

Medial vestibular nucleus Nucleus of fasciculus solitarius Inferior vestibular nucleus Tractus solitarius Reticular formation Inferior cerebellar peduncle Spinal tract and nucleus of trigminal nerve Rubrospinal tract Ventral spinocerebellar tract Nucleus ambiguus

Fascicle of vagus nerve (x) Lateral and ventral spinothalamic tracts and spinotectal tract Principal nucleus of the inferior olivary complex Medial and dorsal accessory olivary nuclei Hypoglossal nerve (xii) Corticospinal and corticobulbar fibers in the pyramid

Medial lemniscus

Figure 10.6  The major nuclei and tracts of the medulla at the level of the lower aspect of the IVth ventricle

divisions. Each division consists of a set of ganglia with both pre- and postganglionic branches (see Figure 10.9). The sympathetic ganglia are located in either the paraspinal chain or the prevertebral plexuses. The sympathetic system originates in the posterior hypothalamus and medulla. Efferents (fibers leaving a nucleus and traveling to a target) travel into the spi­ nal cord where they synapse in the intermediolateral cell column, located between T2 and L1. From here, the preganglionic myelinated fibers travel as white rami communicantes to the paravertebral chain and either synapse and send postganglionic gray (unmy­ elinated) rami communicantes to the spinal nerves or pass through to the prevertebral ganglia that supply autonomic innervation to the viscera (see Figure 10.10). The sympathetic fibers to the head extend from the superior cervical ganglion to follow the branches of the external carotid artery. The preganglionic parasympathetic fibers emerge with cranial nerves III, VII, IX, and X, as well as from the intermediolateral cell column at the S2–S4 levels. These synapse in ganglia much closer to (or actually in) the target organs, such as the heart, gastrointes­tinal tract, and genitourinary system.

Sensory System First order afferents for fine touch and position sense have their nuclei in the dorsal root ganglia

and travel centrally in the dorsal columns of the spi­ nal cord, synapsing in the medullary dorsal column nuclei. They then cross and ascend as the medial lem­ niscus to the ventrocaudal nucleus of the thalamus. From there, third order fibers travel to the sensory cortex. The thalamic homunculus is arranged such that the face is medial, the lower body is lateral, and the upper extremity lies between (see Figure 10.11). Central processes of afferents for pain and tempera­ ture extend from the dorsal root ganglia to synapse in Lissauer’s tract (as described below) and then cross in the cord just ventral to the central canal to form the contralateral ventral spinothalamic tract, with fibers organized with the lower body more laterally and upper body more medially. These ascend to the thala­ mus as well, synapsing primarily in the contralateral sensory thalamic nuclei. Third order neurons from the thalamus then project to the somatosensory cortex. Rexed first described the laminar organization of the spinal gray matter in the 1950s (Rexed, 1952, 1954) (see Figure 10.12). Afferent fibers enter the dorsal horn via the dorso­ lateral fasciculus of Lissauer. Afferent spinothalamic axons may travel vertically several spinal segments in this superficial layer before eventually synapsing with neurons in lamina I, the posteromarginal nucleus. This layer contains nociceptive-specific neurons that respond almost exclusively to noxious stimuli (Carpenter, 1991c; Byers and Bonica, 2001; Terman

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C1

C1 C2 C3 C4

Base of skull Cervical enlargement

C2 C3 C4 C5 C6 C7 C8

C5 C6 C7 T1

T1

T2

T2

T3

T3 T4 T5 T5 T6 T6 T7 T7 T8 T8 T9 T9 T10 T10 T4

Lumbar enlargement

T11

T11

T12

T12

L1

Conus medullaris (termination of spinal cord)

L1 L2

L2

L3 Internal filum terminale of pia mater

L3

L4

Cauda equina

L4 L5 L5 Sacrum

External filum terminale of dura mater

S2

S1

S3 Termination of S4 dural sac S5 Coccygeal nerve Coccyx

Figure 10.7  The organization and anatomy of the spinal cord and spinal roots

and Bonica, 2001). They contain multiple neuropep­ tides, including substance P, calcitonin gene-related peptide (CGRP), enkephalin, and serotonin. Substance P and CGRP in particular play an important role in dorsal horn nociception (Donnerer and Amann, 1992; Donnerer and Stein, 1992; Donnerer et al., 1992a, 1992b). Lamina I cells send axons contralaterally across the ventral aspect of the central canal to form the lateral spinothalamic tract (STT). Lamina I also contains a class of cells that respond to a large vari­ ety of both noxious and non-noxious stimuli. These wide dynamic range (WDR) cells are able to alter their discharge frequency substantially to reflect the type of input stimulus. Noxious stimuli evoke higher frequency discharges from WDR cells. As described below, these cells play an important role in the devel­ opment of chronic neuropathic pain.

Lamina II, the substantia gelatinosa, modulates input from sensory receptors. Nociceptive and thermo­ receptive input is concentrated in the superficial layer of this lamina (IIo) while mechanoreceptor input is targeted to the deeper aspect (IIi) (Carpenter, 1991c; Terman and Bonica, 2001). Projections from substan­ tia gelatinosa neurons terminate in lamina I and in lamina II at other spinal levels. Opiate receptors are plentiful in both laminae I and II. Importantly, each sublayer of lamina II appears to contain distinct sub­ populations of C-fibers. Those C-fibers terminating in lamina IIo are similar to those that terminate in lamina I in that they express substance P and CGRP and con­ tain the trkA receptor for nerve growth factor (NGF). In contrast, the C-fibers terminating in lamina IIi do not express either CGRP or substance P and express the binding site for lectin IB4, an indicator of sensitiv­ ity to glial-derived neurotrophic factor (GDNF). This lamina also contains numerous local circuit neurons whose dendritic arbors may extend into both deeper and more superficial laminae. The A-fibers terminate primarily in lamina III, as do some of the A mechanoreceptive fibers. Lamina IV also serves as a target zone for A-fibers. Some of the cells in this layer project back to layer I, aiding in inte­ gration of sensory information. Lamina V contains a large number of STT projection cells that receive input from A- and C-fibers. A substantial proportion of the cells here are WDR neurons. These have large receptive fields whose center is responsive to both noxious and non-noxious stimuli and a surrounding area respon­ sive primarily to noxious stimuli only. Stimulation of the region surrounding this field causes inhibition of the WDR neuron (Terman and Bonica, 2001). Lamina X encompasses the gray matter surrounding the central canal of the spinal cord. The exact function of the cells here is not clear, but they are thought to play a role in visceral sensation as well as the holo­ spinal integration of nociceptive information. Some A-fibers directly terminate here, possibly carrying both visceral and cutaneous inputs. The trigeminal system has an analogous anatomic arrangement. Cell bodies for facial nociceptors are located in the Gasserian ganglion. The peripheral processes project via the three divisions of the trigem­ inal nerve and the central processes enter the brain stem via the trigeminal sensory root. Trigeminal sen­ sory input is then segregated depending on the type of information. Those cells carrying proprioception have their cell bodies in the trigeminal mesencephalic nucleus. The main sensory nucleus is located in the pons and receives large myelinated A afferents. Caudal to this nucleus is the spinal nucleus, which extends caudally through pons and medulla and is

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Gross structures 3a 3b

S

S

L

Th

C 4a

L 1a Th C 2b

2a

C

Th L S 5a 4b

2b 1b

5b

2d

6

2c

Motor and decending (efferent) pathways (left, red)

Sensory and ascending (afferent) pathways (right, blue)

1. Pyramidal Tracts

3. Dorsal Column Medial Lemniscus System

1a. Lateral corticospinal tract

3a. Gracile fasciculus

1b. Anterior corticospinal tract

3b. Cuneate fasciculus

2. Extrapyramidal Tracts

4. Spinocerebellar Tracts

2a. Rubrospinal tract

4a. Posterior spinocerebellar tract

2b. Reticulospinal tract

4b. Anterior spinocerebellar tract

2c. Vestibulospinal tract

5. Anterolateral System

2d. Olivospinal tract

5a. Lateral spinothalamic tract 5b. Anterior spinothalamic tract

Somatotopy Abbreviations: S: Sacral, L: Lumbar Th: Thoracic, C: Cervical

6. Spino-olivary fibers

(a) Principal fiber tracts of spinal cord Fasciculus gracilis

Ascending pathways Descending pathways Fibers passing in both directions Septomarginal fasciculus (oval bundle) Interfascicular fasciculus (comma tract)

Fasciculus cuneatus

Lateral corticospinal (pyramidial) tract (crossed)

Dorsolateral tract (fasciculus) (of Lissauer)

Rubrospinal tract

Dorsal (posterior) spinocerebellar tract

Lateral (medullary) reticulospinal tract

Lateral spinothalamic tract and spinoreticular tract

Ventral (anterior) or medial (pontine) reticulospinal tract

Ventral (anterior) spinocerebellar tract

Vestibulospinal tract

Spino-olivary tract

Ventral (anterior) corticospinal tract (direct)

Spinotectal tract Ventral (anterior) spinothalamic tract Fasciculus proprius

Tectospinal tract Medial longitudinal (sulcomarginal) fasciculi

(b)

Figure 10.8  The major ascending and descending tracts of the spinal cord

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10.  Anatomy of the nervous system Ciliary

III

Midbrain

Eye Sphenopalaline

VII VII IX

Medulla I C.

Submaxillary X

Olic

Sup. cerv. g.

Lacrimal gland Mucous mem. nose and palate Submaxillary gland Sublingual gland Mucous mem. mouth Parotid gland Heart

I T.

Larynx Trachea

chnic lan

Sma ll s

p

Oreal splanch nic Celiac

Bronchi Esophagus Stomach Blood ves. of abd. Liver and ducts

Superior mesenteric gang. I L. Inferior mesenteric gang.

Pancreas Adrenal Small intestine

Large intestine

I S.

Rectum

Pelvic ne

rve

Kidney Bladder Sexual organs External genitalia

Figure 10.9  The schematic organization of the autonomic nervous system

essentially the extension of lamina I into the brain stem (see Figure 10.13). This structure is further subdivided into several subnuclei. The subnucleus oralis is located most ros­ trally, followed by the subnucleus interpolaris, and the large subnucleus caudalis. The subnuclei oralis and interpolaris share common tactile and pressure input with the main sensory nucleus. Nociceptive

input is directed towards the subnucleus caudalis and the junction between interpolaris and caudalis. Subnucleus caudalis has several levels of somato­ topic organization. The classic model, described by Déjérine, is the onion peel analogy. Fibers from the central portions of the face terminate in the more ros­ tral portions of the subnucleus caudalis, while those in progressively more peripheral rings terminate at

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103

Gross structures

Sympathetic ganglion

Cell of Dogiel 2 6 7

Spinal ganglion

Posterior nerve root Spinal nerve

Sympathetic cord

2 1

Anterior nerve root

6 3

1 3 4 5

Wh

ite r

Gr ay

ram

us c om m

amu

unica n

s co

mm

unic

ans Sympathetic ganglion

s

Figure 10.10  The schematic organization of the gray and white rami communicantes of the autonomic nervous system

CN LD VLc Deep structures

MD VPLc

Cutaneous

CM VPM VPI

IC

Figure 10.11  Like the primary motor and sensory cortices, the motor and sensory thalamic nuclei have a homuncular arrangement with the face more medially located and lower body more laterally located. The distal extremities are located more caudally than the proximal extremities

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10.  Anatomy of the nervous system

Sulcii s1) Dorsal-Median Sulcus s2) Dorsal-Intermediate S. s3) Dorsolateral S. s4) Ventral-Median S. s5) Ventrolateral S.

s1 s2

d g

c

s3 a b e

h

h

s4

f

Rexed Lamina a) Lissauer’s Tract b) Marginal Zone c) Substantia Gelatinosa d) Body of Dorsal Horn e) Intermediate Horn f) Ventral Horn g) Central Canal h) Lower Motor Neurons

s5

Figure 10.12  Rexed’s laminae within the dorsal horn of the spinal cord (http://en.wikipedia.org/wiki/Spinal_cord) MIDBRAIN Mesencephalic nucleus Trigeminal ganglion

Trigeminal nerve

PONS Main sensory nucleus

Spinal nucleus of V

MEDULLA

Figure 10.13  A schematic diagram of the organization of the trigeminal sensory nuclei in the brain stem

more caudal levels. Nociceptive fibers from other cranial nerves (VII, IX, X) synapse in the more medial aspects of the subnucleus. Kunc was able to demon­ strate that a cut along the medial aspect of the spinal trigeminal nucleus produces analgesia in the distri­ bution of these other cranial nerves, sparing most of the trigeminal system. However, his incision also interrupted nociceptive fibers from the mandibular branch of the trigeminal nerve, thus demonstrating another layer or organization. Trigeminal fibers enter the subnucleus caudalis from its dorsal and lateral aspects. Mandibular division fibers are positioned dor­ sally with maxillary and ophthalmic division axons

clustered dorsolaterally and laterally, respectively. Cells in the subnucleus caudalis then form the trigemino­ thalamic tract (TTT). The STT and the TTT project primarily to the con­ tralateral sensory thalamus. This is the ventrocaudal nucleus (Vc) of Hassler’s nomenclature or the ventro­ posterior nucleus (VP) of the Anglo-American system. Once again, a definite somatotopic organization is present. Fibers from the legs and lower body project to the more lateral thalamus (VPL) while the ­trigeminal system sends axons to synapse in the more medial regions of the nucleus (VPM). Distal parts of the limbs are represented more ventrally within the nuclei while inputs from the trunk and other central regions termi­ nate more dorsally (Carpenter, 1991b). The thalamus then sends wide projections to the cerebral cortex. Most of the STT projection cells originate in lami­ nae I and V of the dorsal horn. Smaller contributions come from laminae VII and IX. Their axons then cross ventral to the central canal on their way to the con­ tralateral ventrolateral region (Carpenter, 1991d). The decussation may occur either at the corresponding spi­ nal level or one or two segments higher. This helps to account for the discrepancy between sensory level and injury level observed in spinal cord injury patients. Somatotopy is maintained within the spinothalamic tract. The first fibers to form the tract, those from the lumbosacral region, lie dorsolaterally. Fibers from suc­ cessively more cranial levels then lie progressively more ventral and medial (Carpenter, 1991c). Some of the axons from lamina I, as well as those from laminae VII and IX, project to sites outside of the ventrocaudal thalamus (Carpenter, 1991b; Chudler

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105

Gross structures

To thalamus

From nociceptive endings (A� and C fibers)

Inhibitory interneuron in substantia gelatinosa

�

�

�

� �

Tract cell

Figure 10.14  A schematic diagram of the gate con­ trol theory of pain. Non-nociceptive sensory fibers stim­ ulate the inhibitory interneurons, whereas nociceptive afferents inhibit them. An increase in non-nociceptive input will reduce the rate of firing of the spinothalamic tract neurons

From non-nociceptive endings (A� and A� fibers)

and Bonica, 2001). Known as the paleospinothalamic tract, these axons synapse in the brain stem reticular formation, hypothalamus, or other thalamic nuclei. Many of the axons originating outside of lamina I come from WDR cells, which tend to have a higher conduction velocity than the axons from lamina I noci­ ceptive cells. These cells not only respond to a wide range of stimuli, but also have larger receptive fields than nociceptive cells. It is believed that the smaller fields of the nociceptive cells aid in pain localization and discrimination. The WDR cells may play the inte­ grative role of the “T” cells in Melzack and Wall’s (1965) original description of the gate control theory. In their model, the “T,” or transmission, cells are the convergence point of signals from multiple peripheral afferents. These cells were depicted as being able to handle numerous types of sensory input. The signal transmitted depended on the status of the pain gate (see Figure 10.14). The broader characteristics of the WDR cells are felt to be involved in the affective com­ ponent of pain, hence their projection to the reticular formation, periaqueductal gray, and medial thalamic nuclei sites that have been implicated in modulating this (Willis and Westlund, 1997). Other thalamic nuclei are involved in pain process­ ing. The intralaminar nuclei, such as the nuclei para­ fascicularis (Pf), centrum medianum (CM), centralis medialis, and centralis lateralis, as well as the nucleus medius dorsalis (MD), all receive higher order noci­ ceptive inputs, either directly from the STT or (more commonly) by way of other thalamic nuclei or the brain stem nuclei (Bowsher et al., 1968; Reyes-Vazquez, Prieto-Gomez et al., 1989; Mao et al., 1992; Chudler and Bonica, 2001; Krout et al., 2002). These sites have served as targets for neurosurgeons treating intractable

pain (Richardson and Akil, 1977). Antinociception may be evoked by stimulation (Richardson and Akil, 1977) or infusion of opioids (Reyes-Vazquez, Qiao et al., 1989; Mao et al., 1992; Harte et al., 2000) into these areas. There are many other targets for nociceptive projec­ tion axons (Chudler and Bonica, 2001). These include the midbrain reticular formation, the colliculi, hypo­ thalamus, basal ganglia, amygdala and limbic sys­ tem. Functional imaging has disclosed activation of an extensive list of supraspinal structures in response to pain, including the medullary reticular formation, locus coeruleus, lateral parabrachial region, anterior pretectal nucleus, the medial, lateral and posterior tha­ lamic regions, basal ganglia, and the parietal, cingulate, frontal, insular and orbital cortices (Porro et al., 1999). The thalamus projects to the somatosensory cortex. The primary somatosensory cortex (SI, Brodmann’s areas 3a/b,2,1) corresponds to the postcentral gyrus and the neighboring sulci (Carpenter, 1991a). The secondary somatosensory cortex (SII) is located just posterior to SI on the medial hemisphere. Resection of the SI cortex has been attempted for control of pain without long-term success (Chudler and Bonica, 2001). Most nociceptive afferents terminate in corti­ cal layers III and IV (Chudler et al., 1990). The ventro­ basal thalamus projects cutaneous sensation primarily to areas 3b and 1. It has been demonstrated that the anticipation of painful stimuli can lead to activation of the sensory cortex (Porro et al., 2002). Both SI and SII cortices receive nociceptive input from the thalamus. The SI cortex is basically arranged in Penfield’s classic homuncular pattern, although variations in fine organ­ ization exist. The lower extremities are represented on the medial aspect of the gyrus and even into the

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interhemispheric fissure. Regions such as the hand and face (especially the lips) have an especially generous cortical representation. The SII cortex also is arranged somatotopically and receives some amount of bilateral input. However, the homunculus is reversed, with the face areas for SI and SII aligned (Carpenter, 1991a). Pain appears to be processed sequentially by the SI and SII cortices (Tran et al., 2002). The insula has also been found to play a role in the higher order processing of pain. Painful stimula­ tion can activate the insula, as seen on fMRI (Niddam et al., 2002). Moreover, this effect may be noted bilat­ erally (Hsieh et al., 1995; Frot and Mauguiere, 2003). Interestingly, these pathways seem to require that a certain level of consciousness be present for them to be utilized. Laureys et al. (2002) reported that areas such as the insula, SII, and cingulate cortices showed no activity when patients in a vegetative state were given a painful stimulus. The strength of insular activation is related to the magnitude of the stimulus (Bornhovd et al., 2002). While some have localized insular activation to the pos­ terior insula (Ostrowsky et al., 2002), it is clear that the anterior insula plays an important role as well (Hsieh et al., 1995; Peyron et al., 2000; Treede et al., 2000). In fact, Maihofner et al. (2002) demonstrated that the sensation of cold pain may completely bypass the SI cortex and be primarily processed in the posterior insula. The cingulate cortex is also activated by painful sensations (Peyron et al., 2000; Schnitzler and Ploner, 2000; Rolls et al., 2003). This region receives input from the intralaminar and medial thalamus. It is most likely responsible for the affective and motivational aspects of pain. This is partly indicated by studies (Ploner et al., 2002) showing that “second pain” leads to ante­ rior cingulate activation whereas “first pain” only activates the SI cortex. Moreover, distracting a subject during the application of a painful stimulus attenu­ ates the anterior cingulate activation (Frankenstein et al., 2001). Hofbauer et al. (2001) used hypnosis in an attempt to dissociate the affective and nociceptive components of pain while investigating the cortical representation of each. While their effort was only partially successful, they did demonstrate decreases in anterior cingulate activity when the affective com­ ponent was modulated. Hsieh et al. (1995) noted that the right anterior cingulate appeared to be dominant in that it was activated by both ipsilateral and contral­ ateral stimulation.

Pyramidal Motor System The corticospinal tracts originate from the pri­ mary motor cortex with significant contributions

(about 35%) from the postcentral gyrus and a smaller ­contribution (10%) from the frontal lobe. These fibers pass through the corona radiata and posterior limb of the internal capsule to the brain stem. Modulating collaterals exist to the red nucleus, vestibular nucleus, thalamus, reticular formation, and other structures. After decussating in the medulla, the fibers descend in the lateral aspect of the spinal cord before synapsing in Rexed’s layers VIII and IX of the spinal gray matter. Postsynaptic fibers then form the ventral root contri­ bution to the peripheral nerves. The extrapyramidal motor system will be discussed in more detail in other chapters in this text.

References Bornhovd, K., Quante, M., Glauche, V., Bromm, B., Weiller, C. and Buchel, C. (2002) Painful stimuli evoke different stimulusresponse functions in the amygdala, prefrontal, insula and som­ atosensory cortex: a single-trial fMRI study. Brain 125: 1326–36. Bowsher, D., Mallart, A., Petit, D. and Albe-Fessard, D. (1968) A bul­ bar relay to the centre median. J. Neurophysiol. 31: 288–300. Byers, M.R. and Bonica, J.J. (2001) Peripheral pain mechanisms and nociceptor plasticity. In: J.D. Loeser (ed.), Bonica’s Management of Pain, Vol. 1. Philadelphia, PA: Lippincott Williams & Wilkins, pp. 26–72. Carpenter, M.B. (1991a) The cerebral cortex. In: M.B. Carpenter (ed.), Core Text of Neuroanatomy, Vol. 1. Baltimore, MD: Williams & Wilkins, pp. 390–433. Carpenter, M.B. (1991b) The diencephalon. In: M.B. Carpenter (ed.), Core Text of Neuroanatomy, Vol. 1. Baltimore, MD: Williams & Wilkins, pp. 250–97. Carpenter, M.B. (1991c) Spinal cord: gross anatomy and internal structure. In: M.B. Carpenter (ed.), Core Text of Neuroanatomy, Vol. 1. Baltimore, MD: Williams & Wilkins, pp. 57–82. Carpenter, M.B. (1991d) Tracts of the spinal cord. In: M.B. Carpenter (ed.), Core Text of Neuroanatomy, Vol. 1. Baltimore, MD: Williams & Wilkins, pp. 83–114. Chudler, E.H. and Bonica, J.J. (2001) Supraspinal mechanisms of pain and nociception. In: J.D. Loeser (ed.), Bonica’s Management of Pain, Vol. 1. Philadelphia, PA: Lippincott Williams & Wilkins, pp. 153–79. Chudler, E.H., Anton, F., Dubner, R. and Kenshalo, D.R., Jr (1990) Responses of nociceptive SI neurons in monkeys and pain sen­ sation in humans elicited by noxious thermal stimulation: effect of interstimulus interval. J. Neurophysiol. 63: 559–69. Donnerer, J. and Amann, R. (1992) Time course of capsaicin-evoked release of CGRP from rat spinal cord in vitro. Effect of concen­ tration and modulations by ruthenium red. Ann. N Y Acad. Sci. 657: 491–2. Donnerer, J., Schuligoi, R. and Amann, R. (1992a) Time-course of capsaicin-evoked release of calcitonin gene-related peptide from rat spinal cord in vitro. Effect of concentration and modulation by Ruthenium Red. Regul. Pept. 37: 27–37. Donnerer, J., Schuligoi, R. and Stein, C. (1992b) Increased content and transport of substance P and calcitonin gene-related peptide in sensory nerves innervating inflamed tissue: evidence for a regulatory function of nerve growth factor in vivo. Neuroscience 49: 693–8. Donnerer, J. and Stein, C. (1992) Evidence for an increase in the release of CGRP from sensory nerves during inflammation. Ann. N Y Acad. Sci. 657: 505–6.

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Frankenstein, U.N., Richter, W., McIntyre, M.C. and Remy, F. (2001) Distraction modulates anterior cingulate gyrus activations dur­ ing the cold pressor test. Neuroimage 14: 827–36. Frot, M. and Mauguiere, F. (2003) Dual representation of pain in the operculo-insular cortex in humans. Brain 126: 438–50. Harte, S.E., Lagman, A.L. and Borszcz, G.S. (2000) Antinociceptive effects of morphine injected into the nucleus parafascicularis thalami of the rat. Brain Res. 874: 78–86. Hofbauer, R.K., Rainville, P., Duncan, G.H. and Bushnell, M.C. (2001) Cortical representation of the sensory dimension of pain. J. Neurophysiol. 86: 402–11. Hsieh, J.C., Belfrage, M., Stone-Elander, S., Hansson, P. and Ingvar, M. (1995) Central representation of chronic ongoing neuropathic pain studied by positron emission tomography. Pain 63: 225–36. Krout, K.E., Belzer, R.E. and Loewy, A.D. (2002) Brainstem projec­ tions to midline and intralaminar thalamic nuclei of the rat. J. Comp. Neurol. 448: 53–101. Laureys, S., Faymonville, M.E., Peigneux, P., Damas, P., Lambermont, B., Del Fiore, G. et al. (2002) Cortical processing of noxious somatosensory stimuli in the persistent vegetative state. Neuroimage 17: 732–41. Maihofner, C., Kaltenhauser, M., Neundorfer, B. and Lang, E. (2002) Temporo-spatial analysis of cortical activation by phasic innoc­ uous and noxious cold stimuli – a magnetoencephalographic study. Pain 100: 281–90. Mao, J., Price, D.D., Mayer, D.J. and Hayes, R.L. (1992) Pain-related increases in spinal cord membrane-bound protein kinase C fol­ lowing peripheral nerve injury. Brain Res. 588: 144–9. Melzack, R. and Wall, P.D. (1965) Pain mechanisms: a new theory. Science 150: 971–9. Niddam, D.M., Yeh, T.C., Wu, Y.T., Lee, P.L., Ho, L.T., ArendtNielsen, L. et al. (2002) Event-related functional MRI study on central representation of acute muscle pain induced by electri­ cal stimulation. Neuroimage 17: 1437–50. Ostrowsky, K., Magnin, M., Ryvlin, P., Isnard, J., Guenot, M. and Mauguiere, F. (2002) Representation of pain and somatic sensa­ tion in the human insula: a study of responses to direct electri­ cal cortical stimulation. Cereb. Cortex 12: 376–85. Peyron, R., Laurent, B. and Garcia-Larrea, L. (2000) Functional imaging of brain responses to pain. A review and meta-analysis. Neurophysiol. Clin. 30: 263–88. Ploner, M., Gross, J., Timmermann, L. and Schnitzler, A. (2002) Cortical representation of first and second pain sensation in humans. Proc. Natl Acad. Sci. U S A 99: 12444–8.

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Porro, C.A., Baraldi, P., Pagnoni, G., Serafini, M., Facchin, P., Maieron, M. et al. (1999) CNS pattern of metabolic activity dur­ ing tonic pain: evidence for modulation by beta-endorphin. Eur. J. Neurosci. 11: 874–88. Porro, C.A., Cavazzuti, M., Baraldi, P., Giuliani, D., Panerai, A.E. and Corazza, R. (2002) Does anticipation of pain affect cortical nociceptive systems? J. Neurosci. 22: 3206–14. Rexed, B. (1952) The cytoarchitectonic organization of the spinal cord in the cat. J. Comp. Neurol. 96: 415–96. Rexed, B. (1954) A cytoarchitectonic atlas of the spinal cord in the cat. J. Comp. Neurol. 100: 297–400. Reyes-Vazquez, C., Prieto-Gomez, B. and Dafny, N. (1989) Noxious and non-noxious responses in the medial thalamus of the rat. Neurol. Res. 11: 177–80. Reyes-Vazquez, C., Qiao, J.T. and Dafny, N. (1989) Nociceptive responses in nucleus parafascicularis thalami are modulated by dorsal raphe stimulation and microiontophoretic application of morphine and serotonin. Brain Res. Bull. 23: 405–11. Richardson, D.E. and Akil, H. (1977) Pain reduction by electrical brain stimulation in man. Part 1: Acute administration in peri­ aqueductal and periventricular sites. J. Neurosurg. 47: 178–83. Rolls, E.T., O’Doherty, J., Kringelbach, M.L., Francis, S., Bowtell, R. and McGlone, F. (2003) Representations of pleasant and painful touch in the human orbitofrontal and cingulate cortices. Cereb. Cortex 13: 308–17. Schnitzler, A. and Ploner, M. (2000) Neurophysiology and func­ tional neuroanatomy of pain perception. J. Clin. Neurophysiol. 17: 592–603. Terman, G.W. and Bonica, J.J. (2001) Spinal mechanisms and their modulation. In: J.D. Loeser (ed.), Bonica’s Management of Pain, Vol. 1. Philadelphia, PA: Lippincott Williams & Wilkins, pp. 73–152. Tran, T.D., Inui, K., Hoshiyama, M., Lam, K., Qiu, Y. and Kakigi, R. (2002) Cerebral activation by the signals ascending through unmyelinated C-fibers in humans: a magnetoencephalographic study. Neuroscience 113: 375–86. Treede, R.D., Apkarian, A.V., Bromm, B., Greenspan, J.D. and Lenz, F.A. (2000) Cortical representation of pain: functional charac­ terization of nociceptive areas near the lateral sulcus. Pain 87: 113–19. Willis, W.D. and Westlund, K.N. (1997) Neuroanatomy of the pain system and of the pathways that modulate pain. J. Clin. Neurophysiol. 14: 2–31.

II. FUNDAMENTALS OF NEUROMODULATION

C H A P T E R

11

Fundamentals of Electrical Stimulation J. Thomas Mortimer and Narendra Bhadra

o u t l i n e A Brief Historical Note

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Electrochemistry of Stimulating Electrodes

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Overview

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Some Basic Concepts

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Electrode Behavior Under Pulsed Conditions Monophasic Pulses

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Resting Potential Across the Nerve Membrane

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Biphasic Pulses, Balanced Charge, and Imbalanced Charge

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Voltage-gated Ion Channels

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Action Potentials

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How Stimulus Waveform Choices Impact Tissues

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Electrically Generating Action Potentials

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Current/Voltage Stimulation

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Choosing the Duration of the Stimulus

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References

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In the context of neuromodulation and neuroprostheses, electrical stimulation is applied to restore function to people who are unable to move, see or hear or to alter behavior such as seen in varied disorders of motor, sensory and cognitive functions. Rules have evolved over the past fifty years or so on ways to apply the electrical stimulus so that the response does not diminish as a result of its application. These include the choice of current rather than voltage pulses, biphasic rather than monophasic pulses and charge-balanced pulses rather than chargeimbalanced pulses. The material presented in this chapter is intended to be an explanation of the rules and to provide a basis for forming informed decisions that may seem to be at odds with the rules.

Neuromodulation

A brief historical note Lojze Vodovnik introduced the first author (J.T.M.) to the concept of electrically activating the nervous system in early 1964. Lojze came to Case Institute of Technology (now Case Western Reserve University), in Cleveland, Ohio, as a postdoctoral fellow to work in James B. Reswick’s laboratory. Reswick and his students were developing a pneumatic-powered armassist device. Also closely connected to Reswick’s group was Charles Long, who had published his work on a hand orthosis (Long and Masciarelli, 1963) based on Vladimir Liberson’s foot-drop orthosis (Liberson et al., 1961). Prior to his coming to Cleveland,

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Vodovnik had read about Liberson’s foot-drop orthosis, and the report by Adrian Kantrowitz (1961) on standing a person with paraplegia. Vodovnik began stimulation experiments with Bill Crochetiere (Crochetiere et al., 1967), a PhD student of Reswick’s laboratory, where rapid fatigue of the electrically activated muscle was recognized as a major problem to restoring function by electrically stimulating paralyzed muscles. At about the same time, I was working in C. Norman Shealy’s lab, and became acquainted with animal experiments,1 specifically the basic triceps surae muscle preparation in the cat, which became the mainstay of our later work. In the late 1960s, Charles Long had declared electrical activation of paralyzed muscles a dead idea because of disuse atrophy and rapid fatigue, which became a problem to surmount in the 1970s. In 1968–69 I spent a year in Sweden and came into contact with Lars Edström, who with Eric Kugelberg had characterized muscle fiber types (Edström and Kugelberg, 1968), and, when I saw their results, I realized that the fatigue problem was because the recruitment order, with electrical stimulation of large motor units before small motor units, was the reverse of what occurs in naturally initiated muscle contractions. From there was born the idea of electrically induced exercise to rebuild a paralyzed muscle and convert muscle fibers with anaerobic metabolism to a type with aerobic metabolism and muscle fibers with fast twitch contraction to slow twitch. This was demonstrated by Hunter Peckham in his PhD thesis (Peckham, 1972) to be a viable solution to the problems encountered by both Vodovnik and Long. Had this not been the story, one wonders if Case Western Reserve University would have become the powerhouse it is today in the arena of electrically activating the nervous system. Much has been learned about electrically activating the nervous system since then, which is the topic of this chapter.

Overview When electrical currents are delivered to the nervous system to elicit or inhibit neural activity, two things can happen: first the current creates a potential field that can alter the state of the voltage-gated ion channels, proteins that are embedded in the 1

For this engineer ( J.T.M.), animal experiments were extremely frustrating, and at the end of my master’s degree I declared no more animal experiments for me. However, my experience in Sweden persuaded me that there was a unique opportunity for an engineer willing to undertake animal experiments; the rest is history.

membranes of neural elements; and second, electrochemical reactions occur at the electrode–tissue interface. Altering the state of voltage-gated ion channels can initiate or suppress a propagated action potential, which, in turn, effects the release of neurotransmitter at the terminal end of the axon. Uncontrolled electrochemical reactions, at the electrode-tissue interface, can cause damage to the electrode or injury to the target tissues. There are three ideas that we believe the reader should keep in mind when thinking about neuromodulation: First, electrical activation of the nervous system is more than causing paralyzed limbs to move, sound sensations in the deaf individual, and visual sensations in the blind person; it is about controlled and targeted release of neurotransmitters. Second, the science underpinning electrical activation technology is the knowledge of the voltage-gated ion channel, particularly the voltage-gated sodium ion channel. Third, the electrode is the business end of any neural prostheses; what happens there can determine the long-term viability of the device. Using the above three concepts as a foundation, one can more easily understand the rationale for making decisions about choices for stimulation para­ meters and how these choices impact the utility and longevity of a device intended to modulate the behavior of a neural circuit or activate the nervous system to restore function.

Some basic concepts An electrode forms the interface between the neuro­modulation hardware and the targeted nervous tissue. Electrical stimulation is achieved by connecting two opposite poles of a stimulus source to the tissue. Conventional current flows from the positive pole of a stimulus source to the negative pole, while electrons (negative charges) flow in the opposite direction. Anode and cathode: the electrode at which oxidation reactions occur (increased positive valence or electron removal) is defined as the anode, and the electrode at which reduction occurs (decreased positive valence or electron gain) is defined as the cathode. Voltage and current: neuromodulation is effected by application of electrical charge to the tissues. Voltage is a measure of the energy carried by the charge, being the “energy per unit charge” (Volts), while current is the rate of flow of charge (Amperes).

II.  Fundamentals of neuromodulation



Voltage-gated Ion Channels

Stimulus characteristics: electrical charge applied to effect stimulation of neural tissue can be characterized temporally by its voltage or current. The basic unit of applied charge, a voltage or current pulse, is defined by its duration (pulse width), amplitude (Volts or Amperes) and pulse shape (rectangular, triangular, sinusoidal). The repetition rate of the individual pulses is the stimulus frequency or pulse rate. Electrode characteristics: the size (area) of the electrode–tissue interface determines the charge and current density of the applied stimulus, which decreases with increasing electrode area. The current density of the applied pulse decreases inversely with the distance from the electrode. Effect of axon diameter: the effects of an applied electrical field are greater on the larger diameter axons because the larger diameter axons have a larger separation between nodes of Ranvier. The effect can be either depolarization or hyper-polarization. Smalldiameter axons require higher stimulus amplitude for the generation of action potentials than large-diameter axons. Nerve depolarization/excitation: when the transmembrane potential of an axon is decreased to a level where sufficient numbers of voltage-gated sodium ion channels are switched from the resting-excitable state to an active state, it causes a propagated action potential to be initiated. This state change occurs when a net transmembrane current, flowing from the inside to the outside of the cell occurs, and is usually caused by the application of a cathodic stimulus applied near the site of excitation. Nerve hyperpolarization: when the transmembrane potential is increased from the resting state (becoming more negative), the voltage-gated sodium ion channels are less likely to be gated into the active state. This state change occurs when the net transmembrane current is negative, flowing from the outside of the cell to the inside of the cell, and is usually caused by the application of an anodic stimulus applied near the site of hyperpolarization.

Resting potential across the nerve membrane Three major ions are separated across a nerve membrane at rest.2 The concentration of Na and Cl is much higher in the extracellular space than in the 2 Calcium, Ca, is also a major ion that is in higher concentration outside the neuron, but for the purposes of this discussion, it will not be considered.

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intracellular space, while K is higher on the inside of the cell membrane compared to the extracellular space. The resting potential of the membrane is about 70 mV, inside with respect to outside, which is close to the Nernst potential3 for both K and Cl, a value determined by the difference in ion concentration between the two sides of the membrane. K and Cl concentrations determine resting potential across the nerve membrane. The resting nerve membrane is poorly permeable to Na and the Na Nernst potential is about 55 mV, which drives the inward current flow during the action potential.

Voltage-gated Ion Channels Voltage-gated ion channels are a class of transmembrane proteins that are activated by changes in electrical potential difference across the cell membrane (Armstrong and Hille, 1998). Voltage-gated sodium ion channels (Nav) can have three possible states: closed-activatable, activated (open and conducting), and closed-inactivatable. Nav channels are made up of 1800 to 4000 amino acids with four transmembrane repeat domains. The molecules of the protein interact with each other and surrounding molecules to form a structure that defines its function. Each of the four transmembrane domains contains a voltage-sensitive alpha helix that is displaced in the open or conduction state (Gregerson, 2003). The linker between the III and IV repeat domains act as a ball and chain to fold up into the channel opening to block sodium ions (Na) from moving through the channel in the inactivatable state. When a channel opens Na moves from outside the membrane, through the channel, to the inside following both a concentration gradient and a voltage gradient. Shortly after the channel opens it becomes energetically favorable for the linker between the III and IV repeat to move into the opening and block further Na movement (Doyle, 2004). The opening of Nav is a stochastic process that is potential-dependent, meaning that as the transmembrane potential increases, the probability increases for a resting channel to transition to a conduction state. In the conduction state, each channel is acting as a miniature current source. At resting membrane potentials, say 70 mV, some channels are opening and closing and about 75% of the Nav are in an activatable state, meaning they can be opened and 25% are in the inactivatable state, with the linker between the III and IV 3

Equilibrium potential of the ionic electrochemical gradient across the membrane.

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repeat blocking Na flow through the channel. K outflow keeps the membrane potential from drifting and sodium-potassium pump maintains equilibrium concentrations and membrane potentials. If the membrane potential were to be made more negative, hyperpolarized, the fraction of channels in the activatable state increases, approaching 100% at 100 mV. Each Nav acts as a current source when the channel opens, permitting Na to move from the outside to the inside and depolarize the membrane. The Nav channel density is 2000 channels/m2 in the nodes of Ranvier. By convention, the potential across a membrane is defined as inside with respect to outside, giving rise to the resting potential, which is about 70 mV. Also, positive current flow is defined as positive charge moving from inside to outside, therefore, Na moving from outside to inside is a negative current.

Action potentials Na movement from the outside to the inside depol­ arizes, or raises the transmembrane potential. Nav are concentrated at nodes of Ranvier, several thousand per square micron, so there are tens of thousands of channels involved in generating an action potential at a single node. When a large number of Nav open, in short succession, more Na moves in than K moves out of the membrane and the membrane potential moves positively, which in turn increases the probability that activatable Nav will open, meaning many miniature current sources act in close succession to depolarize the nerve membrane, driving the potential from about 70 mV to approximately 20 mV or higher. This rapid change in membrane potential is recognized as the all or none action potential. Since all Nav close shortly after opening, transition to the inactivatable state, Na movement is terminated and K movement from inside to outside the membrane restores the membrane potential to the resting state. A propagated action potential is created when the transient change in membrane potential at one node of Ranvier gives rise to a potential difference inside the axon between that node and an adjacent node. The transient depolarization causes positive charge to move to the next adjacent node of Ranvier, which depolarizes the adjacent node causing activatable Nav to open in short succession, leading to another action potential and the process continues to the terminal end of the axon where a neurotransmitter is released to act on an adjacent cell or to act systemically when released into the blood.

Electrically generating action potentials Charge can be neither created nor destroyed, which is a fundamental law of physics. However, charge can be separated and when it is separated there exists a potential difference to recombine the charge. The magnitude of the potential difference is inversely proportional to the separation distance. Holding these ideas, two points need to be kept in mind throughout the following presentation. First, at resting membrane potentials charge is separated across a nerve membrane, more positive charge outside and more negative charge inside. Second, if we provide a pathway to inject charge we must provide a pathway to remove it and if charge flows into a cell it must flow out of the cell somewhere else. Charge flow, per unit time, is defined as current. As current flows in a resistive medium, like tissues, a potential difference arises along the pathway it follows. Points where the more charge is flowing have a higher potential gradient compared to points where less charge is flowing. Consider now that we have placed two electrodes in the same conducting tissue space, occupied by an axon, and that one of the electrodes, the stimulating electrode, is much closer to the axon than the other electrode; the distant electrode will be referred to as the return/indifferent electrode. Current injected into the tissue at the stimulating electrode disperses as it moves away from the injection site; the current density4 being highest near the injection site. This means that the potential difference between equally spaced points closer to the injection site will be higher than the potential difference for similarly spaced points further from the injection site. When a 100 s duration cathodic current pulse is applied to the stimulating electrode, negative charge is injected into the tissue at the highest current density close to the stimulating electrode. The negative charge injected counters the positive charge outside the membrane and the negative charge inside the axon moves away from the membrane. A negative charge moving away from the inside of the membrane is effectively the same as a positive charge moving from the inside to the outside of the membrane. This is called a capacitive current. In other words, the membrane capacitance is discharged by the stimulus pulse. So, what has happened is that the cathodic pulse has the effect of driving a positive current from the inside of the axon to the outside of the axon with the bulk of the current flowing through the node of Ranvier that 4

Charge flow per unit area.

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electrically generating action potentials

r1

r1�

Figure 11.1  A stimulating electrode and current entering and exiting nodes of Ranvier for two nerve fibers, the nerve in the lower panel has an axon that is twice the diameter of the axon in the upper panel. The stimulating electrode is the same distance from the node in both cases. However, since r1 is less than r1 the extracellular potential, which is proportional to 1/r at the adjacent nodes, will be less in the case of the larger axon, which means that the activating function, Ve,n12Ve,n Ve,n1 will be larger for the large diameter fiber than it will be for the smaller diameter fiber

is closest to the stimulating electrode. Inward flowing current is distributed over the nodes adjacent to the stimulating electrode. The magnitude of the current density is lowered, by more than half, at nodes flanking the node of Ranvier nearest to the stimulating electrode. Current flow through the relevant nodes is illustrated in Figure 11.1. Current flowing out of the node of Ranvier closest to the stimulating electrode reduces the potential across the membrane at this site and Nav, in this patch of membrane, will have an increased probability of transitioning from the closed-activatable state to the open-conduction state allowing Na to move to the inside of the membrane and further lowering the transmembrane potential. If the net Na inflow exceeds the net K outflow a regenerative action potential will follow with all activatable Nav opening at that node, setting the scene for a propagated action potential along the axon and to cause the release of a neurotransmitter at the terminal end. When the depolarizing current is insufficient to open enough Nav channels before K flows out to repolarize the membrane, it is unable to generate an action potential. This would be termed a subthreshold stimulus. If an anodic pulse, rather than the cathodic pulse, is delivered, the current flow through the respective nodes of Ranvier is reversed. The inward current flow at the node nearest the electrode causes the transmembrane potential to increase (hyperpolarize) and this will not generate an action potential. However, at the flanking nodes, positive current exits the membrane, which causes depolarization, and may potentially trigger an action potential. Note, however, that the exiting current is distributed over many nodes rather than a single node as in the case of the cathodic pulse. For an action potential to be created with an anodic pulse the

current pulse would need to be substantially higher in magnitude than is required for a cathodic pulse. Thus comes the rule of thumb that the threshold for generating a propagated action potential is lower for a cathodic pulse than for an anodic pulse. The change in transmembrane potential, resulting from an applied stimulus, can be described mathematically and is given by the second spatial difference of the electric field along the axon, also referred to as the activation function.

Ve,n1  2 Ve,n + Ve,n1



(11.1)

Here Ve,n is the magnitude of the potential at the node on the extracellular side of Ranvier immediately under the electrode, and Ve,n1 and Ve,n1 are the magnitudes of the potential on the extracellular side of the nodes of Ranvier on either side of the node immediately under the electrode. The potential at any point in space is proportional to 1/r, where r is the separation between the electrode and the point where Ve is measured. This means that if a large axon and a small axon are the same distance from the electrode, Ve,n is the same in both cases, but Ve,n1 and Ve,n1 are both smaller for the larger axon than for the smaller axon, refer to the lower panel in Figure 11.1. The internodal spacing is 100 times the diameter of the axon, i.e. large fibers have a greater internodal spacing compared to smaller diameter fibers. Thus comes the rule of thumb that, the effects of an electrical stimulus are greater on large axons than on small axons and nerve fibers closer to the electrode are more strongly affected by an electrical stimulus than fibers further away. Propagated action potentials can occur following the termination of a prolonged period of membrane hyperpolarization. This phenomena is labeled “anodic

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break,” suggesting that the action potential occurred as a result of the lagging edge of the anodic pulse. Actually the membrane is made hyperexcitable during the hyperpolarization period. During the period of anodic polarization the number of channels in the activatable state is moved from 75% to a much larger fraction, approaching 100%. When the anodic pulse is terminated the membrane potential moves back to resting potential, Nav channels open as the 25% fraction in the inactivatable state is reestablished. When Na flow inward through Nav channel opening is not countered by K outflow, sufficient depolarization occurs to initiate a propagating action potential.

Choosing the duration of the stimulus It is well known and accepted that larger stimulus amplitudes are required for shorter pulse durations to initiate a propagated action potential. This is known as the Strength–Duration characteristic or relationship. An example is shown in Figure 11.2a. As the stimulus duration increases the amplitude required to initiate a propagated action potential asymptotically approaches a minimum value, named the rheobase current, Ir. This curve can be fitted to a mathematical expression, the Hill equation.



Ith 

Ir (

1 e

PD )ln 2 tc



(11.2)

Where Ith is the magnitude of the stimulus, Ir is the rheobase current, PD is the duration of the stimulus pulse, tc is the chronaxie (defined as the time required for a stimulus pulse that is twice Ir), and ln 2 is the natural logarithm of 2. The magnitude of Ir is dependent on the separation between the electrode and target excitable tissues, while the chronaxie, tc is primarily dependent on the tissues, with tc being less than 1 ms for neural tissues and greater than 10 ms for muscle. As pointed out in later sections, the amount of charge injected through the electrode will be an important factor in minimizing the products of electrochemical reactions and drain on the batteries of the pulse generator. Considering a pulse generator that produces regulated current pulses, a Charge-Duration curve can be developed by multiplying Ith by PD, the pulse duration. A plot of the resulting ChargeDuration curve is shown in Figure 11.2b. From this plot it becomes apparent that to minimize charge injection the pulse duration should be as short as possible, where possible is defined as a compromise

Figure 11.2  (a) Strength–Duration characteristic for neural tissues. Short duration pulses require higher amplitudes to initiate a propagated action potential than do longer duration stimuli. The minimum amplitude required to initiate a propagated action potential is defined as the Rheobase current, Ir. The duration of a stimulus pulse that uses a current that is twice the Rheobase current is defined as the chronaxie, tc. (b) Charge–Duration characteristic for neural tissues. Short duration pulses require less charge to initiate a propagated action potential than do long duration pulses. Pulses with durations less than the chronaxie, tc are recommended (With kind permission from Grill and Kirsch (2000). Copyright 2000 Demos Medical Publishing)

between limits imposed on the stimulator through the compliance voltage, which limits the maximum current that a given stimulator can produce. We explain the Charge-Duration curve by recognizing that with longer pulse durations it takes a longer period of time to change the membrane potential, which allows more time for potassium to flow out of the cell, which causes repolarization, in response to sodium flowing into the cell. What pulse duration does one choose? If minimizing the stimulus amplitude is desired, one might

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electrochemistry of stimulating electrodes

Metal

Injection of current into a tissue medium is not quite as simple as it might appear. In metal conductors, current is supported by electron migration in the metal lattice, driven by a potential difference between a pulse generator and the terminal end of an electrode. In the tissue medium, current is supported by ion migration, driven by potential differences in the tissue medium. To create the potential requirements needed to generate a propagated action potential, ions must be caused to move in the vicinity of the target nodes of Ranvier. The generation of this ion movement is a result of electrochemical processes occurring at the metal–tissue interface. In this section we will explore processes that occur on the electrode during stimulation and from this knowledge we will be able to understand why some pulse configurations may be better choices than others. Quantum theory states that there are only certain allowed energy states for an electron and that these are quantized.5 Further, it tells us that no two electrons, in the same system, can occupy the same energy state, and that all the energy states are filled from the lowest levels to the highest levels. In a metal the energy levels of the electrons, in the conduction band, are very close together and the lowest energy levels are filled up to the highest level, which is referred to as the Fermi level. In the electrolyte medium the electrons in the outer shell of molecules also have discrete energy levels and, because the molecules can interact with other molecules in different ways, the energy states are represented as a “density of states” reflecting a probability of a particular energy state being vacant or occupied. For an electron to transfer from an occupied state to a vacant state between the metal electrode and the electrolyte medium, the electron 5

Discontinuous or discrete value for the energy states.

Vacant states Acceptor

O � ne� Reactants

R Products

Donor Filled states N(E)

Electrochemistry of stimulating electrodes

Electrolyte

Energy

choose a long pulse duration. If minimizing charge injection is to be the desired criterion, then one would choose a short duration stimulus pulse. Generally speaking, select the shortest pulse duration that the stimulator can support. A good target is to use a pulse duration close to or less than the chronaxie, tc. If incomplete activation results, widen the pulse duration. Alternatively, using the stimulator in a mode where the pulse magnitude is the maximum the generator can produce, pulse width modulation automatically minimizes the charge injection.

N(E)

As charge is added to or subtracted from the metal, the Fermi level in the metal moves closer to or further from the vacuum level

Figure 11.3  Electron energy: density of states representation of a metal electrode in an electrolyte. On the left-hand side is the metal and on the right-hand side are the “density of states” for the molecules in the electrolyte. All electron energy states in the metal are occupied (shown in blue) below the Fermi level and all electron energy levels are occupied by the electron donor in the electrolyte (shown in green). As cathodic charge is added to the metal, the Fermi level of the electrons in the metal increases, but no electron is transferred until the Fermi level is raised to the level of the vacant states for the acceptor in the electrolyte. Similarly, when anodic charge is added to the metal, the Fermi level in the metal is lowered and charge is only transferred to the metal, from the molecules in the electrolyte, when the electron energies are at the same energy levels. As charge is added or subtracted from the interface, the interface acts as a capacitor, termed the double-layer capacitance. Even though no charge transfer occurs at the interface, current flows in the electrolyte medium as the double layer charges or discharges

energy level of the metal and molecule must have the same value, otherwise radiation would be required to account for the differences in energy levels, radiation free electron transfer (Figure 11.3). Consider now that we are looking at the energy levels of the electrons in the conduction band of the metal, and that we are applying a cathodic current pulse, making the electrode more negative or raising the electron energy of the electrons in the metal electrode. As the cathodic current is applied to the electrode, negative charge builds up on the metal side, raising the electron energy, and positive charge moves to interface on the electrolyte side. No charge, electron, moves across the interface to the electrolyte during this process, which is termed double-layer charging. However, ion movement (current) can occur during the charging of the interface in the electrolyte, and under some circumstances the resulting potential difference in the tissue medium can be sufficient to generate a propagated action potential. As the cathodic current continues to be applied to the electrode the electron energy of the electrons in the metal continues to rise until, in an electrolyte medium, a

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11.  Fundamentals of Electrical Stimulation

vacant, unoccupied, electron energy state of a molecule matches the energy state of the electron where an electron can be transferred from the metal to the molecule in the electrolyte. The electron transfer between molecules and the metal occurs when the two are in close proximity. When considering the electrochemistry that occurs on stimulating electrodes, two things are important: first, the nature of the electron transfer (the reaction products) and second, the potential at which the electron transfer takes place. Knowing the nature of the reaction products enables us to estimate the consequence of electron transfer process and knowing the potential at which it occurs may open an opportunity to avoid the reaction if it is deemed damaging to the living tissues or to the electrode. The cyclic voltammogram provides information about the potential at which a reaction takes place, as evidenced by current flowing across the interface. The cyclic voltammogram (CV), developed by the electrochemists, enables us to assess both the nature of the electron transfer process and the potential at which it occurs. A cyclic voltammogram is a plot of the magnitude and direction of the current flowing across the interface as a function of potential across the interface. Unique to the measurement is a linear, time-varying potential, a saw-tooth potential waveform. The word cyclic conveys the idea that the voltage sweep is repeated multiple times. Cyclic voltammograms provide unique signatures for specific electrode-electrolyte systems. For the purposes of introducing the cyclic voltammogram and how one might use the information obtained for neuromodulation, consider first a cyclic voltammogram for a gold electrode in an oxygenfree sulfuric acid medium (Figure 11.4). The potential

Current density (�m/cm2)

100 50 B

0

�0.5 �50

A

0% Oxygen

C

0

0.5

5% Oxygen

1

D 1.5

2

�100 �150

(c) 0% and 5% oxygen �250 mV to �1.6 V(RHE)

�200 V vs. RHE

Figure 11.4  Slow cyclic voltammograms for gold in sulfuric acid. The solution is equilibrated to 0% and 5% oxygen. The sweep rate was 20 mV/sec and the range of the sweep was 250 mV to 1.6 V, referenced to reversible hydrogen electrode (Reprinted with permission from Merrill et al. (2005). Copyright 2005, The Electrochemical Society)

across the electrode interface is referenced to a reversible hydrogen electrode (RHE). This measurement requires a three-electrode system, the working electrode (the electrode of interest, which may be our stimulating electrode), a return or counter electrode, and a reference electrode. Current flows between the working and counter electrode. No current flows through the reference electrode, so that the interface potential of the reference remains stable during a measurement. The only potential change measured is between the working electrode and the reference electrode, which, excluding the voltage drop associated with current flowing in the electrolyte, reflects the potential across the metal–electrolyte interface. If this measurement were attempted by measuring the potential between the working electrode and the counter electrode the measurement would include the interface potential at both electrodes plus the potential drop in the electrolyte medium, which would not be an accurate reflection of the potential drop across the electrode of interest. Other reference electrodes commonly used in making these measurements are the saturated calomel electrode (SCE) and the silver– silver chloride electrode (Ag/AgCl). Looking at the cyclic voltammogram in Figure 11.4 that was carried out in the oxygen-free electrolyte, starting at 0.5 V(RHE) and moving in the negative direction we see that the current remains nearly constant until about 0.0 V(RHE), at which point the current increases rapidly in the negative direction, with increasing negative potential. During the sweep between 0.5 to 0.0 V(RHE), the electron energy of the metal was increasing, but only a small steady current was measured. The measured current reflects charging of the double layer, a capacitance current. Had the sweep rate been faster, the measured current would have been greater since the current flowing in a capacitor is proportional to the time rate of change of the voltage across the capacitor. At about 0.0 V(RHE) the electron energy is sufficient to transfer to an unoccupied energy state in a water molecule, water reduction. If the electron energy of the metal electrons is increased, the potential made more negative than 0.0 V(RHE), the current increases rapidly. Since water is plentiful, the reaction continues and current continues to flow as long as the potential across the interfaces remains more negative than 0.0 V(RHE). Reversing the sweep direction at 250 mV(RHE), from a negative direction to a positive direction, the current decreases as the potential approaches 0.0 V(RHE) and becomes constant from 0.0 V(RHE) to 1.2 V(RHE). During the positive sweep to 1.2 V(RHE), the steady current indicates that the only process occurring at the electrode interface is double layer charging and that there

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Electrode behavior under pulsed conditions

are no vacant electron energy states available for electron transfer between 0.0 V and 1.2 V(RHE). The current flowing in the electrolyte reflects ion migration to and from the interface to accommodate the charging of the interface. When the potential exceeds 1.2 V(RHE) the current increases, indicating oxidization of the gold. At around to 1.4 V(RHE) the current begins to decrease, indicating that the reaction is limited because gold at the surface is becoming limited. If the positive potential sweep is continued, the current again begins to rise at around 1.6 V(RHE), indicating water oxidation. Reversing the sweep at 1.6 V(RHE) results in a decrease in current (no more water oxidation and the surface of the electrode is fully oxidized). When the potential reaches to 1.1 V(RHE), the gold oxide, formed on the positive sweep, begins to be reduced. Nearing 1.0 V(RHE) on the negative sweep, the negative current begins to decrease, indicating that the oxidized gold is becoming depleted and at 0.8 V(RHE) all of the oxide has been depleted. When dissolved oxygen is present in the electrolyte current begins to flow on the negative sweep. When the electrode potential is about 0.4 V(RHE) an increasing negative current is measured; at  0.2 V (RHE) the current is steady at  30 A/cm2, indicating the electron transfer process is rate-limited by the availability of oxygen at the electrode–electrolyte interface. At about 0.0 V(RHE) the current increases due to water reduction. These data indicate that as long as the interface potential is more negative than 0.4 V(RHE), dissolved oxygen in the electrolyte will be reduced. Oxygen reduction can be a concern because it results in the creation of free radicals that can interact with molecules that make up a cell membrane causing the cell wall to lose integrity, which can result in cell death.

The electrical circuit equivalent is used here to underscore the importance of the double layer capacitance and the role of the charge stored on this element in driving electrochemical reactions. From the discussion in the previous section we know that as long as the electrode potential is between  1.2 V(RHE) and  0.4 V(RHE) no charge is transferred across the interface because no acceptor or donor states of equal energy levels exist at the interface. Therefore only charging of the double layer occurs and it occurs only as long as that interface potential is changing as a function of time. In this potential range, the electrode is behaving as a capacitor with a value of 20 F/cm2, and the current flowing in the system is described by j  C(dV/dt), where j is the current per unit area and C has the units farads per unit area. Oxygen reduction does not take place as long as the interface potential is greater than 0.4 V(RHE). The middle element of the circuit is shown with the voltage-current characteristics to account for current flowing because of oxygen reduction when the interface potential is more negative than 0.4 V(RHE). A current limiting element is in series with the nonlinear element to limit the current to be proportional to the oxygen concentration. Similarly, the current flowing into water reduction can be modeled as a nonlinear circuit element that begins to conduct when the potential across the interface is less than 0.0 V(RHE). Current is not limi­ ted in the third element because the water molecule concentrations does not restrict the current. Metal

0.0 C � 20 �F/cm

Electrode behavior under pulsed conditions Consider now how the electrode operates when a regulated current pulse is applied to the electrode in an electrolyte medium. For this discussion we will introduce an electrical circuit equivalent of the electrode–electrolyte interface and assume our electrode– electrolyte interface is characterized by the cyclic voltammogram, which is a gold electrode operating in sulfuric acid with dissolved oxygen. We will also assume that the electrode is free of an oxide coating prior to the onset of the stimulus pulse. The circuit model for the electrode–electrolyte interface is shown in Figure 11.5.

i

0.4 v 0.0

i

0.4 v

Oxygen reduction

Current proportional to % oxygen

Water reduction

Electrolyte

Figure 11.5  Electronic circuit representation for the electrode– electrolyte interface of a gold electrode operating in sulfuric acid at potentials less than 1.2 V(RHE), refer to the cyclic voltammogram in Figure 11.3. The capacitor represents charge stored on the double layer. The middle element represents current involved in oxygen reduction, which begins at interface potentials less than or equal to 0.4 V(RHE). A current limiter is shown to reflect the mass transport limitations imposed on oxygen reduction. The third element represents water reduction, which begins at an interface potential less than 0.0 V(RHE)

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11.  Fundamentals of Electrical Stimulation

Double layer charging 0

A

Water Oxygen reduction reduction plus plus double layer oxygen reduction charging plus double layer charging

Oxygen reduction plus double layer charging Oxygen reduction

B

A

Water reduction plus oxygen reduction plus double layer charging

Oxygen reduction

A

B

Figure 11.6  Electrode operation under monophasic stimulation conditions. In the top panel are shown two monophasic cathodic pulses. In the bottom panel is shown the resulting electrode interface potential over the course of pulse application. The heavy dashed line is intended to depict the interpulse interval and the light dashed lines are potential lines to guide the reader’s eye. The potential values shown reflect an electrode similar that that depicted in Figures 11.3 and 11.4, and assume the starting potential of the electrode is 0.8 V(RHE). Oxygen reduction can occur when the electrode interface potential is less than 0.4 V(RHE)

Monophasic Pulses Consider now a monophasic stimulus applied to an electrode represented in Figure 11.5. In Figure 11.6 is shown, as a function of time, the current applied to the electrode (top panel) and the resulting electrode– electrolyte potential, as a function of time. For purposes of discussion, it is assumed that the potential of the electrode, at the beginning of the pulse is 0.8 V(RHE). As a negative current is applied to the electrode the interface potential becomes more negative as electrons are added (electron energy is increasing). Until the potential reaches 0.4 V(RHE) no acceptor states in the electrolyte are available, so the charge injected into the electrode has gone into charging the double layer, charging the capacitor in Figure 11.5. Since the current (i) is constant, the rate of change of the electrode potential is dv/dt  C/i, where C is the value of the capacitor. Since i, the current, is negative, dv/dt is negative. Until the potential becomes less than or equal to 0.4 no charge flows across the electrode–electrolyte interface, but current does flow in the electrolyte to balance the negative charge build-up on the metal. As negative current continues to be applied to the electrode, the potential becomes less than 0.4 V(RHE) and electrons can be transferred from the electrode to oxygen molecules (acceptor) at the electrode interface, current begins to flow through the middle element in the model shown in Figure 11.5. The oxygen at the interface becomes rapidly depleted and further electron transfer to oxygen molecules becomes limited by the rate at which oxygen can be transported from the bulk electrolyte to the interface. Since the rate at which current is injected into the electrode exceeds the rate at which electrons can be transferred to oxygen, the electrode potential

becomes increasingly negative, approaching the potential at which electrons can be transferred to water molecules. If current continues to be applied to the electrode, the electrode potential flattens out, more or less, since water reduction is not a ratelimited process. Throughout the duration of the pulse, as long as the potential across the interface is changing, the charge on the double layer increases, in the negative direction. In this illustration, the pulse duration is sufficiently long to drive the electrode into water reduction for some time. At the termination of the current pulse the electrode potential is 0.0 V(RHE), which is sufficiently negative to still permit electrons to be transferred to any oxygen molecules close to the interface. As electrons are transferred to oxygen, the double layer discharges and the interface potential decays, going to 0.4 V(RHE) if the interpulse interval is sufficiently long, which is the case assumed for this discussion. Note that, since there are no acceptor states available between 0.4 and 1.2 V(RHE) (see Figure 11.4), electron transfer does not occur and the interface potential remains at 0.4 V(RHE). When the second current pulse is applied electron transfer reactions, faradic processes, accommodate all charge injection because the interface potential is at 0.4 V(RHE) at the beginning of the current pulse and proceeds to 0.0 V(RHE). Each successive cathodic current pulse produces the same result, in other words, all current injection goes into faradic reactions, which introduces reaction products into the region of the electrode that are either not normally present or in concentrations that are above normal. Two reaction products that might be introduced are super oxide (a free radical) and hydroxyl ions. Since free radical scavengers are normally present and the pH of body tissues are well buffered, body tissues may tolerate some of these reaction products.

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How stimulus waveform choices impact tissues

Current pulse #2 Current delivered to electrode

Current pulse #1 Double layer charging

�1.2 V(RHE) �0.8 V(RHE)

�0.4 V(RHE) �0.0 V(RHE)

Double layer charging

0 Electrode Interface potential

Oxygen reduction plus double layer charging

A

Water reduction plus oxygen reduction plus double layer charging

B

Double layer discharging

Oxide formation plus double layer1 charging D

0

C

A

Oxygen reduction

Figure 11.7  Electrode operation under biphasic stimulation conditions. In the top panel is shown a cathodic pulse followed, after a short delay, by an anodic pulse of equal amplitude and duration as the cathodic pulse. In the lower panel is shown the electrode–electrolyte interface potential during the application of the biphasic stimulus pulse

Biphasic pulses, balanced charge, and imbalanced charge John Lilly (Lilly et al., 1955) reported that when they used low levels of monophasic stimulation they could maintain the excitability of neural preparations. However, during stimulation with higher amplitudes, a balanced biphasic waveform was necessary to prevent loss of excitability. Let us consider the electrode reactions under biphasic conditions, a cathodic current pulse followed by an anodic current pulse. Referring to Figure 11.7, the behavior of the electrode–electrolyte interface potential is the same as it was for the first pulse of the monophasic pulse, in Figure 11.6. Following the termination of the cathodic pulse, there is a short time delay before an anodic pulse is applied. During the short delay period oxygen reduction can continue, as in the previous case. However, when the anodic pulse is applied current discharges the double layer to move the interface potential positive to the potential required to reduce dissolved oxygen, point designated by A, and thus terminating further oxygen reduction. With the further application of current, the double layer discharges to a value equal to the interface potential prior to the start of proceeding cathodic pulse, point labeled B. Note, if we terminated the anodic pulse here, the interface potential would be where we started before the cathodic pulse, less oxygen reduction would have taken place, and the charge (current  time) in the anodic phase would be less than that injected in the cathodic pulse. However, in this example we are working with a balanced biphasic stimulus pulse, so the interface potential continues to rise to the point labeled as C. At this potential, referring to Figure 11.4, the potential is sufficient to transfer electrons from the electrolyte to the metal electrode to

form a metal oxide on the surface of the electrode, and the interface potential continues to rise to the point labeled as D. The oxide-forming reaction can result in reaction products that are soluble, particularly in chloride containing electrolytes, leading to loss of electrode metal, corrosion. To avoid electrode corrosion we need to limit the potential excursions to values below that required for oxide formation, which can be accomplished in a couple of ways. First, we can put less charge in the anodic phase than was put into the cathodic phase (e.g. terminating the anodic pulse when the interface potential reaches the point labeled as C, or something less). Second, if we want to keep the balanced charge biphasic pulse, we would have to reduce the amount of charge injected in the cathodic phase, which restricts neural excitation to excitable tissues closer to the electrode. As a practical matter, the rule of thumb is balanced biphasic stimulation. Now, if we had implantable stimulators with the capacity to measure the interface potential under pulsed conditions we could use a closed-loop control system to automatically avoid electrode corrosion; unfortunately, we don’t have that luxury yet, but we’re sure it will come in the future because we can increase the amount of tissue activated without damaging the electrode.

How stimulus waveform choices impact tissues A bit of the history behind waveforms and stimulus magnitudes: Lilly et al. (1952) reported that he and others had found long-term monophasic, anodic and cathodic stimulation to be injurious; then, in 1955, Lilly et al. reported that balanced charge biphasic

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11.  Fundamentals of Electrical Stimulation

Log (Q/A/phase) � k �log (Q/phase)

Charge Density (�coulombs/cm2/phase)

104

1000

K � 1.85

k � 1.85 314 exp ‘97 Scheiner-Mortimer ’90 safe Brown ‘77 @ 10 Hz (208 hr cont) Agnew ’89 periph nerve #C526 Oct ‘96 McCreery ’88, 89 safe Yeun ‘81 safe Yeun ‘81 unsafe McCreery ’86 unsafe McCreery ’86 safe McCreery ’88, 89 unsafe Bhargava 93 US Cogan, Guzelian et al. ‘04 s Cogan, Guzelian et al. ’04 McCreery et al. ‘02 Medtronic DBS limit

100

10

1 0.001

0.01

0.1

1

10

100

Charge (�coulombs/phase)

Figure 11.8  Graphical plot of Shannon (1992) formulation for safe stimulation. Data shown here are derived from experiments that are published and unpublished. Solid (filled in) symbols were deemed unsafe by the investigators. The open arrowhead symbols are from studies using imbalanced biphasic pulse applied to muscle through intramuscular stimulating electrodes

stimulation could be used for protracted periods without indications of neural injury. In 1975, Pudenz et al. reported rapid vasoconstriction, blood–brain breakdown and thrombus formation at sites stimulated with monophasic pulses (presumably cathodic) (Pudenz et al., 1975a). In an additional 1975 report by Pudenz et al. (Pudenz et al., 1975b) they indicated that biphasic stimulation was injurious, the extent increasing with increasing stimulus magnitude. In 1992 Shannon constructed a mathematical model, from data reported by several investigators, to predict safe levels of stimulation. The model used charge density (Q/A) and charge (Q) and predicts safe stimulus magnitudes to the left of a line described by



Log (Q/A)  k  log (Q), where k is often chosen as 1.85



(11.3)

When stimulus parameters are chosen that are to the right of the line (Figure 11.8), the tissue response is deemed injurious and corrosion of the electrode was frequently reported for experiments where balanced charge biphasic stimuli were applied.

The mechanism for tissue injury, resulting from electrical stimulation, is not known. However, using the information provided in the previous paragraphs, we might speculate on the mechanisms. Oxygen reduction could play a role in tissue injury during monophasic cathodic stimulation. Free radicals created in oxygen reduction could interact with nitric oxide to reduce NO, responsible for blood vessel dilation, leading to vessel constriction and thrombi formation, as observed by Pudenz et al. Switching from monophasic to biphasic stimulation, one of these authors (J.T.M.) has observed rapid vessel dilation, suggesting that, if oxygen reduction is the cause of vessel constriction, then the amount of oxygen reduced during the stimulus, not that reduced in the interpulse interval, is insufficient to effect NO in the vessels, or the endogenous free radical scavengers can accommodate the rate of free radical generation during the pulse (typically 100 sec). The creation of platinum-chloride complexes, which are powerful oxidizing agents, can occur when the interface potential is pushed too far positive. The injection of platinum salts into brain tissues has been reported to result in brain tissue lesions that mimic

II.  Fundamentals of neuromodulation

current/voltage stimulation

those observed from electrical stimulation to brain tissues (Agnew et al., 1977). Since electrode corrosion has been reported along with tissue injury at high stimulus amplitudes, these complexes could interact with cell membranes to cause cell damage and explain tissue injury when balanced-charge biphasic stimulus parameters are on the right-hand side of the Shannon curve. This line of thinking suggests that imbalanced biphasic stimuli, less charge in the anodic phase, might enable larger depolarizing pulses, the cathodic phase, without damaging the electrode through corrosion and creating platinum-chloride complexes that could damage cells near the electrode during the anodic phase.

Current/voltage stimulation The stimulation examples presented in this chapter, thus far, have used current pulses, more correctly, regulated current pulses. The use of current pulses may have started in the laboratory because investigators knew that the potential field created in the neural tissues is constant during the application of a current stimulus. When voltage pulses are used the potential field varies with time because the electrode impedance varies as a function of time (the voltage across the double layer changes as it charges); in general the current flowing in the neural tissue space decreases over the duration of the voltage pulse. Remember, it is the potential field that gives rise to the creation of propagated action potentials. In commercially available pulse generators there are devices that put out either voltage pulses or current pulses. From an excitatory point of view, both types of stimuli can initiate propagated action potentials. From a practical standpoint, at least early on, voltage devices were simpler, requiring fewer electrical components. Devices that produce regulated current pulses require feedback circuitry; circuits that produce voltage pulses do not require feedback circuitry. With the incorporation of integrated circuits into pulse generators, complexity became less of an issue in device construction. However, many commercial producers of voltage pulse devices find the expense to switch to current pulses an economic hurdle. Though not as important now, the ability to control the field in the tissue

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medium through regulated current pulses will become more important as “tunable electrodes” are introduced into the field (Tarler and Mortimer, 2007).

References Agnew, W.F., Yuen, T.G., Pudenz, R. and Bullara, L.A. (1977) Neuropathological effects of intracerebral platinum salt injections. J. Neuropathol. Exp. Neurol. 36: 533–46. Armstrong, C.M. and Hille, B. (1998) Voltage-gated ion channels and electrical excitability. Neuron 20: 371–80. Crochetiere, W.J., Vodovnik, L. and Reswick, J.B. (1967) Electrical stimulation of skeletal muscle – a study of muscle as an actuator. Med. Biol. Eng. 5: 111–25. Doyle, D.A. (2004) Structural changes during ion channel gating. Trends Neurosci. 27: 298–302. Edström, L. and Kugelberg, E. (1968) Histochemical composition, distribution of fibres and fatiguability of single motor units. Anterior tibial muscle of the rat. J. Neurol. Neurosurg. Psychiatry 31: 424–33. Gregerson, K.A. (2003) The voltage sensor of ion channels revealed. Trends Endocrinol. Metabol. 14: 251–2. Grill, W.M. and Kirsch, R.F. (2000) Neuroprosthetic applications of electrical stimulation. Assist. Technol. 12: 6–20. Kantrowitz, A. (1961) Electronic physiologic aids. Proc. 3rd. IBM Med. Symposium: 549. Liberson, W.T., Holmquest, H.J. and Scott, D. (1961) Functional electrotherapy stimulation of the peroneal nerve synchronized with swing phase of the gait of hemiplegic patients. Arch. Phys. Med. Rehabil. 42: 101. Lilly, J.C., Austin, G.M. and Chambers, W.W. (1952) Threshold movements produced by excitation of cerebral cortex and efferent fibers with some parametric regions of rectangular current pulses (cats and monkeys). J. Neurophysiol. 15: 319–41. Lilly, J.C., Hughes, J.R., Alvord, E.C., Jr. and Galkin, T.W. (1955) Brief, noninjurious electric waveform for stimulation of the brain. Science 121: 468–9. Long, C. and Masciarelli, V.D. (1963) An electrophysiologic splint for the hand. Arch. Phys. Med. Rehabil. 44: 499. Merrill, D.R. et al. (2005) The electrochemistry of gold in aqueous sulfuric acid solutions under neural stimulation conditions. J. Electrochem. Soc. 152: 212–21. Peckham, P.H. (1972) Electrical Excitation of Skeletal Muscle: Alterations in Force, Fatigue, and Metabolic Properties. Cleveland, OH: Department of Biomedical Engineering, Case Western Reserve University, pp. 170. Pudenz, R.H., Bullara, L.A., Dru, D. and Tallala, A. (1975a) Electrical stimulation of the brain. II. Effects on the blood–brain barrier. Surg. Neurol. 4: 265–70. Pudenz, R.H., Bullara, L.A., Jacques, S. and Hambrecht, F.T. (1975b) Electrical stimulation of the brain. III. The neural damage model. Surg. Neurol. 4: 389–400. Shannon, R.V. (1992) A model of safe levels for electrical stimulation. IEEE Trans. BME 39: 424–6. Tarler, M.D. and Mortimer, J.T. (2007) Linear summation of torque produced by selective activation of two motor fascicles. IEEE Trans. Neural Syst. Rehabil. Eng. 15: 104–10.

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Neuromodulation and Neuronal Plasticity Alon Y. Mogilner

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Topographic Organization of the Central Nervous System – Historical Overview 123 Neuronal Plasticity in Disease States Chronic Pain Movement Disorders

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modification of CNS topographic maps (for ­example, the homuncular mapping in primary somatosensory and motor cortices) due to changes in neuronal input. This chapter will review what is known about neuronal plasticity, discuss the evidence of plasticity in a number of disease states in which neuromodulation is a potential therapy, and review the evidence of the connection between neuromodulation therapy and neuronal plasticity.

The immediate and dramatic improvements seen seconds after deep brain stimulator (DBS) activation in a patient with Parkinson’s disease, combined with the rapid return of symptoms following DBS shutoff, suggest that its mechanism of action involves modulation of existing neuronal circuitry as opposed to the ­ formation of new neuronal connections. Changes in the computational network state, such as ­disinhibition, rather than sprouting of new axons, can best explain the time course of such changes. In contrast, the delay in symptomatic improvement seen in other forms of neuromodulation therapy (Trost et al., 2006) is more consistent with other mechanisms of action, namely subacute to chronic formation of new neural ­ networks via mechanisms other than simple computational state changes. It is likely, however, that multiple mechanisms of neuromodulation are at play in states of chronic therapy. These mechanisms include representational plasticity, which can be defined as the

Neuromodulation

Neurostimulation and Neuronal Plasticity

Topographic organization of the central nervous system – historical overview In 1937, Penfield and Boldrey reported data obtained via electrical stimulation of frontoparietal cortex in neurosurgical patients, and described orderly maps of body present in the precentral motor cortex as well as the postcentral sensory cortex. The well-known

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to these digits became completely occupied by the representations of the adjacent skin territories, including the adjacent digits, palmar pads, and digit stumps (Merzenich et al., 1984). Similarly, when digits of monkeys were surgically fused, mapping of somatosensory cortical territory in the months subsequent revealed that the normal sharp discontinuity between the ­ individual digit representations was abolished (Lenz et al., 1998). Following upper extremity deafferentation, the upper limb area of cortex ultimately became responsive to stimulation of the lower part of the face, an intracortical distance of approximately 10 mm (Lenz et al., 1998). The spatial extent of such large-scale reorganization suggested that multiple mechanisms account for these changes (Mogilner, 1993), including: 1. Simple computational changes in the relative weights of excitatory and inhibitory inputs to a predefined neural matrix 2. Axonal sprouting 3. Changes in synaptic size, number, and morphology 4. Reorganization at the subcortical level.

Figure 12.1  Somatosensory homunculus (Source: Mogilner, 1993)

homunculi of the precentral and postcentral motor and sensory cortices were further elaborated upon by Penfield and Rasmussen 13 years after the initial reports (Penfield and Rasmussen, 1950) (Figure 12.1). For two decades subsequently, the consensus was that these maps are static, determined at birth or perhaps during an early critical period of development, and that these maps do not significantly change during an individual’s lifetime. In the early 1980s, pioneering work by Merzenich and others demonstrated that, contrary to previous belief, these maps maintain the ability to reorganize in response to a variety of both peripheral and central perturbations, termed cortical plasticity. Following the transection of the median nerve in owl and squirrel monkeys, the somatosensory cortical territory previously responsive to median nerve inputs became almost immediately responsive to inputs from the uninjured radial and ulnar nerve afferents (Merzenich et al., 1983a, 1983b). Ultimately, over a period of months, an entirely new topographic map emerged, with extensive representations of the radial and ulnar nerve territory of the hand ­appearing in areas previously responsive to median nerve inputs. Similarly, following amputation of one or two digits in monkeys, the cortical territory originally responsive

The first direct evidence of similar plasticity occurring in humans was demonstrated in 1993 by the author and colleagues, via magnetoencephalography (MEG), a non-invasive method of brain mapping utilizing recordings and localizations of the weak ­magnetic fields produced by neural activity (Mogilner et al., 1993) (Figure 12.2). The primary somatosensory cortex representation of the hand was mapped in two adults with syndactyly, both prior to and following surgical separation of the fused digits. Prior to surgery, cortical maps were abnormal, demonstrating shrunken hand representations without the usual somatotopy. Within weeks after digit separation, cortical reorganization was noted to occur, spanning distances of approximately 1 cm, and resulting in appropriate somatotopic representations (Figure 12.3). Subsequent functional imaging studies utilizing MEG, and later functional MRI (fMRI), demonstrated evidence of plasticity in patients with a variety of both central and peripheral nervous system injuries including amputation, spinal cord injury, peripheral nerve injury, and stroke (Jang et al., 2005; Rocca and Filippi, 2006; Tecchio et al., 2006; Endo et al., 2007). Reorganization has been demonstrated to occur ­during the rehabilitation period following neurologic injury (Jurkiewicz et al., 2007; Richards et al., 2008). Analogous plastic changes have been demonstrated to occur following short-term motor skill learning (Hlustik et al., 2004), and trained musicians show enlarged representations of both the hand used to play the instrument as well as in the tonotopic map

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Neuronal plasticity in disease states

of the auditory cortex when compared with controls (Pantev et al., 2001).

Neuronal plasticity in disease states A variety of chronic conditions treated with neuromodulation are associated with neuronal plasticity at multiple levels along the neuraxis. Whether this plasticity represents the generator of the pathology or is merely an epiphenomenon remains unclear; nonetheless these findings must be taken into account when postulating mechanisms of action of neuromodulation therapies.

Chronic Pain Flor et al. (1997) demonstrated evidence of cortical reorganization in the primary somatosensory ­cortex of patients with chronic lower back pain via MEG. Cortical localization of stimulation of the painful area in primary somatosensory cortex S1 was

shifted medially in comparison with control subjects. Ramachandran reported psychophysical evidence of cortical reorganization in amputees, with complete somatotopic representations of the amputated upper limb found on adjacent body sides, including the face, chest and axilla (Ramachandran et al., 1992a, 1992b; Ramachandran, 1993). Using MEG, Flor et al. (1995) demonstrated a direct positive correlation between the degree of cortical plasticity and the magnitude of phantom limb pain in patients with upper extremity amputations. Higher pain scores were associated with a higher shift in the focus of cortical responsivity to tactile stimulation of the face. These results suggest that the phenomenon of phantom limb pain might be a result of maladaptive cortical reorganization, and further suggest that a possible mechanism for neuromodulation’s efficacy may be via modification of these already-modified cortical and subcortical sensory and motor representations. Supporting evidence for cortical reorganization’s presence in chronic pain syndromes was reported by Maihöfner and colleagues in a longitudinal study in patients with complex region pain syndrome (CRPS) (Maihöfner et al., 2004). During the acute pain phase,

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Figure 12.2  Somatotopic organization of the hand area of the primary somatosensory cortex in normal adults as demonstrated by MEG. (A and B) MEG dipole source locations for the digits of the hand in one normal adult projected onto a three-dimensional MRI reconstruction of the subject’s brain, with the color key shown in C. (D) Two-dimensional plot of the above dipole locations showing the average (symbols) and standard errors (surrounding gray ovals) of localization for each finger in the yz (coronal) plane. (E) Composite intersubject map of hand area in nine subjects obtained by repetitive least-squares minimization of same-finger distances for all fingers between subjects, noting a distance over 1 cm between the cortical representation of the thumb and little finger (Reproduced with permission from Mogilner et al. (1993). Copyright (1993) National Academy of Sciences, USA)

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Figure 12.3  Cortical plasticity following partial surgical reconstruction of complex syndactyly in an adult. Small finger was separated from central ones, which remained together. Digit 2 was congenitally absent. (A) Three-dimensional MRI reconstruction of the patient’s brain, with the cortex anterior to the postcentral gyrus removed to visualize dipole sources. (B) Pre-surgical map with dipole locations obtained for the thumb and middle and little fingers; the hand is shown on the right with the color-coded key. Coronal (top) and sagittal (bottom) graphs of dipole locations (mean  SEM) are shown for these three digits studied. Maps show significant overlap of digit locations and a reduced inferior-superior extent of the hand area compared to normative data. (C) Hand map following surgical separation of digit 5. Data shown were obtained 7 days post surgery. Coronal (top) and parasagittal (bottom) views illustrate that the fingers have attained distinct cortical locations. (D) Plot of middle–little finger distance over time. The patient was studied preoperatively five times over a period of 6 months and 1, 4, and 6 weeks postoperatively. The thick vertical bar indicates the date of surgery (September 3). The cortical interfinger distance increased by 2.9  1 mm (p  0.001) following surgery, and this increase was observable as soon as 1 week after surgery (Reproduced with permission from Mogilner et al. (1993). Copyright (1993) National Academy of Sciences, USA)

the hemisphere contralateral to the affected upper extremity demonstrated an altered somatotopic organization when compared with the contralateral hemisphere. Specifically, the overall cortical representation of the hand was shrunken when compared with the contralateral hand. One year later, in patients

with decreased pain, the cortical representation of the affected hand regained its normal spatial extent. Microelectrode recordings and microstimulation performed in patients undergoing stereotactic neurosurgery have confirmed aberrant thalamic functional organization in patients with chronic pain syndromes

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neurostimulation and neuronal plasticity

(David et al., 1996). Mapping of the sensory thalamus (Ventralis Caudalis, VC nucleus) was performed in patients with chronic pain as well as in patients with movement disorders. In non-pain patients, the location of the “projected field,” i.e. that part of the body activated by thalamic stimulation, matched the receptive field of the sensory neurons located at that site. In contrast, there was a high incidence of projected field – receptive field mismatches noted in the chronic pain patients. In an earlier study by the same group, the thalamic representation of the trunk was noted to be significantly larger in patients with deafferentation pain in the leg and foot than in patients without pain (Kiss et al., 1994).

Movement Disorders A number of studies have demonstrated abnormalities of the standard cortical and subcortical somatotopic maps in patients with dystonia. Microelectrode recording studies in the globus pallidus and thalamus of patients with dystonia undergoing stereotactic surgery have shown an enlarged sensory representation of the affected limb, with receptive fields that were widened and less specific than reported in normal primates (Lenz and Byl, 1999; Lenz et al., 1998, 1999; Vitek et al., 1999). A functional MRI (fMRI) study in patients with focal right hand dystonia demonstrated an altered somatotopic organization in the left putamen. Furthermore, there was decreased distance in three-dimensional space between the representations of the hand and lip in the dystonic patients which correlated with duration of illness.

Neurostimulation and neuronal plasticity There is an increasing body of evidence, both from the research and clinical arenas, that chronic ­neurostimulation can effect permanent changes in neural organization. Case studies and small case series of patients undergoing motor cortex stimulation for post-stroke pain have demonstrated improved motor function in a subset of patients with motor weakness. Katayama et al. (1997) described improvement in motor function in 8 of 42 patients undergoing MCS for pain control. Motor improvement did not appear to correlate with pain relief. Brown and Pilitsis reported improvement in facial motor function in 3 of 10 patients with neuropathic facial pain who underwent MCS (Brown and Pilitsis, 2005). They suggest that

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motor cortex stimulation may improve motor function by amplifying the activity of marginally functioning motor neurons. These findings were considered in the planning of clinical trials for MCS for stroke, the results of which appear to be promising (Brown et al., 2006; Kim et al., 2008; Levy et al., 2008). Direct evidence of cortical plasticity with neurostimulation has been demonstrated in a primate model of ischemia (Plautz et al., 2003). Following induced ischemia to the motor cortex, subthreshold stimulation of the peri-infarct motor cortex was performed. Along with improvement in motor function, cortical mapping demonstrated the emergence of new motor maps in the peri-infarct motor cortex. A similar study in rats demon­strated a significant increase in the surface density of dendritic processes immunoreactive for cytoskeletal proteins in the animals that underwent 50 Hz cortical stimulation (Adkins-Muir and Jones, 2003). A brief report demonstrated sensory cortical map plasticity in a single patient undergoing chronic spinal cord stimulation for lower extremity complex regional pain syndrome using MEG. The cortical evoked responses to tactile stimulation of the lower extremity shifted with spinal cord stimulation, suggesting dynamic plasticity induced by SCS (Mogilner et al., 2000) (Figure 12.4). Following DBS for dystonia, improvement may be delayed days to weeks following stimulator activation, and may progressively improve over weeks to months, suggesting an element of neuronal plasticity following DBS (Krauss et al., 2003; Yianni et al., 2003; Krause et al., 2004). It should be noted, however, that a similar delay in improvement is also seen with pallidotomy (Krauss et al., 2003; Yianni et al., 2003; Krause et al., 2004). This suggests that, at least in the case of movement disorder surgery, these plasticity phenomena may not be a direct result of DBS per se, but of the effects of DBS on the involved neural networks. Analogously, metabolic changes seen on PET following STN lesioning and STN DBS are similar (Trost et al., 2006). The recent report by Schiff and colleagues of medial thalamic stimulation following severe traumatic brain injury in a single patient suggest that ­neuromodulation may facilitate neuronal reorganization (Schiff et al., 2007). Improvements in several behaviors were noted to persist even after turning the stimulator off for significant periods of time. These findings are consistent with findings in medial thalamic stimulation in the rat, which demonstrated a cumulative effect in cognitive improvement with continuous stimulation (Shirvalkar et al., 2006). This same study reported an up-regulation of c-fos and zif268 gene expression in the cortex, striatum, and hippocampus soon after the

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Figure 12.4  Reversible somatosensory cortical plasticity during spinal cord stimulation (SCS) for lower extremity neuropathic pain. Dipole source locations corresponding to stimulation of the painful lower extremity were obtained with MEG with the stimulation off and on. (A) A medial and inferior shift in the dipole source for the lower extremity was noted with stimulation. (B) Stimulation of the unaffected thumb was used as a control, demonstrating no significant difference in dipole source locations between the stimulation on and stimulation off conditions (Reproduced with permission from Mogilner et al. (1993). Copyright (1993) National Academy of Sciences, USA)

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conclusion

onset of stimulation. Both of these genes are known to be up-regulated during activation due to a variety of conditions, including associative learning.

Conclusion Advances in basic and clinical neurosciences over the past 20 years have brought with them a completely new understanding of the dynamic and evolving nature of both cortical and subcortical representational topography. Neuronal representational plasticity can occur rapidly, over large distances in the nervous system, and across multiple sensory and motor modalities. This plasticity appears in some cases to correlate with improvement in function, but in other cases may in fact result in untoward consequences such as chronic pain. In parallel, over the same time period, we have seen dramatic growth and evolution in the field of neuromodulation. Similar to neuronal plasticity, the beneficial effects of neuromodulation on disease states can occur rapidly and across multiple modalities. The intriguing evidence from a small but ever-increasing clinical and basic science research suggests that neuromodulation may exert its effects via, at least in part, facilitation of beneficial plastic changes in the nervous system, as well as modification of abnormal reorganization occurring as a result of various disease states. Future work will undoubtedly elucidate these interactions in great detail, and will likely allow future neuromodulation technology to harness the innate ability of reorganization and self-repair of the nervous system.

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Thesis, Department of Physiology and Neuroscience, New York University. Mogilner, A., Grossman, J.A., Ribary, U., Joliot, M., Volkmann, J., Rapaport, D. et al. (1993) Somatosensory cortical plasticity in adult humans revealed by magnetoencephalography. Proc. Natl. Acad. Sci. U S A 90: 3593–7. Mogilner, A., Rezai, A., Zonenshayn, M., Ribary, U. and Llinas, R. (2000) Functional Brain Imaging and Neurostimulation: Localization of Cortical Activity with Magnetoencephalography. San Francisco, CA: Presented at American Association of Neurological Surgeons Annual Meeting. Pantev, C., Engelien, A., Candia, V. and Elbert, T. (2001) Representational cortex in musicians. Plastic alterations in response to musical practice. Ann. N Y Acad. Sci. 930: 300–14. Penfield, W. and Boldrey, E. (1937) Somatic motor and sensory representation in the cerebral cortex of man as studied by electrical stimulation. Brain 60: 389–443. Penfield, W. and Rasmussen, T. (1950) The Cerebral Cortex of Man. A Clinical Study of Localization of Function. New York: Macmillan. Plautz, E.J., Barbay, S., Frost, S.B., Friel, K.M., Dancause, N., Zoubina, E.V. et al. (2003) Post-infarct cortical plasticity and behavioral recovery using concurrent cortical stimulation and rehabilitative training: a feasibility study in primates. Neurol. Res. 25: 801–10. Ramachandran, V.S. (1993) Behavioral and magnetoencephalographic correlates of plasticity in the adult human brain. Proc. Natl. Acad. Sci. U S A 90: 10413–20. Ramachandran, V.S., Rogers-Ramachandran, D. and Stewart, M. (1992a) Perceptual correlates of massive cortical reorganization. Science 258: 1159–60.

Ramachandran, V.S., Stewart, M. and Rogers-Ramachandran, D.C. (1992b) Perceptual correlates of massive cortical reorganization. Neuroreport 3: 583-6. Richards, L.G., Stewart, K.C., Woodbury, M.L., Senesac, C. and Cauraugh, J.H. (2008) Movement-dependent stroke recovery: a systematic review and meta-analysis of TMS and fMRI evidence. Neuropsychologia 46: 3–11. Rocca, M.A. and Filippi, M. (2006) Functional MRI to study brain plasticity in clinical neurology. Neurol. Sci. 27 (Suppl. 1): S24–S26. Schiff, N.D., Giacino, J.T., Kalmar, K., Victor, J.D., Baker, K., Gerber, M. et al. (2007) Behavioural improvements with thalamic stimulation after severe traumatic brain injury. Nature 448: 600–3; see supplementary discussion on-line. Shirvalkar, P., Seth, M., Schiff, N.D. and Herrera, D.G. (2006) Cognitive enhancement with central thalamic electrical stimulation. Proc. Natl. Acad. Sci. U S A 103: 17007–12. Tecchio, F., Zappasodi, F., Tombini, M., Oliviero, A., Pasqualetti, P., Vernieri, F. et al. (2006) Brain plasticity in recovery from stroke: an MEG assessment. Neuroimage 32: 1326–34. Trost, M., Su, S., Su, P., Yen, R.F., Tseng, H.M., Barnes, A. et al. (2006) Network modulation by the subthalamic nucleus in the treatment of Parkinson’s disease. Neuroimage 31: 301–7. Vitek, J.L., Chockkan, V., Zhang, J.Y., Kaneoke, Y., Evatt, M., DeLong, M.R. et al. (1999) Neuronal activity in the basal ganglia in patients with generalized dystonia and hemiballismus. Ann. Neurol. 46: 22–35. Yianni, J., Bain, P.G., Gregory, R.P., Nandi, D., Joint, C., Scott, R.B. et al. (2003) Post-operative progress of dystonia patients following globus pallidus internus deep brain stimulation. Eur. J. Neurol. 10: 239–47.

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Gene-Based Neuromodulation Thais Federici, Jonathan Riley, and Nicholas Boulis

o u tl i ne Gene-Based Neuromodulation: An Unmet Need Targeted Strategies for Gene-Based Neuromodulation In vivo Gene Therapy – Background Viral Vector Types Strategies for Regulation for   Transgene Expression Vector Delivery Strategies Ex vivo Gene Therapy

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affect cells within the current field in a relatively indiscriminant fashion. Moreover, this approach requires electronic prosthetic devices that are susceptible to infection or various forms of malfunction. In contrast, the ability to affect specific cells in a constrained anatomical target region can be achieved with the use of implantable microinfusion pumps that are programmable, rechargeable, refillable, and capable of delivering medications directly to the intrathecal space, neural parenchyma, or adjacent to a peripheral nerve. This approach has been employed predominately for the treatment of pain or spasticity. Because pumps deliver pharmacological agents that have cellular specificity, off-target effects can be potentially reduced. However, pumps remain incap­ able of achieving precise anatomic specificity, and require implanted devices that are even more prone to malfunction than stimulators.

Gene-based neuromodulation: an unmet need Neuromodulation has become a principal tool of functional neurosurgery, finding applications in the treatment of clinical syndromes that result from imbalanced signaling within neural networks. To this end, neuromodulatory approaches have been employed in the treatment of movement disorders, pain, spasticity, epilepsy, and psychiatric disorders after they have proven refractory to medical treatment. Historically, neurosurgical intervention to modulate aberrantly functioning neural networks for the indications listed above relied upon focal lesioning. However, ablation is neither adjustable nor reversible and has limited efficacy. As discussed throughout this text, chronically implanted electrodes allow for this adjustment, but

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Because the subcellular machinery underlying synaptic transmission is made up of a variety of proteins, gene delivery encoding these proteins can be used to achieve gene-based neuromodulation. Gene delivery provides temporal and spatial advantages. Because most synaptic proteins are intracellular, gene delivery bypasses the plasma membrane, producing the protein within the target cells. The vectors used for gene delivery can be targeted either through engineering of tropism or the promoters that control gene expression. These features provide potentially improved cellular, and hence functional, specificity. In addition, a lack of implanted neurosurgical hardware removes concerns for deviceassociated limitations and complications. Achieving the potential benefits of gene-based neuromodulation depends on the choice of: appropriate delivery vector, route of administration, therapeutic transgene, and regulatory approach to transgene expression. The fact that advanced generation vectors are capable of delivering genes to terminally differentiated cells like neurons creates the ability to alter the machinery of synaptic activity and neuronal excitability without disruption to the connectivity of existing neural networks. To date, the majority of attempts have entailed delivery of genes for rate-limiting enzymes in the pathways of neurotransmitter production, or for production of the neuropeptide precursors. However, alternative approaches have been designed to augment the machinery of synaptic transmission as well as to generate novel, rationally designed strategies capable of altering specific intracellular compon­ ents of the transmission apparatus. More specifically, gene-based approaches can be used to augment the production of endogenous neurotransmitters, generate signaling receptors or components of the intracellular signaling machinery, and to impact specific events required for synaptic vesicle release, as demonstrated in Figure 13.1. This chapter will further explore the

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range of gene-based strategies that may be used to modulate synaptic transmission and will discuss applications to relevant disease states.

Targeted strategies for gene-based neuromodulation In vivo gene-based neuromodulation refers to the delivery of a desired transgene to a target cell type, with the intention of impacting the process of synaptic transmission. Viral vectors modified to achieve target cell specificity and transgene constructs optimized for both expression and regulation characteristics represent favored strategies to achieve in vivo gene-based neuromodulation. Conversely, ex vivo gene-based neuromodulation refers to the use of a cell construct engineered in vitro to secrete a neuromodulatory gene product. The following sections provide a more detailed description of factors that must be considered to achieve successful, widespread clinical translation of both in vivo and ex vivo gene-based neuromodulation strategies. Current progress, observed barriers to translation, and expected near-term advances are also examined.

In vivo Gene Therapy – Background Standard techniques for genetic manipulation allow for the modification of viruses into transgene delivery vehicles, or vectors. Specifically, the removal of genetic material required for virus replication, termed “­attenuation,” ensures the safety of viral ­vector ­systems and provides room for the insertion of the genetic code supporting the production of a therapeutic gene. By removing the remainder of a virus’ functional genes, in a process called “gutting,” potentially immunogenic viral gene products are removed, further improving the vector’s safety and increasing the “cloning capacity”

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Targeted strategies for gene-based neuromodulation

or room available to incorporate a therapeutic transgene. The desired transgene is inserted along with a promoter element that controls intracellular transgene expression. Promoters bind intracellular factors necessary for initiation of transcription. Therefore, the choice of promoter is crucial to achieve specificity, potency, and reversibility of gene expression. Reversibility can be achieved through the use of modified promoters that are selectively activated or de-activated depending upon the presence or absence of additional protein or small molecule ligands. At present, multiple viral vector types are being explored, each demonstrating unique capabilities and limitations with respect to accommodation of transgene size, target cell-speci­ ficity, transgene expression, and vector-related cellular toxicity and immune response. Vectors derived from adenovirus (AD), herpes simplex virus (HSV), adeno-associated virus (AAV), and lentivirus (LV) can effectively transduce neurons, suggesting that these vectors hold ­therapeutic potential for the ­treatment of neurological disorders. Herein, we discuss the utility of each viral vector type, promoters commonly used to achieve optimal neuronal expression, regulatory mechanisms designed to ensure control of transgene expression, and vector delivery strategies. Viral Vector Types Adenoviral Vectors Adenoviral vectors are non-enveloped doublestranded DNA vectors. Many studies conducted in the early 1990s characterized the neural tropism of adenoviral vectors in vitro and in vivo. Because of their ­ relatively easy production and high levels of ­transgene expression, adenoviral vectors are commonly used as research tools, both in vitro and in small animal models. However, accumulating evidence suggests that inflammatory cytokines terminate gene expression at the level of promoter regulation. The difficulty in achieving prolonged central nervous system (CNS) expression and the development of a pronounced inflammatory response weigh against clinical translation of first generation adenovirus in the nervous system. However, steps have been taken to reduce the observed drawbacks of first generation adenoviral vectors. Advanced generation vectors are gutted and so demonstrate reduced toxicity, increased cloning capacity, and prolonged transgene expression, making them viable for future efforts aimed at clinical translation. Alternatively, the canine adenovirus-2 (CAV-2) has also been observed to undergo high levels of neuronal transduction and appears to be significantly less recognized than human adenoviral vectors used to date (Perreau and Kremer, 2006).

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HSV Vectors Vectors derived from the herpes simplex virus type 1 (HSV-1), a naturally neurotropic enveloped double-stranded DNA virus, are promising for gene therapy applications. This vector has the dual advantage of a large cloning capacity and the potential to remain latent within neurons. Together, these characteristics, including the possibility of insertion of multiple genes, are advantageous for the treatment of neurological disorders (Lachmann, 2004). Recent advances have helped to minimize concerns regarding immunity and transient transgene expression. AAV Vectors Adeno-associated viral vectors (AAV) are based on the adeno-associated virus, a non-pathogenic, singlestranded DNA parvovirus. Recombinant AAV (rAAV) vectors’ excellent safety profile and durable gene expression have made it the preferred vector for gene therapy in the nervous system. An increasing number of AAV serotypes have been described, which display different tissue tropisms and patterns of transduction. Of these, ten have undergone significant characterization. Ongoing efforts are aimed at further improving the transduction efficiency and specificity. Their safety profile and prolonged in vivo gene expression are attractive features. Consequently, all ongoing clinical trials addressing non-oncological diseases of the nervous system utilize AAV vectors. Lentiviral Vectors Lentiviral vectors (LV) are based on the singlestranded RNA lentiviruses, which are a subclass of re­trovirus. They combine the advantages of midrange cloning capacity with stable gene expression. They are able to transduce dividing and non-dividing cells, including neurons, integrate transgenes into the host genome, and promote long-term gene expression (Jakobsson and Lundberg, 2006). Currently, the most widely used lentiviral vectors, for application to the CNS, are based on human immunodeficiency virus type 1 (HIV-1). Other systems, including the nonprimate equine infectious anemia virus (EIAV) and feline immunodeficiency virus (FIV), represent options for human CNS gene transfer. Strategies for Regulation for Transgene Expression Specificity of gene expression can vary depending on the promoter utilized and the neuroanatomic location targeted for delivery. Promoters are responsible for regulation of transgene expression. A given promoter

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can drive varying degrees of transgene expression depending upon the cell-type transduced. Moreover, cell-specific promoters are capable of minimizing inappropriate gene expression in surrounding areas. The neuron-specific enolase (NSE) promoter, for example, provides a means of targeting gene expression to different types of neurons including GABAergic, cholinergic, and dopaminergic cells. In contrast, application of the myelin basic protein (MBP) promoter enhances gene expression in the white matter above levels seen with the ubiquitous cytomegalovirus (CMV), phosphoglycerate kinase (PGK) promoters, or the astrocytespecific glial fibrillary acidic protein (GFAP) promoter (Papadakis et al., 2004). Selective regulation of gene expression represents a separate critical requirement for the development and application of the full potential of gene-based neuromodulation strategies. Specifically, because existing prosthetic-based neuromodulation can be adjusted, gene-based neuromodulation will only provide a comparable therapy if gene expression or the function of the gene product can be controlled. Further, the ability to regulate gene expression may allow for reductions in observed tolerance as adjustment of expression profiles may prevent tonic inhibition or activation of given pathways. In inducible and repressible promoters, the gene is transcribed when the promoter is either induced or not repressed. In the repressible tetracycline system, administration of this antibiotic prevents transgene expression. The “Tet-on” or “Tet-off” systems function by driving the expression of a tetracycline binding protein. In the presence of tetracycline or doxycycline, the drug–protein complex binds a promoter called the “tetracycline response element (TRE),” either driving or inhibiting gene expression depending on the system. However, long-term administration of tetracycline has potentially deleterious effects in vivo. Further, it displays minimal permeability for the blood–brain barrier, limiting its utility for application to the CNS. Alternatively, inducible expression systems promote transgene expression in the presence of the appropriate inducer. The inducible ecdysone promoter system (RheoSwitch) is controlled through the use of small molecule synthetic ligands that are simultaneously non-toxic and permeable to the blood–brain barrier. However, this system remains in preclinical testing stages. To date, no strategy designed to achieve regulation of transgene expression has been translated to clinical application. While choice of the appropriate vector can influence the cellular specificity of transduction and choice of the promoter can help to determine whether expression will be constitutive, inducible, or repressible,

post-translational transgene control may also be achieved. Specifically, the light-activated cation channel (ChR2) Channelrhodopsin-2, from the algae Chlamydomonas reinhardtii, undergoes conformational change and activation when illuminated. This phenomenon is reversible upon removal of the light source and operates on a physiologically relevant millisecond timescale. A recent study by Boyden et al. (2005) has adapted this concept into the production of a ChR2YFP fusion protein which was subsequently placed into an in vitro hippocampal culture through the use of an LV vector construct. They were able to reliably demonstrate milli­second timescale control of neuronal spiking in both excitatory and inhibitory transmission capacities and were further able to reproducibly generate subthreshold depolarizations. Subsequent studies by Zhang et al. (2006) have extended these findings to an in vivo mammalian model by injecting this LV construct into the dentate gyrus of the hippocampal formation. Fiber-optic excitation with blue light and patch clamp recording in ChR2-negative pyramidal cells demonstrated excitatory transmission in the recorded cell, with a magnitude and post-synaptic current that was dependent upon the duration of the light pulses. These in vitro and in vivo findings provide a means to achieve both real-time and persisting control over synaptic activity of localized or dispersed neuronal subpopulations. However, this approach requires a prosthetic for light delivery into neural parenchyma which will presumably carry the classic prosthetic-related complications.

Vector Delivery Strategies Direct Delivery Gene delivery can be achieved by direct administration of viral vectors to the target area (Chiocca, 2003). Modern stereotactic techniques commonly employed for the implantation of neuromodulatory prosthetics can be equally employed to vector injection. Unlike prosthetics, the spread of a vector following injection provides an extra level of complexity. Vector application to genetic and oncological diseases of the nervous system must achieve widespread distribution, while gene-based neuromodulation and the neuroprotective treatment of degenerative diseases requires delivery to precise distributions. As mentioned earlier, alterations in the capsid or envelope of vectors can alter ­cellular tropism and spread. However, understanding the distribution of a specific vector in a given injection protocol is critical to achieving the precision necessary for gene-based neuromodulation.

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Remote Delivery Remote injection represents a minimally invasive alternative to direct injection in an attempt to achieve CNS gene expression following peripheral administration. Gene delivery to spinal cord sensory and motor neurons (MN) can be achieved via retrograde axonal transport of vectors, for the treatment of neuropathic pain states and spasticity, as illustrated in Figure 13.2. HSV vectors have been used as a means to facilitate transgene delivery in animal models of neuropathic pain, as described later. Limited retrograde axonal transport, poor transduction efficiency, and increased axonal length in humans, however, remain as barriers to clinical application.

Ex vivo Gene Therapy The utility of cellular replacement therapies is readily apparent in the treatment of traumatic injury, stroke, or neurodegenerative diseases that beg the replacement of lost tissue and circuits. However, cellbased therapies have also been explored in a neuromodulatory capacity through sustained secretion of a desired peptide product into the local graft micro­ environment. Important considerations when choosing a cellular construct for ex vivo modification include the choice of the cell type, strategy for transgene

expression, desired transgene, and methods to prevent immunologic rejection following graft implantation. Commonly, the implanted cell type is chosen for its inherent secretory ability and so is often of neuroendocrine origin. For this reason, adrenal chromaffin cells have been utilized, as they perform a dedicated physiologic secretory role. In separate trials, fibroblasts have been chosen. The cell type is commonly modified by incorporation of a conditional oncogenic element that may be controlled with laboratory techniques and which simultaneously allows clonal expansion in vitro without concern for in vivo tumorigenesis. Prior to clonal expansion, a transgene-encoding plasmid is stably introduced into the cell in an in vitro environment, providing a means to ensure that the desired peptide is secreted in appropriate quantities. To date, plasmid promoters have been used to drive constitutively high transgene expression in the chosen graft cell type. Ex vivo engineered cellular grafts have employed a wide variety of transgenes, with the end result of dopamine secretion for the treatment of Parkinson’s disease (PD), inhibitory peptide secretion for treatment of epilepsy, and anti-­nociceptive peptide release in treatment of cancer-associated pain. Maintenance of graft viability is ensured by either host immunosuppression or through the use of a selectively permeable capsule that simultaneously achieves immunoisolation of the graft and free diffusion of nutrients, waste

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Figure 13.2  Remote gene delivery. (a) Primary sensory afferents (continuous line) contain a cell body within the dorsal root ganglion (DRG) and synapse on second degree afferents within the dorsal horn of the spinal cord. Conversely, lower motor neuron cell bodies are present in the ventral horn of the spinal cord and synapse peripherally at the neuromuscular junction (dashed line). (b) Viral vector delivery via retrograde axonal transport can be achieved by peripheral, intramuscular injection. The vector is taken up by primary sensory afferents and ultimately reaches the DRG (dotted line)

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products, and the secreted peptide. Multiple clinical trials have examined this latter approach in the treatment of cancer pain.

Current and potential indications Modulation of synaptic transmission can be achieved with transgenes that act to supplement neurotransmitter substrate for endogenous signaling pathways, alter excitatory vs. inhibitory balance at the cellular level, or interact directly with synaptic transmission machinery. Utilization of these different approaches for relevant disease states in preclinical and clinical studies is explored below.

Parkinson’s Disease (PD) The cardinal symptomatology of PD results from a loss in striatal dopamine delivery and subsequent ­disinhibition of the subthalamic nucleus (STN), which drives the globus pallidus interna (GPi) and substantia nigra pars reticularis (SNpr). Current pharmacologic treatments designed to directly impact this process predominately attempt to either replace dopamine, through administration of its precursor form L-DOPA, or block its degradation and uptake. Therefore, several researchers have pursued the transfer of genes for enzymes involved in dopamine synthesis as a means of elevating dopamine levels within the striatum (Chen et al., 2005; Kaplitt and During, 2006). Striatal expression of genes for the pathway-specific enzymes tyrosine hydroxylase (TH) have successfully enhanced dopamine production and reduced the functional consequences of dopamine depletion in parkinsonian rat models using AAV, Ad, and HSV-mediated vector delivery, while AAV has been used to achieve similar result with delivery of aromatic L-amino acid decarboxylase (AADC) in both rat and primate models. Long-term AADC gene expression has been validated out to at least one year and undiminished motor improvement out to six months in the rodent model. Ex vivo TH gene delivery to astrocytes (Lundberg et al., 1996) and myoblasts in rat models transplanted into the striatum have been used to achieve dopamine replacement. Co-transduction of GTP cyclohydrase I (GTPCHI) AAV-GTPCHI, an enzyme responsible for production of a cofactor, BH4, required by TH, with AAV-TH in a rat model increased dopamine production and behavioral recovery compared to AAV-TH alone. This result corroborates those of a similar cellbased delivery approach in which marrow stromal

cells or neural stem cells (NSCs) (Ryu et al., 2005; Kim et al., 2006) were modified ex vivo to express TH and GTPCHI and subsequently injected into the rat striatum. Similarly, behavioral improvement was attained by co-transduction with separate AAV vectors encoding TH and AADC and a single AAV vector encoding both enzymes (bi-cistronic). However, greater effect has been demonstrated in triple transduction experiments where supplementation of TH, AADC, and GTPCHI was simultaneously achieved (Muramatsu et al., 2002). Triple transduction experiments have been achieved by either separate administration of three AAV vectors or single administration of a lentiviral vector system based on the equine infectious anemia virus (EIAV). The use of this tri-cistronic vector, expressing the same TH, AADC, and GTPCHI, increased striatal dopamine production and reduced behavioral deficits over several months. A phase I trial, in which AAV-AADC is stereotactically delivered to the putamen, is currently under way (NCT00229736). Cell-based treatments of Parkinson’s disease have focused on implantation of cell grafts into the striatum modified to secrete dopamine into the adjacent parenchyma (Lu et al., 2005). Alternative treatment strategies for PD include provision of enzymes that either help to promote vesicular dopamine packaging or to reduce aberrant over-activity within the STN as attempts to restore relative balance of neural activity within the basal ganglia. To these ends, both the transporter responsible for synaptic concentration of dopamine, vesicular monoamine uptake transporter-2 (VMAT-2), and glutamate decarboxylase (GAD), the rate-limiting enzyme in GABA production, have been investigated. Despite loss of dopaminergic neurons, increased synaptic dopamine levels, especially in cells transduced with viral vectors designed to promote overexpression of dopamine, is postulated to promote downregulation of the vesicle-associated VMAT-2 transporter. In a parkinsonian rat model, either a tri-cistronic HSV vector encoding AADC, TH, and GTPCHI or a fourgene version that included VMAT-2 was injected. The four-gene transfer resulted in an improved behavioral outcome over the tri-cistronic LV alone. A subsequent trial examined the injection of cultured fibroblasts modified ex vivo to express AADC and VMAT2 in a parkinsonian rat model. Motor fluctuations were lessened when animals chronically administered L-DOPA dually expressed AADC and VMAT2 as opposed to AADC-only or control (Lee et al., 2006). Alternatively, in rat model studies of AAV-GAD delivery, both electrophysiological and microdialysis data suggest that GAD65 gene transfer may convert STN output from excitatory to inhibitory, implying that this approach

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represents a means of focused neural inhibition. A subsequent primate study has recapitulated these findings while simultaneously indicating that FDG PET imaging served as an accurate marker of graft viability and function (Emborg et al., 2007). A separate group has demonstrated improved enhancement of GABA production through use of the JDK, as opposed to CMV promoter (Lee et al., 2005). A phase I trial based upon the premise of AAV-GAD gene transfer to the human STN for PD has recently been completed (During et al., 2001). The results have not yet been published, yet lack of early termination indicates that no overt safety concerns were observed.

Epilepsy Standard of care treatment for medically refractory epilepsy with a known or suspected focus involves resection of the epileptogenic neural structures. Multiple preclinical studies in small animal models have demonstrated the potential utility of gene-based neuromodulation as a nondestructive, less invasive means by which to control aberrant excitability and synaptic activity. The majority of studies to date have examined augmentation of inhibitory signaling within epileptogenic foci through provision of genes responsible for production of inhibitory neurotransmitters or neuropeptides. Alternatively, inhibition of synaptic transmission has been achieved by downregulation of excitatory neurotransmitter cell surface receptor production (NMDAR) and through direct synaptic inhibition achieved by cleavage of the vesicle-associated docking protein, synaptobrevin. Preclinical studies examining overexpression of inhibitory small molecule neurotransmitters have predominately employed ex vivo-based delivery approaches whereas provision of inhibitory neuropeptides and other novel treatment strategies have commonly utilized in vivo approaches (Vezzani, 2004; Kaplitt and During, 2006; Noe et al., 2006). In vivo gene transfer techniques have widely utilized the AAV vector in preclinical studies as a means to deliver inhibitory neuropeptides, predominantly galanin and neuropeptide Y (NPY). AAV delivery of galanin to the hippocampus under control of an inducible promoter increased seizure threshold when stimulation was applied to the inferior colliculus and simultaneously achieved a neuroprotective effect. Galanin expression has also been shown to reduce the number of seizures and the time spent in seizures in a focal delivery of AAV2-NSE-galanin followed 2.5 months later by kainic acid (KA) seizure induction. The anti-convulsant effects of galanin have recently

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been extended to limbic application as epileptiform activity and behavioral seizures were both reduced after AAV-mediated delivery of galanin to the piriform cortex either when tested with KA or with prior and subsequent electrical stimulation in a model of kind­ ling (McCown, 2006). The anti-ictal effects of NPY, a separate inhibitory neuropeptide, have been examined in the rat hippocampus. Following administration of KA, EEG seizures were reduced by 50–75% when the foci had been previously treated with AAV-NSE-NPY. The greater effect was seen when the injected vector was a chimera of AAV1 and AAV2 capsid proteins AAV1/2 as opposed purely to the use of the AAV2 vector. The authors also noted that the AAV1/2 transduced a broader array of hippocampal cells, including subiculum, pyramidal cells, and mossy fibers, as opposed to only hilar interneurons. Aside from the delivery of inhibitory neuropeptides, in vivo gene transfer has also examined the utility of inhibiting excitatory neurotransmission through antisense strategies designed to knock-down the NMDA receptor (NMDAR), overexpression of the enzyme responsible for breakdown of the excitatory neurotransmitter aspartate, and through direct inhibition of the synaptic transmission machinery. In studies of NMDAR knockdown, seizure inhibition versus exacerbation was dependent upon the choice of promoter. Use of the constitutively active CMV promoter resulted in seizure inhibition whereas use of the Tetoff promoter resulted in seizure exacerbation when vectors were injected into the inferior colliculus and the animals subsequently stimulated at the collicular cortex. Intracerebroventricular delivery of an adeno­ viral vector expressing aspartoacylase (ASPA) reduced the occurrence of tonic seizures without affecting the duration of each event in a spontaneously epileptic rat model. The protective effect was lost within two weeks, potentially due to the immunogenic nature and transient gene expression of this first generation adenovirus. Subsequent studies utilizing an AAV vector have appeared to overcome the loss of effect. Our laboratory has recently tested the impact of neuronal tetanus toxin light chain (LC) gene expression mediated by adenoviral vectors on a focal model of penicillininduced neocortical epilepsy, based on initial experiments demonstrating that LC expression could induce focal synaptic inhibition. Clostridial toxin light chain (LC) inhibits synaptic transmission by digesting a critical vesicle-docking protein, synaptobrevin, without directly altering neuronal health. LC expression significantly improved both the EEG (Figure 13.3) and behavioral manifestations of penicillin-induced focal neocortical seizures through synaptobrevin depletion (Yang et al., 2007).

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Ex vivo gene transfer techniques have been used to optimize both secretion of adenosine and GABA through suppression of either adenosine kinase (ADK) or adenosine deaminase (ADA) activity and also through overexpression of GAD65. Initial studies of adenosine-secreting fibroblasts encapsulated in a cage designed to provide immunoisolation indicated complete suppression of generalized seizures in electrically kindled rats. Notably, no systemic side effects were observed, a common problem with systemic adenosine administration. Diminished seizure protection over days 12–24 was attributed to lack of graft viability. Subsequent studies have examined the use

of both ADK-deficient encapsulated embryonic stem cells (Guttinger, Fedele et al., 2005) and myoblasts (Guttinger, Padrun et al., 2005). Only a slight increase in overall graft viability was noted in these studies, yet continued effect was noted in the presence of viable grafts. Delivery of GAD65 has been achieved in multiple cell-based graft studies that have examined separate targets and seizure paradigms. In a model of entorhinal electrical kindling, immortalized mouse cortical neurons and glial cell implantation to the anterior substantia nigra (SN) delayed kindling, while injection to the posterior SN accelerated the process. In a separate study, cell injection to the piriform cortex, followed by stimulation of the amygdala, resulted in higher behavioral threshold for seizure development without an effect on kindling. A subsequent study in a model of pilocarpine-induced status epilepticus evolving to spontaneous seizures examined cell placement in the SN. Fewer spontaneous seizures and fewer epileptiform spikes were observed in rats that expressed GAD65 than in those that also expressed GAD65 with the transgene expression repressor ­doxycycline in their water supply. Most recently, the results of these studies have been extended to the dentate gyrus. Implanted graft raised threshold, shortened the duration of hippocampal afterdischarges elicited by granule cell stimulation, and slowed the appearance of stage 5 seizures when tested in the kind­ ling paradigm (Thompson, 2005). Though multiple studies have corroborated the effectiveness of cellbased grafts in a variety of targets, cell graft viability has been widely varied. Therefore, further improvements will be required prior to serious consideration for clinical translation.

Chronic Pain Chronic nociceptive pain can develop from continued tissue damage and a prolonged inflammatory state, whereas chronic neuropathic pain results from damage to or dysfunction of the neural structures serving as afferents for transmission of nociceptive stimuli. In a chronic pain state, a cascade of molecular events promotes sensitization both at the level of the primary and secondary afferents, lowering the threshold for pain transmission. Though pain processing networks are not fully elucidated, especially with respect to the neural pathways governing affective attachment within cortical and subcortical structures, considerable progress has been made in characterizing the processes of peripheral sensitization, central sensitization, and in understanding of the descending modulatory networks that interact with the lower levels of

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Current and potential indications

afferent transmission processing. Correspondingly, gene-based neuromodulatory approaches target these processes and are reviewed herein (Fink et al., 2003; Garrity-Moses et al., 2003; Riley et al., 2003; Kaplitt and During, 2006). Peripheral sensitization represents a reduction of threshold required for a noxious insult, either mechanical or chemical, to achieve afferent transmission. This process is promoted through the milieu of inflammatory mediators generated at the site of tissue damage. Gene-based strategies designed to inhibit the process of peripheral sensitization have employed viral administration through a remote delivery technique. Specifically, knock-down strategies have been employed to prevent upregulation of the receptors and channels responsible for the process of peripheral sensitization. Yeomans et al. (2005) demonstrated downregulation of the NaV1.7 Na channel paralleling relief from inflammatory-related hyperalgesia in a small animal model. Separately, Jouvenot et al. (2004) established the potential to inhibit expression of other primary afferent contributors to the peripheral sensitization process, including for the TRPV1 receptor, Trk-A receptor, and NaV1.8 Na channel. In a separate study, HSV-mediated expression of the anti-inflammatory cytokine IL-4 failed to alter temperature and tactile sensation in normal animals but delayed the behavioral manifestations of neuropathic pain, and prevented development of some of the biochemical and histologic correlates of neuropathic pain at the spinal level when administered in a model of neuropathic pain, prior to the insult, spinal nerve ligation (Hao et al., 2006). Efforts to directly target the process of central sensitization are more extensive and have been approached with both in vivo and ex vivo gene transfer strategies that have employed remote and intrathecal delivery strategies for expression of opiates, opiate receptors, inhibitory neurotransmitters, cytokines, and other potential analgesic peptides. Wilson et al. have demon­ strated that HSV vectors may be used to transfer the gene for preproenkephalin (PPE) to spinal sensory neurons in a rat model resulting in the production of enkephalin and inhibiting the perception of pain from administration of noxious chemical stimuli, including DMSO or capsaicin, for a minimum of seven weeks after HSV administration. Goss et al. found an antihyperalgesic effect lasting four weeks that could be regained after subsequent remote administration of HSV-PPE. Wolfe et al. have demonstrated the analgesic effect of HSV-encoding endomorphin-2 in both animal models of inflammatory and neuropathic pain. Finally, remote delivery of HSV-GAD, triggering production of GABA by the DRG, has been demonstrated to achieve relief of mechanical allodynia and thermal

139

hyperalgesia in an L5 spinal nerve ligation model persisting for up to six weeks. Intrathecal delivery of gene-based therapeutics to prevent central sensitization has encompassed both ex vivo and in vivo approaches. Cell-based treatment of neuropathic pain states has largely focused on the use of immortalized cell lines to achieve secretion of anti-nociceptive peptides into the local cell graft micro­environment. AtT20, a cell line which naturally secretes B-endorphin, has been subsequently engineered to express PPE. When administered to the subarachnoid space, AtT20/hENK was demonstrated to achieve an anti-nociceptive effect in response to isoproterenol stimulation that was blocked by administration of the opioid antagonist, naloxone. Intrathecal administration of cellular grafts modified to secrete galanin, GABA, and pro-opiomelanocortin (POMC) have also achieved a beneficial effect in models of neuropathic pain. An early attempt to achieve viral delivery to the rat intrathecal space utilized a first generation adenoviral vector encoding -endorphin. Despite evidence to indicate an anti-hyperalgesic effect in the carageenen inflammatory pain model, expression was short-lived, due to the presence of an inflammatory response. Viral vector delivery to the intrathecal space, with the intention of transducing meningeal cells and elevating CSF levels of a desired peptide have also been achieved for the inflammatory cytokines IL-2 and IL-10. Analgesic effects were achieved for approximately one week, with the observed potential of reversing or preventing neuropathic pain in a rat model. More recently, AAV expressing IL-10 has been demonstrated as an effective therapeutic for paclitaxel-initiated peripheral neuropathy in a rat model (Ledeboer et al., 2007). The presence of elevated IL-10 levels was correlated with depressed IL-1, TNF, and immune cell markers observed two weeks following administration.

Spasticity Spasticity is a motor dysfunction that occurs most frequently in cerebral palsy, multiple sclerosis, stroke, spinal cord injury, and head trauma. Severe spasticity is often accompanied by involuntary spasms of the affected limbs and can ultimately lead to the development of chronic pain and disability. Current therapies of spasticity include anti-spasticity medications, botulinum toxin (BoNT), physiotherapy, electrical stimulation, or surgery (Lazorthes et al., 2002). Spasms and spasticity are thought to result from dysfunction of inhibitory signals within the spinal cord that depend on descending motor pathways. As a functional disorder resulting from unadjusted MN activity, spasticity

II.  Fundamentals of neuromodulation

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13.  Gene-Based Neuromodulation

provides a novel approach for gene-based neuromodulation. Genes that modulate neurotransmitter release may be delivered into spastic muscles, by using neurotropic vectors capable of retrograde axonal transport to MN, with consequent disruption of acetylcholine release at the neuromuscular junction. Although BoNT has provided a strategy for the treatment of spasticity that is MN-specific and nonablative, the need for repeated administration of an immunogenic protein has limited its utility. Other potential transgenes capable of focal synaptic inhibition are currently being tested (Johns et al., 1999; Teng et al., 2005).

Additional Indications Aside from the conditions previously discussed, dystonia, tremor, and psychiatric disorders, including depression and obsessive–compulsive disorder, all appear to respond to focal stimulation-based neuromodulation. It is, therefore, likely that as a ­better understanding of the circuits underlying these ­disorders emerges, that gene-based neuromodulatory approaches may become available. In each of these indications, current therapies fail to address the underlying pathogenic mechanism, are palliative, or bear significant limitations.

Current trends towards future therapies As previously described, the co-delivery of transgenes (i.e. the design of vectors encoding two or more genes) has been shown to be a successful strategy, in part due to the potential for achieving additive or synergistic effects. Additionally, the combination of different treatment paradigms may improve the chances of a successful therapeutic intervention. Emerging strategies, such as antisense and RNA interference (RNAi), which are based on modulation or silencing of gene expression, are appealing therapeutic options to target the imbalanced activity of specific neural networks through the potential to achieve functional silencing. RNAi has potential applications through functional silencing of specific molecular targets involved in epilepsy, as well as in chronic pain. This strategy has also been applied to downregulate excitatory GluR1 glutamate receptor in neurons and astrocytes, as a novel strategy for the treatment of disorders associated with increased activity of alpha-MNs (spasticity) (Miyanohara et al., 2005). Although very promising, success and clinical translation of RNAi currently

faces the same challenges as other gene-based neuromodulation strategies, namely precise delivery and regulated expression. Nonetheless, gene-based techniques achieve manipulation of neural structures with a pharmacologic and anatomic specificity currently unrivaled by alternative neuromodulatory approaches, an important impetus for the development of an optimized system that will allow near-term clinical translation for a variety of conditions.

References Boyden, E.S., Zhang, F., Bamberg, E. et al. (2005) Millisecond­timescale, genetically targeted optical control of neural activity. Nat. Neurosci. 8: 1263–68. Chen, Q., He, Y. and Yang, K. (2005) Gene therapy for Parkinson’s disease: progress and challenges. Curr. Gene Ther. 5: 71–80. Chiocca, E.A. (2003) Gene therapy: a primer for neurosurgeons. Neurosurgery 53: 364–73, discussion, 73. During, M.J., Kaplitt, M.G., Stern, M.B. et al. (2001) Subthalamic GAD gene transfer in Parkinson disease patients who are candidates for deep brain stimulation. Hum. Gene Ther. 12: 1589–91. Emborg, M.E., Carbon, M., Holden, J.E. et al. (2007) Subthalamic glutamic acid decarboxylase gene therapy: changes in motor function and cortical metabolism. J. Cereb. Blood Flow Metab. 27: 501–9. Fink, D., Mata, M. and Glorioso, J.C. (2003) Cell and gene therapy in the treatment of pain. Adv. Drug Deliv. Rev. 55: 1055–64. Garrity-Moses, M.E., Liu, J.K. and Boulis, N.M. (2003) Molecular biology and gene therapy in the treatment of chronic pain. Neurosurg. Clin. North Am. 14: 419–35. Guttinger, M., Fedele, D., Koch, P. et al. (2005) Suppression of kind­ led seizures by paracrine adenosine release from stem cellderived brain implants. Epilepsia 46: 1162–69. Guttinger, M., Padrun, V., Pralong, W.F. et al. (2005) Seizure suppression and lack of adenosine a1 receptor desensitization after focal long-term delivery of adenosine by encapsulated myo­ blasts. Exp. Neurol. 193: 53–64. Hao, S., Mata, M., Glorioso, J.C. et al. (2006) HSV-mediated expression of interleukin-4 in dorsal root ganglion neurons reduces neuropathic pain. Mol. Pain 2: 6. Jakobsson, J. and Lundberg, C. (2006) Lentiviral vectors for use in the central nervous system. Mol. Ther. 13: 484–93. Johns, D.C., Marx, R., Mains, R.E. et al. (1999) Inducible genetic suppression of neuronal excitability. J. Neurosci. 19: 1691–97. Jouvenot, Y.F., John, R., Tan, S. et al. (2004) Gene control as a therapeutic intervention: Zinc-finger protein transcription factors as regulators of the molecular determinants of neuropathic pain. Mol. Ther. 9: 90. Kaplitt, M.G.D. and During, M.J. (2006) Gene Therapy of the Central Nervous System: From Bench to Bedside. London: Elsevier. Kim, S.U., Park, I.H., Kim, T.H. et al. (2006) Brain transplantation of human neural stem cells transduced with tyrosine hydroxylase and GTP cyclohydrolase 1 provides functional improvement in animal models of parkinson disease. Neuropathology 26: 129–40. Lachmann, R. (2004) Herpes simplex virus-based vectors. Int. J. Exp. Pathol. 85: 177–90. Lazorthes, Y., Sol, J.C., Sallerin, B. et al. (2002) The surgical management of spasticity. Eur. J. Neurol. 9 (Suppl 1): 35–41, discussion 53–61. Ledeboer, A., Jekich, B.M., Sloane, E.M. et al. (2007) Intrathecal interleukin-10 gene therapy attenuates paclitaxel-induced mechanical allodynia and proinflammatory cytokine expression in dorsal root ganglia in rats. Brain Behav. Immun. 21 (5): 686–98.

II.  Fundamentals of neuromodulation



References

Lee, B., Lee, H., Nam, Y.R. et al. (2005) Enhanced expression of glutamate decarboxylase 65 improves symptoms of rat parkinsonian models. Gene Ther. 12: 1215–22. Lee, W.Y., Lee, E.A., Jeon, M.Y. et al. (2006) Vesicular monoamine transporter-2 and aromatic l-amino acid decarboxylase gene therapy prevents development of motor complications in parkinsonian rats after chronic intermittent l-3,4-dihydroxyphenylalanine administration. Exp. Neurol. 197: 215–24. Lu, L., Zhao, C., Liu, Y. et al. (2005) Therapeutic benefit of Th-­engineered mesenchymal stem cells for Parkinson’s disease. Brain Res. Brain Res. Protoc. 15: 46–51. Lundberg, C., Horellou, P., Mallet, J. et al. (1996) Generation of dopaproducing astrocytes by retroviral transduction of the human tyrosine hydroxylase gene: in vitro characterization and in vivo effects in the rat parkinson model. Exp. Neurol. 139: 39–53. McCown, T.J. (2006) Adeno-associated virus-mediated expression and constitutive secretion of galanin suppresses limbic seizure activity in vivo. Mol. Ther. 14: 63–8. Miyanohara, A., Kinjoh, K., Hefferan, M. et al. (2005) Efficient suppression of Glur1 receptor expression in vitro and in vivo by infection with HIV1 vectors expressing Sirna. Mol. Ther. 11: S372. Muramatsu, S., Fujimoto, K., Ikeguchi, K. et al. (2002) Behavioral recovery in a primate model of Parkinson’s disease by triple transduction of striatal cells with adeno-associated viral vectors expressing dopamine-synthesizing enzymes. Hum. Gene Ther. 13: 345–54. Noe, F., During, M. and Vezzani, A. (2006) Gene therapy for epilepsy. In: M.G.D. Kaplitt and M.J. During (eds), Gene Therapy of the Central Nervous System: From Bench to Bedside. London: Elsevier, pp. 151–64.

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Papadakis, E.D., Nicklin, S.A., Baker, A.H. et al. (2004) Promoters and control elements: designing expression cassettes for gene therapy. Curr. Gene Ther. 4: 89–113. Perreau, M. and Kremer, E.J. (2006) The conundrum between immunological memory to adenovirus and their use as vectors in clinical gene therapy. Mol. Biotechnol. 34: 247–56. Riley, J. and Boulis, N. (2006) Molecular mechanisms of pain: a basis for chronic pain and therapeutic approaches based on the cell and gene. Clin. Neurosurg. 53: 77–97. Ryu, M.Y., Lee, M.A., Ahn, Y.H. et al. (2005) Brain transplantation of neural stem cells cotransduced with tyrosine hydroxylase and GTP cyclohydrolase 1 in parkinsonian rats. Cell Transplant. 14: 193–202. Teng, Q., Tanase, D., Liu, J. et al. (2005) Adenoviral clostridial light chain gene-based synaptic inhibition through synaptobrevin elimination. Gene Ther. 12: 108–19. Thompson, K.W. (2005) Genetically engineered cells with regulatable GABA production can affect afterdischarges and behavioral seizures after transplantation into the dentate gyrus. Neuroscience 133: 1029–37. Vezzani, A. (2004) Gene therapy in epilepsy. Epilepsy Curr. 4: 87–90. Yang, J., Teng, Q., Federici, T. et al. (2007) Viral clostridial light chain gene-based control of penicillin-induced neocortical seizures. Mol. Ther. 15 (3): 542–51. Yeomans, D.C., Levinson, S.R., Peters, M.C. et al. (2005) Decrease in inflammatory hyperalgesia by herpes vector-mediated knockdown of Nav1.7 sodium channels in primary afferents. Hum. Gene Ther. 16 (2): 271–7. Zhang, F., Wang, L.P., Boyden, E.S. et al. (2006) Channelrhodopsin-2 and optical control of excitable cells. Nat. Methods 3: 785–92.

II.  Fundamentals of neuromodulation

C H A P T E R

14

Principles of Electric Field Generation for Stimulation of the Central Nervous System Warren M. Grill

o u t l i ne Introduction

145

Fundamental principles of electric field  generation Resistance and Ohm’s Law Potentials Generated by a Point Source Electrode Anisotropic Electrical Conductivity Inhomogeneous Electrical Conductivity

146 146 146 147 149

Effects of electrode geometry Bipolar Electrodes Electrode–Tissue Interface

150 150 151

Regulated Voltage and Regulated Current   Stimulation Current Density on Electrode vs. Current Density   in the Tissue Influence of Extracellular Voltages on Neurons

153 154

Conclusion

154

References

154

and for restoration of vision (Brindley and Lewin, 1968; Schmidt et al., 1996; Troyk et al., 2003). Understanding the effects of extracellular stimulation on neurons involves a two-step approach. The first step is to calculate the electric potentials generated in the tissue by passage of current through the electrode. The second step is to determine the effect(s) of those potentials on the surrounding neurons. The resulting potential distribution can result in an outward flowing transmembrane current in the neuron, depol­arization, and generation of an action potential. The resulting action potential propagates to the terminal of the neuron leading to release of neurotransmitter that can impact the post-synaptic cell. Alternately, extracellular potentials may modulate or block ongoing neuronal firing depending on the magnitude, distribution, and polarity of the potentials. The focus of this chapter is on determining the voltages generated in the central nervous

Introduction Electrical stimulation is used to study the form and function of the nervous system and is a technique to restore function following disease or injury. Applications of electrical stimulation for restoration of function include generation, inhibition, and modulation of brain activity. Examples of applications of stimulation in the central nervous system (CNS) for treatment of neurological disorders include relief of pain by stimulation of the brain (Coffey, 2001) and spinal cord (Cameron, 2004), treatment of tremor and the motor symptoms of Parkinson’s disease, as an experimental treatment for epilepsy, as well as a host of other neurological disorders. In addition, CNS stimulation is being developed for restoration of hearing by electrical stimulation of the cochlear nucleus (Otto et al., 2002)

Neuromodulation

152

145

© 2008, 2009 Elsevier Ltd.

146

14.  Principles of Electric Field Generation for Stimulation of the Central Nervous System

system by applied currents intended to stimulate, block or modulate neuronal activity.

Fundamental principles of electric field generation Passage of current, I, through tissue generates voltages (or potentials), V, in the tissue (recall Ohm’s Law: V  IR, where R is the electrical resistance), and the impact of applied stimuli on neurons is strongly dependent on the spatial and temporal distribution of the extracellular voltages. The voltages are dependent on the electrode geometry, the stimulus parameters (current magnitude), and the electrical properties of the tissue. The electrical properties of the central nervous system (Table 14.1) are inhomogeneous, meaning that they vary at different positions within the tissue because the neuronal and glial elements have wide-ranging dimensions, varying orientations, and different packing densities. As well, the electrical properties of the central nervous system are anisotropic, meaning that they vary along different directions through the tissue because of the non-random orientation of neural elements. In particular, the white matter has anisotropic conductivity because current can travel more easily in the direction parallel to the axons than in the direction transverse or perpendicular to the axons. These spatial variations in the electrical properties of the tissue can cause changes in the patterns of neural activation (Grill, 1999). In general, biological conductivities have a small reactive component (Eisenberg and Mathias, 1980; Ackman and Seitz, 1984), and thus a relatively small increase in conductivity at higher frequencies (Ranck, 1963; Nicholson, 1965; Ranck and BeMent, 1965). Thus, tissues can be treated as purely resistive for the purposes of calculating the potentials generated by

neural stimulation (Bossetti et al., 2008). As well, the bulk conductivity of tissue is expected to be linear, and the fields for different stimulus current magnitudes are just scaled versions of the original solution (Nicholson and Freeman, 1975). In most cases, to calculate accurately the extracellular potentials generated by extracellular stimulation requires a numerical solution using a discretized model, for example with the finite element method (e.g., Veltink et al., 1989; McIntyre and Grill, 2002).

Resistance and Ohm’s Law From Ohm’s Law, the voltage, V, generated across a resistance, R, is proportional to the current through the resistance, I, V  IR If we consider a cylinder of tissue (Figure 14.1a), the resistance of that cylinder can be calculated from R



L L .  A π r 2

where L is the length of the cylinder,  is the specific electrical conductivity of the tissue (Siemens/m), A is the cross-sectional area, and r is the radius of the cylinder. Consider a 1 cm long, 0.35 cm diameter cylinder, with conductivity of 1 S/m, and the resistance is then 1 k. If we pass 1 mA through the cylinder, then the voltage generated across it, from end to end, is 1 V.

Potentials Generated by a Point Source Electrode However, under most circumstances, the geometry of the problem is not so well defined, and we need

Table 14.1  Electrical conductivity of CNS tissues Tissue type

Electrical conductivity (S/m)

References Haueisen et al., 2002

Skull

0.00625

Dura mater

0.030; 0.065

Holsheimer et al., 1995; Manola et al., 2005

Cerebrospinal fluid

1.5; 1.8

Crile et al., 1922; Baumann et al., 1997

Gray matter

0.20

Ranck, 1963; Li et al., 1968; Sances and Larson, 1975

White matter

Anisotropic

  Transverse

0.6 1.1

Ranck and BeMent, 1965 (cat dorsal columns) Nicholson, 1965 (cat internal capsule)

  Longitudinal

0.083 0.13

Ranck and BeMent, 1965 Nicholson, 1965

Encapsulation tissue

0.16

Grill and Mortimer, 1994

IIA.  Fundamentals of neuromodulation: MECHANISMS



147

Fundamental principles of electric field generation

�

The gradient of the voltage in spherical coordinates, is by definition,

s r

L

V ( r ,  , ϕ ) 

r



�

(a)

(b)

Figure 14.1  Generation of potentials by passage of current. (a) A cylinder of tissue of length, L, specific electrical conductivity, , and radius, r. (b) An idealized point source electrode immersed in a homogeneous, isotropic volume conductor of infinite extent with specific electrical conductivity, 

∂V ^ 1 ∂V ^ 1 ∂V ^ r    ϕ ∂r r ∂ r sin  ∂ϕ

However, the surface of the sphere is equipotential (i.e., the voltage does not vary with  or with ), and thus the second and third terms (partial derivatives) are equal to zero. Therefore, the equation reduces to V ( r ) 



dV dr

Re-arranging and substitution yields to determine the potential generated in a volume of tissue by application of a current (Figure 14.1b). First, consider the simplest case of an idealized point source electrode immersed in a homogeneous, isotropic volume conductor of infinite extent. Ohm’s Law can be generalized to

  J  E

 where J is the current density (A/m2),  is the specific  electrical conductivity of the tissue (S/m) and   E is the electric field (V/m). The arrows over the J and E specify that these are vector quantities that have both a magnitude and a direction. Consider a point source delivering current I, the current density over any closed surface is simply the current divided by the area of the closed surface . For simplicity we choose a spherical surface of radius r and then the current density is



 J (r ) 

I 4π r 2

The electric field is defined as the negative gradient (derivative) of the voltage (or potential) in space, and in Cartesian coordinates is given by



 ∂V ∂V ∂V E  V  xˆ  yˆ  zˆ ∂x ∂y ∂z



By substitution into the generalized Ohm’s Law,

 J   V

and re-arranging and substitution yields



 J I V    4π r 2

V (r )dr 



I dr 4π r 2

Now integrate both sides with respect to r, I dr 4 π r2 and this yields the desired expression, r

r

∫0 V(r )dr  ∫0



V (r ) 

I 4π r

The expression describes the voltage generated at distance r from a point source of current in a homogeneous isotropic medium with the assumption that the voltage is zero at infinity (Figure 14.2a). The point source model is a valid approximation for sharp electrodes with small tips (McIntyre and Grill, 2001). Larger electrodes are typically used for chronic stimulation of the CNS, and the spatial distribution of the potentials in the tissue differs from those produced by a point source electrode (see below).

Anisotropic Electrical Conductivity The extracellular potentials are also dependent on the electrical properties of the tissue. The white matter of the CNS, where there are groups of parallel axons, is anisotropic with a higher conductivity parallel to the nerve fibers (1 S/m) than transverse to the nerve fibers (0.1 S/m), and this directional dependence of the conductivity will influence the spatial distribution of voltages within the tissue. Considering a medium with different conductivities along each of the three principal axes, x, y, and z, a coordinate transformation can be used to derive an expression for the voltages generated in the medium

IIA.  Fundamentals of neuromodulation: MECHANISMS

148

14.  Principles of Electric Field Generation for Stimulation of the Central Nervous System

z (mm)

�x � �z � 0.2 S/m

�x � 0.2 S/m, �z � 1 S/m

�x � 0.2 S/m, �z � 2 S/m

0.5

0.5

0.5

0.25

0.25

0.25

0

0

0 8V

8V

�0.25

�0.25

�0.25

�0.25

0 x (mm)

10 V

10 V

10 V

�0.5 �0.5

8V

0.25

�0.5 �0.5

0.5

(a)

�0.25

0.25

0

�0.5 �0.5

0.5

(b)

0.25

0

0.5

(c)

�1 � 0.2 S/m, �2 � 1 S/m

0.5

�0.25

�1 � 0.2 S/m, �2 � 2 S/m

0.5

0.25

0

0

4V

3.

6V

0.25

�0.25

1.

�0.25

.6

1

�0.5 �0.5 (d)

�0.25

0

0.25

V

0

4.

0.5

�0.5 �0.5 (e)

�0.25

0

0.25

V

0.5

Figure 14.2  Potentials generated by an idealized point source electrode (I  1 mA) in tissues with different electrical properties. (a) Homogeneous isotropic conductor. (b) Homogeneous anisotropic conductor with anisotropy ratio of 5. (c) Homogeneous anisotropic conductor with anisotropy ratio of 10. (d) Isotropic inhomogeneous conductor with conductivity ratio of 5 and the source 0.2 mm from the conductivity interface. (e) Isotropic inhomogeneous conductor with conductivity ratio of 10 and the source 0.2 mm from the conductivity interface

by passing current through a point source electrode (Nicholson, 1967). From the generalized form of Ohm’s  Law, J   V , and the definition of the electric field, E  V  (∂V/∂x ) xˆ  (∂V/∂y ) yˆ  (∂V/∂z) zˆ , expressions for the current densities along each of the three principal axis directions are:



∂V ∂V ∂V J x   x , J y   y , and J z   z ∂x ∂y ∂z

The space variables are then transformed according to the expressions:



x 

 y z 

x , y 

 x z 

y , and z 

 x y 

z

where  is a constant. Substituting the primed Cartesian variables into the expression for the potential

generated by a point source in a homogeneous isotropic medium, V ( x , y , z) 

I 2

4π x  y 2  z 2



yields V ( x, y, z) 

I 2

4π x  y2  z2



and substituting for the primed variables yields V ( x , y , z) 

I 2

4π  y  z x   x z y 2   x y z 2

which describes the voltage generated at position (x,y,z) by a point source of current positioned at the

IIA.  Fundamentals of neuromodulation: MECHANISMS



149

Fundamental principles of electric field generation

�

d

I

�1 �2

Inhomogeneous Electrical Conductivity

x�0 (a)

I

d

d

r1

in Figure 14.2. In an isotropic medium the equipotential contours (i.e., the surfaces on which the voltage is the same) were spherical (Figure 14.2a), but the contours become elliptical in an anisotropic medium. When the conductivity was increased along one axis (z), the equipotential contours were compressed along the axis of lower conductivity (x), and this distortion became more pronounced as the tissue becomes more anisotropic.

I�

r2

V1(x,y,z) � 1 �1 (b)

The electrical conductivity of the tissue also varies with position within the CNS. For example, while gray matter has a conductivity of0.2 S/m the cere­ brospinal fluid has a conductivity of0.05 S/m, and this position dependence of the conductivity will influence the spatial distribution of voltages within the tissue. The method of images (Plonsey, 1969) can be used to solve for the voltage generated in an isotropic semi-infinite inhomogeneous medium (Figure 14.3). Consider the case of a point source of current located in medium 1 with conductivity 1 distance d from a plane interface with medium 2 with conductivity 2. At the boundary between the two media, we must consider two continuity (boundary) conditions. First, there is continuity of voltage (or potential), in other words there is no voltage drop across the boundary,

I�



Further, as the boundary has no ability to store current, there must be continuity of normal current density across the boundary (i.e., that component perpendicular to the boundary)

d r�

V1 ( x  0 , y , z)  V2 ( x  0 , y , z)

V2(x,y,z)

�2 �2

J x 1 ( x  0)  J x 2 ( x  0)



This is more conveniently expressed in terms of the voltages, using the generalized form of Ohm’s Law and the definition of the electric field

(c)

Figure 14.3  Calculating the voltages generated in an isotropic semi-infinite inhomogeneous medium with the method of images. (a) A point source of current located in medium 1 with conductivity 1 distance d from a plane interface with medium 2 with conductivity 2. (b) To calculate the voltages in region 1 a second image source is placed in region 2. (c ) To calculate the voltages in region 2, only the image source in region 1 is considered

origin (0,0,0) in a homogeneous anisotropic medium with the assumption that the voltage is zero at infinity. The effect of anisotropy on the distribution of voltages generated by a point source electrode is illustrated

1

∂V1 ∂x

( x0 )

 2

∂V2 ∂x

( x0 )



To derive an expression for the voltages in region 1, we introduce a second (image) source I present in region 2 (analogous to a reflection in a mirror) and assume that the medium is homogeneous with conductivity 1 (Figure 14.3b). Then, by superposition



V1 ( x , y , z) 

IIA.  Fundamentals of neuromodulation: MECHANISMS

1  I I     4π1  r1 r2 

150

14.  Principles of Electric Field Generation for Stimulation of the Central Nervous System

To derive an expression for the voltages in region 2 (Figure 14.3c), we consider a single source I present in region 1 and assume that the medium is homogeneous with conductivity 2. Then, the voltages are given by



V2 ( x , y , z) 

1  I     4π 2  r  





and, applying the continuity of normal current density yields the equality

Consider the case of two point source electrodes, separated by distance l (Figure 14.4a), which constitute the poles of a bipolar pair (i.e., they deliver equal and opposite currents, I). Since the conductive medium is considered to be linear, superposition applies, and the voltage is the sum of the voltages that would result from each source independently V ( p) 

I  I  I 



Effects of electrode geometry Bipolar Electrodes



Now, applying the continuity of potential condition yields the equality I  I I  1 2

conditions, the potentials in both regions are equal at the interface.

Solving these two equations yields expressions for the image sources

If the distance between the electrodes, l, is much less than the average distance between the electrodes

  2 I  I 1 1   2

and the evaluation point, R  r12  r22 , then the bipolar pair can be treated as a dipole and the voltage at point p is given by





I I I  1 1      . 4π r1 4π r2 4π  r1 r2 



and I  I

2 2 1   2



Finally, substituting these into the original expressions for the voltages yields the desired expressions for the voltages in region 1 (Figure 14.3b) V1 (r ) 

1 1   2  I  1    4π1  r1 r2 1   2 



and the voltages in region 2 (Figure 14.3c) V2 (r ) 

I l cos  π 4 R2 where  is the angle between R and the (horizontal) line joining the source and sink. The fact that the voltages decrease in inverse proportion to the square of the electrode to neuron distance, as compared to in inverse proportion to the distance for a monopolar source led to the suggestion that bipolar stimulation is a means to enhance the selectivity of stimulation. Bipolar electrode geometries were assessed for their ability to activate selectively cells and fibers. A wide range of bipolar electrode configurations and stimulus parameters were tested using a random distribution of cells and fibers, but none of the cases examined exhibited selectivity of either cells or fibers that was superior to that of the monopolar case. Examples of the activation of local cells and passing fibers using bipolar electrode configurations and 200 s duration monophasic stimuli are shown in Figure 14.4. The electrodes were oriented such that their separation would be either horizontal (Figure 14.4b) or vertical (Figure 14.4c) with respect to the orientation of the neurons. The activation of cells and fibers was nearly equal over the entire range of stimulus amplitudes for both types of electrode configuration, and alterations in the interelectrode spacing had little effect on the recruitment. Thus, bipolar electrode geometries did not enhance selective stimulation of passing axons as compared to local cells (McIntyre and Grill, 2000). V ( p) 

I  22    4π 2 r   1  2 



The effect of inhomogeneity on the distribution of voltages generated by a point source electrode is illustrated in Figure 14.2. In a homogeneous medium the equipotential contours (i.e., the surfaces on which the voltage is the same) were spherical (Figure 14.2a), but the inhomogeneity arising from two different conductive media distorted the spherical (circular) equipotential surfaces (lines) both in the region containing the source and the adjoining region (Figure 14.2d). The degree of distortion increased as the difference in conductivity between the two regions was increased (Figure 14.2e), but note that, as required by the boundary

IIA.  Fundamentals of neuromodulation: MECHANISMS



151

Effects of Electrode Geometry

I

(a)

p

1

r2

Volts

r1

(b)

� (a)

0 1.2

100 80

1

Point source

60

DBS electrode 0.8

20 (b)

0

Activation of cells Activation of fibers

Voltage

Percent activation (%)

40

0.6

0.4

100 0.2 80 0

60 40 20 0 (c)

0

2

(c)

Stimulus intensity

4

6

8

10

Distance

Figure 14.5  Effect of electrode geometry on the potentials produced by passage of current into a homogenous region of the CNS. (a) Distribution of potentials generated by an idealized point source electrode. (b) Distribution of potentials generated by a cylindrical electrode intended for deep brain stimulation. (c) Potential as a function of distance from the electrode (spatial decay) for a point source electrode and a larger cylindrical electrode

Figure 14.4  Stimulation with a bipolar pair of electrodes. (a) A pair of idealized point source electrodes immersed in a homo­ geneous, isotropic volume conductor of infinite extent with specific electrical conductivity, . (b), (c) Input–output relations for populations of neurons stimulated by bipolar electrode configurations with 0.2 mm between the electrodes. Excitation was studied using populations of local cells and axons of passage randomly positioned around the electrodes. Electrodes were oriented either horizontally (b) or vertically (c)

The preceding section considered the potentials generated by a point source electrode, and this is an excellent approximation for a sharp-tipped microelectrode. However, most chronic indwelling electrodes have a substantially larger surface area and the potential generated in the tissue depends on the electrode

dimensions. For example, comparatively large cylindrical electrodes (1.27 mm in diameter  1.5 mm in length) are used for deep brain stimulation. The magnitude and distribution of potentials generated by this electrode are different than the potentials generated by a point source electrode (Figure 14.5). The potentials generated by the cylindrical electrode contact decline much more slowly in space than those of the monopolar point source.

Electrode–Tissue Interface To this point we have considered the electric field (voltages) generated by electrodes. However, there

IIA.  Fundamentals of neuromodulation: MECHANISMS

14.  Principles of Electric Field Generation for Stimulation of the Central Nervous System

Regulated Voltage and Regulated Current Stimulation The electronic circuit used to deliver the applied stimulus may be either a constant (regulated) voltage device or a constant (regulated) current device, and this will have a direct impact on the properties of excitation. In

� ve �

ze

itissue

� vtissue

� � Vstim

Electrodetissue interface

� istim Electrodetissue interface

� ve �

ze

(a) 1 0.8 0.6 i(t)

are several important differences between the electrodes that we imagined and real physical electrodes. Electrical stimulation is typically delivered using metal electrodes, which carry current as the flow of electrons, implanted in the body, which carries current as the flow of ions. Thus, there exists an interface between the metal electrode and the ionic conductor of the body. In general this interface has a non-linear impedance, Ze, that is a function of the voltage across the interface, Ve. This interface impedance can impact the properties of stimulation (Butson et al., 2006) and electrochemical reactions at the electrode–tissue interface (Robblee and Rose, 1990; Merrill et al., 2005) can lead to electrode dissolution and/or production of chemical species that may be damaging to tissue. The electrode–tissue interface can be modeled by the parallel combination of a capacitor (C), representing the double-layer capacitance, and a non-linear resistor representing electrochemical charge transfer reactions (Figure 14.6a). The voltage developed across the electrode–tissue interface (Ve) is determined by the amount of charge in the stimulus pulse (Q), since V  Q/C. Recall that charge is the time integral of current, so a rectangular pulse of intensity I and duration PW has charge Q  I*PW. The electrode capacitance is determined by the properties of the material and is proportional to the electrode area (CdlA). Therefore, the potential developed across the interface is proportional to electrode area (Ve  Q/A). This relationship is the basis both for the correlation between charge density and tissue damage and the assertion that the charge density is an indirect measure of the electrochemical contribution to tissue damage (McCreery et al., 1990; Shannon, 1992). The voltage across the interface determines which chemical reactions will take place to enable charge transfer across the interface, and if the interface voltage is kept within certain limits, then chemical reactions can be avoided and all charge transfer will occur by the charging and discharging of the double-layer capacitance (Brummer and Turner, 1977). However, in many instances the electrode capacitance is not sufficient to store the charge necessary for the desired excitation without the electrode voltage reaching levels where reactions will occur (Merrill et al., 2005).

0.4 0.2

Regulated current Regulated voltage

0 0

0.1

0.2

0.3

0.4

0.5

0.6

Time (ms) (b) 0.6 0.5 0.4 Charge

152

0.3 0.2 0.1 0

�0.1

0

0.1

0.2

0.3

0.4

0.5

Time (ms) (c)

Figure 14.6  Electrode tissue interface impedance. (a) Equivalent circuit model of the stimulator (vstim or istim), a pair of electrodes (Ze is the impedance of the electrode–tissue interface), and the tissue represented by a resistance. ve is the voltage across the electrode–tissue interface, itissue is the current flowing through the tissue, and vtissue is the voltage across the tissue. (b), (c) Comparison of the current (b) and charge (c) delivered to the tissue using regulated voltage and regulated current stimulation

general, regulated current stimulators should be used, as this enables direct control  of the extracellular electric field, E (recall that J   E , and J is proportional to the current, I, that is delivered to the tissue). The effect

IIA.  Fundamentals of neuromodulation: MECHANISMS



153

Effects of Electrode Geometry

of electrical stimulation on neurons is mediated by the extracellular electric field (and its spatial derivative), and thus to control neuronal excitation requires control of the electric field. Regulated current stimulators produce the same current flow through the tissue, and thus the same electric field, regardless of impedance of the electrode tissue interface (Figure 14.6b). Therefore, the amplitude and time course of the stimulus can be controlled directly, even in the presence of a non-linear or changing impedance of the electrode tissue interface. Conversely, when using a regulated voltage stimulator, a non-linear or changing impedance of the electrode– tissue interface will lead to changes in the current flow through the tissue, reductions in the amount of charge delivered to the tissue (Figure 14.6c) and thus changes in the excitation of the neurons. Since it is the voltage between the electrodes that is regulated, increases in the interface impedance will reduce the amount of current that flows in the tissue, and decrease excitation, while decreases in the interface impedance will increase the current flow in the tissue and strengthen excitation.

1

Current density

0.8 0.6 0.4 0.2 0 �1

�0.5 0 0.5 Radial position/radius

1

(a) Electrode

�/10

10�

�

Current Density on Electrode vs. Current Density in the Tissue

0.8 0.6 0.4 0.2

Current density (A/m2)

The current density on the surface of a planar metal electrode contact passing current in an ionic conductor is non-uniform. The fact that the surface is equi­potential (i.e., there is no variation in the voltage within the electrode, because it is a very good conductor) means that the component of the current density not normal to the surface must be zero, and this requires that the current density (normal to surface) is non-uniform. For a disk type electrode this results in very high current density at the edge of the disk and much lower current density in the center of the disk (Figure 14.7a). This has been shown analytically by solution of Laplace’s equation (Rubinstein et al., 1987) and verified experimentally (Maus et al., 1999). The current density on the surface of the electrode can be made uniform by recessing the electrode within an insulating substrate (Rubinstein et al., 1987) or by changing the profile of the electrode (Ksienski, 1992). For example, a hemispherical electrode has a uniform current density on its surface. However, it is important to distinguish the current density on the electrode surface from the current density in the tissue, and creating a uniform current density on the electrode contact will not necessarily create a uniform current density in the tissue. If the electrical properties of the tissue are inhomogeneous (electrical conductivity is not the same everywhere in space), then the current density in the tissue is non-uniform

0 (b)

Figure 14.7  Electrode and tissue current density. (a) Nonuniform distribution of current density on the surface of a planar metal stimulating electrode. (b) Non-uniform distribution of current density generated in an inhomogeneous tissue region by a hemispherical electrode

  (recall that J   E ). An example is shown in Figure 14.7b, where current was delivered into an inhomogeneous volume conductor using a hemispherical electrode, which has a uniform current density on its

IIA.  Fundamentals of neuromodulation: MECHANISMS

154

14.  Principles of Electric Field Generation for Stimulation of the Central Nervous System

surface. The volume conductor had conductivity , and two regions of differing conductivity – one that was more conductive and one that was less conductive than the surrounding tissue. The current density was higher in the region of high conductivity, and lower in the region of lower conductivity. The regions of differing conductivity also distorted the distribution of current density through the rest of the region. Thus, there is a clear distinction between the current density on the electrode and the current density in the tissue, and uniform current density on the electrode did not produce uniform current density in the tissue.

Influence of Extracellular Voltages on Neurons Thus far we have considered the generation of potentials or voltages by the passage of current through biological tissue. However, we are ultimately interested in the effects of these voltages on neurons – for example, stimulation, modulation, or block. The effects of electrical stimulation on neurons are mediated by the spatial derivatives of the voltages (V) in the tissue  ( dV/dx  Ex , i.e., the electric field), and the spatial  2 2 deri­vatives of the electric field ( dEx/dx  d V/dx  f x ), termed the activating function (Rattay, 1989; Roth, 1994). Recall that, by Ohm’s Law, the magni­ tudes of the voltages in the tissue, and thus the first and second derivates of the potentials, are proportional to the current flowing through the tissue. That the derivatives of the voltages determine the effects of electrical stimulation on neurons implies that  a spatially uniform electric field (i.e., dEx/dx  0  f x ) will not cause stimulation. However, terminations (Rubinstein, 1993), bending (Tranchina and Nicholson, 1986; Schiefer and Grill, 2006), and tissue inhomogeneity (Grill, 1999) create secondary “sources” so that, in practice, even a uniform field can cause stimulation. Further, this relationship implies that to create low thresholds it is desirable to have an electric field (current density) that is highly non-uniform in space.

Conclusion Passage of current in the CNS can activate, modulate or block neural activity depending on the magnitude and distribution of the extracellular potentials. The potentials generated by applied stimuli are dependent on the electrical properties of the tissue, the electrode geometry, and the properties of the stimulator. The voltages generated in the central nervous system by applied currents can be calculated using quantitative approaches, and the results used to interpret

the observed effects of stimulation and to design electrodes and stimuli appropriate for the intended application.

Acknowledgment Preparation of this chapter was supported in part by grant R01 NS040894 from the US National Institutes of Health.

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Maus, R.G., McDonald, E.M. and Wightman, R.M. (1999) Imaging of non-uniform current density at microelectrodes by electrogenerated chemiluminescence. Anal. Chem. 71: 4944–50. McCreery, D.B., Agnew, W.F., Yuen, T.G. and Bullara, L. (1990) Charge density and charge per phase as cofactors in neural injury induced by electrical stimulation. IEEE Trans. Biomed. Eng. 37: 996–1001. McIntyre, C.C. and Grill, W.M. (2000) Selective microstimulation of central nervous system neurons. Ann. Biomed. Eng. 38: 219–33. McIntyre, C.C. and Grill, W.M. (2001) Finite element analysis of the current-density and electric field generated by metal microelectrodes. Ann. Biomed. Eng. 29: 227–35. McIntyre, C.C. and Grill, W.M. (2002) Extracellular stimulation of central neurons: influence of stimulus waveform and frequency on neuronal output. J. Neurophysiol. 88: 1592–604. Merrill, D.R., Bikson, M. and Jefferys, J.G. (2005) Electrical stimulation of excitable tissue: design of efficacious and safe protocols. J. Neurosci. Meth. 141: 171–98. Nicholson, P.W. (1965) Specific impedance of cerebral white matter. Exp. Neurol. 13: 386–401. Nicholson, P.W. (1967) Experimental models for current conduction in an anisotropic medium. IEEE Trans. Biomed. Eng. 14: 55–7. Nicholson, C. and Freeman, J.A. (1975) Theory of current-source density analysis and determination of conductivity tensor for anuran cerebellum. J. Neurophysiol. 38: 356–68. Otto, S.R., Brackmann, D.E., Hitselberger, W.E., Shannon, R.V. and Kuchta, J. (2002) Multichannel auditory brainstem implant: update on performance in 61 patients. J. Neurosurg. 96: 1063–71. Plonsey, R. (1969) Bioelectric Phenomena. New York: McGraw–Hill, pp. 340-2. Ranck, J.B., Jr (1963) Analysis of specific impedance of rabbit cere­ bral cortex. Exp. Neurol. 7: 153–74. Ranck, J.B., Jr (1963) Specific impedance of rabbit cerebral cortex. Exp. Neurol. 7: 144–52. Ranck, J.B., Jr (1975) Which elements are excited in electrical stimulation of mammalian central nervous system: a review. Brain Res. 98: 417–40. Ranck, J.B., Jr and BeMent, S.L. (1965) The specific impedance of the dorsal columns of the cat: an anisotropic medium. Exp. Neurol. 11: 451–63.

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Rattay, F. (1989) Analysis of models for extracellular fiber stimulation. IEEE Trans. Biomed. Eng. 36: 676–82. Robblee, L.S. and Rose, T.L. (1990) Electrochemical guidelines for selection of protocols and electrode materials for neural stimulation. In: W.F. Agnew and D.B. McCreery (eds), Neural Prostheses: Fundamental Studies. Englewood Cliffs, NJ: Prentice–Hall, pp. 25–66. Roth, B.J. (1994) Mechanisms for electrical stimulation of excitable tissue. Crit. Rev. Biomed. Eng. 22: 253–305. Rubinstein, J.T. (1993) Axon termination conditions for electrical stimulation. IEEE Trans. Biomed. Eng. 40: 654–63 (erratum in: IEEE Trans Biomed Eng. 41, 203). Rubinstein, J.T., Spelman, F.A., Soma, M. and Suesserman, M.F. (1987) Current density profiles of surface mounted and recessed electrodes for neural prostheses. IEEE Trans. Biomed. Eng. 34: 864–75. Sances, A., Jr and Larson, S.J. (1975) Impedance and current density studies. In: A. Sances and S.J. Larson (eds), Electroanesthesia: Biomedical and Biophysical Studies. New York: Academic Press, pp. 114–24. Schiefer, M.A. and Grill, W.M. (2006) Sites of neuronal excitation by epiretinal electrical stimulation. IEEE Trans. Neural Syst. Rehabil. Eng. 14: 5–13. Schmidt, E.M., Bak, M.J., Hambrecht, F.T., Kufta, C.V., O’Rourke, D.K. and Vallabhanath, P. (1996) Feasibility of a visual prosthesis for the blind based on intracortical microstimulation of the visual cortex. Brain 119: 507–22. Shannon, R.V. (1992) A model of safe levels for electrical stimulation. IEEE Trans. Biomed. Eng. 39: 424–6. Tranchina, D. and Nicholson, C. (1986) A model for the polarization of neurons by extrinsically applied electric fields. Biophys. J. 50: 1139–56. Troyk, P., Bak, M., Berg, J., Bradley, D., Cogan, S., Erickson, R. et al. (2003) A model for intracortical visual prosthesis research. Artif. Organs 27: 1005–15. Veltink, P.H., van Veen, B.K., Struijk, J.J., Holsheimer, J. and Boom, H.B. (1989) A modeling study of nerve fascicle stimulation. IEEE Trans. Biomed. Eng. 36: 683–92.

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C H A P T E R

15

Mechanisms of Action of Deep Brain Stimulation: A Review Kendall H. Lee, Charles D. Blaha, and Jonathan M. Bledsoe

o u t l i n e Introduction

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Five Hypotheses for Mechanism/s of Action of DBS Depolarization Block Hypothesis Synaptic Modulation Hypothesis

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Synaptic Depression Hypothesis Neural Jamming/Modulation Hypothesis Synaptic Facilitation Hypothesis Conclusions References

high frequency stimulation (HFS) as a treatment for intractable tremor patients in 1987, deep brain stimulation (DBS) of the thalamus, when compared to lesioning, has proven to have equal therapeutic effect with reduced risk (Benabid et al., 1987, 1994, 1996; Lozano, 2000). DBS has now replaced lesioning as the preferred neurosurgical option for the treatment of several movement disorders, including PD, dystonia and tremor. Significant progress in the areas of neuroimaging and stereotactic neurosurgery have resulted in

Introduction Over the past 30 years, improvements in neurosurgery, electrophysiology, and neuroimaging have led to new strategies for treatment of movement disorders such as Parkinson’s disease (PD). As a result of these technological improvements and understanding of movement disorder pathophysiology, patients with PD have new pharmacological and neurosurgical treatments at their disposal. However, many of the current pharmacological therapies for PD are either not completely effective or not well tolerated by patients. Furthermore, the long-term use of pharmacological therapies may cause complications such as dyskinesias.1 As a result, there has been a significant increase in the use of restorative functional neurosurgical techniques to treat movement disorders. Since Benabid and coworkers first described chronic

Neuromodulation

161 161 162 165 166

1

 Dyskinesia is a symptom of differing discords that distinguish the underlying cause. Involuntary movements, similar to a tic or chorea, are common. When a dyskinesia presents as a result of antipsychotic medication intake such as haloperidol, it is a tardive dyskinesia and is commonly found in the face as tongue “rolling.” A dyskinesia found in a patient with PD is more commonly a jerky, dance-like movement of the arms or head and usually presents after several years of treatment with medication containing levodopa.

157

2009 Elsevier Ltd. © 2008,

158

15.  mechanisms of action of deep brain stimulation: a Review

improved symptom control2 for PD patients through stimulation of the internal part of the globus pallidus (entopeduncular nucleus homologue in rats, but referred to as GP throughout this chapter), subthalamic nucleus (STN), or pedunculopontine tegmentum (PPT) (Benabid, 2003; Mazzone, 2003; Volkmann, 2004; Mazzone et al., 2005). Furthermore, patients with disorders such as depression (Mayberg et al., 2005; Hardesty and Sackeim, 2007; Schlaepfer et al., 2008), obsessive–compulsive disorder (OCD) (Greenberg et al., 2006; Lipsman et al., 2007), epilepsy (Hodaie et al., 2002; Boon et al., 2007; Vonck et al., 2007), Tourette’s syndrome (Maciunas et al., 2007), and chronic pain (Bittar et al., 2005; Rasche et al., 2006), are being investigated to determine if DBS is a viable treatment option. Unfortunately, rapid advances in therapeutic effectiveness and use of DBS have occurred without know­ ledge of the basic science of its mechanism/s. Early hypotheses were developed primarily based on similar symptomatic responses seen with brain tissue lesioning (Benabid et al., 1987; Benazzouz and Hallett, 2000). This would seem to be the case with the rapid therapeutic effect observed when treating tremor patients with neurostimulation (DBS). However, it does not explain the variation in the temporal response of other disorders to DBS, such as dystonia. This would suggest an alteration in the fundamental network more complicated then simply inhibition of a group of cells. Converging evidence from neuroanatomical, electrophysiological and neurochemical, and imaging studies have revealed that the mechanism of DBS is a more complicated story. The Albin and Delong model has provided a foundation for the understanding of the thalamocortical basal ganglia circuit (Albin et al., 1989, 1995; Bergman et al., 1990, 1994). Recent research in the architecture of this complicated network has uncovered new interconnections between nuclei in this circuit, especially the STN (Carpenter et al., 1981; Kitai and Deniau, 1981; Parent and Smith, 1987; Smith and Parent, 1988; Parent and Hazrati, 1995a, 1995b; Hamani et al., 2004; Temel et al., 2005). These afferent and efferent projections may play a major role in the mechanism/s of DBS. Though this information has proven to be very insightful, it does not 2

 It should be stated that not all patients with PD share the same subset of symptoms and it is important to realize that not every person with PD develops all signs or symptoms of the disease. The primary symptoms of PD include: bradykinesia, a phenomenon of a person experiencing slow movements, difficulty initiating movement, and incomplete movements or sudden stopping of movement; postural instability or impaired balance and coordination, symptoms that, combined with bradykinesia, increase the probability of falling. People with balance problems may have difficulty making turns or abrupt movements and may actually “freeze.” Freezing is when a person finds it difficult to commence walking and feels quite fixed to the ground.

answer the basic question surrounding the mechanism/s of DBS: “does it activate or inhibit?” Furthermore, which parts of the neuronal elements (i.e. local soma and axons or fibers of passage) are being affected? Numerous multidisciplinary scientists and clinicians have begun to work in collaboration to investigate this complicated topic of mechanism/s of DBS. As investigational data increase, multiple hypotheses as to the mechanism/s of DBS have been presented and reviewed (Benazzouz and Hallett, 2000; McIntyre and Thakor, 2002; Lozano and Eltahawy, 2004; McIntyre, Savasta et al., 2004a; Perlmutter and Mink, 2006; Uc and Follett, 2007). Five mechanisms that appear to have gained the widest acceptance include hypotheses that involve local changes in the stimulated brain nuclei, as well as hypotheses that explain distal changes in efferent outputs and target nuclei of the stimulated brain nuclei. We review here the foundations for these hypotheses, particularly as they relate to the modulation of neuronal spike generation, neurotransmitter release, and their impact on oscillatory activity within the thalamocortical basal ganglia network.

Five hypotheses for mechanism/s of action of DBS The literature has recently seen an exponential increase in research focused on the mechanism/s of DBS. Five hypotheses have emerged as plausible explanations and are progressively gaining acceptance from the scientific community. These involve the effects of DBS on local changes in the stimulated brain nuclei and distal changes in efferent outputs and target nuclei of the stimulated brain nuclei: 1. inactivation of action potential generation in efferent outputs (depolarization block) 2. activation of neuronal terminals that inhibit and/ or excite efferent outputs (synaptic modulation) 3. depletion of neurotransmitter in terminals of efferent outputs (synaptic depression) 4. anti-oscillatory action on basal ganglion circuitry (network jamming or modulation) 5. sustained enhancement of neurotransmitter release (synaptic facilitation). Here, we describe the evidence for each of these hypotheses.

Depolarization Block Hypothesis An early working hypothesis on the mechanism of action of DBS stated that DBS inhibits neuronal activity

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Five hypotheses for mechanism/s of action of DBS

in the stimulated site leading to decreased output from the stimulated structure. This hypothesis originated from the observation that the clinical effects of DBS are similar to those of a surgical lesion (Benabid et al., 1987; Benazzouz et al., 1995), suggesting that this type of stimulation acts by silencing neurons of the stimulated structure. Additionally, given that in the dopamine depleted (MPTP3) monkey model, lesioning of STN reverses experimental parkinsonism (Bergman et al., 1990), DBS-mediated inhibition of firing in STN, mimicking a surgical lesion, was thought to alleviate many of the cardinal symptoms of PD. In agreement with this hypothesis, Beurrier et al. (2001) used the patch-clamp technique4 in a rat slice preparation to demonstrate that DBS blocked action potential generation in STN neurons in the post-stimulation period, suggesting that the inhibitory effect of HFS was due to blockage of voltage sensitive Na channels (depolarization block). In vivo HFS of the STN in normal and dopamine (6-OHDA5) lesioned rats also resulted in decreased activity in the substantia nigra pars reticulata (SNr) and entopeduncular nucleus, and increased activity in the GP and ventral lateral nucleus of the thalamus (Benazzouz et al., 1995). This suggested that HFS had similar inhibitory effects as STN lesions when considering the basal ganglia network. Similarly, Magarinos-Ascone et al. (2002), using the rat brain in vitro slice technique,6 demonstrated that sustained HFS could depolarize the membrane potential 3

 MPTP (1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine) is a neurotoxin that causes permanent symptoms similar to those exhibited in PD patients by killing dopaminergic neurons in the substantia nigra of the midbrain. It is used to study the disease in monkeys. 4  Patch-clamp technique is a technique that allows the study of individual ion channels in cells. The technique is typically used to study excitable cells such as neurons. In this technique, the recording electrode is a glass micropipette with a smooth open tip of about one micrometer in diameter that, rather than impaling the cell to perform intracellular recordings, attaches to a small “patch” of the cell membrane to allow recordings of ion current flow through single ion channels. 5  6-Hydroxydopamine, or 6-OHDA, is a neurotoxin used by neurobiologists to selectively kill dopaminergic and noradrenergic neurons. 6-OHDA enters the neurons via the dopamine and noradrenaline (or norepinephrine) reuptake transporters. 6-OHDA is often used in conjunction with a selective noradrenaline reuptake inhibitor (such as desipramine) to kill dopaminergic neurons only. 6  In vitro brain slice preparation allows recording from semi-intact neural circuits, with the advantages of mechanical stability and control over the extracellular environment and is used for a wide variety of studies including synaptic plasticity and development, network oscillations, intrinsic and synaptic properties of defined neuronal populations, and many others. Whole-cell recordings in brain slices are often combined with imaging techniques and indicator dyes to measure intracellular pH, calcium concentration, etc. It can also be combined with retrograde tracing techniques to record responses from neurons that project to a certain brain areas.

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and trigger action potentials that subsequently led to total silence of cells within the STN. They suggested that the silencing effect of tetanic stimulation is not due to a frequency-dependent presynaptic depression, but rather from the gradual inactivation of Na-mediated action potentials. These findings suggest that the remission of PD symptoms by treatment with HFS of the subthalamic nucleus in humans may primarily reside on its capacity to suppress the action potential activity of STN neurons. Furthermore, Garcia et al. (2003) showed that HFS of the STN suppressed local neuronal spontaneous activity and spike generation, which were not prevented by systemic pretreatment with metabotropic and ionotropic glutamate receptor or gamma-amino butyric acid (GABA) antagonists. Additionally, Filali et al. (2004) placed a recording electrode within 600 microns of the stimulating electrode in the STN of PD patients and found that stimulation at 100–300 Hz produced inhibition of most recorded cells. Similarly, GPi recordings have shown that HFS of the GPi reduces the firing frequency in the dopamine depleted (MPTP) model (Boraud et al., 1996) and in human GP with PD (Dostrovsky et al., 2000). Additional support for the depolarization block hypothesis was derived from metabolic studies of STN cells during HFS. Salin et al. (2002), using cytochrome oxidase I (CoI) mRNA as a marker of neuronal metabolic activity, found a reduction in STN cells during STN stimulation in dopamine (6-OHDA) lesioned versus normal rats. Tai et al. (2003) used in vivo extracellular recordings and histochemistry to examine the effects of STN stimulation on STN and substantia nigra compacta (SNc) cells of normal and dopamine (6-OHDA) lesioned rats and found a reduction in cellular firing and CoI mRNA (metabolic activity) in both regions.

Synaptic Modulation Hypothesis The synaptic modulation hypothesis states that DBS activates neuronal elements that are in close proximity to the stimulating electrode (depending on the stimulation parameters), which results in local synaptic inhibition via activation of axonal terminals within the stimulated nuclei that release inhibitory neurotransmitters such as GABA. Evidence for this hypothesis has come from electrophysiological recordings with microelectrodes placed within 600 m of a stimulating electrode within the GPi of PD patients undergoing DBS surgery (Dostrovsky et al., 2000). Recordings during HFS revealed an inhibition of spontaneous activity lasting 10–25 ms. This duration of activity corresponds to a typical GABAergic IPSP. These findings suggest that DBS

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within the GPi preferentially excites GABAergic axon terminals of striatal and/or external pallidal origin causing local release of GABA and inhibition of GPi neurons (Dostrovsky et al., 2000) and are consistent with the observation that muscimol, a GABA agonist, applied to the thalamus (Pahapill et al., 1999) and STN (Levy et al., 2001) of PD patients results in comparable therapeutic benefit as DBS of the same regions. A more complete description of the effects of DBS may be that it results in both local synaptic inhibition and excitation by a nonspecific stimulation of the neuronal elements. In line with this hypothesis, using sharp electrode intracellular recording techniques in the rat STN, we demonstrated that HFS induced post­ synaptic potentials that included EPSPs and IPSPs (Lee, Chang et al., 2004). These postsynaptic potentials were completely blocked by bath application of glutamate and GABA antagonists, suggesting that HFS resulted in excitatory and inhibitory neurotransmitter release in the STN. Furthermore, as the excitatory inputs to the STN are thought to originate in the cerebral cortex (Fujimoto and Kita, 1993; Maurice et al., 1998a, 1998b; Nambu et al., 2000) and the inhibitory inputs are derived from the GP (Kita et al., 1983), the EPSPs and IPSPs seen during STN HFS may result from stimulation of both descending cortical inputs to STN, which generate EPSPs via glutamate release, and GP input to STN, which generates IPSPs by releasing GABA. In parallel with local synaptic inhibition and excitation, DBS may result in distal synaptic excitation by activating axons within the stimulated brain region that release excitatory amino acid neurotransmitters, such as glutamate or aspartate. Projections from the STN are thought to be glutamatergic (Robledo and Feger, 1990) and HFS activation of these axons would be expected to increase glutamate release in STN target structures, such as the GP and SNr (Sato et al., 2000). Indeed, the activity of SNr cells has been shown to increase during STN stimulation, likely as a result of activation of glutamatergic subthalamonigral projections since the latency of the evoked excitation was consistent with the conduction time of subthalamonigral neurons (Maurice et al., 2003). In addition, in dopamine (MPTP) lesioned non-human primates, Hashimoto et al. (2003) have shown that STN HFS results in a short-latency excitation and an increase in the mean discharge rate of GPe and GPi neurons, together with the development of a more regular pattern of activity. Furthermore, GPi stimulation has been shown to inhibit thalamic target cells as a result of activation of inhibitory GABAergic GPi efferent axonal projections (Anderson et al., 2003). However, these responses may be secondary to excitation of efferent fibers from the stimulated nuclei but likely contribute

to the therapeutic changes in the temporal firing pattern of the basal ganglia network. Metabolic studies of STN HFS concur with these observations. Dopamine (MPTP) lesioned non-human primates received 10 days of STN HFS followed by evaluation for 2-deoxyglucose (2-DG) (synaptic activity) and CoI (metabolic activity) mRNA (Meissner et al., 2007). This revealed an increase in 2-DG uptake in the STN and decrease in the GPi, with a concurrent increase in CoI mRNA. Thus, in addition to distal synaptic excitation, HFS may result in distal synaptic inhibition by activating efferents of the stimulated nuclei that release inhibitory amino acid neurotransmitters, such as GABA or glycine. Recent studies utilizing microdialysis in rats support the theory that the therapeutic effects of STN HFS may be related to the selective increase in inhibitory and excitatory neurotransmission within target nuclei of STN efferents. Unilateral STN HFS was found to induce significant bilateral increases in striatal glutamate and GABA release, both in intact and in dopamine (6-OHDA) lesioned animals (Bruet et al., 2003). Similar studies of STN HFS caused a significant increase in extracellular glutamate concentration in the ipsilateral GP and SNr, while GABA was augmented only in the SNr (Windels et al., 2003). No modifications of GABA were observed in the GP regardless of the frequencies applied, whereas, in the SNr, GABA increased when HFS increased from 60 to 350 Hz. Glutamate release in the GP and SNr were maximal at 130 Hz with no change through 350 Hz (Windels et al., 2003). Thus, STN HFS produces frequency dependent release of various excitatory and inhibitory neurotransmitters in efferent target nuclei. In support of a distal synaptic modulation hypothesis of DBS, a computational model of a thalamocortical relay cell was exposed to DBS stimulation parameters (McIntyre, Grill et al., 2004). The results of this simulation showed an increase in axonal firing independent of the soma. This decoupling of responses between the axon and soma explains why extracellular recordings will show inhibition of the soma and excitation of efferent targets during DBS. This group continued on to show that this separation between axonal and somatic activity could also be found in the STN and GP cells (McIntyre, Savasta et al., 2004b). Overall, converging electrophysiological evidence points to a combination of effects of DBS that include both local and distal synaptic modulation. The challenge of future investigations will be to determine which of these mechanisms play a more important role in mediating the therapeutic actions of DBS or whether these actions require an interaction between these mechanisms to regulate activity in the basal ganglia network.

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Five hypotheses for mechanism/s of action of DBS

Synaptic Depression Hypothesis Related to the synaptic modulation hypothesis, the synaptic depression hypothesis posits that a neuron that is activated by DBS is unable to sustain high frequency action on efferent targets due to depletion of terminal vesicular stores of neurotransmitters (Wang and Kaczmarek, 1998; Zucker and Regehr, 2002). Patch-clamp recordings from giant synapses in the mouse auditory brain stem have shown that shortterm synaptic depression can be largely attributed to rapid depletion of a readily releasable pool of vesicles. In addition, HFS of presynaptic terminals significantly enhances the rate of replenishment of the vesicular pool and that Ca2 influx through voltage-gated Ca2 ion channels is the key signal that dynamically regulates the refilling of the releasable vesicular pool in response to different patterns of inputs (Wang and Kaczmarek, 1998). Thus, synaptic depletion is usually attributed to depletion of some pool of readily releasable vesicles (Zucker and Regehr, 2002). Urbano et al. (2002) utilized voltage-sensitive dye imaging and field potentials with in vitro studies of thalamocortical afferent axons from mouse brain slices to demonstrate a reduction in cortical activity with incremental increases in thalamic stimulation. Optimal activation frequency was 40 Hz with significant decrease in activity beyond 120 Hz. They concluded that this reduction in cortical activity was secondary to synaptic transmission failure by transmitter depletion.

Neural Jamming/Modulation Hypothesis Neural jamming or modulation hypothesis states that DBS regulates and corrects pathological activity in the basal ganglia network. Significant neurophysiological studies have been performed on normal and pathological states in the thalamocortical basal ganglia network revealing specific changes in cellular activity during seizures and movement disorders, such as PD and essential tremor. Computer simulations have been used to model the effect of different stimulation frequencies and the regularity of neuronal activity on information transfer between synaptically connected neurons. These computer simulations suggest that HFS results in an informational lesion, either by altering the pathological signal to a normal firing pattern or desynchronization of abnormal oscillations (Montgomery and Baker, 2000). Understanding the fundamental principles of neural jamming requires a detailed knowledge of neuronal ionic conductances, as well as normal firing patterns within the thalamocortical basal ganglia network. For example, STN (Bevan et al., 2002b) and thalamic

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neurons (McCormick and Feeser, 1990; Lee and McCormick, 1996) are able to fire in both tonic and burst modes because they possess intrinsic membrane properties that generate rhythmic oscillations (from 10 to 40 Hz) (Bevan et al., 2002a). As described by Bevan, these membrane properties stem from the presence of several ionic conductances (Bevan and Wilson, 1999; Bevan et al., 2002a). These include a tetrodotoxin (TTX)7 sensitive persistent sodium current (INaP), an apamin8 sensitive potassium activated calcium current (ICaK) and a cesium sensitive hyperpolarizing activated current (Ih) (Bevan and Wilson, 1999). The interplay between INaP and ICaK produces rhythmic activity in the 10–30 Hz range. As well as showing slow rhythmic firing at rest, STN neurons also possess the ability to fire at high frequencies, and depending on the input show two preferential frequencies. Indeed, multiple neuronal firing patterns have been described in the STN that include irregular (55–65%), tonic (15–25%), and burst (15–50%) firing (Wichmann et al., 1994). Interestingly, PD patients exhibit large amplitude irregular spike pattern or periodic behavior. Classification of these periodic cells demonstrated tremor cells (2–6 Hz), cells with high (10 Hz) frequency periodic activity, and a combination of each (Levy et al., 2000). Importantly, local field potentials recorded in human STN suggest an increase in oscillatory activity in the beta frequency range may be important in PD (Brown et al., 2002; Brown and Williams, 2005; Weinberger et al., 2006). Although the exact relation between oscillatory activity and PD symptoms remains to be determined, a study using dopamine (MPTP) lesioned non-human primates suggests that STN HFS might at least partially exert its beneficial effects through the reduction of oscillatory activity in the STN network and consequently in the entire thalamocortical basal ganglia network (Meissner et al., 2005). Additional studies are beginning to elucidate the neural network mechanism that may be responsible for these basal ganglia-thalamic oscillatory activities. For example, STN neurons, at least in vitro, have been shown to be part of a neural network involving 7

 Tetrodotoxin (anhydrotetrodotoxin 4-epitetrodotoxin, tetrodonic acid, TTX), derived from Tetraodontiformes, the name of the order that includes the pufferfish, porcupinefish, ocean sunfish or mola, and triggerfish, several species of which carry the toxin. is a potent neurotoxin with no known antidote, which blocks action potentials in nerves by binding to the pores of the voltage-gated, fast sodium channels in nerve cell membranes. (http://en.wikipedia.org/wiki/ Tetrodotoxin) 8  Apamin is a neurotoxin which selectively blocks SK channels, a type of Ca2-activated K channel expressed in the central nervous system. The final 18 amino acid polypeptide is a component of apitoxin (bee venom). (http://en.wikipedia.org/wiki/Apamin)

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reciprocal connections with the GP (Plenz et al., 1998) to generate synchronized oscillations (Gillies et al., 2002; Baufreton et al., 2005). In this system, the GP releases GABA onto STN neurons, causing IPSPs and a subsequent rebound Ca2 spike by activation of a low threshold calcium channel (It). The rebound calcium spike then allows high frequency action potential generation in STN neurons that, in turn, release glutamate onto GP neurons. Glutamate excitation of GP neurons, in turn, set the stage for the next cycle of oscillation within the STN and GP network. These oscillations may be involved in tremor generation in PD patients and the disruption of these oscillations may be an important mechanism whereby STN HFS diminishes oscillations (see below). A remarkably similar circuit mechanism also exists in the thalamus that is able to generate network oscillations such as tremor, absence epilepsy, and spindle waves. Spindle waves are 1–3 second epochs of synchronized, 7–14 Hz oscillations that are generated as a result of interactions between thalamocortical and thalamic nucleus reticularis (nRt) neurons (Bal and McCormick, 1993; von Krosigk et al., 1993; Bal et al., 1995b). During a spindle wave, the generation of a burst of action potentials in the GABAergic neurons of the nRt results in 2–10 mV IPSPs in thalamocortical neurons (Bal et al., 1995a, 1995b). A subset of thalamocortical neurons generate a rebound low threshold Ca2 spike that leads to burst firing activity in corticothalamic neurons. Stimulation of corticothalamic neurons, in turn, elicits a barrage of EPSPs and activation of low threshold Ca2 spikes in nRt neurons, thus initiating the next cycle of the spindle wave (von Krosigk et al., 1993). Spindle waves generalize through the progressive recruitment of neurons into this oscillation, presumably owing to axonal interconnections between thala­ mocortical and nRt neurons (Kim et al., 1995). Spindle waves are normally mediated through the activation of GABA-A receptors on thalamocortical neurons. Surprisingly, when these receptors are blocked with bicuculline (a GABA-A antagonist), the spindle waves are transformed into events that resemble absence seizures. During normal spindle waves, the IPSPs are about 100 msec in duration. Blockade of GABA-A receptors prolongs the IPSPs to 300 msec in duration, and the oscillation slows from 6 to 10 Hz to about 3 Hz. Since the intrinsic harmonics of the thalamocortical cells (3 Hz) match that of the thalamocortical-nRt loop (also at 3 Hz) these bursts become very strong, resulting in the generation of a massive synchronized discharge at 3 Hz. In this manner, normal spindle waves in vitro can be perverted into absence seizurelike events (Bal et al., 1995b, 1995a). Interestingly, both

tremor and absence seizure appear to involve abnormal oscillatory activity in the thalamus, at a frequency of 3–6 Hz for tremor (Lenz et al., 1993, 2002) and 3 Hz for absence seizures (Snead, 1995). Importantly, HFS applied to the area containing tremor cells leads to immediate tremor arrest and a rapid reversal when stimulation ceases (Benabid et al., 1996). The depolarization of thalamocortical neurons likely is capable of abolishing spindle wave, tremor, and 3 Hz absence seizure-like oscillations owing to the inhibition of rebound responses which are required for driving nRt/perigeniculate nucleus neurons to discharge in synchrony. Thalamic slice studies support this hypothesis in that both application of neurotransmitters (Lee and McCormick, 1996, 1997; Lee, Broberger et al., 2004) or HFS (Lee et al., 2005) resulted in a marked depolarization of thalamocortical neurons and abolished both spindle and 3 Hz absence seizure-like oscillations. In this manner, HFS induced neurotransmitter release in the thalamus or STN (Lee et al., 2007) may “jam” abnormal oscillations that lead to tremor and absence epilepsy. Thus, DBS may abolish synchronous oscillatory activities such as those that generate tremor and seizures. Paradoxically, DBS, which is likely excitatory, and a surgical lesion of the ventrointermedius thalamus, which is presumably inhibitory, both suppress tremor. This paradox may be resolved by recognizing that DBS-mediated neuro­ transmitter release and surgical lesion both disrupt the circuit generating abnormal oscillations, albeit by different mechanisms.

Synaptic Facilitation Hypothesis Degeneration of the nigrostriatal dopaminergic pathway is a well-known cause of PD. The synaptic facilitation hypothesis states that DBS results in the release of dopamine from surviving dopaminergic neurons projecting to the basal ganglia to contribute to the therapeutic action of STN HFS in PD patients. One of the target structures of the STN is the SNc containing dopaminergic cell bodies comprising the nigrostriatal projection to the basal ganglia. Glutamate-containing axonal terminals arising from the STN have been identified making synaptic contact on dopaminergic dendrites within the SNr (Kita and Kitai, 1987), suggesting that STN HFS may increase dopaminergic nigrostriatal activity. This notion is supported by electrophysiological studies showing that STN HFS increases firing of identified dopaminergic SNc neurons recorded either extracellularly (Hammond et al., 1978; Benazzouz et al., 2000) or intracellularly (Smith and Grace, 1992; Lee, Chang et al.,

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Figure 15.1  Glutamate release in the STN. Positioning of a glutamate sensor adjacent to a bipolar stimulating electrode in the STN (A) permitted glutamate release to be recorded at the site of stimulation in response to different frequencies (B) and durations (C) of electrical stimulation in the STN of anesthetized rats

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dopaminergic cells via a glutamate NMDA (N-methylD-aspartate) receptor-dependent mechanism (Iribe et al., 1999), as well as increase extracellular dopamine concentrations in the SNc, a neurochemical response requiring depolarization of dopaminergic cell bodies (Mintz et al., 1986; Rosales et al., 1994). Consistent with these findings, several studies in animals using in vivo

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2004). The EPSPs in these neurons are thought to arise from a direct monosynaptic excitatory glutamatergic input from the STN (Smith and Grace, 1992; Kang and Futami, 1999). Similarly, we reported that STN HFS resulted in glutamate release in STN, as shown in Figure 15.1 (Lee et al., 2007). In addition, it was also shown that STN HFS also results in the generation of EPSPs and action potentials in SNc neurons, as shown in Figure 15.2 (Lee, Chang et al., 2004). Thus, STN HFS evoked glutamate release in the SNc may increase firing of dopaminergic neurons that in turn enhances dopamine release in the basal ganglia. In addition to electrophysiological studies, evidence for the synaptic facilitation hypothesis comes from a number of basic neurochemical studies and clinical observations described below. Clinically, bilateral STN stimulation improves the majority of PD symptoms, decreases or eliminates the need for levodopa (Benabid et al., 2000), and ameli­ orates motor fluctuations and dyskinesias in a way that is quantitatively comparable to results obtained with levodopa alone (DBS-study-group, 2001). In addition, the beneficial effects of STN stimulation occur in the dopamine-Off period, but not during the dopamineOn period (Benabid et al., 2000; Deuschl et al., 2006). This latter finding is analogous to an occlusion test in which the presence of excess dopamine occludes the therapeutic response to DBS, suggesting that STN DBS mediates these effects, in part, via modulation of dopaminergic transmission in the basal ganglia. STN HFS may even result in dyskinesias that resemble those seen when excess levodopa is given (Benabid et al., 2000; DBS-study-group, 2001; Deuschl et al., 2006). Thus, an increase in extracellular levels of striatal dopamine may contribute to the efficacy of STN HFS via modulation of the basal ganglia network of PD patients. In agreement with this hypothesis, electrical stimulation of the rat STN has been shown to activate SNc

Action potential (B)

Figure 15.2  STN evoked SNc firing. HFS of the STN in rat brain slices evoked excitatory postsynaptic potentials and action potential generation (red boxes) in dopaminergic neurons in the substantia nigra pars compacta (A). Blow up from (A) of a portion of the stimulated response (red dashed lines) (B)

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15.  mechanisms of action of deep brain stimulation: a Review

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microdialysis have shown that STN HFS in normal and dopamine (6-OHDA) lesioned rats increases striatal extracellular levels of dopamine (Bruet et al., 2001) or dopamine metabolites DOPAC (dihydroxyphenylacetic acid) and HVA (homovanillic acid) (Paul et al., 2000; Meissner et al., 2001, 2002, 2003). With one exception (Bruet et al., 2001), STN HFS evoked increases in striatal dopamine dialysate could not be detected without first inhibiting dopamine reuptake with nomifensine, a dopamine reuptake inhibitor, and stimulating for prolonged durations (20 min) (Meissner et al., 2003). Although in vivo monitoring of slow (min–hrs) changes in dopamine release is easily accomplished using these conventional microdialysis methods, real-time amperometric monitoring9 of dopamine permits detection of more rapid changes in extracellular dopamine release in the absence of dopamine reuptake inhibition that may result from STN HFS (Dugast et al., 1994; Schonfuss et al., 2001; Venton et al., 2002; Forster and Blaha, 2003). Fixed potential amperometry is an electrochemical method for measuring neurotransmitter release in vivo in which carbon-based microelectrodes detect the current associated with oxidation of electroactive compounds such as dopamine. The dynamics of dopamine release in the nucleus 9

 Real-time amperometry uses electrodes that record near instantaneous production of a current resulting from the oxidation (or reduction) of an electroactive compound, such as dopamine, at the electrode’s recording surface when a constant potential (voltage) is applied. A change in the oxidation or reduction current that is continuously recorded is directly proportional to a change in the concentration of the compound in extracellular fluid.

accumbens and striatum during electrical stimulation of ascending dopaminergic pathways in rats has been described and quantified by a number of investigators using fixed potential amperometry and other in vivo electrochemical recording techniques (Dugast et al., 1994; Blaha and Phillips, 1996; Bergstrom and Garris, 1999; Garris et al., 1999; Schonfuss et al., 2001). Using these in vivo electrochemical methods, we examined striatal dopamine responses in the rat evoked by STN HFS or HFS of dopamine axons of passage in the adjacent nigrostriatal dopaminergic pathway (Lee et al., 2006). STN HFS evoked a twocomponent effect on striatal dopamine release with the first characterized by a peak increase in dopamine release within 0.4 sec that decayed back towards prestimulation baseline levels within 1 sec. The second was characterized by a steady-state level of dopamine release sustained 30% above pre-stimulation baseline over the course of HFS (Figure 15.3A). In marked contrast, stimulation of tissue immediately dorsal to STN containing ascending dopaminergic axons resulted in a 10-fold greater increase in the dopamine response that plateaued after 5 sec but remained elevated over the course of HFS. As shown in Figure 15.3B, using comparable stimulation sites and amperometric recording procedures we have observed similar differences in the magnitude and temporal pattern of dopamine release in the striatum of the awake monkey (Gale et al., 2008). Altogether, these data fit well with electrophysiological and microdialysis studies showing that STN HFS increases action potential firing in STN and SNc neurons (Bruet et al., 2001; Meissner et al., 2002; Lee, Chang et al., 2004). The finding that stimulation of

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conclusions

ascending dopaminergic fibers dorsal to the STN resulted in a greater release of striatal dopamine than STN stimulation suggests that DBS of tissue immediately dorsal to the STN may provide a more optimum means of enhancing dopamine release in the basal ganglia. Indeed, several clinical studies have shown that improvement in motor symptoms is correlated with the location and electrical energy of chronic stimulation where the best improvement in symptoms is obtained when the DBS electrode projected onto white matter dorsal to the STN (Saint-Cyr et al., 2002), including the dorsolateral border of the STN (Herzog et al., 2004). The anatomical correlates of this location may be the pallidothalamic bundle (including Field H of Forel and the thalamic fascicle), the pallidosub­ thalamic tract, and/or the zona incerta. The axons of SNc dopaminergic neurons themselves are immediately dorsal to the STN and fall within the region of maximum stimulation efficacy (Prensa et al., 2000). Indeed, several retrograde and anterograde tracttracing studies have shown ascending dopaminergic axons originating from the SNc provide collateral inputs to the STN (Hassani et al., 1997; Prensa et al., 2000). Thus, these results, taken together, suggest that HFS of the STN and tissue dorsal to the STN may activate ascending dopaminergic fibers of passage. Contrary to these results, [(11)C] raclopride10 positron emission tomographic (PET) scanning has failed to show significant differences in [(11)C] raclopride binding, despite significant improvements in Unified Parkinson’s Disease Rating Scale (UPDRS)11 motor scores following unilateral stimulation of the STN (Abosch et al., 2003; Hilker et al., 2003). These imaging data suggest that STN stimulation does not mediate its anti-PD effects via the release of dopamine. However, PET scanning with raclopride has relatively poor temporal resolution and sensitivity that requires an increase of greater than 90% of baseline measures in order to detect a change in dopamine release (Volkow et al., 1993; Hilker et al., 2003). As well, adaptive 10

 Raclopride is a synthetic compound that acts on a subset of dopamine receptors (D2 subtype) as an antagonist. It is typically used as an antipsychotic agent to treat schizophrenia. It can be radiolabeled and used in PET scanning to assess the degree of dopamine binding. 11  Unified Parkinson’s Disease Rating Scale is a rating scale used to follow the longitudinal course of PD (http://en.wikipedia.org/ wiki/unified_parkinson’s_disease_rating_scale). It is made up of the following sections: mentation, behavior, and mood; activities of daily living; motor; complications of therapy; Hoehn and Yahr stage; Schwab and England Activities of Daily Living Scale (DLS). These are evaluated by interviews and clinical observations. Some sections require multiple grades assigned to each extremity. Clinicians and researchers alike use the UPDRS and the motor section in particular to follow the progression of a person’s PD.

changes in dopamine receptor populations (D2 receptor internalization and recycling) occurring over long-term STN HFS has been suggested to interfere with PET quantification of dopamine release in PD patients (Laruelle, 2000). However, a more recent PET study has shown baseline synaptic dopamine levels in PD patients are significantly increased by STN HFS (Nimura et al., 2005). Regardless, confirmation of the synaptic facilitation hypothesis will require a more detailed analysis of dopamine transmission in PD patients implanted with DBS electrodes.

Conclusions All five of these hypotheses are clearly interconnected and thus the importance in the search for the exact mechanism of action of DBS is to identify which of these effects are responsible for giving the best therapeutic benefit and which are epiphenomena. Uncovering the neurochemical mechanisms that mediate the normalization of activity within the thalamocortical basal ganglia network will allow for future development of better more effective DBS. McIntyre, Savasta et al. (2004b) recently addressed several hypotheses on the mechanisms of action of DBS and concluded that stimulation-induced desynchronization of network oscillations represents the hypothesis that best explains the presently available data. These investigators argued that cell body firing does not accurately reflect the efferent output of neurons stimulated with high frequency extracellular pulses, and that decoupling of somatic and axonal activity explains the paradoxical experimental results. They studied stimulation using the combination of a finite-element model of the clinical DBS electrode and a multicompartment cable model of a thalamocortical (TC) relay neuron. Both the electric potentials generated by the electrode and a distribution of excitatory and inhibitory trans-synaptic inputs induced by stimulation of presynaptic terminals were applied to the TC relay neuron. The response of the neuron to HFS was primarily dependent on the position and orientation of the axon with respect to the electrode and the stimulation parameters. Direct activation of TC relay neurons by subthreshold stimulation caused suppression of intrinsic firing (tonic or burst) activity during the stimulus train which was mediated by activation of local inhibitory presynaptic terminals. Suprathreshold stimulation caused suppression of intrinsic firing in the TC soma, but generated efferent output at the stimulus frequency in its axon. This independence of firing in the cell body and axon

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resolves the apparently contradictory experimental results on the effects of DBS, notably depolarization block versus synaptic modulation or facilitation. Overall, the results of this study support the hypothesis of stimulation-induced modulation of pathological network activity as a therapeutic mechanism of DBS (McIntyre, Savasta et al., 2004b). Thus, together with neuronal modeling the results of electrophysiological and neurochemical studies in reduced (in vitro) and intact (in vivo) preparations, including clinical observations, are consistent with the hypothesis that DBS enhances transmission of both excitatory and inhibitory neurotransmitters within the thalamocortical basal ganglia network (hypothesis of synaptic modulation and facilitation). In turn, facilitation of neurotransmitter release in target nuclei of the stimulated structure, such as the STN, likely contributes to normal firing pattern or desynchronization of abnormal oscillations throughout the network (hypothesis of neural jamming or modulation). Our own neurochemical studies suggest that the magnitude of the clinical response to STN HFS may be correlated with the evoked release of dopamine in the basal ganglia. However, it is unresolved whether stimulation of axons of passage in the region of the STN or stimulation of neurons within the STN or both leads to enhanced dopamine release. Interestingly, preliminary studies in our laboratory indicate that STN stimulation evoked striatal dopamine release can be partially blocked by microinfusion of the axonal blocker lidocaine or nonspecific ionotropic glutamate receptor antagonist kynurenate into the SNc, while these treatments fail to attenuate the dopamine response evoked by stimulation of the ascending nigrostriatal dopaminergic pathway (unpublished observations). Although the SNc seems to be the likely source of enhanced dopamine release, other dopaminergic targets driven by DBS may also participate in the response. However, STN activity is increased in patients with active symptoms of PD. Therefore, it is paradoxical that further stimulation of the STN should ameliorate PD. Whether this indicates that increased STN activity is insufficiently compensatory or whether the patterns of neuronal activation and neurotransmitter release by STN stimulation differ in some key way from spontan­ eous activity of the STN remains to be explored in future investigations.

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Computational Modeling of Deep Brain Stimulation Cameron C. McIntyre

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obsessive–compulsive disorder, Tourette’s syndrome, minimally conscious state, and depression. The clinical outcomes achieved with DBS are a testament to the efficacy of the current device technology, surgical implantation techniques, and clinical programming strategies. For example, DBS for movement disorders can provide greater than 50% improvement in clinical ratings of motor symptoms in appropriately selected patients (Walter and Vitek, 2004). However, DBS typically requires highly trained and experienced clinical oversight to achieve maximal therapeutic benefit in each patient (Moro et al., 2006). In turn, an important and necessary step forward for wide scale use of this medical technology is the development of assistive technologies that optimize clinical implementation of DBS. Rate-limiting steps to the clinical optimization of DBS are improved scientific understanding of the effects and therapeutic mechanisms of electrical stimulation of the brain. Experimental neurophysiologists

Over the past two decades DBS has evolved from an experimental technique to a well-established ­therapy for a range of medically refractory neurological disorders (Perlmutter and Mink, 2006). To date, the most effective application of DBS technology has been for the treatment of movement disorders, such as Parkinson’s disease (PD), essential tremor (ET), and dystonia. Thalamic DBS has virtually replaced ablative lesions of the thalamus for the treatment of ET (Benabid et al., 1996). DBS of the subthalamic nucleus (STN) or globus pallidus internus (GPi) has largely replaced pallidotomy for the treatment of the cardinal motor features of Parkinson’s disease (tremor, rigidity, bradykinesia) (Obeso et al., 2001). GPi DBS has established itself as an effective therapy for dystonia (Vidailhet et al., 2005). In addition, multiple studies are examining the utility of DBS for epilepsy,

Conflict of Interest Statement: C.C.M. has authored intellectual property related to the content of this article and holds company shares in IntElect Medical Inc.

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have been addressing the science of extracellular stimulation of neurons for decades (Ranck, 1975; Tehovnik et al., 2006). And, the fundamental purpose of DBS is to modulate pathological neural activity with applied electric fields. However, most clinicians implementing DBS technology do not have a quantitative understanding of the neural response to manipulation of the various stimulation parameters. This problem is compounded by the typical lack of visual reference of the DBS electrode location relative to the underlying neuroanatomy while electrodes are implanted or stimulation parameter adjustments are performed. Fortunately, guidelines do exist for general stimulation parameter settings that are typically effective (Volkmann et al., 2006), but it is infeasible to clinically evaluate each of the thousands of individual stimulation parameter combinations that may be useful to the given patient. As a result, the therapeutic benefit achieved with DBS is strongly dependent on the surgical placement of the DBS electrode and the intuitive skill of the clinician performing the stimulation parameter selection. Fortunately, movement disorder symptoms like tremor respond quickly to the onset of stimulation, allowing the clinician to search the stimulation parameter space with feedback on therapeutic outcomes. However, application of DBS technology to disorders such as epilepsy, dystonia, depression, and obsessive– compulsive disorder are especially problematic because the beneficial effects of stimulation can take days to weeks to manifest. This makes stimulation parameter selection during a short clinical visit difficult, and this problem is compounded by the limited guidelines on optimal stimulation paradigms for these different disorders. Therefore, synergistic combination of clinical experience and scientific knowledge is needed to enable more efficacious application of DBS technology to patients. Recent advances suggest that computational modeling could be a powerful tool to augment that process (McIntyre et al., 2007).

Modeling neurostimulation The electric field generated by an implanted electrode is a three-dimensionally complex phenomenon that is distributed throughout the brain (McIntyre, Mori et al., 2004; Butson, Cooper et al., 2007). This field is applied to the complex three-dimensional geometry of the surrounding neural processes (i.e. axons and dendrites). The response of an individual neuron to the applied field is related to the second derivative of the extracellular potential distribution along each neural

process (McNeal, 1976; Rattay, 1986). In turn, each neuron (or neural process) surrounding the electrode will be subject to both depolarizing and hyperpolarizing effects from the stimulation (McIntyre and Grill, 1999; Rattay 1999). A neuron can be either activated or suppressed in response to extracellular stimulation in different ways and in different neural processes depending on its positioning with respect to the electrode and the stimulation parameters. In general, three classes of neurons can be affected by the stimulation: local cells, afferent inputs, and fibers of passage. Local cells represent neurons that have their cell body in close proximity to the electrode and an axon that may project locally and/or to a different brain region. Afferent inputs represent neurons that project to the region near the electrode and whose axon terminals make synaptic connections with local cells. Fibers of passage represent neurons where both the cell body and axon terminals are far from the electrode, but the axonal process of the neuron traces a path that comes in close proximity to the electrode. Experimental measurements indicate that local cells, afferent inputs, and fibers of passage have similar thresholds for activation (Ranck, 1975). And, local cells can be directly excited by the stimulus and/or have their excitability indirectly altered via activation of afferent inputs that make synaptic connections on their dendritic arbor (Gustafsson and Jankowska, 1976). Neural modeling allows for simultaneous study of the effects of stimulation on all the different types of neurons around the electrode. In addition, models provide a highly controlled environment to study the effects of stimulation on neural activity, something that is difficult to achieve experimentally. However, the strengths of modeling are tempered by the necessary simplifications made in any reasonable model. In turn, modeling should be coupled as closely as possible to experimental work allowing for a synergistic analysis of results. The modeling techniques presently used to predict the neural response to extracellular stimulation date back to McNeal (1976), who was the first to integrate an electric field model and multi-compartment cable model to predict action potential generation (Figure 16.1). This technique has become an important research tool for neurostimulation device development (Frijns et al., 1996; Holsheimer, 1998; Basser and Roth, 2000; Butson and McIntyre, 2006). In general, modeling extracellular stimulation of neurons in the brain relies on two fundamental components: (1) a model of the voltage distribution generated by the stimulating electrode(s), and (2) a model of the neuron(s) being stimulated. Voltage distribution models range from simple (i.e. theoretical point source electrode in an infinite homogeneous isotropic medium) to complex (i.e. finite element volume

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Modeling deep brain stimulation

Ve[n ]

Ve[n�1]

Gm[n ]

Vi[n�1]

Gi[n �1]

Ve[n �1]

Cm[n ]

Vi[n ]

Gi[n ]

Vi[n �1]

Figure 16.1  Multi-compartment cable model of extracellular stimulation. Electrical network representation of a neural process consists of conductances representing the transmembrane ion channels (Gm[n]), the membrane capacitance (Cm[n]), and the intracellular conductances connecting different compartments together (Gi[n]). The extracellular potential (Ve[n]) generated in the tissue medium by an electrode can be applied to the cable to predict the neural response to the stimulus (Adapted from McNeal (1976). Copyright (1976) IEEE)

conductor with explicit representation of electrode geometry, time dependence, and tissue inhomogeneity/anisotropy). Irrespective of the voltage distribution model selected, the simulated extracellular potentials (Ve[n]) at the location of individual compartments of neurons in the surrounding tissue medium can be predicted. The neural response to the stimulation can then be simulated with electrical circuits of conductances (Gm[n]) and capacitors (Cm[n]) in parallel (Hodgkin and Huxley, 1952). The individual compartments of a single neuron are then connected in series by resistors representing the intracellular resistance (Gi[n]) (Rall et al., 1992). Neuron models of this type are commonly referred to as multi-compartment cable models. When extracellular stimulation is applied to the neuron model the membrane current at compartment n is equal to the sum of the incoming axial currents and the sum of the capacitive and ionic currents through the membrane: Cm [n](dVm [n]/dt)  I i [n]  Gi [n  1](Vi [n  1]  Vi [n]  Ve [n  1]  Ve [n]  Gi [n](Vi [n  1]  Vi [n]  Ve [n  1]  Ve [n]) where the transmembrane voltage at each compartment (Vm[n]) is defined by difference between the intracellular (Vi[n]) and extracellular (Ve[n]) potentials (McNeal, 1976) (Figure 16.1).

Modeling deep brain stimulation Neurostimulation models explicitly dedicated to the study of DBS have recently reached a sufficient level of realism to allow for coupled analysis of model predictions with experimental and/or clinical measurements. Traditionally, neurostimulation models were

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used to develop qualitative hypotheses to address a generalized phenomenon. However, the development of new techniques and enhanced computational power has provided opportunities to quantitatively evaluate particular features of DBS in specific patients. DBS electrodes have finite dimensions and are placed within a complex medium. As a result, many simplifying assumptions typically used in analytical equation models of the voltage distribution can cause substantial errors. In turn, most investigators rely on finite element modeling (FEM) techniques to calculate the voltage distribution generated by DBS electrodes. The first DBS FEMs were created by Roy Testerman, at Medtronic Inc., and soon thereafter academic researchers began to investigate the electric fields generated by DBS (McIntyre and Thakor, 2002; Kuncel and Grill, 2004; McIntyre, Grill et al., 2004; McIntyre, Mori et al., 2004; Hemm et al., 2005; Wei and Grill, 2005; Astrom et al., 2006; Sotiropoulos and Steinmetz, 2007). However, these early efforts suffered from significant limitations by ignoring some or all of the following: (1) the actual stimulus waveform generated by DBS implanted pulse generators (Butson and McIntyre, 2005, 2007); (2) the capacitance of the electrode–tissue interface (Butson and McIntyre, 2005); (3) the impedance of the electrode–tissue interface (Butson et al., 2006); and (4) the 3D anisotropy and inhomogeneity of the tissue medium (McIntyre, Mori et al., 2004; Butson, Cooper et al., 2007; Sotiropoulos and Steinmetz, 2007). Over the last few years it has become apparent that each of these issues substantially impacts the magnitude and shape of the electric field generated by DBS. In turn, efforts to develop quantitative predictions on the effects of DBS require anatomically and electrically accurate electric field models. Characterizing the voltage distribution and/or electric field generated in the brain is only the first step in simulating DBS on a subject-specific basis. The fundamental purpose of DBS is to modulate neural activity in the brain; therefore, prediction techniques are needed to estimate the neural response to the applied electric field. Typically this is accomplished with a McNeal-type model described above. Miocinovic et al. (2006) used such an approach to investigate neural activation during therapeutic DBS of the subthala­ mic region in parkinsonian non-human primates (Miocinovic et al., 2006) (Figure 16.2). The general model system integrated three fundamental components: (1) anatomical model; (2) electric field model; and (3) neural activation model. The anatomical model was a histological reconstruction of the monkey DBS electrode implanted in the subthalamic region. The electric field model was an FEM of the monkey DBS electrode. And, the neural activation model coupled populations of

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16.  Computational Modeling of Deep Brain Stimulation (A)

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1V a b

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Figure 16.2  Modeling DBS in the parkinsonian monkey. (A) 3D reconstruction of the DBS electrode location in the neuroanatomy (STN – light gray volume; GPi – dark gray volume) and the DBS polarization of a 3D STN neuron model. (B) Lowercase letters indicate location in the STN neuron where the transmembrane voltage was recorded. a  soma, b  first node of Ranvier, c  30th node of Ranvier, d  50th node of Ranvier. The action potential initiated in the axon and propagated toward the cell body and axonal terminals in the globus pallidus. The traces in the top row represent the stimulus voltage waveform applied to the neuron. (C) Trains of DBS suppressed somatic firing, but enhanced axonal output (Adapted with permission from Miocinovic et al. (2006). American Physiological Society)

multi-compartment cable neuron models to the electric field model to predict action potential generation. The model system predicted that when stimulating STN projection neurons with DBS, action potential initiation always took place in the myelinated axon (Figure 16.2). This resulted in an interesting phenomenon where the soma and axon of the same neuron could exhibit dramatically different firing patterns. During stimulation, somatic firing was suppressed while the axon fired in a nearly one-to-one ratio with the stimulation frequency (Miocinovic et al., 2006) (Figure 16.2). Similar results were previously noted in a model of thalamic DBS (McIntyre, Grill et al., 2004), and this basic model prediction has been used to reconcile seemingly contradictory experimental results on DBS. For example, numerous experimental studies have shown inhibition of somatic firing in the stimulated nucleus (e.g. Meissner et al., 2005), but when recordings are made in efferent nuclei the neural activity changes have been consistent with activation of the stimulated nucleus (e.g. Hashimoto et al., 2003). Model systems have also been developed to analyze DBS in human patients (McIntyre, Mori et al., 2004; Hemm et al., 2005; Butson, Cooper et al., 2007; Sotiropoulos and Steinmetz, 2007; Maks et al., 2008). In general, patient-specific DBS models follow a similar

methodology described above by coupling: (1) anatomical model; (2) electric field model; and (3) neural activation model. Maks et al. (2008) created 10 patientspecific models of STN DBS, each using a series of five steps: (1) definition of the neurosurgical stereotactic coordinate system within the context of preoperative imaging data; (2) entry of intraoperative microelectrode recording locations from neurophysiologically defined thalamic, subthalamic, and substantia nigra neurons into the context of the imaging data; (3) fitting a 3D atlas to the neuroanatomy and neurophysiology of the patient; (4) positioning the DBS electrode in the documented stereotactic location, verified by postoperative imaging data; and (5) calculation of the volume of tissue activated (VTA) by therapeutic stimulation parameters using a diffusion tensor based finite element neurostimulation model (Butson, Cooper et al., 2007). These patient-specific models show that therapeutic benefit was achieved with direct stimulation of a wide range of anatomical structures in the subthalamic region. In turn, it is possible that multiple stimulation target areas exist within the subthalamic region and this hypothesis is supported by numerous anatomical studies on the location of therapeutic DBS electrode contacts (e.g. Yelnik et al., 2003; Herzog et al., 2004; Plaha et al., 2006).

IIA.  fundamentals of neuromodulation: mechanisms



Clinical application of DBS models

Clinical application of DBS models The consensus within the clinical and industrial neuromodulation communities is that DBS will continue to grow over the next decade, especially for the treatment of neuropsychiatric disorders. DBS represents an attractive therapy for a variety of reasons. DBS allows for bilateral procedures without resulting in a high incidence of side effects, the side effects associated with stimulation are reversible, and DBS allows for customization of the therapy to the individual patient needs over time via alteration of the stimulation parameters. Furthermore, DBS does not destroy tissue, allowing patients to potentially benefit from emerging restorative therapies. However, defining the optimal surgical placement for the DBS electrode and programming DBS devices for maximal clinical benefit can be a difficult and time-consuming process. In addition, current DBS electrode designs and stimulation pulsing paradigms were derived empirically and are probably not optimal. In turn, advances in scientific knowledge and technology are laying the groundwork for the re-engineering of DBS technology to better serve clinicians and patients. For example, computer models and software technology are being developed to augment the DBS surgical process. Stereotactic neurosurgery and neurophysiological microelectrode recording (MER) techniques used in DBS implantation procedures are typically performed without visualization tools that could improve data management. To address these limitations, Miocinovic et al. (2007) created a Windows-based software tool (Cicerone) to enable interactive 3D visualization of co-registered magnetic resonance images (MRI), computed tomography (CT) scans, 3D brain atlases, MER data, and DBS electrode(s) with the VTA as a function of the stimulation parameters (Figure 16.3). This software system, and other similar systems (Finnis et al., 2003; D’Haese et al., 2005), are examples of how computer models could be used in the future to augment the DBS surgical procedure. Preoperative planning can allow for definition of the stereotactic anatomical target and trajectory. Intraoperatively, stereotactic microdrive coordinates and MER data can be entered, enabling real-time interactive visualization of the electrode location in 3D relative to the surrounding neuroanatomy and neurophysiology. And, the neurosurgeon can use the combination of anatomical (MRI/CT/3D brain atlas), neurophysiological (MER), and electrical (DBS VTA) data to optimize the placement of the DBS electrode prior to permanent implantation (Miocinovic et al., 2007) (Figure 16.3).

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Once the DBS electrode has been implanted, the device must be programmed by a clinician to define stimulation parameter settings that provide therapeutic benefit. Clinical estimates suggest that 18–36 hours per patient are necessary to program and assess DBS patients with current techniques (Hunka et al., 2005). Much of this time is dedicated to balancing the stimulation with medication adjustments, and plasticity in the nervous system. However, several hours are commonly dedicated to an initial parameter search to identify the electrode contact that provides the best therapeutic benefit (Volkmann et al., 2006). In an attempt to decrease the time and skill needed for this process, Butson, Noecker et al. (2007) developed a postoperative stimulation parameter selection software tool (StimExplorer) to aid DBS programming. Starting from the Cicerone patient-specific model, StimExplorer uses VTA predictions and volume-based optimization algorithms to define a theoretically optimal stimulation parameter setting (Figure 16.3). The optimization algorithm relies on quantitative definition of specific regions of activated tissue associated with therapeutic benefit and side effects, and is therefore specific to the given anatomical nucleus where the electrode is implanted and the disease state of the patient. These theoretically optimal settings can represent the start point of clinical programming of the DBS device; thereby focusing the clinical customization of DBS to an anatomically and electrically logical parameter space (Butson, Noecker et al., 2007). Another area that may benefit from computational modeling is the design of the DBS electrode. The current clinical DBS electrode design (four cylindrical contacts in a linear array) was designed approximately 20 years ago without knowledge of several neurostimulation principles that have only recently been elucidated. In turn, a unique opportunity exists to design DBS electrodes that are customized to the anatomical and electrical constraints of the stimulation target (Butson and McIntyre, 2006; Gimsa et al., 2006). The underlying assumption of such an exercise is that by improving the engineering design of clinical DBS devices it will be possible to improve therapeutic outcome. A recent theoretical analysis of the impact of changes in the DBS electrode geometry on the VTA suggest that the VTA size and shape that can be manipulated with a great deal of flexibility by simple modifications to the cylindrical DBS electrode design (Butson and McIntyre, 2006). In turn, a realistic goal for the future is to develop theoretically optimal DBS electrode designs for specific anatomical targets that are based on scientific principles. In addition to sculpting the electrode contact to control the VTA, the concept of current steering, or the

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(B)

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Figure 16.3  Patient-specific models of DBS. DBS software tools can integrate multiple data sets to improve visualization. (A, B) Cicerone enables microelectrode recording data (yellow dots – thalamus; white dots – white matter; green dots – STN; red dots – SNr) and possible DBS electrode positions (blue shaft with pink electrode contacts) to be viewed in stereotactic space with the MRI and anatomical nuclei (yellow volume – thalamus; green volume – STN). (C,D) StimExplorer provides a target volume of stimulation (black volume) and allows for definition a theoretically optimal stimulation parameter setting that maximizes VTA coverage of the target and minimizes VTA spread out of the target (Adapted with kind permission from Miocinovic et al. (2007) and Butson, Noecker et al. (2007). Springer Science 1 Business Media)

use of multiple stimulation sources to direct ­ current flow through targeted regions of brain tissue, has great potential to expand our ability to control the size and shape of the VTA. Computational models of current steering have shown that balancing current flow through adjacent cathodes increased the VTA magnitude, relative to monopolar stimulation, and allowed the VTA to better fit the subthalamic nucleus (Butson and McIntyre, 2008). These results provide motivation for the integration of current steering technology into clinical DBS systems, thereby expanding opportunities to customize DBS to individual patients. Computer models of neurostimulation will continue to evolve and as they progress they will assist our understanding of the complex interactions between electric fields and the brain. Because many of

these interactions are especially difficult to characterize with traditional experimental techniques, models will play an increasingly important role in the scientific analysis of neurostimulation. Improved scientific understanding will allow for more efficacious application of neurostimulation technology to patients, and once again computer models and software will help reduce the clinical time and expertise necessary to optimally implement these medical devices. Therefore, as neurostimulation devices evolve to incorporate new features (e.g. more electrode contacts, novel electrode contact designs, alternative pulsing paradigms) to allow for better customization of the therapy to the patient they will undoubtedly need advanced computational models and software to effectively implement these advanced features.

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references

Acknowledgments This work was supported by grants from the Wallace H. Coulter Foundation, and National Institutes of Health (NS047388, NS050449, NS059736).

References Astrom, M., Johansson, J.D., Hariz, M.I., Eriksson, O. and Wardell, K. (2006) The effect of cystic cavities on deep brain stimulation in the basal ganglia: a simulation-based study. J. Neural Eng. 3: 132–8. Basser, P.J. and Roth, B.J. (2000) New currents in electrical stimulation of excitable tissues. Annu. Rev. Biomed. Eng. 2: 377–97. Benabid, A.L., Pollak, P., Gao, D., Hoffmann, D., Limousin, P., Gay, E. et al. (1996) Chronic electrical stimulation of the ventralis intermedius nucleus of the thalamus as a treatment of movement disorders. J. Neurosurg. 84: 203–14. Butson, C.R. and McIntyre, C.C. (2005) Tissue and electrode capacitance reduce neural activation volumes during deep brain stimulation. Clin. Neurophysiol. 116: 2490–500. Butson, C.R. and McIntyre, C.C. (2006) Role of electrode design on the volume of tissue activated during deep brain stimulation. J. Neural Eng. 3: 1–8. Butson, C.R. and McIntyre, C.C. (2007) Differential effects of implantable pulse generator waveforms during deep brain stimulation. Clin. Neurophysiol. 118: 1889–94. Butson, C.R. and McIntyre, C.C. (2008) Current steering to control the volume of tissue activated during deep brain stimulation. Brain Stimulation 1: 7–15. Butson, C.R., Cooper, S.E., Henderson, J.M. and McIntyre, C.C. (2007) Patient-specific analysis of the volume of tissue activated during deep brain stimulation. NeuroImage. 34: 661–70. Butson, C.R., Maks, C.B. and McIntyre, C.C. (2006) Sources and effects of electrode impedance during deep brain stimulation. Clin. Neurophysiol. 117: 447–54. Butson, C.R., Noecker, A.M., Maks, C.B. and McIntyre, C.C. (2007) StimExplorer: Deep brain stimulation parameter selection software system. Acta Neurochir. 97 (Suppl.): 569–74. D’Haese, P.F., Cetinkaya, E., Konrad, P.E., Kao, C. and Dawant, B.M. (2005) Computer-aided placement of deep brain stimulators: from planning to intraoperative guidance. IEEE Trans. Med. Imaging. 24: 1469–78. Finnis, K.W., Starreveld, Y.P., Parrent, A.G., Sadikot, A.F. and Peters, T.M. (2003) Three-dimensional database of subcortical electrophysiology for image-guided stereotactic functional neurosurgery. IEEE Trans. Med. Imaging. 22: 93–104. Frijns, J.H., de Snoo, S.L. and ten Kate, J.H. (1996) Spatial selectivity in a rotationally symmetric model of the electrically stimulated cochlea. Hear Res. 95: 33–48. Gimsa, U., Schreiber, U., Habel, B., Flehr, J., van Rienen, U. and Gimsa, J. (2006) Matching geometry and stimulation parameters of electrodes for deep brain stimulation experiments – numerical considerations. J. Neurosci. Methods 150: 212–27. Gustafsson, B. and Jankowska, E. (1976) Direct and indirect activation of nerve cells by electrical pulses applied extracellularly. J. Physiol. 258: 33–61. Hashimoto, T., Elder, C.M., Okun, M.S., Patrick, S.K. and Vitek, J.L. (2003) Stimulation of the subthalamic nucleus changes the firing pattern of pallidal neurons. J. Neurosci. 23: 1916–23. Hemm, S., Mennessier, G., Vayssiere, N., Cif, L., El Fertit, H. and Coubes, P. (2005) Deep brain stimulation in movement disorders: stereotactic coregistration of two-dimensional electrical

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field modeling and magnetic resonance imaging. J. Neurosurg. 103: 949–55. Herzog, J., Fietzek, U., Hamel, W., Morsnowski, A., Steigerwald, F., Schrader, B. et al. (2004) Most effective stimulation site in subthalamic deep brain stimulation for Parkinson’s disease. Mov. Disord. 19: 1050–54. Hodgkin, A.L. and Huxley, A.F. (1952) A quantitative description of membrane current and its application to conduction and excitation in nerve. J. Physiol. 177: 500–44. Holsheimer, J. (1998) Computer modelling of spinal cord stimulation and its contribution to therapeutic efficacy. Spinal Cord 36: 531–40. Hunka, K., Suchowersky, O., Wood, S., Derwent, L. and Kiss, Z.H. (2005) Nursing time to program and assess deep brain stimulators in movement disorder patients. J. Neurosci. Nurs. 37: 204–10. Kuncel, A.M. and Grill, W.M. (2004) Selection of stimulus parameters for deep brain stimulation. Clin. Neurophysiol 115: 2431–41. Maks, C.B., Butson, C.R., Walter, B.L., Vitek, J.L. and McIntyre, C.C. (2008) Deep brain stimulation activation volumes and their association with neurophysiological mapping and therapeutic outcomes. J. Neurol. Neurosurg. Psychiatry (in press). McIntyre, C.C. and Grill, W.M. (1999) Excitation of central nervous system neurons by non-uniform electric fields. Biophys. J. 76: 878–88. McIntyre, C.C. and Thakor, N.V. (2002) Uncovering the mechanisms of deep brain stimulation for Parkinson’s disease through functional imaging, neural recording, and neural modeling. Crit. Rev. Biomed. Eng. 30: 249–81. McIntyre, C.C., Grill, W.M., Sherman, D.L. and Thakor, N.V. (2004) Cellular effects of deep brain stimulation: model-based analysis of activation and inhibition. J. Neurophysiol. 91: 1457–69. McIntyre, C.C., Miocinovic, S. and Butson, C.R. (2007) Computational analysis of deep brain stimulation. Expert Rev. Med. Devices 4: 615–22. McIntyre, C.C., Mori, S., Sherman, D.L., Thakor, N.V. and Vitek, J.L. (2004) Electric field and stimulating influence generated by deep brain stimulation of the subthalamic nucleus. Clin. Neurophysiol. 115: 589–95. McNeal, D.R. (1976) Analysis of a model for excitation of myelinated nerve. IEEE Trans. Biomed. Eng. 23: 329–37. Meissner, W., Leblois, A., Hansel, D., Bioulac, B., Gross, C.E., Benazzouz, A. et al. (2005) Subthalamic high frequency stimulation resets subthalamic firing and reduces abnormal oscillations. Brain 128: 2372–82. Miocinovic, S., Maks, C.B., Noecker, A.M., Butson, C.R. and McIntyre, C.C. (2007) Cicerone: Deep brain stimulation neurosurgical navigation software system. Acta Neurochir. 97 (Suppl.): 561–7. Miocinovic, S., Parent, M., Butson, C.R., Hahn, P.J., Russo, G.S., Vitek, J.L. et al. (2006) Computational analysis of subthalamic nucleus and lenticular fasciculus activation during therapeutic deep brain stimulation. J. Neurophysiol. 96: 1569–80. Moro, E., Poon, Y.Y., Lozano, A.M., Saint-Cyr, J.A. and Lang, A.E. (2006) Subthalamic nucleus stimulation: improvements in outcome with reprogramming. Arch. Neurol. 63: 1266–72. Obeso, J.A., Olanow, C.W., Rodriguez-Oroz, M.C., Krack, P., Kumar, R. and Lang, A.E. (2001) Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson’s disease. N. Engl. J. Med. 345: 956–63. Perlmutter, J.S. and Mink, J.W. (2006) Deep brain stimulation. Annu. Rev. Neurosci. 29: 229–57. Plaha, P., Ben-Shlomo, Y., Patel, N.K and Gill, S.S. (2006) Stimulation of the caudal zona incerta is superior to stimulation of the ­subthalamic nucleus in improving contralateral parkinsonism. Brain 129: 1732–47.

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Rall, W., Burke, R.E., Holmes, W.R., Jack, J.J., Redman, S.J. and Segev, I. (1992) Matching dendritic neuron models to experimental data. Physiol. Rev. 72 (4 Suppl): S159–S186. Ranck, J.B. (1975) Which elements are excited in electrical stimulation of mammalian central nervous system: a review. Brain Res. 98: 417–40. Rattay, F. (1986) Analysis of models for external stimulation of axons. IEEE Trans. Biomed. Eng. 33: 974–7. Rattay, F. (1999) The basic mechanism for the electrical stimulation of the nervous system. Neuroscience 89: 335–46. Sotiropoulos, S.N. and Steinmetz, P.N. (2007) Assessing the direct effects of deep brain stimulation using embedded axon models. J. Neural Eng. 4: 107–19. Tehovnik, E.J., Tolias, A.S., Sultan, F., Slocum, W.M. and Logothetis, N.K. (2006) Direct and indirect activation of cortical neurons by electrical microstimulation. J. Neurophysiol. 96: 512–21.

Vidailhet, M., Vercueil, L., Houeto, J.L., Krystkowiak, P., Benabid, A.L., Cornu, P. et al. (2005) Bilateral deep-brain stimulation of the globus pallidus in primary generalized dystonia. N. Engl. J. Med. 352: 459–67. Volkmann, J., Moro, E. and Pahwa, R. (2006) Basic algorithms for the programming of deep brain stimulation in Parkinson’s disease. Mov. Disord. 21: S284–S289. Walter, B.L. and Vitek, J.L. (2004) Surgical treatment for Parkinson’s disease. Lancet Neurol. 3: 719–28. Wei, X.F. and Grill, W.M. (2005) Current density distributions, field distributions and impedance analysis of segmented deep brain stimulation electrodes. J. Neural Eng. 2: 139–47. Yelnik, J., Damier, P., Demeret, S., Gervais, D., Bardinet, E., Bejjani, B.P. et al. (2003) Localization of stimulating electrodes in patients with Parkinson disease by using a three-dimensional atlas-magnetic resonance imaging coregistration method. J. Neurosurg. 99: 89–99.

IIA.  fundamentals of neuromodulation: mechanisms

S E C T I O N   III

Biomedical Engineering Considerations Introduction Joseph J. Pancrazio and P. Hunter Peckham

Technology is at the interface of the capability to deliver neuromodulatory interventions in neural disorders. Engineering of these interventions is critical to the preservation of the neural structures and to the proper actions of the technology on the neural tissue. In this section, the set of chapters offers an insight into the nature of the fundamental engineering considerations of the electrode interfaces for delivery of electrical current and for recording neural activity. These interfaces may be in the peripheral or the central nervous system, and each provides a set of engineering challenges to maintain an operational interface for extended periods of time, but that can be changed if necessary because of failure or demand. The first two chapters in this section come from authors at the Department of Biomedical Engineering

Neuromodulation

at Case Western Reserve University, Cleveland, Ohio. They are “Electrodes for the Neural Interface” by Dustin J. Tyler, PhD and Katharine H. Polasek, PhD, and “Implantable Neural Stimulators” by P. Hunter Peckham, PhD and D. Michael Ackermann, Jr. They are followed by a chapter on “Designing a Neural Interface System to Restore Mobility” by John P. Donoghue, MD and Leigh Hochberg, PhD, MD, of the Brain Science Program at Brown University, Providence, RI. The section concludes with a discussion of “MRI Safety and Neuromodulation Systems” by Frank G. Shellock, PhD, of the Institute for Magnetic Resonance Safety, Education, and Research, Los Angeles.

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© 2008, 2009 Elsevier Ltd.

C H A P T E R

17

Electrodes for the Neural Interface Dustin J. Tyler and Katharine H. Polasek

o u tline Introduction

182

Neural Science Fundamentals Anatomic Organization Major Divisions of the Nervous System Size Structure and Organization – PNS Somatotopic Organization Organization of the Autonomic   Nervous System Organization of the CNS Organization of the Spinal Cord Summary Vascular Anatomy PNS Vasculature CNS Vasculature Tissue Electrical Impedance Tissue Mechanical Properties Surrounding Space and Tissue Neural Behavior in Response to Applied   Electric Fields Electric Fields Produced by Neural Behavior

182 182 182 184 184 185

Design Principles for Neural Interface Electrode Location Selection Proximity to the Neurons Risk–Benefit Ratio Material and Processing Technology Complexity of Function Required   from the Electrode

194 194 194 195 195

Neuromodulation

Electrical Fields Stimulation Blocking Recording Tissue Response Other Design Considerations Implant Procedure Removability

185 187 188 189 189 189 190 191 192 193 193 194

196 196 197 197 198 199 199 199

Neural Interface Electrode Examples Surface Electrodes Organ-Based Electrodes Muscle Cochlear Retina Peripheral Nervous System Electrodes Extraneural Interfascicular Intrafascicular Regeneration General Central Nervous System Electrodes Superficial and Distal CNS Interfaces Deeper CNS Structures Deep Brain Stimulation (DBS)

199 200 201 201 201 202 202 202 204 205 206 206 206 206 207 208

Conclusion

209

References

209

195

181

© 2008, 2009 Elsevier Ltd.

182

17.  electrodes for the neural interface

Electrodes: 1: a conductor used to establish electrical contact with a nonmetallic part of a circuit Neural: 1: of, relating to, or affecting a nerve or the nervous system Interface: 2a: the place at which independent and often unrelated systems meet and act on or communicate with each other; 2b: the means by which interaction or communication is achieved at an interface Merriam-Webster On-Line Dictionary (2008)

Introduction

Neural science fundamentals

The neural interface can be unidirectional or bidi­ rectional with information from an engineered system transferred to the neural system and/or informa­ tion from the neural system transferred to an engi­ neered system. Historically, transfer of information to the neural system has been called “stimulation” and transfer of information from the neural system has been called “recording.” These terms, however, are limiting. It is more correct, especially in the field of neuro­ modulation, to consider electrical input to the neu­ ral systems as manipulation of membrane potential. Information transferred to the neural system includes traditional neuronal excitation plus important modu­ lation techniques of inhibition, membrane hyper­ polarization, blocked action potential propagation, and modulation of information content. All of these behaviors are controlled by the application of electri­ cal energy to the system. The modes are distinguished based on how the electrical energy is applied, as dis­ cussed in other chapters. Similarly, it is more correct to consider the definition of the transfer of information from the neural system as sensing the flow of ions and transmitters caused by activity of the neural system. Electrically, the interface senses the potential fields resulting from the distribu­ tion of charged molecules and ions in the tissue. The more general definition would also include other trans­ duction methods of converting ion motion to electrical signals. In all cases, the interface is an integral element in the process of information transfer and can set the capa­ bilities of such a transfer. There are many examples of electrodes for the neural interface that have been developed since the electrical interface to the nervous system was first described by Galvani in 1791. As well, there have been several reviews of various interface technologies (e.g. Rutten, 2002; Navarro et al., 2005). The purpose of this present chapter, however, is to provide the reader with a broader perspective of basic design principles in the design of neural interfaces.

Rational electrode design requires knowledge of the biologic environment within which the electrode will interface. The size, morphology, tissues, vasculature, and organization dictate many aspects of the neural interface design. Some of the most important neural science funda­ mentals to consider are shown in Table 17.1.

Anatomic Organization Major Divisions of the Nervous System The anatomy of the nervous system is discussed in greater detail in other chapters. Here, the impor­ tant anatomical features having significant impact on the design of the interface and the considerations imposed by the anatomy are briefly highlighted. It is important to remember that neurons are only one of multiple cell types in the nervous system. Equally prevalent are important supporting glial cells, con­ sisting of microglia and three general types of macro­ glia, including the oligodendrocytes, astrocytes, and Schwann cells. The microglia are the macrophages of the nervous system. The macroglia are the supporting cells that keep the neurons healthy and functioning. The glia are important when considering the response of the nervous system to a neural electrode. These cells are responsible for most of cytokine and chemo­ kine signaling in response to the foreign material of the electrode and the injury caused by its implant and chronic presence. Understanding and controlling their response to the electrode can significantly alter the quality and chronic stability of the neural interface. The nervous system is comprised of several anatomi­ cal divisions (Figure 17.1). The first distinction is between the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS consists of the spinal cord, medulla oblongata, pons, cerebellum, midbrain, diencephalon, and cerebral hemispheres (or telen­ cephalon). The diencephalon includes the thalamus and the hypothalmus. The cerebral hemispheres include the

III.  BIOMEDICAL ENGINEERING CONSIDERATIONS



183

Neural science fundamentals

Table 17.1  How neuroscience principles influence design decisions Neural science fundamentals (Section I)

Related design principles (Section II)

Anatomic organization Vascular anatomy

l

Placement vs. function expected (risk–benefit ratio) l System, i.e. PNS vs. CNS l Compromise of protective tissues Blood–brain barrier Blood–nerve barrier l Electrode size l Lead routing l Applied pressure and vascular interference l Surgical access techniques l Insertion technique and location

Tissue mechanical properties

l

l l

Electrode material selection Electrode anchorage and stabilization l Serviceability of electrode

l

l

l

Tissue electrical impedance Neural behavior in response to applied electrical fields

l

l

l

Electrical fields produced by neural behavior

l

l

Contact placement Number of contacts l Selectivity Contact impedance Contact placement l Minimization of common-mode signal l

Nervous system

Cerebral cortex Basal ganglia

Cerebral hemispheres

Amygdaloid Thalamus Hypothalamus

Peripheral nervous system Autonomic

Rostral

Hippocampus

Central nervous system

Sympathetic Parasympathetic Enteric

Somatic

Diencephalon Midbrain Cerebellum Pons Caudal

Medulla oblongata Spinal cord

Figure 17.1  Organization of the nervous system. The nervous system is categorized by two major divisions, the central and peripheral nervous system. The central nervous system is grossly divided into the six main parts, with a general rostral to caudal orientation: the cerebral hemispheres, diencephalon, midbrain, cerebellum, pons, medulla oblongata, and spinal cord. The peripheral nervous system consists of the autonomic and the somatic components

amygdaloid, hippocampus, basal ganglia, and cerebral cortex. The PNS consists of the autonomic and somatic systems. The autonomic system consists of the sympa­ thetic, parasympathetic and enteric nervous systems. Both divisions of the peripheral nervous system contain both motor (efferent) and sensory (afferent) components. The somatic components are related to voluntary motor control or sensory awareness. The autonomic components

are related to the mostly subconscious, involuntarily controlled organs and physiology. The components of the CNS perform most of the integrative and process­ ing functions of the nervous system. Generally, higher order processing, like behavior and abstraction, occur at the more rostral divisions, e.g. the cerebral hemispheres, while more rudimentary processing, such as reflexes, occurs more caudally, e.g. in the spinal cord.

III.  BIOMEDICAL ENGINEERING CONSIDERATIONS

184

17.  electrodes for the neural interface

Neural interfaces have been developed and studied extensively in the somatic PNS, cerebral cortex, basal ganglia, diencephalon, and spinal cord. Increasing interest is spreading to interfaces for all of the major divisions of the nervous system. Each of the systems has anatomic differences that guide development of neural interfaces. To rationally choose where the inter­ face will be placed, the The motor components of the somatic and autonomic PNS are the last link in the out­ put chain that terminates on an end organ to produce an action or function. The sensory components of the somatic and most of the autonomic PNS are the first input to the processing circuitry of the CNS. Neural interfaces with the PNS interact nearly exclusively with an axon to modulate or sense its activity. The somatic peripheral nervous system has been the most studied in relation to neural interfaces with several interfaces resulting in clinical therapies, such as auditory prosthe­ ses, cardiac pacemakers, and vagal nerve stimulators. Interfaces with CNS are more complicated, however, in that the interface includes cell bodies, dendrites, and cellular circuits in addition to axons. The effects of applied electric fields and the signals recorded by electrodes are significantly more complicated, affect­ ing many more cells and different cell structures. Modulation of CNS structures can directly alter circuit behavior, higher level function, and transfer of infor­ mation between various centers in the CNS. Placement of the neural interface in the CNS is more critical than in the PNS. Size There are several hierarchical levels to the size scales in the nervous system. When considering the electrode design, it is important to know the size of the target tissue for the electrode. The smallest scale typically considered in present-day electrodes is that of the axon and cell body. The size of a cell body is in the range of 4 to 50 m. An axon, if considered as a long uniform, cylindrical tube, has a diameter ranging from about 0.2 m for unmyelinated fibers to 20 m for myelinated fibers. The length of an axon, however, is highly variable, depending on its location. In the CNS, axon length is only a few tens of microns to nearly a meter. In the PNS, axons are generally long, ranging from several centimeters to nearly a meter. The axon of a motor neuron, for example, extends from the ventral horn of the spinal cord to the muscle. Sensory axons extend from the point of sensation, such as the skin, to the dorsal root ganglion (DRG) and into the dorsal horn of the spinal cord. These axons can be up to a meter in length. Cranial nerves extend from their nucleus in the CNS to the end organ. These can range

from several centimeters, such as the optic nerve (IInd CN), to nearly a meter for components of the vagus nerve (Xth CN). Dendrites are microns in diameter and general only microns in length. Electrodes that target individual axons need to be about the size of an axon or tens of microns in cross-sectional dimensions. There are many important collections of cell bodies throughout the nervous system. These are called either nuclei or ganglia in the CNS and are called ganglia in the PNS. They are typically ellipsoidal or capsular in shape, are tens of microns to a millimeter in cross-section and can extend several millimeters. In the spinal cord, for example, the nuclei exist in the gray matter of the cord and will extend over several vertebral segments. This provides for multi-segmental reflex and coordination. Electrodes to target nuclei can be larger than those that target individual axons, but should be smaller than the target nucleus. In the PNS, axons travel in bundles, called periph­ eral nerves. Peripheral nerves are from centimeters up to a meter in length. The cross-sectional dimension of peripheral nerves is from about 0.2 to 20 mm. Electrodes that remain external to the peripheral nerves can be larger than those that interact directly with the axons or cells, but at the expense of selectivity potential. Structure and Organization – PNS In the somatic peripheral nervous system, motor neu­ ron cell bodies are located in the ventral horn of the spi­ nal cord. Sensory neuron cell bodies are located in the dorsal root ganglion (DRG), which is inside the vertebral column, immediately adjacent to the spinal cord. The dendrites of the motor somatic PNS are located in the gray matter of the spinal cord, typically in the ventral horn regions. The axons in the peripheral nervous system are organized into bundles, called fascicles, within long cables, called peripheral nerves (Figure 17.2). The peri­ pheral nerve is composed of three basic tissues: the epineurium, perineurium, and endoneurium. The fasci­ cles are enclosed by the perineurium, which consists of multiple layers of cells connected by zona occludens or tight junctions (Peters et al., 1991). Between each layer of cells, there is a sheet of collagen fibrils (Ushiki and Ide, 1990). The perineurium is a strong membrane, providing mechanical as well as chemical protection to the axons. The space within the fascicles is the endoneurium and it contains the axons. There is very little extra­ cellular space as the axons are well packed into the endoneurium. Schwann cells within the endoneurium wrap the myelinated axons and enclose the unmyeli­ nated fibers. The Schwann cells are important to main­ taining the axon health and repair following injury.

III.  BIOMEDICAL ENGINEERING CONSIDERATIONS



Neural science fundamentals

185

axons, then the electrode must be only a few microns in size. Electrodes that interact with fascicles will be on the order of 1 millimeter and electrodes to interface with entire peripheral nerve will be several millimeters.

P end epi

Somatotopic Organization (A)

Schw (B)

ax

(C)

my

cf

nR

Figure 17.2  Peripheral nerve structure. The peripheral nerve is composed of three basic tissue “layers” consisting of the epineu­ rium (epi), perineurium (p), and endoneurium (end). The axons (ax) are grouped into bundles, call fascicles, by the perineurium and reside within the endoneurium. The most important supporting cell in the endoneurium is the Schwann cell (Schw) that either wraps a single axon to produce a myelinated axon or will enclose several smaller unmyelinated axons (Reproduced with permission from Goran Lundborg (2005) Nerve Injury and Repair, Edinburgh: Churchill Livingstone, Copyright (2005) Elsevier)

The endoneurium also includes fibroblasts, perineu­ rial fibroblasts, and resident macrophages (Chandross, 1998). Between the axons there is a loose connective tissue of mesh-like and longitudinal collagen fibrils (Ushiki and Ide, 1990). The fascicles are embedded within the epineurium, a mesh of adipose and thick collagen fibrils, to form the common nerve trunk. The collagen fibrils are flat, tape-like in shape with a 10–20 m width (Ushiki and Ide, 1990). The collagen fibrils have a wavy course that allows for stretching of the peripheral nerve during nor­ mal motion. The ulnar nerve, for example, will stretch by up to 29% during elbow flexion (Rempel et al., 1999; Topp and Boyd, 2006). Fascicle diameters range from about 100 m to about 1 mm. There is a positive internal pressure of about 1 to 5 mmHg (Myers et al., 1978) in the fascicle relative to the surrounding tissue and fascicles generally have a circular cross-section. Also, as the size of the nerve increases, the fascicles tend to increase only modestly in size, but are limited to about 1 mm in diam­ eter. In larger animals, such as humans, the number of fascicles compared to smaller animals within a nerve increases, not the size of the fascicles. The sizes of the nerves and structures are important as they place limits on the size of the electrode that is both required and allowed. To interact with individual

The pathway and consistency of grouping of axons over the entire length of the peripheral nerve is impor­ tant (Figure 17.3). It is known that the number of fasci­ cles changes significantly over the length of the nerve with fascicles combining and separating all along the length (Sunderland and Ray, 1948; Sunderland, 1953, 1978). As well, several nerves will join and divide, form­ ing several plexiform structures along the length of the nerve. Just proximal to a motor nerve branching from a main trunk, there is an identifiable fascicle or fascicles that contain only fibers to the specific muscle. There is evidence (Stewart, 2003) that as the axons course proxi­ mally through the plexiform structures of the nerve, however, axons tend to maintain a somatotopic organi­ zation (Brushart, 1991). Sensory information from a given region of the fingers will be collocated within the proximal nerves of the brachial plexus (Ekedahl et al., 1997; Wu et al., 1998 1999). Similarly, motor fibers to the same muscle have been shown to be collocated in the proximal nerve sections (Prodanov et al., 2007). Organization of the Autonomic Nervous System The autonomic nervous system (ANS) innervates and controls the visceral organs. The ANS is divided into the sympathetic, parasympathetic, and enteric systems. Unlike in the somatic PNS, where axons travel directly between the spinal cord and target organ, the ANS has ganglia in the periphery where pre- and post-ganglionic fibers connect. The neuron between the spinal cord and the ganglia is the pre-ganglionic cell and the one between the ganglion and the target tissue is the postganglionic cell, irrespective of the direction of informa­ tion flow. The axons of the ANS and somatic PNS often travel in common nerve trunks. Another important difference is that efferent axons of the ANS innervate smooth muscle and tend to spread over the entire target organ in a mesh-like network, while efferent fibers from the somatic PNS innervate striated muscle at a few welldefined motor points. In the somatic PNS it is possible to activate large portions of a skeletal muscle with a single electrode at the motor point on the muscle. Since no single motor point exists for the ANS organs, it is dif­ ficult to activate the entire organ with a single electrode at the organ. To be effective and ANS electrode would need to be further proximal.

III.  BIOMEDICAL ENGINEERING CONSIDERATIONS

186

17.  electrodes for the neural interface I

II A

1 2 3 B

1 2 3 (A)

(B)

Figure 17.3  Somatotopic organization in peripheral nerves. (I) Sunderland described the gross anatomical form of the periph­ eral nerve fascicles, showing that rather than a parallel (I.A) organization, they had a plexiform organization (I.B) that merge and diverge significantly along their course. (II) Investigations into the internal organization of the axons do not suggest that through the plexiform nature of the fascicles the axons are jumbled (II.A), but rather that within the fascicles the axons maintain a somatotopic (II.B) organization (Reproduced with permission from Stewart (2003). John Wiley & Sons Ltd)

Spinal Cord Spinal Nerve

Pia mater Dura mater

Ventral rootlets

Dorsal primary ramus

Dorsal root ganglion Spinal nerve 2 1 6 3 Gr

ay

ram

Sympathetic ganglion

Cell of dogiel

2 6 7 Posterior nerve root Sympathetic trunk Anterior nerve root 13 45

Whit com r mue nicaamus ns

us

comm

Ventral primary ramus

Arachnoid mater Interal vertebral venous plexus Extradural (epidural) fat

Posterior Intercostal artery Spinal nerve Intervertebral foramen

Hemiazygous vein Anterior longitudinal ligament

Aorta

unica

ns

7 4

Sympathetic ganglion

Rami communicantes Transverse process

Thoracic duct

Azygous vein

Vein Intercostal Artery Nerve

Sympathetic trunk

Figure 17.4  Sympathetic chain. The sympathetic chain sits external to and along the spinal column. The axons communicate to the sym­ pathetic ganglia via the gray and white rami communicantes, which arise from the spinal nerve as it exits the vertebral foramen

The sympathetic nervous system arises from the T1 to L3 spinal nerves. It is characterized by a chain of gan­ glia, called the sympathetic chain, that is external, bilat­ eral, and immediately adjacent to the vertebral bodies (Figure 17.4). Fibers from the dorsal and ventral roots

communicate to the sympathetic chain via the gray and white ramus communicans, which are located just distal to the division of the spinal nerve into the ventral and dorsal rami. Fibers extend along the sympathetic trunk that connects the ganglia of the sympathetic chain.

III.  BIOMEDICAL ENGINEERING CONSIDERATIONS



187

Neural science fundamentals

Arachnoid trabeculae

Layers I Molecular

Cortex

Pia mater

II External granular III External pyramidal IV Internal granular

OBB

Granule cell Apical

VI Internal pyramidal

IBB

Basal

Dendrite

Pyramidal cell Axon

VI Multiform

Outer band of baillarger Inner band of baillarger

Figure 17.5  Cortical layers. The cortex (A) is only about 4–6 mm deep and is composed of six distinct layers (B). There are two particular fea­ tures of cortical organization related to the design of electrodes. First, despite the multiplicity of high level functions produced in the cortex, there is a common organization to the cell bodies, the axons, and their interconnection. Second, the system is arranged in a generally columnar fashion (Part (B) from Maria A. Patestas and Leslie P. Gartner (2006) Textbook of Neuroanatomy, Malden: Blackwell Science. Wiley–Blackwell. Reproduced by permission)

The post-ganglionic fibers form multiple plexi between the ganglia and innervations of the target organ. An electrode can possibly interact with the sympathetic system independently of the somatic system through the sympathetic chain and would use similar design principles as for peripheral nerves. The parasympathetic nervous system arises in cranial nerves III, VII, IX, and X, and the S2, S3, and S4 spinal nerves. Cranial nerve X, the vagus nerve, carries nearly 70% of the parasympathetic fibers. The ganglia of the parasympathetic nervous system are located directly at the target organ. The pre-ganglionic fibers travel in welldefined and accessible nerves to the target organ and tend to have few plexi during their course compared to the sympathetic nervous system. The post-ganglionic fibers form a diffuse mesh within the organ. Organization of the CNS The CNS is comprised of six basic divisions (see Figure 17.1). Starting most caudal and progressing ros­ trally, they include the spinal cord, medulla oblongata, pons, midbrain, diencephalon, and cerebral hemispheres.

The divisions, in the order presented, correspond to a progression of higher levels of processing. The dien­ cephalon consists of the thalamus and hypothalamus, which are essentially central relay stations for incom­ ing sensory information to the CNS. The cerebral hemi­ spheres are comprised of the amygdaloid, hippocampus, basal ganglia, and cerebral cortex. For discussion of electrode design, there are a few common anatomical features throughout the CNS to consider. First, the CNS is surrounded by three protec­ tive tissue layers that comprise the protective meninges. These are the outer, mechanically tough dura mater, the vessel-rich arachnoid, and the thin pia mater immedi­ ately adjacent to the neural tissue. Between the arach­ noid and pia mater is a subarachnoid space. Once within these tissue layers, the structures of the CNS are divided by different arrangements of axons and cell bodies, but not separated by significant tissue structures. The cerebral cortex is the outermost 2–4 mm of the cerebral hemispheres. It consists of six distinct layers, numbered from one at the pial surface down to six (Figure 17.5). Generally, the axons and connections are arranged in columnar fashion. Layer 1 does not contain

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17.  electrodes for the neural interface

many neuron bodies, but mostly axons that transverse laterally to synapse on apical dendrites of deeper cells in surrounding cortical regions and glial cells. Layers 2 and 3 contain pyramidal cells providing the output to other cortical regions. Layer 4 has many nonpyramidal cells and receives most of the input from the thalamus. Layer 5 has mostly very large pyramidal cells with out­ put projecting to the basal ganglia, brain stem, and spi­ nal cord. Finally, layer 6 contains pyramidal cells, mostly projecting back to the thalamus. The tissue below layer 6 is largely composed of white matter and axons commu­ nicating between the cortex and other neural structures. Below the cortex, there is a large “highway” of axons traveling various nuclei and tracts, which are the other significant organizational elements of the CNS. A nucleus is a collection of cell bodies where informa­ tion is processed. Fiber tracts are axonal bundles that carry information to and from the nuclei within the CNS and the spinal cord to connect to the PNS. The reader is encouraged to review other sources for infor­ mation about specific nuclei and tracts. The important aspect is that the nuclei and tracts exist at many differ­ ent depths and locations throughout the CNS, requir­ ing longer electrodes that must often penetrate through neural tissue to reach a nucleus. The boundaries of the different anatomical regions are often not well defined Low lumbar

and tracts will run in close proximity to the nuclei. Stimulation and recording from specific nuclei or tracts requires careful electrode design and placement. Nuclei are generally in the range of a few millimeters in size and generally have an ellipsoidal shape. The fiber tracts can be considered cables that are tens to hundreds of microns in diameter and milli­ meters long when communicating between nuclei in the brain. The tracts usually have non-linear paths through the brain, traveling in and around the differ­ ent nuclei. The descending tracts, such as the cortico­ spinal tract, are much longer and can be up to a meter in length. These tracts are usually fairly linear, resem­ bling a peripheral nerve buried in the CNS, and have generally known locations within the CNS. Organization of the Spinal Cord The spinal cord travels down the spine within the canal in the vertebra. The vertebra creates a bony case that surrounds the spinal cord and limits the space available for electrodes. The spinal column is divided into cervical, thoracic, lumbar, and sacral regions. The spinal cord is composed of a butterfly-shaped central region of gray matter surrounded by white matter (Figure 17.6). The gray matter contains cell bodies and

Thoracic

3a

I II III IV V VI VII VIII

S

L

3b

Th C 4a

S L 1a Th

X

IX

C 2b

2a

C Th LS 5a 4b

2b (A)

(C) 2d

Marginal zone Substantia gelatinosa Nucleus proprius Clarke's nucleus Intermediolateral nucleus

Motor nuclei

(B)

1b 2c

5b

6

Motor and decending (efferent) pathways (left, red)

Sensory and ascending (afferent) pathways (right, blue)

1. Pyramidal tracts 1a. Lateral corticospinal tract 1b. Anterior corticospinal tract 2. Extrapyramidal tracts 2a. Rubrospinal tract 2b. Reticulospinal tract 2c. Vestibulospinal tract 2d. Olivospinal tract

3. Dorsal column medial lemniscus system 3a. Gracile fasciculus 3b. Cuneate fasciculus 4. Spinocerebellar tracts 4a. Posterior spinocerebellar tract 4b. Anterior spinocerebellar tract 5. Anterolateral system 5a. Lateral spinothalamic tract 5b. Anterior spinothalamic tract

Somatotopy Abbreviations: S: Sacral L: Lumbar Th: Thoracic C: Cervical

6. Spino-olivary fibers

Figure 17.6  Spinal cord organization. The spinal cord is composed of a butterfly-shaped gray matter surrounded by white matter. The gray matter contains the nuclei where descending efferent commands and incoming afferent information synapse on lower motor and autonomic neurons and ascending neurons. The descending and ascending information travels in tracts in the white matter. The gray matter is characterized by (A) ten somatically organized laminae and (B) several distinct nuclei. (C) The tracts in the white matter have a somatotopic organization (Parts (A) and (B) reproduced with permission from Eric R. Kandel, James H. Schwartz and Thomas M. Jessell (eds) (2000) Principles of Neural Science, New York: McGraw–Hill, Health Professions Division; part (C) http://en.wikipedia.org/wiki/File:Medulla_spinalis_-_tracts_-_ English.svg (accessed August 2008)

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the white matter contains myelinated axons. The axons of the white matter carry information to and from the brain and between the spinal levels. The white matter is divided into the dorsal column, lateral column, and ventral column and a ventral commissure. Generally, somatic sensory information travels in the dorsal col­ umn, motor, sensory, and autonomic information in the lateral column, and pain, thermal, and axial muscle control information travels in the ventral column. Information is transferred between the two sides of the spinal cord across the ventral commissure. The gray matter is divided into ten layers or lamina, starting with lamina I on the dorsal aspect and increas­ ing ventrally through lamina IX on the ventral aspect. Lamina X is in the center, around the central canal. The laminae contain collections of cell bodies that form nuclei for processing and integration of descending pathways and input information. The dorsal laminae generally receive sensory input from peripheral sen­ sors and contain the connection between peripheral sensors and ascending/descending tracts and/or local reflexive circuits. The ventral laminae are generally motor and contain the cell bodies of the lower motor neurons within motor nuclei of the ventral horn. The axons that form the peripheral nerves enter and exit the dorsal and ventral horns in a series of rootlets along the length of the spinal cord. The rootlets within each of the vertebra join to form the dorsal and ventral spinal roots which then combine to form the common spinal root. There is one spinal root on each side that exits the vertebra through a foramen. There are eight cervical nerves, 12 thoracic, five lumbar, and five sac­ ral nerves. The spinal cord is surrounded by the same three meningeal layers as the brain, the dura mater, arach­ noid, and pia matter. The rootlets and spinal roots are only accessible within the meninges. The meninges are continuous with and eventually form the perineurium of the peripheral nerve.

input to the first stages of information processing, such as reflex circuits. Electrodes in the spinal cord can inter­ act with fiber tracts for multilevel influence and some fundamental circuits for motor coordination. Electrodes in the brain stem and diencephalon interact with func­ tional systems, such as respiration, autonomic regula­ tion, and overall motion coordination. Electrodes in the cortex interact with the highest levels of consciousness.

Vascular Anatomy PNS Vasculature The vessels that perfuse peripheral nerves typically run along the nerves and consist of extrinsic and intrin­ sic vessels (Figure 17.7). Larger intrinsic vessels run in the epineurium and communicate with the extrinsic vessels via collateral supplies. This arrangement allows one to free lengths of the nerve from surrounding tis­ sue without significant ischemia. Several centimeters (Orf and Schultheiss, 1981), up to 40 times the nerve diameter (Maki et al., 1997), of the nerve can be exposed and freed from surrounding tissue without significant deficit in perfusion, as long as the extrinsic vascular supply is left intact. To reach the axons, the vessels cross obliquely through the perineurium to transverse between the epineurium and endoneurium. As they pass through the perineurium, they tend to reduce in size and take an ellipsoidal cross-sectional shape (Lundborg, 1979, 1988; Rempel et al., 1999). Within the endoneurium, the bloodflow is dependent on the intrafascicular pressure. Up to 20 mmHg, the capillary and arteriolar blood flow is unaffected and there is only a small decrease in venular flow. As pressure rises above 20 mmHg, the capillary and arteriolar flow begins to decrease. At about 60 mmHg, Inf. gluteal a.

Popliteal a. Small saphenous a. Tibial n. Motor br.

Summary The important anatomical structures and organi­ zation that determine the shape, size, placement, and potential complexity of the interface with the electrode have been reviewed. These anatomical characteristics also dictate the surgical techniques, invasiveness, and tools required to access the neurons and implant the interface. In addition to the physical characteristics of the electrode, functional anatomy dictates the types of interface and influence of function and behavior that is possible at each potential implant location. Typically electrodes on the periphery are easiest to implant. They will control end organs directly or effect the sensory

Post. tibial a.

Sciatic n.

Segment

Peroneal n. 1 2

3

4

5

6

Figure 17.7  Blood supply in peripheral nerves. The blood to a peripheral nerve is supplied by large extrinsic vessels, but extends for several centimeters bidirectionally along the nerve through intrin­ sic vessels. Consequently, as long as the extrinsic vasculature is not damaged, several centimeters of a peripheral nerve can be exposed and freed from surrounding tissue without significant ischemia (Reproduced from Maki et al. (1997). © American Society of Plastic and Reconstructive Surgeons. With permission Lippincott Williams & Wilkins; www.lww.com)

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17.  electrodes for the neural interface

the venular flow is stopped. All blood flow is stopped at approximately 70 mmHg (Rydevik et al., 1981). These pressures correspond to neural damage in compression neuropathies. In the carpal tunnel, for example, the nor­ mal resting pressure is 2.5 mmHg and the maximum pressure at full wrist extension and flexion is approxi­ mately 30 mmHg. In carpal tunnel syndrome, how­ ever, the resting and maximum pressures increase to 32 mmHg and approximately 100 mmHg, respectively. Even at rest, the pressure is high enough to impede blood flow, leading to painful neuropathies (Gelberman et al., 1981, 1993). In addition to blood flow, axonal trans­ port is affected by pressure. Up to 20 mmHg, there is no observed decrease in transport, but above 20 mmHg, there is a significant degradation of transport (Dahlin and McLean, 1986; Olmarker, 1991; Lundborg and Dahlin, 1996). Therefore, 20 mmHg is an important pres­ sure guideline for electrode development and 60 mmHg is a critical value as many of the neural processes in the peripheral nerves are significantly degraded or stopped altogether above this value. In addition to intraneural pressure, blood flow is affected by stretching of the nerve. As with pressure, venular flow is affected first at approximately 8% strain. Arteriolar and capillary flow are first affected at approximately 10% strain. Complete cessation of blood flow occurs at approximately 15% strain (Lundborg and Rydevik, 1973). The permeability of the vessels within the endone­ urium is different than in the epineurium. Large mol­ ecules that can freely cross in and out of the vessels in the epineurium are unable to do so in the endoneu­ rium. This greater selectivity of the endoneurial ves­ sels controls the osmotic and molecular environment within the fascicles to maintain an environment favor­ able to the axon function (Myers et al., 1980; Ask et al., 1983). The selective permeability in the peripheral nerves is referred to as the blood–nerve barrier and is analogous to the blood–brain barrier of the CNS.

are in the superficial pial layers and then descend into the cortical tissue with finer division and more dense structure (Figure 17.8). The vascular network contrib­ utes significantly to the dynamics of the cortical tissue during electrode insertion (Bjornsson et al., 2006) and it is very likely that any device inserted into the tissue will damage some of the vasculature. As in the PNS, the vessels within the brain have a more selective permeability, preventing large molecules from crossing out of the vessels and into the neural tis­ sue, forming the blood–brain barrier (BBB) (Abbott, 2002; Abbott et al., 2006). During insertion of electrodes, it is likely that damage will occur to the weblike micro­ vasculature. The vascular damage disrupts the BBB, allowing foreign molecules and pro-inflammatory cells to enter the neural tissue. This contributes to the inflammatory response (Schnell et al., 1999; Lenzlinger et al., 2001), discussed further elsewhere in this text. The arterial supply to the spinal cord consists pre­ dominately of three vessels that run longitudinally

CNS Vasculature The blood supply to the brain is provided by the internal carotid arteries and the vertebral arteries. These vessels join to form the Circle of Willis from which the anterior cerebral, middle cerebral, posterior cerebral, superior cerebellar, posterior inferior cerebellar, anterior cerebellar, anterior spinal, posterior communicating, and basilar arteries arise to supply the diencephalon and telencephalon CNS regions. The major vessels then continually divided to form a dense mesh network throughout the CNS tissue (Reina-DeLaTorre et al., 1998; Rodriguez-Baeza et al., 1998; Nonaka et al., 2003; Bjornsson et al., 2006). In cortical tissue, the large vessels

Figure 17.8  Microvasculature in cortex. Across the corti­ cal regions, the blood flow is supplied by larger vessels in the pial layers that quickly branch into a dense meshwork of vessels. It is unlikely that an electrode can be placed within the cortex without damage to some of this vasculature (Reproduced with permission from Reina-DeLaTorre et al. (1998), John Wiley & Sons Ltd)

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Neural science fundamentals

white matter. Similar to the arterial supply, but in mirrored arrangement, there are two to four anterior spinal veins and a central posterior spinal vein that run the length of the cord. These veins provide segmental connection to the spinal cord regions to complete the circulatory loop. As with the vasculature of the PNS, the spinal cord PNS is mostly segmental with long con­ necting major vessels that allow exposure of large sur­ faces of the structure without ischemia. The electrodes, however, should avoid damage to these vessels.

along the spinal cord (Figure 17.9). The anterior spinal artery runs along the midline of the anterior surface of the spinal cord with connections via the anterior seg­ mental medullary arteries to the vertebral arteries in the cervical region, the posterior intercostal arteries in the thoracic region, the lumbar arteries in the lum­ bar region, and the sacral arteries in the sacral region. Blood is then distributed segmentally into the gray matter via the anterior sulcal arteries through the ven­ tral median fissure. The ventral and lateral columns of the white matter are segmentally supplied by the anterior segmental medullary arteries through the pial arterial plexus. On the dorsal surface, there are two posterior spinal arteries that run the length of the cord and lateral of midline. These are supplied via the pos­ terior segmental medullary arteries by the vertebral arteries in the cervical region, the posterior intercostals arteries in the thoracic region, the lumbar arteries in the lumbar region, and the sacral arteries in the sacral region. The posterior medullary arteries also supply the dorsal horn of the gray matter. The posterior spinal arteries segmentally supply the dorsal column of the

Tissue Electrical Impedance Having considered the anatomical basics of electrode design, we next need to consider the electrical properties of neural tissues. These properties will determine how currents flow within the neural tissue, and ultimately, the distribution of electrical fields that are created or sensed by the electrode. Note that all current within the body is carried by ionic mechanisms. The conversion from elec­ tron to ion current occurs at the electrochemical interface

Basilar artery Anterior sacral artery

Vertebral artery C3

Vertebral artery

Posterior spinal artery

C3 C5 C5

C6

Posterior internal vertebral venous plexus Posterior segmental radicular vein

Ascending cervical artery

Posterior spinal veins

Posterior Posterior spinal artery

Pial arterial plexus

Pial venous plexus

Anterior segmental medullary artery

T1 Posterior segmental Spinal nerve medullary Intervertebral arteries vein

T2

T3 T5

T6 T9 Posterior intercostal arteries

Posterior intercostal arteries

T7

T10 T11 L1

Posterior segmental medullary arteries

L3

Posterior segmental medullary artery

Spinal nerve Spinal branch

Anterior segmental radicular vein

Anterior spinal artery

Anterior internal vertebral plexus Anterior spinal veins

Basivertebral vein

Anterior

(B)

L3

L5

Branches from lateral sacral artery

Branches from lateral sacral artery

(A)

Figure 17.9  Blood supply to the spinal cord. The spinal cord is supplied by large vessels running parallel to the cord on the ventral and dorsal sides (A). These are the anterior and posterior spinal arteries and veins. They form a plexus surrounding the cord that then extends seg­ mentally into the gray and white matter. (B). Electrode design should minimize occlusion of spinal arteries and veins (Reproduced from Grant’s Atlas of Anatomy, 10th edition (Anne M.R. Agur and Ming J. Lee) (1999). With permission Lippincott Williams & Wilkins; www.lww.com)

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192

17.  electrodes for the neural interface

with the electrode. This is discussed in other sections of this book. Here, tissue impedance is presented in terms of electrical properties (Table 17.2). The most resistive of all tissues is the skin. At 1 kHz, the resistance of a 1 cm2 patch of skin is between 10 and 1000 k (Rosell et al., 1988). This corresponds to a conductance of between 0.00001 and 0.0001 S/m (Pethig, 1987; Gabriel, Gabriel et al., 1996; Gabriel, Lau et al., 1996). The low conductance of the skin signifi­ cantly attenuates and filters the signal, both spatially and temporally. Consequently electrodes outside the skin require the most energy to excite neural tis­ sue, are not very selective in their stimulation, cannot record small signals, and have poor spatial resolution in recording neural signals, such as in EEG recordings. Electrodes placed inside the body will be encapsu­ lated by a collagenous layer of tissue. The impedance of encapsulation tissue is dependent on the maturity and organization of the tissue. Mature, compact tissue is closer to a pure resistor, while loose, poorly formed encapsulation has a significant capacitive component. The conductivity of a well-formed capsule is approxi­ mately 0.15 S/m and is independent of frequency and of encapsulation with loose connective tissue and macrophage infiltrations is frequency dependent, ranging from 0.22 S/m to 0.51 S/m between 10 Hz and 1 kHz, respectively, and stable at 0.51 S/m between 1 kHz and 100 kHz (Grill and Mortimer, 1994). In peripheral nerves, the resistivity of the perineu­ rium, epineurium, and endoneurium are most

Table 17.2  Conductivity of some common tissues related to the neural interface Tissue

Conductivity (S/m)

Reference

Saline

1.3–2.0

(Geddes and Baker, 1967)

Encapsulation

0.2–0.5

(Grill and Mortimer, 1994)

Perineurium

0.002

(Weerasuriya et al., 1984; Choi et al., 2001)

Epineurium

0.083

(Choi et al., 2001)

Endoneurium

0.083 transverse 0.571 longitudinal

(Ranck and Bement, 1965; Choi et al., 2001)

Scalp

0.43

(Oostendorp et al., 2000)

Skull

0.015

(Oostendorp et al., 2000)

Dura mater

0.030

(Holsheimer et al., 1995)

Brain

0.12–0.48

(Foster and Schwan, 1989; Gabriel, Gabriel et al., 1996; Gabriel, Lau et al., 1996; Oostendorp et al., 2000)

Skin

0.00001–0.001

(Gabriel, Gabriel et al., 1996; Gabriel, Lau et al., 1996)

important. The conductivities of these tissue are not exactly known and are quite variable. The following numbers, however, give a range of expected values. The conductivity of the perineurium and epineurium are 0.002 and 0.083 S/m, respectively (Weerasuriya et al., 1984: 266; Choi et al., 2001: 105). The endoneur­ ium, however, is anisotropic, with a conductivity of 0.083 S/m across the axons and 0.571 S/m along the fibers (Ranck and Bement, 1965; Choi et al., 2001). The relatively low conductivity on the perineurium has a significant influence on the field distribution in periph­ eral nerves. If the electrode is external to the perineur­ ium, an applied field is significantly attenuated and typically more uniform within the fascicle than if the perineurium did not exist. This makes stimulation of small subpopulations within the fascicle difficult. In contrast, an electrode within the perineurium will be isolated from other fascicles and is able to selectively activate small axon populations within the fascicle. The perineurium and size of one fascicle will also influence the fields within surrounding fascicles (Grinberg et al., 2008). When recording neural signals, the perineurium significantly attenuates the field produced by neurons, making single unit recording virtually impossible. In central tissues, the meninges have low conduc­ tivity; the dura, for example, is reported to be around 0.030 S/m. The conductivity of the skull is also fairly low at 0.015 S/m. These low conductivities affect the selectivity and sensitivity of recording, i.e. EEG, and stimulation with electrodes on the scalp just as surface electrodes for the peripheral nerves. EEG recording, however, is possible as the brain is relatively large and close to the surface as compared to peripheral nerves.

Tissue Mechanical Properties In general, tissue is a viscoelastic material. The differ­ ent tissues have a wide range of differing moduli. The elastic modulus of neural tissue is in the range of 0.1 to 1.5 kPa (Miller, 1999; Miller, Chinzei et al., 2000; Prange and Margulies, 2002; Taylor and Miller, 2004; Shen, Tay et al., 2006), which is similar to jelly. This includes the endoneurium in the PNS and the gray and white mat­ ters of the CNS. The specific modulus depends on ori­ entation and orientation of axons and the composition of cells bodies and glia vs. axons. The protective tissues of the perineurium in the PNS and meninges in the CNS are much stiffer. The proper­ ties of the spinal dura mater provide has been studied and provides a representation of the modulus values. The dura mater is comprised of a very tough outer fibroelastic layer, an intermediate fibrous layer, and an inner cellular layer with interdigitated cells, little

III.  BIOMEDICAL ENGINEERING CONSIDERATIONS



Neural science fundamentals

extracellular collagen, few tight junctions, and signifi­ cant extracellular space (Vandenabeele et al., 1996). In the lumbral spinal cord, the dura mater has an elastic modulus of 5 to 140 MPa, depending on the orienta­ tion in which it is measured (Runza et al., 1999; Tamura et al., 2007). The perineurium has been estimated to have a modulus between 120 kPa in the frog sciatic (Odman et al., 1987) and 2–10 MPa (Rydevik et al., 1990; Abrams et al. 1998; Layton and Sastry, 2004) in mam­ malian nerves. Surrounding Space and Tissue In designing an electrode for the neural interface, the tissues, structures, and space surrounding the neu­ ral tissues contribute to the electrode limitations and requirements. The electrode will apply forces on the surrounding tissue. Similarly, surrounding tissues will apply forces on the electrode that will be transmitted to the neural tissue if not properly mitigated. For example, cortical electrodes may have a component that extends above the surface of the brain or leads running between the skull and the brain. As the brain moves within the skull, on the order of several millimeters in the rat (Gilletti and Muthuswamy, 2006) and likely much more in the human, the probe may transmit concentrated forces into the neural tissues. This can lead to chronic inflammation, neural degeneration, or probe damage. In the spine, the space within the vertebral column and the vertebral foramen govern electrode design. Peripheral nerves are typically between muscle planes and have fewer size constraints. The surrounding tissues and properties also relate to the amount of motion the interface will experience. In the periphery, nerves will move many millimeters during motion of the limbs. The sciatic nerve, for example, will stretch several centimeters as an individ­ ual bends at the waist to touch their toes (Coppieters et al., 2006). The spinal cord, in contrast, experiences about an order of magnitude smaller motions (Ko et al., 2006). The bony casing of the vertebra and skull of the CNS protect neuron from external forces and the forces from muscle contraction. In the periphery, however, muscles contracting around implanted elec­ trodes place forces on the electrode. In addition to the constraints imposed by the imme­ diate environment contacting the electrode and nerve, the location of the nerve and nature of the surround­ ing tissue will affect the design of electrodes and the surgical techniques required to place them within or upon the intended tissue. Deep tissues are typically harder to access. Nerves typically run in the vicinity of blood vessels or next to important organs. Depending on the significance of the vessel or organ, additional

193

consideration must be given to the electrode implant procedure and design. For example, the vagus nerve (Xth CN) is located in the carotid sheath. When implanting an electrode, one would prefer to minimize the amount of nerve that needs to be exposed in order to minimize the manipulation required of the carotid arteries. Further, the electrode must be designed to eliminate any potential chronic inflammation or dam­ age to the surrounding vessels and tissue. As a final thought related to tissue and implant procedures, the electrode design should consider the general trend in surgical techniques and patient care towards, shorter, less-invasive, and minimal post­ operative in-hospital stay. The less invasive and shorter surgery required to implant an electrode, the better. Simple design features, such as tabs to enhance holding of the electrode for implant or notches for alignment, can greatly enhance the surgical implementation of the electrode.

Neural Behavior in Response to Applied Electric Fields The cable equations (Rattay and Aberham, 1993) and Hodgkin–Huxley non-linear dynamics of voltagesensitive membrane channels (Hodgkin and Huxley, 1952) describe the response of the neural tissue in response to applied electrical fields. These equations provide significant insight to electrode performance and design principles. Details of these models are presented in other chapters of this book. The impor­ tant point to reiterate is that transmembrane flow of current leading to alteration of membrane potential, and hence cellular excitation or inhibition, is closely related to the second spatial difference of the potential field along the axon, cell body, and dendrite. Equations (1) and (2) are the continuous and dis­ crete versions of the generic cable equations describing the membrane voltage response to externally applied electrical fields. The continuous equation corresponds to a non-myelinated axon. The discrete equation rep­ resents a myelinated axon where 2 is the second cen­ tral finite difference. The discrete version assumes that myelin is a perfect insulator and the finite dif­ ferences are calculated at the Nodes of Ranvier. The spacing of the Nodes of Ranvier is dependent on the axon diameter and is nominally equal to 100 times the axon diameter. There are more accurate models, i.e. (Richardson et al., 2000), that account for current flow in and around the myelin. Even in these models, the most significant fundamental factor in electrode design, however, is the second spatial or finite central difference.

III.  BIOMEDICAL ENGINEERING CONSIDERATIONS

194 cm

∑ [gion (Vm , t ) (Vm  Eion )]  ga

 

ion

cm  

∂Vm ∂ 2Vm ( x , t )  ga  ∂t ∂x 2

17.  electrodes for the neural interface

∂ 2Ve ( x , t ) ∂x 2

∂Vm  g a 2Vm (n, t )  ∂t ∑ [gion (Vm , t ) (Vm  Eion )]  ga 2Ve (n, t ) ion



(17.1)

(17.2)

The second fundamental consideration of electrical interface to the neural system is the non-linear dynamics of the membrane channels that carry the ionic current. Fundamentally, these channels are ion-selective and the flow of ions through the channel is dependent on gates within the pore of the channel. There are hundreds of known channels with different non-linear behaviors in response membrane potential, neurotransmitters, heat, mechanical perturbation, and other stimuli. The compo­ sition of the channels in the membrane determines the cell’s response to external stimuli. The non-linear charac­ teristics of the channels to affect the neuron’s response to electrical stimulation can be manipulated by the stimu­ lation waveform and characteristics such as stimulation frequency and stimulus shape. As long as the electrode can faithfully reproduce a desired pattern, the temporal characteristics are not strongly related to the electrode design. The details and subtleties of the non-linear dynamics are expressed in other chapters.

Electric Fields Produced by Neural Behavior As an action potential travels down an axon, ions flow across the membrane. Electrically, this is equivalent to several discrete current sources within the nerve pro­ ducing electrical fields that are linearly superimposed. The magnitude of the current flow in a single Node of Ranvier is on the order of 20 nA peak-to-peak (PerezOrive and Durand, 2000; Yoo and Durand, 2005). The current flow generates a small potential that is sensed by an electrode. The magnitude of the potential sensed is dependent on the relative position of the electrode to the axons, the impedance of the intervening tissue between the axon and the electrode, and the impedance of the electrode–electrolyte interface. Typical signal amplitudes range from 1 to 50 V at a point on the surface of the epineurium and approximately 100–200 V within a few microns of the neuron without any intervening encap­ sulation tissue. When many axons are active synchro­ nously, such as during evoked potential measurements, the linear supposition of the fields produces a larger sig­ nal. However, during normal, spontaneous activation,

the fields are not synchronous and the signal is small relative to the compound action potential. A second fundamental consideration in recording is the signal to noise ratio. The neural signal is very small relative to many sources of environmental, circuit, and biological noise. The neural signal amplitude is in the range of the unavoidable thermal and shot noise of the recording circuitry. Recording requires a very-low-noise, high-gain amplifier system. The neural signal (ENG) is nearly three to four orders of magnitude smaller than the electrical signal that results from muscle contraction (EMG). The EMG activ­ ity is on the order of 10s to 100s of millivolts, which eas­ ily dominates the ENG activity. ENG amplifiers require a very high common mode rejection ratio and an elec­ trode design to minimize signal contamination from muscle sources. The EMG spectrum is generally from 1 to 500 Hz with most the power in the 100–300 Hz range and the ENG is from 100–5000 Hz with most power in the 1–3 kHz range.

Design principles for neural interface electrode The preceding section highlighted important biologi­ cal, mechanical, and electrical properties of the nervous system. These properties are constraints and opportu­ nities that are managed and exploited, respectively, in the design of electrodes for the neural interface. In the next section, several important corresponding design principles are presented.

Location Selection The design of an electrode is constrained by the loca­ tion of the electrode upon or within the body. There are several factors related to choice of electrode location, including required proximity to the neuron, the degree of invasiveness acceptable by clinician and patient, the risk/benefit ratio of a given location, availability of required technology, and knowledge of the neural cir­ cuitry and pathways. Proximity to the Neurons To get high fidelity, high information content, the elec­ trode must be placed as close to the tissue of interest, i.e. the neuron, as possible. The effect of placing electrodes farther from the neurons is a loss of specificity, signal amplitude, and frequency content. Theoretically, stim­ ulation electrodes inside the peripheral nerve fascicle can only be considered unique for stimulation if they

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design principles for neural interface electrode

are separated by at least 250 m (Rutten et al., 1991). In the cortex, an electrode must be less than 50 m for good unit isolation (Schwartz, 2004) and close to the neuron cell body. The encapsulation tissue will typically separ­ ate the neurons from the electrode by 10s to 100s of microns and further electrically isolate the electrode to reduce stimulation specificity and recording capability. There is a trade-off between capability of the elec­ trode and invasiveness. External electrodes, for exam­ ple, cannot interact with individual axons, or even fascicles. Only in favorable anatomical arrangements with a single nerve close to the surface, such as the common peroneal nerve at the knee, can an external electrode stimulate a single whole nerve selectively. The minimally invasive electrodes are advantageous in that they bypass the high skin impedance to reduce power requirements for stimulation and improve the signal strength in recording. In general, however, these are still not selective for stimulation. Further, recording neural activity is difficult, particularly in the peripheral nervous system. For the central nervous system, surface electrodes record brain activity on the scalp, but typi­ cally record field potentials resulting from many active neurons. The most significant advantage of external electrodes is that they do not require surgery to imple­ ment. Consequently, they can be used for a short time, removed, and reapplied for later use. Peroneal nerve stimulation for correction of post-stroke footdrop is an example of a system using surface electrodes (Taylor et al., 1999a, 1999b; Sheffler et al., 2006). Despite some advantages, non-invasive electrodes can be difficult for an untrained user to accurately and repeatably place to obtain optimal functional ben­ efit. The result is typically a highly variable stimula­ tion and recording performance. The need to replace the electrodes each time a system is to be used is bur­ densome, requiring donning and doffing for every use (Taylor et al., 1999b). In contrast, implanted electrodes can be placed on specific nerves and even interact with subsets of the nerves axon population. The other extreme of invasiveness is to place the electrode directly next to the neurons or axons. In the PNS, this means placing contacts within the fascicles, within the perineurium. In the CNS, it means placing electrodes directly in the spinal cord, cortex, or other brain structure, within the meningeal layers. There are several challenges to direct nerve interfaces. First, place­ ment of the electrode is highly invasive and requires penetration of the protective perineurial or meningeal barriers. Electrodes within these tissues must be con­ cerned with damage and violation to the blood–brain and blood–nerve barriers of the central and peripheral nervous system, respectively. Second, damage dur­ ing insertion and the presence of a foreign object result

195

in the inflammatory response (Bjornsson et al., 2006), which ultimately results in encapsulation of the inter­ face that prevents direct neural connection. For any electrode to have direct contact with neurons, it is nec­ essary to limit or prevent the encapsulation response. Risk–Benefit Ratio The risk associated with the interface needs to be bal­ anced with the benefit expected (Figure 17.10). In gen­ eral, an electrode should be placed at the least invasive point possible to accomplish the necessary function. For example, if the goal is to activate a single muscle, an electrode on the peripheral nerve of even on the sur­ face of the skin is a better design than in the portion of the motor cortex responsible for the motor action. The design complexity and risk of the electrode both gener­ ally increase with increasing levels of invasiveness. Material and Processing Technology There are several interdependent factors to con­ sider when choosing the electrode materials, includ­ ing electrode size, material mechanical characteristics, electrode durability, number of contacts, connecting leads to the electrode, and electrochemistry. The ideal electrode would approximate the size of the neurons, have mechanical properties equivalent to the neural tissue, function reliably for at least 20 years, have one contact for each neuron, not require any leads external to the electrode, and neither corrode, introduce foreign molecules to the environment, nor cause oxidation or reduction reactions. Unfortunately, the technology that achieves this perfect combination of properties is yet to be realized. Therefore, the balance of the characteristics will be ultimately determined by the application. In gen­ eral, there are a few guiding principles. First, the elec­ trochemical safety of the interface must be maintained. This becomes more challenging as the surface area of the electrode decreases for smaller electrodes. Second, more invasive electrodes should be smaller, mechani­ cally matched, and durable. Third, the number of con­ necting leads should be kept to the smallest possible number. The number of leads is particularly important in considering the penetration of the protective layers, i.e. the meninges of the CNS or the perineurium of the PNS. Any violation of these membranes should be kept as small and as few as possible. Complexity of Function Required from the Electrode The complexity of the neural signal and circuitry tends to increase moving from the PNS to the spinal cord and up to higher levels of the CNS. Placement of

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DBS

CNS/brain Intracortical Subdural

Spinal cord Peripheral nerve

Regeneration Subdural

Epidural

Risk

Intrafascicular Spinal Roots Interfascicular Heart

Epidural

Retina

Organ-based Surface

Circumneural Cochlea

Muscle

Epineural

Skin Scalp

Benefit expected Figure 17.10  Risk versus potential benefit. As the electrodes are more invasive, they have greater associated risk. However, the greater invasiveness correlates with a potentially more intimate interface with the nervous system and potentially greater benefit to the user. Since the choice of interfaces overlap, the system designer must carefully weigh the final risk-benefit ratio in choosing with of the available design strat­ egies to employ in the neural interface

the electrode should be chosen based on the complexity of the function the electrode is expected to produce. For example, activation of a single muscle would be best accomplished by placing an electrode in the muscle or on the nerve branch specifically to that muscle. At the other extreme, however, modulation of Parkinson’s tremors or eating disorders requires electrodes in the basal ganglia or other higher brain centers.

Electrical Fields There are several forms of neuromodulation, includ­ ing stimulation, blocking, and recording. The electrode design principles for each form of neuromodulation are presented in this section. Stimulation and blocking are two forms of neuromodulation where information is passed into the nervous system by application of elec­ trical fields. Recording is extraction of information by sensing of electrical fields produced by neural activity. Stimulation The neuron responds to applied electrical fields according to the cable equations and Hodgkin–Huxley

dynamics of the membrane channels. Accordingly, the second spatial partial derivative of the field along the length of the axon determines the magnitude of the influence of the field on the neuron. The temporal characteristics of the field influence the channel, and hence, neural behavior. The neural response to various temporal waveforms is considered in greater detail in other chapters of this text. The spatial characteristics of the field, however, are significantly affected by the elec­ trode design. The number of contacts, contact shape, placement of the contacts, and insulation determine the ability of the electrode to manipulate the field shape. The total applied field from a stimulation pulse is deter­ mined by linear summation of fields applied by each of the independent contacts. Therefore, the capabilities of the electrode are determined by the composite of indi­ vidual contacts. The smaller the contact, the more it approximates a point source with the smallest possible spatial distribution. Larger contacts have more diffuse field distributions. Similarly, the more independent contacts available, the greater flexibility in design of a final field shape. The neural anatomy at the location of the electrode implant will guide the development of the contact placement. In the PNS, where axons can be considered

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design principles for neural interface electrode

infinitely long cables and devoid of cell bodies, the most flexible designs would have multiple contacts spaced along the nerve to control the second spatial difference and multiple columns of electrodes around or throughout the cross-section of the nerve to control the spatial selectivity. In the CNS, the design is compli­ cated by the more complex anatomical arrangements of the nuclei and fiber tracts. The design will be depend­ ent on the electrode purpose and location. For example, electrodes designed to stimulate cells and connections within a nucleus need to be designed to avoid stimula­ tion of the axons of passage in surrounding communi­ cations tracts. The design principles, however, remain consistent and computer models are often used to aid in determining and optimizing the fields and neural responses to various electrode designs. Insulation is as important in considering the design of the electrode as the contact. Just as the fields from many contacts can be summed to produce a field, the insula­ tion can be used to shape the field that is produced by each contact. In peripheral nerve electrodes, insulation is used to confine current to a specific nerve or even a spe­ cific region of the nerve. In the CNS, appropriate design of the contact and insulation arrangement can limit fields to a specific nucleus and avoid passing fiber tracts. Stimulation and blocking may seem to be opposite functions, i.e. one to activate and the other to prevent activation. However, both are essentially a manipulation of the membrane voltage of the neuron based on the second spatial difference along the axon. Depolarization, and hence excitation, is produced by a positive second spatial difference at the Nodes of Ranvier. Sufficient depolarization will result in generation of a selfreplicating action potential that will propagate on the axon. Similarly, sub-threshold depolarization will mod­ ulate the neuron response by changing its susceptibility for excitation. In the CNS, stimulation can also refer to the manipulation of the membrane potential of the cell body or dendrites – all result in either direct activation of the cell or changing its susceptibility for excitation. Blocking Blocking refers to either preventing propagation of an action potential or decreasing the propensity of the neuron to generate an action potential. Blocking is a nonpharmacological mechanism for the management of con­ ditions caused by overactivation, such as spasticity, pain, and urge incontinence. The electrode can affect blocking by a negative second spatial derivative to hyperpolarize the membrane and generally prevent action potential generation or propagation. Another approach is to inac­ tivate the membrane channels by sub-threshold depolar­ izing pulses.

197

Whether stimulating or blocking, the electrode pro­ vides the spatial template for design and manipulation of electrical fields. The electrode designer is concerned with producing the optimal spatial distribution of the field. Recording Recording refers to neural interfaces that seek to extract information from the nervous system. Generally, recording is based on the flow of molecules or ions through the cellular membrane. In electrical recording, it is important that the flow is of charged ions, which give rise to current flow. At each Node of Ranvier the transmembrane current is considered a current source that produces a potential field. The total resultant field produced by neural activity is the linear supposition of the fields generated by all the individual nodes and propagated through the resistive tissue media. To record high fidelity signals, such as single unit action potentials, the electrode contact should be as close as possible to the individual nodes, approximately the same size as the nerve, and the impedance should be as low as possible to maximize the signal transferred to the amplifier. Unfortunately, small contacts, however, typically have higher impedance and complicate the recording amplifier design. As the contact moves away from the node, more tissue intervenes and the signal is degraded. The perineurium and meninges are highly resistive and significantly degrade the signal. Electrodes farther than about 100 m in either the PNS or CNS typical cannot typically record single unit activity, but rather local field potentials. Local field potentials are a response of several neural processes. As the fields are filtered by the intervening tissue and due to the sum­ mation of multiple asynchronous fields, the local field potentials typically have lower frequency components and poor spatial resolution. Recording of neural activity is complicated by noise and contaminating signals. In the CNS, which is generally isolated from muscles, noise sources are typically dominated by environmental source, e.g. ACsupply line (i.e. 50/60 Hz) noise and EMF interference. Recording against a common reference is generally acceptable and high-quality instrumentation ampli­ fiers are sufficient to obtain decent recordings. This minimizes the electrode design requirements in the CNS with the most important principles being close proximity and as low electrode impedance as possible. In peripheral nerve, however, recording is com­ plicated by the presence of muscle activity. The field produced by muscles is typically one to three orders of magnitude higher than the field produced by the neurons, i.e. V neural signals compared to mV

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myoelectric signals. The summed field is recorded by a single contact of the electrode. The EMG field will sat­ urate the amplifiers well before the composite signal can be sufficiently amplified for the neural signal. Fortunately, EMG is typically a common signal on the electrodes and can be significantly reduced by differ­ ential recordings and appropriate electrode design. In electrodes that encompass the peripheral nerve, i.e. cuff electrodes, the EMG decays in a nearly linear manner along the electrode. The most common design principle is a balanced tripolar arrangement with three electrodes placed at equal distributions along the length of the nerve. The center contact is recorded dif­ ferentially to the average of the two outer contacts. If the EMG decays perfectly linearly and the electrode is perfectly balanced, the average of the EMG signal of the end contacts is exactly equal to the EMG of the center contact and will be cancelled. If the contacts are spaced appropriately far apart, there will be a differential neu­ ral signal, which is traveling through the electrode. The ideal electrode spacing can be estimated by the conduc­ tion velocity (vAP), and the duration of the action poten­ tial (dAP). An optimal special separation, xOPT, can be computed as xOPT  vAP * dAP. In general, the conduc­ tion velocity of a myelinated axon in mm/ms is 6 times the axon diameter (including the myelin) in m (Kandel et al., 2000). For example, a 12 m diameter fiber has a CV of approximately 72 mm/ms. The typical action potential duration is 1–2 ms. Therefore, the optimal separation between the two end contacts is between 7 and 14.4 cm. While ideal, the length is often limited by anatomical considerations at the implant location, as well as mechanical effects the cuff has on the nerve. Therefore, shorter cuffs are used, but it should be as long as possible. Another design rule-of-thumb applied to the electrode length for optimal recording is to include at least 10 Nodes of Ranvier within the cuff. The distance between the Nodes of Ranvier is 100 times the axon diameter including myelin. For a 12 m diam­eter fiber, this is about 1.2 mm, requiring electrode length of 12 mm or 1.2 cm (Andreasen and Struijk, 2002).

Tissue Response The tissue response is divided into the conforma­ tional changes in the tissue and the cellular and inflam­ matory response. The conformational changes are induced by the forces applied by the electrode to the neural tissue. The cellular and inflammatory response is caused by any device or foreign object placed in the body or any procedure that disturbs the tissues. Similarly, devices remaining in the body will affect a chronic tissue response. The cellular and inflammatory

response to an implant is described elsewhere. The elec­ trode design must minimize and control the response as much as possible. The two most important factors that control the tissue response are the forces applied to the tissue by the device and the surface chemistry of the materials that contact the tissue, including the molecu­ lar and protein attachments to the surface. Material selection, surface modifications, and inflammatory response are described in greater detail elsewhere in this text. Sufficient to say here is that the design of the electrode must minimize the inflammation and encap­ sulation tissue around the electrode. In addition to the surface chemistry and molecu­ lar modification of the material of the electrode, the mechanical design of the electrode is important to briefly highlight. The mechanical aspects can be divided into macromechanics and micromechanics. Macromechanics refer to the gross effects of forces applied by an electrode to the tissue. One obvious limitation in electrode design is physical damage to the neural tissue. In some designs, this includes intentional violation of various tissues, such as the meninges or perineurium to place an elec­ trode within the deeper neural tissue. Typically, how­ ever, unintentional physical damage results from gross design errors such as very stiff materials with sharp edges or chronic motion that wears away at tissue. These are usually avoidable with common sense design. More importantly, however, are the effects of applied force on blood flow and perfusion of tissue. There are two important design guidelines: pressure and strain. The first is to keep the applied forces low enough such that the pressure within the nerve does not rise above 20–60 mmHg as these are the limits of pressure (Rydevik et al., 1981) discussed earlier that reduce or completely restrict blood flow, respectively. The second design principle is to keep the strain in the tissue below 8–15%, which correspond to initial reduction and com­ plete restriction of blood flow, respectively (Lundborg and Rydevik, 1973). Electrodes are typically stiff, fabricated from materi­ als with moduli of 10 GPa or higher. This is much stiffer than the neural tissue. This mechanical mismatch can lead to alterations in the nerve morphology or damage to the tissues. When the electrode stiffness or modu­ lus is several orders of magnitude higher than that of the brain tissue, the pulsatile, respiration-related, and every­day motion of the brain, upwards of 60 m (Gilletti and Muthuswamy, 2006), as well as any dis­ turbance applied to the electrode, result in differential motion between the electrode and surrounding tissue. This induces stress and strain in the tissue (Subbaroyan et al., 2005). As stiff electrodes are left in the cortex, astrocytes adhere more strongly to the electrode surface and maintain a reactive state, as indicated by increasing

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design principles for neural interface electrode

forces required for extraction of the probe and the presence of GFAP astrocytes adhered to the probe (McConnell et al., 2007). Utilizing finite-element mod­ eling, Subbaroyan et al. showed that the effects can be significantly reduced if the modulus of the probe is lowered from approximately 1 GPa of most electrode materials to 6 MPa (Subbaroyan et al., 2005), even though this is still approximately 20 to 1000 times stiffer than the brain. The role of electrode stiffness on tissue response has been examined in vitro and indirectly in vivo. The two modalities for mechanical responses include shearinduced, differential motion and micro/mechanotrans­ duction directly between the cell and electrode surface. Two in vivo studies of implanted tethered and unteth­ ered probes (Kim et al., 2004; Biran et al., 2007) showed that shear-induced, differential motion induced by tethered electrodes is reduced in the untethered elec­ trodes. The extent of reactive astrocyte activity from the implant interface (Biran et al., 2007) in the unteth­ ered electrodes was half that of the tethered electrode. Finite-element modeling demonstrates that softer materials (Subbaroyan et al., 2005) and increased tissue integration (Lee et al., 2005) will alleviate strain, but in vivo studies remain to be conducted to investigate the role of stiffness in strain-alleviation and neuronal integration. Studies have indicated that the formation of stress fibers and non-muscle myosin II A-C are keys in the mechanical response of cells (Clark et al., 2007). Durotaxic cues dictate cell proliferation based on sub­ strate stiffness for various cell types from neurons (Flanagan et al., 2002; Georges et al., 2006; Leach et al., 2007) to fibroblasts (Lo et al., 2000) to smooth muscle (Peyton and Putnam, 2005). In vitro studies (Engler et al., 2006; Georges et al., 2006) have shown that neu­ rons and glial cells are also responsive to the local sub­ strate stiffness directly in contact with the cells. It was shown that substrate stiffness determines distinct cell proliferation in mixed cortical and stem cell cultures. Micromechanical effects refer to the stress and strain applied directly to the cells. Typically, the glia are responsive to the micromechanical affects of the electrode. Small strain in the cell membranes causes ion flow, typically Ca2, in mechanosensitive channels (MSC) in the membrane. The influx of calcium, espe­ cially if excessive and continuous, upregulates several of the pro-inflammatory cytokine cascades and promotes continual inflammatory response until the mechanical irritation is minimized or removed. Consequently, to maintain close long-term proximity to neurons or direct connection to neurons, the electrode mechani­ cal properties should match the tissue mechanical properties.

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Other Design Considerations Finally, a few miscellaneous considerations are mentioned. These are not critical to the success of the electrode, but will influence the patient acceptance and clinical relevance of a given electrode design. Implant Procedure One of the significant barriers to neuromodulation therapies over traditional pharmacological therapy is the perceived invasiveness and complication of the neuromodulation systems. They require the implan­ tation of at least one electrode or neural interface and usually at least one permanent device. When compared to a pill, this is perceived as invasive and complicated, despite the fact that neuromodulation therapies rarely have adverse effects and often require little mainten­ ance after the initial implant. The most significant risk of most neuromodulation systems is from the implant procedure. Since the stimulation device can typically be implanted subcutaneously, the electrode is typically the most invasive component of the system. The opti­ mal electrode design, therefore, would minimize the invasiveness of the implant procedure. Removability Despite years of research and the generally good performance of electrodes for the neural interface, a design should consider the potential need to remove the electrode. In particular, the design of an electrode should ideally allow for its removal without damage or disruption of the neural tissue with which it was interfaced and for placement of a replacement elec­ trode. This is relatively straightforward with less inva­ sive electrodes fabricated from inert materials such as poly(dimethylsiloxane) (PDMS) or poly(perfluoroalyoxyethylene) (PFA). However, as electrodes research increasingly explores other biomimetic and biointe­ grated systems designed for direct molecular attach­ ment to and ingrowth of neurons, removal without damage of the neurons becomes difficult or impossible. The effects of this integration need to be considered.

Neural interface electrode examples All of the key factors guiding design of an electrode for the neural interface have been presented and briefly discussed without any specific design examples. To conclude, several electrodes are presented to highlight the choices designers have made to balance all of the

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factors described in this chapter. This is not an exhaus­ tive list of available electrodes. Rather, it demonstrates several methods for interfaces at various locations within the nervous system, highlights the design tradeoffs, and discusses the uses appropriate for each of the designs.

Surface Electrodes Owing to their simplicity and negligible risk, sur­ face electrodes applied to the skin are widely used in many neuromodulation applications and clinical diagnostic procedures, ranging from ECG and EEG measurement to transcutaneous electrical nerve stim­ ulation (TENS) for pain management and physical therapy (Marchand et al., 1993) to EMG recording for control of amputee prostheses. There are basically two types of surface electrodes: patch and minimally inva­ sive (Figure 17.11). Patch electrodes are large surface area electrodes that adhere to the skin. They may or may not have conductive gels that minimize the elec­ trical impedance of the skin, produce uniform current distribution, and help to prevent electrical burns that could result from improper stimulation. Since the cur­ rents pass through the skin, sensory nerves are also activated and this can cause painful sensation prior to full activation of the muscles. Many uses of patch stimulating electrodes are for short-term therapy, such as after a stroke (Wieler et al., 1999; Daly et al., 2005; Sheffler et al., 2006) or as a temporary non-invasive neuroprosthesis (Hines et al., 1995; Burridge et al., 1997; Prochazka et al., 1997; Popovic et al., 1999; Snoek

et al., 2000). Electrodes are placed on the skin, over the nerve entry point (motor point) of the target muscles. High stimulating currents (25–100 mA) are required to activate the muscles (Prochazka et al., 1997). Surface electrodes are widely used for surface EMG recording in amputee myoelectric prostheses. The electrodes are embedded in the prosthetic socket to minimize procedures for donning and doffing. This is effective. Due to the attenuation of EMG signal by the low skin conductivity, the distant location of the surface electrode in relation to the muscle, varying placement of contacts each usage, and varying skin conductivity with sweat, humidity, and other changes between uses, stabile and repeatable measure from surface electrodes is challenging. As the patient sweats or the socket moves relative to the target muscles, the signal quality and amplitude will change, affecting the control of the myoelectric prosthesis. Minimally invasive electrodes are typically a small percutaneous needle or “corkscrew” that penetrates the skin. The penetration of the skin bypasses its resistance and many skin sensory fibers and signifi­ cantly improves the recording and stimulation from these electrodes. Minimally invasive electrodes are generally used for diagnostic purpose as chronic usage in a therapeutic application would be undesirable. Obstacles to widespread use of surface electrodes include poor muscle selectivity, especially of small or deep muscles, inconsistent muscle or nerve activation due to variations in electrode placement and impracti­ cal donning time (Marsolais and Kobetic, 1983; Waters et al., 1985).

Figure 17.11  Surface and minimally invasive electrodes. (A) Corkscrew electrode used to bypass scalp impedance in recording corti­ cal signals. (B) Patch electrodes for stimulation (Dura-Stick II Self-Adhesive Electrodes, Chattanooga Group. Hixson, TN). Larger electrodes reduce the current density and therefore the painful sensation but make selective activation difficult. (C) Quik-Cap (Compumedics NeuroScan, Charlotte, NC) for high resolution non-invasive cortical recording

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design principles for neural interface electrode

Organ-Based Electrodes

is inserted through the sheath to the same location where the probe had been. When the outer sheath is removed, the barbed tip anchors the electrode in the muscle tissue (Memberg et al., 1994). Many permanent neuroprostheses use implanted muscle-based electrodes connected to an internal stimulator for arm and hand function (Keith et al., 1996; Kilgore et al., 1997; Crago et al., 1998; Memberg et al., 2003), and standing and walking (Kobetic et al., 1999; Davis et al., 2001; Triolo et al., 2001; Uhlir et al., 2004). Implanted systems eliminate the variability due to day-to-day electrode placement and reduce the number of tasks users must perform prior to the device functioning. Intramuscular electrodes have the potential to be implanted laparoscopically. Minimally invasive sur­ gery is used to implant intramuscular type electrodes for cardiac pacemakers, gastric stimulation (Abell et al., 2003) and diaphragm pacing in ventilator-dependent individuals (DiMarco et al., 2002). Another type of muscle-based electrode that can be implanted minimally invasively is the Bion (Advanced Bionics Corp, Valencia, CA). The Bion (bionic neuron) integrates the stimulator and the electrode into a sin­ gle package, eliminating the need for leads (Loeb et al., 2001; Carbunaru et al., 2004). The Bion has been used clinically to correct footdrop (Weber et al., 2005) and to treat incontinence (Groen et al., 2005).

The most distal neural interfaces are located directly at the organs of interest. The distal placement guarantees activation of the organ of interest. Three example organs to which electrodes have been devel­ oped are muscle, cochlea, and retina. Muscle Muscle-based electrodes are used in the somatic peripheral nervous system and take advantage of the somatic PNS characteristic of point-like innervations at the neuro-muscular junctions. By placing an electrode at a few positions, i.e. at the motor points, of a muscle, the entire muscle can be activated. Two common types of muscle-based electrodes are epimysial (Grandjean and Mortimer, 1986), which are sewn on the surface of the muscle, or intramuscular (Memberg et al., 1994; Akers et al., 1997), which are inserted within the muscle (Figure 17.12). They must be placed within a few mil­ limeters of the motor point to get effective stimulation with reasonably small stimulation parameters. Typical parameters for stimulation are pulse amplitudes of 2– 20 mA and pulse widths of 50–250 sec. The challenge for either electrode is a stable anchor to the muscle. The epimysial electrode is typically sewn to the mus­ cle surface. The epimysial electrode implant proce­ dure requires exposure of the muscle, test stimulation of the muscle surface to find the optimal stimulation point, and then surgical stitching of the electrode to the muscle. This typically requires a general anesthe­ sia and open exposure of the muscles. If several mus­ cles are to be implanted the surgery can be lengthy and it can be challenging to implant on deep or small muscles. Intramuscular electrodes can be implanted via needle. A probe is inserted into the muscle either percutaneously or through a small incision and then manipulated to find the optimal stimulation point (Figure 17.12B). Then the outer sheath is slid over the probe and the probe is removed. Finally, the electrode

Cochlear Cochlear implants (Figure 17.13A) take advantage of the distribution and tonotopic organization of the axons innervating the hair cells within the cochlea. The cochlea is a snail-shaped organ that translates the sound waves coming into the ear into perceived sound with higher sounds near the base and lower sounds near the apex. The cochlear electrode (Figure 7.13B) is a long, tapered cylinder with contacts along the surface. The electrode is introduced into the coch­ lea through the round window and advanced through Probe Outer sheath

Slots Tabs (A)

Electrode in carrier

(B)

Figure 17.12  Common muscle-based electrodes. (A) Clinical epimysial (top) and intramuscular (bottom) electrodes. Both electrodes are monopolar (single contact). (B) Schematic of epimysial electrode insertion. First the probe is used to locate the optimal stimulation point. Then the outer sheath is slid over the probe and the probe is removed. Finally, the electrode in the carrier is inserted into the outer sheath until the tabs fit into the slots. The outer sheath and carrier are then removed but the electrode remains in place because of the barbed tio (Reproduced from (A) Akers et al. (1997) and (B) Memberg et al. (1994) by permission of Institute of Electronics and Electrical Engineers. © 1994, 1997 IEEE)

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17.  electrodes for the neural interface

Figure 17.13  Cochlear implant. Inset: A 24-contact electrode is inserted into the cochlea to stimulate the auditory nerve (Courtesy Cochlear Ltd, Lane Cove, New South Wales, Australia)

1.5 to 2 turns of the cochlea. Contacts are placed along the electrode corresponding to frequency representa­ tions within the cochlea. The electrodes are designed to stimulate directly the small regions of the basi­ lar membrane and stimulate the local cochlear nerve fiber. These electrodes take advantage of the coch­ lear anatomy to simplify the implant procedure and achieve selective nerve stimulation. Retina Retinal electrodes (Figure 17.14) are designed to take advantage of the spatial distribution of the retina and the structure of the eyeball. An array of contacts is placed either epiretinal on the inner surface of the ret­ ina or subretinal between the retina/choroid and sclera (Zrenner, 2002). The electrode is designed to confine stimulation to a small region of the retina. The anatomy of the retina is important in determining the perform­ ance of the electrode. The retina contains the main lightsensing elements, the rods and cones at the deepest layer, near the choroid. Above the rods and cones are three layers of neurons arranged in a columnar struc­ ture through the retina, and then the axons of the optic nerve that lay on the inner surface of the retina. The epiretinal electrodes stimulate the axons of the optic nerve on the surface, as well as the columnar axons. The subretinal electrodes are more likely to stimulate the columnar axons because of their proximity.

Peripheral Nervous System Electrodes Organ-based electrodes pose the least risk of implanted electrodes. More proximal, electrodes are designed for implantation directly on the nerves of the

peripheral nervous system. These PNS electrodes are classified as extraneural, interfascicular, intrafascicu­ lar, and regeneration based on their location within the PNS anatomy. Extraneural Extraneural electrodes do not penetrate any of the structures of the peripheral nerve. The least inva­ sive extraneural interfaces include electrodes that are placed near the nerve or sewn onto the nerve. These have been referred to as epineural. Examples of this type of interface include an implanted electrode/stim­ ulator placed near the peroneal nerve for treatment of footdrop (Strojnik et al., 1987) and a ribbon-type elec­ trode that is implanted near the phrenic nerve for dia­ phragm pacing (Glenn and Phelps, 1985). The benefits of stimulating in close proximity to the nerve are that multiple muscles can be activated simultaneously and electrodes that are placed nearer the nerve use less current than muscle-based electrodes. In choosing the epineural electrode design, there is very low risk, but this is gained at the expense of limited ability to selec­ tively activate sub-populations of a common nerve. The next most intimate interfaces encircle the nerve, e.g. circumneural or cuff electrodes. The electrodes are designed to place contacts as close as possible to the nerve without restricting blood flow to the nerve. Hence, the central design parameter for these elec­ trodes related to safety is to keep the intraneural pres­ sure to less than 20–40 mmHg (Rydevik et al., 1981). They must account for normal as well as swollen and inflamed nerves. Closed cylinder electrodes, such as the chambered electrode (Hoffer et al., 1998) (Figure 17.15) must allow extra space for nerve swelling and

III.  BIOMEDICAL ENGINEERING CONSIDERATIONS

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design principles for neural interface electrode

Amacrine cells Horizontal cells Bipolar Pigment cells Ganglion cells epithelium Cornea Lens

Retina Rods

Energy signal Retina

Object

Cones

Epiretinal implant

Optic nerve

Stimulation electrode

Area of loss of rods and cones

Sclera

Vitreous body

Image/light Subretinal implant Axons to brain

Figure 17.14  Electrode placement for retinal stimulation. Retinal stimulation can be accomplished by placing an electrode array on the surface of the inner retina (epiretinal) or in the subretinal space (From Zrenner (2002), Science 295 (5557): 1022–5. Reprinted with permission from the American Association for the Advancement of Science and Dr Alfred Stett) Chambers

F2 F1

F3

F5 N

F4

F7 F6

Figure 17.15  Chambered nerve cuff electrode. The schematic of the chambered electrode on a nerve (N) with seven fascicles. Electrode contacts are shown in red. If nerve swelling occurs, it can expand into the chambers (Reproduced from Hoffer et al. (1998), Simon Fraser University (Burnaby). US Patent No. 5,824,027)

the general design guideline is that the cuff to nerve diameter ratio (CNR) is 1.5. The disadvantage of this design is that the contacts are far from the nerve and selective stimulation of small nerve regions is difficult. Self-sizing electrodes, such as the spiral (Naples et al., 1988) or helix (Agnew et al., 1989), allow for swell­ ing by expanding and contracting without increasing intraneural pressure above 20 mmHg (Figure 17.16). These electrodes maintain tight contact with the nerve and can selectively stimulate small regions of the nerve

(Veraart et al., 1993; Sweeney et al., 1995; Grill and Mortimer, 1996, 1998, 2000; Tarler and Mortimer, 2003, 2004). The spiral electrodes have demonstrated selec­ tive stimulation in the upper extremity of human sub­ jects (Polasek et al., 2007) and have been implemented in standing systems for paraplegic subjects (Fisher et al., 2006). The chronic effects of these extraneural electrodes are well studied and they have been introduced to several clinical applications (Picaza et al., 1977; Waters et al., 1982; Tarver et al., 1992; Broniatowski et al., 2001). The circular cross-section of these electrodes, however, results in a minimum surface for interfacing with the nerve. The cross-section of many peripheral nerves is more oblong than round. Alternate electrode geometries, such as the Flat Interface Nerve Electrode or FINE (Tyler and Durand, 2002; Leventhal and Durand, 2003) (Figure 17.17), optimize the perimeter area, and hence, the interface with the nerve. By keeping intraneural pressure below critical levels to stop blood flow, these electrodes are designed to apply forces to the nerve to change its shape (Tyler and Durand, 2003; Leventhal and Durand, 2004; Leventhal et al., 2006) without sig­ nificant changes in the nerve morphology or function. The loose connective tissue of the epineurium allows the fascicles to freely move relative to each other. If a persistent, but small, force is applied to the fascicles,

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204

17.  electrodes for the neural interface

Negative electrode

Positive electrode

Anchor tether

(A)

(B)

(C)

Figure 17.16  Self-sizing electrodes. (A) CWRU Spiral; (B) Huntington Helix electrode (Courtesy of Cyberonics, Inc.); (C) illustration of self-sizing capability: if nerve swelling occurs, the electrode can open up and accommodate a larger diameter nerve but still have an intimate fit at smaller sizes

8 mm 1.5 mm

(A)

A � 28.3 mm2 C � 19 mm

A � 12 mm2 C � 19 mm

(B)

(C)

Figure 17.17  The Flat Interface Nerve Electrode (FINE). (A) Showing three different views of the electrode. Notice the reusable clasp on the upper electrode. (B,C) Explanation of the ability of the FINE to allow nerve swelling. (B) The cross-section of a FINE that could go on a nerve with an area of 12 mm2 or smaller. (C) If needed, the soft silicone of the rectangular cross-section can expand into a circular cross-section. The same circumference gives more than double the area in this example. The diameter of the circular cross-section is also greater than 1.5 times the diameter of a round nerve with an area of 12 mm2, which is the recommended allowance for post-surgical swelling

even they will change their shape (Tyler and Durand, 2003). The femoral nerve is generally flat in shape and modeling studies have suggested that an electrode that can maintain the flat configuration could pro­ duce required function for both standing and walking selectively with a single device on the common femo­ ral nerve (Schiefer et al., 2008). To improve the selectivity of these electrodes, mul­ tiple contacts are placed around and along the nerve. Multiple contacts along the axon can be implemented to control the second spatial difference for selective stimulation of small populations of fibers. Since the excitation of the axon is dependent on the second spatial derivative at the Nodes of Ranvier, which are dependent on the nerve diameter, altering the spacing of the contacts along the nerve can affect size selectiv­ ity of the stimulation (Lertmanorat and Durand, 2004; Lertmanorat et al., 2006). When recording from periph­ eral nerves with extraneural electrodes, the nerve sig­ nal is nearly three orders of magnitude smaller than the signal from surrounding muscle activation. The arrangement of three contacts along the length of the

nerve into a tripolar configuration can reduce the EMG signal such that the nerve signal can be recorded (Triantis et al., 2005). Interfascicular Interfascicular electrodes are designed to gain greater access to the neurons while still not penetrat­ ing the perineurium around the fascicles. The multi­ groove electrode (Koole et al., 1997), and the Slowly Penetrating Interfascicular Nerve Electrode (SPINE) (Tyler and Durand, 1997) are examples of interfas­ cicular electrodes (Figure 17.18). To implant the multi­ groove electrode, the surgeon dissects the fascicles from the nerve and then inserts them manually into the grooves of the electrode. For the SPINE, the sur­ geon places the electrode around the nerve. The elec­ trode is designed to take advantage of the different mechanical properties of the various neural tissues. It applies a small force to penetrating elements on the surface of the epineurium to insert them into the epineurium, between the fascicles, as the tissue

III.  BIOMEDICAL ENGINEERING CONSIDERATIONS

design principles for neural interface electrode

Fraying cut Slit Opening

205

Beams

Body “Inverse C” Closure tube Element

Contacts

Wires

(A)

(B)

Figure 17.18  Interfascicular electrodes. (A) Slowly penetrating interfascicular nerve electrode. Each element is slowly urged into the epineurium by a small force applied by the beam. (B) Multigroove electrode. Stimulating contacts are located in each groove (shaded rectangles) (Reproduced from (A) Tyler et al. (1997) and (B) Koole et al. (1997) by permission of Institute of Electronics and Electrical Engineers. © 1997, IEEE)

2 mm

L0 Contact pads for ceramic adaptor

Ground

L1

L2

L3

Conductive track

(A)

L4

1mm

(B)

Figure 17.19  Intrafascicular electrodes. (A) Thin-film longitudinal intrafascicular electrode. L0–L4 are electrode contacts that can be configured for recording using L1–L1 as active electrodes and L0 as the indifferent electrode. (B) Utah slant electrode array. The electrode con­ tacts are located on the end of each shaft. The 3D, slanted arrangements allows for access to the entire nerve cross-section (Reproduced from (A) Farina et al. (2008) and (B) Branner et al. (2001), used with permission of the American Physiological Society)

reshapes to accommodate the applied forces. Contacts are placed within the grooves or on the penetrating elements to interface with the individual fascicles. Neither the SPINE nor the multi-groove electrodes have yet been applied to clinical application. Intrafascicular Intrafascicular electrodes penetrate through the perineurium to place contacts directly in contact with the axons. The Longitudinal InterFascicular Electrode (LIFE) (Edell, 1986; Lefurge et al., 1991; Nannini and Horch, 1991; Yoshida and Horch, 1993) and its vari­ ants (Malmstrom et al., 1998; Lawrence et al., 2003) are essentially a very thin wire threaded into a fasci­ cle. The surgeon isolates the fascicles and then inserts each LIFE independently. The next generation thin film (tf-LIFE) arrays (Bossi et al., 2007; Lago, Yoshida et al.,

2007; Farina et al., 2008), have multiple electrodes on a shaft that is inserted through the nerve, placing the contacts into the fascicles (Figure 17.19A). The Utah Slant Electrode Array (USEA) is an array of up to 100 electrode shanks that can all be inserted simultane­ ously (Figure 17.19B) (Branner et al., 2001). They have demonstrated the ability to interact selectively with a small number of axons (Branner et al., 2004). The LIFE has been implanted in the nerves of amputees for short duration (2 week) tests. These electrodes were able to record from motor axons that no longer lead to a muscle and stimulate sensory axons and produce perception in the amputated limb (Dhillon et al., 2004; Dhillon and Horch, 2005; Dhillon et al., 2005). Intrafascicular electrodes present as a powerful tool, capable of inter­ acting with individual axons. Further development is needed to design a safe, stable, intrafascicular electrode for chronic human use.

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17.  electrodes for the neural interface

Regeneration The class of most invasive PNS electrode is the regeneration array (Bradley et al., 1992; Kovacs et al., 1992; Dario et al., 1998; Lago et al., 2005; Lago, Udina et al., 2007). The regeneration arrays typically consist of a micromachined array with via holes encircled by elec­ trical contacts (Figure 17.20). To implant this array, the peripheral nerve is transected. The array is then sutured in place, between the two severed halves of the nerve. The array needs to be designed to allow cytokines and soluble factors to communicate between the ends of the nerve. Over time, the chemical signals lead to axon regeneration with some of the axons growing through the via holes. Electrodes around the holes then stimu­ late or record from the individual axons. This electrode requires intentional damage to the nerve. The capabili­ ties of these electrodes are determined by the number of regenerating axons that actually pass through the holes and the regrowth of the perineurial layer within the vias. The regrowth is controlled by both the size of the vias and the “transparency factor,” which indicated the balance between silicon and open space for regen­ eration. Axon regeneration has been demonstrated through vias as small as 30 m in an array with a 30% transparency factor (Wallman et al., 2001). General Placement of a PNS electrode along the length of a nerve is based on the nerve anatomy, surgical accessi­ bility, and selectivity requirements for the neuromodu­ lation application. To rationally place an electrode and appropriately design its dimensions, a detailed, quan­ titative, and morphologic knowledge of the peripheral

Figure 17.20  Conceptual schematic of regeneration electrode. Axons of a transected nerve grow through via holes surrounded by electrode contacts (From Navarro et al. (2005). Wiley–Blackwell. Reproduced by permission)

nerve anatomy and fascicular arrangement is required. In general, the nerves are more highly organized more distally. Therefore, as a rule-of-thumb, extraneural elec­ trodes are most effective distally and more proximal locations benefit from more invasive electrodes. The potential benefit of more proximal placement is access to a greater number of muscles using a single electrode. This would imply the need for fewer implant locations and greater function.

Central Nervous System Electrodes Superficial and Distal CNS Interfaces The electrode technologies applied to the super­ ficial and distal CNS are similar to the electrodes described for the PNS. The paddle-like electrodes used for epimysial stimulation (Figure 17.21A) have been applied to the dorsal and ventral columns of the spinal cord for stimulation of cough (DiMarco et al., 2006), and respiration function (DiMarco, 2001) and chronic, intractable pain (Barolat, 1999). Arrays of the paddle-like discs are embedded in silicon sheeting and applied over the cortical surface for measurement of the cortical activity (Uematsu et al., 1990). Cuff-like electrodes (Figure 17.21B) are applied to the sacral roots for control of micturition in spinal cord injury (Brindley, 1972; Brindley et al., 1982, 1986). These inter­ faces are reasonable for either exposed fiber tracts, such as the dorsal or ventral columns of the spinal cord or the spinal roots, for recording and stimulation of large populations of fibers, such as cortical recording. The response of the CNS tissue, however, will be more complex as there are multiple cell bodies and neural circuits that the electrode will influence. Sacral root stimulation with the book electrode involves an invasive laminectomy where part of the bones of the spine is removed to allow access to the spinal roots as they come off the spinal cord. Alternative electrodes have been developed to take advantage of the fact that the spinal roots exit the vertebral bodies through a foramen. This is a bony structure that can be accessed with minimally inva­ sive procedures (Spinelli et al., 2003). An electrode with a cylindrical shape and annular contacts (Figure 17.22) is placed in the foramen and stimulates the spinal roots for treatment of bladder and bowel dys­ function (Janknegt et al., 2001; Gstaltner et al., 2008). To stimulate other superficial structures of the spinal cord within the vertebral bodies, the electrode can be advanced further into the epidural space in the spi­ nal column. This requires innovative design of the implant tools to penetrate to and through the verte­ bral foramen and then up the spinal canal.

III.  BIOMEDICAL ENGINEERING CONSIDERATIONS

design principles for neural interface electrode

207

Figure 17.21  Superficial/distal CNS electrodes. (A) Electrodes for stimulating and recording from the surface of the brain or spinal cord. Notice the similarity to epimysial electrodes. (B) Book electrode implanted for stimulation of the sacral roots for restoration of bladder and bowel function after spinal cord injury. Notice the similarity to nerve cuff electrodes (Part (A) courtesy of Ad-Tech Medical Instruments, Racine, WI)

Electrode contacts

Tines

Figure 17.22  Medtronic InterStim system for bladder and bowel control. Inset: Close up of electrode that is inserted into the foramen for stimulation of the sacral roots. Notice the tines to help with electrode fixation, similar to intramuscular electrode designs (Reprinted with the permission of Medtronic, Inc. © 2003)

Deeper CNS Structures Most of the CNS structures of interest, however, are much more complicated than the PNS structures and/or deeper within the CNS tissues. Effective inter­ faces to these regions require smaller, more invasive technologies. In the spinal cord, arrays of fine wires (Mushahwar et al., 2000; Saigal et al., 2004) and arrays of micromachined silicon electrodes (McCreery et al., 2004) have been inserted into the laminar layers of the gray matter (Figure 17.23). These electrodes are intended to interact with individual neurons and small populations of cell bodies. In penetrating the spinal cord, the elec­ trode must avoid the central canal and the dorsal and lateral vessels that provide perfusion to the spinal cord. Cortical interfaces only need to extend up to approximately 5 mm from the surface of the cortex to interact with columnar neuron structures. The basic

type of electrodes that have been developed (see Figure 17.24) include arrays of Tungsten microwire (approximately 25–150 m in diameter) (Williams et al., 1999), silicon arrays of multiple spikes with single recording sites on each spike (Utah array) (Campbell et al., 1991), silicon shanks with multiple contacts along the shank (Michigan probes) (Kipke et al., 2003), and glass cone electrodes that promote neural ingrowth (Kennedy, 1989). The Utah array, manufactured by Cyberkinetics, is undergoing human trials where the arrays have been implanted and able to record indi­ vidual neurons in three subjects, the longest for over a year. The cone electrode has also been implanted in several human subjects with locked-in syndrome to restore communication (Kennedy et al., 2000, 2004). When the objective of the cortical electrodes is to interact with individual neurons, it is especially

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208

17.  electrodes for the neural interface

L4 spinous process

Microwire array

Individual microwires inserted into cord Spinal roots

3 mm (A)

(B)

Figure 17.23  Penetrating electrodes for spinal cord stimulation. (A) Fine wires inserted into the cord. (B) An array of micromachined silicon electrodes (Part (A) modified with permission from Mushahwar et al. (2000), Copyright (2000) Elsevier. Part (B) reproduced from McCreery et al. (2004) by permission of Institute of Electronics and Electrical Engineers; © 2004, IEEE)

(A)

(B)

(C)

Figure 17.24  Cortical probes. (A) An array of microwires. (B) The Utah array with 100 shanks (10  10) with the contact located on the tip of the shank. (C) A Michigan probe. Each shank has multiple electrode sites. The two-dimensional probes can be assembled together to make a three dimensional array (Part (A) reprinted with permission from Williams et al. (1999), Copyright (1999) Elsevier. Part (B) courtesy of Cyberkinetics Inc., Foxborough, MA. Part (C) courtesy of NeuroNexus Technologies, Ann Arbor, MI)

important that the inflammatory response be control­ led. This is still one of the most significant difficulties in developing these interfaces. The materials, size, sur­ face chemistry, surface molecules, and pharmacologi­ cal adjuncts are all under investigation for controlling this response. These are discussed in other chapters of Neuromodulation. Deep Brain Stimulation (DBS) Finally, stimulation in the basal ganglia and other deep structures requires a different type of electrode. They are inserted deep into the cortex using stereotac­ tic techniques in combination with imaging. To accu­ rately place the electrodes, recordings are made during

the insertion. Clinical electrodes are typically 1–3 mm in diameter and rather large compared to the anatomi­ cal nucleus that they target (Figure 17.25A). An addi­ tional deep brain stimulating array has been developed using microelectrodes in an attempt to have greater control over the stimulation (McCreery, Lossinsky et al., 2006) (Figure 17.25). In the area surrounding the elec­ trodes, there are axons in the local nucleus as well as their cell bodies and dendrites. There are also axons passing by the electrode, transmitting signals between different regions of the brain. Analyzing the distribu­ tion of the electric fields generated from computer models can help to understand which element(s) are being affected by stimulation but this is still poorly understood. Modeling studies that take into account

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209

conclusion

lateral 13.5mm

TH GPe

epoxy cap

GPi

alignment cylinder

microelectrodes

STN

5 mm

SN (A)

5 mm

(B)

Figure 17.25  Deep brain stimulating electrodes. (A) Schematic of the Medtronic DBS electrode inserted into the subthalamic nucleus (STN). (B) The deep brain microelectrode array with 16 iridium shafts (Part (A) reprinted with permission from Elder et al. (2005), J Neurosci Methods, Copyright (2005) Elsevier. Part (B) from McCreery et al. (2006) by permission of Institute of Electronics and Electrical Engineers; © 2006, IEEE)

detailed brain anatomy (McIntyre et al., 2004; Butson and McIntyre, 2006; Miocinovic et al., 2006) and alter­ nate contact arrangements (Wei and Grill, 2005) are being developed to learn the mechanism of deep brain stimulation and determine clinically effective stimula­ tion parameters and electrode configurations.

Conclusion The electrode for the neural interface is a criti­ cal component of any neuromodulation system. Development of an effective electrode requires care­ ful consideration of all aspects of the neural anatomy, gross physiology, molecular physiology, and electro­ physiology. Electrodes that interface with large pop­ ulations of axons have been successfully developed and clinically deployed. These have provided signifi­ cant benefit to patients. As technology and our under­ standing of physiology advances, it is increasingly important to continue development of electrodes that can interface with individual neurons. This requires advanced development of materials and molecular level interfaces. Electrodes will progress from biocom­ patible to biointegrated.

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C H A P T E R

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Implantable Neural Stimulators P. Hunter Peckham and D. Michael Ackermann, Jr

o u t line Introduction

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Implantable Neural Stimulator Technology Physical Design and Materials for the Stimulator

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Sensors for Device Command and Closed-Loop Control

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Stimulating and Processing Circuitry

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The Power System

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References

INTRODUCTION

pacemaker (and arguably therefore the first implant­ able neurostimulator) was designed by Dr Rune Elmqvist and implanted on October 8, 1958 by Dr Ake Senning (Elmqvist and Senning, 1959; Ellenbogen et al., 2000). Advances in the understanding of disease pathology and the principles of neurostimulation, along with improvements in implantable technolo­ gies, have since led to highly reliable and specialized neurostimulators which provide restoration of func­ tion for a growing list of neurological diseases and disorders. The primary function of an implantable neuro­ stimulator is to activate or inhibit the nervous system to augment, improve or replace function lost to a neu­ rological disease or disorder. As described in detail in the “Fundamentals of Neuromodulation” section of this reference work, this modulation of neural activ­ ity occurs through the generation of appropriate elec­ tric fields within neural tissues. The neurostimulator

Implantable neurostimulators are the tools used by clinicians to execute the various and diverse neuro­ modulation therapies described in this textbook. Just as it is important for the engineers developing these stimulators to understand the diseases, ­ disorders or injuries the devices will treat, it is important for the clinician using them to understand how these devices operate, the tradeoffs involved in their design and the capabilities and limitations of the technology. Not only does this mutual understanding allow for proper neurostimulator design on the part of the engineer and optimal prescription and programming by the physician, but it also promotes a dialogue that results in further improvements and breakthroughs in tech­ nology and therapy. Implantable neurostimulators have their technical roots in cardiac pacing. The first implantable cardiac

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generates these fields through the application of pre­ scribed currents or voltages to electrodes in contact with the neural tissue. This chapter will describe major aspects of implant­ able neurostimulator technology, focusing on those elements that most impact clinical practice and device implementation. The topics that will be addressed include: physical design and materials for the stimula­ tor; the neural interface – electrodes and leads; stim­ ulation and processing circuitry; the power system; device communication and telemetry; and sensors for device command and closed-loop control.

Implantable neural stimulator technology Physical Design and Materials for the Stimulator The physical form of the neurostimulator is designed based on constraints, requirements, and ideals from both the engineering and clinical realms. The device design must balance the need for a biocom­ patible, hermetically sealed, and mechanically robust package that is capable of housing all of the stimula­ tor components and meeting the clinical demands for minimal invasiveness, conformation to anatomy, facil­ itation of surgical installment, and device cosmesis. Most implantable neurostimulators conform to a fundamental organization consisting of three primary components: a centralized implantable pulse genera­ tor (IPG), one or more leads and one or more elec­ trodes (for stimulating and possibly for recording). Some of the many commercially available stimulators conforming to this organizational paradigm include all commercial cardiac pacemakers and defibrilla­ tors, deep brain stimulators, spinal cord stimulators, and cochlear implants. The stimulator houses some or all of the stimulation circuitry (some devices may have external components), and the leads carry the stimulus current to the electrodes, which provide the electrochemical interface to the nervous system. A dis­ cussion of the leads and electrodes is left to the next section. Stimulator size can range from quite small (Nucleus 24 [Cochlear Ltd, Lane Cove, NSW, Australia] is approximately 6.9 mm thick  22 mm wide  50.5 mm long, with much of the length resulting from an exter­ nal inductive coil [Clark, 2003]) to relatively large (implantable defibrillators with a volume greater than 200 cm3 have been commercially deployed). The shape of the device will depend on where the device is to

be implanted. Most neurostimulators are implanted in a subclavicular pocket or in the abdomen and have a familiar flat, rounded shape. This flat shape is designed to minimize the device profile under the skin and is rounded to facilitate surgical insertion and to minimize tissue erosion at the implantation site. For devices that are implanted in locations other than the thoracic or abdominal regions, device shape and size can vary significantly to fit the anatomy relevant to the particular application. For example, cochlear implants must be small enough for implantation in the mastoid process of the temporal bone of the skull (and often have the telemetry/powering coil exter­ nal to the device can, which is located in a shallow sub­cutaneous pocket behind the ear). Another device exhibiting a conformational shape is the NeuroPace RNS stimulator (NeuroPace, Inc., Mountain View, CA), which is designed for intracranial implantation and therefore has a thin curved profile for conforma­ tion to the cortex. Notable exceptions to the centralized stimulator– lead–electrode design have been developed in response to particular application demands. The Alfred Mann Institute’s Bion (Advanced Bionics/ Boston Scientific, Valencia, CA), as shown in Figure 18.1d, is a single channel stimulator that is fully encapsulated in a glass or ceramic package and is small enough to be inserted via injection into a ­target muscle (for motor FES applications) or near to a target nerve (for applications such as stimulation for migraine headache [Rogers and Swidan, 2007] or uri­ nary applications [Grill et al., 2001]). The Cleveland Functional Electrical Stimulation (FES) Center (in conjunction with Case Western Reserve University, Cleveland, OH) is currently developing a distributed motor FES system (see Figure 18.1e for a model of the system in development) that consists of multiple stim­ ulating and recording modules networked together to form an intrabody network. This system is designed as such to provide a scalable and flexible neuropros­ thesis platform to meet the variable stimulation needs of those suffering from paralysis or paresis (Peckham et al., 2007). Retinal implants, which are working towards the restoration of visual function, also depart from the standard form (see Figure 18.1f), and are compact systems designed to be implanted onto the retinal surface within the eye (Humayun et al., 2003; Chow et al., 2004). A standard centralized stimulator consists of two major components: the hermetic package and ­interconnect header for connection of the leads to the stimulator. The primary function of the hermetic pack­ age is to keep bodily fluids from reaching the stimu­ lator circuitry and to prevent the body from being

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(a)

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(e)

(f)

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Figure 18.1  Images of various implantable neurostimulator designs: (a) Soletra, courtesy of Medtronic, Inc. (b) Case Western Reserve University IST-16. (c) Nucleus Freedom, courtesy of Cochlear Ltd. (d) Alfred Mann Institute RF Bion. (e) Scale models of remote modules and network cable for Case Western Reserve University Networked Neuroprosthesis. (f) Second Sight Argus 16 Retinal Stimulator, courtesy of Second Sight, Inc.

exposed to the potentially harmful chemicals present inside of the stimulator (especially those in the battery, if present, which is sealed in a redundant hermetic can of its own). Most IPG designs use titanium as the material of choice for the hermetic package. Titanium is used because of its biological inertness, very attrac­ tive strength properties, and light weight. There are several implantable grade titanium quali­ ties and alloys. Most devices use commercially pure titanium (e.g. grades 1, 2), although the increasing use of transcutaneous powering and recharge systems (see the section below on the power system) is making some of the more power-efficient alloys more attractive (e.g. grade 23). These alloys tend to be more mechani­ cally brittle than pure titanium, which translates into larger bend radius constraints for can molding, but results in less magnetic eddy current loss during induc­ tive power transfer. The increased ­ inductive ­ coupling afforded by these materials can translate into increased power efficiency, decreased device ­ heating or may permit deeper implantation depths. Other packaging approaches to maintaining power transfer efficiency include using more magnetically transparent packaging

material such as ceramic, or locating the powering coil external to the hermetic metal package using hermetic feedthroughs. For the latter, the coil and the package tend to be potted together in a biocompatible epoxy (e.g. Medtronic’s Mattrix stimulator (Medtronic, Inc., Minneapolis, MN) and the CWRU IRS (Case Western University, Cleveland, OH [Smith et al., 1987] and IST [Smith et al., 1988] motor FES systems) or plastic pol­ ymer (some cochlear implants). For systems imple­ menting monopolar stimulation, the titan­ium package (“can”) is often used as the return (common) anode. When this is the case, the stimulator can is often par­ tially coated with (or partially potted in) an insulat­ ing material to restrict return path current flow to a particular region of the case which will not be in con­ tact with electrically activatable tissue. This is done to prevent unintended activation of muscle (e.g. the pec­ toralis muscles if a subclavicular pocket is used) or sensory fibers (Smith et al., 1988; Medtronic, 2003). The conductors carrying the stimulation current are trans­ ferred through the hermetic metal can using glass or ceramic feedthroughs. These feedthroughs insulate the conductors from each other and from the conductive

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stimulator package and maintain the overall stimula­ tor hermeticity. On the external side of the feedthrough, the conductors either connect directly to permanently attached leads or pass into a header which contains connectors for (a) detachable lead(s) (the header is often cast biocompatible epoxy). The detachable lead(s) is (are) fixed into the connector either by set screws or spring locks. The design of the header and connec­ tor takes into account the fact that some assembly is required by the surgeon/implanter: connectors tend to be large for easy handling and orientation is designed to be unambiguous. Some devices also include radio­ paque markers in the header to facilitate post-implant identification using radiography. It is also of note that implantable stimulators, leads and electrodes can only be sterilized using chemical processes (e.g. ethylene oxide) due to the damaging moisture and high temper­ atures associated with autoclaving.

The neural interface: electrodes and leads The portion of the neurostimulator system that is external to the IPG is a solid, interconnected struc­ ture consisting of the connector(s), the lead(s) and the electrode(s). The basic function of these components is to provide an electrical pathway from the stimulator circuitry to the neural tissue being stimulated. Like the IPG unit, these external components are designed based on restraints and requirements from both the engineering and clinical realms. Functionally, these components must provide an isolated current path­ way (via the conductors), must enable adequate tissue activation and selectivity, must adequately conform to the anatomy and must maintain biocompatibility and reliability throughout the device lifetime. This chapter will refer to the lead as the insulated conductor(s) between the connector and the electrode. Many device manufacturers and clinicians refer to the lead (as it is used here) and the electrode collectively as the “lead.” The connector (aka pin) is usually the most proxi­ mal (to the IPG) of the external components, although some devices do not use a connector (in which case the lead is permanently connected to the IPG body). For most neurostimulators, the connector mates with the IPG header and is secured into place using set screws or a spring-lock mechanism. It should be noted that some stimulators have a short segment of lead permanently connected to the IPG, extending to a more distal mating connector for the lead. Several standard connectors exits, allowing for independ­ ent selection of the IPG and electrode style to match

the needs of a particular patient. Connectors can also simplify and reduce the impact of device replace­ ment procedures since the lead does not have to be removed. Proper installment of the lead connector into the header is incredibly important to the overall reliability of the neurostimulator, and an improper connection can result in high overall lead impedance and/or improper or ineffective stimulation. Several other types of connectors exist for some applications. For example, bifurcated connectors allow a single IPG output (usually voltage control­ led) to drive electrodes on two leads. Adapting con­ nectors, which convert one connector style to another, allow for the replacement of IPGs with expired batter­ ies while leaving previously implanted leads in place regardless of connector type. A specialized connector that is very clinically important is the percutaneous connector system. This system allows direct access to an implanted electrode lead by a device external to the body via a lead that spans the skin, enabling the patient and clinician to engage in a pre-implantation trial/screening period. This screening period allows the clinician and the patient to assess the effectiveness of the therapy before a complete implantation. This approach can allow for finer control of stimulation parameters and serves to reduce cost and invasiveness if it is decided that full implantation is not suitable. Therapies that sometimes utilize this approach include deep brain stimulation (DBS), spinal cord stimulation (SCS) for pain and motor functional electrical stimulation (FES) systems. Similarly, neuromodulation therapies often require intraoperative testing to ensure proper elec­ trode placement, which is often performed using an external stimulator setup similar to the percutaneous system. For example, patients receiving DBS systems for Parkinson’s symptoms are only kept under mild anesthesia while their systems are tested intraopera­ tively. The leads are connected to a hand-held external stimulator, and the patient is evaluated for both posi­ tive expressions of the stimulation (reduced rigidity, bradykinesia or tremor) and negative adverse effects (dystonia, alteration of the visual field) (Medtronic, 2006). The patient may also be asked to perform func­ tional tasks such as drinking from a cup to assess functional outcomes (Medtronic, 2006). The construction of the lead takes into account several factors, including material and mechanical integrity, the safety of the patient, electrical imped­ ance, reliability, and facilitation of surgical implan­ tation. The lead consists of one or more conductors and a material to insulate them from both the other conductors and from the harsh body environment. The arrangement of the conductors within the lead

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Stimulating and processing circuitry

can vary significantly, but will generally be one of several designs: a multi-lumen (side-by-side parallel conductors), coaxial (concentric conductors) or heli­ cal multi-filar design (the conductors are coiled into a long helix). Coiled conductors provide the advantage of reduced stress and torsion during tension, bending and twisting, thus reducing the likelihood of conduc­ tor fracture under these conditions. Multiple strands are sometimes used for each conductor, increasing overall mechanical flexibility and adding redundancy in the event of fracture (most lead fractures occur due to a subclavian crush-compression of the lead between the clavicle and the first rib) (Roelke et al., 1995) while maintaining a low lead impedance. The lead is also designed to facilitate surgical insertion, for example by incorporating elements to allow for insertion with a stylus (Memberg et al., 1989; Medtronic, 2006). Lead conductors must be corrosion-resistant to maintain integrity in the body environment, must have mechanical stability to withstand the twisting, tension and bending to which they are subjected, and must have a low electrical impedance to help ensure power efficiency. Most neurostimulator leads use com­ posite materials to achieve these properties. Drawnfilled tube (Medtronic, 2002) and drawn-brazed strand (Brown and Glaze, 1961; Fisher and Forman, 1967) filament assemblies are commonly used and combine a strong, corrosion-resistant material such as MP35N (a nickel alloy) or stainless steel with a highly con­ ductive core material (namely silver). Lead insulators are generally made of robust, biocompatible flexible polymers such as silicone rubbers or polyurethane. Biocompatible fluoropolymers (e.g. Teflon) are also sometimes used to coat individual filaments within a lead (Medtronic, 2006). Chapter 17, “Electrodes for the Neural Interface,” is devoted to the detailed discussion of electrodes, so they will only be briefly discussed here. The electrode is the interface between the rest of the neurostimulator and the nervous tissue. Its function is to provide suf­ ficient current to selectively activate or inactivate the target neural tissue with which it is interfaced. Charge can be delivered to the tissue through both capacitive and faradic mechanisms at the electrode. Unintended, nonreversible faradic reactions (or those that result in unrecoverable charge) can result in damage to the electrode or the generation of reactive species in the tissue. Reversible faradic reactions can be intended in the design of the electrode and allow for increased safe charge injection densities by providing the elec­ trode with a pseudocapacitive charge transfer ability. Various metals have been used for neurostimulation electrodes including gold, stainless steel, platinum, platinum–iridium and others. The metal chosen for

219

the electrode design is based on biocompatibility, the charge injection required and surface area constraints. The physical form of the electrode is designed to appropriately fit the target anatomy and to achieve the desired spatial activation and selectivity through its physical shape or electrode configuration (e.g. mul­ tiple contacts allowing for multipolar stimulation). Examples of various electrode forms include cylindri­ cal shaft DBS electrodes (Medtronic, 2006), electrodes designed to coil inside of the cochlea (Hansen and Lauridsen, 1981; Kuzma et al., 1996), cardiac pacing and defibrillation electrodes designed for transvenous insertion and anchoring in the atrium or ventricle (Fine and Calfee, 1990), peripheral/cranial nerve cuff electrodes (Bullara, 1986, 1990; Naples et al., 1988), SCS paddle electrodes (Holsheimer and Struijk, 1997; Feler, 2001) and intramuscular electrodes (Memberg et al., 1989). Some of these electrodes are depicted in Figure 18.2.

Stimulating and processing circuitry As described in more complete detail in Chapters 14–16, the stimulus timing, waveform shape, and elec­ trode polarity are of critical importance to the proper activation or inhibition of neural tissue. The stimula­ tion circuitry must be capable of generating the proper waveform on the proper channels with the proper timing for neuromodulation therapy to be effective. Figure 18.3 shows a standard biphasic stimulation waveform for the activation of neural tissue. During the first phase (the cathodic phase), charge is injected into the tis­ sue, activating nerve fibers (assuming the amplitude and pulse width are sufficient for activation). The sec­ ond phase (the anodic phase) does not play a role in tis­ sue excitation. It serves to discharge the capacitance (and possibly pseudocapacitance if an electrode that utilizes charge transfer-enhancing reversible faradic reactions is used), making the electrode potential more neutral and stopping potentially harmful faradic reac­ tions from occurring (e.g. generation of reactive spe­ cies) (Merrill et al., 2005). This waveform is applied to the neural interface (the electrode) and is generated by the stimulation output circuitry of the IPG. Two general classifications of stimulators are used for neurostimulation: voltage-controlled stimulators (which tend to be used in cardiac pacemakers and deep brain stimulators) and current-controlled stimulators (which tend to be used in cochlear implants and motor FES systems). Both types of stimulators output a waveform of similar shape, but current-controlled

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18.  Implantable Neural Stimulators (a)

(b)

(c)

(d)

(e)

(f)

Figure 18.2  Images of various electrode configurations: (a) Medtronic 3387, courtesy of Medtronic, Inc. (b) Contour Advance electrode, courtesy of Cochlear Ltd. (c) Enpath Medical, Inc. MyoPore bipolar epicardial pacing lead. (d) Cyberonics vagus nerve spiral electrode, cour­ tesy Cyberonics, Inc. (e) Lamitrode Tripole 16C spinal cord stimulation paddle lead, courtesy of St. Jude Medical’s neuromodulation division, Advanced Neuromodulation Systems. (f) Case Western Reserve University intramuscular electrode

stimulators output a current waveform with a shape similar to that in Figure 18.3, whereas ­ voltage­controlled stimulators output a voltage waveform with a shape similar to that in Figure 18.3. Each method has its own advantages and disadvantages, but both can effectively be used to excite neural tissue. Voltage-controlled stimulators can potentially have simpler circuitry, can be more power-efficient than current-controlled stimulators (due to the large compliance voltage that the current stimulators must generate) and are better understood than currentcontrolled stimulators by the clinical community (due to the widespread use of voltage-controlled stimulators in cardiac pacemakers and deep brain stimulators). The primary advantage current-controlled stimulators offer is direct control over current injection, the determi­ nant of neuronal membrane depolarization. Currentcontrolled stimulation produces an injected current that is not a function of the electrode or lead imped­ ance (i.e. will not drift provided the compliance volt­ age is sufficient) and provides increased consistency in therapeutic settings between individuals in clinical implementation. In voltage-controlled stimulation,

PW

Amp

T � 1/Freq.

Figure 18.3  Biphasic stimulus waveform

the delivered stimulus current wanes during the cathodic phase due to the charging of the electrode capacitance. This can result in a less predictable activa­ tion of the neural tissue due to the variable cathodic current pulse (Donaldson and Donaldson, 1986).

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The power system

Multichannel neurostimulation systems are of ­particular interest. When multiple electrodes are available, unique design configurations are possible. Multichannel sys­ tems can potentially implement multipolar stimulation paradigms (bipolar, tripolar, etc.). The simplest and most common of these is the bipolar configuration. In bipolar stimulation, current travels from one peripheral electrode to another peripheral electrode (in mono­polar stimulation there is a single return electrode, often the package (can) of the stimulator). Bipolar stimulation results in less current spread than monopolar stimu­ lation and therefore smaller, more selective activation areas (Rattay, 1989). This unfortunately comes at the expense of higher threshold currents, making bipo­ lar stimulation less power efficient than monopolar stimulation. Activation of multiple electrodes simultaneously with varied polarities is sometimes referred to as current steering and can be used to increase the selectiv­ ity of a given configuration of electrodes by activating tissue that could not be activated by driving the elec­ trodes independently (Veraart et al., 1993). Multipolar stimulation is commonly used in DBS, SCS, and coch­ lear implants. Another important aspect of some multi­ channel systems is their reconfigurability (the ability to assign polarities and stimulation parameters to indi­ vidual electrodes after implantation). Exact electrode placement is often difficult to achieve and can be com­ plicated by anatomical complexities, the deep nature of the target (e.g. DBS) or the fact that the target is dif­ fuse (e.g. SCS). Electrodes with multiple contacts and creative geometries aid in achieving functional out­ comes despite inexact electrode placement. For exam­ ple, Medtronic’s DBS electrodes (Medtronic Model 3387 and 3389) have four contacts, each of which can be configured to be an anode or cathode in a monopo­ lar or bipolar configuration. This provides for several candidate stimulation sites and configurations postimplantation, increasing the probability of achieving activation of the target location. The ability to assign electrode function has also resulted in improved func­ tional restoration for cochlear implants by reducing current spread and increasing the spatial selectivity of the cochlear electrodes (Clark, 2003). Similarly, for systems involving multiple discrete electrodes (e.g. motor FES systems), flexibility in electrode assign­ ment allows for simpler surgical installation since electrode function can be defined after implantation. Some multichannel systems utilize a time-division multiplexed output configuration, meaning that each stimulation channel is driven sequentially in time by a single stimulator output stage (or subsets of channels are driven sequentially by a single stimulator output stage). This technique serves to reduce the stimulator

circuitry required (only a single current or voltage reg­ ulator is needed), the instantaneous power demands of the IPG and the total instantaneous return current flowing back to the return electrode. Large return path currents can result in unintended activation of tissue and therefore unintended functional outcomes such as perceived volume changes in early cochlear implants (Wilson et al., 1988), and inappropriate muscle con­ tracture in motor FES systems. The drawback of multiplexed stimulation systems is that multi-contact current steering is not possible if a single stimulator is used. Another important aspect of implantable neuro­ stimulator circuitry is the implanted processing circuitry. Signal processing occurs by both analog and dig­ ital processing elements within the stimulator and is quite important for systems, which include integrated implanted or external sensors (see the section below on sensors for device command and closed-loop con­ trol for more detail on sensor types and their role in neuromodulation systems). Analog signal process­ ing usually involves amplification and filtering of a raw sensor output. If a biopotential is being moni­ tored, then special circuitry may be implemented to handle stimulus artifact and to mitigate the polariza­ tion of the sensing electrodes that can occur when the stimulator is operating. The analog signal is usually then digitized and further processed by an onboard ­microprocessor. Microprocessors are replacing discrete and application-specific logic to become common practice in stimulator design. Not only do they allow for the careful coordination and timing of events and make communication with external devices more straight-forward, but they also make possible the implementation of sensor data processing schemes and complex control algorithms.

The power system All implantable neurostimulators are active devices and therefore require a power source. Generally speaking, power is supplied to an IPG by a source that is either internal to the implantable device or external to the body. Internal power sources are bat­ teries (chemical energy storage devices), which can be further subdivided into primary (single use) and secondary (rechargeable) cells. The powering paradigm chosen for a particular neurostimulator depends on a number of factors, including the power requirements of the device (which is a function of the number of channels, the stimulating characteristics of each channel and other functions the device performs such as telem­ etry), physical constraints (device form factor, volume

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18.  Implantable Neural Stimulators

and mass constraints, etc.), the requirement of an end-of-lifetime indicator (particularly important for life-sustaining cardiac applications) and the intended longevity of the device (five years is a standard target, but commercial DBS IPGs have been shown to last as few as 3 years on average [Ondo et al., 2007]). Batteries convert chemical energy into electrical energy through reduction–oxidation (re-dox) reactions that occur among the materials within the battery. The energy from these reactions drives electrons through an external circuit (the stimulator), performing elec­ trical work. Batteries consist of three primary com­ ponents: the anode, the cathode, and the electrolyte. Oxidation occurs at the anode, generating electrons for the external circuit. Reduction occurs at the cath­ ode, where electrons are returned to the cell. The elec­ trolyte is a non-electrically conductive medium that allows ion exchange at the anode and cathode, per­ mitting the charged species generated in the re-dox reaction to be neutralized. The electrolyte is often inte­ grated into a mechanical separator, which serves to separate the anode and cathode, and can serve as a short-circuit safety feature (see below). The type of battery chemistry and construction used for a particu­ lar device will vary primarily based on the required energy capacity and the current the battery is expected to source. The maximum source current is limited by the equivalent source impedance of the battery. The source impedance can range from very low (a few Ohms) to quite high (multiple kOhms) depending on the battery chemistry, meaning the current a battery can source at a usable voltage also has a large range. The most appropriate battery chemistry for a given appli­ cation will depend on the particular current require­ ments for the application, which vary tremendously: cardiac pacing requires a very low average current of approximately 8–30 A, single channel DBS requires approximately 80 A to 1 mA and an implantable car­ dioverter defibrillator may require as much as several amps when charging its capacitor for defibrillation (Schmidt and Skarstad, 2001). This wide span of cur­ rent demands has resulted in a variety of battery chem­ istries that tend to be used for specific applications. Since primary cells must be replaced, they are used for applications that draw low to moderate aver­ age current. These cells have been the cornerstone of implantable power supplies for decades. They tend to have a charge density that is superior to that of sec­ ondary cells and have evolved to become quite reli­ able and predictable. Implantable primary cells use a lithium anode because of the high voltage, high energy density and stability the metal affords. Several common primary cell cathodes include I2, SVO, CFxSVO hybrid and SOCl2 (Auborn, 1975; Takeuchi

et al., 1988; Terry et al., 1991; Crespi, 1993; Weiss et al., 1993; Schmidt and Skarstad, 2001; Chen et al., 2006; Berberick et al., 2007). Table 18.1 lists each of these chemistries, their salient attributes, and some com­ mon applications for which they are used. Since these cells are a potentially hazardous component of the implanted device, they tend to exhibit safety features that protect against short-circuiting, leakage, and mechanical impact. A heat-sensitive material is often used to construct the battery separator. In the event of a device short-circuit, the high temperatures gener­ ated by the large currents melt the separator, prevent­ ing ion transfer and therefore disabling the barrier (preventing a potentially hazardous condition for the patient) (Hasegawa and Kondo, 2000). The use of rechargeable secondary cells in neuro­ stimulators is on the rise because of increasing stimula­ tor power requirements and advances in lithium-ion technologies. While the use of secondary cells is becom­ ing more frequent, primary cells are still more commonly found in commercial devices than secondary cells due to their higher energy density, established implementation and lack of required patient responsibility. Implantable secondary cells are recharged via an inductive recharg­ ing system, tend to use lithium-ion chemistries and are used for ­ applications consuming moderate to large amounts of current (e.g. FES, SCS, etc.). Lithium-ion cells are very attractive for implantable applications because they exhibit a high voltage, have high-energy densities (relative to other rechargeable technologies), have mini­ mal self-discharge, allow for large brief current draws and maintain significant capacity over a long cycle and calendar life (thousands of cycles or 10 years) (Dodd et al., 2004). Table 18. lists approximate operating charac­ teristics for lithium-ion cells. Care must be taken when operating devices using these cells to ensure safe operation and retention of cycle capacity. Improper or suboptimal cycling, such as a deep low-voltage discharge (caused by over discharge by the patient) can severely reduce energy capacity (Kishiyama et al., 2003). The recently developed Zero Volt (Quallion, Inc., Sylmar, CA) implantable cells (currently used in the Boston Scientific Precision SCS device [Boston Scientific Neuromodulation, Valencia, CA]) alleviate some of these deep discharge effects, allowing for less restrictive device usage patterns (Kishiyama et al., 2003). Several SCS and FES systems that are commercially available or that are in devel­ opment utilize lithium-ion technology, including the Medtronic Restore, the Boston Scientific Precision SCS, the NDI Medical Micropulse (NDI Medical, Cleveland, OH) and the Alfred Mann Institute Bion (Boston Scientific Neuromodulation, Valencia, CA). Discharge characteristics for 3000 discharge cycles of a 200 mAhr

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223

Device communication and telemetry

Table 18.1  List of battery chemistries, their salient attributes and common applications for which they are used Chemistry

Approx. voltage (with load)

Cycle life

Approx. max current

Approx. energy density

Applications

Li/I2

2.5–3.1 V

1

70 A

0.4–0.9 Wh/cm3

Pacemakers

Li/SVO

2.5–3.3 V

1

Several Amps

0.3–0.75 Wh/cm3

ICD

Li/CFx-SVO

3.0 V

1

1 mA

0.55–1.0 Wh/cm3

Cardiac apps

Li/SOCl2

3.5 V

1

Several mAs

1.1 Wh/cm3

DBS, SCS

Li Ion

3.3–3.7 V

1000s

3

50–200 mA

0.2 Wh/cm

SCS, FES

Source: Auborn, 1975; Berberick et al., 2007; Chen et al., 2006; Crespi, 1993; Schmidt and Skarstad, 2001; Takeuchi et al., 1988; Terry et al., 1991; Weiss et al., 1993

4.0

0.25

3.5 0.2

3.0 2.5

0.15

2.0 0.1

1.5 EODV Discharge capacity

1.0

0.05

Discharge capacity (Ahr)

End of discharge voltage (V)

implantable Quallion QL0200I-A cell operating at 37 °C are shown in Figure 18.4. The device is operating at 80% depth of discharge (160 mAhr) until the end of dis­ charge voltage declines to 2.5 V, at which point the dis­ charge capacity is voltage limited and declines. Even after 3000 cycles (more than eight years of once-daily charging/discharging), the battery maintains half of its original capacity (Note: this does not account for an eight-year calendar life decay). If the power requirements for an implantable neu­ rostimulator are high, or if the space into which they are being implanted is small, power can be supplied to the system via an external power source. The most common and almost exclusively used method for transferring power across the skin is inductive radio­ frequency (RF) coupling. Inductive powering relies on the coupling of a magnetic field from an external coil to one implanted in the body (Ko et al., 1977). Given that these powering systems require an external bat­ tery which must be recharged or replaced on a regular basis, they are likely not appropriate for life-sustaining implants such as cardiac pacemakers and defibrilla­ tors. Many commercial and research neurostimulation systems utilize inductive powering, including all major cochlear implants, the Medtronic Mattrix stimulator and the Advanced Neuromodulation Systems Renew stimulator (St. Jude Neuromodulation, Plano, Texas). This powering method also provides a ­ convenient means for telemetry in systems requiring a continuous external control signal (e.g. cochlear implants). Other powering methods have also been explored, including the use of nuclear powered cells and sys­ tems that “harvest” power from the body. Nuclear cells provide incredibly long battery lifetimes (dec­ ades), but only enjoyed short commercial success, in part due to a lack of patient acceptance, the success of lithium technologies and the need to track the radioac­ tive material (Parsonnet et al., 2006). Power harvesting methods such as using body heat (Weijand et al., 2002)

0.5 0

0

500

1000

1500 2000 Cycles

2500

0 3000

Figure 18.4  End of discharge voltage and discharge capacity of a 200 mAhr Quallion QL0200I-A implantable Li-ion cell operat­ ing at 37 °C over 3000 cycles

or muscular contraction (Lewandowski et al., 2007) to provide energy to an implantable device have also been explored, but have not yet proved to be practical enough for commercial implementation.

Device communication and telemetry Communication with implantable neurostimula­ tors is imperative to modern device programming, patient follow-up, device monitoring and for some devices, real-time stimulator control. While percutane­ ous wires and connectors are currently being used by several neural interfacing systems (e.g. the Synapse Biomedical NeuRx Diaphragm Pacing System [Synapse Biomedical, Oberlin, OH] and the Cyberkinetics Brain Gate system [Cyberkinetics, Inc., Foxborough, MA]) and have been shown to have low rates of infection

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224

18.  Implantable Neural Stimulators

and failure (Knutson et al., 2002), device cosmesis, patient acceptance and patient comfort drive a stimu­ lator design that does not span the skin. There are sev­ eral means of wirelessly transferring data to and from an implanted device, including the use of ultrasonic waves (Gheewala et al., 1975), RF inductive-coupled links (Smith et al., 1998; Ghovanloo and Najafi, 2004), RF antenna-coupled links (Mohseni et al., 2005; Neihart and Harrison, 2004) and optical links (Ackermann, 2007). Inductive and RF antenna-coupled links are the most commonly used modalities and are appropriate for low to moderate data rate applications. Inductive communication links are almost ubiqui­ tous in the implantable device landscape and have been used for many years to program and interrogate IPGs in the clinic and to provide continuous real-time control signals to some devices. These systems utilize two coils (one external and one internal coil) to transmit informa­ tion to and from the implanted device. The transmit­ ting coil produces a magnetic field that is modulated based on the data being transmitted, and a result­ ing current is generated and detected in the receiv­ ing coil. Because of the rapid falloff of the magnetic field with distance, these systems require an intimate connection of the external coil with the skin. Systems that rely on an inductive communication link for realtime control signals from external hardware often also receive power over the same link. For example, cochlear implants require constant control signal updates to provide real-time sound cues and thus tend to use inductive communication and powering links (e.g. the Cochlear Nucleus systems), the MED-EL Maestro series (Medel, Corp., Innsbruck, Austria) and the Advanced Bionics Harmony HiResolution system (Advanced Bionics, Sylmar, CA). In addition to coch­ lear implants, motor FES systems such as the CWRU implantable stimulator-telemeter series (CWRU, Cleveland, OH) (Smith et al., 1988) and the original Alfred Mann Institute RF Bion, and retinal prostheses (Weiland et al., 2005) also utilize inductive links for real-time control signals and power. The use of antenna-coupled radio telemetry for communication with implantable stimulators is on the rise. These systems allow for wireless communica­ tion for up to several meters separation between the implant and the transceiver base. The adoption of this technology has been encouraged by the advent of the Medical Implant Communications Service (MICS) band by the Federal Communications Commission, FCC, in 1999. This unlicensed band (402–405 MHz) is dedi­ cated for data communication relating to therapeutic or diagnostic communication with implanted medi­ cal devices (Federal Communications Commission, 2007). Current applications include devices such as

the Medtronic Concerto CRT-D and Virtuoso ICDs (in conjunction with the Carelink Network), which uti­ lize a MICS wireless communication system to enable automatic wireless patient follow-up while the user is at home. Additionally, work is under way to coordi­ nate an antenna-coupled wireless network of Alfred Mann Institute Bion neuromuscular stimulators into a complete FES system (Schulman et al., 2004). At the time this chapter was written, the adoption of an expansion to MICS, the new Medical Data Service, MEDS, bands (401–402 MHz and 405–406 MHz) was pending formal European approval and under consid­ eration in the USA. The dedication of this additional portion of the radio spectrum to medical device com­ munication promises to catalyze the development of devices for body-area networks (primarily for external devices) and will likely further enhance the functional­ ity of devices such as implanted neurostimulators. As IPGs become more complex and integrated with other devices (implanted and external to the body), wireless communications will become increasingly important.

Sensors for device command and closed-loop control Sensors have been developed to measure, monitor, and respond to many of the human body’s most basic and complex signals and processes. Some of these sen­ sors have been integrated into neurostimulation sys­ tems as command sources, sensors for implementing closed-loop control systems, and chronic patient moni­ toring systems. Sensors can be categorized by their modality, and include electrophysiological sensors, force transducers, chemical sensors, and others. Most sensors in use in neurostimulators today are electrophysiologi­ cal sensors or force transducers. The majority tend to be found in cardiac rhythm management devices, but sens­ ing technologies promise to play a major role in other applications as the field of neuromodulation matures. Electrophysiological sensors measure potential dif­ ferences in the body that are generated by muscles, neural tissue or the stimulator itself. These biopoten­ tials allow a window into the body’s own electrical system and can be very powerful tools for the com­ mand and control of neurostimulators. For example, the use of electrophysiological signals for the control and programming of cardiac pacers has become the clinical standard. One very common electrophysiologi­ cal sensor is the use of a cardiac pacing lead to monitor thoracic impedance as an estimate of minute ventila­ tion for closed-loop, rate-adaptive pacing (Simmons et al., 1986). This feedback allows for closed-loop control

III. BIOMEDICAL ENGINEERING CONSIDERATIONS



Future directions in implantable neurostimulator technology

of the pacing frequency based on an estimate of meta­ bolic demands. Lead impedance measurements are also used to assess the integrity of the lead and elec­ trode in many neurostimulation systems. Similarly, ventricular pacing lead impedance has been proposed as a measure of stroke volume for rate-adaptive pac­ ing (Khoury, 1989). The QT interval (the time between the pacing stimulus and the T wave) can also be used as a measure of appropriate pacing frequency for rate-adaptive pacing (Rickards, 1981). Other cardiac applications utilize an internally measured cardiac electrogram, EGM. These applications include the detection of ventricular capture (allowing stimulation currents to track threshold values, extending implant­ able battery life) (Sermasi et al., 1996), measuring the cardiac EGM for chronic cardiac monitoring (avail­ able on many commercial pacemakers), monitoring for atrial tachyarrhythmia and monitoring for ven­ tricular fibrillation. Other stimulator systems also use biopotentials as a command or feedback source, including the use of myoelectric signals of voluntary muscles as a command source for a motor FES system, and ­ electrocorticographic (ECog) activity for seizure detection and subsequent stimulation for prevention of epileptic seizures (the NeuroPace RNS System). At the time this chapter was written, a system is being developed by Case Western Reserve University and Cyberkinetics, Inc. that will use microelectrode record­ ings from the motor cortex (Hochberg et al., 2006) as a command source to control a hand grasp FES system (Smith et al., 1998). Peripheral electroneurogram, ENG, measurements have also been used for neurostimula­ tor control. For example, slip-induced neural activity in the volar digital nerve has been used for closedloop control of lateral hand grasp in a motor FES system, increasing grasp force when the object being held began to slip (Haugland et al., 1999). Given the recent advances in Micro-Electromechanical systems (MEMS) sensor technology and the burgeoning nature of the neurointerfacing field, biopotential sensing promises to play an ever-increasing role in the com­ mand and control of implantable neurostimulators. Force and pressure transducers are also in wide­ spread use in implantable neurostimulators. As with biopotential sensing devices, cardiac pacers equipped with force transducers are becoming the clinical stand­ ard of care. Many pacing devices now come equipped with piezoelectric pressure sensors or onboard accel­ erometers that provide the implanted device with a measure of the user’s activity level for implement­ ing rate-adaptive pacing (Dahl, 1979; Anderson and Brumwell, 1984; Benditt et al., 1987). Implantable accelerometers are also being investigated for the development of a completely implanted cochlear

225

prosthesis, where accelerometers would be attached to the ossicular chain in the middle ear for transduction of sound pressure waves (Zurcher et al., 2006) and for limb position detection for closed-loop motor FES sys­ tems (Tan et al., 2004; Zou et al., 2004). Chemical sensors are also being investigated for use with implantable neurostimulators, but have not yet seen widespread clinical implementation. Implantable pH sensors (Cammilli, 1989) and venous oxygen saturation sensors (Wirtzfeld et al., 1982) have been investigated for rate-adaptive cardiac pacing feedback. Implantable sensors for the detection of neuroactive chemicals are also under development and may eventually play a role in providing feedback for stimulation systems for treating diseases such as Parkinson’s disease and epilepsy (Naware et al., 2003; Johnson et al., 2003; Murari et al., 2005). A major issue facing implantable chemical sensors is their long-term stability and reliability. Other implantable sensors include magnetic field detectors for the reconstruction of limb orientation (Bhadra et al., 2002; Tan et al., 2004), magnetic reed switches for stimulator mode switching (common to most implantable stimulators), and implantable tem­ perature sensors (implemented in the Cleveland FES Center/CWRU Networked Neuroprosthesis). Implantable sensors have become an integral part of neurostimulator function and will become more so as sensor technologies mature. For this to happen, sen­ sors need to be developed that (1) effectively measure a relevant physiological parameter, (2) maintain spe­ cificity to the desired measure, (3) provide consistent, stable, and robust measurements, and (4) maintain simplicity of implementation and signal processing (for example, Leung, Lau and Camm mention in Ellenbogen et al. (2000) that as of the year 2000, no car­ diac pacer requiring a non-standard pacing lead had survived in the commercial clinical environment due to sensor instability). It should be noted that external sensors can also be an integral part of a neurostimulation system. Sensors such as microphones for cochlear implants, cameras for visual prosthetics and joysticks and switches for motor FES systems have long been important to the control of implantable neurostimulator output.

Future directions in implantable neurostimulator technology Implantable neurostimulator technology has emerged from its infancy as a proven technology and

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18.  Implantable Neural Stimulators

is entering a phase where new developments and paradigm shifts will be driven by clinical treatment demands and new research horizons. Areas where technological developments could make the largest functional and clinical impacts include the improve­ ment of electrode technologies, the development and improvement of sensors to allow for closed-loop neu­ rostimulator control, and the integration of wired and wireless communication technologies for the imple­ mentation of implanted intra-body networks and external body area networks. Improving electrode technology perhaps has the most potential to provide improved functionality for neuromodulation therapies. The ability to interface with smaller populations of neurons (or even sin­ gle cells) would allow for low-level control of neural tissue. This could add functionality to existing and evolving therapies such as improving control and acuity in DBS, motor, cochlear and retinal implants, and could make possible new neuroprostheses for applications such as restoration of lost cognitive func­ tion where more precise neural interaction will likely be necessary. Electrodes that allow for stimulation paradigms such as current steering will also help to improve selectivity and specificity. Improved record­ ing electrode technologies could provide similar bene­ fits, particularly for applications involving closed-loop stimulator control and cortical prosthetics. With the exception of the cardiac applications, neuromodulation systems have largely been without sensor feedback and have thus been under open-loop control. Measuring signals that are correlated to func­ tional outcomes and adjusting stimulation parameters based on these measurements would represent a para­ digm shift in treatment that could mean improved functional benefit and improved power efficiency for current applications. Additionally, communication technologies are already beginning to and promise to continue to make major impacts on device functionality and clinical care. Intra-body and body area networks will allow for the integration of implanted stimulators, internal and external sensors, and programming and moni­ toring systems. These technologies not only promise to improve device function, but may transform clini­ cal management of implantable devices by allowing remote patient monitoring and device management. Other areas where technological development has substantial potential to make impacts include device programming paradigms, clinical device interfaces, reductions in surgical invasiveness and complexity, improved power systems allowing for decreased size, increased device longevity, and improved device form and packaging.

The field of neuromodulation is exploding. Clinical demands will continue to drive technological devel­ opment, and likewise, new technologies will continue to expand the horizon for functional restoration and disease management through neuromodulation. The future is bright.

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Designing a Neural Interface System to Restore Mobility John P. Donoghue and Leigh R. Hochberg

o u t line Neural Interface Systems for Persons with Impaired Mobility Causes of Motor Impairment Definition of a Direct NI System to Restore   Communication and Control Terminology Basic Requirements for Sensing Neural Interface Systems Use of Control Signals for AT System Demands Signals for Neural Interface Systems Sources of Movement Signals

Sensors Future Sensors Decoding Decoding Spiking Patterns Decoding FPs Shortcomings of Decoding

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Application of Integrated NI Systems Extending NI to Muscle Control Future of Neural Interface Technology

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system disease. Neurotechnologies produced so far have largely focused on creating systems to inject signals into the nervous system, mainly by applying voltages across neural tissues to influence neural activity. Another form of neurotechnology is evolving from technology that can sense neural activity to read out brain states or to provide command signals that could restore the ability to interact with the world in paralysis. Neural interface (NI) systems that can sense neural activity are integrally linked to neuromodulation systems, but sensing NI systems are at a comparatively earlier stage of development. For example, there are currently no commercially available systems, which is one hallmark of a successful system. However, ongoing pilot human trials indicate that NI systems that

Neural interface systems for persons with impaired mobility The neuromodulation field has now created very successful neural interface technologies that are designed to restore lost or disordered functions of the nervous system. Examples of important technologies now available for human application include the cochlear implant or the deep brain stimulator for movement disorders. The fact that these technologies have been implanted in more than one hundred thousand people and have been shown to last for years, with relatively few complications, demonstrates that neural interfaces have important and promising applications in nervous

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record signals related to neural function, as well as those that combine sensing and stimulating systems, will become available. A sensing NI system is one that can extract information from neural tissue, usually by detecting electrical signals produced by neurons. The information carried in these signals can be used to evaluate the state of the nervous system (e.g., as a monitor or diagnostic aid) or as a command signal to carry movement intent when connections to the body are lost, as in spinal cord injury, motor neuron disease, or limb loss. NI systems can be divided in a number of ways based on the type of sensor used, the targeted signals, and system goals. This chapter focuses on sensing NI systems intended to restore communication and mobility (as opposed to epilepsy monitoring systems, another important sensing NI system, discussed in Chapter 53). In addition, this review identifies systems by the type of signal used: direct, one that is linked to the actual movement intended, and surrogate or indirect, one that substitutes a remaining neural signal related to some other function for the desired action. As will be discussed below, these two types of NI systems largely rely on different types of brain electrical signals. Surrogate systems rely either (1) on a learned association between desired actions and brain signals indirectly or not at all linked to the desired movement, or (2) on stereotyped evoked brain responses to stimuli. Surrogate neural signals may be cognitive, perceptual or sensory. In a sense these systems are in a class similar to assistive technologies for those with limited movement that substitute muscle actions of one body part for those that ordinarily provide control. For example, when the tongue is arbitrarily mapped onto the desired action of a paralyzed body part, such as the hand, for mouse control. However, in the case of a surrogate NI, the signal is derived from brain signals – for example, one might learn to associate the thought of a restful scene to the suppression of a signal that is coupled to the upward motion of a cursor. A second type of surrogate system maps evoked signals in the brain, not necessarily under control, to a desired function. Brain potentials evoked by novel stimuli can be used to select images of interest. The P300 system (Birbaumer et al., 2006), is the most widely studied example of this type of surrogate system. In one implementation, one pays attention to a desired character amongst a matrix of characters and the form of a natural evoked wave at about 300 ms after the flashed stimulus is used to extract user selection of that letter. By contrast, a direct neural interface is one in which the system attempts to reconnect the brain’s own neural signal for a particular movement, such as positioning of a computer mouse with the hand, to that operation (Figure 19.1).

Neural interface system

Brain

Muscles

Action

• Computer • Assistive technology • Robot • Artificial limb • Muscles

Figure 19.1  General form of a neural interface system to return neural control signals. In disorders that disconnect a functional brain from the external world, an NI system aims to provide neural signals to assistive technologies to provide useful actions that restore independence and control. These technologies could include computers or other devices that can be operated through a computer, assistive robots, prosthetic limbs, or in certain cases could drive FES systems to reanimate paralyzed muscles. The goal of a direct interface is to sense those neural signals that actually generate movements of the effectors that would produce desired actions (e.g. point and click actions by using a computer mouse with the hand) and decode them into meaningful control signals. The system must not only make sense of these signals, but also compensate for what is likely a small sample from the target structure and must make up for the parts of the nervous system that are not able to contribute normally to movement, such as spinal cord reflex circuits in the case of SCI. Note that all system arrows are bi-directional, indicating that feedback of various types would be useful to optimize control

The hope of the latter NI system is to provide an interface that is as natural and simple to use as the actual missing action because it relies on the brain’s own mechanisms to produce this action. The promise for such direct systems is the potential to derive all of the missing actions from their source and to not interfere with other natural activity, such as speech, which can be a pitfall of surrogate systems. While both direct and surrogate systems have important potential utility for persons with movement limitations, the present chapter is largely restricted to a review and evaluation of direct systems. Many comprehensive recent reviews of surrogate systems that explain their current state and utility are available (see, e.g., Wolpaw et al., 2002; Pfurtscheller and Neuper, 2006; Birbaumer and Cohen, 2007; Wolpaw, 2007). It is also important to note here that one can divide systems in many other ways, such as degree of invasiveness, type of potential, etc. The two systems share many design features and issues as well as a common goal to help those with paralysis regain independence and control. The direct-surrogate dichotomy is introduced here to restrict this review to a more substantive discussion of the significant

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Neural interface systems for persons with impaired mobility

emerging body of work designed to recouple the motor system to effectors to provide control that will lead to reanimation of the muscles.

Causes of Motor Impairment Direct NI systems have as a goal to relieve the limitations of paralysis caused by mechanisms that leave a source of movement commands in the brain intact. Damage and disease of the brain stem, spinal cord, nerve or muscle cause paralysis by disconnecting the brain from lower motor pathways, such as the spinal motor neurons, or effector structures (i.e. the muscles). Although cerebral movement control areas remain intact, each of these conditions limits the ability to issue motor commands to the muscles, thereby preventing or restricting the normal repertoire of movements. As one example, cervical spinal cord injury (SCI) produces tetraplegia by damaging corticospinal and other descending motor pathways that provide volitional movement signals from the brain to the spinal cord for limb and trunk control, while cerebral structures to plan or initiate movement remain. Note that SCI leads to direct damage of the axons of corticospinal neurons in the corticospinal tract, and thus is not without direct effect on motor cortex neurons. In another example, death of spinal motor neurons in amyotrophic lateral sclerosis (ALS) and other similar neurodegenerative disorders also prevent motor commands from reaching the muscles by destroying the spinal targets of corticospinal neurons as well as affecting cortical neurons directly. Other disorders such as cerebral palsy, subcortical stroke, or muscular dystrophy severely restrict normal movement by cutting descending cerebral motor pathways, although apparently without major compromise of cortical motor structures. Finally, limb loss (due to trauma or vascular or infection disease) can also be considered in the realm of this set of motor dysfunctions because cerebral movement structures remain, but movement commands cannot be implemented by the missing effector. A direct sensing NI system is intended to re-establish communication between CNS motor command structures and actuators that can perform useful function in any of these sources of paralysis.

Definition of a Direct NI System to Restore Communication and Control In its most general and ideal sense, the goal of an NI that provides a movement-based output is to detect the intention to carry out an action and to deliver this as a

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reliable, stable, and flexible command signal to assistive technologies or extant muscles to perform any lost actions without markedly disrupting other functions. Thus, the ideal NI system would allow a person with paralysis (or limb loss) to type while talking as effortlessly as an able-bodied person. Of course, it is likely that initially realizable systems may have much more modest capabilities but even simple actions could nevertheless be of great aid to those lacking useful muscle control. Assistive technologies (AT) can include any device that provides a useful function. Actuators can be external artificial devices to replace a missing function, as simple as the finger movement required to press an emergency call switch or as complex as a robotic assistant that can provide a drink of water or a prosthetic limb that can be used to type. Computers can also be considered as an AT because they are both a tool to interact with the world and a means to connect to nearly any other device that can be controlled by electrical commands. Many of these functions might be achieved by either a direct or surrogate system, although at the cost of interfering with some other function. Most relevant here is the potential for a direct NI system to restore volitional movement by reconnecting neural commands to the muscles themselves. In this case the NI becomes a new physical bridge from the brain to the skeletal motor system or to visceral functions, such as bowel and bladder control. One advantage of a direct NI system is that it could extract signals from topographically distinct neural centers already designed to control the range of neural functions, such as the separate cortical regions for control of left and right leg or the left and right arm. Since these are used independently by the nervous system, they could potentially be accessed separately by NI systems, although this remains to be demonstrated.

Terminology Various terms are used to describe NI systems, including a brain–machine interface (BMI), because the system could connect the brain directly to assistive machines, or a brain–computer interface (BCI), if neural signals are used to operate a computer. BCI has been used to refer to EEG- and ECoG- (see below) based systems, but this limited definition is not formally acknowledged. The term neuromotor prosthesis (NMP) has also been used for this technology to capture the concept of providing a replacement part for movement. The fundamental basis captured by all of these terms is a system that incorporates an interface that senses neural signals, hence we use a more general term – sensing neural interface system – to encompass all such devices.

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Basic requirements for sensing neural interface systems All NI systems, including both direct and surrogate systems, face a similar set of design issues: sense, decode, control (Lebedev and Nicolelis, 2006; Donoghue et al., 2007; Wolpaw, 2007). The goal of the first two steps is to record and transmit a signal that provides useful commands, whereas the control step uses the command signal to effect some desired action through an AT or biological system. Sensing and decoding are currently particularly challenging stages of developing systems because control of any physical or biological system requires a reliable, stable detection interface between a very complex biological signal generator, the brain, and an understanding of its operation well enough to interpret its activity. Sensing is the means of acquiring a neural signal that can be used, for example, for volitional control of an external device via a direct link from the brain, bypassing usual neural and muscular output channels. For sensing, it is necessary to define the type of signal desired, the source or location(s) of that signal in the nervous system, and the type of sensor that is needed to reliably detect that signal over time. Typically, neural electrical signals are the desired source of information, but blood flow, chemical, metabolic or other forms of information representation might also be used (Coyle et al., 2007; Sitaram, Caria et al., 2007; Sitaram, Zhang et al., 2007). At present all but electrical signals lack a sufficiently small sensor, ease of detection, or speed for near-term everyday use for persons with movement limitations. Even for electrical signals there are unsolved challenges to obtain long-term, reliable, and stable electrical signals. Once signals are obtained, the system must decode neural activity into a useful command signal. Decoding is based on algorithms that attempt to extract information related to desired movement from neural signals, it may also perform functions that make up for parts of the nervous system that no longer interact with the neural commands (such as sensory feedback signals). Algorithms are typically based on assumptions of the properties of the signal, such as linearity of responses, and the nature of the underlying signal process. There are fundamental and often unanswered questions of neurophysiology, so that all decoding is based upon at least partially incomplete knowledge. Selection of sensor and decoder are made to provide the most reliable output, the largest number of independent control dimensions, and a speed that ideally compares to biological movement. Both are major areas of active research (Donoghue, 2008).

Use of Control Signals for AT The final element of any NI system, control, is to provide an effective coupling of commands to an AT or to muscles, each of which may make special demands of the control signal. That is, we may not be able to achieve all the richness that is available in the intact motor structure, so we must map a reduced set of dimensions onto the demands or the AT. This compromise will diminish flexibility and limits NI overall usefulness. However, it is important to recognize that humans can achieve many tasks even with a very restricted set of control signals, as has been demonstrated with the skills that can be achieved with functional electrical stimulation (FES) systems or with simple prosthetic limbs. A control signal should be able to direct meaningful functions. Importantly, a range of ATs are already available to carry out actions based upon signals that could be generated from effective sensor-decoder systems. Computers provide a straightforward and flexible tool both as an AT itself or as a gateway to other ATs. An NI often aims to replicate hand actions to accomplish cursor motion. A control signal that allows click and typing features of a mouse and keyboard can allow full control of a computer as well as control of any other technology that can be coupled to a computer, such as switches or electronic controls like a TV remote. The dynamics of complex devices such as robotic limbs or wheelchairs present additional control difficulties that could require special adaptive control, user learning, or other modifications, especially to ensure safety. While not considered in detail here, feedback is essential for effective operation in unpredictable environments, which is the norm in the real world. In current operation, vision is used to close the control loop but systems are likely to incorporate somatic sensory feedback through electrical stimulation of the CNS or through activation of intact sensory systems to enhance control. System Demands A useful NI system for people with mobility and communication impairments will require that the system meet a number of other conditions. It should allow the user to perform functions that are presently difficult, including the rapid control over one’s immediate environment. Actions should be performed without interfering with other ordinary extant actions such as gaze, speech, or attention beyond what happens in able-bodied people. Ideally an NI system would be always on when needed (i.e., not require the assistance of a caregiver), be cosmetically acceptable, and be as

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Basic requirements for sensing neural interface systems

reliable, fast, and accurate as the intact motor systems. A long-term, and possibly fanciful vision would be to restore all neuromuscular capabilities, ranging from volitional control of micturition to dextrous manipulation. However, in its initial application, a NI system that meets only a few of these specifications could be very valuable for those who otherwise require the assistance of others for activities of daily living. Signals for Neural Interface Systems Selecting and extracting signals for movement commands relies heavily on an imperfect knowledge of neural function. The nervous system generates two broad classes of electrical potentials that carry information: action potentials, or “spikes”, and field potentials (FP), which have complex and uncertain relationships to each other (Belitski et al., 2008) and to underlying information about sensation, perception, cognition, and movement. Action Potentials as NI Signals Spikes are widely held to form the major neuron to neuron information coding mechanism in the nervous system (Stevens and Zador, 1995). There are notable examples of non-spiking communication, as in the retina, that are likely to operate widely as well, but are not of direct relevance for NI systems at present. Most CNS neurons generate a 1 ms long spike at rates in the range of 1 up to about 300 impulses per second. Spike sensing in vivo requires a microelectrode in which a small recording surface (typically the tip of a fine conductor) is placed near a neuron; elongated neurons with strong dipoles such as cerebral pyramidal cells produce the largest and easiest to record spikes. Spikes from a particular cell usually require the electrode tip to be within a few tens of microns of the soma (Buzsáki, 2004). Spike rates carry information typically measured as the number of spikes within a defined interval (e.g., count in a 50 msec bin). Other aspects of spiking such as relative timing across cells or instantaneous firing frequency may carry additional information (Maynard et al., 1999; Grammont and Riehle, 2003). It has been firmly established that spike rate in motor cortical areas modulates in conjunction with various aspects of movement, such as hand position, speed, direction, force or motor plan. These movement correlates are potential command signal sources, but it is important to acknowledge that the relationship of these correlates to a true movement “code” has not been established. Further, additional fundamental understanding of coded movement variables from on-going basic science research as well as human clinical

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trials will enhance the ability to extract greater information with more reliability from neurons. Averaging across many neurons (or combining activity in other ways), a form of “population code” is used to overcome unknown sources of variance in neural spiking and to detect higher-order patterns that may carry additional information. It has been surprisingly straightforward to extract information about hand movement from population activity in motor areas because spiking in motor areas correlates well with many natural features of voluntary arm movement, such as hand position, velocity or speed during reading. Studies in monkeys show that it is possible to extract hand trajectories in three dimensions and intended movement direction or targets (goal) from relatively small samples (50) of neurons (Georgopoulos, 1987; Schwartz, 2007; Donoghue, 2008). Effective population-based control signals require longlasting recording multielectrodes to record a sufficiently large population of neurons all at once, a complex sensor development problem discussed in a later section. Field Potentials as NI Signals Field potentials represent a second source of neural control signals for NI systems. Field potentials (FPs) are complex signals that reflect current flow in neurons (Bullock, 1997). Most of the FP is thought to emerge from currents across somatodendritic membranes of a group of neurons generated by synaptic inputs; action potentials contribute little to slower time course FPs unless neurons are spiking synchronously, as in epilepsy or when they are evoked by a time-locked stimulus to generate an evoked potential (EP). Some consider that FPs reflect “input” and spikes reveal “output,” but this is an oversimplification because FPs may include electrical potentials that are both output and input, and can be affected by non-neuronal cells, or subthreshold and conditionally varying signals. Similarly, spikes may miss neural “outputs” that are based on non-spiking electrical coupling of neurons. FP have multiple subtypes named for their frequencies (e.g., alpha, beta, gamma) when they are oscillatory, for their time of appearance (P300 wave appears as a positive going wave 300 ms after a certain stimulus) or for their source (e.g. visual evoked potential). Specific names for various FPs derive from apparent independence (i.e. the named bands, such as alpha, beta, delta, gamma) and their relationship to particular brain states, such as levels of alertness correlated with the alpha rhythm (see Donoghue, 2008 for discussion). FPs are also named for recording location. Field potentials recorded from the scalp are called the electroencephalogram (EEG), while these signals recorded

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from inside the skull, near the cortical surface, are called the electrocortigram (ECoG). FPs recorded within the cortex are called a local field potential (LFP), but this term also reflects the fact that smaller recording electrodes are typically used when the electrode is penetrating, making them more “local” than recordings outside the brain. Recordings of FPs are filtered and volume averaged to varying degrees; they are usually detected by bandpassing neural electrical potentials in the range of DC to 100 Hz. FPs are a mixture of nearby and distant signals that are influenced by the size and location of sensors, the frequency of the signal, neuronal orientation relative to the cortical surface, and other factors, as well as the nature of the sources and sinks that generate them (Bullock, 1997; Buzsáki, 2004). Because low frequency signals travel farther in neural tissue than higher frequency ones all FPs, even if “local,” may contain a mixture of near and far signals. It has been reported that LFPs contain about twice as much information as the ECoG (Mehring et al., 2004), which are in turn higher fidelity than scalp EEG potentials (Freeman et al., 2003) both because there is more high frequency information and the signal to noise ratio is improved. There is no definitive study that catalogs the differences in the information available in these various forms of FP signal. Investigations into the nature of these various forms of FP signals and their relationship to spiking appears to be in a resurgence due to interest in using them as a control source for an NI system. This effort also may help to reveal some of the mechanisms that relate to the sources of FPs and the complex interactions between FPs and APs, which may, in turn, reveal fundamental features of brain information processing. All FP recording methods can detect signals broadly correlated with movement or cognitive events when placed over motor cortical areas, and can thus be a signal source for a direct NI. Signals in the 15–30 Hz range (Beta/mu) typically show suppression around movement onset, while gamma band activity (30 Hz) can show increases related to intended hand or arm actions (see Pfurtscheller and Neuper, 2006). Recent evidence suggests that gamma activity contains considerably more specific information about the hand and sub-actions (hand/fingers) than lower frequencies, but these relationships and the correlation with spiking remain uncertain (Belitski et al., 2008). Control over FP signals appears to require at least some amount of learning, unlike spiking in motor areas in which motor output signals can be immediately substituted for arm control signals in both ablebodied monkeys (Carmena et al., 2003; Donoghue et al., 2007; Schwartz, 2007) or in paralyzed humans (Hochberg et al., 2006). This is not to say that learning

may not also be engaged and helpful when spiking is used. Thus FP and spikes appear to be useful sources of control, though they differ in information content and learning requirements. Ideally, one would consider that both FP and spikes be sources of signals in NI systems, just as the brain uses both of these signals for processing and control. Sources of Movement Signals Spiking signals related to movement are readily detected in the multiple motor areas of the cere­bral cortex. Most NI have attempted to recreate actions performed by the arm both because so much of human interactions with the world engage the arm (including the hand and fingers), because the bulk of electrophysiological studies in non-human primates have dealt with arm control, and because restoration of arm control could radically improve independence in those with tetraplegia. Of course, leg and speech motor control are important volitional functions to recover in paralysis, but limitations in data and complexity of control have hindered advances in NI systems for these actions. Neural control systems for major body parts (face, arm, and leg) are largely spatially segregated in the nervous system (Figure 19.2), with higher order volitional planning and control emerging from cerebral activity. However, nearly all parts of the CNS contribute in some way to movement control and remain potential sources of movement signals. The multitude of cerebral cortical areas for arm control have been extensively examined in monkeys during reaching, grasping, and other skilled movements (Kalaska and Crammond, 1992). The main emphasis of these experimental investigations has been on the relationship of spiking patterns of individual neurons to reaching and other arm movements. More than a dozen regions of the cerebral cortex related to arm actions have been identified. The primary motor cortex (MI), located in the posterior part of the precentral gyrus in humans and macaque monkeys, is well known as a major source of output to the spinal cord and MI has been a main target for NI system signals. Other cortical control areas, such as non-primary motor areas, contain signals related to planning and learned motor associations, which may be able to provide complementary or more flexible movement signals than MI (Pesaran et al., 2006). The current emphasis on the cortex does not rule out other neural structures: thalamic, basal ganglia, brain stem or cerebellar cell groups are potential sources for motor command signals; lack of fundamental data or ease of recording in deeper structures may account for less emphasis on these areas as possible

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Figure 19.2  NI sensor and signals. (Aa) Scanning electron micrograph of a planar, passive multielectrode array used for human pilot NI trials. This 100 microelectrode array has a 4  4 mm platform, with electrodes penetrating 1 or 1.5 mm into the cortex. (Ab) Same array set to scale on a US one cent coin. (Ac) Multielectrode array being developed by Wise and collaborators (Bai et al., 2000) that has a large number of electrodes, many recording sites per electrode and active electronics on the platform on the back of array. (B) Knob area in human precentral cortex which marks the site of the arm/hand region of primary motor cortex in humans. This morphological feature (red arrow) protrudes posteriorly from the precentral gyrus. Leg areas lie medial to this zone and face motor cortex lies laterally along this gyrus, forming a general topographic map. Anterior is to the right. (C) Multielectrode array shown in (Aa), implanted in human MI knob area. A cable that connects the array to a connector can be seen passing across the cortical surface to the cranial surface. (D) Imagined movement-related activity from a person with tetraplegia following a cervical spinal cord injury. The three neurons depicted show elevated activity during imagined hand close and low activity during imagined hand opening. This demonstrates the retention of neural activity in human MI years after injury that can be engaged by imagined action alone. Time base in sec. (Part (D) reproduced with permission from Hochberg et al. (2006). Copyright (2006) Nature Publishing Group)

alternatives. Importantly, it is now known that both spiking and FPs remain in motor cortex years after SCI, stroke or ALS, at least in a restricted early study of humans with tetraplegia (Hochberg et al., 2006). These studies also demonstrate that anatomical landmarks for the human arm/hand area of motor cortex, which is defined by a “knob” in the precentral gyrus, appears to be a reliable functional landmark as well. More significantly, movement intention is sufficient to activate MI neurons (Kennedy et al., 2000; Hochberg et al., 2006), showing that the neurons retain movementlike properties even though movement is not possible. These are critical observations for NI systems. The limited

number of persons tested so far requires that additional validation of these conclusions be obtained. FP signals are readily available to be used as sources of control signals because they can be recorded on the scalp surface (although this seriously filters higher frequency signals, they are subject to greater spatial summation because they are distant from neural sources, and they are prone to artifact because other sources of electrical signals such as the eyes and the scalp muscles are nearby). Once electrodes are implanted internally FP signals are improved in quality, with the best signal to noise available from sensors on (ECoG) or in (LFP) the cortex. FP signals for NIS can either be

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derived from the vicinity of motor control structures themselves (such as the surface of MI) or they can be obtained from areas where cognitive or more indirect signals can be used as a surrogate for a movement command. For example, the P300 response to signal novelty can be used to detect an intended target for movement.

Sensors Sensors are the requisite neural-physical interface to obtain neural signals. Sensors for electrical potentials have a range of designs that are influenced by the types of signals desired, the duration of recordings, and the complexity of obtaining these signals. There is a vast literature on various types of sensors. The present discussion provides an overview of those being developed to provide long-lasting, effective FP and spike recordings for direct human NI systems. Although one can devise various forms to classify them, it is useful to consider grouping sensors as penetrating and non-penetrating because this designation differentiates the types of signals available and major design challenges. Penetrating electrodes (with the correct properties) can record both spikes and FPs, while non-penetrating electrodes can record only FPs. Non-penetrating electrodes can either be non-invasive, as in the common EEG scalp electrodes, or they can be invasive, with sensing surfaces placed on the brain’s surface, epidurally, or in the skull. Here, “invasive” means that placing the sensor requires penetration of the skin. As stated above, sensors closer to neural tissue have access to a richer, more diverse set of neural signals and hence are closer to signals that directly reflect details of movement intent. FPs electrodes are commercially available as scalp EEG electrodes or various subdural electrodes. All of these are currently intended and approved only for short term use, from hours to up to 30 days in the case of subdural grid used for mapping related to epilepsy surgery. Small strips of intracranial electrodes are also used for longer periods as part of closed-loop seizure suppression systems. The electrode is usually a large metal surface, with contacts on the order of 2–4 mm in diameter, so that they collect signals over a relatively large area, but any size recording surface can detect FPs. Scalp electrodes have the major advantage of not requiring surgery, and thus a majority of laboratory-based human brain–computer interface studies have been performed with these electrodes, generally in healthy volunteers. EEG electrodes, however, have several disadvantages. They require conductive pastes or gels to establish good contact; gels must be replaced over time and contact could cause skin

breakdown and infection with prolonged use. Application of many electrodes is time-consuming and these sensors cannot be self-applied by mobilityimpaired users. Scalp electrodes are prone to artifacts from motion or EMG and they are often not cosmetically desirable to users. Implanted non-penetrating electrodes eliminate many of these issues, although they require a surgical procedure, which carries some risk of infection or other complications. For EcoG recordings, subdural grids, which are silicone sheets with a regular array of a few or dozens of disk electrodes, are typically placed on the cortical surface and ordinarily used short term for localization in epilepsy. A smaller set of ECoG electrodes may be used in the future to minimize size and collect more logical signals, although the most useful sensor density and size remains to be determined. There are currently no non-penetrating implanted sensors approved for chronic human use for an NI, although some subdural grids have been implanted long term in ALS patients (Nijboer et al., 2008) and are being evaluated in epilepsy device trials. Penetrating sensors are so named because they are placed within neural tissue. Some consider electrodes that penetrate (i.e., disturb the parenchyma) as more invasive than those that sit below or above the dura, while others consider any electrode requiring a surgical procedure to be invasive. A more precise question is the relative health risk of one sensor vs. another, as well as their relative reliability – that is, will the sensor provide a similar signal every day over many years. Sensors will vary in the amount of risk they create based on their size; the amount of tissue compressed, displaced, or damaged; their tendency to become infected or encapsulated, and many other features. The risks associated with invasive sensors still need to be quantified and understood, and then compared to the relative benefit they provide. However, the experience from tens of thousands of humans who have had penetrating electrodes implanted for deep brain stimulation therapy suggests that the safety of invasive technology is not a fundamental barrier for development of NI systems for mobility. Penetrating sensors containing microelectrodes have the specific advantage of being able to record spikes, while also providing local field potentials (using different filtering processes). The basic penetrating sensor, the microelectrode, has been a main tool of experimental neurophysiological research for decades. The standard research microelectrode consists of a hairthin conductor, tapered to a point and coated with an insulator, except at its tip. Electrode dimensions vary, but have shafts on the order of 0.1 mm or less. The tip must be placed less than 100–150 m of a neuron to detect spikes, which imposes substantial challenges for

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signal stability and reliability if motion between sensor and brain occurs or glial or fluid barriers occur around electrodes. For NI systems, many electrodes are used to detect a population of neurons. A number of implanted multielectrode systems that minimize the challenges of spike recording are being devised for long-term human use (Donoghue, 2008). The desirable properties of such systems are that they produce minimal damage upon insertion and they are biocompatible, biostable, and mechanically stable relative to surrounding parenchyma when in place. Biocompatible sensors will minimize tissue responses that could either block recording or lead to foreign body rejection. Biostable sensors will be resistant to degradation in the biological environment, and mechanical stability implies that any sensor motion will neither cause a deleterious tissue response nor recording instability. All rigid materials inserted into the brain by their nature will cause some damage. The rich microvascularity and high packing density of neural elements in the cortex ensures that there will be some disruption of these elements that could lead to loss of recording (Polikov et al., 2005); meningeal reaction could also encapsulate foreign bodies and prevent signal acquisition. Tissue response to various materials is complex and not yet well enough understood to be controlled. However, electrode fabrication materials with reasonably stable properties have been identified, including metals such as Pt and Ir and insulators such as paralyene. Sensors made of these materials appear to be able to provide signals for years or more, at least with certain sensor designs. Three multielectrode designs will be considered here. One design consists of a flat platform with an array of single microelectrodes, with each one acting as a separate channel. The electrodes can be arranged in a regular grid that spans up to a few millimeters of tissue. The platform, which sits against the piaarachnoid, may help to stabilize the array, and if the wiring to the array is sufficiently flexible, this design allows the system to float with brain motion. Arrays of electrodes of metal or Si have been produced and used in humans (Hochberg et al., 2006) and this same Si electrode platform arrays have been used to record long term in monkeys for over one year (Suner et al., 2005). A second type of multielectrode system has been fabricated from microwires, typically of 20– 50 m diameter arranged in bundles or other patterns. These have been widely used in animal studies, but not in humans for chronic recordings (they are used for short-term depth recordings in epilepsy studies). As currently fabricated, they have the drawback of being attached to the skull so that relative motion with respect to the skull could be substantial

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and induce gliotic reactions to disrupt recording (Kim et al., 2004). It is estimated that the human brain can move several millimeters within the cranium (Sabet et al., 2008), which could lead to substantial damage from any skull-mounted array. Similar to the platform arrays, they have a single recording site/electrode. Microwires often have blunt tips and uniform diameter shanks, which may produce more damage upon insertion compared to a tapered microelectrode, which may account for their generally more often short-lived recordings. Multi-site arrays are a third type of design in development. The most thoroughly developed consist of multiple recordings patches made on a thin planar silicon substrate using semiconductor fabrication methods (Bai et al., 2000). These sensors provide many recording sites for each probe insertion, which is a distinct advantage over one sensor/probe design, but their thin, flexible nature can make them difficult to stabilize and insert. A platform-based array of these sensors in development would have the advantage of providing the possible ease of insertion of a platform and many recording sites (see Donoghue, 2002, 2008). Planar electrodes with patches along the shaft are apparently less successful in recording spikes over long durations compared to sharp-tipped electrodes for reasons that are not clear but are in active investigation (Ludwig et al., 2006). These sensors have also not been tested in humans. One other approach to chronic recording has been successfully applied to humans. Electrodes consisting of fine glass cones containing microwires (Kennedy et al., 2000) have been successfully used to sense spikes in humans and animals. These electrode assemblies, which are effectively microwires in a glass casing, are inserted directly into the cortex and they rely on the tissue damage response and growth factors inside the glass cone to attract neurites towards the microwires, thus forming a long-term neural interface. Each cone has but a few channels so that large neural population recordings would require the insertion of many of these electrodes. Further, the nature or origin of the processes that grow into the cone is not established. However, these have been used successfully both to record motor cortex signals and to create command signals for a human prototype system (Kennedy et al., 2000). Despite daunting concerns about tissue response and stability, initial “proof of concept” success of human recordings has been accomplished using the silicon platform array (Hochberg et al., 2006). To date, this sensor has now has been able to record spikes for more than two years in one participant in an ongoing IDE pilot trial (Hochberg et al., 2006). When coupled to the successes in animals, it appears very promising that sustained multielectrode recordings for neural

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interface systems can be developed, either with this array or with others, and that tissue response is not a formidable barrier to recording both spikes and LFPs. Nevertheless, it remains critical to understand biological responses and material stability to create permanent, reliable neural interfaces. Future Sensors In order to be practical for everyday human use, sensors will need to be wireless (i.e., not requiring percutaneous connectors). Systems practical for everyday use in humans are likely to be fully implanted, to make it easy to move about, aesthetically acceptable, and free of complex connectors or skin penetration. The wide clinical experience with other implanted medical devices in the CNS suggests that these interfaces, which are smaller and more superficial than those now in use for stimulation, should not pose a major safety problem. However, multichannel sensors, especially those capturing spikes and field potentials, have on-board signal processing, signal transmission, and other necessary design features that exceed those in any other clinical system in use today. Implanted, wireless sensors need active many-channel signal amplification at micro scales and processing, as well as high bandwidth transmission and comparatively large powering capabilities, all within the body. Multiple channels of spikes and FPs will require state of the art technology to deal with large amounts of information, which is now just within reach of modern microelectronics. Several groups have designs for large channel count spike/FP, wireless systems that are now approaching initial in vivo testing (Song et al., 2005; Kim, Troyk et al., 2006) (Figure 19.3).

Decoding Translation of neuroelectric potentials into a useful control signal is a second major requirement for an NIS. The signal must both contain enough information to restore useful control and be sufficiently reliable that it can operate whenever needed. Decoding can be approached as an attempt (1) to recover specific information about precise movement intentions from ongoing motor processes or (2) to use one neural signal as a substitute for the actual missing signal. The first decoding type is a form of direct decoding, while the second can be considered surrogate system decoding. The emphasis of this chapter is on the first type although the methods for converting continuous or discrete data into control signals are largely the same. For most studies of direct NIS, the measure of successful decoding has been based on the quality of cursor control when attempting to replicate actions that would ordinarily be performed by the hand, although sometimes other devices have been used to demonstrate control. Quantitative evaluations of decoding are presented in terms of bits, error rate and other measures, but it remains open how best to evaluate the quality of decoding. For example, a low-bit rate signal that provides a critical function might be considered to be very valuable by the user. One would predict that spiking would provide the highest amount of information, but requirements, dimensionality, flexibility, and number of necessary channels for a reliable and stable systems have not definitively been shown using either source of signals. There are considerable ongoing efforts to develop methods to obtain the highest possible number of independent control dimensions with the highest degree of reproducibility. Most applicable

Figure 19.3  Prototype of a fully implantable wireless penetrating multielectrode array. This device has two modules. One (arrow on left) contains the array with active electronics to condition the recording signal integrated into its structure (not visible). This module is implanted under the skull in the cortex. The larger module (arrow on the right) is placed below the skin and above the skull. It contains additional signal processing, amplification, and transmission components. There are currently no high bandwidth, high channel count implantable systems for humans, although the initial steps necessary for such as system are under way in a number of laboratories. (Images courtesy of A. Nurmikko, Brown University)

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mathematical approaches have already been tested for decoding, including a range of linear, non-linear, and neural network methods. The details of these methods are available in the literature (see Maynard et al., 1999; Serruya et al., 2003; Kim, Sanchez et al., 2006 for comprehensive evaluation of approaches) and only a brief overview of the approaches to decoding will be presented here. Decoding Spiking Patterns Spiking patterns derived from populations of neurons in motor areas contain movement correlates that can be used for a direct decoding of movement, either as a continuous estimate or as discrete choices. Continuous direct decoding has been successfully applied to reconstruct hand motions, particularly hand velocity in able-bodied monkeys performing various visuomotor tasks. Using as few as six neurons from MI it is possible to estimate the evolving hand trajectory using a simple linear regression-based model. This estimate improves substantially when populations of 50–100 randomly sampled MI arm area neurons are used in “closed loop control” (Wessberg and Nicolelis, 2004), where the user sees the output of the decoder; monkeys can use these signals in real time to control cursors in two or three dimensions (Serruya et al., 2002; Taylor et al., 2002; Carmena et al., 2003). New approaches to continuous decoding are being introduced as more data from ongoing research is available. This includes use of adaptive systems, non-linear methods, and the use of various cell features to select or reject neurons used in decoders. It is also possible to decode discrete states or choices, such as up, down, left, right, from neural activity by classi­ fying activity patterns in motor cortex (Santhanam et al., 2006). Although not perfect, these approaches have provided the basic elements of point and click actions necessary for useful interface to a computer or other devices. Decoding FPs As continuous signals that vary in strength and frequency content over time, FP are typically decoded using any of a number of standard signal processing methods, either in the amplitude or time domain. For motor areas the most prominent signals related to movement or movement intention are a suppression of activity in the mu (8–12 Hz) and beta range (20 Hz) in both able-bodied individuals (Wolpaw et al., 2002) and in persons with tetraplegia (Birbaumer, 2006; Hochberg et al., 2006). These signals, which are available in EEG, ECoG, and LFP recordings, diminish

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around the onset of movement and it is possible to learn volitional control of these rhythms (see Kubler et al., 2005; Birbaumer et al., 2006; McFarland et al., 2008). More recently, the very broad band gamma signal over motor cortex, which is above 35–50 Hz has been a signal of interest, because it seems to contain greater detail about movement (Palaniappan, 2006). Gamma power signals are best evaluated below the skull due to the substantial filtering of the scalp and bone. The gamma signal increases with intended movement, although the relative amount is small and very wide-band. There are other signals that can be used for discrete decoding, which are typically classification methods. In the real of FP-based NIs discrete and continuous decoding is related to the terms synchronous and asynchronous (Müller-Putz et al., 2006). Many published studies provide detail and review of the variety of approaches to decoding these signals that will not be reviewed here (e.g., Bai et al., 2007). The quality of FP decoding, as for spiking, has been evaluated by measuring control of a cursor or the amount of information obtained during control. Decoded FP signals can be used for continuous control of a cursor in two dimensions to reach targets on a screen (Shenoy et al., 2008; Pistohl et al., 2008). Persons with intact arm function have been able to learn to modulate FP rhythms to move cursors to multiple targets; control of a cursor from motor cortex FP signals in a person with tetraplegia has not yet been demonstrated, but given the retention of these signals this seems likely. While training necessary for cursor control is extensive when (surface) EEG signals are used, successful decoding and closed loop control has been achieved with only a few hours of training using ECoG signals (Schalk et al., 2008). FP-based cursor control has been tested in trials where the cursor is recentered after each trial, so that it cannot be readily compared to spike-based decoding quality, where the cursor motion is continuously decoded and not subject to these computer-based corrections. Nevertheless, both signals can be decoded into a form of control signal that could operate various forms of a computer operating system. FP decoding demonstrates the potential to readily achieve classification of a set of choices without requiring extensive training. Shortcomings of Decoding Ideally it would be possible to decode goals or intentions of all impaired actions, but this seems unlikely given that the input to decoders will be restricted to limited, noisy samples of the FP or spiking processes. Unreliable sensors cause the quality of the signal to change over time which will place demands on the

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decoders. In addition, the nature of neural signaling processes introduces sources of variance that are poorly understood. Decoding strategies attempt to make up for these deficiencies by attempting to emulate functions that are missing, or predicting the goals of a limited set of actions, being adaptive, or being selective in their functions. Decoding takes time to calibrate and establish. This currently takes tens of minutes or more for any type of system. It will be necessary to automate these tasks for the user to have continuous access. If a decoding algorithm is overfit to the application, it may not generalize. For example, continuous spike decoding that is useful for controlling a cursor may not work when applied to a wheelchair controller. Obtaining a maximally information-rich signal may include decoding methods that combine FP and spike signals (as the brain does), and that adapt to changing conditions and features of the user interface.

Application of integrated NI systems A complete NI system is one that integrates the sensor, decoder, and controlled device into a complete system that returns control and independence in a reliable manner, without encumbering other functions. The system ideally restores functions in as natural a way as possible, without requiring excessive attention or effort, when compared to the effort used by ablebodied persons for the same motion. This may remain challenging because systems are likely to depend on a small sample of the very large population of neurons engaged in even the simplest volitional movements and upon the ability to capture the information processing capabilities of parts of the nervous system that are removed as a result of injury or disease. While early stage devices may be quite limited they may be useful when normal movement control is severely limited. Most NI system testing so far has demonstrated that an output signal can be detected and controlled directly from the brain. Demonstrations typically include movement of cursors to targets on a screen or selection of one screen target from another. One area of research has been directed largely at measuring decoding capability and the potential for various areas to provide useful control in able-bodied monkeys, which is essential in defining the limits of spike- or FP-based systems where any sensing and decoding methods can be tested. These studies have investigated the ability to use spiking from populations of neurons in primary and non-primary motor areas to generate continuous or discrete control signals. A second

largely independent group of researchers have investigated the ability to generate control signals in NI systems based on FPs from motor cortex, largely in humans able to use their arms. However, useful human NI systems will need to accomplish meaningful functions to operate assistive technologies and do so for persons who are unable to move normally. There are relatively few studies showing that persons with tetraplegia can use motor cortex signals to perform useful actions, and these are presently at the demonstration level. There are also important observations outside of direct NI use in persons with paralysis of significance. In one pilot clinical trial a person with tetraplegia has used a spike-based direct NI system to control a robot arm to grasp and deliver an object, to use computer software for email, and to operate various switches to control a TV (see online videos association with Hochberg et al., 2006). As would be required of an ideal NI system, no learning was required to operate devices, although a block of time is required to create a decoding filter each day. In addition, control appeared not to require special attention. A spike-based system has been used in an able-bodied monkey to learn to operate a multi­ dimensional robot arm. Although this included the advantage of immediate mapping of motor spiking of natural movement it required adaptation over time to become attuned to the specific requirements of this new “tool.” A P300 system is in use by five persons with tetraplegia (J. Wolpaw, pers. comm.), allowing communication in their home setting, but this NI system is not based on motor cortex signals, requires considerable user attention, and thus does not qualify as a direct NI system, despite its clear potential utility as a surrogate NI system. These various demonstrations of control, communication, and use of less than ideal systems nevertheless show that direct NI systems have substantial future potential.

Extending NI to Muscle Control Beyond connecting to physical devices, NI systems can potentially connect to the muscles themselves, effectively becoming a physical nervous system. Functional electrical stimulation (FES) is an already approved and useful medical device, that is now operated by signals that qualify as surrogates: button pushes or EMG from still-intact movements. One could envision an NI system in which motor cortex signals could become the control source for an FES system thus creating a physical bridge from the brain to the body. With effective, stable, and reliable control signals from the brain there is no reason not to believe

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that a brain to muscle FES system could be realized. Even basic actions such as reach and grasp for selffeeding and sit to stand would provide considerable extension of everyday function for those with tetraplegia. If appropriate neural substrates are found, volitionally controlled functions including bowel and bladder control or sexual function might also be considered. The same approach of neural control could also be applied to restoring control of prosthetic limbs after limb loss, although in these cases remaining peripheral nerves and muscles may be equally or more attractive sources of neural control signals. These expansive concepts require ongoing development of implantable processors, improved understanding of materials in complex biological environments, among other substantial issues. It will also require extensive collaborations between engineers, computer scientists, neuroscientists, and clinicians, as well as end users.

Future of Neural Interface Technology The rapid pace of recent activity coupled with multiple demonstrations of the feasibility of NI systems suggests that useful systems will emerge in the coming decades. Systems may include those that serve only basic functions to those that eventually provide more sophisticated control. It is likely that point and click type control of a computer ordinarily performed by the hand will be readily achievable. Even this simple advance will allow persons with movement limitations to engage in a wide range of activities made possible through computers. In addition, progressive connection of neural control signals to the muscles is also likely to emerge as neural motor commands are used to drive functional electrical stimulation systems.. For those cases where reanimation of muscles is not feasible (as in ALS), robotic assistants may be important aids. Remarkable advances in current robotic capabilities, including safety in close proximity to humans, suggests that very useful assistive machines can be created in the near term to perform actions that would ordinarily employ the arms to provide food, a drink, or grooming or other useful actions. Finally, far reaching advances in the ability to detect rich, reliable, high dimensional control signals that emulate all of our natural motor commands derived from non-invasive sensors would revolutionize this field. The immense complexity of this task suggests that current approaches using implanted sensors will be the most fruitful path for some time. However, such futuristic ideas as using optical reporters to transmit interpretable spiking or FP signals extracranially are on the horizon.

Disclosure JPD was Chief Scientific Officer, director, with stock holdings and compensation, of Cyberkinetics Neurotechnology Systems, Inc. LRH received clinical trial support from Cyberkinetics. Cyberkinetics has ceased operations.

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Polikov, V.S., Tresco, P.A. and Reichert, W.M. (2005) Response of brain tissue to chronically implanted neural electrodes. J. Neurosci. Methods 148 (1): 1–18, Epub 2005 Sep 27. Review. Sabet, A.A., Christoforou, E., Zatlin, B., Genin, G.M. and Bayly, P.V. (2008) Deformation of the human brain induced by mild angular head acceleration. J. Biomech. 41 (2): 307–15, Epub 2007 Oct 24. Santhanam, G., Ryu, S.I., Yu, B.M., Afshar, A. and Shenoy, K.V. (2006) A high-performance brain–computer interface. Nature 442 (7099): 195–8. Schalk, G., Miller, K.J., Anderson, N.R., Wilson, J.A., Smyth, M.D., Ojemann, J.G. et al. (2008) Two-dimensional movement control using electrocorticographic signals in humans. J. Neural Eng. 5 (1): 75–84; BCI R&D Progr, Wadsworth Ctr, NYS Department of Health, Albany, NY, USA. Schwartz, A.B. (2007) Useful signals from motor cortex. J. Physiol. 579 (Pt 3): 581–601, Epub 2007 Jan 25. Review. Serruya, M., Hatsopoulos, N., Fellows, M., Paninski, L. and Donoghue, J. (2003) Robustness of neuroprosthetic decoding algorithms. Biol. Cybern. 88 (3): 219–28. Serruya, M.D., Hatsopoulos, N.G., Paninski, L., Fellows, M.R. and Donoghue, J.P. (2002) Instant neural control of a movement signal. Nature 416 (6877): 1412. Shenoy, P., Miller, K.J., Ojemann, J.G. and Rao, R.P. (2008) Generalized features for electrocorticographic BCIs. IEEE Trans. Biomed. Eng. 55 (1): 273–80. Sitaram, R., Caria, A., Veit, R., Gaber, T., Rota, G., Kuebler, A. et al. (2007) FMRI brain–computer interface: a tool for neuroscientific research and treatment. Comput. Intell. Neurosci. 2007: 25487. Sitaram, R., Zhang, H., Guan, C., Thulasidas, M., Hoshi, Y., Ishikawa, A. et al. (2007) Temporal classification of multichannel near-infrared spectroscopy signals of motor imagery for developing a brain–computer interface. Neuroimage 34 (4): 1416–27. Song, Y.K., Patterson, W.R., Bull, C.W., Beals, J., Hwang, N., Deangelis, A.P. et al. (2005) Development of a chipscale integrated microelectrode/microelectronic device for brain implantable neuroengineering applications. IEEE Trans. Neural Syst. Rehabil. Eng. 13 (2): 220–6. Stevens, C.F. and Zador, A. (1995) Neural coding: The enigma of the brain. Curr. Biol. 5 (12): 1370–71, Review. Suner, S., Fellows, M.R., Vargas-Irwin, C., Nakata, G.K. and Donoghue, J.P. (2005) Reliability of signals from a chronically implanted, silicon-based electrode array in non-human primate primary motor cortex. IEEE Trans. Neural Syst. Rehabil. Eng. 13 (4): 524–41. Taylor, D.M., Tillery, S.I. and Schwartz, A.B. (2002) Direct cortical control of 3D neuroprosthetic devices. Science 296 (5574): 1829–32. Wessberg, J. and Nicolelis, M.A. (2004) Optimizing a linear algor­ ithm for real-time robotic control using chronic cortical ensemble recordings in monkeys. J. Cogn. Neurosci. 16 (6): 1022–35. Wolpaw, J.R. (2007) Brain–computer interfaces as new brain output pathways. J. Physiol. 579 (Pt 3): 613–9, Epub 2007 Jan 25. Review. Wolpaw, J.R., Birbaumer, N., McFarland, D.J., Pfurtscheller, G. and Vaughan, T.M. (2002) Brain–computer interfaces for communication and control. Clin. Neurophysiol. 113 (6): 767–91, Review.

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MRI Safety and Neuromodulation Systems Frank G. Shellock

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Bioeffects of Gradient Magnetic Fields Gradient Magnetic Field-Induced Stimulation   in Human Subjects Acoustic Noise

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Bioeffects of Radiofrequency Fields MRI Procedures and the Specific Absorption   Rate of RF Radiation Thermophysiologic Responses to MRI Procedure  Related Heating MRI Procedure-Related Heating and   Human Subjects MRI Procedure-Related Heating and   Very-High-Field MR Systems

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MRI Safety and Patient Management Screening Patients for MRI Procedures and   Individuals for the MRI Environment Pre-MRI Procedure Screening for Patients MRI Environment Screening for   Individuals Excessive Heating and Burns Associated   with MRI Procedures Pregnant Patients and MRI Procedures

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MRI Procedures and Neuromodulation Systems 254 Programmable Infusion Pumps 255 Bion Microstimulator 259 Vagus Nerve Stimulation (VNS) System,   VNS Therapy System 262 Neurostimulation Systems for Deep Brain   Stimulation 263 Activa Tremor Control System 264 Libra DBS System 270 DBS Neuromodulation Systems: Emphasis   on MRI Safety Issues 272 Spinal Cord Stimulation Systems 273 Itrel 3: 7425; Restore: 37711; Synergy: 7427;  SynergyPlus: 7479; Synergy Versitrel: 7427V; Mattrix: 3272, 3271; and SynergyCompact: 7479B Spinal Cord Stimulation Systems 274 Renew, Genesis, GenesisXP, GenesisRC,   and Eon Spinal Cord Stimulation Systems 278 Precision Spinal Cord Stimulation System 278 Other Neuromodulation Systems 278 InterStim Therapy – Sacral Nerve   Stimulation for Urinary Control 278 Atrostim Phrenic Nerve Stimulator 278 Renova Cortical Stimulation System 278 Enterra Therapy, Gastric Electrical   Stimulation System 278 Conclusions 279 References 279

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INTRODUCTION Magnetic resonance imaging (MRI) procedures have been utilized in the clinical setting for approximately 25 years. During this time, the technology has continued to evolve yielding scanners with higher static magnetic fields, faster and higher gradient magnetic fields, and more powerful radiofrequency (RF) transmission coils. The short-term exposures to the electromagnetic fields used for MRI procedures at the levels currently recommended by the US Food and Drug Administration (FDA) have yielded relatively few problems for the more than 300 million MRI examinations performed to date. Most reported cases of MRI-related injuries and the few fatalities that have occurred have been due to not following safety guidelines or from using inappropriate or outdated information related to the safety aspects of biomedical implants and devices (Shellock, 2008). The preservation of a safe MRI environment requires constant attention to the management of patients and individuals with metallic implants and devices because the variety and complexity of these objects constantly changes (Shellock, 2008). Therefore, to guard against adverse events and other problems in the MRI environment, it is necessary to revise bioeffects and safety information according to changes that have occurred in MRI technology and to use current guidelines for implants and devices. This chapter provides an overview with regard to MRI bioeffects, discusses various MRI safety topics and issues, presents evidence-based guidelines to ensure safety for patients and staff members, and describes safety information for implants and devices with an emphasis on neuromodulation systems.

Bioeffects of static magnetic fields The introduction of MRI technology as a clinical imaging modality in the early 1980s is responsible for a substantial increase in human exposure to strong static magnetic fields (Schenck, 2001). Most MR systems in use today operate with static magnetic fields ranging from 0.2-Tesla to 3-Tesla. Ultra-highfield MR systems exist in the research setting which include several 4-Tesla scanners, several 7-Tesla scanners, one 8-Tesla scanner, and an exceptionally powerful MR system operating at 9.4-Tesla (i.e., located at the University of Illinois at Chicago). According to the guidelines from the US Food and Drug Administration (Zaremba, 2001), clinical MR systems using static magnetic fields up to 8-Tesla are considered a

“non-significant risk” for patients. The exposure of research subjects to fields above 8-Tesla requires approval of the research protocol by an Institutional Review Board and the informed consent of the subjects. Schenck (2001) has presented a comprehensive review of bioeffects associated with exposure to static magnetic fields. With regard to short-term exposures (e.g., those associated with the clinical use of MR systems), the available information for effects of static magnetic fields on biological tissues is extensive. Investigations include studies on alterations in cell growth and morphology, cell reproduction and teratogenicity, DNA structure and gene expression, pre- and post-natal reproduction and development, blood–brain barrier permeability, nerve activity, cognitive function and behavior, cardiovascular dynamics, hematological indices, temperature regulation, circadian rhythms, immune responsiveness, and other biological pro­cesses (Schenck, 2001). The majority of these studies concluded that short-term exposures to static magnetic fields produce no substantial harmful bioeffects. Although there have been some reports of potentially injurious effects of static magnetic fields on isolated cells or organisms, none of these effects has been verified or firmly established as a scientific fact (Schenck, 2001). The relatively few documented injur­ies and few fatalities that have occurred in association with the powerful MR system magnets were attributed to the inadvertent presence or accidental introduction of ferromagnetic objects (e.g., oxygen tanks, aneurysm clips, etc.) into the MRI environment (Schenck, 2001; Shellock, 2008) (Figure 20.1). Regarding the effects of long-term exposures to static magnetic fields, there are interactions between tissues and static magnetic fields that could theoretically lead to pathological changes in human subjects (Schenck, 2001). However, quantitative analysis of these mechanisms indicates that they are below the threshold of significance with respect to long-term adverse bioeffects (Schenck, 2001). Presently, the pertinent literature does not contain carefully controlled studies that demonstrate the absolute safety of chronic exposure to powerful static magnetic fields. With the increased clinical use of interventional MRI procedures, including those used to position electrodes used for neuromodulation systems, there is a critical need for such investigations. However, it may be virtually impossible to demonstrate “absolute safety” in consideration of the various difficulties in conducting such a study to address longterm safety related to exposures to static magnetic fields. In addition, although there is no evidence for a cumulative effect of static magnetic field exposure on health, further studies of the exposed populations

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field-induced stimulation in human subjects (Bourland et al., 1999; Schaefer et al., 2000; Smith et al., 2001). At sufficient exposure levels, peripheral nerve stimulation is perceptible as “tingling” or “tapping” sensations. At gradient magnetic field exposure levels 50–100% above perception thresholds, patients may become uncomfortable or experience pain. At extremely high levels, cardiac stimulation is a concern. However, the induction of cardiac stimulation requires excessively rapid gradient magnetic fields, more than an order of magnitude greater than those used for commercially available MR systems (Bourland et al., 1999; Schaefer et al., 2000; Smith et al., 2001). Fortunately, current safety standards for gradient magnetic fields associated with presentday scanners appear to adequately protect patients from potential hazards or injuries (Zaremba, 2001).

Figure 20.1  Example of an incident related to the accidental introduction of ferromagnetic object (in this case, a floor buffer) into the MRI environment. The 1.5-Tesla MR system had to be quenched in order to remove this relatively large device

(MRI healthcare professionals, patients that undergo repeat studies, etc.) will be helpful in establishing rational guidelines for occupational and patient exposures to static magnetic fields (Schenck, 2001).

Bioeffects of gradient magnetic fields During MRI procedures, gradient or “time-varying” magnetic fields may stimulate nerves or muscles by inducing electrical fields in patients. This topic has been thoroughly reviewed by Schaefer et al. (2000), Smith et al. (2001), and Bourland et al. (1999). The potential for interactions between gradient magnetic fields and biologic tissue is dependent on a variety of factors including the fundamental field frequency, the maximum flux density, the average flux density, the presence of harmonic frequencies, the waveform characteristics of the signal, the polarity of the signal, the current distribution in the body, the electrical properties, and the sensitivity of the particular cell membrane (Schaefer et al., 2000).

Gradient Magnetic Field-Induced Stimulation in Human Subjects Several investigations have been conducted to characterize MR system-related, gradient magnetic

Acoustic Noise Various forms of acoustic noise are produced in association with the operation of an MR system (McJury and Shellock, 2000). The primary source of acoustic noise, however, is the gradient magnetic field activated during the MRI procedure. This noise occurs during rapid alterations of currents within the gradient coils that, in the presence of the scanner’s powerful static magnetic field, produce substantial (Lorentz) forces. Acoustic noise, manifested as loud tapping, knocking, or chirping sounds, is generated when these forces cause motion or vibration of the gradient coils as they impact against their mountings. Problems associated with acoustic noise for patients and healthcare workers include simple annoyance, difficulties in verbal communication, heightened anxiety, and the potential for temporary hearing loss (McJury and Shellock, 2001). Acoustic noise may pose a particular hazard to specific patient groups who are at increased risk. Patients with psychiatric disorders, elderly, and pediatric patients may be confused or suffer from heightened anxiety related to MRI-generated acoustic noise. Variations in scanner-induced acoustic noise occur with alterations in the gradient output (rise time or amplitude) associated with different MRI parameters. Noise levels, pitch, and frequency characteristics are predominantly enhanced by decreases in section thickness, field of view, repetition time, and echo time (i.e., the basic parameters used for the MRI procedure). The physical features of the MR system, especially whether or not it has special sound insulation, and the material and construction of gradient coils and support structures, also affect the transmission of acoustic noise and its perception by the patient.

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The Food and Drug Administration states that MRIrelated acoustic noise levels must be below the level of concern established by pertinent federal regulatory or other recognized standards-setting organizations (Zaremba, 2001). If the acoustic noise is not below this level, the sponsor (i.e., the manufacturer of the MR system) must recommend steps to reduce or alleviate the noise perceived by the patient. A single upper limit of 140 dB is applied to peak acoustic noise associated with MRI examinations. However, the instructions for the use of MR systems must advise the “operator” to provide hearing protection to patients if the acoustic noise level is above 99 dB (Zaremba, 2001). In general, acoustic noise levels recorded by various researchers in association with conventional or routine MRI examinations have been below the maximum limit permissible by the Occupational Safety and Health Administration of the United States (McJury and Shellock, 2001). Importantly, when one considers that the duration of exposure is one of the more important physical factors that determine the effect of noise on hearing, acoustic noise levels associated with MRI procedures do not tend to be problematic because of the relative short exposure periods. Various techniques have been described to attenuate noise and, thus, prevent problems or hazards associated with exposure to MRI-related acoustic noise. The simplest and least expensive means is to use disposable earplugs or commercially available noise abatement headphones. Earplugs, when properly used, can decrease noise by 10–30 dB, which usually affords adequate protection for MRI environments that have relatively loud MR scanners. Regardless of the technique utilized, facilities operating with MR systems that generate substantial acoustic noise should require all patients undergoing examinations to wear protective hearing devices. Exposure of staff members, healthcare workers, and other individuals (e.g., relatives, visitors, etc.) to “loud” MR systems is also of concern. As such, these individuals should likewise be required use an appropriate means of hearing protection if they remain in the room during the operation of the scanner.

Bioeffects of radiofrequency fields The majority of the radiofrequency (RF) power transmitted for MR imaging or spectroscopy (e.g., carbon decoupling, fast spin echo pulse sequences, magnetization transfer contrast pulse sequences, etc.) is transformed into heat within the patient’s tissue as a result of resistive losses (Shellock, 2000). Not

surprisingly, the primary bioeffects associated with exposure to RF radiation are related to the therm­ ogenic qualities of this electromagnetic field. Prior to 1985, there were no published reports concerning thermal or other physiologic responses of human subjects exposed to RF radiation during MR procedures. Since then, many investigations have been conducted to characterize the thermal effects of MRI procedure-related heating. This topic has been reviewed by Shellock and Schaefer (2001).

MRI Procedures and the Specific Absorption Rate of RF Radiation Thermoregulatory and other physiologic changes that a human subject exhibits in response to exposure to RF radiation are dependent on the amount of energy that is absorbed. The dosimetric term used to describe the absorption of RF radiation is the specific absorption rate, or SAR (Shellock, 2000; Schaefer and Shellock, 2001). The SAR is the mass normalized rate at which RF power is coupled to biologic tissue and is typically indicated in units of watts per kilogram (W/kg). The relative amount of RF radiation that an individual encounters during an MRI procedure is characterized with respect to the whole-body averaged and peak SAR levels (i.e., the SAR averaged in one gram of tissue). Measurements or estimates of SAR are not trivial, particularly in human subjects. Notably, this gets even more complicated when a metallic implant is present in a patient (Baker et al., 2004, 2006; Nitz et al., 2005; Woods, 2007). There are several methods of determining this parameter for the purpose of RF energy dosimetry in association with MRI procedures. The SAR that is produced during an MRI examination is a complex function of numerous variables including the frequency (i.e., determined by the strength of the static magnetic field of the MR system), the repetition time, the type of RF coil used, the volume of tissue contained within the coil, the configuration of the anatomical region exposed, the orientation of the body to the field vectors, as well as other factors (Schaefer and Shellock, 2001).

Thermophysiologic Responses to MRI Procedure-Related Heating Thermophysiologic responses to MRI procedurerelated heating depend on multiple physiologic, physical, and environmental factors (Shellock, 2000, 2008). These include the duration of exposure, the rate at which energy is deposited, the status of the patient’s thermoregulatory system, the presence of an underlying

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health condition, and the ambient conditions within the MR system. In regards to the thermoregulatory system, when subjected to a thermal challenge, the human body loses heat by means of convection, conduction, radiation, and evaporation. Each of these mechanisms is responsible to a varying degree for heat dissipation, as the body attempts to maintain thermal homeostasis. If the thermoregulatory effectors are not capable of totally dissipating the heat load, then there is an accumulation or storage of heat along with an elevation in local and/or overall tissue temperatures. Various underlying health conditions may affect an individual’s ability to tolerate a thermal challenge including cardiovascular disease, hypertension, diabetes, fever, old age, and obesity. In addition, medications including diuretics, beta blockers, calcium blockers, amphetamines, muscle relaxants, and sedatives can also greatly alter thermoregulatory responses to a heat load. In fact, certain medications have a synergistic effect with respect to tissue heating if the heating is specifically caused by exposure to RF radiation. The environmental conditions that exist in and around the MR system will also affect the tissue temperature changes associated with RF energy-induced heating. During an MRI procedure, the amount of tissue heating that occurs and concomitant exposure to RF energy that is tolerable are dependent upon environmental factors that include the ambient temperature, relative humidity, and airflow.

MRI Procedure-Related Heating and Human Subjects The first study of human thermal responses to RF radiation-induced heating during an MRI proced­ ure was conducted by Schaefer et al. (1985). Temper­ ature changes and other physiologic parameters were assessed in volunteer subjects exposed to relatively high, whole-body averaged SARs (approximately 4 W/kg). The data indicated that there were no excessive temperature elevations or other deleterious physiologic consequences related to these exposures to RF radiation. Several studies were subsequently conducted involving volunteer subjects and patients undergoing clinical MRI exams with the intent of obtaining information that would be applicable to patient populations typically encountered in the MRI setting. These investigations demonstrated that changes in body temperatures were relatively minor (i.e., less than 0.6°C) (Shellock, 2000). While there was a tendency for stat­ istically significant increases in skin temperatures to occur, there were no serious physiologic consequences.

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MRI Procedure-Related Heating and VeryHigh-Field MR Systems There are more than 300 MR systems operating with static magnetic field strengths at 3-Tesla and higher (Shellock, 2008). These very-high-field MR systems are capable of generating RF power depositions that greatly exceed those associated with a 1.5Tesla scanner. For example, with the doubling of field strength (e.g., 1.5-Tesla vs. 3.0-Tesla), the RF power deposition increases four times for a given MR imaging pulse sequence. Therefore, investigations are needed to characterize thermal responses in human subjects to determine potential thermogenic hazards associated with the use of these powerful MR devices. However, to date, with the exception of work conducted at 8-Tesla by Kangarlu et al. (2003) and Shrivastava et al. (2008) at 9.4-Tesla, few investigations of MRI procedure-related heating have been performed with regard to the use of very-high-field MR systems.

MRI safety and patient management Screening Patients for MRI Procedures and Individuals for the MRI Environment The establishment of thorough and effective screening procedures for patients and other individuals is one of the most critical components of a program that guards the safety of all those preparing to undergo MRI procedures or to enter the MRI environment (Shellock, 2008). An important aspect of protecting patients and individuals from MR system-related accidents and injuries involves an understanding of the risks associated with the various implants, devices, accessories, and other objects that may cause problems in this setting. This requires obtaining information and documentation about these objects in order to provide the safest MRI setting possible. In addition, because MRI-related incidents have been due to deficiencies in screening methods and/or a lack of properly controlling access to the MRI environment (especially with regard to preventing personal items and other potentially problematic objects into the MR system room), it is crucial to set up procedures and guidelines to prevent such incidents from occurring. Various guidelines and recommendations have been developed to facilitate the screening process (MRIsafety.com, 2008; Shellock, 2008). Pre-MRI Procedure Screening for Patients Certain aspects of screening patients for MRI examinations may take place during the scheduling

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process. This must be conducted by a healthcare professional specially trained in MRI safety. That is, this individual must understand the potential hazards and issues associated with the MRI environment and MRI procedures and familiar with the information contained on screening forms for patients and individuals. During pre-MRI screening, it may be ascertained if the patient has any implant that may be contraindicated for the MRI procedure (e.g., a ferromagnetic aneurysm clip, pacemaker, etc.), that requires special attention, or if there is any condition that needs careful consideration (e.g., the patient is pregnant, has a disability, etc.). Preliminary screening helps to prevent scheduling patients who may be inappropriate candidates for MRI examinations. At the facility, every patient must undergo further screening in preparation for the MRI procedure. Comprehensive patient screening involves the use of a printed form to document the screening procedure, a review of the information on the screening form, and a verbal interview to verify the information and allow discussion of any question or concern that the patient may have (MRIsafety.com, 2008; Shellock, 2008). The pre-MRI screening form for patients may be downloaded for review and use from http:/MRIsafety.com. In the event that the patient is comatose or unable to communicate, the screening form should be completed by the most qualified individual (e.g., physician, family member, etc.) that has knowledge about the patient’s medical history and present condition. If the screening information is suspected to be inadequate, it is advisable to look for surgical scars on the patient and/or to obtain plain films of the skull and/ or chest to search for implants that are known to be particularly hazardous in the MRI environment (e.g., ferromagnetic aneurysm clips, cardiac pacemakers, implantable cardioverter defibrillators, etc.). Following the completion of the screening form used for patients, the MRI-safety trained healthcare worker reviews the form’s content. Next, a verbal interview is conducted to verify the information on the form and to allow discussion of any question or concern that the patient may have before undergoing the MRI examination. This allows a mechanism for clarification or confirmation of the answers to the questions posed to the patient so that there is no miscommunication regarding important MRI safety issues. MRI Environment Screening for Individuals Similar to the procedure conducted for screening patients, all other individuals (e.g., MRI technologists, patient’s family members, visitors, allied health professionals, maintenance workers, custodial workers, fire

fighters, security officers, etc.) must undergo screening using appropriate guidelines before being allowed into the MRI environment. This involves the use of a printed form to document the screening procedure, a review of the information on the form, and a verbal interview to verify the information and allow discussion of any question or concern that the individual may have before being permitted entry to the MRI environment. The form designed for screening individuals may be downloaded for review and use from http://MRIsafety.com. Excessive Heating and Burns Associated with MRI Procedures The use of radiofrequency coils, physiologic monitors, electronically activated devices, and external accessories or objects made from conductive materials has caused excessive heating, resulting in burn injur­ ies to patients undergoing MRI procedures (Shellock, 2000, 2008; Smith et al., 2001). Heating of implants and similar devices may also occur in association with MRI examinations, but this tends to be problematic primarily for objects made from conductive materials that have an elongated shape such as electrodes, leads, guidewires, and certain types of catheters (e.g., catheters with thermistors or other conducting components) (Shellock, 2000, 2008; Dempsey et al., 2001; Nakamura et al., 2001; Shellock and Schaefer, 2001; Smith et al., 2001; Finelli et al., 2002; Rezai et al., 2002; Kim et al., 2003; Baker et al., 2005, 2006; Nyenhuis et al., 2005). Notably, more than 30 incidents of excessive heating have been reported in patients undergoing MRI examinations in the USA that were unrelated to equipment problems or the presence of conductive external or internal implants or devices (Shellock, 2008). These incidents included first-, second-, and third-degree burns that were experienced by patients. In many cases, the reports pertaining to these incidents indicated that the limbs or other body parts of the patients were in direct contact with body radiofrequency (RF) coils or other transmit RF coils of the MR systems or there were skin-to-skin contact points believed to be responsible for these injuries. In consideration of the above, guidelines have been developed to prevent excessive heating and burns related to MRI procedures (Box 20.1). The adoption of these guidelines will help to ensure that patient safety is maintained, especially as more conductive materials and electronically activated devices are used in association with MRI technology. Pregnant Patients and MRI Procedures MRI procedures have been used to evaluate obstetrical, placental, and fetal abnormalities in pregnant patients

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Box 20.1 

 Guidelines to prevent excessive heating and burns in association with MRI procedures (i.e., unrelated to implants) 1. Prepare the patient for the MRI procedure by ensuring that there are no unnecessary metallic objects contacting the patient’s skin (e.g., metallic drug delivery patches, jewelry, necklaces, bracelets, key chains, etc.). 2. Prepare the patient by using insulation material (i.e., appropriate padding) to prevent skin-to-skin contact points and the formation of “closed-loops” from touching body parts. 3. Insulating material (minimum recommended thickness, 1 cm) should be placed between the patient’s skin and transmit RF coil that is used for the MRI examination (alternatively, the RF coil itself should be padded). For example, position the patient so that there is no direct contact between the patient’s skin and the body transmit RF coil of the MR system. 4. Use only electrically conductive devices, equipment, accessories (e.g., ECG leads, electrodes, etc.), and materials that have been thoroughly tested and determined to be safe for MRI procedures. 5. Carefully follow specific recommendations for implants made from electrically conductive materials (e.g., bone fusion stimulators, neurostimulation systems, etc.). 6. Before using electrical equipment, check the integrity of the insulation and/or housing of all components including surface RF coils, monitoring leads, cables, and wires. Preventive maintenance should be practiced routinely for such equipment. 7. Remove all non-essential electrically conductive materials from the MR system (i.e., unused surface RF coils, ECG leads, cables, wires, etc.). 8. Keep electrically conductive materials that must remain in the MR system from directly contacting the patient by placing thermal and/or electrical insulation between the conductive material and the patient. 9. Keep electrically conductive materials that must remain within the body RF coil or other transmit RF coil of the MR system from forming conductive loops. Note: The patient’s tissue is conductive and, therefore, may be involved in the formation of a

for more than 20 years (Colletti, 2001). Initially, there were substantial technical problems with the use of MRI primarily due to the presence of image degradation from fetal motion. However, several technological improvements,

10.

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13.

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conductive loop, which can be circular, U-shaped, or S-shaped. Position electrically conductive materials to prevent “cross points.” A cross point is the point where a cable crosses another cable, where a cable loops across itself, or where a cable touches either the patient or sides of the transmit RF coil more than once. Even the close proximity of conductive materials with each other should be avoided because some cables and RF coils can capacitively-couple (without any contact or crossover) when placed close together. Position electrically conductive materials to exit down the center of the MR system (i.e., not along the side of the scanner or close to the body RF coil or other transmit RF coil). Do not position electrically conductive materials across an external metallic prosthesis (e.g., external fixation device, cervical fixation device, etc.) or similar device that is in direct contact with the patient. Allow only properly trained individuals to operate devices (e.g., monitoring equipment) in the MRI environment. Follow all manufacturer instructions for the proper operation and maintenance of physiologic monitoring or other similar electronic equipment intended for use during MRI procedures. Electrical devices that do not appear to be operating properly during the MRI examination should be removed from the patient immediately. Closely monitor the patient during the MRI procedure. If the patient reports sensations of heating or other unusual sensation, discontinue the examination immediately and perform a thorough assessment of the situation. RF surface coil decoupling failures can cause localized RF power deposition levels to reach excessive levels. The MR system operator will recognize such a failure as a set of concentric semicircles in the tissue on the associated MR image or as an unusual amount of image non-uniformity related to the position of the RF coil.

including the development of high-performance gradient systems and rapid pulse sequences provided advances that were especially useful for imaging pregnant patients. Thus, high quality MRI examinations for obstetrical and

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fetal applications may now be accomplished routinely in the clinical setting. Diagnostic imaging is often required during pregnancy. Thus, it is not uncommon to consider using an MRI procedure in a pregnant patient. In 1991, the Safety Committee of the Society for Magnetic Resonance Imaging issued the document entitled, “Policies, Guidelines, and Recommendations for MR Imaging Safety and Patient Management,” which stated (Shellock and Kanal, 1991): MR imaging may be used in pregnant women if other nonionizing forms of diagnostic imaging are inadequate or if the examination provides important information that would otherwise require exposure to ionizing radiation (e.g., fluoroscopy, CT, etc.). Pregnant patients should be informed that, to date, there has been no indication that the use of clinical MR imaging during pregnancy has produced deleterious effects.

These guidelines have been adopted by the American College of Radiology and considered to be the “standard of care” with respect to the use of MRI examinations in pregnant patients. Accordingly, in cases where the referring physician and attending radiologist can defend that the findings of the MRI procedure have the potential to impact the care or management of the mother or fetus (e.g., to address important clinical problems, to identify potential complications, anomalies or complex fetal disorders, etc.), MRI may be performed with verbal and written informed consent, regardless of the trimester (Colletti, 2001). Notably, special consideration must be given to cases that require contrast-enhancement, as there may be potential risks associated with the use of FDA approved MRI contrast agents in pregnant patients.

MRI procedures, and implants and devices: general information The MRI environment may be unsafe for patients or individuals with certain biomedical implants or devices primarily due to movement or dislodgment of objects made from ferromagnetic materials (Shellock, 2008). As previously stated, while excessive heating may also present risks to patients with implants or devices, these problems are typically associated with implants that have elongated configurations and/or that are electronically activated. This includes certain neuromodulation systems (Baker et al., 2004, 2005, 2006, 2007; Bhidayasiri et al., 2005; Finelli et al., 2002; Georgi et al., 2003; Henderson et al., 2005; Kovacs et al., 2006; Larson et al., 2008; Phillips et al., 2006; Rezai et al.,

2001, 2002, 2005; Sharan et al., 2003; Shellock et al., 2006; Spiegel et al., 2003; Utti et al., 2002). To date, more than 1800 objects have been tested relative to the MRI environment, with over 600 evaluated at 3-Tesla or higher (Shellock, 2008). This information is available to healthcare professionals and others on-line at http://www.MRIsafety.com. The topic of MRI safety for implants and devices was recently compiled and presented by Shellock (2008). As such, the intent for the material presented in this chapter is to provide information for implants and devices that emphasizes neuromodulation systems.

Evaluation of Implants and Devices for Safety in the MRI Environment The evaluation of an implant or device with regard to the MRI environment is not a trivial matter and, in fact, may be somewhat challenging (Woods, 2007). The proper assessment of a medical product typically entails characterization of magnetic field interactions (translational attraction and torque), MRI-related heating, induced electrical currents, and artifacts (Woods, 2007; Shellock, 2008). A thorough evaluation of the impact of the MRI environment on the functional and operation aspects of certain implants and devices may also be necessary. Importantly, an object demonstrated to be acceptable for a patient according to one set of MRI conditions, may be unsafe under more “extreme” or other conditions (e.g., higher or lower static magnetic field, higher or lower RF wavelength; greater level of RF power deposition, faster gradient fields, use of a different RF transmit coil, etc.). Accordingly, the specific test conditions for a given implant or device must be known before making a decision regarding whether it is safe for a patient or individual in the MRI environment. This is particularly important for neuromodulation systems (Rezai et al., 2001, 2002, 2005; Finelli et al., 2002; Baker et al., 2004, 2005, 2006, 2007; Bhidayasiri et al., 2005; Henderson et al., 2005; Kovacs et al., 2006; Shellock et al., 2006). New implants and devices are developed on an ongoing basis, which necessitates continuous endeavors to obtain current documentation for these items prior to subjecting a patient or individual to the MRI environment or an MRI examination. In addition, the nuances of MRI testing, especially with respect to the evaluation of MRI-related heating and identifying functional alterations and the terminology applied to label implants and devices must be understood to facilitate patient management (Woods, 2007; Shellock, 2008). Importantly, for electronically activated (e.g.,

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MRI PROCEDURES, AND IMPLANTS AND DEVICES: GENERAL INFORMATION

neuromodulation systems) implants, the labeling that ensures the acceptable use of MRI is highly specific to the conditions that were utilized to assess the device and any deviation from the defined procedures can lead to deleterious effects, severe patient injuries, or fatalities (Rezai et al., 2001, 2004, 2005; Kim et al., 2003; Spiegel et al., 2003; Henderson et al., 2005; Woods, 2007). Magnetic Field-Related Issues Magnetic field-related issues are known to present hazards to patients and individuals with certain implants or devices. Numerous studies have assessed magnetic field interactions for implants and devices by measuring translational attraction and torque associated with the static magnetic fields of MR systems. These investigations demonstrated that, for certain items, MRI procedures may be performed safely if they are nonferromagnetic or “weakly” ferromagnetic (i.e., the object minimally interacts with the magnetic field in relation to its in vivo application), such that the associated magnetic field interactions are insufficient to move or dislodge them, in situ. Furthermore, the “intended in vivo use” of the implant or device must be taken into consideration, because this can impact whether or not a given object is acceptable for a patient undergoing an MRI examination. Notably, sufficient counter-forces may exist to retain even a ferromagnetic implant, in situ (e.g., an orthopedic implant that is screwed into bone). In general, each implant, material, or device should be evaluated using ex vivo techniques before allowing an individual or patient with the object to enter the MRI environment and/or before performing the MRI procedure. By following this guideline, the relative magnetic susceptibility of an object may be determined so that a competent decision can be made concerning possible risks associated with exposure to the MR system. Because movement or dislodgment of an implanted metallic object in a patient undergoing an MRI procedure is the primary mechanism responsible for an injury, this aspect of testing is considered to be of utmost importance and should involve the use of an MR system operating at an appropriate static magnetic field strength. As previously mentioned, it may also be necessary to assess MRI-related heating for a given implant. Various factors influence the risk of performing an MRI procedure in a patient with a metallic object including the strength of the magnetic field, the magnetic susceptibility of the object, the mass of the object, the geometry of the object, the location and orientation of the object in situ, the presence of retentive

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mechanisms (i.e., fibrotic tissue, bone, sutures, etc.) and the length of time the object has been in place. These factors should be carefully considered before subjecting a patient or individual with a ferromagnetic object to an MRI procedure or allowing entrance to the MRI environment. This is particularly important if the object is located in a potentially dangerous area of the body such as a vital neural, vascular, of soft tissue structure where movement or dislodgment could injure the patient. Currently, MR systems used in clinical and research settings operate with static magnetic fields that range from 0.2-Tesla to 9.4-Tesla. Most previous ex vivo tests performed to assess objects for MR safety used scanners with static magnetic fields of 1.5-Tesla or lower (Shellock, 2008). Obviously, this could present problems insofar as it is possible that an object that displayed “weakly” ferromagnetic qualities in association with a 1.5-Tesla MR system may exhibit substantial magnetic field interactions with an MR system operating at a higher static magnetic field strength. Therefore, investigations have been conducted and are on-going using 3-Tesla and higher field strength MR systems to determine safety for implants and devices relative to these powerful scanners (Shellock, 2008). MRI-Related Heating Temperature increases produced in association with MRI procedures have been studied using ex vivo testing techniques to evaluate various metallic implants, devices, and objects of a variety of different sizes, shapes, and metallic compositions. The typical ex vivo experimental set-up for this procedure involves the use of a plastic head/torso phantom that is filled with gelled-saline that simulates the electrical and thermal properties of human tissue (ASTM, 2005; Woods, 2007). The implant is instrumented with fluoroptic thermometry probes and positioned in the phantom. The phantom is then placed in the MR system and the area containing the implant is subjected to relatively high levels of radiofrequency energy. The temperature rise measured during a 15-min scan period is then used to determine if excessive MRI-related heating occurs. In general, published reports have indicated that only minor temperature changes occur in association with MRI examinations involving relatively small metallic objects that are “passive” implants (i.e., those that are not electronically activated), including implants such as aneurysm clips, hemostatic clips, prosthetic heart valves, vascular access ports, and similar devices. Therefore, heat generated during an MRI examination involving a patient with a “small”

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metallic, passive implant does not appear to be a substantial hazard. In fact, to date, there has been no report of a patient being seriously injured as a result of excessive heating that developed in a “passive” metallic implant or device. However, as previously mentioned, heating is potentially problematic for implants that have an elongated shape or those that form a conducting loop of a certain diameter (Dempsey et al., 2001; Nakamura et al., 2001; Rezai et al., 2001, 2002, 2004, 2005; Finelli et al., 2002; Nyenhuis et al., 2005; Shellock, 2008). For example, substantial heating can occur under some MRI conditions for objects that form resonant conducting loops or for elongated implants (e.g., wires) that form resonant antennae (Dempsy et al., 2001; Nakamura et al., 2001; Kim et al., 2003; Nyenhuis et al., 2005). MRI-related heating for certain implants has been reported to be excessive, causing severe injur­ ies to patients (Kim et al., 2003; Spiegel et al., 2003; Rezai et al., 2004, 2005; Henderson et al., 2005). The determination of implant heating is particularly challenging because of the numerous variables that must be considered to properly identify both MRI- and implant-related conditions that can impact the findings (Rezai et al., 2001, 2002, 2005; Finelli et al., 2002; Georgi et al., 2003; Spiegel et al., 2003; Baker et al., 2004, 2005, 2006, 2007; Bhidayasiri et al., 2005; Shellock et al., 2006). Importantly, the position of the implant in the patient relative to the transmit RF coil (i.e., the primary RF coil used for the imaging procedure) of the MR system greatly impacts the resulting heating (Baker et al., 2004, 2005, 2006, 2007; Shellock et al., 2006; Mattei et al., 2007, 2008; Triventi et al., 2007). Also, the length and dimensions of the implant in relation to the wavelength of the MR-related radiofrequency (RF) field inside the patient or phantom is a critical detail to consider when performing heating tests (Shellock, 2007; Woods, 2007) (Figure 20.2). Once “resonant” with the RF field, implant heating can become dangerously high (Dempsey et al., 2001; Nakamura et al., 2001; Smith et al., 2001; Nyenhuis et al., 2005). Importantly, merely considering the length of an implant is too simplistic insofar as other factors significantly influence MRI-related implant heating (Baker et al., 2004, 2005, 2006, 2007; Nyenhuis et al., 2005; Shellock et al., 2006; Mattei et al., 2007, 2008; Triventi et al., 2007). For example, while the length and dimensions of insulated wires (such as those used for certain neuromodulation systems) may impact heating in a somewhat predictable manner, connecting the lead to the pulse generator tends to decrease MRI related heating at both 1.5-T/64  MHz and 3-T/128  MHz (Shellock et al., 2005). In addition, Baker et al. (2005) described

48 43 Temperature (°C)

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38 33 28 23 18

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Figure 20.2  MRI-related heating at 1.5-Tesla/64  MHz (diamond) vs. 3-Tesla/128 MHz (circle) for a lead not connected to a pulse generator. The MR system whole body averaged SAR used at 1.5-Tesla was 1.4  W/kg and 3 W/kg at 3-Tesla. Note the substantial differences in the temperature profiles caused by MRI-related heating of the lead, which illustrates that different resonant effects impact temperature rises for elongated implants. For an implant of a given length, different RF wavelengths will yield different heating effects (i.e., 64 MHz vs. 128 MHz)

how the number of small concentric loops applied to a deep brain stimulation lead directly affected MRIrelated heating. Fewer loops increased heating while additional loops decreased heating (Baker et al., 2005). Obviously, a more complete understanding of how the dimensions and configurations of different implants influence MRI-related heating is needed. Surprisingly, the distribution of the electrical field used by the MR system may be asymmetric and depends on the direction of the B1 field rotation (Amjad et al., 2005; Baker et al., 2005) which, in turn, affects MRI-related implant heating. This asym­ metry likely explains the asymmetric heating patterns reported for various implants, including deep brain stimulation systems (Baker et al., 2004, 2005, 2006; Amjad et al., 2005). As reported by Mattei et al. (2007, 2008) and Triventi et al. (2007), the type of fluoroptic thermometry probe used to record the temperature on the implant impacts the resulting temperature recordings as well as the specific positioning of the probe in relation to the implant. Incorrect probe type and application to the implant may result in grossly underestimated temperature rises associated with RF heating. Therefore, to properly assess MRI-related heating for an implant, fluouroptic thermometry probes should be applied using a contact position that minimizes the maximum error (as determined in pilot experiments). This is accomplished by ensuring that the measurement component of the thermometry probe directly contacts the

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MRI PROCEDURES, AND IMPLANTS AND DEVICES: GENERAL INFORMATION

intended position on the implant where the highest MRI-related heating will occur (Finelli et al., 2002; Rezai et al., 2002; Baker et al., 2004, 2005, 2006, 2007; Amjad et al., 2005; Bhidayasiri et al., 2005; Shellock et al., 2006; Shellock, 2007). The use of MR system reported whole-body-averaged specific absorption rate or SAR is especially problematic with regard to MRI-related implant heating, as demonstrated by Baker et al. (2004, 2006). Thus, the issue that implant heating may be significantly different when using different 1.5-Tesla MR systems is an important problem to understand and is due to the different manners in which two MR systems may estimate the SAR. Significantly different implant heating for a deep brain stimulation lead in association with different 1.5-Tesla scanners (notably from the same manufacturer) was first reported by Baker et al. (2004) and further examined in other investigations (Nitz et al., 2005; Baker et al., 2006; Shellock et al., 2006). Members of the medical community may not be aware of this vital information and, to date, there is no apparent solution to this disconcerting matter. Suffice to say MR system reported SAR values appear to be overestimates or “conservative” estimates intended to be an upper bound and, thus, current FDA approved labels for implants that rely on this information likely function with a margin of safety relative to MRIrelated heating (Shellock, 2007). MRI-related heating of implants and devices will be covered in greater detail in the sections addressing neuromodulation systems. MRI Artifacts The type and extent of artifacts caused by the presence of metallic implants, materials, and devices have been described and tend to be easily recognized on MR images (Graf et al., 2005; Olsrud et al., 2005). Artifacts associated with metallic objects are predominantly caused by a disruption of the local magnetic field that perturbs the relationship between position and frequency, which is crucial for proper image reconstruction. Additionally, artifacts associated with metallic objects may be caused by gradient switching due to the generation of eddy currents. The relative amount of artifact seen on an MR image is dependent on the magnetic susceptibility, quantity, shape, orientation, and position of the object in the body as well as the technique used for imaging (i.e., the specific pulse sequence parameters) and the image processing method. An artifact caused by the presence of a metallic object in a patient during MRI is seen typically as a local or regional distortion of the image and/or as a signal void. In some cases, there may be areas of high signal intensity seen along the

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edges of the signal void, which is usually related to the shape of the implant. Notably, the size of the artifact for a given metallic implant is inherently larger due to the static magnetic field used for MR imaging (e.g., larger at 3-Tesla vs. 1.5-Tesla) (Graf et al., 2005; Olsrud et al., 2005). Fortunately, there are several MRI techniques that are known to minimize the size of a metal-related artifact.

Terminology A recent “Sentinel Alert” from the Joint Commission on Accreditation of Healthcare Organizations states (2008): In general, do not bring any device or equipment into the MRI environment unless it is proven to be MR Safe or MR Conditional. MR Safe items pose no known hazard in all MRI environments, and MR Conditional items have been demonstrated to pose no known hazards in a specified MRI environment with specified conditions of use. The safety of “MR Conditional” items must be verified with the specific scanner and MR environment in which they will be used.

This statement refers to terminology that has been used for labeling of implants and devices since approximately August 2005 and fails to recognize that these terms have not been applied retrospectively by the US Food and Drug Administration. The terminology applied to implants and devices relative to the MRI environment has evolved over the years. In 1997, the US Food and Drug Administration, Center for Devices and Radiological Health, proposed definitions for the terms “MR Safe” and “MR Compatible,” as follows (Woods, 2007): MR Safe – the device, when used in the MRI environment, has been demonstrated to present no additional risk to the patient or other individual, but may affect the quality of the diagnostic information. The MRI conditions in which the device was tested should be specified in conjunction with the term MR Safe since a device which is safe under one set of conditions may not be found to be so under more extreme MRI conditions. MR Compatible – a device shall be considered “MR Compatible” if it is MR Safe and the device, when used in the MRI environment, has been demonstrated to neither significantly affect the quality of the diagnostic information nor have its operations affected by the MR system. The MRI conditions in which the device was tested should be specified in conjunction with the term MR Safe since a device that is safe under one set of conditions may not be found to be so under more extreme MR conditions.

In order to implement this terminology, “MR safety” testing of an implant or object involved assessments of magnetic field interactions, heating, and, in some cases, induced electrical currents while “MR compatibility” testing required all of these as well as

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characterization of artifacts. In addition, it may have been necessary to evaluate the impact of various MRI conditions on the functional or operational aspects of the implant or device (Woods, 2007). Thus, over the years, manufacturers generally used the terms “MR Safe” and “MR Compatible” when labeling medical implants and devices. However, in time it became apparent that these terms were confusing and were often used interchangeably or incorrectly. Therefore, in an effort to clarify the terminology and, more importantly, because the misuse of these terms could result in serious accidents for patients and other individuals, the MR Task Group of the American Society for Testing and Materials (ASTM) International developed a new set of terms with associated icons (ASTM, 2005; Woods, 2007). The new terms, MR Safe, MR Conditional and MR Unsafe are defined by the ASTM International document, as follows: MR Safe – an item that poses no known hazards in all MRI environments. Using the new terminology, “MR Safe” items include non-conducting, non-metallic, non-magnetic items such as a plastic Petri dish. An item may be determined to be MR Safe by providing a scientifically based rationale rather than test data. MR Conditional – an item that has been demonstrated to pose no known hazards in a specified MRI environment with specified conditions of use. Field conditions that define the MRI environment include static magnetic field strength, spatial gradient, dB/dt (time varying magnetic fields), radio frequency (RF) fields, and specific absorption rate (SAR). Additional conditions, including specific configurations of the item (e.g., the routing of leads used for a neurostimulation system), may be required. For MR Conditional items, the item labeling includes results of testing sufficient to characterize the behavior of the item in the MRI environment. In particular, testing for items that may be placed in the MRI environment must address magnetically induced displacement force and torque, and RF heating. Other possible safety issues include but are not limited to, thermal injury, induced currents/voltages, electromagnetic compatibility, neurostimulation, acoustic noise, interaction among devices, and the safe functioning of the item and the safe operation of the MR system. Any parameter that affects the safety of the item should be listed and any condition that is known to produce an unsafe condition must be described. MR Unsafe – an item that is known to pose hazards in all MRI environments. MR Unsafe items include magnetic items such as a pair of ferromagnetic scissors.

The new terminology is intended to help clarify matters related to biomedical implants and devices in order to ensure the safe use of MRI technology. Importantly, as previously indicated, it should be noted that this new terminology has not been applied retrospectively to implants and devices that previously received FDA approved labeling using the terms “MR safe” or “MR compatible.” Accordingly, this should be understood in order to avoid undue confusion regarding the matter of labeling for “older” vs. “newer” implants.

MRI procedures and neuromodulation systems In the past, the presence of an electronically activated implant was considered a strict contraindication for a patient or individual in the MRI environment. However, over the years, various studies have been performed to define safety criteria for electronic devices (Gleason et al., 1992; Liem and van Dongen, 1997; Walter et al., 1997; Rezai et al., 1999, 2002, 2004; Tronnier et al., 1999; Finelli et al., 2002; Lomarev et al., 2002; Shellock et al., 2002a, 2002b, 2004, 2006, in press; Utti et al., 2002; Georgi et al., 2003; Sharan et al., 2003; Baker et al., 2004, 2005, 2006, 2007; Bhidayasiri et al., 2005; Elkelini and Hassouna et al., 2006; Kovacs et al., 2006; Carmichael et al., 2007; De Andres et al., 2007; Larson et al., 2008; Shellock, 2008). In fact, many of these electronically activated devices devices have received approval of labeling claims for MRI procedures from the FDA. As such, if highly specific guidelines are followed, MRI examinations may be conducted safely in patients with various electronically activated implants, including neuromodulation systems. The incidence of patients receiving neuromodulation systems for treatment of neurological disorders and other conditions is increasing (Rise, 2000). Because of the inherent design and intended function of neuromodulation systems, the electromagnetic fields used for MRI procedures may produce a variety of problems for these devices. For example, altered function of a neuromodulation device that results from exposure to the electromagnetic fields of an MRI system may cause discomfort, pain, or injury to the patient. MRI-related heating has been reported to cause the greatest concern for many different devices used for neuromodulation (Nakamura et al., 2001; Rezai et al., 2001, 2002, 2005; Finelli et al., 2002; Georgi et al., 2003; Spiegel et al., 2003; Baker et al., 2004, 2005, 2006, 2007; Bhidayasiri et al., 2005; Shellock et al., 2006). Box 20.2 shows several factors that must be considered for neuromodulation systems because they impact MRI-related heating. The exact criteria for the particular neuromodulation system with regard to the component parts (e.g., implantable pulse generator, leads, electrodes, pumps, etc.) and operational aspects of the device and the MR system conditions must be defined by comprehensive testing and carefully followed to ensure patient safety. Otherwise, serious injuries can occur (Spiegel et al., 2003; Rezai et al., 2004, 2005 Henderson et al., 2005). Examples of various neuromodulation systems that have criteria defined to permit safe MRI examinations are presented in this chapter. When available, labeling approved by the FDA is presented. In all cases, however, healthcare professionals are advised to contact

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Box 20.2 

 Variables that impact MRI-related heating for neuromodulation systems l l

Specific type of neuromodulation system Electrical characteristics of the specific neuromodulation system Field strength and RF wavelength of the MR system Type of transmit RF coil – Transmit/receive body RF coil – Transmit body coil/receive-only head RF coil – Transmit/receive head RF coil l The amount of RF energy delivered-RF power level – The specific absorption rate (SAR) – The technique used to calculate or estimate SAR used by the MR system l The patient’s anatomy imaged – The landmark position or body part undergoing MRI relative to the transmit RF coil l Orientation and configuration of the implantable pulse generator (IPG), extension (e.g., the cable connecting the IPG to the implanted lead), and the lead relative to the source of RF energy l l

the respective manufacturer in order to obtain the latest information to ensure patient safety relative to the use of an MRI procedure.

Programmable Infusion Pumps Implantable, programmable infusion pumps and associated catheters are used for neuromodulation procedures via intrathecal or intravascular administration of various medications (von Roemeling et al., 1991; Anderson and Burchiel, 1999, 2003; Turner, 2003; Smith et al., 2005; Shellock et al., in press). The utilization of these devices for “targeted” drug delivery has several advantages, including significantly decreasing the dosages used (which appears to reduce drugrelated adverse events) and increasing patient mobility (Anderson and Burchiel, 1999; Turner, 2003). Programmable infusion pumps and associated catheters typically contain metallic components and, thus, have certain features that may be impacted by conditions related to MRI (von Roemeling et al., 1991), particularly if the procedure is performed at 3-Tesla (Shellock et al., in press). For example, the MRI-related electromagnetic fields (static, gradient magnetic, and radio frequency fields) may displace this implant, generate excessive heating, alter the programmed settings, damage the device, or create substantial artifacts. Several programmable pumps have undergone comprehensive MRI testing and FDA approved labeling information for these are provided in Boxes 20.3 and 20.4.

An advanced search of the FDA’s Manufacture and User Facility Device Database (MAUDE, 2008) for a commonly used programmable infusion pump (SynchroMed, Medtronic, Inc., Minneapolis, MN) was conducted for the years 1/1/2001 through 12/31/2005 to determine the types of device malfunctions reported to the FDA (Shellock et al., in press). There were 30 reports of device malfunction for this programmable infusion pump. “True” pump malfunction, most often related to motor stall, was the most common complaint (16/30, 53%). Of these 16, four (25%) were associated with the patient having been exposed to an MRI procedure or other electromagnetic diagnostic modality. Notably, this particular pump contains an electromagnetic peristaltic motor for the pump mechanism, which may be responsible for the problems associated with MRI. Ideally, from an MRI consideration, the flow-control mechanism for an implanted, programmable infusion pump should not be comprised of components that are susceptible to the electromagnetic fields used for MRI. Another, programmable infusion pump (MedStream Programmable Infusion Pump, Codman & Shurtleff, Inc., a Johnson & Johnson Company) recently evaluated for MRI issues, has a flow control mechanism designed primarily from nonmagnetic materials, and as such, appears to operate in an acceptable manner in the MRI environment (Shellock et al., in press). To date, the peer-reviewed literature has a report for only one programmable infusion pump that has been evaluated at 3-Tesla (Shellock et al., in press).

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Box 20.3 

 MRI information for the SynchroMed, SynchroMed EL, and SynchroMed II Drug Infusion Systems The following is the MRI information for the SynchroMed, SynchroMed EL, and SynchroMed II Drug Infusion Systems (Medtronic, Inc., Minneapolis, MN).

Models

rise and the 20 minute scan time is representative of a typical imaging session. FDA MRI guidance allows a physiological temperature rise of up to 2 degrees Celsius in the torso, therefore the local temperature rise in the phantom is considered by FDA guidance to be below the level of concern. Implanting the pump more lateral to the midline of the abdomen may result in higher temperature rises in tissues near the pump. In the unlikely event that the patient experiences uncomfortable warmth near the pump, the MRI scan should be stopped and the scan parameters adjusted to reduce the SAR to comfortable levels.

SynchroMed: All models beginning with 8616, 8617, 8618 SynchroMed EL: All models beginning with 8626, 8627 Reference: SynchroMed EL Technical Manual (197768-007) SynchroMed pump performance has not been established in 2.0-T MR scanners and it is not recommended that patients have MRI using these scanners. Magnetic resonance imaging (MRI) will temporarily stop the rotor of the pump motor due to the magnetic field of the MRI scanner and suspend drug infusion for the duration of MRI exposure. The pump should resume normal operation upon termination of MRI exposure. Prior to MRI, the physician should determine if the patient can safely be deprived of drug delivery. If the patient cannot be safely deprived of drug delivery, alternative delivery methods for the drug can be utilized during the time required for the MRI scan. If there is concern that depriving the patient of drug delivery may be unsafe for the patient during the MRI procedure, medical supervision should be provided while the MRI is conducted. Prior to scheduling an MRI scan and upon completion of the MRI scan, or shortly thereafter, the pump status should be confirmed using the clinician programmer. In the unlikely event that any change to the pump status has occurred, a “pump memory error” message will be displayed and the pump will sound a Pump Memory Error Alarm (double tone). The pump should then be reprogrammed and Medtronic Technical Services notified at (800) 707-0933. Testing on the SynchroMed pump has established the following with regard to other MR safety issues:

Time-varying gradient magnetic fields: Presence of the pump may potentially cause a two-fold increase of the induced electric field in tissues near the pump. With the pump implanted in the abdomen, using pulse sequences that have dB/dt up to 20-T/sec, the measured induced electric field near the pump is below the threshold necessary to cause stimulation. In the unlikely event that the patient reports stimulation during the scan, the proper procedure is the same as for patients without implants – stop the MRI scan and adjust the scan parameters to reduce the potential for nerve stimulation. Static magnetic field: For magnetic fields up to 1.5T, the magnetic force and torque on the SynchroMed pump will be less than the force and torque due to gravity. For magnetic fields of 2.0-T, the patient may experience a slight tugging sensation at the pump implant site. An elastic garment or wrap will prevent the pump from moving and reduce the sensation the patient may experi­ ence. SynchroMed pump performance has not been established in 2.0-T MR scanners and it is not recommended that patients have MRI using these scanners.

Tissue heating adjacent to implant during MRI scans

Image distortion

Specific absorption rate (SAR): Presence of the pump can potentially cause a two-fold increase of the local temperature rise in tissues near the pump. During a 20-minute pulse sequence in a 1.5-T GE Signa Scanner with a whole-body average SAR of 1 W/kg, a temperature rise of 1 degree Celsius in a static phantom, was observed near the pump implanted in the “abdomen” of the phantom. The temperature rise in a static phantom represents a worst case for physiological temperature

The SynchroMed pump contains ferromagnetic components that will cause image distortion and image dropout in areas around the pump. The severity of image artifact is dependent on the MR pulse sequence used. For spin echo pulse sequences the area of significant image artifact may be 20–25 cm across. Images of the head or lower extremities should be largely unaffected. Minimizing image distortion: MR image artifact may be minimized by careful choice of pulse sequence parameters

Peripheral nerve stimulation during MRI scans

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and location of the angle and location of the imaging plane. However, the reduction in image distortion obtained by adjustment of pulse sequence parameters will usually be at a cost in signal to noise ratio. The following general principles should be followed: Use imaging sequences with stronger gradients for both slice and read encoding directions. Employ higher bandwidth for both RF pulse and data sampling. l Choose an orientation for read-out axis that minimizes the appearance of in-plane distortion. l Use spin echo (SE) or gradient echo (GE) MR imaging sequences with a relatively high data sampling bandwidth. l Use shorter echo time (TE) for gradient echo technique, whenever possible. l Be aware that the actual imaging slice shape can be curved in space due to the presence of the field disturbance of the pump (as stated above). l Identify the location of the implant in the patient and, when possible, orient all imaging slices away from the implanted pump.

l

Models SynchroMed II: All models beginning with 8637 Reference: SynchroMed II Technical Manual (221311-002) Programmable pump performance has not been established in 1.5-T magnetic resonance scanners, and it is not recommended that patients have MRI using these scanners. MRI will temporarily stop the rotor of the pump motor due to the magnetic field of the MRI scanner and suspend drug infusion for the duration of MRI exposure. This will cause the pump alarm to sound. The pump should resume normal operation upon termination of MRI exposure. [Note: Motor stall and subsequent motor recovery events will be recorded into the pump event log.] Prior to MRI, the physician should determine if the patient can safely be deprived of drug delivery. If the patient cannot be safely deprived of drug delivery, alternative delivery methods for the drug can be utilized during the time required for the MRI scan. If there is concern that depriving the patient of drug delivery may be unsafe for the patient during the MRI procedure, medical supervision should be provided while the MRI is conducted. Prior to an MRI scan and upon completion of the MRI scan, or shortly thereafter, the pump status should be confirmed using the clinician programmer. Testing on programmable pumps has established the following with regard to other MRI safety issues:

Tissue heating adjacent to implant during MRI scans Specific absorption rate (SAR): Presence of the pump can potentially cause a two-fold increase of the local

257

temperature in tissues near the pump. During a 20-minute pulse sequence in a 1.5-Tesla (T) GE Signa scanner with a whole-body average SAR of 1 W/kg, a temperature increase of 1 degree Celsius in a static phantom was observed near the pump implanted in the “abdomen” of the phantom. The temperature increase in a static phantom represents a worst case for physiological temperature increase and the 20-minute scan time is representative of a typical imaging session. FDA MRI guidance allows a physiological temperature increase of up to 2 degrees Celsius in the torso. Therefore, the local temperature increase in the phantom is considered by FDA guidance to be below the level of concern. Implanting the pump more lateral to the midline of the abdomen may result in higher temperature increases in tissues near the pump. In the unlikely event that the patient experiences uncomfortable warmth near the pump, the MRI scan should be stopped and the scan parameters adjusted to reduce the SAR to comfortable levels.

Peripheral nerve stimulation during MRI scans Time-varying gradient magnetic fields: Presence of the pump may potentially cause a two-fold increase of the induced electric field in tissues near the pump. With the pump implanted in the abdomen, using pulse sequences that have dB/dt up to 20-T/s, the measured induced electric field near the pump is below the threshold necessary to cause stimulation. In the unlikely event that the patient reports stimulation during the scan, the proper procedure is the same as for patients without implants – stop the MRI scan and adjust the scan parameters to reduce the potential for nerve stimulation.

Static magnetic field For magnetic fields up to 1.5-T, the magnetic force and torque on the programmable pump will be less than the force and torque due to gravity. For magnetic fields of 2.0-T, the patient may experience a slight tugging sensation at the pump implant site. An elastic garment or wrap will prevent the pump from moving and reduce the sensation the patient may experience.

Image distortion The programmable pump contains ferromagnetic components that will cause image distortion and image dropout in areas around the pump. The severity of image artifact is dependent on the MR pulse sequence used. For spin echo pulse sequences, the area of significant image artifact may be 20–25 cm across. Images of the head or lower extremities should be largely unaffected. Minimizing image distortion: MR image artifact may be minimized by careful choice of pulse sequence parameters

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and location of the angle and location of the imaging plane. However, the reduction in image distortion obtained by adjustment of pulse sequence parameters will usually be at a cost in signal-to-noise ratio. The following general principles should be followed: Use imaging sequences with stronger gradients for both slice and read encoding directions. Employ higher bandwidth for both radio-frequency pulse and data sampling. l Choose an orientation for read-out axis that minimizes the appearance of in-plane distortion. l

Use spin echo or gradient echo MR imaging sequences with a relatively high data sampling bandwidth. l Use shorter echo time for gradient echo technique, whenever possible. l Be aware that the actual imaging slice shape can be curved in space due to the presence of the field disturbance of the pump (as stated above). l Identify the location of the implant in the patient, and when possible, orient all imaging slices away from the implanted pump. l

Box 20.4 

 MRI information for the IsoMed Implantable Constant Flow Infusion Pump The following is the MRI information for the IsoMed Implantable Constant Flow Infusion Pump (Medtronic, Inc., Minneapolis, MN).

Models IsoMed: All models beginning with 8472 Reference: IsoMed Technical Manual (220666-001) Exposure of IsoMed pumps to Magnetic Resonance Imaging (MRI) fields of 1.5-T has demonstrated no impact on pump performance and a limited effect on the quality of the diagnostic information. Testing on the IsoMed pump has established the following with regard to MRI safety and diagnostic issues.

Implant heating during MRI scans Specific absorption rate (SAR): Presence of the pump can potentially cause a two-fold increase of the local temperature rise in tissues near the pump. During a 20 minute pulse sequence in a 1.5-T (Tesla) GE Signa Scanner with a whole-body average SAR of 1 W/kg, a temperature rise of 1 degree Celsius in a static phantom was observed near the pump implanted in the “abdomen” of the phantom. The temperature rise in a static phantom represents a worst case for physiological temperature rise and the 20 minute scan time is representative of a typical imaging session. Implanting the pump in other locations may result in higher temperature rises in tissues near the pump. In the unlikely event that the patient experiences uncomfortable warmth near the pump, the MRI scan

should be stopped and the scan parameters adjusted to reduce the SAR to comfortable levels.

Peripheral nerve stimulation Time-varying gradient magnetic fields: Presence of the pump may potentially cause a two-fold increase of the induced electric field in tissues near the pump. With the pump implanted in the abdomen, using pulse sequences that have dB/dt up to 20 T/s, the measured induced electric field near the pump is below the threshold necessary to cause stimulation. In the unlikely event that the patient reports stimulation during the scan, the proper procedure is the same as for patients without implants – stop the MRI scan and adjust the scan parameters to reduce the potential for nerve stimulation.

Static magnetic field For magnetic fields up to 1.5 T, the magnetic force and torque on the IsoMed pump will be less than the force and torque due to gravity. In the unlikely event that the patient reports a slight tugging sensation at the pump implant site, an elastic garment or wrap may be used to prevent the pump from moving and reduce the sensation the patient may experience.

Image distortion The IsoMed pump will cause image dropout on MRI images in the region surrounding the pump. The extent

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MRI PROCEDURES AND NEUROMODULATION SYSTEMS

of image artifact depends on the pulse sequence chosen with gradient echo sequences generally causing the most image dropout. Spin echo sequences will cause image dropout in a region approximately 50% larger than the pump itself, about 12 cm across, but with little image distortion or artifact beyond that region.

Minimizing image distortion MRI image artifact may be minimized by careful choice of pulse sequence parameters and location of the angle and location of the imaging plane. However, the reduction in image distortion obtained by adjustment of pulse sequence parameters will usually be at a cost in signal-tonoise ratio. These general principles should be followed:

259

Choose an orientation for read-out axis that minimizes the appearance of in-plane distortion. l Use spin echo (SE) or gradient echo (GE) MRI imaging sequences with a relatively high data sampling bandwidth. l Use shorter echo time (TE) for gradient echo technique, whenever possible. l Be aware that the actual imaging slice shape can be curved in space due to the presence of the field disturbance of the pump (as stated above). l Identify the location of the implant in the patient and when possible, orient all imaging slices away from the implanted pump. l

Use imaging sequences with stronger gradients for both slice and read encoding directions. Employ higher bandwidth for both RF pulse and data sampling.

l

The findings for this pump and associated catheters (MedStream Programmable Infusion Pump, 40-mL; SureStream Coil-reinforced Intraspinal catheter, SureStream TI connector, and SureStream Silicone catheter; Codman & Shurtleff, Inc., a Johnson & Johnson Company) (Figure 20.3) indicated that these devices will not pose increased risk to a patient examined using a 3-Tesla MRI, as long as specific safety guidelines are followed, which include interrogation of the pump post-MRI to ensure proper settings (Box 20.5). Artifacts for the programmable infusion pump may impact the diagnostic use of MRI if the area of interest is in the same area or near the device. Notably, the findings pertain to this programmable infusion pump and associated catheters, only, and are relative to the MRI conditions that were used for the evaluation (Shellock et al., in press). Currently, FDA approval for MRI labeling is pending.

Bion Microstimulator Certain neurological disorders are caused by the absence of neural impulses, the disruption of these impulses, or the failure of them to reach their natural destinations in otherwise functional systems. Surgically implanted neurostimulators and electrodes may be utilized to provide functional electrical stimulation of the affected site. However, these devices may be associated with considerable surgical morbidity and expense. As such, there has been an on-going effort to develop technology that would combine the reliability of using an implanted device with a low morbidity

Figure 20.3  Programmable infusion pump and catheter (MedStream Programmable Infusion Pump, 40-mL; SureStream Coil-reinforced Intraspinal catheter, SureStream TI connector, and SureStream Silicone catheter; Codman & Shurtleff, Inc., a Johnson & Johnson Company) at 3-Tesla MR system (Food and Drug Administration approval for MRI labeling is pending) (see Shellock et al., 2008)

and low cost procedure. This effort has yielded a miniaturized, implantable device designed for functional electrical stimulation (Heetderks, 1988; Loeb et al., 1991, 2001, 2006; Cameron et al., 1997; Walter et al., 1997; Zealear et al., 2001; Arcos et al., 2002). In 1988, Heetderks (1988) first demonstrated the feasibility of using a millimeter-sized, neural prosthetic implant. Over the years, this so-called “microstimulator”

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Box 20.5 

 MRI information for the MedStream Programmable Infusion Pump and associated catheters* *MedStream Programmable Infusion Pump, 40-mL; SureStream Coil-reinforced Intraspinal catheter, SureStream TI connector, and SureStream Silicone catheter; Codman & Shurtleff, Inc., a Johnson & Johnson Company) (Food and Drug Administration approval for MRI labeling is pending).

1. Patients may undergo MRI exams at 3-T or less immediately after implantation of this pump and catheter after confirmation that cessation of therapy will not negatively impact the patient. If the cessation of drug therapy will negatively impact the patient but the MRI procedure is still necessary, an alternate means of temporary drug delivery with clinical monitoring should be implemented. 2. Based on the information from this study, while it is not necessary to check the pre-MRI settings for the pump, the need for such a step is left to the discretion of the healthcare professional responsible for the patient. As such, the programmable infusion pump setting would be determined by appropriate personnel using the Programming/Control Unit.

evolved to its present form. The Bion microstimulator (RF Bion 5 bionic neuron, developed by Alfred E. Mann Foundation for Scientific Research, Valencia, CA) now exists as a relatively small, wireless, digitally controlled stimulator that is implanted using a minimally invasive procedure to provide electrical pulses to a muscle or nerve (Loeb et al., 1991, 2001, 2006). This device receives power and command signals by inductive coupling from an externally worn coil that generates a radiofrequency magnetic field. The Bion microstimulator is undergoing clinical trials to assess its therapeutic effect on a variety of neurological disorders including urinary incontinence, shoulder subluxation, dropfoot, ventilator-dependent respiratory deficiencies, and sleep apnea (Loeb et al., 1991, 2001, 2006; Walter et al., 1997; Zealear et al., 2001 Arcos et al., 2002). Because of the potential widespread use of this neuromodulation system, similar to other implants, this device underwent a comprehensive ex vivo evaluation to determine if it is safe for a patient who may need an MRI procedure (Shellock et al., 2004). The Bion microstimulator is a wireless device designed for functional electrical stimulation of the peripheral nervous system. This hermetically sealed implant is a small, lightweight, cylindrical-shaped device (length 16.6 mm; diameter 2.4 mm; mass 0.265 g) made of a ceramic tube closed on each end by titanium caps and contains

3. The exposure to RF energy should be limited to an MR system-reported, whole body averaged SAR of 3 W/kg for 15 min for a given pulse sequence applied to the patient. 4. Upon completion of the MRI examination, the pump parameters should be confirmed and reset, as needed. 5. Exposure to the MR system may cause the programmable pump to alarm. Thus, it is necessary to confirm pump status using the Programmer/ Control Unit for all pumps after MRI exposure and to reinitiate infusion therapy if it has stopped. This should be taken into consideration by healthcare professionals with regard to patient management.

1

2

CENTIMETERS Figure 20.4  The Bion microstimulator (RF Bion, Boston Scientific/Alfred E. Mann Foundation for Scientific Research, Valencia, CA). This is a relatively small, wireless, digitally controlled stimulator that is implanted using a minimally invasive procedure to provide electrical pulses to a muscle or nerve (see Loeb et al., 1991, 2001, 2006)

components made from titanium, gold, copper, ferrite, platinum, iridium, silicon, zirconium, and tantalum (Figure 20.4). The active electrodes are welded on each end cap: an iridium disk on the cathodal side and a platinum-iridium eyelet on the anodal side.

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MRI PROCEDURES AND NEUROMODULATION SYSTEMS

261

Box 20.6 

 MRI information for the Bion microstimulator* *

RF Bion, Alfred E. Mann Foundation for Scientific Research, Valencia, CA. In consideration of the results of the tests conducted to evaluate the Bion microstimulator with regard to MRI, the following safety guidelines are recommended (Shellock et al., 2004): 1. A patient with the Bion microstimulator may undergo MRI at 1.5-Tesla after a post-implantation waiting period of 6 weeks. 2. Only a 1.5-Tesla MR system should be used for the examination. 3. The exposure to RF energy should be limited to an MR system reported whole body averaged SAR of 2.0 W/kg for 15 min. 4. Only pulse sequences similar to those demonstrated to have no affect on the microstimulator’s function should be used for MRI.

The Bion microstimulator receives power and digital commands via a 2 MHz radiofrequency magnetic field link generated from an external coil that is worn by the patient. Notably, the external coil may not be applied to interface with this neuromodulation system if a patient needs an MRI procedure. Because of the small size of this microstimulator, it may be implanted through a specially designed, trocar-based 12- or 14-gauge implant tool or via a small surgical opening for placement near a nerve or at the motor unit of a muscle. MRI-related safety issues and other concerns were evaluated for the Bion microstimulator in association with the use of a 1.5-Tesla MR system (Shellock et al., 2004). While magnetic field interactions were shown to be larger than gravitational force and torque, given the small mass of the device and in consideration of the existence of stabilizing means for this device (when implanted in-vivo the application of a suture and tissue encapsulation that occurs over time), after a suitable post-implant waiting period (e.g., 6 weeks), the Bion is unlikely to move during exposure to a 1.5-Tesla MR system. Furthermore, the MRI-related heating evaluation indicated that the Bion microstimulator will not cause increased risk to a patient with this device undergoing an MRI examination according to the conditions used for this evaluation (i.e., MR system reported whole body averaged SAR of 4.0 W/kg

5. The patient should be monitored continuously throughout the MRI procedure using visual and audio means (e.g., intercom system). 6. Instruct the patient to alert the MR system operator of any unusual sensations or problems so that, if necessary, the MR system operator can immediately terminate the procedure. 7. Provide the patient with a means to alert the MR system operator of any unusual sensations or problems. 8. Do not perform MRI if the patient is sedated, anesthetized, confused or otherwise unable to communicate with the MR system operator. 9. After MRI, an evaluation of the microstimulator’s function should be performed to ensure that it is operating properly.

for 15 min.). The functional aspects of the microstimulator were shown to be unaffected by 15 different pulse sequences that may be used for clinical MRI procedures. Artifacts for the Bion microstimulator were relatively large in relation to the implant’s size due to the presence of the material, ferrite. This may impact the diagnostic use of MRI if the area of interest is in the same area or near where this implant is located. Another safety issue that was considered is the theoretical risk of the Bion microstimulator generating stimulation pulses while the patient is undergoing an MRI procedure at 1.5-Tesla/64 MHz. However, the RF field generated by this scanner is not of sufficient intensity to power this implanted device. In its normal operational mode, the Bion microstimulator is powered and controlled by a radio frequency link at 2 MHz. The equivalent magnetic field strength required to bring the digital circuits of the microstimulator out of a “reset state” is 45 microTesla. The receiving circuit, inside the device, has a resonant frequency centered at 2 MHz and a quality factor of 30. This forms a band pass filter at 2 MHz with 66 KHz bandwidth, which provides 36 dB attenuation at 64 MHz. An MR system would need to produce continuous 2.83 mT (milliTesla) at 64 MHz to generate enough power to “awaken” the BION microstimulator. Box 20.6 displays the guidelines for performing an MRI examination in a patient with this neuromodulation system.

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Vagus Nerve Stimulation (VNS) System, VNS Therapy System Vagus nerve stimulation (VNS) therapy is a technique whereby a pulse generator is used to deliver intermittent electrical pulses via electrodes placed on the left vagus nerve at the cervical level (Benbadis et al., 2001; Lomarev et al., 2002; Narayanan et al., 2002; Kosel and Schlaepfer, 2003; Physician’s Manual, VNS Therapy, 2003; Shellock et al., 2006). VNS is an approved treatment for epilepsy and treatment-resistant depression and is under investigation as a therapy for other disorders, including anxiety, Alzheimer’s disease, morbid obesity, and migraine headaches (Benbadis et al., 2001; Lomarev et al., 2002; Narayanan et al., 2002; Kosel and Schlaepfer, 2003; Physician’s Manual, VNS Therapy, 2003; Groves and Brown, 2005). Currently, this is the only neuromodulation system approved by the FDA for vagus nerve stimulation. MRI is often needed to manage patients with the VNS Therapy System (Vagus Nerve Stimulation, Vagal Nerve Stimulator, VNS Therapy, NeuroCybernetic Prosthesis, NCP, System [Cyberonics, Inc., Houston, TX]) (Figure 20.5a) and has been utilized to elucidate the mechanisms responsible for the success or failure of vagus nerve stimulation (Benbadis et al., 2001; Lomarev et al., 2002; Narayanan et al., 2002; Kosel and Schlaepfer, 2003). Importantly, to ensure the safe use of MRI in patients with this device, scanning may only be performed by following specific guidelines (Box 20.7). Of note is that the current product labeling states (Physician’s Manual, VNS Therapy, 2003):

(A)

Magnetic resonance imaging (MRI) should not be performed with a magnetic resonance body coil. The heat induced in the lead by an MRI body scan can cause injury. If it is necessary to perform an MRI, only a transmit and receive type of head coil should be used [Figure 20.5b]. Thus, protocols must not be used which utilize local coils that are RF receiveonly, with RF-transmit performed by the body coil. Note that some RF head coils are receive-only, and that most other local coils, such as knee and spinal coils, are also RF receiveonly. These coils must not be used in patients with the VNS Therapy System.

These guidelines apply to MR systems operating at 2-Tesla and a specific absorption rate (SAR) of 1.3 W/kg. The rationale for these recommendations is that, similar to other neurostimulation systems (Shellock, 2008), MRI-related heating is the primary safety concern for this device. Unfortunately, the safety recommendations for the VNS Therapy System are limiting for patients for the following reasons: (1) many present-day 1.5-Tesla scanners use a transmit RF body coil and a receiveonly head coil to image the head/brain, not a transmit/receive head coil; (2) the utilization of 3-Tesla MR

(B)

Figure 20.5  (A) Schematic showing the VNS Therapy System (Vagus Nerve Stimulation, Vagal Nerve Stimulator, VNS Therapy, NeuroCybernetic Prosthesis, NCP, System [Cyberonics, Inc., Houston, TX]). Note the position of the pulse generator, lead, and electrode, which is placed around the vagus nerve. (B) Illustration of the relative position of the VNS Therapy System as it would be in a patient undergoing an MRI procedure using a transmit/receive RF head coil (shaded area). The positioning scheme and the MRI conditions minimize the coupling of RF energy to the VNS Therapy System and, thus, the possibility for substantial MRI-related heating

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263

Box 20.7 

 MRI information for the Vagus Nerve stimulation Vagal Nerve Stimulator, VNS Therapy, NeuroCybernetic Prosthesis (NCP) System* *Cyberonics, Inc., Houston, TX. This information was obtained from the Cyberonics website, 5/2008, www.Cyberonics.com.

MRI Safety Information (MRI) should not be performed with a magnetic reson­ ance body coil in the transmit mode. The heat induced in the lead by an MRI body scan can cause injury. If an MRI should be done, use only a transmit and receive type of head coil. Magnetic and RF fields produced by MRI may change the Pulse Generator settings (change to reset parameters) or activate the device. Stimulation has been shown to cause the adverse events reported in the “Adverse Events” section of this manual. MRI compatibility was demonstrated using a 1.5T General Electric Signa Imager with a Model 100 only. The Model 102 and Model 102R are functionally equivalent to the Model 100. Testing on this imager as performed on a phantom indicated that the following Pulse Generator and MRI procedures can be used safely without adverse events: Pulse Generator output programmed to 0 mA for the MRI procedure, and afterward, retested

l

systems for MRI examinations is increasing, therefore, safety needs to be assessed with regard to MRI-related heating at 3-T; and (3) the current labeling does not provide guidance for other body parts, which prevents the important diagnostic modality of MRI from being used to manage patients with conditions unrelated to the head/brain area (Shellock et al., 2006). Recently, an investigation was conducted by Shellock et al. (2006) to characterize MRI-related heating for the VNS Therapy System to determine if guidelines could be expanded to include the use of a transmit RF body coil and receive-only RF head coil at 1.5-Tesla, along with the ability to perform MRI examinations at 3-Tesla. With respect to the transmit RF coil issues, it should be noted that MRI-related heating of implants tends to be substantially less when using a transmit/receive head or transmit/receive extremity coil compared with a transmit RF body coil because the overall area subjected to RF energy is minimized and the whole body averaged SAR level for a given pulse sequence is inherently less (Finelli et al., 2002; Rezai et al., 2002; Baker et al., 2006). The VNS Therapy System was assessed using in vitro techniques to evaluate MRI-related heating



l l



l



l

by performing the Lead Test diagnostics and reprogrammed to the original settings Head coil type: transmit and receive only Static magnetic field strength: up to and including 2.0-Tesla Specific-rate absorption (SAR):  1.3 W/kg for a 154.5 lb (70 kg) patient Time-varying intensity:  10-Tesla/sec

Use caution when other MRI systems are used, since adverse events may occur because of different magnetic field distributions. Procedures in which the RF is transmitted by a body coil should not be done on a patient who has the VNS Therapy System. Thus, protocols must not be used that utilize local coils that are RF-receive only, with RF-transmit performed by the body coil. Note that some RF head coils are receive-only, and that most other local coils, such as knee and spinal coils, are also RF receive-only. These coils must not be used in patients with the VNS Therapy System.

at 1.5- and 3-Tesla using different leads, positioning configurations, transmit RF coils (body and head), levels of RF power (SAR), and scans on different body regions. This investigation identified potentially unsafe (Figure 20.6) as well as safe conditions with regard to MRI-related heating (Shellock et al., 2006). Device function was unaffected by MRI procedures performed at 1.5- and 3-Tesla. Thus, by following specific conditions, the safety guidelines for the VNS Therapy System could be expanded beyond those currently recommended by the manufacturer (Shellock et al., 2006). However, the data from this study are currently undergoing review by the FDA and, thus, labeling is pending that would address new MRI conditions, providing guidelines to safely scan patients with the VNS Therapy System using 1.5- and 3-Tesla scanners.

Neurostimulation Systems for Deep Brain Stimulation Deep brain stimulation (DBS) is one of the most rapidly growing areas in neurosurgery, with over 50 000

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50 46 Temperature (°C)

42 38 34 30 26 22 18

0

200

400

600

800

1000

1200

1400

Time (sec) Probe 1

Probe 2

Probe 3

Figure 20.6  MRI-related heating for the VNS Therapy System: 1.5-Tesla MR system using the transmit body RF coil and an MR system reported whole body averaged SAR of 1.4 W/kg. The experimental conditions included an unattached lead (i.e., no pulse generator connected) and the scan site involved the area of the cervical spine/shoulder. The lead was positioned to form a strain relief bend and a strain relief loop. The site of the highest temperature change was the proximal electrode of the lead, 29.2 °C (probe 1, distal electrode; probe 2, proximal electrode; probe 3, lead connector). Obviously, these conditions must be avoided due to the excessive heating for the VNS Therapy System (see Shellock et al., 2006)

DBS implants worldwide and FDA-approved indications for treating Parkinson’s disease, essential tremor, and dystonia. In addition, a number of clinical trials are under way assessing the role of DBS to treat epilepsy, chronic pain, cluster headaches, obsessive–compulsive disorder, major depression, and other conditions. Despite rapid growth in neurostimulation technology and clinical application, there have been relatively few studies directed at assessing the safety of performing MRI procedures on patients with DBS neuromodulation systems (Rezai et al., 1999; Finelli et al., 2002; Starr et al., 2002; Utti et al., 2002; Georgi et al., 2003; Sharan et al., 2003; Spiegel et al., 2003; Baker et al., 2004, 2005, 2006, 2007; Bhidayasiri et al., 2005; Kovacs et al., 2006; Phillips et al., 2006; Shellock et al., 2006; Carmichael et al., 2007; Larson et al., 2008), especially considering the many types of MRI conditions that must be taken into consideration. The current management of patients with DBS devices referred for MRI procedures involves various approaches. Certain centers routinely scan these patients based on the premise that there have been no previous problems in those scanned in the past. Other MRI facilities scan patients with DBS implants only by following highly specific guidelines. In other facilities, the use of MRI examinations in patients with these neuromodulation systems is strictly prohibited.

Importantly, the necessity for the use of MRI procedures in the DBS patients is implicit. The MRI examination is frequently important for the diagnosis of hemorrhage, stroke or other intracranial lesions, assessing progression of neurodegenerative disorders, and for evaluation of spinal disorders. In addition, MRI is beneficial for determining postoperative DBS lead location, crucial for the evaluation of patients with suboptimal results or side effects, as well as for targeting in revision or additional DBS or other cranial surgeries. MRI-guided procedures may also be used to optimally position the electrodes used for DBS and, thus, substantially decrease the time required for implantation (Starr et al., 2002). Furthermore, functional MRI is proving to be greatly beneficial for helping us to understand the mechanisms of DBS as well as the pathophysiology of the disorders (Phillips et al., 2006; Carmichael et al., 2007). The necessity to use MRI in DBS patients has prompted several groups to systematically study the various safety concerns. Investigations were conducted to define specific recommendations to permit the safe use of this imaging modality in patients with implanted DBS neuromodulation systems. Importantly, these studies have resulted in the current manufacturer’s guidelines for the use of MRI in a patient with a neurostimulation system used for DBS. Activa Tremor Control System Various investigations have evaluated MRI issues, with an emphasis on MRI-related heating, for the DBS neuromodulation system, Activa Tremor Control System (Medtronic, Inc., Minneapolis, MN) (Rezai et al., 1999, 2002; Finelli et al., 2002; Starr et al., 2002; Utti et al., 2002; Georgi et al., 2003; Sharan et al., 2003; Baker et al., 2004, 2005, 2006, 2007; Bhidayasiri et al., 2005; Kovacs et al., 2006; Phillips et al., 2006; Shellock et al., 2006; Larson et al., 2008), which is approved by the FDA for use in chronic deep brain stimulation. This device is a fully implantable, multiprogrammable device designed to deliver electrical stimulation to the thalamus or other brain structures. The basic implantable system is comprised of the neurostimulator (or implantable pulse generator, IPG), DBS lead, and an extension that connects the lead to the IPG. This neuromodulation device delivers high frequency electrical stimulation to a multiple contact electrode placed in the ventral intermediate nucleus of the thalamus or other anatomic sites. Various investigations performed on this particular DBS system indicated that MRI safety issues are highly dependent on a number of critical factors. To simulate a “worst-case” clinical application of DBS, these investigations evaluated bilateral DBS applications such that

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Temperature change (°C)

30.00

R-Probe M-Probe L-Probe

25.00 20.00 15.00 10.00 5.00 0.00

0

200

400

Temperature change (°C)

30.00

two pulse generators, two extensions, and two leads were assessed during in vitro experiments (Finelli et al., 2002; Rezai et al., 2002) (Figure 20.7). Different configurations were evaluated for the bilateral neuromodulation systems to characterize worst-case and clinically relevant positioning scenarios. MRI procedures were performed on a gelled-saline-filled, head/torso phantom designed to approximate the head and torso of a human subject. Temperature changes were studied in association with MRI examinations conducted at 1.5Tesla/64  MHz at various levels of RF energy using the transmit/receive RF body and transmit/receive head RF coil. The findings from these studies indicated that substantial heating occurs under certain conditions while others produced relatively minor, physiologically inconsequential temperature increases (Finelli et al., 2002; Rezai et al., 2002) (Figure 20.8). Furthermore, factors that strongly influenced local temperature increases at the electrode tip included the positioning of the neuromodulation system (especially the electrode), the type of transmit RF coil used, the specific absorption rate (SAR) used for the MRI procedure, and how the SAR level was calculated by the MR system (Finelli et al., 2002; Rezai et al., 2002; Georgi et al., 2003;

800

1000

1200

800

1000

1200

Seconds

(A)

Figure 20.7  The Activa Tremor Control System showing the Soletra Model 7426 neurostimulator, Model 7495 quadripolar extension, and Model 3389 DBS lead (Medtronic, Inc., Minneapolis, MN). This configuration for the DBS device was used to assess a worstcase clinical situation for MRI-related heating for this DBS neuromodulation system (see Rezai et al., 2002)

600

R-Probe M-Probe L-Probe

25.00 20.00 15.00 10.00 5.00 0.00

0

200

(B)

400

600

Seconds

Figure 20.8  Examples of temperature changes recorded during assessment of MRI-related heating for bilateral neurostimulation systems used for DBS. (A) Graph corresponds to the use of a transmit/received body RF coil, an MR system reported wholebody averaged SAR of 3.9 W/kg, and imaging location through the implantable pulse generators (IPG). The leads were placed in direct routes from the IPG to the deep brain positions. Note the rapid increases in temperatures recorded by fluoroptic thermometry probes on the tips of the right and left leads. (B) Graph corresponds to the use of a transmit/received body RF coil, an MR system reported whole-body averaged SAR of 0.98 W/kg, and imaging location through the IPGs. Each lead was placed with two small loops (approximately 2.5 cm in diameter) in an axial orientation at the top of the head portion of the phantom (see Rezai et al., 2002)

Sharan et al., 2003; Baker et al., 2004, 2005, 2006, 2007; Bhidayasiri et al., 2005; Phillips et al., 2006). According to the study by Rezai et al. (2002), MRIrelated heating does not appear to present a major safety concern for patients with the bilateral neuromodulation systems that underwent testing, as long as highly specific guidelines pertaining to the positioning of these devices and parameters used for MR imaging are carefully adhered to. Furthermore, Finelli et al. (2002) reported that MRI sequences commonly used for clinical procedures could be performed safely in patients with bilateral DBS neuromodulation systems at 1.5-Tesla

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with the utilization of a transmit/receive RF head coil. However, it should be noted that most present-day, highfield-strength MR systems use the body coil to transmit RF energy with a receive-only head RF coil. MRI information for the Activa Tremor Control System provided by the manufacturer is shown in Box 20.8. For the Activa Tremor Control System, additional concerns prompted a revision of the safety recommendations from the manufacturer (Medtronic, Inc.,

Minneapolis, MN) for the use of MRI, which included a recommendation to limit the specific absorption rate (SAR) for the MRI sequences to less than 0.1 W/kg (Box 20.8). A study by Larson et al. (2008) reported that following these SAR recommendations in “real-world situations is problematic for a variety of reasons.” This investigation involved a review of their experience scanning patients with implanted DBS systems over a 7-year period using a variety of scanning techniques

Box 20.8 

 MRI information for the Activa Tremor Control System, deep brain stimulation system* *From: The Effects of Magnetic Resonance Imaging (MRI) on Deep Brain Stimulation System (Activa) for Movement Disorders (Medtronic, Inc., Minneapolis, MN); MRI Guidelines for DBS at www.medtronic.com/physician/activa/mri.html (accessed May 2008).

Models Kinetra: 7428; Soletra: 7426; Itrel II: 7424 Reference: Kinetra Technical Manual (220822-001)

MRI and Activa therapy Introduction It is important to read this section in its entirety before conducting an MRI examination on a patient with any implanted Activa System component. Contact Medtronic at 1-800-707-0933 if you have any questions. Due to the number and variability of parameters that affect MRI compatibility, the safety of patients or continued functioning of Activa Systems exposed to MRI cannot be absolutely ensured. MRI systems generate powerful electromagnetic fields that can produce a number of interactions with implanted components of the Activa neurostimulation system. Some of these interactions, especially heating, are potentially hazardous and can lead to serious injury or death. However, with appropriate control measures, particularly with respect to the selection of MRI parameters and RF coils, it is generally possible to safely perform an MRI head scan on an Activa patient. In addition, Activa System components can affect the MRI image, potentially impacting the diagnostic use of this modality. The following information describes the potential interactions and control measures that should be taken to minimize the risks from these interactions.

Contraindication Implantation of an Activa Brain Stimulation System is contraindicated for patients who will be exposed to

magnetic resonance imaging (MRI) using a full body transmit radio-frequency (RF) coil, a receive-only head coil, or a head transmit coil that extends over the chest area. Performing MRI with this equipment can cause tissue lesions from component heating, especially at the lead electrodes, resulting in serious and permanent injury including coma, paralysis, or death.

Warnings Do not conduct an MRI examination on a patient with any implanted Activa System component until you read and fully understand all the information in this section. Failure to follow all warnings and guidelines related to MRI can result in serious and permanent injury including coma, paralysis, or death. l In vitro testing has shown that exposure of the Activa neurostimulator system to MRI at parameters other than those described in this guideline can induce significant heating at the lead electrodes or at breaks in the lead. Excessive heating may occur even if the lead and/or extension are the only part of the Activa System that is implanted. Excessive heating can result in serious and permanent injury including coma, paralysis, or death. l MRI examinations of patients with an implanted Activa System should only be done if absolutely needed and then only if these guidelines are followed. MRI should not be considered for Activa patients if other potentially safer diagnostic methods such as CT, X-ray, ultrasound, or other methods will provide adequate diagnostic information. l A responsible individual with expert knowledge about MRI, such as an MRI radiologist or MRI physicist, l

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MRI PROCEDURES AND NEUROMODULATION SYSTEMS

must assure all procedures in this guidelines are followed and that the MRI scan parameters, especially RF specific absorption rate (SAR) and gradient dB/dt parameters, comply with the recommended settings, both for the pre-scan (tuning) and during the actual MRI examination. The responsible individual must verify that parameters entered into the MRI system meet the guidelines in this section. l Do not conduct an MRI examination if the patient has any other implants or limiting factors that would prohibit or contraindicate an MRI examination.

Cautions The neurostimulator, especially those without filtered feedthroughs such as the Itrel II Model 7424, may be reset or potentially damaged when subjected to an MRI examination. If reset, the neurostimulator must be reprogrammed. If damaged, the neurostimulator must be replaced. l MRI images may be severely distorted or image target areas can be completely blocked from view near the implanted Activa System components, especially near the neurostimulator. If the MRI targeted image area is near the neurostimulator, it may be necessary to move the neurostimulator to obtain an image, or use alternate imaging techniques. Do not remove the neurostimulator and leave the lead system implanted as this can result in higher than expected lead heating. l Carefully weigh any decision to perform magnetic resonance imaging (MRI) examinations on patients who require the neurostimulator to control tremor. Image quality during MRI examinations may be reduced, because the tremor may return when the neurostimulator is turned off. l If possible, do not sedate the patient so that the patient can provide feedback of any problems during the examination. l Monitor the patient during the MRI examination. Verify that the patient is feeling normal and is responsive between each individual scan sequence of the MRI examination. Discontinue the MRI immediately if the patient becomes unresponsive to questions or experiences any heating, pain, shocking sensations/ uncomfortable stimulation, or unusual sensations. l

Note: The MRI guidelines provided here may significantly extend the MRI examination time or prevent some types of MRI examinations from being conducted on Activa patients.

General information on MRI An MRI system produces three types of electromagnetic fields that may interact with implanted

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neurostimulation systems. All three of these fields are necessary to produce an MRI image. Each of these fields can also produce specific but different types of interactions with implanted neurostimulator systems. These fields include: Static magnetic field. This is a steady state nonvarying magnetic field that is normally always ON, even when no scan is under way. In a 1.5-Tesla MRI system, the static magnetic field is approximately 30 000 times greater than the magnetic field of the earth. l Gradient magnetic field. This is a low-frequency pulsed magnetic field that is only present during a scan. The gradient magnetic field can induce voltages onto the lead system that may result in unintended stimulation or functional interactions with the neurostimulator. l RF field. This is a pulsed radio frequency (RF) field that is only present during a scan. It can be produced by a variety of transmission RF coils such as a whole body transmit coil or an extremity coil such as a transmit/receive head coil. Only a transmit/receive head coil should be used as the other RF coils can expose more of the lead system to RF energy, thereby increasing the risk of excessive heating and thermal lesions possibly resulting in coma, paralysis, or death.

l

MRI interactions with implanted Activa systems MRI/neurostimulation system interactions are various, and the risk to the patient can range from minimal to severe. These interactions include the following: Heating. The MRI RF field induces voltages onto the lead system that can produce significant heating effects at the lead electrode–tissue interface or at the location of any breaks in the neurostimulator lead system. Component heating from the MRI RF field is the most serious risk from MRI exposure. Failure to follow these MRI recommendations can result in thermal lesions possibly resulting in coma, paralysis, or death. l Magnetic field interactions. Magnetic field interactions such as force and torque effects are produced by the static magnetic field. Any magnetic material will be attracted to the static magnetic field of the MRI. The force and torque effects may produce movement of the neurostimulator that can be uncomfortable to the patient, open a recent incision, or both. Activa System components are designed with minimal magnetic materials. l Induced stimulation. Gradient magnetic fields may induce voltages onto the lead system that may cause unintended stimulation. The voltage of the induced stimulation pulses is proportional to the

l

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time rate of change (dB/dt) of the gradient pulses, the effective loop area created by the neurostimulator lead system, and the location of the lead system with respect to the gradient coils of the MRI. l Effects on neurostimulator function. The static, gradient, and RF fields of the MRI may affect the neurostimulator operation and programming. The static magnetic field may cause the neurostimulator to turn ON or OFF if the neurostimulator uses a magnetically controlled switch that allows the patient to control stimulation by the application of a handheld magnet. Additionally, the MRI RF, static, and gradient fields may temporarily affect or disable other functions, such as telemetry or stimulation pulses. Parameters will need to be reprogrammed if the MRI causes a POR (Power On Reset) of the neurostimulator. l Image artifacts and distortion. The neurostimulation system components, particularly the neurostimulator, can cause significant imaging artifacts and/or distortion of the MRI image, particularly if the neurostimulator components contain magnetic material. The neurostimulator can cause the MRI image to be completely blocked from view (i.e., signal loss or signal “void”) or severely distorted within several inches of the neurostimulator.

MRI procedure Scope These MRI/neurostimulator exposure guidelines apply to Activa Systems comprising combinations of the following components: Neurostimulator Models: Itrel II 7424, Soletra 7426, Kinetra 7428 l Lead Extension Models: 7495, 7482 l Lead Models: DBS 3387, 3389 l

Supervision A responsible individual such as an MRI radiologist or MRI physicist must assure these procedures are followed. If the MRI is operated by an MRI technician, it is strongly recommended the responsible individual verifies that the MRI recommendations are followed.

an MRI examination. Do not conduct an MRI examination if any are found. 3. Verify that all proposed MRI examination parameters comply with the “MRI Operation Settings” on Table B. If not, the parameters must be modified to meet these requirements. If this cannot be done, do not perform an MRI. 4. If the patient has implanted leads but does not have an implanted neurostimulator, perform the following steps: – Wrap the external portion of the leads/ percutaneous extensions with insulating material. – Keep the external portion of the leads/percutaneous extensions out of contact with the patient. – Keep the external leads/percutaneous extensions straight, with no loops, and running down the center of the head coil. 5. If the patient has an implanted neurostimulator, perform the following steps: – Review the neurostimulator with a clinician programmer and print out a copy of the programmed parameters for reference. – Test for possible open circuits by measuring impedance and battery current on all electrodes in unipolar mode (see Table A). If an open circuit is suspected, obtain an X-ray to identify whether the open circuit is caused by a broken lead wire. If a broken lead wire is found, do not perform an MRI. Warning: An MRI procedure should not be performed in a patient with an Activa System that has a broken lead wire because higher than normal heating may occur at the break or the lead electrodes which can cause thermal lesions. These lesions may result in coma, paralysis, or death. – If the Activa System is functioning properly and no broken lead wires are found, program the neurostimulator to the settings provided in Table B. Table A  Measurement values indicating possible open circuits Neurostimulator

Impedance

Battery current

Itrel II Model 7424

2000

10 A

Soletra Model 7426

2000

10 A

Preparation Do the following prior to performing an MRI examination on an Activa patient: 1. Inform the patient of the risks of undergoing an MRI. 2. Check if the patient has any other implants or conditions that would prohibit or contraindicate

MRI operation settings Prior to the MRI examination, a responsible individual such as an MRI radiologist or MRI physicist must assure the examination will be conducted according to the following MRI requirements. If standard MRI pulse

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MRI PROCEDURES AND NEUROMODULATION SYSTEMS

– If MRI parameters must be manually adjusted after the initial automatic MRI prescan, do not make any adjustments that will increase the SAR value. Some MRI machines may not automatically update the displayed SAR value if manual adjustments are made. This may lead to higher than expected temperature increases in the Activa System, particularly at the lead electrodes. – Limit the gradient dB/dt field to 20-Tesla/second or less.

Table B  Recommended neurostimulator settings for MRI Parameter

Setting

Stimulation output

OFF (all programs)

Stimulation mode

Bipolar (all programs)

Amplitude

0 Volts (all programs)

Magnetic (reed) switch

Disabled (Kinetra Model 7428 only)

sequences will be used, they must meet these requirements. If they do not, the pulse parameters must be adjusted so that they comply with these requirements. Warning: In vitro testing has shown that exposure of the Activa System to MRI under conditions other than described in this guideline can induce excessive heating at the lead electrodes or at breaks in the lead to cause lesions. These lesions may result in coma, paralysis, or death. – Use only a 1.5-Tesla horizontal bore MRI (do not use open sided or other field strength MRI systems). – Use only a transmit/receive head coil. Contraindication: Implantation of an Activa Brain Stimulation System is contraindicated for patients who will be exposed to magnetic resonance imaging (MRI) using a full body transmit radio-frequency (RF) coil, a receive-only head coil, or a head transmit coil that extends over the chest area. Performing MRI with this equipment can cause tissue lesions from component heating, especially at the lead electrodes, resulting in serious and permanent injury including coma, paralysis, or death. – Enter the correct patient weight into the MRI console to assure the head SAR is estimated correctly. – Use MRI examination parameters that limit the head SAR to 0.1 W/kg or less for all RF pulse sequences. Warnings: – Ensure the SAR value is the value for head SAR. Some MRI systems may only display SAR, whole body SAR, or local body SAR. Make sure the value being limited to 0.1 W/kg is for head SAR. Excessive heating may occur if the wrong SAR value is used.

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Note: The recommendations provided are based on in vitro testing and should result in a safe MRI examination of a patient with an implanted Medtronic Activa System. However, due to the many variables that affect safety, Medtronic cannot absolutely ensure safety or that the neurostimulator will not be damaged. The user of this information assumes full responsibility for the consequences of conducting an MRI examination on a patient with an implanted Activa System.

Prior to the MRI examination Prior to the scan examination, the responsible individual must verify the MRI examination parameters comply with these guidelines: Patients with implanted Activa Systems should be informed of the risks of undergoing an MRI. l If possible, do not use sedation so the patient can inform the MRI operator of any heating, discomfort, or other problems. l Instruct the patient to immediately inform the MRI operator if any discomfort, stimulation, shocking, or heating occurs during the examination. l

During the MRI examination Monitor the patient both visually and audibly. Check the patient between each imaging sequence. Discontinue the MRI examination immediately if the patient is unable to respond to questions or reports any problems. l Conduct the examination using only the MRI pulse sequence that the MRI radiologist or physicist has confirmed meets the MRI requirements above. l

Post-MRI examination review Verify that the patient is feeling normal. Verify that the neurostimulator is functional. l Reprogram the neurostimulator to pre-MRI settings. l l

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and four scanning platforms. Data were reviewed for 405 patients with 746 implanted DBS systems imaged using 1.5-Tesla MR systems with SARs up to 3 W/kg. Many of the DBS systems were imaged multiple times, for a total of 1071 MRI events in this group of patients with no adverse events. Larson et al. (2008) concluded that these findings strongly suggested that the 0.1 W/kg recommendation for SAR may be unnecessarily low for the prevention of MRI-related adverse events.

Libra DBS System The Libra DBS System (Advanced Neuromodulation Systems, a St. Jude Medical Company, Plano, TX) recently received a FDA Investigational Device Exemption (IDE) to investigate the safety and efficacy of this neuromodulation system to treat essential tremor. The recommended MRI information for managing patients with this device is shown in Box 20.9.

Box 20.9 

 MRI information for the Libra DBS System* *Advanced Neuromodulation Systems, a St. Jude Medical Company, Plano, TX (Advanced Neuromodulation Systems (2008) http:// www.ansmedical.com)

Contraindications Patients for whom test stimulation is unsuccessful. Patients who are unable to properly operate the system. l Patients with demand-type cardiac pacemakers. l Patients exposed to diathermy. Do not use shortwave diathermy, microwave diathermy, or therapeutic ultrasound diathermy (all now referred to as diathermy) on patients implanted with a deep brain stimulation system. Energy from diathermy can be transferred through the implanted system and can cause tissue damage at the location of the implanted electrodes, resulting in severe injury or death. Diathermy is further prohibited because it may also damage the deep brain stimulation system components. This damage could result in loss of therapy, requiring additional surgery for system replacement. Injury or damage can occur during diathermy treatment whether the deep brain stimulation system is turned on or off. All patients are advised to inform their healthcare professional that they should not be exposed to diathermy treatment. l Patients exposed to magnetic resonance imaging (MRI). Do not use a full body radio-frequency (RF) coil or other extremity coils on patients implanted with a deep brain stimulation system. Because energy from MRI can be transferred through the implanted system, the potential for heat generation at the location of the electrodes exists. This isolated temperature rise may cause tissue damage at the location of the implanted electrodes, possibly resulting in severe injury or death. Injury can occur l l

during MRI treatment whether the deep brain stimulation system is turned on or off. All patients are advised to inform their health care professional that they should not be exposed to MRI. In the instance that MRI must be performed, follow the guidelines provided in Appendix E precisely.

Appendix E: Libra and Libra XP Systems and MRI safety MRI ASTM Guidelines Risks The MRI environment has the potential to induce mechanical forces, such as deflection and torque, on the device. The potential also exists for heat generation at the location of the implanted electrodes due to MRI energy transferred through the implanted system. This isolated temperature rise may cause tissue damage at the location of the implanted electrodes, possibly resulting in severe injury or death. Additionally, implanted medical devices can interfere with the MRI to create artifacts in the resulting image. ASTM Test Standards have been developed to quantify these effects in order to evaluate the safety concerns involving MRI scans on patients with an implanted medical device.

Testing and results from ASTM Guidelines The following testing was performed using a 1.5T GE Medical Systems LX Echospeed System with 9.0 software. The system’s magnet was a super conducting, cylindrical self-shielded, LCC magnet (CX-K4) manufactured by GE Medical Systems. The results of the testing depend on the scanner specifications (as listed above),

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MRI PROCEDURES AND NEUROMODULATION SYSTEMS

including the magnet strength, the software used, and the parameters under which the scans were conducted.

Mechanical forces Testing was conducted on the Libra and LibraXP DBS Systems (also referred to as the ANS DBS System) to determine the effect of the MRI environment on the implanted system. The MRI environment induced no mechanical forces on the leads or extensions used with the ANS DBS System. This is explained by the lack of magnetic materials in these system components. The Libra and LibraXP IPGs experienced less MRIinduced deflection than the maximum deflection on the device due to gravity and roughly the same amount of MRI-induced torque as the maximum torque on the device due to gravity. The ASTM standards consider the induced mechanical forces of torque and deflection from gravity to be a conservative criterion.

Induced heating Quantitative analysis of radio-frequency (RF) induced heating on the ANS DBS System was conducted in vitro using a 16-rung, quadrature birdcage, transmit/receive headcoil (GE Medical Systems, Model 46-282118G2). Three Libra configurations were tested with one loop approximately 3.5 cm in diameter at the burr hole site and either 1.5 loops approximately 4 cm in diameter (on the phantom’s left side) or two loops approximately 3.5 cm in diameter (on the phantom’s right side) beneath the IPG. The third configuration bilaterally combined each unilateral setup. The LibraXP was tested using the same configuration as the unilateral Libra configuration on the patient’s left side. RF heating analysis was quantified in reference to an average Specific Absorption Rate (SAR) in the head. SAR is a measurement of Watts of RF energy absorbed per kilogram of tissue. However, not all MRI scanners calculate SAR and each scanner may calculate SAR differently depending on the specific software. Because the variation in calculating SAR is unknown, the behavior of an implanted medical device using other scanners, field strengths or software is also unknown and could cause tissue damage resulting in severe injury or death. MRI safety testing was conducted with the lead tip within 0.5 cm, the extensions within 5.7 cm, and the IPG center within 9 cm of the magnet bore centerline. The IPG was placed in the upper torso, 28 cm below the landmark and within 9 cm of the centerline. A loop approximately 3.5 cm in diameter was placed at the burr hole and oneand-a-half loops approximately 4 cm in diameter, on the phantom’s left side, and two loops approximately 3.5 cm in diameter, on the phantom’s right side, were placed beneath the IPG.

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For the Libra unilateral configurations, the maximum temperature rise occurred in the configuration on the phantom’s right side with 2  3.5 cm diameter loops beneath the IPG. At a SAR of 3.1 W/kg, the maximum temperature rise was 4.6 degrees Celsius; and at a SAR of 1.7 W/kg, the maximum temperature rise was 2.5 degrees Celsius. When the two Libra unilateral configurations are combined for a bilateral setup, the maximum heating still occurred in the system implanted on the phantom’s right side. At a SAR of 3.1 W/kg, the maximum temperature rise was 6.2 degrees Celsius; and at a SAR of 1.7 W/kg, the maximum temperature rise was 2.4 degrees Celsius. For the LibraXP unilateral configuration, the maximum temperature rise was 3.8 degrees Celsius at a SAR of 3.1 W/kg. For the LibraXP bilateral configuration, the extensions were placed less than 0.25 cm apart. At a SAR of 1.6 W/kg, the maximum temperature rise was 4 degrees Celsius at the left tip electrode and 2.9 degrees Celsius at the right tip electrode. Note: Reversible thermal lesions occur between 5 and 7 degrees above normal body temperature of 37 degrees Celsius, and irreversible thermal lesions occur at temperatures greater than 8 degrees above normal body temperature of 37 degrees Celsius (Rezai et al., 2002). Artifact testing was conducted on the ANS DBS System to determine the extent of image distortion. Artifacts were reported to occur within 1.0 cm of the lead, 2.8 cm of the extension, 10.4 cm of Libra, and 12.7 cm of LibraXP. These artifact distances should be referenced to anticipate image distortion due to the implanted device. Implanted devices are unlikely to impair the diagnostic use of MRI when the area of interest is beyond the artifact distance listed for the specific device.

MRI Safety Guidelines Implant recommendations The ANS DBS System should be implanted as close to the centerline of the patient as possible, avoiding unnecessary offset of system components. Based on the testing results in this Appendix, placement of system components further from the centerline will induce increased system heating at the exposed electrodes and may result in greater patient risk of severe injury or death. l Variations in device location and/or the location, number and size of loops of the lead or extension may cause increased system heating and tissue damage resulting in severe injury or death. Refer to the testing data provided in this Appendix for information. l

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Avoid implanting the IPG in the mid- to lower-torso of the patient and avoid unnecessary offset of the system. l Avoid separation of the extensions when implanting LibraXP in a bilateral configuration. Unnecessary separation of the extensions may contribute to increased offset of the system along the y-axis of the magnet which may result in greater patient risk of severe injury or death.

Caution: Due to the risk of localized heating that may result in tissue damage, MRI procedures should not be performed on patients with an ANS DBS system that is suspected to have a broken lead or extension wire(s). If a broken lead or extension wire is suspected, an X-ray should be obtained prior to an MRI to verify the presence of the broken wire. Additionally, Libra Clinician Programmer may be used to test for an open circuit due to broken lead or extension wires.

Prescan preparation

MRI scanner parameters and settings

An appropriate healthcare professional with access to a Libra Clinician Programmer should be available to assist and prepare the patient’s device for the MRI procedure as described below:

MRI Safety testing was conducted on a 1.5T GE Medical Systems LX Echospeed System with 9.0 software and all testing data and guidelines are limited to this system. Select imaging parameters to perform MRI at a specific absorption rate (SAR) that does not exceed 0.4 W/kg in the head. Caution: Due to the lack of supporting evidence otherwise, it must be assumed that the automatic calculations determining SAR may be different for each MR scanner, inclusive to brands and models. The inherent variations in SAR calculations per scanner must be taken into consideration with respect to the data and recommendations reported in this Appendix. Increased system heating from inconsistent SAR calculations may cause tissue damage resulting in severe injury or death. Therefore, MRI scans should be treated as conservatively as possible since calculated SAR values cannot be assumed equivalent for all scanners. MRI safety testing was conducted using a 16-rung, quadrature birdcage, transmit/receive headcoil (GE Medical Systems, Model 46-282118G2), and the guidelines provided are limited to this system. Do not use a whole body RF coil, a head coil that extends over the chest area, a head coil that is not both a transmit and receive type RF coil, or other extremity coils.

l

– Use an approved diagnostic imaging technique to review the patient’s implant configuration, including system offset from patient centerline and loop quantity, size and placement. – The patient should be in a position such that the implanted system is positioned along the centerline of the magnet. – If the IPG has already been implanted, record the patient’s current therapeutic settings. Then set the IPG’s amplitude to 0 mA, the Magnet mode to “off,” and turn the IPG output to Off. – Instruct the patient to alert the MRI system operator of any problems, such as heating, shocks, vision impairment, or any sensation or discomfort, so the operator can terminate the MRI if necessary. Note: Energy from MRI transferred through the implantable system occurs very rapidly. In cases that excess heat generation does occur, the onset may be immediate and can cause tissue damage at the location of the implanted electrodes, resulting in severe injury or death.

DBS Neuromodulation Systems: Emphasis on MRI Safety Issues Because of the importance of following guidelines developed to ensure safety when using MRI in patients with DBS neuromodulation systems, this section provides a discussion of serious patient injuries that occurred in association with not using inappropriate MRI conditions. In 2003, Spiegel et al. (2003) reported that a 73-year-old patient with bilateral implanted DBS electrodes for Parkinson’s disease exhibited dystonic and partially ballistic movements of the left leg immediately after undergoing an MRI procedure of the head. This scan was performed using a transmit/receive head coil on a 1-Tesla MR system

(Expert; Siemens, Erlangen, Germany) with the leads externalized and not connected to pulse generators. As such, these conditions substantially deviated from the neurostimulation system manufacturer’s highly specific safety guidelines, which recommend performing MRI at 1.5-Tesla using a transmit/receive head coil only (Medtronic, 2005). Spiegel et al. (2003) speculated that this adverse effect was due to induced current in the implanted leads that caused excessive heating and subsequent thermal tissue damage. In 2005, Henderson et al. (2005) described a case of a serious, permanent neurological injury secondary to a radiofrequency lesion produced by heating of the electrode of a deep brain stimulation system during MRI of

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the lumbar spine in a patient with Parkinson’s disease. Because the patient was an avid hunter, one of the pulse generators for the DBS neuromodulation system was implanted on his “shooting” side (the left) and placed in the abdomen rather than the infraclavicular region, to avoid interference with the butt of his rifle. Seven months after pulse generator placement, the patient underwent an MRI of the lumbar spine for the evaluation of back and left leg pain. Multiple scan sequences were performed using a 1-Tesla MR System (Expert; Siemens Medical Solutions, Erlangen, Germany) with a transmit/receive body RF coil. Following the MRI procedure, the patient was reported to have sustained a neurological deficit. According to the written MRI report, “Upon removal of the patient from the MR scanner he had developed a new right hemiparesis.” The patient was subsequently evaluated by his neurologist who stated in an office note that he exhibited “obtunded aphasia with right hemiplegia, bilateral extensor plantar responses, and skew deviation, right eye below left.” A computed tomography (CT) scan performed immediately following the lumbar spine MRI revealed hemorrhage surrounding the left electrode. MRI of the brain was performed two days following the lumbar MRI on a 1.5-Tesla MR system. The MRI report described “subacute hemorrhage with met hemoglobin in the left thalamus, posterior limb of the left internal capsule, and left cerebral peduncle. This hemorrhage was just adjacent to the tip of a deep brain stimulator electrode. There was surrounding edema on T2-weighted sequences” (Figure 20.9). Seven months following the lumbar MRI procedure, the patient was evaluated and found to have severe dysarthria that made his speech nearly impossible to understand at times. He had persistent right hemiparesis with falling toward the right and clumsiness of his right hand. This patient continued to have some mild dysconjugate gaze. Tremor and bradykinesia remained improved on the left side, similar to prior postoperative evaluations. Notably, this patient’s neurological deficits were identified immediately upon his removal from the MR system, implicating a direct relationship between MRI procedure and the subsequent brain lesion. In addition, the hemorrhage and edema demonstrated on subsequent brain imaging surround the DBS electrode circumferentially, as would be expected of a lesion generated by radiofrequency heating. MRI-related heating of DBS systems has been studied in vitro (Henderson et al., 2003). Of further note is that this patient suffered from a lesion on the left side of the brain, corresponding with the left-sided lead and implanted, pulse generator in the region of the abdomen. No lesion was produced on the right side, where the lead and

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Figure 20.9  T2-weighted spin echo MRI of the brain showing edema around the left DBS electrode in a patient with permanent neurological deficit secondary to excessive MRI-related heating (see Henderson et al., 2005 and Rezai et al., 2005)

implantable pulse generator were in the standard infraclavicular position. This serious accident as well as the case described by Spiegel et al. (2003) emphasizes the fact that, while MRI may be performed safely in patients with DBS devices by following specific guidelines, the generalization of these conditions to other neurostimulation system positioning schemes, other scanners, and other imaging scenarios can lead to significant injuries (Henderson et al., 2005; Rezai et al., 2005). In both serious incidents, the performance of the MRI substantially deviated from the manufacturer’s recommendations (Medtronic, 2005). In order to prevent similar catastrophic incidents, the manufacturer’s guidelines must be followed carefully because they are known to result in the safe performance of MRI examinations.

Spinal Cord Stimulation Systems Spinal cord stimulation (SCS) is used to treat chronic pain of neurologic origin. Several types of pulse generators and many different types of electrodes are used to administer SCS. Thus, equipmentrelated factors significantly complicate the MRI issues

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related to these neuromodulation systems (Liem et al., 1997; De Andres et al., 2007). Importantly, depending on the level of stimulation along the spinal cord, the lead length used for SCS varies, presenting challenges for the evaluation of MRI-related heating for these devices. As such, to date, in order to ensure patient safety, MRI examinations are generally limited to scans involving the head/brain area, using a transmit/receive RF head coil at 1.5-Tesla, only. Other safety procedures must also be implemented, which are quite extensive. While several different SCS products exist, currently just those from a single manufacturer (i.e., Medtronic, Inc., Minneapolis, MN) have

approval from the FDA to permit MRI procedures in patients. Itrel 3: 7425; Restore: 37711; Synergy: 7427; SynergyPlus: 7479; Synergy Versitrel: 7427V; Mattrix: 3272, 3271; and SynergyCompact: 7479B Spinal Cord Stimulation Systems MRI-related labeling provided for the Itrel 3: 7425; Restore: 37711; Synergy: 7427; SynergyPlus: 7479; Synergy Versitrel: 7427V; and SynergyCompact: 7479B Spinal Cord Stimulation Systems (Medtronic, Inc., Minneapolis, MN) is shown in Box 20.10 (Medtronic 2005).

Box 20.10 

 MRI Information for the Itrel 3: 7425; Restore: 37711; Synergy: 7427; SynergyPlus: 7479; Synergy Versitrel: 7427V; Mattrix: 3272, 3271 and SynergyCompact: 7479B Spinal Cord Stimulation Systems MRI labeling information provided for the Itrel 3: 7425; Restore: 37711; Synergy: 7427; SynergyPlus: 7479; Synergy Versitrel: 7427V; and SynergyCompact: 7479B Spinal Cord Stimulation Systems (Medtronic, Inc., Minneapolis, MN) is, as follows:

MRI and neurostimulation therapy for chronic pain Introduction Medtronic recommends that you do not conduct an MRI examination of any part of the body on a patient using a radio-frequency (RF) transmit body coil. If all of the instructions stated in this section are followed, MRI examinations of the head only using an RF transmit/ receive head coil may be safely performed. It is important to read this information in its entirety before conducting an MRI examination on a patient with any implanted component of a Medtronic neuro­ stimulation system for chronic pain. These instructions do not apply to other implantable products or other devices, products, or items. Contact Medtronic at 1-800707-0933 if you have any questions. Due to the number and variability of parameters that affect MRI compatibility, the safety of patients or continued functioning of neurostimulation systems exposed to MRI cannot be absolutely ensured. MRI systems generate powerful electromagnetic fields that can produce a number of interactions with implanted components of the neurostimulation system. Some of these interactions,

especially heating, are potentially hazardous and can lead to serious injury or death. However, when all instructions stated in this section are followed, MRI examinations of the head only may be safely performed. In addition, neurostimulation system components can affect the MRI image, potentially impacting the diagnostic use of this modality. The following information describes the potential interactions and control measures that should be taken to minimize the risks from these interactions. The instructions in this section describe how to conduct a head-only MRI examination of a patient with a neuro­ stimulation system implanted for chronic pain, using a transmit/receive head coil of a 1.5-Tesla horizontal bore MRI. MRI examinations of any other part of the body are not recommended, as these require the use of the MRI RF transmit body coil, which may produce hazardous temperatures at the location of the implanted lead electrodes.

Warnings MRI RF transmit body coil – Medtronic recommends that you do not conduct an MRI examination using an RF transmit body coil on a patient with any implanted neurostimulation system component because the interaction of the MRI with the neurostimulation system may lead to serious injury or death. See the section “Risks associated with MRI examination.” MRI transmit/receive head coil – An MRI examination of the head only (no other part of the body) can be conducted safely using an RF transmit/receive head coil when all instructions in this section are followed.

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MRI PROCEDURES AND NEUROMODULATION SYSTEMS

Limitations – MRI should not be considered for patients with neurostimulation systems if other potentially safer diagnostic methods such as CT, X-ray, ultrasound, or others will provide adequate diagnostic information. – These instructions apply only to Medtronic neurostimulation therapies for chronic pain for approved indications. – The instructions in this section apply to all Medtronic fully implantable neurostimulators, leads, and extensions used for chronic pain therapy. Note: The instructions contained in this section are not applicable to MRI examinations of patients with radiofrequency (RF) neurostimulators. Medtronic recommends physicians not prescribe MRI for a patient who has an implanted Itrel 3 Model 7425 Neurostimulator. The Itrel 3 Neurostimulator is highly susceptible to reset or damage when subjected to an MRI examination. If reset, the neurostimulator must be reprogrammed. If damaged, the neurostimulator must be replaced. The Itrel 3 Neurostimulator has an increased risk of induced electrical current, which may stimulate or shock the patient. Contact Medtronic at 1-800-707-0933 for information about newer models or any updates. – The RF transmit/receive head coil must not cover any implanted system component. – If the patient has any other implants or products that prohibit or contraindicate an MRI examination, follow the instructions from the manufacturer. The instructions in this section apply only to the Medtronic products listed above. – Do not conduct an MRI examination if the patient’s neurostimulation system has a broken lead wire, because higher than normal heating may occur at the break or lead electrodes. Excessive heating can cause tissue damage and result in severe injury or death. – Physicians should not prescribe MRI for patients undergoing trial neurostimulation and having systems that are not fully implanted. If the MRI targeted image area is near the neurostimulator, it may be necessary to move the neurostimulator to obtain an image, or use alternate imaging techniques. MRI images may be severely distorted or image target areas can be completely blocked from view near the implanted neurostimulation system components, especially near the neurostimulator.

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– Do not remove the neurostimulator and leave the lead system implanted as this can result in higher than expected lead heating. Excessive heating can cause tissue damage and result in severe injury or death. Risks associated with MRI examination – Exposing a patient with an implanted neurostimulation system or component to MRI may potentially injure the patient or damage the neurostimulator. The known potential risks are as follows: – Induced electrical currents from the MRI to the neurostimulation system or component may cause heating, especially at the lead-electrode site, resulting in tissue damage. Induced electrical currents may also stimulate or shock the patient. Note: This warning applies even if only a lead or extension is implanted. Factors that increase the risks of heating and patient injury include, but are not limited to, the following: – High MRI specific absorption rate (SAR) RF power levels. – Low impedance leads or extensions (Medtronic product names or model numbers designated by a “Z,” an “LZ,” or “low impedance”). – MRI RF transmit/receive coil that is near or extends over the implanted lead system. – Implanted lead systems with small surface area electrodes. – Short distances between lead electrodes and heatsensitive tissue. – Exposure to gradients exceeding a dB/dt limit of 20-Tesla per second may result in overstimulation or shocking, particularly for unipolar-capable devices. – MRI may permanently damage the neurosti­ mulator, requiring explant or replacement. – MRI may affect the operation of the neurostimulator. The MRI may also reset the parameters to power-on-reset settings, requiring reprogramming with the clinician programmer. The Itrel 3 Model 7425 Neurostimulator is highly susceptible to reset or damage when subjected to an MRI examination. If reset, the neurostimulator must be reprogrammed. If damaged, the neurostimulator must be replaced. An Itrel 3 neurostimulator also might exhibit unpredictable behavior if subjected to an MRI examination. The neurostimulator may move within the implant pocket and align itself with the MRI field, which may cause patient discomfort or a recent neurostimulator implant incision to open.

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Cautions Patient interaction during MRI – If possible, do not sedate the patient so that the patient can provide feedback of any problems during the examination. Monitor the patient during the MRI examination. Verify that the patient is feeling normal and is responsive between each individual scan sequence of the MRI examination. Discontinue the MRI immediately if the patient becomes unresponsive to questions or experiences any heating, pain, shocking sensations/uncomfortable stimulation, or unusual sensations.

MRI procedure using an RF transmit/receive head coil Supervision If all of the instructions stated in this section are followed, MRI examinations of the head using an RF transmit/receive head coil may be safely performed. Prior to the MRI examination, an individual with the proper knowledge of MRI equipment such as an MRI radiologist or MRI physicist must ensure the MRI examination will be conducted according to the information outlined in this section. Note: Due to the additional requirements in these instructions, MRI examination time maybe significantly extended.

MRI exposure requirements Prior to an MRI examination, determine whether the patient has multiple active medical device implants (such as deep brain stimulation systems, implantable cardiac defibrillators, and others). The most restrictive MRI exposure requirements must be used if the patient has multiple active medical device implants. Contact the appropriate manufacturers of the devices if you have questions. If the following requirements cannot be met, do not proceed with the MRI examination. – Use only an RF transmit/receive head coil.* – Use only a 1.5-Tesla horizontal bore MRI (do not use open sided or other field strength MRI systems). – Enter the correct patient weight into the MRI console to ensure the head SAR is estimated correctly. The MRI scan sequences must meet the following requirements. If they do not, the pulse parameters must be adjusted so that they comply with these requirements. – Use MRI examination parameters that limit the head SAR to 1.5 W/kg or less for all RF pulse sequences.

– Limit the gradient dB/dt field to 20-Tesla per second or less. Note: The requirements provided are based on in vitro testing and should result in a safe MRI examination of a patient with an implanted Medtronic neurostimulation system when all instructions in this section are followed. However, due to the many variables that affect safety, the safety of patients or continued functionality of neurostimulator systems exposed to MRI cannot be absolutely ensured. The user of this information assumes full responsibility for the consequences of conducting an MRI examination on a patient with an implanted neurostimulation system.

Preparation for the MRI examination Do the following prior to performing an MRI examination on a patient with an implanted neurostimulation component: 1. Inform the patient of all of the risks of undergoing an MRI examination as stated in this section. 2. If possible, do not use sedation so the patient can inform the MRI operator of any heating, discomfort, or other problems. 3. Instruct the patient to immediately inform the MRI operator if any discomfort, stimulation, shocking, or heating occurs during the examination. 4. Determine if the patient has any other implants or conditions that would prohibit or contraindicate an MRI examination. If you are unclear what implants may be present, perform an X-ray to determine implant type and location. Do not conduct an MRI examination if any conditions or implants that would prohibit or contraindicate an MRI are present. 5. Verify that all proposed MRI examination parameters comply with the “MRI exposure requirements” (see above). If not, the parameters must be modified to meet these requirements. If parameters cannot be modified, do not perform an MRI. 6. If the patient has implanted leads but does not have an implanted neurostimulator, perform the following steps: (a) Wrap the external portion of the leads/ percutaneous extensions with insulating material, such as dry gauze. (b) Keep the external portion of the leads/ percutaneous extensions out of contact with the patient. (c) Keep the external leads/percutaneous extensions straight, with no loops, and running down the center of the head coil.

*Important: If you are unsure if your MRI has RF transmit/receive head coil capability or if it displays “head SAR,” check with your MRI manufacturer. III.  BIOMEDICAL ENGINEERING CONSIDERATIONS



MRI PROCEDURES AND NEUROMODULATION SYSTEMS

7. If the patient has an implanted neurostimulator, perform the following steps: (a) Review the neurostimulator with a clinician programmer and print out a copy of the programmed parameters for reference. (b) Test for possible open circuits by measuring impedance on all electrodes. An impedance measurement greater than 4000 for Synergy Plus, Synergy Compact, Synergy Versitrel, Synergy, or Itrel 3 indicates a possible open circuit. An impedance measurement greater than 3600 for Restore indicates a possible open circuit. (c) If an open circuit is suspected, obtain an X-ray to identify whether the open circuit is caused by a broken lead wire. If a broken lead wire is found, do not perform an MRI examination. Warning: Do not conduct an MRI examination if the patient’s neurostimulation system has a broken lead wire, because higher than normal heating may occur at the break or lead electrodes. Excessive heating can cause thermal lesions and result in severe injury or death. 8. If the system is functioning properly and no broken lead wires are found, program the neurostimulator to the settings provided below:

Recommended neurostimulator settings for MRI examinations Parameter setting: Stimulation output OFF (all programs) Stimulation mode Bipolar (all programs) Amplitude 0 Volts (all programs) Magnetic (reed) switch Disabled (Itrel 3 Model 7425 only) Other parameters: Do not change

During the MRI examination – Monitor the patient both visually and audibly. Check the patient between each imaging sequence. Discontinue the MRI examination immediately if the patient is unable to respond to questions or reports any problems. – Conduct the examination using only the MRI pulse sequence that the MRI radiologist or physicist has confirmed meets the “MRI exposure requirements” outlined in this section.

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Models: Mattrix 3272, 3271 Reference: Pain Therapy IFP (221351-001) Medtronic recommends physicians not prescribe an MRI for a patient who has any implanted component of a [Mattrix] system. Exposing a patient with a [Mattrix] system or component to an MRI may potentially injure the patient and/or damage the receiver. The known potential risks are as follows: – Induced electrical currents from the MRI to the [Mattrix] system or component may cause heating, especially at the lead electrode site, resulting in tissue damage. Induced electrical currents may also stimulate or shock the patient. Note: This warning applies even if only a lead or extension is implanted. Heating risks are affected by a number of factors involving the MRI equipment and the implanted [Mattrix] system. Factors that increase the risks of heating and patient injury include, but are not limited to, the following: – High MRI Specific Absorption Rate (SAR) radio frequency (RF) power levels. – Low impedance leads or extensions (Medtronic product names or model numbers designated by a “Z,” an “LZ,” or “low impedance”). – MRI RF transmit coil that is near or extends over the implanted lead system. – Implanted lead systems with small surface area electrodes. – Short separation distances between lead electrodes and thermally sensitive tissue. – An MRI may permanently damage the receiver, which may require explant or possible replacement. – An MRI may affect the functional operation of the receiver. – The receiver may move within the implant pocket and align itself with the MRI field, which may cause patient discomfort or a recent receiver implant incision to open. In addition, the image details from MRI may be degraded, distorted, or blocked from view by the implanted [Mattrix] system.

Post-MRI examination review – Verify that the patient feels normal. – Verify that the neurostimulator is functional. – Reprogram the neurostimulator to pre-MRI settings.

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Renew, Genesis, GenesisXP, GenesisRC, and Eon Spinal Cord Stimulation Systems The Genesis, GenesisXP, GenesisRC, and Eon (IPG) neuromodulation systems (Advanced Neuro­modulation Systems, a St. Jude Medical Company, Plano, TX) used for spinal cord stimulation (SCS) are indicated as aids in the management of chronic intractable pain of the trunk and/or limbs including unilateral or bilateral pain associated with any of the following: failed back surgery syndrome, and intractable low back and leg pain. The Renew neuromodulation system (Advanced Neuromodulation Systems, a St. Jude Medical Company, Plano, TX) is indicated for spinal cord stimulation (SCS) in the treatment of chronic pain of the trunk and limbs, either as the sole mitigating agent or as an adjunct to other modes of therapy used in a multidisciplinary approach. Certain Renew models are also indicated to stimulate electrically peripheral nerves to relieve severe intractable pain. The 2008 labeling information from Advanced Neuromodulation Systems for each afore-mentioned product states. Magnetic Resonance Imaging (MRI) – Patients with implanted neurostimulation systems should not be subjected to MRI. The electromagnetic field generated by an MRI may forcefully dislodge implanted components, damage the device electronics, and induce voltage through the lead that could jolt or shock the patient. Precision Spinal Cord Stimulation System The Precision Spinal Cord Stimulation System (Boston Scientific Corporation) is a neurostimulation device that transmits electrical signals to the spinal cord to decrease chronic pain in the body, arms, and legs. The device consists of two parts: a stimulator device (signal generator) implanted under the skin that transmits electrical signals to the spinal cord through an insulated lead wire, and an external remote control that programs the treatment delivered by the signal generator. The MRI information for this neuromodulation system states: Patients with the Precision SCS system should not be subjected to MRI. MRI exposure may result in dislodgement of implanted components, heating of the neurostimulator, damage to the device electronics and/or voltage induction through the leads and stimulator causing an uncomfortable “jolting” sensation.

MN) is a treatment for urinary urge incontinence, nonobstructive urinary retention, and significant symptoms of urgency-frequency in patients who have failed or could not tolerate more conservative treatments. The implantable InterStim System uses mild electrical stimulation of the sacral nerve that influences the behavior of the bladder, sphincter, and pelvic floor muscles. The labeling information for this neuromodulation system relative to the use of MRI examinations in patients states (Medtronic, 2005): Patients with an implanted device should not be exposed to the electromagnetic fields produced by magnetic resonance imaging (MRI). Use of MRI may potentially result in system failure or dislodgment, heating, or induced voltages in the neurostimulator and/or lead. An induced voltage through the neurostimulator or lead may cause uncomfortable, “jolting,” or “shocking,” levels of stimulation. Clinicians should carefully weigh the decision to use MRI in patients with an implanted neurostimulation system, and note the following: –  M  agnetic and radio-frequency (RF) fields produced by MRI may change the neurostimulator settings, activate the device, and injure the patient. –  Patients treated with MRI should be closely monitored and programmed parameters verified upon cessation of MRI.

Atrostim Phrenic Nerve Stimulator Phrenic nerve stimulators (PNS) are used to stimulate the phrenic nerves of patients to maintain artificial respiration. The most common patient groups who benefit from the use of these neuromodulation systems are patients suffering from respiratory muscle paralysis or central alveolar hypoventilation. The use of PNS requires normal function of phrenic nerves and diaphragm muscle. The Atrostim Phrenic Nerve Stimulator (ASTROTECH OY, Tampere, Finland) is a product that is utilized to stimulate the phrenic nerve. This neuromodulation device is considered unsafe for patients referred for MRI examinations. Renova Cortical Stimulation System The Renova Cortical Stimulation System (Northstar Neuroscience, Seattle, WA) is currently contraindicated for patients referred for MRI procedures (pers. comm., 5/2008, Brad Gliner, Northstar Neuroscience). Enterra Therapy, Gastric Electrical Stimulation System

Other Neuromodulation Systems InterStim Therapy – Sacral Nerve Stimulation for Urinary Control InterStim Therapy – Sacral Nerve Stimulation (SNS) for Urinary Control (Medtronic, Inc., Minneapolis,

Gastric Electrical Stimulation (GES) performed using a specialized neuromodulation device (The Enterra Therapy, Gastric Electrical Stimulation (GES) System, Medtronic Minneapolis, MN) is indicated for treatment of patients with chronic, intractable nausea and

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CONCLUSIONS

vomiting secondary to gastroparesis of diabetic or idiopathic etiology. GES uses mild electrical pulses to stimulate the stomach to help control symptoms associated with gastroparesis. The GES device is comprised of a neurostimulator, an implantable intramuscular lead, and an external programming system. Currently, the use of MRI procedures in patients with this device is contraindicated due to possible hazards related to dislodgment or heating of the neurostimulator and/or the leads used for gastric electrical stimulation. Additionally, the voltage induced through the lead and neurostimulator may cause uncomfortable “jolting” or “shocking” levels of stimulation (Medtronic, 2005).

Conclusions With the continued advancements in MRI technology and development of more sophisticated implants and devices, there is an increased potential for hazardous situations to occur in the MRI environment. Therefore, to prevent incidents and accidents, it is necessary to be cognizant of the latest information pertaining to MRI bioeffects, to use current guidelines to ensure safety for patients and staff members, and to follow proper recommendations pertaining to implants and devices.

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specific absorption rate as a dosimeter of MRI-related implant heating. Journal of Magnetic Resonance Imaging 20: 315–20. Baker, K.B., Tkach, J.A., Phillips, M.D. and Rezai, A.R. (2006) Variability in RF-induced heating of a deep brain stimulation implant across MR systems. J. Magn. Reson. Imaging 24: 1236–42. Benbadis, S.R., Nyhenhuis, J., Tatum, W.O., IV, Murtagh, F.R., Gieron, M. and Vale, F.L. (2001) MRI of the brain is safe in patients implanted with the vagus nerve stimulator. Seizure 10: 512–5. Bhidayasiri, R., Bronstein, J.M., Sinha, S., Krahl, S.E., Ahn, S., Behnke, E.J. et al. (2005) Bilateral neurostimulation systems used for deep brain stimulation: In vitro study of MRI-related heating at 1.5-Tesla and implications for clinical imaging of the brain. Magn. Reson. Imaging 23: 549–55. Bourland, J.D., Nyenhuis, J.A. and Schaefer, D.J. (1999) Physiologic effects of intense MRI gradient fields. Neuroimaging Clin. North Am. 9: 363–77. Cameron, T., Loeb, G.E., Peck, R.A., Schulman, J.H., Strojnik, P. and Troyk, P.R. (1997) Micromodular implants to provide electrical stimulation of paralyzed muscles and limbs. IEEE Trans. Biomed. Eng. 44: 781–90. Carmichael, D.W., Pinto, S., Limousin-Dowsey, P., Thobois, S., Allen, P.J., Lemieux, L. et al. (2007) Functional MRI with active, fully implanted, deep brain stimulation systems: safety and experimental confounds. Neuroimage 37: 508–17. Colletti, P.M. (2001) Magnetic resonance procedures and pregnancy. In: F.G. Shellock (ed.), Magnetic Resonance Procedures: Health Effects and Safety. Boca Raton, FL: CRC Press, pp. 149–82. De Andres, J., Valía, J.C., Cerda-Olmedo, G., Quiroz, C., Villanueva, V., Martinez-Sanjuan, V. et al. (2007) Magnetic resonance imaging in patients with spinal neurostimulation systems. Anesthesiology 106: 779–86. Dempsey, M.F., Condon, B. and Hadley, D.M. (2001) Investigation of the factors responsible for burns during MRI. J. Magn. Reson. Imaging 13: 627–31. Elkelini, M.S. and Hassouna, M.M. (2006) Safety of MRI at 1.5-Tesla in patients with implanted sacral nerve neurostimulator. Eur. Urol. 50: 311–16. Finelli, D.A., Rezai, A.R., Ruggieri, P., Tkach, J., Nyenhuis, J., Hridlicka, G. et al. (2002) MR-related heating of deep brain stimulation electrodes: an in vitro study of clinical imaging sequences. AJNR 23: 1795–802. Georgi, A-C., Stippich, C., Tronnier, V.M. and Heiland, S. (2003) Active deep brain stimulation during MRI: a feasibility study. Magn Reson Med. 51: 380–8. Gleason, C.A., Kaula, N.F., Hricak, H. et al. (1992) The effect of magnetic resonance imagers on implanted neurostimulators. Pacing Clin. Electrophysiol. 15: 81–94. Graf, H., Lauer, U.A., Berger, A. and Schick, F. (2005) RF artifacts caused by metallic implants or instruments which get more prominent at 3-T: an in vitro study. Magn. Reson. Imaging 23: 493–9. Groves, D.A. and Brown, V.J. (2005) Vagal nerve stimulation: a review of its applications and potential mechanisms that mediate its clinical effects. Neurosci. Biobehav. Rev. 29: 493–500. Heetderks, W.J. (1988) RF powering of millimeter- and submillimetersized neural prosthetic implants. IEEE Trans. Biomed. Eng. 35: 323–7. Henderson, J., Tkach, J., Phillips, M., Baker, K., Shellock, F.G. and Rezai, A. (2005) Permanent neurological deficit related to magnetic resonance imaging in a patient with implanted deep brain stimulation electrodes for Parkinson’s disease: Case report. Neurosurgery 57: E1063.

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Joint Commission on Accreditation of Healthcare Organizations, USA (2008) Preventing accidents and injuries in the MRI suite. Sentinel Event Alert Feb. 14: 1–3. Kangarlu, A., Shellock, F.G. and Chakeres, D. (2003) 8.0-Tesla MR system: temperature changes associated with radiofrequencyinduced heating of a head phantom. J. Magn. Reson. Imaging 17: 220–6. Kim, L.J., Sonntag, V.K., Hott, J.T., Nemeth, J.A., Klopfenstein, J.D. and Tweardy, L. (2003) Scalp burns from halo pins following magnetic resonance imaging. Case Report. J. Neurosurg. 99: 186. Kosel, M. and Schlaepfer, T.E. (2003) Beyond the treatment of epilepsy: new applications of vagus nerve stimulation in psychiatry. CNS Spectr. 8: 515–21. Kovacs, N., Nagy, F., Kover, F. et al. (2006) Implanted deep brain stimulator and 1.0-Tesla magnetic resonance imaging. J. Magn. Reson. Imaging 24: 1409–12. Larson, P.S., Richardson, R.M., Starr, P.A. and Martin, A.J. (2008) Magnetic resonance imaging of implanted deep brain stimulators: experience in a large series. Stereotact. Funct. Neurosurg. 86: 92–100. Liem, L.A. and van Dongen, V.C. (1997) Magnetic resonance imaging and spinal cord stimulation systems. Pain 70: 95–7. Loeb, G.E., Peck, R.A., Moore, W.H. and Hood, K. (2001) BION system for distributed neural prosthetic interfaces. Med. Eng. Phys. 23: 9–18. Loeb, G.E., Richmond, F.J. and Baker, L.L. (2006) The BION devices: injectable interfaces with peripheral nerves and muscles. Neurosurg. Focus 20: E2. Loeb, G.E., Zamin, C.J., Schulman, J.H. and Troyk, P.R. (1991) Injectable microstimulator for functional electrical stimulation. Med. Biol. Eng. Comput. 29: NS13–NS9. Lomarev, M., Denslow, S., Nahas, Z., Chae, J.H., George, M.S. and Bohning, D.E. (2002) Vagus nerve stimulation (VNS) synchronized BOLD fMRI suggests that VNS in depressed adults has frequency/dose dependent effects. J. Psychiatr. Res. 36: 219–27. Mattei, E., Triventi, M., Calcagnini, G., Censi, F., Kainz, W., Bassen, H.I. et al. (2007) Temperature and SAR measurement errors in the evaluation of metallic linear structures heating during MRI using fluoroptic probes. Phys. Med. Biol. 52: 1633–46. Mattei, E., Triventi, M., Calcagnini, G., Censi, F., Kainz, W., Mendoza, G. et al. (2008) Complexity of MRI induced heating on metallic leads: experimental measurements of 374 configurations. Biomed. Eng. Online 3 (7): 11. MAUDE (2008) www.fda.gov/cdrh/maude.html (accessed May 2008). McJury, M. and Shellock, F.G. (2000) Auditory noise associated with MR procedures: a review. J. Magn. Reson. Imaging 12: 37–45. Medtronic Neurological Technical Services Department (2005), Tech Note. MRI. Guidelines for Neurological Products, Issue No. NTN 04-03 Rev 2, July 2005. MRIsafety.com (2008) http://MRIsafety.com (accessed May 2008). Nakamura, T., Fukuda, K., Hayakawa, K., Aoki, I., Matsumoto, K., Sekine, T. et al. (2001) Mechanism of burn injury during magnetic resonance imaging (MRI)-simple loops can induce heat injury. Front Med. Biol. Eng. 11: 117–29. Narayanan, J.T., Watts, R., Haddad, N., Labar, D.R., Li, P.M. and Filippi, C.G. (2002) Cerebral activation during vagus nerve stimulation: a functional MR study. Epilepsia 43: 1509–14. Nitz, W.R., Brinker, G., Diehl, D. and Frese, G. (2005) Specific absorption rate as a poor indicator of magnetic resonancerelated implant heating. Invest. Radiol. 40: 773–6. Nyenhuis, J.A., Park, S.M., Kamondetdacha, R., Amjad, A., Shellock, F.G. and Rezai, A. (2005) MRI and implanted medical devices: basic interactions with an emphasis on heating. IEEE Trans. Device Mater. Reliability 5: 467–78.

Olsrud, J., Latt, J., Brockstedt, S., Romner, B. and BjorkmanBurtscher, I.M. (2005) Magnetic resonance imaging artifacts caused by aneurysm clips and shunt valves: dependence on field strength (1.5 and 3T) and imaging parameters. J. Magn. Reson. Imaging 22: 433–7. Phillips, M.D., Baker, K.B., Lowe, M.J. et al. (2006) Parkinson disease: pattern of functional MR imaging activation during deep brain stimulation of subthalamic nucleus – initial experience. Radiology 239: 209–16. Physician’s Manual, VNS Therapy (2003) Pulse Model 102 Generator and VNS Therapy, Pulse Duo Model 102R Generator, and Physician’s Manual, VNS Therapy Lead, Model 302. Houston, TX: Cyberonics, Inc. Rezai, A.R., Baker, K., Tkach, J., Phillips, M., Hrdlicka, G., Sharan, A. et al. (2005) Is magnetic resonance imaging safe for patients with neurostimulation systems used for deep brain stimulation (DBS)? Neurosurgery 57: 1056–62. Rezai, A.R., Finelli, D., Nyenhuis, J.A., Hrdlick, G., Tkach, J., Ruggieri, P. et al. (2002) Neurostimulator for deep brain stimulation: Ex vivo evaluation of MRI-related heating at 1.5-Tesla. J. Magn. Reson. Imaging 15: 241–50. Rezai, A.R., Finelli, D., Ruggieri, P., Tkach, J., Nyenhuis, J.A. and Shellock, F.G. (2001) Neurostimulators: potential for excessive heating of deep brain stimulation electrodes during MR imaging. J. Magn. Reson. Imaging 14: 488–9. Rezai, A.R., Lozano, A.M., Crawley, A.P., Joy, M.L., Davis, K.D., Kwan, C.L. et al. (1999) Thalamic stimulation and functional magnetic resonance imaging: localization of cortical and subcortical activation with implanted electrodes. J. Neurosurg. 90: 583–90. Rezai, A.R., Phillips, M., Baker, K., Sharan, A.D., Nyenhuis, J., Tkach, J. et al. (2004) Neurostimulation system used for deep brain stimulation (DBS): MR safety issues and implications of failing to follow guidelines. Invest. Radiol. 39: 300–3. Rise, M.T. (2000) Instrumentation for neuromodulation. Arch. Med. Res. 31: 237–47. von Roemeling, R., Lanning, R.M. and Eames, F.A. (1991) MR imaging of patients with implanted drug infusion pumps. J. Magn. Reson. Imaging 1: 77–81. Schaefer, D.J., Barber, B.J., Gordon, C.J. (1985) Thermal effects of magnetic resonance imaging. In: Book of Abstracts, Society for Magnetic Resonance in Medicine. Berkeley, CA, 2: 925. Schaefer, D.J., Bourland, J.D. and Nyenhuis, J.A. (2000) Review of patient safety in time-varying gradient fields. J. Magn. Reson. Imaging 12: 20–9. Schenck, J.F. (2001) Health effects and safety of static magnetic fields. In: F.G. Shellock (ed.), Magnetic Resonance Procedures: Health Effects and Safety. Boca Raton, FL: CRC Press, pp. 1–30. Sharan, A., Rezai, A.R., Nyenhuis, J.A., Hrdlicka, G., Tkach, J., Baker, K. et al. (2003) MR safety in patients with implanted deep brain stimulation systems (DBS). Acta Neurochir. Suppl. 87: 141–5. Shellock, F.G. (2000) Radiofrequency energy-induced heating during MR procedures: a review. J. Magn. Reson. Imaging 12: 30–6. Shellock, F.G. (2002a) Biomedical implants and devices: assessment of magnetic field interactions with a 3.0-Tesla MR system. J. Magn. Reson. Imaging 16: 721–32. Shellock, F.G. (2002b) MR safety update 2002: Implants and devices. J. Magn. Reson. Imaging 16: 485–96. Shellock, F.G. (2007) Guest Editorial. Comments on MRI heating tests of critical implants. J. Magn. Reson. Imaging 26: 1182–5. Shellock, F.G. (2008) Reference Manual for Magnetic Resonance Safety, Implants, and Devices: 2008 Edition. Los Angeles, CA: Biomedical Research Publishing Group. Shellock, F.G. and Kanal, E. (1991) Policies, guidelines, and recommendations for MR imaging safety and patient management. SMRI Safety Committee. J. Magn. Reson. Imaging 1: 97–101.

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S E C T I O N   IV

 Neuromodulation for chronic Pain Introduction Elliot S. Krames, Ali R. Rezai, and Andre G. Machado

The use of electricity for painful disorders is not new; the first use of therapeutic electrical stimulation occurred in about 15 AD. As the story is reported (Stillings, 1971), a freed slave of Emperor Tiberius was suffering from painful gout. He accidentally stepped on an electric torpedo fish and suffered a sudden severe shock. Afterward, he had much less gout pain. The Emperor’s physician, Scribonius, wrote that thereafter he recommended the torpedo fish treatment for chronically persistent pain. By the end of the seventeenth century, electricity was identified as a form of energy. Its ability to cause sudden shock and muscle contraction was recognized. One of the first to report that phenomenon in 1774 was Benjamin Franklin (Isaacson, 2003). In addition to his scientific side, he amused his friends and admirers at his home by literally shocking them as they touched a contact charged by a static electricity generator. The remarkable breadth of his contributions is all the more impressive when one recognizes that this report antedated the demonstration of electrical contraction of frog muscle by Galvani in 1780 (Pruel, 1997).

Neuromodulation

Modern use of electricity for pain was reintroduced after Melzack and Wall put forward the gate control theory of pain in 1965. Wall and Sweet (1967) identified that, by stimulating a peripheral nerve, pain could be abolished. Shortly afterwards, Shealy, Mortimer, and Reswick (1967) introduced the use of dorsal column stimulation for the treatment of chronic pain. Chronic pain is among the most common causes of chronic disability in the general population. Chronic pain is estimated to be the third largest healthcare problem in the world, afflicting around 30% of the worldwide population. Surgical and minimally invasive techniques for the management of chronic pain have been available for decades. Neuromodulatory techniques, unlike approaches aimed at selective destruction of the central or peripheral nervous system, are reversible and less likely to be complicated by deafferentation pain. Neuromodulation for chronic pain can be delivered by means of electrical stimulation or drug infusion therapies directed at peripheral nerves, spinal cord, cranial nerves, and the brain.

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284 IV.  Neuromodulation for chronic Pain This section covers the entire spectrum of neuromodulation for pain control. The chapters are organized into the fundamentals, spinal cord stimulation, peripheral nerve and peripheral subcutaneous field stimulational, intrathecal therapies, and brain stimulation for pain control. Fundamental and background chapters include a discussion about the physiology and pathophysiology of pain, and targets for neuromodulation by Dr Rosenow, the endogenous neuromodulation system by Dr Basbaum, and an overview discussion of chronic pain management strategies by Dr Gallagher. These foundational chapters are followed in sequence by a subsection on peripheral and spinal cord stimulation (Section A), a section on intrathecal therapies (Section B), and a section on cerebral stimulation (Section C). The peripheral and spinal cord stimulation section consists of the following chapters: Transcutaneous Neural Stimulation by Dr Smith; Mechanisms of Spinal Cord Stimulation for Pain by Drs Linderoth, Meyerson, and Foreman; Outcomes and Cost–Benefit Analysis of Spinal Cord Stimulation by Dr North; neurostimulation for painful neuropathies, by Dr Barolat; Spinal Cord Stimulation for CRPS by Dr Joshua Prager; Peripheral Nerve Stimulation for Peripheral Neuralgia and CRPS by Dr Stanton-Hicks; Peripheral Nerve Stimulation for Occipital Neuralgia and Headache by Dr Weiner; and Subcutaneous Peripheral Nerve Stimulation by Dr Goroszeniuk. The intrathecal therapy section includes chapters on the relevant anatomy for spinal delivery of medications by Dr Deer; rationale for use of intrathecal opioids by Dr Harb; a review on intrathecal non-opioid analgesics by Dr Reig; issues related to the compounding intrathecal agents by Dr Rauck; and a comparative discussion on the intraventricular delivery of analgesics by Dr Levy. In the final subsection, on intracranial procedures for chronic pain syndromes, three leading functional neurosurgical groups provide their experience and opinion on intracranial neuromodulatory procedures for severe and refractory pain syndromes. Deep brain stimulation (DBS) for pain has a complex history marked by periods of enthusiasm and periods of concerned skepticism and lack of interest. In the USA, DBS is not currently an FDA-approved therapy for pain and is performed infrequently in certain specialized centers. Motor cortex stimulation is a relatively newer technique as compared to DBS. It was first reported in 1991 by Tsubokawa in Japan. To this date, a few groups have reported significant experience with this technique for neuropathic facial pain and post-stroke pain. The chapters in this section summarize the outcomes from years of experience with brain neuromodulation

while providing valuable comments on the rationale, mechanisms of action, patient selection, and technical aspects of the procedures. Although the treatment of chronic pain by cortical or deep brain stimulation remains challenging and at times controversial, these authors are to be complimented for their great efforts and dedication in advancing this field and helping some of the most difficult to treat patients. Tipu Aziz and the functional neurosurgery group at the John Radcliffe Hospital, Oxford, UK, provide an introductory review on the history of DBS for chronic pain syndromes followed by their accumulated experience in patient selection, techniques, and outcomes. Their work provides a new wave of cautious enthusiasm involving DBS for non-malignant chronic pain. Deep brain stimulation is proposed as a valid therapeutic alternative, to be considered not necessarily as a last resort after failure of all other less invasive surgical options such as spinal cord stimulation. Patients were selected as potential candidates based more on clinical findings than on the origin of the pain as long as the etiology was consistent with probable plastic reorganization of the neuromatrix. In addition, the concept that stimulation of the sensory thalamus is indicated primarily for neuropathic pain while stimulation of the periventricular/peri­aqueductal gray matter region should be reserved for nociceptive pain syndromes is challenged and further expanded upon. Angelo Franzini and colleagues report on the pioneering experience of the group at the Istituto Nazionale Neurologico “Carlo Besta,” Milan, Italy, with stimulation of the posterior hypothalamic region for the management of chronic cluster headaches (CCH). This hypothesis-driven investigation was initially based on data indicating the involvement of the hypothalamus in the genesis of the CCH. To this date, the authors have demonstrated the feasibility and safety of DBS for CCH. Although not all patients experience the same extent of pain alleviation, it is remarkable that DBS could help this otherwise disabling condition, sometimes referred to as “suicide headaches.” The neurosurgical unit at Créteil, France, embraced motor cortex stimulation (MCS) soon after it was first reported by Tsubokawa and colleagues. In their chapter, J.P. Nguyen and colleagues provide an excellent review on the origins and proposed mechanisms of action of MCS along with a summary of their outcomes, categorized by pain etiology. The techniques for implantation have evolved over the years. A summary of the current technical preferences and pitfalls is reported for the surgical approach, image guidance for anatomical localization, and intraoperative electrophysiology. Overall, this section will be an important read not only for neurosurgeons dedicated to stereotactic and

IV.  Neuromodulation for chronic Pain

IV.  Neuromodulation for chronic Pain

functional neurosurgery but for all those interested in the technological and clinical aspects of neuromodulation for chronic pain.

References Isaacson, W. (2003) Benjamin Franklin: An American Life. New York: Simon & Schuster. Melzack, R. and Wall, P.D. (1965) Pain mechanisms: a new theory. Science 150: 971–9.

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Pruel, M.C. (1997) A history of neuroscience from Galen to Gall. In: S.H. Greenblatt, T.F. Dagi and M.H. Epstein (eds), A History of Neurosurgery. Park Ridge, IL: American Association of Neurological Surgeons, pp. 99–130. Shealy, C.N., Mortimer, J.T. and Reswick, J.B. (1967) Electrical inhibition of pain by stimulation of the dorsal columns. Preliminary clinical report. Anesth. Analg. 46: 489–91. Stillings, D. (1971) The first use of electricity for pain treatment. Medtronic Archive on ElectroStimulation, Minneapolis, MN: Medtronic, Inc. Wall, P.D. and Sweet, W.H. (1967) Temporary abolition of pain in man. Science 155: 108–9.

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C H A P T E R

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Physiology and Pathophysiology of Chronic Pain Joshua M. Rosenow

o u t l i n e Introduction

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Antinociception Supraspinal and Descending Systems

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an anatomic region not subject to noxious stimulation, even if the physiologic changes sustaining it are not located in that area. This type of pain reflects damage to and improper functioning of neural tissue. Nociception involves the perception of certain affer­ ent signals from sensory receptors as noxious. Sensory stimuli lead to the induction of an inward transmem­ brane ion current (usually sodium) produced by the sensory receptor. The cell bodies of these receptors most often reside in the spinal dorsal root ganglia (DRG). Mechanical stimuli open receptor transmem­ brane channels via direct physical deformation. Chemical stimuli bind directly to receptor sites. While the exact mechanism for the transduction of thermal stimuli is not known, it is believed that extreme ther­ mal stimuli result in tissue damage, thus initiating cur­ rent flow. An action potential is transmitted towards the DRG and the dorsal horn of the spinal cord when membrane depolarization due to the summation of these excitatory currents exceeds the threshold for action potential generation. Lowering the threshold for

Melzack and Wall’s landmark 1965 articulation of the gate control theory of pain marked the beginning of the modern era of understanding and managing chronic pain. Subsequent years have seen the introduction of neuroaugmentative therapies and the demise of many destructive procedures for the treatment of pain. This chapter presents an overview of the anatomy and physiology of the pain system and the neurobiologi­ cal changes that occur in the establishment and main­ tenance of chronic pain states.

Physiology/anatomy of nociception Nociceptive pain reflects ongoing tissue damage, inflammation, and noxious stimulation in intact tissues. In contrast, neuropathic pain appears to emanate from

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21.  Physiology and Pathophysiology of Chronic Pain

Sulcii s1) Dorsal-Median Sulcus s2) Dorsal-Intermediate S. s3) Dorsolateral S. s4) Ventral-Median S. s5) Ventrolateral S.

s1 s2

d g

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Rexed Lamina a) Lissauer’s Tract b) Marginal Zone c) Substantia Gelatinosa d) Body of Dorsal Horn e) Intermediate Horn f) Ventral Horn g) Central Canal h) Lower Motor Neurons

s5

Figure 21.1  Rexed’s laminae within the dorsal horn of the spinal cord (http://en.wikipedia.org/wiki/Spinal_ cord)

action potential generation leads to sensitization of the receptor. Increasing it results in desensitization. Most tissues are innervated by several different types of sensory nerve fibers. Nociception is prima­ rily carried by two types of fibers. A-fibers are small (1–6 mm diameter) myelinated fibers that conduct at relatively slow speeds (5–30 m/sec) and are responsible for the pricking pain known as “first pain.” C-fibers are unmyelinated and do not have encapsulated sensory endings. They are the smallest fibers (1.5 mm diam­ eter) and conduct at the slowest speed (0.5–2 m/sec). Both of these fibers terminate as free nerve endings in tissue. C-fibers are felt to be responsible for “second pain,” the slow-onset, poorly localized pain with a burning quality that begins in a slightly delayed fash­ ion after injury and lasts beyond the time of the first pain (Koltzenburg et al., 1994). Sensory stimuli are integrated and encoded for cen­ tral transmission in a specialized portion of the sen­ sory axon near the sensory receptor that is densely populated with sodium channels. Encoding is highly specific to each sensory ending and may be altered by compounds such as anticonvulsants and local anesthet­ ics that alter sodium channel function, as well as sodium channel density. This is in contrast to sensory trans­ duction, which is not sensitive to these compounds. Encoded sensory impulses are transmitted centrally toward the cell body in the dorsal root ganglion (DRG). No synapses are made in the DRG and the signals are then transmitted to the dorsal horn of the spinal cord. More than half of the DRG cells utilize the excitatory

amino acid glutamate as a neurotransmitter. A sub­ stantial portion of these cells co-localize substance P, a neuropeptide with a significant facilitatory role in pain transmission (Emson et al., 1977; Jessell and Iversen, 1977; Battaglia and Rustioni, 1988; De Biasi and Rustioni, 1988). Postsynaptic glutamate receptors are often co-localized with presynaptic neurons containing substance P (Aicher et al., 1997). Smaller myelinated and unmyelinated fibers cluster in the lateral aspect of the dorsal root as it approaches the dorsal horn of the spinal cord and enter Lissauer’s tract, as opposed to the larger myelinated fibers (subserving propriocep­ tion and light touch) that cluster in the medial aspect of the root, closer to the dorsal columns. Rexed first described the laminar organization of the spinal gray matter in the 1950s (Rexed, 1952, 1954) (Figure 21.1). Afferent fibers enter the dorsal horn via the dorsolateral fasciculus of Lissauer. Afferent spino­ thalamic axons may travel vertically several spinal segments in this superficial layer before eventually synapsing with neurons in lamina I, the posteromarginal nucleus. This layer contains nociceptive-specific neu­ rons that respond almost exclusively to noxious stimuli (Carpenter, 1991c; Byers and Bonica, 2001; Terman and Bonica, 2001). They contain multiple neuropeptides, including substance P, calcitonin gene-related peptide (CGRP), enkephalin, and serotonin. Substance P and CGRP in particular play an important role in dorsal horn nociception (Donnerer and Amann, 1992; Donnerer and Stein, 1992; Donnerer et al., 1992a, 1992b). Lamina I cells send axons contralaterally across the ventral

Iv. NEUROMODULATION FOR chronic PAIN

physiology/anatomy of nociception

20

Aβ

ms 0

250

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3

4

1

2

3

4

1 (control)

2 (30 min)

3 (60 min)

4 (LA)

Aδ

ms

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1000 C

ms

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Figure 21.2  Raster dot displays of a single biceps femoris unit activated by stimulation of the sural nerve 1 every 2 seconds before an ipsilateral thermal injury (control), 30 and 60 minutes post injury, and 10 minutes after the injured foot has been completely anesthe­ tized with local anesthetic. Each dot represents an action potential. In the pre-injury state, only an A- input was evoked. Thirty min­ utes after injury a C-fiber response begins to occur, whereas at 60 minutes both A- and C-evoked responses are present. Note the development of wind-up of C responses. Ten minutes after the local anesthetic (administered 80 minutes post injury) the sural C-evoked responses remain higher than before the injury, suggesting a central component of the sensitization (Reproduced from Woolf (1983), Nature, p. 687, with permission. Copyright 1983)

aspect of the central canal to form the lateral spino­ thalamic tract (STT). Lamina I also contains a class of cells that respond to a large variety of both noxious and non-noxious stimuli. These wide dynamic range (WDR) cells are able to alter their discharge frequency substantially to reflect the type of input stimulus. Noxious stimuli evoke higher frequency discharges from WDR cells (see Figure 21.2). As described below, these cells play an important role in the development of chronic neuropathic pain.

289

Lamina II, the substantia gelatinosa, modulates input from sensory receptors. Nociceptive and thermo­ receptive input is concentrated in the superficial layer of this lamina (IIo) while mechanoreceptor input is targeted to the deeper aspect (IIi) (Carpenter, 1991c; Terman and Bonica, 2001). Projections from substantia gelatinosa neurons terminate in lamina I and in lamina II at other spinal levels. Opiate receptors are plentiful in both laminae I and II. Importantly, each sublayer of lamina II appears to contain distinct subpopulations of C-fibers. Those C-fibers terminating in the outer region, lamina IIo, are similar to those that terminate in lamina I in that they express substance P and CGRP and contain the tyrosine kinase A (trkA) receptor, the high affinity catalytic receptor for the neurotrophin, Nerve Growth Factor (NGF). In contrast, the C-fibers terminating in the inner region, lamina IIi, do not express either CGRP or substance P, but instead express the binding site for lectin IB4, an indicator of sensitivity to glial-derived neurotrophic factor (GDNF). This lamina also contains numerous local circuit neurons whose dendritic arbors may extend into both deeper and more superficial laminae. The Aß-fibers terminate primarily in lamina III, as do some of the A mechanoreceptive fibers. Lamina IV also serves as a target zone for Aß-fibers. Some of the cells in this layer project back to layer I, aid­ ing in integration of sensory information. Lamina V contains a large number of STT projection cells that receive input from A- and C-fibers. A substantial proportion of the cells here are WDR neurons. These have large receptive fields whose center is responsive to both noxious and non-noxious stimuli and a sur­ rounding area responsive primarily to noxious stimuli only. Stimulation of the region surrounding this field causes inhibition of the WDR neuron (Terman and Bonica, 2001). Lamina X encompasses the gray matter surround­ ing the central canal of the spinal cord. This region is thought to play a role in visceral sensation as well as the holospinal integration of nociceptive information. Some A-fibers directly terminate here, possibly carry­ ing both visceral and cutaneous inputs. The STT projects primarily to the contralateral sensory thalamus, the ventrocaudal nucleus (Vc) of Hassler’s nomenclature or the ventroposterior nucleus (VP) of the Anglo-American system. Once again, a definite somatotopic organization is present. Fibers from the legs and lower body project to the more lateral thala­ mus (VPL) while the trigeminal system sends axons to synapse in the more medial regions of the nucleus (VPM). Distal parts of the limbs are represented more ventrally within the nuclei while inputs from the trunk and other central regions terminate more dorsally

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(Carpenter, 1991b). The thalamus then sends wide pro­ jections to the cerebral cortex. Most of the STT projection cells originate in lami­ nae I and V of the dorsal horn. Smaller contributions come from laminae VII and IX. Their axons then cross ventral to the central canal on their way to the contralateral ventrolateral region (Carpenter, 1991d). The decussation may occur either at the correspond­ ing spinal level or 1 or 2 segments higher. This helps to account for the discrepancy between sensory level and injury level observed in spinal cord injury patients. Somatotopy is maintained within the spinothalamic tract. The first fibers to form the tract, those from the lumbosacral region, lie dorsolaterally. Fibers from suc­ cessively more cranial levels then lie progressively more ventral and medial (Carpenter, 1991c). Some of the axons from lamina I, as well as those from laminae VII and IX project to sites outside of the ventrocaudal thalamus (Carpenter, 1991b; Chudler and Bonica, 2001). Known as the paleospinothalamic tract, these axons synapse in the brain stem reticular formation, hypothalamus, or other thalamic nuclei. Many of the axons originating outside of lamina I come from WDR cells, which tend to have a higher conduc­ tion velocity than the axons from lamina I nociceptive cells. These cells not only respond to a wide range of stimuli, but also have larger receptive fields than nociceptive cells. It is believed that the smaller fields of the nociceptive cells aid in pain localization and discrimination. The WDR cells may play the integrative role of the “T” cells in Melzack and Wall’s (Melzack and Wall, 1965) original description of the gate control theory. In their model, the “T,” or transmission, cells are the convergence point of signals from multiple peripheral afferents. These cells were depicted as being able to handle numerous types of sensory input. The signal transmitted depended on the status of the pain gate. The broader characteristics of the WDR cells are felt to be involved in the affective component of pain, hence their projection to the reticular formation, periaque­ ductal gray, and medial thalamic nuclei, sites that have been implicated in modulating this (Willis and Westlund, 1997). Other thalamic nuclei are involved in pain process­ ing. The intralaminar nuclei, such as the nuclei para­ fascicularis (Pf), centrum medianum (CM), centralis medialis, and centralis lateralis, as well as the nucleus medius dorsalis (MD), all receive higher order nocicep­ tive inputs, either directly from the STT or (more com­ monly) by way of other thalamic nuclei or the brain stem nuclei (Bowsher et al., 1968; Reyes-Vazquez et al., 1989a; Mao et al., 1992; Chudler and Bonica, 2001; Krout et al., 2002). These sites have served as targets for

DLPFC Ins

Ins

S2

S2

Cu

Ins S2

PCC

Figure 21.3  Bilateral representation in the anterior insula of unilateral cold allodynia stimulation of the upper extremity as dem­ onstrated with functional MRI

neurosurgeons treating intractable pain (Richardson and Akil, 1977). Antinociception may be evoked by stimula­ tion (Richardson and Akil, 1977) or infusion of opi­oids (Mao et al., 1992; Reyes-Vazquez et al., 1989b; Harte et al., 2000) into these areas. There are many other targets for nociceptive pro­ jection axons (Chudler and Bonica, 2001). These include the midbrain reticular formation, the colliculi, hypothalamus, basal ganglia, amygdala, and limbic system. Functional imaging has disclosed activation of an extensive list of supraspinal structures in response to pain, including the medullary reticular formation, locus coeruleus, lateral parabrachial region, anterior pretectal nucleus, the medial, lateral, and posterior thalamic regions, basal ganglia, and the parietal, cin­ gulate, frontal, insular, and orbital cortices (Porro et al., 1999). The thalamus projects to the somatosensory cortex. The primary somatosensory cortex (SI, Brodmann’s areas 3a/b,2,1) corresponds to the postcentral gyrus and the neighboring sulci (Carpenter, 1991a). The secondary somatosensory cortex (SII) is located just posterior to SI on the medial hemisphere. Most noci­ ceptive afferents terminate in cortical layers III and IV (Chudler et al., 1990). The ventrobasal thalamus projects cutaneous sensation primarily to areas 3b and 1. Both SI and SII cortices receive nociceptive input from the thalamus. The insula has also been found to play a role in the higher order processing of pain. Painful stimula­ tion can activate the insula, as seen on fMRI (Niddam et al., 2002). Moreover, this effect may be noted bilater­ ally (Hsieh et al., 1995; Frot and Mauguiere, 2003) (see Figure 21.3). Interestingly, these pathways seem to require that a certain level of consciousness be present for them to be utilized. Laureys et al. (2002) reported that areas such as the insula, SII, and cingulate cortices showed no activity when patients in a vegetative state were given a painful stimulus. The strength of insu­ lar activation is related to the magnitude of the stimu­ lus (Bornhovd et al., 2002). While some have localized

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insular activation to the posterior insula (Ostrowsky et al., 2002), it is clear that the anterior insula plays an important role as well (Hsieh et al., 1995; Peyron et al., 2000; Treede et al., 2000). In fact, Maihofner et al.(2002) demonstrated that the sensation of cold pain may completely bypass the SI cortex and be primarily processed in the posterior insula. The cingulate cortex is also activated by painful sensations (Peyron et al., 2000; Schnitzler and Ploner, 2000; Rolls et al., 2003). This region receives input from the intralaminar and medial thalamus. It is most likely responsible for the affective and motivational aspects of pain. This is partly indicated by studies (Ploner et al., 2002) showing that “second pain” leads to anterior cingulate activation whereas “first pain” only activates the SI cortex. Moreover, distracting a subject during the application of a painful stimulus attenuates the anterior cingulate activation (Frankenstein et al., 2001). Hsieh et al. (1995) noted that the right anterior cingulate appeared to be dominant in that it was acti­ vated by both ipsilateral and contralateral stimulation.

Physiology of pain A variety of peripheral nociceptors have been described (Carpenter, 1991c; Devor, 1999; Byers and Bonica, 2001). These include mechanical nociceptors, heat nociceptors, mechanoheat nociceptors, and cold nociceptors. The majority of A-fibers are associated with mechanical or heat nociceptors. While many sensory receptors are specific to one type of stimulus, a group of polymodal receptors exists that respond to a variety of stimuli, including neurotransmitters, neuropeptides, ions, steroids, amines, amino acids, and growth factors. Many polymodal receptors are C-fibers that serve to maintain tissue homeostasis by monitoring the overall tissue environment. Sensory receptors often produce graded receptor potentials in response to stimuli of progressively increas­ ing strength. An action potential is generated once the receptor potential results in depolarization sufficient to cross the threshold level. Moreover, some recep­ tors have another threshold for generating repetitive action potentials.

Peripheral Sensitization Sensitization is the process by which the action potential threshold is shifted toward less intense stimuli. Chemical mediators released during the inflammatory response such as serotonin, histamine, bradykinins, capsaicin, glutamate, prostaglandins, and

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other cytokines such as tumor necrosis factors may play an important role in establishing and maintain­ ing a sensitized state. Macrophages, PMN leukocytes, fibroblasts, and other neurons all modulate receptor activity. A substantial proportion of nociceptors are not active during other states, even in the presence of strong stimuli, but are activated only when sensitized during inflammatory states. Prolonged tissue inflammation alters the conduction velocity and action potential duration of C and Afibers. Of importance to the genesis of neuropathic pain, A-fibers may also be sensitized by inflamma­ tory mediators. Moreover, repetitive stimulation from ongoing injury may also result in sensitization. Peripheral sensitization is manifested clinically as hyperalgesia, an increased response to a suprathreshold­ noxious stimulus. While compounds released during inflammation only alter the stimulus threshold for receptor firing, injury to tissue, and thus also to nociceptors and/or free nerve endings, may evoke aberrant electrical activity in nerve fibers that is perceived as pain. This neuropathic pain does not respond well to narcotic medications or may respond to higher doses and is often described by patients as “burning” or “searing.” Injured nerves not only develop abnormal hyperexcit­ ability at their terminals, but also at previously inac­ tive sites along the axon. Nerve injury results in the sprouting of new termi­ nals as part of the normal process of peripheral nerve regeneration. However, these new extensions may be hyperexcitable and exhibit ectopic electrical dis­ charges. Neuromas are one clinical manifestation of this process. When a neuroma has arisen at the site of a previous peripheral nerve injury, it is frequently pos­ sible to evoke paresthesiae (Tinel’s sign) by tapping the skin over the neuroma. When only paresthesiae result, it is likely that only large A-fibers are involved. However, stinging, shooting, burning, and aching sensations may signal the involvement of A- and Cfibers as well. England et al. (England et al., 1996) reported that post-traumatic neuromas may have as many as 50% more sodium channels than normal peripheral nerve. Importantly, sodium channels were clustered at nodes of Ranvier in normal nerve, whereas injured nerves were shown to have frequently lost their myelin sheath and subsequently develop multiple dense patches of sodium channel accumulation along the axon. Accumulation was especially noted at the regenerat­ ing neurite tips. Matzner et al. (Matzner and Devor, 1994) selectively blocked sodium, potassium, and calcium channels in a neuroma model. Only block­ ade of voltage-gated sodium channels with lidocaine

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and tetrodotoxin (TTX) reduced neuroma action poten­ tial firing. Moreover, impulse initiation was reduced significantly more than impulse propagation. The beneficial effects on neuropathic pain of sodium channel-blocking anticonvulsants such as phenytoin and carbamezepine provide further evidence of the importance of these channels in the pathophysiology of chronic pain. The significantly reduced thresholds of injured and regenerating fibers to mechanical, thermal, and chemical irritants are likely due to the accumulation of various other types of transmembrane channels and receptors at the fiber terminal, site of injury, or demy­ elinated region in addition to sodium channels. Injury to the nerve (excluding the cell soma) does not slow the process of transmembrane channels synthesis in the cell soma at the DRG. These channels are sub­ sequently transported down the axon to the terminal receptor. In injured nerves, these channels accumulate at the site of axotomy or demyelination. Neuromas and other damaged sensory fibers respond to the same stimuli as the undamaged nerve, but at altered thresholds (Devor et al., 1990; Welk et al., 1990). Neurotrophic growth factors have also been impli­ cated in peripheral pain transmission and sensitiza­ tion (Lewin and Mendell, 1993). Nerve growth factor (NGF) produced by local fibroblasts is a powerful neu­ ral survival factor early in development for a large group of neural subtypes, including neurons contain­ ing substance P, a neuromodulatory peptide important in pain transmission. There is dissociation between NGF-induced behavioral hyperalgesia and mechani­ cal hyperalgesia due to peripheral sensitization of Afibers (Lewin et al., 1993; Lewin and Mendell, 1993; Ritter et al., 1993). In these studies, systemic administra­ tion of NGF resulted in both behavioral and mechanical hyperalgesia in neonatal animals but only behavioral effects in juveniles. Interestingly, while adult animals also developed both behavioral and mechanical phe­ nomena, there was no mechanical hypersensitivity. This led the investigators to postulate a central mechanism for the actions of NGF in adults. Moreover, anti-NGF serum can block increases in substance P and calci­ tonin gene-related peptide (CGRP) in the DRG usually evoked by tissue inflammation (Donnerer et al., 1992b). Studies of various cells types involved in peripheral injury revealed that primary afferents and mast cells appear to mediate NGF’s effects in the periphery (Woolf et al., 1996). Nitric oxide (NO) is a diffusible gas that has multiple physiologic roles through its interaction with the gua­ nyl cyclase second messenger pathway. Both endog­ enous and exogenously administered NO result in hyperalgesia, albeit via different pathways (Aley et al.,

1998). The endogenous NO contributes to hyper­ algesia induced by prostaglandin E2 (PGE2) via a cyclic adenosine monophosphate (cAMP)-dependent mechanism independent of guanyl cyclase. In contrast, exogenously administered NO increases guanyl cyclase activity. Nitric oxide synthase (NOS) has been found to be upregulated in the dorsal root ganglia following injury, and blockade of NOS inhibits neuroma-induced hyperalgesia (Wiesenfeld-Hallin et al., 1993). Further evidence for the peripheral effects of NO comes from successful trials of topical NO donors as adjuvants for analgesia (Lauretti et al., 2002; Yuen et al., 2002). It is most likely true that release of NO by fibroblasts or vascular endothelium after tissue injury also facilitates local blood flow and healing. Thus the hyperalgesic actions of NO may serve a protective function. Injury also induces peripheral nociceptive fibers to increase the number of -adrenergic receptors present. These may be responsible for sympatheticallymediated excitation in 65% of fibers that ended in neur­omas (Chen et al., 1996). Moreover, sympathetic terminals may release substances (noradrenaline, PGE2, PGI2) in the presence of inflammation that aid in establishing and maintaining peripheral sensitiza­ tion (Janig et al., 1996). Devor et al. found that sympa­ thetic innervation of the DRG augmented abnormal activity in a majority of axotomized sciatic nerve fibers (Devor et al., 1994).

Central Sensitization Ongoing tissue damage or inflammation as well as nerve injury results in both short- and long-term changes in the central nervous system. Central mech­ anisms can account for both of the phenomenon of secondary hyperalgesia (the decreased pain threshold outside of the original area of injury and outside the inflammatory flare region) as well as the development of allodynia, the perception of a nonpainful stimulus as painful. Using a double thermal injury model, Raja et al. (Raja et al., 1984) found that the areas of primary and secondary hyperalgesia had different response charac­ teristics. While the area of primary hyperalgesia dis­ played sensitivity to both heat and mechanical stimuli, only secondary hyperalgesia to mechanical stimuli was present. Moreover, thermal hypalgesia existed in the region between the two burns. Moreover, selective blockade of C- and A-fibers does not abolish hyper­ algesia in patients with neuropathic pain (Campbell et al., 1988). However, selectively blocking A-fibers may do so. This demonstrates that signals from non-nociceptive afferents could mediate chronic pain

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physiology of pain

To thalamus

From nociceptive endings (Aδ and C fibers)

Inhibitory interneuron in substantia gelatinosa

� �

� � �

Tract cell

From non-nociceptive endings (Aα and Aβ fibers)

Figure 21.4  Simple illustration of the gate control theory of pain. Non-nociceptive sensory fibers stimulate the inhibitory interneurons, whereas nociceptive afferents inhibit them. An increase in non-nociceptive input will reduce the rate of firing of the spinothalamic tract neurons (http://instruct.uwo.ca/anatomy/530/gatepain.gif)

states, most likely via a central mechanism (Price et al., 1992; Koltzenburg et al., 1994). Nociceptor cutaneous receptive fields expand in response to thermal injury. Moreover, some of the periph­ eral receptors become responsive to bilateral stimulation, likely due to spinal mechanisms (Woolf, 1983; Hylden et al., 1989). Moreover, continued C-fiber activity can lead to a state of central excitability (Cook et al., 1986, 1987; Woolf and Wall, 1986). After axotomy, A-fiber efferents expanded their terminal arborizations from lamina III up into lamina II, the location of most Cnociceptor terminals (Markus et al., 1984; Woolf et al., 1992; Mannion et al., 1996). Peripheral nerve section causes reorganization in the dorsal horn with dorsal horn cells responding to new receptive fields after loss of the natural field (Devor and Wall, 1981a, 1981b). Depolarization of DRG afferents leads to the cross-excitation of neigh­ boring neurons without obvious electrical connection between the cells (Devor and Wall, 1990; Utzschneider et al., 1992; Amir and Devor, 1996). Moreover, this cross-depolarization resulted in a lowering of the fir­ ing threshold. A concurrent increase in membrane conductance was noted, presumably due to a diffus­ ible chemical mediator. It was believed that this obser­ vation could help to explain not only the expansion of cutaneous receptive fields, but also allodynia, in part. This mechanism may also play a role in the “lightning pains” of trigeminal neuralgia (Devor, 1999).

Stimulation of the A-fibers in the dorsal columns is at the heart of the gate control theory and forms the basis of TENS and epidural spinal cord stimula­ tion as therapies for pain. These modalities produce pain relief that is not reversible by the administra­ tion of naloxone (Terman and Bonica, 2001). According to Melzack and Wall (1965), activation of large myeli­ nated afferents “closes the pain gate” in the substan­ tia gelatinosa by enhancing the inhibitory actions of local circuit neurons in the dorsal horn on central transmission cells (see Figure 21.4). They postulate that pain states are maintained by the continuous firing of unmyelinated and small myelinated efferents. A pro­ portionately greater increase in the activation of large myelinated afferents serves to close the gate via pre­ synaptic inhibition. This theory has held up for sev­ eral decades with only empirical evidence to support it and the lack of competing theories with the experi­ mental weight to refute it. Molecular techniques have allowed further expla­ nation of initiation and maintenance of chronic pain. Much of the work focuses on the central role of gluta­ mate, the primary excitatory neurotransmitter in the dorsal horn (Coderre et al., 1993). Several ionotropic glutamate receptors have been cloned and named for their selective ligands and include the kainate receptor, the AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazole­ propionate) receptor, and the NMDA (N-methylDaspartate) receptor. The kainate and AMPAsubtypes

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Glutamate AMPA receptors Na� Na�

P

K�

P

Na

K�

NMDA receptor � � Ca2 Mg2�

New AMPA receptor

P

K�

Ca2�-calmoduline

Adenylate cyclase

cAMP

CaM kinase II

MAP kinase

PKA CREB Genes activated

Figure 21.5  A diagram of the pathways affected by NMDA receptor activation. Influx of calcium via the receptor causes acti­ vation of cellular pathways via Ca-calmodulin complexes which activate adenylate cyclase and various kinases. This results in longer-term changes in gene transcription (http://thebrain.mcgill.ca/flash/a/a_07/a_07_m/a_07_m_tra/a_ 07_m_tra_1a.gif)

are stereotypical ligand-gated ion channels in which binding of the ligand (glutamate) to the extracellu­ lar binding site produces a conformational change in the receptor, allowing ions (primarily sodium) to flow down their concentration gradient into the postsynaptic terminal. Metabotropic glutamate receptors have also been identified in the dorsal horn (Kawai and Sterling, 1999). These glutamate receptors are coupled to Gprotein systems that in turn affect the level of phospho­ rylation of cytosolic proteins via protein kinases. While AMPA receptors have been localized to sev­ eral laminae in the dorsal horn (Willcockson et al., 1984), it is the NMDA receptor that has garnered the most attention. At the cell membrane’s resting poten­ tial, the ion channel of the NMDA receptor is blocked by a magnesium ion, preventing ion entry into the cell, even in the presence of a receptor agonist (Mayer

et al., 1984). However, repeated membrane depolari­ zation as in continuous nociception can remove the magnesium ion block allowing ions to enter the cell. The NMDA receptor also has an additional binding site for glycine, which acts as a co-agonist. This is of inter­ est because glycine is traditionally thought of as an inhibitory neurotransmitter. NMDA receptors exhibit dual conductance, in that the opening of the NMDA receptor channel leads to a significant influx of both calcium and sodium into the cell (Chen et al., 2000). It is calcium’s significant second messenger effects that have fueled further detailed investigation of NMDA receptors. Calcium entry into the cytosol leads to a host of other effects, and appears to be the point of intersection for the mechanisms of numerous substances related to nociception (Coderre et al., 1993). Phospholipase C (PLC) may be activated either by substance P binding to NK-1 receptors or glutamate binding to metabotropic glutamate receptors. Substance P and glutamate may also act synergistically (Murase et al., 1989; Randic et al., 1990; Dougherty and Willis, 1991a; Dougherty et al., 1993). Activated PLC subsequently catalyzes the hydrolysis of phosphotidylinositol bisphosphate (PIP2) into diacylglycerol (DAG) and inositol triphosphate (IP3). DAG then activates protein kinase C, leading to phosphorylation of other cellular proteins and wide-ranging effects on gene expression and other processes including the enhancement of cal­ cium currents (DeRiemer et al., 1985). In addition, IP3 causes the release of calcium from intracellular stores such as the endoplasmic reticulum. These effects can entrain a positive feedback loop whereby more cal­ cium enters the cell and the calcium-dependent proc­ esses are further activated (Chen and Huang, 1991, 1992). This may be important in the development of “wind-up,” the progressive increase in response that comes with repetitive C-nociceptor stimulation in neuropathic pain states. Wind-up may be prevented experimentally by NMDA receptor antagonists (Davies and Lodge, 1987; Dickenson and Sullivan, 1987; Thompson et al., 1990; Dougherty and Willis, 1991b; Woolf and Thompson, 1991). Moreover, once central sensitization has been induced by repetitive stimula­ tion, NMDA receptor blockade may be able to return the spinal cord to its original state (Haley et al., 1990; Woolf and Thompson, 1991) and also block the expan­ sion of nociceptor receptive fields induced by inflam­ mation (Dubner and Ruda, 1992). Calcium entry also induces nitric oxide (NO) synthase. As previously stated, NO may be associated with hyperalgesia (Grzybicki et al., 1996) (Figure 21.5). Increased cellular calcium levels brought about by the combined actions of excitatory amino acids,

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substance P and CGRP leads to activation of transcrip­ tion factors and an increase of expression of certain genes. One in particular, the proto-oncogene, c-fos, is significantly upregulated in dorsal horn cells in response to substance P and glutamate. NMDA antagonists have been shown to decrease Fos expres­ sion (Hudspith et al., 1999; Munglani et al., 1999). The NMDA receptor agonist-related increase in c-fos expres­ sion is not limited to the spinal cord (Szekely et al., 1989; Lerea et al., 1992). The product of c-fos, Fos, then acts as a transcription factor to induce the expression of endogenous opioid peptides such as preprodynor­ phin and preproenkephalin (Iadarola et al., 1988b). Although, there is a resulting increase in dynorphin levels, there is no subsequent increase in enkephalin levels. Dynorphin has been associated with the pro­ duction of expanded receptive fields and facilitation of responses in a percentage of dorsal horn cells at low doses (Hylden et al., 1991). An ongoing nociceptive barrage would be expected to sustain and propagate this process, with the co-release of excitatory amino acids and peptides having rapid effects via AMPA receptors and delayed, sustained effects through NMDA and metabotropic receptors leading to chronic pain states. While these alterations in gene expression at the central level would appear to be able to maintain cen­ tral sensitization independent of peripheral input, there remains some debate as to whether continued peripheral input is required to perpetuate these central changes. Gracely et al. (1992) have argued that contin­ ued noci­ceptive input is necessary. They point to the disappearance of allodynia after applying a local anes­ thetic block to a separate discrete painful focus. Once the short-term local block wore off, the allodynia returned. This effect was not observed with intravenous anesthetic infusions or local blocks of other regions in the painful area. Other studies (Woolf and Wall, 1986; Woolf and Thompson, 1991) have also shown that, although allo­ dynia may persist after the nociceptive component has been blocked, the central hypersensitivity will return to normal over time. This theory has been tested clinically by using preemptive analgesia, anesthetizing an area before the application of a painful stimulus. It is hoped that by preventing the afferent barrage from reaching the dorsal horn, the myriad of changes described above can be prevented. Excellent reviews of the numerous studies are available (Collins et al., 1995; Niv and Devor, 1999). Patients who do receive preoperative analgesia, whether by local infiltration, by the epidural route, or by intravenous administration, generally have a lower opioid requirement in the postoperative period. Some of the most interesting results have come from studies

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of phantom limb pain. Several studies of patients undergoing amputation have found that preoperative analgesic blockade of the painful limb can significantly reduce the postoperative development of phantom limb sensation and pain (Bach et al., 1988; Jahangiri et al., 1994; Schug et al., 1995). Also, some investiga­ tors (Flor et al., 1995) have reported that those patients with preamputation pain have a higher likelihood of developing phantom limb pain.

Antinociception The nervous system also maintains a complex sys­ tem for damping nociceptive inputs. This complex system involves both local systems in the spinal cord as well as descending supraspinal inputs. The neu­ rotransmitters involved in this process include the endogenous opioids, GABA, and other neuropeptides such as neuropeptide FF, galanin, and neuropeptide Y (Terman and Bonica, 2001). Gamma-aminobutyric acid (GABA) is the pri­ mary inhibitory neurotransmitter in the CNS. It exerts a potent inhibitory effect throughout the CNS via two major receptors, GABAa and GABAb. The GABAa receptor is a ligand-gated chloride channel that initiates a flow of negatively charged chloride ions into the cell down their concentration gradient, thus hyperpolarizing the postsynaptic cell. This recep­ tor has binding sites not just for GABA, but also for benzodiazepines and barbiturates. It is believed that ethanol exerts part of its effects on the CNS via this receptor (Aguayo et al., 2002). The GABAb receptor is a metabotropic receptor coupled to intracellular G-protein systems whose activation by ligands such as baclofen leads to inhibition of excitatory calcium and activation of inhibitory potassium currents. GABA receptor agonists have been shown to reduce allody­ nia in experimental models (Hwang and Yaksh, 1997; Wiesenfeld-Hallin et al., 1997). In addition to GABA-a and GABA-b receptors, GABA-c receptors have also been identified, however their function in antinocic­ eption has not been elucidated. Some primary afferents maintain high intracellu­ lar chloride concentrations via active transport into the cell. Ligand binding to GABAa receptors then results in an outward flow of chloride, thus depolarizing the cell. Activation of this type, known as primary afferent depolarization (PAD), has been hypothesized to play a role in presynaptic inhibition of such neurotransmitters as substance P (Terman and Bonica, 2001). Three main types of opioid receptors have been identified, each with its own subtypes. The primary type, mu, makes up 70% of spinal opioid receptors

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(Terman and Bonica, 2001). This receptor has the highest affinity for morphine and is responsible for mediating not only the analgesic effects of morphine (via mu1 receptors), but also its respiratory depres­ sant effects (via mu2) (Pasternak et al., 1980a, 1980b). The kappa receptor is the target of dynorphin and makes up about 6% of spinal opioid receptors. Delta receptors bind the enkephalins with high affinity and represent about 24% of the spinal opioid receptor population. Like GABA receptors, opioid receptors are metabo­ tropic, G-protein-coupled receptors whose actions alter the membrane conductances for inhibitory and excitatory ion currents. They may also affect the activ­ ity of protein kinase A (PKA), leading to changes in the phosphorylation state of intracellular proteins. A host of other protein kinases have also been impli­ cated in mediating opioid effects, including PKC, MAP kinase, and calmodulin-dependent kinase (CamK) (Terman and Bonica, 2001). The inhibi­ tory effects of mu opioid agonists are likely medi­ ated via reduced presynaptic calcium entry and thus reduced neurotransmitter release from the presynap­ tic terminal (Hori et al., 1992). However, postsynap­ tic mechanisms have also been identified (Schneider et al., 1998). There may be some interaction between NMDA and opioid receptors as well. Ligand binding to NMDA receptors leads to activation of PKC. This enzyme phosphorylates opioid receptors, thus inac­ tivating them, leading to the development of opioid insensitivity or tolerance (Mayer et al., 1995). This may aid in explaining why the effects of central sensitiza­ tion, such as allodynia, are so poorly responsive to opioid medications. The ability for NMDA receptor antagonists to block opioid tolerance has been demon­ strated in multiple studies (Mao et al., 1995; Manning et al., 1996; Mao et al., 1998; Price et al., 2000). NMDA receptor antagonists, therefore, may play a dual role in preventing opioid tolerance as well as encouraging excitotoxic damage and central sensitization. As previously mentioned, the endogenous opioid, dynorphin, plays a key part in the centralization of pain. Dynorphin is cleaved from pro-enkephalin B and is plentiful in the dorsal horn, primarily in lami­ nae I and V, origination sites for thalamic projection neurons (Terman and Bonica, 2001). Pain modulation sites in the brain stem, such as the periaqueductal gray and the midbrain reticular formation, are also plentiful in dynorphin (Cruz and Basbaum, 1985; Basbaum et al., 1986). Inflammation can cause a large increase in dynorphin synthesis (Draisci and Iadarola, 1989; Draisci et al., 1991) that is not accompanied by a downregulation in the number of opioid receptors (Iadarola et al., 1988a).

Neuropeptide FF is an 8-amino acid peptide found in laminae I and II of the dorsal horn (Gouarderes et al., 2000). The mechanism of action for this pep­ tide’s effects is not known, but it has a complex inter­ action with the opioid system (Dupouy and Zajac, 1997). Direct infusion may antagonize opioid analge­ sia indirectly, since neuropeptide FF has no significant affinity for opioid receptors (Dupouy and Zajac, 1995; Roumy and Zajac, 1998; Courteix et al., 1999). However, intrathecal administration can actually lead to antinoci­ ceptive effects (Dupouy and Zajac, 1997; Courteix et al., 1999). Neuropeptide Y acts primarily in the superficial dorsal horn via a G-protein coupled system. It also has both pro- and antinociceptive effects (Munglani et al., 1996; White, 1997) and may be co-localized with GABA in dorsal horn neurons (Rowan et al., 1993). Neurotensin is another small (13 amino acid) peptide found in neurons in laminae I and II of the dorsal horn. It is believed to exert antinociceptive effects by acti­ vating inhibitory interneurons (Terman and Bonica, 2001). In addition to NGF, brain-derived neurotrophic factor (BDNF) has been studied for its role in central sensitization. BDNF has been extensively investigated as a factor for inducing neural stem cells to proceed towards a neuronal, rather than glial, fate (Goldman, 1998; Pincus et al., 1998; Benraiss et al., 2001; Louissaint et al., 2002). BDNF expression in the dorsal horn is increased after nerve injury (Michael et al., 1999; Miletic and Miletic, 2002) and inducing a state of BDNF overexpression can attenuate hyperalgesia and allodynia (Eaton et al., 2002). While infusion of BDNF into the PAG and NRM leads to local increases only in b-endorphin, dorsal horn levels of neuropeptide Y, substance P, and b-endorphin are all dramatically ele­ vated (Siuciak et al., 1995). Despite the local increase in substance P, BDNF infusion induces a naloxonesensitive state of analgesia. In opposition to this, it has been demonstrated that intrathecal BDNF can inhibit dorsal horn release of substance P and increase local GABA release (Pezet et al., 2002). Other recent evidence (Deng et al., 2000) that anti-BDNF serum can inhibit dorsal horn fiber sprouting in neuropathic pain and that antibodies to BDNF can block the development of thermal hyperalgesia (Yajima et al., 2002) shows that BDNF’s effects are most likely complex.

Supraspinal and Descending Systems The existence of powerful endogenous descending antinociceptive systems was dramatically demon­ strated in 1969 by Reynolds, who was able to perform

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physiology of pain

animal surgery with analgesia provided only by stim­ ulation of the periaqueductal region of the midbrain. Since then, this system has been extensively studied and remains a therapeutic target for deep brain stim­ ulation for intractable pain. See the excellent chapter by Basbaum and Porreca on the Endogenous Neuro­ modulation System in this present book. The two major supraspinal sites mediating antinociception are the midbrain periaqueductal gray (PAG) and the nucleus raphe magnus (NRM) of the rostral ventral medulla (RVM). The PAG has been shown to have a complex set of interactions with other systems besides nocicep­ tion. Stimulation of the PAG evokes both behavioral and autonomic effects in addition to antinociception. Bandler et al. (Heinricher, 2002) delineated two distinct cell divisions within the PAG in rats. Stimulation of the lateral column leads to behavioral responses associated with antinociception, such as tachycardia and defense behaviors. However, stimulation in the ventrolateral column leads to depressor effects such as inactivity, bradycardia and hypotension. The PAG receives input from multiple limbic structures, includ­ ing the hypothalamus, insula, and amygdala (Terman and Bonica, 2001). Its principal descending target is the NRM, leading to speculation that the NRM is the actual mediator for the antinociceptive effects of PAG stimulation (Heinricher, 2002). Its direct connection to the dorsal horn is considered to be of lesser impor­ tance (Heinricher, 2002). Opioids may act directly on the PAG to cause descending inhibition of dorsal horn cells. Direct stim­ ulation of PAG mu opioid receptors reduces dorsal horn cell firing in response to noxious stimuli by almost two-thirds (Budai and Fields, 1998; Budai et al., 1998). In addition, this effect may be mediated in the dorsal horn via both presynaptic and postsynap­ tic 2-adrenergic receptors. In these studies, the PAG was activated using bicuculline, a GABAa antagonist, giving rise to the concept that activation of the PAG may represent blocking of inhibition. The PAG is known to have cells containing endogenous opioids and these compounds are believed to exert their influ­ ence by causing antinociceptive neurons to be released from tonic inhibition (Depaulis et al., 1987; Vaughan and Christie, 1997; Terman and Bonica, 2001). This inhibition of transmitter release is mediated by opioidinduced changes in presynaptic potassium conduct­ ance (Vaughan et al., 1997). Interestingly, these opioid mechanisms are potentiated by cyclooxygenase inhib­ itors, helping to explain some of the beneficial effects of combination analgesic preparations. In contrast to the PAG, the NRM has diffuse projec­ tions to the dorsal horn laminae, including laminae

297

I, IIo, IV, and V. When injected into the NRM, opi­oids have antinociceptive effects (Jensen and Yaksh, 1986; Yaksh et al., 1977). These actions are modulated by both serotonergenic and noradrenergic systems (Hammond and Yaksh, 1984) and are not always sensitive to naloxone. Electrical or chemical manipulation of the NRM causes increased release of noradrenaline and serotonin in the spinal cord (Hammond et al., 1985). Evidence for the presence of both inhibitory and facili­ tatory systems mediating antinociception is provided by studies of the NRM which demonstrate several dis­ tinct populations of cells (Fields and Heinricher, 1985). “Off cells” usually fire spontaneously but exhibit a characteristic pause in firing just at the onset of anti­ nociceptive reflexes (Barbaro et al., 1986; Terman and Bonica, 2001; Heinricher, 2002). At the initiation of the reflex, a second class of cells, “ON cells,” shows increased activity. Opioids inhibit the pain-related inhi­ bition of OFF cells (Heinricher et al., 1994). This effect may be mediated by excitatory amino acids and the NMDA receptor (Heinricher et al., 1999, 2001). Studies of spinal serotonergenic influences from the NRM have demonstrated an extensive network of serotonin-reactive processes in contact with neur­ ons in the dorsal horn, especially in laminae I and IV (Terman and Bonica, 2001; Polgar et al., 2002). Serotonin antagonists can reverse stimulation-induced analgesia in animals (Hammond and Yaksh, 1984). This is not sensitive to naloxone, suggesting that serotonin’s effects are not mediated by endogenous opioids. In addition, mice lacking serotonin reuptake transporters do not develop thermal hyperalgesia after nerve injury, even though allodynia is present (Vogel et al., 2003). Fluoxetine, an inhibitor of sero­ tonin reuptake, also potentiates the antinociceptive effect of serotonin (Singh et al., 2001). Serotonin infu­ sion may accelerate the development of tolerance to opioids, an effect that may be attenuated by spinal serotonin depletion (Li et al., 2001). However, intrath­ ecal serotonin has been demonstrated to be effective only in certain models of local pain and not in models of generalized pain (Bardin et al., 2000b). Of the numerous subtypes of serotonin receptors identified, the 5-HT3 receptors are the most likely mediators of these effects (Bardin et al., 2000a). The PAG and NRM have projections to the noradren­ ergic system, including the nucleus subcoeruleus (cell group A7) (Clark and Proudfit, 1991b; Bajic and Proudfit, 1999; Bajic et al., 2000; Heinricher, 2002). These sites in the lateral pons then send diffuse projec­ tions to the ipsilateral dorsal horn (Clark and Proudfit, 1991a; Yeomans and Proudfit, 1992). It has been previ­ ously stated that norepinephrine is released from the spinal cord after NRM stimulation (Hammond et al.,

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21.  Physiology and Pathophysiology of Chronic Pain

1985). Blocking the adrenergic system leads to a reduc­ tion in opioid analgesia or the production of hyperal­ gesia (Hammond and Yaksh, 1984; Sagen and Proudfit, 1984). However, lesions of the NRM have been shown to decrease nociceptive thresholds without an effect on norepinephrine systems, demonstrating some independence between the monoaminergic projec­ tions (Proudfit, 1980). However, this is not complete, since the administration of adrenergic blockers into the NRM has the ability to increase both serotonin and norepinephrine release in the spinal cord (Sagen and Proudfit, 1987). The spinal effects appear to be medi­ ated by 2-adrenergic receptors (Sagen and Proudfit, 1984). Substance P may serve as an excitatory neuro­ modulator for the NRM-A7 interactions (Proudfit and Monsen, 1999; Yeomans and Proudfit, 1992). Given all of the aforementioned physiologic changes at the peripheral and spinal level accompa­ nying chronic pain, it is logical to look at the changes in higher order structures. Kiss et al. (Gorecki et al., 1989; Kiss et al., 1994) have demonstrated an increase in the thalamic representation of somatic regions adja­ cent to the denervated area in patients with deaffer­ entation pain. Several animal studies have noted that cortical reorganization takes place after amputation, with the adjacent digits gaining cortical representation (Merzenich et al., 1984; Jenkins et al., 1990). Moreover, this process can continue for extended periods of time (Pons et al., 1991) and involve shifts of over 10 mm in animals and over 30 mm in humans (Flor et al., 1995) for various cortical representations. In fact, in some deafferented animals, the cortical representation for the deafferented area is eventually totally eliminated (Pons et al., 1991). The shift appears to be greater in those patients with pain after deafferentation (Flor et al., 1995). Amputees will often incorrectly localize pain­ ful sensations to the phantom limb, including stimuli contra­lateral to the phantom limb (Knecht et al., 1995, 1996). It may be true that nociceptive input drives cor­ tical reorganization, in that the degree of rearrange­ ment is directly correlated with the frequency with which a patient mislocalizes painful stimuli (Knecht et al., 1996) and that pain relief can attenuate reorganiza­ tion (Birbaumer et al., 1997; Huse et al., 2001). It may occur rapidly enough that even intense acute pain evokes some reorganization, even if only temporarily (Soros et al., 2001).

Conclusion In the years since the gate control theory was pro­ posed, much has been learned about the mechanisms underlying the perception of pain and the maintenance

of chronic pain states. This research has shed light onto the reasons why pain responds to some treatments but not to others. Moreover, it has facilitated the develop­ ment of new targeted pain therapies and has opened the door to the possibilities of many others in the future.

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The Endogenous Neuromodulation System Allan I. Basbaum, Joao Braz, Michael H. Ossipov, and Frank Porreca

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Bidirectional, inhibitory, and facilitatory descending controls

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Introduction

which corresponds to the topographically, highly organized lemniscal pathway, regulates the outflow of the protopathic system, which corresponds to the poorly localized “pain” transmission pathway. In contrast to the controls that result from the inhibition of spinal cord pain transmission neurons, the control exerted by the epicritic system was presumed to be exerted at the level of the thalamus, involving corticothalamic controls. The Thalamic Syndrome of Dejerine and Roussy (1906) was considered to result from a loss of lemniscal inhibitory controls of the “pain” transmission pathway. Although largely long forgotten, it is also worth noting that internal capsule stimulation was one of the earliest approaches to using electrical stimulation for the control of pain (Adams et al., 1974).

The concept of an endogenous pain control system has taken on different meanings as more details of the circuits and neurochemistry of pain regulatory networks have been elucidated. That there are networks in the brain that regulate the transmission of “pain” messages is certainly not a new idea. Indeed, many were described well before endorphin-mediated control systems were first reported. For example, as early as the turn of the twentieth century, based on the consequences of peripheral nerve injury, Head and Sherren (1905) distinguished two major ascending pathways that transmit somatosensory information. These authors hypothesized that an epicritic system,

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Presumably that stimulation approach inhibited the flow of information at the level of the thalamus. It is also possible that the inhibitory controls exerted upon pain processing by motor cortex stimulation (Lazorthes et al., 2007) involves regulation at the level of the thalamus. It was not until the 1950s that attention turned to the controls that originate in the brain stem and that regulate the processing of nociceptive information at the level of the spinal cord. Following pioneering work of Hagbarth and Kerr (1954), studies from Anders Lundberg’s laboratory in Sweden (Engberg et al., 1965, 1968) provided a detailed analysis of brain stem monoaminergic control of flexor reflex afferentevoked polysynaptic inputs to motoneurons. These studies came on the heels of the discovery of brain stem spinal serotonergic and noradrenergic pathways (Hillarp et al., 1966). Surprisingly, the strong evidence for descending inhibitory controls that regulate noxious stimulus evoked firing of motoneurons was not extensively discussed as a basis for pain control. In fact, it was generally seen as a motor control regulation. On the other hand, it is significant, and also largely forgotten, that the early descending control studies emphasized that there were parallel facilitatory and inhibitory descending controls that originate from the brain stem. The presence of such parallel, yet opposing controls operating on spinal pain transmission networks is now generally accepted (see below).

The history of electrical brain stimulation for the relief of pain The breakthrough in our understanding of the functional and indeed clinical significance of these control systems came with the demonstration that electrical stimulation of specific brain stem regions can produce a profound analgesia, largely free of adverse effects. As is often the case in science, the first observation was serendipitous. Thus, Reynolds (1969) was seeking a way to produce electroanesthesia, not analgesia. Careful observations on his part, of course, led to his recognition that the electrical stimulation did not produce generalized anesthesia. Rather it selectively blocked the response to noxious stimulation. This seminal observation was followed by the critical studies of Mayer et al. (1971) in the laboratory of the late John Liebeskind. These authors used electrical stimulation to produce an antinociceptive effect in freely moving rats and highlighted the importance

of the midbrain periaqueductal gray matter (PAG) as a critical locus for evoked analgesia. Soon after these reports, our laboratory turned its attention to the circuits through which these controls were generated. What was striking was that electrical stimulation not only blocked the behavioral responses to a noxious stimulus (such as vocalization, or attempts to remove a noxious stimulus), but it also blocked the withdrawal reflexes that the stimulus produced. As the reflexes were organized at the level of the spinal cord, we hypothesized that the brain stem-derived controls must involve the activation of inhibitory pathways that regulate the output of spinal cord networks that process noxious stimuli. We tested this hypothesis by evaluating whether cutting different spinal cord pathways (to disconnect the brain stem from the spinal cord) influenced the descending controls. The results from those studies were unequivocal. Only a lesion of the dorsal part of the lateral funiculus (DLF) of the spinal cord interrupted the inhibitory controls (Basbaum et al., 1977). Furthermore, because the spinal cord lesion was made at thoracic levels, the analgesia was only lost in the hindlimbs; it was preserved in the forelimbs. That observation established that the loss of a response to a painful stimulus was not secondary to the rewarding effects of the stimulation, which often occurred concomitantly given the particular targets that were involved (e.g. dorsal raphe) in the early studies. Rather it must have arisen from activation of powerful descending inhibitory controls that could be interrupted by lesions of the DLF. The next question was the origin of the inhibitory pathway that courses in the DLF. Using a combination of anterograde and retrograde tracing procedures, we demonstrated that the rostral ventral medulla is the source of the DLF pathway (Basbaum et al., 1978; Basbaum and Fields, 1979). In related studies, we determined that there are few direct projections from the PAG to the cord. We assumed, and subsequently demonstrated that the PAG neurons, in fact, target the neurons of the serotonin-rich nucleus raphe magnus (NRM) of the rostral ventral medulla (RVM; Abols and Basbaum, 1981). These studies appeared concurrently with the reports from the Besson laboratory that electrical stimulation of the RVM, and specifically the NRM, also produces a profound suppression of pain behavior in animals (for review see Besson et al., 1981). Consistent with those observations we also demonstrated that electrical stimulation of the RVM produces selective inhibition of pain responsive neurons in the spinal cord and that a lesion of the DLF blocked the inhibition (Basbaum et al., 1976). Taken together, these observations led to our description of a descending control model that describes a brain

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on and off cells: contrasting inhibitory and facilitatory descending controls

stem spinal circuit through which opiates and electrical brain stimulation were hypothesized to act (Basbaum and Fields, 1978, 1984). Subsequent studies in fact provided considerable support for the contribution of both serotonergic (5HT) and noradrenergic (NA) systems to descending controls. For example, spinal administration of both 5HT (Yaksh and Wilson, 1979) and noradrenergic agonists (Kuraishi et al., 1979; Reddy et al., 1980) produce a dose-dependent analgesia. Furthermore, electrical stimulation of RVM or PAG neurons produces antinociception that is associated with spinal release of both 5HT and NA (Hammond et al., 1985; Sorkin et al., 1993). Finally, the analgesic effect of electrical stimulation in the RVM or the PAG can be reduced by intrathecal injections of both 5HT- and NA-receptor antagonists (Barbaro et al., 1985).

Bidirectional, inhibitory, and facilitatory descending controls As noted above, however, it is now clear that the brain stem exerts both facilitatory as well as inhibitory controls on the processing of nociceptive information at the level of the spinal cord. In fact, the nature of the postsynaptic effect of the monoamines depends directly on actions at specific receptor subtypes and on the intracellular machinery that is coupled to these receptors. For example, seven distinct families of 5HT receptors have now been described, comprising at least 15 different subtypes, each with relatively unique pharmacological, behavioral, and anatomical profiles (Barnes and Sharp, 1999). Depending on the subtype activated, 5HT influences on spinal cord processing of pain messages can either be inhibitory, i.e. analgesic, or facilitatory, i.e. pronociceptive. These respective effects appear to be exerted via the 5HT1A and 1B/D receptors or the 5HT1A, 2A, and 3 receptors (Sufka et al., 1992; Green et al., 2000; Porreca et al., 2002; Zeitz et al., 2002; Suzuki et al., 2004; Sasaki et al., 2006). A recent provocative study used a genetic approach to ablate 5HT neurons in mice and provided further evidence for bidirectional serotonergic controls (Zhao et al., 2007). In these animals inflammatory pain (i.e. produced by tissue injury) is enhanced but responsiveness to mechanical stimulation is decreased. The effects of NE also appear to be bidirectional (Pertovaara, 2006). Thus, although most studies emphasize that the noradrenergic inhibitory controls are exerted by an action at the 2-adrenergic receptor, the likely target through which intrathecal clonidine

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exerts its pain-relieving effects, others found that 1-adrenergic receptor agonists actually decrease nociceptive thresholds, i.e. enhance “pain” transmission (Proudfit, 1988). Adding to this complexity is the fact that serotonergic and noradrenergic systems interact, to enhance antinociception (Archer et al., 1986; Nakagawa et al., 1990). For example, at the level of the spinal cord, synergistic interactions have been reported between 2- and 5HT-2/5HT1B receptor agonists (Danzebrink and Gebhart, 1991). Clearly, translating these observations to the clinic requires a very good understanding of the particular receptor types that are involved in the descending controls, and the extent to which any particular drug targets subsets of monoamine receptors.

ON and OFF cells: contrasting inhibitory and facilitatory descending controls In addition to their direct spinal projections, 5HT and NE neurons establish connections with other brain stem pain control networks. In fact, the influence of 5HT and NE may, to a great extent, be attributed to their actions on two non-monoaminergic classes of brain stem neurons, the so-called “ON” and “OFF” cells of the RVM (Fields et al., 1988; Potrebic et al., 1994). The ON and OFF cell categorization is an electrophysiological one: ON cells increase and OFF cells decrease their firing just prior to the initiation of noxious stimulus-evoked nocifensive reflexes, such as a tail flick withdrawal to noxious heat (for reviews see Fields et al., 1991; Fields, 2004). These observations, together with the fact that ON and OFF cells project to the dorsal horn of the spinal cord, led to the proposal that ON cells facilitate whereas OFF cells inhibit the processing of nociceptive messages at the level of the spinal cord. The most compelling evidence in support of this hypothesis is that opioids inhibit the firing of ON cells, but increase the firing of OFF cells (Barbaro et al., 1986). The integrative output of these opioid effects on OFF and ON cells would, of course, be enhanced inhibitory controls arising from the medulla, i.e. greater pain control. Not surprisingly, opioid injection into the PAG, which produces a profound analgesia, and which is presumed to activate the same circuits engaged by electrical stimulation of the PAG, also profoundly activates OFF cells and decreases the firing of ON cells (Cheng et al., 1986). One of the puzzles arising from the characterization of the ON and OFF cell neuronal populations is that the early studies reported that neither the ON nor OFF

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cells correspond to the 5HT neurons of the RVM, but rather to a different class called the neutral cell. The firing of neutral cells showed little or no relationship to noxious stimulation or to reflex evoked by such stimuli, and subsequent studies reported that many neutral cells were, in fact, 5HT expressing. Given that the 5HT neurons were originally considered to be at the origin of descending inhibitory controls, this result was unexpected. More recent studies, however, suggest that the 5HT cells may indeed relate to nociceptive processing, but not in the relatively direct fashion proposed for the ON and OFF cells. Specifically, studies of Mason and colleagues reported that the firing of ON and OFF cells, as well as the firing of 5HT neurons, is state-dependent, being modulated differentially across sleep/wake cycles (Mason, 2001; Fields, 2004).

Endogenous pain control mechanisms: relevance to clinical pain At the moment, we have partial validation of the importance of these systems in modulating function in patients. Nevertheless, detailed information as to how and when descending modulation affects clinical pain states requires further exploration. In the case of descending inhibition, clinical validation has been achieved in several ways. First, and as noted above, electrical stimulation applied to the midbrain PAG and other regions was, in fact, demonstrated to produce intense reversible analgesia in chronic pain patients (Adams, 1976; Hosobuchi et al., 1977). Such stimulation-induced analgesia was shown to be naloxone-reversible, emphasizing the role of an opioidsensitive pain modulatory circuit. Second, an opioid-dependent descending pain inhibitory system has been demonstrated to mediate analgesia resulting from placebo. Studies have shown that the expectation of pain relief may activate pain inhibitory systems from the brain (Levine et al., 1978) providing a basis for placebo-induced analgesia. Early studies found that naloxone abolished placeboinduced attenuation of pain in subjects undergoing extraction of impacted molars (Levine et al., 1978). Studies with human volunteers showed that the expectation that an intravenous injection would be analgesic also induced a naloxone-reversible analgesia (Amanzio and Benedetti, 1999). The same pain modulatory system may also mediate analgesia linked to reward (see Fields, 2004 for review). Imaging studies in human volunteers showed that the expectation of a reward, in

the form of analgesia, activated the same brain regions that were activated by opiate administration (Amanzio and Benedetti, 1999; Petrovic et al., 2002). Clinical studies employing patients with various neurological ailments, including Parkinson’s disease and depression, provided further evidence that descending inhibitory systems may mediate placebo-induced analgesia (de la Fuente-Fernández et al., 2002). Third, stress-induced analgesia has been strongly linked to descending inhibition and also demonstrated to be naloxone-reversible. Vegetative reflexes in response to repeated noxious stimuli and to the anticipation of pain in human volunteers were enhanced by administration of naloxone, which itself produced hyperalgesia (Willer and Albe-Fessard, 1980; Willer et al., 1981). In a study performed with Vietnam veterans with PTSD, exposure to a stressor, in the form of a combat videotape, produced a naloxone-reversible decrease in response to a noxious thermal stimulus (van der Kolk et al., 1989; Pitman et al., 1990), whereas those without PTSD did not show any changes in responses. Double-blind conditioning trials provided further evidence that stress-induced analgesia was dependent upon endogenous opioid-mediated pain inhibitory systems that may contribute to the development of chronic pain (Flor et al., 2002). These clinical observations are bolstered by many animal studies employing, for example, inescapable shock, or exposure to predators and techniques to block descending pain inhibitory systems, all of which substantiate the concept that descending inhibition from the brain stem mediates stress-induced analgesia through an opioid-sensitive circuit (see Fields, 2004 for review). Finally, the robust analgesic effects of opiate agonists such as morphine are likely to depend on mechanistic synergy resulting from opioid-induced activation (through disinhibition) of descending pain inhibitory projections from the medulla and inhibition of primary afferent input. The clinical relevance of descending inhibition is exemplified by the utility and maximal efficacy of morphine in treating severe pain, in spite of its receptor characteristics that suggest that this compound is a partial agonist. Based on purely biochemical and pharmacokinetic characteristics, morphine should be much less potent and efficacious than it actually is. Multiple studies have reinforced the concept that the powerful analgesic effect of morphine is due to a synergistic interaction between its activity at the spinal cord and morphine-mediated descending pain inhibitory systems (Yeung and Rudy, 1980; Bian et al., 1999). Manipulations that abolish the descending inhibitory component substantially diminish the antinociceptive effect of systemic morphine (see Bodnar,

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pharmacological insights into descending control

2000 for review) reducing the potency of morphine by approximately 30-fold. As described above, preclinical studies have also shown that activation of descending inhibition, as would occur with morphine administration, results in the release of norepinephrine that can activate 2-adrenergic receptors. Activation of mu opioid receptors and 2-adrenergic receptors has been repeatedly demonstrated to produce strong antinociceptive synergy (Ossipov et al., 1990), presumably by inhibiting the nociceptive inputs from afferent fibers (Kawasaki et al., 2003) as well as inhibiting transmission of noxious signals postsynaptically (Stone and Wilcox, 2004). Without such synergy associated with activation of descending inhibition, much higher doses of morphine would be required for clinical pain relief and such doses would likely be associated with intolerable side effects. In this context, it is reasonable to propose that tricyclic antidepressants (TCAs), selective NE reuptake blockers and serotonin–norepinephrine (SNRI’s) reuptake blockers all exploit the role of descending inhibition in producing clinical pain relief (see Mico et al., 2006, for review). Unlike descending inhibition, clinical validation for a role of descending facilitation in modulation of pain has not yet been achieved. Evidence for the importance of descending facilitation in the modulation of pain remains indirect and is derived from preclinical studies. In early studies demonstrating facilitation of nociception Gebhart and colleagues demonstrated that varying the level of chemical or electrical stimulation applied to the RVM resulted in either facilitation or inhibition of nociceptive behavioral and electrophysiologic responses (Urban and Gebhart, 1997, 1999; Zhuo and Gebhart, 1997). These studies suggested that low levels of RVM activation resulted in pain facilitation, whereas higher levels of stimulation produced an over-riding pain inhibitory effect. Numerous studies subsequently supported the role of specific mediators of facilitation including, for example, glutamate, nitric oxide, neurotensin, cholecystokinin (CCK), substance P and BDNF, all of which are likely endogenous substrates that activate pain facilitation in the RVM (Urban and Gebhart, 1997, 1999; Zhuo and Gebhart, 1997; Ossipov and Porreca, 2006). The mechanisms by which these substances promote facilitation from cells in the RVM are likely to ultimately occur by direct or indirect activation of pain facilitation cells. The ON cells of the RVM, described above, are uniquely suited as mediators of this descending pain facilitatory system and for this reason, the identification and recognition of the characteristics of these cells, and the specific receptors through which these substances act may provide new targets for analgesic therapy.

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Pharmacological insights into descending control: well beyond opioids A significant limitation, however, is the current inability to visualize, characterize, and functionally evaluate the anatomy and physiology of pain facilitation (i.e., ON) cells in the rostral ventromedial medulla. Nevertheless, the role of these cells in mediating facilitation has been demonstrated in numerous ways. Repeated exposure of the tail or hindpaw of a rat to noxious thermal stimuli results in facilitation of withdrawal responses to subsequent noxious stimuli that correlates with an enhancement of ON-cell activity (Morgan and Fields, 1994) and these enhanced responses were abolished by application of lidocaine into the RVM. Microinjection of substances that promote nociceptive responses appear to either activate ON cells, inhibit OFF cells, or both. Neurotensin selectively activates ON-cell activity in a dose-dependent manner that correlates with enhanced nociceptive responses (Neubert et al., 2004). Local application of CCK into the RVM results in direct activation of ON cells, as well as inhibition of OFF cells resulting in both hyperalgesia and an anti-opiate effect (Heinricher and Neubert, 2004). Activation of peripheral nociceptors with capsaicin enhances ON cell activity and enhances the responses of ON cells to NMDA microinjected into the RVM (Xu et al., 2007). Similarly, application of the irritant mustard oil to a hindlimb produces thermal hyperalgesia and increases the activity of ON cells, responses that are blocked by microinjection of an NMDA antagonist within the RVM (Xu et al., 2007). Local application of an NK1 receptor agonist ([Sar9,Met(O2)11]-substance P) also enhances ON cell activity and produces hyperalgesia (Budai et al., 2007). Most recently, it was established that brainderived neurotrophic factor (BDNF) in the RVM likely promotes descending facilitation via activation of the trkB receptor and subsequent phosphorylation of the NR2A subunit of the NMDA receptor; the enhanced nociceptive responses to thermal stimuli following RVM BDNF are blocked by the NMDA antagonist AP5 (Guo et al., 2006). Collectively, these studies provide convincing evidence that activation of pain facilitation cells of the RVM mediate facilitation of nociceptive responses. Interestingly, chronic pain states may reflect an increase in net pain facilitation arising from the RVM. A considerable number of clues indicate that des­ cending facilitation may be critical in mediating chronic abnormal pain that may be associated with

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inflammation or with injury to peripheral nerves. Enhanced net facilitation from the RVM may also be important in mediating dysfunctional pain, or pain without organic origin. Such dysfunctional pain states may include patients with fibromyalgia, IBS, CRPS type-I, and perhaps even migraine and tension type headache. Behavioral signs of hyperalgesia induced by inflammation in response to peripheral injections of carrageenan or complete Freund’s adjuvant are abolished by blockade of RVM activity with lidocaine or ibotenic acid (see Porreca et al., 2002, for review). Furthermore, responses of rats to noxious colorectal distension (CRD) are exaggerated by visceral inflammation induced by zymosan, and such visceral hyperalgesia is abolished by nitric oxide synthase inhibitors or NMDA antagonists administered into the RVM (Coutinho et al., 2001). Very recent studies showed that peripheral inflammation is accompanied by timedependent upregulation of mRNA for subunits of the NMDA receptor in the RVM. Thus, Dubner and colleagues provided the important insight of a potential phenotype switch with a time-dependent alteration in the presence of ON cells and OFF cells, favoring activation of descending pain facilitatory systems at early post-injury time points when pain is maximal (Miki et al., 2002). Peripheral inflammation also results in a time-dependent upregulation of the trkB receptor in the RVM and of BDNF in PAG neurons projecting to the RVM. Finally, sequestration of RVM BDNF with antisera or knock-down of trkB in the RVM with siRNA attenuated hyperalgesia due to peripheral inflammation (Guo et al., 2006). Enhanced abnormal pain due to peripheral nerve injury is also maintained by descending facilitation from the RVM. Behavioral signs of neuropathic pain in animal models were abolished by disrupting descending facilitation from the RVM and by selective lesioning of the putative pain facilitation cells in the RVM (see Porreca et al., 2002; Heinricher et al., 2003, for reviews). Thermal hyperalgesia and tactile allodynia induced by peripheral nerve injury have been abolished by microinjection of lidocaine or CCK2 antagonists into the RVM and by physical disruption of descending tracts from this region (see Porreca et al., 2002, for review). Interestingly, disruption of descending facilitation from the RVM does not abolish behavioral signs of neuropathic pain immediately following nerve injury, but does so after 6 days, indicating that the descending pain facilitatory system is likely to maintain, but not initiate, chronic neuropathic pain conditions.

Other evidence indicates that hyperalgesic states mediated through descending pain facilitatory systems may also result in secondary changes in spinal cord function, which are likely to contribute to the maintenance of a state of central sensitization following injury. Peripheral tissue injury (e.g., inflammation, nerve injury, bone cancer) are often accompanied by increased expression of spinal dynorphin, which produces some antinociceptive activity (Xu et al., 2004) as well as prominent pronociceptive actions by promoting enhanced sensory inputs, in part, through enhancement of excitatory transmitter release. Following nerve injury, manipulations that abolish descending facilitation and enhanced pain, such as DLF lesions, also block upregulation of spinal dynorphin and the enhanced evoked release of CGRP. Recent evidence suggests that enhanced pathological levels of dynorphin may interact with spinal bradykinin receptors to promote enhanced nociceptive inputs (Lai et al., 2006). Dynorphin-mediated activation of bradykinin receptors enhances calcium currents and may promote release of transmitters from primary afferent terminals and enhance excitability of second-order dorsal horn neurons (Lai et al., 2006). It has also been shown that chronic pain states may activate a spinal/supraspinal/spinal loop that maintains an enhanced pain state. Selective destruction of projection neurons expressing the NK1 receptor abolishes behavioral, electrophysiological and biochemical parameters indicative of enhanced pain states after nerve injury or inflammation (Suzuki and Dickenson, 2005). Double-labeling studies in the NRM detected a population of serotonergic neurons responsive to noxious stimulation, and the serotonergic terminals from the serotonergic RVM neurons are juxtaposed with cell bodies in the intermediate laminae of the dorsal horn, some of which also express the NK1 receptor, which is targeted by the neuropeptide, substance P (Suzuki et al., 2004). Depletion of serotonin or administration of the 5-HT3 antagonist, ondansetron, abolished behavioral and electrophysiological parameters of enhanced pain (Suzuki et al., 2004). Moreover, the effects of ondansetron were blocked by disrupting enhanced RVM activity through the ablation of NK1-expressing dorsal horn neurons with substance P-saporin conjugate, indicating that the 5HT3 receptors were activated by serotonin resulting directly or indirectly from descending pain facilitation in the RVM (Suzuki et al., 2004). These studies indicate that persistent noxious inputs activate ascending nociceptive pathways that elicit neuroplastic changes in the RVM, resulting in an enhancement of a descending

IV.  NEUROMODULATION FOR chronic PAIN

pharmacological insights into descending control

309

Anterior cin cort gu ex

e lat

Som at co os r

y sor en x e t

Thalamus

Figure 22.1  Schematic representation of ascending sensory infor-

PAG

PB

Medial lemniscus RVM nG

Dorsal column Peripheral afferent fiber (mechanosensory)

Spinothalamic tract (STT)

DRG

DRG PSDCSTT

Peripheral afferent fiber (nociceptor)

pain facilitatory system that maintains an enhanced pain state. As noted above, net descending facilitation, which may occur either as a consequence of injury or perhaps in the absence of injury, as mimicked by medication-induced adaptations, may be important in multiple chronic pain conditions including dysfunctional pain. It should be noted that pregabalin, which is clinically effective against neuropathic pain, is also effective in fibromyalgia pain (Owen, 2007). Similarly, norepinephrine and serotonin reuptake inhibitors have also been demonstrated to be effective against both neuropathic pain and in fibromyalgia (Arnold, 2007; Rooks, 2007). Reuptake inhibitors could enhance descending inhibition by increasing the amount of released norepinephrine and/or serotonin in the spinal cord, as described above. Moreover inhibition of afferent inputs by essentially quieting peripheral nerve activity may result in disrupting the ascending link in the spinal/supraspinal pain facilitatory loop described above.

mation. Ascending pathways that transmit noxious (red) and innocuous (blue) information. Noxious stimuli activate the free nerve endings (nociceptors) of peripheral afferent fibers, which relay this information to the dorsal horn of the spinal cord, where the primary afferent terminals synapse on second-order neurons. Central to this circuit are the projection neurons of the spinothalamic tract (STT), which transmit sensory inputs to the thalamus. Collateral projections from the STT target the parabrachial region (PB) and the mesencephalic reticular formation, as well as the periaqueductal gray (PAG). Innocuous sensory information, such as light touch and vibration, are transmitted via large diameter myelinated primary afferent fibers that project directly to the dorsal column nuclei (n. gracilis and n. cuneatus). These primary afferent fibers project to the dorsal horn, where they synapse on postsynaptic dorsal column (PSDC) neurons, which also target the dorsal column nuclei. Although not shown on this schema, some PSDC neurons also receive noxious inputs from visceral nociceptors. The dorsal column nuclei communicate with the thalamus via the medial lemniscus. Sensory inputs that reach the thalamus are relayed to the somatosensory cortex and to limbic structures, including the amygdala and anterior cingulate cortex, where the pain experience is interpreted in the context of environmental, emotional, and other cues

Conclusion Recent years have seen tremendous progress in our understanding of the mechanisms by which injury messages are processed and transmitted from the periphery to the brain and most importantly have established circuits through which these inputs engage both pain control and pain facilitatory circuits (Figure 22.1). The fact that descending modulatory circuits participate in both the expression and the relief of pain, underscores what is a dramatic change from the earlier view of a unidirectional pain inhibitory system. As the anatomical, physiological, and pathophysiological features of these powerful facilitatory as well as inhibitory descending pain modulatory systems are unraveled (Figure 22.2), the hope is that this will spur the development of new strategies that can be implemented to provide improved therapies for the treatment of presently intractable and persistent pain.

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Anterior c cort ing ex

Som at co os r

ate ul

y so r en x te

Amygdala limbic

Thalamus Hypothalamus

PAG

Figure 22.2  Schematic representation of descending controls that influence the

LC/ A5

PB

ON

OFF

RVM DRG

Peripheral afferent fiber

STT

processing of sensory information. Ascending sensory inputs from the periphery to the brain result in the activation of descending pain modulatory systems. The relative activation of inhibitory (blue) and facilitatory (red) controls determines whether there is a net antinociceptive or pronociceptive effect. In the model illustrated in this figure, the somatosensory cortex, limbic regions, thalamus, and hypothalamus communicate with one another and with the PAG. Critically, the PAG is a predominant pain-inhibitory locus with reciprocal communications with the rostroventromedial medulla (RVM). The RVM receives pain facilitatory signals from the anterior cingulate cortex (ACC), which also communicates with limbic structures. Because the RVM receives inhibitory and facilitatory signals from rostral structures and is at the origin of both facilitatory and inhibitory projections to the spinal dorsal horn, the RVM acts as a final relay for the integration of descending pronociceptive or antinociceptive pain modulatory systems. In addition to the RVM-derived pain regulatory system, inhibitory signals also may be evoked from noradrenergic nuclei, including the A7, A5 cell groups and the locus coeruleus (LC), the axons of which project directly or via the RVM, to the spinal cord. Finally, the parabrachial region (PB) and the dorsal reticular nucleus (DRT) also enhance pain transmission, either via direct projections to the spinal cord or indirectly via circuits in the RVM

Acknowledgment This work was supported by NIH grants: NS14627 and 48499 (AIB) and DA11823, DA12656 (FP).

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Management Strategies for Chronic Pain Rollin M. Gallagher

o u tli n e Introduction

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Management of Acute Pain in the Context  of Chronic Pain

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The Evaluation, Treatment Planning, and  Treatment of Chronic Pain Pain and Emotions Clinical Evaluation and Treatment Planning   in Pain Management The Biopsychosocial Model Pain Assessment Formulating an Integrated   Treatment Plan

Goal-Directed Management Planning Integrated Treatment in Pain Management Pharmacotherapy The Pain Diary for Evaluation and   Management of Pain Physical Therapy and Occupational Therapy Interventional Pain Medicine Psychotherapies and Behavioral Therapies Record Keeping

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Conclusion and Looking to the Future

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References

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experience, such as the ability to: (1) identify the pain generators that activate or perpetuate pain; (2) differentiate types of pain associated with pain generators (e.g., inflammatory/nociceptive, neuropathic, visceral, myofascial, central) and their pathophysiologic mechanisms; (3) identify salient biopsychosocial factors contributing to the activation and perpetuation of pain; (4) create a working alliance with the patient to foster effective decision-making, goal-oriented management planning, and participation in and adherence to treatment plans; (5) create interdisciplinary collaborations that support and enable implementation of selective, integrated, biopsychosocial, goal-oriented treatment; and (6) develop psychomotor skills in pain procedures. Factors perpetuating chronic pain may themselves

Introduction The prior two chapters have outlined in detail the pathophysiologies of chronic pain conditions and diseases that become targets for neuromodulation. Effective pain management requires building on this conceptual foundation to acquire knowledge in several domains: (1) the phenomenology of each chronically painful condition and pain disease; (2) the mechanisms of action of each treatment; (3) the evidence basis for the effectiveness of each treatment for each clinical condition. Effective pain management also requires the application of clinical skills in the clinical encounter, acquired through training and

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become clinical co-morbidities (e.g., depression, addiction, GI bleed) that contribute to impairment and mediate treatment response. The clinical system that can identify and remediate the pathologies generating pain and mitigate the negative effects of co-morbidities and other contributing factors most completely will obtain the best treatment results. These “best outcomes” result from a supple, individualized, goaloriented treatment planning that often integrates several therapies under the domain of pain medicine but may also require the special knowledge and skills of other disciplines or medical subspecialists. When such multidisciplinary treatment is either not available or not affordable, as is the case in most societies, the individual physician is challenged to develop functional collaborative care partnerships with other providers to meet the needs of their patients. This chapter briefly reviews the treatment continuum for managing chronic pain as a chronic disease, what we will define here as maldynia (as opposed to normal pain or eudynia), and where neuromodulation fits into that continuum. Effective pain management begins with understanding chronic pain pathophysiology, which is covered more completely in earlier chapters, and for purposes of this chapter constitute three categories. The first pathophysiologic category, chronic nociceptive pain, is caused by remnants of tissue damage or a disease process, often auto-immune, that periodically or persistently activate tissue nociceptors through an inflammatory process or trauma, leading to peripheral sensitization. Familiar and common examples include arthritis, caused by disease (rheumatoid arthritis or osteoarthritis) or persistent or recurrent trauma (gait changes from a knee injury or arthritis, regular occupational heavy lifting and twisting) causing stress on facet joints and discs in the lumbar spine, or years of long-distance running causing breakdown of cartilage in the hip or knee. The second pathophysiologic category, chronic neuropathic pain, involves damage to the peripheral pain sensory system by disease, such as diabetic neuropathy, or by trauma, such as crush injury or amputation. Such injury may lead to atrophy of sensory neurons that modulate pain sensation or to a persistent firing of damaged pain sensory fibres activating ascending pathways in the CNS, thereby transmitting the signal of the sensation of pain to the rostral neural networks governing the experience of pain perception. Persistence of this peripheral signal can also cause changes in the CNS at both the molecular and structural level, altering the actual neuronal-glial networks of the CNS through a process broadly termed neuroplasticity. These processes of central sensitization may result in a state whereby pain can be activated or worsened by normally non-painful stimuli including emotional arousal (e.g., anger, anxiety), movement,

loud noise, bright lights, cold temperature or light touch, such as in allodynia. Consider the patient with migraine who cannot tolerate noise, bright light or touch to the face, or the patient with complex regional pain syndrome (CRPS) of the limb who cannot tolerate clothing on skin or movement of an extremity and develops kinesophobia (fear of movement). Consider the patient with neuropathic pain who avoids interpersonal stress because it worsens their pain. Vulnerability to neuronal hyperexcitability – nociception to peripheral sensitization to central sensitization – may be, in part, genetically determined. Migraine, which involves peripheral and central sensitization of the trigeminovascular system and the trigeminal nucleus caudalis, runs in families, and is the most common of the painful syndromes that involve this process of sensitization. The pathophysiology of these systems extends rostrally to the brain, where centers involved in the perception of pain undergo neuroplastic changes such as the enlargement of receptive fields, and sensitized neural networks augment pain perception. The third pathophysiologic category, central pain, is defined by anatomic damage to parts of the central nervous system (CNS) governing pain signal transmission, perception or modulation caused by diseases such as multiple sclerosis, thalamic stroke, tumor, and Parkinson’s disease or by injury such as spinal cord injury or compression, brain tumor or brain surgery. Certain diseases or injuries may have mixed pathologies. Complex regional pain syndrome (CRPS 1 [RSD] or CRPS 2 [causalgia]) may involve pathophysiology in nociceptors, the peripheral nervous system (PNS) and the CNS. Traumatic brain injury may damage several sites in the cranium and cervical spine that may trigger episodes of severe migraine-type headaches. Degenerative disc disease of the lumbar spine may be associated with all three categories as well: strain on facet joints activating nociceptors and muscle spasm causing chronic pain of the first category; leaking intervertebral disc material or herniated disc irritating or compressing nerve roots, activating chronic pain of the second category (radiculopathy); and chronic activation of the perceptual system in the spinal cord and brain leading to secondary changes in brain processing centers that govern the emotional aspects of pain, such as the cingulate gyrus, and in cognitive centers affecting executive functioning and coping skills (Rainville et al., 1997; Rome and Rome, 2000). These changes may contribute to risk for adverse outcomes such as accidents, depression, disability, and suicide. Figure 23.1 outlines the cycle of events leading to and perpetuating chronic pain as a self-perpetuating disease. Importantly, the physician treating pain must understand that the severity of pain and its functional

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Introduction

Pathophysiology of maintenance -

5

8

Radiculopathy Neuroma traction Myofascial sensitization Brain pathology (loss, reorganization)

Secondary pathology - Muscle atrophy, weakness - Bone loss - Depression - Cortical loss - Immunocompromise

4 Psychopathology of maintenance - Encoded anxiety dysregulation - PTSD - Emotional “allodynia” - Mood disorder

Acute injury 1

Disability 3

Neurogenic inflammation 6

7

Central sensitization - NMDA receptors - Gene expression

2

- Glial activation - Pro-inflammatory cytokines - Blood–nerve barrier dysruption

- Less active, kinesophobia - Decreased motivation - Increased isolation - Role loss

4

Peripheral sensitization - Na� channels - Lower threshold 6

Figure 23.1  The chronic pain cycle

outcome is dependent on more than just the pathophysiology of maldynia, but as suggested above, also is dependent on the many other biopsychosocial factors and CNS processes that influence the activity of these systems. In brief, pain is highly conditionable so that the environmental context of the pain experience impacts suffering. Every new episode or change in pain intensity, character or localization activates cognitive processes and emotions that are influenced by current context and meaning which is conditioned by past pain experience. These processes involve interacting neural networks, subserved by a myriad of chemical messengers that communicate amongst sensory systems, including the pain perception and modulating system and various cognitive-emotional processing and behavioral systems. For example, the acute pelvic pain associated with the tissue damage and nerve injury of a normal delivery in childbirth in a stable and hopeful family environment usually is forgotten. The acute pelvic pain associated with the tissue damage and nerve injury of the forced sexual trauma of rape or repeated sexual abuse is never forgotten – encoded in neural networks with long-lasting effects on chronic pain, psychiatric disorder and selfconcept. Past pain experience informs the immediate contextual meaning of an episode of pain: Consider the football (American) player who goes down on the field with a knee injury – in most cases, the implications for his livelihood, the threatened loss of a career, are far greater than if he had sprained or broken an arm or elbow.

Consider the middle-aged construction worker, with little education or occupational mobility, who, 3 years following a microdiscectomy for herniated disc, feels a twinge of low back pain while working. This progresses to daily pain towards the end of each working day, particularly during overtime – he is saving for a vacation home in the mountains. Does it mean his back is going bad on him, threatening his livelihood? Let’s raise the stakes – will he be able to continue working overtime to pay for his son’s cancer treatment? In the first circumstance, he will likely cut back his work time and his pain may subside. In the latter instance, he feels he has no choice but to continue working overtime, his pain escalates, he requires higher doses of medication to stay at work, and eventually he cannot go to work at all …

An environmental challenge at a critical time may shut down pain: A fireman continues rescuing victims from a conflagration, despite severe injuries including burns, but collapses in agony after additional help arrives.

Chronic pain encoded in the CNS, such as in causalgia or phantom pain, particularly when linked to emotional trauma, may perpetuate pain for a lifetime: A 20-year-old soldier hit by shrapnel in the thigh causing extensive tissue damage (which later surgery reveals as a non-displaced fractured femur, extensive destruction of muscle tissue, and EMGconfirmed injuries to the sciatic and lateral femoral cutaneous nerves) somehow drags his buddy, who suffered a severe chest wound from the same mortar shell, to a staging area where they are rescued by helicopter. The soldier feels little pain during this ordeal; but after his helicopter safely lands on a hospital ship, he watches his buddy’s helicopter fall into the sea with a loss of all hands on-board. For years thereafter, memories of the firefight and terror of battle, encoded in post-traumatic stress disorder

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(PTSD), are activated by various environmental stimuli, including pain, sudden loud noises, or anger, which in turn activate and worsen the pain from causalgia related to his leg wounds and nerve damage years earlier. Treatment, which enables him to stay at work, involves group psychotherapy, cognitive-behavioral therapy, and pharmacologic management with venlafaxine, lidocaine patches, low dose quetiapine, pregabalin, methadone, and transmucosal fentanyl for breakthrough pain. A peripheral neurostimulator trial is contemplated.

Less dramatic instances of the effects of cognition, attention, and emotions on pain occur commonly in our everyday lives, such as when low back pain is minimized during an engrossing work activity towards a deadline. This chapter emphasizes that neurological activity induced by noxious stimuli or by damage to the neurological pathways is not pain, but a stimulus that initiates or perpetuates pain. Instead pain is considered a conscious, psychological, perceptual state that is always subjective, its intensity and interpretation always affected, more or less, by the psychological processing and interpretation of environmental context (Merskey and Bogduk, 1994). In other words, pain is always in the brain.

Management of acute pain in the context of chronic pain MacIntyre and colleagues, in the Faculty of Pain Medicine of the Australia New Zealand College of Anesthetists (2005), recently completed an evidencebased treatise on acute pain management that belongs on every hospital physician’s bookshelf. The management of acute pain involves one or more of the following activities. Preventing transduction by immobilizing injured tissue (e.g., splints, casts, etc.), by reducing tissue damage (e.g., using an arthroscope rather than an open incision for knee surgery), and by minimizing activation of nociceptors (e.g., using steroids and NSAIDs). l Reducing transmission with a sodium-channel blocker, such as a lidocaine patch, tricyclic cream or nerve block at the site of the injury, and reducing transmission at the spinal level with blocks and/or counter-stimulation techniques such as icing, acupuncture, transcutaneous electric nerve stimulator (TENS), and spinal cord stimulators. l Reducing perception with opioid analgesics and sedation. l Enhancing modulation with distraction, relaxation techniques, hypnosis. l Reducing anxiety-induced augmentation of pain with education, reassurance, relaxation, and anxiolytics. l

Physicians must know how to treat acute pain in the context of managing chronic pain. Since chronic pain affects up to 25% of our adult population and since 100% of these individuals will suffer either a worsening of their condition or new conditions causing pain (e.g., surgeries or new injuries or diseases), acute pain management is inevitable. A particular problem occurs when patients already taking opioid analgesics, whether for chronic pain or because of addiction, present in the hospital for surgery or a painful injury. These patients require much higher doses of opioid analgesics for pain control than opioid-naïve patients (Rapp et al., 1995; Doverty et al., 2001; MacIntyre et al., 2005). Unfortunately, these patients are often the victims of poor care related to provider-bias, a combination of their clinicians’ ignorance about the need for higher doses of opioids, misconceptions about the nature of chronic pain (e.g., chronic pain is psychogenic), and stigma, particularly in patients with addiction disorder, or ethnic and racial identity (Green et al., 2003; Meghani and Gallagher, 2008). In the absence of adequate training, even when a noci­ceptive signal is clearly intense (e.g., after major surgery or injury), the patient’s behavior in response to the pain (e.g., stoic, dependent, pleading, anxious, angry) may trigger emotions in the provider that determine his or her behavior, rather than a rational consideration of the patient’s needs. Pre-emptive analgesia with Cox-II inhibitors, which do not inhibit platelet aggregation, intraoperative epidural or nerve blocks, and infusion of analgesics (e.g., morphine) in perioperative tissue or spreading of capsaicin may reduce pain postoperatively (MacIntyre et al., 2005).

The evaluation, treatment planning, and treatment of chronic pain In contrast to our presently well-established ability to prevent, minimize, and manage acute pain, for several reasons the management of chronic pain often presents a daunting challenge in clinical practice. As described earlier in this chapter, the pathophysiology of pain after initial onset becomes much more complex almost immediately – the longer the pain, the more complex the process. The challenge for clinicians treating chronic pain is to formulate, for each patient, to the degree feasible in a particular clinical setting, the interaction of biopsychosocial factors and neural processes that activate and perpetuate pain, and to devise a treatment program that has the best chance of remediating the most salient factors (Gallagher, 1999, 2005).

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the evaluation, treatment planning, and treatment of chronic pain

Pain and Emotions Emotional states that activate sympathetic arousal, such as anxiety or anger, can increase any episode of acute pain and re-activate or worsen any chronic pain condition. Depressive disorders and anxiety disorders are common co-morbidities in chronic pain, aggravate chronic pain, and adversely affect function and treatment outcome (Mossey and Gallagher, 2004; Gallagher and Verma, 2004; Miller et al., 2005). The reverse holds as well – without good pain treatment, treatment of co-morbid psychiatric conditions is less successful (Ohayon and Schatzberg, 2003). Moreover, certain personal traits, such as external locus of control (Gallagher et al., 1989) and a tendency to catast­ rophize (Turner et al., 2000) also predict poorer outcomes. Finally co-morbid substance abuse reduces the effectiveness of all modalities of treatment. Thus identifying and treating these co-morbidities is critical to effectively treating pain. The causal direction of the relationships amongst chronic pain disorders and psychiatric co-morbidities and the relative influence of environmental factors and genetic/familial factors, “nature vs. nurture,” are also being studied at a level of examination and analysis that is beyond the scope of this chapter. We know that chronic pain and its stress cause depression in those not vulnerable by family or personal history (Dohrenwend et al., 1999), that pain and mood co-vary seasonally (Gallagher et al., 1995b) and that states of central pain processing dysfunction, states such as fibromyalgia, share genetic vulnerabilities with major depressive disorder (MDD) (Raphael et al., 2004a; Arnold et al., 2006). These studies suggest a shared pathogenesis, such as dysfunction of serotonin and norepinephrine systems in fibromyalgia (Russell et al., 1992a, 1992b; Schwarz et al., 1999) and in depression (Charney, 1998; Hirschfeld, 2000) and that a functional polymorphism in the promoter region of the serotonin transporter gene affects the influence of stressful life events on depression (Caspi et al., 2003) and fibromyalgia (Bondy et al., 1999; Offenbaecher et al., 1999; Ebstein et al., 2001; Gursoy, 2002). Thus, fibromyalgia and MDD appear to share a genetic and/or biologically mediated vulnerability to respond to stressful or traumatic events with psychological and pain-related symptoms (Raphael et al., 2004b). The strong experimental association between anxiety and pain and epidemiological association between anxiety disorders and pain conditions (McWilliams et al., 2003) is mediated in part by the amygdala’s role in the up- or downregulation of the emotional response to pain, which through the integrating function of the hippocampus can affect the development of

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“pain memory” after central sensitization (Abraham and Robins, 2005). Thus events associated with high emotional content paired with painful injury, such as a car accident, being wounded in battle, and sexual and physical abuse tend to be remembered in greater detail, as in PTSD, than those with little emotional significance (back pain on your drive to work every morning or working in the garden on the weekend). Animal research demonstrating that exposure to novel, “interesting” environments can reverse hippocampal sensitization in pain experiments (Abraham and Robins, 2005) provides the neural mechanism underlying our clinical studies and experience suggesting that involvement in motivating, engrossing activities during rehabilitation improves outcome in chronic pain (Gallagher, 2006). Centers in the neural circuits for complex emotional experience within the limbic system associated with fear, such as the fusiform gyrus, prefrontal gyrus, and anterior cingulate gyrus, suggest that the cortex plays an essential role in the categorization, appraisal, and attenuation of our reactions to fearful stimuli such as pain and a biological basis for the effects of behavioral treatments used widely in chronic pain, such as relaxation and cognitive behavioral therapy with progressive functional training. They also suggest specific sequential targets for neuromodulation therapies.

Clinical Evaluation and Treatment Planning in Pain Management Chronic pain’s high prevalence and costs would seem to dictate a societal and medical imperative for its effective treatment. However, clinicians who treat pain and patients in pain face many barriers to effective pain management, including: inadequate knowledge of physicians (Salgo, 2003); fragmented medical care due to pain being treated solely as symptom of a traditional specialty’s condition of interest or as inevitable in aging rather than a neuropathological disease (Gallagher, 1999; Fishman et al., 2004); l health policy and patient-related barriers to effective pain management (Ruiz Moral et al., 1997; Stieg et al., 1999; Fishman et al., 2004); l inadequate education of providers (Gallagher, 2002; Turner and Weiner, 2002; Fishman et al., 2004) and disparities in treatment (Green et al., 2003). l l

Third-party medical examiners who evaluate disability or workman’s compensation claims usually lack training in pain medicine and may not be retained by employers or insurers if their decisions are not

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economically favorable. Systematic bias against psychiatric co-morbidity (Gallagher et al., 1995b) and race (Chibnall and Tait, 2005) has been demonstrated to influence workers’ compensation decisions.

The Biopsychosocial Model

exhibit signs and symptoms indicating specific neuronal pathology and muscle trigger points and spasm often generate considerable pain. Tables 23.1, 23.2, and 23.3 list some of the assessment functions available to the provider caring for a patient with chronic pain. Formulating an Integrated Treatment Plan

The biopsychosocial model of chronic pain, now irrefutably documented by epidemiologic studies and its mechanisms revealed through the lens of neuroscience (Dubner and Ren, 1999), is today considered the most appropriate conceptual framework for understanding the clinical course of persistent pain and for organizing treatment (Gallagher et al., 1990; Gallagher and Verma, 2004). Thus, training should focus on developing a conceptual fluidity that incorporates an understanding of how physical, psychological, and social factors affect the neurophysiology of nociception, pain perception, pain modulation, suffering, and pain behavior (Haddox, 1996). Factors including a patient’s attitudes, beliefs, expectations, mood, compensation case status and social support system can all affect a patient’s report of pain, response to treatment, and disability level (Gallagher et al., 1995a; Turk, 2003, 2004; Martelli et al., 2004). The strong evidence for the positive effects of behavioral treatments for chronic pain (NIH Technology Panel, 1996), particularly relevant when combined with other treatments found in multidisciplinary pain centers, highlights the importance of integrated treatment, which is more effective than conventional strictly biomedical treatment (Mayer et al., 1987; Cutler et al., 1994; Turk, 1996; Fishbain et al., 1997; Guzman et al., 2001, 2002). Pain Assessment The history and physical examination reveal considerable information about the initiating and perpetuating causes of chronic pain. Pain history should include: a detailed history of initiating injury; the pain pattern, such as factors that precipitate, ameliorate, and maintain pain; l specific information about prior treatment and responses to treatment, particularly knowing details of clinical trials to assess their adequacy. l l

From the history, diagnostic hypotheses are generated, and further confirmed or suggested by a focused and selective physical examination, which can be diagnostically quite specific (Gallagher and Verma, 1999). Neuropathic pain diseases and disorders may

The busy clinician practicing within the biopsychosocial model faces the problem of efficiency. How does one develop a systematic, reliable, yet practical, approach to formulating rationally the interaction of biopsychosocial factors along the causal pathway to chronicity, including a prioritized problem list and goal-oriented management plan (Gallagher, 1999, 2005; Gallagher and Verma, 2004)? In daily practice, however, the organization of large amounts of complex clinical information relating to biopsychosocial factors contributing to chronic pain remains a challenge. A tool has been developed that organizes clinical information to facilitate the clinician’s conceptualization of the complex interaction of physical, psychological, and social factors over the course of an illness, categorized along the biopsychosocial axis and the temporal axis. This is the Biopsychosocial Diagnostic Net (Gallagher 1999, 2005). Figure 23.2 illustrates a diagnostic net developed to categorize salient factors in a patient with low back pain, as in Case No. 1. Case No. 1 A 60-year-old woman is referred to the pain clinic by her niece, a doctor, for severe low back and knee pain. She is disabled from her job as a director of international sales for a corporation, her role as grandmother, and her athletic and traveling hobbies. Her referring orthopedist says she has osteoarthritis of her joints and spinal stenosis. Six years ago she successfully underwent total hip replacement. She was able to continue her active lifestyle by taking high daily doses of nonsteroidal anti-inflammatory drugs (NSAIDs). These drugs suppressed pain, and although she kept functioning, pain gradually caused her to develop gait disturbance, altering the mechanics of her spine. On a trip with friends to Asia, she perforated a silent duodenal ulcer, nearly bleeding to death. She must stop NSAIDs – the back pain worsens despite injections, so she is unable to work, pursue hobbies, or play with her grandchildren. She is demoralized by her loss of role in her career and family, and slips into depression.

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Table 23.1  Simple bedside sensory examination findings and their meaning Type of allodynia or hyperalgesia

Typical patient complaints

Assessment

Likely mechanism

Mechanical static

Cannot bear weight of clothing against skin, wear shoes or carry items

Light manual pressure on skin

Peripheral sensitization (sunburn)

Mechanical dynamic

Brushing of shirt against skin or covers over feet are painful. Avoids being touched

Stroke skin with very soft brush or cotton

Central sensitization/C-fiber input C-fiber loss (CRPS 1 or 2)

Thermal warm

Pain worsens in sun, cannot cover feet at night

Touch skin with objects at 40 °C; pain relieved by contact with cold

Peripheral sensitization (sunburn)

Thermal cold

Using metal knife/fork is painful; pain is increased in cold room or near freezers in market

Touch skin with objects at 20 °C

Central sensitization Central inhibition (CRPS 1 or 2)

Mechanical pinprick

Walking barefoot on beach feels like walking on broken glass

Manual pinprick of skin with pin; von Frey filament

Central sensitization A-fiber input

Thermal cold

Ophthalmic PHN: cannot tolerate below-freezing temperatures

Touch skin with coolants (acetone)

Not known

Thermal heat

Handling hot plates is intolerable

Touch skin with hot object

Peripheral sensitization

A: Mechanical allodynia

B: Thermal allodynia

C: Hyperalgesia

Source: Adapted with permission from Jensen and Baron (2003). Copyright (2003) Elsevier

Table 23.2  Assessment tools commonly utilized for the evaluation of chronic pain Assessment tool

Comment

Physical examination

Finds areas of tenderness, motion-related pain, and resistance-related pain and identifies specific mechanisms in neuropathic pain (see Table 23.1) and muscle pain

Pain diary Brief Pain Inventory (Daut et al., 1983)

Provides detailed information about pain pattern in response to daily activities, stress, and various treatments as well as effects of pain on mood and activities

Numerical rating scales, including 0–10 (11-point) pain intensity scale (Farrar et al., 2001)

Validated to measure changes in pain, sleep, and mood in the longitudinal course of chronic pain

Topical Assessment of Pain (TOPS) (Rogers et al., 2000; Mossey et al., 2005)

Pain-specific outcomes questionnaire adapted from the SF-36

Plain films (X-ray)

Low specificity and predictive value for spine pain Low sensitivity to soft tissue pathology

Computed tomogram (CT scan) with myelography

Demonstrates over 90% of herniated disks, but can have false-positives (McCall and Wiesel, 2003)

Magnetic resonance imaging (MRI)

Excellent soft tissue images, including spinal disks and nerves, of all areas of body. Must correlate with history and physical findings to establish clinical relevance (many false-positives for clinical significance) (Jensen et al., 1994)

Thermography

Can be used for confirmation of autonomic dysfunction in conditions such as CRPS

Electromyography (EMG) and nerve conduction studies including quantitative sensory testing (QST)

Objectively assess severity, location, and extent of nerve and muscular lesions. EMGs produce false negatives for small pain fibre disease, which are identified by QST

Laboratory tests

Useful for screening for infection, auto-immune disease, endocrinopathy, tumor, or other systemic diseases causing or contributing to pain

Source: Adapted from Bloodworth et al. (2001) by permission of WB Saunders/Elsevier

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Table 23.3  Appropriate and inappropriate uses of psychological and psychiatric assessment Appropriate uses

Inappropriate uses

 To determine specific psychological and behavioral contributions to a patient’s pain and concomitant behaviors, disability, and suffering

l

 To identify specific psychiatric co-morbidities leading to pharmacologic and non-pharmacologic treatment recommendations

l

l

l

 To establish prioritized, goal-oriented plans to address identified problems

 To determine if pain is organic (physical) or functional (psychogenic)  To justify withholding of pain treatment, such as in cases of co-morbid psychiatric disorder or addiction disorder (psychogenic)

l

 To provide essential information on particular aspects of a patient’s psychosocial background and current situation that may be affecting the pain problem and will affect treatment outcome

l

  To detect malingerers   To justify transferring more difficult patients to another service

l l

Source: Adapted with permission from Grabois (2005). Lippincott, Williams & Wilkins; www.lww.com

Temporal dimension

Predisposing factors

Precipitating factors

Pattern of response

Perpetuating factors

Osteoarthritis knees/spine; spinal stenosis; high NSAID use

Frequent twisting/lifting; gait change causing back muscle strain and stress on facets; surgery

Back/leg pain; stress response– pain causing sympathetic arousal; GI bleed

Foraminal encroachment; muscle spasm, imbalance; deconditioned

Psychological/ behavioral

Adaptive coping style with denial of illness and pain; NSAID reliance

Hurried behavior at work

Fear of job loss; anxiety; increase in NSAID use; posture/gait “grocery cart sign”

Untreated depression; prolonged driving and traveling

Increased workload

Social/ cultural

Family support/ MD reluctance to control pain and inability to confront patient’s lifestyle

Difficulty working; unable to play

Joblessness; delay in referral to pain specialty treatment

Biological

Figure 23.2  Organizing the plethora of biopsychosocial factors that determine outcome in a patient with chronic low back pain (Case No. 1) (After Gallagher, 1999. Copyright (1999) Elsevier)

The diagnostic net helps the clinician categorize the multiple biopsychosocial factors in an individual patient with chronic pain, to formulate the interaction of these factors, and to derive a prioritized problem list. The next step is to respond to the problem list by developing a goal-directed, comprehensive treatment plan designed to improve both pain control and functional outcome. Goal-Directed Management Planning The list of goals and corresponding plans for Case No. 1 are outlined in Table 23.4. Note they are prioritized as immediate (must manage how to halt disease process or function and/or psychosocial deterioration),

pivotal (the actual diagnostic entities causing pain), and background (the problems that contribute to perpetuating pain).

Integrated Treatment in Pain Management Pharmacotherapy Pharmacotherapy has a central role in integrated treatment planning for chronic pain. Analgesic medications act both peripherally and centrally by a variety of mechanisms to modulate nociception, pain perception, and, ultimately, pain behavior (Costigan and Woolf, 2000; Woolf, 2004). Medications are provided

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Table 23.4  Prioritized problem list and goal oriented management plan: osteoarthritis, spinal stenosis in 60-year-old executive/grandmother Goal statement

Plan

Pain from osteoarthritic knees and spine

Obtain pain control

Opioid titration (LA oxycodone and percocet for BtP), lidocaine 5% patches

Radicular pain from spinal stenosis

Obtain pain control

Nerve root block trials: gabapentin 2400 mg nortriptyline 10–20 mg

Threatened job loss

Obtain medical leave to buy time for functional capacity evaluation and pain control

Crisis counseling for medical leave and to retain benefits

Spinal stenosis and myofascial pain

Improve posture and recondition spine muscles

Physical rehabilitation program Trigger point therapy tizanedine 4 mg

Osteoarthritis with gait disturbance, myofascial pain, deconditioning

Reduce weight, retrain gait, recondition muscles Rofecoxib Rehabilitation program including trigger point therapy

Depression with neurovegetative impairments

Achieve remission of symptoms and impairments

Pain control Sertraline 100 mg

Adjustment to functional and social losses

Facilitate job change and “readiness for change”

Establish functional capacity for occupational change Focal psychotherapy

Loss of family role

Restore meaningful role in family

Family therapy for acceptance of disease, treatment plan (e.g., opioids) and role change

Immediate problems

Pivotal problems

Background problems

through several routes: oral, topical patches and gels, intramuscular and intrafascial, intravenous, transdermal, subcutaneous, transmucosal (nasal, buccal, rectal), epidural, and intrathecal. Nonsteroidal anti-inflammatory drugs (NSAIDs) act primarily in the periphery to reduce noci­ ception through the inhibition of prostaglandin. Anticonvulsants, usually acting on sodium and/or calcium channels, and tricyclic antidepressants, acting on sodium channels, stabilize neuronal membranes to reduce ectopic nerve impulse generation and neuropathic pain. Topical lidocaine patches also act on sodium channels to inhibit pain transmission in both peripheral and central sensitization. Serotonin-nor­ epinephrine reuptake inhibitors (SNRIs), as well as the tricyclic antidepressants (TCAs), are effective in neuropathic pain, purportedly by inhibiting reuptake of norepinephrine and serotonin, thereby enhancing descending pain modulating systems. TCAs in gel form have been shown to be effective topically, presumably by sodium channel activity. Opioids, which can be provided in local, oral, rectal, transmucosal, intramuscular, intravenous, and intrathecal forms, act on opioid receptors distributed widely in the peripheral tissues and the CNS. Topical opioids can be applied directly on wounds to effect.

Adequate analgesia by itself, when effective, can modify maladaptive emotional and behavioral responses. Some analgesic drugs powerfully influence emotions and behavior. Opioids, besides having strong analgesic effects, calm agitated patients. Antidepressants such as the tricyclics, selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine re-uptake inhibitors (SNRIs) (e.g., duloxetine and venlafaxine) effectively treat depression or anxiety and may modify maladaptive emotional and behavioral responses to pain. For example, by alleviating secondary depression or anxiety, antidepressants may improve patients’ ability to comply with pain management instructions and regimens for exercise, pacing, relaxation, and medication intake. These improvements also may enable patients to cope more effectively with the negative consequences of pain such as job stress or loss, relationship stress, and workers compensation stress. When designing a treatment plan, the physician should consider not only how the intervention will affect the pathophysiologic processes causing chronic pain (Figure 23.1) but also each intervention’s potential for adverse effects and drug interactions. For example, physi­ cal therapy may aggravate nerve injury and/or muscle damage. Interventional procedures are associated with medication complications and high cost, and steroids

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Table 23.5  Principles for prescribing medication in patients for chronic pain Principle

Examples

(1) Prioritize safety in nonmalignant chronic pain

Older patients are at greater risks for falls if given tricyclic antidepressants or anticonvulsants. Low dose opioids may be safer. Patients with COPD are at greater risk for clinically significant respiratory depression when titrating opioids when combined with benzodiazepines. Patients with substance abuse histories are more likely to develop aberrant behaviors and relapse to active addiction if exposed to opioid analgesics

(2) Prioritize effectiveness in terminally ill patients with pain

Titrating opioid analgesia to sedation may be the only way to assure the relief of suffering in a dying cancer patient

(3) Consider potential interactions with existing medical conditions and other medications

Gabapentin titration must be slow and at lower doses in patients with renal disease. Methadone must be titrated cautiously in patients taking antidepresssants and anticonvulsants for depression, pain or seizures because of individual differences in their effects on the CYP450 isoenzymes in the liver

(4) Selectively choose drugs for pain disorders and comorbid psychiatric disorder

Consider efficacy for individual pain diseases – for example, tricyclics, which have proven efficacy in diabetic neuropathy, have not demonstrated efficacy in clinical trials for HIV neuropathy

(5) Balance side-effect profile and toxicity risk against efficacy

TCAs are effective in neuropathic pain in lower doses than needed for depression, thus avoiding much of the side-effect burden, particularly in younger patients. SSRIs and SNRIs (antidepressants) are much more likely to cause sexual side effects than buproprion when treating depression in patients with chronic pain. Regular long-term use of NSAIDs associated with higher organ system risk (e.g., nenal, GI) than opioids

(6) Consider cognitive and behavioral effects

Tricyclics are more likely than SSRIs to cause cognitive impairment in older persons. Benzodiazepines may inhibit learning new coping skills in patients with chronic pain

(7) Select combinations of medications from difference classes based on complementary mechanisims of action

For neuropathic pain, SNRIs enhance descending modulating systems, TCAs combine SNRI and Na channel blocking effects, gabapentin and pregabalin act at voltage-gated calcium channels, and opioids act at opioid receptor sites

(8) Monitor pain and activity levels and response measures during therapeutic trials

Use pain and activity diaries to establish effectiveness of treatment

(9) Avoid irrational polypharmacy and optimize methods of medication delivery

Look for potential drug interactions, such as SSRIs and tegretol affecting methadone metabolism through effects on cytochrome P-450 enzymes in the liver

(10) Integrate medications with behavioral and physical therapies

Not all pain must be treated with medications. Neuromodulation with simple techniques such as icing, stretching, TENS, and acupuncture and behavioral techniques such as pacing, relaxation, and hypnosis should be used by the patient to minimize unnecessary reliance on medications

used repeatedly may be toxic to already damaged neurons and cause osteopenia. Thus interventional procedures, including neuromodulation therapies, should be undertaken within the context of a selectively comprehensive treatment plan that addresses the most salient factors contributing to pain and functional impairment (Krames, 1996, 1999). Otherwise, even if they temporarily relieve pain, they often fail to improve longitudinally. The Pain Diary for Evaluation and Management of Pain At initial presentation, patients may be taking a variety of medications. Barring an immediate medical reason to change medications, clinicians should consider asking the patient to keep a pain diary for 1–2 weeks to assess baseline pain and functional status on their

existing medications. Having this baseline will help the clinician evaluate and monitor the response to various treatments. Diaries can provide important information about factors that alleviate or worsen pain, about patient behavior and coping, and about the effects of treatment. The diary should be reviewed subsequently at each visit until a stable medication regimen is obtained. This procedure also encourages adherence to treatment plans and gives the patient some responsibility for outcome. Diaries are a critical patient skill for maximizing the effectiveness of pharmacological intervention. The author recommends ten general principles when prescribing medication for patients with chronic noncancer or cancer pain, as in Table 23.5. More detailed information about pharmacological doses and regimens in specific clinical situations is available in other work (Gallagher and Verma, 2004).

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Importantly, clinicians should consider specific problems with different medication classes. Overuse of some drugs, such as NSAIDs or acetaminophen, is associated with serious risks such as gastrointestinal bleeding or liver disease, respectively. Benzodiazepines must be used cautiously, especially in the elderly or those operating machinery, because they increase the risk for falls and accidents, they can cause dependency, they increase the risk of respiratory depression when combined with opioids, and they inhibit new learning, which may be problematic in pain treatment requiring that patients learn new coping skills (see below). Opioids, with organ system toxicity limited to constipation and hypogonadism in some cases, and with less drug or disease interactions than most other medications used for pain, can be safe and effective, especially when used within a comprehensive pain program (Bloodworth, 2005; Gallagher, 2005, 2006). However, animal literature and clinical experience suggests that some patients develop tolerance and even hyperalgesia after long-term exposure to opioids for pain (Ballantyne and Mao, 2003; Mao, 2004) through the activation of N-methyl-D-aspartate (NMDA) receptors and protein kinase C as well as the regulation of glutamate transporters. As yet, we cannot predict which patients will develop tolerance, although clinical experience indicates that psychiatric co-morbidity, particularly sensitized states such as PTSD, appear to be associated with such tolerance. Preliminary evidence suggests several promising methods for overcoming opioid tolerance such as using ketamine, an NMDA receptor antagonist. To reduce the risks of misuse and diversion, all patients prescribed regular opioids for pain should be asked basic substance abuse questions to identify the potential for activating premorbid addiction or worsening existing addiction disorder (Gourlay et al., 2005); when risks or aberrant behavior become apparent, structured risk management programs should be applied (Wiedemer et al., 2007). In terminally ill patients, pain management’s highest priority is to maintain quality of life. Treatment aims not only to reduce pain and suffering, but importantly to improve function, such as enabling the patient quality time with family and friends and time to organize business and personal affairs. In these cases, it is important to continuously reassess the riskto-benefit ratio of medications, in an attempt to control pain while minimizing undesirable physiologic, cognitive, and emotional and behavioral effects. More discussion of these clinical points will occur later in this chapter. In persistent, non-terminal pain, the safety of medications when two or more are used together, or when there is co-morbid illness (e.g., diabetes,

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heart disease, cancer, rheumatoid arthritis) should be evaluated, especially in older patients. A key example in this area of risk assessment is cardiac toxicity, such as heart block, orthostatic hypotension leading to falls, and urinary retention associated with tricyclic antidepressants. In addition, the pharmacokinetics and metabolism of many drugs are altered in the elderly and those taking certain antidepressants and anticonvulsants, leading to toxicity or altered effectiveness. For example, 5–10% of Caucasians are poor metabolizers via the cytochrome P450 enzyme 2D6 system, which is inhibited by SSRIs such as paroxetine and fluoxetine, lowering the rate of methadone metabolism and inadvertent overdose (Ener et al., 2003). Figure 23.3 presents a general evidence-based algorithm for considering the classes of medications appropriate for nociceptive and neuropathic pain with and without sleep disturbance, commonly co-morbid with chronic pain, and with and without depression. The efficacy and adverse effects of a particular drug should be evaluated in the context of every clinical encounter with the individual patient. For example, an overweight patient with radicular low back pain should not be prescribed amitriptyline, which, although effective for neuropathic pain, often causes weight gain and further biomechanical strain on spinal structures. Gabapentin, pregabalin, and other anticonvulsants (topiramate, oxycarbazine, lamotrigene, etc.), SNRI antidepressants (e.g., duloxetine and venlafaxine), and the lidocaine patch which has no systemic effects, may be preferred. Neuropsychologic functions such as learning, memory, and psychomotor performance, which are critical to improving functional outcomes in rehabilitation, can be interfered with by benzodiazepines, which also disinhibit anger, a frequent co-morbidity of disabled workers. An outline of the rationale for polypharmacy is presented in Box 23.1 (Raffa et al., 2003; Fishbain, 2005; Gallagher, 2005). When combining analgesics, it is reasonable to combine medications with pharmacological activity at different receptor sites in the pain pathway (e.g., combined use of a centrally acting opioid, a TCA or SNRI, an anticonvulsant, and a peripherally acting NSAID) (Fishbain 2005; Gallagher, 2006). If treatment with a specific medication fails, it is often useful to consider a trial with an alternate drug in the same therapeutic class but with a different purported mechanism of action (e.g., when using an anticonvulsant, switch from a sodium channel blocker, such as topiramate) to a calcium channel blocker (gabapentin, pregabalin); or when using an antidepressant switch from a selective serotonin reuptake inhibitor (SSRI – paroxetine, fluoxetine, sertraline, citalopram) to an serotonin

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23.  Management strategies for chronic pain

Nociceptive pain

Neuropathic pain

Secondary depression

Pain condition � depression Primary D.

Evaluate risks

Short-term NSAIDs, Cox-II(?), opioids

Secondary sleep disturbance

Persists after adequate analgesia

Evaluate risks

Persists after adequate analgesia SSRI, buproprione

Evaluate risks

Evaluate risks SNRIs: venlafaxine, duloxetine

Antihistamine, zolpidem, low-dose benzodiazepine

Lidocaine patch; gabapentin and other AED (Ca�and Na� channels); α 2 agonists (tizanidine, clonidine); opioids

Trazodone Low-dose TCA

Titrate TCAs (Na� channels and SNRI): desipramine, nortriptyline

Figure 23.3  Algorithm for medication selection for chronic pain with and without co-morbid depression. (Note: This information concerns uses that have not been approved by the US FDA)

Box 23.1

Indications for polypharmacy To minimize treatment intolerance to a medication by utilizing a second drug which enables a lower dose of the first agent (this may increase compliance) l To create analgesic efficacy for different parts of the day by giving immediate-release medications combined with long-acting agents (e.g., to control breakthrough pain in a patient on long-acting opioids when certain unavoidable tasks, which predictably activate nociception, must be completed at work; or when a stumble or fall activates nociception) l To utilize a lower dose of a drug by utilizing a second medication for purposes other than reduction of adverse effects (e.g., opioid-sparing, as in using an NSAID for osteoarthritic low back pain) l To utilize a second drug in order to facilitate synergy (the combination of the two medications given l

norepinephrine reuptake inhibitor (SNRI – duloxetine or venlafaxine) or dopamine-norepinephrine reuptake inhibitor (bupropion). Common reasons for pharmacotherapy failure are underdosing (e.g., a drug trial that is too short or at a dose that is too low), noncompliance, or inadequate use

together has greater efficacy than the mathematically combined efficacy of the two agents given individually) l To address non-response or partial response to monotherapy by utilizing a second drug to increase the efficacy of treatment either by administering two medications for the same indication but with different mechanisms of action (e.g., a tricyclic at bedtime to help structure sleep and treat neuropathic pain from radiculopathy, while also using gabapentin or pregabalin for neuropathic pain) or by utilizing an augmentation strategy (e.g., addition of a pharmacological agent not considered to have analgesic properties but which may boost or enhance the effect of analgesic or, as another example, to add an NMDA receptor antagonist to an opioid to boost efficacy or decrease tolerance)

of rational polypharmacy. When patients report that pain is unrelieved or increased, do not reflexively increase the dose of an agent before considering other factors potentially contributing to inadequate response, such as drug interactions, adverse effects, toxicity, behavioral effects, increased activity level, disease progression or nondisease

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Box 23.2

Clinical strategies and tactics in the pharmacotherapy of chronic pain 1. Identify pain pattern and pain diagnosis and formulate mechanisms. A database should include a complete medical and pain history, selective physical, mental status, and laboratory examinations, response to other treatment trials, and a baseline record of pain levels (using a daily pain diary for at least one week) 2. Inquire about patient’s and significant others’ knowledge, beliefs, and attitudes about medication. Family, social and cultural values may strongly influence a patient’s adherence to medication trials and response to adverse effects. When necessary and appropriate, meet with significant others to establish rapport and common goals 3. Develop a goal-oriented management plan for each problem. Specify time-limited target outcome measures such as pain relief, improved sleep, less social irritability, and improved function at home and at work 4. Select medication carefully. Choose medication according to diagnosis, efficacy, tolerability, ease of use, and cost (if this applies). Consider the mechanism of pain (e.g., nociceptive, neuropathic), mechanisms perpetuating pain (e.g., deconditioning, sleep disturbance, depressive illness, poor compliance with treatment), medical problems (co-morbid illness or psychiatric disturbance) and psychosocial factors that might influence treatment 5. Plan medication trials carefully with patient. Establish outcome measures with patient. Be sure adequate trials are achieved. If patient achieves a 2-point or greater reduction in pain intensity on a 0–10 (11-point) scale, remain on the lowest dose that achieves that effect and is also tolerable; then add

factors (e.g., a change in activity or stress). Often patients improve enough to resume activities that activate damaged tissues exacerbating either or both neuropathic and musculoskeletal pain. Some useful clinical strategies to optimize pharmacotherapy incorporate the biopsychosocial approach to treatment and are detailed in Box 23.2. Physical Therapy and Occupational Therapy Physical conditioning programs that include a cognitive-behavioral approach plus intensive physical training, given or supervised by a physiotherapist or multidisciplinary team, are effective in reducing the number of sick days for some workers with chronic back

another medication that addresses a different mechanism (add a sodium-channel blocker to a calcium-channel blocker, add an SNRI or tricyclic to an anti-convulsant, add an opioid to any, etc). 6. When titrating medication, closely follow patients at least every 2 weeks until stable, occasionally with contact several times weekly, to establish optimal dosing and to maximize adherence. This behavioral approach facilitates the completion of an adequate medication trial 7. Consider alternate management strategies for pain fluctuations. Often, physical therapy interventions (e.g., icing, TENS, stretching, exercise), behavioral techniques (e.g., avoidance of nociceptive activity, relaxation training, pacing, cognitive restructuring, stress management) and trigger point therapies (e.g., spray and stretch with ethyl chloride or injections) can control pain without the need for additional medications. For psychological symptoms, reassurance, brief support and cognitive-behavioral techniques may be sufficient to restore a patient’s sense of control and comfort, without the need for a full therapeutic trial of psychotropic medication 8. If a drug trial fails to help, or if the physician or patient is uncertain if it is helping, gradually reduce the dose (while keeping other medications stable) and closely monitor the response, before initiating a trial with another medication. If a patient stops a medication suddenly, this may precipitate a withdrawal reaction, including seizures in the case of anticonvulsants or short-acting benzodiazepines. The physician should counsel the patient to discuss concerns and ideas about medication before making a change

pain, when compared to usual care (Schonstein et al., 2003). Skilled physical therapy relies upon behavioral medicine principles, with therapists using positive reinforcement to instruct, guide, and encourage the patient to engage in physical activities that improve strength, endurance, and flexibility (Lackner et al., 1996; Geisser et al., 2004; Woby et al., 2004). The physician can play an important role by encouraging patients in an exercise program by providing reassurance of ability and safety, by providing pain control with appropriate medications, trigger point therapies, epidural steroids, radio­ frequency ablations and neuromodulation. The fear of movement, kinesophobia, is highly conditioned in many patients with pain disorders and if present needs to be addressed very directly. For some neuropathic

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Box 23.3

Psychological co-morbidities found within patients  with chronic pain Search for cure and unrealistic expectations for treatment success l Hostility/anger at physician for failure to diagnose or cure or for perceived incorrect input into legal situation l Anger at employer negligence in injury or for forced job loss l Loss of income causing financial stress and family stress l Dissatisfaction with healthcare system, including workers’ compensation and insurance carrier, either for failure to diagnose/cure or for inability to get perceived necessary medical care (usually as a result of non-authorization by carrier) l Anger at carrier for above or for other issues, such as late payment of benefits l

conditions related to nerve injury, such as brachial plexopathy (Schwartzman and Maleki, 1999), care must be taken to avoid further damage to injured nerves or activation of sensitized neuropathic pain. The managed care approach of “carve-outs” of physical therapy treatments (physical therapy provided in a different setting unrelated to the rehabilitation program) from integrated combined treatment approach is self-defeating, compromising positive treatment outcomes from pain rehabilitation (Robbins et al., 2003). An integrated approach with the pain physician offering reassurance, analgesics, and education about the management of flare-ups (e.g., 1–2 days of bed rest and pain control) as well as physical therapists’ instructions on other interventions that may interrupt pain transmission safely and effectively (e.g., icing to numb the affected area, stretching to relax taut muscle bands associated with trigger points, TENS) should be routine. Occupational therapists may assist the patient care team in completing functional capacities examinations at baseline and with vocational counselors to establish fitness to return to work after treatment. Interventional Pain Medicine Various procedures may be useful to relieve painful syndromes to enable functional restoration (Krames, 1999). Trigger point injections or epidural blocks may be used to help control pain while initiating physical

Litigation stress, such as dissatisfaction with lawyer Confusion over conflicting diagnoses and recommendations l Anger with spouse over-solicitousness or under-solicitousness l Loss of intimacy and sexuality l Spousal depression l Poor coping strategies l Spousal problems/stress such as perceived nonsupport or blaming or not believing the patient’s pain l Fear of pain l Poor self-esteem l Pre-injury job stress l Childhood victimization l l

therapy in low back pain. Implantable pumps for continuous or episodic infusion of medications, spinal cord stimulation (SCS), peripheral nerve stimulation (PNS), occipital nerve stimulation (ONS) for headache occipital neuralgia, motor cortex stimulation (MCS), and even deep brain stimulation (DBS) may be used when systemic pain control is ineffective. A detailed discussion of the use of these techniques in managing pain can be found in earlier and later chapters. Psychotherapies and Behavioral Therapies Box 23.3 lists several common psychological and psychiatric morbidities that must be identified and managed or they may disrupt treatment. The literature supports the routine use of cognitive-behavioral therapies in pain management (Gale et al., 2002; Lang et al., 2003; Keller et al., 2004). Many of these are amen­ able to group therapy, as listed in Box 23.4. The Behavioral Pharmacology Group, which the author has evolved in several different settings, helps patients learn to integrate medications, physical therapies, and cognitive behavioral techniques into their own personal formula for longitudinal pain management (Gallagher et al., 1990). The typical group of 10–12 sessions, using cognitive-behavioral and supportive techniques, can be very helpful in managing psychosocial morbidities and in supporting effective medication management and physical rehabilitation. Box 23.4 outlines the sequential tasks in pain management training

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Box 23.4

Sequential tasks in pain management training 1. Rationalize pharmacology. Review pain physiology and the specificity of medication for different aspects of the pain cycle (see text for details) 2. Teach pain/tension cycle and biopsychosocial pain physiology; instruct in use of pain diaries to record daily and hourly fluctuations in pain. This skill will assist in planning medication trials and evaluating their outcome, and to help plan and implement appropriate physical therapies and behavioral life style changes 3. Begin psychophysiologic relaxation training. Group training is supplemented by daily home practice with tapes, which can be ordered commercially or made by any behavioral clinician. Relaxation training, particularly in combination with pharmacologic treatment, has been shown to be effective in reducing pain and improving coping in several painful conditions. Biofeedback may enhance learning of the relaxation response, but is usually not needed. Portable biofeedback devices are more practical for home use 4. Continue baseline data collection. Review recordkeeping practice and skill with diaries 5. Introduce pacing skills. Daily diaries will help correlate activities, treatments and symptoms and establish patterns of precipitation and amelioration. Patients learn to pace activities to avoid flare-ups 6. Review relaxation training, pacing skills. Frequent review reinforces practice and training principles. Mistakes include using tapes to fall asleep or to

in these groups, which can be run by one or a combination of pain psychologists, nurse specialists, and physicians. Education is a critical element of treatment, whether done by the physician while seeing patients in regular office practice, or as part of a pain program. The website of the National Pain Foundation (www. nationalpain­foundation.org), helps patients and their families find extensive peer reviewed information about pain and its treatment written for a lay audience. If the goal of treatment is return-to-work, the last several sessions of pain management training focus particularly upon problems integrating new skills into the workplace. If available the occupational therapist and vocational rehabilitation counselor can evaluate the demands of the actual or hypothetical work environment and simulate these demands in the rehabilitation

  7.

  8.

  9. 10.

11.

12.

13.

reduce pain before the relaxation skills have been learned through regular practice Assess environmental, cognitive, biological, and behavioral precipitants and consequences of pain. Construct dynamic flow charts of interacting factors using BPS treatment to interrupt causal pathways Plan how to integrate medication use with behavioral and physical therapies. The physician should participate in this session Introduce stress management and cognitive interventions Continue stress management – communication skills training, assertion training, cognitive distortions. This task includes learning effective communication skills with the physician, and may include the physician for all or part of a session for role playing and problem-solving Develop pain management protocols (PMP) for individual patients. Include medication, physical therapy techniques (ice, TENS, stretching, exercise), stress management (relaxation, cognitiveemotional-behavioral-pain cycles) Reinforce pain management protocol (PMP) and establish maintenance program. This session may take place after a 2-week gap to allow patients an opportunity to “field test” their PMPs for individual patients are discussed At regularly scheduled follow-up visits, re-evaluate and refine pain management protocol

program. Actual visits to the job site will reveal helpful strategies. Record Keeping Keeping accurate and clear records of all treatment plans, treatments, and patient encounters is just good medicine and required by the licensing laws of each and every state. As stated above, patients should also keep adequate records of their treatment and outcome to treatment. Box 23.5 lists the functions of patient record-keeping. Family therapy can provide education and support to the patient and family members, so they work together constructively in the patient’s rehabilitation. Groups for chronic pain patients and their spouses have proven helpful in reducing anxiety,

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23.  Management strategies for chronic pain

Box 23.5

Functions of record keeping A major problem for pain treatment is the lack of an objective test of improvement. Patients learn a scaling system that has intra-rater reliability l Patients deliver an accurate record of the pain, which is notoriously poorly remembered (Raphael and Marbach, 1997). Thus they can establish a baseline for daily pain levels that will enable monitoring of treatment effects l By recording circumstances of pain, patients may learn about the multiple other biopsychosocial factors that may precipitate and perpetuate their pain l

depression, and interpersonal sensitivity (Langelier and Gallagher, 1989).

Ethical challenges in pain management Ethical dilemmas often occur during pain management of chronic pain disease as physicians struggle with various influences on clinical decision-making, including the following: demands of income generation, poorly reimbursed comprehensive care, the influences of the pharmaceutical and medical device industries, the influence of third party reimbursement, confidentiality, and conflicts of interest. At the end-of-life, clinicians and families struggle with ethical concerns in making decisions that will affect a patient’s dignity and quality of life while reducing his or her suffering. Issues beyond the scope of this chapter, such as determining a patient’s competence and legal guardianship, and assisted suicide in some states, may emerge. A detailed consideration of the ethics of pain and palliative care can be found in a series of articles in a special issue of Pain Medicine (Lebovits, 2001), dedicated to ethical care in pain management, and in the ethics charter of the American Academy of Pain Medicine (Dubois et al., 2005).

Conclusion and looking  to the future The treatment of patients with persistent pain challenges the best in us – our professional knowledge and

Record-keeping is therapeutic. The patient finally can do something that helps their treatment, an activity that improves, often immediately, their sense of control and self-efficacy l By providing a numerical scale to communicate pain levels record-keeping serves to extinguish maladaptive pain behaviors that serve as patients’ only means of communicating pain levels and distress and tend to isolate them socially l

skills, our patience, our empathy, and our values. The rewards are many. We participate in an exciting and rapidly growing field of neuroscience, behavioral science, and biopsychosocial medicine that utilizes and builds on our entire medical training and experience. Our clinical skills can help patients restore and maintain a meaningful life, a life that before our intervention seemed hopeless and empty to them and their loved ones. Pain medicine practice has advanced rapidly in the latter half of this century through adoption of the biopsychosocial rehabilitation approach, which is now an accepted standard of care; and by integrating new technologies such as neuromodulation therapies and medications to enhance pain control. Effective implementation of this model requires a conceptual fluidity, as well as a selective and skillful integration and coordination of treatment resources. Used effectively in appropriate patients, this approach can help prevent chronic impairments and disability and their negative consequences. Physicians who adopt this approach will likely be more successful in managing both complex patients with chronic pain and those with common chronic pain problems, such as headache and backache. Current reimbursement models primarily stem from the traditional biomedical model, often without an evidence basis; they reward procedures, not integrative medicine and results. This tendency is already changing, however, as policy-makers, in efforts to rein in spiraling costs, are beginning to develop actuarial models that emphasize outcomes, not procedures. The future of pain treatment rests with several rapidly developing interdependent domains: 1. The mechanism-based and disease-specific phenomenological classification of pain diseases and disorders.

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references

2. Biogenetically accelerated advances in the behavioral sciences and neurosciences, leading to new and more effective interventions, with a capacity for targeting specific receptors and mechanisms using smart drugs and stimulation to modulate both the peripheral stimulus and its transmission to the spinal cord and brain, but also neuromodulation of specific brain centers that will re-program encoded pain networks that perpetuate pain and suffering. 3. Evidence-based, mechanism-specific, and disorderspecific applications of treatments and combinations of treatment in the context of the biopsychosocial complexity of individual patients with pain. 4. The evolution of new administrative structures in the health system that will enable more patients to have timely access to integrated, evidence-based pain medicine and rehabilitation services that are well reimbursed because they save money and improve clinical outcomes.

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C H A P T E R

24

Transcutaneous Electrical Nerve Stimulation (TENS): A Review Kathleen A. Sluka, Howard S. Smith, and Deirdre M. Walsh

o u tl i ne Introduction

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TENS Terminology

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General Principles of Application of TENS

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Theories of TENS Analgesia and Effects of TENS in Animal Models

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Analgesic Mechanisms of TENS High Frequency (50–100 Hz) TENS

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introduction

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Translation of Mechanisms of TENS Analgesia to the Clinic

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The Clinical Efficacy of TENS

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Summary Points

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References

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nerve fibers. This gate could be closed by a range of stimuli which activate large diameter afferent fibers such as touch, pressure, and electrical currents. Shortly after the theory was published, initial studies emerged which showed the effective use of percutan­ eous electrical stimulation for chronic neuropathic pain (Wall and Sweet, 1967). However, it was Dr Norman Shealy who made a significant discovery for the use of transcutaneous electrical nerve stimulation for pain relief. Around this time, dorsal column stimulation (DCS), a new technique for pain relief, was developed. DCS, now called spinal cord stimulation or SCS, involved the surgical implantation of electrodes over the dorsal columns of the spinal cord which were then activated by an external battery-operated device (Shealy et al., 1967). Today, SCS involves the placement of

Transcutaneous electrical nerve stimulation (TENS) involves the application of electrical currents to the skin primarily for the purposes of pain relief. It is a safe, non-invasive treatment that can be self-administered. Natural forms of electricity have been used as a method of pain relief since the Egyptian era with early prototypes of TENS units available by the late 1800s (Walsh, 1997). However, the use of electrical currents for pain relief was met with a degree of skepticism until a theoretical foundation for this electroanalgesia was established. This came in the form of Melzack and Wall’s gate control theory of pain (Melzack and Wall, 1965), which proposed that a gate existed in the dorsal horn of the spinal cord which could regulate the amount of incoming nociceptive traffic via small diameter afferent

Neuromodulation

Low Frequency (10 Hz) TENS Autonomic Effects of Low Frequency TENS

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either percutaneous or laminotomy electrode lead arrays within the epidural space overlying the dorsal columns of the spinal cord, which are activated by either an external battery source to an implanted radio receiver (RF device), an implanted neuropulse generator (IPG) with either an externally rechargeable or a non-rechargeable battery. Shealy used an early TENS device as a screening tool prior to proceeding with DCS for the management of his patients with chronic pain (Shealy, 1974). Interestingly, Shealy discovered that some of his patients responded better to the TENS therapy than when he used DCS, and so TENS subsequently emerged as a viable modality for the management of pain. Meyer and Fields (1972) were among the first to report on the clinical use of TENS for the relief of chronic pain. Technological advances have subsequently produced today’s wide range of stimulators with an even wider range of stimulation parameters for clinicians to choose from. Despite widespread use, the clinical efficacy of TENS remains ambiguous. This chapter provides an overview of the pertinent research relating to the theory and clinical application of TENS.

Figure 24.1  Select TENS unit (Courtesy of Empi, St Paul, MN)

remains equivocal (McDowell et al., 1999; Adedoyin et al., 2002; Cheing and HuiChan, 2003; Johnson and Tabasam, 2003; Reichstein et al., 2005). For the purposes of this chapter, the term TENS will be used to describe those types of electrical current with a frequency of less than 200 Hz and a pulse duration less than 400 s.

TENS terminology

General principles of application of TENS

A TENS unit may be considered as any device generating appropriate cutaneously applied pulsed current through surface electrodes to overcome the impedance of the skin’s conductive barrier and result in excitation of peripheral nerves (see Figure 24.1). There are many types of transcutaneous currents that fall under the umbrella term of TENS, e.g. interferential currents, H-wave therapy etc. Interferential currents involve the application of two medium frequency currents (typically around 4000 Hz) to the skin to theoretically produce an amplitude modulated low frequency current (range 1–150 Hz) within the tissues. Medium frequency currents are applied in order to overcome skin impedance which is inversely proportional to the frequency of the applied current. It is suggested that the resulting low frequency amplitude modulated current can stimulate deeper tissues as less current is required to overcome skin resistance; however, evidence supporting the theory behind this is lacking (Ozcan et al., 2004). In contrast, H-wave therapy employs a biphasic exponentially decaying waveform with a fixed pulse duration (approximately 15 ms) delivered at frequencies ranging from 2 Hz to 60 Hz. Research to date on the hypo­algesic effects of both types of electrical current

The clinical application of TENS involves the delivery of a low voltage electrical current from a small battery-operated device to the skin via surface electrodes. The majority of TENS devices offer variable frequency (pulse rate), pulse duration, intensity (amplitude), and type of output (the pattern in which the pulses are delivered: burst, continuous, or modulated). A modulated output is produced by varying pulse duration, frequency, and/or amplitude in a regular and cyclical manner with the hope of avoiding accommodation of nerve fibers to a constant stimulus (e.g. amplitude modulation involves a cyclical modulation in amplitude from zero increasing gradually to a preset peak level, and then decreasing gradually back to zero again). TENS devices typically use a pulsed current with a rectangular shaped waveform; waveforms are usually monophasic, symmetrical biphasic, or asymmetrical biphasic. The amplitude is directly related to the magnitude or intensity of the current being delivered. Intensity is measured in milliamperes (mA) (or millivolts if the device is designed to deliver constant voltage) and generally ranges from 30 to 100 mA, often yielding sensations of tingling or pins-and-needles. The pulse duration is the length of time during which

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General principles of application of TENS

Time � 0.1 s

Intensity (mA)

Intensity (mA)



Intensity (mA)

Conventional TENS

Time � 1 s

Acupuncture-like TENS

Time � 1 s

Burst TENS

Figure 24.2  TENS stimulation modes

each pulse is delivered. Longer pulse durations give rise to increases in the total electrical charge delivered. As the pulse duration is increased in the usual range from 40 to 400 microseconds (s), the patient may feel a spreading/radiating and/or deepening/penetrating sensation. The pulse rate (frequency) is the number of pulses delivered per second (Hz). The range of pulse rate is generally 1 Hz to 200 Hz. Combinations of these different stimulation parameters are used to produce four main modes of TENS (Walsh, 1997): Conventional or high frequency TENS (frequency typically above 100 Hz, short pulse duration (50–80 s), low intensity); Acupuncture-like or low frequency TENS (frequency usually 1–4 Hz, long pulse duration (200 s), high intensity); Burst TENS (high internal frequency trains of pulses (100 Hz) delivered at a low frequency, typically 1–4 Hz); and Brief–Intense TENS (high frequency and long pulse duration pulses delivered at a high intensity) (see Figure 24.2). Conventional TENS (high frequency TENS with frequencies typically above 100 Hz, short pulse duration (50–80 s), low intensity) stimulates large diameter afferents and produces paresthesia in the area under the electrodes whereas the production of muscle twitches is desirable with Acupuncture-like TENS (low frequency TENS with frequencies usually between 1 and 4 Hz with long pulse durations of ~200 s, high intensity). In Acupuncture-like TENS, the electrodes should be positioned to produce visible non-painful muscle contractions (twitching type) (e.g. over a myotome related to the painful area). Burst TENS, consisting of high frequency trains of pulses delivered at low frequencies,

may produce more comfortable muscle contractions. Brief–Intense TENS, which consists of high frequency (100–150 Hz) and long duration (150–250 s) pulses delivered at the patient’s highest tolerable intensity for short periods of time (15 minutes), is sometimes used for painful procedures (e.g. skin debridement) (see Figure 24.2). In terms of application, the clinician has four different electrode placement sites to choose from: the painful area; the peripheral nerve supply to the painful area, spinal nerve roots dermatomal distribution, and acupuncture/motor/trigger points. Self-adhesive electrodes are most commonly used although some clinicians still use a carbon rubber electrode and gel application. If tape is required to secure the latter type of electrode in place, care must be taken to ensure the tape is applied evenly to ensure uniform distribution of the current. Relatively few adverse effects have been reported with TENS. Precautions for and contraindications to TENS are mostly empirical, reflecting “common sense” and include: impaired sensation, impaired alertness/ cognition, use in the region of the anterior neck or eyes (e.g. where carotid sinuses are located), history of contact allergy to the electrode gel (which commonly contains propylene glycol) or tape, epilepsy, use over broken or irritated skin, use while operating machinery, or pregnancy (however, TENS is frequently used for pain relief during labor). In addition, TENS has been shown to interfere with some types of pacemakers (Broadley, 2000; Pyatt et al., 2003). The successful application of TENS involves a degree of trial and error. Several attempts are typically required

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24.  Transcutaneous Electrical Nerve Stimulation (TENS): A Review

before the optimal stimulation parameters and electrode site are determined for a patient. It is recommended that the first trial of TENS involve Conventional TENS applied over the painful area as the paresthesia experi­ enced is usually more comfortable for the patient. Following this initial trial, other modes of TENS should also be sequentially tried to determine which produces the maximum pain relief. The application time should be kept to 30 minutes for the first trial to allow monitoring for adverse effects and subsequently increased to one hour at a time, repeated as many times as necessary. A 30 minute break between applications over the same skin area is recommended to avoid skin irritation associated with prolonged use. The intensity of the TENS should be increased to produce what the patient feels is a “strong but comfortable” sensation. As muscle contraction is desirable with Acupuncture-like TENS, the intensity should be increased until muscle twitching is observed. Due to perceived accommodation of nerve fibers, the intensity can be increased during treatment to maintain this subjective sensation of being “strong but comfortable.” However, the effect of perceived accommodation has not been rigorously examined in the clinical setting. A recent study by Defrin et al. (2005) on interferential currents suggests that it is not necessary to adjust current intensity during treatment to obtain pain relief. No significant differences in treatment outcomes were found between groups of patients with chronic pain in which the current intensity was constantly adjusted to prevent fading of sensation versus those in which the intensity was not adjusted and in which patients reported fading of sensation.

Theories of TENS analgesia and effects of TENS in animal models Two theories are commonly utilized to support the use of TENS. The gate control theory of pain is most commonly utilized to explain the inhibition of pain by TENS. According to the gate control theory of pain, stimulation of large diameter A afferents inhibits nociceptive C-fiber evoked responses within the dorsal horn. There is now much more detailed data on mechanisms of actions of TENS that includes anatomical pathways, neurotransmitters and their receptors, and the types of neurons involved in the inhibition. Release of endogenous opioids has been used to explain the actions of TENS, particularly low frequency stimulation. Recent data support this theory for low frequency TENS as well as for high frequency TENS stimulation (Sluka et al., 1999; Kalra et al., 2001).

Early studies on the mechanisms of action of TENS were performed in normal, uninjured animals. These studies provided valuable information regarding potential mechanisms of action of TENS. More recent studies have translated and extended these data by examining mechanisms of action of TENS in animal models of pain. The studies in animal models of pain have revealed pharmacological and anatomical pathways that mediate the reduction of pain produced by TENS. The current data suggest that different frequencies of TENS produce analgesia through actions on different neurotransmitters and receptors. Below we describe the neurotransmitters and receptors involved in TENS analgesia. In animals without tissue injury, the behavioral responses to noxious thermal stimuli are increased (Woolf et al., 1977; Woolf et al., 1980) and dorsal horn neuron activity is reduced (Lee et al., 1985; Sjolund, 1985, 1988; Garrison and Foreman, 1994, 1997) by either high or low frequency TENS. In animal models of cutaneous, joint or muscle inflammation, primary and/or secondary hyperalgesia is reversed by either low frequency (4 Hz) or high frequency (100 Hz) TENS at sensory intensities (Sluka et al., 1998; Gopalkrishnan and Sluka, 2000; deResende et al., 2004; Ainsworth et al., 2006; Vance et al., 2007). Interestingly, when bilateral hyperalgesia occurs, application of TENS to the inflamed or the contralateral non-inflamed muscle equally reduces the hyperalgesia (Ainsworth et al., 2006; Sabino et al., 2008). Furthermore, increased responsiveness of dorsal horn neurons that occurs after peripheral inflammation is also reduced by either high or low frequency TENS (Ma and Sluka, 2001). In animal models of neuropathic pain, either high or low frequency TENS reduces hyperalgesia that normally occurs in these models (Somers and Clemente, 1998; Nam et al., 2001). Similarly, the responsiveness of spinal neurons to innocuous mechanical stimulation is inhibited by TENS in neuropathic animals (Leem et al., 1995).

Analgesic mechanisms of TENS High Frequency (50–100 Hz) TENS In animals that were spinalized to remove descending inhibitory pathways, inhibition of the tail flick by high frequency TENS still occurs but is reduced by about 50% (Woolf et al., 1980). Thus, these studies suggest that both spinal and descending inhibition are involved in the analgesia produced by high frequency TENS. A later study showed that high frequency TENS prevents the antihyperalgesia by blockade of -opioid

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Analgesic mechanisms of TENS Low frequency TENS

High frequency TENS

Thalamus and reticular formation Dorsal column nuclei

Thalamus and reticular formation Dorsal column nuclei

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Figure 24.3  Mechanisms of low frequency and high frequency TENS (Reproduced with permission from Maeda et al., 2007. Copyright (2007) Elsevier)

receptors in the rostral ventral medial medulla (RVM) further supporting a role for supraspinal pathways in TENS analgesia (Kalra et al., 2001). Pharmacologically, opioid peptides mediate the effects of high frequency TENS. Concentrations of -endorphins increase in the bloodstream and cerebrospinal fluid, and methionine–enkephalin in the cerebrospinal fluid were found in human subjects following administration of high frequency TENS (Salar et al., 1981; Han et al., 1991). Blockade of -opioid receptors in the spinal cord or the RVM reverses the antihyperalgesia produced by high frequency TENS in animals with carrageenan induced knee joint inflammation (Sluka et al., 1999; Kalra et al., 2001). Repeated application of high frequency, motor intensity TENS produces tolerance (reduced effectiveness) to the antihyperalgesic effects of TENS and at spinal -opioid receptors (Chandran and Sluka, 2003). In addition, the excitatory neurotransmitters glutamate and substance P are decreased in the spinal dorsal horn by high frequency TENS (Sluka et al., 2005; Liu et al., 2007); this decrease in glutamate is mediated through activation of -opioid receptors (Sluka et al., 2005). Other neurotransmitters commonly involved in spinal inhibition are also involved in TENS inhibition: muscarinic receptors (M1, M3) in the spinal cord also prevent the antihyperalgesia produced by high frequency TENS (Radhakrishnan and

Sluka, 2003). There is also an increased release of GABA in response to high frequency TENS, and the antihyperalgesia is reduced by blockade of GABAA receptors in the spinal cord (Maeda et al., 2007). However, blockade of serotonin or noradrenergic receptors in the spinal cord has no effect on the reversal of hyperalgesia produced by high frequency TENS (Radhakrishnan et al., 2003). Thus a complicated neural circuitry is activated in response to high frequency TENS that utilizes descending opioid inhibitory pathways to reduce excitability of dorsal horn neurons through decreasing release of glutamate and increasing release of GABA to result in reduction of nociception and consequently pain (see Figure 24.3). TENS could have effects on autonomic function, blood flow, and peripheral afferent fibers (reviewed in Sluka and Walsh, 2003). The reported effects of high frequency TENS at different sensory or motor intensities are mixed with some studies showing increases in blood flow, and others showing no change (Indergand and Morgan, 1994; Wikström et al., 1999; Cramp et al., 2000; Chen et al., 2007; Sandberg et al., 2007). The primary afferent neuropeptide, substance P, which is normally increased in injured animals is reduced in dorsal root ganglia neurons by high frequency, sensory intensity TENS in animals injected with the inflam­matory irritant, formalin (Rokugo et al., 2002).

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24.  Transcutaneous Electrical Nerve Stimulation (TENS): A Review

The antihyperalgesia produced by high frequency TENS in animals with joint inflammation is reduced in 2A-noradrenergic receptor knockout mice, and prevented by peripheral blockade of 2-noradrenergic receptors (but not by spinal or supraspinal blockade) (King et al., 2005). Thus, evidence is beginning to emerge that some of the analgesic effects of TENS may be mediated through actions on primary afferent fibers and modulation of autonomic activity.

Low Frequency (10 Hz) TENS Low frequency TENS antihyperalgesia is prevented by blockade of -opioid receptors in the spinal cord or the RVM (Sluka et al., 1999; Kalra et al., 2001). Repeated application of TENS produces tolerance to the antihyperalgesic effects of TENS and of spinal -opioid receptors (Chandran and Sluka, 2003). The effects of low frequency, sensory intensity TENS is also reduced by blockade of GABAA, serotonin 5-HT2A and 5-HT3, and muscarinic M1 and M3 receptors in the spinal cord (Radhakrishnan and Sluka, 2003; Radhakrishnan et al., 2003; Maeda et al., 2007). Similarly, serotonin is released during low frequency TENS in animals with joint inflammation (Sluka et al., 2006). Taken together, these studies suggest that low frequency TENS utilizes classical descending inhibitory pathways which utilize opioid, GABA, serotonin and muscarinic receptors in the spinal cord to reduce dorsal horn neuron activity, nociception and the consequent pain (see Figure 24.3).

Autonomic Effects of Low Frequency TENS The effect of low frequency intensity TENS on cold allodynia is reduced by administration of systemic phentolamine to block -adrenergic receptors (Nam et al., 2001). Using laser Doppler, blood flow increases during low frequency TENS applied over a peripheral nerve or the trapezius muscle (Wikstrom et al., 1999; Cramp et al., 2000; Chen et al., 2007; Sandberg et al., 2007). Similarly, the antihyperalgesia produced by low frequency TENS in animals with joint inflammation is reduced in 2A-noradrenergic receptor knockout mice, and prevented by peripheral blockade of 2-noradrenergic receptors (but not by spinal or supraspinal blockade [King et al., 2005]). Transient increases in blood flow with low frequency, burst-mode (2 Hz) TENS were observed at the area of stimulation if intensity was 25% above the motor threshold, but not just below (sensory intensity) or just above motor threshold (Sherry et al., 2001). Thus, peripheral effects of TENS may involve changes in sympathetic activity utilizing local 2A-noradrenergic receptors.

Translation of mechanisms of TENS analgesia to the clinic Clinically, TENS will more than likely not be the only treatment the patient is receiving. TENS is a complementary and adjunct treatment to control pain. Medically, the patient will more than likely be taking prescription medications such as nonsteroidal anti-inflammatories (NSAIDs), opioids (e.g. fentanyl, oxycodone, etc.), 2-adrenergic agonists (e.g. clonidine) and/or muscle relaxants (e.g. cyclobenzaprine). The most common procedural interventions in physical therapy are therapeutic exercise and functional training. Physical therapists that treat pain, particularly chronic pain, utilize a combination of exercise and functional training. Electrotherapeutic modalities, or TENS, are utilized by physical therapists as an adjunct to modulate and reduce pain, and the use of TENS in the absence of other interventions is not considered physical therapy. However, in some conditions and patients, pain limits the ability of a patient to perform an adequate exercise program. Once the pain is controlled, the patient should be better able to perform an active exercise program, activities of daily living or return to work. Understanding the mechanisms will better assist the clinician in the appropriate choice of pain control treatment. Parameters of stimulation can be based on the basic knowledge and use of a particular modality such as electrical stimulation can be utilized in a more educated manner. Specific examples will be given below to address these issues. Use of TENS (in combination with other therapies) will allow the patient to increase activity level, reduce hospital stay and improve function. Indeed, treatment with TENS increases joint function in patients with arthritis (Mannheimer et al., 1978; Mannheimer and Carlsson, 1979; Kumar and Redford, 1982; Abelson et al., 1983; Zizic et al., 1995). In patients with chronic low back pain, improvements in the physical and mental compon­ent summary of the SF-36 quality of life survey occurs with TENS (Ghoname et al., 1999). Postoperative TENS treatment in patients following thoracic surgery reduces recovery room stay and improves pulmonary function as measured by postoperative PO2, vital capacity, and functional residual capacity when compared to sham controls (Ali et al., 1981; Warfield et al., 1985; Rakel and Frantz, 2003). Thus, decreasing pain with TENS may increase function and allow the patient to tolerate other therapies and activities, resulting in an improved quality of life. One should be aware of the medication a person is taking and the effects of these medications on the

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The clinical efficacy of TENS

effects of TENS. By understanding the mechanisms of action of TENS, more appropriate treatment strategies can be tried. If a patient is taking opioids (currently those available activate -opioid receptors), high frequency TENS may be more appropriate. Repeated application of opioids produces tolerance to the opioid such that a higher dose is necessary to produce the same effect. This is based on the fact that low frequency TENS, but not high frequency, is ineffective if given in animals tolerant to morphine (Sluka et al., 2000). Clinically, Solomon et al. (1980) demonstrated that in patients who had taken enough opioids to become tolerant to morphine, TENS was ineffective in reducing postoperative pain. Furthermore, daily treatment with either low frequency or high frequency TENS in animals with knee joint inflammation produces tolerance to TENS and a cross tolerance to either spinally administered - or -opioid agonists, respectively (Sluka and Chandran, 2002). Thus, TENS is ineffective if morphine tolerance is present and shows opioid tolerance with repeated use. It might be possible to enhance the analgesic effects of TENS clinically if given in combination with certain agonists or antagonists. Either high or low frequency TENS is more effective in reducing primary hyperalgesia if given in combination with acute administration of morphine (Sluka, 2000) or clonidine (Sluka and Chandran, 2002). Synergism between -adrenergic agonists and opioid agonists (- and -) has been shown in pharmacological studies (Fairbanks, Nguyen et al., 2000; Fairbanks, Posthumus et al., 2000). Since low frequency TENS works by activation of -opioid receptors, this enhanced antihyperalgesia is probably a result of synergistic interaction between 2-noradrenergic receptors and endogenous opioids. Use of TENS in combination with morphine or clonidine should reduce the dosage of morphine or clonidine necessary to reduce hyperalgesia and thus reduce side effects of morphine and increase analgesia. In fact, clinically, intake of opioids is reduced in patients using TENS (Rosenberg et al., 1978; Solomon et al., 1980; Smith et al., 1983; Wang et al., 1997; Ghoname et al., 1999). Further there is a reduction in nausea, dizziness, pruritis associated with morphine intake when taken in association with TENS (Wang et al., 1997). Based on the known pharmacology presented above, one could hypothesize that selective serotonin norepinephrine reuptake inhibitors would prolong the effects of low frequency TENS; combining NSAIDs with TENS could enhance the effectiveness of TENS, or patients taking ACE inhibitors for cardiac disease might have a reduced effectiveness of TENS. Therefore, understanding the neurotransmitters and pathways involved in TENS antihyperalgesia could

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help explain conflicting data with respect to the patient population studies and TENS. It will further assist the clinician in the treatment choice for a particular patient. The clinical use of TENS and further clinical outcome studies should be carefully evaluated with respect to the current medication of the patient. Combinations of commonly administered pharmaceutical agents and TENS should be addressed in a clinical population.

The clinical efficacy of TENS Several non-analgesic applications of TENS have been reported including effects on circulation (e.g. soft tissue healing) and antiemetic effects (Burssens et al., 2005; Kabalak et al., 2005). However, TENS is most commonly used for the management of both acute and chronic pain. Research on TENS for pain relief has suffered from a lack of rigorous randomized controlled trials (RCTs). Several Cochrane systematic reviews (see Table 24.1) have highlighted the common problems with research to date: small numbers of participants, heterogeneous study populations, and inconsistent or lack of details on TENS application. The majority of these Cochrane reviews have, not surprisingly, been inconclusive. Carroll et al. (2000) published a systematic review on the application of TENS for chronic pain; conditions included arthritis, low back pain, myofascial pain, and diabetic neuropathy. The authors highlighted the inadequacy of the level of reporting in the included trials which obviously renders replication impossible. They also referred to inadequate treatment durations in the majority of the studies reviewed. A more recent RCT on TENS for chronic low back pain in people with multiple sclerosis compared self-applied low frequency, high frequency, and placebo TENS (Warke et al., 2006). In contrast to previous studies, patients were instructed to apply TENS at least twice daily, for 45 minutes, and at any time a painful episode occurred over a six week time period. Changes in VAS from baseline of greater than 20 mm were interpreted as clinically important. Results showed that high frequency TENS (110 Hz) was more effective for pain relief during the 6-week period whereas low frequency TENS (4 Hz) showed a more sustained effect at the 32-week follow up; placebo effects were also observed during this trial. Although this modality is viewed primarily as an intervention for chronic pain, it is also used for acute pain conditions such as low back pain, labor pain, and postoperative pain (Carroll et al., 1997; Bertalanffy et al., 2005). TENS for labor pain is applied via two pairs of electrodes placed over the T10–L1 and S2–S4 spinal

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24.  Transcutaneous Electrical Nerve Stimulation (TENS): A Review

Table 24.1  Summary of Cochrane Systematic Reviews on TENS for pain management Authors

Condition

Number of studies meeting inclusion criteria

Khadilkar et al., 2005

Chronic low back pain

 2

Evidence is limited and inconsistent

Brosseau et al., 2003

Rheumatoid arthritis of the hand

 3

Acupuncture-like TENS helps decrease hand pain in people with rheumatoid arthritis

Proctor et al., 2002

Primary dysmenorrhoea

 9

High frequency TENS more effective than placebo; low frequency TENS no more effective than placebo

Osiri et al., 2000

Knee osteoarthritis

 7

Conventional TENS and Acupuncture-like TENS effective over placebo

Carroll et al., 2000

Chronic pain

19

Inconclusive

nerve roots to target afferent fibers coming from the uterus, cervix, and perineum. Conventional TENS is applied during contractions and Acupuncture-like TENS is applied between contractions. Early research studies on this topic demonstrated high levels of consumer satisfaction with TENS as it offers patients an active role in pain management (Bortoluzzi, 1989). However, Carroll et al.’s (1997) systematic review concluded that there was no significant effect of TENS on labor pain. Clinical trials of TENS for postoperative pain have used the incision site (i.e. painful area) and corresponding spinal nerve roots as electrode placement sites. A recent meta-analysis of the studies published on TENS for postoperative pain (Bjordal et al., 2003) highlighted the need to interpret the results of systematic reviews with a degree of caution. Bjordal and colleagues only included those studies that used what they termed “optimal” stimulation parameters whereas a previous systematic review by Carroll et al. (1996) did not impose this as an inclusion criterion. Carroll et al. concluded the majority of RCTs showed no benefit whereas the metaanalysis concluded that TENS can significantly reduce analgesic consumption for postoperative pain. From the current literature, it can be concluded that further evidence is required on the efficacy, parameterspecific effects, and indeed cost-effectiveness of TENS. Optimal stimulation parameters and treatment durations should be considered while interpreting the outcome of systematic reviews on TENS.

Summary points TENS is a safe, non-invasive modality widely used in clinical practice. TENS can be used to treat both acute and chronic pain.

Outcome

The clinical application of TENS involves a degree of trial and error in determining the most appropriate stimulation parameters and electrode placement sites. Low frequency and high frequency TENS produce analgesia through different mechanisms that primarily involve central inhibitory mechanisms. Systematic reviews have highlighted several deficiencies in TENS clinical trials including small numbers of participants, heterogeneous populations, and lack of details on TENS parameters.

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24.  Transcutaneous Electrical Nerve Stimulation (TENS): A Review

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Sluka, K.A., Bailey, K., Bogush, J., Olson, R. and Ricketts, A. (1998) Treatment with either high or low frequency TENS reduces the secondary hyperalgesia observed after injection of kaolin and carrageenan into the knee joint. Pain 77: 97–102. Sluka, K.A., Deacon, M., Stibal, A., Strissel, S. and Terpstra, A. (1999) Spinal blockade of opioid receptors prevents the analgesia produced by TENS in arthritic rats. J. Pharmacol. Exp. Ther. 289: 840–6. Sluka, K.A., Judge, M.A., McColley, M.M., Reveiz, P.M. and Taylor, B.M. (2000) Low frequency TENS is less effective than high frequency TENS at reducing inflammation induced hyperalgesia in morphine tolerant rats. Eur. J. Pain 4: 185–93. Sluka, K.A., Lisi, T.L. and Westlund, K.N. (2006) Increased release of serotonin in the spinal cord during low, but not high, frequency transcutaneous electric nerve stimulation in rats with joint inflam­mation. Arch. Phys. Med. Rehabil. 87: 1137–40. Sluka, K.A., Vance, C.G. and Lisi, T.L. (2005) High-frequency, but not low-frequency, transcutaneous electrical nerve stimulation reduces aspartate and glutamate release in the spinal cord dorsal horn. J. Neurochem. 95: 1794–801. Smith, C.R., Lewith, G.T. and Machin, D. (1983) TNS and osteoarthritis: preliminary study to establish a controlled method of assessing transcutaneous electrical nerve stimulation as a treatment for pain caused by osteoarthritis. Physiotherapy 69: 266–8. Solomon, R.A., Viernstein, M.C. and Long, D.M. (1980) Reduction of postoperative pain and narcotic use by transcutaneous electrical nerve stimulation. Surgery 87: 142–6. Somers, D.L. and Clemente, F.R. (1998) High-frequency transcutaneous electrical nerve stimulation alters thermal but not mechanical allodynia following chronic constriction injury of the rat sciatic nerve. Arch. Phys. Med. Rehabil. 79: 1370–6. Vance, C.G., Radhakrishnan, R., Skyba, D.A. and Sluka, K.A. (2007) Transcutaneous electrical nerve stimulation at both high and low frequencies reduces primary hyperalgesia in rats with joint inflammation in a time-dependent manner. Phys. Ther. 87: 44–51. Wall, P.D. and Sweet, W.H. (1967) Temporary abolition of pain in man. Science 155: 108–9. Walsh, D.M. (1997) TENS: Clinical Applications and Related Theory. Edinburgh: Churchill Livingstone. Wang, B., Tang, J., White, P.F., Naruse, R., Sloninsky, A., Kariger, R. et al. (1997) Effect of the intensity of transcutaneous acupoint electrical stimulation on the postoperative analgesic requirement. Anesth. Analg. 85: 406–13. Warfield, C.A., Skein, J.M. and Frank, H.A. (1985) The effect of transcutaneous electrical nerve stimulation on pain after thoracotomy. Ann. Thorac. Surg. 39: 462–5. Warke, K., Al-Smadi, J., Baxter, D., Walsh, D.M. and LoweStrong, A.S. (2006) Efficacy of transcutaneous electrical nerve stimulation (TENS) for chronic low-back pain in a multiple sclerosis population: a randomized, placebo-controlled clinical trial. Clin. J. Pain 22: 812–9. Wikström, S.O., Svedman, P., Svensson, H. and Tanweer, A.S. (1999) Effect of transcutaneous nerve stimulation on microcirculation in intact skin and blister wounds in healthy volunteers. Scand. J. Plast. Reconstr. Surg. Hand Surg. 33: 195–201. Woolf, C.J., Barrett, G.D., Mitchell, D. and Myers, R.A. (1977) Naloxone-reversible peripheral electroanalgesia in intact and spinal rats. Eur. J. Pharmacol. 45: 311–4. Woolf, C.J., Mitchell, D. and Barrett, G.D. (1980) Antinociceptive effect of peripheral segmental electrical stimulation in the rat. Pain 8: 237–52. Zizic, T.M., Hoffman, K.C., Holt, P.A., Hungerford, D.S., Odell, J.R., Jacobs, M.A. et al. (1995) The treatment of osteoarthritis of the knee with pulsed electrical stimulation. J. Rheumatol. 22: 1757–61.

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Mechanisms of Spinal Cord Stimulation in Neuropathic and Ischemic Pain Syndromes Bengt Linderoth, Robert D. Foreman, and Björn A. Meyerson

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reflexes that can modify the function of different organ systems. Possible effects of SCS on different organ systems when applied at various sites are illustrated in Figure 25.1. Depending on the targeted organ, the mechanisms involved may be quite different; for example, the mode of action for producing pain relief differs fundamentally when SCS is applied in neuropathic and in ischemic pain conditions (Linderoth and Meyerson, 2001; Meyerson and Linderoth, 2003; Linderoth and Foreman, 2006). In this chapter the physiological bases for the use of SCS for neuropathic pain and for ischemic extremity pain will be elucidated. There is also a short discussion regarding the use of animal models for this type of research. The putative mechanisms behind the use of SCS therapy for severe, treatment-resistant angina pectoris and for various visceral pain conditions are discussed in other chapters within Neuromodulation (for a review, see Linderoth and Foreman, 2006). For obvious reasons, the possibilities of exploring the mode(s) of action of neuromodulation in patients

Background Spinal cord stimulation (SCS) has long been utilized for neuropathic pain of peripheral origin, in ischemic pain states, e.g. peripheral arterial occlusive disease and in vasospastic conditions, and in angina pectoris. It is estimated that, at present, more than 18 000 new systems for SCS are implanted annually, worldwide. The mode of action of SCS is still only partially understood, although in recent years more data on the underlying physiological mechanisms have been published (Linderoth and Foreman, 1999, 2006; Meyerson and Linderoth, 2006). The medical profession demands knowledge of physiological mechanisms, and this is a prerequisite for the implementation of evidencebased and mechanism-directed therapies as well as for further development of the techniques used in neuromodulation (cf. Woolf et al., 1998). Depending on the level of the neuroaxis where SCS is applied, the stimulation may also affect v­iscero-somatic

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25.  Mechanisms of spinal cord stimulation in neuropathic and ischemic pain syndromes Target organ

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Figure 25.1  Besides the effects on neuropathic pain, SCS applied to different levels of the spinal cord may induce functional changes in different target organs brought about by alterations of local autonomic activity, dorsal root reflexes, or of viscero-somatic reflexes. The numbers next to the red SCS symbol correspond with the numbers listed under Organ Response. Some of these SCS-induced changes in target organ function may be utilized therapeutically (Reproduced with permission from Linderoth and Foreman (2006). John Wiley & Sons Ltd)

exposed to the therapy are limited, and such investigations therefore have to be supplemented by a­nimal experiments. In the 1970s and 1980s a number of experimental SCS studies were performed. However, the relevance of these studies is questionable because only noxious and phasic peripheral stimuli were applied. SCS was commonly applied for short periods of time (less than one minute) and with parameters different from those used clinically; more importantly, the animals were anesthetized and were normal and intact. Furthermore, the fact that SCS may be efficacious for neuropathic but not nociceptive forms of pain was not taken into account in the design of these experiments. Therefore, data derived from normal animals provide little information and may even be misleading. For example, the dynamics of the neurotransmitter change occurring in the spinal dorsal root ganglion and dorsal horn as a result of peripheral nerve injury will be missed in experiments performed on intact animals (Hökfelt et al., 1994; Ji et al., 1994; Brumovsky, 2005). Nevertheless, studies conducted in normal animals have provided us with background data that are indispensable for the interpretation of the results gathered from animal models of disease (e.g. Chandler et al., 1993). There is an on-going discussion between clinicians and basic scientists about the clinical relevance of animal data (e.g. Hansson, 2003), particularly so when a model is designed to mimic a condition like pain that cannot be assessed objectively,

but only by employing behavioral measures. One of the major problems with animal models of chronic pain is that the repertoire of behavioral signs of, or responses to, nociception is limited and biochemical alterations may be difficult to relate directly to on­going or evoked pain. On the other hand, translational pain research that implies a reciprocal approach between bench and bedside is the most effective way of promoting the further advancement and refinement of treatments (Mao, 2002). This, however, calls for the development of better animal models that more adequately mimic specific pain conditions as well as further and translational investigations to confirm animal findings in human experimental and clinical studies. When selecting an animal pain model for the study of SCS it should be recalled that this treatment modality does not appear to influence either acute or chronic nociceptive forms of pain (Linderoth and Meyerson, 1995). However, a few students in the field have claimed that, for example, the axial, lumbar component in “back pain syndromes” may be effectively amelior­ ated in spite of the fact that it is, at least partially, a nociceptive form of chronic pain (Barolat et al., 2001; Ohnmeiss and Rashbaum, 2001; North et al., 2005). Conversely, the majority of experienced clinicians consider SCS to predominantly influence the “radiating pain component” or “pain in the leg” that should instead rather be referred to as lumbosacral rhizopathy in a mixed pain syndrome (North et al., 1993). In early clinical reports on SCS it was already stated that the threshold of induced cutaneous pain was not elevated (Nashold et al.,1972). In 1975, Lindblom and Meyerson studied the perception of cutaneous mechanical pain produced using a calibrated flat forceps in patients undergoing SCS treatment. The stimulus was applied in regions both inside and outside the field of SCS-produced paresthesiae. The thresholds were significantly increased only in sites displaying hyperalgesia and allodynia. In normal skin there was no effect on the thresholds. Similar differential effects were recorded on thermal sensibility assessed by Quantitative Sensory Testing (Lindblom and Meyerson 1976; review, see Linderoth and Meyerson 1995).

Animal models of neuropathic pain Many models of nerve injury-induced “pain-like behavior” have been described (e.g. Bennet and Xie, 1988; Seltzer et al., 1990; Kim and Chung, 1992; Gazelius et al., 1996; Decosterd and Wolff, 2000). After a nerve lesion (sciatic nerve or its peripheral branches; spinal

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roots), the animals develop a change in the posture of the nerve-injured extremity as well as increased sensitivity in the hindpaw to peripheral stimuli. In fact, the principal symptom in such animals is hypersensitivity to innocuous mechanical and thermal stimuli, which can be quantitatively assessed in various ways. The most common method of evaluating the resultant tactile hypersensitivity is to determine the threshold that induces a withdrawal response to innocuous stimuli produced by prodding the lesioned hindpaw with von Frey filaments. Normal rats generally tolerate a relatively stiff filament (i.e.  30 g of bending force) without producing withdrawal while nerve-lesioned animals can develop severe hypersensitivity (similar to clinical static mechanical allodynia) that leads to a brisk withdrawal in response to the application of filaments calibrated to 2–7 g of bending force. This quantifiable “symptom” thus mimics a stimulus-evoked pain-like reaction that can be interpreted as being equivalent to the “allodynia” observed in patients with painful neuropathic syndromes. Hypersensitivity, or “allodynia,” is in fact the most common behavioral sign that serves to monitor “pain” in animal models of neuropathy, but the pathophysio­ logical mechanisms behind this phenomenon are still not fully identified or understood. Several mechanisms have been proposed to be crucial: l l l l

peripheral sensitization of A/C-fibers; activation of silent nociceptors; transition of the phenotype of A-fibers; loss of A-mediated inhibition in the dorsal horn; central sensitization; sprouting of mechanoreceptive fibers to superficial laminae in the dorsal horn, establishing contact with nociceptive neurons (however, this sprouting mechanistic theory seems less probable because of the fact that, in some animal models, the symptoms may be present shortly after the lesion); l tonic activation of descending facilitation of spinal circuitry from the brain stem; l reduction/disappearance of inhibitory functions in the dorsal horn (review, see Woolf et al., 1998). l l

In fact, if we are unable to describe in detail the pathophysiological mechanisms behind the neuropathic painful conditions, it is obvious that determining mechanisms underlying the beneficial effects of SCS on such symptoms poses a very difficult task to the researcher – and even more so to the clinician who is trying to translate the knowledge from animal data to their patients. A major concern for the experimental study of SCS effects on neuropathic pain is that not more than 20– 40%, at most, of patients with neuropathic pain present with mechanical allodynia (e.g. Hansson, 2003),

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whereas tactile hypersensitivity (allodynia) usually occurs in a much larger proportion of the nerve-injured rats. Another aspect regarding the clinical relevance of animal models of “neuropathic pain” is that these animals almost never display behavioral signs indicating the presence of ongoing, spontaneous pain. These characteristics of animal models assumed to mimic neuropathic pain should be taken into account when findings in studies using such animals are interpreted in terms of clinical signs and symptoms, i.e. when data are translated from bench to bedside.

Dorsal horn and spinal circuitry It is universally accepted that the presence of paresthesiae produced by SCS, indicating the activation of the dorsal columns (DC), is a prerequisite for pain relief. However, it has also been suggested that the tingling and vibratory sensations could be merely epiphenomena. If so, the therapeutic effects could instead be exerted via the direct activation of pathways other than the DC, notably the dorsolateral funiculus (DLF), containing pain modulating pathways connecting the brain stem to the spinal cord. However, the latter pathway is known to run rostro-caudally at a distance from an SCS electrode overlying the DCs and conceivably has higher activation thresholds than dorsal root fibers entering the spinal cord horizontally (Holsheimer, 1998). Activation of the roots would then generate segmental paresthesiae at the level of the active electrodes (Feirabend et al., 2002). A more likely mode of action is that the pain suppressive effect of SCS is produced by antidromic DC activation and that the perception of paresthesiae as a result of orthodromic signals is epiphenomenal. On the other hand, the orthodromic DC signals relayed via the cuneate and gracilis nuclei may activate brain stem circuits, eventually involving inhibitory medullo-spinal projections. The pivotal role of the DCs is further supported by the observation that preservation of somatosensory responses evoked from the painful region is, as a rule, a prerequisite for a positive effect. This is also indicated by the observation that pain associated with extensive deafferentation or direct injury of the DC fibers (where it is not possible to obtain paresthesiae at the painful site) fails to respond to SCS (Sindou et al., 2003). However, studies have noted beneficial effects in vascular pain conditions even with SCS applied below the threshold for paraesthesiae (Linderoth, 1995; Eddicks et al., 2007), but for neuropathic pain most clin­icians consider paresthesia-covering of the painful area as a requirement for a beneficial effect.

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The possibility that SCS may also inhibit nociceptive input at a segmental spinal level (Foreman et al., 1976; Chandler et al., 1993) has gained some support by the finding that the stimulation may depress a nociceptive flexor reflex both in patients (Garcia-Larrea et al., 1989) and in animals (Saadé et al., 1986). Electrical stimuli applied to the sural nerve territory induce a contraction of the biceps femoris when the intensity of the stimulation is perceived as a “pricking” pain sensation. This flexor response conceivably represents the activation of A afferent fibers. It has been demonstrated that this reflex may be attenuated by SCS. This effect seems to relate to clinical pain relief and has been proposed as an objective correlate to SCS efficacy. This relationship, however, is difficult to reconcile with the fact that SCS does not otherwise influence either novel acute pain or evoked, experimental pain resulting from A-fiber activation. In order to explore the mechanisms behind the SCS effects in neuropathic pain a number of studies have been performed by our research group at the Karolinska Institute, Stockholm, using “models of mono­ neuropathy,” i.e. rats with injury of the sciatic nerve or its branches resulting in hindpaw hypersensitivity (Meyerson and Linderoth, 2003, 2006). A miniaturized SCS system is implanted into these animals and the effect of stimulation on evoked pain is monitored in the awake, freely moving animal. It has been demonstrated that in some of the rats SCS may effectively suppress the hypersensitivity in a way that mimics the SCS effect on hypersensitivity seen in patients (Harke et al., 2005). Thus, SCS applied for 20–30 minutes with stimulus parameters similar to those employed clinically may lead to a significant elevation of the abnormally low withdrawal threshold to innocuous mechanical (von Frey filaments) and thermal stimuli after nerve injury, and this effect outlasts the SCS for up to one hour. There is much evidence that the phenomenon of tactile allodynia is mediated mainly via low threshold A-fibers and that it is associated with a state of central hyperexcitability (Woolf and Doubell, 1994). The plasticity changes in the spinal cord following peripheral nerve injury are manifested by persistently augmented responsiveness and a high degree of spontaneous discharge of primarily wide-dynamic-range dorsal horn neurons. In acute experiments we have demonstrated that SCS may induce a significant and long-lasting inhibition of both the after-discharges and the exaggerated principal response in such neurons in nerve-lesioned rats (Yakhnitsa et al.,1999). In the clinical setting, this suppression of dorsal horn neuronal activity could correspond to the clinical benefit of SCS, not only on allodynia, but also on the spontaneous neuropathic pain. These observations suggest that SCS

may preferentially influence A-fiber-related functions. This notion is further supported by the finding that the threshold of the early component of the flexor reflex, which is A-fiber-mediated, is elevated whereas the late C-fiber-dependent late phase is unaffected by SCS in nerve-injured animals (Meyerson et al., 1995). It has also been reported, however, that the C-fiber flexor reflex can be significantly attenuated, but this observation was made in normal, intact animals (Saadé et al., 1986). Recently, it has been shown that SCS significantly decreased the duration of long-term-potentiation (LTP) response to C-fiber activation from about 6 hours to 30 minutes (Wallin et al., 2003). It should be noted that in these experiments only the sensitized C-fiber response was influenced while neither the normal C- nor A functions were affected. The mechanisms involved in the phenomenon of cutaneous hypersensitivity and ongoing pain as a result of nerve injury are incompletely understood, and the emphasis on large, low-threshold fiber-related functions as pivotal for explaining the effect of SCS is necessarily an oversimplification. It might well be that the mode of action of SCS relates more to, for example, sensitized or awakened nociceptors, a generalized state of central sensitization, descending spinal facilitation, etc. The conceptual basis for SCS presupposes antidromic activation of ascending dorsal column fibers and this implies that the region of action is segmental. Our experimental data have supported this interpretation but a research group in Beirut has provided evidence that, instead, the major effect may be exerted via a supraspinal loop (El-Khoury et al., 2002; Saadé et al., 2006; see also review: Saadé and Jabbur, 2008). Ongoing experimental collaborative studies (American University of Beirut and Karolinska Institute, Stockholm) suggest that the segmental and the supraspinal modes of action operate in concert.

Possible transmitter mechanisms involved in SCS For obvious reasons, the application of electric current onto the dorsal aspect of the spinal cord activates a host of transmitter–receptor systems and little is known about which ones are critically involved in the attenuation of chronic, neuropathic pain. Human data from analyses of lumbar CSF in conjunction with SCS are sparse and inconclusive. It appears, however, that opioid mechanisms conceivably are not involved. There is some evidence that the substance P (SP) content in human CSF and the spinal release of SP and

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serotonin in cats tend to increase as a result of SCS (Meyerson et al., 1985; Linderoth et al., 1992). It might well be, however, that the SCS-induced changes of SP are not necessarily related to its pain-relieving effect. In a series of acute experiments using microdialysis in the dorsal horn of nerve-lesioned rats we have demonstrated that SCS reduces the release of excitatory amino acids (glutamate, aspatate) and at the same time the GABA release is augmented (Cui et al., 1997a). It is of special interest that this effect on the GABA system occurred only in rats that in preceding experiments had been found to respond to SCS with significant suppression of hindpaw hypersensitivity (Stiller et al., 1996). These results confirm earlier observations that the state of central hyperexcitability manifested in the development of allodynia after peripheral nerve injury relates to dysfunction of the spinal GABA systems, and it appears that SCS may act by restoring normal GABA levels in the dorsal horn. These findings were supplemented by behavioral experiments where we showed that the allodynia-suppressive effect of SCS could be counteracted by intrathecal injection of a GABAB antagonist whereas the GABAA antagonist bicuculline was less effective. Conversely, intrathecal administration of GABA or a GABAB agonist, baclofen, markedly enhanced the effect of SCS (Cui et al., 1996). In subsequent studies it was found that rats that were non-responders to SCS, i.e. their hindpaw mechanical hypersensitivity was not attenuated, could be converted to responders with intrathecal administration of low, by themselves ineffective, doses of baclofen. The same potentiating effect was found with adenosine and it can thus be concluded that both the GABA- and the adenosine-related systems are directly involved in the pain-relieving effect of SCS (Cui et al., 1997b). These results initiated a clinical study where it was demonstrated that it is possible to enhance the SCS effect by simultaneous intrathecal administration of baclofen in low doses (Lind et al., 2004, 2008). This appears to be a relevant example of translational research enabling direct transfer of results “from the bench to bedside.” Later it was demonstrated that gabapentin, pregabalin, and clonidine may additionally have similar potentiating effects in non-responding rats (Wallin et al., 2002; Schechtmann et al., 2004). In particular, the results obtained with clonidine are of interest since it is known that the antinociceptive effect of this substance may relate to an interference with the spinal cholinergic system (Obata et al., 2005), and if so, the effect of SCS might act also via activation of such mechanisms. In fact, recent studies in the rat demonstrate the possible involvement of the cholinergic system (Schechtmann et al., 2008). In these studies, SCS-induced release of acetylcholine was demonstrated in the dorsal horn

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of rats responding to SCS while the non-responders showed no change. Further behavioural studies using i­ntrathecal antagonists indicate the pivotal importance of activation of the muscarinic M4 and M2 receptors for the SCS effect. Recent immunohistochemical studies confirm the crucial role of the M4 muscarinic receptor in response to SCS after partial peripheral nerve lesions (Song et al., 2007). In conclusion, a cascade of transmitters is probably released by SCS, and recent publications point to the complex interactions among the different neuronal circuits that may be involved in the effect (e.g. Obata et al., 2002; Zhang et al., 2005; Wang et al., 2006). Figure 25.2 depicts a tentative scheme of some essential features of the mode of action of SCS when applied for neuropathic pain. This conceptualization of SCS is incomplete, in particular with regard to the putative involvement of transmitter–receptor mechanisms. Furthermore, the model is primarily based on experiments performed on animal models with mononeuropathy but without definite signs of ongoing, spontaneous pain. Thus, such data should be interpreted with caution.

Clinical pain states associated with dysautonomia There is much recent evidence that SCS may be efficacious in complex regional pain syndromes (CRPS) (Kumar et al., 1997; Kemler et al., 2000a; Harke et al., 2005). In pain conditions associated with signs of sympathetic dysfunction (skin temperature changes, sweating, change in dermal hairing, atrophy, etc.) that may be present in CRPS of both types (reflex sympathetic dystrophy – RSD, as well as in causalgia), a sympathicolytic action of SCS may be part of the mode of action behind the pain-relieving effect (e.g. Baron et al., 1999; Wasner et al., 1999). However, these effects are only partially understood and are still a matter of controversy (Max and Gilron, 1999; Kemler et al., 2000b; Ather et al., 2003). SCS may positively influence CRPS type I that has not been responsive to sympathetic blocks (e.g. Olsson et al., 2008), although the probability of a positive effect seems more likely in patients responding to diagnostic sympathetic blocks (Kumar et al., 1997; Harke et al., 2005). The effects of SCS in ischemic states (to be further discussed below) has in many animal studies been found to depend also on antidromic activation of large diameter afferents that may result in the release of vasoactive substances. Interest has been focused specifically on the possible role of stimulation-induced peripheral release

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Figure 25.2  Schematic representation of the possible mode of action of SCS in neuropathic pain based on present knowledge derived predominantly from experiments performed on animal (rat) models of mononeuropathy. Both segmental and supraspinal mechanisms are represented. Possible supraspinal relays are not included because of insufficient knowledge about the organization of a proposed supraspinal loop. Broken arrow lines represent antidromic, and full line arrows ortodromic activation in the dorsal columns, their collaterals and in primary A-afferents. The diagram does not depict a possibly direct SCS activation of descending pathways. It is conceivable that numerous transmitters and modulators are involved in the modulation exerted by interneurons (represented by “X”). Descending control of second order neurons is here represented as both an inhibitory and a facilitatory supraspinal input. (SP – substance P; EAA – excitatory amino acids (glutatmate, aspartate); Ach – acetylcholine) (Reproduced from Meyerson and Linderoth (2006), with permission. Copyright (2006) Elsevier)

of calcitonin gene-related peptide (CGRP) (Croom et al., 1997). This type of mechanism could c­onceivably also be involved in the effects of SCS in CRPS. However, it has been argued that SCS-induced peripheral vasodilation is not a prerequisite for pain relief in CRPS I (Kemler et al., 2000b; Ather et al., 2003). Thus, in pain syndromes with signs of autonomic disturbance, SCS may hypothetically act on the symptoms in several ways: by a direct inhibitory action onto central hyperexcitable neurons (as indicated above); l by decreasing sympathetic efferent output acting on the sensitized adrenoreceptors on the damaged sensory neurons; l by reducing peripheral ischemia both by a sympaticolytic action and via antidromic mechanisms. l

This third action is related to the “indirect-c­oupling hypothesis” for dysautonomic pain conditions where the damaged afferent neurons are supposed to develop hypersensitivity to even mild hypoxia (cf. Michaelis, 2000). Some animal models of CRPS have been developed (e.g. Coderre et al., 2004; Guo et al., 2006) but their clinical significance has been questioned (Baron, 2004)

and there is as yet no data from such models where SCS has been applied.

Ischemic pain Ischemic pain is considered to be essentially nociceptive. There is considerable evidence from several studies indicating that SCS does not alleviate acute nociceptive pain (e.g. Nashold, 1977; Lindblom and Meyerson, 1995; Linderoth and Foreman, 2006). However, a beneficial effect of SCS in ischemic extremity pain is presumably due to attenuation of tissue ischemia being the primary event that occurs as a result of either increasing/redistributing blood flow to the ischemic area or of decreasing tissue oxygen demand. There are no established animal models of peripheral arterial occlusive disease that gives rise to ischemic pain. Therefore, anaesthetized normal rats have been used to study acute changes in peripheral blood flow during SCS (Linderoth et al., 1991, 1994; Linderoth, 1995; Croom et al., 1997, 1998). Cutaneous blood flow has been recorded with laser Doppler flow perfusion monitors placed on the glabrous surfaces of the hindpaws, ipsi- and contralateral to SCS. The values of blood flow were presented as the percentage of the

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Ischemic pain

basal blood flow. In addition, cutaneous vascular conductance was calculated from the blood flow value divided by mean blood pressure. Skin temperature was measured with a thermistor probe placed on the plantar aspect of the foot, distal to the footpad and next to the laser Doppler probe. This type of protocol has been used to establish underlying mechanisms with the introduction of hexamethonium, the CGRP antagonist (CGRP 8-37), adrenergic agonists and antagonists, nitric oxide synthase inhibitors, effects of sympathetic denervation, dorsal rhizotomies, and local paw cooling. These experimental studies support the notion that SCS suppresses efferent sympathetic activity resulting in diminished peripheral vasoconstriction and secondary relief of ischemic pain. In addition, evidence also indicates that antidromic mechanisms are activated by SCS intensities far below the motor threshold and that this may result in release of peripheral CGRP with subsequent peripheral vasodilation. An interesting observation is that SCS-induced vasodilation of a cooled hindpaw (25 °C) consisted of an early phase of vasodilation via activation of primary afferents and a late phase with suppression of the sympathetic efferent activity (Tanaka et al., 2003a). Which mechanism is dominant is most likely related to the activity level of the sympathetic system and possibly also to genetic and dietary differences. Later studies confirm that sensory fibers are important mediators of SCS-induced vasodilation and that at higher, but not painful, SCS amplitudes, fibers of the C-group may also participate in the effect (Tanaka et al., 2003b, 2004; Wu et al., 2006; for a review, see Wu et al., 2008). Another way to demonstrate the effects of SCS on vasospasm and ischemia is by using a skin flap model in rats (Linderoth et al., 1995; Gherardini et al., 1999). These studies were designed to explore whether preemptive SCS could increase the survival of a longterm groin skin flap and identify possible neuromediators. The superficial epigastric artery was identified and a detachable microvascular clip was used to occlude the single feeding branch to the flap. The clip was removed after 12 hours. SCS was applied for 30 minutes prior to the occlusion and they were compared to control animals. Another group received the CGRP-antagonist. After seven days, the flaps of the control groups were necrotized, but the majority of flaps in animals receiving preemptive SCS survived the 12-hour occlusion. In addition, decreased survival was observed in a group of animals receiving the CGRP-antagonist, CGRP 8-37. These results provide evidence that pre-emptive SCS may counteract ischemic conditions and that CGRP is involved in the effect. The hypothetical mechanisms behind SCS-induced peripheral vasodilation are outlined in Figure 25.3. Updated information about SCS

SCS

Afferent nerves

CGRP NO 5

STT

� 1

�

4

�

�

2

3 Sympathetic efferent fibers

Figure 25.3  A diagram illustrating effects of SCS applied to the L1–L2 dorsal columns on mechanisms that produce vasodilation of peripheral blood vessels. SCS activates interneurons that may (1) reduce the activity of spinothalamic tract (STT) cells; (2) decrease the activity of sympathetic preganglionic neurons; (3) reduce the release of norepinephrine from sympathetic postganglionic neurons; (4) activate antidromically the dorsal root afferent fibers; and (5) release CGRP and nitric oxide (NO). In addition (not illustrated) intracellular changes increasing survival probability of the target cells in the case of severe ischemia may be induced by the electrical activation (Reproduced with permission from Linderoth and Foreman (2006). John Wiley & Sons Ltd)

effects in coronary ischemia and in various types of visceral dysfunction is presented in other chapters within Neuromodulation.

Conclusions SCS may induce effects in multiple organ systems and the benefit for a certain condition may depend on (1) the site of spinal cord activated and (2) the rele­ vance of the released transmitters and other neuronal changes for a certain painful syndrome. Knowledge about physiological mechanisms behind the beneficial effects provides a cornerstone for further development of neurostimulation as well as for strategies to support the technique with receptor-active pharmaceuticals in cases with unsatisfactory response to stimulation per se (Lind et al., 2004, 2008). In order to further explore the physiological mechanisms of SCS for various painful (and other) conditions a continuous dialogue between clinicians and basic researchers is essential. Questions generated by the clinician should furnish research problems for the basic scientist who has the means to test the ideas in well-controlled systems.

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25.  Mechanisms of spinal cord stimulation in neuropathic and ischemic pain syndromes

SCS is a therapy that is effective in some pain syndromes that are otherwise resistant to other treatments, is well tolerated by patients, is minimally invasive, is reversible and, when compared to chronic pharmaco­ therapies, has fewer adverse effects. Furthermore, in some syndromes, SCS may have its primary effect by improving organ function, resulting in reduction of pain and other uncomfortable symptoms associated with the disease. We firmly believe that SCS at present is an underused treatment modality. Today, as mentioned in our introduction above, healthcare providers and the greater medical community are demanding “evidence-based” and “mechanism-oriented” therapies. This demand intensifies the need to expand our knowledge based on research aimed at further exploration of physiological mechanisms that are activated by neurostimulation.

Acknowledgments Data reported from the research groups of Karolinska Institutet and Oklahoma Health Sciences Center have been obtained with support of The Swedish Medical Research Council, several NIH funds, Karolinska Institutet Funds, and from Medtronic Europe SA.

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C H A P T E R

26

The Cost-effectiveness of Spinal Cord Stimulation Richard B. North, Jane Shipley, and Rod S. Taylor o u tli n e Introduction General Considerations About Spinal Cord Stimulation (SCS) Cost Studies Ways to Study Cost

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Immediate Cost Savings with SCS vs. Bypass Surgery A Proposed Retrospective Method of Data Collection: Simple Yet Problematic A Retrospective Cost–Benefit Analysis of Two Neurostimulation Techniques for Several Indications A Long-term Prospective Multi-site Cost-effectiveness Analysis The Second Cost–Utility Analysis in Angina Patients A Retrospective Cost–Benefit Study in Angina Patients The First Review of SCS Cost Literature A Model for Analyzing the Cost-effectiveness and Cost–Utility of SCS in FBSS Patients A National Effort to Link SCS Reimbursement with Continuous Quality Improvement The Cost of SCS in Belgium and a Comparison with The Netherlands Another Look at CRPS A Cost Description in Patients with Renal Failure and Ischemia A Retrospective Consideration of the Cost of Complications Three-way Analysis of Long-term cost–utility and Cost-effectiveness from a Crossover RCT of SCS vs. Reoperation for FBSS 6-Month RCT Comparison of SCS vs. Medical Management Healthcare Costs, Health Resources use, and Quality of Life in FBSS

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Review of SCS Cost Studies 357 The First SCS Cost Study 357 The First SCS Cost–utility Analysis  358 Modeling the Cost of Implantable Therapies in FBSS Patients 358 A Health Technology Assessment   from the Who 358 SCS vs. “Chronic Maintenance” 358 More Early Indications that SCS is Cost-effective 358 A Report Makes Claims but Withholds Vital Details 359 Problems Cast Doubt on Cost and Effectiveness Conclusions of an RCT 359 Reduction of Hospitalizations in Angina Patients Reduces Costs 360 Patients Serving as their own Controls Reveal Pay-Back Date 361 In Angina 361 In FBSS 361 Long-term Costs in FBSS Patients Who Passed vs. Those Who Failed an SCS Screening Trial 361 The Cost of SCS in Patients with CRPS 361 A Randomized Comparison of SCS Plus   Physical Therapy vs. Physical Therapy   Alone 361 A Prospective Study 362

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362 363 363 363 364 364 364 365 365 366 366 367 367 367 371

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26.  The Cost-effectiveness of Spinal Cord Stimulation

Modeling the Impact of Rechargeable Batteries on Cost How Can the Cost-effectiveness of SCS be  Optimized? Appropriate Patient Selection Appropriate Techniques Improving Equipment

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Introduction General Considerations About Spinal Cord Stimulation (SCS) Cost Studies For chronic pain syndromes, the least expensive therapy is the one that offers sufficient clinical bene­ fit to reduce the patient’s consumption of health care resources by a sufficient degree for a sufficient amount of time to recapture the cost of the therapy. An additional bonus accrues if the pain therapy pro­ vides more than symptomatic relief and improves the underlying condition that is causing the pain. How does SCS fit into this scheme? Like most medi­ cal devices, SCS incurs high up-front costs and must substantially improve the health of patients and/or pro­ duce later savings to be cost-effective. This review will show that SCS can improve a patient’s state of health, which has a direct impact on the patient’s quality of life, and lead to savings associated with a reduced consump­ tion of healthcare resources. The lifetime value of these benefits can be estimated by extrapolation. Because SCS has competition from other therapies, both interventional and non-interventional, clinicians must produce compelling evidence that it is effec­ tive and cost-effective. Thus, a search of the PubMed database using the keywords “cost” and “spinal cord stimulation” yields 61 entries, 18 of which have “cost” in the title. In contrast, a search using the keywords “cost” and “pacemakers” yields 34 citations, only one of which (a comparison of the cost of single versus dual-chamber pacemakers) includes the word “cost” in its title. Most of the pacemaker “cost” literature sim­ ply debates the merits of reusing pacemakers. Not one of the SCS reports considers recycling used equipment. What does this tell us? Primarily that pacemakers, although expensive, do not compete with other thera­ pies and, thus, invoke no cross-discipline competi­ tion for patients. In addition, no critic suggests that

Additional Considerations The Position of SCS on Treatment Algorithms The Cost Impact of Conducting a Screening Trial

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Conclusions

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References

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pacemakers must keep patients alive for decades. Instead, even modest extensions of life are deemed worth their expense. In contrast and despite the elu­ sive nature of pain (which can change location and intensity without provocation) and our inability to remember pain, SCS is criticized soundly if every patient does not maintain the pain relief reported at the start of therapy, even when the baseline pain memory is several years old (Turner et al., 2007). This chapter reviews every readily available cost study on the use of SCS to treat failed back surgery syndrome (FBSS), complex regional pain syndrome (CRPS), peripheral vascular disease (PVD), refrac­ tory angina, and spinal cord injury. The studies differ widely in design; yet, despite the fact that many clini­ cal studies include patient satisfaction with treatment as a valid outcome measure, not one adopts the soci­ etal perspective, which would analyze patient and non-healthcare costs related to the patient’s condition. In fact, it would be difficult for clinician/investigators to capture these costs, which would also be subject to a great deal of individual variability. Just as pacemakers can prolong lives, SCS can make lives worth living. Among the benefits that have been documented in patients with SCS thera­ pies are improved quality of life/ability to engage in the activities of daily living (see, for example, North et al., 1991a; Budd, 2002; Kumar et al., 2002; Blond et al., 2004), reduction in the symptoms of depression (see, for example, Burchiel et al., 1996; May et al., 2002; Kumar et al., 2006), improved neurologic function (see, for example, Budd, 2002; Kumar et al., 2002), and abil­ ity to return to work (see, for example, Bel and Bauer, 1991; North et al., 1991a; Budd, 2002). Many studies beyond those that specifically exam­ ine cost have found that SCS reduces consumption of healthcare resources (including analgesics) (see, for example, North et al., 1991a; Calvillo et al., 1998; Quigley et al., 2003; Allegri et al., 2004; De Andres et al., 2007).

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Review of SCS cost studies

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Box 26.1   

Key terms used in economic evaluations Describes costs without examining alternatives or consequences Provides a short-term snapshot Considers only monetary cost (not consequences) Considers monetary cost and monetary benefits Examines monetary cost and a variety of outcomes. When the data derive from an RCT, this is sometimes referred to as a “cost-efficacy” study A type of cost-effectiveness study that determines the least costly of therapies with similar outcomes A type of cost-effectiveness study that expresses its result in terms of life expectancy adjusted by the quality (or “utility”) of the patient’s state of health using a cost-utility ratio (the incremental cost of an intervention per QALY (see below) Incremental cost effective- Cost per success ness ratio (ICER) Incremental cost utility Cost per QALY (see below) ratio (ICUR) Quality-adjusted life year An outcome measure of a cost utility analysis; the result of adjusting life expectancy by (QALY) the quality (or “utility”) of a patient’s state of health Cost description Cost consequences Cost analysis Cost–benefit analysis Cost-effectiveness analysis Cost-minimization analysis Cost–utility analysis

Sensitivity analyses

Tests the robustness of results by varying key assumptions

Discounting

Determines present value by discounting future costs and benefits by a predetermined percentage (the discount rate can be the subject of a sensitivity analysis)

Source: North et al. (2007)

Ways to Study Cost The various means of studying the cost of an inter­ vention are defined in Box 26.1 along with explanations of “discounting” and “sensitivity analysis.” A com­ plete healthcare economic evaluation requires iden­ tifying, measuring, valuing, and comparing the costs and effects of alternative interventions (Korthals-de Bos et al., 2004). Few SCS cost studies accomplish this.

Review of SCS cost studies In this review, we have attempted to include every report that can be remotely construed as dealing with the cost of SCS. We also, for the most part, move through time, presenting the reports as they appear from 1991 through 2008 (the reasons for exceptions will be obvious).

The First SCS Cost Study In 1991, several investigators published data on a total of more than 400 SCS patients with pain of various

origins, including failed back surgery syndrome (FBSS), complex regional pain syndrome (CRPS), unstable angina, and peripheral vascular disease (PVD) (Blond et al., 1991; Claeys and Horsch, 1991; Devulder et al., 1991; González-Darder et al., 1991; Kumar et al., 1991; North et al., 1991a; Simpson, 1991; Spiegelmann and Friedman, 1991; Steude et al., 1991). The same year, Holsheimer et al. (1991) pro­ duced important work on contact combinations and on the effect of anatomic and electrode geometry (Holsheimer and Struijk, 1991), Barolat et al. (1991) published a computer analysis that shed light on the impact of electrode position and contact separation on paresthesia, and North’s investigative team reported that clear advantages could be gained through the use of multichannel stimulators (North et al., 1991b). In the midst of this flurry of activity, Bel and Bauer (1991) published the first report on the cost of SCS, which they referred to as “dorsal column stimulation.” These investigators tracked the cost of healthcare resource use in 14 FBSS patients during a two-year period starting before and continuing after the implantation of their stimulators. In these patients, SCS reduced healthcare resource expenditures (by

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26.  The Cost-effectiveness of Spinal Cord Stimulation

decreasing consumption of medication and clinical treatment time) and reduced the level of disability. Bel and Bauer concluded that these advantages more than offset the initial high cost of SCS equipment.

The First SCS Cost–utility Analysis  (published in Danish) The next year, Danish investigators published a cost– utility analysis of SCS that analyzed both the cost of SCS and its effect on quality-adjusted life years (QALYs) in 16 consecutive patients suffering other­ wise intractable angina who had received an SCS system between August 1988 and December 1989 (Rasmussen et al., 1992). The investigators compared healthcare costs the patients incurred the year before SCS implantation with costs of and following SCS treatment. Despite the fact that the patients were hos­ pitalized for an average of 9.4 days post-SCS implanta­ tion, a savings of 56 489 Danish kroner (approximately US$10 000) per year per patient accrued from a reduc­ tion in subsequent hospitalization and in non-hospital healthcare costs. Quality-of-life data gathered by iden­ tical pre/post questionnaires covering four dimensions were weighted as follows: pain  0.38, mobility  0.32, physical activity  0.17, and ability to perform activi­ ties of daily life  0.13. The patients gained an average 1.93 QALYs from SCS treatment.

Modeling the Cost of Implantable Therapies  in FBSS Patients A Health Technology Assessment from the Who In 1993, the Health Technology Assessment Infor­ mation Service (Anon., 1993), a branch of a World Health Organization collaborating center, calculated the cost-effectiveness of SCS for FBSS at various levels of efficacy and concluded that “SCS appears to be cost-effective versus alternative therapies costing US$20 000 per year or more, with 78% or less efficacy.” SCS vs. “Chronic Maintenance” A few years later, another model was published for estimating the annual cost in FBSS patients of SCS versus “chronic maintenance” (Bell et al., 1997). These investigators defined “chronic maintenance” as the typical mix of surgical procedures and non-surgical interventions offered as treatment for FBSS. Thus, the model expected chronic maintenance to start with a repeat operation and considered it probable that the patient would then receive ongoing diagnostic,

rehabilitative, and therapeutic interventions, includ­ ing additional operations. That is, the model made the reasonable assumption that the first reoperation probably would not be successful in alleviating the patient’s chronic pain. The investigators then compared the costs that would be incurred by a patient who receives chronic maintenance with the costs that would be incurred by two identical SCS patients: one who receives an externally powered radiofrequency generator and one who receives a generator powered by a primary cell battery (rechargeable batteries were not available for SCS generators at that time). The investigators acknowledged, but did not attempt to include, the dif­ ficult-to-estimate economic value of successful SCS to FBSS patients and their families, but the analysis did consider rates of successful screening and efficacy and such factors as the probable frequency of complica­ tions and parameter adjustment. Based on clinical experience at the time, any given patient had a 17% probability of failing the screening trial and reverting immediately to chronic maintenance and a 46% probability of enjoying long-term clini­ cal efficacy with SCS. Should SCS fail after implanta­ tion, any given patient would have a 15% probability of requesting system removal before entering chronic maintenance. (Failure to request system removal was presumed to imply some pain relief and, therefore, entry into chronic maintenance without another surgi­ cal procedure.) With these assumptions in place, the model pre­ dicted that the pay-back date or time to “cost neu­ trality” (the time required for effective treatment to compensate for the high initial cost of SCS and poten­ tial clinical failure) would be 4.3–5.0 years for batterydriven SCS systems and 3.2–3.7 years for systems with externally powered stimulators (radiofrequency coupled devices). The difference between the two, of course, reflected the cost of surgically removing and replacing the SCS generator upon battery depletion. Sensitivity analyses based on a 10% change in efficacy, complications, internal system battery life, and non-SCS surgical procedures revealed that only improving clinical efficacy would increase the savings associated with SCS. Thus, the model predicted that clinically efficacious SCS in FBSS patients would pay for itself within 2.1 years.

More Early Indications that SCS  is Cost-effective Two additional reports published during this period encouraged further study of the cost-effectiveness

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of SCS. In one, Devulder et al. (1997) interviewed 69 FBSS patients treated during a period of 13 years to determine outcomes and cost and reported that the average annual cost associated with SCS treatment was US$3660 per patient. The other, a simple case report, was the second publication to appear on the cost–benefit of SCS in patients with angina (all of which have been pub­ lished by European investigators because ischemia is the main indication for SCS in Europe). This report (Laffey et al., 1998) compared selected pre/post-SCS costs (equipment, hospitalization, and follow-up vis­ its) in one patient. Despite its up-front expense, SCS became cost-effective in its first year in this patient by reducing the amount of medical attention the patient required. The “win–win” referred to in the title of this report was, thus, improved health for the patient at a reduced cost.

A Report Makes Claims but Withholds  Vital Details In that same year, Midha and Schmid (1998) pub­ lished the only report to date on the cost-effectiveness of SCS as a treatment for spasticity. In its title, this publication claimed that SCS “lacks long-term efficacy and is not cost-effective” for this indication; however, examination of the article allows us to conclude that the matter remains open on both points. From 1993 to 1995, the investigators attempted to contact 29 patients who received SCS for spasticity during the period of 1986 to 1988. Of the 17 patients whom they were able to contact, the indication for SCS was spasm in 12 and spasm plus pain in 5. With apparently no follow-up data to consult, all data for this study were collected by telephone or in-person (no third-party data-collector is mentioned) and relied on patient memory for duration of symp­ tom relief after SCS implantation. The investigators note that 10 patients still had stimulators and that 7 had received more than one because of “failure of the original unit.” Because they later state that 9 implanta­ tions failed to provide relief from day one as a result of “failure of the unit,” we must assume that the equip­ ment was not the problem; instead, this immediate failure in 9/17 patients, which precipitated reim­ plantation in 7, raises doubts about the implantation technique. In these 17 patients, 14 systems were removed within a mean of 3.4 years (5 days to 7 years), in most cases because the patient experienced “an actual increase in spasticity and pain with the epidural unit,” which raises questions about the stimulation parameters used.

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Nevertheless, the investigators report that the patients achieved “symptom relief” for a mean of 6 months postimplantation (0–96 months), with the relief (of spasm) continuing in one patient. This report, Midha and Schmidt’s only SCS pub­ lication, fails to provide important data about the patients, the duty-cycle of the stimulation, the site of stimulation, and the stimulation parameters used. By 1998, most studies on the use of SCS for spasm dis­ tinguished patients with complete versus incomplete spinal cord injury, and clinicians who implanted stim­ ulators below the lesion were reporting excellent suc­ cess (see Barolat et al., 1988, for example). Since that time, Austrian investigators have published details of stimulation location and parameters that success­ fully reduce the severity of spasm in patients with traumatic spinal cord injury (Pinter et al., 2000). Thus, despite the title of Midha and Schmidt’s report, we cannot rule out SCS as a cost-effective treatment for spasm and its associated pain.

Problems with Patient Selection, Techniques, and Equipment Cast Doubt on the Cost  and Effectiveness Conclusions of an RCT  in Patients with PVD The next year saw publication of the first report on the cost of SCS in patients with critical limb ischemia (Klomp et al., 1999). This is also one of only five cost studies to date that are based on randomized control­ led trial (RCT) data (the other four are Kemler and Furnee, 2002; Andréll et al., 2003; North et al., 2007; Manca et al., 2008). In this case, 120 patients with criti­ cal limb ischemia who were not candidates for vascu­ lar reconstruction were evenly randomized to receive SCS plus conservative medical management (CMM) or CMM alone. The clinical outcomes were survival of life and limb at 2 years. During the study, the investigators collected cost data on hospitalization and inpatient rehabilitation, operative procedures, SCS implantation, professional home or nursing home care, outpatient care, medica­ tion, medical supplies, and non-medical health-related expenses. The investigators then applied a cost-minimization analysis,1 which assumes no difference in clinical out­ come. And, while by the end of the study the number of patients alive in each group was almost equal, at 40 1 

A cost-minimization analysis is considered an appropriate form of economic analysis only when the study has been powered for equivalence (which did not occur in this case) (Briggs and O’Brien, 2001).

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26.  The Cost-effectiveness of Spinal Cord Stimulation

(67%) in the SCS group versus 41 (68%) in the CMM group, a non-significant trend in the two-year amputa­ tion rate favored SCS (25 in the SCS group versus 29 in the CMM group, or 52% SCS limb survival versus 46% CMM limb survival). Also, although the investigators collected quality-of-life data with the EuroQoL (EQ-5D), which weighs patient responses against those of a sample of the general population and assigns patients a utility score based on the state of their health, the cost minimization analysis required them to ignore the slight between-group difference in the EQ5D score, which favored SCS. The mean per patient cost (adjusted for mortality) was significantly higher in the SCS group than in the CMM group (69 066 versus 52 407 1989 Dutch guil­ ders), a difference almost entirely accounted for by the 15 900 guilders cost of implanting the SCS system. The story from this study could end here, with the conclusion that SCS is not effective (and therefore not cost-effective) in these patients except for three clinically important observations that override these results. First, in order to be effective, a therapy must be offered to the appropriate patients. At the time of this study, clinicians were only beginning to use microcirculatory skin blood flow to assist with appro­ priate patient selection (Petrakis and Sciacca, 1999; Ubbink et al., 1999). The importance of this criterion was supported by the results of an RCT (Amann et al., 2003) that also provided data on the specific transcuta­ neous oxygen pressure parameters that could predict the ability of SCS to improve limb salvage (Ubbink et al., 2003). This parameter is now widely used and augmented with an additional diagnostic tool, video­ capillaromicroscopy. As Claeys et al. (2007) explained, these tests are needed “to evaluate the [patient’s] remaining microcirculatory reserve capacity likely to be exploited by SCS.” A second problem with Klomp et al.’s findings is that a large percentage of the patients had undergone sym­ pathectomy (35% SCS; 32% medical management) prior to SCS treatment. Several years prior, Linderoth et al. (1991) had reported that complete lumbar sympathec­ tomy in laboratory animals abolished the beneficial vasodilatory effects of SCS on skin and muscle tissue. In some animals, even an incomplete sympathetic den­ ervation led to partial loss of SCS’s vasodilatory benefit. This indicates that sympathectomy destroys the neural substrate that is vital for successful SCS therapy. Thus, more than a third of the SCS group might have been doomed to failure from the outset. A third problem that calls Klomp et al.’s. conclu­ sions into question is that the investigators encoun­ tered expensive problems arising from their SCS techniques and equipment. Within the first month,

three electrodes required repositioning, and an addi­ tional 13 electrodes migrated during the study period, leading to 11 repositionings and one reimplantation. Within 18 months, the batteries failed in three stimu­ lators. The investigators calculate that these complica­ tions made 8 patients (13%) experience “suboptimal stimulation.” New techniques in use today have vir­ tually eliminated electrode migration (Renard and North, 2006), and the SCS rechargeable batteries that are now available are less likely to fail than were the primary cell batteries in use in 1999. Although Klomp et al.’s study does not, there­ fore, provide useful conclusions about the costeffectiveness of SCS for critical limb ischemia, it does serve as another effective example of the importance of assessing patient selection criteria and implanta­ tion techniques and equipment when determining the “shelf-life” of a cost study. Unfortunately, journal reviewers do not always critique the patient selection criteria of the study that provides data for a cost analysis. Thus, in 2006, The European Journal of Vascular and Endovascular Surgery published a version of Klomp et al.’s 1999 study that claimed in its title that SCS is not cost-effective for patients with critical limb ischemia and is identical in its conclusion that the SCS overall treatment costs were 28% higher than was the cost of treating patients with CMM (Klomp et al., 2006). The additional infor­ mation presented in the 2006 report merely consists of tables detailing the costs that were summarized in the previous paper.2

Reduction of Hospitalizations in Angina Patients Treated with SCS Reduces Costs The only other SCS cost paper published in 1999 was an investigation into the effect of SCS on the number of acute hospitalizations for chest pain among 19 consecutive patients with refractory angina treated between 1987 and 1997 (Murray et al., 1999). For this study, the investigators compared retrospec­ tive data on hospitalizations related to chest pain or ischemic heart disease for the period from revascu­ larization (n  15) or decision against revasculariza­ tion (n  4) versus the period from SCS implantation to at least 6 months follow-up or the study’s end date (31 December 1997). On an annual per patient basis, the comparison revealed that SCS treatment caused a significant decline in the rate of hospitalization (0.97 to 0.27) and in the mean number of hospitalized days (8.3 to 2.5). The investigators estimated that reduction 2 

 For additional criticisms of Klomp’s analysis, see Hudorovic (2007).

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in hospital costs alone led to an impressive annual savings associated with SCS treatment (from 2241 £ sterling before SCS to £316 after SCS). This figure, of course, does not include the cost of the SCS system.

Patients Serving as their own Controls Reveal the SCS Pay-Back Date In Angina The cost of SCS treatment in patients with intracta­ ble angina in whom revascularization was contraindi­ cated drew the attention of New Zealand investigators the following year (Merry et al., 2001). In this study, medical resource use data were collected for three periods: the 12 months (or 18 if available) before SCS implantation, the implantation period, and the first 12 (or 18) months of SCS treatment. Eight consecutive patients were considered, but two were ruled out when it proved to be “technically impossible to implant a stimulator.” Compared with the pre-implantation period, these six patients reduced days hospitalized and healthcare resource use significantly in the postimplantation period. Conversely, the two unsuccess­ ful patients increased the number of days hospitalized and healthcare resource use after the SCS implanta­ tion attempt. The investigators concluded that the time to cost neutrality for SCS equipment in patients with intractable angina is approximately 15 months. In FBSS Returning to FBSS, Budd (2002) collected pre- and post-implantation cost data on 20 patients who were not candidates for a repeat surgical procedure. His cost calculation was based on records from general practi­ tioners and hospitals and on information provided by the patients for the year before and five years after SCS implantation. The outcomes evaluated were social benefits, employment, pain, quality of life, mobility and sleep pattern, and analgesic use. Patients were enrolled in the study for one year pre-implantation, and their previous surgical procedure took place at least two years prior to enrollment. Budd’s study analyzed the cost of SCS versus the cost of CMM. The pre-implant costs of clinical visits and hospitalization resulted in a mean annual £1954 cost of treatment. These same costs fell in the first post-implantation year, but adding the cost of equip­ ment increased this figure. Despite the increase in capital outlay caused when premature generator bat­ tery depletion occurred in 25% of patients, prompting the investigators to switch these patients to externally powered generators during the study, and other sur­ gical adjustments to the SCS equipment in 20% of the

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patients, the investigators were still able to conclude that SCS became cost-neutral after five years of treat­ ment and to predict that improvements in equipment and patient management would reduce the cost recov­ ery time to 3.4 years.

long-term Costs in Fbss Patients  Who Passed vs. Those Who Failed an Scs Screening Trial That same year, Kumar et al. (2002) published the results of a controlled cost-effectiveness study in FBSS patients. In this study, the investigators divided con­ secutive patients into two groups: 60 who passed the screening trial and received SCS systems and 44 who failed the screening trial and received CMM. During a five-year period, the investigators calculated all costs associated with diagnosis and treatment (e.g., SCS, analgesics, physiotherapy, chiropractic treatment, mas­ sage, and hospitalization for breakthrough pain) and collected data on quality-of-life outcomes. Only for the first 2.5 years did the cost of SCS treatment exceed that of CMM (reflecting the upfront expense of the SCS equipment); from that time forward, the cost of CMM exceeded the cost of SCS therapy. The cumulative cost of SCS in year-2000 Canadian dollars was $29 123 per patient, compared with $38 029 per patient for CMM. Generator replacement in the fourth year of SCS ther­ apy brought the SCS cost for that year close to (but still under) the CMM cost. When the investigators extrapo­ lated the costs over a 10-year period, the SCS cost sav­ ings “magnified.” Kumar et al. (2002) were also able to show that SCS improved the quality of life in 27% of patients, while CMM had the same benefit in 12%. In addition, 15% of the SCS patients versus none of the CMM patients returned to work. (Return to work, of course, is a problematic outcome measure, because many factors beyond health have an impact on a patient’s employ­ ment prospects.)

The Cost of SCS in Patients with CRPS A Randomized Comparison of SCS Plus Physical Therapy vs. Physical Therapy Alone Kemler and Furnee (2002) presented the first eco­ nomic evaluation of SCS in patients with chronic reflex sympathetic dystrophy (also known as CRPS) and the first in this patient group based on RCT data. The trial randomized 36 patients to SCS plus physical therapy (SCS group) and 18 to physical therapy alone (PT group). To analyze cost-effectiveness, the investi­ gators collected standard pain (visual analogue scale)

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26.  The Cost-effectiveness of Spinal Cord Stimulation

and cost data during the first year of the study (per patient costs of physical therapy and out-of-pocket expenses for each group did not differ and were excluded). To analyze cost utility, the investigators collected quality-of-life data using the EQ-5D, which weighs patient responses against those of a sample of the general population and assigns patients a util­ ity score based on the state of their health. To extrapo­ late lifetime costs from the one-year data, they chose a 67% rate of screening trial success, a 40-year patient life expectancy, a 5-year generator life expectancy, and a 30% annual complication rate. Despite the fact that only 24 of 36 SCS patients passed the screening trial, the investigators con­ ducted an intent-to-treat analysis, which kept a third of the patients in the SCS group even though they had failed to progress to SCS implantation. This strat­ egy obviously reduced the overall clinical gain of the group. On the other hand, it also reduced the overall cost accumulated by the SCS group during the first year (when the expensive generators are implanted). Despite this effectiveness handicap, the SCS group reported significantly more pain relief and gained sig­ nificantly more QALYs than did the PT group. The per patient cost (in 1998 Euro) of the SCS group was 9805€, that of the PT group was 5741€, and, as could be expected, that of the 24 patients who actually received implanted systems was 12 721€. The investigators also discounted cost-effectiveness at a rate of 3% per year and conducted sensitivity analyses that varied the discount rate (0–10%), implantation rate (67–100%), life expectancy (2–50 year), pulse generator life (1–7 years), and complication rate (30–50%), and reduced the routine cost of treating CRPS patients to zero. Kemler and Furnee concluded that SCS would become and remain less expensive than CMM after three years. Over a lifetime, the per patient cost of SCS would be 60 000€ less than CMM. Only if the genera­ tor failed within one year or the patient died within 2 years would SCS be more expensive than CMM. While these are obviously good results for SCS, two points about the lifetime analysis are worth noting: first, in our experience, most SCS complications occur during the first year, which means that the complica­ tion rate could reasonably be expected to diminish over time, and second, the investigators extrapolated QALY gains to death without considering how long a patient might remain in a specific state associated with a specific utility score (see, for example, Taylor and Taylor [2005], below). Finally, although the investiga­ tors account for the fact that only 24 of 36 patients in the SCS group actually received an implanted system when they chose the complication percentage for life­ time extrapolation, and they did tabulate the one-year

cost data for the 24 patients, they did not provide oneyear pain data or QALYs for this sub-group or other­ wise adjust for the presence of 12 non-SCS patients in the SCS group in the lifetime analysis.

A Prospective Study Three years later, Harke et al. (2005) published a report on 29 patients severely disabled by CRPS who were enrolled in a trial of SCS treatment from 1995 to 2001. In this group, the average cost of the implanta­ tion procedure including hospitalization was €11 844, which is comparable with the €12  721 reported by Kemler and Furnee (2002, see above). What Harke et al. termed “aftercare charges” (follow-up, correction of electrode migration, device reimplantation, and hospitalization, which would be roughly compara­ ble with Kemler and Furnee’s “complications” cat­ egory) amounted to €1335/patient/year, a little more than 10% of the implantation cost (versus the 30–50% assumed by Kemler and Furnee). Harke et al. reported significant reduction in pain as well as significant improvement in functional ability in these patients at a mean follow-up of nearly 3 years.

Immediate Cost Savings with SCS vs.  Bypass Surgery In 2003, investigators (Andréll et al., 2003) published a report on the cost-effectiveness, complications, mor­ bidity, and causes of death in the Danish RCT of SCS versus coronary artery bypass surgery for patients with otherwise intractable angina (Mannheimer et al., 1998). In this “ESBY” (Electrical Stimulation versus Coronary Artery Bypass Surgery in Severe Angina Pectoris) study, the only gain anticipated from either treatment was symptom relief; thus, 53 patients were randomized to SCS versus 51 to receive a bypass. Similar symptom relief was noted in both groups, but the SCS group experienced significantly lower mortality and cerebro­ vascular morbidity. Contrary to the case among patients with FBSS, among this group of patients with coronary artery dis­ ease, the initial cost of SCS was lower than the cost of the standard, alternative treatment (bypass surgery). Even though follow-up interventions cost more in the SCS group than in the bypass group, the overall cost of SCS treatment was significantly lower than that in the bypass group. Fewer SCS patients than bypass patients died (5 SCS, 10 bypass) or had a cerebrovas­ cular event, but these differences were not statistically significant. No SCS patient death could be attributed

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to SCS implantation, but 4 of the 10 bypass patient deaths (Ekre et al., 2002) could reasonably be attrib­ uted to the bypass surgical procedure. Crossover (deemed medically necessary) occurred in 5 SCS patients and 5 bypass patients. Of 57 patients who received SCS systems, 48 reported symptomatic relief. Reporting beyond the two-year period, the inves­ tigators noted that the average life of the pulse genera­ tors was 3.3 years and that 17 were replaced within five years of implantation. Of these, three were replaced within the two-year study period due to battery deple­ tion and one due to pulse generator pocket infection. All other SCS complications were minor.

a Proposed Retrospective Method of Data Collection: Simple Yet Problematic Collecting cost data is a time-consuming, often tedious, and complicated process. In recognition of this, Willis (2003) proposed a simple method that clinicians could use to collect therapeutic- and costeffectiveness data. In this system, cost benefit is achieved when a 50% reduction occurs in a “composite use parameter” that calculates the number of visits to healthcare facilities per month pre- and post-implant. The conspicuous absence of consideration of the cost of medication contributes to the simplicity of this measurement scheme but might also skew the results. Willis applied his idea to a consecutive series of 89 SCS patients (diagnosis not noted), and the third-party interviewers were able to contact 60 with a mean 5.8 years post-implant. Of these, 55 provided enough information to determine therapeutic outcome (36 met the criteria for clinical success) and 50 to deter­ mine cost outcome (39 met the criteria for cost–benefit success). Combined success was achieved by 25 of the 48 patients who provided sufficient data. If the 41 patients who could not be contacted are ruled entirely out of the consideration, we can conclude that SCS is successful and cost-effective. Obviously, however, if these patients were all costly failures, this assumption would fail. Hospital records indicated that the group of those lost to analysis versus those who provided data did not differ in terms of demographic or out­ come parameters, but we do not know how long the hospital records followed the patients. The short-comings of this method are that (1) it relies on patient memory to collect data on contacts with healthcare personnel over a period of several years pre-implant and (0.13–8.1 years) post-implant; (2) it gives each cost category (from physician visits to surgical procedures) the same weight; and (3) it

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expresses some cost categories as a per month aver­ age and others as a per year average. In addition, every patient–healthcare system encounter does not incur the same cost. Nevertheless, the findings are in line with those of other studies, and the methods call attention to the difficulty of data collection.

A Retrospective Cost–Benefit Analysis  of two Neurostimulation Techniques  for Several Indications The next year, investigators from the Cleveland Clinic (Mekhail et al., 2004) published a retrospective review of data from 222 consecutive patients who were treated with neurostimulation at a single facil­ ity between 1990 and 1998. This review does many things right (including using a disinterested thirdparty to contact the patients). Unfortunately for our purposes, however, the report combines data from patients receiving a variety of treatments (168 SCS, 20 PNS, and 8 both) for several different indications (FBSS, CRPS, PVD, polyneuropathy and plexopathy, mononeuropathy, and post-herpetic neuralgia). The investigators examined medical records for demographic information and to determine per patient reimbursements for screening trials, outpati­ ent and inpatient implantations, generator replace­ ments, electrode revisions, system removals, and short-term follow-up visits. In addition, 128 patients completed a 57-item questionnaire that relied on patient memory (the authors acknowledge this to be a threat to validity) to detail healthcare resource use from the year before implantation through the year after. After calculating the net pre-/post-implantation differences, the investigators modeled the data to year 2000 Medicare Fee Schedule and Healthcare Financing Administration cost data. Excluding pharmacotherapy and the anesthesia fee, the mean per patient reimbursement for neuros­ timulation was US$38 187. This study concluded that by reducing demand on healthcare resources neuros­ timulation led to a net annual saving of approximately $17 900 per patient.

A Long-term Prospective Multi-site  Cost-effectiveness Analysis A prospective analysis, of course, obviates some of the problems native to a retrospective analysis, such as the ones reviewed above, and the following year French investigators (Blond et al., 2004) reported the results of a prospective cost–benefit analysis of SCS for

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FBSS. Despite the extra burden created by conducting a multi-site study (nine hospitals), the investigators col­ lected cost and pain data from 43 patients before SCS treatment and at 6, 12, and 24-month follow-up points. At 24 months the investigators reported a 70% success rate for sciatica, a 29% success rate for low back pain, and a 39% improvement in the mean quality-of-life score. In addition, SCS reduced the cost of pain treat­ ment by a mean 64% per patient per year. Like many SCS cost studies, this does not include the cost of screening patients, some of whom are expected to be screening failures (although, of course, the screening cost is less than that of implantation of an SCS system).

The Second Cost–Utility Analysis  in Angina Patients In 2004 Rasmussen et al. conducted their second cost–utility analysis based, this time, on cost and qual­ ity of life data from 18 consecutive intractable angina patients who had undergone transcutaneous electric nerve stimulation (TENS) for 2–11 months prior to SCS implantation. Data on the cost of medical treat­ ment (including all hospitalizations for whatever reason) were gathered from medical records and a national database for the year prior to TENS treatment and the year after SCS implantation. By the year before TENS, the patients had exhausted all expensive treatments, including coronary artery bypass grafting and angioplasty. The analysis assumes that the costs occurred during the year before TENS would be similar to those the patients would incur for the duration of their lives if they did not receive SCS treatment. (Cost data for the TENS period were collected but not included in the analysis to permit comparison with the 1992 study [see above], where the patients did not undergo TENS. In another depar­ ture from their previous study, the current patients were hospitalized for an average of 2.4 days post SCSimplantation as opposed to the average 9.4 reported in 1992.) Data on quality of life were gathered via iden­ tical questionnaires at baseline (before TENS) and one year post-SCS implantation. As in the previous study, the investigators report that SCS reduced the number of hospitalizations and other medical expenses. In Danish kroner, the total medical costs were 150 547 for the year before TENS; 62 594 for implantation of the SCS system, and 52 156 for the year after SCS. It is obvious that even includ­ ing the cost of implantation, the cost of SCS treatment was recovered in the first year in these patients. In addition, the patients reported improvements in all dimensions of quality of life (pain, mobility, physical

activity, and ability to fulfill the functions of daily life, which, in this study, were given equal weight) and gained an average of 1.59 QALYs. The investigators conducted a sensitivity analysis to capture the impact of length of time on the cost savings, and calculated values that reflect 0, 3, 5, and 10% cost discounting. As the percentage discounted increased, the accumulated cost savings associated with SCS treatment decreased over time but remained positive. Thus, this study provides additional evidence that SCS rapidly improves quality of life and reduces health-related expenses in patients with angina.

A Retrospective Cost–Benefit Study  in Angina Patients Another study in angina patients (Yu et al., 2004) simply reviewed the medical records of 24 patients who received SCS to treat refractory angina and found that at 18 months post-implant, among the 19 patients who provided pertinent data, anginal frequency and nitroglycerin intake had decreased significantly. This was associated with a significant improvement in the patients’ mean Canadian Cardiovascular Society score. During the three years prior to SCS treatment, the median per patient annual duration of hospitalization in these 24 patients had increased from 3 to 10 days. No patient was hospitalized during the year after implan­ tation. By thus eliminating the cost of hospitalization, the cost recovery period for SCS occurred within 16 months of implantation, which the investigators calcu­ lated to be less than 40% of the generator’s life.

The First Review of SCS Cost Literature From 2004 through 2006, Rod Taylor’s health serv­ ice research group published three reports on the costeffectiveness of SCS. In the first (Taylor et al., 2004), the investigators reviewed the SCS cost literature and evaluated 14 of the studies we cover in this chapter (6 on FBSS, 5 on angina, 1 on CRPS, 1 on critical limb ischemia, and 1 on patients with spinal injury). On the basis of their review, the investigators concluded that SCS is cost-effective for FBSS, angina, and CRPS. This conclusion is undoubtedly valid, especially given the fact that Taylor’s group used an extremely strict definition of “comparator,” which did not include the popular research technique of using patients as their own controls (in the case of cost studies, by comparing pre- and post-SCS health care costs). Thus, Taylor et al. (2004) deemed 8 of the 14 studies “cost descriptions” lacking comparators. Also, the exclusion criteria used

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in this review did not consider the clinical quality of the studies – whether proper patient selection took place and proper procedures were followed – or the “shelf-life” of a report’s clinical conclusions. Instead, the “quality” of the studies was evaluated solely according to the following economic indicators: the source of the costs and whether or not the investiga­ tors conducted sensitivity analyses and cost discount­ ing calculations.

A Model for Analyzing the Cost-effectiveness and Cost–Utility of SCS in FBSS Patients In the second Taylor SCS cost study (Taylor and Taylor, 2005), the investigators estimated the cost util­ ity (incremental QALY) of SCS versus CMM for FBSS patients by developing and applying a decision-tree and modeling technique. The model quantified the pain relief achieved with SCS and CMM, imputed the associated quality of life, and considered the combination of utility and costs in (1) the short-term (two years) and (2) extrapolated over the patient’s lifetime. Application of the model relied on data from the RCT of SCS versus reoperation in patients with FBSS (North et al., 2005), an RCT com­ paring CMM versus reoperation in patients with FBSS (Fritzell et al., 2001), and a longitudinal cohort study of health-related quality of life (Fryback et al., 1993). The decision-tree adds “complications” to previ­ ously published patient outcome flowcharts (North et al., 2005). Thus, the FBSS patients start by receiv­ ing SCS screening or CMM. Next the patients who fail screening join the CMM group. With the assumption that CMM will not cause complications, the CMM group further devolves into those with satisfactory pain relief and those without pain relief. In contrast, the SCS patients form four groups based on complica­ tions (or none) and pain relief (or not). In addition to the conservative assumption that CMM does not cause complications versus an esti­ mated 18% annual SCS complication rate, the investi­ gators assumed that the patients in each group have an equivalent probability of survival (even though the majority of the CMM patients would continue to experience unremitting pain, which could easily translate into behavior that further deteriorates their health and shortens their life). The investigators fur­ ther assumed that 80% of patients undergoing an SCS screening trial would receive implanted systems, and that any pain relief achieved with CMM would not be lost over time versus a 6% annual reduction in the number of SCS patients reporting satisfactory pain relief. These assumptions, of course, deliberately and properly underestimated the cost-effectiveness of SCS.

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The utility values of 0.83 for satisfactory and 0.59 for unsatisfactory pain relief (on a scale where 1.0 is perfect health and 0 is death) and a utility loss of 0.05 for each SCS complication were derived using previ­ ously published methods (Malter et al., 1996) and vali­ dated using individual patient data from an RCT of SCS versus CRPS (Kemler et al., 2000). The Taylors used Kumar et al.’s study (2002) to determine costs (translating Canadian year 2000 dollars into 2003 Euro values), conducted a series of sensitiv­ ity analyses to test uncertainties, and followed stand­ ard discounting guidelines. Based on this analysis, SCS proved to be more effective, but also more expensive, than CMM during the first two years of treatment. Over the patient’s lifetime, however, SCS became both more effective and less expensive. As might be expected, the cost-effectiveness of SCS was highly sensitive to clinical effectiveness and to the complication rate. An additional assumption included in a tabulated list of parameter values was that the SCS generator battery life would extend for only four years. Thus, the investigators used a four-year cycle during the SCS lifetime analysis, which meant that an SCS patient’s specific cost and utility value would change only once every four years after the first two-year period; a CMM patient’s category (satisfactory or unsatisfactory pain relief) would remain the same as their two-year outcome. This means that an SCS patient with a com­ plication would be assigned the lower utility score associated with that complication for an entire fouryear period, even though the complication might be resolved quickly. Another way of handling the occur­ rence of complications would be to allow complica­ tion resolution immediately to place the patient in a higher utility state; this would require a much shorter time cycle. At any rate, as they continue to refine their model, the Taylors will have to revisit their decision about the length of this cycle in light of the (presum­ ably) greatly extended life of SCS generators with rechargeable batteries, a development that we expect will improve the cost-effectiveness of SCS.

A National Effort to Link SCS Reimbursement with Continuous Quality Improvement We will detour from our discussion of Taylor et al.’s work to consider another report published in 2005 that, instead of describing a study, explains how the Dutch national health insurance continuous quality improvement system became linked with a method of payment for SCS treatment (Beersen et al., 2005). SCS was introduced in The Netherlands in 1970. By 1994, reimbursement problems limited SCS access to

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only a few patients. This situation inspired a group of clinicians to form the Dutch Neuromodulation Group (DNG), which promoted high quality patient care and advocated for a structured method of SCS reimbursement. The DNG struck a bargain with the national insurance board: if the DNG developed a quality system applicable to a national neuromodula­ tion network, the insurance board would support SCS reimbursement. To fulfill its side of the bargain, the DNG had to justify the high up-front cost of SCS while simulta­ neously instituting a formal quality assurance and accountability system that would ensure continuous improvement and monitoring (as opposed to conduct­ ing a simple health technology assessment exercise). After adopting the parameters of a quality assur­ ance system from the industrial sector, the DNG ini­ tiated a process to standardize the SCS treatment protocol. This necessitated the collection of data on variations in practice, outcomes (including critical decision points and factors that could influence out­ comes), and cost. On the quality-of-care front, comparisons of prac­ tices among various treatment centers led to a series of discussions that culminated in a determination of best practices and formulation of performance indicators. The DNG then created a neuromodulation founda­ tion to oversee continuous quality improvement and conduct on-going collection, analysis and reporting of data. While each hospital in The Netherlands has permission to offer SCS, the foundation will control which hospitals participate in the continuous quality improvement effort and, thus, receive reimbursement for SCS (at a minimum, participating hospitals must treat six SCS patients annually). Recognizing that every potential SCS patient does not receive and/or continue the therapy, the DNG col­ lected prospective cost data from the national database as well as profiles of each patient considered for SCS (whether or not the patient proceeded to implantation) from each treatment center that offered SCS. Patients were followed for up to 18 months post-implantation, when applicable. This protocol yielded information on 344 patients in the intake phase: 233 underwent a screening trial and 165 received an implanted system. The DMG included not only direct treatment costs but also the costs of running the continuous quality improvement system, SCS-specific equipment, and medical continuing education. Based on these data and information on the (differ­ ent) unit costs of general and teaching hospitals, average costs could be derived for each item considered. The result of using average costs to reimburse facilities for SCS treatment would be to inspire the hospitals to

reduce the incidence of complications that can drive up costs beyond the reimbursement levels, which were set at €5793 for a teaching hospital (€4647 for a general hospital) during the intake and screening trial phase, €19 921 for a teaching hospital (€11 481 for gen­ eral) for implantation through the first year, and €1667 for a teaching hospital (€1312 for general) for the postyear-one follow-up period. The report makes no effort to show that SCS reduces the medical expenses the patients would oth­ erwise incur over time and does not mention clinical effectiveness. Instead, the authors simply note that some patients will drop out after implantation and others will use SCS indefinitely.

The Cost of SCS in Belgium and a Comparison with The Netherlands In 2005, researchers from Belgium and The Netherlands (van Zundert and van Kleef, 2005) reviewed the incidence of and treatment options for low back pain. In Belgium, in 1999, the per patient cost of SCS was €9150. This was the highest interven­ tional pain management per patient cost for that year (followed by intrathecal drug delivery at €6992); how­ ever, the authors provided no information about the duration of SCS treatment (i.e., how many patients might have achieved cost neutrality) or the incidence of complications. In 1999, the number/1000 residents of Belgium treated with SCS was 0.02 (n  233) versus 0.001 (n  89) in the Netherlands. Thus, the formation of the Dutch Neuromodulation Group (see above) was obviously a matter of urgency.

Another Look at CRPS In 2006, Taylor’s team (Taylor et al., 2006) pub­ lished the result of a systematic review of the clinical literature on SCS for CRPS, including a discussion of prognostic factors and Kemler’s economic evaluation (Kemler and Furnee, 2002, see above) that Taylor et al. had reviewed in 2004. It is not surprising, given that this paper itself is a systematic review, that Taylor’s group assigned a high level of credibility (evidence) to meta-analyses and systematic reviews in its grading scheme. Nevertheless, the investigators did not include information from the previous systematic reviews and merely referred to the conclusions of the previous work as supporting those of the present effort. An interesting aspect of this study is that Taylor et al. gave a grade of “A” to the evidence for the

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Review of SCS cost studies

effectiveness of SCS in treating CRPS I and a grade of “D” for CRPS II. “Evidence” to the contrary, how­ ever, their univariate analysis of data from all of the studies they reviewed revealed a single significant prognostic factor for the effectiveness of SCS: CRPS II patients achieved more pain relief than did CRPS I patients.

a Cost Description in Patients with Renal Failure and Ischemia Brümmer et al. (2006) included a description of the cost of SCS in their report on SCS outcomes in 8 patients with renal failure and critical lower-limb ischemia. In US dollars (presumably at the time the study was conducted, 2001–2002), the mean cost of the SCS procedure was $9750. The investigators sug­ gested that the substantial pain relief and significant reduction in analgesic use achieved by their patients justified this cost.

A Retrospective Consideration of the Cost  of Complications The cost of treating an SCS complication can exceed that of the initial implantation and, thus, has a con­ siderable impact on the cost-effectiveness of SCS (see “Appropriate techniques” below). In recognition of this, Kumar et al. published a retrospective study in 2006 that detailed the incidence and cost of compli­ cations from a series of 160 patients treated during a 10-year period (Kumar et al., 2006). The investigators gathered health service resource use from a hospital database and reported costs in year-2005 Canadian dollars (they explain why these costs are likely lower than those incurred in other countries). More than 70% of the patients in this series reported long-term (mean 41.6 months) pain relief. Of the 51 adverse events that occurred in 42 patients, 39 were categorized as hardware-related (including electrode migration, electrode fracture, and malfunc­ tion but not premature battery failure) and 12 as bio­ logical (infection or hematoma). The mean per patient cost of treating the complications was $7092 ($130 to $22 406). (The authors also reported mean per patient costs of $23 205 for implantation, of $24 809 for implan­ tation including explanting failures, and of $3609 for annual maintenance.) The authors reviewed the causes of each complica­ tion reported in the literature and suggested ways to reduce the complication rate. To test their own progress in this regard, they presented a table comparing their

experience in these 160 patients with that of their entire series of 424 SCS patients treated during a 23-year period. The rate of every complication except infection decreased in the 160 patients (infection increased from 3.5 to 4.4%), but the authors nevertheless noted their intention to apply the measures outlined in the report to reduce the complication rates further. The appendix of this report details every cost asso­ ciated with SCS treatment in Canada.

Three-way Analysis of Long-term cost–utility and Cost-effectiveness from a Crossover RCT of SCS vs. Reoperation for FBSS In 2007 our investigative team published a cost study (North et al., 2007) based on data from the first 40/42 (of 50) patients enrolled in our RCT, which com­ pared the results of treating FBSS patients with SCS versus reoperation (North et al., 2005). Our cost study was the first to use RCT data in FBSS patients, and our RCT was the first to approximate real-life medi­ cal decision-making by including crossover as both an option and an endpoint signaling failure of the rand­ omized treatment. (Neither Klomp et al.’s [1999] nor Kemler et al.’s [2000] RCT protocol allowed crossover, the ESBY study permitted crossover only when the alternative therapy proved to be contraindicated.) To determine cost-effectiveness, we divided the dif­ ference in the SCS and reoperation per patient cost (from the perspective of the health services provided in a hospital) by the difference in the proportion of patients achieving success (not crossing over and reporting at least 50% pain relief and satisfaction with Randomization

19 SCS $31 530/patient

21 reop. $38 160/patient Crossover

7/14 SCS success $48 357/success

5/13 reop. to SCS success $117 901/success

2/8 reop. success $105 928/success

0/5 SCS to reop. success $260 584/0

Figure 26.1  Per patient cost of success (US$). (Note that for crossover to reoperation, the total expenditure yielded no success; division by zero is deferred) (with permission from North et al. (2007). Lippincott, Williams & Wilkins; www.lww.com)

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Mean difference in cost �$6629� (95% CI �$17 754� to $4148) P�0.234

19 SCS mean cost $31 530 SD $3782

21 reop. mean cost $38 160 SD $3932

5 failures mean cost $22 742

13 failures mean cost $19 279 8 long-term reop. mean cost $26 482

14 long-term SCS mean cost $24 179

13 reop. to SCS mean cost $26 068

5 SCS to reop. mean cost $29 375

Long-term follow-up

1 lost 6 failures 7 successes

8 failures 5 successes

7 (36.8%) successes 2.14 QALYs (SD 0.08)

1 lost 4 failures 0 successes

6 failures 2 successes

7 (33.3%) successes 2.10 QALYs (SD 0.07)

Absolute risk reduction 3.5% (95% CI �26.1� to 33%), P �0.816 Mean difference in QALYs 0.04 (95% CI �0.15� to 0.24), P �0.660

Figure 26.2  In the intention-to-treat cost-effectiveness analysis (all costs (US$) and outcomes assigned to the randomized group), SCS is dominant (more effective and less expensive) in the incremental cost-effectiveness ratio (cost per success) and the incremental cost–utility ratio (cost per QALY) (with permission from North et al. (2007). Lippincott, Williams & Wilkins; www.lww.com)

treatment) for each procedure. We obtained long-term clinical data for 38 patients; both losses had been ran­ domized to SCS (one had crossed to reoperation). To determine cost-utility, we assigned a score of 0.59 to treatment failure and 0.83 to treatment success (when 1.0 equals perfect health and 0 equals death). We assigned utility scores at crossover and at the study’s end, assumed that neither treatment group would have an inherent survival advantage, and cal­ culated the incremental QALY by integrating the time each patient spent within a particular utility during

the study. We then divided the difference in the SCS and reoperation per patient cost by the difference in the mean QALY for each procedure. By the end of the mean 3.1-year (1.6–4.7) follow-up period, 13/21 (62%) patients randomized to reopera­ tion crossed to SCS, and a significantly smaller number (5/19) crossed from SCS to reoperation. Because patients, thus, took advantage of the crossover option, we conducted three cost-effectiveness analyses that considered: (1) intention-to-treat, with costs and ulti­ mate outcomes (including successes and failures after

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Review of SCS cost studies

Mean difference in cost �$6 629� (95% CI <$17 754> to $4148), P �0.234

21 reop. mean cost $38 160 SD $3932

19 SCS mean cost $31 530 SD $3782

5 failures mean cost $22 742

13 failures mean cost $19 279

14 long-term SCS mean cost $24 179

8 long-term reop. mean cost $26 482

5 SCS to reop. mean cost $29 375

13 reop. to SCS mean cost $26 068

Long-term follow-up

1 lost 11 failures 7 successes

19 failures 2 successes

7 (36.8%) successes 2.25 mean QALYs (SD 0.09)

2 (9.5%) successes 2.09 mean QALYs (SD 0.10)

Absolute risk reduction 27.3% (95% CI 2.2 to 52.3%), P �0.038 Mean difference in QALYs 0.16 (95% CI �0.13� to 0.45), P �0.273

Figure 26.3  In the treated-as-intended cost-effectiveness analysis (all costs (US$) are assigned to the randomized group with crossover counted as a failure), SCS is dominant (more effective and less expensive) in the incremental cost-effectiveness ratio (cost per success) and the incremental cost-utility ratio (cost per QALY) (with permission from North et al. (2007). Lippincott, Williams & wilkins; www.lww.com)

crossover) assigned to randomized group; (2) treatedas-intended, with costs and outcomes including cross­ over failures (per protocol) assigned to randomized group; and (3) all costs and outcomes assigned to final treatment group. At long-term follow-up, significantly more patients randomized to SCS 7/17 (41%) versus 2/21 (10.5%) randomized to reoperation reported success from

their randomized treatment (p 0.025). Counting both losses as failures (worst case analysis), we achieved success in 7/19 (37%) randomized to SCS (all with SCS) and 7/21 (33%) randomized to reoperation (2 with reoperation, 5 after crossing to SCS). As an initial intervention, the mean cost of SCS was US$1778 more than that of reoperation. As a cross­ over intervention, however, the mean cost of SCS was

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26.  The Cost-effectiveness of Spinal Cord Stimulation

Mean difference in cost �$1 971� (95% CI <$14 045> to $10 696) P �0.754

13 reop. mean cost $36 341 SD $5782

27 SCS mean cost $34 371 SD $3060

5 failed SCS mean cost $22 742

13 failed reop. mean cost $19 279

14 long-term SCS mean cost $24 179

8 long-term reop. mean cost $26 482

13 reop. to SCS mean cost $26 068

5 SCS to reop. mean cost $29 375

Long-term follow-up

1 lost 6 failures 7 successes

8 failures 5 successes

12 (45%) successes 2.18 mean QALYs (SD 0.06)

1 lost 4 failures 0 successes

6 failures 2 successes

2 (15%) successes 2.00 QALYs (SD 0.07)

Absolute risk reduction 29% (2 to 56%), P �0.07 Mean difference in QALYs 0.18 (<0.03> to 0.35), P �0.09

Figure 26.4  In the final treatment cost-effectiveness analysis (all costs (US$) and outcomes are assigned to the final treatment group), SCS is dominant in the incremental cost-effectiveness ratio (cost per success) and in the incremental cost–utility ratio (cost per QALY) (With permission from North et al. (2007). Lippincott, Williams & Wilkins; www.lww.com)

$3307 less than that of reoperation. Thus, the mean cost of randomization to SCS (intention-to-treat) was $31 530 versus $38 160 for reoperation, which is a non­ significant differential favoring SCS (see Figure 26.1). In the intention-to-treat analysis (see Figure 26.2), which counts the five reoperation patients who achieved success only after crossing to SCS as reoper­ ation successes, the proportion achieving success and QALYs did not differ significantly between the two groups. Patients randomized to SCS did, however, achieve economic dominance by experiencing a higher

percentage of treatment success and gaining more QALYs at a lower cost. We conducted an intentionto-treat bootstrap simulation for incremental costs and QALYs, which confirmed that SCS was a less costly and more effective treatment than reoperation for these FBSS patients. The treated-as-intended cost per patient success (see Figure 26.3) was a mean $48 357 for SCS (n   7/14) and $105 928 for reoperation (n  2/8). The mean cost per success was $117 901 for reoperation patients who crossed to SCS (n  5/13). Conversely,

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Review of SCS cost studies

Incremental Cost (US$)

15000 10000 5000 0 �0.4

�0.3

�0.2

�0.1 5000 0

0.1

0.2

0.3

0.4

�10000 �15000 �20000 �25000 Incremental QALTs

Figure 26.5  This cost-effectiveness plane illustrates the results of the bias-corrected non-parametric bootstrapping (outcomes cal­ culated for 1000 random samples assumed to represent the parent population) that determined the 95% confidence intervals for the mean differences for incremental costs and effects (QALYs). The length of the lines represents the width of the confidence inter­ vals; the mean is the point where the lines cross. The probability that SCS is less costly and more effective than reoperation is con­ firmed because 59% of the results fall in the south-east quadrant (the other quadrants represent the other possible combinations of costly and effective). Also, 72% of the simulation results fall below the US$40 000 per QALY “maximum willingness to pay” costeffectiveness threshold widely used by policy-makers in the USA (With permission from North et al. (2007). Lippincott, Williams & Wilkins; www.lww.com)

despite a mean $260 584 per patient expenditure, no SCS patient who crossed to reoperation achieved success (n  0/5). SCS achieved treated-as-intended economic dominance by achieving statistically signifi­ cance advantages in cost, outcome, and QALYs. The final treatment cost per patient success (see Figure 26.4) was $34 371 for SCS and $36 341 for reoperation. Despite this lack of statistically signifi­ cant difference in final treatment cost, the difference in outcome was statistically significant, with SCS final treatment patients experiencing a higher percentage of treatment success and gaining more QALYs at a lower cost than reoperation final treatment patients; thus, SCS achieved economic dominance. These results indicate not only that SCS is costeffective in the treatment of selected patients with FBSS (see Figure 26.5) but also that 1) SCS is most costeffective when FBSS patients forego a repeat operation and 2) reoperation is unlikely to be successful if SCS fails.  

6-Month RCT Comparison of SCS vs.  Medical Management Healthcare Costs, Health Resources use, and Quality of Life in FBSS: Predictable Results, Interesting Problems Using RCT data from the PROCESS trial (Kumar et al., 2007), Manca et al. (2008) compared SCS versus CMM in FBSS patients in terms of cost, quality of life,

371

and resource consumption from baseline to 6 months of treatment. The investigators collected data on all costs associated with SCS and CMM (e.g., screening, implantation, treatment of complications, medication, length of hospitalization, number of weeks of CMM therapy, and length and type of medication use). Costs at year 2005–2006 were determined for Canada and the United Kingdom, the two countries that provided the most patients in this multinational trial. The inves­ tigators assessed quality of life with the EQ-5D, which weighs patient responses against those of a sample of the general population and assigns patients a utility score based on the state of their health. Any careful reader of our chapter could predict the results of the PROCESS cost study. At 6 months, the cost of treating patients with SCS plus CMM was significantly higher than treatment with CMM alone. During the 6-month period, SCS patients reduced consumption of some healthcare resources (anal­ gesic medication, non-medical pain treatment) and increased the use of others (hospitalization, healthcare technology). And, at both the 3-month and 6-month point, SCS patients experienced significantly imp­ roved quality of life compared with the improvement experienced by CMM patients. The PROCESS study permitted crossover to the alternative treatment at 6 months; however, three patients randomized to CMM received trial stimula­ tors during the 6-month pre-crossover period. This intervention in these three patients was associated with hospital stays ranging from 2 to 19 days, the pur­ chase of three electrodes, and interventions lasting a mean of 70 minutes. No data are given on resource use associated with removing the screening trial elec­ trodes in these CMM patients, but one CMM patient required an electrode associated with implantation (no data are given on the cost of a generator for this patient). Thus, the CMM costs were driven up (and the clinical outcome data confounded) by violations of the study protocol. On the other hand, SCS resource use in the PROCESS trial was higher than other physicians might experience. For example, the mean duration of inpatient stay and the mean length of the intervention were more that double North’s experience. Thus, this increased resource use increased costs beyond those incurred by other clinicians. The PROCESS clinicians reduced costs, however, by performing a single imaging study (an X-ray in one patient) during the trial. In practice, North requires an MRI of the thoracic spine before a patient undergoes a screening trial (and 80–90% of the patients have not had this done before we see them). This would obviously increase the SCS-related cost (it also increases patient safety during

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insertion of the electrode, which can reduce complica­ tions and their attendant costs). Another variation in physician practice that has an impact on the cost of SCS is whether or not the trial electrode is implanted for chronic use at the time of the screening trial (as it apparently was in the PROCESS study [Kumar et al., 2007]). (See below for a discussion on the cost impact of conducing a screening trial.)

Modeling the Impact of Rechargeable  Batteries on Cost It is appropriate that we end our chapter with a review of the first published report that models the impact of rechargeable batteries on SCS costs to esti­ mate the lifetime cost of a non-rechargeable versus a rechargeable SCS system in a typical FBSS patient (Hornberger et al., 2008). This report provides yet another conceptual model of how SCS treatment “flows.” Unfortunately, the model as illustrated fails to account for a repeat SCS procedure (reimplantation) should a complication require system removal and replacement. The authors have assured us, however, that the full model takes this eventuality into account. This explains why the tabulated calcula­ tion of total costs includes replacement costs. The authors also made a few debatable assump­ tions. First, they posit that approximately 80% of patients undergoing a screening trial receive an implanted system. Yields as high as this have been reported in some clinical trials with selected patients, but the figure likely is smaller in clinical practice, in which the trial is offered more liberally and perhaps evaluated more critically (Kumar et al., 2007). Second is the comment that SCS systems are programmed to achieve at least 80% pain/paresthesia overlap (lacking a citation; again, this may be a study artifice [Kumar et al., 2007]). While 100% overlap does not occur in 100% of patients, complete overlap is and should remain our goal. Third, the age of the base-case patient is 46 years (derived from a patient population with mixed indications for SCS and peripheral nerve stimulation (Mekhail et al., 2004); this contrasts with the reported average age of approximately 50 years for FBSS patients undergoing SCS (North et al., 2005). Given the author’s assumed non-rechargeable bat­ tery life of 49 months and life expectancy of 80.2 years, a base-case age of 46 versus 50 years would lead to an additional generator replacement for battery deple­ tion and, thus, increase the life-time cost-effectiveness of the rechargeable system. The model, however, lim­ its the total number of SCS implantations to six (initial plus five replacements), which would not cover the life expectancy of the base-case patient.

In fact, however, the authors calculate that the basecase patient would need 5.9 “replacement procedures,” but our math leads to a different result (an 80.2 year life expectancy minus 46 years at first implantation equals 34.2 years of remaining life, which is approxi­ mately 408 months to be divided by the 49-month non-rechargeable battery life, which equals 8.3 batter­ ies, which means 7.3 replacements). The investigators also conclude that the base-case patient would need 2.2 replacements for a recharge­ able system, given its assumed life of 17.5 years (range 10–25), but the original implantation would serve the 46-year-old patient until age 63.5, and one replace­ ment would bring his age to 81 (exceeding his life expectancy). Taking into account these discrepancies in number of replacements required, the case for the cost-effectiveness of the rechargeable system would have been more compelling than the analysis based on these calculations suggests. The investigators conducted a one-way sensitivity analysis that predicted that cost savings found with the rechargeable system in every scenario would diminish if non-rechargeable battery life lengthened, recharge­ able life became shorter, the discount rate increased, age at first implantation increased, or life-expectancy decreased. They did not, however, examine the impact of changing their assumed calculation of the cost dif­ ferential between on-going SCS and CMM. Despite the study aim of modeling the cost of SCS with each battery type in a base-case patient, the investigators veered into an investigation of the cost of CMM after permanent removal of the system and consider the range in cost savings with the recharge­ able system to be “a consequence of the uncertainty at what state in the cycle a permanent SCS removal … trigger[s] the higher CMM …” This report, thus, is challenging to interpret in detail. Nevertheless, we agree with the conclusion that, despite increasing the time to cost neutrality, the rechargeable battery ultimately increases cost savings significantly.

How can the cost-effectiveness of SCS be optimized? In this section we consider several of the obvious ways that we can improve the cost-effectiveness of SCS.

Appropriate Patient Selection Because SCS is not effective in every patient, the cost-effectiveness of the therapy can obviously be

IVA. periphery and spinal cord electrical stimulation for non-visceral pain



Additional considerations

improved by appropriate application of the best avail­ able patient selection criteria. This does not mean that every carefully selected patient will pass an SCS screening trial or benefit from an implanted system. Appropriate patient selection does, however, reduce the overall cost associated with SCS by reducing the number of failures. Patient selection criteria should be published for every study. As we have seen, some cost studies were unfortunately based on trials that proceeded after less-than-ideal patient selection, resulting in less-thanoptimal effectiveness. Patient selection criteria are being continually eval­ uated and updated, and clinicians, investigators, and peer-reviewers alike must stay informed about all new discoveries in the application of SCS therapy, includ­ ing (and perhaps especially) how to select appropriate patients. (For a list of patient selection criteria for neu­ ropathic pain, see the SCS practice parameters [North et al., 2007]).

Appropriate Techniques Another way of improving cost and effectiveness is adjusting stimulation parameters to maximize par­ esthesia coverage and optimize battery life (North et al., 2004). Maximizing paresthesia coverage maxi­ mizes the therapeutic effect of SCS. Maximizing battery life reduces the times a patient with a batteryoperated generator must return to the operating room for a replacement (risking complications, including the loss of pain relief). The impact of rechargeable bat­ teries on cost-effectiveness, however, remains to be defined. We can also optimize cost-effectiveness by minimiz­ ing the incidence of complications, especially those, such as infection, that require removal and replace­ ment of an implanted system (Kumar et al., 2006). Meticulous attention to implantation technique can reduce complications; for example, new methods of securing percutaneous electrodes can eliminate longi­ tudinal migration (Renard and North, 2006).

Improving Equipment Improving equipment can result in cost savings if the improvement increases the number of successful patient outcomes, for example, by making the implan­ tation technique failsafe (many clinicians have noted that the implantation of electrodes with multiple con­ tacts arrayed in two columns has increased success rates among clinicians who have technical difficulty capturing the ideal stimulation target area with a single column of contacts).

373

Additional considerations The Position of SCS on Treatment Algorithms The fact that SCS is reversible and minimally inva­ sive are two assets that should yield a favorable position for the therapy on treatment algorithms. Nevertheless, because of various factors, including its high up-front cost and the existence of competing therapies, SCS has generally been reserved as a last resort (that is, the com­ peting interests have given up on these patients). Yet, as we have shown, SCS can provide greater benefits to patients than many alternatives, and this SCS advantage might be enhanced if SCS therapies begin before the treatment alternatives are exhausted. Thus, for example, SCS-eligible FBSS patients in whom yet another repeat operation is not medically necessary (e.g., to correct a disabling neurological deficit caused by remediable compression, critical cauda equina compression, or gross instability) should be evaluated for SCS before undergo­ ing another surgical procedure (North et al., 2005). The timing of SCS treatment is also of the utmost importance in patients with critical lower-limb ischemia, since SCS can promote healing only if trophic ischemic lesions have not progressed to 3 cm2 (Broseta et al., 1986; Brümmer et al., 2006). Furthermore, because it apparently treats the cause as well as the symptom of ischemia, SCS could well play an important treat­ ment role in patients suffering angina (as it does for patients with Raynaud’s disease and frostbite); thus, the indication of SCS for angina might be expanded beyond patients with otherwise intractable pain. The timing of SCS treatment should not be influ­ enced unduly by its high up-front cost or by the exist­ ence of alternative therapies. The fact that the timing of SCS influences its effectiveness (and thus its cost) argues for an earlier SCS position on the treatment continuum for angina, FBSS, and PVD. Appraisal of the impact of timing on effectiveness must continue as the indications for SCS expand (e.g., to patients with visceral disorders). In any event, an SCS-eligible patient should always have an SCS trial before undergoing an ablative ther­ apy, such as sympathectomy (see Linderoth et al., 1991) or dorsal root gangliectomy (see North et al., 1991a), which we believe destroys the neural substrate required for SCS to be successful.

The Cost Impact of Conducting  a Screening Trial One of the advantages of SCS is that it is minimally invasive and reversible; thus, it is possible to conduct

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26.  The Cost-effectiveness of Spinal Cord Stimulation

a screening trial that mimics the definitive proce­ dure. A screening trial is not used for all indications (e.g., angina, where the yield is very high, and where SCS might have a positive impact on the underlying disease state as well as on pain) but is considered a valuable patient-selection tool when SCS treatment is considered for FBSS, CRPS, and PVD. The cost-effectiveness of SCS screening trials and their contribution to the cost-effectiveness of the ther­ apy as a whole remains to be examined. In addition, we do not know the cost-effectiveness impact of vari­ ous screening trial techniques; for example, some clini­ cians routinely remove the screening electrode, which means that insertion and removal can take place in a fluoroscopy suite versus an operating room (reducing the expense) but also means that the screening elec­ trode is an additional expense. Other clinicians implant screening electrodes and anchor them surgically so that they can be used chronically; this lengthens the implantation and potential removal procedures and requires use of an operating room for both (increasing the expense) but saves the cost of a second electrode (this strategy was used in the PROCESS trial [Kumar et al., 2007]; see Table 1 in Manca et al., 2008).

Conclusions The fact that SCS studies lack homogeneity is well known and lamentable. Definitions of “success,” the choice of outcome measures and techniques, and the technical ability of implanters (which is never meas­ ured or mentioned) all can and do vary widely. We have seen how less than optimal patient selection cri­ teria (see above, Klomp et al., 1999) and problems with study design and reporting (for example, when we are left with unanswered questions about the implanta­ tion technique – see above, Midha and Schmidt, 1998) can have an adverse impact on the effectiveness of SCS and, thus, on conclusions about the cost-effectiveness of the therapy. The types of cost studies that have been conducted also vary from simple cost descriptions to full eco­ nomic evaluations, and no cost evaluation has been performed from a societal perspective. Which costs are identified, how they are measured and valued, and how the data are collected are all important fac­ tors of cost studies (Korthals-de Bos et al., 2004). In addition, SCS poses special challenges for healthcare economists who are developing models and analyti­ cal techniques for conducting economic evaluations (for example, the impact on generator life cycle of the new rechargeable batteries has to be determined and

factored into the models; the introduction of other innovative technology will require the same effort). While we await additional evidence of the costeffectiveness of SCS and the adoption of study designs for clinical trials that will facilitate cross-study com­ parisons (not because cross-study comparisons, or “meta-analyses” are necessarily helpful but because they will be performed), we can comfortably conclude that, if the best patient selection criteria are adopted and reasonable techniques are used by properly trained clinicians, SCS is cost-effective in the treatment of angina, PVD, FBSS, and CRPS. We can also conclude that the approximate times to cost neutrality are: immediate in patients who would otherwise receive coronary artery bypass surgery for symptom relief; l after one year for patients with angina who are not candidates for coronary artery bypass surgery; l after three years for patients with FBSS or CRPS. l

As we have noted, the cost-effectiveness of SCS can be enhanced in many ways. Some will involve techno­ logical development; others are already available and simply require that the right clinician apply the right techniques and implant the right equipment in the right patient.

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C H A P T E R

27

Spinal Cord Stimulation for Painful Neuropathies Giancarlo Barolat

o u t l i ne Introduction

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Diabetic Neuropathy

380

Post-herpetic Neuralgia (PHN)

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Mechanisms of Action of Neurostimulation on Peripheral Neuropathic Pain

378

Conclusions

383

General Clinical Series

379

References

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INTRODUCTION

tissue (Ropper and Brown, 2005). Common causes of acquired peripheral neuropathies include diabetes, herpes zoster infections, adverse effects of many chemo­ therapeutic drugs, electrical injuries, to name a few. Inherited forms of peripheral neuropathy are caused by inborn errors in the genetic code or by new genetic mutations (Ropper and Brown, 2005). One common manifestation of peripheral neuropa­ thy is pain. The pain of peripheral neuropathy is often characterized as burning in quality, with occasional shooting electrical-like sensations and is accompanied by loss of sensation and paresthesiae (Hughes, 2002; Ropper and Brown, 2005). The pain can become severe and can be the main presenting symptom or the only symptom of the neuropathy. Currently, no consensus on the optimal management of neuropathic pain exists and practices vary greatly, worldwide (Chong and Bajwa, 2003). Possible expla­ nations for this lack of consensus include difficulties in developing agreed diagnostic protocols and the coex­ istence of neuropathic, nociceptive and, occasionally, idio­pathic pain, all in the same patient. Also, the clinical

More than 100 types of peripheral neuropathies have been identified, each with its own characteristic set of symptoms, pattern of development, and progno­ sis. Impaired function and symptoms depend on the type of nerves – motor, sensory, or autonomic – that are damaged. Some people may experience tempor­ ary numbness, tingling, and/or pricking sensations, sensitivity to touch, or muscle weakness. Others may suffer more extreme symptoms that include burning pain (especially at night), muscle wasting, paralysis, or organ or gland dysfunction. Peripheral neuropathy may be either inherited or acquired. Causes of acquired peripheral neuropathy include physical injury (trauma) to a nerve, tumors, toxins, autoimmune responses, nutritional deficiencies, alcoholism, and vascular and metabolic disorders. Acquired peripheral neuropathies are caused by systemic disease, trauma from external agents including some pharmacologic agents such as some of the antiretrovirals, radiation-induced injury, infections, or autoimmune disorders affecting nerve

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27.  Spinal Cord Stimulation for Painful Neuropathies

perceived complaints of any one individual when com­ pared to the clinical perceived complaints of another individual with the same disease or disorder may be entirely due to differing neuropathic metabolic mechan­ isms, even though the perceived complaints are the same. Because multiple mechanisms downstream to the perception of pain upstream cause the same perceived symptoms, such as allodynia, hyperalgesia, pseudo­ motor change, vascular change, etc., it is difficult to form consensus for treatment (Woolfe and Mannion, 1999). A combined etiologic/mechanistic classification might improve neuropathic pain management. The treatment of neuropathic pain is largely empirical, often relying heavily on data from small, generally poorly designed clinical trials or anecdotal evidence. Consequently, diverse treatments are used, including relatively non-invasive drug therapies (antidepressants, antiepileptic drugs and membrane stabilizing drugs), invasive therapies (nerve blocks, ablative surgery), and alternative therapies (e.g., acupuncture). Neuropathy pain can be very difficult to treat, even with strong opioid analgesics. In general, neuropathic pain relief with opioids remains controversial. Neuropathic pain may be less responsive to opioids than other types of pain, and often requires the addition of one of the pre­ viously discussed agents to provide relief (Watson and Babul, 1998; Rowbotham et al., 2003). Several classes of medications not normally utilized as analgesics are often effective, alone or in combination with opi­oids. These include tricyclic antidepressants such as amitriptyline, anticonvulsants such as gabapentin and pregabalin, and serotonin norepinephrine reuptake inhibitors (SNRI) such as duloxetine. Antidepressants usually reduce neuropathy pain more quickly and with smaller doses than they relieve depression. The postulated mechanism of action of anticonvulsants such as gabapentin and pregabalin is by blocking ion channels in damaged peripheral neurons (Pappagallo, 2003). The anticonvulsants carbamazepine and oxcar­ bazepine are especially effective on trigeminal neural­ gia neuropathy (Bennetto et al., 2007). In peripheral neuropathies, in general, the antide­ pressants seem to be most effective on the continuous burning pain and disesthesiae, while the anticonvul­ sants seem to work best on sudden, lancinating pain attacks that might be caused by the improper firing of large numbers of peripheral nerves (Gorson et al., 1999; Ropper and Brown, 2005). In some forms of neu­ ropathy, especially post-herpetic neuralgia, the topi­ cal application of local anesthetics such as lidocaine can provide relief (Kingery, 1997). Ketamine (NMDA receptor antagonist) Gel has also been reported to be effective for treating peripheral neuropathy (Gammaitoni et al., 2000; Quan et al., 2003).

Neurostimulation has traditionally had a limited but important role in the management of neuropathic pain that has been refractory to medical treatment. Neurostimulation for painful peripheral neuropathies has taken the form of either spinal cord stimulation or peripheral nerve stimulation. No large prospective studies have been conducted on the use of neurostim­ ulation for intractable pain in peripheral neuropathies.

Mechanisms of action of neurostimulation on peripheral neuropathic pain Girlanda et al. (2000) showed that ulnar neuro­pathy could induce a rearrangement of reciprocal inhibi­ tion circuits at the spinal cord level and motor cortex excitability which could predispose to painful focal dystonia. Eleven of 12 patients studied with ulnar neuropathy showed a loss of alternation and of wellformed bursts in both flexor and extensor muscles. Evaluation of reciprocal inhibition in these patients revealed a reduction in the amount of inhibition in the disynaptic and presynaptic phases. Miki et al. (2000) found that a dorsal columnthalamic pathway is involved in thalamic hyperexcit­ ability following peripheral nerve injury in rats with experimental mononeuropathy. The findings of their study suggest that the gracile nucleus–thalamic path­ way conveys, or modulates, nociceptive information to the VPL nucleus following peripheral nerve injury, resulting in an increase in VPL nucleus response to noxious stimuli that contributes to the development of mechanical hyperalgesia. The mechanisms underlying the relief of neuro­ pathic pain of peripheral origin by spinal cord stim­ ulation (SCS) are poorly understood. Yakhnitsa et al. (1999) studied the effects of SCS on evoked and spon­ taneous discharges in dorsal horn neurons in intact and in nerve-injured rats subjected to partial sciatic nerve ligation. A significantly increased frequency of spontaneous discharge and of responsiveness to brush and pressure was found in the group of allo­ dynic, as compared with non-allodynic and control rats. The majority (63%) of the investigated neurons in these animals displayed an after-discharge phenom­ enon in response to pressure stimulation. SCS caused a significant depression of both the principal response and the afterdischarge phenomenon in the allodynic rats. These inhibitory effects on evoked responses in allodynic rats outlasted SCS by 10.5  1.7 min. In non-allodynic and control rats, SCS had no signifi­ cant depressive effects on the evoked responses and

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General clinical series

spontaneous discharge. The results of their inves­ tigation suggest that SCS may provide a suppres­ sive action on dorsal horn neuronal hyperexcitability which is associated with signs of peripheral neuropa­ thy. The suppressive effect of SCS on tactile allodynia, as previously observed in behavioral experiments, presumably corresponds to a normalization of the excitability of wide dynamic range neurons (WDRN) in response to innocuous stimuli. Meyerson et al. (1995) studied the effects of SCS on the withdrawal response and the flexor reflex in rats subjected to chronic sciatic nerve ligation. SCS pro­ duced a marked increase of the withdrawal thresh­ olds to innocuous mechanical stimuli from von Frey filament stimulation. This threshold elevation lasted for up to 40 min after 10 min of SCS. In about onehalf of the animals there was also a moderate, but short-lasting increase in threshold withdrawal of the intact leg. The degree and duration of the withdrawal threshold elevation was proportional to the intensity of SCS which was kept below motor threshold. In a second series of experiments the author studied the effect of SCS, applied acutely via a laminectomy, on the early component (latency: 8–12 msec) of the flexor reflex. As a result of nerve ligation, the thresholds for evoking the early as well as the late component in the nerve-ligated leg were significantly lower than in the intact one. SCS produced a marked and long-lasting increase of the threshold of the early component in the nerve-ligated leg. The late component, which is medi­ ated by C-fibers, was not influenced by SCS. The first component of the flexor reflex is most likely medi­ ated by A-fiber activation and corresponds to the withdrawal response induced by innocuous mechani­ cal stimuli. In the author’s opinion, the lack of effect of SCS on the late reflex component indicates that it selectively influences transmission of A-fiber activ­ ity. Cui and Linderoth demonstrated in the rat that a peripheral nerve lesion causing neuropathic pain causes an increased basal release of excitatory amino acids (glutamate and aspartate) that is due in part to a deficit in local GaBAergic function (Cui et al., 1997). One component in the pain-relieving effects of SCS may result from induction of increased GABA release, thereby also suppressing the exaggerated excita­ tory amino acids activity, possibly through activation mainly of the GABAb receptors. It is well known that not all patients with periph­ eral nerve lesions respond to neurostimulation. The reasons are unknown. Li et al. (2006) studied the effects of SCS on rats that were prepared with vari­ ous types of lesions of different branches of the sciatic nerve and then tested for paw mechanical hypersen­ sitivity. A miniature electrode system for SCS was

implanted at the T10–T11 vertebral level. Stimulation was applied in awake, freely moving animals with parameters comparable to those employed clinically. Suppression of paw hypersensitivity was considered a positive response to SCS. The incidence of mechanical hypersensitivity (“allodynia”) in the different models was: sciatic nerve injury, 53%; peroneal axotomy, 45%; tibial axotomy, 68%; tibial tight ligation, 73%; and par­ tial tibial tight ligation, 50%. The response to SCS dif­ fered between models with the lowest response rate in the original sciatic nerve injury model (8%) while the others demonstrated rates in the order of 40–50%. There was a tendency for the efficacy of SCS in sup­ pressing allodynia to be inversely related to the sever­ ity of the hypersensitivity. The authors concluded that different types of nerve lesions can generate different types of neuropathic pain with different susceptibility to neurostimulation. Ellrich and Lamp (2005) demon­ strated in an elegant study that electric stimulation of peripheral A-fibers reliably suppresses A-fiber noci­ ceptive processing in human volunteers.

General clinical series Ebel et al. (2000) treated 6 patients suffering from pain of complex regional pain syndrome (CRPS), type II, secondary to nerve injury with either periph­ eral nerve stimulation (PNS) or SCS with a mean follow-up of 39.5 months. Evaluated by visual ana­ logue scales, all patients reported good to excellent pain relief (75–100%). The authors concluded that PNS was better indicated in cases of mononeuropathic pain syndromes, whereas neuropathic pain syndromes that were not assignable to a singular nerve lesion, can often be managed more effectively by SCS. Kim et al. (2001) compared the outcome of SCS in 122 patients with nonspecific limb pain versus patients with neuropathic pain syndromes and in patients with spon­ taneous versus evoked pain. All patients first under­ went a trial of SCS with a monopolar epidural electrode. Seventy-four patients had a successful trial and under­ went permanent implantation of the monopolar elec­ trode used for the trial (19 patients), or a quadripolar electrode (53 patients), or a paddle-type quadripolar electrode via laminotomy (2 patients). Of the 74 patients, 60.7% underwent implantation of a permanent device and were followed for an average of 3.9 years (range, 0.3–9 years). Early failure (within 1 year) occurred in 20.3% of patients, and late failure (after 1 year) occurred in 33.8% of patients. Overall, 45.9% of patients were still receiving SCS at latest follow-up. Successful SCS (50% reduction in pain for 1 year) occurred in 83.3%

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of patients with nonspecific leg pain, 89.5% of patients with limb pain associated with root injury, and 73.9% of patients with nerve neuropathic pain. SCS was less effective for the control of allodynia or hyperpathia than for spontaneous pain associated with neuropathic pain syndromes. Third-party involvement did not influence outcome. Kumar et al. (1996) reported their experience with epidural spinal cord stimulation in 30 patients diag­ nosed with peripheral neuropathy. The mean age of the 16 men and 14 women in the study was 62.4 years. The anatomic sources of pain included thorax, as well as upper and lower limbs. Causes of intractable pain included post-herpetic neuralgia, intercostal neuralgia, causalgic (CRPS II) pain, diabetic neuropathy, and idi­ opathic neuropathy. Nineteen patients reported relief of pain with trial stimulation and had their systems permanently implanted. At an average of 87 months’ follow-up, 14 of the 19 (74%) patients achieved longterm success in control of chronic pain (47% of all patients included in this study). Six patients reported excellent pain relief (75% pain relief), eight described good results (50% pain relief), and six had poor pain relief (50% pain relief). The authors concluded that SCS is an effective therapy for pain syndromes asso­ ciated with peripheral neuropathy. Pain of causal­ gia (CRPS II) and diabetic neuropathic pain seemed to respond relatively well, whereas post-herpetic pain and intercostal neuralgia syndromes seemed to respond less favorably to SCS. Eisenberg et al. (2004) conducted a retrospective study to carefully assess the long-term efficacy and safety of PNS in the treatment of painful nerve inju­ ries. Patients suffering from intractable pain due to peripheral nerve injuries underwent PNS after care­ ful selection. Long-term results were evaluated based upon patients’ reports of pain intensity on a visual analog scale (VAS) and their consumption of anal­ gesics. Two categories of results were chosen: good, referring to 50% or more relief of pain with abstinence from analgesic medications; and poor, with less than 50% improvement. Of 154 referred patients, 46 (26 women and 20 men) were found suitable for PNS. Four etiologic factors for nerve pain were identified, the most common being nerve lesion following an operation in the region of the hip or knee. Other etiol­ ogies for nerve pain included entrapment neuropathy, pain following nerve graft, and painful neuropathy following a traumatic injection. The follow-up period in this study was 3–16 years. Of the 46 patients who underwent implant of a peripheral nerve stimulator, the results were classified as good in 36 (78%) patients and as poor in 10 (22%) patients. The pain intensity dropped from a VAS of 69  12 before surgery to

24  28 postoperatively (p 0.001) in the 36 patients with good results. Novak and Mackinnon (2000) eval­ uated the usefulness of an implanted peripheral nerve stimulator in patients with pain following injury to a peripheral nerve. The patient sample consisted of 7 men and 10 women with a mean age of 48 years. The mean follow-up time since implantation of the stimulator was 21 months. Workers’ compensation and/or litigation were involved in 11 of the 17 cases. Peripheral nerve stimulators were placed in the upper extremity in 12 patients and in the lower extremity in 5 patients. Pain relief following implantation was rated as excellent by 5 patients, good by 6 patients, fair by 4 patients, and poor by 2 patients. A statistically significant decrease in reported pain level was found postoperatively (p 0.0003). There was no statisti­ cally significant difference in postoperative pain level between men and women (p  0.30), between cases involving workers’ compensation or litigation and those not involving these issues (p  1.0), or between patients who received an upper-extremity implant and those who received a lower-extremity implant (p  0.56). Of the 12 patients who were unable to work before the operation, 6 returned to work after the operation. The authors concluded that peripheral nerve stimulators can be useful in decreasing pain in carefully selected patients with severe neuropathic pain following nerve injuries. Murphy et al. (1998) reported the case of a 47-year-old man with peripheral neuropathy secondary to celiac disease. The patient had an 11-year history of gener­ alized aches and pains in the lower limbs which had become more symptomatic and shooting in character. During the previous year he suffered from nausea, vom­ iting, and weight loss, and a subsequent jejunal biopsy specimen yielded a diagnosis of celiac disease. Nerve conduction studies showed no evidence of large fiber peripheral neuropathy. A one-year trial with glutenfree diet as well as pharmacological therapy with intra­ venous lidocaine and oral gabapentin was unsuccessful in treating this patient’s pain. In view of his ongoing symptoms and decreasing physical function, a spinal cord stimulator was implanted. The position of the lead was not reported in the manuscript and neuropathic pain relief was assessed by visual analogue scale. Pain was reduced by about 60–70%, and within two months the patient was able to return to full employment.

Diabetic neuropathy An estimated 10–65% of patients with diabetes have some form of peripheral neuropathy (Galer et al., 2000).

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Diabetic neuropathy

Neuropathy is present in 7.5% of patients at the time diabetes is diagnosed. About 50% of patients exhibit distal symmetric polyneuropathy, and 25% have com­ pression or entrapment neuropathies (mainly carpal tunnel syndrome). Diabetic neuropathy can occur at any age but is more common with increasing severity and duration of diabetes. Symptomatic presentation is most com­ mon in patients older than 50 years. Some theories suggest that diabetic neuropathy begins early in the hyperglycemic process, often before the clinical diag­ nosis of diabetes is made. Endoneurial ischemia as well as various metabolic factors, including formation of advanced glycosyla­ tion end products, have been implicated in the patho­ physiology of diabetic neuropathy. The end results are capillary damage, inhibition of axonal transport, reduced Na/K-ATPase activity, and finally, axonal degeneration. Many medications are available for the treatment of diabetic neuropathic pain. These include tricyclic anti­ depressants, the antiepileptic agents such as gabap­ entin and pregabalin, topical lidocaine, oral lidocaine analogs such as mexilitene, and duloxetine, a serotonin norepinephrine reuptake inhibiting antidepressant. Other medications such as the anti­epileptic agents car­ bamazepine, oxcarbazepine, phenytoin, lamotrigine, and opioids have also been used. In some patients, particularly the ones with more localized pain, topi­ cal therapy with capsaicin or lidocaine patches may be indicated. Neurostimulation should be considered only in patients who have severe neuropathic pain and who have failed extensive medical treatment. Tesfaye et al. (1996) tested electrical spinal-cord stimulation for the management of chronic neuropathic pain secondary to diabetes. Ten diabetic patients who did not respond to conventional treatment were studied. The electrode was implanted in the thoracic/lumbar epidural space. Immediate neuropathic pain relief was assessed by change to visual analogue scale (VAS) before and after connecting the electrode, in a random order, to a per­ cutaneous electrical stimulator or to a placebo stimu­ lator. Exercise tolerance was assessed on a treadmill. Eight subjects had statistically significant pain relief with the electrical stimulator (p 0.02) and were there­ fore converted to a permanent system. Statistically significant relief of both background and peak neu­ ropathic pain was achieved at 3 months, 6 months, and 14 months. At 14 month follow-up 6 patients continued to gain significant pain relief and used the stimulator as the sole treatment for their neuropathic pain. For example, median background and peak pain scores at the end of study, were, respectively, 77 and

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81 with the stimulator off and 23 and 20 with the stim­ ulator on. Exercise tolerance significantly improved at 3 months and at 6 months. Electrophysiological tests, vibration perception-threshold, and glycemic control were unchanged. The authors concluded that electri­ cal spinal-cord stimulation offers an effective way of relieving chronic diabetic neuropathic pain and improves exercise tolerance and that the technique should be considered in patients with neuropathic pain who do not respond to conventional treatment. Daousi et al. (2005) studied the efficacy and com­ plication rate of SCS implanted at least 7 years previ­ ously in 8 patients with painful diabetic neuropathy. Following a trial period of percutaneous stimulation, 8 male patients were implanted with a permanent system. Mean age at implantation was 53.5 years and all patients were insulin treated with stage-3, severe, disabling, chronic, peripheral diabetic neuropathy of at least 1 year’s duration. Six patients were reviewed at the mean time of 3.3 years following implantation. With the stimulator off, McGill pain questionnaire (MPQ) scores (a measure of the quality and sever­ ity of pain) were similar to MPQ scores prior to SCS insertion. Pain scores (visual analogue scale) were measured with the stimulator off and on, respectively: background pain and pain obtained statistically sig­ nificant reductions. Four surviving patients were reassessed at 7.5 (range 7–8.5) years: MPQ scores for background pain ranged between 65 and 77 mm with the stimulator on versus 28–36 mm with the stimulator off. Median peak pain was 81–94 mm with the stimu­ lator on versus 31–53 mm with the stimulator off. One patient had a second electrode implanted in the cer­ vical region which relieved typical neuropathic hand pains. The authors concluded that SCS can continue to provide significant pain relief over a prolonged period of time with minimal associated morbidity. Petrakis and Sciacca (1999) studied the effects of SCS on microcirculatory blood flow and neuropathic pain. The aim of this study was to evaluate, using a retrospective data analysis, what prognostic param­ eters, if any, existed that would prognosticate success of SCS for this disease. To perform this evaluation, 64 diabetic patients (39 men, 25 women; mean age 69 years) classified as Fontaine’s stage III and IV, with peripheral arterial occlusive disease, were treated with SCS for rest pain and trophic lesions with dry gangrene, after failing conservative or surgical treat­ ment. After 58 months of follow-up (range 20–128 months), pain relief greater than 75% and limb sal­ vage were achieved in 38 diabetic patients. A partial success was obtained in nine patients with pain relief greater than 50% and limb salvage for at least 6 months. The method failed in 17 patients and the

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limb was amputated in these patients. TcPO2 was assessed on the dorsum of the foot. Clinical improve­ ment and SCS success were associated with increase of TcPO2, before, during the trial, and after implanta­ tion. Limb salvage was achieved in the patients who had significant TcPO2 increase within the 2 weeks of the testing period, independently of the stage of the disease. A TcPO2 increase of more than 50% in the first 2 months after implantation was predictive of success, and was related to the presence of adequate paresthe­ siae in the painful area during the trial period. TcPO2 significantly increased after long-term follow-up in all patients with limb salvage (from 22.1 to 43.1 mmHg in the rest pain patients, from 15.8 to 36.4 mmHg in those with trophic lesions of less than 3 cm2, and from 12.1 to 28.1 in those with trophic lesions of greater than 3 cm2; p 0.01). The authors concluded that in patients with painful diabetic neuropathy and periph­ eral arterial occlusive disease, SCS increases the skin blood flow and is associated with significant pain relief. Significant TcPO2 increase within the 2-week test period was a predictive index of therapy success and should be considered before the final decision in terms of cost effectiveness, before the permanent implantation.

Post-herpetic neuralgia (PHN) Herpes zoster is a viral infection that usually presents as a childhood infection of the varicella virus. The pathogen is the human herpesvirus-3 (HHV-3), also known as the varicella-zoster virus. Following the acute phase, the virus enters the sensory nerv­ ous system, and resides dormant in the geniculate, trigeminal, or dorsal root ganglia for many years. With advancing age or immunocompromised states, the virus reactivates and an eruption (i.e., shingles) occurs. Even after the acute rash subsides, pain can persist or recur in shingles-affected areas. This condi­ tion is known as post-herpetic neuralgia (PHN). In the US, the frequency, 1 month after onset of shingles, is 9–14.3% of the population; at 3 months, about 5%; at 1 year, 3% of the population continue to have severe pain (Choo et al., 1997). A study from Iceland demonstrated variations in risk of PHN asso­ ciated with different age groups (Helgason et al., 2000). No patient younger than 50 years described severe pain at any time. Patients older than 60 years described severe pain: 6% at 1 month and 4% at 3 months from the onset of shingles. Some patients with PHN appear to have abnormal function of unmyelinated nociceptors and sensory

loss (Ebel et al., 2000). Pain and temperature detec­ tion systems are hypersensitive to light mechani­ cal stimulation, leading to severe pain (allodynia). Allodynia may be related to formation of new conn­ ections involving central pain transmission neurons. Other patients with PHN may have severe, spontan­ eous pain without allodynia, possibly secondary to increased spontaneous activity in deafferented central neurons or reorganization of central connections. An imbalance involving loss of large inhibitory fibers and an intact or increased number of small excitatory fib­ ers has been suggested. This input on an abnormal dorsal horn containing deafferented hypersensitive neurons supports the clinical observation that both central and peripheral areas are involved in the pro­ duction of pain. The natural history of PHN involves slow resol­ ution of the pain syndrome. In those patients who develop PHN, most will respond to analgesic agents such as tricyclic antidepressants. A subgroup of patients may develop severe, long-lasting pain that does not respond to medical therapy. Ablative proce­ dures have been reported to have some success, but the author’s personal experience is that they are often plagued with severe complications and that their effect is often short-lived (Rath et al., 1996). Harke et al. (2002) studied the effects of SCS on post-herpetic neuralgia (PHN). Data of 28 patients were prospectively investigated over a median period of 29 months. In addition, four patients with acute herpes zoster (HZ) pain were studied simultan­ eously. After intractable pain for more than 2 years, long-term pain relief was achieved in 23 (82%) PHN patients during SCS treatment as confirmed by a median decrease from 9 to 1 on the visual analog scale (p  0.001). Spontaneous improvement was always confirmed or excluded by SCS inactivation tests at quarterly intervals. Eight patients discontinued SCS permanently because of complete pain relief after stimulation periods of 3–66 months, whereas two patients re-established SCS because of recurrence of the pain after 2 and 6 months. Considerable impair­ ments in everyday life, objectified by the pain disabil­ ity index, were also significantly improved (p 0.001). Four patients with acute HZ pain reported immediate relief with SCS. The stimulation could be stopped after a median period of 2.5 months because of complete pain cessation. The authors concluded that SCS seems to be a therapeutic option for patients with PHN who do not respond to pharmacological measures. Meglio et al. (1989) retrospectively analyzed the results obtained in 10 patients suffering from PHN. An epidural electrode was implanted, aiming the tip in a position where stimulation could produce

IVA. periphery and spinal cord electrical stimulation for non-visceral pain



Conclusions

paraesthesiae over the painful area. At the end of the test period, 6 of 10 patients reporting a mean anal­ gesia of 52.5% underwent a permanent implant. At mean follow-up (15 months) all 6 patients were still reporting satisfactory pain relief (74% of mean anal­ gesia). These figures remained unchanged at the next follow-up session (max. 46 months). The authors con­ cluded that, although positive in only 60% of suffer­ ers, the results were remarkably stable over time and therefore PHN warrants a test trial with spinal cord stimulation. Johnson and Burchiel (2004) evaluated the effects of PNS in severe trigeminal neuropathic pain (TNP) after facial trauma or herpes zoster infection. They con­ ducted a retrospective case series of 10 patients who received implanted subcutaneous pulse generators and quadripolar electrodes for peripheral stimulation of the trigeminal nerve supraorbital or infraorbital branches. Long-term treatment results were deter­ mined by retrospective review of medical records (1998–2003) and by independent observers interview­ ing patients using a standard questionnaire. Surgical complication rate, preoperative symptom duration, degree of pain relief, preoperative and postoperative work status, postoperative changes in medication usage, and overall degree of therapy satisfaction were assessed. The mean follow-up was 26.6  4.7 months. Stimulation provided at least 50% pain relief in 70% of patients with TNP or post-herpetic neuralgia. Medication use fell in 70% of patients, and 80% indi­ cated that they were satisfied with treatment overall. There were no treatment failures (50% pain relief and a lack of decrease in medication use) in the post­ traumatic group, and two failures (50%) occurred in the post-herpetic group. This author’s personal experience with SCS for PHN has been less positive. Some patients perceive the stimulation as irritating. Others, because of old age, have a significant difficulty in grasping the opera­ tional aspects of the modality and eventually abandon it. Nevertheless, it is the author’s opinion that, in the appropriate candidate, severe intractable PHN pain syndrome should warrant a SCS trial.

Conclusions Neurostimulation, either in the form of intraspinal or peripheral nerve stimulation, has a definite role in the management of intractable pain syndromes secondary to peripheral neuropathies. One could actually argue that the pain that stems from a peripheral neuropathy, being neuropathic by definition, should be the ideal

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pain to be treated with neurostimulation. Although that is true for a substantial number of conditions belonging to that category, some of them, such as advanced PHN, are notoriously resistant to most treatment modalities. Nevertheless, since a neurostimulation trial is a fully reversible and relatively non-invasive modality, and since it potentially could result in significant relief from the pain, it should be considered in a large percentage of neuropathic pain syndromes that are not satisfac­ torily managed by medications.

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posttraumatic neuropathic pain: a pilot study. Neurosurgery 55 (1): 135–41. Kingery, W.S. (1997) A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syn­ dromes. Pain 73: 123–39. Kim, S.H., Tasker, R.R. and Oh, M.Y. (2001) Spinal cord stimulation for nonspecific limb pain versus neuropathic pain and sponta­ neous versus evoked pain. Neurosurgery 8 (5): 1056–64. Kumar, K., Toth, C. and Nath, R.K. (1996) Spinal cord stimulation for chronic pain in peripheral neuropathy. Surg. Neurol. 46 (4): 363–9. Li, D., Yang, H., Meyerson, B.A. and Linderoth, B. (2006) Response to spinal cord stimulation in variants of the spared nerve injury pain model. Neurosci. Lett. 400 (1-2): 115–20. Meglio, M., Cioni, B., Prezioso, A. and Talamonti, G. (1989) Spinal cord stimulation (SCS) in the treatment of postherpetic pain. Acta Neurochir. Suppl. (Wien) 46: 65–6. Meyerson, B.A., Ren, B., Herregodts, P. and Linderoth, B. (1995) Spinal cord stimulation in animal models of mononeuropa­ thy: effects on the withdrawal response and the flexor reflex. Pain 61 (2): 229–43. Miki, K., Iwata, K., Tsuboi, Y., Morimoto, T., Kondo, E., Dai, Y. et al. (2000) Dorsal column-thalamic pathway is involved in thalamic hyperexcitability following peripheral nerve injury: a lesion study in rats with experimental mononeuropathy. Pain 85 (1-2): 263–71. Murphy, D., Laffy, J. and O’Keeffe, D. (1998) Electrical spinal cord stimulation for painful peripheralneuropathy secondary to coeliac disease. Gut 42 (3): 448–9. Novak, C.B. and Mackinnon, S.E. (2000) Outcome following implan­ tation of a peripheral nerve stimulator in patients with chronic nerve pain. Plast. Reconstr. Surg. 5 (6): 1967–72.

Pappagallo, M. (2003) Newer antiepileptic drugs: possible uses in the treatment of neuropathic pain and migraine. Clinical Therapeutics 25 (10): 2506–38. Petrakis, I.E. and Sciacca, V. (1999) Epidural spinal cord electrical stimulation in diabetic critical lower limb ischemia. J. Diabet. Compl. 13 (5-6): 293–9. Quan, D., Wellish, M. and Gilden, D. (2003) Topical ketamine treat­ ment of postherpetic neuralgia. Neurology 60: 1391–2. Rath, S.A., Braun, V., Soliman, N. et al. (1996) Results of DREZ coag­ ulations for pain related to plexus lesions, spinal cord injuries and postherpetic neuralgia. Acta Neurochir. (Wien) 138 (4): 364–9. Ropper, A. and Brown, R. (2005) Diseases of the peripheral nerves, ch. 42 in Adams and Victor’s Priciples of Neurology, 8th edn. New York: McGraw–Hill, pp. 1110–77. Rowbotham, M.C., Twilling, L., Davies, P.S., Reisner, L., Taylor, K. and Mohr, D. (2003) Oral opioid therapy for chronic periph­ eral and central neuropathic pain. N. Engl. J. Med. 348 (13): 1223–32. Tesfaye, S., Benbow, S.J., Pang, K.A., Miles, J. and Macfarlane, I.A. (1996) Electrical spinal-cord stimulation for painful diabetic peripheral neuropathy. Lancet 348 (9043): 1698–701. Watson, C.P. and Babul, N. (1998) Efficacy of oxycodone in neu­ ropathic pain: a randomized trial in postherpetic neuralgia. Neurology 50 (6): 1837–4. Woolfe, C.J. and Mannion, R.J. (1999) Neuropathic pain: aetiol­ ogy, symptoms, mechanisms and management. Lancet 353: 1959–64. Yakhnitsa, V., Linderoth, B. and Meyerson, B.A. (1999) Spinal cord stimulation attenuates dorsal horn neuronal hyperexcitability in a rat model of mononeuropathy. Pain 79 (2-3): 223–33.

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Neurostimulation in the Treatment of Complex Regional Pain Syndrome Joshua P. Prager

o u tl i ne Introduction

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The Efficacy of Spinal Cord Stimulation  in Treating CRPS

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The Benefits and Risks of Spinal  Cord Stimulation

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Patient Selection for a Screening Trial

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The Role of SCS in the Comprehensive  Interdisciplinary Treatment Model of CRPS

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Introduction

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Patient Management

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Cost-effectiveness

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Conclusions

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References

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sympathetic dystrophy” in 1946, noting sustained sympathetic responses and subsequent trophic changes (Evans, 1946). The clinical course begins with pain, which often follows a minor injury but is disproportionately greater than the extent of tissue damage. Patients describe a constant burning sensation in the superficial and deep tissues of the palm or plantar surface. The pain usually spreads from a nerve or dermatomal area to a larger region. Nails and hair in the affected region grow rapidly, and skin changes, such as abnormal color, hyperhidrosis, cyanosis and diffuse mottling, are common. The patient experiences increasing pain as the disease progresses, and in some cases dystrophy and atrophy. Five types of symptoms predominate: pain, autonomic dysfunction, edema, movement disorder, and dystrophy or atrophy (Schwartzman, 2000).

Because time is of the essence, failure to progress should be seen as a trigger to introduce regional anesthesia or neuromodulatory methods to support the progressive rehabilitation. (Michael Stanton-Hicks, MD, Cleveland Clinic Foundation) Complex regional pain syndrome (CRPS), as an indication for spinal cord stimulation (SCS), is well accepted as an indication for the therapy. Mitchell first described the clinical signs of CRPS as “causalgia” in 1864, but the condition’s many variations and puzzling pathophysiology created a formidable diagnostic challenge. Evans coined the term “reflex

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Box 28.1

Signs and symptoms of complex regional pain syndrome Sensory: pain (burning), hyperesthesia, hyperalgesia, allodynia l Motor: decreased range of motion, weakness, tremor, dystonia l

In 1994 the International Association for the Study of Pain (IASP) replaced the name “reflex sympathetic dystrophy” with “complex regional pain syndrome” (CRPS) (Stanton-Hicks et al., 1995). The change acknowledged the unclear role of the sympathetic nervous system in the disorder, and the fact that dystrophy does not occur in all patients. Instead, two forms of CRPS were defined: Type I, in which all the features of reflex sympathetic dystrophy are present but with no definable nerve injury; and Type II (formerly called causalgia), in which the nerve injury is definable (Schwartzman, 2000). A further subdivision separated sympathetically maintained pain (SMP), which can be stopped by sympathetic fiber interruption, from sympathetically independent pain (SIP). The newer definitions avoided the concept of syndrome stages, which had shed little light on the neurophysiology or management of CRPS. The IASP set out stringent diagnostic criteria, including pain, impaired function, symptoms beyond the area of trauma, and temperature changes in the affected area as absolute criteria, and edema, increased nail and hair growth, hyper­hidrosis, abnormal skin color, hypoesthesia, hyperalgesia, mechanical or thermal allodynia or both, and patchy demineralization of bone as relative criteria (Box 28.1) (Kemler et al., 2000). The diagnosis of CRPS relies on a detailed clinical history coupled with evidence from the physical examination (Bennett and Cameron, 2003). Signs and symptoms of CRPS can be categorized as sensory, motor, autonomic, and trophic. The diagnosis of CRPS is based on these clinical criteria. In addition, tests can provide information about autonomic, sensory, and motor function or dysfunction. These tests include radiologic imaging, bone scintigraphy, thermography, electromyography and nerve conduction studies, quantitative sensory testing, quantitative sudomotor axon reflex testing, and sympathetic nerve blocks. The differential diagnosis of CRPS requires considering unrecognized local pathology, neuropathic pain syndromes, peripheral neuropathies, inflammatory and infectious diseases, and vascular disorders (Wasner et al., 1998). Differentiating CRPS from trauma proves critical to a correct diagnosis (Birklein et al.,

Autonomic: edema, vasomotor (temperature and color changes), sudomotor (sweating changes) l Trophic: skin, hair, nails l

2001). Specifically, motor signs, trophic changes, and increased sweating differentiate CRPS from trauma, which lacks these clinical signs. Pain, edema, and temperature asymmetry occur in both presentations and are clinically indistinguishable. The majority of patients develop CRPS after injury or surgery: 29% after sprain or strain, 24% after surgery, 23% due to spontaneous or unknown causes, 15% after fracture, and 8% after contusion or crush injuries (Allen et al., 1999). CRPS also includes movement disorders, namely in­ability to initiate movement, weakness, tremor, muscle spasms, and dystonia. The mechanisms responsible for dystonia are not known. Nociceptive flexor withdrawal reflexes may be enhanced, or presynaptic inhibition of nociceptive afferents blocked by the release of gammaaminobutyric acid (GABA). Dystonia can precede the pain, appear suddenly, or occur on the opposite side of the body from the original injury. The dystonia can rob the affected limb of any useful function. In the early stages of CRPS, sympathetic blockade sometimes alleviates these motor symptoms (Schwartzman, 2000). Current evidence suggests that central pathway abnormalities support CRPS (Bennett and Cameron, 2003). One hypothesis proposes that the initial peripheral injury leads to the release of inflammatory mediators that produce free radicals. These, in turn, sensitize C-fiber and A-fiber nociceptors and facilitate peripheral swelling. Increased glutamate bombardment of NMDA receptors increases the transduction of afferent signals, eventually setting up an afferent–efferent loop that centralizes the pain at the spinal segmental and suprasegmental levels. Many cases of CRPS include myoclonic activity, probably the best physical indicator pointing to a central mechanism (Sandroni et al., 1998).

The efficacy of spinal cord stimulation in treating CRPS Complex regional pain syndrome has traditionally been treated with physical therapy in an attempt to

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The efficacy of spinal cord stimulation in treating CRPS

prevent contractures, minimize atrophy, and facilitate return to function. Several pain-relieving therapies have been offered to enhance the patient’s ability to participate in physical therapy. Sympathetic nerve blocks can be used if they provide a sufficient duration of analgesia, or if the period of post-procedure anal­gesia increases with each block. Numerous systemic medications have been administered to provide “balanced” analgesia during physical therapy, including serotonin/ norepinephrine reuptake blockers, nonsteroidal antiinflammatory drugs, steroids, opioids, alpha-adrenergic blocking agents, membrane stabilizers, and NMDA antagonists (Bennett and Cameron, 2003). Continuous epidural infusion of anesthetics, clonidine or opioids can also provide analgesia during rehabilitation, although the technique is labor-intensive, expensive and prone to complications such as infection or catheter occlusion. Neuroablation of the sympathetic chain provides longer-lasting analgesia but is fraught with complications, irreversible, and not uniformly effective (Furlan et al., 2001). In light of the emerging understanding of peripheral–cord–brainstem interactions, neurodestructive techniques should be considered as last-resort therapies (Bennett and Cameron, 2003). The Neuromodulation Therapy Access Coalition found excellent evidence supporting the use of SCS to treat CRPS (North et al., 2007). These authors identified three randomized controlled trials (RCTs), six longterm follow-up studies, six short-term follow-up studies, 10 case studies, and numerous studies of CRPS in mixed indications. Kemler and colleagues reported results of the first RCT in 2000 (Kemler et al., 2000). Enrolled patients met the diagnostic criteria for CRPS Type 1 established by the IASP, and all of the patients had experienced severe pain that was unresponsive to conventional treatment for at least 6 months. Patients were randomly assigned to receive SCS plus physical therapy (n  36) or physical therapy alone (n  18). The stimulator was implanted only if trial stimulation was successful. Intention-to-treat analysis demonstrated a significant reduction in pain for patients in the SCS group compared to patients in the physical therapy group (p 0.001). Thirty-nine percent of patients in the SCS group had a much improved global-perceivedeffect score compared with 6% in the control group (p  0.01). None of the patients had clinical improvement in functional status. The quality of life (QOL) improved by 11% overall, but only in the 24 patients who actually underwent stimulator implantation. Six of these patients required additional procedures due to complications, including removal of one device. These same researchers reported on their original patients after 2-year follow-up (Kemler et al., 2004). The SCS plus physical therapy group still had significantly

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improved pain relief and global perceived effect compared with the physical therapy-only group (p 0.001). There was no clinically important improvement in functional status for either group. The investigators concluded that SCS provided long-term pain reduction and improved the health-related QOL in these patients treated for CRPS. At 5-year follow-up, the effects of SCS or physical therapy alone were equivalent with regard to all measured variables (Kemler et al., 2008). Global perceived effect for SCS patients (n  20) was still significantly better (p  0.02) than for physical therapy patients (n  13), but there was no difference in pain relief (p  0.06). Despite the diminishing effect of SCS over time, the overwhelming majority (95%) of SCStreated patients said they would repeat the treatment for the same result. The third RCT compared the analgesic effects of carbamazepine (600 mg/day) or sustained-release morphine (90 mg/day) in patients with CRPS who were pretreated with SCS (Harke et al., 2001). Forty-three patients had SCS switched off before receiving the pain medications or placebo. They could reactivate SCS if the pain became intolerable. Compared with placebo, carbamazepine significantly delayed a pain increase but morphine did not, perhaps because the dose was too low. Two patients taking carbamazepine and one taking morphine preferred to continue the medication. Thirty-five returned to SCS. Most of the published studies describing treatment of CRPS with SCS have been retrospective. In reviewing 10 of these, Bennett and Cameron (Bennett and Cameron, 2003) found an overall success rate of 82% (148/180) for patients with CRPS I and 79% (23/29) for patients with CRPS II treated with SCS. These results are encouraging, considering that many physi­ cians reserve SCS until all other conservative therapies have failed. These results were also obtained with relatively limited stimulation systems having few electrode contacts and limited output capabilities. More sophisticated stimulation systems, though not yet tested in RCTs, have demonstrated statistically significant improvements in pain scores and overall patient satisfaction compared with baseline (Bennett et al., 1999). For example, these authors found greater improvement in patients with dual octapolar leads versus a single quadripolar lead, most probably because octapolar leads can safely deliver higher frequencies and be carefully programmed to maximize paresthesia coverage. They believe that the more flexibility afforded by a stimulation system – through numbers or arrays of electrodes, range of pulse width, frequency and amplitude, dual-channel capabilities, and programming options – the more attractive the system is for treating CRPS.

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Current thinking regarding CRPS suggests that early intervention provides a higher probability of complete reversal of symptoms or a greater degree of symptom resolution (Boas, 1996). Given the demonstrated efficacy of SCS in treating longerstanding cases, Prager and Chang reported on the temporary use of SCS to provide adjuvant analgesia while patients underwent inter-disciplinary treatment that commenced within 8 weeks of their injury (Prager and Chang, 2000). Eight patients had a triple-lead stimulation system (tripolar configuration) implanted to facilitate physical therapy. The lead was to remain for 4 weeks, with permanent implantation performed if stimulation was required after that. A second set of 16 patients, who had failed 4 weeks of comprehensive therapy, had permanent SCS system implants and continued comprehensive treatment. When patients indicated that SCS was no longer necessary, the stimulator was turned off for 1 month. After that time, if the patient desired explantation, the system was removed. Five of the eight patients (62.5%) had sufficient symptom resolution to remove the lead. Of the 16 patients with permanent SCS systems, two (12.5%) had their systems explanted (at 5 and 18 months) and are relatively symptom free 2 years later. Temporary SCS is relatively inexpensive compared to multiple serial sympathetic blocks or maintenance of an epidural infusion. In addition, an implanted SCS lead without an internal pulse generator can be converted

to a permanent totally implanted system, if necessary, after functional rehabilitation is completed. Ample evidence in the current literature supports the efficacy of SCS in treating pain due to CRPS I and II when compared to other modalities such as physical therapy and medication. Its greatest utility, however, may be in combination with other therapies early in the course of CRPS, when therapeutic interventions may prevent or moderate disability.

The benefits and risks of spinal cord stimulation Any pain treatment plan must balance benefit against risk. Consequently, the classic chronic pain treatment continuum begins with less invasive and costly options and progresses if they fail (Krames, 1999). In this context, SCS had been relegated to the status of last resort therapy. The potential benefits of SCS are listed in Table 28.1, and they should be discussed along with risks before patient and physician commit to SCS. The Neuromodulation Therapy Access Coalition, in drawing up their practice parameters for SCS, classified its reported benefits as useful for information, in part because there are no generally accepted standards for measuring many of the benefits and only two RCTs for consideration.

Table 28.1  Potential benefits of spinal cord stimulation in treating CRPS* Benefit

Comments

Pain relief (North et al., 1993; Kumar et al., 2007)

The primary outcome measure of SCS success is patient-reported pain relief, generally using a standard pain scale such as the Visual Analog Scale (VAS), Functional Rating Index, McGill Pain Questionnaire (North et al., 2007) A majority of patients may experience at least 50% reduction in pain

Increased activity levels or function (North et al., 1993; May et al., 2002; Kumar et al., 2006)

As demonstrated by activities of daily living, such as walking, climbing stairs, sleeping, engaging in sex, driving a car and sitting at a table (North et al., 2006). Measured by the Oswestry Disability Index (specific for low back pain), the Sickness Impact Profile (for general health), Functional Rating Index, Pain Disability Index

Reduced use of pain medications (Harke et al., 2005)

Patients in whom SCS is successful should be able to reduce or eliminate their intake of pain medication (North et al., 2007)

Improvement in quality of life (May et al., 2002; North et al., 2007) Patient satisfaction with treatment (Alo’ et al., 1999; Bennett et al., 1999; May et al., 2002; Kumar et al., 2006; North et al., 2007)

Would repeat treatment to achieve the same result (North et al., 2007)

Fewer symptoms of depression (Oakley and Weiner, 1999; May et al., 2002; Kumar et al., 2006; North et al., 2007)

Measured by the Beck Depression Inventory

*  Consult “Practice parameters for the use of spinal cord stimulation in the treatment of chronic neuropathic pain” (North et al., 2007) for a comprehensive bibliography of studies that support the benefits of spinal cord stimulation in treating complex regional pain syndrome (CRPS). Selected long-term or seminal studies are cited here; short-term studies and case reports are not

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The benefits and risks of spinal cord stimulation

Pain relief is the most obvious benefit of SCS and its intended goal. The criterion of 50% pain reduction has been used as a definition of success for decades (Long and Erickson, 1975), but lacks standardization because pain itself fluctuates and the perception of pain is highly subjective and idiosyncratic. The commonly used Visual Analog Scale (VAS) creates an individual framework for the assessment of pain over time, with a reduction in score considered a measure of success. Yet patients reporting relatively modest reductions in VAS may have disproportionately greater gains in function or decreases in pain medication. Given the intractable nature of the chronic pain syndromes treated with SCS, patients may view any reduction in pain as advantageous, particularly if it allows functional improvement and less reliance on pain medications. One newly emerging and intriguing benefit of SCS is the possibility of favorably altering the pathogenesis of pain by early application of SCS (Simpson, 2006). The chance of halting the debilitating effects of CRPS merits additional examination. In their review, the Neuromodulation Therapy Access Coalition (North et al., 2007) found studies that demonstrated increased ability to undertake activities of daily living (ADL) or improved QOL for patients treated with SCS. Seven years after SCS implantation, a majority of patients in one retrospective, consecutive series of 205 patients had maintained improvements in ADLs (North et al., 1993). In a retrospective long-term (mean 37.5 months) follow-up of 81 patients with SCS, 80% reported an improvement in QOL (May et al., 2002). They experienced significant reductions in the Oswestry Disability Index (p 0.01), the Hospital Anxiety and Depression (HAD) Index (p 0.01), and VAS scores (p 0.001). In the same study, patients in two “control” groups, who had no trial of SCS or a failed trial of SCS, deteriorated over time. In their RCT of patients with Type I CRPS, Kemler and co­workers found that the QOL improved by 11% overall, but only for patients who actually underwent stimulation implantation (Kemler et al., 2000). No standard measure of patient satisfaction with treatment exists. Among 153 patients followed for 4 years after implantation in Belgium, 68% rated their result as excellent to good (Van Buyten et al., 2001). One convincing measure of patient satisfaction with SCS is the fact that, in the RCTs, patients were significantly less likely to cross over to reoperation or conventional medical management than staying with SCS (Kumar et al., 2007). At 5-year follow-up, 95% of patients with CRPS Type I who were treated with SCS said they would repeat implantation for the same result (Kemler et al., 2008). Several studies have noted fewer symptoms of depression in patients successfully treated with SCS

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(Oakley and Weiner, 1999; Kumar et al., 2006; North et al., 2007). In a prospective study, Oakley and Weiner (1999) observed a trend toward improvement (p 0.06) in the Beck Depression Inventory scores, which dropped from 13.18 pre-implant to 5.18 postimplant, at an average follow-up of 7.9 months in patients being treated for CRPS. However, May et al. (2002) did not find any correlation between initial depression scores and subsequent levels of pain relief. The risks of SCS relate to surgery, to the implanted devices, or to stimulation itself. Infection ranks as the primary surgery-related risk. In a survey of 31 studies, perioperative infections were reported in 5% of cases (0% to 12%) (Turner et al., 1995). Two decades of experience with SCS turned up a similar 5% incidence of infections, but no spinal cord injury, meningitis, or life-threatening infection (North et al., 1993). Surgical risks exclusive of infections include spinal fluid leaks, hemorrhage, or neurologic injury, which reportedly occur in approximately 9% of cases (0% to 42%) (Oakley, 2004). Many practitioners administer antibiotic prophylaxis intravenously 1 hour before a procedure to minimize the chance of infection. Device-related complications present the greatest challenge to successful implantation, occurring in as many as 30% of cases in a review of 13 studies published in 1995 (Turner et al., 1995). Electrode migration posed the biggest difficulty, accounting for 24% of device-related complications and frequently resulting in loss of paresthesia coverage. Surgical revision or replacement of a system component was necessary in 12 of 219 (5%) patients tracked by Burchiel and colleagues (Burchiel et al., 1996). Multichannel systems have proven significantly more reliable than singlechannel laminectomy or percutaneous leads (North et al., 1993). Remarkable technological advances in the past decade promise to further decrease the number of complications attributable to equipment. Patients occasionally report that stimulation has become uncomfortable or increases underlying pain. Stimulation-related complications vary widely, and few studies have examined the precise reasons for failure. Five of 219 patients (3%) in one series (Burchiel et al., 1996) reported discomfort or loss of pain relief. Posture-induced changes in paresthesia are sometimes cited. Oakley reviewed 126 patients with 2-year followup, 26 (20%) of whom had discontinued stimulation or requested removal of the system (Oakley, 2004). He found three reasons for failure: disease progression in 12 patients (55% of failures), appropriate paresthesia with loss of pain relief in nine patients (41% of failures), and painful hardware at the implant site in one patient. Four patients (3%) enjoyed such successful pain resolution that they no longer required SCS.

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On balance, the risks of SCS must also be judged against those of other possible therapies or the option of doing nothing. In this calculus, the patient should be told of the deleterious adverse effects of opioid medications, such as mental impairment, sedation, nausea, constipation, and weight gain (Oakley, 2004). In the USA medical therapies are often favored over surgical ones by physicians, payers, and patients. Yet the most frequent and serious complications of SCS are not related to stimulation itself or to its long-term use. Thus, a preimplantation screening trial (to determine efficacy) combined with careful immediate post-implant management offers the potential to resolve adverse effects early in the course of treatment. The adverse effects of pain medications, however, can persist as long as their use endures. Every patient contemplating SCS should be engaged in a detailed discussion of the risks and benefits that might be experienced personally. A well-informed patient becomes an active partner in the treatment plan. Patients should be aware that they have responsibilities, and their committed participation in preoperative, postoperative, and maintenance therapy will influence outcome.

Patient selection for a screening trial Pain specialists are virtually unanimous in emphasizing the importance of appropriate patient selection if SCS is to be successful. Pain treatment algorithms rely on a stepwise approach that begins with therapies that are less invasive, likely to have few adverse effects and can be reversed. SCS is a minimally invasive procedure and should, therefore, follow appropriate noninvasive therapies. By the same reasoning, a screening trial of SCS should precede ablative therapy, for example sympathectomies in CRPS patients. Most candidates for SCS have a long medical history and reviewing it is a crucial first step in the selection process. In addition, specific criteria exist for making a diagnosis of CRPS Types I and II. An MRI should be performed in any suspected case of stenosis, disk herniation, or other anatomic abnormality that might increase the procedural risk of SCS (North et al., 2007). Some clinicians rely on an MRI to gain information about the depth of dorsal cerebrospinal fluid and the position of the spinal cord, dimensions that vary among individuals and affect electrode selection, placement, and adjustment. Others forgo a routine, pre-trial MRI because of the cost. Box 28.2 lists patient inclusion and exclusion cri­ teria (Oakley, 2004) and relative and absolute contraindications for SCS (North et al., 2007). These should

be considered carefully, as inappropriate patient selection undoubtedly accounts for some of the disparate results of SCS reported in the literature. The valuable and continuing work performed by the International Neuromodulation Society and its chapters, the IASP, and other groups has contributed to a more precise understanding of the patient selection criteria associated with successful neurostimulation, and their insights should not be overlooked. Where controversies exist, such as the necessity for psychological testing, clinical judgment comes to the fore. Medicare and many health insurers already require psychological screening as a condition for SCS (Doleys and Olson, 1997). Information from a psychological assessment can expose psychological factors that should be treated, guide specific treatments that can help resolve psychological risk factors, facilitate patient selection, and provide clues as to the patient’s possible response to treatment. On the other hand, no psychological assessment can confirm the cause of pain or the relative contribution of organic versus psychological factors. Doleys and Olson (Doleys and Olson, 1997) recommend looking for an accumulation of risk factors or an overall level of distress when conducting psychological testing. Severe pain by itself can cause psychological disturbances, and behavioral therapy can help patients control pain (Turk and Gatchel, 2002). Thus, a psychological assessment could uncover treatable psychological factors that would improve the chances for success. In this context, a psychological assessment is designed to ensure that no significant psychological dysfunction precludes a screening trial.

The role of SCS in the comprehensive interdisciplinary treatment model of CRPS Stanton-Hicks published the interdisciplinary treatment protocol for CRPS that was developed by an international multidisciplinary closed group in Malibu, California, under the aegis of the IASP (Stanton-Hicks et al., 2002). The principles of this protocol (Figure 28.1) are that physical therapy should be the mainstay of such treatment and that other modalities are introduced when there is a failure to progress with physical therapy alone. As such, behavioral intervention is introduced early as necessary. Similarly, invasive pain management is imperative when the patient cannot progress in physical therapy due to pain, despite appropriate systemic pharmacotherapy. Nerve blocks such as sympathetic blockade

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Box 28.2

Traditional patient selection criteria and relative and absolute contraindications for spinal cord stimulation in CRPS

Inclusion criteria (Oakley, 2004)

Abnormal or inconsistent pain ratings Predominance of nonorganic signs (e.g., Waddell’s signs) l Alternative therapies with a risk–benefit ratio comparable to that of SCS remain to be tried l Pregnancy at time of the surgical implantation (use of fluoroscopy) l Occupational risk (e.g., employment requires climbing ladders or operating certain machinery) l Local or systemic infection l Presence of a demand pacemaker or cardiac defibrillator l Foreseeable need for an MRI in the region of the stimulator l Anticoagulant or antiplatelet therapy l l

l l l l

Established diagnosis of CRPS Pain of at least 6 months’ duration Informed consent Clearance after psychological evaluation

Exclusion criteria (Oakley, 2004) Evidence of active, disruptive psychiatric disorder; active drug abuse; personality disorders that might affect pain perception, compliance with intervention, or ability to evaluate therapy l Patients who have not received an adequate course of conservative care l Patients who have failed a previous SCS trial l

Relative contraindications (North et al., 2007) An unresolved major psychiatric comorbidity l The unresolved possibility of secondary gain l An inappropriate dependency on pharmaceuticals (especially controlled substances) l Inconsistency among the patient’s history, pain description, physical examination, and diagnostic studies l

are introduced early to support physical rehabilitation, and if the result of sympathetic blockade is not either sustained or progressively longer with each injection during interdisciplinary care, then a trial of SCS is indicated. An interdisciplinary approach is the cornerstone of this treatment protocol (Figure 28.1). Although the traditional model of care mandates that SCS follow a prolonged systematic course of conservative care, more modern thinking suggests (Figure 28.2) that earlier aggressive treatment may produce better outcomes. When failure to rapidly progress occurs, the treatment algorithm should be sufficiently flexible to allow introduction of SCS earlier. SCS likely has more profound effects than sympathectomy alone and Furlan et al. (2000) suggest that irreversible destructive procedures be used with caution and that their risks be clearly explained. It is likely that SCS has a salutary end-organ effect that sympathectomy does not produce. What has been learned with SCS and vascular

Absolute contraindications (North et al., 2007) Inability to control the device Coagulopathy, immunosuppression, or other condition associated with an unacceptable surgical risk l Need for therapeutic diathermy (a contraindication for implantable devices) l l

disease probably has implications in CRPS, and more work is necessary to convincingly demonstrate this.

Conducting a screening trial According to the Neuromodulation Therapy Access Coalition, there is excellent evidence that screening trials of SCS provide valid patient selection information (North et al., 2007). Indeed, one of the advantages of SCS is that trials offer both the physician and patient an opportunity to evaluate SCS before committing to it. Approximating the conditions of long-term therapy during the trial seems to offer the best chance for assessing efficacy and tolerance. The trial should answer two fundamental questions: Is the patient’s pain responsive to SCS therapy, and can the patient tolerate the treatment? In CRPS, the trial is an opportunity

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28.  Neurostimulation in the treatment of complex regional pain syndrome Diagnosis CRPS Care Continuum Pain management with oral and topical drugs Psychological treatment with educational focus

Psychological Treatment

Reactivation Desensitization

• Increase frequency/intensity of psychotherapy

Progress

Isometrics Flexibility Edema control Peripheral E-stim Treat secondary MFP

Minimally invasive • Sympathic nerve block(s) • IV regional block(s) • Somatic nerve block(s)

ROM (gentle!) Stress loading Isotonic strengthening Aerobic conditioning Postural normalization

Ergonomics Movement therapies Normalization of use Vocational/ functional rehab

Failure to Progress in Rehab

Progress

Failure to Progress in Rehab

• Assess for Axis I disorders • Pain coping skills • Biofeeback/relaxation training • Cognitive behavioral therapy for treatment of Axis I disorders

Inadequate or partial response

Interventional Pain Management

Rehabilitation Pathway

Inadequate or partial response More invasive • Epidural and plexus catheter blocks • Neurostimulation • Intrathecal drug therapy (e.g. baclofen) Inadequate or partial response

Surgical or experimental therapies • Sympathectomy • Motor cortex stimulation

EXCELLENT RESPONSE

FOLLOW-UP RELAPSE REPEAT PATHWAY

Figure 28.1  Multidisciplinary care continuum for chronic regional pain syndrome. Psychological, rehabilitative, and interventional pain management are simultaneous and time-contingent in the interdisciplinary clinical protocol developed under the aegis of the International Association for the Study of Pain. Therapeutic options are determined by the patient’s clinical progress along the rehabilitation pathway (Adapted with permission from Stanton-Hicks et al., 2002. John Wiley & Sons Ltd)

to determine whether the patient can tolerate the interdisciplinary care required for functional rehabilitation (Figure 28.1). The physician and patient should agree in advance on the goals of the trial and on the measures used to assess those goals. In general, candidates should proceed to implantation if their pain can be reduced by at least 50% and they can participate in functional rehabilitation (Caudill et al., 1996), the area of paresthesia is tolerable and concordant with the area of pain (Oakley, 2004), analgesic medication intake remains stable or can be decreased, and functional improvement has been assessed (different

clinics employ different tools for physical evaluation). As many as a third of potential SCS candidates will be eliminated during the screening trial (Oakley, 2004). Patient questionnaires can cover pain history, current medication and other therapies, disability status, and a VAS for rating current pain (Prager and Jacobs, 2001). An initial clinical interview can also elicit the patient’s subjective experience of pain. Information provided by the patient should be carefully reviewed against records from the referring physician to provide corroborative evidence and supply results from earlier diagnostic studies. The physical examination, including complete neurologic assessment, will document the patient’s current pain symptoms. In some cases, a complete diagnostic workup may be necessary to rule out reversible or identify treatable causes of pain. Numerous screening protocols exist and none can be considered superior or definitive based on the current literature (Prager and Jacobs, 2001). Multiple factors influence the choice of protocol, including the patient’s overall condition, the physician’s preference and experience, available facilities and resources, practice environment, and payer coverage. Medicare requires a screening trial before reimbursing for SCS therapy and may dictate some trial conditions. Generally trials last for 1 week or longer, and use externalized lead wires and a temporary external transmitter. Most screening trials use percutaneous electrodes placed under fluoroscopy, because they provide access to many levels of the spine with the use of a single epidural needle (North et al., 2007). A surgical plate/paddle can be used in the minority of patients in whom the epidural space is otherwise inaccessible. Whenever possible, electrodes should be placed under local anesthetic so that the patient can describe paresthesia coverage, react to changes in stimulation, and report any unusual intraoperative events. Because patient cooperation is fundamental to the success of SCS, the evaluation process should include a discussion of the patient’s and family’s expectations for therapy. Patients should know in advance that complete pain relief is unlikely, that regular follow-up appointments are necessary, and that many patients experience post-implantation complications. This knowledge must be balanced against the functional benefits afforded by substantial pain relief.

Patient management Candidates for  SCS typically have suffered unresolved pain for years, and they may approach the procedure with fears, skepticism, or wildly unrealistic

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393

Cost-effectiveness

• Different time frames • Multiple therapies at one time • Different starting points Chiropractic care, adjuvant meds, behavioral programs

Corrective surgery

Physical therapy, TENS

NSAIDS/COX2 Examination and diagnosis

Aggressive pharmacotherapy

Neuromodulation

Chronic pain patient

Neuroablation

Figure 28.2  A flexible pain management continuum (Reproduced from Prager and Jacobs (2001) with permission. Lippincott, Williams & Wilkins; www.lww.com)

expectations. These should be addressed when reviewing the new patient’s history and through continuing patient education. Patients should know that SCS reduces but does not eliminate pain. They should also know that SCS can be used with other pain treatments, as there is no indication of cross-tolerance (North et al., 2007). Follow-up is mandatory, especially in the first 6–8 weeks when most system adjustments are made. On postoperative day 7–14, staples or sutures will be removed and any necessary SCS adjustments made. In CRPS, patient mandates include participation in a functional rehabilitation program once the wounds from the implantation are healed. Mere implantation of a device without rehabilitation is unlikely to produce an excellent functional outcome. After completion of rehabilitation, follow-up visits should be scheduled as necessary to ensure safe and effective operation of the SCS system. Initially, this may mean monthly visits, which can be gradually tapered to yearly visits. Patients with SCS units implanted elsewhere should be followed up as new patients, so that the physician can become familiar with the patient’s pain condition and response. Every patient should know how to contact the implanting phys­ician and device manufacturer in case of emergency.

Cost-effectiveness Payers generally view SCS as a costly therapy because of the initial investment necessary to pay for the screening trial and equipment. Yet there is excellent evidence, including RCTs, to support the costeffectiveness of SCS in treating CRPS (North et al.,

2007). In an RCT, in The Netherlands, the per patient cost of treatment for CRPS in the first year after implantation was $4000 higher for SCS than for phys­ ical therapy (Kemler and Furnee, 2002). However, in the lifetime analyses, SCS was $60 000 less expensive per patient than the control therapy. In addition, at 1-year follow-up, pain relief (p 0.001) and healthrelated QOL (p  0.004) were both significantly better for the SCS patients. A British RCT of patients treated for CRPS I found a lifetime cost saving of approximately US$60 800 for the SCS group when compared to the physical therapy group (Taylor et al., 2006). Another cost–benefit study compared the cost of SCS with conventional pain therapy for a consecutive series of 104 patients treated in a constant health care delivery environment (Kumar et al., 2002). Over a 5-year period, the mean cumulative cost was Canadian $29 123 for SCS compared with $38 029 for conventional pain management. Costs for the SCS group exceeded those for the conventional management group during the first 2.5 years, but dipped below for the rest of the follow-up period.

Conclusions SCS is a valuable tool for the treatment of CRPS. Perhaps its greatest advantages are that a trial of SCS can be conducted before committing to implantation, SCS can provide sufficient analgesia to facilitate early physical therapy, and SCS is reversible. In the experience over more than two decades of clinical implantation of SCS, the therapy has no detectable

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28.  Neurostimulation in the treatment of complex regional pain syndrome

detrimental effect on the nervous system, and no significant adverse effects at the usual stimulation levels. SCS has also been shown to be cost-effective or neutral over time when compared to ongoing conservative medical management including physical therapies and medication management. Continuing improvements in our understanding of neurophysiology and in stimulator technology should enable pain specialists to further refine the application of SCS for improved outcomes in treating CRPS.

References Allen, G., Galer, B.S. and Schwartz, L. (1999) Epidemiology of complex regional pain syndrome: a retrospective chart review of 134 patients. Pain 80: 539–44. Alo’, K.M., Yland, M.J., Charnov, J.H. and Redko, V. (1999) Multiple program spinal cord stimulation in the treatment of chronic pain: follow-up of multiple program SCS. Neuromodulation 2 (4): 266–72. Bennett, D.S. and Cameron, T.L. (2003) Spinal cord stimulation for complex regional pain syndromes. In: B.A. Simpson (ed.), Electrical Stimulation and the Relief of Pain. Pain Research and Clinical Management, Vol. 15. Amsterdam: Elsevier, pp. 111–29. Bennett, D.S., Alo’, K.M., Oakley, J. and Feler, C. (1999) Spinal cord stimulation for complex regional pain syndrome (RSD): a retrospective multicenter experience from 1995–1998 of 101 patients. Neuromodulation 2: 202–10. Birklein, F., Kunzel, W. and Sieweke, N. (2001) Despite clinical similarities there are significant differences between acute limb trauma and complex regional pain syndrome I (CRPS I). Pain 93: 165–71. Boas, R.A. (1996) Complex regional pain syndromes: symptoms, signs and differential diagnosis. In: W. Janig and M.D. StantonHicks (eds), Reflex Sympathetic Dystrophy: A Reappraisal. Progress in Pain Research and Management. Seattle, WA: IASP Press, pp. 79–92. Burchiel, K., Anderson, V.C., Brown, F.D. et al. (1996) Prospective, multicenter study of spinal cord stimulation for relief of chronic back and extremity pain. Spine 21 (23): 2786–94. Caudill, M.A., Holman, G.H. and Turk, D. (1996) Effective ways to manage chronic pain. Patient Care 31 (11): 154–66. Doleys, D.M. and Olson, K. (1997) Psychological Assessment and Intervention in Implantable Pain Therapies. Minneapolis, MN: Medtronic Neurologic. Evans, J.A. (1946) Reflex sympathetic dystrophy. Surg. Gynecol. Obstet. 82: 36–43. Furlan, A.D., Lui, P.W. and Mailis, A. (2001) Chemical sympathectomy for neuropathic pain: does it work? Case report and systematic literature review. Clin. J. Pain 17 (4): 327–36. Furlan, A.D., Mailis, A. and Papagapiou, M. (2000) Are we paying a high price for surgical sympathectomy? A systematic literature review of late complications. J. Pain 14: 245–57. Harke, H., Gretenkort, P., Ladleif, H.U. et al. (2001) The response of neuropathic pain and pain in complex regional pain syndrome I to carbamazepine and sustained-release morphine in patients pretreated with spinal cord stimulation: a double-blinded randomized study. Anesth. Analg. 92 (2): 488–95. Kemler, M.A. and Furnee, C.A. (2002) Economic evaluation of spinal cord stimulation for chronic reflex sympathetic dystrophy. Neurology 59: 1203–9. Kemler, M.A., Barendse, G.A.M., van Kleef, M. et al. (2000) Spinal cord stimulation in patients with chronic reflex sympathetic dystrophy. N. Engl. J. Med. 343: 618–24.

Kemler, M.A., De Vet, H.C., Barendse, G.A. et al. (2004) The effect of spinal cord stimulation in patients with chronic reflex sympathetic dystrophy: two years’ follow-up of the randomized controlled trial. Ann. Neurol. 55 (1): 13–18. Kemler, M.A., De Vet, H.C., Barendse, G.A. et al. (2008) Effect of spinal cord stimulation for chronic complex regional pain syndrome Type I: five-year final follow-up of patients in a randomized controlled trial. J. Neurosurg. 108: 292–8. Krames, E. (1999) Interventional pain management appropriate when less invasive therapies fail to provide adequate analgesia. Med. Clin. North Am. 83 (3): 787–808. Kumar, K., Hunter, G. and Demeria, D. (2006) Spinal cord stimulation in treatment of chronic benign pain: challenges in treatment planning and present status, a 22-year experience. Neurosurgery 58 (3): 481–96. Kumar, K., Malik, S. and Demeria, D. (2002) Treatment of chronic pain with spinal cord stimulation versus alternative therapies: cost-effectiveness analysis. Neurosurgery 51 (1): 106–15. Kumar, K., Taylor, R.S., Jacques, L. et al. (2007) Spinal cord stimulation versus conventional medical management for neuropathic pain: a multicentre randomised controlled trial in patients with failed back surgery syndrome. Pain 132 (1-2): 179–88. Long, D.M. and Erickson, D.E. (1975) Stimulation of the posterior columns of the spinal cord for relief of intractable pain. Surg. Neurol. 4: 134–41. May, M.S., Banks, C. and Thomson, S.J. (2002) A retrospective, longterm, third-party follow-up of patients considered for spinal cord stimulation. Neuromodulation 5 (3): 137–44. North, R.B., Kidd, D.H., Zahurak, M., James, C.S. and Long, D.M. (1993) Spinal cord stimulation for chronic, intractable pain: two decades’ experience. J. Neurosurg. 32: 384–95. North, R., Shipley, J. et al. (2007) Practice parameters for the use of spinal cord stimulation in the treatment of chronic neuropathic pain. Pain Med. 8: S200–S275. Oakley, J.C. (2004) Chapter 13. Spinal cord stimulation for the treatment of chronic pain. In: K.A. Follett (ed.), Neurosurgical Pain Management. Philadelphia: W.B. Saunders, pp. 131–44. Oakley, J.C. and Weiner, R.L. (1999) Spinal cord stimulation of complex regional pain syndrome: a prospective study of 19 patients at two centers. Neuromodulation 2: 47–50. Prager, J.P. and Chang, J.H. (2000) Transverse Tripolar Spinal Cord Stimulation Produced by a Percutaneously Placed Triple Lead System. Presented at the International Neuromodulation Society World Pain Congress, San Francisco, August 2000. Abstract. Prager, J.P. and Jacobs, M. (2001) Evaluation of patients for implantable pain modalities: medical and behavioral assessment. Clin. J. Pain 3: 206–14. Sandroni, P., Low, P.A., Ferrer, T. et al. (1998) Complex regional pain syndrome I (CRPS I): prospective study and laboratory evaluation. Clin. J. Pain 14: 282–9. Schwartzman, R.J. (2000) New treatments for reflex sympathetic dystrophy. N. Engl. J. Med. 343: 654–6. Simpson, B.A. (2006) The role of neurostimulation: the neurosurgical perspective. J. Pain Symptom Manage. 31 (4S): S3–S5. Stanton-Hicks, M., Janig, W., Hassenbusch, S.J. et al. (1995) Reflex sympathetic dystrophy: changing concepts and taxonomy. Pain 3: 127–33. Stanton-Hicks, M.D., Burton, A.W., Bruehl, S.P. et al. (2002) An updated interdisciplinary clinical pathway for CRPS: report of an expert panel. Pain Pract. 2: 1–16. Taylor, R.S., Van Buyten, J-P. and Buchser, E. (2006) Spinal cord stimulation for complex regional pain syndrome: a systematic review of the clinical and cost-effectiveness literature and assessment of prognostic factors. Eur. J. Pain 10 (2): 91–101.

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Turk, D.C. and Gatchel, R. (eds) (2002) Psychological Approaches to Pain Management: A Practitioner’s Handbook, 2nd edn. New York: Guilford Publications. Turner, J.A., Loeser, J.D. and Bell, K.G. (1995) Spinal cord stimulation for chronic low back pain: a systematic synthesis. Neurosurgery 37: 1088–96. Van Buyten, J-P., van Zundert, J., Vueghs, P. and Vanduffel, L. (2001) Efficacy of spinal cord stimulation: 10 years of experience in a pain centre in Belgium. Eur. J. Pain 5 (3): 299–307.

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Wasner, G., Backonja, M. and Baron, R. (1998) Traumatic neuralgias: complex regional pain syndromes (reflex sympathetic dystrophy and causalgia): clinical characteristics, pathophysiological mechanisms and therapy. Neurol. Clin. 16 (4): 851–68.

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C H A P T E R

29

Peripheral Nerve Stimulation for Pain Peripheral Neuralgia and Complex Regional Pain Syndrome Michael Stanton-Hicks

o u t l i ne Historical Perspective

397

Pertinent Anatomy, Physiology, and Disease Pathophysiology Nerve Trunks Fascicular Anatomy Blood Supply of Peripheral Nerves

398 399 399 399

Peripheral Nerve Stimulation (PNS) – Indications 400

402

Stimulation Parameters

403

Outcomes Review of Most Recent Literature Assessment and Cost-effectiveness

403 403 404

References

406

of Melzack and Wall, used needle electrodes to stimulate the ulnar nerve. also used needle electrodes to test the effect on their own infraorbital nerves. Both transcutaneous and percutaneous neurostimulation were clinically applied to three patients in whom either complete or partial relief of pain was achieved (Wall and Sweet, 1967; Sweet, 1968). Although it was Shealy who was the first to demonstrate the use of spinal cord stimulation in animals (Shealy et al., 1967), he then went on to implant the first spinal cord stimulator by laminectomy at T2–3 in a patient with inoperable bronchogenic carcinoma (Shealy et al., 1970;

Historical perspective Undoubtedly, the gate theory of pain mechanisms (Melzack and Wall, 1965) propelled the basic science of neurostimulation into clinical practice. With the seminal publication of stimulation produced analgesia (SPA) by Reynolds (1969), a coalition of clinicians and basic scientists, working both independently and in collabo­ration, undertook animal and human experimentation to test the gate theory. The neurosurgeon William Sweet, working with Ronald Melzack

Neuromodulation

Surgical Technique

397

2009 Elsevier Ltd. © 2008,

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29.  Peripheral Nerve Stimulation for Pain Peripheral Neuralgia and Complex Regional Pain Syndrome

Shealy, 1975). This device was actually made at Case Western Reserve University in Cleveland, Ohio, by Dr Thomas Mortimer (see Chapter 11), then a predoctoral medical engineering student. This institution has become the premier biomedical laboratory for the study and development of devices with the associated neural interface for functional electrical stimulation. Dr Long at Johns Hopkins, also in collaboration with Shealy, developed cutaneous electrical stimulators (Long and Carolan, 1974; Long and Hagfors, 1975). The term transcutaneous electrical stimulation (TENS) was given by Burton (1973) for this modality. A growing interest in neurostimulation by a number of manufacturers including Medtronic, Avery Laboratories, Cordis, and Neuromed, all helped to propel the development of neurostimulation. While interest in neurostimulation has tended to focus on the central nervous system, it was clear to these early investigators that, in many cases, neuropathic pain localized to a specific nerve territory whether cranial, peripheral or a visceral nerve complex, would frequently not respond to spinal cord stimulation (SCS). Thus, the combination of SCS and peripheral nerve stimulation (PNS) was also pursued as a modality during the 1970s. The initial enthusiasm with which many surgical implanters engaged in this new therapeutic modality was tempered by the failure in many cases of PNS to achieve consistent analgesia. The technique also suffered from the fact that there was inadequate scientific research, poor patient selection, and in many cases, less than optimal surgical skills were employed, resulting in a high morbidity and poor surgical outcomes. By the end of the 1970s, peripheral nerve stimulation had practically disappeared other than in the hands of some enthusiastic surgeons who realized its early potential and who persisted with its development as a major clinical tool for the treatment of neuropathic pain that was refractory to all other measures.

Pertinent anatomy, physiology, and disease pathophysiology The mammalian nerve is comprised basically of a core or axon surrounded by an axolemma that is contained within a complex sheath that varies in diameter and is either dependent or not on the presence of myelin. Myelinated fibers are made up of many laminae called internodes that, depending on the diameter of the nerve fiber, are interrupted at variable distances. This myelin sheath is contained within a membrane termed the endothelial tube. In unmyelinated fibers

Epineurium Fascicle Perineurium Endoneurium and axon Interfascicular epineurium (A)

Epineurium

Interfascicular epineurium Perineurium

(B)

Figure 29.1  Nerve fiber anatomy (Redrawn with permission from D.G. Kline and A.R. Hudson (1995) Nerve Injuries: Operative Results for Major Nerve Injuries, Entrapments, and Tumors. Philadelphia: W.B. Saunders, p. 3. Copyright (1995) Elsevier)

these tubes may contain several axons in comparison with the single axon of a myelinated fiber. Throughout its length, the diameter of an axon may vary from as little as 2 m to 11.75 m (Barnard, 1974; Peters et al., 1976) (see Figure 29.1). Nerve fibers, throughout their length, undergo extensive branching, not only in the regions they supply, but also within their parent trunks. This has the effect that the total number of nerve fibers is greater distal than in proximal sections of the nerve trunk (Sunderland, 1991). This efficient anatomical disposition enables a single neuron to influence a comparatively large mass of tissue. The corollary to this arrangement is that nociception from an injured branch may, as a result of multiple branching, be referred to undisturbed tissue, and in addition by way of the axon reflex in branching axons is responsible for the algesic substances released in non-injured tissue. Axon reflexes occur in unmyelinated cutaneous

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pertinent anatomy, physiology, and disease pathophysiology

399

Table 29.1  Nerve conduction properties Nerve fiber

Nerve fiber (diameter in m)

Conduction velocity (M/s)

Function

A

12–20

70–120

Motor, extrafusal muscle fibers, proprioceptors

A

5–12

30–70

Touch, pressure

A

3–6

15–30

Motor, intrafusal muscle fibers

A

2–5

10–30

Nociceptors, touch, temperature

B

1.5–3

3–15

Preganglionic sympathetic fibers

Figure 29.2  Fascicular structure of a nerve (Redrawn with permission from Sunderland, 1991, p. 32. Copyright (1991) Elsevier)

nociceptive fibers which, when stimulated, generate both orthodromic and antidromic impulses in efferent collateral fibers to blood vessels and skin. These aspects have a significant bearing, not only on the effects of central neurostimulation, but also peripheral neurostimulation. The main physiologic types of nerve fibers are sensory fibers, varying in diameter from 1.5 to 20 m, nodal fibers with diameters varying from 2 to 20 m and postganglionic sympathetic fibers that are less than 2 m in diameter (see Table 29.1).

Nerve Trunks Nerve trunks consist of fasciculae which are invested with a thin, laminated sheath of perineural cells and collagen. The endoneural tubes investing each nerve fiber are contained within this framework. The fasciculae within a nerve trunk are surrounded by loose areolar tissue termed the epineurium.

Fascicular Anatomy As a result of a lifetime spent studying the microanatomy of peripheral nerves, Sunderland (1945) has given us an accurate picture of the fascicular anatomy. This anatomy has a great bearing on peripheral nerve stimulation and electrode design. The disposition of fasciculae are not in parallel groups, but rather repeatedly divide, unite, and re-divide to form extensive plexuses that occur throughout the length of a nerve. This arrangement continues to the terminal branches such as digital nerves. Fasciculae vary in size from 0.04 to 2 mm, but occasionally, as in the sciatic nerve, may

be as large as 4 mm. Where a nerve crosses a joint, the fasciculae are more numerous and, for example, in the median and ulnar nerves, fewer fasciculae are found proximal to the elbow when compared to the numbers of fasciculae of the nerves in the forearm. Further variability is found in some nerves where nerve fibers are contained within a single fasciculus for a short distance, e.g., the ulnar nerve behind the medial humeral epicondyle, the radial nerve in the spiral groove, the axillary nerve behind the shoulder, and the common peroneal nerve in the lower thigh (Di Rosa et al., 1988) (see Figure 29.2). As would be expected, the localization of specific fasciculae, while random in the proximal portion of their nerve trunks, will begin to orientate in functional terms as they approach their terminal branches (see Figure 29.2). The nerve fascicles throughout their length are supported by and receive their nutrition from the epineurium. It is the epineurium that provides the distinctive cord-like structure that identifies a nerve within its surrounding tissue. The amount of epineural tissue varies between 30% in the intercostal nerve to 88% in a sciatic nerve. This fact also influences the amount of electrical energy necessary to achieve a clinical effect during neurostimulation. The epineural tissue, the thin, dense sheath investing each fasciculus, acts as a diffusion barrier that effects local anesthetic action. Furthermore, those nerves having fewer fasciculae and a thicker perineurium are more difficult to block.

Blood Supply of Peripheral Nerves The vasa nervorum are an irregular source of nutrition that supplies each peripheral nerve from adjacent

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blood vessels. These nutrient vessels of necessity are tortuous to allow for considerable freedom of translational movement of peripheral nerves, particularly in the vicinity of joints. In addition, the nutrient vessels are more numerous near joints. After entering a nerve, a nutrient artery will branch into plexuses that may be seen on the surface or, in some cases, lying parallel to the nerve. These form anastomoses at intervals throughout the course of the nerve, reinforcing the blood supply within the epineurium in a manner similar to the blood supply of the spinal cord. Where a considerable interval between the supplying nutrient vessels occurs, there will be a natural “watershed” area of a nerve that may experience stress from ischemia should a nutrient vessel be injured (see Figure 29.3). However, unlike the blood supply to the spinal cord, which consists of end-arteries, these nutrient vessels form an extensive microvascular network that maintains the nutrition of all elements within a nerve trunk. In the case of ulnar nerve near the elbow, nutrient vessels can be sacrificed without impairing its blood supply as long as care is taken to ensure that the blood vessels are separated well away from the nerve in order to maintain satisfactory blood flow to the longi­tudinal arterial chain that is required for an effective collateral circulation. Studies by Ogata and Naito (1996) demonstrated that transposing a 2–3 cm segment of the ulnar nerve anterior to the medial humeral epicondyle reduces the intraneural flow for three days. Smith (1966a, 1966b) demonstrated that mobilization of proximal and distal segments of a nerve to achieve an end-to-end union should not exceed the critical limit of 8 cm. Sunderland also alluded to this in his earlier studies (Sunderland, 1991) (see Figure 29.3). A frequent factor in the early morbidity associated with peripheral nerve stimulation during the 1970s undoubtedly

Figure 29.3  Major nutrient arteries in interfascicular tissues (Redrawn with permission from Sunderland, 1991, p. 53. Copyright (1991) Elsevier)

resulted from interference with the nutritional blood supply as a result of intra-epineural sclerosis and extraneural constriction. It cannot be overemphasized that disturbance to adjacent anastomotic vessels should be kept to a minimum during the course of any surgical procedure to a nerve.

Peripheral nerve stimulation (PNS) – indications Peripheral nerve stimulation is indicated for painful neuralgias affecting any peripheral or cranial nerve. Box 29.1 summarizes common sites of neuropathic pain that are amenable to PNS. Box 29.1

 Common neuropathic pain sites amenable to PNS Cranial nerves (a) trigeminal nerve and divisions (b) supraorbital, infraorbital, mental l Occipital nerves l Segmental nerves (a) nerve root (b) intercostal (c) ilioinguinal (d) iliohypogastric (e) genitofemoral l Upper and lower limbs ulnar, median, radial, lateral cutaneous, forearm, sciatic, anterior and posterior tibial nerves l Brachial plexus l Lumbosacral plexus l

Peripheral nerve stimulation can be a highly effective clinical modality for the management of neuropathic pain. While the use of large surface electrodes has tended to influence electrode design, this would seem to be counterintuitive if selective fascicular stimulation is the means by which an optimal clinical response is to be achieved. Percutaneous electrodes have been used to test the viability of PNS (Campbell and Long, 1976; Nashold et al., 1979). A trial of PNS after implantation of electrodes on the target nerve can be undertaken by attaching the lead cable to an externalized pulse generator. To ensure optimal efficacy the following tests are recommended: Electrophysiological studies, including electro­ myography (EMG) or somatosensory evoked

l

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peripheral nerve stimulation (pns) – indications

potentials (SSEP) that demonstrate abnormalities in the distribution of the peripheral nerve. l At least two nerve blocks that are effective in relieving pain in the affected region. l A percutaneous trial stimulation proximal to the nerve pathology that provides at least 50% pain relief. The functional improvement during trial stimulation should include a reduction of allodynia/hyperalgesia, improvement in blood flow and motor function, and a 50% or better relief of pain would be quite acceptable. A prelude to PNS is psychological evaluation and counseling to ensure that patients understand the limitations and complexities of this therapy. It is important that patients realize that PNS by itself is only one factor in the overall management of neuropathic pain and associated disability. It can be an excellent tool to facilitate functional restoration. To date, there are no prospective randomized controlled studies describing PNS. All of the early reports that catalogued the medical conditions in which PNS has been successful are retrograde or case series reports. The early electrodes were button, bipolar or cuff design. One author (Nashold and Friedman, 1972; Nashold et al., 1982) used functional nerve mapping by circumferential electrical stimulation to localize sensory fascicles (see Figure 29.4). As shown in Figure 29.2 and/or as already mentioned, Sunderland (1945, 1978) demonstrated that the regional motor and sensory components are more random in the proximal segments of extremities, e.g. arm and thigh, and more localized or

12

R TO

UMB

SENSORY MO

3

TH

9

DIGIT 3 4

5

F FINGERS SO OR IGIT D 2

FL 4 3 EX

12

B

MO

TOR

OR

4

DI

GI

FL

T

Right median nerve at elbow

SENSORY

T 3 DIGI

9

B M

S SO F FI N G E R

TH U

6

EX

M

2 INDEX

TH

U

6

Figure 29.4  Functional mapping of a median nerve at elbow (Redrawn from Nashold and Goldner, 1975)

3

401

discrete in the distal extremity, forearm and leg. Law et al. (1981) reported a success rate of 60% after mapping patients in whom all had upper extremity postherpetic or traumatic neuropathies. A number of reports (Kirsch, et al., 1975; Picazza, et al., 1975; Campbell and Long, 1976; Sweet, 1976; Waisbrod et al., 1985; Gybels and Kupers, 1987) showed poor outcomes with lower extremity PNS. They concluded that weight-bearing, movements of the lower extremity, and greater translational movement of nerves like the sciatic nerve could adversely interfere with successful PNS. Also, the greater proportion of epineural tissue (88%) and the deeper location of sensory fascicles influences the efficiency of any surface electrode interface during PNS. As reported by Goldner et al. (1982), the stimulation amplitude required to achieve the threshold for afferent fascicular stimulation is quite close to the threshold for motor stimulation. Nevertheless, introduction of paddle type electrodes that were originally developed for spinal cord stimulation did improve the efficacy of peripheral nerve stimulation (Racz et al., 1988, 1990). These authors also described the use of a thin layer of fascia or tendon that was interposed between the paddle electrode and nerve. Several reports in the literature acknowledge the success of this modification (Strege et al., 1994; Hassenbusch et al., 1996; Cooney, 1997; Novak and McKinnon, 2000). Notwithstanding the absence of dedicated electrodes, the scope of PNS has increased markedly during the past decade. An increasing number of implanting surgeons are using PNS for upper and lower extremity neuropathic pain, the neural targets include cranial nerves, occipital, sacral, genitofemoral, ilioinguinal, and ileo-hypogastric nerves. The most commonly used electrodes are either a paddle type electrode (Resume or On-Point, Medtronic Inc.), a percutaneous electrode of the type used for SCS, or a small bipolar or multi-contact electrode similar to that which is used for functional electrical stimulation. In the USA, PNS is approved by the Food and Drug Administration (FDA) in conjunction with a Resume or On-Point electrode shown in Figure 29.5. The On-Point electrode has a Gor-Tex mesh surrounding the paddle (see Figure 29.4). Originally these electrodes were approved for use with a radiofrequency (RF) receiver– transmitter system, but this approval has recently been extended to cover a fully implantable pulse generator (IPG). In practice, flat paddle electrodes with four button contacts cannot provide uniform stimulation to a nerve trunk, the diameter of which may vary in size from 3 to 17 mm. In addition, the stability of such an interface will be directly influenced by a number of factors, two of which are: (1) the dynamic nature of the tissues in which it is placed; (2) the type of fibrosis and

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29.  Peripheral Nerve Stimulation for Pain Peripheral Neuralgia and Complex Regional Pain Syndrome

Figure 29.5  Experimental eight-contact “saddle” electrode on sciatic nerve

scarring that result from surgery. The physical nature of a “paddle” type electrode is such that it will be subject to forces of lateral rotation, translation, distraction either separately or together, resulting in the degradation or complete loss of nerve fiber recruitment, and loss of analgesic effect. Such electrodes are, moreover, rigid and therefore not compliant with the consistency of the neural structures to which they are placed. One attempt to obviate this problem and, in addition, provide more selective stimulation is the development of a “saddle” electrode with eight contacts that can be placed on the sciatic nerve. A prototype is shown in Figure 29.5. The improvement in stimulation, analgesia, and reduction in current compared with two “OnPoint” electrodes is described by two patients whose previous systems had failed due to technical causes. A minimalist approach has been undertaken by Buschman and Oppel (1999), who used small platinum multiple contact electrodes placed sub-epineurially. These electrodes have undergone extensive development for functional (efferent motor) electrical stimulation (Brummer and Turner, 1977a, 1977b, 1977c). Until such time as an array of electrodes designed for specific nerves is made available for clinical use, peripheral nerve stimulation will languish as a therapeutic tool alongside other more developed applications of neurostimulation.

Surgical technique Given the constraints of contemporary bioelectrode availability, the main neural targets for which this technique is used are the median, ulnar, and radial

Figure 29.6  On-Point electrode (Medtronic, Inc., Minneapolis, MN) shown attached to the ulnar nerve. NB: 4.0 monofilament sutures through nylon gauze and epineurium

nerves in the upper extremity, and the sciatic, common peroneal, posterior tibial, femoral, saphenous, and sural nerves in the lower extremity. The usual site for median and ulnar surgery is the brachial groove at the level of the mid-humerus and, at the same level, the radial nerve in the spiral groove. Access to the common peroneal and sciatic nerves is gained behind the biceps femoris muscle superior to the popliteal space. The site for posterior tibial nerve placement is proximal to the medial malleolus. After exposure of the nerve, a length sufficient to accommodate an On-Point electrode is carefully dissected from its surrounding structures in a manner that maintains the vaso nervorum and minimizes the subsequent degree of scar formation. While a number of centers have ceased to use a fascial graft between the electrode and nerve, the description that follows addresses this particular procedure. Either a free graft of fascia from an adjacent muscle or a pedicle flap is interposed between the electrode and nerve. This is retained in situ using 4-0 or 5-0 monofilament nylon sutures through the epineurium graft and nylon mesh. Three or four sutures are sufficient to stabilize the electrode (see Figure 29.6). If a two-stage procedure is utilized, the electrode lead is connected to an externalized extension through a stab wound at some distance from the main incision and is connected to an external IPG. A trial of one to two days is usually adequate to determine the effectiveness of PNS. For procedures in the upper extremities, a pocket for the IPG may be fashioned underneath the pectoralis muscle close to its tendon. An extension is drawn through a tunnel to the electrode and IPG, and connected at each end. This latter is retained by absorbable sutures to the fascia overlying the intercostal

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outcomes

Box 29.2

 Criteria and indications for patient selection Pain in an extremity or nerve distribution that is neuropathic l Demonstration by 1–3 targeted nerve blocks that pain is relieved l EMG demonstration of axonal impact, if appropriate l Pain reduction with a trial of TENS l Psychological testing to exclude psychiatric pathology or specific pain-related behavior l

muscles. A similar procedure is undertaken for PNS of nerves in the lower extremity. A pocket can be fashioned underneath the fascia of the biceps femoris muscle adjacent to and within the same wound, or a second excision and pocket for the IPG is made in the buttock, also requiring a tunnel through which the extension is drawn and connected to the electrode and IPG. In either case these procedures may be carried out as two-stage surgeries or as at the author’s center, where for the past 15 years all procedures have been undertaken as a single stage surgery. It should be noted that for PNS surgery on the sciatic nerve, two On-Point electrodes are required to address both tibial and peron­eal divisions. A two-channel IPG (Synergy Versitrel or Synergy, Medtronic, Inc.) is required. Because of its size, a pocket can be fashioned either on the surface of the fascia overlying the gluteus medius muscle or underneath the fascia in thin people. The same IPG can in most individuals be also placed underneath the fascia overlying the biceps femoris muscle with good cosmetic results. It is quite clear that the success of single stage surgery is directly the result of careful selection criteria as discussed and shown in Box 29.2.

Stimulation parameters Because of the proximity of motor and sensory fascicles in mixed nerve trunks, the parameters used for peripheral nerve stimulation differ significantly from those employed in spinal cord stimulation. Also, while some nerves are purely sensory, the majority of nerves that are suitable targets for peripheral nerve stimulation are mixed sensory and motor. This means that because of the fascicular architecture in a mixed nerve, electrical

energy that is applied to its surface will generate a field whose response will depend on the respective thresholds of sensory and motor axons in the fascicular bundles and their depth from the surface. In general, only very small currents are needed in comparison with the stimulation currents necessary for SCS, and the window of stimulation between sensory and motor elements is very small. Therapeutic parameters for peripheral nerves range from 0.1 to 2 volts and a pulse width that varies between 120 and 180 milliseconds. Rates are also much lower than those commonly used for spinal cord stimulation, varying between 50 and 90 Hz (Racz et al., 1990; Weiner, 2000). Because of the extremely small current requirements, it is not unusual for the power source in current IPGs to last ten years. Unlike the somatotopic programming that is performed during spinal cord stimulation in the awake patient, the current electrode systems available for PNS do not allow for fine mapping of peripheral nerves. At most, one can determine motor stimulation in the appropriate distribution of mixed peripheral nerves. It is, therefore, not necessary for patients to be conscious during programming. With the future availability of electrodes dedicated to fascicular mapping, it should be possible with postoperative programming to achieve optimal analgesia in the distribution of the affected nerve.

Outcomes Review of Most Recent Literature During the past 15 years, a number of case series describing the results of PNS in patients with neuropathic pain have been published. Cooney (1991) and Strege et al. (1994) have together followed 60 patients for two years. Relief in 80% of these patients was described as almost complete with another 20% achieving moderate pain relief (tolerable – the author’s term). The authors also emphasized the importance of psychiatric assessment and the need to achieve complete relief of symptoms after local anesthetic block of the ipsilateral nerve. A fact emphasized by the authors was the longstanding pain that had proved refractory to all conservative measures prior to PNS. Hassenbusch et al. in 1996 described 30 patients managed for CRPS II. The success rate of 63% is similar to the functional improvement described by Cooney and Strege. These data were subjected to Kaplan–Meier analysis which demonstrated about 35% reduction in analgesia during the first and second year, but maintenance of the residual analgesia at three years. Sixteen patients have now been followed for 15 years with no further diminution

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in their analgesia. Of note is the fact that 23% of those patients achieving good analgesia returned to either full-time work or changed from no employment to part-time employment. A total of 203 patients have now received PNS implants for CRPS II and other mononeuropathies at the Cleveland Clinic Foundation, replicating the earlier findings. Shetter et al. (1997) reported 117 patients who underwent trial stimulation followed by implant of their IPG and were followed for 53 months. They described 70% and 80% relief of pain in males and females respectively with increased daily activity in 65%. Seventy-five percent of these patients were happy with the outcome of their therapy. Subepineural platinum electrodes have been described by Buschman and Oppel (1999). These were implanted after an externalized trial in a large variety of nerves in the extremities, head, neck, and upper trunk in 52 patients. The results were good to excellent in 80% of patients, but more significant is the observation that 22 patients returned to either full-time or part-time work; and two patients changed their occupation. This is a remarkable occupational salvage. Novak and Mackinnon (1999) reported their experience in 17 patients. At 21 months, 11 patients had good to excellent pain relief, 4 had fair, and 3 had poor relief. Six of these patients returned to work. An interesting review of work undertaken at three centers, the Red Cross Pain Center in Mainz, Germany, The Institute for Back Care in Bad Kreuznach, Germany, and the Linn Medical Center in Haifa, from 1993 to 1995 has been combined for analysis (Eisenberg et al., 2004). The earlier work by Waisbrod and Gerbershagen, has been published in 1985 and 1986 respectively. A total of 46 patients were included. Box 29.1 lists the specific target nerves. All patients failed to respond to all other treatment and all patients obtained relief following a diagnostic local anesthetic block. The results were classified as good in 26 (78%) and poor in 10 (22%). Overall pain intensity before and after surgery was a mean of 69 and 24 respectively (using a scale of 0–100 mm) (p 0.001). Johnson and Birchiel (2004) reported the successful implantation of PNS for supraorbital and infra­orbital neuropathic pain after post-herpetic neuralgia or facial trauma. In 8 patients the supraorbital nerve was affected and in 3 the infraorbital nerve. All patients subsequently received an IPG implant and one patient who had sustained an injury to the infraorbital nerve had no response. At a mean of 26.6  4.7 months, at least 50% pain relief was sustained in 70% of the patients studied. Medication use declined by 70% and the only two failures that occurred belonged to the post-herpetic group. This presumably reflects the degree of deafferentation in these patients.

A most recent paper by Mobbs et al. (2007) described the results of 42 patients who underwent trial stimulation for neuropathic pain resulting from blunt or sharp nerve trauma, iatrogenic injuries associated with surgery for fracture reduction, penetration injury by needle or cannula, and neuropraxia during the course of neurolysis in the presence of entrapment or tumor. The authors defined 50% improvement in the verbal pain scores (VPS) of 61% of patients where the mean VPS preoperatively was 9 with an SD  0.96. At one month this value was 5.1 with a SD  2.73, and subsequently by an independent evaluation at which time the VPS was 5.2, SD  2.29. Activity levels were improved in 47%, unchanged in 37%, and worse in 16%. Sixty-three percent of the patients reduced or eliminated their use of oral analgesics. A two-tailed Ttest indicated that the difference between the reported levels of postoperative and preoperative pain was significant (p  0.034). Contrary to popular perception that Worker’s Compensation patients will do worse than those without industrial claims, in this study, those with and those without industrial claims had identical outcomes (p 0.05). All of the foregoing studies are retrospective in nature as the authors in latter studies point out. While a randomized controlled trial (RCT) in which the best medical treatment cohort is compared to peripheral nerve stimulation might be ideal, such a study is already precluded by the fact that patients who ultimately become subjects for peripheral nerve stimulation will have already failed “best medical treatment.”

Assessment and Cost-effectiveness Most third party payers have come to use an empirical standard of 50% improvement in pain relief as a requirement to justify the expense of neurostimulation procedures. Coupled with this practice is the approval by a clinical psychologist that no behavioral factors would preclude a patient from undergoing a trial and subsequent implantation of a neurostimulation device before the associated expenses will be reimbursed. These arbitrary requirements have been universally adopted. It should be noted that current practice is to use a simple pain scale, e.g., visual analog score (VAS) or similar numerical rating scale (NRS). These are arithmetic scales that are validated in terms of acute pain measurement, and have been extended for use in chronic pain assessment. All metrics of pain, however, suffer from the fact that they are subjective measurements and are applied to biologic processes that are logarithmic functions. An attempt to refine and define clinical improvement in both functional and holistic terms is the

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outcomes

introduction of quality of life measures (QoL). In fact, years of clinical experimentation with neuroaugmentation devices suggests that pain as a marker of improvement or worsening, for many patients, is not nearly as important as an improvement in function. In fact, when asked how their trial of neurostimulation affected their pain, many will say, “there is little improvement” or “no it is just the same as it was,” yet are very enthusiastic about the sudden improvement in function as measured by “walking for the first time in years,” or being able to do things, “I can now open a can,” a typical function of an upper extremity that had been precluded by their disability and neuropathic pain. The difficulty of using pure pain measures has been discussed by Turk et al. (1988) and Birchiel et al. (1996). Obviously, return to work as frequently mentioned in the clinical examples already discussed, is perhaps one of the most telling outcome markers of success through neuromodulation. This, in today’s preoccupation with evidence-based medicine, obviously does not meet level I or level II measures of therapeutic effectiveness. North et al. (1991) have emphasized the need for a “disinterested” third party assessment of clinical outcome. Yet, many of their patients who claim to have not experienced 50% or greater pain relief during their trial, or never had any pain relief, continue to use their neurostimulators. It is not possible to design a fully randomized controlled trial (RCT) of neuromodulation because the associated paresthesiae cannot be blinded. In the recent review by Taylor et al. (2006), they concluded that evidence from a wellcontrolled prospective RCT supports the conclusion that SCS, combined with physical therapy, is a clinically useful and cost-effective treatment for CRPS type I. It is this type of study design to assess the effectiveness of PNS that is urgently needed. Future studies must include QoL measures and functional improvement scores such as the SF36 which was developed to assess the effectiveness of back pain treatment. Also, cost-effectiveness of comparative treatments will help to anchor this modality in an era of cost containment. Case selection should center on degree of disability, the severity of neuropathic pain and the associated ischemic component with its irreversible affects in the affected nerve distribution. A change in attitude regarding the way in which simple measures such as pain reduction measured by the VAS must give way to an assessment of function and quality of life measures, notwithstanding the placebo effect that can influence the patient’s perception of the treatment. It must also be emphasized that because of the chronicity of symptoms in patients with neuropathic pain that have proved refractory to all previous measures, any slight improvement will be perceived by a patient

405

as a light year change; yet the occasional patient may not experience the benefits in the long term. The use of a trial in PNS patients as already mentioned may be moot. In the 203 patients that have been implanted at the Cleveland Clinic Foundation, less than 5% of PNS systems have been explanted either as the result of long-term failure or because the patient felt their symptoms had improved to the point whether they no longer needed the device. As a modality peripheral nerve stimulation offers significant advantages. It is reversible, non-destructive, and using telemetry can be “dosed” by the patient. One disadvantage of peripheral nerve stimulation that limits its wider acceptance, is that the procedure is invasive requiring the expertise of a trained surgeon. Infection occurs in less than 4% of patients and the approximately 10% decrement of effect that is observed during the first 18 months after implantation is not a factor that materially affects the long-term efficacy of this modality. The current incidence of technical failure is directly related to equipment currently available. In most cases it is a result of distraction from the target nerve due to scarring. A more appropriately designed electrode that accommodates to the shape and size of peripheral nerves would not only obviate this problem, but would also reduce the procedural time as surgeons try to compensate for the inadequacy of current electrode design with fascial flaps, adding mesh to the electrode (Mobbs et al., 2007), and the extra time taken to dissect a length of nerve only to accommodate an inappropriately large paddle electrode in an attempt to prevent dislodgement of the electrode. While percutaneous electrodes, described elsewhere in this volume, have an important part to play in PNS, a family of dedicated electrodes having an appropriate interface with their particular nerves and the reduction in size of their implanted current source, together with wireless technology will ultimately enable the full development of peripheral nerve stimulation to flourish. It is envisioned that in many cases, future PNS systems will be implanted prophylactically at the time of elective peripheral nerve surgery, whether following trauma, at the time of neurolysis for entrapment or in patients with longstanding neuropathic pain after either of the foregoing iatrogenic measures. When peripheral electrode systems for pain control have reached the same level and art of development now attained by functional electrical stimulation, the scope for this modality in painful neuropathy is tremendous. As much as two-thirds of surgical cases currently managed by spinal cord stimulation for neuropathic pain in the distribution of one or two nerves in the lower extremity and most cases of intractable neuropathic pain in the upper extremities are amenable to peripheral nerve stimulation. The advantages over

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29.  Peripheral Nerve Stimulation for Pain Peripheral Neuralgia and Complex Regional Pain Syndrome

spinal cord stimulation are greater stability, specific regional stimulation, low current requirements and no ancillary stimulation.

References Barnard, E.A. (1974) In J.I. Hubbard (ed.), The Peripheral Nervous System. New York: Plenum Press. Birchiel, K.J., Anderson, V.C., Brown, F.D., Fessler, R.G., Friedman, W.A. et al. (1996) Prospective, multicenter study of spinal cord stimulation for relief of chronic back and extremity pain. Spine 21: 2786–94. Brummer, S.B. and Turner, M.J. (1977a) Electrochemical considerations for safe electrical stimulation of the nervous system with platinum electrodes. IEEE Trans. Biomed Eng. 24: 59–63. Brummer, S.B. and Turner, M.J. (1977b) Electrical stimulation with Pt electrodes. I: a. method for determination of “real” electrode areas. IEEE Trans. Biomed. Eng. 34: 436–9. Brummer, S.B. and Turner, M.J. (1977c) Electrical stimulation with Pt electrodes. II: estimation of maximum service redox (theoretical non-gassing) limits. IEEE Trans. Biomed. Eng. 24: 440–3. Burton, C. (1973, March) Pain Suppression Through Peripheral Nerve Stimulation. Paper presented at the Annual Houston Neurological Symposium. Houston, Texas. Buschman, D.N. and Oppel, F. (1999) Periphere nervenstimulation. [Peripheral nerve stimulation for pain relief in CRPS II and phantom-limb pain]. Schmerz 13: 113–20 [in German]. Campbell, N. and Long, D.M. (1976) Peripheral nerve stimulation in the treatment of intractable pain. J. Neurosurg. 45: 692–9. Cooney, W.P. (1991) Chronic pain treatment of direct electrical nerve stimulation. In: R.H. Gelberman (ed.), Operative Nerve Repair and Reconstruction, Vol. II. Philadelphia: J.B. Lippincott, pp. 1551–61. Cooney, W.P. (1997) Electrical stimulation in the treatment of complex regional pain syndrome of the upper extremities. Hand Clin. 13: 519–26. DiRosa, F., Giuzzi, P. and Battiston, B. (1988) Radial nerve anatomy and vesicular arrangement. In: G. Brunelli (ed.), Textbook of Microsurgery. Milan: Masson, p. 571. Eisenberg, E., Waisbrod, H. and Gerbershagen, H.U. (2004) Longterm peripheral nerve stimulation for painful nerve injuries. Clin. J. Pain 20: 143–6. Gerbershagen, U. (1986) Organized treatment of pain – determination of status. Internist (Berl.) 27: 459–69 [in German]. Goldner, J.L., Nashold, B.S., Jr. and Hendrix, P.C. (1982) Peripheral nerve electrical stimulation. Clin. Orthop. Relat. Res. 163: 33–41. Gybels, J. and Kupers, R. (1987) Central and peripheral electrical stimulation of the nervous system in the treatment of chronic pain. Acta Neurochir 38 (Suppl.): 64–75. Hassenbusch, S.J., Stanton-Hicks, M., Schoppa, D. et al. (1996) Longterm peripheral nerve stimulation for reflex sympathetic dystrophy. J. Neurosurg 84: 415–23. Johnson, M.D. and Birchiel, K.J. (2004) Peripheral stimulation for the treatment of trigeminal postherpetic neuralgia and trigeminal posttraumatic neuropathic pain: a pilot study. Neurosurgery 55: 135–42. Kirsch, W.M., Lewis, J.A. and Simon, R.H. (1975) Experience with electrical stimulation devices for the control of chronic pain. Med. Instr. 9: 217–20. Law, J.T., Swett, J. and Kirsch, W. (1981) Retrospective analysis of 22 patients with chronic pain treated by peripheral nerve stimulation. J. Neurosurg 52: 482–5. Long, D.M. and Carolan, M.T. (1974) Cutaneous afferent stimulation in the treatment of chronic pain. In: J.J. Hubbard (ed.), Advances

in Neurology. International Symposium on Pain, Edited by J.J. Bonica. New York: Raven Press, pp. 755–9. Long, B.M. and Hagfors, N. (1975) Electrical stimulation in the nervous system: the current status of electrical stimulation of the nervous system for relief of pain. Pain 1: 109–23. Melzack, R.A. and Wall, P.D. (1965) Pain mechanisms: a new theory. Science 150: 971–9. Mobbs, R.J., Nair, S. and Blum, X.P. (2007) Peripheral nerve stimulation for the treatment of chronic pain. J. Clin. Neurosci. 14: 216–21. Nashold, B.S., Jr. and Friedman, H. (1972) Dorsal column stimulation for control of pain. Preliminary report on 30 patients. J. Neurosurg 36: 590–7. Nashold, B.S., Jr. and Goldner, J.L. (1975) Electrical stimulation of peripheral nerves for relief of intractable pain. Med. Instrum. 9: 224–5. Nashold, B.S., Jr, Mullen, J.B. and Avery, R. (1979) Peripheral nerve stimulation for pain relief using a multi-contact electrode system. J. Neurosurg 51: 872–3. Nashold, B.S., Jr, Goldner, J.L., Mullen, J.B. and Bright, D.S. (1982) Long-term pain control by direct peripheral nerve stimulation. J. Bone Joint Surg. 64: 1–10. North, R.B., Ewend, M.G., Lawton, M.T., Kidd, D.H. and Piantadosi, S. (1991) Failed back surgery syndrome: 5-year follow-up after spinal cord stimulator implantation. Neurosurgery 28: 692–9. Novak, C.V. and Mackinnon, S.D. (2000) Outcome following implantation of peripheral nerve stimulator in patients with chronic pain. Plast. Reconstr. Surg. 105: 1967–72. Ogata, K. and Naito, M. (1996) Blood flow of peripheral nerves: affects of dissection, stretching and compression. J. Hand Surg. 11b: 10. Peters, A., Palay, S.L. and Webster, H.deF. (1976) The Fine Defined Structure of the Nervous System: The Neuron and Supporting Cells. Philadelphia: W.B. Saunders. Picazza, J.A., Cannon, B.W., Hunter, S.E., Boyd, A.S., Guma, J. and Maurer, D. (1975) Pain suppression by peripheral nerve stimulation. Part II. Observations with implanted devices. Surg. Neurol. 4: 115–26. Racz, G.B., Brown, N.T. and Lewis, R. (1988) Peripheral stimulator implant for treatment of causalgia caused by electrical burns. Tex. Med. 84: 45–50. Racz, G.B., Lewis, R., Heavner, J.E. et al. (1990) Peripheral nerve stimulator implant for treatment of causalgia. In: M. StantonHicks (ed.), Pain and the Sympathetic Nervous System. Boston, MA: Kluwer Academic Publishers, pp. 225–39. Reynolds, D.B. (1969) Surgery in the rat during electrical analgesia induced by central brain stimulation. Science 164: 444–5. Shealy, C.M. (1975) Dorsal column stimulation: optimization of application. Surg. Neurol. 4: 142–5. Shealy, C.M., Mortimer, J.T. and Hagfors, N.R. (1970) Dorsal column electroanalgesia. J. Neurosurg. 32: 560–4. Shealy, C.M., Mortimer, J.T. and Reswick, J.B. (1967) Electrical inhibition of pain by stimulation of the dorsal columns; preliminary clinic report. Anesth. Analg. 46: 489–91. Shetter, A.G., Racz, G.B., Lewis, R. and Heavner, J.E. (1997) Peripheral nerve stimulation. In: R.B. Nort and R.M. Levy (eds), Management of Pain. New York: Springer-Verlag. Smith, J.W. (1966a) Factors influencing nerve repair. I. Blood supply of peripheral nerves. Arch. Surg. 93: 335–41. Smith, J.W. (1966b) Factors influencing nerve repair. II. Collateral circulation of peripheral nerves. Arch. Surg. 93: 433–7. Strege, W., Cooney, W.G., Wood, M.B. et al. (1994) Chronic peripheral nerve pain treated with direct electrical nerve stimulation. J. Hand Surg. (Am.) 19: 931–9.

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Sunderland, S. (1945) The intraneural topography of the radial, median and ulnar nerves. Brain 64: 242–99. Sunderland, S. (1978) Nerves and Nerve Injuries, 2nd edn. Edinburgh: Churchill Livingstone. Sunderland, S. (1991) Nerve Injuries and Their Repair: A Critical Appraisal. Edinburgh: Churchill Livingstone, pp. 31–45. Sweet, W.H. (1968) Lessons on pain control from electrical stimulation. Trans. Stud. Coll. Physicians. Phila. 35: 171–84. Sweet, W.H. (1976) Control of pain by direct electrical stimulation of peripheral nerves. Chem. Neurosurg. 23: 103–11. Taylor, R.S., VanBuyten, J.P. and Buchser, E. (2006) Spinal cord stimulation for complex regional pain syndrome: a systematic

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review of the clinical and cost effectiveness literature and assessment of prognostic factors. Eur. J. Pain 10: 91–101. Turk, D.C., Rudy, T.E. and Stieg, R.L. (1988) The disability of determination dilemma: toward a multiaxial solution. Pain 34: 217–29. Waisbrod, H., Panhan, C., Hansen, D. et al. (1985) Direct nerve stimulation for painful peripheral neuropathies. J. Bone Joint Surg. 67B: 470–2. Wall, P.D. and Sweet, W.H. (1967) Temporary abolition of pain in man. Science 155: 108–9. Weiner, L. (2000) The future of peripheral nerve neurostimulation. Neurol. Res. 22: 299–303.

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C H A P T E R

30

Occipital Neurostimulation for Treatment of Intractable Headache Syndromes Richard L. Weiner and Kenneth M. Alo’

o u tline Introduction

409

Results Stimulation Usage Complications

413 413 414

Treatment of Migraine Headaches

410

Literature Review

410

Positioning and Sedation

414

Surgical Technique Intraoperative Stimulation Testing Electrode Fixation and Tunneling Pulse Generator Implantation

411 412 412 412

Mechanisms of Action

414

Conclusions

414

References

415

occipital neuralgia, affect almost 40 million Americans and many more millions worldwide (Silberstein et al., 2002). It is estimated that up to 5% of these headache sufferers experience daily or near daily headaches (transformed migraine, chronic daily headaches) and 1–2% are so poorly responsive to medication para­ digms that this failure can lead to narcotic depend­ ence, severe restrictions in daily activities, failed personal and career objectives and an overwhelming sense of hopelessness and despair. Specifically, chronic daily headache refers to a group of non-paroxysmal headaches, including those associated with overuse of symptomatic medications, that present on a daily or near daily basis with a dura­ tion greater than four hours a day and lasting longer than six months (Newman et al., 1994). Its preva­ lence in the general population varies from 0.5 to 6%, approximating 2.2 million patients (Spierings et al., 1998). Due to episodic migraines, annual direct costs

introduction Primary headache disorders are a dominant pres­ entation in many neurology, pain management and primary care practices worldwide. A greater under­ standing of the various headache types has been facil­ itated by the recent reclassification scheme developed by the International Headache Society (IHS) in 2004 (Headache Classification Scheme, 2004). Clarification of the diagnosis criteria for various migraine and ten­ sion headache syndromes, as well as the addition of previously unrecognized conditions such as hemi­ crania continua, and a more precise definition of sec­ ondary headaches such as occipital neuralgia, are extremely important in the formulation of successful treatment strategies by the clinician. Intractable migraine, chronic daily headache, cervi­ cogenic, and secondary headache syndromes such as

Neuromodulation

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30.  Occipital Neurostimulation for Treatment of Intractable Headache Syndromes

are over $1 billion, costing American employers $13 billion/year due to absenteeism (Lipton et al., 2001). Seventy-eight percent of patients with chronic daily headache have had episodic migraine in the past. Episodic migraine sufferers tend to range in age from 25 to 45 years with peak prevalence at age 40. Women are five times more likely to experience migraines than men. Females tend to have more frequent occurrences of migraine. There are an estimated 28 000 000 migraine sufferers in the USA. Only 15% have migraine with aura and 85% have migraine without aura (Silberstein et al., 2001). With increased frequency of episodic migraine and time, migraine patients show a progressive change or loss of specific migraine characteristics, and present with a daily or near daily headache, with mixed clinical features of migraine and tension type headache (Saper, 1990). These patients typically have an 80% chance of symptomatic overuse of medicines including simple analgesics, narcotics, and other symptomatic medi­ cations (Silberstein and Lipton, 2001). Interestingly, these patients with transformed migraine, which only make up approximately 5% of the headache preva­ lence, are responsible for the vast majority of treatment costs. These patients commonly present with episodic migraine early in life, which later becomes chronic and progressive. The natural progression of disease is that of relapsing progressive disease. Migraine transformation is a critical aspect of patient treatment. Physicians play a pivotal role in preventing chronic daily headache. It is important to control acute medications as well as to insure that acute migraine attacks are controlled prop­ erly. Symptomatic overuse should also be addressed.

Treatment of migraine headaches Treatment options for almost all headache syndromes have centered around a variety of medication manage­ ment paradigms including acute pain relieving as well as preventative measures. Pain medication options fall into categories including NSAIDs, Tryptans, opioids, ergot compounds, and sedatives. Preventative medi­ cations include anticonvulsants, antidepressants, beta blockers and serotonin antagonists. Additionally, efforts to identify and treat any underlying migraine triggers, whether physical or emotional in nature, can produce significant relief. Acupuncture and other alternative treatment options including biofeedback, massage and diet control are commonly employed. Migraines continue to be under-diagnosed and undertreated (Mueller, 2007). Therefore, the true nature of the degree of disability and suffering with these

headache conditions, despite a variety of conservative management schemes, may, indeed, be under-reported and under-appreciated. Neuromodulation for treatment of chronic pain dis­ orders over the past 35 years has centered on spinal cord stimulation (SCS) and peripheral nerve stimulation (PNS) using implanted electrode and generator devices to modulate perception of abnormal pain signals to the brain. Examples are SCS for FBSS (Van Buyten, 2006), SCS for CRPS (Stanton-Hicks, 2006), and PNS or sacral nerve stimulation for bladder pain and dysfunction (Mayer and Howard, 2008). More recently, multiple authors (Weiner and Reed, 1999; Weiner et al., 2000, 2001; Alo’ and Holsheimer, 2002) have reported that successful neuromodulation for occipital headache syndromes can be accomplished with subcutaneous regional electrode placement at or near the level of C1 without direct contact with a specific peripheral nerve. It has been postulated that nociceptive transmission and pain modulation at this level can both prevent central sensitization and modulate the dorsal hornbrainstem by altering the trigeminocervical pathway (Goadsby et al., 1997; Popeney and Alo’, 2003; Alo’ and Popeney, 2004).

Literature review Occipital nerve neurolysis and/or neurectomy have been part of the neurosurgical armamentarium in treating intractable occipital headaches for many years. Though occasionally very effective, the not-infrequent development of delayed deafferentation pain in the distribution of the affected occipital nerve limits the long-term usefulness of the procedure. C2 ganglionec­ tomy (Lozano et al., 1998) for posttraumatic C2 pain syndromes has resulted in an 80% good to excellent outcome with a 3-year follow-up. Patients with nontraumatic C2 pain did not fare nearly as well as those with traumatic C2 pain and subtle but significant morbidity, including postoperative dizziness or gait disturbances, may be a persistent problem. C2 nerve decompression (Pikus and Phillips, 1997) can achieve up to a 79% success rate with 33% com­ plete pain relief and 46% adequate pain relief over 2 years. C1–2 fusion (Joseph and Kumar, 1994) can cor­ rect focal instability and may be indicated on occasion. C1–3 posterior rhizotomy (Dubuisson, 1995) via vent­ rolateral DREZ lesioning at C1–3 can be an effective but highly invasive surgical technique. Neurolysis of the greater occipital nerve (Bovim et al., 1992) can be effective in the short term but most patients tend to have significant recurrences within one to two years.

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411

Surgical technique

Picaza et al. (1977–8) reported pain suppression by peripheral nerve stimulation on six patients with occipital neuralgia using a cuff electrode technique, with 50% of patients reporting a good outcome. Waisbrod et al. (1985) reported a very good result from stimulation of the greater occipital nerve for painful peripheral neuropathy. Experience with peripheral nerve electrical stimu­ lation for painful mononeuropathies and complex regional pain syndromes involving major peripheral nerves led to the sentinel observation (Weiner, 2006) that subcutaneous tissue can conduct and propagate electri­ cal impulses in a dermatomal and/or myotomal distri­ bution of one or more peripheral nerves without direct nerve contact producing pain relief in the region of the electrically induced local paresthesiae. This has led to the development and refinement of a percutaneous neu­ rostimulation procedure implanted transversely into the subcutaneous space nominally at or just above the level of C1 (Weiner and Reed, 1999; Weiner, 2000; Weiner et al., 2000; Weiner et al., 2001; Alo’ and Holsheimer, 2002; Popeney and Alo’, 2003; Alo’ and Popeney, 2004; Oh et al., 2004) as a minimally invasive treatment alter­ native for intractable occipital headache syndromes.

off with a more vertical lead placement in the occipi­ tal region. In this case the stimulation does not affect directly the main trunks of the occipital nerve, but rather its peripheral branches. Surgical paddle electrodes can also be implanted subcutaneously, though somewhat more invasively, using sharp dissection techniques with the electrode contacts oriented towards the fascia It is very important to include in the prepped area not only the needle entry point, but also the whole area of the trajectory of the needle/lead. This is to obviate the inad­ vertent piercing of the skin by the tip of the needle in a non-sterile area (Weiner and Reed, 1999; Oh et al., 2004). Rapid needle insertion usually obviates the need for even a short-acting general anesthetic once the surgeon

Beveled edge needle opening

Greater occipital nerve Lesser occipital nerve Third occipital nerve

Surgical technique Using local anesthesia at the incision site only, a ver­ tical 2 cm incision is made at the level of the C1 lamina either medial and inferior to the mastoid process or in the midline posteriorly under fluoroscopic control extending to but not into the cervicodorsal fascia. The patient may be positioned laterally or prone depend­ ing on the incision entry point. The subcutaneous tis­ sues immediately lateral to the incision are undermined sharply to accept a loop of electrode created after place­ ment and tunneling to prevent electrode migration. A Tuohy needle is gently curved to conform to the transverse posterior cervical curvature (bevel concave) and without further dissection is passed transversely in the subcutaneous space across the base of the affected grater and/or lesser occipital nerves which at the level of C1 are located within the cervical musculature and overlying fascia (see Figures 30.1 and 30.2). Single or dual quadripolar or octapolar electrodes may be passed from a midline incision to either affected side or alter­ natively placed to traverse the entire cervical curvature bilaterally from a single side or via two opposing inci­ sions. Alternatively, if paresthesiae coverage does not reach high enough in the occipital region, the lead(s) can be placed either vertically or more obliquely in the posterior occipital area. Some implanters prefer to start

Introducer needle

Figure 30.1  Curved needle placement

Figure 30.2  Curved needle at the level of C1

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412

30.  Occipital Neurostimulation for Treatment of Intractable Headache Syndromes

becomes facile with the technique. Short-acting deep intravenous sedation might be necessary if the needle placement is difficult or the patient is hypersensitive to pain. Following placement of the electrode into the Tuohy needle, the needle is withdrawn and the elec­ trode connected to an extender cable for intraopera­ tive testing.

Intraoperative Stimulation Testing After lead placement, stimulation is applied using a temporary RF transmitter to various select electrode combinations enabling the patient to report on the table the stimulation location, intensity, and overall sensation. Most patients have reported an immediate stimulation in the selected occipital nerve distribution with voltage settings from 1 to 4 volts with midrange pulse widths and frequencies. A report of burning pain or muscle pulling should alert the surgeon the elec­ trode is probably placed either too close to the fascia, intramuscularly, or too far above or below the C1 level and should be repositioned. Repeated needle passage for electrode placement can lead to subcutaneous edema and/or hematoma formation with loss of elec­ trode conductivity thereby blocking evaluation for per­ manent lead positioning.

Electrode Fixation and Tunneling

and a rechargeable implantable pulse generator. The RF and rechargeable systems generally allow for more continuous higher voltage outputs, while the pri­ mary cell requires less programming interaction. Most patients currently opt for the implantable pulse gen­ erator system, which is currently an off-labeled appli­ cation for peripheral use. With the voltage settings usually required for occipital stimulation, the primary cell lithium ion battery can last 3–5 years while the rechargeable may last 7–9 years before replacement. Generator placement appears to influence both patient positioning during the procedure and the risk of postoperative migration, particularly if strain relief is not generously applied. Typical implant locations are: Upper buttock – facilitates single-stage electrode and generator placement in the prone position. l Abdomen – usually done with the patient in the lateral position. l Upper chest – lateral or supine positions favor this location. l

With upper buttock generator placement there is significant stretching of extension wire when a patient bends forward, creating excessive tugging on the cervically placed electrodes. This could be one of the major factors, along with anchoring technique, mitigating electrode migration. Thus, abdominal or anterior chest placement might reduce migration potential.

Probably the most important aspect of the procedure involves techniques to prevent electrode migration (pullback) from its transverse subcutaneous position in the highly mobile upper cervical region. Following successful stimulation, the electrode is sutured to the underlying fascia with the supplied silicone fastener and 2-0 silk sutures. A small dab of medical grade sili­ cone glue is placed between the fastener and electrode using a small angiocath to ensure fixation. A loop of electrode (Figure 30.3) is also sutured loosely in the previously prepared subcutaneous pocket to reduce migration risk as well. This allows for strain relief to mitigate the stress of cervical motion. A short-acting general anesthetic is used to tunnel the electrode(s) or extender wire to the distal site for connection and implantation of the receiver or generator.

Pulse Generator Implantation There are three options available for the system power source: an external RF transmitter/receiver system, a primary cell implantable pulse generator,

Figure 30.3  Loop of electrode

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413

Results

Results The authors combined implant experience from 1993 through 2005 has consistently shown an approxi­ mately 75% good and excellent long-term pain relief with a 15% fair and 10% poor response in over 150 implanted patients with long-term follow-up. The total headache years in this population was approxi­ mately 1200 years with mean headache duration of 8 years in 77% females and 23% males. Most of the patient population exhibited some degree of bilateral pain with one side typically dominant. Preoperative VAS scores ranged from 5 to 10 with a mean of 9. Postoperative VAS ranged 0 to 6 with a mean of 3. A review of published ONS outcomes to date (Table 30.1) lends significant support for consideration of neuromodulation implant techniques for intractable headache syndromes. Though all of the studies report small numbers, the overall success rate of 70–100% in short-term follow-ups, with 70–75% long-term follow-up, appears to be meaningful and reproducible

(Weiner and Reed, 1999; Hammer and Doleys, 2001; Jones, 2003; Oh et al., 2004; Kapural et al., 2005; Rodrigo-Royo et al., 2005; Johnstone and Sundaraj, 2006; Slavin et al., 2006; Weiner, 2006; Burns et al., 2007; Magis et al., 2007; Melvin et al., 2007; Schwedt et al., 2007; Trentman et al., 2008).

Stimulation Usage Patients report using the devices in a variety of scen­ arios, including intermittent stimulation for migraine with aura, cervicogenic headache, occipital neuralgia, post-herpetic neuralgia, tension headache and cluster headaches. Continuous use with chronic daily head­ aches (transformed migraine) and even deafferentation post-traumatic pain is common as well. Objective PET scan changes have also been shown to correlate with patient activation/deactivation of the device (Goadsby et al., 1997). Common stimulation parameters and use patterns have been described (Weiner and Reed, 1999; Weiner, 2000; Popeney and Alo’, 2003; Oh et al., 2004).

Table 30.1  Published outcomes of occipital neurostimulation, 1999–2008 Authors

No. patients

Weiner and Reed (1999) Hammer and Doleys (2001) Popeney and Alo’ (2003) Jones (2003)

Results

Follow-up

13

Perc. leads

All good to excellent

1–6 yr

1

Perc. lead

90% improvement

9 mth

25 3

Oh et al. (2004)

Method

20

Perc. lead

100% satisfied

18 mth

Perc. and paddle leads

Excellent

Not specified

Paddle leads

16 pts excellent

6 mth to 5 yr

2 pts worse Kapural et al. (2005)

6

Perc. trial, paddle perm.

100% improved

Rodrigo-Royo et al. (2005)

4

Perc. leads

All good or very good

6 mth 4–16 mth 12 yr

Weiner (2006)

150

Perc. and paddle leads

70–75% 50% success

Schwedt et al. (2007)

2 (cluster headaches)

Bion implant

70% improvement

Short-term

Slavin et al. (2006)

10/14 implanted

Perc. leads

70% had 60–90% relief

Mean 22 mth

Burns et al. (2007)

9 (cluster headaches)

Perc. leads

2 pts 90–95% improvement

Median 20 mth

3 pts 40% improvement 1 pt 25% improvement Magis et al. (2007)

8

Schwedt et al. (2007)

15

Paddle leads

Overall 50% decreased attacks

16–22 mth

Perc. leads

52% overall pain reduction

5–42 mth

Melvin et al. (2007)

11

Perc. leads

82% excellent and good

12 wk

Trentman et al. (2008)

10

Perc. leads

All improved

Mean 20 mth

Paddle leads

5/7 reduced VAS

Mean 25 mth

Johnstone and Sundaraj (2006)

7

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414

30.  Occipital Neurostimulation for Treatment of Intractable Headache Syndromes

Complications Most complications have revolved around lead migration (15%), skewed more towards the early years of implant technique development. Improved anchors and anchoring techniques as well as continuing edu­ cation opportunities for implanters should minimize this concern. Generator placement and future devel­ opment of localized leads and mini-generators should also have a positive impact on reducing or even elimi­ nating migration problems. Lead breakage or discon­ nection (8%) is probably a function of the lead implant location in a highly mobile area. Infection was rela­ tively uncommon (3%), however, attention to meticu­ lous surgical technique is essential to avoid primary contamination of the implanted equipment even from skin contaminants such as Staphylococcus epidermidis. Subsequent wound dehiscence with external exposure of any of the implant requires explantation of the total device. In our experience, a previously infected area can be successfully re-implanted after suitable treat­ ment (Goadsby et al., 1997; Weiner and Reed, 1999; Weiner, 2000; Weiner et al., 2000; Weiner et al., 2001; Alo’ and Holsheimer, 2002; Alo’ and Popeney, 2003; Popeney and Alo’, 2003; Oh et al., 2004).

Positioning and sedation Most electrode implants can be performed in the lateral position utilizing a midline incision for bilateral electrode placement with lead tunneling and generator pocketing either in the chest, upper buttock or abdo­ men. This allows greater access to the airway during short-acting sedation. Surgical paddle placement, espe­ cially bilaterally, is facilitated in the prone position on a horseshoe or similar frame; however, airway access is limited and sedation agents should be chosen that do not significantly alter respiration (i.e. ketamine, etc).

Mechanisms of action The mechanisms of action for the paresthesia pat­ terns and pain relief obtained from this therapy are incompletely understood but would appear to involve the following elements: l l l l l

l l l

Subcutaneous electrical conduction Dermatomal stimulation Myotomal stimulation Sympathetic stimulation Local blood flow alteration

l

Peripheral nerve stimulation Peripheral and central neurochemical mechanisms Trigeminovascular system Trigeminocervical tract

The most important of these mechanisms appear to be the involvement of the trigeminovascular and trigeminocervical systems (Goadsby et al., 1997; Bahra et al., 2001; Popeney and Alo’, 2003; Alo’ and Popeney, 2004; Matharu et al., 2004). For example, direct electri­ cal stimulation of the greater occipital nerve (Goadsby et al., 1997) has shown an increase in metabolic activity in the trigeminal nucleus caudalis and cervical dorsal horn cells in the cat by 220% ipsilateral to the stimula­ tion and by a lesser amount contralaterally. The dorsal horn activity was at the level of C1, C2 and interaction with the trigeminal innervated structures suggests that the frontally radiating occipital headaches occur as a consequence of overlap of nociceptive informa­ tion processing at the level of the second order neu­ rons. PET scan studies in episodic migraine headache patients (Bahra et al., 2001) further demonstrate spe­ cific areas of brainstem activation in the dorsal rostral pons. In fact, a PET study of 8 patients with chronic migraine headaches (Matharu et al., 2004) showed excellent responses to implanted bilateral suboccipi­ tal stimulators demonstrating activation of the dorsal rostral pons that persisted after alleviation of headache pain. These combined observations suggest the pres­ ence of a central trigger mechanism for a variety of headache pain conditions (Goadsby et al., 1997; Bahra et al., 2001; Popeney and Alo’, 2003; Alo’ and Popeney, 2004; Matharu et al., 2004). Finally, peripheral, subcu­ taneous electrical stimulation may influence blood flow within these activated regions or be involved in descending pathways that control pain via stimula­ tion of the trigeminovascular and trigeminocervical systems at the level of the upper cervical spine. This may occur by electromodulation reducing abnormal excitation of these peripheral nociceptive afferent fib­ ers, and preventing central sensitization of trigeminal nociceptive pathways, potentially reducing on-cell activity, and positively modulates the descending mod­ ulatory system at the level of the dorsal horn (Goadsby et al., 1997; Bahra et al., 2001; Popeney and Alo’, 2003; Alo’ and Popeney, 2004; Matharu et al., 2004).

Conclusions Medical management is the mainstay of treatment for the spectrum of chronic headache syndromes listed in the International Headache Society ICHD-II Compendium (2004). These include, but are not limited

IVA. periphery and spinal cord electrical stimulation for non-visceral pain

references

to, primary headache disorders such as migraine syn­ dromes tension headaches and cluster headaches, secondary headache disorders such as medication overuse migraines or increased intracranial pressure, and the third main category of cranial neuralgias and face pain including occipital neuralgia and trigemi­ nal neuralgia. Clinicians are increasingly faced with growing numbers of patients refractory to current multi­ modality approaches to chronic headache control with estimates of between one half to one million marginally controlled headache sufferers in the USA alone. Peripheral occipital subcutaneous field neurostimu­ lation for a variety of intractable headache syndromes is a safe, reasonably effective, and uncomplicated treatment modality to be considered when deal­ ing with patients refractory to conventional therapy. Multicenter studies are under way to further define the safety and efficacy of this treatment modality while further defining the mechanism and pathophys­ iology effects described to date. Recent advances in commercially available neurostimulator products in terms of electrode design and generator rechargeabil­ ity and miniaturization hold promise for more focused use of neuromodulation for the headache indications.

References Alo’, K.M. and Holsheimer, J. (2002) New trends in neuromodula­ tion for the management of neuropathic pain. Neurosurgery 50 (4): 690–704. Alo’, K.M. and Popeney, C.A. (2004) Peripheral nerve stimulation (PNS) relieves the symptoms of transformed migraine and reduces associated disability. Neurocontact (Newsletter/Articles from the Editorial Board – Summarial Abstract from Headache 2003; 43: 369-73), Summer 2004, Medicus International, pp. 1–4. Bahra, A., Matharu, M.S., Buchel, C., Frackowiak, R.S.J. and Goadsby, P.J. (2001) Brainstem activation specific to migraine headache. Lancet 357: 1016–17. Bovim, G., Fredriksen, T.A., Stolt-Nielsen, A. and Sjaastad, O. (1992) Neurolysis of the greater occipital nerve in cervicogenic head­ ache. A follow up study. Headache 32 (4): 175–9. Burns, B., Watkins, L. and Goadsby, P. (2007) Treatment of medically intractable cluster headache by occipital nerve stimulation: longterm follow-up of eight patients. Lancet 369 (9567): 1099–106. Dubuisson, D. (1995) Treatment of occipital neuralgia by partial pos­ terior rhizotomy at C1–3. J. Neurosurg. 82 (4): 581–6. Goadsby, P.J., Knight, Y.E. and Hoskin, K.L. (1997) Stimulation of the greater occipital nerve increases metabolic activity in the trigeminal nucleus caudalis and cervical dorsal horn of the cat. Pain 73 (1): 23–8. Hammer, M. and Doleys, D. (2001) Perineuromal stimulation in the treatment of occipital neuralgia: a case study. Neuromodulation 4 (2): 47–51. Headache Classification Committee of the International Headache Society (2004) The International Classification of Headache Disorders (2nd edn). Cephalalgia 24 (Suppl. 1): 1–160. Johnstone, C.S. and Sundaraj, R. (2006) Occipital nerve stimula­ tion for the treatment of occipital neuralgia – eight case studies. Neuromodulation 10 (3): 41–7.

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Jones, R. (2003) Occipital nerve stimulation using a Medtronic Resume II electrode array. Pain Physician 6: 507–8. Joseph, B. and Kumar, B. (1994) Gallie’s fusion for atlantoaxial arthrosis with occipital neuralgia. Spine 19 (4): 454–5. Kapural, L., Mekhail, N., Hayak, S.M., Stanton-Hicks, M. and Malak, O. (2005) Occipital nerve electrical stimulation via the midline approach and subcutaneous surgical leads for treatment of severe occipital neuralgia: a pilot study. Anesth. Analg. 101 (1): 171–4. Lipton, R., Humelsky, S. and Stewart, W. (2001) Epidemiology and impact of headache. In: S. Silberstein, R. Lipton and D. Nalessio (eds), Wolff’s Headache and Other Head Pain, 7th edn. Oxford: Oxford University Press, pp. 85–107. Lozano, A.M., Vanderlinden, G., Bachoo, R. and Rothbart, P. (1998) Microsurgical C-2 ganglionectomy for chronic intractable occipital pain. J. Neurosurg. 89 (3): 359–65. Magis, D., Allena, M., Bolla, M., Pasqua, V.D., Remacle, J.M. and Schoenen, J. (2007) Occipital nerve stimulation for drug-resistant chronic cluster headache: a prospective pilot study. Lancet Neurol. 6: 314–21. Matharu, M.S., Bartsch, T., Ward, N., Frackowiak, R.S., Weiner, R. and Goadsby, P.J. (2004) Central neuromodulation in chronic migraine patients with suboccipital stimulators: a PET study. Brain 127 (pt 1): 220–30. Mayer, R.D. and Howard, F.M. (2008) Sacral nerve stimulation: neu­ romodulation for voiding dysfunction and pain. Neurotherapeutics 5 (1): 107–13, Review. Melvin, E.A., Jr., Jordan, F.R., Weiner, R.L. and Primm, D. (2007) Using peripheral stimulation to reduce the pain of C2-mediated occipi­ tal headaches: a preliminary report. Pain Physician 10: 453–60. Mueller, L.L. (2007) Diagnosing and managing migraine headache. J. Am. Osteopath. Assoc. 107 (10 Suppl. 6): ES10–16. Newman, L.C., Lipton, R.B., Solomon, S. and Stewart, W.F. (1994) Daily headaches in a population sample: results from the American migraine study. Headache 34 (5): 295 (Abstract). Oh, M.Y., Ortega, J., Bellotte, J.B., Whiting, D.M. and Alo’, K. (2004) Peripheral nerve stimulation for the treatment of occipital neural­ gia and transformed migraine using a C1-2-3 subcutaneous paddle style electrode: a technical report. Neuromodulation 7 (2): 103–12. Picaza, J.A., Hunter, S.E. and Cannon, B.W. (1977–8) Pain sup­ pression by peripheral nerve stimulation. Chronic effects of implanted devices. Appl. Neurophysiol. 40 (2–4): 223–34. Pikus, H.J. and Phillips, J.M. (1997) Outcome of surgical decom­ pression of the second cervical root for cervicogenic headache. Neurosurgery 40 (5): 1105–6. Popeney, C.A. and Alo’, K.M. (2003) C1-2-3 peripheral nerve stim­ ulation (PNS) for the treatment of disability associated with transformed migraine. Headache 43: 369–73. Rodrigo-Royo, M., Azcona, J.M., Quero, J., Lorente, M.C., Acin, P. and Azcona, J. (2005) Peripheral neurostimulation in the management of cervicogenic headache: four case reports. Neuromodulation 8 (4): 241–8. Saper, J.R. (1990) Daily chronic headache. Neurol. Clin. 8 (4): 891–901. Schwedt, T.J., Dodick, D.W., Hentz, J., Trentman, T.L. and Zimmerman, R.S. (2007) Occipital nerve stimulation for chronic headache – long term safety and efficacy. Cephalalgia 27: 153–7. Silberstein, S. and Lipton, R. (2001) Chronic daily headache includ­ ing transformed migraine, chronic tension type headache, and medication overuse. In: S. Silberstein, R. Lipton and D. Nalessio (eds), Wolff’s Headache and Other Head Pain, 7th edn. Oxford: Oxford University Press, pp. 247–82. Silberstein, S.D., Lipton, R.B. and Goadsby, P.J. (2002) Headache in Clinical Practice, 2nd edn. London: Martin Dunitz. Silberstein, S., Super, J. and Freitag, F. (2001) Migraine: diagnosis and treatment. In: S. Silberstein, R. Lipton and D. Nalessio (eds),

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Wolff’s Headache and Other Head Pain, 7th edn. Oxford: Oxford University Press, pp. 121–237. Slavin, K.V., Nersesyan, H. and Wess, C. (2006) Peripheral neu­ rostimulation for treatment of intractable occipital neuralgia. Neurosurgery 58: 112–9. Spierings, E.L.H., Schroevers, M., Honkoop, P.C. and Sorbi, M. (1998) Presentation of chronic daily headache: a clinical study. Headache 38: 191–6. Stanton-Hicks, M. (2006) Complex regional pain syndrome: mani­ festations and the role of neurostimulation in its management. J. Pain Symptom Manage. 31 (4 Suppl.): S20–S24, Review. Trentman, T.L., Zimmerman, R.S., Seth, N., Hertz, J.G. and Dodick, D.W. (2008) Stimulation ranges, usage ranges, and paresthesia mapping during occipital nerve stimulation. Neuromodulation 11 (1): 56–61. Van Buyten, J.P. (2006) Neurostimulation for chronic neuropathic back pain in failed back surgery syndrome. J. Pain Symptom Manage. 31 (4 Suppl.): S25–S29, Review.

Waisbrod, H., Panhans, C., Hansen, D. and Gerbershagen, H.U. (1985) Direct nerve stimulation for painful peripheral neuropa­ thies. J Bone Joint Surg. 67B (3): 470–2. Weiner, R.L. (2000) The future of peripheral nerve neurostimulation. Neurol. Res. 22: 299–304. Weiner, R.L. (2006) Occipital neurostimulation (ONS) for treatment of intractable headache disorders. Pain Med. 7: S137–S139. Weiner, R.L. and Reed, K.L. (1999) Peripheral neurostimulation for the control of intractable occipital neuralgia. Neuromodulation 2: 369–75. Weiner, R.L., Alo’, K.M. and Reed, K. (2000) Peripheral neurostimu­ lation for control of intractable occipital headaches. Abstracts of the World Pain Meeting 2000, President Elliot Krames, San Francisco, CA July 2000. Weiner, R.L., Alo’, K.M., Reed, K.L., Fuller, M.L. (2001) Subcutaneous neurostimulation for intractable C2 mediated headaches. Abstracts from the American Association of Neurological Surgeons, Pain Section Newsletter, Toronto, Canada.

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C H A P T E R

31

Subcutaneous Targeted Stimulation Teodor Goroszeniuk and Sandesha Kothari

o u tl i n e Historical Perspective

417

Pertinent Anatomy, Physiology, and Disease Pathophysiology

420

Indications and Rationale for Selection Indications Rationale for Selection

420 420 420

Patients Selection and Approach

421

Implantation Procedure Programming Outcomes Complications and Contraindications What the Future Holds Conclusions References

Historical perspective

appreciate the microanatomy of the nerve’s function. (See the excellent contribution on peripheral nerve stimulation by Stanton-Hicks, Chapter 29.) Until 1999, less than 500 cases of PNS were reported in the literature, reporting a varied range of effectiveness of 25–90% and a complication rate between 5 and 43% (Gybels and Nuttin, 2000). During this period, a neuropathic pain syndrome in a mononeural distribution remained the main indication for PNS, which was exclusively practiced surgically by direct placement of the stimulating electrode on or around the exposed nerve. This was the main practice for peripheral nerve stimulation until the percutaneous and subcutaneous placement of electrodes for occipital neuralgia by Weiner and Reed (1999) stimulated its revival. This paper was soon followed by several case reports regarding the percutaneous introduction of a peripheral lead for the treatment of other mononeural neuralgias (Hammer and Doleys, 2001; Stinson et al.,

Subcutaneous targeted nerve stimulation (TS) is a new concept in neuromodulation and due to its effectiveness and simplicity it is rapidly gaining widespread acceptance. The terminology, however, has not yet been firmly and clearly established in the literature; there remains some confusion. The concept of peripheral nerve stimulation (PNS) was initiated by Wall and Sweet (1967). They applied stimulating needles percutaneously to one another’s infraorbital nerves, achieving hypoesthesia and analgesia distal to the point of stimulation. Although peripheral neuromodulation or peripheral nerve stimulation (PNS) was introduced into clinical practice following the publication of the gate theory by Melzack and Wall (1965), several years earlier than the introduction of spinal cord stimulation (SCS) by Shealy et al. (1967), its lack of popularity was largely due to unreliable equipment and failure to

Neuromodulation

421 422 422 424 425 425 425

417

2009 Elsevier Ltd. © 2008,

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31.  subcutaneous targeted stimulation

2001; Dunteman, 2002; Monti, 2004). Ghoname et al. (Ghoname et al., 1999, Hamza et al., 2000) produced results that were considered good with the application of percutaneous electrical nerve stimulation (PENS), a multiple needle stimulation technique using alternating frequency of 15 and 30 Hz for diabetic neuropathic pain and for low back pain, respectively. Percutaneous implantation at multiple locations using a stimulating needle improved the precision of the therapy, thus allowing the expansion of indications for PNS to neural structures such as the brachial plexus (Goroszeniuk et al., 2007a), the lumbar plexus (Petrovic et al., 2007), single peripheral nerves (Goroszeniuk, 2003a), the paravertebral space (Ather et al., 2001), and the sympathetic chains (Kothari and Goroszeniuk, 2004). In January of 2000, the author (Goroszeniuk) introduced a stimulating monoelectrode (Epimed Inc., Johnstown, NY, USA) percutaneously near the ulnar nerve in the forearm of a patient suffering from a neuropathic pain syndrome within the distribution of the ulnar nerve. To our surprise, short stimulation using a low frequency of 2 Hz resulted in 11 weeks of complete pain relief for the patient. This initial experience initiated the development of a simplified version of the therapeutic and diagnostic neurostimulation test using a single stimulating needle applied directly to single nerves and plexuses (Goroszeniuk, 2003c). Patients with non-dermatomal distributions of their pain, however, presented a problem for us, in that a single identifying target for stimulation did not exist. However, a later study of the low-frequency needle stimulation test, wherein the stimulating needle was positioned at the epicenter of the painful area, resulted in the encouraging results of effective and reproducible pain relief and pointed a way to a new and valuable therapy (Goroszeniuk, 2003c). Applying the concept of peripheral nerve stimulation (PNS) to pain in a non-dermatomal distribution by targeting the stimulation via a stimulating needle or subcutaneous placement of a stimulating electrode array to the epicenter of the painful area, lead us to the discovery of an important new concept that we named “targeted stimulation (TS).” Rather than focusing on specific neural structures, this new method of stimulation targets the most distal pain receptors (Goroszeniuk, 2003c; Goroszeniuk et al., 2006a) (see Figure 31.1). Subsequent introductions of nervemapping appliances (PEG) into clinical practice by Urmey and Grossi (2002) led to the application of this device for the treatment of neuropathic pain and resulted in the development of a new concept termed “external neuromodulation” (EN) (Goroszeniuk and Kothari, 2004; Kothari and Goroszeniuk, 2006; Goroszeniuk et al., 2007a). The adoption of a nerve mapping probe in a

similar way to previous applications of single episode needle stimulation or stimulating catheter placement proved to be as effective as direct needle or stimulating catheter application, despite being non-invasive (Goroszeniuk, 2003a; Goroszeniuk, 2003c). External neuromodulation (EN) involves application of electrical stimulation via an external nerve mapping probe connected to an impulse generator. The probe is placed within the proximity of the nerves covering the distribution of the painful areas or directly to the epicenter of the painful area (target). The stimulating ball shape probe (Neuro-Trace, HDC Corporation, Milpitas, California, USA; Pajunk GmbH, Geisingen, Germany) is directed at nerves, plexuses or target areas in patients mainly with chronic neuropathic pain syndromes. The amplitude of the device is adjusted to a perceivable paresthesia level. It should be stated here that EN should not be confused with transcutaneous nerve stimulation (TENS), in that the effects of EN do not correlate with TENS applied externally over the same area. Although EN creates a local electrical field as does TENS, the field is narrower and produces a higher current density. EN appears to be more clinically effective when compared to TENS, however this needs to be validated in randomized controlled studies. The external application allows the procedure to be performed on an outpatient basis (Goroszeniuk et al., 2007a). Preliminary reports in the literature regarding EN demonstrate strong evidence for its effectiveness (Goroszeniuk and Kothari, 2004; Kothari and Goroszeniuk, 2006) and it appears that EN will play an important and integral role as an initial, non-invasive screening for patients (present data – neuropathic pain) suitable for PNS and TS, which should lead, in turn, to a more effective selection of patients (Goroszeniuk et al., 2007a). In cases where the duration of pain relief exceeds 6 hours with a single application, it can be used as non-invasive self-administration pain control modality (Goroszeniuk and Kothari, 2004; Kothari and Goroszeniuk, 2006; Goroszeniuk et al., 2007a). The addition of EN as a modality of applied peripheral neurostimulation allows for the staging of PNS that incorporates all types of stimulation ranging from non-invasive, single episodes of stimulation to the more invasive practice of permanently implanting and applying stimulation modalities including mononeural stimulation, plexus stimulation and TS. This staged stimulation algorithm of care is as follows: Stage I: external neuromodulation → Stage II: needle neuromodulation → Stage III: temporary catheter trial → Stage IV: permanent neuromodulating implant (Goroszeniuk et al., 2007a, Goroszeniuk et al., 2007b) (see Figures 31.1, 31.2).

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Historical perspective

Figure 31.1  (A) External neuromodulation. (B) Direct, one-shot stimulation. (C) Monoelectrode trial. (D) Permanent implant (With permission from Goroszeniuk, Kothari and Hamann (2006). Copyright (2006) Elsevier) DIAGNOSIS �� Rx

Interventions PHYSIO

Further Rx

EXTERNAL Positive

Non-conclusive

Further External

Needle Stimulation

Positive SELF Administration

PHYSIO

Temporary Trial Positive

Negative

Pain Management Programme Pre-implantation

Other Treatments PERMANENT IMPLANT

Figure 31.2  Algorithm (Goroszeniuk and Kothari, Pain Management and Neuromodulation Centre, Guy’s & St Thomas’ Hospital, London, UK) (With permission from Goroszeniuk, Kothari and Hamann (2006). Copyright (2006) Elsevier) IvA. periphery and spinal cord electrical stimulation for non-visceral pain

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31.  subcutaneous targeted stimulation

The introduction of TS by this author (Goroszeniuk) 7 years ago was followed by the introduction of a similar concept by O’Keeffe and coworkers (Khan et al., 2005) in Dublin, Ireland, which he calls subcutaneous electrical nerve stimulation (SENS). Buchser et al. (2005) used this principle (of targeted stimulation), which they called subcutaneous peripheral nerve stimulation (SPNS), for application in patients with failed back surgery syndrome (FBSS) and presented their findings at the 11th World Congress on Pain in Sydney.

Pertinent anatomy, physiology, and disease pathophysiology Skin, subcutaneous tissue, and fascia are supplied with free nerve endings and a range of nociceptors (Byers and Bonica, 2001a). The function of peripheral afferent end terminals (nociceptors) in neuropathic and other forms of pain syndromes is severely c­ompromised causing the alteration of local conductance activity and changed terminal chemistry (Byers and Bonica, 2001b). The delivery of neurostimulation to an affected painful area close to free nerve endings can act as a catalyst that reduces this abnormal electrical activity, subsequently returning neuronal conductance back to normal sodium-channel transmission (Priestley, 2004; Devor, 2006). This picture may be somewhat simplistic as mechanoreceptors and sympathetic efferent fibers also have a role in the development of pain and subsequent response to peripheral neuromodulation (Na et al., 1993). The local release of neurotransmitters and neuromodulators may also play a role following neurostimulation (Linderoth et al., 1993). The beneficial effects of peripheral stimulation, percutaneous stimulation, and TS, using low frequency modulation, can be partially explained by the interruption of the input of nociceptive afferents (Wall and Gutnik, 1974). The intact nociceptors theory is currently being investigated and may play a role in the development of neuropathic pain (Campbell and Meyer, 2005). Local suppression of A-fiber activity by TS is another attractive mechanistic hypothesis, but central mechanisms have been also implicated for the effects seen from peripheral neuromodulation (Taub and Campbell, 1974; Chung et al., 1984). Specific changes in post-synaptic excitation in the dorsal horn are independent of which group of primary afferent is activated. Stimulation of Afibers causes direct excitation as well as pre- and postsynaptic segmental inhibition of wide dynamic range neurons (Randic et al., 1993; Sandkuhler et al., 1997).

Stimulation of A-fibers also results in excitation. In addition, low frequency stimulation causes long-term depression (LTD) of monosynaptic as well as poly­ synaptic excitatory post-synaptic potentials (EPSPs) in substantia gelatinosa neurons lasting up to several hours (Sandkuhler et al., 1997). This may provide an explanation for the successful response to slow frequency (2–10 Hz) stimulation in our cases.

Indications and rationale for selection Indications Subcutaneous neuromodulation may be considered when other simple interventions such as conservative medical management, nerve blocks, or neuroablation have been tried and fail to provide adequate relief in patients with chronic pain in a localized non-dermatomal area. When selecting a patient for TS, it is important to consider the level of invasiveness of the procedure, the efficacy of the procedure and the cost of the procedure when compared to other interventions. At present, there are few reports of TS in the literature and the reported success rate has been as high as 70–100% (Goroszeniuk, 2003c; Theodosidis et al., 2004; Khan et al., 2005; Goroszeniuk et al., 2006a; Goroszeniuk et al., 2007a; Goroszeniuk et al., 2007b; Theodosidis et al., 2008) for neuropathic pain syndromes and as low as 50–80% for low back pain (Buchser et al., 2005; Koulousakis et al., 2006, Paicius et al., 2007). The indications for this procedure, however, are expanding in the literature and include TS for angina (Kothari et al., 2004; Goroszeniuk et al., 2006b). It is our belief that in the future other targets and indications for efficacious stimulation will be reported.

Rationale for Selection The neurostimulation coverage of a painful target area with an electrical field applied subcutaneously or oriented to deeper structures allows for effective direct stimulation and therefore neuromodulation of a whole range of peripheral receptors in the affected area without specific direct application to either nerves or plexuses, themselves. Stimulation must be localized within the topographical area of pain for it to be effective; however, in our experience, outcomes may still be positive, even if the stimulation does not cover the marginal areas of the pain complaint. Based on our experience, we also believe that the position of the stimulating lead array, if an array is used, should preferably be within

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Implantation procedure

the closest possible proximity to the epicenter of the painful area to provide optimal coverage and outcome. The application of stimulation via multicontact leads (and present technology permits 16 contacts), which are situated directly at the epicentre of the painful area and targeted to the site of pain as directed by the patients is safe, simple, and an effective mode of treatment. This principle of implantation has been successfully used in our institution.

Patient selection and approach TS is still at its infancy and therefore the number of cases reported in the literature is limited. However, there is some evidence that this therapy has some clinical efficacy in a wide range of disorders including pain within the post-sternotomy scar (Goroszeniuk et al., 2006a), post-mastectomy pain syndrome (Khan et al., 2005, T. Muldoon, pers. comm. 2005), post-herpetic neuralgia (T. Muldoon, pers. comm. 2005, Yakovlev and Peterson, 2007), costochondritis (Goroszeniuk et al., 2006a), back pain (Buchser et al., 2005; Koulousakis et al., 2006; Paicius et al., 2007; Krutsch et al., 2008; Verrills, 2009), coccycodynia (Theodosiadis et al., 2004), CRPS (Khan et al., 2005; Goroszeniuk et al., 2006a; Goroszeniuk et al., 2007a; Theodosiadis et al., 2008), and abdominal wall pain (Paicius et al., 2006). The application of TS for intractable severe angina, not suitable for surgery and not responding to medication, has been successful, even in cases where previous SCS has had a limited impact on pain control (Kothari et al., 2004; R. Cooper, pers. comm., 2005; Goroszeniuk et al., 2006b). We have found that the correct selection of patients suitable for targeted stimulation depends on the rigorous application of initial diagnostic testing using external or needle neuromodulation techniques (Goroszeniuk et al., 2006a) (see Figure 31.1a and b). It is our opinion that, according to the algorithm developed in our center, patients in whom initial testing demonstrates more than 50% pain relief over a duration shorter than a few hours are candidates for a subcutaneous electrode trial (Goroszeniuk et al., 2007a; Goroszeniuk et al., 2007b). It is our practice, for initial testing, to use the simple Stimulong monoelectrode (Pajunk, GmbH, Geisingen, Germany) (see Figure 31.1c). Trial leads have also been successful as an indicator of efficacy when percutaneous neurostimulation techniques are used (Goroszeniuk et al., 2007b). These monoelectrodes, however, in our belief, are more cost-effective than standard commercial trial leads. In the majority of cases, these simple

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trials provide sufficient information for permanent implantation (Goroszeniuk et al., 2007b). When testing with electrode arrays is inconclusive because the targeted painful area is too large, an expansion of the maximum number (16 electrodes) of stimulating points permitted under the current technology might be needed. However, at present, we use dual octrode leads systems from various manufacturers to stimulate large painful areas (Advanced Neuromodulation Systems, Inc., Plano, TX; Medtronic, Inc., Minneapolis, MN; Boston Scientific Neurological, Boston, MA) for both testing and final stimulation protocols. At present there is no specifically designed technology for TS and we use the same technology that is used for SCS. As stimulating requirements are more basic than those used for stimulation of the spinal cord (SCS), sophisticated stimulation programming, in our opinion, is not needed and stimulation coverage of the painful area is the primary objective. To cover a large painful area, 16 stimulating electrodes, either two octrodes or four quadrapolar leads, suffices. With smaller areas of pain, single electrodes, either quadrapolar or octopolar leads, or two quadrapolar leads, is usually sufficient. The present selection of implantable pulse generators (IPGs) or rechargeable devices is not as vital to success as much as for the choice of electrode arrays to deliver an effective electrical field to the target area. Radiofrequency (RF) external systems do still offer small size, excellent value, and possible stimulation parameters to use 16 stimulating contacts, when required.

Implantation procedure The implantation technique for PNS of specifically designed cuff, bipolar or button leads has remained standard for many years and still requires surgical incision and exposure of the targeted peripheral nerve. The introduction of the percutaneous implantation of a stimulating (SCS) lead into the proximity of the greater occipital nerve (Weiner and Reed, 1999) introduced a vast simplification of the technique for PNS and, as stated above, is used for a wide variety of indications. Following a successful trial, we use an algorithm that we have developed in our center (Goroszeniuk et al., 2007a). The stimulating leads are implanted under continuous stimulation to localize a target area at the epicenter of pain subcutaneously or even targeted deeper to the source of pain. The stimulation is continued until it reaches the epicenter of pain, which is confirmed by the patient. In our institution, this continuous stimulation

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31.  subcutaneous targeted stimulation

approach has improved the success rate of this therapy. The lead/s position is confirmed by fluoroscopy. Stabilization and anchoring of the lead/s is performed according to standard practice for fixation of leads as previously reported, with attention paid to avoiding fat or muscle (Oakley, 2003). The final position of the IPG, rechargeable generator or RF receiver is selected for patient convenience and surgeon’s choice.

Programming Since the conception of PNS, programming requirements have taken into account the mixed composition of peripheral nerves that often contain large motor fibers. Stimulation frequencies between 50 and 90 Hz with more focused pulse widths than those used for SCS, in the range of 120 to 180 ms, had been typically used (Racz et al., 1990). Various attempts have been made to achieve precise stimulation of sensory fibers excluding motor components, but have not been successful. It is emerging from reported material, that the pattern of stimulation with low frequencies (2–10 Hz) and wide pulse widths offers the most optimal programming for this technique (Khan et al., 2005; Goroszeniuk et al., 2006a; Goroszeniuk et al., 2006b; Goroszeniuk et al., 2007a; Goroszeniuk et al., 2007b; Theodosiadis et al., 2008). Low frequencies have been also been effective with SCS and DBS (Shimoji et al., 1977; Bittar et al., 2005). We, in our center, provide low frequency stimulation between 2 and 10 Hz, but other centers report the use of higher frequencies between 30 and 80 Hz. We adjust amplitudes of stimulation to below those that produce motor stimulation, usually between 2 and 20 volts. The precise duration of stimulation that provides optimal benefit needs to be further investigated; however, in most cases reported to date (Ather et al., 2001; Goroszeniuk, 2003a, 2003b; Goroszeniuk and Kothari, 2004; Theodosiadis et al., 2004; R. Cooper, pers. comm. 2005; Khan et al., 2005; T. Muldoon, pers. comm. 2005; Goroszeniuk et al., 2006a; Kothari and Goroszeniuk, 2006; Goroszeniuk et al., 2007a; Goroszeniuk et al., 2007b; Goroszeniuk et al., 2007c; Petrovic et al., 2007; Theodosiadis et al., 2008), it has emerged that frequently only short duration of stimulation is required to provide patients with substantial pain relief that lasts hours or days, which confirms our initial observations (Goroszeniuk, 2003c).

Outcomes At the time of this writing, the available publications on the topics of TS, EN, field stimulation, etc. is limited

to a few published case reports and several abstracts. Information regarding this new method has been complemented through presentations at meetings, lectures, and personal communications. The initial report of percutaneous TS was presented at the European Federation of IASP chapters’ (EFIC) 2003 Congress in Prague (Goroszeniuk, 2003c). As reported, the use of low frequency, 2 Hz stimulation in 37 patients with neuropathic pain of different etiologies, applied to single nerves, plexuses, and the area of pain in nondermatomal distributions, resulted in excellent pain relief of similar levels, independent of the location of the stimulation target. Effective stimulation to pains of non-dermatomal distribution proved to be equally successful for achieving pain control to the stimulation provided to definitive neural structures such as nerves or plexuses. Overall levels of pain relief were reported to be equal to or more than 80% in all cases, with varying durations of relief from several hours to up to 3 months. O’Keeffe et al. (2006), in 50 patients, used the same technique in their patients and, as previously stated, called their technique subcutaneous electrical neurostimulation (SENS-One Shot), which is targeted to the site of neuropathic pain. Eighty-two percent of patients responded to treatment. Fifty percent of the 41 patients reported pain reductions between 80 and 100%. Duration of pain relief was extended beyond 30 days in 35% of patients. We have published our exper­ ience regarding this technique, which we call TS, in three patients for the treatment of neuropathic pain (see Figures 31.3, 31.4, 31.5). The technique of implantation, in our hands, is simple and there have been no complications. To date, these patients continue to have pain relief of more than 90%. The first permanent implant took place in 2002. Patients with post-thoracotomy scar, post-sternotomy scar and costochondritis had similar features of severe neuropathic pain. Octrode leads connected to radiofrequency stimulation (Renew) were used in all patients (Advanced Neuromodulation Systems (ANS), Inc., Plano, TX). Subsequent to implantation of the permanent stimulation systems, analgesic medication was discontinued in all patients (Goroszeniuk et al., 2006a). Khan et al. (2005) reported on the success of this approach in two patients, calling their approach, as the O’Keeffe group, SENS. One of the two cases had a combination of SCS single electrode and three leads targeted to the area of severe post-mastectomy neuropathic pain with excellent pain control. Buchser et al. (2005) presented their ongoing studies for refractory low back pain with subcutaneous PNS, with subjective improvement in their cases of between 52 and 63%. Paresthesia coverage of at least 80% of the

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Outcomes

Figure 31.3  (A) Pain distribution. (B) Permanent implant

Figure 31.4  (A) Two monoelectrode trial. (B) Permanent implant

Figure 31.5  Permanent implants at the both sides of the sternum

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31.  subcutaneous targeted stimulation

painful area was achieved in all patients. Paicius et al. (2006) reported on the application of peripheral nerve field stimulation for chronic abdominal pain, including chronic pancreatitis, post liver transplant, and inguinal pain. The beneficial frequencies used by these authors were between 30 and 82 Hz, which provided excellent pain control in three patients. This same group (Paicius et al., 2007) published their recent report on six patients with chronic back pain who failed conventional therapies. All patients reported decreased pain intensities and use of pain medications and an increase in their level of activity. T. Muldoon (pers. comm. 2005) successfully carried out permanent implantation using a targeted electrode for PHN and post-mastectomy pain, resulting in 90–95% relief of pain. Theodosiadis et al. (2008) reported successful permanent implantation for the treatment of patients with low frequency stimulation targeted to shoulder post-traumatic n­europathic pain syndrome. Koulousakis et al. (2006) performed implantation of percutaneous electrodes in 31 patients for mainly nociceptive pain syndromes and achieved over 50% pain relief in 30% of patients. We have presented our initial reports on the targeted subcutaneous stimulation for intractable angina that is not amenable to revascularization (Kothari and Goroszeniuk, 2004; Kothari et al., 2004; Goroszeniuk et al., 2006b). The stimulating leads were placed in the front of the chest at the center of the patient’s pain. The results of our first four permanent implants look very promising and comparable to the effects of SCS which is a well established modality for treatment of angina (Mannheimer et al., 1988). When compared to SCS, the technique of TS has the added advantage of being less invasive, safer and with less morbidity (Kothari and Goroszeniuk, 2004; Kothari et al., 2004; Goroszeniuk et al., 2006b). R. Cooper (pers. comm. 2005), also has used this approach for intractable angina where SCS failed to relieve the symptoms and their patients achieved over 90% reduction in pain. Reports on the effects of EN for angina support these findings and warrant further research (Goroszeniuk et al., 2006b; Kothari and Goroszeniuk, 2006), especially when comparative studies of the effects of TENS as a therapy for angina (Mannheimer et al., 1985) are clearly defined. These available data are indicative of the effectiveness of this new technique and emphasize its simplicity. The most promising indication is neuropathic pain, but other indications are evolving. No serious complication to date has been reported. It appears that stability of the implanted leads does not present a problem. Low frequency stimulation has been the

most successful in the majority of our patients, providing them with the best outcome so far and confirming the initial observations (Ather et al., 2001; Goroszeniuk, 2003a, 2003b; Goroszeniuk and Kothari, 2004; Kothari and Goroszeniuk, 2004; Theodosiadis et al., 2004; Khan et al., 2005; T. Muldoon, pers. comm. 2005; R. Cooper, pers. comm. 2005; Goroszeniuk et al., 2006a; Kothari and Goroszeniuk, 2006; Goroszeniuk et al., 2007a; Goroszeniuk et al., 2007b; Petrovic et al., 2007; Theodosiadis et al., 2008). In other reports higher frequencies of 30–80 Hz were used (Buchser et al., 2005; Kouloukakis et al., 2006; Paicius et al., 2006). The recent study using direct percutaneous peripheral stimulation and fMRI on volunteers, with capsaicininduced hyperalgesia, showed a significant reduction of symptoms with PNS compared with sham application (Hu et al., 2008).

Complications and contraindications As with every new development in medicine, the exact rate of complications from targeted stimulation is not evident at this initial stage of therapy use. However, due to the simplicity of the technique and the fact that the applications are usually targeted away from major neural structures such as the spinal cord, nerve roots, and plexuses, we anticipate that this procedure will be performed extensively with few complications. Infection, as with other implantable neuromodulation therapies, is and will remain the most challenging complication of this procedure. We can expect a similar rate of infection to other established neuromodulation techniques, which is currently in the range of 5% (Turner et al., 1995). Lead displacement and local nerve trauma is, in theory, always a possibility, but has not yet been reported. Absolute contraindications to this procedure include generalized sepsis, local infection in the area of lead and/or generator placement, and pathological skin conditions at the side of implantation. Anticoagulation therapy always presents a challenge to implantable technologies, however, due to the minimally invasive character of this technique, targeting areas away from major neural structures such as spinal cord, brain, peripheral plexus and nerves, anticoagulation therapy should be considered as a relative, not absolute risk. Should local hematoma develop as a result of the anticoagulation, because of the very nature of this technique being subcutaneous, the hematoma would not present a serious risk to the individual.

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Conclusions

What the future holds We predict that the next five years will see an intensive, industry-driven, miniaturization of equipment and further simplification of the TS technique. The design and development of purpose-specific neuromodulation devices and implantation accessories will make the technique effortless and allow the insertion of a stimulating unit with multiple stimulating points as close as possible to the target area in order to be minimally invasive and to cover a large area if required. This will subsequently improve the precision, efficacy, and safety of this method. A combined dual approach of PNS as TS (Khan et al., 2005) or Plexus Stimulation (Di Vadi et al., 2007) with SCS will expand to allow patients and implanters select the best possible option of stimulation treatment. With the spiralling cost of healthcare, the price of neuromodulation equipment has to be taken into consideration when choosing a therapy for any diagnosis. Therefore, in the future, simpler and less expensive designs may have a greater impact and role for the treatment of painful problems, especially for TS. This development will lead to further popularization and expansion of the technique outside of specialist referral centers. The “out-of-favor,” older RF systems are likely to return to favor for TS as they do offer an attractive, relatively inexpensive solution to spiralling costs of healthcare for pain syndromes, especially when neuromodulation devices are used. Of equal importance to the general acceptance of this procedure is that uncomplicated initial testing with EN and the use of basic and inexpensive testing leads should allow better selection of patients and will generally expand its applications. Summarizing the last 30 years of development in their chapter in The Paths of Pain, 1975–2005, Campbell and Meyer stated, “How is it that we control [neuropathic] pain so poorly if all we have to do is to reduce the input of the single class of afferents? If the past 30 years is any measure, we will have overcome this challenge 30 years from today.”

Conclusions Targeted stimulation (TS) is a new development for neuromodulatory therapies which is dynamically expanding in acceptance, popularity, and use, due to its minimally invasive, simple approach and its therapeutic and cost effectiveness. Not much has been published in the literature regarding this new technique

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and there have been no studies providing us with level 1 evidence (randomized controlled studies) for its effectiveness. Presently, this therapy is being used for numerous and differing neuropathic pain syndromes, back pain, and angina; however, further clinical studies, particularly prospective, randomized controlled trials (RCTs) are needed to determine true efficacy, the best indications and most appropriate parameters of stimulation. The experimental and basic research into the mechanism of the action of TS will help gain understanding of its effects on pain and on improving organ function. The positive preliminary results from several centers as reported in this chapter have fully supported the initial reports on this application. A simple mode of stimulation in this approach opens new possibilities. The integrated pre-implantation range of tests is an important way of refining patient selection leading to better pain control and the expansion of both the targeted technique and of peripheral neuromodulation in general.

References Ather, M.H., Goroszeniuk, T. and Sanderson, K. (2001) The use of paravertebral neurostimulation for thoracic neuropathic pain. Int. Monitor 13 (3): 68. Bittar, R.G., Kar-Purkayastha, I., Owen, S.L., Bear, R.E., Green, A., Wang, S. et al. (2005) Deep brain stimulation for pain relief: meta-analysis. J. Clin. Neurosci. 12 (5): 515–19. Buchser, E.E., Martin, Y., Koeppel, C., Jacob, M., Coronado, I., Smit, A. et al. (2005) Subcutaneous Peripheral Nerve Stimulation for Refractory Low Back Pain. Proceedings of the 11th World Congress on Pain, Sydney, Australia, Presentation 1749–P252, p. 8. Byers, M.R. and Bonica, J.J. (2001a) Peripheral pain mechanisms and nociceptor plasticity, 82. In: J.D. Loeser (ed.), Bonica’s Management of Pain, 3rd edn. Philadelphia: Lippincott Williams & Wilkins, p. 72. Byers, M.R. and Bonica, J.J. (2001b) Peripheral pain mechanisms and nociceptor plasticity. In: J.D. Loeser (ed.), Bonica’s Management of Pain, 3rd edn. Philadelphia: Lippincott Williams & Wilkins, p. 92. Campbell, J.N. and Meyer, R.A. (2005) Neuropathic pain from the nociceptor to the patient. In: H. Merskey, J.D. Loeser and R. Dubner (eds), Paths of Pain 1975–2005. Seattle, WA: IASP Press, pp. 236–7. Chung, J.M., Fang, Z.R., Hori, Y., Lee, K.H. and Willis, W.D. (1984) Prolonged inhibition of primate spinothalamic tract cells by peripheral nerve stimulation. Pain 19: 259–75. Cook, A.W. (1976) Percutaneous trial for implantable stimulating devices. J. Neurosurg. 44: 650–1. Devor, M. (2006) Sodium channels and mechanisms of neuropathic pain. J. Pain 7 (1 Suppl. 1): S3–S12. Di Vadi, P.P., Goroszeniuk, T., Kothari, S., Petrovic, Z. and O’Keeffe, J.D. (2007) Combined trial of spinal cord and peripheral neurostimulation. Reg. Anesth. Pain Med. 32 (5 Suppl.1): 62. Dooley, D.M. (1975) Percutaneous electrical stimulation of the spinal cord. Proceedings, Assoc. Neurol. Surg. Bal Harbor, Florida. Dunteman, E. (2002) Peripheral nerve stimulation for unremitting ophthalmic post-herpetic neuralgia. Neuromodulation 5 (1): 32–7.

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Ghoname, E.A., Craig, W.F., White, P.F. et al. (1999) Percutaneous electrical nerve stimulation for low back pain: a randomized crossover study. JAMA 282: 941–2. Goroszeniuk, T. (2003a) Short-term peripheral neuromodulation trial via stimulating catheter in neuropathic pain treatment. Reg. Anesth. Pain Med. 28 (5 Suppl. 1): 64. Goroszeniuk, T. (2003b) Percutaneous insertion of permanent peripheral stimulating electrode in patients with neuropathic pain. Proceedings of 6th INS Congress, June 25–28, Madrid, Spain, p. 59. Goroszeniuk, T. (2003c) Short neuromodulation trial in neuropathic pain produces varying duration but reproducible pain relief. Proceedings of the 4th Congress of EFIC, September 2–6, Prague, Czech Republic, p. 326. Goroszeniuk, T. and Kothari, S. (2004) Targeted external area stimulation. Reg. Anesth. Pain Med. 29 (4 Suppl. 5): 98. Goroszeniuk, T., Kothari, S. and Hamann, W. (2006a) Subcutaneous neuromodulating implant targeted at the site of pain. Reg. Anesth. Pain Med. 31 (2): 168–71. Goroszeniuk, T., Kothari, S. and Sanderson, K. (2006b) Targeted subcutaneous permanent neuromodulation in treatment of intractable angina. Eur. J. Pain 10: 158. Goroszeniuk, T., Hamann, W. and Kothari, S. (2007a) Percutaneous implantation of the brachial plexus electrode for management of pain syndrome caused by a traction injury. Neuromodulation 10 (2): 148–55. Goroszeniuk, T., Pratap, N., Kothari, S. and Sanderson, K. (2007b) An algorithm for peripheral neuromodulation in neuropathic pain. Proceedings of 8th World Congress of INS and 11th Annual Meeting of NANS, pp. 25–6, 169–70, December 9–12, Acapulco, Mexico. Goroszeniuk, T., Pratap, N., Sanderson, K. and Kothari, S. (2007c) Therapeutic trial of peripheral neuromodulation using inexpensive monoelectrode temporary stimulating catheters. Proceedings of 8th World Congress of INS and 11th Annual Meeting of NANS, p. 150, December 9–12, Acapulco, Mexico. Gybels, J.M. and Nuttin, B.J. (2000) Peripheral nerve stimulation. In: J.D. Loeser (ed.), Bonica’s Management of Pain, 3rd edn. Philadelphia: Lippincott, pp. 1851–55. Hammer, M. and Doleys, D.M. (2001) Perineuromal stimulation in the treatment of occipital neuralgia: a case study. Neuromodulation 4 (2): 47–51. Hamza, M.A., White, P.F., Craig, W.F., Ghoname, E.S., Ahmed, H.E., Proctor, T.J. et al. (2000) Percutaneous electrical nerve stimulation: a novel analgesic therapy for diabetic neuropathic pain. Diabetes Care 23 (3): 365–70. Hu, P., Lee, M.C., O’Keeffe, J.D. and Tracey, I. (2008) Peripheral nerve stimulation in capsaicin induced secondary hyperalgesia: a psychophysical evaluation. Proceedings of 12th World Congress on Pain, Glasgow, 2008 (in press). Khan, E.I., O’Keeffe, J.D., Walsh, R. and Goroszeniuk, T. (2005) Subcutaneous electrical nerve stimulation (SENS): modality for treatment of neuropathic pain. Anaesthesia 60 (3): 305–6. Kothari, S. and Goroszeniuk, T. (2004) Sympathetic plexus stimulation: a novel case study. Reg. Anesth. Pain Med. 29 (5 Suppl. 2): 99, (Abstr. 241). Kothari, S. and Goroszeniuk, T. (2006) External neuromodulation as a diagnostic and therapeutic procedure. Eur. J. Pain 10 (Suppl. 1): S158. Kothari, S., Goroszeniuk, T. and Al-Kaisy, A. (2004) Peripheral percutaneous stimulation for refractory angina pectoris. Reg. Anesth. Pain Med. 29 (5 Suppl. 2): 99 (Abstr. 305). Koulousakis, A., Ntouvali, A., Krasodakis, A. and Koutsoumbelis, G. (2006) Peripheral nerve field stimulation. Eur. J. Pain 10 (Suppl. 1): S158.

Krutsch, J.P., McCeney, M.H., Barolat, G., Al Tamimi, M. and Smolenski, A. (2008) A case report of subcutaneous peripheral nerve stimulation for the treatment of axial back pain associated with failed back surgery syndrome. Neuromodulation 11 (2): 112–5. Linderoth, B., Stiller, C.O., Gunasekera, L., O’Connor, W.T., Franck, J., Gazelius, B. and Brodin, E. (1993) Release of neurotransmitters in the CNS by spinal cord stimulation: survey of present state of knowledge and recent experimental studies. Stereotact. Funct. Neurosurg. 61: 157–70. Mannheimer, C., Carlsson, C.A., Emmanuelsson, H., Vedin, A., Waagstein, F. and Wilhelmsson, C. (1985) The effects of transcutaneous electrical nerve stimulation in patients with severe angina pectoris. Circulation 71: 308–16. Mannheimer, C., Augustinsson, L.-E., Carlsson, C.-A., Manhem, K. and Wilhelmsson, C. (1988) Epidural spinal electrical stimulation in severe angina pectoris. Br. Heart J. 59: 56–61. Melzack, R. and Wall, P.D. (1965) Pain mechanisms: a new theory. Science 150: 971. Monti, E. (2004) Peripheral nerve stimulation: a percutaneous minimally invasive approach. Neuromodulation 7 (3): 193–6. Na, H.S., Leem, J.W. and Chung, J.M. (1993) Abnormalities of mechanoreceptors in a rat model of neuropathic pain: possible involvement in mediating mechanical allodynia. J. Neurophysiol. 70 (2): 522–8. O’Keeffe, J.D., O’Donnell, B.D., Tan, T. and Roets, M. (2006) Subcutaneous electrical nerve stimulation (SENS one shot) in the treatment of neuropathic pain. Proceeding of the 9th Meeting of the NANS, Neuromodulation, Vol. 9 (1): 8–20. Oakley, J.C. (2003) Spinal cord stimulation for neuropathic pain. In: B.A. Simpson (ed.), Electrical Stimulation and the Relief of Pain. Pain Research and Clinical Management, Vol. 15. Amsterdam: Elsevier, pp. 87–109. Paicius, R.M., Bernstein, C.A. and Lempert-Cohen, C. (2006) Peripheral nerve field stimulation in chronic abdominal pain. Pain Phys. 9: 261–6. Paicius, R.M., Bernstein, C.A. and Lempert-Cohen, C. (2007) Peripheral nerve field stimulation for the treatment of chronic low back pain: preliminary results of long-term follow-up: a case series. Neuromodulation 10 (3): 279–90. Petrovic, Z., Goroszeniuk, T. and Kothari, S. (2007) Percutaneous lumbar plexus. Stimulation in the treatment of intractable pain. Reg. Anesth. Pain Med. 32 (5 Suppl. 1): 1. Priestley, T. (2004) Voltage-gated sodium channels and pain. Curr. Drug Targets CNS Neurol. Disord. 3 (6): 441–56. Racz, G.B., Lewis, R., Heavner, J.E. and Scott, J. (1990) Peripheral nerve stimulator implant for treatment of causalgia. In: M. StantonHicks, W. Janing and R.A. Boas (eds), Reflex Sympathetic Dystrophy,. Norwalk, CT: Kluwer, pp. 135–41. Randic, M., Jiang, M.C. and Cerne, R. (1993) Long-term potientiation and long-term depression of primary afferent neurotransmission in rat spinal cord. Neuroscience 13 (12): 5228–41. Sandkuhler, J., Cheng, J.G., Cheng, G. and Randic, M. (1997) Low frequency stimulation of afferent A delta-fibres induces longterm depression at primary afferent synapses with substantia gelatinosa neurons in the rat. J. Neurosci. 17 (16): 6483–91. Shealy, C.N., Mortimer, J.T. and Reswick, J.B. (1967) Electrical inhibition of pain by stimulation of the dorsal columns: preliminary clinical report. Anesth. Analg. 46 (4): 489–91. Shimoji, K., Higashi, H. and Kano, T. (1971) Electrical management of intractable pain. Jpn J. Anesthesiol. 20: 444–7. Shimoji, K., Matsuki, M., Shimizu, H., Iwane, T., Takahashi, R., Maruyama, M. et al. (1977) Low frequency, weak extradural stimulation in the management of intractable pain. Br. J. Anesth. 49: 1081–86.

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Stinson, L.W., Roderer, G.T., Cross, N.E. and Davis, B.E. (2001) Peripheral subcutaneous. electrostimulation for control of intractable post-operative inguinal pain; a case report series. Neuromodulation 4: 99–104. Taub, A. and Campbell, J.N. (1974) Percutaneous local electrical analgesia: peripheral mechanisms. In: J.J. Bonica (ed.), International Symposium on Pain, Advances in Neurology, Vol. 4. New York: Raven Press, pp. 727–732. Theodosiadis, P., Kothari, S., Goroszeniuk, T. and Grosomanidis, V. (2004) Coccycodynia treated with direct catheter neurostimulation. Reg. Anesth. Pain Med. 29 (5 Suppl. 2): 11. Theodosiadis, P., Samoladas, E., Grosomanidis, V., Goroszeniuk, T. and Kothari, S.A. (2008) A case of successful treatment of neuropathic pain after a scapular fracture using subcutaneous targeted neuromodulation. Neuromodulation 11 (1): 62–5. Turner, J.A., Loeser, J.D. and Bell, K.G. (1995) Spinal cord stimulation for chronic low back pain: a systematic literature synthesis. Neurosurgery 37 (6): 1088–96.

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Urmey, W. and Grossi, P. (2002) Percutaneous electrode guidance (PEG); a noninvasive technique for pre-location of peripheral nerves to facilitate nerve block. Reg. Anesth. Pain Med. 27: 261–7. Verrills, P., Mitchell, B., Vivian, D. and Sinclair, C. (2009) Peripheral nerve stimulation: a treatment for chronic low back pain and failed back surgery syndrome? Neuromodulation 12 (1): 68–75. Wall, P.D. and Gutnik, M. (1974) Properties of peripheral nerve impulses originating from neuroma. Nature 248: 740–3. Wall, P.D. and Sweet, W.H. (1967) Temporary abolition of pain in man. Science 155: 108–9. Weiner, R.L. and Reed, K.L. (1999) Peripheral neurostimulation for control of intractable occipital neuralgia. Neuromodulation 2: 217–21. Yakovlev, A.E. and Peterson, A.T. (2007) Peripheral nerve stimulation in treatment of intractable post herpetic neuralgia. Neuromodulation 10 (4): 373–5.

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C H A P T E R

32

Relevant Anatomy for Spinal Delivery Timothy R. Deer, Matthew T. Ranson, and Douglas Stewart

o u tline Introduction Delivery Systems for Pharmaceutical Agents Factors Influencing Access to the Spine for   Neuromodulation Device- and Technique-Related Factors Intrathecal Placement Epidural Placement Radiological Confirmation of Catheter   Placement Anatomical Factors Spinal Cord Anatomy

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Nerve Root Anatomy Vertebral Column Anatomy The Epidural Space Anatomical Issues for the Spinal Cord and   Surrounding Structures

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Distribution of Intrathecal Agents in the  Spinal Fluid

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Conclusion

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References

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region. If the access to the spine is not performed successfully and safely, the ability to provide this treatment is negated.

In order to provide successful neuromodulation therapies, the practitioner must have vigilance with several steps in the process. Important components are diagnosis, patient selection, decision-making, and algorithmic treatment applications. Once the decision is made to move forward, the clinician must access the spine in a successful and appropriate manner. This chapter will review the important procedural steps for entering the spinal space desired for implant, and also review critical anatomical components that are important in the outcome of accessing the anatomical

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Delivery Systems for Pharmaceutical Agents The delivery of a drug or digital drug to the human body is a complicated issue. Why not just take a pill? Why would we deliver drugs by an intrathecal or epidural catheter? These issues should be considered prior to examining the issue of accessing the spine for the delivery of neuromodulation. The routes of delivery should be considered on an individual basis with

431

2009 Elsevier Ltd. © 2008,

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32.  Relevant Anatomy for Spinal Delivery Epidural space

Dura mater Arachnoid

Posterior spinal aa. Subarachnoid space Dorsal (sensory) spinal root Pia mater

Denticulate ligament

Posterior (sensory) horn Anterior (motor) horn

Ventral (motor) spinal root

Dorsal (posterior) primary ramus

Dorsal root ganglion

Ventral (anterior) primary ramus

Vertebral a.

Internal venous plexus

Anterior spinal a.

Body of the fifth cervical vertebra

Figure 32.1  A posterior view of the human spinal anatomy at the lower thoracic level, where many intrathecal catheters dwell (©jamespublishing.com. Reproduced by permission)

each patient, and the risk–benefit ratios should be evaluated prior to moving forward. Transdermal systems may bypass the first pass effect, but have downsides including a lengthy upfront load, skin irritation, unreliable absorption secondary to skin temperature and texture, and difficulty with ongoing dosing secondary to failure to adhere to the tissue. The primary benefit of oral agents is the ease of taking the medication, but the disadvantages include loss of drug to the first pass effect and tissue cascade that the drug undergoes before reaching its target in the central or peripheral nervous system. Oral agents can also be effected by gastric and bowel motility, other dietary confounders, use of alcohol, and stomach acidity. Intrathecal and epidural routes have the advantages of marked dose reduction and direct delivery. The major drawback is the need to perform an interventional procedure to deliver the desired agent. The relevant anatomy is also important for each route of delivery. Factors that should be consid­ered for the gastrointestinal system for oral delivery are a history of gastric bypass, small bowel bypass or colostomy. For transdermal delivery, factors to be considered include skin topography and skin character which can vary on the basis of age, race, systemic mediations, nutritional status, and disease state. With

intrathecal delivery the importance of several factors can influence drug uptake and distribution of drug in that space, including arterial blood supply, CSF bulk flow, diffusion through the dura and the meninges (Reisfiled and Wilson, 2004).

Factors Influencing Access to the Spine for Neuromodulation The presence of a need for the infusion of an intrathecal or epidural infusion is determined by the workup, history, physical exam, and imaging of a patient. The placement of the device is determined by the choice of device, proper technique in placing the device, and the anatomical variations in the spine that may affect the success of obtaining access (Figure 32.1).

Device- and Technique-Related Factors Intrathecal Placement Positioning the Patient Once the patient has been properly prepared for surgery the proper positioning of the patient will have an impact on the overall procedure. The physician should

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instruct the team on the desired position for the surgery. The majority of pumps are placed in the lateral decubitus position as this position allows for access of the spine and abdominal wall without the need for repositioning and re-draping. In this position it is important to align the shoulders, minimize lordosis, flex the hips, and properly expose the abdominal wall to assure a sterile field. The patient may be limited in some cases to proper position because of pain, arthritis in the joints, metastatic involvement, paraplegia, spasticity, scoliosis, or other anatomic restrictions. In these cases it is important to achieve the best position possible with a focus on sterility and patient safety. It is also important to correct any anatomical tilt with fluoroscopic compensation. Fluoroscopic Imaging Once the patient has been adequately positioned, widely prepped and draped, and prepared for the procedure, the fluoroscopic imaging device should be used to perform an initial scout film. An anteroposterior scout film can be used to align the end-plates and facet joints to improve the accuracy of the angle. In cases where the angle is not in proper alignment because of improper positioning or failure to correct with the fluoroscopy beam, the needle may be represented falsely on the image screen creating a parallax error and increasing the risk of incorrect needle placement. The use of laser-guided imagery may improve the ability to correct needle direction and make changes with the catheter as it is advanced.

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Catheter Placement The placement of the intrathecal catheter should be performed after the confirmation of free flow of cerebral spinal fluid through the intrathecal needle. The catheter should be placed without resistance. It is advisable to have the patient remain alert and communicative during this phase to reduce the risk of nerve injury or spinal cord damage. In the event the catheter meets resistance, or the patient experiences a paresthesia or shooting pain, the needle and catheter should be removed and the needle should be repositioned. The catheter should never be withdrawn or pulled back while in the needle since this may lead to catheter shearing or fracture. The catheter often travels laterally upon initial entry into the intrathecal space. When possible the catheter should be redirected to the posterior intrathecal space for the final tip position. This is recommended, but not always possible due to anatomical variation. In the event of intrathecal mass formation the risks of motor compromise will be reduced in the more posterior position. The site of the catheter tip varies on physician preference. Some clinicians prefer to place the catheter tip at the site of the pain generator to allow direct delivery of drugs. This may increase the efficacy of the agents that are more lipophilic, although this hypothesis has never been confirmed in prospective studies. Some clinicians prefer to place the catheter tip below the conus. The theory behind this concept is that by placing the tip below the conus the risk of injury will be reduced in the event of a granuloma. This concept has not been shown to have any value in prospective studies.

Needle Placement In the early days of neuromodulation most clinicians recommended a classic spinal injection approach to the spine. This method involves a midline needle placement with a 90 degree angle to enter the spine. This approach led to easy needle entry to the spine, but is fraught with problems. Difficulties with the midline approach include nerve injury, catheter dislodgement, catheter fracture, catheter occlusion, and chronic spinal leak. Current thought advocates a technique that involves using a paramedian approach to the interlaminar space (Follett et al., 2003). This technique allows the needle to avoid the supraspinous ligament, the spinous processes, and acute angles. By entering the skin at the inferior aspect of the pedicle one and a half spaces below the planned entry site a blunt angle of 30–45 degrees can be employed. The combination of a paramedian approach and a shallow angle leads to decreased catheter torque, improved catheter angles, and improved outcomes.

Needle Removal Once spinal access is confirmed, a purse string suture is secured around the needle and the needle is removed. Placement of the purse string suture may prevent CSF leakage and formation of a hygroma. At this critical part of the procedure it is important to hold the catheter steady and not remove the catheter or fracture the catheter. Epidural Placement Overview When placing an epidural catheter for infusion the same principles exist as noted for intrathecal drug delivery. The patient should be properly selected, positioned, and the fluoroscopic image should be properly aligned. The recommended needle approach is a paramedian shallow angle to minimize the angle

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Anatomical Factors The spinal canal is a complex and miraculous part of the human anatomy. The neurospinal fibers are protected by the dura mater, the arachnoid membrane, and the pia mater. A potential space exists between the dura and arachnoid that is termed the subdural space. The CSF flows between the arachnoid and pia mater in the subarachnoid space. The epidural space extends from the foramen magnum to the end of the dural sac at the level of S2. It is bounded anteriorly by the vertebral bodies and posteriorly by the laminae and ligamentum flavum. The epidural space is filled with connective tissue, adipose, and venous plexuses. The spinal nerves travel through this space surrounded by dura. Spinal Cord Anatomy

Figure 32.2  Myelogram: (A) lateral and (B) anteroposterior views. The placement of contrast into the intrathecal space results in a classic outline of the nerves and cord of the cerebral spinal fluid (Reproduced with permission from: Neal, J.M. and Rathmell, J.P. (2007) Complications in Regional Anesthesia and Pain Medicine. Philadelphia: Saunders Elsevier. Copyright (2007) Elsevier)

of catheter entry. The catheter is placed into the epidural space with attention to X-ray position and the avoidance of paresthesia. Catheter and Needle Issues The catheter tip is often placed at the site of the pain generator. Again, it is important to avoid withdrawing the catheter while the needle is in place to avoid sheering. The catheter is often advanced slightly as the needle is retracted to avoid dislodgement of the catheter. Radiological Confirmation of Catheter Placement With intrathecal catheter placement free flow of CSF should be seen. However, in some cases flow is intermittent or poor. On the contrary, epidural placement should result in no fluid being produced from the needle. In some cases it is difficult to discern whether CSF or intravascular catheter placement has occurred because of bleeding from needle placement, counter flow of a test dose, or placement of saline in the loss of resistance technique. In these situations a preservative-free, neuroaxis-compatible contrast medium can be injected to ensure proper catheter placement and exclude intravascular placement (see Figure 32.2).

The spinal cord originates at the foramen magnum as a continuation of the medulla oblongata. The termination of the spinal cord is at the conus medullaris, which is normally at L1 in adults and L2 or L3 in children and infants (Figure 32.3). The pia mater continues to end at the filum terminale which attaches the spinal cord to the posterior aspect of the coccyx. The dural sac ends at the second sacral vertebra. The spinal cord is composed of white matter surrounding a core of gray matter. The gray matter has both anterior and posterior horns which are the motor and sensory fibers, respectively. Nerve Root Anatomy The spinal nerves are composed of 31 pairs of nerves. Each of these nerves contains a motor root and a sensory root. The spinal nerves exit the spine at the intervertebral foramen formed by the superior and inferior vertebrae. The eight cervical nerves exit above the corresponding vertebral body with the C8 nerve exiting between C7 and T1. Distal to that level the nerves exit below the corresponding vertebrae. Vertebral Column Anatomy The vertebral column is complicated by a series of angulations in the anterior to posterior plane. The normal spine has a cervical lordosis and a thoracic and sacral xyphosis. These curvatures may have an effect on drug spread and CSF circulation particularly in abnormal spinal anatomy. The vertebral column is supported by the spinal ligaments. Ligaments of the Spine The ligaments of the spine are critical to the anatomical stability of the spinal structures. The primary

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Anatomical Factors

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ligaments of the spine are the ligamentum flavum, anterior longitudinal ligament, and the posterior longitudinal ligament. Subarachnoid space

2 3

Cervical enlargement (of spinal cord)

4 5 6 7 8 1

Pedicles of vertebrae

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C1 C2 C3 C4 C5 C6 C7 C8 T1 T2 T3

5

T4

6

T5

7

T6

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T7

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T12 L1 L2

Arachnoid mater

L3

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End of subarachnoid space-sacral vertebra II

The ligamentum flavum is critical in that it forms a cover protecting the dura mater. The dura mater protects the spinal cord. l The anterior longitudinal ligament is a vertical structure that attaches to the anterior portion of each vertebrae. l The posterior longitudinal ligament is a vertical structure that attaches to the posterior portions of each vertebra. l Other ligaments of the spine also play critical roles. These include the interspinous ligaments, occipitoatlantal ligament complex, occipitoaxial ligament complex, altantoaxial ligament complex, and the cruciate ligament complex. l Figure 32.4 depicts some of the critical ligaments to be considered when accessing and instrumenting the spine. l

1

S1 S2 S3 S4 S5 Co

© Elsevier.

Figure 32.3  The spinal cord (© Elsevier. Drake et al. Gray’s Anatomy for Students. www.studentconsult.com. Reproduced with permission)

Blood Supply to the Spinal Cord The blood supply to the spinal cord is delivered by a single anterior spinal artery and two posterior spinal arteries. The two PSA arteries travel longitudinally along the posterior surface of the spinal cord in concert with the nerve roots. These arteries are intertwined by anastomoses that form longitudinal vessels. Additional collaterals are delivered by segmental arteries that travel via the intervertebral foramina. The anterior spinal artery is critical in that is supplies the anterior two-thirds of the spinal cord. In the cervical spinal cord, the anterior spinal artery receives its blood flow from the vertebral arteries that normally arise from the subclavian artery, enter the spinal canal in the upper cervical vertebral column, ascend to the anterior midline of the brain stem, and merge to become the basilar artery. Two small branches of the vertebral artery descend towards the anterior midline, merge, and form the ASA which descends to the lumbar cord (Figure 32.5). The anterior thoracic spinal blood supply is more complicated and potentially more prone to disastrous complications. In this region the anterior spinal artery receives only a minimal number of collateral radicular arteries from the aorta. The artery of Adamkiewicz, first described in 1882, reinforces the supply at the level of T9 in most humans. The artery can vary in its side of origin, which is the left side in 78% of cases and in its level of origin which can vary from T8 to L3. Injury to this artery can lead to major neurological sequelae, including the possibility of paraplegia.

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32.  Relevant Anatomy for Spinal Delivery

Posterior longitudinal ligament

Ligamentum flavum Supraspinous ligament Interspinous ligament

Ligamentum flavum Supraspinous ligament

Anterior longitudinal ligament (A)

(B)

© Elsevier.

Figure 32.4  (A) Anterior and posterior longitudinal ligaments of vertebral column; (B) interspinous ligaments (© Elsevier. Drake et al. Gray’s Anatomy for Students. www.studentconsult.com. Reproduced with permission)

The thoracic segmental arteries come directly from the aorta. At this level these arteries are called intercostal arteries. The intercostals arteries network longitudinally in both the ventral and dorsal spine. This networking complex can lead to redundant supply which provides an improved degree of safety for ischemic spinal events. Branches of the segmental arteries supply flow to the vertebral bones and the structures of the spinal canal. Each intercostal artery splits into several branches. One of these large branches enters the foramen and splits into a radicular artery and several dural branches. The dural branches supply the dura and the cauda equina.

safety. Venous drainage of the spinal cord occurs mainly through pial veins which are on the surface. Venous congestion can play an important role in ischemia of the cord (Figure 32.6). The Epidural Space The epidural space is the space just outside the dura of the spinal canal. The epidural space is a potential space extending from the base of the skull to the sacral hiatus. This space contains blood vessels, fatty tissue, and fibrous tissue. The Vacuum Effect

Spinal Cord Venous System The venous system is important for drainage of blood and metabolic substrates. Compromise of the venous system may lead to delayed ischemia of the cord and severe sequelae. The spinal venous system follows the arterial system and is segmentally organized. The venous system has several redundant and collateral flow patterns that provide an additional margin of

The epidural space is entered when the needle passes through the ligamentum flavum into the desired location. The loss of resistance that occurs when going from the ligament to the epidural space can be detected by using a pressurized syringe that suddenly has a drop in pressure as the potential space is entered from the high pressure, dense ligament. The change of pressure can also be detected by the hanging drop technique in

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Device- and Technique-Related Factors

Anterior radicular artery Segmental spinal artery

Posterior spinal arteries

Posterior radicular artery Posterior radicular artery Anterior radicular artery Segmental medullary artery

Segmental medullary artery Segmental spinal artery Anterior spinal artery

Left posterior intercostal artery

Right posterior intercostal artery

Segmental spinal artery

Aorta

© Elsevier.

Figure 32.5  Arterial supply of the spinal cord (© Elsevier. Drake et al. Gray’s Anatomy for Students. www.studentconsult.com. Reproduced with permission) Posterior spinal vein

Anterior spinal vein

the epidural space into the spinal fluid. This difference reduces, but does not eliminate, the need for epidural test dosing, and contrast imaging. Anatomical Detail of the Epidural Space

Dura mater

Extradural fat Internal vertebral plexus © Elsevier.

Figure 32.6  Venous drainage of the spinal cord (© Elsevier. Drake et al. Gray’s Anatomy for Students. www.studentconsult.com. Reproduced with permission)

which the sudden change in pressure leads to a sudden retraction of the drop which is allowed to hang at the surface of the needle hub. In normal anatomy the pressure gradient between the CSF and the epidural space would be noticed quickly as one passes through

The epidural contents are not uniform. The structures are found in a circumferential and segmented fashion grouped in compartments. The steeply arched ligamenta flava are fused in the midline to a variable degree based on the spinal level of consideration. The anterior epidural space has a concentrated number of veins and is separated from the remaining epidural space by a membranous lateral extension of the posterior longitudinal ligament. This anatomical structure is important to the overall mechanics and pharmaco­ kinetics of epidural injections and infusions. (Hogan, 1991). The pharmacokinetics of the epidural space suggest the hydrophilic infused drugs spread widely with diffuse spread in the CSF. The lipophilic drug classes spread locally and result in high serum concentrations and high local drug concentrations in the area infused. Some studies have refuted these findings and suggest

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32.  Relevant Anatomy for Spinal Delivery

the overall drug availability is variable based on epidural fat and venous supply (Bernards et al., 2003). Anatomical Issues for the Spinal Cord and Surrounding Structures Innervation of the Spinal Dura The dura has a complicated pattern of innervation that is important for understanding pain produced during spinal access and for the detection of complications in the chronic pain patient. The ventral dura contains a very complicated large chain of nerves that create a nerve complex. The contributions to the ventral dura include the nerve plexus of the posterior longitudinal ligament, the nerve plexus of the radicular branches of the segmental arteries, and the sinuver­tebral nerves. The ventral dural nerves extend for eight segments and have a large amount of overlap. This may be a factor involved in referred dural pain. The dorsal dura has a much simpler nerve supply that does not create a plexus at the level of the dura mater. The nerves of the dura can be activated in flexion, extension, and during injection therapies. Cerebral Spinal Fluid Dynamics, Flow, Production, Volume, and Overview The CSF is primarily formed in the choroid plexus of the cerebral ventricles. The CSF flows through the ventricles and cisterna magnum to the spinal cord. CSF formation occurs at a rate of 0.3–0.4 ml/min and is reabsorbed at the same rate in normal subjects. In normal humans the CSF volume in the brain ranges from 100 to 150 ml or approximately 2 ml/kg. The volume below the lower thoracic spine varies widely. The cerebrospinal fluid volume is important as a diluent for drugs given by intrathecal infusion. The volume of CSF in an individual can vary greatly based on height, body habitus, and abdominal pressure. MRI imaging has demonstrated that there is great variability in CSF/ root volume as the spine is assessed based on level. From the T11–T12 disc space to the sacral terminus of the dural sac the mean volume of normal individuals is approximately 50 ml with a range of 28 to 81 ml. The volume is significantly less in obese people and in those with abdominal compression from obesity or pregnancy. This difference can lead to less dilution of the intrathecal drugs being delivered to that area (Greitz, 1993). CSF density has been found to impact the extent and duration of spinal anesthesia, although the effect on intrathecal infusions has not been studied (Higuchi et al.¸ 2004). Imaging studies have shown the CSF has a pulsating flow which creates an effective mixing of the existing fluid. The pulsatile flow is produced by an alternating pressure gradient created by intracranial artery expansion.

This process makes the process of bulk flow an immaterial issue since the pulsatile nature of the flow makes bulk flow irrelevant. The CSF is absorbed in a minor fashion by the Pacchionian granulations with the majority of absorption occurring in the paravascular and extracellular spaces of the central nervous system. The intracranial dynamics of the CSF is based on interplay between the four components of the cranium. These components, which include the arterial blood, venous blood, brain volume and CSF, determine the flow and production of the CSF. This interaction has a time offset in the cerebral hemispheres in a ventral to dorsal direction during the cardiac cycle. This interaction is referred to as the frontooccipital volume wave. The outflow from the aqueduct is directly proportional to the brain expansion, which is negligible in healthy subjects. This expansion is very important, however, since it occurs simultaneously with an inflow of CSF which is directed towards the ventricular system. The brain expansion is in part responsible for the normal transcerebral pressure gradient which has an effect on normal CSF outflow. The outflow of CSF from the cranial region to the cervical subarachnoid area is variable. It is dependent on the size of the intracranial arterial girth which changes during systole. The main reabsorption of CSF occurs from the central nervous system to the blood (Greitz and Hannerz, 1996). Nerve Root Size and Volume Studies have shown a major variability of the size of the thoracic and lumbosacral nerve roots. In most subjects the lower lumbar and sacral nerve roots are much larger than the lower thoracic nerve roots based on area and diameter of the root. This difference may create a variability of response to intrathecal agents and to the ease of nerve injury and recovery (Hogan, 1996). Spinal Tracts The spinal tracts have been mapped out in detail. These tracts have several areas of focused function. These include motor function (ventral), sensory function (ventral), proprioception (dorsal), and pain (lateral). These tracts are delineated in Figure 32.7.

Distribution of Intrathecal Agents in the Spinal Fluid Several factors may affect the distribution of agents when infused into the spinal fluid. These factors can be summarized as: total dosage lipophilicity

l l

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Distribution of Intrathecal Agents in the Spinal Fluid

Often called the posterior white columns. Sensory tracts Carry discriminative touch and conscious Ascending tracts proprioception Fasciculus gracilis Fasciculus cuneatus Posterior spinocerebellar tract Anterior spinocerebellar tract Lateral spinothalamic tract Anterior spinothalamic tract

Motor tracts Descending tracts Lateral corticospinal tract Rubrospinal tract Anterior reticulospinal tract Lateral reticulospinal tract Olivospinal tract Anterior corticospinal tract Vestibulospinal tract Tectospinal tract

Lead to the thalamus, the pathway for crude touch, pain, temperature, pressure From the spinal cord to the cerebellum. Carry subconscious proprioceptive stimuli. Proprioception is ‘body sense’ and ‘muscle sense,’ the perception of body position and muscle position necessary for coordinating movements

© Elsevier.

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These tracts come from a variety of locations in the brain, as a group are termed the ‘extra-pyramidal tracts,’ and are generally associated with balance and muscle tone The corticospinal tracts carry voluntary motor stimuli from the cerebral cortex to motor neurons in the spinal cord. They are also called the ‘pyramidal tracts’ because some of them cross in the pyramids of the medulla

Figure 32.7  The spinal tracts

Figure 32.8  Magnetic resonance imaging study of a patient with an inflammatory mass surrounding the tip of an implanted intrathecal drug delivery catheter. (A) Midline, sagittal, T2-weighted image. The inflammatory mass involves the dorsal aspect of the spinal cord at the level of the inferior end plate of T10. (B) Axial, T2-weighted image through the inflammatory mass. The mass displaces the spinal cord toward the left (Reproduced with permission from: Neal, J.M. and Rathmell, J.P. (2007) Complications in Regional Anesthesia and Pain Medicine. Philadelphia: Saunders Elsevier, Figure 23.1. Copyright (2007) Elsevier)

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32.  Relevant Anatomy for Spinal Delivery

baricity patient position patient CSF volume based on anatomy level of injection patient height intra-abdominal pressure granuloma

systems. Understanding the technical and anatomical issues is critical in determining the long-term success of the patients receiving intrathecal therapies.

References

In addition to the initial factors listed in the table, the physician should also be aware of the possibility of scar formation developing around the catheter which can lead to encapsulation of the catheter tip and potential changes in the delivery of the infused drug into the spinal fluid. It is important to note that height, aside from extremes of normalcy, has not been shown to consistently affect the spread of intrathecal medications (Figure 32.8).

Conclusion The process of implanting the intrathecal space or epidural space with a catheter is a skill that can be developed in a competent physician over a relatively short period of time. The process is only a small part of what it takes to become a well-accomplished implanter. Proper training in surgical techniques is mandatory prior to attempting implantation of neuroaxial delivery

Bernards, C.M., Shen, D., Sterling, E.S., Adkins, J., Risler, L., Phillips, B. and Ummenhofer, W. (2003) Epidural, cerebrospinal fluid, and plasma pharmacokinetics of epidural opioids (Part 1): Differences among opioids. Pain Reg. Anesth. Anesthesiol. 99 (2): 455–65. Follett, K.A., Burchiel, K., Deer, T.R., DuPen, S., Prager, J., Turner, M.S. and Coffey, R.J. (2003) Prevention of intrathecal drug delivery catheter-related complications. Neuromodulation 6 (1): 32–41. Greitz, D. (1993) Cerebrospinal fluid circulation and associated intracranial dynamics. A radiologic investigation using MR imaging and radionuclide cisternography. Acta Radiol. 386 (Suppl.): 1–23. Greitz, D. and Hannerz, J. (1996) A proposed model of cerebrospinal fluid circulation: observations with radionuclide cisternography. Am. J. Neuroradiol. 17 (3): 431–8. Higuchi, Hideyuki, Hirata, Jyun-ichi, Adachi, Yushi and Kazama, Tomiei (2004) Influence of lumbosacral cerebrospinal fluid density, velocity, and volume on extent and duration of plain bupivacaine spinal anesthesia. Pain Reg. Anesth. Anesthesiol. 100 (1): 106–14. Hogan, Q. (1991) Epidural anatomy: lumbar epidural anatomy a new look by cryomicrotome section. Clin. Invest. Anesthesiol. 75 (5): 767–75. Hogan, Q. (1996) Size of human lower thoracic and lumbosacral nerve roots. Clin. Invest. Anesthesiol. 85 (1): 37–42. Reisfiled, G.M. and Wilson, G.R. (2004) Intrathecal drug therapy for pain #98. J. Palliat. Med. 7 (1): 76.

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C H A P T E R

33

The Rational Use of Intrathecal Opioid Analgesics Elliot S. Krames and Mouchir Harb

outli n e Introduction

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Indications for IT Therapy

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Trials for IT Delivery

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Implantable Drug Delivery Systems Intrathecal Opioid Delivery Morphine Hydromorphone Fentanyl

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Introduction

An Algorithmic Approach to Intrathecal Therapy

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Conclusion

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References

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agents for both cancer and non-cancer-related pain. A complete review of the use of IT non-opioid analgesic agents will be presented by Reig, Abejón and Krames in Chapter 35.

In 1979, the first clinical reports regarding the analgesic effect of intrathecal (IT) and epidural morphine started to emerge in the literature (Behar et al., 1979; Wang et al., 1979). Since the publication of these early reports, intraspinal, and in particular, IT therapy has achieved a great deal of refinement and development that would never had happened without the earlier discovery of the opioid receptor (Goldstein et al., 1971) and its existence in neural tissues (Kuhar et al., 1973; Pert and Snyder, 1973). In addition to the discovery of opioid receptors, the identification of the pain modulating effect of gaba-aminio-butyric acid (GABA), adrenergic, cholinergic, and glutamate receptors, amongst others, have fueled the development of more and more agents to be used for IT therapy. This chapter will focus on the IT delivery of opioid analgesic

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Sufentanil Methadone Meperidine

Indications for IT therapy In approaching patients with chronic nonmalignant pain and cancer pain, it is essential and foundational to understand both the mechanism/s of pain and the psychological and behavioral factors that work on perpetuating and sustaining chronic pain before designing a treatment plan for the patient (Krames, 2001). Because there are multiple therapies for chronic pain, both interventional and non-interventional, the treatment of chronic pain should follow a logical plan or algorithm that should take into account efficacy,

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33.  the rational use of intrathecal opioid analgesics A pain treatment continuum

There are no serious untreated drug addictions. There are no psychological barriers to successful

l l

• exercise • cognitive therapies • over-the-counter analgesics • NSAIDs • adjunctive medications: TCAs, anticonvulsants, membrane stabilizing drugs • physical therapeutic modalities • TENS • behavioral therapies • oral opioids • spinal cord stimulation • intraspinal analgesics • neuroablation

Figure 33.1  An example of a pain treatment continuum that lists therapies for nonmalignant pain by order of invasiveness (Adapted with permission from Krames, 1996. Copyright (1996) Elsevier)

cost, and invasiveness. Because of the multiplicity of therapies for chronic pain and because there are very few intra-therapy comparative data, it is logical to use the KISS principal (Keep It Sweet and Simple) by starting the least invasive and least costly therapies before progressing, based on response, to more invasive modalities (Krames, 1999b). Because of its cost, its risks, and because it requires surgery to perform, chemical neuromodulation (IT therapies) should belong relatively last on this algorithm for treatment (pain treatment continuum) for nonmalignant chronic pain (see Figure 33.1). For use in cancer pain, there is a prospective randomized controlled study (RCT) that tested conservative medical management (CMM) of cancer pain compared to the IT delivery of analgesic medication (Smith et al., 2002). This RCT showed that, not only was IT delivery more efficacious than CMM, those patients subjected to the IT delivery of analgesic agents lived longer than those subjected to CMM. Initially, IT therapy was used to treat cancer pain, but over the years it has gained a more broad spectrum of application (Krames, 1996) that includes neuropathic pain of nonmalignant origin (Winkelmuller M and Winkelmuller W, 1996), FBSS (Hassenbusch et al., 1991; Schuchard, Krames et al., 1998), CRPS (Barolat et al., 1981) as a distinct neuropathic syndrome, and head and neck pain (Nitescu et al., 1995), to name a few. This treatment, a relatively invasive and costly one, should be considered only when certain criteria have been met, which include (Krames, 1996): Failure of less costly and less invasive therapies

l

including spinal cord stimulation (SCS), when applicable. l Objective pathology exists that is concordant with the pain complaint. l Further surgical interventions are not indicated.

outcome.

There are no absolute contraindications for

l

implantation.

A trial, ruling in efficacy and ruling out toxicity,

l

has been performed.

It is also important, when choosing therapies for cancer and noncancer pain, to know whether the patient’s pain is primarily nociceptive, neuropathic or mixed nociceptive/neuropathic in nature. Some pain syn­ dromes respond to certain medications and some do not. For example, patients with a primary nociceptive pain syndrome will most usually respond to opioids and NSAID therapies, while patients with a primary neuropathic pain syndrome may or may not respond to opioid or NSAID therapies, but may respond better to a membrane stabilizing agent such as an antiepileptic medication (e.g. gabapentin, pregabalin, topiratate, etc.). Likewise, when choosing implantable technologies for pain control such as spinal cord stimulation (SCS) or IT therapy with opioids, it is equally important to know whether the patient’s pain is nociceptive, neuropathic, or mixed nociceptive/neuropathic. Neuropathic pain is amenable to SCS for pain, while nociceptive pain is not. IT opioid therapy is useful for nociceptive pain, but might not be efficacious when used for patients with primary neuropathic pain syndromes. IT therapy with non-opioids such as local anesthetics (Krames and Lanning, 1993), alpha-adrenergic agents (Hassenbusch et al., 2002) or voltage sensitive, N-type calcium-channel blocking agents such as ziconotide (Ellis et al., 2008) have been shown to be effective for neuropathic pain syndromes. Because IT therapies are moderately efficacious for neuropathic pain syndromes when using non-opioid IT analgesics such as clonidine, bupivacaine, and/or ziconotide, alone, or when mixed with an opioid as an admixture, there exists no clear-cut boundaries when choosing between SCS or IT analgesic therapies for neuropathic pain syndromes. Figure 33.2 represents a Venn diagram that presents relatively clear-cut diagnoses which should respond better to IT analgesics and those that should respond better to stimulation therapies. The overlapping gray area represents diagnoses that will respond to both therapies when using the appropriate agents. IT therapy with opioids and non-opioids alike is only indicated when trials of sequential, long-acting, potent opioids have failed. Failure might be defined as failure to provide analgesia but is also defined as the development of intolerable and intractable side effects when using all of the long-acting opioids that

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trials for it delivery

Spinal cord/brain/ peripheral nerve stimulation 1. Spinal radiculopathies 2. Diabetic neuropathy 3. Traumatic neuropathy 4. Entrapment neuropathy 5. Occipital neuralgia 6. Trigeminal neuralgia 7. Atypical facial pain 8. Dejarine Roussy syndrome 9. Migraine 10. Movement disorders 11. Epilepsy 12. Psychiatric disorders 13. Urinary incontinence/frequency disorders

Intrathecal delivery of analgesics

1. FBSS 2. CRPS 3. Pancreatitis 4. Sensitized bowel disorder 5. Inflammatory bowel disease 6. Interstitial cystitis

1. Generalized cancer pain 2. Fibromyalgia 3. Widespread arthritis 4. Generalized diffuse visceral pain 5. Generalized myopathies

Figure 33.2  Venn diagram representing diagnoses that will respond better to stimulation therapies (spinal cord stimulation, peripheral nerve stimulation, deep brain stimulation, and motor cortex stimulation) on the left and better with intrathecal analgesic drug delivery on the right. The shaded area represents chronic painful diagnoses that will respond equally to both

are available and trialed. If the patient tolerates high doses of any given opioid without analgesic efficacy and has no side effects, that patient, by definition, has opioid non-responsive pain and most probably will not respond to IT opioid therapy alone, but may respond to IT clonidine, bupivacaine or ziconotide alone or in combination with an IT opioid. There are some points to remember when planning for IT therapies and systems for patients with chronic, nonmalignant pain, when compared to patients with end-of-life, terminal pain. Patients with nonmalignant pain will live long lives not ended abruptly by their disease and therefore are candidates for continuous, totally implanted IT systems (catheter and pump). Patients with terminal illness, with greater than 3 months to end of life, also are candidates for totally implanted systems; however, those with disease of terminal illness, with less than 3 months to end of life, are not candidates for totally implanted IT systems, but are candidates for external delivery of IT agents (Bedder et al., 1991).

Trials for IT delivery When a patient meets all criteria for IT analgesic delivery and that patient has failed conservative therapies, that patient should undergo a trial for IT therapy. Trials for IT therapy can be performed epidurally, intrathecally, by single “shot” of an agent, or

by continuous delivery. In these authors’ estimation, it is only the continuous IT delivery of analgesic agents that mimics the “end product,” the system that consists of a pump and IT catheter, delivering continuous IT analgesia. In order to mitigate nonspecific or placebo responses, and thus avoiding implanting an expensive device in the wrong patient, trials should be conducted for as long as logistically possible. It is our belief that continuous external delivery of agents through an implanted IT catheter, for as long as possible, is the only trial that can not only mitigate strong, nonspecific, placebo responses, but allows sequential trialing of agents, should one or more fail to provide analgesia. We call this implanted IT catheter/external pump trial a “functional trial” (Krames, 1999a). A functional trial requires a surgical incision to implant an IT catheter. The IT catheter, once inserted into the thecal sac, is anchored to either the paravertebral or supraspinous fascia and is connected to an intervening Silastic catheter, which is tunneled away from the insertion site to exit a small stab wound. The incision is closed and then sterilely dressed, as is the exit site. The external catheter, with two 0.22 m filters, is then connected to an external pump for the trial. All patients, except Medicare nonmalignant pain patients, are then discharged home for their trials, which, in our institution will last between 1 and 3 weeks. Medicare will only pay for outpatient IT trials in cancer patients. If the patient tolerates the initial drug and dose without producing adequate analgesia, the dose of

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the infused IT agent is adjusted by programming the pump to accelerate delivery. If the patient does not tolerate the initial drug trialed and is in need of trial of a second agent, only the external drug reservoir, the existing tubing and the first 0.22 m filter, which is proximal to the more distal filter (filter nearest the catheter exit site), is changed. Because it is known that the infection rate of these systems is proportional to the “fiddle-factor,” when personnel handle the external IT system, we, in our practice, have adopted a hands-off policy to system (external tubing) and dressing changes. We first change the dressing of the system within 48 hours of surgery and then, unless the dressing becomes wet, we only change the dressing once every 7 days. We recommend that only physicians or nurses familiar with this system be involved in dressing changes and that all patients with an externalized IT catheter be placed on appropriate antibiotics. A reduction of pain by 50% and/or improved function with reduced systemic (oral or transdermal) intake of opioids indicates a successful trial. Evaluation for efficacy of spinal analgesia should be individualized, taking into consideration analgesic improvement and/ or improvement in function, as well. To prevent withdrawal from the patient’s systemic opioids during the IT trial and because the equianalgesia between oral delivery and IT delivery is vastly different, we give the patient 50% of the orally administered dose as an equivalent IT dose, allowing continued oral intake of 50% of the original oral or systemic dose. On each subsequent day during the trial, the oral dose is decreased by 20% and the IT dose is increased by 20% until all of the original oral dosing is supplanted by IT dosing. It has been said that the oral to IT ratio for morphine is 300 mg to 1 mg; however, this notion has, to the knowledge of these authors, never been scientifically challenged or proven (Krames, 1996).

Implantable drug delivery systems To be complete regarding IT delivery of analgesic agents, we will discuss existing systems for IT delivery here. For a more detailed description of existing IT and epidural pump systems, see the excellent chapter in this textbook by Bedder (Chapter 34). The first drug delivery system approved for the delivery of intraspinal analgesics was the Shiley Infusaid, model #400 pump, which is no longer manufactured. This pump was nonprogrammable with a factory-fixed flow rate. Today, there are other FDA

approved fixed-rate pumps, including the Codman Model 400 pump and the Medtronic Isomed Pump. These pumps utilize a charging fluid that remains a fluid at room temperature, but becomes a gas exerting pressure on a metal bellows that extrudes drug at a fixed rate when implanted into a patient. Because the rate of these fixed-rate pumps is preset and nonprogrammable, dosing changes are made by changing concentrations of the drug. The Medtronic Synchromed system is the only totally implantable and programmable pump that is approved in the USA and Europe. Other companies, including Codman (a Johnson & Johnson company), Advanced Neuromodulation Systems, and Advanced Bionics (a Boston Scientific company), are developing totally implantable and programmable, IT, drug delivery systems. Rate and therefore dose of drug are externally programmable utilizing an external telemetry system coupled to an internal radio receiver.

Intrathecal Opioid Delivery Morphine HO

O H

N

HO

Morphine is an opiate analgesic drug and is the principal active agent in opium. The word “morphine” is derived from Morpheus, the Greek god of dreams. Morphine is the only approved FDA opioid for IT delivery, and because of its extensive literature it remains the gold standard for delivery (Krames, 2002). Like other opioids, morphine works at the substantia gelatinosa of the dorsal horn of the spinal cord to produce analgesia by activation of G-protein-coupled inward-rectifier K conductance (Santos et al., 2004). Morphine’s efficacy as an IT analgesic is well documented. The dose of IT morphine differs from patient to patient and depends on the age of the patient, the type of pain that the patient is suffering from, and the dose of opioid before implantation. In general, higher IT doses are needed for patients with neuropathic pain, whereas the elderly need lower doses for analgesia when compared to younger patients. In one study with a mean follow-up of (29  12 months), IT morphine reduced pain score for all types of pain by 57%. In this study, IT morphine was more efficacious in neuropathic pain syndromes, when compared to nociceptive

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implantable drug delivery systems

pain by 75% to 61%, respectively (Kumar et al., 2001). Burton et al. found that after institution of intraspinal analgesic therapy, there was a significant reduction in the proportion of patients with severe pain (defined as a “pain worst” score in the severe range of 7–10), from 86% to 17%, which was statistically significant. At follow-up, the numerical pain scores decreased significantly from 7.9  1.6 to 4.1  2.3. There was no difference noted between the IT and epidural groups (Burton et al., 2004). A report from the national outcomes registry for IT analgesia of prospective data collected in 136 patients who received intraspinal analgesia via an implanted device for low back pain stated that 47% of patients showed improvement in the Oswestry Low Back Pain Disability Scale ratings and 31% showed improvement in leg pain. Of notice was that 81% of those patients received morphine (Deer et al., 2004). In a multicenter retrospective study of 19 patients who were given morphine via an implanted pump for chronic noncancer pain (dose 1–10 mg/d), the satisfaction rate was 90%, with a 67.8% analgesic effect and 49.2% reduction in VAS score (Njee et al., 2004). The onset and duration of an IT opioid’s effect, its uptake and distribution, and availability for supra­ spinal centers depends on its lipophilicity and opioid receptor affinity, relative to morphine (Cousins et al., 1988). With high hydrophilicity and high receptor affinity, morphine has a slow onset, but prolonged analgesic effect. On the other hand, this high hydrophilicity of morphine prolongs its stay within the cerebrospinal fluid (CSF) to have an analgesic effect on higher supraspinal centers, while at the same time increases its chance of producing side effects such as nausea, vomiting, and respiratory depression. During the course of IT treatment with morphine, hyperalgesia, dysesthesia, allodynia, and/or myoclonus may evolve. It is known that the elevated morphine-3-glucuronide (M3G) plasma or CSF concentration or the CSF concentration ratio of M3G/ M6G, both morphine metabolites, may play a pathogenic role in development of this morphine hyperalgesia (Sjogren et al., 1988). In another study it was shown that the pronociceptive actions of sustained opioid administration require specific interaction with opiate receptors, and these actions are unlikely to be the result of accumulation of potentially excitatory metabolic products such as M3G, but rather related to plasticity that is initiated by opiate receptor interaction (Gardell et al., 2006). The administration of MK-801, an n-methyl-d-aspartate (NMDA) receptor antagonist, attenuated the hyperalgesia seen in naltrexon-treated mice, demonstrating a role for this receptor in morphine hyperalgesia, which was unrelated to its effect upon morphine analgesia. In this study, hyperalgesia

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was restored after infusing the lower but not higher morphine dose. In addition, acute injections of M3G caused hyperalgesia that was cross-adaptive with the lower morphine dose only. These data demonstrate that morphine hyperalgesia is independent of prior or concurrent opioid receptor activity or analgesia and is unrelated to analgesic tolerance (Juni et al., 2006). It seems that there must be an intimate interaction of IT high-dose morphine with tachykinin neurokinin-1 (NK1) receptors and multiple sites on the NMDA receptor complex in the dorsal spinal cord. Since the effect of NMDA receptor activation and the associated Ca2 influx results in production of nitric oxide (NO) by activation of NO synthase, it seems that spinal NO also plays an important role in nociception, evoked by IT high-dose morphine. M3G has been found to evoke nociceptive behavior similar to that of IT high-dose morphine. It is plausible that M3G may be responsible for nociception seen after IT high-dose morphine treatment. The demonstration of neural mechanism underlying morphine-induced nociception provides a pharmacological basis for improved pain management with morphine at high doses (Sakurada et al., 2005). As is the case with other opioids, IT morphine delivery is known to be associated with thalamic pituitary dysfunction. In one study of 93 patients with noncancer-related pain, the majority of patients (73/93) who received IT morphine at a mean dose of 4.8 mg/d for a mean duration of 26.6 months, and 20/93 patients, comprising a group with comparable pain syndromes and not treated with IT morphine, developed hypogonadotrophic hypogonadism and 15% developed central hypocortisolism and growth hormone deficiency when compared to none in the control group. Decreased libido occurred in 96% and 69% of men and women, respectively, compared to 10% and 20% in the untreated men and women group, respectively. Hormonal supplements ameliorated the decreased libido in 10 of 14 men and 7 of 12 premenopausal women (Abs et al., 2000). The use of all intrathecal agents except sufentanil and possibly fentanyl is associated with the development of intrathecal granuloma, an inflammatory, intraspinal but extramedullary mass (Yaksh et al., 2002). This problem is mostly associated with high doses and concentrations of morphine. The first case report of a granuloma identified at the tip of an IT catheter used for IT analgesic infusion for the treatment of chronic intractable pain was published in 1991 by North et al. (North et al., 1991). A survey to implanters in both Europe and the USA regarding the neurologic sequelae of IT therapies revealed 6 new cases of granulomatous mass formations at catheter tips and 27 cases of neurological sequelae due to other etiologies (Schuchard, Lanning et al., 1998).

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The authors concluded that “the problem of postimplant neurological sequelae is potentially devastating.” By November 2000, a total of 41 case reports of catheter-related inflammatory masses in patients receiving IT analgesics for pain had been published in the medical literature, reported to Medtronic, Inc. (Minneapolis, MN), or reported to the US Food and Drug Administration (FDA) (Medtronic, 2001). Intrathecal granuloma appears to be the most devastating complication of IT therapies and has been associated with all opioids, except sufentanil, baclofen (Deer, Raso et al., 2007) and clonidine (Toombs et al., 2005). For an excellent review of the subject see the article by Deer et al. (2008). Hydromorphone CH3 H

N CH2

H CH2 OH

O

HCI

O

Hydromorphone is primarily a mu () agonist that activates kappa () and delta () receptors to a lesser extent. It is a hydrogenated ketone of morphine that is 8–10 times more lipid-soluble (Mahler and Forest, 1975; Shulman et al., 1987) and 5–10 times more potent than morphine. Because of its higher lipophilicity compared to morphine, it has a shorter latency of onset and a shorter duration of action. The incomplete cross-tolerance among opioids makes the switching from morphine to hydromorphone a consideration when morphine is associated with poor analgesia or side effects. As is the case with morphine, hydromorphone metabolizes to hydromorphone-3-glucuronide, which has been found to be neurotoxic and cause seizure in rats (Wright et al., 1998). The hydromorphone metabolite, hydromorphone-3-glucuronide, could be responsible for decreased efficacy seen in chronic pain patients treated with hydromorphone (Smith, 2000). Hydromorphone is analgesic when given intra­ thecally. Anderson et al. studied 37 patients with intra­ thecal hydromorphone for chronic nonmalignant pain after failure of intraspinal morphine (Anderson et al., 2001). Morphine was replaced with hydromorphone because of pharmacological complications (21/37; 57%) or inadequate analgesic response (16/37; 43%) after an average of 11 months of intrathecal therapy. Pharmacological complications, particularly nausea and vomiting, pruritus, and sedation, were reduced by hydromorphone in most patients. Peripheral edema

was improved by hydromorphone but tended to recur with prolonged hydromorphone exposure. Analgesic response was improved by at least 25% in six of 16 patients who were switched to hydromorphone because of poor pain relief. DuPen et al. performed a retrospective analysis of patients receiving IT hydromorphone in the Pacific Northwest (DuPen et al., 2006). All data collected within 30 days of the patient’s 3-month, 6-month, and 12-month anniversary of implant were analyzed. There were 24 patients in the study: 13/24 had eligible pain data at 1 month, 10/24 had pain data at 3 months, and 7/24 had pain data available at 12 months after initiation of intrathecal hydromorphone. The authors found that the average pain scores decreased significantly (p  0.03) and side effect and pain-interference scores remained essentially unchanged in this small sample of patients. In an analysis of its stability, hydromorphone retained stability at 95% of its initial potency in an infusion system at 37 °C for 4 months, as evidenced by the HPLC method of analysis. Ninetysix percent of the intact molecule was recovered from the drug (1.5 mg/ml and 80 mg/ml) stored in plastic syringes for 60 days at 4 °C and 23 °C, and for 2 days at 20 °C and 37 °C (Trissel et al., 2002). Intrathecal hydromorphone, at a dose 20% of that of morphine, induces an equianalgesic response to IT morphine (Johansen et al., 2004), while improving the incidence of side effects, including nausea and vomiting, pruritus, and sedation. In animal models, there appears to be controversy regarding the development of intrathecal granuloma with hydromorphone. In a study, in sheep, implanted with IT catheters (Johansen et al., 2004), the sheep were subjected to receive either 1.5, 3, or 6 mg/day of hydromorphone HCL or saline control. An additional three sheep received a dose of 12 mg/d. All animals were examined daily for changes in behavior and neurologic function and the CSF was analyzed for protein, cytology, and hydromorphone concentrations. After sacrifice the spinal cord was removed from each sheep and analyzed both microand macroscopically. All sheep receiving intrathecal hydromorphone exhibited gaiting deficits and biting behavior over the caudal lumbar area above the infusion site. Animals treated with 12 mg/day were sedate and lethargic, and exhibited repeated biting behavior over the caudal lumbar area during the study. No lesions were noted in any animal upon gross evaluation of the spinal cord. Microscopic changes were comparable between hydromorphone- and salinetreated animals with one exception. Mild inflammation, 5 cm cranial to the catheter tip, was present in two of three sheep receiving 12 mg/day and in one of three sheep receiving 1.5 mg/day. Mild chronic inflammation in the vicinity of the catheter was also

ivb. infusional therapies for pain

447

implantable drug delivery systems

presented in saline-treated animals. The authors concluded that hydromorphone was not associated with inflammatory mass formation in the sheep model. Contrary to these findings, Allen et al. found that the chronic IT infusion of a maximum tolerated dose of hydromorphone did cause the formation of intradural granuloma in a sheep model (Allen et al., 2006). Hydromorphone is known to cause IT granuloma in humans. A published case report on the formation of granuloma in a patient receiving high-dose intrathecal hydromorphone suggests that the longterm use of intraspinal opioids, including hydromorphone, poses a risk for the development of granuloma (Fernandez et al., 2003). Fentanyl

O

N N

Fentanyl, an anilinopiperidine analogue and phenylpiperidine derivative, a highly lipophilic molecule with a partition coefficient (octanol : water) 100 times that of morphine, is a synthetic opioid that was introduced into clinical practice in 1960 (Bennett, Serafín et al., 2000; Miyoshi and Leckband, 2001; Ribeiro and Zeppetella, 2003). It binds preferentially to mu receptors. It has a fast onset of action in the order of 5 minutes with peak effect of 20 minutes when given epidurally. Because of this high lipophilicity, its effect is largely segmental, although IT administration is associated with receptor saturation and mixing with CSF with related supraspinal effects and side effects. As fentanyl is 75–100 times more potent than morphine sulfate, lower doses are needed to produce similar analgesia. Thus, considerations for side effects should be made, especially since those associated with fentanyl have been noted to be more severe than those of morphine sulfate. Cephalad spread of fentanyl to supraspinal areas of the brain, which could lead to respiratory depression does occur, but, because of its lipophilicity, less so than morphine. Although it is uncertain whether fentanyl’s exact location of action is systemic or spinal, the systemic mode of action appears to be favored by some (Loper et al., 1990). While scientific data regarding the epidural and IT delivery of fentanyl are evolving, there does appear to be a role for fentanyl in treating both acute and

chronic pain processes. Two retrospective studies regarding IT fentanyl have been reviewed. One study of 122 patients examined the complications associated with implantable drug delivery systems. This study included two patients with the combination of fentanyl and bupivacaine (Kamran and Wright, 2001) and neither of these patients experienced serious adverse events. In another study, eight patients out of a total of 29 patients with IT therapy received IT fentanyl, 10.5–115 g/day for a mean duration of 31 months (Willis and Doleys, 1999). The authors reported a 68% reduction in pain and an overall satisfaction of 3.25 on a scale of 1 (poor) to 4 (excellent) in all eight patients. The role that fentanyl has in the formulation of IT granulomatous masses remains controversial. Two sets of experiments were performed in dogs to evaluate analgesia and toxicity of different IT opioid infusions including morphine, hydromorphone, D/L-methadone, L-methadone, D-methadone, fentanyl, DAMGO, a pure mu agonist, naloxone, or saline (Allen et al., 2006). Six-hour IT infusions of the above produced analgesia in rats and mice. Dose-limiting motor dysfunction and sedation, and hypersensitivity were observed at higher concentrations. Continuous IT infusion of the maximum tolerated dose was administered for up to 28 days to determine toxicity and spinal pathology. Analysis showed 100% intradural granuloma formation occurring after infusion with morphine, hydromorphone, L-methadone, and naloxone. Parenchymal necrosis resulting from D/L- and D-methadone was associated with the N-methyl-D-aspartate antagonist action of the D-isomer. DAMGO produced a mass in only one of three animals. Of importance, animals receiving IT saline and IT fentanyl did not exhibit any granulomas. In a study of 92 patients undergoing opioid treatment for pain, one patient was diagnosed with an inflammatory mass while receiving IT fentanyl; however, there was no information in this report whether this patient had been exposed to other IT analgesics besides fentanyl (Waara-Wolleat et al., 2006).

Sufentanil OCH3 O N N S

Sufentanil, like fentanyl, is an anilino piperidine with a lipid partition coefficient 1000 times higher than

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448

33.  the rational use of intrathecal opioid analgesics

that of morphine. Therefore, it has a much more rapid onset of action, and a much shorter duration of action than morphine when delivered intrathecally. Due to being extremely lipid-soluble, it largely diffuses into the central neural tissue when administered intrathecally, leaving less bulk drug available for rostral movement, and thus fewer central side effects such as nausea, vomiting, itching, urinary retention, and respiratory depression. Because of this lipid-solubility, after IT administration, sufentanil concentrations in the CSF decrease more quickly when compared to morphine. The mean residence time in the CSF, i.e., the time required to eliminate 63.2% of the drug, is approximately 0.9 hours after injection of 15 g sufentanil (Hansdottir et al., 1991) while that of morphine (0.05 mg/kg) is 2.3 hours (Ionescu et al., 1988). Few clinical reports on the use of IT sufentanil or fentanyl for chronic pain are available (Waara-Wolleat et al., 2006). Although results confirm potency and efficacy with IT administration, further studies are needed to support the long-term use of either opioid in chronic pain management (Waara-Wolleat et al., 2006). The higher affinity of sufentanil to mu opioid receptors when compared to morphine gives sufentanil a potential benefit in delaying tolerance to the drug. It has been postulated that agents with high efficacy and receptor reserve, i.e. sufentanil, should produce less tolerance than agents of lower efficacy and lower receptor reserve, i.e. morphine (Sosnowski and Yaksh, 1990). Rats develop, over time, less tolerance to IT sufentanil when compared to morphine. Also, sufentanil requires the occupancy of fewer -receptors to produce antinociception than does morphine. In a survey performed by Hassenbusch and Portenoy (2000) nearly 20% of pain clinicians have used either fentanyl or sufentanil in IT drug delivery systems; however, there are no clinical data of long-term use of IT sufentanil in humans. It is known that in humans a 10 g bolus of IT sufentanil produces analgesia within 5 minutes with a duration of about 19 minutes (Camann et al., 1992). In a randomized double-blind study IT opioid was associated with a dose-dependent decrease in bladder function. However, the recovery of normal detrusor contractility and sensation of urge was significantly faster after IT sufentanil than after IT morphine (Kuipers et al., 2004). Because of its high lipophilicity, this agent is used when more hydrophilic drugs produce excessive supraspinal side effects. When converting morphine to sufentanil in an implanted pump, we, based on the potency ratio of sufentanil to morphine, arbitrarily use a dose conversion of 1 g of sufentanil to 1000 g (that is 1 mg of morphine).

Animal toxicology studies of IT sufentanil have shown no detectable pathological effects on spinal cord histology. However, in a study performed in sheep, which have relatively smaller IT spaces, a rather large dose of 7.5 g/kg of sufentanil did produce demonstrable neurotoxic changes. These authors did demonstrate a low-grade inflammatory response to the IT catheter itself and concluded that the response was thought to represent a foreign body response (Rawal et al., 1991). To this date, there are no reports of inflammatory masses from the IT delivery of sufentanil in humans. Methadone N O

Methadone, a synthetic opioid analgesic, was developed in Germany in 1937 and has long been viewed as an alternate to morphine and hydromorphone for patients with severe pain (Inturrisi, 2002). Its bioavailability, defined as the percentage of drug that is detected in the systemic circulation after its administration, is 85%, and from single dose studies, its oral to parenteral potency ratio is 1 : 2. Its plasma half-life averages 24 hours but may range from 13 to 50 hours, whereas the duration of analgesia is often only 4–8 hours (Inturrisi, 2002). In vitro studies suggest that methadone induces desensitization of the delta opioid receptor by uncoupling the receptor from its underlying G-protein. This delta opioid activity is critical for the development of morphine-induced tolerance and dependence and explains why methadone is effective in the treatment of morphine dependence (Jing-Gen Liu et al., 1999). Recently, because of its efficacy as an opioid alternative, its cost (one month’s supply in 2004 costs approximately US $20.00), and because methadone has N-methyl-D-aspartate (NMDA) receptor antagonist activity, the interest in the use of methadone has re-emerged. Ebert et al. (1995) found that methadone exhibited NMDA receptor antagonist activity in a ligand binding assay and a neonatal rat spinal cord electrophysiological preparation. Methadone has an asymmetric carbon atom resulting in two enantiomeric forms, the d and l isomers. The racemic mixture (d/l-methadone) is the form commonly used clinically and in laboratory studies. The l isomer possesses analgesic activity while the d isomer is inactive or weak

ivb. infusional therapies for pain

implantable drug delivery systems

as an opioid (Davis and Inturrisi, 1999). Gorman et al. (1997) reported that both the d and the l isomers bind, with similar affinities, to the non-competitive site of the NMDA receptor in rat forebrain and spinal cord synaptic membranes. Shimoyama et al. (1997) found that while IT d-methadone is inactive in the tail-flick test, it is antinociceptive in the rat formalin test, a model that is commonly used for neuropathic pain states. This antinociception is not affected by the opioid antagon­ ist naloxone, and appears to be a result of the NMDA receptor antagonist activity of d-methadone. Davis and Inturrisi (1999) reported that d-methadone affects the development of morphine tolerance after systemic or IT administration. After IT treatment with increasing doses of morphine, there is a shift to the right of the morphine dose–response curve (day 5 with saline  morphine). The relative potency of morphine was decreased by approximately 38-fold on day 5 in the saline  morphine group. In contrast, no significant shift was seen in the dose–response curve or in the morphine ED50 value when IT d-methadone was co-administered with each dose of morphine during the 3-day treatment period (Inturrisi, 2005). Studies of the prolonged use of IT methadone for cancer and noncancer pain showed overall effectiveness between 37.5% and 80% for those populations studied based on greater than 50% reduction (Shir et al., 1991; Mironer et al., 1999; Mironer and Tollison, 2001) in pain or pain reduction combined with improved scores on quality of life questionnaire. These studies involved both cancer and noncancer patients. Methadone was administered at total daily dosages of 5–60 mg and the duration of treatment ranged from 3 days to 37 months. Meperidine CH3 N HCI

COOC2H5

Meperidine is a phenyl piperidine derivative with physical characteristics, molecular weight and pK similar to those of local anesthetics. Meperidine, originally synthesized in 1939 as an antimuscarinic agent (Latta et al., 2002), also has structural similarities to atropine and other tropane alkaloids and may have some of their effects and side effects (RxList, 2008). Because meperidine is more lipid-soluble than morphine and hydromorphone it has a quicker onset and more segmental action

449

(localized effect at the segment of the spinal cord delivered) than either morphine or hydromorphone. Meperidine is the only member of the opioid family that has clinically important local anesthetic activity in doses used for analgesia. Because of this quality of meperidine, it is the only opioid in current use that is active as a sole agent for spinal anesthesia (not analgesia). Surgical procedures to the lower limbs, inguinal area, perineum or c-section have been performed using spinal meperidine alone (Patel et al., 1990; Thi et al., 1992). Meperidine has been used for labor analgesia and found not to increase C-section deliveries (Sharma et al., 2004). A 0.5 mg/kg IT dose of meperidine produces anesthesia for up to 6 hours or longer (Patel et al., 1990). A dose of 1 mg/kg or a total dose of 100 mg has been associated with respiratory depression, bradycardia, and hypotension (Cozian et al., 1986; Ong and Segstro, 1994). There is limited literature on the use of continuous IT meperidine via implantable infusion pumps. In a case report by Harvey et al. (1997), a woman with chronic low back pain, who failed other medical interventional treatment modalities, achieved significant pain relief with a continuous infusion of IT meperidine. Another case report also showed similar success (Mironer and Grumman, 1999). According to Chrubasik et al., the dose of meperidine should be 25–30 times higher than morphine to maintain equianalgesia (Chrubasik et al., 1992). A dose of up to 60 mg per day appears to be safe (Mironer, 2002). In a study by Vranken et al. (2005), 10 patients with neuropathic cancer pain, not responding to conventional opioid therapy, were treated with continuous IT administration of meperidine. In three patients, the plasma concentrations of meperidine and normeperidine increased rapidly. In one patient, the plasma normeperidine concentration was higher than the meperidine concentration. One patient demonstrated transient symptoms suggestive of central nervous system excitation. Three weeks following the start of treatment, seven patients were available for evaluation of their quality of life. Pain relief and overall quality of life improved during the IT treatment (Vranken et al., 2005). In a case report, the authors reported a case of severe cancer pain refractory to conventional IT medications and cordotomy that was successfully managed by the addition of meperidine to the IT regimen (Souter et al., 2005). Intrathecally administered opioid therapy certainly belongs irrevocably to our clinical armamentarium for pain control in cancer and nonmalignant pain patients. As stated previously, in the USA, morphine remains the only opioid analgesic approved by the FDA for intraspinal use. Because many patients

ivb. infusional therapies for pain

450

33.  the rational use of intrathecal opioid analgesics

develop tolerance to their opioid analgesic, have neuropathic pain, or develop these pain syndromes during their intraspinal opioid therapy, it has become clear that intraspinal opioid therapy alone is not sufficient to provide adequate analgesia for many patients. This has led scientists and clinicians to look for other intraspinal pharmacological solutions for these opioid-resistant pain syndromes, including the use of intrathecal non-opioid analgesics alone or in combination with the IT opioid, and since 2005, the Food and Drug Administration of the USA has approved ziconotide, a non-opioid analgesic, for intrathecal use. As stated above, Chapter 35 by Reig, Abejón, and Krames reviews the IT use of non-opioids.

An algorithmic approach to intrathecal therapy The use of a therapy, where multiple choices exist, demands that a practitioner of the science and art use a logical approach to the therapy. Since 1996, guidelines for the appropriate treatment of chronic pain, both malignant and nonmalignant, have been offered as a guide to the practitioner of IT therapies. Krames was the first to publish guidelines for the use of IT therapy, in 1996. Based on rather non-rigorous supporting data on the safety and efficacy of both opioid and non-opioid intrathecal medications, the Polyanalgesic Consensus Conference (PCC) 2000, a panel of experts, formed a set of guidelines for intrathecal use. This panel reviewed existing data on the subject and formulated an algorithm of care for drug selection when using intrathecal polyanalgesia based on “best evidence” and expert opinion, described current practice and decision-making, and described future directions for IT care (Bennett, Burchiel et al., 2000; Bennett, Deer et al., 2000; Bennett, Serafín et al., 2000; Hassenbusch et al., 2000). To update the first PCC, a second expert panel convened for the Polyanalgesic Consensus Conference, 2003. The tasks of this panel were to review the pertinent medical literature on intraspinally administered medications published since 1999, update the algorithm for intraspinal drug selection, introduce guidelines for optimizing drug concentration and dosage during therapy, and clarify existing regulations and guidelines relating to the use of compounded medications for intrathecal delivery. The findings and guidelines of the Polyanalgesic Conference 2003 were published in 2004 (Hassenbusch et al., 2004). Following the same rationale as used in the two previous conferences for updating relevant information and guidelines, a consensus conference of experts in

the field of intrathecal therapies, a third polyanalgesic conference, Polyanalgesic Conference 2007, was convened and the resulting guidelines were published in 2007 (Deer, Krames et al., 2007). The tasks of the Polyanalgesic Conference 2007 were as follows: Review the conclusions and guidelines of the Polyanalgesic Conference 2000 and Polyanalgesic Conference 2003. l Evaluate the current guidelines for intrathecal drug infusion. l Review survey responses of fellow peers in the field of intrathecal analgesics for pain management and use the findings to guide discussion during the conference. l Review preclinical and clinical data relevant to intrathecal analgesics published since 2000. l Formulate consensus opinions on critical issues for intrathecal polyanalgesic therapy. l Modify and update the intrathecal analgesic drug selection algorithm, as appropriate, based on “best evidence” from published pertinent data and expert consensus opinion. l Identify areas, including promising under-researched and experimental analgesic agents, for future evidencebased research that will advance the clinical practice of intrathecal drug infusion therapy. l Disseminate the consensus opinions and primary conclusions of the expert panelists to the medical community through data-driven articles published in appropriate peer-reviewed biomedical journals.

l

These guidelines, seen in Figure 33.3, were created using best preclinical and clinical evidence gleaned from the literature, consensus of expert opinion, and built on the guidelines of the two previous PCCs. What is new regarding these guidelines is the movement of ziconotide, the only FDA approved non-opioid for IT use and the only agent besides sufentanil not associated with the development of IT granuloma, to a line 1 drug along with morphine and hydromorphone, and an update of concentration and dosing guidelines for intrathecal agents to mitigate the problem of intraspinal granuloma. The rational for the above algorithm, as published by the authors, is as follows. The rationale for the line 1 approach was that morphine and ziconotide (Prialt) were the only opioid and non-opioid analgesics, respectively, to be approved by the FDA for long-term intrathecal use and that there was increasing evidence of the analgesic use and safety of hydromorphone in the literature to support its use as a line 1 agent. Ziconotide was moved to a line 1 agent as a stand-alone analgesic because of the substantial data from preclinical and clinical studies and the fact that, to this day, it has not been associated with the development of intrathecal granuloma. Since both morphine

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an algorithmic approach to intrathecal therapy

Line 1:

(a) morphine

(b) hydromorphone

(c) ziconotide

Line 2:

(d) fentanyl

(e) morphine/hydromorphone � ziconotide

(f) morphine/hydromorphone � bupivacaine/clonidine

Line 3:

(g) clonidine

(h) morphine/hydromorphone/fentanyl bupivacaine �/clonidine � ziconotide

Line 4:

(i) sufentanil

(j) sufentanil � bupivacaine �/clonidine � ziconotide

Line 5:

(k) ropivacaine, buprenophine, midazolam meperidine, ketorolac Experimental drugs

Line 6:

gabapentin, octreotide, conpeptide, neostigmine, adenosine, XEN2174, AM336, XEN, ZGX 160

Figure 33.3  Polyanalgesic algorithm for intrathecal therapies, 2007 Line 1: morphine (a) and ziconotide (c) are approved by the FDA of the USA for intrathecal analgesic use and are recommended for 1st line therapy for nociceptive, mixed, and neuropathic pain. Hydromorphone (b) is recommended based on clinical widespread usage and apparent safety Line 2: because of its apparent granuloma-sparing effect and because of its wide apparent use and identified safety, fentanyl (d) has been upgraded to a line 2 agent by the consensus conference when the use of the more hydrophilic agents of line 1(a, b) result in intractable supraspinal side effects. Combinations of opioid  ziconotide (e) or opioid  bupivacaine or clonidine (f) are recommended for mixed and neuropathic pain and may be used interchangeably. When admixing opioids with ziconotide, attention must be paid to the guidelines for admixing ziconotide with other agents Line 3: clonidine (g) alone or opioids such as morphine/hydromorphone/fentanyl with bupivacaine and/or clonidine mixed with ziconotide (h) may be used when agents in line 2 fail to provide analgesia or side effects occur when these agents are used Line 4: because of its proven safety in animals and humans and because of its apparent granuloma-sparing effects, sufenta alone (i) or mixed with bupivacaine and/or clonidine plus ziconotide (j) is recommended in this line. The addition of clonidine, bupivacaine, and/or ziconotide is to be used in patients with mixed or neuropathic pain. Because of literature that suggests that midazolam and methadone may be neurotoxic, these agents have been relegated to experimental use Line 5: these agents (k), although not experimental, have little information about them in the literature and use is recommended with caution and obvious informed consent regarding the paucity of information regarding the safety and efficacy of their use Line 6: experimental agents (l) must only be used experimentally and with appropriate IRB approved protocols (Reproduced with the permission of the authors from Deer, Krames et al. (2007) Neuromodulation: Technology at the Neural Interface 10 (4): 300–28. John Wiley & Sons Ltd)

and hydromorphone are associated with a known concentration-dependent risk of catheter-tip granuloma formation, physicians were advised to titrate doses of these two opioids not beyond an a priori upper limit that has been determined from clinical experience. Line 2 contains fentanyl alone or morphine or hydromorphone combined with either ziconotide or bupivacaine or clonidine. According to consensus, data was still too limited to accurately calculate the comparative risks versus benefits of line 2 single medications and drug combinations. Fentanyl, was chosen as a reasonable first choice for a line 2 drug, especially for patients with nociceptive pain, because cumulative data to the date of publication strongly suggested that this medication was not related to the development of inflammatory masses in humans, and therefore, when compared to other IT opioids, was safe. It was

also suggested by this panel of experts that fentanyl, because of its lipophilicity, was a good option for an IT opioid if the more hydrophilic agents, morphine and hydromorphone, produce intractable supraspinal side effects such as sedation or nausea and vomiting. If line 2 monotherapy or polytherapy failed to provide adequate analgesia or if it produced intolerable side effects, the panel suggested that the clinician may try changing to clonidine alone or one of the alternative line 2 combinations plus ziconotide. Line 3 regimens, as suggested by this panel, consist of the addition of ziconotide to four possible combinations of either bupivacaine or clonidine added to either morphine or hydromorphone. If the initial drug combination was unsatisfactory, then physicians could switch to another combination within the line 3 approach before proceeding to line 4. However, the panel felt that preference

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33.  the rational use of intrathecal opioid analgesics

should be given first to a combined therapy of either opioid plus bupivacaine. If all failed then the panel recommends that the clinician move to a line 4 approach. Sufentanil, the primary line 4 medication, would be tried for analgesic efficacy, if line 3 approaches were ineffective. Although there were no long-term safety and efficacy data for this drug, the panel did note that sufentanil, the only opioid agent found in clinical practice and the preclinical literature not to be associated with the development of IT granuloma, was used in clinical practice with safety. Although sufentanil and fentanyl are both lipophilic opioids with much greater potency than morphine, sufentanil was placed two lines below fentanyl. Minimal evidence suggested to this panel that fentanyl was safe and possibly effective. By contrast, there were no long-term safety and efficacy data on sufentanil to support its use as a line-2 agent. Line 5 constitutes a special box for medications that are available but have limited data on safety, including toxicology, and efficacy, or that have either putative or established risks of toxicity, as determined through clinical experience. Medications in this category include ropivacaine, buprenophin, midazolam, meperidine, and ketorolac. There are either no or few published clinical data and/or very limited clinical experience, except for midazolam, to support the use of agents on line 5 for chronic intrathecal drug infusions for nonmalignant pain. The panelists felt that, although there were clinical data supporting the use of midazolam for noncancer patient populations, there were data that established intrathecal toxicities for this drug. It was felt by the panelists that medications from line 5 should be administered only for severe and disabling pain that has not been mitigated by any drug or drug combination above this line. Line 6, for the panelists, represented a special box of experimental therapies that warranted further research as possible future therapies. Medications in this category had no or minimal preclinical and/or clinical data. Line 6 agents, including gabapentin, octreotide, conpeptides, neostigmine, adenosine, XEN2174, AM336, and ZGX 160 or moxonidine, according to consensus, should be used only in cases of severe and disabling pain that is refractory to more conventional treatments and only in patients at end of life. The panel, in 2007, allowed for special circumstance regarding baclofen, midazolam, and end-of-life care. The panel noted the FDA approval for the IT use of baclofen for spasticity but felt that there was a paucity of evidence for its use as an analgesic. Furthermore, the panel, noting the recent evidence in the literature that IT baclofen was causal for IT granulomatous masses (Deer et al., 2008), cautioned its widespread use for analgesia.

Table 33.1  Concentrations and doses of intrathecal agents recommended by the Polyanalgesic Consensus Panelists, 2007 Drugs

Maximum concentration (mg/g/ml)

Maximum dose (mg)

Morphine

20 mg/ml

15 mg

Hydromorphone

10 mg/ml

4 mg

Fentanyl

2 mg/ml

No known upper limit

Sufentanil

50 g/ml

No known upper limit

Bupivacaine

20 mg/ml

24 mg

Clonidine

2 mg/ml

1.0 mg

Ziconotide

100 g/ml

19.2 g per Elan recommendations

From Deer, Krames et al. (2007) Polyanalgesic Consensus Conference 2007: Recommendations for the Management of Pain by Intrathecal (Intraspinal) Drug Delivery: Report of an Interdisciplinary Expert Panel. Neuromodulation: Technology at the Neural Interface 11 (4): 300–28. John Wiley & Sons Ltd

The panel noted that midazolam HCL was being used with growing frequency in Europe to treat severe pain in advanced cancer, however the panel noted that there was conflicting evidence for its safety, when used intrathecally. The panel felt that its use should be limited to end-of-life care. To prevent severe side effects and mitigate the development of intrathecal granuloma, the panel recommended that when starting intrathecal therapy or when changing drugs used for intrathecal therapy that physicians should start low and go relatively slow. In general, the panel recommended that dosing changes should be accelerated in the cancer population and young and robust, and kept to changes weekly in the frail and the elderly. The panel also recommended that changes in IT dosing be between 20 and 30% in the non-end-of-life population and up to 50% in the endof-life population, guided by each individual’s needs and tolerances. The panels recommendations for dose and concentration limits are seen in Table 33.1.

Conclusion We have presented here, in this chapter on the use of IT opioid analgesics, a review of the relevant literature on the preclinical use of multiple opioids that are being used in clinical practice, their clinical uses, and their toxicities. Finally, we have presented a review of the relevant previous and present guidelines for the

ivb. infusional therapies for pain

references

use of intrathecal agents. The following two chapters within this volume deal with intrathecal analgesic systems (Chapter 34 by Marshall Bedder) and the use of IT non-opioid analgesics (Chapter 35 by Reig, Abejón and Krames).

References Abs, A., Verhelst, J., Maeyaert, J., Van Buyten, J.P., Opsomer, F et al. (2000) Endocrine consequence of long term intrathecal administration of opioids. J. Clin. Endocrinol. Metabol. 85 (6): 2215–22. Allen, J.W., Horais, K., Tozier, N.A. and Yaksh, T.L. (2006) Opiate pharmacology of intrathecal granulomas. Anesthesiology 105 (3): 590–8. Anderson, V.C., Cooke, B. and Burchiel, K.J. (2001) Intrathecal hydromorphone for chronic nonmalignant pain: a retrospective study. Pain Med. 9 (4): 287–97. Barolat, G., Schwartzman, R.J. and Aries, L. (1981) Chronic intrathecal morphine infusion for intractable pain in reflex sympathetic dystrophy. In: Proceedings of the 8th Meeting of the European Society for Stereotatic and Functional Neurosurgery. Budapest, Hungary, p. 81. Bedder, M.D., Burchiel, K. and Larson, A. (1991) Cost analysis of two implantable narcotic delivery systems. J. Sympt. Manag. 6: 368–73. Behar, M., Olshwang, D., Magora, F. et al. (1979) Epidural morphine in treatment of pain. Lancet i: 527–8. Bennett, G., Burchiel, K., Buchser, E. et al. (2000) Clinical guidelines for intraspinal infusion: report of an expert panel. J. Pain Symptom Manage. 20: S37–S43. Bennett, G., Deer, T., DuPen, S. et al. (2000) Future directions in the management of pain by intraspinal drug delivery. J. Pain Symptom Manage. 20: S44–S50. Bennett, G., Serafín, M., Burchiel, K. et al. (2000) Evidence-based review of the literature on intrathecal delivery of pain medication. J. Pain Symptom Manage. 20 (2): S12–S36. Burton, A.W., Rajagopal, A., Shah, H.N., Mendoza, T., Cleeland, C. and Hassenbusch, S.J. (2004) Epidural and intrathecal analgesia is effective in treating refractory cancer. Pain Med. 5 (3): 239–47. Camann, W.R., Denny, R.A., Holby, E.D. et al. (1992) A comparison of intrathecal, epidural, and intravenous sufentanil for labor analgesia. Anesthesia 77: 351–3. Chrubasik, J., Chrubasik, S., Friedrich, G. et al. (1992) Long-term treatment of pain by spinal opiates: an update. Pain Clin. 5: 147–56. Cousins, M.J., Cherry, D.A. and Gourlay, G.K. (1988) Acute and chronic pains use of spinal opioids. In: M.J. Cousins and P. Bridenbaugh (eds), Neural Blockade in Clinical Anesthesia and Management of Pain, 2nd edn. Philadelphia: JB Lippincott, pp. 955–1029. Cozian, A., Pinand, M., Lepage, J.Y. et al. (1986) Effects of meperidine spinal anesthesia on hemodynamics, plasma catecholamines, angiotensin I, aldosterone, and histamine concentrations in elderly men. Anaesthesia 64: 815–9. Davis, A.M. and Inturrisi, C.E. (1999) d-Methadone blocks morphine tolerance and N-methyl-D-aspartate-induced hyperalgesia. J. Pharmacol. Exp. Ther. 289: 1048–53. Deer, T., Chapple, I., Classen, A. et al. (2004) Intrathecal drug delivery for treatment of chronic low back pain: report from the National Outcomes Registry for Low Back Pain. Pain Med. 5 (1): 6–13. Deer, T.R., Krames, E.K., Hassenbusch, S. et al. (2007) Polyanalgesic Consensus Conference 2007: Recommendations for the Manage­ ment of Pain by Intrathecal (Intraspinal) Drug Delivery: Report of an Interdisciplinary Expert Panel. Neuromodulation: Technology at the Neural Interface 10 (4): 300–28.

453

Deer, T.R., Krames, E.S., Hassenbusch, S. et al. (2008) Management of IT catheter-tip inflammatory masses: an updated 2007 consensus statement from an expert panel. Neuromodulation 11 (2): 77–91. Deer, T.R., Raso, L.J. and Garten, T.G. (2007) Inflammatory mass of an intrathecal catheter in patients receiving baclofen as a sole agent: a report of two cases and a review of the identification and treatment of the complication. Pain Med. 8: 259–62. DuPen, S., DuPen, A. and Hillyer, J. (2006) Intrathecal hydromorphone for intractable nonmalignant pain: a retrospective study. Pain Med. 7 (1): 10–5. Ebert, B., Andersen, S. and Krogsgaard-Larsen, P. (1995) Ketobemidone, methadone and pethidine are non-competitive N-methyl-D-aspartate (NMDA) antagonists in the rat cortex and spinal cord. Neurosci. Lett. 187: 165–8. Ellis, D.J., Dissanayake, S., McGuire, D., Charapata, S.G., Staats, P.S., Wallace, M.S. et al. (2008) Continuous intrathecal infusion of ziconotide for treatment of chronic malignant and nonmalignant pain over 12 months: a prospective, open-label study. Neuromodulation 11 (1): 40–9. Fernandez, J., Madison-Michael, L. and Feler, C.A. (2003) Catheter tip granuloma associated with sacral region intrathecal drug administration. Neuromodulation 6: 225–8. Gardell, L.R., King, T., Ossipov, M.H., Rice, K.C., Lai, J., Vanderah, T.W. et al. (2006) Opioid receptor-mediated hyperalgesia and antinociceptive tolerance induced by sustained opiate delivery. Neurosci. Lett. 396 (1): 44–9. Goldstein, A., Lowney, L.I. and Pal, P.K. (1971) Stereospecific and nonspecific interactions of the morphine congenitor levorphanol in subcellular fractions of mouse brain. Proc. Natl Acad. Sci. U S A 68: 1742–47. Gorman, A.L., Elliott, K.J. and Inturrisi, C.E. (1997) The d- and l-isomers of methadone bind to the non-competitive site on the N-methyl-D-aspartate (NMDA) receptor in rat forebrain and spinal cord. Neurosci. Lett. 223: 5–8. Hansdottir, V., Hedner, T., Woestenborghs, R. et al. (1991) The CSF and plasma pharmacokinetics of sufentanil after intrathecal administration. Anesthesiology 74: 264–9. Harvey, S.C., O’Neil, M.G. et al. (1997) Continuous intrathecal meperidine via an implantable pump for chronic, nonmalignant pain. Ann. Pharmacother. 31 (11): 1306–8. Hassenbusch, S.J. and Portenoy, R.K. (2000) Current practices in intraspinal therapy – a survey of clinical trends in decision making. J. Pain Symptom Manage. 20: S4–S11. Hassenbusch, S.J., Gunes, S., Wachsman, S., Willis, K.D. et al. (2002) Intrathecal clonidine in the treatment of intractable pain: a phase I/II study. Pain Med. 3 (2): 85–91. Hassenbusch, S., Portenoy, R., Cousins, M., Buchser, E., Deer, T. et al. (2004) Polyanalgesic Consensus Conference 2003: An Update on the Management of Pain by Intraspinal Drug Delivery – Report of an Expert Panel. J. Pain Symptom Manage. 27 (6): 540–63. Hassenbusch, S.J., Stanton-Hicks, M.D., Soukup, J. et al. (1991) Sufentanil citrate and morphine/bupivacaine as alternative agents in chronic epidural infusion for intractable non-cancer pain. Neurosurgery 29: 76–82. Inturrisi, C.E. (2002) Clinical pharmacology of opioids for pain. Clin. J. Pain 18: S3–S13. Inturrisi, C.E. (2005) Pharmacology of methadone and its isomers. Minerva Anestesiol. 71: 435–7. Ionescu, T.I., Drost, R.H., Roelofs, J.M. et al. (1988) The pharmacokinetics of intradural morphine in major abdominal surgery. Clin. Pharmacokinet. 14: 178–86. Jing-Gen, Liu, Xiao-Ping, Liao, Ze-Hui, G. and Boy-Yi, Q. (1999) Methadone-induced desensitization of the -opioid receptor is mediated by uncoupling of receptor from G-protein. Eur. J. Pharmacol. 347 (2): 301–8.

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Johansen, M.J., Satterfield, W.C., Baze, W.B., Hildebrand, K.R., Gradert, T.L. and Hassenbusch, S.J. (2004) Continuous intrathecal infusion of hydromorphone: safety in the sheep model and clinical implications. Pain Med. 5 (1): 14–25. Juni, A., Klein, G. and Kest, B. (2006) Morphine hyperalgesia in mice is unrelated to opioid activity, analgesia, or tolerance: evidence for multiple diverse hyperalgesic systems. Brain Res. 1070 (1): 35–44. Kamran, S. and Wright, B.D. (2001) Complications of intrathecal drug therapy. Neuromodulation 4: 111–5. Krames, E.S. (1996) Intraspinal opioid therapy for chronic nonmalignant pain: current practice and clinical guidelines. J. Pain Symptom Manage. 11: 333–52. Krames, E.S. (1999a) Practical issues when using neuraxial infusion. Oncology 13 (5, Suppl. 2): 37–44. Krames, E. (1999b) Interventional pain management appropriate when less invasive therapies fail to providee adequate analgesia. Med. Clin. North Am. 83 (3): 787–808. Krames, E.S. (2001) Intraspinal analgesia for nonmalignant pain. In: Steve D. Waldman (ed.), Interventional Pain Management, 2nd edn. Philadelphia: Saunders, pp. 609–20. Krames, E. (2002) Best practice and research. Clin. Anesthesiol. 4: 619–49. Krames, E.S. and Lanning, R.M. (1993) Intrathecal infusional analgesia for nonmalignant pain: analgesic efficacy of intrathecal opioid with or without bupivacaine. J. Pain Symptom Manage. 8: 539–58. Kuhar, M.H., Pert, C.B. and Snyder, S.H. (1973) Regional distribution and opiate receptor binding in monkey and human brain. Nature 245: 447–50. Kuipers, P.W.M.D., Kamphuis, E.T. et al. (2004) Intrathecal opioids and lower urinary tract function: a urodynamic evaluation. Pain Reg. Anesth. Analg. 100 (6): 1497–503. Kumar, K., Kelly, M. and Pirlot, T. (2001) Continuous intrathecal morphine treatment for chronic pain of nonmalignant etiology: long-term benefits and efficacy. Surg. Neurol. 55: 79–86, discussion 86-88. Latta, K.S., Ginsberg, B. and Barkin, R.L. (2002) Meperidine: a critical review. Am. J. Ther. 9 (1): 53–68. Loper, K.A., Ready, B.L., Downey, M. et al. (1990) Epidural and intravenous fentanyl infusion are clinically equivalent after knee surgery. Anesth. Analg. 70: 72–5. Mahler, P.L. and Forest, W. (1975) Relative analgesic potencies of morphine and hydromorphone in postoperative pain. Anesthesia 42: 602–7. Medtronic (January 2001) Letter: Important Message Regarding the Occurrence of Inflammtory Masses at the Tip of Intraspinal Catheters. Minneapolis, MN: Medtronic. Mironer, Y.E. (2002) Neuraxial opioid therapy. In: C.D. Tollison, J.R. Satterthwaite and J.W. Tollison (eds), Practical Pain Management, 3rd edn. Philadelphia, PA: Williams & Wilkins, pp. 135–54. Mironer, Y.E. and Grumman, S. (1999) Experience with alternative solutions in intrathecal treatment of chronic nonmalignant pain. Pain Dig. 9: 299–302. Mironer, Y.E. and Tollison, C.D. (2001) Methadone in the intrathecal treatment of chronic nonmalignant pain resistant to other neuroaxial agents: the first experience. Neuromodulation 4: 25–31. Mironer, Y.E., Haasis, J.C., III, Chapple, E.T. et al. (1999) Successful use of methadone in neuropathic pain: a multicenter study by the national forum of independent pain clinicians. Pain Dig. 9: 191–3. Miyoshi, H.R. and Leckband, S.G. (2001) Systemic opioid analgesics, ch. 84. In: J.D. Loeser (ed.), Bonica’s Management of Pain, 3rd edn. Philadelphia, PA: Lippincott Williams & Wilkins.

Nitescu, P., Joberg, M., Applegren, L. et al. (1995) Complications of intrathecal opioids and bupivacaine in the treatment of refractory cancer pain. Clin. J. Pain 11: 45–62. Njee, T.B., Irthum, B., Roussel, R. and Peragut, J.C. (2004) Intrathecal morphine infusion for chronic non-malignant pain: a multiple center retrospective survey. Neuromodulation 7 (4): 249–59. North, R.B., Cutchis, P.N., Epstein, J.A. et al. (1991) Spinal cord compression complicating subarachnoid infusion of morphine: case report and laboratory experience. Neurosurgery 29: 778–84. Ong, B. and Segstro, R. (1994) Respiratory depression associated with meperidine spinal anesthesia. Can. J. Anesth. 41: 725–7. Patel, D., Janardhan, Y., Meri, B. et al. (1990) Comparison of intrathecal meperidine and lidocaine in endoscopic urologic procedures. Can. J. Anesth. 37: 567–70. Pert, C. and Snyder, S. (1973) Opiate receptor: demonstration in nerve tissue. Science 48: 1011–14. RxList.  http://fdb.rxlist.com/drugs/search.aspx?querydemerol (retrieved 25 January 2008). Rawal, N., Nuutinen, L., Raj, P.P. et al. (1991) Behavioral and histologic effects following intrathecal administration of butorphanol, sufentanil, and nalbuphine in sheep. Anesthesia 75: 1029–34. Ribeiro, M.D.C. and Zeppetella, G. (2003) Fentanyl for chronic pain (protocol for Cochrane Review), (date of most recent substantive amendment: 28 September 2001) The Cochrane Library, Issue 4. Chichester, UK: John Wiley and Sons. Sakurada, T., Komatsu, T. and Sakurada, S. (2005) Mechanisms of nociception evoked by intrathecal high-dose morphine neurotoxicology. Neurotoxicology 26 (5): 801–9. Santos, S., Melnick, I. and Safronov, B. (2004) Selective post synaptic inhibition of tonic firing neurons in substantia gelatinosa by -opioid agonist. Anesthesiology 101 (5): 1177–83. Schuchard, M., Krames, E.S. and Lanning, R.M. (1998) Intraspinal analgesia for nonmalignant pain: a retrospective analysis for efficacy, safety and feasibility in 50 patients. Neuromodulation 1: 46–56. Schuchard, M., Lanning, R., North, R., Reig, E. and Krames, E. (1998) Neurologic sequelae of intraspinal drug delivery systems: results of a survey of american implanters of implantable drug delivery systems. Neuromodulation 1: 137–48. Sharma, S.K., McIntire, D.D., Wiley, J. et al. (2004) Labor analgesia and cesarean delivery: an in patient meta-analysis of nulliparous women. Anesthesiology 100: 142–8. Shimoyama, N., Shimoyama, M., Elliott, K.J. and Inturrisi, C.E. (1997) d-Methadone is antinociceptive in the rat formalin test. Pharm. Exp. Ther. 283 (2): 648–52. Shir, Y., Shapiras, S., Shenkman, Z. et al. (1991) Continuous epidural methadone treatment for cancer pain. Clin. J. Pain 7: 339–41. Shulman, M.S., Walkerlin, G., Yamaguchi, L. et al. (1987) Experience with epidural hydromorphone for post thoracotomy pain relief. Anesthes. Analg. 66: 567–70. Sjogren, P., Thunedborg, L.P., Christrup, L. et al. (1988) Is development of hyperalgesia, allodynia and myoclonus related to morphine metabolism during long-term administrating: six case histories. Acta Anaesthesiol. Scand. 42: 1070–75. Smith, M.T. (2000) Neuroexcitatory effects of morphine and hydromorphone: evidence implicating the 3-glucuronide metabolites. Clin. Exper. Pharmacol. Physiol. 27 (7): 524–8. Smith, T.J., Staats, P.J., Pool, G. et al. (2002) Randomized clinical trial of an implantable drug delivery system compared with comprehensive medical management for refractory cancer pain: Impact on pain, drug-related toxicity, and survival. J. Clin. Oncol. 20: 4040–9. Souter, K.J., Davies, J.M., Loeser, J.D. and Fitzgibbon, D.R. (2005) Continuous intrathecal meperidine for severe refractory cancer pain: a case report. Clin. J Pain 21 (2): 193–6.

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Wang, J.K., Naus, L.A. and Thomas, J.E. (1979) Pain relief by intrathecally applied morphine in man. Anesthesiology 50: 149–51. Willis, K.D. and Doleys, D.M. (1999) The effects of long-term intraspinal infusion therapy with noncancer pain patients: evaluation of patient, significant-other, and clinic staff appraisals. Neuromodulation 2: 241–53. Winkelmuller, M. and Winkelmuller, W. (1996) Long-term effect of continuous intrathecal opioid treatment in chronic pain of nonmalignant etiology. J. Neurosurg. 85: 458–67. Wright, A.W.E., Nocente, M.L. and Smith, M.T. (1998) Hydro­ morphone-3-glucuronide: biochemical synthesis and preliminary pharmacological evaluation. Life Sci. 63 (5): 401–11. Yaksh, T.L., Hassenbusch, S., Burchiel, K., Hildebrand, K.R., Page, L.M. and Coffey, R.J. (2002) Inflammatory masses associated with intrathecal drug infusion, a review of preclinical evidence and human data. Pain Med. 3: 300–12.

ivb. infusional therapies for pain

C H A P T E R

34

Intrathecal Analgesics, Choice of System Marshall D. Bedder

o u t li n e Historical Development

457

Current Implantable Systems Medtronic Synchromed Pumps Medtronic Isomed Pump Codman (Johnson & Johnson) Arrow 3000 Advanced Neuromodulation Systems   (St. Jude Medical) AccuRx Pump

457 458 459 459

Cost Efficacy Intrathecal Baclofen for Spasticity

460 461

459

Historical development

462

Conclusion

465

References

465

463 464 464

pump, the Archimedes pump, which is being marketed in the USA by Medtronic as the Isomed pump (see Figure 34.5). The latest generation constant flow rate pump, a non-gas-powered elastomeric device, the AccuRx, is available in Europe only at the time of publication from ANS (St. Jude Medical) (see Figure 34.7). Medtronic Inc. introduced the first fully implantable pump (Synchromed I) with external programmability in 1988, which became commercially available for cancer and chronic pain in 1991 (see Figure 34.1).

The first totally implantable drug administration system was developed at the University of Minnesota in 1969 (Blackshear et al., 1970). These constant flow rate pumps, marketed as the Infusaid pump by Strato-Infusaid, were utilized in establishing the early efficacy of intraspinal opioids (Blackshear et al., 1970; Onofrio et al., 1981; Coffey et al., 1983; Krames et al., 1985; Paice et al., 1996). Therex Corporation developed a constant flow rate pump, which, when sold to Arrow Corporation in 1994, became the Arrow 3000 and then the Codman 3000 pump, when Arrow sold the pump to Codman, a Johnson & Johnson subsidiary (see Figure 34.6). In Europe Tricumed developed a constant flow rate

Neuromodulation

Complications General Complications of Intrathecal   Drug Delivery Systems Outcome Data Choice of System

Current implantable systems The commercially available implantable pumps are either fully programmable or constant infusion in

457

2009 Elsevier Ltd. © 2008,

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34.  Intrathecal Analgesics, Choice of System

design. The constant infusion systems are further subdivided into gas-driven or an elastomeric mechanism.

Medtronic Synchromed Pumps (Figures 34.1–34.4) First and only programmable pump, first marketed as the Synchromed I (see Figure 34.1) l Synchromed II-18 cc and Synchromed EL- 6 cc pump reservoirs (see Figures 34.2, 34.3) l

New external remote, the Personal Therapy Manager (PTM) for the Synchromed II (Figure 34.4). Allows for patient-activated preprogrammed supplemental doses of physician-prescribed medication with preprogrammed lock-out intervals. l Metal mesh covered separate side access port and non-sideport models. Synchromed I non-sideport, Synchromed II mesh-covered sideport l Peristaltic flow control l Battery and vapor pressure (CFC-114) power supply

l

Figure 34.1  Synchromed 1, with either sideport or no sideport, Isomed, Synchromed EL, and Synchromed II pumps. Also shown is a Synchromed II telemetry programmer (Photo courtesy of Medtronic, Inc., Minneapolis, MN)

Figure 34.2  Synchromed II

Figure 34.3  Synchromed EL

(Photo courtesy of Medtronic, Inc., Minneapolis, MN)

(Photo courtesy of Medtronic, Inc., Minneapolis, MN)

IVB. infusional therapies for pain



Current implantable systems

Medtronic Isomed Pump (Figure 34.5) l l l l l

l

Previously known as the Archimedes pump  Fixed rate pump Three reservoir sizes, 20 ml, 35 ml, and 60 ml Separate side access port Capillary flow restrictor flow control Vapor pressure (CFC-11) power supply

459

Codman (Johnson & Johnson) Arrow 3000 (Figure 34.6) Previously known as the Therex and Arrow pump  Redesigned as Arrow 3000 with three pump reservoirs l Integrated center fill port with separate needle to access bolus port. No confusion with single large fill port. l Vapor pressure- (N-butane gas) driven l Multiple capillary flow restrictors (high, medium, and low) for their 16 ml, 30 ml, and 50 ml models l Also manufacture the Microject (external) Functional trial system with Flex-tip plus intraspinal catheter l l

Advanced Neuromodulation Systems (St. Jude Medical) AccuRx Pump (Figure 34.7) Gas-free implantable pump unaffected by pressure changes and less temperature-sensitive. No preoperative warming needed and low reservoir pressure for easy refilling l Polymeric diaphragm inexhaustible power source l Peripheral catheter access port l Integrated suture loops l Five constant flow rates available: 0.4–1.5 ml per 24 hours l 27 ml reservoir model l Least costly l

Figure 34.4  Personal therapy manager (Photo courtesy Medtronic, Inc., Minneapolis, MN)

Figure 34.5  The Isomed constant flow rate pump

Figure 34.6  The Codman Arrow 3000 pump

(Photo courtesy of Medtronic, Inc., Minneapolis, MN)

(Photo courtesy of Johnson & Johnson)

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34.  Intrathecal Analgesics, Choice of System

pain. He suggests expanding and recognizing the following costs: Physiologic costs l Neurophysiologic, endocrine, metabolic l Physical costs l Disability l Effects of prolonged bed rest   Pulmonary embolism   Osteoporosis   Muscle wasting l Costs to the family l Lost work hours l Dysfunctional relationships l Loss of consortium l Loss of income l Costs to society l Increased unemployment l Increased governmental transfers   Social security   Workers compensation l Increased insurance rates l Increased cost of goods and services l

Figure 34.7  The AccuRx pump (Photo courtesy of Advanced Neuromodulation Systems/St. Jude Medical)

Cost efficacy In this age of expanding medical costs to insurers, governments, and patients, medical expense and efficacy are being scrutinized more and more closely. The mantra of evidence-based decision-making in clinical practice is, most appropriately, gaining wider universal acceptance. Pain medicine outcome data, however, are often much more difficult to come by because of the subjective nature of pain. Indeed, the very nature of the patients chosen for intrathecal therapies often presents the clinician or investigator with significant ethical considerations. Is it ethical to offer alternative therapies (which have failed or they would not be IT candidates) or no therapy as control groups? Traditionally the costs associated with intrathecal therapy have been broken simply into:

There are four traditional methods used to establish the cost-efficacy of a particular therapy:

Short-term economic considerations l Purchase price of the pump l Hospital follow-up episodes including inpatient stays and outpatient appointments l Drug costs l Long-term economic considerations l Costs relating to time off work l Disruption to life and debilitating costs of chronic pain

1. Cost minimization analysis (CMA) l CMA focuses primarily on direct medical costs. It assumes that the outcomes of alternative therapies are similar. Provides basis for choosing the lowest cost therapy 2. Cost-effectiveness analysis (CEA) l CEA compares alternative means to achieving a defined outcome (for example, 50% reduction in pain). Offers more complete comparative information about costs and benefits of alternatives. 3. Cost–utility analysis (CUA) l CUA groups disparate outcomes under a common measure. A commonly used measure is quality-adjusted life years (QALYs). Provides information useful to patients, who are typically concerned about utility of a procedure, and to physicians, who are concerned with costeffective clinical decision-making. 4. Cost–benefit analysis (CBA) l CBA answers the question as to whether the benefits are worth the cost. It expresses costs and benefits in dollars and a cost–benefit ratio is calculated.

Johnson (1997) has suggested that when calculating the savings of the prevention and alleviation of morbidity, one must remember the high cost of unrelieved

The cost-effectiveness analysis appears to be the most appropriate analysis utilized when analyzing the cost of IT therapy. Cost-effectiveness analysis assumes

l

IVB. infusional therapies for pain



461

Cost efficacy

Table 34.1  Studies showing cost saving with intrathecal baclofen Author

Study design

Number of patients

Cost savings parameters

Estimated savings in total cost of care

Charles River Associates Economic Model, 1992

Medical and economic component analysis

N/A

Total associated costs of care

39%  $9000/year

Nance et al., 1995, Can. J. Neurol.,

Prospective

7 spinal cord injury and MS patients

Inpatient hospital day comparison 2 yr prior and 2 yr post implant

$153 120 for the 6 prospective patients

Becker et al., 1995, Can. J. Neurol.

Prospective

9 spinal origin spasticity patients

Total number of hospital days 1 yr before and after implant

$23 970/patient

Ordia et al., 1996, J. Neurosurg.

Prospective

10 patients with severe spinal origin spasticity

Hospitalizations and altered length of stay 1 yr before and after implant

$6750/pt

Payback of pump implant cost  2.5 yr Becker et al., 1997, J. Neurology

Prospective

18 patients. with cerebral origin spasticity

Oral anti-spasticity meds

Daily savings of up to 3.26 Deutschmarks/day

Gertszen et al., J. Neurosurg., 1998

Retrospective

48 CP patients

Need for planned ortho surgery

64% no longer needed surgery

Postma et al., 1999, Pharmacoeconomics

Prospective, multicenter randomized, placebocontrolled

18 patients. and 15 match patients

Direct and indirect costs 1 yr prior and 2 yr prospective

$8811–$9661/yr

that if several alternative therapies are equivalent in regard to efficacy then the least costly should be chosen. This analysis offers more complete comparative information regarding the costs and benefits of alternative therapies or devices. Generally the evidence on costs and comparative analysis from published studies are based on computerized cost-modeling studies or studies analyzing actual costs. Significant cost-efficacy data exist for intrathecal therapy in two main distinct groups: (1) intrathecal baclofen therapy (ITB) for spasticity and (2) intrathecal analgesics for pain. The studies, study design, number of patients, and outcomes will be looked at separately in these two groups in order to compare these different patient populations more appropriately.

Intrathecal Baclofen for Spasticity ITB has evolved into the standard treatment for severe spasticity. A wealth of clinical outcome studies bolsters this impression (Table 34.1). In analyzing the data from these studies, one must keep in mind that there are increased costs in year 1 of treatment, associated with the initial cost of the pump implant, itself. There appears to be an immediate, and across all studies, reduction in oral anti-spasm medication. This benefit

Table 34.2  Cost savings of intrathecal therapy Medical component

Economic component

Pain

Hospitalization costs

Contractures

Physician fees

Skin breakdown

Attendant care costs

Bladder and bowel dysfunction

Other anti-spasticity medications

Impaired ambulation ability

Disability income costs

Impaired sleep patterns

Orthopaedic surgical release operation costs

Impaired respiratory function Hypertension

continues and may increase as the patient is further weaned down or off their oral medication. The cost savings are often broken down further into a medical component and an economic component (Table 34.2). One of the first studies on cost efficacy for intrathecal analgesic systems looked at actual costs and compared a tunneled epidural system versus a totally implanted programmable pump system (Bedder et al., 1991). These authors showed that the initial cost for an

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34.  Intrathecal Analgesics, Choice of System

Table 34.3  Studies showing cost savings of intrathecal opioids Author

Study design

No. of patients

Cost savings parameters

Estimated savings in total cost of care

Bedder et al., 1991

Cost analysis of implanted pump vs. exteriorized system

20

System initiation and follow-up costs

Savings accrue when treatment exceeds 3 months for implanted pump

Hassenbusch et al., 1997

Modeling study Cost minimization Cost-effectiveness

Total charges for drugs (oral, transdermal, subq/i.v.) and pump

Cost-effectiveness of intrathecal pain therapy vs. medical therapy in 10–22 months for FBSS

de Lissovoy et al., 1997

Computer modeling Cost-effectiveness

Direct costs, adverse event costs, treatment scenarios by a panel of experts

Cost-effectiveness of intrathecal morphine therapy vs. medical management when therapy exceeds 12–22 months

Mueller-Schwefe et al., 1997

Cost analysis

Daily cost of intrathecal morphine (ITM) pump maintenance over the life of the pump vs. equivalent sustained release morphine dose

ITM maintenance US $7.10 Sustained release morphine at 800 mg/day US $39.00

12

implantable system was high owing to purchase costs, but after 3 months, the costs were lower than for the external system because of higher drug and dispensing charges associated with these systems. The available cost data for intrathecal analgesic systems shows a lack of actual patient data that is available for analysis. The computerized cost-modeling data are very strong and are unequivocal in their support for intrathecal analgesic therapy for certain patient groups. Hassenbusch’s study (Hassenbusch et al., 1997) on the economics of intrathecal therapy very clearly demonstrates that with even a 5% increase in patient dose the economics of intrathecal therapy becomes even more beneficial, and with further increments in dose increase intrathecal therapy rapidly becomes less expensive that even oral and intravenous morphine (Table 34.3).

Complications Clinical case reports describing motor or sensory dysfunction in patients implanted with drug administration devices were first published in 1999 (Langsam, 1999). The initial reports involved patients receiving intrathecal morphine via intrathecal catheters. Histopathologic analysis of these masses revealed the presence of macro­ phages, neutrophils and monocytes with a necrotic center and no evidence of infectious processes. It has been reconfirmed in both the canine and sheep model that these masses are accumulation of granulation tissue and do not meet the formal histopathologic classification of granuloma, which requires the presence of giant cells.

The literature, however, continues to utilize the term intrathecal granuloma. Recent studies have characterized the role of morphine dose and concentration in the role of granuloma formation (Allen et al., 2006). Using serial MRI analysis it was shown that a modest mass could be observed in 3 days and this mass became substantial in all dogs by 10 days. These authors’ work clearly showed that reversal of the mass occurred with termination of infusion over an interval of 7–14 days. In dogs, CSF sampling revealed extraordinarily high concentrations of the drug near the catheter tip. The authors’ conclusions highlight the important role for local concentration in the development of catheter tip granulomas. The incidence of intrathecal granuloma in humans is unknown but in all likelihood is underreported. A cohort of seven patients receiving intrathecal analgesic drug therapy for chronic intractable pain underwent radio-contrast myelography and CT scanning to screen for catheter-associated intrathecal masses (McMillan et al., 2003). Three of the seven patients had intraspinal masses associated with the tip of the drug infusion catheter, whereas only the index patient was symptomatic with neuropathic pain and paralysis of the left lower extremity. In one asymptomatic patient, regression of the mass was seen with cessation of the therapy. An analysis of their data revealed statistical significance for younger age and larger morphine dose in the group with intrathecal masses. A review of all reported cases of inflammatory mass lesions at the tip of intraspinal drug administration catheters was undertaken using data available from the medical literature and FDA reports by the manufacturer (Medtronic) as of 30 November 2000 (Coffey and

IVB. infusional therapies for pain



463

Complications

Burchiel, 2002). Sixteen were cases previously reported in the medical literature and 25 others were reported that were not previously published in the literature. It was found that most masses were located in the thoracic region although there is an initial case report of permanent neurologic deficit with a catheter caudal to the S1 vertebral body (Murphy et al., 2006). Intrathecal drugs included morphine or hydromorphone, either alone or mixed with other drugs, in 39 of 41 cases. They did not find any case where baclofen was the only intrathecal medication. However, there was a first report out of Australia (Fernandez et al., 2003) reporting an intrathecal granuloma associated with isolated baclofen infusion. We now have a very recent case report of inflammatory masses in two patients receiving baclofen as a sole agent (Deer et al., 2007). There is also a case report of a spinal cord lesion after long-term intrathecal clonidine and bupivacaine treatment for intractable pain (Perren et al., 2004). Of the 41 patients in the review, 30 patients underwent surgery to relieve spinal cord or cauda equina compression. Eleven patients remained paralyzed and one died of a pulmonary embolus. Recommendations for patients with intraspinal drug administration catheters have included: Close follow-up l Increased vigilance for patients on higher dose infusion l Awareness that pain may precede signs and symptoms of neurological deterioration l Serial neurologic exam at each pump refill l MRI or CT myelogram via pump sideport to detect catheter-tip granuloma if suspicious l Whenever feasible, position the catheter in the lumbar thecal sac and/or keep the daily intrathecal dose as low as possible for as long as possible l Open surgery may not be necessary if the infusion is discontinued l Awareness and vigilance are the hallmarks for early detection l

Table 34.4  Complications associated with intrathecal drug delivery systems Complication

No. patients experiencing a complication (n  122)

% patients in analysis (n  97)

Pharmacologic

75

77.3%

3

3.1%

  Meningitis

1

1.03%

 Chronic pump pocket infection

1

1.03%

Catheter-related

16

16.5%

  Distal catheter occlusion

1

1.03%

 Shearing at spinal entry site

2

2.06%

 Shearing with subarachnoid segment

2

2.06%

 Retraction, paraspinal coiling/kinks

4

4.12%

 Leakage at connection site between catheters

6

6.2%

  Spinal headache

3

3.09%

 CSF leakage at the catheter and pump connection site with a small seroma

1

1.03%

  Pump failure

1

1.03%

 Pump torsion with port occlusion

1

1.03%

2

2.06%

3

3.09%

Procedural Minor infections  Superficial wound infection Serious infections

Equipment

Pump-related

Programming errors   Pump misprogramming Psychological category  Distorted body image pumps removed

General Complications of Intrathecal Drug Delivery Systems As with any invasive procedure there are complications and side effects associated with intrathecal drug delivery systems (Table 34.4). The issue of drug-specific side effects will be dealt with in the appropriate chapter. Complications directly associated with the implant include: Procedural Equipment l Infection l l

Catheter disconnection/dislodgement Programming errors l Psychological l l

A retrospective review of 122 patients was undertaken, with 97 patients included in the final analysis; 25 patients were excluded because of incomplete data (Kamran and Wright, 2001). Patients were implanted for failed back surgery (n  15), cervical or lumbar

IVB. infusional therapies for pain

464

34.  Intrathecal Analgesics, Choice of System

spondylosis (n  10), complex regional pain syndrome (n  5), compression fractures (n  8), non­operative disc herniations with radiculopathies (n  4), peripheral neuropathies (n  6), and spasticity (n  2). These patients were followed for an average of 5.8 years with the range being 6 months to 9 years. Overall 43.3% of patients reported various complications. Most of these were pharmacologic in nature. A total of seven pumps were explanted, three due to distortion of body image. It appears the majority of equipment complications involved catheters. Catheter-related complications resulted in the majority of repeat surgeries. It was noted that with a paramedian catheter placement shearing was not seen. The authors also felt that the use of nonabsorbable sutures (pursestring suture at the catheter) was a contributing factor to catheter shearing. They did not specifically look for catheter tip granulomas, but felt that the one case of catheter tip occlusion represented this complication. Their conclusion stressed meticulous attention to the implant technique to further reduce complications.

Outcome Data The recent clinical data is more rigorous in design and therefore more robust in its conclusions for improved clinical success in pain control for both cancer and noncancer pain patients. A randomized clinical trial compared intrathecal drug delivery systems (IDDS) with comprehensive medical management (CMM) versus CMM alone for refractory cancer pain. The authors enrolled 202 patients at 9 centers (Smith et al., 2002). Not only did IDDS improve success in pain control and reduction in pain, it also significantly reduced common drug toxicities. Most interestingly, IDDS therapy, through enhanced pain control or lessened toxicity, improved survival in patients with refractory cancer pain. The authors went on to complete a randomized crossover clinical trial to further assess if efficacy, drug toxicity benefits, and survival were maintained over time (Smith et al., 2005). Their conclusions were that IDDS improved clinical success, reduced pain scores, relieved most toxicity of pain control drugs, and was associated with increased survival rates for the duration of the 6 month trial. At 6 months, only 32% of the group randomized to CMM and those who did not cross over to IDDS were alive, compared with 52–59% for patients in those groups who received IDDS. The data for chronic low back pain treated with IDDS have also been looked at in a prospective manner using the National outcomes registry for low back pain (Deer et al., 2004). This multicenter trial involved 166 patients who had successful trials with 6 month

Table 34.5  Comparison of programmable vs. constant flow pumps Programmable pump

Constant flow pump

Programmability





Cost





Requires programmer





External remote bolus





Requires replacement when power source depleted





Multiple reservoir sizes

 (2)

 (multiple)

Ambient pressure and temperature affect



 (AccuRx only)

and 12 month follow-ups. It is remarkable for its analysis of chronic low back patients using IDDS and for the follow-up period. At 12 month follow-ups, implanted patients experienced reductions in numeric back and leg pain ratings, improved Oswestry scores, and high satisfaction with the therapy (80%). In the IDDS group 42% had decreased their systemic opioid usage compared with the 6 month follow-up.

Choice of System Programmable pumps have had the widest commercial acceptance and have continued to be the most favored by clinicians for a variety of reasons. The most obvious reason is the ability to change the program without having to access the pump reservoir. This is less costly and less invasive for the patient. The downside to the current programmable pumps is the greater initial cost and the need to replace them when the battery becomes depleted. The individual medical practice must also have a computer programmer and have personnel trained on how to program these pumps. The negative aspects () and positive () aspects of programmable pumps versus constant flow pumps are summarized in Table 34.5 (Cameron et al., 2002). The emerging new technologies need to be balanced against the realities of healthcare financing and the accessibility of technology to patients. Technology change is a major escalator of healthcare expenditure (Okunad et al., 2002). New political initiatives for a single-payer healthcare system in the USA may see changes in technology availability and funding. Current access to this technology is determined not only by Medicare CPT’s but also in their rates of reimbursement and in what settings they can be implanted. Many physicians are already only breaking even or

IVB. infusional therapies for pain



Conclusion

losing money on pump refills. In the USA there is no national CMS (Medicare) policy on drug refill reimbursement. Professional fees for pump implantation and refills, which carry significant risk, are extremely low. Combining these difficulties, with the newly recognized problem of intrathecal inflammatory mass at catheter tips, suggests that there appear to be serious impediments to the growth of intrathecal analgesia with implantable pump technology. The resolution of catheter-related problems and healthcare funding may well determine the future of this otherwise very effective modality.

Conclusion The history of the use of intrathecal therapy has been described, with past and present technologies described for familiarization. Understanding the limitations and complications of this modality allows us to better define patient selection, correct implant techniques, and achieve better outcomes for our patients. We have access to advanced technology that serves as a great platform for drug delivery at the neuraxis. Clinicians are awaiting more selective and targeted medications that will further the utility of intrathecal infusions and even broaden the applications (i.e. peptide infusions for Alzheimer patients). The future of implantable technology for intrathecal infusion rests upon the political and socioeconomic decisions that will be made by local and national governments and healthcare payers. Hopefully we will see continued growth and development of this modality to better serve our patients in need.

References Allen, J.W., Horais, K.A., Tozier, N.A., Wegner, K., Corbeil, J., Mattrey, R.F. et al. (2006) Time course and role of morphine dose and concentration in intrathecal granuloma formation in dogs. Anesthesiology 105: 581–9. Becker, R., Alberti, O. and Bauer, B.L. (1997) Continuous intrathecal baclofen infusion in severe spasticity after traumatic or hypoxic brain injury. J. Neurol. 244: 160–6. Becker, W.J., Harris, C.J., Long, M.L., Ablett, D.P., Klein, G.M. and DeForge, D.A. (1995) Long term intrathecal baclofen therapy in patients with intractable spasticity. Can. J. Neurol. Sci. 22: 208–17. Bedder, M.D., Burchiel, K. and Larson, A. (1991) Cost analysis of two implantable narcotic delivery systems. J. Pain Symptom Manage. 6: 368–73. Blackshear, P.J., Dorman, F.D., Blackshear, P.J., Jr., Varco, R.L. and Buchwald, H. (1970) A permanently implantable self-recycling low flow constant rate multipurpose infusion pump of simple design. Surg. Forum 21: 136–7. Cameron, T., Wigness, B.D. and Bedder, M.D. (2002) Operating principles and clinical implications of constant flow pumps. Neuromodulation 5: 160–6.

465

Coffey, R.J. and Burchiel, K. (2002) Inflammatory mass lesions associated with intrathecal drug infusion catheters: report and observations on 41 patients. Neurosurgery 50 (1): 78–87. Coffey, R.J., Burchiel, K., Coombs, D.W., Saunders, R.L., Gaylor, M. S., Block, A.R. et al. (1983) Relief of continuous chronic pain by intraspinal narcotics infusion via an implanted reservoir. JAMA 250: 2336–9. Deer, T., Chapple, I., Classen, A., Javery, K., Stoker, V., Tonder, L. et al. (2004) Intrathecal drug delivery for treatment of chronic low back pain: Report from the national outcomes registry for low back pain. Pain Med. 5: 6–13. Deer, T.R., Raso, L.J. and Garten, T.G. (2007) Inflammatory mass of an intrathecal catheter in patients receiving baclofen as a sole agent: a report of two cases and a review of the identification and treatment of the complication. Pain Med. 8: 259–62. Fernandez, J., Madison-Michael, L., II and Feler, C.A. (2003) Catheter tip granuloma associated with sacral region intrathecal drug administration. Neuromodulation 4: 225–8. Gerszten, P.C., Albright, A.L. and Johnstone, G.F. (1998) Intrathecal baclofen infusion and subsequent orthopedic surgery in patients with spastic cerebral palsy. J. Neurosurg. 88: 1009–13. Hassenbusch, S.J., Paice, J.A., Patt, R.B., Bedder, M.D. and Bell, G.K. (1997) Clinical realities and economic considerations: Economics of intrathecal therapy. J. Pain Symptom Manage. 14: S36–S45. Johnson, B.W. (1997) Economic outcome and practical efficacy of implantable drug administration systems. In: W.C.V. Parris (ed.), Cancer Pain Management, Principles and Practice. Oxford: Butterworth–Heinemann, pp. 165–70. Kamran, S. and Wright, B. (2001) Complications of intrathecal drug delivery systems. Neuromodulation 4: 111–15. Krames, E.S., Gershow, J., Glassberg, A., Kenefick, T., Lyons, A., Taylor, P. and Wilkie, D. (1985) Continuous infusion of spinally administered narcotics for the relief of pain due to malignant disorders. Cancer 56: 696–702. Langsam, A. (1999) Spinal cord compression by catheter granulomas in high-dose intrathecal morphine therapy: Case report. Neurosurgery 44: 689–91. de Lissovoy, G., Brown, R.E., Halpern, M., Hassenbusch, S.J. and Ross, E. (1997) Cost-effectiveness of long-term intrathecal morphine for pain associated with failed back surgery syndrome. Clin. Ther. 19: 96–112. McMillan, M.R., Doud, T. and Nugent, W.S. (2003) Catheter-associated masses in patients receiving intrathecal analgesic therapy. Anesth. Analg. 96 (1): 186–90. Mueller-Schewefe, G., Hasssenbusch, S.J. and Reig, E. (1997) Cost effectiveness of intrathecal therapy for pain. Neuromodulation 2: 77–84. Murphy, P.M., Skouvaklis, D.E., Amadeo, R.J., Haberman, C., Brazier, D.H. and Cousins, M.J. (2006) Intrathecal catheter granuloma associated with isolated baclofen infusion. Anesth. Analg. 102: 848–52. Nance, P., Schryvers, O., Schmidt, B. and Dubo, H. (1995) Intrathecal baclofen therapy for adults with spinal spasticity: therapeutic efficacy and effect on hospital admissions. Can. J. Neurol. Sci. 22: 22–9. Okunad, A.A. and Murthy, M.V. (2002) Technology is a “major driver” of healthcare costs: a cointegration analysis of the Newhouse conjecture. J. Health Econ. 1: 149–59. Onofrio, B.M., Yaksh, T.L. and Arnold, P.G. (1981) Continuous low dose intrathecal morphine administration in the treatment of chronic pain of malignant origin. Mayo Clin. Proc. 56: 516–20. Ordia, J.I., Fischer, E., Adamski, E., Chagnon, K.G. and Spatz, E.L. (1996) Chronic intrathecal delivery of baclofen by a programmable pump for the treatment of severe spasticity. J. Neurosurg. 85: 452–7.

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Paice, J.A., Penn, R.D. and Shott, S. (1996) Intraspinal morphine for chronic pain: a retrospective multicenter study. J. Pain Symptom Manage. 80: 71–80. Perren, F., Buchser, E., Chedel, D., Hirt, L., Maeder, P. and Vingerhoets, F. (2004) Spinal cord lesion after long-term intrathecal clonidine and bupivacaine treatment for the management of intractable pain. Pain 109 (1-2): 189–94. Postma, M., Oenema, D., Terpstra, S., Bouma, J., Kuipersupmeijer, H., Staal, M.J. et al. (1999) Analysis of the treatment of severe spinal spasticity with a continuous intrathecal baclofen infusion system. PharmacoEconomics 15: 395–404.

Smith, T.J., Coyne, P.J., Staats, P.S., Deer, T., Stearns, L.J., Rauck, R. L. et al. (2005) An implantable drug delivery system (IDDS) for refractory pain provides sustained pain control, less drugrelated toxicity, and possibly better survival compared with comprehensive medical management (CMM). Ann. Oncol. 16: 825–33. Smith, T.J., Staats, P.S., Deer, T., Stearns, L.J., Rauck, R.L., Boortz-Marx, R.L. et al. (2002) Randomized clinical trial of an implantable drug delivery system compared with comprehensive medical management for refractory cancer pain: Impact on pain, drug related toxicity, and survival. J. Clin. Oncol. 20: 4040–9.

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C H A P T E R

35

Intrathecal Non-Opioid Analgesics for the Control of Pain Enrique Reig, David Abejón, and Elliot S. Krames

o u t line Introduction

467

Local Anesthetics Bupivacaine Ropivacaine

468 469 470

Adrenergic Agonists Clonidine

471 471

Other Intrathecal Agents

472

Ziconotide Ketamine Baclofen Midazolam Gabapentin Adenosine Conclusions

477

References

478

and the infusion system to improve analgesic efficacy. Morphine has traditionally been and still is the most widely used agent for the treatment of chronic pain. In fact, it is the only opioid agent approved by the Food and Drug Administration (FDA) of the USA for intrathecal use along with ziconotide, an N-type, voltage-sensitive calcium channel blocking agent for the treatment of chronic pain, along with baclofen, approved by the FDA for the treatment of spasticity (Hassenbusch and Portenoy, 2000). Because intrathecal infusion is increasingly used more often for the treatment of chronic pain, the number of intrathecal agents used and the range of combinations of these agents that are used has grown exponentially. Approximately, 35% of patients treated with intrathecal morphine do not obtain acceptable analgesia and it is often necessary to combine intrathecal morphine with other non-opioid agents in order to reduce pain. According to the latest consensuses of experts, all

Introduction Since the discovery of -receptors in the spinal cord (Yaksh and Rudy, 1976), spinal infusion of analgesics, through totally implantable systems, is one of the most widely used therapeutic options for patients with chronic pain who do not respond to other, less invasive therapies. This route of analgesic administration, which was initially used exclusively for cancer patients, is today one of the main therapies in the interventional armamentarium for chronic pain of noncancer origin. Improved systems and knowledge of the medications used as well as the development of new medications has led to a constant increase in the number of indications and use of this therapy for various painful disorders (Gilmer-Hill et al., 1999). Use of this therapy requires a medication that is safe, effective, stable, and compatible with other medications

Neuromodulation

472 474 474 476 476 477

467

2009 Elsevier Ltd. © 2008,

468

35.  Intrathecal Non-Opioid Analgesics for the Control of Pain

Table 35.1  Non-opioid drugs that can be used for the treatment of chronic pain by the spinal route

Table 35.2  Opioid drugs used for the treatment of chronic pain by the intrathecal route

Local anesthetics

Morphine

Bupivacaine

Shaladi, A., Saltari, M.R., Piva, B., Crestani, F., Tartari, S., Pinato, P., Micheletto, G. and Dall’ara R. (2007) Continuous intrathecal morphine infusion in patients with vertebral fractures due to osteoporosis. Clin. J. Pain 23 (6): 511–17

Ropivacaine Tetracaine Adrenergic agonists

Fentanyl

Clonidine

Do Ouro, S., Esteban, S., Sibirceva, U., Whittenberg, B., Portenoy, R. and Cruciani, R.A. (2006) Safety and tolerability of high doses of intrathecal fentanyl for the treatment of chronic pain. J. Opioid Manage. 2 (6): 365–8

Tizanidine NMDA antagonists Ketamine

Methadone

Other

Baclofen

Mironer, Y.E. and Tollison, C.D. (2001) Methadone in the intrathecal treatment of chronic nonmalignant pain resistant to other neuroaxial agents: the first experience. Int. Neuromodulation Soc. 4: 25–31

Droperidol

Meperidine

Gabapentin

Mironer, Y.E. and Grumman, S. (1999) Experience with alternative solutions in intrathecal treatment of chronic nonmalignant pain. Pain Dig. 9: 299–302

Adenosine Aspirin

Ketorolac Midazolam

Hydromorphone

Octreotide

Hildebrand, K.R., Elsberry, D.E. and Anderson, V.C. (2001) Stability and compatibility of hydromorphone hydrochloride in an implantable infusion system. J. Pain Symptom Manage. 22: 1042–7

Neostigmine Ziconotide

Sufentanil

expert in intrathecal therapies (Bennett, Serafín et al., 2000; Bennett, Burchiel et al., 2000, Hassenbusch et al., 2004; Deer et al., 2007), currently available non-opioid agents for intrathecal delivery include local anesthetics, clonidine, midazolam, baclofen, and others that are to be used only in very selected cases when there is no other way to treat the patient’s pain (Tables 35.1 and 35.2). Figure 35.1 represents the present recommended algorithm of care for intrathecal administration of opioid and non-opioid analgesics.

Local anesthetics Local anesthetics, sodium (Na) channel blocking agents, cause a reversible blockade of nerve impulse conduction by preventing the propagation of action potentials in the axons of autonomic, sensory, and motor nerve fibers. Local anesthetics cause a blockade of nerve conduction by reducing the permeability of the membrane to Na. This reduction in permeability to Na decreases the depolarization velocity of the membrane and increases the threshold to electrical excitability. Local anesthetics diffuse through the nerve membrane in its unionized form. The low intracellular pH generates the ionized form of the

Boersma, F.P., Heykants, J., Ten Kate, A. et al. (1991) Sufentanil concentrations in the human spinal cord after long-term epidural infusion. Pain Clinic 4: 199–203

local anesthetic, which blocks the Na channel by reversibly binding to the D4–D6 part of the -subunit of the channel. Sodium flow is reduced and the action potential slows. If a sufficient number of Na channels are blocked, the action potential is not reachable and the nerve impulse cannot be transmitted. The resting membrane and threshold potential remain constant, but the action potential is temporarily reduced. In addition to its effects on the intracellular portion of the Na channel, the unionized portion of the local anesthetic also disrupts the intra-membrane portion of the channel and causes alterations in the membrane. Blockade of Na channels may be augmented by blockade of potassium channels, calcium channels, and G-protein-coupled receptors (Olschewski et al., 1998; Xiong and Strichartz, 1998; Hollman et al., 2001). Chemically, local anesthetics are composed of a lipophilic aromatic ring and a hydrophilic amine group. These are linked by a chain whose structure can be used to classify the agent as an amide or ester, although the linkage can also be created via a ketone or an ether (see Figure 35.2).

IVB. infusional therapies for pain



469

Local anesthetics

Line 1:

(a) morphine

(b) hydromorphone

(c) ziconotide

Line 2:

(d) fentanyl

(e) morphine/hydromorphone � ziconotide

(f) morphine/hydromorphone � bupivacaine/clonidine

Line 3:

(g) clonidine

(h) morphine/hydromorphone/fentanyl bupivacaine �/clonidine � ziconotide

Line 4:

(i) sufentanil

(j) sufentanil � bupivacaine �/clonidine � ziconotide

Line 5:

(k) ropivacaine, buprenophine, midazolam meperidine, ketorolac Experimental drugs

Line 6:

gabapentin, octreotide, conpeptide, neostigmine, adenosine, XEN2174, AM336, XEN, ZGX 160

Figure 35.1  Polyanalgesic recommendations for 2007 (Reproduced with the permission of the authors from Deer, Krames et al. (2007) Neuromodulation: Technology at the Neural Interface 10 (4): 300–28. John Wiley & Sons Ltd) H

[base]

pH � pK a � log [acid]

N

Figure 35.3  The Henderson–Hasselbach equation

N O

Figure 35.2  Molecular structure of lidocaine, an amide local anesthetic

Nerve membranes are composed of lipids and lipoproteins. Local anesthetics must pass through this barrier to gain access to the intracellular portion of the Na channels. Consequently, lipid solubility is an important factor in determining the ability of the drug to cross the membrane. This lipid solubility is quantified by measuring the relative distribution of the local anesthetic between the aqueous phase (e.g. water or buffer at physiological pH) and a non-aqueous phase (e.g. octanol, Z-heptane, hexane). The distribution of the substance between these two phases enables calculation of a partition coefficient. The higher the partition coefficient, the higher the lipid solubility and the more easily the substance will cross the membrane and vice versa. Another important characteristic of local anesthetics is the degree of ionization. Local anesthetics are weak bases (pKa 7.6–8.9) and are poorly soluble in water. In solution, the local anesthetic exists either as a cationic molecule or as the neutral base. The proportion in each state follows the Henderson–Hasselbach equation, varying with the dissociation constant (pKa) of that local anesthetic and the solution pH (see Figure 35.3).

Because the pKa is constant for the local anesthetic, the ambient pH is the determining factor for dissociation and ultimate transport across cell membranes. Current anesthetic agents have a pKa greater than physiological pH, so on injection into tissue a greater proportion of the drug exists in the cationic form. However, it is the unionized form that penetrates the cell to block the channel. Protein binding is also an important property of these agents. Local anesthetics bind to plasma proteins (albumin, a1-acid glycoprotein) and tissue proteins. This property of protein binding appears to be related to the duration of action for the local anesthetic used. Metabolism of local anesthetics depends on their bond. The local anesthetics used for intrathecal treatment belong to the amide group. Amide-type local anesthetics are metabolized through a complex process of biotransformation in the liver, followed by excretion in the kidneys.

Bupivacaine

IVB. infusional therapies for pain

H N

N O

470

35.  Intrathecal Non-Opioid Analgesics for the Control of Pain

Bupivacaine is composed of a lipophilic benzene ring attached to a hydrophilic tertiary amine group by means of a hydrocarbon chain and an amide bond. Bupivacaine is used for infiltration, nerve block, epidural, and spinal anesthesia. Bupivacaine is prepared as a water-soluble salt with a pH of 6.0 to improve chemical stability. It is a weak base (pKa 8.1) and less than 50% of the drug is in the unionized form at physiological pH, allowing the lipid soluble form to reach the sodium channels of the axons. Onset of action is slow but duration of action is two to three times longer than lidocaine (240–480 minutes). Like all local anesthetics, bupivacaine causes a blockade of nerve conduction by reducing the permeability of the membrane to Na. This reduction in permeability reduces the depolarization velocity of the membrane and increases the threshold of electrical excitability. The blockade produced by bupivacaine affects all nerve fibers, but the effect is greater on autonomic than sensory and motor fibers as determined by fiber size. The effects of bupivacaine on motor function depend on the concentration used: a concentration of 0.25% produces incomplete motor block, while concentrations of 0.5% and 0.75% usually produce complete motor block. According to the latest recommendations of experts in the field of intrathecal therapy, use of this drug intrathecally for the treatment of chronic pain is considered a second-line treatment, when morphine, ziconotide or hydromorphone has not had the desired analgesic effects (Deer et al., 2007). It is also often used when the patient has neuropathic pain or when, despite acceptable analgesia with a primary opioid, the patient has unacceptable side effects; in these cases therapy requires a second line of action and the use of bupivacaine is indicated (Bennett, Burchiel et al., 2000). The stability of the intrathecal formulation of bupivacaine (Trissel and Pham, 2002) and compatibility with the existing SynchroMed drug delivery system (Medtronic, Inc., Minneapolis, MN) have been tested (Hildebrand et al., 2001), varying with respect to the original values by about 5%. According to Shields et al., an admixture containing 25 g/ml ziconotide and 5 mg/ml bupivacaine hydrochloride was 90% stable at 22 days and 80% stable at 45 days in the SynchchroMed pump (Medtronic, Inc., Minneapolis, MN) (Shields et al., 2007a). Several authors have reported excellent results with the use of intrathecal bupivacaine alone or in combination with other agents for the management of patients with untreatable chronic pain of cancer or noncancer origins (Krames and Lanning, 1993; Sjoberg et al., 1994; Anderson and Burchiel, 1999). One study, the only

study randomized and controlled, showed no efficacy with the addition of intrathecal bupivacaine to the opioid alone (Mironer et al., 2002). The authors of this study concluded that the drug improved quality of life, although it did not appear to have any effect on the degree of analgesia produced. Other authors, however, have shown a reduction in pain and a decreased need for systemic opioids (Anderson and Burchiel, 1999; Deer et al., 2002). Dosing of this drug has not been well established in the literature. It is a drug that requires continuous evaluation both during the trial period and after implantation of the infusion pump. Although there are cases reported in the literature in which the mean dose rose to a maximum dose of 90 mg/day (Lundborg et al., 1999), most authors recommend an initial dose of bupivacaine between 2–3 mg/day (Bennett, Burchiel et al. 2000). Earlier expert panels recommended a maximum dose of 30 mg/day (Bennett, Burchiel et al., 2000; Bennett, Deer et al., 2000) and a maximum concentration of 38 mg/ml (Lundborg et al., 1999). The latest expert panel recommendations of 2007 are for a maximum dose of 30 mg/day and a maximum concentration of 40 mg/ml for bupivacaine (Deer et al., 2007). The recommendations for maximum doses and concentrations are made to prevent the occurrence of tip granuloma. Drug safety studies in both humans and animals have shown that bupivacaine is a safe drug at the doses normally used in clinical practice. Studies conducted in animals at higher doses than those used in clinical practice have confirmed the safety of the drug. Even in experimental studies in spinal cord injury models, it has been suggested that the use of this drug can improve the spinal cord injury by reducing the release of catecholamines and hence the necrosis they cause (Rezaian and Shams, 1979; Hotvedt et al., 1985; Li et al., 1985; Karlsson et al.,1994).

Ropivacaine

IVB. infusional therapies for pain

O

N NH



Adrenergic agonists

Ropivacaine is an amide group local anesthetic with a propyl group derived from N-alkyl pipecoloxylidine. It is a pure S-isomer and less potent than bupivacaine, so, when compared to bupivacaine, higher doses of ropivacaine are required. Compared with bupivacaine, a 23% higher daily dose is required to obtain the same effect, but with a lower rate of side effects (Markham and Faulds, 1996; Scott et al., 1997). Ropivacaine is an anesthetic with higher affinity for A- and C-fibers and lower affinity for A-fibers. In low concentrations it produces a differential block: it blocks sensory and autonomic fibers but does not block motor fibers (Cederholm, 1997; Yamashita et al., 2003), but when the concentration is increased this characteristic is lost. Its low solubility confers another advantage to the drug, since it has a higher concentration in CSF and better dermatomal spread than bupivacaine. The profile of this drug seems to be ideal for intraspinal use: it has fewer side effects, especially cardiac side effects, and a higher concentration at the site of action. Although it is included among local anesthetics, this drug is not routinely used and there are few references on its use for the treatment of chronic pain. Because of its higher costs than bupivacaine and because there do not appear to be any advantages of this agent over bupivacaine, the 2000 consensus panel failed to recommend its use (Deer et al., 2007).

Adrenergic agonists Adrenergic agents induce a dose-dependent antihypersensitivity effect to mechanical stimuli in a rat model of neuropathic pain involving activation of 2adrenoceptors (Obata et al., 2004). In a study evaluating the antihyperalgesic effects of IT clonidine (0.3–3.0 g) and tizanidine (1.0–5.0 g) in a rat model of neuropathic pain, IT clonidine, 3.0 g or tizanidine, 5.0 g significantly reversed both thermal and mechanical hyperalgesia (Kawamata et al., 2003).

Clonidine CI

N NH CI HN

471

Clonidine, a selective 2-adrenergic agonist, is a lipophilic agent that has analgesic effects when used intrathecally (Canavero et al., 2006). It is indicated for patients with chronic neuropathic pain. It shares a common site of action with morphine. The mechanism of action of its analgesic effects is through activation of 2-adrenergic receptors in the dorsal horn of the spinal cord (Yaksh, 1985), which reduces the response to painful stimuli. Although the primary action of clonidine is thought to be by activation of these 2-adrenergic receptors (adrenaline and noradrenaline), it has been postulated that there are other sites of action in the central nervous system, mainly in the caudorostral nucleus of the spinal cord (rostral ventral medulla) (Rainov et al., 2001; Hassenbusch et al., 2002). The analgesic effects of clonidine may be mediated by inhibition of pre- and postsynaptic interactions of the nociceptive afferent pathway in the dorsal horns and by inhibition of release of substance P at the presynaptic receptor level and blockade of activation of the second-order nociceptive neuron (Hassenbusch et al., 1999; Osenbach and Harvey, 2001). Clonidine is a stable drug, retaining 94% of its original concentrations when used alone or in combination with morphine or bupivacaine, and it is compatible with the widely used SynchroMed infusion system at body temperature (37 °C). Shields and Montenegro (2007) showed that a ziconotide– clonidine admixture was 90% stable for 60 days and a ziciconotide–clonidine–morphine admixture was 70% stable for 20 days. To our knowledge, there is only one study in which it was shown that the drug undergoes precipitation when the drug is mixed with morphine and maintained at a temperature of 4 °C. Therefore, it is not recommended to store mixtures of morphine and clonidine in refrigerators (Trissel and Pham, 2002; Hildebrand et al., 2003). The analgesic efficacy of the drug has been demonstrated when used either as monotherapy (Kawamata et al., 2003), or when used in combination with other agents (Uhle et al., 2000; Ackerman et al., 2003). Pain relief with this therapy has been reported to be between 70 and 100% (Hassenbusch et al., 1999; Osenbach and Harvey, 2001). As with the use of bupivacaine, it is difficult to establish an effective dose for this agent, and continuous monitoring and follow-up is required, both at the start of treatment and during subsequent use. The recommended dose for efficacy and avoidance of neurotoxicity ranges between 10 and 1000 g/day, taking into account that side effects are more significant at higher doses infused. The present, 2007, expert panel for intrathecal therapy recommends a maximum dose of 1.0 mg/day and a maximum concentration of 2.0 mg/ml (Deer et al., 2007). As with bupivacaine, these recommendations

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472

35.  Intrathecal Non-Opioid Analgesics for the Control of Pain

Table 35.3  Side effects caused by the use of clonidine Dry mouth Somnolence (sleepiness) Dizziness Constipation Tiredness Headache Nervousness

Possible causes for this rebound effect are failure to refill the infusion system in a timely manner, infusion pump failure, catheter dysfunctions or obstruction to the catheter tip, as in tip granuloma. The 2007 expert consensus panel recommends that clonidine be used as an adjuvant medication with a primary opioid such as morphine and hydromorphone or non-opioid ziconotide as a line 2, 3, and 4 medication (Deer et al., 2007).

Decreased sexual ability Stomach upset

Other intrathecal agents

Vomiting Fainting

Ziconotide

Altered heart rate Edema in lower limbs

H2N

Source: Hassenbusch et al., 2002. John Wiley & Sons Ltd

O H2N

are made to prevent the formation of granuloma. Although it appears that clonidine has a sparing effect on the development of granuloma in dogs (Yaksh et al., 2003), the advent of granuloma has been reported, even when clonidine was used in conjunction with an opioid (Toombs et al., 2005). The intrathecal use of clonidine is not without the advent of side effects (Table 35.3). The predominant side effects reported in both animals and humans are dose-dependent. These side effects observed are supraspinal, spinal and/or cardiovascular effects (bradycardia and/or blood pressure changes) (Claes et al., 1998; Gautier et al., 1998, Mercier et al., 1998; De Kock et al., 1999; Mercadante, 1999; Siddall et al., 2000). The most frequently occurring side effect of intrathecal clonidine is arterial hypotension. The onset of hypotension from intrathecal clonidine is usually gradual and dose-dependent. This onset starts with orthostatic systolic hypotension at low doses and, as the dose of intrathecal clonidine is increased, systolic hypotension develops, although it may disappear over time. If the dose of intrathecal clonidine is increased slowly or the patient is maintained on the same dose for long periods of time, hypotension does not appear to develop, and in some patients, especially in those with higher dosing of intrathecal clonidine, blood pressure levels might even become higher than the levels seen at the start of therapy. Bradycardia, if it occurs, usually appears late and always after hypotension. Other side effects that have been related to the use of this drug are confusion, somnolence, fatigue, and headache. The possible occurrence of rebound hypertension when the clonidine is discontinued should not be forgotten (Rupp et al., 1996; Kroin et al., 2003).

O

S O

N H

O

H N

N H

O

N H

N H

S

OH

NH

O

H N O

NH H2N

NH

NH

OH

O

NH

O

O H2N

S

O

HN

H N

OH HO

HN O

O O

H N

N H

O

O

S O

H N

H N

N H

O

O

O

NH

N H

O

O

H N

OH

NH NH

HO

O

H N

N H

S S O

H2N

H2N

S H2N

NH

NH2

O O

NH HO O

H-Cys-Lys-Gly-Lys-Gly-Ala-Lys-Cys-Ser-Arg-Leu-Met-Tyr-Asp-Cys-CysThr-Gly-Ser-Cys-Arg-Ser-Gly-Lys-Cys-NH2

Ziconotide is a new-generation intrathecal drug that was approved by the FDA in 2004 after exhaustive animal and human safety and efficacy studies. It was known as SNX-111 in early clinical trials and is currently marketed under the brand name of Prialt. Ziconotide is an analog of the  conopeptide, obtained from the venom of a giant marine snail called Conus magus. This snail captures its prey by shooting out an appendix that secretes venom to paralyze its victim, which is then swallowed. This conopeptide blocks N-type calcium channels, preventing nerve transmission. The calcium channels are primarily located in laminae I and II, where the presynaptic sensory nerve endings are found. Regulation of neuronal excitability and release of the different neurotransmitters depends on influx

IVB. infusional therapies for pain



Other intrathecal agents

of calcium through calcium channels. Ziconotide is a much more potent blocker of calcium channels than morphine and so this drug offers other alternatives for producing analgesia (http://en.wikipedia. org/wiki/Ziconotide). Three clinical trials have been conducted to demonstrate its utility in the treatment of refractory chronic pain. The first was conducted between 1996 and 1998 by Staats et al. (2004) in patients with pain from cancer or AIDS. This was a double-blind, placebo-controlled trial conducted at 32 centers in the USA, which included 111 patients. Analgesic results were good, with moderate to complete pain relief in 52.9% of patients of the ziconotide group compared with 17.5% in the placebo group. However, the limiting factor for its use was the large amount and variety of adverse effects. The second clinical trial was conducted by Wallace et al. (2006) in 255 patients with chronic noncancer pain (169 in the ziconotide group and 86 in the placebo group). It also showed significantly superior analgesia in the ziconotide group, and as in the previous study, the high incidence of ziconotide-associated adverse effects (abnormal gait and vision, nausea, nystagmus, urinary retention, and vomiting) was a limitation for chronic therapy. One of the conclusions of this study was that very rapid titration of the daily dose clearly increased the incidence of adverse effects. The third clinical trial was published by Rauck et al. (2006). It was also a double-blind, placebocontrolled trial and included 220 patients with chronic pain (112 in the ziconotide group and 108 in the placebo group). The mean dose at the end of the study was 0.29 g/hour (6.96 g/day). The ziconotide group obtained significantly superior analgesia than the placebo group. The trial recommended slow titration of the daily dose of the drug. The stability of ziconotide in present intrathecal delivery systems is an important clinical issue. Oxidation of the methionine sulfoxide form of ziconotide is known to result in the degradation of ziconotide. Admixtures that are prepared using a powdered opioid agent and are sparged (to add a gas, in this instance, nitrogen) to remove or decrease the presence of additional dissolved oxygen, should show enhance stability. For this reason, both Elan Pharmaceuticals, Inc., the manufacturers of ziconotide (Prialt) and the 2007 Polyanalgesic Conference Expert Panelists recommend sparging (with nitrogen) admixtures containing ziconotide plus either powdered morphine or hydromorphone in lieu of using commercial solutions (Deer et al., 2007). Ziconotide, at less than 1 g/ml is not very stable, but is stable at concentrations greater than 1 g/cc. Stability is also an issue when certain agents are compounded for clinical use (Trissel, 2000). Morphine and

473

hydromorphone are known to accelerate the rate of ziconotide degradation, so combinations of ziconotide with lower concentrations of the compounded opioid agent are expected to be more stable. Shields et al. (2005) showed that when ziconotide is added to morphine or hydromorphone at 25 g/ml, the ziconotide pump concentration with morphine declined to 79% of initial in 17 days, and to 88% of initial after 25 days with hydromorphone. Ziconotide concentrations in control vials stored at 37°C displayed similar rates of decay, but vials stored at 5°C exhibited no ziconotide loss. A statistical evaluation of the two combinations shows ziconotide–hydromorphone retaining 80% stability for 40 days (extrapolated), compared to 15 days for ziconotide–morphine. Morphine and hydromorphone were stable in the presence of ziconotide under all conditions. As stated above, when ziconotide at 25 g/ml is added to bupivacaine, 5 mg/ml, the bupivacaine is quite stable, retaining 99.4% of its original concentration at 30 days, but the stability of the ziconotide was affected, retaining only 80% of its initial concentration at 30 days (Shields et al., 2007a). Ziconotide, at 25 g/ ml, when added to clonidine at 2 mg/ml was 90% stable for 60 days; however, when added to clonidine– morphine, its stability decreased to 70% for 20 days (Shields and Montenegro, 2007). The 2003 Polyanalgesic Consensus Conference called for future studies to evaluate the stability of ziconotide admixtures with lower concentrations of morphine and hydromorphone (30 mg/ml) that fall below the maximum recommended dosage for these two opiates (Bennett, Burchiel et al., 2000). In theory, because fentanyl has higher intrinsic analgesic activity than morphine, a relatively smaller amount of this drug combined with ziconotide should show greater stability. However, future research is needed to determine the stability of fentanyl combined with ziconotide in an intrathecal admixture. Clonidine, 2 g/ml, added to ziconotide is quite stable, but bupivacaine added to ziconotide shows slightly less stability. Ziconotide/baclofen admixtures revealed 80% stability through 30 days, rendering this admixture somewhat more stable than a combination containing morphine and ziconotide (Shields et al., 2005). Combinations of morphine or hydromorphone with bupivacaine are known to be stable (Hildebrand et al., 2001). Because of its efficacy, because of the extent of type A data supporting its efficacy, because of its safety (to this date, no human has developed intrathecal granuloma with its use), and because of the absence of a withdrawal syndrome when the agent is suddenly stopped, the polyanalgesic consensus conference

IVB. infusional therapies for pain

474

35.  Intrathecal Non-Opioid Analgesics for the Control of Pain

of intrathecal therapy experts has recommended that intrathecal ziconotide be a line 1 agent to be used alone or in an admixture with other agents (Deer et al., 2007). Based on expert opinion, this panel also suggested that the recommended starting dose of 2.4 g/ day be reduced to 0.5–1 g/day to prevent unwanted side effects. They suggested a treatment plan of “starting low and going slow.”

Ketamine NHMe O CI

The n-methyl, d-aspartate (NMDA) receptor is, together with AMPA (adenosine monophosphate), the most important excitatory receptor in the nervous system, since glutamate, the main excitatory amino acid in the central nervous system, exerts its action when it is coupled with them (http://en.wikipedia. org/wiki/Glutamate). The NMDA receptor is possibly the most interesting glutamate receptor in terms of physiology and pathology (Carpenter and Dickenson, 1999). Occupation of these receptors by glutamate depolarizes the membrane and increases intracellular calcium, as well as Na and K. There are numerous agents that can reduce the amount of calcium released and thus reduce the action of glutamate. These drug classes include the following: competitive blockade of the receptor by drugs such as AP5 (http://en.wikipedia.org/wiki/APV), CPP, and CGS19755 (Millan et al., 2000) l blockade of the channel by drugs such as ketamine (http://www.bristol.ac.uk/synaptic/info/ pharmacology/NMDA.html) l Memantine (Carpenter and Dickenson, 1999), MK801 (Muallã et al., 1993; Yoon, Choi et al., 2005), or CNS5161 (Walters et al., 2002) l blockade of glycine, the coagonist required for opening of the channels by drugs such as 7-Cl-kynurenic acid (Mennini et al., 1997) or the drug ACEA 1021 (Lutfy and Weber, 1996).

great majority of agents that have been synthesized interfere with NMDA receptor function and are usually dose-dependent noncompetitive antagonists (Bion, 1984; Bormann, 1989; Chen et al., 1992; Coderre and Melzack, 1992; Dunbar and Yaksh, 1996; Chaplan et al., 1997; Dunbar and Pulai, 1998; Burton et al., 1999). There is only one study analyzing the stability and compatibility of ketamine (Walker et al., 2001). The study shows the stability of the drug in combination with hydromorphone for a period of 24 days at room temperature. Few data exist for the use of ketamine within a clinical protocol of intrathecal infusion. We only found two studies on its clinical utility in the past 6 years. Satisfactory results were obtained with the use of ketamine in both studies, both in the case of treatment of neuropathic pain (Sator-Katzenschlager et al., 2001) and in the case of refractory visceral pain that required the combination of four intrathecal drugs (Stotz et al., 1999). The use of this type of agent is promising because it is implicated at the heart of the metabolic processes of tissue and nerve injury pain processing and opioid tolerance. The principal problem with this agent is its poor safety profile. Vascular distribution of these agents may cause supraspinal side effects at therapeutic doses similar to those found when they are used systemically (sedation, personality changes and hypermobility). Experimental studies of spinal administration have found a certain degree of inflammation and injury to brain parenchyma with its intrathecal use (Martin et al., 1997). The 2007 expert consensus panel, based on the safety profile of this agent in animal studies, only recommends that ketamine be used at end of life when all other agents have failed (Deer et al., 2007).

Baclofen

l

The great interest raised by the development of agents affecting this receptor is due to their implication in the plasticity of the nervous system. The

O N O

CI

Baclofen (the B4-chlorophenyl derivative of gammaaminobutyric acid) was introduced for the treatment of spasticity as a stereospecific agonist of the gamma-aminobutyric acid (GABA) receptor, type B. It is capable of crossing the blood–brain barrier and

IVB. infusional therapies for pain



Other intrathecal agents

causes inhibition of mono-and polysynaptic excitation of spinal motor neurons and interneurons, probably mediated by an action associated with voltagedependent Ca channels and a reduction in the release of facilitatory neurotransmitters. It exerts its action at the presynaptic level by inhibiting the release of excitatory neurotransmitters, although when high concentrations are attained in the central nervous system, it may also cause its action at the postsynaptic level by the same mechanism (Davidoff, 1985; Albright et al., 1991; Becker et al., 1997). Because of its low lipid solubility, even in high doses oral baclofen does not cross the blood–brain barrier and is unable to reach its site of action or, if it does, it does so in too low of a concentration to alleviate spasticity (Yoshiharu et al., 1997). The high plasma concentrations of oral baclofen required to achieve the necessary concentrations in the CNS may be the origin of the side effects caused by the drug. Intrathecal baclofen occupies GABA-B receptors in the spinal cord and is a safe and effective treatment for spasticity, minimizing the side effects of its oral use due to the low plasma concentrations attained (Knutsson et al., 1974). The drug has been shown to be stable at room temperature in combination with clonidine, retaining 99% of its initial concentration (Goodwin et al., 2001) and stable with ziconotide (Shields and Montenegro, 2007). In a later study, Shields et al. (2007b) showed that baclofen stability was not affected by the addition of ziconotide at 25 g/ml. However, the stability of the ziconotide was affected and was concentrationand preparation-dependent by this admixture. When the ziconotide at 25 g/ml was mixed with baclofen powder at 2.0 mg/ml, the stability of the ziconotide declined to 87.4% of its original concentration at 30 days, but when mixed with the commercially available concentrations of 1.5 ms/ml, the concentration at 30 days declined to 82.2% of its original concentration. Spasticity of spinal or supraspinal etiology is the main indication for intrathecal baclofen. There have been several inconsistent reports that baclofen is a priori antinociceptive in humans (Taira et al., 1995; Zuniga et al., 2000; Slonimski et al., 2004), but there are reports that baclofen is antinociceptive in animal models of neuropathic pain (Malan et al., 2002). In a rat model of neuropathic pain, the addition of intrathecal baclofen to spinal cord stimulation restored antinociception in a group of rats that did not respond to stimulation alone (Cui et al., 1998). The efficacy of baclofen has been demonstrated in various syndromes, all related to spasticity syndromes or dystonias (van Hilten et al., 2000; Gatscher et al., 2002; Zuniga et al., 2002). It is used in spasticity secondary to spinal cord injury or in patients with multiple

475

sclerosis or brain injury (Loubser and Akman, 1996; Nuttin et al., 1999; Ochs et al., 1999; Ordia et al., 2002). Most patients show an improvement in spasticityrelated symptoms with few side effects, which in all cases are dose-dependent. Initial dosing of baclofen is usually carried out in the first 60 days after implantation, followed by monthly dose increases (10–30% in adults and 5–15% in pediatric patients). The stable maintenance dose is usually achieved 6–12 months after pump implantation (Azouvi et al., 1996). Typical dosing of baclofen ranges from 20 to 77 g/day, and a dose of 200– 300 g/day is common. The etiology of the adverse effects associated with the use of baclofen is controversial. There are two types of GABA receptors in the central nervous system: GABA receptor type A and GABA receptor type B. The commercially available form of baclofen for intrathecal use is a racemic mixture of the L and D isomers. The L isomer, acting on GABA receptor type B, is responsible for the antispastic effect and is associated with vasodilation, hypotension, and bradycardia. The D isomer of baclofen causes vasoconstriction and hypertension, which explains the diversity of possible side effects. Ascending diffusion of baclofen within the CSF causes an effect on the bulbar region, which manifests as hypotension, reflex tachycardia, and respiratory depression (Knutsson et al., 1974). The occurrence of this type of adverse events is related to the doses used. As with other drugs, two types of side effects may occur with baclofen infusion: effects related to the surgical procedure and pharmacological effects. A review by Ochs et al. (1999) showed that of 474 patients who had intrathecal baclofen pumps implanted until 1992, only 9 patients had to discontinue the treatment. The side effects of the drug itself are rarely the cause of treatment discontinuation (Table 35.4). Finally, three possible clinical situations should be considered as adverse events regarding the use of intrathecal baclofen: drug overdose, development of tolerance, and onset of a withdrawal syndrome. Drug overdose manifests as tiredness, hypotonia (especially rostral progression), arreflexia, blood pressure changes, respiratory depression, dizziness, seizures, coma, and even death (Ordia et al., 1996); tolerance has been shown to occur in 8% of patients with this type of infusion in an interval after implant ranging from 3 to 31 months. The withdrawal symptom to baclofen can be life-threatening and can be diagnosed when the patient develops a state of muscular hyperactivity with hyperreflexia, headache, dizziness, disorientation, seizures, fever, and hallucinations (Imran and Asif, 2004).

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476

35.  Intrathecal Non-Opioid Analgesics for the Control of Pain

Table 35.4  Side effects caused by the use of baclofen Central nervous system

Euphoria, excitement, depression, hallucinations, paresthesia, muscle pain, tinnitus, coordination disorder, tremor, dystonia, ataxia, nystagmus, strabismus, miosis, mydriasis, diplopia. Following intrathecal administration respiratory depression, amnesia, anxiety, hypothermia, burning sensation in feet, cerebellar dysmetria, stroke, depression, somnolence, dysphagia, and vertigo have been reported

Gastrointestinal system

Xerostomy, anorexia, dysgeusis, abdominal pain, diarrhea, blood in stool

Cardiovascular system

Palpitations, chest pain, diaphoresis, syncope. Following intrathecal administration, bradycardia, deep venous thrombosis, orthostatic hypotension, and edema of lower limbs may additionally occur

Urogenital system

Enuresis (urinary incontinence), urinary retention, dysuria, impotence, ejaculation dysfunction, nocturia, hematuria (rare). Intrathecal administration may also cause bladder spasms and sexual dysfunction

Respiratory system

Dyspnea, nasal congestion, pneumonia

Other

Rash, pruritus, ankle edema, weight gain, suicidal ideation or attempt, elevated transaminases, alkaline phosphatase, and glucose levels

Midazolam

use. In some cases, as discussed below, they are used only experimentally or to continue investigating the optimum doses or specific indications for each drug.

N

H3C N

•HCI CI

Gabapentin

N

CH2 NH2

F

CH2 CO2 H

Midazolam is a benzodiazepine that exerts its effect via the GABA receptor type A, unlike baclofen which acts on the GABA receptor type B. When a bolus of midazolam is injected into the CSF, it produces analgesia of long duration, and probably has a synergistic effect with bupivacaine (Nishiyama and Hanaoka, 2003). No studies have been conducted on the stability of the drug or its compatibility with the infusion pump, but there are some experimental studies in animals and humans that have demonstrated the safety of the drug when it is administered in the intrathecal space (Goodchild and Noble, 1987; Erdine et al., 1999; Nishiyama et al.,1999; Nishiyama and Hanaoka, 2001; Canavero et al., 2006; Johansen et al., in press). Because of its obvious neurotoxicity in animal models and because there is no type A or B evidence for its safety and efficacy, the polyanalgesic consensus expert panel for 2007 recommends its only being used at end of life (Deer et al. 2007). Other agents such as gabapentin, adenosine, ketorolac, neostigmine or octeotride or even tricyclic antidepressants are examples of agents used intrathecally for experimental purposes (Deer et al., 2007). These agents are proposed as last line agents for intrathecal

Gabapentin, an anticonvulsant, appears to act upon voltage-dependent calcium ion channels at the postsynaptic dorsal horns and in turn interrupts the events associated with neuropathic pain sensation (Cheng et al., 2004; Coderre et al., 2005; Cheng et al., 2006). Gabapentin, when administered to supraspinal sites, produces antinociception via inhibitory action on NMDA receptors (Hara and Sata, 2007) and activates the descending noradrenergic system to produce analgesic effects following peripheral nerve injury (Yoon, Bae et al., 2005a; Takeuchi et al., 2007). Gabapentin has been evaluated in rodents when administered by bolus intrathecal injection (100– 1000 g), and was effective in alleviating allodynia and hyperalgesia (Hwang and Yaksh, 1997; Xiao and Bennett, 1997; Yoon and Yaksh, 1999). It is analgesic in patients with central sensitization, tissue injury, inflammation, and nerve injury (Rose and Kam, 2002). Intrathecal gabapentin caused a synergistic effect when used in combination with clonidine, ibuprofen, and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (Hassenbusch et al., 2004). This drug is compatible with present intrathecal systems, although further studies are needed in other species to determine the safety, toxicity and efficacy of the drug. Studies also need to be conducted in humans to determine the

IVB. infusional therapies for pain



477

Conclusions

compatibility and stability of the drug, as well as its efficacy for the treatment of somatic or neuropathic pain (Bennett, Deer et al., 2000). Gabapentin should only be used by experimental protocol (Deer et al., 2007).

Adenosine NH2 N N N

N

HOCH2 H H

O H H

OH

OH

Adenosine, a putative neurotransmitter, is the decarboxylation product of the amino acid arginine and is known to be involved in antinociception at the spinal level (Kekesi et al., 2004). Adenosine is involved in modulating nociceptive transmission at the spinal level via four types of spinal adenosine receptors, A1, A2A, A2B, and A3 (Yoon, Bae et al., 2005a; Yoon, Bae et al., 2005b; Yoon et al., 2006). It is an agent that is classified among the drugs that interfere with NMDA receptor function, and has a pharmacological spectrum of action similar to that explained for other agents in its class (Rupp et al., 1996). Adenosine and its analogues cause antinociception after both systemic and IT delivery administration in animal models (Rane et al., 2004). Intrathecal adenosine has been used to treat neuropathic pain in humans. Belfrage et al. (1999) performed an open-label study of intrathecal (IT) adenosine administration for the evaluation of efficacy and safety in 14 patients with chronic neuropathic pain with tactile hyperalgesia and/or allodynia. The effects of IT adenosine (500 g [n  9] or 1000 g [n  5]) were studied. Spontaneous and evoked pain (visual analog scale score 0–100) and tactile pain thresholds were assessed before and 60 min after injection. The injection caused transient pain (60 min) in the lumbar region in five patients, however there were no other side effects. Spontaneous and evoked pain was reduced (median score from 65 to 24 [p 0.01] and from 71 to 12 [p 0.01], respectively). Areas of tactile hyperalgesia/allodynia were reduced (median reduction

90%; p 0.001). Twelve patients experienced pain relief (median 24 hours). The authors concluded that IT adenosine transiently causes lumbar pain in a subgroup of patients and may reduce various aspects of chronic neuropathic pain. In several phase 1 studies, Eisenach et al. (2002) studied 65 volunteers in two separate trials. Blood pressure, heart rate, end-tidal carbon dioxide, and sensory, motor, and reflex neurologic functions were examined for 24 h after injection of intrathecal adenosine doses of 0.25–2.0 mg (25 subjects) and either placebo or adenosine at 2 mg (40 subjects). The authors concluded that their data supported further investigation of intrathecal adenosine for analgesia in humans and suggested that adenosine does not produce a high incidence of severe side effects. Despite these encouraging results, in a study (n  90) in females undergoing elective abdominal hysterectomy, IT adenosine, 1000 g, was not effective in relieving postoperative pain when administered 30 min before delivery of anaesthesia (Sharma et al., 2006). A comparative study on intravenous versus intrathecal adenosine reported that intrathecal, but not intravenous adenosine was effective in reducing allodynia and mechanical hyperalgesia (Eisenach et al., 2003). The Polyanalgesic Conference, 2007, only recommends the use of intrathecal adenosine as part of a study protocol and only after failure of the use of more conservative agents (Deer et al., 2007). Octeotride, a derivative of somatostatin, has been studied for the treatment of chronic pain (Penn et al., 1992; Deer et al., 2005). In the study by Deer, the drug was shown to be safe, but it did not appear, in a wellcontrolled study, to demonstrate efficacy superior to placebo.

Conclusions We have presented preclinical and clinical information on the intrathecal use of non-opioid analgesics. Most of the published clinical material on the use of intrathecal non-opioid analgesics, either alone or in combination with opioid intrathecal analgesics, is anecdotal and not well controlled, with some exceptions as stated above, including bupivacaine, clonidine, and ziconotide. Well-controlled studies of these intrathecal agents are needed before hard and fast recommendations can be made regarding their use. In spite of the paucity of data, these agents are known to be clinically effective and several consensus conferences of experts have recommended their use with caution (Bennett, Burchiel et al., 2000; Bennett, Serafín et al. 2000; Hassenbusch et al., 2004; Deer et al., 2007).

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Ziconotide is the only non-opioid that is approved in Europe and the USA for intrathecal use. It is the most widely studied agent for intrathecal use and when used either alone or in conjunction with an opioid, is safe and efficacious. Polyanalgesia Conference, 2007, has moved this agent to a line 1 agent, either alone or as an admixture with other agents. Stability of this agent is an issue and we have presented data of its stability with and without other agents.

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Xiong, Z. and Strichartz, G.R. (1998) Inhibition by local anesthetics of Ca2 channels in rat anterior pituitary cells. Eur. J. Pharmacol. 363 (1): 81–90. Yaksh, T. (1985) Pharmacology of spinal adrenergic systems which modulate spinal cord nociceptive processing. Pharmacol. Biochem. Behav. 22: 323–30. Yaksh, T.L. and Rudy, T.A. (1976) Analgesic mediated by direct spinal action of narcotic. Science 192: 1357–8. Yaksh, T.L., Horais, K.A., Tozier, N.A. et al. (2003) Chronically infused IT morphine in dogs. Anesthesiology 99: 174–87. Yamashita, A., Matsumoto, M., Matsumoto, S. et al. (2003) A comparison of the neurotoxic effects on the spinal cord of tetracaine, lidocaine, bupivacaine, and ropivacaine administered intrathecally in rabbits. Anesth. Analg. 97: 512–19. Yoon, M.H. and Yaksh, T.L. (1999) The effect of intrathecal gabapentin on pain behavior and hemodynamics on the formalin test in the rat. Anesth. Analg. 89: 434–9. Yoon, M.H., Bae, H.B. and Choi, J.I. (2005a) Antinociceptive interactions between intrathecal gabapentin and MK801 or NBQX in rat formalin test. Korean Med. Sci. 20 (2): 307–12. Yoon, M.H., Bae, H.B. and Choi, J.I. (2005b) Antinociception of intrathecal adenosine receptor subtype agonists in rat formalin test. Anesth. Analg. 101 (5): 1417–21.

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Yoon, M.H., Bae, H.B., Choi, J.I., Kim, S.J., Chung, S.T. and Kim, C.M. (2006) Roles of adenosine receptor subtypes in the antinociceptive effect of intrathecal adenosine in a rat formalin test. Pharmacology 78 (1): 21–6. Yoon, M.H., Choi, J.I., Park, H.C., Bae, H.B., Jeong, S.W. and Jeong, C.Y. (2005) Analysis of interactions between serotonin and gabapentin or adenosine in the spinal cord of rats. Pharmacology 74 (1): 15–22. Yoshiharu, D., Nozawa, K., Yamada, S., Yokoyama, Y. and Kimura, R. (1997) Quantitative evaluation of brain distribution and blood– brain barrier efflux transport of probenecid in rats by microdialysis: possible involvement of the monocarboxylic acid transport system. Pharm. Exp. Ther. 280 (2): 551–60. Zuniga, R.E., Perera, S. and Abram, S.E. (2002) Intrathecal baclofen: a useful agent in the treatment of well established complex regional pain syndrome. Reg. Anesth. Pain Med. 27: 90–3. Zuniga, R.E., Schlict, C.R. and Abram, S.E. (2000) Intrathecal baclofen is analgesic in patients with chronic pain. Anesthesiology 92: 876–80.

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C H A P T E R

36

Compounding Intrathecal Drugs Richard L. Rauck

o u tli n e Introduction

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Regulations

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What is Compounding?

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Legal Side of Compounding

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History

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Considerations for Compounded  Formulations for Intraspinal Pumps

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Important Issues for Intrathecal  Drug Compounding

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Polyanalgesic Consensus Guidelines

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The United States Pharmacopoeia

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Summary

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Risk Levels

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References

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Introduction

General Chapter 797, 2008). Compounded sterile products intended for delivery into the central nervous system that are incorrectly prepared or contaminated can potentially produce catastrophic effects (Sasich and Sukkari, 2008). The issues surrounding the compounding of drugs for use in the intrathecal space are further complicated by the fact that the majority of preservatives (agents that could protect the solution from contaminants) produce neurotoxicity when injected into the subarachnoid space.

The only drugs currently approved in the USA by the Food and Drug Administration (FDA) for the intrathecal management of pain include preservativefree morphine sulfate solution Infumorph, Baxter; Astramorph, AstraZeneca) and ziconotide (Prialt, Elan). Concentrations of morphine greater than 25 mg/ml require compounded formulations. Ziconotide is not compounded when used as monotherapy unless it is diluted or otherwise altered. Combinations of morphine and ziconotide, and other drugs and combinations of drugs require compounded formulations. Compounding demands impeccably clean facilities with high air quality standards, personnel trained in the specifics of aseptic practices, and thorough knowledge of sterilization and solution stability issues (USP

Neuromodulation

What is compounding? Drug compounding is defined as the mixing of ingredients to prepare a medication for human use. This may include a single drug or multiple drugs. Compounding

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also includes dilution, repackaging, admixture, reconstitution, and many other manipulations of sterile products. Improper procedures in the compounding process can lead to differing types of problems. For many routes of drug delivery these risks may be minor on not life-threatening. Incorrectly prepared or contaminated compounded sterile products that are intended for administration into the central nervous system must be considered particularly dangerous.

History Pharmaceutical compounding dates to ancient times when hunter–gatherers developed knowledge of medicinal properties of organic and inorganic material in their environment. Early civilizations compounded oils from plants and animals, made ointments for wounded patients, and perfumes (Coyne et al., 2003; Compounding Wikipedia). Early religious texts, including the Bible, list many compounded drugs. Medieval Muslim physicians also recorded their methods for compounding drugs. Modern pharmacy is often traced to the early nineteenth century with the isolation of various compounds from coal tar for production of synthetic dyes. This later led to antibacterial sulfa drugs and phenolic compounds. Pharmacists began raising, preparing, and compounding crude drugs such as opium. These drugs were commonly extracted using water or alcohol to form the desired delivery system (Compounding Wikipedia). As pharmacists developed the ability to isolate medications from crude drugs, drugs companies began to form. Thus, pharmacists had the skill set to compound the preparations of the drug companies during the early years, but they were only able to do so on a small scale and in an efficient manner. Pharmaceutical companies took advantage of the compounding pharmacists’ skills and leveraged it with economies of scale. The twentieth century saw the death of several patients from sulfa drugs that used ethylene glycol as a base. The Food and Drug Administration was formed in 1938 by the US government, and regulations were imposed on drug companies to ensure that new medications that were brought to the public would be safe (Tamer and Sweet, 2002). During this decade it was estimated that over 80% of all prescriptions dispensed from a pharmacy were compounded drugs. By the 1950s and continuing through the 1960s big drug companies grew powerful and dominated the pharmaceutical business. Pharmaceutical compounding became less common. Eventually, physicians realized

that limited dosage strengths, limited dosage forms, drug shortages, intravenous admixtures, discontinued drugs, orphan drugs, and other clinical situations demanded compounding to meet the needs of special patient populations. The compounding pharmacist was “reborn” and currently, in 2006, it is estimated that greater than 30 million compounded prescriptions were dispensed (Compounding Wikipedia; Nordenberg, 2000). This number excludes admixtures and injectable drugs compounded in the hospitals across the USA. Intrathecal compounding of drugs has developed along many of these paths. For years, only morphine came in a suitable form for intrathecal injection. Even morphine requires compounding for the majority of patients because of its limited concentration (Infumorph: 25 mg/ml). After two decades of preclinical and clinical research and development, Prialt was approved as the second available, on-label drug for intrathecal monotherapy. As implanters and physicians managing intrathecal delivery systems became familiar with different drugs such as clonidine, hydromorphone, bupivacaine, fentanyl, and others, compounding of intrathecal drugs grew into a more formalized business. Small and mediumsized compounding pharmacies began providing the above mentioned drugs and others in many different dosage strengths and combinations to prescribing physicians. The safety implications of this widespread compounding will be discussed in this chapter along with other issues for the managing physician to consider.

Important issues for intrathecal drug compounding Most commercially available, sterile, injectable drugs that have FDA approval and are labeled for other routes of administration would not be considered acceptable for intrathecal use. The most common reason for a drug’s unacceptable nature for intrathecal consideration is the preservatives or other excipients that are contained with the drug. These preservatives and/or excipients (an inactive ingredient added to a drug to dilute it or to give it form or consistency) are often neuro­toxic, especially when delivered intrathecally. Benzyl alcohol, phenol, formaldehyde, sodium metabisulfite and methylparaben are among the preservatives and antioxidants reported as neurotoxic. It must also be remembered that certain formulations that are labeled as preservative-free may contain buffers or other excipients that can be incompatible with the delivery system used to administer the drug into the intrathecal space. For example, acetate buffers, sodium metabisulfite, ethanol

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The united states pharmacopoeia

concentrations of 10% or greater, pH of the solution below 4 or above 9, and certain drug products have all been reported as incompatible with the SynchroMed (Medtronic) brand of implantable pump. Similarly, dopamine, mitomycin C, cyclosporine A, apomorphine, meperidine, octreotide pH, less than 4.11, interleukin II, with 25 mg human serum albumin (HAS)/ml and diamorphine have been reported as incompatible with, and cause malfunction of the SynchroMed infusion system. This list is not considered exhaustive by Medtronic, Inc. (Minneapolis, MN) which has clearly not tested all injectable drugs with its intrathecal delivery systems (Medtronic Educational Brief October 2002/2.03a; MHRA Medical Device Alert 2003/007/023/121/003, issued October 2003). Drugs approved by the FDA for intrathecal injection undergo rigorous preclinical (animal) testing. While efficacy is important, safety is especially important in preclinical tests for intrathecal drugs. FDA currently requires small and large animal tests that demonstrate no neurotoxicity. This must be demonstrated with both single injection, and more importantly, repeat injections and/or continuous infusion. Spinal cords are subjected to direct histopathologic sectioning to rule out direct neurotoxicity. Drugs are commonly tested at different concentrations, and safety must be shown at concentrations exceeding the final, approved strength/concentration of the agent tested. The issue is that compounded concentrations can, and, in the case of intrathecal drugs often do, exceed the tested concentration during the approval process. A drug that has been shown to be safe at one concentration does not confer safety at all concentrations. This is a particular concern for intrathecal drugs where the margin of neurotoxicity safety may be narrow.

The united states pharmacopoeia The United States Pharmacopoeia (USP) and the American Society of Health System Pharmacists (ASHP) have independently issued standards on compounded sterile products that have clinical, legal, and practical significance (American Society of HealthSystem Pharmacists, 2003; Hung, 2004a; USP General Chapter 797 , 2008). These standards apply to compounding of solutions by various routes including neuraxial administration. These standards or guidelines are updated frequently with revisions and updated bulletins published online. The websites for the most up-to-date information from these respective agencies are: www.usp.org and www.ashp.org.

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The most relevant chapter of the US Pharmacopoeia regarding compounding is Chapter 797  “Pharmace­ utical Compounding Sterile Preparations” (USP General Chapter 797, 2008). The facts and guidelines are applicable to all compounded sterile products (CSPs). The most recent chapter can be downloaded free in a pdf file without purchase of the entire book at www. usp.org/pdf/EN/USPNF/generalChapter797.pdf. This includes the recent revision bulletin. Those individuals interested in staying current are encouraged to check the website frequently for updates. The ASHP Guidelines on Quality Assurance for Pharmacy-Prepared Sterile Products (“ASHPGuidelines”) apply to pharmaceutical services on the topic of compounded products. Hospital and pharmacy accreditation may be affected by noncompliance by either the USP or ASHP guidelines (American Society of Health-System Pharmacists, 2003). The USP and ASHP guidelines define CSPs to include medications prepared by dilution, admixture, repackaging, or reconstitution that includes sterile preparations prepared according to the manufacturer’s labeled instructions, if the original contents are exposed to potential contamination. By applying USP Chapter 797, a compounded sterile product includes preparations prepared according to the manufacturer’s labeled instructions and other manipulations when preparing sterile products that expose the original contents to potential contamination, as well as preparations that contain non-sterile ingredients or employ non-sterile components and devices that must be sterilized before use. By applying the ASHP guidelines, compounding is further defined as mixing of ingredients to prepare a medication for patient use, including dilution, admixture, repackaging, reconstitution, and other manipulations of sterile products. USP 797 became effective in January 2004 and has undergone updating along with revision bulletins. The most current revisions became effective on June 1, 2008. Its impact continues to unfold on the practice of compounding. State pharmacy boards have primary responsibility for interpreting and enforcing the USP standards. At the national level, the Food and Drug Administration (FDA) may choose to take enforcement action if they believe the compounding pharmacy is engaged in drug manufacturing. Other chapters and sections of the US Pharmacopoeia are also of interest to the compounding pharmacist. They include Chapter 795 Pharma­ceutical Compounding – Nonsterile Preparations, Chapter 1075 Good Compounding Practices, and Chapter 1160 Pharmaceutical Calculations in Prescription Compound­ing. In addition, there are over 200 monographs related to pharmacy-compounded drugs in the

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US Pharmacopoeia-National Formulary (US Food and Drug Administration, 2003).

Risk levels The USP and ASHP guidelines impose similar requirements, despite minor differences in the wording and structure of the document (American Society of Health-System Pharmacists, 2003; USP General Chapter 797, 2008). Both sets of guidelines comprise three risk levels, with the risk level primarily based upon the probability of microbial or foreign material contamination, and tailor the requirements to the risk level. In earlier editions, both the USP and ASHP guidelines classified any CSP that did not contain a broad-spectrum antibacteriostatic substance and was administered over several days (for example via an external or implanted infusion device) as a minimum Level 2 (Medium Risk). Current publications state that Level 3 (High Risk) conditions are present in all “CSPs that lack effective antimicrobial preservatives.” This would apply to all preservative-free compounded drugs and drug combinations for intrathecal delivery. Level 3 (High Risk) has always included products exposed to an inadequately controlled environment, even if the preparation was sterilized before use and products prepared from non-sterile ingredients or non-sterile components, containers, or equipment before terminal sterilization (American Society of Plastic Surgeons; American Society for Aesthetic Plastic Surgery, 2006; USP General Chapter 797, 2008). Using these standards, no compounded sterile, preservative-free preparation administered via an intrathecal delivery system is classified at Level 1 (Low Risk). In earlier publications, some compounded preparations were classified at Level 2 (Medium Risk). An example might have been the one-time, closed-system transfer of a sterile, preservative-free medication from an ampoule or vial to a sterile syringe, without dilution or admixture being considered a Level 2 (Medium Risk). In current publications all compounded drugs for intrathecal delivery are classified as Level 3 (High Risk). Preparations of a sterile solution from a nonsterile powder are always considered at a Level 3 risk (USP General Chapter 797 , 2008).

Regulations Compounding pharmacies are regulated by federal and state agencies (Breaux, 1998; Thompson, 2003). State boards of pharmacy in each of the 50 states and

the District of Columbia license and regulate compounding pharmacies. These license requirements and the regulations imposed differ from state to state. However, pharmacies across the country follow the guidelines of the USP. Federal compliance is handled by the FDA (Crawford, 2002; Young, 2002). As described in the next section, considerable strife currently exists between compounding pharmacies and federal guidelines. While it is a changing landscape at the present time, compounding pharmacies are considered exempt from some FDA regulations. They must remain state-compliant and compound drugs pursuant to valid prescriptions. The FDA did win a recent court battle that allows them to continue inspecting the facilities that compound or supply manufacturers with active pharmaceutical ingredients. The controversy that has led to many of the court battles between FDA and compounding pharmacies centers on regulatory jurisdiction. The FDA has taken the position that all compounded drugs are new drugs and should therefore be considered illegal (James, 1997). Their position is that compounded drugs cannot be considered safe since they have not undergone the degree of testing of approved and marketed drugs. Questions about some compounded intrathecal drugs and drug combinations raise FDA concerns. Are intrathecal compounded drugs at higher concentration as safe as drugs compounded at lower concentrations? What scientific evidence supports the compatibility of intrathecal drugs currently being compounded together? What is the stability of different drug combinations? These are only a few of the concerns of the FDA. The FDA also expresses concern that some compounding pharmacies are acting as large-scale manufacturers of new drugs, a condition listed in Box 36.1 that would make them subject to the many rules and regulations of any commercial drug maker. The FDA has stated that it will use its “enforcement discretion” in determining when a compounding pharmacy has violated the compliance policy guidelines. The FDA sends warning letters (see website address below) to compounding pharmacies who they believe have not been compliant. The International Academy of Compounding Pharmacies has been a vocal body that supports drug compounding and compounding pharmacies. They have taken a leadership position and repeatedly express concerns about the role of FDA in regulating compounding pharmacies. Their position is that compounding licenses and regulations should be a state issue and handled at the state level. In 2004 a group of eight pharmacy organizations joined together to create the Pharmacy Compounding Accreditation Board (PCAB). The board has created a

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Legal side of compounding

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Box 36.1

Pharmacy compounding: FDA’s position developed from the Compliance Policy Guide (CPG) 1. Compounding of drugs in anticipation of receiving prescriptions, except in very limited quantities in relation to the amounts of drugs compounded after receiving valid prescriptions. 2. Compounding drugs that were withdrawn or removed from the market for safety reasons. Appendix A provides a list of such drugs that will be updated in the future, as appropriate. (For updated information on Appendix A please visit the FDA website: http:// www.cfsan.fda.gov/~pn/cpgpn6.html) 3. Compounding finished drugs from bulk active ingredients that are not components of FDA approved drugs without an FDA sanctioned investigational new drug application (IND) in accordance with 21 U.S.C Section 355(i) and 21 CFR 312. 4. Receiving, storing, or using drug substances without first obtaining written assurance from the supplier that each lot of the drug substance has been made in an FDA-registered facility. 5. Receiving, storing, or using drug components not guaranteed or otherwise determined to meet official compendia requirements.

voluntary system of high quality standards for compounding pharmacies. Not all states have compounding pharmacies boarded by PCAB, although the majority have either a few representative pharmacies boarded or pending. Their website is found at www. pcab.info/. They acknowledge on their home page that all PCAB-accredited pharmacies and applicants will be required to comply with the official revisions (effective June 1, 2008) to USP 797 Chapter of the US Pharmacopoeia.

Legal side of compounding The US Food and Drug Administration (FDA) was established in 1938 with the passage of the Federal Food, Drug and Cosmetic Act in the same year. The FDA was formed, in part, to enforce the standards for manufactured drugs. Section 503A of the Federal Food Drug, and Cosmetic Act (FDCA) was added in 1997 by the Food and Drug Administration Modernization Act (FDAMA). A group of seven

6. Using commercial scale manufacturing or testing equipment for compounding drug products. 7. Compounding drugs for third parties who resell to individual patients or offering compounded drug products at wholesale to other state licensed persons or commercial entities for resale. 8. Compounding drug products that are commercially available in the marketplace or that are essentially copies of commercially available FDA-approved drug products. In certain circumstances, it may be appropriate for a pharmacist to compound a small quantity of drug that is only slightly different than an FDA-approved drug that is commercially available. In these circumstances, FDA will consider whether there is documentation of the medical need for the particular variation of the compound for the particular patient. 9. Failing to operate in conformance with applicable state law regulating the practice of pharmacy.

compounding pharmacists brought action against the FDA in November 1998 and the restrictions imposed by Section 503A against the practice of compounding. The original District Court found that the advertising restrictions of Section 503A violated the First Amendment of the Constitution but felt that the rest of Section 503A could be left in place. Subsequently, the Ninth Circuit Court of Appeals agreed that the advertising restrictions were unconstitutional, but went further and struck down Section 503A in its entirety (Harteker, 2001). The Supreme Court of America agreed to hear the case as Thompson v. Western States Medical Center. The opinion was issued on April 29, 2002 and Justice Sandra Day-O’Connor wrote for the five-vote majority. The government attorneys had argued that prior to FDCA all compounding was illegal and violated the “new drug” provisions in the FDCA. The Supreme Court disagreed and sided with the District Court that “Section 503A’s provisions regarding advertisement and promotion amount to unconstitutional restriction on commercial speech … .”

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While this decision was a direct affront to FDA authority on compounding drugs and compounding pharmacies in general, the Court recognized the role of FDA in this area. All members of the Court agreed that it was appropriate for the FDA to require largescale drug compounding to go through the new drug approval process. They did not accept the government’s position that all compounding was illegal and recognized the long-standing history of compounding and its value in serving special medical needs. After the end of Section 503A, the regulatory void did not last long. The FDA reissued (initial issue date was March 16, 1992) the Compliance Policy Guide (CPG) for staff and industry on May 29, 2002, exactly 1 month after the Supreme Court decision. The relevant section on compounding is found in Chapter 4, Sub Chapter 460, Section 460.200: Pharmacy Compounding. In determining how to enforce the policy of the FDA nine points were enumerated and are reproduced in Box 36.1. These points were designed for response when the FDA feels that “the scope and nature of a pharmacy’s activities raise the kinds of concerns normally associated with a drug manufacturer and result in significant violations of the new drug, adulteration, or misbranding provision of the Act … .” The FDA continues to maintain that it will defer to state authorities regarding less significant violations of the Act related to compounding. Since 2002 there have continued to be issues between FDA and compounding pharmacies. In 2005 the US Court of Appeals for the Third Circuit upheld a lower federal district court decision filed by Wedgewood Pharmacy that a compounding pharmacy was exempt from FDA inspections. Further, the Third Circuit stated that the FDA “could use prescription volume to gauge a compounding pharmacy’s eligibility for the exemption given to pharmacies that compound drugs in the normal course of their retail business.” In 2006 a US District Court judge in the Medical Center Pharmacy v. Gonzalez case issued a preliminary ruling that questioned the FDA’s jurisdiction over compounded medications. Whether this ruling will be appealed is unknown. The International Academy of Compounding Pharmacies and their executive director, L.D. King, state that the federal position on compounding of drugs is unfounded and state boards of pharmacy can deal with whatever patient safety issues may exist. One way to monitor FDA activity in the area of compounding is through the Center for Drug Evaluation and Research (CDER) web site: www.fda. gov/cder/pharmcomp/. Warning letters that have been sent by the FDA to compounding pharmacies are listed by year. For example, four letters were sent in 2007 and seven warning letters have been sent in the

first five months of 2008. It appears that none of these warning letters deals with compounding of intrathecal drugs. The 2008 letters all deal with “bio-identical” hormone therapy as it relates to menopausal women. It would seem prudent of any physician involved in intrathecal therapy to stay abreast of rulings and court cases involving the FDA and compounding pharmacies (Hung, 2004b; ACOG Committee Opinion No. 387, 2007). Those physicians who use compounding pharmacies may want to inquire as to how their pharmacy stays compliant with FDA considerations. Interplay continues between state pharmacy boards and the FDA, and one would expect that the playing field will continue to change and be challenged in the years ahead concerning the topic of compounding of drugs and the legal extent to which compounding can be performed.

Considerations for compounded formulations for intraspinal pumps Compounded drugs intended for intrathecal delivery represent a special class for consideration. As stated in this chapter, any intrathecal compounded drug is considered Level 3 (High Risk). This “highest risk” status reflects, in part, the sensitivity of neural tissue in the spinal canal to neurotoxins, endotoxins, excipients, preservatives, and many other compounds. The potentially catastrophic consequences of toxicity from poorly prepared compounded drugs, ill-conceived combinations of drugs, drugs of unsafe concentrations, or a variety of other situations are obvious to most clinicians. The spinal cord, the nerve roots emerging from the spinal cord, and the spinal fluid react to drugs, different combinations of drugs, and differing concentrations in unexpected fashion. Clinicians practicing in this area should stay current as new information becomes available. Preclinical testing of compounded drugs for intrathecal delivery constitutes the initial and vital step in determining the safety of an intrathecal drug. Morphine (Infumorph and Astramporph) and ziconotide (Prialt) represent the only drugs approved for long-term intrathecal therapy for pain and baclofen, for spasticity, is the only other intrathecal agent approved by the FDA. The process and cost of FDA approval exclude many intrathecal drugs from the commercial pathway of drug development. This does not mean that clinicians can inject any drug of theoretical interest into the spinal fluid. Preclinical testing in a small and large animal model should be sought whenever possible. The value of this testing has been discussed

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compounded formulations for intraspinal pumps

by Eisenach and Yaksh (2002). Absent sufficient animal testing, several drugs have been introduced in terminal cancer patients under dire clinical conditions. While these humanitarian conditions may be acceptable when other alternatives do not exist, extrapolation to larger populations of patients should only be considered when safety issues have been resolved. Combinations of drugs and drugs in differing concentrations represent additional challenges. Paracelsus, a German physician (1493–1541) and lay religion writer, wrote, “all things are poison and not without poison; only the dose makes a thing not a poison.” Thus, commonly used local anesthetics are injected intrathecally and safely on a daily basis by anesthesiologists but can be neurotoxic at different concentrations and under different circumstances. This “fact” has become well accepted with lidocaine and tetracaine. Whether it is true with bupivacaine is unclear. To date, there have been no reported cases of neurotoxicity with bupivacaine and the many different concentrations used for long-term intrathecal delivery. However, one can argue that sufficient preclinical testing has not been done to support the use of bupivacaine in higher concentrations. Other considerations, relevant to use of commercial formulations labeled for systemic (e.g., intravenous, oral) delivery, apply to compounded formulations intended for intrathecal delivery of drugs. These considerations exist in addition to the US Pharmacopoeia (USP) and the American Society of Health System Pharmacists (ASHP) sterile compounding recommendations and include the following (American Society of Health-System Pharmacists, 2003; USP General Chapter 797, 2008): 1. Avoiding preservatives, antioxidants and solubility enhancers, since they may be neurotoxic and/or incompatible with the delivery system. 2. Using buffers that are compatible with the delivery system. For example, acetate buffers are not compatible with the SynchroMed infusion system. 3. Using a pH that is physiologically appropriate and is consistent with the drug solubility and delivery system. Generally, one should consider a solution in the range of pH 4–8. For example, morphine and hydromorphone are most stable at lower pH (4–5), but a pH lower than 4 may degrade certain delivery system components. 4. Using solutions that are, ideally, isotonic with normal CSF (approximately 300 mOsm/l). The relatively poor mixing of the CSF compartment can result in prolonged exposure of spinal tissues adjacent to the tip of the catheter. Thus, solutions that are close to isotonic are preferred. The osmotic contribution of each analgesic and each excipient,

5.

6.

7. 8.

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such as sodium chloride or buffer ions, should be considered. Sterile water for injection may be a better diluent than sterile saline to achieve appropriate tonicity for solutions that contain multiple drug components or drug(s) at high concentration. Preparing the solution in a manner that does not alter the solubility of the constituents. The solubility of one agent may be affected by the presence of another. The order in which powdered components are dissolved, the choice of diluent, and the pH of the solution can all affect solubility. Solubility enhancers should be avoided, as they may be neurotoxic or incompatible with the delivery system. Verifying the chemical and physical stability of the preparation under relevant conditions in accordance with the USP and ASHP publications. Stability information on the most common formulations may be found in the published literature. Verifying the sterility of the preparation in accordance with the USP and ASHP publications. Ensuring appropriate control of bacterial endotoxins (pyrogens). Bacterial endotoxins are a safety concern, even for a product that is terminally sterilized, because sterilization does not remove endotoxins. Endotoxin-contaminated intrathecal preparations can induce aseptic meningitis. Validated bacterial endotoxin test methods for specific and commonly compounded analgesic preparations are reported in the literature (Trissel, 2000).

Polyanalgesic Consensus Guidelines The commercial market for intrathecal drugs is limited by many factors. The therapy has been reserved for patients with chronic pain refractory to other less invasive modalities. Therefore, commercial development of drugs has been virtually nonexistent, with Prialt (ziconotide) the only exception over the past two decades. Intrathecal gabapentin is currently in phase II testing and several other compounds are currently in phase I clinical testing. Hopefully, the future will find additional intrathecal drugs approved through the commercial development process of FDA. Until future drugs are commercially developed and FDA-approved, the majority of drugs and all intrathecal drug combinations for pain control are prepared by compounding methods and administered off-label. Can clinicians feel confident that the intrathecal therapy they provide is safe for their patients? Groups of

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clinicians who have extensive experience in the area of intrathecal drug delivery, clinical researchers with experience in intrathecal drug research, neuroscientists with extensive preclinical and clinical research experience with intrathecal drugs, and others have convened on several occasions to address the above question, among others. These groups had met in 2000, 2003, and 2007 in various locations (see previous chapters by Deer et al. (Chapter 32), Krames and Harb (Chapter 33) and Reig et al. (Chapter 35) on intrathecal drug delivery in this text regarding these polyanalgesic consensus conferences). These meetings have involved extensive literature reviews, discussions, and debates about a variety of intrathecal drug topics. Publications have resulted in peer-reviewed journals from the several consensus meetings that have convened (Hassenbusch et al., 2004). The 2003 meeting spent considerable time discussing the issue of intrathecal drug compounding. Updates were discussed during the 2007 meeting. While these guidelines should not be misconstrued as standard of care documents, they do provide clin­ icians with a resource to many of the questions and issues posed in this chapter.

Summary For the majority of practitioners who use intrathecal drugs for chronic pain management compounding represents the only mechanism to obtain the drugs and drug combinations necessary for some of their patients. The legal right to compound drugs, including intrathecal drugs, has been recently decided in a favorable way for compounding pharmacies by the US Supreme Court. The limits of compounding continue to be defined through the court system. Beyond legal issues clinicians need to be concerned about the safety of compounding intrathecal drugs for their patients (Williams, 2006). Guidelines such as the Polyanalgesia Consensus Guidelines are published to aid clinicians with state-of-the-art information about intrathecal drugs and drug combinations. Information changes between consensus guidelines and practitioners should stay abreast of new safety, compatibility, and stability publications. The clinician bears some responsibility for using ethical and respected compounding pharmacies. The attempt by the Pharmacy Compounding Accreditation Board to provide high-quality standards for compounding pharmacies will help clinicians feel comfortable that the pharmacy they use is compliant in this

area. Standards, regulations, guidelines, and continued scientific research ultimately lead to safer drugs and processes for our patients.

References ACOG Committee Opinion No. 387 (2007) Pharmaceutical compounding. Obstet. Gynecol. 110 (5): 1213–14. American Society of Health-System Pharmacists (2003) ASHP guideline on quality assurance for pharmacy-prepared sterile products. Am. J. Health Syst. Pharm. 60: 1440–6. American Society of Plastic Surgeons; American Society for Aesthetic Plastic Surgery (2006) Injectables and fillers: legal and regulator risk management issues. Plast. Reconstr. Surg. 118 (3 Suppl.): 129S–132S. Breaux, P.J. (1998) Application of federal law to compounding of prescription orders. J. La State Med. Soc. 150 (6): 275–8. Compounding-Wikepedia: www.wikipedia.org/wiki/compounding (accessed 5 December 2008) Coyne, P.J., Hansen, L.A. and Watson, A.C. (2003) Compounded drugs. Are customized prescription drugs a salvation, snake oil, or both? Am. J. Nurs. 103 (5): 78–9, 81, 84–5. Crawford, L.M., Jr. (2002) From the food and drug administration: Pharmacy compounding guidance. JAMA 288 (13): 1579. Eisenach, J.C. and Yaksh, T.L. (2002) Safety in numbers: how do we study toxicity of spinal analgesics? Anesthesiology 97 (5): 1250–3. Harteker, L.R. (2001) Federal court strikes down compounding regulations. Am. J. Health Syst. Pharm. 58 (8): 638, 640, 643. Hassenbusch, S.J., Portenoy, R.K., Cousins, M., Buchser, E., Deer, T.R., Du Pen, S.L. et al. (2004) Polyanalgesia consensus conference 2003: an update on the management of pain by intraspinal drug delivery-report of an expert panel. J. Pain Symptom Manage. 27 (6): 540–63. Hung, J.C. (2004a) USP general chapter (797) pharmaceutical compounding-sterile preparations. J. Nucl. Med. 45 (6): 20N, 28N. Hung, J.C. (2004b) The potential impact of usp general chapter (797) on procedures and requirements for the preparation of sterile radiopharmaceuticals. J. Nucl. Med. 45 (6): 21N–26N. James, J.S. (1997) FDA reform signed into law. Food and drug administration. AIDS Treat. News Dec. 5 (No. 284): 6–7. Nordenberg, T. (2000) Pharmacy compounding: customizing prescription drugs. FDA Consum. 34 (4): 11–12. Sasich, L.D. and Sukkari, S.R. (2008) Unknown risks of pharmacycompound drugs. J. Am. Osteopath. Assoc. 108 (2): 86. Tamer, H.R. and Sweet, B.V. (2002) Compounding pharmaceuticals for investigational use. Am. J. Health Syst. Pharm. 59 (18): 1716–19. Thompson, C.A. (2003) USP publishes enforceable chapter on sterile compounding. Am. J. Health Syst. Pharm. 60 (18), 1814, 1817–18, 1822. Trissel, L.A. (2000) Trissel’s™ Stability of Compounded Formulations, 2nd edn. Washington, DC: APhA Publications. US Food and Drug Administration (2003) Compliance policy guide on chapter 4 human drugs: section 460.200 pharmacy compounding. J. Pain Palliat. Care Pharmacother. 17 (1): 99–106. USP General Chapter 797 Pharmaceutical Compounding – Sterile Preparations. US Pharmacopeia, June 1, 2008. Williams, R.L. (2006) Official USP reference standards: metrology concepts, overview, and scientific issues and opportunities. J. Pharm. Biomed. Anal. 40 (1): 3–15. Young, D. (2002) FDA seeks comments on compounding guide. Am. J. Health Syst. Pharm. 59 (14): 1318.

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Intracerebroventricular Opioid Administration for Chronic Pain Katherine E. Groothuis and Robert M. Levy

o u t li n e Introduction

491

Clinical Results

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ICV Drug Administration: Mechanisms of Action

492

Side Effects and Complications

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General Indications and Preoperative Evaluation

492

ICV Opioids for the Treatment of Pain of Nonmalignant Origin

495

Surgical and Drug Administration Techniques

493

References

495

Introduction

The basis of intracerebroventricular (ICV) opioid administration as an alternative local administration of opioids in the cerebrospinal fluid (CSF) rests on preclinical studies of the rat and primate (Pardridge, 1997; Kronenberg et al., 1998). These studies showed that morphine injection in the spinal CSF induces a powerful analgesia that is of metameric caudal distribution, dose-dependent, stereospecific, and is naloxone-reversible. After the noticed efficacy of intrathecal spinal administration of opioids, the ICV technique underwent a rapid transfer from animal to clinical research. While ICV administration is effective and reversible, it is more invasive than intrathecal administration as it requires the placement of a catheter through the brain parenchyma and into the lateral ventricles. ICV administration of morphine has been shown to be effective for the treatment of upper body, head, and neck pain, as well as diffuse pain secondary to cancer

Drugs obtained from Papaver somniferum, more commonly known as the opium poppy, have historically been used to aid those suffering from pain. While over 20 alkaloid compounds have been extracted from the opium poppy, the most efficacious of these compounds is morphine (Henderson, 2002). Morphine was first isolated in 1806 and has since been used in conditions requiring analgesic effects without the loss of consciousness. However, its use has been limited by side effects such as respiratory depression and a high potential for addiction. Research into the mechanisms responsible for the analgesic effects of morphine revealed certain opioid-specific receptor sites within the spinal gray matter, which led to the concept of an intrathecal spinal administration of morphine for pain relief. More recently, the intracerebroventricular method has been examined.

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(Lazorthes et al., 2002). Many clinical studies have confirmed this as a low-risk, highly effective technique. Although direct ICV morphine administration for the treatment of chronic cancer pain remains a welldocumented therapeutic alternative, its therapeutic indications are decreasing due to several factors. Galenic forms of oral opioids with a slow-releasing mechanism requiring only one daily dose, and the development of improved routes of systemic administration, such as rectal, transdermal, and patient-controlled intravenous administration, have decreased the overall need for invasive techniques for opioid administration. Furthermore, there is increasing knowledge surrounding the limitations related to the administration technique for ICV drug delivery. Recognition of these risks and complications has made clinicians less enthusiastic to refer patients for chronic ICV drug administration. The increasing accumulation of clinical data has allowed for the expansion of this technique to the treatment of chronic pain of non-malignant origin in addition to pain resulting from cancer. However, controversy still exists surrounding the effectiveness of ICV drug delivery for the management of persistent pain of non-malignant origin.

ICV drug administration: mechanisms of action As early as 1962, Tsou and Tang showed that analgesic effects could be felt following the microinjection of morphine into the gray matter of the wall of the third ventricle and the periaqueductal gray matter. By 1970, the existence of opioid receptors had been suggested, but Pert and Synder (1973) were the first to actually provide evidence for the existence of such receptors within the central nervous system. There appears to be a higher density of opioid receptors in the locus coeruleus, the periaqueductal gray matter, and the thalamus (Herz et al., 1970). It is believed that when morphine is introduced directly to the lateral ventricle, pain modulation results from the activation of supraspinal opioid receptors, inhibiting the transmission of nociception at the level of the spinal cord (Gebbart, 1982). Using ICV administration, it is possible to use smaller amounts of medication as well as avoid many adverse effects typically experienced with systemic doses. There are many potential reasons that favor the ICV route for drug administration. After a drug is infused into the ventricular compartment, minimal amounts of the drug diffuse into the brain parenchyma (Pardridge, 1977). This is primarily because the rate of

bulk flow of CSF through the ventricles and subarachnoid space is rapid compared to the relatively slow rate of solute diffusion within the brain itself (Davson et al., 1987). Opioids can further directly act upon the opioid receptors of the ventricular walls and thus are particularly useful. CSF originating in the lateral ventricle moves through the foramen of Munro to the third ventricle, through the cerebral aqueduct to the fourth ventricle, into the cisterns of the base of the brain, over the brain surface, and finally is cleared into the peripheral blood stream via absorption at the arachnoid villi into the superior sagittal sinus. Because of this rapid rate of CSF flow from the ventricles into the peripheral blood stream, ICV drug delivery may be regarded as equivalent to a slow intravenous infusion of the drug (Lazorthes et al., 2002). The fact that ICV drug infusion readily distributes drug to blood but not to brain has been shown repeatedly. The ICV infusion of [beta]-interferon in primates results in the presence of the cytokine in blood, but not in brain (Billiau et al., 1981). That is, a drug infused into the ventricles is distributed into the peripheral blood stream, and reenters the brain via transport through the blood–brain barrier (Aird, 1984). The infusion of a drug into the lateral ventricle results in distribution of drug only to the ipsilateral ependymal surface (Lobato et al., 1983). Thus, while ICV drug infusion may result in minimal penetration of a drug into the brain parenchyma, the ependymal surface of the central nervous system is exposed to very large concentrations of the drug. The ICV injection of opioid peptides therefore results in profound analgesia. In addition, because ICV opioids enter the systemic circulation and interact with the periaqueductal and periventricular gray opioids without significant penetration of the drug into the brain matter, the potential side effects are limited. However, this is because the site of action of the opioids is in the periaqueductal gray matter, which is adjacent to the natural flow of CSF (Herz et al., 1970).

General indications and preoperative evaluation According to the World Health Organization, the use of opioids for the treatment of chronic pain, whether of malignant or non-malignant origin, is indicated in the third stage of the hierarchical scale of analgesic prescription (Mercadante, 1999). Oral opioid delivery or other systemic delivery methods should always be the first line of approach. Alternative methods such as the ICV route are used only when the oral

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SURGICAL AND DRUG ADMINISTRATION TECHNIQUES

493

SS

LV

LV

3

4

Figure 37.2  Ventricular reservoirs (above) are available in Figure 37.1  Stylistic representation of CSF pathways in the brain. The cerebrum, cerebellum, brain stem and spinal cord are represented as a solid gray structure. The outside black line represents the dura. CSF-containing spaces are white. CSF is formed by the choroid plexuses in the lateral ventricles (LV) and fourth ventricle (4), and by bulk flow from the surface of the brain into the subarachnoid space. Once formed in the lateral ventricle, the CSF moves through the foramen of Munro into the third ventricle (3), through the cerebral aqueduct and into the fourth ventricle (4). CSF leaves the fourth ventricle through the foramina of Luschka and Magendie, into the subarachnoid space, where it moves around the surface of the brain, leaving through the arachnoid granulations into the sagittal sinus (SS). Except for the formation of CSF at the choroid plexuses, the movement of CSF through the ventricular system, around the brain, and into the arachnoid granulations is entirely by bulk flow, i.e., along a pressure gradient (Courtesy of Dr Dennis R. Groothuis)

route or systemic route is deemed unsuccessful due to difficulties with this administration or absorption or significant side effects. If such circumstances exist, the implantation of a permanent system of ICV drug delivery should only follow a thorough patient screening process. This process should define the underlying mechanism of the chronic pain, confirm that morphine is physiologically effective for the treatment of such pain, confirm that less invasive means have been exhausted and determine whether the patient has any psychological contraindications to interventional pain management. Typically, patients will have head or neck pain secondary to cancer or will have failed prior attempts at intraspinal drug delivery. Furthermore, once a patient is deemed appropriate, a screening trial should be

several configurations differentiated by inlet connector orientation and dome diameter. The reservoirs are designed to allow multiple punctures with a 25-gauge or smaller needle (Courtesy of Medtronic, Inc., Minneapolis, MN)

performed to ensure that ICV morphine provides significant relief without unacceptable side effects.

Surgical and drug administration techniques The most common reservoir used for ICV administration is the standard Ommaya reservoir, usually with a 2 ml capacity (Leavens et al., 1982; Lobato et al., 1983).  In preparation for reservoir implantation, the patient is placed in the supine position, usually under general anesthesia. Using a burr-hole, generally placed 1 cm anterior to the coronal suture and 2.5 cm from the midline, a catheter is advanced through the opened dura and the brain parenchyma into the frontal horn of the lateral ventricle or, less commonly, into the third ventricle (Brazenor, 1987; Lazorthes et al., 2002). Some investigators, however, prefer to use the temp­ oral horn of the lateral ventricle or the cisterna magna as the site of catheter placement for ICV drug delivery (Lobato et al., 1983; Brazenor, 1987). Stereotactic guidance may improve the accuracy, and thus safety, of catheter placement. The ICV catheter is then connected to the reservoir in the subcutaneous space. Regular injections of a sterile, preservative-free morphine solution are then administered percutaneously

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Table 37.1  Clinical trials of intracerebroventricular morphine therapy Study

No. of patients

ICV morphine dose (mg/24 h) Range (Average)

Days of follow-up Range (Average)

Pain relief Excellent  Good (%)

Leavens et al., 1982

 4

0.5–7 (1)

2–90 (85)

80

Lazorthes et al., 1985

16

0.1–1.5 (0.5)

12–160 (68)

88

Lenzi et al., 1985

38

0.5–2

4–292 (65)

95

Lobato et al., 1983

44

0.25–16

6–150 (55)

97

Roquefeuil et al., 1984

 8

0.4–7

8–120 (73)

80

Thiebaut et al., 1985

32

0.1–15

4–230 (50)

90

Obbens et al., 1987

20

3–60

7–510 (98)

50

Blond, 1989

79

0.05–3

3–152 (65)

94

Lajat et al., 1992

63

0.5–2.4

NR (75)

75

Lazorthes et al., 1985

82

0.1–60 (initial 0.3, final 2.5)

12–443 (66)

80

Karavelis et al., 1996

90

0.25–4 (1)

1–1362 (95)

82

into the reservoir. These injections are typically administered every 12–24 hours; some investigators have proposed connecting the reservoirs to implanted programmable pumps for continuous drug administration (Brazenor, 1987; Pardridge, 1997).

Clinical results Leavens et al. reported in 1982 that low doses of morphine administered by ICV to four patients presenting intractable cancer pain produced profound analgesic effects (from 80% to 100%) without any severe adverse effects (Leavens et al., 1982). Since that time, many clinical studies have confirmed this observation. Many types of cancer pain have been treated successfully by ICV opioid use. In 1990, Lee and colleagues reported a single case study of a patient suffering from advanced craniofacial neoplasm (Lee et al., 1990). This patient was experiencing intractable pain secondary to carcinoma of the palate. The patient had already undergone surgery and radiosurgery, and previous attempts of orally ingested morphine did not provide sufficient relief. An Ommaya reservoir was placed, and ICV morphine administration resulted in complete pain relief. The patient experienced no adverse effects. Table 37.1 summarizes the reported results of ICV opioid administration for chronic pain of malignant origin. All of the patients had previously tried and failed the systemic delivery of medication, and most patients had attempted intrathecal spinal administration of opioids, but had experienced incomplete relief. Comparative analyses of these clinical studies show significant and durable effectiveness of small doses of ICV morphine.

Between the years 1982 and 1996, a total of 476 patients receiving ICV opioids have been reported in the literature in 11 studies. These studies range in size from the initial report of four patients (Leavens et al., 1982) to several large series reporting 60 or more patients (Blond, 1989; Lajat et al., 1992; Lazorthes et al., 1995; Karavelis et al., 1996). ICV morphine doses, ranging from 0.05 to 60 mg per day, have been reported. Doses of up to 60 mg per day were reported in only two studies (Obbens et al., 1987; Lazorthes et al., 1995); while Obbens and cowork­ ers did not report the mean dose used, Lazorthes and coworkers noted that mean ICV opioid doses were 0.3 mg per day initially and 2.5 mg per day at longest follow-up. Thus, in most studies, doses ranged from 0.1 to 16 mg per day and in the majority of patients, doses ranged from 0.1 to 3 mg per day. Reflecting the fact that most treated patients had pain related to cancer, the mean length of follow-up in these 11 studies, 72 days, was quite short. Follow-up ranged, however, from 1 day to nearly four years. On average, 83% of patients reported good to excellent pain relief with ICV morphine therapy. Of note is not only the high degree of successful therapy but also the consistency of reported efficacy. All of the studies except one report success rates ranging from 75 to 97%; one study did not specifically report their success rate (Obbens et al., 1987).

Side effects and complications Adverse effects of ICV opioids include nausea, drowsiness, somnolence and mental clouding, visual hallucinations, miosis, headache, dizziness, pruritis,

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Table 37.2  Summary of adverse effects in 11 studies Study

Number of patients

Respiratory depression

Somnolence

Confusion

Nausea

Total adverse effects

Leavens et al., 1982

 4

0

0

0

0

0

Lazorthes et al., 1985

16

2 (13%)

NR

NR

NR

9 (57%)

Lenzi et al., 1985

38

1 (0.3%)

5 (13%)

NR

NR

6 (16%)

Lobato et al., 1983

44

3 (0.7%)

5 (11%)

NR

NR

8 (18%)

Roquefeuil et al., 1984

 8

0

2 (25%)

NR

NR

2 (25%)

Thiebaut et al., 1985

32

1 (0.3%)

6 (19%)

NR

NR

7 (22%)

Obbens et al., 1987

20

NR

3 (15%)

NR

NR

3 (15%)

Blond, 1989

79

2 (0.3%)

NR

NR

NR

2 (0.3%)

Lajat et al., 1992

63

NR

NR

NR

NR

NR

Lazorthes et al., 1985

82

2 (0.3%)

NR

NR

NR

13 (16%)

diaphoresis, urinary retention, and constipation (Lazorthes et al., 1995; Karavelis et al., 1996; see Table 37.2). The most commonly reported adverse effect of ICV opioids was somnolence, with five of the 11 studies reporting two or more patients suffering significant somnolence. Somnolence was specifically reported in 41 of 386 patients (11%). Seven of the studies reported patients with respiratory depression secondary to ICV opioid administration (12 of 476 patients; 0.3%). One study (Karavelis et al., 1996) reported that nausea occurred in 22% of patients receiving ICV opioids; this high number was not reflected in the experience of other investigators. The regular use of antiemetics may be required to combat treatment-related nausea. Surgical complications related to ICV opioid administration include infection, which may require device explantation. Several other severe complications have been reported that include intracerebral hemorrhage from chronic reservoir use, reservoir leakage, and seiz­ ures (Karavelis et al., 1996; Kronenberg et al., 1998).

ICV opioids for the treatment of pain of nonmalignant origin The prescription of opioids for the management of chronic pain of nonmalignant origin is controversial, whether the administration is oral, intrathecal, or ICV (Portenoy, 1996). Various publications have shown the effectiveness of opioids such as morphine, bupren­ orphine and pentazocine in some neuropathic states (Portenoy et al., 1986, 1990; McQuay et al., 1992). Very few studies have occurred that further analyze the ability of ICV opioid administration to aid patients with benign pain. In order to determine if there may be future

implications of ICV in those with chronic pain of nonmalignant origin, more studies should be conducted.

References Aird, R.B. (1984) A study of intrathecal, cerebrospinal fluid-to-brain exchange. Exp. Neurol. 86: 342–58. Billiau, A., Heremans, H., Ververken, D., Van Damme, J., Carton, H. and de Somer, P. (1981) Tissue distribution of human interferons after exogenous administration in rabbits, monkeys, and mice. Arch. Virol. 68: 19–25. Blond, S. (1989) Morphinothérapie intra-cérébro-ventriculaire: à propos de 79 cas. Neurochirurgie 35: 52–7. Brazenor, G.A. (1987) Long-term intrathecal administration of morphine: a comparison of bolus injection via reservoir with continuous infusion by implanted pump. Neurosurgery 21: 484–91. Davson, H., Welch, K. and Segal, M.B. (1987) Secretion of the cerebrospinal fluid. The Physiology and Pathophysiology of the Cerebrospinal Fluid. London: Churchill Livingstone, p. 201. Gebbart, G.F. (1982) Opiate and opioid peptide effects on brainstem neurons: relevance to nociception and antinociceptive mechanisms. Pain 12: 93–140. Henderson, J.M. (2002) Intrathecal opioids: mechanisms of action. In: K.J. Burchiel (ed.), Surgical Management of Pain. New York: Thieme Medical. Herz, A., Albus, K., Metys, J., Schubert, P. and Teschemacher, H.J. (1970) On the central sites for the antinociceptive action of morphine and fentanyl. Neuropharmocol. 9: 539–51. Karavelis, A., Foroglou, G., Selviaridis, P. and Fountzilas, G. (1996) Intraventricular administration of morphine for control of intractable cancer pain in 90 patients. Neurosurgery 39: 57–62. Kronenberg, M.F., Laimer, I., Rifici, C. et al. (1998) Epileptic seizure associated with intracerebroventricular and intrathecal morphine bolus. Pain 75: 383–7. Lajat, Y., Menagalli-Bogelli, D., Bensignor, M. and Resche, F. (1992) Intracerebral morphine therapy in cancer patients. Can. Anesthesiol. 40: 477–83. Lazorthes, Y.R., Sallerin, B.A.M. and Verdié, J.C.P. (1995) Intracerebroventricular administration of morphine for control of irreducible cancer pain. Neurosurgery 37: 422–8; comment by K. J. Burchiel: 428–9.

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Lazorthes, Y., Sallerin, B., Verdié, J.C. and Sol, J.C. (2002) Intrathecal and intracerebroventricular opioids: past uses and current indications. In: K.J. Burchiel (ed.), Surgical Management of Pain. New York: Thieme Medical. Lazorthes, Y., Verdié, J.C., Bastide, R., Lavados, A. and Descouens, D. (1985) Spinal versus intra-ventricular chronic opiate administration with implantable drug delivery devices for cancer pain. Appl. Neurophysiol. 48: 234–41. Leavens, M.E., Hill, C.S., Cech, D.A., Weyland, J.B. and Weston, J.S. (1982) Intra-thecal and intra-ventricular morphine for pain in cancer patients: initial study. J. Neurosurg. 56: 241–5. Lee, T.L., Kumar, A. and Baratham, G. (1990) Intraventricular morphine for intractable craniofacial pain. Singapore Med J. 31: 273–6. Lenzi, A., Galli, G., Gandolfini, M. and Marini, G. (1985) Intraventricular morphine in paraneoplastic painful syndrome of the cervico-facial region: experience in thirty-eight cases. Neurosurgery 17: 6–11. Lobato, R.D., Madrid, J.L., Fatela, L.V., Rivas, J.J., Reig, E. and Lamas, E. (1983) Intraventricular morphine for control of pain in terminal cancer patients. J. Neurosurg. 59: 627–33. Mercadante, S. (1999) World health organization guidelines: problem areas in cancer pain management. Cancer Control 6: 191–7. McQuay, H.J., Jadad, A.R., Carroll, D. et al. (1992) Opioid sensitivity of chronic pain: a patient controlled analgesia method. Anaesthesia 47: 757–67.

Obbens, E.A., Hill, C.S., Leavens, M.E., Ruthenbeck, S.S. and Otis, F. (1987) Intra-ventricular morphine administration for control of chronic cancer pain. Pain 28: 61–8. Pardridge, W.M. (1997) Drug delivery to the brain: a review. J. Cereb. Blood Flow. Metab. 17: 713–31. Pert, C.B. and Synder, S.H. (1973) Opiate receptor: demonstration in nervous tissue. Science 179: 1011–14. Portenoy, R.K. (1996) Opioid therapy for chronic nonmalignant pain: a review of the critical issues. J. Pain Symptom Manage. 11: 203–16. Portenoy, R.K. and Foley, K.M. (1986) Chronic use of opioid analgesics in nonmalignant pain: report of 38 cases. Pain 25: 171–86. Portenoy, R.K., Foley, K.M. and Inturissi, C.E. (1990) The nature of opioid responsiveness and its applications for neuropathic pain: new hypotheses derived from studies of opioid infusions. Pain 43: 273–386. Roquefeuil, B., Benezech, J., Blanchet, P., Batier, C., Frerebeau, Ph. and Gros, C. (1984) Intra-ventricular administration of morphine in patients with neoplastic intractable pain. Surg. Neurol. 21: 155–8. Thiebaut, J.B., Blond, S., Farcot, J.M. et al. (1985) La morphine par voie intra-ventriculaire dans le traitement des douleurs néoplasiques. Méd. Hyg. 43: 636–46. Tsou, K. and Tang, C. (1962) Analgesic effect of intraventricular or intracerebral microinjection of morphine. Acta Physiol. Sinica. 25: 119–28.

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Deep Brain Stimulation for Pain Erlick A.C. Pereira, Liz Moir, Alexander L. Green, and Tipu Z. Aziz

o u t l i n e Introduction

499

Efficacy and Safety of Deep Brain Stimulation

503

Current Indications for Deep Brain Stimulation

500

Future Prospects

503

Patient Assessment and Selection

500

Conclusions

505

Fundamentals of the Stimulation Technique

501

References

505

Introduction

and medial (VPL/VPM) thalamic nuclei and adjacent structures as putative targets for DBS came from ablative surgery (Mark and Ervin, 1965), leading anesthesia dolorosa to be treated by thalamic DBS (Hosobuchi et al., 1973). Pioneers also targeted the internal capsule and more medial thalamic nuclei, including the centromedian–parafascicular complex (Cm–Pf) (Adams et al., 1974; Thoden et al., 1979). Two multi-center trials of DBS for pain were conducted to seek US FDA approval, the first in 1976 using the Medtronic Model 3380 electrode (196 patients) and the second in 1990 with the Model 3387 (50 patients) that superceded it (Coffey, 2001). They were an amalgam of prospective case series, neither randomized nor case-controlled, suffering from poor enrollment and high attrition. Other shortcomings included heterogeneous case mixes with underspecified patient selection criteria, and subjective and unblinded assessment of patient outcomes. Deep brain sites stimulated, numbers of electrodes used per patient and stimulation parameters chosen varied greatly. Improvements made to the later trial

Deep brain stimulation (DBS) is a neurosurgical intervention whose safety, efficacy, and utility have been robustly demonstrated in movement disorders. The concept of relieving persistent pain by DBS is half a century old and precedes gate theory. After rodent self-stimulation experiments and reported analgesia in psychiatric patients receiving septal DBS (Olds and Milner, 1954; Pool et al., 1956) malignant pain had been ameliorated by intermittent stimulation by 1960 (Heath and Mickle, 1960; Gol, 1967). Further impetus for DBS was provided by the development of permanently implantable peripheral nerve and spinal cord stimulators (SCS) (Shealy et al., 1967; Sweet and Wepsic, 1968) and their commercial availability (Mullett, 1978). Rodent stimulation experiments suggested periventricular and periaqueductal gray (PVG/PAG) regions as DBS targets (Reynolds, 1969), and these findings translated to humans in 1977 (Hosobuchi et al., 1977; Richardson and Akil, 1977). Evidence supporting ventral posterior lateral

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38.  Deep Brain stimulation for pain

included limiting deep brain sites stimulated to two per patient and using visual analogue scores (VAS) to rate pain intensity, but the number of cases included per center was tiny. Neither trial satisfied efficacy criteria of at least half of patients reporting at least 50% pain relief one year after surgery. US FDA approval for analgesic DBS was therefore not sought. However, vast loss of patients to follow-up resulted in a steady increase with time in the proportion of patients with 50% pain relief; two years after implantation they comprised 18 out of the 30 remaining patients (60%) followed-up in the Model 3380 trial and five out of the ten in the Model 3387 trial (50%). Nonetheless, pain was decreed “off-label,” precluding approval by medical insurers (Coffey, 2001). Consequently few trials of DBS for pain using current technology and techniques have been reported. PVG/PAG and VPL/VPM remain common targets. We consider anatomical distinction between PVG/ PAG and Cm–Pf redundant as accuracy is limited by neuroimaging slice thickness. Moreover, ultimate electrode position adjustment is optimally directed by awake patient reports of somaesthetic localization during intraoperative stimulation – which may alter final position by up to 5 mm from preoperative target coordinates. A guiding principle is the established somatotopy of both regions. Human microelectrode studies reveal a mediolateral somatotopy in the contralateral ventroposterior thalamus, with the homuncular head medial and feet lateral (Lenz et al., 1988). Subjective observation of a rostrocaudally inverted sensory homunculus in contralateral PVG/ PAG (Bittar, Nandi et al., 2005), has been confirmed objectively by human macroelectrode recordings of somatosensory evoked potentials (Pereira et al., 2007).

Current indications for deep brain stimulation One thousand three hundred recipients of DBS for pain have been reported (Gybels, 2000; Krauss et al., 2002; Levy, 2003; Hamani et al., 2006; Owen et al., 2006a; Rasche et al., 2006) compared to 400 with MCS (Smith et al., 2001; Brown and Barbaro, 2003) and 4000 with SCS (Cameron, 2004; Taylor et al., 2005). Six centers have reported contemporary series of more than six patients (Krauss et al., 2002; Marchand et al., 2003; Nandi et al., 2003; Bittar, Otero et al., 2005; Green, Owen et al., 2006; Hamani et al., 2006; Owen et al., 2006a, 2006b; Rasche et al., 2006; Yamamoto et al., 2006). Our experience is that DBS is superior to MCS for selected refractory pain syndromes and more appropriate than SCS

Table 38.1  Indications treated in 51 patients treated by deep brain stimulation over 8 years from 1999 to 2007 Indication

Patients

Stroke (12 subcortical, 1 SAH)

24 (47%)

Amputation (phantom and stump)

  7 (14%)

Anesthesia dolorosa

  7 (14%)

Spinal cord injury and failed back

  4 (8%)

Brachial plexus damage

  3 (6%)

Malignancy (tonsil)

  1 (2%)

Multiple sclerosis

  1 (2%)

Other (AVM; chiari decompression; syrinx decompression; unknown)

  4 (8%)

for certain pain etiologies (Nandi et al., 2002). One group’s retrospective studies have compared all three modalities of central neurostimulation, but the results are obfuscated by different treatments trialled both between and sequentially within patients and by limited outcome information (Katayama et al., 2001a, 2001b). During the past decade, we have treated over 50 patients with analgesic DBS, the majority remaining implanted and amenable to follow-up (Bittar, Otero et al., 2005; Green, Owen et al., 2006; Owen et al., 2006a, 2006b). Indications from our current experience are given in Table 38.1. Pain etiologies with good outcomes in contemporary series are stroke (Owen et al., 2006b), amputation (Bittar, Otero et al., 2005), anesthesia dolorosa (Green et al., 2003; Green, Owen et al., 2006), and plexopathies, with success also seen in multiple sclerosis (Hamani et al., 2006) and malignancy (Owen et al., 2006).

Patient assessment and selection Historically, clinical approaches to DBS have sought to categorize patients first by cause of pain and second by dichotomizing the pain into such categories as nociceptive or deafferentation, “epicritic” or “protopathic,” peripheral or central. Such distinctions are largely unhelpful to patient selection as functional neuroimaging and electrophysiological evidence suggests that chronic pain arises concomitant with centrally mediated changes related to neuronal plasticity (Coderre et al., 1993). Thus, chronic pain refractory to medical treatment is largely central and thus neuropathic. Challenges to patient selection are then twofold – first confirmation that the patient’s pain is neither factitious nor psychogenic, and second, the selection of those who are likely to derive benefit from DBS.

IVC.  Brain stimulation for pain

501

Fundamentals of the stimulation technique

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Essential to the process is assessment by a multidisciplinary team consisting as a minimum of a pain specialist, neuropsychologist, and neurosurgeon. Neuropsychological evaluation excludes psychiatric disorders and ensures minimal cognitive impairment (Shulman et al., 1982). Quantitative assessment of the pain and health-related quality of life is a requirement of preoperative patient selection. Both VAS (scale 1–10) to rate pain intensity and the McGill pain questionnaire (MPQ) should be used (Melzack, 1975), the latter giving additional qualitative information alongside quality of life assessments. Patients record VAS twice daily in a pain diary over 12 days. The 24 VAS scores are reviewed to ensure consistency. Most patients who describe “burning” pain in the MPQ derive benefit from DBS, regardless of DBS target. The chronic pain etiology is less important than its symptom history, which may involve hyperalgesia, allodynia, and hyperpathia. The pain must have a definable organic origin with the patient refractory to or poorly tolerant of pharmacological treatments. Surgical treatments may have been attempted; however, failure of other neurostimulatory therapies is not considered a prerequisite for DBS. DBS can be trialled instead of SCS or MCS in carefully selected patients wherever the etiologies of chronic pain are consistent with neuronal reorganization at multiple levels of the central neuromatrix. The greater body of clinical studies of SCS (Taylor, 2006; Turner et al., 2004) coupled with ours and others’ lack of success with DBS (Hamani et al., 2006; Owen et al., 2006), favors SCS over DBS as a more appropriate first-line neurostimulatory intervention for spinal injuries, including spinal cord injury where central reorganization is likely to be mostly at a spinal level. However, our experience of DBS for pain after limb or plexar injury (Bittar, Otero et al., 2005; Owen et al., 2006a), together with the recent paradigm shift towards central brain reorganization with autonomic dysfunction as the mechanism underlying it (Janig and Baron, 2003), encourages us to consider DBS rather than SCS as first-line treatment for complex regional pain syndromes (in other words, for plexar injuries and stump pain after amputation as well as phantom limb pain). However, to select patients for DBS primarily by etiology rather than by clinical findings is to risk poor outcomes. Preference in patient selection is determined after multidisciplinary assessment demonstrating quantitatively severe pain refractory to medication for at least one year with significantly impaired quality of life and likely neuropathic etiology with unlikely spinal involvement. Medical contraindications to DBS include uncorrectable coagulopathy obviating neurosurgery and ventriculomegaly sufficient to preclude direct electrode passage to the surgical target.

Figure 38.1  Efficacy by indication in 51 patients treated by deep brain stimulation over 8 years from 1999 to 2007. Patients receiving full implantations are in green (40 in total, 78%) and those whose deep brain stimulators are explanted are in red (11 in total, 22%). MS, multiple sclerosis; FBS, failed back syndrome

Fundamentals of the stimulation technique Informed consent is obtained, with counseling given for procedure duration of two to four hours under moderate sedation and local anesthesia with the head fixed and cranial stereotaxis applied. Specific complications consented for are infection (5%), stroke (1%), seizures (1%), hemorrhage (0.3%), death (0.1%), and the need for implantable pulse generator (IPG) revision surgery every 3–5 years (10%). Patients are also counselled for the possibility that they may derive no benefit from DBS or not tolerate it well, again necessitating its removal; no specific percentage is quoted as each case is best considered individually, but our case series give removal rates of 20% (Figure 38.1). A week prior to surgery, patients have a T1 weighted MRI scan. For surgery, a Cosman–Roberts– Wells base ring is applied to the patient’s head under local anesthesia. A stereotactic CT scan is performed and the MRI volumetrically fused to it. Coordinates for the PVG/PAG and VPL or VPM and entry trajectory are then calculated (Table 38.2). A frontal trajectory avoiding the lateral ventricles is preferred. DBS targets are contralateral to the painful side. After a 3 cm parasagittal scalp incision and separate 2.7 mm twist drill craniotomy per electrode, targets are implanted with Medtronic model 3387 quadripolar electrodes (Figure 38.2). PVG/PAG is implanted first; excellent intraoperative analgesia obviates implantation of a second electrode in VPL/VPM in 50% of patients. Final electrode position is determined by intraoperative clinical assessment reliant upon subjective reporting by the awake patient – microelectrode recording is not routinely used. At either target, DBS at lower frequencies (50 Hz) is analgesic and higher frequencies (70 Hz) hyperalgesic. Stimulation of 5–50 Hz

IVC.  Brain stimulation for pain

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38.  Deep Brain stimulation for pain

Table 38.2  Locations, stereotactic coordinates and adjacent structures to the deep brain targets for pain Anatomical target

Location

VPL

1–3 mm medial (leg 1–2 mm, arm 2–3 mm) to internal capsule at level of posterior commissure

VPM

Midway between wall of 3rd ventricle and internal capsule, at level of posterior commissure

PVG/PAG

2–3 mm lateral to wall of 3rd ventricle, at level of posterior commissure

Stereotactic coordinates

Adjacent structures

10–13 mm posterior to midcommissural point, 14–18 mm lateral, 2–5 mm vertical

Internal capsule laterally; centromedian and parafascicular thalamic nuclei medially; thalamic fasciculus, zona incerta, subthalamic nucleus inferiorly; thalamic nucleus ventralis intermedius anteriorly; pulvinar thalamic nucleus posteriorly

10 mm posterior to midcommissural point, 2–3 mm lateral, 0 mm vertical

Medial lemniscus laterally; superior colliculus inferoposteriorly; red nucleus inferoanteriorly

VPL, ventroposterolateral thalamic nucleus; VPM, ventroposteromedial thalamic nucleus; PVG/PAG, periventricular/periaqueductal gray matter

Figure 38.2  Intraoperative deep brain stimulation for pain (A) and an axial MRI of deep brain stimulators in situ (B). The thalamic electrode contact is lateral, the periventricular gray electrode passing medially

is performed initially, pulse width 200–450 s, amplitude 0.5–3 V. VPL/VPM stimulation aims to supplant painful sensation by pleasant paresthesia and PVG/ PAG stimulation to induce a sensation of warmth or analgesia in the painful area. Adjustment is primarily somatotopic so as to evoke appropriate topographic responses, but the assessor should be alert to pyramidal signs suggesting capsular involvement with VPL/ VPM DBS, and with PVG/PAG DBS for oscillopia and reports of visual disturbances caused by super­ ior collicular involvement or facial paresthesia arising from medial lemniscus stimulation. Each electrode

is fixed to the skull by a miniplate and its leads externalized parietally via temporary extensions. A postoperative CT confirms electrode position, with MRI sometimes performed for further anatomical target corroboration (Figure 38.2). After a week of postoperative clinical assessment, a decision is made whether to permanently implant the electrodes in a second operation under general anesthesia. They are connected to an IPG (Medtronic Synergy or Kinetra) implanted subcutaneously, usually infra-clavicularly or alternatively intra-abdominally in subcutaneous fascia.

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503

Future prospects

During postoperative assessment, the patient records VAS scores at least twice daily and is kept blinded to DBS settings. Targets are trialled individually then together for 1–2 days each using the stimulator parameters described to determine which electrode contact polarities confer maximum analgesia. Monopolar stimulation is trialled if bipolar settings fail. Full implantation of the efficacious electrode(s) is performed and DBS commenced at the optimized stimulation parameters. The decision to implant PVG/PAG, VPL/VPM or dual site is made by demonstrable efficacy in each individual patient. Patients ideally leave the hospital the day after IPG implantation and we endeavour to follow their progress with clinic appointments at three months, six months and then yearly thereafter. Initially, they are given a pain diary to record their VAS and stimulator settings weekly for review at follow-up. In addition to being able to switch the DBS on and off at will, they are usually only given control over its voltage which is typically limited by the clinician to a maximum efficacious amplitude of up to 6 V.

Efficacy and safety of deep brain stimulation Published case series of at least six patients using current DBS targets are listed together with their reported efficacy in Table 38.3. Where the same authors reviewed their clinical data more than once, only their latest or largest patient series were considered. Pain relief scores showing 50% or more improvement or verbal ratings of “good” or “excellent” after surgery were considered successful outcomes and patients not permanently implanted included as failed outcomes. Not all authors reported such failures, however, leading to overestimation of efficacy in some reports. The literature is obfuscated by varying and simplistic outcome measures with a paucity of double-blind, placebo-controlled studies. Only four groups to our knowledge have published studies of at least six patients using current standards of target localization and currently available models of deep brain stimulator with adequate follow-up and description of outcomes (Marchand et al., 2003; Hamani et al., 2006; Owen et al., 2006a; Rasche et al., 2006). All other primary studies are based on cases first implanted more than a decade ago, some targeting the internal capsule. The efficacy by etiology of our 51 patient prospective case series is summarized in Figure 38.1 and included in Table 38.3. Seventy-eight percent

of patients gained pain relief during the week postprocedure and proceeded to full implantation. DBS remained analgesic for 63% of implanted patients more than one year after surgery. Twenty-one patients had PVG/PAG implantation, five VPL/VPM implantation, and 25 dual target implantation. Five patients from the cohort died of unrelated causes more than one year after their surgery. Two patients developed wound infections that resolved with antibiotics, one required complete system removal, and four patients required replacement of leads damaged by falls. Detailed outcomes by etiology from our patient cohort are described elsewhere (Nandi and Aziz, 2004; Green et al., 2004; Bittar, Otero et al., 2005; Green, Owen et al., 2006; Owen et al., 2006a, 2006b).

Future prospects While the analgesic mechanisms of DBS are unknown, altered rhythmic activity in VPL/VPM and PVG/PAG neurons is likely to play an important role in pain pathophysiology. Analgesic DBS may therefore augment pathologically diminished low frequency synchronous oscillations in the thalamic and reticular components of a reticulo-thalamo-corticofugal pain neuromatrix. A positive correlation has been shown between analgesic efficacy at either DBS site and the amplitude of slow frequency (1 Hz) VPL/VPM local field potentials (LFPs) (Nandi et al., 2002, 2003). Patients in pain also have characteristically enhanced low frequency (8–15 Hz) power spectra of both PVG/PAG and VPL/VPM LFPs. Further research is required to elucidate if such neuronal signatures could aid patient selection or enable “smart” demand-driven stimulation, in particular if combined with technical advances in noninvasive electrophysiological techniques to characterize functional neuronal connectivity. The PVG/PAG is a structure optimally sited anatomically to integrate interoceptive function, both from adjacent mesencephalic cardiovascular centers and more distal pain processing areas. Its autonomic effects have been well studied in animals (Behbehani, 1995), and changes noted with DBS (Young and Rinaldi, 1997). A positive correlation has been shown between degree of analgesia in patients receiving PVG/PAG DBS and magnitude of blood pressure reduction (Green, Owen et al., 2006). Such findings advance investigations for objective markers of chronic pain and also potentially the selection of patients who may respond best to PVG/PAG DBS. An obstacle yet to be surmounted in the quest to understand the mechanisms of analgesic stimulation

IVC.  Brain stimulation for pain

504

38.  Deep Brain stimulation for pain

Table 38.3  Summary of prospective case series of thalamic and periventricular deep brain stimulation for pain Study

Number of patients implanted

Deep brain target

% success: long-term (initially)

Follow-up time (mth): range (mean)

Evaluation method used

Mazars et al., 1979

84 121

PVG/PAG VPL/VPM

0 69

n/a

Verbal report

Richardson and Akil, 1977; Akil et al., 1978

30

PVG/PAG

70

1–46 (18)

Self report; NRS

Gybels, 1980

7

PVG/PAG

16

Schvarcz, 1980

6

PVG/PAG

33

6–42

Verbal report

Ray and Burton, 1980

28

PVG/PAG

76

1–33 (14)

n/a

Turnbull et al., 1980; Shulman et al., 1982

24

VPL/VPM

67

1–47 (10)

Verbal report; HRQoL; analgesic use

Dieckmann and Witzmann, 1982

26 20

PVG/PAG VPL/VPM

28

6–54

Three category rating

Plotkin, 1982

48 12

PVG/PAG VPL/VPM

79

6–42 (36)

VAS

Tsubokawa et al., 1985

24

VPL/VPM

63

n/a

Three category rating; activity; analgesic use

Meyerson, 1983

41

PVG/PAG VPL/VPM

41

n/a

VAS; HRQoL

Hosobuchi et al., 1977; Hosobuchi, 1987

65 77

PVG/PAG VPL/VPM

77 (82) 58 (68)

14–168

Verbal report; analgesic use

Levy et al., 1987

141

PVG/PAG VPL/VPM

31 (59)

24–168 (80)

Verbal report

Siegfried, 1987

89

VPL/VPM

67

n/a

VAS; verbal report; analgesic use

Gybels et al., 1993

36

VPL/VPM

30 (61)

(48)

Nociceptive stimuli

Kaplitt et al., 2004

25 43 12

VPL/VPM Both Other

14

n/a

Verbal report

Young and Rinaldi, 1997

178

PVG/PAG

50 (80)

12–180 (90)

VAS; analgesic use; HRQoL

Nociceptive stimuli

VPL/VPM Kumar et al., 1997

68

PVG/PAG VPL/VPM

62 (78)

6–180 (78)

VAS, MPQ

Krauss et al., 2002

12

PVG/PAG

n/a

n/a

n/a

Brown and Barbaro, 2003

8 3 45

PVG/PAG VPL/VPM Both

63 33 38

6–66

n/a

Marchand et al., 2003

6

VPL/VPM

83

(42)

NRS, nociceptive and placebo stimuli

Hamani et al., 2006

21

PVG/PAG VPL/VPM

24 (62)

2–108 (24)

VAS, use of DBS

Yamamoto et al., 2006

18

VPL

78

n/a

VAS

Nandi et al., 2002, 2003; Green, Owen et al., 2006; Owen et al., 2006a

21 5 25

PVG/PAG VPL/VPM Both

57 (76) 40 (80) 68 (80)

3–96 (45)

VAS, MPQ, HRQoL

PVG/PAG, periventricular and periaqueductal gray and adjacent mid-line thalamic nuclei; VPL/VPM, ventroposterolateral and ventroposteromedial thalamic nuclei; VAS, visual analogue scale; MPQ, McGill Pain Questionnaire; HRQoL, health-related quality of life; NRS, numerical rating scale

IVC.  Brain stimulation for pain



Conclusions

is the lack of adequate animal models of chronic pain. In addition to their limited homology in chronic pain paradigms, the smaller brains of rodent and murine models increase targeting inaccuracies for small brain stem structures. Such experience emphasizes the important opportunities presented by patient-based translational research into DBS to study the mechanisms underlying its efficacious analgesia. Contemporary case series suggest that at least a quarter of patients successful during trial stimulation do not experience long-term success beyond one year after surgery. To address the predicament, alongside improving case selection, further challenges are to identify predictors of long-term efficacy and investigate the putative phenomenon of tolerance. Progressive increases of stimulus amplitude or insertion of a second electrode have proven unhelpful (Kumar et al., 1997). Our experience is that tolerance is often overcome by subtle alterations of either pulse width by 30–90 s, frequency by 5–20 Hz, or both. Developments in stimulator technology such as the development of rechargeable and demand-driven stimulators may not only obviate the need for IPG replacement and improve cost-effectiveness, but also create the prospect of patient-controlled analgesia and potentially overcome tolerance.

Conclusions Although not a new therapy, DBS has metamorphosed considerably over the past decade, concomitant with advances in both stimulator technology and neuroimaging techniques, and by corollary improvements in efficacy and reductions in complications. Few centers have published detailed studies of patients treated during the past decade. Current results suggest that DBS gives analgesia most consistently to patients with pain after stroke, amputation (either phantom or stump) and anesthesia dolorosa. The improved outcomes in patients with stroke who describe their pain as “burning” in character illustrate how important thorough assessment and selection are (Owen et al., 2006b). Objective adjuncts to current pain assessments are desirable to enhance selection and outcomes. Our preference for PVG/PAG DBS over VPL/VPM together with the correlations revealed between cardiovascular effects, analgesic efficacy and burning hyperesthesia point towards autonomic measures as potential objective markers (Green, Wang et al., 2006). Sustained analgesia by DBS has been shown for myriad indications, our own experience including

505

multiple sclerosis and dyspareunia, for example. Each case must be considered individually. Poor outcomes for pain after spinal cord injury suggest that predominantly spinal neuropathic changes may not respond favorably to cerebral stimulation. Conversely, causes of chronic pain not traditionally treated by DBS, for example visceral pain where PVG/PAG changes are seen (Dunckley et al., 2005), have potential worthy of further investigation. The large variability of results in case series to date reflects not just limitations in pain assessment tools and study design and execution, but moreover individual differences between patients as to what constitutes success. A good outcome may be the removal of a particular component of pain, for example burning hyperesthesia, without quantitative reduction in pain scores. Conversely, complete pain eradication by DBS may accompany unease, motor complications, or other sequelae precipitating intolerance of stimulation. Thus, investigators should endeavor to include quality of life measures in outcome assessment to overcome the limitations of using pain questionnaires alone. At present, our experience guides us broadly towards whom to offer DBS to, which targets to select, and tentatively towards prognostication. For both DBS targets, the relative contributions of local interactions and wider functional neuroanatomical circuitry are yet to be fully elucidated. In addition, research attention should turn to focus upon improving patient selection. When successful, results are frequently spectacular and life-transforming. DBS should only be performed in experienced, specialist centers willing to carefully study their patients and publish their results. The intensive experimental study of small groups of patients generates hypotheses creating opportunity for larger randomized, case-controlled, clinical trials.

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Krauss, J.K., Pohle, T., Weigel, R. and Burgunder, J.M. (2002) Deep brain stimulation of the centre median-parafascicular complex in patients with movement disorders. J. Neurol. Neurosurg. Psychiatry 72 (4): 546–8. Kumar, K., Toth, C. and Nath, R.K. (1997) Deep brain stimulation for intractable pain: a 15-year experience. Neurosurgery 40 (4): 736–46, discussion 746–7. Lenz, F.A., Dostrovsky, J.O., Tasker, R.R., Yamashiro, K., Kwan, H. C. and Murphy, J.T. (1988) Single-unit analysis of the human ventral thalamic nuclear group: somatosensory responses. J. Neurophysiol. 59 (2): 299–316. Levy, R.M. (2003) Deep brain stimulation for the treatment of intractable pain. Neurosurg. Clin. North Am. 14 (3): 389–99, vi. Levy, R.M., Lamb, S. and Adams, J.E. (1987) Treatment of chronic pain by deep brain stimulation: long term follow-up and review of the literature. Neurosurgery 21 (6): 885–93. Marchand, S., Kupers, R.C., Bushnell, M.C. and Duncan, G.H. (2003) Analgesic and placebo effects of thalamic stimulation. Pain 105 (3): 481–8. Mark, V.H. and Ervin, F.R. (1965) Role of thalamotomy in treatment of chronic severe pain. Postgrad. Med. 37: 563–71. Mazars, G., Merienne, L. and Cioloca, C. (1979) Comparative Study of Electrical Stimulation of Posterior Thalamic Nuclei, Periaqueductal Gray, and Other Midline Mesencephalic Structures in Man. New York: Raven Press. Melzack, R. (1975) The McGill Pain Questionnaire: major properties and scoring methods. Pain 1 (3): 277–99. Meyerson, B.A. (1983) Electrostimulation procedures: effects, presumed rationale, and possible mechanisms. Adv. Pain Res. Ther. 5: 495–534. Mullett, K. (1978) Electrical brain stimulation for the control of chronic pain. Med. Instrum. 12 (2): 88–91. Nandi, D. and Aziz, T.Z. (2004) Deep brain stimulation in the management of neuropathic pain and multiple sclerosis tremor. J. Clin. Neurophysiol. 21 (1): 31–9. Nandi, D., Aziz, T., Carter, H. and Stein, J. (2003) Thalamic field potentials in chronic central pain treated by periventricular gray stimulation – a series of eight cases. Pain 101 (1–2): 97–107. Nandi, D., Liu, X., Joint, C., Stein, J. and Aziz, T. (2002) Thalamic field potentials during deep brain stimulation of periventricular gray in chronic pain. Pain 97 (1-2): 47–51. Nandi, D., Smith, H., Owen, S., Joint, C., Stein, J. and Aziz, T. (2002) Peri-ventricular grey stimulation versus motor cortex stimulation for post stroke neuropathic pain. J. Clin. Neurosci. 9 (5): 557–61. Olds, J. and Milner, P. (1954) Positive reinforcement produced by electrical stimulation of septal area and other regions of rat brain. J. Comp. Physiol. Psychol. 47 (6): 419–27. Owen, S.L.F., Green, A.L., Nandi, D., Bittar, R.G., Wang, S. and Aziz, T.Z. (2006a) Deep brain stimulation for neuropathic pain. Neuromodulation 9 (2): 100–6. Owen, S.L., Green, A.L., Stein, J.F. and Aziz, T.Z. (2006b) Deep brain stimulation for the alleviation of post-stroke neuropathic pain. Pain 120 (1-2): 202–6. Pereira, E.A., Green, A.L., De Pennington, N. et al. (2007) From brainstem somatotopy to neural correlates of consciousness: painful revelations from deep brain stimulation. British Neurosurgical Research Group Annual Meeting 2007: Manchester, UK. Plotkin, R. (1982) Results in 60 cases of deep brain stimulation for chronic intractable pain. Appl. Neurophysiol. 45 (1-2): 173–8. Pool, J.L., Clark, W.D., Hudson, P. and Lombardo, M. (1956) Steroid Hormonal Response to Stimulation of Electrodes Implanted in the Subfrontal Parts of the Brain. Springfield, IL: Charles C Thomas. Rasche, D., Rinaldi, P.C., Young, R.F. and Tronnier, V.M. (2006) Deep brain stimulation for the treatment of various chronic pain syndromes. Neurosurg. Focus 21 (6): E8.

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Taylor, R.S., Van Buyten, J.P. and Buchser, E. (2005) Spinal cord stimulation for chronic back and leg pain and failed back surgery syndrome: a systematic review and analysis of prognostic factors. Spine 30 (1): 152–60. Thoden, U., Doerr, M., Dieckmann, G. and Krainick, J.U. (1979) Medial thalamic permanent electrodes for pain control in man: an electrophysiological and clinical study. Electroencephalogr. Clin. Neurophysiol. 47 (5): 582–91. Tsubokawa, T., Katayama, Y., Yamamoto, T. and Hirayama, T. (1985) Deafferentation pain and stimulation of the thalamic sensory relay nucleus: clinical and experimental study. Appl. Neurophysiol. 48 (1-6): 166–71. Turnbull, I.M., Shulman, R. and Woodhurst, W.B. (1980) Thalamic stimulation for neuropathic pain. J. Neurosurg. 52 (4): 486–93. Turner, J.A., Loeser, J.D., Deyo, R.A. and Sanders, S.B. (2004) Spinal cord stimulation for patients with failed back surgery syndrome or complex regional pain syndrome: a systematic review of effectiveness and complications. Pain 108 (1-2): 137–47. Yamamoto, T., Katayama, Y., Obuchi, T. et al. (2006) Thalamic sensory relay nucleus stimulation for the treatment of peripheral deafferentation pain. Stereotact. Funct. Neurosurg. 84 (4): 180–3. Young, R.F. and Rinaldi, P.C. (1997) Brain Stimulation. New York: Springer-Verlag.

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Deep Brain Stimulation of the Posterior Hypothalamus in Chronic Cluster Headache Angelo Franzini, Giuseppe Messina, Massimo Leone, Gennaro Bussone, Carlo Marras, Giovenni Tringali, and Giovanni Broggi o u t l i n e Introduction

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consider the role of DBS in CCH with respect to other less invasive emerging procedures such as vagal nerve stimulation (Mauskop, 2005), occipital nerve stimulation (Burns et al., 2007; Leone, Franzini et al., 2007) and sphenopalatine ganglion radiosurgical ablation.

Since the first reported series of patients affected by chronic cluster headache (CCH) treated with deep brain stimulation (DBS) in 2003 (Leone et al., 2001; Franzini et al., 2003, 2007; Headache Classification Committee of the International Headache Society, 2004), several other series of patients have been reported in the USA and Europe (Schoenen et al., 2005; Starr et al., 2007; Bartsch et al., 2008). This combined experience led to questions concerning the target, the selection criteria, and the safety of this procedure. Physiopathological data on the etiology of cluster headaches point to the hypothalamus as a crucial site for the development of the disease (May et al., 1998; Lodi et al., 2006; Leone, Proietti Cecchini et al., 2007). Our current experience on surgical targeting, patient selection and long-term follow-up may be helpful in understanding the role of DBS of the posterior hypothalamus (pHyp) in the management of the most severe cluster headache patients. Finally, we have to

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Patients Patients in this series were diagnosed with CCH according to the criteria of the International Headache Classification (Headache Classification Committee of the International Headache Society, 2004) and supported by two neurologists involved in the patient’s treatment. All patients have been considered refractory to pharmacological therapy, including steroids, triptans and prophylactic drug treatments including lithium and beta blockers (Leone et al., 2006). All patients underwent sphenopalatine ganglion endoscopic block with local anesthetics. Sphenopalatine block alleviated headaches in approximately 10%

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of patients. Since 2005 a preliminary trial with great occipital nerve (GON) stimulation was performed in all patients prior to DBS. GON stimulation was effective in 75% of CCH patients (six patients out of eight) (Burns et al., 2007). Sixteen patients fulfilled the selection criteria (including unresponsiveness to the GON stimulation and sphenopalatine blocks). The mean age of the group was 43 years. Fourteen patients were male and two of these patients had bilateral pain bouts.

Surgical technique Surgery was performed with the Leksell frame (Eleckta, Stockholm, Sweden) under local anesthesia. Preoperative antibiotics were administrated to all patients. A preoperative brain MRI (axial volum­ etric fast spin echo inversion recovery and T2 images) was used to obtain high-definition images for precise determination of both anterior and posterior commissures and midbrain structures below the commissural plane, such as the mammillary bodies and the red nucleus. MR images were merged with software assistance (Frame-link 4.0, Steathstation, Medtronic, Inc., Minneapolis, MN) with a volumetric stereotactic CT acquired with 2 mm thick slices. Coordinates for the pHyp ipsilateral to the involved side were also set at 5 mm below the intercommissural plane and 2 mm lateral from the midline. Target planning of the anteroposterior coordinate relying exclusively on midcommissural point-based coordinates may lead to electrode misplacement (Franzini et al., 2004). This stereotactic error is due to the anatomical variability of the angle between the brain stem and the intercommissural plane. In order to correct for this possible error we introduced a third anatomical landmark. We have named this landmark the “interpeduncular point” (Franzini et al., 2007), which is defined as the apex of the interpeduncular cistern 8 mm below the commissural plane at the level of the maximum diameter of the mammillary bodies as visible in axial section (Figure 39.1). The final antero­ posterior coordinate for the pHyp target was selected 1–2 mm posterior to the interpeduncular point. In most patients this location is 3 mm posterior to the midcommissural point. A dedicated program and atlas for targeting the hypothalamus have been developed by our group and are freely available online at www.angelofranzini.com/BRAIN.html. A rigid cannula was inserted through a 3 mm coronal paramedian twist-drill hole to an off set 10 mm dorsal to the target. This cannula was used as both a guide for microrecording and placement of the

Figure 39.1  An example of an axial brain MRI section where we can recognize the (as we call it) “interpeduncular point” between the two cerebral peduncles (Image obtained with the virtual workstation. Dextroscope, Volume Interactions, Bracco, Singapore)

definitive electrode (Model 3389; Medtronic). Patients with bilateral pain bouts underwent a bilateral procedure.

Microelectrode recording The three patients that underwent awake microelectrode recording did not receive any headache prophylactic drugs for the 24 hours preceding surgery. The other patients did not undergo awake surgery and were allowed to receive their usual prophylactic drugs. For all of the patients, continuous physiological recordings with the Leadpoint system (Medtronic) began as the microelectrode reached the presumptive target area. Postoperative data analysis was performed with the Spike2 analysis package (CED, Cambridge, UK). Single-unit events were discriminated using template-matching spike sorting function. The firing rate was calculated by dividing the total number of the isolated spikes by the length of the recording. Properties of the firing pattern were inspected by plotting interspike interval histograms (ISIH; 5 ms bin width and lag up to 100 ms). Autocorrelograms (5 ms bin width and lags up to 1000 ms) were plotted to evaluate the rhythmicity of the spike trains. The average firing rate was approximately 24 spikes/s. For most of the recording time all the neurons generated isolated action potentials; in fact the inter-spike interval (ISI), as shown in the oscilloscope, was in the 10–15 ms range, with only 7.2% of ISI shorter than 5 ms, which reflects very high

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intraburst frequencies. Autocorrelograms of two cells did not display any regularity in the occurrence of peaks and troughs, which indicates a lack of periodicity of the firing discharge. Only one autocorrelogram displayed some regularity in the occurrence of peaks and troughs, with an oscillatory pattern at around 1 Hz. In one patient, firing rate was reduced by contralateral but not by ipsilateral tactile stimulation of the cutaneous territory innervated by the ophthalmic branch of the trigeminal nerve (Cordella et al., 2007).

Macrostimulation at the target In the patients who underwent awake surgery, macrostimulation was tested at 60 Hz frequency and 60 ms pulse width. Amplitude was increased progressively. Ocular deviation toward the stimulated side was observed at 3–4 Volts, followed by ipsilateral IIIrd nerve motor responses (4–5 V). At higher voltages (5–6 V), a sensation of fear and panic was reported. Vegetative responses and/or cardiovascular effects were not evoked by intraoperative macrostimulation at these amplitudes. When side effects were ruled out at the amplitudes expected to be used postoperatively (1–3 Volts), the guiding cannula was removed and the DBS electrode was secured to the skull with microplates. We never observed adverse effects related to electrode insertion. However, a microlesional effect was noted in three patients who had immediate disappearance of pain bouts after DBS implantation without active stimulation. Postoperative stereotactic CT was always performed to rule out complications and was merged with the preoperative MRI to verify the electrode placement (Ferroli et al., 2004). A tridimensional reconstruction of the merged images was created (Figure 39.2). Internal pulse generators (IPG) (Soletra, Medtronic) were placed in subclavicular subcutaneous pockets and connected to the DBS electrode for chronic continuous electrical stimulation. Since 2005 the deep brain electrode has been connected to the subclavicular dual-channel IPG (Kinetra, Medtronic), previously implanted for Great Occipital Nerve (GON) stimulation; the only limitation of the use of the dual pulse generator was the need of stimulating at the same frequency with both the intra­ cranial and the occipital electrode.

Figure 39.2  Tridimensional reconstruction of the preoperative MRI fused with the postoperative CT showing the electrode (white arrow) stimulating the posterior hypothalamus. Image has been obtained with the virtual workstation Dextroscope (Volume Interactions, Bracco, Singapore). In the upper part of the image, the neuronal activity at the target is shown

events was reached. The parameters for chronic stimulation after their gradual increase were 185 Hz, 60–90 sec and amplitude ranging between 1 and 3 Volts in unipolar configuration with case positive. Patients tolerated higher frequencies during chronic stimulation titration than during intraoperative macrostimulation testing.

Results The mean follow-up is 24 months (range 12–62 months). The results have been recently reported in detail (Leone et al., 2006) and are summarized here:

Chronic stimulation parameters

71% of postoperative days were pain-free and the intensity and duration of pain bouts was significantly reduced. l Medication intake was reduced to less than 20% of the preoperative baseline. l The mean time to reach a stable benefit (pain-free or pain reduction) was 42 days (range 1–86 days). l The mean stimulation amplitude was 2.4 V (range: 0.6–3.3 V).

The implantable pulse generators were activated a few days or weeks after surgery. The amplitudes were progressively increased until the threshold for adverse

Twelve of the stimulators (9 patients) have been switched off at least once in single-blind fashion. After deactivation, pain recurred after an average interval of 2 months, without a clear correlation to the duration

l

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of chronic stimulation. The pain improved or disappeared when the stimulator was turned back on. In patients with bilateral pain, activation and deactivation of a single pulse generator abolished or led to recurrence of pain only on the ipsilateral side.

Conclusion and discussion DBS in CCH patients was well tolerated and resulted in significant reduction of pain bouts. Transient, reversible diplopia was the main stimulation-related side effect and limited the use of higher amplitudes for chronic stimulation. Before the operation none of the patients was able to work. As a result of stimulation, most patients’ lives have gradually returned to normal and most have resumed work. Nevertheless, some crucial points were learned from our experience: The diagnosis of CCH must be precise and supported by the headache classification criteria (Headache Classification Committee of the International Headache Society, 2004). Comorbidity with other facial pain syndromes or personality disorders (Torelli and Manzoni, 2003) may lead to a wrong diagnosis. To avoid this bias in patient selection we recommend a multidisciplinary team approach including headache neurologists, psychiatrists and headachededicated Operative Units. PHyp stimulation benefits only CCH patients but is not effective for other facial pain syndromes such as atypical facial pain and neuropathic pain (data in press). l About 30% of CCH patients may have significant improvement after peripheral neuromodulation procedures (GON), suggesting the existence of different subtypes of patients in the same diagnostic category. In some CCH patients, the peripheral component may contribute more to the genesis of the pain than the central components (Meyer et al., 1970). In order to ascertain that DBS would be offered only to patients with central predominant CCH we suggested GON stimulation and sphenopalatine ganglion local anesthetic blocks prior to DBS surgery. In the future, PET and functional brain MR studies may provide preoperative imaging of hypothalamic involvement that could correlate with the central mediation of the pain (Lodi et al., 2006). This imaging marker would indicate that the patient is likely to be a good candidate for DBS surgery. l

Currently, the collective experience from the literature suggests that 50–60% of patients respond to DBS

(Schoenen et al., 2005; Starr et al., 2007; Bartsch et al., 2008). In our opinion, refinement of targeting and patient selection will further improve the success rate of pHyp stimulation in CCH patients. Regardless, DBS has introduced hope to the otherwise limited options for medically refractory CCH patients and can be tested in carefully selected individuals. CCH is a dramatic and disabling condition that often leads to abuse of steroids (two patients of the operated series were unable to walk due to severe leg myopathy induced by chronic steroid abuse). Likewise, triptan abuse can be life-threatening (one patient died before DBS implantation due to myocardial infarction). The cost of the procedure is largely compensated by one year of pain remission even if the disease cannot be cured by DBS. The experience of pHyp stimulation in cluster headache patients led us to treat other refractory diseases in which the pHyp is presumed to be involved, such as disruptive behaviour (Franzini et al., 2007) and multifocal epilepsy (data in press). We suggest that this target, originally explored by Sano with radio­ frequency lesions (Sano et al., 1970), should be considered the node of a complex network modulating the neurovegetative system as well as seizure threshold and nociception of the first trigeminal branch.

References Bartsch, T., Pinsker, M.O., Rasche, D., Kinfe, T., Hertel, F., Diener, H.C. et al. (2008) Hypothalamic deep brain stimulation for cluster headache: experience from a new multicase series. Cephalalgia 28 (3): 285–95. Burns, B., Watkins, L. and Goadsby, P.J. (2007) Treatment of medically intractable cluster headache by occipital nerve stimulation: long-term follow-up of eight patients. Lancet 369: 1099–106. Cordella, R., Carella, F., Leone, M., Franzini, A., Broggi, G., Bussone, G. et al. (2007) Spontaneous neuronal activity of the posterior hypothalamus in trigeminal autonomic cephalalgias. Neurol. Sci. 28 (2): 93–5. Ferroli, P., Franzini, A., Marras, C., Maccagnano, E., D’Incerti, L. and Broggi, G. (2004) A simple method to assess accuracy of deep brain stimulation electrode placement: pre-operative stereotactic CT-postoperative MR image fusion. Stereotact. Funct. Neurosurg. 82: 14–19. Franzini, A., Ferroli, P., Leone, M. and Broggi, G. (2003) Stimulation of the posterior hypothalamus for treatment of chronic intractable cluster headaches: first reported series. Neurosurgery 52: 1095–9. Franzini, A., Ferroli, P., Leone, M., Bussone, G. and Broggi, G. (2004) Hypothalamic deep brain stimulation for the treatment of chronic cluster headaches: a series report. Neuromodulation 7: 1–8. Franzini, A., Marras, C., Tringali, G., Leone, M., Ferroli, P., Bussone, G. et al. (2007) Chronic high frequency stimulation of the posteromedial hypothalamus in facial pain syndromes and behaviour disorders. Acta Neurochir. (Suppl.) 97 (Pt 2): 399–406. Headache Classification Committee of the International Headache Society (2004) The International Classification of Headache Disorders, 2nd edn. Cephalalgia 24: 1–195.

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Leone, M., Franzini, A. and Bussone, G. (2001) Stereotactic stimulation of posterior hypothalamic gray matter in a patient with intractable cluster headache. N. Engl. J. Med. 345: 1428–9. Leone, M., Franzini, A., Broggi, G. and Bussone, G. (2006) Hypothalamic stimulation for intractable cluster headache: long-term experience. Neurology 67 (1): 150–2. Leone, M., Franzini, A., Proietti Cecchini, A., Broggi, G. and Bussone, G. (2007) Stimulation of occipital nerve for drug-resistant chronic cluster headache. Lancet Neurol. 6 (4): 289–91. Leone, M., Proietti Cecchini, A., Mea, E., Curone, M., Tullo, V., Casucci, G. et al. (2007) Functional neuroimaging and headache pathophysiology: new findings and new prospects. Neurol. Sci. 28 (Suppl 2): S108–S113. Lodi, R., Pierangeli, G., Tonon, C., Cevoli, S., Testa, C., Bivona, G. et al. (2006) Study of hypothalamic metabolism in cluster headache by proton MR spectroscopy. Neurology 66 (8): 1264–66. May, A., Bahra, A., Buchel, C., Frackowiak, R.S. and Goadsby, P.J. (1998) Hypothalamic activation in cluster headache attacks. Lancet 352: 275–8.

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Meyer, J.S., Binns, P.M., Ericsson, A.D. and Vulpe, M. (1970) Sphenopalatine gangionectomy for cluster headache. Arch. Otolaryngol. 92 (5): 475–84. Mauskop, A. (2005) Vagus nerve stimulation relieves chronic refractory migraine and cluster headaches. Cephalalgia 25 (2): 82–6. Sano, K., Mayanagi, Y., Sekino, H., Ogashiwa, M. and Ishijima, B. (1970) Results of stimulation and destruction of the posterior hypothalamus in man. J. Neurosurg. 33: 689–707. Schoenen, J., Di Clemente, L., Vandenheede, M., Fumal, A., De Pasqua, V., Mouchamps, M. et al. (2005) Hypothalamic stimulation in chronic cluster headache: a pilot study of efficacy and mode of action. Brain 128: 940–7. Starr, P.A., Barbaro, N.M., Raskin, N.H. and Ostrem, J.L. (2007) Chronic stimulation of the posterior hypothalamic region for cluster headache: technique and 1-year results in four patients. J. Neurosurg. 106 (6): 999–1005. Torelli, P. and Manzoni, G.C. (2003) Pain and behaviour in cluster headache. A prospective study and review of the literature. Funct. Neurol. 18: 205–10.

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Motor Cortex Stimulation for the Treatment of Neuropathic Pain Jean Paul Nguyen, Jean Pascal Lefaucheur, Sylvie Raoul, Vincent Roualdes, Yann Péréon, and Yves Keravel o u tl i ne Introduction

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and coworkers observed that central lesions in animals could induce the development of abnormal neuronal hyperactivity in the thalamus, which he interpreted as reflecting deafferentation, and that this hyperactivity could be reduced by chronic stimulation of the sensorimotor cortex. The results of a first series of patients with thalamic pain (Tsubokawa et al., 1993) demonstrated that chronic cortical stimulation was effective on this type of pain. In this series, 67% of patients obtained marked and lasting improvement, corresponding to much better results than those obtained with thalamic stimulation. Surprisingly, MCS was found to be the most effective, as stimulation of the sensory cortex would even occasionally accentuate the pain. In 1993, Meyerson and co­workers showed that MCS was effective for neuropathic facial pain and most subsequent studies have confirmed these results (Hosobuchi, 1993; Canavero, 1995;

Neuropathic pain secondary to a brain lesion (central pain) or a trigeminal nerve lesion (neuropathic facial pain) is generally difficult to treat. Drug treatments usually have limited efficacy and spinal cord stimulation (SCS) techniques are inappropriate and ineffective. Stimulation of the ventral posterior lateral (VPL) nucleus of the thalamus, which should theoretically improve neuropathic facial pain, has been found to be disappointing regarding efficacy (Gybels, 1992; Tasker and Vilela Filho, 1995). On the other hand, pain secondary to a thalamic lesion is generally refractory to thalamic stimulation. For these reasons, the motor cortex stimulation (MCS) technique, first proposed in 1991 by Tsubokawa et al., appeared to be a very useful alternative. Tsubokawa

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IFS

LF

Figure 40.1  Anatomical landmark of the central region and correlations with functional zones of the MC. General view of the central region (curvilinear reconstruction) showing the position of the central fissure (CF), lateral fissure (LF), midline (ML), infer­ ior frontal sulcus (IFS), and superior frontal sulcus (SFS), which is connected to the superior precentral sulcus (SpcS). The functional zone corresponding to the representation of the face (f) is situated just anteriorly to the central fissure (CF), between the lateral fissure (LF) and the inferior frontal sulcus (IFS). The upper limb(s) is represented in a zone limited inferiorly by the inferior frontal sulcus (IFS) and superiorly by the superior frontal sulcus (SFS). The lower part of the body, including the lower limb, is represented in a zone (i) situated between the interhemispheric fissure (ML) and the super­ior frontal sulcus (SFS). At this level, the MC extends anteriorly beyond the superior precentral sulcus (SpcS)

Herregodts et al., 1995; Peyron et al., 1995; Ebel et al., 1996; Nguyen et al., 1997, 1999; Rainov et al., 1997; Yamamoto et al., 1997; Katayama et al., 1998, 2001, 2003; Mertens et al., 1999; Garcia-Larrea et al., 1999; Carroll et al., 2000; Saitoh et al., 2000, 2001, 2003; Mogilner and Rezai, 2001; Smith et al., 2001; Sol et al., 2001; Canavero and Bonicalzi, 2002; Velasco et al., 2002; Son et al., 2003; Brown and Pilitsis, 2005; Nuti et al., 2005; Pirotte et al., 2005; Slawek et al., 2005; Hirayama et al., 2006; Rasche et al., 2006). These studies have also shown that MCS can be effective for the treatment of other types of neuropathic pain, especially after spinal cord lesions (Nguyen et al., 1999; Tani et al., 2004). In this review, we will successively describe the various steps of progress of the surgical procedure, the current state of the main indications and an hypothesis regarding the analgesic mechanism of action/s of chronic MCS.

Technique Preoperative Localization of the Motor Cortex Previous clinicopathological and electrophysiological studies have established that the primary

MC (Brodmann area 4 [Lefaucher et al., 2006]) is situated in the anterior part of the central fissure (area 4b) and part of the cortex situated immediately anteriorly to this fissure (area 4a). The studies by Penfield and Rasmussen (1950) also confirmed the somatotopic representation of this cortex, with the lower limbs, upper limbs, and face represented on the superior, middle, and inferior parts of the precentral region, respectively, the so-called motor homunculus. The motor cortex (MC) can therefore be indirectly located by identifying the anatomical position of the central fissure, which can be visualized by computerized tomography (CT) scan and even more clearly visualized by magnetic resonance imaging (MRI). However, conventional axial, frontal, and sagittal slices are not very suitable for recognition of the various zones (superior, middle, and inferior) of the central and precentral regions. Progress in digital imaging processing now allows identification of these various zones. Images obtained after curvilinear reconstruction along the curvature of the cortical surface allow very precise recognition of these various structures (Figure 40.1). Visualization of inferior and superior frontal sulci as well as the interhemispheric fissure and lateral fissure allows objective delineation of the three main functional zones of the precentral region. Theoretically, in order to treat facial neuropathic pain, the lower part of the precentral region corresponding to the representation of the face on the motor homunculus would need to be stimulated. According to studies by Penfield and Rasmussen (1950), Woolsey et al. (1979), and McCarthy et al. (1993), this zone is limited inferiorly by the frontoparietal operculum and lateral fissure, and superiorly by a horizontal line extending posteriorly in the direction of the infer­ ior frontal sulcus. At this level, the MC occupies the most posterior portion of the precentral gyrus. For the treatment of deafferentation pain of the upper limb, the zone to be stimulated is situated between the infer­ ior and superior frontal sulci and extends anteriorly almost as far as the superior precentral sulcus. The MC situated between the superior frontal sulcus and the interhemispheric fissure corresponds to the representation of the trunk and the proximal part of the lower limbs. Classically, the distal part of the lower limbs is mainly represented on the internal surface of the hemisphere. However, Woolsey et al. (1979) has shown that in some cases, this representation can extend to the superior part of the convexity, even as far as the superior frontal sulcus. At this level, the MC has a larger anterior extension, beyond the level of the superior precentral sulcus. These various functional zones are easy to identify by using neuronavigation systems (Peyron et al., 1995;

IVC.  Brain stimulation for pain



Technique

517

anesthesia over the simple burr-hole approach initially recommended by Tsubokawa et al. (1991). By allowing suspension of the dura mater, a true craniotomy limits the risk of postoperative extradural hematoma. A craniotomy 4–5 cm in diameter allows sufficient exploration of the central region to detect the appropriate segment of MC to be stimulated.

ML

CF

Intraoperative Electrophysiology SFS

Figure 40.2  Reconstruction of the cortical surface: The marker corresponds to the target chosen to stimulate the zone corresponding to the upper limb. CF (central fissure), ML (midline), SFS (super­ ior frontal sulcus)

Nguyen et al., 1999; Tirakotai et al., 2004). Reconstructed images of the cortical surface (Figure 40.2) can be used, but it is not always easy to recognize the various sulci of the region. In this case, views parallel to the cortical surface can be used, as they provide better visualization of the various anatomical structures (Figure 40.3). The neuronavigation system allows very exact positioning of the centre of the craniotomy over the target (Figure 40.4). Other examinations can be helpful for preoperative localization of the target, especially functional MRI and repetitive transcranial magnetic stimulation (rTMS). Functional MRI allows good visualization of the sensorimotor cortex and its spatial resolution is sufficient to allow somatotopic mapping (Rao et al., 1995; Roux et al., 2001). The results of functional MRI are concordant with those provided by direct cortical stimulation and intraoperative somatosensory evoked potentials (SSEPs) (Sol et al., 2001; Pirotte et al., 2005) (Figure 40.5). rTMS is another technique that can be used to locate the MC (Migita et al., 1995; Lefaucheur, 2006). It can be linked to a neuronavigation system, allowing precise determination of the cortical zone stimulated.

Craniotomy Several authors (Peyron et al., 1995; Ebel et al., 1996; Nguyen et al., 2003) have demonstrated the advantages of craniotomy performed under general

The first step of intraoperative electrophysiology is to confirm the position of the central fissure detected by the neuronavigation system by recording SSEPs. Inversion of the polarity of the potentials recorded 20–25 milliseconds after stimulation of the median nerve at the wrist (N20–P25 phase shift) theoretically occurs across the central fissure. The N20 potential recording zone is situated anteriorly to this sulcus and globally corresponds to the part of the MC corresponding to representation of the hand. Potentials recorded after stimulation of the posterior tibial nerve or labial commissure are difficult to interpret and are consequently rarely used to locate the central fissure. In our experience, an excellent correlation has always been observed between SSEP data and the anatomical position of the central fissure indicated by neuronavigation (Nguyen et al., 2003). SSEPs can be difficult or impossible to record in the presence of severe deafferentation. The second step of intraoperative electrophysiology consists of confirming the position of the MC by stimulation. The objective of this step is to stimulate the contacts of the grid placed over the MC to trigger muscle twitches in the zone corresponding to the site of the pain. In the case of upper limb pain, those contacts providing the highest N20 potentials will be stimulated. For pain of the face and lower half of the body, contacts situated below or above this zone will be stimulated. We currently prefer to stimulate the cortex by using a single shock with a pulse width of 2 ms (two 1 ms pulses separated by a very short interval). Under these conditions, even when using stimulation intensities greater than 50 mA, the risk of seizures is almost nonexistent. The amplitude of the motor response largely depends on the depth of anesthesia which can be evaluated by using the bispectral (BIS) index (Lobo and Beiras, 2007). First we determine the threshold for motor twitch and then the amplitude of the muscle response is measured for a fixed stimulation intensity. The contact inducing motor responses at the lowest limit stimulation intensity can therefore be easily determined. It is generally the same contact that also induces the largest response. According to

IVC.  Brain stimulation for pain

518

40.  Motor Cortex Stimulation for the Treatment of Neuropathic Pain

1

2 1

2 CF CF

(A) (B)

(C)

CF CF

1 SFS

SFS

2

IFS (E)

(D)

Figure 40.3  Reconstructions parallel to the surface of the cortex. Postoperative fusion of CT images with preoperative MRI showing the position of the electrode contacts. (A) Four-contact electrode, parasagittal view. (B) Position of contact 1 (over the central fissure), axial view. (C) Position of contact 2 (over area 4a), axial view. (D) Position of contact 2 on a view parallel to the surface of the cortex. (E) Position of contact 1 on a view parallel to the surface of the cortex. Views parallel to the surface of the cortex allow more reliable identification of the various anatomical structures of the central region. CF (central fissure), SFS (superior frontal sulcus), IFS (inferior frontal sulcus)

Dura T

Figure 40.4  Craniotomy centered on the target. The target (T) was determined on preoperative imaging. The marker, corresponding to the image of the laser beam, is situated on the dura mater (Dura). It is important to verify, at each step of craniotomy, that the target remains in the centre of the craniotomy

the data of the literature, anodal stimulation (positive pole) generally induces the best response and defines the position of the contact to be placed on the surface of the MC. Cathodal stimulation of this contact (negative pole) is used for chronic stimulation. Positioning of the electrode(s) (Resume, Medtronic, Inc., Minneapolis, MN) (we generally use two electrodes; see Figure 40.5) is determined by comparison of anatomical and electrophysiological data. We usually place the two electrodes perpendicularly to the direction of the central sulcus so that the two contacts of each electrode are situated anteriorly to the central sulcus. The distance between electrodes depends on the extent of the territory to be stimulated. To treat facial pain, we place the two electrodes in contact with each other. In the case of pain affecting the upper limb and the face, the distance between electrodes depends on the results of the electrophysiological study. Electrodes are sutured to the dura mater by two sutures (see Figure 40.5).

IVC.  Brain stimulation for pain



519

Technique

ML

SFS

A

(B)

CF (A)

a

(C)

(D)

Figure 40.5  Functional MRI in a case of pain related to paraplegia. (A) Activation of the precentral cortex situated close to the midline on functional MRI (A, C and D) while the patient imagines a movement of the lower limbs. Activation is predominantly observed on the right side (image A). A zone of more lateral zone of activation is also observed (a in image C). A Resume electrode was placed over the main activation zone and a second electrode was placed more laterally (image B). Contact 1 of the most median electrode (images B and D) is positioned over the main activation zone. Chronic cathodal stimulation of this contact induced significant pain relief. CF (central fissure), ML (midline), SFS (superior frontal sulcus)

When anatomic and electrophysiological data are concordant, we connect the electrode, during the same operation, to the pulse generator implanted subcutaneously, generally in the infraclavicular region. When anatomical and electrophysiological data are not concordant, the electrode is connected to an extension lead and its distal end is externalized to allow testing of the efficacy of stimulation for several days. Electrophysiological studies are repeated during this period (particular single shock stimulation) with the patient fully conscious. In this way, the true threshold to induce motor twitch can be determined without a risk of inducing seizures. In our experience, the stimulation intensity required for chronic stimulation is about 30% of motor threshold. Some teams

(Henderson et al., 2004) have obtained good results with higher stimulation intensities corresponding about to 70–80% of the motor threshold (Meyerson et al., 1993; Tsubokawa et al., 1993).

Stimulation Parameters In our experience (Nguyen et al., 1999), mean stimulation parameters for responding patients are as follows: frequency 40 Hz (25–55); pulse width 82.4 s (60–180); amplitude 2.1 V (1, 3–4). Bipolar stimulation is used in most cases with the negative pole placed over the MC and the positive pole placed immediately posteriorly over the central fissure or primary sensory

IVC.  Brain stimulation for pain

520

40.  Motor Cortex Stimulation for the Treatment of Neuropathic Pain Central pain

100 80

80

60

60 40

83.2

40 20

Trigeminal neuropathic pain

100

83.7

20

39

36

0

0 Pre Post Figure 40.6  Significant improvement of VAS in 35 patients with central pain (p  0.0001). First column (pre): preoperative score. Second column (post): postoperative score (mean follow-up: 89 months). Error bars: standard error of the mean

cortex. Studies by Manola et al. (2007) have shown that this combination can be used to stimulate horizontal and vertical fibres situated in area 4a as well as area 4b.

Indications and results We reviewed the results of a series of 100 patients operated on in our service at Henri Mondor hospital in Créteil, France, between May 1993 and October 2004 and the main series that are published in the literature. The Créteil series concerns 43 women and 57 men aged 21–84 years (mean age: 55 years), with a history of neuropathic pain for an average of 7 years (range: 1–30 years). Thirty-five patients suffered from central pain, 33 patients presented with neuropathic facial pain, 23 cases had peripheral pain, and 9 cases had pain related to a spinal cord lesion. The mean follow-up was 89  41 months (range: 29–170 months). In every case, the intensity of pain was evaluated preoperatively and postoperatively by visual analogue scale (VAS) (Huskisson et al., 1976; Jensen et al., 1994). In 43 cases, we evaluated the pain using the McGill Pain Questionnaire (MPQ) (Melzack, 1975), the Wisconsin Brief Pain Questionnaire (WBPQ) (Daut et al., 1983), and the Medication Quantification Score (MQS) (Steedman et al., 1992). Statistical analysis was performed using Wilcoxon’s test.

Pre

Post

Figure 40.7  Significant improvement of VAS in 33 patients with neuropathic facial pain (p  0.0001). Detail as for Figure 40.6

in 13/35 patients (37.1%), and a satisfactory result (between 40% and 60% improvement of VAS) was obtained in 15/35 patients (42.8%). The result was insufficient (less than 40% improvement of VAS) in 7 patients (20%). The mean improvement was 53% for VAS (p  0.0001) (Figure 40.6), 56.7% for total MPQ score (p  0.02), 62.7% for WBPQ (p  0.01), and 32.9% for MQS (p  0.06).

Neuropathic Facial Pain In the series of 33 patients with neuropathic facial pain, pain was secondary to thermocoagulation of the trigeminal ganglion in 14/33 cases, treatment of a neurovascular conflict in 3 cases, alcohol injection of the trigeminal ganglion in 1 case, a dental procedure in 4 cases, ENT surgery (to the maxillary sinus) in 4 cases, surgery to brain stem lesion in 2 cases, surgery to a temporal lesion close to the cavernous sinus in 2 cases, ophthalmic herpes zoster in 2 cases, and trauma to the base of the skull in 1 case. A good result was obtained in 15 patients (45.4%), a satisfactory result was obtained in 10 patients (30.3%), and the result was considered to be insufficient in 8 patients (24.2%). The mean improvement was 55% for VAS (p  0.0001) (Figure 40.7), 40.6% for total MPQ score (p  0.04), 24.2% for WBPQ (p  0.04), and 41.9% for MQS (p  0.06). Good or satisfactory results were obtained in 93% of patients with pain secondary to thermocoagulation, in 75% of patients with pain secondary to dental or sinus surgery, and in 66% of patients with pain secondary to treatment of a neurovascular conflict.

 Central Pain

Peripheral Pain

In the series of 35 patients with central pain, pain was related to deep intracerebral hemorrhage in 15 cases, ischemic stroke in 17 cases, head injury in 2 cases, and thalamic abscess in 1 case. A good result (greater than 60% improvement of VAS) was obtained

In the series of 23 patients with peripheral pain, pain was secondary to amputation in 3 cases, a surgical incision in 2 cases, a brachial plexus avulsion in 11 cases, and a peripheral nerve lesion in 7 cases (neurofibroma in 3 cases and trauma in 2 cases). SCS was performed

IVC.  Brain stimulation for pain



521

Complications

whenever there was a possibility of improvement using this technique. A good result was obtained by MCS in 11/23 patients (47.8%), a satisfactory result was obtained in 4/23 patients (17.4%), and an insufficient result was observed in 8/23 patients (34.8%). Among the patients with pain secondary to a brachial plexus avulsion, a good result was obtained in 3 patients (27.3%), a satisfactory result was obtained in 1 patient (9.1%), and the result was insufficient in 7 patients (63.6%). Among patients with pain secondary to a peripheral nerve lesion, a good result was obtained in 3 patients (60%), a satisfactory result was obtained in 1 patient (20%), and the result was insufficient in 1 patient (20%). Among the 3 patients with pain secondary to an amputation, a good result was obtained in 1 patient and a satisfactory result was obtained in the other 2 patients.

Pain Secondary to a Spinal Cord Lesion Pain was secondary to trauma in 5 cases, syringo­ myelia in 3 cases, and surgery for treatment of a thoracic disk herniation in 1 case. A good result was obtained in 5/9 patients (55.5%) and an insufficient result was observed in 4/9 patients (44.5%). Among the 5 patients with pain secondary to vertebral and spinal cord injury, 3 obtained a good or satisfactory result. Two out of 3 patients with pain secondary to syringomyelia obtained a good result. Patients whose VAS score improved by at least 40% were generally satisfied with the operation. This was the case for 80% of patients with central or peripheral pain, 75.7% of patients with neuropathic facial pain, 55.5% of patients with pain secondary to a spinal cord lesion, and 36.4% of patients with pain related to a brachial plexus avulsion (see Table 40.1).

Data from the Literature We reviewed the papers published since 1991 in order to compare our results with the results published in the literature. In 1991, 332 cases had been published, but only nine series reported more than 10 cases (Meyerson et al., 1993; Tsubokawa et al., 1993; Smith et al., 2001; Canavero and Bonicalzi, 2002; Katayama et al., 2003; Saitoh et al., 2003; Nuti et al., 2005; Pirotte et al., 2005; Rasche et al., 2006). We selected only the most recent publications of the various teams, as they generally summarize the cases reported in previous publications. Comparison of series is difficult, as they do not always use the same efficacy criteria. No study has reported a systematic analysis of the results with and without stimulation, as has been performed to evaluate the results of SCS (Monhemius and Simpson, 2003).

We defined a good result as those cases in which the VAS score was improved by 40% or more. These series concern a total of 155 patients (Table 40.1). Globally, regardless of the indication, 92 patients were considered to be improved (64.8%). These publications included 89 cases of central pain, with a good result in 53 cases (59.5%), and 24 cases of neuropathic facial pain, with a good result in 18 cases (75%). These various results are globally concordant with those of our series. Published results for pain related to a brachial plexus avulsion are also concordant with our series, with almost identical results, between 40% and 50% of good or satisfactory results. The same applies to patients with pain related to a spinal cord lesion, as 60% of cases were improved in the literature, while, in our experience, a good or a satisfactory improvement was observed in 55.5% of cases. Our results differ from those of the literature for patients with phantom limb pain following amputation. In the literature, only 10 of the 19 published cases were improved (53%); in the series by Katayama and coworkers (1998) only 20% of patients were improved, while, in our series, all 3 patients were improved.

Complications In our series of 100 patients, 3 patients experienced an infection of the stimulator situated in the pectoral region (3%). These stimulators were removed and reimplanted 6 months after explant. Dehiscence of the skull incision site was observed in one patient with a favourable course after surgical revision. One patient experienced a postoperative ischemic stroke contralateral to the operative site, with a favourable outcome. In 2 patients who did not obtain improvement with MCS, the entire system was removed. In one patient, a trial of high intensity stimulation (8 V) triggered an episode of focal epilepsy. In the main published series that we reviewed (9 series, 155 patients), 29 patients (18.7%) developed seizures during clinical testing, but none experienced seizures during chronic stimulation. This risk is theoretically greater when the electrode is placed subdurally than when it is placed epidurally (Bezard et al., 1999). An infection occurred in 9 patients (5.8%), a local skin problem (skin ulceration) occurred in 2 patients (1.3%), and a hemorrhagic complication was observed in 2 patients (1.3%). These hemorrhagic complications resulted in serious consequences in 2 patients (one death and one case of major neurological sequelae). These two complications occurred in the same series using subdural implantation of the electrodes (Saitoh et al., 2003). Canavero and coworkers (1999) reported one case in which MCS triggered phantom pain.

IVC.  Brain stimulation for pain

522

Table 40.1  Summary of data concerning the main published series and the Créteil series of 100 patients Year

No. patients

Age (yr)

M/F

Indications

Fair–excellent results

Adverse and side effects

Technique

Rate

Amplitude

Pulse width

Tsubokawa et al.

1993

11

58.9 (52–72)

4/7

11 post-stroke

6/11 (54.5%), FU  2 yr

None

Epidural

5–120 Hz

3–8 V

200 (100–500) s

Meyerson et al.

1993

10

51.2 (44–71)

3/7

3 post-stroke 5 TGN 2 PNI

Post-stroke: 0/3 (0%) TGN: 5/5 (100%) PNI: 1/2 (50%) % VAS  50%, FU  4–28 mth

Generalized seizures in most patients during clinical test 1 epidural clot leading to marked aphasia 1 skin ulceration

Epidural

50 Hz

20–30% less than the motor threshold

300 s

Katayama et al.

1998

31

ND

20/11

28 post-stroke 3 Wallenberg

23/31 (74%) % VAS  60%, FU  2 yr

1 infection 3 generalized epileptic seizures during clinical test

Epidural

25–50 Hz

2–8  V

0.2  ms

Smith et al.

2001

12

60.7 (39–80)

6/6

6 post-stroke 3 phantom limb 1 head trauma 1 PNI 1 plexus avulsion

Post-stroke: 3/6 (50%) Phantom limb: 2/3 (67%)

1 subdural hematoma 3 infections 2 revisions of the system

Epidural

15–75 Hz

2.1–7 V

450 s

Head trauma: 1/1 PNI: 0/1 Plexus avulsion: 0/1

Canavero and Bonicalzi

2002

12

ND

ND

6 central pain 5 TGN 1 phantom limb

TGN: 5/5 (100%) ND: 7/12

1 super­ nu­merary phantom arm

Epidural

ND

ND

ND

Saitoh et al.

2003

19

30–68

16/3

9 post-stroke 6 plexus avulsion 2 phantom limb 1 SCI 1 pontine injury

14/19 (73.6%)

2 cerebral hemorrhages (1 vegetative state, 1 died) 2 infections

Subdural (in the fissure)

25–50 Hz

0.9–5 V

201 s

FU  6–50 mth

40.  Motor Cortex Stimulation for the Treatment of Neuropathic Pain

IVC.  Brain stimulation for pain

Study



2005

31

27–72

ND

22 central pain 4 SCI 4 plexus avulsion 1 head trauma

Central pain: 14/22 (63.6%) SCI: 4/4 (100%) Plexus avulsion: 3/4 (75%) % VAS  40%, FU  49 mth

8 focal seizures 1 infection 2 surgical wound healing

Epidural 29 Subdural 2

30–80 Hz

ND

60–330 s

Pirotte et al.

2005

12

55.6 (33–70)

5/7

4 TGN 3 post-stroke 3 plexus avulsion 1 SCI (ependymoma) 1 cervical syrinx

TGN: 3/4 (75%) Post-stroke: 3/3 (100%) Plexus avulsion: 1/3 (33%) SCI: 0/1 Cervical syrinx: 1/1

1 subdural infection 1 focal seizure

Epidural

40 Hz

1–5  V

100 s

Rasche et al.

2006

17

65.1 (44–82)

4/13

10 TGN 7 central pain

TGN: 5/10 (50%) Central pain: 3/7 (42.8%) % VAS  50%, FU  49.7 mth

7 intraoperative seizures 1 infection 1 speech arrest for 3 mth

Epidural

50–85 Hz

3.5–6 V

210–360 s

100

55 (21–84)

57/44

35 central pain

Central pain: 28/35 (80%) TGN: 25/33 (75.7%) PNI: 7/12 (58.3%) Plexus avulsion: 4/11 (36.3%) SCI: 5/9 (55.5%) % VAS  40%, FU  89 mth

3 infections 1 skin ulceration 1 contralateral stroke 2 removal of the system due to poor results

Epidural

41.3 Hz (25–60)

2.3 V (1–3.5)

68.8 s (60–150)

Nguyen et al.

33 TGN 12 PNI 11 plexus avulsion 9 SCI

Complications

IVC.  Brain stimulation for pain

Nuti et al.

1 focal seizure

ND, data not available; TGN, trigeminal neuropathic pain; PNI, peripheral nerve injury; SCI, spinal cord injury

523

524

40.  Motor Cortex Stimulation for the Treatment of Neuropathic Pain

Mechanism of action The mechanism of action of MCS has not been fully elucidated. In his first publications, Tsubokawa proposed the hypothesis that MCS antidromically activated neurons of the sensory cortex (Tsubokawa et al., 1991), allowing descending impulses to activate structures inhibiting the abnormal thalamic hyperactivity that is seen after deafferentation. However, several results tended to refute this hypothesis. The clinical improvement after MCS of some patients with infarction of the postcentral region argued against this role, as did the absence of modification of cerebral blood flow in the postcentral region on PET scan during MCS (Garcia-Larrea et al., 1999). These studies showed that the most marked changes in regional blood flow in response to MCS mainly occurred in the ventral lateral nucleus and the ventral anterior nucleus of the thalamus. These structures are directly connected to the MC and direct activation of these nuclei can explain the effects of MCS on motor disorders such as improvement of spasticity (Katayama et al., 2003), tremor (Nguyen et al., 1998) or other abnormal movements (Franzini et al., 2000). MCS also induces changes in blood flow in other structures more directly known to be involved in pain mechanisms, especially the midline thalamic nuclei, the anterior cingulate gyrus, insula, and the cephalad part of the brainstem (Garcia-Larrea et al., 1999). The role of the anterior cingulate gyrus and insula in pain mechanisms and their relations with the midline thalamic nuclei have been clearly established (Garcia-Larrea et al., 1999). The results of MCS obtained in patients with phantom limb pain showed that the possible modifications of somatotopy that can be demonstrated by functional MRI and/or TCMS must also be taken into account (Roux et al., 2001; Sol et al., 2001). The direct action of the pyramidal tract on the posterior horn of the spinal cord certainly plays a role in the analgesic effects of MCS (Coulter et al., 1974). It is now fairly well established that the analgesic effect of MCS depends on the zone of the MC which is stimulated. It is therefore essential to take the somatotopic organization of the cortex into account when using this therapy. Our studies (Nguyen et al., 1999) have demonstrated that the sites of stimulation effective on pain correspond to the sites at which intraoperative stimulation triggers motor responses, which clearly corresponds to MCS. Recent studies have emphasized the role of the MC in modulation of pain phenomena (Farina et al., 2003; Raij et al., 2004; Lefaucheur et al., 2006). In a series of patients with neuropathic pain of the distal extremity of the upper limb, Lefaucheur et al. (2006)

showed that these patients presented with cortical disinhibition within the MC corresponding to the representation of the painful limb. rTMS at 10 Hz to this cortical zone restored normal cortical inhibition, which was correlated with significant improvement of pain. Stimulation at 1 Hz had no effect on pain and cortical disinhibition. These results suggest that MCS may act upon intracortical GABAergic circuits. Studies by Manola and coworkers (2007) suggest that stimulation mainly activates fibres parallel to the cortical surface. The analgesic effect of MCS might be explained by predominant stimulation of GABAergic interneurons whose projections are arranged horizontally within the cortex and by modulation of fibres derived from the thalamus (VPL) that are also arranged horizontally in layer 1, the most superficial layer of the cortex (Villanueva and Fields, 2004). These fibres are activated by cathodal stimulation of area 4a, which is generally used with this therapy, while anodal stimulation induces the opposite effect. In contrast, anodal stimulation of area 4b induces activation of fibres that run perpendicular to the surface of the cortex. These data could explain why the best analgesic result of MCS is generally obtained by bipolar stimulation with the cathode situated over area 4a (cortex situated immediately anteriorly to the central fissure) and the anode situated over area 4b (contact situated over the central fissure) (see Figure 40.3). Because there are generally no immediate clinical signs (such as paresthesia) to guide adjustment of the stimulator, adjustment of other stimulation parameters is difficult and remains empirical. The analgesic effect of MCS is almost always delayed by 24–48 hours after the onset of stimulation, and therefore, it is illogical to try several different settings on the same day. In rare cases, the analgesic effects of MCS has been obtained after only minutes following the start of stimulation. In these patients, the best effect was obtained with a relatively low stimulation amplitude, about 2  mA (2 V for an impedance of 1000 Ohms) at a frequency of about 40 Hz with a pulse width of 60 s.

Conclusions MCS, first recommended by Tsubokawa, is a promising treatment modality for deafferentation pain. It is essentially indicated for the treatment of pain that cannot be controlled by SCS: central pain and neuropathic facial pain. Optimal selection of the best indications must be based on a technique that precisely identifies the zone to be stimulated. A relatively large craniotomy and the use of neuronavigation systems appear to be essential. Other indications need to be confirmed: pain

IVC.  Brain stimulation for pain



References

in paraplegic patients, phantom limb pain, especially plexus avulsion pain. More systematic use of functional MRI and transcranial magnetic stimulation will probably contribute to the extension of indications for MCS. Further progress also needs to be made in our understanding of the mechanisms of action of MCS.

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Slawek, J., Reclowicz, D., Zielinski, P., Sloniewski, P. and Nguyen, J.P. (2005) Motor cortex stimulation in the central pain syndrome. Neurol. Neurochir. Pol. 39: 237–40. Smith, H., Joint, C., Schlugman, D., Nandi, D., Stein, J.F. and Aziz, T.Z. (2001) Motor cortex stimulation for neuropathic pain. Neurosurg. Focus 11: Article 2. Sol, J.C., Casaux, J., Roux, F.E., Lotterie, J.A., Bousquet, P., Verdié, J.C. et al. (2001) Chronic motor cortex stimulation for phantom limb pain: correlations between pain relief and functional imaging studies. Stereotact. Funct. Neurosurg. 77: 172–6. Son, B.C., Kim, M.C., Moon, D.E. and Kang, J.K. (2003) Motor cortex stimulation in a patient with intractable complex regional pain syndrome Type II with hemibody involvement. J. Neurosurg. 98: 175–9. Steedman, S.M., Middaugh, S.J., Kee, W.G., Carson, D.S., Harden, R.N. and Miller, M.C. (1992) Chronic-pain medications: equivalence levels and method of quantifying usage. Clin. J. Pain, 8: 204–14. Tani, N., Saitoh, Y., Hirata, M., Kato, A. and Yoshimine, T. (2004) Bilateral cortical stimulation for deafferentation pain after spinal cord injury. Case report. J. Neurosurg. 101: 687–9. Tasker, R.R. and Vilela Filho, O. (1995) Deep brain stimulation for neuropathic pain. Stereotact. Funct. Neurosurg. 65: 122–4. Tirakotai, W., Riegel, T., Sure, U., Rohlfs, J., Gharabaghi, A. and Bertalanffy, H. (2004) Image-guided motor cortex stimulation in patients with central pain. Minim. Invas. Neurosurg. 47: 273–7. Tsubokawa, T., Katayama, Y., Yamamoto, T., Hirayama, T. and Koyama, S. (1991) Chronic motor cortex stimulation for the treatment of central pain. Acta Neurochir. (Suppl.) 52: 137–9. Tsubokawa, T., Katayama, Y., Yamamoto, T., Hirayama, T. and Koyama, S. (1993) Chronic motor cortex stimulation in patients with thalamic pain. J. Neurosurg. 78: 393–401. Velasco, M., Velasco, F., Brito, F., Velasco, A.L., Nguyen, J.P. and Marquez, I. (2002) Motor cortex stimulation in the treatment of deafferentation pain. I. Localization of the motor cortex. Stereotact. Funct. Neurosurg. 79: 146–67. Villanueva, L. and Fields, H.L. (2004) Endogenous central mechanisms of pain modulation. In: L. Villanueva, A.H. Dickenson and H. Ollat (eds), Progress in Pain Research and Management, Seattle: IASP Press 31: pp. 223–43. Woolsey, C.N., Erickson, T.C. and Gilson, W.E. (1979) Localization in somatic sensory and motor areas of human cerebral cortex as determined by direct recording of evoked potentials and electrical stimulation. J. Neurosurg. 51: 476–506. Yamamoto, T., Katayama, Y., Hirayama, T. and Tsubokawa, T. (1997) Pharmacological classification of central post-stroke pain: comparison with the results of chronic motor cortex stimulation therapy. Pain 72: 5–12.

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Movement Disorders: Anatomy and Physiology Relevant to Deep Brain Stimulation Bradley C. Hiner, Gregory F. Molnar, and Brian Harris Kopell

o u t l i n e Introduction

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Introduction

underpinning the beneficial effects of deep brain stimulation for movement disorders will be discussed.

Functional neurosurgery has revolutionized the treatment of movement disorders such as Parkinson’s disease, essential tremor and dystonia. Concurrent with the development of deep brain stimulation have been advances in the understanding of the physiology of the target structures and the pathophysiological basis of movement disorders. Common targets for DBS are the subthalamic nucleus, the globus pallidus pars internus, and the ventralis intermedius nucleus of the thalamus. The fundamental concept of the corticostriato-pallido-thalamocortical (CSPTC) loop will be explored in the context of deep brain stimulation. Finally, current understandings of the mechanisms

Neuromodulation

Historical events in the development of functional neurosurgery for movement disorders Prior to the work of Russell Meyers in the late 1930s, most of the neurosurgical procedures for movement disorders involved ablation of some level of the pyramidal tract, beginning with Horsley’s 1890 precentral gyrus ablation but later extending to brain

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stem and spinal cord sectioning procedures (Meyers, 1958). In 1951 Mackay summarized the status of movement disorder surgery by stating, “The surgical relief of the extrapyramidal hyperkinesias seems to boil down to the artificial production of paralysis. On the whole, surgery has little application in this vast field” (Mackay, 1952). Fortunately, the basal ganglia had become a region of interest for movement disorders surgery beginning with pioneering work by Russell Meyers. Based on previous work by Browder, who proposed that abnormal movements originated in the neopallidum, Meyers extirpated the anterior two-thirds of the head of the caudate through an anterior transventricular approach in a patient with tremor (Browder, 1947; Meyers, 1958). He found that open surgery directed against the pallidofugal system was capable of reducing tremor and rigidity without the sacrifice of motor power. In 1947, Spiegel and Wycis modified the Horsley–Clarke instrument and introduced stereotactic surgery for use in humans, thus obviating the disadvantages of open craniotomy (Spiegel et al., 1947). Seven years later, Cooper inadvertently but serendipitously observed the virtual disappearance of tremor and rigidity without the loss of motor strength in a parkinsonian patient in whom the anterior choroidal artery was ligated (Cooper, 1954). This further implicated the role of the basal ganglia and the thalamus in movement disorder physiology/surgery. Hassler similarly pioneered stereotactic surgery in the ventrolateral thalamus in the 1950s by introducing the parcellation of the motor thalamus that is still the current surgical convention (Hassler et al., 1965). Svennilson and Leksell reported the beneficial effects of pallidotomy (particularly the posteroventral portion of the globus pallidus internus (GPi) in the last 19 patients in a series of 81 Parkinson’s disease (PD) patients) in 1960 (Svennilson et al., 1960), but it was not until the 1990s that this procedure with modern updates was favorably re-explored by Laitinin et al. (1992). Although lesioning procedures such as pallidotomy and thalamotomy were effective for many patients, they unfortunately carried a significant complication rate related to potential damage of neighboring structures (e.g., internal capsule, optic tract). In the 1980s Benabid and others, drawing on the historical observation that high frequency electrical stimulation (HFS) of intended lesion targets often mimicked the clinical results of the lesion itself, began applying deep brain stimulation (DBS) successfully in ventralis intermedius (Vim), GPi, and subthalamic nucleus (STN), thus obviating the need for lesioning with its attendant potential for side effects (Benabid et al., 1989).

Physiology of parkinson’s disease Seminal work by DeLong and others in the 1970s describing normal basal ganglia physiology in primates later led to characterization of pathologically hyperactive GPi and STN neuronal discharges in primate models of PD (DeLong, 1971, 1990). Many authors credit the Alexander and Delong “rate” model of basal ganglia (Alexander et al., 1990; DeLong, 19909) for the generation of further research into the pathophysiology of movement disorders and for the resurgence of stereotactic ablation and deep brain stimulation (DBS) surgeries to treat symptoms of PD and other movement disorders (Albanese, 1998; Lang and Lozano, 1998a, 1998b; Mink, 1998; Lozano and Hamani, 2004). The rate model of basal ganglia structure and function, originally proposed in the 1980s, was largely based on animal models of hypokinetic movement disorders and from observations of PD patients who underwent stereotactic surgery (Hassler et al., 1970; Alexander et al., 1986; Albin et al., 1989; DeLong, 1990; Alexander and Crutcher, 1991; Marsden and Obeso, 1994; Parent and Hazrati, 1995; Mink, 1996; Goodman et al., 1998; Lang and Lozano, 1998b; Wichmaann and DeLong, 2003). The basal ganglia consist of a group of four subcortical nuclei that modulate cortical activity: (1) the striatum, which includes the caudate and the putamen, (2) the external and internal segments of the globus pallidus (GPe, GPi, respectively), (3) the subthalamic nucleus (STN), and (4) the substantia nigra, which includes the substantia nigra pars compacta (SNc) and pars reticulata (SNr). The input structure within the basal ganglia circuitry is the striatum (caudate and putamen), which receives excitatory glutamatergic (Glut) projections from the cortex and dopaminergic (DA) projections from the SNr. The major outputs of the basal ganglia are inhibitory GABAergic (GABA) projections from the GPi and the SNr to ventral lateral thalamus which then projects to both the cortex and the pedunculopontine nucleus (PPN) which in turn projects mainly to the spinal cord. Within the basal ganglia there are two major pathways: the direct pathway and the indirect pathway (Figure 41.1(A). The direct pathway involves direct inhibitory projections from the striatum to GPi/SNr. Activation of this pathway results in disinhibition of excitatory thalamocortical projections, which is considered to facilitate cortically initiated movement. The indirect pathway involves inhibitory projections from the striatum to the GPe. From the GPe there are inhibitory projections to the STN. The STN has excitatory glutamatergic

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Figure 41.1  The firing rate model of the basal ganglia for Parkinson’s. The normal state shows the connections of the various nuclei and the nature of the connection (A). In the parkinsonian state (B) the loss of dopamine in the SNc triggers a change in the intrinsic firing rates of the various nuclei and a shift in the balance of the direct and indirect pathways that ultimately causes dysfunction and the development of motor symptoms. The lightning bolts indicate areas where surgical lesions and deep brain stimulations (albeit different mechanisms) work to improve symptoms. The thickness of arrows indicates relative changes in firing intensity. Please see text for abbreviations and details

projections to GPi/SNr and GPe. Activation of the indirect pathway leads to increased inhibition of thalamocortical projections. Dopaminergic input from SNc is theorized to facilitate transmission along the direct pathway via excitatory D1 receptors in the striatum, but inhibit transmission over the indirect pathway via inhibitory D2 receptors. The PD pathology and the 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP) primate model of parkinsonism involves degeneration of the dopaminergic nigrostriatal projections due to a substantial loss of dopaminergic neurons in SNc (Langston and Ballard, 1984). The subsequent changes in striatal output are believed to cause the hypokinetic symptoms (i.e. akinesia, bradykinesia, rigidity, and tremor). According to the rate model, loss of DA input from SNc to D1 excitatory receptors and D2 inhibitory receptors in the striatum changes the relative weighting of function along the direct and indirect pathways. Reduced D1 activation decreases the excitation of the inhibitory projection from the striatum to GPi/SNr via the direct pathway and results in hyperactivity of GPi/SNr. Reduced D2 input decreases the inhibition of the inhibitory projection to GPe from the striatum, which disinhibits the STN and leads to increased excitation of GPi via the indirect pathway. Thus, these direct and indirect pathway changes lead to increased firing in GPi and overall

results in increased inhibitory tone in the motor thalamus. This overall inhibitory effect leads to inhibition of intended, voluntary movement (Figure 41.1B).

Deep brain stimulation: mechanism of action Today, DBS has become the gold standard for the surgical treatment of Parkinson’s disease and other movement disorders. This has occurred in part because programmers can reverse or minimize side effects and optimize clinical benefit by modifying the contacts at which electrical pulses are delivered and altering the stimulation parameters of those pulses. The indication for DBS of Vim DBS is confined largely to tremor while DBS of STN and GPi is used to address all the cardinal motor symptoms of PD as well as levodopa-induced dyskinesias and motor fluctuations. In addition, the largest published experience of DBS for dystonia targets the GPi (Kupsch et al., 2006). Despite the proven and durable benefits of DBS for PD, the exact mechanism underlying its beneficial effects remains a matter of debate (Benabid et al., 1989; Dostrovsky and Lozano, 2002; Vitek, 2002). The initial hypothesis that DBS acted like a functional lesion

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stemmed from the observation that stereotactic lesions and high-frequency electrical stimulation have similar clinical results with respect to tremor, rigidity and other cardinal features of the disorder. Subsequent work, however, has suggested that stimulation may actually mediate its beneficial effects by increasing output from the stimulated structure, not merely by suppressing local neuronal activity (Benabid et al., 2002). Evidence for this suggestion derives from neurophysiological recordings made during human DBS surgery in which a stimulating electrode was closely paired with a recording electrode in the target area. The recordings indicated that bursts of microstimulation in nearby structures inhibited the spontaneous activity of target neurons (Dostrovsky et al., 2000; Wu et al., 2001; Filali et al., 2004). These studies concluded that the activation of local inhibitory axons synapsing on the somas could be responsible. Whether this local stimulation caused activation of inhibitory elements or resulted in direct neuronal blockage could not be clarified. The weight of growing recent evidence suggests that the mechanism of DBS is more than simply a functional ablation secondary to depolarization blockade or synaptic inhibition. Electrical stimulation affects not just local cell bodies, but also dendrites, axon hillocks, and fibers of passage. Nowak and Bullier (1998) demonstrated in chronaxie experiments that axons are the most sensitive elements to electrical stimulation of cortical gray matter. Myelinated neurons have been modeled to follow external stimulation at frequencies of 500 Hz or greater (Krauthamer and Crosheck, 2002) and certain synapses have been determined to follow these high frequencies without failure (Taschenberger and von Gersdorff, 2000; Futai et al., 2001). This 500 Hz frequency is much higher than the effective therapeutic frequencies of 130–185 Hz used with DBS (Benabid et al., 1996; Moro et al., 2002; Vaillancourt et al., 2003; Kuncel and Grill, 2004). A recent DBS modeling study demonstrated that the activity of the soma and the activity of the axon can be decoupled, such that efferent output from the axon follows the stimulation frequency while at the same time the soma is inhibited (McIntyre et al., 2004). Indeed, several groups have reported clinical benefit of HFS in areas adjacent to the STN (prelemniscal radiation, posterior zona incerta) which are largely acellular regions containing pallidofugal and cerebellothalamic tracts where HFS stimulation would potentially have the greatest effects on network function (Kitagawa et al., 2005; Plaha et al., 2006; Carrillo-Ruiz et al., 2007). Further, evidence from computational modeling of the basal ganglia also suggests that effective STN DBS involves activation of pallidothalamic tracts (Figure 41.2).

There are several studies that support the hypothesis that DBS increases the output of neurons in the target nucleus. Using microstimulation techniques, Montgomery and colleagues reported that highfrequency stimulation of the GPi resulted in inhibition of thalamic activity, consistent with increased GPi output (Montgomery, 2006). Similarly, Hashimoto found that stimulation of the STN increased the firing rate of GPi neurons suggesting activation of the glutamatergic pathway (Hashimoto et al., 2003). Neurochemical studies have also shown evidence to support the stimulation effects of DBS. Using microdialysis, Windels et al. (2003) found a significant increase in glutamate in GPi and SNr and a significant increase in GABA in SNr downstream from trains of HFS. Stefani et al. (2005) found in an intraoperative microdialysis study that HFS of the STN resulted in elevated extracellular cyclic GMP levels in the GPi, consistent with an augmentation and not an inactivation of STN output (Stefani et al., 2005). Functional imaging data also supports the excitatory influence of DBS on neural networks. PET and fMRI studies have consistently demonstrated increased metabolism/BOLD signal changes in various structures along the subcortical network described above with STN and GPi DBS such as the putamen, pallidum, subthalamic nucleus, and thalamus. The increased PET and fMRI signals, which reflect local changes in synaptic activity, corroborate the presumed driving effect of DBS on axonal elements. Furthermore, increases in local synaptic activity have also been demonstrated in cortical areas directly connected to this subcortical network, especially supplementary motor area in the case of STN DBS and primary motor cortex in the case of Vim DBS (Rascol et al., 1994; Haslinger et al., 2001; CeballosBaumann, 2003). Extracellular stimulation results in both orthodromic and antidromic action potentials, the former from effects on local cell bodies and axons and the latter by stimulation of presynaptic axons and terminals (Grill and McIntyre, 2001). Since stimulation of axonal fibers occurs at a lower threshold than that required for cell bodies, this stimulation may result both in facilitated synaptic transmission as well as retrograde effects. Recent work utilizing computational models demonstrated that antidromic activation of axon terminals may lead to widespread activation or inhibition of targets remote from the site of stimulation (Grill et al., 2007). Antidromic potentials could thus potentially modulate orthodromic activity emanating within pathological basal ganglia-thalamocortical loops. Conversely, high frequency stimulation of axonal fibers can lead to downstream synaptic failure by neurotransmitter depletion (Urbano et al., 2002).

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Figure 41.2  Modeling evidence that predicts the role of fiber tract activation contributing to the benefit from DBS. Using finite element models of the monkey basal ganglia and DBS lead (A), it was predicted that effective stimulation involved activation of pallidothalamic/GPi fibers (B, C). Str  striatum; Th  thalamus; OT  optic tract; Sn  substantia nigra (Adapted with permission from Miocinovic et al., 2006. American Physiological Society)

In 2000, Montgomery and Baker suggested utilizing the concept of stochastic resonance in which a subthreshold normal signal, lost in the noise of a deranged neural network, is amplified by the addition of a regular noise (in this case HFS) by a constructive interference paradigm. An improvement in signal-to-noise ratio may occur in non-linear systems when noise is added to a subthreshold “weak” signal; while speculative, subthreshold basal ganglia output might be enhanced by the addition of extrinsically applied interference, i.e., DBS (Moss et al., 2004). Thus, there are apparent conflicting data in the literature regarding the inhibitory and/or excitatory effects of DBS. Certainly, inherent differences in experimental paradigms may explain some contradictions; however, the beneficial effects of DBS may involve apparently contradictory mechanisms.

Rate model Increased rates of GPi and STN firing that are observed through microelectrode recordings in PD

patients and in MPTP-treated primates corroborate the rate model (see Figure 41.1) (Filion and Tremblay, 1991; Filion et al., 1991; Hutchison et al., 1994; Lozano et al., 1995; Benabid, 2003). In addition, pallidal-receiving areas of thalamus exhibit reduced spontaneous firing rates in PD patients (Molnar et al., 2005). Although the rate model has been very influential in the selection of modern surgical targets, it has also become the subject of controversy. The model predicts that lesioning of the GPi should worsen dyskinesias or cause hyperkinesias; however, evidence shows that lesions and DBS of the GPi dramatically improve dyskinetic/hyperkinetic states (Marsden and Obeso, 1994). Similarly, lesions in the thalamus improve PD symptoms even though the rate model predicts that lesions should worsen akinesia (Marsden and Obeso, 1994; Albanese, 1998; Mink, 1998; Parent and Cicchetti, 1998). Recent anatomical evidence also suggests that the rate model requires significant revision. The descending projections to PPN and spinal cord from the basal ganglia are mistakenly neglected, and may play a vital role in axial symptoms of PD, including postural instability and disorders of gait (Breit et al., 2001,

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41.  Movement Disorders: Anatomy and physiology relevant to deep brain stimulation Cortex

GPe

STN

Cortical motor areas Striatum

Antikinetic �10 Hz

GPi/SNr

11−30 Hz

Prokinetic �70 Hz

Basal Ganglia STN GPi/SNr

Thalamus Excitatory Inhibitory

Figure 41.3  Evolution of the firing rate model of the basal ganglia to the oscillation model. Several lines of evidence have revealed that the basal ganglia nuclei function as a circuit and are dominated by oscillations in the alpha and beta bands (30 Hz) in Parkinson’s disease patients in their unmedicated state. These beta oscillations are considered akinetic as they are associated with parkinsonian symptoms. Gamma oscillations (70 Hz) are considered prokinetic and are under-represented in the parkinsonian state (Adapted with permission from Hutchison et al., 2004. Society for Neuroscience)

2004; Pahapill and Lozano, 2000; Nandi, Stein et al., 2002; Nandi, Aziz et al., 2002). Also largely neglected are projections from the PPN to the SNc (which in PD could be excitotoxic to DA neurons and further worsen the disease) (Lavoie and Parent, 1994; Forster and Blaha, 2003). Other components that likely play a role in motor control include direct cortical projections to the STN from the pre-motor cortex, primary motor cortex, and supplemental motor area, termed the hyperdirect pathway. These connections likely mediate sensory inputs to the basal ganglia as well as play a role in synchronization and desynchronization of oscillatory activity in the cortex and subcortical networks (Wichman, 2000). Furthermore, STN has direct projections to SNc and reciprocal projections to GPe and the centromedian-parafascicular complex (CMPf) of the thalamus. The GPe projects directly to the GPi, SNr, and the reticularis nucleus of the thalamus (Hazrati and Parent, 1991; Magil et al., 2000). As more components and lines of evidence are incorporated into the basal ganglia model, clinicians will be better able to select an “ideal target” for neuromodulation in alleviation of tremor and other movement disorders.

Pathophysiologic oscillations Current evidence suggests that the loss of dopaminergic stimulation in the basal ganglia in parkinsonism results not just in impaired signal generation or transmission but also pathologic network activity that can be disrupted by high frequency electrical stimulation. There is evidence that, without normal basal ganglia function, slow idling rhythms (11–30 Hz) are predominant in the cortex and synchronization in the gamma band is impaired (Figure 41.3).

Brown and colleagues (Brown et al., 2001, 2002, 2004; Brown, 2003) and Levy and colleagues (Levy et al., 2000, 2002) have contributed greatly to an oscillation model of the basal ganglia function, which predicts that the dominance of certain frequency bands may account for PD symptoms. The coherence of oscillations between STN and GPi in unmedicated PD patients was dominated by “antikinetic” beta bands (30 Hz) (Figure 41.4A). With dopaminergic medication the beta band reduced and a new peak in the “prokinetic” gamma band (70 Hz) occurred (Figure 41.4B). Similar recordings in healthy alert rats. in which gamma band activity dominated STN activity, further supported the model (Brown et al., 2002). Increases in the gamma band occurred in these rats during motor activity or with injection of dopamine agonists. In medicated PD patients, beta band corticothalamic coherence at rest decreased approximately 0.5 seconds prior to the onset of self-paced movement (Paradiso et al., 2004). The effects of DBS in driving the basal ganglia into higher frequency bands may explain its benefits (Brown et al., 2004). This model suggests that gamma oscillations are physiological in nature and provides a substrate for treatments that restore motor function.

Thalamocortical dysrhythmia Thalamocortical dysrhythmia (TCD) has been postulated by Llinas, Jeanmonod, and others to be responsible for several domains of neurological and neuropsychiatric disorders, including Parkinson’s disease (Llinas et al., 1999; Jeanmonod et al., 2003; Sarnthein and Jeanmonod, 2007). In PD, hyperpolarization of thalamic relay neurons from below (e.g., increased GPi inhibitory output) results in the de-inactivation of

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Vim thalamus/parkinsonian and essential tremor (ET)

10 uV 2.00 ms

0.5 Increase beta

0.25

0

LFP power (uV)

LFP power (uV)

0.5

Decrease beta increase gamma 0.25

0

0 10 20 30 40 50 60 70 80 90 100 Frequency (Hz) (A) PD Off L-DOPA

0 10 20 30 40 50 60 70 80 90 100 Frequency (Hz) (B) On L-DOPA

Figure 41.4  Oscillations recorded from DBS electrodes in the STN of PD patients off and on medication. Raw local field recording (top) and power spectrum (bottom) reveal a dominance of oscillations in the beta range in unmedicated PD patients (A). In the on medication state, the local field recording (top) and power spectrum (bottom) reveal reduction in the beta band and presence of energy in the gamma range (B) (Adapted with permission from Brown and Williams, 2005. Copyright (2005) Elsevier)

T-type calcium channels which sets these thalamic cells into a bursting activity mode known as low-threshold calcium spiking (LTS). This 4–8 Hz (theta band) activity results in a resonant interaction (oscillation) between the thalamus and cortex, which then entrains the intralaminar nuclei. By virtue of their widespread cortical connections, the intralaminar nuclei promote largescale low frequency oscillations that result in both “negative” symptoms of PD (bradykinesia) and “positive” symptoms (tremor and rigidity). According to Llinas et al. (2005), the intralaminar nuclei promote low frequency (theta band) oscillations resulting in “negative” PD symptoms of bradykinesia, while at the same time causing abnormal gamma-band activity generated by a disinhibitory cortical “edge effect” resulting in positive symptoms of tremor and rigidity. The authors of this model purport that surgical approaches can focus on either (1) reduction of thalamic inhibition (from GPi) with a lesion placed in the pallidothalamic tract or (2) reduction of low frequency synchronization with lesions placed in the medial thalamus (primarily CL). While initial reports appear promising, the findings need to be replicated and extended before they will lead to supplanting of the more widely accepted targets for the treatment of movement disorders.

GPi/dystonia Dystonia, characterized by abnormal postures with muscular co-contraction both at rest and with attempted movement, occurs in a variety of settings.

Childhood dystonia is often generalized, while adultonset dystonia is more likely to be focal or lateralized in nature. Nevertheless, all dystonia whether focal or generalized, genetic or sporadic, is felt to be the consequence of pathophysiology in the basal ganglia. Soon after the introduction of lesioning (pallidotomy) for the treatment of PD, it was found that the same procedure could benefit individuals with medically intractable dystonia. Unlike PD, however, there is no suitable animal model of dystonia, thus limiting investigations of the circuit abnormalities underlying the disorder. Nevertheless, studies suggest that unlike PD, the direct pathway appears to be overactive resulting in a net reduction in GPi/SNr activity (Starr et al., 2005). As a result, reduced output to the thalamus may then enhance thalamocortical activation, magnified by abnormal somatosensory processing. While commonly taking longer to take effect (up to a year), DBS has proven to be a highly effective modality for drug treatment-resistant dystonia (Hung et al., 2007).

Vim thalamus/parkinsonian  and essential tremor (ET) In 1951 Hassler and Reichert identified pallidalreceiving thalamic relay nuclei wherein lesions in the anterior portion (ventralis oralis anterior or Voa) were found to be effective for relief of rigidity, while those in the posterior portion (ventralis oralis posterior or Vop) were effective for relief of parkinsonian tremor (Hassler and Reichert, 1955). Subsequent work aided by microelectrode recording found an area just

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posterior to that, the Vim, that was largely a cerebellarreceiving area, which has become the gold standard target first in lesioning and thereafter for DBS in the treatment of tremor disorders. Because of the high incidence of dysarthria and disequilibrium associated with bilateral thalamotomies, Benabid and colleagues introduced DBS of the Vim, which has provided remarkable tremor reduction in the majority of patients (Benabid et al., 1991; Hariz et al., 2008). The pathophysiology of ET likely involves oscillation within cerebello-olivary pathways that is relayed to the thalamic cerebellar receiving area, the Vim. The inferior olive has been found to have spontaneous oscillatory potential, which may then be amplified by the cerebellum and subsequently entrain thalamocortical and brain stem/spinal cord structures in the 8–12 Hz frequency range that is characteristic of ET. Functional imaging results (PET, fMRI, 1H-MR spectroscopy) have generally been in agreement showing hypermetabolism in these structures, although one PET study showed red nuclear and cerebellar but no olivary activation associated with essential tremor (Wills et al., 1994). Using transcranial magnetic stimulation (TMS), Molnar et al. (2004) have studied the effects of thalamic DBS on the excitability of the cerebellothalamocortical (CTC) pathway in six patients with ET, and noted facilitation of the CTC with DBS turned on, and reduction with DBS off. They suggested that activation of the thalamus may prevent tremor signals from reaching the cortex, pointing out that, “rather than abolishing thalamic relay to the cortex … DBS may drive a pattern of firing that prevents the passage of pathological signal to the cortex.” Further it was also shown by this group that clinically effective DBS in the Vim of ET patients resulted in increased excitability of the primary motor cortex (M1). Since M1 is the direct output of the excitatory Vim thalamocortical neurons, it further supports that neuromodulation through activation of the thalamocortical circuits ameliorates the tremor signal (rather than by blockage of neuronal firing?) (Molnar et al., 2005).

Conclusion While the role of dopamine in Parkinson’s disease has been incontrovertible since the 1960s, it was not until the 1980s and beyond that the physiologic underpinnings of the disorder have become illuminated. The insights gained from the MPTP model of PD led first to the development of the “rate model” and then later recognition of abnormal oscillations and increased synchronization between structures that

normally fire independently in the presence of dopamine. Restoration of this desynchronization appears to be at the heart of clinical efficacy. Exploring the functional organization of basal ganglia-thalamocortical circuits has thus been an evolving field, improving both patient care and understanding of the anatomical and physiological basis of PD and other movement disorders. Ultimately neuromodulation is physiological intervention. Improved insight into the pathophysiology of a neurological disorder has led to an evolution of DBS from experimental modality to the treatment of choice in advanced movement disorders. Neuromodulation has an indisputable role in the treatment of other medically intractable neurological disorders such as chronic pain, obsessive–compulsive disorder, and depression, which may arise from dysfunction in non-motor circuits. Treatment of these conditions may be revolutionized by technologies originally developed for the treatment of movement disorders.

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Deep Brain Stimulation in Parkinson’s Disease Karl A. Sillay and Philip A. Starr

o u t l i n e History and Theory of Deep Brain Stimulation for Parkinson’s Disease History of Surgical Intervention for PD Pathophysiologic Basis of DBS for PD Limitations of Medical Therapy for PD

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Preoperative Evaluation and Surgical Indications Preoperative Screening Evaluation Indications for DBS Contraindications to DBS

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Surgical Technique Intended Target Location Preoperative Preparation and Frame Placement Image Acquisition Coordinate Systems and Target Selection Positioning and Anesthesia Technique Surgical Exposure

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References

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ganglia in a Parkinson’s patient when he performed partial caudate resections for control of parkinsonian unilateral tremor (Meyers, 1942; Gildenberg, 1998). In the 1950s, Dr Cooper, after accidentally damaging the anterior choroidal artery during a planned mes­ encephalic pedunculotomy, ligated the artery in the process of aborting the surgery, and observed reduc­ tion in tremor and rigidity without the loss of motor strength (Cooper, 1953). Lesions produced by this procedure variably included parts of the thalamus,

History and theory of deep brain stimulation for Parkinson’s disease History of Surgical Intervention for PD Surgical intervention for Parkinson’s disease (PD) began with ablative surgery. In 1942, Dr R. Meyers first reported the effects of ablative surgery of the basal

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42.  Deep brain stimulation in parkinson’s disease

globus pallidus, or internal capsule. Human stereo­ taxy was introduced in 1947 by Spiegel and Wycis (Spiegel et al., 1947), providing a reproducible method of navigating to an intended surgical target. Dr Hassler described lesioning of the ventral intermedi­ ate nucleus of the thalamus for parkinsonian tremor using stereotaxy in 1954 (Hassler and Riechert, 1954). Surgery for movement disorders was then widely per­ formed until Dr Cotzias introduced in 1968 a clinically practical form of levodopa therapy (Cotzias, 1968), which temporarily suspended the apparent need for movement disorders surgery. Lesional stereotactic surgery for PD reemerged in the 1990s for patients experiencing complications of levodopa therapy. Stereotactic targets included the: ventrolateral thala­ mus, globus pallidus internus (GPi), and subthalamic nucleus (STN) (Starr et al., 1998). Early in the development of stereotactic lesional surgery, neurostimulation was observed to reduce parkinsonian tremor (Hassler et al., 1960). These obser­ vations led to the development of implantable electri­ cal stimulation devices as an alternative to stereotactic lesional surgery for Parkinson’s disease. The first per­ manent implant subthalamic nucleus stimulator to treat all cardinal signs of Parkinson’s disease was per­ formed by Dr Alim Benabid in Grenoble, France in 1993 (Limousin et al., 1995). Today, deep brain stimu­ lation (DBS) has become the “gold standard” for the surgical treatment of PD. Unlike ablation, DBS is rela­ tively safe, non-destructive, reversible, and adjustable.

Pathophysiologic Basis of DBS for PD Parkinson’s disease is now recognized as a diffuse disease of the central nervous system with a predict­ able progression of neuronal involvement in olfactory, autonomic, limbic, and somatomotor systems (Braak et al., 2006). The early motor manifestations are likely due to the loss of dopaminergic cells in the substan­ tia nigra pars compacta (SNpc). SNpc cells termi­ nate in the striatum and are excitatory to the striatal cells originating the direct pathway and inhibitory to the striatal cells originating the indirect pathway. SNpc cell loss leads to increases in activity in the STN through the indirect pathway and in the major output nucleus of the basal ganglia, the GPi through both pathways (Bergman et al. 1990). The increase of activity in the GPi causes increased inhibitory output to the motor thalamus and therefore decreased motor cortical activity. In addition to changes in firing rate, the Parkinsonian state is associated with abnormal oscillatory activity in the 2–30 Hz frequency range in basal ganglia nuclei

(Silberstein et al., 2003), as well as abnormal synchro­ nization between neuronal pathways that normally function independently (Goldberg et al., 2002; Heimer et al., 2002). Inactivation of the GPi or STN reverses parkinsonism in the MPTP-treated nonhuman primate (Bergman et al., 1990; Baron et al., 2002) and forms the basis for neuromodulation of these two structures. Although global network effects of DBS relieve the cardinal symptoms of PD, the mechanism of action of DBS is a subject of ongoing research. DBS of the STN does not appear to alter striatal dopamine levels (Abosch et al., 2003). At a cellular level, DBS has com­ plex effects, driving or inhibiting neuronal elements depending upon location and stimulation param­ eters (Bar-Gad et al., 2004). The current theory of the mechanism action of DBS on the STN or GPi is that DBS “paces” abnormal basal ganglia output, replac­ ing it with an artificial signal that is less noxious to downstream cortical function. DBS may suppress excess pallidal outflow, suppress pathological oscilla­ tory activity, or desynchronize parallel neuronal chan­ nels across frequency ranges where such synchrony is detrimental. The exact mechanism, however, by which DBS improves parkinsonian motor signs, is unknown.

Limitations of Medical Therapy for PD Following the diagnosis of Parkinson’s disease, patients may start to receive a variety of medications including levodopa/carbidopa (Sinemet), dopamine agonist therapy, anticholinergic therapy, or monoam­ ine oxidase MAO(B) inhibitor therapy. Medical ther­ apy is usually very effective for the early years of PD; however, with progression of the disease, patients receiving chronic administration of levodopa develop motor fluctuations in spite of frequent medication dosing. These “on–off” motor fluctuations, are rapid and unpredictably timed transitions between effec­ tively medicated (“on”) and effectively unmedicated (“off”) states. Patients may also develop medication induced side effects including levodopa-induced dys­ kinesias. Combination medication therapy, such as COMT inhibitors with levodopa may decrease but do not eliminate such side effects.

Preoperative evaluation and surgical indications Preoperative Screening Evaluation The diagnosis of idiopathic PD should be confirmed by a movement disorders neurologist. To establish

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baseline preoperative function, a videotaped neuro­ logical examination should be performed using the Unified Parkinson’s Disease Rating Scale (UPDRS), both on and 12 hours off of antiparkinsonian medica­ tions. The “on” score should be at least 30% improved, and ideally more than 50% improved, compared to the “off” score. Magnetic resonance imaging (MRI) is performed to rule out excessive surgical risk factors or imaging features suggestive of atypical Parkinsonism. Cognitive function may be assessed using the Folstein Mini-Mental Status Exam (MMSE) and referred for formal neuropsychological testing if the MMSE is bor­ derline (27). Patients and families are counseled that DBS is an intrinsically complex therapy requiring sub­ stantial family support.

Surgical technique Intended Target Location DBS of either STN or GPi may be used to treat the hallmark symptoms of rigidity, bradykinesia, gait dis­ order, and tremor. Figure 42.1 shows typical active contact locations for both the STN and GPi in relation to the target nuclei with respect to a drawing of the nuclear boundaries. Figure 42.2 shows these lead loca­ tions on postoperative MRI.

Preoperative Preparation and Frame Placement Under intravenous sedation and local anesthetic administration, a standard stereotactic frame is applied

Indications for DBS DBS should be offered to patients with a clear diagnosis of idiopathic PD who experience disabling motor fluctuations in spite of optimal medical man­ agement by a movement disorders neurologist. The single best predictor of response to DBS surgery is improvement in the cardinal motor manifestations of PD in response to levodopa, albeit this improvement may be short, variable in time of onset, or complicated by dyskinesias (Charles et al., 2002). Patients should be ambulatory in the best “on” state. Surgery should be performed in patients with retained cognitive abilities before they have lost the ability to perform the activi­ ties most important to them.

GPi IC

STN RN

ML (A) STN

1cm

Putamen GPe

Contraindications to DBS Contraindications to DBS therapy include poor levodopa response, a questionable diagnosis of idi­ opathic PD, poor cognitive status, severe freezing of gait in the “on” state, advanced age (75), and major surgical comorbidity such as cardiovascular disease, severe hypertension, or severe diabetes. In patients with pre-existing cognitive impairment, bilateral STN DBS may cause permanent worsening of cognitive function (Saint-Cyr et al., 2000). A Mini-Mental Status Exam (MMSE) score less than 24 or a Mattis Dementia Rating Scale score of less than 125 should raise ques­ tions. In patients who are cognitively tenuous, a rea­ sonable approach may be to stage the DBS implants into unilateral procedures separated by several months. Neuropsychological testing may be repeated after the first implant to confirm stable cognitive func­ tion. Additional relative contraindications include severe postural instability and hypophonia as they are poorly responsive to DBS.

AC

GPi 3rd V.

PC (B) GPi

Figure 42.1  Typical active contact locations (shown as black dots) with respect to axial plane anatomy drawn from the Schaltenbrand and Wahren human brain atlas. The axial planes selected are those from the atlas that are closest to the vertical position of the average active contact. (A) STN active contact, shown on the plane 4.5 mm inferior to the intercommissural line. (B) GPi active con­ tact, shown on the plane passing through the intercommissural line. IC  internal capsule; ML  medial lemniscus; 3rd V  third ventricle (Adapted from G. Schaltenbrand and W. Wahren (1977) Introduction to Stereotaxis with an Atlas of the Human Brain. Stuttgart, Thieme, with permission)

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(A)

(B)

Figure 42.2  Electrode locations on postoperative MRI, at the axial level of the active contacts following programming for optimal clini­ cal benefit. Axial FSE images (Phillips Intera; slice thickness 2 mm; TR 3000; TE 40; TI 200; matrix 256    512, signal excitations 3, bandwidth 120 Hz/pixel, interleaved, scan time 11:48). (A) GPi, at the level of the AC and PC. (B) STN, at an axial plane 4 mm inferior to the AC–PC line. The artifact generated by the lead is indicated with an arrow (From Starr (2002), p. 141, Fig. 10, with permission from S. Karger AG, Basel)

(Leksell series G, Elekta, Atlanta, GA) with earbars used to align the frame with the external auditory canals. This constrains the x- and y-axes of the frame to be orthogonal and parallel, respectively, to the patient’s midsagittal plane. The frame is rotated such that the y-axis is parallel to a line between the glabella and inion, which is approximately parallel to the midcom­ missural line. After slight tightening of the pins, the ear bars are removed and the skull pins fully tightened.

Image Acquisition Following frame placement, the patient is trans­ ferred to a 1.5 T MRI. A three-dimensional gradient echo (3D-GRE) post-contrast sequence is obtained. This scan serves as the primary reference image set for frame registration. Additional image sets are tailored to the specific target. In targeting the STN, coronally acquired T2 images are obtained, whereas axially acquired inversion recovery (IR) images are obtained in targeting the GPi. MRI images are transferred to a stereotactic planning system (Frame-link 5.0, Sofamor Danek Stealthstation, Medtronic, Minneapolis, MN or iPlan Stereotaxy, BrainLAB, Feldkirchen, Germany) for image fusion, computational reformatting, target selection, stereotactic coordinate determination, and trajectory planning.

Coordinate Systems and Target Selection Spatial coordinates of subcortical nuclei are often defined with respect to the line between the anterior

commissure (AC) and posterior commissure (PC), with the origin of the coordinate system at the midpoint of the AC–PC line. The x-axis (measured lateral distance) is defined as perpendicular to the midsagittal plane. The y-axis (measuring anterior–posterior distance) is measured along the AC–PC line. The z-axis (measur­ ing superior–inferior distance) is defined in the coronal plane through the AC–PC line midpoint. Coordinates may be expressed in millimeters from the AC–PC mid­ point or as percentages of AC–PC distance from the anterior commissure, midcommissural point, or poster­ ior commissure. Lateral distances are defined from the AC–PC line or from the third ventricular wall. Defining coordinates as a percentage of AC–PC length may have the advantage of normalizing for brain size, to the extent to which the spatial distribution of basal ganglia nuclei correlate with AC–PC line length. For STN, the intended target is the center of the STN motor territory. The typical initial anatomic target for this subregion is 4 mm below the midcommissural plane, 12 mm lateral to the origin, and 3 mm poste­ rior to the midcommissural point. Using T2-weighted images, which usually show the borders of the STN, these “standard” target coordinates are then adjusted to account for individual variations in the location and shape of the STN. For GPi, the intended target is the motor territory of the internal pallidum, near the border of the exter­ nal globus pallidus (GPe), 3–4 mm from the internal capsule. Figure 42.1 shows the intended active con­ tact locations for the GPi. The typical initial anatomic target for the internal segment of the globus pallidus is 5 mm below the midcommissural plane, 17.5 mm

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from the lateral aspect of the third ventricular wall, and 2 mm anterior to the midcommissural point. The trajectory with either STN or GPi is typically planned with an approach angle approximately 30 degrees from vertical in sagittal projection and 0–15 degrees from vertical in coronal projection. This tra­ jectory is examined and adjusted to ensure that it does not cross the ventricle, sulci, or cortical veins.

Positioning and Anesthesia Technique Patient position and anesthetic management are designed to minimize risks of hemorrhage, infection, air embolism, frame slippage, and airway compromise. Preoperative antibiotics (cefazolin 1 g or vancomycin 1 g if allergic) are given within one hour prior to skin incision. Stereotactic frame pins are rechecked for evi­ dence of loosening. Excessive neck flexion is avoided to minimize risk of airway compromise. Patients are posi­ tioned with the head at a 45 degree angle from supine. This represents a compromise position between risk­ ing air embolism (exacerbated with more upright posi­ tion) and risking posterior brain shift from intracranial air entry (exacerbated with more supine position). The surgical table is placed in the “beach chair” position with the back up, maximum Trendelenburg at the mid­ section of the table, and feet down. Systolic blood pres­ sure is kept less than 140 mmHg. Sedation (propofol infusion) is used for the surgical opening but is stopped prior to physiological mapping.

Surgical Exposure Skin incisions are planned to cross posterior to burr-hole hardware rather than directly over the hardware to reduce the risk of erosion and infection. In at least one series, linear incisions in the sagittal plane crossing the burr-hole has been associated with an increased risk of infection (Constantoyannis et al., 2005). Once the burr-hole is drilled, the skull edges are covered with bone wax to reduce the risk of air embo­ lism. Then the base ring for a lead anchoring device (StimLock, Medtronic Inc., Minneapolis, MN) is fixed over the burr hole, recessed in the skull several milli­ meters to lower its profile. The stereotactic arc is applied to the frame in sterile fashion. A micropositioner that provides fine control for advancing instruments into the brain (FHC, Brunswick, ME or Elekta, Norcross, GA) is then attached to the stereotactic frame. The predetermined approach angle is then set on the stereotactic ring and arc. Fluoroscopy is strongly recommended when a surgeon is early in his/her experience, or when a

543

new positioning device or new model of intracranial hardware is introduced. Fluoroscopy may be used to verify location of the positioning guide tubes, micro­ electrodes, or DBS electrodes. This is most straightfor­ ward in the lateral view, using radiopaque alignment grids mounted in the laterally placed stereotactic rings. Single-plane lateral fluoroscopy does not assess the lateral position of the lead. The dura is opened in a cruciate manner and coagu­ lated. The coagulated pia is then opened with the No. 11 blade. A guide tube with stylet is inserted. Sealing the burr-hole with Gelfoam and Tisseel (Baxter, Deerfield, IL) may reduce the risk of air emboli, reduce brain shift which can occur progressively during equilibration of ambient and intracranial pressures, and dampen pulsa­ tion artifact in subsequent single unit recordings.

Microelectrode Recording Image-based stereotactic targeting, using images acquired prior to surgery, is subject to many limitations: inherent nonlinearities in MRI scan acquisition, imper­ fect image fusion, mechanical errors in the stereotactic system or micropositioner hardware, and dynamic brain shift during the operation. Due to these limitations, microelectrode recording (MER) is utilized to further localize, in real time, the target in reference to stereo­ tactic space for placement of the DBS electrode (Starr, 2002). Judicious use of microelectrode recording poses a relatively low risk of hemorrhage (Binder et al., 2005). Patterns of spontaneous activity in basal gan­ glia nuclei are specific to PD. As the microelectrode advances from cortical surface to target, MER charac­ teristics allow identification of structures at the micro­ electrode tip as it passes through nuclear groups and white matter tracts (Figure 42.3). In targeting the STN, for example, structures that may be identified dur­ ing MER include the caudate, thalamus, subthalamic nucleus, and then substantia nigra, pars reticulata. When approaching the STN on a typical trajectory, MER are characterized by an increase in background signal and STN firing rates of 20–50 spikes/second. In targeting the GPi, structures that may be iden­ tified during MER include the caudate/putamen, external pallidum, cholinergic “border” cells, internal pallidum, and the optic tract (Binder et al., 2001, 2005). When approaching the GPi on a typical trajectory, MER passage from GPe to GPi is typically marked by an increase in firing rate to 80–100 spikes/second. After successfully navigating to the target nucleus, somatotopy is used to evaluate the microelectrode loca­ tion within the motor territory. The examiner listens for modulation of action potential discharge in relation to

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Striatum

GPe bursting cell

Dorsal thalamus

GPe pausing cell

STN

‘Border’ cell

SNr

Gpi

(A) STN region

(B) GPi region

Figure 42.3  Microelectrode recordings of spontaneous neuronal activity from the thalamus and basal ganglia in the region of STN (A) and GPi (B). Each trace represents a 1-second recording in a patient with PD (Modified from P.A. Starr (2003) Technical considerations in movement disorders surgery, in M. Schulder (ed.), The Handbook of Stereotactic and Functional Neurosurgery. New York: Dekker, pp. 269-89, with permission from Dekker Publishing)

passive movements of the contralateral limbs. Findings of only leg-related activity along an MER trajectory within STN or GPi indicate a relatively medial locali­ zation within the respective motor territories. During globus pallidus recording, as the microelectrode exits the base of the GPi, the room lights are darkened and the examiner uses a light stimulus directly in front of the patient’s eye to assess for light-evoked action potential discharges indicative of the successful target­ ing to the dorsal border of the optic tract.

Lead Insertion and Intraoperative Test Stimulation Once microelectrode recording has confirmed a satisfactory trajectory, the microelectrode and micro­ electrode reducing tube are removed and the guide tube for DBS lead implantation placed to terminate 10–15 mm from the intended target. This may be veri­ fied with lateral fluoroscopy. A DBS lead is selected and a target depth agreed upon. Currently available DBS-lead choices are quadripolar with contacts spaced over 7.5 mm or 10 mm (Medtronic model 3389 or 3387, respectively). For STN, the DBS-lead target depth is chosen such that the second most inferior contact is placed in the motor territory of the STN. For GPi, the distal contact is placed 1 mm superior to the optic tract. After implantation, improvement in wrist rigidity during test stimulation may be assessed as it appears to improve rapidly with effective stimulation and return to baseline rapidly with cessation of stimula­ tion (Pollak et al., 2002). Testing is then performed to ensure stimulation-induced adverse effects will not limit delivery of therapeutic stimulation.

Test stimulation of the STN is initiated with the fol­ lowing stimulation parameters: contact 0 positive ver­ sus contact 1 negative, frequency of 185 Hz, and pulse width of 60 ms. Low voltage paresthesiae (1–2 V) are due to medial lemniscal activation and may indicate placement is too posteromedial. Dysarthria and/or facial contractions are due to corticobulbar tract acti­ vation and should be absent at lower voltages; how­ ever, these unwanted movements may occur with increased voltage in the 6–10 V range. Other side effects include: (1) mood changes possibly due to anteromedial spread to the limbic portion of the STN or inferior spread to SNr (Voon et al., 2006) and (2) contralateral gaze deviation due to simulation of the frontopontine bundle anterior to the STN. Test stimulation of the GPi is initially begun with contact 0 negative, 3 positive with a frequency of 185 Hz and pulse width of 90 ms. Dysarthria and tonic facial contraction should be absent until stimulation voltage is increased to 6–10 V. Activation of the optic tract using the lowest contact may occur. After satisfactory completion of test stimulation, the lead is secured in place with a lead anchoring device (StimLock, Medtronic) and the excess portion of the lead is coiled into a subcutaneous pocket under the parietal scalp, with a protective cap placed on the end to facilitate palpation of the lead end during the implantation of the remaining hardware.

IPG/Lead Extenders The lead extenders and implantable pulse gen­ erator (IPG) may be placed immediately following lead implantation, or in a separate surgical session

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at a later date. After induction of general anesthe­ sia, the patient is prepped again with the patient’s head turned away from the side of the subcutaneous pocket. An incision about 6 cm in length is made in the infraclavicular location about 1 cm below the bor­ der of the clavicle. An additional 2 cm incision is made horizontally behind the patient’s ear over the end of the DBS lead in the subcutaneous pocket. The leads are identified and externalized at their distal 2 cm. A pocket large enough for the pulse generator is created over the pectoralis fascia. For pulse generator placement, the surgeon changes outer gloves and places the IPG from its sterile pack­ age immediately into the patient. The lead extenders are tunneled down the neck and attached to the IPG.

Alternative technical approaches New technologies in DBS placement include frame­ less neuronavigation (Holloway et al., 2005), presur­ gical fabrication of an insertion platform designed to aim to the desired target, customized to the individ­ ual patient’s anatomy (STarFix, FHC, Bowdoin, ME) (Fitzpatrick et al., 2005), and placement of the lead using real-time high-field interventional MRI. The frameless neuronavigation and STarFix approaches allow the stereotactic imaging to be performed days before the surgery, which may improve efficiency on the day of surgery. Both require the implantation of bone-mounted fiducial markers. At our institution, the interventional MRI approach is especially useful for patients unable to tolerate awake surgery for the DBS case (Martin et al., 2005).

Device programming Device programming early after implantation (2 weeks) may be confounded by the “microlesion effect,” or temporary alleviation of motor signs due to localized edema around the leads. It is helpful to per­ form initial programming with the patients off all antiparkinsonian medications. Contact selection is based on intraoperative physiology, postoperative imaging, or the examiner’s assessment of stimulation-induced improvements during programming. Improvements in wrist rigidity are often used as a reliable and effi­ cient sign of effective programming. For both STN and GPi DBS, frequencies of 100–200 Hz are most beneficial (Moro et al., 2002). Typical pulse widths are

60–120 s. Voltages are increased to determine thera­ peutic voltage as well as the threshold for persistent adverse effects, including persistent paresthesiae, or tonic muscle contraction due to corticobulbar or corti­ cospinal tract activation. Target voltages range from 2 to 4 V, but may vary by individual patient.

Outcomes The results of STN stimulation are better docu­ mented than those of GPi stimulation. There are now in excess of one thousand patients with STN DBS with outcomes documented in the medical literature. Few studies, however, provide Class I evidence. Those that do so are detailed along with a recent meta-analysis in Table 42.1 (DBS Study Group, 2001; Anderson et al., 2005; Deuschl et al., 2006; Kleiner-Fisman et al., 2006; Schupbach et al., 2007). The effects of surgical treat­ ment of PD are summarized in Table 42.1. When compared to preoperative examinations, patients show significant improvement in motor scores and motor fluctuations, and a decrease in medication-induced side effects leading to an overall improvement in quality of life. UPDRS-III scores in patients off medications after surgery with stimulation are 39 to 69% lower relative to their preoperative “off” scores. UPDRS-III scores in the best “on-medication” state are reduced by 13.8 to 24.6%. Following STNDBS, levodopa equivalent dosages were decreased after surgery with active neurostimulation by 37.3– 57%. Patients also experienced a major reduction in the severity and duration of “off” times. In two of the randomized, controlled studies listed in Table 42.1, cognition as measured by the Mattis Dementia Rating Scale was unchanged at six months and 18 months versus preoperative evalu­ ation (Deuschl et al., 2006; Schupbach et al., 2007). Other work, however, demonstrates potential declines in frontal executive function after bilateral STN DBS (Saint-Cyr et al., 2000).

Choosing the Stimulation Target: STN vs. GPi The Federal Drug Administration (FDA) has approved DBS for both the GPi and STN for the treat­ ment of Parkinson’s disease. As of this writing, the only Class I study to compare GPi versus STN has shown no difference (Anderson et al., 2005). Some small studies in which leads were inserted in both targets in the same patient suggest greater efficacy of

V.  neuromodulation for movement disorders

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42.  Deep brain stimulation in parkinson’s disease

Table 42.1  Class I outcome studies of DBS for PD Deuschl et al., 2006

Schupbach et al., 2007

Kleiner-Fisman et al., 2006

DBS Study Group, 2001

Anderson et al., 2005

Study design

Randomized pairs trial

Randomized pairs trial

Meta-analysis

Prospective, double-blind, non-randomized crossover study

Prospective, doubleblind, randomized pilot study

Target

STN

STN

STN

STN

GPi

STN

GPi

Number of patients

156

20

Meta

96

38

12

11

Duration of disease at surgery (yr)

13.4

8.6

14.1

14.4

14.5

15.6

10.3

Age at surgery (yr)

60.7

48.5

58.6

59.0

55.7

61

54

Design and demographics

Preoperative analysis (UPDRS-III scores) UPDRS-III off medication

46.9

29.0

Absent

54.0

50.8

51

50

UPDRS-III on medication

18.1

2.75

Absent

23.6

24.1

20

18

UPDRS-III decrease “on” vs. “off”

61.4%

90.5%

60.3%

56.3%

52.6%

Absent

Absent

Outcomes analysis (postoperative state with neurostimulation compared to preoperative medicated state) Postoperative follow-up time (mth)

6

18

Varies

6

6

12

12

UPDRS-III off medication

39.0%

69%

52%

52.4%

33.3%

48%

39%

UPDRS-III on medication

22.8%

13.8%

Absent

24.6%

31.5%

0%

5.6%

Dyskinesias (from patient diaries)

53.7%

83%

69%

69.6%

65%

Absent

Absent

“Off” time immobility (from patient diaries)

67.7%

Absent

68.2%

69.2%

35.1%

Absent

Absent

Levodopa equivalent dosage

49.2%

57%

55.9%

37.3%

2.7%

38%

3%

PDQ-39 – Quality of life

23.9%

24%

35.5%

Absent

Absent

Absent

Absent

Abbreviations: STN  subthalamic nucleus; GPi  globus pallidus internus; UPDRS  Unified Parkinson’s Disease Rating Scale; PDQ-39  Parkinson Disease Questionnaire 39

STN (Houeto et al., 2000; Scotto di Luzio et al., 2001); however, the location of leads within GPi may not have been optimal.

Predictors of Outcome for STN DBS Predictors of positive outcomes after STN DBS for PD include levodopa responsiveness and younger age (Charles et al., 2002). Age has also been identified as an independent predictor in a recent report of 52 con­ secutive patients at 2-year follow-up with similar pre­ operative UPDRS reduction during the L-DOPA test. “Off-medication”, “on-stimulation” scores in patients over 70 years may not improve in response to stimu­ lation as much as in their younger counterparts, and “on-medication” scores in older patients may worsen postoperatively (Russmann et al., 2004).

Complications The most serious intraoperative or early postopera­ tive complication of DBS is intracranial or intracerebral hemorrhage. In our series the risk of symptomatic hem­ orrhage from DBS surgery on a per patient basis was 2.1% (6/280) and age was not a significant predictor of stroke risk (Binder et al., 2005). In the Class I studies cited in Table 42.1, the risk of morbidity from hemor­ rhage stroke in DBS for PD ranged from 0% to 3.9%. In our series another 5.7% of patients (10/280) had asymp­ tomatic hemorrhages found only through postoperative imaging (Binder et al., 2005). In the Class I studies cited in Table 42.1, there was a total of 8 deaths (0.65%) in the perioperative period from all causes, including cerebral hematoma (1), infected chronic subdural hematoma (1), pulmonary embolism (3), myocardial infarction (1), sui­ cide (1), and pneumonia (1).

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KEY POINTS

Early postoperative complications include men­ tal status changes and hardware infection. In our series, the incidence of perioperative device (within 6 months) infection, requiring return to the operating room for partial or complete hardware removal, was 4.5% per patient (Sillay et al., 2008). Long-term hard­ ware-related complications include skin erosion, lead fracture, pulse generator migration, and lead twisting. The incidence of lead fracture, and other hardware complications increases with longer postoperative follow-up time, and have been shown to be as high as 8.4% per electrode year (Oh et al., 2002). Postoperative stimulation related complications include induced dysarthria, blepharospasm, and cogni­ tive and mood changes (Chen et al., 2003). Symptoms of dysarthria, when present, may be minimized with stimulation parameter alteration (Tornqvist et al., 2005). Long-term cognitive and mood sequelae must also be taken into serious consideration with DBS for PD. In a study of 11 patients undergoing STN DBS for PD, working memory, speed of mental processing, pho­ nemic fluency, and long-term consolidation of verbal material and encoding of visuospatial material were shown to be decreased at 6 months postoperatively (Saint-Cyr et al., 2000). These findings were more pro­ nounced in patients over 70 years of age. Preexisting cognitive deficit is also a risk factor for further cogni­ tive decline. Depression has been shown to compli­ cate STN stimulation in 8% of patients (Temel et al., 2006). Suicide occurred in 6 DBS patients (4.3%) for movement disorders in a recent series (Burkhard et al., 2004). The exact locus of chronic simulation-induced mood changes is not clear, though it can evidently occur at stimulation settings that are appropriate for motor improvement.

Future directions DBS hardware must be improved with smaller, more efficient, rechargeable systems with afferent technology. Reduction in pulse generator size should allow placement under the scalp, and patients with higher voltage stimulation parameters will undergo fewer surgeries for battery replacement. The biology of DBS in PD is poorly understood. Evolving theories of the pathophysiology of move­ ment disorders, emphasizing pathological oscillations in specific frequency bands, may elucidate the mecha­ nism of DBS-induced motor improvements (Gatev et al., 2006). There is not yet clear evidence of neuropro­ tection resulting from DBS therapy even with five-year follow-up (Benabid et al., 2006), although neuroprotective

mechanisms have been proposed (Rodriguez et al., 1998). One recent publication (Schupbach et al., 2007), and new ongoing trials (Charles, 2006) are examining the role of DBS when performed closer to the time of diagnosis of PD rather than waiting for the develop­ ment of complications of medical treatment.

Conclusions DBS should be considered when patients begin to develop motor fluctuation or dyskinesias despite opti­ mal medical management, and before the progression of PD has significantly restricted a patient’s quality of life. Many patients achieve a significant reduction of motor fluctuations, improvement of the cardinal symptoms of PD, and reduction of levodopa equiva­ lent intake resulting in decreased medication-induced side effects, although this is dependent upon disease state, target of neurostimulation, and final electrode position. The most significant shortcomings of DBS therapy are the lack of evidence for neuroprotection, the inherent complexity of the therapy, and the rela­ tively high incidence of long-term hardware related complications.

Key points DBS disrupts abnormal basal ganglia activity causing a clinical improvement in the major cardinal signs of Parkinson’s disease. l Patients should be considered for DBS when complications of medical therapy develop despite optimal medical management by a movement disorders neurologist. l The best predictor of outcome is the persistence of a motor benefit in response to levodopa. l The technical approach to DBS implantation described here includes MRI-based stereotaxy, single unit microelectrode recording, and intraoperative test stimulation for stimulationinduced adverse effects. l The relative roles of subthalamic versus globus pallidus stimulation have not been defined, and both procedures are described here. l

References Abosch, A. et al. (2003) Stimulation of the subthalamic nucleus in Parkinson’s disease does not produce striatal dopamine release. Neurosurgery 53: 1095–102, discussion 1102–5. Anderson, V.C. et al. (2005) Pallidal vs subthalamic nucleus deep brain stimulation in Parkinson disease. Arch. Neurol. 62: 554–60.

V.  neuromodulation for movement disorders

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Bar-Gad, I. et al. (2004) Complex locking rather than complete ces­ sation of neuronal activity in the globus pallidus of a 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine-treated primate in response to pallidal microstimulation. J. Neurosci. 24: 7410–19. Baron, M.S. et al. (2002) Effects of transient focal inactivation of the basal ganglia in parkinsonian primates. J. Neurosci. 22: 592–9. Benabid, A.L. et al. (2006) Might deep brain stimulation of the subthalamic nucleus be neuroprotective in patients with Parkinson’s disease? Thalamus Rel. Syst. 2: 95–102. Bergman, H. et al. (1990) Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science 249: 1436–8. Binder, D.K. et al. (2005) Risk factors for hemorrhage during micro­ electrode-guided deep brain stimulator implantation for move­ ment disorders. Neurosurgery 56: 722–32. Braak, H. et al. (2006) Stanley Fahn Lecture 2005: The staging proce­ dure for the inclusion body pathology associated with sporadic Parkinson’s disease reconsidered. Mov. Disord. 21: 2042–51. Burkhard, P.R. et al. (2004) Suicide after successful deep brain stimu­ lation for movement disorders. Neurology 63: 2170–2. Charles, P.D. (2006) DBS for early stage Parkinson’s disease. Nashville, TN: Vanderbilt University Medical Center, Phase I Clinical Trial (NCT00282152). Charles, P.D. et al. (2002) Predictors of effective bilateral subthalamic nucleus stimulation for PD. Neurology 59: 932–4. Chen, C.C. et al. (2003) Short-term effect of bilateral subthalamic stimulation for advanced Parkinson’s disease. Chang Gung Med. J. 26: 344–51. Constantoyannis, C. et al. (2005) Reducing hardware-related compli­ cations of deep brain stimulation. Can. J. Neurol. Sci. 32: 194–200. Cooper, I.S. (1953) Ligation of the anterior choroidal artery for invol­ untary movements–parkinsonism. Psychiatric Q. 27: 317–19. Cotzias, G.C. (1968) L-Dopa for Parkinsonism. N. Engl. J. Med. 278: 630. DBS Study Group (2001) Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson’s disease. N. Engl. J. Med. 345: 956–63. Deuschl, G. et al. (2006) A randomized trial of deep-brain stimula­ tion for Parkinson’s disease. N. Engl. J. Med. 355: 896–908. Fitzpatrick, J.M. et al. (2005) Accuracy of customized miniature ster­ eotactic platforms. Stereotact. Funct. Neurosurg. 83: 25–31. Gatev, P. et al. (2006) Oscillations in the basal ganglia under normal conditions and in movement disorders. Mov. Disord. 21: 1566–77. Gildenberg, P.L. (1998) History of Stereotactic and Functional Neurosurgery. New York: McGraw–Hill. Goldberg, J.A. et al. (2002) Enhanced synchrony among pri­ mary motor cortex neurons in the 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine primate model of Parkinson’s disease. J. Neurosci. 22: 4639–53. Hassler, R. and Riechert, T. (1954) Indications and localization of stereotactic brain operations. Nervenarzt. 25: 441–7. Hassler, R. et al. (1960) Physiological observations in stereotaxic oper­ ations in extrapyramidal motor disturbances. Brain 83: 337–50. Heimer, G. et al. (2002) Dopamine replacement therapy reverses abnormal synchronization of pallidal neurons in the 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine primate model of parkin­ sonism. J. Neurosci. 22: 7850–5. Holloway, K.L. et al. (2005) Frameless stereotaxy using bone fiducial markers for deep brain stimulation. J. Neurosurg. 103: 404–13. Houeto, J.L. et al. (2000) Failure of long-term pallidal stimulation cor­ rected by subthalamic stimulation in PD. Neurology 55: 728–30.

Kleiner-Fisman, G. et al. (2006) Subthalamic nucleus deep brain stimulation: summary and meta-analysis of outcomes. Mov. Disord. 21 (Suppl. 14): S290–S304. Limousin, P. et al. (1995) Effect of parkinsonian signs and symptoms of bilateral subthalamic nucleus stimulation. Lancet 345: 91–5. Martin, A.J. et al. (2005) Placement of deep brain stimulator elec­ trodes using real-time high-field interventional magnetic reso­ nance imaging. Magn. Reson. Med. 54: 1107–14. Meyers, R. (1942) The modification of alternating tremors, rigidity and festination by surgery of the basal ganglia. Res. Publ. Assoc. Res. Nerv. Ment. Dis. 21: 602–65. Moro, E. et al. (2002) The impact on Parkinson’s disease of electrical parameter settings in STN stimulation. Neurology 59: 706–13. Oh, M.Y. et al. (2002) Long-term hardware-related complications of deep brain stimulation. Neurosurgery 50: 1268–74, discussion 1274–6. Pollak, P. et al. (2002) Intraoperative micro- and macrostimulation of the subthalamic nucleus in Parkinson’s disease. Mov. Disord. 17 (Suppl. 3): S155–S161. Rodriguez, M.C. et al. (1998) Subthalamic nucleus-mediated exci­ totoxicity in Parkinson’s disease: a target for neuroprotection. Ann. Neurol. 44: S175–S188. Russmann, H. et al. (2004) Subthalamic nucleus deep brain stimula­ tion in Parkinson disease patients over age 70 years. Neurology 63: 1952–4. Saint-Cyr, J.A. et al. (2000) Neuropsychological consequences of chronic bilateral stimulation of the subthalamic nucleus in Parkinson’s disease. Brain 123 (Pt 10): 2091–108. Schupbach, W.M. et al. (2007) Neurosurgery at an earlier stage of Parkinson disease: a randomized, controlled trial. Neurology 68: 267–71. Scotto di Luzio, A.E. et al. (2001) Which target for DBS in Parkinson’s disease? Subthalamic nucleus versus globus pallidus internus. Neurol. Sci. 22: 87–8. Silberstein, P. et al. (2003) Patterning of globus pallidus local field potentials differs between Parkinson’s disease and dystonia. Brain 126: 2597–608. Sillay, K.A. et al. (2008) Deep brain stimulator hardware-related infections: incidence and management in a large series. Neurosurgery 62: 360–6, discussion 366–7. Spiegel, E.A. et al. (1947) Stereotaxic apparatus for operations on the human brain. Science 106: 349–50. Starr, P.A. (2002) Placement of deep brain stimulators into the subthalamic nucleus or globus pallidus internus: technical approach. Stereotact. Funct. Neurosurg. 79: 118–45. Starr, P.A. et al. (1998) Ablative surgery and deep brain stimulation for Parkinson’s disease. Neurosurgery 43: 989–1013, discussion 1013–15. Temel, Y. et al. (2006) Behavioural changes after bilateral subtha­ lamic stimulation in advanced Parkinson disease: a systematic review. Parkinsonism Relat. Disord. 12: 265–72. Tornqvist, A.L. et al. (2005) Effects of different electrical param­ eter settings on the intelligibility of speech in patients with Parkinson’s disease treated with subthalamic deep brain stimu­ lation. Mov. Disord. 20: 416–23. Voon, V. et al. (2006) Deep brain stimulation: neuropsychological and neuropsychiatric issues. Mov. Disord. 21 (Suppl. 14): S305–S327.

V.  neuromodulation for movement disorders

C H A P T E R

43

Deep Brain Stimulation for Tremor Adam P. Burdick, Michael S. Okun, and Kelly D. Foote

o u tl i n e Historical Perspective

549

Pertinent Anatomy, Physiology, and Disease Pathophysiology

550

Rationale for Neuromodulation, Target Selection, and Approach

553

Indications and Patient Selection Criteria

554

Implant Procedure Details

554

Historical perspective

555

Outcomes (Review of Most Recent Literature)

555

Complications and Avoidance

556

What the Future Holds (Next 5 Years)

557

Conclusions

557

References

557

Sympathetic ramisectomy, ganglionectomy, rhizotomy, sectioning of the pyramidal and extrapyramidal tracts, and motor cortex ablation were all tried to treat tremor in the early twentieth century (Parrent, 1998). In the 1930s, Meyers pioneered basal ganglia surgery for tremor while working with post-encephalitic patients, but the morbidity of these open procedures was prohibitive. In the 1950s, Spiegel and Wycis successfully introduced safer stereotactic techniques, performing pallidotomies, pallidoansotomies, and campotomies on tremor-afflicted PD patients. Subthalamic lesions in Forel’s fields, the zona incerta (ZI), and the prelemniscal radiations (RAPRL) for PD tremor continued into the 1970s. Hassler first targeted the ventrolateral t­halamus for PD symptoms in 1952, and Cooper did the same for MS tremor in 1967. Autopsy work on their lesioned patients suggested that the ventralis oralis posterior (Vop) and ventralis intermedius (Vim) nuclei were involved in tremor (Parrent, 1998).

Tremor, the involuntary and rhythmic oscillation of a body part, is classified according to its presumed etiology, or alternatively by its phenomenology (description of the affected body area, frequency, and condition in which it manifests). Common tremor conditions include essential tremor (ET), Parkinson’s disease (PD), dystonic tremor, cerebellar tremor, Holmes tremor, physiologic/enhanced physiologic tremor, palatal tremor, neuropathic tremor, drug/toxin-induced tremors, and psychogenic tremor (Deuschl et al., 2001). The body areas affected may include proximal or distal limbs, as well as the trunk, head, or voice. Tremor may manifest during rest, with specific postures, or with action (e.g., intention). The history of the surgical treatment of tremor is remarkable for the evolution of therapies based on empirical observation.

Neuromodulation

Programming and Other Points of Consideration

549

© 2008, 2009 Elsevier Ltd.

550

43.  Deep Brain Stimulation for Tremor

Although effective, ablative procedures have significant drawbacks. Lesions are irreversible, and tremor recurrence is not uncommon (Hirai et al., 1983). Adverse motor, sensory, and speech effects limit the size and (in some cases) the efficacy of lesions, and significant neuropsychological deficits and pseudobulbar symptoms may accompany bilateral lesions (Koller et al., 1997; Matsumoto et al., 1984). When Benabid observed (as had others) that intra-operative high-frequency macro­ electrode stimulation during lesioning procedures suppresses tremor, he considered chronic stimulation as an alternative to ablation (Lozano, 2000). Benabid reported adequate tremor control and few side effects with chronic stimulation of Vim (Benabid et al., 1989). Moreover, bilateral treatment was safer and tremor relief in short-term studies was persistent (Benabid et al., 1996). Today, DBS has generally supplanted lesioning where available, although lesion therapy still has a role in select cases (Hooper et al., 2008).

Pertinent anatomy, physiology, and disease pathophysiology Four theoretical pathophysiological mechanisms of tremor etiology have been proposed: a mechanical

source; reflexes resulting in oscillatory activity; central oscillators; or unstable feed-forward or feed-back systems (Deuschl et al., 2001). The efficacy of DBS is believed to result from the interruption of a pathological oscillation in a group of cells or a circuit that begets tremor. Benabid has proposed that resonance properties of the motor control circuit may be basic features of the motor system, and therefore a central oscillatory mechanism of a transcortical reflex loop passing through Vim generates tremor (a cerebello-thalamocortical loop) (Benabid et al., 1991; Benabid et al., 1996). Nevertheless, the anatomy and pathophysiology of tremor remain somewhat unclear. In this chapter, we will focus on the central nervous system structures and pathways commonly described in the tremor literature, using Hassler’s abbreviations for thalamic nuclei. There are two principle anatomic pathways implicated in tremor production. One is the cerebellothalamic pathway, in which axons of the deep cerebellar nuclei exit via the superior cerebellar peduncle, ascending to and passing by, the contralateral red nucleus (Figure 43.1). These projections continue superiorly into the subthalamic area, and enter the Vim region of the thalamus at its ventral aspect. Vim is located anterior to ventralis caudalis (Vc), the sensory receiving nucleus, and posterior to the ventro-oralis complex (Voa/Vop), a

To motor cortex

Thalamus

Vim nucleus of thalamus

Red nucleus Decussation

Superior cerebellar peduncle Dentate nucleus

Middle cerebellar peduncle

Cerebellum

Inferior cerebellar peduncle Inferior olive

Figure 43.1  A schematic representation of the cerebellothalamic pathway, with axons of the deep cerebellar nuclei ascending to the contralateral thalamus. See text for details

v. NEUROMODULATION FOR MOVEMENT DISORDERS



551

Pertinent anatomy, physiology, and disease pathophysiology

pallidal-receiving area (Benabid et al., 1996; Krack et al., 2002) (Figure 43.2). The other main pathway implicated in tremor is the pallidothalamic pathway, best studied in models of PD. Dopaminergic nigral connections project to the striatum (caudate/putamen) and then project both indirectly (via the globus pallidus externus) (GPe), which contains GABAergic neurons, and STN, glutamatergic) and directly to the globus pallidus internus (GPi) (GABA). GPi has two outflow tracts to the thalamus. One, the ansa lenticularis, loops around the internal capsule, while the other, the lenticular fasciculus, directly pierces the internal capsule and passes dorsal to STN and ventral to the ZI. Upon exiting the internal capsule, the lenticular fasciculus is classically called field H2 of Forel (Gallay et al., 2008). Both outflow tracts join with each other in the subthalamic area of field H of Forel (prerubral field) (Carpenter, 1991), to form the thalamic fasciculus (field H1 of Forel), which enters the thalamus at its ventral aspect, terminating on Voa/Vop (Figure 43.3). The densely complex subthalamic area (STA) contains the ZI and prelemniscal radiation (RAPRL), and has been targeted for tremor despite being less well understood. The ZI sits superolateral to the red nucleus and superior and posteromedial to the STN; posteromedial to the ZI, and immediately anterior to

the medial lemniscus is the RAPR (Velasco et al., 2001; Figure 43.4). The ZI has been hypothesized to synchronize neuronal assemblies, particularly the basal ganglia and the cerebellothalamic pathway, in addition to having efferent connections to the midbrain extrapyr­ amidal area and the medial reticular formation, which are involved with axial and proximal limb muscles (Plaha et al., 2008). The RAPRL contains cerebellothalamic fibers and may also connect with the midbrain tegmentum (Jimenez et al., 2000; Herzog et al., 2007). As described above, the pallidothalamic projections also pass through the subthalamic area. The anatomy and function of this region is less certain (Herzog et al., 2007; Gallay et al., 2008), but its use as a target for tremor has been growing (Velasco et al., 20001; Murata et al., 2003; Herzog et al., 2007; Plaha et al., 2008). Several lines of evidence implicate the cerebellothalamic pathway in tremor, and stimulating its thalamic terminus is the most established method of tremor suppression. ET, the most common movement

Superior Caudate al Later le ic r t ven

Superior

Inte r cap nal sule

Voa

te

Vim

An

Vc

Pulvinar

r

Voa

2 1 ML

3

ZI

RAPRL

1 Medial lemniscus 2 Cerebellothalamic tract 3 Thalamic fasciculus/Forel’s field H1 4 Lenticular fasciculus/Forel’s field H2 5 Ansa lenticularis

4

l na er ule t In ps ca

LF

ZI

rio

Vop

Putamen GPe

GPi

H2 H1

H

STN AL

II

GPi

STN 5 II

Figure 43.2  A sagittal schematic of the thalamus, showing the terminations of the medial lemniscus, cerebellothalamic pathway, and the pallidothalamic pathway on Vc, Vim, and Voa/Vop, respectively. II: optic tract. GPi: globus pallidus interna. ML: medial lemniscus. RAPRL: prelemniscal radiation. STN: subthalamic nucleus. Vc: ventralis caudalis. Vim: ventralis intermedius. Voa: ventralis oralis anter­ ior. Vop: ventralis oralis posterior. ZI: zona incerta. See text for details

Amygdala

Cerebral peduncle Uncus

Figure 43.3  A coronal schematic demonstrating the relationships of the pallidothalamic pathway. AL: ansa lenticularis. Same key as Figure 43.2. GPe: globus pallidus externa. H: Forel’s field H. H1: Forel’s field H1. H2: Forel’s field H2. LF: lenticular fasciculus. See text for details

v. NEUROMODULATION FOR MOVEMENT DISORDERS

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43.  Deep Brain Stimulation for Tremor Anterior

Caudate

Putamen Ante

GPe

rior

com

miss

ure

Fx GPi

5 4 3

Mtt

STN

Internal capsule

2 ZI

RAPRL

Vc

1

Red nucleus

ML

MGN Pulvinar

Figure 43.4  An axial schematic demonstrating the anatomy of the subthalamic area. Approximate regions for the cerebellothalamic tract (2) and the pallidothalamic tract (3) are indicated. Same key as Figures 43.2 and 43.3. 1/ML: medial lemniscus. 2: cerebellothalamic tract. 3: pallidothalamic tract. 4: lenticular fasciculus. 5: ansa lenticularis. Fx: fornix. MGN: medial geniculate nucleus. Mtt: mammillothalamic tract. See text for details

disorder after physiological tremor, is characterized by postural and intention tremor; cerebellar tremor is described more classically as an intention tremor, without a resting component (Dueschl et al., 2001). Posture and intentional movements are considered classic cerebellar functions, although clinicians should note there may be overlapping symptoms and atypical cases. PET (positron emission tomography) scans reveal cerebellar hyperactivity in ET patients that decreases after alcohol consumption, which is known to clinically improve tremor in this group (Boecker et al., 1996). Intraoperative microelectrode recordings can identify Vim (and some Vop – Krack et al., 2002) cells firing in synchronicity with the patient’s tremor. Recent pathologic evidence has shown an increase in Purkinje cell axonal swellings (torpedoes) and reduced numbers of Purkinje cells in ET cases (Axelrad et al., 2008) A more diffuse pathology that includes mesencephalic cerebellothalamic pathways

is thought to cause posttraumatic tremor, and red nucleus lesions have been found in pathological studies in such patients (Umemura et al., 2004). Similar to the cerebellothalamic pathway, the exact mechanism of tremor production in the pallidothalamic pathway is uncertain, although clinical and PET evidence link it to resting tremor (Deuschl et al., 2001; Romanelli et al., 2003; Goto and Yamada, 2004; Foote and Okun, 2005; Foote et al., 2006). PD patients, whose primary dysfunction is attributed to the pallidothalamic pathway, can suffer from disabling rest and postural tremor. Similarly, resting tremor is a diagnostic criterion for Holmes tremor, which presents as lowfrequency mild to moderate resting tremor that becomes severe with posture or intention. PET evidence in PD and Holmes tremor patients has suggested that resting tremor occurs when pathology affects nigrostriatal connections (Deuschl et al., 2001), and both conditions have been successfully treated with stimulation of the pallidothalamic pathway: STN for PD (Diamond et al., 2007) and simultaneous targeting of both pathways (GPi, STN, Voa/Vop, Vim) for Holmes tremor (Romanelli et al., 2003; Goto and Yamada, 2004; Foote and Okun, 2005; Foote et al., 2006). Twenty to sixty percent of MS patients may develop tremor (Berk et al., 2002; Koch et al., 2007) and the phenomenology is heterogeneous, presumably due to the variable extent of multiple plaques. Dysfunction of the thalamus (Feys et al., 2005; Wishart et al., 2003), midbrain (Berk et al., 2002), and the cerebellum or its tracts (Alusi et al., 1999, 2001) has been implicated in these cases. Action, postural, and intention tremor are more prominent than resting tremor in MS, and this may indicate a role for the cerebellum in tremori­genesis (Berk et al., 2002; Hammond and Kerr, 2008). However, not only does a low-frequency postural tremor often persist after DBS surgery, but MS tremor often recurs, and functional improvements may be less robust than those seen in other tremor disorders. These findings point to a diffuse dysfunction that is not easily treated with focal procedures (Alusi et al., 2001; Lim et al., 2007). Because DBS does not reverse primary cerebellar damage, MS patients who exhibit significant cerebellar dysfunction in addition to their rhythmic tremor often experience suboptimal results. DBS may interrupt the pathological oscillations in the affected circuits and suppress the tremor, but if the tremor is associated with severe ataxia, dysmetria, and dysdiadochokinesia, then mitigation of the rhythmic tremor may not result in significant reduction of functional impairment. Because cerebellar dysfunction affects an estimated 75% of MS patients, this becomes an important predictor of success or failure of DBS therapy in this population and should be considered carefully during patient selection.

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Rationale for neuromodulation, target selection, and approach

Rationale for neuromodulation, target selection, and approach The etiology and phenomenology of tremor guide the choice of DBS target. Target selection and indications for DBS are in a state of continual refinement. The mainstay of DBS tremor therapy has been Vim DBS (Benabid et al., 1989, 1991). Although most commonly used to treat ET, its reported successful use in PD tremor, MS tremor, Holmes tremor, and tremors associated with phenylketonuria, spinocerebellar ataxia, mercury poisoning, tumors, and genetic syndromes shows it is a common element in a wide variety of tremor conditions (Alesch et al., 1995; Benabid et al., 1996; Geny et al., 1996; Kudo et al., 2001; Nikkhah et al., 2004; Payne et al., 2005; Schramm et al., 2005; Freund et al., 2007; Hamel et al., 2007). While most practitioners conceptualize Vim to be the target, DBS leads are usually placed at the Vim/Vop border. Therefore electrical current also spreads into Vop, which may actually enhance tumor suppression. Theoretically, stimulating this waystation in the cerebellothalamic circuit (Vim) abolishes the pathologic oscillations that draw cortical neurons into tremor. Although two decades of experience has cemented its role in the treatment of tremor, this exper­ ience has also unmasked some limitations. Outcomes for disparate tremor conditions (such as MS tremor, Holmes tremor, and proximal versus distal tremor) are sufficiently distinct as to suggest differing pathophysiologies and treatment requirements (Benabid et al., 1991; Benabid et al., 1996; Geny et al., 1996; Murata et al., 2003; Yamamoto et al., 2004; Bittar et al., 2005). And although unilateral Vim DBS has shown limited efficacy for head, voice, and midline tremors, bilateral Vim stimulation has been more effective (Taha et al., 1999; Berk and Honey, 2002; Deuschl and Bain, 2002). A new approach for MS tremor and Holmes tremor, which have been difficult to treat with Vim DBS, is the simultaneous treatment of the cerebellothalamic and pallidothalamic pathways (Schuurman et al., 2000; Lim et al., 2007). Most studies of DBS for MS tremor have targeted Vim, the cerebellothalamic terminus, though some preferred Vop, the termination of pallidothalamic projections (Critchley and Richardson, 1998; Alusi et al., 2001; Wishart et al., 2003). Romanelli treated a Holmes tremor patient, who had prior Vim DBS and control of intention and postural tremor, with STN DBS to suppress a residual pallidothalamic resting tremor (Romanelli et al., 2003). Goto added pallidotomy to a Holmes tremor patient with prior Vim DBS, noting a differential response to the cerebellothalamic and pallidothalamic interventions. Vim DBS ameliorated the

553

distal tremor and the subsequent pallidotomy abolished the proximal tremor (Goto and Yamada, 2004). The authors theorized that GPi intervention may affect descending projections to the pedunculopontine nucleus, which is related to the mesencephalic tegmental field that controls axial and proximal appendicular musculature via the reticulospinal tract. Bittar has also used separate targets for proximal and distal tremor: Vop for distal tremor, and ZI for proximal tremor (Bittar et al., 2005). Foote achieved improved tremor control in a post-traumatic Holmes tremor patient with duallead stimulation of both Vim and Voa/Vop, simultaneously stimulating the thalamic terminations of both the pallido- and cerebellothalamic circuits (Foote and Okun, 2005). This method was further tested on two more post-traumatic Holmes tremor patients and one MS tremor patient, again with tremor control that surpassed Vim monotherapy (Foote et al., 2006). Yamamoto has also used this method of dual-lead stimulation in post-stroke tremor (Yamamoto et al., 2004). This trend toward modulating both cerebello- and pallidothalamic tracts is also illustrated by DBS of the subthalamic area (STA). Although earlier lesional work in the STA for tremor was not continued on a large scale due to adverse effects, this target has been revisited with DBS. Investigators report STA DBS to be effective for axial, proximal, and distal tremor, as well as for the cardinal symptoms of PD. Herzog analyzed the optimal electrode position in 10 ET and 11 MS patients implanted in the Vim thalamus and found that the subthalamic area was significantly superior to thalamic stimulation for tremor (Herzog et al., 2007). The best contacts clustered within the RAPRL, which the authors considered to be the post­erior extension of field H of Forel, and an efficient way to stimulate the cerebellothalamic tract. Hamel also found STA DBS to be superior to VL thalamus DBS for the control of intention tremor in eight ET and two MS patients, with cerebellothalamic fibers, ZI, and RAPRL as the structures possibly involved (Whittle et al., 2004). Nandi reported an MS patient with severe proximal and distal arm tremor with sustained tremor control after ZI DBS; he notes connections between ZI and the brain stem, and the belief that the ZI is a principal component of the subthalamic locomotor region (Nandi et al., 2002). Plaha also achieved axial, proximal, and distal tremor control with bilateral caudal ZI DBS in 18 patients with a variety of diagnoses: PD, Holmes tremor, cerebellar tremor, ET, MS tremor, and dystonic tremor (Plaha et al., 2008). Murata reported axial, proximal and distal tremor control by targeting the posterior STA (ZI/RAPRL) in eight ET patients with severe proximal tremor (Murata et al., 2003). Based on the success of dual-lead stimulation in other case

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43.  Deep Brain Stimulation for Tremor

reports, Freund placed an electrode straddling Vim/ Vop (upper two contacts) and the underlying ZI/cere­ bellothalamic tract (lower two contacts) in a patient with spinocerebellar ataxia and severe postural tremor, reporting near-complete tremor arrest (bipolar stimulation: contacts 0-2 and 4-5 negative, contacts 3 and 7 positive) (Freund et al., 2007). ZI/RAPRL DBS has been applied to tremor-predominant PD patients, improving not only tremor but posture, gait, rigidity, and akinesia (Jimenez et al., 2000; Velasco et al., 2001; Kitagawa et al., 2005). One theory proposed to explain why STA stimulation might be more effective than thalamic stimulation is that it efficiently modulates the compact fiber bundles before their wide dispersal in the thalamus (Velasco et al., 2001; Murata et al., 2003). This small body of work on STA DBS is promising, but requires further characterization and validation.

Indications and patient selection criteria Because DBS is an elective procedure, the fundamental principle in patient selection is that of a favorable risk–benefit ratio. Appropriate risk versus benefit analysis requires several fundamental elements: First, accurate characterization and classification of the patient’s tremor to predict the likelihood of successful tremor suppression. Second, establishment that appropriate medical therapy has been adequately tried and failed. Third, estimation of the potential improvement in the patient’s functional capacity and quality of life that would result if the tremor were substantially diminished. Finally, assessment of the patient’s fitness for surgery, factoring in age, cognitive function and medical comorbidities, in order to better predict the likelihood of patient-specific adverse events. This extensive analysis is best accomplished by a multidisciplinary team that includes a movement disorders specialized neurologist, neurosurgeon, and neuropsychologist. For selected patients, involvement of a psychiatrist, physical therapist, occupational therapist, speech therapist, or social worker may also be indicated. For centers where such specialists are not readily available, simpler screens have been designed to help identify potential candidates for DBS (Deuschl and Bain, 2002; Okun et al., 2004; Okun, Fernandez et al., 2007; Okun, Rodriguez et al., 2007; Rodriguez et al., 2007). Patients with tremor secondary to MS present unique challenges. Thalamotomy for MS tremor has been hindered by a reputation for poor outcomes due to tremor recurrence, disease progression, and unclear patient selection criteria (Critchley and

Richardson, 1998), lessons applicable to DBS for MS tremor. Exclusion criteria for MS patients, when mentioned, include rapidly progressive disease, poor cognition, and disabling limb weakness or numbness (Matsumoto et al., 2001; Berk et al., 2002; Hooper et al., 2002). To avoid unrealistic expectations, it is important to clarify to these patients that while DBS is likely to suppress their tremor, it is not expected to improve other neurologic deficits they may have as a result of their disease (Critchley and Richardson, 1998; Whittle et al., 1998; Berk et al., 2002; Hooper et al., 2002). Distinguishing ataxia from tremor is a difficult but important task, as ataxia will not predictably improve with DBS (Whittle et al., 1998; Matsumoto et al., 2001; Deuschl and Bain, 2002; Hooper et al., 2002). Despite these caveats, a certain amount of flexibility can be maintained regarding exclusion criteria, because the benefits can be different for different cate­ gories of patients. For example, debilitated patients might gain only modest limb control but enjoy less fatigue, whereas higher-functioning patients may see marked improvement in activities of daily living (Wishart et al., 2003; Geny et al., 2006). Although higher complication rates in MS patients have been reported (Hooper et al., 2002), there are no data to suggest that postsurgical MS exacerbation rates are worse than presurgical baselines (Wishart et al., 2003). Many of these principles pertaining to MS patient selection may also be applicable to patients with tremor secondary to head trauma, stroke, or other etiologies.

Implant procedure details Successful DBS lead placement requires not only stimulation of the desired target, but also avoiding the spread of current into undesirable neighboring structures. Stimulation of the internal capsule (IC) causes involuntary muscle contraction; of Vc, paresthesiae; of the medial lemniscus, hemibody paresthesiae; and of oculomotor fibers, ipsilateral eye deviation. An understanding of the relative anatomical positions of various structures in the region of stimulation is critical to successful DBS lead implantation. The most common target for tremor, Vim, is bordered laterally by the IC and posteriorly by Vc. The electrode is typically placed at the anterior border of Vim to ensure that stimulation does not extend posteriorly into Vc and induce intolerable paresthesiae. Various coordinates relative to the midcommissural point have been reported as the ideal site for Vim stimulation (Benabid et al., 1991; Ondo et al., 1998; Krauss et al., 2001; Papavassiliou et al., 2004). Most commonly, the AC–PC plane has been

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programming and other points of consideration

cited as the optimal axial position. Recommendations for optimal AP and lateral positions are approximately 5 mm posterior and 13 mm lateral to the midcommissural point. The optimal lateral coordinate may vary with the degree of brain atrophy and associated ventriculomegaly. Some have therefore advocated the use of distance from the third ventricular wall (e.g. 10 mm) as a better method of initial target selection (Benabid et al., 1991; Papavassiliou et al., 2004; Lee and Kondziolka, 2005; Pahwa et al., 2006). Intraoperative microelectrode recording with concurrent physiologic testing can be helpful to identify the upper extremity somatotopy in the thalamus to guide the laterality of lead placement. It can also be used to localize the anterior border of Vc. The anterior border of Vim (the desired site for lead implantation) abuts the posterior border of Vop, and is approximately 2 mm anterior to the Vc border. After careful initial targeting and microelectrode mapping to refine the target selection, it remains critically important to test the implanted lead with intraoperative macrostimulation using a temporarily connected external pulse generator. In addition to verifying that successful tremor suppression can be achieved with stimulation, thresholds for stimulation-induced side effects can be measured. Thresholds for intolerable parasthesiae (Vc), or involuntary muscle contraction (IC) should be 4 V or greater at therapeutically effective contacts. If they are below 4 V, the lead should be repositioned and retested to optimize outcome. Extra care must be taken with MS patients, whose brains can have atypical MER signatures (Whittle et al., 1998) in addition to anatomic distortions from demyelination and ex-vacuo hydrocephalus (Whittle et al., 2004).

Programming and other points of consideration As with all DBS, programming for tremor suppression is a process of balancing thresholds for side effects against stimulation-induced benefits. The choice of contact(s) for stimulation is empirically selected based on trial and error, but the deeper contacts nearer to the AC–PC plane tend to be most clinically effective. While high frequency stimulation ( 90 Hz) is generally required for optimal tremor suppression, no additional improvement in efficacy was observed at frequencies greater than 130 Hz (Ushe et al., 2004; Kuncel et al., 2006). In one study, frequencies greater than 100 Hz led to side effects at lower voltage thresholds, narrowing the therapeutic window (the difference between the

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intensity that results in tremor suppression and the intensity that causes side effects) (Kuncel et al., 2006). Current data support the use of short pulse widths (e.g. 60–90 s), which minimize the injected current and reduce the risk of tissue or electrode damage, but have a minimal effect on tremor or side effects (Kuncel et al., 1966). Long pulse widths ( 120 s) have been associated with mild cognitive morbidity and speech dysfunction in ET patients (Woods et al., 2003). In order to maximize the life of the pulse generator, the minimal effective voltage should be prescribed. When more than 4 V are required for tremor suppression, or when tremor suppression is not achievable without intolerable side effects, consideration should be given to the possibility that lead position is suboptimal. Postoperative imaging for lead localization should be performed in all cases, but in cases with suboptimal clinical benefit, reasonable practice requires a careful assessment of lead location for troubleshooting. In such cases, removal and replacement of a suboptimally positioned DBS lead can frequently salvage a good outcome. Several investigators have noted a general trend of increasing voltage to maintain adequate tremor suppression over time (Limousin et al., 1999; Sydow et al., 2003; Yamamoto et al., 2004). Disease progression, loss of microthalamotomy effect, or possibly conservative programming at the outset, may have been responsible (Alesch et al., 1995). Benabid postulated that tissue changes around the electrode require increasing amplitude in the weeks after the operation, and that later increases in amplitude could be due to tolerance or habituation (Benabid et al., 1996). For targets other than Vim and conditions other than ET, programming data are scarce. Stimulation parameters in MS patients have often included higher voltages and wider pulse widths than PD or ET patients, with less tremor control. These settings, which distribute current to a larger anatomic area, but commonly achieve less effective tremor suppression, suggest potential pathological involvement of multiple basal ganglia circuits or a need to stimulate a greater somatotopic distribution in many cases of MS-related tremor (Berk et al., 2002). A need for frequent programming to maintain optimum tremor control is also common in MS tremor (Geny et al., 1996; Whittle et al., 1998; Montgomery et al., 1999; Wishart et al., 2003).

Outcomes (review of most recent literature) Multiple studies with short- and long-term follow-up have documented the remarkable efficacy of Vim DBS

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for tremor. Reported rates of tremor reduction range from 50 to 90%, with the majority falling in the 70–80% range (Blond et al., 1992; Hubble et al., 1996; Koller et al., 1997; Benabid et al., 1989, 1991, 1996; Alesch et al., 1995; Ondo et al., 1998; Limousin et al., 1999; Schuurman et al., 2000; Krauss et al., 2001; Sydow et al., 2003; Lee and Kondziolka, 2005; Pahwa et al., 2006). Although deterioration of effective tremor suppression has been reported in 18.5–21% of patients over time (Benabid et al., 1996; Koller et al., 1999), other reports with up to 6 years’ follow-up document sustained tremor reductions of 46–86% (Koller et al., 2001; Pahwa et al., 2006; Sydow et al., 2009). The literature for MS tremor DBS is more complicated to interpret, being comprised of short-term case reports and small series that use a wide variety of surgical techniques and outcome measures. Most investigators have targeted Vim, but more recently a few have explored the subthalamic area, or used dual-lead stimulation (Nandi et al., 2002; Foote et al., 2005, 2006; Bittar et al., 2005). The majority of MS tremor patients experienced some sustained benefit. In Wishart’s review of DBS for MS tremor covering 12 studies with 65 patients, 88% had improved

tremor, and of 25 patients in six studies, 76% experienced improvements in daily functioning. Koch’s review of the MS DBS literature similarly concluded that 69–100% of patients had improved tremor, but functional outcomes were variable or not reported (Koch et al., 2007). Despite the reported benefit from MS tremor DBS, incomplete tremor suppression, diminishing benefit over time, and frequent reprogramming were recurrent themes. Successful treatment of Holmes tremor, post-stroke tremor, post-traumatic tremor, and other rarer tremor types has also been documented in case reports and small series (Kudo et al., 2001; Romanelli et al., 2003; Goto and Yamada, 2004; Yamamoto et al., 2004; Foote et al., 2005, 2006).

Complications and avoidance The range of reported DBS-related adverse events is widely variable, both in terms of rates (from 0% to over 40% – Hubble et al., 1996; Krauss et al., 2001) and events (Table 43.1). Comparing results across centers is

Table 43.1  Range of adverse events reported in the literature Stimulation-related

Surgery-related

Hardware-related

Temporary paresthesiae, 16–81%

Headache, 4–24%

Lead replacement NOS, 20%

Permanent paresthesiae, 6–16%

Asymptomatic hemorrhage, 2.5–8%

Erosion, 10–12%

Dysarthria, 2–36%

Symptomatic hemorrhage, 2.5–5%

Infection, 1.8–10%

Disequilibrium, 2.7–23%

Pain, 25–38%

Skin irritation, 10%

Gait disorders, 0–23%

Seizure, 1.7–2.5%

Wire breakage, 2–10%

Dystonia, 0.9–16%

Lead misplacement, 4.5–10%

Lead migration, 4–9%

Mild paresis, 4–16%

Subcutaneous hematoma, 3–5%

Extension replacement, 8%

Increased salivation, 0.8–16%

Cardiovascular, 4.2%

Intermittent stimulation, 5%

Hypophonia, 2.6–11%

Paresis, 5%

Loss of effect NOS, 10–25%

Bone fracture (also surgery-related), 10–11%

Stroke, 3.7%

IPG malfunction, 1.6–5%

Depression, 2.6–18%

Cardiac ischemia, 2%

Sleepiness, 2–11%

Venous infarct, 1%

Tremor rebound, 36% Incoordination, 33% Dysphagia, 24% Asthenia, 18% Altered mental status/thinking, 2–16% Insomnia, speech disorder, 13% Accidental injury, bradykinesia, hallucinations, 11% Dizziness, facial weakness, nausea, 2.6% Diplopia, 2% Studies reported by: Benabid et al., 1991, 1996; Blond et al., 1992; Alesch et al., 1995; Koller et al., 1997; Koller et al., 1999; Limousin et al., 1999; Schuurman et al., 2000; Krauss et al., 2001; Sydow et al., 2003; Lee et al., 2005; Pahwa et al., 2006

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557

Conclusions

complicated by differences in recording methods and definitions of adverse events. The wide variation of reported DBS adverse event rates has been attributed to the variable level of experience among implanting centers (Hariz, 2002). While experience level undoubtedly accounts for some of this variation, it is likely that variability in the rigor with which adverse events are tracked and reported is an even more important contributor to this disparity in reported adverse events. Adverse events following DBS are usually categor­ ized as related to surgery, hardware, or stimulation. Surgical side effects are generally reported to be low. Deaths and cardiovascular events, when reported, are variably interpreted as unrelated to the surgical procedure (Hubble et al., 1996; Limousin et al., 1999) or counted as adverse events (Krauss et al., 2001). The range of published hardware-related adverse events, which increases with length of follow-up, may be as high as 27% (Pahwa et al., 2006) at 5 years. Overall, stimulation-related adverse events occur in 10–42.5% of patients (Krauss et al., 2001; Pahwa et al., 2006) with more side effects seen in bilaterally (52%) than unilaterally (31%) implanted patients (Krauss et al., 2001). Bilateral systems are associated with more persistent side effects that do not respond to reprogramming (Pahwa et al., 2006). A higher complication rate can also be expected in older patients with pronounced brain atrophy. The most commonly reported stimulationrelated adverse events are paresthesiae, dysarthria, gait disorders, and disequilibrium, but they are frequently viewed as mild and tolerable, or amenable to reprogramming (Benabid et al., 1991; Koller et al., 1994; Limousin et al., 1999; Krauss et al., 2001; Pahwa et al., 2006).

What the future holds (next 5 years) As the hardware available for DBS therapy continues to improve, and the general level of experience increases among implanting centers, the risk of adverse events should decline. As DBS practitioners become more sophisticated, and our understanding of the neural circuitry and pathogenesis of various tremor disorders increases, new targets and stimulation strategies are being introduced. Because modern medical practice increasingly requires that therapies be based on reliable evidence (especially expensive, invasive interventions with significant associated risk), high quality clinical trials using kinematic analyses and validated outcome instruments (for tremor, functional status, and quality of life) and rigorous, standardized complication reporting, will accurately characterize the effect

of new applications of DBS therapy on a wide variety of tremor disorders. Applications of DBS will become more specific and effective for a given patient’s tremor. As efficacy and safety improve, the indications for DBS should broaden, and more patients will benefit from DBS for various tremor disorders.

Conclusions Vim thalamic deep brain stimulation has become a safe and highly effective mainstay in the treatment of medically refractory essential tremor and other tremor disorders. Because of a perceived lower risk and equivalent or increased tremor suppression, DBS has largely supplanted ablative therapies such as thalamotomy. As our understanding of the neural circuitry and pathophysiology of various tremor disorders increases, new targets and techniques for the application of DBS therapy are being proposed and carefully studied. The evolution of DBS therapy for tremor suppression should result in a more patient-tailored approach, in which the target selection and technique will vary depending upon the etiology and phenomenology of a given patient’s tremor. As patient selection, efficacy, and safety continue to improve, and indications for DBS broaden, increasing numbers of patients may benefit from DBS for various disabling tremor disorders.

References Alusi, S.H., Aziz, T.Z., Glickman, S., Jahanshahi, M., Stein, J.F. and Bain, PG. (2001) Stereotactic lesional surgery for the treatment of tremor in multiple sclerosis: a prospective case-controlled study. Brain 124 (Pt 8): 1576–89. Alusi, S.H., Glickman, S., Aziz, T.Z. and Bain, P.G. (1999) Tremor in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 66 (2): 131–4. Alesch, F., Pinter, M.M., Helscher, R.J., Fertl, L., Benabid, A.L. and Koos, W.T. (1995) Stimulation of the ventral intermediate thalamic nucleus in tremor dominated Parkinson’s disease and essential tremor. Acta Neurochir. (Wien) 136 (1-2): 75–81. Axelrad, J.E., Louis, E.D., Honig, L.S., Flores, I., Ross, G.W., Pahwa, R. et al. (2008) Reduced Purkinje cell number in essential tremor: a postmortem study. Arch Neurol. 65 (1): 101–7. Benabid, A.L., Pollak, P., Gao, D., Hoffmann, D., Limousin, P., Gay, E. et al. (1996) Chronic electrical stimulation of the ventralis intermedius nucleus of the thalamus as a treatment of movement disorders. J. Neurosurg. 84 (2): 203–14. Benabid, A.L., Pollak, P., Gervason, C., Hoffmann, D., Gao, D.M., Hommel, M. et al. (1991) Long-term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus. Lancet 337 (8738): 403–6. Benabid, A.L., Pollak, P., Hommel, M., Gaio, J.M., de Rougemont, J. and Perret, J. (1989) [Treatment of Parkinson tremor by chronic stimulation of the ventral intermediate nucleus of the thalamus]. Rev. Neurol. (Paris) 145 (4): 320–3. Berk, C. and Honey, C.R. (2002) Bilateral thalamic deep brain stimulation for the treatment of head tremor. Report of two cases. J. Neurosurg. 96 (3): 615–18.

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Berk, C., Carr, J., Sinden, M., Martzke, J. and Honey, C.R. (2002) Thalamic deep brain stimulation for the treatment of tremor due to multiple sclerosis: a prospective study of tremor and quality of life. J. Neurosurg. 97 (4): 815–20. Bittar, R.G., Hyam, J., Nandi, D., Wang, S., Liu, X., Joint, C. et al. (2005) Thalamotomy versus thalamic stimulation for multiple sclerosis tremor. J. Clin. Neurosci. 12 (6): 638–42. Blond, S., Caparros-Lefebvre, D., Parker, F., Assaker, R., Petit, H., Guieu, J.D. et al. (1992) Control of tremor and involuntary movement disorders by chronic stereotactic stimulation of the ventral intermediate thalamic nucleus. J. Neurosurg. 77 (1): 62–8. Boecker, H., Wills, A.J., Ceballos-Baumann, A., Samuel, M., Thompson, P.D., Findley, L.J. et al. (1996) The effect of ethanol on alcohol-responsive essential tremor: a positron emission tomography study. Ann. Neurol. 39 (5): 650–8. Carpenter, M.B. (1991) Core Text of Neuroanatomy, 4th edn. Baltimore, MD: Williams & Wilkins. Critchley, G.R. and Richardson, PL. (1998) Vim thalamotomy for the relief of the intention tremor of multiple sclerosis. Br. J. Neurosurg 12 (6): 559–62. Deuschl, G. and Bain, P. (2002) Deep brain stimulation for tremor [correction of trauma]: patient selection and evaluation. Mov. Disord. 17 (Suppl. 3): S102–S111. Deuschl, G., Raethjen, J., Lindemann, M. and Krack, P. (2001) The pathophysiology of tremor. Muscle Nerve 24 (6): 716–35. Diamond, A., Shahed, J. and Jankovic, J. (2007) The effects of subthalamic nucleus deep brain stimulation on parkinsonian tremor. J. Neurol. Sci. 260 (1-2): 199–203. Feys, P., Maes, F., Nuttin, B., Helsen, W., Malfait, V., Nagels, G. et al. (2005) Relationship between multiple sclerosis intention tremor severity and lesion load in the brainstem. Neuroreport 16 (12): 1379–82. Foote, K.D. and Okun, M.S. (2005) Ventralis intermedius plus ventralis oralis anterior and posterior deep brain stimulation for posttraumatic Holmes tremor: two leads may be better than one: technical note. Neurosurgery 56 (2 Suppl.), E445; discussion E. Foote, K.D., Seignourel, P., Fernandez, H.H., Romrell, J., Whidden, E., Jacobson, C. et al. (2006) Dual electrode thalamic deep brain stimulation for the treatment of posttraumatic and multiple sclerosis tremor. Neurosurgery 58 (4 Suppl. 2), ONS-280-5; d­iscussion ONS-5-6. Freund, H.J., Barnikol, U.B., Nolte, D., Treuer, H., Auburger, G., Tass, P.A. et al. (2007) Subthalamic–thalamic DBS in a case with spinocerebellar ataxia type 2 and severe tremor – an unusual clinical benefit. Mov. Disord. 22 (5): 732–5. Gallay, M.N., Jeanmonod, D., Liu, J. and Morel, A. (2008) Human pallidothalamic and cerebellothalamic tracts: basis for functional stereotactic neurosurgery. Brain Struct. Funct. ( Jan 10) Geny, C., Nguyen, J.P., Pollin, B., Feve, A., Ricolfi, F., Cesaro, P. et al. (1996) Improvement of severe postural cerebellar tremor in multiple sclerosis by chronic thalamic stimulation. Mov. Disord. 11 (5): 489–94. Goto, S. and Yamada, K. (2004) Combination of thalamic Vim stimulation and GPi pallidotomy synergistically abolishes Holmes’ tremor. J. Neurol. Neurosurg. Psychiatry 75 (8): 1203–4. Hamel, W., Herzog, J., Kopper, F., Pinsker, M., Weinert, D., Muller, D. et al. (2007) Deep brain stimulation in the subthalamic area is more effective than nucleus ventralis intermedius stimulation for bilateral intention tremor. Acta Neurochir. (Wien) 149 (8): 749–58, discussion 758. Hammond, E.R. and Kerr, D.A. (2008) Ethanol responsive tremor in a patient with multiple sclerosis. Arch. Neurol. 65 (1): 142–3. Hariz, M.I. (2002) Complications of deep brain stimulation surgery. Mov. Disord. 17 (Suppl. 3): S162–S166.

Herzog, J., Hamel, W., Wenzelburger, R., Potter, M., Pinsker, M.O., Bartussek, J. et al. (2007) Kinematic analysis of thalamic versus subthalamic neurostimulation in postural and intention tremor. Brain 130 (Pt 6): 1608–25. Hirai, T., Miyazaki, M., Nakajima, H., Shibazaki, T. and Ohye, C. (1983) The correlation between tremor characteristics and the predicted volume of effective lesions in stereotaxic nucleus ventralis intermedius thalamotomy. Brain 106 (Pt 4): 1001–18. Hooper, A.K., Okun, M.S., Foote, KD., Fernandez, HH., Jacobson, C., Zeilman, P. et al. (2008) Clinical cases where lesion therapy was chosen over deep brain stimulation. Stereotact. Funct. Neurosurg. 86 (3): 147–52. Hooper, J., Taylor, R., Pentland, B. and Whittle, I.R. (2002) A prospective study of thalamic deep brain stimulation for the treatment of movement disorders in multiple sclerosis. Br. J. Neurosurg. 16 (2): 102–9. Hubble, J.P., Busenbark, K.L., Wilkinson, S., Penn, R.D., Lyons, K. and Koller, W.C. (1996) Deep brain stimulation for essential tremor. Neurology 46 (4): 1150–3. Jimenez, F., Velasco, F., Velasco, M., Brito, F., Morel, C., Marquez, I. et al. (2000) Subthalamic prelemniscal radiation stimulation for the treatment of Parkinson’s disease: electrophysiological characterization of the area. Arch. Med. Res. 31 (3): 270–81. Kitagawa, M., Murata, J., Uesugi, H., Kikuchi, S., Saito, H., Tashiro, K. et al. (2005) Two-year follow-up of chronic stimulation of the posterior subthalamic white matter for tremor-dominant Parkinson’s disease. Neurosurgery 56 (2): 281–9, discussion 289. Koch, M., Mostert, J., Heersema, D. and De Keyser, J. (2007) Tremor in multiple sclerosis. J. Neurol. 254 (2): 133–45. Koller, W.C., Lyons, K.E., Wilkinson, S.B. and Pahwa, R. (1999) Efficacy of unilateral deep brain stimulation of the VIM nucleus of the thalamus for essential head tremor. Mov. Disord. 14 (5): 847–50. Koller, W.C., Lyons, K.E., Wilkinson, S.B., Troster, A.I. and Pahwa, R. (2001) Long-term safety and efficacy of unilateral deep brain stimulation of the thalamus in essential tremor. Mov. Disord. 16 (3): 464–8. Koller, W., Pahwa, R., Busenbark, K., Hubble, J., Wilkinson, S., Lang, A. et al. (1997) High-frequency unilateral thalamic stimulation in the treatment of essential and parkinsonian tremor. Ann. Neurol. 42 (3): 292–9. Krack, P., Dostrovsky, J., Ilinsky, I., Kultas-Ilinsky, K., Lenz, F., Lozano, A. et al. (2002) Surgery of the motor thalamus: problems with the present nomenclatures. Mov. Disord. 17 (Suppl. 3): S2–S8. Krauss, J.K., Simpson, R.K., Jr., Ondo, W.G., Pohle, T., Burgunder, J.M. and Jankovic, J. (2001) Concepts and methods in chronic thalamic stimulation for treatment of tremor: technique and application. Neurosurgery 48 (3): 535–41, discussion 41–3. Kudo, M., Goto, S., Nishikawa, S., Hamasaki, T., Soyama, N., Ushio, Y. et al. (2001) Bilateral thalamic stimulation for Holmes’ tremor caused by unilateral brainstem lesion. Mov. Disord. 16 (1): 170–4. Kuncel, A.M., Cooper, S.E., Wolgamuth, B.R., Clyde, M.A., Snyder, S.A., Montgomery, E.B., Jr. et al. (2006) Clinical response to varying the stimulus parameters in deep brain stimulation for essential tremor. Mov. Disord. 21 (11): 1920–8. Lee, J.Y. and Kondziolka, D. (2005) Thalamic deep brain stimulation for management of essential tremor. J. Neurosurg. 103 (3): 400–3. Lim, D.A., Khandhar, S.M., Heath, S., Ostrem, J.L., Ringel, N. and Starr, P. (2007) Multiple target deep brain stimulation for multiple sclerosis related and poststroke Holmes’ tremor. Stereotact. Funct. Neurosurg 85 (4): 144–9. Limousin, P., Speelman, J.D., Gielen, F. and Janssens, M. (1999) Multicentre European study of thalamic stimulation in parkinsonian and essential tremor. J. Neurol. Neurosurg. Psychiatry 66 (3): 289–96.

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Plaha, P., Khan, S. and Gill, S.S. (2008) Bilateral stimulation of the caudal zona incerta nucleus for tremor control. J. Neurol. Neurosurg. Psychiatry 79: 504–13. Rodriguez, R.L., Fernandez, H.H., Haq, I. and Okun, M.S. (2007) Pearls in patient selection for deep brain stimulation. Neurologist 13 (5): 253–60. Romanelli, P., Bronte-Stewart, H., Courtney, T. and Heit, G. (2003) Possible necessity for deep brain stimulation of both the ventralis intermedius and subthalamic nuclei to resolve Holmes tremor. Case report. J. Neurosurg. 99 (3): 566–71. Schramm, P., Scheihing, M., Rasche, D. and Tronnier, V.M. (2005) Behr syndrome variant with tremor treated by VIM stimulation. Acta Neurochir. (Wien) 147 (6): 679–83, discussion 83. Schuurman, P.R., Bosch, D.A., Bossuyt, P.M., Bonsel, G.J., van Someren, E.J., de Bie, R.M. et al. (2000) A comparison of continuous thalamic stimulation and thalamotomy for suppression of severe tremor. N. Engl. J. Med. 342 (7): 461–8. Sydow, O., Thobois, S., Alesch, F. and Speelman, J.D. (2003) Multicentre European study of thalamic stimulation in essential tremor: a six year follow up. J. Neurol. Neurosurg. Psychiatry 74 (10): 1387–91. Taha, J.M., Janszen, M.A. and Favre, J. (1999) Thalamic deep brain stimulation for the treatment of head, voice, and bilateral limb tremor. J. Neurosurg. 91 (1): 68–72. Umemura, A., Samadani, U., Jaggi, J.L., Hurtig, H.I. and Baltuch, G.H. (2004) Thalamic deep brain stimulation for posttraumatic action tremor. Clin. Neurol. Neurosurg. 106 (4): 280–3. Ushe, M., Mink, J.W., Revilla, F.J., Wernle, A., Schneider Gibson, P., McGee-Minnich, L. et al. (2004) Effect of stimulation frequency on tremor suppression in essential tremor. Mov. Disord. 19 (10): 1163–8. Velasco, F., Jimenez, F., Perez, M.L., Carrillo-Ruiz, J.D., Velasco, A.L., Ceballos, J. et al. (2001) Electrical stimulation of the prelemniscal radiation in the treatment of Parkinson’s disease: an old target revised with new techniques. Neurosurgery 49 (2): 293–306, discussion 308. Whittle, I.R., Hooper, J. and Pentland, B. (1998) Thalamic deep-brain stimulation for movement disorders due to multiple sclerosis. Lancet 351 (9096): 109–10. Whittle, I.R., Yau, Y.H. and Hooper, J. (2004) Mesodiencephalic targeting of stimulating electrodes in patients with tremor caused by multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 75 (8): 1210. Wishart, H.A., Roberts, D.W., Roth, R.M., McDonald, B.C., Coffey, D.J., Mamourian, A.C. et al. (2003) Chronic deep brain stimulation for the treatment of tremor in multiple sclerosis: review and case reports. J. Neurol. Neurosurg. Psychiatry 74 (10): 1392–7. Woods, S.P., Fields, J.A., Lyons, K.E., Pahwa, R. and Troster, A.I. (2003) Pulse width is associated with cognitive decline after thalamic stimulation for essential tremor. Parkinsonism Relat. Disord. 9 (5): 295–300. Yamamoto, T., Katayama, Y., Kano, T., Kobayashi, K., Oshima, H. and Fukaya, C. (2004) Deep brain stimulation for the treatment of parkinsonian, essential, and poststroke tremor: a suitable stimulation method and changes in effective stimulation intensity. J. Neurosurg. 101 (2): 201–9.

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C H A P T E R

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Infusion Therapy for Movement Disorders Joseph C. Hsieh and Richard D. Penn

o u tline Introduction

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Baclofen for Spasticity Perspective on Spasticity Baclofen Oral Baclofen Intrathecal Baclofen Details on Baclofen Therapy Patient Selection Pump Implantation and Programming Risks Current State of Therapy

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Glial Cell-Line Derived Neurotrophic Factor  (GDNF) for Parkinson’s Disease 565 Perspective on Parkinson’s Disease 565 Glial Cell-Line Derived Neurotrophic Factor (GDNF) 566 Details on GDNF Therapy 566 Preliminary Studies 566 Amgen’s GDNF Phase II Trial 567 Current State of Therapy 567 568

References

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Infusion therapies like baclofen and GDNF have two prerequisites. The first is that more conservative therapies are insufficient. Specifically, the disease in question must be severe enough that the disability due to disease outweighs the risks involved with surgical implantation of a drug infusion system and prolonged treatment with that drug. Such diseases are often long-standing with little possibility of cure. The second prerequisite is that the drug cannot be given effectively through less invasive means. This point is critical as some oral analogs have poor bioavailability in the targeted CNS region because of inability to cross the blood–brain barrier or have significant side effects when taken systemically. Both baclofen for spasticity and GDNF for PD meet the two prerequisites. Both spasticity and PD are

Introduction The chronic delivery of medications to the central nervous system (CNS) has been made practical by the introduction of implantable drug pumps. Several different medications and targets for delivery have been investigated over the last twenty-five years. Medications for pain, spasticity, infectious agents, and degenerative diseases have been tested and, in some cases, been successful. This chapter will focus on two medications that modulate motor function: a wellestablished one for spasticity (intrathecal baclofen) and a promising yet unproven one for Parkinson’s disease (PD) (glial cell line-derived neurotrophic factor, also known as GDNF).

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debilitating conditions of chronic duration which are often inadequately controlled by oral medications. The respective drugs in question, baclofen and GDNF, lack adequate CNS penetration. However, this is where the similarity between the two therapies ends. Baclofen is currently the most widely used and accepted drug for the treatment of spasticity. In contrast, GDNF has been abandoned by some for PD therapy although others claim that it has been unfairly evaluated and warrants future investigation.

Baclofen for spasticity Baclofen is the mainstay of spasticity therapy. The oral form provides significant relief for less severe forms of the disease. Intrathecal baclofen is considered when dose escalation of oral baclofen is ineffective or when the side effects of oral baclofen become untenable. While there are risks associated with intrathecal therapy, the benefits on spasms, pain, and quality of life are significant for many severely affected patients.

Perspective on Spasticity Spasticity is defined as a motor disorder characterized by velocity-dependent increases in tonic stretch reflexes with exaggerated tendon jerks (Growdon and Fink, 1994). The simplicity of spasticity’s description, however, belies the seriousness of the disease. The excessive involuntary motor activity associated with spasticity can result from lesions of the motor system at cerebral, capsular, midbrain, pontine and spinal levels. It may manifest in several forms, including a Babinski response, exaggerated phasic stretch reflexes, hyper­ active cutaneous reflexes, increased autonomic reflexes, and abnormal postures (Young, 1989). In short, spasticity remains a multifaceted entity, and several treatment modalities for its treatment have been attempted. Spasticity remains a challenge to medical and surgical therapy. Conservative options like traditional rehabilitative therapies show limited efficacy. Oral pharmacotherapy includes agents that affect peripheral cholinergic activity at the neuromuscular junction (e.g. botulinum toxin), inhibit the release of calcium from the sarcoplasmic reticulum (e.g. dantrolene sodium), or act centrally (e.g. baclofen, diazepam, and clonidine) (Montane et al., 2004). Oral agents, however, may have significant side effect profiles. Surgical interventions are also non-optimal. Modern selective dorsal rhizotomy involves the surgical sectioning of dorsal nerve roots exhibiting abnormal EMG activation. Dorsal

rhizotomy may increase voluntary mobility and reduce rigidity, but it may also cause poor sphincter control, sensory loss, and symptom recurrence (Fasano et al., 1978, 1979, 1980). Other surgical lesioning options such as ventral rhizotomy, cordectomy, or midline mye­lotomy have even worse morbidity profiles (Penn, 1990). Perhaps the most promising and widespread surgical therapy for spasticity has been the delivery of intrathecal baclofen via implanted pump.

Baclofen Oral baclofen was approved by the Food and Drug Administration for spasticity in 1977 and is currently the most effective and widely used drug for treatment of spinal cord or cerebral spasticity. Baclofen, also known as 4-amino-3 ([-chlorophenyl) butyric acid (trade name Lioresal), is an analogue to gammaamino-butyric-acid (GABA) that specifically binds to the GABA-B receptor (Bowery et al., 1979). Orally delivered GABA, a hydrophilic agent, is an ineffective antispastic medication because it does not penetrate the blood–brain barrier and is rapidly degraded by neural tissue. Baclofen is slightly more lipid-soluble and crosses the blood–brain barrier if given in high concentrations. Baclofen is not broken down by neural tissue. Baclofen binds to presynaptic GABA-B receptors within the brain stem, dorsal horn of the spinal cord, and other central nervous system sites (Bowery, 2006; Bowery and Smart, 2006). However, its main clinical target appears to be at the spinal level. When administered to isolated spinal cord preparations, baclofen inhibits both monosynaptic and polysynaptic effects (Zieglgansberger, 1988). Presynaptically, baclofen decreases calcium influx during action potentials leading to reduced neurotransmitter release. Oral Baclofen Oral baclofen (usual dose: 60–100 mg/day) has been shown to be an effective agent in spasticity caused by multiple sclerosis, spinal cord injury, head trauma, and cerebral palsy (Montane et al., 2004). In openlabel studies baclofen improved spasticity in 70–87% of patients and reduced spasms in 75–96% of patients (Dario and Tomei, 2004). Double-blind, crossover placebo-controlled trials of oral baclofen demonstrate statistically significant improvements in spasticity. The supratentorial side effects of baclofen can be severe and include drowsiness and mental confusion (Hsieh and Penn, 2006). Other risks of baclofen incl­ ude seizures, psychic symptoms, and hyperthermia

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Baclofen for spasticity

although symptoms may be mitigated by the reintroduction of baclofen. Because of these central side effects, severe spasticity is rarely controlled by oral baclofen alone. Intrathecal Baclofen A solution to oral baclofen’s side effects has been direct delivery of baclofen into the spinal subarachnoid space with an implantable pump. Intrathecal delivery bypasses the blood–brain barrier and provides therapeutic concentrations of the drug directly to the site of action without systemic side effects. As baclofen is only slightly lipid-soluble, it remains within the cerebral spinal fluid with a relatively long half-life of 90 minutes (Kroin et al., 1993). Slow infusion maintains a high concentration of baclofen in the region of the spinal cord and reduces supratentorial effects. Proof of principle was demonstrated during initial trials in which a single 50 g bolus of baclofen introduced into the lumbar region reduced severe rigidity of spinal cord injury patients to normal tone for over 8 hours (Penn and Kroin, 1984). An implanted drug pump provides continuous infusion within the lumbar subarachnoid space and therefore makes it possible to sustain the antispastic effect. Dosing can be titrated to the desired tone simply by adjusting the rate of infusion (Penn et al., 1995). An early double blind cross-over study evaluated patients with severe spinal spasticity refractory to oral therapy in an “on” and “off” state and demonstrated significant reduction in both Ashworth and spasm-frequency scores (Penn et al., 1989). Although the dose of baclofen may increase in early therapy, baclofen’s effect stabilizes and remains indefinitely. In its current configuration, the infusion system consists of an intrathecal catheter, a pump with a reservoir, and an external programmer. The casing of the pump is titanium and is roughly the size of a hockey puck. The pump is powered by a lithium battery that cannot be recharged and therefore must be surgically exchanged every 5–7 years. Refill intervals are usually between 2 and 3 months in a 20 ml pump and double that in a 40 ml pump. The current commercial concentrations of baclofen are 500 and 2000 g/ml.

Details on Baclofen Therapy Patient Selection Patient selection requires that the benefits of intrathecal therapy outweigh the risks of pump implantation. As such, adequate patient screening includes a complete physical examination, neurological assessment,

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and thorough history of spasticity and prior treatment regimens. One set of reasonable criteria for inclusion is: 1. Severe chronic hypertonia in the lower extremities of at least 3 months’ duration including an Ashworth score of at least 3 in an affected extremity or a Penn Spasm frequency score of at least 2 during screening. The Ashworth Scale (1–5) scores muscle tone in the legs (including hip abduction, hip flexion, knee flexion, and ankle dorsiflexion) and arms (including shoulder abduction, elbow extension, elbow flexion, and wrist extension). The Penn Spasm Frequency Scale (0–4) scores the severity of spontaneous sustained flexor and extensor muscle spasms. 2. Failure to respond to maximum recommended doses of antispasm medications including baclofen and possibly diazepam, clonidine, tizanidine, or dantrolene sodium. One way of determining what the effects of chronic intrathecal baclofen will be is to perform a trial injection. After injection, the patient is observed for 4–8 hours. A positive response consists of a significant decrease in muscle tone, as well as the frequency or severity of spasms. Initial doses of 50 g may be increased to 75 or 100 g after a period of 24 hours if effect is insufficient. In our experience, trials are not necessary when the patient has clear spasticity due to a known disease since almost all patients with clinical spasticity respond to intrathecal baclofen. Latash et al. (1989) tested patients with chronic refractory spasticity treated with a single bolus of intrathecal baclofen. Both mono- and polysynaptic reflexes in the lower extremities were observed as were muscle responses during attempts at voluntary movements. EMG responses to joint movements, H-reflexes, ankle clonus, and defensive reactions in the lower extremities were significantly reduced in 30–45 minutes and almost completely suppressed by 2 hours. There was also improvement in selective voluntary activation of leg muscles in those with residual motor control. Pump Implantation and Programming Implantation of the pump is a relatively uncomplicated surgical procedure (Penn et al., 1989; Ethans, 2007). Pump insertion is performed under general or monitored anesthesia with the patient in the lateral decubitus position. The intrathecal catheter is best placed under fluoroscopic guidance via percutaneous technique with a Tuohy needle into an appropriate lumbar interspace. Needle entry should be off midline to avoid the spinous ligaments, and the needle trajectory should be oblique and upwards to ease catheter introduction. The catheter is then threaded to the high lumbar (L1) region.

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A more rostral catheter tip placement may be desired for upper extremity spasticity. The pump is then generally placed in the abdominal wall and connected to the tunneled catheter. Subfascial pump placement may be necessary in thin adults or children. Ease of pump-refilling, patient comfort, and postoperative recovery should be considered in pump placement. Optimal pump programming is unique to each patient and cannot be predicted before implantation. The most critical period is the initial 1–6 month stabilization period when dose adjustments are frequently made. Drug tolerance rarely occurs if adequately dosed, and, when it does occur, may be mitigated by a drug holiday. Some centers report success with intrathecal morphine during this holiday, while others have used intrathecal fentanyl although it has not been FDA approved for this indication (Erickson et al., 1989). Progressive disease, decubitus ulcers, or infections (urinary or systemic) that increase spasticity may also require dosing adjustments. Risks Several risks are involved with intrathecal baclofen therapy (Stempien and Tsai, 2000; Teddy et al., 1992). Common test-dose complications are nausea/vomiting (2.6%) and sedation (2.2%). Pump implantation complications include cerebrospinal fluid (CSF) leak (3.3%), constipation (2.9%), and headache (2.4%). Common long-term complications are catheter kink or migration (4%) and infection (1.2%). Seromas may require percutaneous drainage. CSF leak may be minimized by standard measures including reducing CSF pressure at the level of the defect (e.g. having the patient lie flat), placing a blood patch, or using an abdominal binder. Infection is relatively rare in baclofen pumps. In general, infection rates for implanted pumps range from 1 to 2% (Stempien and Tsai, 2000). Infection risk is highest following initial pump placement, with common skin flora (i.e. Staphylococcus aureus or Staphylococcus epidermidis) the most likely agents. Chronic percutaneous refills bear a lower risk. The host-derived albumin coating of the pump pocket may reduce the risk of colonization. Further, the pump itself has a bacteriostatic filter at the catheter port. There are also reports of contamination of implanted pump reservoirs by bacteria and fungus without clinical sequelae, suggesting the filter may be effective (Penn, 1992). Intrathecal use of baclofen does not completely eradicate the systemic risks. Frequent drug-related side effects are related to bolus overdose (Penn and Kroin, 1987; Delhaas and Brouwers, 1991; Teddy et al., 1992; Dressnandt et al., 1996; Bell, 2001; Leung et al., 2006). Symptoms of overdose include progressive drowsiness, dizziness, constipation, muscular hypotonia, respiratory

depression, hypotension, bradycardia, and ultimately coma. Overdose may be observed by a progression of hypotonia in the trunk and upper extremities followed by brain stem effects as the baclofen travels rostrally by bulk CSF flow. Continuous infusion is therefore safer than bolus infusion. Malfunction in prototype pumps has been noted in the literature resulting in milligram levels of baclofen release and coma, although newer pump models have not shown this defect. In cases of overdose, the pump should be immediately stopped and, if necessary, resuscitation initiated with mechanical ventilation, intravenous fluids, and vasopressors. The pump should be interrogated, the infusion stopped, and the medicine removed as necessary. High volume lumbar puncture is useful only if done immediately following the overdose and is ineffective once baclofen has traveled far enough rostrally to produce brain stem effects. While baclofen has no direct antagonist, drowsiness and respiratory depression may be reversed with intravenous physostigmine (Muller-Schwefe and Penn, 1989). Sudden withdrawal of baclofen can also cause serious harm (Coffey et al., 2002). Causes include catheter failure, pump malfunction, or low pump reserves. Symptoms of withdrawal include pruritis without a rash, diaphoresis, hyperthermia, hypotension, mental status changes, and aggravation of spasticity. Severe withdrawal may mimic autonomic dysreflexia, sepsis, malignant hyperthermia, or neuroleptic-malignant syndrome and can cause rhabdomyolysis and multiple organ failure. Diagnostic evaluation includes eliciting a history of recent painful stimuli, listening for pump alarms, pump interrogation, appropriate plain/ CT films, or indium-111 DTPA infusion studies to evaluate for catheter fracture and baclofen extravasation (Rosenson et al., 1990; O’Connell et al., 2004). Once a diagnosis is made, oral baclofen may be administered. However, in severe withdrawal, intrathecal baclofen administration through lumbar puncture may be necessary. Additional intravenous benzodiazepine therapy titrated to effect may also prove useful. Both overdose and withdrawal of baclofen can induce seizures, especially in cases of supraspinal spasticity. Rates of intrathecal baclofen related seizure activity range as high as 10.3% in cases of spasticity of supraspinal origin (Kofler et al., 1994). Seizures related to overdose may be caused by rostral baclofen bulk flow with bolus administration. Conversely, withdrawal seizures may occur as baclofen is eliminated from brain tissue (Kofler and Arturo, 1992). The seemingly paradoxical anticonvulsant and proconvulsant effects of baclofen may be related to location of GABA-B related inhibition (e.g. on excitatory or inhibitory neurons in traumatized neuronal tissue). In each

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Glial cell-line derived neurotrophic factor (GDNF) for Parkinson’s disease

case, a sudden change in drug level seems the most critical factor in seizure activity.

Current State of Therapy There is little doubt that intrathecal baclofen therapy plays a critical role in the treatment of spasticity. The primary benefit of intrathecal baclofen is the relief of severe spasms and spasticity when oral therapy has failed. When dosed to reduce spasticity, baclofen preserves voluntary movement leading to increased independence, mobility and self care (Boviatsis et al., 2005). Urinary function improves in cases where detrussor hyperreflexia and bladder contractions are curtailed. Muscle pain and fatigue are minimized as baclofen reduces spasms and acts as a substance P antagonist, suppressing central pain (Herman et al., 1992). Oral baclofen may be weaned slowly over several weeks to prevent withdrawal symptoms of delirium, hallucinations, or seizures. Intrathecal baclofen reduces nocturnal disturbance caused by spasticity and improves sleep. Spasticity is a major contributor to disrupted sleep in persons with lower extremity spasticity (Kravitz et al., 1992). Specifically, tibialis anterior EMG activity per hour during sleep was reduced in baclofen infusion leading to reduced disturbance. Post-awakening muscle contractions are reduced, thereby minimizing secondary insomnia during transient awakenings. Baclofen is effective in patients suffering from spinal spasticity (Ordia et al., 1996). Ordia and coworkers studied 59 patients suffering from severe spasticity of spinal cord origin (e.g. spinal cord injury, multiple sclerosis, familial spastic paraparesis, spinal cord tumor, cervical spondylotic myelopathy, transverse myelitis, and amyotrophic lateral sclerosis) refractory to oral baclofen. In this series, the mean Ashworth rigidity score significantly decreased from 4.3 to 1.4 and spasm frequency score decreased from 3.6 to 0.5. Baclofen works in patients suffering from cerebral spasticity. Meythaler and coworkers studied 17 stroke patients with chronic spasticity greater than 6 months that had reduced an average of 2 points on the Ashworth lower extremity scores during screening (Meythaler et al., 2001a). At 12 months following pump implantation, the average lower extremity Ashworth score declined from 3.7 to 1.8, the spasm score from 1.2 to 0.6, and reflex score from 2.4 to 1.0. The average upper extremity Ashworth score declined significantly from 3.2 to 1.8. In another study, Meythaler et al. evaluated 13 cerebral palsy patients with intractable spastic hypertonia and quadriparesis refractory to oral medications that had reduced an average of 2 points on lower

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extremity Ashworth scores (Meythaler et al., 2001b). At 1 year following pump implantation, the average lower extremity Ashworth score declined significantly from 3.4 to 1.5 and reflex score from 2.5 to 0.7. The average upper extremity Ashworth score declined significantly from 3.0 to 1.7, spasm score from 1.2 to 0.2, and reflex score from 2.3 to 0.5. Intrathecal baclofen appears to be cost-beneficial at an institutional level. Sampson et al. evaluated the cost–benefit ratio for continuous intrathecal baclofen infusion in the treatment of severe spasticity in the United Kingdom. Their literature review found that benefits are related to costs per quality adjusted life year (QALY) in the range of US$10 550–-$19 570 (Sampson et al., 2002). In a review of spasticity in children with cerebral palsy in the USA, de Lissovoy et al. (2007) evaluated intrathecal baclofen versus alternative therapy over a five year period. They found an incremental cost-effectiveness ratio of $42 000 per QALY, which is within the $50 000 to $100 000 range that is widely accepted as offering good value.

Glial cell-line derived neurotrophic factor (GDNF)  for Parkinson’s disease The story of glial cell-line derived neurotrophic factor (GDNF) in the treatment of PD is a stark contrast to that of baclofen. While baclofen encountered few roadblocks in its implementation, GDNF suffered several more challenges. To this day, it is unclear whether infused GDNF will ever be fully tested.

Perspective on Parkinson’s Disease Parkinson’s disease (PD) is a devastating movement disorder usually of middle or later life. Clinically, it is recognized by the stiffness and slowness of movement, fixed facial expression, postural instability, and rhythmic tremor which subsides on active willed movement or complete relaxation (Beal et al., 1994). The primary cause is loss of dopaminergic neurons of the substantia nigra leading to reduction in striatal dopamine content. The severity of symptoms is proportional to the deficiency. A long preclinical stage without symptoms is known to occur, and only when a majority of nigral dopamine is lost does the clinical syndrome manifest. While there are several medical approaches to PD therapy, the gold-standard remains L-DOPA, the immediate precursor to dopamine that can cross the blood– brain barrier. However, this treatment does not reverse

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morphologic changes or arrest disease progression. Over time, increasing dosages lead to significant side effects including dyskinesias and psychiatric side effects. Neurosurgical interventions for PD are wellestablished (Ansari et al., 2002; Lozano and Mahant, 2004; Schuurman and Bosch, 2007). Pallidotomy involves the creation of a small thermal lesion at the posteroventral globus pallidus internus (GPi) and has been found to improve contralateral tremor, stiffness, and dyskinesia. Deep brain stimulation involves implantation of electrodes within the subthalamic nuclei or GPi. While both demonstrate efficacy in the treatment of advanced PD, neither has been found to protect from further loss of dopaminergic neurons. Experimental therapies such as fetal cell transplants have unclear efficacy and may worsen dyskinesias and dystonias (Freed et al., 2001, 2003).

Glial Cell-Line Derived Neurotrophic  Factor (GDNF) Glial cell-line derived neurotrophic factor (GDNF) is a relatively new therapeutic consideration in PD therapy. GDNF was first identified in 1993 as a member of the GDNF family of ligands (GFLs) that also includes neurturin (NRTN), artemin (ARTN), and persephin (PSPN). GFLs play a role in a number of biological processes including cell survival, neurite outgrowth, cell differentiation and cell migration (Airaksinen and Saarma, 2002; Airaksinen et al., 2006). GFLs share approximately 40% amino acid sequence identity and are related to the transforming growth factor- (TGF-) superfamily of proteins (Ibanez, 1998). GFLs do not signal through transforming growth factor beta receptors and as such are not members of this superfamily. It is believed GFLs function as homodimers that are initially synthesized as inactive precursor molecule, preproGFL. The “pre” signal sequence is removed upon protein secretion. The “pro” sequence is then cleaved to produce active GFL, possibly at the surface of target cells (Arighi et al., 2005). The GFLs signal through a multicomponent receptor complex, consisting of a high affinity glycosylphosphatidylinositol-anchored binding component (GFR1-GFR4) and the receptor tyrosine kinase RET (Baloh, Enomoto et al., 2000, Baloh, Tansey et al., 2000). While cross-talk does occur, studies suggest that each GFL has a preferred GFR receptor, specifically GDNF to GFR1, NRTN to GFR2, and ARTN to GFR3. The GFL/GFR complex brings together two RET receptor tyrosine kinases to initiate autophosphorylation and begin intracellular signal transduction. Heparan

sulphate glycosaminoglycans may be necessary at the cell surface for RET-mediated GDNF signaling to occur (Barnett et al., 2002). The GFLs have several biologic functions. In addition to PD, GDNF may prove effective in the treatment of motor neuron disease, drug addiction, and alcoholism treatment (Henderson et al., 1994; Airavaara et al., 2004; He et al., 2005). The clinical implications of other GFLs are less well defined but potentially viable. For instance, both NRTN and PSPN increase survival of basal forebrain cholinergic neurons (Golden et al., 2003). PSPN has been implicated in stroke recovery while ARTN may have a role in chronic pain (Tomac et al., 2002; Gardell et al., 2003). Clinically targeting the GFR/RET receptor complex is difficult. GFLs have a very small volume of distribution in neural tissues. They are also positively charged polypeptides and therefore do not readily cross the blood–-brain barrier. It is therefore necessary to directly deliver them into the central nervous system to use them in therapy.

Details on GDNF Therapy Preliminary Studies Since its discovery, GDNF has been known to nourish and foster the growth of dopamine-generating neurons. Gash and coworkers first evaluated the effects of GDNF injected intracerebrally in Rhesus monkeys made parkinsonian by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Gash et al., 1996). The recipients of GDNF displayed significant improvements in bradykinesia, rigidity and postural instability. Administration of GDNF every four weeks maintained functional recovery. On the lesioned side of GDNF-treated animals, dopamine levels in the midbrain and globus pallidus were twice as high, and nigral dopamine neurons were 20% larger and had increased fiber density as compared to controls. In 1997, Choi-Lundberg et al. demonstrated that GDNF delivered to the rat brain via an adenoviral vector protected nigral dopaminergic neurons from death due to neurotoxin 6-OHDA (Choi-Lundberg et al., 1997). Kordower and coworkers then performed the first study of GDNF gene therapy in a Rhesus model (Kordower et al., 2000). Once again, GDNF reversed MPTP-induced functional deficits and prevented nigrostriatal degeneration. These findings initiated further research into GDNF delivery in human clinical trials. Amgen initiated a large multicenter human randomized double-blind cohort trial to examine the efficacy of chronic intraventricular GDNF in PD (Nutt et al.,

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Glial cell-line derived neurotrophic factor (GDNF) for Parkinson’s disease

2003). The trial involved 50 subjects evaluated over a period of 8 months. The results were not promising. GDNF did not improve parkinsonism symptoms as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS). Moreover, patients experienced a spectrum of adverse events such as nausea, weight loss, paresthesiae, and hyponatremia. Researchers hypothesized that the drug was not adequately delivered to the putamen and substantia nigra due to poor diffusion from the ventricle through brain tissue. To overcome the diffusion dilemma, Gill et al. implanted GDNF infusion catheters directly into the putamen of five PD patients in a phase I safety trial (Gill et al., 2003). After one year, they found no serious side effects and noted significant clinical improvement including a 39% improvement in the off-medication motor sub-score of the UPDRS, a 61% improvement in the UPDRS activities of daily living sub-score, and a 64% reduction of medication-induced dyskinesias. Further, 18F-fluorodopa uptake positron emission tomography (PET) showed a 28% increase in putamen dopamine storage after 18 months. Slevin et al. also published results of a 6-month trial of unilateral intraputaminal GDNF infusion in ten patients with advanced PD using an “on” and “off” state paradigm (Slevin et al., 2005). At 6 months, patients had significantly improved total UPDRS scores in the “off” and “on” states by 33 and 34%, respectively. Improvements were bilateral and persisted even when GDNF was washed out. Side effects were limited to transient Lhermitte’s responses in two patients. Despite striking results, many felt that the outcome of these open-label study may have been due to placebo effect. Amgen’s GDNF Phase II Trial To test the validity of these results, Amgen proceeded in 2003 with a multicenter randomized double-blind trial of direct intraputaminal infusion of recombinant human GDNF in 34 advanced PD patients (Lang et al., 2006). Patients were randomized 1 to 1 to receive bilateral continuous infusion of GDNF or placebo. The primary endpoint was the change in UPDRS motor score in the “off” state at 6 months; secondary endpoints included other UPDRS sub-scores, motor tests, dyskinesia ratings, patient diaries, and 18 F-fluorodopa uptake PET. Ultimately, the results were disappointing. No differences were found in the primary endpoints. The only significant secondary endpoint was a strong local increase in 18F-fluorodopa uptake. Adverse events were also concerning. Device-related events required surgical repositioning of two catheters and device-removal

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in another. Further, neutralizing anti-GDNF antibodies were found in three patients, although no clinical effects associated with these antibodies were found. While the results of this trial were not formally published until March 2006, Amgen announced in July 2004 that the trial failed to demonstrate any clinical improvement. By September 2004, Amgen had halted all clinical trials of GDNF, citing participant safety issues. Specifically, the company cited loss of cerebellar neurons in non-human primates that had been treated with high dose intraputaminal GDNF for six months, as well as the neutralizing antibodies in study participants as reasons to discontinue GDNF trials in humans.

Current State of Therapy In retrospect, the wrong dose of GDNF may have been infused in the Amgen study. Other trials have delivered higher doses delivered in a different fashion. Differences in GDNF distribution and concentration could have accounted for the differing outcomes of the open and blinded trials. Indeed, results from the open trials continue to be positive. When GDNF was no longer available in the Slevin et al. group, the 10 enrolled patients continued to be monitored for an additional year with the delivery system reprogrammed to deliver saline alone (Slevin et al., 2007). In follow-up, the UDPRS scores after 1 year of therapy improved by 42% and 38% in the “off” and “on” states respectively. However, benefits from treatment were lost by 9–12 months after GDNF infusion was halted. These patients returned to their baseline UPDRS scores and required higher levels of conventional PD drugs to treat symptoms. Antibodies to GDNF developed in seven patients with no evidence of clinical sequelae. There was also no evidence of GDNF-induced cerebellar toxicity. Follow-up was also performed on the five patients in the Bristol open-label trial where GDNF was infused continuously into the posterior putamen (Patel et al., 2005). These patients were found to be doing well. After 2 years of continual GDNF infusion, there were no serious clinical side effects and no significant detrimental effects on cognition. Patients showed a 57% and 63% improvement in their off-medication motor and activities of daily living subscores of the UDPRS respectively. Similarly, health-related quality of life measures also improved. Researchers in Bristol also demonstrated for the first time that the infusion of GDNF directly into the brain of a patient with PD could induce the regrowth of dopamine nerve fibers (Love et al., 2005). This information was discovered through an autopsy

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of a 62-year-old man treated for 43 months with continuous direct-brain infusions of GDNF who had died of a heart attack 3 months after Amgen halted clinical trials in September 2004. Autopsy revealed a five-fold concentration of tyrosine hydroxylase, the rate-limiting enzyme in the dopamine biosynthetic pathway, in the right posterior putamen compared to the corresponding, nontreated left posterior putamen. Expression of growth-associated protein 43 on the right posterior putamen further suggested nerve fiber sprouting in the substantia nigra. Indeed, at 24 months, his UDPRS scores had improved 38% in the “off” state bilaterally. There was also an 18% increase in uptake of 18F-fluorodopa in the entire putamen on the infused side compared to a 7.4% decrease in the non-infused side. This evidence suggests that GDNF has an effect on the dopamine system, but does not conclusively demonstrate that GDNF promotes neuronal growth in humans. Although GDNF has been shelved for several years, work on GDNF and its analogs continues. Ceregene, Inc. is currently conducting trials to evaluate CERE-120, an adeno-associated virus vector carrying the gene for another GFL member, neurturin. In one study, Rhesus monkeys received unilateral injections of CERE-120 into the caudate and putamen, with each animal therefore serving as its own control. PET revealed significant increases in 18F-fluorodopa uptake in the injected striatum compared with the uninjected side at 4 and 8 months. Treated versus untreated sides also showed more tyrosine hydroxylase immunoreactive fibers and tyrosine hydroxylase immunoreactive cells in the striatum and activation of phosphorylated extracellular signal-regulated kinase immunoreactivity in the substantia nigra (Herzog et al., 2007). In a phase I human trial, patients demonstrated a mean 36% improvement in their UPDRS motor “off” scores 12 months after administration by UPDRS (www.ceregene.com). A phase II trial is currently ongoing.

Conclusion The use of intrathecal baclofen for spasticity and intraparenchymal GDNF for Parkinson’s disease highlights the dichotomy that exists within drug development and usage. In several ways, baclofen and GDNF are similar. Both are therapies for chronic debilitating conditions that are often inadequately controlled by oral medications. Both are amenable to infusion delivery. However, this is where the similarity between the two modalities ends. Baclofen is currently the gold standard for spasticity therapy while GDNF remains

an unfulfilled possibility in the pipeline of promising therapies for Parkinson’s disease.

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Penn, R.D., Savoy, S.M., Corcos, D., Latash, M., Gottlieb, G., Parke, B. and Kroin, J.S. (1989) Intrathecal baclofen for severe spinal spasticity. N. Engl. J. Med. 320: 1517–21. Penn, R.D., York, M.M. and Paice, J.A. (1995) Catheter systems for intrathecal drug delivery. J. Neurosurg. 83: 215–17. Rosenson, A.S., Ali, A., Fordham, E.W. and Penn, R.D. (1990) Indium-111 DTPA flow study to evaluate surgically implanted drug pump delivery system. Clin. Nucl. Med. 15: 154–6. Sampson, F.C., Hayward, A., Evans, G., Morton, R. and Collett, B. (2002) Functional benefits and cost/benefit analysis of continuous intrathecal baclofen infusion for the management of severe spasticity. J. Neurosurg. 96: 1052–7. Schuurman, P.R. and Bosch, D.A. (2007) Surgical considerations in movement disorders: deep brain stimulation, ablation and transplantation. Acta Neurochir. Suppl. 97: 119–25. Slevin, J.T., Gash, D.M., Smith, C.D., Gerhardt, G.A., Kryscio, R., Chebrolu, H. et al. (2007) Unilateral intraputamenal glial cell line-derived neurotrophic factor in patients with Parkinson disease: response to 1 year of treatment and 1 year of withdrawal. J. Neurosurg. 106: 614–20.

Slevin, J.T., Gerhardt, G.A., Smith, C.D., Gash, D.M., Kryscio, R. and Young, B. (2005) Improvement of bilateral motor functions in patients with Parkinson disease through the unilateral intraputaminal infusion of glial cell line-derived neurotrophic factor. J. Neurosurg. 102: 216–22. Stempien, L. and Tsai, T. (2000) Intrathecal baclofen pump use for spasticity: a clinical survey. Am. J. Phys. Med. Rehabil. 79: 536–41. Teddy, P., Jamous, A., Gardner, B., Wang, D. and Silver, J. (1992) Complications of intrathecal baclofen delivery. Br. J. Neurosurg. 6: 115–18. Tomac, A.C., Agulnick, A.D., Haughey, N., Chang, C.F., Zhang, Y., Backman, C. et al. (2002) Effects of cerebral ischemia in mice deficient in Persephin. Proc. Natl Acad. Sci. U S A 99: 9521–6. Young, R.R. (1989) Treatment of spastic paresis. N. Engl. J. Med. 320: 1553–5. Zieglgansberger, W. (1988) Dorsal horn neuropharmacology: baclofen and morphine. Ann. N Y Acad. Sci. 531: 150–6.

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C H A P T E R

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Deep Brain Stimulation for Torsion Dystonia Ron L. Alterman and Michele Tagliati

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Diagnosis and Classification of Dystonia

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Medical Therapy for Dystonia

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Surgical Therapy for Dystonia

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Deep Brain Stimulation: Surgical Technique Anatomical Targeting Microelectrode Recording Macroelectrode Stimulation

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Implantation of the Pulse Generator Programming the Device

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Clinical Results Pallidal DBS for Secondary Dystonia Complications of DBS Therapy

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Conclusions

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References

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dystonia. The observation that both pallidal ablation and stimulation improve off-medication dystonia in PD patients (Lozano et al., 1995) shifted attention from the thalamus to the globus pallidus pars internus (GPi) as the target of choice for dystonia. The result has been one of the most successful applications of neuromodulation technology yet described.

Torsion dystonia is a movement disorder characterized by involuntary repetitive movements which result in twisting, often painful postures (Fahn, 1994). Dystonia is not one disease; rather, it is a neurological manifestation of numerous conditions, many of which are poorly characterized. A variety of procedures, targeting both the peripheral and central nervous systems, have been developed to treat dystonia. Scattered case reports and small surgical cohort studies relate mixed or conflicting outcomes. Long-term results are scarce. The successful application of deep brain stimulation (DBS) for the treatment of medically refractory Parkinson’s disease (PD) and essential tremor (ET) prompted investigations of its utility for treating

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Diagnosis and classification  of dystonia Dystonia may be classified in three ways: by the anatomical distribution of the abnormal movements; by the age at symptom onset (early vs. late); and by the absence or presence of a specific underlying etiology

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(primary vs. secondary) (Fahn, 1994). Focal dystonias (e.g. writer’s cramp, spasmodic torticollis) are limited to a single body region; segmental dystonia affects contiguous body parts; and widespread involvement of the axial and limb musculature characterizes generalized dystonia. Patients with early symptom onset (age 26) are more likely to have a heritable form of dystonia and are more likely to suffer generalized symptoms (Bressman et al., 2000). A dystonia is classified as primary or idiopathic when no structural brain abnormality or specific toxic, metabolic, or infectious etiology is identified. The heritable forms of dystonia are traditionally included in this group. At least 13 different mutations are now associated with dystonia, each mutation occurring at a unique gene locus (Bressman, 2003). The most common form of genetic dystonia results from a GAG deletion of the gene encoding the protein torsin A (Bressman, 2003). This mutation, referred to as DYT1, is associated with a form of childhood onset dystonia formerly known as dystonia musculorum deformans. DYT1-associated dystonia is inherited in an autosomal dominant pattern but with a penetrance of just 30–40%, suggesting that additional genetic and/or environmental factors contribute to the dystonia phenotype (Brossman, 2003). When a structural brain abnormality or specific underlying etiology is identified, a dystonia is classified as secondary or symptomatic (Fahn, 1994). Symptomatic dystonias are more prevalent than primary dystonias and may arise from a variety of causes. Consequently, this is a heterogeneous patient population with varied pathophysiologies and responses to treatment.

Medical therapy for dystonia In most cases, medical therapy for dystonia is limited to symptom control and is marginally effective (Geyer et al., 2006). Anticholinergic medications (e.g. trihexyphenidyl) are the mainstay of medical therapy but often yield only modest improvements and, at the high doses employed for dystonia, may cause significant side effects. Additional medications for dystonia include baclofen, benzodiazepines, and tetrabenazine. A minority of patients with symptomatic generalized dystonia will benefit from specific therapy targeted at the underlying disorder. Children and adolescents with clinically “pure” dystonia of unknown etiology should be evaluated for Wilson’s disease and should also undergo a trial of levodopa therapy, as a small sub-population with DOPA-responsive dystonia will

experience a profound and sustained response to this medication (Geyer et al., 2006). Targeted injections of botulinum toxin (BOTOX) can alleviate focal dystonias, but this intervention is impractical in patients with generalized symptoms (Fahn, 1994; Geyer et al., 2006). Some patients will not respond to BOTOX initially and up to 10% may develop resistance through the production of blocking antibodies (Greene et al., 1994).

Surgical therapy for dystonia Surgical intervention for dystonia should be considered when symptoms are disabling and the response to medical therapy is either inadequate or limited by side effects. Historically, surgical interventions for dystonia have targeted both the peripheral and central nervous systems. Peripheral denervation procedures for focal dystonias have largely been supplanted by chemical denervation with BOTOX (Geyer et al., 2006). Chronic intrathecal baclofen infusions can alleviate dystonia of the lower extremities, but this intervention may not be appropriate for dystonias affecting the arms and neck, and positive responses may not result in significant functional gains (Ford et al., 1996). Advances in stereotactic technique and the observation that pallidotomy improves off-medication dystonia in PD patients (Lozano et al., 1995) renewed interest in basal ganglia interventions for torsion dystonia. Pallidotomy improves symptoms of primary generalized dystonia (PGD) (Ondo et al., 1998); however, unilateral pallidotomy may not sufficiently treat generalized symptoms (Ondo et al., 1998) and bilateral pallidotomy entails significant risk, including cognitive dysfunction, dysarthria, dysphagia, and limb weakness (Hua et al., 2003). Consequently, deep brain stimulation, which is reversible and may be employed bilaterally with relative safety, has emerged as a preferable alternative to neuroablation.

Deep brain stimulation:  surgical technique Medtronic, Inc. (Minneapolis, MN) manufactures the only FDA-approved DBS system. The device has three primary components that are implanted in two stages (Figure 45.1). During the first stage, the stimulating lead(s) is implanted into the GPi stereotactically. The extension cable(s) and pulse generator(s) are implanted during the second procedure, which may be performed on the same day or shortly thereafter.

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Deep brain stimulation: surgical technique

Neurostimulator

Extension Lead

Figure 45.1  The deep brain stimulation system (Activa, Medtronic, Inc., Minneapolis, MN) has three primary components: (1) the stimulating lead, which is implanted stereotactically into the desired target; (2) the programmable neurostimulator, which generates the electrical impulses; (3) the extension cable, which is tunneled subcutaneously and connects the stimulator to the lead

It is acceptable to implant DBS leads bilaterally during the same procedure. Dystonia patients are relatively young and, in our experience, tolerate the bilateral frontal lobe penetrations without difficulty. The first stage of the DBS procedure is ideally performed with the patient fully awake, but this may not be possible for children or adults with severely contorted postures. Anticholinergic medications, benzodiazepines and baclofen are withheld on the morning of surgery as these medications may interfere with intraoperative microelectrode recording (MER). If painful muscular spasms or abnormal postures make awake surgery arduous, conscious sedation with propofol or dexmedetomidine can be employed. Antibiotics are administered intravenously during application of the headframe, so that serum levels are therapeutic during the implantation procedure.

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tomography provides the most geometrically accurate images for fiducial registration. The images are transferred to an independent workstation for surgical planning. We target the GPi site first, described by Leksell, which lies 19–22 mm lateral, 2–3 mm anterior, and 4 mm inferior to the midcommissural point (MCP) (Laitinen et al., 1992). The target point is visualized on both axial and coronal images and should lay 2–3 mm superior and lateral to the optic tract (Figure 45.2B). Our preferred trajectory is 60–65° above the intercommissural plane and 0–10° lateral to the vertical axis. This trajectory allows one to avoid the lateral ventricle and still employ parasagittal trajectories, simplifying the process of mapping the intraoperative microelectrode recording data (see below). Microelectrode Recording We employ single cell microelectrode recording (MER) to refine our anatomical targeting. The finer details of our MER technique are beyond the scope of this chapter but are provided elsewhere (Shils et al., 2002). The MER data are mapped onto scaled sagittal sections of the Schaltenbrand and Wahren stereotactic atlas in order to determine the anatomic location of the recording trajectory (Shils et al., 2002). Acceptable trajectories for implantation include a 3–4 mm span of globus pallidus pars externa (GPe) and at least 7.5 mm of GPi. Such a trajectory passes through the heart of the GPi and allows three or four contacts to be positioned comfortably within the nucleus, depending on the lead employed (Figure 45.3). The detection of kinesthetic cells confirms that the trajectory traverses the sensorimotor sub-region of the GPi. Identification of the optic tract 2–3 mm inferior to the GPi provides an additional level of confidence that the lead will be well positioned; but this should not be viewed as an absolute requirement for implantation.

Anatomical Targeting

Macroelectrode Stimulation

The stereotactic headframe is applied on the morning of surgery, after which the patient is transported to radiology. We employ axial and coronal fast spin echo/inversion recovery (FSE/IR) MRI for anatomic targeting (Figure 45.2). These high resolution images are sufficient for performing DBS implants with microelectrode guidance; however, additional image sets may also be employed. Gadolinium-enhanced, three-dimensional T1-weighted sequences (e.g. SPGR) maintain high image resolution during reformatting and are useful both for fiducial registration and for selecting safe, trans-gyral entry points. Computerized

The lead is inserted along the desired trajectory leaving the deepest contact (contact 0) at the physiologically defined inferior border of the GPi (Figure 45.3). C-arm fluoroscopy is employed to confirm that the lead has traveled to the desired point. Before it is secured, the acute effects of stimulation via the lead are tested. Testing is performed in bipolar mode employing the following parameters: pulse width 60 s; frequency 130 Hz, amplitude 0–4 V. The initial test is performed with the deepest pair of contacts (i.e. 0, 1), as these are most likely to generate adverse effects. If no adverse effects are observed, testing

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AC GPi

GPi PC

OT (A)

(B)

Figure 45.2  Fast spin echo inversion recovery MRI. We employ both axial (A) and coronal (B) FSE/IR images for targeting the GPi. The anterior and posterior commissures (AC and PC, respectively) are readily visible on the axial image, as is the posteroventral GPi. The target is the posteroventral GPi, 20–21 mm lateral to the midline (B, black arrow) and 2–3 mm superior and lateral to the optic tract (B, white arrow)

D GPe

GPi A

P

Optic Tract

V

Figure 45.3  Pallidal lead implantation. Our preferred lead position within the GPi is depicted. A schematic of the model 3387 lead (Medtronic Inc.), which has four 1.5 mm long cylindrical contacts with 1.5 mm inter-electrode spacing, is superimposed on a sagittal image, 20 mm lateral of midline, derived from the Schaltenbrand and Wahren atlas. With the deepest contact (contact 0) positioned at the inferior border of the GPi, three contacts can fit within the nucleus

continues in a ventral to dorsal sequence (i.e. 1, 2, etc.). Unlike Parkinson’s disease, dystonia requires days to weeks of stimulation therapy before improvements are apparent. Therefore, a lack of improvement

during intraoperative stimulation should not be viewed as an indicator of poor lead placement. In our experience, if the microelectrode recordings meet our implantation criteria and there are no AE with up to 4 V of stimulation, the lead is well positioned. Sustained, time- and voltage-locked contractions of the contralateral hemi-body and/or face indicate that stimulation is activating the corticospinal tract, in which case the lead is placed too medially and/or posteriorly. The induction of phosphenes in the contralateral visual field suggests that stimulation is activating the optic tract and that the lead is too deep. Stimulation within the sensorimotor GPi may induce transient paresthesiae; however, sustained paresthesiae at low stimulation amplitudes indicate that the lead is positioned very posterior, and is activating thalamocortical projections in the posterior limb of the internal capsule. If any of these adverse effects occur, the lead should be re-positioned accordingly. The lead is secured at the skull employing a “cap” that also covers the burr-hole. Fluoroscopy is used to confirm that the lead is not displaced from its desired position during fixation. The free end of the lead is encircled around the cap and left in the sub-galeal space. The incision is irrigated with antibiotic saline and closed anatomically. Postoperative MRI is performed to document lead position and confirm that there has been no hemorrhage (Figure 45.4).

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Clinical results

Figure 45.4  Postoperative MRI. A MRI is performed on all patients immediately after lead implantation in order to document lead position and to rule out intracerebral hemorrhage. A coronal FSE/IR MRI is depicted demonstrating proper lead position within the GPi

Implantation of the Pulse Generator The remaining components of the DBS system(s) are implanted under general anesthesia, usually within two weeks of the lead implant. This relatively simple procedure involves the following steps: 1. creating a subclavicular, subcutaneous pocket for the implantable pulse generator (IPG) 2. identifying the free end of the DBS lead in the subgaleal space 3. tunneling the extension cable subcutaneously from the IPG pocket to the free end of the DBS lead, and 4. establishing dry, clean, and secure connections between the components. The connection between the lead and the extension cable is placed under the galea, just lateral to the cranial incision, limiting exposure of the lead to potential fracture through movement.

Programming the Device The device(s) is activated two to four weeks after implantation, allowing the surgical incisions to heal. There is no consensus regarding the optimal settings for treating dystonia as few systematic evaluations of varying stimulus parameters have been conducted. Instead, therapy is currently guided by published case series, which report positive responses with wide pulses (210–400 s) and high frequencies (130 Hz or higher) (Coubes et al., 1999). Though effective, these parameters rapidly deplete the PGs, necessitating their

frequent replacement (12–24 months). In our exper­ ience, stimulation at lower frequencies (60–80 Hz) may be just as effective as high frequency stimulation (Alterman, Shils et al., 2007; Alterman, Miravite et al., 2007). Because these settings deliver less electrical energy to the brain, they may enhance the tolerability of stimulation and prolong battery life. At the initial programming session, the effects of unipolar stimulation with each of the contacts are assessed. In particular, the stimulation thresholds for inducing adverse effects are noted. We employ for therapy the ventral-most contact that does not induce adverse effects with stimulation of up to 3.5 V. We prefer to treat with unipolar stimulation but use bipolar settings if unipolar stimulation is not tolerated. Patients are initially treated at 2.0–2.5 V. The stimulation amplitude may be increased over time; however, every effort should be made not to exceed 3.6 V, as the IPG must invoke a “doubling circuit” to deliver this amplitude, shortening battery life out of proportion to the energy delivered. If more energy is required, it is better to increase frequency or pulse width from the standpoint of battery preservation. Patients return every two to four weeks for evaluation during the first three months, and every three to six months after that. During each visit the patient is assessed employing a variety of standardized clinical rating scales (Volkmann and Benecke, 2002).

Clinical results The safety and efficacy of pallidal DBS for primary dystonia is supported by both retrospective and prospective studies. Yianni et al. (2003) reported on 25 patients with various forms of dystonia, finding that all patient sub-groups were improved. Coubes et al. (2004) reported a mean 79% improvement in the Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS) motor sub-score and a 65% mean improvement in the disability sub-score two years after surgery in 31 patients with Primary Generalized Dystonia (PGD) (Coubes et al., 2004). Patients improved steadily over the first year of therapy. Children fared marginally better than adults. Vidailhet et al. (2005) prospectively examined 22 PGD patients treated with bilateral pallidal DBS. Double-blind evaluations conducted three months after surgery showed significantly better motor function with neurostimulation than without. One year after surgery the mean BFMDRS motor score was improved 51% with one-third of the patients exper­ iencing a greater than 75% improvement. Phasic

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symptoms improved more rapidly than fixed postures. Improvement in these patients has been maintained for three years (Vidailhet et al., 2007). Kupsch et al. (2006) have published the only double-blind, sham stimulation-controlled study of pallidal DBS for dystonia. Forty patients with primary segmental or generalized dystonia underwent pallidal DBS surgery. Twenty were randomized to therapeutic stimulation and 20 to sham stimulation for a period of three months, at which time their clinical status was assessed by blinded raters employing the BFMDRS. The BFMDRS motor sub-scores in the patients who received therapeutic stimulation improved 40% at three months as compared to 5% in the control group who then received therapeutic stimulation, with a resulting equivalent improvement (37%) over the subsequent three months. Preliminary data suggest that cervical dystonia (CD) is also responsive to bilateral pallidal DBS with improvements in the Toronto Western Spasmodic Torticollis Rating Scale ranging from 40 to 70%; however, the published case series are quite small (max. 10 patients) and only open-label data are presently available (Bittar et al., 2005; Hung et al., 2007).

Pallidal DBS for Secondary Dystonia The impact of pallidal DBS on secondary dystonia appears to be less impressive and more variable than in primary dystonia (Bronte-Stewart, 2003; Kupsch et al., 2003; Yianni et al., 2003). These patients represent a heterogeneous population with regard to etiology, clinical signs, and long-term prognosis. In addition, many of them may have neurological issues besides dystonia, including seizures, spasticity, cerebrovascular disease, and dementia, that can limit their functional response to surgery. Most studies report little or no benefit (Ghika et al., 2002; Kupsch et al. 2003) and even worsening of symptoms after DBS in secondary dystonia (Vercueil et al., 2001). Our own exper­ience treating five patients with secondary dystonia of various causes confirms that responses in this group are more modest than the results obtained in primary dystonia; however, we have operated on a 12-year-old boy with severe generalized dystonia secondary to perinatal anoxic brain injury who responded quickly (within two weeks) and dramatically to bilateral GPi DBS. Despite his prolonged anoxia and the severity of his dystonia, his brain anatomy was well preserved. This patient is similar to patient 9 in the report by Zorzi et al. (2005), whose BFMDRS score improved 65% following pallidal DBS surgery. The responses of these two patients as well as reports of positive

responses to DBS in patients with tardive dystonia (Starr et al., 2004; Franzini et al., 2005; Trottenberg et al., 2005) suggest that there are some individuals with secondary dystonia who will respond favorably to DBS. Dramatic improvement in patients with pantothenate kinase-associated neurodegeneration (PKAN) have also been reported (Krauss et al., 2003; Castelnau et al., 2005) but the response may be temporally limited. The preoperative indicators of a positive response in secondary dystonia are currently unknown, but a normal brain MRI may be a predictor of favorable outcome (Vercueil et al., 2002).

Complications of DBS Therapy Overall, both DBS surgery and chronic electrical stimulation of the internal pallidum are well tolerated. In our series of 60 dystonia patients (55 primary, 5 secondary) there have been no intracerebral hemorrhages or adverse neurological events. Four patients (6.7%) developed perioperative infections that necessitated removal of five devices. Each patient was successfully treated with antibiotics and underwent re-implantation surgery without any additional adverse events. Two patients (3.3%) developed fractures of an extension cable, a complication that is reported to occur more frequently in dystonia than in PD or ET (Yianni et al., 2004) and is easily repaired.

Conclusions Deep brain stimulation at the internal pallidum has emerged as the treatment of choice for medically refractory primary torsion dystonia. Multiple openlabel studies demonstrate that pallidal DBS is highly effective in patients with PGD and is well tolerated. Children and patients who are DYT1-positive may fare best of all. The response to stimulation is more gradual than that observed in Parkinson’s disease or essential tremor and the full benefit of surgery may not be realized for a year or more. When prolonged dystonia has resulted in fixed contractures, additional orthopedic surgery may be required to maximize functional gains. The response to DBS allows for significant reductions in medications, often resulting in improved school performance. Patients with secondary dystonia respond more modestly and inconsistently than do primary dystonia patients, reflecting the physiologic and anatomic heterogeneity of this population. Among these, patients with tardive dystonia, PKAN and dystonia secondary to anoxic brain injury, but with preserved basal

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Conclusions

ganglia anatomy, may respond well to DBS therapy. Conversely, patients with obvious structural abnormalities and those with metabolic disorders appear to be poor DBS candidates. Standard stimulation parameters for treating dystonia currently include frequencies of 130 Hz or more and pulse widths of 210–400 s, settings that may rapidly deplete the implanted pulse generators. Stimulation at lower frequencies may prove to be as efficacious as high frequency stimulation, may make stimulation more tolerable in some cases, and should prolong battery life. Therefore, a more complete evaluation of low frequency stimulation for primary dystonia should be undertaken. Additional research efforts should be directed toward developing a greater understanding of dystonia pathophysiology and the neurophysiological changes induced by chronic electrical stimulation. This will lead to more rational stimulation paradigms and better clinical results. Preoperative indicators of a positive response to DBS must be sought in order to improve patient selection. In particular, functional imaging studies of dystonia patients, pre- and postDBS surgery, are currently lacking and should be pursued. Finally, continued explorations of other targets for therapy are appropriate, particularly for the many patients with secondary dystonia who may not be candidates for pallidal DBS.

Acknowledgments The authors wish to thank Donald Weisz, PhD for his assistance with the production of Figure 45.3.

References Alterman, R., Miravite, J., Shils, J. et al. (2007) 60 Hertz pallidal deep brain stimulation for primary torsion dystonia. Neurology 69: 681–8. Alterman, R., Shils, J., Miravite, J. et al. (2007) A lower stimulation frequency can enhance tolerability and efficacy of pallidal deep brain stimulation for dystonia. Mov. Disord. 22: 366–8. Bittar, R.G., Yianni, J., Wang, S.Y. et al. (2005) Deep brain stimulation for generalized dystonia and spasmodic torticollis. J. Clin. Neurosci. 12 (1): 12–16. Bressman, S.B. (2003) Dystonia: phenotypes and genotypes. Rev. Neurol. (Paris) 159: 849–56. Bressman, S.B., Sabatti, C., Raymond, D. et al. (2000) The DYT1 phenotype and guidelines for diagnostic testing. Neurology 54: 1746–52. Bronte-Stewart, H. (2003) Surgical therapy for dystonia. Curr. Neurol. Neurosci. Rep. 3 (4): 296–305. Castelnau, P., Cif, L., Valente, E.M. et al. (2005) Pallidal stimulation improves pantothenate kinase-associated neurodegeneration. Ann. Neurol. 57 (5): 738–41.

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Coubes, P., Cif, L., El Fertit, H. et al. (2004) Electrical stimulation of the globus pallidus internus in patients with primary generalized dystonia: long-term results. J. Neurosurg. 101: 189–94. Coubes, P., Echenne, B., Roubertie, A. et al. (1999) Treatment of early-onset generalized dystonia by chronic bilateral stimulation of the internal globus pallidus. Apropos of a case. Neurochirurgie 45: 139–44. Fahn, S. (1994) Idiopathic torsion dystonia. In: D.B. Calne (ed.), Neurodegenerative Diseases. Philadelphia: W.B. Saunders, pp. 705–15. Ford, B., Greene, P., Louis, E.D. et al. (1996) Use of intrathecal baclofen in the treatment of patients with dystonia. Arch. Neurol. 53: 1241–6. Franzini, A., Marras, C., Ferroli, P. et al. (2005) Long-term highfrequency bilateral pallidal stimulation for neuroleptic-induced tardive dystonia. Report of two cases. J. Neurosurg. 102: 721–5. Geyer, H.L., Tagliati, M., Blatt, K. and Bressman, S.B. (2006) Generalized torsion dystonia. In: J. Noseworthy (ed.), Neurological Therapeutics: Principles and Practice, 2nd edn. London: Taylor and Martin, pp. 2853–63. Ghika, J., Villemure, J.G., Miklossy, J. et al. (2002) Postanoxic generalized dystonia improved by bilateral Voa thalamic deep brain stimulation. Neurology 58: 311–13. Greene, P., Fahn, S. and Diamond, B. (1994) Development of resistance to botulinum toxin type A in patients with torticollis. Mov. Disord. 9: 213–17. Hua, Z., Guodong, G., Qinchuan, L. et al. (2003) Analysis of complications of radiofrequency pallidotomy. Neurosurgery 52: 89–99. Hung, S.W., Hamani, C., Lozano, A.M. et al. (2007) Long-term outcome of bilateral pallidal deep brain stimulation for primary cervical dystonia. Neurology 68: 457–9. Krauss, J.K., Loher, T.J., Weigel, R. et al. (2003) Chronic stimulation of the globus pallidus internus for treatment of non-dYT1 generalized dystonia and choreoathetosis: 2-year follow up. J. Neurosurg. 98: 785–92. Kupsch, A., Benecke, R., Muller, J. et al. (2006) Pallidal deep-brain stimulation in primary generalized or segmental dystonia. N. Engl. J. Med. 355: 1978–90. Kupsch, A., Kuehn, A., Klaffke, S. et al. (2003) Deep brain stimulation in dystonia. J. Neurol. 250 (Suppl. I): I47–I52. Laitinen, L.V., Bergenheim, A.T. and Hariz, M.I. (1992) Leksell’s posteroventral pallidotomy in the treatment of Parkinson’s disease. J. Neurosurg. 76: 53–61. Lozano, A.M., Lang, A.E., Galvez-Jimenez, N., Miyasaki, J., Duff, J., Hutchinson, W.D. and Dostrovsky, J.O. (1995) Effect of GPi pallidotomy on motor function in Parkinson’s disease. Lancet 346: 1383–7. Ondo, W.G., Desaloms, J.M., Jankovic, J. and Grossman, R.G. (1998) Pallidotomy for generalized dystonia. Mov. Disord. 13: 693–8. Schaltenbrand, G. and Wahren, W. (1977) Introduction to Stereotaxis with an Atlas of the Human Brain. Stuttgart: Thieme. Shils, J., Tagliati, M. and Alterman, R. (2002) Neurophysiological monitoring during neurosurgery for movement disorders. In: V. Deletis and J. Shils (eds), Neurophysiology in Neurosurgery. San Diego: Academic Press, pp. 393–436. Starr, P.A., Turner, R.S., Rau, G. et al. (2004) Microelectrode-guided implantation of deep brain stimulators into the globus pallidus internus for dystonia: techniques, electrode locations, and outcomes. Neurosurg. Focus 17: E4. Trottenberg, T., Volkmann, J., Deuschl, G. et al. (2005) Treatment of severe tardive dystonia with pallidal deep brain stimulation. Neurology 64 (2): 344–6. Vercueil, L., Pollak, P., Fraix, V. et al. (2001) Deep brain stimulation in the treatment of severe dystonia. J. Neurol. 248: 695–700.

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Vercueil, L., Krack, P. and Pollak, P. (2002) Results of deep brain stimulation for dystonia: a critical reappraisal. Mov. Disord. 17 (Suppl. 3): S89–S93. Vidailhet, M., Vercueil, L., Houeto, J.L. et al. (2005) Bilateral deep brain stimulation of the globus pallidus in primary generalized dystonia. N. Engl. J. Med. 352: 459–67. Vidailhet, M., Vercueil, L., Houeto, J.L. et al. (2007) Bilateral, pallidal, deep-brain stimulation in primary generalised dystonia: a prospective 3 year follow-up study. Lancet Neurol. 6 (3): 223–9. Volkmann, J. and Benecke, R. (2002) Deep brain stimulation for dystonia: patient selection and evaluation. Mov. Disord. 17 (Suppl. 3): S112–S115.

Yianni, J., Bain, P.G., Gregory, R.P. et al. (2003) Post-operative progress of dystonia patients following globus pallidus internus deep brain stimulation. Eur. J. Neurol. 10: 239–47. Yianni, J., Bain, P., Giladi, N. et al. (2003) Globus pallidus internus deep brain stimulation for dystonic conditions: a prospective audit. Mov. Disord. 18 (4): 436–42. Yianni, J., Nandi, D., Shad, A. et al. (2004) Increased risk of lead fracture and migration in dystonia compared with other movement disorders following deep brain stimulation. J. Clin. Neurosci. 11: 243–5. Zorzi, G., Marras, C., Nardocci, N. et al. (2005) Stimulation of the globus pallidus internus for childhood-onset dystonia. Mov. Disord. 20: 1194–200.

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Deep Brain Stimulation in Tourette’s Syndrome Veerle Visser-Vandewalle, Yasin Temel, and Linda Ackermans

o u tli n e Introduction Clinical Characteristics and Prevalence of TS Treatment of TS

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Clinical and Surgical Evaluation Patient Selection Inclusion of Patients Exclusion of Patients Surgical Procedure Perioperative Evaluation Postoperative Evaluation Programming

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or grunting. Complex tics involve a larger number of muscles acting in a coordinated pattern to produce complicated movements that may resemble purposeful voluntary movements (Mink, 2001). Complex tics include head shaking, scratching, throwing, touching or uttering short phrases. Uttering obscene words (coprolalia) only occurs in 10% or less of patients. Tics increase with stress and decrease with relaxation or when the individual is engaged in acts that require selective attention. Tics may in some cases be tempor­ arily suppressed by an effort of will or concentration, but may rebound afterwards (Berardelli et al., 2003). The onset of tics in TS most commonly occurs in early childhood, with a mean age of 7 years (Robertson, 2000). The severity of tics typically increases during the

Clinical Characteristics and Prevalence of TS Tourette’s syndrome (TS) is a chronic complex neuropsychiatric disorder characterized most prominently by tics. Tics are sudden, rapid, recurrent, nonrhythmic, stereotyped muscle contractions (motor tics) or sounds produced by moving air through the nose, mouth, or throat (vocal tics) (Mink, 2001). They may be abrupt in onset, fast and brief (clonic tics), or may be slow and sustained (dystonic or tonic tics) (Robertson, 2000). The motor patterns of tics may involve individual muscles or small groups of muscles with discrete contractions (simple tics) like eye blinking, nose-twitching, sniffing

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prepubescent years, and often declines in frequency and intensity by the beginning of adulthood. Ninety percent of TS patients will experience substantial remission, and more than 40% will be symptom-free by age 18. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV TR) (APA, 2000), TS is defined by the presence of both multiple motor tics and one or more vocal tics throughout a period of more than one year, during which period there is absence of a tic-free period of more than three consecutive months (Hoekstra et al., 2004). The tic repertoire of an individual with TS includes fluctuations in type of tic, body location, and the impairment it produces (Mink, 2001). An important feature of TS is its association with a wide range of co-morbid behavioral abnormalities which, in some patients, are far more disabling than the tics themselves (Hoekstra et al., 2004). Attention deficit hyperactivity disorder (ADHD), obsessive– compulsive behavior (OCB), and self-injurious behavior (SIB) are strongly linked to TS and are probably an integral part of the syndrome. The occurrence of ADHD in TS patients ranges from 21 to 90% of clinical populations (Robertson, 2000). Symptoms consist of inattention and distractibility with or without behavioral hyperactivity. OCB may occur in up to 50% of TS patients. The more severe obsessions in TS may involve sexual, violent, religious, aggressive, and symmetrical themes; the compulsions may manifest with symptoms such as checking, counting, forced touching, and self-damage. Like tics, OCB-symptoms often wax and wane during the course of the illness. Robertson (2000) reported that over one-third of clinical TS patients carried out SIB. The most frequent type of SIB was head banging. While once thought to be rare, TS is now recognized as a relatively common disorder with an estimated worldwide prevalence of 4–5/10 000 and occurs three to four times more commonly in males (Riederer et al., 2002). There is a considerable variation among studies reporting on the prevalence of TS which is most likely due to variations in sex, age, diagnostic criteria, and assessment methods (Leckman, 2002).

Treatment of TS For many patients, especially those with mild symptomatology, psychobehavioral strategies provide sufficient treatment. Pharmacological treatment may be considered when symptoms interfere with social interactions, academic or job performance, or with activities of daily living. The most commonly prescribed medications for more severe TS are dopamine antagonists such

as tetrabenazine and dopamine blocking agents such as haloperidol or other antipsychotic drugs (Robertson, 2000). Clonidine, clonazepam, and injections with botulinum toxin are also widely used. Selective serotonin reuptake inhibitors are recommended for the treatment of obsessive–compulsive behavior but are not helpful for tics. Psychostimulants, such as methylphenidate, are the treatment of choice for ADHA (Silay and Jankovic, 2005). Surgery may be considered as a treatment of last resort for patients who are refractory to any behav­ ioral and medical treatment. Although no precise numbers are available, this seems to represent a very small percentage of patients with TS.

History of neurosurgical treatment of TS In the past, several attempts have been made to treat these patients through neurosurgical ablative procedures (Temel and Visser-Vandewalle, 2004). The target sites have been diverse and have included the frontal lobe (prefrontal lobotomy and bimedial frontal leucotomy), the limbic system (limbic leucotomy and anterior cingulotomy), the thalamus, and the cerebellum (Figure 46.1). Combined approaches have also been tried such as anterior cingulotomy plus infrathalamic lesions. In most of these studies, patient selection was not standardized, assessments typically were not blinded, and outcome was not quantified. The results were often unsatisfactory and major side effects occurred such as hemiplegia or dystonia. Deep brain stimulation (DBS) was first introduced as a new surgical technique for the treatment of intractable TS in 1999. Vandewalle et al. (1999) performed chronic bilateral stimulation of the medial part of the thalamus, at the cross point of the centromedian nucleus (Ce, or CM), substantia periventricularis (Spv), and nucleus ventro-oralis internus (Voi) (Figure 46.2). This target was chosen on the basis of the favor­ able results of thalamotomy in this location previously described by Hassler and Dieckmann in 1970. DBS of this single target was thought to most accurately mimic the lesions performed by Hassler and Dieckmann. Visser-Vandewalle et al. (20003) described the promising effects of bilateral thalamic DBS in three patients in greater detail in 2003. With a followup period of 5 years, 1 year and 8 months respectively, there was an improvement both in tics (reduction of 90%, 72% and 83% respectively with stimulation on compared with stimulation off) and in associated behavioral disorders. Stimulation induced side

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targets

1

2 7 5

4 6

10 12

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8 9

3

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15

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Figure 46.1  Brain areas that have been targeted in surgery for TS syndrome and other relevant neuroanatomical structures. The frontal lobe (3) was targeted during prefrontal lobotomy and bimedial leucotomy. In limbic leucotomy and anterior cingulotomy, the cingulate cortex (1) was lesioned. The thalamus (7) was targeted for lesions of the midline, intralaminar and ventrolateral thalamic nuclei and for DBS. Infrathalamic lesions were performed at the level of the H fields of Forel (11) and the zona incerta (5). Cerebellar surgery invloved lesioning of the dentate nucleus (16). The surrounding brain areas include: (2) corpus callosum, (4) caudate-putamen complex, (6) globus pallidus, (8) subthalamic nucleus, (9) substantia nigra, (10) posterior commissure, (12) superior colliculus, (13) inferior colliculus, (15) superior cerebellar peduncle and (14) optic chiasm

effects consisted of drowsiness and changes in sexual functioning (Visser-Vandewalle et al., 2003; Temel et al., 2004).

Targets After the initiation of thalamic DBS as a potential treatment for patients with refractory TS, several other targets have been used. Published reports are sparse however (Vandewalle et al., 1999; Van der Linden et al., 2002; Visser-Vandewalle et al., 2003; Diederich et al., 2004; Egidi et al., 2005; Flaherty et al., 2005; Houeto et al., 2005; Servello et al., 2005, 2008; Bajwa et al., 2007; Kuhn et al., 2007; Shahed et al., 2007) and the low number of cases may reflect the very small group of potential candidates for surgery. To date, five sites have been targeted for DBS in 33 TS patients: medial thalamus, at the cross point of CM-SpvVoi (Vandewalle et al., 1999; Visser-Vandewalle et al., 2003; Egidi et al., 2005; Servello et al., 2005, 2008;Bajwa et al., 2007) l thalamus, CM-Pf (Houeto et al., 2005) l

posteroventral globus pallidus internus (GPi) (Van der Linden et al., 2002; Diederich et al., 2004) l anteromedial GPi (Houeto et al., 2005) l nucleus accumbens (NAC) and anterior limb of internal capsule (IC) (Flaherty et al., 2005; Kuhn et al., 2007). l

Servello et al. (2008) reported on the beneficial effects of DBS of the same target described by Vandewalle in 18 patients with TS, with a follow-up of 3–17 months. In this report there was an improved response of motor tics when compared to phonic tics due to thalamic DBS. These authors also reported positive effects on behavioral disorders. More recently, Bajwa et al. (2007) described the beneficial effects of DBS of the same target in a 50-year-old patient, with a 66% tic reduction at 24 months follow-up and positive effects on mood and obsessive–compulsive symptoms. The positive effects of bilateral DBS at the posteroventral (motor) GPi in a single TS patient were first described by Van der Linden et al. in 2002. At 6 months follow-up, a tic reduction of 95% was noted. In 2004, Diederich et al. described the beneficial effects of chronic stimulation of the same target in another patient,

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electrode

III Voi

Ce Spv

Thalamus

Except for a small hematoma around the tip of one electrode, no serious surgical complications have been reported to date in the published literature. Unexpected stimulation-induced side effects such as drowsiness, reduced energy, changes in sexual behavior, and mild dysarthria have been noted in the majority of reported cases (Visser-Vandewalle et al., 2003; Temel et al., 2004; Servello et al., 2008). One patient with bilateral thalamic and bilateral anteromedial GPi DBS appeared to be more depressed with pallidal stimulation (Houeto et al., 2005). The stimulation-dependent changes in the execution of movements in one case with posteroventrolateral pallidal stimulation probably had to do with a small haematoma (Diederich et al., 2004).

Figure 46.2  Schematic representation of the electrode being positioned in the medial part of the thalamus, at the cross point of the centromedian nucleus (Ce; as part of the intralaminar thalamic nuclei), the substantia periventricularis (Spv; as part of the midline thalamic nuclei), and the Voi (nucleus ventro-oralis internus)

Neuroanatomic basis for deep brain stimulation in TS

with a follow-up of 14 months. However, there was no change in the patient’s “very mild compulsive tendencies.” The effects of GPi DBS in a 16-year-old boy were described by Shahed et al. (2007). The authors reported a significant effect on tics and behavior at 6 months follow-up. However, a body shield was needed for 4 weeks because the patient compulsively pushed on the implantable pulse generators (IPGs). Houeto and coworkers (2005) described the effects of bilateral pallidal and thalamic stimulation in one patient. The pallidal target was located in the anteromedial (limbic) part of the GPi. In this patient, both thalamic and pallidal stimulation had similar effects on tics, but thalamic stimulation was superior for the treatment of the associated behavior disturbance. Flaherty and coworkers (2005) described the effects of bilateral stimulation of the anterior portion of the internal capsule in a single patient with TS who suffered from severe tics without associated behavioral disorder. After 18 months, there was a 25% reduction in tics. In this patient, the ventral-most electrode contacts produced mild depression while the dorsal contacts caused hypomania. The effects of DBS of the nucleus accumbens, with two electrode contacts at the level of the anterior capsule, were described in a 26-year-old male patient suffering from severe TS, OCB, and SIB. The best effect on tics, with a 40–50% tic reduction on the Yale Global Tic Severity Scale (YGTSS) (Leckman et al., 1989) after 2.5 years, were obtained by monopolar stimulation of all poles of the quadripolar electrode. Also, a clear amelioration of obsessive and compulsive symptoms was noticed (Kuhn et al., 2007).

The pathophysiology of TS remains poorly understood. It is widely believed that abnormalities in dopamine neurotransmission play a fundamental role in the pathogenesis of TS. This hypothesis arises from the clinical observation that dopamine D2 receptor-blocking drugs and agents that deplete presynaptic dopamine successfully suppress tics in many cases, whereas potentiation of dopamine transmission with stimulant medications often increases the number and severity of tics (Mink, 2001). Moreover, positron emission tomography (PET) studies have revealed abnormalities in dopamine transporter and dopamine receptor binding in the striatum of TS patients (Singer et al., 2002). Alterations in striatal function have also been demonstrated in TS patients during active tic suppression, with a decreased activity in putamen, ventral pallidum, and thalamus bilaterally, and an increased activity of the head of the right caudate nucleus, and frontal and temporal cortices (Peterson et al., 1998). Dopamine has a strong regulatory function on striatal activity. Within the brain, there are anatomically segregated, parallel circuits representing different functions (motor, oculomotor, cognitive and limbic). These basal ganglia circuits traverse the cortex, striatum, globus pallidus, and thalamus. Each circuit includes a direct and an indirect pathway. Dopaminergic hyperactivity in TS is hypothesized to inhibit the indirect pathway, leading to an overactivity of thalamocortical drive. Other cortical–subcortical loops may also be implicated in TS pathophysiology. The excitatory feedback loops from the centromedian-parafascicular complex (CM-Pf) of the thalamus to the motor region of the striatum, and the midline thalamic nuclei (substantia periventricularis or Spv), to the limbic part of the striatum are implicated in the pathophysiology of TS and explain the efficacy of

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DBS in this location. Several studies have suggested that both the sensorimotor and the limbic parts of the basal ganglia, including the dorsal and ventral striatum, are involved in the pathophysiology of TS (Graybiel, 2000; Groenewegen et al., 2003; Peterson et al., 2003; Stern et al., 2000). This may also explain the presence of both motor and non-motor symptoms in this disorder.

Rationale for Targeting the Medial Thalamus In 1970 Hassler and Diekman reported on the beneficial effects of lesioning the intralaminar and midline thalamic nuclei in patients suffering from TS and, in patients with facial tics, also the Voi nucleus (ventrooralis internus). High frequency stimulation of a nucleus has similar clinical effects as an ablative lesion but has the advantages of being adjustable and reversible (Lozano and Mahant, 2004). Thus, it was attractive to postulate that DBS of the intralaminar and midline thalamic nuclei and Voi, might have a good effect on symptoms in TS. In line with this hypothesis, high frequency stimulation of the thalamus and more specifically of the nuclei projecting to the cortex ipsilaterally and back to the contralateral striatum, would decrease cortical drive, and interrupt the circuit that was enhancing thalamic hyperactivity. The Voi projects directly to the premotor cortex. The CM projects back to the dorsal (motor) striatum, and Spv projects back to the ventral (limbic) striatum. Thus, DBS of the medial part of the thalamus had the potential to impact both motor and limbic symptoms in patients with intractable TS. This hypothesis was confirmed in three patients (Visser-Vandewalle et al., 2003).

Rationale for Targeting the Globus Pallidus The GPi is a large nucleus in which the posteriorly located motor portion is relatively far from the anter­ ior limbic portion. In other words one has to choose whether the motor or limbic part of the GPi will be targeted during DBS. This stands in contrast to the thalamus, in which motor and limbic-related nuclei are located close together (Visser-Vandewalle et al., 2003). Posterolateral Part of the GPi Prior to the introduction of subthalamic DBS, DBS of the posteroventrolateral GPi was performed in patients with advanced PD. Improvements in PD symptoms and an anti-dyskinesia effect were noted (Follett, 2004). More recently, GPi DBS has been widely performed in patients suffering from dystonia (Krause et al., 2004; Vidailhet et al., 2005). The good results obtained are not

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so much a consequence of the effect on muscular tone as on the associated hyperkinetic movements. As tics may also be regarded as hyperkinesias, clinicians decided to target the motor (posteroventrolateral) part of the GPi in TS (Van der Linden et al., 2002; Diederich et al., 2004; Shahed et al., 2007). Anteromedial Part of the GPi As mentioned above, both sensorimotor and limbic circuits of the basal ganglia have been implicated in the pathophysiology of TS. While Van der Linden et al. (2002) have targeted the motor GPi, other authors have reported good results with DBS at the anterior, limbic-related, part of the GPi (Houeto et al., 2005).

Rationale for Targeting the Nucleus Accumbens TS and OCD share many clinical similarities and a strong comorbidity. DBS of the nucleus accumbens (NAC) has been performed in patients suffering from OCD (Sturm et al., 2003). It has been hypothesized that a neuropathological model based on NAC mechanisms may be central to the pathology and physiology of TS. This model assumes that external and internal events occurring during the development of the nervous system induce modular changes in the NAC (Brito, 1997). Considering this, it is possible that the reported mild effects of ventral IC stimulation in a single patient with TS (Flaherty et al., 2005) might be explained by spread of current to the subjacent NAC.

Clinical and surgical evaluation Patient Selection As mentioned in the first section, TS symptoms typically wane before or at the onset of adolescence. Not all patients require therapy and, of those who do, only a minority fail to respond to medical treatment. The TS patients considered for DBS should comprise only very severe cases who have received careful trials of standard therapies without adequate benefit. The Dutch– Flemish Tourette Surgery Study Group has established guidelines for DBS in TS (Visser-Vandewalle et al., 2006), and recently the Movement Disorders Society published a position statement on the matter (Mink et al., 2006). These statements include the following selection criteria.

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Inclusion of Patients Patients should meet the following criteria: 1. The patient has definite Tourette’s syndrome, established by two independent clinicians. The diagnosis is established according to DSM- IVTR criteria (APA, 2000) and with the aid of the Diagnostic Confidence Index (DCI) (Robertson et al., 1999). 2. The patient has severe and incapacitating tics as his/her primary problem. 3. The patient is treatment-refractory. This means that the patient either has not or very partially responded to three different medication regimes, each for at least 12 weeks in duration, and in adequate doses, or has been proven not to tolerate medications due to side effects. Three different groups of neuroleptics should have been tried: “classic” dopamine-2 antagonists (haloperidol, pimozide or clonidine) modern anti-psychotic medications (e.g. risperidone, olanzapine, clozapine, sulpiride, aripiprazole) experimental medications (e.g. pergolide). 4. Finally, a trial of at least 10 sessions of behavioral therapy for tics, such as habit reversal or exposure in vivo, may be attempted. 5. The patient should be over 25 years of age. Exclusion of Patients Patients should be excluded from neurosurgical treatment if they have a tic disorder other than TS, severe psychiatric comorbid conditions (other than associated behavioral disorders), or mental deficiency. Contraindications for surgical treatment for DBS in TS are severe cardiovascular, pulmonary or haematological disorders and structural MRI-abnormalities as well as active suicidal ideation.

Surgical Procedure The technique of DBS applied to TS is similar to that used for more classical indications like Parkinson’s disease. Targets for TS, such as the nuclei of the medial portion of the thalamus, are not visible with current imaging techniques. Moreover, TS patients may pull themselves out of the stereotactic frame because of the frequent motor tics which occur in the head region. One solution is to operate with the patient under general anaesthesia (Diederich et al., 2004; Houeto et al., 2005); however, because of the uncertainty of the ideal target and the importance of intraoperative findings, it is preferable for the patient to be awake and

cooperative during surgery. To avoid general anaesthesia, patients may be sedated with a combination of lormetazepam and clonidine (Visser-Vandewalle et al., 2003) or with a Propofol Target Controlled Infusion (Van der Linden et al., 2002). These regimens reduce tics sufficiently to improve the safety and efficacy of the stereotactic procedure. With the patient awake their symptoms can be assessed so that acute stimulationinduced side effects can be detected and the position of the electrode adjusted as needed.

Perioperative Evaluation It is of paramount importance that the exact location of the DBS electrode and in particular the contact providing the greatest efficacy is precisely determined and that all effects (positive and negative) are meticulously described. A more comprehensive survey of guidelines for the perioperative assessment of the effects of DBS in TS is available elsewhere (Mink et al., 2006).

Postoperative Evaluation A careful and detailed description of the effect of DBS on tics and associated behavioral disorders as well as stimulation-induced side effects is mandatory. The most commonly used scale for tic rating is the Yale Global Tic Severity Scale (YGTSS) (Leckman et al., 1989). The Rush Videotape scale is also commonly used. For a more objective evaluation, the patient should be recorded on video with and without stimulation. The tics should be rated on video by two independent investigators. Ideally, the patient and investigator should be blinded to the status of the stimulation. A careful psychiatric and neuropsychological evaluation should be performed at regular intervals. Clinical effects should be correlated to the exact position of the electrode. The most prudent approach may be to perform a CT scan postoperatively and fuse these images with preoperative MR images, although many centers successful employ other imaging approaches. Only if these prerequisites are fulfilled and a maximum amount of data are exchanged between centers, can the optimal target one day be established.

Programming According to our experience with DBS in the medial portion of the thalamus, the best effect in the majority of patients is obtained with a frequency between 75

V. NEUROMODULATION FOR MOVEMENT DISORDERS

Other considerations

and 100 Hz and a pulse width of 210 s. From day one postoperatively bipolar stimulation is started (to obtain the most selective effect), with each pole made active during four consecutive days (e.g. day 1: pole 0 , pole 1 ; day 2: pole 1 , pole 2 , etc.). During programming, the voltage is progressively increased until unwanted side effects occur. Thereafter, the combination of electrodes may be altered (for example 2 electrodes negative), or monopolar stimulation may be chosen, as suggested by clinical effects. As for other DBS indications, programming is a matter of “trial and error” as directed by the best clinical effects with the fewest adverse effects.

Other considerations The selection of specific targets for DBS in the treatment of TS has thus far been based on the historical experience with ablation at that target or the effects of DBS at that target on similar symptoms in other disorders. DBS in TS is still investigational and the best target has yet to be determined. The effects of stimulation of the currently used targets are not fully appreciated. Surgery with the patient sufficiently awake to be cooperative during test stimulation makes the intraoperative detection of acute stimulation induced side effects possible, so that the position of the electrode can be changed before its final fixation. Nevertheless, negative effects may sometimes become prominent later in the course of postoperative follow-up, such as changes in sexual behavior. Patients should be carefully informed about this before surgery. Because so few cases have been published, continuous informational exchange and on-going assessment of clinical experience is of utmost importance. Moreover, large (multicenter) prospective studies will significantly help to define the optimal target for DBS in TS, or, will help clinicians to choose the best target for each individual case.

References APA (2000) Diagnostic and Statistical Manual of Mental Disorders, 4th edn. Washington, DC: American Psychiatric Association. Bajwa, R.J., de Lotbiniere, A.J., King, R.A., Jabbari, B., Quatrano, S., Kunze, K. et al. (2007) Deep brain stimulation in Tourette’s syndrome. Mov. Disord. 22: 1346–50. Berardelli, A., Curra, A., Fabbrini, G., Gilio, F. and Manfredi, M. (2003) Pathophysiology of tics and Tourette syndrome. J. Neurol. 250: 781–7. Brito, G.N. (1997) A neurobiological model for Tourette syndrome centered on the nucleus accumbens. Med. Hypotheses 49: 133–42. Diederich, N.J., Bumb, A., Mertens, E., Kalteis, K., Stamenkovic, M. and Alesch, F. (2004) Efficient internal segment pallidal stimulation in Gilles de la Tourette syndrome: a case report. Mov. Disord. 19: S440.

585

Egidi, M., Carrabba, G., Priori, A., Rampini, P., Locatelli, M., Bossi, B. et al. (2005) Thalamic DBS in Tourette`s syndrome: case report. Proceedings of the 14th Meeting of the WSSFN, Rome, Italy, 13–17 June. Flaherty, A.W., Williams, Z.M., Amimovin, R., Kasper, E., Rauch, S.L., Cosgrove, S.L. and Eskander, E.N. (2005) Deep brain stimulation of the internal capsule for the treatment of Tourette syndrome: technical case report. Neurosurgery 57: E403. Follett, K.A. (2004) Comparison of pallidal and subthalamic deep brain stimulation for the treatment of levodopa-induced dyskinesias. Neurosurg. Focus 17: E3. Hassler, R. and Dieckmann, G. (1970) Traitement stereotaxique des tics et cris inarticulés ou coprolaliques considérés comme phénomène d’obsession motrice au cours de la maladie de Gilles de la Tourette. Rev. Neurol. (Paris) 123: 89–100. Graybiel, A.M. (2000) The basal ganglia. Curr. Biol. 10: R509–R511. Groenewegen, H.J., van den Heuvel, O.A., Cath, D.C., Voorn, P. and Veltman, D.J. (2003) Does an imbalance between the dorsal and ventral striatopallidal systems play a role in Tourette’s syndrome? A neuronal circuit approach. Brain Dev. 25: S3–S14. Hoekstra, P.J., Anderson, G.M., Limburg, P.C., Korf, J., Kallenberg, C.G. and Minderaa, R.B. (2004) Neurobiology and neuroimmunology of Tourette’s syndrome: an update. Cell. Mol. Life. Sci. 61: 886–98. Houeto, J.L., Karachi, C., Mallet, L., Pillon, B., Yelnik, J., Mesnage, V. et al. (2005) Tourette’s syndrome and deep brain stimulation. J. Neurol. Neurosurg. Psychiatry 76: 904. Krause, M., Fogel, W., Kloss, M., Rasche, D., Volkmann, J. and Tronnier, V. (2004) Pallidal stimulation for dystonia. Neurosurgery 55: 1361–8; discussion 1368–70. Kuhn, J., Lenartz, D., Mai, J.K., Huff, W., Lee, S.H., Koulousakis, A., Klosterkoetter, J. and Sturm, V. (2007) Deep brain stimulation of the nucleus accumbens and the internal capsule in therapeutically refractory Tourette-syndrome. J. Neurol. 254: 963–5. Leckman, J.F. (2002) Tourette’s syndrome. Lancet 360: 1577–86. Leckman, J.F., Riddle, M.A., Hardin, M.T., Ort, S.I., Swartz, K.L., Stevenson, J. et al. (1989) The Yale Global Tic Severity Scale: initial testing of a clinician-rated scale of tic severity. J. Am. Acad. Child. Adolesc. Psychiatry 28: 566–73. Lozano, A.M. and Mahant, N. (2004) Deep brain stimulation surgery for Parkinson’s disease: mechanisms and consequences. Parkinsonism Relat. Disord. 10: S49–S57. Mink, J.W. (2001) Basal ganglia dysfunction in Tourette’s syndrome: a new hypothesis. Pediatric Neurology 25: 190–8. Mink, J.W., Walkup, J., Frey, K.A., Como, P., Cath, D., DeLong, M.R. et al. for the Tourette Syndrome Association, Inc. (2006) Recommended guidelines for deep brain stimulation in Tourette syndrome. Mov. Disord. 21: 1831–8. Peterson, B.S., Skudlarski, P., Anderson, A.W., Zhang, H., Gatenby, J.C., Lacadie, C.M. et al. (1998) A functional magnetic resonance imaging study of tic suppression in Tourette syndrome. Arch. Gen. Psychiatry 55: 326–33. Peterson, B.S., Thomas, P., Kane, M.J., Scahill, L., Zhang, H., Bronen, R., King, R.A., Leckman, J.F. and Staib, L. (2003) Basal ganglia volumes in patients with Gilles de la Tourette syndrome. Arch. Gen. Psychiatry 60: 415–24. Robertson, M.M. (2000) Tourette syndrome, associated conditions and the complexities of treatment. Brain 123: 425–62. Robertson, M.M., Banerjee, S., Kurlan, R., Cohen, D.J., Leckma, J.F., McMahon, W. et al. (1999) The Tourette syndrome diagnostic confidence index: development and clinical associations. Neurology 53: 2108–12. Riederer, F., Stamenkovic, M., Schindler, S.D. and Kasper, S. (2002) [Tourette’s syndrome – a review]. Nervenarzt 73: 805–19.

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Servello, D., Porta, M., Sassi, M., Brambilla, A. and Robertson, M.M. (2008) Deep brain stimulation in 18 patients with severe Gilles de la Tourette Syndrome refractory to treatment; the surgery and stimulation. J. Neurol. Neurosurg. Psychiatry 79 (2): 136–42. Servello, D., Sassi, M., Geremia, L. and Porta, M. (2005) Bilateral thalamic stimulation for intractable Tourette syndrome. Proceedings of the 14th Meeting of the WSSFN, Rome, Italy, 13–17 June. Shahed, J., Poysky, J., Kennedy, C., Simpson, K. and Jankovic, J. (2007) GPi deep brain stimulation for Tourette syndrome improves tics and psychiatric comorbidities. Neurology 68: 159–60. Silay, Y.S. and Jankovic, J. (2005) Emerging drugs in Tourette syndrome. Expert Opin. Emerg. Drugs 10: 365–80. Singer, H.S., Szymanski, S., Giuliano, J., Yokoi, F., Dogan, A.S., Brasic, J.R. et al. (2002) Elevated intrasynaptic dopamine release in Tourette’s syndrome measured by PET. Am. J. Psychiatry 159: 1329–36. Stern, E., Silbersweig, D.A., Chee, K.Y., Holmes, A., Robertson, M.M., Trimble, M. et al. (2000) A functional neuroanatomy of tics in Tourette syndrome. Arch. Gen. Psychiatry 57: 741–8. Sturm, V., Lenartz, D., Koulousakis, A., Treuer, H., Herholz, K., Klein, J.C. and Klosterkotter, J. (2003) The nucleus accumbens: a target for deep brain stimulation in obsessive–compulsive- and anxiety-disorders. J. Chem. Neuroanat. 26: 293–9. Temel, Y. and Visser-Vandewalle, V. (2004) Surgery in Tourette syndrome. Mov. Disord. 19: 3–14.

Temel, Y., van Lankveld, J.J., Boon, P., Spincemaille, G.H., van der Linden, C. and Visser-Vandewalle, V. (2004) Deep brain stimulation of the thalamus can influence penile erection. Int. J. Impot. Res. 16: 91–4. Van der Linden, C., Colle, H., Vandewalle, V., Alessi, G., Rijckaert, D. and De Waele, L. (2002) Successful treatment of tics with bilateral internal pallidum (GPi) stimulation in a 27-year-old male patient with Gilles de la Tourette’s syndrome. Mov. Disord. 17: S341. Vandewalle, V., van der Linden, C., Groenewegen, H.J. and Caemaert, J. (1999) Stereotactic treatment of Gilles de la Tourette syndrome by high frequency stimulation of thalamus. Lancet 353: 724. Vidailhet, M., Vercueil, L., Houeto, J.L., Krystkowiak, P., Benabid, A.L., Cornu, P. et al. French Stimulation du Pallidum Interne dans la Dystonie (SPIDY) Study Group (2005) Bilateral deepbrain stimulation of the globus pallidus in primary generalized dystonia. N. Engl. J. Med. 352: 459–67. Visser-Vandewalle, V., Temel, Y., Boon, P., Vreeling, F., Colle, H., Hoogland, G., Groenewegen, H. and van der Linden, C. (2003) Chronic bilateral thalamic stimulation: a new therapeutic approach in intractable Tourette syndrome. J. Neurosurg. 99: 1094–100. Visser-Vandewalle, V., Van der Linden, C., Ackermans, L., Temel, Y., Tijssen, M.A., Schruers, K. et al. (2006) Deep brain stimulation in Gilles de la Tourette’s syndrome. Guidelines of the Dutch– Flemish Tourette Surgery Study Group. Neurosurgery 58: E590.

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C H A P T E R

47

Surgical Management of Hemifacial Spasm and Meige Syndrome Hyun Ho Jung and Jin Woo Chang

o u t l i n e Hemifacial Spasm

587

Operative Results and Clinical Outcome

591

Complications

592

Clinical Symptoms and Differential Diagnosis of HFS

588

Conclusions

592

Neurodiagnostic Evaluation of HFS

588

Meige Syndrome

592

Operative Technique and Microsurgical Anatomy for HFS Operative Procedures/Patient Positioning Scalp Incision and First Drill Hole Dural Incision and Exposure Decompression of the Offending Vessel Closure Intraoperative Monitoring

Clinical Symptoms and Pathophysiology

593

589 589 590 590 590 591 591

Surgical Management Surgical Procedure of Bilateral Pallidal   Deep Brain Stimulation Outcome and Complications

593

Conclusion

595

References

595

Hemifacial spasm

in frequency and severity, and spread downward to the other facial muscles of the affected side. In 1875, Schultze first described the concept of vas­ cular compression after autopsy of a patient with left HFS revealed that a giant aneurysm arising from the left vertebral artery was compressing the facial nerve root (Schultze, 1875). Gardner reported his first case of HFS treated with posterior fossa vascular decompres­ sion surgery in 1960 (Gardner, 1960). In 1970, Jannetta expanded his neurovascular compression theory, which initially applied only to trigeminal neuralgia, by including HFS, and he demonstrated how neuro­ vascular compression causes HFS (Jannetta et al., 1977).

Hemifacial spasm (HFS) is a benign, chronic, invol­ untary movement of one side of the face, characterized by twitching, tonic spasm, and synkinesis1 of the mus­ cles innervated by the facial nerve. It typically starts with intermittent twitches in the orbicularis oculi muscle. The symptoms usually progress gradually 1 

Synkinesis is involuntary muscular movement that accompanies voluntary movement and is the result of miswiring of nerves after trauma.

Neuromodulation

593 593

587

2009 Elsevier Ltd. © 2008,

588

47.  Surgical management of hemifacial spasm and meige syndrome

Jannetta’s observations regarding neurovascular com­pression as a cause of HFS have been proven by other investigators (Neagoy and Dohn, 1974; Fabinyi and Adams, 1978; Maroon, 1978; Wilson et al., 1980; Wilkins, 1981; Yeh et al., 1981; Fairholm et al., 1983; Fukushima, 1984). The microvascular decompression (MVD) procedure has become standard of care for the above conditions. Two different hypotheses have been put forth to explain the pathogenesis of HFS. The ephaptic trans­ mission hypothesis (the peripheral hypothesis) states that vascular contact with a portion of the facial nerve that is still covered by a central (oligodenderocyte) type of myelin can injure the myelin, thereby allowing bare axons to come closer or even contact each other. This close contact between bare axons promotes direct electrical communication between the individual nerve fibers (Gardner, 1962; Nielsen, 1984a, 1984b). The second hypothesis, the hyperactivity hypothesis (the central hypothesis), states that the symptoms of HFS are the result of abnormal functioning of the facial motor nucleus. This abnormal functioning could be the result of the facial nerve being irritated by a blood vessel (Ferguson, 1978; Esteban and MolinaNegro, 1986; Roth et al., 1990; Valls-Sole and Tolosa, 1989). The kindling phenomenon has been added to this second hypothesis, the hyperactivity hypoth­ esis, in that the abnormal activity is generated by the offending vessel which is irritating the facial nerve and that this irritation affects the facial nucleus as well (Moller and Jannetta, 1984, 1985, 1986a, 1986b). Jannetta hypothesized that the compression must be at the root entry zone of the cranial nerve to cause symptoms (Jannetta, 1979). But others (Leclercq et al., 1980; Moller, 1999; Ryu et al., 1999) suggest that com­ pression can occur at any point along the cranial nerve, especially at the transitional region between the cen­ tral and peripheral portions of the root, so called the “transitional zone” by some. In addition, there is con­ siderable evidence that any arterial or venous vascular contact can cause the symptoms of the disorder.

Clinical symptoms and differential diagnosis of HFS In most patients, the spasm of HFS begins at the lower eyelid, gradually progressing to involve the entire orbicularis oculi muscle and then moving on to the orbicularis oris or perioral muscles. In advanced cases, the platysma and, less frequently, the frontalis muscle of the forehead can also be affected. Whereas the most common type of HFS has gradual downward

spread of twitching to the lower face from its onset involving the orbicularis oculi muscle, atypical HFS, a much less common entity, begins in the lower or midfacial region and spreads upward to involve the fron­ talis muscle. These two distinct types of HFS have different compression sites; one being commonly com­ pressed at the anteroinferior aspect of the nerve root exit zone and the other at the posterosuperior aspect of the facial nerve at the brain stem (Jannetta, 1998; Ryu et al., 1998a). HFS is seen almost exclusively in middle-aged and older patients, with a female predominance. The occurrence in childhood and adolescence is extremely rare. The estimated prevalence rate of HFS is 1–3% (Jho and Jannetta, 1987; Kobata et al., 1995; Chang et al., 2001; Tan and Chan, 2006). It is well known that the symptoms of HFS can be aggravated or induced by emotional stress, psychological tension and/or fatigue. HFS can also be provoked by grimacing. Other facial movement disorders such as blepharo­ spasm, tic, facial myokymia, and postparalytic synki­ nesis may mimic HFS. Blepharospasm is a bilateral forced contraction of the musculature about the eye. It differs from HFS in being bilateral and involves only the musculature about the eye rather than presenting with steady progression down the face. l Tic is brief, repetitive, stereotyped and involuntary movements. It is similar to the movement of habitual spasm and is associated with more tonic components than HFS. l Facial myokymia is characterized by unilateral, undulating, worm-like, continuous muscle contractions associated with intrinsic brain stem pathology, which has a distinct and diagnostic electromyographic pattern. Other cranial nerve defects may be associated with facial myokymia. l Postparalytic synkinesis may occur after aberrant regeneration of the facial nerve after Bell’s palsy. A history of antecedent Bell’s palsy with these movements developing on regeneration of the nerve is helpful in excluding this condition. l

Neurodiagnostic evaluation of HFS Patients with typical HFS generally do not require a neuroradiologic examination because the pathogen­ esis of this condition is generally attributed to vascu­ lar compression of the facial nerve, usually at the root exit zone, however, in less than 1% of patients the compression may be due to tumors or alternatively,

V. NEUROMODULATION FOR MOVEMENT DISORDERS

Operative technique and microsurgical anatomy for HFS

demyelinating conditions (Tarnaris et al., 2007). For this reason a preoperative image workup should be performed. Because of the soft tissue nature of the disorder, computed tomography (CT) is obviously an unsatisfactory investigation. Although the routine sequence of magnetic resonance imaging (MRI) can exclude causes other than neurovascular compression, more detailed sequences are required to demonstrate neurovascular compression. The “constructive inter­ ference in the steady state” (CISS) sequence is a T2weighted refocusing three-dimensional gradient echo sequence that is useful for assessing neurovascular compression due to its high signal-to-noise ratio, high spatial and contrast resolution, and less cerebrospinal fluid (CSF) flow artifact. Recently, three-dimensional short-range (3D-TOF) magnetic resonance angiography (MRA) has become the method of choice for investigating neurovascular relationships among patients with HFS or trigeminal neuralgia. Furthermore, 3D-TOF MRA can demon­ strate postoperative changes in vessels and the root exit zone of the facial nerve after MVD. The findings may be useful for the postoperative evaluation of per­ sistent or recurrent HFS and for decision-making on whether to perform a second surgical procedure or to simply observe the patient’s clinical course (Chang et al., 2002). In our institution, we use 3D-TOF MRA and CISS imaging for preoperative evaluation of patients with HFS, and, if needed, a postoperative image is taken for persistent or recurrent HFS (Figure 47.1). Virtual endoscopic imaging by three-dimensional fast asymmetric spin echo (3D FASE) cisternography has been used as preoperative surgical simulation (Ishimori et al., 2003) and fusion imaging of threedimensional magnetic resonance cisternograms and angiograms is used for preoperative and postopera­ tive assessment of MVD in patients with HFS (Satoh et al., 2007).

Operative technique and microsurgical anatomy for HFS Although botulinum toxin injection is efficacious for HFS, it is not a definitive treatment and requires repeat injections, which, over time may become costly. Therefore, MVD is now considered the treatment of choice for HFS because of its low morbidity and its long-term benefit of symptom relief. Since there are a variety of operative techniques involving MVD, depending on the surgeon’s preference and patient’s condition, we will describe here our own operative technique of MVD.

589

(A)

(B)

Figure 47.1  Preoperative (A) and postoperative (B) 3D-TOF MRA scans demonstrating vascular decompression of the facial nerve after MVD

Operative Procedures/Patient Positioning Like every operation, positioning of the patient is important and essential to a successful surgical expo­ sure. After anesthesia induction and intubation, the patient is placed in the lateral position with the head fixed using a Mayfield, three-point head clamp. One pin should be on the front side over the hairline, and two on the inion and near the vertex so that the clamp should hold the head against gravity. The neck should be bent at the end of positioning to allow for the drill­ ing procedure. The head is rotated slightly away from the affected side, and flexed with lateral bending of about 10–15°, so that the digastric notch is positioned at the top. In this head position, to preserve venous return and to minimize postoperative neck pain due to bending, about two-fingers breadth of distance must be left between the chin and sternum, as well as between the mandibular angle and clavicle. Two large, soft pillows are inserted beneath the patient’s body and leg, and one pillow is placed between the legs to prevent compression of the fibular peroneal nerve. An axillary roll is placed under the dependent axilla and the forearm, opposite to the incision site, is wrapped with air-bead wrapping in order to secure the space between the head and shoulder. The “up” shoulder is taped down and away from the operator’s field.

V. NEUROMODULATION FOR MOVEMENT DISORDERS

590

47.  Surgical management of hemifacial spasm and meige syndrome

Scalp Incision and First Drill Hole The mastoid eminence is defined with a marker, and a line is drawn from the inion to the external auditory canal along which the transverse sinus is located. The digastric groove line will show the junc­ tion of the transverse and sigmoid sinuses. In MVD for HFS, exposure of transverse sinus is not needed, so the incision line is rather inferior to that made for trigeminal neuralgia. A linear incision line is created medial and parallel to the hairline, measuring about 40 mm in length. If the patient has a short and thick neck, the incision line must be rather medially (pos­ teriorly) positioned, approximately slightly greater than 10 mm in distance from the hairline, to allow for a freer movement of the operator’s hands and instru­ ments during the microsurgery. We suggest making an “S”- shaped incision at the end to render a wider exposure for short- and thick-necked patients. After the scalp incision is made, the subcutaneous tissue is undermined and a small self-retaining retrac­ tor is applied. Fascia is incised and the muscle layers are split using monopolar cauterization. There are two muscle layers, one is the sternocleidomastoid muscle and the other is the suboccipital muscle. In most cases, the anastomosis of the superficial temporal artery and occipital artery passes through the second layer of fas­ cia and must be sacrificed with bipolar coagulation and then cut. After the muscles are split, a burr-hole is created with a cranial perforator at the flat occipital squama contain­ ing the mastoid emissary vein, located at the superior– lateral corner. The craniectomy is extended to about 2    25 mm in size using a rongeur until the sigmoid sinus is exposed at its lateral (anterior) margin. During craniectomy, all bleeding from bone and the opened mastoid air cell must be fully sealed with bone-wax.

resulting flaps are secured with tenting sutures to widen the exposure. After the dural incision, the cerebellum is elevated superiorly (cephaladly) using a tapered retractor to expose the XIth cranial nerve. With gentle retraction, all of the arachnoid membranes around the lower cra­ nial nerve are incised sharply with microscissors. The dissection is advanced towards the IXth and Xth cra­ nial nerves for further exposure. When the choroid plexus of the lateral recess is exposed, the retractor is moved in such a way to retract the cerebellum slightly from the lateral to the medial side, taking care not to cause mechanical traction injury to the cochlear nerve. Some small bridging veins are occasionally met and, as a policy, we do not coagulate and divide them unless these tiny veins cannot be mobilized during retraction after full dissection of the arachnoid layer. While exposing the root exit zone of the facial nerve and the seventh and eighth nerve complex, one must avoid placing the retractor deeper than the choroid plexus since the ventral cochlear nucleus and the proximal portion of the cochlear nerve is located just beneath it. Retracting this area could lead to severe hearing loss. Therefore, it is necessary to pull the choroid plexus up with a retractor and then retract the flocculus and the choroid plexus.

Decompression of the Offending Vessel In our experience with 1964 cases that have under­ gone MVD for HFS since 1978, 1554 cases were fol­ lowed up for more than 6 months after the operation and were analyzed. In almost all cases, the artery was the compressing vessel, but in four cases, the vein was the compressing vessel (see Table 47.1). Once the offend­ ing vessel is visualized, it must be carefully dissected freely enough to be mobilized. But if the vertebral artery or its branches are involved, transposing them may not

Dural Incision and Exposure After relaxing the brain with mannitol, using the microscope, a small dural incision of less than 5 mm in length is started at the caudal–lateral corner. The CSF is aspirated using a small cottonoid until the cerebel­ lum becomes more relaxed. If relaxation is not suffi­ cient, the small dura incision is extended to allow the advancement of a retractor blade in order to expose and tear the cisterna magna or lateral cerebellomedul­ lary cistern to drain out more CSF. The dura is incised in a “T”-shaped fashion. The longer side of this “T”shaped incision (stem) is created curvilinearly along the sigmoid sinus and the shorter side (arm) of the “T”-shaped incision to the caudal–medial corner. The

Table 47.1  Type of offending vessel Vessel

No. of patients

PICA

648 (41.5%)

AICA

612 (39.2%)

Multiple

184 (11.8%)

VA

106 (6.8%)

Vein

4 (0.3%)

Total

1554

PICA  posterior inferior cerebellar artery; AICA  anterior inferior cerebellar artery; VA  vertebral artery

V. NEUROMODULATION FOR MOVEMENT DISORDERS

Operative results and clinical outcome

be easy because of their large caliber and frequent asso­ ciated atherosclerotic change. Vascular compression is frequently caused by two or more vessels, therefore completely exposing and dissecting them may be diffi­ cult, especially for those offenders with tiny perforators into the brain stem. If an offender is not found, we try to find it utilizing minimal retraction with a suction tip or micro-mirror behind the “VII–VIIIth” nerve complex. There are some case reports of vascular compres­ sion of the distal portion of the facial nerve causing HFS. We also experienced a similar rare case of the distal part of the facial nerve being indented by a loop of the posterior inferior cerebellar artery. Ryu empha­ sized that neurosurgeons should keep in mind that an offender may be positioned at distal parts of the facial nerve when it is not in the root exit zone or when the MVD of the root exit zone does not result in resolution of the HFS (Ryu et al., 1998b). Materials used for MVD include muscle–fascial graft, Gelfoam, Ivalon sponge, Teflon felt, artificial dura, and others. In our institution, we use only Teflon felt because shredded Teflon is easy to manipulate in the small field of operation and is conveniently shaped into balls of variable sizes or into sheet forms. Teflon felt can also be used when performing a sling technique to transpose the offender away from the root exit zone. At the end of the decompression, a few drops of fibrin glue are placed around the Teflon felt for fixation. There are two methods for MVD: interposition and transposition. Interposition technique is useful for almost all cases, but the transposition technique may be better for a compressing vertebral artery when decompression is not sufficient with interposition because of strong com­ pression by or immobility of the vertebral artery. In these situations, the transposition technique using fenestrated clips (Laws et al., 1986), thin silastic rubber (Rawlinson and Coakham, 1988), Prolene sutures (Bejjani and Sekhar, 1997) and/or Teflon felt with glue can be used.

Closure The dura is closed in a watertight fashion via sub­ cutaneous fascial grafting or with a small amount of muscle grafting. The craniectomy site is covered with autologous bone chips which were collected during perforating and rongeuring at opening. Muscles and fascia are sutured layer by layer.

Intraoperative Monitoring Facial electromyography (EMG) is used intraopera­ tively for the purpose of predicting the adequacy of

591

decompression of the affected nerve. The lateral spread response (LSR) is recorded at the other branches of the facial nerve when one branch of the facial nerve is elec­ trically stimulated. The rationale for this monitoring method is based on the ephaptic transmission theory. However, there continue to be debates regarding the clinical usefulness of EMG during MVD because the clinical results are not always consistent with the intraoperative EMG findings (Hatem et al., 2001; Sindou, 2005). Monitoring brain stem auditory evoked potentials (BAEP) is used for the purpose of preventing damage to the VIIIth cranial nerve, the cochlear nerve. Amongst other waves, the amplitude and latency of the V wave are important (Tokimura et al., 1990). If, during moni­ toring, the V decreases in amplitude to less than one half of the preoperative value or there is a latency delay of more than 1 ms, the operation should be stopped temporarily, the retraction released, and time allowed for recovery. The V wave will usually recover in 5–10 minutes after the release of traction. All patients for MVD in our institution are monitored with BAEP by a neurologist, and if a warning sign is noticed, we stop retracting the brain, order the anesthetist to give one ampoule of dexamethasone intravenously, and wait until the wave returns to the previous pattern.

Operative results and clinical outcome Our 1554 cases that were followed for more than 6 months were classified into the following five cat­ egories of success based on the degree of HFS present after MVD: l l l l l

“excellent” for absence of HFS “good” for more than 90% of HFS resolved “fair” for more than 50% “poor” for less than 50% “failure” for no improvement or recurrence of HFS.

An excellent to good result was recorded in 93.7% (1457 patients); fair in 3.9% (60 patients); poor in 1.3% (20 patients); and the procedure was assessed as a failure in 1.1% (17 patients) (see Table 47.2). The time course of improvement for HFS after MVD was not constant. We analyzed 1136 patients of our “excel­ lent” group for more than 18 months. Immediate improvement of HFS after MVD was seen in 753 patients (66.3%) and delayed improvement was seen in 383 (33.7%). In the delayed improvement group, it took from 2 days to 2.9 years for HFS to disappear

V. NEUROMODULATION FOR MOVEMENT DISORDERS

592

47.  Surgical management of hemifacial spasm and meige syndrome

Table 47.2  Surgical outcomes of MVD for HFS in 1554 patients Outcome

No. of patients

Excellent  Good

1362  95 (93.7%)

Fair

60 (3.9%)

Poor

20 (1.3%)

Failure

17 (1.1%)

Outcome categories: Excellent  complete resolution of HFS; Good  improvement 90%; Fair  improvement 50–90%; Poor  improvement 50%; Failure  no improvement or recurrence

after MVD, with a median period of 8 weeks. The extremely delayed response group, comprising only about 0.9% of responders, needed more than one year after MVD for improvement to occur. Among them, 9 patients had improvement of symptoms between 1 to 2 years after decompression and 1 patient felt signifi­ cant relief after 2.9 years. In this delayed improvement group, although not of the same intensity and frequency as the spasms occurring before the operation, the spasms in 159 patients disappeared immediately after surgery but reappeared within several days. This silent, symptomfree period between MVD and reappearance of spasm lasted up to 7 days after MVD in most cases. The remaining 224 patients continued to have spasms postoperatively but with decreased intensity and frequency. The immediate resolution of HFS after MVD could be due to the disappearance of the spontaneous or ectopic excitation of the affected nerve caused by the pulsatile compressive force of the offending vessel. The delayed resolution, on the other hand, could be attributed to the complete regeneration and repair of the micro-injured facial nerve or the gradual stabiliza­ tion of the facial motor nucleus (Sanders, 1989; Saito et al., 1993). It is therefore prudent to wait for at least one year after MVD in persistent or recurrent HFS for evidence of improvement, if there is no definite com­ pressing vessel on 3D-TOF MRA.

Complications Hearing loss and facial weakness after MVD are the most problematic complications seen, but the inci­ dence rate is low. In our series, some minor complica­ tions such as lower cranial nerve palsy, CSF leakage, and infections were temporarily encountered. The inci­ dence of permanent facial weakness and permanent

mild hearing loss was 2.2% and 1.2%, respectively. Hemorrhage was found in about 0.3% of cases and was treated conservatively. In several cases there was delayed facial palsy which occurred between the first and second week after surgery. The reported incidence of delayed facial palsy was 2.8 to 7.5% (Lovely et al., 1998; Rhee et al., 2006). The pathophysiology of delayed facial palsy is not fully understood but some have suggested that this may be due to neural edema or transient ischemia through vasa nervorum vasospasm (Menovsky and van Overbeeke, 1999; Scheller et al., 2004). For this condition we use steroid therapy, and almost all of the patients developing delayed facial palsy recover fully without deficit.

Conclusions Although HFS is not a life-threatening disorder, involuntary intermittent twitching of unilateral facial muscles is disfiguring to most patients and with­ drawal from society and work may occur. Medical therapies and botulinum toxin injection therapy offer only partial and temporary relief. Since Jannetta established the technique of MVD using an operating microscope and after many neu­ rosurgeons reported good to excellent outcomes after MVD for HFS, MVD is now widely accepted as the therapy of choice for hemifacial spasm. We have pre­ sented here our technique of choice for MVD and our results.

Meige syndrome In 1910, Henry Meige, a French neurologist, coined the term spasme facial median to describe a form of spasmodic torticollis consisting of spontaneous adult-onset dystonic movements of facial muscles that causes blepharospasm and a variety of dystonic spasms of the lower face, jaw, and neck (Meige, 1910). The term “Meige syndrome” was used by Paulson to describe spontaneous, involuntary spasm involving the facial muscles. In addition to the blepharospasm and oromandibular dystonia, some patients with this syndrome develop or show spasmodic dysphonia and dystonia of the neck, trunk, arms, and legs (Paulson, 1972). Therefore, this syndrome is now considered a variant of adult-onset torsion dystonia or idiopathic cranial-cervical dystonia, which is considered a seg­ mental dystonia.

V. NEUROMODULATION FOR MOVEMENT DISORDERS



Surgical management

Clinical symptoms and pathophysiology Abnormal spontaneous involuntary spasms occur at the orofacial muscles with blepharospasm, and sometimes this segmental dystonia involves the cervi­ cal area. Jankovic reported a series of 100 patients with blepharospasm and orofacial–cervical dystonias. In that series, the age at onset was between 34 and 75, with women outnumbering men by three to two. Most of the patients presented with blepharospasm (58%) and 61 patients had blepharospasm and oromandibu­ lar dystonia. Sixty patients had neck or generalized dystonia (Jankovic and Ford, 1983). As with other primary focal dystonias, the etiology, pathophysiology, and exact symptom progression of Meige syndrome are not well known. Some reports show that the neuronal arcs of the facial reflexes in blepharospasm and oromandibular dystonia are nor­ mal. It is believed that there probably is an abnormal excitatory drive, perhaps from the basal ganglia, to the facial motor neurons and the interneurons which mediate facial reflexes in the brain stem (Berardelli et al., 1985).

Surgical management Current medications for Meige syndrome are only partly efficacious and some patients are refractory to treatment. Botulinum toxin injection produces only temporary relief of blepharospasm, facial and oro­ mandibular dystonia, and cervical dystonia. There are several recent reports of bilateral pallidal deep brain stimulation (DBS) effectively controlling symptoms in medication refractory Meige syndrome (Muta et al., 2001; Vercueil et al., 2001; Bereznai et al., 2002; Capelle et al., 2003; Foote et al., 2005; Houser and Waltz, 2005; Opherk et al., 2006; Ostrem et al., 2007). Our experiences with 6 patients are in line with these previous reports.

Surgical Procedure of Bilateral Pallidal Deep Brain Stimulation After fixing the frame onto the patient, an MRI sequence is taken. Preoperative target localization is made either directly (image-based) or indirectly (coordinate-based). The point of direct targeting is to place the electrode in the posteroventral portion of the globus pallidus interna (GPi) with its trajectory at the dorsolateral border of the optic tract. The coordinates

593

for indirect targeting are 18–22 mm lateral to the inter­ commissural line, 2 mm anterior to the midpoint of the line and 4 mm below the line. To prevent side effects of continuous stimulation, the internal capsule must be positioned at least 4 mm far from the target posteriorly, and the optic tract 2 mm inferiorly (see Figure 47.2). Under local anesthesia, usual DBS procedures are performed using microelectrode recordings and micro­ stimulation to verify our safe target. In our practice, quadripolar DBS electrodes (model 3387, Medtronic Inc., Minneapolis, MN) are inserted into the target. After confirming the location of the electrodes and that there are no complications such as intracerebral hem­ orrhage using imaging (MRI or CT), an implantable pulse generator (IPG) Soletra, Model 7426 (Medtronic, Inc., Minneapolis, MN) is placed in the infraclavicu­ lar subcutaneous pocket. Postoperatively, the IPG is turned on for several days, activating each electrode to find the contact/s resulting in the least adverse effect.

Outcome and Complications There are only a few cases of Meige syndrome, either isolated or advanced, that have been treated with bilateral GPi DBS. The first report was from Vercueil and coworkers, involving patients with seg­ mental cranio-cervical dystonia. In this study there was a 66% improvement in the Burke–Fahn–Marsden (BFM) dystonia scale at 6 months follow-up (Vercueil et al., 2001). Capelle et al., in 2003, reported on the use of bilateral pallidal stimulation for blepharospasm, oromandibular dystonia and isolated Meige syn­ drome. These authors reported a 92% improvement of BFM scale of eye score, 75% improvement in the mouth score, and 33% improvement in speech and swallowing at 24 months after operation (Capelle et al., 2003). Foote and coworkers performed staged DBS for isolated Meige syndrome and suspected that bilat­ eral stimulation would be necessary for the long-term improvement of midline and axial symptoms (Foote et al., 2005). They reported good efficacy in 10 cases using bilateral GPi DBS (Table 47.3). Our personal exper­ ience with six cases that have been followed for more than 12 months is also good. In this experience, blephar­ ospasm and facial dystonia respond to treatment better than speech and swallowing symptoms (Figure 47.3). To date, there have been complications reported with bilateral GPi DBS for Meige syndrome, how­ ever, it is our belief that this zero report of compli­ cations is most probably due to the small number of cases in which it has been performed. We assume that there will be a similar complication rate related to this DBS procedure that has been reported for DBS

V. NEUROMODULATION FOR MOVEMENT DISORDERS

594

47.  Surgical management of hemifacial spasm and meige syndrome

(A)

(B)

(C)

Figure 47.2  Stereotactic targeting of the GPi. Getting indirect coordinates by using navigation system (A) and Gammaplan (B); getting direct coordinates by using Surgiplan system (C)

V. NEUROMODULATION FOR MOVEMENT DISORDERS



595

Conclusion

Table 47.3  Previous reports of GPi DBS for isolated or advanced Meige syndrome Study

Age/Sex

Type

F/u (mth)

Improvements

Vercueil et al., 2001

59/F

Meige syn.  torticollis  upper limb jerks

6

66% (BFM)

Bereznai et al., 2002

78/F

Meige syn.  antecollis

6

Not specified

Muta et al., 2001

61/F

Meige syn.  cervical dystonia  truncal dystonia

1

80% (BFM)

Capelle et al., 2003

60/F

Isolated Meige syn.

24

92%/75%/33% (e/m/s BFM)

Foote et al., 2005

47/M

Isolated Meige syn.

15

69% (UDRS)

Houser and Waltz, 2005

44/F

Isolated Meige syn.

6

75% (BFM), 85% (UDRS), 80% (GDS)

Opherk et al., 2006

65/M

Meige syn.  spasmodic torticollis

4

No data provided

Ostrem et al., 2007

52–70a M

Meige syn.  cervical dystonia (5)b

6

72% (BFM), 54% (TWSTRS)

Isolated Meige syn. (1)

b

F/u: follow-up, expressed in months; BFM: Burke–Fahn–Marsden Dystonia Rating Scale; e: eyes; m: mouth; s: speech and swallowing; UDRS: Unified Dystonia Rating Scale; GDS: Global Dystonia Scale; TWSTRS: Toronto Western Spasmodic Torticollis Rating Scale a Age range; bNumber of patients

9 8 7

Pre Post

P�0.021 P�0.008

P�0.003

6

25 P�0.049

Pre Post

P�0.008

20 15

5

P<0.080

4

10

3 2

5

1 0

0 (A)

Eye

Mouth

Ss

(B)

Severity

Disability

Pain

Figure 47.3  Improvement of mean score of BFMDRS (A) and TWSTRS (B) after bilateral pallidal stimulation for Meige syndrome in our six cases at 12 months after surgery. (A) Mean score of Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS); ss  speech and swallowing. (B)  Mean score of Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)

for other disorders. Some adverse effects that have been reported include worsening of handwriting, typ­ ing, balancing, and walking. But these adverse effects were mild and not evident on objective examination (Ostrem et al., 2007).

Conclusion Although the exact mechanism behind the thera­ peutic effects of bilateral pallidal DBS in Meige syn­ drome is not known, previous trials and our results with DBS have been promising. Further studies are

necessary to elucidate the mechanism and the longterm results of this treatment method.

References Bejjani, G.K. and Sekhar, L.N. (1997) Repositioning of the vertebral artery as treatment for neurovascular compression syndromes. Technical note. J. Neurosurg. 86: 728–32. Berardelli, A. et al. (1985) Pathophysiology of blepharospasm and oromandibular dystonia. Brain 108 (Pt 3): 593–608. Bereznai, B. et al. (2002) Chronic high-frequency globus pallidus internus stimulation in different types of dystonia: a clinical, video, and MRI report of six patients presenting with seg­ mental, cervical, and generalized dystonia. Mov. Disord. 17: 138–44.

V. NEUROMODULATION FOR MOVEMENT DISORDERS

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Capelle, H.H. et al. (2003) Bilateral pallidal stimulation for blepharospasm-oromandibular dystonia (Meige syndrome). Neurology 60: 2017–18. Chang, J.W. et al. (2001) Microvascular decompression of the facial nerve for hemifacial spasm in youth. Childs Nerv. Syst. 17: 309–12. Chang, J.W. et al. (2002) Role of postoperative magnetic resonance imaging after microvascular decompression of the facial nerve for the treatment of hemifacial spasm. Neurosurgery 50: 720–5, discussion 726. Esteban, A. and Molina-Negro, P. (1986) Primary hemifacial spasm: a neurophysiological study. J. Neurol. Neurosurg. Psychiatry 49: 58–63. Fabinyi, G.C. and Adams, C.B. (1978) Hemifacial spasm: treatment by posterior fossa surgery. J. Neurol. Neurosurg. Psychiatry 41: 829–33. Fairholm, D. et al. (1983) Hemifacial spasm: results of microvascular relocation. Can. J. Neurol. Sci. 10: 187–91. Ferguson, J.H. (1978) Hemifacial spasm and the facial nucleus. Ann. Neurol. 4: 97–103. Foote, K.D. et al. (2005) Staged deep brain stimulation for refrac­ tory craniofacial dystonia with blepharospasm: case report and physiology. Neurosurgery 56: E415; discussion E415. Fukushima, T. (1984) Results of posterior fossa microvascular decom­ pression in the management of hemifacial spasm. Facial Nerve Res. Japan 4: 9. Gardner, W.J. (1960) Five-year cure of hemifacial spasm. Report of a case. Cleve Clin. Q. 27: 219–21. Gardner, W.J. (1962) Concerning the mechanism of trigeminal neu­ ralgia and hemifacial spasm. J. Neurosurg. 19: 947–58. Hatem, J. et al. (2001) Intraoperative monitoring of facial EMG responses during microvascular decompression for hemifacial spasm. Prognostic value for long-term outcome: a study in a 33patient series. Br. J. Neurosurg. 15: 496–9. Houser, M. and Waltz, T. (2005) Meige syndrome and pallidal deep brain stimulation. Mov. Disord. 20: 1203–5. Ishimori, T. et al. (2003) Virtual endoscopic images by 3D FASE cis­ ternography for neurovascular compression. Magn. Reson. Med. Sci. 2: 145–9. Jankovic, J. and Ford, J. (1983) Blepharospasm and orofacial-cervical dystonia: clinical and pharmacological findings in 100 patients. Ann. Neurol. 13: 402–11. Jannetta, P.J. (1979) Microsurgery of cranial nerve cross-compression. Clin. Neurosurg. 26: 607–15. Jannetta, P.J. (1998) Typical or atypical hemifacial spasm. J. Neurosurg. 89: 346–7. Jannetta, P.J. et al. (1977) Etiology and definitive microsurgical treat­ ment of hemifacial spasm. Operative techniques and results in 47 patients. J. Neurosurg. 47: 321–8. Jho, H.D. and Jannetta, P.J. (1987) Hemifacial spasm in young people treated with microvascular decompression of the facial nerve. Neurosurgery 20: 767–70. Kobata, H. et al. (1995) Hemifacial spasm in childhood and adoles­ cence. Neurosurgery 36: 710–14. Laws, E.R., Jr. et al. (1986) Clip-grafts in microvascular decompres­ sion of the posterior fossa. Technical note. J. Neurosurg. 64: 679–81. Leclercq, T.A. et al. (1980) Retromastoid microsurgical approach to vascular compression of the eighth cranial nerve. Laryngoscope 90: 1011–17. Lovely, T.J. et al. (1998) Delayed facial weakness after microvascular decompression of cranial nerve VII. Surg. Neurol. 50: 449–52. Maroon, J.C. (1978) Hemifacial spasm. A vascular cause. Arch. Neurol. 35: 481–3. Meige, H. (1910) Les convulsions de la face: une forme clinique de convulsion faciale, bilaterale et mediane. Rev. Neurol. (Paris) 10: 437–43.

Menovsky, T. and van Overbeeke, J.J. (1999) On the mechanism of transient postoperative deficit of cranial nerves. Surg. Neurol. 51: 223–6. Moller, A.R. (1999) Vascular compression of cranial nerves: II: pathophysiology. Neurol. Res. 21: 439–43. Moller, A.R. and Jannetta, P.J. (1984) On the origin of synkinesis in hemifacial spasm: results of intracranial recordings. J. Neurosurg. 61: 569–76. Moller, A.R. and Jannetta, P.J. (1985) Microvascular decompression in hemifacial spasm: intraoperative electrophysiological obser­ vations. Neurosurgery 16: 612–18. Moller, A.R. and Jannetta, P.J. (1986a) Blink reflex in patients with hemifacial spasm. Observations during microvascular decom­ pression operations. J. Neurol. Sci. 72: 171–82. Moller, A.R. and Jannetta, P.J. (1986b) Physiological abnormalities in hemifacial spasm studied during microvascular decompression operations. Exp. Neurol. 93: 584–600. Muta, D. et al. (2001) Bilateral pallidal stimulation for idiopathic seg­ mental axial dystonia advanced from Meige syndrome refrac­ tory to bilateral thalamotomy. Mov. Disord. 16: 774–7. Neagoy, D.R. and Dohn, D.F. (1974) Hemifacial spasm secondary to vascular compression of the facial nerve. Cleve Clin. Q. 41: 205–14. Nielsen, V.K. (1984a) Pathophysiology of hemifacial spasm: I. Ephaptic transmission and ectopic excitation. Neurology 34: 418–26. Nielsen, V.K. (1984b) Pathophysiology of hemifacial spasm: II. Lateral spread of the supraorbital nerve reflex. Neurology 34: 427–31. Opherk, C. et al. (2006) Successful bilateral pallidal stimulation for Meige syndrome and spasmodic torticollis. Neurology 66: E14. Ostrem, J.L. et al. (2007) Pallidal deep brain stimulation in patients with cranial-cervical dystonia (Meige syndrome). Mov. Disord. 22: 1885–91. Paulson, G.W. (1972) Meige’s syndrome. Dyskinesia of the eyelids and facial muscles. Geriatrics 27: 69–73. Rawlinson, J.N. and Coakham, H.B. (1988) The treatment of hemifa­ cial spasm by sling retraction. Br. J. Neurosurg. 2: 173–8. Rhee, D.J. et al. (2006) Frequency and prognosis of delayed facial palsy after microvascular decompression for hemifacial spasm. Acta Neurochir. (Wien) 148: 839–43, discussion 843. Roth, G. et al. (1990) Cryptogenic hemifacial spasm. A neurophysi­ ological study. Electromyogr. Clin. Neurophysiol. 30: 361–70. Ryu, H. et al. (1998a) Atypical hemifacial spasm. Acta Neurochir. (Wien) 140: 1173–6. Ryu, H. et al. (1998b) Hemifacial spasm caused by vascular com­ pression of the distal portion of the facial nerve. Report of seven cases. J. Neurosurg. 88: 605–9. Ryu, H. et al. (1999) Neurovascular compression syndrome of the eighth cranial nerve. Can the site of compression explain the symptoms? Acta Neurochir. (Wien) 141: 495–501. Saito, S. et al. (1993) Abnormal response from the sternocleidomas­ toid muscle in patients with spasmodic torticollis: observations during microvascular decompression operations. Acta Neurochir. (Wien) 124: 92–8. Sanders, D.B. (1989) Ephaptic transmission in hemifacial spasm: a single-fiber EMG study. Muscle Nerve 12: 690–4. Satoh, T. et al. (2007) Fusion imaging of three-dimensional magnetic resonance cisternograms and angiograms for the assessment of microvascular decompression in patients with hemifacial spasms. J. Neurosurg. 106: 82–9. Scheller, C. et al. (2004) Delayed facial nerve paresis following acoustic neuroma resection and postoperative vasoactive treat­ ment. Zentralbl. Neurochir. 65: 103–7. Schultze, F. (1875) Linksseitiger Facialis Krampf in Folge eines Aneurysma der Arteria vertebralis sinistra. Virchows Arch. 65: 385.

V. NEUROMODULATION FOR MOVEMENT DISORDERS

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Sindou, M.P. (2005) Microvascular decompression for primary hemi­ facial spasm. Importance of intraoperative neurophysiological monitoring. Acta Neurochir. (Wien) 147: 1019–26, discussion 1026. Tan, E.K. and Chan, L.L. (2006) Young onset hemifacial spasm. Acta Neurol. Scand. 114: 59–62. Tarnaris, A. et al. (2007) A comparison of magnetic resonance angi­ ography and constructive interference in steady state-threedimensional Fourier transformation magnetic resonance imaging in patients with hemifacial spasm. Br. J. Neurosurg. 21: 375–81. Tokimura, H. et al. (1990) Intraoperative ABR monitoring during cerebello-pontine angle surgery. No Shinkei Geka 18: 1023–7. Valls-Sole, J. and Tolosa, E.S. (1989) Blink reflex excitability cycle in hemifacial spasm. Neurology 39: 1061–6.

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Vercueil, L. et al. (2001) Deep brain stimulation in the treatment of severe dystonia. J. Neurol. 248: 695–700. Wilkins, R.H. (1981) Hemifacial spasm: treatment by microvascular decompression of the facial nerve at the pons. South Med J. 74: 1471–4. Wilson, C.B. et al. (1980) Microsurgical vascular decompression for trigeminal neuralgia and hemifacial spasm. West J. Med. 132: 481–7. Yeh, H.S. et al. (1981) Microsurgical treatment of intractable hemi­ facial spasm. Neurosurgery 9: 383–6.

V. NEUROMODULATION FOR MOVEMENT DISORDERS

C H A P T E R

48

Deep Brain Stimulation of the Medial Thalamus for Movement Disorders: The Role of the Centromedian–Parafascicular Complex Paolo Mazzone and Eugenio Scarnati o u tline Introduction

599

Anatomy of the CM–Pf Complex The Centromedian Nucleus (CM) Afferent Connection Fibers of the CM Efferent Connection Fibers of the CM The Parafascicular Nucleus (Pf) Afferent and Efferent Connection of the Pf

600 601 601 602 602 602

Experience Derived from Functional Neurosurgery The CM–Pf Complex and Movement   Disorders The CM–Pf DBS in the Treatment of   Hyperkinetic Movements

603 603 604

Introduction

604 605

Discussion A New Look Towards the PPTg/CM–Pf   Projection and Extrapyramidal Disorders

611

Summary and Perspectives

612

References

613

605 608 608 609 609

612

early onset of the disease, patients with longer disease duration, patients with more severe disease, and patients who take higher levodopa (L-DOPA) doses. In the past decade, deep brain stimulation (DBS) has become an established therapy for PD patients whose response to drug therapy is poor or unsatisfactory. Chronic DBS has the advantage of being adjustable according to the patient’s needs and is reversible. Conventionally, the first target of choice for DBS for PD is the subthalamic nucleus (STN). The practice parameters of the American Academy of Neurology (AAN)

Parkinson’s disease (PD) is a neurodegenerative disorder, clinically characterized by tremor, bradykinesia, and rigidity, that is progressive in nature. Dopaminergic therapy is effective, but, over years, becomes complicated by motor fluctuations (“on” and “off” states) and drug-induced involuntary movements, including chorea and dystonia. These motor complications, which can seriously impair quality of life (QOL) for patients and cause disability, are more common in patients with

Neuromodulation

Data Interpretations Patient Selection Surgical Planning and 3D Stereotactic   Anatomy Neurophysiological Investigations Patient Evaluation Data Analysis Results

599

2009 Elsevier Ltd. © 2008,

600

48.  deep brain stimulation of the medial thalamus for movement disorders

(Pahwa et al., 2006) state that “DBS of the STN may be considered as a treatment option in PD patients to improve motor function and to reduce motor fluctuations, dyskinesia, and medication usage.” Recently, some authors have stressed the importance of adapting DBS to the specific symptoms of each patient by using alternative targets (Mazzone, 2003; Mazzone et al., 1999, 2004, 2005a, 2005b, 2006, 2007a) to the STN. In this context, we have rediscovered previously forgotten targets for PD such as the medial thalamus, and have introduced a potential new target, the pedunculopontine nucleus (PPTg) (Mazzone, Lozano et al., 2005; Mazzone, Stanzione et al., 2005; Stefani et al., 2007). Among the “forgotten” (Krauss et al., 2001, 2002) sites of stimulation, of particular relevance is the centromedian–parafascicular (CM–Pf) complex. These thalamic nuclei are a classic target for the stereo­tactic treatment of chronic refractory neuropathic pain (Andy, 1980; Krauss et al., 2001), however, CM–Pf complex DBS has also been used for epilepsy (Velasco et al., 1995, 2007a, 2007b, 2007c) and for some vegetative states (Tsubokawa et al., 1990; Yamamoto et al., 2003, 2005). Another relevant issue for future development of DBS for PD and other movement disorders that we will discuss in this chapter is the use of multiple implants. The fact that lesions of the thalamic centromedian nucleus (CM) are usually associated with lesions of other targets is the “lesional analogy” to the use of multiple target sites of DBS for PD and other movement disorders (Adams and Rutkin, 1965; Mazzone, 2003; Mazzone et al., 2004, 2005b, 2007a). We have recently implanted DBS electrodes into the CM–Pf complex of patients with PD who were also implanted in other targets such as the STN or the globus pallidus internus (GPi). In this chapter, we will review the anatomic connectivity of the CM–Pf complex, its role in the pathophysiology of movement disorders, and describe the relationship between anatomic stereotactic planning, and surgical and clinical outcome. A stereotactic 3D reconstruction of the entire thalamus, obtained for surgical planning purposes, is shown in Figure 48.1.

Anatomy of the CM–Pf complex Burdach, in 1912, defined the medial region of the thalamus as the “thalamus internus” (Hassler, 1959). Macroscopically, the dorso-medial thalamus is surrounded by the lamella medialis on its anterior, lateral, and inferior boundaries (Le Gros Clark, 1932; Jones, 1985). Its length is 18–20 mm according to the distance between the anterior third of the massa intermedia and the habenular commissural plane. The thalamic central

Figure 48.1  3D representation of the thalamus, based on sagittal slides of the Schaltenbrand and Wahren atlas. The reconstruction was done by means of the 3P-Maranello 3D stereotactic planning system (Mazzone, 2001, 2006; Mazzone et al., 2007b)

gray represents its medial boundary. The medial thalamus constitutes the wall of the IIIrd ventricle, and it extends superiorly above the plane of the stria medullaris thalami. Because of its extension and size, the medial thalamus is commonly defined as the “nuclear medial region,” or “medial territorium” (Le Gros Clark, 1932; Hassler, 1959; Jones, 1985) and its main efferent projections are directed to prefrontal cortex (Glees and Wall, 1946). The medial thalamus can be divided on the basis of its histological structure into a medial region (“the pars magnocellularis”) and a lateral region (“the pars parvic­ellularis”). It can be further subdivided into the following nuclei: the nucleus medialis fibrosus, the nucleus medialis fasciculosus, the nucleus medialis fasciculosus superior, and the nucleus medialis caudalis (internal, external, paralamellaris). A stereotactic 3D reconstruction of the medial thalamus is shown in Figure 48.2. Three thalamic regions are generally considered to be “independent” from the specific thalamocortical connections (Simma, 1951; Starzl et al., 1951), namely: 1. the thalamic central gray, or midline nuclei (immediately below the ependyma, surrounding the massa intermedia) 2. the habenular ganglion, which is considered as a part of the thalamus by Schaltenbrand but often not included in the thalamus by other authors 3. the nuclei surrounding the medial thalamus, commonly (but inappropriately) termed intralaminar nuclei (IL) or lamella medialis. The IL nuclei are the interlaminaris, the centromedian, the parafascicularis, the limitans, the cucullaris, the commissuralis, the fasciculosus (at the entrance of

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Figure 48.2  3D representation of dorso-median nuclei, surrounded by the nuclei of lamella medialis. The reconstruction was done by means of the 3P-Maranello 3D stereotactic planning system (Mazzone, 2001, 2006; Mazzone et al., 2007b)

the inferior thalamic peduncle), and the parataenialis (below the stria medullaris). On the basis of anatomical and functional data, the midline and the IL nuclei seem to be involved in a variety of limbic motor, cognitive, and sensorimotor processes (Van der Werf et al., 2002). The main focus of this chapter will be on the centromedian and parafascicular nuclei.

The Centromedian Nucleus (CM) This nucleus is indicated in the literature with different terminologies, such as nucleus centralis thalami, center median of Luys (1865), nucleus centrum medianum, and centre median. It coincides with the nucleus initially defined as “mb” by Vogt and Vogt (1941) and appears to be particularly developed in humans and anthropomorphic primates. Le Gros Clark (1932) proposed that it should be consider apart from the other components of the intralaminar system. In humans, this nucleus represents the largest neuronal aggregate within the medial lamella system. The CM can be further subdivided into a ventral–caudal subregion, represented by the pars parvocellularis (Ce.pc), and a dorso-rostral portion, represented by the pars magnocellularis (Ce.mc). These two subregions give different projections to the basal ganglia, the former to the putamen and the latter to the caudate nucleus. Histologically, the pars parvocellularis is a dense network of thick fibers, interspersed with small, darkstaining bundles. The lamella medialis accessoria, in the dorsal pars of the nucleus, is an aggregate of these fibers, which run in a dorsolateral direction. The

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neurons with light nuclei are of medium size and contain a moderate amount of Nissl substance. In the pars parvocellularis there is a higher concentration of glial cells in comparison to nerve cells. The interneurons, which are not richly branched, contain diffusely dark nuclear inclusions which are delimited by thin membranes, interspersed within the nucleus. The nerve cells are grossly triangular, whereas in the pars magnocellularis they are pear- or cube-shaped with an abundant content of Nissl substance. The fiber network in the pars magnocellularis is dense, with single thick fibers running in a dorsolateral direction. The cellular bodies are arranged in a dorsolateral direction, that is, parallel to fibers. The pars parvocellularis is lighter and contains an even lighter region, which, however, shares the same cytoarchitecture with the rest of the nucleus, and therefore it cannot be considered as an individual nucleus. Afferent Connection Fibers of the CM The medial lemniscus divides, in the rostral part of mesencephalon, into a lateral and a medial component. The medial component enters the thalamus through the ventral pars of the CM. Therefore, the medial lemniscus forms a sort of capsule which covers the ventral and caudal parts of the CM. Degeneration studies and thalamic potentials evoked by cutaneous stimulation demonstrate that these fibers run through the CM and terminate into the nucleus ventralis, which is part of the thalamic trigeminal representation. The CM, according to results of animal studies (Albe-Fessard and Kruger, 1962), plays a major role in the perception of pain, as also clinically confirmed by the fact that pain relief is obtained following its coagulation (Sugita et al., 1972; Sano, 1977). Many authors (McLardy, 1948; Jones and Leavitt, 1974; Matsumoto et al., 2001) have stated that fibers running in the brachium conjunctivum reach the CM. In humans, these fibers originate in the nucleus emboliformis of the cerebellum. Other afferent fibers arise from the reticular formation. Moreover, fibers from the Forel’s tegmental fascicle (FFO) reach the CM caudally and ventrally, and, in part, run through its ventral region. These FFO fibers represent the rostral pars of the dorsolateral tegmental fasciculum, which runs in the midbrain dorsally with respect to the tegmental fasciculum. This structure represents the secondary dorsal trigeminal tegmental pathway of Wallemberg, which is considered to be the only ipsilateral trigeminal pathway. Many fibers innervating the CM nucleus arise from the ipsilateral vestibular nuclei. In the cat, stimulation of these pathways induces horizontal ipsilateral head turning, which is in agreement with their vestibular nature. The fibers forming these pathways run through the

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CM, and terminate into the internal pars of the nucleus ventralis intermediaris (Vim). This particular pathway was considered to form the ascending pars of the ipsilateral brachium conjunctivum by Carrea and Mettler (1954). Fibers that directly end into the to CM originate from the anterior midbrain reticular formation (reticulothalamic pathway); these fibers are involved in the longdelayed electrophysiological responses which can be recorded in the CM following stimulation of peripheral sense organs. These responses are very similar to those recorded following stimulation of midbrain or pontine reticular formation. Efferent Connection Fibers of the CM Efferent fibers form dark bundles that emerge from the lateral portion of the CM nucleus (Monakow, 1895; Le Gros Clark, 1932; Starzl et al., 1951; Jones and Leavitt, 1974). Afferents from the pars parvicellularis run caudally and ventrally in respect to those originating from the pars magnocellularis, which leave the nucleus in the dorso-rostral tip and cross the Vim, and the ventralis oralis posterior (Vop), until reaching the internal capsule. Once reaching the internal capsule, they cannot be followed any further. It is known that they do not reach the cortex. In fact, CM neurons do not degenerate after decortication or hemispheric deafferentation. Vogt and Vogt (1941) demonstrated that the majority (two-thirds) of output fibers from the CM reach the striatum. In cats, electron microscopic examination after coagulation of the pars parvicellularis of CM has shown synaptic degeneration in the putamen. Likely these projections are cholinergic, because the acetylcholinesterase activity in the striatum decreased after coagulation of the CM. The pars magnocellularis projects to the caudate nucleus whereas the pars parvicellularis sends fibers to the putamen. According to the studies of Percheron and coworkers in macaques, neurons located in the CM project to the sensorimotor territories of the striatum (Fenelon et al., 1991). Moreover, through the thalamic circuitry the putamen and the caudate receive indirect projections from the cerebellum and the reticular formation.

The Parafascicular Nucleus (Pf) The term parafascicular nucleus (Pf) was originally proposed by D’Hollander (1922) because of its relationship to the Meynert’s retroflexus fascicle. The Pf is the medial projection of the CM and no clear separation of their neurons and fibers exists in mammals. The difference is even more difficult to observe when examining the thalamus of lower mammals. Consequently, it

has been suggested that a certain separation of the two structures is specific only in humans. The shape of the Pf is trapezoid, with a large ventral base. Its anatomic boundaries are as follows: rostrally, the intralaminar nucleus; ventrally, the zona incerta; caudally, the pretectal region, the arcuate nucleus, and the nucleus limitans; medially, the nucleus endimalis. Histologically, the Pf is distinguishable from the CM because it contains a lower number of fibers. The density of fibers increases in the rostral portion towards the lamella medialis. Medially, it is hardly distinguishable from the medial central gray. The Pf neurons are similar to the neurons of the pars magnocellularis of the CM, though they are darker and a tear-drop shape. Nissl substance is present in coarse particles, which are distributed in the dendrites. The nuclear membrane and the nucleolus are dark and the nucleolus is vacuolized. The Pf contains many interneurons, with an indistinct nucleus.

Afferent and Efferent Connection of the Pf The Pf receives afferent projections from the midbrain reticular formation which originate from the vestibular nuclei, particularly from the secondary vestibular pathways (Glees and Wall, 1946; Simma, 1951). Efferent Pf fibers run rostrally within the lamella medialis and enter the inferior thalamic peduncle, through which they leave the thalamus. As the CM, the Pf does not degenerate after decortication. According to Vogt and Vogt (1941) the efferent fibers of the Pf run directly to the medial portion of the caudate and the putamen. Brockhouse considered these fibers to be involved in the “fundus striati.” Experimental surgical coagulation of the Pf demonstrated degeneration of synapses within the nucleus accumbens septi and in the fundus striati. This latter structure, though containing the same neurotransmitters present in the caudate and in the putamen, contains more noradrenaline and GABA, and a reduced amount of dopamine (Castle et al., 2005). In the macaque, neurons located in the PF nucleus appeared to selectively innervate the associative territories of the striatum (Fenelon et al., 1991). These latter results, obtained with the use of selective neuronal tracing techniques, deserve greater attention than those obtained with electrocoagulative methods since the latter, in addition to destruction of nerve cells, also cause degeneration of fibers “en passage” within the coagulated nucleus, thus causing generalized degenerative processes in structures that otherwise would be presumed to be reached by specific fibers alone. A 3D representation of the CM–Pf complex, created for surgical planning, is given in Figure 48.3.

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Figure 48.3  3D representation of the CM and Pf nuclei, in right and left sagittal views, and in axonometric perspective. The reconstruction was done by means of the 3P-Maranello 3D stereotactic planning system (Mazzone, 2001, 2006; Mazzone et al., 2007b). mc  pars magnocellularis; pc  pars parvocellularis

Experience derived from functional neurosurgery The first report concerning the functional neurosurgery of thalamic nuclei was published by Hécaen et al. (1949), who performed a successful medial thalamotomy involving the CM–Pf complex for the treatment of intractable pain in humans two years after Spiegel and Wycis had introduced the functional stereotactic surgery technique. This early success was followed by a large number of medial thalamotomies aimed at alleviating intractable nociceptive and neuropathic pain (Weigel and Krauss, 2004). Because of the confusion present in some early reports regarding the nomenclature of thalamic nuclei (medial thalamus proper or intralaminar nuclei), and because there were relatively poor clinical definitions of the symptoms (neuropathic pain or nociceptive pain), the interpretation of these early results is questionable. The first medial thalamic radiosurgical lesions were performed by Leksell and coworkers in 1972 (Leksell et al., 1972) while Richardson (Richardson, 1983, 1995) presented the first results of his treatment of pain by using DBS. It is important to remember that, in the pre

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CT and MRI era, electrode positioning could only be performed visually. The target chosen by Richardson was the periventricular gray, but post-mortem studies revealed that the medial Pf was the optimum target for pain relief. Recently, in a paper by Caparros Lefebvre, the improvement of L-DOPA-induced dyskinesias and/ or tremor observed following thalamic DBS appeared to depend on a slight variation of the electrode placement which could differently influence stimulation of the CM-Pf complex (Caparros-Lefebvre et al., 1999). After the pioneering experience of Cooper et al. (1965), in 1978 DBS of the CM was applied with the aim of controlling epileptic seizures, in particular tonic–clonic seizures and atypical absences (Velasco et al., 1995, 2007a, 2007b, 2007c). DBS of the CM was attempted on the basis of its spatial and topographical features, and also because the CM was considered to be a relay in the non-specific reticulo-thalamo-cortical pathway (Albe-Fessard and Besson, 1973) (“centro­ encephalic,” Penfield and Boldrey, 1937) that is involved in the generalization of seizures. More recently, using in vitro and in vivo techniques, it has been shown that the nucleus reticularis plays a major role in the propagation of epileptic discharges. Although, at the time, there was no animal evidence, Arduini and Lairy-Bounes (1951) showed that stimulation of the midbrain reticular formation could inhibit strychnine-dependent thalamic spikes. Low-frequency stimulation of the CM was reported to induce EEG synchronization, while highfrequency stimulation had an opposite, desynchronizing, effect (Velasco et al., 1995, 2007a, 2007b, 2007c).

The CM–Pf Complex and Movement Disorders On the basis of experimental data (Benabid et al., 1983; Duncan et al., 1998), we have considered the CM–Pf complex as a candidate target for patients affected by movement disorders. Indeed, if, on the one hand, it is know that medial thalamotomy is effective in controlling movement disorders (Andy, 1980), on the other hand , there is evidence, derived from post-mortem studies and consequent re-evaluation of a series of Vimimplanted patients, that slight movement of the stimulating electrode towards the CM–Pf complex leads to improved efficacy. To explain these results, there are two alternative hypotheses: (1) the salient effect on dyskinesias and tremor might depend on the spreading of currents to the Vim and ventralis oralis (Vo) nuclei; and (2) the benefits observed might also be a consequence of a direct stimulation of the CM–Pf complex. Anatomic and physiologic data support the latter hypothesis since stimulation of the CM–Pf complex could in turn affect

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the GPi through the Nauta–Mehler circuit, the second largest efferent/afferent pathway connecting the CM–Pf complex and the GPi , which is also known to be involved in levodopa dyskinesias as its inactivation suppresses the levodopa-induced abnormal movements. Moreover, stimulation of the CM–Pf complex only improves choreic dyskinesias whereas off-period dystonias are improved by thalamic stimulation. This result is quite different from what it is observed in simultan­ eous Vim  Vo lesions. This differential effect is a strong argument supporting the segregation of pallidal pathways involved in either choreic or dystonic dyskinesias inside the thalamus. Electrophysiological studies in animals and humans do not allow to fully understand the pathogenesis of tremor. Some authors (McLardy, 1948; Albe-Fessard and Kruger, 1962) have described rhythmic activity in thalamic neurons, particularly in the Vim, that is synchronous with tremor. There is also evidence supporting a major role of the basal ganglia in the generation of tremor likely due to an abnormally synchronized oscillatory activity at multiple levels of the basal gangliathalamo-cortical loop (Deuschl et al., 2000; Magnin et al., 2000; Bergman and Deuschl, 2002; Hammond et al., 2007). Moreover, suppression of tremor through stimulation of the Vim or by treatment with levodopa results in a reduction of regional cerebral blood flow, not only in the premotor and motor cortex but also in the striatum and in the cerebellar deep nuclei (Duncan et al., 1998). Recently, some authors have suggested that the cholinergic pathway that emerges from the pedunculopontine nucleus (PPTg) and projects to the parafascicular region of the CM–Pf complex might be involved in motor processes, and, in particular, in the genesis of tremor. Therefore, it might be hypothesized that anticholinergic drugs might act at this level, rather than at intrastriatal sites. Further data have shown that the CM–Pf exerts a powerful control on the basal ganglia through its glutamatergic excitatory projections to both the STN and the GPi (Féger, 1977; Féger et al., 1977). The CM–Pf complex also projects to the striatum and the cerebral cortex. Different studies suggest that the CM–Pf complex and the Vo are involved in motor functions, as several pallidal axons, ending in the ventrolateral region, have collateral branches that reach the CM–Pf (Féger et al., 1977; Guillazo-Blanch et al., 1999). From the experience with DBS, it is commonly agreed (however, not always demonstrated) that the position of the DBS electrode is strongly related to its therapeutic effects (and vice versa). Thus, it is believed that there is a strong spatial-functional relationship within brain structures, particularly within the basal ganglia and thalamus. Patients experiencing improvement in both tremor and levodopa-induced dyskinesias are supposed

to be stimulated in the CM–Pf complex (or at least at the level of afferents reaching at the same time the CM–Pf complex afferents and the Vim afferents). As a result, we believe that there is enough evidence to consider the CM–Pf complex as a potential new target for DBS and this belief is strongly supported by clinical experience and observation.

The CM–Pf DBS in the Treatment of Hyperkinetic Movements The CM–Pf complex may play a key role in alleviating L-DOPA-induced involuntary movements. In particular, peak dose dyskinesias that follow standardized, 200 mg therapy, L-DOPA are modulated by CM–Pf DBS. In a study by Krauss, 12 patients were implanted with a DBS electrode into the medial thalamus to optimize drug-insensitive control of pain. In 3 out of the 12 patients, manifesting co-morbidity with movement disorders, high-frequency stimulation dramatically affected coincident involuntary movements. In one woman choreoathetosic movements of her right foot ceased, whereas in a 72-year-old man a sustained reduction in his stump dyskinesias was observed. Data Interpretations What is the mechanism that underlies this small but consistent effect of CM–Pf DBS? We primarily hypothesize that DBS, delivered into the CM–Pf, affects thalamostriatal pathway and, in turn, striatopallidal projections. Since the early 1990s, the CM output to the sensorimotor territories of the striatum and the widespread output of the Pf within the matrix compartment have been well described by utilizing anterograde axonal tracers. As emphasized by Kimura (2004), CM–Pf output fibers reaching the putamen belong to reverberant circuits (Pf–caudate–GPi–Pf and CM–putamen–GPi–CM), thus defining an intra-basal ganglia loop, parallel to the well-known corticostriatal–STN– GPi. Therefore, CM–Pf output fibers may affect, consistently with a function of selection gating, the execution (or the dysfunction) of movement controlled by the corticostriatal–nigral pathways. By establishing asymmetric synapses with dendrites of medium-sized spiny cells, ipsilateral fugal axons may re-shape the input/ output ratio of corticostriatal projections over dendritic spines, where the interaction between dopamine and glutamate takes place and have a clinical relevance. In addition, neurons of the CM–Pf complex supply striatal neurons with information concerning behaviorally significant sensory events that, in turn, can activate conditional responses of striatal neurons in combination with

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dopamine-mediated nigrostriatal inputs. The CM–Pf complex, indeed, may conveys sensory information to the striatum, thus influencing the responsiveness of striatal neurons to salient stimuli during the preparation and execution of rewarded sensorimotor or attentive tasks. Thus, the possibility to remodulate the glutamatergic outputs to the striatal targets according to exogenously administered L-DOPA may be of utmost importance for the functioning of the CM–Pf complex. In such a way not only the occurrence of dopaminemediated dyskinesias may be reduced, but also their duration, quality, and severity. Patient Selection In our series, targeting the CM–Pf complex for DBS, patients were selected according to the following criteria: diagnosis of Parkinson’s disease responding to L-DOPA l age less than 65 years l no regard to gender l extremely painful symptoms at onset and during the course of the disease l disease of duration less than 20 years l absence of any psychiatric disorder l presence of freezing of gait, dyskinesias, and tremor. l

On the basis of these above criteria, 9 patients, 6 men and 3 women, with a mean age of 56.1  8.3 years (range: 51–64), a disease duration of 12.5  8.4 years (range: 8–17), and a mean L-DOPA daily intake of 890  195 mg (range: 600–1200) were enrolled into the study. Seven patients received bilateral implantation into the CM–Pf complex plus bilateral implantation into the GPi (because of the prevalence of dyskinesias), whereas two patients were implanted into the CM–Pf complex plus bilateral STN (because of the prevalence of tremor). The first three patients implanted received their leads into the CM of one side (right hemisphere  1 patient; left hemisphere  2 patients) and leads into the Pf nucleus of the contralateral side (left hemisphere  1 patient; right hemisphere  2 patients). The main purpose of these early procedures was to identify, in each of the patients, the most effective target. After this preliminary experience, all patients were bilaterally implanted into the Pf nucleus. Surgical Planning and 3D Stereotactic Anatomy To reach targets within the thalamus, in particular the CM–Pf nuclei, it was necessary to adjust our initial

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classic planning procedure. This procedure, based on non-telemetric ventriculography with intraventricular contrast injection and overlapping of individualized 2D sections of the Schaltenbrand and Wahren atlas, was replaced by informatic ventriculography, performed through stereotactic angio-CT scans (axial planes) superimposed with individualized 2D atlas slides fitted on the basis of clearly detectable borders of the CA–CP plane. The 3D reconstruction of the thalamic nuclei, in particular the CM–Pf complex, was made utilizing the sagittal 2D slides provided by the atlas (Schaltenbrand and Wahren, 1977) (Medico Cad 2D and 3D Planning System, 3P Maranello sterotactic system, CLS–Srl, Forlì, Italy). This novel tridimensional modeling was included into the 3D planning system, enhancing the precision of the presurgical planning. This tool allowed us to produce a model of every single thalamic nucleus and to directly verify, within a 3D model, the spatial relationships between leads and targets. This model also could be fitted onto anatomical landmarks measurements made for each individual patient. The 3D planning also made it possible to overlap the 2D sections obtained from the atlas to the 3D reconstruction (Figure 48.4). We added a Multi Planar Reconstruction (MPR) of the CT scan to this procedure. In such a way it was possible to choose the single axial CT slide on which the computation of the x, y, and z coordinates should be performed (Fast TC, 3P Maranello sterotactic system, CLS–Srl, Forlì, Italy). The values for the x, y, and z coordinates were then systematically compared with those obtained from informatic ventriculography, in order to verify any correspondence or difference in coordinates. For the CM: y was at 3–5 mm (2/12) anterior to the posterior commissure (PC), x was at 8–10 mm lateral to the commissural line, and z was at AC–PC. For the Pf, y was at 3–5 mm (2/12) anterior to the PC, x was at 6–6.5 mm lateral to the commissural line, and z was at 2/3 mm with respect to the AC–PC line. The trajectory from the outside to inside was angled at about 20 degrees, and the trajectory from forwards to backwards was about 12/15 degrees, extraventricularly. The macroelectrode that we used for the IL thalamic complex was the Medtronic, 3389 electrode array with four platinum–iridium cylindrical electrodes (1.27 mm diameter and 1.5 mm length) and a center-to-center separation of 2 mm (Medtronic Inc., Minneapolis, MN). Micro-recordings with tungsten microelectrodes were occasionally performed since most patients were under general anesthesia. In all implanted patients somatosensory evoked potentials (SSEPs) were recorded (Figure 48.5). Fifteen to 30 days following surgery, we implanted a double Kinetra pulse generator (Medtronic, Inc., Minneapolis, MN) into the infraclavicular region.

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(A)

(B)

(C)

(D)

Figure 48.4  3D planning. (A) 3D reconstruction of the bilateral CM–Pf complex, with representation of the leads trajectories, respectively reaching the CM (on the right side) and the Pf (on the left side). (B) targeting of the Pf nucleus, with overlapped 2D sagittal slide taken from the Schaltembrand atlas (sl 6.5). (C) Targeting of the Pf nucleus, with superimposed 2D slide from the Schaltembrand atlas in sagittal and coronal projection (in blue). The electrode (in red) and the CM (pars parvicellularis, in green) are visible. (D) Targeting of the Pf nucleus; the electrode (in red) and the axonometric view of the 3D CM–Pf complex are visible, together with the 2D slide from the Schaltembrand atlas in sagittal and coronal (in blue) projections

Figure 48.5  Median somatosensory evoked potentials obtained from the lead contact inserted in the CM and in the Pf. MRI in postsurgical controls was performed in order to compare lead position and recording sites. On left and right sides of the MR imaging (middle), SSEP traces are shown

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A relevant matter in the technological evolution of the targeting procedure was the implementation of 3D cerebral angiography, reconstructed from the stereotactic angio-CT scan and included into the 3D planning system. The angiogram is not influenced by screw artifacts (carbon tips) and allows evaluation of the risk of conflict between leads and vessels (Figure 48.6).

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Also, after our initial experience with this procedure, we modified the instrumentation used. In our early implantations, we used the classical 3P Maranello stereotactic apparatus, which has an autocarrying hemiarch and a robotic microdrive with multiple independent tracks, placed on the arch system and controlled via an infra-red remote control device. In later implantations,

Figure 48.6  Pre-surgical planning: the 3D angiography (lateral view; in red) allowed evaluation of the risk of conflict between the leads and the brain vessels. The lower panel shows an enlargement of the angiographic planning: 3D representation of the target, the lead and, in background, the axial CT scan slide on which the targeting was performed

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we utilized a skull-applied low profile, multiple microdrive system without a hemiarch or, in very recent procedures, without any frame at all (Mazzone, 2001, 2006; Mazzone et al., 2007b) (Figure 48.7). Neurophysiological Investigations The utilization of deep anesthesia in 14 out of 18 surgery sessions did permit consistent investigations of the firing pattern of extracellularly recorded CM–Pf neurons. Moreover, the neuronal activity recorded did not prove useful to define the target boundaries. However, previous investigations did describe a mixed population composed of tonic and bursting units in the CM–Pf complex (the latter less frequent than in classical thalamic motor nuclei). Magnin and coauthors (2000), in a pioneering work , showed the coexistence, within the human IL complex of (1) rhythmic classical bursts, sustained by low-threshold calcium spikes, but not synchronous with rest tremor, and (2) tremor-locked units detectable in the center of the IL complex, “precisely in phase with EMG-recorded tremor.” Thus, we can postulate that the powerful effects of DBS on tremor, as described in this chapter, might depend upon a direct modulation of these pacemaker thalamic tremor units. However, the effectiveness of CM–Pf DBS on the contralateral tremor may also be due to other mechanisms. At first, axons branch and send axon collaterals to specific cortical regions that might provide functional modulation of cortico-fugal excitatory outputs that affect tremor. Alternatively, both the CM and Pf nuclei might modulate extensive projections directed to discrete areas of the lenticular nuclei. In this regard it is noteworthy that Pf neurons innervate cholinergic interneurons, the dendritic shafts of putamen projection cells and,

intriguingly, the head of the caudate. These pathways underlie the hypothesized “associative”‘ role of IL in PD patients. Within this context, the Pf-mediated control of tremor could, at least partially, depend upon a peculiar effect on the endogenous chronic integration of sensory and limbic circuits impinging on the motor effectors. This hypothesis is corroborated by the observation that intraoperative switch ON of CM–Pf DBS (when anecdotally tested in one out of four surgery session and in one implanted patient) provided small or negligible impact on tremor, at odds with the consistent effect that is detectable with chronic DBS. Finally, we should also consider the possibility that the CM–Pf DBS affects other thalamic nuclei (such as the ventralis oralis anterior (Voa) and the Vim, whose roles in influencing tremor have been unequivocally established (see Benabid et al., 1983; Caparros-Lefebre et al., 1999). Yet we believe that our careful surgical targeting – and, in particular, our specific coordinates (see discussion of planning above) – minimize the spreading of the electrical field. Patient Evaluation After surgery and post-surgical neuroradiological (MRI) imaging for appropriate electrode positioning, DBS was activated (switched on) for 24 h/day into one single target – into the GPi, the STN, or the CM–Pf. Sometimes the DBS was switched on simultaneously for both implantations. At the same time, PD medication therapy was progressively reduced until optimal stimulation parameters were achieved. The main side effects of stimulation that we have seen included paresthesiae, facial contractions or dystonia, and, in order to avoid these unwanted side effects, the intensity of the stimulus was individually adjusted. The stimulation parameters for the CM or the Pf that we used were as follows: unipolar cathodal stimulation using the “0” contact as negative and the case as positive; in every patient, this configuration of stimulation was subject to change according to clinical improvement l frequency: 185 Hz rate l pulse width: 90 sec l amplitude: 1.5–2.5 V amplitude

l

Figure 48.7  Intraoperative picture showing the multiplemicrodrive, archless, skull-applied system

In a tremor study in two patients, we used bipolar stimulation with 2 and 3 V amplitudes respectively (Peppe et al., 2001, 2004). To matrix the clinical response to our procedure, we used the Unified Parkinson’s Disease Rating Scale Section III (UPDRS-III) and the Abnormal Involuntary Movements (AIM) Scale. To make these evaluations comparable, these scales should be administered in the morning, at least one month

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EXPERIENCE DERIVED FROM FUNCTIONAL NEUROSURGERY

after tapering the dopaminergic therapy to the minimal efficacious level, and following an overnight drug suspension. Evaluation in the condition of DBS-OFF was always performed. The stimulator was switched off in the evening (21:00h) and kept off during the entire night. In the following morning, a drug-response test was performed as follows: L-DOPA at a dose of 200 mg was administered followed by clinical scoring (including the evaluation of freezing). Thereafter an evaluation was repeated every 60 minutes. After this DBS-OFF test was performed, a DBS-ON test was done. One hour after the end of the DBS-OFF test, the stimulus was switched on in the GPi (or the STN), or in the CM–Pf, or in both targets, until the following morning. Again, clinical measurements were performed before and after a single L-DOPA dose of 200 mg. In order to identify the optimal stimulation and effect of L-DOPA on each stimulus modality (DBS-ON/drug ON), the procedures were repeated, in a random order. UPDRS mean values, before and after surgery, were measured in the following conditions: worst OFF and best ON (under L-DOPA), before and after bilateral implantation; best ON under IL–STIM (no drug); best ON under GPi–STIM (no drug); best ON stimulation of both targets; the latter plus L-DOPA. As for any surgical procedure, all patients involved in our study were clearly informed by neurologists and neurosurgeons of the risks and benefits associated with the intended procedures. We received approval by our

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Local Ethics Committee and a written, informed consent was obtained from each patient who participated in the study. Data Analysis The effect of different DBS modalities on UPDRS was separately studied by means of nonparametric, oneway Friedman ANOVA test in the drug-OFF condition (STIM-OFF, GPi-ON, CM–Pf-ON, and GPI  CM–PfON). The effect of L-DOPA-ON was separately studied with a one-way Freidman ANOVA test and compared to the baseline condition for each DBS situation (STIMOFF, GPI-ON, CM–Pf-ON, and GPI  CM–Pf-ON). The effect of each different DBS combination (STIM-OFF, GPI-ON, CM–Pf-ON, and GPI  CM–Pf-ON) on AIMs was studied using a one-way Friedman ANOVA test. When statistically significant effects were found, comparisons were made by means of the Wilcoxon matchedpairs test. The accepted significance level was p 0.05. Results The usual trajectory for implantation of the electrode array into either the CM or the Pf is shown in Figure 48.4. For an example of a postoperative MRi with bilateral GPi and CM–PF DBS, see Figure 48.8 (Mazzone et al., 2005b). Intriguingly, OFF scores were significantly improved in the postsurgical period (UPDRS-III 62.3 vs. 71.4). Stimulation-ON produced a statistically significant

Figure 48.8  Post-surgical, T1-weighted MRI scans, showing the electrode tips implanted in the CM–Pf complex and in the GPi. On the right: CM implantation in the right thalamus, Pf lead in the left. On the left: bilateral Pf implantation

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48.  deep brain stimulation of the medial thalamus for movement disorders

reduction of UPDRS when compared to the OFF condition in all modalities (Friedman ANOVA, main effect “Modality”: p 0.005). The Wilcoxon matched-pairs test showed a statistically significant UPDRS reduction during CM–Pf (p 0.01) and GPi (p 0.01) stimulation. In particular, GPi DBS produced a mean reduction of 41.5%, CM–Pf DBS, a mean reduction of 35.4%, but with a relatively modest impact on rigidity (data not shown). Most importantly, however, the combined stimulation of both nuclei reduced UPDRS by 49.9% (statistically significant when compared to CM–Pf or GPi alone). The Wilcoxon matched-pairs test showed a statistically significant mean reduction during CM–Pf

(or the combined STIM) (p 0.001) compared to GPi DBS alone (no effect) (Figure 48.9). Finally, a significant change in the L-DOPA-induced AIMs was observed during GPi DBS, when compared to the STIM-OFF condition. The GPi-related impact on AIMs was particularly prominent (Friedman ANOVA, main effect: p 0.0002). There were no severe adverse events (i.e., hemorrhage) during the surgical procedures. In one patient the macro-electrodes in the left hemisphere had to be removed as a result of infection. One year later, the patient was reimplanted into the same targets with a full replication of the favorable former response to DBS.

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Figure 48.9  Top: (left) mean value of UPDRS-III in preoperative and postoperative time: OFF and ON therapy and during CM–Pf DBS; (middle) mean value of UPDRS-III in preoperative and postoperative time: OFF and ON therapy and during GPi DBS; (right) mean value of UPDRS-III in preoperative and postoperative time: OFF and ON therapy and during GPi/CM–Pf DBS. Below: mean value of UPDRS-III subscore for rigidity, freezing, akinesia, and dyskinesias in preoperative and postoperative time: OFF and ON therapy and during DBS with a single and both targets activated

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DISCUSSION

Discussion After 3 years of follow-up, our data reveal that the combination of CM–Pf DBS and GPi DBS still provides a slightly better effect than GPi DBS alone on involuntary movements. Aside from the specific impact on AIMs, IL DBS produced a significant reduction of UPDRS-III when compared to the OFF condition in all modalities (Friedman ANOVA: main effect “Modality”: p 0.005). The Wilcoxon matched-pairs test showed a significant UPDRS-III reduction during CM–Pf DBS (p 0.01); however, in the immediate postsurgery phase, the mean reduction of UPDRS-III was 35.4%, and the impact on rigidity modest. Of utmost importance is the fact that the combined stimulation of both nuclei reduced UPDRS-III by 49.9% (statistically significant when compared to CM–Pf DBS or GPi DBS alone) (Figure 48.9). At 3-year follow-up, the effectiveness of CM–Pf DBS (and its association with GPi DBS) declines slightly. In our patient population, we were able to observe the effects of CM–Pf DBS on tremor in two women with a 7- and 12-year disease history, respectively, affected by idiopathic PD. Both women were selected for dual bilateral implantation within the STN and the CM–Pf,

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in consideration of rather disabling and drug-resistant tremor (and a persistent prominence of sensory symptoms in OFF). The main post-surgery results in these women can be summarized as follows: STN DBS induced an improvement of extrapyramidal symptoms as CM–Pf DBS, as determined by the UPDRS-III (Tab. II). l In UPDRS-III item 20, focusing on resting tremor, there was maximal reduction when CM–Pf DBS was switched ON (Figure 48.10). l

Electrophysiological assessments corroborated this clinical data (Figure 48.10; Peppe et al., 2001, 2004 ). In fact, although the mean and maximal acceleration of the contralateral hand tremor was strongly reduced by the differing DBS conditions during CM–Pf DBS, it was diminished more than when STN DBS was turned ON. It should be noted that stimulation of both targets together did not induce a further reduction of acceleration values when compared to stimulation of CM–Pf alone. Moreover, CM–Pf DBS seemed to be particularly effective on muscle burst frequency, as shown by the EMG power spectrum data. In fact, the abnormal muscle activity, synchronized at 4.5 Hz, which represents the standard PD tremor frequency, was not strongly changed by STN DBS. In contrast,

Figure 48.10  Accelerometric tracings of tremor in patients before and during DBS of the CM–Pf nuclei, or STN (Reprinted from Peppe et al., 2008 with permission. Copyright (2008) Elsevier)

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during CM–Pf DBS, all patients did not show tremorrelated muscle activity.

A New Look Towards the PPTg/CM–Pf Projection and Extrapyramidal Disorders All of our patients were subjected to routine neuropsychological testing and psychological counselling. Among others, all patients were tested with the Beck Depression Inventory (BDI) for measuring mood levels, the State–Trait Anxiety Inventory for assessing anxiety, and all underwent a Structured Clinical Interview (DSM-IV-R Axis II Disorders – SCID-II) to investigate personality traits. It is important to note that, to this date, our CM–Pf implanted PD patients (n  9, with prolonged clinical follow-up 3 years in 8 patients) manifested no prominent psychic, depressive, or cognitive sequelae of their procedure. There was, however, an actual documented improvement in mood in 3 patients. In recent years, we have also performed the innovative implantation of the PPTg, usually associated with stimulation of either the STN or the GPi. Actually, aside from the different degree of gait amelioration provided by low-frequency PPTg DBS, it is worth considering the profile of non-motor effects driven by PPTg DBS at low frequency(25 Hz). First, none of the PD patients implanted in the brain stem have shown any cognitive or psychiatric deficits as a result of implantation and stimulation. Secondly, these patients have manifested a clear increase in their quality of life and a peculiar amelioration of disordered sleep structure. Of great interest, the neuropsychological tests administered (mostly designed to investigate attention and frontal executive functions) suggest (1) a transient but consistent feeling of “well-being” and (2) significant amelioration in gait analysis and verbal fluency. These observations fit well with extensive increase of metabolic activity in associative regions of the frontal cortex observed via FDG-PET scans. It is clear that our multitarget strategy involving structures such as the CM–PF and the PPTg, and designed for patients with severe PD, has a great potential for success without causing cognitive or psychic side effects. Of course, our results in this small cohort of patients require further corroboration by implanting and collecting appropriate date in a much larger number of patients. We are also studying whether FDG-PET consumption augments in frontal regions during clinically efficacious CM–PF DBS. In this regard it is important to take into account that: (1) both the CM–Pf and PPTg degenerate at a given extent in PD (in particular, Henderson et al. (2000) showed a 30–40% apoptotic-like loss of neuronal elements in Parkinsonian patients, irrespective of disease stage);

(2) a robust projection from the PPTg in animals and in humans is directed towards the CM–Pf complex which, in turn provides a powerful excitatory drive to the putamen trough PF fibers. By combining the above findings it is reasonable to hypothesize that a deranged “PPTg–CM–PF pathway” may be correlated with clinical aspects of “late” PD such as emotional fragility, alterations of sleep and deficit in working memory. Conversely, by targeting the PPTg–CM–PF pathways, we might ensure a re-modulation of thalamic outputs towards cortical and basal ganglia associative regions, with potential benefits for patients (Nakano et al., 1990). Resurgent hypotheses indicate that the efficacy of DBS is not simply a consequence of a “jamming” or of a “shunting” device effect but, instead, relies on a likely “activating” role in rescuing high-frequency oscillations shared by the whole circuit.

Summary and perspectives According to Jones’ thought, the intralaminar thalamic nuclei represent the “forgotten components of the great loop of connections joining the cerebral cortex through the basal ganglia to the thalamus” (Davis et al., 1998; Tasker, 2001). In human anatomy, these nuclei are involved in the sensorimotor basal ganglia circuitry. They receive strong inputs from the striatum, the brain stem, and the cerebellum. The CM receives relevant afferents from the GPi. Notably, among the brain stem nuclei the PPTg nucleus projects to the Pf through cholinergic neurons and the electrical stimulation of this pontine nucleus is known to modulate the discharge pattern of Pf neurons (Capozzo et al., 2003). For this reason, in our personal experience, the surgery of the Pf and the clinical results obtained from the DBS of this nucleus, have provided the rationale for developing the targeting and implantation procedures of the PPTg. The glutamatergic efferent projections of the CM–Pf complex are essentially directed towards the striatum and the cortex (Matsumoto et al., 2001). As mentioned above, it has been suggested that even the activity of the STN is regulated by afferents from the Pf (Féger, 1977). Overall, these observations support a crucial role of the DBS of the CM–Pf complex for the treatment of movement disorders. Nevertheless, the following limitations of the available data must be considered. 1. The effects of stereotactic lesions of the CM–Pf complex on movement disorders in earlier studies are difficult to assess, because in most cases additional lesions occurred in neighboring nuclei; on the other hand, medial thalamotomy for the

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2.

3.

4.

5.

6.

SUMMARY AND PERSPECTIVES

treatment of movement disorders is now rarely performed. Spread of the electrical field and current to adjacent structures of the thalamus, in particular, to the centro-lateral nucleus (another forgotten target) (Krauss et al., 2001, 2002, cannot be excluded. The effect of the DBS of the CM–Pf complex, as well as the effect of selective lesions, might depend on its impact on different neuronal substrates within the CM–Pf complex. The neuronal degeneration in the CM–Pf complex, which commonly occurs in PD patients, may affect preferentially some neuronal subpopulations, and this might modify the effects of the DBS. No study reported in the literature directly refers to patients specifically implanted in the CM–Pf complex for the treatment of movement disorders with the exception of that reported by Mazzone et al. (2006). Some reports (Caparros-Lefebvre et al., 1999) described the serendipitous effect of CM–Pf stimulation in patients implanted in Vim; whereas other reports, focused on patients implanted for pain treatment, in whom modifications of motor performance were observed as well. Results reported in the literature often refer to short-term follow-up methodologies, which were not completed by long-term observations (Krauss et al., 2001, 2002). A larger series of patient is therefore necessary to fully evaluate the safety and efficacy of CM–PF DBS in the treatment of motor disorders.

Acknowledgment This chapter is dedicated to Rita and Giovanni Mazzone.

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seizures of the temporal lobe. Acta Neurochir. (Suppl.) 97 (Pt 2): 329–32. Velasco, F., Velasco, A.L., Velasco, M., Jiménez, F., Carrillo-Ruiz, J.D. and Castro, G. (2007b) Deep brain stimulation for treatment of the epilepsies: the centromedian thalamic target. Acta Neurochir. (Suppl.) 97 (Pt 2): 337–42. Velasco, F., Velasco, M., Velasco, A.L., Jiménez, F., Marquez, I. and Rise, M. (1995) Electrical stimulation of centromedian thalamic nucleus in control of seizures: long term studies. Epilepsia 36: 63–71. Velasco, A.L., Velasco, F., Velasco, M., Trejo, D., Castro, G. and Carrillo-Ruiz, J.D. (2007c) Electrical stimulation of the hippo­ campal epileptic foci for seizure control: a double-blind, longterm follow-up study. Epilepsia 48 (10): 1895–903. Vogt, C. and Vogt, O. (1941) Thalamusstudien. 1. Zur Einführung. 2. Homogenität und Grenzgestaltung der Grisea des Thalamus. 3. Das Griseum central centrum medianum Luys. J. Psychol. Neurol. 50: 32–154. Weigel, R. and Krauss, J.K. (2004) Center median–parafascicular complex and pain control. Review from a neurosurgical perspective. Stereotact. Funct. Neurosurg. 82: 115–26. Yamamoto, T., Katayama, Y., Kobayashi, K., Kasai, M., Oshima, H. and Fukaya, C. (2003) DBS therapy for a persistent vegetative state: ten years follow-up results. Acta Neurochir. 87 (Suppl.): 15–18. Yamamoto, T., Kobayashi, K., Kasai, M., Oshima, H., Fukaya, C. and Katayama, Y. (2005) DBS therapy for the vegetative state and minimally conscious state. Acta Neurochir. 93 (Suppl.): 101–4.

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C H A P T E R

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Epilepsy: Anatomy, Physiology, Pathophysiology, and Disorders David King-Stephens

o u t l i n e Introduction

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Conclusion

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Pathophysiology

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References

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Interictal to Ictal Transition

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behavioral characteristics of a seizure depend upon the location of the origin of the electrical abnormality and subsequent involvement of other structures. The dif­ ferent seizure types are classified according to whether they originate focally or in a generalized manner (Commission on Classification and Terminology …, 1989). Focal seizures may or may not involve alteration of consciousness or have secondary generalization. Generalized-onset seizures include primary general­ ized tonic–clonic, myoclonic, atonic, and absence. This classification is important in terms of the implications for treatment as narrow-spectrum anticonvulsant medications, such as phenytoin or carbamazepine, can exacerbate generalized-onset seizures, while cer­ tain pharmaco-resistant syndromes (that usually, but not exclusively, involve focal-onset seizures) may be amenable to surgical resection or therapy with neurostimulation. The different epilepsy syndromes thus reflect differ­ ent pathophysiologic disturbances. There is no unify­ ing mechanism that describes and is responsible for epileptogenesis. It has been hypothesized that a com­ bination of factors, such as anatomic reorganization

Introduction Epilepsy, the neurological disorder characterized by recurrent, unprovoked seizures, is the third most common neurological disorder reported around the world. The sudden and unpredictable nature of sei­ zures is one of the most disabling aspects of the dis­ ease. It may be associated with other neurological symptoms, such as mood or cognitive deficits, and result in severe psychosocial limitations. Epilepsy is a heterogeneous disorder with diverse syndromes and etiologies that include structural abnormalities (i.e. stroke, tumors, malformations of cortical development, etc.), functional abnormalities (involving ion channels, as in autosomal dominant frontal lobe epilepsy due to an acetylcholine channel­ opathy) or a combination of both (familial temporal lobe epilepsy with audiogenic seizures). The different syndromes are classified as to whether the etiology is secondary, as in localization-related epilepsies due to structural lesions, or primary, as in idiopathic general­ ized epilepsies, as in juvenile myoclonic epilepsy. The

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(i.e., sprouting of new connections within a population of neurons leading to increased synchronization and/ or recurrent collateral excitation), change in distribu­ tion, function and/or expression of ion-, ligand- or voltage-gated channels, and/or reduction of inhibitory influences can lead to epileptogenesis. Advances in the understanding of the role of voltage-gated and ligandgated ion channels in the epileptogenesis of genetic and acquired epilepsies have been reported recently (Celesia, 2001). For example, voltage-gated sodium channels are essential for action potentials and their mutations are the substrate for generalized epilepsy with febrile seizures plus and benign familial neonatal infantile seizures. Voltage-gated potassium channels are essential in the repolarization and hyperpolariza­ tion, and mutations are reported in benign neonatal epilepsy. Voltage-gated Ca2 channels are involved in neurotransmitter release and in the generation of absence seizures, and mutations have been reported in juvenile myoclonic epilepsy. Mutations in the voltagegated chloride channels, implicated in GABA(A) trans­ mission, have been described in juvenile myoclonic epilepsies, epilepsy with grand mal seizures on awak­ ening or juvenile absence epilepsy. Hyperpolarizationactivated cation channels have been implicated in spike-wave seizures and in hippocampal epileptiform discharges. Mutations in the chloride ionophore of the GABA(A) receptor have been reported in juven­ile myoclonic epilepsy or generalized epilepsy with febrile seizures plus. Finally, mutations in the nicotinic acetylcholine receptor are the substrates for the noctur­ nal frontal lobe epilepsy.

Pathophysiology In symptomatic epilepsies, alterations in anatomi­ cal or functional properties can lead to chronic distur­ bances in the ionic microenvironment, water, energy and/or pH metabolism that could result from glial changes accompanying neuronal damage (de Lanerolle and Lee, 2005). Such changes in the vicinity of a lesion might give rise to intermittent synchronized burst dis­ charges within neuronal populations which could then induce enduring reorganization of neuronal connec­ tions that enhances synchronization. It has been postulated that changes in gene expres­ sion, after an initiating event such as trauma, stroke or febrile seizures, accompany cellular changes such as selective neuronal loss and gliosis that can also lead to the development of epileptogenesis. In a study with micro-array gene analysis in a rat model of epilepsy fol­ lowing status epilepticus (SE) induced by hippocampal

electrical stimulation, increased expression of genes related to cell death, inflammation, and gliosis (vimen­ tin, S-100-related protein, GFAP, heat shock proteins, and interleukins), were found within one day after the induction of SE. In the chronic phase (90 days post SE), genes regulating neuronal activity, such as brainderived growth factor and neuropeptide Y, were also upregulated, with reduction in the alpha 5 subunit of the gamma-amino-butyric acid (GABA) receptor. These results suggest that pathways and processes that relate to inflammatory, immune responses and oxida­ tive stress may play a role in the initial process of epi­ leptogenesis (Stefan et al., 2006). Given that the epileptogenic zone, the area sufficient to induce seizure activity, is localized in medial tem­ poral lobe structures of the majority of patients who undergo surgical treatment and whose tissue is read­ ily available to perform molecular and physiological studies, this review will focus on medial temporal lobe epilepsy (MTLE). MTLE, a highly pharmaco-resistant syndrome, is characterized by the presence of partial seizures, with or without secondary generalization. Even in this relatively stereotyped epileptic syndrome, more than one type of seizure can occur because of more than one pathophysiologic mechanism and anatomic substrate (Spencer et al., 1992; Schiller et al., 1998). Some ictal onsets are characterized by a build-up of low-voltage fast activity, consistent with a disinhibi­ tory mechanism. More commonly, onsets are hyper­ synchronous, suggesting a strong role for enhanced inhibition (King and Spencer, 1995). Both can occur during a single seizure, evolve from one another, and occur at the site of the ictus or in propagated areas. Mesial temporal sclerosis (MTS), the most common pathological substrate of MTLE, is characterized by atrophy, neuronal loss, and astroglial proliferation in the Hc. The molecular mechanisms underlying MTLE include excessive synaptic excitation mediated by glutamate interacting with ionotropic and metabotorpic glutamate receptors. In hippocampal resections from MTLE patients, alterations in the number and distribu­ tion of AMPA, kainate, and NMDA receptor subunits have been reported (Mathern et al., 1998, 1999). Recent studies report alteration in the expression of mGluR5, a G protein-coupled receptor involved in the regula­ tion of glutamatergic transmission. mGluR5 immuno­ reactivity is significantly upregulated in pyramidal and glia-like cells of patients with MTLE. It is not known whether this change is an underlying cause or con­ sequence of seizure activity but may contribute to the hyperexcitability of the Hc (Notenboom et al., 2006). The anatomical and functional organization of the medial temporal lobe structures provides insights into their predisposition for the development of epileptiform

VI. NEUROstimulation FOR EPILEPSY



Pathophysiology

activity. The major input to the hippocampus (Hc) is from the entorhinal cortex through the perforant path­ way and ends primarily on granule cells of the dentate gyrus. These cells then project via mossy fibers pre­ dominantly to pyramidal neurons in the CA3 region. In turn, CA3 neurons project Schaffer collaterals to the CA1 region. Hippocampal pyramidal cells send their axons to the subiculum and adjacent areas of the tempo­ ral neocortex, septum, and mammillary bodies via the fornix. Axon collaterals return and connect on dendrites of other pyramidal cells and produce recurrent excita­ tion. Interspersed between principal neurons are inhibi­ tory interneurons, including basket cells, which receive excitatory input from afferent axons entering the hippo­ campus as well as from efferent axons exiting the HC. The axonal processes of the interneurons are widely dis­ tributed. These interneurons can inhibit principal neu­ rons by feed-forward or feed-back inhibition, mediated through the action of GABA. Differences in excitability patterns exist between dif­ ferent regions within the hippocampus. Spontaneous bursting occurs in CA3 pyramidal cells, presumably due to dendritic calcium currents that sustain depol­arization at the axon hillock. This results in repetit­ive action potentials, until the burst is turned off by calciumdependent potassium currents and synaptic input from inhibitory interneurons. Under normal circum­ stances, bursting in the CA3 region is asynchronous. Theoretically, in the epileptic hippocampus the CA3 region bursting neurons become synchronized and act as pacemaker to drive CA1 pyramidal cells. CA1 cells may not be capable of generating bursts sponta­ neously but do generate bursts in response to afferent input from CA3 (Schwartzkroin, 1983a, 1983b). In CA3, pyramidal cells can fire intrinsic bursts, after a brief stimulus, as a result of activating a slow voltage-gated inward current. The tendency of CA3 pyramidal neu­ rons to fire bursts of four or five action potentials can increase the probability of recruiting the post­synaptic neurons into the discharge approximately 10-fold. It is estimated that fewer than 10% of neurons fire abnor­ mally in synchronous bursts in TLE (Colder et al., 1996). In vitro studies have shown that trains of stimuli lasting a fraction of a second can result in periods of rhythmic synchronized neuronal firing, at gamma and beta frequencies, lasting a few seconds. The excitatory drive for this comes from metabotropic glutamate acti­ vation; a paradoxical effect of depolarizing by GABA (Bracci et al., 2001) and extracellular accumulation of potassium (Kaila et al., 1997). Intrinsic cellular properties, synaptic interactions and electrical coupling via gap junctions (junctions that allow flow of electrical signals and small molecules between cells promoting neuronal synchrony) all can

621

contribute to anomalous population activities charac­ teristic of seizures (Traub et al., 2005). Interictal and ictal epileptiform discharges do not simply reflect enhanced excitation and/or decreased inhibition (Nusser et al., 1998). Excitation may be enhanced, but often inhibition is enhanced as well. Increased inhibitory tone can be demonstrated in the epileptogenic zone by a variety of methods, including pair-pulse stimulation. Both increased and decreased afterdischarge thresh­ olds have been reported with electrical stimulation of human epileptogenic temporal lobe structures (Cherlow et al., 1977; Bernier et al., 1987). Paired pulse suppression (the absence of an enhanced response in the dentate gyrus after two pulses applied to entorhi­ nal cortex), a measure of enhanced inhibitory tone, is reported in the human epileptogenic hippocampus (Wilson et al., 1987). In patients with MTLE, pairedpulse facilitation can be seen with stimulation of asso­ ciation pathways, such as the Schaffer collaterals in the epileptic hippocampus, but paired-pulse suppression more commonly occurs with stimulation of the per­ forant path, demonstrating that enhanced interictal inhibition selectively involves specific local circuits (Wilson et al., 1998). Excitatory mechanisms and inhibitory connections are thus responsible for synchronization of large num­ bers of neurons and both contribute to the abnormal interaction of neuronal populations that underlie epi­ leptiform events. Simultaneous inhibition of a large number of neurons plays a prominent role in synchro­ nization, because all these neurons then become avail­ able at the same time to respond to a second excitatory input. If a second input occurs at the proper interval, just as the inhibited neurons all recover their rest­ ing potential, they are all synchronously excited. The resultant post-excitation inhibition then increases the available neuronal pool even further. Because of this inhibitory mechanism, excitatory input at the proper frequency is capable of recruiting greater numbers of neurons into the synchronous discharge. One theory of epileptogenesis rests on the hypoth­ esis that reduced inhibition within neuronal networks causes hyperexcitability. Histochemical studies have demonstrated reduced numbers of GABA receptor subunits as well as loss of GABAergic interneurons. GABAergic interneuron loss has also been reported in MTLE. Additionally, GABAergic dysfunction has been reported in MTLE (Isokawa, 1996). GABAergic responses in dentate granule cells appear to be normal with single-pulse stimulation protocols but strongly decrease with repetitive stimulation; these responses recover significantly slower when compared to nonsclerotic tissue. The dormant cell hypothesis proposes that the loss of mossy cells would make the surviving

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49.  Epilepsy: Anatomy, Physiology, Pathophysiology, and Disorders

GABAergic basket cells dormant thus disinhibiting granule cells (Sloviter, 1991). Paradoxically, GABAa receptor-mediated events can synchronize neuronal networks and contribute to the spread of synchronous activity in the subiculum (Cohen et al., 2003). Given the strategic position of the subicu­ lum within the hippocampal–parahippocampal region, the hyperexcitability of this structure would allow for propagation of epileptiform events to other structures both in the limbic and extralimbic systems. This hypoth­ esis suggests that in this population of subicular “pace­ maker cells,” the accumulation of intracellular chloride results in a depolarizing action upon GABAa recep­ tor activation. Such a depolarizing mechanism may be caused by delayed expression or downregulation of the KCC2 transporter consequent to deafferentation from CA1, as seen in MTS (Rivera et al., 2004). GABA depolarization results from prolonged acti­ vation of GABAa receptors, which causes intracellular accumulation of chloride, so that bicarbonate becomes the major charge carrier through the GABAa receptor. GABA release contributes to the subsequent potas­ sium accumulation because potassium gradients are used to drive the transporters for GABA and chlo­ ride. Repetitive synchronous discharges are likely to promote epileptic activity by potentiating excitatory synapse (Bliss and Collingridge, 1993) and by mak­ ing inhibitory synapse fade (Bracci et al., 2001). Thus, GABA receptor-mediated depolarizations contribute to synchronize limbic networks and may serve a prorather than an antiepileptic role (Kohling et al., 2001).

Interictal to ictal transition In the Hc and entorhinal cortex of epileptic rats, activity with a frequency of 250–500 Hz, termed ripples, appears to reflect field events composed of hypersyn­ chronous action potentials and may be an EEG ana­ log of epileptiform abnormalities consisting of bursts of population spikes (Buzsaki et al., 1992; Ylinen et al., 1995). In vivo microelectrode recordings in patients with MTLE have demonstrated fast oscillations in the order of 250–500 Hz, termed fast ripples, perhaps rep­ resenting population spikes (Bragin et al., 1999a; 1999b; Bragin, Mody et al., 2002). Fast ripples can be evoked by electrical stimulation in areas in which they occur spontaneously and can be synchronized between the dentate gyrus and entorrhinal cortex. They are only reported in areas generating spontaneous seizures and have been postulated to reflect pathologic processes responsible for epileptogenesis, as opposed to non­ specific changes, given that spontaneous ictal events

in a kainite rat model of epilepsy typically involve fast ripples (Bragin et al., 1999c). Fast ripples may represent a much more robust way to identify regions where small clusters of epileptogenic neurons exist (Bragin, Wilson et al., 2002).

Conclusion A number of recent studies have attempted to increase our understanding of the dynamics of ictogen­ esis in humans. Nevertheless, our understanding of the mechanisms that lead to the occurrence of epilep­ tic seizures is incomplete. On the level of neuronal networks, focal seizures are assumed to be initiated by abnormally discharging neurons that recruit and entrain neighboring neurons into a critical mass. This build-up might be mediated by an increasing syn­ chronization of neuronal activity that is accompanied by a loss of inhibition, or by processes that facilitate seizures by lowering the threshold for excitation or synchronization. Since the interictal–ictal state is not always an abrupt phenomenon (Martinerie et al., 1998; Jerger et al., 2001; Le Van Quyen et al., 2001) it might be possible to detect a pre-seizure state of several min­ utes, anticipating the electrical onset of a seizure. If certain types of oscillations reliably precede the onset of seizures, then this would suggest methods for pre­ dicting seizure onset. If initial very fast oscillations are the relevant cellular events, developing a technology that detects these oscillations may possibly increase the yield for effective therapy.

References Bernier, G.P., Saint-Hilaire, J.M., Giard, N., Bouvier, G. and Mercier, M. (1987) Intracranial electrical stimulation. In: J. Engel, Jr. (ed.), Surgical Treatment of the Epilepsies. New York: Raven Press, pp. 323–34. Bliss, T.V.P. and Collingridge, G.L. (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 61: 501–11. Bracci, E., Vreugdenhil, M., Hack, S.P. et al. (2001) Dynamic modula­ tion of excitation and inhibition during stimulation at gamma and beta frequencies in the CA1 hippocampal region. J. Neurophysiol. 85: 2412–22. Bragin, A., Engel, J. Jr., Wilson, C.L., Fried, I. and Buzsaki, G. (1999a) High-frequency oscillations in human brain. Hippocampus 9: 137–42. Bragin, A., Engel, J. Jr., Wilson, C.L. et al. (1999b) Hippocampal and entorhinal cortex high frequency oscillations (100–500 Hz) in kai­ nic acid rats with chronic seizures and human epileptic brain. Epilepsia 40: 127–37. Bragin, A., Engel, J. Jr., Wilson, C.L. et al. (1999c) Electrophysiologic analysis of a chronic seizure model after unilateral hippocampal KA injection. Epilepsia 40: 1210–21. Bragin, A., Mody, I., Wilson, C.L. and Engel, J. Jr. (2002) Local gen­ eration of fast ripples in epileptic brain. J. Neurosci. 22: 2012–21.

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Bragin, A., Wilson, C.L. and Engel, J. Jr. (2002) Chronic epileptogenesis requires development of a network of pathologically intercon­ nected neuron clusters: a hypothesis. Epilepsy Res. 41: S144–S152. Buzsaki, G., Horvath, Z., Urioste, R., Hetke, J. and Wise, K. (1992) High frequency network oscillation in the hippocampus. Science 256: 1025–7. Celesia, Gastone C. (2001) Disorders of membrane channels or chan­ nelopathie. Clin. Neurophysiol. 112: 2–18. Cherlow, D.G., Dymond, A.M., Crandall, P.H., Walter, R.D. and Serafetinides, E.A. (1977) Evoked response and afterdischarge threshold to electrical stimulation in temporal lobe epileptics. Arch. Neurol. 34: 527–31. Cohen, A.S., Lin, D.D., Quirk, G.L. and Coulter, D.A. (2003) Dentate granule cell GABA(A) receptors in epileptic hippocampus: enhanced synaptic efficacy and altered pharmacology. Eur. J. Neurosci. 17: 1607–16. Colder, B.W., Wilson, C.L., Frysinger, R.C. et al. (1996) Neuronal syn­ chrony in relation to burst discharge in epileptic human tempo­ ral lobes. J. Neurophysiol. 75: 2496–508. Commission on Classification and Terminology of the International League Against Epilepsy (1989) Proposal for revised classifica­ tion of epilepsies and epileptic syndromes. Epilepsia 30: 389–99. de Lanerolle, N.C. and Lee, T-S. (2005) New facets of the neuro­ pathology and molecular profile of human temporal lobe epi­ lepsy. Epilepsy Behav. 7: 190–203. Isokawa, M. (1996) Decrement of GABA(A) receptor-mediated inhib­ itory post-synaptic currents in dentate granule cells in epileptic hippocampus. J. Neurophysiol. 75: 1901–8. Jerger, K., Netoff, T.I., Francis, J.T. et al. (2001) Early seizure detec­ tion. J. Clin. Neurophysiol. 18: 259–68. Kaila, K., Lamsa, K., Smirnov, S. et al. (1997) Long-lasting GABA-mediated depolarization evoked by high-frequency stimulation in pyramidal neurons of rat hippocampal slice is attributable to a network-driven, bicarbonate-dependent K transient. J. Neurosci. 17: 7662–72. King, D. and Spencer, S.S. (1995) Invasive electroencephalography in mesial temporal lobe epilepsy. J. Clin. Neurophysiol. 12: 42–5. Kohling, R., Vreugdenhil, M., Bracci, E. and Jefferys, J.G. (2001) Ictal epileptiform activity is facilitated by hippocampal GABAa receptor-mediated oscillations. J. Neurosci. 20: 6820–9. Le Van Quyen, M., Martinerie, J., Navarro, V. et al. (2001) Anticipation of epileptic seizures from standard EEG recordings. Lancet 357: 183–8. Martinerie, J., Adam, C., Le Van Quyen, M. et al. (1998) Epileptic sei­ zures can be anticipated by non-linear analysis. Nat. Med. 4: 1173–6. Mathern, G.W., Pretorius, J.K., Kornblum, H.I., Mendoza, D., Lozada, A., Leite, J.P. et al. (1998) Altered hippocampal kainitereceptor mRNA levels in temporal lobe epilepsy patients. Neurobiol. Dis. 5: 151–76. Mathern, G.W., Pretorius, J.K., Mendoza, D., Leite, J.P., Chimelli, L., Born, D.E. et al. (1999) Hippocampal NMDA receptor subunit

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mRNA levels in temporal lobe epilepsy patients. Ann. Neurol. 46: 343–58. Notenboom, R.G.E., Hampson, D.R., Janse, G.H., van Rijen, P.C., van Veelen, C.W.M., van Nieuwenhuizen, O. et al. (2006) Upregulation of hippocampal metabotorpic glutamate receptor 5 in temporal lobe epilepsy patients. Brain 129: 96–107. Nusser, Z., Hajos, N., Somogyi, P. et al. (1998) Increased number of synaptic GABAa receptors underlies potentiation at hippocam­ pal inhibitory synapse. Nature 395: 172–7. Rivera, C., Voipio, J., Thomas-Crusells, J., Li, H., Emir, Z. et al. (2004) Mechanisms of activity-dependant downregulation of the neuron-specific K-Cl cotransporter KCC2. J. Neurosci. 24: 4683–91. Schiller, Y., Cascino, G., Busacker, N. et al. (1998) Characterization and comparison of local onset seizure and remote propagated electrographic seizures recorded with intracranial electrodes. Epilepsia 39: 380–8. Schwartzkroin, P.A. (1983a) Local circuit considerations and intrin­ sic neuronal properties involved in hyperexcitability and cell synchronization. In: H.H. Jasper and N.M. Van Gelder (eds), Basic Mechanisms of Neuronal Hyperexcitability. New York: Alan R. Liss, pp. 75–105. Schwartzkroin, P.A. (1983b) Mechanism of cell synchronization in epileptiform activity. Trends Neurosci. 6: 157–60. Sloviter, R.S. (1991) Permanently altered hippocampal structure, excitability and inhibition after experimental status epilepticus in the rat: the dormant basket cell hypothesis and its possible relevance to temporal lobe epilepsy. Hippocampus 1: 41–66. Spencer, S.S., Guimares, P., Katz, A. et al. (1992) Morphological patterns of seizures recorded intracranially. Epilepsia 33: 537–45. Stefan, H., Lopes de Silva, F.H., Loscher, W., Schmidt, D., Perucca, E., Brodie, M.J. et al. (2006) Epileptogenesis and rational therapeu­ tic strategies. Acta Neurol. Scand. 113: 139–55. Traub, R.D., Contreras, D. and Whittington, M.A. (2005) Combined experimental/simulation studies of cellular and network mecha­ nisms of epileptogenesis in vitro and in vivo. J. Clin. Neurophysiol. 22 (5): 330–42. Wilson, C.L., Isokawa-Akerson, M., Babb, T.L., Engel, J. Jr., Cahan, L.D. and Cranall, P.H. (1987) A comparative view of local and inter­ hemispheric limbic pathway in humans: an evoked poten­ tial analysis. In: J. Engel, Jr., G.A. Ojemann, H.O. Luders, and P.D. Williamson (eds), Fundamental Mechanisms of Human Brain Function. New York: Raven Press, pp. 27–38. Wilson, C.L., Khan, S.U., Engel, J., Jr. et al. (1998) Paired pulse sup­ pression and facilitation in human epileptogenic hippocampal formation. Epilepsy Res. 31: 211–30. Ylinen, A., Gragin, A., Nadasdy, Z., Jando, G., Szabo, I., Sik, A. et al. (1995) Sharp wave-associated high-frequency oscillation (200 Hz) in the intact hippocampus: network and intracellular mecha­ nisms. J. Neurosci. 15: 30–46.

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C H A P T E R

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Vagus Nerve Stimulation Arun Paul Amar, Michael L. Levy, Charles Y. Liu, and Michael L.J. Apuzzo

o u t l i ne Introduction

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Operative Procedure: General Considerations

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NCP Device Components

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Operative Procedure: Relevant Anatomy

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Theoretical Basis of VNS

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Operative Procedure in Detail

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Clinical Utility of VNS

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Lead Removal or Revision

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Patient Selection

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Surgical Complication Avoidance and Management 635

Alternative Uses of VNS

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References

the central nervous system. In previous publications, we have comprehensively reviewed the theoretical rationale, practical background, and clinical application of VNS (Amar et al., 1998; Amar, Heck et al., 1999; Amar, DeGiorgio et al., 1999; Amar et al., 2001, 2004) as well as the operative procedure for inserting the NCP device (Amar et al., 1998; Amar et al., 2000; DeGiorgio et al., 2001). This chapter summarizes the relevant considerations pertaining to VNS and reviews pragmatic issues such as patient selection and surgical technique.

Introduction Vagus nerve stimulation (VNS) delivered via the implantable Neurocybernetic Prosthesis (NCP) from Cyberonics, Inc. (Houston, TX) is gaining increasing popularity and credibility as a treatment option for patients with intractable epilepsy. It has also emerged as a novel adjunct in the management of patients with refractory depression and potentially other disorders. Clinical experience with VNS began in 1988 with the first human implantation of the NCP system. Since then, more than 40 000 patients worldwide have received VNS therapy, and 100 000 patient-years of experience have accrued (Cyberonics, data on file). The NCP device delivers intermittent electrical stimulation to the left cervical vagus nerve trunk, which secondarily transmits rostral impulses to exert widespread effects on neuronal excitability throughout

Neuromodulation

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NCP device components Figure 50.1 depicts a schematic representation of VNS therapy. A pulse generator inserted in the subcutaneous tissues of the upper left chest delivers intermittent electrical stimulation to the cervical vagus nerve trunk via a bifurcated helical lead.

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2009 Elsevier Ltd. © 2008,

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Figure 50.1  Schematic representation of VNS therapy. A pulse generator inserted in the subcutaneous tissues of the upper left chest delivers intermittent electrical stimulation to the cervical vagus nerve trunk via a bifurcated helical lead (Reproduced with permission from Cyberonics, Inc.)

In addition to the pulse generator (Figure 50.2) and implantable lead (Figure 50.3), the NCP system includes a number of peripheral components, such as a tele­metry wand that interrogates and programs the pulse generator noninvasively (Figure 50.4). This programming wand is powered by batteries and is interfaced with a Dell Axim handheld that runs a menu-based software package furnished by Cyberonics. The system also includes a hand-held magnet that patients may carry with them in order to alter the character of stimulation that the generator delivers. The NCP pulse generator has approximately the same size and shape as a cardiac pacemaker. It contains an epoxy resin header with a receptacle that accepts the connector pin extending from the bifurcated lead (Figure 50.2). The generator is powered by a single lithium battery encased in a hermetically sealed titanium module. The projected battery life of the generator varies with the stimulus parameters but can be as long as 6–10 years under normal conditions. Once it has expired, the generator can be replaced with the patient under local anesthesia during a simple outpatient procedure. The generator contains an internal antenna that receives radiofrequency signals emitted from the tele­ metry wand and transfers them to a microprocessor that regulates the electrical output of the pulse generator. The generator delivers a charge-balanced waveform

Figure 50.2  NCP pulse generator and lead (Reproduced with permission from Cyberonics, Inc.)

Figure 50.3  NCP Helical lead array (Reproduced with permission from Cyberonics, Inc.)

characterized by five programmable parameters: output current, signal frequency, pulse width, signal-ON time, and signal-OFF time. These variables are titrated empirically in the outpatient setting, according to individual patient tolerance and seizure frequency. Altering the parameters of stimulation will have various consequences on VNS efficacy, side effects, and battery life. In clinical application, the most common parameters are 0.25–2.0 mA current (titrated to effect and tolerance),

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Theoretical basis of VNS

Figure 50.4  NCP programming wand interfaced to Dell Axim Handheld (Reproduced with permission from Cyberonics, Inc.)

30 Hz frequency, 500 s pulse width, and 30-second ON/5-minute OFF duty cycle. The generator has two accessories. One is a hairpinshaped resistor that is used during preliminary electrodiagnostic testing prior to implantation, in order to test the internal impedance of the generator. The other is a hexagonal torque wrench that is used to tighten the set screws that secure the lead connector pins to the epoxy resin header of the generator. While the generator is still contained within its package, it can be interrogated by the telemetry wand. The generator must pass this system check before it is opened onto the sterile field. The failure rate of the generator is extremely low, but it is recommended that a backup generator be available in the operating room at all times. The bipolar lead is insulated by a silicone elastomer, and can thus be safely implanted in patients with latex allergies. One end of the lead contains a connector pin that inserts directly into the generator, while the opposite end contains an electrode array consisting of three discrete helical coils that wrap around the vagus nerve. The middle and distal coils represent the positive and negative electrodes, respectively, while the most proximal one serves as an integral anchoring tether that prevents excessive force from being transmitted to the electrodes when the patient turns his/her neck. The leads come in two sizes, measured by the internal diameter of each helix. Although the majority of patients can be fitted with the 2 mm coil, it is desirable to have the 3 mm one available in the operating room as well. Each electrode helix contains three loops (Figure 50.3). Embedded inside the middle turn is a platinum ribbon coil that is welded to the lead wire. This shape permits the platinum ribbon to maintain optimum

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mechanical contact with the nerve. Suture tails extending from either end of the helix permit manipulation of the coils without injuring these platinum contacts. The electrode is intended to fit snugly around the nerve while avoiding compression, thus allowing the electrode to move with the nerve and minimizing abrasion from relative movement of the nerve against the electrode. Damage to the nerve is greatly reduced by the self-sizing, open helical design of the NCP electrode array, which permits body fluid interchange with the nerve. Thus, compared with cuff electrodes, mechanical trauma and ischemia to the nerve are minimized. Histological examination of the vagus nerve following VNS has revealed no axonal loss, demyelination, lymphocytic infiltration, or other evidence of permanent damage resulting from electrical stimulation (Amar et al., 1998). Other observations have confirmed the safety of chronic nerve stimulation when the duty cycle (the fraction of time the nerve undergoes stimulation) is less than 50%. The hand-held magnet performs several functions. When briefly passed across the chest pocket where the generator resides, it manually triggers a train of stimulation superimposed upon the baseline output. Such on-demand stimulation can be initiated by the patient or a companion at the onset of an aura, in an effort to diminish or even abort an impending seizure. The parameters of this magnet-induced stimulation may differ from those of the prescheduled activation. Alternatively, if the device appears to be malfunctioning or if the patient wishes to terminate all stimulation for any other reason, the system can be indefinitely inactivated by applying the magnet over the generator site continuously. Finally, patients are instructed to test the function of their device periodically by performing magnet-induced activation and verifying that stimulation occurs. Most patients can perceive the stimulation as a slight tingling sensation in the throat.

Theoretical basis of VNS As with many other anticonvulsant therapies, information about the neural mechanisms underlying VNS lags behind the appreciation of its clinical efficacy. The exact means by which VNS modulates seizure activity and its locus of action in the brain remain uncertain (Amar et al., 1998). The suggestion that afferent stimulation may modulate seizure activity dates back at least 2000 years to the teachings of Pelops, the master of Galen. He described a technique using ligatures applied to the limb in which partial seizures began as a means of

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aborting the progression of a focal seizure or preventing its generalization. Subsequent studies have confirmed that stimulation of cutaneous afferent fibers and other sensory pathways, including direct stimulation of the cervical vagus nerve, can affect electroencephalogram (EEG) synchronization and sleep cycles. Because highly synchronized patterns are characteristic of electrographic seizures, these studies of EEG rhythmicity form the neuroanatomic and neurophysiologic foundations for the hypothesis that appropriately timed stimulation of the vagus nerve might prevent or abort paroxysmal epileptiform activity. Although the vagus nerve is typically regarded for its efferent projections that innervate the striated muscle of the larynx and provide parasympathetic control of the heart, lungs, and gastrointestinal tract, over 80% of its fibers are special visceral and general somatic afferents leading towards the brain (Rutecki, 1990). While it was initially proposed that VNS works by recruiting afferent C-fibers and A-fibers, this contention has been recently challenged by observations that VNS retains its antiepileptic effects even after selective destruction of these small unmyelinated fibers by capsaicin treatment (Krahl et al., 2001). Vagal afferent fibers originate from receptors in the viscera and terminate in diffuse areas of the central nervous system, many of which are potential sites of epileptogenesis. These include the cerebellum, diencephalon, amygdala, hippocampus, insular cortex, and multiple brain stem centers. Some of these projections relay through the nucleus tractus solitarius, while others form direct, monosynaptic connections with their targets. Although it remains unclear which of these pathways underlie the mechanism of VNS action, the locus coeruleus and raphe nucleus appear to be key intermediaries, since bilateral chemical lesions of these centers abolish the seizure-suppressing effects of VNS therapy in animal models (Krahl et al., 1998). These results imply that norepinephrine and serotonin, which are diffusely released by the locus coeruleus and raphe nucleus, respectively, may mediate the anticonvulsant actions of VNS. Indeed, these two neurotransmitters are known to modulate seizure threshold in some parts of the brain by inducing interneurons to release gamma-amino butyric acid (GABA), leading to widespread inhibition of neuronal excitability throughout the brain. However, the levels of GABA and serotonin metabolites in the cerebrospinal fluid of patients undergoing VNS appear to be inversely correlated with the efficacy of treatment, and the neurotransmitter systems that mediate the antiepileptic actions of VNS remain uncertain (Amar et al., 1998). At the stimulation parameters typically used for human application, VNS has no effect on background

electroencephalography (EEG) rhythms. Vagal stimulation induces evoked responses from regions as disparate as the cerebral cortex, hippocampus, brain stem, thalamus, and cerebellum, and many authors have proposed that its antiepileptic actions relate to effects on the brain stem reticular activating system, which then projects to these forebrain structures (Amar et al., 1999). However, positron emission tomography (PET) experiments measuring regional cerebral blood flow (rCBF) in response to VNS reveal changes confined to more circumscribed regions, such as the ipsilateral anterior thalamus and cingulate gyrus, contralateral thalamus and ipsilateral cerebellum, or bilateral activation of the hypothalami and insular cortices (Amar et al., 1998; Amar, Heck et al., 1999). The reasons for this disparity in activated rCBF patterns from study to study are not immediately apparent, but may relate to differences in stimulation parameters, individual patient variation, and other factors (Amar et al., 1998). Inconsistencies between PET studies acquired during the acute versus longterm phases of VNS may reflect chronic adaptation to central processing, which attenuates responses to individual trains of VNS. Furthermore, PET studies have been confounded by multiple methodological limitations, such as seizures occurring during PET acquisition, the effects of prior cranial surgery, etc. (Amar et al., 1998). In any case, the central consequences of VNS on rCBF are not as diffuse as might be expected were its effects mediated through the brain stem reticular substance (Amar, Heck et al., 1999). Right- versus left-sided vagal stimulation is equally effective in controlling seizures in animal models, and bilateral stimulation produces no measurably greater effect than unilateral stimulation (Amar et al., 1998). Using techniques such as EEG and immunolabeling against fos, a nuclear protein expressed under conditions of high neuronal activity, these studies suggest that unilateral afferent vagal impulses generate bilaterally symmetric responses in the cerebral cortex and subcortical structures (Amar et al., 1998). In contrast, vagal efferent innervation appears asymmetric. In some species the right vagus nerve innervates the sinoatrial node while the left one preferentially supplies the atrioventricular node (Amar et al., 1998). Canine studies have shown that stimulation of the right vagus nerve produces greater cardiac slowing than similar stimulation of the left vagus. For these reasons, the NCP VNS system is generally inserted on the left side, although anecdotal experience with right-sided VNS in humans has been well tolerated. Some animal studies have shown that cardiac and respiratory function are adversely affected by VNS while others have not, depending on the species used, the

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Clinical utility of VNS

stimulation parameters applied, and other variables (Amar et al., 1998). Such side effects do not occur in humans because stimulation can be performed distant from the site at which the cardiac branches originate from the cervical vagus trunk (Amar et al., 2000; DeGiorgio et al., 2001).

Clinical utility of VNS Since 1988, more than 1000 patients have participated in seven corporate-sponsored clinical trials throughout 26 countries, and greater than 3000 patient-years of data have accrued. These studies confirm the longterm safety, efficacy, feasibility, and tolerability of VNS, as well as the durability of the NCP device (Amar et al., 1998; Amar, DeGiorgio et al., 1999; Morris and Mueller, 1999). VNS gained approval for the treatment of medically refractory epilepsy by the US Food and Drug Administration (FDA) in 1997. Post-marketing exper­ience validates the earlier clinical trials, and in 1999, the Therapeutics and Technology subcommittee of the American Association of Neurology declared VNS “safe and effective,” based on a preponderance of class I evidence (Fisher and Handforth, 1999). Although VNS requires a large initial investment due to the price of the device itself as well as its surgical insertion, cost–benefit analysis suggests that the expense of VNS is recovered within two years of follow-up (Boon et al., 1999). When interpreting the results of VNS studies, it is important to understand the rationale behind the outcome measures used to substantiate efficacy in clinical trials of antiepileptic therapies. The most intuitive parameter is the percent reduction in seizure frequency, expressed as the mean for the entire cohort of patients. The response to VNS is not normally distributed, however. Usually, the histogram depicting response rates is skewed to the left, reflecting the disproportionate influence of the few patients who derive no benefit from therapy. Thus, a more valid summary statistic of central tendency for this non-parametric data is the median reduction in baseline seizure frequency. Patients who enter clinical trials of new antiepileptic therapies such as VNS generally have the most intractable form of the disease. Because these patients are often pharmaco-resistant, they are not expected to become completely seizure-free by the addition of a new investigational agent. Furthermore, many patients are predicted to fail completely. Therefore, the primary outcome measure of most antiepileptic medication trials has been the 50% responder rate (the proportion of patients who achieve a 50% or greater reduction in seizure frequency). Although complete

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eradication of seizure activity always remains the goal of therapy, even 50% reductions can dramatically improve the quality of patients’ lives. In addition to seizure control, quality of life also depends on the side effects and toxicity of the treatment being rendered. Improvements in cognitive function and mood not related to seizure frequency per se are also reflected in these latter indices. Recently, a meta-analysis was performed of the 454 patients enrolled in one of five controlled, multicenter clinical trials (two double blind and three open-label studies) conducted in the USA (Morris and Mueller, 1999). For the study population as a whole, the median reduction in seizure frequency was 35% at 1 year, 43% at 2 years, and 44% at 3 years. These results were obtained using a “last visit carried forward” analysis, which minimizes selection bias by extrapolating data from non-responders who exit the trial and thus tends to underestimate the efficacy among responders. For patients persisting in the trial (declining N analysis), sustained efficacy was even greater. An important observation is that the response to VNS is maintained during prolonged stimulation, and unlike the case with chronic medication therapy, seizure control actually improves with time. The response of individual patients to VNS varies widely. While 1–2% of subjects enjoy complete seizure cessation, others derive no benefit. The remainder experience intermediate results. In the collective study experience, the proportion of patients who sustained a 50% reduction in baseline seizure frequency was approximately 23% at 3 months (Morris and Mueller, 1999). Although this figure is similar to the initial results of many new drug trials, the 50% responder rate also showed substantial increases with time, reaching 43% after two years (Morris and Mueller, 1999). These improvements occurred in a highly refractory population of patients who typically had an average of 1.7 seizures per day despite administration of more than two antiepileptic medications. In spite of the well-known functions of the vagus nerve as the principal efferent component of the parasympathetic nervous system, VNS has not been shown to adversely effect any aspect of physiological function, including cardiac rhythm (as assessed by EKG and ambulatory Holter monitoring), pulmonary function, gastrointestinal motility and secretion (Schachter and Saper, 1998). It is especially significant that, unlike many antiepileptic medications, VNS therapy does not impair cognition, balance, or emotion during extensive testing. Plasma concentrations of antiepileptic medications remain unchanged. Some adverse effects do occur with VNS, however. At three months of therapy during the acute phase

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studies, hoarseness, cough, paresthesiae, and other symptoms were common, occurring in up to half of patients. These effects were rated as mild or moderate 99% of the time (Schachter and Saper, 1998). They tend to occur concomitant with stimulus delivery and not throughout the day, unlike the side effects of antiepileptic medications. Furthermore, the side effects of VNS are generally transient, and their long-term incidence is much lower. The most common complaints after 1 year of treatment were hoarseness (28%) and paresthesiae (12%) (Morris and Mueller, 1999). At 2 years they were hoarseness (19.8%) and headache (4.5%), and after 3 years shortness of breath (3.2%) was the principal side effect (Morris and Mueller, 1999). Surgical complications are rare but include infection requiring explantation (1.1%), transient vocal cord injury (1%), and temporary lower facial paresis (1%) (Bruce, unpublished data, 1998). Device failures are also uncommon. More serious adverse events are rare. Although some deaths have occurred among the 454 study patients receiving VNS, none was definitely attributed to VNS therapy itself (Morris and Mueller, 1999). In fact, some studies suggest that the incidence of sudden unexplained death in epilepsy patients (SUDEP) is actually lower after treatment with VNS (Annegers et al., 1998). Patient satisfaction with VNS therapy is generally high. One way to quantify this parameter is to measure the percentage of patients who continue their therapy after completing the acute phase of a clinical trial. Continuation rates in the collective study experience were 97%, 85%, and 72% after 1, 2, and 3 years of therapy, respectively (Morris and Mueller, 1999). A related measure of patient satisfaction is the percentage of patients who opt to undergo replacement of the generator after the battery has expired. With a previous model of the NCP device, battery expiration typically occurred 4–5 years after initiating therapy, and about 75% of patients elected to change it at that time (Morris and Mueller, 1999). Long-term continuation rates reflect the unique profile of safety, efficacy, and tolerability that VNS provides. An additional measure of patient satisfaction is assessment of overall quality of life (QOL). In randomized controlled trials, improvements in QOL were independently documented by the patient, the blinded physician, and the patient’s companion using a visual analog scale (Schachter and Saper, 1998; Morris and Mueller, 1999). Presently, VNS is only approved by the FDA “as an adjunctive therapy in reducing the frequency of seiz­ ures in adults and adolescents over 12 years of age with partial onset seizures which are refractory to anti­ epileptic medications.” However, the NCP device has

been successfully used in infants and youths. Subgroup analysis of the children and adolescents treated in one of the five multicenter trials suggests that they derived substantial benefit from VNS, achieving median reductions in seizure frequency and 50% responder rates at least as favorable as those in adults. Subsequently, small uncontrolled trials exclusively studying pediatric patients have been reported. The results of these latter studies appear even more salutary than those in the older populations (Amar et al., 2001). A total of 60 pediatric patients were treated as part of the five prospective VNS studies conducted prior to FDA approval (Murphy, 1999). Children 12–18 years old were included in the double-blinded, controlled trials, while patients as young as 3½ years old were studied in the openlabel compassionate-use protocol. After 3 months of stimulation, the median reduction in seizure frequency among these 60 patients was 23%. Using a last visit carried forward analysis, this figure improved to 31% at 6 months, 37% at 12 months, and 44% at 18 months. At 12 months, the 50% responder rate was 29%. These results are similar to those achieved by adults in the same trials. Analysis of seizures by type failed to identify any classification that was more responsive to VNS than others. Stratification into symptomatic versus idiopathic epilepsy was likewise unrevealing, since children with both types appeared to benefit from VNS in some cases. Adverse events were also similar to those in adults, and none of them necessitated termination of therapy (Murphy et al., 1998; Murphy, 1999). Serious complications included aspiration pneumonia and necrosis of the skin overlying the generator site, each occurring in one child. Similarly, VNS has been successfully applied for the off-label treatment of patients suffering from generalized-onset seizures, such as those with Lennox Gastaut syndrome (Amar et al., 2001). Even the most refractory patient populations, such as those with persistent seizures after failed cranial surgery, derive significant benefit from VNS (Amar et al., 2004). In clinical practice, VNS appears to offer several advantages over pharmacotherapy and other surgical modalities. VNS avoids cerebral toxicity and the attendant impairments of cognition, emotion, and coordination that often complicate antiepileptic medication. The pre-programmed, computer-controlled characteristic of the NCP system permits complete and involuntary treatment compliance. VNS is potentially reversible, unlike cerebral surgery. Unlike the case with many medications, the effectiveness of VNS is maintained during prolonged therapy and, in fact, overall seizure frequency diminishes with time; furthermore, there are no adverse drug interactions. The improved quality of life and cognitive function perceived by patients during

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alternative uses of vns

VNS trials is a testimony to this unique combination of efficacy and favorable side effect profile. In addition, the ability to initiate stimulation during an aura restores an element of sovereignty to patients’ lives, which are severely disrupted by the unpredictability of epilepsy. Thus, VNS is both a preventive and abortive therapy.

Patient selection Epilepsy affects up to 1% of the general population and is the second most common neurological disorder overall. Despite recent advances in our understanding of the molecular and cellular basis of epilepsy and the development of several new medications directed against these mechanisms, satisfactory seizure control remains elusive in 30–40% of patients. In the USA alone, there are at least 300 000 people with medically refractory seizures of partial onset. Although there is disagreement as to which of these patients should undergo cerebral surgery, it is estimated that only 30 000 to 100 000 patients are appropriate candidates for temporal lobectomy, focal cortical resection, callosotomy, hemispherectomy, subpial transection, and other extant procedures (Amar et al., 1998). The selection criteria for insertion of the NCP system remain in evolution and reflect current governmental standards as well as institutional biases and general guidelines from prior clinical trials. As noted, the “off-label” use of VNS to treat children less than 12 or those with primarily generalized epilepsy has been rewarding. Patients with both idiopathic epilepsy and seizures of structural etiology are considered appropriate candidates. The definition of medical intractability varies from center to center. Standards from previous studies commonly required a frequency of at least six seizures per month and a seizure-free interval of no longer than 2–3 weeks despite therapy with multiple medications. However, seizure frequency, seizure type, severity of attacks, drug toxicity, and overall impact on quality of life must all be considered before a patient is deemed refractory to pharmacotherapy. As noted above, the response to VNS is highly variable, and previous clinical trials have failed to characterize the demographic factors that predict a favorable outcome. Furthermore, VNS is rarely curative. Although reductions in seizure frequency can dramatically improve patients’ quality of life, residual seizures may still preclude them from driving a car, maintaining employment, or other basic functions. Therefore, we do not consider the NCP device an alternative to conventional methods of epilepsy surgery

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that offer a higher likelihood of seizure cessation, and we generally reserve VNS for patients in whom such operations are not indicated. These include those patients whose seizure focus is bilateral, not associated with a structural abnormality, or cannot be completely resected due to overlap with functional cortex. For obvious reasons, the NCP system cannot be inserted in patients who have undergone a prior left cervical vagotomy. Furthermore, the safety of VNS has not been tested in several conditions in which impairment of vagus nerve function might produce deleterious effects. Thus, relative contraindications include progressive neurologic or systemic diseases, pregnancy, cardiac arrhythmia, asthma, chronic obstructive pulmonary disease, active peptic ulcer disease, and insulin-dependent diabetes mellitus.

Alternative Uses of VNS In the course of studying VNS for the treatment of epilepsy, a number of serendipitous effects have been observed. Many patients report an improvement in mood, cognition, and well-being not related to seizure control per se (Amar et al., 1998; Schacter and Saper, 1998; Morris and Mueller, 1999). Stimulation of the vagus nerve has been shown to enhance retention in verbal learning tasks, confirming the hypothesis that vagus nerve activation modulates memory formation similarly to arousal. In addition, VNS has been shown to exert an antinociceptive effect in rats. As a result of these fortuities, VNS has been proposed as a possible treatment of a number of diverse neurologic conditions. One of the potential applications that has received much notoriety is depression. Several lines of evidence support this practice (George et al., 2000). First is the clinical observation of substantial improvements in mood during VNS trials for epilepsy that were not attributable to seizure control alone. Second, neuroanatomic studies of vagal afferent connections suggest that the NTS and locus coeruleus project to the amygdala, stria terminalis, and other limbic structures involved in mood regulation (Rutecki et al., 1990). In VNS trials for epilepsy, for instance, PET studies have shown decreased blood flow to the hippocampus, amygdala, and cingulate gyrus reminiscent of the effects of selective serotonin reuptake inhibitors and other antidepressant drugs (George et al., 2000). In addition, many anticonvulsant medications have mood-stabilizing effects and are useful treatments for the depressive phase of bipolar affective disorder (George et al., 2000). Conversely, electroconvulsive therapy – the most effective antidepressant therapy currently available – has potent anticonvulsant effects. Furthermore, VNS alters

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the CNS concentrations of norepinephrine, serotonin, glutamate, and other monoamine neurotransmitters implicated in the pathogenesis of major depression. Finally, it is well established that depressed patients have autonomic system dysfunction that is mediated by the vagus nerve. If depressed patients have abnormalities in brain regions that control the vagus nerve from the top down, then perhaps stimulating the vagus nerve might engage this dysfunctional circuit from the bottom up (George et al., 2000). A corporate-sponsored, nonrandomized clinical trial of VNS for depression was recently conducted (Rush et al., 2000). In this open-label pilot study, 30 patients with treatment-resistant depression were enrolled. All had failed at least two pharmacological trials, and more than half had failed ECT as well. Following a baseline period with stable medication regimens, patients underwent insertion of the NCP device. A 2-week singleblind recovery period was followed by a 10-week period of active stimulation, using parameters similar to those employed for epilepsy. Functional status was assessed by several scales, with response defined by a 50% or greater reduction in baseline scores. For both the 28-item Hamilton Depression Rating Scale and the Clinical Global Impressions-Improvement index, the response rate was 40%. For the MontgomeryAsberg Depression Rating Scale the response rate was 50%. Seventeen percent of patients had complete remission. Symptomatic responses and functional improvements have been sustained during follow-up as long as 9 months (Rush et al., 2000). The promising results of the pilot study have been replicated in larger, randomized acute phase trials (Rush et al., 2005). Based on these and other studies, the NCP device gained FDA approval in July 2005 “for the adjunctive long-term treatment of chronic or recurrent depression for patients 18 years of age or older who are experiencing a major depressive episode and have not had an adequate response to four or more adequate antidepressant treatments.” Other hints suggest that VNS may have utility for additional neuropsychiatric illnesses. For instance, several theories of anxiety purport faulty or erratic interpretation of peripheral information that flows into the CNS (George et al., 2000). By affecting the flux of this information, VNS might have therapeutic potential in treating anxiety disorders. Similarly, the vagus nerve is known to transmit signals pertaining to hunger, satiety, and pain. For those reasons, potential applications for obesity, addiction, and pain syndromes seem plausible. The effects of VNS on feeding behavior were investigated in a canine model (Reddy, unpublished observations, 1999). Six dogs underwent bilateral VNS at

parameters similar to those used for epilepsy. Feeding times, amount consumed, and weight were serially monitored and compared with baseline. In response to VNS, feeding behavior changed following a variable period of latency. Both the rate of consumption and the amount consumed decreased, leading to weight loss. When stimulation was suspended, eating returned to baseline in 3–5 days, but resuming the stimulation reproduced the initial dietary changes. A phase I clinical trial of the effects of VNS on obesity is currently in progress. In rodent models, VNS has been shown to enhance long-term potentiation, and human studies suggest a favorable impact on recognition memory (Clark et al., 1999). Based on these observations, a pilot study for the treatment of Alzheimer’s disease been conducted (Merrill et al., 2006). In this trial of 17 patient, 7 (42%) and 12 (70%) demonstrated improved or improved Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) and Mini-Mental State Examination (MMSE) scores, respectively, after 1 year of stimulation. Furthermore, there was a median reduction of cerebrospinal fluid tau protein, a marker of Alzheimer’s disease severity, by 4.8% (p  0.057) after 1 year. Moreover, the NTS sends fibers to the dorsal raphe and other areas of the reticular formation known to control levels of consciousness (Rutecki, 1990). Thus, VNS has been considered as potential treatment for disorders of sleep or alertness such as narcolepsy and coma. VNS is also a possible treatment for additional conditions such as movement disorders, migraine, and others. Preliminary results in patients suffering from both epilepsy and autism suggest that VNS may exert beneficial effects in treatment of the latter condition alone (Berta et al., 2005). Finally, the NCP device permits the delivery of VNS at different amplitudes, frequencies, pulse widths, and duty cycles (Amar et al., 1998). At present, these settings are titrated empirically according to desired effect and tolerability. Varying these parameters in different combinations will likely affect different regions of the brain, thereby influencing distinct pathologic conditions. As more becomes known about the physiology of afferent autonomic stimulation, the utility of VNS is likely to broaden.

Operative procedure: general considerations Insertion of the NCP device takes less than two hours and is typically performed under general anesthesia, thus minimizing the possibility that an intraoperative

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Operative procedure: relevant anatomy

seizure might compromise the surgery. However, regional cervical blocks have also been used in awake patients. While it can be performed as an outpatient procedure, it may be desirable to observe patients overnight for vocal cord dysfunction, dysphagia, respiratory compromise, or seizures induced by anesthesia, even though these complications are rare. Prophylactic antibiotics are administered preoperatively and maintained for 24 hours postoperatively. The implantation procedure is conceptually straightforward. The first step involves creation of a chest pocket that accommodates the pulse generator. Next, through a separate incision, the carotid sheath is opened, the internal jugular vein mobilized, and the vagus nerve trunk isolated. The lead is tunneled within a subcutaneous tract between the two incisions. The helical electrodes are applied to the vagus nerve, and the lead connector pins are attached to the generator. After additional electrodiagnostic testing, the lead and generator are secured to adjacent tissue, and the wounds are closed in standard, multilayer fashion. Others have described access to both the cervical and chest regions through a single supraclavicular incision (Patil et al., 2001). The operating room should be organized to ease the surgeon’s access and to minimize traffic within the area. Following endotracheal intubation, we rotate the table 90 degrees clockwise from the anesthesia setup, which thus lies alongside the patient’s right foot. This permits the surgeon to stand at the patient’s left while the surgeon’s assistant stands at the patient’s right. The scrub technician is positioned at the patient’s head, affording ready access to each surgeon on either side. The electrophysiology staff remain behind the assistant’s back but within reach of the scrub technician, in order to conduct pre-implant diagnostic testing once the generator has been placed within the sterile field. Finally, prior to insertion of the first VNS system, team rehearsals should be conducted with all members of the surgical staff within the venue of the operating suite in order to review the room organization and reduce traffic within the area. These precautions may minimize the risk of hardware infection during the actual procedure. The importance of the surgeon’s preoperative preparation cannot be overemphasized. Planning for placement of the VNS system requires thorough anatomic understanding of the relevant neural, vascular, and muscular components of the anterior cervical triangle in order to minimize hazard to the ansa cervicalis, recurrent laryngeal nerve, tributaries to the internal jugular vein, and other structures. A full understanding of the anatomy of the superior and inferior cardiac branches will also reduce the rare occurrence of intraoperative bradycardia during the lead test.

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In addition to anatomic review, electrode model drills with practice devices supplied by the manufacturer help familiarize the surgeon with the technique and strategy of helix placement. The surgeon is also advised to review the VNS physician’s manual and surgical implantation video provided by the manufacturer prior to performing the procedure.

Operative procedure:  relevant anatomy Several branches of the vagus nerve arise cephalad to the midcervical trunk, where the VNS electrodes are applied (DeGiorgio et al., 2001). These include projections to the pharynx and carotid sinus, as well as superior and inferior cervical cardiac branches leading to the cardiac plexus. As indicated above, both the right and left vagus nerves carry cardiac efferent fibers, but anatomical studies in dogs suggest that those on the right side have a greater projection to the SA node of the heart, while those on the left side preferentially innervate the AV node (Rutecki et al., 1990). For this reason, the NCP system is generally inserted on the left side. Nevertheless, stimulation of the left vagus nerve may rarely cause bradycardia or asystole, even at FDA approved settings. As mentioned, the NCP device is generally applied to the midcervical portion of the vagus nerve trunk, distal to the origin of the superior and inferior cervical cardiac branches; this may represent another reason why the incidence of bradycardia is low. Nonetheless, the diameter, appearance, and location of the cardiac branches may approximate those of the nerve trunk itself, and care must be taken to avoid mistaking the two. If the cardiac branches are stimulated directly, small currents as low as 0.8 mA may produce significant bradycardia (Asconape et al., 1999). The superior laryngeal nerve arises rostral to the carotid bifurcation before descending towards the larynx, and high currents applied to the midcervical vagus nerve trunk may recruit these fibers, leading to tightness or pain in the pharynx or larynx. The recurrent laryngeal nerve travels with the main trunk and branches caudally at the level of the aortic arch before ascending in the tracheo-esophageal groove. As a result, hoarseness is a common occurrence during periods of stimulation or after VNS implantation. In addition to branches of the vagus nerve trunk, several other nerves in the vicinity of the carotid sheath risk hazard from the implantation procedure itself or from subsequent stimulation. The hypoglossal nerve arises cephalad to the midcervical region,

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making unilateral tongue weakness an infrequent complication of VNS implantation. The phrenic nerve lies deep to a fascial plane beneath the carotid sheath, and hemiparalysis of the diaphragm has been reported with stimulation at high output currents, though not as an operative complication. The sympathetic trunk lies deep and medial to the common carotid artery. It gives off fibers that ascend with the internal carotid artery (ICA) towards the intra­ cranial contents. We are aware of one case of Horner’s syndrome following insertion of the VNS device, due either to manipulation of the sympathetic plexus itself or to traction on the sympathetic fibers around the ICA. Weakness to the muscles of the lower face may result from injury to branches of the facial nerve, which ramify through the caudal aspect of the parotid gland. In general, hypoglossal and facial nerve injury are more common sequelae of carotid endarterectomy incisions, which tend to be higher than those used for placement of the VNS device.

Operative procedure in detail The following section draws upon Amar et al. (2000) and DeGiorgio et al. (2001). The patient is positioned supine with a shoulder roll beneath the scapulae in order to provide mild neck extension. This facilitates passage of the tunneling tool that connects the two incisions. The head is rotated 30–45 degrees towards the right, bringing the left sternocleidomastoid muscle into prominence. Many options exist for placement of the skin incisions. Often, a 5 cm transverse chest incision is made approximately 8 cm below the clavicle, centered above the nipple. The underlying fat is dissected to the level of the pectoralis fascia, and a subcutaneous pocket is fashioned superiorly. Although others have suggested a deltopectoral incision with inferior dissection to create the pocket, we believe that the scar tissue formed beneath the pectoral incision helps prevent caudal migration of the generator. Recently, we have been employing a lateral incision along the anterior fold of the axilla, which affords better cosmetic results, especially among women. Implantation of the device beneath the pectoralis muscle has also been described (Bauman et al., 2006). Next, a 5 cm longitudinal incision is made along the anterior border of the sternocleidomastoid muscle, centered over its midpoint. Generally, this incision is a little lower than that for an endarterectomy. Alternatively, a transverse skin incision at C5/6, similar to the approach for an anterior cervical discectomy, can be made. For the inexperienced surgeon, the longitudinal incision

permits a wider exposure, which facilitates electrode placement through this aperture. The platysma muscle is divided vertically, and the investing layer of deep cervical fascia is opened along the anterior border of the sternocleidomastoid, allowing it to be mobilized laterally. Following palpation of the carotid pulse, the neurovascular bundle is identified and sharply incised to reveal its contents. Selfretaining retractors with blunt blades expedite this stage of the procedure. Care is taken to limit the exposure between the omohyoid muscle and the common facial vein complex, thus minimizing potential hazard to adjacent neurovascular structures. Within the carotid sheath at the level of the thyroid cartilage, the vagus nerve is generally encountered deep and medial to the internal jugular vein, encased in firm areolar tissue lateral to the common carotid artery. Great variability exists in the relative position of these structures, however, and the strategy by which the nerve is isolated from the remainder of the neurovascular bundle must account for such individual diversity. We attempt to minimize direct manipulation of the nerve itself. Instead, we prefer to mobilize the vessels away from the nerve. Dissection generally commences with isolation and retraction of the internal jugular vein using vessel loops. Next, the nerve trunk is identified and dissected with the aid of the operating microscope or surgical loupes. At least 3–4 cm of the nerve must be completely freed from its surrounding tissues. At this stage, we have found that the insertion of a blue background plastic sheet between the nerve and the underlying vessels greatly facilitates the subsequent steps of the procedure. The technique of mobilizing the vessels away from the nerve usually preserves the vasa nervosum. This nuance may reduce the incidence of postoperative complications such as hoarseness. A tunneling tool is then used to create a subcutaneous tract between the two incisions. The tool is directed from the cervical to pectoral sites, in order to minimize potential injury to the vascular structures of the neck. Depending on the relative size of the exposed nerve, either a small or large helical electrode is then selected for insertion. The lead connector pin is passed through the tunnel and emerges from the chest incision, while the helical electrodes remain exposed in the cervical region. Before applying the electrodes, the lead wire should be directed parallel and lateral to the nerve, with the coils occupying the gap between them. Each coil is applied by grasping the suture tail at either end and stretching the coil until its convolutions are eliminated. The central turn of this unfurled coil is applied either obliquely or perpendicularly across

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Surgical complication avoidance and management

or beneath the vagus trunk and wrapped around the surface of the nerve. The coil is then redirected parallel to the nerve as the remainder of its loops are applied proximal and distal to this midpoint. The memory within the elongated coil will cause it to reassume its helical configuration and conform to the nerve snugly. Either the positive or negative terminal may be applied first, but the anchoring tether is generally applied last. While all these maneuvers are taking place, additional electrodiagnostic testing of the generator is simultaneously carried out between the neurology team and the scrub technician. With the hairpin resistor inserted into the receptacles for the lead connector pins, the telemetry wand interrogates the device from within a sterile sheath to measure its internal impedance. Once the generator passes this pre-implant diagnostic test, it is ready for insertion. The lead connector pin is connected to the pulse generator and secured to its receptacle with set screws, using the hexagonal torque wrench. It is important to completely insert the hex wrench into its socket in the epoxy header, in order to decompress the backpressure that builds up as the connector pins enter the receptacles. This step is essential in order to form a good contact between the lead and the generator. If the connector pin fails to make such contact, the generator may attempt to overcome the resulting increased impedance by augmenting the output current, leading to intermittent symptoms of overstimulation. Additional electrodiagnostic examination is then performed in order to appraise the coupling of all connections and to verify the integrity of the overall system. Then, a 1-minute lead test is performed at a frequency of 20 Hz and a pulse width of 500 s. The current should start at 0.25 mA and then ramp up in small increments to 1 mA. During this test stimulation, the response of the patient’s vital signs and electrocardiogram are monitored. Rarely, profound bradycardia will result, necessitating the use of atropine. The incidence of this event is thought to be about 1 in 1000. If it occurs, attention should be directed to the lead to assure that the electrodes encircle the vagus nerve trunk itself rather than one of its cardiac branches. Following the test stimulation, the generator is restored to its inactive status until 1 to 2 weeks postoperatively. This waiting period allows for resolution of postoperative edema and proper fixation of the electrode to the nerve. The redundant portion of the lead between the generator and electrode is secured to several areas of the cervical fascia with Silastic tie-downs. The objective is to form superficial and deep restraint configurations that help prevent excessive traction from being transmitted to the electrodes during repetitive neck motion.

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First, a U-shaped strain relief bend is made inferior to the anchoring tether, and the distal lead is secured to the fascia of the carotid sheath. Next, a strain relief loop is established by securing the lead to the superficial cervical fascia between the sternocleidomastoid and platysma muscles. Care is taken not to sew the lead directly to the muscle. Finally, the generator is retracted into the subcutaneous pocket and secured to the pectoralis fascia with O-Prolene or similar nonabsorbable suture, using the suture hole contained within the epoxy resin header. Any excess lead is positioned in a separate pocket at the side of the generator. To prevent abrasion of the lead, however, it should not be placed behind the pulse generator. Wound closure then proceeds in standard multilayer fashion, using a subcuticular stitch for the skin. The cosmetic results are generally very good.

Lead removal or revision In some circumstances it may become necessary to remove and/or replace the electrodes that encircle the vagus nerve trunk. Although fibrosis and adhesions may develop in the vicinity of the vagus nerve, Espinosa and coworkers (1999) have demonstrated that the spiral electrodes may be safely removed from the nerve, even years after they were implanted. The extent of scarring does not appear related to the duration of implant.

Surgical complication avoidance and management In the meta-analysis mentioned above, the most commonly observed surgical complication was infection. The site of the infection was either at the generator in the chest or near the leads in the neck. The overall infection rate was 2.86%, but more than half of these patients were successfully treated with antibiotic therapy alone, while only about 1.1% required explantation of the device. The causative organisms have not been reported. In many cases, the device has been replaced successfully after removal for infection. Transient vocal cord paralysis is the second most common surgical complication of VNS implantation. The incidence of this event in the collective study experience was only 0.7%. However, since video strob­ oscopy and formal swallowing assessments are rarely performed after surgery, it is possible that more cases went undetected, and the true prevalence of vocal cord paresis is poorly known. Fortunately, most reported

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cases resolve clinically. Vocal cord dysfunction should be minimized by careful manipulation of the vagus nerve, with preservation of its rete vascular supply and avoidance of excessive traction on the nerve. Temporary lower facial hypesthesia or paralysis occurred in another 0.7% of patients in the metaanalysis. As stated above, excessively high surgical incisions could have been a cause. To our knowledge, only one case of Horner’s syndrome has occurred. This complication is more commonly reported after carotid endarterectomy and may be due to injury or manipulation of the sympathetic plexus immediately below the carotid sheath, or from traction on the sympathetic fibers on the internal carotid. Lead breakage occurred commonly with earlier versions of the NCP system but has only rarely been described since device modification. Data from the manufacturer indicate that there have been a total of six lead breaks in the first 5000 implants since FDA approval (lead breakage rate  0.12%) (DeGiorgio, et al., 2001). Suturing directly to the lead body was a possible cause in one extremely early case, and generator movement that caused excessive forces on the lead electrode may have been the cause in two others (in both cases the generator was placed in breast tissue in women and the suture loop in the generator may not have been used). In another case, no strain relief loop was used. In the first 10000 implantation procedures, only nine cases of intraoperative bradycardia or asystole have been reported, accounting for an incidence less than 0.1%. All events occurred during the lead test. Asconape and coworkers (1999) have analyzed the factors that potentially contribute to this event and the means of their prevention. As mentioned, the superior or inferior cervical cardiac branches might be mistaken for the vagus trunk itself, and correct positioning of the electrodes on the intended nerve must be verified. Proper placement of the skin incision, centered over the midcervical portion of the nerve, will also help avert this complication. Current spread to the cardiac nerves can be minimized by measures that insulate them from the midcervical vagus trunk during the lead test, such as placement of a plastic dam beneath the nerve trunk and removal of pooled blood or saline from the vicinity. Finally, the current should be ramped up in small increments during the lead test, starting with 0.25 mA. Variants of the surgical procedure described above have been described for certain high-risk populations. For instance, patients with cognitive delay are prone to wound tampering, leading to breakdown of the incision and secondary infection. In such patients, placement of the pulse generator between the scapulae

may reduce the frequency of this event. In one study of cognitively delayed children, no infections occurred in the nine who underwent interscapular pulse generator placement, in contrast to two of 14 (14%) who required device externalization after infection of their subclavicular wound (Lee et al., 2002).

References Amar, A.P., Apuzzo, M.L.J. and Liu, C.Y. (2004) Vagus nerve stimulation (VNS) therapy after failed cranial surgery for intractable epilepsy: results from the VNS therapy patient outcome registry. Neurosurgery 55: 1086–93. Amar, A.P., DeGiorgio, C.M., Tarver, W.B. and Apuzzo, M.L.J. E05 Study Group (1999) Long-term multicenter experience with vagus nerve stimulation for intractable partial seizures: results of the XE5 trial. Stereotact. Funct. Neurosurg. 73: 104–8. Amar, A.P., Heck, C.N., DeGiorgio, C.M. and Apuzzo, M.L.J. (1999) Experience with vagus nerve stimulation for intractable epilepsy: some questions and answers. Neurol. med-chir. 39: 489–95. Amar, A.P., Heck, C.N., Levy, M.L., Smith, T., DeGiorgio, C.M., Oviedo, S. et al. (1998) An institutional experience with cervical vagus nerve trunk stimulation for medically refractory epilepsy: rationale, technique, and outcome. Neurosurgery 43: 1265–80. Amar, A.P., Levy, M.L. and Apuzzo, M.L.J. (2000) Vagus nerve stimulation for intractable epilepsy. In: S. Rengechary (ed.), Neurosurgical Operative Atlas, Vol. 9. Chicago: American Association of Neurological Surgeons, pp. 179–88. Amar, A.P., Levy, M.L., McComb, J.G. and Apuzzo, M.L.J. (2001) Vagus nerve stimulation for control of intractable seizures in childhood. Pediatr. Neurosurg. 34: 218–23. Annegers, J.F., Coan, S.P., Hauser, W.A., Leetsma, J., Duffell, W. and Tarver, B. (1998) Epilepsy, vagal nerve stimulation by the NCP system, mortality, and sudden, unexplained death. Epilepsia 39: 206–12. Asconape, J.J., Moore, D.D., Zipes, D.P., Hartman, L.M. and Duffel, W.H. (1999) Bradycardia and asystole with the use of vagus nerve stimulation for the treatment of epilepsy: a rare complication of intraoperative device testing. Epilepsia 40: 1452–54. Bauman, J.A., Ridgway, E.B., Devinsky, O. and Doyle, W.K. (2006) Subpectoral implantation of the vagus nerve stimulator. Neurosurgery 58: 322–6. Berta, S., Park, M.S., Meltzer, H.S., Amar, A.P., Apuzzo, M.L.J., Levy, K.M. et al. (2005) Vagus nerve stimulation therapy in patients with autism spectrum disorder: results from the vagus nerve stimulation therapy patient outcome registry. Neurosurgery 57: 417–18 (abstr.). Boon, P., Vonck, K., Vandekerckhove, T., D’have, M., Nieuwenhuis, L., Michielsen, G., Vanbelleghem, H., Goethals, I., Caemaert, J., Calliauw, L. and DeReuk, J. (1999) Vagus nerve stimulation for medically refractory epilepsy: efficacy and cost–benefit analysis. Acta Neurochir. 141: 447–53. Clark, K.B., Naritoku, D.K., Smith, D.C., Browning, R.A. and Jensen, R.A. (1999) Enhanced recognition memory following vagus nerve stimulation in human subjects. Nat. Neurosci. 2: 94–8. DeGiorgio, C.M., Amar, A. and Apuzzo, M.L.J. (2001) Surgical anatomy, implanatation technique, and operative complications. In: S.C. Schachter (ed.), Vagus Nerve Stimulation. London: Dunitz, pp. 31–50. Espinosa, J., Aiello, M.T. and Naritoku, D.K. (1999) Revision and removal of stimulating electrodes following long-term therapy with the vagus nerve stimulator. Surg. Neurol. 51: 659–64. Fisher, R.S. and Handforth, A. (1999) Reassessment: vagus nerve stimulation for epilepsy. Neurology 53: 666–9.

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references

George, M.S., Sackeim, H.A., Rush, A.J., Marangell, L.B., Nahas, Z., Husain, M.M. et al. (2000) Vagus nerve stimulation: a new tool for brain research and therapy. Biol. Psychiatry 47: 287–95. Krahl, S.E., Clark, K.B., Smith, D.C. and Browning, R.A. (1998) Locus coeruleus lesions suppress the seizure-attenuating effects of vagus nerve stimulation. Epilepsia 39 (Suppl. 7): 709–14. Krahl, S.E., Senanayake, S.S. and Handforth, A. (2001) Destruction of peripheral C-fibers does not alter subsequent vagus nerve stimulation-induced seizure suppression in rats. Epilepsia 42: 586–9. Lee, H., Chico, M., Hecox, K. and Frim, D. (2002) Interscapular placement of a vagal nerve stimulator pulse generator for prevention of wound tampering. Technical note. Pediatr. Neurosurg. 36: 164–6. Merrill, C.A., Jonsson, M.A., Minthon, L., Ejnell, H., C-son Silander, H., Blennow, K. et al. (2006) Vagus nerve stimulation in patients with Alzheimer’s disease: additional follow-up results of a pilot study through 1 year. J. Clin. Psychiatry 67: 1171–8. Morris, G.L. and Mueller, W.M. (1999) Long-term treatment with vagus nerve stimulation in patients with refractory epilepsy. The Vagus Nerve Stimulation Study Group E01–E05. Neurology 53: 1731–5.

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Murphy, J.V. (1999) Left vagal nerve stimulation in children with medically refractory epilepsy. J. Pediatr. 134: 563–6. Murphy, J.V., Hornig, G.W., Schallert, G.S. and Tilton, C.L. (1998) Adverse events in children receiving intermittent left vagal nerve stimulation. Pediatr. Neurol. 19: 42–4. Patil, A., Chand, A. and Andrews, R. (2001) Single incision for implanting a vagal nerve stimulator system (VNSS): technical note. Surg. Neurol. 55: 103–5. Rush, A.J., George, M.S., Sackeim, H.A., Marangell, L.B., Husain, M.M., Giller, C. et al. (2000) Vagus nerve stimulation (VNS) for treatmentresistant depressions: a multicenter study. Biol. Psychiatry 47: 276–86. Rush, A.J., Marangell, L.B., Sackeim, H.A., George, M.S., Brannan, S.K., Davis, S.M. et al. (2005) Vagus nerve stimulation for treatmentresistant depression: a randomized, controlled acute phase trial. Biol. Psychiatry 58: 346–54. Rutecki, P. (1990) Anatomical, physiological, and theoretical basis for the antiepileptic effect of vagus nerve stimulation. Epilepsia 31 (Suppl. 2): S1–S6. Schachter, S.C. and Saper, C.B. (1998) Progress in epilepsy research: vagus nerve stimulation. Epilepsia 39: 677–86.

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C H A P T E R

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Deep Brain Stimulation for Epilepsy Casey H. Halpern, Uzma Samadani, Brian Litt, Jurg L. Jaggi, and Gordon H. Baltuch

o u t l i n e Introduction

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Deep Brain Stimulation for Epilepsy:  Evidence from Animal Studies

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Deep Brain Stimulation of the Anterior  Nucleus of the Thalamus Rationale Indications Targeting and Surgical Procedure Pilot Studies Complications

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Open- versus Closed-Loop Systems

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Conclusion

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patients opt to have a vagus nerve stimulator (VNS) placed as an adjunct to medical therapy, associated with up to a 50% reduction in seizure frequency (Vagus Nerve Stimulation Study Group, 1995). However, most of these patients will not be seizure-free. Thus, due to the success of deep brain stimulation (DBS) for movement disorders (Krack et al., 2003; Halpern et al., 2007) combined with its advantages of adjustability, reversibility, and less risk of permanent neurologic deficits then surgical ablation (Schuurman et al., 2000), there has been an explosion of research into implantable devices for treating pharmaco-resistant epilepsy (Litt and Baltuch, 2001; Litt, 2003).

Approximately one-third of patients with epilepsy will have persistent seizures despite maximal antiepileptic drug (AED) therapy (Juul-Jensen, 1986; Sander, 1993; Sillanpaa and Schmidt, 2006). Resective brain surgery is typically indicated for patients with refractory partial seizures and can result in at least a 90% reduction in seizure frequency, though permanent neurologic deficits or death can occur in nearly 4% of cases (ILAE Commission Report, 1997). At least 50% of patients are not candidates for resection or choose not to undergo such an invasive procedure. Some of these

Neuromodulation

Other Anatomic Targets for Deep Brain  Stimulation for Epilepsy Centromedian Nucleus of the Thalamus Subthalamic Nucleus Caudate Nucleus Cerebellum Hippocampus

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The mechanism by which DBS may diminish seizures is not completely understood. However, stimulationinduced disruption of unopposed network activity is one hypothesis that appears to be consistent with available data (Lee et al., 2003; McIntyre et al., 2004). Evidence from subthalamic nucleus (STN) DBS suggests that high frequency stimulation may block epileptiform activity in the cortex (Monnier et al., 1960, M. Velasco and F. Velasco, 1982; Lado et al., 2003), whereas low frequency stimulation may drive or synchronize cortical activity.

Deep brain stimulation for epilepsy: evidence from  animal studies Seizure suppression with electrical stimulation of deep brain structures is effective in animal models using various neural targets, including the cerebellum, hippocampus, caudate nucleus, thalamus, STN, and mammillary nuclei (Mutani, 1969; Mirski et al., 1986; Shandra and Godlevsky, 1990; Vercueil et al., 1998; Bragin et al., 2002). We will focus on animal studies of DBS of the anterior nucleus of the thalamic (ANT), which is currently being studied in an ongoing doubleblind randomized trial (SANTE), evaluating its efficacy for epilepsy treatment (Fisher, 2006). As of 27 March 2006, 58 patients at 15 centers had been implanted with deep brain stimulators in ANT. Animal studies investigating efficacy of ANT DBS for epilepsy primarily reflect the work of Mirski and colleagues. Bilateral electrolytic lesions of the tracts connecting the mammillary bodies to the ANT in guinea pigs resulted in essentially complete protection from pentylenetetrazole-induced seizure activity (Mirski and Ferrendelli, 1984). This finding was supported by observations of enhanced glucose metabolism in ANT following administration of both pentylenetetrazole and ethosuximide to guinea pigs (Mirski and Ferrendelli, 1986). Recently, high frequency DBS (100 Hz) of the ANT has been shown to increase the clonic seizure threshold in a pentylenetetrazole-induced seizure model (Mirski et al., 1997). Interestingly, low frequency (8 Hz) DBS was proconvulsant as found in earlier studies (Dempsey and Morrison, 1941; Lado et al., 2003). In addition, bilateral ANT DBS may prolong the latency of onset of status epilepticus following administration of pilocarpine, while seizures were eliminated by bilateral anterior nuclear thalamotomy (Hamani et al., 2004). Efficacy of ANT DBS for epilepsy in animal models is still unclear given reports of lack of effect, as well as exacerbation of seizure frequency by chronic ANT DBS (Hamani et al., 2004; Lado, 2006).

Deep brain stimulation of the anterior nucleus of the thalamus Rationale In 1937, James W. Papez described a circuit linking hippocampal output via the fornix and mammillary nuclei in the posterior hypothalamus to ANT. ANT projects to the cingulum bundle deep to the cingulate gyrus, which travels around the wall of the lateral ventricle to the parahippocampal cortex, then completing the circuit by returning to the hippocampus (Carpenter, 1991). Atrophy, MRI signal change or sclerosis of structures within the classic circuit of Papez has been noted in mesial temporal sclerosis, as well as other forms of epilepsy (Oikawa et al., 2001). Stimulation of targets within this circuit is hypothesized to result in direct anterograde cortical stimulation. ANT is a preferred target for DBS because of its relatively small size and projections to limbic structures ultimately affecting wide regions of neocortex. Furthermore, it is not as deep or close to basal vascular structures as the mammillary nuclei. ANT has been lesioned stereotactically resulting in improved seizure control in humans (Mullan et al., 1967). These anatomic connections and precursor ablative techniques have motivated investigation of ANT DBS for epilepsy.

Indications ANT DBS is indicated for partial onset epilepsy with or without secondary generalization associated with frequent seizures, resulting in falls, injuries and impaired quality of life, refractory to 12–18 months of at least two therapeutically dosed antiepileptic agents (Hodaie et al., 2002; Kerrigan et al., 2004; Lim et al., 2007; Osorio et al., 2007). Patients should be without evidence of progressive neurologic or systemic disease and have failed surgical resection and/or vagal nerve stimulation. Scalp video-EEG monitoring is necessary to characterize seizure types and demonstrate bilateral or non-localizing findings. Preoperative imaging should rule out any lateralizing structural abnormalities. Subjects, family, or the legal guardian must be capable of recognizing the patient’s seizures and maintaining an accurate seizure diary.

Targeting and Surgical Procedure General endotracheal anesthesia or local anesthesia is administered prior to placement of the Leksell frame

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Deep brain stimulation of the anterior nucleus of the thalamus

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Figure 51.1  Diagram demonstrating simulation of the planned trajectory to the anterior nucleus of the thalamus for deep brain stimulation using a surgical navigation system (Medtronic Stealth navigation, Medtronic, Inc. Minneapolis, MN) with a superimposed standard stereotactic atlas

(Hodaie et al., 2002; Kerrigan et al., 2004; Andrade et al., 2006; Lim et al., 2007; Osorio et al., 2007; Samadani and Baltuch, 2007). Frame tilt should be parallel to the lateral canthal–external auditory meatal line which is itself approximately parallel to the anterior commissure– posterior commissure (AC–PC) line. After attachment of the magnetic resonance imaging (MRI) localizer, a 1.5 Tesla MRI is obtained with both fast spin echo inversion recovery and standard T2 images. Computed tomography (CT) can also be used. Target sites were selected from MRI by using 1 mm thick axial, coronal, and sagittal spoiled gradient echo pulse sequences. Indirect localization of ANT is performed with reference to a standard stereotactic atlas (Schaltenbrand and Wahren, 1977) by identifying the AC–PC line on the sagittal image. AC and PC coordinates

relative to the center of the frame are obtained to calculate the midcommissural point (MCP). ANT is 5 mm lateral and 12 mm superior to MCP. Since ANT is visible in the floor of the lateral ventricle on MRI, direct localization is possible and frame coordinates are calculated. Simulation of the planned trajectory from entry point to ANT is performed using a surgical navigation system (Medtronic Stealth navigation, Medtronic, Inc. Minneapolis, MN; Stryker Leibinger, Inc., Kalamazoo, MI) to confirm avoidance of sulcal vessels (Figure 51.1). The MRI is downloaded into the Stealth station computer. Inputting the entry point at or anterior to the coronal suture plots the trajectory, as well as the anterior–posterior and lateral arc coordinates for the Leksell frame. The patient is placed in a supine or semisitting position, and after Mayfield fixation, sterile preparation

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51.  Deep Brain Stimulation for Epilepsy

of the unshaven head, and local infiltration with 1% xylocaine 1:100 000 epinephrine, an incision is made overlying the coronal suture. Burr-holes are placed, and the dura and pia are sharply incised and cauterized. A guide cannula is inserted through the burr-hole and advanced deep into the brain to a point 10 mm from the desired target under direct fluoroscopic and Leksell frame guidance. Under local anesthesia, monopolar single-unit recording electrode (Advanced Research Systems, Atlanta, GA, or FHC, Bowdoinham, ME) can be introduced to confirm anatomic depth for entry into thalamic tissue after traversing the lateral ventricle. No units are recorded while positioned in the ventricle, but the electrode tip is advanced until recordings are first heard (ANT superficial surface) and then until units cease (intralaminar region) and recommence (dorsomedian nucleus of the thalamus) (Figure 51.2). Extracellular action potentials are amplified with a GS3000 (Axon Instruments, Sunnyvale, CA) or Leadpoint (Medtronic, Minneapolis, MN) amplifier and simultaneously recorded using standard recording techniques (300–10 000 Hz), together with a descriptive voice channel. ANT neurons are identified based on (1) regional characteristics, (2) a firing rate previously described for human recordings (Kerrigan et al., 2004), (3) and a characteristic burst firing pattern. After removing the single-unit recording electrode, a stimulation lead (Radionics Stimulation/Lesioning Probe, Burlington, MA) is introduced to elicit the driving response, suggestive of ANT placement (Figure 51.3). ANT DBS has been associated with recruiting rhythms on cortical EEG in patients with the most pronounced seizure frequency reduction (Hodaie et al., 2002). These changes in EEG signal morphology can, however, be elicited from several other thalamic nuclei (Dempsey and Morrison, 1941). Once this lead is removed, the DBS lead is advanced to ANT, ensuring that all contacts of the lead are within thalamic parenchyma. The cannula and lead stylet are withdrawn under fluoroscopy, after test stimulation demonstrates no adverse effects. Another fluoroscopic image is done to show that the electrode is secure. The stimulation leads we use are Medtronic 3387 DBS Medtronic (Minneapolis, MN) depth electrodes with four platinum–iridium stimulation contacts 1.5 mm wide with 1.5 mm edge-to-edge separation, since ANT is relatively larger than other DBS targets. The lead is secured to a burr-hole cap, and the skin incision is closed. The Leksell frame is removed and the head, neck and infraclavicular regions are sterilized in preparation for placement of the implantable pulse generator (IPG) (model Itrel II, Soletra, or Kinetra; Medtronic) in a subclavicular pocket bilaterally. The scalp incision is reopened for connection of the lead to an extension wire (Medtronic 7495 Lead Extension,

Electrode track (circles � recordings) A. Pr

V.III.

In ventricle (no units)

D.M.

In anterior nucleus

0.1s

In dorsal medial n.

Figure 51.2  Sagittal representation with planned trajectory of electrode implantation for the anterior nucleus of the thalamus. Recordings from single-unit monopolar electrode shown at right from various depth levels, identifying entry into thalamic tissue after traversing the lateral ventricle (Adapted with permission from Kerrigan et al., 2004. John Wiley & Sons Ltd)

Medtronic, Minneapolis, MN), which is tunneled subcutaneously to an IPG. After reversal and recovery from anesthesia, placement location of the DBS leads is confirmed by MRI or CT (Figure 51.4). Generally, patients should undergo postoperative monitoring in the epilepsy-monitoring unit, where simultaneous scalp and thalamic EEGs through the implanted leads can be recorded. Patients are discharged to home two days postoperatively, but multiple outpatient visits are usually necessary to optimize stimulation parameters. Stimulators are turned on approximately 10–14 days postoperatively. For initial stimulation, frequency is set at 90–130 Hz, pulse width at 60–90 s, and pulse amplitude at 4–5 V, and the contact inducing the optimal clinical effect at minimal voltage and with the fewest side effects is identified. The benefits of bipolar versus monopolar stimulation remain to be determined as do “cycling” versus “continuous” stimulation. A recent study of bilateral ANT DBS in four patients with refractory epilepsy showed no significant difference in seizure frequency between cycling and continuous stimulation period using within-group comparisons (Lim et al., 2007). One proposed method of cycling or intermittent stimulation using an “open-loop” device (discussed below) is through a “duty cycle” of 1 min ON and 5 min OFF (Litt, 2003). Intermittent stimulation may increase the battery life of the IPG, is theoretically safer for neural tissue than chronic, continuous stimulation, and has been successful in clinical trials for vagus nerve stimulation for epilepsy (Hodaie et al., 2002).

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Deep brain stimulation of the anterior nucleus of the thalamus

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Stimulation L anterior nucleus: driving response 6 V, 10 cps, 330 usec pulse width Stimulation Starts FP1-F7 F7-T3 T3-T5 T5-O1 FP2-F8 F8-T4 T4-T6 T6-O2 50µV

LFF 1.0, HFF 35

1 Sec

Figure 51.3  Scalp EEG driving response to left-sided anterior nucleus of the thalamus stimulation (Adapted with permission from Kerrigan et al., 2004. John Wiley & Sons Ltd)

Stimulating electrode, 4 contacts

Electrode

(B)

(A)

Figure 51.4  A T1-weighted sagittal (A) and T2-weighted axial (B) magnetic resonance image demonstrating lead placement for deep brain stimulation of the anterior thalamic nucleus

Pilot Studies Unfortunately, we are limited to small sample human pilot studies in evaluating ANT DBS as a treatment for pharmaco-resistant epilepsies, though a multicenter randomized clinical trial of intermittent bilateral ANT DBS for medically intractable seizures is currently under way (Fisher, 2006). Despite significant individual variation in outcome, overall bilateral high-frequency ANT DBS appears to be safe, well tolerated, and effective in some subjects with inoperable, refractory epilepsy. Table 51.1 summarizes the results of six pilot studies of ANT DBS.

Upton and coworkers (1987) reported on four of six patients with intractable epilepsy who experienced a significant reduction in seizure frequency, one of whom was completely seizure-free at follow-up. This may be due to microthalamotomy or lesioning of the ANT, an effect that has been noted previously (Tasker, 1998). In fact, electrode implantation appears to decrease seizure frequency itself, and activation of the IPG and multiple subsequent adjustments to stimulatory parameters or contacts stimulated may not be linked to any further benefit in seizure control (Andrade et al., 2006; Lim et al., 2007). However, in one patient, the IPGs were turned off after 3 years of

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51.  Deep Brain Stimulation for Epilepsy

Table 51.1  Clinical outcome following ANT DBS in six pilot studies in humans Series

No.

Average postop. follow-up

Stimulation-type

% reduction seizure frequency/mth

Osorio et al. (2007)

4

36

Cycling

76a 75

Lee et al. (2006)

3

13

Cycling

Lim et al. (2007)

4

44

Continuousb

51

Hodaie et al. (2002)

5

15

Cycling

54c

Kerrigan et al. (2004)

5

12

Cycling

Andrade et al. (2006) a

6

48

Cycling

14d e

51f

p 0.01

b

Intermittent stimulation was later used to prolong battery life although the timescale was not reported

c

p 0.05

d

This study noted more than a 50% reduction in serious seizure (generalized tonic–clonic seizures and complex partial seizures) frequency e

Multiple changes in stimulation parameters, including continuous vs. cycling were performed in this study

f

4 of 6 patients had a significant decrease in the frequency of seizures/month (p 0.05), but significance for overall mean reduction was not reported

DBS with maintenance of improved seizure control for more than one year. Thus, it is difficult to distinguish the relative effects of electrode insertion and stimulation on the reduction in seizure frequency. The effect of microthalamotomy on seizure propagation, however, remains to be debated as a recent study was unable to detect a lesion effect during the immediate postoperative period (Osorio et al., 2007). Other pilot studies of intermittent ANT DBS have reported significant reduction in frequency and propagation of generalized tonic–clonic seizures and complex partial seizures in four of five patients (Kerrigan et al., 2004). However, only one of the five patients showed a statistically significant reduction in total seiz­ure frequency. Importantly, discontinuation of DBS resulted in an immediate increase in seizure frequency and intensity that improved when stimulation was resumed. This suggests that ANT DBS-induced inhibition is at least in part implicated in reducing seizure frequency (Kerrigan et al., 2004; Lim et al., 2007; Osorio et al., 2007). The beneficial response to closed-loop stimulation (described below) provides further support for a beneficial role of electrical stimulation. A recent study reporting long-term follow-up noted that electrode implantation and stimulation in ANT was followed by more than a 50% seizure reduction in five of six patients. However, significant benefit in two patients was not seen until years 5 and 6, respectively, with the addition of further adjuvant AEDs (Andrade et al., 2006). There is evidence for a longterm effect of ANT DBS on the propensity to develop

seizures (Andrade et al., 2006), and indeed, ongoing clinical benefit after cessation of DBS has been noted in tremor (Lang and Lozano, 1998). Bitemporal mesial epilepsy, as opposed to extratemporal or poorly localized seizures (Hodaie et al., 2002; Kerrigan et al., 2004; Andrade et al., 2006), may be most responsive to ANT DBS given a recent report of more than a 75% reduction in seizure frequency (Osorio et al., 2007). Seizure frequency decreased by 93% in one patient, which is the most dramatic response reported in the literature. Alternatively, a higher mean frequency (157  Hz) may at least in part explain this impressive response.

Complications ANT DBS appears to be a safe, well-tolerated treatment of refractory seizures with all of the reported complications and stimulation-induced adverse effects being mild and transient. Reported adverse effects due to stimulation are paranoid ideation, intermittent nystagmus with cycling stimulation, auditory hallucinations, anorexia, and lethargy (Andrade et al., 2006; Osorio et al., 2007; Samadani and Baltuch, 2007). Complications due to the surgical procedure or hardware include a small right frontal hemorrhage without any permanent neurologic deficit, scalp erosion necessitating removal of the implanted system, infection of the right anterior chest, and accidental turning-off of the stimulator (Hodaie et al., 2002; Lee et al., 2006; Lim et al., 2007).

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Other anatomic targets for deep brain stimulation for epilepsy

Other anatomic targets for deep brain stimulation for epilepsy Although the SANTE trial will only be evaluating ATN DBS, other neural targets are worth discussing in order to provide a more thorough review of the potential for DBS in epilepsy. Some open-label clinical trials have reported on DBS of various targets to treat pharmaco-resistant seizures, demonstrating marginal efficacy in stimulating the centromedian nucleus (CM) of the thalamus, caudate nucleus, cerebellum, and STN.

Centromedian Nucleus of the Thalamus Velasco and colleagues have contributed to the majority of work addressing CMT DBS. As first hypothesized by Penfield (1938), CMT is an integral part of an ascending subcortical system, arising from the brain stem and diencephalons and projecting diffusely to cerebral cortex, supporting a role for CMT in the pathophysiology of generalized seizures (M. Velasco et al., 2000). The beneficial effect of CMT DBS on seizure control may be due to desynchronization and hyperpolarization of the ascending reticular and cortical neurons (M. Velasco et al., 2000). A very recent open-label trial in 13 patients with Lennox–Gastaut syndrome reported overall seiz­ ure reduction of 80% with significant improvement in quality of life (A.L. Velasco et al., 2006). While CMT DBS may be effective in controlling frequency of generalized seizures, results in patients with complex partial seiz­ ures are unclear (F. Velasco et al., 1987, 1995; F. Velasco, Velasco, Jimenez et al., 2001; M. Velasco et al., 1993). In contrast to the results of these open-label studies, a trial of CMT DBS in seven patients using a double-blind, crossover design, revealed no significant difference in seizure frequency (Fisher et al., 1992), and a recent report showed no short-term benefit in two patients, one of whom was subsequently implanted with electrodes in ANT (Andrade et al., 2006).

Subthalamic Nucleus Extensive experience of STN DBS for the treatment of movement disorders makes STN an appealing target (Halpern et al., 2007). The substantia nigra pars reticulata (SNr) is known to play a role in gating and control of seizures through its GABAergic nigrotectal projections to the superior colliculus (Gale, 1986). Inhibition of GABAergic SNr neurons results in suppression of partial and generalized epileptic seizures in animal models of epilepsy (Iadarola and Gale, 1982). The subthalamic nucleus (STN) exerts excitatory control

645

on the nigral system. Indeed, pharmacological or electrical inhibition of STN leads to seizure suppression (Vercueil et al., 1998). A case study of high-frequency bilateral STN DBS for a child with inoperable epilepsy due to focal centroparietal dysplasia observed an 81% improvement in seizure frequency at 30 months follow-up (Benabid et al., 2001). An 80% improvement in two of five patients with partial-onset seizures treated with STN DBS for 16 months has been reported (Loddenkemper et al., 2001). Another open-label study of STN DBS demonstrated significant improvement of seizures in four of five patients (mean reduction of seizure frequency 64.2%) (Chabardes et al., 2002). Most recently, two cases with refractory partial-onset seiz­ ures were treated with bilateral STN DBS (Handforth et al., 2006). The first patient had a 50% reduction in seiz­ure frequency, but seizure-related injuries continued to occur. The second case noted seizure frequency to be reduced by one-third, but seizures were milder and caused fewer injuries, thus improving the quality of life of this patient. STN DBS may hold significant future potential as a treatment for epilepsy; however, larger randomized, double-blind clinical trials are necessary.

Caudate Nucleus The head of the caudate nucleus (HCN), thalamus, and neocortex communicate as a functional entity known as the “caudate loop” (Heuser et al., 1961). Activation of HCN has been shown to correlate with hyperpolarization of cortical neurons, suggesting that suppression of epileptic activity may be a result of stimulation-induced inhibition on the cortex. Indeed, low-frequency stimulation (4–8 Hz) of the ventral part of HCN has been shown to suppress interictal epileptic activity, focal amygdalahippocampal discharges, and generalization of seizures (Chkhenkeli and Chkhenkeli, 1997; Chkhenkeli et al., 2004), however, clinical seizure data were not assessed. Thus, controlled clinical studies are necessary to further evaluate the caudate as a target for DBS in epilepsy.

Cerebellum Cerebellar stimulation (CS) likely activates inhibitory Purkinje cells, which suppress the excitatory cerebellar output to the thalamus, decreasing the excitatory thalamocortical projection to motor cortex, resulting in a transient suppression of cortical excitability (Molnar et al., 2004). Cooper and colleagues were the first to report on CS for epilepsy in an open-label trial, demonstrating that 18 of the 34 patients experienced at least a 50% reduction in seizures (Cooper et al., 1973).

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51.  Deep Brain Stimulation for Epilepsy

A more recent uncontrolled study reported that 23 (85%) of 32 patients benefited overall from long-term CS (Davis and Emmonds, 1992); however, controlled, double-blind trials demonstrated improvement in only two of (14%) 14 patients (Van Buren et al., 1978; Wright et al., 1984). Very recently, a double-blind trial of five patients showed a significant reduction in generalized tonic–clonic seizures (GTCSs) and tonic seiz­ ures (TSs) at 2 years follow-up (F. Velasco et al., 2005). Improvement in GTCSs occurred sooner, however, and was more significant than that for TSs. Therefore, as suggested in animal studies, CS may act mainly at the supradiencephalic level (Laxer et al., 1980). Larger clinical trials are necessary to further assess the role of CS in epilepsy treatment.

Hippocampus Enough evidence exists to suggest that temporal lobe seizures are initiated from and/or propagated through the hippocampal formation (Sperling et al., 1992; Swanson, 1995). Furthermore, the hippocampus is an integral component of the circuit of Papez (Papez, 1937; Carpenter, 1991; Oikawa et al., 2001). Subacute hippocampal stimulation (HS) using bilateral depth electrodes or unilateral electrode grids abolished complex partial and secondarily GTCs and significantly decreased the number of interictal EEG spikes at the focus in seven of 10 patients with intractable temporal lobe seizures. A subsequent report by the same group of chronic HS in three patients demonstrated persistently blocked epileptogenesis with no negative effect on short-term memory (A.L. Velasco et al., 2000). As a follow-up, continuous high-frequency HS for about two weeks in 10 patients revealed a significant decrease in seizures and interictal paroxysmal activity (F. Velasco, Velasco, Velasco et al., 2001). A small open series of three patients with complex partial seizures reported that DBS of the amygdalohippocampal region resulted in greater than 50% reduction in seizure frequency at 5 months follow-up (Vonck et al., 2002). More recently, these investigators reported that at a mean follow-up of 14 months, bilateral amygdalohippocampal DBS in seven patients resulted in one patient who was free of complex partial seizures (Vonck et al., 2005). Three other patients had more than a 50% reduction in seizure frequency, while two of the seven patients had a reduction of 25%. Only one patient had no change in seizure frequency. Controlled studies with larger sample sizes are mandatory to identify a potential treatment population for HS and optimal stimulation parameters.

Open- versus closed-loop  systems Closed-loop systems are “intelligent” brain devices that can produce bursts of stimulation that react to and terminate physiological changes such as epileptiform activity (Litt, 2003). These stimulators may provide comparable or even more effective seizure suppression than their “blind,” “open-loop” counterparts (described above) that stimulate continuously or intermittently without reacting to any physiological changes. Penfield and Jasper (1954) were the first to apply focal electrical stimulation to a human’s brain and successfully terminated spontaneous seizures detected by electrocorticography during resective surgery. Closed-loop devices are more efficient and should be better tolerated than an open-loop modality because of lower daily doses of stimulation (Osorio et al., 2001). “Intelligent” detection may be less toxic than intermittent and continuous stimulation. A research group at the University of Pennsylvania, using EEG recordings in mesial temporal lobe epilepsy, identified a spontaneous progression of changes in brain activity that can lead to a full-blown convulsive seizure (Litt et al., 2001). These changes can last up to 7 hours before the seizure, and, if detected, can be successfully suppressed by an implanted stimulator. Mapping cortical networks involved in seizure generation and determining the most effective time of stimulation relative to seizure onset still require further investigation. A trial of four patients with refractory seizures treated with responsive cortical stimulation noted suppression of clinical seizures and resolution of electrographic seizure activity (Kossoff et al., 2004). Recently, high-frequency stimulation was performed in eight patients with a closed-loop system, in which stimulation was delivered either to the epileptogenic cortex (n  4) or ATN (n  4) after automated seizure detection (Osorio et al., 2005). Three of the four patients in which stimulation was delivered to the cortex and two of four patients with ATN DBS responded with decreased seizure frequency. A multi-institutional clinical trial of a cranially implanted responsive neuro­ stimulator (RNS, NeuroPace, Inc., Mountain View, CA) is currently under way in patients with pharmacoresistant partial onset seizures. The RNS IPG continuously analyzes the patient’s electrocortigram and triggers stimulation whenever the characteristics programmed by the clinician are indicative of seizures or epileptiform precursors. A feasibility study of this closed-loop device has already described about a 45% decrease in seizure frequency in the majority of patients at 9 months follow-up (Fountas et al., 2005).

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Conclusion

Conclusion There are a considerable number of patients suffering from medically refractory epilepsy who are not candidates for resective brain surgery. Some of the patients may benefit from DBS. There are many potential targets for stimulation for epilepsy; however, evidence is limited to open-label pilot studies and very small double-blind clinical trials. While there is an ongoing prospective double-blind randomized trial for ANT DBS (SANTE), it is difficult at this time to make any definitive judgments about the efficacy of targeting ANT with stimulation for epilepsy treatment. Further work is necessary to identify a potential patient population for whom this technique would be indicated, which target is most efficacious, optimal stimulation parameters, and the ideal mode of stimulation.

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Schaltenbrand, G. and Wahren, W. (1977) Atlas for Stereotaxy of the Human Brain. Stuttgart: Thieme. Schuurman, P.R., Bosch, D.A., Bossuyt, P.M. et al. (2000) A comparison of continuous thalamic stimulation and thalamotomy for suppression of severe tremor. N. Engl. J. Med. 342 (7): 461–8. Shandra, A.A. and Godlevsky, L.S. (1990) Antiepileptic effects of cerebellar nucleus dentatus electrical stimulation under different conditions of brain epileptisation. Indian J. Exp. Biol. 28 (2): 158–61. Sillanpaa, M. and Schmidt, D. (2006) Natural history of treated childhood-onset epilepsy: prospective, long-term populationbased study. Brain 129 (Pt 3): 617–24. Sperling, M.R., O’Connor, M.J., Saykin, A.J. et al. (1992) A noninvasive protocol for anterior temporal lobectomy. Neurology 42 (2): 416–22. Swanson, T.H. (1995) The pathophysiology of human mesial temp­ oral lobe epilepsy. J. Clin. Neurophysiol. 12 (1): 2–22. Tasker, R.R. (1998) Deep brain stimulation is preferable to thalamotomy for tremor suppression. Surg. Neurol. 49 (2): 145–53; discussion 153–4. Upton, A.R., Amin, I., Garnett, S. et al. (1987) Evoked metabolic responses in the limbic-striate system produced by stimulation of anterior thalamic nucleus in man. Pacing Clin. Electrophysiol. 10 (1 Pt 2): 217–25. Vagus Nerve Stimulation Study Group (1995) A randomized controlled trial of chronic vagus nerve stimulation for treatment of medically intractable seizures. Neurology 45 (2): 224–30. Van Buren, J.M., Wood, J.H., Oakley, J. and Hambrecht, F. (1978) Preliminary evaluation of cerebellar stimulation by doubleblind stimulation and biological criteria in the treatment of epilepsy. J. Neurosurg. 48 (3): 407–16. Velasco, A.L., Velasco, F., Jimenez, F. et al. (2006) Neuromodulation of the centromedian thalamic nuclei in the treatment of generalized seizures and the improvement of the quality of life in patients with Lennox–Gastaut syndrome. Epilepsia 47 (7): 1203–12. Velasco, A.L., Velasco, M., Velasco, F. et al. (2000) Subacute and chronic electrical stimulation of the hippocampus on intractable temporal lobe seizures: preliminary report. Arch. Med. Res. 31 (3): 316–28. Velasco, F., Carrillo-Ruiz, J.D., Brito, F. et al. (2005) Double-blind, randomized controlled pilot study of bilateral cerebellar stimulation for treatment of intractable motor seizures. Epilepsia 46 (7): 1071–81. Velasco, F., Velasco, M., Jimenez, F. et al. (2001) Stimulation of the central median thalamic nucleus for epilepsy. Stereotact. Funct. Neurosurg. 77 (1-4): 228–32. Velasco, F., Velasco, M., Ogarrio, C. and Fanghanel, G. (1987) Electrical stimulation of the centromedian thalamic nucleus in the treatment of convulsive seizures: a preliminary report. Epilepsia 28 (4): 421–30. Velasco, F., Velasco, M., Velasco, A.L. et al. (1995) Electrical stimulation of the centromedian thalamic nucleus in control of seizures: long-term studies. Epilepsia 36 (1): 63–71. Velasco, F., Velasco, M., Velasco, A.L. et al. (2001) Electrical stimulation for epilepsy: stimulation of hippocampal foci. Stereotact. Funct. Neurosurg. 77 (1-4): 223–7. Velasco, M. and Velasco, F. (1982) State Related Brain Stem Regulation on Cortical and Motor Excitability: Effects on Experimental Focal Motor Seizures. Orlando, FL: Academic Press. Velasco, M., Velasco, F., Velasco, A.L. et al. (1993) Effect of chronic electrical stimulation of the centromedian thalamic nuclei on various intractable seizure patterns: II. Psychological performance and background EEG activity. Epilepsia 34 (6): 1065–74. Velasco, M., Velasco, F., Velasco, A.L. et al. (2000) Acute and chronic electrical stimulation of the centromedian thalamic

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C H A P T E R

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Cerebellar Stimulation for Epilepsy Steven Falowski, Ashwini D. Sharan, Amanda Celii, and Ross Davis

o u t l i n e Introduction

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Discussion

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approved for partial seizures since 1997. However, seiz­ ure frequency is reduced at least 50% in one-third of patients (Handforth et al., 1998; Vonck et al., 2002; Vonck et al., 2007). Other stimulation targets for epilepsy have included the cerebellum, thalamus, caudate nucleus, subthalamic nucleus, and the epileptic focus (Loddenkemper et al., 2001; Hodaie et al., 2002; Goodman, 2004; Kanner, 2004; Fountas et al., 2005; Graves and Fisher, 2005; Hamani et al., 2005; Andrade et al., 2006; Fountas and Smith, 2007; A.L. Velasco et al., 2007; F. Velasco et al., 2007; Halpern et al., 2008). The obvious advantages of neural stimulation are reversibility and stimulation adjustment. This review will focus on the application of cerebellar stimulation in the treatment of epilepsy.

Epilepsy affects a large percent of the population, 5–10 per 1000 population in North America (Hauser and Hesdorffer, 1990; Wiebe et al., 1999, 2001). Onethird of the patients with epilepsy will not have satisfactory control by medication alone (Kwan and Brodie, 2000). Within this group, surgery has been an effective treatment in 50% of these patients (Wiebe et al., 2001). Resective surgery has been used in these cases, and success rates in seizure freedom vary. This still leaves 15–40% patients without relief (Vonck et al., 2002). Neural stimulation has become a promising nondestructive alternative for the treatment of medically intractable epilepsy (Loddenkemper et al., 2001; Hodaie et al., 2002; Goodman, 2004; Kanner, 2004; Fountas et al., 2005; Graves and Fisher, 2005; Hamani et al., 2005; Andrade et al., 2006; Fountas and Smith, 2007; A.L. Velasco et al., 2007; F. Velasco et al., 2007; Halpern et al., 2008). Vagus-nerve stimulation (VNS) has been FDA

Neuromodulation

Cerebellar organization The cerebellum can be divided into the flocculonodular, anterior, and posterior lobes. Functional divisions

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include the vermis, the intermediate zone, and the lateral zone. The flocculonodular lobe coordinates balance and eye movements. The anterior cerebellum is involved in muscle tone and proprioception via the spinocerebellar tracts. The posterior lobe receives input from the motor cortex and is involved in fine motor control. The vermis receives inputs mainly from the spinocerebellar tracts and carries information on the position and balance of the trunk. The intermediate zone receives input from the corticopontocerebellar fibers and is integrated in movement. The lateral zone receives input via pontocerebellar fibers from the parietal cortex and is involved with position sense. The cerebellum has a rich connection with many regions of the neuroaxis, and may have control in learning, sensory, and motor processing (Silveri et al., 1994; Schmahmann, 1997). It is tonically active and exerts a stabilizing influence on motor function (Llinas, 1981), with its outflow tracts being inhibitory (Cooper et al., 1978). This tonic suppression or inhibitory effect is also seen on the amygdala and hippocampus in animal models (Maiti and Snider, 1975). The firing rate of cerebellar neurons modulates movements (Llinas, 1981; Bloedel, 1985), cerebellar neurons have shown neuroplasticity (Lee and Thompson, 2006; Ohyama et al., 2006) and they have an integrative function for cognition and motor functioning. Hence, loss of muscle tone, weakness, and lack of coordination are seen with cerebellar injury. The somatotopic organization of the cerebellum may serves as a guide to determining placement of electrodes. This organization is seen with the climbing fiber input to the Purkinje cell (Davis and Bloedel, 1984: 109–24). The orientation of particular body surfaces is most pronounced in Lobule V and VI. The medial vermis represents neck and upper back while the lateral vermis represents the limbs. This was important with studies pertaining to cerebral palsy, dystonia, and spasticity. This discrete organization of the cerebellum may play an important role in placement of the electrodes for epilepsy. Misplacement of electrode position may produce marked differences in effect, most specifically modification of motor activity. This could lead to untoward side effects that could limit the efficacy of stimulation. The most studied area for cerebellar stimulation in epilepsy patients has been the superior cerebellar cortex (Davis and Emmonds, 1992; Davis, 2000; F. Velasco et al., 2005).

Research leading to cerebellar stimulation for epilepsy Cerebellar stimulation has been previously reported in the treatment of cerebral palsy, spasticity, dystonia,

and epilepsy (Moruzzi, 1950; Dow et al., 1962; Cooper et al., 1978; Davis et al., 1982; Davis and Emmonds, 1992; Davis, 2000). Pioneering work in the area of cere­bellar stimulation began with animal studies that demonstrated that stimulation of the anterior vermis would lead to an inhibition of decerebrate rigidity (Lowenthal and Horsley, 1897; Sherrington, 1898; Moruzzi, 1950). The inhibitory role of the cerebellum was further demonstrated by excitation of the anter­ ior and paramedian lobes that lead to inhibition of cortically induced movements (Snider et al., 1948) and Moruzzi’s monograph was released in 1950 discussing cerebellar stimulation. It was thought that stimulation of the cerebellum would lead to an activation of bulbar inhibitory pathways. An initial important contribution of this work was that frequencies of 10 per second failed to produce a response, but frequencies of 200–300 per second had an inhibitory effect on postural rigidity (Cooper, 1984). These early observed effects also lead to the investigation of cerebellar stimulation for the treatment of epilepsy. Moruzzi (1950) and Cooke (Cooke and Snider, 1953) showed that cerebellar stimulation could terminate seizure activity. Cat models demonstrated that cerebellar stimulation altered seizure patterns and low voltage stimulation could stop a seizure (Cooke and Snider, 1953). Other studies in rat models demonstrated the inhibitory influences on chronic epileptic activity (Dow et al., 1962). These lead to studies in humans that demonstrated decreased cortical seizure activity, inhibition of spinal reflexes, and cortical sensory evoked responses (Upton, 1978). Cooper took interest in this early work, becoming a pioneer for brain stimulation in the treatment of epilepsy (Rosenow et al., 2002). He implanted the first stimulator on the anterior cerebellum in a patient with epilepsy in 1972. This patient was seizure-free for the duration of the implantation. However, subsequent studies varied in placement of the electrodes as well as in patient selection (Cooper, Amin et al., 1976; Cooper, Riklan 1976; Cooper et al., 1977). In those reports, there was at least a 50% improvement in seizure frequency in more than 50% of patients. Subsequently, animal studies have shown efficacy (Maiti and Snider, 1975; Heath et al., 1978; Culic et al., 1994; Godlevskii et al., 2003). Cerebellar stimulation of the midline cortex shortened or terminated electrical discharges from the amygdala and hippocampus i­ndicating its ability to exert a tonic suppressor influence on these centers of the brain (Maiti and Snider, 1975). This was followed by another study showing inhibition of the hippocampus with stimulation of the posterior vermis, fastigial nucleus, and intervening midline folia of the cerebellum (Heath et al., 1978).

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Although these inhibitory effects are observed in the hippocampus and amygdala, the question arose whether cerebellar stimulation led to the suppression of EEG seizure activity. Culic et al. demonstrated in rats that cerebellar stimulation evoked the decrease of mean total EEG activity (Culic et al., 1994). This was further observed by suppression of spike and ictal discharges in other rat models. These animal studies on EEG suppression were further confirmed in a human trial that demonstrated that stimulation of the cerebellar dentate nucleus suppressed the subclinical epileptic discharges from intracerebral electrodes (Chkhenkeli et al., 2004).

Effect of stimulation The effects of cerebellar stimulation were still being investigated. Upton et al. demonstrated in two patients with cerebral palsy the effects of stimulation of the cerebellar cortex on the amplitude of somatosensory evoked potentials (SSEPs) (Upton, 1978; Davis and Bloedel, 1984: 141). SSEPs were significantly larger within hours and days after the stimulators were switched off and there was a reduction in amplitude when the stimulators were turned on. Additionally, positron emission tomography (PET) demonstrated a reduction in cerebral cortical glucose metabolism when the stimulators were off and return to normal when the stimulators were on. These findings positively corresponded with a clinical decrease in spasticity in these two patients. The effects of chronic stimulation to the cerebellar cortex were studied in three autopsied patients (Davis and Bloedel, 1984: 109–24). In two of the patients there were no observed histological findings or clinically observed neurologic deficits. In one case under abnormally higher stimulation levels there was histological damage to the cerebellar folia under the electrode with loss of Purkinje cells followed by glial proliferation. This was seen with 11 days of stimulation in the range of 1.8–6.8 C/cm2/phase followed by 32 days at 14–25 C/cm2/phase. There was also microscopic evidence of leptomeningeal thickening in this patient. These findings encompassed a very small area of the cerebellar cortex (1%) and were not associated with any observed neurologic deficit. Experimental work in monkey cerebellar cortex by Brown et al. revealed a charge density of 7.4 C/cm2/ phase to be safe and destruction of cerebellar conducting elements at charge density above 10 C/cm2/phase (Brown et al., 1977). Experience from Davis (2000) has revealed that charge density 0.8 C/cm2/phase or

4–5 C/cm2/phase is associated with loss of clinical effects. This has suggested that there is a “window effect” associated with cerebellar stimulation.

Clinical experience Many uncontrolled studies of cerebellar stimulation for epilepsy have been performed and the majority show favorable results (Krauss and Fisher, 1993). These demonstrated that 31 of 115 patients became seizurefree, another 56 improved, and 27 were unchanged after cerebellar stimulation (Davis and Emmonds, 1992). Bidzinski et al. (1981) demonstrated epileptic seizures were abolished in 5 of 14 cases in his case study, and another patient had reduction in frequency. This was followed by another study demonstrating an overall benefit in 85% of patients after cerebellar stimulation in a 17-year follow-up (Davis and Emmonds, 1992). Additionally, Davis followed up this earlier work of his with a double-blind study of chronic cerebellar stimulation of the supero-medial cortex demonstrating an 85% reduction in spasticity for cerebral palsy patients. Intractable seizures occurred in many of these cerebral palsy patients and chronic cerebellar stimulation showed a 53% seizure-free population and another 32% with reduced seizures (Davis, 2000). Chkhenkeli et al. (2004) demonstrated that stimulation of the cere­ bellar dentate nucleus suppressed subclinical epileptic discharges on EEG recordings from intracerebral electrodes and correlated with the reduction of the frequency of generalized, complex partial, and secondary generalized seizures. These uncontrolled studies were followed by two controlled studies in 5 and 12 patients respectively with discouraging results (Van Buren et al., 1978; Wright et al., 1984). It was reported that only 2 of 14 patients improved, while the others were unchanged. Although these were controlled studies, they included a very small number of patients and the observation period was for only 6 months. Dow reviewed Van Buren’s data and found that the first four patients showed a decrease in seizure rate of 73%, 69%, 73%, and 85% during the “on” phase when compared to the “off” period (Davis, 2000; F. Velasco et al., 2005). In the trial by Wright et al. (1984), 11 of the patients on review considered that the trial had helped them. Results were further analyzed in 9 patients and one had the device removed secondary to infection. In 4 of the remaining 8 patients, seizure reduction amounted to 11%, 43%, 20%, and 97% (Davis, 2000; F. Velasco et al., 2005). Most recently, with a double-blind randomized controlled study on 5 patients with medically refractory

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motor seizures was reported (F. Velasco et al., 2005). Implants were placed on the supero-medial surface of the cerebellum. Patients served as their own controls, comparing frequency of seizures in a pre-implant phase and a post-implant phase from 10 months to 4 years. After implantation the patients were randomized into two groups – “stimulator on” and “stimulator off” – which was blinded to both the patient and evaluator. After an initial 4-month period all stimulators were turned on. The results showed no reduction in seizure activity in the initial “off” group. In the initial “on” group there was a 33% reduction in seizures. At the end of 6 months there was a mean reduction of seizure rate of 41% across all groups, with an optimum reduction of 75% observed in the patients. This effect shows generalized tonic–clonic seizure reduction after 1–2 months and continues to decrease over the first 6 months and then maintains this effectiveness over the study period of 2 years and beyond (F. Velasco et al., 2005).

Surgical technique The literature reveals that the most common method of electrodes placement was via two suboccipital burrholes, as opposed to a suboccipital craniotomy for exposure of the posterior fossa (Bidzinski et al., 1981; F. Velasco et al., 2005). The most common placement of electrodes is the supero-medial cerebellar cortex (Davis and Emmonds, 1992; Davis, 2000; F. Velasco et al., 2005), although some have used the cerebellar dentate nucleus (Chkhenkeli et al., 2004) and effects have been seen in animal models with stimulation of the poster­ ior vermis, fastigial nucleus, and midline fovia (Heath et al., 1978). Placement could be confirmed on postoperative imaging or intraoperative fluoroscopy. Frequency and strength of stimulation varied. A monograph released in 1950 by Moruzzi stated that frequencies of 10 Hz failed to produce a response, but frequencies of 200–300 Hz had an inhibitory effect on postural rigidity (Moruzzi, 1950). Cooper used 1 min of stimulation to each electrode, alternating sides (Cooper et al., 1978). Chkhenkeli et al. (2004) demonstrated effects with 50–100 Hz to the cerebellar dentate nucleus. However, F. Velasco et al. (2005) described stimulation frequency at 10 Hz rather than a higher frequency (100–200 pps), which is shown to be effective in reducing spasticity. Davis effectively used an “on” stimulation period of 4 minutes followed by an “off” period of 4 minutes in a 24-hour period (Davis and Bloedel, 1984: 53–67, 141; Davis and Emmonds, 1992).

Discussion Epilepsy surgery has largely revolved around removal of structural or physiologically abnormal areas of the brain. Present use of EEG and EcoG data from both scalp and intracranial electrodes permits resection of regions of epileptiform activity. Other palliative surgical options can include callosotomy and subpial transection. Following surgical excisions, only two-thirds of patients are improved and one-third are seizure free (Blume and Schomer, 1988). A viable alternative to these ablative surgeries is neuromodulation. Vagus nerve stimulation has been studied in large clinical trials (Handforth et al., 1998; Vonck et al., 2007), and the results from controlled trials are under way for stimulation of the anterior nuclei of the thalamus and responsive seizure focus cortical stimulation. Some experience is known in stimulation of the cerebellum, centromedian thalamus, subthalamus, caudate, and hippocampus for the treatment of epilepsy (Oommen et al., 2005). A review of the literature has shown favorable outcomes for epilepsy patients with chronic cerebellar stimulation. However, the number of patients in controlled studies in chronic cerebellar stimulation is quite few. Long-term follow-up, like those outcomes shown by Davis and Emmonds (1992) over 17 years and by F. Velasco et al. (2005) over 4 years, has demonstrated that there are long-standing effects that maintain the effectiveness of cerebellar stimulation. Earlier inconsistent results with cerebellar stimulation (Cooper, 1984) stemmed from different cortical stimulation levels and frequencies, and from different locations of the leads on the cerebellar cortex, difference in animal models, variability in the diseases being treated, and problems with the device and complications with the technology. On-going clinical investigation in the use of this therapeutic modality is still necessary.

References Andrade, D.M., Zumsteg, D., Hamani, C., Hodaie, M., Sarkissian, S., Lozano, A.M. and Wennberg, R.A. (2006) Long-term follow-up of patients with thalamic deep brain stimulation for epilepsy. Neurology 66 (10): 1571–3. Bidzinski, J., Bacia, T., Ostrowski, K. and Czarkwiani, L. (1981) [Effect of cerebellar cortical electrostimulation on the frequency of epileptic seizures in severe forms of epilepsy.] Neurol. Neurochir. Pol. 15 (5-6): 605–9. Bloedel, J.R. (1985) The physiologic basis of conjugate eye movements. Am. J. Otol. (Suppl.): 35–8. Blume, H.W. and Schomer, D.L. (1988) Surgical approaches to e­pilepsy. Annu. Rev. Med. 39: 301–13. Brown, W.J., Babb, T.L., Soper, H.V., Lieb, J.P., Ottino, C.A., Crandall, P.H. et al. (1977) Tissue reactions to long-term electrical stimulation of the cerebellum in monkeys. J. Neurosurg. 47: 366–79.

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References

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Hauser, W.A. and Hesdorffer, D.C. (1990) Incidence and prevalence. In: W.A. Hauser and D.C. Hesdorffer (eds), Epilepsy: Frequency, Causes and Consequences. New York: Demos, pp. 1–51. Heath, R.G., Dempsey, C.W., Fontana, C.J. and Myers, W.A. (1978) Cerebellar stimulation: effects on septal region, hippocampus, and amygdala of cats and rats. Biol. Psychiatry 13 (5): 501–29. Hodaie, M., Wennberg, R.A., Dostrovsky, J.O. and Lozano, A.M. (2002) Chronic anterior thalamus stimulation for intractable epilepsy. Epilepsia 43 (6): 603–8. Kanner, A.M. (2004) Deep brain stimulation for intractable epilepsy: which target and for which seizures? Epilepsy Curr. 4 (6): 231–2. Krauss, G.L. and Fisher, R.S. (1993) Cerebellar and thalamic stimulation for epilepsy. Adv. Neurol. 63: 231–45. Kwan, P. and Brodie, M.J. (2000) Early identification of refractory epilepsy. N. Engl. J. Med. 342 (5): 314–19. Lee, K.H. and Thompson, R.F. (2006) Multiple memory mechanisms in the cerebellum? Neuron 51 (6): 680–2. Llinas, R.R. (1981) Cerebellar modelling. Nature 291 (5813): 279–80. Loddenkemper, T., Pan, A., Neme, S., Baker, K.B., Rezai, A.R., Dinner, D.S. et al. (2001) Deep brain stimulation in epilepsy. J. Clin. Neurophysiol. 18 (6): 514–32. Lowenthal, J. and Horsley, V. (1897) On the relations between the cerebellar and other centers (namely cerebral and spinal) with special reference to the action of antagonistic muscles. Proc. R. Soc. Lond. 61: 20. Maiti, A. and Snider, R.S. (1975) Cerebellar control of basal forebrain seizures: amygdala and hippocampus. Epilepsia 16 (3): 521–33. Moruzzi, G. (1950) Problems in Cerebellar Physiology. Springfield, IL: Charles C. Thomas. Ohyama, T. et al. (2006) Learning-induced plasticity in deep cerebellar nucleus. J. Neurosci. 26 (49): 12656–63. Oommen, J., Morrell, M. and Fisher, R.S. (2005) Experimental electrical stimulation therapy for epilepsy. Curr. Treat. Options Neurol. 7 (4): 261–71. Rosenow, J., Das, K., Rovit, R.L. and Couldwell, W.T. (2002) Irving S. Cooper and his role in intracranial stimulation for movement disorders and epilepsy. Stereotact. Funct. Neurosurg. 78 (2): 95–112. Schmahmann, J.D. (1997) Therapeutic and research implications. Int. Rev. Neurobiol. 41: 637–47. Sherrington, C.S. (1898) Decerebrate rigidity, and reflex coordination of movements. J. Physiol. 22 (4): 319–32. Silveri, M.C., Leggio, M.G. and Molinari, M. (1994) The cerebellum contributes to linguistic production: a case of agrammatic speech following a right cerebellar lesion. Neurology 44 (11): 2047–50. Snider, R.S., McCullock, W.S. and Magoun, H.W. (1948) A cerebellobulbo-reticular pathway for suppression. J. Neurophysiol. 12: 325. Upton, A.R.M. (1978) Neurophysiological mechanisms in modification of seizures. In: I.S. Cooper (ed.), Cerebellar Stimulation in Man. New York: Raven Press, p. 39. Van Buren, J.M., Wood, J.H., Oakley, J. and Hambrecht, F. (1978) Preliminary evaluation of cerebellar stimulation by doubleblind stimulation and biological criteria in the treatment of epilepsy. J. Neurosurg. 48 (3): 407–16. Velasco, A.L., Velasco, F., Velasco, M., Jiménez, F., Carrillo-Ruiz, J. D. and Castro, G. (2007) The role of neuromodulation of the hippocampus in the treatment of intractable complex partial seizures of the temporal lobe. Acta Neurochir. (Suppl.) 97 (Pt 2): 329–32. Velasco, F., Carrillo-Ruiz, J.D., Brito, F., Velasco, M., Velasco, A.L., Marquez, I. and Davis, R. (2005) Double-blind, randomized controlled pilot study of bilateral cerebellar stimulation for treatment of intractable motor seizures. Epilepsia 46 (7): 1071–81. Velasco, F., Velasco, A.L., Velasco, M., Jiménez, F., Carrillo-Ruiz, J.D. and Castro, G. (2007) Deep brain stimulation for treatment of

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the epilepsies: the centromedian thalamic target. Acta Neurochir. (Suppl.) 97 (Pt 2): 337–42. Vonck, K., Boon, P., Achten, E., De Reuck, J. and Caemaert, J. (2002) Long-term amygdalohippocampal stimulation for refractory temporal lobe epilepsy. Ann Neurol. 52 (5): 556–65. Vonck, K., Boon, P. and Van Roost, D. (2007) Anatomical and physiological basis and mechanism of action of neurostimulation for epilepsy. Acta Neurochir. (Suppl.) 97 (Pt 2): 321–8.

Wiebe, S., Bellhouse, D.R., Fallahay, C. and Eliasziw, M. (1999) Burden of epilepsy: the Ontario Health Survey. Can. J. Neurol. Sci. 26 (4): 263–70. Wiebe, S., Blume, W.T., Girvin, J.P. and Eliasziw, M. (2001) A randomized, controlled trial of surgery for temporal-lobe epilepsy. N. Engl. J. Med. 345 (5): 311–18. Wright, G.D., McLellan, D.L. and Brice, J.G. (1984) A double-blind trial of chronic cerebellar stimulation in twelve patients with severe epilepsy. J. Neurol. Neurosurg. Psychiatry 47 (8): 769–74.

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C H A P T E R

53

Closed-Loop Stimulation in the Control of Focal Epilepsy Joseph R. Smith, Kostas Fountas, Anthony M. Murro, Yong D. Park, Patrick D. Jenkins, David A. Greene, and Rosana Esteller

o u tli n e Introduction

657

Methods and Materials External Responsive Neurostimulation Responsive Neurostimulation Candidates Neurostimulator System Components Implantable Pulse Generator Electrodes Programmer

658 658 658 658 658 658 658 658

Neurostimulator System Features ECoG Storage Detection Algorithms Therapeutic Stimulation Technique of Neurostimulator System Implantation Results Conclusions References

659 661 661 662

stimulation (Fisher et al., 1992), and neither showed a significant effect on seizures. Vagal nerve stimulation (VNS), which is a cyclical type of open-loop stimulation, has been shown to reduce seizures with statistical significance (Labar, 2004). In 1999 a study of brief stimulation of induced afterdischarges (ADs) showed that induced ADs could be aborted (Lesser et al., 1999). The authors entertained the possibility that an implanted closed loop device could both detect and abort epileptiform activity. A closed-loop system with therapeutic stimulation contingent on seizure detection was reported in 2001, but to date no controlled studies of its efficacy on seiz­ ures have been carried out (Osorio et al., 2001).

Introduction Uncontrolled open-loop stimulation studies have shown varying control of drug-resistant seizures with stimulation of cerebellar cortex (Cooper and Upton, 1978), cerebellar dentate nucleus (Sramka et al., 1976), anterior thalamic nucleus (Kerrigan et al., 2004), centromedian thalamic nucleus (Velasco, Velasco, Jiménez et al., 2001), caudate head (Sramka et al., 1976), hippocampus (Velasco, Velasco, Velasco et al., 2001), and subthalamic nucleus (Benabid et al., 2004). The only controlled studies involved cerebellar cortex (Van Buren et al., 1978) and thalamic centromedian nucleus

Neuromodulation

658 658 659 659

657

© 2008, 2009 Elsevier Ltd.

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53.  closed-loop stimulation in the control of focal epilepsy

We are currently participating in a multicenter study of a closed-loop neurostimulation system called the RNS (responsive neurostimulator) system (NeuroPace, Inc., Mountain View, CA). We will describe our initial results with the RNS system at our center.

Methods and materials External Responsive Neurostimulation Initially, an external neurostimulator system was used to study the safety of responsive stimulation. The external neurostimulator system was connected to grid, strip, and depth leads implanted for temporary monitoring of epileptiform activity. A laptop computer was used for interrogation and programming of the external neurostimulator system through wired telemetry. The automated seizure detection and stimulation characteristics were nearly the same as the subsequent cranially implanted neurostimulator system. The external neurostimulator system was run in parallel with the epilepsy monitoring unit recording system. After sufficient seizures were captured for seizure focus localization, but prior to lead removal, responsive stimulation trials were conducted. This study was conducted under a Food and Drug Administration (FDA) Investigational Device Exemption, and was approved by the Institutional Review Board (IRB) of each participating center. Informed consents were obtained from all patients. One report noted that of 27 patients studied with the external neurostimulator system, 11 (41%) exhibited a positive EEG effect on electrographic seizure activity and no serious adverse events related to the external neurostimulator system occurred (Murro et al., 2003). In addition, studies were performed using an animal model to assess the safety of strip and depth leads used with the neurostimulation system (Munz et al., 2003). Subsequently, the FDA permitted the totally implanted neurostimulation system human feasibility study to begin in August 2003.

Responsive Neurostimulation Candidates Candidates for responsive neurostimulation implantations had histories and electrographic findings consistent with drug-resistant focal epilepsy. They were either not candidates for resective surgery due to the location of the focus in functional cortex, or did not desire to have resective surgery. All candidates were required to have an average of four disabling seizures

per month over a 3-month period before final consideration for implantation. Approval was obtained from the Medical College of Georgia IRB prior to beginning the study, and informed consents were obtained from all patients prior to implantation. The first four patients were done open label. The next five cases were randomized, and are now in the open label extension.

Neurostimulator System Components Implantable Pulse Generator The implantable pulse generator (IPG) is a hermetically sealed neurostimulator containing electronics, battery, telemetry coil, and connector hardware that accommodates one or two 4-contact electrodes. The IPG continuously analyzes the patient’s ECoGs and triggers electrical stimulation when it detects specific ECoG characteristics programmed by the clinician as indicative of interictal or ictal epileptiform activity. The IPG then stores diagnostic information that details detections and stimulations, including multichannel stored ECoGs. The IPG is curved in shape to facilitate cranial implantation. It is positioned in a tailored cranial defect (Figure 53.1A) and held in place with a ferrule or holder, as shown in Figure 53.1B. Electrodes Depth electrodes are quadripolar and designed for stereotactic implantation. They are available with 3.5 mm and 10 mm intercontact spacings, with lengths of 30 cm and 44 cm. Subdural strip electrodes are quadripolar with 4 mm diameter circular electrodes and intercontact spacings of 10 mm. They are available in 15 cm and 25 cm lengths. All electrodes are composed of platinum and iridium. Programmer The programmer is a laptop computer with specialized software and a telemetry wand that communicates with the IPG. The programmer downloads diagnostic and ECoG data from the IPG. In addition, the programmer has an electrophysiology test stimulation mode, which allows real-time stimulation with simultaneous ECoG viewing.

Neurostimulator System Features ECoG Storage The neurostimulator system has a limited ECoG memory buffer. The number of ECoGs stored depends

VI. NeurostImulAtion for epilepsy



Technique of neurostimulator system implantation

Figure 53.1A  Rectangular craniectomy for ferrule and IPG. Arrow points to the burr-hole which will accommodate the fixation tab used to secure the IPG in the ferrule (see B)

659

channels. The line length and area tools compare the average contained within a shorter sample time window to the average contained within a longer-term trend window. When activity within the sample window exceeds the trend activity by a specified percentage, detection occurs. The line length tool is more commonly used to detect high frequency, low amplitude activity that diverges in amplitude little from the baseline electrographic amplitude, but has significant summed line length (Esteller et al., 2001). The area tool is more commonly used for slower rhythmic higher amplitude epileptiform activity with large integrated areas. The half wave tool measures half waves of specified duration and amplitude. When a specified number of half waves of predetermined duration and amplitude are detected programmed therapeutic stimulation is delivered. This tool acts like a bandpass filter.

Therapeutic Stimulation

Figure 53.1B  Ferrule secured in position with self-tapping screws in the four tangs at the corners of the ferrule. Note the fixation tab (arrow) which is accommodated by the burr-hole. Note single depth electrode inserted in connector port

on the number of recording channels and the recording time selected. Typically, two bipolar recording channels are selected with a 60-second pre-trigger and 30-second post-trigger duration which allows nine ECoGs to be stored. Any additional ECoGs overwrite the previous recordings. ECOG storage can be triggered by any of several electrographic events, including seizure onset. Detection Algorithms The neurostimulator system utilizes any of three seiz­ure detection tools (line length tool, area tool, and half wave tool) operating on one or two detection

The neurostimulator system delivers chargebalanced biphasic pulses with amplitude programm­ able from 0.5 mA to l2 mA, pulse width programmable from 40 to 1000 µs, and frequency programmable from 1 Hz to 333 Hz. Any of the electrode contacts or the pulse generator housing may be programmed as anode or cathode. After a pulse-train therapy has been delivered, a redetection algorithm determines if the epileptiform activity is still present. If so, up to four additional therapies may be delivered per episode. Also, each therapy may consist of one or two bursts. The parameters of each therapy and each burst may be the same or varied. The neurostimulator system has a builtin charge density limit that will allow no more than 25 µCoulombs/cm2/phase charge density to be delivered. Figure 53.2 shows an example of a successfully aborted epileptiform discharge that was aborted before it developed into an electrographic seizure.

Technique of neurostimulator system implantation Currently we utilize invasive monitoring in all cases to determine seizure focus localization and therefore, optimization of the location and type of electrodes used. For example, patients with a seizure focus in the left lateral temporal neocortex would receive two 1  4 subdural electrodes (Figure 53.3A). If the seiz­ ure focus were bilateral hippocampal, right and left 1  4 (10 mm contact spacing) depth electrodes would be implanted (Figure 53.3B). If the seizure focus were

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53.  closed-loop stimulation in the control of focal epilepsy

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Figure 53.2  Successfully aborted electrographic seizure. Left arrows point to the onset of seizure detection (DO) and the right arrow points to the therapeutic stimulation (TR). Lower tracing is zoomed-in view of the bracketed portion of the upper tracing

Figure 53.3A  Example of RNS with two 4-contact sub-

Figure 53.3B  Example of RNS with bilateral 4-contact hippo­

dural strip electrodes implanted over the left superior and middle tempor­al gyri. The three arrows left to right point to the connector port, microchip, and battery of the IPG

campal depth electrodes implanted in a case with bilateral independent hippocampal foci

left hippocampal in a patient in whom Wada memory testing revealed absence of contralateral memory support, a 1  4 hippocampal depth electrode and an ipsilateral anterior subtemporal 1  4 subdural ­ electrode would be implanted (Figure 53.3C). In general, the

type and location of electrode implantation will be tail­ ored to the individual patient. Implantation site for the IPG will be determined by the implantation site of the two electrodes. If depth ­electrodes alone are used a large skin flap will be needed

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661

conclusions

a­ cquisition study. We utilize contrast in order to outline and avoid surface cortical vessels near the entry point. If the depth electrode implant is bilateral the entire procedure is done with the patient in the stereotactic frame using local anesthesia and intravenous propofol and alfenta. If the implant is unilateral we tunnel the tail of the depth electrode to the planned craniotomy site, close the current incision, and remove the frame. The subsequent craniotomy is then done under general anesthesia.

Results Figure 53.3C  Example of RNS with one 4-contact depth and one 4-contact subdural strip electrode implanted in a case with left hippocampal seizure onset and absence of contralateral memory support as determined by previous Wada test

to expose enough skull to incorporate the IPG and its ferrule as well as the two 14 mm diameter burr-holes and their burr-hole rings and covers (Figure 53.3B). In the case of a previous craniotomy this area may be reexposed for both the implantation of subdural electrodes and the IPG and ferrule (Figure 53.3A). If a hippocampal depth electrode is implanted through an occipital entry in a case requiring repeat craniotomy for implantation of a subdural electrode (Figure 53.3C) then the tail of the depth electrode will need to be tunneled into the area of the previous craniotomy exposure. Passing the tail of the depth electrode through the appropriate length of Silastic tubing provided in the depth electrode kit will protect the electrode tail when the craniotomy incision is subsequently reopened for subdural strip electrode and IPG placement. A ferrule template is provided than can be laid on the exposed skull to find an area where the convex contour of the template best fits that of the skull. We use the monopolar cutting current to mark off this rectangular area. A single burr-hole is placed at either end of the rectangle and a Penfield #3 dissector is used to separate dura from skull prior to using the craniotome to cut out the rectangle of bone. We prefer a full-thickness craniectomy in order to minimize protrusion of the IPG. Note that one burr-hole of the craniectomy should be off center to accommodate the fixation tab that secures the IPG in the ferrule (Figures 53.1A,B). We prefer to place depth electrodes using a framebased system (Leksell, Stockholm, Sweden) and carry out depth implant planning with a commercially ­available computer workstation (BrainLab, Heimstetten, Germany). Typically, we perform a single volume

Our institution has performed nine implants. All cases have had greater than one year follow-up. However, one of these nine (the only case without preoperative invasive monitoring) was an insulindependent juvenile diabetic who was subsequently found to have anti-GAD antibody. This patient never responded to the neurostimulator system and her initial IPG was not replaced when the battery depleted. Follow-up on the other eight cases ranged from 19 to 32 months. All of these eight cases underwent preimplant invasive monitoring with discrete seizure focus localization. The median seizure frequency reduction has been 56% and the mean reduction has been 65%. The range in seizure frequency reduction has been 43–100% (see Table 53.1). Seven cases have required replacement of IPGs due to battery depletion. Time to IPG replacement has ranged from 12 to 26 months with a median of 22 months and a mean of 21 months. To date there has been one infection requiring explantation of the system. This occurred 16 months after implantation of a new IPG (28 months after the original implantation). There have been no adverse neurological events.

Conclusions Open-loop studies on the effect of electrical stimulation on induced afterdischarges (ADs) have shown that ADs can be aborted (Lesser et al., 1999), and that there may be optimal parameters for this (Motamedi et al., 2002). External responsive neurostimulation studies have shown that closed-loop stimulation can significantly affect duration of spontaneously occurring electrographic seizure activity (Peters et al., 2001; Murro et al., 2002, 2003). Early seizure detection and stimulation of multiple contacts in the immediate vicinity of the seizure focus have improved the frequency of suppression of epileptiform activity. Observations of the

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53.  closed-loop stimulation in the control of focal epilepsy

Table 53.1  Results of medical college of georgia RNS implants Case

Invasive localization

Lead implant location

Current seizure reduction (%)

Follow-up (mth)

1a

Left hippocampus

Left hippocampal depth

100

32

2

Left superior temporal gyrus

Two left superior temporal strips

100

32

3b

Left superior and mid-temporal gyri

Left superior and mid-temporal strips

  43

28

4

Bilateral hippocampus

Bilateral hippocampal depths

  75

29

5

a

Left anteromesial temporal area

Left hippocampal depth  subtemporal strip

  57

28

6a

Left hippocampus

Left hippocampal depth  subtemporal strip

  65

24

7

Bilateral hippocampus

Bilateral hippocampal depths

  65

24

8

Left anterior insula

Left anterior insular and orbitofrontal depths

  60

19

a

High risk for memory decline based on neuropsychology and Wada test results Explanted due to infection; 43% decrease in seizures at that time

b

currently described closed-loop neurostimulator system also support the ability of this automated seizure detection/therapeutic stimulation device to positively influence electrographic seizure activity. However, the study is still in a preliminary phase and a great deal more data will be required in order to define optimal stimulation parameters as well as patient candidacy for seizure control.

References Benabid, A.-L., Koudsie, A., Chabardes, S., Vercueil, L., Benazzouz, A., Minotti, L. et al. (2004) Subthalamic nucleus and substantia nigra pars reticulata stimulation: the Grenoble experience. In: H.O. Luders (ed.), Deep Brain Stimulation and Epilepsy. London: Martin Dunitz, pp. 335–48. Cooper, I.S. and Upton, A.R. (1978) Effects of cerebellar stimulation on epilepsy, the EEG and cerebral palsy in man. Electroencephalogr. Clin. Neurophysiol. 34 (Suppl.): 349–54. Esteller, R., Echauz, J., Tcheng, T., Litt, B. and Pless, B. (2001) Line length: an efficient feature for seizure onset detection. Proceedings of the 23rd IEEE International Conference on Medicine and Biology (EMBS), October, 2001, Istanbul, Turkey, pt 2, vol. 2, pp. 1707–10. Fisher, R.S., Uematsu, S., Krauss, G.L., Cysyk, B.J., McPherson, R., Lesser, R.P. et al. (1992) Placebo-controlled pilot study of centromedian thalamic stimulation in treatment of intractable seiz­ ures. Epilepsia 33 (5): 841–51. Kerrigan, J.F., Litt, B., Fisher, R.S., Cranstoun, S., French, J.A., Blum, D.E. et al. (2004) Electrical stimulation of the anterior nucleus of the thalamus for the treatment of intractable epilepsy. Epilepsia 45 (4): 346–54. Labar, D. (2004) Vagal nerve stimulation: effects on seizures. In: H.O. Luders (ed.), Deep Brain Stimulation and Epilepsy. London: Martin Dunitz, pp. 255–62. Lesser, R.P., Kim, S.H., Beyderman, L., Miglioretti, D.L., Webber, W.R., Bare, M. et al. (1999) Brief bursts of pulse stimulation terminate afterdischarges caused by cortical stimulation. Neurology 53 (9): 2073–81.

Motamedi, G.K., Lesser, R.P., Miglioretti, D.L., Mizuno-Matsumoto, Y., Gordon, B., Webber, W.R. et al. (2002) Optimizing parameters for terminating cortical afterdischarges with pulse stimulation. Epilepsia 43 (8): 836–46. Munz, M., Sweasey, R., Barrett, C., Loftman, A.P., Vinters, H., Popovska, Z., et al., (2003) Implantation and testing of responsive neurostimulator (RNS) system for epilepsy. Platform presentation at American Society for Stereotactic and Functional Neurosurgery, New York, 2003 (unpublished). Murro, A.M., Park, Y.D., Bergey, G.K., Kossoff, E.H., Ritzl, E.K., Karceski, S.C. et al. (2003) Multicenter study of acute responsive stimulation in patients with intractable epilepsy. Epilepsia 44 (Suppl. 9): 326. Murro, A., Park, Y., Greene, D., Smith, J., Ray, P., King, D. et al. (2002) Closed loop neurostimulation in patient with intractable epilepsy. Platform presentation at American Clinical Neurophysiology Society, New Orleans, 2002 (unpublished). Osorio, I., Frei, M.G., Manly, B.F., Sunderam, S., Bhavaraju, N.C. and Wilkinson, S.B. (2001) An introduction to contingent (closedloop) brain electrical stimulation for seizure blockage, to ultrashort-term clinical trials, and to multidimensional statistical analysis of therapeutic efficacy. J. Clin. Neurophysiol. 18 (6): 533–44. Peters, T.E., Bhavaraju, N.C., Frei, M.G. and Osorio, I. (2001) Network system for automated seizure detection and contingent delivery of therapy. J. Clin. Neurophysiol. 18 (6): 545–9. Sramka, M., Fritz, G., Galanda, M. and Nadvornik, P. (1976) Some observations in treatment stimulation of epilepsy. Acta Neurochir. (Wien) 23 (Suppl.): 257–62. Van Buren, J.M., Wood, J.H., Oakley, J. and Hambrecht, F. (1978) Preliminary evaluation of cerebellar stimulation by double-blind stimulation and biological criteria in the treatment of epilepsy. J. Neurosurg. 48 (3): 407–16. Velasco, F., Velasco, M., Jiménez, F., Velasco, A.L. and Marquez, I. (2001) Stimulation of the central median thalamic nucleus for epilepsy. Stereotact. Funct. Neurosurg. 77 (1-4): 228–32. Velasco, F., Velasco, M., Velasco, A.L., Menez, D. and Rocha, L. (2001) Electrical stimulation for epilepsy: stimulation of hippo­ campal foci. Stereotact. Funct. Neurosurg. 77 (1-4): 223–7.

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NEUROMODULATION FOR PSYCHIATRIC DISORDERS Introduction Benjamin D. Greenberg The chapters that follow are written by investigators at the forefront of these developments. Each emphasizes different aspects of the current landscape of psychiatric neuromodulation, and therapeutic uses that are at different stages of maturation. Linda L. Carpenter, MD, Margaret C. Wyche, BS, Gerhard M. Friehs, MD, and John O’Reardon, MD, of Departments of Psychiatry at Brown University Medical School, Providence, Rhode Island, and the University of Philadelphia, Pennsylvania, review the development and current status of vagus nerve stimulation as a clinical treatment for depression. Kris van Kuyck, PhD, Loes Gabriëls, MD, PhD,, and Bart Nuttin, MD, PhD, of University Hospitals, Leuven, Belgium, emphasize contributions of basic and translational research to understanding potential mechanisms of action of deep brain stimulation for OCD, which represents the first modern use of DBS in psychiatry and was pioneered by the same group. My own chapter (Benjamin D. Greenberg, MD, PhD, Department of Psychiatry and Human Behavior, Brown University, Providence, Rhode Island) reviews the evolution of DBS for depression in the context of psychiatric neurosurgery

Despite conventional medication and behavioral treatments that are generally effective in psychiatry, a minority of severely affected patients do not benefit adequately. Neuromodulation approaches, which have become standards of care in neurology, offer individuals suffering with severe and poorly treatment-responsive psychiatric illness a measure of hope. The chapters in this section describe some recent developments in a field that has generated a remarkable degree of interest across disciplines, and which is evolving rapidly internationally. One such therapy, vagus nerve stimulation, is one of very few approved adjunctive treatments for refractory major depression in the USA. Deep brain stimulation is now approved for humanitarian use for intractable obsessive–compulsive disorder (OCD) in the USA, on the basis primarily of open-label studies. To obtain more definitive data, at least one controlled trial is now under way using DBS for OCD. Larger-scale controlled trials are also under way using DBS as an adjunctive therapy for refractory major depression. And there are a number of areas, including addiction among others, where neuromodulation research is at a very early stage.

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more generally. Finally, Bomin Sun, MD, Shikun Zhan, MD, Dianyou Li, MD, and Hemmings Wu, MD, of the Center for Functional Neurosurgery, Shanghai Jiaotong University Rui Jin Hospital, describe the very early work using ablation and DBS for addiction in China. These applications of neuromodulation all raise a number of important issues, which may be expected to remain highly salient despite anticipated improvements in the techniques used, in understanding the pathophysiologies of illnesses treated, and advances in appreciating the mechanisms by which these “anatomically based” therapies might work. We will collectively need to remember lessons of the earlier era of “psychosurgery” and act accordingly to maximize the benefits that accrue to patients, and reduce their exposure to risks inevitably entailed by procedures that are not innocuous (Fins et al., 2006). Another central problem is that psychiatrists and neurosurgeons, who share a focus on illness resulting from brain dysfunction, have until recently shared relatively little else. For the individuals who wish to engage in this work, more interdisciplinary interactions in training and clinical practice will need to occur, beyond those that have begun in research (Greenberg et al., 2006).

Proper consideration of these issues should reduce some major risks. First is the selection of inappropriate patients for surgery. Another is the risk that patients may not have long-term access to follow-up at specialized centers, with the appropriate multidisciplinary expertise and psychiatric leadership. A related problem is that patients themselves may be unable to continue the necessary long-term care owing to illness-related impairments or for financial reasons. Enthusiasm for psychiatric neuromodulation appears justified by developments to date, and those that seem in the offing. But attention to the demands that this field of endeavor places on practitioners and patients will be essential for its promise to be realized.

References Fins, J.J., Rezai, A.R. and Greenberg, B.D. (2006) Psychosurgery: avoiding an ethical redux while advancing a therapeutic future. Neurosurgery 59 (4): 713–16. Greenberg, B.D., Nuttin, B. and Rezai, A.R. (2006) Education and neuromodulation for psychiatric disorders: a perspective for practitioners. Neurosurgery 59 (4): 717–19.

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C H A P T E R

54 Electroconvulsive Therapy, Transcranial Magnetic Stimulation, and Vagus Nerve Stimulation for Depression Linda L. Carpenter, Margaret C. Wyche, Gerhard M. Friehs, and John P. O’Reardon

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(n  3671), who were participating in a stepwise progression through multiple, serially administered, adequate antidepressant treatment trials, the cumulative remission rate was only 67% (Rush et al., 2006). Nonpharmacological neurostimulation therapies may therefore offer new hope, especially for depressed patients who have failed to respond to standard psychotherapy and pharmacological therapies. Electroconvulsive therapy (ECT) is the oldest and most widely used neurostimulation technique for depression. Vagus nerve stimulation (VNS) was approved by the US Food and Drug Administration (FDA) in 2005 as an adjunctive treatment for treatmentresistant major depression, and a device for the delivery of transcranial magnetic stimulation (TMS) was

Major depression is a common and debilitating disorder. Standard antidepressant therapies are largely ineffective at achieving remission for the majority of patients treated for the disorder. It has been estimated that half of depressed patients treated with antidepressant medications do not show evidence of adequate response (Fava, 2003). A recently completed US National Institute of Mental Health-sponsored, multicenter clinical trial was designed to examine the relative effectiveness of serial antidepressant treatment interventions (STAR*D [Sequenced Treatment Alternatives to Relieve Depression]; www.star-d.org). In the large, broadly representative sample of depressed patients enrolled

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approved in October of 2008 for treatment for depression that has not responded to an adequate antidepressant medication trial.

ELECTROCONVULSIVE THERAPY (ECT) ECT, considered the most effective treatment for severe forms of depression, has been in use since the 1930s, although a device manufactured for the delivery of ECT was approved by the FDA for treatment of depression as recently as 1979. In light of the importance currently associated with the regulatory process of evaluation and approval of new therapeutic drugs and devices, it is noteworthy that the efficacy and safety data typically required for approval of novel therapies today were not available or required when the ECT delivery device was officially FDA-approved via “grandfather clause.” In addition to being considered the “gold standard” with regard to efficacy for treatment of severe depression, ECT has been used to treat various other severe psychiatric disorders, including mania, schizophrenia, and catatonic states (Weiner and Coffey, 1988). ECT involves the unilateral or bilateral application of a brief electrical impulse directly to the scalp to induce seizures. Some experts maintain that to be effective, an ECT stimulus must produce a tonic–clonic seizure movement pattern in addition to a characteristic tracing on a scalp electroencephalograph recording for 20 s (Bolwig, 2003). Patients receive general anesthesia during modern ECT, and anesthesia-induced muscle relaxation prevents motor convulsions during the course of each session. A typical acute course of ECT consists of between six and 12 treatments at a frequency of two to three treatments per week. ECT is typically administered by a specially trained psychiatrist in an inpatient or outpatient hospital setting. Two recent meta-analyses, incorporating data from randomized controlled trials and observational studies, have confirmed the efficacy of ECT for depressive disorders (UK ECT Review Group, 2003; Pagnin et al., 2004). In the first, ECT was found to be more effective than sham treatment in an analysis of six trials (n  256), as evidenced by a standardized effect size (SES) of 0.91 (95% confidence interval [CI] 1.27 to 0.54). Analysis of data from 18 trials (n  1144) suggested that ECT was significantly more effective than pharmacotherapy (SES 0.80, 95% CI 1.29 to 0.29). In addition, bilateral ECT was found to have greater efficacy than unipolar ECT (22 trials, n  1408; SES 0.32, 95% CI 0.46 to 0.19) (UK ECT Review Group, 2003). The second meta-analysis, which included data

from both randomized and non-randomized controlled trials published from 1956 to 2003, confirmed the superiority of ECT in comparisons with simulated ECT, placebo, antidepressants in general, tricyclic antidepressants, and monoamine oxidase inhibitors (Pagnin et al., 2004). ECT tolerability and efficacy vary according to the specific treatment parameters and the patient sample used. Adjustable parameters include electrode placement, stimulus intensity, and the number and frequency of treatments. Current ECT devices enable manipulation of the electric stimulus itself, allowing for adjustment of pulse frequency, width, amplitude, and duration. Sackeim and colleagues (1993) reported that the clinical efficacy of ECT is dependent on electrode placement (i.e., bilateral treatment superior to unilateral) and stimulus intensity as a function of an individual’s seizure threshold (i.e., higher doses superior to lower doses). Conversely, the absolute electrical dose was shown to be unrelated to clinical efficacy. A relatively high dose (relative to seizure threshold) and bilateral electrode placement appear to be most effective for alleviating depressive symptoms, although these parameters are also associated with greater impairment of short-term cognitive function. This relationship is particularly notable in the elderly population receiving bifrontal ECT (Stoppe et al., 2006). While low-dose, right-sided unilateral ECT is considered the least effective type of ECT (Sackeim et al., 1993), further refinement of right-sided unilateral stimulation parameters, specifically the use of a stimulus pulse width of 0.1–0.3 ms and an electrical dose that adequately exceeds the seizure threshold, can produce a response equivalent to that achieved with standard bilateral ECT (Sackeim, Prudic et al., 2001). Published efficacy data from ECT research protocols are impressive (response rates in the 70–90% range), but an analysis of treatment in community settings has revealed ECT remission rates that are considerably lower than those achieved in clinical trials, ranging from 30 to 47% depending on the specific remission criteria applied (Prudic et al., 2004). In a naturalistic 6-month follow-up study, comorbid personality disorders, depressive episode chronicity, and schizoaffective disorder were associated with poorer outcomes. However, among those who did achieve remission, 64% relapsed during follow-up despite continuation pharmacotherapy or ECT as dictated by treating psychiatrists. Sustaining antidepressant benefits achieved with ECT remains a significant challenge. Relapse rates as high as 84% have been reported within 6 months of initial ECT response in the absence of active treatment continuation, but this is reduced by the use of optimal

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antidepressant pharmacotherapy (Sackeim, Haskett et al., 2001). Naturalistic data provide additional support to the notion that a combination of maintenance ECT plus antidepressant medication is superior to medication alone for preventing relapse (Gagne et al., 2000). A multicenter, randomized, 6-month trial that compared continuation ECT with pharmacotherapy following ECT-induced remission showed no significant difference between the two treatments in relapse prevention, with both treatment arms generating relapse rates 30% (Kellner et al., 2006). A naturalistic study examining follow-up outcomes 4–8 years after ECT in 26 patients found an overall recurrence rate (i.e. a new episode requiring treatment) of 42.3% and determined that future recurrence was not associated with clinical outcome in the 6 months immediately following the initial course of ECT (van Beusekom et al., 2007). Despite the relatively robust efficacy data associated with ECT, many factors other than the high relapse rate limit the desirability for the treatment. Patient access to ECT is limited because of the required hospital setting, high cost, exposure to anesthesia, and risk of side effects, most notably amnesia (Sackeim et al., 1993). Immediate post-ECT side effects include a short-term memory loss and cognitive impairment, specifically selective attention and executive tasks (Fujita et al., 2006; Moscrip et al., 2006). The extent and duration of longer-term cognitive side effects appears highly variable, and recent investigation has targeted various aspects of treatment that may have a potential effect on cognition (Sackeim, Brannan et al., 2007). Anterograde memory deficits have been shown to significantly improve within 1 week of the ECT procedure, and the administration of pulse-wave ECT appears to have lesser effects on attention and executive functions than sine-wave ECT (Fujita et al., 2006). Several studies have evaluated the prominence of ECT-induced short-term memory loss and cognitive impairment over time and found persistent or residual effects to be minimal. One research group found baseline memory function returned to the level measured at (depressed) baseline 1 month after brief-pulse ECT, with a more substantial improvement in memory function relative to baseline at 6-month follow-up (Calev et al., 1991). Another recent report of 6-month outcomes concluded that three ECT sessions produced superior clinical benefits to standard pharmacotherapy, including improvement in overall memory function relative to that at depressed baseline, especially when clinical benefits were marked (Criado et al., 2007). A small naturalistic follow-up study of 10 ECT patients found evidence of slightly subnormal performance on working memory and verbal/visual episodic memory tasks over 2 years, but no severe

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persistent side effects of ECT or clinically significant signs of residual mood disorder (Johanson et al., 2005). Results of a large-scale, multicenter, prospective study examining the cognitive effects of ECT were recently published (Sackeim, Prudic et al., 2007), confirming a link between persistent retrograde amnesia and bilateral application of ECT. In addition, sinewave stimulation was associated with a pronounced slowing of reaction time, both immediately and in the 6 months following ECT. Advancing age, lower premorbid intellectual function, and female gender were found to be associated with greater cognitive deficits. These data underscore the need for a safer and more tolerable neuromodulation therapy for severe depressive syndromes.

TRANSCRANIAL MAGNETIC STIMULATION (TMS) The basic physical principle underlying TMS dates back to the work of Michael Faraday, who, in 1839, discovered that a magnetic field can produce an electrical current in a conductive substance, the principle of electromagnetism. In 1985, Barker and Cain developed the first TMS device that was capable of stimulating the human cortex, although at that time their initial goal was stimulation of spinal roots rather than stimulation of the brain. Shortly thereafter, TMS was first suggested as a possible treatment for depression (Bickford et al., 1987). During TMS a small, insulated electromagnetic coil is placed on the scalp. A bank of capacitors is then rapidly discharged into the coil, which converts the electrical activity into a pulsed magnetic field that then passes through the cranium with minimal impedance. The magnetic field induces an electrical field in the underlying cerebral cortex based on the counter-current principle (Roth, Cohen et al., 1991; Roth, Saypol et al., 1991). Upon delivery of sufficiently intense TMS to the targeted area, the cortical neurons depolarize and action potentials are generated. Currently employed technology generates a magnetic field of approximately 1.5 Tesla (comparable to that of a standard MRI), which penetrates to approximately 3 cm beneath the coil surface (Demitrack, 2007). The pulsing frequency of the field and the excitatory or inhibitory function of the activated underlying neurons together determine whether the ultimate effects on neural circuitry are excitatory or inhibitory. In general terms, TMS at frequencies of less than or equal to 1 Hz (slow TMS) are inhibitory and frequencies greater than 1 Hz (fast TMS) are excitatory (Chen et al., 1997; Nakamura et al., 1997; Burt et al., 2002). The pulses administered

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can be single, paired, or in a series (also called a “train,” which in turn can vary in its duration). When TMS is delivered in a series of pulses, or a train, this is termed “repetitive TMS” (abbreviated, rTMS). Single and paired pulse TMS are more frequently used for neurodiagnostic purposes, whereas rTMS is believed to have therapeutic potential in psychiatric disorders (TMS is used in a generic sense, to refer to repetitive trains of therapeutic stimulation, throughout this chapter). Unlike ECT, which produces a widespread current distribution, the TMS device is able to induce currents in localized areas (Epstein et al., 1990). The minimal amount of energy required to activate the motor strip of a particular individual is called the motor threshold (MT) and is determined by titrating the amount of energy from the TMS device until a visible twitching movement of the contralateral thumb is reliably produced following single pulses of TMS. In the treatment of depression, determination of the MT on the left motor cortex guides the dosing for the power of treatment delivered (expressed as a percent of MT), usually in the 80–120% range. The point of the optimal derived MT on the scalp also guides the anatomical placement of the coil for TMS treatment. The coil is moved 5 cm anteriorly in a parasagittal plane from the site of MT determination on the scalp overlying the left dorsolateral prefrontal cortex (DLPFC). Other TMS stimulation treatment variables include the inter-train interval (the time in between trains of stimulation when no stimulation is occurring, an important safety parameter), frequency of pulsing of the magnetic field (expressed in Hz), and number of trains per session and the duration of the session. As an example, the dose of TMS per session for an individual patient who is being treated for depression might be expressed as: 50 trains at 10 Hz, 5 second trains, with a 25 second inter-train interval at 120% of MT. This would then translate into a dose of 50 pulses per train, for a total of 2500 pulses per session at 120% MT over a session length of 25 minutes. Generally, only a single session is conducted per treatment day, with 5 sessions per treatment week given for acute treatment. The duration of treatment has varied across published clinical TMS trials. In earlier studies, the total number of treatment sessions was approximately 10–20 delivered in 3–4 weeks (O’Reardon et al., 2006), but more recent research in this area witnessed an expansion of the acute treatment phase duration to 6 or more weeks (Fitzgerald, Benitez et al., 2006; O’Reardon et al., 2007). Similar to ECT, the putative biological mechanism of action of TMS is not known. TMS has demonstrated effects in animal models that act as standard assays for antidepressant efficacy. For example, daily TMS has been shown in the Porsolt forced-swim test

to reduce immobility time in rats, a model of learned helplessness (Sachdev et al., 2002; Hedges et al., 2003; Hargreaves et al., 2005). Additionally, preclinical TMS studies have reported that forebrain serotonin output is enhanced and that serotonin receptor function is modulated (Ben-Shachar et al., 1997; Juckel et al., 1999) by the treatment. In human studies, functional MRI imaging of 1 Hz TMS over the left dorsolateral prefrontal cortex (DLPFC) produced activation of deeper structures, including the insula, putamen, hippocampus, and thalamus, via frontal-subcortical neuronal circuits (Li et al., 2004). Clinical neuroendocrine correlates of successful TMS include increased concentrations of thyroid-stimulating hormone (Szuba et al., 2001) and “normalization” of cortisol secretion as measured by the dexamethasone suppression test (Pridmore, 1999). Other mechanism of action studies of TMS (reviewed by Richelson, 2007) include increases in expression of brain-derived neurotrophic factor (BDNF) in rat brain (Muller et al., 2000) as well as increases in concentration of BDNF in human serum (Shimizu et al., 2003). Although TMS was first suggested as a possible treatment for depression in 1987 by Bickford et al., initial studies in patients with major depression were essentially case reports or case series (Hoflich et al., 1993; George et al., 1995). It was not until 1996 that TMS was first systematically examined in the treatment of depression (George et al., 1997). Possible cortical targets were initially investigated using fast frequency TMS (Pascual-Leone and Rubio, 1996). In a sample of patients with treatment-resistant psychotic depression (n  17), 5 days of TMS at 10 Hz were administered to different sites on the scalp in a double-blind, sequential crossover design. The left dorsolateral prefrontal cortex (DLPFC) stimulation site yielded the best therapeutic effects; after 5 days of stimulation at that site, researchers reported a 65% response rate that was maintained for the subsequent 2 weeks. Since that time, the majority of studies that have shown efficacy have delivered stimulation to the DLPFC. Klein et al. (1999) were the first group to demonstrate in a well-controlled trial that slow-frequency TMS at 1 Hz on the right rather than the left prefrontal cortex could also have antidepressant properties. This early study, in conjunction with the data from Pascual-Leone, demonstrates the potential flexibility of TMS as a therapy. Benefits derived from different hemisphere targets and with opposing TMS pulse frequencies suggest a variety of stimulation parameters may ultimately be available to customize the treatment for individuals with depressive symptoms. Over the past 10 years there have been on the order of 30 single-center, controlled trials of TMS in

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depression, most of which have included both bipolar and unipolar depressed patients. Early studies were limited by conservative stimulation parameters and relatively short courses of treatment (usually 1–2 weeks). Perhaps as a consequence, some trials were negative while others yielded statistically significant but clinically modest results. An analysis of treatment parameters associated with optimal TMS outcomes in patients with depression revealed that longer courses (10 days of TMS sessions compared with 10 days), higher-intensity motor thresholds (100–110% versus 80–90%) and a greater number of pulses per day (1200–1600 versus 800–1000) were superior (Gershon et al., 2003). Whereas TMS response rates of 30% were observed in studies that used the suboptimal dosing parameters (Gershon et al., 2003; Cohen et al., 2004), higher rates have been reported by studies using optimized dosing parameters (Fitzgerald, Huntsman et al., 2006; Gross et al., 2007). The results of a large, multicenter, double-blind, monotherapy TMS study that randomized 325 medication-free patients with major depression have recently been published (O’Reardon et al., 2007). TMS was delivered 5 times per week for 4–6 weeks at 10 pulses/second, 120% of MT, 3000 pulses/session. All patients met diagnostic criteria for major depressive disorder (MDD) and were moderately treatmentresistant, having failed to respond to at least one antidepressant but not more than four during the current episode. In the evaluable sample (n  301), active TMS was superior to sham treatment on the primary outcome measure at week 4, and on the secondary outcome measure at weeks 4 and 6. The initial blinded phase of this study resulted in a 24.5% response rate for TMS compared with 13.7% for sham (O’Reardon et al., 2007). Comparison of the standardized effect size for these results (0.55) with those of currently marketed antidepressants (0.49) presents a favorable profile for TMS (Demitrack, 2007). Examination of predictors of response to TMS in the recently completed randomized trial showed shorter duration of current depressive episode, and lack of anxiety co-morbidity may confer an increased likelihood of favorable outcome (Lisanby et al., 2009). At the end of this acute-phase trial, patients who did not respond to stimulation, regardless of their treatment condition, were invited to cross over to an open-label TMS trial consisting of a similarly designed 6-week phase. Patients remained blinded to their original treatment condition in order that additional data for evaluation of the efficacy of acute TMS could be generated (i.e. in patients originally assigned to sham stimulation) in concert with data on late TMS responders (i.e. in patients initially assigned to

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active treatment who did not respond). A third phase of the study allowed for the transition of TMS into a 24-week continuation phase, with antidepressants available for optional pharmacotherapy in the event of symptom worsening. Results suggest that the outcomes for those who crossed to the open-label study are comparable with those observed in the blinded acute phase (42–43% response and 20–27% remission rates, depending on the scale used) (Avery et al., 2008). Maintenance of the beneficial effects of TMS is suggested from preliminary 24-week data showing lower relapse rates among those who received active (8%) rather than sham (15%) treatment (Avery et al., 2007). Safety data confirmed that common side effects, such as application site pain, muscle twitching, toothache, and discomfort in the facial/eye area, were mild-tomoderate and rapidly accommodated by the patient (Janicak et al., 2008). Researchers continue to explore ways to enhance the efficacy of TMS for depression. Fitzgerald and colleagues recently investigated the combined application of fast TMS over the left DLPFC and slow TMS over the right DLPFC in a sample of treatmentresistant patients (n  50) (Fitzgerald, Benitez et al., 2006). Slow TMS on the right was followed by fast TMS on the left (a sequenced, combination approach) versus a sham condition with similar duration of stimulation on both the right and left side. Those who received active TMS over a period of up to 6 weeks had a 44% response rate and a 36% remission rate on the primary outcome measure. In another investigation of sequenced TMS in a combination-treatment fashion, high-frequency stimulation (20 Hz) to the left PFC and low-frequency stimulation (1 Hz) to the right PFC resulted in significantly greater decreases in depressive symptomatology than did sham control treatment (Garcia-Toro et al., 2006), but no additional clinical advantage was obtained by focusing TMS on areas identified by single-photon emission tomography as showing high versus low levels of functional activity. TMS is a non-invasive neurostimulation procedure that does not require anesthesia and can be performed on an outpatient basis; therefore, the logistics of TMS differ significantly from other neuromodulation interventions such as VNS and ECT. Patients are not sedated during the TMS treatment and can normally leave immediately afterward without a recovery period. Due to its ease of use, favorable tolerability profile (Loo et al., 2008), and high patient acceptance, TMS offers a potential viable alternative for some patients who would otherwise in the context of refractory depression have no choice except to progress to ECT. The cognitive profile of adverse effects is clearly more

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benign with TMS than ECT (Schulze-Rauschenbach et al., 2005). The literature presents conflicting evidence, however, concerning the relative antidepressant efficacy of TMS compared with ECT. At least two studies (McLoughlin, 2004; Eranti et al., 2007) have found TMS to be inferior to ECT. Others have shown them to be comparable. Rosa reported similarly low response and remission rates for both TMS (50% and 10%, respectively) and ECT (40% and 20%, respectively) in a medication-free, nonpsychotic sample of patients with refractory depression (Rosa et al., 2006). In a sample of medication-free, depressed patients (n  40) randomly assigned to receive either 20 sessions of TMS or a course of ECT, ECT was shown to be significantly more effective than TMS (Grunhaus et al., 2000), particularly among the subgroup of psychotic depressed patients. Analyses limited to non-psychotic patients showed similar response rates for the two treatments. A subsequent study limited to non-psychotic major depression demonstrated equivalent response rates (55% with TMS and 60% with ECT) (Grunhaus et al., 2003). Research by the same group suggested that relapse rates 6 months after TMS were not different than those seen 6 months after ECT treatment, with both groups transitioned to maintenance antidepressant medication (Dannon et al., 2002). More studies will be needed to evaluate the relative efficacy of TMS and ECT and to optimally position TMS in a treatment algorithm for depression. In general, TMS seems to be a very safe treatment and well tolerated. The most significant risk associated with the therapy is inadvertent induction of a seizure. Remaining within the recommended stimulation parameters, however, confers a margin of safety that should be combined with careful screening for underlying organic brain disease (Wassermann, 1998). Overall, the risk of an unwanted seizure appears to be less than 1 per 1000 TMS sessions, and compares favorably to the risk of seizures with marketed antidepressant drugs such as bupropion and tricyclic antidepressants. The administration of a self-reported safety questionnaire (TMS Adult Safety Screen or TASS) is an additional useful safety-screening device (Keel et al., 2001). Post-treatment headaches may affect about 10% of patients but are generally mild, brief, and easily managed with non-narcotic oral analgesics. Scalp pain at the site of stimulation during the treatment session also tends to be mild and limited to the time of stimulation during the treatment session. Because the TMS device emits clicking sounds with each train of magnetic pulses, there is the potential for TMS devices to have adverse effects on hearing. Mild but transient and clinically insignificant shifts in auditory

thresholds have been found in studies that evaluated hearing in subjects exposed to TMS (Loo et al., 2001; Pascual-Leone et al., 1992). To minimize any auditory risks patients should wear earplugs during the procedure. Induction of mania is not a widely recognized side effect of TMS, but case reports of switching into mania have been described (Dolberg et al., 2001). Improvement in neuropsychological functioning has been reported following TMS administration for major depression, but it has not proved possible to clearly separate this effect from the observed improvements in mood (Schulze-Rauschenbach et al., 2005). Overall, the burden of side effects associated with TMS is low and contrasts favorably with the weight gain and sexual dysfunction typical of many medications and with the negative cognitive effects of ECT.

VAGUS NERVE STIMULATION (VNS) VNS has been approved by the FDA for the treatment of pharmacoresistant epilepsy since 1997. Mood elevations observed in seizure patients initially prompted the investigation of VNS as a treatment for depression (Ben-Menachem et al., 1994; Handforth et al., 1998; Elger et al., 2000; Harden et al., 2000). Clinical trials were conducted and subsequent data (reviewed below) resulted in the FDA approval of VNS as an adjunct therapy for treatment-resistant depression in July 2005. VNS therapy consists of repetitive, cyclical stimulation applied to the vagus nerve (cranial nerve X) in the left cervical region, by a surgically implanted device. In addition to observed mood-elevating effects of VNS in patients with epilepsy, the rationale for investigating VNS as a possible treatment for depression is based on preclinical investigation of VNS in animal models demonstrating the direct effects of VNS on central cortical function, and on human neuroimaging data demonstrating that VNS affects the function of various important limbic structures. Furthermore, the demonstrated efficacy of anticonvulsant medications as mood stabilizers in mood disorders (Ballenger and Post, 1980; Post et al., 1998; Calabrese et al., 1999) provides an additional link between two therapeutic areas. Investigations in both animals and humans show that VNS alters concentrations of neurotransmitters implicated in mood disorders (i.e. serotonin, norepinephrine, gamma aminobutyric acid, and glutamate) within the central nervous system (reviewed in detail below). VNS is thought to improve mood via ascending projections through the nucleus tractus solitarius to the parabrachial nucleus and the locus

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coeruleus (Krahl et al., 1998). This is the site of many norepinephrine-containing neurons that have important connections to the amygdala, hypothalamus, insula, thalamus, orbitofrontal cortex, and other limbic regions linked to mood and anxiety regulation (Van Bockstaele et al., 1999). In 1938, Bailey and Bremer described the synchronized activity of the orbital cortex produced by VNS in cats in one of the first published report suggesting that VNS directly affected central function. Dell and Olson (1951) also noted slow-wave response in anterior rhinal sulcus and amygdala to VNS in awake cats with high cervical spinal section. Primate studies also provided further evidence of VNS effects on basal limbic structures, thalamus, and cingulate (MacLean, 1990). Based on these findings, Zabara (1985a, 1985b) hypothesized and further investigated in dogs that VNS would have anticonvulsant action. Zabara postulated that the antiepileptic mechanisms of action of VNS would involve both direct termination of an ongoing seizure as well as seizure prevention when he observed VNS-induced cortical electroencephalogram changes and seizure cessation in dogs (Zabara, 1992). The effects of VNS on the brain have been studied using a variety of neuroimaging techniques, such as positron emission tomography (PET), single photon emission computed tomography (SPECT), and functional magnetic resonance imaging (fMRI) (Chae et al., 2003; Conway et al., 2006; Nahas et al., 2007). Garnett et al. (1992) showed using PET that left VNS in epilepsy caused increased regional cerebral blood flow (rCBF) in the ipsilateral anterior thalamus and the cingulate gyrus. Ko et al. (1996) found increased blood flow in the contralateral thalamus and posterior temporal cortex, and ipsilateral putamen and inferior cerebellum with left VNS. Henry and colleagues studied both acute and chronic effects of VNS on the brain (Henry et al., 1998a, 1998b, 1999; Henry, 2000). Highlevel (500 μs, 30 Hz, 30 s on, 5 min off, mean 0.5 mA) left VNS stimulation increased the blood flow to the rostral and dorsal medulla oblongata as well as bilateral orbitofrontal gyri, right entorhinal cortex, and right temporal pole, whereas both high- and low-level (130 μs, 1 Hz, 30 s on, 180 min off, mean 0.85 mA) stimulation increased the blood flow to the right thalamus, right postcentral gyrus, bilateral inferior cerebellum as well as bilateral hypothalamus and anterior insula. VNS stimulation also decreased blood flow to the bilateral amygdala, hippocampus, and posterior cingulate gyrus (Henry et al., 1998a, 1998b; Henry, 2000). More recently, Conway et al. (2006) also found acute VNS-induced rCBF changes consistent with brain structures associated with depression and the afferent pathways of the vagus nerve.

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Various SPECT studies (Ring et al., 2000; Van Laere et al., 2000; Vonck et al., 2000) have demonstrated decreased thalamic activity, possibly reflecting the chronic changes in the brain or the acute “off” effect of the VNS since SPECT was performed immediately after it was turned off or during the period when VNS was mostly off (Chae et al., 2003). Devous (2001) demonstrated in six depressed patients receiving VNS in the open-label study that the patients had reduced rCBF to the left dorsolateral prefrontal, anterolateral temporal, and perisylvian temporal structures, including posterior insula. Zobel and colleagues (2005) reported rCBF changes in multiple limbic structures following 4 weeks of VNS in 12 patients with TRD. Decreased activity in cingulate gyrus, an area implicated in the pathoetiology of depression, has been associated with symptom relief in various studies (Ebert et al., 1994; Bremner et al., 1997; Mayberg et al., 1997). Therefore, modulation of activity in the cingulate gyrus by VNS, along with VNS effects on the activities of the brain stem, limbic system, and other central nervous system areas, implicates a similar mechanism for VNS antidepressant activity (George et al., 2000). Both clinical and animals studies have shown that VNS induces neurochemical changes in the central nervous system, thus providing possible mechanisms of antiseizure and neuropsychiatric effects of VNS (Nemeroff et al., 2006). Studies in rats undergoing VNS reveal increases in cellular activity, as measured through the oncogene C-fos level, in amygdala, cingulate, locus coeruleus (LC), and hypothalamus (Naritoku et al., 1995). The work of Zuo and colleagues (Zuo et al., 2007) investigating the modulatory effect of VNS on the development of long-term potentiation (LTP) in the dentate gyrus suggested VNS modulates synaptic plasticity in the hippocampus. Preclinical work has also demonstrated modulation of serotonin (Dorr and Debonnel, 2006), norepinephrine (Krahl et al., 1998), gamma-aminobutyric acid (GABA), and glutamate (Walker et al., 1999). A study of lumbar cerebro-spinal fluid (CSF) analytes in epilepsy patients sampled before and after 3 months of VNS showed significant increases in CSF concentrations of GABA and trend-level decreases in glutamate (Ben-Menachem et al., 1995). Other provocative findings from CSF studies are VNS-induced increases in levels of the major metabolite of dopamine, homovanillic acid (Carpenter et al., 2004), and the major metabolite of serotonin, 5-hydroxyindoleacetic acid (Ben-Menachem et al., 1995). Dorr and Debonnel recently published their findings of increased basal firing rates of dorsal raphe nucleus and LC following long-term VNS treatment in a rodent electrophysiology study, suggesting a novel mechanism of antidepressant action (Dorr and

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Debonnel, 2006). Indeed, emerging data appear to provide converging lines of evidence that VNS exerts measurable effects in brain regions and neurotransmitter systems implicated in mood disorders. However, a putative VNS antidepressant mechanism of action remains obscure (Nemeroff et al., 2006), as it does for ECT and TMS. VNS surgery is considered a procedure of low complexity and is typically performed in an outpatient surgical setting with general anesthesia. A pulse generator is implanted subcutaneously into the left wall of the chest and is connected to bipolar electrodes, which are attached to the left vagus nerve within the neck. After a 2-week post-surgical recovery period, the device is turned on and stimulation is titrated to optimal treatment levels. Device “dosing” – including selection of stimulus intensity, duration, and off-interval – is noninvasive and adjusted by an external telemetric wand. A typical programming cycle consists of 30 seconds of stimulation followed by a 5-minute “off” period (Labiner and Ahern, 2007). The safety of VNS is well established from its use in the treatment of epilepsy (Ben-Menachem, 2001). In total, 40 000 patients have been implanted with the VNS device worldwide since the 1990s (Cyberonics, Houston, TX, personal communication). The side effects of VNS are generally mild and are associated with stimulation (i.e. the “on” phase of the cycle). Voice alteration, dyspnea, and neck pain were the most frequently reported adverse events in a long-term followup study of VNS in patients with depression (Rush, Sackeim et al., 2005). Patients with sleep apnea may require additional monitoring when VNS is titrated (Papacostas et al., 2007). Adjustments in stimulation pulse width and frequency can also be performed to manage side effects and optimize therapy (Labiner and Ahern, 2007). VNS has been safely combined with ECT in some patients (Burke and Husain, 2006). Data supporting the antidepressant efficacy of VNS come from open-label and naturalistic studies where the neuromodulation therapy was added to ongoing, stable doses of psychotropic medication. In an openlabel pilot study, 60 patients with treatment-resistant major depressive episodes who had not responded to at least two trials of medication from different antidepressant classes received 12 weeks of adjunctive VNS (Sackeim, Rush et al., 2001). Response rates ranged from 31 to 37%, depending on the scale used. The most common side effect was voice alteration or hoarseness, which was generally mild and related to output current intensity. VNS appeared to be most effective in patients with low-to-moderate, but not extreme, antidepressant resistance. A naturalistic follow-up study was conducted to determine whether the initial

promising effects were sustained in a subgroup (n  30) following exit from the 3-month acute study (Marangell et al., 2002). At 1-year follow-up, response rates for the subgroup were sustained (40–46%) and remission rates significantly increased (17–29%), although psychotropic medications and VNS stimulus parameters varied during the follow-up interval. Subsequent follow-up data from a larger number (i.e., 59 patients from the original pilot study cohort) who completed the study and who continued with adjunctive VNS demonstrated a response rate of 44% at 1 year, which was largely sustained (42%) after 2 years of active treatment (Nahas et al., 2005). Remission rates demonstrated a similar pattern, rising to 27% at 1-year follow-up and to 22% after 2 years of stimulation. Following these promising open-label pilot study results, a larger controlled trial was undertaken. The large (n  235), randomized, sham-controlled, multicenter study of adjunctive VNS did not find a significant difference in acute-phase response between active and sham groups (15% and 10%, respectively) at the 12-week endpoint (Rush, Marangell et al., 2005). However, follow-up observations of this cohort over the subsequent year suggested a cumulative beneficial effect of treatment over time (Rush, Sackeim et al., 2005), leading to speculation that positive VNS response requires more time than that typically seen with antidepressant medications and ECT. As the initial active VNS group continued with stimulation for another 9 months, the initial sham group crossed over to receive 12 months of active VNS. Participants received antidepressant treatments and VNS, both of which could be adjusted. Data from this open study revealed response rates of 27–34% and a remission rate of 15.8% at one year (Rush, Sackeim et al., 2005). To better understand the long-term effects of VNS combined with treatment-as-usual (TAU), 12-month VNS  TAU outcomes (n  205) were compared with those of a similar group of patients with treatmentresistant depression (TAU; n  124) in a nonrandomized, naturalistic study (George et al., 2005). An analysis comparing the VNS  TAU group (monthly data) with the TAU group (quarterly data) according to scores on a self-report depression symptom scale showed adjunctive VNS associated with significantly greater improvement per month than TAU across 12 months, and response rates were 27% for VNS  TAU and 13% for TAU, supporting the finding of greater antidepressant benefit in VNS patients (George et al., 2005). A subsequent 24-month follow-up study of patients treated with adjunct VNS therapy found a decline in suicide attempts, diminished levels of suicidal ideation, and fewer hospitalizations for worsening depression (Burke and Moreno, 2006). Recently published longer-term

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REFERENCES

data indicate that patients identified as early (i.e. by 3 months) and late (i.e. by 12 months) responders maintained their response at a rate of 76.7% and 65%, respectively, at 24-month follow-up assessment (Sackeim, Brannan et al., 2007). Thus, while modest response and remission rates appear to accompany VNS therapy, available data suggest a high level of durability of response for those who experience clinical benefits.

CONCLUSION ECT remains the “gold standard” neuromodulation therapy for pharmaco-resistant depression, but side effects such as cognitive dysfunction greatly reduce enthusiasm for the treatment. VNS and TMS are two new neuromodulation therapies that hold considerable promise for the treatment of depression. Refinements in the device technology and discoveries related to optimization of targets and stimulation parameters are likely to continue to inform development and enhance the appeal of this treatment modality for depression and other psychiatric disorders during the next decade.

DISCLOSURES Dr Carpenter has received research grant support, speaker honoraria, and/or consultant fees from Cyberonics, Medtronic, and Neuronetics. Dr O’Reardon has received grant support from Cyberonics, Magstim, Neuronetics, acted as consultant for Neuronetics, and is a member of the Speakers Bureau for Cyberonics. Ms Wyche and Dr Gerhard Friehs make no disclosures.

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55 Electrical Brain Stimulation in TreatmentResistant Obsessive–Compulsive Disorder: Parcellation, and Cyto- and Chemoarchitecture of the Bed Nucleus of the Stria Terminalis – a Review Kris van Kuyck, Loes Gabriëls, and Bart Nuttin

O U T L I N E Introduction

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Nomenclature of Divisions of the BST

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Cytoarchitecture of the BST

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Chemoarchitecture of the BST Neuropeptides Oxytocin and Vasopressin Neuropeptide Y Somatostatin Opioid Peptides Galanin Cocaine- and Amphetamine-regulated Transcript Pituitary Adenylate Cyclase Activating Polypeptide Neurotensin Luteinizing Hormone-Releasing Hormone Tachykinins

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Vasoactive Intestinal Polypeptide The Granin Family Calcium-Binding Proteins The Acetylcholinergic System Limbic System-Associated Membrane Protein The Catecholaminergic System Nerve Growth Factor Brain-Derived Neurotrophic Factor Steroids Steroid Receptors Sex Hormone-Binding Globulin FF1 Receptor Angiotensin II Receptor

681 681 682 682 682

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Sexual Dimorphism

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Remarks and Conclusion

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References

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© 2008, 2009 Elsevier Ltd.

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INTRODUCTION Obsessive–compulsive disorder (OCD) affects ca. 2% of the general population (Rasmussen and Eisen, 1992). The cardinal symptoms of OCD are intrusive thoughts (obsessions) and/or repetitive behaviors (compulsions) that persist against the patient’s attempts to eliminate them. The obsessions and compulsions are accompanied by marked, overwhelming anxiety and are distressing and time-consuming. Co-morbidity of OCD with depression is considerable: up to 67% of patients with primary OCD have a lifetime history positive for major depressive disorder (Rasmussen and Eisen, 1988). Notwithstanding the important advances in the efficacy, safety, and tolerability of treatments for OCD made over the past decades, up to 7.1% of patients show persistent disabling symptoms in spite of combined pharmacological and psychotherapeutic treatment (Zitterl et al., 2000). A last resort in treatment-resistant OCD patients is a neurosurgical brain lesion, which aims at selectively destroying part of the pathological circuitry. For capsulotomy, an elongated lesion is made in the anterior limbs of the internal capsule and part of the ventrally located nucleus accumbens. Its effects on psychiatric symptoms are probably exerted by interrupting ventral fibers in the anterior internal capsule, which originate from the orbitofrontal and subgenual anterior cingulate cortex and project via the ventral striatum to medial, dorsomedial, and anterior thalamic nuclei (Kopell et al., 2004). Functional brain imaging reveals orbitofrontal and basal ganglia hypermetabolism in patients with OCD at rest and during symptom provocation that normalizes with response to treatment (Rauch and Baxter, 1998; Saxena et al., 1998; Saxena and Rauch, 2000). The irreversibility of side effects in capsulotomy (e.g. apathy) was the main driving force to investigate the effect of electrical brain stimulation in the same brain region. Electrodes were implanted in the anterior limbs of the internal capsule with the most distal contact in the nucleus accumbens. The results were promising but high stimulation amplitudes were required to induce symptom relief. As the patient series increased in number, a target location versus outcome analysis revealed a better outcome with a more posterior location of the electrodes (Greenberg et al., 2008). This brain region is the caudal part of the bed nucleus of the stria terminalis (BST). In this chapter we will review the parcellation, and the cytoand chemoarchitecture of the BST, based on postmortem studies in humans.

NOMENCLATURE OF DIVISIONS OF THE BST The term “bed nucleus of the stria terminalis” was introduced in 1923 to describe a brain nucleus embedding (part of) the stria terminalis (Johnston, 1923). The main part of the BST is the paraseptal sector, located immediately posterior to the nucleus accumbens and surrounding the crossing of the anterior commissure, caudoventral to the septum. Other (more distantly located) sectors of the BST are the intra-amygdaloid and the supracapsular sector. Neuroanatomists parcelled the paraseptal sector of the human BST based on cytoarchitectonic studies. Gross divisions recognized by de Olmos (1990) are the medial, lateral, and posterior BST, which were further subdivided in an anterior and posterior part (medial BST), a dorsal, ventral, posterior, and juxtacapsular part (lateral BST), and a medial, intermediate, and lateral part (posterior BST). Previously, Brockhaus (1942a,b) and Andy and Stephan (1968) also divided the BST in three parts. In the latter report, the pars anterior, interna, and externa coincided respectively with the anterior and posterior medial BST, and the lateral BST in the scheme of de Olmos. The pars medialis and paracaudata of Strenge (Strenge et al., 1977) correspond respectively to the medial and lateral posterior BST of de Olmos. The subdivisions depicted in the atlas of Mai, Assheuer, and Paxinos (2004) merely coincide with the parcellation of de Olmos, with the exception that an additional central subdivision is recognized. Although, the electrodes for electrical brain stimulation in patients with obsessive–compulsive disorder were initially implanted more anteriorly, the active electrode contact is currently placed in the region posterior to the crossing of the anterior commissure (see Figures 55.1, 55.2, 55.3). The BST divisions posterior to the crossing of the anterior commissure are the caudal part of the dorsal division of the lateral BST, the posterior part of the lateral and medial BST, and the juxtacapsular division of the BST according to the parcellation of de Olmos, and the posterior, central, and juxtacapsular divisions of the BST according to the atlas of Mai, Assheuer, and Paxinos.

CYTOARCHITECTURE OF THE BST The BST contains a heterogenous cell population with small (10–14 μm) and large neurons (15–20 μm; Gaspar et al., 1985). Only the cytoarchitecture of the BST

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CYTOARCHITECTURE OF THE BST

FLV

CdM

FLV LSD MS sv

ic CdV SCGP

LSI tsv ac fx LSV 3V

ImI

Pu

BSTL BSTM

BSTC EGP

TS ac mml DPe

FIGURE 55.1

Coronal T1-weighted MR slice through the electrodes implanted in a treatment-resistant OCD patient with maximal visualization of contact 0. The white lines indicate the position of the electrodes. 3V: third ventricle; ac: anterior commissure; FLV: frontal horn of the lateral ventricle

divisions where the distal electrode contact is located (see previous paragraph) will be discussed, based on two publications in which the cytoarchitecture of the entire BST is addressed (de Olmos, 1990; Martin et al., 1991). In the dorsal subdivision of the lateral BST central and capsular subdivisions are discerned. The central subdivision contains loosely packed, randomly organized medium-sized neurons and only a few glial cells. The capsular subdivision is a sparsely celled zone with neurons that are larger in size, predominantly spindleshaped, and oriented parallel to the contours of the dorsal division of the lateral BST. The dorsal subdivision of the lateral BST is scarce in myelinated fibers except for the capsular division, where myelinated fibers of stria terminalis pass. The posterior division of the lateral BST contains small-sized cells oriented dorsoventrally and is rich in glial-cell nuclei. Medium-sized, round-to-fusiformshaped neurons, with some large neurons in between, were also observed. The number of myelinated fibers in this division and in the juxtacapsular BST tends to increase caudally. The posterior division of the medial BST can be parted in three along a dorsoventral orientation: (1) a medial subdivision with small, densely packed, round-to-oval, well-staining neurons with scattered among them, larger triangular, darkly staining neurons; (2) an intermediate subdivision with medium-sized, more loosely arranged, lightly staining, spindle- and angular-shaped neurons, most of them oriented parallel to the incoming fibers of the stria terminalis (it contains less glial

ac VP

GTI

MPO

PaD

BSTV

PaP

mfb db PaMc 3V

FPU

ul

SSTI TuTI

SxD

PuV

PirF lo

Tu SO

ox

PirT

SCh

PAA

PA InfS

Un

BM

FIGURE 55.2 Coronal section through the posterior border of the crossing of the anterior commissure at the same level of the MR slice in Figure 55.1. 3V: third ventricle; ac: anterior commissure; BM: basomedial amygdaloid nucleus; BSTC: bed nucleus of the stria terminalis, central division; BSTL: bed nucleus of the stria terminalis, lateral division; BSTM: bed nucleus of the stria terminalis, medial division; BSTV: bed nucleus of the stria terminalis, ventral division; CdM: medial caudate nucleus; CdV: ventral caudate nucleus; db: diagonal band; DPe: dorsal periventricular hypothalamic nucleus; EGP: external globus pallidus; FLV: frontal horn of lateral ventricle; FPU: putaminal fundus region; fx: fornix; GTI: great terminal island; ic: internal capsule; InfS: infundibular stalk; lml: external medullary lamina of the globus pallidus; lo: lateral olfactory tract; LSD: dorsolateral septal nucleus; LSI: intermediodorsal septal nucleus; LSV: ventrolateral septal nucleus; mfb: medial forebrain bundle; mml: medial medullary lamina of the globus pallidus; MPO: medial preoptic nucleus; MS: medial septal nucleus; ox: optic chiasm; PAA: periamygdalar area; PaD; paraventricular nucleus, dorsal part; PaMc: paraventricular nucleus, magnocellular part; PaP: paraventricular nucleus, parvocellular part; PirF: piriform cortex, frontal area; PirT: piriform cortex, temporal area; Pu: putamen; PuV: ventral putamen; SCGP: supracapsular part of the globus pallidus; SCh: suprachiasmatic nucleus; SO: supraoptic nucleus; sv: septal vein; SSTI: substriatal terminal island; SxD: sexual dimorphic nucleus; TS: triangular septal nucleus; tsv: thalamostriate vein; Tu: olfactory tubercle; TuTl: tubercular terminal island(s); Un: uncus; VP: ventral pallidum (Reproduced from the atlas of Mai, Assheuer and Paxinos (2004) with permission from Elsevier/Academic Press. Copyright (2004) Elsevier)

cell nuclei compared to the medial subdivision); (3) a lateral subdivision with large and loosely arranged neurons. The posterior division of the medial is richest in myelinated fibers, especially at the border between the medial and intermediate subdivision.

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55. ELECTRICAL BRAIN STIMULATION IN TREATMENT-RESISTANT OBSESSIVE–COMPULSIVE DISORDER

(A)

a

b

c d

e f

(B)

FIGURE 55.3 Axial brain scans of the same patient as in Figure 55.1 (bottom of each scan is posterior). (A) Preoperative T2weighted MR images at approximately the same levels as in B. The inclination of the slices is about the same as in B but not perfectly. Slice thickness of 1 mm, scan interleaf of 1 mm. (B) Postoperative MPRAGE MR-images from the caudal tips of the electrodes (lower left image) to more cranial slices (lower right). Slice thickness of 2 mm, scan interleaf of 0 mm. a: right electrode; b: left electrode; c: anterior commissure; d: third ventricle; e: head of the caudate nucleus; f: anterior limb of the internal capsule

The juxtacapsular BST is made up of slender columns of neurons that are smaller in size, more darkly staining, and more densely packed than those in the other subdivisions of the lateral BST. Medium-sizedto-large triangular or spindle-shaped neurons are scattered among these neurons. The juxtacapsular BST is also rich in glial cell nuclei oriented dorsoventrally. The continuity of the juxtacapsular BST is sometimes interrupted by very small islands of granule-like neurons.

CHEMOARCHITECTURE OF THE BST Neuropeptides Oxytocin and Vasopressin Oxytocin and vasopressin are two closely related nonapeptides, which are involved in sexual, maternal, social, and stress-related behaviors (Gimpl and Fahrenholz, 2001). Both peptides are hypothesized to play a role in psychiatric disorders. In OCD, both normal (Altemus et al., 1999) and elevated CSF oxytocin levels have been observed, correlating with the severity of the disorder (Gimpl and Fahrenholz, 2001). CSF vasopressin was elevated in adults but a negative correlation with symptom severity was observed in children and adolescents (McDougle et al., 1999). In patients with depression, a 23% and 56%

increase in the number of oxytocin- and vasopressinimmunoreactive neurons, respectively, was observed in the paraventricular nucleus of the hypothalamus (Purba et al., 1996). In contrast, oxytocin and vasopressin CSF levels respectively are reduced and elevated during the starvation phase in patients with anorexia nervosa (Kaye, 1996; Gimpl and Fahrenholz, 2001). Oxytocin and vasopressin fibers were both observed in the BST with no apparent differences in expression between males and females. The incidence of vasopressin fibers in the BST was the highest compared to the rest of the limbic system. Both beaded and unbeaded vasopressin fibers were observed. Few vasopressin-reactive cells were observed in only two of the 13 subjects investigated. On a more caudal level, many vasopressin cells were found in a third subject, some of which were magnocellular (Fliers et al., 1986). Neuropeptide Y Neuropeptide Y is one of the most potent endogenous stimulants of eating behavior within the nervous system and is expressed in the BST. In patients with Huntington’s disease, neuropeptide Y concentrations were significantly increased in the basal ganglia and other regions in the basal forebrain including the BST. Neuropeptide Y CSF levels were normal in OCD patients, decreased in patients with treatmentrefractory unipolar depression, and elevated in underweight anorexics (Altemus et al., 1999; Kaye, 1996; Heilig et al., 2004). Somatostatin Somatostatin inhibits hormone secretion from the pituitary, the pancreas, and other endocrine sites. In addition, it is a widely distributed neurotransmitter substance in the brain (Olias et al., 2004). Within the rostral and dorsal part of the BST, a considerable number of somatostatin immunoreactive cells were observed. In addition, scattered somatostatin immunoreactive cell bodies were observed adjacent to the rostral and medial regions of the anterior commissure. Extremely dense accumulations of immunoreactive varicose fibers and ribbon-like processes were observed (Bennett-Clarke and Joseph, 1986; Candy et al., 1985). This somatostatin-stained volume of the central BST significantly increased with age in males, even during adulthood, whereas no further increase was observed after puberty in females. These changes in the somatostatin-stained volume of the BST seemed not to be subject to marked increases in gonadal steroid levels during adulthood (Chung et al., 2002). In patients with OCD, somatostatin in CSF was

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elevated (Altemus et al., 1993). In accordance, central administration of somatostatin in rats induces stereotyped behaviors (Havlicek et al., 1976). In patients with MDD, it was decreased (McDougle et al., 1999). In Huntington’s disease, changes in somatostatin expression were observed in the basal forebrain but not in the BST (Beal, Mazurek et al., 1988). Opioid Peptides The opioid peptides are a family of endogenous opiate-like peptides which bind to opioid receptors. They are coded by three different precursor genes. A first, preproenkephalin, is expressed by the majority (60–100%) of the BST neurons and encodes, inter alia, met-enkephalin (Sukhov et al., 1995; Hurd, 1996). Immunohistochemistry revealed met-enkephalin-positive cell bodies in the center of the supracommissural BST while met-enkephalinpositive fibers were observed throughout the entire rostrocaudal lateral BST, with scarce or no labeling in the medial BST (Haber and Watson, 1985). These fibers were the so-called woolly fibers which are composed of an unstained central core (a non-reactive dendrite), ensheathed in a dense plexus of thin striatal enkephalin-positive efferents. For the BST, these enkephalinpositive woolly fibers are hypothesized to originate in the nucleus accumbens. The second precursor gene, preprodynorphin, was present in only a few BST neurons and encodes, amongst others, dynorphin A (Sukhov et al., 1995; Hurd, 1996). At the intersection of the internal capsule and anterior commissure, fibers containing dynorphin A, together with enkephalin and substance P, were observed to traverse the internal capsule into the BST, forming a thin stratum covering the medial surface of the internal capsule. Caudal to the anterior commissure, very few dynorphin-positive fibers were found (Haber and Watson, 1985). Finally, preproopiomelanocortin was not observed in the BST (Sukhov et al., 1995). The prodynorphin and proenkephalin opioid systems have distinct physiological and pharmacological profiles with often opposing actions within several CNS functions including memory, mood, and drug reward (Hurd, 1996). Galanin The BST is the area with the heaviest concentration of galanin-like terminal staining in the basal forebrain. Galanin staining of terminals was observed throughout the entire nucleus but, at the level of the anterior commissure, heavier in the ventral and lateral portion of the BST compared to the medial and dorsal aspects. Nerve fiber staining was also detected in the entire BST but the fiber plexus was predominantly located in the lateral

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BST. Extremely high densities of galanin receptors were observed within the BST with a distribution overlapping with the pattern of galanin-immunoreactive fibers seen within this region of the human brain. Galanin immunoreactive neurons were observed within the BST but the few galanin-immunoreactive neurons seen within the basal forebrain cannot account for the extensive galanin-immunoreactive fiber innervation found in these regions. It is hypothesized that the origin of these fibers might be located in the amygdala or the locus coeruleus. Co-localization experiments revealed that 90% of galanin-immunoreactive neurons within the basal forebrain also expressed the receptor for nerve growth factor, an excellent marker for primate cholinergic forebrain neurons (see Nerve Growth Factor below). Galanin is hypothesized to modulate the cholinergic tone within the basal forebrain system (Kordower and Mufson, 1990; Mufson et al., 1993; Deecher et al., 1998). In Alzheimer’s disease, the galanin-immunoreactive fibers coursing to and within the BST appeared hypertrophic. Fibers were greatly enlarged, bulbous, and contorted in appearance as compared to the fine slender-beaded axons seen in aged controls. In addition, the GAL-ir terminal-like staining observed within the BST tended to be denser than seen in aged controls. In Down syndrome, galanin fibers appeared more like that seen in control brains (Mufson et al., 1993). The galanin system is hypothesized to play a role in stressbehavior, depression, and anxiety disorders and to be a potential new target in the treatment of depression (Weiss et al., 1998). In patients with anorexia nervosa who regained weight, galanin CSF was reduced, which is in accordance with the excitatory role of galanin in appetite and fat consumption (Frank et al., 2001). Cocaine- and Amphetamine-regulated Transcript Cocaine- and amphetamine-regulated transcript (CART) is a neuropeptide that is upregulated after injection of cocaine or amphetamine. Its wide distribution in the hypothalamus and its activation upon administration of leptin suggests a role in energy homeostasis and motivated behavior. Outside the hypothalamus, a dense innervation of CART fibers was observed in the BST (Elias et al., 2001). Repetitive ritualistic behavior may be seen in persons taking dopamine agonist amphetamine (Koizumi, 1985). Pituitary Adenylate Cyclase Activating Polypeptide Pituitary adenylate cyclase activating polypeptide is a member of the secretin/glucagon/vasoactive polypeptide family of peptides. It may act as a neurohormone in

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the hypothalamo-pituitary system, and may function as a neurotransmitter/neuromodulator in other regions of the central nervous system. The BST contains very high levels of pituitary adenylate cyclase activating polypeptide (4769 pg/mg protein; Palkovits et al., 1995). Neurotensin Neurotensin is a peptide that can be released upon nerve depolarization. At post-synaptic sites it binds to specific receptors as either a hyperpolarizing or a depolarizing agent, depending on the neuronal type affected. CSF neurotensin is decreased in patients with schizophrenia but unaffected in patients with depression or eating disorders (Nemeroff et al., 1989). Immunoreactive cell groups were found in the BST close to the anterior commissure. Most immunoreactive neurons accumulate laterally at the medial border of the capsula interna. Within subcortical telencephalic structures, the most conspicuous accumulation of neurotensin-immunoreactive fibers is seen around the head of the anterior commissure, predominantly the septal area and the BST (Mai et al., 1987). In addition, high neurotensin receptor-binding densities were observed in BST. A particular dense column of NT-labeling was found along the lateralmost boundary of the BST, immediately adjacent to the internal capsule. Both the lateral, intensely reactive zone and the medial, moderately reactive segment exhibited a fairly homogeneous distribution of label over perikarya and neuropil (Szigethy et al., 1990). Luteinizing Hormone-Releasing Hormone Luteinizing hormone-releasing hormone (LHRH, also called gonadotropin-releasing hormone) is a decapeptide essential for mammalian reproduction. As a hormone, it stimulates the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). There is evidence that LHRH also acts as a neurotransmitter or neuromodulator. Small numbers of LHRH-neurons were identified in the BST, curving laterally toward the amygdala in the BST–amygdala continuum. These neurons consisted of small, sparsely labeled cells, with oval or round somata (Rance et al., 1994). Tachykinins The tachykinin family of peptides includes substance P, neurokinin A and B, neuropeptide K and neuropeptide γ (Chawla et al., 1997). Tachykinins in the region of the hypothalamus are involved in the control of anterior pituitary function and sexual behavior. Only a few SP neurons (5% of the neurons) were detected in the BST. Small areas containing numerous

substance P-immunoreactive varicose fibers and puncta, occasionally forming tubular profiles, covered the medial surface of the internal capsule in the lateral BST. At the intersection of the internal capsule and anterior commissure, these fibers contained enkephalin and dynorphin in addition to substance P. The rest of the BST was much more weakly stained. Caudal to the anterior commissure, there is no clear evidence of substance P immunoreactivity. Like in other regions of the basal forebrain, substance P in the BST was markedly depleted (60% reduction) in patients with Huntington’s disease compared to healthy controls. Neurokinin B neurons were numerous in the BST, with 5–30% of the BST cells containing neurokinin B mRNA (Haber and Watson, 1985; Beal, Ellison et al., 1988; Chawla et al., 1997; Prensa et al., 2003). Neurokinin receptor antagonists are being developed for the treatment of conditions associated with an excess or imbalance of tachykinins, particularly substance P. Such conditions include affective disorders such as anxiety, depression, obsessive–compulsive disorder, bulimia, and panic disorder (Kramer et al., 1998; Rosen et al., 1998; Papp et al., 2000; Gentsch et al., 2002; Varty et al., 2002). Vasoactive Intestinal Polypeptide In the brain, vasoactive intestinal polypeptide mediates the release of somatostatin and luteinizing hormone. Immunocytochemistry revealed vasoactive intestinal polypeptide staining in the central BST. The volume of this stained region differed between sexes (see below) and increased with age. Low to moderate vasoactive intestinal binding sites were observed in the BST, mainly in its dorsal part, just ventral to the anterior commissure (Chung et al., 2002). The Granin Family Intracellularly, granins contribute in the formation of secretory granules, and the modulation of peptide hormone and neuropeptide processing, while they contribute in autocrine and paracrine inhibition of secretion extracellularly (Taupenot et al., 2003). The distribution and the degree of proteolytic processing of chromogranin B within the brain was investigated using an antiserum against PE-11. The BST was one of the brain regions with the highest expression levels. Immunostaining revealed prominent immunoreactivity in its medial, lateral, and ventral part. In the lateral part, a core of PE-11-immunoreactive perikarya was found to be surrounded by woolly fibers with intensely stained varicosities (Marksteiner et al., 1999). Secretoneurin is derived by endoproteolytic processing from secretogranin II, previously also named

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chromogranin C. This peptide is released from neurons and induces dopamine release in striatal slice preparations. Strongly secretoneuron-immunoreactive fibers were observed throughout the course of the stria terminalis and a high immunoreactivity was found in the BST, mainly appearing as punctate profiles and beaded fibers. These BST fibers frequently formed pericellular contacts. Woolly fibers were also observed. Immunoreactive cells were small-to-medium sized and scattered throughout the BST (Marksteiner et al., 1993; Kaufmann et al., 1997).

Calcium-Binding Proteins Calcium-binding proteins have a vital role in calcium homeostasis by buffering and probably also have a neuroprotective function. Fluctuations in intracellular calcium (Ca2) are central to orderly neurotransmission and the operation of a wide range of cellular functions. In the lateral BST, a few calbindin D-28k-immunoreactive neurons were scattered in a moderately stained neuropil (Kaufmann et al., 1997; Prensa et al., 2003). Staining of calretinin, another calcium-binding protein, was intense in the rostral pole of the lateral BST, continuous with the caudal ventral striatum. Small calretininimmunoreactive cell bodies were observed in the lateral BST, but their dendrites could not be clearly visualized because of the intensity of background staining (Prensa et al., 2003).

The Acetylcholinergic System Acetylcholine is an excitatory neurotransmitter synthesized in the cell body and nerve terminal from acetyl-CoA and choline, catalyzed by choline acetyl transferase (ChAt). Upon release in the synaptic cleft, acetylcholine is bound to acetylcholine receptors or degraded by acetylcholine esterase (AChE) to acetate and choline. ChAt and AChE are both enzymes that are used as markers for the acetylcholinergic system (Tohyama and Takatsuji, 1998). Moderate ChAt and AChE staining was observed in the BST neuropil with a mosaic-like pattern of lightly stained zones embedded in a more densely stained background, particularly in the lateral BST. Medium- and small-size cells immunoreactive to AChE were also observed in the BST (Gaspar et al., 1985; Szigethy et al., 1990; Prensa et al., 2003).

Limbic System-Associated Membrane Protein Limbic system-associated membrane protein is an adhesion molecule, which mediates the formation of

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specific pathways during development and the maintenance of various limbic system connections. The lateral BST displayed a moderate immunostaining for limbic system-associated membrane protein restricted to the neuropil within the gray matter (Prensa et al., 2003).

The Catecholaminergic System Tyrosine hydroxylase and dopamine-β-hydroxylase were used as markers to investigate the distribution of the catecholaminergic system. Tyrosine hydroxylase catalyzes the conversion of tyrosine into L-DOPA, the precursor of dopamine, which is in turn converted into noradrenalin by dopamine-β-hydroxylase (Tohyama and Takatsuji, 1998). Functional neuroimaging studies in patients with OCD suggest higher synaptic concentrations of dopamine in the basal ganglia. Moreover, antipsychotics that modulate the dopaminergic brain activity are effective in OCD but only when supplemented to SSRIs (Denys et al., 2004). It was demonstrated with both markers that catecholaminergic fibers traverse the septal nuclei and enter the BST forming a vertically oriented axonal bundle which follows the lateral border of the BST medially to the internal capsule (Gaspar et al., 1985). Tyrosine-hydroxylase immunoreactive innervation was observed with dense oval patches vertically aligned along the lateral edge and in basket-like pericellular formations in the central BST. Tyrosine hydrolase-innervation was less dense in the medial BST, except for a denser zone underneath the ventral tip of the lateral ventricle. Finally, tyrosine hydroxylase-immunoreactive axons in the ventrolateral (subcommissural) BST were mainly of the smooth non-varicose type. A rostrocaudal decreasing gradient of TH terminals was also noted in the BST, particularly caudally of the anterior commissure where labeled fibers became scarce. Of note, a close correspondence was observed between the dense TH-clusters and the intensely AChE reactive patches in the BST (Gaspar et al., 1985; Lesur et al., 1989). The topography of tyrosine hydroxylase and dopamine-β-hydroxylase in the BST were complementary to each other. Abundant dopamine-β-hydroxylase fibers were concentrated in the medial portion of the nucleus, the lateral portion being scarcely innervated. The expression of noradrenalin in the BST is with 0.98 mg/g tissue one of the highest in the limbic forebrain. In schizophrenia patients, a more than two-fold increase in noradrenalin was observed in the BST and a three-fold increase in the septum. These changes appeared to be localized as they were not observed in some other limbic regions. Although unlikely, it cannot be excluded that the increase in BST noradrenalin was treatment-related (Farley and Hornykiewicz, 1977; Farley et al., 1978).

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Dopamine 1 receptor mRNA in the BST equaled the relative dopamine 1 receptor expression in the caudate nucleus, while dopamine 2 receptor mRNA expression in the BST was moderate, with only 80–85% of label relative to the caudate nucleus (Hurd, 1996).

observed in neurons of the lateral BST. Nuclear staining was observed in males in the medial and central BST. A striking estrogen receptor β-ir was observed in (beaded) fibers of the stria terminalis and central BST, with additional strong “basket-like” stainings, suggestive of the presence of nerve terminal appositions (Kruijver et al., 2003).

Nerve Growth Factor Nerve growth factor modulates cholinergic neurons in the basal forebrain. In line, receptors for nerve growth factor coexist in 95% of the cholinergic neurons in the basal forebrain. Immunoreactive neurons were observed in the human BST (Mufson et al., 1989).

Brain-Derived Neurotrophic Factor Brain-derived neurotrophic factor belongs to the neurotrophins, which are assumed to be essential for the survival and differentiation of neurons during embryonic development. Brain-derived neurotrophic factorstaining in the BST was almost entirely limited to fibers, which formed a very dense and strongly stained plexus. Several non-stained neuronal profiles were completely enveloped by immunoreactive terminal boutons and fibers. BST staining was not different in patients with Alzheimer’s disease (Murer et al., 1999).

Steroids Steroid Receptors Testosterone, the primary circulating sex hormone in adult men, binds to androgen receptors within the neuron, eventually after conversion to 5-adihydrotestosterone. Testosterone participates in the regulation of reproductive behavior in males and maybe also to a limited extent in females. Androgen receptor staining has been observed in scattered cells in all subdivisions of the BST. Staining was diffuse and transparent in nuclei without cytoplasmatic staining. In general, expression was weak compared to hypothalamic nuclei. Although in some nuclei (e.g. medial mammillary nucleus) a larger androgen receptor expression was observed in men compared to women, no sex differences were observed in the expression of this receptor in the BST (FernandezGuasti et al., 2000). Estrogen receptors α and β are targets for estrogens. Weak estrogen receptor-α staining was present in the medial, central, and lateral BST. Nuclear staining was observed in both sexes whereas cytoplasmic staining was only observed in males. No fibers were stained (Kruijver et al., 2002). Predominant cytoplasmic estrogen receptor β-immunoreactivity was

Sex Hormone-Binding Globulin Sex hormone-binding globulin is a glycoprotein that may bind to a membrane receptor to induce rapid steroid effects. Immunoreactive cells and fibers were found in the magnocellular portions of the BST (Herbert et al., 2005). FF1 Receptor FF1 receptors bind neuropeptides with C-terminal RFamide and are implicated in a wide variety of functions including nociception and autonomic and neuroendocrine regulation. The posterior part of the BST had the highest number of FF1-immunostained neurons in the basal forebrain. Stained cells presented as both multipolar and bipolar, of medium to large size. Areas with FF1 were in some sections divided into separate cellular islands by ventrolaterally oriented bundles of FF1-stained fibers. The large multipolar FF1 neurons within such cellular islands had one or more thick dendrites and often send their axon to the neighbouring FF1-positive and -negative cells. The FF1 fiber bundles in the posterior BST appeared mostly as single strands of FF1-immunostained punctate fiber varicosities. A dense network of FF1-stained fibers was observed around the anterior commissure at the level of the BST. These fibers were observed as single strands of punctate varicosities (Goncharuk et al., 2004).

Angiotensin II Receptor Moderate densities of angiotensin II (Ang II) binding sites were observed in the BST. In the central nervous system, Ang II may influence cardiovascular function, fluid and electrolyte balance, pituitary hormone release, and memory and learning (Allen et al., 1991).

SEXUAL DIMORPHISM The BST is one of the brain areas that exhibit volumetric and neurochemical differences between males and females. Inferolateral to the tip of the fornix, there is a region in the posteromedial BST that is intensely

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stained on thionin-stained sections and was therefore called the “darkly staining posteromedial component” of the BST (BST-dspm). The volume of the BSTdspm is 2.47 greater in males (3.37  0.53 mm2) than in females (1.37  0.29 mm2) (Allen et al., 1991). Immunocytochemistry revealed a 71% higher number of somatostatin neurons in the central part of the BST of heterosexual men compared to heterosexual women. While hetero- and homosexual men had a similar number of neurons in the central BST, the number of central BST neurons in male-to-female transsexuals was comparable to that of females, and vice versa. Of note, this difference did not seem to depend on estrogen treatment, orchidectomy or hormonal changes in adulthood. Since transsexuals experience themselves as being of the opposite sex, despite having the biological characteristics of one sex, it is believed that the central BST is involved in sexual identity (Kruijver et al., 2000). Also in the central BST, the volume stained for vasoactive intestinal polypeptide is on average 44% larger in heterosexual men (2.49  0.16 mm2) compared to women (1.73  0.13 mm2). Like for somatostatin, male-to-female transsexuals presented with volumes comparable in size to females (1.30  0.23 mm2). This was not observed outside the BST in hypothalamic nuclei. There is no evidence that the small central BST size in transsexuals was due to differences in adult sex hormone levels (Zhou et al., 1995). Finally, sex differences in receptor expression were observed within the BST. Cytoplasmic estrogen receptor-α label was more intense in the medial BST of males compared to females, with no sex differences in the central and posterior BST (Kruijver et al., 2002). Nuclear estrogen receptor β was more abundant in men as compared to women in neurons of the medial and central part of the BST, while more cytoplasmic staining was found in the posterior BST of women. For the male subjects with relatively high circulating levels of estrogens, nuclear or cytoplasmic ERβ-ir appeared to be expressed in typical female levels in areas such as the BST (Kruijver et al., 2003).

REMARKS AND CONCLUSION Cyto- and chemoarchitectonic studies demonstrate that the BST is a highly complex structure. Currently there is no direct evidence that the neurotransmitters, neuropeptides, and receptors observed in the BST are involved in the pathophysiology of obsessive– compulsive disorder. Nevertheless, there is some evidence from plasma and CSF studies that several of

these neurotransmitters and neuropeptides are affected in OCD (see Chemoarchitecture of the BST above). Postoperative structural magnetic resonance imaging indicates that the distal electrode contact is located posterior to the crossing of the anterior commissure (see Figure 55.3), corresponding to the caudal part of the dorsal division of the lateral BST, the posterior part of the lateral and medial BST, and the juxtacapsular division of the BST according to the parcellation of de Olmos (1990). Of note, the BST is rather small and it is therefore reasonable that surrounding structures, like the septal nuclei, the lateral hypothalamus, etc., are also stimulated to some extent, depending on the stimulation parameters. The therapeutic effects of electrical stimulation in patients with OCD may therefore be (partly) obtained by stimulation of these structures.

ACKNOWLEDGMENTS We acknowledge the financial support of the Research Fund K.U. Leuven (project VIS/02/007 and OT/03/57), the Institute for the Promotion of Innovation by Science and Technology in Flanders (SBO50151), and the Fonds voor Wetenschappelijk Onderzoek – Vlaanderen (G.0598.06 and SB/0661236).

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Herbert, Z., Gothe, S., Caldwell, J.D. et al. (2005) Identification of sex hormone-binding globulin in the human hypothalamus. Neuroendocrinology 81 (5): 287–93. Hurd, Y.L. (1996) Differential messenger RNA expression of prodynorphin and proenkephalin in the human brain. Neuroscience 72 (3): 767–83. Johnston, J.B. (1923) Further contributions to the study of the evolution of the forebrain. J. Comp. Neurol. 35: 337–481. Kaufmann, W.A., Barnas, U., Maier, J., Saria, A., Alheid, G.F. and Marksteiner, J. (1997) Neurochemical compartments in the human forebrain: evidence for a high density of secretoneurin-like immunoreactivity in the extended amygdala. Synapse 126 (2): 114–30. Kaye, W.H. (1996) Neuropeptide abnormalities in anorexia nervosa. Psychiatry Res. 62 (1): 65–74. Koizumi, H.M. (1985) Obsessive–compulsive symptoms following stimulants. Biol. Psychiatry 20 (12): 1332–3. Kopell, B.H., Greenberg, B. and Rezai, A.R. (2004) Deep brain stimulation for psychiatric disorders. J. Clin. Neurophysiol. 21 (1): 51–67. Kordower, J.H. and Mufson, E.J. (1990) Galanin-like immunoreactivity within the primate basal forebrain: differential staining patterns between humans and monkeys. J. Comp. Neurol. 294 (2): 281–92. Kramer, M.S., Cutler, N., Feighner, J. et al. (1998) Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 281 (5383): 1640–5. Kruijver, F.P., Balesar, R., Espila, A.M., Unmehopa, U.A. and Swaab, D.F. (2002) Estrogen receptor-alpha distribution in the human hypothalamus in relation to sex and endocrine status. J. Comp. Neurol. 454 (2): 115–39. Kruijver, F.P., Balesar, R., Espila, A.M., Unmehopa, U.A. and Swaab, D.F. (2003) Estrogen-receptor-beta distribution in the human hypothalamus: similarities and differences with ER alpha distribution. J. Comp. Neurol. 466 (2): 251–77. Kruijver, F.P., Zhou, J.N., Pool, C.W., Hofman, M.A., Gooren, L.J. and Swaab, D.F. (2000) Male-to-female transsexuals have female neuron numbers in a limbic nucleus. J. Clin. Endocrinol. Metabol. 85 (5): 2034–41. Lesur, A., Gaspar, P., Alvarez, C. and Berger, B. (1989) Chemoanatomic compartments in the human bed nucleus of the stria terminalis. Neuroscience 32 (1): 181–94. Mai, J.K., Assheuer, J. and Paxinos, G. (2004) Atlas of the Human Brain, 2nd edn. Amsterdam: Elsevier/Academic Press. Mai, J.K., Triepel, J. and Metz, J. (1987) Neurotensin in the human brain. Neuroscience 22 (2): 499–524. Marksteiner, J., Bauer, R., Kaufmann, W.A., Weiss, E., Barnas, U. and Maier, H. (1999) PE-11, a peptide derived from chromogranin B, in the human brain. Neuroscience 91 (3): 1155–70. Marksteiner, J., Saria, A., Kirchmair, R. et al. (1993) Distribution of secretoneurin-like immunoreactivity in comparison with substance P- and enkephalin-like immunoreactivities in various human forebrain regions. Eur. J. Neurosci. 5 (12): 1573–85. Martin, L.J., Powers, R.E., Dellovade, T.L. and Price, D.L. (1991) The bed nucleus-amygdala continuum in human and monkey. J. Comp. Neurol. 309 (4): 445–85. McDougle, C.J., Barr, L.C., Goodman, W.K. and Price, L.H. (1999) Possible role of neuropeptides in obsessive compulsive disorder. Psychoneuroendocrinology 24 (1): 1–24. Mufson, E.J., Bothwell, M., Hersh, L.B. and Kordower, J.H. (1989) Nerve growth factor receptor immunoreactive profiles in the normal, aged human basal forebrain: colocalization with cholinergic neurons. J. Comp. Neurol. 285 (2): 196–217. Mufson, E.J., Cochran, E., Benzing, W. and Kordower, J.H. (1993) Galaninergic innervation of the cholinergic vertical limb of the diagonal band (Ch2) and bed nucleus of the stria terminalis in aging, Alzheimer’s disease and Down’s syndrome. Dementia 4 (5): 237–50.

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C H A P T E R

56 Deep Brain Stimulation for Highly Refractory Depression Benjamin D. Greenberg

O U T L I N E Introduction Pharmacotherapies Treatment of Refractory Patients Other Brain Stimulation Techniques

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Development of DBS in Neuropsychiatry History Affect and Mood Effects Observed During Depth Electrode Stimulation DBS for Obsessive–Compulsive Disorder

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Technical Aspects of DBS Implantation Stimulation Technique Customizing Therapy

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DBS for Primary Depressive Illness Stimulation Targets for Depression

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Inferior Thalamic Peduncle (ITP) Subgenual Cingulate Region Ventral Capsule/Ventral Striatum (VC/VS) Issues Independent of DBS Target Mechanism(s) of Action of DBS

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Adverse Effects

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Ethical Considerations

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Perspective Long-Term Follow-Up Research Protocols for Investigational Treatment with DBS

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addition to marked distress. Impairment in marital, parental, social, vocational, and academic functioning can be pervasive. Depression, in fact, ranked as the leading cause of adult disability in developed countries in the Global Burden of Disease Study (Murray and Lopez, 1997). One study found that disability due to unipolar depression approached almost three times the rate of that due to chronic obstructive pulmonary disease (Lopez and Murray, 1998). Death from suicide

“Depression” connotes a group of conditions imposing a serious public health burden (Fava and Davidson, 1996). Prevalence of unipolar major depressive disorder (MDD) has been conservatively estimated at 2.6–5.5% in men and 6.0–11.8% in women (Kessler et al., 1994). Most (50–85%) patients have recurrent depressive episodes. Depression can cause profound disability in

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is a major complication (Joukamaa et al., 2001). And when depression and cardiovascular disorders or cancer coexist, mortality increases (Glassman and Shapiro, 1998; Wulsin et al., 1999). As in clinical practice, depression is usually treated as a categorical construct in research. However, current definitions allow considerable heterogeneity of presenting symptoms within the category of MDD. Depressive syndromes can also be described along continuous symptom dimensions. When depression severity questionnaire items are factor analyzed, a variety of dimensional structures results. Some of this is undoubtedly due to differences among the scales used, as well as symptom heterogeneity within the groups of depressed patients studied. Some major dimensions that emerged after factor analyses are: depressed mood (a bias toward negative emotion); anhedonia (loss of pleasurable experiences); amotivation (impaired goal-directed behavior); impaired sense of energy or vitality; somatic or “neurovegetative” symptoms (disturbances in psychomotor activity, sleep, feeding, and body weight); depressive cognitions (pessimistic thoughts, feelings of guilt, low selfesteem, and suicidal ideation); cognitive impairments; and anxiety. These dimensions may be differentially associated with activity in brain networks (Dunn et al., 2002; Milak et al., 2005; Perico et al., 2005). As for psychiatric illnesses more generally, understanding of the pathogenesis of depressive conditions remains elusive. It appears that many genetic and environmental factors are relevant to depressive symptomatology at the group level. And at the individual level, interactive models of genetic and environmental susceptibilities have been proposed (Wong and Licinio, 2001; Nestler et al., 2002; Caspi et al., 2003; Berton and Nestler, 2006; Berton et al., 2006; Svenningsson et al., 2006). Hypotheses about pathophysiology, as opposed to pathogenesis, may be somewhat better developed. Research into associations between brain networks and depressive phenomenology has a relatively long history. Over two decades ago ideas were put forward that disruption in normal reinforcement contingencies due to cortical-limbic-thalamic-striatal dysfunction might contribute to affective components of neuropsychiatric conditions (Swerdlow and Koob, 1987). Cortico-basal circuits implicated in modulation of mood as well as reward signals have also figured prominently in more recent neuroanatomical models based largely on functional neuroimaging (Mayberg, 2002; Phillips et al., 2003). Recent reviews described how this circuitry may relate to symptom improvement after lesion procedures that, though derived largely empirically (Greenberg et al., 2003; Rauch, 2003), target different nodes within these networks of interest.

Pharmacotherapies The early antidepressants iproniazid and imipramine were first developed for tuberculosis and psychosis, respectively. Their antidepressant effects were discovered serendipitously; patients treated for those other illnesses had reduced depressive symptoms. The insight that these and related agents affected monoamine neurotransmission allowed the field to “improve on serendipity”. Thus drugs such as selective serotonin reuptake inhibitors (SSRIs) were developed and eventually became first-line antidepressants due to their better tolerability and reduced lethality in overdose. However, the earlier classes of antidepressants remain in use as second- or third-line medications in refractory cases. More than twenty antidepressants are commonly used. The drugs are usually grouped by their chemical classes or pharmacological actions, such as: (1) tricyclics and tetracyclics; (2) serotonin reuptake inhibitors (SRIs), which include the more selective SSRI medications; (3) monoamine oxidase inhibitors (MAOIs); and (4) those affecting other or combinations of biogenic amine systems. Medications from different classes are frequently combined, particularly in refractory cases.

Treatment of Refractory Patients While efficacy of antidepressants is well demonstrated, they benefit many but not all patients. A key point to emphasize at the outset is that there are a number of different degrees of refractoriness or “treatment resistance.” It is instructive to review classifications of levels of poor responses to treatment (e.g., Rush et al., 2003). The important methodological point here is that entry criteria for studies of “resistant patients” may vary substantially. This applies to trials of any potential antidepressant treatment, including neurosurgical therapies. Thus, differences in the degree of refractoriness, along with other characteristics of study patients, may be expected to affect efficacy rates of any given trial. This can complicate attempts to compare outcomes from different studies. It appears beyond dispute that affected individuals who have an inadequate response to all of the treatments discussed below – medications, psychotherapies, and ECT – currently have little prospect of sustained recovery. But how specific differences in refractory or resistance criteria might affect outcomes remains poorly understood. But by any measure the limits of conventional treatments remain a serious problem. It is actually a relatively small proportion of patients who experience remission with their first antidepressant trial. Overall, antidepressant monotherapy may bring about and maintain

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DEVELOPMENT OF DBS IN NEUROPSYCHIATRY

remission in about half of patients. The most affected group remains refractory to all standard medication treatments for depression (Rush et al., 2003). A proportion of this group might improve after more aggressive “augmentation” trials where other classes of psychotropic medications are added to antidepressants. Augmenting agents include mood stabilizers (lithium or anticonvulsants), neuroleptics, thyroid hormone, and other medications. Use of certain dietary supplements, or “nutraceuticals” including omega 3 fatty acids and sadenosyl methionine, appears to be increasing (though systematic data are scant). The few agents approved for augmentation in refractory depression in the USA include the second-generation antipsychotic aripiprazole, and the prescription “medical food” methylfolate. Psychotherapies for depression, while considered first line in their own right, are very often used together with medications, especially in depressions of moderate or greater severity. Various forms of psychotherapy have been studied to different degrees. There is strong evidence for efficacy of cognitive-behavior therapy (and variants), interpersonal therapy, and family therapy for depression. For example, for one family therapy this has included studies of relapse prevention in patients with illness severe enough to require psychiatric hospitalization (Miller et al., 2005). But, as noted above, many patients remain severely affected despite aggressive use of the conventional treatments such as those above. Electroconvulsive therapy (ECT) remains a therapeutic gold standard after 75 years. In ECT, electrical current is delivered to the brain across the large electrical resistance of the scalp and skull. ECT, however, can be associated with significant adverse effects, particularly memory loss, which can limit its acceptance. Moreover, ECT’s therapeutic effects are transient in a large proportion of patients, and so continuation or “maintenance” treatment may be needed (Gagne et al., 2000). On the other hand, the recent development of an ECT technique using much briefer electrical pulses to induce convulsions reported a much lower rate of adverse effects on cognition, and is seeing expanded clinical use.

Other Brain Stimulation Techniques An increasing array of stimulation methods have been subject of research as potential treatments for depression. These device-based stimulation modalities can alter brain electrical activity directly or indirectly. Transcranial magnetic stimulation (TMS) magnetically induces electrical currents in brain tissue using an electromagnetic coil placed on the scalp. As for ECT, variations in how TMS is delivered are beginning to be explored. These include magnetic seizure therapy, different magnetic

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pulse sequences or markedly different designs of the electromagnetic coils themselves. Variations in coil design can result in advantages such as markedly lower requirements for electric current. Intriguing new TMS devices create magnetic field geometries that should allow effective stimulation deeper in the brain. Vagus nerve stimulation (VNS), in contrast, uses electrodes wrapped around the left vagus nerve in the neck to activate its afferent projections to target nuclei and related neural circuits (see Chapter 54 in this present work). Two additional techniques that have very recently been explored in depression are intracranial cortical stimulation and transcranial direct current stimulation. While all these brain stimulation methods are under active investigation, neurosurgery remains an option for patients with otherwise untreatable and severe psychiatric illnesses, primarily depression and obsessive–compulsive disorder (OCD). Stereotactic ablative procedures like anterior cingulotomy and anterior capsulotomy continue in small-scale and/ or research use in North America, Europe, and elsewhere. Therapeutic improvement has been reported in between one-third to two-thirds of otherwise intractably ill patients after lesion procedures. The potential for long-lasting or permanent serious adverse effects remains a major concern. However, rates of persistent serious adverse effects have been generally modest at the most experienced expert centers (for review see Greenberg et al., 2003). But this is not true when the volume of tissue lesioned has been large, particularly for some procedures such as thermocapsulotomy or high dose, multiple target gamma knife procedures (e.g., Rück et al., 2008). An advantage of DBS compared to ablative neurosurgery is that the effects of stimulation itself are reversible, though long-term or even irreversible side effects of brain lead implantation have occurred. Another key issue in assessing the risks and burdens of DBS versus lesion procedures is the need for patients to have access to highly specialized expert treatment centers, essentially in perpetuity. This model of care, with all its advantages, can impose important logistical and financial burdens on patients, who by virtue of long-term disability and psychosocial dysfunction may have few resources.

DEVELOPMENT OF DBS IN NEUROPSYCHIATRY History DBS for psychiatric illness, and specifically for depression, is not a new idea. But the devices are new, and there are now empirical findings from stereotactic

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lesion procedures and neuroimaging that have allowed theoretical models of depression neurocircuitry to advance dramatically since attempts earlier in the twentieth century. In 1948, Pool (1954) used a silver electrode implanted in the caudate nucleus to try to treat a woman with depression and anorexia. And over subsequent decades, Heath, Sem-Jacobsen, and Delgado exemplified an earlier era of intracranial stimulation (see below). Over the past twenty years, the introduction and refinement of DBS for movement disorders has resulted in a renaissance in this branch of functional neurosurgery, and in the field more generally. In the USA, DBS is approved for tremor and Parkinson disease and, under a Humanitarian Device Exemption, for dystonia. Worldwide, DBS is or is becoming a standard of care for such patients. The developments above spurred renewed interest in the use of such procedures for the treatment of other refractory neurologic conditions. As of this writing, DBS remains investigational for primary psychiatric disorders. Investigational uses of DBS for neurologic illness include epilepsy, pain, cluster headaches, tardive dyskinesia, Gilles de la Tourette syndrome, brain injury, and persistent vegetative states. DBS was conceived as a treatment for psychopathology by the 1940s, when caudate nucleus stimulation was tried for treatment of depression and anorexia. In work that began soon afterwards, and was contemporary with Sem-Jacobsen’s, Heath and colleagues stimulated the “septal region,” an area including the ventral anterior capsule (VC) and ventral striatum (VS) that was just posterior to our current target. Heath chose it, in part, because tumors there and nearby in the forebrain had been related to psychiatric symptoms. Heath and colleagues selected 20 patients with heterogeneous symptoms including delusions, hallucinations, poverty of speech or near mutism, depression, and compulsions, though all had a formal diagnosis of schizophrenia (Monroe and Heath, 1954a, b). Stimulation was limited to 1–3 days after electrode implantation, at amplitude of 2–15 mA. Three of the 20 patients had “no objective signs,” and a further two “could not be evaluated,” during stimulation. The others had these acute effects: “patients became more alert [13 of 15]; … had increased motor activity and spontaneous [speech] production; … [in] previously almost inaudible or expressionless [subjects], speech became louder and enunciation clearer and inflection more appropriate [in 5 who had been the least verbal].” One of these, “who had been almost mute, became talkative and later almost hypomanic.” Three patients appeared acutely more tense, two less so (Monroe and Heath, 1954a, b).

Accompanying behavioral changes included improved social interaction and enhanced emotional expression. As observed by Monroe and Heath, DBS subjects demonstrated “ability to relate to other people, increased responsiveness to pleasure, gradual appearance of a sense of humor, and more overt expression of anxiety and ambivalence,” as well as improved functioning, e.g., “Less negativism … everyday problems were approached more realistically and more interest was shown in ward activities.” Eleven patients, described as generally “idle, seclusive, and withdrawn before operation, afterward participated actively in some or all of the ward activities.” Improved emotional responsiveness in social settings was “even more dramatic.” “Twelve patients showed significant improvement in their ability to relate to other people,” one of the “outstanding aspects” of which was the “emergence of pleasurable feelings.” Nine patients showed the “development of humor.” Some of these effects apparently persisted following after stimulation ceased, though for how long is not fully clear. Monroe and Heath believed that “patients who respond particularly well … [were those] whose main abnormalities seem to consist of flattened affect or disturbed motor behavior.” The time course and persistence of therapeutic benefit after stimulation ceased is not entirely clear in this work, although effects apparently could be transient. Some lasting or emerging benefit might have been due to concerted multidisciplinary therapies also used in these patients, described as a “total push” approach – which had, however, also been tried before stimulation without improvement. In our own experience to date, and that of others, ongoing DBS has been required for persistent behavioral and emotional change. A potential exception to this, however, is the sustained benefit seen in two OCD patients after chronic stimulation. In these individuals, stimulation facilitated completion of courses of behavioral therapy (exposure and ritual prevention), which had been impossible for these patients before DBS treatment (Greenberg, Malone et al., 2006). In this sense, lasting effects after DBS ceases might be possible. This intriguing possibility will require systematic study. It is important to note that the early work, from the 1950s and later, predated modern research methods. Diagnostic and severity measures used did not meet current standards for reliability or construct validity, limiting interpretation. However, recorded observations of acute and subacute DBS effects (in patients diagnosed with schizophrenia), have high face validity as manifestations of affective state. These include enhanced production, volume, and prosody of speech; greater affective range, social relatedness, sense of humor, functioning, and increased level of activation or hypomania.

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Affect and Mood Effects Observed During Depth Electrode Stimulation Understanding where brain stimulation effects may converge at a systems level is now a reasonable goal. Observations of how DBS for movement disorders affects affect and mood continue to accumulate. They point to neural networks that might represent potential therapeutic targets for primary psychiatric illness. Taken together with early attempts with focal brain stimulation, they suggest that multiple stimulation sites may be useful for depression. In this context, considering efforts of an earlier era is worthwhile, with a view towards integrating them with evolving anatomical models of pathophysiology. In the early 1950s, Sem-Jacobsen began recording effects of acute and chronic (several days) stimulation in 220 movement-disordered patients over more than two decades (Sem-Jacobsen, 1968). Most patients subsequently underwent lesion procedures for Parkinson’s disease, but some were studied before ablative surgery. Stimulation of sites throughout the frontal lobes induced affective/mood changes, with apparent selectivity noted for stimulation of ventromedial brain areas. Positive effects, ranging from mild relaxation and feelings of tranquility (most common) to marked euphoria, were observed twice as often as negative mood effects. The latter ranged from mild tension and/or sadness (most common), to more pronounced sadness and overt sobbing necessitating stimulation cessation. The same responses were elicited by unilateral stimulation on the right (at 327 sites) or left (316 sites), with no significant laterality differences (Sem-Jacobsen, 1968), suggesting stimulation of many different brain loci could induce positive and negative mood states. Further, effects of opposite affective valence (e.g., mild tension and sadness vs. mild euphoria) were sometimes seen with stimulation of sites 5–10 mm apart in the same individual. Modern DBS for movement-disordered patients has at times entailed dramatic effects on the affective state of patients. Case reports have described effects ranging from induction of depressive dysphoria, anhedonia, apathy, and blunted affect to hypomania, merriment, and involuntary laughter. These findings are extremely intriguing, especially given the possibility of mood effects when the STN is stimulated to treat OCD. Case reports of DBS of the STN in two patients with severe Parkinson’s disease who also had moderately severe OCD produced improvement in OCD symptoms by two weeks after the start of therapy. In one of the two patients, OCD improvement was seen despite little change in Parkinson symptoms. A controlled trial of STN stimulation for OCD itself by a collaborative group in France was published in 2008.

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Yale-Brown OCD Scale (YBOCS) scores decreased from 30 to 19 after three months of active stimulation in eight patients who received active DBS first. In contrast, in the sham group, YBOCS severity declined from 31 at baseline to 26 after three months of sham stimulation. The YBOCS score was 24 at the end of three months of the subsequent active DBS period. There were 15 serious adverse effects, including hemorrhage and infection (Mallet et al., 2008).

DBS for Obsessive–Compulsive Disorder Work using DBS for OCD, the first contemporary report of DBS for psychiatric illness, is described more fully in Chapter 55 of this present work. The rationale for development of DBS for OCD in large part paralleled that for tremor, Parkinson disease, and dystonia, where DBS was applied to structures where lesions had therapeutic effects. Case studies of severely ill, highly treatment-refractory OCD patients treated with DBS of the anterior limb of the internal capsule and/or the adjacent striatum were published beginning in 1999 (Nuttin et al., 1999, 2003; Anderson and Ahmed, 2003; Sturm et al., 2003; Aouizerate et al., 2004; Abelson et al., 2005). These reports have supported the therapeutic potential of DBS in this population, and have suggested that DBS is generally well tolerated (Gabriëls et al., 2003). For any surgery for psychiatric illness, a key issue is long-term outcome, as is true in established uses of DBS in movement disorders. Treatment decisions need to be based on the probability that therapeutic effects will be durable while taking into account burdens imposed by potential adverse effects. A related issue is the need to determine the likely rate at which therapeutic effects will develop in multiple domains. This is in part necessary to give patients and family members a realistic idea of the potential unfolding of benefits when they occur. Based on our own experience and that of others with lesion procedures for OCD (Greenberg et al., 2003), even cases with ultimately positive outcomes take time to improve. Beneficial changes in symptom severity, functioning, and quality of life may develop gradually (and at different rates) in individuals who have had chronic and severely impairing illnesses that have disrupted not only the patients’ functional capacities but also their family and social relationships. A related point is that a description of therapeutic outcomes that will be most meaningful to patients and families needs to go beyond symptom severity reductions and take into account functioning and quality of life. In 2006, our research group reported on ten OCD patients meeting stringent criteria for severity and treatment resistance who underwent DBS of a ventral

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internal capsule/ventral striatum target (Greenberg, Malone et al., 2006). This work followed and was based upon the pioneering work by Nuttin and colleagues which began in 1998, which was itself influenced by earlier results of anterior capsulotomy for OCD. The OCD patients, who met rigorous criteria for diagnosis and failure to respond to multiple adequate conventional treatments, had quadripolar stimulating leads implanted bilaterally in the VC/VS. DBS was activated openly three weeks later. Mean YBOCS scores decreased significantly from baseline to 36 months (p 0.001). Four patients had at least 35% threshold decrease in YBOCS severity at 36 months, and scores declined between 25% and 35% for two others, consistent with the categorical response definition commonly used in modern treatment trials for OCD. Mood and non-OCD anxiety symptoms improved in these patients, and there was evidence of improvements in self-care, independent living, and work, school, and social functioning. Surgical adverse effects included asymptomatic hemorrhage (n  1), intraoperative seizure (n  1), and superficial infection (n  1). Psychiatric adverse effects included transient mood elevation, which met diagnostic criteria for a hypomanic episode in one of the ten patients. Long-term effects observed by our research group during open-label VC/VS DBS include worsened depression followed by a more gradual exacerbation of OCD symptoms, at the point when DBS is interrupted by stimulator battery depletion. These observations are in accord with a hypothesis of overlapping neurocircuitry mediating at least some dimensions of depression and OCD. Another interesting observation from this OCD patient series is that two patients had sufficient improvement with VC/VS DBS to be able to engage in adjunct cognitive behavioral therapy (CBT). More recently, we have found a similar overall picture of benefits and adverse effect burden in an expanded series including these ten individuals and 16 others (Greenberg et al., 2008). In this combined series it was easier to discern a “learning curve,” in which patients in the second or third cohorts implanted did better over the long term than those enrolled when experience was more limited. This pattern held irrespective of study center, and seemed to be a function of the close collaboration across centers. An association between the gains in outcome measures and a modified surgical target became particularly clear.

TECHNICAL ASPECTS OF DBS Implantation Since aspects of DBS technique are described in detail throughout this book, they will be reviewed

only briefly here. Implantation typically combines MRI and CT imaging, computerized navigation, and often, physiological mapping. Intracranial structures can be targeted with millimeter precision, with multi-contact brain leads placed in subcortical nuclei or specific white matter tracts, or spanning both kinds of structures. The subject is typically sedated but awake during the surgery. Intraoperative physiological mapping is routinely done for movement disorders, where targets are cell nuclei with characteristic physiological signatures, such as the globus pallidus interna (GPi), subthalamic nucleus (STN), or thalamic nuclei. Microelectrode and semi-microelectrode recording attempt to define the boundaries of a given structure based on its known spontaneous and/or evoked electrical activity. Patients’ responses to intraoperative macrostimulation may help guide the final positioning of the electrodes. The utility of such intraoperative stimulation for psychiatric disorders remains unclear at this point. In a second surgical phase (on the same or on a subsequent day), the surgeon places the stimulator (also known as an implantable neurostimulator (INS) or implantable pulse generator (IPG), subdermally, usually in the upper chest. The stimulator(s) are then connected via extension wires tunneled under the skin (which required general anesthesia), to the brain electrodes.

Stimulation Technique The electrode used is typically referred to as a “lead.” Each lead has multiple electrode contacts, which are the sites of stimulation. A commonly used lead is 1.27 mm in diameter. There are typically four or more platinum/iridium electrode contacts on each lead. Usually one lead is implanted on each side, allowing bilateral stimulation. Available DBS device systems are undergoing rapid technical refinements [Medtronic, Inc. (Minneapolis, MN), Advanced Neuromodulation Systems, Inc. (Plano, TX) or NeuroPace, Inc. (Mountain View, CA)]. Currently only the Medtronic devices are approved for therapeutic brain stimulation, and others remain officially “investigational.” The leads have independently programmable electrode contact sites, so the anatomical extent of stimulation is adjustable. By configuring positive or negative charges at different contacts along a lead, the shape and size of the stimulation field can be varied greatly. Chronic stimulation can thus be unipolar, bipolar or multipolar, as each of the electrode contacts can be used as an anode or cathode (or may be set as inactive). The frequency, intensity, and pulse width are programmable for each lead, within safety limits that restrict the maximum density of the electrical charge induced.

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These limits are intended to prevent tissue damage due to excessive current. Stimulation parameters available include frequency ranges of 2–185 Hz, a voltage range of 0–10.5 V, and pulse widths ranging from 60 to 450 microseconds. High frequency DBS (HF-DBS) is used most often for neurological conditions, a practice that has been followed for psychiatric indications. The stimulators are programmed via portable devices, which communicate with the implanted stimulators via telemetry. The patient holds the programming “wand” up to his/her chest wall area over clothing while the programming clinician enters the desired stimulation parameters or interrogates the system for data regarding system integrity and battery status through a handheld or laptop computer. Stimulation can be delivered continuously or intermittently, cycling on and off during fixed time intervals. Patient self-programming devices are also available. These allow patients to activate and deactivate the stimulator via handheld controllers, and to modify a subset of the stimulation parameters within given limits set by the programming clinician. Such patient controller devices are not typically used in the controlled phases of clinical trials, to protect the masked status of treatment for those periods.

Customizing Therapy That DBS is adjustable provides an opportunity to optimize the therapy. But the large potential parameter space creates a challenge in doing so. In this sense, DBS is similar to rTMS (repetitive TMS) and VNS, in having a large number of potential combinations of stimulation parameters. As data have accumulated, the task has gradually become easier, in that the range of parameter sets that are associated with improvement becomes increasingly better delineated. Further advances in DBS optimization will also be made possible by multidisciplinary work that defines the relevant anatomical networks in greater detail and precision. This work will also advance our understanding of the physiological and cellular bases of stimulation efficacy. Together the knowledge obtained will allow better targeting and improved stimulation parameter selection. Design of stimulation devices would also be expected to improve as a result.

DBS FOR PRIMARY DEPRESSIVE ILLNESS Development of DBS for refractory depression has been supported by data from a number of related areas

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of research. Lesion procedures demonstrated the feasibility of focal brain interventions in both neurologic and psychiatric illness. Here it is of particular interest that the same lesion procedures (e.g., anterior capsulotomy, anterior cingulotomy, and subcaudate tractotomy) were associated with improvements in OCD and depression (or other conditions, including intractable pain). The ventral capsule/ventral striatum (VC/VS) stimulation target for depression was initially based on anterior capsulotomy (used for OCD or depression). Notably, in many OCD cases, improvements in mood and other affective symptoms (e.g., motivation, anhedonia, and resilience) were observed to improve faster than obsessions and compulsions, the “core” symptoms in OCD. Those observations in turn resonated with work on the anatomy and physiology of cortico-basal systems that underlie similar dimensions of behavior across species. Thus, observations that DBS at the same target appears to benefit patients with either OCD or depression are consistent with the decades-long experience from lesion procedures. Further, both lesions and DBS may have effects in common that cut across traditional categorical diagnostic boundaries. There is no compelling reason that this will not apply to other stimulation targets as well. As noted above, the potential for dramatic effects on mood, affect and other dimensions of affective illness has been observed throughout the evolution of DBS treatment for neurologic conditions, suggesting that stimulation sites related to those used in movement disorders may find application in psychiatry. The other key impetus for application of DBS to depression has been functional neuroimaging. The overall literature is vast and so will not be summarized here. But a systematic series of studies by Mayberg and colleagues has led directly to the use of DBS targeting the subgenual region for depression (discussed below). Here it is very noteworthy that the same research group that pursued imaging-based models of depression neurocircuitry then translated those findings into a new therapeutic approach. It can be safely stated that the research-to-therapy paradigm exemplified by this work remains rare. Results of research investigating DBS for primary depressive syndrome have been described for stimulation at several different neuroanatomical targets, as reviewed below. Randomized controlled trials, the scientific standard for antidepressant efficacy, are in various stages as of this writing.

Stimulation Targets for Depression As in movement disorders, development of specific structural targets for DBS for psychiatric illness

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has derived, in part, from clinical outcomes observed following lesion procedures. A group of lesion procedures with overlapping targets within cortico-basalthalamic circuits (anterior capsulotomy, subcaudate tractotomy, and limbic leucotomy) have appeared effective in severe and resistant depression in multiple open studies, including large series (more than 1000 patients) for subcaudate tractotomy.

Inferior Thalamic Peduncle (ITP) A case report presented at the World Stereotactic and Functional Neurosurgery Society Meeting, Rome, 2005 described effects of bilateral DBS lead placement and stimulation in the ITP in a woman with refractory depression (Jiménez et al., 2005). Stimulation at this target, via effects propagated by ITP fibers that continue rostrally in the ventral portion of the anterior limb of the internal capsule, would be expected to modulate projections of the dorsolateral prefrontal cortex (DLPFC), of the orbitofrontal cortex (OFC), and of the ventromedial striatum, as they extend to the dorsomedial and intralaminar thalamus. A substantial period of clinical benefit was observed following lead insertion itself, before initiating stimulation of ITP, perhaps reflecting a “microlesion” effect (mass effect of the peri-electrode edema after implantation), a placebo response, or the natural waxing/waning course of the depressive illness itself. With subsequent, chronic IPT stimulation, however, longer-term improvements were noted, particularly in association with relatively low stimulation intensities. This is of interest given that fibers coursing from rostral structures become more compact as they enter the ITP. Further exploration and follow-up will be necessary to establish whether this approach is both safe and beneficial.

Subgenual Cingulate Region Recently, researchers armed with a body of functional neuroimaging research have targeted neuronal networks implicated in both the normal experience of sadness, in symptoms of depressive illness, and in responses to treatment (Mayberg et al., 2005). Using positron emission tomography (PET), the group observed a link between changes in metabolism in subgenual cingulate cortex (SCC), including Brodmann area 25 (BA25), and response to antidepressant medications. They then used DBS to target these networks in refractory depression. Six patients were selected for notable but not extreme levels of treatment resistance, and for a relative lack of psychiatric

co-morbidity. Unblinded stimulation of white matter tracts adjacent to SCC was associated with rapid improvement, with substantial mean benefit at one week after stimulation initiation. Chronic DBS for up to 6 months was associated with sustained remission of depression in 4 of the 6 patients. Three patients showed decreased metabolism in BA25 compared with preoperative baseline PET scans, consistent with studies of responses to some other therapeutic modalities for depression. It is intriguing that the subgenual white matter tracts targeted appear to overlap with those targeted by clinically beneficial 1970s lesion procedures to treat mixed depressive and anxiety pathology (Vilkki, 1977).

Ventral Capsule/Ventral Striatum (VC/VS) Results from small-scale or case studies of severely ill, treatment-resistant OCD patients treated with DBS of the anterior limb of the internal capsule and/or the adjacent striatum have supported the therapeutic potential of DBS in OCD. Onset of VC/VS stimulation was associated with the rapid onset of mood enhancing and anti-anxiety effects in OCD patients. Rapid worsening in these same clinical domains was noted with cessation of VC/VS stimulation. DBS-induced changes in mood and nonspecific anxiety symptoms seemed to precede observable changes in core OCD symptoms. In line with these observations in our OCD patient population, we undertook long-term studies of DBS at this same target in patients with severe and disabling primary major depression. The depressive syndromes of the patients who volunteered for VC/VS DBS were refractory to multiple adequate trials of antidepressant medications, to medication combinations from multiple classes and with augmenting agents, to standard psychotherapy, and to bilateral ECT. Results indicate clinically significant antidepressant responses in half of the 15 patients studied at last follow-up (Malone et al., 2009). Induction of transient, reversible mood elevation, which has occasionally reached the diagnostic threshold for hypomania, has been the most significant adverse effect of active stimulation. This effect has appeared to be stimulation intensitydependent, and has become less problematic following refinements to our stimulation titration methodology. Issues Independent of DBS Target How does co-morbidity affect long-term outcomes? Experience at centers with continuous experience with psychiatric neurosurgery suggests that the psychopathology in most patients who might be referred

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for such interventions tends to be complicated. The complexity of individual patients is usually expressed diagnostically in two ways: a “primary” illness is identified and other conditions are designated as “secondary” or co-morbid. The terms are not mutually exclusive. Here it is helpful to bear in mind that the terms primary and secondary illness tend to be used differently in neurology, where a “primary” mechanism of disease implicates, if not pathogenesis, at least central pathophysiologic processes mediating key features of a disorder. In contrast, descriptive psychopathology in psychiatry often designates a diagnosis as primary when its symptoms are what a patient finds most distressing and for which the patient seeks treatment, as opposed to resulting from some known pathogenetic event or process. In this tradition, which understandably arose in a field where the pathogeneses of illnesses were (and remain) unknown, disorders that appear later in the clinical course, or those judged to be less pressing clinical and psychosocial issues, can be viewed as secondary or often simply co-morbid. While advances in psychiatric neuroscience might be gradually moving the field towards a position more familiar to neurologists, that is not the situation at present. Moreover, co-morbidities can take several forms, including: co-occurring illnesses considered as other diseases (e.g., panic disorder in a patient with depression); variation in personality structures at the extremes along dimensions of behavioral traits (personality disorders); or illnesses where marked disorder in motivated behaviors are most salient (e.g., addiction). How pathology in any of these spheres may affect the long-term risks and benefits of therapeutic DBS remains unknown. Do early effects of stimulation have prognostic value? The question of the predictive value of immediate or very early changes in behavior or physiology is a key issue. If such effects prove to be predictive, they might be very useful during lead placement and also during subsequent stimulation adjustment. At this point it is unclear whether effects demonstrated during intraoperative lead testing or early in the post-implantation course reliably predict long-term treatment success. However, as has been evidenced through many years of experience with psychotherapeutic, pharmacologic, and electroconvulsive treatments, dramatic or immediate shifts in affect are generally not reasonable therapeutic goals in psychiatric illness. This situation may be in contrast to observations of virtually immediate benefit during DBS for tremor. On the other hand, a slower tempo of therapeutic improvement appears to be the norm during DBS for dystonia. The most compelling treatments will be safe, effective, and sustainable over the long term.

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Mechanism(s) of Action of DBS Most likely, brain stimulation exerts its effects via a number of differing but interrelated mechanisms – across system, neuronal and genetic levels – each of which may come into play depending on the site of stimulation, the illness being treated, and the stimulation parameters used. A putative mechanism of antidepressant or antianxiety action of DBS is not known, but there is evidence supporting a number of potential mechanisms. HF-DBS (approximately 100 Hz or greater) has been proposed to modify neurotransmission, for example, via synaptic fatigue or “neural jamming” (the functional suppression of spontaneous neuronal signaling within the affected circuits) (Benabid, 2005; Benabid et al., 2005; Rauch et al., 2006). Either of these phenomena would in effect produce a “functional lesion,” mimicking the effect of ablative lesion procedures via a nondestructive mechanism. This is not an exact parallel, since the clinical effects of lesions and of DBS in movement disorders do not always correspond. The limited data currently available from DBS therapy for psychiatric disorders suggest a time course for effect onset which is not consistent with that observed for therapeutic lesion procedures. For example, some therapeutic effects of stimulation appear more rapidly than those seen following lesions. Other proposed mechanisms of DBS action include direct inhibition of spike initiation at the level of the neuronal membrane via blockade of voltage-gated ion channels, and activation of GABA-ergic inhibitory terminals. A process known as stochastic resonance, in which stimulation actually enhances information flow within key neural pathways, may work to reduce symptoms by reducing chaotic information processing. It is possible that highfrequency electrical stimulation produces several of these effects simultaneously or sequentially within the brain, with the specific therapeutic effects depending on variables such as the spatial distributions of voltages and currents relative to the relevant group of neural elements (Benabid, 2005). It is also possible that the effect of DBS on the functional state of a structure or pathway changes as distance from the electrode increases. Most likely, the clinical effects seen with DBS reflect the complex combination of inhibition and activation of cell bodies and axons, and depend on the orientation of the electrode, the cytoarchitecture of the structure being stimulated, and the quality (i.e., frequency, pulse width, and duration) of stimulation. Active research in clinical and preclinical laboratories is expected to help identify which of the proposed physiological mechanisms are most relevant to the clinical effects of DBS. Ongoing research efforts by our group and others include investigating the acute and long-term

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functional effects of DBS for OCD and MDD using PET imaging, as well as work examining potential predictors of response to DBS for OCD. Recent findings regarding the compatibility of DBS devices with certain MRI systems have opened additional avenues for research on neuroanatomical networks affected by DBS. The MRI-based DBS research remains technically challenging, but will be superior to PET techniques for study designs that require reproducible scan conditions. Such investigations hold considerable promise for elucidating the therapeutic mechanism of action of DBS for psychiatric disorders. Until a putative DBS mechanism of therapeutic action for psychiatric disorders can be demonstrated, available data from functional neuroimaging studies suggest hypotheses about activity in neural networks that may be associated with clinical OCD symptomatology. A considerable body of published imaging research findings implicate fronto-basal brain networks in mediating OCD symptoms and, possibly, in mediating the response to conventional OCD treatments. The most common findings in untreated obsessive–compulsive patients are increased glucose metabolism or blood flow in the medial and orbitofrontal cortex (OFC) and anterior cingulate gyrus, in the caudate nucleus, and, to a lesser extent, in the thalamus. These imply a pathophysiologic dysregulation in the basal ganglia/limbic striatal circuits that modulate neuronal activity in and between the OFC and the dorsomedial thalamus. The observed localized elevations in brain activity are, to varying degrees, accentuated during symptom provocation, and effective treatment of OCD with medications or behavior therapy tends to normalize activity in these same regions. One might speculate that modulation of these circuits by DBS could exert therapeutic effects by reducing drive to engage in repetitive, stereotyped behaviors and alleviating the negative emotional charge associated with such behaviors. With regard to the neuroanatomy of major depressive disorder, several regions have been indirectly implicated. Sadness and depressive illness are both associated with decreased activity in dorsal neocortical regions, and with relatively increased activity in ventral limbic and paralimbic areas. Relative to that measured in healthy control subjects, MDD patients have shown increased regional cerebral blood flow and metabolism in the amygdala, orbitofrontal cortex, and medial thalamus, while relative decreases have been observed for MDD patients in the dorsomedial/dorsal anterolateral PFC, subgenual ACC, and dorsal ACC (Mayberg, 2002). Though these primarily cross-sectional findings cannot distinguish primary processes relevant to pathogenesis from

more “downstream” pathophysiologic consequences, dysregulation in these regions is thought to be related to the clinical syndrome characteristic of major depression (i.e. mood, motor, cognitive, vegetative symptoms), and as such may be involved in the mechanism of DBS antidepressant action. Other important regions implicated in the pathoetiology of depressive syndromes include the hippocampus, insula, and midbrain monoamine nuclei, as well as structural abnormalities such as reduction in volume or glia density. Future DBS research examining the impact of therapeutic stimulation on these structures, pathways, and regions in MDD populations will help clarify the biological basis of the disorder and inform our understanding of how the treatment produces relief from MDD symptoms.

ADVERSE EFFECTS The complications of DBS can be separated into those related to the surgical procedure, to active stimulation, and to the device. Some adverse effects such as clinical deterioration observed in clinical trials of DBS therapy may of course also be related to the natural course of the underlying illness. The major risks of device implantation include seizure, intracerebral hemorrhage, and infection. Experience with DBS for movement disorders indicates that these adverse effects range from less than 1% per procedure for seizure, to about 2–3% for hemorrhage (with a mortality rate up to 1.6%), to 4–9% for infection. The devicerelated complications include fracture of leads, disconnection, lead movement, and malfunction. These are less common with increasing surgical expertise and evolution of device technology. In addition, there have been rare but very serious side effects when patients with implanted DBS systems were exposed to therapeutic ultrasound or diathermy. Not surprisingly, when DBS is effective, subsequent battery depletion may result in symptom re-emergence. Adverse effects due to the actual stimulation are the most common type observed, but these are fully reversible with changes in stimulation parameters. Many stimulation-related effects have proven transient, even without changes in parameters. Stimulation-induced sensorimotor effects can include paresthesiae, muscle contraction, dysarthria, and diplopia. DBS has produced marked mood/affective changes in movementdisordered patients (Landau and Perlmutter, 1999; Takeshita et al., 2005). Side effects in memory, impulsivity, and cognition have also been reported (Witt et al., 2004). As in movement disorder populations, patients with primary neuropsychiatric illness may experience

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PERSPECTIVE

untoward effects, including changes in mood, suicidality, impulsivity, anxiety (e.g., panic), and other symptoms (e.g., obsessive thoughts or compulsive urges). Distinguishing adverse effects of stimulation from symptomatology of the illness being treated may represent a challenge at times.

ETHICAL CONSIDERATIONS As discussed above, DBS is now a conventional therapeutic option for intractable movement disorders. The efficacy of the procedure is well established, although questions remain about the optimal stimulation targets and “dosing” techniques for movement disorders. While serious adverse events are possible, the overall side effect burden is favorable for individuals who cannot benefit substantially from standard therapies. DBS has therefore become a useful therapeutic option in an otherwise untreatable group of patients who experience tremendous suffering and functional impairment. Recent rapid growth in interest in DBS as a potential treatment for patients with severe neuropsychiatric illness is not surprising. Patients with treatment-resistant depression as well as those with other severe disorders of mood, thought, and emotion regulation experience extreme distress and inability to participate in social and occupational life. Hopelessness and suicide are common outcomes for individuals who feel they have exhausted all available treatment options without relief. While there are strong parallels between the existing application of DBS for intractable neurological illness and its potential use in neuropsychiatry, there are also noteworthy differences. The most salient of these arises from historical experience in treatment for profoundly mentally ill persons. Special concern arising over the use of modern neurosurgical interventions for psychiatric illnesses is mainly the legacy of the widespread use of early destructive procedures, particularly frontal lobotomy, in the mid-twentieth century. Many patients underwent frontal lobe surgery before adequate longterm safety data were obtained, and without careful characterization of their primary disorder. Tragic consequences were reported and remain a vivid reminder of the need for caution in this area. The current practice of psychiatric neurosurgery in place for DBS research trials is much more refined, restricted, and regulated. Candidates must meet stringent criteria for symptom severity and for resistance to conventional, multimodal therapies. DBS is an invasive procedure, and while it is non-ablative in nature and theoretically reversible with interruption of stimulation, evidence

supporting its use in psychiatric disorders is limited to the experiences observed for relatively small numbers of OCD or MDD patients worldwide.

PERSPECTIVE Long-Term Follow-Up For any surgical intervention for psychiatric illness, a key issue is long-term outcome. Treatment decisions, particularly when surgical intervention is required, need to be made based on the probability that therapeutic effects will be durable, and that the balance of potential side effect burden and efficacy is reasonable. Patients with severe, chronic, and highly resistant psychiatric illness typically require multiple treatment modalities to support their daily struggles and process of recovery. Particularly with DBS, frequent and long-term (i.e. over 5 of more years) follow-up visits are necessary to adequately assess the extent of clinical response across multiple symptomatic and functional domains. Particular attention should be placed on feelings of hopelessness that may arise in patients undertaking investigational treatments thought to represent “last resort” measures. Suicide has been reported in patients placed on waiting lists for psychiatric neurosurgery and for an OCD patient who actually experienced improvement in an investigational trial of DBS (Abelson et al., 2005).

Research Protocols for Investigational Treatment with DBS An interdisciplinary group of collaborators, which began to systematically study the effectiveness and safety of DBS in psychiatric illness in the late 1990s, has set forth recommendations for psychiatrists and neurosurgeons contemplating use of DBS for psychiatric indications. Until FDA approval, treatment with DBS should be limited to that delivered in approved research protocols that are subjected to initial and on-going review by an institutional review board (US) or ethics committee. In the USA there is additional review of IRB-approved DBS studies required by the FDA, via the Investigational Device Exemption (IDE) mechanism. Careful psychiatric assessment with regard to diagnosis, illness severity, and suitability of a candidate for inclusion in a DBS protocol, is essential. Procedures for establishing a history of resistance to standard therapies also should include detailed consideration of the adequacy and quantity of past and ongoing psychosocial/behavioral, pharmacological, and somatic treatment approaches

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undertaken for each individual subject. It has also been proposed that potential candidates for psychiatric DBS also undergo independent consideration by an interdisciplinary review committee with appropriate expertise, including bioethics. DBS research is optimally conducted at a specialized academic center with expertise in the treatment of patients with the neuropsychiatric condition being studied, and with a neurosurgical team experienced in DBS procedures. Recent experience with DBS in psychiatry has produced updated recommendations and guidelines for research teams (Fins et al., 2006). In anticipation of gradual expansion of research and clinical uses of DBS in psychiatry, issues of training and interdisciplinary collaborations are starting to be addressed (Greenberg, Nuttin et al., 2006).

SUMMARY DBS as an investigational treatment in neuropsychiatry has generated considerable interest. Preliminary data with OCD and MDD patients are encouraging. The pathophysiology of these conditions is poorly understood, leading to investigation of therapeutic effects at several different DBS targets. Although its mechanisms of therapeutic action are not completely understood, DBS can precisely target regions and circuits deep within the brain that are hypothesized to be centrally involved in neuropsychiatric disorders. Relative to surgical lesion therapies, DBS offers the advantages of reversibility and adjustability, which might permit effectiveness to be enhanced or side effects to be minimized. While results from pilot studies suggest DBS may offer a degree of hope for patients with severe and highly treatment-resistant neuropsychiatric illness, controlled trials have not yet been conducted to fully evaluate efficacy and safety. Research to realize the potential of DBS in this domain requires a considerable commitment of resources and time across disciplines including psychiatry, neurosurgery, neurology, neuropsychology, bioengineering, and bioethics. Limited evidence available at present suggests that, with the appropriate multidisciplinary work, cautious optimism about the role of DBS in psychiatric treatment is justified.

ACKNOWLEDGMENT The author thanks Cynthia Read, MA for her highly capable editorial assistance.

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57 Surgical Treatment for Refractory Drug Addictions Bomin Sun, Shikun Zhan, Dianyou Li, and Hemmings Wu

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finally, two criteria correspond to focusing of instrumental behavior over drug taking:

The definition of “dependence” (i.e. addiction) provided by the DSM-IIIR and DSM-IV (American Psychiatric Association) consists of a list of seven criteria or conditions, at least three of which should be present at the same time to allow a diagnosis of dependence. Two of these criteria correspond to physiological adaptive changes:

(6) important social, familial, and recreational activities given up or reduced because of drug-seeking (7) expenditure of a great deal of time and activity in relation to drugs. Drug abuse and dependence are common worldwide. The death rate is very high in drug abusing populations, for example, more than 1% of all heroin addicts in the USA die each year. The span of drug dependence varies over a wide range, depending on type of drug abused, administration of proper treatment, personal and social conditions, and many other factors. In general, the physical component of drug dependence lasts for about a week, while the psychological components last much longer, even lifelong in some cases. Many addicts share similar clinical features, including frequent presence of marked depression and anxiety, antisocial personality disorder, etc. Treatment of

(1) tolerance (2) physical dependence three of them correspond to loss of control over drug taking: (3) persistent desire and unsuccessful attempts to quit (4) use of drugs in larger amounts and for longer period than intended (5) continued use in the face of medical, familial or social problems

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addiction involves stopping the drugs and termination of craving. The goal of treatment of severe addictions includes: (1) reduction of psychological, social, and other problems directly related to drug use; (2) reduction of psychological, social, and other problems not directly attributable to drug use; (3) reduction of harmful or violent behaviors associated with drug use; (4) abstinence from the main problem drugs. Treatments include psychosocial and psychopharmacological treatments (e.g. methadone detoxification or methadone maintenance). Usually physical symptoms (physical dependence) are fairly well controlled but psychological symptoms (psychological dependence) are very difficult to eliminate. There is a very high relapse rate for drug substitute therapy. It is reported that 80–85 % of drug addicts suffer drug relapse within one month and 97% of them suffer drug relapse within 6 months with substitute therapy (Qing, 1999). In addition to the physical and psychological dependency, the accompanying psychiatric symptoms are even more difficult to deal with. Although basic research and clinical application of surgical treatment for drug addiction are still premature, we are experiencing a growing interest in surgical treatment for drug addiction. Several factors underlie this interest. First, the limitations of current medical treatment have made it necessary to search for alternative and more effective treatment strategies. Secondly, deep brain stimulation (DBS) has demonstrated success in movement disorders for many years and recently for psychiatric disorders such as obsessive–compulsive disorders (OCD) and depression. DBS is minimally invasive, reversible, and is an adjustable surgical procedure to explore new therapies. Thirdly, increases in the understanding of the relations between drug addiction and mesocortical/ mesolimbic dopamine circuits have provided further scientific rationale for neurosurgical intervention. In this chapter we briefly outline the rationale for surgery, the surgical procedure and perioperative patient management, and the surgical results.

RATIONALE FOR NUCLEUS ACCUMBENS AS THE TARGET OF SURGERY Drug addiction and dependence induced by substance abuse include physical dependence and psychological dependence. There is insufficient data to substantiate the optimal surgical target. However, it is widely accepted that the initial reinforcing effects of most drugs of abuse rely on the induction of large and

rapid increases in the level of dopamine (DA) in the nucleus accumbens (NAcc). Physical dependence is related to withdrawal syndrome with a noradrenergic hyperactivity in locus coeruleus. Physiological detoxification and elimination of withdrawal syndrome could be achieved successfully by means of replacement therapies or other therapies such as DA transporter blockers, non-DA drugs, cannabinoid antagonists etc. Psychological dependence is related to drug-seeking behavior, and eliminating psychological dependence is very difficult, which results in a high relapse rate even several months to one year after detoxification. Psychological dependence correlates with dopaminergic activity in the mesolimbic pathway, especially in the shell of the NAcc (Di Chiara et al., 2004). The significant action of the NAcc in a drug addiction mechanism has also been demonstrated in animal studies. Microdialysis studies in animals have shown that addictive drugs preferentially increase extracellular DA in the NAcc. Brain imaging studies, while extending these findings to humans, have shown a correlation between psychostimulant-induced increase of extracellular DA in the striatum and self-reported measures of liking and “high” (euphoria). Although a correlate of drug reward independent from associative learning and performance is difficult to obtain in animals, conditioned taste avoidance (CTA) might meet these requirements. Addictive drugs induce CTA to saccharin most likely as a result of anticipatory contrast of saccharin over drug reward. Consistent with a role of DA in drug reward, D2 or combined D1/D2 receptor blockade abolishes cocaine, amphetamine and nicotine CTA. Intracranial self-administration studies with mixtures of D1 and D2 receptor agonists point to the NAc shell as the critical site of DA reward. NAcc shell DA acting on D1 receptors is also involved in Pavlovian learning through pre-trial and post-trial consolidation mechanisms and in the utilization of spatial short-term memory for goal-directed behavior. Stimulation of NAcc shell DA transmission by addictive drugs is shared by a natural reward like food but lacks its adaptive properties (habituation and inhibition by predictive stimuli). These peculiarities of drug-induced stimulation of DA transmission in the NAcc shell result in striking differences in the impact of drug-conditioned stimuli on DA transmission. It is speculated that drug addiction results from the impact exerted on behavior by the abnormal DA stimulant properties acquired by drug-conditioned stimuli as a result of their association with addictive drugs. Excitotoxic lesion of bilateral NAcc can completely change drug-seeking behavior of rats in an addiction model (Alderson et al., 2001). Electrolytic lesion can also obviously change place preference behavior

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(psychological dependence) of rats in an addiction model (He et al., 2001). It was found in the 1940s that surgery could palliate dependence of some drug addictions when frontal leucotomy was performed on advanced cancer patients with severe pain, and narcotic dependence of those patients was eliminated dramatically without withdrawal symptoms after surgery. Since 1978, stereotactic neurosurgery has been used for opioid addiction throughout the world. Kanaka and colleagues reported cingulotomy for drug addiction in 60 patients, with excellent results in 60–80% (Kanaka and Balasabramaniam, 1978). Medvedev used bilateral cingulotomy for 348 drug addiction patients: 187 patients underwent more than 2 years of follow-up and 45% of them were cured (complete cessation of use of drug and termination of craving) (Medvedev et al., 2003). Recently both Gao and Sun and colleagues reported ablation of the NAcc for opiate drug dependence patients (Gao et al., 2003; Sun et al., 2005b). The results demonstrated that bilateral NAcc lesion has excellent effects for opiate-drug-dependent patients and the relapse rate also decreased significantly after 15 months of follow-up (Gao et al., 2003).

INDICATIONS AND PATIENT SELECTION CRITERIA Since few publications and limited experience are available, at present no definitive guideline can be given as to the choice of the indications and patient selection criteria. However, there is presently general consensus about selection criteria for drug addiction surgery, which in our center is as follows: 1. Patients must be consistent with the diagnosis of (DSM-IV and ICD10). 2. Patients’ history of drug dependence must be more than 3 years and patients must have undergone at least three ineffective substitute medication therapies. 3. Patients’ craving influences their health and severely affects the quality of life of themselves and family members. 4. Patients seek to stop drug use and termination of craving on their own initiative without being forced by others. 5. Patients and their families have complete understanding of the surgical procedures, have provided signed informed consents, and are able to cooperate with our surgical team. 6. Patients have a suitable living environment and adequate postoperative care, and they must be able to have follow-up visits at 3, 6, 12, 24, and 36 months postoperatively.

SURGICAL PROCEDURE There is no optimal target or procedure for drug addiction at this time. We have been exploring minimally invasive NAcc ablation and DBS procedures for drug addiction. This procedure using MRI guided stereotactic techniques, which is similar to stereotactic capsulotomy, was carried out as previously described (Sun et al., 2005a). This allows more accurate placement of the lesions or DBS electrodes. Placement of the head frame should be done as nearly as possible before surgery in order to minimize the time before arrival in the operation room. A Leksell stereotactic frame was mounted on the patient’s head under local anesthesia or mild sedation. The base of the frame should be placed approximately parallel to the anterior–posterior commissure (AC–PC) line. Once the frame is placed, the patient is taken for preoperative MRI targeting immediately. Although MRI, CT, and ventriculography can all be used for stereotactic imaging, MRI is necessary for drug addiction surgery, because NAc can be recognized directly in both the axial and coronal section image (Figure 57.1A, 57.1B) with high resolution MRI. T2 and inversion recovery images are beneficial for direct targeting of the NAcc and surrounding areas. The bottom of the nucleus was targeted for drug addiction surgery, which is approximately 3 mm anterior to the AC, 4 mm from the midline and 6 mm below the AC–PC level. We measure the entrance trajectory which is 18–20 degrees laterally in the coronary plane and 45 degrees anterior in the sagittal plane. The procedure of NAcc ablation or electrodes implantation is performed under local or general anesthesia depending on the patient’s cooperation during the surgery. After calculation of stereotactic target coordinates, local bilateral coronal scalp incisions are made and burr-holes are placed bilaterally anterior to the coronal suture and about 3–4 cm from the midline depending on the measured entrance trajectory. After dural opening and cauterization of the pia-arachnoid, a standard thermistor-equipped thermocoagulation electrode (Radionics, Burlington, MA) with a 2 mm uninsulated tip is employed for impedance measurement, followed by stimulation test and actual lesion. Microelectrode recording is unnecessary for this procedure. Impedance measurement is important during this procedure, because the NAcc is located at the bottom of the lateral ventricle, and the electrode must pass through a lower impedance area (cerebrospinal fluid) before accessing the target. After the electrode reaches the target, a high frequency stimulation (180 Hz, 90 ms, 1–6 V) is applied to observe side effects. With the high

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FIGURE 57.1 In T2 inversion recovery MRI image: nucleus accumbens could be recognized directly in both axial (A) and coronal (B) section image

FIGURE 57.2 MRI follow-up of bilateral lesions of nucleus accumbens in axial (A) and coronal (B) section image

frequency stimulation, the patient should experience an intense feeling of heat, and mild sweating could be seen at the face and upper trunk, and meanwhile heart rate and blood pressure also increase significantly. It is very important to see these signs because these confirm the electrode is in the NAcc. In those patients who receive ablative procedure, the radiofrequency lesions were made by radiofrequency electrode heated to 80 °C for 60 seconds. During lesioning, neurological testing is carried out to ensure that there is no impairment of motor or sensory functions etc. After adequate cooling, the electrode is withdrawn 2 mm and an additional lesion is made using the same parameters to ensure the complete ablation of the target. During the lesioning, severe sweating on the face and upper trunk of the patient will reappear. For those

patients who receive DBS, electrodes (3389 Medtronic, Minneapolis, MN) are placed in the same target and trajectory as lesioning procedures. Stimulation generators (Soltra, Medtronic) were implanted under general anesthesia. The day after surgery a postoperative MRI is obtained to document the placement and extent of the lesions and electrodes (Figures 57.2A, 57.2B, 57.3).

PERIOPERATIVE PATIENT MANAGEMENT Because of their long-term narcotic history, drug addicts are very different from other neurosurgery patients; their mental status is not stable and frequently presents irritation and anxiety. Patients should

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FIGURE 57.3

MRI follow-up of bilateral deep brain stimulation electrodes implantation in coronal section image

be allowed to keep their normal lifestyle and habitus, including continuing narcotics, after hospitalization. A thorough review of the medical history record and physical examination must be carried out by a psychosurgery team, which in our practice consists of three attending psychiatrists, a neurologist, a nurse, and three neurosurgeons to ensure indication for surgical therapy. Because of long-term substance abuse and use of contaminated syringes, most drug addicts have abnormal liver function, kidney function, etc., and infective diseases may be present, so more detailed preoperative screening such as electrocardiograms and appropriate blood tests are obtained to assess potential medical risks. The specific preoperative psychiatric and psychological evaluations are also performed by experienced psychiatrists and clinical psychologists, such as a cognitive performance function test, WAIS IQ and memory test, personality test, Hamilton anxiety rating scale, Hamilton depression rating scale, psychiatric status rating scale, and quality of life assessment. In our medical center a formal documentation of each patient, including detailed history of drug addiction (names and dose of the narcotics, applying method, etc.), diagnostic and therapeutic history, especially previous detoxification and abstinence history, physical, psychiatric and psychological examinations, preoperative evaluations and surgical plans, is reported to the medical ethical committee for approval. All of the evaluation results, along with the surgical plan and informed consent, must be explained to patients and their families, and they must agree to cooperate with the surgical team and participate in the postoperative follow-up program. To avoid severe and sudden withdrawal symptoms, so that the patients can maintain normal mental and physical status, patients will be allowed to use

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previous narcotics as usual on the morning of surgery. During stereotactic frame placement and MRI targeting, a small amount of intravenous sedation is given if necessary. Several hours after surgery most patients present restlessness, mild orientation deficit, and confusion, which will recover in a couple of days. Buprenorphine 3 mg and chlorpromazine 100 mg per day can be used intravenously directly after surgery and then decrease to half doses on the following day. Three days after surgery, buprenorphine and chlorpromazine may be withdrawn completely and only a small dose of anxiolytic could be used in patients with anxiety or insomnia. After discharge from hospital, patients and their families are requested to attend the outpatient clinic or take part in a phone interview for evaluation at 3 months, 6 months, 12 months, and 24 months postoperatively. A follow-up questionnaire includes assessment of desire for narcotics, physical withdrawal symptoms, and repeat preoperative psychological and psychiatric evaluation and rating scales for documentation. For suspected relapsing patients, a regular narcotics urinalysis test is necessary to confirm postoperative use of narcotics.

PROGRAMMING AND OTHER POINTS OF CONSIDERATION Currently, Medtronic (Minneapolis, MN) is the only manufacturer providing clinically approved DBS devices. The commercial DBS systems consist of a quadripolar electrode with 1.27 mm diameter and 1.5 mm length electrode contacts, an extension cable, and an implantable pulse generator (IPG) either controlling one (Itrel II, Soletra) or two (Kinetra) electrodes. We use Soletra IPG and 3389 DBS electrodes with an intercontact distance of 0.5 mm (model 3389). On the first day after the DBS system had been implanted, we start multiple programming sessions to screen the best stimulation combination. First, we use a fixed pulse width of 90 μs and the frequency of stimulation is held constant at 145 Hz. The patients are tested individually at each lead and each contact (0, 1, 2, 3) utilizing monopolar stimulation. Stimulation amplitude is systematically increased at 0.5 V steps in each patient from the starting value of 0 V, in an attempt to obtain an acute response that could be recorded. If no response is seen at 6 V stimulation intensity, we increase the pulse width to 120 and then 150 μs. With just several seconds of 2.5–4 V stimulation at contact 0 and contact 1, most patient can feel transient heart-throb and the heart rate may increase about 20–50% from baseline. When stimulation increases

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another 0.5 to 1.0 V, the patient can experience a feeling of heat flushing at the stimulation side and may even sweat on the trunk. Several minutes after the stimulation is switched down by 1 volt, this feature will fade away and the patient will feel quite relaxed. It usually needs much higher stimulation intensity (from 4 to 6 V) to induce these responses at contact 2 and contact 3. Some patients also experience a feeling of fear and nervousness. We select the contact that can induce heart rate increase and flushing at the lowest stimulation threshold, and then set the stimulation intensity at 1 V below for chronic stimulation.

complete cessation of narcotic use and termination of craving without any drug withdrawal symptoms 3–4 days after surgery. Among these nine lesioned patients, only one (the case with dolantin addiction) relapsed within one month, while eight cases of heroin addiction were drug-free (without any craving or drug using activity). Of two cases with bilateral NAcc DBS implantation, one has completely stopped using narcotics without any craving, the other took only a small dose of methadone q.d. orally and without any heroin injection.

SIDE EFFECTS AND COMPLICATIONS SURGICAL OUTCOMES So far only a few clinical retrospective studies have been published. These publications report cingulotomy and NAcc lesioning to have been used for drug addition. However, based on research findings in neuropsychiatric circuits, the orbitofrontal cortex, frontothalamic pathways, and limbic system are also potential targets for treatment of drug addiction. In fact, targets at any place on the orbitofrontal-striate-thalamic-limbic-frontal circuit seem to be functionally equipotent, and a lesion in any part of the circuit may directly or indirectly affect others. With currently available data it is impossible to determine whether there is an optimal surgical technique or strategy. In recent years, many centers in China have been trying to use neurosurgical therapy for drug addiction. However, most publications are in Chinese and many obstacles have prevented a direct comparison of results across centers, including diagnostic inaccuracies, non-standard preoperative evaluations, center bias, non-standard surgical procedures, and varied outcome assessment systems. Gao et al. (2003) reported radiofrequency lesioning of NAcc for patients with drug addiction: 26.7% patients were cured in 15 months with low complications (2 patients had possible personality changes and there were 4 cases with shortterm memory deficit). In our center, there were 11 cases with severe drug addiction, in which nine cases underwent bilateral NAcc ablation and two underwent bilateral NAcc DBS implantation. There were 10 males and one female, with an age range from 23 to 35 years (average 28.5 years). History of drug addiction ranged from 3 to 8 years (average 4.3 years). In all 11 patients, only one used dolantin intravenously and the rest used heroin intravenously two or three times per day. All of these 11 patients have a follow-up period from 28 to 37 months (average 33.5 months). All patients who underwent bilateral NAcc ablation experienced

In all publications, side effects and complications are similar. No severe complications such as hemiplegia, aphasia, intracranial hematomas or death directly caused by surgery were reported. Nine patients with lesioning of NAcc experienced acute side effects on the first day after surgery. Similar to anterior capsulotomy patients, mild transient deterioration in mental status, such as memory deficits and confusion, presented in most patients postoperatively. However, all of these side effects disappeared automatically without any specific treatment. Six patients with lesioning of the NAcc experienced delayed side effects such as mild fatigue, apathy, inactivity and lack of interest. It is very interesting that almost all patients with NAcc lesioning presented with emotional fragility. These side effects recover within 1–2 years of surgery and do not affect patients’ quality of life. Only a few need to see a psychiatrist for medication assistance because of mild anxiety. There were no side effects and complications in patients with bilateral DBS.

CONCLUSION NAcc is the main source of the initial reinforcing effects of most drug abuse. It is located at the base of the frontal lobe, and does not play a primary role in motor or sensory function. Lesioning or stimulation of the NAcc appears to be a safe and effective surgical procedure without long-term severe side effects or complications. It provides an alternativ for refractory drug addiction patients. Most patients are cured or significantly improved after surgery, and the rate of complications and side effects appears low. It is important for this surgical procedure to be carried out in close collaboration with a group of experts functioning as a multidisciplinary team and be accompanied by an appropriate psychological rehabilitation plan and family-social support program.

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REFERENCES

Chronic electrical stimulation of the central nervous system via implanted electrodes and pulse generators is an established treatment for intractable and severe movement disorders and more recently OCD, depression, and epilepsy. Our preliminary data on DBS for addictions demonstrate benefit for these patients with no permanent side effects.

References Alderson, H.L., Parkinson, J.A., Robbins, T.W. and Everitt, B.J. (2001) The effects of excitotoxic lesions of the nucleus accumbens core or shell regions on intravenous heroin self-administration in rats. Psychopharmacology (Berl.) 153: 455–63. Di Chiara, G., Bassareo, V., Fenu, S. et al. (2004) Dopamine and drug addiction: the nucleus accumbens shell connection. Neuropharmacology 47 (Suppl. 1): 227–241. Gao, G.D., Wang, X.L., He, S.H.M. et al. (2003) Clinical study for alleviating opiate drug psychological dependence by a method

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of ablating the nucleus accumbens with stereotactic surgery. Stereotact. Funct. Neurosurg. 81: 96–104. Kanaka, T.S. and Balasabramaniam, V. (1978) Stereotactic cingulotomy for drug addiction. Appl. Neurophysiol. 41: 86–92. He, S.H.M., Gao, G.D. and Wang, X.L. (2001) The effect of the nucleus accumbens and ventral pallidum lesions on seeking behavior in rats. Mod. Rehabil. 5: 62–3. Medvedev, S.V., Anichkov, A.D. and Polyakov, Y.I. (2003) Physiological mechanisms of effectiveness of bilateral stereotactic cingulotomy against strong psychological dependence in drug addicts. Hum. Physiol. l29 (4): 117–23. Qing, B.Y. (1999) The present state of drug abuse and therapy in China. Chin. J. Drug Depend. 8: 73–4. Sun, B., Zhan, S.K. and Shen, J.K. (2005a) Improved capsulotomy for refractory Tourette syndrome. Stereotact. Funct. Neurosurg. 83: 55–6. Sun, B., Zhan, S.K. and Shen, J.K. (2005b) Lesioning and deep brain stimulation for drug addiction. Proceedings, 14th Meeting of the World Society for Stereotactic and Functional Neurosurgery, Rome, Italy.

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S E C T I O N   VIII

 Neuromodulation for functional restoration Introduction P. Hunter Peckham Neuromodulation for the restoration of sensory and motor function are some of the most challenging of the concepts of neuromodulation and neurostimulation. These interventions deal with some of the most disabling disorders that are encountered with nervous system dysfunction: deafness, blindness, seizures, and paralysis due to spinal cord injury or stroke. In the chapters in this section the authors provide a current perspective of the state of development in each of these areas, and outline the direction of the future approaches that are likely to yield greater functional benefits to persons whose lives are dramatically changed by neuroprosthetic interventions. The chapters are: “Stimulation for the Return of Hearing” by Blake S. Wilson, from the Division of Otolaryngology, Head & Neck Surgery, Duke University Medical Center, Durham, NC, and Michael F. Dorman, from the Department of Speech and Hearing Science, Arizona State University, Tempe; “The Development of Visual Prosthetic Devices to Restore Vision to the

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Blind” by Muhammad Memon and Dr Joseph F. Rizzo III, from the Department of Neuro-Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard University, Boston, Massachusetts; “Stimulation for Return of Function after Stroke” by John Chae, MD, Jayme Knutson, PhD, and Lynne Sheffler, MD, of the Cleveland Functional Electrical Stimulation Center, Case Western Reserve University, Cleveland, Ohio; “Cortical Stimulation for the Treatment of Motor Deficits following Ischemic Stroke” by Janna Silverstein, BA and Robert M. Levy, MD, of the Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; “Stimulation for Return of Upper and Lower Extremity Function” by Kevin L. Kilgore, PhD, Michael W. Keith, MD, and P. Hunter Peckham, PhD, of MetroHealth Medical Centre, Case Western Reserve University, Cleveland, Ohio; and “A Neural Prosthesis for Obstructive Sleep Apnea” by Dominique M. Durand, PhD, of the Neural Engineering Center, at Case Western Reserve University, Cleveland, Ohio.

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systems supported significantly higher levels of speech reception than their single-channel and single-site predecessors. Later, in the late 1980s and continuing to the present, new and better processing strategies, in conjunction with multi-electrode implants, have produced additional large gains in performance. Indeed, a principal conclusion of the 1995 NIH Consensus Conference on Cochlear Implants in Adults and Children (National Institutes of Health, 1995) was that “A majority of those individuals with the latest speech processors for their implants will score above 80 percent correct on high-context sentences, even without visual cues.” This degree of functional restoration is remarkable and is far greater than that achieved to date with any other type of neural prosthesis. The primary purpose of this chapter is to indicate how electrical stimulation at the auditory nerve can bring a person from total deafness or a severe hearing loss to useful hearing. In addition, some possibilities for

Deafness and severe hearing impairments were hopeless conditions until only recently. Controlled electrical stimulation of the auditory nerve changed that, and this is widely regarded as one of the great achievements of modern medicine. The device that produces and presents the electrical stimuli is called a cochlear implant (CI). Just 30 years ago, CIs provided little more than a sensation of sound and sound cadences. The implants were useful for an alerting function (e.g., hearing a loud sound that might be an oncoming car) and as an adjunct to lipreading. Many experts in otology and the hearing sciences at the time were highly skeptical that implants could ever support useful speech reception with hearing alone. In the 1980s, however, implant systems with multiple channels of processing and multiple sites of stimulation in the cochlea were developed and these

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further improvements in the design and performance of CIs are mentioned. Additional information about these topics is presented in several detailed reviews published during the past several years, including Dorman and Wilson (2004) and Wilson (2004, 2006, 2008). Comprehensive treatments of the fascinating history of CIs are offered by Finn et al. (1998), Niparko and Wilson (2000), Eisen (2006), and Wilson and Dorman (2008a).

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substance increase discharge activity in the nearby neurons, whereas decrements in the substance inhibit activity. Changes in neural activity thus reflect events at the BM. These changes are transmitted to the brain via the auditory nerve, the collection of all neurons that innervate the cochlea. The steps described above are illustrated in the top panel of Figure 58.1. This shows a cartoon of the main anatomical structures, including the tympanic membrane, the three bones of the middle ear, the oval window, the BM, the IHCs, and the adjacent neurons of the auditory nerve.

Aspects of Normal Hearing In normal hearing, sound waves traveling through air reach the tympanic membrane via the ear canal, causing vibrations that move the three small bones of the middle ear. This action produces a piston-like movement of the stapes, the third bone in the chain. The “footplate” of the stapes is attached to a flexible membrane in the bony shell of the cochlea called the oval window. Inward and outward movements of this membrane induce pressure oscillations in the cochlear fluids, which in turn initiate a traveling wave of displacement along the basilar membrane (BM), a highly specialized structure that divides the cochlea along its length. This membrane has graded mechanical properties. At the base of the cochlea, near the stapes and oval window, it is narrow and stiff. At the other end, near the apex, the membrane is wide and flexible. These properties give rise to the traveling wave and to points of maximal response according to the frequency or frequencies of the pressure oscillations in the cochlear fluids. The traveling wave propagates from the base to the apex. For an oscillation with a single frequency, the magnitude of displacements increases up to a particular point along the membrane and then drops precipitously thereafter. High frequencies produce maxima near the base of the cochlea, whereas low frequencies produce maxima near the apex. Motion of the BM is sensed by the inner hair cells (IHCs) in the cochlea, which are attached to the top of the BM in a matrix of cells called the organ of Corti. Each hair cell has fine rods of protein, called stereocilia, emerging from one end. When the BM moves at the location of a hair cell, the rods are deflected as if hinged at their bases. Such deflections in one direction increase the release of a chemical transmitter substance at the base (other end) of the cells, and deflections in the other direction inhibit the release. The variations in the concentration of the chemical transmitter substance act at the terminal ends of auditory neurons, which are immediately adjacent to the bases of the IHCs. Increases in chemical transmitter

Loss of Hearing The principal cause of hearing loss is damage to or complete destruction of the sensory hair cells. Unfortunately, the hair cells are fragile structures and are subject to a wide variety of insults, including but not limited to genetic defects, infectious diseases (e.g., rubella and meningitis), overexposure to loud sounds, certain drugs (e.g., kanamycin, streptomycin, and cisplatin), and aging. In the deaf or deafened cochlea, the hair cells are largely or completely absent, severing the connection between the peripheral and central auditory systems. The function of a cochlear prosthesis is to bypass the (missing) hair cells by stimulating directly the surviving neurons in the auditory nerve. The anatomical situation faced by designers of CIs is illustrated in the bottom panel of Figure 58.1. The panel shows a complete absence of hair cells. In general, a small number of cells may remain for some patients, usually in the apical (low frequency) part of the cochlea. Without the normal stimulation provided by the hair cells, the peripheral parts of the neurons – between the cell bodies in the spiral ganglion and the terminals within the organ of Corti – undergo “retrograde degeneration” and eventually die (Hinojosa and Marion, 1983). Fortunately, the cell bodies are far more robust. At least some usually survive, even for prolonged deafness or for virulent etiologies such as meningitis (Hinojosa and Marion, 1983; Miura et al., 2002; Leake and Rebscher, 2004).

Electrical Stimulation of the Auditory Nerve Direct stimulation of the nerve is produced by currents delivered through electrodes placed in the scala tympani (ST), one of three fluid-filled chambers along the length of the cochlea. A cutaway drawing of the implanted cochlea is presented in Figure 58.2. The figure shows a partial insertion of an array of electrodes

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FIGURE 58.2 Cutaway drawing of the implanted cochlea. Illustrated is the electrode array developed at the University of California at San Francisco (Loeb et al., 1983). That array includes eight pairs of bipolar electrodes, spaced at 2 mm intervals and with the electrodes in each pair oriented in an “offset radial” arrangement with respect to the neural processes peripheral to the ganglion cells in the intact cochlea. Only four of the bipolar pairs are visible in the drawing, as the others are “hidden” by cochlear structures. This array was used in the UCSF/Storz and Clarion 1.0 devices (Reproduced from Leake and Rebscher (2004) with permission of Springer Science  Business Media) Middle ear

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FIGURE 58.1 Anatomical structures in normal and deafened ears. Note the absence of sensory hair cells in the deafened ear. Also note the incomplete survival of spiral ganglion cells and of neural processes peripheral to cells that are still viable. For simplicity, the illustrations do not reflect the details of the structures or use a consistent scale for the different structures (Reproduced from Dorman and Wilson (2004), Fig. 5, with permission. Sigma Xi, The Scientific Research Society)

into the ST. The array is inserted through a drilled opening made by the surgeon in the bony shell of the cochlea overlying the ST (called a “cochleostomy”) and close to the base of the cochlea. Alternatively, the array may be inserted through the second flexible membrane of the cochlea, the round window membrane, which also is close to the basal end of the cochlea and ST. Different electrodes in the implanted array may stimulate different subpopulations of neurons. As described above, neurons at different positions along the length of the cochlea respond to different frequencies of acoustic stimulation in normal hearing. Implant systems attempt to mimic or reproduce this “tonotopic” encoding by stimulating basally situated electrodes (first turn of the

cochlea and lower part of the drawing) to indicate the presence of high-frequency sounds, and by stimulating electrodes at more apical positions (deeper into the ST and ascending along the first and second turns in the drawing) to indicate the presence of sounds with lower frequencies. Closely spaced pairs of bipolar electrodes are illustrated here, but arrays of single electrodes that are each referenced to a remote electrode outside the cochlea also may be used. This latter arrangement is called a “monopolar coupling configuration” and is used in all present-day implant systems that are widely applied worldwide. The spatial specificity of stimulation with an ST electrode most likely depends on a variety of factors, including the orientation and geometric arrangement of the electrodes, the proximity of the electrodes to the target neural structures, and the condition of the implanted cochlea in terms of nerve survival and ossification. An important goal of electrode design is to maximize the number of largely non-overlapping populations of neurons that can be addressed with the electrode array. Present evidence suggests, however, that no more than 4–8 independent sites are available using current designs, even for arrays with as many as 22 electrodes (e.g., Fishman et al., 1997). Most likely, the number of independent sites is limited by

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substantial overlaps in the electric fields from adjacent (and more distant) electrodes. The overlaps are unavoidable for electrode placements in the ST, as the electrodes are sitting in the highly conductive fluid of the perilymph and additionally are relatively far away from the target neural tissue in the spiral ganglion. A closer apposition of the electrodes next to the inner wall of the ST would move them a bit closer to the target cells (see Figure 58.2), and such placements have been shown in some cases to produce an improvement in the spatial specificity of stimulation (Cohen et al., 2006). However, a large gain in the number of independent sites may well require a fundamentally new type of electrode, or a fundamentally different placement of electrodes. The many issues related to electrode design, along with prospects for the future, are discussed, for example, by Wilson and Dorman (2008a) and Spelman (2006). Figure 58.2 shows a complete presence of hair cells (in the labeled organ of Corti) and a pristine survival of cochlear neurons. However, the number of hair cells is zero or close to it in cases of total deafness. In addition, survival of neural processes peripheral to the ganglion cells (the “dendrites”) is at least unusual in the deafened cochlea, as noted before. Survival of the ganglion cells and central processes (the axons) ranges from sparse to substantial. The pattern of survival is in general not uniform, with reduced or sharply reduced counts of cells in certain regions of the cochlea. In all, the neural substrate or target for a CI can be quite different from one patient to the next. A detailed review of these observations and issues is presented by Leake and Rebscher (2004).

Components of Cochlear Implant Systems The essential components in a cochlear prosthesis system are illustrated in Figure 58.3 and include (1) a microphone for sensing sound in the environment; (2) a speech processor to transform the microphone input into a set of stimuli for the implanted array of electrodes; (3) a transcutaneous link for the transmission of power and stimulus information across the skin; (4) an implanted receiver/stimulator to decode the information received from the radio-frequency signal produced by an external transmitting coil and then to generate stimuli using the instructions obtained from the decoded information; (5) a cable to connect the outputs of the receiver/stimulator to the electrodes; and (6) the array of electrodes. These components must work together as a system to support excellent performance and a weakness in a component can degrade performance significantly. For example, a

External transmitter Implanted receiver/ stimulator

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Components of a cochlear implant system. The TEMPO system is illustrated, but all present-day implant systems share the same basic components. The microphone, battery pack, and speech processor are incorporated into a behind-the-ear (BTE) housing in the illustrated system, much like the BTEs of hearing aids. A thin cable connects the output of the speech processor (a radiofrequency signal with encoded stimulus information) to an external transmitting coil that is positioned opposite to an implanted receiver/stimulator. The transmitting coil is held in place with a pair of magnets, one in the center of the coil and the other in the case of the implanted receiver/stimulator. The receiver/stimulator is implanted in a flattened or recessed portion of the skull, posterior to and slightly above the pinna. The reference (or “ground”) electrode is implanted at a location remote from the cochlea, usually in the temporalis muscle. For some implant systems, a metallic band around the outside of the receiver/stimulator package serves as the reference electrode. An array of active electrodes is inserted into the scala tympani (ST) through the round window membrane or through a larger drilled opening in the bony shell of the cochlea (a cochleostomy) near the round window (Diagram courtesy of MED-EL GmbH, of Innsbruck, Austria)

limitation in the data bandwidth of the transcutaneous link can restrict the types and rates of stimuli that can be specified by the external speech processor and this in turn can limit performance. One “component” that is not illustrated in Figure 58.3 is the biological part central to the auditory nerve (colored yellow in the figure), including the auditory pathways in the brain stem and the auditory cortices of the implant recipient. As described in detail in Wilson and Dorman (2008a), this part varies in its functional integrity and capabilities across patients, and is at least as important as the other parts in determining outcomes with implants.

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FIGURE 58.4 Block diagram of the continuous interleaved sampling (CIS) strategy. The input to the strategy is indicated by the filled circle in the left-most part of the diagram. This input can be provided by a microphone or alternative sources such as an FM wireless link in a classroom. Following the input, the strategy uses a pre-emphasis filter (Pre-emp.) to attenuate strong components in speech below 1.2 kHz. This filter is followed by multiple channels of processing. Each channel includes stages of bandpass filtering (BPF), envelope detection, compression, and modulation. The envelope detectors generally use a full-wave or half-wave rectifier (Rect.) followed by a lowpass filter (LPF). A Hilbert Transform or a half-wave rectifier without the LPF also may be used. Carrier waveforms for two of the modulators are shown immediately below the two corresponding multiplier blocks (circles with a “x” mark within them). The outputs of the multipliers are directed to intracochlear electrodes (EL-1 to EL-n), via a transcutaneous link (or a percutaneous connector in some earlier systems). The inset shows an X-ray micrograph of the implanted cochlea, to which the outputs of the speech processor are directed (Block diagram adapted from Wilson et al. (1991) and reproduced with permission of the Nature Publishing Group. Inset from Hüttenbrink et al. (2002) reproduced with permission of Lippincott Williams & Wilkins; www.lww.com)

Transformation of a Microphone Input into Stimuli for the Implant An important aspect of the design for any type of sensory neural prosthesis is how to transform an input from a sensor or array of sensors into a set of stimuli that can be interpreted by the nervous system. The stimuli can be electrical or tactile, for example, and usually involve multiple sites of stimulation, corresponding to the spatial mapping of inputs and representations of those inputs in the nervous system. One approach to the transformation – and probably the most effective approach – is to mimic or replicate at least to some extent the damaged or missing physiological functions that are bypassed or replaced by the prosthesis. For CIs, this part of the design is called the processing strategy. As noted previously, advances in processing strategies have produced quite large

improvements in the speech reception performance of implant patients, from recognition of a tiny percentage of monosyllabic words with the first strategies and multi-site stimulation, for example, to recognition of a high percentage of the words with current strategies and multi-site stimulation. One of the simpler and most effective approaches for representing speech and other sounds with present-day CIs is illustrated in Figure 58.4. This is the continuous interleaved sampling (CIS) strategy (Wilson et al., 1991), which is used as the default strategy or as a processing option in all implant systems now in widespread clinical use. The CIS strategy filters speech or other input sounds into bands of frequencies with a bank of bandpass filters. Envelope variations in the different bands are represented at corresponding electrodes in the cochlea with modulated trains of biphasic electrical pulses. The envelope signals extracted from the

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PERFORMANCE WITH PRESENT-DAY UNILATERAL IMPLANTS Each of the processing strategies in current widespread use supports recognition of monosyllabic words on the order of 50% correct (using hearing alone), across populations of tested subjects (Wilson, 2006). Variability in outcomes is high, however, with some subjects achieving scores at or near 100% correct and with other subjects scoring close to zero on this most difficult of standard audiological measures. Standard deviations of the scores range from about 10% to about 30% for the various studies conducted to date. Results from a large and carefully controlled study are presented in Figure 58.5, which shows scores for 55 users of the MED-EL COMBI 40 implant system and

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bandpass filters are compressed with a nonlinear mapping function prior to the modulation, in order to map the wide dynamic range of sound in the environment (around 90 dB) into the narrow dynamic range of electrically evoked hearing (about 10 dB or somewhat higher). The output of each bandpass channel is directed to a single electrode, with low-to-high channels assigned to apical-to-basal electrodes, to mimic at least the order, if not the precise locations, of frequency mapping in the normal cochlea. The pulse trains for the different channels and corresponding electrodes are interleaved in time, so that the pulses across channels and electrodes are nonsimultaneous. This eliminates a principal component of electrode interaction, which otherwise would be produced by direct vector summation of the electric fields from different (simultaneously stimulated) electrodes. The corner or “cutoff” frequency of the lowpass filter in each envelope detector typically is set at 200 Hz or higher, so that the fundamental frequencies of speech sounds are represented in the modulation waveforms. CIS gets its name from the continuous sampling of the (compressed) envelope signals by rapidly presented pulses that are interleaved across electrodes. Between 4 and 22 channels (and corresponding stimulus sites) have been used in CIS implementations to date. Other strategies also have produced outstanding results. Among these are the n-of-m (Wilson et al., 1988), spectral peak (SPEAK) (Skinner et al., 1994), advanced combination encoder (ACE) (Kiefer et al., 2001) and “HiResolution” (HiRes) (Koch et al., 2004) strategies. Detailed descriptions of these and prior strategies are presented by Wilson (2006) and Wilson and Dorman (2008a, 2008b).

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FIGURE 58.5 Percent correct scores for 55 users of the MED-EL COMBI 40 implant and the CIS processing strategy. Scores for recognition of the Hochmair–Schultz–Moser (HSM) sentences are presented in the top panel, and scores for recognition of the Freiburger monosyllabic words are presented in the bottom panel. The solid line in each panel shows the median of the scores, and the dashed and dotted lines show the interquartile ranges. The data are an updated superset of those reported in Helms et al. (1997), kindly provided by Patrick D’Haese of MED-EL GmbH, in Innsbruck, Austria. The experimental conditions and implantation criteria are described by Helms et al. (1997). All subjects took both tests at each of the indicated intervals following initial fitting of their speech processors. Identical scores at a single test interval are displaced horizontally for clarity. Thus, for example, the horizontal “line” of scores in the top right portion of the top panel all represent scores for the 24-month test interval (Reproduced from Wilson (2006) with permission of Whurr Publishers Ltd, a subsidiary of John Wiley & Sons Ltd)

the CIS processing strategy. Scores for the Hochmair– Schultz–Moser (HSM) sentences are presented in the top panel, and scores for recognition of the Freiburger monosyllabic words are presented in the bottom panel. Results for five measurement intervals are shown, ranging from one month to two years following the initial fitting of the speech processor. The solid line in each panel shows the median of the individual scores and the dashed and dotted lines show the interquartile ranges. The data are a superset of those reported

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FIGURE 58.6 Means and standard errors of the means for 54 of the 55 subjects in Figure 58.5. (One of the subjects did not take the sentence test for the expanded range of intervals in Figure 58.6.) An additional interval before and two intervals after those indicated in Figure 58.5 were used for the sentence test (Reproduced from Wilson (2006) with permission of Whurr Publishers Ltd, a subsidiary of John Wiley & Sons Ltd)

by Helms et al. (1997), which include scores for additional subjects at various test intervals. Most of the subjects used an eight-channel processor with a pulse rate of about 1500/s/electrode. Some of the subjects used fewer channels and a proportionately higher rate. As is evident from the figure, scores are broadly distributed at each test interval and for both tests. However, ceiling effects are encountered for the sentence test for many of the subjects, especially at the later test intervals. At 24 months post fitting, 46 of the 55 subjects score above 80% correct, consistent with the 1995 NIH Consensus Statement. Scores for the recognition of monosyllabic words are much more broadly distributed. For example, at the 24-month interval only 9 of the 55 subjects have scores above 80% correct and the distribution of scores from about 10% correct to nearly 100% correct is almost perfectly uniform. An interesting aspect of the results presented in Figure 58.5 is an apparent improvement in performance over time. This is easiest to see in the lower ranges of scores, e.g., in the steady increase in the lower interquartile lines (the dotted lines) across test intervals. Improvements over time are even more evident in plots of mean scores for sentences and for words, as shown in Figure 58.6 for these same data and for additional test intervals for the sentence test. The mean scores increase for both the sentence and word tests up to 12 months and then plateau thereafter. The mean scores for the sentence test asymptote at about 90% correct, and the mean scores for the word test asymptote at about 55% correct. Such results typify

performance with the best of the modern CI systems and processing strategies, for electrical stimulation on one side with a unilateral implant. These results are especially remarkable for the top scorers, given that only a maximum of eight broadly overlapping sectors of the auditory nerve are stimulated with this device and the implementation of CIS used with it. This number is quite small in comparison to the normal complement of approximately 30 000 neurons in the human auditory nerve. The results also show a learning or accommodation effect, with continuous improvements in scores over the first 12 months of use. This suggests the likely importance of brain function in determining outcomes, and the reorganization or “knitting” (brain plasticity) that must occur to utilize such sparse inputs to the maximum extent possible.

RECENT ADVANCES Two recent advances in the design and performance of CIs are (1) electrical stimulation of both ears with bilateral CIs and (2) combined electric and acoustic stimulation (EAS) of the auditory system for persons with residual hearing at low frequencies. Bilateral electrical stimulation may reinstate at least to some extent the interaural amplitude and timing difference cues that allow people with normal hearing to lateralize sounds in the horizontal plane and to selectively “hear out” a voice or other source of sound from among multiple sources at different locations. Additionally, stimulation on both sides may allow users to make use of the acoustic shadow cast by the head for sound sources off the midline. In such cases, the signal-to-noise ratio (S/N) may well be more favorable at one ear compared to the other for multiple sources of sound, and users may be able to attend to the ear with the better S/N. Combined EAS may preserve a relatively-normal hearing ability at low frequencies, with excellent frequency resolution and other attributes of normal hearing, while providing a complementary representation of high frequency sounds with the CI and electrical stimulation. Various surgical techniques and drug therapies have been developed to preserve low-frequency hearing in an implanted cochlea, to allow combined EAS of the same ear following an implant operation. These techniques and therapies are reviewed in Wilson and Dorman (2008a) and include deliberately short insertions of the electrode array. Each of these approaches – bilateral electrical stimulation and combined EAS – has produced large improvements in speech reception performance compared to

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control conditions (see review in Wilson and Dorman, 2008a). In particular, bilateral stimulation can provide a substantial benefit in recognizing difficult speech materials such as monosyllabic words and in recognizing speech presented in competition with spatially distinct noise, in comparison to scores obtained with either unilateral implant alone. In addition, use of both implants supports an improved ability to lateralize sounds, again compared with either unilateral implant. (This ability is nonexistent or almost nil with a unilateral implant.) Combined EAS also provides a substantial benefit for listening to speech in quiet, in noise, or in competition with a multi-talker babble, compared with either electric stimulation only or acoustic stimulation only. In addition, identification of melodies and reception of musical sounds is greatly improved with combined EAS compared to electric stimulation alone. (Scores with acoustic stimulation alone closely approximate the scores with combined EAS, for melody and music reception.) In cases of symmetric or nearly symmetric hearing loss, the benefits of combined EAS can be obtained with the acoustic stimulus delivered either to the ear with the CI or to the opposite ear or to both ears. Large benefits also can be obtained in cases of complete or nearly complete loss of residual hearing on the implanted side and delivery of the acoustic stimulus to a still-sensitive ear on the contralateral side. (This observation is good news for recipients of a fully inserted CI on one side, and residual hearing on the contralateral side, in that any residual hearing on the implanted side generally is lost with a full insertion of the electrode array.) A detailed discussion of possible mechanisms underlying the benefits of bilateral CIs and of combined EAS is presented by Wilson and Dorman (2008b). Each of these relatively new approaches utilizes or reinstates a part of the natural system. Two ears are better than one, and use of even a part of normal or nearly normal hearing at low frequencies can provide a highly significant advantage.

POSSIBILITIES FOR THE FUTURE Tremendous progress has been made in the design and performance of cochlear prostheses. However, much room remains for improvements. Patients with the best results still do not hear as well as listeners with normal hearing, particularly in demanding situations such as speech presented in competition with noise or other talkers. Users of standard unilateral implants do not have much access to music and other sounds that are more complex than speech. Most importantly, a wide range of outcomes persists, even

with the current processing strategies and implant systems, and even with bilateral implants or combined EAS. Fortunately, major steps forward have been made recently – with bilateral implants and combined EAS – and multiple other possibilities for further improvements are on the horizon. Some of the possibilities include: ●

●

●

●

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Refinement and optimization of processing strategies and other aspects for bilateral implants and for combined EAS, each of which are in their nascent stages. Continued development of surgical techniques and adjunctive drug therapies for better preservation of residual hearing during and after surgeries for combined EAS. Reinstatement of the normal spontaneous discharges of neurons in the auditory nerve, using “conditioner pulses” or other methods (e.g., Rubinstein et al., 1999). Representation of “fine structure” or “fine frequency” information with implants, using novel patterns of electrical stimuli or the acoustic stimulation part of combined EAS or both (e.g. Smith et al., 2002; Nie et al., 2005; Wilson et al., 2005; Zeng et al., 2005; Wilson and Dorman, 2008b). A closer mimicking of the complex and interactive processing that occurs in the normal cochlea (Wilson et al., 2005; Wilson et al., 2006).

Each of these possibilities may produce improvements in performance, especially for patients with good or relatively good function in the central auditory pathways and in the cortical areas that process auditory information. Further improvements for all patients might be produced by somehow increasing the number of effective channels supported by CIs. Two possibilities for this are to bring the stimulating electrodes closer to the neural target, e.g., with placements of electrodes directly within the auditory nerve in the modiolus (Badi et al., 2003; Spelman, 2006; Middlebrooks and Snyder, 2007), or to bring the target closer to the electrodes, e.g., with drug-induced growth of neurites from the ganglion cells and toward the electrodes of ST implants (Roehm and Hansen, 2005; Pettingill et al., 2007; Rejali et al., 2007; Vieira et al., 2007). These and other possibilities are described in detail by Wilson and Dorman (2008a). Each of the approaches mentioned above is aimed at improving the representation at the periphery. A fundamentally new approach may be needed to help those patients presently at the low end of the performance spectrum, however. They may have compromised “auditory brains” as suggested above and by

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REFERENCES

many recent findings (for detailed reviews see Wilson and Dorman, 2008a, 2008b). For them, a “top-down” or “cognitive neuroscience” approach to implant design may be more effective than the traditional “bottomup” approach. In particular, the top-down approach would ask what the compromised brain needs as an input in order to perform optimally, in contrast to the traditional approach of replicating insofar as possible the normal patterns of activity at the auditory nerve. The patterns of stimulation specified by the new approach are quite likely to be different from the patterns specified by the traditional approach. A related possibility that may help all patients at least to some extent is directed training to encourage and facilitate desired plastic changes in brain function (or, to put it another way, to help the brain in its task to learn how to utilize the inputs from the periphery provided by a CI). Such training if well designed may reduce the time needed to reach asymptotic performance and may produce higher levels of auditory function at that point and beyond. The ideal training procedure for an infant or young child may be quite different from the ideal procedure for older children or adults owing to differences in brain plasticity. For example, the “step size” for increments in the difficulty of a training task may need to be much smaller for adults than for infants and young children (Linkenhoker and Knudsen, 2002). However, all patients may benefit from appropriately designed procedures, that respect the differences in brain plasticity according to age. The brain is a critical part of a prosthesis system. For patients with a fully intact brain, the bottom-up approach to implant design probably is appropriate, i.e., an ever-closer approximation to the normal patterns of neural discharge at the periphery is likely to provide the inputs that the brain “expects” and is configured to receive and process. For patients with a compromised brain, such inputs may not be optimal. In those cases, the top-down approach to implant design, or a combination of top-down and bottomup approaches, may produce the best results. For example, the top-down approach – combined with techniques to increase the independence of the stimulating electrodes at the periphery – may be especially effective for patients presently shackled with poor outcomes.

ACKNOWLEDGMENTS Parts of this chapter were drawn or adapted from several recent publications, including Dorman and

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Wilson, 2004; Wilson, 2006; Wilson and Dorman, 2007, 2008a, 2008b; Wilson et al., 2005, 2006. Work contributing data and ideas to the chapter was supported in part by NIH project N01-DC-2-1002 (to BSW) and its predecessors, all titled “Speech Processors for Auditory Prostheses,” and by NIH project 5R01DC000654 (to MFD) and its predecessors, all titled “Auditory Function and Speech Perception with Cochlear Implants.”

References Badi, A.N., Kertesz, T.R., Gurgel, R.K., Shelton, C. and Normann, R.A. (2003) Development of a novel eighth-nerve intraneural auditory neuroprosthesis. Laryngoscope 113: 833–42. Cohen, L.T., Saunders, E., Knight, M.R. and Cowan, R.S. (2006) Psychophysical measures in patients fitted with Contour and straight Nucleus electrode arrays. Hear. Res. 212: 160–75. Dorman, M.F. and Wilson, B.S. (2004) The design and function of cochlear implants. Am. Scientist 92: 436–45. Eisen, M.D. (2006) History of the cochlear implant. In: S.B. Waltzman and J.T. Roland, Jr. (eds), Cochlear Implants, 2nd edn. New York: Thieme Medical Publishers, pp. 1–10. Finn, R., with the assistance of Hudspeth, A.J., Zwislocki, J., Young, E. and Merzenich, M. (1998) Sound from silence: the development of cochlear implants. In: Beyond Discovery: The Path from Research to Human Benefit. Washington, DC: National Academy of Sciences, 1998: 1–8. (Available online at http://www.beyonddiscovery.org/includes/DBFile.asp?ID  83). Fishman, K.E., Shannon, R.V. and Slattery, W.H. (1997) Speech recognition as a function of the number of electrodes used in the SPEAK cochlear implant speech processor. J. Speech Lang. Hear. Res. 40: 1201–15. Helms, J., Müller, J., Schön, F., Moser, L., Arnold, W. et al. (1997) Evaluation of performance with the COMBI 40 cochlear implant in adults: a multicentric clinical study. ORL J. Otorhinolaryngol. Relat. Spec. 59: 23–35. Hinojosa, R. and Marion, M. (1983) Histopathology of profound sensorineural deafness. Ann. N Y Acad. Sci. 405: 459–84. Hüttenbrink, K.B., Zahnert, T., Jolly, C. and Hofmann, G. (2002) Movements of cochlear implant electrodes inside the cochlea during insertion: an x-ray microscopy study. Otol. Neurotol. 23: 187–91. Kiefer, J., Hohl, S., Sturzebecher, E., Pfennigdorff, T. and Gstoettner, W. (2001) Comparison of speech recognition with different speech coding strategies (SPEAK, CIS, and ACE) and their relationship to telemetric measures of compound action potentials in the Nucleus CI 24M cochlear implant system. Audiology 40: 32–42. Koch, D.B., Osberger, M.J., Segal, P. and Kessler, D. (2004) HiResolution and conventional sound processing in the HiResolution Bionic Ear: using appropriate outcome measures to assess speech-recognition ability. Audiol. Neurootol. 9: 214–23. Leake, P.A. and Rebscher, S.J. (2004) Anatomical considerations and long-term effects of electrical stimulation. In: F.-G. Zeng, A.N. Popper and R.R. Fay (eds), Auditory Prostheses: Cochlear Implants and Beyond. New York: Springer-Verlag, pp. 101–48. Linkenhoker, B.A. and Knudsen, E.I. (2002) Incremental training increases the plasticity of the auditory space map in adult barn owls. Nature 419: 293–6. Loeb, G.E., Byers, C.L., Rebscher, S.J., Casey, D.E., Fong, M.M., Schindler, R.A. et al. (1983) Design and fabrication of an experimental cochlear prosthesis. Med. Biol. Eng. Comput. 21: 241–54.

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Miura, M., Sando, I., Hirsch, B.E. and Orita, Y. (2002) Analysis of spiral ganglion cell populations in children with normal and pathological ears. Ann. Otol. Rhinol. Laryngol. 111: 1059–65. National Institutes of Health (1995) Cochlear implants in adults and children. NIH Consensus Statement 13 (2): 1–30. (This statement also is available in JAMA 1995; 274: 1955-61.) Nie, K., Stickney, G. and Zeng, F.G. (2005) Encoding frequency modulation to improve cochlear implant performance in noise. IEEE Trans. Biomed. Eng. 52: 64–73. Niparko, J.K. and Wilson, B.S. (2000) History of cochlear implants. In: J.K. Niparko, K.I. Kirk, N.K. Mellon, A.M. Robbins, D.L. Tucci and B.S. Wilson (eds), Cochlear Implants: Principles and Practices. Philadelphia: Lippincott Williams & Wilkins, pp. 103–7. Middlebrooks, J.C. and Snyder, R.L. (2007) Auditory prosthesis with a penetrating array. J. Assoc. Res. Otolaryngol. 8: 258–79. Pettingill, L.N., Richardson, R.T., Wise, A.K., O’Leary, S.J. and Shepherd, R.K. (2007) Neurotrophic factors and neural prostheses: potential clinical applications based upon findings in the auditory system. IEEE Trans. Biomed. Eng. 54: 1138–48. Rejali, D., Lee, V.A., Abrashkin, K.A., Humayun, N., Swiderski, D.L. and Rapheal, Y. (2007) Cochlear implants and ex vivo BDNF gene therapy protect spiral ganglion neurons. Hear Res. 228: 180–7. Roehm, P.C. and Hansen, M.R. (2005) Strategies to preserve or regenerate spiral ganglion neurons. Curr. Opin. Otolaryngol. Head Neck Surg. 13: 294–300. Rubinstein, J.T., Wilson, B.S., Finley, C.C. and Abbas, P.J. (1999) Pseudospontaneous activity: stochastic independence of auditory nerve fibers with electrical stimulation. Hear. Res. 127: 108–18. Skinner, M.W., Clark, G.M., Whitford, L.A., Seligman, P.M., Staller, S.J. et al. (1994) Evaluation of a new spectral peak (SPEAK) coding strategy for the Nucleus 22 channel cochlear implant system. Am. J. Otol. 15 (Suppl. 2): 15–27. Smith, Z.M., Delgutte, B. and Oxenham, A.J. (2002) Chimaeric sounds reveal dichotomies in auditory perception. Nature 416: 87–90. Spelman, F.A. (2006) Cochlear electrode arrays: past, present and future. Audiol. Neurootol. 11: 77–85.

Vieira, M., Christensen, B.L., Wheeler, B.C., Feng, A.S. and Kollmar, R. (2007) Survival and stimulation of neurite outgrowth in a serum-free culture of spiral ganglion neurons from adult mice. Hear Res. 230: 17–23. Wilson, B.S. (2004) Engineering design of cochlear implant systems. In: F.-G. Zeng, A.N. Popper and R.R. Fay (eds), Auditory Prostheses: Cochlear Implants and Beyond. New York: SpringerVerlag, pp. 14–52. Wilson, B.S. (2006) Speech processing strategies. In: H.R. Cooper and L.C. Craddock (eds), Cochlear Implants: A Practical Guide, 2nd edn. London and Philadelphia: Whurr Publishers, pp. 21–69. Wilson, B.S. and Dorman, M.F. (2007) The surprising performance of present-day cochlear implants. IEEE Trans. Biomed. Eng. 54: 969–72. Wilson, B.S. and Dorman, M.F. (2008a) Interfacing sensors with the nervous system: lessons from the development and success of the cochlear implant. IEEE Sensors J. 8: 131–47. Wilson, B.S. and Dorman, M.F. (2008b) Cochlear implants: current designs and future possibilities. J. Rehab. Res. Devel. 45: 695–730. Wilson, B.S., Finley, C.C., Farmer, J.C., Jr., Lawson, D.T., Weber, B.A., Wolford, R.D. et al. (1988) Comparative studies of speech processing strategies for cochlear implants. Laryngoscope 98: 1069–77. Wilson, B.S., Finley, C.C., Lawson, D.T., Wolford, R.D., Eddington, D.K. and Rabinowitz, W.M. (1991) Better speech recognition with cochlear implants. Nature 352: 236–8. Wilson, B.S., Schatzer, R. and Lopez-Poveda, E.A. (2006) Possibilities for a closer mimicking of normal auditory functions with cochlear implants. In: S.B. Waltzman and J.T. Roland, Jr. (eds), Cochlear Implants, 2nd edn. New York: Thieme Medical Publishers, pp. 48–56. Wilson, B.S., Schatzer, R., Lopez-Poveda, E.A., Sun, X., Lawson, D.T. and Wolford, R.D. (2005) Two new directions in speech processor design for cochlear implants. Ear Hear. 26: 73S–81S. Zeng, F.-G., Nie, K., Stickney, G.S., Kong, Y.Y., Vongphoe, M., Bhargave, A. et al. (2005) Speech recognition with amplitude and frequency modulations. Proc. Natl Acad. Sci. U S A 102: 2293–8.

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C H A P T E R

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The Development of Visual Prosthetic Devices to Restore Vision to the Blind Muhammad Memon and Joseph F. Rizzo, III

o u tl i n e Introduction

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Titanium Case and Feedthrough Technology

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Various Approaches to Treat Neural Forms of Blindness

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Design and Fabrication of the Stimulating Electrode Array

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Development of a Visual Prosthesis to Restore Vision to the Blind

Iridium Oxide Electrodes

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Methods of Surgical Implantation

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The Approach of the Boston Retinal Implant Project

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Ocular Biocompatibility

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Human Test Results to Date

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Overview of Specific Technologies Needed to Build a Retinal Prosthesis

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Significant Long-Term Problems

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Electronics

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Conclusion

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Microfabrication of Thin-Film, Flexible Circuits

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References

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Considerations for Encapsulation of Implanted Microelectronic Components

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Introduction

The term “blindness” is used generically and does not provide insight into the severity of blindness. For instance, patients who have no vision often are referred to as being “blind,” but so are patients who have moderately reduced visual acuity (e.g. 20/80) and difficulty reading. The term blindness also does not provide insight into the cause of blindness, which differs significantly across the world (Figure 59.1) (National Advisory Eye Council, 1993; Foster and Johnson, 1993; National Eye Institute, 2002; Congdon et al.,

Blindness is a major health problem that reduces patients’ ability to live independently by compromising their ability to work and perform activities of daily living. There are substantial psychological consequences for being blind, and a very large economic burden to patients, society, and the government, which collectively is estimated to amount to $35.4 billion per year (Rein et al., 2006).

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© 2008, 2009 Elsevier Ltd.

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59.  The Development of Visual Prosthetic Devices to Restore Vision to the Blind

Figure 59.1  Major causes of blindness worldwide divided into diseases that primarily affect the structures in the front vs. the back of the eye. In general, the diseases that involve the front of the eye are related to poor nutrition, infection or cataract, all of which are treatable. These diseases are substantially more common in non-industrialized countries. In contrast, the diseases that involve the back of the eye cause blindness by damaging either the retina or the optic nerve. These diseases predominate in industrialized countries. In general, vision cannot be restored once damage has occurred to neural structures. A list is provided of the most significant conditions and the relative prevalence of these conditions (expressed as percentage) as a cause of blindness on a global scale (National Advisory Eye Council, 1993; Congdon et al., 2004; Resnikoff et al., 2004)

2004; Friedman et al., 2004; Resnikoff et al., 2004). In non-industrialized countries, where the largest number of people are blind, disease of the front part of the eye, including either the cornea or the crystalline lens of the eye, are the leading causes of blindness (Foster and Johnson, 1993; Resnikoff et al., 2004). Poor nutrition and to a lesser extent infection are the primary factors that cause scarring of the cornea, which causes “optical” blindness by interfering with the passage of light into the eye. Similarly, opacification of the crystalline lens, known as a cataract, also produces a very common cause of “optical” blindness (Foster and Johnson, 1993; Resnikoff et al., 2004). Each of these conditions is treatable. Conversely, in industrialized countries the most common forms of blindness are “neural” and occur because of disease of either the retina or the optic nerve (Resnikoff et al., 2004). The most common form of retinal blindness is agerelated macular degeneration (AMD), which currently affects roughly 2 million Americans and the percentage of affected individuals is expected to increase by

50% by the year 2020. More than 15% of Caucasian women older than 80 years of age have some form of AMD (Congdon et al., 2004; Friedman et al., 2004). This disease causes loss of central vision; fortunately peripheral vision is spared, which allows patients to navigate without much difficulty. Retinitis pigmentosa (RP) is the most common cause of inherited blindness throughout the world (Council NAE, 1993). RP causes a slowly progressive loss of peripheral vision with eventual involvement of central vision. For both of these diseases, the blindness is caused by a loss of the photoreceptors of the retina. The photoreceptors are the only cells that can convert incoming light into an electrical signal that can be carried to the brain (via the optic nerve) to create conscious vision. No form of neural blindness is easily treatable, although we are at the verge of a major breakthrough in this regard (see below). Both AMD and RP result in blindness because of a loss of photoreceptors (i.e. the rods and cones), which are the only cells in the body that can convert light into

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Various approaches to treat neural forms of blindness

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Figure 59.2  The conceptual approach underlying the development of retinal prosthetic devices as a potential treatment for blindness caused by loss of the photoreceptors of the retina. A cross-section of the retina (i.e. the photoreceptive nerve tissue that hues the back of the eye) is shown on the lower left. In this projection, light enters the retina from the top (which would face toward the front of the eye). The incoming light rays penetrate through the transparent retina to reach the outermost layer of cells known as photoreceptors (i.e. the rods and cones). These cells capture energy from the incoming light and initiate neural signals that propagate back toward the inner surface of the retina through an intricate neuronal network. Ultimately, the signals reach the sole output cell of the eye, the ganglion cells. Each of the roughly 1.2 million ganglion cells (in humans) has an extension (i.e. an axon), and all axons converge on the surface of the retina to form the optic nerve head. The optic nerve is the only connection between the eye and the rest of the brain. The lower middle figure shows an absence of the photo­receptors, as occurs to varying degrees in age-related macular degeneration and retinitis pigmentosa. Affected patients are rendered blind because there are no photoreceptive elements to generate conscious vision. Large numbers of nerve cells toward the inner retina survive the loss of photoreceptor input, although considerable intra-retinal pathology is induced by the photoreceptor degeneration. The conceptual foundation of a retinal prosthesis is to place an electrode array on either the epi- or subretinal surface (as shown to the lower right) to deliver stimulation to the surviving nerve cells. Once stimulated by the electrical input, the ganglion will send electrical signals to the brain to create visual “percepts.” (NFL: nerve fiber layer; RPE: retinal pigment epithelium)

neural signals that produce conscious vision (Figure 59.2). In both of these conditions, generally there is significant survival of large numbers (hundreds of thousands) of other types of retinal neurons, including the retinal ganglion cells (RGCs) that connect the eye to the brain (Curcio et al., 1993), although at least for RP, the surviving cells may develop significant pathologies, seemingly in response to loss of the natural input from the photoreceptors, and these pathologies may complicate attempts to restore sight with a prosthesis (see section on pathology for more details). Another common form of blindness, diabetic retinopathy, damages the RGCs and therefore diabetic retinopathy is not amenable to treatment with a retinal prosthesis. Further along the visual pathway from the eye to the visual part of the brain, another very common form of

blindness, glaucoma, causes visual loss in over 1% of the population of the USA by damaging the optic nerve (Report NEI, 2002). Glaucoma causes a slowly progressive loss of peripheral vision and, like other forms of neural blindness, causes irreversible blindness. Given that the optic nerve is further along the visual pathway, a retinal prosthesis would not be a reasonable treatment option for this condition. Other treatment options for neural forms of blindness are discussed below.

Various approaches to treat neural forms of blindness The desire to develop treatments for blindness must take into account the cause and severity of blindness

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59.  The Development of Visual Prosthetic Devices to Restore Vision to the Blind

as well as the degree and type of functional limitations experienced by patients. Historically, attempts to treat patients with neural forms of blindness like AMD or RP have been restricted to the use of optical devices, like telescopes (to enhance distance viewing), highpowered convex lenses (to enhance near viewing), and the use of assistive devices like closed circuit monitors that can greatly enlarge images of objects on a screen to enhance viewing. The time-honored use of a white cane provides substantial assistance for mobility and enhances the independence of patients. The fairly recent availability of specialized computer software is allowing blind patients to effectively use a computer and engage in Internet communications. Collectively, these treatments are provided to patients in the form of “Visual Rehabilitation” therapy, which is administered by specially trained professionals. Many blind patients are able to benefit from one or more of these treatment options, but those patients who are successful with these methods must still make significant adjustments in their daily routines because of residual visual limitations. Clearly, much more needs to be done to restore visual function to patients who have currently untreatable forms of neural blindness. One very important need faced by all severely blind patients is the ability to walk safely in an unfamiliar environment. The use of a white cane certainly helps, but the cane can only inform the user about the lower part of the environment that is 3–4 feet in front of their outstretched hand. The cane does not inform the user about any hanging obstacles and has other significant limitations. To enhance ambulation, researchers have developed various forms of “sensory substitution” therapies in which a customized device is used to capture visual information and then transform the information into another, non-visual sensory, like the tactile or the auditory system (Bach-y-Rita, 2004). One advanced auditory-based device that uses a camera to capture visual images that are then electronically modified (by configuring the loudness, frequency, and inter-ear disparity) to create an auditory landscape has allowed some blind patients to effectively navigate through complex and unfamiliar environments (Amedi et al., 2007). Although there is promise in the use of sensory substitution therapy, the lack of visible use of these devices on the streets attests to the challenges in trying to implement some artificial means of assisting blind patients that can provide a real improvement in quality of life in a manner that is practical, affordable, and low-risk to the patients. These various approaches have the potential to improve the function of the patient but they cannot restore vision that has already been lost, which is the ultimate goal of vision rehabilitation therapy. A wide

range of therapies is being explored to restore lost visual function, including: (1) transplantation of stem cells, embryonic or adult cells; (2) neurotrophic factors that can enhance the survival of cells that might otherwise die; and (3) molecular approaches that are designed to rectify the abnormalities of DNA that cause death of specific types of nerve cells, like the photoreceptors. Transplantation of cells that are either destined to die (like the photoreceptors) or that are believed to contribute to the degeneration of photoreceptors (like the retinal pigment epithelium) has been explored as therapy for disease of the outer retina for roughly 20 years (Algvere et al., 1997; del Cerro et al., 1997; Kaplan et al., 1997; Das et al., 1999; Radtke et al., 1999, 2002, 2004; Weisz et al., 1999; Humayun et al., 2000; Sagdullaev et al., 2003; Abe et al., 2007; Ng et al., 2007). More recently, the identification of stem cells, which are potentially able to transform into essentially any type of cell in the body, also has attracted significant interest as a means of replacing damaged or degenerating nerve cells, including those within the visual pathway. In very brief summary, despite considerable advances in these fields, the various forms of transplantation have not yet produced significant improvements in vision in a significant number of patients to justify widespread use of these therapies. However, it should be appreciated that transplanted cells are well tolerated by the eye and that selected patients seem to have benefited visually (Algvere et al., 1997; del Cerro et al., 1997; Kaplan et al., 1997; Das et al., 1999; Radtke et al., 1999, 2002, 2004; Weisz et al., 1999; Humayun et al., 2000; Sagdullaev et al., 2003; Abe et al., 2007; MacLaren and Pearson. 2007). Continued investigation of these therapies is on-going and it is possible that these approaches will contribute to the set of options available to patients in the future. One significant challenge faced by this approach is the need for the transplanted cells to develop synaptic connections with the host nerve cells in some logical order to create a neural architecture that will yield some useful level of vision. Several types of naturally occurring “tropic” factors have been shown to support the survival of nerve cells, including photoreceptors that are destined to degenerate because of a genetic mutation. In particular, one type of neurotrophic growth factor, ciliary neurotrophic factor (CNTF), is released normally in response to cellular injury and has been shown in some animal models to provide significant protection to photo­ receptors (LaVail et al., 1992; Zeiss et al., 2006). Use of cells that have been modified by viral vectors to continuously secrete CNTF (and which were implanted into the eye within microspheres) is currently under

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Development of a visual prosthesis to restore vision to the blind

FDA investigation as a treatment for blindness caused by RP (Sieving et al., 2006). The use of CNTF has also been shown to reduce the electrical activation thresholds for retinal neurons (Kent et al., 2008), which are normally quite elevated in RP and which increases the challenge of using a retinal prosthesis as a means of restoring vision to blind patients (see below). The molecular genetic approach perhaps offers the best and most elegant long-term treatment option. Inherited forms of blindness are usually the result of retinal disease and usually manifest as a degeneration of photoreceptors. The loss of the photoreceptors leads to blindness because the photoreceptors are the only cells that can convert energy from incoming light into nerve impulses that produce conscious perception. More than one hundred genetic defects have been recognized as causing various forms of retinal degeneration. The discovery of these gene defects makes it possible to attempt a molecular genetic repair of the abnormal photoreceptors (Bainbridge et al., 2006). A recent breakthrough has occurred in the use of molecular strategy to treat blindness. Three patients with a congenital form of blindness known as Lebers congenital amaurosis (LCA) demonstrated “modest improvement in measures of retinal function” after having received an injection into the eye of a recombinant, adeno-associated virus that carried a complementary DNA copy of the defective gene that caused the blindness (Maguire et al., 2008). These positive results combined with the lack of any seemingly significant complication will surely accelerate attempts to use a similar molecular approach to treat other types of genetic defects that cause blindness. In pre-clinical trials, these same researchers also had achieved significant success in treating severely blind dogs that had the same genetic defect that caused the blindness in humans (Acland et al., 2001). Given the wide range of genetic abnormalities that can cause retinal degeneration, a molecular approach would have to be customized for each type of genetic abnormality. The recent success may or may not translate into similar benefits for patients with molecular abnormalities of the photoreceptors (vs. the retinal pigment epithelium), but the recent proof-of-concept of success in human patients should be recognized as a major milestone toward the goal of treating neural forms of blindness. It is now clear that a single intraocular injection can induce stable expression of genes for several years and that the availability of numerous viral vectors can be used to produce desired levels and durations of gene expression. These and other accomplishments have substantiated and validated the use of gene therapy as a strategy to treat some forms of genetic blindness (Bainbridge et al., 2006).

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Development of a visual prosthesis to restore vision to the blind A prosthesis is a device that is designed to replace a damaged part of the body. Compared to most of the other therapeutic options mentioned above, a visual prosthesis has the significant advantage that restoration of function could be achieved by stimulation of nerve fibers that had been properly established during development – no new connections would have to be developed, as would be the case for transplanted cells, for instance. Mechanical prostheses, such as artificial limbs, have been in use for many decades and provide obvious benefits to patients. Electronic prostheses have been more challenging to develop but significant successes have been achieved with cardiac pacemakers and defibrillators (especially the more recent devices that can diagnose and electrically intervene to correct a cardiac arrhythmia) and with cochlear implants that can restore hearing to deaf patients. The success of cochlear implants in improving a sensory dysfunction certainly was a factor that motivated the development of retinal prostheses. Almost all retinal prostheses under development are intended to deliver electrical pulses to the retina. Alternative approaches to electrical stimulation include use of biological agents, like neurotransmitters or potassium, to activate retinal neurons (Theogarajan, 2007; Kent et al., 2008). These approaches offer the important, potential advantage of avoiding the potentially damaging use of electrical pulses, but these concepts require more complicated engineering. Not surprisingly, the development of these devices lags behind that of the electronic devices, which can take advantage of well-developed methods used for the microelectronic industry. To provide vision to blind patients, a microelectronic retinal prosthesis must: (1) capture visual images; (2) convert light energy into electrical pulses; and (3) deliver electrical pulses to the retina. One approach to the embodiment of these features is shown in Figure 59.3, which provides a schematic overview of how various functional elements of a prosthesis could be arranged to create a geometry that would be compatible with human implantation. Visual prostheses could interface with the visual pathway at multiple locations. A full range of devices are being developed that either provide electrical stimulation to the retina, optic nerve, lateral geniculate body or visual cortex (Figure 59.4). The first initiative to develop a visual prosthesis for human

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59.  The Development of Visual Prosthetic Devices to Restore Vision to the Blind

Figure 59.3  Digital images of a more recent design of our retinal prosthesis. Left: A pair of glasses supports a small camera (red arrow) that collects visual images. The components of the retinal prosthesis are otherwise not visible. Middle: The black plastic surface of the glasses has been removed to reveal a wire (white arrow) that extends along the length of the sidebar to an external processing unit (not shown) that would be worn in a pocket. Also revealed are two “primary” radiofrequency (RF) coils, seen as reddish-brown and gray circles (yellow arrow). This image provides an impression of the location of the implanted components of the prosthesis. Right: Isolated view of the eye to better illustrate the implanted components of this particular embodiment of our prosthesis, which conforms to the contour of the eye. The secondary RF coils (yellow arrow) are positioned just behind the circumference of the cornea. The titanium case (white arrow) provides a hermetic environment for the integrated circuit chip. The electrode array enters the eye through a small slit (red arrow) in the sclera

Figure 59.4  Potential sites at which a visual prosthesis could interface with the afferent visual system, that is, the part of the visual system that captures and processes visual information that is transmitted to the primary visual cortex that is located at the back of the brain. From the primary visual cortex, visual information is sent along two widely distributed “parallel” pathway systems that provide higher level processing of visual information

patients occurred nearly four decades ago when a visual cortical device was designed and ultimately tested on a blind patient (Brindley, 1970; Dobelle and Mladejovsky, 1974; Humayun et al., 1996, 2003; Rizzo et al., 2001; Zrenner, 2002; Loewenstein et al., 2004). Efforts to develop a retinal prosthesis began about 20 years ago by our group and another at Duke University, North Carolina. Since then, partially due to rapid advances in the field of microelectronic technology, the field of visual prosthetics has expanded considerably and now includes more than 20 research programs worldwide (see Table 59.1). Most devices under development are designed to electrically stimulate the retina, and both epi- and subretinal devices are being pursued. Each approach has advantages and disadvantages, and there is not yet enough evidence to know which approach(es) might be preferable. It is

likely that there will not be a uniform benefit for one type of prosthesis across a range of diseases.

The approach of the Boston Retinal Implant Project This section concentrates on the technology of our Boston Retinal Implant Project (BRIP), but the focus on our group should not be misconstrued as suggesting that our strategic approach or technology are superior to those of any other group. Rather, this material should be viewed as merely displaying the range of technologies that are required to build any type of implantable visual prosthesis.

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The approach of the Boston Retinal Implant Project

Table 59.1  Summary of worldwide visual prosthetics research programs Research group/company

Principal investigators/ group leaders

Primary location

Biomedical Physics and Ophthalmic Technology

Daniel Palanker, PhD

Stanford University, CA

Boston Retinal Implant Project

Joseph F. Rizzo III, MD John Wyatt, PhD

Massachusetts Eye and Ear Infirmary – Harvard Medical School; Massachusetts Institute of Technology; Boston VA Health Care System, MA

Optobionics Inc.

Alan Chow, MD Vincent Chow, PhD

Naperville, IL

SUBRET Consortium/Retina Implant GmbH

Eberhart Zrenner, MD

Tübingen/Reutlingen, Germany

Biohybrid Retinal Implant

Tohru Yagi, PhD Watanabe, PhD

Tokyo Institute of Technology, Tokyo, Japan

Japan Retina Implant Group/NIDEK Co.

Yasuo Tano, MD Yasushi Ikuno, MD Jun Ohta, PhD

Osaka, Japan

C-Sight: Chinese Project for Sight

Xiaoxin Li, MD Quishi Ren, PhD

People’s Hospital–Peking University Medical School, Beijing, China

Mark Humayun, MD James D. Weiland, PhD R.J. Greenberg

Doheny Eye Institute, University of Southern California/Sylmar, Los Angeles, CA

Ligon Research Center of Vision

Raymond Iezzi, MD Greg Auner, PhD Gary Abrams, MD

Wayne State University, Detroit, MI

Intelligent Medical Implants (IMI)

Gisbert Richard, MD

University of Bonn, Germany

3-D Stacked Retinal Prosthesis

Makoto Tamai, MD Hiroshi Tomita Mitsumasa Koyanagi

Tohoku University, Tohoku, Japan

Nano Bioengineering System Resarch Center/Nano Artificial Vision Center

Sung June Kim, PhD Hum Chung, PhD

Seoul National University Hospital–Seoul National University School of Medicine, Seoul, Korea

Australian Vision Prosthesis Group

Nigel Lovell PhD Gregg Suaning, PhD

University of New South Wales/University of Newcastle, Sydney, Australia

Jean Delbeke, MD, PhD Claude Veraart, PhD

Brussels, Belgium

John S. Pezaris, PhD R. Clay Reid, MD, PhD Emad N. Eskandar, MD

Massachusetts General Hospital–Harvard Medical School, Boston, MA

Utah Visual Neuroprosthesis Program

Richard Normann, PhD

Salt Lake City, UT

Bionic Eye Research Project

Vivek Chowdhury, MD, Minas T.Coroneao; PhD

Prince of Wales Hospital, Randwick, Australia

CORTIVIS

Eduardo Fernandez, MD

Universidad Miguel Hernandez, Alicante, Spain

Intracortical Visual Prosthesis/Illinois Institute of Technology

Phil Troyk, PhD

Illinois Institute of Technology, Chicago, IL

Subretinal

Epiretinal

Optic nerve Neural Rehabilitation Engineering Laboratory, Brussels; Université Catholique de Louvain, Belgium LGB Reid Lab

Cortical

PolySTIM Research Group

Mohamad Sawan, PhD

Polystim Neurotechnologies Laboratory, Ecole Polytechnique, University of Montreal, Montreal, Canada (Continued)

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Table 59.1  Continued Research group/company

Principal investigators/ group leaders

Primary location

Toshikhiko Matsuo, MD

Okayama City, Japan

Neurotransmitter-based Photoelectric Dye-Coupling/ Hahashibara Co.

Note: All the programs are ongoing except Optobionics Inc. This company is no longer investigating electrical stimulation of the retina. Instead it is investigating the trophic effect of implanting a device in the subretinal space

Overview of specific technologies needed to build a retinal prosthesis The development of a visual prosthesis requires the merger of many types of engineering and biological expertise. This section will provide a brief overview of some aspects of this type of multidisciplinary collaboration to offer insight into how a visual prosthetic system can be built. The design details presented here represent choices made by our BRIP, and clearly there are many other ways to build a prosthesis. This presentation should be considered as merely representing one set of design options. Almost every design element has some appeal but at the same time creates other potential problems, hence the frequent alterations in designs that we and other groups have made over time. Many of the specific details of the design that are discussed here continue to evolve to improve the effectiveness of the device.

Electronics Our MIT-based engineering team has developed a complete neural prosthetic system guided by the understanding that creation of detailed visual images would require a relatively large bandwidth for data transmission. High data rates require a high frequency carrier, but power transmission at high frequencies is inefficient. Our device therefore transmits power very efficiently at a relatively low frequency (125 kHz), while visual scene data are transmitted at a relatively high frequency (13.56 MHz). Our system employs a highefficiency class D oscillator to transmit power; a lowerefficiency class A amplifier is sufficient to transmit data. The core of our electronic system is our IC “stimulator chip.” This chip (which was designed by Luke Theogarajan of our group) contains 30 000 transistors and employs aggressive strategies to achieve

ultra-low power performance – the chip dissipates only about 1.5 mW at low data rates (100 kilobyte/ sec), and about 2.5 mW at higher data rates (500 kilobyte/sec). Our chip is capable of providing 800 A for each of our 15 electrodes. The pulse width is externally controlled and shared by all electrodes on a given stimulation cycle. The chip produces variable current pulse durations, amplitudes, and inter-pulse intervals, and it can address individual electrodes. Our design is readily expandable to address as many electrodes as will be included in upcoming generations of our device that will be used for human testing. Figure 59.5 shows the design architecture of our stimulator chip. The chip is powered via an inductive link. Current from the power secondary coil is rectified and filtered using off-chip diodes and capacitors, using a nominal supply voltage of2.5 V. Digital data are transmitted as an amplitude-shift keyed (ASK) waveform. The carrier frequencies of the power and data are 125 kHz and 13.56 MHz, respectively. The analog front end decouples data from power, while the delay-locked-loop demodulates and restores the data signal to digital levels and extracts the clock signal from the input waveform. Symbols are encoded as pulse width modulated signals with the rising edge representing a clock pulse. A 50–50% duty cycle encodes a logical “0”, and 30–70% duty cycle encodes a logical “1”. Clock controls and data are fed to the control logic block, which instructs the current driver block, which sends biphasic pulses to the electrode array.

Microfabrication of thin-film, flexible circuits A common feature of all of our designs has been the incorporation of a highly flexible circuit. Initially, we decided to use very thin (10 m) polyimide for our electrode array to minimize any mechanical trauma to the retina. In our more recent designs, a similarly thin

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Considerations for encapsulation of implanted microelectronic components

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Figure 59.5  Design architecture of our stimulator chip illustrating the roles of the analog front-end for transmitter input (upper left); delay-lockedloop (DLL), control logic block (CLB), and the current driver block, which delivers charge to the electrodes

substrate is also used to assemble all of the electronic components of our device. Specifically, both the electrode array and the test IC are attached to a core flexible circuit (i.e. the “flex” circuit) by a gold stud bump flipchip bonding technique (Gingerich et al., 2004). We have developed two generations of flexible circuits that have been microfabricated with wire-bondable, electroplated, gold traces (50 m wide; 3 m thick) within either a polyimide or parylene substrate. Parylene is a biocompatible polymer with low water absorption, which makes it ideally suited for implantation because of its ability to serve as both substrate for microfabrication and hermetic encapsulant for the embedded circuitry. The same microfabrication techniques are used to make our stimulating electrode arrays (see below).

Considerations for encapsulation of implanted microelectronic components The development of a sophisticated microelectronic prosthetic system will be useless without a means of encapsulation to prevent transport of ions and moisture. Sodium ions, even in minute quantities, and moisture would destroy the function of delicate transistors or cause short-circuits of the implant power supplies. The challenge of developing an effective hermetic barrier was originally achieved with cardiac

pacemakers, which use a titanium shell as the encapsulant. A titanium capsule, or some other such enclosure, however, is not a practical option for use inside of the eye, which is one of our reasons we changed our design to position the most delicate microelectronics outside of the sclera. Our prototype wireless prosthesis that was designed for short-term animal surgical trials was encapsulated with commercially available packaging technologies, either vapor-deposited parylene-C, medical grade silicone, or both. These materials, or the processes we are using for depositing these materials, proved to be imperfect – in vitro saline soak testing1 of our coated prototypes showed saline-induced corrosion of the exposed metal return electrode and significant blistering of the encapsulant after only 4–6 weeks (Figure 59.6). This result was not surprising in that it represented the then-current state-of-the-art for polymeric materials. Nonetheless, this approach allowed us to perform some preliminary animal trials while we were developing more effective means to encapsulate the implanted electronic components. 1

 The use of “soak testing” is a fairly standard means to test the durability of coatings used to protect electronic components in a salt water environment. For this experiment the electrodes had been immersed in physiological saline solution at constant body temperature of 375 °C. Failure of the coating is recorded as a rise in leakage current, which we can measure down to 10–13 A. “Accelerated” life testing can be used to estimate very long-term survival (10 years in the body) by placing devices in saline solution held at 87 °C.

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59.  The Development of Visual Prosthetic Devices to Restore Vision to the Blind

In consideration of human implantation, the FDA requires electronic survival of 10 years (which is estimated with “accelerated” lifetime testing). This is a significant design challenge, especially if the plan includes the goal of driving a relatively large number (100, for instance) of electrodes. Each electrode needs to have a feed wire (which connects to the stimulator chip) to deliver electrical current and each feed wire must pass through the confines of the hermetic seal. Each “feedthrough” via is a potential risk as a site for leakage of sodium ions. An alternative approach is to have only a small number of wires penetrate the hermetic encapsulant and employ an “external” demulti­plexing circuit which would then address many electrodes. But, this multiplex circuit must also be encapsulated, and in our design that encapsulation would have to be on our thin-film “flex circuit” (see above), which creates a different type of significant engineering problem. To extend the lifetime of our device, we have used a titanium shell to encapsulate the stimulator chip (Figure 59.7). This technology is fairly mature, and we have combined this technology with customized methods to achieve the capability for 100 feedthroughs (see below), which will be more than adequate to perform our initial human studies.

Figure 59.6  Highly magnified scanning electron micrographs of one of our parylene-C coated “flex circuits.” Top: Before immersion in saline. Bottom: Appearance after immersion in our saline “soak testing” environment for 3 weeks. There is obvious corrosive change in the appearance of the gold metal electrode (large yellow structure) and numerous, small moisture droplets (above the electrode) that permeated the encapsulant

Titanium Case and Feedthrough Technology Our engineering team has already developed a package design concept (Figure 59.7) that includes a 10  11  12 mm titanium enclosure that will house

Figure 59.7  Graphic image of our proposed titanium case with feedthrough connections made with a solid modeling, computer-aided design software program. A ceramic “header” containing the 18 pin-ceramic assemblies is inserted into the titanium frame case. The titanium frame is 10  11 mm

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Design and fabrication of the stimulating electrode array

the active electronics and a customized flexible substrate (i.e. “flex circuit”) that will support and interconnect the electronics within the shell (see above). Based upon feedback from our surgical team, the titanium can is contoured to match the curvature of the outer wall of the back of the eye. A second flex circuit, external to the titanium case, that is fabricated using biocompatible Ti/Au conductors serves as the interconnect circuit for the separately microfabricated electrode array (see below). The challenge of this titanium case approach is the creation of the feedthrough channels. We have approached this problem by modifying a well-honed, commercially available ceramic-based process to encapsulate platinum wire feedthrough vias (Figure 59.7). The feedthrough vias are surrounded by a thin cuff of ceramic insulation that is then surrounded by a thin ring of gold. In our initial design, 18 pin-ceramic assemblies, each of which is roughly 200 m in diameter, is inserted through a hole in a ceramic “header” which is embedded within a titanium frame. The header plus feedthrough assembly is heated at high temperature to melt the gold rings to the ceramic header to form a ceramic-to-metal seal. This braised assembly with feedthrough vias is then laser-welded to a titanium shell, which contains the stimulator circuit and discrete electronic components. These feedthrough vias connect the enclosed components to a silicone-molded external assembly of the electrode array and coils. This approach will provide our device with ample numbers (100) of feedthrough vias to enable our first round of long-term human implants. The choice of using a titanium case was initially complicated by feedback from our surgeons who reported that our initial design, which pushed the limits of fabrication to create a seemingly small package, was too tall (2 mm) for use around the outer wall of the eye. A package that is too bulky cannot be appropriately covered by the soft tissue surrounding the eye (i.e. the conjunctiva) and risks the possibility of “exposure” of the device to bacteria on the surface of the eye, which could lead to an infection around the device and potentially in the eye. One solution to the problem was to reduce the volume of the case, but the need to house some discrete electronic components (capacitors) within the case and the dimensions of the ceramic assembly (see above) imposed limitations on our ability to reduce the volume of the case. Although we slightly reduced the vertical height of the ceramic feedthrough assembly, we basically solved the problem of the too bulky case simply by placing the case more deeply into to the eye socket, where there is more room to house a device.

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Design and fabrication of the stimulating electrode array Well-established microfabrication methods make it possible to reproducibly create microelectrodes that can be used for neural stimulation (Figure 59.8. top). The use of thin film, polymeric materials (e.g. polyimide, paralyene) has been an attractive option for use in a retinal prosthesis because these films are very flexible and they have good biocompatibility properties (Montezuma et al., 2006). However, their use for applications that require long-term survival has historically been considered impractical because of their permeability of sodium ions over long periods of time. We, like many others before us, learned of this reality through soak testing experiments. More recently, the use of inorganic encapsulants, such as diamond-like carbons, has provided long-term survival properties for thin films that now make these arrays reasonable considerations for long-term use in human implants (Sweitzer et al., 2006).

Figure 59.8  Scanning electron microscopy of two different 400 m diameter, stimulation electrodes coated with electrodeposited iridium oxide. Top: Electrode with wire traces as seen after fabrication and coating processing. Bottom: Appearance after 1 week of pulsing with no evidence of damage

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59.  The Development of Visual Prosthetic Devices to Restore Vision to the Blind

Our goal is to create a human prosthesis with 100 s of electrodes. The use of this number of electrodes and the interconnecting wires has a practical limit if these elements are distributed within a single plane, given that there is a preferred limitation on the width of the surgical incision through the sclera. We have preferred to use incisions that are 3 mm long through which the electrode array is passed to reach the subretinal space. Based on our previous experience in building electrode arrays for human testing, we learned that the highest quality arrays were made with wire traces that were 50 m across, with a wire-to-wire separation of equal width. Thus, the notion of using a relatively large number of wire traces (for some fixed width of the thin-film substrate) could only be accomplished by using a multi-planar microfabrication method. Multiplanar fabrication is feasible but it creates its own set of problems in that each wire trace, now at multiple levels, must be encapsulated to prevent the development of short circuits, which would develop if sodium ions were to penetrate the polyimide substrate, which would almost certainly occur over a long period of time.

Iridium oxide electrodes The FDA has mandated that retinal prosthetic devices be capable of surviving for longer than 10 years in the body, as judged by accelerated lifetime environment testing (at 87 °C). This is a significant challenge, especially given that the device must pass moderately high levels of current, which are needed to activate retinas of blind patients (Rizzo, Loewenstein et al., 2003; Mahadevappa et al., 2005; Hornig et al., 2007). To achieve this demanding goal, we chose to fabricate iridium oxide (IrOx) electrodes (Figure 59.8, bottom), which have substantially greater charge-carrying capacity than do platinum electrodes (Robblee et al., 1983), which is the current standard for bio-implantable devices. Use of IrOx or similar low impedance coating is valuable for the implementation of a retinal prosthesis because this approach will permit use of arrays with much smaller electrodes that will be able to deliver higher levels of charge more safely than would be the case with electrodes made with noble metals (Robblee et al., 1983). However, the methods of reliably applying the oxide coating and the methods for sustaining the integrity of these electrodes are not widely known or practiced. We explored the various methods of fabrication of IrOx electrodes including: (1) activation of iridium

Figure 59.9  Comparison of cyclic voltammograms of electro-deposited iridium oxide (EIROF) on a multi-electrode array intended for retinal prostheses. The EIROF was pulsed for 700 hr without degradation. This tracing was obtained with the electrode shown in Figure 59.8, bottom

metal (AIROF); (2) electro-deposition from aqueous solutions containing Ir  3/Ir  4 ions (EIROF); and (3) reactive sputtering from iridium metal (SIROF). With these techniques, we have successfully developed durable IrOx electrodes that can pass high charge density. We have demonstrated that our IrOx films made on flexible polyimide multi-electrode arrays can be pulsed in an inorganic in vitro model of cerebrospinal fluid (CSF) for at least 700 hours without degradation at charge per phase levels (1.2 C/phase) that were many times above perceptual thresholds in blind humans (Figure 59.9) (Rizzo, Loewenstein et al., 2003; Mahadevappa et al., 2005; Hornig et al., 2007). As such, it appears that IrOx electrodes are practical for use with a retinal prosthesis. These and other engineering elements must be combined to create a fully working, implantable device. Some important aspects needed for a fully functioning device, like the methods for RF communication, have not been addressed in this brief summary but are as integral to success as some of the topics that have been included. In addition to the individual challenge of each engineering aspect to the design, the various components must be integrated and the “assembly and packaging” presents its own set of technical challenges. Much of the success for assembly and packaging relates to the use of numerous steps that are most appropriately described as being in the realm of “technical know-how” rather than novel scientific advances. For a complicated device like a retinal prosthesis, “know-how” can be as important as some of the fundamental scientific methods that are incorporated into the device.

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Methods of surgical implantation

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Figure 59.10  Digital renditions of a side view of the back of the eye to demonstrate some basic steps of the ab externo surgical technique used by Boston Retinal Implant Project to implant subretinal electrode arrays. Left: Surgery begins by making a flap on the sclera for insertion of electrode array into the eye; a fluid-filled retinal bleb is raised (arrow) to move the retina (pink layer, shown at green arrow) away from the site of insertion. A guide (yellow line) that will be used to assist with the insertion of the electrode array is introduced through the choroid (white arrow). Middle: The electrode array (white arrow) is inserted under the guide. The retinal bleb deflates following puncture through the choroid. Right: The guide is removed, and the scleral flap is sutured closed (not shown)

Methods of surgical implantation To provide a proof-of-concept demonstration of the efficacy of a prosthesis, the device needs to survive implantation and function properly thereafter. The eye always responds to intraocular surgery with some degree of inflammation, which is typically short-lived and well-controlled by use of anti-inflammatory eye drops. Performing intraocular surgery also carries the potential risk of creating an intraocular infection (i.e. endophthalmitis), which can be devastating and result in the need to remove a blind and painful eye. As such, the design of the device and the development of the surgical methods to implant the device should be created with the goal of minimizing the potential for adverse biological reactions. The design of our prosthetic system is partially motivated by a desire to minimize the amount of surgery that needs to be performed and the amount of foreign material that is placed into the eye. We use a minimally invasive, ab externo surgical approach (from the Latin, meaning “from the outside,” in this case indicating that our approach to the retina is from the outside of the sclera rather than through the inner vitreous cavity) to introduce the electrode array through the back wall of the eye, which avoids the need to pass the array through the interior of the eye to reach the subretinal space (Figure 59.10) (Sun et al., 2004). We have experimented with several design architectures in this regard and our present device is designed to maintain almost the entire bulk of the device outside and around the back of the eyeball (see Figure 59.3). The need for less intraocular surgery should enhance the biocompatibility of our device by minimizing

Figure 59.11  Photograph of the retina of a pig eye which had received a subretinal electrode array implant 3 months previously. The eye showed no visible inflammation, and the device remained in position during the period of follow-up

the amount of intraocular surgery that is required to implant the device. Our approach to the subretinal space (by entering around the back of the eye) is complicated by the need to traverse the choroid, which is the most vascularized tissue in the body and thus prone to hemorrhage. Over time, we have learned to substantially minimize the potential for hemorrhaging by (gently) cauterizing the choroidal surface. Our surgical methods have evolved gradually to yield improved safety and reliability of the implantation. Presently, we are able to implant the electrode arrays into pig eyes with a 90% success rate, which is judged by the lack of any obvious injury to the eye or retina and the lack of any obvious postoperative inflammation (Figure 59.11). In those cases in which the

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59.  The Development of Visual Prosthetic Devices to Restore Vision to the Blind

implant was implanted without significant complications, the histological studies of these eyes three months later have shown equally promising results (see below). The ability to perform histological and other studies of these implants provides important “pre-clinical” information that the FDA will use to consider the appropriateness of allowing long-term human implants.

Ocular biocompatibility There are only two studies of the biological responses to the implanted materials, and both of these studies have examined reactions on the subretinal side (Montezuma et al., 2006; Sweitzer et al., 2006). With respect to the response of the eye and retina to the implanted materials themselves, our group has studied the biological reactions induced by 3-month implantations of six materials into the subretinal space of 24 pigs (four control animals were also studied). These materials, which were chosen because of their potential use in a prosthesis, included: plain polyimide, or polyimide coated with amorphous aluminum oxide; amorphous carbon (AC); parylene; poly(vinyl pyrrolidone) (PVP); or poly(ethylene glycol) (PEG). We studied 15 criteria to survey the histological responses of the eye. All implants produced some pathology, but arrays coated with AC, parylene, PVP, and PEG fared the best, producing reactions only 10 m thick (Montezuma et al., 2006). This outcome is more favorable than we had anticipated. Two examples of common findings from our studies are shown in Figure 59.12. Only a couple of studies have addressed the biological responses to electrical stimulation (Shah et al.,

2006; Colodetti et al., 2007). None of these studies is exhaustive, and the available studies have only been performed on the epiretinal side, where it is more difficult to obtain a flush apposition of the stimulating electrodes to the retina. Only a small separation between the two can greatly diminish the apparent consequences of stimulation on the retina and thus provide false reassurance of the potential for electrically induced damage. Hence, the available studies have the potential to underestimate the potential for electrical-induced damage to the retina. One study provided evidence that electrical stimulation (0.09 MC/phase) for only one hour (at 100 Hz) increases the amount of damage to the retina over what occurs simply from the mechanical effects of electrode placement on the inner retinal surface (Colodetti et al., 2007).

Human test results to date Human testing of the psychophysical effects of electrical stimulation of the retina has been performed by five groups worldwide (two from the USA; three from Germany), of which four have performed longterm studies that have lasted for at least 30 days. One group has also performed electrical stimulation of the optic nerve of a blind patient (Veraart et al., 2003; Duret et al., 2006). Most of the long-term studies have been performed by companies and most of the results are not yet being openly discussed. Despite this limitation, it is possible to draw several important general conclusions from this body of work. First, the most fundamental achievement of these studies is the determination of the psychophysical

Figure 59.12  Histology of pig retinae 3 months after subretinal implantation of coated, non-electronic implants (red arrows). Left: Relatively little anatomical alteration following implantation of parylene. Right: Retinal pigment epithelial (RPE) cell clumping (arrow) over a polyimide implant. The implants were 0.5  0.5 mm strips and 10 m thick. Hematoxylin and eosin stain

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Human test results to date

threshold. Many studies have reported the threshold for creation of visual percept by electrical stimulation to be less than 1 mC/cm2. At this threshold, most scientists would likely agree, long-term electrical stimulation of the retina can probably be performed safely assuming that effective charge-balancing of stimulation is achieved (Humayun, 2003; Mahadevappa et al., 2005; Yanai et al., 2007; Richard et al., 2008). The lowest average perceptual threshold for a given patient has been 24 nC/phase (delivered through 250 m diameter electrode, which yields a (quite low) charge density of 50 C/cm2 (Mahadevappa et al., 2005). The single lowest threshold from this same work was 12 nC/ phase, although in this same article the thresholds from the two other patients were substantially higher. The thresholds were also quite variable among their patients. Some threshold values have approached 1 mC/cm2 (Mahadevappa et al., 2005). Another group that also performed epiretinal stimulation reported thresholds that ranged from 0.2 to 1.4 mC/cm2 among 19 of their patients from whom they obtained perceptual thresholds (Hornig et al., 2007). Secondly, the psychophysical thresholds have been significantly higher (often four times higher) for patients who are blind from RP compared to normally sighted patients (Humayun et al., 1996; Rizzo, Loewenstein et al., 2003). This discrepancy might be the result of pathology that develops in degenerated retinas (Marc and Jones, 2003; Marc et al., 2003), among other factors. The high stimulation thresholds are worrisome given that there is greater risk that electrical stimulation might damage the neural substrate. Following implantation of electrode arrays, thresholds

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typically change, sometimes declining and sometimes increasing (Humayun et al., 1996). For epiretinal stimulation, elevation of thresholds after months of implantation (Mahadevappa et al., 2005) could be explained by increased separation between the stimulating electrodes and the retina, given that the activation thresholds for neurons increase as the square of the distance from the stimulating electrode (Jensen et al., 2003). Long-term thresholds from subretinal stimulation have not yet been reported. From a design standpoint, the most favorable outcome in terms of lowering stimulation thresholds would likely be attained by placing the stimulating electrodes as close to the neural elements as possible. There are challenges for minimizing the distance between stimulating electrode and retinal neurons on either side of the retina. As mentioned above, on the epiretinal side, it is difficult to obtain conformal alignment of electrodes over a wide area of the curved epiretinal surface. All approaches to date on the epiretinal side have relied on tacks to implant the electrode arrays onto the retinal surface, but this approach cannot easily achieve conformal alignment over a wide stretch of the cantilevered segment and the tacks have the potential to loosen (or even separate) from their mooring. On the subretinal side, the potential for development of a subretinal glial scar could increase the resistivity of the tissue by creating a potential physical separation between the electrodes and the retinal neurons. Some of the physical constraints could potentially be ameliorated by the use of neurotrophic factors, which has been demonstrated to effectively reduce electrical stimulation thresholds in degenerated retinas (Kent et al., 2008).

Figure 59.13  Psychophysical result from one trial of electrical stimulation of the retina in one of our legally blind patients. Left: Schematic of the electrode array, showing the pattern of stimulation delivered to the retina through four (400 m diameter) electrodes, shown within the red box. Right: Drawing by the patient of the percept that was elicited by the stimulus

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59.  The Development of Visual Prosthetic Devices to Restore Vision to the Blind

In addition to the threshold results, a considerable body of qualitative information has been obtained from human patients (Dagnelie, 2008). In our own acute human trials, our best outcomes occurred when patients provided a description of the geometry of the percepts that at least coarsely matched the geometric pattern of electrical stimulation that was delivered to the retina (Figure 59.13). In our studies, no patient could recognize a percept as detailed as a letter. Many reasons could have explained this limitation in our outcomes. The fact that our one normally sighted volunteer fared similarly provided evidence that our (undoubtedly) suboptimal stimulus parameters accounted for the inability to create more spatially detailed vision (Rizzo, Loewenstein et al., 2003; Rizzo, Wyatt et al., 2003). Clearly, short-term testing (lasting only hours) does not provide sufficient time for patients to begin to learn how to interpret the new artificial percepts. Longer testing time would also provide the researchers with opportunities to try many stimulus paradigms to learn which methods produced the most desirable results. These beliefs raised optimism about the potential for the longer-term “chronic” studies of human patients. The first group to perform chronic human testing was Optobionics, Inc. (Wheaton, IL), which developed a photodiode array that has been implanted into the eyes of 12 patients who were blind from RP (Chow et al., 2004). This device was designed to operate only from the power of incident light reaching the retina, which was widely considered to be insufficient to drive retinal neurons (DeMarco et al., 2007). The intensity of light needed to drive the retinal neurons was excessive (similar to the brightness of the summer sun at noon) for practical use of the device (DeMarco et al., 2007). This company declared bankruptcy in 2007 and no new information is available from the roughly 20 patients who had been implanted with their devices. The longer-term studies from the other three companies that have performed chronic implantations in humans have produced an array of results that substantiate and extend the results of the earlier shortterm tests. Collectively, the results show, without question, that humans who have been severely blind for decades can see images in response to electrical stimulation of the retina and that these percepts vary in response to modifications of the stimulus paradigms, including variations in the strength and duration of the stimuli and with respect to the size and number of electrodes that are used for stimulation (Humayun et al., 1996, 2003; Mahadevappa et al., 2005; Yanai et al., 2007; Zrenner et al., 2007; Richard et al., 2008). The first group to report information on the qualitative outcomes of stimulation experiments was the Second Sight Medical Products Co. (Table 59.1). Some

of their patients have been able to identify: (1) which of the two electrodes had been activated in a two-point discrimination task; (2) the direction of “movement” when electrodes were activated sequentially in a particular direction; and (3) whether electrodes were activated in rows or columns (Weiland et al., 2004; Yanai et al., 2007). The perceptual detail that could be extracted by the patients increased considerably when they were allowed to move their head to scan the visual field. With scanning, the subjects could, for instance, locate and count the number of objects that were presented to them and identify the orientation of the long limb of the letter “L” (Yanai et al., 2007). Interestingly, the patients failed to perform better than chance when they had to keep their head stationary. Patients are now being allowed to use the second generation device outside of the laboratory. Scientific data has not yet been presented on the functional value of the device to the patients, although non-scientific statements by some of the patients are clearly very positive. Intelligent Medical Implants (IMI, based in Zug, Switzerland) has also developed an epiretinal prosthesis that incorporates a thin-film electrode array. This company is currently in the process of performing a multicenter clinical trial in Europe. Their preliminary reports on this work included perceptual descriptions by patients that included their ability to ascertain different impressions of their brightness, shape, color, and duration of stimuli. With practice, the patients became able to differentiate the localization of stimuli and to recognize basic patterns such as lines and spots, and detect motion (Hornig et al., 2007). Generally similar qualitative results have been obtained by Retina Implant AG, which is using a subretinal approach to stimulate the retina (Wickelgren, 2006; Zrenner et al., 2006, 2007; Zrenner, 2007). The prosthesis made by the Retina Implant AG company incorporates a supplemental power source to help drive the output of a subretinal photodiode array, with 1500 light-sensitive elements and also a 4  4 array of hard-wired electrodes. Experiments conducted by photic activation of the photodiode array allowed three patients to perceive light in certain shapes and patterns. Percepts elicited by the photodiode array were studied by using a scanning laser ophthalmoscope to selectively drive small areas of the chip with incident light; with this technique, some patients detected single spots of light of only 100–400 m in diameter. One patient was able to locate white dinner plates on a dark tablecloth (Zrenner et al., 2006). Only one of the two groups that are working on an optic nerve prosthesis has performed longterm human tests (Veraart et al., 2003; Duret et al., 2006). This group, led by Veraart and Delbeke, have

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Significant long-term problems

performed implants of a cuff with four electrodes that has been placed around the optic nerve of two patients with RP. Using a camera-based system to capture visual images, their two patients have been able to assess perceptual attributes such as the shape, size, basic structure, location, and brightness of the electrically induced phosphenes. One of their patients has retained the ability to provide this type of detail for the several years over which she has been tested. Collectively, long-term human testing of prosthetic devices has clearly shown that: (1) severely blind patients can see phosphenes in response to electrical stimulation of the retina or optic nerve; and (2) variation in the electrical stimulus paradigms modifies the perceptual experiences of the patients. Although the perceptual results have generally been crude (from a spatial standpoint), patients with either a retinal or optic nerve prosthesis have been able to identify the location of an object on a table and reach out and grab the object. This achievement could easily be undervalued unless one appreciates the severity of the compromises that severely blind patients experience in many of the tasks of everyday living. As mentioned at the beginning of this chapter, the target patient populations for visual prosthetic devices suffer from blinding conditions for which there are no available treatments. The ability to improve the quality of life for severely blind patients, if only to help them deal with their routine daily activities like taking a walk, would be an enormous achievement for this field of research, which is still in its formative years, given that the sophisticated implantable devices that are being tested have been available for only a handful of years. At this time, the question of whether visual prosthetic devices will be able to truly improve the quality of life for blind patients in their home and local environments remains unproven, but the early results are in some ways quite encouraging. No group has yet demonstrated visual detail that even remotely approximates normal visual detail, but as was true in the history of cochlear implants (Gates and Miyamoto, 2003), accrued experience in learning how to deliver electrical stimulation of the retina has a reasonably good chance of eventually producing a level of vision that would justify the widespread recommendation of physicians to consider some form of visual prosthetic device.

Significant long-term problems Several significant engineering and biological challenges still confront this emerging field of research. Although there would undoubtedly be considerable

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debate about which problems are most worrisome, there would probably be consensus on the following considerations, which impact almost every group working in this field. The notion of using a visual prosthesis conjures images of creating spatially detailed vision, which leads to the concept of using a large number (hundreds or perhaps thousands) of stimulating electrodes. However, there are quite significant engineering challenges to develop such a device for the eye, including the problem of being able to individually address such a large number of electrodes, which for hard-wired electrodes, must be done either by developing very high-density hermetic feedthrough channels (much higher density than currently available) or by employing demultiplexing circuits in relatively thin film, which creates its own problems in terms of hermetic encapsulation. Further, use of such a large number of electrodes would almost certainly be combined with the use of relatively small electrodes, which depending upon the positioning with respect to the neurons, would need to be made of materials that could safely accommodate the relatively higher-charge densities that would develop with the smaller surface areas of the electrodes. However challenging these problems might appear at present, it is very likely that engineering solutions will become available to address these issues over the next decade or so. Given these challenges, the idea of using embedded photodiode arrays with very small stimulating electrodes, as is being done by Daniel Palanker, PhD and his group at Stanford University and by E. Zrenner in Tübingen, Germany (Brueckner et al., 2002; Loudin et al., 2007) offers an appealing strategy to use incoming light to deliver high density electrical stimulation to the retina in a pattern that conforms to the visual landscape. It should also be appreciated that the field has not yet convincingly demonstrated that long-term electrical stimulation of the retina will not eventually lead to neuronal cell death. The major long-term problem, it seems, is the challenge of learning how to use the electronically sophisticated implants to create vision. We have learned, mostly from the studies of Robert Marc about the significant degree of “reorganization” that occurs in the retina in response to blindness (Marc and Jones, 2003; Marc et al., 2003), and there are significant (although different) changes related to neural “plasticity” that occur in the visual cortex of humans who become blind from age-related macular degeneration and retinitis pigmentosa (Ferrandez et al., 2003; Ptito et al., 2005; Poggel, 2006). Somehow, we must learn how to deliver electrical impulses in a manner that the brain will ultimately learn to interpret as a useful visual percept. To date, no group has convincingly demonstrated

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that the quality of life for blind patients can be improved by using a retinal prosthesis, or that such a device justifies the risks that are attendant with longterm implantation of a device. The lack of success in this regard should not be taken as evidence of a failure given that the attempts to study the potential benefits to blind patients have only recently begun. Biological considerations define what attributes are needed from an implantable device that is designed to restore vision to blind patients. Engineering initiatives enable the opportunities to restore vision by creating the sophisticated devices to interface with this visual pathway. To enjoy success, the fields of engineering and biology must continue to work together for much longer to merge their intellectual and scientific resources within well-focused, multidisciplinary consortia, as have now developed in numerous countries throughout the world.

Conclusion The major early achievements of the field of visual prosthetic research include the demonstration that: (1) severely blind patients can be made to see phosphenes; (2) the appearance of the phosphenes can be influenced by the electrical stimulus parameters; and (3) fairly sophisticated microelectronic devices can be implanted into and around the eye without inducing obviously adverse biological consequences. These three achievements clearly justify continued commitment to develop visual prosthetics, especially given that there are no alternative treatments to restore vision to patients who have suffered acquired forms of neural blindness. Much of the early success has come from engineering contributions, although the general demonstration of reasonably good biocompatibility of implanted devices has reduced concerns about the safety of long-term implantation of foreign materials into the eye. The greatest future challenges will likely lie in the biological realm, mostly with respect to learning how to deliver electrical stimulation to create vision that will be helpful to blind patients.

References Abe, T., Yoshida, M., Yoshioka, Y. et al. (2007) Iris pigment epithelial cell transplantation for degenerative retinal diseases. Prog. Retin. Eye Res. 26: 302–21. Acland, G.M., Aguirre, G.D., Ray, J. et al. (2001) Gene therapy restores vision in a canine model of childhood blindness. Nat. Genet. 28: 92–5. Algvere, P.V., Berglin, L., Gouras, P., Sheng, Y. and Kopp, E.D. (1997) Transplantation of RPE in age-related macular degeneration: observations in disciform lesions and dry RPE atrophy. Graefes Arch. Clin. Exp. Ophthalmol. 235: 149–58.

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after retinal sheet transplantation in retinitis pigmentosa patients. Am. J. Ophthalmol. 128: 384–7. Radtke, N.D., Aramant, R.B., Seiler, M.J., Petry, H.M. and Pidwell, D. (2004) Vision change after sheet transplant of fetal retina with retinal pigment epithelium to a patient with retinitis pigmentosa. Arch. Ophthalmol. 122: 1159–65. Radtke, N.D., Seiler, M.J., Aramant, R.B., Petry, H.M. and Pidwell, D.J. (2002) Transplantation of intact sheets of fetal neural retina with its retinal pigment epithelium in retinitis pigmentosa patients. Am. J. Ophthalmol. 133: 544–50. Rein, D.B., Zhang, P., Wirth, K.E. et al. (2006) The economic burden of major adult visual disorders in the United States. Arch. Ophthalmol. 124: 1754–60. Resnikoff, S., Pascolini, D., Etya’ale, D. et al. (2004) Global data on visual impairment in the year 2002. Bull. World Health Org. 82: 844–51. Richard, G., Keserue, M., Feucht, M., Post, N. and Hornig, R. (2008) Visual perception after long-term implantation of a retinal implant. Invest. Ophthalmol. Vis. Sci. 49, E-Abstract 1786. Rizzo, J., Loewenstein, J., Kelly, S. and Shire, D. (2003) Methods and perceptual thresholds for short-term electrical stimulation of human retina with microelectrode arrays. Invest. Ophthalmol. Vis. Sci. 44: 5355–61. Rizzo, J.F., III, Wyatt, J., Humayun, M. et al. (2001) Retinal prosthesis: an encouraging first decade with major challenges ahead. Ophthalmology 108: 13–14. Rizzo, J., Wyatt, J., Loewenstein, J., Kelly, S. and Shire, D. (2003) Perceptual efficacy of electrical stimulation of human retina with a microelectrode array during short-term surgical trials. Invest. Ophthalmol. Vis. Sci. 44: 5362–9. Robblee, L., Lefko, J. and Brummer, S. (1983) Activated Ir: an electrode suitable for reversible charge injection in saline. J. Electrochem. Soc. 130: 731–3. Sagdullaev, B.T., Aramant, R.B., Seiler, M.J., Woch, G. and McCall, M.A. (2003) Retinal transplantation-induced recovery of retinotectal visual function in a rodent model of retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 44: 1686–95. Shah, H.A., Montezuma, S.R. and Rizzo, J.F., 3rd (2006) In vivo electrical stimulation of rabbit retina: effect of stimulus duration and electrical field orientation. Exp. Eye Res. 83: 247–54. Sieving, P.A., Caruso, R.C., Tao, W. et al. (2006) Ciliary neurotrophic factor (CNTF) for human retinal degeneration: phase I trial of CNTF delivered by encapsulated cell intraocular implants. Proc. Natl Acad. Sci. U S A 103: 3896–901. Sun, J., Montezuma, S., Loewenstein, J. and Rizzo, J. (2004) Progress toward minimally invasive, ab externo technique for subretinal prosthetic implantation. Invest. Ophthalmol. Vis. Sci. 45, E-Abstract 4190.. Sweitzer, R., Scholz, C., Montezuma, S. and Rizzo, J.F., 3rd (2006) Evaluation of subretinal implants coated with amorphous aluminum oxide and diamond-like carbon. J. Bioact. Compat. Polymers, 21: 5–22. Theogarajan, L. (2007) Supramolecular architectures for neural prostheses. Electrical Engineering and computer science. PhD thesis, Massachusetts Institute of Technology, Cambridge, MA. Veraart, C., Wanet-Defalque, M.C., Gerard, B., Vanlierde, A. and Delbeke, J. (2003) Pattern recognition with the optic nerve visual prosthesis. Artif. Organs 27: 996–1004. Weiland, J.D., Yanai, D., Mahadevappa, M. et al. (2004) Visual task performance in blind humans with retinal prosthetic implants. Conf. Proc. IEEE Eng. Med. Biol. Soc. 6: 4172–3. Weisz, J.M., Humayun, M.S., De Juan, E., Jr. et al. (1999) Allogenic fetal retinal pigment epithelial cell transplant in a patient with geographic atrophy. Retina 19: 540–5.

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Wickelgren, I. (2006) Biomedical engineering. A vision for the blind. Science 312: 1124–6. Yanai, D., Weiland, J.D., Mahadevappa, M., Greenberg, R.J., Fine, I. and Humayun, M.S. (2007) Visual performance using a retinal prosthesis in three subjects with retinitis pigmentosa. Am. J. Ophthalmol. 143: 820–7. Zeiss, C.J., Allore, H.G., Towle, V. and Tao, W. (2006) CNTF induces dose-dependent alterations in retinal morphology in normal and rcd-1 canine retina. Exp. Eye Res. 82: 395–404. Zrenner, E. (2002) Will retinal implants restore vision? Science 295: 1022.

Zrenner, E. (2007) Restoring neuroretinal function: new potentials. Doc. Ophthalmol. 200: 56–9. Zrenner, E., Besch, D., Bartz–Schmidt, K. et al. (2006) Subretinal chronic multi-electrode arrays implanted in blind patients. Invest. Ophthalmol. Vis. Sci. 47, E-Abstract 1538. Zrenner, E., Wilke, R., Zabel, T. et al. (2007) Psychometric analysis of visual sensations mediated by subretinal microelectrode arrays implanted into blind retinitis pigmentosa patients. Invest. Ophthalmol. Vis. Sci. 48, E-Abstract 659.

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C H A P T E R

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Stimulation for Return of Function after Stroke John Chae, Jayme Knutson, and Lynne R. Sheffler

o u t l i n e Introduction

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Motor Relearning Upper Limb Applications Lower Limb Applications

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Shoulder Pain Surface NMES Intramuscular NMES

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to provide function. This chapter addresses two major therapeutic applications. The first is the use of NMESmediated repetitive movement training for motor relearning, defined as “the recovery of previously learned motor skills that have been lost following localized damage to the central nervous system” (Lee and van Donkelaar, 1995). The second is the use of NMES for the treatment of post-stroke shoulder pain. Functional application, also known as functional electrical stimulation (FES), refers to the use of NMES to activate paralyzed muscles in precise sequence and intensity so as to directly accomplish functional tasks. A neuroprosthesis is a device or system that provides FES. This chapter reviews the development and effectiveness of upper and lower limb neuroprostheses for self-care tasks and mobility, respectively. Specific clinical indications and contraindications will be presented in the context of each application.

Stroke is the leading cause of disability or activity limitation among older adults in the United States. More than 700,000 strokes occur each year, with a prevalence of approximately 4 million (AHA, 1997). Hemiparesis or motor impairment of one side of the body is a major consequence of stroke and is associated with significant activities limitation and reduction of quality of life. This chapter reviews the clinical uses of neuromuscular electrical stimulation (NMES) to mitigate the effects of motor impairment following stroke. NMES refers to the electrical stimulation of an intact lower motor neuron (LMN) to contract paralyzed or paretic muscles. Clinical applications of NMES in stroke rehabilitation provide either a therapeutic or functional benefit. Therapeutic applications of NMES are to produce specific effects that may enhance function, not directly

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60.  Stimulation for return of function after stroke

However, there are several general contraindications that are relevant to all NMES applications. Absolute contraindications include demand pacemakers, implanted defibrillators, and severely impaired cognition. Although the effect of electrical stimulation on the fetus is not known, pregnancy should be considered an absolute contraindication. NMES should be applied to individuals with insensate skin with caution and frequent monitoring for electrical burns. Other frequently cited “contraindications” include cardiac arrhythmias and seizure disorders. However, the theoretical and empirical rationale for these “contraindications” has not been well documented.

Motor relearning Emerging basic and clinical data suggest that repetitive movements that are novel, goal-oriented, and functionally relevant facilitate motor relearning following stroke or brain injury (Nudo et al., 2001). The use of NMES for motor relearning is based on the premise, if novel, goal-oriented repetitive movement therapy facilitates motor relearning, NMES-mediated goal-oriented repetitive movement therapy may also facilitate motor relearning. For a complete presentation of the theoretical basis for electrical stimulation for motor relearning, the reader is directed to a recent comprehensive review (Sheffler and Chae, 2007).

Upper Limb Applications The use of NMES to achieve upper limb motor relearning in hemiplegia has been the topic of numerous studies over the past 20 years. Three NMES paradigms have been used for upper limb motor relearning: cyclic NMES, EMG-triggered NMES, and neuroprosthetic NMES. The main feature that distinguishes these paradigms is the method by which the patient controls the electrical stimulation. In cyclic NMES, stimulation activates the paretic muscles according to a preset duty cycle and with preprogrammed intensities. Surface electrodes are typically placed over the motor points of the finger and wrist extensors. The individual has no role in controlling the stimulation. The approach is indicated for persons with some or no residual motor function. Several randomized clinical trials investigating the efficacy of cyclic surface NMES in enhancing upper limb motor recovery have been reported (de Kroon et al., 2002, 2005). In EMG-triggered NMES, the stimulation is provided only when the patient produces a suprathreshold

electromyographic (EMG) signal by contracting the paretic muscle, at least partially. Once a suprathreshold EMG burst is detected, the stimulation produces wrist extension and/or hand opening for a preprogrammed number of seconds. The same surface electrodes that detect the EMG signal also provide the stimulation. This approach is indicated for patients who can partially activate a paretic muscle but are unable to generate sufficient muscle contraction for adequate exercise or function. Whereas the patient is a passive participant when using cyclic NMES, EMG-triggered NMES requires greater cognitive investment, which may result in greater therapeutic benefit. There are several FDA-approved EMG-triggered NMES devices on the market, including Neuromove NM900 (Zynex Medical, Inc., Littleton, CO), Care ETS (Care Rehab and Orthopaedic Products, Inc., Mclean, VA), and Biomove 3000 (Curatronic Ltd, Heshmonayim, Israel). The initial survey of the literature suggested that cyclic and EMG-triggered NMES were efficacious in reducing motor impairment, but not activities limitation (de Kroon et al., 2002). The review suggested that the effect was more significant for those with milder motor impairments. A follow-up review by the same group further suggested that EMG-triggered NMES was more effective than cyclic NMES (de Kroon et al., 2005). However, a more recent meta-analysis concluded that EMG-triggered NMES was no more efficacious than “usual care” (Meilink et al., 2008). They did note that most studies were with chronic stroke survivors and results might be different for acute stroke survivors. Consistent with this more recent conclusion, two small randomized clinical trial failed to demonstrate the superiority of EMG mediated NMES over cyclic NMES (de Kroon and IJzerman, 2008) or usual care (Chae et al., in press) among chronic stroke survivors. While acute studies are ongoing, at present, there does not appear to be sufficient evidence that cyclic and EMG mediated NMES are efficacious in facilitating upper limb motor relearning among chronic stroke survivors. A third paradigm for upper extremity motor relearning is the use of NMES as a neuroprosthesis. In this strategy, repetitive movement training is performed in the context of meaningful, functional behavioral tasks. This paradigm has a theoretical advantage over both cyclic and EMG-triggered NMES because it incorporates tasks that are meaningful to the patient and require skill development. Studies evaluating hand neuroprostheses for persons with hemiplegia are reviewed later in the chapter. Although the primary objective of these studies was to demonstrate a neuroprosthetic effect, nearly all reported some evidence of improved motor ability when the device was turned off. An early study by Alon and associates reported significant motor

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relearning effect after 5 weeks of training with a hybrid orthosis-surface NMES neuroprosthesis (Alon et al., 2003). Two follow-up preliminary randomized clinical trials yielded results consistent with these earlier findings (Alon et al., 2007, 2008). A third randomized clinical trial of multichannel NMES also resulted in significant improvement in upper limb motor function (Thrasher et al., 2008). Several novel neuroprosthesis approaches with encouraging preliminary results are presently being explored, including implantable microstimulators (Turk et al., 2008), contralaterally controlled surface electrical stimulation (Knutson et al., 2009) and the incorpor­ ation of work stations (Kowalczewski et al., 2007).

Lower Limb Applications The potential motor relearning effect of NMES in lower limb post-stroke rehabilitation was first described in 1961. W.T. Liberson noted, “On several occasions we observed, after training with the electrophysiologic brace [peroneal nerve stimulator] … patients acquire the ability of dorsiflexing the foot by themselves” (Liberson et al., 1961: 103). Since then, controlled studies using single- or dual-channel surface cyclic NMES have corroborated these findings (Sheffler and Chae, 2007). In a recent double-blind randomized clinical trial, Yan and associates (2005) reported that cyclic NMES reduces spasticity, strengthens ankle dorsiflexors, reduces ankle dorsiflexors/ plantarflexor co-contractions, improves mobility and increases home discharge rate after acute inpatient stroke rehabilitation. Since gait deviation in hemiplegia is not limited to ankle dysfunction, multichannel surface stimulation systems have been investigated. However, as the number of electrodes increases, surface systems become increasingly difficult to implement clinically due to difficulty of donning and doffing of multiple electrodes, pain of stimulation and poor reliability of electrode placement and muscle contractions. Accordingly, multichannel percutaneous systems are presently being explored for motor relearning (Daly et al., 2006). Although there are theoretical bases for expecting that neuroprostheses and EMG or biofeedback NMES would be more effective than cyclic NMES, there are no direct comparison studies demonstrating the superiority of one over the other. Nevertheless, to date, the weight of the scientific evidence suggests that lower limb NMES-mediated repetitive movement therapy reduces motor impairment in hemiplegia. A recent meta-analysis concluded that as a motor relearning tool, “FES is effective at improving gait speed in subjects post-stroke”(Robbins et al., 2006: 853).

In summary, there are now numerous controlled studies evaluating the efficacy of NMES in facilitating motor relearning among stroke survivors. Although earlier studies suggested that cyclic and EMG-­mediated NNMES reduces upper limb motor relearning, more recent data, especially among chronic stroke survivors, raise considerable doubts regarding their therapeutic benefits. These approaches may be efficacious among acute stroke survivors, but there are insufficient data to confirm this. While the efficacy of cyclic and EMGmediated NMES in facilitating motor relearning remains uncertain, the implementation of neuroprostheses will likely have significant clinical impact due to the higher functional content. Future studies should focus on identifying the optimum dose and the patient characteristics predictive of successful treatment outcomes. Trials should be substantially larger, with more rigorous methodology, outcomes that focus on function and quality of life, and designs that demonstrate effectiveness.

Shoulder pain Nearly a third of all stroke survivors experience shoulder pain during the course of their recovery (Lindgren et al., 2007). The exact etiology of post-stroke shoulder pain is unknown. However, given the high mobility of the glenohumeral joint and reliance on muscles for its stability, the role of motor impairment in its pathogenesis is likely. Figure 60.1 shows a theoretical framework describing the genesis and maintenance of hemiplegic shoulder pain (Sheffler and Chae, 2007).

Surface NMES The use of NMES to reduce glenohumeral subluxation and improve biomechanical integrity and thereby reduce pain is a promising treatment option. Numerous randomized clinical trials of surface NMES have been reported, which are reviewed in greater depth elsewhere (Sheffler and Chae, 2007). In general, these studies enrolled stroke survivors within 3 months of their stroke. They exhibited moderate to severe shoulder pain with glenohumeral subluxation. Posterior deltoid and the supraspinatus muscles were most commonly stimulated. Skilled personnel ensured reliability of electrode placement and muscle contraction. Patients were treated for up to 6 hours a day for up to 6 weeks. Improvement in subluxation was the most consistent findings while some studies also showed improvements in pain-free range of motion and motor impairment. Two meta-analyses have been reported. The Cochrane review (Price and Pandyan, 2001) concluded

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Figure 60.1  Theoretical framework describing the genesis and maintenance of hemiplegic shoulder pain (Reproduced with kind permission from Sheffler and Chae, Muscle Nerve (2007). John Wiley & Sons Ltd)

that NMES improves pain-free range of motion and reduces subluxation. Ada and Foongchomechey (2002) concluded that NMES reduces or prevents subluxation and improves motor impairment in the acute phase, but not in the chronic phase. Based on the available data, surface NMES is indicated for stroke survivors with moderate to severe shoulder pain who exhibit glenohumeral subluxation. Surface NMES may also be effective in preventing the development of glenohumeral subluxation and the emergence of pain. Whether surface NMES is effective for treating post-stroke shoulder pain without glenohumeral subluxation remains uncertain.

Intramuscular NMES Despite the evidence for therapeutic benefit, the clinical use of surface NMES for shoulder subluxation and pain has been limited due to discomfort of surface stimulation and difficulty with reliable electrode placement. In order to address these limitations, two intramuscular NMES systems are under development: an injectable microstimulator system with an external antenna and a percutaneous system with an external stimulator. The injectable microstimulator functions as stimulator, electrode, and receiver and is injected into or near the target neural tissue via a minimally invasive procedure. A recent case report suggested the effectiveness of the microstimulator for the treatment of post-stroke shoulder subluxation and pain (Shimada et al., 2006). The percutaneous system includes helical intramuscular electrodes, which are percutaneously placed under a minimally invasive procedure, a “pager”-size stimulator, which is worn on a belt, and a connector, which connects the electrodes to the stimulator. A multicenter clinical trial demonstrated

Figure 60.2  Results of a multicenter randomized clinical trial of percutaneous intramuscular electrical stimulation (ES) for the treatment of hemiplegic shoulder pain. Per-protocol (PP, dashed lines) and intent-to-treat (ITT, solid lines) approaches both showed that percutaneous intramuscular ES significantly reduces hemiplegic shoulder pain (Brief Pain Inventory Question 12) for up to 12 months after completion of treatment compared to controls who were treated with a cuffed hemisling (Reproduced with permission from Chae et al. (2005). Lippincott, Williams & Wilkins; www.lww.com)

the effectiveness of the system in reducing hemiplegic shoulder pain and improving shoulder pain-related quality of life of chronic stroke survivors (Figure 60.2) (Chae et al., 2005). In summary, surface NMES appears to be efficacious in reducing shoulder subluxation, improving pain-free range of motion, and facilitating motor recovery, especially among acute stroke survivors. However, it is unclear whether these improvements translate into more functional use of the hemiparetic upper limb or improved quality of life. Most studies

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used small sample sizes with limited follow-up, and optimum dose and patient characteristics predictive of successful treatment outcome remain unknown. Thus, similar to motor relearning, larger, well-­controlled studies that address the outcomes and ­methodological issues are needed to more definitively address the question of clinical efficacy. Intramuscular systems may be able to address some of the clinical implementation issues associated with surface NMES. However, these are still investigational devices and are not yet available to clinicians.

Neuroprosthesis Large segments of the chronic stroke population exhibit minimal to no residual motor function and thus are not candidates for motor relearning strategies. For this population, a neuroprosthesis may be the only viable option for return of motor function. A neuroprosthesis electrically stimulates the paretic muscles of the upper and lower limbs and produces movements that make it possible to perform specific activities of daily living and mobility tasks.

Upper Limb Applications Most research on an upper limb neuroprosthesis for chronic hemiplegia has focused on restoring hand function, especially hand opening. The earliest studies used surface stimulation of the finger and thumb extensors (Rebersek and Vodovnik, 1973; Merletti et al., 1975). Users controlled the stimulation by making movements of the opposite shoulder, which were detected by a shoulder-mounted transducer. Progressive improvements in the ability to manipulate various objects were noted, but in some cases, voluntary effort to control the paretic limb produced tremors and spasticity. The NESS H200 (Bioness, Inc., Valencia, CA, Figure 60.3) is a commercially available hand neuroprosthesis that was originally developed for tetraplegia (Snoek et al., 2000) but is also applicable to stroke survivors (Alon et al., 2002). The device is a wrist–forearm orthosis with five embedded surface electrodes that provide patterned stimulation to the finger and thumb flexors and extensors to produce selected hand movements. The user controls hand opening and closing by pressing buttons on the stimulator. After 3 weeks of using the H200, stroke survivors could successfully perform activities of daily living they selected (Alon et al., 2002). However, long-term use of the device as a neuroprosthesis has not been reported.

Figure 60.3  A hybrid brace-surface neuroprosthesis system that is worn on the hand and forearm (NESS H200, courtesy, Bioness Inc., Valencia, CA)

Although surface neuroprostheses have the advantage of being non-invasive, they have both practical and functional disadvantages that make them less likely to succeed clinically. Merletti and associates (1975) suggested that an implanted system would best meet the clinical needs of persons with hemiplegia. Implanted neuroprostheses may be advantageous to surface systems for several reasons: (a) eliminate daily donning of electrodes; (b) greater specificity of stimulation; (c) access to deep muscles; (d) access to more muscles for greater functional capabilities; and (e) elimination of discomfort of surface stimulation. As a step toward an implanted neuroprosthesis, a study was undertaken using multiple percutaneous electrodes to stimulate hand opening and closing in four persons with hemiparesis (Chae and Hart, 2003). Percutaneous stimulation was able to open a spastic hemiparetic hand as long as the upper limb was in a resting position, the wrist and proximal forearm were supported, participants did not try to assist the stimulation, and an individual other than the participant controlled the stimulation. However, when the participants assisted the stimulation, stimulated hand opening was significantly reduced due to increased finger flexor hypertonia. Similarly, the degree of stimulated hand opening was significantly reduced following voluntary hand closure.

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At the present time, a clinically viable hand neuroprosthesis system for long-term use is not available for persons with hemiparesis. Implantable technology that has been successfully implemented in tetraplegic patients may be suitable for stroke patients who have been screened for prohibitive flexor hypertonia. The advanced technology eliminates external transducers by using EMG-sensing electrodes, which are implanted on muscles that the individual retains the ability to contract (Kilgore et al., 2004). The EMG control technology provides the prospect of using internally derived natural control signals from ipsilateral volitional muscles to control the hand, an advance expected to make the control scheme more intuitive, natural, and non-interfering with the user’s residual contralateral function. While these technology improvements may make implantable neuroprostheses feasible for carefully selected stroke patients, most patients will not be able to benefit until a method of suppressing flexor hyper­ tonia is developed. Emerging technology that uses high-frequency stimulus waveforms to block action potential in nerves (Bhadra and Kilgore, 2005) may prove capable of suppressing hypertonia. Such spasticity suppressing stimulation could be added to a neuroprosthesis and considerably widen its applicability.

Lower Limb Applications The initial application of neuroprostheses in hemiplegia focused on surface peroneal nerve stimulation (PNS) to facilitate ankle dorsiflexion and eversion during the swing phase of gait (Liberson et al., 1961). The active electrode is typically placed over the common peroneal nerve just below the head of the fibula with the return electrode placed over the belly of the tibialis anterior. Both the deep and superficial branches of the common peroneal nerve are stimulated for activation of tibialis anterior and the peroneal muscles for ankle dorsiflexion and eversion, respectively. Clinically available PNS systems use either a tilt sensor or a pressure-­sensitive heel switch as a command-controller. A systematic review evaluated seven case series and one randomized clinical trial of surface PNS for hemiplegic gait. The pooled improvement in walking speed with the device relative to no device was 38% (Kottink et al., 2004). Singlechannel surface PNS appears effective in enhancing gait relative to no device and may be equivalent to an ankle foot orthosis (AFO) (Sheffler et al., 2006). Recent FDA approval of three devices: (1) Walkaide System (Innovative Neurotronics Inc., Austin, TX), (2) Odstock Dropped-Foot Stimulator (Salisbury District Hospital, Salisbury, UK), and the (3) Ness L300 (Figure 60.4, Bioness Inc., Valencia, CA) may facilitate broader

Figure 60.4.  A wireless peroneal nerve stimulator (L200, courtesy Bioness Inc., Valencia, CA)

clinical prescription and usage of these devices. Clinical indications include footdrop requiring compensatory strategies such as circumduction, hip hike or vaulting to clear the toes on the hemiparetic side. The patient should have sufficient balance, endurance, and motor ability to ambulate at least 30 feet with minimal assist or better. The PNS should dorsiflex the ankle to neutral with balanced eversion/inversion while the patient is standing. PNS provides limited knee control. Thus, patients who require an ankle–foot orthosis for the prevention of knee flexion collapse or severe genu recurvatum are not appropriate for PNS. The neuroprosthetic application of multichannel surface devices may have clinical applicability in the future. However, as previously noted, as the number of electrodes increases, surface systems become increasingly difficult to implement clinically. Implantable systems may address some of the difficulties by activating individual muscles via direct nerve or motor point stimulation to provide enhanced convenience, cosmesis, reliability, and repeatability. A dual channel implanted device developed at the University of Twente and Roessingh Research and Development, the Netherlands (Figure 60.5, STIMuSTEP, Finetech Medical Ltd, Welwyn Garden City, Herts, UK) was associated with increased walking

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conclusions

Conclusions

Figure 60.5  A two-channel implantable peroneal nerve stimulator (STIMuSTEP, courtesy Department of Medical Physics and Biomedical Engineering, Salisbury District Hospital, Salisbury, UK)

speed and may allow better control of eversion and inversion (Kottink et al., 2007). A three-dimensional inertial sensing system has been proposed for automated tuning of the implanted two-channel footdrop stimulator (Veltink et al., 2003). Implantable devices offer additional advantages, including the ability to selectively activate grouping of fibers within the nerve and theoretically provide more selective control and balance of motor response. A four-channel device, developed at Aalborg University (ActiGait, Neurodan A/S, Aalborg, Denmark), utilizes a nerve cuff with four tri-polar electrodes, oriented to activate different nerve fibers within the common peroneal nerve (Burridge et al., 2007). In summary, neuroprostheses have the potential to restore motor function for those with severely impaired motor function who are not amenable to motor relearning strategies. Although upper limb neuroprostheses for tetraplegia have been largely successful, the application to upper limb hemiplegia presents unique challenges. Clinical implementation must await additional technological advances that address flexor hypertonia and control issues. In contrast, lower limb applications appear to be ready for significant clinical impact. Surface peroneal nerve stimulators are now clinically available with emerging clinical efficacy data. It has the potential to equal (or perhaps supplant) the ankle–foot orthosis as the standard of care for post-stroke footdrop. In view of the known limitations of surface PNS, implanted PNS systems are also being developed. However, lower limb impairment in hemiplegia is rarely limited to the ankle and multichannel neuroprostheses to control the knee and hip will be necessary. A multichannel surface stimulation system will be difficult to implement clinically. Thus, for this clinical indication implanted multichannel systems should be developed.

The principal goal of rehabilitation management of persons with hemiparesis is to maximize quality of life. Recent advances in clinical medicine and biomedical engineering make the clinical implementation of NMES systems to enhance the function of stroke survivors more feasible. NMES in the form of neuroprostheses for motor relearning is a promising application of goal-oriented repetitive movement therapy. Studies of NMES for the treatment of shoulder subluxation and pain have yielded encouraging results. While multichannel lower limb neuroprosthesis systems are still under development, the peroneal nerve stimulator appears to be effective in enhancing the mobility of stroke survivors. Accordingly, these applications are now ready for confirmatory large-scale multicenter clinical trials. However, the development of hand neuroprostheses for persons with hemiplegia is in its infancy and must await further technical and scientific developments if it is to be applicable to the broader stroke population. After decades of development, the clinical utility of NMES systems is finally becoming realized. Scientists and clinicians must continue to explore new ideas and improve upon the present systems. Components will be smaller and more durable, and reliable. The issues of cosmesis and ease of donning and doffing will require some systems to be fully implanted. Control issues will remain central, and the availability of cortical control will dictate the nature of future generations of neuroprosthesis systems. In the present healthcare environment where cost is an overwhelming factor in the development and implementation of new technology, the consumer will become one of technology’s greatest advocates. Finally, the usual drive toward greater complexity will be tempered by the practical issues of clinical implementation where patient and clinician acceptances are often a function of a tenuous balance between the “burden and cost” associated with using a system and the system’s impact on the user’s quality of life.

Acknowledgments The preparation of this chapter was supported in part by grants K24HD054600, R01HD49777, and R01HD044816 from the National Institute of Child Health and Human Development and grant KL2RR024990 from the National Center for Research Resource.

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Kottink, A.I., Oostendorp, L.J., Buurke, J.H., Nene, A.V., Hermens, H.J. and IJzerman, M.J. (2004) The orthotic effect of functional electrical stimulation on the improvement of walking in stroke patients with a dropped foot: a systematic review. Artif. Organs 28 (6): 577–86. Kottink, A.I., Hermens, H.J., Nene, A.V., Tenniglo, M.J., van der Aa, H.E., Buschman, H.P. et al. (2007) A randomized controlled trial of an implantable 20-channel peroneal nerve stimulator on walking speed and activity in poststroke hemiplegia. Arch. Phys. Med. Rehabil. 88 (8): 971–8. Kowalczewski, J., Gritsenko, V., Ashworth, N., Ellaway, P. and Prochazka, A. (2007) Upper extremity functional electrical stimulation-assisted exercises on a workstation in the subacute phase of stroke recovery. Arch. Phys. Med. Rehabil. 88 (7): 833–9. Knutson, J.S., Hisel, T.Z., Harley, M.Y. and Chae, J. (2009) A novel functional electrical stimulation treatment for recovery of hand function in hemiplegia: 12-week pilot study. Neurorehabil. Neural Repair 23 (1): 17–25. Lee, R.G. and van Donkelaar, P. (1995) Mechanisms underlying functional recovery following stroke. Can. J. Neurol. Sci. 22 (4): 257–63. Liberson, W.T., Holmquest, H., Scot, D. and Dow, M. (1961) Functional electrotherapy: Stimulation of the peroneal nerve synchronized with the swing phase of the gait of hemiplegia patients. Arch. Phys. Med. Rehabil. 42: 101–5. Lindgren, I., Jonsson, A.C., Norrving, B. and Lindgren, A. (2007) Shoulder pain after stroke: a prospective population-based study. Stroke 38 (2): 343–8. Meilink, A., Hemmen, B., Seelen, H. and Kwakkel, G. (2008) Impact of EMG-triggered neuromuscular stimulation of the wrist and finger extensors of the paretic hand after stroke: a systematic review of the literature. Clin. Rehabil. 22 (4): 291–305. Merletti, R., Acimovic, R., Grobelnik, S. and Cvilak, G. (1975) Electrophysiological orthosis for the upper extremity in hemiplegia: feasibility study. Arch. Phys. Med. Rehabil. 56 (12): 507–13. Nudo, R.J., Plautz, E.J. and Frost, S.B. (2001) Role of adaptive plasticity in recovery of function after damage to motor cortex. Muscle Nerve 24 (8): 1000–19. Price, C.I. and Pandyan, A.D. (2001) Electrical stimulation for preventing and treating post-stroke shoulder pain: a systematic Cochrane review. Clin. Rehabil. 15 (1): 5–19. Rebersek, S. and Vodovnik, L. (1973) Proportionally controlled functional electrical stimulation of hand. Arch. Phys. Med. Rehabil. 54 (8): 378–82. Robbins, S.M., Houghton, P.E., Woodbury, M.G. and Brown, J.L. (2006) The therapeutic effect of functional and transcutaneous electric stimulation on improving gait speed in stroke patients: a meta-analysis. Arch. Phys. Med. Rehabil. 87 (6): 853–9. Sheffler, L.R. and Chae, J. (2007) Neuromuscular electrical stimulation in neurorehabilitation. Muscle Nerve 35 (5): 562–90. Sheffler, L.R., Hennessey, M.T., Naples, G.G. and Chae, J. (2006) Peroneal nerve stimulation versus an ankle foot orthosis for correction of footdrop in stroke: impact on functional ambulation. Neurorehabil. Neural Repair 20 (3): 355–60. Shimada, Y., Davis, R., Matsunaga, T., Misawa, A., Aizawa, T., Itoi, I. et al. (2006) Electrical stimulation using implantable radiofrequency microstimulators to relieve pain associated with shoulder subluxation in chronic hemiplegic stroke. Neuromodulation 9: 234–8. Snoek, G.J., IJzerman, M.J., in ‘t Groen, F.A., Stoffers, T.S. and Zilvold, G. (2000) Use of the NESS handmaster to restore handfunction in tetraplegia: clinical experiences in ten patients. Spinal Cord 38 (4): 244–9.

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61 Cortical Stimulation for the Treatment of Motor Deficits following Ischemic Stroke Janna L. Silverstein and Robert M. Levy

O U T L I N E Introduction

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Over the past two decades, there has developed evolving evidence of plasticity of the nervous system; it is this neuroplasticity that has been used to explain the functional recovery after stroke. Human and animal studies suggest that the cerebral cortex is capable of functional and structural reorganization following injury. In addition, motor experience can result in neurophysiological and neuroanatomical changes that can take place in the surrounding undamaged tissues (Nudo et al., 2003). Preclinical and clinical studies have suggested the potential of electrical stimulation of the motor cortex to improve motor dysfunction (AdkinsMuir and Jones, 2003). There is an extensive literature available on motor cortex stimulation (MCS) for treating chronic strokerelated pain syndromes, which include frequent subjective patient reports of improvements in motor deficits (Tsubokawa et al., 1991a, 1991b, 1993; AdkinsMuir and Jones, 2003). MCS studies have focused on treating pain secondary to thalamic infarction or trigeminal nerve injury (Tsubokawa et al., 1991a, 1991b, 1993; Hosobuchi, 1993; Meyerson et al., 1993;

INTRODUCTION Stroke is the third leading cause of death in the USA, where approximately 780 000 people suffer a stroke each year (Rosamond et al., 2008). Moreover, stroke is the leading cause of long-term disability, with more than 200 000 stroke survivors becoming severely or permanently disabled annually (Hurst, 2002). There are more than 5 million stroke survivors in the USA and more than 1 100 000 stroke survivors report difficulty with activities of daily living and experience functional limitations as a result of stroke. Unilateral weakness is the most common neurological deficit among stroke survivors and thus a substantial contributor to post-stroke disability (Rosamond et al., 2008). Presently, rehabilitative therapy is the only proven treatment available to patients with residual motor deficits. Most patients achieve less than satisfactory functional improvement from rehabilitation therapy and the lack of recovery of hand and arm function remains particularly problematic for these patients.

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61. CORTICAL STIMULATION FOR THE TREATMENT OF MOTOR DEFICITS FOLLOWING ISCHEMIC STROKE

Katayama et al., 1994, 1997, 1998; Peyron et al., 1995; Garcia-Larrea et al., 1997; Rainov et al., 1997; van der Lee et al., 2001; Brown et al., 2006). In patients who suffered both central pain and paresis secondary to stroke, their paresis appeared to improve with CS. Katayama and coworkers found that MCS improved in 19% of patients with infarcts who received epidural cortical stimulation for pain control (Katayama et al., 1998). Similarly, Garcia-Larrea and colleagues observed improvements in motor function of patients receiving cortical stimulation for pain management and relief of spasticity in some of their stroke patients (Garcia-Larrea et al., 1997, 1999). Franzini et al. (2003) noted a decreased stroke-related dystonia and intentional myoclonus in conjunction CS for pain relief. Both Katayama and Franzini and their coinvestigators observed that there was significantly reduced pain relief in regions of moderate or severe weakness (Katayama et al.,1998). Katayama found that 73% of patients with absent or mild weakness in the painful region received satisfactory pain relief, whereas only 15% of patients with moderate or severe motor weakness in the painful region obtained satisfactory pain control (Katayama et al., 1998). Therefore, it appears that the analgesic effects of MCS are mediated through the motor system (Katayama et al., 1997). Direct stimulation is hypothesized to enhance the function of specific regions of the motor cortex by improving neuronal function, facilitating cortical remodeling, or inhibiting dysfunctional subcortical brain activities (Brown, 2003). The use of MCS concurrent with rehabilitation therapy to improve motor recovery following stroke has the potential to provide greater efficacy than stimulation or rehabilitative strategies alone. Several preclinical studies of rodent and primate stroke models have substantiated the observation of improved motor recovery of the peri-infarct area following cortical stimulation (Adkins-Muir and Jones, 2003; Kleim et al., 2003; Plautz et al., 2003; Plautz and Nudo, 2005). In addition, these studies suggest that cortical stimulation enhances neuroplasticity and the post-stroke recovery process by recruiting new areas of the cortex to participate in the motor control of the affected limb (Kleim et al., 2003; Plautz et al., 2003).

ANIMAL STUDIES When animals are treated with concurrent cortical stimulation and rehabilitation therapy, enhanced behavioral function is associated with increased dendritic plasticity (Adkins-Muir and Jones, 2003),

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FIGURE 61.1 The effects of peri-lesion electrical stimulation on the Montoya staircase task. Rats that received 50 Hz stimulation during training had greater rate of improvement on the task over days of training than did rats receiving training only (no stimulation) (Adapted from Adkins-Muir and Jones (2003). Maney Publishing)

enlarged microstimulation evoked motor maps (Kleim et al., 2003; Plautz et al., 2003), and enhancement in the polysynaptic component of evoked potentials (Teskey et al., 2003) in the peri-infarct area of the cortex. Adkins-Muir and Jones assessed the behavioral and dendritic structural effects of combining subdural motor cortical stimulation with rehabilitative training following focal cortical ischemic injury in rats. Rats were pre-trained in a skilled forelimb food-pellet reaching task, the Montoya staircase test, and then underwent endothelium-1-induced sensorimotor cortical lesioning. A subdural electrode was then implanted overlying the injured cortex. Rats underwent rehabilitation training 10–14 days later using three different treatment protocols: rehabilitation training with no stimulation, rehabilitation training with 50 Hz stimulation, or rehabilitation training with 250 Hz stimulation. Low frequency intermittent stimulation of 50 Hz concurrent with skilled training significantly improved performance on the forelimb retrieval task, whereas rehabilitation training and high frequency stimulation at 250 Hz were found not to improve performance (Figure 61.1). In addition, surface density of dendritic processes immunoreactive for microtubule associated protein2 (MAP2) was evaluated to identify any corresponding neural morphological changes. MAP2 is localized in dendrites and is associated with dendritic growth and restructuring. In parallel to the behavioral performance results, only the animals that received 50 Hz stimulation during training had a significant increase in dendritic density in layer V of the peri-lesion cortex. Thus, cortical stimulation administered at 50 Hz may promote restorative plasticity by stimulationinduced growth and/or preservation of dendrites (Adkins-Muir and Jones, 2003).

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CS must be concurrent with rehabilitation for motor recovery in rats 45

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A subsequent study investigating neuronal density and cell proliferation in the peri-lesional cortex was performed using a similar rodent model except rehabilitation therapy was supplemented in the stimulation arms of the study with either anodal or cathodal 100 Hz cortical stimulation (Adkins et al., 2006). Both groups receiving cortical stimulation showed significant enhanced task performance post-infarct compared with unstimulated controls. The group that received cathodal cortical stimulation also showed an increase in neuronal density in the peri-lesion cortex. However, cortical stimulation did not appear to increase neural proliferation (Adkins et al., 2006). The work by Teskey and coworkers further confirms the benefit of cortical stimulation concurrent with rehabilitative therapy to enhance motor recovery following ischemic injury to the cortex. The efficacy of cortical stimulation in conjunction with rehabilitation training was assessed by skilled forelimb behavior, neocortical evoked potentials, and movement thresholds following focal ischemic injury in rats. Animals were first trained to a pasta matrix retrieval task requiring skilled use of both forelimbs. A focal ischemic injury was then produced on the caudal forelimb area of the sensorimotor cortex contralateral to the preferred limb. During the same procedure, a stimulating electrode was placed over the area of infarct and additional electrodes were positioned anterior to the lesion to record evoked potentials. Evoked potentials were measured because the polysynaptic component displays the most consistent change after stroke and demonstrates the propagation of horizontal activity through the cortex. One week post-implantation, the animals received cortical stimulation while they performed the skilled task. Rats receiving concurrent cortical stimulation while performing the task were able to return to pre-infarct retrieval levels whereas those animals receiving no stimulation were not (Teskey et al., 2003) (Figure 61.2). The superior performance of the rats receiving cortical stimulation was the result of an initial shift in forelimb preference. The authors hypothesize that the shift in forelimb preference was an effect of cortical stimulation to reduce cortical hyperexcitability in the impaired hemisphere. Additionally, rats that received cortical stimulation had larger polysynaptic potentials and this potentiation was generated in deeper levels of the cortex. The resulting horizontal corrections may lead to cortical reorganization. Overall, cortical stimulation concurrent with rehabilitation therapy led to functional motor recovery that may be the result of augmented synaptic plasticity (Teskey et al., 2003). Kliem and colleagues used a rodent model of focal ischemia and intracortical microstimulation (ICMS)

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FIGURE 61.2 Number of pasta pieces removed in 20 minutes vs. rehabilitation session number. Cortical stimulation (CS) during rehabilitation returned performance to pre-stroke levels while stimulation or rehabilitation alone did not (Adapted from Teskey et al. (2003). Maney Publishing)

to assess the behavioral and physiological effects of cortical stimulation in conjunction with motor rehabilitation. After animals were trained to a food pellet retrieval task, ICMS was used to derive detailed maps of forelimb movement contralateral to the trained paw. All animals then received a focal ischemic infarct by bipolar electrocoagulation within the motor map and cortical surface electrodes were placed over the ischemic cortex and remaining forelimb motor region. The motor cortex was then stimulated at 50 Hz during a 10-day rehabilitative training period and ICMS was used to develop a second motor map. In rats receiving the stimulation and rehabilitation training, a significantly higher percentage of the peri-infarct cortical area contained forelimb movement representations than in the animals trained without cortical stimulation. The authors hypothesize that this increased motor representation is a result of enhanced synaptic function and restoration of cortical circuitry (Kleim et al., 2003). Plautz and colleagues (2003) studied the efficacy of cortical stimulation in a nonhuman primate model in a similar investigation of neural plasticity and functional recovery post-infarct. This primate study corroborated the findings of the rodent studies and suggested that the combination of stimulation and rehabilitation acts through evolutionarily conserved neural mechanisms (Kleim et al., 2003). The animals received pretreatment training to perform pellet retrieval tasks and the authors used ICMS to map the proximal forelimb motor cortex (M1). An ischemic infarct was produced by bipolar electrocoagulation that affected the M1 distal forelimb area and some of the surrounding proximal forelimb area. After 2–3 weeks, a second

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FIGURE 61.3

Recovery of motor skill following an ischemic infarct in the primary motor cortex hand area. The scores were based on motor performance on a food pellet retrieval task. Primates receiving cortical stimulation concurrent with rehabilitation training showed greater percent recovery than those in the control group receiving rehabilitation therapy alone (Adapted with permission from Nudo et al., ILAR Journal 44 (2), 2003. Institute for Laboratory Animal Research, The Keck Centre of the National Academies, Washington, DC; www.nationalacademies.org/ilar)

motor map was derived to guide the implantation of a subdural electrode over the intact peri-infarct motor cortex. Once spontaneous motor recovery had stabilized and animals exhibited significant persistent motor impairments, the animals began either a combination of subthreshold cortical stimulation with rehabilitation therapy or rehabilitation therapy alone. The animals’ performance was tracked for several months post-therapy and it was found that while all the monkeys benefited from their respective therapies (Plautz et al., 2003), the group that received stimulation concurrent with therapy showed a more rapid recovery profile and a greater magnitude of recovery than the group treated with therapy alone (Plautz and Nudo, 2005) (Figures 61.3, 61.4). A third cortical map was derived to examine changes in motor representations. Cortical mapping of the group that had combined stimulation with rehabilitation demonstrated significant expansion of new hand representations in the peri-infarct motor area, especially in the area under the electrode (Plautz et al., 2003). The authors also observed that motor recovery was maximized when an increase in task-related functional representations was present in multiple cortical areas. Thus, the authors concluded that the application of cortical stimulation facilitated positive involvement of cortical regions that may not normally be involved in the motor recovery process.

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FIGURE 61.4 Follow-up performance level remained near final therapy level in the treatment group with cortical stimulation concurrent with rehabilitation training (Adapted with permission from Nudo et al., ILAR Journal 44 (2), 2003. Institute for Laboratory Animal Research, The Keck Centre of the National Academies, Washington, DC; www.nationalacademies.org/ilar)

Another novel finding from the primate studies was that successful post-stroke interventions to enhance motor recovery are not limited to the immediate post-stroke time interval. The improvement of motor function in these chronically impaired animals suggests that cortical stimulation and rehabilitation therapy activated neural mechanisms that had been inactive or inhibited as a result of the chronic condition (Plautz et al., 2003). This finding suggests that cortical stimulation may potentially benefit a wider population of individuals, including those who are chronically disabled after stroke and have long-term, fixed motor deficits. The substantial evidence from the preclinical studies in both rodents and nonhuman primates has provided support for the further development of this therapeutic approach in humans.

HUMAN STUDIES The first feasibility study performed in humans was performed to determine the safety of using targeted subthreshold epidural cortical stimulation for functional motor recovery in stroke patients. This prospective, randomized, unblinded, multicenter study was supported by Northstar Neuroscience (Seattle, WA) and named the ADAMS study. This safety trial included stroke patients with residual motor deficits resulting from nonhemorrhagic cortical or subcortical infarction that occurred at least 4 months prior to enrollment (Brown et al., 2006). Patients were randomized into one of two groups: (1) the investigational group that was implanted with a 3 3 grid electrode

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(Ad-Tech, Racine, WA) and received epidural electrical stimulation (50 Hz, 50% of the current needed to evoke gross motor movement) using an investigational external pulse generator (Northstar Neuroscience, Seattle, WA) concurrent with 3 weeks of rehabilitation therapy and (2) the control group that received 3 weeks of the rehabilitation therapy without device implantation and cortical stimulation. Stimulation was active only during rehabilitation therapy sessions; at all other times the external stimulator was disconnected so that no stimulation was delivered. While many outcomes were measured to suggest the feasibility of cortical stimulation for improving motor recovery, the primary objective was to determine the safety of this treatment. Neurological function was measured using the Upper Extremity subscale of the Fugl-Myer scale (UEFM), the Stroke Impact Scale (SIS) and the Arm Motor Ability Test (AMAT). Stroke studies commonly use the UEFM because it indexes the subject’s neurological and motor function, such as ability to control their arm, wrist and hand (Fugl-Meyer et al., 1975; Sanford et al., 1993; Bezard et al., 1999). The scores for the UEFM range from 0 to 66, with more normal functioning represented by higher scores. The AMAT measures the activities of daily living (ADLs) based on quality, function, and time scores. These assessments were measured in both groups at baseline prior to randomization, during each week of treatment and during follow-up physician visits at 1, 4, 8, and 12 weeks after the final rehabilitation session. Several safety outcomes were monitored, including death and medical morbidity, among them myocardial infarction, pneumonia, wound infection, or deep venous thrombosis. The occurrence of clinically definite generalized tonic–clonic seizures was monitored as well as decrements in neurological status, as defined by a decrease of 20% on either the UEFM scale or the hand function subscore of the Stroke Impact Scale. The study included patients who had suffered either cortical or capsular ischemic infarction that occurred at least 4 months prior to enrollment and that was evident on computerized tomography (CT) or magnetic resonance imaging (MRI). Patients were enrolled who had an Upper Extremity Fugl-Myer score between 20 and 50; the lower end of this scale reflects patients who are severely paretic. Patients were excluded if another stroke, preceding their index stroke, resulted in incomplete motor recovery. Study subjects underwent functional magnetic resonance imaging (fMRI) to identify the primary hand/ arm motor cortex of the affected hemisphere (Figure 61.5). Assuming that fMRI adequately localized the motor cortex, subjects were then randomized to either the investigational or control group. Investigational

Neuroplastic area associated with hand function

Region of stroke (A)

(B)

FIGURE 61.5 Functional MR images obtained in a patient during active wrist extension, illustrating the associated site of motor cortex activation and target for epidural electrode placement

patients underwent electrode implantation under general anesthesia. A circular 4 cm craniotomy was performed and both intraoperative cortical mapping and stereotactic guidance were used to locate the hand activation site. The electrode was placed epidurally over this activation area. Transdural electrical stimulation at 50 Hz was delivered to verify that gross motor movement or electromyographic activity could be evoked. The electrode wire was tunneled to a supraclavicular exit site. Patients were discharged the day after surgery and started rehabilitation therapy one week later. All patients received rehabilitation therapy 5 days per week for 1.5 hour sessions per day for 3 weeks. The objective of the occupational therapy was to strengthen and improve the function of the affected shoulder, arm, and hand. At the beginning of each therapy week, patients in the investigational group underwent motor threshold testing. The motor threshold testing was performed using 3 second pulse trains at 50 Hz, 250 μs pulse width, starting at 1 mA and increasing until movement was evoked or a maximum of 15 mA was reached. At the beginning of each therapy session, the stimulation was turned on and set to 50% of movement threshold or at 6.5 mA if no movement was evoked. Biphasic stimulation was supplied through the outer two rows of electrodes, with one side serving as the cathode and the opposite side serving as the anode. When the patient completed each therapy session, the stimulation was turned off. After the rehabilitation portion of the study was complete, the patients in the investigational group had the device explanted. A total of 10 patients were randomized, six to the investigational group and four patients to the control group. Only eight patients, four in each group,

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completed the study, however, because two patients in the investigational group withdrew due to complications in their treatment. No significant demographic differences were found between the groups. There were no patient deaths or seizures in either study group. During the period of assessment, no patients developed new neurological deficits. The two complications that arose were related to infection, one of which resulted from a surgical protocol violation in which the lead was tunneled to within 2 cm of the craniotomy wound instead of to the supraclavicular site. In the second complication, an electrode lead broke because of tension on the lead and was removed. After the electrode was removed, the patient fell and traumatically reopened the wound leading to an infection. Safety was also evaluated by looking for a decline in motor status, which was measured by the UEFM scores over the 16 weeks of study assessments. None of the patients receiving cortical stimulation had a 10% or greater decline in Fugl-Myer score compared to baseline measurements. In contrast, one patient in the control group had a 16% decline during follow-up. The efficacy data from this study suggested that cortical stimulation with rehabilitation therapy might lead to significant gains in motor function. In the investigational group, the UEFM scores from baseline to study week 16 improved by 10 points whereas patients in the control group improved by only 1.9 points (p 0.05). Additionally, patients in the investigational group showed improvements in UEFM scores from rehabilitation week 3 into follow-up week 1 and these improvements were maintained through the 12 week follow-up assessment. In contrast, patients in the control group showed lesser improvements within the first 2 weeks and the improvements decreased over time. This study also demonstrated the accuracy of the fMRI for identifying motor cortex. During intraoperative testing, muscle activity in the contralateral arm/hand was evoked by direct epidural stimulation over the center of the fMRI “hot spot” in five of the six investigational patients. Overall, this study provided data that demonstrated the safety of this cortical stimulation procedure and confirmed that it did not cause additional deterioration in neurological function. The motor function assessments suggested that cortical stimulation concurrent with rehabilitation therapy might enhance functional recovery. Therefore this study provided a foundation and interest in larger clinical studies to confirm and assess the efficacy of this treatment. A subsequent small multicenter feasibility study (Levy et al., 2008) was thus conducted. The BAKER

study was designed as an unblinded, prospective, randomized, multicenter safety and efficacy study. BAKER study inclusion criteria were similar to those of the ADAMS trial. Patients were randomized into either the control or investigational group; investigational subjects underwent implantation of an investigational fully implanted cortical stimulation device system (Northstar Neuroscience, Seattle, WA), including both the implanted electrode and a programmable pulse generator. Investigational subjects received cortical stimulation concurrent with rehabilitation therapy while the control group received the same rehabilitation therapy without device implantation or cortical stimulation. A total of 24 patients completed this study, with 12 patients in each treatment group (Levy et al., 2008). The primary outcome measures of this study were again the UEFM and the AMAT. Investigators agreed a priori that a 3.5-point improvement in the UEFM was clinically meaningful in chronic stroke patients. For the AMAT, it was determined a priori that a 0.21point improvement was clinically significant (Kopp et al., 1997). Assessments were made at baseline prior to randomization, during the rehabilitation therapy period, and at follow-up with the primary endpoint of the study defined as 4 weeks after rehabilitation therapy was completed. The BAKER brain imaging protocol included both a structural MRI and an fMRI that was performed prior to randomization to identify the primary motor cortex of the stroke-affected hemisphere that controlled hand movement. Refined from the protocol used in the ADAMS trial, the BAKER fMRI protocol detected the area of cortical activation by having patients perform one of three motor tasks depending on motor ability. These fMRI studies were used alone to target the location for epidural electrode placement and cortical stimulation site (Levy et al., 2008). BAKER trial surgeons implanted a new investigational stimulation electrode with six element electrodes configured with three elements along one edge as anodes and three elements on the opposite side as cathodes providing approximately 1.8 cm2 of effective stimulation area (Figure 61.6). The electrode lead was threaded subcutaneously to a subclavicular pocket where it was attached to an implanted programmable pulse generator (IPG) (Levy et al., 2008). The intensity of cortical stimulation was based on motor threshold data periodically recorded prior to rehabilitation sessions. The current level was adjusted in 3 second pulses to determine the minimum current required to elicit motor movement and the stimulation level used during therapy was 50% of this motor threshold. If no stimulation evoked movement was

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Caution: Investigational device. Limited by federal (or US) law to investigational use.

FIGURE 61.6 Cortical stimulation system called the Northstar Stroke Recovery Treatment System (SRTS GEN II). It is a small, battery-operated generator with an attached electrode

detected, a stimulation intensity of 6.5 mA, the maximum continuous current output of the implanted device, was used. During therapy, stimulation was delivered at either 50 or 101 Hz with a pulse duration of 250 μs (Levy et al., 2008). The rehabilitation protocol consisted of 6 weeks of therapy emphasizing upper extremity motor function of the affected limb, especially targeting the hand and wrist. The standardized rehabilitation program

focused on functional tasks in self-care and mobility skills as well as increasing range of motion, improving strength, and optimizing coordination. Patients also worked on individualized activities of daily living determined by the Canadian Occupational Performance Measure. Daily rehabilitation sessions were 2.5 hours long divided into a 90 minute rehabilitation session near maximum intensity, a break period, and another 60 minute session with intensity adjusted to patient fatigue (Levy et al., 2008). At the conclusion of the 6 weeks of therapy, the patients in the investigational group had the device system explanted. Twenty-four patients were randomized to the protocol across seven clinical sites. There were no significant differences in patient demographic characteristics between the treatment groups. The average patient age was 56.8  13.5 (range  26–81) years. At baseline, the average UEFM was 32.4  8.2 (range  20–50), indicating moderate to moderately severe motor impairment. For patients in the investigational group, the average current delivered during rehabilitation therapy was 5.1  0.9 mA (range  3.3–6.5) (Levy et al., 2008). Based on the primary outcome measures of UEFM and AMAT, patients in the investigational treatment group improved more than the patients in the control group (Figure 61.7). The UEFM scores for the investigational group improved by 5.5  4.4 (range  0–17) points, representing a clinically significant improvement, whereas the scores for the control group improved by only 1.9  4.4 (range  3–11)

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FIGURE 61.7

Combined data for the ADAMS and BAKER trials showing the improvement in Upper Extremity FuglMeyer (UEFM) score from baseline. Patients in the investigational group had statistically significant improvements in function

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points (p  0.03). Moreover, 67% of patients in the investigational treatment group had clinically significant improvements in the UEFM compared to 25% of control patients (Levy et al., 2008). The investigational patients also improved in the AMAT scores from baseline by 0.4  0.6 (range  0.5–1.5) points, whereas control patients had an increase from baseline by 0.2  0.4 (range  0.3–1.0) points, although this change was not statistically significant (p  0.2) (Levy et al., 2008). Of significance is whether improvements in motor function as measured by the UEFM translated into improvements in activities of daily living as measured by the AMAT. In the investigational group, 50% of patients had clinically meaningful improvements in both the UEFM and AMAT scores (at least a 3.5 point improvement and a 0.21 point improvement on the respective tests), whereas only 8% of control patients showed clinically meaningful improvements in both assessments (p  0.03) (Levy et al., 2008) (Figure 61.8). The other main objective of the BAKER study was to evaluate the safety of MCS for stroke rehabilitation. No patients suffered new deterioration in neurological function related to the implantation of the cortical stimulation device or from the cortical stimulation with rehabilitation. Only one patient experienced a seizure, which did not occur during delivery of cortical stimulation. The subject experienced a seizure 36 hours after implant surgery and prior to the delivery of electrical stimulation; the seizure was presumably

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FIGURE 61.8

Combined data from the ADAMS and BAKER trials showing clinically meaningful changes in the UEFM score from baseline. At follow-up week 4, 75% of patients in the investigational group had clinically meaningful improvements. Clinically meaningful improvements in the UEFM were determined by a 3.5 point increase from baseline score

secondary to the surgery and not related to cortical stimulation. The patient recovered without sequelae and completed the 6 week rehabilitation concurrent cortical stimulation without any further seizures. Another subject experienced a seizure 5 months after the device was explanted; this event appeared to be stroke- rather than implant- or therapy-related (Levy et al., 2008). Other medical complications reported during this study resulted from anticipated surgery-related complications in the investigational group. These included local swelling (2), pain at the incision/implant site (2), bleeding at the incision site (1), and headache (2). The complications were minor and resolved without additional treatment (Levy et al., 2008). The results from this study and the previous study (Brown et al., 2006) in conjunction with prior experience of implanting similar devices for chronic MCS for pain control suggest that epidural cortical stimulation is safe for use in stroke patients. While there is a known risk of provoking seizures from surgical procedures and super-threshold stimulation, no reports of seizures provoked by sub-threshold stimulation have been observed. However, survivors of primary hemorrhagic stroke were excluded from the study as a conservative measure because that patient population may be more susceptible to seizures. Additional research supporting safety of cortical stimulation at levels used in this clinical trial was published by Bezard and coworkers in a study that assessed the potential risk of provoking epileptic seizures by using chronic MCS with similar frequency, but for longer duration, than the parameters used in this clinical trial (Bezard et al., 1999). It was found that seizures could only be induced at intensities approximately twice the motor movement threshold, which further supports that delivery of cortical stimulation below motor movement is safe (Bezard et al., 1999). The clinical efficacy results from this prospective, randomized control trial closely match the results in the previous, smaller study. Patients in both the control and treatment groups appeared to improve from rehabilitation therapy; however, patients in the investigational group improved to a greater degree. Furthermore, the magnitude of recovery appears to be greater than for patients treated with constraintinduced therapy (CIT). In previous motor recovery studies in chronic stroke patients, the improvements in the UEFM scores in patients receiving CIT were less than half that observed in this study with subjects receiving CS (van der Lee et al., 1999, 2001). This finding suggests that CS is more effective than CIT in enhancing motor recovery in the hemiparetic stroke survivors.

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In light of the safety and efficacy results of these two small multicenter clinical feasibility studies, a phase III prospective, randomized, single-blind, multicenter study, the EVEREST trial, was undertaken. While inclusion criteria were similar to those for the ADAMS and BAKER trials, there were some potentially significant differences. Patients were required to have had an ischemic stroke above the level of the midbrain and the UEFM scores ranged from 28 to 50. Thus, patients with brainstem strokes, and those with the most severe paresis reflected by UEFM scores of under 28, were excluded. Patients were randomly assigned, using a computer-generated, site-specific block design, in a 2:1 ratio, to either the test group (CS  rehabilitation) or the control group (rehabilitation alone). Investigational group patients were implanted with the investigational stimulation device and underwent 6 weeks of rehabilitation with CS. Patients in the control group did not have a stimulation device implanted, nor did they undergo sham surgery. To parallel the timing of rehabilitation in the test group, rehabilitation for patients in the control group was initiated 2–4 weeks after randomization and lasted for 6 weeks. Both the test and control groups were followed up for 24 weeks after completing the rehabilitation program, with visits occurring at weeks 1, 4, 12, and 24. Magnetic resonance imaging and fMRI were used to verify the anatomical location of each patient’s stroke and to identify the target cortical area associated with movement and recovery of the affected extremity. The surgical and cortical sites for electrode placement were then determined using stereotactic neuronavigation and guided by the fMRI data only. Postoperatively, motor threshold evaluation and stimulation intensities were used during rehabilitation just as in the prior studies. Targeted subthreshold CS was initiated approximately 5 minutes before the start of each rehabilitation session and continued throughout each session. The stimulation device was turned off at the end of each session. The stimulation system was removed approximately 8 weeks after completion of the rehabilitation protocol. The 6 week rehabilitation program mirrored that described by Bravi and Stoykov (Bravi and Stoykov, 2007) and consisted of approximately 2.5 hours of therapy per day, split into two sessions of 60–75 minutes each. Rehabilitation was conducted 5 days per week for the first 4 weeks of therapy and 3 days per week for the next 2 weeks, for a total of 26 days. The first rehabilitation session of the day focused on motor activities and movements appropriate for the patient (i.e., improvements in coordination and the abilities to grasp, release, and reach). After a rest break, the next

761

session focused on activities of daily living (ADLs, e.g., self-care). Upon completion of the rehabilitation protocol, patients were advised on exercises to perform at home. Investigators instructed patients not to participate in additional physical/occupational therapy during the rehabilitation program and the first 4 weeks of follow-up. Of course, patients and the clinicians who were charged with direct patient care could not be blinded. However, the raters of outcome measures were blinded to patient treatment group assignment. To maintain rater blinding during assessments, all patients wore covering garments that hid any evidence of the neurosurgical procedure. The primary efficacy variable was the proportion of patients with clinically meaningful improvement from baseline to follow-up at 4 weeks on both the AMFM scale and the function component of the AMAT. Different from the prior trials, clinically meaningful improvement was defined as an improvement of 4.5 points for the AMFM scale and 0.21 points for the AMAT. A successful outcome was defined as the investigational treatment group achieving an improvement in the primary efficacy end point that was 20% that achieved by the control group. The proportions of patients with clinically meaningful improvement on the AMAT and UEFM were determined through week 24. Safety was evaluated by monitoring adverse events (AEs), serious adverse events (SAEs), and other specific events occurring between enrollment and the end of rehabilitation, and included events such as death, medical morbidity, generalized tonic–clonic seizures, and a decrement in neurological status. Safety was assessed at baseline, after surgeries for both implantation and explantation, and at follow-up visits through week 24. Fourteen procedure-related significant AEs were reported in 12 investigational EVEREST subjects, including four infections and four patients with pain, headache or nausea. Six other SAEs included clinically significant epidural hemorrhage (1), pulmonary embolism from preexisting thrombophlebitis (1), premature ventricular contractions (1), epidural fibrosis (1), and the need for cystoscopy to assist in placement of a Foley catheter (1). There was one death in the surgical arm of the study, which occurred 76 days after the device was explanted secondary to respiratory failure following a subsequent stroke. Of note is that 75% of the significant adverse events, which were unrelated to the surgical procedure, occurred more than 30 days after the device was explanted. Thus, cortical stimulation continued to demonstrate an excellent safety profile in the stroke patient population. Unfortunately, the percentage of patients in the investigational arm who reached the composite primary

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% of patients with clinically meaningful improvement

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FIGURE 61.9

EVEREST primary efficacy endpoint results. This bar graph shows the percentage of investigational and control patients that achieved a clinically meaningful result for both the UEFM and AMAT at the 4 week endpoint. The percentage of patients in the investigational arm that achieved a clinically meaningful result was not significantly different from the percentage of patients in the control arm

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FIGURE 61.10 Long-term follow-up on UEFM scores. There was no significant difference in the mean change in UEFM score from baseline through 24 week follow-up between investigational and control subjects

efficacy endpoint, that is the percentage of investigational patients who achieved a clinically meaningful result for both the UEFM and AMAT at the 4 week endpoint, was not significantly different than those in the control arm (31.9% vs. 29.1%; NSD). There was also no significant difference between the control and investigational groups in the degree of improvement on the UEFM or the AMAT. Unexpected was the large percentage of control patients demonstrating benefit of the rehabilitation protocol at this 4 week endpoint (Figure 61.9). Analysis of the longitudinal data through the 24 week follow-up period showed no significant difference in the mean change in UEFM score from baseline between investigational and control subjects (Figure 61.10), although there was a suggestion that the beneficial effect on the control group was beginning to wane over time. There was, however, a statistically

significant difference in the mean change in AMAT score from baseline, with an improvement of 0.35 in the investigational group and of 0.17 in controls (treatment effect p  0.02) (Figure 61.11). One obvious flaw in the study, however, was that there was no confirmation that the electrodes were properly placed nor that sufficient current was reaching the target to actually produce cortical stimulation. The site of hand motor activation was often deep within a cortical sulcus; this combined with the depth of the cerebrospinal fluid layer in the setting of brain atrophy and the relatively low current output of the implanted pulse generator made it likely that cortical stimulation was not actually accomplished in many implanted subjects. Furthermore, unlike the ADAMS study, neither BAKER nor EVEREST included intraoperative electrocorticography to confirm adequate electrode placement or the ability to stimulate the motor cortex.

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AMAT mean scores vs. time 3.6 Mean change in AMAT score from baseline

AMAT mean scores

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0.37

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0.26

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3.1

p  0.12∗ Overall treatment effect p  0.02∗ Treatment effect at 24 weeks

3 2.9 Baseline

4 wk

12 wk

∗ Repeated measures analysis

24 wk

(A)

(B)

FIGURE 61.11

Long-term follow-up on AMAT scores. There was no significant difference in the mean change in AMAT score from baseline through 24 week follow-up between investigational and control subjects

% of patients with clinically meaningful improvement

69.2%

Investigational No. success

No. total

%

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9

13

69.2%

Control

16

55

29.1%

Control

29.1%

p  0.002∗ Treatment difference: Investigational–Control  40.1% ∗ Post-hoc analysis, 1-sided p-value

UEFM  AMAT (A)

(B)

FIGURE 61.12

EVEREST primary efficacy endpoint results in a subset of the investigational patients that achieved motor threshold. The bar graph shows the percentage of investigational MT and control patients that achieved a clinically meaningful result for both the UEFM and AMAT at the 4 week endpoint. The treatment difference between MT investigational patients and control subjects was 40.1%

One verification of adequate electrode placement and sufficient stimulation intensity is the ability to establish a motor stimulation threshold. Motor threshold testing was performed three times during the EVEREST rehabilitation protocol. In only 13 of 94 investigational patients (13.8%) was a repeatable motor threshold demonstrated. When the results of these investigational patients (MT) are compared to control subjects, the EVEREST results are highly significant (Figure 61.12). The percentage of investigational MT patients that achieved a clinically meaningful result for both the UEFM and AMAT at the 4 week endpoint was 69.2% as compared to 29.1% of controls (p  0.002). The treatment difference between MT investigational patients and control subjects was 40.1%. The changes in the UEFM scores (p  0.02) and

AMAT scores (p  0.04) were also significant between MT investigational patients and control subjects. These significant differences were also seen in long-term follow-up. At 24 weeks, the mean change in UEFM score from baseline was 6.1 for MT patients and 3.8 for controls (p  0.07) (Figure 61.13); and the mean change in the AMAT score from baseline was 0.46 for MT patients and 0.17 for controls (p  0.04) (Figure 61.14). The treatment effect at 24 weeks was also significant (p  0.03). This prospective, randomized, blinded, multicenter trial has thus demonstrated that cortical stimulation appears to be safe in a stroke patient population. The data further suggest that, at least acutely, aggressive rehabilitation for chronic stroke patients can make a difference in motor performance. While EVEREST did

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UEFM mean scores

UEFM mean scores vs. time 47 46 45 44 43 42 41 40 39 38 37 36 35 Baseline

Mean change in UEFM score from baseline lnvestigational

Control

4 wk

12 wk

24 wk

Investigational

7.2

6.5

6.1

Control

4.0

4.6

3.8

p  0.07∗ Overall treatment effect p  0.01∗ Treatment effect at 4 weeks 4 wk

12 wk

∗ Repeated measures analysis

24 wk

(A)

(B)

FIGURE 61.13 Long-term follow-up on UEFM scores in investigational MT patients. There was significant difference in the mean change in UEFM score from baseline through 24 week follow-up between investigational MT and control subjects

AMAT mean scores vs. time 3.6 Mean change in AMAT score from baseline

AMAT mean scores

3.5

lnvestigational 4 wk

12 wk

24 wk

Investigational

0.51

0.45

0.46

Control

0.26

0.26

0.17

3.4 3.3 Control

3.2 3.1

p  0.04∗ Overall treatment effect p  0.03∗ Treatment effect at 24 weeks

3 2.9 Baseline

4 wk

12 wk

∗ Repeated measures analysis

24 wk

(A)

(B)

FIGURE 61.14 Long-term follow-up on AMAT scores in investigational MT patients. There was significant difference in the mean change in AMAT score from baseline through 24 week follow-up between investigational MT and control subjects

not meet its primary efficacy endpoint, it was due in part to the large number of patients in whom stimulation did not evoke motor activity. This suggests that one of several problems was encountered. Surgical targeting or electrode placement could have been improper. Certainly, the question of inadequate power output of the stimulation system must be entertained. The inability to sufficiently stimulate the cortex could well have been related to the depths of the cortical target and the cerebrospinal fluid space. It should be expected that these depths would be increased in elderly and stroke patients with significant brain atrophy and in patients whose cortical site of hand motor activity lies at the depth of a cortical sulcus. Finally, these patients could have suffered a complete functional transection of the corticospinal tract and the implications of this to the potential impact of cortical stimulation on neuroplasticity must be considered. Nonetheless, subjects in whom movement was evoked with cortical stimulation showed significantly

superior results as compared to controls. The results to date call for follow-up studies to address these important issues. It appears that cortical stimulation, when combined with rehabilitation therapy, may have important clinical applications for patients with stroke-related motor deficits.

DISCUSSION Cortical stimulation combined with rehabilitation appears to be both safe and effective for the treatment of motor deficits following ischemic stroke, although considerable work needs to be done before this therapy is available for widespread clinical use. Some have suggested that noninvasive methods of stimulation might provide similar outcomes to surgically implanted stimulation systems. Although they have the advantage of being noninvasive, when other methods of

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REFERENCES

cortical stimulation such as transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are compared to targeted subthreshold CS, these methods have a number of disadvantages. Stereotactically guided, localized stimulator placement is not used in either rTMS or tDCS (Berardelli et al., 1998; Nitsche and Paulus, 2001; Gangitano et al., 2002). Additionally, patients must be stationary during stimulation (Plautz et al., 2003; Dieckhöfer et al., 2006), which makes rehabilitative therapy difficult. Wide intra-individual and inter-individual variability exists in the effect of treatment on cortical excitability (Maeda et al., 2000; Nitsche and Paulus, 2001; Gangitano et al., 2002). Finally, results from short-term studies suggest that the effectiveness of rTMS and tDCS may be transient (Hummel et al., 2005; Takeuchi et al., 2005) and repeat visits may be required; however, results from longterm studies are needed. The results of human clinical trials thus far support the findings of the earlier animal studies that enhanced neuroplasticity contributes to improvements in motor function that are associated with rehabilitation therapy concurrent with CS (Heller et al., 1987; Adkins-Muir and Jones, 2003; Fasoli et al., 2004; Hummel et al., 2005; Dieckhöfer et al., 2006; Fischer et al., 2007). These results highlight the potential this treatment approach holds in improving the quality of life for stroke survivors. The improvements in upper extremity motor function appear to translate into clinically meaningful improvements in activities of daily living and in patient reports of quality of life. Further investigation is necessary to further define the optimal patient population, targeting and stimulation, and rehabilitation protocols to make this an important addition to our therapeutic armamentarium.

References Adkins, D.L., Campos, P., Quach, D., Borromeo, M., Schallert, K. and Jones, T.A. (2006) Epidural cortical stimulation enhances motor function after sensorimotor cortical infarct in rats. Exp. Neurol. 200: 356–70. Adkins-Muir, D.L. and Jones, T.A. (2003) Cortical electrical stimulation combined with rehabilitative training: enhanced functional recovery and dendritic plasticity following focal cortical ischemia in rats. Neurol. Res. 25: 780–8. Berardelli, A., Inghilleri, M., Rothwell, J.C. et al. (1998) Facilitation of muscle evoked responses after repetitive cortical stimulation in man. Exp. Brain Res. 122 (1): 79–84. Bezard, E., Boraud, T., Nguyen, J.P., Velasco, F., Keravel, Y. and Gross, C. (1999) Cortical stimulation and epileptic seizure: a study of the potential risk in primates. Neurosurgery 45: 346–50. Bravi, L. and Stoykov, M.E. (2007) New directions in occupational therapy: implementation of the task-oriented approach in conjunction with cortical stimulation after stroke. Top. Stroke Rehabil. 14 (6): 68–73. Brown, J.A. (2003) Guest Editorial. Neurol. Res. 25 (2): 115–17.

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Brown, J.A., Letsup, H.L., Weinand, M. and Cramer, S.C. (2006) Motor cortex stimulation for the enhancement of recovery from stroke: a prospective multicenter safety study. Neurosurg. 58 (3): 464–73. Dieckhöfer, A., Waberski, T.D., Nitsche, M., Paulus, W., Buchner, H. and Gobbelé, R. (2006) Transcranial direct current stimulation applied over the somatosensory cortex – differential effect on low and high frequency SEPs. Clin. Neurophysiol. 117 (10): 2221–7. Fasoli, S.E., Krebs, H.I., Stein, J., Frontera, W.R., Hughes, R. and Hogan, N. (2004) Robotic therapy for chronic motor impairments after stroke: follow-up results. Arch. Phys. Med. Rehabil. 85 (7): 1106–11. Fischer, H.C., Stubblefield, K., Kline, T., Luo, X., Kenyon, R.V. and Kamper, D.G. (2007) Hand rehabilitation following stroke: pilot study of assisted finger extension training in a virtual environment. Top. Stroke Rehabil. 14 (1): 1–12. Franzini, A., Ferroli, P., Dones, I., Marras, C. and Broggi, G. (2003) Chronic motor cortex stimulation for movement disorders: a promising perspective. Neurol. Res. 25: 123–6. Fugl-Meyer, A.R., Jaasko, L., Leyman, I., Olsson, S. and Steglind, S. (1975) The post-stroke hemiplegic patient I: A method for evaluation of physical performance. Scand. J. Rehabil. Med. 7: 13–31. Gangitano, M., Valero-Cabré, A., Tormos, J.M., Mottaghy, F.M., Romero, J.R. and Pascual-Leone, A. (2002) Modulation of input– output curves by low and high frequency repetitive transcranial magnetic stimulation of the motor cortex. Clin. Neurophysiol. 113 (8): 1249–57. Garcia-Larrea, L., Peyron, R., Mertens, P., Gregoire, M.C., Lavenne, F., Bonnefoi, F. et al. (1997) Positron emission tomography during motor cortex stimulation for pain control. Stereotact. Funct. Neurosurg. 68: 141–8. Garcia-Larrea, L., Peyron, R., Mertens, P., Gregoire, M.C., Lavenne, F., Le Bars, D. et al. (1999) Electrical stimulation of motor cortex for pain control: a combined PET-scan and electrophysiological study. Pain 83: 259–73. Heller, A., Wade, D.T., Wood, V.A., Sunderland, A., Hewer, R.L. and Ward, E. (1987) Arm function after stroke: measurement and recovery over the first three months. J. Neurol. Neurosurg. Psychiatry 50 (6): 714–19. Hosobuchi, Y. (1993) Motor cortical stimulation for control of central deafferentation pain. Adv. Neurol. 63: 215–17. Hummel, F., Celnik, P., Giraux, P. et al. (2005) Effects of non-invasive cortical stimulation on skilled motor function in chronic stroke. Brain 128 (pt 3): 490–9. Hurst, W. (2002) The Heart, Arteries and Veins, 10th edn. New York: McGraw–Hill. Katayama, Y., Fukaya, C. and Yamamoto, T. (1997) Control of poststroke involuntary and voluntary movement disorders with deep brain or epidural cortical stimulation. Stereotact. Funct. Neurosurg. 69: 73–9. Katayama, Y., Fukaya, C. and Yamamoto, T. (1998) Poststroke pain control by chronic motor cortex stimulation: neurological characteristics predicting a favorable response. J. Neurosurg. 89: 585–91. Katayama, Y., Tsubokawa, T. and Yamamoto, T. (1994) Chronic motor cortex stimulation for central deafferentation pain: experience with bulbar pain secondary to Wallenberg syndrome. Stereotact. Funct. Neurosurg. 62: 295–9. Kleim, J.A., Bruneau, R., VandenBerg, P., MacDonald, E., Mulrooney, R. and Pocock, D. (2003) Motor cortex stimulation enhances motor recovery and reduces peri-infarct dysfunction following ischemic insult. Neurol. Res. 25: 789–93. Kopp, B., Kunkel, A., Flor, H., Platz, T., Rose, U., Mauritz, K.H. et al. (1997) The arm motor ability test: reliability, validity, and sensitivity to change of an instrument for assessing disabilities in activities of daily living. Arch. Phys. Med. Rehabil. 78: 615–20.

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Levy, R.M., Ruland, S., Weinand, M., Lowry, D., Dafer, R. and Bakay, R. (2008) Cortical stimulation for the rehabilitation of patients with hemiparetic stroke: a multicenter feasibility study of safety and efficacy. J. Neurosurg. 108 (4): 707–14. Maeda, F., Keenan, J.P., Tormos, J.M., Topka, H. and Pascual-Leone, A. (2000) Modulation of corticospinal excitability by repetitive transcranial magnetic stimulation. Clin. Neurophysiol. 111 (5): 800–5. Meyerson, B.A., Lindblom, U., Linderoth, B., Lind, G. and Herregodts, P. (1993) Motor cortex stimulation as treatment of trigeminal neuropathic pain. Acta Neurochir. (Suppl.) 58: 150–3. Nitsche, M.A. and Paulus, W. (2001) Sustained excitability elevations induced by transcranial DC motor cortex stimulation in humans. Neurology 57 (10): 1899–901. Nudo, R.J., Larson, D., Plautz, E.J., Friel, K.M., Barbay, S. and Frost, S.B. (2003) A squirrel monkey model of poststroke motor recovery. ILAR J. 44 (2): 161–73. Peyron, R., Garcia-Larrea, L., Deiber, M.P., Cinotti, L., Convers, P., Sindou, M. et al. (1995) Electrical stimulation of precentral cortical area in the treatment of central pain: electrophysiological and PET study. Pain 62: 275–86. Plautz, E.J. and Nudo, R. (2005) Neural plasticity and functional recovery following cortical ischemic injury. Conf. Proc. IEEE Eng. Med. Biol. Soc. 4: 4145–8. Plautz, E.J., Barbay, S., Frost, S.B., Friel, K.M., Dancause, N., Zoubina, E.V. et al. (2003) Post-infarct cortical plasticity and behavioral recovery using concurrent cortical stimulation and rehabilitative training: a feasibility study in primates. Neurol. Res. 25: 801–10. Rainov, N.G., Fels, C., Heidecke, V. and Burkert, W. (1997) Epidural electrical stimulation of the motor cortex in patients with facial neuralgia. Clin. Neurol. Neurosurg. 99: 205–9. Rosamond, W., Flegal, K., Furie, K., Go, A., Greenlund, K., Haase, N. et al. (2008) Heart Disease and Stroke Statistics – 2008 Update:

A Report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 117: e25–e146. Sanford, J., Moreland, J., Swanson, L.R., Stratford, P.W. and Gowland, C. (1993) Reliability of the Fugl-Meyer assessment for testing motor performance in patients following stroke. Phys. Ther. 73: 447–54. Takeuchi, N., Chuma, T., Matsuo, Y., Watanabe, I. and Ikoma, K. (2005) Repetitive transcranial magnetic stimulation of contralesional primary motor cortex improves hand function after stroke. Stroke 36 (12): 2681–6. Teskey, G.C., Flynn, C., Goertzen, C.D., Monfils, M.H. and Young, N.A. (2003) Cortical stimulation improves skilled forelimb use following a focal ischemic infarct in the rat. Neurol. Res. 25: 794–800. Tsubokawa, T., Katayama, Y., Yamamoto, T., Hirayama, T. and Koyama, S. (1991a) Chronic motor cortex stimulation for the treatment of central pain. Acta Neurochir. (Suppl.) 52: 137–9. Tsubokawa, T., Katayama, Y., Yamamoto, T., Hirayama, T. and Koyama, S. (1991b) Treatment of thalamic pain by chronic motor cortex stimulation. Pacing Clin. Electrophysiol. 14: 131–4. Tsubokawa, T., Katayama, Y., Yamamoto, T., Hirayama, T. and Koyama, S. (1993) Chronic motor cortex stimulation in patients with thalamic pain. J. Neurosurg. 78: 393–401. van der Lee, J.H., Beckerman, H., Lankhorst, G.J. and Bouter, L.M. (2001) The responsiveness of the Action Research Arm test and the Fugl-Meyer Assessment scale in chronic stroke patients. J. Rehab. Med. 33: 110–13. van der Lee, J.H., Wagenaar, R.C., Lankhorst, G.J., Vogelaar, T.W., Deville, W.L. and Bouter, L.M. (1999) Forced use of the upper extremity in chronic stroke patients: results from a single blind randomized clinical trial. Stroke 30: 2369–75.

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C H A P T E R

62 Stimulation for Return of Upper and Lower Extremity Function Kevin L. Kilgore, Michael W. Keith, and P. Hunter Peckham

O U T L I N E Historical Perspective

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About the same time as the work of Long and Masciarelli, Kantrowitz (1960) was testing surface stimulation to bring a paraplegic subject from the seated position to standing by activation of the quadriceps and gluteal muscles. Brindley developed an implanted stimulator and electrode system, which was used to provide simple walking in paraplegic subjects (with the knee fixed) (Brindley et al., 1979). These systems were further refined with the addition of more stimulus channels (Kralj et al., 1980; Marsolais and Kobetic, 1987). A critical development in the application of FES in SCI was the discovery that electrical stimulation of muscle results in muscle conditioning, increased strength, and increased fatigue resistance. Early applications of FES had little success because not enough muscle force could be generated and maintained for

HISTORICAL PERSPECTIVE The first modern practical application of neuroprostheses to move paralyzed limbs was to correct footdrop in hemiplegic subjects (Liberson et al., 1961). Based on the success of the Ljubljana footdrop system, Long and Masciarelli (1963) became the first to apply electrical stimulation in spinal cord injury (SCI) for functional purposes. Long and Masciarelli used a splint that passively held the fingers closed and achieved finger opening by electrical activation of the finger extensors. This work led directly to the work of Peckham and colleagues with C5 tetraplegic subjects (Peckham et al., 1980). The first implanted motor neuroprosthetic systems in spinal cord injury came from researchers in Cleveland, OH (Keith et al., 1989) and London (Perkins et al., 1994).

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functional tasks, especially in SCI where atrophy can be quite severe. Peckham et al. (1976) and Salmons and Henricksson (1981) showed that chronic application of electrical stimulation to paralyzed muscles not only conditioned the muscle, but actually changed the muscle fiber from type 2 (fast twitch, fast fatiguing) to type 1 (slow twitch, slow fatiguing). Protocols for muscle conditioning are now part of the standard implementation of any motor neuroprosthesis.

voluntary control. In many incomplete injuries, stimulated and voluntary functions are intertwined, making outcome assessment more difficult. Despite this, recent advances in system design have made neuroprostheses more applicable to incomplete injuries (Knutson et al., 2004; Hardin et al., 2007; Dutta et al., 2008).

RATIONALE FOR NEUROMODULATION TARGET SELECTION AND APPROACH PERTINENT ANATOMY, PHYSIOLOGY, AND DISEASE PATHOPHYSIOLOGY Traumatic spinal cord injury can result in paralysis below the level of the spinal cord lesion. The American Spinal Injury Association (ASIA) defines the neurological Level of Injury as the most caudal segment of the spinal cord with normal motor and sensory function on both sides (ASIA, 2002). Tetraplegia is defined as the impairment or loss of motor and/or sensory function in the cervical segments of the spinal cord due to damage of neural elements within the spinal canal (ASIA, 2002). Paraplegia is defined as the impairment or loss of motor and/or sensory function in the thoracic, lumbar, or sacral segments of the spinal cord. A key physiological factor is muscle denervation and atrophy that results from lower motor neuron damage (Gorman et al., 1997). Although spinal cord injury is considered primarily an upper motor neuron disease, there is typically a region of lower motor neuron damage within the spinal cord. If this region is extensive, it severely limits the ability to utilize FES to produce movement. In some cases it is possible to use electrical activation of paralyzed but innervated agonists to make up for the inability to activate denervated muscle (Keith et al., 1996). Upper extremity systems have been primarily applied to individuals with C5 and C6 ASIA SCI. These individuals have the ability to position their hand in space, flex their elbow and, for the C6 level, extend their wrist. For more severe injuries (C4 and above), the difficulties in producing useful whole-arm movements have not yet been overcome, although this is an area of current research. Lower extremity systems have been primarily applied to individuals with T1–T12. Injuries in the cauda equina result in denervation of lower extremity muscles. Historically, neuroprostheses have been implemented with individuals who had complete (ASIA A) spinal cord injuries. In a complete injury it is usually straightforward to separate the function provided by the electrical stimulation and the function under

Electrical activation of paralyzed muscles takes maximum advantage of the remaining physiological function for an individual with spinal cord injury. Stimulation of paralyzed muscles is placed under the direct control of the individual, and is coordinated with any remaining voluntary movement that the individual retains, as shown in Figure 62.1. The control signal is derived from an action that the user has retained voluntary control over, which can include hand function (for paraplegic individuals), shoulder movement, recorded muscle activity, respiration or voice control. A coordinated stimulation pattern is developed so that the muscles are activated in a sequence that produces the desired function. Individuals with these devices appreciate the fact that they can still use their own limbs to enable them to stand or to eat, even though the direct connection to the CNS has been disrupted. Although many researchers have demonstrated that closed loop control incorporated into a motor neuroprosthesis results in improved results, to date

Lower extremity Implant

Upper extremity

FIGURE 62.1 Implanted and external components for motor neuroprostheses, including the electrodes, stimulator, control source and control unit. Implantable components are common for upper and lower extremity systems, while the external components are distinct

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PROGRAMMING AND OTHER POINTS OF CONSIDERATION

there are no clinically deployed implanted systems that include closed loop control. This is primarily due to the difficulty in creating reliable sensors and robust feedback loops.

INDICATIONS AND PATIENT SELECTION CRITERIA Implanted upper and lower extremity neuroprostheses are applied to individuals with spinal cord injury who are otherwise in good health and who are good surgical candidates. It is common practice to wait until at least one year after injury before implementing an implanted neuroprosthesis in order to insure that any recovery from the injury is complete. The subject must not have excessive limitations in the range of motion of the joints to be activated. Spasms, if present, must be controlled pharmacologically. The subject must have sufficient integrity of the lower motor neuron (peripheral nerve) to the muscles to be stimulated (see above). Therefore individuals with lower motor neuron disease, such as brachial plexus injury or amyotrophic lateral sclerosis, are not candidates for neuroprostheses. Most candidates for neuroprosthetic implantation are skeletally mature because of the concern that skeletal growth would result in stretching of the leads in the extremities, possibly resulting in tension failure in the leads or connectors of the system. However, research by Akers et al. (1999) has shown that appropriate routing of leads can accommodate significant growth.

IMPLANT PROCEDURE DETAILS The primary effort in the surgical installation of implanted neuroprostheses for upper or lower extremity function is the proper placement of the electrodes so that the desired muscle contraction response is obtained. A mapping electrode or probe is used to deliver stimulation to various portions of an exposed muscle or nerve in order to determine if the desired response is obtained. Leads from electrodes in the extremities are routed to the torso for connection to the implant stimulator. Recently, nerve cuff electrodes have been utilized in motor neuroprostheses. These electrodes encircle the target nerve and have one or more contacts located circumferentially around the nerve. Placement of these electrodes requires surgical exposure of a few centimeters of nerve trunk. The electrode is wrapped around the nerve and the stimulated response is tested.

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The stimulator device is located either in the chest or abdomen. Leads exiting from the stimulator terminate in connectors. The use of connectors allows the electrodes and leads to be placed individually, and then tunneled to the connector site. This allows servicing of either the leads or stimulator at a later date. Proper functioning of the neuroprosthesis depends on the responses obtained from each electrode. The stability of the electrode is critical. Electrodes are the most susceptible to movement during the days immediately following implantation. As a result, subjects are often immobilized through casting or restrictions on their mobility for up to 3 weeks post-implant.

PROGRAMMING AND OTHER POINTS OF CONSIDERATION Neuroprostheses for motor control rely on patterned activation of multiple muscles in order to provide function. For the lower extremity, patterned activation is typically time-based because of the cyclic nature of tasks like walking. The pattern, such as for standing up or taking a single step forward, is triggered by the user. Once triggered, the stimulation pattern then proceeds without further intervention until completion or until another pattern is triggered by the user. In the upper extremity, it is necessary for the user to have more intimate control over grasp function. Even in the upper extremity, however, the movement is produced by a pre-programmed pattern. The user controls the degree of grasp opening and closing proportionally, but the stimulation to each muscle is determined by the stimulus pattern. A comparison of the stimulus patterns for upper and lower extremity neuroprostheses is shown in Figure 62.2. The development of the stimulation pattern to produce a desired movement typically begins with the evaluation of the muscle response produced by each electrode. This process is referred to as “electrode profiling” (Kilgore et al., 1989). During the electrode profiling process, the muscle response to stimulation through each electrode is evaluated individually. The outcome of the electrode profiling is to establish initial minimum and maximum stimulation levels for each electrode. The information gained from the electrode profile is used to develop an initial stimulation pattern. This pattern describes the stimulus level to each electrode as a function of the control input parameter, which is typically time for lower extremity applications and command percent (opening to closing) for upper extremity applications. This pattern is tested

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Pulse duration (uS)

Hand grasp stimulus pattern 160 140 120 100 80 60 40 20 0 0

20

40 60 Command level (%)

Finger extensor Thumb abductor

80

100

Finger flexor Thumb flexor

Gait stimulus pattern Pulse duration (uS)

300 250 200 150 100 50 0 0

0.5

Hamstrings Quadriceps

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1.5 2 2.5 Time (seconds)

3

3.5

4

Gluteus Flexors

FIGURE 62.2

Example of stimulus maps for upper extremity and lower extremity systems. Upper extremity systems allow proportional control of grasp and are typically command-level based so that the stimulus parameters vary with the degree of opening or closing. Lower extremity systems are typically time-based and keyed to the phase of the gait cycle. A single switch triggers a full gait cycle (or multiple cycles)

and then iteratively and interactively modified until the desired functional results are obtained. The control algorithm for lower extremity function is switch-based and does not vary from subject to subject. Standing and stepping with FES is usually controlled by a set of ring-mounted switches worn on the index finger and activated by the thumb while holding on to a walker. From quiet standing, a single depression of one of the switches triggers swing on one leg. After return to static double limb stance, successive activation of the same switch triggers swing of the opposite limb. In this way, reciprocal stepping is achieved. Stepping can also be accomplished automatically by triggering the swing on one leg after detecting heel contact and loading of the stance limb via insole-mounted switches or pressure sensors. In contrast to the lower extremity, the control algorithms for the upper extremity are customized for each subject, particularly the proportional aspect of

the algorithm. Proportional control of grasp is gained through contralateral shoulder movement (Johnson and Peckham, 1990), ipsilateral wrist movement (Hart et al., 1998), or myoelectric signal activity (Kilgore et al., 2008). In all cases, the controller gain, which defines the magnitude of voluntary activity that corresponds to the entire command range of grasp open to grasp closed, must be customized for each subject. Control of grasp using myoelectric signals recorded from two independent muscles is the most recent advance in motor neuroprosthetics (Kilgore et al., 2008). Myoelectric control algorithms are customized for each user, but follow a common template. Typically, bursts of muscle activity in the shoulder or neck are used to turn the system on, to switch between grasp patterns, and to produce an “unlock” command. Direct proportional control of the degree of hand opening and closing is obtained through voluntary forearm musculature (either brachioradialis or extensor carpi radialis longus). Strong contraction of this muscle results in hand closing, whereas relaxation of the muscle results in hand opening. The user can also independently activate other functions, such as elbow extension or forearm pronation, by producing a specific pattern of myoelectric activity in the shoulder. Myoelectric control is also beginning to be applied for lower extremity systems. Myoelectric signals from a stronger limb can be used to trigger stimulation to the weaker limb. Myoelectric signals from proximal muscles could also be used to determine gait cycle timing.

OUTCOMES The implanted neuroprosthetic systems for motor control that have undergone clinical evaluation have all benefited from significant preliminary effort and analysis. Motor systems have been, for the most part, first tested using surface-based or percutaneous-based systems where the external components for control and stimulation can be easily modified as necessary. These early feasibility studies served to enable significant refinement of the approach prior to the introduction of implanted systems. A comparison of implanted neuroprosthetic approaches is shown in Table 62.1.

Implanted Upper Extremity Neuroprostheses Upper extremity implanted neuroprostheses for motor control in spinal cord injury have been implemented and evaluated by researchers in Cleveland (Peckham et al., 2001, 2002; Kilgore et al., 2008), London (Perkins et al., 1994), and by research groups initially

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OUTCOMES

TABLE 62.1

Current status of implanted systems for upper and lower extremity function

System name

Group (City)

Functions

Features

Subjects Implanted

IRS-8 (Freehand)

Cleveland/NeuroControl Corp.

Grasp

8 stimulus channels, external shoulder position control

225

IST-10

Cleveland

Grasp, reach

10 stimulus channels, implanted wrist position control

5

IST-12

Cleveland

Grasp, reach

12 stimulus channels, 2 channels myoelectric signal acquisition

12

IRS-8

Cleveland

Standing

8 stimulus channels, joystick control

17

IRS-8

Philadelphia

Standing

8 stimulus channels, joystick control

9

IST-16

Cleveland

Stepping

16 stimulus channels, joystick control

2

Praxis-24

NeoPraxis/Maine/ Philadelphia

Stepping  bladder

24 stimulus channels, both nerve and muscle based electrodes

5

LARSI

London

Stepping

Stimulation of 12 nerve roots

3

SUAW

Montpellier

Stepping

16 stimulus channels, interchangeable nerve and muscle based electrodes

2

trained by the Cleveland group (Davis et al., 1998; Carroll et al., 2000; Taylor et al., 2002; Cornwall and Hausman, 2004). Roughly 250 spinal cord injured subjects have received upper extremity systems worldwide since the mid 1980s. The progression of features in upper extremity neuroprostheses is shown in Figure 62.3. The largest clinical trial of an upper extremity neuroprosthesis was the Freehand trial, initiated by the Cleveland FES Center (Kilgore et al., 1997; Davis et al., 1998; Carroll et al., 2000; Biering-Sorensen et al., 2000; Fromm et al., 2001; Peckham et al., 2001; Taylor et al., 2002; Cornwall and Hausman, 2004; Rupp and Gerner, 2007). The Freehand neuroprosthesis used an eight-channel receiver-stimulator (IRS-8), epimysial or intramuscular electrodes, leads, and connectors. Electrodes were surgically placed on or in the paralyzed muscles of the forearm and hand, and an inductive link provided the communication and power to the implanted pulse generator. The external components of the neuroprosthesis were an external control unit, a transmitting coil, and an external shoulder position transducer. The results of the first 50 subjects were used to support premarketing approval from the Food and Drug Administration (Peckham et al., 2001). The Freehand neuroprosthesis produced increased pinch force in every recipient, and there was a significant increase in the ability to manipulate objects of different size and weight (Wuolle et al., 1994; Peckham, et al., 2001). The independence provided by the neuroprosthesis was directly compared to the maximum independence that could be provided by any other means, e.g. orthotics or tendon transfers. With the neuroprosthesis, 100% of the

(A)

(B)

(C)

(D)

FIGURE 62.3 Progression of upper extremity neuroprosthetic system development. These systems have developed from (A) external shoulder position control to (B) external wrist position control to (C) implanted wrist position control and (D) implanted myoelectric control

participants (n  28) improved in independence in at least one task, and 78% were more independent using the neuroprosthesis in at least three tasks (Bryden et al., 2008). All participants preferred to use the neuroprosthesis for at least one task and 96% preferred to use the neuroprosthesis for at least three tasks.

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62. STIMULATION FOR RETURN OF UPPER AND LOWER EXTREMITY FUNCTION

Inmann and Haugland (2004) reported on the addition of an implanted sensory nerve cuff electrode to an individual with the Freehand System. The results demonstrated that the mean grasp force could be reduced through the use of the sensory feedback system. Based on the success of the Freehand System, development of a second generation neuroprosthesis began in the early 1990s at the Cleveland FES Center. A key feature of the second generation system was the introduction of implanted control sensors. Two types of sensors were developed: an implanted joint angle sensor for the wrist (Peckham et al., 2002), and implanted myoelectric signal recording (Kilgore et al., 2008). Both options were successful, but it was found that myoelectric control is very successful and provides the maximum flexibility in applying the neuroprosthesis to patients with differing functional capacity. To date, 11 subjects have been implanted with the second generation neuroprosthesis with 12 stimulus channels with two channels of myoelectric signal acquisition, known as the Implantable StimulatorTelemeter (“IST-12”) System (Kilgore et al., 2008). Subjects are able to successfully use the myoelectric signal from their extensor carpi radialis longus (C6) or brachioradialis (C5) for proportional control of grasp opening and closing. Subjects have also demonstrated the ability to generate myoelectric signals from trapezius, platysma, deltoid, biceps, and auricularis posterior muscles. The study results to date indicate that every subject has demonstrated improvement in at least two activities and as many as nine activities.

(A)

(B)

Lower Extremity Neuroprostheses Four separate research groups have developed implanted neuroprostheses for both standing and walking: Cleveland (Davis et al., 2001), London (Perkins et al., 2002), Montpellier, France (von Wild et al., 2001), and the Neopraxis devices implanted in Maine and Philadelphia (Davis et al., 1994; Johnston et al., 2005). These approaches are represented in Figure 62.4 and the outcomes of these studies are reviewed in the following paragraphs. At present, there are approximately 40 SCI subjects with implanted standing or stepping systems, although usage of surface stimulation for standing is significantly more widespread through the commercial availability of the Parastep system (Graupe and Kohn, 1998). Triolo and colleagues (Davis et al., 2001; Bieri et al., 2004) performed a clinical trial of an eight-channel implanted stimulator for lower extremity exercise and standing function. Stimulation is delivered via eight electrodes on the knee and hip extensor muscles and at the T12–L2 spinal roots for trunk extension. Of the first 17 subjects studied, all were able to exercise and all 14 subjects that completed the rehabilitation phase of the study were able to rise from the seated position, assume a quiet standing posture, and complete standing transfer maneuvers with minimal assistance (Mushahwar et al., 2007). Eleven out of 13 subjects were able to stand with an average of 85% of their body weight on their legs and could release one hand to manipulate the controls of the external controller or other objects in the environment. Seven out of 11 individuals were also able to achieve swing-to ambulation in a walker or with crutches. (C)

(D)

FIGURE 62.4

Comparison of the approaches for lower extremity implant design. Approach A: Eight electrodes are muscle based for standing. Approach B: electrodes are nerve based plus electrodes for bladder (Praxis-24). Approach C: electrodes are nerve cuff based and muscle based (SUAW). Approach D: electrodes are spinal root based (LARSI)

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WHAT THE FUTURE HOLDS

Subjects who completed the standing phase of the Triolo study could proceed to receive a second eightchannel implant to activate the muscles required for stepping, for a total of 16 stimulus channels (Kobetic et al., 1999). These dual-implant mobility systems have been successfully implanted in two additional subjects with motor and sensory complete paraplegia. One subject was able stand for several minutes and step repeatedly for distances approaching 50 feet. The second subject uses the system primarily to exercise. Hardin et al. (2007) have demonstrated that a similar approach can be used to provide walking function after incomplete spinal cord injury. Johnston et al. (2003) reported on the use of the eight-channel Freehand implant to provide upright mobility in nine pediatric spinal cord-injured subjects. The implanted neuroprosthesis provided subjects with enhanced functional abilities when compared to traditional long leg braces. The need for physical assistance was decreased during neuroprosthesis use. A lower extremity implanted system based on epineural stimulation was developed based on a cochlear implant design (Cochlear Ltd, Australia) and became the Praxis FES24 system (Neopraxis, Australia). This system was implanted in five spinal cord-injured subjects between 1991 and 2003 (Davis et al., 1994, 2006; Johnston et al., 2005). The system utilized 18 nerve-based electrodes to produce motor function and also had electrodes for stimulation of the sacral roots for bladder and bowel function. Four of the five subjects were able to achieve standing for periods of 2–60 minutes and three were able to demonstrate the ability to stand up from a standard chair, sit down in a standard chairs and walk 6 meters. Two of the three subjects were able to maneuver into a bathroom stall, ascend and descend stairs, and walk for at least 6 minutes (Johnston et al., 2005). Two of the devices were removed due to infection (Davis et al., 2006). Researchers in London developed the LumboSacral Anterior Root Stimulator Implant (LARSI) for lower extremity motor control, based on their successful sacral root stimulator for bladder control (Rushton et al., 1997). The LARSI system activated 12 spinal roots, six on each side using nerve-based “book” electrodes. Each channel therefore produced a pattern of movement based on the muscles innervated by each root. Three subjects have received this system. Using the system, subjects were able to stand and were successful in using the neuroprosthesis to power a cycle for transportation and exercise (Perkins et al., 2002). The investigators identified significant electrical crosstalk between stimulation channels, thus limiting the functional outcomes (Donaldson et al., 2003).

The European project Stand Up And Walk (SUAW) developed an implanted stimulator specifically targeted for lower extremity applications (von Wild et al., 2002). The SUAW stimulator had 16 channels of stimulation and could utilize either muscle-based epimysial electrodes or nerve-based half-cuff electrodes. Two paraplegic subjects were implanted and the first subject has demonstrated the ability to stand for periods of 15 minutes continuously and is able to walk in the laboratory for up to 30 minutes (with breaks) (Guiraud et al., 2006). The second subject developed an infection resulting in removal of the device before functional evaluations could commence.

COMPLICATIONS AND AVOIDANCE The most serious potential medical complication with respect to implanted neuroprostheses is the risk of infection. Individuals with SCI are particularly susceptible to infections such as urinary tract infections, pressure ulcers, and pneumonia. For the Freehand study, less than 2% of electrodes implanted have become infected (Kilgore et al., 2003) and less than 3% of the implant stimulators. Lower extremity implants may have a higher rate of infection than upper extremity implants, but there are not enough data at present to make a definitive statement. Rapid and aggressive treatment of an implanted lead, including removal of the lead, can prevent the infection from tracking along the implanted leads to the entire system. The most common technical complication is failure of the external components, particularly any external cabling. Because all motor neuroprostheses to date require inductive powering, a transmitting coil with a cable must be routed from the subject’s skin to an external control module located somewhere on the subject’s body or wheelchair. These cables will invariably fail due to repeated bending or due to being pulled apart. The implanted electrodes used in the Freehand study have been shown to be extremely durable, with Kaplan–Meier survival analysis indicating a 98.7% probability for an electrode to remain intact for at least 16 years (Kilgore et al., 2003). There have been a few reports of device or lead failure in lower extremity systems (Uhlir et al., 2004).

WHAT THE FUTURE HOLDS The potential of implanted neuroprosthetic systems to provide grasping and standing functions has been

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clearly demonstrated through the first generation of clinical trials. Improvements on these first generation systems have included adding more channels to provide more functions and improving the method of control. One limiting factor has been the relatively slow development of new implanted technology. To date, a completely new device has been developed in order to introduce each new feature (more channels, improved control, new sensors). This is expected to change with the development of implanted systems based on a modular concept. Two modular systems have been proposed, including the use of micromodular implants (the Bion, Alfred Mann Foundation/ Boston Scientific, Valencia, CA) (Loeb et al., 2006) and the networked neuroprosthesis (Kirsch and Kilgore, 2004). Until very recently, each subject received a single neuroprosthesis addressing a single area of disability. Since spinal cord injury typically results in multiple disabilities, this means that only a subset of an individual’s needs have been addressed. In the future, it is expected that one obvious advance will be the application of combined systems. Future advances in neuroprosthetics are likely to provide practical function to individuals with high tetraplegia (Bryden et al., 2005). The introduction of cortical control systems may enable these individuals to obtain good control of their stimulated extremities despite their severe paralysis (Hochberg et al., 2006). The use of motor neuroprostheses is fully compatible with other strategies of functional restoration, such as neuroregeneration and retraining of neural circuitry by body weight supported walking. While the extent of the functional restoration that will be achieved through these approaches is yet unknown, it is unlikely that full and normal control will be achieved. With neuroprostheses, weak pathways can be supplemented and aberrant function could be overcome.

CONCLUSIONS Implanted motor neuroprosthetic systems have been shown to restore function that cannot be obtained through any other means. Individuals with tetraplegia can gain control of grasp and release, enabling them to perform various activities of daily living, such as eating, drinking, and brushing teeth, as well as other tasks such as writing and taking money out of a wallet. Individuals with paraplegia can gain the ability to stand, enabling the individual to retrieve objects from shelves or to work at a counter. In addition, the

ability to stand can simplify transfers in and out of the wheelchair, reducing the strain on an attendant. Walking function has also been demonstrated, including the ability to go up and down steps. Further, the impact of motor neuroprosthetics on rehabilitation is not only limited to improved function, but can also improve health and quality of life due to the benefits of muscle conditioning, exercise, and joint movement.

References Akers, J.M., Smith, B.T. and Betz, R.R. (1999) Implantable electrode lead in a growing limb. IEEE Trans. Rehab. Eng. 7: 35–45. ASIA (American Spinal Injury Association) (2002) International Standards for Neurological Classification of Spinal Cord Injury. Chicago, IL: American Spinal Injury Association, pp. 1-23. Bieri, C., Rohde, L., Danford, G.S., Steinfeld, E., Snyder, S. and Triolo, R.J. (2004) Development of a new assessment of effort and assistance in standing pivot transfers with functional electrical stimulation. J. Spinal Cord Med. 27 (3): 226–35. Biering-Sorensen, F., Gregersen, H., Hagen, E., Haugland, M., Keith, M., Larsen, C.F. et al. (2000) Improved function of the hand in persons with tetraplegia using electric stimulation via implanted electrodes. Ugeskr. Laeger. 162: 2195–8. Brindley, G.S., Polkey, C.E. and Rushton, D.N. (1979) Electrical splinting of the knee in paraplegia. Paraplegia 16 (4): 428–37. Bryden, A.M., Kilgore, K.L., Kirsch, R.F., Memberg, W.D., Peckham, P.H. and Keith, M.W. (2005) An implanted neuroprosthesis for high tetraplegia. Top. Spinal Cord Inj. Rehabil. 10 (3): 38–52. Bryden, A.M., Kilgore, K.L., Keith, M.W. and Peckham, P.H. (2008) Assessing activity of daily living performance after implantation of an upper extremity neuroprosthesis. Top. Spinal Cord Inj. Rehabil. 13 (4): 37–53. Carroll, S., Cooper, C., Brown, D., Sormann, G., Flood, S. and Denison, M. (2000) Australian experience with the Freehand system for restoring grasp in quadriplegia. Aust. N Z J. Surg. 70: 563–8. Cornwall, R. and Hausman, M.R. (2004) Implanted neuroprostheses for restoration of hand function in tetraplegic patients. J. Am. Acad. Orthop. Surg. 12: 72–9. Davis, J.A., Triolo, R.J., Uhlir, J., Bieri, C., Rohde, L., Lissy, D. et al. (2001) Preliminary performance of a surgically implanted neuroprosthesis for standing and transfers – where do we stand? J. Rehabil. Res. Dev. 38 (6): 609–17. Davis, R., Houdayer, T., Johnston, T., Smith, B., Betz, R. and Barriskill, A. (2006) Development of a multi-functional 22channel functional electrical stimulator for paraplegia. In: J.D. Bronzino (ed.), Biomedical Engineering Fundamentals. Boca Raton, FL: CRC Press. Davis, R., MacFarland, W. and Emmons, S. (1994) Initial results of the nucleus FES-22-implanted stimulator for limb movement in paraplegia. Stereotact. Funct. Neurosurg. 63: 192–7. Davis, S.E., Mulcahey, M.J., Smith, B.T. and Betz, R.R. (1998) Selfreported use of an implanted FES hand system by adolescents with tetraplegia. J. Spinal Cord Med. 21: 220–6. Donaldson, N. de N., Rushton, D.N., Perkins, T.A., Wood, D.E., Norton, J. and Krabbendam, A.J. (2003) Recruitment by motor nerve root stimulators: significance for implant design. Med. Eng. Phys. 25 (7): 527–37. Dutta, A., Kobetic, R. and Triolo, R.J. (2008) Ambulation after incomplete spinal cord injury with EMG-triggered functional electrical stimulation. IEEE Trans. Biomed. Eng. 55 (2): 791–4.

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Kirsch, R.F. and Kilgore, K.L. (2004) The future of motor neuroprostheses. In: K. Horsch and G. Dhillon (eds), Neuroprosthetics: Theory and Practice. River Edge, NJ: World Scientific publishing Co. Knutson, J.S., Hoyen, H.A., Kilgore, K.L. and Peckham, P.H. (2004) Simulated neuroprosthesis state activation and hand position control using myoelectric signals from wrist muscles. J. Rehab. Res. Develop. 41 (3B): 461–72. Kobetic, R., Triolo, R.J., Uhlir, J.P., Bieri, C., Wibowo, M., Polando, G. et al. (1999) Implanted functional electrical stimulation system for mobility in paraplegia: a follow-up case report. IEEE Trans. Rehabil. Eng. 7 (4): 390–6. Kralj, A., Bajd, T. and Turk, R. (1980) Electrical stimulation providing functional use of paraplegia patient muscles. Med. Prog. Technol. 7: 3–9. Liberson, W.T., Holmquest, H.J., Scot, D. and Dow, M. (1961) Functional electrotherapy: stimulation of the peroneal nerve synchronized with the swing phase of the gait of hemiplegic patients. Arch. Phys. Med. Rehabil. 42: 101–5. Loeb, G.E., Richmond, F.J.R. and Baker, L.L. (2006) The BION devices: injectable interfaces with peripheral nerves and muscles. Neurosurg. Focus 20 (5): 1–9. Long, C. and Masciarelli, V.D. (1963) An electrophysiologic splint for the hand. Arch. Phys. Med. Rehabil. 44: 499–503. Marsolais, E.B. and Kobetic, R. (1987) Functional electrical stimulation for walking in paraplegia. J. Bone Joint Surg. 69A: 728–33. Mushahwar, V.K., Jacobs, P.L., Normann, R.D., Triolo, R.J. and Kleitman, N. (2007) New functional electrical stimulation approaches to standing and walking. J. Neural. Eng. 4: S181–S197. Peckham, P.H., Keith, M.W., Kilgore, K.L., Grill, J.H., Wuolle, K.S., Thrope, G.B. et al. (2001) Efficacy of an implanted neuroprosthesis for restoring hand grasp in tetraplegia: a multicenter study. Arch. Phys. Med. Rehabil. 82: 1380–8. Peckham, P.H., Kilgore, K.L., Keith, M.W., Bryden, A.M., Bhadra, N. and Montague, F.W. (2002) An advanced neuroprosthesis for restoration of hand and upper arm control employing an implantable controller. J. Hand Surg. 27A (2): 265–76. Peckham, P.H., Mortimer, J.T. and Marsolais, E.B. (1976) Alterations in the force and fatigability of skeletal muscle in quadriplegic humans following exercise induced by chronic electrical stimulation. Clin. Orthop. 114: 326–34. Peckham, P.H., Mortimer, J.T. and Marsolais, E.B. (1980) Controlled prehension and release in the c5 quadriplegic elicited by functional electrical stimulation of the paralyzed forearm musculature. Ann. Biomed. Eng. 8: 369–88. Perkins, T.A., Brindley, G.S., Donaldson, N.D., Polkey, C.E. and Rushton, D.N. (1994) Implant provision of key, pinch and power grips in a C6 tetraplegic. Med. Biol. Eng. Comput. 32 (4): 367–72. Perkins, T.A., Donaldson, N. de N., Hatcher, N.A.C., Swain, I.D. and Wood, D.E. (2002) Control of leg powered paraplegic cycling using stimulation of the lumbo-sacral anterior spinal roots. IEEE Trans. Rehab. 10: 158–64. Rupp, R. and Gerner, H.J. (2007) Neuroprosthetics of the upper extremity – clinical application in spinal cord injury and challenges for the future. Acta Neurochir. (Suppl.) 97 (Pt. 1): 419–26. Rushton, D.N., Donaldson, N.D., Barr, F.M., Harper, V.J., Perkins, T. A., Taylor, P.N. et al. (1997) Lumbar root stimulation for restoring leg function: results in paraplegia. Artif. Organs 21: 180–2. Salmons, S. and Henriksson, J. (1981) The adaptive response of skeletal muscle to increased use. Muscle Nerve 4: 94–105. Taylor, P., Esnouf, J. and Hobby, J. (2002) The functional impact of the Freehand system on tetraplegic hand function, clinical results. Spinal Cord 40: 560–6.

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Uhlir, J.P., Triolo, R.J., Davis, J.A. and Bieri, C. (2004) Performance of epimysial stimulating electrodes in the lower extremities of individuals with spinal cord injury. IEEE Trans. Neural Syst. Rehabil. Eng. 12 (2): 279–87. Von Wild, K., Rabischong, P., Brunelli, G., Benichou, M. and Krishnan, K. (2001) Computer added locomotion by implanted

electrical stimulation in paraplegic patients (SUAW). Acta Neurochir. 79 (Suppl.): 99–104. Wuolle, K.S., Van Doren, C.L., Thrope, G.B., Keith, M.W. and Peckham, P.H. (1994) Development of a quantitative hand grasp and release test for patients with tetraplegia using a hand neuroprosthesis. J. Hand Surg. 19A: 209–18.

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C H A P T E R

63 A Neural Prosthesis for Obstructive Sleep Apnea Dominique M. Durand

O U T L I N E Introduction

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Control of Airway Patency Through Tongue Muscles

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Prosthetic Design for OSA

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Single Electrode Closed Loop Prosthesis Design for OSA

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782

Conclusion

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upper airway occlusions (Figure 63.1) related to the prolapse of the tongue and its surrounding structure into the pharynx. This prolapse has been attributed to diminished neuromuscular activity in the upper airway dilating muscles (Decker et al., 1993) during an occlusion as indicated by EMG (electromyogram) recording from the main protruder of the tongue, the genioglossus muscle. During wakefulness, OSA patients have an augmented genioglossus activity compared to normal. However, this neuromuscular compensation may be lost during sleep thereby generating a collapse of the airways (Mezzanotte et al., 1992). Obstructive sleep apnea (OSA) is also associated with arterial oxygen desaturation and consequent arousals from sleep (Badr, 1999; Malhotra and White, 2002). It has been suggested that OSA, which is often referred to as the “snorer’s disease,” involves a gradual degeneration of the upper airways (UAW) mucosal receptors in addition to a progressive deposition of

INTRODUCTION Obstructive sleep apnea (OSA) affects 2–4% of the adult population and is most commonly seen in middleaged, overweight men. A study at the University of Wisconsin showed that 4% of men and 2% of women aged 30–60 have undiagnosed sleep apnea (Young et al., 2002). A 2004 report from MedTech Insight indicates that the prevalence of OSA in the USA is 28.2 million patients. Of these, 12 million, 8.8 million, and 8.1 million respectively are diagnosed with mild, moderate, and severe OSA (MedTech, 2004). The degree of severity is determined by the apnea–hypopnea index (AHI) – the number of apneic and hypopneic episodes per hour. The AHI can reach up to 60 for patients with severe OSA. From the 16.4 million patients with either moderate (AHI 15) or severe (AHI 50) OSA, 15.6 million patients are untreated. These patients develop

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Small or receding jaw

Tongue Soft palate Epiglottis Uvula

Site of occlusion

FIGURE 63.1

The upper airways. The most common site of the occlusion is the oropharynx or nasopharynx (Modified from an illustration by Christy Krames ©1999)

lipid tissue in the UAW lumen (Friberg et al., 1997; Friberg, 1999). This gradual loss in muscle tone and inherently narrow UAW anatomy, both of which facilitate larger negative intraluminal pressure swings during inspiration, are considered the main factors that predispose individuals to OSA. There are several other predispositions to obstructive sleep apnea such as obesity (Gami et al., 2003), ethnicity (Tan et al., 1999), pharyngeal wall thickness, enlargement of the tongue and retroposition of the mandible and/or hyoid bone (Jamieson et al., 1986; Schwab et al., 2003). The frequent and repeated nocturnal episodes of occlusion produce micro-arousals and lead to excessive daytime sleepiness (EDS). Aside from the chronic fatigue associated with EDS and increased risk for automobile accidents, OSA patients exhibit a greater likelihood for developing more serious long-term pathologic sequelae: hypertension, right-sided heart failure, arrhythmia, and stroke (Victor, 1999; Malhotra and White, 2002; Shamsuzzaman et al., 2003). The preliminary treatment of OSA is a series of lifestyle changes followed by non-surgical treatment options. The most common non-surgical treatment is continuous positive airway pressure (CPAP). It has been shown to be effective in reducing the symptoms of OSA in patients who use it on a regular basis (George, 2001; Becker et al., 2003; Shamsuzzaman et al., 2003), however, there is a high rate of noncompliance (⬃40%) (Stepnowsky et al., 2002; Engleman and Wild, 2003), mostly due to patient discomfort. Surgical procedures for the treatment of OSA include opening one or more of the sites of breathing

obstruction, via adenoidectomy, tonsillectomy, nasal polyp removal, airway abnormality correction, uvulopalatopharyngoplasty (UPPP), or, in the most severe cases, tracheotomy or surgical jaw reconstruction, nasal airway surgery, palate implants, tongue reduction, genioglossus advancement, hyoid suspension, maxillomandibular procedures, bariatric surgery or combinations of these procedures. Many of these procedures are very invasive and not always effective. The most common surgery for OSA patients (UPPP) is initially successful but the success rate drops to 46% after a 13 months period (Levin and Becker, 1994). However, the physiology and anatomy of the UAW muscles suggest that the UAW patency could be preserved during sleep through electrical stimulation of the tongue muscles (Sahin and Huang, 2007). Stimulation of the hypoglossal nerve has been shown to co-activate the tongue protrudor and retractor muscles resulting in airway clearance (Yoo and Durand, 2005). This conclusion is based on results obtained from both animal and human experiments.

CONTROL OF AIRWAY PATENCY THROUGH TONGUE MUSCLES Although there are many muscles in the upper airways that affect patency, the most important ones are controlled by the hypoglossal (HG) nerve. The HG nerve innervates the geniohyoid muscle (the hyoid branch of the medial branch), the intrinsic muscles of the tongue, and the extrinsic muscles of the tongue, i.e. the genioglossus muscle (medial branch), the styloglossus and hyoglossus muscles (lateral branch) (Figure 63.2). The genioglossus (GG) and the geniohyoid (GH) muscles are the primary ones involved in dilation of the pharynx. Contraction of genioglossus provides tongue protrusion, hence widens the pharyngeal opening. Activation of the geniohyoid along with a tone present in the sternohyoid muscle pulls the hyoid bone ventrally, thus again dilating the pharynx. On the other hand, hyoglossus and styloglossus are considered as tongue retractor muscles. Several methods have been tested to activate the UAW muscles with electrical stimulation in OSA patients such as (1) stimulation of genioglossus using submental transcutaneous stimulators, (2) direct stimulation of genioglossus with wire electrodes, and (3) direct stimulation of the HG nerve. Transcutaneous stimulation of genioglossus has given inconsistent results and sometimes failed to prevent obstructions without causing arousals during sleep (Miki, Hida, Chonan et al., 1989; Miki, Hida,

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CONTROL OF AIRWAY PATENCY THROUGH TONGUE MUSCLES

Hypoglossal nerve (XII) (in hypoglossal canal)

Meningeal branch

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Superior longitudinal Intrinsic muscles of tongue

Transverse and vertical

Styloglossus muscle

Inferior longitudinal

Occipital condyle Inferior ganglion of vagus nerve Ventral rami of C1, 2, 3 form ansa cervicalis of cervical plexus Superior cervical sympathetic ganglion Superior root of ansa cervicalis

Genioglossus muscle

Internal carotid artery

Geniohyoid muscle (via C1)

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Thyrohyoid muscle (via C1) Omohyoid muscle (superior belly)

Internal jugular vein

Sternohyoid muscle

Common carotid artery

Sternothyroid muscle Efferent fibers

Omohyoid muscle (inferior belly)

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FIGURE 63.2 Neuromuscular anatomy of the UAW. The hypoglossal nerve innervates the intrinsic and extrinsic muscles of the tongue. The genioglossus is considered as the main tongue protrusor of the extrinsic muscles and the hyoglossus and styloglossus as the retractor muscles of the tongue. Geniohyoid is not considered as one of the tongue muscles but can contribute to UAW opening (Modified from NetterImages.com)

Shindoh et al., 1989; Edmonds et al., 1992). The poor efficiency of transcutaneous stimulations can be attributed to nonspecific activation of genioglossus because of the tissue present between the stimulator and the

target muscle. Direct stimulation of the genioglossus using intraoral wire electrodes was effective in dilating the upper airways in OSA patients (Schwartz et al., 1996). However, this method does not lend itself to an

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implantable FES device since it uses EMG wire electrodes, which cannot be implanted chronically. Electrical stimulation of the hypoglossal (XII) nerve directly has been investigated as an alternative mode of therapy to compensate for the increased airway collapsibility observed in OSA patients: diminished or insufficient nocturnal activity of UAW dilators (Wiegand et al.,1989, 1990). Stimulation of the HG by percutaneously inserted wire electrodes provided tongue protrusion with minimal discomfort in humans yet terminated only 23% of the apneic events (Decker et al., 1993). The inefficiency of the HG nerve stimulation with wire electrodes could be due to the inappropriate placement of the electrodes resulting in the recruitment of retractor muscles before the protruder muscles of the tongue. It has been demonstrated in humans by another group that the flow of inspired air is doubled by stimulation of the main branch of the hypoglossal nerve (Eisele et al., 1995). Stimulation of the medial branch was nearly as efficient and was superior to stimulation of other branches. However, human experiments suggest that it might be easier to prevent an obstruction by instead opening the airways during an obstruction (Fairbanks and Fairbanks, 1993). In both animal and human experiments, experiments have shown significant improvements in UAW resistance (RUAW) and stability (Pcrit) in response to electrical stimulation (Miki, Hida, Shindoh et al., 1989; Schwartz et al., 1993; Eisele et al., 1995, 1997; Hida et al., 1995; Oliven et al., 1996; Goding et al., 1998; Mann et al., 2002). Pcrit is the critical pressure in the UAW capable of inducing flow limitation. A low Pcrit indicates an UAW resistant to collapse. Reduction of the AHI is associated with a decrease in Pcrit (Oliven et al., 2003). Although long-term studies in OSA patients have demonstrated significant decrease in AHI, an effective neuroprosthetic design for OSA has not yet been developed.

PROSTHETIC DESIGN FOR OSA Since it has been shown that electrical stimulation of the UAW muscles that control the tongue can prevent the collapse of upper airways and decrease the AH index (Fairbanks and Fairbanks, 1993), one could consider the design of an implantable prosthetic device to maintain patency by stimulation of the hypoglossal nerve. Three methods of stimulation have been considered. The first involves open-loop continuous stimulation (modulation) to maintain tone in the muscles thereby preventing a collapse. The fact that the stimulation levels required to open the airway are below the

4

5

3 2

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1

12

11

13

FIGURE 63.3

Neural prosthesis for OSA: method and apparatus for synchronized treatment of obstructive sleep apnea (US Patent 6,269,269)

threshold for awakening the patients suggests that this method might work. Another method is also open loop but with intermittent stimulation whereby electrical stimulation is applied during inspiration at the natural respiration frequency and duty cycle of the patient. The stimulation and the patient’s respiration are not synchronized, but the patient could learn to breathe only during the time when the stimulator is activated. Such a method was proposed and tested using a Bion (Tran et al., 2004). The Bion (Advanced Bionics Corp., Valencia, CA) is a small implantable stimulator that was injected with a syringe close to the medial branch of the hypoglossal nerve from the mouth. Continuous stimulation was applied to prevent the collapse of the upper airways. Although initially promising, this method was not pursued. A third method involves synchronization of the stimulation with inspiration. The fact that synchronization is important is suggested by studies showing that once the collapse of the upper airways has occurred, it is difficult, even with a strong stimulus, to restore patency (Oliven et al., 2001). This synchronization allows the stimulus to restore tone in the upper airways muscles when the upper airway is most sensitive to a collapse generated by the negative pressure generated during inspiration. A closed-loop synchronous prosthesis was developed by Medtronic (Minneapolis, MN). Figure 63.3 shows the design of the device designed to relieve obstruction. A sensor is placed around the diaphragm (11,12) to sense the respiration effort by impedance plethysmography. Stimulation is applied through an electrode positioned on the hypoglossal nerve (4).

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SINGLE ELECTRODE CLOSED LOOP PROSTHESIS DESIGN FOR OSA

FIGURE 63.4

Cuff electrode used in a prototype OSA prosthesis discussed in Eisele et al. (1997) (Reproduced with permission. Copyright (1997) American Medical Association)

The stimulator (1) senses the effort and can synchronize the stimulation to the respiration signal (Ottenhoff and Michels, 2001). Other sensing devices have been proposed and tested, such as a sensor capable of detecting intrathoracic pressure and allowing the stimulation of the hypoglossal nerve to be synchronized with the inspiration (Testerman, 1996a, 1996b). A prototype of this device was tested in a chronic study involving eight patients with OSA. A C-shape electrode (Figure 63.4), stimulator and pressure sensor were implanted for 6 months (Schwartz et al., 2001). Stimulation was synchronized with respiration and applied at 33 Hz, with 91 μs pulses. The results show that the stimulation was well tolerated and did not produce any significant adverse effects. The AHI decreased significantly during both REM and non-REM sleep. Both the quality of sleep and the oxygen saturation were improved in these patients. A more recent acute study to test the device was carried in 14 patients (Oliven et al., 2003). Electrical stimulation of the hypoglossal nerve was compared to direct muscle stimulation. Five patients were implanted with a C-shape cuff electrode shown in Figure 63.4. Nine patients were implanted with fine wires in the genioglossus muscle. The ability of the stimulation to maintain patency in the airways was quantified by measuring the critical pressure capable of inducing flow limitations (Pcrit) and the AHI. In both sets of patients, Pcrit was significantly decreased by the application of the stimulation and the decrease in this critical pressure was also accompanied by a decrease in AHI. The results also indicated that the greatest improvement with hypoglossal stimulation was found in patients with low (sub-atmospheric) Pcrit. Taken together, these results suggest that electrical stimulation of the hypoglossal nerve can clearly

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improve the patency of the airways in patients with OSA. Given the fact that so many patients could benefit from this technology, it is unclear why such a device has not yet been deployed in large numbers. One difficult issue is the fact that synchronization may be important since improvements of the AHI were dependent on the degree of synchronization (Schwartz et al., 2001). However, the detection of the respiratory signal requires an additional sensor and the synchronization has been difficult to achieve. This difficulty arises from the fact that the stimulation should be applied just before inspiration in order to maximize the effect of the stimulus. However, the respiratory cycle is not very regular, particularly during REM sleep, making the synchronization difficult.

SINGLE ELECTRODE CLOSED LOOP PROSTHESIS DESIGN FOR OSA Another approach to the design of a prosthesis for OSA is to use the same electrode for stimulation and recording. The hypoglossal nerve contains mostly motor efferents for the tongue muscles. Therefore, the activity of the nerve should reflect the attempts of the nervous system to open the airway during breathing (or during occlusion) and produce a detectable signal. In particular, hypoglossal activity should precede phrenic nerve activity to open the airways. Moreover, the activity should increase during an obstruction. To test that hypothesis, recording electrodes were placed on the hypoglossal nerve in two dogs and recordings were obtained in a chronic preparation for more than a year (Sahin et al., 1999, 2000). Obstruction was generated by applying a force to the submental region during sleep. Figure 63.5 shows an example of signals recorded during non-REM sleep. The applied force was applied with a ramping waveform. The corresponding increase in esophageal pressure is shown below the force waveform (Pes). The rectified and integrated HG activity is also shown and indicates that during each breadth a small spike of activity in HG activity is detectable just before inspiration. The amplitude of each spike of these increases significantly with obstruction. Therefore, the HG nerve activity is related to breathing and obstruction, indicating that the ENG (electroneurogram) from the hypoglossal nerve could be used as a control signal for the stimulator activating the same electrode. This closed-loop system was implemented and tested successfully in two dogs (Sahin et al., 2000). The results are also shown in Figure 63.5. Following a single ramping obstruction maneuver with submental force, stimulation is applied with the same electrodes (Stim).

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Time (s) FIGURE 63.5 Closed-loop control of UAW patency with a single electrode in a chronic dog preparation. Force: submental force applied externally to produce an obstruction. Pes: esophageal pressure. HG: rectified and integrated hypoglossal ENG. ABD: respiration signal measured with an abdominal sensor. Stim: applied stimulation to the HG electrode. EEG: scalp EEG (Reproduced with permission from Sahin and Durand, 2000. © (2000) IEEE)

The ENG is saturated as expected but the esophageal pressure is clearly reduced during the application of the stimulation. The area under the esophageal pressure waveform was measured and is plotted. When the submental force is applied the pressure is increased, indicating an occlusion. With increasing current amplitudes applied to the hypoglossal nerve, the pressure returns to pre-occlusion levels, indicating opening of the airways. The animal remained asleep during this event, as indicated by the EEG (Figure 63.5). The single electrode design is simpler than the previous design since it requires only a cuff electrode and a stimulator (Figure 63.6). The stimulator must be able to amplify the ENG signal and generate a trigger signal for the stimulation of the nerve. The advantage of the technique is that the hypoglossal indicates when an obstruction is occurring and the nerve activity comes prior to inspiration as required for synchronization. However, the ENG signal is small and difficult to record. Moreover, it has not yet been shown that hypoglossal ENG signals can be obtained from patients with OSA. In fact, human data based on EMG recordings suggest that the activity in the hypoglossal nerve is decreased during an obstruction (Figure 63.2).

The electrode design used for this experiment was a tripolar cuff design with three electrodes similar to the ones shown in Figure 63.4 with the difference that the electrode completely surrounded the nerve. The electrode could record from the nerve and also stimulate the whole nerve. However, the hypoglossal nerve is made up of several fascicles innervating the various muscles that control both the retraction and the protrusion of the tongue. Therefore, it is possible that selective stimulation of the various fascicles could provide additional functional benefits.

OSA PROSTHESIS WITH SELECTIVE STIMULATION Although electrical stimulation studies in OSA patients have shown improvements in the AHI, there is a significant subpopulation of individuals with limited or unpredictable outcomes. Therefore, other critical factors such as stimulation-induced arousal (Schwartz et al., 2001) or UAW compliance could be involved in modulating the effect of electrical stimulation. UAW

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FIGURE 63.7 The canine XIIth nerve and the innervated mus-

FIGURE 63.6 Single electrode prosthesis concept for OSA. An electrode capable of recording and stimulation is placed on the hypoglossal nerve. A stimulator can detect an obstruction and activate the hypoglossal to restore patency with the same electrode (© 2005 Western Reserve Medical Art; used with permission)

compliance (i.e., decreased UAW stiffness), is thought to be involved with the maintenance of patency. To test this hypothesis, co-activation of antagonistic muscles innervated by the hypoglossal nerve, the hyoglossus (HG)/styloglossus (SG), and the medial branch has been investigated. Experiments showed that the added effects of the HG (tongue retraction and depression) and the SG (retraction and elevation of lateral aspect of tongue) significantly improved the outcome of GG activation: increased maximum rate of airflow and mechanical stability of the UAW in animals and also in humans (Eisele et al., 1995, 1997; Fuller et al., 1999). Given the functional influence of the different XIIth nerve branches on the mechanical characteristics of the UAW, it is apparent that selective stimulation of all branches could maximize the therapeutic effects of functional electrical stimulation. This method could provide multiple modes of stimulation to enhance UAW dilation and stability for the subpopulation of patients that exhibit limited or no therapeutic response to activating only the tongue protrudor muscle (Schwartz et al., 2001; Mann et al., 2002). Various multi-contact electrodes capable of selectively activating individual fascicles within nerves

cles are shown in (A): geniohyoid (GH), genioglossus (GG), hyoglossus (HG), and the styloglossus (SG) muscles. In this image, the GH has been elevated to expose the neuromuscular anatomy. Note that the HG muscle is located underneath the nerve, while the GG is adjacent to the GH muscle. (B) A FINE is implanted just proximal to the point divergence, where the functional branches are identified as branches 1, 2, and 3. (C) Normalized EMG response of the muscles as a result of electrically stimulating (monophasic cathodic pulses; PW  50 μs; f  2 Hz; n  16) each nerve branch. The averaged EMG signal was used for HG/SG (Reproduced with permission from Yoo et al., 2002. © (2002) IEEE)

have been developed (Goodall et al., 1996; Loeb and Peck, 1996; Branner et al., 2001; Tyler and Durand, 2002; Tarler and Mortimer, 2004). The flat interface nerve electrode (FINE) takes advantage of the fact that nerves are relatively flat (Tyler and Durand, 2002). This electrode can reshape or maintain the nerve into a flat configuration in order to maximize the number of contacts close to fascicles. A single multi-contact cuff FINE electrode can be placed on a nerve with minimal surgical manipulation. Furthermore, activation of each individual fascicle can be controlled (i.e., selective stimulation) without compromising the perineurium or using steering currents to spatially localize the excitation (Grill and Mortimer, 1995). Selective stimulation of the hypoglossal nerve was tested in beagle dogs (Figure 63.7a) (Yoo et al., 2004). A 13-contact FINE was placed on the nerve just before the branching point (Figure 63.7b). Both EMG and ENG recording electrodes were placed on each of the branches to determine the degree of selectivity. Figure 63.7c shows that each fascicle could be activated fully with only minimal activation of the other branches

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Baseline Branch 2 Branches 23 

0 2.5

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FIGURE 63.8 Effect of selective XIIth nerve stimulation on measured nasopharyngeal pressure (Pn; abscissa) and inspiratory flow (V; ordinate). The point of flow-limitation is indicated by the circles where the corresponding pressure and flow (Pcrit and Vmax) for baseline, branch 2, branches 2  3, and whole nerve (XII) stimulation are (A) 1.2 cmH2O, 4.7 l/min; (B) 1.6 cmH2O, 5.5 l/min; (C) 2.0 cmH2O, 9.7 l/min; and (D) 2.4 cmH2O, 13.4 l/min, respectively (Unpublished data: Yoo and Durand, 2003)

(note that the SG and HG were grouped as a single branch). The effect of selective stimulation on airway resistance and Pcrit was also determined by stimulating either each branch selectively or a combination of branches. Figure 63.8 shows that stimulation of the two branches that produce protrusion (GG and GH) can produce a larger decrease in Pcrit with more flow than stimulation of the whole nerve or branch two alone (GG) (Yoo and Durand, 2005). The results also indicate that stimulation of the whole nerve is also effective at lowering Pcrit. These studies show that electrical stimulation of the XIIth nerve can modulate the mechanical characteristics of an isolated canine UAW and that this effect can be achieved with a single implanted multicontact FINE. Both selective (i.e., individual branch) and non-selective modes of stimulation demonstrated significant increases in UAW caliber during simulated expiration, while UAW patency during inspiration was achieved via co-activation of protruder and retractor branches and also through whole nerve stimulation. While simplifying the clinical implementation of this technology (e.g., single-contact nerve electrode) may benefit the long-term reliability of the implanted device, the observed complex interactions among the muscles innervated by the XIIth nerve suggest a higher degree of control may be required to (a) optimize specific activation levels and combinations

of different muscle groups and (b) account for interpatient variations. Another study with multi-contact selective stimulation electrode showed that stimulation of various combinations of contacts generated different activation patterns of the tongue muscles (Huang et al., 2005). Visualization of the root of the tongue is essential since only the base of the tongue has to move to relieve an obstruction. Since the location of the obstruction can vary from patient to patient, a flexible technique such as selective stimulation could increase the size of the patient population who can benefit from HG nerve stimulation as a treatment method for obstructive sleep apnea. The design of this selective stimulation prosthesis for OSA would require a multi-contact nerve electrode capable of recording and selective stimulation as well as a programmable stimulator capable of activating any electrode of combination of electrodes. The technology for such an electrode does exist (Tyler and Durand, 2002) and selective stimulation could be an important method to refine the stimulation protocol. The electrode would be placed on the nerve and the parameters of the stimulation – electrode site, pulsewidth, frequency – would be programmed to produce the largest possible decrease in the AHI. These various studies suggest that a prototype device capable of whole nerve stimulation with an external sensor is not only feasible but also effective to prevent obstruction in patients with OSA. Other designs with a single electrode and/or selective stimulation have significant potential to improve the performance of the prosthesis but are untested clinically.

CONCLUSION The number of patients affected by this disorder is very large and the consequences of OSA can be very severe. Since the only therapeutic approaches, CPAP mask and surgery, are either tolerated or effective in about 50% of cases, an alternative approach is needed. It is clear from experiments both in humans and animals that electrical stimulation of the hypoglossal nerve can maintain patency of the upper airways. Therefore, stimulation may be the method of choice for patients who either have failed surgery or cannot tolerate the mask. The implant of the cuff electrode in the neck is an invasive approach but not as invasive as other surgical therapeutic approach such as maxillomandibular advancement. Nerve cuff electrodes are currently being implanted in the neck and placed on the vagus nerve for suppression of seizures in patients with epilepsy. This is

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REFERENCES

an outpatient procedure that is well tolerated and safe. Although, hypoglossal nerve stimulation has also been shown to be safe and well accepted in patients, there are still many unsolved problems. Only few chronic studies have been done and there were problems associated with over-stimulation, micro-arousals, lead breakage as well as ineffective synchronization. The procedure has not yet been FDA approved and the development of such a device will require a significant effort, particularly in the area of synchronization. However, this device, if successful, has the potential to increase significantly the quality of life and prevent the development of the many severe symptoms associated with OSA in a large number of patients.

ACKNOWLEDGMENT I would like to thank Saifur Rashid for editing the manuscript of this chapter.

References Badr, M.S. (1999) Pathogenesis of obstructive sleep apnea. Prog. Cardiovasc. Dis. 41 (5): 323–30. Becker, H.F., Jerrentrup, A., Ploch, T., Grote, L., Penzel, T., Sullivan, C.E. et al. (2003) Effect of nasal continuous positive airway pressure treatment on blood pressure in patients with obstructive sleep apnea. Circulation 107 (1): 68–73. Branner, A., Stein, R.B. and Normann, R.A. (2001) Selective stimulation of cat sciatic nerve using an array of varying-length microelectrodes. J. Neurophysiol. 85 (4): 1585–94. Decker, M.J., Haaga, J., Arnold, L., Atzberger, D. and Strohl, K.P. (1993) Functional electrical stimulation and respiration during sleep. J. Appl. Physiol. 75 (3): 1053–61. Edmonds, L.C., Daniels, B.K., Stanson, A.W., Sheedy, P.F., III and Shepard, J.W., Jr. (1992) The effects of transcutaneous electrical stimulation during wakefulness and sleep in patients with obstructive sleep apnea. Am. Rev. Respir. Dis. 146 (4): 1030–6. Eisele, D.W., Schwartz, A.R., Hari, A., Thut, D.C. and Smith, P.L. (1995) The effects of selective nerve stimulation on upper airway airflow mechanics. Arch. Otolaryngol. Head Neck Surg. 121 (12): 1361–4. Eisele, D.W., Smith, P.L., Alam, D.S. and Schwartz, A.R. (1997) Direct hypoglossal nerve stimulation in obstructive sleep apnea. Arch. Otolaryngol. Head Neck Surg. 123 (1): 57–61. Engleman, H.M. and Wild, M.R. (2003) Improving CPAP use by patients with the sleep apnoea/hypopnoea syndrome (SAHS). Sleep Med. Rev. 7 (1): 81–99. Fairbanks, D.W. and Fairbanks, D.N. (1993) Neurostimulation for obstructive sleep apnea: investigations. Ear Nose Throat J. 72 (1): 52–4, 57. Friberg, D. (1999) Heavy snorer’s disease: a progressive local neuropathy. Acta Otolaryngol. 119 (8): 925–33. Friberg, D., Gazelius, B., Hokfelt, T. and Nordlander, B. (1997) Abnormal afferent nerve endings in the soft palatal mucosa of sleep apnoics and habitual snorers. Regul. Pept. 71 (1): 29–36. Fuller, D.D., Williams, J.S., Janssen, P.L. and Fregosi, R.F. (1999) Effect of co-activation of tongue protrudor and retractor muscles

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on tongue movements and pharyngeal airflow mechanics in the rat. J. Physiol. 519 (Pt 2): 601–13. Gami, A.S., Caples, S.M. and Somers, V.K. (2003) Obesity and obstructive sleep apnea. Endocrinol. Metab. Clin. North Am. 32 (4): 869–94. George, C.F. (2001) Reduction in motor vehicle collisions following treatment of sleep apnoea with nasal CPAP. Thorax 56 (7): 508–12. Goding, G.S., Jr., Eisele, D.W., Testerman, R., Smith, P.L., Roertgen, K. and Schwartz, A.R. (1998) Relief of upper airway obstruction with hypoglossal nerve stimulation in the canine. Laryngoscope 108 (2): 162–9. Goodall, E.V., de Breij, J.F. and Holsheimer, J. (1996) Positionselective activation of peripheral nerve fibers with a cuff electrode. IEEE Trans. Biomed. Eng. 43 (8): 851–6. Grill, W.M. and Mortimer, J.T. (1995) Stimulus waveforms for selective neural stimulation. Engineering in Medicine and Biology Magazine, IEEE 14 (4): 375–85. Hida, W., Kurosawa, H., Okabe, S.Y., Kikuchi, J., Midorikawa, Y., Chung, T. et al. (1995) Hypoglossal nerve stimulation affects the pressure-volume behavior of the upper airway. Am. J. Respir. Crit. Care Med. 151 (2 Pt 1): 455–60. Huang, J., Sahin, M. and Durand, D.M. (2005) Dilation of the oropharynx via selective stimulation of the hypoglossal nerve. J. Neural Eng. 2 (4): 73–80. Jamieson, A., Guilleminault, C., Partinen, M. and Quera-Salva, M.A. (1986) Obstructive sleep apneic patients have craniomandibular abnormalities. Sleep 9 (4): 469–77. Levin, B.C. and Becker, G.D. (1994) Uvulopalatopharyngoplasty for snoring: long-term results. Laryngoscope 104 (9): 1150–2. Loeb, G.E. and Peck, R.A. (1996) Cuff electrodes for chronic stimulation and recording of peripheral nerve activity. J. Neurosci. Methods 64 (1): 95–103. Malhotra, A. and White, D.P. (2002) Obstructive sleep apnoea. Lancet 360 (9328): 237–45. Mann, E.A., Burnett, T., Cornell, S. and Ludlow, C.L. (2002) The effect of neuromuscular stimulation of the genioglossus on the hypopharyngeal airway. Laryngoscope 112 (2): 351–6. MedTech (2004) US Markets for Home Healthcare Products. MedTech Insight: 300. Mezzanotte, W.S., Tangel, D.J. and White, D.P. (1992) Waking genioglossal electromyogram in sleep apnea patients versus normal controls (a neuromuscular compensatory mechanism). J. Clin. Invest. 89 (5): 1571–9. Miki, H., Hida, W., Chonan, T., Kikuchi, Y. and Takishima, T. (1989) Effects of submental electrical stimulation during sleep on upper airway patency in patients with obstructive sleep apnea. Am. Rev. Respir. Dis. 140 (5): 1285–9. Miki, H., Hida, W., Shindoh, C., Kikuchi, Y., Chonan, T., Taguchi, O., Inoue, H. and Takishima, T. (1989) Effects of electrical stimulation of the genioglossus on upper airway resistance in anesthetized dogs. Am. Rev. Respir. Dis. 140 (5): 1279–84. Oliven, A., O’Hearn, D.J., Boudewyns, A., Odeh, M., De Backer, W., van de Heyning, P. et al. (2003) Upper airway response to electrical stimulation of the genioglossus in obstructive sleep apnea. J. Appl. Physiol. 95 (5): 2023–9. Oliven, A., Odeh, M. and Schnall, R.P. (1996) Improved upper airway patency elicited by electrical stimulation of the hypoglossus nerves. Respiration 63 (4): 213–16. Oliven, A., Schnall, R.P., Pillar, G., Gavriely, N. and Odeh, M. (2001) Sublingual electrical stimulation of the tongue during wakefulness and sleep. Respir. Physiol. 127 (2-3): 217–26. Ottenhoff, F.A.M. and Michels, K. (2001). Method and apparatus for synchronized treatment of obstructive sleep apnea. US Patent, 6269269.

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Sahin, M. and Huang, J. (2007) Obstructive sleep apnea: electrical stimulation treatment. Encyclopedia of Biomedical Engineering, Vol. 6. NY: Wiley InterScience, pp. 1–10. Sahin, M., Durand, D.M. and Haxhiu, M.A. (1999) Chronic recordings of hypoglossal nerve activity in a dog model of upper airway obstruction. J. Appl. Physiol. 87 (6): 2197–206. Sahin, M., Durand, D.M. and Haxhiu, M.A. (2000) Closed-loop stimulation of hypoglossal nerve in a dog model of upper airway obstruction. IEEE Trans. Biomed. Eng. 47 (7): 919–25. Schwab, R.J., Pasirstein, M., Pierson, R., Mackley, A., Hachadoorian, R., Arens, R. et al. (2003) Identification of upper airway anatomic risk factors for obstructive sleep apnea with volumetric magnetic resonance imaging. Am. J. Respir. Crit. Care Med. 168 (5): 522–30. Schwartz, A.R., Bennett, M.L., Smith, P.L., De Backer, W., Hedner, J., Boudewyns, A. et al. (2001) Therapeutic electrical stimulation of the hypoglossal nerve in obstructive sleep apnea. Arch. Otolaryngol. Head Neck Surg. 127 (10): 1216–23. Schwartz, A.R., Eisele, D.W., Hari, A., Testerman, R., Erickson, D. and Smith, P.L. (1996) Electrical stimulation of the lingual musculature in obstructive sleep apnea. J. Appl. Physiol. 81 (2): 643–52. Schwartz, A.R., Thut, D.C., Russ, B., Seelagy, M., Yuan, X., Brower, R.G. et al. (1993) Effect of electrical stimulation of the hypoglossal nerve on airflow mechanics in the isolated upper airway. Am. Rev. Respir. Dis. 147 (5): 1144–50. Shamsuzzaman, A.S., Gersh, B.J. and Somers, V.K. (2003) Obstructive sleep apnea: implications for cardiac and vascular disease. JAMA 290 (14): 1906–14. Stepnowsky, C.J., Jr, Marler, M.R. and Ancoli-Israel, S. (2002) Determinants of nasal CPAP compliance. Sleep Med. 3 (3): 239–47. Tan, Y.K., Khoo, K.L., Low, J.A., Wong, Z.W., Theng, C.T., Ong, T.H. et al. (1999) Ethnicity, obstructive sleep apnoea and ischaemic heart disease. Ann. Acad. Med. Singapore 28 (2): 214–16. Tarler, M.D. and Mortimer, J.T. (2004) Selective and independent activation of four motor fascicles using a four-contact nerve-cuff electrode. IEEE Trans. Neural Syst. Rehabil. Eng. 12 (2): 251–7.

Testerman, R. (1996a) Method and apparatus for impedance detecting and treating obstructive airway disorders. US Patent, 6269269. Testerman, R. (1996b). Method and apparatus for pressure detecting and treating obstructive airway disorders. US Patent, 5540731. Tran, W., Loeb, G., Ahmed, R.R.F.R., Clark, G. and Haberman, P. (2004) First subject evaluated with simulated BIONtrade mark treatment in genioglossus to prevent obstructive sleep apnea. Conf. Proc. IEEE Eng. Med. Biol. Soc. 6: 4287–9. Tyler, D.J. and Durand, D.M. (2002) Functionally selective peripheral nerve stimulation with a flat interface nerve electrode. IEEE Trans. Neural Syst. Rehabil. Eng. 10 (4): 294–303. Victor, L.D. (1999) Obstructive sleep apnea. Am. Fam. Physician 60 (8): 2279–86. Wiegand, D.A., Latz, B., Zwillich, C.W. and Wiegand, L. (1990) Upper airway resistance and geniohyoid muscle activity in normal men during wakefulness and sleep. J. Appl. Physiol. 69 (4): 1252–61. Wiegand, L., Zwillich, C.W. and White, D.P. (1989) Collapsibility of the human upper airway during normal sleep. J. Appl. Physiol. 66 (4): 1800–8. Yoo, P.B. and Durand, D.M. (2005) The effects of selective hypoglossal nerve stimulation on canine upper airway mechanics. J. Appl. Physiol. 99 (3): 937–43. Yoo, P.B., Sahin, M. and Durand, D.M. (2002) Selective Stimulation of the Hypoglossal Nerve: A FINE Approach to Treating Obstructive Sleep Apnea. Proceedings of the Second Joint EMBS/BMES Conference, Houston, TX, USA, IEEE. Yoo, P.B., Sahin, M. and Durand, D.M. (2004) Selective stimulation of the hypoglossal nerve using a multi-contact cuff electrode. Ann. Biomed. Eng. 32 (4): 511–19. Young, T., Peppard, P.E. and Gottlieb, D.J. (2002) Epidemiology of obstructive sleep apnea: a population health perspective. Am. J. Respir. Crit. Care Med. 165 (9): 1217–39.

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NEUROMODULATION OF BODY ORGANS Introduction Elliot S. Krames Toronto General Hospital. Paul Zoll made smaller but still bulky transcutaneous pacing devices in the following years using a large rechargeable battery as the power supply (Harvard Gazette). In 1957 Dr William L. Weirich of the University of Minnesota demonstrated the restoration of heart rate, cardiac output, and mean aortic pressures in animal subjects with complete heart block through the use of a myocardial electrode (Weirich et al., 1957). The development of the silicon transistor and its first commercial availability in 1956 was the pivotal event which led to rapid development of practical cardiac pacemaking. In 1957 engineer Earl Bakken of Minneapolis, Minnesota produced the first wearable external pacemaker for a patient of Dr C. Walton Lillehei. The first clinical implantation into a human of a fully implantable pacemaker was in 1958 at the Karolinska University Hospital in Solna, Sweden, using a pacemaker designed by Rune Elmqvist and surgeon Åke Senning, connected to electrodes attached to the myocardium of the heart by thoracotomy. The device failed after 3 hours. A second device was then implanted which lasted for 2 days.

The history of neuromodulation as a bioengineering/neuroscience/clinical field of endeavor has its beginnings with the first introduction of a stimulation device to alter abnormal pacing of the heart. In 1928 Dr Mark C. Lidwell of the Royal Prince Alfred Hospital of Sydney devised a portable apparatus where one pole of the device was applied to a skin pad soaked in strong salt solution while the other pole consisted of a needle insulated except at its point, which was plunged into the appropriate cardiac chamber. Lidwell’s device was used to revive a stillborn infant whose heart continued “to beat on its own accord,” at the end of 10 minutes of stimulation (Lidwell, 1929; Mond et al., 1982). In 1932 American physiologist Albert Hyman, working independently, described an electro-mechanical instrument of his own, powered by a spring-wound hand-cranked motor. Hyman himself referred to his invention as an “artificial pacemaker,” the term continuing in use to this day (Furman et al., 2005; Aquilina, 2006). An external pacemaker was designed and built by the Canadian electrical engineer John Hopps in 1950 based upon observations by cardiothoracic surgeon Wilfred Gordon Bigelow at

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The world’s first implantable pacemaker patient, Arne Larsson, went on to receive 26 different pacemakers during his lifetime. He died in 2001, at the age of 86. In February 1960 an improved version of the Swedish Elmqvist design was implanted in Montevideo, Uruguay in the Casmu Hospital by Drs Fiandra and Rubio. That device lasted until the patient died of other ailments 9 months later. The early Swedish-designed devices used rechargeable batteries, which were charged by an induction coil from the outside. Implantable pacemakers constructed by engineer Wilson Greatbatch entered use in humans from April 1960 following extensive animal testing. The Greatbatch innovation varied from the earlier Swedish devices in using primary cells (mercury battery) as the energy source. The first patient lived for a further 18 months. In the late 1960s, several companies, including ARCO in the USA, developed isotope-powered pacemakers, but this development was overtaken by the development in 1970 of the lithium-iodide cell by Wilson Greatbatch. Lithium-iodide or lithium anode cells became the standard for future pacemaker designs (Adams, 1999). Since the work of these early pioneers of cardiac pacing, engineering, neuroscientific, and clinical work has moved to electrical stimulation to improve organ function of the stomach, the intestines, and the bladder. This section on neurostimulation for body organs is edited by Dr Marc Penn (Subsection A: Cardiovascular), Dr Beverly Greenwood-van Meerveld (Subsection B: Gastrointestinal), and Dr Firouz Daneshgari, and Dr Hunter Peckham (Subsection C: Urogenital). In the cardiovascular subsection, first Dr Jeffrey Ardell of the Department of Pharmacology at East Tennessee State University of Johnson City, Tennessee, and Professor Robert Foreman, Professor of Physiology at the University of Oklahoma, Oklahoma City, Oklahoma, discuss the “Neuronal Control of the Heart,” then Dr Thomas Dresing, staff cardiologist at the Cleveland Clinic Department of Cardiovascular Medicine, Section of Electrophysiology and Pacing, in the Cleveland Clinic Heart and Vascular Institute, Cleveland, Ohio, discusses “Disorders of Pacing,” followed by a chapter by Guy Amit, MD, MSc and Kara Quan, MD, of the Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio, discussing “Cardiac Pacemakers – Past, Present, and Future.” In the following chapters Thomas Dresing, again, discusses cardiac defibrillators; Professor Svante Horsch, Department of Vascular Surgery, Hospital Porz am Rhein, Academic Teaching Hospital of the University of Cologne, Germany, and Dr Stefan Schulte of the Center for Vascular Medicine and Vascular Surgery, MediaPark Clinic, Cologne, Germany, discuss SCS for vascu-

lar disorders; Drs Mike DeJongste, cardiologist of the University of Groningen, Groningen, the Netherlands, and Robert Foreman of the Department of Physiology, University of Oklahoma, Oklahoma City, Oklahoma, discuss SCS for refractory angina; Drs Tara Mastracci, of the Department of Surgery, Division of Vascular Surgery, McMaster University, Hamilton, Ontario, Canada, and Roy K. Greenberg of the Department of Vascular and Endovascular Surgery, Cleveland, Ohio, discuss neurostimulation at the vascular system; Sandra Machado, MD, of the Department of Anesthesiology, Kwangdeok Lee, PhD, of the Department of Stem Cell Biology and Regenerative Medicine, and Marc Penn, MD, PhD, of the Bakken Heart Brain Institute of Cardiovascular Medicine, Stem Cell Biology and Regenerative Medicine and Biomedical Engineering, of the Cleveland Clinic, Cleveland, Ohio, discuss neurostimulation for heart failure and arrhythmias. In the next subsection the focus is on neuromodulation for gastrointestinal disorders. Dr Beverly Greenwoodvan Meerveld, PhD, FACG, Professor of Physiology, Presbyterian Health Foundation Chair in Neuroscience, Director, Oklahoma Center for Neuroscience, Oklahoma and Dr Foreman discuss the abdominal organs and neuronal control; Dr Leonardo Kapural, of the Department of Pain Medicine, Department of Anesthesiology, the Cleveland Clinic, Cleveland, Ohio, discusses SCS for GI painful disorders; Dr Cristian Sevcencu, from the Center for Sensory-Motor Interaction, Department of Health Science and Technology, Aalborg University, Aalborg, Denmark, writes on “Gastric Stimulation for Obesity and Dysmotility Disorders” and Drs Jieyun Yin and Jiande Chen from the Division of Gastroenterology, Department of Internal Medicine, University of Texas Medical Branch at Galveston, Texas, write on “Intestinal Electrical Stimulation.” In the third subsection the focus is on neuromodulation for urogenital disorders. First is the excellent chapter by Dr Firouz Daneshgari, MD, Professor and Chairman, Department of Urology & Female Pelvic Surgery, Upstate Medical University, Syracuse, New York, and Dr William C. de Groat, Professor of Pharmacology at the University of Pittsburgh Medical School, Pennsylvania, on genitourinary function and nervous system control, which is followed by chapters on “Sacral Nerve Root Stimulation for Painful Bladder Disorders” by Drs Adnan Al-Kaisy, Chairman of the Pain Clinic at Guys and St Thomas’s Hospital, London, UK, and K. Riaz Khan of the same clinic, and on “Neuromodulation for Voiding Dysfunction” by Sarah McAchran, MD, Department of Urology at the Case Western School of Medicine, Cleveland, Ohio, and Drs Raymond Rackley and Sandip Vasavada of the Department of Urology at the Cleveland Clinic, Cleveland, Ohio.

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References Adams, John (1999) Making hearts beat. Innovative Lives – The Smithsonian’s Lemelson Center for the Study of Invention and Innovation. Smithsonian Institution (retrieved 19 April 2008). Aquilina, O. (2006) A brief history of cardiac pacing. Images Paediatr. Cardiol. 27: 17–81. Furman, S., Szarka, G. and Layvand, D. (2005) Reconstruction of Hyman’s second pacemaker. Pacing Clin. Electrophysiol. 28 (5): 446–53.

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Harvard Gazette (2001) Paul Maurice Zoll http://www.hno.harvard. edu/gazette/2001/04.19/12-zoll.html (retrieved ???) Lidwell, M.C. (1929) Cardiac disease in relation to anaesthesia, 2-7 September. Transactions of the Third Session. Sydney, Australia: Australasian Medical Congress, p. 160. Mond, H., Sloman, J. and Edwards, R. (1982) The first pacemaker. Pacing Clin. Electrophysiol. 5 (2): 278–82. Weirich, W., Gott, V. and Lillehei, C. (1957) The treatment of complete heart block by the combined use of a myocardial electrode and an artificial pacemaker. Surg. Forum, 8: 360–3.

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64 Neuronal Control of the Heart Jeffrey L. Ardell and Robert D. Foreman

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stimulation, SCS) sites, is one such emerging therapy and it has a clinical history of over 20 years in treating cardiac pain, especially in patients refractory to conventional surgical or pharmacological approaches (Mannheimer et al., 2002). At present, more than 3000 cases have been implanted for this indication, with approximately 400 being added annually (Mannheimer et al., 2002). When first introduced, SCS neuromodulation-based therapy met with skepticism, especially from cardiologists, with the primary criticism based on the erroneous assumption that cardiac pain would be masked by the therapy, rather than the clinical condition being improved. Subsequent clinical studies demonstrated that chronic SCS exerts its anti-anginal effects without impeding signs of critical cardiac ischemia (Mannheimer et al., 2002). Recognized patient benefits to SCS include reduced ST segment alterations induced during exercise (Sanderson et al., 1992), improved myocardial lactate metabolism (Mannheimer et al., 1993) and increased workload tolerance (Sanderson et al., 1992). While the precise mechanisms that produce beneficial effects in heart disease from this mode

HISTORY OF THE BASIC DISCOVERY OR TECHNOLOGY Myocardial ischemia evokes a myriad of responses from the heart itself, to the neurohumoral systems that modulate it, to behavioral consequences including the perception of pain. Armour (Armour, 1999) recently reviewed the interdependent cardiac and neurohumoral response to myocardial ischemia. We consider herein the basis and potential of neuromodulation therapy in treating such cardiac pathology. The treatment of myocardial ischemia and resultant cardiac pain has evolved from bed rest, to the advent of pharmacological and surgical approaches targeted at coronary blood flow and heart muscle, to the concept of therapies based upon modulating the interdependent interactions between the heart and its associated neurohumoral control systems (Kim et al., 2002; Mannheimer et al., 2002; Armour, 2004). Neuromodulation therapy, using electrical stimulation of peripheral (TENS) or central (spinal cord

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of therapy are not fully understood, recent basic science studies have indicated the SCS modifies/modulates not only myocytes themselves (Cardinal, Ardell et al., 2004; Southerland et al., 2007), but also the primary neural control mechanisms that regulate the heart (Armour et al., 2002). The end result to SCS is an effective “cardioprotection” to transient cardiac stress with the potential to reduce cell death, stabilize cardiac electrical function, and sustain contractile function.

cardiac function of the normal heart. Figure 64.1 summarizes our current working hypothesis for the neurohumoral interactions occurring within this hierarchy (Ardell, 2004). Efferent neural function is dependent upon (a) the information transduced within the intrathoracic neuronal hierarchy (Armour, 2004; Armour and Kember, 2004); (b) the direct effects of various circulating agents on cardiac efferent neurons (e.g. angiotensin II acting on sympathetic soma and pre-junctional sites) (Horackova and Armour, 1997; Farrell et al., 2001); and (c) the influence of descending projections from central neurons to the intrathoracic cardiac nervous system (Andresen et al., 2004) (Figure 64.1). Recent studies, in animal models, have evaluated the potential for SCS to impact on various levels of hierarchy for cardiac control. In a series of studies in anesthetized canines, electrical stimulation with “clinical parameters” (50 Hz, 90% motor threshold) of the dorsal

CURRENT STATE OF BASIC SCIENCE OR TECHNICAL KNOWLEDGE Anatomical and functional data collected over the past two decades have led us to propose the presence of a complex neuronal hierarchy that controls regional

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FIGURE 64.1 Schematic of proposed interactions that occur within and among intrathoracic autonomic neurons and between them and central neurons. Intrinsic cardiac ganglia possess afferent neurons, sympathetic (Sympath) and parasympathetic (Parasym) efferent neurons and interconnecting local circuit neurons (LCN). Contained within intrathoracic extracardiac ganglia are afferent neurons, local circuit neurons, and sympathetic efferent neurons. Neurons in these intrinsic cardiac and extracardiac networks form separate and distinct nested feedback loops that act in concert with CNS feedback loops involving the spinal cord and medulla to coordinate regional cardiac function on a beat-to-beat basis. Circulating humoral factors including catecholamines and angiotensin II also influence this neuronal hierarchy. Symbols: Aff., afferent; DRG, dorsal root ganglia; Gs, stimulatory guanine nucleotide binding protein; Gi, inhibitory guanine nucleotide binding protein; AC, adenylate cyclase; β1, β1-adrenergic receptor; M2, M2-muscarinic receptor (Adapted from Ardell (2004) and used with permission of Oxford University Press) IXA. NEUROMODULATION FOR CARDIOVASCULAR DISORDERS

CURRENT STATE OF BASIC SCIENCE OR TECHNICAL KNOWLEDGE

columns at T1–T2 segments reduced activity generated by the intrinsic cardiac neurons ⬃70% in their basal conditions, as well as when activated in the presence of regional ventricular ischemia (Figure 64.2) (Foreman et al., 2000a). The intrinsic cardiac nervous system functions as the final common pathway for neural control of cardiac control (Armour, 2004), and modulation of its activity is a primary determinant for subsequent changes in cardiac function (Ardell, 2001). In this regard, SCS similarly reduced intrinsic cardiac neuronal activity, whether it was applied before, during or following the onset of transient coronary artery occlusion (Foreman et al., 2000a). Transection of the ansae subclavian (a nerve that connects the middle and inferior cervical ganglion and loops around the subclavian artery) eliminated the suppressor effects of SCS on intrinsic cardiac neural activity, indicating that the responses were due primarily to the influence of spinal cord neurons acting via the sympathetic nervous system (Foreman et al., 2000a). In a follow-up study (Armour et al., 2002), the suppressing effects of SCS on intrinsic cardiac neuronal activity persisted for at least 45 min after SCS was terminated. This observation, supported by clinical studies (Ekre et al., 2003), indicates that a cardioprotective benefit may persist even after SCS therapy is discontinued. While memory is a well-recognized phenomenon in behavioral science, its contribution to neurohumoral control of cardiac function is less appreciated. Slow responding cardiac multimodal receptors display

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FIGURE 64.2 Change in intrinsic cardiac neuronal (ICN) activity induced by transient occlusion of the left anterior descending artery (Coronary occl.). Note the increased activity within the intrinsic cardiac nervous system evoked by transient coronary occlusion and reperfusion (left panels). Onset of SCS neuromodulation (T1–T3 dorsal horn) resulted in prompt suppression of neuronal activity within the ICN that was maintained even during the stress of concurrent transient myocardial ischemia. *p 0.05 from control (Adapted from Foreman et al. (2000a) and used with permission of Oxford University Press)

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“memory” function, being affected by past events in the cardiac interstitium and providing major inputs to slow latency reflexes involved in long-term cardiac control (Armour and Kember, 2004). As demonstrated above, SCS likewise can exert effects on peripheral aspects of the cardiac nervous system that far outlive the cord stimulus duration (Armour et al., 2002). Centrally mediated effects of SCS show a divergence from peripheral effects with respect to memory. Specifically, it has been demonstrated that cervical and high thoracic SCS modifies the cardiac nociceptive activity of spinothalamic tract neurons within the T3–T4 segments (Foreman et al., 2000b). However, in contrast to the long-lasting effects of SCS on the activity of the intrinsic cardiac neurons (Armour et al., 2002), the evoked activity of spinothalamic tract cell neurons was suppressed only during SCS (Chandler et al., 1993). The specific neurotransmitters subserving the immediate and longer-term effects of SCS remain to be determined, but likely candidates include catecholamines (Southerland et al., 2007) and neuropeptides including CGRP and substance P (Armour et al., 1993; Croom et al., 1997; Hoover et al., 2000). Excessive reflex activation of the cardiac nervous system during progressive cardiac disease exacerbates the resultant cardiac pathology (Armour, 1999; Tallaj et al., 2003; Dell’Italia and Ardell, 2004). As such, blunting/stabilization in that reflex response, as with SCS, should mitigate against principal adverse consequences of such a stress, including apoptosis (cell death). In anesthetized rabbits, pre-emptive, but not reactive, SCS (C8–T2) reduced infarct size to transient myocardial ischemia (Figure 64.3) (Southerland et al., 2007). This SCS-mediated infarct reduction was eliminated by α1-adrenergic blockade and blunted by β-adrenergic blockade (Figure 64.3). These data demonstrate that such SCS-mediated cardioprotection involves cardiac adrenergic neurons. The ineffectiveness of reactive SCS to reduce infarct size in the acute setting represents a therapeutic limitation. However, in clinical practice, SCS has been shown to be a long-term adjunct therapy for patients with chronic angina pectoris (Mannheimer et al., 2002). It should be considered that as an unrecognized benefit to chronic SCS therapy, these patients may experience a relative state of cardioprotection to transient periods of myocardial ischemia. In patients with ischemic heart disease, SCS reduced the magnitude of ST segment changes induced during exercise (Sanderson et al., 1992). To model this disease state, in chronic canine models, an Ameroid constrictor was implanted around the proximal left circumflex coronary artery (Cardinal, Ardell et al., 2004; Cardinal, Rousseau et al., 2004). This constrictor produces a slow and gradual obstruction of blood flow through the artery, creating a chronic regionalized myocardial

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FIGURE 64.3 Infarct size plotted as a percentage of risk zone for control animals subjected to ischemia (coronary artery occlusion, CAO) versus animals with 50 Hz pre-emptive SCS  CAO. The preemptive SCS groups received vehicle or selective adrenergic blockade (prazosin or timolol) 15 minutes (Rx) prior to SCS onset. *p 0.05 compared to CAO alone; #p 0.05 compared to vehicle control (Adapted from Southerland et al. (2007), Fig. 3, and used with permission of the American Physiological Society)

metabolic stress substrate (Cardinal, Rousseau et al., 2004). When evaluated at 6 weeks post implant, angiotensin II activation of cardiac sympathetic efferents induces ST segment deviations, primarily restricted to the ischemic zone downstream from the occluder (Figure 64.4). When SCS was initiated concurrent with the angiotensin II activation of cardiac nervous system, the induced ST segment deviations were mitigated (Cardinal, Ardell et al., 2004). In contrast, in this model, SCS was ineffective in modifying the regional ST segment responses induced by transient periods of rapid ventricular pacing (Cardinal, Ardell et al., 2004). These data indicate that the effectiveness of SCS to impact on electrical instability of the heart is stress dependent. Imbalances in nerve activity within the cardiac nervous system can lead to arrhythmia formation, including fibrillation (Cardinal and Pagé, 2004). Figure 64.5 shows an example of transient atrial fibrillation induced by trains of electrical stimuli delivered to intrathoracic mediastinal nerves (Cardinal et al., 2006). After SCS, the potential to generate atrial arrhythmias via mediastinal nerve stimulation was reduced (Figure 64.5, bottom panel). After bilateral stellectomy, SCS no longer

200 ms

6.7 mV

FIGURE 64.4 ST segment changes in response to intracoronary angiotensin II (Ang II) administration and its subsequent activation of the cardiac nervous system. Left hand panels indicate regional electrical response to Ang II (top panel), with representative site a residing in the normal perfused LV myoardium and site b localized to the ischemic-stressed zone (bottom panels). In the same animal, right hand panels indicate response Ang II challenge in the presence of SCS. Note that SCS attenuated the Ang II evoked ST segment deviations (Adapted from Cardinal, Ardell et al. (2004), Fig. 4, with permission. Copyright (2004) Elsevier)

influenced mediastinal stimulation-induced arrhythmias (Cardinal et al., 2006). These data indicate that SCS obtunds the induction of atrial arrhythmias resulting from excessive activation of intrinsic cardiac neurons and that such protection depends upon nerves coursing from the spinal cord via the stellate ganglia and ansae subclavia. The relative contributions of sympathetic efferents versus afferents in mediating this stabilizing effect on cardiac electrical function remain to be determined.

USE OF KNOWLEDGE OR TECHNOLOGY IN CLINICAL APPLICATIONS SCS for treatment of angina pectoris has proved to be much more effective and dependable than when used for neuropathic pain conditions (Foreman et al., 2004). The success rate for relieving angina pectoris is often in the range of 80% or greater after several years of followup (Mannheimer et al., 2002; Foreman et al., 2004). In fact a randomized, prospective study in 104 patients shows

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WHAT IS NEEDED TO FILL THESE GAPS/DEFICITS

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GAPS IN KNOWLEDGE OR TECHNOLOGY FOR CLINICAL APPLICATIONS

Basal

SCS

5 sec

FIGURE 64.5 In basal conditions, stimulation of mediastinal nerves coursing closely adjacent to the ascending common pulmonary artery induced a 10 sec run of atrial tachycardia (arrows indicate two shortduration pulse trains delivered during atrial refractory period). With pre-emptive SCS, even in the face of repeated stimulation (arrows) of these same nerves, the atrium maintained stability

that SCS is equally effective as bypass surgery in eliminating angina at 6 month follow-up but that the thoracic surgery carried significantly more instances of morbidity and even mortality (Ekre et al., 2002). Besides the reduction in angina pectoris, clinical studies have shown that SCS also reduces the ischemia associated with exertional stress (Sanderson et al., 1992), while maintaining the pain response to critical levels of ischemia (Mannheimer et al., 2002). Importantly, these SCS-mediated effects show minimal adaptation with time (Ekre et al., 2003). Typically, chronic stable angina can be treated with revascularization procedures such as percutaneous transluminal angioplasty or coronary artery bypass surgery and/or with medications such as ACE inhibitors, beta blockers and calcium-channel blockers (Kim et al., 2002). However, a significant number of patients have chronic refractory angina pectoris, i.e. they do not get sufficient pain relief or restoration of function even from available surgical and optimal medical treatment. Based on conservative criteria, it has been estimated that approximately 100 000 patients per year in North America and an equal number in Europe are diagnosed as suffering from this chronic condition. To standardize adjunct treatments and therapeutically assess these patients, an algorithm has been developed by the European Society of Cardiology Joint Study Group (Mannheimer et al., 2002). In their report, and the review by Kim et al. (2002), it is concluded that at present electrical neuromodulation may be one of the best available adjunct therapies for refractory angina.

While basic science has provided important mechanistic insights into the effects of electrical neuromodulation therapy to impact the cardiac nervous system and the cardiac tissues it innervates, clinical correlates for this data are lacking. In the clinical literature, conclusions are made with regards to neuromodulationinduced improvements in supply/demand balance of the heart (Hautvast et al., 1996; Mannheimer et al., 2002), but clinical data indicating the specific neurotransmitter and signal transduction basis for such changes are lacking. With the advent of intrathoracic neural recording techniques in humans (Arora et al., 2001), it is now feasible to address such questions. It should also be considered clinically that SCS may alter central processing of cardiac specific inputs, both within the spinal cord and within higher central structures, an idea that has substantial basic science support (Foreman et al., 2000b). Finally, it is evident from basic science studies that neuromodulation therapy has therapeutic potential besides its well-recognized anti-anginal and anti-ischemic properties (Mannheimer et al., 2002), specifically in myocyte viability (Southerland et al., 2007) and electrical stabilization (Cardinal, Ardell et al., 2004; Issa et al., 2005; Cardinal et al., 2006) of the diseased heart.

WHAT IS NEEDED TO FILL THESE GAPS/DEFICITS SCS may depend on the hierarchical control of the spinal cord to influence the function of the final common neuronal pathway of the heart, the intrinsic cardiac nervous system, in the presence of ischemic challenge. These observations suggest that SCS could limit myocardial ischemia by modifying heart tissues and stabilizing the neuronal circuits of the cardiac nervous system that could otherwise induce arrhythmias leading to more generalized ischemic threats. In either case, effects of SCS on the activity of the intrinsic cardiac nervous system support the important concept of a regulatory hierarchy for cardiac function. We believe that the activity elicited at each level in the hierarchy, from the brain stem to the spinal cord, and further to the intrathoracic neurons, is eventually transmitted to the intrinsic cardiac nervous system. Very little information has been published to address underlying mechanisms that could explain how the central and cardiac nervous systems interact to maintain adequate

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64. NEURONAL CONTROL OF THE HEART

efferent neuronal input to the heart. Disease processes could change the balance between the central and peripheral neurons involved in such regulation. A disturbance in the fine balance within the whole cardiac neuroaxis might result in dramatic changes in cardiac efferent neuronal outflow. As a result, these disturbances could lead to the development of dysrhythmias that might progress to ventricular fibrillation. Such disturbances may also accelerate the progression into congestive heart failure. Future research should be directed at understanding the short- and long-term effects of neuromodulation therapy on peripheral and central elements of the cardiac nervous system as well as those evoked at the end-terminus cardiomyocytes. It should also be considered that optimum stimulus parameters and the site of optimum stimulation (thoracic versus cervical cord; SCS versus TENS) may differentiate depending which cardiac function (electrical or mechanical) is being targeted. Finally, clinical studies should consider the potential efficacy of moving neuron-stimulatory therapies up the treatment ladder and not just as therapy utilized for patients in which all other therapeutic options have been exhausted.

References Andresen, M.C., Kunze, D.L. and Mendelowitz, D. (2004) Central nervous system regulation of the heart. In: J.A. Armour and J. L. Ardell (eds), Basic and Clinical Neurocardiology. New York: Oxford University Press, pp. 187–219. Ardell, J.L. (2001) Neurohumoral control of cardiac function. Heart Physiology and Pathophysiology. New York: Academic Press, pp. 45–59. Ardell, J.L. (2004) Intrathoracic neuronal regulation of cardiac function. In: J.A. Armour and J.L. Ardell (eds), Basic and Clinical Neurocardiology. New York: Oxford University Press, pp. 118–52. Armour, J.A. (1999) Myocardial ischemia and the cardiac nervous system. Cardiovasc. Res. 41: 41–54. Armour, J.A. (2004) Cardiac neuronal hierarchy in health and disease. Am. J. Physiol. Regul. Integr. Comp. Physiol. 287: R262–71. Armour, J.A. and Kember, G. (2004) Cardiac sensory neurons. In: J.A. Armour and J.L. Ardell (eds), Basic and Clinical Neurocardiology. New York: Oxford University Press, pp. 79–117. Armour, J.A., Huang, M.H. and Smith, F.M. (1993) Peptidergic modulation of in situ canine intrinsic cardiac neurons. Peptides 14: 191–202. Armour, J.A., Linderoth, B., Arora, R.C., DeJongste, M.J.L., Ardell, J. L., Kingma, J.G. et al. (2002) Long-term modulation of the intrinsic cardiac nervous system by spinal cord neurons in normal and ischemic hearts. Auton. Neurosci. 95: 71–9. Arora, R.C., Hirsch, G.M., Hirsch, K.J., Friesen, C.H. and Armour, J. A. (2001) Function of human intrinsic cardiac neurons in situ. Am. J. Physiol. Regul. Integr. Comp. Physiol. 280: R1736–40. Cardinal, R. and Pagé, P.L. (2004) Neuronal modulation of atrial and ventricular electrical properties. In: J.A. Armour and J.L. Ardell (eds), Basic and Clinical Neurocardiology. New York: Oxford University Press, pp. 315–39. Cardinal, R., Ardell, J.L., Linderoth, B., Vermeulen, M., Foreman, R. D. and Armour, J.A. (2004) Spinal cord activation differentially

modulates ischemic electrical responses to different stressors in canine ventricles. Auton. Neurosci. 111: 37–47. Cardinal, R., Pagé, P.L., Vermeulen, M., Bouchard, C., Ardell, J.L., Foreman, R.D. et al. (2006) Spinal cord stimulation suppresses bradycardias and atrial tachyarrhythmias induced by mediastinal nerve stimulation in dogs. Am. J. Physiol. Regul. Integr. Comp. Physiol. 291: R1369–R1375. Cardinal, R., Rousseau, G., Bouchard, C., Vermeulen, M., Latour, J.-G. and Pagé, P.L. (2004) Myocardial electrical alterations in canine preparations with combined chronic rapid pace and progressive coronary artery occlusion. Am. J. Physiol. Heart Circ. Physiol. 286: H1496–H1506. Chandler, M.J., Brennan, T.J., Garrison, D.W., Kim, K.S., Schwartz, P. J. and Foreman, R.D. (1993) A mechanism of cardiac pain suppression by spinal cord stimulation: implications for patients with angina pectoris. Eur. Heart J. 14: 96–105. Croom, J.E., Foreman, R.D., Chandler, M.J. and Barron, K.W. (1997) Cutaneous vasodilation during dorsal column stimulation is mediated by dorsal roots and CGRP. Am. J. Physiol. 272: H950–H957. Dell’Italia, L.J. and Ardell, J.L. (2004) Sympathetic nervous system in the evolution of heart failure. In: J.A. Armour and J.L. Ardell (eds), Basic and Clinical Neurocardiology. New York: Oxford University Press, pp. 340–67. Ekre, O., Eliasson, T., Norrsell, H., Wahrborg, P. and Mannheimer, C. (2002) Long-term effects of spinal cord stimulation and coronary artery bypass grafting on quality of life and survival in the ESBY study. Eur. Heart J. 23: 1938–45. Ekre, O., Norrsell, H., Wahrborg, P., Eliasson, T. and Mannheimer, C. (2003) Temporary cessation of spinal cord stimulation in angina pectoris- effects on symptoms and evaluation of longterm determinants. Coron. Artery Dis. 14: 323–7. Farrell, D.M., Wei, C.C., Tallaj, J., Ardell, J.L., Armour, J.A., Hageman, G.R. et al. (2001) Angiotensin II modulates catecholamine release into interstitial fluid of canine ventricle in vivo. Am. J. Physiol. Heart Circ. Physiol. 281: H813–22. Foreman, R.D., DeJongste, M.J.L. and Linderoth, B. (2004) Integrative control of cardiac function by cervical and thoracic spinal neurons. In: J.A. Armour and J.L. Ardell (eds), Basic and Clinical Neurocardiology. New York: Oxford University Press, pp. 153–86. Foreman, R.D., Linderoth, B., Ardell, J.L., Barron, K.W., Chandler, M.J., Hull, S.S. et al. (2000a) Modulation of intrinsic cardiac neurons by spinal cord stimulation: implications for therapeutic use in angina pectoris. Cardiovasc. Res. 47: 367–75. Foreman, R.D., Linderoth, B., DeJongste, M.J.L., Ardell, J.L. and Armour, J.A. (2000b) Central and peripheral mechanisms evoked by spinal cord stimulation (SCS) for angina pectoris. In: E. Krames and E. Reig (eds), Management of Acute and Chronic Pain. Bologna: Monduzzi, pp. 597–604. Hautvast, R.W., Blanksma, T.K., DeJongste, M.J.L., Pruim, J., van der Wall, E.E., Vaalburg, W. et al. (1996) Effect of spinal cord stimulation on myocardial blood flow assessed by positron emission tomography in patients with refractory angina pectoris. Am. J. Cardiol. 77: 462–7. Hoover, D.B., Chang, Y., Hancock, J.C. and Zhang, L. (2000) Actions of tachykinins within the heart and their relevance to cardiovascular disease. Jpn J. Pharmacol. 84: 367–73. Horackova, M. and Armour, J.A. (1997) ANG II modifies cardiomyocyte function via extracardiac and intracardiac neurons: in situ and in vitro studies. Am. J. Physiol. 272: R766–R775. Issa, Z.F., Zhou, X., Ujhelyi, M.R., Rosenberger, J., Bhakta, D., Groh, W.J. et al. (2005) Thoracic spinal cord stimulation reduces the risk of ischemic ventricular arrhythmias in a post-infarction heart failure canine model. Circulation 111: 3217–20.

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REFERENCES

Kim, M.C., Kini, A. and Sharma, S.K. (2002) Refractory angina pectoris: mechanism and therapeutic options. J. Am. Coll. Cardiol. 39: 923–34. Mannheimer, C., Camici, P., Chester, M.R., Collins, A., DeJongste, M.J.L., Eliasson, T. et al. (2002) The problem of chronic refractory angina: Report from the ESC Joint Study Group on Treatment of Refractory Angina. Eur. Heart J. 23: 355–70. Mannheimer, C., Eliasson, T., Andersson, B., Bergh, C.H., Augustinsson, L.E., Emanuelsson, H. et al. (1993) Effects of spinal cord stimulation in angina pectoris induced by pacing and possible mechanisms of action. Br. Med. J. 307: 477–80. Sanderson, J.E., Brooksby, P., Waterhouse, D., Palmer, R.B. and Neubauer, K. (1992) Epidural spinal electrical stimulation for

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severe angina: a study of its effects on symptoms, exercise tolerance and degree of ischemia. Eur. Heart J. 13: 628–33. Southerland, E.M., Milhorn, D., Foreman, R.D., Linderoth, B., DeJongste, M.J.L., Armour, J.A. et al. (2007) Preemptive, but not reactive, spinal cord stimulation mitigates transient ischemiainduced infarction via cardiac adrenergic neurons. Am. J. Physiol. Heart Circ. Physiol. 292: H311–H317. Tallaj, J., Wei, C.C., Hankes, G.H., Holland, M., Rynders, P., Dillon, A.R. et al. (2003) β1-adrenergic receptor blockade attenuates angiotensin II-mediated catecholamine release into the cardiac interstitium in mitral regurgitation. Circulation 108: 225–30.

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C H A P T E R

65 Disorders of Pacing Thomas Dresing

O U T L I N E History of Cardiac Pacing

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Additional Programming and Features

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Cardiac Resynchronization Therapy (CRT)

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Implant Procedure

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epicardial electrodes that were passed through the skin. In Sweden in 1958 the first implantable pacemaker attached to epicardial leads was implanted though its lifespan was only a few hours before a replacement that only lasted several days was needed. The first transvenous pacing lead was inserted in the USA in 1959 via the basilic vein by Sy Furman and was reported in the New England Journal of Medicine (Furman and Schwedel, 1959). Battery and pulse generator technologies developed in the early 1960s and 1970s resulted in the devices that resemble today’s pacemakers. The recent developments have been focused on the circuitry and processing as well as data storage and programmability features of the devices, as well as the lead technology.

HISTORY OF CARDIAC PACING The drive behind the development and accessibility of cardiac pacing was largely impelled by cardiothoracic surgeons in the early days of open heart surgery. Complete atrioventricular block was a frequent complication of early open heart surgery which hampered survival despite the technical success of the procedure. It had been shown that external stimulation of a sufficient strength could capture the myocardium and result in contraction by Zoll and others in the early 1950s, though these devices were quite large, painful and truly dangerous with a small margin of error for initiating ventricular fibrillation. Perhaps 25 years earlier, although similar but more invasive attempts at cardiac pacing had been demonstrated to be efficacious, they met with resistance due to the ethical climate of the day. By the late 1950s Earl Bakken, who had founded Medtronic several years earlier to produce small medical electronic devices, had produced a small wearable external pacemaker which was attached to

Neuromodulation

BASIC ELEMENTS OF A PACEMAKER SYSTEM A cardiac pacemaker typically consists of two elements: a pulse generator and anywhere from one to

801

2009 Elsevier Ltd. © 2008,

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three leads, depending on the type of system, as will be detailed below. The hermetically sealed titanium case of the pulse generator contains the power source, which is most commonly a lithium iodide battery, and the circuitry. The circuitry is a sophisticated collection of microprocessors and circuits which control the sensing, timing, and output of the pulse generator. The two basic features of the pulse generator are sensing and pacing. Sensing refers to the information that is delivered to the pacemaker via the leads or other sensors incorporated into the pacemaker, such as impedance measurements and activity sensors. Pacing refers to the electrical output of the pacemaker. The leads are composed of conductors (coils) and insulation (typically silicone rubber or polyurethane), as well as two distinctly different ends. As the majority of leads implanted today are done transvenously, bipolar leads are almost always used. Exceptions would include epicardial leads, which are more commonly unipolar and implanted on the outside surface of the heart during an open thoracotomy. Bipolar leads have two in-line electrodes at each end which are insulated from each other and attached to two coaxial coils, separated by insulation. At the end attached to the pulse generator, a connector pin extending from the inner coil and having () polarity, and an electrode attached from the outer coil with () polarity are inserted into the so-called “header” of the pulse generator and attached with a screw to ensure proper contact. At the end that interfaces with the cardiac surface are the two electrodes and a fixation device. The distal electrode is attached to the inner coil and has () polarity. The proximal electrode is attached to the outer coil and has () polarity. In order to ensure longterm contact with the cardiac surface, the distal end has a fixation device. Active fixation leads have a screw that is either fixed or extendable–retractable, and this is embedded in the endocardial surface. Passive fixation leads have small, finger-like projections (tines) that extend from the leads and catch on the endocardial surface. Over time, fibrosis occurs at the lead/ endocardial surface interface and the passively fixated lead becomes adherent to the surface. Unipolar leads have only a single () electrode at each end of the lead and have a () electrode within the pacemaker pulse generator. While unipolar leads offer the advantage of improved sensing of low-amplitude signals, they are more prone to oversensing of non-cardiac signals, such as pectoralis muscle activity, and the current of stimulation may capture skeletal muscle in the path, such as the pectoral muscles causing twitches in these muscles. The coronary sinus leads used in a cardiac resynchronization pacing system will be discussed below.

IMPLANT PROCEDURE The vast majority (95%) of pacemaker implants today are done transvenously. Exceptions would include the pediatric congenital heart population, owing to size and the issue of rapid growth of the patient, and the population requiring epicardial leads due to the presence of prosthetic heart valves, congenital heart disease, recurrent intravascular infection or inability to place intravascular leads. The most common sites for implantation are the pre-pectoral regions below the clavicles, using the subclavian or cephalic veins for access to the venous system. While access to the cephalic vein is usually direct using a cut-down technique, the subclavian veins are usually accessed via venipuncture of the veins under the clavicle using fluoroscopic guidance for landmarks and or venography. Once the veins are accessed, the leads are either directly inserted into the veins after cut-down or inserted through sheaths placed in the veins over guidewires. The leads are then fluoroscopically guided into position and fixated into the desired chamber. The leads are then secured to the fascia and attached to the pulse generator. The leads and generator are then placed into a subcutaneous or submuscular pocket which is then closed. Rarely, conditions will dictate that the venous access is in another site, such as the iliac or jugular veins. Acute complications account for approximately 1% of implants and are chiefly bleeding, pneumothorax, hematoma, cardiac perforation/tamponade, infection, and lead dislodgment. The incidence of chronic complications is not entirely clear due to inconsistencies in reporting, but complications include infection, venous thrombosis, and device malfunction. The unique techniques used in placing coronary sinus leads for cardiac resynchronization therapy will be discussed below.

BASIC TERMINOLOGY, PROGRAMMING, AND TIMING CYCLES Table 65.1 demonstrates the five-position NBG pacemaker programming code. Position I indicates the chamber(s) paced. A device pacing in only one chamber will be given the designation “A” (atrial) or “V” (ventricular), whereas a device pacing both chambers will be given the designation “D” (dual, meaning atrial and ventricular). Some companies permit programming the pacing function “off” and this is designated “O”. Some manufacturers will use “S” in position I for a device that can be attached to a lead in either the atrium or ventricle. Position II represents the chamber(s) from which sensed events will be processed by the pacemaker.

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TABLE 65.1

Five-position programming code

I

II

III

IV

V

Chamber(s) paced

Chamber(s) sensed

Response to sensed event

Programmable functions

Antitachycardia functions

O  None

O  None

O  None

O  None

O  None

V  Ventricle

V  Ventricle

T  Triggered

R  Rate modulated

P  Paced

A  Atrium

A  Atrium

I  Inhibited

C  Communicating

S  Shocks

D  Dual (A  V)

D  Dual (A  V)

M  Multiprogrammable

D  Dual (P  S)

D  Dual (T  I)

P  Simple programmable

Again the symbols A, V, and D are used, as above. The designation O applies when the sensing function is programmed off. Again, some manufacturers will use S in position II for a device that will sense either only the atrium or ventricle. Position III represents the response of the pacemaker to a sensed event. Position III is directly tied to position II, since there cannot be a response unless a sensed event occurs. The designations for position II are “I” (inhibit), “T” (trigger) or D for dual (in this case dual refers to both inhibit and trigger). Again, O is used for a device with this feature off, which is an obligatory situation if position II is turned off. If position III is occupied by an I, then the device will inhibit output to the chamber(s) from which a sensed event arrives. In an AAI device, sensed atrial activity will inhibit atrial output (pacing). In a DDI device, sensed activity from either the atrium or ventricle will inhibit pacing in the chamber from which a sensed event occurs. A T in position III is rarely encountered, but refers to the situation wherein a sensed event “triggers” pacing. This is best demonstrated by a sensed atrial event triggering a ventricular output at a pre-determined delay to maintain atrioventricular (AV) synchrony. If position III is occupied by a D, the device can both inhibit and trigger based on a sensed event. Thus a DDD pacemaker works by pacing and sensing both chambers, and a sensed atrial event simultaneously inhibits atrial pacing and triggers a ventricular paced beat if a naturally occurring ventricular beat fails to inhibit pacing by the time the pre-set AV delay expires. Position IV refers to the programmable features of the device, and in clinical practice it is rare to use any of the designations except “R” (rate-responsive) when referring to a pacemaker. A device with rate responsiveness on will use sensors (described below) to accelerate the heart rate to match increased metabolic demand. The other designations in position IV are “C” (communicating), “M” ( multiprogrammable), “S” (simple programmable), and O for none. There are virtually no non-communicating devices implanted; likewise

simple programmable devices with three or fewer programmable features are virtually never encountered. Position V refers to the antitachycardia features of the device. With respect to a pacemaker, only two designations are possible: “P” (pacing) or O (none). Antitachycardia pacing would refer to so-called overdrive pacing in which the pacemaker briefly accelerates the pacing to a pre-programmed percentage of the sensed intrinsic rate in that chamber (typically the atrium for a pacemaker-only system) in an attempt to terminate the tachyarrhythmia. This may be delivered as a burst of pacing like 3–8 beats, or for several minutes followed by gradual slowing to see if any intrinsic beats “break through” thus re-initiating the higher rate pacing. An implanted defibrillator could offer shocks (“S”) or both shocks and pacing (“D”), in addition to O (none) and P. Basic programming parameters include the pacing mode, the base pacing rate, the upper pacing rate(s), the AV delays, and the amplitude and pulse width of the output. The mode of pacing should be chosen to address a particular patient’s needs. A patient with exclusively sinus node dysfunction may be sufficiently treated by a single chamber atrial pacing device, programmed to the AAI mode. This device would pace only in the atrium and sense exclusively from the atrium. In response to a sensed atrial event, the pacemaker would inhibit pacing. While such a device is rarely implanted in the USA, programming can be accomplished which essentially makes a dual chamber device into a single chamber device, as will be discussed below. A patient with permanent atrial fibrillation and bradycardia may benefit from a single chamber ventricular pacemaker programmed to the VVI mode. This device would pace and sense only in the ventricle and would be inhibited by intrinsic ventricular events. A patient with advanced AV block would be more likely to benefit from a dual chamber pacemaker programmed DDD such that both chambers would be paced and sensed, and sensed events would both trigger and inhibit pacemaker output, depending upon the need. As an option, if there were no

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issue of sinus node dysfunction, such a patient could be programmed VDD, such that only the ventricle would be paced though sensing would occur from both chambers and the dual response to sensed events would still occur in the ventricle. The AV delay or time between the atrial event (sensed or paced) and the ventricular event (sensed or paced) can also be programmed. The natural delay on a surface ECG is expressed as the PR interval and it typically ranges from 120 to 200 milliseconds (msec) at rest and may shorten significantly with activity. The AV delays in a pacemaker are usually programmed within this range, with a slightly shorter delay following sensed atrial events as compared with paced atrial events. This accounts for the short delay within the atrium between the impulse traveling from the sinus node to the lead and then to the pulse generator. Shortening of the AV delay with acceleration of heart rates, as occurs physiologically, is another feature that can be selected on most pacemakers, which permits programming of higher upper rates, and a more physiologic response to exercise. The output of the pacemaker is controlled by two parameters, the amplitude and the pulse width. Amplitude refers to the amount of voltage delivered with each impulse. Most devices can be varied to deliver from 0.1 to 7 milliamps (mA), and this value is usually determined by performing amplitude threshold testing then delivering 2–3 times the threshold value, depending on physician preference and other factors. The pulse width refers to the amount of time that the current is delivered and can usually be programmed from 0.1–1.5 msec. Again, the setting is preference-based and can be set based on a multiple of the threshold value determined by slowly decreasing the pulse width at a fixed amplitude until capture is lost. The base rate of the pacemaker can be programmed, generally in the range of 35–140 beats per minute. Typically this is set between 50 and 70, depending upon the patient. The pacemaker thus never allows the heart rate to go below this minimum rate. An upper rate to which the pacemaker will either accelerate the heart rate, or “track” (see below) an intrinsic sinus rate can also be determined. Again, this is determined by the patient age, activity level, and overall health, and can be limited by other parameters, as will be discussed below. Of course, in the presence of an intact conduction system, a patient can generate intrinsic heart rates in excess of the programmed parameters, but a patient with complete AV block will be unable to have a pulse rate greater than the programmed upper rate unless the rhythm is ventricular in origin (i.e., ventricular tachycardia). When the sensor is programmed on, as will be discussed below, the upper rate that the sensor will accelerate the heart rate to also needs to be chosen.

Timing cycles govern pacemaker activity and a pacemaker operates based on the interactions of a series of timers. For instance, the base rate is governed by a timer, which determines if an impulse will be delivered. So, for example, if the base rate is 60 (or one beat every second), then the absence of an intrinsic heart beat before the timer reaches 1 second will result in a paced beat. Once this beat is delivered, the timer starts over. If an intrinsic beat occurs before the timer expires, the timer starts over at that point. In the case of a dual chamber system, once a beat is sensed or paced in the atrium, a timer starts representing the programmed AV delay. If the timer expires, a beat is delivered to the ventricle, resetting the base rate timer. Advanced concepts and interactions in timing cycles are beyond the scope of this discussion.

ADDITIONAL PROGRAMMING AND FEATURES The field of cardiac pacing continues to evolve rapidly. There are new features constantly incorporated into pacemakers such that it is difficult to discuss all of these features; however, certain common features are now being incorporated into virtually all pacemakers and these should be discussed. The first of these is so-called “mode-switch” algorithms. As discussed above, a sensed event in the atrium will trigger a paced event in the ventricle unless a ventricular event occurs naturally. Such a rhythm with atrial sensed events and ventricular paced events is often referred to as “ventricular tracking.” Thus a patient with complete heart block would potentially have a rapidly paced rhythm if the pacemaker were trying to track a rapid atrial arrhythmia. Thus, an algorithm exists in modern devices to prevent this. The device that senses a rapid, non-physiologic atrial rhythm will alter its programming, or mode-switch to prevent tracking at the upper programmed rate of the pacemaker. The most common modes to switch to in order to prevent tracking are VVI, DDI, and VDI, since these modes only inhibit pacing based on lack of intrinsic events and do not trigger pacing in the ventricle. Rate responsiveness can still be programmed on during all of these modes. Upon resolution of the tachycardia, the device switches back to the originally programmed mode. Another newer example of mode switching involves devices that switch from atrial pacing only to dual chamber pacing upon detection of loss of ventricular sensing. Such devices help to minimize right ventricular pacing, shown to be deleterious in a number of trials, particularly in patients with reduced left ventricular function

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CARDIAC RESYNCHRONIZATION THERAPY (CRT)

(Wilkoff et al., 2002). Similarly, upon resumption of ventricular sensing, the device can switch back to atrial pacing only. The occurrence of such events is accurately logged by the device with respect to onset and duration of events, percentage of time spent in such events, and maximum heart rates in each chamber during such events, as well as internal electrograms from the leads during such events (Gillis et al., 2006). As the artificial pacemaker is implanted due to failure of the intrinsic cardiac conduction system, and the most common reason is sinus node dysfunction, the sensors have been developed in order to simulate the natural heart rate response to increased metabolic demands. The simplest and most widely used of these are the piezoelectric motion detector and accelerometer, though they suffer from being the least physiologic. Other, more physiologic sensors include impedance sensors that sense changes in chest wall impedance or minute ventilation, QT interval sensors based on measurement of the evoked response from ventricular pacing, and sophisticated sensors which sense temperature or mixed venous oxygen saturation. None of these physiologic sensors are in widespread use, due more to technical issues and cost than to proven benefit. The rate at which the acceleration occurs as well as the rate to decay back to baseline can usually be programmed based on patient needs. Pacemakers continue to become more automated, performing daily assessments of their measured data such as battery voltage and impedances, pacing lead impedances, measured sensing of the intrinsic cardiac P and R waves, and capture thresholds, even adjusting outputs based on this data. Even parameters such as amount of daily activity by the patient can be tracked. The data are compiled and stored in the device, permitting logging of long-term data trends. Alarms alerting the patient and doctor to significant variations can be programmed on. Much of this data can now be transmitted to the physician transtelephonically even on a daily basis, which can permit improved follow-up and earlier diagnosis of pacemaker problems as well as clinical issues such as arrhythmias and heart failure onset ( Joseph et al., 2004; Schoenfeld et al., 2004).

CARDIAC RESYNCHRONIZATION THERAPY (CRT) Both inter- and intraventricular dyssynchrony are implicated in the development and worsening of congestive heart failure (CHF). This lack of synchrony is usually manifest as a conduction delay on ECG with a QRS duration of greater than or equal to 120 msec in a patient with CHF and an ejection fraction (EF) of less

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than or equal to 35%. While early trials of resynchronization therapy evaluated only patients with left bundle branch block (LBBB), subsequent trials included right bundle branch block (RBBB) and other nonspecific intraventricular conduction defects and showed consistent benefits for resynchronization therapy, with respect to parameters such as perceived wellness, exercise capacity, and CHF hospitalizations. Subsequently, trials have demonstrated a benefit in terms of mortality for CRT. At present it is believed that ECG criteria identify only a fraction of the patients with dyssynchrony, thus new methods of evaluation such as tissue Doppler imaging are being assessed to potentially expand the pool of patients who might potentially benefit from CRT. Technically, the resynchronization is accomplished by implanting a lead for left ventricular pacing, usually in the coronary sinus (CS). This lead is placed from the same transvenous access in the subclavian vein and directed via long sheaths and angioplasty guidewires into a branch of the CS and wedged into position. This can be limited by valves over the CS, location of the CS ostium, CS branch location, CS branch size, CS branch tortuosity, and occlusions/stenoses. Leads specifically designed for use in the CS have been developed allowing unipolar and bipolar pacing using a number of different anodal and cathodal locations to maximize chances for successful implant. Unlike the intracardiac leads, a reliable fixation method has yet to be developed, thus different shapes and curves have been designed into the leads to try to prevent dislodgment of the leads, which may still occur up to 10% of the time with these leads. Also, because of their epicardial location, stimulation of the diaphragm remains a significant risk with these devices, even when it is not producible in the operating room at the time of implant. The original CRT devices “tied” the output and sensing from both the right ventricle and left ventricle, which resulted in problems due to sensing and pacing since the intrinsic signals from both ventricles were “counted” by the devices resulting in pacing inhibition and inappropriate ICD therapies, as well as premature battery depletion due to increased pacing outputs sometimes required to maintain capture. Newer devices have separately programmable ports for each ventricular lead and sense from only one lead. Even with improved implant techniques and devices, the non-responder rates remain significant on the order of 20–30%. This may reflect a selection issue, as QRS duration alone does not necessarily identify the entire population with dyssynchrony and may erroneously identify patients with little or no dyssynchrony. Also, the location of the left ventricular lead may be critical to restoring synchrony and prospective methods of identifying the best place for the lead with respect to the actual anatomy have not yet been identified (Bristow et al., 2004; Cleland et al., 2005).

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FUTURE DIRECTIONS The future of cardiac pacing remains promising. An expanding aging population will increase the need for cardiac pacemakers for the standard indications such as sinus node dysfunction and AV block. The role of pacemakers in the therapy of other common disorders such as neurocardiogenic syncope is unclear, as some trials have demonstrated a role for pacing, but recent doubleblinded controlled trials in Canada and Europe have failed to demonstrate the value of pacing (Connolly et al., 2003; Raviele et al. 2004). As methods of identifying patients with dyssynchrony evolve, it is likely that the indications for this therapy will expand beyond the requirement for a wide QRS complex, as well as for patients with less advanced stages of congestive heart failure. The modern devices are capable of storing and communicating important clinical data beyond the heart rhythm data they were implanted to remedy, thus as this technology is proven, these devices will likely take on additional responsibilities and will enhance our ability to provide more comprehensive patient care.

References Bristow, M.R., Saxon, L.A., Boehmer, J., Krueger, S., Kass, D.A., De Marco, T. et al. (2004) Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N. Engl. J. Med. 350 (21): 2140–50.

Cleland, J.G., Daubert, J.C., Erdmann, E., Freemantle, N., Gras, D., Kappenberger, L. et al. (2005) The effect of cardiac resynchronization on morbidity and mortality in heart failure. N. Engl. J. Med. 352 (15): 1539–49. Connolly, S.J., Sheldon, R., Thorpe, K.E., Roberts, R.S., Ellenbogen, K.A., Wilkoff, B.L. et al. (2003) Pacemaker therapy for prevention of syncope in patients with recurrent severe vasovagal syncope: Second Vasovagal Pacemaker Study (VPS II): a randomized trial. JAMA 289 (17): 2224–9. Furman, S. and Schwedel, J.B. (1959) An intracardiac pacemaker for Stokes-Adams seizures. N. Engl. J. Med. 261: 943–8. Gillis, A.M., Purerfellner, H., Israel, C.W., Sunthorn, H., Kacet, S., Anelli-Monti, M. et al. (2006) Reducing unnecessary right ventricular pacing with the managed ventricular pacing mode in patients with sinus node disease and AV block. Pacing Clin. Electrophysiol. 29 (7): 697–705. Joseph, G.K., Wilkoff, B.L., Dresing, T., Burkhardt, J. and Khaykin, Y. (2004) Remote interrogation and monitoring of implantable cardioverter defibrillators. J. Interv. Card. Electrophysiol. 11 (2): 161–6. Raviele, A., Giada, F., Menozzi, C., Speca, G., Orazi, S., Gasparini, G. et al. (2004) A randomized, double-blind, placebo-controlled study of permanent cardiac pacing for the treatment of recurrent tilt-induced vasovagal syncope. The vasovagal syncope and pacing trial (SYNPACE). Eur. Heart J. 25 (19): 1741–8. Schoenfeld, M.H., Compton, S.J., Mead, R.H., Weiss, D.N., Sherfesee, L., Englund, J. et al. (2004) Remote monitoring of implantable cardioverter defibrillators: a prospective analysis. Pacing Clin. Electrophysiol. 27 (6 Pt 1): 757–63. Wilkoff, B.L., Cook, J.R., Epstein, A.E., Greene, H.L., Hallstrom, A. P., Hsia, H. et al. (2002) Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial. JAMA 288 (24): 3115–23.

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C H A P T E R

66 Cardiac Pacemakers – Past, Present, and Future Guy Amit and Kara J. Quan

O U T L I N E Historical Perspective

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Pacing for Heart Failure

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Technical Aspects Stimulation Sensing Endocardial Pacing Leads Implantation Techniques

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Other Indications for Pacing Neurally Mediated Syncope Syndromes Carotid Sinus Hypersensitivity Hypertrophic Cardiomyopathy Pacing for Tachyarrhythmia

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Cardiac “Electrical” Anatomy

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Pacemaker-Related Complications

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Pacing for Sinus Node Dysfunction

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Future Directions

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Pacing for Atrioventricular Block

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References

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HISTORICAL PERSPECTIVE

The first pacemaker devices could only externally stimulate the heart. Output voltage and stimulation rates were controlled from the front panel of the pacemaker. The electrodes were two one-inch diameter metal discs placed on the right and left sides of the chest, held in place by a rubber strap. Stimulation required up to 100 V, and it was painful to the patient. Later, electrodes were placed surgically over the heart, which decreased voltage to one-tenth (Furman, 2002). However, infection was a frequently fatal complication of these devices, and after transistors became available, the implantation of smaller fully implantable pacemaker units became possible (Elmquist, 1978). The first implantable device

The classical description of syncope is a collapse without warning, associated with loss of consciousness lasting a few seconds. The affected individual is pale initially, and some seizure-like activity can be noted if the attack is prolonged. William Stokes’ mid-nineteenth century description of syncope associated with a slow pulse was similar to case reports by Robert Adams and Giovanni Battista Morgagni (Stokes, 1846). It took 100 years to develop effective therapy with pacemakers, which could treat bradycardia and save lives (Zoll et al., 1955).

Neuromodulation

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2009 Elsevier Ltd. © 2008,

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66. CARDIAC PACEMAKERS – PAST, PRESENT, AND FUTURE 100 90

Percentage adoption

80 70 60 50 40 30 20

Transvenous lead

10

Programmability Dual chamber

0 1965

1971

1973

1975

1978 1981 Survey year

1985

1989

1993

*1971 Transvenous lead estimated percentage of 75% was used to represent the USA as a whole

FIGURE 66.1 Major trends in pacemaker technological innovations (Adapted from Jeffrey and Parsonnet (1998) by permission of Lippincott Williams & Wilkins; www.lww.com)

had a diameter of 55 mm and thickness of 19 mm, had two stainless steel electrodes sutured to the epicardium, and was rechargeable from the outside (every month). The main developments during the early years were lead technology, capsule housing, and mainly battery life (Luderitz, 2002). The transvenous route for placing electrodes became available in 1959 (Furman and Schwedel, 1959). The method was slowly adopted at the beginning, but eventually, as lead technology improved, it became the main lead implanting technique (Parsonnet and Bernstein, 1989) (Figure 66.1). Furthermore, since the introduction of central vein catheterization access, non surgeons (cardiologists) started to implant pacemakers (Littleford et al., 1979). Early pacers were asynchronous with the patient’s own rhythm, and were only capable of delivering an electrical stimulus to the heart at a steady rate. The pacemaker could not sense the patient’s rhythm (VOO – Table 66.1). A mistimed pacing stimulus could potentially have caused fatal arrhythmias. Synchronous pacing was introduced in 1963 (Nathan et al., 1963), and this included the ability of the device to sense the patient’s own electrical activity and to “inhibit” the device’s action (pacing) upon sensing of such an event (VVI – Table 66.1). This “recycling” of the pacer timer was the first introduction of “demand” pacemakers (Zuckerman et al., 1967). The next challenge in pacemaker technology was to attempt to restore atrioventricular synchrony.

TABLE 66.1 Pacing codes I

II

III

IV

Chamber(s) paced

Chamber(s) sensed

Response to sensed event

Rate modulation

O  None A  Atrium V  Ventricle D  Dual (A  V)

O  None A  Atrium V  Ventricle D  Dual (A  V)

O  None T  Triggered I  Inhibited D  Dual (T  I)

O  None R  Rate modulation

The pacemaker capabilities are defined by a four-letter code (e.g. AAIR, meaning atrial pacing, atrial sensing, inhibition in response to a sensed atrial event, and ability to rate modulation). Some devices can switch automatically from mode to mode, and all current pacemakers are mode-programmable. Rate modulation  the ability of the pacemaker to increase its pacing rate according to the patient’s demand (i.e. during exercise)

A “bifocal” pacemaker was introduced, which could pace the atria, and after an appropriate “AV interval” would pace the ventricle. It could also inhibit itself upon sensing ventricular activity (Castillo et al., 1971) (DVI – Table 66.1). This led the way to current dual chamber pacemakers, which can pace and sense in both the atria and ventricle and can be “triggered” by pacing the ventricle after a sensed atrial activity (DDD – Table 66.1) (Furman et al., 1973). During the early years of implantation, the devices had very limited flexibility in terms of energy output

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Amplitude (volts)

TECHNICAL ASPECTS

Chronaxie approximation

Rheobase approximation

Pluse width (ms)

FIGURE 66.3 Strength–duration curve (Reproduced with permission from Medtronic, Inc.)

FIGURE 66.2 A current pacemaker and leads (Reproduced with permission from Medtronic, Inc., Minneapolis, MN)

and pacing rate. Changes could only be applied via minor invasive surgery. With time, some changes could be programmed by magnet application (Parsonnet et al., 1973), and this led the way to fully programmable devices with telemetry capabilities. This allowed for increasing pacemaker longevity, as well as adjustment for several conduction abnormalities without the need to re-implant a new device (MacGregor et al., 1978) (Figure 66.1). Another area of major improvement was the energy source for the pulse generators. Rechargeable nickel-cadmium batteries were used in the beginning of pacemaker implants. The shortcomings were short lifetime of the device, and the patient’s responsibility to recharge the battery (Parsonnet, 1972). Second generation (non-rechargeable) devices utilizing a mercury-zinc battery were developed. These devices could last for two years; however, the discharge of the battery released hydrogen into the pacemaker that at times caused electrical shorting and premature failure. In addition, it was difficult to anticipate battery depletion with a mercury-zinc battery (Mallela et al., 2004). Alternative types of batteries included bio-energy (using the aortic pulsation to produce energy) (Zucker

et al., 1964), and nuclear plutonium-based batteries (Laurens, 1979). However, public uneasiness about nuclear safety and the invention of long-lived lithiumbased batteries made the latter the predominant pacemaker energy source (Mallela et al., 2004). Current pulse generators (Figure 66.2) are based on lithium/ iodine batteries. The high energy density of this combination enabled manufacturers to downsize the batteries significantly. In a recent industry-independent survey (Hauser et al., 2007), the average time ( SD) from implantation to elective battery replacement was 7.3 ( 3.1) years, with only 5% of devices being replaced prematurely for technical/clinical reasons.

TECHNICAL ASPECTS Stimulation In order for an electrical current to capture (stimulate) the heart tissue, it should have sufficient energy, and it should be applied when the tissue is electrically excitable. The other important factors affecting the ability to capture include proximity of the electrode to the tissue, size and shape of the electrode, tissue pathology, as well as electrolyte balance and drug effects. The total energy delivered is determined by the voltage (pulse amplitude), the current, and the duration (pulse width). The interaction of pulse amplitude and width defines a strength–duration curve (Figure 66.3). The curve is made by measuring threshold at the point of gain/loss of capture. A stimulus of short duration must be of greater intensity in order to capture the heart. However, above 1 msec, further increase in the pulse duration will have little effect on the energy delivered (Coates and Thwaites, 2000). The amplitude at this point is the rheobase, and twice the

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66. CARDIAC PACEMAKERS – PAST, PRESENT, AND FUTURE

amplitude of that defines the chronaxie point. This is the point with minimum energy needed for capture.

Sensing When a wave of tissue depolarization passes the electrode tip of the lead, it creates a deflection on the continuous electrogram (EGM) recorded from that tip. This signal is filtered and amplified by the device. The device then decides whether it detected a “sensed” event according to predefined (and partly programmable) criteria. A voltage deflection would be detected if there were a difference in voltage between two electrodes that are attached to the heart (bipolar configuration), or one electrode and the pacemaker device (unipolar configuration). The EGM amplitude, measured in mV, is dependent upon the chamber being sensed, lead type, tissue pathology, time from lead implantation, as well as other factors (Myers et al., 1978).

Endocardial Pacing Leads Pacing leads are defined as “unipolar” or “bipolar.” In “unipolar” configuration the current flows from the negatively charged (cathode) tip through the heart muscle to the pulse generator (anode), and then back via the lead. In “bipolar” configuration both poles are in proximity to the heart tissue at the tip of the lead, making the circuit much smaller, and excluding the pulse generator from it. There is a continuous trend toward using bipolar pacing leads mainly because they are less prone to sensing artifacts either from the adjacent chamber or from outside the heart (Wiegand et al., 2001). The current pacing electrode surface area measures 1.2–6 mm. A decrease in the surface area which is in contact with the heart results in a higher lead impedance and a lower current need for capture. This results in less current drain from the battery (Ellenbogen et al., 1999). Current pacemaker leads are composed of a conductor (two in a bipolar lead), insulation material, and a fixation system. Conductors are composed of a central core of highly conductive material, like silver, surrounded by a more durable corrosion-resistant material like MP35N (Mond and Grenz, 2004). Insulation is made of silicone or polyurethane (De Voogt, 1999). Transvenous leads may be fixated to the heart tissue actively or passively. Active-fixation leads incorporate tips that invade the heart muscle, whereas passive-fixation leads promote fixation by indirect means. When correctly implanted, both fixation mechanisms result in high rates of stability (Hidden-Lucet et al., 2000).

Implantation Techniques Pacemakers are implanted either in an operating room, catheterization laboratory, or a dedicated electrophysiology laboratory (Stamato et al., 1992). These procedures are sterile surgical procedures, done with fluoroscopic guidance. Operators were traditionally thoracic surgeons. However, with the current intravascular endocardial leads, and the required knowledge of electrophysiology, most operators are specifically trained cardiologists or electrophysiologists (Hayes et al., 1994). Most procedures are performed with local anesthesia, sometime with the addition of mild sedation. Several techniques are available for the transvenous implantation of pacing leads that involve either venous cut-down (of the cephalic vein), vascular access by the Seldinger method (usually axillary or subclavian vein) or both. In addition to direct visualization and fluoroscopy, the operator can use contrast venography, ultrasound, and Doppler as aids for locating the target vein. After introducing the lead into the venous system, each lead is advanced to the heart and placed at the targeted chamber under fluoroscopic guidance. The leads are then connected to the pulse generator, which is placed in a subcutaneous or a submuscular pocket (Bellott and Reynolds, 2007).

CARDIAC “ELECTRICAL” ANATOMY Myocardial tissue and the specialized conduction system can both allow conduction of electrical impulses. Cells in the specialized cardiac conduction system also depolarize spontaneously, which enables these cells to function as cardiac pacemakers (Dobrzynski et al., 2005). The elements comprising the conduction system are the sinoatrial (SA) node, the atrioventricular (AV) node, the Bundle of His, the bundle branches, and the Purkinje network (Figure 66.4). The inherent spontaneous rate of depolarization is progressively slower from the SA node down to the Purkinje fibers. The normal rate of spontaneous depolarization in the SA node ranges from 60 to 100 beats/minute, which is faster than other cardiac pacemakers (i.e., His bundle, Purkinje network, etc.); therefore, it is the dominant pacemaker. Impulses from the SA node suppress other potential pacemakers of the heart; their activity is normally recognized only when sinus rates fall below those of other pacemakers. The emergence of lower pacemakers to sustain a heart rate when the dominant pacemaker fails is called an escape mechanism. SA nodal impulse initiates the electrical depolarization of the heart. It activates the internodal tracts as well as the atrial myocardium. The impulse then depolarizes

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PACING FOR ATRIOVENTRICULAR BLOCK

TABLE 66.2 Common pacing indications in sinoatrial node dysfunction (SND)

Left atrium Sinoatrial (SA) node

Bundle of his

Right atrium

Class I: General consensus that pacing is indicated

SND with documented symptomatic bradycardia Symptomatic chronotropic incompetence

Class II: Divergence of opinion on need for pacing

IIa: SND with heart rate 40 bpm when a clear association between significant symptoms consistent with bradycardia and the actual presence of bradycardia has not been documented Syncope of unexplained origin when major abnormalities of sinus node function are discovered or provoked in electrophysiologic studies IIb: In minimally symptomatic patients, chronic heart rate less than 40 bpm while awake

Left bundle branch

Atrioventricular (AV) node

Left ventricle

Right ventricle Right bundle branch

FIGURE 66.4 The cardiac conduction system (Reproduced with permission from St. Jude Medical)

the AV node (located at the inter-atrial septum above the septal leaflet of the tricuspid valve), the His bundle, the bundle branches, the Purkinje network, and the ventricular myocardium.

PACING FOR SINUS NODE DYSFUNCTION SA node dysfunction (SND) is the second most common indication for cardiac pacemaker implantation (after atrioventricular block), accounting for approximately 28% of cases (Mond et al., 2004). Common symptoms of SND include dizziness, syncope (temporary loss of consciousness), fatigue, and decrease in exercise tolerance. ECG manifestations of SND include sinus bradycardia, pauses or arrest, and chronotropic incompetence (inability to increase the heart rate during exercise). Bradycardia alternating with tachycardia is also common in SND. Left untreated, SND disease tends to have an unfavorable outcome. A related adverse outcome was reported in 35%, 49%, and 63% of untreated patients at 1, 2, and 4 year follow-up (Menozzi et al., 1998). Although, prospective data are lacking, it seems that patients with SND treated with pacemakers have the same survival as the general matched population (Jahangir et al., 1999). Table 66.2 summarizes the current indications for pacing in SND. The choice of a pacing system in SND depends on several variables. The future risk of developing AV conduction block (making AAI pacing ineffective) is 1.8% per year and is much higher in patients with bundle branch or intraventricular conduction block. Thus implanting a

ventricular-based (VVI) or dual chamber pacing system (DDD) might avoid future adding of an additional lead.

PACING FOR ATRIOVENTRICULAR BLOCK Atrioventricular (AV) conduction block occurs when there is slowing or blocking of the conducted impulse from the atria to the ventricles. AV block is classified as first-, second-, or third-degree (complete) block; anatomically, it is defined as supra-, intra-, or infra-His. First-degree AV block is defined as abnormal prolongation of the PR interval. Second-degree AV block is subclassified as type I and type II. Type I second-degree AV block is characterized by progressive prolongation of the PR interval before a blocked beat and is usually associated with a narrow QRS complex. Type II seconddegree AV block is characterized by fixed PR intervals before and after blocked beats and is usually associated with a wide QRS complex. Advanced second-degree AV block refers to the block of two or more consecutive P waves but with some conducted beats, indicating some preservation of AV conduction. Third-degree AV block (complete heart block) is defined as absence of AV conduction. The higher the grade, the more severe is the block. Patients can be asymptomatic with milder degree of block, but are usually becoming symptomatic when the heart rate slows at higher degree block. Symptoms include syncope, fatigue, dizzy spells, shortness of breath, and chest pain. AV block can be acquired secondary to fibrodegenerative disease of the

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66. CARDIAC PACEMAKERS – PAST, PRESENT, AND FUTURE

TABLE 66.3

Common pacing indications in atrioventricular block

Class I: General consensus that pacing is indicated

Third-degree and advanced second-degree AV block at any anatomic level with: (a) Bradycardia and symptoms (including heart failure) presumed due to AV block (b) Arrhythmias and other medical conditions requiring drugs that result in symptomatic bradycardia (c) Documented asystole 3.0 sec. or escape rate 40 bpm in awake, symptom-free patients (d) Post AV junction ablation (e) Postoperative AV block not expected to resolve after cardiac surgery (f) Neuromuscular diseases with AV block, with or without symptoms Second-degree AV block regardless of type or site of block, with associated symptomatic bradycardia

Class IIa: Divergence of opinion on need for pacing

Asymptomatic third-degree AV block at any anatomic site with average, awake ventricular rate 40 bpm, especially if cardiomegaly or LV dysfunction is present Asymptomatic type II second-degree AV block with a narrow QR Asymptomatic type I second-degree AV block at intra- or infra-His levels at EP study First- or second-degree AV block with symptoms similar to “pacemaker syndrome”

heart (most common), to myocardial infarction or other causes, or it can be congenital. AV block can be transient or permanent (Gregoratos et al., 2002). The decision to implant a pacemaker in a patient with AV block is based on a correlation of symptoms, likelihood of progression to high-degree block, and whether or not the block is expected to be permanent (Table 66.3). Reversible causes of AV block, such as electrolyte abnormalities, should be corrected first. Some diseases may follow a natural history to resolution (during acute myocardial infarction), and some AV block can be expected to reverse. Non-randomized studies strongly suggest that permanent pacing does improve survival in patients with permanent third-degree AV block, especially if syncope has occurred (Edhag and Swahn, 1976). Few historical retrospective data, some nonrandomized studies (Connolly et al., 1996), as well as subgroup analysis of prospective studies (Skanes et al., 2001), suggested that dual chamber pacing (DDD/ R) may be beneficial in patients with AV block compared with single chamber pacing (VVI/R) in reducing symptoms, improving quality of life, reducing atrial fibrillation occurrence, and improving survival. However, the UKPACE prospective trial (Toff et al., 2005) enrolled more then 2000 patients with AV block to single chamber pacing (VVI or VVIR) vs. dual chamber pacing (DDDR). They found no difference in the annual mortality rate, as well as no significant differences between the groups in the rates of atrial fibrillation, heart failure, or a composite of stroke, transient ischemic attack, or other thromboembolism.

PACING FOR HEART FAILURE In a significant number of patients with heart failure due to systolic dysfunction (pump failure), there

is left bundle branch block (LBBB) (Baldasseroni et al., 2002). The occurrence of LBBB in these patients is associated with decreased survival mainly due to worsening heart failure (Shamim et al., 1999). In patients with LBBB, conduction of the wave of depolarization in the left ventricle is markedly altered, proceeding from the anterior septum through the left ventricular myocardium to the inferior and lateral left ventricular walls. As a result, left ventricular contraction is dyssynchronous, with the interventricular septum contracting before the left ventricular free wall. Dyssynchronous contraction is mechanically inefficient, leading to decreases in the left ventricular ejection fraction (LVEF) and cardiac output (Turner et al., 2004). These observations led to the concept of simultaneous pacing of both the left and right ventricles (biventricular pacing). With biventricular pacing, separate pacing leads stimulate the right and left ventricles to resynchronize ventricular contraction (cardiac-resynchronization therapy or CRT) (Abraham and Hayes, 2003). In order to pace the left ventricle, a specifically designed pacing lead is inserted into the coronary sinus (from the right atrium) that courses parallel to the AV groove of the heart. The lead is then passed into a venous branch running along the posterolateral free wall of the left ventricle. In patients in whom this cannot be achieved by a transvenous approach the left ventricular electrode can be placed over the heart by minimally invasive thoracic surgery (Navia et al., 2005). Early studies have consistently demonstrated improvement in heart contraction mechanism, as well as symptoms in patients undergoing CRT (Auricchio et al., 2002). Combining all small size studies into a meta-analysis also demonstrated a survival benefit (Salukhe et al., 2004). This was recently confirmed in a large-scale randomized prospective study (Cleland et al., 2005) that showed 36% relative reduction in mortality rate over 29 months follow-up. Current guidelines recommend CRT to patients with medically refractory, symptomatic, heart failure,

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PACEMAKER-RELATED COMPLICATIONS

conduction abnormality manifest on the ECG by QRS interval of at least 130 msec, left ventricular enddiastolic diameter of at least 55 mm, and significant left ventricular dysfunction (LVEF less than or equal to 0.30) (Hunt, 2005).

OTHER INDICATIONS FOR PACING Neurally Mediated Syncope Syndromes This term refers to a variety of clinical scenarios in which triggering of a neural reflex results in a usually self-limited episode of systemic hypotension characterized by both bradycardia and peripheral vasodilation (also known as “vasovagal syncope”) (Benditt et al., 1996). Pacing is indicated in a subset of patients who have predominantly slow heart rate response as can be documented by tilt-table testing (Petersen et al., 1994).

813

variety of pacing patterns, including programmed stimulation and short bursts of rapid pacing (Attuel et al., 1998). There are on-going studies to evaluate the benefit of atrial pacing and atrial pacing sites for the prevention of atrial fibrillation (Ellenbogen, 2007). Potential recipients of antitachyarrhythmia devices that interrupt arrhythmias should undergo extensive testing before implantation to ensure that the devices safely and reliably terminate the arrhythmia without accelerating the tachycardia or inducing ventricular fibrillation (VF). These patients are usually unresponsive to antiarrhythmic drugs (Lau et al., 1988). Permanent antitachycardia pacing as monotherapy for VT is no longer indicated, given that antitachycardia pacing algorithms are available in implantable cardioverter-defibrillators that also incorporate the capability of cardioversion and defibrillation in cases when antitachycardia pacing is ineffective, or accelerates the treated tachycardia. In these cases, patients need to be evaluated to see if they are candidates for implantable cardioverter-defibrillators.

Carotid Sinus Hypersensitivity This is a type of syncope or presyncope resulting from an extreme reflex response to carotid sinus stimulation. It is an uncommon cause of syncope. Permanent pacing for patients with pure excessive cardioinhibitory response to carotid stimulation (defined as ventricular asystole of greater than 3 seconds’ duration) is effective in relieving symptoms (Sugrue et al., 1986). Pure carotid sinus hypersensitivity may be treated with AAI pacing.

Hypertrophic Cardiomyopathy In this genetic condition there is an abnormal muscle hypertrophy (thickening) with or without an obstruction to blood flow in the left ventricle outflow tract. In patients with an obstruction, pacing the right ventricular apex may reduce the left ventricular outflow gradient by creating a regional dyssynchrony. Pacing, however, is currently indicated only in medically refractory, symptomatic patients with significant resting or provoked left ventricular outflow obstruction (Fananapazir et al., 1994).

Pacing for Tachyarrhythmia Prevention of arrhythmias by pacing (antitachyarrhythmia pacing) has been demonstrated in certain situations (Peters et al., 1985). Reentrant rhythms including atrial flutter, paroxysmal reentrant supraventricular tachycardia, and some types of ventricular tachycardia (Eldar et al., 1987) may be terminated by a

PACEMAKER-RELATED COMPLICATIONS Complications can be divided into the long-term effects or risks of chronic pacing as well as device-, lead-, or implantation-related complications. An early study randomized 225 patients with SND to atrial (AAI) vs. ventricular (VVI) pacing. After a mean follow-up of 3.5 years, there were increased cardiac deaths in the ventricular pacing group (Andersen et al., 1997). Larger randomized studies in patients with SND comparing DDD vs. VVI pacing did not reproduce these results (Connolly et al., 2000; Lamas et al., 2002). However, the amount of ventricular pacing was directly related to the future risk of atrial fibrillation (Sweeney et al., 2003), and minimizing ventricular pacing consistently decreased the risk of atrial fibrillation (Nielsen et al., 2003). Another consideration for the choice of dual chamber pacing is the increased risk of heart failure with only ventricular pacing (Wilkoff et al., 2002). Data accumulated in recent years are emerging which convincingly indicate that the iatrogenic variety of LBBB produced by conventional right ventricular apical pacing technique (pacing the right ventricular apex) on both otherwise healthy individuals and heart failure patients is harmful. The main detrimental effects of right ventricular apical pacing include left ventricular electrical and mechanical dyssynchrony, left ventricular remodeling, abnormalities in myocardial histopathology, left ventricular dysfunction (both systolic and diastolic), and congestive heart failure

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(Manolis, 2006). This has led to the current practice of minimizing ventricular pacing, studying alternative right ventricular pacing sites (Giudici et al., 1997), as well as studying the benefit of CRT pacing in patients necessitating continuous ventricular pacing (usually complete AV block) (Doshi et al., 2005). Device-related complications mainly include “hardware” failure (battery, lead conductor, or lead insulation), and tissue injury (from stress, infection, or allergic reaction). Many of these complications can result in failure to pace or sense, and some can be life-threatening. Current estimates of pulse generator hardware failure are low as 0.7 per 1000-person years, and this rate is continuously decreasing as device technology evolves (Maisel, 2006). Lead failure is somewhat more difficult to predict secondary to the variety of existing leads. The 5-year lead survival rate for recently implanted leads was reported to be around 99% (Arnsbo and Moller, 2000). Pacemaker related infections may involve cardiac tissue, leads, and the cutaneous and subcutaneous tissue. These infections may occur up to 6% over a 3-year period (Kearney et al., 1994). Treatment options include antibiotic therapy, removal of the implanted system, and tissue debridement (Chua et al., 2000).

FUTURE DIRECTIONS Even with the current fully programmable, smallsize devices, new features are constantly being added and evaluated in clinical settings. Automated energy control (the Autocapture system) confirms the response to each stimulation and automatically adjusts output. This minimizes energy consumption and prolongs longevity of the battery (Madrid et al., 2000). As discussed above, unnecessary right ventricular stimulation can have deleterious effects. However, preservation of a normal ventricular activation sequence (ventricular synchrony) is difficult to achieve with conventional DDD/R, when intrinsic atrioventricular (AV) intervals change with changing heart rate. The minimal (or managed) ventricular pacing (MVP) is an atrial-based dual-chamber pacing mode designed to preserve normal AV conduction and ventricular activation. During normal operation only the atrium is paced (resembling AAI/R), while the ventricle is monitored to verify intact AV conduction. Higher-level AV conduction failure causes mode switching to DDD/R to prevent ventricular asystole. Tests for a return of normal AV conduction (by inhibiting ventricular pacing for one cycle) are conducted at progressive time intervals beginning at one minute. If AV conduction is detected, the mode of operation returns to AAI/R (Sweeney et al., 2006).

The growing demands for implantable device follow-up increase the demand for device clinic follow-up. Many institutions’ device clinics are at their maximum capacity. Home monitoring of devices may be one solution. This may impact patient’s quality of life as well. Various manufacturers of pacing systems have introduced devices that are placed in the patient’s home, and these home-based devices can retrieve all programmed settings and diagnostic data. These data are then transmitted by phone or over the Internet, and the receiver center prepares a report for the clinician. An option for future over-the-phone device programming by the physician exists as well. New CRT devices are emerging that not only monitor pacing but can monitor pulmonary volume status by measuring intrathoracic impedance (Ypenburg et al., 2007). This can alert the patient/physician at early stages of decompensation of heart failure, which may potentially allow the adjustment of therapy on an outpatient basis and prevent hospitalization. Other innovations such as leadless pacing technology, and “genomic tailored” pacing, will continue to reshape the future pacemaker. As the indications for implantable defibrillators are increasing, more of the implantable devices will incorporate capabilities for treatment of bradycardia, tachycardia, as well as heart failure.

References Abraham, W.T. and Hayes, D.L. (2003) Cardiac resynchronization therapy for heart failure. Circulation 108: 2596–603. Andersen, H.R., Nielsen, J.C., Thomsen, P.E., Thuesen, L., Mortensen, P.T., Vesterlund, T. et al. (1997) Long-term follow-up of patients from a randomized trial of atrial versus ventricular pacing for sick-sinus syndrome. Lancet 350: 1210–16. Arnsbo, P. and Moller, M. (2000) Updated appraisal of pacing lead performance from the Danish Pacemaker Register: the reliability of bipolar pacing leads has improved. Pacing Clin. Electrophysiol. 23: 1401–6. Attuel, P., Pellerin, D., Mugica, J. and Coumel, P. (1988) DDD pacing: an effective treatment modality for recurrent atrial arrhythmias. Pacing Clin. Electrophysiol. 11: 1647–54. Auricchio, A., Stellbrink, C., Sack, S., Block, M., Vogt, J., Bakker, P. Pacing Therapies in Congestive Heart Failure (PATH-CHF) Study Group et al. (2002) Long-term clinical effect of hemodynamically optimized cardiac resynchronization therapy in patients with heart failure and ventricular conduction delay. J. Am. Coll. Cardiol. 39: 2026–33. Baldasseroni, S., Opasich, C., Gorini, M., Lucci, D., Marchionni, N., Marini, M.PItalian Network on Congestive Heart Failure Investigators et al. (2002) Left bundle-branch block is associated with increased 1-year sudden and total mortality rate in 5517 outpatients with congestive heart failure: a report from the Italian network on congestive heart failure. Am. Heart J. 143: 398–405. Bellott, P.H. and Reynolds, D.W. (2007) Permanent pacemaker and implantable cardioverter-defibrillator implantation. In: K.A. Ellenbogen, G.N. Kay, C.P. Lau and B.L. Wilkoff (eds), Clinical

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Cardiac Pacing Defibrillation, and Resynchronization. Philadelphia: Saunders, pp. 551–64. Benditt, D.G., Ferguson, D.W., Grubb, B.P., Kapoor, W.N., Kugler, J., Lerman, B.B. et al. (1996) Tilt table testing for assessing syncope. J. Am. Coll. Cardiol. 28: 263–75. Castillo, C.A., Berkovits, B.V., Castellanos, A., Jr., Lemberg, L., Callard, G. and Jude, J.R. (1971) Bifocal demand pacing. Chest 59: 360–4. Chua, J.D., Wilkoff, B.L., Lee, I., Juratli, N., Longworth, D.L. and Gordon, S.M. (2000) Diagnosis and management of infections involving implantable electrophysiologic cardiac devices. Ann. Intern. Med. 133: 604–8. Cleland, J.G.F., Daubert, J-C., Erdmann, E., Freemantle, N., Gras, D., Kappenberger, L. and Tavazzi, L. (2005) Cardiac ResynchronizationHeart Failure (CARE-HF) Study Investigators. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N. Engl. J. Med. 352: 1539–49. Coates, S. and Thwaites, B. (2000) The strength-duration curve and its importance in pacing efficiency: a study of 325 pacing leads in 229 patients. Pacing Clin. Electrophysiol. 23: 1273–7. Connolly, S.J., Kerr, C.R., Gent, M., Roberts, R.S., Yusuf, S., Gillis, A. M. et al. (2000) Effects of physiologic pacing versus ventricular pacing on the risk of stroke and death due to cardiovascular causes. N. Engl. J. Med. 342: 1385–91. Connolly, S.J., Kerr, C., Gent, M. and Yusuf, S. (1996) Dual-chamber versus ventricular pacing: critical appraisal of current data. Circulation 94: 578–83. de Voogt, W.G. (1999) Pacemaker leads: performance and progress. Am. J. Cardiol. 83: 187D–191D. Dobrzynski, H., Li, J., Tellez, J., Greener, I.D., Nikolski, V.P., Wright, S.E. et al. (2005) Computer three-dimensional reconstruction of the sinoatrial node. Circulation 111: 846–854. Doshi, R.N., Daoud, E.G., Fellows, C., Turk, K., Duran, A., Hamdan, M.H. and Pires, L.A. (2005) PAVE Study Group. Left ventricular-based cardiac stimulation post AV nodal ablation evaluation (the PAVE study). J. Cardiovasc. Electrophysiol. 16: 1160–5. Edhag, O. and Swahn, A. (1976) Prognosis of patients with complete heart block or arrhythmic syncope who were not treated with artificial pacemakers: a long-term follow-up study of 101 patients. Acta Med. Scand. 200: 457–563. Eldar, M., Griffin, J.C., Abbott, J.A. et al. (1987) Permanent cardiac pacing in patients with the long QT syndrome. J. Am. Coll. Cardiol. 10: 600–7. Ellenbogen, K.A. (2007) Pacing therapy for prevention of atrial fibrillation. Heart Rhythm 4: S84–S87. Ellenbogen, K.A., Wood, M.A., Gilligan, D.M., Zmijewski, M. and Mans, D. (1999) Steroid eluting high impedance pacing leads decrease short and long-term current drain: results from a multicenter clinical trial. CapSure Z investigators. Pacing Clin. Electrophysiol. 22: 39–48. Elmquist, R. (1978) Review of early pacemaker development. Pacing Clin. Electrophysiol. 1: 535–6. Fananapazir, L., Epstein, N.D., Curiel, R.V., Panza, J.A., Tripodi, D. and McAreavey, D. (1994) Long-term results of dual-chamber (DDD) pacing in obstructive hypertrophic cardiomyopathy: evidence for progressive symptomatic and hemodynamic improvement and reduction of left ventricular hypertrophy. Circulation 90: 2731–42. Furman, S. (2002) Early history of cardiac pacemaker and defibrillators. Indian Pacing Electrophysiol J. 2: 2–3. Furman, S. and Schwedel, J.B. (1959) An intracardiac pacemaker for Stokes-Adams seizures. N. Engl. J. Med. 261: 943–8. Furman, S., Reicher-Reiss, H. and Escher, D.J.W. (1973) Atrioventricular sequential pacing and pacemakers. Chest 63: 783–9. Giudici, M.C., Thornburg, G.A., Buck, D.L., Coyne, E.P., Walton, M.C., Paul, D.L. and Sutton, J. (1997) Comparison of right ventricular

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outflow tract and apical lead permanent pacing on cardiac output. Am. J. Cardiol. 79: 209–12. Gregoratos, G., Abrams, J., Epstein, A.E., Freedman, R.A., Hayes, D.L., Hlatky, M.A. et al. (2002) American College of Cardiology/ American Heart Association Task Force on Practice Guidelines American College of Cardiology/American Heart Association/ North American Society for Pacing and Electrophysiology Committee. ACC/AHA/NASPE 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices: summary article. A report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. J. Cardiovasc. Electrophysiol. 13: 1183–99. Hauser, R.G., Hayes, D.L., Kallinen, L.M., Cannom, D.S., Epstein, A.E., Almquist, A.K. et al. (2007) Clinical experience with pacemaker pulse generators and transvenous leads: an 8-year prospective multicenter study. Heart Rhythm 4: 154–60. Hayes, D.L., Naccarelli, G.V., Furman, S. and Parsonnet, V. (1994) Report of the NASPE Policy Conference training requirements for permanent pacemaker selection, implantation, and followup. North American Society of Pacing and Electrophysiology. Pacing Clin. Electrophysiol. 17: 6–12. Hidden-Lucet, F., Halimi, F., Gallais, Y., Petitot, J.C., Fontaine, G. and Frank, R. (2000) Low chronic pacing thresholds of steroid-eluting active-fixation ventricular pacemaker leads: a useful alternative to passive-fixation leads. Pacing Clin. Electrophysiol. 23: 1798–1800. Hunt, S.A. (2005) American College of Cardiology; American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). J. Am. Coll. Cardiol. 46: e1–e82. Jahangir, A., Shen, W.K., Neubauer, S.A., Ballard, D.J., Hammill, S.C., Hodge, D.O. et al. (1999) Relation between mode of pacing and longterm survival in the very elderly. J. Am. Coll. Cardiol. 33: 1208–16. Jeffrey, K. and Parsonnet, V. (1998) Cardiac pacing, 1960–1985: a quarter century of medical and industrial innovation. Circulation 97: 1978–91. Kearney, R.A., Eisen, H.J. and Wolf, J.E. (1994) Nonvalvular infections of the cardiovascular system. Ann. Intern. Med. 121: 219–30. Lamas, G.A., Lee, K.L., Sweeney, M.O., Silverman, R., Leon, A., Yee, R. Mode Selection Trial in Sinus-Node Dysfunctionm et al. (2002) Ventricular pacing or dual-chamber pacing for sinusnode dysfunction. N. Engl. J. Med. 346: 1854–62. Lau, C.P., Cornu, E. and Camm, A.J. (1988) Fatal and nonfatal cardiac arrest in patients with an implanted antitachycardia device for the treatment of supraventricular tachycardia. Am. J. Cardiol. 61: 919–21. Laurens, P. (1979) Nuclear-powered pacemakers: an eight-year clinical experience. Pacing Clin. Electrophysiol. 2: 356–60. Littleford, P.O., Parsonnet, V. and Spector, S.D. (1979) Method for the rapid and atraumatic insertion of permanent endocardial pacemaker electrodes through the subclavian vein. Am. J. Cardiol. 43: 980–2. Luderitz, B. (2002) We have come a long way with device therapy: historical perspective on arrhythmic electrotherapy. J. Cardiovasc. Electrophysiol. 13: S2–S8. MacGregor, D.C., Furman, S., Dreifus, L.S. and Cuddy, T.E. (1978) The utility of the programmable pacemaker. Pacing Clin. Electrophysiol. 1: 254–9. Madrid, A.H., Olague, J., Cercas, A., del Ojo, J.L., Munoz, F., Moro, C. et al. (2000) A prospective multicenter study on the safety of a pacemaker with automatic energy control: influence of the

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electrical factor on chronic stimulation threshold. PEACE Investigators. Pacing Clin Electrophysiol. 23: 1359–64. Maisel, W.H. (2006) Pacemaker and ICD generator reliability: metaanalysis of device registries. JAMA 295: 1929–34. Mallela, V.S., Ilankumaran, V. and Rao, N.S. (2004) Trends in cardiac pacemaker batteries. Indian Pacing Electrophysiol. J. 4: 201–12. Manolis, A.S. (2006) The deleterious consequences of right ventricular apical pacing: time to seek alternate site pacing. Pacing Clin. Electrophysiol. 29: 298–315. Menozzi, C., Brignole, M., Alboni, P., Boni, L., Paparella, N., Gaggioli, G. et al. (1998) The natural course of untreated sick sinus syndrome and identification of the variables predictive of unfavorable outcome. Am. J. Cardiol. 82: 1205–9. Mond, H.G. and Grenz, D. (2004) Implantable transvenous pacing leads: the shape of things to come. Pacing Clin. Electrophysiol. 27: 887–93. Mond, H.G., Irwin, M., Morillo, C. and Ector, H. (2004) The world survey of cardiac pacing and cardioverter defibrillators: calendar year 2001. Pacing Clin. Electrophysiol. 27: 955–64. Myers, G.H., Kresh, Y.M. and Parsonnet, V. (1978) Characteristics of intracardiac electrograms. Pacing Clin. Electrophysiol. 1: 90–103. Nathan, D.A., Center, S., Wu, C-Y. and Keller, J.W. (1963) An implantable synchronous pacemaker for long-term correction of complete heart block. Circulation 27: 682–5. Navia, J.L., Atik, F.A., Grimm, R.A., Garcia, M., Vega, P.R., Myhre, U. et al. (2005) Minimally invasive left ventricular epicardial lead placement: surgical techniques for heart failure resynchronization therapy. Ann. Thorac. Surg. 79: 1536–44. Nielsen, J.C., Kristensen, L., Andersen, H.R., Mortensen, P.T., Pedersen, O.L. and Pedersen, A.K. (2003) A randomized comparison of atrial and dual-chamber pacing in 177 consecutive patients with sick sinus syndrome: echocardiographic and clinical outcome. J. Am. Coll. Cardiol. 42: 614–23. Parsonnet, V. (1972) Power sources for implantable cardiac pacemakers. Chest 61: 165–73. Parsonnet, V. and Bernstein, A.D. (1989) Transvenous pacing: a seminal transition from the research laboratory. Ann. Thorac. Surg. 48: 738–40. Parsonnet, V., Cuddy, T.E., Escher, D.J.W., Furman, S., Morse, D., Gilbert, L. et al. (1973) A permanent pacemaker capable of external noninvasive programming. Trans. Am. Soc. Artif. Intern. Org. 19: 224–8. Peters, R.W., Scheinman, M.M., Morady, F. and Jacobson, L. (1985) Long-term management of recurrent paroxysmal tachycardia by cardiac burst pacing. Pacing Clin. Electrophysiol. 8: 35–44. Petersen, M.E., Chamberlain-Webber, R., Fitzpatrick, A.P., Ingram, A., Williams, T. and Sutton, R. (1994) Permanent pacing for cardioinhibitory malignant vasovagal syndrome. Br. Heart J. 71: 274–81. Salukhe, T.V., Dimopoulos, K. and Francis, D. (2004) Cardiac resynchronization may reduce all-cause mortality: meta-analysis of preliminary COMPANION data with CONTAK-CD, InSync ICD, MIRACLE and MUSTIC. Int. J. Cardiol. 93: 101–3. Shamim, W., Francis, D.P., Yousufuddin, M., Varney, S., Pieopli, M.F., Anker, S.D. et al. (1999) Intraventricular conduction delay: a prognostic marker in chronic heart failure. Int. J. Cardiol. 70: 171–8. Skanes, A.C., Krahn, A.D., Yee, R., Klein, G.J., Connolly, S.J., Kerr, C.R. Canadian Trial of Physiologic Pacing, for the CTOPP

Investigators et al. (2001) Progression to chronic atrial fibrillation after pacing: the Canadian Trial of Physiologic Pacing. J. Am. Coll. Cardiol. 38: 167–72. Stamato, N.J., O’Toole, M.F. and Enger, E.L. (1992) Permanent pacemaker implantation in the cardiac catheterization laboratory versus the operating room: an analysis of hospital charges and complications. Pacing Clin. Electrophysiol. 15: 2236–9. Stokes, W. (1846) Observations of some cases of permanently slow pulse. Dublin Q. J. Med. Sci. 11: 73–85. Sugrue, D.D., Gersh, B.J., Holmes, D.R., Wood, D.L., Osborn, M.J. and Hammill, S.C. (1986) Symptomatic “isolated” carotid sinus hypersensitivity: natural history and results of treatment with anticholinergic drugs or pacemaker. J. Am. Coll. Cardiol. 7: 158–62. Sweeney, M.O., Ellenbogen, K.A., Miller, E.H., Sherfesee, L., Sheldon, T. and Whellan, D. (2006) The Managed Ventricular Pacing versus VVI 40 Pacing (MVP) Trial: clinical background, rationale, design, and implementation. J. Cardiovasc. Electrophysiol. 17: 1295–8. Sweeney, M.O., Hellkamp, A.S., Ellenbogen, K.A., Greenspon, A. J., Freedman, R.A., Lee, K.L. and Lamas, G.A. (2003) MODE Selection Trial Investigators. Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction. Circulation 107: 2932–7. Toff, W.D., Camm, A.J. and Skehan, J.D. (2005) United Kingdom Pacing and Cardiovascular Events Trial Investigators. Singlechamber versus dual-chamber pacing for high-grade atrioventricular block. N. Engl. J. Med. 353: 145–55. Turner, M.S., Bleasdale, R.A., Vinereanu, D., Mumford, C.E., Paul, V., Fraser, A.G. et al. (2004) Electrical and mechanical components of dyssynchrony in heart failure patients with normal QRS duration and left bundle-branch block: impact of left and biventricular pacing. Circulation 109: 2544–9. Wiegand, U.K., Bode, F., Bonnemeier, H., Tolg, R., Peters, W. and Katus, H.A. (2001) Incidence and predictors of pacemaker dysfunction with unipolar ventricular lead configuration. Can we identify patients who benefit from bipolar electrodes? Pacing Clin. Electrophysiol. 24: 1383–8. Wilkoff, B.L., Cook, J.R., Epstein, A.E., Greene, H.L., Hallstrom, A. P., Hsia, H. et al. (2002) Dual Chamber and VVI Implantable Defibrillator Trial Investigators. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial. JAMA 288: 3115–23. Ypenburg, C., Bax, J.J., van der Wall, E.E., Schalij, M.J. and van Erven, L. (2007) Intrathoracic impedance monitoring to predict decompensated heart failure. Am. J. Cardiol. 99: 554–7. Zoll, P.M., Linenthal, A.J., Norman, L.R., Paul, M.H. and Gibson, W. (1955) Use of external electronic pacemaker in cardiac arrest. JAMA 159: 1428–31. Zucker, I.R., Parsonnet, V., Myers, G.H., Lotman, H. and Asa, M.M. (1964) Self-energized pacemakers: the possibilities of using biological energy sources. Circulation 29: 157–60. Zuckerman, W., Zaroff, L.I., Berkovits, B.V., Matloff, J.M. and Harken, D.E. (1967) Clinical experiences with a new implantable demand pacemaker. Am. J. Cardiol. 20: 232–8.

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the development of smaller, portable units that could be placed in ambulances. The discovery that a biphasic waveform could successfully defibrillate with smaller amounts of energy in greater than 90% of patients has allowed both the external and internal devices to become even smaller. The earliest implanted devices had limited capabilities with respect to pacemaker function, stored telemetry, and arrhythmia discrimination ability. The only criterion for detection of potentially lethal arrhythmias was heart rate. Up to 40% of the early recipients of ICDs received inappropriate shocks. The first recipients were “ survivors of multiple cardiac arrests refractory to antiarrhythmic therapy” (Mirowski et al., 1982). The device weighed 250 g and had a volume of 145 ml, compared with the modern device which weighs ⬃70 g at a volume of less than 40 ml. The modern devices can perform virtually all the functions of a pacemaker

The implantable cardioverter–defibrillator (ICD) was the vision of Michel Mirowski, who first implanted a defibrillator in Baltimore in 1980, after more than 10 years of development. The devices were not approved by the US Food and Drug Administration for widespread use until 1985. The discovery that defibrillation could successfully restore sinus rhythm to a fibrillating dog heart was made in the late 1800s in Switzerland and was applied in humans with an external alternating current defibrillator in 1947 by Claude Beck at University Hospitals in Cleveland during open heart surgery using paddles applied to the myocardial surface. By the mid 1950s, external closed chest defibrillators had been developed, and by the late 1950s alternating current was replaced by direct current power sources. As units became smaller, the 1960s saw

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including cardiac resynchronization therapy pacing, store large amounts of arrhythmia and other physiologic data, and have the ability to discriminate between physiologic tachycardias, as well as non-physiologic tachycardias of supraventricular origin. Defibrillator devices initially required an open thoracotomy for placement of epicardial shocking electrodes or patches. Today the overwhelming majority of ICDs are placed with transvenous leads for pacing and shocking.

BASIC ELEMENTS OF AN ICD SYSTEM The ICD system has two basic elements: a pulse generator and a lead. As ICDs now have virtually all of the capabilities of pacemakers, including cardiac resynchronization therapy pacing, the number of leads may vary from 1 to 3. The leads placed in the atrium or in the coronary sinus as part of a dual chamber or cardiac resynchronization system are simply pacemaker leads as described in the previous chapter. The lead that is typically placed in the right ventricle (RV) is unique to an ICD in that it contains one or two shocking coils, through which the high voltage output necessary to deliver the defibrillation energy is channeled. The lead also serves as a pacemaker lead, thus it has to have pacing and sensing capabilities. Like pacemaker leads (see previous chapter) the leads are composed of electrodes, conductors, and insulation as well as distinctly different ends. A fixation mechanism, either passive or active, is at the distal end in contact with the myocardium. Connectors that interface with the ICD generator are at the opposite end. All sensing in an ICD is done in a bipolar configuration. The sensing may be between the distal end of the lead and a ring electrode placed 1–2 cm from the end of the lead. This type of ICD lead is referred to as a dedicated or true bipolar lead. The coils may also serve as the ring electrode in an ICD lead, in which sensing occurs between the end of the lead and the distal right ventricular lead defibrillation coil. This is referred to as integrated bipolar sensing. The first ICDs required open-chest procedures for lead placement on the epicardial surface. Most systems now utilize transvenous leads. Even so, occasionally an epicardial system is required today. Leads placed on the epicardium may serve as the sensing leads. These are typically sewn on or screwed into the myocardium. Epicardial defibrillation patches are placed inside or outside the pericardium over the left ventricle (LV) and RV. The coil or coils are positioned in the RV in a single coil lead system and in the RV and superior vena cava (SVC) in a dual coil lead system. There have been some data to suggest lower and more reliable defibrillation

thresholds with dual coil systems over single coil systems, but this remains an area of some debate. The vector of the defibrillation wavefront can be from the ICD generator (“can”) (or can and SVC) to the RV or from the RV to the can (or can and SVC). Some manufacturers offer the option of making the can “cold” or inactive, then shocking only between the two coils. The preferable vector is similarly an area of debate, with different manufacturers offering different configurations, though reversing the manufacturer’s default polarity setting is usually a programming option. An equally important part of a defibrillator system is the programmer. This is an external device used to interrogate and program the ICD. Each company that manufactures ICDs makes its own programmer which is used for the same purpose in a pacemaker system. The ICD now stores tremendous amounts of data, documenting its function and therapies. In order to obtain this data, the programmer sends and receives radiofrequency signals from the ICD. This has been accomplished until the recent past by placing a wand attached to the programmer over the device, essentially in contact with the device. Devices are now being manufactured with wireless capabilities using a unique frequency thus potentially eliminating or at least decreasing the need for the wand. The stored data can be downloaded to the programmer and reviewed, printed, and even stored. These data include patient characteristics and demographic data, implant dates and lead data, as well as the pacing history, the history of arrhythmias recorded by the device (both supraventricular and ventricular), the history of therapies delivered by the device including electrograms recorded by the device used to determine the necessity of therapy, and the results of the therapy. Newer devices are even reporting parameters such as patient activity, thoracic impedance as a surrogate of LV filling pressures, heart rate variability as a surrogate of clinical congestive heart rate failure, and right ventricular pressures. As many of these devices are providing data useful to the clinicians caring for the patient, home monitoring units that can transmit this telemetry data via phone lines to Internet sites accessible universally to caregivers have been developed.

IMPLANT PROCEDURE DETAILS The ICD is most commonly implanted using a technique similar to that used for pacemaker implantation. The defibrillator lead and ICD generator are positioned so that the vector of the defibrillating wavefront passes through as much myocardium as possible. This is typically accomplished by inserting the lead transvenously into the left upper extremity peripheral veins into

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FUNCTION, PROGRAMMING, AND OTHER POINTS OF CONSIDERATION

the right ventricle via the tricuspid valve. Placing the device via the right-sided upper extremity veins, and even the lower extremity veins is certainly possible, but compromises defibrillation efficacy slightly. The ICD generator is then placed subcutaneously into a pocket in the pre-pectoral fat, though some physicians place the device under the pectoralis muscle. The lead may be placed anywhere from the apex of the right ventricle to the right ventricular outflow tract, depending on the optimal balance between stability, sensing of the ventricular signal, and pacing threshold. Unique to the ICD implant procedure is the testing of the ICD’s ability to defibrillate the heart. There are two methods commonly employed: defibrillation threshold testing (DFT) and upper limit of vulnerability testing. The former is by far the most commonly used method. In defibrillation threshold testing, ventricular fibrillation (VF) is induced either with a low amplitude shock on the T-wave, intracardiac application by the device of a 9 V pulse of direct current energy, or with rapid ventricular pacing. The device is then observed to detect and convert the rhythm back to normal. If the DFT is not achieved within a reasonable safety margin (usually 10 J less than the maximum output of the ICD) then options include moving the right ventricular lead to change the vector, adding a subcutaneous shocking coil or array of coils, changing the wavefront electronically or reversing the vector of the wavefront. The other method of defibrillation assessment involves testing to determine the lowest amount of energy, which is typically between 10 and 20 Joules, which does not induce VF when it is delivered on the T-wave. This should approximate the DFT and has the advantage of not inducing VF in most cases. The mortality from ICD implant is typically much less than 1%. Complications such as bleeding, pneumothorax, hematoma, cardiac perforation/tamponade, infection and lead dislodgment occur in 1–2% of cases. As with pacemakers, the incidence of chronic complications is not entirely clear due to inconsistencies in reporting, but include infection, venous thrombosis and device malfunction resulting in shock failure or inappropriate shocks.

FUNCTION, PROGRAMMING, AND OTHER POINTS OF CONSIDERATION As described above, the modern era ICD is a fully functional pacemaker. Pacemaker function and programming have been described in the previous chapter. The unique function and programming of an ICD relates to its ability to detect and treat malignant tachyarrhythmias. The two key concepts in this regard are

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detection and therapies. Detection refers to the heart rate at which the device will begin to classify the patient’s rhythm as potentially requiring a shock or other therapy. Therapy refers to the treatments, either shocks or rapid ventricular pacing, often referred to as overdrive pacing. An ICD is programmed to detect and treat ventricular arrhythmias according to heart rate, not surface morphology. As such, a programming physician may choose different therapies for tachycardias of different rates. For instance, a minimum heart rate of 175 bpm may be chosen as a cutoff for treatment by the ICD. If the heart rate is greater than 200 bpm, however, the physician may choose a more aggressive response by the ICD than they might for the tachycardia at 175 bpm. These heart rate ranges are frequently referred to as zones. A monitor-only zone may be programmed on some devices to record and store information without delivering any therapies. This might be done to document significant ventricular arrhythmias which may be occurring clinically even though they are not resulting in potentially lethal consequences, while trying to avoid inappropriate therapies for sinus tachycardia or atrial arrhythmias with rapid ventricular rates. In general, up to three zones are programmable, sometimes including and sometimes in addition to a monitor-only zone, depending upon the manufacturer. The fastest heart rate zone is usually referred to as the VF (ventricular fibrillation) zone and the other zones may be called the VT (ventricular tachycardia), VT-1 or FVT (fast VT) zones. These heart rate cutoffs represent the starting point for an ICD to initiate its algorithm to decide whether or not to deliver therapy. Because there can be overlap from malignant and benign heart rhythms based on rate alone, the devices use several other criteria to quickly (within seconds) classify a detected tachycardia as requiring therapy or not. Amongst the most commonly used other criteria are stability, onset, and atrioventricular relationship. An ICD constantly analyzes the interval from one R wave recorded from the lead in the RV to the next. The detection of a tachycardia is thus based on these R–R intervals. Ventricular tachycardia is less likely to have significant variation in the R–R interval than atrial fibrillation, thus an ICD programmed for therapies at 175 bpm may withhold therapy for a patient with a heart rate of 180 bpm due to the fact that the R–R intervals are very unstable. Sinus tachycardia may have very stable R–R intervals, but is likely to have had a gradual onset, compared with ventricular tachycardia, which most often has an abrupt onset. Also, in sinus tachycardia, one would expect a P wave to be present if there is a lead in the atrium before each R wave, and in ventricular tachycardia one is more likely to see dissociation between the P wave and the R wave, often with more R waves than P waves.

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67. CARDIAC DEFIBRILLATORS

Obviously there is no perfect discriminator, so most devices err on the side of delivering therapy if discrimination cannot be made within a certain time period, which may also be programmable. Discriminator technology continues to improve. Newer devices can often compare a template of the sensed RV signal to currently sensed RV signal and determine if the morphology has significantly changed from the native R wave as would be expected with most VTs. ICD therapies are largely limited to two categories: high voltage shocks and anti-tachycardia pacing (ATP). Shocks vary in size from 1 Joule up to 41 Joules. This is compared with external defibrillators that deliver from 5 to 360 Joules. Internal shocks are generally less subject than external defibrillators to the issues of impedance imposed by the chest wall and skeletal structures. Therefore lower voltages are necessary. As noted above, shocks are delivered from the ICD to the coils on the lead. Some manufacturers favor a vector that delivers the shock to the RV coil from the ICD and SVC coil, and others favor a reversal of this vector. Reversing the programmed polarity is possible based on physician preference. These therapies are certainly felt by the patient and are frequently delivered before the patient has developed any symptoms from the tachyarrhythmias. Even so, it is rare for a patient to be injured or even incapacitated more than momentarily by a shock such that patient concerns that they will be put off their feet or lose control of a car are usually unfounded. Healthcare workers administering to an ICD recipient will not be harmed by an ICD shock, even if they are in contact with the patient during a shock. Shocks can be associated with a significant negative impact on quality of life, particularly in recipients of repeated shocks be they appropriate or inappropriate. The finding in the electrophysiology lab that many VTs can be terminated with rapid ventricular overdrive pacing led to the development of such painless therapies for ICDs. Sophisticated pacing therapies are now available in most ICDs which allow for sequentially more aggressive pacing therapies in a graduated fashion based on response to pacing prior to delivering shocks. Newer models will even attempt pacing while charging for a shock for heart rates up to 250 bpm, based on the results of the PAINFREERX trial (Wathen et al., 2004).

INDICATIONS AND PATIENT SELECTION CRITERIA The selection of patients for implantation continues to be an evolving process. Based on the MADIT

(Multicenter Automatic Defibrillator Implantation Trial) trial in 1996 (Moss et al., 1996), the ICD was first demonstrated to be superior to conventional medical therapy in a randomized controlled trial. Patients were randomized to ICD or medical therapy if they had a history of previous myocardial infarction and an ejection fraction of 36% after documentation of nonsustained ventricular tachycardia and an electrophysiologic study which documented sustained ventricular tachycardia that could not be suppressed by intravenous procainamide. A secondary prevention trial, the AVID (Antiarrhythmics Versus Implantable Defibrillators) trial, was published in 1997, showing that defibrillators were superior to medical therapy in patients who had been resuscitated from near-fatal ventricular fibrillation or who had undergone cardioversion from sustained ventricular tachycardia. These findings were duplicated, though without statistical significance, in the CIDS (Canadian Implantable Defibrillator Study) (Connolly et al., 2000) and CASH (Cardiac Arrest Study, Hamburg) (Kuck et al., 2000) studies. Until recently, most recipients of ICDs had undergone an electrophysiologic study which had demonstrated inducible sustained ventricular arrhythmias. The MADIT II trial (Moss et al., 2002) showed a greater than 30% mortality reduction for defibrillators compared with optimal medical therapy in patients with an ejection fraction 31% and a prior history of myocardial infarction. No electrophysiologic testing or observed arrhythmias were required for entry into the study. This resulted in a major shift away from electrophysiologic testing as a prerequisite for a defibrillator in the population with ischemic cardiomyopathy. The DEFINITE (Defibrillators in Non-Ischemic Cardiomyopathy Evaluation) trial (Kadish et al., 2004) showed a statistically non-significant 35% mortality risk reduction in non-ischemic patients with ejection fractions 35%. Subsequently, the SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial) trial (Bardy et al., 2005) showed a significant survival benefit for defibrillators but not amiodarone in patients with an ejection fraction 36% and New York Heart Association class II or III congestive heart failure symptoms for any reason. Thus the indications for ICD expanded to the large population of patients with a non-ischemic basis for their low ejection fraction. Two trials to date showed no benefit for the ICD. The first was the CABG-PATCH (Coronary Artery Bypass Graft Patch) trial (Bigger, 1997). Epicardial ICD patches were placed at the time of bypass surgery and patients with ejection fractions 36% and an abnormal signal-averaged electrocardiogram (SAECG) were randomized to medical therapy or an abdominal ICD. Among the many factors that may have contributed to

IXA. NEUROMODULATION FOR CARDIOVASCULAR DISORDERS

FUTURE DIRECTIONS

the inability to show an advantage for the ICD are the facts that there were no transvenous leads used, and that the SAECG has been essentially abandoned as a screening tool for arrhythmia risk stratification. The second trial was the DINAMIT (Defibrillators In Acute Myocardial Infarction) trial (Hohnloser et al., 2004). In this trial, patients with an ejection fraction of 35% or less and a recent myocardial infarction within the last 6–40 days, as well as depressed heart rate variability (a marker of increased risk of ventricular arrhythmias), were randomized to ICD or medical therapy. The ICD did not demonstrate any survival benefit. The common thread in both of these trials was the large proportion of patients who had just undergone a coronary revascularization procedure, which may have acutely decreased the arrhythmia risk significantly. At present a patient with an ejection fraction of 35% or less regardless of mechanism is felt to be a candidate for ICD implantation, provided there has been sufficient time to establish that the ejection fraction is not an acute, potentially reversible finding.

FUTURE DIRECTIONS It is entirely plausible that more ICDs will soon be put in than pacemakers. The impact of sudden cardiac death on society is enormous, as it ranks amongst the leading causes of death in the developed world. The majority of individuals that die suddenly of a cardiac cause are not known to have any heart disease. Thus the potential for ICDs to save lives is almost limitless. As we develop more sophisticated ways to identify individuals at risk new indications for ICD implants may arise. Certainly in the population of patients known to have heart disease the indications for ICD implant have expanded dramatically with the publication of trials such as MADIT-II and SCD-HeFT. Determining which of these patients are likely to benefit remains an area of intense research, given the cost of these devices, which is often in excess of $25 000. With the development of cardiac resynchronization therapy (CRT) pacing, this technology has been incorporated into ICDs now, and the vast majority of CRT devices in this country are defibrillators at present. As the ability to identify more patients who would benefit from CRT improves, there will potentially be even more indications for ICDs. There is considerable interest in developing a leadless ICD system, as this would limit the intravascular

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infection risk from ICDs as well as the morbidity and mortality associated with implantation and extraction of these leads. Also, the current inability of ICD recipients to have magnetic resonance imaging (MRI) studies represents another area of intense interest, as MRI studies are becoming a more common part of the work-up of many common diseases.

References AVID (1997) A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from nearfatal ventricular arrhythmias. The Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators. N. Engl. J. Med. 337 (22): 1576–83. Bardy, G.H., Lee, K.L., Mark, D.B., Poole, J.E., Packer, D.L., Boineau, R. et al. (2005) Amiodarone or an implantable cardioverterdefibrillator for congestive heart failure. N. Engl. J. Med. 352 (3): 225–37. Bigger, J.T. (1997) Prophylactic use of implanted cardiac defibrillators in patients at high risk for ventricular arrhythmias after coronaryartery bypass graft surgery. Coronary Artery Bypass Graft (CABG) Patch Trial Investigators. N. Engl. J. Med. 337 (22): 1569–75. Connolly, S.J., Gent, M., Roberts, R.S., Dorian, P., Roy, D., Sheldon, R.S. et al. (2000) Canadian implantable defibrillator study (CIDS): a randomized trial of the implantable cardioverter defibrillator against amiodarone. Circulation 101 (11): 1297–302. Hohnloser, S.H., Kuck, K.H., Dorian, P., Roberts, R.S., Hampton, J.R., Hatala, R. et al. (2004) Prophylactic use of an implantable cardioverter-defibrillator after acute myocardial infarction. N. Engl. J. Med. 351 (24): 2481–8. Kadish, A., Dyer, A., Daubert, J.P., Quigg, R., Estes, N.A., Anderson, K.P. et al. (2004) Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N. Engl. J. Med. 350 (21): 2151–8. Kuck, K.H., Cappato, R., Siebels, J. and Ruppel, R. (2000) Randomized comparison of antiarrhythmic drug therapy with implantable defibrillators in patients resuscitated from cardiac arrest: the Cardiac Arrest Study Hamburg (CASH). Circulation 102 (7): 748–54. Mirowski, M., Mower, M.M., Reid, P.R., Watkins, L. and Langer, A. (1982) The automatic implantable defibrillator. New modality for treatment of life-threatening ventricular arrhythmias. Pacing Clin. Electrophysiol. 5 (3): 384–401. Moss, A.J., Hall, W.J., Cannom, D.S., Daubert, J.P., Higgins, S.L., Klein, H. et al. (1996) Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N. Engl. J. Med. 335 (26): 1933–40. Moss, A.J., Zareba, W., Hall, W.J., Klein, H., Wilber, D.J., Cannom, D.S. et al. (2002) Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N. Engl. J. Med. 346 (12): 877–83. Wathen, M.S., DeGroot, P.J., Sweeney, M.O., Stark, A.J., Otterness, M.F., Adkisson, W.O. et al. (2004) Prospective randomized multicenter trial of empirical antitachycardia pacing versus shocks for spontaneous rapid ventricular tachycardia in patients with implantable cardioverter-defibrillators: Pacing Fast Ventricular Tachycardia Reduces Shock Therapies (PainFREE Rx II) trial results. Circulation 110 (17): 2591–6.

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C H A P T E R

68 Spinal Cord Stimulation for Peripheral Vascular Disorders Svante Horsch and Stefan Schulte

O U T L I N E Introduction

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Complications and Avoidance

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History of Stimulation for PAD

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Outcomes

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Indications and Patient Selection Criteria

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Conclusion and Future Expectations

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Implant Procedure Details and Programming

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References

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INTRODUCTION

The prognosis of the affected limb is determined by the extent of the arterial disease, the acuity of limb ischemia, and the feasibility and rapidity of restoring arterial circulation to the foot. For the patient with chronic peripheral arterial occlusive disease and continued progression of symptoms to critical limb ischemia (CLI) (e.g., development of ulcer, rest pain or gangrene), the prognosis is very poor unless revascularization is established. The management of patients with PAD is often challenging due to the fact that the therapy has to be planned, not only in the context of the natural history and epidemiology of the disease (including risk factors and markers predicting spontaneous detoriation), but also in the context of its high co-morbidity and mortality rates. Despite ongoing progress in revascularization procedures such as distal bypasses and increasingly complex endovascular procedures, the fate of patients with CLI is still poor. It is estimated that 10–30% of the patients with CLI will die within

Peripheral arterial disease (PAD) includes a diverse group of disorders that lead to progressive stenosis or occlusion of the aorta and its noncoronary branch arteries, including the carotid, upper extremity, visceral, and lower extremity arteries. The most common cause of lower extremity PAD worldwide is atherosclerosis and thus the epidemiology and clinical consequences of PAD are closely associated with classic atherosclerosis risk factors (e.g. smoking, diabetes, hypertension, hyperlipidemia and family history). The prevalence of lower extremity PAD has been defined by a series of epidemiological investigations that have used either claudication as a symptomatic marker of PAD or an abnormal ankle-to-brachial systolic blood pressure to define the population affected, which is in the range of 3–10% in people younger than 60 years. The prevalence increases to 15–20% in persons older than 70 years.

Neuromodulation

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2009 Elsevier Ltd. © 2008,

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68. SPINAL CORD STIMULATION FOR PERIPHERAL VASCULAR DISORDERS

6 months of its onset and another 25–35% will undergo major amputation (Dormandy et al., 1999; Hirsch et al., 2006; Norgren et al., 2007). However, although technical advances in vascular surgery may have resulted in a decrease of amputation rates, there remain patients in whom repeated vascular reconstructions do not have a realistic chance of success. In these patients, ischemic pain is often disabling, adversely affecting their quality of life and severely limiting their activity level, and this, in turn, hinders treatment of their underlying disease. Such patients are at a high risk for amputation.

HISTORY OF STIMULATION FOR PAD In 1973 Cook and Weinstein were the first to describe a significant increase in regional blood flow of the lower extremities in patients with multiple sclerosis treated by spinal cord stimulation (SCS) for limb pain and spasm. Three years later, this same group was the first to treat the ischemic pain of peripheral vascular disease with SCS. They reported a significant relief of pain of the stimulated limbs, increased blood flow and skin temperature and, moreover, a sustained healing of ischemic ulcers in nine patients with PAD. They postulated that SCS might slow or delay amputation of ischemic limbs and suggested further investigation (Cook et al., 1976). In the ensuing years other authors concordantly drew the same conclusions regarding the effects of SCS in PAD. SCS provides good pain relief (60–80% of the patients), provides an improvement in claudication distance, and provides an improvement in activities of daily living (ADLs) (Tallis et al., 1983; Augustinsson et al., 1985; Fiume et al., 1989; Rickman et al., 1994). TABLE 68.1

These apparent benefits of SCS in patients with PAD have been attributed to improvement of the microcirculation in the affected limb. In several studies, the status of the microcirculation was obtained using different variables such as capillary blood flow, capillary density (Jacobs et al., 1988, 1990; Tesfaye et al., 1996), skin temperature, transcutaneous oxygen tension (TcpO2), and laser Doppler flowmetry (Sciacca et al., 1991; Claeys et al., 1994; Kumar et al., 1997), measured on the dorsum of the foot. Most of these studies were clinical retrospective data collections and only a few were randomized or controlled. For a long time, the overall effects on limb salvage and other endpoints were not sufficiently established. During the 1990s, the first randomized controlled studies were conducted comparing the results of SCS treatment to the results of “optimal medical management” (see Table 68.1). The “Swedish prospective randomized controlled study” published by Jivegård et al. (1995) evaluated the hypothesis that SCS improves limb salvage in patients with non-reconstructible critical leg ischemia. During a 5 year period, 51 patients, including 10 patients with diabetes, having ischemic rest pain and/or ulcerations, were randomized to either “SCS  per-oral analgesic treatment” (n  25) or “per-oral analgesic treatment alone” (n  26). The endpoints for this study were pain relief, tissue loss, and limb salvage. Long-term pain relief occurred only in the group treated with SCS and tissue loss was less. Limb salvage after 18 and 60 months tended to be higher in the SCS than in the control group (62% vs. 45% and 51% vs. 35%, respectively) (Jivegård et al., 1995). The randomized controlled multicenter trial in Belgium included 38 patients with severe limb ischemia unsuitable for surgery (Suy et al., 1994). All patients received “optimal medical treatment” consisting of platelet

Results of reported randomized controlled trials (RCT)

Authors and treatment

Patients (Control vs. SCS-treated) [Fontaine stage]

Mean follow-up (mth)

Pain relief at follow-up (Control vs. SCS-treated)

Limb salvage at follow-up (Control vs. SCS-treated)

Jivegård et al. (1995) Per-oral analgesic vs. SCS  per-oral analgesic treatment

n  26 vs. 25 [14 vs. 15 stage IV]

18

Significant reduction of VAS only in SCS group (6–12 months)

45% vs. 62% (n.s.)

Suy et al. (1994) Medical treatment vs. SCS  medical treatment

n  18 vs. 20 [13 vs. 13 stage IV]

20

28% vs. 70% painlessness

n.s.

Claeys and Horsch (1995) PGE1 vs. SCS  PGE1

n  41 vs. 45 [41 vs. 45 stage IV]

12

10% vs. 40% achieved outcome of stage II (no rest pain, no ulcers)

65% vs. 68% (n.s.)

Klomp et al. (1999) Best medical treatment (analgesic, ASA, coumarins, vasoactive) vs. SCS  best medical treatment

n  60 vs. 60 [41 vs. 38 stage IV]

18

Difference of pain reduction between control and SCS group not significant, but significant less pain medication in SCS group

24% vs. 48% (significant increase of limb salvage in patients subgroup with “intermediate” skin microcirculation and SCS)

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INDICATIONS AND PATIENT SELECTION CRITERIA

anti-aggregation therapy, rheological therapy (improvement in flow characteristics), and analgesic medication. Twenty patients were randomized to receive additional SCS treatment. There were no significant differences regarding forefoot salvage during the 24 months of study in either group. However, when evaluating “clinical success,” defined as pain relief, ability to walk, and quality of life, life-table analysis did show a significantly better result in favor of the SCS group (Suy et al., 1994). In a study by Claeys and Horsch (1995), 86 inoperable patients with ischemic ulcers, including 13 patients with diabetes, were randomized into two groups receiving intravenous prostaglandin E1 (PGE1), with or without adjunctive SCS treatment. Ulcer healing occurred significantly more in the SCS group (69%) when compared to the PGE1 group (17%). Pain relief was also more frequently seen in the group with the additional SCS treatment (40% vs. 10%). There was, however, no difference in major amputation frequency when comparing the two groups (15% vs. 20%). After a follow-up of 12 months, TcpO2 values increased significantly in the group treated with PGE1 and SCS. A TcpO2 increase above 26 mmHg correlated with ulcer healing, whereas a TcpO2 less than or equal to 10 mmHg predicted poor outcome (Claeys and Horsch, 1995). The “Dutch randomized controlled multicenter trial,” studying SCS, enrolled 120 patients with non-reconstructible chronic critical limb ischemia (Klomb et al., 1999). Treatment strategies in this study included “optimal medical treatment” vs. “optimal medical treatment plus SCS.” The primary endpoints of the study were limb salvage, pain relief, quality of life, and cost-effectiveness. The secondary endpoints of the study included healing of ischemic lesions, level of amputation, effects on the macro- and microcirculation, and complications of the therapies. An additional strategy of this study was the evaluation of the prognostic value of microcirculatory data. A 2 year follow-up revealed significant pain relief, but no differences in limb salvage. A subgroup analysis, dividing the patients according to their microcirculatory status, showed better results in a group of patients with an “intermediate” microcirculatory function (Ubbink et al., 1999). The results of the randomized studies are summarized in Table 68.1.

INDICATIONS AND PATIENT SELECTION CRITERIA To optimize patient selection criteria, several studies have been undertaken in the past (Klomb et al., 1999;

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Petrakis and Sciacca, 2000; Amann et al., 2003). All of these studies generally agree on appropriate indications for the treatment of non-reconstructible, stable, CLI. Interventional treatment modalities and vascular reconstructive surgery are the therapies of choice for patients with ischemic rest pain, non-healing ischemic ulcers, and gangrene. Nevertheless, there are patients that do remain in whom vascular intervention has no realistic chance of success (mainly due to a lack of an autologous vein for distal bypass surgery or poor distal arterial run-off). Ischemic pain is often disabling in these patients, adversely affecting quality of life and severely limiting their ADLs. The European Peripheral Vascular Disease Outcome Study (SCS-EPOS) showed that patient selection, on the basis of transcutaneous oxygen tension (TcpO2) measurement and the results of trial screening, may help to increase the probability of limb survival after SCS therapy (Amann et al., 2003). The study suggested two main factors regarding patient selection that may lead to a benefit from SCS for the treatment of patients with non-reconstructible PAD: 1. patients with a baseline, fair local microcirculation on the basis of their local TcpO2 (10–30 mmHg) before SCS-treatment, and those patients with a poor baseline TcpO2 (10 mmHg) before treatment who, after test stimulation with SCS, showed an increase in TcpO2 to at least 20 mmHg; and 2. patients who during the test period showed, based on repeated TcpO2 measurements, an improvement in local oxygen supply. The authors of this study therefore recommended a test stimulation period with repeated TcpO2 measurements (pre-and post-trial screening) to confirm good pain relief (through adequate paresthesia coverage) and a positive microcirculatory response to SCS, prior to final implantation of the pulse generator (Amann et al., 2003). Besides the known clear indications for SCS in patients with non-reconstructible PAD such as PAD patients with ischemic rest pain and/or ischemic ulcers and gangrene, it is worth while to consider expanding these indications for SCS to include patients with claudication and patients who are questionably indicated for distal bypass surgery (i.e. poor arterial run-off). The rates of limb salvage obtained with SCS in these patients can be comparable to the rates of limb salvage seen with infra-inguinal vascular reconstruction. The results are even better when they are compared to the results that are seen from patients who receive synthetic and alternative vascular grafts for distal bypass surgery when there is a lack of an autologous vein for the surgery (Leng et al., 2000).

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826 TABLE 68.2

68. SPINAL CORD STIMULATION FOR PERIPHERAL VASCULAR DISORDERS

Indications for spinal cord stimulation in peripheral vascular disorders

Good indication for SCS ●

●

Non-reconstructible peripheral arterial disease (PAD) with stable critical limb ischemia (ischemic rest pain and/or localized tissue necrosis (ischemic ulcer or gangrene) Grade III  IV of the Fontaine’s classification, categories 4–6 of the Rutherford’s classification

Unclear indications for SCS (poor evidence from literature) ●

● ● ● ● ● ●

Non-recontructible PAD with claudication and recontructible PAD with less promising surgical perspectives (i.e. poor peripheral arterial run-off) Thrombangiitis obliterans (Buerger’s disease) Raynaud’s disease Diabetic angiopathy Vasospasic disorders, systemic vasculitis Frostbite, etc. Upper extremity vascular disorders

To date, there is no evidence in the literature to answer the question of whether SCS will or will not improve primary patency rates of distal bypass surgery. Besides atherosclerosis, other pathologies including diabetic peripheral angiopathy, vasospastic disorders, and inflammatory/autoimmune diseases (i.e. Raynaud´s disease, thrombangiitis obliterans, systemic vasculitis etc.) lead to peripheral vascular disease. SCS might be effective in these disorders; however, while the literature is replete with case studies or small series that often report good results with the therapy, there is a lack of conclusive large studies. The indications of SCS in vascular disorders are summarized in Table 68.2. The known medical contraindications to the use of SCS include uncontrolled bleeding disorders or ongoing anticoagulant therapy, systemic or local sepsis, and/or the presence of demand type cardiac pacemakers or implanted defibrillators.

IMPLANT PROCEDURE DETAILS AND PROGRAMMING The procedure should be performed in a sterile environment, most importantly an operating theatre that is suitable for surgical implants. The procedure must be performed using fluoroscopy to place the electrodes within the appropriate level of the epidural space. Under local anesthesia and with the patient lying in the prone position, a vertical lumbar skin incision is performed. Some centres prefer a complete percutaneous approach. A multipolar electrode

array is placed into the epidural space percutaneously using an appropriate epidural needle (Tuohy needle). Entry sites are usually at the intervertebral spaces between L2/L3 or L3/L4. The epidural needle is placed through the thoracolumbar fascia using a paramedian approach under fluoroscopic guidance. In order to avoid advancement of the needle through the dura mater and into the thecal sac, the epidural space is “found” using either a “loss of resistance” or a “hanging drop” technique. The electrode array is then advanced under fluoroscopic guidance through the needle into the epidural space until the tip is at the T11–T12 level for stimulation of the lower extremities. If the patient has bilateral pain either the electrode array should be placed in the midline or two electrodes should be placed on either side of the anatomic midline. If the patient has unilateral pain the electrode array should be placed slightly eccentric to the side of the pain. Once the leads are anatomically appropriately placed, intraoperative testing is performed. In order to achieve therapeutic success, the patient must feel paresthesia over the area of his/her pain. If the paresthesiae do not cover the exact area of the pain, the electrode array or arrays are moved under fluoroscopic guidance until the patient does feel paresthesiae in the distribution of his/her pain. Once this is achieved, an implantable pulse generator is placed into a surgically formed subcutaneous pocket in the abdominal wall or over the buttock for long-term stimulation. It is common practice in some centers to connect these implanted electrodes to an external stimulating device using connected extensions for a trial of stimulation before proceeding to insertion of a permanent implantable pulse generator or rechargeable battery. This latter procedure allows for a period of trial stimulation during which pain relief and improvement of the microcirculatory status may be assessed. The average initial settings used in our center are a pulse amplitude between 1.0 and 6.0 V, a frequency of between 70 and 120 Hz, and a pulse width of 180– 450 ms. All patients are different and programmed settings are based on individual needs. The goals of programming are (1) provision of concordant comfortable paresthesia over the area of the patient’s perceived pain and (2) preservation of battery life. This latter goal of battery preservation is not as important for patients implanted with rechargeable batteries. During the first year after implantation, stimulation is usually performed continuously, especially in patients with good clinical improvement. Over time, however, most centres frequently change from continuous stimulation to intermittent stimulation to prolong battery life.

IXA. NEUROMODULATION FOR CARDIOVASCULAR DISORDERS

OUTCOMES

COMPLICATIONS AND AVOIDANCE Major complications of SCS are rare. The most frequent reported complications are lead migration or dislocation of the lead, resulting in loss of paresthesia coverage over the affected limb or unwanted stimulation, and lead fracture. To avoid these complications, surgeon implanters must attend to appropriate careful fixation of the electrode array to the thoracolumbar fascia (Spincemaille et al., 2000; Henderson et al., 2006; Kumar et al., 2007). In cases of lead migration, the lead can easily be replaced surgically, under fluoroscopic guidance. Infections of the lead or subcutaneous generator pocket occur with a reported incidence between 0 and 6% (Henderson et al., 2006; Kumar et al., 2007). In many cases the infection will not resolve until the stimulating system is explanted. However, superficial low-grade infections of the generator pocket are fairly common and, although there is no published evidence, considerable anecdotal evidence exists for the efficacy of conservative management that includes temporary explantation of the SCS generator alone, while leaving the electrodes in situ until the generator can be reimplanted. Although there is also minimal published evidence regarding the use of antibiotic prophylaxis before implantation, most implanting centers recommend the intravenous administration of antibiotic prophylaxis. Antibiotics should be given as a single shot dose 30 min before the implant procedure. The most common infecting pathogens after surgical foreign body implantation are Staphylococcus aureus and Staphylococcus epidermidis. A meta-analysis of controlled trials by Ubbink et al. (2004) showed a mean incidence of complications of SCS treatment, comprising infections of leads and impulse generator pockets, dislocation and lead breakage, and early depletion of the battery, to be 20.9%. The higher complication rate typical for multicenter studies enrolling few patients per center suggests that this treatment should be carried out by specialists with expertise in units that have a large experience.

OUTCOMES The most recent systematic review and meta-analysis of controlled trials of SCS and CLI was published by Ubbink et al. in 2004. The authors analyzed nine reports that described six trials, one from Belgium, one from Sweden, one from Germany, two from the Netherlands, and one European multinational, randomized, controlled trial (Suy et al., 1994; Claeys

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and Horsch, 1995; Jivegård et al., 1995; Klomb, 1999; Ubbink et al., 1999; Petrakis and Sciacca, 2000). The primary endpoint for defining success of SCS for the treatment of PAD is limb survival. Five of the above studies did not show any significant difference in amputation rates after 12, 18, and 24 months after initiating SCS, although all studies did show a trend towards better limb salvage in the SCS group (Suy et al., 1994; Claeys and Horsch, 1995; Jivegård et al., 1995; Klomb, 1999; Ubbink et al., 1999; Petrakis and Sciacca, 2000). In subgroups of patients that were selected by baseline TcpO2 (before SCS implant), the trend was stronger than the average. The European Peripheral Vascular Disease Outcome Study (SCSEPOS) showed a significantly better limb survival rate with SCS when compared to conservative treatment with patient selection based on baseline TcpO2 and response to trial stimulation (Amann et al., 2003). When pooled data were analyzed, there was a statistically significant decrease in amputation rates in the group of patients treated with SCS. “A number needed to treat” (NNT) analysis showed that it would take eight patients treated with SCS to prevent one major amputation. When pain relief was evaluated as an endpoint, the SCS group did significantly better after 3 months (Klomb et al., 1999) and 12 months (Jivegård et al., 1995) when compared to those patients who received conservative treatment with antiplatelet aggregation therapy and analgesic medication. Patients with an SCS system also demonstrated significantly lower use of non-narcotic and narcotic pain medication than those treated conservatively (Klomb et al., 1999; Spincemaille et al., 2000). Two studies demonstrated a greater improvement in Fontaine classifications from III and IV (rest pain and ulcer/gangrene) to stage II (claudication) in those patients receiving SCS when compared to those that did not (Suy et al., 1994; Claeys and Horsch, 1995). Using an NNT analysis, only three patients needed to be treated with SCS for one patient to reach Fontaine stage II. Also two studies reported healing of ischemic ulcers (Claeys and Horsch, 1995; Klomb et al., 1999). Pooled data did not show significant differences between SCS-treated and conservative groups in wound healing, or a difference in diabetic vs. non diabetic patients. To assess the functional status and the quality of life in patients treated with SCS for their peripheral arterial vascular disease, different questionnaires were used in some of the studies during follow-up (e.g., the SF-12 questionnaire, the Nottingham Health Profile (NHP), and the Euroqol). The overall score of the NHP showed an improvement during followup in both groups, but the mobility score showed a

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significantly better status in patients treated with SCS (Spincemaille et al., 2000). TcpO2-measurement is the best tool to describe the microcirculatory status as a result of a better perfusion after SCS treatment This measurement was used in all of the conducted studies even though the measurement showed a lack of reproducibility and the testing has to be carried out using a standardized setting. Most of the studies observed a similar increase of TcPO2 in both the SCS and the conservative groups and was significantly higher in the SCS group after 12 months of treatment (Claeys and Horsch, 1995). Only the mean TcpO2 results after 12 months could be pooled without detection of significant differences. These beneficial effects of SCS on the vascular system can also be found in patients who suffer from non-atherosclerotic peripheral vascular diseases such as Buerger’s disease or Raynaud’s disease. Unfortunately, published studies on the effect of SCS on these diseases is rare and only conducted with small numbers of patients. In a clinical, retrospective study published in 2005, the data from 29 patients who received SCS for the treatment of Buerger’s disease were analyzed (Donas et al., 2005). Twenty-nine patients (22 men, 7 women), with a mean age of 33.7 years, were included. The mean Regional Perfusion Index (RPI) at baseline (before SCS treatment) was 0.27. After three months of SCS, the RPI increased significantly to 0.38. During follow-up, a sustained increase of microcirculation was recorded (RPI at 1 year: 0.49; at 3 years: 0.52). The most pronounced improvement of TcpO2 was found in the group of patients with ulcers and gangrene (from 0.17 before SCS-treatment to 0.40 after a mean follow-up of 5.7 years). During follow-up, two minor and two major amputations were performed. Overall limb survival was 93.1% (Donas et al., 2005). Because of the significant improvement in microcirculation and improvement in limb survival, because of the prevention of new trophic lesions with SCS and because of the diffuse, distal, segmental nature of the disease, SCS should be considered as an alternative treatment modality in patients with Buerger’s disease.

CONCLUSION AND FUTURE EXPECTATIONS Epidural spinal cord stimulation has been shown to be an alternative and efficacious treatment modality for patients with non-reconstructible peripheral atherosclerotic vascular disease. In these patients, SCS might improve limb survival, allowing avoidance or

postponement of major amputation, relieve ischemic pain, and improve microcirculation and ulcer healing. Furthermore, the careful selection of patients on the basis of their local microcirculation and positive response to a period of trial stimulation can further improve the probability of limb salvage. Because of these benefits of SCS for CLI, we believe that further studies are needed to clearly define appropriate selection criteria for optimal results after SCS treatment in patients with peripheral vascular disease. Microcirculatory investigations such as TcPO2 do help us understand which patients will and which patients will not derive benefit from SCS. However, more precise tools with better reproducibility and greater sensibility are needed to analyze the microcirculatory status before treatment and during follow-up. The development of these newer more precise tools may also help us to expand the indications of this therapy to patients with intermittent claudication and patients with questionable indications for distal bypass surgery (i.e. poor arterial run-off). The question of whether SCS can increase the patency rates of distal bypass surgery in patients with poor outflow vessels should also be answered in the following years. Buerger’s disease should no longer be questionable as an indication for SCS, because of the reported encouraging high success rates and minimal complication rates of the therapy for this disease. It is our opinion that withholding this treatment modality from these patients is both inhumane and non-scientific.

References Amann, W., Berg, P., Gersbach, P. et al. (2003) Spinal cord stimulation in the treatment of non-reconstructible stable critical leg ischaemia: Results of the European Peripheral Vascular Disease Outcome Study (SCS-EPOS). Eur. J. Vasc. Endovasc. Surg. 26: 280–6. Augustinsson, L.E., Holm, J. and Carlsson, A.C. (1985) Epidural electrical stimulation in severe limb ischemia. Evidences of pain relief, increased blood flow and a possible limb-saving effect. Ann. Surg. 202: 104–11. Cook, A. and Weinstein, S.P. (1973) Chronic dorsal column stimulation in multiple sclerosis preliminary report. N Y State J. Med. 73: 2868–72. Cook, A., Oxygar, A., Baggenstos, P. et al. (1976) Vascular disease of extremities: electrical stimulation of spinal cord and posterior roots. N Y State J. Med. 76: 366–8. Claeys, L. and Horsch, S. (1995) Epidural spinal cord stimulation (SCS) following intravenous prostaglandin E1 therapy in non reconstructible peripheral arterial occlusive disease stage IV. In: S. Horsch and L. Claeys (eds), Spinal Cord Stimulation II: An Innovative Method in the Treatment of PVD and Angina. Darmstadt: Steinkopff Springer International, pp. 147–52. Claeys, L., Ktenidis, K. and Horsch, S. (1994) Transcutaneous oxygen tension in patients with critical limb ischemia treated by spinal cord stimulation. In: S. Horsch and L. Claeys (eds), Spinal Cord Stimulation: An Innovative Method in the Treatment of PVD. Darmstadt: Steinkopff Springer International, pp. 145–52.

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REFERENCES

Donas, K.P., Schulte, S., Ktenidis, K. et al. (2005) The role of spinal cord stimulation in the treatment of Buerger´s disease. J. Vasc. Surg. 41: 830–6. Dormandy, J.A., Heek, L. and Vig, S. (1999) The fate of patients with critical leg ischemia. Semin. Vasc. Surg. 12 (2): 142–7. Fiume, D., Palombi, M., Sciacca, V. et al. (1989) Spinal cord stimulation (SCS) in peripheral ischemic pain. Pacing Clin. Electrophhysiol. 12: 698–704. Henderson, J.M., Schade, C.M., Sasaki, J. et al. (2006) Prevention of mechanical failures in implanted spinal cord stimulation systems. Neuromodulation 9: 183–91. Hirsch, A.T., Haskal, Z.J., Hertzer, N.R. et al. (2006) ACC/AHA 2005 Practice guidelines for the management of patients with peripheral arterial disease. Circulation 113 (11): e463–654. Jacobs, M.J.H.M., Jörning, P.J.G., Beckers, R.Y. et al. (1990) Foot salvage and improvement of microvascular blood flow as a result of epidural spinal cord electrical stimulation. J. Vasc. Surg. 12: 354–60. Jacobs, M.J.H.M., Jörning, P.J.G., Joshi, S.R. et al. (1988) Epidural spinal cord electrical stimulation improves microvascular blood flow in severe limb ischemia. Ann. Surg. 207: 179–83. Jivegård, L.E., Augustinsson, L.E., Holm, J. et al. (1995) Effects of spinal cord stimulation (SCS) in patients with inoperable severe lower limb ischaemia: a prospective randomized controlled study. Eur. J. Vasc. Endovasc. Surg. 9: 421–5. Klomb, H.M., Spincemaille, G.H., Steyerberg, E.W. et al. (1999) Spinal-cord stimulation in critical limb ischaemia: a randomised study. ESES study group. Lancet 353: 1040–4. Kumar, K., Buchser, E., Linderoth, B. et al. (2007) Avoiding complications from spinal cord stimulation: practical recommendations from an international panel of experts. Neuromodulation 10: 24–33. Kumar, K., Toth, C., Nath, R.K. et al. (1997) Improvement of limb circulation in peripheral vascular disease using epidural spinal cord stimulation: a prospective study. J. Neurosurg. 86: 662–9. Leng, G.C., Davis, M. and Baker, D. (2000) Bypass surgery for chronic lower limb ischaemia. Cochrane Database Syst. Rev. 3, CD002000.

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Norgren, L., Hiatt, W.R., Dormandy, J.A. et al. (2007) TASC II Working Group. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J. Vasc. Surgery 45: S1–S68. Petrakis, E. and Sciacca, V. (2000) Prospective study of transcutaneous oxygen tension (TcPO2) measurement in the testing period of spinal cord stimulation in diabetic patients with critical lower leg ischaemia. Int. Angiol. 19: 18–25. Rickman, S., Wuebbels, B.H. and Holloway, G.A., Jr. (1994) Spinal cord stimulation for relief of ischemic pain in end-stage arterial occlusive disease. J. Vasc. Nurs. 12: 14–20. Sciacca, V., Mingoli, A., Maggiore, C. et al. (1991) Laser doppler flowmetry and transcutaneous oxygen tension with severe arterial insufficiency treated by epidural spinal cord stimulation. Vasc. Surg. 25: 165–70. Spincemaille, G.H., Klomp, H.M., Steyerberg, E.W. et al. (2000) Technical data and complications of spinal cord stimulation: data from a randomized trial on critical limb ischemia. Stereotact. Funct. Neurosurg. 74 (2): 63–72. Suy, R., Gybels, J., Van Damme, H. et al. (1994) Spinal cord stimulation for rest pain. The Belgian Randomized Study. In: S. Horsch and L. Claeys (eds), Spinal Cord Stimulation: An Innovative Method in the Treatment of PVD. Darmstadt: Steinkopff Springer International, pp. 197–202. Tallis, R.C., Sedgwick, E.M., Hardwidge, C. et al. (1983) Spinal cord stimulation in peripheral vascular disease. J. Neurol. Neurosurg. Psychiatry 46: 478–84. Tesfaye, S., Watt, J., Benbow, S. et al. (1996) Electrical spinal cord stimulation for painful diabetic peripheral neuropathy. Lancet 348: 1698–701. Ubbink, D.Th., Spincemaille, G.H.I.J., Prins, M.H. et al. (1999) Microcirculatory investigations to determine the effect of spinal cord stimulation for critical leg ischaemia: the Dutch multicenter randomized controlled trial. J. Vasc. Surg. 30: 236–44. Ubbink, D.T., Vermeulen, H., Spincemaille, G.H.J.J. et al. (2004) Systematic review and meta-analysis of controlled trials assessing spinal cord stimulation for inoperable critical leg ischemia. Br. J. Surg. 91: 948–55.

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C H A P T E R

69 Spinal Cord Stimulation for Refractory Angina Mike J.L. DeJongste and Robert D. Foreman

O U T L I N E Pertinent Anatomy, Physiology, and Disease Pathophysiology Angina Pectoris Therapy-Refractory Angina Neural Hierarchy in Cardiac Control

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Historical Perspective of Neurostimulation Electrical Neuromodulation

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Patient Selection, Incidence, and Prevalence

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Implant Procedure

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Outcomes Review of Most Recent Literature

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Complications and Avoidance

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What the Future Holds (the next 5 years)

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Conclusions

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References

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to be associated with muscular ischemia caused by an imbalance of the oxygen demand/supply ratio (Lewis, 1932). At rest, the heart extracts about 50% of the oxygen supplied from the coronary arteries, although this oxygen extraction may vary widely among normal subjects. Because of the kinetics of oxygen dissociation from hemoglobin, this extraction accounts for a physiologically available oxygen extraction of at least 65%, which is relatively high compared to other organs and considered optimal under normal operating conditions. So, the oxygen supply to the myocardium through the coronary arteries is sufficient to meet the metabolic demands of the heart, at rest. During exercise the oxygen demand can only be met by increased coronary blood flow and usually not by an increased extraction. The oxygen demand increases proportional

Angina Pectoris Angina pectoris has been defined by Heberden in 1772 as follows: “The seat of it, and sense of strangling and anxiety with which it is attended, may make it not improperly be called angina pectoris.” He concluded “but it is not to be expected, that much can have been done towards establishing the method of cure for a distemper hitherto so unnoticed, that it has not yet, as far as I know, found a place or a name in the history of diseases.” However, it was not until Keefer and Resnik in 1928 that angina was recognized as being caused by irreversible ischemia (i.e. myocardial infarction). Four years later, angina pectoris was suggested

Neuromodulation

Programming and Other Points for Consideration

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with a rise in both heart rate and blood pressure. This product of systolic blood pressure and heart rate (i.e. the rate pressure product (RPP) or double product) is linearly related to myocardial oxygen consumption. However, oxygen supply to the myocardium can only be augmented through vasodilation of the coronary arteries in order to meet the increased metabolic demand. Subsequently, limitation in the ability of the coronary arteries to dilate reduces oxygen supply. The modern concept for angina pectoris is that during either physical or mental stress, in the presence of an atherosclerotic narrowing in one or more coronary arteries (i.e. 75% narrowing of the luminal diameter), oxygen supply soon becomes insufficient for the myocardial needs since the stenotic coronary arteries are not capable of dilating sufficiently in order to meet the increased oxygen demand. This detrimental shift in the oxygen balance is most often reversible and, when reversed, is followed by relief of myocardial ischemia (Figure 69.1). Demand ischemia, usually resulting from atherosclerotic narrowing of a coronary artery, provokes chronic (stable) angina that is characterized by a retrosternally localized discomfort during stress which is relieved by rest or nitrate consumption. On-going atherosclerosis may reduce the coronary artery luminal diameter so that even at rest oxygen supply cannot meet oxygen demand (supply ischemia). Supply ischemia is the consequence of coronary vasospasm, unstable plaque, or coronary occlusion that mostly follows plaque rupture, or a combination of these conditions. In general, supply ischemia of the myocardium results from acute coronary syndromes (unstable angina or myocardial infarction). The latter is characterized by deterioration of pre-existing angina pectoris complaints, or with de novo presentation of angina at rest. Myocardial ischemia  decreased ratio of

Oxygen supply Oxygen demand

As a separate entity, some patients suffer from angina without epicardial coronary artery disease, the so-called angina with normal coronary arteries (NCA), or microvascular angina, small vessel disease or cardiac syndrome X (Maseri, 1995). The etiology of angina in patients with NCA has not yet been clarified (Hurst et al., 2006). These patients with NCA are reported to have an abnormal cardiac pain perception (Chauhan et al., 1994), as well as evidence of endothelial dysfunction (Bellamy et al., 1998), whether or not in the presence of subendocardial ischemia during the day (Camici, 2007). In concert with several proposed definitions to address the problem of angina in patients with NCA (Panting et al., 2002), and the unknown underlying mechanism(s), these patients exhibit a variety of subjective and objective symptoms (Pasceri et al., 1998). As discussed above, myocardial ischemia is divided into demand and supply ischemia. Angina pectoris may accompany both types of ischemia and be separated into chronic angina (angina occurring during stress) and acute angina (either worsening of pre-existing angina, or de novo presentation of angina at rest). Acute coronary syndromes implicate patients with unstable angina and patients with myocardial infarction – with either ST-segment elevation myocardial infarction (STEMI) or without ST-segment elevation, i.e. non-ST-segment elevation myocardial infarction (non-STEMI). It should be noted that in the sequence of events following a (temporary) occlusion of a coronary artery, changes in diastolic left ventricular function usually precede ECG alterations and chest pain (Figure 69.2). Finally, in regard to typifying patients with differing types of coronary syndromes, there also exists a category of patients with objective evidence of myocardial ischemia, but without angina. This condition of myocardial ischemia without angina is called “silent ischemia” (Xanthos et al., 2008). All of these patients with differing types of coronary syndromes are depicted in Figure 69.3.

Therapy-Refractory Angina Supply Demand Demand ischemia: Ischemia during stress (physical/emotional)

Supply ischemia: Ischemia in rest

Determinants of demand – Heart rate – Systolic blood pressure – Myocardial wall stress – Myocardial contractility

Determinants of supply – Coronary artery diameter and tone – Collateral blood flow – Perfusion pressure – Heart rate (duration of diastole)

FIGURE 69.1 Schematic representation of myocardial ischemia and determinants of oxygen supply/demand ratio (see text for details)

The goals of therapy for stable angina are to relieve symptoms, prevent disease progression and future cardiac events, and improve survival. As shown in Figure 69.1, treatment should be aimed at increasing oxygen supply or decreasing oxygen demand. Anti-ischemic medications, in part, improve the supply–demand balance by reducing O2 demand (beta blockers among others) and/or enhancing supply (e.g. nitrates) (see Table 69.1 for details). Oxygen supply may also be improved by restoring adequate blood supply to the myocardium with revascularization

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PERTINENT ANATOMY, PHYSIOLOGY, AND DISEASE PATHOPHYSIOLOGY

Occlusion/ 0 stenosis

10

20

30 sec

Silent ischemia Relaxation disturbances

chemicalinflammatory-

Contraction alterations

mechanical-

Systolic pressure ä

neuronalactivations

ECG changes

Angina pectoris

FIGURE 69.2 Sequence of events following (temporary) myocardial occlusion

No angina (silent ischemia)

Normal epicardial coronary arteries

Ischemia

Coronary artery disease

FIGURE 69.3 Coronary artery disease usually causes chronic stable angina, which is sometimes accompanied by (periods) of silent ischemia. Silent ischemia is, however, more often present during acute coronary syndromes, i.e. unstable angina, non ST-segment elevation myocardial infarction (non-STEMI) or ST/segment elevated myocardial infarction (STEMI)

Angina

Chronic

Acute

Optimal drug therapy for patients with anginaa

TABLE 69.1 Anti-ischemic agents

Direct effect of agents on: Supply

Demand

Inotropy

Chronotropy

Thrombus/ plaque

Nitrates

↑

↓

(↑)

—

—

Calcium antagonists

↑

↓

↓

↓or↑

↓?

Beta blockers

—

↓

↓

↓

↓?

Angiotensin converting enzyme inhibitors

↑

↓

—

—

↓?

Inhibitors of thrombocyte aggregation

—

—

↑

—

↓

Statins

—

—

(↑)

—

↓

Sinus node rate ↓

—

↓

—

↓

?

a

b

Therapy consists traditionally of drugs from the following groups: beta blockers, calcium-channel blockers, nitrates, thrombocyte aggregation inhibitors (salicylates; clopidogrel), angiotensin converting enzyme (ACE) inhibitors, statins, and maybe newer therapies that reduce sinus node rate increase during exercise (SN rate↓) b Dependening on type of calcium antagonist: for instance, verapamil reduces heart rate whereas nifedipine may increase heart rate (due to a reflex mechanism)

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procedures such as percutaneous coronary intervention (PCI), previously called percutaneous transluminal coronary angioplasty (PTCA), that dilates the affected coronary artery or by creation of a bypass vessel with coronary artery bypass surgery (CABS). Patients with long-lasting severe angina, despite the use of optimal pharmacological therapy, usually undergo coronary angiography to assess revascularization options. A study of 500 patients with symptomatic obstructive coronary artery disease and documented ischemia, undergoing coronary angiography at a tertiary referral center, showed that a substantial proportion (12%) of patients were not candidates for revascularization procedures such as PCI or CABS. Eligibility for revascularization was determined by consensus among reviewers and the angiographer. Patients were deemed to be unsuitable for PCI if one or more of the following conditions existed: chronic total occlusion with unfavorable morphological features (65%), degenerated vein graft (24%), and multiple restenosis (1.6%); for CABG: poor target (mainly related to diffuse CAD disease) (75%), no conduit (5%), and co-morbidities (3%) (Mukherjee et al., 1999). With the use of criteria that include documented ischemia (in 20% of the left ventricle) and angina class 2, an ejection fraction of 25%, approximately 7% (up to 12% with more liberal criteria) of patients would be eligible for alternative adjunct methods of therapy. These current alternative methods for the treatment of severe angina are electrical neuromodulation (TENS and SCS), peripheral and central nervous blocks, and, since the 1990s, transmyocardial laser revascularization, enhanced counterpulsation, urokinase, and treatments aimed at the formation of new blood vessels (Mulcahy et al., 1994; Schoebel et al., 1997; DeJongste et al., 2002, 2004; Kim et al., 2002; Svorkdal, 2004; Yang et al., 2004; Gowda et al., 2005; Stanik-Hutt, 2005; Yang and Barsness, 2006). To address this increasing patient population with refractory angina and the lack of a standardized therapeutic approach to the problem, a Joint Study Group of the European Society of Cardiology (ESC) for refractory angina was formed in 2002 (Mannheimer et al., 2002). This study group defined refractory angina as a chronic condition characterized by the presence of angina caused by coronary insufficiency in the presence of coronary artery disease which cannot be controlled by a combination of medical therapy, angioplasty and coronary bypass surgery. The presence of reversible myocardial ischemia should be clinically established to be the cause of the symptoms. Chronic is defined as a duration of more than 3 months.

Based on “positive effects on symptoms and ischaemia and a favorable side-effect profile” of neuromodulation, the study group recommends electrical

neuromodulation as “the first therapeutic alternative” for patients with chronic refractory angina. This is in accord with the recommendations by Mulcahy et al. (1994) and the outcomes of the literature (see below).

Neural Hierarchy in Cardiac Control (for Extensive Review, see Foreman et al., 2004) Lewis proposed that the pain accompanying ischemia resulted from a local substance release during an ischemic event that might excite sensory neurons and subsequently provoke painful sensations (Lewis, 1932). Adenosine is one substance that fulfils all three of these criteria (release, excite, and provoke) and is hypothesized to be the molecular basis of angina (Lagerqvist, 1990). Adenosine release, which may increase 1000-fold during myocardial ischemia, modifies cardiomyocytes and intrinsic cardiac neuronal tissues, and induces symptoms of angina pectoris when injected intravenously in healthy volunteers (Edlund et al., 1983). It still remains unclear, however, whether adenosine determines the angina threshold in patients with so-called silent ischemia (Sadigh-Lindell et al., 2003). Furthermore, ischemic challenges also cause the increased release of other molecules such as potassium, lactate, bradykinin, and prostaglandins (Sylvén, 1989) (see Figure 69.4). These substances activate and sensitize mechanical and chemical receptors of high threshold sensory nerve endings in the myocardium, the adventitia of coronary arteries, and the sub-epicardial tissue. These nerve endings have fibers that travel within sympathetic and vagal nerves and are recruited during transient myocardial ischemic periods (Foreman et al., 2004). Chemical and mechanical information is transmitted via unmyelinated and small myelinated fibers uninterrupted through the paravertebral ganglia to the dorsal spinal roots of the upper thoracic spinal segments. Some information is carried in afferent vagal neural pathways to the nucleus tractus solitarius, a cell group in the brain stem (medulla) that receives visceral sensory information and taste from the facial (VII), glossopharyngeal (IX), and vagus (X) cranial nerves, as well as the cranial part of the accessory nerve (XI), and then is relayed to the C1–C2 spinal segments (Foreman, 1999). The gate control theory, published by Melzack and Wall in 1965, provides a model for a possible mechanism for pain relief by neurostimulation. Melzack and Wall theorized that stimulation of large, myelinated, rapidly conducting, A-fibers modulates the processing of “pain” signals in the nonmyelinated, slower-conducting C-fibers in the dorsal

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Anginal pain Cortex Thalamocortical tract Thalamus

Spinothalamic tract

Dorsal horn

Cardiac afferent nerve Adenosine

Ischemia

FIGURE 69.4 Pathway and putative neurotransmitter for trans-

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It has been demonstrated that spinal cord stimulation (SCS) controls information from afferent signaling neuronal pathways terminating in cardiovascular brain centers – venterolateral part of the periaqueductal gray, dorsomedial part of the thalamus, medial prefrontal cortex (Brodman areas 9, 10), Brodman areas 24 and 30, posterior inferior part of insular cortex, and Brodman area 40, amongst others (Hautvast et al., 1997). Moreover, the limbic system (a group of structures in the brain including the hippocampus and amygdala that support several functions including emotion, behavior and long-term memory), and the frontal lobes are equipped to transfer this information through efferent (i.e. autonomic) neural pathways involved in regulation of cardiac function. Upon this afferent and efferent neural loop, electrical neuromodulation is capable of restoring the disturbed balance of sensitized signals in the distressed nervous system resulting from an ischemic cardiac insult. This restoration of the disturbed cardioneuronal axis requires a restitution of the neural hierarchy, in which electrical neuromodulation is considered as a dominant controller, affecting functions of neurons in the peripheral nervous system and of the heart.

mitting nociceptive information from the heart (ischemia) to the cortex where the information is interpreted as anginal pain

horn, via interneurons. Noxious information from the heart ascends via the spinothalamic tract system to the thalamus. In addition to the gate control theory, the thalamus is considered as a second gate that modulates afferent pain signals. Finally, this information is projected to the prefrontal lobe of the cortex, where it provokes angina, or the perception of pain from the heart/chest. There is considerable support in the literature to assume that autonomic functions may be influenced by electrical neurostimulation (see Chapter 64 by Ardell and Foreman). These effects require visceral reflex mechanisms that are controlled from higher centers. Since the myocardium is innervated by sympathetic fibers it is therefore plausible to suggest that stimulation of the thoracic spinal cord induces changes in myocardial blood flow. It should also be noted from basic science studies that, in addition to the wellrecognized antianginal and anti-ischemic effects of neuromodulation therapy, this therapy improves myocyte viability and has the potential for stabilizing the intrinsic cardiac nervous system (Foreman et al., 2000; Armour et al., 2002) and subsequently the electrical activity of the diseased heart (Cardinal et al., 2004, 2006; Issa et al., 2005) (see Chapter 64 by Ardell and Foreman for review).

HISTORICAL PERSPECTIVE OF NEUROSTIMULATION Electrical Neuromodulation The earliest recorded human use of electrical neuromodulation appears to be that of the Mesopotamian healer Scribonius Largus (CE 46), who was court physician to the Roman emperor Claudius. He drew up a list of 271 “Compositiones” (1983), among which he prescribed electrotherapy for pain relief, literally from head to toe. The available source of electricity at that time was the natural electricity produced by Torpedo marmorata (the torpedo ray), Malopterurus electricus (the electric catfish), and Electrophorus electricus (the electric eel). Later, in South America, the remedial properties of these fish were described in a letter written in 1754 by Storm van Gravesande, Governor of Surinam, to the Dutch physicist Allamand (1756): It has been observed, that various people who to some degree had gouty pains, and who touched the torpedo [fish] had been completely cured, two or three minutes after contact. The experiment has been repeated at various times but always with the same result.

From that time forward, the accessibility of therapeutic electricity evolved from fish to devices, from

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modified pacemakers to transcutaneous electrical nerve stimulation devices (TENS) and implantable spinal cord stimulation (SCS) devices. In 1967 Braunwald reported that electrical modulation of the nervous system reduced angina (Braunwald et al., 1967). Later, in his personal reflections on the following period, Braunwald wrote: It took just 10 weeks from the development of the idea to its clinical execution and we were gratified that severe angina could be readily relieved … we were preparing to conduct a large Phase III trial on this approach, when Favolaro and Effler described a new operation – coronary artery bypass grafting – which was very successful in restoring the balance between myocardial O2 supply and demand by directly increasing supply. This operation immediately made our more indirect approach obsolete. (Braunwald, 2002)

suffering from therapeutically refractory angina pectoris per cardiologist, the prevalence of this condition can be calculated to be 1:10 000 (DeJongste, 1994). Based on the number of coronary angiograms performed, about 5% of these patients have significant coronary artery disease without adequate therapeutic options. Therefore, the incidence can be calculated to be 1:20 000. This translates to an estimated equal number of patients in Europe and the USA of 100 000– 200 000 persons with therapeutically refractory angina (Mukherjee et al., 1999).

IMPLANT PROCEDURE

In 1982, Mannheimer was the first to report on the beneficial effect of TENS in severe angina (Mannheimer et al., 1982). Five years later Murphy and Giles published the first report on the antianginal effect of SCS (Murphy and Giles, 1987).

PATIENT SELECTION, INCIDENCE, AND PREVALENCE Patients are candidates for electrical neuromodulation when they suffer from disabling chest pain resulting from coronary artery disease, have reversible myocardial ischemia, are unresponsive to pharmacotherapy, and are not candidates for revascularization (Figure 69.5). Given the estimate of 3–5 of patients

The standard procedure for SCS for angina is performed under local anesthesia. Local anesthesia is essential to the success of this operation because the surgeon places the electrodes of the SCS system into the epidural space and moves and activates the electrodes until the awake patient perceives stimulation paresthesiae concordant to the area of their perceived pain. Concordant paresthesia is thought by the SCS community to be essential for therapeutic success when stimulation is used for neuropathic pain syndromes such as failed back surgery syndrome (FBSS), complex regional pain syndrome (CRPS), neuropathies, etc. However, the necessity of eliciting paresthesiae for the beneficial effects of neuromodulation in patients with angina is debatable. In a recent article by Eddicks et al. (2007), the necessity of paresthesiae for a beneficial effect of SCS was questioned. The authors

Indications Quality of life severely limited by chronic stable angina pectoris?

NO

Candidate for neurostimulation

YES

NO

YES Documented significant coronary artery disease?

NO

YES Myocardial ischemia verified?

NO

YES No benefit from or not a candidate for revascularization?

NO

Unsurmountable spine anatomy? NO Short life expectancy? NO Pacemaker dependent or implanted defibrillator? NO

YES Can patient understand and comply with treatment?

Contraindications?

NO

Exclude patient!

Insufficient improvement angina with pharmacological treatment?

NO

Acute coronary Syndrome  3 months?

FIGURE 69.5 Flow chart inclu-

YES

sion and exclusion criteria

IXA. NEUROMODULATION FOR CARDIOVASCULAR DISORDERS

PROGRAMMING AND OTHER POINTS FOR CONSIDERATION

undertook a randomized study, making use of four different consecutive treatment arms (i.e. 2 h stimulation 3/day, continuous stimulation, subthreshold stimulation, and stimulation with 0.1 V output) in 12 responders to SCS for refractory angina pectoris. Each phase lasted for four weeks. Subthreshold stimulation and adequate paresthesiae had comparable outcomes, with respect to exercise and angina. However, during sham stimulation with 0.1 V, walking distance was significantly reduced, in conjunction with an increase in angina frequency. This made it necessary in 25% of the patients to prematurely terminate this phase and resume active SCS. The authors concluded that, given the outcomes, paresthesiae are not necessary and subthreshold stimulation can be used as “placebo SCS” in further larger randomized studies. For placement of a stimulating electrode for angina, a small incision is made under sterile conditions at the T4–T5 level of the patient who is in the prone position on a fluoroscopic table. Under fluoroscopic control, either a quadripolar (four electrode contacts) or octopolar (eight electrode contacts) lead is introduced through a Tuohy epidural needle into the dorsal epidural space, immediately dorsal to the dural sac. The distal electrode of the lead is moved to and positioned at the C7–T1 level, slightly left of midline. An external stimulator is used to provoke paresthesiae perceived by the awake patient. When the anginal region of perceived pain is covered by active stimulation paresthesiae, the electrode array (lead) is anchored and fixed in that position to the supra- or paraspinous fascia and tunneled either directly or by way of a lead extension wire to the pulse generator, which is placed in a subcostal, retrofascial, surgically created pocket.

PROGRAMMING AND OTHER POINTS FOR CONSIDERATION To ensure the long-term benefit of neuromodulation, this author (M.D.J.) uses an interdisciplinary team approach. Initially the cardiologist relates the history of the patient and the indications for neuromodulation to a team consisting of the patient’s physician, cardiologists, cardiac interventionalists, and cardiothoracic surgeons who make the decision whether or not there are options for revascularization. If there are no options to revascularize, planning for electrical neuromodulation (TENS, SCS) procedure is the responsibility of our “refractory angina” team. This team consists of the implanting physician (usually an anesthesiologist or a neurosurgeon), a neurologist, a nurse practitioner, a physiotherapist,

837

and a psychologist. The psychologist is consulted in situations when doubts are raised concerning the psychological competence of the patient. In this situation, personality domains, such as social inadequacy of the patient, will be assessed (De Vries et al., 2006). The team uses a treatment algorithm that includes a rehabilitation program since we believe that this rehabilitation program is essential for the success of neuromodulation therapies in chronic pain patients (Moore et al., 2005). Often times, before implantation, transcutaneous electrical neurostimulation (TENS) is applied to the patient so that he/she feels and becomes comfortable with the sensation of paresthesiae. It should be noted by the reader that we do not use this TENS as a screening method for SCS, but only to accustom the patient to the sensation of paresthesiae. At the same time that we initiate paresthesiae with TENS, the patient is informed about the SCS implantation procedure and risks of the procedure, the handling of the programmer, and is instructed regarding clinical follow-up. The day before the implantation, a medical evaluation is performed. We use bipolar stimulation. In continuous interaction with the patient the current is tailored by a neuromodulation technician or one of the staff to provide concordant paresthesia that is most comfortable for the patient. The day after implantation of the SCS system, the programmed settings of the system are adjusted by our staff to optimize battery longevity while providing concordant stimulation paresthesia. In order to optimize longevity of the battery, in conjunction with providing optimal results, the upper and lower limits of the device are set at the lowest comfortable limits for the patient. This is most often at the mean of the sensory threshold (the moment at which the patient began to feel paresthesiae) and the motor threshold (i.e. the moment where paresthesiae become unpleasant) (DeJongste, Nagelkerke et al., 1994). At the same time, we provide to the patient information on quality of life, movement restrictions, positional dependency of the stimulation, duration of the stimulation, and safety aspects with regard to magnetic fields and magnetic resonance imaging (MRI). According to our expert opinion, we advise the patient to stimulate 3 1 hour per day and additionally when an angina attack is felt. Others stimulate 4 2 hours per day or even continuously. To date, it is not clear which is the best stimulation regime, however for control of angina 3 1 hour is usually sufficient to control the angina burden of the patient. This antianginal effect is termed post-stimulation analgesia or carry-over effect (Murray et al., 2004). Table 69.2 summarizes average settings.

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69. SPINAL CORD STIMULATION FOR REFRACTORY ANGINA

TABLE 69.2 Average settings in patients with refractory angina treated with unipolar SCS Stimulation settings

Average (range)

Pulse width

210 (180–250) μs

Frequency

60 ( 30–110) Hz

Output amplitude

4.6 (2.2–10.5) V (comfortable paresthesiae)

Stimulation protocol

3 1 h; 4 2h; continuously at own discretion

Unipolar/bipolar

10% / 90%

OUTCOMES REVIEW OF MOST RECENT LITERATURE Both open observational (see reviews DeJongste et al., 2000, 2004; Kim et al., 2002; Mannheimer et al., 2002; Gowda et al., 2005; Stanik-Hutt, 2005) and randomized (Mannheimer et al., 1998; McNab et al., 2006; Eddicks et al., 2007) studies have repeatedly demonstrated that the reduction in frequency and duration of angina during SCS safely and effectively improves patients’ complaints and subsequent quality of life (Vulink et al., 1999; Di Pede et al., 2003; Cameron, 2004; De Vries, DeJongste et al., 2007). A recent published meta-analysis of executed randomzed control studies on SCS for angina confirms the efficacy of this adjunct therapy (Börjesson et al., 2008). Even though the analgesic effect of SCS in patients with chronic stable therapy-refractory angina pectoris caused by coronary artery disease has been established and accepted by the American Heart Association (Class II, level of evidence B) (Gibbons et al., 2003), the antiischemic effects of SCS are still under debate. This debate continues, in spite of the fact that many studies on electrical neuromodulation for refractory angina pectoris, with various study designs, methods, and different endpoints have been performed and published with favorable outcomes (Börjesson et al., 2008). Study methods to demonstrate anti-ischemic effects of electrical neuromodulation have included induced stress to the heart by means of right atrial pacing (Mannheimer et al., 1993; Norsell et al., 1997), exercise (DeJongste, Hautvast et al., 1994; Sanderson et al., 1994; Hautvast, DeJongste et al., 1998; Mannheimer et al., 1998; Eddicks et al., 2007), ambulatory ECG recording (DeJongste, Haaksma et al., 1994; Hautvast, Brouwer et al., 1998; Di Pede et al., 2001), perfusion techniques (nuclides or positron emission tomography) (Hautvast et al., 1996; Diedrichs et al., 2005), and flow measurement (Chauhan, 1994; Jessurun et al., 1998; De Vries, Anthonio et al., 2007).

The rise in the angina threshold by neuromodulation, causing the delayed onset of angina, is thought to be related to redistribution of coronary blood flow from normally perfused (non-ischemic) to impaired perfused (ischemic) myocardial regions, causing a homogenization of myocardial perfusion (the Robin Hood phenomenon of stealing from the rich and giving to the poor) (Hautvast et al.,1996). By homogenization of myocardial perfusion, the moment of critical balance between myocardial oxygen supply and demand is deferred, by either improving supply, or through a reduction in demand. In addition to this favorable shift in oxygen balance, electrical neuromodulation is also thought to make the heart more restistent to myocardial ischemia by improving ischemic tolerance. Ischemic tolerance is the result of both preconditioning and collateral recruitment within the heart. The increased angina threshold was first emphasized by a study in which patients with refractory angina and SCS were stressed by right atrial pacing until the ischemic threshold was reached and the heart produced endorphins (Mannheimer et al., 1993). During SCS, the angina threshold was higher, perhaps secondary to its anti-ischemic effect, albeit all patients ultimately did report angina. In a letter to the editor of the British Medical Journal it was claimed that the results of this study could be alternatively explained by so-called ischemic preconditioning (Marber et al., 1993). Ischemic preconditioning is the metabolic adaptation of the heart to ischemic stress that follows a brief episode of non-lethal myocardial ischemia. In effect, there is an increased resistance to myocardial infarction. In addition to ischemic preconditioning, the heart is also protected during reperfusion by ischemic postconditioning, which protects the heart after the manifestation of the ischemic event through signal transduction pathways. There is evidence that both phenomena, preconditioning and postconditioning, recruit a similar signaling pathway at time of myocardial reperfusion that produces protein kinase cascades. (Hausenloy and Yellon, 2007). With respect to “conditioning” of the heart by SCS, it is important to note that during SCS the heart appears to produce endorphins (Eliasson et al., 1998) and that SCS is suggested to affect the alpha-adrenergic receptor (Norsell et al., 1997; Southerland et al., 2007). Since adenosine has vasodilatory effects and is involved in pain transmission, adenosine may couple the involved neural and cardiac interactions (Seiler et al., 1998). Moreover, dipyridamole, an adenosine re-uptake inhibitor, blunts the effect of SCS (Hautvast et al., 1996). Finally, the intake of caffeine, which influences the adenosine handling via xanthine metabolism, has been observed to impair the effects of neuromodulation (Marchand et al., 1995). All

IXA. NEUROMODULATION FOR CARDIOVASCULAR DISORDERS

COMPLICATIONS AND AVOIDANCE

Putative Mode of Action of SCS in Ischemic Preconditioning

Receptors

G-protein Coupled Receptors

Ischemic Preconditioning

δ1,(μ?) opioid A1-adenosine

PKC

the patient level should be performed in other patient groups, such as those with unstable angina (De Vries, DeJongste et al., 2007), single vessel coronary artery disease (Jessurun et al., 1998), and cardiac syndrome X (Sgueglia et al., 2007), since the results can provide information on both the working mechanism of neurostimulation and the relation between ischemia and pain (i.e. angina).

KATP channel

COMPLICATIONS AND AVOIDANCE

α-adrenergic

FIGURE 69.6

839

Putative mode of action of SCS in ischemic

preconditioning

these three factors (i.e. endorphins, alpha-adrenergic receptor, and adenosine) are involved in the upregulation of G protein-coupled receptors that, in turn, upregulate protein kinase C, which is thought to phosphorylate the ATP-sensitive K-channel that plays a key role in preconditioning (Figure 69.6). It should also be noted that studies performed by our group recently demonstrated an improved collateral perfusion, as an alternative pathway of blood supply towards the ischemic myocardial area, following electrical neuromodulation (De Vries, Anthonio et al., 2007). Whether this improvement in collateral perfusion is the result of altered vasomotor properties of coronary collateral vessels through, for instance, an increase in total body norepinephrine (Norsell et al., 1997) or by (antidromic) activation of the sympathetic nervous system (Tanaka et al., 2004) or altered adenosine handling (Seiler et al., 1998) remains to be elucidated. In experimental studies it has been demonstrated that, at the spinal level during myocardial ischemia, electrical stimulation is modulating the release of numerous molecules, such as substance P, GABA, neurokinin-1, and also affects the expression of receptors like the vanilloid receptor type 1 (Ding et al., 2007; see also Chapter 64). Based on the above observations we hypothesize that neuromodulation employs its cardioprotective effect by decreasing myocardial ischemia, through improving local oxygen supply. However, as an alternative explanation for the beneficial effect of electrical neuromodulation on myocardial ischemia a reduction in oxygen demand may also be possible (Mannheimer et al., 1993). In conclusion, electrical neuromodulation improves the ischemic threshold in patients with refractory angina pectoris by activation of mechanisms that induce both preconditioning and recruitment of collaterals. Additional studies of the effects of neurostimulation at

Though electrical neuromodulation is a reversible therapy, as in all implanted SCS devices, complications during and following the implantation may occur, such as loss of paresthesiae, lead dislodgment, infections, etc. (Eliasson et al., 1994; Jessurun et al., 1997). Furthermore, a drawback of both implantable neuromodulatory devices and TENS is that they may interfere electromagnetically with other devices. From this perspective, TENS or the implantation of an SCS in a patient whose life depends on a bradycardia pacemaker or on an implantable cardioverter defibrillator (ICD) is not considered to be safe, even if essential precautions have been taken (De Vries, Staal et al., 2007). Although the delivered energy and frequencies of SCS and cardiac heart rate devices are different, it is feasible that SCS artifacts may mask, for instance, ventricular arrhythmias, resulting in inappropriate inhibition of the ICD. It is also conceivable that the ICD may interpret SCS pulses as a ventricular arrhythmia and deliver a shock, as has been demonstrated for machines that operate at 50 Hz (Sabate et al., 2001). Vice versa, an ICD shock may induce a complete reset of the SCS system, as has been recently reported (Tavernier et al., 2000). A literature search reveals many reports that deal with electromagnetic interference of external (for example: transcutaneous electrical nervous stimulation) or internal source stimulation (like SCS) and an ICD. On the other hand, several articles advocate the safety of combined stimulation devices when the necessary precautions have been taken (Iyer et al., 1998). These safety measures include: to use multiprogrammable devices with the best electro-magnetic interference (EMI) filters, bipolar systems, and extensive testing procedures focusing on inter-device interference (Ekre et al., 2003). However, medicolegal decisions need to be made when a patient’s quality of life already has been substantially improved by an implanted neurostimulator and another device, meant to save the life of a person, is indicated. In this respect it is important not to allow the patient to alter the SCS settings,

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69. SPINAL CORD STIMULATION FOR REFRACTORY ANGINA

even within limits set by an estimation of safety margins. Finally, the use of magnetic resonance imaging (MRI) may be contraindicated in patients with implanted stimulators such as pacemakers, ICDs, SCS, deep brain stimulators, and pumps. Since 1997, the American Society for Testing and Materials (ASTM International) has been developing standard test methods for determining the safety of MRI for implantable active medical devices. Risks of MRI use in patients with neurostimulators are, among others, permanent damage to the device through the very powerful radiofrequency fields of the MRI that induce currents that overheat the lead wires of the implanted device, neural damage to the patient by this overheating of the lead wires, projectile effects from the magnetic field, or twisting effects of the device. On the other hand, several observational reports have been published on the relative safety of MRI for pacemaker patients, albeit under highly controlled conditions. So, given the high need for MRI as a diagnostic tool, a physician, with the fully informed consent of a patient with an implanted device, may need to ignore these contraindications and weigh the risk and benefit factors of each instance (Stecco et al., 2007; Woods, 2007). Sometimes, removal of the device before performing a needed MRI is a compromise that must be made. In conclusion, there might be a future for combinations of implantable devices in humans, but only when all technical, medical-ethical, and medicolegal issues have been settled. To date, this is clearly not the situation, since interference may occur when circumstances change.

WHAT THE FUTURE HOLDS (THE NEXT 5 YEARS) Research on neuromodulation for angina so far has focused on patients with angina pectoris having either significant stenotic (usually “end stage”) coronary artery disease (CAD) or myocardial ischemia in the presence of normal coronary arteries (microvascular angina or cardiac syndrome X). To further investigate possible mechanisms of action, future research should also be aimed at patients with so-called “silent ischemia.” In these patients diagnostic techniques demonstrate myocardial ischemia, although these patients do not suffer from the perceived pain of angina. Figure 69.7 represents, on the left and in the middle, the two patients groups that are already being studied, and the patient group on the right that should be studied in future. Patients who suffer angina without epicardial coronary artery disease

Pain

Ischemia

Substrate

Electrical neurostimulation

Angina without macroscopic coronary artery disease

Macroscopic coronary artery disease without angina

Goal Analgesia

Anti-ischemia

FIGURE 69.7 Classification of patients with and without coronary artery disease and the underlying substrate for each group. The intended goal of electrical stimulation is also presented for each group

are positioned in the left circle. In these patients the main treatment goal is analgesia. Patients with silent ischemia are positioned in the right circle: they do not suffer angina but have ischemia caused by coronary artery disease. In these patients the main goal is treatment and prevention of ischemia. In the center of this spectrum are the patients with angina caused by significant coronary artery disease. An important next step with regard to the anti-ischemic effect would be to know whether the anti-ischemic effect can exist alone, without the analgesic effect. Finally, new stimulation techniques will become available. In this regard identifying specific pulse waves, defining optimal settings, and locating the most favorable application site for the stimulation (transcutaneous, subdermally intracostal, spinal cord, or even deep brain stimulation) needs to be studied.

CONCLUSIONS Patients with chronic refractory angina pectoris are a growing and underestimated problem. Though the problem of chronic refractory angina is identified, it is unlikely whether it can be considered as a separate (from chronic stable angina) cardiac condition. In this chapter we discussed pathophysiological backgrounds for the occurrence of (refractory) angina and myocardial ischemia. Moreover, we provided evidence for the underlying neural and cardiac mechanisms of action of electrical neuromodulation used as an adjunct therapy for severely disabled no-option patients suffering from chronic refractory angina pectoris. To ensure careful follow-up, patients with refractory angina should only be treated in centers with experience with refractory angina. Moreover, the medical professionals in these centers must be willing to practice their skills and collaborate as a team. This

IXA. NEUROMODULATION FOR CARDIOVASCULAR DISORDERS

CONCLUSIONS

means that sufficient knowledge on indications, selection criteria, implant procedures, complications, and follow-up is present in the team. Notwithstanding a skilled team, to improve the efficacy outcomes even further, cardiological, neurological, and psychological selection criteria for neuromodulatory therapies have to be painstakingly defined. The class II indication of SCS for refractory angina pectoris is mainly based on level B evidence (randomized controlled studies (RCTs) of moderate quality) to indicate that SCS has comparable efficacy and safety and potentially reduced costs to other interventional procedures for the management of refractory angina. Further well-conducted large multicenter RCTs on SCS are needed to confirm efficacy and to demonstrate acceptable cost effectiveness and safety. Since patients with refractory angina may be considered as survivors of their disease they subsequently do not experience severe arrhythmias and usually maintain their left ventricular function. So, clinical studies on the effect of electrical neuromodulation on arrhythmias and heart failures are lacking.

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Di Pede, F., Zuin, G., Giada, F., Pinato, G., Turiano, G., Bevilacqua, M. et al. (2001) Long-term effects of spinal cord stimulation on myocardial ischemia and heart rate variability: results of a 48-hour ambulatory electrocardiographic monitoring. Ital. Heart J. 2: 690–5. Eddicks, S., Maier-Hauff, K., Schenk, M., Müller, A., Baumann, G. and Theres, H. (2007) Thoracic spinal cord stimulation improves functional status and relieves symptoms in patients with refractory angina pectoris: the first placebo-controlled randomised study. Heart 93 (5): 585–90. Edlund, A., Fredholm, B.B., Patrignani, P., Patrono, C., Wennmalm, A. and Wennmalm, M. (1983) Release of two vasodilators, adenosine and prostacycline, from isolated rabbit hearts during controlled hypoxia. J. Physiol. 340: 487–501. Ekre, O., Börjesson, M., Edvardsson, N., Eliasson, T. and Mannheimer, C. (2003) Feasibility of spinal cord stimulation in angina pectoris in patients with chronic pacemaker treatment for cardiac arrhythmias. Pacing Clin. Electrophysiol. 26: 2134–41. Eliasson, T., Jern, S., Augustinsson, L.E. and Mannheimer, C. (1994) Safety aspects of spinal cord stimulation in severe angina pectoris. Coron. Artery Dis. 5: 845–50. Eliasson, T., Mannheimer, C., Waagstein, F., Andersson, B., Bergh, C.H., Augustinsson, L.E. et al. (1998) Myocardial turnover of endogenous opioids and calcitonin-gene-related peptide in the human heart and the effects of spinal cord stimulation on pacinginduced angina pectoris. Cardiology 89 (3): 170–7. Foreman, R.D. (1999) Mechanisms of cardiac pain. Annu. Rev. Physiol. 61: 143–67. Foreman, R.D., DeJongste, M.J. and Linderoth, B. (2004) Integrative control of cardiac function by cervical and thoracic spinal neurons. In: J.A. Armour and J.L. Ardell (eds), Basic and Clinical Neurocardiology. New York: Oxford University Press, pp. 153–86. Foreman, R.D., Linderoth, B., Ardell, J.L., Barron, K.W., Chandler, M.J. and Hull, S.S. (2000) Modulation of intrinsic cardiac neurons by spinal cord stimulation: implications for therapeutic use in angina pectoris. Cardiovasc. Res. 47: 367–75. Gibbons, R.J., Abrams, J., Chatterjee, K., Daley, J., Deedwania, P.C., Douglas, J.S. et al. (2003) A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Chronic Stable Angina). ACC/AHA 2002 Guideline Update for the Management of Patients with Chronic Stable Angina – Summary Article. Circulation 107 (1): 149–58. Gowda, R.M., Khan, I.A., Punukollu, G., Vasavada, B.C. and Nair, C.K. (2005) Treatment of refractory angina pectoris. Int. J. Cardiol. 101: 1–7. Hausenloy, D.J. and Yellon, D.M. (2007) The evolving story of “conditioning” to protect against acute myocardial ischaemiareperfusion injury. Heart 93 (6): 649–51. Hautvast, R.W., Blanksma, P.K., DeJongste, M.J., Pruim, J., van der Wall, E.E., Vaalburg, W. et al. (1996) Effect of spinal cord stimulation on myocardial blood flow assessed by positron emission tomography in patients with refractory angina pectoris. Am. J. Cardiol. 77: 462–7. Hautvast, R.W., Brouwer, J., DeJongste, M.J. and Lie, K.I. (1998) Effect of spinal cord stimulation on heart rate variability and myocardial ischemia in patients with chronic intractable angina pectoris – a prospective ambulatory electrocardiographic study. Clin. Cardiol. 21: 33–8. Hautvast, R.W., DeJongste, M.J., Staal, M.J., van Gilst, W.H. and Lie, K.I. (1998) Spinal cord stimulation in chronic intractable angina pectoris: a randomized, controlled efficacy study. Am. Heart J. 136 (6): 1114–20. Hautvast, R.W., TerHorst, G.J., DeJong, B., DeJongste, M.J., Blanksma, P.K., Paans, A.M. et al. (1997) Relative changes in

regional blood flow during spinal cord stimulation in patients with refractory angina pectoris. Eur. J. Neurosci. 9: 1178–83. Heberden, W. (1772) Some account of a disorder of the breast. Med. Trans. 2: 59–67. Hurst, T., Olson, T.H., Olson, L.E. and Appleton, C.P. (2006) Cardiac syndrome X and endothelial dysfunction: new concepts in prognosis and treatment. Am. J. Med. 119 (7): 560–6 (Review). Issa, Z.F., Zhou, X., Ujhelyi, M.R., Rosenberger, J., Bhakta, D., Groh, W.J. et al. (2005) Thoracic spinal cord stimulation reduces the risk of ischemic ventricular arrhythmias in a post-infarction heart failure canine model. Circulation 111: 3217–20. Iyer, R., Gnanadurai, T.V. and Forsey, P. (1998) Management of cardiac pacemaker in a patient with spinal cord stimulator implant. Pain 74 (2-3): 333–5. Jessurun, G.A., ten Vaarwerk, I.A., DeJongste, M.J., Tio, R.A. and Staal, M.J. (1997) Sequelae of spinal cord stimulation for refractory angina pectoris. Reliability and safety profile of long-term clinical application. Coron. Artery Dis. 8: 33–8. Jessurun, G.A., Tio, R.A., De Jongste, M.J., Hautvast, R.W., Den Heijer, P. and Crijns, H.J. (1998) Coronary blood flow dynamics during transcutaneous electrical nerve stimulation for stable angina pectoris associated with severe narrowing of one major coronary artery. Am. J. Cardiol. 82: 921–6. Keefer, S. and Resnik, W. (1928) Angina pectoris: a syndrome caused by anoxemia of the myocardium. Arch. Intern. Med. 41: 769–807. Kim, M.C., Kini, A. and Sharma, S.K. (2002) Refractory angina pectoris: mechanism and therapeutic options. J. Am. Coll. Cardiol. 39: 923–34. Lagerqvist, B., Sylvén, C., Beerman, B., Helmius, G. and Waldenström, A. (1990) Intracoronary adenosine causes angina pectoris like pain – an inquiry into the nature of visceral pain. Cardiovasc. Res. 24: 609–13. Lewis, T. (1932) Pain in muscular ischemia – its relation to anginal pain. Arch. Intern. Med. 79: 713–27. Mannheimer, C., Camici, P., Chester, M.R., Collins, A., DeJongste, M., Eliasson, T. et al. (2002) The problem of chronic refractory angina; report from the ESC Joint Study Group on the Treatment of Refractory Angina. Eur. Heart J. 23: 355–70. Mannheimer, C., Carlsson, C.A., Ericson, K., Vedin, A. and Wilhelmsson, C. (1982) Transcutaneous electrical nerve stimulation in severe angina pectoris. Eur. Heart J. 3: 297–302. Mannheimer, C., Eliasson, T. and Andersson, B. (1993) Effects of spinal cord stimulation in angina pectoris induced by pacing and possible mechanisms of action. Br. Med. J. 307: 477–80. Mannheimer, C., Eliasson, T., Augustinsson, L.E., Blomstrand, C., Emanuelsson, H., Larsson, S. et al. (1998) Electrical stimulation versus coronary artery bypass surgery in severe angina pectoris: the ESBY study. Circulation 97 (12): 1157–63. Marber, M., Walker, D. and Yellon, D. (1993) Spinal cord stimulation or ischaemic preconditioning? Br. Med. J. 307 (6906): 737. Marchand, S., Li, J. and Charest, J. (1995) Effects of caffeine on analgesia from transcutaneous electrical stimulation. N. Engl. J. Med. 333: 325–6. Maseri, A. (1995) Syndrome X and microvascular angina, ch. 18. In: A. Maseri (ed.), Ischemic Heart Disease. New York: Churchill Livingstone. McNab, D., Khan, S.N., Sharples, L.D., Ryan, J.Y., Freeman, C., Caine, N. et al. (2006) An open label, single-centre, randomized trial of spinal cord stimulation vs. percutaneous myocardial laser revascularization in patients with refractory angina pectoris: the SPiRiT trial. Eur. Heart J. 27 (9): 1048–53. Melzack, R. and Wall, P.D. (1965) Pain mechanisms: a new theory. Science 150: 971–9. Moore, R.K., Groves, D., Bateson, D., Barlow, P., Hammond, C., Leach, A.A. and Chester, M.R. (2005) Health related quality of life

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of patients with refractory angina before and one year after enrolment onto a refractory angina program. Eur. J. Pain 9 (3): 305–10. Mukherjee, D., Bhatt, D.L., Roe, M.T., Patel, V. and Ellis, S.G. (1999) Direct myocardial revascularizat ion and angiogenesis–how many patients might be eligible? Am. J. Cardiol. 84: 598–600, A8. Mulcahy, D., Knight, C., Stables, R. and Fox, K. (1994) Lasers, burns, cuts, tingles and pumps: a consideration of alternative treatments for intractable angina. Br. Heart J. 71 (5): 406–7. Murray, S., Collins, P.D. and James, M.A. (2004) An investigation into the “carry over” effect of neurostimulation in the treatment of angina pectoris. Int. J. Clin. Pract. 58: 650–2. Murphy, D.F. and Giles, K.E. (1987) Dorsal column stimulation for pain relief from intractable angina pectoris. Pain 28: 365–8. Norsell, H., Eliasson, T., Mannheimer, C., Augustinsson, L.E., Bergh, C.H., Andersson, B., Waagstein, F. and Friberg, P. (1997) Effects of pacing-induced myocardial stress and spinal cord stimulation on whole body and cardiac norepinephrine spillover. Eur. Heart J. 18: 1890–6. Pasceri, V., Lanza, G.A., Buffon, A., Montenero, A.S., Crea, F. and Maseri, A. (1998) Role of abnormal pain sensitivity and behavioral factors in determining chest pain in syndrome. X. J. Am. Coll. Cardiol. 31: 62–6. Sabate, X., Moure, C., Nicolas, J., Sedo, M. and Navarro, X. (2001) Washing machine associated 50 HZ detected as ventricular fibrillation by an implanted cardioverter defibrillator. Pacing Clin. Electrophysiol. 24: 1281–3. Sadigh-Lindell, B., Sylvén, C., Berglund, M. and Eriksson, B.E. (2003) Role of adenosine and opioid-receptor mechanisms for pain in patients with silent myocardial ischemia or angina pectoris: A double blind, placebo-controlled study. J. Cardiovasc. Pharmacol. 42: 757–63. Sanderson, J.E., Ibrahim, B., Waterhouse, D. and Palmer, R.B. (1994) Spinal electrical stimulation for intractable angina – long-term clinical outcome and safety. Eur. Heart J. 15: 810–14. Schoebel, F.C., Frazier, O.H., Jessurun, G.A., De Jongste, M.J., Kadipasaoglu, K.A., Jax, T.W. et al. (1997) Refractory angina pectoris in end-stage coronary artery disease: evolving therapeutic concepts. Am. Heart J. 134: 587–602. Scribonius, Largus (1983) Compositiones. BSB B.G. Teubner Verlagsgesellschaft. Seiler, C., Fleisch, M., Garachemani, A. and Meier, B. (1998) Coronary collateral quantitation in patients with coronary artery disease using intravascular flow velocity or pressure measurements. J. Am. Coll. Cardiol. 32: 1272–9.

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Sgueglia, G.A., Sestito, A., Spinelli, A., Cioni, B., Infusino, F., Papacci, F. et al. (2007) Long-term follow-up of patients with cardiac syndrome X treated by spinal cord stimulation. Heart 93 (5): 591–7. Southerland, E.M., Milhorn, D.M., Foreman, R.D., Linderoth, B., DeJongste, M.J., Armour, J.A. et al. (2007) Preemptive, but not reactive, spinal cord stimulation mitigates transient ischemiainduced myocardial infarction via cardiac adrenergic neurons. Am. J. Physiol. Heart Circ. Physiol. 292 (1): H311–H317. Stanik-Hutt, J.A. (2005) Management options for angina refractory to maximal medical and surgical interventions. AACN Clin. Issues 16: 320–32. Stecco, A., Saponaro, A. and Carriero, A. (2007) Patient safety issues in magnetic resonance imaging. Radiol. Med. 112: 491–508. Svorkdal, N. (2004) Treatment of inoperable coronary disease and refractory angina: spinal stimulators, epidurals, gene therapy, transmyocardial laser, and counterpulsation. Semin. Cardiothorac. Vasc. Anesth. 8: 43–58. Sylvén, C. (1989) Angina pectoris: clinical characteristics, neurophysiological and molecular mechanisms. Pain 36: 145–67. Tanaka, S., Komori, N., Barron, K.W., Chandler, M.J., Linderoth, B. and Foreman, R.D. (2004) Mechanisms of sustained cutaneous vasodilatation induced by spinal cord stimulation. Auton. Neurosci. 114: 55–60. Tavernier, R., Fonteyne, W., Vandewalle, V., de Sutter, J. and Gevaert, S. (2000) Use of an implantable cardioverter defibrillator in a patient with two implanted neurostimulators for severe Parkinson’s disease. Pacing Clin. Electrophysiol. 23 (6): 1057–9. Vulink, N.C.C., Overgaauw, D.M., Jessurun, G.A.J., TenVaarwerk, I.A.M., Kropmans, T.J.B., Van der Schans, C.P. et al. (1999) The effects of spinal cord stimulation on quality of life in patients with therapeutically refractory angina pectoris. Neuromodulation 2 (1): 29–36. Woods, T.O. (2007) Standards for medical devices in MRI: present and future. J. Magn. Reson. Imaging 26: 1186–9. Xanthos, T., Ekmektzoglou, K.A. and Papadimitriou, L. (2008) Reviewing myocardial silent ischemia: specific patient subgroups. Int. J. Cardiol. 124: 139–48. Yang, E.H., Barsness, G.W., Gersh, B.J., Chandrasekaran, K. and Lerman, A. (2004) Current and future treatment strategies for refractory angina. Mayo Clin. Proc. 79: 1284–92. Yang, E.H. and Barsness, G.W. (2006) Evolving treatment strategies for chronic refractory angina. Expert Opin. Pharmacol. 7: 259–66.

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70 Neuromodulation and Hypertension Tara M. Mastracci and Roy K. Greenberg

O U T L I N E Introduction

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Physiology of Blood Pressure Control by the Nervous System Autonomous Nervous System: Anatomy and Normal Physiology The Baroreflex Pharmacologic Neuromodulation Historical Use of Non-Pharmacologic Neuromodulation Techniques to Control Blood Pressure

Carotid Sinus Experiments Involving Animal Models Carotid Sinus Experiments Involving Humans Role of the Aortic Arch Ongoing Trials Future Prospects

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treatment of hypertension is the standard of care when diet and lifestyle modification are insufficient; despite this, however, many factors may contribute to an under-treatment of the disorder, leading some researchers to report that almost 50% of patients treated remained hypertensive (Di Martino et al., 2008). Although patient noncompliance due to financial limitations or behavior may play a role in apparently “refractory” hypertension, even in compliant patients pharmacotherapy may fall short of the goal of reestablishing the normotensive state, and alternate methods of blood pressure control are sought. Furthermore, the side effects of many antihypertensive agents are significant, and detrimentally affect patient compliance, and thus overall blood pressure control.

Hypertension is a disease state where the systolic blood pressure is consistently above 140 mmHg and/ or the diastolic blood pressure is consistently above 90 mmHg, and it afflicts more than 72 million people in the USA (American Heart Association, 2008). It has been estimated that the morality rate per 100 000 population from hypertension or related causes is 15.6 for white males, 49.9 for black males, 14.3 for white females, and 40.6 for black females in 2004 (American Heart Association, 2008). This represents a 15.5% increase from 1994 to 2004, which translates into an increase in the actual number of deaths to 41.8% (American Heart Association, 2008). Pharmacologic

Neuromodulation

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PHYSIOLOGY OF BLOOD PRESSURE CONTROL BY THE NERVOUS SYSTEM Autonomous Nervous System: Anatomy and Normal Physiology Autonomic control of blood pressure is mediated by both parasympathetic and sympathetic efferent fibers (Figure 70.1). End organ effects for both systems may vary depending on the caliber and location of blood vessel and nerve fiber, and therefore it is best to define these fibers by the neurotransmitters present at their nerve termini. Sympathetic fibers are most commonly responsible for excitation and related changes in the vascular bed, and are most commonly adrenergic, or norepinephrine secreting. Sympathetic stimulation leads to peripheral vasoconstriction, tachycardia, and coronary vasodilation. The sympathetic pathway is characterized by short preganglionic fibers, resulting in ganglia that may be remote from their target blood vessel. Parasympathetic fibers, however, are most responsible for cardiac function. These nerve

Vasomotor center Pons Medulla

Vagus n.

SA node AV node

Blood vessels Sympathethic chain

FIGURE 70.1 The autonomic nervous system and its role in neuromodulation of the blood pressure. The vasomotor center of the brain stem uses both sympathetic and parasympathetic fibers to exert control over the heart and peripheral vessels

termini commonly secrete acetylcholine or nitric oxide, and have long nerve fibers that reside in close proximity to the target vessel. The autonomic nervous system acts as a buffer for arterial pressure fluctuations, such that peripheral changes in blood pressure are sensed by baroreceptors, transmitted centrally and then an appropriate response that restores the system to its natural set point is delivered to the heart and target vessels. Baroreceptors most commonly work on a negative feedback response (Bennaroch et al., 1999). The afferent fibers in this system are most commonly carried in the glossopharyngeal or vagal nerves. The solitary tract nucleus (STN) receives signals from baroreceptors in the periphery and regulates activity in the vasomotor center (O’Rourke et al., 2006). Central control of the cardiovascular function is situated in the vasomotor center, which resides bilaterally in the lateral aspects of the reticular formation in the bulbar area of the brain stem). The “buffer” effect of autonomic blood pressure control requires both parasympathetic and sympathetic activity. An increase in arterial pressure leads to increasing “firing” in the STN, which results in increased vagal efferent activity to create a slower heart rate. Simultaneously, inhibition of sympathetic activity occurs causing peripheral vasodilation. The effects are complementary and may vary in extent depending upon the circumstance. If a decrease in arterial pressure is sensed, parasympathetic inhibition and sympathetic stimulation occur resulting in tachycardia and vasoconstriction respectively (Bennaroch et al., 1999). Evidence of the neuromodulatory “buffer effect” of the baroreceptors is readily observed in patients during the induction of spinal anesthesia, where arterial blood pressure may fall precipitously in the setting of a total block. This obligates the administration of norepinephrine systemically to oppose the hypotensive effect resulting from the massive sympathetic block. The sympathetic control of blood pressure is mediated by changes in resistance and compliance to the peripheral vascular bed. Axons from the vasomotor center descend via the intermediolateral column as the bulbospinal tract to the preganglionic sympathetic cell bodies, which then carry the sympathetic outflow to the peripheral vessels (Figure 70.2) (O’Rourke et al., 2006). Preganglionic sympathetic axons exit the spinal canal through ventral roots following the white rami of the thoracic and first two lumbar nerves (Bennaroch et al., 1999). The sympathetic ganglia are located in the sympathetic chain, situated on either side of the vertebral column. The density of nerves within each vessel does vary, and nerves reside along

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PHYSIOLOGY OF BLOOD PRESSURE CONTROL BY THE NERVOUS SYSTEM

or within the adventitia of arteries and the media of veins (O’Rourke et al., 2006). Sympathetic stimulation causes constriction of small arteries and arterioles, and decreases the circulating venous volume. This serves to increase peripheral resistance as well as shunt volume to the heart (Bennaroch et al., 1999). There is also some direct sympathetic enervation to the heart, and stimulation which can lead to increased heart rate and stroke volume. Parasympathetic enervation of the cardiovascular system is primarily focused on cardiac function. The parasympathetic nerves follow the path of the cranial nerves, and three-quarters of all parasympathetic nerve fibers run through the vagus nerve (X) (Bennaroch et al., 1999). Preganglionic vagal fibers are located in the nucleus ambiguus, and directly innervate the SA node and the AV conduction system. Stimulation will lead to decreased heart rate and reduced contractility by decreasing excitability of SA and AV nodes on the heart. The neurotransmitter at the terminal end of parasympathetic nerves is acetylcholine, an intravenous injection of which may induce bradycardia (Monahan, 2007).

Glossopharyngeal n.

Hering’s n.

Carotid body Carotid sinus Vagus n.

Aortic baroreceptors

FIGURE 70.2 Representative diagram of parasympathetic and sympathetic enervation of the carotid and aortic distribution

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The Baroreflex Neuromodulation of blood pressure in humans is thought to be due to the “baroreflex,” which adjusts systemic pressure based upon feedback from the stretch receptors in the aortic arch and carotid sinus (Monahan, 2007). It has been established that the nucleus of the tractus solitarius (NTS) plays a central role in this reflex (Andresen and Kunze, 1994). The functions of the carotid sinus and aortic arch baroreceptors may be different, but the independent role of each group of baroreceptors has not been clearly delineated. Despite traditional thinking that the baroreflex is blunted with prolonged hypertension, sustained activation of the baroreceptor pathway has been demonstrated in both acute and chronic hypertension, although the mechanisms of action may be different (Lohmeier et al., 2000). The short-term reflex responds to increased signal generated from receptors in the vessel wall due to hypertension, and the efferent nerves carry inhibitors to the sympathetic outflow, which decrease vascular tone, heart rate, and inotropy, and increase parasympathetic outflow thus reducing cardiac chronotropy. The long-term effect of this reflex may work via inhibiting renal sympathetic nerve activity, resulting in reno-humoral modulation of the blood pressure (Lohmeier et al., 2004; Barrett et al., 2005). It has been suggested that suppression of renin activity may be one method by which chronic baroreceptor stimulation plays a role in chronic hypertension. Additionally, the role of atrial natriuretic peptide is also under investigation, given that there is incomplete cessation of antihypertensive activity with renal denervation. This implies that part of the neuromodulatory pathway remains under humoral control. Baroreceptors in the carotid and aortic arch may also respond to different stimuli, and some research suggests that carotid receptors respond to local pressure changes, whereas the aortic arch receptors are programmed to respond to downstream changes involving the entire peripheral vascular bed (Kember et al., 2004, 2006). Autonomic dysfunction is important because it has been implicated in sudden cardiac death. Baroreceptor sensitivity (BRS) describes the reflexive increase in vagal activity and decrease in sympathetic activity in response to a sudden blood pressure elevation (La Rovere et al., 1998). In fact, a low cardiovagal baroreceptor sensitivity has been associated with increased risk of sudden cardiac death after acute myocardial infarction (Schwartz et al., 1992), and shown to be an independent predictor of poor outcomes in a multicenter prospective trial (Figure 70.3) (La Rovere et al., 1998). The circadian rhythm noted in myocardial events may also be associated with sympathetic activity, as

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70. NEUROMODULATION AND HYPERTENSION

this also coincides with the sympathetic surge observed during the morning hours.

Proportion surviving

1.00 BRS >6.1

0.98

BRS 3.0–6.1

0.96 0.94 0.92

0

0.5

1.0

1.5

2.0

403 270 112

268 159 64

575 390 165

517 342 146

1.00 SDNN >105

0.98

SDNN 70–105

0.96 0.94 0.92

Log rank  23.20 (p <0.0001)

0.90 0

0.5

SDNN <70 1.0

1.5

2.0

407 274 119

247 182 73

Time (years)

Number at risk SDNN >105 586 SDNN 70–105 410 SDNN <70 174

569 389 150

512 345 145

1.00 BRS >3, SDNN >70

0.98 0.96 Proportion surviving

BRS >3, SDNN <70 0.94 BRS <3, SDNN >70

0.92 0.90 0.88 0.86

BRS <3, SDNN <70

0.84 Log rank  37.24 (p <0.0001)

0.82 0.80 0 Number at risk BRS >3,SDNN >70 BRS >3,SDNN <70 BRS <3,SDNN >70 BRS <3,SDNN <70

0.5

1.0

1.5

2.0

567 71 66 32

368 41 40 18

Time (years) 827 102 93 56

800 98 86 48

716 87 79 42

Deaths/total

Relative risk (95% CI)

p

LVEF (%) >50 35–50 <35

9/589 18/483 22/204

1 2.5 (1.13–5.62) 7.3 (3.34–15.8

0.023 <0.0001

SDNN (ms) >105 70–105 <70

11/586 16/410 17/174

1 2.1 (0.97–4.53) 5.3 (2.49–11.4)

0.057 <0.0001

BRS (ms per mm Hg) >6.1 3.0–6.1 <3.0

13/589 18/414 17/179

1 2.1 (1.00–4.19) 4.5 (2.17–9.24)

0.047 <0.0001

VPC per h <10 >10

30/976 14/194

1 2.4 (1.27–4.53)

0.006

FIGURE 70.3

PHARMACOLOGIC NEUROMODULATION

Time (years)

Number at risk BRS >6.1 589 BRS 3.0–6.1 414 BRS <3.0 179 Proportion surviving

BRS <3.0

Log rank  19.24 (p <0.0001)

0.90

Kaplan Meier survival curves for total cardiac mortality according to BRS, SDNN, and their combination. Note the statistically significant difference in mortality for patients with poor ventricular function and altered baroreflex sensitivity. Also shown, the univariate relative risk of cardiac mortality in the three groups in this study (Table). BRS  baroreflex sensitivity; SDNN  standard deviation of all normal beats (From La Rovere et al. (1998), p. 480. Reprinted from The Lancet, 1998; 351: 478–84. Copyright (1998) with permission from Elsevier)

The autonomic control of blood pressure has been manipulated using pharmacologic means for many years. Post-ganglionic receptors, specifically α-adrenergic, β-adrenergic, and dopamine receptors, have been targeted, and both agonists and antagonists play an important role in critical care through blood pressure control. Mechanisms of drugs will act directly on the receptors, or stimulate the release of the neurotransmitter to exert their neuromodulatory effects. α1- and α2-receptors are present in both the peripheral vessels and the heart, and exert their main effects on smooth muscle. When stimulated, these induce vasoconstriction to arteries in the heart and peripheral veins, and prolong cardiac contraction, with little cardiac chronotrophic effect. Phenylephrine is a drug with pure α-receptor activity. There are three types of β-receptors, and their primary cardiovascular effect is to increase the cardiac output when stimulated. The β1-receptor has this effect by increasing the heart rate in the sinoatrial and atrioventricular nodes (chronotropic) and increases atrial and ventricular cardiac muscle contractility. β1-receptors in the kidney may also increase secretion of renin. β2-receptors have similar, but lesser effect on cardiac output, as well as increasing the coronary perfusion by dilating coronary arteries. β3-receptors have a minimal role in cardiovascular physiology. Both epinephrine and norepinephrine can be administered for beta-adrenergic stimulation, however they also exert effects on the α-receptors. Pure β-receptor stimulation is seen with use of dobutamine and isoproterenol. There are five different subtypes of dopaminergic receptors, which have effects in tissues throughout the body. Dopamine receptors in the cardiovascular system primarily act to increase myocardial contractility and cardiac output, with minimal chronotropic effects. Dopamine receptors are also present in the kidney, and can increase diuresis and naturesis on stimulation. Exogenous dopamine can be given to provide dopamine receptor stimulation, and at higher concentrations will also stimulate α- and β-receptors. For antihypertensive control, β-receptor antagonists have been developed. Beta agonists will decrease blood pressure by decreasing the heart rate and cardiac output. The degree of reactivity with different β-receptors will vary the effect (Metra et al., 2001). Selective beta blockers will exert an effect on heart rate, with no

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PHARMACOLOGIC NEUROMODULATION

other pleotrophic effects. However, nonselective beta blockers, including labetalol, may have additional α1-receptor agonist effects, which lead to additional arteriolar vasodilation. The use of beta blockers has been supported by multiple randomized controlled trials, and a meta-analysis reveals a reduced longterm mortality and reinfarction rate in patients who have had previous myocardial infarction (Freemantle et al., 1999). Alpha-adrenergic agonists have also been used. α1-adrengeric blockers include doxazosin, terazosin, and prazosin. These agents cause hypotension by blocking α1-receptors, decreasing peripheral sympathetic tone, and inhibiting the baroreceptor reflex, which in turn may lead to lightheadedness and orthostatic hypotension. Use of alpha blockers may also cause a reflex tachycardia. α1a-selective agonists, such as tamsulosin, have been found to have fewer orthostatic hypotension side effects. In resistant hypertension, α2-agonists have also been administered. Clonidine is a centrally acting α2-agonist that can decrease blood pressure in the setting of intact autonomic function. The drug has the opposite effect in patients with autonomic dysfunction. Other α-receptor antagonists, such as phentolamine, have been used intravenously in the treatment of hypertensive emergencies. Dopaminergic blockade can also be exploited in the control of hypertension; fenoldopam is a peripheral dopamine-1 receptor antagonist.

Historical Use of Non-Pharmacologic Neuromodulation Techniques to Control Blood Pressure From the first discovery of vasomotor nerves in 1851, the scientific community has endeavored to find the neurologic mechanisms used to control blood pressure (Bernard, 1851). This required elegant experimentation on animal models and in the clinical realm. Carotid Sinus Experiments Involving Animal Models The field of neuromodulation and hypertension has evolved over the past century through a series of progressive canine experiments. Early experiments performed in 1927 by Hering established the role of the carotid sinus in blood pressure control by noting the hypotensive effect of carotid massage (Hering, 1927). Subsequently, “Hering’s nerve” was discovered and an anatomic link between the hypotensive reflex and the carotid sinus was determined. In 1950, Heymans established the adaptive response of baroreceptors to the application of vasoactive agents to the carotid arterial

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wall (Heymans and van den Heuvel-Heymans, 1950). This hypothesis was furthered with McCubbin’s work in 1956 with a renin-induced canine hypertensive model which demonstrated a decreased electrical activity in hypertensive subjects, suggesting that carotid sinus activity maintained normotension, rather than opposed it in hypertensive subjects (McCubbin et al., 1956). This stimulated interest in the carotid sinus, which was furthered by Warner in 1958, who was able to induce a decrease in blood pressure with electrical stimulation of the carotid sinus in normotensive dogs. This hypotension was maintained for 90 minutes (Warner, 1958). Schwartz and Griffith, in 1963, applied the same methods to a renal-induced hypertensive canine model, and found a reversal of hypertension when electrical stimuli were applied (Griffith and Schwartz, 1964). This finding was reproducible by other investigators, and is directly related to the development of carotid sinus stimulation therapy for refractory hypertension that is currently being investigated for commercial use (Bilgutay and Lillehei, 1965; Parsonnet et al., 1966). Subsequent investigators carried forward the hypothesis to determine the amplitude of voltage necessary for maximal stimulation (Schwartz et al., 1967); however, progress of this technology required refinement of power source, and the ability to create a device that would adapt to heart rate. Despite the compelling evidence of effect, and the transition of many investigators into the clinical realm, Lohmeier and coworkers have continued to interrogate the animal model with the aim of determining a more specific physiologic pathway by which this phenomenon of carotid-stimulated hypotension is successful, and whether sustained effect would be possible. Lohmeier’s ability to stimulate prolonged (7 day) hypotension in normotensive dogs (Lohmeier et al., 2004) was seen as significant because of the inability of many antihypertensive medical treatments to create a hypotensive state in a normotensive subject (Figure 70.4) (Mohaupt et al., 2007). He also demonstrated a decrease in serum norepinephrine levels, which returned to baseline with the blood pressure, when stimulation was stopped (Lohmeier, Dwyer et al., 2007), and had an effect even in the presence of renal denervation (Lohmeier, Hildebrandt et al., 2007). However, the same blood pressure reductions were not reproduced in canine models rendered hypertensive by angiotensin II infusions (Lohmeier et al., 2005). Combining this data with experiments of renal denervation in which a hypotensive state was also achieved despite discontinuation of all enervation to the kidneys points to a neurohumoral mechanism for chronic blood pressure control, possibly circulating norepinephrine. Further investigation in this field is needed.

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Effect of 7 days of baroreflex activation on heart rate and mean arterial pressures. Note the marked decrease in arterial pressure during the period of baroreflex activation, and then return to normal parameters when activation was discontinued (Reproduced by permission of Wolters Kluwer Health from Lohmeier et al., Hypertension, 2004, Fig. 1, p. 308. © Lippincott Williams & Wilkins; www.lww.com)

Carotid Sinus Experiments Involving Humans As canine models had provided encouraging results for the control of hypertension using carotid sinus stimulation, human experiments were developed. In 1942, Moller showed that carotid massage in hypertensive patients could decrease blood pressure, which substantiated the putative link between the carotid sinus and hypertensive control that had been established in canine experiments (Moller, 1942). In 1958, Carlsten et al. reproduced the canine findings in humans by applying electrical stimulation to five patients undergoing head and neck surgery and finding a rapid decrease in mean arterial pressure and heart rate, which returned to baseline when the stimulus was removed (Carlsten et al., 1958). In 1956 Bilgutay described the implantation of a portable baropacer in a 40-year-old male which decreased mean arterial pressure while implanted (Bilgutay and Lillehei, 1965). Parsonnet then demonstrated that bilateral stimulation provided the best response (Parsonnet et al., 1966). Schwartz followed these experiments with 11 additional patients into whom he implanted a bilateral carotid nerve stimulator, and demonstrated a sustained decrease in mean arterial pressure for a period ranging from 5 months to 2.5 years. There were eight patients with long-term follow-up, in whom the “sustained reductions in blood pressure ranged between 30 and 100 mmHg systolic and 24 and 80 mmHg diastolic (mean of 48/42 mmHg)” (Griffith and Schwartz, 1964).

Similar results were demonstrated by Tuckman et al. (1966).

Role of the Aortic Arch Although postulations as to the interaction between the carotid and aortic arch baroreflex have been investigated, the clinical application of aortic arch baroreceptors in the treatment of hypertension has been less well investigated in the literature. This is likely owing to the easily accessible nature of the carotid sinus, and the early and substantial success of experimental models of carotid sinus stimulation. Canine experiments have demonstrated that the area of the arch seeded with baroreceptors is primarily on the lesser curve, extending distally approximately 150 mm (Figure 70.5) (Armour, 1973). The higher density of receptors in this area in the canine model may also be true in humans. Some research suggests that the arch and carotid baroreceptors may have different roles in hypertension (Ito and Scher, 1979). Denervation of aortic baroreceptors in a canine model has produced hypertension, and suggests that loss of aortic baroreceptor sensitivity may be one cause of essential hypertension (Ito and Scher, 1979). In contrast, denervation of carotid baroreceptors in unanesthetized dogs did not have a sustained hypertensive response (Ito and Scher, 1978). The receptors in the two anatomically distinct areas seem to have a complex interaction

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FIGURE 70.5 Distribution and relative volume of cardiovascular receptors in the aortic arch. Black dots represent receptors (Reproduced from Armour (1973), Fig. 9, p. 182, with permission of the American Physiological Society)

that has been described using experiments where the aortic arch and carotid arteries are isolated in canine models (Figure 70.6) (Brunner et al., 1984). Most researchers agree that the threshold and saturation of the aortic arch reflex is higher than that of the carotid sinus (Figure 70.7) (Donald and Edis, 1971; Brunner et al., 1984), and may reflect a response to pressure along the entire aortic wall (Thoren, 1977; Kember et al., 2006), as opposed to the more localized control sensed and exerted by the carotid nerves. Certainly, decreases in compliance of the aortic wall attributable to natural senescence seem to lead to a decreased sensitivity to baroreception (Monahan, 2007). However, the mechanism of the “smart baroreception,” so termed because of the ability of aortic baroreceptors to sense remote changes in pressure distribution, has not been elucidated, although mathematical models have been proposed (Kember et al., 2006).

Ongoing Trials Development of a device-based treatment for hypertension has focused mostly on electrostimulators

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implanted adjacent to the carotid sinus, which dates back to trials in the 1960s. However, early experience was limited because the frequency and amount of electrical stimulation was variable between patients, and the technology did not exist to have variable output on devices. Patients were noted to experience bradycardia and orthostatic hypotension, as well as local nerve stimulation. However, carotid stimulation devices have been refined, and are both more compact and controllable using ex vivo equipment. Additionally, insulation of electrodes has prevented current spread from the device to other nervous structures, which may have caused discomfort in the implanted patient. Once a device was developed with an ex vivo control of radiofrequency, better results were recorded. The first of these more adjustable devices was implanted by Tuckman (Tuckman et al., 1966). The next important innovation was reported by Peters, who implanted a device that was able to synchronize the heart rate to stimulator frequency. This is based on the assumption that increased heart rate is a surrogate indicator of a need for greater baroreflex stimulation (Peters et al., 1989). Further experience demonstrated that the drop in blood pressure associated with implanted devices was voltage-dependent, and had synergistic effects when the patient was on maximum beta blockage. A device, now commercially available in Europe, has now been developed called the Rheos system (CVRx Inc., Maple Grove, MN). This device consists of bilateral carotid electrodes which are affixed to the adventitial layer of the carotid bifurcation surgically, and then connected to a battery-powered impulse generator which is tunneled to a pocket in the chest wall. The first attempt at implantation of this device for hypertensive treatment was the BRASS trial (BaroReflex Activating System Study). This was a proof of concept trial involving 11 patients in Sweden who were undergoing elective carotid surgery. In this trial a carotid stimulus device was applied to the carotid sinus to determine whether electrical stimulation using the Rheos device modulated blood pressure (Schmidli et al., 2007). Once proof of concept was established, multicenter trials were conducted in Europe and North America. In Europe, there were 17 patients studied with severe hypertension despite multi-drug therapy (5 drugs) (Tordoir et al., 2007). After 3 months of continuous carotid stimulation, a significant drop in the heart rate, as well as the systolic and diastolic blood pressures, was observed. This effect appeared to be sustained through the course of the limited follow-up (p  0.0001, p  0.003 and p  0.0001, respectively). Additionally, a significant decrease in the number of doses of antihypertensive required (p  0.0001) was noted. Adverse events in the first 4 months of

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Three-dimensional graft comparing arterial pressure with intra-carotid sinus and aortic pressure for one representative canine. This depicts the interaction between carotid and aortic reflexes (Reproduced by permission of Wolters Kluwer Health from Brunner et al., Circulation Research, 1984, Fig. 6, p. 746. © Lippincott Williams & Wilkins; www.lww.com)

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follow-up included 1 wound infection, 1 nerve injury, 2 patients who experienced intraoperative bradycardia, 5 patients who complained of postoperative pain, 2 anesthesia complications, and 16 “other complications” that are not described by the authors. Cessation of carotid stimulation at the 4 month point for assessment revealed no rebound hypertension, which is a finding reproduced by other authors. The report of the North American experience with the same device found similar outcomes, and also included a single report of infection in their cohort of 10 patients (Illig et al., 2006). Further evaluation of this device is intended in the setting of multicenter controlled trials, and longer-term follow-up of currently implanted patients. Certainly, technological advances in renewable power sources and compact stimulation modules will only improve this therapy.

FIGURE 70.7 Bar graph representing the variable response to denervation of carotid and aortic baroreceptors in the canine model. The first bar represents response with only cervical nerves cut, the second with right cervical and left thoracic vagal nerves cut, and the third with bilateral thoracic vagal branches cut (Reproduced by permission of Wolters Kluwer Health from Ito and Scher, Circulation Research, 1979, Fig. 4, p. 30. © Lippincott Williams & Wilkins; www.lww.com)

Future Prospects Most research in baroreceptor stimulation and devicebased therapy for hypertension has been focused on the carotid sinus. This reflex arc has been well studied

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REFERENCES

in animals, and there is accumulating human experience that has allowed for the development of implantable devices, with some success. However, the implications of understanding the mechanism of the baroreflex are quite broad, and will be broader if extended to all pathways contributing to NTS stimulation, including the aortic arch. Further investigation is needed to determine the role that arch receptors play in neuromodulatory control of hypertension.

References American Heart Association. High blood pressure statistics. http:// www.americanheart.org/ presenter.jhtml?identifier  4621 (accessed January 2008). Andresen, M.C. and Kunze, D.L. (1994) Nucleus tractus solitarius – gateway to neural circulatory control. Annu. Rev. Physiol. 56: 93–116. Armour, J.A. (1973) Physiological behavior of thoracic cardiovascular receptors. Am. J. Physiol. 225: 177–85. Barrett, C.J., Guild, S.J., Ramchandra, R. and Malpas, S.C. (2005) Baroreceptor denervation prevents sympathoinhibition during angiotensin II-induced hypertension. Hypertension 46: 168–72. Bennaroch, E., Freeman, R. and Kaufman, H. (1999) Autonomic nervous system. In: C.J. Goetz and E.J. Pappert (eds), Textbook of Clinical Neurology. Philadelphia: Saunders, p. 350. Bernard, C. (1851) Influence du grand sympathique sur la sensibilité et sur la calorification. C R Soc. Biol. (Paris), 3: 163–70. Bilgutay, A.M. and Lillehei, C.W. (1965) Treatment of hypertension with an implantable electronic device. JAMA 191: 649–53. Brunner, M.J., Greene, A.S., Kallman, C.H. and Shoukas, A.A. (1984) Interaction of canine carotid sinus and aortic arch baroreflexes in the control of total peripheral resistance. Circ. Res. 55: 740–50. Carlsten, A., Folkow, B., Grimby, G., Hamberger, C. and Thulesius, O. (1958) Cardiovascular effects of direct stimulation of the carotid sinus nerve in man. Acta Physiol. Scand. 44: 138–45. Di Martino, M., Veronesi, C., Degli, E.L., Scarpa, F., Buda, S., Didoni, G. et al. (2008) Adherence to antihypertensive drug treatment and blood pressure control: a real practice analysis in Italy. J. Hum. Hypertens. 22: 51–3. Donald, D.E. and Edis, A.J. (1971) Comparison of aortic and carotid baroreflexes in the dog. J. Physiol. 215: 521–38. Freemantle, N., Cleland, J., Young, P., Mason, J. and Harrison, J. (1999) Beta blockade after myocardial infarction: systematic review and meta regression analysis. BMJ 318: 1730–7. Griffith, L.S. and Schwartz, S.I. (1964) Reversal of renal hypertension by electrical stimulation of the carotid sinus nerve. Surgery 56: 232–9. Hering, H.E. (1927). Die Karotissinusreflexe auf Herz und Gefässe, vom normalphysiologischen, pathologisch-physiologischen und klinischen Standpunkt. Dresden, Germany. Heymans, C. and van den Heuvel-Heymans, G. (1950) Action of drugs on arterial wall of carotid sinus and blood pressure. Arch. Int. Pharmacodyn. Ther. 83: 520–7. Illig, K.A., Levy, M., Sanchez, L., Trachiotis, G.D., Shanley, C., Irwin, E. et al. (2006) An implantable carotid sinus stimulator for drug-resistant hypertension: surgical technique and short-term outcome from the multicenter phase II Rheos feasibility trial. J. Vasc. Surg. 44: 1213–18. Ito, C.S. and Scher, A.M. (1978) Regulation of arterial blood pressure by aortic baroreceptors in the unanesthetized dog. Circ. Res. 42: 230–6.

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Ito, C.S. and Scher, A.M. (1979) Hypertension following denervation of aortic baroreceptors in unanesthetized dogs. Circ. Res. 45: 26–34. Kember, G.C., Armour, J.A. and Zamir, M. (2006) Mechanism of smart baroreception in the aortic arch. Phys. Rev. E Stat. Nonlin. Soft Matter Phys. 74: 031914. Kember, G.C., Zamir, M. and Armour, J.A. (2004) “Smart” baroreception along the aortic arch, with reference to essential hypertension. Phys. Rev. E Stat. Nonlin. Soft Matter Phys. 70: 051914. La Rovere, M.T., Bigger, J.T., Jr., Marcus, F.I., Mortara, A. and Schwartz, P.J. (1998) Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators. Lancet 351: 478–84. Lohmeier, T.E., Dwyer, T.M., Hildebrandt, D.A., Irwin, E.D., Rossing, M.A., Serdar, D.J. and Kieval, R.S. (2005) Influence of prolonged baroreflex activation on arterial pressure in angiotensin hypertension. Hypertension 46: 1194–200. Lohmeier, T.E., Dwyer, T.M., Irwin, E.D., Rossing, M.A. and Kieval, R.S. (2007) Prolonged activation of the baroreflex abolishes obesity-induced hypertension. Hypertension 49: 1307–14. Lohmeier, T.E., Hildebrandt, D.A., Dwyer, T.M., Barrett, A.M., Irwin, E.D., Rossing, M.A. and Kieval, R.S. (2007) Renal denervation does not abolish sustained baroreflex-mediated reductions in arterial pressure. Hypertension 49: 373–9. Lohmeier, T.E., Irwin, E.D., Rossing, M.A., Serdar, D.J. and Kieval, R.S. (2004) Prolonged activation of the baroreflex produces sustained hypotension. Hypertension 43: 306–11. Lohmeier, T.E., Lohmeier, J.R., Haque, A. and Hildebrandt, D.A. (2000) Baroreflexes prevent neurally induced sodium retention in angiotensin hypertension. Am. J. Physiol. Regul. Integr. Comp. Physiol. 279: R1437–R1448. McCubbin, J.W., Green, J.H. and Page, I.H. (1956) Baroceptor function in chronic renal hypertension. Circ. Res. 4: 205–10. Metra, M., Nodari, S. and Dei, C.L. (2001) Beta-blockade in heart failure: selective versus nonselective agents. Am. J. Cardiovasc. Drugs, 1: 3–14. Mohaupt, M.G., Schmidli, J. and Luft, F.C. (2007) Management of uncontrollable hypertension with a carotid sinus stimulation device. Hypertension 50: 825–8. Moller, V.F. (1942) Der karotish Ruckversuch beim Normalen bei der Hypertonic und Anderen ver anderten Kreislaufeinstell ungen im Zusammerihang mit der reflektorischen Sezvststeverving. Arch. Kreislaufforsch, 10. Monahan, K.D. (2007) Effect of aging on baroreflex function in humans. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293: R3–R12. O’Rourke, S.T., Vanhoutte, P.M. and Miller, V.M. (2006) Vascular pharmacology. In: D.L. Creager (ed.), Vascular Medicine. Pittsburg: Saunders Elsevier, pp. 71–85. Parsonnet, V., Myers, G.H., Holcomb, W.G. and Zucker, I.R. (1966) Radio-frequency stimulation of the carotid baroreceptors in the treatment of hypertension. Surg. Forum, 17: 125–7. Peters, T.K., Koralewski, H.E. and Zerbst, E. (1989) Blood pressure and heart rate changes during physical activity upon heart rate feedback-controlled electrical carotid sinus nerve stimulation. Int. J. Cardiol. 22: 389–92. Schmidli, J., Savolainen, H., Eckstein, F., Irwin, E., Peters, T.K., Martin, R. et al. (2007) Acute device-based blood pressure reduction: electrical activation of the carotid baroreflex in patients undergoing elective carotid surgery. Vascular 15: 63–9. Schwartz, P.J., La Rovere, M.T. and Vanoli, E. (1992) Autonomic nervous system and sudden cardiac death. Experimental basis and clinical observations for post-myocardial infarction risk stratification. Circulation 85: 177–91.

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Schwartz, S.I., Griffith, L.S., Neistadt, A. and Hagfors, N. (1967) Chronic carotid sinus nerve stimulation in the treatment of essential hypertension. Am. J. Surg. 114: 5–15. Thoren, P.N. (1977) Characteristics of left ventricular receptors with nonmedullated vagal afferents in cats. Circ. Res. 40: 415–21. Tordoir, J.H., Scheffers, I., Schmidli, J., Savolainen, H., Liebeskind, U., Hansky, B. et al. (2007) An implantable carotid sinus baroreflex activating system: surgical technique and short-term outcome from a multi-center feasibility trial for the treatment of resistant hypertension. Eur. J. Vasc. Endovasc. Surg. 33: 414–21.

Tuckman, J., Reigh, T., Goodman, B., Friedman, E. and Jacobson, J. H.I. (1966) Effect of radio frequency carotid sinus nerve stimulators in patients with severe hypertension. Circulation (Suppl. III) 34: 231. Warner, H.R. (1958) The frequency-dependent nature of blood pressure regulation by the carotid sinus studied with an electric analog. Circ. Res. 6: 35–40.

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C H A P T E R

71 Neuromodulation of Cardiac Dysfunction Sandra Machado, Kwangdeok Lee, and Marc S. Penn

O U T L I N E Introduction

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Neuromodulation for Chronic Heart Failure

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Neurostimulation for Acute Heart Failure

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Sympathetic Neuromodulation for Arrhythmia Parasympathetic Neuromodulation for Arrhythmias

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following myocardial infarction is more than just the loss of contractile tissue (Heymans et al., 1999; Askari et al., 2003), but is also determined by the remodeling process in response to myocardial necrosis (Vasilyev et al., 2005). Currently available therapies to alter the remodeling process and the progression to CHF remain limited, and death rates from CHF continue to rise. Increased morbidity and mortality associated with CHF is derived from both the mechanical and electrical consequences of myocardial tissue loss and remodeling. The mechanical causes of morbidity and mortality of cardiac dysfunction are a result of loss of contractile tissue and pump dysfunction. The electrical consequences of cardiac dysfunction are a result of the development of abnormal electrical conduction leading to substrate for reentrant arrhythmias and ventricular tachycardia and sudden cardiac death. The mechanical abnormalities associated with CHF are currently being addressed with pharmacologic therapy, which in some can delay and improve the morbidity and mortality of CHF, electrical therapy

INTRODUCTION Over the past two decades the many efforts to maximize therapy for patients with acute myocardial infarction (AMI) has yielded significant benefits. Initially through the use of thrombolytic therapy for AMI, and more recently mechanical re-establishment of antegrade flow through primary percutaneous coronary intervention for AMI, the 30 day mortality rate for acute transmural cardiac ischemic events has decreased from almost 15% in clinical trials in the late 1980s (ISIS, 1987) to under 5% in recent primary percutaneous coronary intervention trials (Stone et al., 2002). Ischemia remains the leading cause of chronic heart failure (CHF), and now, many patients diagnosed with CHF are surviving what in the past might have been fatal events. Over the past decade the prevalence of congestive heart failure has significantly increased, with now more than 10% of the US population over 65 years of age having the diagnosis. The development of CHF

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including cardiac resynchronization therapy, left ventricular remodeling surgery, and mechanical therapy with the recent approval of the first left ventricular assist device for destination therapy. In the setting of increasing prevalence of CHF combined with the lack of definitive therapy to prevent and treat mechanical and electrical failure of damaged myocardium the need for new therapies is great. There is increasing evidence that interactions between the heart and the brain may offer novel strategies for the treatment of many chronic disease states. There is a rich literature that demonstrates the intricate neural control of cardiac function. Below we will discuss how these pathways may be exploited to modulate mechanical and electrical function of the damaged myocardium.

NEUROMODULATION FOR CHRONIC HEART FAILURE CHF is characterized by activation of a complex neurohumoral compensatory response via the sympathoadrenal and renin–angiotensin–aldosterone pathways. The process of cardiac remodeling in CHF is an interaction between the hemodynamic changes induced by the sympathoadrenal system and the local production of neurohormones (angiotensin, aldosterone, and norepinephrine), growth factors and reactive inflammatory substances (Askari et al., 2003). There is a strong correlation between the degree of neurohormonal activation and mortality in patients diagnosed with severe congestive heart failure (Swedberg et al., 1990). The sympathetic response to cardiac dysfunction is generated by a complex cardiovascular sequence of reflexes that increase the local release of norepinephrine. The sustained activation of β-adrenergic receptors as a short-term adaptive response can lead to elevated heart rate, preload and myocardial contractility, and increase the number of contractile elements to compensate for the cardiac dysfunction. In the long term, however, increased levels of catecholamines cause adverse effects on cardiac myocyte biology (Mann et al., 1992), myocardial remodeling, and alter β-adrenergic signal transduction system (Delehanty et al., 1994). The cardiotoxic effects of norepinephrine lead to an increase in intracellular calcium through the effects of cAMP and a direct interaction of calcium channels with the stimulatory G-proteins. Ultimately this process leads to an increased cellular load of calcium which promotes cell death through both apoptotic and necrotic pathways (Communal et al., 1999; Saito et al., 2000; Akyurek et al., 2001; Narula et al., 2001).

The understanding of the physiopathology of the disease has been guiding the current therapy in order to retard and sometimes reverse the progressive damage and further cardiac fibrosis. Medical interventions such as angiotensin-converting enzyme inhibition, aldosterone inhibitors and beta blockers result in a reduction in the harmful long-term consequences of the activation of the sympathoadrenal and renin–angiotensin– aldosterone systems, and potentially altering the natural history of heart failure and improving patient outcomes (Eichhorn and Bristow, 1996; Eichhorn et al., 2003; Bauman and Talbert, 2004; Roffman, 2004). The neurohormonal activation that occurs in CHF has inspired some to assess the effects of direct neuromodulation on cardiac function. Vagal nerve stimulation has been shown (Li et al., 2004) to improve the long-term survival of rats in CHF. Fifty-two rats were divided in three groups: sham-operated rats with sham stimulation, CHF rats with sham stimulation, and CHF rats treated with vagal stimulation. The vagal nerve was stimulated with rectangular pulses of 0.2 ms, duration at 20 Hz for 10seconds every minute for 6 weeks. It was reported that the treated CHF group had significantly lower LVEDP, higher dP/dt max, and decreased ventricular weight. The authors attribute the improvements in cardiac function to different mechanisms, such as: inhibition of adrenergic signaling cascade through the G-protein coupled receptors, induction of negative chronotropic effect, facilitation of nitric oxide release in the coronary vasculature, and suppression of norepinephrine and tumor necrosis factor (TNF)-α release. The effects of vagal nerve stimulation for modulating inflammation such as that observed in CHF has been suggested as well. Tracey (2002) describes the regulation of the inflammatory response through sensory pathways and hypothalamus which is modulated by parasympathetic stimulation. Vagal nerve stimulation prevents inflammation and inhibits the release of cytokines such as TNF. The discovery that cholinergic neurons inhibit acute inflammation suggests a selective approach of neuromodulation to downregulate the inflammation associated with CHF. Consistent with this hypothesis, recent data have demonstrated that vagotomy in the mouse prior to myocardial infarction leads to increased inflammation, greater adverse ventricular remodeling, and worse cardiac function (Zhou et al., 2008).

NEUROSTIMULATION FOR ACUTE HEART FAILURE Acute heart failure (AHF), or acute exacerbation of chronic heart failure, is a complex syndrome that is

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NEUROSTIMULATION FOR ACUTE HEART FAILURE

usually a consequence of myocardial ischemia or infarction, valvular abnormalities, hypertension, myocarditis or sustained cardiac arrhythmias. The main goal of short-term therapy for AHF is to improve hemodynamics while preserving organ function until the underlying problem can be treated. The management of AHF requires rapid identification of the condition, with specific treatment focused at reversing the associated abnormal pathophysiologic state. The role of current agents used to “life support” patients in AHF, such as positive inotropic drugs, remains controversial. Although these agents increase myocardial contractility and stabilize the patient’s condition, clinical trials of inotropic agents have consistently demonstrated an overall excess of mortality and adverse clinical events (O’Connor et al., 1999; Cuffe et al., 2002). Cardiac arrhythmias and increase in the myocardium oxygen consumption are the cause of much of the excess mortality and are independent of the specific agent administered. The autonomic nervous system plays a major role in regulating the cardiovascular function. The activation of parasympathetic cardiac fibers leads to bradycardia, slowed atrioventricular conduction, negative inotropism, and some degree of coronary vasodilation. The sympathetic stimulation counteracts the mentioned effects through an increase in heart rate, rhythm, and ventricular function and coronary blood flow modulation. The sympathetic trunk provides the major cardiopulmonary sympathetic fibers that join parasympathetic fibers to form two cardiopulmonary plexuses. These structures unite in the base of the heart and project into the myocardium (Thomas and Gerdisch, 1990). Further understanding of the physiology and topography of the cardiac autonomic system can expand the opportunities for support of patients in acute episodes of heart failure. The possibility of selective stimulation of neural inputs that specifically modulate inotropic function of the myocardium could theoretically acutely, and perhaps chronically, impact on the long-term survival of these patients. Furthermore, device-based modulation of inotropic function could offer the potential of re-establishing a circadian rhythm within the heart, something that is not achievable with pharmacological therapy. The sympathetic pathways mediating main cardiac functions have been described in animal models of ansae subclavia stimulation. The authors described an agglomerate of right sympathetic (RS) fibers at the common pulmonary artery and within the pulmonary artery nerves (Ardell et al., 1988). Those projections possibly modulate the ventricular contractile force. RS influencing heart rate and right atrial contractily course between the superior vena cava and ascending aorta. Left sympathetic (LS) fibers that course through

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the common pulmonary artery, within the pulmonary artery nerves, influence the ventricular contractile tissue. Alternatively, the LS fibers related to rate control course between the right pulmonary artery and left superior pulmonary vein. This work of Ardell et al. is important because it demonstrates that inotropy and chronotropy are mediated by segregated pathways, thus potentially allowing for selective neuromodulation of inotropy without impacting rate. Brandys et al. (1986) studied the major mediastinal cardiopulmonary nerves between the aorta and pulmonary artery in dogs. They reported a selective augmentation of the left ventricular ventral intramyocardial pressure (IMP) deflagrated by stimulation of right dorsal mediastinal cardiac nerve. Stimulation of the middle dorsal mediastinal cardiac nerve led to decreased right atrial contractile force with simultaneous augmentation of right and left ventricular IMP and increase in the left ventricular intracavity pressure (IVP). Tachycardia and increased left ventricular IMP were noted with left lateral cardiac nerve stimulation. Murphy and Armour (1992) reported the cardiovascular responses elicited in 12 patients undergoing cardiac operations by direct electrical stimulation of cardiopulmonary nerves located between the aortic root and pulmonary artery. The electrical stimulation parameters were 10 Hz, 5 ms, and 4 V. Increased and decreased effects on heart rate were observed depending on the nerve stimulated. Further, stimulation of efferent sympathetic neurons improved ventricular function as indicated by a substantial augmentation in right and left IMP. It appears that these nerves primarily innervate the anterior wall of the ventricle and, to a lesser extent, the posterior wall of the left and right ventricles. A recent study by Zarse et al. (2005) has demonstrated the potential of hemodynamic control through subclavian artery transvascular stimulation of the right and left sympathetic fibers inside the ansae subclavia. Electrical stimulation of this area induced a 60% increase in the cardiac output and a greater than 100% increase in systolic blood pressure. It was also reported a 40 and 70% increase in heart rate according to the side stimulated (left and right, respectively). They did not observe any affect on peripheral vascular resistance, suggesting that the affects were limited to the heart. This study confirms the feasibility of sympathetic fibers neurostimulation resulting in selective effects on cardiovascular parameters. There is extensive literature describing anatomical features of sympathetic and parasympathetic cardiopulmonary fibers in the base of the heart, including in animals. However, until now, there has been little on how to approach and stimulate these structures in order to treat cardiac dysfunction in humans, and the

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severely debilitated patients in a clinical scenario of an acute heart failure.

NEUROSTIMULATION FOR ARRHYTHMIAS Cardiac arrhythmia is one of the conditions in which electrical activity of the heart is more irregular, faster or slower than normal rhythm. A heart rate higher than 100 bpm is considered as tachycardia and, subsequently, if ventricularly driven, can induce ventricular fibrillation (VF), which is a life-threatening form of the cardiac arrhythmias that can lead to sudden death. Several pharmacological or electrical methods such as calcium-channel blockers, beta blockers, electrical cardioversions (implantable cardioverter defibrillator [ICD]), and radiofrequency ablation have been applied clinically over several decades for the prevention and treatment of tachycardia and fibrillation. Conversely, patients with CHF can develop bradycardia (60 beats per minute), which is usually not life-threatening but may produce hypotension. This can deteriorate to chronotropic incompetence, acute on chronic heart failure, and death. Permanent pacemaker implantation is necessary when these symptoms continue. Since the pioneering work by Hunt (1895), the effect of neuronal sympathetic and parasympathetic activation on cardiac functionality has drawn extensive attention. Hunt for the first time demonstrated direct and reflex acceleration of the mammalian heart by observing the inhibitory and accelerator nerves. The autonomic nervous system regulates heart rate through a balance of sympathetic and parasympathetic inputs. An increase in sympathetic tone increases heart rate and decreases heart rate variability. In contrast, increases in parasympathetic tone decrease heart rate and increase heart rate variability. Beyond heart rate control parasympathetic activation induces decreased atrioventricular node conduction, decreased atrial contractility, and mild coronary vasodilation. The regulatory malfunction in autonomic tone is known as a contributing factor for arrhythmogenesis. Furthermore, in conjunction with myocardial ischemia (MI), it plays an important role in sudden cardiac death. Reduced heart rate variability is a contributor to worse clinical outcome in patients with cardiovascular disease (Task Force, 1996). The specific anatomy of cardiac nerve projections into the heart has been extensively studied (Mizeres, 1955; Randall, Szentivanyi et al., 1968; Armour and Randall, 1975; Thomas and Gerdisch, 1990). Neuronal pathways involved in arrhythmogenesis have been defined

by either electrical stimulation or denervation of various central nervous system structures (Armour et al., 1972; Ardell et al., 1988). Functional laterality is known to exist in sympathetic efferent nerve that regulates the heart (Levy et al., 1966; Schuessler et al., 1986; Miyano et al., 1998). Autonomic nerves on the right side arise either from the right stellate ganglion or from the anterior/posterior ansa subclavia with several branches that course caudally to the dorsal surface of the right atrium. The right stellate cardiac nerve has pure sympathetic response in which the electrical stimulation results in profound sinus tachycardia (Armour et al., 1972). The right recurrent laryngeal nerve gives rise to the recurrent cardiac nerve that produces mixed responses in either inhibiting or exciting sympathetic nerves activity, depending on electrical stimulation parameters (Bachoo and Polosa, 1985; Huangfu and Guyenet, 1991). The craniovagal and caudovagal cardiac nerves that originate from the vagosympathetic trunk have mixed response, both sympathetic as well as parasympathetic, fibers. Autonomic nerves on the left side arising either from the left stellate ganglion or from ansa subclavia project to a left stellate cardiac nerve that penetrates to the right atrium and has profound chronotropic effect with some inotropic effect. The ventromedial cardiac nerve arises from medial left thoracic vagus and also receives input from the caudal cervical ganglion. This nerve also has mixed responses, with both sympathetic and parasympathetic efferent fibers. The ventrolateral cardiac nerve arises from the lateral aspect of the cervical ganglion. This nerve primarily carries sympathetic input. The stimulation of this nerve induces a profound inotropic response, especially in the left ventricular base, and produces great dispersion of pacemaker activity (Randall, Wechsler et al., 1968; Goldberg, 1975). Neuromodulation for the treatment of cardiac arrhythmia has been applied in two distinct ways: suppressing the sympathetic nerve activity and augmenting the parasympathetic nerve activity.

Sympathetic Neuromodulation for Arrhythmia Sympathetic activation affects rate and rhythm as well. It has become progressively clear that the sympathetic nervous system plays an important role in the genesis of many instances of life-threatening arrhythmias. During sympathetic nerve stimulation there is an increase in heart rate and LV pressure that can alter cardiac vulnerability and predispose the heart to ventricular fibrillation. Right-sided sympathetic stimulation induces only sinus tachycardia. The stimulation of nerve fibers originating from the left stellate ganglion produces a variety of rhythm disorders. Not always,

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but occasionally, stimulation of the left stellate ganglion induces ventricular tachycardia, even in the intact heart. Furthermore, the importance of sympathetic nervous input to the heart is the fatal response to pathophysiologic stresses such as MI and hypertrophy. For the treatment of arrhythmias induced by hypersympathetic tone, the antiarrhythmic effects of left stellectomy have been confirmed by several experimental studies (Schwartz and Stone, 1980; Schwartz et al., 1984). The major effect of stellectomy is to increase ventricular refractoriness and ventricular fibrillation thresholds; furthermore it increases myocardial hyperemia. In addition to the antiarrhythmogenic effect, it can reduce the infarct size by approximately 25% (Schwartz et al., 1985). In idiopathic long Q–T syndrome left stellectomy significantly reduced mortality rate to a level commensurate with that seen with beta blockade. Thus the use of sympathectomy declined owing to the advent of beta blockers not because of lack of efficacy. Interestingly, while left stellectomy increases the threshold of ventricular fibrillation, right stellectomy has an opposite effect (Schwartz, Stone et al., 1976). This does not imply that right stellate ganglion stimulation may have a protective role in arrhythmogenesis, but it corroborates the laterality of the response, a dominant effect of the left stellate ganglion, in sympathetic nerve stimulation. The excitation of sympathetic afferents not only increases efferent cardiac sympathetic activity, but it can also inhibit the activity of efferent cardiac vagus nerve reflexively and selectively. This sympathovagal reflex can impair the vagally mediated maintenance of heart rate, and thus facilitate the occurrence of tachycardias (Schwartz, Foreman et al., 1976). Recently, Mahajan et al. (2005) reported a clinical management of cardiac sympathetic tone using thoracic epidural anesthesia. This application effectively managed ventricular arrhythmogenesis in those patients who had severe ischemic cardiomyopathy, with unrevascularized coronary artery disease, and ventricular arrhythmias refractory to conventional medical therapies.

Parasympathetic Neuromodulation for Arrhythmias Atrial fibrillation (AF) is a common clinical arrhythmia. Up to 40% of CHF patients have AF, and rapid ventricular response to AF has been shown to worsen long-term ventricular function because of tachycardiainduced cardiomyopathy. Pharmacological treatments such as calcium-channel blockers, beta blockers, and angiotensin-converting enzyme inhibitors may exert untolerated negative inotropic side effects on the ventricle, cause atrial hypotension, and induce peripheral

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vasodilation. The alternative atrioventricular (AV) nodal ablation and ventricular pacemaker can be efficacious in patients with high ventricular rates during AF, but right ventricular pacing may promote or worsen the preexisting heart failure (Lamas et al., 1998). Recently, two major strategies of the treatment of AF – rhythm and rate control – were found to be equally effective (Wyse et al., 2002). Zhuang et al. (2002) demonstrated that ventricular rate control by parasympathetic stimulation is superior to rhythm regulation by AV nodal ablation and ventricular pacing during AF. It has been reported that rate control is a more effective and cost-effective treatment option of the AF patient than rhythm control (Marshall et al., 2004). However, intracardiac parasympathetic nerve stimulation inevitably affects adjacent myocardial tissue thereby potentially inducing AF. Taken together, controlling chronotropic and dromotropic response without any side effects is the treatment goal of AF. Either direct or endovascular electrical stimulation to the efferent parasympathetic nerve could be an effective alternative modality for control of the ventricular rate alone. It is taken for granted that noninvasive endovascular nerve stimulation or minimally invasive direct nerve stimulation is the preferred clinical application. Cardiac parasympathetic ganglia reside at distinct epicardial sites and are surrounded by adipose connective tissue that is often referred to as the cardiac fat pads. In a canine model, two fat pads were described to project nerves to the sinus node in slowing sinus rate. One was localized at a similar site as in humans between the right superior pulmonary vein, superior vena cava, and right atrium (Lazzara et al., 1973; O’Toole et al., 1986). The other fat pad was localized at an area between the aortic root, superior vena cava, and right pulmonary artery (Chiou et al., 1997). Electrical stimulation of vagal efferent axons induces a profound depressing effect in sinus rate, either directly or indirectly, atrioventricular conduction, depressor effects on the atria, to a lesser degree, and ventricular contractility. Thompson et al. (1998) studied direct or intravascular stimulation, which is adjacent to the superior vena cava, of the vagus nerve in a canine model. They demonstrated that the heart rate decreased up to about 80% during electrical stimulation to the right thoracic vagus by both a direct and indirect method. Nerve activity resulting in bradycardia was augmented by increases in voltage amplitude and frequency, but it was independent of the pulse duration. Cooper et al. (1980) demonstrated neural effects on the sinus rate and atrioventricular conduction induced by transvascular electrical stimulation of preganglionic parasympathetic efferent nerve fibers in a canine model. They identified atrial complexes in the proximal right pulmonary artery next to the pulmonary trunk and placed a multipolar

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electrode catheter. They found that the threshold for inducing atrial fibrillation diminished from the proximal to the distal part of the right pulmonary artery. Schauerte et al. studied parasympathetic nerve stimulation to induce stable sinus rate control by an indirect transvascular approach (Schauerte et al., 1999, 2000). They positioned an electrode basket in the superior vena cava (SVC) and right pulmonary artery (RPA). This stimulation resulted in a decrease in the heart rate up to 50 % and prolonged bradycardia that was maintained for over 10 hours. A decrease in heart rate was observed even in the presence of β-adrenergic stimulation by isoproterenol. Furthermore they demonstrated a consistent negative dromotropic effect during AF by electrical stimulation in the inferior vena cava (IVC). During the stimulation ventricular rate slowed 4.5-fold compared to baseline. These effects were abolished by atropine and blunted by hexamethonium. Following the canine studies, the same group demonstrated reversible chronotropic and dromotropic effect by endovascular parasympathetic stimulation in patients (Schauerte et al., 2001). They stimulate the parasympathetic nerve through the SVC and coronary sinus (CS) for the treatment of supraventricular tachycardia and atrial fibrillation in patients with congestive heart failure. For these studies, the SVC was stimulated using the same application that was used in earlier animal studies. However, to avoid AF induced by electrical CS stimulation, they used high frequency nerve stimuli (200 Hz) within the atrial refractory period. Although vagal nerve stimulation is beneficial to minimize atrial and ventricular arrhythmias, the mechanism during myocardial infarction remains unclear. Ando et al. (2005) have demonstrated that antiarrhythmogenic properties of vagal stimulation during acute myocardial infarction are related to the preservation of gap junction components of connexin 43, a principal electrical coupling protein in ventricular myocytes (Ando et al., 2005). In an in vitro study, Zhang et al. (2006) demonstrated that acetylcholine (Ach), a parasympathetic neurotransmitter, inhibits hypoxia-induced reduction of connexin 43 in cultured cardiomyocytes. Their findings indicate that the effect of Ach is not restricted to the passive preservation of connexin 43, but it actively regulates expression of connexin 43 that could inhibit arrhythmias. Pain perception in the patients should be carefully examined in clinical trials for the endovascular electrical nerve stimulation. The specification of the efferent nerve stimulation without inducing reflex that could elicit pain perception needs to be considered. Sophisticated current density control around the tissue layer is required to reduce lesion formation and tissue damage by the high temperatures. Proportionally

increasing pain perception by voltage increase should also be examined in future clinical applications.

SUMMARY As discussed above, there is a great need for decreasing the morbidity and mortality associated with chronic heart failure. Through our previous successes in decreasing the mortality in patients who present with acute myocardial infarction, we have significantly increased the number of patients who are at significant risk of sudden cardiac death and/or low output cardiac failure. Device-based therapies, such as ICDs and biventricular pacemakers, have demonstrated significant reduction in morbidity and mortality in patients with decreased cardiac function. Given these previous successes and our increasing knowledge of the neuroanatomy and neurophysiology of the heart, one can expect that in the near future, device-based neuromodulation of cardiac function may have a significant impact in patients with chronic heart failure.

References Akyurek, O., Akyurek, N., Sayin, T., Dincer, I., Berkalp, B., Akyol, G. et al. (2001) Association between the severity of heart failure and the susceptibility of myocytes to apoptosis in patients with idiopathic dilated cardiomyopathy. Int. J. Cardiol. 80: 29–36. Ando, M., Katare, R.G., Kakinuma, Y., Zhang, D., Yamasaki, F., Muramoto, K. et al. (2005) Efferent vagal nerve stimulation protects heart against ischemia-induced arrhythmias by preserving connexin 43 protein. Circulation 112: 164–70. Ardell, J.L., Randall, W.C., Cannon, W.J., Schmacht, D.C. and Tasdemiroglu, E. (1988) Differential sympathetic regulation of automatic, conductile, and contractile tissue in dog heart. Am. J. Physiol. 255: H1050–H1059. Armour, J.A. and Randall, W.C. (1975) Functional anatomy of canine cardiac nerves. Acta Anat. (Basel) 91: 510–28. Armour, J.A., Hageman, G.R. and Randall, W.C. (1972) Arrhythmias induced by local cardiac nerve stimulation. Am. J. Physiol. 223: 1068–75. Askari, A., Brennan, M.L., Zhou, X., Drinko, J., Morehead, A., Thomas, J.T. et al. (2003) Myeloperoxidase and plasminogen activator inhibitor-1 play a central role in ventricular remodeling after myocardial infarction. J. Exp. Med. 197: 615–24. Bachoo, M. and Polosa, C. (1985) Properties of a sympathoinhibitory and vasodilator reflex evoked by superior laryngeal nerve afferents in the cat. J. Physiol. 364: 183–98. Bauman, J.L. and Talbert, R.L. (2004) Pharmacodynamics of betablockers in heart failure: lessons from the carvedilol or metoprolol European trial. J. Cardiovasc. Pharmacol. Ther. 9: 117–28. Brandys, J.C., Randall, W.C. and Armour, J.A. (1986) Functional anatomy of the canine mediastinal cardiac nerves located at the base of the heart. Can. J. Physiol. Pharmacol. 64: 152–62. Chiou, C.W., Eble, J.N. and Zipes, D.P. (1997) Efferent vagal innervation of the canine atria and sinus and atrioventricular nodes. The third fat pad. Circulation 95: 2573–84. Communal, C., Singh, K., Sawyer, D.B. and Colucci, W.S. (1999) Opposing effects of beta(1)- and beta(2)-adrenergic receptors on

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modulate left ventricular remodeling but not infarct size after myocardial infarction. Circulation 112: 2812–20. Wyse, D.G., Waldo, A.L., DiMarco, J.P., Domanski, M.J., Rosenberg, Y., Schron, E.B. et al. (2002) A comparison of rate control and rhythm control in patients with atrial fibrillation. N. Engl. J. Med. 347: 1825–33. Zarse, M., Plisiene, J., Mischke, K., Schimpf, T., Knackstedt, C. and Gramley, F. (2005) Selective increase of cardiac neuronal sympathetic tone: a catheter-based access to modulate left ventricular contractility. J. Am. Coll. Cardiol. 46: 1354–9. Zhang, Y., Kakinuma, Y., Ando, M., Katare, R.G., Yamasaki, F., Sugiura, T. et al. (2006) Acetylcholine inhibits the hypoxiainduced reduction of connexin 43 protein in rat cardiomyocytes. J. Pharmacol. Sci. 101: 214–22. Zhou, X., Khalil, M., Lee, K., Wang, K. and Penn, M.S. (2008) Decreased parasympathetic tone worsens left ventricular remodeling following myocardial infarction. J. Am. Coll. Cardiol. 51 (Suppl.): A182. Zhuang, S., Zhang, Y., Mowrey, K.A., Li, J., Tabata, T., Wallick, D.W. et al. (2002) Ventricular rate control by selective vagal stimulation is superior to rhythm regularization by atrioventricular nodal ablation and pacing during atrial fibrillation. Circulation 106: 1853–8.

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72 Neural Control of the Colon Beverley Greenwood-Van Meerveld and Robert D. Foreman

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colorectal distension (CRD) (Mayer and Gebhart, 1994). The visceral hypersensitivity associated with colonic distension in IBS patients has been proposed to be due to a generalized pain response in these patients where innocuous sensations are perceived as painful (Mertz et al., 1995). In addition to heightened visceral sensitivity, IBS patients often exhibit co-morbidity with somatic symptoms such as headache or fibromyalgia. There is now accumulating evidence that this strong association between visceral and possibly somatic hypersensitivity in patients with IBS likely arises from abnormalities in the complex bidirectional communication between the central nervous system (CNS) and the enteric nervous system in the periphery (Figure 72.1). It seems reasonable to infer that reflex arcs involved in regulating gut function in either, or more likely both, of these nervous systems may become defective and contribute significantly to abnormal visceral sensation. Visceral pain and dysmotility are transmitted to supraspinal structures via the post-synaptic dorsal

BACKGROUND Functional bowel disorders, including the irritable bowel syndrome (IBS), are common abnormalities of the gastrointestinal tract (GI) that are associated with abdominal cramping and pain, with abnormal bowel habits. The etiology and pathophysiology of IBS are unknown and its diagnosis is often made through a tedious and time-consuming process of exclusion. Many patients who seek medical help for their IBS undergo numerous negative tests, and they are too frequently dismissed as having a psychosomatic disorder. However, there is evidence to suggest that the symptoms are due, at least in part, to disturbed GI motility, characterized by hypercontractility (Connell et al., 1965; Kumar and Wingate, 1985; Kellow and Phillips, 1987). Nevertheless, symptoms cannot be explained by changes in GI motility alone, and an important observation is that many patients with IBS exhibit alterations in visceral perception characterized by heightened awareness of visceral stimuli including

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Brain Stress c

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PAIN experience

g

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Enteric N.S.

Spinal cord

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FIGURE 72.1

The brain–gut axis. Neural control of sensation and motility from the colon occurs primarily at the enteric nervous system (Enteric N.S.), the spinal cord, and the brain stem and brain. Increased neuronal activity at any of these regions could explain the hypersensitivity observed in functional bowel disorders such as IBS: (a) inflammatory substances may sensitize nociceptors to trigger hypersensitivity or may continuously stimulate the endings to maintain hypersensitivity; (b) continuous and increased noxious visceral sensory input sensitizes neurons in the dorsal horn of the spinal cord; (c) psychosocial stressors such as depression may initiate the onset of function bowel disorders (Adapted and used with permission from Mertz (2003). John Wiley & Sons Ltd)

column pathway and the spinothalamic tract (STT) pathway (for a detailed review see Krames and Foreman, 2007). Human and animals studies have shown that visceral nociceptive information from the colon is transmitted in spinal afferent fibers to the cells of origin of the postsynaptic dorsal column neurons in the lumbosacral spinal cord (Hirshberg et al., 1996; Al-Chaer et al., 1998). The axons of these cells project in the dorsal column to the nucleus gracilis and from there relay to the ventrobasal thalamus. Visceral nociceptive information from the colon is also transmitted in the STT pathway (Ness, 2000; Chandler et al., 2002). There is evidence to suggest that these two pathways interact in that the postsynaptic dorsal column pathway enhances the responsiveness of STT cells and other ascending pathways (Palecek, 2004). The enhanced responses may result from activation of a descending facilitatory pathway originating in the rostral ventral medulla. The somatic hypersensitivity that results from visceral pain such as irritable bowel syndrome most likely occurs because somatic and visceral afferent fibers converge on the same spinal neurons and neurons with ascending projections. Visceral hyperalgesia in IBS patients may develop as a result of an acute irritating event followed by

development of hypersensitivity of undamaged tissues. Neuroactive chemicals such as substance P, glutamate, and calcitonin gene-related peptide (CGRP) might participate in the increased excitability of spinal and supraspinal neurons and contribute to a “memory” of the initial peripheral insult of colorectal inflammation (Willis, 1993a, 1993b). The post-injury sensitization pain resulting from tissue damage is a primary contributor to this noxious memory. As a result of this sensitization, the pain experienced from subsequent stimulation can be initiated by innocuous stimuli and is prolonged and exaggerated. These observations agree with recent findings from our laboratories in which colonic hypersensitivity was prolonged following an acute sensitizing insult (Greenwood-Van Meerveld et al., 2003). The strong association between visceral and possibly somatic hypersensitivity in patients with IBS led us to speculate that SCS might reduce the hypersensitivity and pain resulting from this disease. Enhanced sensitivity in IBS patients was once thought to be limited to the gut as these patients were not hypersensitive to either ice water immersion or electrical stimulation of the hand (Cook et al., 1987; Accarino et al., 1995; Zighelboim et al., 1995). However, more recent data have shown that IBS patients display cutaneous hyperalgesia in the hand and foot (Chang et al., 2000; Bouin et al., 2001; Verne et al., 2001). Since SCS is beneficial in reducing some types of visceral pain and effectively suppresses hyperexcitable somatosensory and viscero-somatic (bladder) reflexes in patients experiencing spasticity, we reasoned that SCS might relieve the somatic symptoms associated with IBS. In summary, previous data in the literature suggest that a strong scientific rationale exists for the use of SCS for the treatment of patients with functional bowel disorders, such as IBS.

CURRENT STATE OF BASIC SCIENCE Based on the rationale discussed in the previous section, our research team (Greenwood-Van Meerveld et al., 2003, 2005) decided to study the effects of SCS as a potential therapy for visceral pain originating from the GI tract. An animal model of visceral hypersensitivity has been adapted to resemble the patient condition of IBS by infusing a low concentration of acetic acid into the colon, which causes hypersensitivity in the absence of mucosal damage (Langlois et al., 1996; Plourde et al., 1997; Gunter et al., 2000) or following an acute inflammatory insult using trinitrobenzenesulfonic acid (TNBS) (Greenwood-Van

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Meerveld et al., 2005). In these experiments we quantified the level of visceral pain in rats by measuring abdominal muscle contractions that represent a nociceptive reflex induced by colorectal distension (Ness and Gebhart, 1988). In this model, a spinal cord electrode was implanted chronically as described in a previous study (Linderoth et al., 1993). After one week, animals were anesthetized briefly with isoflurane (0.7–1.5%) to suture a strain gauge force transducer to the right external oblique abdominal muscle. The signal from the strain gauge was amplified and recorded on a penwriter. A colorectal balloon was then used to distend normal colons and colons made hypersensitive with acetic acid; the number of abdominal contractions was recorded both with and without SCS. The results showed that SCS significantly suppressed the visceromotor responses that were produced with colorectal distension in both normal rats and those with sensitized colons (Figure 72.2A) (Greenwood-Van Meerveld et al., 2003). In a more recent study, illustrated in Figure 72.2B, SCS significantly reduced abdominal contractions during innocuous distension of the colon in a rat model of post-inflammatory colonic hypersensitivity using TNBS (Greenwood-Van Meerveld et al., 2005). In another series of studies we used a rodent model to examine the duration of the anti-nociceptive effect of SCS (Greenwood-Van Meerveld et al., 2003). In these experiments we performed a colorectal distension at nociceptive levels (60 mmHg) prior to SCS and measured the visceromotor responses that were produced with colorectal distension. SCS was then applied for 30 min and the colorectal balloon distensions were repeated at 10, 30, 50, 70, and 90 min post SCS. In this study, SCS caused a significant inhibition of the abdominal contractions during distension of the colon for up to 70–90 min following termination of SCS (Figure 72.3). Thus, the ability of SCS to suppress colonic sensitivity provides evidence that SCS may have therapeutic potential for the treatment of visceral pain of GI origin associated with abdominal cramping and painful abdominal spasms. Recently, we designed a study in rats to examine and compare the effects of SCS applied to the dorsal columns of the upper cervical and lumbar segments on responses of lumbosacral spinal neurons to noxious colorectal stimulation (Qin et al., 2007). The stimulating electrodes were placed on the C1–C2 and L2–L3 segments. The extracellular recordings were made from the L6–S2 spinal neurons. The results showed that C1–C2 or L2–L3 SCS using clinical stimulation parameters (90% of motor threshold, 50 Hz, 200 μs) significantly reduced excitatory responses to noxious CRD in L6–S2 spinal neurons. The suppressive effects of SCS persisted for several minutes after

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FIGURE 72.2 Effects of SCS on CRD-induced abdominal contractions in animals with acute (A) and post-inflammatory (B) sensitization. (A) The first column (Non-sensitized) represents the abdominal contractions produced with low levels of CRD (30 mmHg for 10 min) from a non-sensitized colon. The second column (Sensitized) is CRD-induced abdominal contractions in the colon following sensitization with intracolonic administration of acetic acid (0.6%). The third column shows the effects of SCS in an acutely sensitized colon (Sensitized  SCS). SCS significantly reduced the effects of colonic distensions on abdominal contractions. (B) The first two columns (Pre SCS, Post SCS) represent the effects of SCS (90% motor threshold, 200 μs, 50 Hz, 30 min) on CRD-induced (30 mmHg for 10 min) abdominal contractions after intracolonic saline. The last two columns (Pre SCS, Post SCS) represent the effects of SCS on CRDinduced abdominal contractions 30 days (post-inflammatory) after the onset of colitis using trinitrobenzenesulfonic acid (TNBS). The number of CRD-induced abdominal contractions was significantly reduced following SCS. *p 0.01 compared to pre-stimulation TNBS (Reproduced with permission from Greenwood-Van Meerveld et al. (2003). Copyright (2003) Elsevier)

terminating the stimulation. SCS did not affect inhibitory responses to CRD in this model (Figure 72.4A,B). Transection of the C7–C8 dorsal columns but not a complete transection of the spinal cord at the cervicomedullary junction abolished the C1–C2 SCSinduced effects. These results showed that the upper cervical SCS most likely antidromically activated large afferent fibers of the dorsal column and did not require supraspinal pathways to produce the suppressive effects on spinal neurons in the lumbosacral spinal cord. To our knowledge, this study is the first that describes suppressive effects of SCS on spinal neuronal neurons receiving inputs from noxious stimulation of pelvic visceral organs. Generally, these observations

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were similar to previous studies in which SCS effects were examined on noxious somatic inputs in STT and spinal neurons of monkeys and rats (Foreman et al., 1976; Lindblom et al., 1977; Saade et al., 1985; Yakhnitsa et al., 1999; Wallin et al., 2003) and on cardiac inputs in STT neurons of monkeys (Chandler et al., 1993). Taken together, this study supports the idea that SCS might be useful therapy for the management of patients with colonic hypersensitivity observed in IBS.

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FIGURE 72.3 Long-lasting inhibitory effects of CRD-induced (60 mmHg) abdominal contractions following SCS (90% motor threshold, 200 μs, 50 Hz, 30 min). The arrowhead on the abscissa represents the time where SCS was applied for 30 min.The abdominal contractions were significantly suppressed for 70 min post SCS. *p 0.05 (Reproduced with permission from Greenwood-Van Meerveld et al. (2003). Copyright (2003) Elsevier)

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Based upon experimental results in animals, the use of SCS in a patient suffering from IBS was performed and demonstrated that SCS reverses the diarrhea and pain in a patient who had suffered from IBS for several years (Krames and Mousad, 2004). Khan et al. (2005), in a retrospective study, have also shown that SCS can be used effectively to treat a variety of visceral pain syndromes, including generalized abdominal pain, chronic nonalcoholic pancreatitis, and pain following post-traumatic splenectomy. The human studies support the observations made in the animal studies and provide further evidence to support the notion that SCS might be used to treat a variety of diseases that originate in the visceral organs.

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FIGURE 72.4 Effects of L2–L3 (A) or C1–C2 (B) SCS (90% MT, 200 μs, 50 Hz) on excitatory responses of lumbosacral spinal neurons to noxious colorectal distension (CRD, 60 mmHg, 20 s). Total responses (impulses) represent a change in activity of spinal neurons from the onset of increased activity to CRD until evoked activity returned to control. CRD was applied after the onset of SCS and was continued after CRD was terminated. *p 0.05 compared to corresponding activity before and after L2–L3 SCS and before C1–C2 SCS (Reproduced with permission from Qin et al. (2007). Copyright (2007) Elsevier)

Although clinical data have shown some new and exciting observations with SCS in IBS patients, the results of additional randomized control trials of SCS in IBS patients represent a gap in our knowledge; however studies are in progress and hopefully will be published soon. Furthermore, the underlying mechanisms responsible for the inhibitory effects of SCS have yet to be resolved; however, previous studies suggest synaptic modification in spinal and supraspinal pathways (Figure 72.5) (Linderoth and Foreman, 1999; Linderoth and Meyerson, 2002). In support of a central mechanism, SCS suppresses pathological hyperexcitability of wide dynamic range spinal neurons after peripheral nerve lesions (Yakhnitsa et al., 1999). Furthermore, evidence in a rodent model of peripheral vasodilation suggests that SCS depresses sympathetic nervous activity (Linderoth et al., 1991; Linderoth et al., 1994). Taken together, these neuronal pathways may activate gating mechanisms similar in principle to those proposed by Melzack and Wall (1965), to suppress visceral hypersensitivity

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CURRENT AND FUTURE DIRECTIONS

mechanisms by which SCS affects the brain, spinal cord, and the enteric nervous system (see Figure 72.5).

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FIGURE 72.5 A diagram illustrating effects of SCS of the L2– L3 or C1–C2 dorsal columns on potential neural mechanisms that reduce visceral pain and dysmotility resulting from functional bowel disorders. SCS most likely activates interneurons that may (1) reduce the activity of postsynaptic dorsal column cells and STT cells; (2) modulate the activity of sympathetic preganglionic neurons; and (3) activate antidromically the dorsal root afferent fibers. The question marks represent unanswered questions about the neurotransmitters, neuromodulators, and interneuronal processing (dashed circle) that participate in the effects of SCS on visceral pain

originating from the GI tract. The involvement of higher level central circuits, e.g. a dorsal column–brain stem–spinal loop has also been implicated in the effects of SCS but remains controversial (Saade et al., 1985). Such central pathways may contribute to the effects of SCS in IBS, though the mechanisms remain unresolved. SCS also acts to increase blood flow via antidromic activation of sensory afferents that release neuromodulatory substances at the target organ (Croom et al., 1996; Tanaka et al., 2001). Such a mechanism may also play a role in the inhibitory effect of SCS on the visceromotor responses induced by colonic distension. However, we believe that this is less likely since previous studies have shown that colonic inflammation, nociceptive colonic distension in a normal colon (Roza and Reeh, 2001), or stress-induced degranulation of colonic mast cells (Gue et al., 1997) causes the release of sensory neurotransmitters such as CGRP and substance P. These substances are believed to sensitize mechanosensory afferents and recruit silent nociceptors that cause enhanced responses to a previously innocuous stimulus, such as luminal distension (Gue et al., 1997; Bueno and Fioramonti, 1999).

We believe that the future research directions should follow two paths in order to further develop SCS as a novel therapeutic to treat IBS. The first path is to use preclinical models to refine the parameters of SCS that can be used clinically to relieve abdominal pain of GI origin. Currently, the electrical parameters that are used in IBS patients were determined based upon data from patients with neuropathic pain and not IBS. Thus experiments to determine the optimal stimulation parameters and even the duration of stimulation are needed for optimal effectiveness of SCS in IBS. The second path for future development of SCS is to perform research that explores the mechanisms, i.e. neurotransmitters and neuromodulators responsible for the effect of SCS. In particular, the mechanism or mechanisms that explain the persistent effectiveness despite termination of the stimulation need to be explored. Our own findings demonstrating that the antinociceptive effects of SCS are not stimulus-locked and persist after the stimulation was terminated, suggest that stimulation induces processes that require some time for normalization. In a rat model of cutaneous allodynia (increased reactivity to tactile innocuous stimuli) SCS at 60% motor threshold for 30 min suppressed this over-reactivity for approximately 30–60 min post SCS (Meyerson and Linderoth, 1999). Furthermore, SCS of the T1–T2 spinal levels for 15 minutes suppresses activity generated by the intrinsic cardiac neurons for a prolonged period after the stimulus was stopped (Armour et al., 2002). In our study we also showed that within 10 min of initiating SCS there was a significant inhibition of the visceromotor responses induced by colonic distension. Taken together, the fairly rapid onset of action and prolonged duration of effect despite cessation of SCS suggests that multiple complex changes in neuronal activity and neurotransmitter release occur in response to SCS rather than a simple conduction block. Thus future experiments are necessary to tease out these effects of SCS. Elucidation of these mechanisms would enhance the possibility of treating IBS and other visceral diseases more effectively.

WHAT IS NEEDED TO FILL THESE GAPS References To further develop SCS as a safe and effective therapy in the treatment of IBS there is an obvious need to perform focused research to understand the

Accarino, A.M., Azpiroz, F. and Malagelada, J.R. (1995) Selective dysfunction of mechanosensitive intestinal afferents in irritable bowel syndrome. Gastroenterology 108: 636–43.

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Al-Chaer, E.D., Feng, Y. and Willis, W.D. (1998) A role for the dorsal column in nociceptive visceral input into the thalamus of primates. J. Neurophysiol. 79 (6): 3143–50. Armour, J.A., Linderoth, B., Arora, R.C., DeJongste, M.J., Ardell, J.L., Kingma, J.G., Jr. et al. (2002) Long-term modulation of the intrinsic cardiac nervous system by spinal cord neurons in normal and ischaemic hearts. Auton. Neurosci. 95 (1-2): 71–9. Bueno, L. and Fioramonti, J. (1999) Effects of inflammatory mediator on gut sensitivity. Can. J. Gastroenterol. 13 (Suppl. A): 42A–46A. Bouin, M., Meunier, P., Riberdy-Poitras, M. and Poitras, P. (2001) Pain hypersensitivity in patients with functional gastrointestinal disorders: a gastrointestinal-specific defect or a general systemic condition? Dig. Dis. Sci. 46: 2542–48. Chandler, M.J., Brennan, T.J., Garrison, D.W., Kim, K.S., Schwartz, P.J. and Foreman, R.D. (1993) A mechanism of cardiac pain suppression by spinal cord stimulation: implications for patients with angina pectoris. Eur. Heart. J. 14 (1): 96–105. Chandler, M.J., Zhang, J., Qin, C. and Foreman, R.D. (2002) Spinal inhibitory effects of cardiopulmonary afferent inputs in monkeys: neuronal processing in high cervical segments. J. Neurophysiol. 87 (3): 1290–302. Chang, L., Mayer, E.A., Johnson, T., Fitzgerald, L.Z. and Naliboff, B. (2000) Differences in somatic perception in female patients with irritable bowel syndrome with and without fibromyalgia. Pain 84: 297–307. Connell, A.M., Jones, F.A. and Rowlands, E.N. (1965) Motility of the pelvic colon. IV. Abdominal pain associated with colonic hypermotility after meals. Gut 6: 105–12. Cook, I.J., Van Eeden, A. and Collins, S.M. (1987) Patients with irritable bowel syndrome have greater pain tolerance than normal subjects. Gastroenterology 93: 727–33. Croom, J.E., Barron, K.W., Chandler, M.J. and Foreman, R.D. (1996) Cutaneous blood flow increases in the rat hindpaw during dorsal column stimulation. Brain Res. 728 (2): 281–6. Foreman, R.D., Beall, J.E., Coulter, J.D. and Willis, W.D. (1976) Effects of dorsal column stimulation on primate spinothalamic tract neurons. J. Neurophysiol. 39 (3): 534–46. Greenwood-Van Meerveld, B., Johnson, A.C., Foreman, R.D. and Linderoth, B. (2003) Attenuation by spinal cord stimulation of a nociceptive reflex generated by colorectal distension in a rat model. Auton. Neurosci. 104 (1): 17–24. Greenwood-Van Meerveld, B., Johnson, A.C., Foreman, R.D. and Linderoth, B. (2005) Spinal cord stimulation attenuates visceromotor reflexes in a rat model of post-inflammatory colonic hypersensitivity. Auton. Neurosci. 122 (1-2): 69–76. Gue, M., Del Rio-Lacheze, C., Eutamene, H., Theodorou, V., Fioramonti, J. and Bueno, L. (1997) Stress-induced visceral hypersensitivity to rectal distension in rats: role of CRF and mast cells. Neurogastroenterol. Motil. 9 (4): 271–9. Gunter, W.D., Shepard, J.D., Foreman, R.D., Myers, D.A. and Greenwood-Van Meerveld, B. (2000) Evidence for visceral hypersensitivity in high-anxiety rats. Physiol. Behav. 69 (3): 379–82. Hirshberg, R.M., Al-Chaer, E.D., Lawand, N.B., Westlund, K.N. and Willis, W.D. (1996) Is there a pathway in the posterior funiculus that signals visceral pain? Pain 67 (2-3): 291–305. Kellow, J.E. and Phillips, S.F. (1987) Altered small bowel motility in irritable bowel syndrome is correlated with symptoms. Gastroenterology 92: 1885–93. Khan, Y.N., Raza, S.S. and Khan, E.A. (2005) Application of spinal cord stimulation for the treatment of abdominal bowel syndrome: a case report. Neuromodulation 8: 14–27. Krames, E. and Mousad, D.G. (2004) Spinal cord stimulation reverses pain and diarrheal episodes of irritable bowel syndrome: a case report. Neuromodulation 7: 82.

Krames, E.S. and Foreman, R.D. (2007) Spinal cord stimulation modulates visceral nociception and hyperalgesia via the spinothalamic tracts and postsynaptic dorsal column pathways: a literature review and hypothesis. Neuromodulation 10: 224–37. Kumar, D. and Wingate, D.L. (1985) The irritable bowel syndrome: a paroxysmal motor disorder. Lancet ii: 973–7. Langlois, A., Pascaud, X., Junien, J.L., Dahl, S.G. and Riviere, P.J. (1996) Response heterogeneity of 5-HT3 receptor antagonists in a rat visceral hypersensitivity model. Eur. J. Pharmacol. 318 (1): 141–4. Lindblom, D., Tapper, D.N. and Wiesenfeld, Z. (1977) The effect of dorsal column stimulation on the nociceptive response of dorsal horn cells and its relevance for pain suppression. Pain 4 (2): 133–44. Linderoth, B. and Foreman, R.D. (1999) Physiology of spinal cord stimulation: review and update. Neuromodulation 2: 150–64. Linderoth, B. and Meyerson, B.A. (2002) Spinal cord stimulation. I. Mechanisms of action. In: K. Burchiel (ed.), Surgical Management of Pain. New York: Thieme. Linderoth, B., Gunasekera, L. and Meyerson, B.A. (1991) Effects of sympathectomy on skin and muscle microcirculation during dorsal column stimulation: animal studies. Neurosurgery 29 (6): 874–9. Linderoth, B., Herregodts, P. and Meyerson, B.A. (1994) Sympathetic mediation of peripheral vasodilation induced by spinal cord stimulation: animal studies of the role of cholinergic and adrenergic receptor subtypes. Neurosurgery 35 (4): 711–19. Linderoth, B., Stiller, C.O., O’Connor, W.T., Hammarstrom, G., Ungerstedt, U. and Brodin, E. (1993) An animal model for the study of brain transmitter release in response to spinal cord stimulation in the awake, freely moving rat: preliminary results from the periaqueductal grey matter. Acta Neurochir. Suppl. (Wien) 58: 156–60. Mayer, E.A. and Gebhart, G.F. (1994) Basic and clinical aspects of visceral hyperalgesia. Gastroenterol. 107: 271–93. Melzack, R. and Wall, P.D. (1965) Pain mechanisms: a new theory. Science 50: 971–9. Mertz, H. (2003) Review article: visceral hypersensitivity. Aliment. Pharmacol. Ther. 17 (5): 623–33. Mertz, H., Naliboff, B., Munakata, J., Niazi, N. and Mayer, E.A. (1995) Altered rectal perception is a biological marker of patients with irritable bowel syndrome. Gastroenterology 109: 40–52. Meyerson, B.A. and Linderoth, B. (1999) Electric stimulation of the central nervous system. In: M. Max (ed.), PAIN 1999 – An Updated Review. Seattle, WA: IASP Press, pp. 269–80. Ness, T.J. (2000) Evidence for ascending visceral nociceptive information in the dorsal midline and lateral spinal cord. Pain 87 (1): 83–8. Ness, T.J. and Gebhart, G.F. (1988) Colorectal distension as a noxious visceral stimulus: physiologic and pharmacologic characterization of pseudaffective reflexes in the rat. Brain Res. 450 (1-2): 153–69. Palecek, J. (2004) The role of dorsal columns pathway in visceral pain. Physiol. Res. 53 (Suppl. 1): I25–S130. Plourde, V., St-Pierre, S. and Quirion, R. (1997) Calcitonin generelated peptide in viscerosensitive response to colorectal distension in rats. Am. J. Physiol. 273 (1 Pt 1): GI91–GI96. Qin, C., Lehew, R.T., Khan, K.A., Wienecke, G.M. and Foreman, R.D. (2007) Spinal cord stimulation modulates intraspinal colorectal visceroreceptive transmission in rats. Neurosci. Res. 58 (1): 58–66. Roza, C. and Reeh, P.W. (2001) Substance P, calcitonin gene related peptide and PGE2 co-released from the mouse colon: a new model to study nociceptive and inflammatory responses in viscera, in vitro. Pain 93 (3): 213–19. Saade, N.E., Tabet, M.S., Banna, N.R., Atweh, S.F. and Jabbur, S.J. (1985) Inhibition of nociceptive evoked activity in spinal neurons

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73 Spinal Cord Stimulation for Gastrointestinal Painful Disorders Leonardo Kapural

O U T L I N E Introduction Epidemiology Model of Pain Transmission in the Abdomen Dorsal Column Pathways in Visceral Nociception Visceral Hyperalgesia

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and the constant need of treatment for chronic abdominal pain presents a significant burden on our healthcare system. Characteristics of visceral pain have been described extensively in the literature as poorly localized, referred to somatic structures, and not evoked by all viscera (Giamberardino and Vecchiet, 1997).

INTRODUCTION Epidemiology Patients’ most common symptoms for seeking medical attention in the USA include back pain, headache, chest pain, abdominal, and knee pain (Koch, 1986). Estimates on the prevalence of abdominal pain have varied from 20 to 46% in the USA (Taylor, 1985; Graney, 2001). In fact, pain is the most prevalent symptom in any gastroenterological clinic (Russo et al., 2004). Patients with chronic abdominal pain often undergo a multitude of imaging studies and surgeries before they are referred to a chronic pain specialist. Despite adequate clinical and laboratory evaluations by multiple physicians, the etiology of some abdominal pains remains elusive. Chronic abdominal pain is debilitating and has significant effects on the patient’s socioeconomic status. Additionally, chronic abdominal pain produces strong affective responses (Derbyshire, 2007). Disability from

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Model of Pain Transmission in the Abdomen Pain from all viscera is poorly localized and referred to somatic structures. Spinal and vagal afferent fibers convey sensory information from the upper gastrointestinal tract to the central nervous system. Vagal afferents transmit predominantly physiological information, while spinal afferents transmit noxious information (Grundy, 2002). The dorsal root ganglia of the spinal nerves contain cell bodies of both vagal and spinal afferents. Vagal afferents enter the brain stem whereas spinal afferents enter the spinal cord, making synaptic connections with second order neurons,

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thereby conveying visceral information to the central nervous system. The ascending spinal pathways project to the thalamic nuclei. Afferent fibers with visceral and somatic information converge onto spinothalamic and spinoreticular pathways. Visceral nociceptors are capable of responding to a variety of noxious stimuli such as mechanical (i.e. abdominal distension) and chemical (i.e. inflammation) stimuli. However, pain is not necessarily evoked from all of the viscera or from visceral injury. Some internal organs lack nociceptors and can be damaged quite extensively without the individual perceiving pain. The role of the dorsal column pathway in transmission/amplification of visceral pain has been described more recently by Palacek and Willis (Palacek and Willis, 2003; Palecek, 2004; Figure 73.1) and its role as participating in the neuromodulation of visceral painful information by spinal cord stimulation has been hypothesized most recently by Krames and Foreman (2007). Still, the spinothalamic tracts are considered to be the major pathways for visceral nociception (Palecek et al., 2003).

non-nociceptive information, specifically large fiber and low threshold mechanical information such as touch. However, recent experiments in animals and humans have significantly challenged this notion. Palecek and Willis recently described and detailed the role of the dorsal columns in the modulation of visceral pain (Palecek and Wilis, 2003; Palecek, 2004; Figure 73.1). Human and animal evidence is growing regarding the role of the dorsal columns in visceral nociception. In 1984, Drs Gildenberg and Hirshberg (Gildenberg and Hirshberg, 1984) reported on a series of 20 patients with cancer, 16 of whom underwent only myelotomy and four underwent myelotomy and unilateral cordotomy. A midline myelotomy was performed in which a small mechanical or radiofrequency lesion was made at the center of the spinal cord. The lesion was created at a single segment at the thoracolumbar junction or at C1. Ten of 14 patients or 71.5% that underwent myelotomy at the thoracolumbar junction only, had satisfactory relief of pain without complications or untoward side effects. In a 1996 study a series of eight patients with refractory pelvic pain underwent limited midline myelotomy at T10. Positive clinical results in all patients were obtained without untoward neurologic sequelae (Hirshberg et al., 1996). Later, Nauta reported a series of six patients with cancer and visceral pain who underwent punctate

Dorsal Column Pathways in Visceral Nociception Traditional teaching has it that the predominant role of the dorsal column system is transmission of

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Spinal Primary afferents

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FIGURE 73.1 Visceral dorsal column (DC) pathway. Midline lesion of DC interrupted primary afferents and axons of PSDC neurons ascending in the DC. Dr Palacek hypothesized that the visceral pain perception is amplified by the descending pathways from medulla. The DC lesion leads to reduction of thalamic activation by visceral stimuli and decreased pain perception. (PAG, periaqueductal gray; RVM, rostroventral medulla; PSDC, postsynaptic dorsal column; STT, spinothalamic tract; DC, dorsal column) (Reproduced with permission from Palecek, 2004. © 2004 Institute of Physiology, Academy of Sciences of the Czech Republic)

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SPINAL CORD STIMULATION FOR VISCERAL PAIN

midline myelotomy. Their periods of clinical follow-up were from 3 to 31 months. Patients were noted to have significant reductions in pain ratings and opioid use (Nauta, 2000). This clinical success of midline myelotomy reported in cancer patients led to further experiments with animals. These experiments were conducted to determine whether there was a visceral nociceptive pathway within the dorsal columns. The results of these studies suggest that the dorsal columns are more important than the ventral lateral columns for modulating nociceptive signals (Hirshberg et al., 1996; Nauta, 2000; Ness, 2000; Palecek, 2004). Additionally, Palecek suggested that the post-synaptic dorsal column pathway is part of an “amplification loop” for nociceptive information (Palecek, 2004). This “amplification loop,” according to Palecek, could possibly lead to potentiation of the responsiveness of spinal cord neurons and responses of different projection neurons within spinothalamic and dorsal column tracts (see Figure 73.1; Palecek, 2004).

Visceral Hyperalgesia The dorsal horn of the spinal cord is critical to the modulation of normal and abnormal sensation. In an animal model of cutaneous hypersensitivity, alterations in the dorsal horn can be induced by peripheral tissue injury. Previously, it was seen that silent nociceptive neurons in the dorsal horn become activated by tissue injury and can remain active after the injury heals (Cervero et al., 1992). Such hypersensitivity can also occur in functional bowel disorders (Moshiree et al., 2006). Spinal hypersensitivity, after tissue injury, is characterized as a leftward shift in pain sensation/ behavior (hyperalgesia) and enlargement of receptive fields within cutaneous areas able to activate the dorsal horn neuron (allodynia). This pattern is analogous to the change in functional bowel disorders, where a leftward shift in the stimulation-pain curve and enlargement of the somatic referral area occurs (Ritchie, 1973; Ness et al., 1990; Whitehead et al.,1990). Central mechanisms may play an important role in visceral sensations. Mechanisms that contribute to peripheral/somatic hyperalgesia/allodynia also play a similar role in the development of visceral hyperalgesia, a phenomenon that has been well demonstrated in animals and humans. Hylden et al. (1989) described this phenomenon in rats. This phenomenon has also been studied in humans and described by other investigators (Cervero et al., 1992). The expansion of convergent cutaneous fields after repetitive distension of a viscus indicates the presence of a central mechanism

875

contributing to the alteration of excitability of central neurons. Repetitive distension of the colon in humans can also lead to an increase in the size of the referred sensation. A change in the quality and increase in the intensity of stimulus has been reported with consecutive colonic distensions. In one particular experiment, 10 consecutive distensions were made at 60 mmHg, 4 minutes apart. The first distension was perceived to be virtually painless, whereas, the tenth distension was perceived to be extremely painful. (Ness et al., 1990). These experiments provide evidence that visceral hyperalgesia may, in fact, be a peripheral visceral manifestation of central sensitization.

SPINAL CORD STIMULATION FOR VISCERAL PAIN Electrical stimulation of the dorsal columns of the spinal cord (or spinal cord stimulation) has been used for many years to treat chronic pain. However, recent technological advances in design and system capabilities make SCS commonly available to treat many, chronic, neuropathic, pain syndromes. Spinal cord stimulation uses low energy current to deliver an electrical field to the spinal cord. In this way, efferent pain signals can be modulated. Because efferents within the post-synaptic dorsal column pathway have the capacity to be modulated and amplified or deamplified, SCS could very likely be an effective way to treat visceral pain (Krames and Foreman, 2007).

SCS in Visceral Pain: Animal Data Greenwood-Van Meerveld et al. (2003) studied the effects of SCS in a rat model of post-inflammatory colonic hypersensitivity. They produced a postinflammatory visceral hypersensitivity state in rats by colonic distension and instillation of trinitrobenzenesulfonic acid, producing sensitization of the nociceptors. A spinal cord stimulation electrode (cathode), combined with a paravertebral anode, was placed on the dorsal surface of the rat L1 dura. The effect of SCS on visceromotor behavioral response (VMR), induced by colorectal distension in normal rats was then studied. These authors found a marked inhibition of the VMR produced by colorectal distension at 60 mmHg after SCS (Figure 73.2). The effect of SCS on VMR induced by colorectal distension following sensitization of the colon with acid was also studied and after SCS there was a significant decrease in the VMR to

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50 ns 40 Contractions/10 min

ns

ns

30

20

p 0.01

10

0 Pre SCS

Post SCS

FIGURE 73.2 Described here by Greenwood-Van Meerveld et al. is a suppression of the visceromotor behavioral response (VMR) produced by 60 mmHg distension of the balloon within the rat’s colon. Repeated rectal distension for 10 min with a 10 min recovery induced marked and reproducible increase in the VMR. After 30 min of SCS, VMR was markedly suppressed despite the continuous stimuli (Reproduced with permission from Greenwood-Van Meerveld et al. (2003). Copyright (2003) Elsevier)

levels that resembled those seen prior to sensitization (Greenwood-Van Meerveld et al., 2003). Also, inhibition of the VMR induced by SCS persisted after the stimulation was terminated, suggesting that stimulation induces mechanisms that require some time for normalization. The authors suggested that such prolonged duration of effect despite cessation of SCS may be caused by rather complex changes in neuronal activity and neurotransmitter release in response to SCS, similar to the effects observed after SCS for persistent angina pectoris and other previously described visceral disorders (Linderoth and Foreman, 1999). Foreman and colleagues have recently presented more of these data (Qin et al., 2007). Using the same model of colorectal distension in rats, Qin et al. were able to suppress the responses of lumbosacral spinal neurons to noxious colorectal stimuli by SCS of the lumbar or cervical dorsal column. These authors suggest that such reflex suppression by SCS may be the result of antidromic activation of primary afferent fibers within the dorsal column (Qin et al., 2007).

SCS in Visceral Pain: Possible Mechanisms of Pain Relief in Humans Possible mechanisms involved in suppression of visceral abdominal and pelvic pain in humans by SCS

remain unclear. Animal studies suggested (see SCS in visceral pain: animal data) antidromic activation of primary efferent fibers within the dorsal columns as one of the possible mechanisms of visceral pain suppression (Qin et al., 2007). Spinal gating mechanisms (Melzack and Wall, 1965) might also be operant as an explanation for the reduction in pain transmission of small diameter visceral fibers by stimulating large afferents using relatively low-intensity electrical stimulation (Melzack and Wall, 1965). It remains to this day unclear whether neural modulation by SCS, relieving visceral pelvic pain, is operant at the recently described midline dorsal column pathway, however, it is known that interruption of this pathway relieves visceral pelvic pain in cancer patients (Gildenberg and Hirshberg, 1984; Hirshberg et al., 1996; Nauta, 2000; Ness, 2000; Palecek and Willis, 2003; Palecek, 2004). It is not clear, however, at this time whether this pathway and “amplification loop” can be modulated, excited or suppressed by SCS. Suppression of the sympathetic outflow could play a significant role in control of the abdominal visceral pain (Steege, 1998). Significant pain relief is achieved with chemical or surgical neurectomy/sympathectomy involving the superior hypogastric or celiac plexus (Rauck, 1992; Steege, 1998). Segmental and supraspinal downregulation of the sympathetic nervous system has been proposed as an important mechanism of pain suppression in intractable angina (Linderoth and Foreman, 2006). It may be that segmental suppression of sympathetic outflow by SCS plays a role in suppression of chronic visceral abdominal pain (Kapural et al., 2006; Khan et al., 2006) as well.

SCS in Visceral Pain: Human Data Currently, studies on the use of SCS for treatment of visceral pain are limited to case reports or case series (Table 73.1). There are compelling data that suggest SCS may decrease pain and improve functional capacity in patients with various visceral chronic pain syndromes. It may require years, however, to accumulate sufficient clinical evidence, particularly type A evidence. The first report of SCS for the treatment of abdominal pain came from Ceballos and coworkers, who described the case of a 78-year-old male with chronic, unrelieved pain due to mesenteric ischemia. The patient had severe postprandial pain relieved with a celiac plexus local anesthetic block for only a short period of time. He experienced full pain relief after an SCS lead was placed epidurally at T6 with the stimulation from SCS activation producing abdominal paresthesiae (Ceballos et al., 2000).

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TABLE 73.1

Abdominal visceral pain conditions where SCS could be effective

Conditions treated with SCS

Study

Irritable bowel syndrome Chronic non-alcoholic pancreatitis

Krames and Mousad, 2005 Khan et al., 2005; Kapural and Rakic, 2007

Post-traumatic splenectomy Generalized chronic abdominal pain Pelvic visceral pain Familial Mediterranean Fever Mesenteric ischemia Gastroparesis Esophageal pain

Khan et al., 2005 Khan et al., 2005

Kapural SCS implant

877 Clev clinicpain mgmt.

Kapural et al., 2006 Kapur et al., 2006 Ceballos et al., 2000 Tiede et al., 2006 Jackson and Simpson, 2004

Krames and Mousad (2005), extrapolating the evidence from the model of visceral hyperalgesia, as described by Greenwood-Van Meerveld et al. (2003), applied SCS of the thoracic cord to a patient with irritable bowel syndrome (IBS). They described a case involving a 43-year-old female who suffered from 11–14 daily diarrheal episodes per day and extreme pain from IBS, who, after placement of a thoracic SCS system, became immediately diarrhea-free, although the initial reduction in pain relief was not sustained. This patient did not experience abdominal paresthesiae, but experienced paresthesia into her distal extremities with her stimulation. These authors thought that abdominal paresthesiae were an epiphenomenon and not necessary for visceral pain control. The patient, at some later point, had an intrathecal pump implanted for abdominal pain control. Still, this patient was extremely satisfied with the frequency reduction of daily diarrheal episodes when using her SCS system (Krames and Mousad, 2005). Khan et al. (2005) described a series of nine patients with abdominal pains due to various conditions including non-visceral truncal pains that were treated with SCS. Five of the treated patients were diagnosed with non-alcoholic pancreatitis. Overall, there was a mean decrease of 4.9 points in the VAS scores for pain intensity and a greater than 50% decrease in narcotic use. Both single and dual leads were used with the lead tips placed at the T5–T7 vertebral height in the posterior epidural space (Khan et al., 2005). Contrary to the opinion of Mousad and Krames, Khan opined that paresthesiae to the abdomen were necessary for abdominal pain control. To challenge Dr Khan’s observations that SCS is an effective treatment for non-alcoholic pancreatitis the present authors performed SCS on a 38-year-old female patient after a differential retrograde epidural

91 kVp 1.73 mA 11

52 51

FIGURE 73.3

Two spinal cord stimulation octrode leads, appropriately positioned within the epidural space (tips positioned at top of T6 vertebral body). Such placement appears to be common during SCS for epigastric pains

block (block that may differentiate visceral from somatosensory or central pain) and celiac plexus block confirmed that the source of her abdominal pain was completely visceral. She had a long-standing (13 year) history of chronic abdominal pain as well as multiple surgeries including 22 ERCPs (endoscopic retrograde cholangiopancreatography). Two epidural octopolar leads with the tips positioned at the T6 level were implanted (see Figure 73.3). There was an improvement in functional capacity, measure by the Pain Disability Index (PDI) from 64 to 19 and the VAS pain score decreased from 8 to 1 (Kapural and Rakic, 2007). This pain relief and improvements in function were maintained over the patient’s entire first year of stimulation. There are a few more reports on the treatment of epigastric visceral and esophageal chronic pain using SCS. Tiede et al. described improvements in pain scores after SCS was implanted in two patients with complex medical histories and generalized abdominal pain (Tiede et al., 2006). Jackson and Simpson (2004) reported improved pain control and swallowing in a patient with a rather complicated history of esophageal problems. A most recent published report describes two cases of Familial Mediterranean Fever (FMF) where painful abdominal intermittent attacks responded positively to SCS at T8–9 and T7–8 respectively. Because painful episodes in patients with FMF

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10

60 PDI score

VAS score

8 6 4

20

2 0 (A)

40

0 Pre SCS

Post SCS

(B)

Pre SCS

Post SCS

FIGURE 73.4 The improvements in (A) pain score (VAS) and (B) functional capacity (PDI) in six women treated with SCS for pelvic visceral pain (Used with permission from Kapural et al. (2006). John Wiley & Sons Ltd)

come in waves and cannot be predicted, the spectre of intermittent use, not continuous use of SCS, is raised by these two cases. Significant pain relief was sustained for longer than 3 years in one case and 3 months in the other. Both patients were weaned off their opioids. One of the most challenging chronic visceral pain syndromes to treat is the pelvic pain syndrome. The first reported case series on the use of SCS for treatment of visceral pelvic pain were on six female patients with the diagnosis of long-standing pelvic pain secondary to long-standing endometriosis. Most of the patients were found to have multiple pelvic adhesions for which they were unsuccessfully surgically treated. The position of the lead tip was at T12–L1 spinal level and frequently two leads were used. The median VAS pain score decreased from 8 to 3; all patients had more than 50% pain relief. Pain disability index (PDI), as measurement of patient’s functional capacity, improved significantly (see Figure 73.4). Opiate use also decreased in long-term followup (Kapural et al., 2006). So, having reported on the literature of both animal and human data regarding the use of SCS for chronic visceral pain, the appropriate place for SCS within a pain treatment continuum for the treatment of chronic visceral painful disorders, today, is still unclear. The treatment of these disorders, directed at reducing pain and improving emotional and functional capacity, should be individualized. Following a multidisciplinary evaluation, which should include, but should not be limited to, a medical evaluation for localizing pain generators and medical co-morbidities and cognitive and functional capacity evaluations, an interdisciplinary treatment plan should be established. Treatments for visceral painful disorder include cognitive and behavioral therapies for reducing stressors and improving coping styles, functional restoration

for disuse and exercise, pharmacologic pain management that should include the use of opioids, membrane stabilizers and antidepressants for analgesia, adjuvant therapies for co-morbidities including the management of sleep disturbances, nausea/vomiting, diarrhea, etc., and interventional diagnostic and therapeutic nerve blocks including retrograde epidural differential block, splanchnic, celiac plexus and hypogastric blocks. Based on the evidence from animal models and the limited human experience reported in the literature, SCS might be indicated when conservative therapies as listed above fail to improve analgesia and function. Psychological evaluation for implantable devices and case discussion within the interdisciplinary medical team should precede SCS trialing. Further studies are needed to establish proper place of SCS in the visceral pain treatment continuum.

CONCLUSIONS Based on the animal preclinical and human data presented here, spinal cord stimulation for abdominal and pelvic visceral pain is a new and exciting therapeutic option for the millions of people who suffer from severe visceral pain. The importance of the dorsal column post-synaptic pathway in mediating visceral pain has only recently been elucidated and its role, if any, in modulating visceral nociception still needs to be proven. Case series have reported encouraging results with the clinical use of spinal cord stimulation for visceral painful disorders. The data in support of SCS for visceral pain presently are encouraging. However no randomized controlled trials are available to support the use of SCS for visceral pain. Exciting new studies providing class A evidence need to be initiated in order to support the role of SCS for visceral pain.

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REFERENCES

References Ceballos, A., Cabezudo, L., Bovaira, M., Fenollosa, P. and Moro, B. (2000) Spinal cord stimulation: a possible therapeutic alternative for chronic mesenteric ischaemia. Pain 87 (1): 99–101. Cervero, F., Laird, J.M.A. and Pozo, M.A. (1992) Selective changes of receptive field properties of spinal nociceptive neurons induced by noxious visceral stimulation in the cat. Pain 51: 335–42. Derbyshire, S.W. (2007) Imaging visceral pain. Curr. Pain Headache Rep. 11 (3): 178–82. Giamberardino, M.A. and Vecchiet, L. (1997) Pathophysiology of visceral pain. Curr. Pain and Headache Rep. 1: 23–33. Gildenberg, P.L. and Hirshberg, R.M. (1984) Limited myelotomy for the treatment of intractable cancer pain. J. Neurol. Neurosurg. Psych. 47 (1): 94–6. Graney, D.O. (2001) General considerations of abdominal pain. In: J.D. Loesser (ed.), Bonica’s Management of Pain, 3rd edn. Philadelphia, PA: Lippincott, Williams & Williams, pp. 1235–68. Greenwood-Van Meerveld, B., Johnson, A.C., Foreman, R.D. and Linderoth, B. (2003) Attenuation by spinal cord stimulation of a nociceptive reflex generated by colorectal distension in a rat model. Auton. Neurosci. Basic Clin. 104: 17–24. Grundy, D. (2002) Neuroanatomy of visceral nociception: vagal and splanchnic afferent. Gut 51 (Suppl. I): 2–5. Hirshberg, R.M., Al-Chaer, E.D., Lawand, N.B., Westlund, K.N. and Willis, W.D. (1996) Is there a pathway in the posterior funiculus that signals visceral pain? Pain 67: 291–305. Hylden, J.L.K., Nahin, R.L., Traub, R.J. and Dubner, R. (1989) Expansion of receptive fields of spinal lamina I projection neurons in rats with unilateral adjuvant-induced inflammation: the contribution of dorsal horn mechanisms. Pain 37: 229–43. Jackson, M. and Simpson, K.H. (2004) Spinal cord stimulation in a patient with persistent oesophageal pain. Pain 112: 406–8. Kapur, S., Mutagi, H. and Raphael, J. (2006) Spinal cord stimulation for relief of abdominal pain in two patients with familial Mediterranean fever. Br. J. Anaesth. 97: 866–8. Kapural, L. and Rakic, M. (2007) Spinal cord stimulation for chronic visceral pain secondary to chronic non-alcoholic pancreatitis: a case report. Clin. Gastroenterol. Hepatol. 42 (6): 750–1. Kapural, L., Narouze, S.N., Janicki, T.I. and Mekhail, N. (2006) Spinal cord stimulation is an effective treatment for the chronic intractable visceral pelvic pain. Pain Med. 7 (5): 440–3. Khan, Y., Raza, S. and Khan, E. (2005) Application of spinal cord stimulation for the treatment of abdominal visceral pain syndromes: case reports. Neuromodulation 8: 14–27. Khan, Y.N., Raza, S.S. and Khan, E.A. (2006) Spinal cord stimulation in visceral pathologies. Pain Med. 7 (s1): S121–S125. Krames, E.S. and Foreman, R. (2007) Spinal cord stimulation modulates visceral nociception and hyperalgesia via the spinothalamic tracts and the postsynaptic dorsal column pathways: a literature review and hypothesis. Neuromodulation 10 (3): 224–37. Krames, E. and Mousad, D.G. (2005) Spinal cord stimulation reverses pain and diarrheal episodes of irritable bowel syndrome: a case report. Neuromodulation 8: 82–8.

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Koch, H. and National Center for Health Statistics (1986) The management of chronic pain in office-based ambulatory care: National Ambulatory Medical Care Survey. In: Adv. Data Vital Health Stat. No. 123. DHHS Pub. No. (PHS). Hyattsville, MD: Public Health Service, pp. 86–1250. Linderoth, B. and Foreman, R.D. (1999) Physiology of spinal cord stimulation: review and update. Neuromodulation 2: 150–64. Linderoth, B. and Foreman, R.D. (2006) Mechanisms of spinal cord stimulation in painful syndromes: role of animal models. Pain Med. 7 (S1): S14–S26. Melzack, R. and Wall, P.D. (1965) Pain mechanisms: a new theory. Science 150: 971–9. Moshiree, B., Zhou, Q., Price, D.D. and Verne, G.N. (2006) Central sensitisation in visceral pain disorders. Gut 55: 905–8. Nauta, H.J. (2000) Punctate midline myelotomy for the relief of visceral cancer pain. J. Neurosurg. 92 (2S): 125–30. Ness, T.J. (2000) Evidence for ascending visceral nociceptive information in the dorsal midline and lateral spinal cord. Pain 87 (1): 83–8. Ness, T.J., Metcalf, A.M. and Gebhart, G.F. (1990) A psychophysiological study in humans using phasic colonic distension as a noxious visceral stimulus. Pain 43: 377–86. Palecek, J. (2004) The role of dorsal columns pathway in visceral pain. Physiol. Res. 53 (Suppl. 1): S125–S130. Palecek, J. and Willis, D. (2003) The dorsal column pathway facilitates visceromotor responses to colorectal distension after colon inflammation in rats. Pain 104 (3): 501–7. Palecek, J., Paleckova, V. and Willis, W.D. (2003) Fos expression in spinothalamic and postsynaptic dorsal column neurons following noxious visceral and cutaneous stimuli. Pain 104 (1-2): 249–57. Rauck, R.L. (1992) Sympathetic nerve blocks. In: P.P. Raj (ed.), Practical Management of Pain, 2nd edn. St Louis, MI: Mosby Year Book, pp. 778–812. Ritchie, J. (1973) Pain from distension of the pelvic colon by inflating a balloon in the irritable colon syndrome. Gut 14 (2): 125–32. Qin, C., Lehew, R.T., Khan, K.A., Wienecke, G.M. and Foreman, R.D. (2007) Spinal cord stimulation modulates intraspinal colorectal visceroreceptive transmission in rats. Neurosci. Res. 58: 58–66. Russo, M.W., Wei, J.T., Thiny, M.T., Gangarosa, L.M., Brown, A., Ringel, Y. et al. (2004) Digestive and liver diseases statistics. Gastroenterology 126: 1448–53. Steege, J.F. (1998) Superior hypogastric block during microlaparoscopic pain mapping. J. Am. Assoc. Gynecol. Laparosc. 5: 265–7. Taylor, H.S. (1985) The Nuprin Pain Report. New York, NY: Lou Harris Associates. Tiede, J.M., Ghazi, S.M., Lamer, T.J. and Obray, J.B. (2006) The use of spinal cord stimulation in refractory abdominal visceral pain: case reports and literature review. Pain Practice 6 (3): 197–202. Whitehead, W.E., Holtkotter, B., Enck, P., Hoelzl, R., Holmes, K.D., Anthony, J. et al. (1990) Tolerance for rectosigmoid distension in irritable bowel syndrome. Gastroenterology 98 (5 Pt 1): 1187–92.

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C H A P T E R

74 Gastric Stimulation for Dysmotility Disorders and Obesity Cristian Sevcencu

O U T L I N E Historical Perspective Gastric Stimulation to Activate Gastric Transit Gastric Stimulation to Induce Weight Loss Gastric Stimulation for the Treatment of Gastroparesis and Obesity Stomach Anatomy and Mechanisms of Gastric Propulsion Gastroparesis and Obesity Rationale for Neuromodulation Target and Approach Indications and Patient Selection Criteria Implant Procedure and Stimulation Parameters

881 881 882

Implant Procedure Details Programming and Stimulation Parameters

882 882 883 883 884 884

HISTORICAL PERSPECTIVE

Gastric Stimulation – Present and Future Outcomes Mechanisms Activated by Electrical Stimulation of the Stomach Complications and Contraindications What the Future Holds

886 886

Conclusions

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References

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colleagues were the first who stimulated the human stomach with electrodes placed in the gastric wall (intramural stimulation) (Miedema et al., 1992). This method was further developed and applied with good results in patients with gastroparesis to attenuate symptoms such as nausea, vomiting and pain (Sevcencu, 2007a). In 1996, the gastric electrical stimulation therapy (GES, also called “Enterra Therapy”, Medtronic Inc., Minneapolis, MN) received approval from the US Food and Drug Administration (FDA) through a “humanitarian device exemption” (applicable to devices intended to be implanted in less than 4000 patients). Since then, numerous clinical studies have shown that GES is able to improve the quality of life in patients with various types of drug-resistant gastroparesis (Zhang and Chen, 2006).

Gastric Stimulation to Activate Gastric Transit The first attempts to stimulate the stomach for therapeutic purposes were made in 1963 by Bilgutay and colleagues, who reported increased gastric emptying in patients subjected to stimulation with electrodes placed in the luminal cavity of the stomach (intraluminal stimulation) (Bilgutay et al., 1963). In the years that followed, various gastric stimulation patterns have been used in animal models to activate the spontaneous electrical activity of the stomach, accelerate gastric emptying, and attenuate adverse symptoms such as vomiting (see for review Sevcencu, 2007a). In 1992, Miedema and

Neuromodulation

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881

2009 Elsevier Ltd. © 2008,

882

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Gastric Stimulation to Induce Weight Loss In 1996, Cigaina and coauthors published the first results showing that gastric stimulation is able to inhibit feeding (Cigaina et al., 1996). The authors observed that stimulation of the gastric antrum in pigs decreased the food intake and induced weight loss in the animals. Based on these results, Cigaina investigated the possibility of using gastric stimulation to reduce food intake in humans. In 1995, Cigaina implanted the first four obese patients out of a total of 24 with gastric stimulation electrodes. After more than 3 years of experiments, it was concluded that electrical stimulation of the stomach changed the feeding behavior of these patients, which resulted in decreased food intake and weight loss (Cigaina, 2002). Similar successful results with gastric stimulation to induce weight loss were obtained later in various other studies on human subjects (Miller et al., 2002, 2006). As a result, an implantable gastric stimulator (IGS, Medtronic Inc., Minneapolis, MN), although not yet approved for clinical use, has been registered by the FDA as an investigational device for obesity treatment (Abell et al., 2006).

Esophagus Fundus

Lesser curvature

Corpus

Electrodes for obesity treatment

Greater curvature

Duodenum Electrodes for gastroparesis treatment Main pacemaker region Pylorus

Antrum

(A) Serosa

Longitudinal muscles

GASTRIC STIMULATION FOR THE TREATMENT OF GASTROPARESIS AND OBESITY

Circular muscles

Oblique muscles (B)

Stomach Anatomy and Mechanisms of Gastric Propulsion

FIGURE 74.1 Stomach anatomy and electrodes positioning. (A)

The stomach consists of four anatomical regions: the fundus, the corpus, the antrum, and the pylorus (Figure 74.1a). The right (lateral) side of the stomach is called the greater curvature and the left (medial) side is called the lesser curvature. Histologically, the stomach wall consists of three layers: the gastric mucosa (the innermost), the muscular wall, and the gastric serosa (the outermost). The muscular wall of the stomach is thick, and is comprised of three layers (Figure 74.1b): the outer longitudinal layer, the middle circular layer, and an internal oblique layer, which is present only at the distal part of the stomach. The stomach musculature is responsible for the adaptive relaxation of the stomach during feeding, for mixing gastric contents, and for propelling chyme into the duodenum when gastric digestion is complete. Gastric propulsion is supported by peristaltic reflexes, which consist of coordinated contraction and relaxation of the longitudinal and circular muscles from consecutive gastric segments (Wood et al., 1999). Peristaltic reflexes are triggered and modulated by intrinsic excitatory and inhibitory neurons, which are

located in the gastric wall and belong to the enteric nervous system (ENS) (Wood et al., 1999). These neurons activate and inhibit contraction of the gastric muscles by releasing excitatory neurotransmitters such as acetylcholine (ACh) (Yokotani et al., 1993), and inhibitory neurotransmitters such as nitric oxide (NO) (Yoneda and Suzuki, 2001). To regulate motor activity of the stomach, the ENS neurons receive central inputs through sympathetic and parasympathetic fibers and interact with non-neural components, such as gastrointestinal hormones and the interstitial cells of Cajal (Figure 74.2). Thus, stimulation of cholinergic fibers results in the release of cholecystokinin, which is one of the hormones that modulates gastric motility and the activity of the enteric neurons (Katschinski et al., 1995; Vergara et al., 1996). The interstitial cells of Cajal (ICC) are pacemaker cells, which regulate the basal electrical rhythm within

Anatomical regions of the stomach and location of the electrodes used for gastric stimulation. (B) Schematic representation of the gastric muscles

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GASTRIC STIMULATION FOR THE TREATMENT OF GASTROPARESIS AND OBESITY

Sy

883

Psy

Secretory cells

Cajal cells

Cajal cells

Muscle cells

Inhibitory motor neurons

Excitatory motor neurons

Intermediary neurons

Sensory neurons

Distension

FIGURE 74.2

Chemical agents

Extrinsic and intrinsic components that control the activity of the gastric muscle cells. Sy, sympathetic system; Psy, parasym-

pathetic system (Reproduced from Sevcencu, 2007b, by permission the International Modulation Society and Blackwell Publishing)

gastric muscles by generating pacemaker potentials. These pacemaker potentials develop into depolarization waves (usually called “slow gastric waves” or “pacesetter potentials”) that support spike potentials which activate muscle cells and initiate contraction (Lee et al., 1999; Wood et al., 1999). As studies have shown, the ICC can be activated or inhibited through inputs from extrinsic or intrinsic gastric nerves, and this may change the activity of the gastric muscles (Hirst et al., 2002).

Gastroparesis and Obesity Dysfunction of the gastric muscles and/or the mechanisms controlling gastric motility results in gastroparesis. This disease is characterized by delayed gastric emptying and symptoms such as nausea, vomiting, abdominal pain, and/or early satiety. Gastroparesis may be caused by various conditions such as abdominal surgery (postoperative gastroparesis), metabolic disorders (diabetes, hypothyroidism, renal failure), rheumatologic conditions (scleroderma and systemic lupus erythematosus), neurological disorders (Parkinson’s disease), and infections (Epstein–Barr virus) (Rabine and Barnett, 2001; Zhang and Chen, 2006). About 25–35% of the patients with

gastroparesis have no apparent etiology and are diagnosed with idiopathic gastroparesis. Unlike gastroparesis, obesity does not originate from impaired stomach motility, but from excessive consumption of food and alcohol. Among the causes that lead to excessive weight gain, genetic, environmental, and psychological factors are the most common. Besides these most common causes, obesity may result from diseases such as hypothyroidism and Cushing’s disease, or from treatment with medications such as steroids, opioids, and antidepressants. A person is considered obese when her or his body mass index (BMI, equal to weight [kg] divided by height [m] squared) is greater than 30. Patients with BMI greater than 40 have morbid obesity and are subjected to a high risk of morbidity and mortality due to diabetes, stroke, heart disease, high blood pressure, high cholesterol, and kidney and gallbladder disease.

Rationale for Neuromodulation Target and Approach As shown above, the gastric wall is comprised of several types of excitable cells, which are all susceptible

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to depolarization by current pulses applied to the stomach. Whether the stomach reacts to stimulation by contraction or relaxation depends on the stimulated structure, the pulse parameters, and the location of the electrodes relative to the anatomical region of the organ (Sevcencu, 2007b). As mentioned above, the basal electrical rhythm within gastric muscles is regulated by the interstitial cells of Cajal. Although these pacemaker cells are present in all gastric regions, the pacemaker site which dominates the motor activity of the stomach (highest density of pacemaker cells with the fastest firing rate) is located in the corpus (Suzuki, 2000). Consequently, the slow gastric waves that drive gastric transit are generated within the corpus and spread distally towards the pylorus. While gastric stimulation to activate gastric emptying should therefore target the corpus (proximal stimulation), electrical stimulation that is applied to distal gastric locations (the antrum or the pylorus) generates anti-peristalsis and inhibits gastric emptying. Indeed, experiments in animal and human models have shown that proximal gastric stimulation with electrodes located at the greater curvature of the stomach entrains slow wave activity that activates gastric transit (Lin et al., 1998), while stimulation of the gastric antrum reverses the antral peristalsis and delays gastric emptying (Eagon and Kelly, 1993). Typically, gastric stimulation is currently performed with electrodes implanted at the greater curvature in patients with gastroparesis, and at the lesser curvature to inhibit gastric transit and induce satiety in obese patients.

Indications and Patient Selection Criteria Present conservative medical management therapies for gastroparesis use pharmacologic prokinetics to accelerate gastric emptying and antiemetic drugs to control symptoms. However, many patients with gastroparesis do not respond properly to these medications, and there are many others who do not tolerate these therapies because their inherent toxicities produce side effects (Rabine and Barnett, 2001). At present, in such clinical situations where medications are ineffective and/or produce too many side effects, the gastroparetic stomach is either bypassed using jejunostomy tubes for artificial feeding and hydration, or subtotally removed to improve gastric emptying. Stomach bypassing or resection (bariatric surgery) are also “last resort” options when dietary restrictions and medications fail to improve morbid obesity. However, these surgical procedures applied in patients with morbid obesity are associated with high risks of mortality and morbidity. Therefore, they are restricted to patients

with BMI greater than 40, or those with BMI of 35 to 39, who, otherwise, are exposed to life-threatening risks as a result of their obesity (Saber, 2004; Champion et al., 2006). As studies have shown, electrical stimulation of the stomach attenuates gastroparesis symptoms, or changes the feeding behavior in obese patients even when medication fails to induce these effects. Therefore, Enterra (Medtronic, Inc., Minneapolis, MN) Therapy (GES) is presently recommended for use in patients with chronic, drug-refractory nausea and vomiting secondary to gastroparesis of diabetic or idiopathic etiology (www.medtronic.com), and the implantable gastric stimulator (IGS) in patients with morbid obesity. However, the patient populations that can benefit from gastric stimulation therapy still need to be defined, and a set of selection criteria for such patients does not exist yet. For example, gastric stimulation to reduce body weight is exclusively applied in patients with morbid obesity. Yet, this therapy may also be beneficial for patients with low BMI to prevent further increase in their body weight (Champion et al., 2006). On the other hand, not all of the patients subjected to gastric stimulation respond properly to this therapy, and screening methods to select subjects for chronic implantation of gastric stimulators are currently under investigation (Liu et al., 2006).

Implant Procedure and Stimulation Parameters Implant Procedure Details A fully implantable gastric stimulator consists of the leads and a pulse generator. Presently, monopolar leads are used for gastroparesis treatment and bipolar leads for obesity treatment. In patients with gastroparesis, two monopolar leads are implanted on the greater curvature of the stomach, at about 10 cm proximal to the pylorus. These two electrodes are inserted approximately 10 mm apart and parallel, one to the other. When gastric stimulation is performed in patients with obesity, either one (Miller et al., 2002) or two (Champion et al., 2006) bipolar leads are placed at the lesser curvature of the stomach. Independent of the number and the location of the leads (obesity/paresis), the procedures used for their implantation are similar. The ski needle at the tip of the electrode (see Figure 74.3a) is used to penetrate the gastric serosa and pull the electrode into the muscular layer of the stomach (see Figure 74.3b). After the needle is detached from the lead (see Figure 74.3c), the electrode is secured with two sutures, one at the proximal penetration point (see Figure 74.3d), and the other at the distal end of the electrode (see Figure 74.3e). The electrode leads are

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FIGURE 74.3 The electrode lead and surgical implantation of its active site in the gastric wall: (a) the electrode lead (modified from www. medtronic.com); (b) insertion of the needle in the gastric wall; (c) the needle is detached from the lead; (d) securing of the electrode at the penetration point; (e) securing of the distal end of the electrode (Reproduced with permission from Miller et al., 2002. © Georg Thieme Verlag KG, Stuttgart)

then connected to the pulse generator, which is placed in a subcutaneous pocket within the superficial layers of the abdomen (Lonroth and Abrahamsson, 2004). Currently, either an open surgery technique or a laparoscopic technique are employed for electrodes implantation (Miller et al., 2002; Lonroth and Abrahamsson, 2004). In the open surgical technique, the electrodes are implanted through an upper midline incision. The laparoscopic implantation of the electrodes requires 3–6 ports (Miller et al., 2002; Lonroth and Abrahamsson, 2004). Penetration of the gastric wall and fixation of the electrodes are the same in the two techniques. Programming and Stimulation Parameters The commercially available pulse generator for gastric stimulation (ITREL 3 Model 7425G Neurostimulator, Medtronic Inc., Minneapolis, MN) is a battery-powered implantable stimulator with a battery life estimated to be between 5 and 10 years for gastroparesis treatment and 4–5 years for obesity treatment (www.medtronic. com). Depending on the level of electrical stimulation

appropriate for the patient, the pulse generator is programmed using an external programmer, which consists of the Model 7432 Physician Programmer and the Model 7457 MemoryMod Software Cartridge (Medtronic Inc., Minneapolis, MN). Gastric stimulation is currently performed using rectangular pulses with constant current. Although most of the studies with gastric stimulation have been performed using pulses with pulse duration in the order of milliseconds (Figure 74.4a), no implantable device able to generate pulses longer than 2 ms is currently available on the market (Zhang and Chen, 2006). Instead, the currently used gastric stimulators are capable of generating short pulses (1 ms, Figure 74.4b), and these short pulses are delivered in trains with various number of pulses and inter-pulse duration (Figure 74.4c) (Zhang and Chen, 2006). The standard Enterra Therapy for the treatment of gastroparesis (Medtronic Inc., Minneapolis, MN) is performed using one pair of about 5 mA, 0.3 ms pulses delivered at an interval of 72 ms. These two pulses are repeated every 5 s.

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10–600 ms

(A)

Long pulse ~300 μs

(B)

Short pulse

x sec ‘on’ (C)

y sec ‘off’ Trains of short pulses

FIGURE 74.4 Shape and duration of pulses used for gastric stimulation (Reproduced from Zhang and Chen, 2006. © Wiley–Blackwell)

The current gastric stimulation pattern for obesity treatment (IGS, Medtronic Inc., Minneapolis, MN) uses trains of pulses with the following parameters: pulse amplitude, 5–10 mA; pulse duration, approximately 0.3 ms; pulse rate within a pulse train, 40 Hz; train “on” time, 2 s; train “off” time, 3 s (Zhang and Chen, 2006).

GASTRIC STIMULATION – PRESENT AND FUTURE Outcomes As reviewed by Zhang and Chen (2006), Enterra Therapy reduces the number of hospitalizations, reduces the use of medications and improves the quality of life in patients with drug-refractory diabetic, idiopathic or post-surgical gastroparesis (Abell et al., 2002, 2003). In 2005, a comparative study conducted for three years on 18 patients with gastroparesis concluded that electrical stimulation is superior to the pharmacological approach when treating gastroparesis, with respect to both efficiency and costs (Cutts et al., 2005). The most significant achievement with this therapy is an important attenuation of nausea and vomiting. This was first shown by Familoni and colleagues, who reported significant reduction of nausea, vomiting,

and pain in a patient subjected to stimulation using 2 mA, 0.3 ms, 0.2 Hz pulses (Familoni et al., 1997). These findings were later confirmed in clinical studies involving large groups of gastroparetic patients, where stimulation was performed using similar values for pulse parameters, resulting in major attenuation of nausea and vomiting (Abell et al., 2002; Abell et al., 2003). After performing his first experiments in pigs (Cigaina et al., 1996) and testing the stimulation methods in humans (Cigaina, 2002; Cigaina and Hirschberg, 2003), Cigaina published, in 2004, a summary of the results obtained with gastric stimulation in 65 obese patients included in a 10 years project (Cigaina, 2004). In all of these subjects, the major result was a change in the feeding behavior leading to significant weight loss. This was accompanied by attenuation of gastroesophageal reflux symptoms in patients with gastroesophageal reflux disease, and a decrease of blood pressure in hypertensive patients. More recently, Miller et al. (2006) reported the results of the Laparoscopic Obesity Stimulation Survey (LOSS), a complex multicentered study which was conducted in 16 European hospitals. A total of 91 patients with an average weight of 116 kg were involved in this study and all underwent implantation of gastric stimulators for their obesity. The mean excess weight loss in these patients was 20% at 12 months after the surgery and 25% at 2 years after implantation, which is similar to the results obtained in the DIGEST study (DualLead Implantable Gastric Electrical Stimulation Trial), conducted in the United States on 30 patients (Abell et al., 2006). Although successful, all of these studies were open-label studies and therefore placebo effects on the reported weight loss are possible, too.

Mechanisms Activated by Electrical Stimulation of the Stomach Electrical stimulation of gastric strips (Smits and Lefebvre, 1996), or of the gastric wall in in vivo studies (Yokota et al., 1997), results in ACh release from enteric neurons, which in turn triggers contraction. While current pulses shorter than 10 ms seem to activate muscles through neural activation exclusively (Sakai and Daniel, 1984; Mintchev et al., 1998), it is likely that current pulses longer than 10 ms, besides activating enteric neurons, directly depolarize muscle cells. Electrical stimulation of gastric muscles can also induce relaxation, which is mediated through NO transmission (Todorov et al., 2003; Xing et al., 2003; Xing and Chen, 2006). In addition to directly acting on the muscle membranes, NO also activates adrenergic fibers, which consequently amplifies muscle inhibition and gastric relaxation (Sotirov and Papasova, 2000).

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Whether the stomach reacts by contraction or relaxation to electrical stimulation seems to depend on stimulation frequencies used. Yoneda and Suzuki (2001) stimulated muscle strips dissected from guineapig stomach and evoked cholinergic excitatory junction potentials when using 0.5 Hz pulses. Increasing the stimulation rate to higher than 1 Hz resulted in the activation of NO-releasing fibers, which, in turn, inhibited the excitatory junction potentials. As shown above, the tonic activity of gastric muscles is driven by slow depolarization waves, and several studies investigated the effects of electrical stimulation on gastric slow wave activity. In 1974, Kelly was the first who reported that stimulation of the stomach in dogs entrained gastric slow waves (Kelly, 1974). Since then, several authors observed that improvement of gastric emptying or symptoms in response to electrical stimulation in both animals (Sarna et al., 1976; Qian et al., 1999) and humans (Lin et al., 1998; McCallum et al., 1998) was accompanied by changes in gastric slow wave activity. Since slow waves are generated by the ICC, at least some of the motor effects induced by electrical stimulation of the stomach could be mediated by changes in the ICC pacemaker activity. Besides activating enteric neurons, ICC or muscle cells directly, electrical stimulation of the stomach may also activate sympathetic and parasympathetic terminals within the gastric wall. Yokotani et al. (1998) report that stimulation of periarterial nerves in the isolated rat stomach induces noradrenaline release from sympathetic fibers. This observation was later confirmed by studies in dogs, which showed that gastric stimulation inhibits postprandial gastric contractions (Zhu and Chen, 2005) and antral motility (Ouyang et al., 2005) through sympathetic mechanisms. On the other hand, Liu et al. (2004) showed that gastric electrical stimulation increases vagal activity, and Ouyang et al. (2003b) observed that an increased gastric contractility in response to gastric stimulation is accompanied by increased vagal tone. By contrast, electrical stimulation to inhibit myoelectrical activity results in inhibition of parasympathetic activity (Ouyang et al., 2003a). Regarding central effects of gastric stimulation, studies have shown that stomach stimulation with parameters used for treating obesity activates hypothalamic neurons involved in controlling gastric motility and the feeding behavior in rats (Sun et al., 2006).

Complications and Contraindications The most frequently reported adverse events related to the use of gastric stimulators are: infection at the pulse generator site, abdominal pain, incisional site

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pain, and stomach wall perforation (Lin et al., 2004; Lin et al., 2005; Champion et al., 2006). A case of volvulus about the wires, which required resection of part of the small intestine and removal of the stimulation system, 16 months after the implant, was also reported (Lin et al., 2004). In addition, lead impedance out of range and device erosion or migration has been observed as well (www.medtronic.com). Other potential complications of the procedure include changes in the stimulation threshold, shifts in electrode position, loose electrical connections or lead fractures, hemorrhage, hematoma, and possible gastrointestinal complications due to implant procedures, migration of leads or stimulator, seroma at the stimulator site, allergenic or immune system response to implanted materials, and loss of therapeutic effect (www.medtronic.com). Apart from contraindication in patients banned from surgical procedures, such as sepsis, anticoagulation, etc., and/or anesthesia due to physical or mental conditions (www.medtronic.com), no other specific reasons to avoid gastric stimulation have been reported to this date.

What the Future Holds Gastric stimulation is an evolving concept for the treatment of gastroparesis and obesity, and this approach could be extended to other stomach dysfunctions, such as the gastroesophageal reflux. Future research in this field should be focused on better understanding the mechanisms induced by electrical stimulation of the stomach wall and on improving the stimulation devices and methods. Depending on the values of the stimulation parameters used, electrical stimulation of the stomach can activate enteric neurons or muscle cells directly, excitatory and inhibitory enteric neuronal circuits, the ICC, sympathetic and parasympathetic gastric terminals, and neural centers regulating gastric motility (see above). How these different effects of electrical stimulation result in a unitary motor response of the stomach is largely unknown, and so are the secretory and motility effects induced by gastric stimulation in other regions of the gastrointestinal tract. Such mechanistic knowledge is important so that we can control and optimize stimulation patterns according to desired effects and avoid undesirable side effects. The gastric stimulation patterns that have been developed until now have had limited effects, so far. Gastric stimulation using short pulses is able to improve gastroparetic symptoms such as nausea and vomiting, but has little effect on gastric emptying. In contrast, gastric stimulation using long pulses is able to

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entrain gastric slow waves, normalize gastric dysrhythmia, and improve gastric emptying, but is less effective on improving gastroparesis symptoms (Lin et al., 1998; McCallum et al., 1998). Thus, a combination of short and long pulses may be a better option to simultaneously attenuate gastroparetic symptoms and activate gastric emptying in patients with gastroparesis (Zhang and Chen, 2006). In addition, synchronization of electrical stimulation delivery with the spontaneous electrical activity of the stomach may increase the effectiveness of gastric stimulation and decrease power consumption (Zhang and Chen, 2006). Further research is thus necessary to investigate new stimulation patterns and improve the gastric stimulation devices.

CONCLUSIONS Gastric stimulation attenuates the symptoms in patients with gastroparesis and changes the feeding behavior causing excessive weight loss in obese patients. Therefore, this therapy may become a valuable alternative to medication and surgical procedures in the treatment of gastroparesis and obesity, and eventually could be extended to other stomach dysfunctions. However, further improvement of the stimulation devices and methods is essential.

ACKNOWLEDGMENTS The author thanks Dr Elliot Krames and Dr Jiande Chen for useful suggestions and help in editing this text.

References Abell, T., McCallum, R., Hocking, M., Koch, K., Abrahamsson, H., Leblanc, I. et al. (2003) Gastric electrical stimulation for medically refractory gastroparesis. Gastroenterology 125: 421–8. Abell, T.L., Minocha, A. and Abidi, N. (2006) Looking to the future: electrical stimulation for obesity. Am. J. Med. Sci. 331: 226–32. Abell, T.L., Van Cutsem, E., Abrahamsson, H., Huizinga, J.D., Konturek, J.W., Galmiche, J.P. et al. (2002) Gastric electrical stimulation in intractable symptomatic gastroparesis. Digestion 66: 204–12. Bilgutay, A.M., Lillehei, C.W., Wingrove, R., Griffen, W.O. and Bonnabeau, R.C. (1963) Gastrointestinal pacing: a new concept in the treatment of ileus. Biomed. Sci. Instrum. 25: 377–83. Champion, J.K., Williams, M., Champion, S., Gianos, J. and Carrasquilla, C. (2006) Implantable gastric stimulation to achieve weight loss in patients with a low body mass index: early clinical trial results. Surg. Endosc. 20: 444–7. Cigaina, V. (2002) Gastric pacing as therapy for morbid obesity: preliminary results. Obes. Surg. 12 (Suppl. 1): 12S–16S. Cigaina, V. (2004) Long-term follow-up of gastric stimulation for obesity: the Mestre 8-year experience. Obes. Surg. 14 (Suppl. 1): S14–S22.

Cigaina, V. and Hirschberg, A.L. (2003) Gastric pacing for morbid obesity: plasma levels of gastrointestinal peptides and leptin. Obes. Res. 11: 1456–62. Cigaina, V., Saggioro, A., Rigo, V., Pinato, G. and Ischai, S. (1996) Long-term effects of gastric pacing to reduce feed intake in swine. Obes. Surg. 6: 250–3. Cutts, T.F., Luo, J., Starkebaum, W., Rashed, H. and Abell, T.L. (2005) Is gastric electrical stimulation superior to standard pharmacologic therapy in improving GI symptoms, healthcare resources, and long-term health care benefits? Neurogastroenterol. Motil. 17: 35–43. Eagon, J.C. and Kelly, K.A. (1993) Effects of gastric pacing on canine gastric motility and emptying. Am. J. Physiol. 265: G767–G774. Familoni, B.O., Abell, T.L., Voeller, G., Salem, A. and Gaber, O. (1997) Electrical stimulation at a frequency higher than basal rate in human stomach. Dig. Dis. Sci. 42: 885–91. Hirst, G.D., Dickens, E.J. and Edwards, F.R. (2002) Pacemaker shift in the gastric antrum of guinea-pigs produced by excitatory vagal stimulation involves intramuscular interstitial cells. J. Physiol. 541: 917–28. Katschinski, M., Steinicke, C., Reinshagen, M., Dahmen, G., Beglinger, C., Arnold, R. et al. (1995) Gastrointestinal motor and secretory responses to cholinergic stimulation in humans. Differential modulation by muscarinic and cholecystokinin receptor blockade. Eur. J. Clin. Invest. 25: 113–22. Kelly, K.A. (1974) Differential responses of the canine gastric corpus and antrum to electric stimulation. Am. J. Physiol. 226: 230–4. Lee, J.C., Thuneberg, L., Berezin, I. and Huizinga, J.D. (1999) Generation of slow waves in membrane potential is an intrinsic property of interstitial cells of Cajal. Am. J. Physiol. 277: G409–G423. Lin, Z., Forster, J., Sarosiek, I. and McCallum, R.W. (2004) Treatment of diabetic gastroparesis by high-frequency gastric electrical stimulation. Diabetes Care 27: 1071–6. Lin, Z.Y., McCallum, R.W., Schirmer, B.D. and Chen, J.D. (1998) Effects of pacing parameters on entrainment of gastric slow waves in patients with gastroparesis. Am. J. Physiol. 274: G186–G191. Lin, Z., McElhinney, C., Sarosiek, I., Forster, J. and McCallum, R. (2005) Chronic gastric electrical stimulation for gastroparesis reduces the use of prokinetic and/or antiemetic medications and the need for hospitalizations. Dig. Dis. Sci. 50: 1328–34. Liu, J., Hou, X., Song, G., Cha, H., Yang, B. and Chen, J.D. (2006) Gastric electrical stimulation using endoscopically placed mucosal electrodes reduces food intake in humans. Am. J. Gastroenterol. 101: 798–803. Liu, J., Qiao, X. and Chen, J.D. (2004) Vagal afferent is involved in short-pulse gastric electrical stimulation in rats. Dig. Dis. Sci. 49: 729–37. Lonroth, H. and Abrahamsson, H. (2004) Laparoscopic and open placement of electronic implants for Gastric Electrical Stimulation (GES): technique and results. Minim. Invas. Ther. Allied Technol. 13: 336–9. McCallum, R.W., Chen, J.D., Lin, Z., Schirmer, B.D., Williams, R.D. and Ross, R.A. (1998) Gastric pacing improves emptying and symptoms in patients with gastroparesis. Gastroenterology 114: 456–61. Miedema, B.W., Sarr, M.G. and Kelly, K.A. (1992) Pacing the human stomach. Surgery 111: 143–50. Miller, K., Hoeller, E. and Aigner, F. (2006) The implantable gastric stimulator for obesity: an update of the European experience in the LOSS (Laparoscopic Obesity Stimulation Survey) Study. Treat. Endocrinol. 5: 53–8. Miller, K., Holler, E. and Hell, E. (2002) Intragastric stimulation (IGS) for treatment of morbid obesity. Zentralbl. Chir. 127: 1049–54.

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Mintchev, M.P., Sanmiguel, C.P., Otto, S.J. and Bowes, K.L. (1998) Microprocessor controlled movement of liquid gastric content using sequential neural electrical stimulation. Gut 43: 607–11. Ouyang, H., Xing, J. and Chen, J.D. (2005) Tachygastria induced by gastric electrical stimulation is mediated via alpha- and beta-adrenergic pathway and inhibits antral motility in dogs. Neurogastroenterol. Motil. 17: 846–53. Ouyang, H., Yin, J. and Chen, J.D. (2003a) Therapeutic potential of gastric electrical stimulation for obesity and its possible mechanisms: a preliminary canine study. Dig. Dis. Sci. 48: 698–705. Ouyang, H., Yin, J., Zhu, H., Xu, X. and Chen, J.D. (2003b) Effects of gastric electrical field stimulation with long pulses on gastric emptying in dogs. Neurogastroenterol. Motil. 15: 409–16. Qian, L., Lin, X. and Chen, J.D. (1999) Normalization of atropineinduced postprandial dysrhythmias with gastric pacing. Am. J. Physiol. 276: G387–92. Rabine, J.C. and Barnett, J.L. (2001) Management of the patient with gastroparesis. J. Clin. Gastroenterol. 32: 11–18. Saber, A.A. (2004) Gastric pacing: a new modality for the treatment of morbid obesity. J. Invest Surg. 17: 57–9. Sakai, Y. and Daniel, E.E. (1984) Multiple responses to electrical field stimulation in circular muscle of canine gastric corpus. Can. J. Physiol. Pharmacol. 62: 912–18. Sarna, S.K., Bowes, K.L. and Daniel, E.E. (1976) Gastric pacemakers. Gastroenterology 70: 226–31. Sevcencu, C. (2007a) A review of electrical stimulation to treat motility dysfunctions in the digestive tract: effects and stimulation patterns. Neuromodulation 10: 85–99. Sevcencu, C. (2007b) Gastrointestinal mechanisms activated by electrical stimulation to treat motility dysfunctions in the digestive tract: a review. Neuromodulation 10: 100–12. Smits, G.J. and Lefebvre, R.A. (1996) Development of cholinergic and inhibitory non-adrenergic non-cholinergic responses in the rat gastric funds. Br. J. Pharmacol. 118: 1987–94. Sotirov, E. and Papasova, M. (2000) Nitric oxide modulates release of noradrenaline in guinea-pig gastric fundus. Brain Res. Bull. 51: 401–5. Sun, X., Tang, M., Zhang, J. and Chen, J.D. (2006) Excitatory effects of gastric electrical stimulation on gastric distension responsive neurons in ventromedial hypothalamus (VMH) in rats. Neurosci. Res. 55: 451–7.

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Suzuki, H. (2000) Cellular mechanisms of myogenic activity in gastric smooth muscle. Jpn J. Physiol. 50: 289–301. Todorov, S., Pozzoli, C., Zamfirova, R. and Poli, E. (2003) Prejunctional modulation of non-adrenergic non-cholinergic (NANC) inhibitory responses in the isolated guinea-pig gastric fundus. Neurogastroenterol. Motil. 15: 299–306. Vergara, P., Woskowska, Z., Cipris, S., Fox-Threlkeld, J.E. and Daniel, E.E. (1996) Mechanisms of action of cholecystokinin in the canine gastrointestinal tract: role of vasoactive intestinal peptide and nitric oxide. J. Pharmacol. Exp. Ther. 279: 306–16. Wood, J.D., Alpers, D.H. and Andrews, P.L. (1999) Fundamentals of neurogastroenterology. Gut 45 (Suppl. 2): II6–II16. Xing, J.H. and Chen, J.D. (2006) Effects and mechanisms of longpulse gastric electrical stimulation on canine gastric tone and accommodation. Neurogastroenterol. Motil. 18: 136–43. Xing, J.H., Brody, F., Brodsky, J., Larive, B., Ponsky, J. and Soffer, E. (2003) Gastric electrical stimulation at proximal stomach induces gastric relaxation in dogs. Neurogastroenterol. Motil. 15: 15–23. Yokota, M., Ando, N., Ozawa, S., Imazu, Y. and Kitajima, M. (1997) Enhanced motility of the vagotomized canine stomach by electrical stimulation. J. Gastroenterol. Hepatol. 12: 338–46. Yokotani, K., Okuma, Y., Nakamura, K. and Osumi, Y. (1993) Release of endogenous acetylcholine from a vascularly perfused rat stomach in vitro; inhibition by M3 muscarinic autoreceptors and alpha-2 adrenoceptors. J. Pharmacol. Exp. Ther. 266: 1190–5. Yokotani, K., Okuma, Y. and Osumi, Y. (1998) Involvement of N-type voltage-activated Ca2 channels in the release of endogenous noradrenaline from the isolated vascularly perfused rat stomach. Jpn J. Pharmacol. 78: 75–7. Yoneda, S. and Suzuki, H. (2001) Nitric oxide inhibits smooth muscle responses evoked by cholinergic nerve stimulation in the guinea pig gastric fundus. Jpn J. Physiol. 51: 693–702. Zhang, J. and Chen, J.D. (2006) Systematic review: applications and future of gastric electrical stimulation. Aliment. Pharmacol. Ther. 24: 991–1002. Zhu, H. and Chen, J.D. (2005) Implantable gastric stimulation inhibits gastric motility via sympathetic pathway in dogs. Obes. Surg. 15: 95–100.

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75 Intestinal Electrical Stimulation: Methodologies, Effects, Mechanisms, and Applications Jieyun Yin and Jiande D.Z. Chen

O U T L I N E Introduction

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Physiology and Pathophysiology of Intestinal Motility Small Intestinal Motility Small Intestinal Myoelectrical Activity Intestinal Motility Disorders

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Intraluminal or Mucosal Electrodes Effects and Mechanisms of IES on Intestinal Functions Effects on Intestinal Slow Waves Effects on Intestinal Slow Wave Dysrhythmia Effects and Mechanisms on Intestinal Motility Effects and Mechanisms on Intestinal Transit and Absorption Effects on Other Organs

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motor cortex stimulation. In the earliest study regarding intestinal stimulation, published in 1963, Bilgutay et al. reported the use of intraluminal electrical stimulation via the tip of a nasogastric tube to induce peristalsis and shorten the recovery period from ileus after laparotomy (Bilgutay et al., 1963); an increase in gastric contractions as well as gastric emptying was reported in both dogs and humans. However, subsequent

INTRODUCTION Although the earliest study of electrical stimulation of the gut was reported more than 40 years ago, the development of the field is slow compared to cardiac pacing or other areas of neuromodulation, including spinal cord stimulation, deep brain stimulation, and

Neuromodulation

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randomized controlled studies failed to produce consistent or promising results (Moran and Nabseth, 1965; Quast et al., 1965; Berger et al., 1966). Before the 1960s there was a lack of understanding of gastrointestinal electrophysiology, which only became a topic of interest in the later 1960s and early 1970s (Bunker et al., 1967; Szurszewski et al., 1970; Hermon-Taylor and Code, 1971; Sarna et al., 1976; Hinder and Kelly, 1977). From the 1970s to early 1990s, Kelly and colleagues made significant contributions to our understanding of the electrical stimulation of the gut; numerous studies in both dogs and humans were reported by the group (Kelly and La Force, 1972; Becker et al., 1983; Richter and Kelly, 1986). During the past decade, more progress has been made on the methodologies, effects, mechanisms and clinical applications of gastrointestinal electrical stimulation. Numerous reports are available in the literature on electrical stimulation of various organs of the gastrointestinal tract, such as the stomach, small intestine, colon, and rectum for the treatment or therapeutic potentials of various conditions such as gastroparesis, short bowel syndrome, intestinal pseudo-obstruction, and fecal incontinence (Kelly, 1992; McCallum et al., 1998; Abell et al., 2003; Zhang and Chen, 2006). This chapter will focus on intestinal electrical stimulation (IES). Topics on gastric electrical stimulation can be found in a separate chapter of this book and a number excellent reviews (Kelly, 1992; Miedema et al., 1992; Eagon and Soper, 1993; Bortolotti, 2002; Lin and Chen, 2002; Lin et al., 2003; Zhang and Chen, 2006). The major difference between electrical stimulation of the gut and neuromodulation lies in the affecter and effecter. With neuromodulation, nerves or nervous systems are stimulated and organs associated with the nerves or nervous systems are affected. With electrical stimulation of the gut, an organ of the gut is stimulated and the functions of the organ, in turn, are altered. These altered organ functions may be attributed to either/or the local or peripheral effects of the stimulation or the central neuronal effects of the stimulation. In addition to this, the stimulation methodologies of IES may be different from other aspects of neuromodulation, mainly for the following two reasons: (1) the gastrointestinal organ is composed of smooth muscles. The response of smooth muscles to electrical stimulation is slow and therefore long pulses (in the order of milliseconds instead of microseconds) are typically required in order to alter the function of the organ being stimulated; (2) the gastrointestinal organ has intrinsic myoelectrical activity and therefore the electrical stimulation of the gut may be designed to enhance or alter this intrinsic myoelectrical activity.

PHYSIOLOGY AND PATHOPHYSIOLOGY OF INTESTINAL MOTILITY Small Intestinal Motility The main function of the stomach is to accommodate ingested food, grind and fix the food, and finally “pump” it out of the stomach to the small intestine. The accommodation of the ingested food is achieved by relaxation of the proximal stomach via the release of an inhibitory neurotransmitter called nitric oxide, whereas emptying of the stomach is accomplished by sequentially propagated contractions, called peristalsis, from the corpus to the distal antrum. The main function of the small intestine is to absorb various nutrients from the ingested food, emptied from the stomach. Intestinal motility is organized in such a way that the organ has sufficient time to absorb needed nutrients from the ingested food and then transport the remaining contents down to the ileum and the colon. Accordingly, intestinal motility, after a meal, is characterized by segmental contractions with different propagation directions, including antegrade, retrograde, and simultaneous contractile patterns. The force of the postprandial intestinal contractions is moderate, about 50–70% of the maximum strength. The intestinal motility pattern in the fasting state undergoes cycles of periodic fluctuation divided into three phases, called migrating motor complex or MMC: phase I (no contractions, 40–60 minutes), phase II (intermittent contractions, 20–40 minutes), and phase III (regular rhythmic contractions, 2–10 minutes). Typical gastric and intestinal contractions in the fasting state are shown in Figure 75.1. The maximum frequency of the stomach is about 3 cycles/min (cpm) in the stomach and 12 cpm in the most proximal small intestine (duodenum) and 8–9 cpm in the most distal intestine (ileum) (Yamata et al., 1995).

Small Intestinal Myoelectrical Activity It is important to understand electrophysiology of the small intestine for IES because (1) intestinal motility is regulated by intestinal myoelectrical activity, and (2) to alter the function of the small intestine, electrical stimuli may have to be designed to enhance or inhibit this intrinsic intestinal myoelectrical activity. Myoelectrical activity of the small intestine is similar to that of the stomach. It consists of two components: pacesetter potentials or slow waves, and spike potentials. A typical recording showing intestinal slow waves and spikes is shown in Figure 75.2. Small intestinal slow waves originate from a region in the

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Phase III

5 min

FIGURE 75.1 Migrating motor complex in the fasting state in the stomach (top two tracings) and small intestine. From top to bottom: 6 cm, 3 cm, 10 cm, 20 cm, and 30 cm from the pylorus. Strong contractions (phase III) migrate from the stomach to the distal small intestine

Slow waves Spikes

FIGURE 75.2 One-min intestinal slow waves and spikes measured from a dog

proximal 1 cm of the duodenum and propagate as an annular wave front in an aborad1 direction (HermonTaylor and Code, 1971). It determines the frequency and the direction of propagation of intestinal contractions. Spike potentials are superimposed on the slow waves and are electrical counterparts of contractions (Sarna et al., 1976). In the dog, the proximal 10–30% of the small intestine (30–115 cm of duodenum and jejunum) maintains the same slow wave frequency, 18–20 cpm, in a region called the “frequency plateau” (Szurszewski et al., 1970). Aborad to this point, there is a diminishing slow wave frequency gradient along the small bowel to a rate of 14 cpm in the distal ileum (Bunker et al., 1967; Soper, Geisler et al., 1990). In humans, slow waves in the duodenum and proximal jejunum occur at about 12 cpm with an aborad gradient to about 9 cpm in the terminal ileum (Christensen et al., 1966; Soper, Saar et al., 1990). Whether a proximal plateau of identical Aborad  direction away from the mouth.

1

frequencies is present in the human duodenum and proximal jejunum has not been clearly shown (Soper, Saar et al., 1990). Transection and reanastomosis of the small bowel decrease the slow wave frequency in the distal segment in both dogs (Akwari et al., 1975) and man (Richter and Kelly, 1986). In addition, at least in dogs, the propagation of slow waves in the distal segment becomes abnormal, with a high percentage of these slow waves propagating in an orad2 rather than an aborad direction (Karlstrom et al., 1989). Studies have indicated that intestinal myoelectrical dysrhythmia is associated with intestinal motor disorders in some clinical settings (Sullivan et al., 1977; Schuffler, 1981; You et al., 1981; Abell et al., 1988). It is known that abnormalities in the frequency of the intestinal slow waves are associated with intestinal hypomotility and that uncoupled or dysrhythmic intestinal myoelectrical activity leads to a lack of coordinated intestinal contractions or peristalsis. Orad  direction towards the mouth.

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Intestinal Motility Disorders Intestinal dysmotility is often seen in patients with irritable bowel syndrome (IBS) and patients with chronic intestinal pseudo-obstruction.3 Intestinal dysmotility is featured with altered MMC patterns in the fasting state and hypotensive or hypertensive postprandial contractions. Altered MMC patterns include a complete loss of the fasting MMC pattern, a loss of phase III and a prolonged phase II, and abnormal propagation of phase III activities. Postprandial contractile abnormalities include a continuation of fasting MMC pattern, absence or decreased amplitude of contractions, and abnormal propagation of contractions. Uncoordinated hypertensive contractions may also occur in patients with neuropathy.

10–600 ms

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Long pulse ~300 μs

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METHODOLOGIES Methodologies of intestinal electrical stimulation include patterns of stimuli, placement of electrodes and delivery time of stimuli. In this section, various methods published in the literature are summarized and critically discussed.

Long-Pulse Stimulation This method is most frequently reported in the literature because it is able to “pace” or entrain natural slow waves. It is also called electrical pacing or intestinal pacing. In this method, the electrical stimulus is composed of repetitive single pulses with a pulse width in the order of milliseconds (10–600 ms for IES), and a stimulation frequency in the vicinity of the physiological frequency of the intestinal slow wave (see Figure 75.3A). However, it should be noted that currently there are no implantable devices available in the market capable of generating pulses with a width longer than 2 ms.

Short-Pulse Stimulation In contrast to long-pulse stimulation, the pulse width in this method is substantially shorter and is in the order of a few hundred microseconds (μsec). The 3

Intestinal pseudo-obstruction is the decreased ability of the intestines to push food through, and often causes dilation of various parts of the bowel. It can be a primary condition (idiopathic or inherited from a parent) or caused by another disease (secondary). The clinical and radiological findings are often similar to true intestinal obstruction (http://en.wikipedia.org/wiki/Pseudo-obstruction, retrieved 29 January 2008).

x sec ‘on’ (C)

y sec ‘off’ Trains of short pulses

FIGURE 75.3 Configurations of electrical stimuli: (A) long pulses; (B) short pulses; (C) trains of pulses

stimulation frequency is usually a few times higher than the physiological frequency of the intestinal slow wave (see Figure 75.3B). Most of commercially available cardiac pacemakers or nerve stimulators are capable of generating short pulses.

Pulse Train In this method, the stimulus is composed of repetitive trains of pulses and is derived from the combination of two signals: (a) continuous short pulses with a high frequency (in the order of 5–100 Hz); (b) a control signal to turn the pulses on and off, such as x seconds “on” and y seconds “off”. The addition of x and y then determines the frequency of the pulse train (Figure 75.3C). This kind of stimulation has been frequently used in nerve stimulation. Commercially available stimulators are capable of generating trains of pulses with a pulse width of below 2 ms.

Dual Pulses A novel method of IES, called dual pulse IES, has recently been proposed by combining short and long pulses (Qi et al., 2007). In this method, the stimulus is composed of a short pulse (in the order of a few hundred μs) followed with a long pulse (in the order of a

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advantage of this method is the guaranteed contact and direct effect on the targeted organ. The disadvantage is its invasiveness. Laparotomy or laparoscopy under general anesthesia is required.

Short pulse Long pulse

Repetitive frequency

FIGURE 75.4

Dual pulse electrical stimuli: a short pulse is followed with a long pulse

Intestinal slow waves

Synchronized pulses

FIGURE 75.5 Synchronized intestinal electrical stimulation. Electrical stimuli are delivered at the occurrence of each intestinal slow wave peak

few hundred ms) (see Figure 75.4). A canine study has shown that dual pulse IES is capable of both normalizing intestinal dsyrhythmia and improving symptoms suggestive of nausea and vomiting induced by infusion of vasopressin (Qi et al., 2007). Apparently, the proposed method of dual pulse IES is more attractive than the conventional method of electrical stimulation in which only short pulses or long pulses but not both are utilized.

Synchronized Stimulation Conventionally, electrical stimulation is performed at a fixed frequency delivered at random without consideration of the occurrence of the intrinsic intestinal slow waves. A novel method has recently been proposed: synchronized intestinal electrical stimulation (Yin and Chen, 2007). Synchronized IES requires the implantation of two pairs of electrodes, one for the detection of intestinal slow waves and the other for stimulation. In this proposed method, each electrical stimulus is delivered upon the detection of an intrinsic slow wave peak, that is, IES is performed at the occurrence of cyclic physiological electrical events of the small intestine (Figure 75.5). By synchronizing each electrical stimulus with the intrinsic physiological electrical activity it is hypothesized that it is capable of enhancing intestinal contractions. A recent canine study showed that synchronized IES in the fed state significantly accelerated intestinal transit (Yin and Chen, 2007).

Placement of Stimulation Electrodes Serosal Electrodes Most commonly, stimulation electrodes are placed on the serosal surface of the small intestine. The

Intraluminal or Mucosal Electrodes Alternatively, stimulation electrodes may be placed on the mucosal surface of the small intestine via a nasojejunal tube. Typically, ring electrodes are attached to the tip of a catheter that is placed into the small intestine via the nose (Liu, Hou et al., 2005). The advantage of this method is that no surgical procedures are required. The intubation of the catheter can be accomplished with or without the aid of endoscopy. The disadvantage is that this method may not be adequate for chronic stimulation.

EFFECTS AND MECHANISMS OF IES ON INTESTINAL FUNCTIONS Effects of IES on intestinal motility and possible mechanisms related to IES have been investigated in a number of studies. IES has been shown to be able to pace or entrain intestinal slow waves and normalize intestinal slow wave dysrhythmia. Intestinal contractions can be inhibited with IES of high stimulation energy but may be enhanced with synchronized IES. Similarly, intestinal transit may be inhibited or enhanced with IES of appropriate parameters, resulting in an alteration in absorption. Moreover, the effects of IES on organs along the gut have also been explored.

Effects on Intestinal Slow Waves The effect of IES or intestinal pacing on intestinal slow waves was investigated systematically in a canine model (Collin et al., 1979; Bjorck et al., 1987; Lin, Peters et al., 2000). Long pulses with a pulse width of 50–150 ms are required to entrain or pace the intrinsic intestinal slow waves. It has been reported that intestinal slow waves can only be entrained when IES is delivered at a frequency higher than the frequency of the intrinsic slow waves; a complete entrainment of intestinal slow waves can be achieved only when the stimulation frequency is equal to or below 110% of the intrinsic frequency. When the stimulation frequency is higher than 110% of the intrinsic frequency, only partial entrainment is possible, as shown in Figure 75.6. Similarly, entrainment of intestinal slow waves can also be accomplished with IES using intraluminal ring electrodes (Lin, Peters et al., 2000).

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200 0 200

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FIGURE 75.6 Effects of intestinal electrical stimulation on intestinal slow waves. (A) Entrainment of intestinal slow waves with intestinal pacing. The entrainment is demonstrated by phase-locking between the stimulation artifacts and natural slow waves. (B) Percentage of slow wave entrainment with intestinal pacing at various pacing frequencies. (IF: intrinsic frequency of natural slow waves) (Part (B) reproduced from Lin, Peters et al. (2000), p. 654, Fig. 4. With kind permission from Springer Science  Business Media)

100 80 60 40 20 0

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Effects on Intestinal Slow Wave Dysrhythmia Compared with gastric electrophysiology, little is known on intestinal electrophysiology due to lack of noninvasive measurement methods. Unlike gastric slow waves that can be accurately measured using a noninvasive method of electrogastrography (Chen and McCallum, 1995), intestinal slow waves cannot be accurately measured using abdominal surface electrodes due to the following reasons: (1) the intestinal slow wave signal is much weaker than the gastric slow wave; (2) the frequencies of slow waves in different segments of the small intestine are different and the abdominal surface recording is unable to reflect slow waves at a specific segment of the small intestine (Chen et al., 1993). Consequently, little is known about pathophysiology of intestinal slow waves. However, a number of studies did report intestinal slow wave dysrhythmia in a number of clinical settings such as nausea and vomiting, intestinal pseudo-obstruction and intestinal ischemia (Sullivan et al., 1977; Schuffler, 1981; You et al., 1981; Abell et al., 1988; Golzarian et al., 1994; Ladipo et al., 2003). Abnormalities in intestinal slow waves include dysrhythmia, reduced frequency, and uncoordinated slow waves along the intestine, and are associated with impaired intestinal contractions. Normalization of intestinal slow wave dysrhythmia was reported in a canine study (Abo, Kono et al., 2000). Impaired slow waves were induced with intestinal balloon distension. IES with long pulses and parameters similar to those used in pacing intestinal slow waves was able to normalize intestinal dysrhythmia as shown in Figure 75.7. The improvement or normalization of intestinal dysrhythmia is of clinical

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FIGURE 75.7 Effects of IES on duodenal distension-induced intestinal slow wave dysrhythmia. (A) Normal intestinal slow waves at baseline; (B) impaired slow waves during duodenal distension; (C) normalized intestinal slow waves during duodenal distension with IES (Reproduced from Abo, Liang et al. (2000), p. 133, Fig. 6. With kind permission from Springer Science  Business Media)

significance since intestinal dysrhythmia leads to impaired intestinal motility.

Effects and Mechanisms on Intestinal Motility While intestinal slow wave dysrhythmia can be reliably and consistently improved with IES or intestinal

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20 mmHg

5 min (A)

Saline

IES

20 mmHg

5 min (B)

Hexamethonium

IES

20 mmHg

5 min (C)

Guanethidine

IES

FIGURE 75.8 Manometric tracings showing the effects of IES with long pulses on small intestinal motility in saline session (A), hexamethonium session (B), and guanethidine (C). The inhibitory effect of IES on intestinal contractions was blocked by guanethidine, suggesting an adrenergic pathway involved with IES

pacing, conventional IES has not been reported to be able to improve intestinal contractions. Only recently, it was reported that synchronized IES had an ameliorating effect on intestinal contractions. In this method of synchronized IES, the electrical stimuli were delivered at the occurrence of each slow wave peak. Each stimulus was composed of a train of pulses lasting 0.5 sec, and the pulses in the train had a frequency of 20 Hz, pulse width of 2 ms and amplitude of 4 mA. It was found that synchronized, but not non-synchronized, IES induced small intestinal contractions in the fasting state in normal dogs. In the fed state, synchronized IES improved glucagon-induced small intestinal postprandial hypomotility. Consequently, small intestinal transit delayed by glucagon was also improved. The excitatory effect of synchronized IES was blocked by atropine (Yin and Chen, 2007). Similarly, gastric contractions were improved with synchronized, but not conventional, gastric electrical stimulation (Zhu et al., 2007). With appropriate parameters (high output, in general), IES can consistently inhibit intestinal contractions. IES with long pulses (frequency of 20 cpm, pulse width of 200 ms and amplitude of 10 mA) significantly inhibited postprandial intestinal contractions

in healthy dogs (Liu, Liu et al., 2006). Intestinal motility of the entire measured segment (40–220 cm distal to the stimulation electrodes) was inhibited by 60–74% with the single channel IES of long pulses. The percentage of inhibition in intestinal contractions with IES was proportional to the pulse width and amplitude. Hexamethonium, guanethidine, phentolamine, propranolol partially, but not L-NNA, ondansetron, and naloxone prevented the inhibitory effect of IES on intestinal motility (Figure 75.8). These findings demonstrate that the inhibitory effect induced by IES with long pulses is mediated via sympathetic but not nitrergic, serotoninergic 5-HT3 and opiate pathways.

Effects and Mechanisms on Intestinal Transit and Absorption Regarding intestinal transit and absorption, IES is classified into forward and backward stimulation. If stimulation electrodes are placed in the proximal intestine or the proximal portion of an interested segment, IES is considered as forward IES; if the stimulation electrodes are placed in the distal intestine

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with trains of short pulses were more effective than IES with long pulses in accelerating jejunal transit and reducing fat absorption. The effects of IES with trains of short pulses on the transit and fat absorption were partially abolished with the treatment of lidocaine, suggesting possible involvement of the enteric nerves (Sun and Chen, 2004).

Effect of pacing on Intestinal transit 60 mM oleate to distal half gut (n  5) Cumulative % 99m-Tc recovered

90 80

Paced

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60 50 40 30

Effects on Other Organs

20 10 0 0

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FIGURE 75.9 Intestinal pacing or IES substantially increase intestinal transit slowed by ileal brake in dogs (Reproduced from Chen and Lin (2003), p. 254, Fig. 2. With kind permission from Springer Science  Business Media)

or the distal portion of an interested segment, IES is regarded as backward stimulation. Forward IES is able to accelerate intestinal transit (Soper, Geisler et al., 1990; Chen and Lin, 2003; Zhang and Chen, 2006). It was reported that forward jejunal electric stimulation accelerated intestinal transit slowed by fat-induced ileal brake in a canine model (Figure 75.9). Backward IES was found to delay gastric emptying or intestinal transit (Kelly and Code, 1977; O’Connell and Kelly, 1987). IES may also influence small bowel absorption independent of alterations in the intestinal slow waves. It was reported that backward jejunal electric stimulation slowed or reversed the flow of liquid chyme through the paced segment and led to enhanced absorption of water, nutrients, and electrolytes in canines (Sarr et al., 1981; Bjorck et al., 1987) and in rats (Sawchuk et al., 1986). Postprandial backward electric stimulation induced an increase in body weight and a decrease in fecal fat and nitrogen losses during the test period in a canine model of short bowel syndrome (Layzell and Collin, 1981). The enhanced enteric absorption with backward IES was mediated in part by an α-adrenergic mechanism (Bjorck et al., 1987). Forward IES slightly decreased the output of water, glucose, and sodium from the jejunal segment (Collin et al., 1979). The effects of forward IES on fat absorption and related mechanisms were investigated in a recent rodent study. IES with long pulses or pulse trains accelerated intestinal transit measured by the recovery of phenol red and increased the percentage of triglycerides recovered from the distal segment. IES

Reflex among different organs of the gut is well known. For example, ingestion of food into the stomach induces changes not only in the stomach but also in the small intestine and colon. Similarly, distension of the rectum results in alterations in motility functions not only in the rectum but also in the stomach and intestine (Kerlin et al., 1983; Bampton et al., 2002). A number of recent studies have demonstrated similar reflexive effects of electrical stimulation along the gut (Liu, Hou et al., 2005; Liu, Wang et al., 2005; Ouyang et al., 2006; Yin, Ouyang et al., 2007; Yin, Zhang et al., 2007; Xu et al., 2008). IES with long pulses inhibits both upper gastrointestinal motility and lower gastrointestinal motility. In dogs, IES were found to reduce gastric tone, inhibit antral contractions, and delay gastric emptying (Ouyang et al., 2006; Yin, Ouyang et al., 2007); similarly, rectal tone was also reduced with IES (Xu et al., 2008). A similar inhibitory effect of IES on gastric emptying was also noted in rats (Yin, Zhang et al., 2007). In humans, long pulse IES delivered via intraluminal ring electrodes attached to a feeding tube placed in the duodenum reduced gastric accommodation and delayed gastric emptying (Liu, Hou et al., 2005).

POTENTIAL APPLICATIONS OF IES Although promising results have been reported in the literature, demonstrating potential applications of IES for treating gastrointestinal motility disorder and obesity, no FDA-approved device is available at the moment. Almost all of basic and clinical research studies published in the literature utilized long pulses as stimuli, whereas, no commercial implantable devices are available capable of generating long pulses. The lack of an adequate implantable device and the invasive nature of the placement of stimulation electrodes have limited clinical research in exploring applications of IES. Based on the effects of IES on intestinal motility, forward IES may be used to treat intestinal motility disorders related to slow intestinal transit, such as

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Weekly food intake (g)

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chronic intestinal pseudo-obstruction. On the other hand, backward IES can be used to delay intestinal transit and therefore may be used to treat patients with dumping syndrome or short bowel syndrome (Richter and Kelly, 1986; Karlstrom and Kelly, 1989; Kelly, 1992; Zhang and Chen, 2006). A number of early studies also demonstrated the application of IES in enhancing intestinal absorption (Collin et al., 1979; Bjorck et al., 1987; O’Connell and Kelly, 1987). Potential applications of IES for the treatment of obesity have been reported in a number of recent studies (Layzell and Collin, 1981; Yin, Ouyang et al., 2007; Yin, Zhang et al., 2007). Obesity is one of the most prevalent public health problems in the USA, claiming over 400 000 lives and costing over $100 billion in the USA every year (Bray and Greenway, 1999). It results from an imbalance between energy expenditure and caloric intake. The current therapeutic strategies for the treatment of obesity are not satisfactory: behavior modification and pharmacotherapy are effective only for a short term (AACE/ ACE, 1998; Bray and Greenway, 1999). The surgical treatment induces satisfactory long-term weight loss; its application is, however, very limited because of the substantial risks and complications involved (Sagar, 1995). Recently, there is a growing interest in electrical stimulation for the treatment of obesity. Gastric electrical stimulation (GES), as a potential therapy for obesity, has been extensively studied in both animals and humans. Previous open-label studies have shown promising results in food intake and weight loss with GES (Cigaina et al., 1996; Cigaina, 2002; Ouyang et al., 2003; De Luca et al., 2004). Although there is a lack of clinical studies on the therapeutic potential of IES for obesity, basic and clinical research has yielded promising results. In rats, IES was reported to reduce food intake and body weight in both lean and diet-induced obese rats (Figure 75.10), via the inhibition of gastric emptying, acceleration of intestinal transit and reduction of fat absorption (Sun and Chen, 2004; Yin, Zhang et al., 2007). Mechanisms involving gastrointestinal hormones have also been elucidated. In a recent rodent study, IES was found to decrease a prominent hunger hormone, ghrelin, in gastric tissue and increase one of the major satiety hormones, cholecystokinin in the duodenal tissue (Xu, McNearney et al., 2007). Vagal neuronal mechanisms have also been reported with IES (Sun et al., 2005). In dogs, IES was noted to induce gastric distension and the IES-induced gastric distension was correlated with reduced food consumption (Ouyang et al., 2006). Similarly, IES also delayed gastric emptying and the delay in gastric emptying is believed to reduce food intake and increase satiety during inter-meal periods.

35 p  0.049

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100 ms Off

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FIGURE 75.10 Effect of IES on food intake and weight change in diet-induced obese rats. (A) IES significantly reduced food intake (p  0.03), the reduction was even more with the higher pulse width of 300 ms (p  0.01). (B) IES significantly inhibited weight gain (p  0.049), similar to the food intake, the inhibition was even more with the higher pulse width of 300 ms (p  0.036) (Reproduced from Yin, Zhang et al. (2007), p. R81, Fig. 4 and used with permission of the American Physiological Society)

A feasibility study of IES was performed in healthy volunteers (Liu, Qiao et al., 2006). IES was performed using long pulses via intraluminal ring electrodes attached to a feeding tube that was placed through the nose into the duodenum. IES was found to reduce gastric accommodation and delay gastric emptying. The subjects tolerated the procedure well and IES did not induce any adverse events.

DISCUSSION AND CONCLUSIONS In neuromodulation, short pulses are commonly used, whereas in IES, repetitive long pulses with a frequency lower than 1 Hz are typically used. This sort of parameter is chosen to alter intestinal muscle functions. Long pulses are needed for IES because the intestinal tissue is composed of smooth muscles that have a large time constant. Stimulation electrodes can be placed surgically by laparoscopy or laparotomy.

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However, for temporary IES, intraluminal electrodes may be an excellent alternative, which does not involve any surgical procedures. IES with long pulses has been shown to entrain intrinsic intestinal slow waves and improve or normalize intestinal slow wave dysrhythmia. Intestinal contractions can be consistently inhibited with the conventional method of IES with relatively high output. However, it seems that only synchronized IES is capable of inducing or enhancing intestinal contractions. Intestinal transit has been reported to be accelerated with forward IES but decreased with backward IES. IES may have promising applications for treating motility disorders associated with altered intestinal contractile activity. Most recent studies have revealed possible applications of IES for the treatment of obesity. Basic research results are promising; however, further clinical studies are needed to bring IES from bench to bedside. The major hindrance in the advancement of IES is similar to that of GES, including the invasive nature of the methodology and the lack of implantable device suitable for IES. Accordingly, a less invasive method of placing stimulation electrodes would be of great significance, such as endoscopic placement of electrodes (Xu, Pasricha et al., 2007). The other issue is the development of a suitable implantable stimulator. Current implantable stimulators used for gastrointestinal electrical stimulation are designed for cardiac or nerve stimulation. Cardiac muscles and nerves have a rapid response to electrical stimulation and thus there is no need to use long pulses. The small intestine, however, is composed of smooth muscles which are slow in response to electrical stimulation and thus long pulses are needed to alter their functions. Accordingly, a new generation of devices capable of generating long pulses is needed.

ACKNOWLEDGMENT This work is partially supported by National Institutes of Health grants DK063733, DK055437 and DK075155.

References AACE/ACE (1998) Position statement on the prevention, diagnosis, and treatment of obesity. Endocrine Practice 4: 297–330. Abell, T.L., Kim, C.H. and Malagelada, J.R. (1988) Idiopathic cyclic nausea and vomiting – a disorder of gastrointestinal motility? Mayo Clin. Proc. 63: 1169–75.

Abell, T., McCallum, R., Hocking, M., Koch, K., Abrahamsson, H., Leblanc, I. et al. (2003) Gastric electrical stimulation for medically refractory gastroparesis. Gastroenterology 125: 421–8. Abo, M., Kono, T., Wang, Z. and Chen, J.D. (2000) Impairment of gastric and jejunal myoelectrical activity during rectal distension in dogs. Dig. Dis. Sci. 45: 1731–6. Abo, M., Liang, J., Qian, L.W. and Chen, J.D. (2000) Distensioninduced myoelectrical dysrhythmia and effects of intestinal pacing in dogs. Dig. Dis. Sci. 45: 129–35. Akwari, O.E., Kelley, K.A., Steinbach, J.H. and Code, C.F. (1975) Electric pacing of intact and transected canine small intestine and its computer model. Am. J. Physiol. 229: 1188–97. Bampton, P.A., Dinning, P.G., Kennedy, M.L., Lubowski, D.Z., Jr and Cook, I.J. (2002) The proximal colonic motor response to rectal mechanical and chemical stimulation. Am. J. Physiol. Gastrointest. Liver Physiol. 282: G443–49. Becker, J.M., Sava, P., Kelly, K.A. and Shturman, L. (1983) Intestinal pacing for canine postgastrectomy dumping. Gastroenterology 84: 383–7. Berger, T., Kewenter, J. and Kock, N.G. (1966) Response to gastrointestinal pacing: antral, duodenal and jejunal motility in control and postoperative patients. Ann. Surg. 164: 139–44. Bilgutay, A.M., Wingrove, R., Griffen, W.O., Bonnabeau, R.C. Jr. and Lillehei, C.W. (1963) Gastro-intestinal pacing: a new concept in the treatment of ileus. Ann. Surg. 158: 338–48. Bjorck, S., Kelly, K.A. and Phillips, S.F. (1987) Mechanisms of enhanced canine enteric absorption with intestinal pacing. Am. J. Physiol. 252: G548–G553. Bortolotti, M. (2002) The “electrical way” to cure gastroparesis. Am. J. Gastroenterol. 97: 1874–83. Bray, G.A. and Greenway, F.L. (1999) Current and potential drugs for treatment of obesity. Endocrinol. Rev. 20: 805–75. Bunker, C.E., Johnson, L.P. and Nelsen, T.S. (1967) Chronic in situ studies of the electrical activity of the small intestine. Arch. Surg. 95: 259–68. Chen, J.D. and Lin, H.C. (2003) Electrical pacing accelerates intestinal transit slowed by fat-induced ileal brake. Dig. Dis. Sci. 48: 251–6. Chen, J. and McCallum, R.W. (1995) Electrogastrography: Principles and Applications. New York: Raven. Chen, J.D., Schirmer, B.D. and McCallum, R.W. (1993) Measurement of electrical activity of the human small intestine using surface electrodes. IEEE Trans. Biomed. Eng. 40: 598–602. Christensen, J., Schedl, H.P. and Clifton, J.A. (1966) The small intestinal basic electrical rhythm (slow wave) frequency gradient in normal men and in patients with variety of diseases. Gastroenterology 50: 309–15. Cigaina, V. (2002) Gastric pacing as therapy for morbid obesity: preliminary results. Obes. Surg. 12 (Suppl. 1): 12S–16S. Cigaina, V.V., Saggioro, A., Rigo, V.V., Pinato, G. and Ischai, S. (1996) Long-term effects of gastric pacing to reduce feed intake in swine. Obes. Surg. 6: 250–3. Collin, J., Kelly, K.A. and Phillips, S.F. (1979) Absorption from the jejunum is increased by forward and backward pacing. Br. J. Surg. 66: 489–92. De Luca, M., Segato, G., Busetto, L., Favretti, F., Aigner, F., Weiss, H. et al. (2004) Progress in implantable gastric stimulation: summary of results of the European multi-center study. Obes. Surg. 14 (Suppl. 1): S33–S39. Eagon, J.C. and Soper, N.J. (1993) Gastrointestinal pacing. Surg. Clin. North Am. 73: 1161–72. Golzarian, J., Staton, D.J., Wikswo, J.P., Jr, Friedman, R.N. and Richards, W.O. (1994) Diagnosing intestinal ischemia using a noncontact superconducting quantum interference device. Am. J. Surg. 167: 586–92.

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Hermon-Taylor, J. and Code, C.F. (1971) Localization of the duodenal pacemaker and its role in the organization of duodenal myoelectric activity. Gut 12: 40–7. Hinder, R.A. and Kelly, K.A. (1977) Human gastric pacesetter potential. Site of origin, spread, and response to gastric transection and proximal gastric vagotomy. Am. J. Surg. 133: 29–33. Karlstrom, L. and Kelly, K.A. (1989) Ectopic jejunal pacemakers and gastric emptying after Roux gastrectomy: effect of intestinal pacing. Surgery 106: 867–71. Karlstrom, L.H., Soper, N.J., Kelly, K.A. and Phillips, S.F. (1989) Ectopic jejunal pacemakers and enterogastric reflux after Roux gastrectomy: effect of intestinal pacing. Surgery 106: 486–95. Kelly, K.A. (1992) Pacing the gut. Gastroenterology 103: 1967–9. Kelly, K.A. and Code, C.F. (1977) Duodenal-gastric reflux and slowed gastric emptying by electrical pacing of the canine duodenal pacesetter potential. Gastroenterology 72: 429–33. Kelly, K.A. and La Force, R.C. (1972) Pacing the canine stomach with electric stimulation. Am. J. Physiol. 222: 588–94. Kerlin, P., Zinsmeister, A. and Phillips, S. (1983) Motor responses to food of the ileum, proximal colon, and distal colon of healthy humans. Gastroenterology 84: 762–70. Ladipo, J.K., Bradshaw, L.A., Halter, S. and Richards, W.O. (2003) Changes in intestinal electrical activity during ischaemia correlate to pathology. West Afr. J. Med. 22: 1–4. Layzell, T. and Collin, J. (1981) Retrograde electrical pacing of the small intestine – a new treatment for the short bowel syndrome? Br. J. Surg. 68: 711–13. Lin, X., Hayes, J., Peters, L.J. and Chen, J.D. (2000) Entrainment of intestinal slow waves with electrical stimulation using intraluminal electrodes. Ann. Biomed. Eng. 28: 582–7. Lin, X., Peters, L.J., Hayes, J. and Chen, J.D. (2000) Entrainment of segmental small intestinal slow waves with electrical stimulation in dogs. Dig. Dis. Sci. 45: 652–6. Lin, Z. and Chen, J.D. (2002) Advances in gastrointestinal electrical stimulation. Crit. Rev. Biomed. Eng. 30: 419–57. Lin, Z., Forster, J., Sarosiek, I. and McCallum, R.W. (2003) Treatment of gastroparesis with electrical stimulation. Dig. Dis. Sci. 48: 837–48. Liu, J., Qiao, X. and Chen, J.D. (2006) Therapeutic potentials of a novel method of dual-pulse gastric electrical stimulation for gastric dysrhythmia and symptoms of nausea and vomiting. Am. J. Surg. 191: 255–61. Liu, S., Hou, X. and Chen, J.D. (2005) Therapeutic potential of duodenal electrical stimulation for obesity: acute effects on gastric emptying and water intake. Am. J. Gastroenterol. 100: 792–6. Liu, S., Liu, J. and Chen, J.D. (2006) Neural mechanisms involved in the inhibition of intestinal motility induced by intestinal electrical stimulation in conscious dogs. Neurogastroenterol. Motil. 18: 62–8. Liu, S., Wang, L. and Chen, J.D. (2005) Cross-talk along gastrointestinal tract during electrical stimulation: effects and mechanisms of gastric/colonic stimulation on rectal tone in dogs. Am. J. Physiol. Gastrointest. Liver Physiol. 288: G1195–G1198. McCallum, R.W., Chen, J.D., Lin, Z., Schirmer, B.D., Williams, R.D. and Ross, R.A. (1998) Gastric pacing improves emptying and symptoms in patients with gastroparesis. Gastroenterology 114: 456–61. Miedema, B.W., Sarr, M.G. and Kelly, K.A. (1992) Pacing the human stomach. Surgery 111: 143–50. Moran, J.M. and Nabseth, D.C. (1965) Electrical stimulation of the bowel. A controlled clinical study. Arch. Surg. 91: 449–51. O’Connell, P.R. and Kelly, K.A. (1987) Enteric transit and absorption after canine ileostomy. Effect of pacing. Arch. Surg. 122: 1011–17.

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Ouyang, H., Yin, J. and Chen, J.D. (2003) Therapeutic potential of gastric electrical stimulation for obesity and its possible mechanisms: a preliminary canine study. Dig. Dis. Sci. 48: 698–705. Ouyang, H., Yin, J. and Chen, J.D. (2006) Gastric or intestinal electrical stimulation-induced increase in gastric volume is correlated with reduced food intake. Scand. J. Gastroenterol. 41: 1261–6. Qi, H., Liu, S. and Chen, J.D. (2007) Dual pulse intestinal electrical stimulation normalizes intestinal dysrhythmia and improves symptoms induced by vasopressin in fed state in dogs. Neurogastroenterol. Motil. 19: 411–18. Quast, D.C., Beall, A.C., Jr. and Debakey, M.E. (1965) Clinical evaluation of the gastrointestinal pacer. Surg. Gynecol. Obstet. 120: 35–7. Richter, H.M., III and Kelly, K.A. (1986) Effect of transection and pacing on human jejunal pacesetter potentials. Gastroenterology 91: 1380–5. Sagar, P.M. (1995) Surgical treatment of morbid obesity. Br. J. Surg. 82: 732–9. Sarna, S.K., Bowes, K.L. and Daniel, E.E. (1976) Gastric pacemakers. Gastroenterology 70: 226–31. Sarr, M.G., Kelly, K.A. and Gladen, H.E. (1981) Electrical control of canine jejunal propulsion. Am. J. Physiol. 240: G355–G360. Sawchuk, A., Nogami, W., Goto, S., Yount, J., Grosfeld, J.A., Lohmuller, J. et al. (1986) Reverse electrical pacing improves intestinal absorption and transit time. Surgery 100: 454–60. Schuffler, M.D. (1981) Chronic intestinal pseudo-obstruction syndromes. Med. Clin. North Am. 65: 1331–58. Soper, N.J., Geisler, K.L., Sarr, M.G., Kelly, K.A. and Zinsmeister, A.R. (1990) Regulation of canine jejunal transit. Am. J. Physiol. 259: G928–G933. Soper, N.J., Saar, M.G. and Kelly, K.A. (1990) Human duodenal myoelectric activity after operation and with pacing. Surgery 107: 63–8. Sullivan, M.A., Snape, W.J., Jr., Matarazzo, S.A., Petrokubi, R.J., Jeffries, G. and Cohen, S. (1977) Gastrointestinal myoelectrical activity in idiopathic intestinal pseudo-obstruction. N. Engl. J. Med. 297: 233–8. Sun, Y. and Chen, J. (2004) Intestinal electric stimulation decreases fat absorption in rats: therapeutic potential for obesity. Obes. Res. 12: 1235–42. Sun, Y., Qin, C., Foreman, R.D. and Chen, J.D. (2005) Intestinal electric stimulation modulates neuronal activity in the nucleus of the solitary tract in rats. Neurosci. Lett. 385: 64–9. Szurszewski, J.H., Elveback, L.R. and Code, C.F. (1970) Configuration and frequency gradient of electric slow wave over canine small bowel. Am. J. Physiol. 218: 1468–73. Xu, J., McNearney, T.A. and Chen, J.D. (2007) Gastric/intestinal electrical stimulation modulates appetite regulatory peptide hormones in the stomach and duodenum in rats. Obes. Surg. 17: 406–13. Xu, X., Lei, Y., Liu, S. and Chen, J.D. (2008) Inhibitory effects of gastrointestinal electrical stimulation on rectal tone are both organspecific and distance-related in dogs. Dis. Colon Rectum, 51: 467–73. Xu, X., Pasricha, P.J. and Chen, J.D. (2007) Feasibility of gastric electrical stimulation by use of endoscopically placed electrodes. Gastrointest. Endosc. 66: 981–6. Yamata, T., Alpers, D.H., Owyang, C., Powell, D.W. and Silverstein, F.E. (1995) Textbook of Gastroenterology. Philadelphia: J.B. Lippincott. Yin, J. and Chen, J. (2007) Excitatory effects of synchronized intestinal electrical stimulation on small intestinal motility in dogs. Am. J. Physiol. Gastrointest. Liver Physiol. 293: G1190–95. Yin, J., Ouyang, H. and Chen, J.D. (2007) Potential of intestinal electrical stimulation for obesity: a preliminary canine study. Obesity (Silver Spring) 15: 1133–8.

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Yin, J., Zhang, J. and Chen, J.D. (2007) Inhibitory effects of intestinal electrical stimulation on food intake, weight loss and gastric emptying in rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293: R78–R82. You, C.H., Chey, W.Y., Lee, K.Y., Menguy, R. and Bortoff, A. (1981) Gastric and small intestinal myoelectric dysrhythmia associated with chronic intractable nausea and vomiting. Ann. Intern. Med. 95: 449–51.

Zhang, J. and Chen, J.D. (2006) Systematic review: applications and future of gastric electrical stimulation. Aliment. Pharmacol. Ther. 24: 991–1002. Zhu, H., Sallam, H., Chen, D.D. and Chen, J.D. (2007) Therapeutic potential of synchronized gastric electrical stimulation for gastroparesis: enhanced gastric motility in dogs. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293: R1875–R1881.

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C H A P T E R

76 Neurophysiology of the Genitourinary Organs William C. de Groat and Firouz Daneshgari

O U T L I N E Introduction

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Lower Urinary Tract Anatomy Innervation Parasympathetic Pathways Sympathetic Pathways Neural Modulatory Mechanisms Somatic Pathways Afferent Pathways Urothelial-Afferent Interactions Reflex Mechanisms Controlling the Lower Urinary Tract Anatomy of Central Nervous Pathways Controlling the Lower Urinary Tract Pathways in the Spinal Cord Pathways in the Brain Organization of Urine Storage and Voiding Reflexes Sympathetic Pathways Somatic Pathways to the Urethral Sphincter

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Voiding Reflexes Neurotransmitters in Micturition Reflex Pathways Excitatory Neurotransmitters Inhibitory Neurotransmitters Neurogenic Dysfunction of the Lower Urinary Tract Spinal Injury

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INTRODUCTION

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Sex Organs Innervation Parasympathetic Pathways Sympathetic Pathways Somatic Pathways Erection Peripheral Mechanisms Central Mechanisms Glandular Secretion Emission–Ejaculation Central Reflex Pathways

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References

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vagina, testes, ovaries, and uterus, which are involved in reproductive activity. The urogenital system is affected by a variety of neuropathologic conditions and often is the site of the first symptoms produced by diffuse neurologic diseases, such as diabetic neuropathy or multiple sclerosis (Beck, 1999; Betts, 1999; Sakakibara and Fowler, 1999; Goldstein et al.,

The urogenital system has two major subdivisions: (1) the urinary tract, consisting of the kidneys, ureters, urinary bladder, and urethra, which is responsible for the production, storage and elimination of urine; and (2) the genital tract, consisting of the penis, clitoris,

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2000; Lundberg et al., 2000; Sáenz de Tejada et al., 2000; Morrison et al., 2002; Wein, 2002; Das Gupta and Fowler, 2003). This sensitivity to neurogenic disorders is not surprising in view of the complexity and importance of neural mechanisms in the regulation of urogenital function (Torrens and Morrisson, 1986; de Groat and Booth, 1993a; de Groat et al., 1993; Sáenz de Tejada et al., 2000; Chancellor and Yoshimura, 2002; Morrison et al., 2002). Many functions of the urogenital system are controlled by autonomic (parasympathetic and sympathetic) and somatic efferent pathways originating in the lumbosacral spinal cord (Figure 76.1). These pathways regulate the activity of smooth muscles, striated muscle, epithelial cells, and exocrine glands in the urogenital organs via the release of multiple transmitters, including acetylcholine (ACh), norepinephrine, adenosine triphosphate

(ATP), nitric oxide (NO), and neuropeptides. The peripheral pathways are in turn regulated by complex neural pathways in the brain and spinal cord. Some urogenital functions (penile erection) are purely involuntary and mediated by reflex pathways in the spinal cord or brain stem, whereas others (micturition) are more complex, involving voluntary control by the cerebral cortex. It is noteworthy that the activity of the lower urinary tract and certain sex organs is almost totally dependent on central nervous control, whereas many other visceral systems, in particular the gastrointestinal tract and cardiovascular system, continue to function in the absence of extrinsic neural input. This chapter will review the central neural circuitry and neurotransmitters involved in (1) the control of urine storage and release by the lower urinary tract and (2) the control of male sexual organs.

Lumbar spinal cord

Sacral spinal cord

Dorsal root ganglia SCG ISN IMG

Pelvic N.

HGN

Pudendal N.

Pelvic plexus

Urinary bladder PG

Penis EUS IC BC

U VD

FIGURE 76.1

Diagram showing the sympathetic, parasympathetic, and somatic innervation of the urogenital tract of the male cat. Sympathetic preganglionic pathways emerge from the lumbar spinal cord and pass to the sympathetic chain ganglia (SCG) and then via the inferior splanchnic nerves (ISN) to the inferior mesenteric ganglia (IMG). Preganglionic and postganglionic sympathetic axons then travel in the hypogastric nerve (HGN) to the pelvic plexus and the urogenital organs. Parasympathetic preganglionic axons which originate in the sacral spinal cord pass in the pelvic nerve to ganglion cells in the pelvic plexus and to distal ganglia in the organs. Sacral somatic pathways are contained in the pudendal nerve, which provides an innervation to the penis, the ischiocavernosus (IC), bulbocavernosus (BC), and external urethral sphincter (EUS) muscles. The pudendal and pelvic nerves also receive postganglionic axons from the caudal sympathetic chain ganglia. These three sets of nerves contain afferent axons from the lumbosacral dorsal root ganglia. Abbreviations: ureter (U), prostate gland (PG), vas deferens (VD)

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LOWER URINARY TRACT

is attributed to the layer of superficial umbrella cells which are interconnected by tight junctions and have an unusual asymmetrical unit membrane on their apical surface which consists of an outer leaflet of plaques composed of proteins called uroplakins. Umbrella cells have large numbers of discoid vesicles with asymmetrical membrane structure located just under the apical surface. It is believed that trafficking of these vesicles to the apical surface during stretch allows the umbrella cells to increase their surface area during bladder distension (Truschel et al., 2002). Urothelial cells also have neuronal-like properties including the ability to release neurotransmitters (ATP and NO) in response to stretch or chemical stimulation (Figure 76.2) (Ferguson et al., 1997; Birder et al., 1998, 2003; Vlaskovska et al., 2001; Birder, Nealen et al., 2002). Transmitter release may be mediated by exocytosis associated with vesicle trafficking. Transmitters released from the urothelial cells may act in an autocrine/paracrine manner within the urothelium or on subepithelial myofibroblasts, nerves or blood vessels to influence various functions including the urothelial barrier, local blood flow or sensory

Anatomy The storage and periodic elimination of urine is controlled by the activity of two functional units in the lower urinary tract: (1) a reservoir (the bladder) and (2) an outlet (consisting of bladder neck, urethra, and striated muscles of the pelvic floor). Two regions of the bladder have been distinguished based on neural innervation and responses to pharmacologic agents (Torrens and Morrison, 1986; DeLancey et al., 2002; Morrison et al., 2002). According to this approach, the bladder can be divided circumferentially at the level of the ureteral orifices into cranial and caudal segments termed body and base, respectively. The luminal surface of the bladder is covered by a multilayered urothelium which functions as a highly efficient barrier to movement of water and ionized substances across the bladder wall (Lavelle et al., 2000; Lewis, 2000; Chancellor and Yoshimura, 2002; DeLancey et al., 2002). The primary urine-plasma barrier

Action potentials P2X TRPV1

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NK-2 Inflammatory mediators

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FIGURE 76.2 Diagram showing: (1) receptors present in the urothelium and in sensory nerve endings in the bladder mucosa and (2) putative chemical mediators that are released by the urothelium, nerves or smooth muscle that can modulate the excitability of sensory nerves. Urothelial cells and sensory nerves express common receptors (P2X, TRPV1, and TRPM8). Distension of the bladder activates stretch receptors and triggers the release of urothelial transmitters such as ATP, ACh, and NO that may interact with adjacent nerves. Receptors in afferent nerves or the urothelium can respond to changes in pH, osmolality, high K concentration, chemicals in the urine or inflammatory mediators released in the bladder wall. Neuropeptides (neurokinin A) released from sensory nerves in response to distension or chemical stimulation can act on NK-2 autoreceptors to sensitize the mechanosensitive nerve endings. The smooth muscle can generate force which may influence some mucosal endings. Nerve growth factor released from muscle or urothelium can exert an acute and chronic influence on the excitability of sensory nerves via an action on Trk-A receptors. Abbreviations: ACh , acetylcholine; MAChR, muscarinic acetylcholine receptor; TRPV1, transient receptor potential vanilloid receptor 1 sensitive to capsaicin; TRPM8, menthol/cold receptor; NO, nitric oxide, Trk-A, tyrosine kinase A receptor

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mechanisms (Ferguson et al., 1997; Cockayne et al., 2000; Birder et al., 2003; Drake et al., 2003; Sui et al., 2004). An anatomic sphincter between the bladder and the urethra has not been identified; however, radiographic studies and measurements of urethral pressure indicate the existence of a physiologic internal sphincter that maintains urinary continence by closure of the bladder neck and proximal urethra (Chancellor and Yoshimura, 2002). The sphincter-like properties

INFANT

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60

of this region have been attributed to the abundance of elastic tissue in the submucosa and the tone of the urethral smooth muscle. Continence is thought to be dependent on a combination of factors, including urethral wall tension, the caliber of the urethral lumen, and the functional length of the urethra. The striated muscles surrounding the urethra are not essential for urinary continence, but are important in the voluntary termination of urine flow (Figure 76.3) and in the

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FIGURE 76.3 Combined cystometrograms and sphincter electromyograms (EMG) comparing reflex voiding responses in an infant (A) and in a paraplegic patient (C) with a voluntary voiding response in an adult (B). The abscissa in all records represents bladder volume in milliliters and the ordinates represent bladder pressure in cmH2O and electrical activity of the EMG recording. On the left side of each trace the arrows indicate the start of a slow infusion of fluid into the bladder (bladder filling). Vertical dashed lines indicate the start of sphincter relaxation which precedes by a few seconds the bladder contraction in A and B. In part B note that a voluntary cessation of voiding (stop) is associated with an initial increase in sphincter EMG followed by a reciprocal relaxation of the bladder. A resumption of voiding is again associated with sphincter relaxation and a delayed increase in bladder pressure. On the other hand, in the paraplegic patient (C) the reciprocal relationship between bladder and sphincter is abolished. During bladder filling, transient uninhibited bladder contractions occur in association with sphincter activity. Further filling leads to more prolonged and simultaneous contractions of the bladder and sphincter (bladder–sphincter dyssynergia). Loss of the reciprocal relationship between bladder and sphincter in paraplegic patients interferes with bladder emptying

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prevention of stress incontinence (Tanagho and Miller, 1970; Chancellor and Yoshimura, 2002). The urinary bladder and urethral outlet exhibit a reciprocal relationship in effecting the storage and elimination of urine (Figure 76.3). During storage, the bladder neck and proximal urethra are closed, the sphincter electromyogram (EUS-EMG) gradually increases during bladder filling, and maximal intraurethral pressures range from 20 to 50 cmH20. The detrusor muscle, on the other hand, is quiescent, allowing intravesical pressure to remain low (5–15 cm H20) over a wide range of bladder volumes (100–400 ml). During voluntary micturition the initial event is a reduction of intraurethral pressure, which reflects a relaxation of the pelvic floor and the paraurethral striated muscles (Figure 76.3) (Tanagho and Miller, 1970). These changes in the urethra are followed in a few seconds by a detrusor contraction and a rise in intravesical pressure that is maintained until the bladder empties. Reflex inhibition of the smooth and striated muscles of the urethra also contributes to the reduction of outlet resistance during micturition. These changes are coordinated by neural pathways at the thoracolumbar and sacral levels of the spinal cord.

muscle. Histochemical studies of the ganglia and nerves supplying the human lower urinary tract have shown that a large proportion of ganglion cells contain acetylcholinesterase (AChE) as well as vesicular acetylcholine transporter (VAChT) and therefore are presumably cholinergic. AChE and VChT-positive nerves are abundant in all parts of the bladder but are less extensive in the urethra (de Groat and Booth, 1993b; DeLancey et al., 2002; Morrison et al., 2002). Neuropeptide Y (NPY) and nitric oxide synthase (NOS) have also been identified in a large percentage (40–95%) of intramural ganglia of the human bladder. Several populations of axonal varicosities have been detected in close proximity to intramural ganglion cells including: substance P (SP) and calcitoningene related peptide (CGRP) positive axons, which Cerebral cortex Pontine micturition center

Hypothalamus PVN MPOA PeriVN

Innervation The innervation of the lower urinary tract is derived from three sets of peripheral nerves: sacral parasympathetic (pelvic nerves), thoracolumbar sympathetic (hypogastric nerves and sympathetic chain), and sacral somatic nerves (primarily the pudendal nerves) (see Figure 76.1) (Torrens and Morrison, 1986; de Groat et al., 1993).

Raphe nuclei

A5

Virus

Virus

Spinal interneurons

The sacral parasympathetic outflow, which in humans originates from the S2 to S4 segments of the spinal cord, provides the major excitatory input to the bladder (Chancellor and Yoshimura, 2002; DeLancey et al., 2002). Cholinergic preganglionic neurons located in the sacral parasympathetic nucleus in the intermediolateral region of the sacral spinal cord (Figures 76.4, 76.5) send axons to cholinergic ganglion cells in the pelvic plexus and in the bladder wall (Steers et al., 1990). Transmission in bladder ganglia is mediated by a nicotinic cholinergic mechanism, which is sensitive to modulation by various transmitter systems, including muscarinic, adrenergic, purinergic, and peptidergic (Table 76.1) (de Groat and Saum, 1972; de Groat et al., 1990; Keast et al., 1990; de Groat and Booth, 1993b). The ganglion cells in turn excite the bladder smooth

Virus

LC

Red nucleus

Preganglionic N.

Postganglionic N.

Parasympathetic Pathways

PAG

Virus

Urinary bladder

FIGURE 76.4 Structures in the brain and spinal cord of the adult and neonatal rat labeled after injection of pseudorabies virus into the urinary bladder or the urethra. Virus is transported transneuronally in a retrograde direction (dashed arrows). Normal synaptic connections are indicated by solid arrows. At long survival times the virus can be detected in neurons at specific sites in the spinal cord and brain, extending to the pontine micturition center in the pons (i.e. Barrington’s nucleus) and to the cerebral cortex. Other sites in the brain labeled by the virus are: (1) the paraventricular nucleus (PVN), medial preoptic area (MPOA) and periventricular nucleus (PeriVN) of the hypothalamus; (2) periaqueductal gray (PAG); (3) locus coeruleus (LC) and subcoerulueus; (4) red nucleus; (5) medullary raphe nuclei; and (6) the noradrenergic cell group designated as A5

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DH

DCM

(a)

LT

Bladder afferents

c-fos

DH

SPN

SPN

CC

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CC

Virus tracing

I III II IV V X

VI VII IM

IL

VIII Co IX VM

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(d)

FIGURE 76.5 Comparison of the distribution of bladder afferent projections to the L6 spinal cord of the rat (a) with the distribution of c-fos positive cells in the L6 spinal segment following chemical irritation of the lower urinary tract of the rat (b) and the distribution of interneurons in the L6 spinal cord labeled by transneuronal transport of pseudorabies virus injected into the urinary bladder (c). Afferents labelled by WGAHRP injected into the urinary bladder. c-fos immunoreactivity is present in the nuclei of cells. DH, dorsal horn; SPN, sacral parasympathetic nucleus; CC central canal. (d) Drawing shows the laminar organization of the cat spinal cord

are presumably collaterals of extrinsic sensory nerves; tyrosine hydroxylase (TH) and NPY axons, which are likely to be sympathetic axons; and vasoactive intestinal polypeptide (VIP), galanin (Gal), and NPY containing axons, which are presumably preganglionic nerve terminals (DeLancey et al., 2002). Parasympathetic neuroeffector transmission in the bladder is mediated by ACh acting on postjunctional muscarinic receptors (Morrison et al., 2002). Both M2 and M3 muscarinic receptor subtypes are expressed bladder smooth muscle (Table 76.1); however examination of subtype selective muscarinic receptor antagonists and studies of muscarinic receptor knockout mice have revealed that the M3 subtype is the principal receptor involved in excitatory transmission (Matsui et al., 2000, 2002). In bladders of various animals stimulation of parasympathetic nerves also produces a noncholinergic contraction that is resistant to atropine and other

muscarinic receptor-blocking agents. Activation of M3 receptors triggers intracellular Ca2 release; whereas activation of M2 receptors inhibits adenylate cyclase. The latter may contribute to bladder contractions by suppressing adrenergic inhibitory mechanisms which are mediated by beta-3 adrenergic receptors and stimulation of adenylate cyclase. Adenosine triphosphate (ATP) (Table 76.1) has been identified as the excitatory transmitter mediating the noncholinergic contractions (Ralevic and Burnstock, 1998; Burnstock, 2001). ATP excites the bladder smooth muscle by acting on P2X receptors which are ligand-gated ion channels. Among the seven types of P2X receptors that have been identified in the rat bladder, P2X1 is the major subtype expressed in the rat and also in the human bladder smooth muscle. Although purinergic excitatory transmission is not important in the normal human bladder it appears to be involved in bladders from patients with pathological conditions such as chronic urethral

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TABLE 76.1 Receptors for putative transmitters in the lower urinary tract Tissue

Cholinergic Adrenergic Other

Bladder body

 (M2)  (M3)

 (β2)  (β3)

 Purinergic (P2X1)  VIP  Substance P (NK2)

Bladder base

 (M2)  (M3)

 (α1)

 VIP  Substance P (NK2)  Purinergic (P2X)

Urothelium

 (M2)  (M3)

α β

 TRPV1  TRPM8  P2X  P2Y  Substance P Bradykinin (B2)

Urethra

 (M)

 (α1)  (α2)  (β)

 Purinergic (P2X)  VIP  Nitric oxide

Adrenergic  (M4) nerve terminals  (M1)

 (α2)

 NPY

Cholinergic  (M4) nerve terminals  (M1)

 (α1)

 NPY

Sphincter  (N) striated muscle

 Purinergic (P2X2/3) TRPV1

Afferent nerve terminals Ganglia

 (N)  (M1)

 (α1)  (α2)  (β)

 Enkephalinergic (δ)  Purinergic (P1)  Substance P

Abbreviations: VIP, vasoactive intestinal polypeptide; NPY, neuropeptide Y; TRP, transient receptor potential. Letters in parentheses indicate receptor type, e.g., M (muscarinic) and N (nicotinic). Plus and minus signs indicate excitatory and inhibitory effects

outlet obstruction or interstitial cystitis (Palea et al., 1993; Lee et al., 2000; Burnstock, 2001; Morrison et al., 2002; O’Reilly et al., 2002). Parasympathetic pathways to the urethra induce relaxation during voiding. In various species the relaxation is not affected by muscarinic antagonists and therefore is not mediated by ACh. However inhibitors of NOS block the relaxation in vivo during reflex voiding or block the relaxation of urethral smooth muscle strips induced in vitro by electrical stimulation of intramural nerves, indicating that NO is the inhibitory transmitter involved in relaxation (Ho et al., 1999; Burnett et al., 1997; Morrison et al., 2002). In some species neurally evoked contractions of the urethra are reduced by muscarinic receptor antagonists or by desensitization of P2X purinergic receptors, indicating that ACh or ATP are involved in excitatory transmission to urethral smooth muscle (Zoubek et al., 1993).

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Sympathetic Pathways Sympathetic preganglionic pathways that arise from the T11 to L2 spinal segments pass to the sympathetic chain ganglia and then to prevertebral ganglia in the superior hypogastric and pelvic plexuses (see Figure 76.1) and also to short adrenergic neurons in the bladder and urethra (de Groat et al., 1993; DeLancey et al., 2002). Sympathetic postganglionic nerves that release norepinephrine provide an excitatory input to smooth muscle of the urethra and bladder base, an inhibitory input to smooth muscle in the body of the bladder as well as inhibitory and facilitatory input to vesical parasympathetic ganglia (de Groat and Booth, 1993b; DeLancey et al., 2002). Histofluorescence microscopy in animals and humans has shown that the smooth muscle of the bladder base is richly innervated by adrenergic terminals, but the bladder body has a considerably weaker adrenergic innervation (Torrens and Morrison, 1986; Morrison et al., 2002). Vesical parasympathetic ganglion cells and the smooth muscle of the proximal urethra also receive an extensive adrenergic innervation (de Groat and Booth, 1993b; de Groat et al., 1993). Radioligand receptor binding studies showed that α-adrenergic receptors are concentrated in the bladder base and proximal urethra, whereas β-adrenergic receptors are most prominent in the bladder body (Anderson, 1993). These observations are consistent with pharmacological studies showing that sympathetic nerve stimulation or exogenous catecholamines produce β adrenoceptor-mediated inhibition of the body and α-adrenoceptor-mediated contraction of the base, dome and urethra. Molecular and contractility studies have shown that β3-adrenergic receptors elicit inhibition and α1-adrenergic receptors elicit contractions. The α1A-adrenergic receptor subtype is most prominent in the normal bladders but the α1D subtype is upregulated in bladders from patients with outlet obstruction, raising the possibility that α1-adrenoceptor excitatory mechanisms in the bladder might contribute to irritative lower urinary tract symptoms in patients with benign prostatic hyperplasia (de Groat and Yoshimura, 2001; Morrison et al., 2002).

Neural Modulatory Mechanisms Presynaptic modulatory mechanisms and synaptic communication between parasympathetic and sympathetic pathways to the bladder have been demonstrated in bladder ganglia and at postganglionic nerve terminals. In the cat, stimulation of the hypogastric (sympathetic) nerves elicits an initial inhibitory and a delayed facilitatory modulation of cholinergic

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transmission in parasympathetic bladder ganglia mediated by α2- and α1-adrenergic receptors, respectively (de Groat and Saum, 1972; Keast et al., 1990; de Groat and Booth, 1993b), indicating that sympathetic pathways can influence neural input to the bladder as well as directly affecting the bladder smooth muscle (Table 76.1). Transmission in cat bladder ganglia is also modulated by enkephalins released as cotransmitters along with ACh from preganglionic nerve terminals (de Groat and Kawatani, 1989; Kawatani et al., 1989). The inhibitory effect of enkephalins can be blocked by the opioid antagonist naloxone and occurs by a presynaptic inhibitory mechanism. Adenosine presumably derived from ATP released in the bladder ganglia also exerts an inhibitory action on nicotinic cholinergic transmission in cat bladder ganglia (de Groat and Booth, 1993b). Adrenergic and enkephalinergic inhibitory mechanisms in cat bladder ganglia are frequency dependent, being prominent at low frequencies (0.25–0.5 Hz) and markedly reduced at higher frequencies (1–10 Hz). This phenomenon is presumably related to the marked temporal facilitation that occurs in cat bladder ganglia at frequencies of preganglionic nerve stimulation above 0.5 Hz (de Groat and Saum, 1976; Booth and de Groat, 1979). It has been speculated that cat bladder ganglia function as high pass filters eliminating parasympathetic input to the bladder when preganglionic activity is low during urine storage, but significantly amplifying the input to the bladder when firing is increased during voiding (de Groat and Booth, 1993b). Thus the ganglion acts like a gating circuit. Frequency-dependent adrenergic and enkephalinergic inhibitory mechanisms complement this gating function by effectively inhibiting transmission during urine storage but turning off during voiding to allow complete bladder emptying. In the rat, transmission at synapses in the major pelvic ganglion occurs with a high safety factor, exhibits very little frequency-dependent modulation, and is relatively resistant to the actions of inhibitory transmitters (de Groat and Booth, 1993b). However, the autonomic pathways to the rat urinary bladder are susceptible to modulation at postganglionic sites (de Groat and Booth, 1993b; Zoubek et al., 1993; Tran et al., 1994; Somogyi et al., 1995, 1996, 1997, 1998). For example, NPY, which is a cotransmitter in cholinergic and adrenergic nerves in the rat, can act prejunctionally to suppress the release of both ACh and norepinephrine in the bladder and urethra (Zoubek et al., 1993; Tran et al., 1994). The NPY inhibition is also frequencydependent, being most prominent at low frequencies of nerve stimulation. In addition, in the rat urinary

bladder ACh released from parasympathetic nerves can induce a heterosynaptic facilitation of norepinephrine release from sympathetic nerves by acting on prejunctional M1 muscarinic receptors on the adrenergic terminals. Prejunctional M1 facilitatory and M2/4 inhibitory muscarinic modulatory mechanisms have also been identified on parasympathetic nerve terminals in the rat bladder (Somogyi et al., 1996, 1997, 1998). These receptors mediate positive and negative cholinergic feedback mechanisms, respectively, and regulate the release of ACh. Inhibitory M2/4 mechanisms are dominant at low frequencies of nerve activity and therefore could contribute to urine storage; whereas M1 facilitatory mechanisms are dominant at high frequencies of nerve stimulation and could contribute to an enhancement of neurally evoked bladder contractions during micturition to induce complete bladder emptying. Somatic Pathways The external urethral sphincter (EUS), which is composed of striated muscle, receives a somatic innervation via the pudendal nerve from anterior horn cells in the third and fourth sacral segments (see Figure 76.1). Branches of the pudendal nerve and other sacral somatic nerves also carry efferent impulses to muscles of the pelvic floor and proprioceptive afferent signals from these muscles, as well as sensory information from the urethra. Analysis of urethral closure mechanisms in the female rat during sneeze-induced stress conditions revealed that the major rise in urethral pressure occurred in the mid urethra and was mediated by efferent pathways in the pudendal nerve to the EUS as well as pathways in nerves to the iliococcygeus and pubococcygeus muscles but not by pathways in the sympathetic or parasympathetic nerves (Kamo et al., 2003). Studies of the biomechanical properties of the intact female rat urethra in vitro have confirmed the large contribution of striated muscle activity and nicotinic receptor mechanisms to the contractions of the mid urethra (Jankowski et al., 2004). Afferent Pathways Afferent axons innervating the urinary tract are present in the three sets of nerves (Bors and Comarr, 1971; de Groat et al., 1980, 1993; Bahns et al., 1986; de Groat, 1986). The most important afferents for initiating micturition are those passing in the pelvic nerve to the sacral spinal cord. These afferents are small myelinated (Aδ) and unmyelinated (C) fibers which convey information from receptors in the bladder

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wall to second order neurons in the spinal cord. Aδ bladder afferents in the cat respond in a graded manner to passive distension as well as active contraction of the bladder and exhibit pressure thresholds in the range of 5–15 mmHg, which are similar to those pressures at which humans report the first sensation of bladder filling (Morrison et al., 1999, 2002; Chancellor and Yoshimura, 2002). These fibers also code for noxious stimuli in the bladder. On the other hand, C-fiber bladder afferents in the cat have very high thresholds and commonly do not respond to even high levels of intravesical pressure (Habler et al., 1990; Morrison et al., 2002). However, activity in some of these afferents is unmasked or enhanced by chemical irritation of the bladder mucosa. These findings indicate that C-fiber afferents in the cat have specialized functions, such as the signaling of inflammatory or noxious events in the lower urinary tract. Nociceptive and mechanoceptive information is also carried in the hypogastric nerves to the thoracolumbar segments of the spinal cord (Bahns et al., 1986). In the rat, A-fiber and C-fiber bladder afferents are not distinguishable on the basis of stimulus modality; thus both types of afferents consist of mechanosensitive and chemosensitive populations (Sengupta and Gebhart, 1994; Morrison et al., 1999; Shea et al., 2000; Rong et al., 2002). C-fiber afferents that respond only to bladder filling have also been identified in the rat bladder and appear to be volume receptors possibly sensitive to stretch of the mucosa. C-fiber afferents are sensitive to the neurotoxins, capsaicin and resiniferatoxin as well as to other substances such as tachykinins, NO, ATP, prostaglandins, and neurotrophic factors released in the bladder by afferent nerves, urothelial cells, and inflammatory cells (Chuang et al., 2001; Vlaskovska et al., 2001; Lee et al., 2002; Morrison et al., 2002; Rong et al., 2002). These substances can sensitize the afferent nerves and change their response to mechanical stimuli. The properties of lumbosacral dorsal root ganglion cells innervating the bladder, urethra, and external urethral sphincter in the rat have been studied with patch clamp recording techniques in combination with axonal tracing methods to identify the different populations of neurons (Yoshimura and de Groat, 1997, 1999; Yoshimura et al., 1996, 2001; Yoshimura, Seki et al., 2003). Based on responsiveness to capsaicin, it is estimated that approximately 70% of bladder afferent neurons in the rat are of the C-fiber type. These neurons exhibit high threshold tetrodotoxinresistant sodium channels and action potentials and phasic firing (one to two spikes) in response to prolonged depolarizing current pulses. Approximately

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20% of the bladder C-fiber afferent neurons also are excited by ATP, which induces a depolarization and firing of afferent neurons by activating P2X3 or P2X2/3 receptors. These neurons express isolectin-B4 binding, which is commonly used as a marker for ATP responsive sensory neurons. On the other hand, A-fiber afferent neurons are resistant to capsaicin and ATP, exhibit low threshold tetrodotoxin-sensitive sodium channels and action potentials and tonic firing (multiple spikes) to depolarizing current pulses. C-fiber bladder afferent neurons also express a slowly decaying A-type K channel that controls spike threshold and firing frequency (Yoshimura et al., 1996; Yoshimura and de Groat, 1997, 1999). Suppression of this K channel induces hyperexcitability of bladder afferent nerves. These properties of dorsal root ganglion cells are consistent with the different properties of A-fiber and C-fiber afferent receptors in the bladder. Immunohistochemical studies have shown that a large percentage of bladder afferent neurons contain the peptides CGRP, vasoactive intestinal polypeptide (VIP), pituitary-adenyl cyclase activating peptide (PACAP), tachykinins, galanin, and opioid peptides (de Groat, 1987; Keast and de Groat, 1992; Maggi, 1993; Morrison et al., 2002). In the spinal cord, peptidergic nerve terminals have a distribution very similar to the distribution of pelvic nerve afferents labeled with HRP. Nerves containing these peptides are also common in the bladder, in the submucosal and epithelial layers, and around blood vessels (DeLancey et al., 2002). Peptidergic bladder afferent neurons in the rat also express TrkA, a high affinity receptor for nerve growth factor (NGF) and receptors for capsaicin (TRPV1) and tachykinins (NK-2 and NK-3 receptors). Capsaicin, a neurotoxin that can release peptides from afferent terminals, produces inflammatory responses, including plasma extravasation and vasodilation, when applied locally to the bladder in experimental animals (Maggi, 1993). These findings suggest that the neuropeptides may be important transmitters in the afferent pathways from the lower urinary tract. Tachykinins may also act back on afferent terminals in an auto-feedback manner to modulate the excitability of the terminals (Morrison et al., 2002). Urothelial-Afferent Interactions Recent studies have revealed that the urothelium, which has been traditionally viewed as a passive barrier at the bladder luminal surface (Lavelle et al., 2000; Lewis, 2000), also has specialized sensory and signaling properties that allow urothelial cells to respond to their chemical and physical environment and to

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engage in reciprocal chemical communication with neighboring nerves in the bladder wall (Figure 76.2) (Ferguson et al., 1997; Birder et al., 1998, 2001, 2003; Cockayne et al., 2000; Vlaskovska et al., 2001; Birder, Nakamura et al., 2002; Birder, Nealen et al., 2002; Morrison et al., 2002). These properties include: (1) expression of nicotinic, muscarinic, tachykinin, adrenergic, and capsaicin (TRPV1) receptors; (2) responsiveness to transmitters released from sensory nerves; (3) close physical association with afferent nerves; and (4) ability to release chemical mediators such as ATP and NO that can regulate the activity of adjacent nerves and thereby trigger local vascular changes and/or reflex bladder contractions. The role of ATP in urothelial-afferent communication has attracted considerable attention because bladder distension releases ATP from the urothelium and intravesical administration of ATP induces bladder hyperactivity, an effect blocked by administration of P2X purinergic receptor antagonists that suppress the excitatory action of ATP on bladder afferent neurons (Morrison et al., 2002). Mice in which the P2X3 receptor was knocked out exhibited hypoactive bladder activity and inefficient voiding (Cockayne et al., 2000), suggesting that activation of P2X3 receptors on bladder afferent nerves by ATP released from the urothelium was essential for normal bladder function. It has also been reported that urothelial cells obtained from patients or cats with a chronic painful bladder condition (interstitial cystitis) released significantly larger amounts of ATP in response to mechanical stretching than urothelial cells from normal patients (Sun et al., 2001; Birder et al., 2003). This raises the possibility that ATP-mediated signally between the urothelium and afferent nerves is involved in the triggering of painful bladder sensations.

TABLE 76.2

Reflex Mechanisms Controlling the Lower Urinary Tract The neural pathways controlling lower urinary tract function are organized as simple on–off switching circuits (Figure 76.3) that maintain a reciprocal relationship between the urinary bladder and urethral outlet (de Groat et al., 1981, 1993). The principal reflex components of these switching circuits are listed in Table 76.2 and illustrated in Figure 76.4. Intravesical pressure measurements during bladder filling in both humans and animals reveal low and relatively constant bladder pressures when bladder volume is below the threshold for inducing voiding (Figure 76.3). The accommodation of the bladder to increasing volumes of urine is primarily a passive phenomenon dependent upon the intrinsic properties of the vesical smooth muscle and quiescence of the parasympathetic efferent pathway. In addition, in some species urine storage is also facilitated by sympathetic reflexes that mediate an inhibition of bladder activity, closure of the bladder neck, and contraction of the proximal urethra (Table 76.2, Figure 76.6) (de Groat and Lalley, 1972; de Groat et al., 1981). During bladder filling the activity of the sphincter electromyogram (EMG) also increases (Figure 76.3), reflecting an increase in efferent firing in the pudendal nerve and an increase in outlet resistance which contributes to the maintenance of urinary continence. The storage phase of the urinary bladder can be switched to the voiding phase either involuntarily (reflexly) or voluntarily (Figure 76.3). The former is readily demonstrated in the human infant (Figure 76.2a) or in the anesthetized animal when the volume of urine exceeds the micturition threshold. At this point, increased afferent firing from tension receptors

Reflexes to the lower urinary tract

Afferent pathway

Efferent pathway

Central pathway

Urine storage Low level vesical afferent activity (pelvic nerve)

1. External sphincter contraction (somatic nerves)

Spinal reflexes

2. 3. 4. 5. 6.

Spinal reflex

Afferent activity from the external urethral sphincter Micturition High level vesical afferent activity (pelvic nerve)

Internal sphincter contraction (sympathetic nerves) Detrusor inhibition (sympathetic nerves) Ganglionic inhibition (sympathetic nerves) Sacral parasympathetic outflow inactive Inhibition of parasympathetic outflow

1. Inhibition of external sphincter activity

Spinobulbospinal reflexes

2. Inhibition of sympathetic outflow 3. Activation of parasympathetic outflow to the bladder 4. Activation of parasympathetic outflow to the urethra

Spinal reflex

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more complicated central organization involving spinal and spinobulbospinal pathways (Figure 76.6b).

in the bladder reverses the pattern of efferent outflow, producing firing in the sacral parasympathetic pathways and inhibition of sympathetic and somatic pathways. The expulsion phase consists of an initial relaxation of the urethral sphincter (Figure 76.3) followed in a few seconds by a contraction of the bladder, an increase in bladder pressure, and flow of urine. Relaxation of the urethral outlet is mediated by activation of a parasympathetic reflex pathway to the urethra that triggers the release of NO, an inhibitory transmitter, as well as by removal of adrenergic and somatic cholinergic excitatory inputs to the urethra. Secondary reflexes elicited by flow of urine through the urethra facilitate bladder emptying (de Groat et al., 1993). These reflexes require the integrative action of neuronal populations at various levels of the neuraxis (Figure 76.6). Certain reflexes, for example, those mediating the excitatory outflow to the sphincters and the sympathetic inhibitory outflow to the bladder, are organized at the spinal level (Figure 76.6a), whereas the parasympathetic outflow to the detrusor has a

Anatomy of Central Nervous Pathways Controlling the Lower Urinary Tract The reflex circuitry controlling micturition consists of four basic components: spinal efferent neurons, spinal interneurons, primary afferent neurons, and neurons in the brain that modulate spinal reflex pathways (de Groat et al., 1998; Morrison et al., 2002). Transneuronal virus tracing, measurements of gene expression, and patch clamp recording in spinal cord slice preparations have recently provided many new insights into the morphological and electrophysiological properties of these reflex components. Neurotropic viruses, such as pseudorabies virus (PRV), have been particularly useful since they can be injected into a target organ (urinary bladder, urethra, urethral sphincter) and then move intra-axonally from the periphery

PAG

Pontine micturition center

Pontine storage center

Hypogastric nerve

()

Hypogastric nerve

()

contracts bladder outlet  inhibits detrusor

Bladder

Pelvic nerve

Bladder

Pelvic nerve

()

()

() ()

() EUS (a)

Pudendal nerve

EUS

Pudendal nerve

(b)

FIGURE 76.6 Diagram showing neural circuits controlling continence and micturition. (a) Urine storage reflexes. During the storage of urine, distention of the bladder produces low level vesical afferent firing, which in turn stimulates (1) the sympathetic outflow to the bladder outlet (base and urethra) and (2) pudendal outflow to the external urethral sphincter. These responses occur by spinal reflex pathways and represent guarding reflexes, which promote continence. Sympathetic firing also inhibits detrusor muscle and modulates transmission in bladder ganglia. A region in the rostral pons (the pontine storage center) increases external urethral sphincter (EUS) activity. (b) Voiding reflexes. During elimination of urine, intense bladder afferent firing activates spinobulbospinal reflex pathways passing through the pontine micturition center, which stimulate the parasympathetic outflow to the bladder and urethral sphincter smooth muscle and inhibit the sympathetic and pudendal outflow to the urethral outlet. Ascending afferent input from the spinal cord may pass through relay neurons in the periaqueductal gray (PAG) before reaching the pontine micturition center

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to the central nervous system where they replicate and then pass retrogradely across synapses to infect second and third order neurons in the neural pathways (Nadelhaft and Vera, 1995; Vizzard et al., 1995; Sugaya et al., 1997). Since PRV can be transported across many synapses it could sequentially infect all of the neurons that connect directly or indirectly to the lower urinary tract (Figures 76.4 and 76.5). Pathways in the Spinal Cord Spinal Cord Anatomy The spinal cord gray matter is divided into three general regions: (1) the dorsal horn, which contains interneurons that process sensory input; (2) the ventral horn, which contains motor neurons; and (3) the intermediate region, which is located between the dorsal and ventral horns and which contains interneurons and autonomic preganglionic neurons. These regions are further subdivided into layers or laminae which are numbered starting with the superficial layer of the dorsal horn (lamina I) and extending to the ventral horn (lamina IX) and the commissure connecting the two sides of the spinal cord (lamina X) (Figure 76.5d). Efferent Pathways Parasympathetic preganglionic neurons innervating the lower urinary tract are located in the intermediolateral gray matter (laminae V–VII) in the sacral segments of the spinal cord (Morgan et al., 1979; de Groat et al., 1982; Araki and de Groat, 1997; Miura et al., 2001), whereas sympathetic preganglionic neurons are located in both medial (lamina X) and lateral sites (laminae V–VII) in the intermediate gray matter of the rostral lumbar spinal cord. Parasympathetic preganglionic neurons send dendrites to discrete regions of the spinal cord including the lateral and dorsal lateral funiculus, lamina I on the lateral edge of the dorsal horn, the dorsal gray commissure (lamina X); and gray matter and lateral funiculus ventral to the autonomic nucleus (de Groat et al., 1993, 1998). As discussed below, this dendritic structure very likely indicates the origin of important synaptic inputs to these cells. Pudendal motor neurons innervating the external urethral sphincter (EUS) in the cat are located in the ventrolateral division of Onuf’s nucleus and send dendritic projections into the lateral funiculus, lamina X, intermediolateral gray matter, and rostrocaudally within the nucleus (de Groat et al., 1998). The dendritic distribution of sphincter motor neurons (i.e., lateral, dorsolateral and dorsomedial) is similar to that of sacral preganglionic neurons, indicating that these two populations of neurons may receive synaptic inputs

from the same interneuronal sites and fiber tracts in the spinal cord. Afferent Projections in the Spinal Cord Afferent pathways from the LUT project to discrete regions of the dorsal horn that contain the interneurons as well as the soma and/or dendrites of efferent neurons innervating the LUT. Pelvic nerve afferent pathways from the urinary bladder of the cat and rat project into Lissauer’s tract at the apex of the dorsal horn and then pass rostrocaudally giving off collaterals that extend laterally and medially through the superficial layer of the dorsal horn (lamina I) into the deeper layers (laminae V–VII and X) at the base of the dorsal horn (Figure 76.5a) (Morgan et al., 1981; Steers et al., 1991). The lateral pathway which is the most prominent projection terminates in the region of the sacral parasympathetic nucleus (SPN) and also sends some axons to the dorsal commissure (Figure 76.5a). Pudendal afferent pathways from the urethra and urethral sphincter exhibit a similar pattern of termination in the sacral spinal cord (de Groat et al., 1993; Morrison et al., 2002), whereas pudendal afferent pathways from cutaneous receptors (e.g., penis) have a prominent projection to deeper layers of the dorsal horn and the dorsal commisssure. The overlap of bladder and urethral afferents in the lateral dorsal horn and dorsal commissure indicates these regions are likely to be important sites of viscerosomatic integration and be involved in coordinating bladder and sphincter activity. Spinal Interneurons As shown in Figure 76.5(b) and (c), interneurons retrogradely labeled by injection of pseudorabies virus into the urinary bladder of the rat are located in the regions of the spinal cord receiving afferent input from the bladder (Nadelhaft and Vera, 1995). Interneuronal locations also overlap in many respects with the dendritic distribution of the efferent neurons. A similar distribution of labeled interneurons has been noted following injections of virus into the urethra (Vizzard et al., 1995) or the external urethral sphincter, indicating a prominent overlap of the interneuronal pathways controlling the various target organs of the lower urinary tract. The spinal neurons involved in processing afferent input from the lower urinary tract have been identified by the expression of the immediate early gene, c-fos (Figure 76.5b). In the rat noxious or non-noxious stimulation of the bladder and urethra increases the levels of Fos protein, primarily the dorsal commissure, the superficial dorsal horn, and in the area of the sacral

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parasympathetic nucleus (Figure 76.5b). Some of these interneurons send long projections to the brain; whereas others make local connections in the spinal cord and participate in segmental spinal reflexes. Patch clamp recordings from parasympathetic preganglionic neurons in neonatal rat spinal slice preparation have revealed that interneurons located immediately dorsal and medial to the parasympathetic nucleus make direct monosynaptic connections with the preganglionic neurons (PGN) (Araki and de Groat, 1997). Microstimulation of interneurons in both locations elicits glutamatergic, N-methyl-D-aspartic acid (NMDA), and non-NMDA excitatory postsynaptic currents in PGN. Stimulation of a subpopulation of medial interneurons elicits GABAergic and glycinergic inhibitory postsynaptic currents. Thus local interneurons are likely to play an important role in both excitatory and inhibitory reflex pathways controlling the preganglionic outflow to the lower urinary tract. Glutamatergic excitatory inputs have also been elicited by stimulation of the projections from lamina X and the lateral funiculus (Miura et al., 2001, 2003). Pathways in the Brain The neurons in the brain that control the lower urinary tract have been studied with a variety of anatomical tracing techniques in several species. In the rat transneuronal virus tracing methods have identified many populations of central neurons that are involved in the control of the bladder, urethra, and the urethral sphincter including: Barrington’s nucleus (the pontine micturition center, PMC), medullary raphe nucleus, which contains serotonergic neurons, the locus coeruleus, which contains noradrenergic neurons, periaqueductal gray, and the A5 noradrenergic cell group. Several regions in the hypothalamus and the cerebral cortex also exhibited virus-infected cells. Neurons in the cortex were located primarily in the medial frontal cortex. Other anatomical studies in which anterograde tracer substances were injected into brain areas and then identified in terminals in the spinal cord are consistent with the virus tracing data. Tracer injected into the paraventricular nucleus of the hypothalamus labeled terminals in the sacral parasympathetic nucleus as well as the sphincter motor nucleus. On the other hand, neurons in the anterior hypothalamus project to the pontine micturition center (PMC). Neurons in the PMC in turn project primarily to the sacral parasympathetic nucleus and the lateral edge of the dorsal horn and the dorsal commissure, areas containing dendritic projections from the preganglionic neurons, sphincter motor neurons, and afferent inputs from the bladder. Conversely, projections from neurons in the lateral

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pons terminate rather selectively in the sphincter motor nucleus. Thus the sites of termination of descending projections from the PMC are optimally located to regulate reflex mechanisms at the spinal level.

Organization of Urine Storage and Voiding Reflexes Sympathetic Pathways The integrity of the sympathetic input to the lower urinary tract is not essential for the performance of micturition (Torrens and Morrison, 1986; de Groat et al., 1993). However, physiologic experiments in animals indicate that during bladder filling the sympathetic system does provide a tonic inhibitory input to the bladder as well as an excitatory input to the urethra. This sympathetic input is physiologically significant since surgical interruption or pharmacologic blockade of the sympathetic innervation can reduce urethral outflow resistance, reduce bladder capacity, and increase the frequency and amplitude of bladder contractions recorded under constant volume conditions. Sympathetic reflex activity is elicited by a sacrolumbar intersegmental spinal reflex pathway which is triggered by vesical afferent activity in the pelvic nerves (Figure 76.6a) (de Groat and Lalley, 1972). The reflex pathway is inhibited when bladder pressure is raised to the threshold for producing micturition. This inhibitory response is abolished by transection of the spinal cord at the lower thoracic level, indicating that it originates at a supraspinal site, possibly the pontine micturition center. Thus, the vesicosympathetic reflex represents a negative feedback mechanism whereby an increase in bladder pressure tends to increase inhibitory input to vesical ganglia and smooth muscle thus allowing the bladder to accommodate large volumes (Figure 76.6a). Increased sympathetic excitatory input to the bladder base and urethra would complement these mechanisms by increasing outflow resistance. Somatic Pathways to the Urethral Sphincter Motor neurons innervating the striated muscles of the urethral sphincter exhibit a tonic discharge which increases during bladder filling. This activity is mediated in part by low-level afferent input from the bladder (Figure 76.6a). During micturition the firing of sphincter motor neurons is inhibited. This inhibition is dependent in part on supraspinal mechanisms, since it is not as prominent in chronic spinal animals. Electrical stimulation of the PMC induces sphincter relaxation, suggesting that bulbospinal pathways from the pons may be responsible for maintaining the normal

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reciprocal relationship between bladder and sphincter (Blok, 2002; Chancellor and Yoshimura, 2002). Voiding Reflexes

Cortical diencephalic mechanisms ()

Spinobulbospinal Micturition Reflex Pathway Micturition is mediated by activation of the sacral parasympathetic efferent pathway to the bladder and the urethra (Figure 76.6b) as well as reciprocal inhibition of the somatic pathway to the urethral sphincter (Table 76.2) (Figure 76.6b). Studies in animals using brain lesioning techniques revealed that neurons in the brain stem at the level of the inferior colliculus (i.e. the PMC) have an essential role in the control of the parasympathetic component of micturition (Torrens and Morrison, 1986; Mallory et al., 1991; de Groat et al., 1993). Removal of areas of the brain above the inferior colliculus by intercollicular decerebration usually facilitates micturition by elimination of inhibitory inputs from more rostral centers (Yokoyama et al., 2000). However, transections at any point below the colliculi abolish micturition. Bilateral lesions in the rostral pons in the region of the locus coeruleus in cats or Barrington’s nucleus in rats also abolish micturition, whereas electrical or chemical stimulation at these sites triggers bladder contractions and micturition (Mallory et al., 1991). These observations led to the concept of a spinobulbospinal micturition reflex pathway that passes through the pontine micturition center (PMC) (Figure 76.6b). The pathway functions as an “on–off” switch that is activated by a critical level of afferent activity arising from tension receptors in the bladder and is in turn modulated by inhibitory and excitatory influences from areas of the brain rostral to the pons (e.g., diencephalon and cerebral cortex) (Figure 76.7) (Torrens and Morrison, 1986; de Groat et al., 1993). In contrast to the reflex control of the bladder, the parasympathetic control of the urethra in the rat appears to be dependent on pathways organized in the spinal cord that are modulated by input from the brain. Nitric oxide-mediated relaxation of the urethra that occurs in response to bladder distension is reduced but not eliminated by acute transection of the spinal cord (Kakizaki et al., 1997). The reflex relaxation of the urethra is also very prominent in chronic spinal cord transected rats. Electrophysiological studies in cats and rats have confirmed that the parasympathetic efferent outflow to the urinary bladder is activated by a long latency supraspinal reflex pathway (de Groat et al., 1981, 1982, 1998; Mallory et al., 1989; Cheng et al., 1999). In cats, recordings from sacral parasympathetic preganglionic neurons innervating the urinary bladder show that

Brain stem switch

Spinal tract neurons

MYELINATED AFFERENTS (Aδ)

Capsaicin block Spinal efferent mechanisms

UNMYELINATED AFFERENTS (C)

Ganglia

Cold stimulation excites

VESICAL AFFERENTS

Detrusor

FIGURE 76.7 Diagram showing the organization of the parasympathetic excitatory reflex pathway to the detrusor muscle. Scheme is based on electrophysiologic studies in cats. In animals with an intact spinal cord, micturition is initiated by a supraspinal reflex pathway passing through a center in the brain stem. The pathway is triggered by myelinated afferents (Aδ-fibers), which are connected to the tension receptors in the bladder wall. Injury to the spinal cord above the sacral segments (X) interrupts the connections between the brain and spinal autonomic centers and initially blocks micturition. However, over a period of several weeks following cord injury, a spinal reflex mechanism emerges, which is triggered by unmyelinated vesical afferents (C-fibers); the A-fiber afferent inputs are ineffective. The C-fiber reflex pathway is usually weak or undetectable in animals with an intact nervous system. Stimulation of the C-fiber bladder afferents by instillation of ice water into the bladder (cold stimulation) activates voiding responses in patients with spinal cord injury. Capsaicin (20–30 mg, subcutaneously) blocks the C-fiber reflex in chronic spinal cats, but does not block micturition reflexes in intact cats. Intravesical capsaicin also suppresses detrusor hyper-reflexia and cold-evoked reflexes in patients with neurogenic bladder dysfunction

reflex firing occurs with a long latency (65–100 msec) following stimulation of myelinated (Aδ) vesical afferents in the pelvic nerve. Afferent stimulation also evokes negative field potentials in the rostral pons at latencies of 30–40 msec; whereas electrical stimulation in the pons excites sacral preganglionic neurons at latencies of 45–60 msec. The sum of the latencies for the spinobulbar and bulbospinal components of the reflex pathway approximate the latency for the entire reflex. In cats it is believed that the ascending afferent pathways from the spinal cord project to a relay station in the periaqueductal gray (PAG) which then connects to the PMC (Figure 76.6b) (Blok, 2002). Pontine Micturition Center (PMC) Physiological and anatomical experiments have provided substantial support for the concept that neuronal circuitry in the PMC functions as a switch

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LOWER URINARY TRACT

Pre-frontal cortex

Insula

Anterior cingulate gyrus

PAG

Pons

FIGURE 76.8 Regions in the human brain identified in PET imaging studies that exhibit differences in activity based on whether the bladder was full or empty (PAG, periaqueductal gray)

in the micturition reflex pathway. The switch seems to regulate bladder capacity and also coordinate the activity of the bladder and external urethral sphincter. Electrical or chemical stimulation in the PMC of the rat, cat, and dog induces: (1) a suppression of urethral sphincter EMG, (2) firing of sacral preganglionic neurons, (3) bladder contractions, and (4) release of urine (Torrens and Morrison, 1986; Mallory et al., 1989; de Groat et al., 1993; Blok, 2002). On the other hand, microinjections of putative inhibitory transmitters into the PMC of the cat can increase the volume threshold for inducing micturition and in high doses completely block reflex voiding indicating that synapses in this region are important for regulating the set point for reflex voiding and also are an essential link in the reflex pathway (Mallory et al., 1989). Brain imaging studies using positron emission tomography (PET) or functional magnetic resonance imaging (FMRI) have identified increased neuronal activity in the PMC and PAG during voiding (Figure 76.8) (Athwal et al., 1999, 2001; Blok et al., 1997, 1998). Suprapontine Control of Micturition The organization of suprapontine pathways controlling micturition is less well defined, despite the fact that there is a large body of literature dealing with the responses of the lower urinary tract to lesions or electrical stimulation of the brain. In brief, it appears that the voluntary control of micturition in humans is dependent (1) upon connections between the frontal cortex and the septal and the preoptic regions of the hypothalamus, and (2) connections between the paracentral lobule and the brain stem and spinal cord (Torrens and Morrison, 1986; de Groat et al.,

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1993). Lesions to these areas of cortex resulting from tumors, aneurysms or cerebrovascular disease, appear to remove inhibitory control over the anterior hypothalamic area which normally provides an excitatory input to micturition centers in the brain stem (Yokoyama et al., 2000). Electrical stimulation of anterior and lateral hypothalamic regions in animals induces bladder contractions and voiding, whereas stimulation of posterior and medial hypothalamic areas inhibits bladder activity. According to results obtained in cats, the inhibitory and excitatory effects of hypothalamic stimulation are believed to be mediated, respectively, by activation of sympathetic inhibitory pathways and activation of parasympathetic excitatory pathways to the bladder. Human PET scan studies have revealed that two cortical areas (the right dorsolateral prefrontal cortex and the anterior cingulate gyrus) were active (i.e., exhibited increased blood flow) during voiding (Figure 76.8) (Blok et al., 1997, 1998; Blok, 2002). The hypothalamus including the preoptic area as well as the pons and the PAG also showed activity in concert with voluntary micturition. It is noteworthy that the active areas were predominately on the right side of the brain, which is consistent with reports that urge incontinence is correlated with lesions in the right hemisphere. Other PET studies that examined the changes in brain activity during filling of the bladder revealed that increased activity occurred in the PAG, the midline pons, the mid-cingulate gyrus, and bilaterally in the frontal lobes (Athwal et al., 1999, 2001; Matsuura et al., 2002). It was concluded that the results were consistent with the notion that the PAG receives information about bladder fullness and then relays this information to other brain areas involved in the control of bladder storage. A PET study was also conducted in adult female volunteers to identify brain structures involved in voluntary control of pelvic floor muscles (Blok et al., 1997). The results revealed that the superomedial precentral gyrus, the most medial portion of the motor cortex, is activated during pelvic floor contraction. In addition the right anterior cingulate gyrus was activated during sustained pelvic floor straining.

Neurotransmitters in Micturition Reflex Pathways Excitatory Neurotransmitters Excitatory transmission in the central pathways to the lower urinary tract may depend on several types of transmitters, including: glutamic acid, neuropeptides (substance P, VIP, PACAP), norepinephrine, acetylcholine, and nitric oxide (de Groat et al.,

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1993; Morrison et al., 2002). Experiments in rats have revealed that glutamic acid is an essential transmitter in the ascending, pontine and descending limbs of the spinobulbospinal micturition reflex pathway and in the reflex pathways controlling the external urethral sphincter. NMDA and non-NMDA glutamatergic synaptic mechanisms appear to interact synergistically to mediate transmission in these pathways. Inhibitory Neurotransmitters Damage to central inhibitory mechanisms following disease or injury to the nervous system leads to failure of urine storage and bladder hyperactivity and incontinence (Fowler et al., 1992; Yoshimura et al., 1998; Yokoyama et al., 2000, 2002; Wein, 2002; Yoshimura, Kuno et al., 2003). Animal studies indicate that transmission in the PMC and spinal cord is regulated by multiple transmitters, including opioid peptides (enkephalins), inhibitory amino acids (GABA, glycine), 5-hydroxytryptamine, acetylcholine, and dopamine (de Groat et al., 1993; Yoshimura et al., 1998; Morrison et al., 2002; Yokoyama et al., 2002; Yoshimura, Kuno et al., 2003). Experiments in anesthetized animals indicate that GABA and enkephalins exert a tonic inhibitory control in the PMC and regulate bladder capacity. The inhibitory effects are mediated by GABAA and μ opioid receptors, respectively. Administration of GABAA or opioid-receptor antagonists into the PMC reduces the micturition volume threshold indicating that setpoint for reflex voiding is regulated by inhibitory mechanisms in the brain (Figure 76.6) (Mallory et al., 1991; de Groat et al., 1993; de Groat and Yoshimura, 2001). GABA and enkephalins also have inhibitory actions in the spinal cord. Baclofen, a GABAB agonist that mimics the inhibitory effect of GABA, has been used clinically via intrathecal administration in patients with hyperactive bladders to suppress bladder activity and to promote urine storage. Patients with idiopathic Parkinson’s disease often exhibit bladder hyperactivity, suggesting a role of dopamine in the control of bladder function. Animal models for Parkinson’s disease have been developed in monkeys and rats by administering neurotoxins (MPTP or 6-hydroxydopamine) to destroy dopamine neurons (Yoshimura et al., 1998; de Groat and Yoshimura, 2001; Yoshimura, Kuno et al., 2003). Following treatment, the animals show motor symptoms typical of Parkinson’s disease and also have hyperactive bladders. Pharmacological studies in MPTP-treated monkeys revealed that the bladder hyperactivity was due to the loss of dopaminergic inhibition mediated by D1 dopaminergic receptors. D2

dopaminergic receptors can mediate a facilitation of micturition. Activation of these receptors also contributes to the bladder hyperactivity after cerebral infarction in the rat (Yokoyama et al., 2002).

Neurogenic Dysfunction of the Lower Urinary Tract Neurogenic disturbances of micturition can be classified into two general categories: failure to store and failure to eliminate urine (Wein, 2002). Problems with storage occur with differing degrees of severity, ranging from reduced bladder capacity and frequency of urination to urgency and incontinence. A common finding is that disorders affecting the brain, particularly suprapontine areas, produce hyperactive or uninhibited bladders. Cerebrovascular accidents, Parkinson’s disease, tumors, or demyelinating diseases are common causes of this problem (Bors and Comarr, 1971; Fowler et al., 1992; Betts, 1999; Sakakibara and Fowler, 1999; DasGupta and Fowler, 2003). Failure to eliminate urine occurs in various conditions that interrupt the detrusor to detrusor excitatory reflex pathway or that interfere with the coordination between detrusor and sphincters (Chancellor and Yoshimura, 2002; Wein, 2002). Areflexic bladders can occur with (1) lower motor neuron lesions, including damage to the pelvic nerve or the sacral spinal cord, (2) lesions of the afferent pathways (e.g., diabetes, tabes dorsalis, pernicious anemia, herniated intervertebral disc), or (3) the acute stage of spinal cord injury (an upper motor neuron lesion). Spinal Injury Complete spinal cord injury rostral to the lumbosacral level eliminates voluntary and supraspinal control of voiding, leading initially to an areflexic bladder and complete urinary retention followed by a slow development of automatic micturition and bladder hyperactivity mediated by spinal reflex pathways (Bors and Comarr, 1971; Torrens and Morrison, 1986; Wein, 2002). Following recovery of reflex bladder activity these patients usually still exhibit urinary retention, owing to a loss of coordination between the bladder and sphincter (detrusor–sphincter dyssynergia), Since sphincter dyssynergia is rarely seen in patients with suprapontine lesions who also exhibit hyperactive bladders, the condition has been attributed to the elimination of bulbospinal inhibitory pathways, which originate in the pontine micturition center (Figure 76.7). A similar mechanism may account for dyssynergia of the smooth muscle sphincter, which is mediated by sympathetic

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LOWER URINARY TRACT

efferent pathways. Dyssynergia is treated surgically (sphincterotomy) or with drugs (skeletal muscle relaxants, botulinum toxin, adrenergic blocking agents) that depress somatic or sympathetic reflex pathways. The mechanisms contributing to the recovery of bladder function have been studied in rats and cats using electrophysiologic techniques (de Groat et al., 1982; Mallory et al., 1989; de Groat et al., 1990; Yoshimura and de Groat, 1997; Cheng et al., 1999; Morrison et al., 2002). These studies revealed that the micturition reflex pathways in spinal intact and chronic spinal animals are markedly different. In both species, the central delay for the micturition reflex in chronic spinal animals is considerably shorter (5 msec in rats; 15–40 msec in cats) than in intact animals (60–75 msec). In addition, in chronic spinal cats the afferent limb of the micturition reflex consists of unmyelinated (C-fiber) afferents, whereas in intact cats it consists of myelinated (Aδ) afferents (Figure 76.7). This was not only demonstrated with electrophysiological recording but also by administering capsaicin, a neurotoxin known to disrupt the function of C-fiber afferents. In normal cats, capsaicin injected systemically in large doses did not block reflex contractions of the bladder or the Aδ-fiber evoked bladder reflex. However, in chronic spinal cats (3–6 weeks after spinal transection) capsaicin completely blocked the rhythmic bladder contractions induced by bladder distension and blocked the C-fiber evoked reflex firing recorded on bladder postganglionic nerves (Cheng et al., 1999). These data indicate that two distinct central pathways (supraspinal and spinal) utilizing different peripheral afferent limbs (A and C fiber) can mediate detrusor to detrusor reflexes in the cat (Figure 76.7). The properties of the peripheral C-fiber afferent receptors also appear to be changed in the spinal-injured cat. C-fiber bladder afferents in the cat usually do not respond to bladder distension (i.e., silent C-fibers) (Habler et al., 1990). However, in chronic spinal cats bladder distension initiates automatic micturition by activating C-fiber afferent neurons (de Groat et al., 1990; Cheng et al., 1999). Thus, spinal injury must change the properties of C-fiber afferent receptors in the bladder. Experiments in spinal cord-injured rats revealed that C-fiber dorsal ganglion neurons innervating the bladder increase in size (Kruse et al., 1995; Yoshimura and de Groat, 1997), exhibit increased excitability related in part to a downregulation of A-type K channels, and exhibit a shift in the expression of Na channels from high threshold TTX-resistant subtype to TTX-sensitive subtype of Na channels. Neurotrophic factors appear to contribute to this change because after spinal cord injury expression of neurotrophic factors including NGF increases in the bladder in concert

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with bladder hypertrophy (Morrison et al., 2002). The latter most likely occurs owing to overdistension-elicited detrusor-sphincter dyssynergia and urinary retention. A contribution of NGF to the change in bladder afferent neuron excitability and detrusor hyperreflexia in spinal cord-injured rats is supported by several observations, including: (1) administration of exogenous NGF to the bladder or spinal cord can induce bladder hyperactivity and increased excitability of bladder afferent neurons accompanied by downregulation of A-type K channels; (2) immunoneutralization of NGF in the spinal cord reduces the bladder hyperreflexia in spinal cord-injured rats and reduces the NGF levels in the lumbosacral dorsal root ganglia (Seki et al., 2002). The effects of NGF immunoneutralization can be duplicated by systemic or intravesical administration of C-fiber neurotoxins, capsaicin or resiniferatoxin (de Groat et al., 1990; Cheng et al., 1999). Intravesical administration of these toxins in patients with neurogenic bladder dysfunction also reduces bladder hyperactivity, incontinence episodes, and increases bladder capacity (de Groat and Yoshimura, 2001; Morrison et al., 2002). Other reflexes that are unmasked following spinal cord injury also appear to be mediated by C-fiber afferents. For example, it is known that instillation of cold water into the bladder of patients with upper motor neuron lesions induces reflex voiding (the Bors Ice Water Test) (Bors and Comarr, 1971; de Groat et al., 1993; Chancellor and Yoshimura, 2002). This reflex does not occur in normal patients. Recently, it has been shown in the cat that C-fiber bladder afferents are responsible for cold-induced bladder reflexes (Figure 76.7). The Ice Water Test is also positive in patients with multiple sclerosis, cerebrovascular disease, Parkinson’s disease, and benign prostatic hypertrophy, as well as in normal infants. These observations suggest that cold evoked bladder reflexes are mediated by a primitive spinal pathway that is present in the immature nervous system and then is suppressed during postnatal development as supraspinal mechanisms assume the dominant role in controlling micturition. However, when supraspinal controls are eliminated by spinal cord injury or neurologic diseases, such as multiple sclerosis, it appears that the spinal reflexes re-emerge. Other reflexes also emerge after spinal cord injury. For example, arterial pressor responses induced by bladder distension (autonomic dysreflexia) occur in spinal-injured patients and animals. In normal and spinal-injured rats the increase in blood pressure induced by isometric bladder contractions or distension is suppressed by capsaicin, the C-fiber neurotoxin (Chuang et al., 2001). This suggests that C-fiber afferents

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mediate bladder-vascular reflexes in this species. Similar capsaicin-sensitive afferents may be responsible for autonomic dysreflexia, in quadriplegic patients (Chancellor and Yoshimura, 2002).

SEX ORGANS The physiologic changes initiated by erotic stimuli can be divided into four distinct phases (excitement, plateau, orgasm, and resolution) which have been designated collectively “the sexual response cycle” (Masters and Johnson, 1966). Although anatomic differences obviously preclude identical responses in male and female during each phase of the cycle, it is clear that similar vascular responses (skin flush, penile and clitoral erection), secretory responses (stimulation of the prostate, bulbourethral gland, glands of Littre in the male; Bartholin’s and paraurethral glands in the female), and the responses of smooth and striated muscles occur in both sexes (Semans and Langworthy, 1938; Sachs and Meisel, 1988; de Groat and Booth, 1993a; Andersson and Wagner, 1995; Beck, 1999; Sáenz de Tejada et al., 2000; Burnett and Truss, 2002). This section will review the neural control of the principal autonomic and somatic responses in the male sexual response cycle (erection, secretion, emission, and ejaculation).

Innervation Parasympathetic Pathways As described earlier with regard to micturition, three sets of nerves provide an innervation to the urogenital system (see Figure 76.1). Parasympathetic preganglionic axons from the sacral spinal cord provide

the efferent outflow to erectile tissue in the penis and to the seminal vesicles, prostate, and urethral glands (Table 76.3). The sacral pathways have cholinergic ganglionic relay stations in the pelvic plexus and possibly in the effector organs. The postganglionic parasympathetic neurons synthesize and release several transmitters, including NO, ACh, VIP, and ATP. NO is thought to be the major transmitter mediating neurally induced erections (Elbadawi and Goodman, 1980; Burnett et al., 1992, 2002; de Groat and Booth, 1993a; Anderson, 1993; Andersson and Wagner, 1995; Argiolas and Melis, 1995; Andersson, 2001, 2003; Burnett, 2002), whereas ACh appears to be important in stimulating secretion in glands (Bruschini et al., 1978). The functions of VIP and ATP are uncertain.

Sympathetic Pathways The sympathetic innervation of the genital organs consisting of preganglionic neurons in the thoracolumbar segments of the spinal cord and postganglionic neurons in the paravertebral and prevertebral ganglia (inferior mesenteric and pelvic ganglia) provides an input to the penile erectile tissue as well as to the smooth muscle of ductus deferens, seminal vesicles, urethra, and prostate (Table 76.3) (Newman et al., 1982; de Groat and Booth, 1993a; Anderson, 1993; Andersson and Waganer, 1995; Kihara and de Groat, 1997; Lundberg et al., 2000; Andersson, 2003; Andersson and Wyllie, 2003). Sympathetic postganglionic axons are carried in the pudendal nerve and in nerves arising from the pelvic plexus. Most sympathetic postganglionic neurons are noradrenergic and release norepinephrine, ATP and neuropeptides such as NPY. These nerves produce constriction of blood vessels and cause a contraction of the vas deferens and urethra-bladder neck (Diederichs et al., 1990;

TABLE 76.3 Male sexual reflexes Response

Afferent nerves

Efferent nerves

Central pathway

Effector organ

Penile erection Reflexogenic

Pudendal nerve

Sacral parasympathetic

Sacral spinal reflex

Dilation of arterial supply to corpus cavernosum and corpus spongiosum

Auditory, imaginative, visual

Sacral parasympathetic, lumbar sympathetic

Supraspinal origin

Glandular secretion

Pudendal nerve

Sacral parasympathetic, lumbar sympathetic

Sacral spinal reflex

Seminal vesicle and prostate

Seminal emission

Pudendal nerve

Lumbar sympathetic

Intersegmental spinal reflex (sacrolumbar)

Contraction of vas deferens, ampulla, seminal vesicles, prostate, and closure of bladder neck

Ejaculation

Pudendal nerve

Somatic efferents in pudendal nerve

Sacral spinal reflex

Rhythmic contractions of bulbocavernosus and ischiocavernosus muscles

Psychogenic

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SEX ORGANS

de Groat and Booth, 1993a). Some sympathetic nerves arising in the pelvic plexus release NO and presumably induce vasodilation (Semans and Langworthy, 1938; Root and Bard, 1947; de Groat and Booth, 1993a; Sáenz de Tejada et al., 2000). Somatic Pathways The pudendal nerve arising from the S2 to S4 segments of the spinal cord provides an efferent excitatory input to the striated muscles (bulbocavernosus and ischiocavernosus) involved in ejaculation (Marson and McKenna, 1996). The pudendal nerve also contains the principal afferent pathway from the penis (Table 76.3) and from the clitoris and vagina in the female. Afferent innervation to the uterine cervix and uterus travel in the pelvic and sympathetic nerves.

Erection Peripheral Mechanisms Penile erection, which is one of the first responses to occur during sexual arousal, is a vascular phenomenon resulting from a neurally mediated increase in blood flow to the penile erectile tissue (corpora cavernosa and corpus spongiosum) (Sáenz de Tejada et al., 2000; Burnett, 2002; Andersson, 2003). The erectile tissue consists of large venous sinuses that contain very little blood when the penis is flaccid, but distend considerably when blood flow is increased. Dilation in the arterial supply to the cavernous tissue coupled with a relaxation of the sinusoidal smooth muscle in the trabecular tissue (increased compliance) is responsible for erection. During the initiation of erection, corpus blood flow increases 7 to 30 times (Sáenz de Tejada et al., 2000). The neural pathways producing erection arise from both the sacral (parasympathetic) and the thoracolumbar (sympathetic) segments of the spinal cord (Table 76.3). The postganglionic neurons in these pathways express nNOS and all smooth muscle regions of the penis are richly innervated by nerves containing nNOS (Burnett et al., 1992, 2002; Andersson, 2001; Burnett, 2002). The endothelial cells in the penis also express eNOS and can release NO in response to mechanical stimuli (shear stress) associated with changes in blood flow (Burnett, 2002; Burnett et al., 2002; Hurt et al., 2002; Andersson, 2003). NO directly activates soluble guanylate cyclase in the penile smooth muscle to increase the formation of cGMP which in turn activates cGMP-dependent protein kinases (cGK I) (Hedlund et al., 2000; Sáenz de Tejada et al., 2000; Hashitani et al., 2002; Andersson, 2003). Inactivation of cGK I in mice

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severely reduces reproductive function and markedly reduces the ability of corpus cavernosal tissue to relax in response to neurally, endothelially or exogenously administered NO (Hedlund et al., 2000; Andersson, 2003). cGK I is thought to act by multiple mechanisms including suppression of membrane and sarcoplasmic reticulum Ca2 channels and suppression of IP3 induced intracellular Ca2 release. The effects of NO are terminated by the enzymatic breakdown of cGMP by phosphodiesterase. Pharmacologic studies in animals have shown that erections elicited by stimulation of autonomic nerves are reduced by NOS inhibitors and enhanced by phosphodiesterase (PDE) inhibitors (Burnett et al., 1992; Burnett, 2001, 2002). One type of PDE (PDE-5) is highly expressed in penile tissues. Several PDE5 inhibitors are currently used to treat erectile dysfunction (Goldstein et al., 1998). Endothelial NOS has also been implicated in neurally mediated erections (Hurt et al., 2002; Andersson, 2003). It has been suggested that synthesis of NO in nerves by nNOS initiates erections. However, this response, which is relatively brief, triggers increased blood flow and expansion of the penile vasculature and sinusoidal spaces. The resulting shear force on the endothelium activates a phosphatidylinositol 3-kinase (PI3-kinase) pathway that in turn stimulates the serine/threonine protein kinase, Akt, causing direct phosphorylation of eNOS in endothelial cells. After phosphorylation the Ca2 requirement for eNOS activity is reduced causing increased production of NO which induces a prolonged penile erection. Intercellular communication via gap junctions is thought to promote the spread of signals throughout the smooth muscle of the penis and amplify the relaxation (Andersson, 2003). Exogenous ACh acts on postjunctional muscarinic receptors to elicit a contraction or relaxation of corpus cavernosum preparations. The latter effect is mediated by M3 receptors and release of NO from the endothelium. However, the failure of exogenous acetylcholine to produce erection and the failure of atropine to block erections indicates that cholinergic mechanisms are not essential for neurally mediated increases in penile blood flow (de Groat and Booth, 1993a). On the other hand, ACh may act on prejunctional inhibitory receptors on adrenergic nerve terminals to suppress the release of norepinephrine and thereby facilitate NOmediated erections (Sáenz de Tejada et al., 2000). VIP activates G-protein coupled receptors to stimulate adenylate cyclase and increase cAMP which in turn stimulates cAMP-dependent kinases to suppress contractile mechanisms in vascular smooth muscle and smooth muscle of the trabecular tissue of the penis (Anderson, 1993; Andersson and Wagner, 1995;

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Andersson, 2001). While it is clear that exogenous VIP can relax human cavernosal tissue strips in vitro, it has never been shown that VIP released from nerves is responsible for relaxation of penile smooth muscle in vitro or in vivo. The adrenergic innervation of the penis which provides an excitatory or constrictor input to penile blood vessels is thought to be involved primarily in detumescence (Diederichs et al., 1990; Anderson, 1993; de Groat and Booth, 1993a; Andersson and Wagner, 1995; Chitaley et al., 2001, 2002; Mills and Chitaley, 2001; Andersson, 2003). Electrical stimulation of sympathetic axons in either the hypogastric or pudendal nerves in various animals produces a substantial reduction in penile blood flow (Sachs and Meisel, 1988; de Groat and Booth, 1993a). The effect is blocked by α-adrenergic blocking agents. In some animals, a partial erection can be elicited by the administration of α-adrenergic blocking agents, suggesting that tonic sympathetic vasoconstrictor mechanisms may have an inhibitory influence on erection (de Groat and Booth, 1993a). Several mechanisms have been implicated in the noradrenergic vasoconstrictor effect, including activation of phospholipase C followed by formation of IP3 and DAG which leads to release of intracellular Ca2 as well as sensitization of contractile mechanisms to Ca2 (Anderson, 1993; Andersson, 2001, 2003; Chitaley et al., 2001, 2002; Mills et al., 2001). Ca2 sensitization has been linked to activation of an intracellular signaling pathway involving Rho kinase which can be stimulated by G protein couple receptors such as α-adrenergic and endothelin receptors, both of which can elicit contraction of penile smooth muscle. Activation of Rho kinase leads to a change in the phosphorylation state of myosin light chain kinase resulting in phosphorylation of myosin and subsequent smooth muscle contraction. Administration of a Rho kinase inhibitor triggered a significant increase in intracavernous pressure and an NO independent erection (Chitaley et al., 2001). Similarly the expression of a dominant negative construct to downregulate Rho kinase enhanced erectile function in rats (Chitaley et al., 2002). Other studies have revealed that NO may act to relax penile smooth muscle by suppressing Rho kinase activity (Andersson, 2003). These studies have raised the possibility that antagonism of Rho kinase activity may yield new treatments for erectile dysfunction. Central Mechanisms Penile erection is primarily an involuntary or reflex phenomenon that can be elicited by a variety of stimuli and by at least two distinct central mechanisms (Table 76.3). For example, psychogenic erections are initiated

by supraspinal centers in response to auditory, visual, olfactory, tactile, and imaginative stimuli (Masters and Johnson, 1966; Andersson and Wagner, 1995; McKenna, 1998; Sáenz de Tejada et al., 2000). The efferent limb of the reflex pathway can be in either the thoracolumbar or the sacral autonomic outflow (Root and Bard, 1947; Chapelle et al., 1980). Reflexogenic erections, which are initiated by exteroceptive stimulation of the genital regions, are mediated by a sacral spinal reflex mechanism having an afferent limb in the pudendal nerves and an efferent limb in the sacral parasympathetic nerves. Electrophysiological studies in animals have revealed that the reflex occurs with a short central delay and is not altered by transection of the spinal cord above the lumbar level (Steers et al., 1988). In patients with lower motor neuron lesions involving the sacral spinal cord, reflexogenic erections are abolished but psychogenic erections may still occur via the sympathetic innervation to the penis (Chappelle et al., 1980; Sachs and Meisel, 1988; de Groat and Booth, 1993a). In patients with spinal cord lesions above the level of T12 psychogenic erections are abolished but reflexogenic reactions persist. Under normal conditions it is likely that psychic and reflexogenic stimuli act synergistically in producing erections. It is also known that psychologic factors, such as guilt and hostility, or endocrine disturbances that influence libido or supraspinal centers, can interfere with erectile reflexes (Masters and Johnson, 1966; Beck, 1999; Betts, 1999; Sakakibara and Fowler, 1999; Goldstein et al., 2000; Lundberg et al., 2000; DasGupta and Fowler, 2003). In addition, any factor that restricts blood flow to erectile tissue will alter erection. Thus, atherosclerosis, thrombosis, or a depression of autonomic transmission by either disease or drugs can compromise the vascular responses necessary for tumescence. In adult diabetics, where both vascular and neural pathology are common, the incidence of erectile dysfunction is very high (Melman et al., 1980; Goldstein et al., 2000; Burnett, 2001).

Glandular Secretion During the second phase of the sexual response cycle (plateau), activity in parasympathetic pathways stimulates mucus secretion from bulbourethral and Littre’s glands and secretion from the seminal vesicles and the prostate gland (Masters and Johnson, 1966; Bruschini et al., 1978; Sachs and Meisel, 1988). Mucus secretion contributes to lubrication of the penis, whereas secretions from the seminal vesicles and prostate provide the bulk of the fluid and chemical factors that contribute to the viability and motility of the spermatozoa. Glandular secretion is thought

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SEX ORGANS

to be mediated by the parasympathetic system; however, the transmitters have not been identified. Acetylcholine may be involved since cholinomimetic agents stimulate secretion from some glands and acetylcholinesterase-containing nerves have been identified in the prostate and seminal vesicles. However, VIP-containing nerves are also present in these organs. The seminal vesicles and prostate gland are also sensitive to the levels of sex hormones, as evidenced by the stimulation of glandular size and secretion by testosterone and the reverse effects after the administration of estrogens or castration. Emission–Ejaculation The third phase of the sexual act (orgasm), which is accompanied by emission and ejaculation of semen, involves the coordination of autonomic and somatic reflex mechanisms at different levels of the lumbosacral spinal cord. During the first step in this process (emission), reflex activity in the thoracolumbar sympathetic outflow elicits rhythmic contractions of the smooth muscle of the seminal vesicles, prostate, ductus deferens, and ampulla, resulting in the ejection of sperm and glandular secretions into the urethra and at the same time a closure of the vesical neck to prevent the backflow of semen into the bladder (Elbadawi and Goodman, 1980; Newman et al., 1982; Lundberg et al., 2000). Pharmacologic studies have shown that these responses are mediated by the adrenergic transmitters, norepinephrine and ATP, interacting with α-adrenergic receptors and purinergic receptors, respectively (Kedia and Markland, 1975; Beck, 1999). Thus, surgical interruption of sympathetic nerves or the administration of drugs that either block α-adrenergic receptors (e.g., tamsulosen), deplete norepinephrine stores, or block norepinephrine release (e.g., guanethidine) blocks emission (Kedia and Markland, 1975; Andersson and Wyllie, 2003). Seminal emission may also be modulated by activity in cholinergic nerves. For example, physostigmine, an anticholinesterase agent, or exogenous acetylcholine depress the responses of the ductus deferens and other sex organs to electrical stimulation of the sympathetic nerves. The depression, which is accompanied by a reduction in norepinephrine release, is blocked by atropine. These findings suggest that one action of the cholinergic innervation to the sex organs is a muscarinic suppression of excitatory adrenergic transmission. After emission of semen into the proximal urethra, rhythmic contractions of the bulbocavernosus, ischiocavernosus, and the paraurethral striated muscles result in ejaculation. The afferent and efferent limbs

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of the ejaculation reflex are contained in the pudendal nerve (Table 76.3). The sensations accompanying ejaculation constitute the orgasm (Newman et al., 1982). Orgasm is not necessarily affected by sympathectomy, provided that the pudendal nerves remain intact. Thus, neither afferent fibers in the sympathetic nerves nor contractions of smooth muscles of the seminal vesicles and ductus deferens are essential for the occurrence of orgasm.

Central Reflex Pathways In the spinal cord, ascending fibers carrying sensory information from the sex organs seem to lie primarily within the anterolateral tracts. Thus, bilateral cordotomy usually diminishes or completely abolishes orgasm. Cordotomy also severely compromises ejaculatory and erectile mechanisms, although the latter may recover over a period of time. With more extensive damage of the spinal cord in paraplegics, when the site of injury is located rostral to T12, ejaculation occurs in a relatively small percentage of patients in comparison to reflexogenic erections, which are readily elicited (Grossiord et al., 1978; Chapelle et al., 1980, 1988). This observation is consistent with the greater complexity of spinal reflex pathways underlying ejaculation and indicates a considerable dependence of these pathways on supraspinal coordinating mechanisms. Brain imaging studies using functional MRI or PET during sexual arousal induced by erotic visual stimuli have identified several brain regions in both males and females that are activated during sexual stimulation (Stoleru et al., 1999; Redoute et al., 2000; Park et al., 2001; Arnow et al., 2002; Mouras et al., 2003). PET studies in males detected activation in three general regions including limbic/paralimbic areas (anterior cingulate gyrus, orbitofrontal cortex), the striatum (head of the caudate nucleus), and posterior hypothalamus. Strong signals specifically associated with penile turgidity were observed in the right subinsular region (claustrum, caudate, cingulate gyrus) using fMRI. A PET study also showed increased blood flow in the right prefrontal cortex during orgasm in males whereas all other cortical areas showed decreases in blood flow (Tiihonen et al., 1994). It has been suggested that the activation of paralimbic areas is correlated with the emotional and motivational states associated with sexual arousal; whereas the activation of the anterior cingulate and hypothalamic regions is related to the affective, autonomic, and endocrine responses (Arnow et al., 2002). More recent fMRI studies in males have also detected activation in parietal areas known to be involved in attentional

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processes (Mouras et al., 2003). The human data correlate well with results from animal experiments that indicate that connections between the limbic system and the hypothalamus (medial preoptic, MPOA, and paraventricular nucleus) are essential for the stimulation of the descending autonomic projections to the spinal cord that trigger psychogenic penile erections (de Groat and Booth, 1993a; McKenna, 1998). Recent studies in rats have identified a population of lumbar spinal neurons located around the central canal in lamina X and medial lamina VII that participate in the ejaculatory reflex (Truitt and Coolen, 2002). These neurons express neurokinin-1 receptors, receive afferent input from the penis, and project to thalamus. It was initially hypothesized that these neurons might function primarily in transmitting sensory information from the penis to pleasure centers in the brain. However, it was discovered that the neurons were only activated during ejaculation and not during other components of male sexual behavior. When the neurons were destroyed by intrathecal administration of a toxin (saporin-SSP) that selectively destroys neurons expressing neurokinin-1 receptors, ejaculatory responses were completely abolished without altering other components of copulatory behavior (penile erection, mounting, intromission). It was concluded that the neurons may be part of a spinal ejaculation generator. Pharmacological studies in animals have implicated many neurotransmitter systems in the central control of sexual function (de Groat and Booth, 1993; Argiolas and Melis, 1995; McKenna, 1998; Burnett, 2001; Andersson, 2003). The dopaminergic system in the medial preoptic area (MPOA) and the oxytocin and nitric oxide systems in the paraventricular nucleus exert major excitatory effects on erection while the serotonergic pathways arising in the raphe nuclei seem to be inhibitory. Elsewhere in the brain noradrenergic, GABAergic, and serotonergic pathways are generally inhibitory, whereas dopaminergic, nitric oxide, and oxytocin pathways facilitate sexual function. NO appears to tonically modulate the hypothalamic excitatory circuitry because intracerebroventricular injections of NOS inhibitors prevented the penile erectile responses induced by dopamine agonists and oxytocin (Sato et al., 2001). It is uncertain whether all of these findings in animals are entirely applicable to man. However, recently apomorphine, a nonselective dopamine receptor agonist that stimulates sexual behavior and penile erection in animals, has been marketed to treat penile erectile dysfunction in patients (Burnett, 2001).

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Habler, H.J., Janig, W. and Koltzenburg, M. (1990) Activation of unmyelinated afferent fibres by mechanical stimuli and inflammation of the urinary bladder in the cat. J. Physiol. 425: 545. Hashitani, H., Fukuta, H., Dickens, E.J. and Suzuki, H. (2002) Cellular mechanisms of nitric oxide-induced relaxation of corporeal smooth muscle in the guinea-pig. J. Physiol. 538: 573. Hedlund, P., Aszodi, A., Pfeifer, A., Alm, P., Hofmann, F., Ahmad, M. et al. (2000) Erectile dysfunction in cyclic GMP-dependent kinase I-deficient mice. Proc. Natl Acad. Sci. U S A 97: 2349. Ho, K.M., Ny, L., McMurray, G., Andersson, K.E., Brading, A.F. and Noble, J.G. (1999) Co-localization of carbon monoxide and nitric oxide synthesizing enzymes in the human urethral sphincter. J. Urol. 161: 1968. Hurt, K.J., Musicki, B., Palese, M.A., Crone, J.K., Becker, R.E., Moriarity, J.L. et al. (2002) Akt-dependent phosphorylation of endothelial nitric-oxide synthase mediates penile erection. Proc. Natl Acad. Sci. U S A 99: 4061. Jankowski, R.J., Prantil, R.L., Fraser, M.O., Chancellor, M.B., de Groat, W.C., Huard, J. et al. (2004) Development of an experimental system for the study of urethral biomechanical function. Am. J. Physiol. Renal Physiol. 286: F225. Kakizaki, H., Fraser, M.O. and de Groat, W.C. (1997) Reflex pathways controlling urethral striated and smooth muscle function in the male rat. Am. J. Physiol. 272: R1647. Kamo, I., Torimoto, K., Chancellor, M.B., de Groat, W.C. and Yoshimura, N. (2003) Urethral closure mechanisms under sneeze-induced stress condition in rats: a new animal model for evaluation of stress urinary incontinence. Am. J. Physiol. Regul. Integr. Comp. Physiol. 285: R356. Kawatani, M., Shioda, S., Nakai, Y., Takeshige, C. and de Groat, W.C. (1989) Ultrastructural analysis of enkephalinergic terminals in parasympathetic ganglia innervating the urinary bladder of the cat. J. Comp. Neurol. 288: 81. Keast, J.R. and de Groat, W.C. (1992) Segmental distribution and peptide content of primary afferent neurons innervating the urogenital organs and colon of male rats. J. Comp. Neurol. 319: 615. Keast, J.R., Kawatani, M. and de Groat, W.C. (1990) Sympathetic modulation of cholinergic transmission in cat vesical ganglia is mediated by alpha 1- and alpha 2-adrenoceptors. Am. J. Physiol. 258: R44. Kedia, K. and Markland, C. (1975) The effect of pharmacological agents on ejaculation. J. Urol. 114: 569. Kihara, K. and de Groat, W.C. (1997) Sympathetic efferent pathways projecting bilaterally to the vas deferens in the rat. Anat. Rec. 248: 291. Kruse, M.N., Bray, L.A. and de Groat, W.C. (1995) Influence of spinal cord injury on the morphology of bladder afferent and efferent neurons. J. Auton. Nerv. Syst. 54: 215. Lavelle, J.P., Meyers, S.A., Ruiz, W.G., Buffington, C.A., Zeidel, M.L. and Apodaca, G. (2000) Urothelial pathophysiological changes in feline interstitial cystitis: a human model. Am. J. Physiol. Renal Physiol. 278: F540. Lee, H.Y., Bardini, M. and Burnstock, G. (2000) Distribution of P2X receptors in the urinary bladder and the ureter of the rat. J. Urol. 163: 2002. Lewis, S.A. (2000) Everything you wanted to know about the bladder epithelium but were afraid to ask. Am. J. Physiol. Renal Physiol. 278: F867. Lundberg, P.O., Brockett, N.L., Denys, P., Chartier-Kastler, E., Sonksen, J. and Vodusek, D.B. (2000) Neurological disorders: erectile and ejaculatory dysfunction. In:Erectile Dysfunction. Jersey: Health Publications Ltd., p. 591. Maggi, C.A. (1993) The dual sensory and efferent functions of the capsaicin-sensitive primary sensory neurons in the urinary bladder

and urethra. In: C.A. Maggi (ed.), The Autonomic Nervous System, Vol. 3. London: Harwood Academic Publishers, p. 383. Mallory, B.S., Roppolo, J.R. and de Groat, W.C. (1991) Pharmacological modulation of the pontine micturition center. Brain Res. 546: 310. Mallory, B., Steers, W.D. and de Groat, W.C. (1989) Electrophysiological study of micturition reflexes in rats. Am. J. Physiol. 257: R410. Marson, L. and McKenna, K.E. (1996) CNS cell groups involved in the control of the ischiocavernosus and bulbospongiosus muscles: a transneuronal tracing study using pseudorabies virus. J. Comp. Neurol. 374: 161. Masters, W.H. and Johnson, V.E. (1966) Human Sexual Response. Boston, MA: Little Brown & Co. Matsui, M., Motomura, D., Fujikawa, T., Jiang, J., Takahashi, S., Manabe, T. et al. (2002) Mice lacking M2 and M3 muscarinic acetylcholine receptors are devoid of cholinergic smooth muscle contractions but still viable. J. Neurosci. 22: 10627. Matsui, M., Motomura, D., Karasawa, H., Fujikawa, T., Jiang, J., Komiya, Y. et al. (2000) Multiple functional defects in peripheral autonomic organs in mice lacking muscarinic acetylcholine receptor gene for the M3 subtype. Proc. Natl Acad. Sci. U S A 97: 9579. Matsuura, S., Kakizaki, H., Mitsui, T., Shiga, T., Tamaki, N. and Koyanagi, T. (2002) Human brain region response to distention or cold stimulation of the bladder: a positron emission tomography study. J. Urol. 168: 2035. McKenna, K.E. (1998) Central control of penile erection. Int. J. Impot. Res. 10 (Suppl. 1): S25. Melman, A., Henry, D.P., Felten, D.L. and O’Connor, B. (1980) Effect of diabetes upon penile sympathetic nerves in impotent patients. South Med. J. 73: 307. Mills, T.M., Chitaley, K. and Lewis, R.W. (2001) Vasoconstrictors in erectile physiology. Int. J. Impot. Res. 13 (Suppl. 5): S29. Miura, A., Kawatani, M. and de Groat, W.C. (2001) Excitatory synaptic currents in lumbosacral parasympathetic preganglionic neurons elicited from the lateral funiculus. J. Neurophysiol. 86: 1587. Miura, A., Kawatani, M. and de Groat, W.C. (2003) Excitatory synaptic currents in lumbosacral parasympathetic preganglionic neurons evoked by stimulation of the dorsal commissure. J. Neurophysiol. 89: 382. Morgan, C., Nadelhaft, I. and de Groat, W.C. (1979) Location of bladder preganglionic neurons within the sacral parasympathetic nucleus of the cat. Neurosci. Lett. 14: 189. Morgan, C., Nadelhaft, I. and de Groat, W.C. (1981) The distribution of visceral primary afferents from the pelvic nerve to Lissauer’s tract and the spinal gray matter and its relationship to the sacral parasympathetic nucleus. J. Comp. Neurol. 201: 415. Morrison, J., Steers, W.D., Brading, A., Blok, B., Fry, C., de Groat, W.C. et al. (2002) Neurophysiology and neuropharmacology. In:Incontinence. Jersey: Health Publications Ltd., p. 83. Morrison, J., Wen, J. and Kibble, A. (1999) Activation of pelvic afferent nerves from the rat bladder during filling. Scand. J. Urol. Nephrol. 201 (Suppl.): 73. Mouras, H., Stoleru, S., Bittoun, J., Glutron, D., Pelegrini-Issac, M., Paradis, A.L. et al. (2003) Brain processing of visual sexual stimuli in healthy men: a functional magnetic resonance imaging study. Neuroimage 20: 855. Nadelhaft, I. and Vera, P.L. (1995) Central nervous system neurons infected by pseudorabies virus injected into the rat urinary bladder following unilateral transection of the pelvic nerve. J. Comp. Neurol. 359: 443. Newman, H.F., Reiss, H. and Northup, J.D. (1982) Physical basis of emission, ejaculation, and orgasm in the male. Urology 19: 341.

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C H A P T E R

77 Sacral Nerve Root Stimulation for Painful Bladder Syndrome/Interstitial Cystitis Adnan A. Al-Kaisy and K. Riaz Khan

O U T L I N E Nomenclature and Epidemiology

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Etiology, Pathophysiology, and Research Evidence

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Clinical Features and Diagnosis

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Management

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Sacral Nerve Stimulation (SNS) Historic Overview Rationale Behind Neuromodulation for Chronic Painful Conditions of the Pelvis and Painful Bladder Syndromes Indications and Contraindications for Sacral Nerve Root Stimulation Preoperative Assessment Pelvic Neuroanatomy Techniques of Sacral Nerve Stimulation

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Sacral Transforaminal Approach The Retrograde (Cephalocaudal) Approach Anterograde (via Sacral Hiatus) Approach Retrograde Laminotomy Technique Laparoscopic Implantation of Neuroprosthesis (the LION Procedure) Programming Summary of Evidence of Efficacy and Complications Alternative Techniques of Sacral Nerve Stimulation Pudendal Nerve Stimulation Using the Bion Percutaneous and Implant-Driven Tibial Nerve Stimulation Intrathecal Drug Delivery

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References

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a nineteenth-century textbook by Skene (Skene, 1887). The International Continence Society (ICS), in 2002, redefined interstitial cystitis, calling it painful bladder syndrome (PBS), as characterized by suprapubic pain related to bladder filling, accompanied by other symptoms such as increased daytime and night-time frequency, in the absence of proven urinary infection or other obvious pathology (Abrams et al., 2002). Since then, a number of international bodies have endorsed the concept of bladder pain as an integral

NOMENCLATURE AND EPIDEMIOLOGY Interstitial cystitis (IC) is a chronic debilitating disorder of the urinary tract characterized by chronic pelvic pain, irritative voiding symptoms, and sterile and cytologically negative urine. The etiology is unknown and the treatment is controversial. It has been known to physicians for over 150 years and the term dates to

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part of IC; several have suggested the term PBS/IC. The European Society for Study of Interstitial Cystitis (ESSIC) recently proposed the term bladder pain syndrome (BPS/IC) in a pain syndrome approach to this debilitating condition (Baranowski et al., 2008). Chronic pelvic pain syndrome (CPPS) affects approximately 1 of 60 adults in the USA and is associated with significant disability and poor quality of life. Painful bladder syndrome/interstitial cystitis (PBS/IC) has emerged as a major cause of CPPS along with irritable bowel syndrome (IBS), endometriosis, and chronic prostatitis (CP) (Theoharides and O’Leary, 2006). There is also a greater than normal incidence of irritable bowel syndrome, fibromyalgia, migraines, asthma, environmental allergies, lupus, rheumatoid arthritis, endometriosis, vulvodynia, and anxiety disorders in patients with PBS/IC (Theoharides, 2007). Interpretation of epidemiologic studies of PBS/IC is hampered due to lack of consensus on definition, etiology, pathophysiology, and lack of diagnostic markers. Most epidemiologic information about BPS/IC has come from anecdotal reports, case series, and population-based studies. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK, in Bethesda, MD) has, exclusively for epidemiologic research purposes, recommended certain diagnostic criteria to allow comparison of data from published research (Gillenwater and Wein, 1988). Reviews of case control studies as well as population-based studies from worldwide research report variable outcomes regarding prevalence, severity of pain, quality of life, and treatment outcomes. The first population-based study included almost all the patients with IC in Helsinki in a population of 1 000 000 persons. The prevalence of IC in women alone was 18.1 per 100 000 but the joint prevalence in both sexes was 10.6 cases per 100 000. Annually 1.2 cases were diagnosed per 100 000 women. Severe cases accounted for 10% of the total, and 10% of cases were in men. The onset was noted to be generally subacute rather than insidious, with the full development of the classic symptom complex taking place over a relatively short time. In this study, Oravisto noted that the disease reaches its final state rapidly, and that subsequent major deterioration in symptom severity was the exception rather than the rule. The duration of symptoms before diagnosis was 3–5 years (Oravisto, 1975). Another population-based study in the USA by Held and coworkers reported an incidence twice that of the Helsinki study and a 50% temporary spontaneous remission rate. The median age of onset was 40 years and a higher incidence was found in those with childhood bladder problems, urinary tract infections, and those of Jewish descent (Held et al.,

1990). Jones and Nyberg (1997) published a study relying on self-report of a previous diagnosis of IC in the 1989 National Household Interview Survey of 20 561 adults. They calculated that 1 000 000 people in the USA would report having a diagnosis of IC in 1990, more than double the maximum figure in the Held study. Using the Nurses’ Health Study I and II as the basis of information, Curhan and colleagues concluded that the prevalence of IC was between 52 and 67 per 100 000, figures at least 50% greater than reported by Held (Curhan et al., 1999). Several case series have also suggested a similar prevalence and morbidity. There are publications that studied the incidence of disease in children, adolescent girls, and men (Hanash and Pool, 1969; Geist and Antolak, 1970; Farkas et al., 1977). A survey by Koziol and colleagues found a female predominance (89.8%) and caucasian (94.1%) preponderence, with a mean age of 53.80.7 years and age at the first symptoms of 42.50.8 years. Of the women surveyed, 44.4% reported undergoing hysterectomy and 38.2% of the patients had strong sensitivities or allergic reactions to medication. Frequency and urgency were reported by 91.7% and 89.3% of the patients, respectively, while pelvic pain, pelvic pressure, and bladder spasms were reported by more than 60% of respondents and burning by 56%. More than 60% of the patients were unable to enjoy usual activities or were excessively fatigued and 53.7% reported depression. Travel, employment, leisure activities, and sleeping were adversely affected in more than 80% of the patients. There was an apparent plateau in the frequency and urgency among patients after approximately 5 years with symptoms (Koziol et al., 1993). A similar study in the UK concurred with the findings of the above study (Tincello and Walker, 2005). Familial and hereditary occurrences have also been suggested (Dimitrakov, 2001; Warren et al., 2001).

ETIOLOGY, PATHOPHYSIOLOGY, AND RESEARCH EVIDENCE PBS/IC is a chronic clinical syndrome, the etiology and treatment of which is still controversial. Though the terms painful bladder syndrome and interstitial cystitis suggest bladder as the primary culprit and inflammation as a major cause, in many cases the evidence is to the contrary and the bladder is the victim of unknown pathology rather than the cause. Based on cystoscopy, two types of IC are recognized. In the more common type 1 disease, submucosal strawberrylike hemorrhages called glomerulations are seen on

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CLINICAL FEATUERS AND DIAGNOSIS

bladder distension. Similar lesions are also seen in healthy bladders after distension, hence not specific to type 1 disease (Waxman, 1998). In type 2 disease, which accounts for up to 10% of cases, the dome and lateral walls of bladder show “Hunner’s ulcers” in addition to glomerulations and congestion (Sant, 1997). It may be an inflammatory process of the bladder interstitium, and supratrigonal cystectomy and cystoplasty provides significant symptomatic relief (Peeker et al., 1998; Peeker and Fall, 2002). In contrast, type 1 disease may be an idiopathic pain syndrome of neuropathic origin. Clinical and experimental evidence gives an insight into the possible pathophysiologic disease processes. Hypotheses as to the causes of IC include infection, urinary toxins, increased epithelial permeability, mast cell involvement, neurogenic mechanisms, autoimmune or genetic abnormalities, or a combination of these. However, no studies to date have conclusively proven any of these mechanisms as the contributing factors. One area of research on the cause of IC has focused on the lining of the bladder, the glycocalyx, made up primarily of mucins and glycosaminoglycans (GAGs) which protect the bladder wall from toxic effects of urine and its contents. This layer of the bladder was “leaky” in about 70% of IC patients examined and may allow substances in urine to pass into the bladder wall and trigger IC symptoms. The researchers also found that patients with Hunner’s ulcers had “leakier” bladders than patients without the ulcers (Parsons et al., 1991; Erickson et al., 1997, 1998). Some people are diagnosed with IC after taking antibiotics for a presumed urinary tract infection. It is possible that the infection started an autoimmune response against the bladder, the patient’s original symptoms were from IC all along, or an infecting organism is in bladder cells but is not detectable through routine tests. A main pathologic finding is the increased number of activated mast cells in the bladder wall of patients with PBS/IC. Classic PBS/IC with Hunner’s ulcer has more mast cells in the detrusor, than the common PBS/IC (Theoharides et al., 2001). Results from the Interstitial Cystitis Database Study indicated that the only bladder pathological feature of PBS/IC that correlated with symptoms (nocturia) was the high number of tryptase-positive bladder mast cells (Tomaszewski et al., 2001). Tryptase induces hyperexcitability of submucosal neurons, while histamine directly stimulates substance P and calcitonin gene-related peptide (CGRP) containing neurons. This may lead to widespread inflammation and neuronal hyperexcitability (Theoharides and Cochrane, 2004). Mast cells are located perivascularly in close proximity to nerve endings, especially those containing

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substance P, which can activate mast cells (Keith et al., 1995; Pang et al., 1995, 1996; Suzuki et al., 1999). Intravesical administration of substance P induced bladder inflammation through NK-1 receptors (Saban et al., 1997, 2000). The involvement of the nervous system is supported by evidence that antidromic stimulation of the lumbosacral dorsal roots induced vascular permeability in the rat urinary bladder and bladder inflammation was induced by CNS infection by pseudo rabies virus that could not develop in mast cell depleted mice (Pinter and Szolcanyi, 1995; Jasmin et al., 2000). A recent breakthrough for IC has been the discovery of antiproliferative factor (APF). APF has been shown to be a specific protein associated with interstitial cystitis, although its role in the pathogenesis of IC remains unknown. Research shows that APF modulates the cell cycle and in fact might lead to blockade of G2 phase of mitotic cell cycle and the production of epithelial polyploidy. Inhibition of protein synthesis during G2 phase prevents the cell from undergoing mitosis. This would in effect prevent regeneration of bladder epithelial cells, therefore possibly causing the epithelial thinning and/or ulceration associated with IC. Greater understanding of APF’s mechanism of action could aid in the diagnoses and treatment of interstitial cystitis (Rashid et al., 2004).

CLINICAL FEATURES AND DIAGNOSIS PBS/IC is a clinical syndrome characterized by supra- or retropubic pain, increasing pain as bladder filling occurs, frequency, urgency, and nocturia. The urine is sterile and cytologically negative. There is no identifiable cause (Messing, 1992). The diagnosis is mainly clinical. Male patients often complain of perineal and scrotal pain. Onset is usually between 30 and 50 years of age with a 90% female preponderance. The onset is usually preceded by an event such as a urinary tract infection or pelvic surgery (Badenoch, 1971). IC is characterized by periods of exacerbation followed by variable periods of remission. Usually 3–7 years elapse before a diagnosis is made. The course is usually progressive but plateaus after about 5 years (Koziol et al., 1993). Patients with IC are more likely to have prior gynecologic surgery and/or a history of urinary tract infections and are 10–12 times more likely to report childhood bladder problems. Associations exist with chronic illnesses, including inflammatory bowel disease, systemic lupus erythematosus, irritable bowel syndrome, fibromyalgia, and atopic allergy (Theoharides, 2007).

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There are no specific investigations for the disorder. The Pelvic Pain Urgency/Frequency (PUF) Patient Survey, created by C. Lowell Parsons, is a short questionnaire that can help physicians identify whether pelvic pain could be coming from the bladder (Parsons et al., 2002). The Potassium Sensitivity Test uses a mild potassium solution to test the integrity of the bladder wall. Though this test is not specific for IC, it has been determined to be helpful in predicting the use of compounds, such as pentosan, which are designed to help repair the GAG layer (Sairanen et al., 2007). The previous “gold standard” test for IC was the use of hydrodistension with cystoscopy. This is not specific for IC and the procedure itself can contribute to the development of glomerulations often found in IC (Ottem and Teichman, 2005). Thus, a diagnosis of IC is one made by review of clinical symptoms and is one of exclusion.

MANAGEMENT The treatment of IC is challenging and should be multimodal and multidisciplinary from the outset. Conservative therapies include: ● ● ● ●

Regulation of fluid intake and diet Behavioural therapy Pelvic floor rehabilitation and bladder retraining Intermittent catheterization

Pharmacological agents used for IC include: ● ● ● ● ●

Simple analgesics Opioids Antibiotics Antidepressants and antiepileptics Immunosuppressants such as cyclosporine, suplatast tosilate, misoprostal, cimetidine and hydroxyzine

Intravescical therapy for IC includes: ●

● ● ●

Sodium pentosan polysulfate instillation into bladder Dimethyl sulfoxide BCG vaccine Vanilloids

Neuromodulation therapy for IC includes Sacral nerve stimulation (SNS) (Theoharides and O’Leary, 2006) (It is the authors’ opinion that sacral nerve stimulation should be tried before resorting to the more invasive surgical procedures.) ●

Surgical options are: ● ● ●

Bladder distension Endourological ablation of bladder tissue Urinary diversion and cystoplasty

SACRAL NERVE STIMULATION (SNS) Historic Overview Neuromodulation may be defined as manipulation of the function of the nervous system through implanted electrodes to control the malfunction of various body systems. The International Neuromodulation Society defines neuromodulation as: a field of science, medicine and bioengineering that encompasses implantable and non-implantable technologies, electrical or chemical, that improves life for humanity. It is a technology that impacts upon neural interfaces.

This can be accomplished either electrically through spinal cord stimulation (SCS), deep brain stimulation (DBS) or motor cortex stimulation (MCS) or chemically by targeting delivery of medication/s into the spinal canal, i.e. intrathecal drug delivery systems (IDDS). This chapter will focus on sacral nerve stimulation (SNS) as a modality of treatment for painful bladder syndrome/IC. The novel approach of stimulation of the spinal cord for the relief of chronic pain by Shealy in 1967 was the beginning of a new era (Shealy et al., 1967). Since that time neurostimulation of the bladder and pelvic innervation has been considered a viable option by a number of urologists for the treatment of various voiding disorders. Tanagho and Schmidt reported the first direct SNS implant in 1982 for urinary urge incontinence, urge frequency, and non-obstructive urinary retention. Since then many studies reporting the success of SNS for disorders of urinary and bowel incontinence have been published. Prior experience of stimulation of the bladder innervation had focused generally on the placement of an electrode array using either a sacral transforaminal approach to target specific sacral nerve roots directly or a caudocephalad (antegrade) approach via the epidural route to target the cauda equina (Siegel, 1992; Bosch and Groen, 1995). The Food and Drug Administration of the USA (FDA) has already approved a device for the sacral transforaminal approach to the sacral nerve roots (InterStim, Medtronic, Minneapolis, MN) for the syndrome of urge incontinence. In August 2003, sacral nerve stimulation was approved by the National Institute for Clinical Excellence (NICE) in the UK for

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urge incontinence (www.nice.org.uk, 2004). More recently a retrograde cephalocaudal approach to stimulation of the sacral nerve roots had been introduced (Alo’ et al., 1999) and is becoming popular particularly amongst pain physicians. The antegrade approach to target the neural structures of the cauda equina in a consistent and successful manner has met with only limited success due to the unique anatomy of the lumbosacral spine at the cauda equina level. There are many factors that contribute to the inability to directly target these neural structures of the cauda equina using the antegrade epidural approach, including: ●

●

●

The dorsal cerebrospinal fluid layer, the dCSF (distance from the cord to the posterior dural layer), at the level of the conus medullaris is quite wide, significantly insulating the spinal cord at that level from an electrical field produced by the epidurally placed electrodes. Because the conus is quite mobile, there is difficulty in maintaining consistent paresthesiae when the electrodes are placed in that position and concordant paresthesiae produced by the electrical field over the conus appear necessary for positive clinical outcomes. Due to the depth of sacral fibres within the dorsal columns, stimulation of the conus results in the stimulation of more proximal neural fibers subserving areas such as the distal legs, the feet and the buttocks rather than the fibers subserving the sacral neural structures.

Because of the above “barriers” to effective stimulation of sacral neural structures by stimulation of the cauda equina at the conus using an antegrade approach, there has been a great desire to find a technique that provided consistent stimulation to the sacral nerve roots without penetrating the posterior and anterior sacral foramina. Indeed, Alo’ et al. described a novel approach of stimulating the spinal nerve roots by applying a retrograde approach, advancing electrode arrays from the upper lumbar epidural space in a retrograde fashion until the electrodes came to lie within the sacral epidural space over the sacral nerve roots (Alo’ et al., 1999).

Rationale Behind Neuromodulation for Chronic Painful Conditions of the Pelvis and Painful Bladder Syndromes Some chronic pelvic pain syndromes such as IC appear to be neuropathic in nature, displaying

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characteristics of allodynia and hyperalgesia. Low volume filling of the bladder with as little as 20 ml is painful and non-painful intravesicular contents such as potassium cause discomfort in interstitial cystitis (Feler et al., 2003). Edema of the bladder wall can be generated by direct stimulation of lumbar roots (Pinter and Szolcanyi, 1995) or pelvic nerves (Koltzenburg and McMahon, 1986). Animal models, with isolated central nervous system lesions (e.g. due to viral infection) do produce clinical pictures that are very similar to IC (Jasmin et al., 1998). Clinically, up to 40% of women who develop IC had undergone a prior or recent hysterectomy before the onset of their symptoms (Koziol, 1994; Curhan et al., 1999). In addition, when examining tissue biopsies, presence of a combination of degenerative and regenerative neuroplastic features such as marked edema due to extravasation of plasma, injury to blood vessels, nervous tissue and muscularis layer, and presence of chronic mastocytosis are histologically consistent with self-perpetuating neurogenic inflammatory processes (Elbadawi and Light, 1996). All of this evidence implies that neuropathic inflammatory processes may underlie the pathogenesis of pelvic pain syndromes and IC. In animal studies, antidromic stimulation of the dorsal nerve roots results in plasma extravasation and neurogenic inflammation of the bladder wall (Pinter and Szolcanyi, 1995). Therefore by blocking or modulating these apparent circuits, as with SNS, it could be possible to disrupt or “modulate” these neurogenic inflammation cycles. It is this relationship that suggests that neuromodulation, through neurostimulation, may be a useful therapeutic modality for these syndromes. In humans, stimulation of sacral nerve roots has recently been shown to be effective for the pain of interstitial cystitis. In addition to improving clinical variables such as pain and urgency of micturition, stimulation of the S3 nerve root is associated with increases of urinary concentration, reduction of heparin-binding epidermal growth factor, and reduced concentration of antiproliferative factor, urinary markers that correlate with the symptoms of interstitial cystitis (Chai et al., 2000).

Indications and Contraindications for Sacral Nerve Root Stimulation SNS has been used to improve bladder and bowel function including urge incontinence, urgency/frequency, and urinary retention (Shaker and Hassouna, 1998a,b), bowel incontinence (Kenefick et al., 2002a),

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and chronic constipation (Kenefick et al., 2002b). It has also been successfully used to treat interstitial cystitis (Shaker and Hassouna, 1998a), prostatodynia, vulvodynia, coccydynia, and vaginal pain (personal experience). Absolute contraindications for SNS include low mental capacities (cannot understand the operation of the device) in patients who otherwise are candidates for the procedure and failure to respond to a trial of stimulation. Other absolute contraindications for invasive procedures into the neural canal such as localized infection, sepsis, anticoagulation, low platelet count, etc., also apply. A relative contraindication to the procedure is spina bifida occulta (Michael et al., 2002). There have been reports of safe use of spinal cord stimulators in patients with cardiac pacemakers (Romano et al., 1998), but one should check with manufacturers as the implanted cardioverter defibrillators may misbehave. MRI scans and diathermy treatments are also contraindicated because of heating of the electrodes themselves which might result in neural damage.

and appropriate laboratory studies including a blood count, coagulation studies, and groin and nose swabs for culture and sensitivities to exclude methicillin resistant staphylococcus aureus (MRSA). Before implanting a permanent SNS system, patients are screened for potential therapeutic benefit by undergoing a temporary percutaneous trial in which an electrode is introduced to stimulate left or right S3 nerve root either epidurally or transforaminally and attached to an external device, which provides continuous stimulation during the trial period. The length of a screening trial ranges from 3 to 7 days. Patients are asked to keep a voiding diary and must demonstrate a positive therapeutic response to qualify for implantation. The criteria for a positive response vary slightly; however, at least a 50% improvement in one or more primary symptoms is considered the standard for a clinically significant response (Schmidt et al., 1999).

Pelvic Neuroanatomy Preoperative Assessment Appropriate and careful patient selection is a key factor for a positive outcome when applying SNS for bladder and pelvic disorders. Patients with pelvic pain syndromes usually have multiple system complaints that include voiding dysfunction, pelvic pain, and genitourinary hypersensitivity. The uncertainty regarding a diagnosis and treatment might lead to frustration and depression in patients because of therapeutic failure, which may lead them, in turn, to develop complex psychological adaptive and maladaptive methods of coping with pain, thus adversely affecting their lives. Hence appropriate selection of patients for any major intervention, including SNS, should rely on a multidisciplinary team of professionals including an implant coordinator, a psychologist, a pain nurse and a physiotherapist. Patients who are deemed appropriate candidates for the therapy must be free of overwhelming psychological disorder and secondary gain and must be able to understand how to use their stimulator, be motivated for cure or reduction in pain or improvement in function, and have an active role in their management. Once the decision is made to implant an SNS device, it is essential that a full medical evaluation be performed, which should include a complete history and physical, including a complete neurological examination, performance of imaging studies (plain X-rays of the lumbar spine and the sacrum are essential to exclude severe osteoarthritis and spondylolisthesis, which can make a retrograde approach difficult),

The pelvis is innervated by a complex of sympathetic, parasympathetic, and somatic structures. The sympathetic outflow to the bladder originates from the T12–L2 spinal cord levels and the parasympathetic innervation from S2–S4 levels. Most of the sympathetic outflow to the pelvic viscera arises within the thoracolumbar spinal cord segment and is conveyed through the superior hypogastric plexus. Parasympathetic outflow is by the S2–S4 nerve roots that converge into preganglionic pelvic splanchnic nerves. Somatic efferent and afferent innervation to the pelvis originates from the sacral spinal cord levels, S2–S4. Nerves originating from the S3 sacral level primarily supply the anterior perineal musculature. Because of this, the S3 nerve roots are typical targets for neurostimulation procedures for treating pelvic floor dysfunctions. However, sensations from the pelvic floor are mainly conveyed by way of the sacral afferent parasympathetic system (S2–S4) with less input from the thoracolumbar sympathetic supply. Therefore, any neuromodulation procedure aimed at treating pelvic pain syndromes should include stimulation of the S2, S3, and S4 nerve roots. Innervation of the bladder is considered to be bilateral, as each half of the bladder has its own defined innervation (Ingersoll et al., 1957; Diokno et al., 1973). The small bladder afferent Aδ- and C-fibres conduct noxious stimuli from the bladder and also the sensations of urge and bladder distension (de Groat, 1993). They are also considered to be bilateral via the pelvic nerves. Because of this bilaterality of neural

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structures of the bladder, unilateral stimulation (neuromodulation) might only be partially effective in ameliorating the problem intended to treat, either by not influencing the entire bladder or by allowing the formation of new pathophysiological pathways. Consequently, bilateral neuromodulation was introduced and has been promoted as a more effective method for the treatment of bladder dysfunctions, including frequency, urge incontinence, and pain, than stimulation of unilateral, individual sacral nerve roots (Hohenfellner et al., 1998, 2000).

Cable

Exit site

Electrical stimulator

Bladder

Techniques of Sacral Nerve Stimulation Sacral Transforaminal Approach This technique is commonly used by urologists as well as colorectal surgeons but not often used by pain physicians (Lavano et al., 2006). A trial period known as the “percutaneous nerve evaluation” (PNE) is carried out before full implantation. The trial electrode is placed in either the right or left S3 posterior sacral foramen using local anesthesia. Surface markings and fluoroscopy identify the site of the posterior sacral foramen and a Tuohy needle is used to pass the electrode to be threaded into position. Correct positioning of the electrode is determined by both motor and sensory responses. An external pulse generator provides stimulation and the trial period is usually for 3–5 days. The patient provides subjective information regarding their response to the PNE, while objective data come from accurately completed frequency/volume charts. Only those patients who gain significant benefit from the trial proceed to full implantation. The trial is considered successful if there is at least 50% improvement in the main voiding symptom. Although results vary between studies in the literature, in general approximately 50% of patients will respond well to the trial stimulation and go on to receive a definitive implant. The full implant requires the placement of a sacral foraminal electrode via a transcutaneous Tuohy introducer, and under fluoroscopic control under local anesthesia and sedation. A pulse generator is implanted either in the buttock or anterior abdominal wall and is connected to the lead/s. Despite some success, this method has been associated with technical failures (lead migration, inconsistent outcomes, etc.) (Medtronic Neurological, 1998). These failures may be due to a number of anatomic and/or physiological possibilities, including the perpendicular “path” of the sacral root relative to the trans-sacral electrode as it courses through the foramen and the extreme variability and unpredictability of the sacral bony and neural relationships between different individuals. An example of a

Tailbone

Nerves

FIGURE 77.1

Representation of Medtronic Inc.’s InterStim device for urge incontinence

custom-made device for sacral transforaminal nerve stimulation is the InterStim, approved by FDA in the USA in 1997 for urinary frequency, urgency and incontinence (see representation in Figure 77.1). The Retrograde (Cephalocaudal) Approach This approach was originally described by Alo’ et al. (Feler et al., 1999; Alo’ and Zidan, 2000; Alo’ and McKay, 2001; Alo’ et al., 2001). It is most commonly used by pain practice physicians who are familiar with using the percutaneous technique for spinal cord stimulation (SCS). This technique, when compared to the transforaminal sacral approach has many advantages, including an ability to anatomically stabilize the electrodes within the epidural space and/or sacral root sleeve, the ability to maintain “parallel electrode symmetry” (bilaterality) and contact with the respective sacral nerve roots, and the ability to cover more than one sacral nerve root, at any one time. Potential disadvantages of this approach to the sacral nerve roots includes the inability to successfully identify the interlaminar epidural space (technique failure), the inability to overcome the abnormal intraspinal anatomy due to spondylolisthesis, scar sensitive dura, steep lumbosacral angulation and, as with any new technique, the learning curve is rather slow. When using this approach, either for a trial of stimulation or for the permanent placement of the lead

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(A)

(B)

FIGURE 77.2 (A) Placement of the epidural needles into the anatomic midline of the epidural space using a retrograde, cephalocaudal approach to the sacral nerve roots. (B) The epidural leads in the sacral epidural space

(A)

(B)

FIGURE 77.3

Intraoperative photographs showing the anteroposterior and lateral views of bilateral quadripolar and octipolar percutaneous cephalocaudal intraspinal electrodes

array, the patient is comfortably positioned with two pillows under the abdomen to offset the natural lumbar lordosis and flatten the back. The procedure should be carried out under fluoroscopic guidance with monitored anesthesia care. Using image-intensified fluoroscopy, the epidural space is entered proximal to the L5/S1 interspace preferably at L1–2 or L2–3 interspaces to allow steering of the lead (electrode array) in a cephalocaudal fashion. Using the paramedian approach to enter the epidural space it is essential to keep the tip of the Tuohy needle right at the anatomical

midline (see Figure 77.2a and b). The lead (electrode array) should be, by fluoroscopically controlled steering, kept in the anatomic (radiographic) midline until it passes the L5/S1 junction (sacral promontory), at which point, it is turned towards the desired sacral foramina. A second lead can be inserted at the same entry point if two leads are desired. To insure stimulation covers the desired sacral nerve roots bilaterally, it is the authors, practice to insert a third lead (usually an octad lead) in the midline of the sacral canal (see Figure 77.3).

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Once the leads are anatomically positioned at or around the intended target, intraoperative testing is carried out to ensure that not only the leads are in the appropriate anatomic position but that the paresthesiae produced by electrical stimulation of sacral nerve roots cover the painful area or the target area. When treating interstitial cystitis, it is essential to ensure that S3 stimulation leads to a “bellows” response, which is a contraction and relaxation of the levator ani and external anal sphincter and plantar flexion of the ipsilateral first and second toes. Also when stimulating S3, the patient should feel paresthesiae (pins and needles sensation) in the vagina/scrotum, perineum, and the perianal region. Once the bellows response occurs and the patient feels paresthesiae in the desired location, the needle/s are removed and the leads are secured. In the percutaneous/non-surgical technique for trial stimulation, the lead/s are looped and taped to the skin with a sterile dressing covering the exit site of the leads. In the percutaneous surgical technique the lead/s are secured to supraspinous ligament, connected to an extension and the extension is tunnelled away from the incision to one side. A dressing is also applied over the skin site of the exiting extension. Anterograde (via Sacral Hiatus) Approach The sacral hiatus presents an alternative entry method for SNS (Falco et al., 2003; Alo’ et al., 2001). The main advantages of this approach when compared to the cephalocaudal approach to SNS are that this technique may be technically easier for entering the sacral epidural space, has ease of steering the lead within the sacral canal to reach the appropriate sacral nerve roots, and avoids some difficulties that are encountered during the retrograde approach, i.e. previous surgery, spondylolisthesis etc. However, there are associated risks with this approach, including the entering of the lead through a potentially contaminated area with resultant infection and pain at the entry zone post procedure and long term. Moreover the sacrococcygeal area does not provide the best site for securing lead anchors due to the inherent lack of subcutaneous tissues in this region, which could potentially cause the patient discomfort when sitting and may lead to skin breakdown, adhesions, and possible wound infections. However, having stated this, it is not always necessary to anchor leads in this area when performing SNS (see Figure 77.4). Retrograde Laminotomy Technique This technique requires a minimally invasive laminotomy/laminectomy at the level of S1/S2 and

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FIGURE 77.4 Caudocephalad passage of leads via sacral hiatus

requires the expertise of a spinal or neurosurgeon. The technique allows for passage of a paddle electrode array until the tip of the array is between S3 and S4 vertebral levels. The main advantage of the laminotomy technique is that it not only displaces the dura toward the cauda and nerve roots, but also allows for placement of an electrode whose resultant field is 180° rather than 360°, resulting in a significantly lower stimulus amplitude requirement and therefore greater battery longevity. Another advantage of this approach is that it overcomes any anatomical abnormalities, i.e. spondylolisthesis, spina bifida, adhesions resulting from previous back surgery. The data suggest that electrodes placed via laminectomy can be expected to provide good or excellent pain reduction in approximately 90% of patients, with fair pain reduction in the remaining 10%. Laminectomy-style electrodes appear to provide better long-term effectiveness than those placed percutaneously (North et al., 1999; Villavicencio et al., 2000). Laparoscopic Implantation of Neuroprosthesis (the LION Procedure) Possover et al. (2007) described a case report of placement of the sacral nerve electrodes laparoscopically under general anesthesia for neuromodulation to pelvic and/or abdominal nerves in a 44-year-old female patient with intractable neuralgia of the sciatic nerve and hyperactive bladder secondary to multiple sclerosis. She had complete relief of sciatica and resolution of bladder hyperactivity with increase in urine volumes.

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Programming Spinal cord stimulation is a well-established method of managing a variety of chronic neuropathic pain conditions. The mechanism/s of success of this method was originally thought to be due to gating mechanisms of the gate control theory of Melzack and Wall (1965) and introduced as dorsal column stimulation (DCS) by Norman Shealy two years later (Shealy et al., 1967). The gate control theory postulates that neural transmission within large diameter cutaneous afferents (Aβ-fibres) inhibits transmission of pain signals to brain from small Aδ- and C-fibers, thus closing the “gate” to pain signals. For SCS to be clinically effective, the stimulationinduced paresthesiae (“pins and needles sensations”) must cover the entire painful area and should be maintained consistently, otherwise the clinical effect will be lost (North et al., 1991). These paresthesiae must be comfortable and not painful. This “golden rule” of “no paresthesiae, no pain relief” also applies to the majority of pelvic pain syndromes with the exception of some patients with interstitial cystitis. That is, some patients with IC have dermatomal (e.g. para-coccygeal) pain and referred visceral pain, e.g. supra-pubic pain. Such complaints may improve, without the induction of paresthesiae to those regions. When using bipolar stimulation, to create an electrical field from a lead array, at least one other electrode must be programmed as a cathode (negative electrode) and at least one electrode must be programmed as an anode (positive electrode). Because the sacral nerve roots are mixed sensory and motor nerve roots, programming one cathode and one anode often leads to painful contractions of muscles subserved by the nerve root stimulated. To prevent activation of motor function while preserving stimulation of sensory pain fibers, multiple cathodes (more than one) are activated with one anode activated. This technique, whereby multiple cathodes are activated at one time to spread the field of stimulation out, is called “feathering.” Variable and individualized stimulation parameters are programmed with frequency ranges of 20–70 Hz and pulse width ranges of 200–400 msec. Stimulation requirements for individual patients are established during the stimulation trial period (i.e. externalizing an extension lead from permanently positioned electrode rays). During the trial period, which might last 1–2 weeks or longer, one can establish the exact parameters needed for an individual patient’s problem is established. A period of 3–6 months after full implantation (permanent placement of electrode array and generator) may be necessary to find the final parameters of stimulation that lead to the best clinical

response for the patient’s pain relief or voiding disorder, the stimulation that is least bothersome and the stimulation parameters that lead to battery longevity.

Summary of Evidence of Efficacy and Complications Evidence (Brazzelli et al., 2004, 2006) from the randomized controlled trials and case series showed that about 70% of patients achieved continence or exhibited an improvement of 50% in their main incontinence symptoms after SNS. This is compared to the only 4% of patients in the control groups who were receiving conservative treatments while waiting for an implant had improvement of 50% in their incontinence. Case series studies had similar results with 68% of patients becoming dry or achieving a 50% improvement in their symptoms post-implantation. Incontinence episodes, severity of leakage, frequency of voids, and pad usage were all significantly lower after implant. Benefits of SNS were reported to persist at follow-up of 3–5 years after implantation. The overall surgical revision rate for the implanted patients was 33%. Most common complications were pain at the implant site (24%), lead migration (16%), wound problems (7%), adverse effects on bowel function (6%), infection (5%), and pulse generator problems (5%). In 15% of patients, the implanted pulse generator was replaced or relocated and in 9% required permanent explantation of the pulse generator. There were no reports of long-lasting neurological adverse events.

Alternative Techniques of Sacral Nerve Stimulation Pudendal Nerve Stimulation Using the Bion The Bion ( bionic neuron; Advanced Bionics Corp./Boston Scientific, Valencia, CA) is a miniature, wireless, implantable, one-channel neurostimulator that is approximately 2.3 mm long and 3 mm in diameter. The first generation Bion requires multiple recharges during the day. However a newer generation has longer battery life and does not require frequent recharges (personal communication). The Bion is currently in clinical trials for the treatment of chronic pudendal neuralgia and for chronic pudendal nerve stimulation for the relief of urinary urge incontinence. The procedure requires a special introducer/stimulator which is used to locate the nerve and implant the Bion adjacent to the pudendal nerve within Alcock’s canal. This minimally invasive, wireless,

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A

FIGURE 77.6 FIGURE 77.5 The Bion device in Alcock’s canal for pudendal neuralgia (Reproduced with permission from Urology Clinics of North America, vol. 32: J.L.H.R. Bosch, The BION device, pp. 109–12. Copyright (2005) Elsevier)

and well-tolerated procedure may reduce the degree of detrusor overactivity incontinence, even in patients in whom sacral neuromodulation fails (Bosch, 2005; Groen et al., 2005) (see Figure 77.5). Percutaneous and Implant-Driven Tibial Nerve Stimulation Percutaneous tibial nerve stimulation (PTNS) has been proposed as an alternative therapy for the treatment of detrusor hyperreflexia, with reported clinical success rates of 63–71%. The tibial nerve is a mixed (sensory and motor) nerve that originates from the spinal level L4–S3. The physiological mechanism leading to outcome is still unknown, but it is presumed that signals from and towards the bladder are modulated by afferent stimulation through the sacral plexus. Sacral reflex pathways seem to be involved in this mechanism and not pain, sympathetic or cervicothoracic reflex pathway activation. Surface electrodes can be used for tibial nerve stimulation and are placed 5 cm above the medial malleolus over the anterior tibia usually once every 2–3 weeks and this procedure can be administered by the patients themselves. An innovative subcutaneous implant – Urgent-SQ (CystoMedix Inc., Anoka, MN) – that enables self-treatment has been developed. It has two electrodes which are placed parallel to the neurovascular bundle over the anterior tibia, 5–7 cm above the medial malleolus, through a skin incision, under local anesthesia. A radiofrequency receiver is attached to these leads and implanted as well and is stimulated by an external RF pulse generator (see Figure 77.6). At 12-month follow-up,

Urgent-SQ (CystoMedix Inc., Anoka, MN) (Reproduced from Van der Pal et al. (2006), Fig. 2, with permission of Wiley–Blackwell)

when compared to the results of PTNS, voiding and quality of life parameters were similar without significant differences. More experience is needed with this technique before recommending it routinely (Van der Pal et al., 2005, 2006). Intrathecal Drug Delivery Intrathecal analgesic medication delivery, through an implanted intrathecal catheter, tunnelled to an implanted drug delivery system (IDDS), is another technique of neuromodulation that may be used for sacral pain syndromes and pelvic dysfunction. Using this technique, medications are targeted and delivered directly to opioid and non-opioid receptors in the spinal cord via direct and targeted medication delivery into the cerebrospinal fluid and the intrathecal space. The rationale for this approach is that it produces high concentrations of agent(s) at the dorsal horn of the spinal cord. Such concentrations are never achieved by the systemic route of administration (oral, transdermal, intravenous, intramuscular), even if severe side effects were judged to be acceptable. Because of this targeted and direct delivery of agent/s, smaller doses of the agent/s are needed to achieve the desired outcome when compared to other, indirect and non-targeted systems of drug delivery, which results in less side effects and more potent direct effects of the agent infused. Moreover this route of drug administration allows for delivery of certain agents that cannot be delivered systemically, such as local anesthetics and zicotonide, an n-type, voltagesensitive calcium-channel blocking agent and analgesic (Wallace et al., 2006). For a review of intrathecal drug delivery for opioids, see the chapter by Krames

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and Harb in this book (Chapter 33); of intrathecal drug delivery for non-opioid analgesics see the chapter by Reig et al. (Chapter 35); and of IDDS, see the chapter by Bedder (Chapter 34).

References Abrams, P., Cardozo, L., Fall, M., Griffiths, D., Rosier, P., Ulmsten, U. et al. (2002) Report from the Standardisation Sub-committee of the International Continence Society. Am. J. Obstet. Gynecol. 187 (1): 116–26. Alo’, K.M. and McKay, E. (2001) Selective nerve root stimulation (SNRS) for the treatment of intractable pelvic pain and motor dysfunction a case report. Neuromodulation 4 (1): 19. Alo’, K.M. and Zidan, A.M. (2000) Selective nerve root stimulation (SNRS) in the treatment of end stage, diabetic, peripheral neuropathy: a case report. Neuromodulation 3 (4): 201. Alo’, K.M., Gohel, R. and Corey, C.L. (2001) Sacral nerve root stimulation for the treatment of urge incontinence and detrusor dysfunction utilizing a cephalocaudal intraspinal method of lead insertion: a case report. Neuromodulation 4 (2): 53. Alo’, K.M., Yland, M.J., Redko, V. et al. (1999) Lumbar and sacral nerve root stimulation (NRS) in the treatment of chronic pain: a novel anatomic approach and neuro stimulation technique. Neuromodulation 2: 23–31. Badenoch, A.W. (1971) Chronic interstitial cystitis. Br. J. Urol. 43 (6): 718–21. Baranowski, A.P., Abrams, P., Berger, R.E., Buffington, C.A.T., de C Williams, A.C., Hanno, P. et al. (2008) Urogenital pain – time to accept a new approach to phenotyping and, as a consequence, management. European Urology 53: 33–6. Bosch, J.L.H.R. (2005) The BION device: a minimally invasive implantable ministimulator for pudendal nerve neuromodulation in patients with detrusor overactivity incontinence. Urol. Clin. North Am. 32: 109–12. Bosch, J. and Groen, J. (1995) Sacral (S3) segmental nerve stimulation as a treatment for urge incontinence in patients with detrusor instability: results of chronic electricity stimulation using an implantable prosthesis. J. Urol. 154: 507. Brazzelli, M., Murray, A. and Fraser, C. (2006) Efficacy and safety of sacral nerve stimulation for urinary urge incontinence: a systematic review. J. Urol. 175 (3): 835–41. Brazzelli, M., Murray, A., Fraser, C. and Grant, A. (2004) Systematic review of the efficacy and safety of sacral nerve stimulation for urinary urge incontinence and urgency-frequency. In: Review Body Report Submitted to the Interventional Procedures Programme, National Institute for Clinical Excellence. Health Services Research Unit, University of Aberdeen. Chai, T.C., Zhang, C. and Warren, J.W. (2000) Percutaneous sacral third nerve root neurostimulation improves symptoms and normalizes urinary HB-EGF levels and antiproliferative factor in patients with interstitial cystitis. Urology 55: 643–46. Curhan, G.C., Speizer, F.E. and Hunter, D.J. (1999) Epidemiology of interstitial cystitis: a population based study. J. Urol. 161: 549–52. De Groat, W.C. (1993) Anatomy and physiology of the lower urinary tract. Urol. Clin. North Am. 20: 383. Dimitrakov, J.D. (2001) A case of familial clustering of interstitial cystitis and chronic pelvic pain syndrome. Urology 58 (2): 281. Diokno, A.C., Davis, R. and Lapides, J. (1973) The effect of pelvic nerve stimulation on detrusor contraction. Invest. Urol. 11: 178. Elbadawi, A.E. and Light, J.K. (1996) Distinctive ultrastructural pathology of nonulcerative interstitial cystitis: new observations and their potential significance in pathogenisis. Urol. Int. 56: 137–62.

Erickson, D.R., Ordille, S. and Martin, A. (1997) Urinary chondroitin sulfates, heparan sulfate and total sulfated glycosaminoglycans in interstitial cystitis. J. Urol. 157: 61–4. Erickson, D.R., Sheykhnazari, M. and Ordille, S. (1998) Increased urinary hyaluronic acid and interstitial cystitis. J. Urol. 160: 1282–4. Falco, F.J.E., Rubbani, M. and Heinbaugh, J. (2003) Anterograde sacral nerve root stimulation (ASNRS) via the sacral hiatus: benefits, limitations, and percutaneous implantation technique. Neuromodulation 6 (4): 219–24. Farkas, J., Waisman, J. and Goodwin, W.E. (1977) Interstitial cystitis in adolescent girls. J. Urol. 118: 837. Feler, C.A., Whitworth, L.A. and Brookoff, D. (1999) Recent advances: sacral nerve root stimulation using retrograde method of lead insertion for the treatment of pelvic pain due to interstitial cystitis. Neuromodulation 2: 211–16. Feler, C., Whitworth, L. and Fernandez, J. (2003) Sacral neuromodulation for chronic pain conditions. Anesthesiol. Clin. North Am. 21 (4): 785–95. Geist, R.W. and Antolak, S.J. (1970) Interstitial cystitis in children. J. Urol. 104: 922. Gillenwater, J.Y. and Wein, A.J. (1987) Summary of the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases Workshop on Interstitial Cystitis, National Institutes of Health, Bethesda, MD, August 28–29, 1987. J. Urol. 140 (1): 203–6. Groen, J., Amel, C. and Bosch, J.L. (2005) Chronic pudendal nerve neuromodulation in women with idiopathic refractory detrusor overactivity incontinence: results of a pilot study with a novel minimally invasive implantable mini-stimulator. Neurourol. Urodyn. 24 (3): 226–30. Hanash, K.A. and Pool, T.L. (1969) Interstitial cystitis in men. J. Urol. 102: 427–8. Held, P.J., Hanno, P.M. and Wein, A.J. (1990) Epidemiology of interstitial cystitis: 2. In: P. Hanno, D. Staskin, R. Krane and A. Wein. (eds), Interstitial Cystitis. London: Springer-Verlag, pp. 29–48. Hohenfellner, M., Dahms, S.E. and Matzel, K. (2000) Sacral neuromodulation for treatment of lower urinary tract dysfunction. BJU Int. 85 (Suppl.): 10. Hohenfellner, M., Schultz-Lampel, D. and Dahms, S. (1998) Bilateral chronic sacral neuromodulation for the treatment of lower urinary tract dysfunction. J. Urol. 160: 821. Ingersoll, E.H., Jones, L.L. and Hegre, E.S. (1957) Effect on urinary stimulation of pelvic nerves in the dog. Am. J. Physiol. 189: 167. Jasmin, L., Janni, G. and Manz, H.J. (1998) Activation of CNS circuits producing a neurogenic cystitis: evidence for centrally induced peripheral inflammation. J. Neurosci. 18 (23): 10,016–29. Jasmin, L., Janni, G. and Ohara, P.T. (2000) CNS induced neurogenic cystitis is associated with bladder mast cell degranulation in the rat. J. Urol. 164: 852–5. Jones, C.A. and Nyberg, L. (1997) Epidemiology of interstitial cystitis. Urology 49 (Suppl. 5A): 2–9. Keith, I.M., Jin, J. and Saban, R. (1995) Nerve–mast cell interaction in normal guinea pig urinary bladder. J. Comp. Neurol. 363: 28–36. Kenefick, N.J., Vaizey, C.J. and Cohen, R.C. (2002a) Medium-term results of permanent sacral nerve stimulation for faecal incontinence. Br. J. Surg. 89 (7): 896–901. Kenefick, N.J., Vaizey, C.J. and Cohen, R.C. (2002b) Double-blind placebo-controlled crossover study of sacral nerve stimulation for idiopathic constipation. Br. J. Surg. 89 (12): 1570–1. Koltzenburg, M. and McMahon, S.B. (1986) Plasma extravasation in the rat urinary bladder following mechanical, electrical and chemical stimuli: evidence for a new population of chemosensitive primary sensory neurons. Neurosci. Lett. 72: 352–6. Koziol, J.A. (1994) Epidemiology of interstitial cystitis. Urol. Clin. North Am. 21: 7–20.

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Koziol, J.A., Clark, D.C., Gittes, R.F. and Tan, E.M. (1993) The natural history of interstitial cystitis: a survey of 374 patients. J. Urol. 149 (3): 465–9. Lavano, A., Volpentesta, G., Piragine, G., Lofrida, G., De Rose, M., Abbate, F. et al. (2006) Sacral nerve stimulation with percutaneous dorsal transforamenal approach in treatment of isolated pelvic pain syndromes. Neuromodulation 9 (3): 229–33. Medtronic Neurological (1998) InterStim Report. Minneapolis, MN: Medtronic, Inc. Melzack, R. and Wall, P. (1965) Pain mechanisms: a new theory. Science 150: 971–8. Messing, E.M. (1992) Interstitial cystitis and related syndromes. In: Campbell’s Urology, 6th edn. Philadelphia: W.B. Saunders, pp. 982–1005. Michael, L.M., II, Whitworth, L.A. and Feler, C.A. (2002) Spina bifida occulta as a relative contraindication for percutaneous retrograde lead insertion for sacral nerve root stimulation. Neuromodulation 5 (1): 38–40. North, R.B., Ewend, M.G., Lawton, M.T., Kidd, D.H. and Piantadosi, S. (1991) Failed back surgery syndrome: 5-year follow-up after spinal cord stimulator implantation. Neurosurgery 28 (5): 692–9. North, R.B., Kidd, D., Davis, C., Olin, J. and Sieracki, J.M. (1999) Spinal cord stimulation electrode design: a prospective randomized, controlled trial comparing percutaneous and laminectomy electrodes. Stereotact. Funct. Neurosurg. 73: 134. Oravisto, K.J. (1975) Epidemiology of interstitial cystitis. Ann. Chir. Gynaecol. Fenniae. 64: 75–7. Ottem, D.P. and Teichman, J.M. (2005) What is the value of cystoscopy with hydrodistension for interstitial cystitis? Urology 66 (3): 494–9. Pang, X., Boucher, W. and Triadafilopoulos, G. (1996) Mast cell and substance P-positive nerve involvement in a patient with both irritable bowel syndrome and interstitial cystitis. Urology. 47: 436–8. Pang, X., Marchand, J. and Sant, G.R. (1995) Increased number of substance P positive nerve fibers in interstitial cystitis. Br. J. Urol. 75: 744–50. Parsons, C.L., Dell, J. and Stanford, E.J. (2002) Increased prevalence of interstitial cystitis: previously unrecognized urologic and gynecologic cases identified using a new symptom questionnaire and intravesical potassium sensitivity. Urology 60: 573–8. Parsons, C.L., Lilly, J.D. and Stein, P. (1991) Epithelial dysfunction in nonbacterial cystitis (interstitial cystitis). J. Urol. 145: 732–5. Peeker, R. and Fall, M. (2002) Toward a precise definition of interstitial cystitis: further evidence of differences in classic and nonulcer disease. J. Urol. 167: 2470–2. Peeker, R., Aldenborg, F. and Fall, M. (1998) The treatment of interstitial cystitis with supratrigonal cystectomy and ileocystoplasty: difference in outcome between classic and nonulcer disease. J. Urol. 159: 1479–82. Pinter, E. and Szolcanyi, J. (1995) Plasma extravasation in the skin and pelvic organs evoked by antidromic stimulation of the lumbosacral dorsal roots in the rat. Neuroscience 68: 603–14. Possover, M., Baekelandt, J. and Chiantera, V. (2007) The laparoscopic implantation of neuroprothesis (LION) procedure to control intractable abdomino-pelvic neuralgia. Neuromodulation 10 (1): 18–23. Rashid, H., Reeder, J.E., O’Connell, M.J., Zhang, C-O., Messing, E.M. and Keay, S.K. (2004) Interstitial cystitis antiproliferative factor (APF) as a cell-cycle modulator. BMC Urol. 4: 3. Romano, M., Brusa, S., Grieco, A., Zucco, F., Spinelli, A. and Allaria, B. (1998) Efficacy and safety of permanent cardiac ddd pacing

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with contemporaneous double spinal cord stimulation. PACE 21 (2): 465–7. Saban, M.R., Saban, R. and Bjorling, D.E. (1997) Kinetics of peptideinduced release of inflammatory mediators by the urinary bladder. Br. J. Urol. 80: 742–7. Saban, R., Saban, M.R. and Nguyen, N.B. (2000) Neurokinin-1 (NK-1) receptor is required in antigen-induced cystitis. Am. J. Pathol. 156: 775–80. Sairanen, J., Tammela, T.L., Leppilahti, M., Onali, M., Forsell, T. and Ruutu, M. (2007) Potassium sensitivity test (PST) as a measurement of treatment efficacy of painful bladder syndrome/interstitial cystitis: a prospective study with cyclosporine A and pentosan polysulfate sodium. Neurourol. Urodyn. 26 (2): 267–70. Sant, G.R. (ed.) (1997) Interstitial Cystitis. Philadelphia: Lippincott– Raven, p. 284. Schmidt, R.A., Jonas, U., Oleson, K.A., Janknegt, R.A., Hassouna, M.M. and Siegel, S.W. (1999) Sacral nerve stimulation for treatment of refractory urinary urge incontinence. Sacral Nerve Stimulation Study Group. J. Urol. 162 (2): 352–7. Shaker, H.S. and Hassouna, M. (1998a) Sacral nerve root neuromodulation: an effective treatment of refractory urge incontinence. J. Urol. 159: 1516–19. Shaker, H.S. and Hassouna, M. (1998b) Sacral root neuromodulation in idiopathic non-obstructive chronic urinary retention. J. Urol. 1476–8. Shealy, C., Mortimer, J. and Reswick, J. (1967) Electrical inhibition of pain by stimulation of the dorsal columns: preliminary report. Anesth. Analg. 46: 489–91. Siegel, S.W. (1992) Management of voiding dysfunction with an implantable neuroprosthesis. Urol. Clin. North Am. 19: 163–70. Skene, A.J.C. (1887) Diseases of the Bladder and Urethra in Women. New York: Wm Wood. Suzuki, R., Furuno, T. and McKay, D.M. (1999) Direct neurite–mast cell communication in vitro occurs via the neuropeptide substance P. J. Immunol. 163: 2410–15. Tanagho, E.A. and Schmidt, R.A. (1982) Bladder pacemaker: scientific basis and clinical future. Urology 20 (6): 614–19. Theoharides, T.C. (2007) Treatment approaches for painful bladder syndrome/interstitial cystitis. Drugs 67 (2): 215–35. Theoharides, T.C. and Cochrane, D.E. (2004) Critical role of mast cells in inflammatory diseases and the effect of acute stress. J. Neuroimmunol. 146: 1–12. Theoharides, T.C. and O’Leary, M. (2006) Painful bladder syndrome/ interstitial cystitis: current concepts and role of nutraceuticals. Semin. Prev. Altern. Med. 2: 6–14. Theoharides, T.C., Kempuraj, D. and Sant, G.R. (2001) Mast cell involvement in interstitial cystitis: a review of human and experimental evidence. Urology 57: 47–55. Tincello, D.G. and Walker, A.C. (2005) Interstitial cystitis in the UK: results of a questionnaire survey of members of the Interstitial Cystitis Support Group. Eur. J. Obstet. Gynecol. Reprod. Biol. 118: 91–5. Tomaszewski, J.E., Landis, J.R. and Russack, V. (2001) Biopsy features are associated with primary symptoms in interstitial cystitis: results from the interstitial cystitis database study. Urology 57: 67–81. Van der Pal, F., Heesakkers, J., Debruyne, F. and Bemelmans, B. (2005) Percutaneous tibial nerve stimulation to modulate the micturition reflex: an experimental study in female cats. ICS 2005 Scientific Programme. Van der Pal, F., van Balken, M.R., Heesakkers, J.F.P.A., Debruyne, F. M.J. and Bemelmans, B.L.H. (2006) Implant-driven tibial nerve stimulation in the treatment of refractory overactive bladder syndrome: 12-month follow-up. Neuromodulation 9 (2): 163–71.

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Villavicencio, A.T., Leveque, J.C., Rubin, L., Bulsara, K. and Gorecki, J.P. (2000) Laminectomy versus percutaneous electrode placement for spinal cord stimulation. Neurosurgery 46 (2): 399–405. Wallace, M.S., Charapata, S.G. and Fisher, R. (2006) Intrathecal ziconotide in the treatment of chronic nonmalignant pain: a randomized, double-blind, placebo-controlled clinical trial. Neuromodulation 9 (2): 75–86.

Warren, J.W., Keay, S.K., Meyers, D. and Xu, J. (2001) Concordance of interstitial cystitis in monozygotic and dizygotic twin pairs. Urology 57 (Suppl. 6A): 22–5. Waxman, J.A. (1998) Cystoscopic findings consistent with interstitial cystitis in normal women undergoing tubal ligation. J. Urol. 160 (5): 1663–7. www.nice.org.uk/ip082 Overview (accessed March 2005).

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C H A P T E R

78 Neuromodulation for Voiding Dysfunction Sarah McAchran, Raymond Rackley, and Sandip Vasavada

O U T L I N E Introduction

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History

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Putative Mechanism of Action of Sacral Neuromodulation Putative Mechanism of Action of Sacral Neuromodulation in Overactive Bladder Putative Mechanism of Action of Sacral Neuromodulation in Urinary Retention

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Electrical Stimulation for Storage Disorders Patient Selection Predictors of Success

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Special Populations Multiple Sclerosis (MS) Spinal Cord Injury (SCI)

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Contraindications

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Outcomes

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Complications

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Selective Nerve Stimulation Pudendal Nerve Dorsal Genital Nerve Posterior Tibial Nerve

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Electrical Stimulation for Emptying Disorders Electrical Stimulation Directly to the Bladder and Spinal Cord Electrical Stimulation to the Nerve Roots

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Sacral Neuromodulation of Emptying Disorders

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Conclusions

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24 hour period. Many of the afflicted patients complain of the need to void more than once per hour, a practice which can be profoundly disruptive to daily activities. Nocturia is the interruption of sleep by the urge to void. Often, patients with overactive bladder will complain about sleepless nights punctuated by hourly trips to the bathroom. Urinary urgency is the extreme desire to void, which, if not heeded, may result in incontinence (urge incontinence) or pain. Urge incontinence is caused

INTRODUCTION The refractory overactive bladder represents one of the most challenging problems in urology as well as a clinical problem that significantly erodes patient quality of life. Symptoms include urinary frequency, urgency, urge incontinence, and nocturia. Urinary frequency is defined as voiding more than eight times in a

Neuromodulation

Surgical Technique Bilateral Neuromodulation

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2009 Elsevier Ltd. © 2008,

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by an involuntary bladder contraction and has many etiologies, including neurologic disease, bladder outlet obstruction, and senile and idiopathic causes. Obviously, the embarrassment and social stigma of incontinence is the predominant symptom which these patients, many of them in their 40s to 60s, seek to correct. Initial treatment for patients with overactive bladder without any remediable anatomic cause is anticholinergic therapy. For patients who are not candidates for, refractory to, or who cannot tolerate anticholinergic pharmacotherapy, options are limited. Augmentation cystoplasty, in which a piece of small or large intestine is used to enlarge the bladder, has traditionally been offered as a last resort. However, this is a major operation with significant potential short-term and long-term complications. As Leng and Chancellor point out, even without complications most patients are troubled by the need for lifelong intermittent bladder catheterization after such reconstructive procedures (Leng and Chancellor, 2005). Neuromodulation offers an alternative to patients who have failed more conservative treatments and may be considering irreversible surgical options. Electrical stimulation has been used to treat a broad range of disorders of both bladder filling/storage and emptying/voiding, with varying degrees of success (Table 78.1). As illustrated in the table, the stimulation can be applied peripherally or centrally; acutely, subacutely, or chronically; and by nonimplantable or implantable electrodes – all depending on the purpose of the therapy. Since its graduation from experimental technique to proven clinical option in 1997, sacral neuromodulation has offered a minimally invasive solution with long-term efficacy and safety to this patient population as well as to patients with idiopathic, or non-obstructive, urinary retention. This chapter will focus on the application and clinical outcomes of neurostimulation and neuromodulation therapies for the treatment of voiding dysfunction.

HISTORY In the 1860s Giannuzzi stimulated the spinal cord in dogs and concluded that the hypogastric and pelvic nerves are involved in bladder regulation. In 1878, Saxtorph attempted to treat patients with urinary retention by directly stimulating the bladder with intravesical electrodes (Madersbacher, 1999). Built on this foundation, the neuromodulation which we practice today has its roots in the 1960s work of Boyce, Dees, Caldwell, and Nashold, who experimented with

TABLE 78.1 Potential applications of electrical stimulation in the treatment of voiding dysfunction Facilitate filling/storage Inhibit detrusor contractility Increase bladder capacity Decrease urgency and frequency

Vaginal

Neuromodulation

Anal Suprapubic Posterior tibial Common peroneal Sacral roots Intravesical

Decrease nociception

Vaginal Anal Suprapubic Sacral roots

Neuromodulation

Increase outlet resistance

Vaginal

Direct stimulation (efferent nerves or roots)

Anal Sacral roots Facilitate emptying Stimulate detrusor contraction (spinal cordinjured patient)

Sacral anterior (ventral) roots

Direct stimulation (efferent nerves or roots)

Restore micturition reflex (idiopathic retention)

Sacral roots Intravesical

Neuromodulation

Adapted from A. Wein, Neuromuscular dysfunction of the lower urinary tract and its management, in P.C. Walsh et al. (2002) Campbell’s Urology, 8th edn (Philadelphia: Saunders), p. 981

various modes of bladder stimulation including a transurethral approach, direct detrusor stimulation, pelvic nerve and pelvic floor stimulation, and finally spinal cord stimulation (Caldwell, 1963; Dees, 1965; Nashold et al., 1971, 1972). In the last century the pioneering work of Tanagho, Brindley, and Schmidt demonstrated that stimulation of sacral root S3 generally induces detrusor and sphincter action and led to clinical trials of implantable devices to treat genitourinary disorders including erectile dysfunction, urinary incontinence, and urinary retention. The US Food and Drug Administration approved sacral nerve stimulation (SNS) for intractable urge incontinence in 1997, and for urgency–frequency and nonobstructive urinary retention in 1999. Later labeling was changed to include “overactive bladder” as an appropriate diagnostic category. Since its inception, more than 20 000 InterStim neurostimulators (Medtronic Inc., Minneapolis, MN) have been implanted for the three approved indications for SNS of the lower urinary tract.

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ELECTRICAL STIMULATION FOR STORAGE DISORDERS

PUTATIVE MECHANISM OF ACTION OF SACRAL NEUROMODULATION Two main theories exist regarding the mechanism of action of sacral neuromodulation. First, direct activation of efferent fibers to the striated urethral sphincter reflexively causes detrusor relaxation. Second, selective activation of afferent fibers causes inhibition at spinal and supraspinal levels. Accumulating evidence suggests that activation of somatic sacral afferent inflow at the sacral root level that, in turn, affects the storage and emptying reflexes in the bladder and central nervous system accounts for the positive effects of neuromodulation on both storage and emptying functions of the bladder (Leng and Chancellor, 2005). By monitoring somatosensory evoked potentials (SEP) during sacral neuromodulation, Malaguti et al. concluded that sacral neuromodulation therapy works by sacral afferent activity and concomitant activation of the somatosensory cortex (Malaguti et al., 2003). Since sacral neuromodulation has been proven clinically effective for both storage (urgency–frequency and urgency incontinence) and emptying (non-obstructive urinary retention) dysfunctions of the bladder, isolating the mechanism of action has been challenging.

Putative Mechanism of Action of Sacral Neuromodulation in Overactive Bladder The ability to volitionally store and evacuate urine is modulated by several centers in the brain. It is thought that patients with overactive bladder may have suffered an insult that effectively unmasks involuntary bladder contractions (Figure 78.1). Sacral neuromodulation of these primitive reflexes may restore normal micturition (de Groat and Saum, 1976). Sacral neuromodulation may affect detrusor overactivity by suppressing or inhibiting interneuronal transmission in the bladder reflex pathway (de Groat and Saum, 1976; Kruse and de Groat, 1993; Leng and Chancellor, 2005). This inhibition may, in part, modulate the sensory outflow from the bladder through the ascending pathways to the pontine micturition center (PMC), thereby, preventing involuntary contractions by modulating the micturition reflex circuit. In clinical practice, sacral neuromodulation improves abnormal bladder sensations, involuntary voids, and detrusor contractions. Interestingly, voluntary voiding is preserved. This may be due to selective avoidance of normal sensory ascending outflow pathways of the bladder from Aδ-fibers to the PMC, as well as initiation

Infection, inflammation, anatomic abnormalities

Voluntary micturition control

Involuntary reflex mechanisms SNS therapy

Neurological diseases

FIGURE 78.1 The concept of SNS is to modulate the abnormal involuntary reflexes of the lower urinary tract and restore voluntary control (After Leng and Chancellor (2005), Urology Clinics of North America, vol. 32, pp. 11–18. Copyright (2005) Elsevier)

of the descending pathways from the PMC to sacral efferent outflow pathways.

Putative Mechanism of Action of Sacral Neuromodulation in Urinary Retention To allow for complete bladder empyting, detrusor contractions must be coordinated with urethral sphincteric relaxation. When the suprasacral pathways that coordinate sphincteric activity are altered, the guarding and urethral reflexes that allow for urine storage without leakage still exist and cannot be turned off. This may result in urinary retention and is seen in certain patients with spinal cord injury and detrusor sphincter dyssynergia. These patients have functional detrusor contractions but are unable to coordinate this with a relaxed urethral sphincter resulting in urinary retention. Inhibition of the guarding reflexes may improve urinary retention. Sacral neuromodulation is postulated to turn off excitatory flow to the urethral outlet and facilitate bladder emptying.

ELECTRICAL STIMULATION FOR STORAGE DISORDERS Patient Selection Since many lower urinary tract symptoms and dysfunctions are secondary to neuromuscular etiologies, a thorough history and physical examination will often reveal the nature (acute vs. chronic) and help to classify the causes (neurogenic, anatomic, post-surgical, functional, inflammatory, and/or idiopathic). Urinalysis is routinely performed. Urine cytology should be considered in patients who present with refractory

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symptoms of dysuria, urgency or frequency as both bladder cancer and bladder carcinoma in situ may present with irritative bladder symptoms without hematuria (Siegel, 2005). Urodynamic studies (UDS) including cystometrogram, pressure-flow studies, and electromyography (EMG) of sphincters and pelvic floor muscles, are performed on a selected basis. Many patients without known neurologic disorders can be thoroughly evaluated with the use of a voiding diary and a focused history and physical examination of the pelvis. EMG is recommended in suspected cases of neurogenic bladder dysfunction, detrusor sphincter dyssynergia or Fowler’s syndrome and may be considered for evaluation of inappropriate pelvic floor muscle behavior (Fowler, 1999). The pathophysiology of neurogenic bladders, as seen in patients with multiple sclerosis and spinal cord injury, can change with time and disease progression. As such, these patients will require reevaluation with urodynamics at regular intervals, or when symptoms change despite active medical intervention. Cystourethroscopy may be helpful. Urethral strictures and bladder neck contractures or fibrosis can be diagnosed. Bladder wall trabeculation may help to confirm a clinical suspicion of bladder outlet obstruction or neurogenic pathology. Baseline upper tract imaging is performed in patients with neurologic disease, or if indicated by physical or baseline studies or a patient’s history.

To date only one published study has prospectively evaluated preoperative factors associated with cure in patients with intractable urge incontinence (Amundsen et al., 2005). Amundsen et al. evaluated 105 patients between 2000 and 2003. Fifty-five were implanted and the average age at implantation was 60 years. Cure was defined as no daily leakage episodes after permanent implantation. Three factors were associated with lower cure rates: age greater than 55 years, three or more chronic conditions, and neurologic conditions. Individuals younger than 55 years had a cure rate of 65% vs. 37% for older individuals. Age older than 55 years and more than three chronic conditions were found to be independent risk factors for failure. The most common medical co-morbidities present in this population included arthritis, hypertension, diabetes, and depression. Neurologic conditions included a history of back surgery in the majority of patients, multiple sclerosis, Parkinson’s disease, and cerebrovascular accident. The authors suggest that the aged population may have profound changes in the central neural control systems of the bladder as well as the bladder itself. Studies of cerebral function in older incontinent individuals using single photon emission computed tomography have reported that underperfusion is present in the frontal lobe. This is not seen in younger incontinent women (Griffiths, 1998). SNS targets spinal circuits. If the central control mechanism is impaired, it seems reasonable that SNS will be less efficacious.

Predictors of Success Currently, sacral neuromodulation is prescribed for those patients with urgency, frequency, and urge incontinence who have failed traditional conservative measures such as bladder retraining, pelvic floor biofeedback, and medications and for whom more invasive procedures such as enterocystoplasty or urinary diversion might be inadvisable or has been declined. Recently, several studies have tried to more accurately identify which patients will or will not respond to sacral neuromodulation, however, predictive factors remain elusive (Koldewijn, Rijkhoff et al., 1994; Bosch and Groen, 2000; Scheepens et al., 2003). Koldewijn’s study found that neither gender, nor patient age, history, or diagnosis was a predictor of success in sacral neuromodulation of lower urinary tract dysfunction (Koldewijn, Rosier et al., 1994). Urodynamic predictors of success have been equally hard to identify. One recent study found that both patients with and patients without demonstrable detrusor overactivity, or involuntary detrusor contractions noted on urodynamics, may have a positive response to sacral neuromodulation (South et al., 2007).

SPECIAL POPULATIONS Indications for neuromodulation are expanding. Several populations of patients with voiding dysfunction have some component of the indicated symptom complex that includes urgency, frequency, urge incontinence, or urinary retention. The current expansion of indications for neuromodulation has developed into areas of neurogenic bladder (Parkinson’s disease, multiple sclerosis), spinal cord injury, and pediatric voiding dysfunction. Painful bladder syndrome, pelvic pain, fecal incontinence, and bowel disorders will be discussed elsewhere.

Multiple Sclerosis (MS) Multiple sclerosis can cause a variety of voiding dysfunction scenarios including neurogenic detrusor overactivity, detrusor sphincter dyssynergy (DSD), areflexia or any combination of these. Bladder problems affect up to 90–100% of patients during the

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course of their disease (Minardi and Muzzonigro, 2005). MS patients were excluded from the original sacral neuromodulation trials because of the theoretical change in the disease state that may be potentiated by neuromodulation (Hassouna et al., 2000). No prospective randomized trials exist on the use of neuromodulation in management of MS-related bladder dysfunction, but small series have shown encouraging results (Ruud Bosch and Groen, 1996; Minardi and Muzzonigro, 2005). It appears that the best candidates are ones with mild, non-progressive MS, with little functional decompensation who also have detrusor overactivity or retention but not areflexia.

Spinal Cord Injury (SCI) Patients with spinal cord injury present with a variety of clinical and urodynamic findings ranging from detrusor areflexia to neurogenic detrusor overactivity with or without concomitant sphincteric dyssynergy. The goal of treatment of these patients is to prevent the urologic sequelae of SCI, such as infections, stones, and obstruction, while ensuring a bladder that functions well, empties at a low pressure to protect the kidneys, and maintains a good capacity and continence. Basic science data suggest that at least some communication should exist between sacral outflow and the pontine micturition center to allow processing for the reflexes that may be inhibited by the brain (de Groat et al., 1981). Thus, patients with complete spinal cord lesions may not have the same potential benefit from neuromodulation as does one with an incomplete lesion. However, this fact has yet to be proven clinically. Few studies exist in neurogenic patients alone for whom sacral neuromodulation was performed. Andrews reported on a T8 paraplegic with urinary urgency and urge incontinence who underwent percutaneous tibial nerve stimulation (Andrews and Reynard, 2003). This patient experienced almost a two-fold increase in bladder capacity.

normal pelvic organ function, such as patients with functional urinary incontinence and patients who are non-compliant, should not be offered this therapy. Sacral neuromodulation is relatively contraindicated for those patients who have an anticipated need for future magnetic resonance (MR) imaging and patients who plan to become pregnant. The main concern with MRI and implantable stimulator/ pacemaker-type devices is that heating of the leads has been demonstrated in vivo and in vitro (Roguin et al., 2004; Martin, 2005). While some question the clinical significance of the small temperature changes with the leads, the potential exists to elicit nerve damage. Additionally, there is some concern that the magnetic field from MR imaging may damage the pulse generator. Many radiologists are reluctant to provide MR imaging services for patients with implantable electrical stimulation devices despite the anecdotal evidence that no adverse events have occurred when MR imaging has inadvertently or purposefully been done for emergent reasons or in small trials (Roguin et al., 2004). For patients who have InterStim devices in place, we advocate removal of the neuroelectrode lead only with preservation of the pulse generator in preparation for elective MR imaging. Following the MR imaging procedure, a new neuroelectrode may be placed and connected to the previous implanted and preserved pulse generator. Due to the unknown teratogenic potential of electrical stimulation it has been considered contraindicated in pregnant women with various voiding dysfunctions. One study that evaluated the effect of electrical stimulation on pregnant rats and their fetuses was unable to find any adverse effects and thus concluded that termination of pregnancy is not advised for prospective mothers when electrical stimulation has been performed unknowingly in early pregnancy (Wang and Hassouna, 1999). Women with electrical stimulation devices for pelvic health conditions who become pregnant may simply turn off their devices when considering and during pregnancy.

CONTRAINDICATIONS SURGICAL TECHNIQUE There are several important contraindications to sacral neuromodulation. In patients with anatomic changes such as bony abnormalities of the sacrum, transforaminal access may be difficult or impossible. Patients with cognitive impairment rendering them incapable of operating the device or giving appropriate feedback regarding the level and comfort of stimulation are poor candidates. Finally patients with physical limitations that prevent them from achieving

The procedure consists of two stages: a testing stage or first stage and an implantation stage or second stage. Since its introduction, several modifications have been made in the technology, with resultant changes in the surgical technique. The most significant of these changes was the shift from peripheral nerve evaluation to the anchored lead staged procedure, and finally to the current tined

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lead staged procedure. The tined lead was introduced in 2002 and offers the advantage of simplified placement of the stimulation lead through a percutaneous approach without the need for lead anchoring to the fascia (Spinelli et al., 2003). The lead is secured through the action of the tines. Another surgical modification was the movement of the location of the implantable pulse generator (IPG) unit from the lower anterior abdominal wall to the posterior gluteal region. For Stage I, preoperative intravenous antibiotics are given and standard aseptic techniques for the implantation of foreign bodies are implemented. The patient is prone and the buttocks are held apart using wide tape retraction so that the anus is visible during test stimulation. The anus and tape are prepped in a sterile fashion and then covered with a separate plastic drape until visualization of the anus is needed during the procedure. The patient’s feet will also need to be visible during the procedure. The S3 foramen, the desired location of the tined lead, can be localized via surface landmarks or fluoroscopic methods. The S3 foramen is generally located 2–3 cm off the midline on either side approximately 9–11 cm cephalad to the tip of the coccyx. If the sciatic notch can be palpated this provides a useful landmark as well. A line is drawn connecting the sciatic notches bilaterally and an intersecting line is drawn at the midline of the sacrum. The S3 foramen can be located approximately 1 fingerbreadth lateral to the midline of the sacrum along the line connecting the sciatic notches. Less reliably, one can look for the least curved portion of the sacrum. In 2001, Chai introduced the use of the “cross-hair” fluoroscopic technique for S3 localization (Chai and Mamo, 2001). Fluoroscopy is intended to help the surgeon identify a specific region to start attempting percutaneous access; it does not allow the surgeon to visualize the S3 foramen directly. More importantly, the use of lateral imaging allows the surgeon to determine the depth required for implanting the lead once the S3 foramen is identified. Janknegt first described the staged implantation approach in which an implanted S3 lead, rather than the temporary lead, was used for initial testing (Janknegt et al., 2001). The staged technique bypasses the problems with percutaneous needle examination (PNE), which included a high risk of lead migration and the fact that the original response of the patient obtained by the temporary wire may not be reproduced by the permanent lead. Several reports later confirmed higher response rates and a lesser rate of lead migration obtained by the staged approach (Hijaz et al., 2006). At the previously marked S3 foramen, the foramen needle is inserted. Because the pelvic plexus and pudendal nerve run alongside the pelvis, the needle

should be placed just inside the ventral foramen. Fluoroscopy is used to confirm needle position. The nerve is tested for the appropriate motor response: dorsiflexion of the great toe and bellows contraction of the perineal area (Table 78.2). The so-called bellows reflex represents contraction of the levator muscles. The foramen needle is exchanged for the introducer sheath and the lead is passed so that the electrodes, numbered 0 through 3, are positioned with electrode 2 and 3 straddling the ventral surface of the sacrum (Figure 78.2). Test stimulation is repeated on each electrode and the responses are observed. An S3 response should be noted at a minimum of two of the four electrodes. Once satisfied with the position, the sheath is removed, releasing the tines that anchor the lead. Confirmation of an S3 sensory response, a sensation of stimulation in the perineum, is not required to confirm proper placement if the correct S3 motor response is observed (Cohen et al., 2006). However, if a motor response is

TABLE 78.2 Sacral nerve responses Sacral nerve

Motor and sensory response

S2

Motor: Plantar flexion of the entire foot with lateral rotation and clamp movement of the anal sphincter Sensory: Sensations in the leg and buttock

S3

Motor: Dorsiflexion of the great toe and a Bellows reflex (anal wink) Sensory: Paresthesiae or sensation of pulling in the rectum, scrotum, or vagina

S4

Motor: Bellows reflex only Sensory: Sensation of pulling in the rectum only

FIGURE 78.2 Optimal lead placement with the lead positioned with electrodes 2 and 3 straddling the ventral surface of the sacrum (Reprinted with the permission of Medtronic, Inc. © 2006)

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absent despite what appears to be fluoroscopically appropriate placement, the patient’s sedation can be lightened and sensory responses can be elicited. Patient verification of the correct sensory response can then confirm proper localization. A 2–4 cm incision into the subcutaneous tissues in the upper lateral buttock is made below the beltline or below the level of the ischial wings for connecting the permanent lead to the percutaneous extension lead wire. If the screening trial is successful, this connection site will be the site of implantation for the IPG. The permanent lead is transferred to the medial aspect of the lateral buttock incision using the tunneling device. The lead is then connected to the extension wire and the tunneling device is used again to transpose the extension wire from the medial aspect of the incision to an exit point on the contralateral side of the back. This transfer and long tunnel reduces the occurrence of infection from the percutaneous exit site of the wire. The extension wire is connected to the external pulse generator. Patients are able to resume their normal activities immediately, but are advised to limit their excessive movement-related activities such as high impact exercises for the duration of the trial period. The external generator can be flexibly programmed for the duration of the intended trial while the patient records their symptoms and bladder function in a voiding diary. If there is greater than 50% improvement in the symptoms or voiding function, a Stage II procedure is performed. At the Stage II procedure, the IPG is placed. No fluoroscopy is required during Stage II when a permanent neuroelectrode has been placed for the Stage I procedure; however, if a PNE was performed for Stage I, then fluoroscopic confirmation of the neuroelectrode placement is advised. The buttock incision overlying the lead connections is opened, the percutaneous extension wire is removed, and the extension lead is secured to the permanent lead and subsequently to the IPG. The newer generation IPG is connected directly to the permanent lead without the need for an extension lead. The IPG pocket should be large enough to accommodate the IPG without tension and deep enough to prevent erosion and provide cosmetic results.

Bilateral Neuromodulation There is no consensus as to whether one or two implanted S3 leads should be performed at the first stage. Bilateral implantation allows for testing of both the left and right S3 nerve roots. At the time of the second stage, the lead which produced the most robust response can be attached to the IPG and the other lead

removed. Bilateral stimulation has been suggested for potential salvage of patients who have failed unilateral lead placement (van Kerrebroeck et al., 2005). The theory behind the additive effects of bilateral stimulation is based on animal studies that demonstrated bilateral stimulation yielded a more profound effect on bladder inhibition than did unilateral stimulation (SchultzLampel et al., 1998a; Schultz-Lampel et al., 1998b). The only clinical study comparing unilateral to bilateral test stimulation was unable to find any significant difference with regards to urge incontinence, frequency, or severity of leakage in the OAB group (Scheepens et al., 2002). The retention group patients had better parameters of emptying (volume per void) in bilateral as compared with unilateral stimulation. However, the numbers were too small in the retention group to make adequate conclusions. Studies are ongoing regarding bilateral stimulation for this indication.

OUTCOMES Outcomes of SNS for the indications of idiopathic urgency–frequency and urge incontinence are derived from two studies that have randomized patients to active or delayed therapy, as well as reports from numerous prospective and retrospective reviews of case series and registry databases. Schmidt et al. (1999) reported on SNS therapy in 76 patients with refractory urge incontinence. During the 6 month study period, at 16 different centers, patients were randomized to active or delayed therapy (control group). Of the 34 patients receiving active SNS therapy, 16 (47%) were completely dry, and an additional 10 (29%) demonstrated a greater than 50% reduction in incontinence episodes. In a similar study design, Hassouna et al. (2000) reported the outcomes of SNS for refractory urgency–frequency conditions in 51 randomized patients (Hassouna et al., 2000). At 6 months patients in the active SNS group showed improvement in the number of daily voids (16.99.7 to 9.35.1), volume voided (11874 to 226124 ml), degree of urgency (rank score of 2.20.6 to 1.60.9), and quality of life measures. At 6 months post implant, stimulators in the active group were turned off and urinary symptoms returned to baseline values. After reactivation of SNS, sustained efficacy was documented at 12 and 24 months. Limited but confirmational results of the earlier randomized trials have been obtained from prospective series (Shaker and Hassouna, 1998; Siegel et al., 2000; Janknegt et al., 2001) and registry studies (Spinelli et al., 2001; Hedlund et al., 2002) evaluating

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efficacy, safety, and quality of life measures. The results for the US registration trial that led to FDA approval for SNS (Pettit et al., 2002) reveal that 37 of 62 patients (60%) with refractory urgency–frequency or urge incontinence achieved a 50% or more improvement in their condition.

COMPLICATIONS The sacral nerve stimulation study group has published several reports on the efficacy and safety of the procedure for individual indications (Siegel et al., 2000). The complications were pooled from the different studies based on the fact that the protocols, devices, efficacy results, and safety profiles were identical. Of 581 patients recruited, 219 underwent implantation of the InterStim system. The complications were divided into both percutaneous test stimulation related and post implant related problems. Of the 914 test stimulation procedures done on the 581 patients, 181 adverse events occurred in 166 of these procedures (18.2% of the 914 procedures). The vast majority of complications were related to lead migration (108 events, 11.8% of procedures). Technical problems and pain represented 2.6% and 2.1%, respectively, of the adverse events. For the 219 patient who underwent implantation of the InterStim system (lead and generator), pain at the neurostimulator site was the most commonly observed adverse effect at 12 months (15.3%). Surgical revisions of the implanted neurostimulator or lead system were performed in 33.3% of cases (73 of 219 patients) to resolve an adverse event. These included relocation of the neurostimulator because of pain at the subcutaneous pocket site and revision of the lead for suspected migration. Explantation of the system was performed in 10.5% for lack of efficacy. One should consider the fact that, at the time, the generator was implanted in the lower abdomen. Everaert reported the complications related to SNS itself. Among the 53 patients who had undergone implantation of the quadripolar electrode (Medtronic InterStim, Model 3886 or 3080) and subcutaneous pulse generator in the abdominal site (Medtronic InterStim: Itrel 2, IPG) between 1994 and 1998, device-related pain was the most frequent problem, occurring in 18 of the 53 patients (34%) and occurring equally in all implantation sites (sacral, flank or abdominal). Pain responded to physiotherapy in 8 patients and no explantation was done for pain reasons. Current-related complications occurred in 11%. Fifteen revisions were performed in 12 patients. Revisions for prosthesis-related pain (n  3) and for late failures (n  6) were not successful.

Hijaz et al. (2006) reported the complications in a review of 214 patients who underwent SNS. Of the 214 patients, 161 underwent IPG implantation during a mean follow-up of 16 months. The second-stage explantation and revision rate was 10.5% and 16.1%, respectively. The indications for explantation were infection in 8 of 17 and failure to maintain response in 9 of 17. Revisions were performed for decreases in response (17/26), IPG site discomfort (4/26), draining sinus at the IPG site (4/26), and lead migration (1/26). It should be pointed out that the need for revision does not indicate unsuccessful treatment. As noted in the previous studies, all of the complications were minor, further solidifying the safety of this procedure. Hijaz et al. (2006) have also presented algorithms for troubleshooting of the SNS problems. Generator site infection is best treated with explantation of the whole system. Despite attempts to salvage some of these patients, follow-up revealed that the infection persisted in all and eventual explantation was inevitable. The troubleshooting algorithm includes the search for causes of (a) pocket (IPG site) discomfort; (b) recurrent symptoms; (c) stimulation occurring in the wrong area of pelvis; (d) no stimulation; and (e) intermittent stimulation.

SELECTIVE NERVE STIMULATION Pudendal Nerve Sacral neuromodulation is thought to improve bladder storage by inhibiting the micturition reflex via electrical stimulation of sensory afferent fibers, in particular by depolarization of Aα and Aγ somatomotor fibers that affect the pelvic floor and external sphincter and thus inhibit detrusor activity (Hohenfellner et al., 1992, 1998). Many of the sensory afferent nerve fibers contained in the sacral spinal nerves originate in the pudendal nerve, thereby making the pudendal nerve an ideal target for neuromodulating inhibition of the micturition reflex. Direct pudendal nerve neuromodulation stimulates more pudendal afferents than SNS and may do so without the side effects of off-target stimulation of leg and buttock muscles. Thus, techniques for direct pudendal nerve stimulation at alternative locations to the sacral foramen are being developed.

Dorsal Genital Nerve The most superficial, terminal branch of the pudendal nerve is the dorsal genital nerve (dorsal nerve of the penis in males, clitoral nerve in females). In both

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genders the dorsal genital nerve is located at the level of the symphysis pubis and is a pure sensory afferent branch carrying sensory information from the glans of the penis or clitoris. As a pure sensory afferent nerve branch of the pudendal nerve, the dorsal genital nerve contributes to the pudendal-pelvic nerve reflex that has been proposed as a mechanism of bladder inhibition. In experimental and clinical studies, direct electrical stimulation of the dorsal genital nerve appears promising in producing an inhibition of the micturition reflex. Results in laboratory animals and in persons with spinal cord injury have demonstrated that electrical stimulation of the dorsal genital nerves inhibits bladder contractions (Craggs and McFarlane, 1999). Stimulation of the dorsal penile nerve has been tested in patients with spinal cord injury and has been shown to increase bladder volume and reduce bladder overactivity (Wheeler et al., 1992, 1994). Dorsal penile nerve stimulation was painless and no side effects noted. Similar experiments have shown that stimulation of the dorsal nerve of the penis abolishes reflexive bladder contractions and increases bladder capacity in persons with spinal injury (Lee and Creasey, 2002). Feasibility trials using MedStim (Medtronic, Minneapolis, MN), an implantable neuroelectrode and pulse generator originally conceived by NDI, are under way for otherwise healthy patients with idiopathic detrusor overactivity.

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et al., 2003; Vandoninck et al., 2003; Congregado Ruiz et al., 2004), and for urinary retention (van Balken et al., 2001; Vandoninck et al., 2003). Overall, results are comparable to those seen with anticholinergic pharmacologic therapy (Cooperberg and Stoller, 2005). Proponents argue that relative to SNS, other surgical modalities, and chronic medical therapy, PTNS offers a much more economical alternative.

ELECTRICAL STIMULATION FOR EMPTYING DISORDERS This section concentrates exclusively on the use of electrical stimulation to facilitate emptying in those patients with urinary retention. Failure to empty can be caused by decreased detrusor contractility, urethral obstruction due to iatrogenic causes after antiincontinence surgery, obstructive benign prostatic hyperplasia, urethral strictures, and detrusor-sphincter dyssynergia. Urinary retention has a significant adverse effect on patient quality of life and can lead to deterioration of overall health because of recurrent urinary tract infections, reflux nephropathy with consequent renal insufficiency or failure, and, often, overflow incontinence.

Electrical Stimulation Directly to the Bladder and Spinal Cord Posterior Tibial Nerve The posterior tibial nerve is a mixed sensory and motor nerve containing fibers originating from spinal roots L4 through S3 which modulate the somatic and autonomic nerves to the pelvic floor muscles, bladder and urinary sphincter. Based on translational findings of traditional Chinese acupuncture practices, McGuire et al used transcutaneous stimulation of the common peroneal or posterior tibial nerve to inhibit detrusor overactivity (McGuire et al., 1983). Percutaneous tibial nerve stimulation (PTNS) (Urgent PC, CystoMedix, Anoka, MN) is approved by the FDA. A small gauge stimulating needle is inserted approximately 5 cm cephalad to the medial malleolus and just posterior to the tibia. Electrical stimulation is then applied at a level just below the somatic sensory threshold for a total of thirty minutes. Sessions are repeated weekly for 10–12 weeks. PTNS is minimally invasive and well tolerated. Clinical trials using PTNS have been performed for detrusor overactivity with and without pelvic pain (Klingler et al., 2000; Govier et al., 2001; van Balken

Direct electrical stimulation of the bladder to facilitate emptying in patients with hypotonic or areflexic bladders was originally tested in 1940, but has met with only partial success and intermittent enthusiasm over the years (Wein and Barrett, 1988). Success, defined as low post-void residual urine volumes, was achieved in only 50–60% of patients, and was short-lived due to complications related to fibrosis, electrode malfunction, bladder erosion, or other equipment malfunction. Additionally, the stimulus thresholds for other pelvic structures are lower than those for the bladder, and untoward side effects ensued such as abdominal, pelvic, and perineal pain; a desire to defecate or defecation; pelvic and leg muscle contraction; and erection and ejaculation in males. Furthermore, the increased intravesical pressures that were generated were not necessarily coordinated with bladder neck opening and pelvic floor relaxation. Similar problems were found with attempts to apply direct electrical stimulation to the sacral spinal cord. Enthusiasm for both of these approaches has waned considerably, and their resurrection seems unlikely.

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Electrical Stimulation to the Nerve Roots The Brindley device is indicated for patients with inefficient or non-reflex micturition after SCI. Madersbacher and Fisher describe the patient prerequisites as follows: intact neural pathways between the sacral cord nuclei of the pelvic nerve and the bladder, and a bladder that is capable of contracting (Fischer et al., 1993; Madersbacher and Fischer, 1993). The Brindley device provides electrical stimulation directly to the nerve roots. Electrodes are applied intradurally to S2, S3, and S4 nerve roots. The pairs can be activated independently and micturition, defecation, and erection programs are possible, with stimulus patterns set specifically for each patient (Brindley, 1994a). Simultaneous bladder and striated sphincter stimulation is obviated by sacral posterior rhizotomy, usually complete, which eliminates reflex incontinence and improves low bladder compliance, if present (Brindley, 1994b). Bladder emptying as achieved by the Brindley stimulator is based on the principle of post-stimulus voiding, a term first introduced by Jonas and Tanagho (1975). Relaxation time of the striated sphincter after a stimulus train is shorter than the relaxation time of the detrusor smooth muscle. When interrupted pulse trains are used, voiding occurs because the bladder continues to contract after the striated sphincter has relaxed. This concept and other methods that are available to overcome the stimulation-induced sphincter dyssynergia and allow low-pressure emptying, are nicely reviewed by Rijkhoff et al. (1997). Post-stimulus voiding has a several shortcomings: first voiding occurs at above normal bladder pressures; second, incorrectly adjusted stimulus parameters can lead to elevated detrusor pressures and consequent upper urinary tract damage; finally, stimulation can cause cumbersome, inadvertent leg movements. The Brindley system is an invasive procedure for a very select population, but within that population success rates have been promising (Brindley, 1994b; van Kerrebroeck et al., 1997; Dahms et al., 2000). It has become an accepted treatment modality for the SCI patient with lower urinary tract dysfunction and further evolution will doubtless occur.

SACRAL NEUROMODULATION OF EMPTYING DISORDERS Sacral neuromodulation using the InterStim system has been successful in patients with idiopathic non-obstructive retention, retention secondary to deafferentation of the bladder after hysterectomy, and in

patients with Fowler’s syndrome, a syndrome of urinary retention in young, premenopausal women without overt neurologic disease (Swinn et al., 2000). The success rate, however, is not as robust as that seen for the treatment of urgency, frequency, and urge incontinence. Additionally, improvement in patients with retention may not be as rapid as in patients undergoing sacral root stimulation for other reasons. Therefore, an extended Stage I trial is recommended. Furthermore, as previously described, bilateral lead placement may prove to be more effective (Scheepens et al., 2002). A recent study retrospectively evaluating 29 patients with urinary retention due to a wide variety of etiologies found that those patients able to volitionally void more than 50 ml at presentation were more likely to proceed to Stage II and permanent implantation (Goh and Diokno, 2007). Finally, a novel approach involving the placement of bilateral tined leads into the caudal epidural space was recently described for those patients with refractory urinary retention (Maher et al., 2007). This remains an experimental approach. A large, prospective randomized multi-center trial to evaluate the efficacy of sacral nerve stimulation for urinary retention was performed by Jonas et al. (2001). Of those patients evaluated with chronic, non-obstructive urinary retention, 68, or 38%, proceeded to permanent implantation after PNE. Patients were randomly assigned to the treatment or control group, in which treatment was delayed for 6 months. Improvement in volitional voiding was seen in 83% of patients who received the implant, and 69% were able to discontinue intermittent catheterization entirely. At 18 months, 71% of the patients available for follow-up had continued improvement. Aboseif et al. evaluated the efficacy and change in quality of life in patients with idiopathic, chronic, nonobstructive functional urinary retention (Aboseif et al., 2002). Thirty-two patients with idiopathic retention requiring intermittent catheterization underwent PNE. Twenty patients proceeded to permanent implantation. Eighteen of these patients were able to void and no longer required intermittent catheterization. Average voided volumes increased from 48 ml to 198 ml and post-void residuals decreased from 315 ml to 60 ml.

CONCLUSIONS While clearly still in its infancy, neuromodulation has enjoyed wide success in the field of voiding dysfunction with applications to a broad range of problems including both storage and emptying disorders. Due to refinements in technique and technology it is a

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REFERENCES

truly minimally invasive therapy which has provided inestimable quality of life improvements for certain patient populations, particularly those with overactive bladder. Expanding indications for neuromodulation will likely dominate the literature in the years to come as comfort with technology increases and more challenging patient subgroups such as the neurogenic and pediatric populations are addressed.

References Aboseif, S., Tamaddon, K., Chalfin, S., Freedman, S., Mourad, M.S., Chang, J.H. and Kaptein, J.S. (2002) Sacral neuromodulation in functional urinary retention: an effective way to restore voiding. BJU Int. 90: 662–5. Amundsen, C.L., Romero, A.A., Jamison, M.G. and Webster, G.D. (2005) Sacral neuromodulation for intractable urge incontinence: are there factors associated with cure? Urology 66: 746–50. Andrews, B.J. and Reynard, J.M. (2003) Transcutaneous posterior tibial nerve stimulation for treatment of detrusor hyperreflexia in spinal cord injury. J. Urol. 170: 926. Bosch, J.L. and Groen, J. (2000) Sacral nerve neuromodulation in the treatment of patients with refractory motor urge incontinence: long-term results of a prospective longitudinal study. J. Urol. 163: 1219–22. Brindley, G.S. (1994a) Electrical stimulation in vesicourethral dysfunction: general principles; practical devices. In: A.R. Mundy, T.P. Stephenson and A.J. Wein (eds), Urodynamics: Principles, Practices, Application. London: Churchill Livingstone, pp. 481–8. Brindley, G.S. (1994b) The first 500 patients with sacral anterior root stimulator implants: general description. Paraplegia 32: 795–805. Caldwell, K.P. (1963) The electrical control of sphincter incompetence. Lancet 2: 174–5. Chai, T.C. and Mamo, G.J. (2001) Modified techniques of S3 foramen localization and lead implantation in S3 neuromodulation. Urology 58: 786–90. Cohen, B.L., Tunuguntla, H.S. and Gousse, A. (2006) Predictors of success for first stage neuromodulation: motor versus sensory response. J. Urol. 175: 2178–80, discussion 2180–1. Congregado Ruiz, B., Pena Outeirino, X.M., Campoy Martinez, P., Leon Duenas, E. and Leal Lopez, A. (2004) Peripheral afferent nerve stimulation for treatment of lower urinary tract irritative symptoms. Eur. Urol. 45: 65–9. Cooperberg, M.R. and Stoller, M.L. (2005) Percutaneous neuromodulation. Urol. Clin. North Am. 32: 71–8, vii. Craggs, M. and McFarlane, J. (1999) Neuromodulation of the lower urinary tract. Exper. Physiol. 84: 149–60. Dahms, S.E., Hohenfellner, M. and Thuroff, J.W. (2000) Sacral neurostimulation and neuromodulation in urological practice. Curr. Opin. Urol. 10: 329–35. De Groat, W.C. and Saum, W.R. (1976) Synaptic transmission in parasympathetic ganglia in the urinary bladder of the cat. J. Physiol. 256: 137–58. De Groat, W.C., Nadelhaft, I., Milne, R.J., Booth, A.M., Morgan, C. and Thor, K. (1981) Organization of the sacral parasympathetic reflex pathways to the urinary bladder and large intestine. J. Auton. Nerv. Syst. 3: 135–60. Dees, J.E. (1965) Contraction of the urinary bladder produced by electric stimulation. Preliminary report. Invest. Urol. 2: 539–47. Fischer, J., Madersbacher, H., Zechberger, J., Russegger, L. and Huber, A. (1993) [Sacral anterior root stimulation to promote micturition in transverse spinal cord lesions]. Zentralbl. Neurochir. 54: 77–9.

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Fowler, C.J. (1999) Neurological disorders of micturition and their treatment. Brain 122 (Pt 7): 1213–31. Goh, M. and Diokno, A.C. (2007) Sacral neuromodulation for nonobstructive urinary retention – is success predictable? J. Urol. 178: 197–9, discussion 199. Govier, F.E., Litwiller, S., Nitti, V., Kreder, K.J., Jr and Rosenblatt, P. (2001) Percutaneous afferent neuromodulation for the refractory overactive bladder: results of a multicenter study. J. Urol. 165: 1193–8. Griffiths, D. (1998) Clinical studies of cerebral and urinary tract function in elderly people with urinary incontinence. Behav. Brain Res. 92: 151–5. Hassouna, M.M., Siegel, S.W., Nyeholt, A.A., Elhilali, M.M., van Kerrebroeck, P.E., Das, A.K. et al. (2000) Sacral neuromodulation in the treatment of urgency-frequency symptoms: a multicenter study on efficacy and safety. J. Urol. 163: 1849–54. Hedlund, H., Schultz, A., Talseth, T., Tonseth, K. and van der Hagen, A. (2002) Sacral neuromodulation in Norway: clinical experience of the first three years. Scand. J. Urol. Nephrol. 36 (Suppl. 210): 87–95. Hijaz, A., Vasavada, S.P., Daneshgari, F., Frinjari, H., Goldman, H. and Rackley, R. (2006) Complications and troubleshooting of two-stage sacral neuromodulation therapy: a single-institution experience. Urology 68: 533–7. Hohenfellner, M., Schultz-Lampel, D., Dahms, S., Matzel, K. and Thuroff, J.W. (1998) Bilateral chronic sacral neuromodulation for treatment of lower urinary tract dysfunction. J. Urol. 160: 821–4. Hohenfellner, M., Thuroff, J.W. and Schultz-Lampel, D. (1992) Sacral root stimulation to treat micturation disorders [sakrale neuromodulation zur therapie von Miktionsstorungen]. Aktuelle Urol. 23: 1–10. Janknegt, R.A., Hassouna, M.M., Siegel, S.W., Schmidt, R.A., Gajewski, J.B., Rivas, D.A. et al. (2001) Long-term effectiveness of sacral nerve stimulation for refractory urge incontinence. Eur. Urol. 39: 101–6. Jonas, U. and Tanagho, E.A. (1975) Studies on the feasibility of urinary bladder evacuation by direct spinal cord stimulation. II. Poststimulus voiding: a way to overcome outflow resistance. Invest. Urol. 13: 151–3. Jonas, U., Fowler, C.J., Chancellor, M.B., Elhilali, M.M., Fall, M., Gajewski, J.B. et al. (2001) Efficacy of sacral nerve stimulation for urinary retention: results 18 months after implantation. J. Urol. 165: 15–9. Klingler, H.C., Pycha, A., Schmidbauer, J. and Marberger, M. (2000) Use of peripheral neuromodulation of the S3 region for treatment of detrusor overactivity: a urodynamic-based study. Urology 56: 766–71. Koldewijn, E.L., Rijkhoff, N.J., van Kerrebroeck, E.V., Debruyne, F.M. and Wijkstra, H. (1994) Selective sacral root stimulation for bladder control: acute experiments in an animal model. J. Urol. 151: 1674–9. Koldewijn, E.L., Rosier, P.F., Meuleman, E.J., Koster, A.M., Debruyne, F.M. and van Kerrebroeck, P.E. (1994) Predictors of success with neuromodulation in lower urinary tract dysfunction: results of trial stimulation in 100 patients. J. Urol. 152: 2071–5. Kruse, M.N. and de Groat, W.C. (1993) Spinal pathways mediate coordinated bladder/urethral sphincter activity during reflex micturition in decerebrate and spinalized neonatal rats. Neurosci. Lett. 152: 141–4. Lee, Y.H. and Creasey, G.H. (2002) Self-controlled dorsal penile nerve stimulation to inhibit bladder hyperreflexia in incomplete spinal cord injury: a case report. Arch. Phys. Med. Rehabil. 83: 273–7. Leng, W.W. and Chancellor, M.B. (2005) How sacral nerve stimulation neuromodulation works. Urol. Clin. North Am. 32: 11–18.

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Madersbacher, H. (1999) [Conservative therapy of neurogenic disorders of micturition]. Urologe A 38: 24–9. Madersbacher, H. and Fischer, J. (1993) Sacral anterior root stimulation: prerequisites and indications. Neurourol. Urodyn. 12: 489–94. Maher, M.G., Mourtzinos, A., Zabihi, N., Laiwalla, U.Z., Raz, S. and Rodriguez, L.V. (2007) Bilateral caudal epidural neuromodulation for refractory urinary retention: a salvage procedure. J. Urol. 177: 2237–40, discussion 2241. Malaguti, S., Spinelli, M., Giardiello, G., Lazzeri, M. and van den Hombergh, U. (2003) Neurophysiological evidence may predict the outcome of sacral neuromodulation. J. Urol. 170: 2323–6. Martin, E.T. (2005) Can cardiac pacemakers and magnetic resonance imaging systems co-exist? Eur. Heart J. 26: 325–7. McGuire, E.J., Zhang, S.C., Horwinski, E.R. and Lytton, B. (1983) Treatment of motor and sensory detrusor instability by electrical stimulation. J. Urol. 129: 78–9. Minardi, D. and Muzzonigro, G. (2005) Lower urinary tract and bowel disorders and multiple sclerosis: role of sacral neuromodulation: a preliminary report. Neuromodulation 8: 176–81. Nashold, B.S., Jr, Friedman, H. and Boyarsky, S. (1971) Electrical activation of micturition by spinal cord stimulation. J. Surg. Res. 11: 144–7. Nashold, B.S., Jr, Friedman, H., Glenn, J.F., Grimes, J.H., Barry, W.F. and Avery, R. (1972) Electromicturition in paraplegia. Implantation of a spinal neuroprosthesis. Arch. Surg. 104: 195–202. Pettit, P.D., Thompson, J.R. and Chen, A.H. (2002) Sacral neuromodulation: new applications in the treatment of female pelvic floor dysfunction. Curr. Opin. Obstet. Gynecol. 14: 521–5. Rijkhoff, N.J., Wijkstra, H., van Kerrebroeck, P.E. and Debruyne, F.M. (1997) Selective detrusor activation by electrical sacral nerve root stimulation in spinal cord injury. J. Urol. 157: 1504–8. Roguin, A., Zviman, M.M., Meininger, G.R., Rodrigues, E.R., Dickfeld, T.M., Bluemke, D.A. et al. (2004) Modern pacemaker and implantable cardioverter/defibrillator systems can be magnetic resonance imaging safe: in vitro and in vivo assessment of safety and function at 1.5 T. Circulation 110: 475–82. Ruud Bosch, J.L. and Groen, J. (1996) Treatment of refractory urge urinary incontinence with sacral spinal nerve stimulation in multiple sclerosis patients. Lancet 348: 717–19. Scheepens, W.A., de Bie, R.A., Weil, E.H. and van Kerrebroeck, P.E. (2002) Unilateral versus bilateral sacral neuromodulation in patients with chronic voiding dysfunction. J. Urol. 168: 2046–50. Scheepens, W.A., van Koeveringe, G.A., de Bie, R.A., Weil, E.H. and van Kerrebroeck, P.E. (2003) Urodynamic results of sacral neuromodulation correlate with subjective improvement in patients with an overactive bladder. Eur. Urol. 43: 282–7. Schmidt, R.A., Jonas, U., Oleson, K.A., Janknegt, R.A., Hassouna, M.M., Siegel, S.W. and van Kerrebroeck, P.E. (1999) Sacral nerve stimulation for treatment of refractory urinary urge incontinence. Sacral Nerve Stimulation Study Group. J. Urol. 162: 352–7. Schultz-Lampel, D., Jiang, C., Lindstrom, S. and Thuroff, J.W. (1998a) Experimental results on mechanisms of action of electrical neuromodulation in chronic urinary retention. World J. Urol. 16: 301–4. Schultz-Lampel, D., Jiang, C., Lindstrom, S. and Thuroff, J.W. (1998b) Summation effect of bilateral sacral root stimulation. Eur. Urol. 33: 61.

Shaker, H.S. and Hassouna, M. (1998) Sacral nerve root neuromodulation: an effective treatment for refractory urge incontinence. J. Urol. 159: 1516–19. Siegel, S.W. (2005) Selecting patients for sacral nerve stimulation. Urol. Clin. North Am. 32: 19–26. Siegel, S.W., Catanzaro, F., Dijkema, H.E., Elhilali, M.M., Fowler, C.J., Gajewski, J.B. et al. (2000) Long-term results of a multicenter study on sacral nerve stimulation for treatment of urinary urge incontinence, urgency-frequency, and retention. Urology 56: 87–91. South, M.M., Romero, A.A., Jamison, M.G., Webster, G.D. and Amundsen, C.L. (2007) Detrusor overactivity does not predict outcome of sacral neuromodulation test stimulation. Int. Urogynecol. J. 18 (12): 1395–8. Spinelli, M., Bertapelle, P., Cappellano, F., Zanollo, A., Carone, R., Catanzaro, F. et al. (2001) Chronic sacral neuromodulation in patients with lower urinary tract symptoms: results from a national register. J. Urol. 166: 541–5. Spinelli, M., Giardiello, G., Gerber, M., Arduini, A., van den Hombergh, U. and Malaguti, S. (2003) New sacral neuromodulation lead for percutaneous implantation using local anesthesia: description and first experience. J. Urol. 170: 1905–7. Swinn, M.J., Kitchen, N.D., Goodwin, R.J. and Fowler, C.J. (2000) Sacral neuromodulation for women with Fowler’s syndrome. Eur. Urol. 38: 439–43. Van Balken, M.R., Vandoninck, V., Gisolf, K.W., Vergunst, H., Kiemeney, L.A., Debruyne, F.M. and Bemelmans, B.L. (2001) Posterior tibial nerve stimulation as neuromodulative treatment of lower urinary tract dysfunction. J. Urol. 166: 914–18. Van Balken, M.R., Vandoninck, V., Messelink, B.J., Vergunst, H., Heesakkers, J.P., Debruyne, F.M. et al. (2003) Percutaneous tibial nerve stimulation as neuromodulative treatment of chronic pelvic pain. Eur. Urol. 43: 158–63, discussion 163. Van Kerrebroeck, E.V., Scheepens, W.A., de Bie, R.A. and Weil, E.H. (2005) European experience with bilateral sacral neuromodulation in patients with chronic lower urinary tract dysfunction. Urol. Clin. North Am. 32: 51–7. Van Kerrebroeck, E.V., van der Aa, H.E., Bosch, J.L., Koldewijn, E.L., Vorsteveld, J.H. and Debruyne, F.M. (1997) Sacral rhizotomies and electrical bladder stimulation in spinal cord injury. Part I: Clinical and urodynamic analysis. Dutch Study Group on Sacral Anterior Root Stimulation. Eur. Urol. 31: 263–71. Vandoninck, V., van Balken, M.R., Finazzi Agro, E., Petta, F., Micali, F., Heesakkers, J.P., Debruyne, F.M., Kiemeney, L.A. and Bemelmans, B.L. (2003) Percutaneous tibial nerve stimulation in the treatment of overactive bladder: urodynamic data. Neurourol. Urodyn. 22: 227–32. Wang, Y. and Hassouna, M.M. (1999) Electrical stimulation has no adverse effect on pregnant rats and fetuses. J. Urol. 162: 1785–7. Wein, A. and Barrett, D. (1988) Voiding Function and Dysfunction – A Logical and Practical Approach. Chicago, IL: Year Book Medical. Wheeler, J.S., Jr, Walter, J.S. and Sibley, P. (1994) Management of incontinent SCI patients with penile stimulation: preliminary results. J. Am. Paraplegia Soc. 17: 55–9. Wheeler, J.S., Jr, Walter, JS. and Zaszczurynski, P.J. (1992) Bladder inhibition by penile nerve stimulation in spinal cord injury patients. J. Urol. 147: 100–3.

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S E C T I O N

X

NEUROMODULATION FOR EMERGING APPLICATIONS Introduction Elliot S. Krames and Ali R. Rezai

What is a visionary? Most of us think of visionaries as people who rise above the tide to create new, wonderful and useful ideas, technologies or products. Quite different definitions of a visionary are offered on the Web, however. A visionary, according to WebNet (http://wordnetweb.princeton.edu/perl/ webwn?svisionary), is “a person given to fanciful speculations and enthusiasms with little regard for what is actually possible;” while Answers.com (http:// www.answers.com/topic/visionary) offers (among others) definitions of visionary as: ● ● ●

● ●

where would we be today? Who could have thought that rubbing two sticks together would produce fire? Who would have thought that man would outfly birds? No textbook on the field of neuromodulation is complete without a discussion of the use of devices for emerging applications. Section X is dedicated to this discussion and we thank these authors, all visionaries, who will take us to another fanciful level. This section starts with Drs Michael Oh, Associate Professor, David Cohen, Assistant Professor, and Donald M. Whiting, Associate Professor at Drexel University College of Medicine, Division of Neuromodulation, Department of Neurosurgery, Allegheny General Hospital, Pittsburgh, Pennsylvania, discussing “Deep Brain Stimulation for Obesity,” and is followed by Drs Erlick Pereira, Alexander Green, and Tipu Aziz, from Oxford Functional Neurosurgery Unit, Department of Neurological Surgery, the John Radcliffe Hospital, Oxford, UK, discussing “Deep Brain Stimulation for Blood Pressure Control,” and Drs Brian Kopell and David Friedland of the

Having the nature of fantasies or dreams; illusory Existing in imagination only; imaginary Characterized by or given to apparitions, prophecies, or revelations Given to daydreams or reverie; dreamy Not practicable or realizable; utopian: visionary schemes for getting rich

If it weren’t for the “fanciful and daydreaming persons who had little regard for the real in the world,”

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Departments of Neurosurgery and of Otolaryngology & Communication Sciences, respectively, of the Medical College of Wisconsin, discussing “Neuromodulation for Tinnitus.” In the following chapters Dr Daniel Abrams, of the Departments of Psychiatry and Neurosurgery, University of Colorado at Denver, and Health Sciences Center, Denver, Colarado, focus on brain infusion therapies and related technologies, Dr Nicholas Schiff, Director, Laboratory of Cognitive Neuromodulation, Associate Professor of Neurology and Neuroscience,

Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, considers neuromodulation for brain injury, and the section concludes with a discussion of “Novel Neuromodulation Approaches for Alzheimer’s Disease and Other Neurodegenerative Conditions” by Dr Julie Pilitsis and Dr Roy Bakay, Department of Neurosurgery, Rush University Medical Center, Chicago, Illinois.

X. NEUROMODULATION FOR EMERGING APPLICATIONS

C H A P T E R

79 Deep Brain Stimulation for Obesity Michael Y. Oh, David B. Cohen, and Donald M. Whiting

O U T L I N E Background Definition Classification and Epidemiology Health and Economic Costs Treatment

959 959 959 960 960

Hypothalamic Anatomy and Physiology

961

962

Human Studies of Hypothalamic Lesioning and Stimulation

963

References

964

Lew and Garfinkel, 1979; Larsson et al., 1981), stroke (Hubert et al., 1983; Walker et al., 1996; Rexrode et al., 1997), gallbladder disease (Stampfer et al., 1992; Khare et al., 1995), osteoarthritis (Hart and Spector, 1993; Hochberg et al., 1995; Cicuttini et al., 1996), sleep apnea and respiratory problems (Shepard, 1992; Young et al., 1993; Millman et al., 1995), and endometrial, breast, prostate, and colon cancers (Garland et al., 1985; Chute et al., 1991; Bostick et al., 1994). In addition to the health risks stated above, obese individuals may also suffer from social stigmatization and discrimination.

BACKGROUND Definition It is generally agreed that men with more than 25% body fat and women with more than 30% body fat are obese. However, precisely measuring a person’s body fat is difficult and requires specialized instruments; hence, alternative measurements, including weight-for-height tables and body mass index (BMI), are frequently used. BMI (Table 79.1) calculated as weight divided by height squared (kg/m2), is preferred over weight-for-height tables because BMI is a single number derived using a standard mathematical formula that takes into account both a person’s height and weight. A classification of obesity based on BMI is given in Table 79.2. Obesity substantially raises the risk of morbidity from hypertension (Stamler et al., 1978; Association of Life Insurance Medical Directors of America, 1980; Criqui et al., 1982; Dyer and Elliott, 1989), type 2 diabetes (Westlund and Nicolaysen, 1972;

Neuromodulation

Animal Studies of Hypothalamic Stimulation

Classification and Epidemiology The most recent National Health and Nutrition Examination Survey, conducted in 2003–2004, found that 32.2% of adults in the USA were obese (defined as a body mass index (BMI) 30). Additionally, 2.8% of men and 6.9% of women were extremely obese (BMI 40), and between 1980 and 2002 the prevalence of obesity doubled in adults age 20 and older (Ogden et al., 2006).

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79. DEEP BRAIN STIMULATION FOR OBESITY

TABLE 79.1 Sample of a BMI table 36

37

38

39

40

41

42

43

Height (in.)

44

45

46

47

48

49

50

51

52

53

54

Body weight (lb)

58

172

177

181

186

191

196

201

205

210

215

220

224

229

234

239

244

248

253

258

59

178

183

188

193

198

203

208

212

217

222

227

232

237

242

247

252

257

262

267

60

184

189

194

199

204

209

215

220

225

230

235

240

245

250

255

261

266

271

276

61

190

195

201

206

211

217

222

227

232

238

243

248

254

259

264

269

275

280

285

62

196

202

207

213

218

224

229

235

240

246

251

256

262

567

273

278

284

289

295

63

203

208

214

220

225

231

237

242

248

254

259

265

270

278

282

287

293

299

304

64

209

215

221

227

232

238

244

250

256

262

267

273

279

285

291

296

302

308

314

65

216

222

228

234

240

246

252

258

264

270

276

282

288

294

300

306

312

318

324

66

223

229

235

241

247

253

260

266

272

278

284

291

297

303

309

315

322

328

334

67

230

236

242

249

255

261

268

274

280

287

293

299

306

312

319

325

331

338

344

68

236

243

249

256

262

269

276

282

289

295

302

308

315

322

328

335

341

348

354

69

243

250

257

263

270

277

284

291

297

304

311

318

324

331

338

345

351

358

365

70

250

257

264

271

278

285

292

299

306

313

320

327

334

341

348

355

362

369

376

71

257

265

272

279

286

293

301

308

315

322

329

338

343

351

358

365

372

379

386

72

265

272

279

287

294

302

309

316

324

331

338

346

353

361

368

375

383

390

397

73

272

280

288

295

302

310

318

325

333

340

348

355

363

371

378

386

393

401

408

74

280

287

295

303

311

319

326

334

342

350

358

365

373

381

389

396

404

412

420

75

287

295

303

311

319

327

335

343

351

359

367

375

383

391

399

407

415

423

431

76

295

304

312

320

328

336

344

353

361

369

377

385

394

402

410

418

426

435

443

Source: National Institutes of Health, 1998

TABLE 79.2 Classification of overweight and obesity by BMI Obesity class

BMI (kg/m2)

Underweight

18.5

Normal

18.5–24.9

Overweight Obesity

25.0–29.9 I

30.0–34.9

II

35.0–39.9

III

40

Source: National Institutes of Health, 1998

Health and Economic Costs As the second leading cause of preventable death in the USA today (McGinnis and Foege, 1993), overweight and obesity pose a major public health challenge. A BMI above 25 has been associated with increased mortality, and a BMI above 30 is associated with markedly increased mortality (VanItallie, 1985; Manson et al., 1987). Individuals in obesity Class III (BMI 40) and Class II (BMI 35 and 40 with co-morbid conditions

such as cardiovascular disease, sleep apnea, and type 2 diabetes) are at significantly greater health risk than non-obese individuals and are candidates for weight reduction surgery. In the USA, the direct costs associated with obesity represent 5.7% of the national health expenditure (Wolf, 1998) and the indirect cost attributable to obesity is $47.6 billion. These economic costs are comparable to the costs of cigarette smoking (Wolf and Colditz, 1994, 1998). Most of the direct health care costs of obesity are from type 2 diabetes, coronary heart disease, and hypertension. Indirect costs represent the value of lost output caused by morbidity and mortality, and may have a greater impact than direct costs at the personal and societal levels. Cost savings of treating obesity are comparable to those of treating other chronic diseases, yet it has received disproportionately less attention until recently.

Treatment While there is general agreement about the health risks of obesity, there is less agreement about its

X. NEUROMODULATION FOR EMERGING APPLICATIONS

HYPOTHALAMIC ANATOMY AND PHYSIOLOGY

TABLE 79.3

Complications of gastric bypass surgery (14 year follow-up)

Vitamin B12 deficiency

239

39.9%

Readmit for various reasons

229

38.2%

Incisional herni

143

23.9%

Depression

142

23.7%

Staple line failure

90

15%

Gastritis

79

13.2%

Cholecystitis

68

11.4%

Anastomotic problems

59

9.8%

Dehydration, malnutrition

35

5.8%

Dilated pouch

19

3,2%

961

In addition to the numerous complications associated with gastrointestinal surgery (Table 79.3), this kind of surgery does not directly address the central mechanisms involved in the pathophysiology of obesity. Rather, the currently available procedures attempt to modify or bypass portions of the alimentary tract that are functionally normal. There has, therefore, been interest recently in the possibility of applying deep brain stimulation (DBS) techniques to address the underlying mechanism of obesity (Sani et al., 2007; Halpern et al., 2008).

HYPOTHALAMIC ANATOMY AND PHYSIOLOGY

Source: Pories et al., 1995 (with permission of Lippincott Williams & Wilkins; www.lww.com)

management. The reason for this lack of consensus is that, to date, no single treatment has been universally successful. The tremendous redundancy in the neural and hormonal regulation of energy expenditure makes it difficult for any single approach to address the great number of adaptation mechanisms. Some have argued against treating obesity because of the difficulty in maintaining long-term weight loss and of potentially negative consequences of the frequently seen pattern of weight cycling in obese subjects. Others argue that the potential hazards of treatment do not outweigh the known hazards of being obese. The treatments available include dietary therapy, physical activity, behavior modification, pharmacotherapy, and weight loss surgery (National Institutes of Health, 1998). Extremely obese persons often do not benefit from the more conservative treatments for weight loss and weight maintenance. Many believe that this is due to a genetically determined sensitivity to weight gain. Obesity severely impairs quality of life, and these individuals are at higher risk for premature death. As a result, the National Institutes of Health Consensus Development Conference consensus statement, “Gastrointestinal Surgery for Severe Obesity” (National Institutes of Health, 1992), concluded that the benefits outweigh the risks and that a more aggressive approach is reasonable in individuals who strongly desire substantial weight loss and have life-threatening co-morbid conditions. Gastric surgery has been found to be effective in limiting caloric intake and thereby inducing weight loss (Hall et al., 1990) with a lower risk of long-term mortality, although there may be an increase in other causes of mortality in gastric bypass patients (Adams et al., 2007). The effectiveness of gastric bypass surgery is also limited by complications and the risk of longterm failure.

The hypothalamus is the main regulator of central autonomic activity and also plays a key role in hormonal regulation and emotional activity via the limbic system. Functionally, hypothalamic cell populations are divided into parasympathetic nuclei which are mainly located anteriorly and laterally, and sympathetic nuclei which are mostly located posteriorly and medially (Parent, 1996). Anatomically, the mammillothalamic tract and anterior column of the fornix form the medial border of the lateral hypothalamic area (LHA), while the lateral boundary is formed by the medial border of the internal capsule and subthalamus. The lateral hypothalamus is continuous with the lateral preoptic nucleus rostrally and the ventral tegmental area of the midbrain caudally (Parent, 1996). The lateral hypothalamic area receives input from limbic and association structures including the prefrontal cortex, nucleus accumbens, amygdala, hippocampus, and nucleus of the solitary tract, as well as the arcuate nucleus. The arcuate nucleus, a circumventricular organ that is influenced by the systemic circulation, may play a crucial role in the regulation of feeding (Sani et al., 2007; Halpern et al., 2008). In turn, the lateral hypothalamus has widespread projections to the cortex, basal ganglia, limbic regions, other parts of the hypothalamus, midbrain and pontine reticular formation, periaqueductal gray, nucleus of the solitary tract, and spinal ventral horn. Physiologically, the lateral hypothalamus appears to be involved in the neuroendocrine regulation of metabolism; there is a complex interaction of adipokine and enterokine hormonal signals influencing the hypothalamus (Figure 79.1). In 1900, Frohlich recognized an association between hypothalamic injury and obesity along with sexual immaturity, resulting in the eponymous syndrome (Lee and Korner, 2008). Later, classic lesioning experiments in rats found that lesions in the ventromedial hypothalamus resulted in obesity, while lesions in the lateral hypothalamus caused hypophagia

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Food intake Neurons of PVN

Neuron MCR-4

Y1r

α-MSH Food intake

Food intake

AGRP/ NPY

Y1r MCR - 3

Third ventricle

Ghrelin

MCR - 3

α-MSH 

Arcuate nucleus

POMC/ CART

LepR 

To nucleus tractus solitarius (NTS) • Sympathetic activity • Energy expenditure

LepR 

Insulin, leptin, CCK

FIGURE 79.1 The neuroendocrine regulation of metabolism (Reprinted with permission from Guyton & Hall, Textbook of Medical Physiology, 11th edn. Copyright (2006) Elsevier. www.studentconsult.com)

(Hetherington and Ranson, 1940; Stevenson, 1949; Anand and Brobeck, 1951a, 1951b). This led to the naming of the ventromedial hypothalamus as the “satiety center” and the lateral hypothalamus as the “feeding center.” It is the lateral hypothalamus that is currently of primary interest as a means to control obesity. The hormones leptin and insulin are both regarded as “adiposity signals,” in that they circulate in the blood at levels proportional to body fat. Their administration causes a decrease in food intake and body weight, while their deficiency leads to hyperphagia. In addition, insulin has been found to affect glucose metabolism by acting on ATP-sensitive potassium channels in the arcuate nucleus, and both insulin and leptin have been postulated to affect the ventromedial hypothalamus directly (Morton, 2007). Higher circulating levels of leptin and insulin stimulate neurons in the arcuate nucleus to release proopiomelanocortin, which is subsequently enzymatically cleaved to yield α-melanocyte stimulating hormone, which inhibits feeding and increases energy expenditure. At the same time, leptin and insulin suppress the activity of neurons containing agouti-related protein and neuropeptide Y, both of which stimulate feeding and

reduce energy expenditure (Sobocki et al., 2005; Lee and Korner, 2008). Lateral hypothalamic neurons express orexin, a neuropeptide involved in arousal and feeding, and melanin concentrating hormone, a potent orexigen (Lee and Korner, 2008). It is believed that there is a central “adipostat” that is programmed in the perinatal period through the interaction of circulating levels of ghrelin and leptin, leading to synaptic plasticity and neurotrophic growth. The density of synaptic projections between the arcuate nucleus, paraventricular nucleus, lateral hypothalamus, and dorsomedial nucleus are thought to be determined in this way (Coll et al., 2007). These projections are felt to determine the “energy set point” that the body uses to regulate metabolism and weight (Lenz and Diamond, 2008).

ANIMAL STUDIES OF HYPOTHALAMIC STIMULATION Animal studies have shown the central role of the hypothalamus in regulating appetite, body weight, and long-term energy balance. Lesions in the LHA

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HUMAN STUDIES OF HYPOTHALAMIC LESIONING AND STIMULATION

are known to induce a hypermetabolic state and rapid weight loss (Harrell et al., 1975; Kolb et al., 1979). In a recent report by Sani et al. (2007) electrodes were placed bilaterally in the lateral hypothalamic areas of 16 rats, after measuring their food intake and weight gain for seven days preoperatively. Proper placement of the electrodes was verified histologically after completion of the experiment. Eight rats served as controls, while the other eight received stimulation beginning on postoperative day 7. Weight and food and water intake was monitored until postoperative day 24. The authors found that all animals experienced a decreased rate of weight gain initially after surgery, but the control group then recovered and resumed a linear weight gain curve. The stimulation group did not gain any weight and their body mass remained below the mean baseline, resulting in significant weight loss between the two groups. On postoperative day 24, compared to the day of surgery, the control group showed a mean weight gain of 13.8% while the stimulation group had a 2.3% mean weight loss, yielding a 16.1% difference between the groups. Interestingly, there was no difference between the groups in food or water intake. It is possible that there was a difference in excretion between the two groups, although this was not measured in the study. Alternatively, stimulation may have led to metabolic changes resulting in weight loss, such as an increase in sympathetic drive and/or mobilization of adipose tissue, although these parameters were also not measured in the study. Lesions of the lateral hypothalamus in animals cause weight loss at a more rapid rate than fooddeprived controls. Also, lesioned rats exhibit higher rates of energy expenditure when at the same weight as non-lesioned rats, leading to the view that rats with lateral hypothalamic lesions regulate weight around a new “set point.” Raising a lesioned rat’s weight to that of the non-lesioned controls will cause it to become hypermetabolic (Keesey et al., 1984). Lesion size is important, and increases in hypothalamic tissue damage have been shown to be associated with more instances of aphagia and greater weight loss and gastric pathology (Schallert et al., 1977). However, the chronic weight loss seen in animals with LHA lesions is not a secondary consequence either of having disrupted the pituitary–thyroid axis, or of having changed the animals’ spontaneous activity levels (Von Der Porten and Davis, 1979). Lesioning genetically obese (ob/ob) mice will also cause weight loss and subsequent stabilization of body weight at a lower level than sham-operated obese mice (Chlouverakis and Berenadis, 1972). Along these lines, lesions of the ventromedial hypothalamus in rats have been shown to result in

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obesity even when access to food is restricted, implicating autonomic imbalance and the regulation of energy expenditure in the development of obesity (Lee and Korner, 2008). Lac´an et al. (2008) implanted electrodes bilaterally in the ventromedial hypothalamus of two monkeys, with histologic verification of lead placement. Stimulation parameters were selected so as to evoke minimal autonomic activity as determined by test stimulation (monopolar stimulation, 2.5–3.5 V, 90 μsec, 185 Hz). As would be expected on the basis of lesioning experiments, stimulation resulted in an increase in food consumption. No significant adverse behavioral effects were noted, although the animals displayed transient agitation at the beginning of the stimulation periods, suggesting that at certain settings stimulation may activate, rather than inhibit, nervous tissue.

HUMAN STUDIES OF HYPOTHALAMIC LESIONING AND STIMULATION Studies of humans with hypothalamic insults have similarly shown hormonal alterations and decreased activity levels that could contribute to weight gain (Lee and Korner, 2008). Most commonly, case reports of lesions in or near the hypothalamus have described hyperphagia and obesity (Suzuki et al., 1990; Roth et al., 1998). Some reports, though, have described anorexia and weight loss in association with infiltrating hypothalamic tumors (Heron and Johnston, 1976; Goldney, 1978; Weller and Weller, 1982). One report describes a 41-year-old woman with multiple sclerosis, with profound weight loss and cachexia, who was found to have demyelinating lesions in the lateral hypothalamus at autopsy (Kamalian et al., 1975). The earliest reported stereotactic surgery performed upon a human hypothalamus was by Spiegel and Wycis in 1949 (Spiegel et al., 1953). Most hypothalamic lesioning procedures have been performed on the posterior, medial, and inferior areas (Hunter, 1998) for the treatment of aggressive and hyperkinetic states, pain, and sexual delinquency (Sano et al., 1970; Dieckmann et al., 1988; Ramamurthi, 1988; Sano and Mayanagi, 1988). Some of these patients were noted to have an increased appetite and weight gain after posteromedial hypothalamotomy (Dieckmann et al., 1988). One case report (Hamani et al., 2008) described elicitation of vivid memories during hypothalamic stimulation for the treatment of obesity, although this was probably due to stimulation of the fornix. Longterm stimulation in this patient resulted in improvements in memory function.

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In addition to the report by Hamani et al. (2008), a much earlier study (Quaade et al., 1974) examined the possibility of hypothalamic lesioning for the treatment of obesity. Quaade and associates operated on five hyperphagic, severely obese patients who had failed conventional obesity treatment. In all, intraoperative stereotactic stimulation of the lateral hypothalamus was performed. In two of the patients, no clear hunger sensation was induced and no lesion was made. In the other three patients, stimulation elicited a sensation of hunger, and electrocoagulation was used to create a lesion at that site. In one of these patients, a contralateral lesion was made three months later. The two patients who did not receive lesions demonstrated no change in their food intake or body weight. In the three patients who received lesions, a significant difference in caloric intake was noted, but there was only a slight and temporary decrease in body weight. None of the patients developed endocrine abnormalities. Deep brain stimulation (DBS), used experimentally for decades (Iskandar and Nashold, 1995), has come into widespread, mainstream use over the past 15 years. Advantages of DBS, relative to lesioning techniques, include its adjustability, reversibility, and lack of tissue destruction. Well-conducted trials have demonstrated the efficacy and safety of DBS for Parkinson’s disease (Schuurman et al., 2000; Deuschl et al., 2006), essential tremor (Lee and Kondziolka, 2005; Pahwa et al., 2006), and dystonia (Kupsch et al., 2006; Mueller et al., 2008), resulting in FDA approval for these indications. Research is ongoing to explore the role of DBS in other neurologic and psychiatric disorders, including depression, obsessive–compulsive disorder, and epilepsy (Nuttin et al., 2003; Theodore and Fisher, 2007; Larson, 2008). Stimulation of the posterior hypothalamus has recently been shown to be safe and effective for the treatment of cluster headaches (Leone et al., 2005; Bartsch et al., 2008). Given the experimental results described herein, as well as the proven efficacy and safety of DBS for other disorders, the time has come for the investigation of DBS for obesity. Of the various potential CNS targets for the treatment of obesity, the lateral hypothalamus, the “feeding center,” seems to have the most data to suggest its usefulness (Hamani et al., 2008). Weight adjustment can potentially be achieved by DBS of the lateral hypothalamus through a combination of intake control, urge control, and metabolism modulation. In this manner, the predetermined “energy set point” can potentially be readjusted, something that no present treatment, including gastric bypass surgery, can accomplish. The modulation capabilities of DBS make this particularly attractive.

The nucleus accumbens is another potential target in the hypothalamus. This nucleus is similar in size to the subthalamic nucleus, and is located inferior to the anterior limb of the internal capsule. The nucleus accumbens is associated with reward behavior and the palatability of foods. It has been proposed that DBS stimulation in this area may modulate dietary preferences and consumption through reward sensation, potentially leading to weight control through better dietary choices (Halpern et al., 2008). Although advances in laparoscopic techniques have reduced some of the morbidity associated with gastric bypass and gastric banding, these peripheral approaches do not address the complex neurohormonal interactions that cause obesity. Whatever the target or targets chosen, DBS in the CNS offers a potential treatment for severe obesity that directly addresses these interactions and may provide benefits similar to those presently obtained in movement disorders.

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Stampfer, M.J., Maclure, K.M., Colditz, G.A., Manson, J.E. and Willett, W.C. (1992) Risk of symptomatic gallstones in women with severe obesity. Am. J. Clin. Nutr. 55: 652–8. Stevenson, J.A.F. (1949) Effects of hypothalamic lesions on water and energy metabolism in the rat. Recent Prog. Horm. Res. 4: 363–94. Suzuki, N., Shinonaga, M., Hirata, K., Inoue, S. and Kuwabara, T. (1990) Hypothalamic obesity due to hydrocephalus caused by aqueductal stenosis. J. Neurol. Neurosurg. Psychiatry 53: 1102–3. Theodore, W.H. and Fisher, R. (2007) Brain stimulation for epilepsy. Acta Neurochir. (Suppl.) 97: 261–72. Von Der Porten, K. and Davis, J.R. (1979) Weight loss following LH lesions independent of changes in motor activity or metabolic rate. Physiol. Behav. 23 (5): 813–19. VanItallie, T.B. (1985) Health implications of over-weight and obesity in the United States. Ann. Intern. Med. 103: 983–8. Walker, S.P., Rimm, E.B., Ascherio, A., Kawachi, I., Stampfer, M.J. and Willett, W.C. (1996) Body size and fat distribution as predictors of stroke among US men. Am. J. Epidemiol. 144: 1143–50. Weller, R.A. and Weller, E.B. (1982) Anorexia nervosa in a patient with an infiltrating tumor of the hypothalamus. Am. J. Psychiatry 139: 824–5. Westlund, K. and Nicolaysen, R. (1972) Ten-year mortality and morbidity related to serum cholesterol: a follow-up of 3,751 men aged 40–49. Scand. J. Clin. Lab. Invest. (Suppl.) 127: 1–24. Wolf, A.M. (1998) What is the economic case for treating obesity? Obesity Res. 6 (Suppl. 1): 2S–7S. Wolf, A.M. and Colditz, G.A. (1994) The cost of obesity: the U.S. perspective. Pharmacoeconomics 5: 34–7. Wolf, A.M. and Colditz, G.A. (1998) Current estimates of the economic costs of obesity in the United States. Obes. Res. 6: 97–106. Young, T., Palta, M., Dempsey, J., Skatrud, J., Weber, S. and Badr, S. (1993) The occurrence of sleep-disordered breathing among middle-aged adults. N. Engl. J. Med. 328: 1230–5.

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80 Deep Brain Stimulation for Blood Pressure Control Erlick A.C. Pereira, Alexander L. Green, and Tipu Z. Aziz

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INTRODUCTION

hypotensive in animals (Bandler et al., 2000). Electrical stimulation of the PAG in animals elicits such defence reactions, dorsal regions being associated with active coping and hypertensive effects and ventral regions with passive coping and hypotensive effects (Bandler et al., 1991). Thus, it is likely that PAG stimulation affects not only pain modulation pathways, but also cardiovascular autonomic pathways. PAG DBS has been related to hypertensive and chronotropic cardiovascular effects (Young and Rinaldi, 1997; Bendok et al., 2003). Current research confirms cardiovascular effects including blood pressure changes (Green et al., 2005, 2006a, 2006b).

Hypertension and orthostatic hypotension refractory to medical treatment present a considerable disease burden, with high associated morbidity and mortality. Up to 27% of hypertension is poorly controlled (McBride et al., 2003), with 3% refractory to pharmacotherapy (Aldermann et al., 1988), and considerably increased risk of both cerebrovascular and cardiovascular adverse events (Almgren et al., 2005; Wang et al., 2005). The periaqueductal gray area (PAG) is established as a region important to the modulation of pain that has been targeted by deep brain stimulating (DBS) electrodes for the treatment of chronic, intractable neuropathic pain for three decades (Richardson and Akil, 1977). In mammals, the region is instrumental to “defence” reactions (Bittencourt et al., 2004), integrating descending responses from forebrain to cardiovascular effector organs to assist survival by modulating active sympathetic “flight” or passive “withdrawal” responses (Hunsperger, 1956; Carrive, 1993). Whether the coping is active or passive seems to determine whether the sympathetic response is pressor or

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CLINICAL OUTCOMES In a study of 15 chronic neuropathic pain patients (two patients having bilateral implants), blood pressure and heart rate were continuously measured while DBS parameters were altered from 10 to 50 Hz (Bittar et al., 2005). Cardiovascular responses to stimulation were consistent, as measured on at least three occasions, for any pair of electrode contacts used. Arterial blood

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FIGURE 80.1 Changes in cardiovascular parameters associated with reduced blood pressure (A) and increased blood pressure (B). Patterned area  period of stimulation. Grey area   one standard error of the mean. SBP  systolic blood pressure; DBP  diastolic blood pressure; PP  pulse pressure; RR interval  time period between R waves on electrocardiogram; dP/dt  change of systolic blood pressure with time (Reproduced from Green, Wang, Owen and Aziz, 2007, with kind permission from Springer Science  Business Media)

pressure reduced significantly overall in seven pairs of electrode contacts in seven patients. Conversely, blood pressure increased significantly in six pairs of contacts in six patients (p 0.05, ANOVA; Figure 80.1). For subjects with reductions in blood pressure, average reduction was 14.23.6 mmHg (range 7– 25 mmHg), or 13.9%, after 300 s stimulation. The concomitant fall in systolic (SBP) and diastolic pressures (DBP) implicates a vasodilatory mechanism. However, the greater systolic reduction with consequently reduced pulse pressure suggests additional central cardiovascular influences. The reduction rate of SBP (maximum dP/dt, i.e. the gradient of the blood pressure curve), a known marker of cardiac contractility (Brinton et al., 1997), implies reduced myocardial contractility. In contrast, the R–R interval, a measure of heart rate, remained largely unchanged throughout the stimulation period, refuting parasympathetic (vagal) mechanisms. For those subjects experiencing increased blood pressure, the mean SBP rise was 16.7 mmHg 5.9 (p 0.001,

single factor ANOVA, n  6, range 16–31 mmHg), equivalent to 16.4% at the end of a 300 s period. Identical stimulation parameters both raised and lowered blood pressure in different contact pairs. As with blood pressure reduction, increases were accompanied by a smaller rise in DBP of 4.9 mmHg 2.8 or 6.4% (p  0.04, single factor ANOVA, n  6, range  2.4–12.1 mmHg), together with an increase in mean pulse pressure. Maximum dP/dt increased without R–R interval changes. Thus pressor- and hypotensive-related cardiac effects of stimulation appear to mirror each other with reciprocal mechanisms. Six control patients with other implanted neurostimulatory interventions were investigated (six thalamic electrodes, one spinal cord stimulator) without significant blood pressure alterations. Because blood pressure changes in animals vary depending on whether the electrode is in ventral or dorsal PAG, electrode position was assessed (Mai et al., 1998). Those electrodes that reduced blood pressure were placed ventrally and those that increased

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CONCLUSIONS

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FIGURE 80.2 Sagittal positions of the electrodes in patients in whom there were changes in blood pressure (A) and coronal positions (B). For clarity, patients with no changes are not shown. Note that patients No. 1–7 all had reduction in BP (black contacts) and are the most ventral electrodes. Conversely, No. 8–11 and the upper two contacts of No. 1 and No. 6 had a rise in BP (patterned contacts). Gray contacts are those that, when stimulated, had no effect on BP. AC  anterior commissure, PC  posterior commissure, PVG  periventricular gray, PAG  periaqueductal gray, SC  superior colliculus (the level of which is depicted by the dotted circle in 1B), RN  red nucleus, III  third ventricle, Aq  aqueduct. Inset of A shows the ACPC plane, inset of B shows the slice position (Reproduced from Green, Wang, Owen and Aziz, 2007, with kind permission from Springer Science  Business Media)

blood pressure, dorsally (Figure 80.2). Of the four out of 15 patients without blood pressure changes, four of the five electrodes available for plotting were dorsal to the group that raised BP and hence probably beyond the PAG. The remaining electrode was in mid-PAG. The demonstration that PAG deep brain stimulation can increase as well as decrease blood pressure raises the possibility that orthostatic or postural hypotension might be treatable by neurosurgery. In the normal subject, assumption of an upright posture leads to pooling of venous blood in the lower extremities and splanchnic circulation. The resulting decrease in venous return to the heart leads to a compensatory, centrally mediated increase in sympathetic and decrease in parasympathetic activity (known as the baroreceptor reflex). Such activity normally causes a transient fall in SBP (5–10 mmHg), a small rise in DBP (5–10 mmHg), and a rise in heart rate of 10–25 beats per minute. In orthostatic hypotension, patients suffer troublesome low blood pressure on standing or symptoms of cerebral hypoperfusion (Consensus Statement, 1996). Occurring in up to 20% of people over 65 years of age, its treatment may lead to troublesome raised

blood pressure (Rutan et al., 1992; Kaplan, 1993). The presented evidence for pressor effects of dorsal PAG stimulation (Green et al., 2006a), together with supportive animal experiments showing baroreflex vagal bradycardia inhibition with stimulation in rats (Inui and Nosaka, 1993) suggest that such stimulation could influence the baroreceptor reflex. In healthy subjects, baroreflex sensitivity decreases on standing (Sanderson et al., 1996; Cooper and Hainsworth, 2001). In autonomic neuropathy, such as that of diabetes, it has been shown that it is lower in the supine position with a diminished reduction on standing compared to normal subjects (Sanderson et al., 1996). The evidence is that postural blood pressure changes reversed by dorsal PAG DBS act via a central mechanism to increase baroreceptor sensitivity (Green et al., 2006a).

CONCLUSIONS The results presented give theoretical foundations for the treatment of both essential hypertension and orthostatic hypotension by DBS. Essential hypertension

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treated without drugs appeals because their adverse effects would be avoided. Similarly, drug treatment of orthostatic hypotension cannot differentiate between the supine and standing positions and may therefore lead to nocturnal hypertension (Rutan et al., 1992; Kaplan, 1993), a predicament potentially resolved by demand-driven or posturally sensitive DBS. A myriad of related and difficult-to-treat autonomic syndromes, for example orthostatic hypertension (Fessel and Robertson, 2006), may also respond to neural stimulation of central autonomic brain centers. Sustained changes demonstrated by ambulatory blood pressure monitoring, long-term efficacy and favorable risk-benefit (and ideally cost-benefit) over lifelong medication alone should be assessed before the treatment reaches the clinic.

References Alderman, M.H., Budner, N., Cohen, H., Lamport, B. and Ooi, W.L. (1988) Prevalence of drug resistant hypertension. Hypertension 11 (3 Pt 2): II71–75. Almgren, T., Persson, B., Wilhelmsen, L., Rosengren, A. and Andersson, O.K. (2005) Stroke and coronary heart disease in treated hypertension – a prospective cohort study over three decades. J. Intern. Med. 257 (6): 496–502. Bandler, R., Carrive, P. and Zhang, S.P. (1991) Integration of somatic and autonomic reactions within the midbrain periaqueductal grey: viscerotopic, somatotopic and functional organization. Prog. Brain Res. 87: 269–305. Bandler, R., Keay, K.A., Floyd, N. and Price, J. (2000) Central circuits mediating patterned autonomic activity during active vs. passive emotional coping. Brain Res. Bull. 53 (1): 95–104. Bendok, B.R., Levy, R.M. and Onibukon, A. (2003) Deep brain stimulation for the treatment of intractable pain. In: H.H. Batjer and C.M. Loftus (eds), Textbook of Neurological Surgery: Principles and Practice. Philadelphia: Lippincott Williams & Wilkins, pp. 2673–81. Bittar, R.G., Burn, S.C., Bain, P.G. et al. (2005) Deep brain stimulation for movement disorders and pain. J. Clin. Neurosci. 12 (4): 457–63. Bittencourt, A.S., Carobrez, A.P., Zamprogno, L.P., Tufik, S. and Schenberg, L.C. (2004) Organization of single components of defensive behaviors within distinct columns of periaqueductal gray matter of the rat: role of N-methyl-D-aspartic acid glutamate receptors. Neuroscience 125 (1): 71–89. Brinton, T.J., Cotter, B., Kailasam, M.T. et al. (1997) Development and validation of a noninvasive method to determine arterial pressure and vascular compliance. Am. J. Cardiol. 80 (3): 323–30.

Carrive, P. (1993) The periaqueductal gray and defensive behavior: functional representation and neuronal organization. Behav. Brain Res. 58 (1-2): 27–47. Consensus Statement (1996) Consensus statement on the definition of orthostatic hypotension, pure autonomic failure, and multiple system atrophy. The Consensus Committee of the American Autonomic Society and the American Academy of Neurology. Neurology 46 (5): 1470. Cooper, V.L. and Hainsworth, R. (2001) Carotid baroreceptor reflexes in humans during orthostatic stress. Exp. Physiol. 86 (5): 677–81. Fessel, J. and Robertson, D. (2006) Orthostatic hypertension: when pressor reflexes overcompensate. Nat. Clin. Pract. Nephrol. 2 (8): 424–31. Green, A.L., Wang, S., Owen, S.L. and Aziz, T.Z. (2007) The periaqueductal grey area and the cardiovascular system. Acta Neurochir. Suppl. 97 (Pt 2): 521–8. Green, A.L., Wang, S., Owen, S.L., Paterson, D.J., Stein, J.F. and Aziz, T.Z. (2006a) Controlling the heart via the brain: a potential new therapy for orthostatic hypotension. Neurosurgery 58 (6): 1176–83, discussion 1176-83. Green, A.L., Wang, S., Owen, S.L., Xie, K., Bittar, R.G., Stein, J.F. et al. (2006b) Stimulating the human midbrain to reveal the link between pain and blood pressure. Pain 124 (3): 349–59. Green, A.L., Wang, S., Owen, S.L., Xie, K., Liu, Z., Paterson, D.J. et al. (2005) Deep brain stimulation can regulate arterial blood pressure in awake humans. Neuroreport 16 (16): 1741–5. Hunsperger, R.W. (1956) [Affective reaction from electric stimulation of brain stem in cats.]. Helv. Physiol. Pharmacol. Acta 14 (1): 70–92. Inui, K. and Nosaka, S. (1993) Target site of inhibition mediated by midbrain periaqueductal gray matter of baroreflex vagal bradycardia. J. Neurophysiol. 70 (6): 2205–14. Kaplan, N.M. (1993) The promises and perils of treating the elderly hypertensive. Am. J. Med. Sci. 305 (3): 183–97. Mai, J.K., Assheuer, J. and Paxinos, G. (1998) Atlas of the Human Brain. San Diego: Academic Press. McBride, W., Ferrario, C. and Lyle, P.A. (2003) Hypertension and medical informatics. J. Natl Med. Assoc. 95 (11): 1048–56. Richardson, D.E. and Akil, H. (1977) Long term results of periventricular gray self-stimulation. Neurosurgery 1 (2): 199–202. Rutan, G.H., Hermanson, B., Bild, D.E., Kittner, S.J., LaBaw, F. and Tell, G.S. (1992) Orthostatic hypotension in older adults. The Cardiovascular Health Study. CHS Collaborative Research Group. Hypertension 19 (6 Pt 1): 508–19. Sanderson, J.E., Yeung, L.Y., Yeung, D.T. et al. (1996) Impact of changes in respiratory frequency and posture on power spectral analysis of heart rate and systolic blood pressure variability in normal subjects and patients with heart failure. Clin. Sci. (Lond.) 91 (1): 35–43. Wang, J.G., Staessen, J.A., Franklin, S.S., Fagard, R. and Gueyffier, F. (2005) Systolic and diastolic blood pressure lowering as determinants of cardiovascular outcome. Hypertension 45 (5): 907–13. Young, R.F. and Rinaldi, P.C. (1997) Brain Stimulation. New York: Springer-Verlag.

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C H A P T E R

81 Neuromodulation for Tinnitus Brian Harris Kopell and David Friedland

O U T L I N E Introduction

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tinnitus alone. The aging population is leading to increases in the number of patients with this disorder.

Tinnitus is the perception of sound in the absence of environmental stimuli. Subjective tinnitus is the most common form of tinnitus and is the result of sound generated within the auditory pathways and brain. Subjective tinnitus includes sounds often described as tones, beeps, ringing, buzzing or crickets. It is almost always associated with sensorineural hearing loss and is present in approximately 10–15% of the general population with a much higher prevalence in the aged (Henry et al., 2005). About 15% of those with tinnitus are severely disturbed by the percept to a point of seeking medical intervention or having functional disability (Axelsson and Ringdahl, 1989). The prevalence is much higher in occupations involving noise exposure such as the military. In fiscal year 2006 the US government spent $539 million in veterans’ compensation for

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PHYSIOLOGY Tinnitus is postulated to represent a central nervous system pathology involving the auditory brain stem, higher auditory pathways, and their associated connections. Integral to the perception of tinnitus are two fundamental processes: deafferentation and neural plasticity. Deafferentation, the loss of neural input into a receptive neural field, is clinically evident in most forms of tinnitus. Nearly all subjective tinnitus patients have a measurable sensorineural hearing loss, typically involving the high frequencies. This loss is the result of damage to hair cells in the cochlea from a variety of genetic and environmental factors. Tinnitus in animal models

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has been generated by intense noise exposure sufficient to cause peripheral hair cell loss and functional deafferentation of the central pathways. The resultant activity changes in the central auditory system are thought to be secondary to neural plastic mechanisms causing spontaneous activity along the auditory pathway (Schaette and Kempter, 2006). Once deafferentation occurs, neural structures undergo distinct changes in their patterns of activity. Hyperactivity in the dorsal cochlear nucleus, inferior colliculus, and auditory cortex has been identified in humans with tinnitus and in animal models of tinnitus and hearing loss (Kaltenbach and Afman, 2000; Yang et al., 2007). These changes may involve increases in spontaneous activity in excitatory neurons, alterations in activity in inhibitory neurons, or the formation of self-perpetuating feedback loops among several different cell classes or regions (Moller, 2006; Bartels et al., 2007a; Kaltenbach and Zhang, 2007). Another consequence of deafferentation is the induction of pathological neural plasticity. Under normal circumstances, neural plasticity is the brain’s ability to adapt to a changing environment by changing the weights of the connections between neurons or groups of neurons. However, these plastic changes can also result in dysfunction. This is postulated to be the case in peripheral hearing loss with tinnitus being a secondary result of central compensation to deafferentation. Recent functional imaging evidence gives support for this model. Studies utilizing MEG have demonstrated a marked shift of the cortical representation of the tinnitus frequency into an area adjacent to the expected tonotopic location. In addition, a strong positive correlation was found between the subjective strength of the tinnitus and the amount of cortical reorganization, indicating the amount of abnormal plasticity is directly related to tinnitus severity (Muhlnickel et al., 1998). Llinás et al. (2005) have proposed a model how deafferentation followed by cortical plasticity could result in a neurological disorder such as tinnitus. Under normal circumstances, in the awake state, thalamic cells fire in the beta and gamma frequency range and in the theta band in the sleeping state. When thalamic auditory cells are deafferented from loss of input due to peripheral damage to the auditory system, they begin to burst in the theta band much like they would in the sleeping state. This theta band oscillation is in turn reflected at the cortical level via thalamocortical interactions. At the cortical level plastic changes as a result of this now-dominant theta band oscillation results in the loss of lateral inhibition with a resultant halo of gamma-band activity, known as the edge effect. It is hypothesized that this spontaneous and constant gamma-band hyperactivity is inherent to the percept of tinnitus (Figure 81.1).

(A) Negative symptoms

(B) Positive symptoms Disinhibit

Deafferented or over-inhibited Low-frequency oscillation Theta rhythm (48 Hz)

High-frequency oscillation Gamma rhythm (3550 Hz)

Proposed thalamocortical circuits dynamics. Simplified schematics for the thalamocortical circuit organization of two neighboring cortical regions supporting the negative (A) and positive (B) symptoms that characterize thalamocortical dysrhythmia. The specific pathway (yellow, on the left of each panel) activates layer 5 and 6 pyramidal cells (blue) and inhibitory interneurons (upper red neurons), producing cortical oscillations by direct activation and feedforward inhibition. Collaterals of this projection produce thalamic feedback inhibition through the reticular nucleus (lower red circles.) The return corticothalamic pathway (curved green arrow on the left of each panel) from layer-6 pyramidal cells (blue) returns this oscillatory loop to specific and reticular thalamic nuclei (yellow and lower red circles, respectively). The non - specific thalamocortical pathway (green, on the right of each panel) projects to the most superficial layer of the cortex and gives collaterals to the reticular nucleus. Pyramidal cells (blue) return the oscillation to the non-specific and reticular thalamic nuclei (green and lower red circles, respectively), establishing a second resonant loop (curved green arrow on the right of each panel). The conjunction of the specific and non-specific loops is proposed to generate functional binding by temporal coincidence. During thalamocortical dysrhythmia, protracted hyperpolarization of thalamic cells increases low-frequency neuronal oscillations. Either disfacilitation, as occurs after deafferentation (e.g. in neurogenic pain or tinnitus), or excess inhibition caused by pallidal over-activity (e.g. in Parkinson's disease), hyperpolarizes the cells sufficiently to deinactivate T-type Ca2 channels and increase thalamic oscillations at the theta (4 –8 Hz) range. Such oscillations can entrain thalamocortical loops and generate increased coherence in affected brain regions (a). At the cortical level, low-frequency activation of intracortical inhibitory neurons [red, arrow between (a) and (b)] can reduce lateral inhibitory drive and result in high-frequency, phase-locked coherent activation of neighboring cortical modules. This is described as the edge effect, and is illustrated here by greater line thicknesses for connections that show increased activity when symptoms of thalamocortical dysrhythmia are apparent.

FIGURE 81.1 Diagram demonstrating how a combination of deafferentation and cortical plasticity can lead to the tinnitus percept (Based on Llinás et al. (1999) and reproduced with permission from Llinás et al. (2005), Fig. 5. Copyright (2005) Elsevier)

CONVENTIONAL TREATMENT Pharmacological treatment of tinnitus can improve the emotional and psychological reaction to tinnitus but has been disappointing in altering the tinnitus percept

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(Patterson and Balough, 2006). Tinnitus masking and tinnitus retraining therapy can require long periods of time and considerable patient compliance to be effective (Henry et al., 2006). These reduce the patient’s emotional response to tinnitus but generally leave the percept unaffected. Multiple alternative therapies also exist for the treatment of tinnitus, ranging from herbal supplements to chiropractory to acupuncture.

SURGERY FOR TINNITUS VIIIth Nerve Rhizotomy Historically, various forms of rhizotomy and nerve sectioning of the VIIIth nerve has been employed in order to treat refractory tinnitus. This was done under the assumption that the generator of the tinnitus percept was peripherally located within the primary sensory auditory apparatus, the cochlear and VIIIth nerve. In general, there are only sporadic case reports of this technique in the literature and often associated with vestibular schwannoma resections. While successes are reported, there are also well-documented failures, including worsening of tinnitus symptoms underscoring the primary role that deafferentation plays in the genesis of the tinnitus percept (House and Brackmann, 1981).

Microvascular Decompression (MVD) for Tinnitus Another method has sought to treat tinnitus symptoms by means of vascular decompression. This approach theorizes that tinnitus symptoms are generated by vascular compression of the VIIIth nerve, typically by AICA (anterior inferior cerebellar artery). These tinnitus patients have a specific, narrow-band hearing loss compared to most tinnitus patients who have a hearing loss across broader frequencies. Studies of this technique have demonstrated 33% of patients with significant improvement and 10% with worsening (Vasama et al., 1998).

NEUROMODULATION FOR TINNITUS More recently, various techniques of neuromodulation have been employed to treat refractory tinnitus. Underscoring the role of deafferentation in the genesis of tinnitus, implantation of cochlear auditory prostheses has been demonstrated to significantly reduce tinnitus in patients. Recent studies have demonstrated

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up to 86% of patients have a significant reduction in their tinnitus percept after cochlear implantation (Quaranta et al., 2004). The limitation of this approach is that many tinnitus sufferers have retained functional hearing in the affected ear or have remaining hearing in the opposite ear thus disqualifying them from insurance-covered implantation. Also addressing the problem of peripheral deafferentation has been a recent study looking at chronic stimulation of the VIIIth nerve. Utilizing a customdesigned ring electrode, a group from the Netherlands performed chronic electrical stimulation of the VIIIth nerve in six patients. Four patients experienced an improvement in their tinnitus symptoms. The specific manifestations of this improvement suggest a modulation of plasticity in the auditory system by the chronic electrical stimulation: The effect was not immediate with clinically relevant changes taking up to six months of chronic stimulation. Furthermore, only two of the responders had a perceptible change in tinnitus loudness. Rather, all four responders described a change of their tinnitus percept into a less-obtrusive, more pleasant sound suggesting a stimulation-induced reorganization of tonotopic organization or secondary auditory processing structures with downstream limbic influences (Bartels et al., 2007b) (Figures 81.2, 81.3). Tinnitus is considered to involve both a generator and a perceiver (Hazell and Jastreboff, 1990). While neither of these has been definitively localized, it is likely that the auditory cortex plays a major role in perception. As such, recent studies have examined the role of direct and indirect central nervous system stimulation for the suppression of tinnitus (Hazell and Jastreboff, 1990; Kleinjung et al., 2005; De Ridder et al., 2006; Bartels et al., 2007b). These include transcranial magnetic stimulation (TMS) studies which have shown the ability to suppress tinnitus perception acutely, and to produce longer-lasting effects after repetitive stimulation (Folmer et al., 2006; Langguth et al., 2006). Direct current stimulation along the superior temporal gyrus can also acutely alter sound and tinnitus perception (Fenoy et al., 2006) (Figure 81.4). Peripheral neuromodulatory approaches assume that the generator of tinnitus is in subcortical regions and can be modified with a bottom-up approach. As the evidence above suggests, many tinnitus patients have dysfunction at the level of the thalamocortical module. If these peripheral approaches cannot modulate pathological activity in higher centers, they will ultimately fail. Modulation of cortical structures should be successful in treating tinnitus as it addresses the perceiver of tinnitus regardless of the site of generation. Several studies have employed chronic stimulation targeted toward the auditory cortex for

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FIGURE 81.4 Locations along the posterior superior temporal gyrus where tinnitus suppression has been achieved via direct electrical stimulation (Reproduced with permission from Fenoy et al. (2006), Fig. 3. Copyright (2006) Elsevier)

FIGURE 81.3 The modified electrode of the Bartels et al. study in situ (Reproduced with permission from Bartels et al. (2007b), Fig. 2. Copyright (2007) S. Karger AG, Basel)

the amelioration of severe tinnitus (De Ridder et al., 2006; Fregni et al., 2006; Friedland et al., 2007). Some of these studies have demonstrated benefits consistent with the modulation of neural plasticity (Friedland et al., 2007).

CONCLUSION The significant unmet need of tinnitus sufferers underscores the utility of neuromodulation for tinnitus. Recent clinical and laboratory evidence points to deafferentation and disordered neural plasticity as integral mechanisms underlying the genesis of tinnitus. Neuromodulatory strategies such as rTMS and chronic electrical stimulation have been shown to alter these processes with beneficial results.

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REFERENCES

References Axelsson, A. and Ringdahl, A. (1989) Tinnitus – a study of its prevalence and characteristics. Br. J. Audiol. 23: 53–62. Bartels, H., Staal, M.J. and Albers, F.W. (2007a) Tinnitus and neural plasticity of the brain. Otol. Neurotol. 28: 178–84. Bartels, H., Staal, M.J., Holm, H.F., Mooij, H.H.J. and Albers, F.W.J. (2007b) Long-term evaluation of the treatment of chronic, therapeutically refractory tinnitus by neurostimulation. Stereotact. Funct. Neurosurg 85: 150–7. De Ridder, D., De Mulder, G., Verstraeten, E. et al. (2006) Primary and secondary auditory cortex stimulation for intractable tinnitus. ORL J. Otorhinolaryngol. Relat. Spec. 68: 48–54, discussion 55. Fenoy, A.J., Severson, M.A., Volkov, I.O. et al. (2006) Hearing suppression induced by electrical stimulation of human auditory cortex. Brain Res. 1118: 75–83. Folmer, R.L., Carroll, J.R., Rahim, A. et al. (2006) Effects of repetitive transcranial magnetic stimulation (rTMS) on chronic tinnitus. Acta Otolaryngol. 126 (Suppl. 556): 96–101. Fregni, F., Marcondes, R., Boggio, P.S. et al. (2006) Transient tinnitus suppression induced by repetitive transcranial magnetic stimulation and transcranial direct current stimulation. Eur. J. Neurol. 13: 996–1001. Friedland, D.R., Gaggl, W., Runge-Samuelson, C. et al. (2007) Feasibility of auditory cortical stimulation for the treatment of tinnitus. Otol. Neurotol. 28 (8): 1005–12. Hazell, J.W. and Jastreboff, P.J. (1990) Tinnitus. I: Auditory mechanisms: a model for tinnitus and hearing impairment. J. Otolaryngol. 19: 1–5. Henry, J.A., Dennis, K.C. and Schechter, M.A. (2005) General review of tinnitus: prevalence, mechanisms, effects, and management. J. Speech Lang. Hear Res. 48: 1204–35. Henry, J.A., Schechter, M.A., Zaugg, T.L. et al. (2006) Clinical trial to compare tinnitus masking and tinnitus retraining therapy. Acta Otolaryngol. 126 (Suppl. 556): 64–9. House, J.W. and Brackmann, D.E. (1981) Tinnitus: surgical treatment. Ciba Found. Symp. 85: 204–16. Kaltenbach, J.A. and Afman, C.E. (2000) Hyperactivity in the dorsal cochlear nucleus after intense sound exposure and its resemblance

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to tone-evoked activity: a physiological model for tinnitus. Hear Res. 140: 165–72. Kaltenbach, J.A. and Zhang, J. (2007) Intense sound-induced plasticity in the dorsal cochlear nucleus of rats: evidence for cholinergic receptor upregulation. Hear Res. 226: 232–43. Kleinjung, T., Eichhammer, P., Langguth, B. et al. (2005) Long-term effects of repetitive transcranial magnetic stimulation (rTMS) in patients with chronic tinnitus. Otolaryngol. Head Neck Surg. 132: 566-9. Langguth, B., Hajak, G., Kleinjung, T. et al. (2006) Repetitive transcranial magnetic stimulation and chronic tinnitus. Acta Otolaryngol. 126 (Suppl. 556): 102–4. Llinás, R.R., Ribary, U., Jeanmonod, D., Kronberg, E. and Mitra, P.P. (1999) Thalamocortical dysrhythmia: A neurological and neuropsychiatric syndrome characterized by magnetoencephalography. Proc. Natl Acad. Sci. USA 96: 15222–7. Llinás, R., Urbano, F.J., Leznik, E. et al. (2005) Rhythmic and dysrhythmic thalamocorticaldynamics: GABA systems and the edge effect. Trends Neurosci. 28: 325–33. Moller, A.R. (2006) Neural plasticity in tinnitus. Prog. Brain Res. 157: 365–72. Muhlnickel, W., Elbert, T., Taub, E. and Flor, H. (1998) Reorganization of the auditory cortex in tinnitus. Proc. Natl Acad. Sci. USA 95: 10340–3. Patterson, M.B. and Balough, B.J. (2006) Review of pharmacological therapy for tinnitus. Int. Tinnitus J. 12: 149–59. Quaranta, N., Wagstaff, S. and Baugley, D.M. (2004) Tinnitus and cochlear implantation. Int. J. Audiol. 43: 245–51. Schaette, R. and Kempter, R. (2006) Development of tinnitus-related neuronal hyperactivity through homeostatic plasticity after hearing loss: a computational model. Eur. J. Neurosci. 23: 3124–38. Vasama, J.P., Moller, M.B. and Moller, A.R. (1998) Microvascular decompression of the cochlear nerve in patients with severe tinnitus. Preoperative findings and operative outcome in 22 patients. Neurol. Res. 20: 242–8. Yang, G., Lobarinas, E., Zhang, L. et al. (2007) Salicylate-induced tinnitus: behavioral measures and neural activity in auditory cortex of awake rats. Hear Res. 226: 244–53.

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82 Brain and Cerebrospinal Fluid Infusion Therapies for the Treatment of CNS Disease Daniel J. Abrams

O U T L I N E Introduction

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(Medtronic, Inc. Minneapolis, MN) since the late 1980s. (Note: there is no other FDA approved programmable pump currently in the US market.) The Medtronic pump has proven to be durable, with a low failure rate that has been acceptable to patients and physicians. The most common complication with the implantable pump is related to blocking or kinking in the catheter. There is also a relatively rare occurrence of granulomatous collections associated with higher dose lumbar intrathecal morphine administration (Allen et al., 2006). Recently, there are renewed efforts for the development of drug therapies via central administration for CNS diseases which are refractory to conventional oral agents. These efforts are built upon the concepts of reverse targeting (local administration of medications to avoid systemic exposure issues), controlled precise administration to the CNS (with options for computerized programmable dosing), and the opportunity for relatively infrequent refilling of the pump reservoir (1–3 months). These advantages are particularly important when matched to the substantial unaddressed suffering

INTRODUCTION Administration of drugs directly into the brain or cerebrospinal fluid (CSF) has many advantages over oral dosing, but this therapeutic route is still underdeveloped. The direct administration of drugs into the brain has been investigated as a potential treatment for central nervous system (CNS) disorders, starting in the late 1960s (Blasberg et al., 1975, 1977; Laschka et al., 1976; Blasberg 1977). Initially, small molecule kinetics were investigated in larger animals for the potential treatment of CNS cancer and pain. Conotoxin is an example of a small molecule used for the treatment of spinal-mediated pain. Interestingly, spasticity subsequently has pushed the study of central administration for spinally mediated disease ahead of brain disease treatment (see Chapters 33, 34, 44 and 90 in this book). The routine use of centrally targeted therapy has been made possible through an implantable, refillable, computerized programmable pump made by Medtronic

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TABLE 82.1 Therapeutic treatment areas considered in brain infusion therapies ● ●

● ● ● ● ● ● ● ● ● ● ●

Pain Psychiatric disease (major depression, bipolar disorder and schizophrenia) Stroke Parkinson’s disease Huntington’s chorea Genetic metabolism disease – mucopolysaccharidoses Epilepsy Neoplasia Movement disorders Viral Bacterial infections Dystonia Alzheimer’s disease

in psychiatric and neurologic disease. From a theoretical perspective, the ideal CNS administered agent is one where central administration offers an advantage when compared with oral (from a distribution and/or toxicity perspective such as is the case with intrathecally administered baclofen and morphine). Also, computerized control of central kinetics offers a treatment advantage, coupled with a chronic disease where the right drugs and much-improved compliance facilitates better outcomes when the severity of the disease justifies the added cost and risk to the patient. Direct administration into the brain or CSF delivers the therapeutic agent “behind” the blood–brain barrier. Efficacy then depends on the movement of the therapeutic agent from the point of administration to the target area in the brain at sufficient concentrations without toxicity. This, however, must be accomplished without the concentration of medication falling to below effective levels by clearance mechanisms within the brain and CSF compartments. Therapeutic administration formulations have included liquid, wafer, and cell suspension. Types of therapeutic agents that have been tested include small molecules, DNA, RNA, and viral vectors. Diseases targeted have included Parkinson’s disease, Alzheimer’s disease, and glioblastoma multiforme. Potential CNS clinical targets for direct drug administration are listed in Table 82.1. In Table 82.2, therapeutic agents and formulations for direct brain infusion are listed.

SCIENTIFIC BACKGROUND FOR CNS DRUG DELIVERY To better understand the setting in which central drug administration will be most advantageous, we

TABLE 82.2 Therapeutic agents considered in brain infusion therapies ● ● ● ● ● ● ● ● ● ●

Proteins Conjugate proteins Antibodies Peptides DNA RNA and antisense Plasmids Viral vectors Small molecules Modified and unmodified cellular delivery agents

will review relevant anatomy, elements of interstitial fluid and cerebrospinal fluid (CSF) production and drainage, and principles of pharmacokinetics that are applicable to this route of administration. The relevant CNS anatomy includes the types of cells in the brain, functional histological units, and a review of relevant molecular structures that support these functions. The relevant cells of the brain parenchyma include neurons, glia, ependymal cuboidal cells that line the ventricle, arachnoid cells that comprise a layer that covers the brain outside the ventricle, and the tough dura layers that cover the brain and spinal cord. The blood–brain barrier (BBB) has been extensively studied and is comprised of specialized endothelial cells which contain tight junctions that limit interchange between the blood and the brain. The BBB has differences between the luminal and abluminal surfaces in terms of different proteins in the cellular surfaces as well as differences in the molecular ultrastructures. The arachnoid granulations are a specialized combination of arachnoid cells which project into the venous sinuses and are functionally important in bulk flow CSF drainage. The choroid plexus is a specialized combination of arachnoid and endothelial cells which contributes to CSF production and has a blood–CSF barrier with somewhat different characteristics than the BBB. At the molecular level, the cells and layers have proteins that facilitate these functions. In the BBB, there are specialized amino acid and other transporters (carrier-mediated transport, active efflux transport, and receptor-mediated transport) (Pardridge, 2007) that are responsible for selective transport into and out of the BBB and the choroid plexus between the blood–brain and CSF brain compartments. Aquaporins, a family of proteinbased water channels, likely facilitate interstitial flow (through the ependymal cells) and bulk flow (through the arachnoid granulations). Another important channel that has been described is a DNA channel that could facilitate movement of DNA into neurons and

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SCIENTIFIC BACKGROUND FOR CNS DRUG DELIVERY

transport within the brain (Shi et al., 2007). The submicroscopic anatomy of the brain interstitium has recently been studied using microdot technology. In these studies, the submicroscopic structure has been demonstrated to be highly complex, restricts diffusing particles to less than 35 nanometers in diameter, and becomes smaller after brain insults like cerebrovascular accidents (Thorne and Nicholson, 2006). Many of these discoveries are relatively recent and reflect the pace of recent CNS molecular and structural discovery. Interstitial fluid is produced and modified in the brain parenchyma and the choroid plexus. Hydrostatic and osmotic pressure and aquaporins are part of the forces and structures that contribute to fluid production and flow within the brain. The interstitial fluid flows into the ventricle which becomes the CSF that is contiguous throughout the subarachnoid space. The brain is highly lipophilic and the composition of CSF is a tightly regulated fluid of electrolytes that is relatively acellular with only a small amount of protein (some of which is IgG, which limits the spread of CNS viruses). The flow of CSF then continues through the lateral ventricles into the central 3rd and 4th ventricles up over the convexity of the brain. There is little mixing of ventricular CSF with spinal cord CSF. The ventricular CSF progresses from the convexities to the arachnoid granulations into the venous system at the superior sagittal sinus at the apex of the skull or alternatively through the arachnoid sleeves of the cranial nerves in the base of the skull into the head and neck lymph before mixing back with the venous blood (Johnston and Papaiconomou, 2002; Johnston et al., 2004). Increases in drainage of CSF through the arachnoid granulations may occur in response to CSF pressure and is similar to the mechanism of fluid transfer in Schlemm’s canal of the eye (Grzybowski et al., 2006). The total human CSF volume is approximately 125 ml and re-circulates every 5–8 hours. Intracranial pressure changes the dynamics and balance of these systems and the lymphatic-based system may become more important in CSF drainage. The relative role of bulk fluid drainage on protein and small molecule clearance has been studied to a limited extent. Recently, there have been efforts to quantify interstitial clearance and flow rates for proteins delivered in the brain. Small proteins in brain interstitial fluid are cleared differently from different locations at the rate of 0.18 to 0.29 μl per gram of brain per minute (Szentistványi, 1984). Other mechanisms of potential therapeutic exit from the brain could include transfer out to the blood across the blood–brain barrier directly or through cell-bound proteins (p-glycoproteins and ABC amino acid transporters).

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Regulation of extracellular fluid in the brain is through physiologic mechanisms that can be disrupted in pathologic conditions of limited CSF absorption (e.g. hydrocephalus) or by disruption of the BBB (e.g. brain tumors). Brain edema acutely (e.g. trauma and stroke) is thought to be a result of the loss of cell integrity within the brain and the endothelial cells of the BBB that results in an increase in brain fluid that can be lifethreatening. Hydrocephalus can also be thought of as a deficit of CSF communication (non-communicating hydrocephalus) or absorption (communicating hydrocephalus), both of which are treated routinely with CSF diversion through placement of CSF shunts. Recently, there are data suggesting that there is a role for hormonal control of brain fluid production and absorption. The hormone somatostatin may act at the choroid plexus and arachnoid granulations to influence interstitial and CSF fluid; similar to other hormonally modifiable systems (e.g. the kidney and vascular systems) (Katz et al., 2002). Oral drug delivery to the brain may be described by pharmacokineticists as delivery to a brain compartment from the body across a physiologic barrier (BBB). When potential small molecule therapeutics useful for treating epilepsy were screened, it was empirically determined that hydrophobic molecules less than 450 MW could penetrate the BBB and be active when administered peripherally (Pardridge, 2007). Modeling of direct administration within the brain potentially builds on this experience and we must consider to what extent the compartment concept applies. For example, because ethanol is so freely diffusible into and out of the brain, the two-compartment model is a limited conceptualization. On the other hand, vancomycin is a large molecule used to treat gram-positive brain shunt infection which is routinely administered as a bolus through a ventricular cannula and is believed to remain in the CSF-defined space. This is similar to what happened when vancomycin is administered orally and IV; the molecule does not cross membranes with significant barriers like the GI tract. Morphine is a molecule that falls in between in molecular size and when it is administered ICV (intracerebroventricular) in single bolus administrations of 2–10 mg the drug binds to periventricular brain receptors and egresses along with CSF bulk flow (Teschemacher et al., 1973). An additional concept demonstrated in acute bolus studies has examined the role of diffusion in penetration of molecules into the brain. Diffusion of lipid molecules in these studies has fallen off logarithmically with distance in brain tissue and obeys Fick’s Law. When this happens, the ICV infusion goes across the BBB into the vascular space and the molecule develops a systemic level

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similar to a slow intravenous infusion (Pardridge, 1997). Clarifying the kinetics of drugs administered into the brain in terms of the precise mechanisms of drug clearance, how the kinetics impact the total dose delivered, as well as the kinetics into the brain at steady state are largely unexplored. Drug delivery depends not only on the characteristics of the BBB but also on the chemical and pharmacologic characteristics of the therapeutic agent, including the molecular size, hydrophobicity, protein binding, and binding to brain cellular receptors. For therapeutic agents to demonstrate efficacy, they will need to be effective in animal models of disease and will need to be quantified at the site of action, to allow the characterization of CSF pharmacokinetics, including clearance, volume of distribution and halflife, along with toxicologic evaluation. From a practical perspective, several technical and practical hurdles have limited efforts on the development of direct CNS therapies. These hurdles include the lack of widespread expertise required to do animal neurosurgery for therapeutic implantation and sampling of CSF. Additionally, the expense and availability of large animal models is a practical issue. Larger animals are required to take into account the larger brains of humans for therapeutic CNS distribution. Clinical experience and experiments from delivery to spinal CSF support the fact that highly lipophilic small molecules rapidly exit the intrathecal lumbar CSF of the CNS into the blood via the epidural fat of the spinal cord and do not widely distribute (Bernards, 2006). Separate chapters in this book (Chapters 33 and 35) discuss medications administered in the lumbar spinal CSF, including ziconotide, morphine, baclofen and clonidine, which stay more within the CSF, and others (e.g. sufentanil), which are more rapidly cleared to fat tissues and achieve systemic blood levels prior to achieving therapeutic effect. Furthermore, spinal drug action was thought to exert its action by penetrating only a short distance into the spinal cord; limiting distribution into the parenchyma, that fortunately reflected the distribution of the receptor targets, also located in these areas. This experience with spinal small molecules did not encourage further small molecule exploration for ventricular CSF delivery because it was felt that small molecules will not effectively move from the ventricle to the site of action. These conclusions have been supported by the fact that bulk water-based CSF flow is in the wrong direction, the ependyma is a barrier with aquaporins pushing water and other molecules away, and the early findings that suggested fat-soluble drugs would rather partition to plasma than to the brain, which may be the most important factor.

HISTORY OF DIRECT CNS DRUG THERAPY The first small molecule studies in the late 1960s and early 1970s focused on opiates and chemotherapeutics. Herz and Teschemacher investigated the distribution of morphine and fentanyl into the CNS and found that drug distribution was restricted to the periventricular regions and periaqueductal gray area relatively rich in opiate receptors and adjacent to areas of ventricular CSF flow after ICV injection (Teschemacher et al., 1973). Soon afterwards Blasberg explored different chemotherapeutic compounds (hydroxyurea, methotrexate, thiotepa, BCNU, and cytosine arabinoside) and investigated how the octanol/water p was related to small molecule penetration across the ependyma and distribution into the caudate nucleus (Blasberg et al., 1975, 1977; Blasberg, 1977). His findings suggested that though lipophilic drugs move rapidly into the brain, their concentration logarithmically decreases with each millimeter of penetration into the periventricular area. Furthermore, though lipophilic drugs were taken into the brain tissue they were rapidly redistributed out of the brain into the blood. Several studies have looked at different drugs, but focused less on questions of distribution and have found that certain drugs preferentially leave the CNS rather than penetrate the brain tissue. Parallel findings suggested that hydrophilic drugs tended to stay within the CSF but also did not penetrate into the brain tissue (Pardridge, 1997). Theoretical issues to consider with ICV administration for the brain parenchyma include the hydrostatic pressure across the ventricular wall, aquaporins, the directionality of flow of water in the ventricle, the barrier of the ependymal lining, and lastly, the entry and spread of the therapeutic within the brain parenchyma. To date, there has been no drug successfully developed for ICV administration for the treatment of CNS parenchymal disease state. ICV and IT (intrathecal) administration of small molecules has only successfully treated arachnoid disseminated disease, including iatrogenic meningitis primarily from shunts and carcinomatous meningitis. At the same time, clinical use of spinal CSF administered agents was significantly expanded for the treatment of refractory chronic pain, for refractory spasticity, and for use with epidural therapeutics. The establishment of chronic spinal drug administration for spasticity and pain are in the regular armentarium for physicians. This has largely occurred in part because of the commercial availability of an implantable pump and catheter. In 1988, Medtronic developed a pump with an 18 ml reservoir, a microprocessor,

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and a battery that would last several years. Some years later, a more reliable catheter system was also established for a functional delivery system for spinal administration. This system has now been used in over 150 000 patients with the vast majority having been implanted for spinal treatment of pain and spasticity using the approved morphine and baclofen (Ordia et al., 1996; Korenkov et al., 2002; Guillaume et al., 2005; Sadiq and Wang, 2006). Some physicians have used other products, produced by compounding pharmacies, for treatment of pain through the delivery system (Becker et al., 1997; Skold et al., 1999; Francisco and Boake, 2003; Bernards, 2004; Rizzo et al., 2004). The pump itself has fewer problems than the catheter and after the approval of the morphine product an approximately 2% incidence of an aseptic granulomatous mass was discovered related to opiate infusion. Medtronic has an interest in development of a new intrathecal treatment for pain (personal communication). Recently, the Codman subsidiary of Johnson & Johnson has made plans to release a programmable pump within the EU for spinal baclofen therapy. Codman reportedly has plans to start spinal intrathecal baclofen trials for the US market with its implantable pump. Reportedly, the Codman Medstream program is in animal phase testing of therapeutics for brain-related treatment of Parkinson’s disease based on their implantable therapy platform. (personal communication). Recently our group, based at the University of Colorado, has started the development of direct CNS infusions of therapeutics for several psychiatric and neurologic disorders.

CONVECTION ENHANCED DELIVERY (CED) AND CED-BASED THERAPEUTIC PROGRAMS Direct intraparenchymal administration, called convection enhanced delivery (CED), was reported in the early 1990s using several different agents and several disease targets, starting under the leadership of Dr Edward H. Oldfield at NIH (Bobo et al., 1994). This technology does not rely on the implantable pump system which had been used in spinal drug administration. Oldfield initially targeted glioblastoma multiforme, where he used various agents to penetrate the brain parenchyma around the resected boundary of the tumor. The technique used targeted injection under constant fluid flow and positive pressure (4.5 μl per minute) intra-parenchymally for at least several hours of administration in order to achieve uniform distribution at therapeutic levels into volumes as large

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as 5 ml within the brain (total brain volume is 1500 ml) (Hall et al., 2003; Raghavan et al., 2006). Drug administered directly into a site within the brain parenchyma will concentrate more locally in the brain at the site in which it was injected unless administered under pressure. The strategy to create more uniform distribution in areas of pathology or particular anatomic locations has been addressed by delivering the drug under pressure. Dilation of perivascular spaces is theorized to be the route of drug delivery for CED. In general, CED development has focused on developing the instrumentation, imaging precise locations of drug distribution, and identifying the proper flow rates and methods of administration while establishing efficacy in the disease model of interest. This work has been expanded to other diseases such as epilepsy and Parkinson’s disease and the therapeutics that have been used include small molecules, proteins, nucleic acids, and viral vectors. Current work has focused on technical improvements in this modality in order to facilitate reliable and repeatable location of injections in differing surgical hands. Approaches have included standardizing location sites, sizes of injection catheters, and fluid injection rates. CED is not yet FDA-approved and potentially dilates Robins–Virchow spaces, which could facilitate complications in the elderly who have cerebral atrophy. From a theoretical perspective, clarifying how CED differs from infusion will be helpful in further developing the therapy. In summary, CED has successfully gone through initial development of several products for focal brain delivery of biologic and small molecule treatments for brain tumors, epilepsy, and Parkinson’s disease, and will hopefully overcome its challenges to make successful treatments available for patients. For other common brain diseases in which brain localization is more elusive (e.g. bipolar disorder, schizophrenia, and Alzheimer’s disease), a CED approach likely would add a level of morbidity and complication for the physician to manage multiple drug delivery procedures and processes that makes it less likely to be adopted.

OTHER DRUG PRODUCTS, ROUTES OF ADMINISTRATION, AND COMMERCIAL ENVIRONMENT During the same years as CED development, small and large pharma groups pursued large molecules for the treatment of CNS diseases (see Chapter 44 on infusion therapy for movement disorders). The longest efforts were in the study of the growth factor GDNF

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which was explored as a treatment of amyotrophic lateral sclerosis and Parkinson’s disease. GDNF went through preclinical and clinical development twice and ultimately did not make it through FDA approval (Schulte-Herbrüggen et al., 2007; Evans and Barker, 2008). The growth factor NGF was explored preclinically as a treatment for Alzheimer’s disease without moving beyond the preclinical stage. Leptin is a protein that was explored as a treatment for obesity and conotoxin is a peptide for treatment of epilepsy, both of which were preclinically explored (Tang-Christensen et al., 1999). Other therapies including stem cell implantation for treatment of Parkinson’s disease were also pursued by several groups (Björklund et al., 2003). While this is not an exhaustive list of past efforts with intraparenchymal and ICV non-small molecule efforts, the reasons for failure of these therapies varied and included biologic effectiveness, drug distribution, relevance of animal models to human disease, toxicity, and clinical trial endpoints. From a clinical perspective, there has been some practical experience with intracerebroventricular morphine in more than 250 cancer patients with medically unresponsive severe pain (Ballantyne and Carwood, 2005). In that review the efficacy was high, the complication rate was low, and the kinetics suggested a halflife of more than several hours even with more dated pump and catheter equipment. In addition to morphine, ICV baclofen has been used in 10 pediatric and one adult case to treat secondary dystonia or heredodegenerative dystonia, with dosing determined empirically (L. Albright, personal communication). In terms of chemotherapeutic agents to treat CSF primary or metastatic disease, Depocyt is a commercial delayed release liposomal-based product using cytosine arabanoside to treat meningeal metastasis. Depocyt is administered through lumbar injections. Gliadel (BCNU) is an alklyating agent slow release polymer which has been approved for treatment of malignant brain cancer as a locally released surface chemotherapy placed physically in the tumor bed. Other ICV chemotherapeutics that have been investigated but not developed include aziridinylbenzoquinone (Zimm et al., 1984).

CONCLUSION Despite the fact that direct brain infusion therapeutics were initially investigated in the 1960s and the substantial patient need, relatively few therapeutics have been developed and few patients impacted. The technical hurdles to enter this area are not insubstantial and the paucity of successful results to date

has probably contributed to this field’s lag behind other approaches to drug development. The successful development of Depocyt and Gliadel, continued research using new therapeutics, the convection enhanced delivery efforts, and the changing pharma device environments are among the factors suggesting that the next 5–10 years may herald new therapeutic options for patients with medically refractory brain diseases. Further contributing to the environment is the necessity of establishing drug device development collaboration, which can be fairly complicated as it requires resolution of cultural differences between organizations. This is important not just for successful business relationships but also in positively and effectively engaging with the regulatory agencies for drug approval. Other issues that have yet to be addressed and will be important in new therapeutic development include patient and physician acceptance and reimbursement issues that will play out in the marketplace.

ACKNOWLEDGMENTS I would like to thank Bill Elmquist, Bob Boyd, Greg Stewart, Ilo Leppik, Karen E. Stevens, Tom Anchordoquy, Ashwini D. Sharan, and Ali R. Rezai for suggestions and comments on the text of this chapter.

References Allen, J.W., Horais, K.A., Tozier, N.A. et al. (2006) Time course and role of morphine dose and concentration in intrathecal granuloma formation in dogs: a combined magnetic resonance imaging and histopathology investigation. Anesthesiology 105 (3): 581–9. Ballantyne, J.C. and Carwood, C.M. (2005) Comparative efficacy of epidural, subarachnoid, and intracerebroventricular opioids in patients with pain due to cancer. Cochrane Database Syst Rev. (1), CD005178. Review. Becker, R., Alberti, O. and Bauer, B.L. (1997) Continuous intrathecal baclofen infusion in severe spasticity after traumatic or hypoxic brain injury. J. Neurol. 244: 160–6. Bernards, C.M. (2004) Recent insights into the pharmacokinetics of spinal opioids and the relevance to opioid selection. Curr. Opin. Anaesthesiol. 17 (5): 441–7. Bernards, C.M. (2006) Cerebrospinal fluid and spinal cord distribution of baclofen and bupivacaine during slow intrathecal infusion in pigs. Anesthesiology 105 (1): 169–78. Blasberg, R.G. (1977) Methotrexate, cytosine arabinoside, and BCNU concentration in brain after ventriculocisternal perfusion. Cancer Treat. Rep. 61 (4): 625–31. Blasberg, R.G., Patlak, C. and Fenstermacher, J.D. (1975) Intrathecal chemotherapy: brain tissue profiles after ventriculocisternal perfusion. J. Pharmacol. Exp. Ther. 195 (1): 73–83. Blasberg, R.G., Patlak, C.S. and Shapiro, W.R. (1977) Distribution of methotrexate in the cerebrospinal fluid and brain after intraventricular administration. Cancer Treat. Rep. 61 (4): 633–41. Björklund, A., Dunnett, S.B., Brundin, P., Stoessl, A.J., Freed, C.R., Breeze, R.E. et al. (2003) Neural transplantation for the treatment of Parkinson’s disease. Lancet Neurol. 2 (7): 437–45.

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Bobo, R.H., Laske, D.W., Akbasak, A., Morrison, P.F., Dedrick, R.L. and Oldfield, E.H. (1994) Convection-enhanced delivery of macromolecules in the brain. Proc. Natl Acad. Sci. U S A 91 (6): 2076–80. Evans, J.R. and Barker, R.A. (2008) Neurotrophic factors as a therapeutic target for Parkinson’s disease. Expert Opin. Ther. Targets 12 (4): 437–47. Francisco, G. and Boake, C. (2003) Improvement in walking speed in poststroke spastic hemiplegia after intrathecal baclofen therapy: a preliminary study. Arch. Phys. Med. Rehabil. 84: 1119–94. Grzybowski, D.G., Holman, D.W., Katz, S.E. and Lubow, M.I. (2006) In vitro model of cerebrospinal fluid outflow through human arachnoid granulations. Invest. Ophthalmol. Vis. Sci. 47: 3664–72. Guillaume, D., Van Havenbergh, A., Vloeberghs, M., Vidal, J. and Roeste, G. (2005) A clinical study of intrathecal baclofen using a programmable pump for intractable spasticity. Arch. Phys. Med. Rehabil. 86: 2165–71. Hall, W.A., Rustamzadeh, E. and Asher, A.L. (2003) Convectionenhanced delivery in clinical trials. Neurosurg. Focus 14 (2): e2. Johnston, M. and Papaiconomou, C. (2002) Cerebrospinal fluid transport: a lymphatic perspective news. Physiol. Sci. 17 (6): 227–30. Johnston, M., Zakharov, A., Papaiconomou, C., Salmasi, G. and Armstrong, D. (2004) Evidence of connections between cerebrospinal fluid and nasal lymphatic vessels in humans, non-human primates and other mammalian species. Cerebrospinal Fluid Res. 10 (1): 2. Katz, S.E., Klisovic, D.D., O’Dorisio, M.S., Lynch, R. and Lubow, M. (2002) Expression of somatostatin receptors 1 and 2 in human choroid plexus and arachnoid granulations: implications for idiopathic intracranial hypertension. Arch. Ophthalmol. 120 (11): 1540–43. Korenkov, A.I., Niendorf, W.R., Darwish, N., Glaeser, E. and Gaab, M.R. (2002) Continuous intrathecal infusion of baclofen in patients with spasticity caused by spinal cord injuries. Neurosurg. Rev. 25: 228–30. Laschka, E., Teschemacher, H., Mehraein, P. and Herz, A. (1976) Sites of action of morphine involved in the development of physical dependence in rats. II. Morphine withdrawal precipitated by application of morphine antagonists into restricted parts of the ventricular system and by microinjection into various brain areas. Psychopharmacologia 46 (2): 141–7. Ordia, J.I., Fisher, E., Adamski, E. and Spatz, E.L. (1996) Chronic intrathecal delivery of baclofen by a programmable pump for the treatment of severe spasticity. J. Neurosurg. 85: 452–7.

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Pardridge, W.M. (1997) Drug delivery to the brain. J. Cereb. Blood Flow Metab. 17 (7): 713–31. Pardridge, W. (2007) Blood–brain barrier delivery. Drug Discovery Today 12 (1/2). Raghavan, R., Brady, M.L., Rodríguez-Ponce, M.I., Hartlep, A., Pedain, C. and Sampson, J.H. (2006) Convection-enhanced delivery of therapeutics for brain disease, and its optimization. Neurosurg. Focus 20 (4): E12. Rizzo, M., Hadjimichael, O.C., Preiningerova, J. and Vollmer, T.L. (2004) Prevalence and treatment of spasticity reported by multiple sclerosis patients. Multiple Sclerosis 10: 589–95. Sadiq, S.A. and Wang, G.C. (2006) Long-term intrathecal baclofen therapy in ambulatory patients with spasticity. J. Neurol. 253 (5): 563–9. Schulte-Herbrüggen, O., Braun, A., Rochlitzer, S., Jockers-Scherübl, M.C. and Hellweg, R. (2007) Neurotrophic factors – a tool for therapeutic strategies in neurological, neuropsychiatric and neuroimmunological diseases? Curr. Med. Chem. 14 (22): 2318–29. Shi, F., Gounko, N.V., Wang, X., Ronken, E. and Hoekstra, D. (2007) In situ entry of oligonucleotides into brain cells can occur through a nucleic acid channel. Oligonucleotides 17 (1): 122–33. Skold, C., Levi, R. and Seiger, A. (1999) Spasticity after traumatic spinal cord injury: nature, severity, and location. Arch. Phys. Med. Rehabil. 80: 1548–57. Szentistványi, I. (1984) Drainage of interstitial fluid from different regions of rat brain. Am. J. Physiol. F835. Tang-Christensen, M., Havel, P.J., Jacobs, R.R., Larsen, P.J. and Cameron, J.L. (1999) Central administration of leptin inhibits food intake and activates the sympathetic nervous system in rhesus macaques. J. Clin. Endocrinol. Metabol. 84 (2): 711–17. Teschemacher, H., Schubert, P. and Herz, A. (1973) Autoradiographic studies concerning the supraspinal site of the antinociceptive action of morphine when inhibiting the hindleg flexor reflex in rabbits. Neuropharmacology 12 (2): 123–31. Thorne, R.G. and Nicholson, C. (2006) In vivo diffusion analysis with quantum dots and dextrans predicts the width of brain extracellular space. PNAS 103 (14): 5567–72. Zimm, S., Collins, J.M., Curt, G.A., O’Neill, D. and Poplack, D.G. (1984) Cerebrospinal fluid pharmacokinetics of intraventricular and intravenous aziridinylbenzoquinone. Cancer Res. 44 (4): 1698–701.

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83 Deep Brain Stimulation for Cognitive Neuromodulation Nicholas D. Schiff Following early experimental observations, clinical investigators in the late 1960s and 1970s began attempts at electrical stimulation of the brain stem (tegmental midbrain), thalamus (posterior intralaminar nuclei – centromedian parafascicularis complex) and basal ganglia (globus pallidus interna) for treatment of prolonged unconsciousness (Sturm et al., 1979; see additional references cited in Cohadon et al., 1985; Tsubokawa and Katayama, 1990; Hosobuchi and Yingling, 1993). Most patients in the initial clinical studies of deep brain stimulation (DBS) to restore consciousness had remained in conditions consistent with either near brain death or vegetative state following severe traumatic or anoxic brain injury. Although eye opening and some fragmentary movements were generally observed with electrical stimulation consistent with an arousal effect, no examples of recovery of sustained interactive behavior were noted nor were formal behavioral assessments obtained to link DBS to clinical improvement. In the late 1980s a multicenter study was initiated by Medtronic, Inc. involving neurosurgeons in France, Japan, and the United States (Cohadon et al., 1985; Tsubokawa and Katayama, 1990; Hosobuchi and Yingling, 1993) to apply DBS in the centromedian thalamus and cervical spinal cord to a group of ⬃50 patients in the vegetative state (VS). Despite clear clinically judged increases in arousal and physiological responses to brain stimulation in many patients, including changing of the frequency content of the EEG and increases in cerebral metabolic rates measured using positron emission tomography, substantive clinical improvements were not identified in the VS patients treated with DBS. A small number of patients with traumatic brain injury (studies included

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anoxic, traumatic, and other etiologies) were reported to show significant improvement but all of these patients were studied within the known time frames for spontaneous recovery and without formal behavioral assessment linking DBS to behavioral changes. More recently the patients who showed further recovery in these studies have been acknowledged to not fulfill the VS criteria (Yamamoto and Katayama, 2005) at the time of initiation of DBS, having in retrospect been judged to have recovered evidence of behavioral responsiveness consistent with the minimally conscious state (MCS) (Giacino et al., 2002). MCS patients have a longer time frame for significant functional recovery (Lammi et al., 2005). The experimental studies of Morruzi and Magoun (1949) first demonstrated that electrical stimulation of the brain stem reticular formation and midline thalamus could produce desynchronization of the EEG similar to that seen in wakeful states. Based on these and other related experimental findings, a concept of an ascending reticular activating system arose with an essential role for the midbrain and intralaminar regions of the thalamus. A precise anatomical demonstration of a pathway from the midbrain reticular formation (MRF) to the intralaminar nuclei of the thalamus (ILN), as suggested by the original Moruzzi and Magoun studies, was identified three decades later by Steriade and Glenn (1982) using electroanatomical and single-unit recording methods. More recently, human imaging studies have shown that activation of this pathway between MRF and ILN is associated with increasing levels of attentional focus during simple reaction time tasks (reviewed in Schiff and Purpura, 2002). At present, however, the nuclei within the central

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FIGURE 83.1 Electrode lead placements in central thalamus of minimally conscious state. Electrode lead placements within central thalamus of patient’s right (R) and left (L) hemispheres displayed in T1 weighted MRI coronal imag (Reproduced with permission from Schiff et al. (2007) Nature 2007; 448: 600–613. © 2007)

thalamus are considered to play a more intermediate role in arousal state control with a primary role of activation assigned to brain stem monoaminergic and cholinergic neuronal groups and neurons within the basal forebrain. Importantly, inputs from the brain stem and basal forebrain arousal system converge strongly on the intralaminar and surrounding regions of the central thalamus suggesting that these neurons can be recruited through many types of arousal (Schiff and Purpura, 2002). In a recent report, following on earlier proposals outlining the strategic approach (Schiff et al., 2000, 2002; Schiff and Purpura, 2002) and experimental studies (Schiff et al., 2002; Shirvalkar et al., 2006), Schiff and coworkers (2007) reported findings from a study of DBS electrodes implanted bilaterally in the central thalamus as part of a pilot clinical trial in a 38-yearold male who remained in a minimally conscious state for 6 years following a severe traumatic brain injury. Although the patient was unable to communicate reliably, prior characterization of brain function using fMRI showed preservation of bi-hemispheric largescale cerebral language networks (Schiff et al., 2005). PET imaging revealed that cerebral metabolism during wakefulness was markedly depressed. DBS electrodes targeted the anterior intralaminar thalamic nuclei and adjacent paralaminar regions of thalamic association nuclei (Figure 83.1). In contrast to the earlier human neurosurgical studies discussed that targeted the centromedian nucleus (Cm) of the thalamic posterior intralaminar system, spinal cord, and globus pallidus, emphasis was placed on the more anterior components of the intralaminar system that are heavily innervated

by the brain stem arousal systems and are the principal thalamic targets of the midbrain reticular projection (Schiff and Purpura, 2002). These anterior intralaminar neurons have strong connections with medial frontal cortical systems that regulate arousal level (see Schiff and Purpura, 2002 for review). A 6 month double-blind alternating crossover study carried out in this single subject showed that bilateral DBS of the central thalamus improved behavioral responsiveness, increasing the frequency of specific cognitively mediated behaviors and functional limb control and oral feeding during periods in which DBS was on, as compared with periods in which it was off (Figure 83.2). The investigators interpreted the observed DBS effects as evidence of partial functional restoration of frontal cortical systems involved in arousal regulation and behavioral drive. Direct activation of neocortical and basal ganglia neurons via stimulation of the central thalamus was proposed as compensating for a loss of arousal regulation that is normally controlled by the frontal lobe in the intact brain and supported by the central thalamic regions targeted. These findings provide the first evidence that DBS can promote significant late functional recovery from severe traumatic brain injury and motivate further research. The rationale for DBS in MCS patients is different in several important aspects, focusing on a subset of MCS patients with relatively widely preserved brain structure and clear evidence of interactive behavior with elements of language function (command following, verbalization, or inconsistent communication). DBS in this patient group may improve arousal regulation of functionally connected but inconsistently active cerebral networks that are expected to be absent in permanent VS patients. For such MCS patients restoration of reliable communication or response initiation and persistence would have functional significance. In comparison, the general failure of applying DBS to VS patients can be understood in the context of the underlying pathology of VS, which when not a transient condition, demonstrates a consistent neuropathology in chronic stages of widespread death of thalamic and cortical neurons (Adams et al., 2000). Developing deep brain stimulation (DBS) for severely brain-injured patients to improve cognitive function will require new ethical frameworks that establish proportionate goals of care and protection of vulnerable research subjects (Adams et al., 2000; Fins, 2005). There are several additional limitations that must be addressed to advance this area of investigation. Importantly, there are few scientifically vetted outcome measures developed for patients with marked cognitive impairment following brain injury. More precise

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* *

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Frequency of maximal score rating

0.8 0.7 * 0.6 0.5 0.4 0.3 0.2 0.1 ‡ 0 e On Off re On Off re On Off re On Off re On Off re On Off P P P P P CRS-R CRS-R CRS-R Limb Oral Object Arousal Comm Motor Control Feeding Naming

Pr

FIGURE 83.2

Comparison of pre-surgical baselines and DBS “On” and DBS “Off” periods during a 6 month crossover trial of central thalamic DBS in a patient with severe traumatic brain injury. Presurgical baselines and crossover trial observations are displayed, with 95% confidence intervals for binomial distributions with n observations for three primary behavioral outcome measures on the Coma Recovery Scale Revised (CRS-R subscales) measuring attentive responsiveness (arousal n  185 Off, 189 On); communication (n  185 Off, 189 On); motor function (n  185 Off, 189 On), and secondary measures of limb control (n  336 Off, 261 On); oral feeding (n  54 Off, 53 On), and object naming (n  206 Off, 235 On). Asterisks indicate significant differences “On” versus “Off” for CRS-R arousal, limb control, and oral feeding measures at p 0.001 established by Pearson Chi-square (two-tail). ‡ Symbol indicates that formal assessments not available for oral feeding during Pre stimulation phase of study. Patient had remain on gastrotomy tube feeding at that time (Reproduced from Schiff et al. (2000) with permission from Maney Publishing)

evaluation of cognitive, motor, and emotional capacities will be needed to quantitatively assess the impact of potentially therapeutic interventions. These tools are needed to develop accurate selection criteria to appropriately categorize and risk-stratify patients for DBS studies in this diverse population.

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SUMMARY POINTS ●

In early clinical efforts unconscious patients were analogized to experiments in anesthetized animals with intact neuronal populations and structural connectivity. Several studies attempted to use electrical stimulation of brain stem, thalamic and basal ganglia targets to change arousal state in chronically unconscious patients from a background of diffusely abnormal cortical activity to a normal wakeful conscious state.

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Prior studies did not demonstrate efficacy or linkage of DBS to clinical changes. The targets of electrical stimulation used in these studies are now recognized to play an intermediate role in the process of brain activation and arousal, both regulating arousal level and integrating a broad array of arousal inputs. Patients with clear evidence of interactive behavior, intact large-scale cerebral networks and spontaneous recovery of the basic electrophysiological pattern of wakeful states may be the first group likely to benefit from neuromodulation efforts in non-progressive brain injuries. Schiff et al. have demonstrated in pilot studies in a single human subject that DBS in central thalamus facilitated functional recoveries of attentive responsiveness, speech, oral feeding, and motor control late after severe traumatic injury resulting in a chronic minimally conscious state. (Summarized from Schiff and Fins, 2007)

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ACKNOWLEDGMENT The author acknowledges the support of the NINDS, Charles A. Dana Foundation, James S. McDonnell Foundation, and IntElect Medical Inc.

DISCLOSURE The author is an inventor at Cornell University of some of the technology discussed in this review and a paid consultant and advisor to IntElect Medical Inc., to which the technology has been licensed by Cornell University and in which Cornell University has an equity interest. IntElect Medical Inc. provided partial support for the clinical studies reported in Schiff et al. (2007).

References Adams, J.H., Graham, D.I. and Jennett, B. (2000) The neuropathology of the vegetative state after acute insult. Brain 123: 1327–38. Cohadon, F., Richer, E., Bougier, A., Deliac, P. and Loiseau, H. (1985) Deep brain stimulation in cases of prolonged traumatic unconsciousness. In: Y. Lazorthes and A.R.M. Upton (eds), Neurostimulation: An Overview. Mt Kisco, NY: Futura Publishers, pp. 247–50. Fins, J.J. (2000) A proposed ethical framework for interventional cognitive neuroscience: a consideration of deep brain stimulation in impaired consciousness. Neurol. Res. 22: 273–8. Fins, J.J. (2005) Clinical pragmatism and the care of brain damaged patients: toward a palliative neuroethics for disorders of consciousness. Prog. Brain Res. 150: 565–82. Giacino, J.T., Ashwal, S., Childs, N., Cranford, R., Jennett, B., Katz, D.I. et al. (2002) The minimally conscious state: definition and diagnostic criteria. Neurology 58: 349–53. Hosobuchi, Y. and Yingling, C. (1993) The treatment of prolonged coma with neurostimulation. In: O. Devinsky, A. Beric and M. Dogali (eds), Electrical and Magnetic Stimulation of the Brain and Spinal Cord. New York: Raven Press, pp. 247–52.

Lammi, M.H., Smith, V.H., Tate, R.L. and Taylor, C.M. (2005) The minimally conscious state and recovery potential: a follow-up study 2 to 5 years after traumatic brain injury. Arch. Phys. Med. Rehabil. 86: 746–54. Moruzzi, G. and Magoun, H.W. (1949) Brainstem reticular formation and activation of the EEG. Electroencephalogr. Clin. Neurophysiol. 1: 455–73. Schiff, N.D. and Fins, J.J. (2007) Deep brain stimulation and cognition: moving from animal to patient. Curr. Opin. Neurol. 20 (6): 638–42. Schiff, N.D. and Purpura, K.P. (2002) Towards a neurophysiological basis for cognitive neuromodulation. Thal. Relat. Syst. 2: 55–69. Schiff, N.D., Giacino, J.T. and Kalmar, K. (2007) Behavioral improvements with thalamic stimulation after severe traumatic brain injury. Nature 448: 600–13. Schiff, N.D., Hudson, A.E. and Purpura, K.P. (2002) Modeling wakeful unresponsiveness: characterization and microstimulation of the central thalamus. Society for Neuroscience 31th Annual Meeting, Abstract 62.12. Schiff, N.D., Plum, F. and Rezai, A.R. (2002) Developing prosthetics to treat cognitive disabilities resulting from acquired brain injuries. Neurol. Res. 24: 116–24. Schiff, N.D., Rezai, A. and Plum, F. (2000) A neuromodulation strategy for rational therapy of complex brain injury states. Neurol. Res. 22: 267–72. Schiff, N.D., Rodriguez-Moreno, D., Kamal, A., Kim, K.H., Giacino, J.T., Plum, F. et al. (2005) fMRI reveals large-scale network activation in minimally conscious patients. Neurology 64: 514–23. Shirvalkar, P., Seth, M., Schiff, N.D. and Herrera, D.G. (2006) Cognitive enhancement through central thalamic deep brain stimulation. Proc. Natl Acad. Sci. USA 103: 17007–12. Steriade, M. and Glenn, L.L. (1982) Neocortical and caudate projections of intralaminar thalamic neurons and their synaptic excitation from midbrain reticular core. J. Neurophysiol. 48: 352–71. Sturm, V., Kuhner, A., Schmitt, H.P., Assmus, H. and Stock, G. (1979) Chronic electrical stimulation of the thalamic unspecific activating system in a patient with coma due to midbrain and upper brain stem infarction. Acta Neurochirurg. 47: 235–44. Tsubokawa, T. and Katayama, K. (1990) Deep-brain stimulation in a persistent vegetative state: follow-up results and criteria for selection of candidates. Brain Inj. 4: 315–27. Yamamoto, T. and Katayama, Y. (2005) Deep brain stimulation therapy for the vegetative state. Neuropsychol. Rehabil. 15: 406–13.

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84 Novel Neuromodulation Approaches for Alzheimer’s Disease and Other Neurodegenerative Conditions Julie G. Pilitsis and Roy A.E. Bakay

(Carson et al., 2006), until the question of whether well-differentiated cells can be generated and tumorigenic cells eliminated. Neuromodulation with neurotrophic factors in PD, AD, and HD have all reached clinical trials. In PD, intraventricular and infusion-based delivery of glial cell line-derived neurotrophic factor (GDNF) met with poor results and was limited by side effects (Nutt et al., 2003; Lang et al., 2006). For more targeted delivery, three clinical trials with adeno-associated virus (AAV)-based delivery for PD are under way based on preclinical successes, including a phase II trial of putaminal injections of neurturin, a phase I trial on delivery of aromatic amino acid decarboxylase, and a phase I trial on glutamic acid decarboxylase injections into the subthalamic nucleus. In HD, a phase I trial in 6 patients with intraventricular injections of encapsulated xenograft producing human ciliary neurotrophic factor (CNTF) also has been completed (Bloch et al., 2004). No clinical improvement or adverse events were noted; rates of CNTF secretion of the explanted cells were relatively low. Ineffective ex vivo delivery and successes with in vivo delivery in PD have prompted preclinical focus on viral vectors. Specifically, AAV–GDNF via striatal injection in transgenic HD mice improved behavioral and pathological outcome (McBride et al., 2006). In AD, studies with nerve growth factor (NGF) began with an intraventricular trial (Eriksdotter et al., 1998). The next trial examined fibroblasts, manipulated ex vivo to produce NGF, that were injected into the basal forebrain of 8 patients with mild AD (Tuszynski

INTRODUCTION Surgical approaches being investigated for the treatment of neurodegenerative diseases focus on neurotransplantation and neuromodulation (Figures 84.1, 84.2). The majority of this work has focused on Parkinson’s disease (PD), beginning with implantation of chromaffin cells and progressing to fetal mesencephalic transplants. Both had disappointing results, and even more disappointing side effects of debilitating “off” state dyskinesias (Freed et al., 2001). An alternate dopaminergic strategy with pigmented epithelial cells is now in phase II investigation (Stover et al., 2005). Transplantation studies in Huntington’s disease (HD) are on-going. In a pilot study, human fetal neuroblasts were transplanted in striata and 3 of 5 patients showed increased metabolic activity on FDG-PET, with concurrent motor, psychiatric, and functional benefit; these effects faded at 4–6 year follow-up (Bachoud-Levi et al., 2006). The phase II data are being collected; interestingly 5 of 13 patients with grafts developed HLA I antibodies to donor antigens and one developed rejection (Krystkowiak et al., 2007). Owing to ethical, availability, and immunological issues, it is unlikely that fetal tissue is feasible for generalized therapy. Embryonic stem cells (ESC), neural progenitor cells (NPC), and somatic stem cells (SC) from different sources are being evaluated. Despite promising results in vitro and in models, ESC and NPC cellular therapy remains a laboratory endeavor

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Cell-based strategies

Parthenogenetic

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No benefit in primary endpoint 2 phase II trials in PD Phase 2 trial on-going in HD

Human retinal pigment epithelium (L-DOPA producing) in PD Phase 2 trial in progress

Adult neural progenitor cells

Embryonic

Hematopoietic (Bone marrow or umbilical cord blood)

NPCs improve motor recovery in HD rats and PD models

ESC improve outcome in transgenic AD mice and PD models

Improved outcome in transgenic AD mice and PD models

FIGURE 84.1

Preclinical and clinical cellular transplantation strategies in neurodegenerative diseases

Neurotrophic factors Alternative strategies Preclinical improvements in outcome in transgenic AD mice with immune and RNAi therapies

Intraventricular (infusion-based) Poor success in clinical trials for PD/HD/AD multiple side effects

Intraparenchymal (vector-based)

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Preclinical improvements in outcome in transgenic HD mice with RNAi therapy

Ex vivo transfection

In vivo transfection

NGF via autologous fibroblasts in AD CNTF via encapsulated xenograft in HD

Clinical trials in progress in PD Phase II with AAV–neurturin Phase I with AADC and GAD Preclinical in HD with GDNF Clinical trial AAV–NGF in AD

FIGURE 84.2

Preclinical and clinical cellular transplantation strategies in neurodegenerative diseases

et al., 2005). The rate of cognitive decline was significantly reduced and FDG cortical uptake significantly improved. Autopsy of one patient revealed NGF graft expression and sprouting of cholinergic axons. An AAV–NGF trial is under way. In the preclinical arena, AD restorative therapies have focused on reducing the amyloid beta (Aβ) burden, resulting in clinical trials of Aβ vaccination. This trial resulted in side effects, which may be averted with hippocampal AAV-anti Aβ antibodies, shown in transgenic mice to reduce Aβ burdens (Fukuchi et al., 2006). Studies in HD transgenic mice demonstrated that RNA interference (RNAi) induced by short hairpin RNA (shRNA), i.e. an RNA-guided mechanism for inhibition of gene expression, reduced mutant huntingtin (htt) expression and improved behavioral outcomes (Harper et al., 2005). In the future, more upstream

events will likely be targeted as in vitro work has demonstrated that RNAi-mediated alteration of a chaperonin affects htt aggregation (Kitamura et al., 2006). Many advances in viral-based vectors for gene delivery and cell replacement therapies have been achieved. However, improvements are still needed for safe and efficient therapies. Combinations of cell and gene therapy to create an optimal environment for recovery or neuroprotection may be required.

References Bachoud-Levi, A.C., Gaura, V., Brugieres, P. et al. (2006) Effect of fetal neural transplants in patients with Huntington’s disease 6 years after surgery: a long-term follow-up study. Lancet Neurol. 5: 303–9. Bloch, J., Bachoud-Levi, A.C., Deglon, N. et al. (2004) Neuroprotective gene therapy for Huntington’s disease, using polymerencapsulated cells engineered to secrete human ciliary neurotrophic factor: results of a phase I study. Hum. Gene Ther. 15: 968–75.

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REFERENCES

Carson, C.T., Aigner, S. and Gage, F.H. (2006) Stem cells: the good, bad, and barely in control. Nat. Med. 12 (11): 1237–8. Eriksdotter, J.M. et al. (1998) Intracerebroventricular infusion of nerve growth factor in three patients with Alzheimer’s disease. Dement. Geriatr. Cogn. Disord. 9: 246–57. Freed, C.R., Greene, P.E., Breeze, R.E. et al. (2001) Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N. Engl. J. Med. 344: 710–19. Fukuchi, K., Tahara, K., Kim, H.D. et al. (2006) Anti-Abeta singlechain antibody delivery via adeno-associated virus for treatment of Alzheimer’s disease. Neurobiol. Dis. 23: 502–11. Harper, S.Q., Staber, P.D., He, X. et al. (2005) RNA interference improves motor and neuropathological abnormalities in a Huntington’s disease mouse model. Proc. Natl Acad. Sci. USA, 102: 5820–5. Kitamura, A., Kubota, H., Pack, C.G. et al. (2006) Cytosolic chaperonin prevents polyglutamine toxicity with altering the aggregation state. Nat. Cell Biol. 8: 1163–70. Krystkowiak, P., Gaura, V., Labalette, M. et al. (2007) Alloimmunisation to donor antigens and immune rejection following foetal neural

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grafts to the brain in patients with Huntington’s disease. PLoS ONE 2: e166. Lang, A.E., Gill, S., Patel, N.K. et al. (2006) Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann. Neurol. 59: 459–66. McBride, J.L., Ramaswamy, S., Gasmi, M. et al. (2006) Viral delivery of glial cell line-derived neurotrophic factor improves behavior and protects striatal neurons in a mouse model of Huntington’s disease. Proc. Natl Acad. Sci. USA 103: 9345–50. Nutt, J.G., Burchiel, K.J., Comella, C.L. et al. (2003) Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology 60: 69–73. Stover, N.P., Bakay, R.A.E., Subramanian, T. et al. (2005) Intrastriatal implantation of human retinal pigment epithelial cells attached to microcarriers in advanced Parkinson disease. Arch. Neurol. 62: 1833–7. Tuszynski, M.H., Thal, L., Pay, M. et al. (2005) A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat. Med. 11: 551–5.

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S E C T I O N   XI

Neuromodulation Device Implant Techniques Introduction Elliot S. Krames No reference work on neuromodulation would be complete without some discussion of techniques of implantation and Section XI is dedicated to this topic. Implantation techniques belong to multiple specialties depending on the area of implantation. Obviously implantation of neurostimulation devices into the brain (DBS) or on the brain (MCS) belong to neurosurgery while implantation of neurostimulation devices over the spinal cord, over and around nerves, and subcutaneously belong to multiple specialties including but not limited to neurosurgery, anesthesia, and pain medicine. This section has something for everyone. The chapters include: “Deep Brain Stimulation: Surgical Technique” by Drs Andre Machado and Ali Rezai, of the Department of Neurosurgery at the Cleveland Clinic, Cleveland, Ohio, and Dr Alon Mogilner of the Department of Neurosurgery of the North Shore Long Island Jewish Hospital, New York; “Spinal Cord Stimulation: Placement of Surgical Leads via Laminotomy – Techniques and

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Benefits” by a Canadian team of Krishna Kumar, FRCS (C), FACS, Goran Lind, MD, Jaleh Winter, RN, Shivani Gupta, MD, and Sharon Bishop, BNurs, MHSci, with Dr Bengt Linderoth of Stockholm, Sweden; “Techniques for Peripheral Nerve Stimulation Implantation” by Dr Michael Stanton-Hicks of the Cleveland Clinic, Cleveland, Ohio; “Techniques for Subcutaneous Peripheral Nerve Field Stimulation for Intractable Pain” by Dr Giancarlo Barolat, Past President of the INS and Director of the Barolat Institute of Denver, Colorado; “Surgical Placement of Leads for Occipital Nerve Stimulation” by Dr Richard Weiner, Chairman, Department of Neurosurgery, Presbyterian Hospital of Dallas, Texas; and “Surgical Technique for Intrathecal Medication Delivery System Implantation”, by Joshua Rosenow, and “Surgical Technique for Vagus Nerve Stimulator Implantation” by Jeffrey W. Cozzens, both from the Department of Neurosurgery, Northwestern University Feinberg School of Medicine, Evanston, Illinois.

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85 Deep Brain Stimulation: Surgical Technique Andre G. Machado, Alon Y. Mogilner, and Ali R. Rezai

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INTRODUCTION

through a microelectrode (microstimulation), the DBS electrode (macrostimulation), or both. Both traditional stereotactic frames as well as newer so-called “frameless” systems, which utilize a small number of fiducial markers screwed directly into the cranium, can be used. Stereotactic targeting can be accomplished in a number of commercially available navigation systems using reformatted stereotactic imaging sets. Targets can be identified with indirect or direct methods, although a combination of these is often preferred (Zonenshayn et al., 2000). Surgical implantation of implantable pulse generators (IPG) and DBS lead(s) can be completed on the same day or as staged procedures. Programming the IPGs can be considered a continuation of surgery and influences outcomes. It is safe to say, regardless of the disease entity, that accurate lead placement is most likely to yield the best clinical results with less complex programming.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus pars interna (GPi) is currently indicated for the treatment of motor symptoms of advanced Parkinson’s disease (PD). Stimulation of the ventral intermediate nucleus of the thalamus is aimed at alleviation of essential tremor while DBS of the GPi is considered beneficial for the treatment of medically refractory dystonia. Although there are reports of successful DBS surgery performed completely under general anesthesia (Vayssiere et al., 2000), DBS is typically performed under conscious sedation or local anesthesia, in order to provide awake physiologic confirmation of the target. Physiologic confirmation of the target can be achieved via microelectrode recording (MER), usually combined with direct stimulation of the target either

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One of the fundamental advantages of DBS over lesioning procedures such as pallidotomy or thalamotomy is reversibility. As with most neuromodulation technologies, stimulation related side effects can be reversed. When programming alone cannot achieve the desired benefits without unacceptable adverse effects, re-implantation of the electrode is an option. Several reports have discussed in detail the target-specific surgical and microelectrode recording techniques for the surgical treatment of movement disorders (Kelly, 1980; Kelly et al., 1987; Bakay et al., 1997; Lozano et al., 1997; Lozano et al., 1998; Starr et al., 1998; Vitek et al., 1998; Hariz and Fodstad, 1999a; Lombardi et al., 2000; Zonenshayn et al., 2000; Benazzouz et al., 2002; Lozano and Hutchison, 2002; Pollak et al., 2002; Sterio et al., 2002; Priori et al., 2003; Coenen et al., 2004; AndradeSouza et al., 2005; Hamani et al., 2005; Chen et al., 2006; Gross et al., 2006; Machado et al., 2006; Rezai et al., 2006; Starr et al., 2006; Levy et al., 2007). The purpose of this chapter is to briefly discuss the overall techniques for DBS surgery.

STEREOTACTIC FRAME OR FRAMELESS PROCEDURE There are several stereotactic headframe and arc systems available and the choice depends largely on the surgeon’s experience and preference. Figure 85.1 shows the Leksell (Elekta, Stockholm) stereotactic headframe and arc system fully assembled, as used in DBS implantation surgery. The headframe is placed usually on the morning of the surgical procedure with the patient awake or sedated and the scalp is anesthetized at each pin site with local anesthetics. The canthal–meathal line can be used as a reference to align the frame as parallel as possible to the anterior commissure – posterior commissure (AC–PC) plane. In addition, care should be taken to avoid any roll, pitch, or yaw with the placement as this care will minimize errors when changing the coordinates for additional electrode penetrations during surgery. After placement of the headframe, computerized tomography (CT) and/or magnetic resonance images (MRI) are acquired with a localization device attached to the frame. The stereotactic fiducials become part of the imaging data set and from that moment on, planning and stereotactic localization will rely on the constant stability of the frame in relation to the patient’s head. So-called “frameless” stereotactic devices are now approved by the Food and Drug Administration (FDA) for use in the USA and are a valid alternative to traditional frame-based stereotaxis. The expected

FIGURE 85.1 Elekta G model headframe and arc, assembled as used in DBS surgery. The headframe is secured to the skull using sharp pins. The stereotactic images are acquired with the fiducial box loaded on the headframe. In the operating room the arc is assembled on the headframe and set to the planned stereotactic coordinates

advantages of these systems include less discomfort associated with the frame placement, as well as the ability to obtain imaging studies and perform the majority of the surgical targeting in the days prior to the actual surgery, thus potentially decreasing surgical time. Frameless devices are also indicated for patients with severe kyphotic deformities that preclude CT/ MRI image acquisition with a frame in place. These potential advantages have to be weighed against the less robust plastic disposable frameless equipment. Costs may vary regionally but the frame typically represents a large one-time capital expense that can be applied repeatedly for several years (with maintenance) while the frameless disposable system adds significant cost to each individual surgery. The reference system used for frameless surgery consists of at least four skull fiducials typically implanted in the office setting under local anesthesia in the day(s) preceding surgery. A stab wound is created with a scalpel and the fiducial’s self-tapping screw is fixed to the skull.

PREOPERATIVE IMAGING MRI is the imaging modality of choice in stereotactic targeting and planning, allowing for accurate

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AC

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(B)

FIGURE 85.2 The AC (arrowhead) and PC (arrow) are shown in (A) axial and (B) sagittal views. The midpoint of the line traced between these two landmarks is the midcommissural point

identification of the anterior commissure (AC) and posterior commissure (PC) (Figure 85.2) and direct identification of targets or landmarks. However, magnetic distortion may hamper the geometry of the stereotactic space. Our preference is to acquire the MRI in the weeks that precede surgery and then fuse the images to a stereotactic CT scan obtained on the day of surgery. The objective is to benefit from the excellent resolution of MR images while relying on CT for stereotactic accuracy. CT-based stereotaxis may be the only option in patients with implantable cardiac pacemakers/defibrillators, in which indirect AC–PC-based targeting (see below) is the primary targeting method.

TARGET LOCALIZATION Determining the initial stereotactic target is a crucial decision that is likely to influence the surgical outcome, operative time, and safety. The target can be localized either by directly identifying the structure in the preoperative images (Figures 85.3 and 85.4) or indirectly. Indirect targeting relies on coordinates referenced to the midcommissural point (the midpoint of the AC–PC line) or on atlas-based outlines of subcortical structures fused and reformatted to fit the patient’s preoperative images (Figure 85.5). For example, typical coordinates for targeting the subthalamic nucleus are 11–13 mm lateral to the midline, 3–4 mm posterior to

FIGURE 85.3 The subthalamic nucleus can be visualized on an axial T2 view (arrow). Note the red nucleus medial and posterior to the STN. The anterior border of the red nucleus serves as an anterior–posterior reference for selecting the STN target (line). The images were acquired as volumetric coronal T2 scans and then reformatted to the axial view

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FIGURE 85.4 The globus pallidus is seen on preoperative IR scans (arrow). The genu and posterior limb of the internal capsule serve as a reference for the medial border of the posterior GPi. The target for pallidotomies is defined in the posterior-ventral region. However, DBS electrodes may be implanted more anteriorly to allow for current spread within the nucleus without affecting the internal capsule fibers medially

the midcommissural point and 4–5 mm inferior to the intercommissural plane. In practice, we utilize a combination of indirect targeting methods and direct visualization of the nucleus to determine the final stereotactic target. In addition, other regional anatomic structures such as the red nucleus (Figure 85.3), substantia nigra, and the optic tract (Figure 85.6) can be visualized and serve as landmarks for localization (Starr et al., 2002, 2006; Theodosopoulos et al., 2003). Once the target is defined, the entry point and angle of approach are determined. We prefer to use contrast-enhanced volumetric T1 image sets to facilitate visualization of intracranial vessels to be avoided in the planned trajectories. Typically, an entry point is selected at or just anterior to the coronal suture at an angle that is approximately 10–20 degrees from the parasagittal plane. The trajectory is altered in such a way as to avoid sulci, the lateral ventricles, periventricular vessels or any large vessels highlighted by gadolinium enhancement in order to prevent hemorrhagic complications.

FIGURE 85.5 The Schaltenbrand and Wahren atlas is loaded on commercially available computerized planning stations and can be overlaid on the patient’s MR or CT images. The atlas can then be reformatted to attempt to fit the patient’s anatomy. Current systems allow only for two-dimensional adjustments in height and width. Due to this limitation, it is often not possible to “fit” the atlas contours correctly on all basal ganglia and diencephalic structures. In this sagittal view, a characteristic trajectory to the subthalamic nucleus is seen, crossing the anterior thalamus and then the zona incerta before reaching the STN. Note that although the optimal region for stimulation is likely to be the dorsal STN, the target is defined on the ventralposterior aspect of the nucleus. In this fashion, the DBS electrode’s tip is placed at the ventral region while the more proximal contacts flank the dorsal subthalamic region for chronic stimulation

FIGURE 85.6

The optic tract (arrow) is an important landmark for targeting the GPi. It is located ventral to the nucleus and can be identified during microelectrode recordings. Light stimulation can elicit visually evoked responses and microstimulation may elicit phosphenes in the patient’s visual field. Identification of the optic tract during MER corroborates the anatomical targeting of the GPi

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THE SURGICAL PROCEDURE The patient is positioned supine and the head frame is fixed to the table. In the case of frameless surgery, a modified rigid cervical collar is used to support the patient’s neck and head while maintaining access to the surgical site and skull fiducials. The patient’s feedback is solicited to find the neck in a position that is well tolerated. Sedation is initiated for exposing and drilling the burr-hole(s) and setting up the stereotactic apparatus. In general, we prefer to perform the subsequent physiological localization of the subcortical target after recovering the patient from sedation to optimize the data from microelectrode recordings and to obtain the best patient feedback during macrostimulation. Tight blood pressure control (systolic blood pressure 130 mmHg) is helpful to minimize the risk of intracranial hemorrhage. We prefer to drill the burr-holes coaxial to the planned stereotactic trajectory and not perpendicular to the skull. In this fashion the inner and outer rims of the burr-hole are equally aligned, preventing cannula deflection from the bone edges. The dura mater is opened and the pia and arachnoid are coagulated and opened to facilitate the penetration of the cannula without resistance. The electrodes are inserted to a predetermined offset dorsal to the final target. We utilize Gelfoam and/or fibrin glue around the cannula in the burr-hole to prevent CSF loss and subsequent pneumocephalus and brain shift. Figure 85.7 illustrates the stereotactic assembly of a frame-based procedure. When using a frameless device, the apparatus is assembled on a base that is fixed to the skull with self-tapping screws (Figure 85.8). The burr-hole continues to be accessible from the sides but the working window is reduced (Figure 85.9).

MICROELECTRODE RECORDINGS A hydraulic or electrical microdrive is used to advance the microelectrode in submillimetric steps. Microelectrode recording (MER) is started at the offset determined location dorsal to the final target. We usually begin MER 15–20 mm above the target. Several strategies exist for MER, with the goal always being to add intraoperative physiological information to the preoperative plan based on direct and indirect targeting (Bakay et al., 1997; Gross et al., 1999; Hariz and Fodstad, 1999b; Benazzouz et al., 2002; Pollak et al., 2002; Starr, 2002; Sterio et al., 2002; Gross et al., 2006; Rezai et al., 2006; Levy et al., 2007; Moyer et al., 2007).

FIGURE 85.7 In the frame-based procedure, the microdrive is assembled on the stereotactic arc. The cannula (arrow) is passed through the drive into the opened surface of pia mater and the microelectrode inserted (arrow head). The electrode is then connected by the active, reference and ground cables, which should not touch to prevent shorts or noise

In the case of subthalamic DBS implantation, for example, MER can demonstrate that the trajectory had a long course through the sensorimotor territory of the STN, corroborating the anatomical plan. If shorter segments of the nucleus are identified, the trajectory is likely to be near one of the borders of the nucleus. Microstimulation, i.e. direct stimulation through the microelectrode used for recording, can add additional information via stimulation evoked paresthesiae or focal motor contractures which indicate the relative position of the trajectory within the nucleus due to stimulation of the medial lemniscus or the corticobulbar/corticospinal tracts, respectively. MER and microstimulation are also used for confirmation and refinement of anatomical localization when targeting the thalamus or the GPi for the treatment of tremor, dystonia or PD. MER systems can accommodate multiple electrodes in parallel (Benazzouz et al., 2002; Pollak et al., 2002). However, we choose to use single electrodes in a serial fashion, so that only one signal needs to be interpreted at a given time.

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FIGURE 85.9 The frameless stereotactic device occupies most of the burr-hole exposure. There is limited lateral access to the burrhole, which can be used to add fibrin glue after each penetration to limit CSF loss and control any superficial bleeding

FIGURE 85.8 The Medtronic NexFrame system is shown. It is composed of a plastic base that is centered on the burr-hole and fixed to the skull with self-tapping screws. The fiducials are registered and the base aligned and locked to the planned trajectory, aiming at the desired target. The microdrive (black arrow) is assembled on the base (white arrow) and the cannula-microelectrode systems inserted in a similar fashion to frame-based procedures

ELECTRODE IMPLANTATION AND FIXATION In surgical targets used for the treatment of movement disorders, the most distal (closest to the tip) contact of the quadripolar electrode (contact 0) is positioned at the physiologically defined ventral border of the nucleus. The coronal burr-hole determines a trajectory that is dorsal-medial and anteroposterior. In this fashion, the remaining contacts will span for 10.5 mm (model 3387, Medtronic, Minneapolis, MN) or 7.5 mm (model 3389). Once implanted, macrostimulation is initiated with an external pulse generator. Test electrical stimulation through the implanted DBS electrode (macrostimulation) with clinically therapeutic parameters is important to confirm that the implant site will yield good clinical results.

Alleviation of some symptoms such as tremor and rigidity can be observed with intraoperative test macrostimulation but others may only improve with chronic stimulation. Identifying the thresholds to side effects such as motor phenomena (contracture of the face/hand, conjugate ocular deviation, dysarthria), ipsilateral ocular deviation, uncomfortable and persistent paresthesiae or visual phosphenes during macrostimulation is just as important as identifying clinical benefits. Side effects observed during intraoperative macrostimulation are likely to be reproduced during postoperative programming at possibly lower thresholds. Identification of side effects at low thresholds may indicate the need to replace the DBS electrode at another location. Typical intraoperative macrostimulation parameters mirror settings used for chronic stimulation: 1–5 V, 90 ms PW, 130 Hz. Once the final DBS electrode location is determined, the electrode is fixed to the burrhole in a stable fashion. Today, each DBS electrode is provided with a burr-hole anchoring device (StimLoc, Medtronic, Minneapolis, MN), which is fixed to the skull with self-tapping screws and then clips the electrode in position. Fluoroscopy can be useful to ensure that there is no change in electrode position while the mechanical stereotactic apparatus is disassembled around the lead (Figure 85.10). The distal tip of the electrode is then coiled with the rest of the excess electrode in the subgaleal space, where it will be found again at the time of IPG implantation. The tip has electrical contacts and should not be left unprotected but, rather, covered by a connector or plug.

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IPG IMPLANTATION The IPG is typically implanted in the infraclavicular region and connected to the DBS lead with an extension wire. In patients with thin subcutaneous tissue, the IPG can be implanted under the pectoral fascia, adding one more layer to prevent erosion of the hardware. Currently, there are two types of available IPGs: single channel (Medtronic Soletra) and dual channel (Medtronic Kinetra). This part of the procedure is performed under general anesthesia due to the need to tunnel through subcutaneous tissue from the head to the chest. A subcutaneous pocket is created for the IPG in the infraclavicular region and a small incision is opened where the distal tip of the electrode was placed at the end of the DBS lead implantation procedure. The proximal end of the extension wire is connected to the DBS electrode and the distal part is connected to the IPG, which is internalized in the subcutaneous pocket. The connector between the DBS electrode and the extension wire should not be tunneled to the neck because, in our experience, it is associated with a high rate of failure of the DBS electrode (see below, “Complications”). Rather, the connector should be placed not lower than the retroauricular region or mastoid. In that fashion, the excess DBS lead is left cranial to the connector in the subgaleal space.

COMPLICATIONS DBS-related complications can be divided in two groups: (a) implantation- and hardware-related and (b) stimulation-related. The most serious complications related to implantation of the electrodes are intracerebral hemorrhages that can be associated with serious neurological deficits such as hemiplegia and cognitive decline. Intracranial hemorrhage can result from direct trauma to arterial vessels, or in a delayed fashion, secondary to venous infarction, which may occur when a large surface vein is coagulated following the dural opening. Strict blood pressure control in the intraoperative and perioperative period is thought to minimize the possibility of an arterial hemorrhage. Rarely, a subdural hematoma may present in subacute to chronic fashion, days to weeks following implantation. In the immediate postoperative period, particularly with bilateral STN implantation, transient confusion may occur, which is perhaps more common in older patients. While these symptoms are usually transient, many surgical teams prefer to stage bilateral implantations in older patients to minimize any permanent cognitive/behavioral worsening.

FIGURE 85.10 Fluoroscopy is aligned to the lateral view prior to implantation of the electrode. The electrode’s tip should be centered in the cross hairs or a deflection may have occurred. While disassembling the microdrive, we use repeat fluoroscopy images to ascertain that the electrode was not dislodged

Infections are most commonly associated with the IPG implant and not the DBS electrode itself. Although complete removal of the DBS system may be necessary to successfully treat the infection and prevent intracerebral progression, it has been shown that some infections can be treated after removal of the distal segments only (IPG and extension wire) while preserving the DBS electrode (Sillay et al., 2008). This allows for future connection of the electrode to a new extension and IPG once the infection is clear without the need for a repeat stereotactic procedure. Wound erosion may occur in a delayed fashion, either over the cranial incision or the IPG site. Wound erosion resulting in exposed hardware will lead to a wound infection, and thus prompt recognition and surgical repair is indicated. Occasionally, scalp rotation flaps may be necessary in cases of wound erosion (Spiotta et al., 2008). DBS lead fracture or extension lead fracture may occur. Typically, the patient may complain of either loss of stimulation efficacy, or a shock-like sensation in the scalp and contralateral extremities. Abnormally high impedance measurements are consistent with an open circuit, either due to lead fracture or extension lead fracture. While X-rays may occasionally show a disconnection, the combination of the above clinical signs with abnormal impedance values indicate the need for replacement of the malfunctioning component. The IPG itself is rarely the source of a malfunction other than the expected battery end-of-life. Abrupt cessation of stimulation secondary to IPG battery end-of-life may result in severe symptomatic exacerbation in the PD patient, and thus continued monitoring of battery voltage and prophylactic replacement are preferred.

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Stimulation-dependent adverse events are common. In fact, most patients will experience some side effects while programming the IPGs at high amplitudes. Well-located electrodes produce good clinical improvements at low amplitudes with high thresholds for side effects.

PROGRAMMING Programming is usually done as an outpatient. Due to the possibility of a “microlesion effect,” i.e. transient improvement in symptomatology just from electrode placement, initial programming is usually delayed a number of days or weeks until the patient has returned to the symptomatic baseline. Patients with PD should be initially programmed in the “Off”medication state in order to easily observe the effects of stimulation. The process is methodical and the goal is to identify which contact/s and stimulation parameters produce the best clinical results without side effects. We initiate this process with a monopolar survey of each contact, evaluating the effects and adverse effects observed at each stepwise increment in amplitude. Typical parameters of stimulation include high frequency (130 Hz), pulse widths ranging from 90 to 120 μs (longer pulses may be used in the GPi) in either monopolar or bipolar settings. DBS programming for PD and movement disorders can have many nuances (Kumar, 2002; Volkmann et al., 2002, 2006; Hunka et al., 2005; Stewart et al., 2005) that are beyond the scope of this procedural chapter.

References Andrade-Souza, Y.M., Schwalb, J.M., Hamani, C., Eltahawy, H., Hoque, T., Saint-Cyr, J. et al. (2005) Comparison of three methods of targeting the subthalamic nucleus for chronic stimulation in Parkinson’s disease. Neurosurgery 56: 360–8, discussion 368. Bakay, R.A., Starr, P.A., Vitek, J.L. and DeLong, M.R. (1997) Posterior ventral pallidotomy: techniques and theoretical considerations. Clin. Neurosurg. 44: 197–210. Benazzouz, A., Breit, S., Koudsie, A. et al. (2002) Intraoperative microrecordings of the subthalamic nucleus in Parkinson’s disease. Mov. Disord. 17 (Suppl. 3): S145–S149. Chen, S.Y., Lee, C.C., Lin, S.H., Hsin, Y.L., Lee, T.W., Yen, P.S. et al. (2006) Microelectrode recording can be a good adjunct in magnetic resonance image-directed subthalamic nucleus DBS for parkinsonism. Surg. Neurol. 65: 253–60, discussion 260-1. Coenen, V.A., Gielen, F., Rohde, I., Fromm, C., Kronenbürger, M., Dammert, S. et al. (2004) Subthalamic nucleus stimulation for advanced Parkinson’s disease: how to find a far medial STN. Minim. Invas. Neurosurg. 47: 373–7. Gross, R.E., Krack, P., Rodriguez-Oroz, M.C., Rezai, A.R., Benabid, A.L. et al. (2006) Electrophysiological mapping for the implantation of deep brain stimulators for Parkinson’s disease and tremor. Mov. Disord. 21 (Suppl. 14): S259–S283.

Gross, R.E., Lombardi, W.J., Hutchison, W.D., Narula, S., Saint-Cyr, J.A., Dostrovsky, J.O. et al. (1999) Variability in lesion location after microelectrode-guided pallidotomy for Parkinson’s disease: anatomical, physiological, and technical factors that determine lesion distribution. J. Neurosurg. 90: 468–77. Hamani, C., Richter, E.O., Andrade-Souza, Y., Hutchison, W., Saint-Cyr, J.A. and Lozano, A.M. (2005) Correspondence of microelectrode mapping with magnetic resonance imaging for subthalamic nucleus procedures. Surg. Neurol. 63: 249–53, discussion 253. Hariz, M. and Fodstad, H. (1999a) Do microelectrode techniques increase accuracy or decrease risks in pallidotomy and DBS. Stereotact. Funct. Neurosurg. 72: 157–69. Hariz, M.I. and Fodstad, H. (1999b) Do microelectrode techniques increase accuracy or decrease risks in pallidotomy and DBS? A critical review of the literature. Stereotact. Funct. Neurosurg. 72: 157–69. Hunka, K., Suchowersky, O., Wood, S., Derwent, L. and Kiss, Z. (2005) Nursing time to program and assess deep brain stimulators in movement disorder patients. J. Neurosci. Nurs. 37: 204–10. Kelly, P.J. (1980) Microelectrode recording for the somatotopic placement of stereotactic thalamic lesions in the treatment of parkinsonian and cerebellar intention tremor. Appl. Neurophysiol. 43: 262–6. Kelly, P.J., Kail, B.A., Goerss, S.J. and Earnest, F. (1987) Computerassisted stereotactic ventralis lateralis thalamotomy with microelectrode recording control in patients with Parkinson’s disease. Mayo Clin. Proc. 62: 655–64. Kumar, R. (2002) Methods for programming and patient management with DBS of the globus pallidus for the treatment of advanced Parkinson’s disease and dystonia. Mov. Disord. 17 (Suppl. 3): S198–S207. Levy, R., Lozano, A.M., Hutchison, W.D. and Dostrovsky, J.O. (2007) Dual microelectrode technique for deep brain stereotactic surgery in humans. Neurosurgery 60: 277–83, discussion 283-4. Lombardi, W.J., Gross, R.E., Trepanier, L.L., Lang, A.E., Lozano, A.M. and Saint-Cyr, J.A. (2000) Relationship of lesion location to cognitive outcome following microelectrode-guided pallidotomy for Parkinson’s disease: support for the existence of cognitive circuits in the human pallidum. Brain 123 (Pt 4): 746–58. Lozano, A.M. and Hutchison, W.D. (2002) Microelectrode recordings in the pallidum. Mov. Disord. 17 (Suppl. 3): S150–S154. Lozano, A.M., Hutchison, W.D., Tasker, R.R., Lang, A.E., Junn, F. and Dostrovsky, J.O. (1998) Microelectrode recordings define the ventral posteromedial pallidotomy target. Stereotact. Funct. Neurosurg. 71: 153–63. Lozano, A.M., Lang, A.E., Hutchison, W.D. and Dostrovsky, J.O. (1997) Microelectrode recording-guided posteroventral pallidotomy in patients with Parkinson’s disease. Adv. Neurol. 74: 167–74. Machado, A., Rezai, A.R., Kopell, B.H., Gross, R.E., Sharan, A.D. and Benabid, A.L. (2006) DBS for Parkinson’s disease: surgical technique and perioperative management. Mov. Disord. 21: S247–S258. Moyer, J.T., Danish, S.F., Keating, J.G., Finkel, L.H., Baltuch, G.H. and Jaggi, J.L. (2007) Implementation of dual simultaneous microelectrode recording systems during DBS surgery for Parkinson’s disease: technical note. Neurosurgery 60: ONSE177– 78, discussion ONSE178. Pollak, P., Krack, P., Fraix, V., Mendes, A., Moro, E., Chabardes, S. et al. (2002) Intraoperative micro- and macrostimulation of the subthalamic nucleus in Parkinson’s disease. Mov. Disord. 17 (Suppl. 3): S155–S161. Priori, A., Egidi, M., Pesenti, A., Rohr, M., Rampini, P., Locatelli, M. et al. (2003) Do intraoperative microrecordings improve

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REFERENCES

subthalamic nucleus targeting in stereotactic neurosurgery for Parkinson’s disease? J. Neurosurg. Sci. 47: 56–60. Rezai, A.R., Kopell, B.H., Gross, R.E., Vitek, J.L., Sharan, A.D., Limousin, P. et al. (2006) DBS for Parkinson’s disease: surgical issues. Mov. Disord. 21 (Suppl. 14): S197–S218. Sillay, K.A., Larson, P. and Starr, P. (2008) Deep brain stimulator hardware-related infections: incidence and management in a large series. Neurosurgery 62: 360–6, discussion 366–7. Spiotta, A.M., Bain, M.D., Deogaonkar, M., Boulis, N.M., Rezai, A.R., Hammert, W. and Lucas, A.R. (2008) Methods of scalp revision for deep brain stimulator hardware: case report. Neurosurgery 62: 249–50, discussion 250. Starr, P.A. (2002) Placement of deep brain stimulators into the subthalamic nucleus or globus pallidus internus: technical approach. Stereotact. Funct. Neurosurg. 79: 118–45. Starr, P.A., Christine, C.W., Theodosopoulos, P.V., Lindsey, N., Byrd, D. and Mosley, A. (2002) Implantation of deep brain stimulators into the subthalamic nucleus: technical approach and magnetic resonance imaging-verified lead locations. J. Neurosurg. 97: 370–87. Starr, P.A., Turner, R.S., Rau, G., Lindsey, N., Heath, S., Volz, M. et al. (2006) Microelectrode-guided implantation of deep brain stimulators into the globus pallidus internus for dystonia: techniques, electrode locations, and outcomes. J. Neurosurg. 104: 488–501. Starr, P.A., Vitek, J.L. and Bakay, R.A. (1998) Ablative surgery and DBS for Parkinson’s disease. Neurosurgery 43: 989–1013, discussion 1013–15.

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Sterio, D., Zonenshayn, M., Mogilner, A.Y., Rezai, A.R., Kiprovski, K., Kelly, P. et al. (2002) Neurophysiological refinement of subthalamic nucleus targeting. Neurosurgery 50: 58–67, discussion 67–9. Stewart, R.M., Desaloms, J.M. and Sanghera, M.K. (2005) Stimulation of the subthalamic nucleus for the treatment of Parkinson’s disease: postoperative management, programming, and rehabilitation. J. Neurosci. Nurs. 37: 108–14. Theodosopoulos, P.V., Marks, W.J., Jr, Christine, C. and Starr, P.A. (2003) Locations of movement-related cells in the human subthalamic nucleus in Parkinson’s disease. Mov. Disord. 18: 791–8. Vayssiere, N., Hemm, S., Zanca, M., Picot, M.C., Bonafe, A., Cif, L. et al. (2000) Magnetic resonance imaging stereotactic target localization for DBS in dystonic children. J. Neurosurg. 93: 784–90. Vitek, J.L., Bakay, R.A., Freeman, A., Evatt, M., Green, J., McDonald, W. et al. (1998) Microelectrode-guided pallidotomy: technical approach and its application in medically intractable Parkinson’s disease. J. Neurosurg. 88: 1027–43. Volkmann, J., Herzog, J., Kopper, F. and Deuschl, G. (2002) Introduction to the programming of deep brain stimulators. Mov. Disord. 17 (Suppl. 3): S181–S187. Volkmann, J., Moro, E. and Pahwa, R. (2006) Basic algorithms for the programming of DBS in Parkinson’s disease. Mov. Disord. 21 (Suppl. 14): S284–S289. Zonenshayn, M., Sharma, S., Hymes, K., Knopp, E.A., Golfinos, J.G., Zagzag, D. et al. (2000) Comparison of anatomic and neurophysiological methods for subthalamic nucleus targeting. Neurosurgery 47: 282–92, discussion 292–4.

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86 Spinal Cord Stimulation: Placement of Surgical Leads via Laminotomy – Techniques and Benefits Krishna Kumar, Goran Lind, Jaleh Winter, Shivani Gupta, Sharon Bishop, and Bengt Linderoth

O U T L I N E Introduction

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Anesthetic Techniques Local Anesthesia General Anesthesia EMG/SSEP during SCS Implant Surgery Spinal Anesthesia

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INTRODUCTION Since its introduction in 1967 by Shealy et al. (1967), following the publication of the gate control theory two years earlier (Melzak and Wall, 1965), spinal cord stimulation (SCS) has developed into a highly valued part of the armamentarium for the treatment of intractable chronic pain syndromes. SCS is steadily gaining support as a reversible and non-destructive method of pain control and has become an established therapy. The evidence base on the exact mechanism by which SCS relieves pain is still fragmentary (Meyerson and Linderoth, 2000). The electrical impulses from the

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electrodes are thought to activate dorsal column fibers which antidromically transmit the activity to paininhibiting neuronal circuits within the dorsal horn, inducing patient-perceived paresthesia. This occurs as a consequence of the orthodromic activation of the dorsal columns of the spinal cord (Krames, 2001). The electrical fields of SCS can be delivered either via percutaneous (cable) leads that are implanted percutaneously, for example, Pisces-Sigma, Pisces-Quadripolar, Pisces-Octapolar (Medtronic, Inc., Minneapolis, MN); Phase III Linear, (Boston Scientific, Valencia, CA); Quatrode, Octrode (Advanced Neuromodulation Systems, Inc., Plano, TX) or via surgical (paddle) leads

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that are implanted through a small laminotomy, for example, Resume, Symmix, Specify, and Specify 5-6-5 (Medtronic, Inc., Minneapolis, MN); Artisan (Boston Scientific Neurological, Valencia, CA); Lamitrode (Advanced Neuromodulation Systems, Inc., Plano, TX) (Figure 86.1a,b,c). Although percutaneous leads are used more frequently, surgical leads become a necessity in patients in whom anatomy prevents the percutaneous placement of leads; when repeated lead revisions are required due to displacement or fracture; or when change in the distribution of paresthesia occurs that cannot be recaptured with percutaneous lead revision. Surgical leads are also useful in situations when a percutaneous lead fails to achieve the desired paresthesia coverage during trial stimulation. Furthermore, surgical leads have a better survival time than percutaneous leads (Kumar et al., 1998). Surgical leads are also gaining more popularity in situations where axial pain is more predominant than radicular pain. This is primarily due to their superior programming capabilities (Barolat et al., 2001; North et al., 2002). In the early stages of dorsal column and spinal cord stimulation, surgical leads had a larger surface contact area, for example the Myelostat lead (Medtronic, Inc., Minneapolis, MN), which required a laminectomy for its installation. These leads were first placed subdurally and were maintained in position by suturing them to the dura. Later, “endodural” placement was attempted. Both of these techniques were plagued by the complication of cerebrospinal fluid leakage. With advancements in technology, surgical leads have now become thinner and more pliable and can be installed via a small laminotomy, rather than a laminectomy. The present surgical leads allow for steering of the electrical field and therefore optimal paresthesia; they are more stable and less likely to move or fracture, which results in persistent paresthesia coverage of painful areas (Holsheimer et al., 1998; Villavicencio et al., Advanced neuromodulation systems

(A)

Boston scientific

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2000; North et al., 2002; Sharan et al., 2002). Due to these advantages, some centers prefer to use surgical leads as their first choice. Implantation of these leads can be performed using local anesthesia, supplemented by conscious sedation, general anesthesia or spinal anesthesia. In this chapter we describe the surgical technique and outline the pros and cons of the types of anesthesia that can be utilized. We then go on to present our combined case series data to support our partiality for using spinal anesthesia as the preferred method of anesthetic choice. We believe that this case series will demonstrate that this approach is feasible, provides superior outcomes and that intraoperative testing can be performed without problems.

TECHNIQUE Surgical Technique Implantation of a surgical electrode requires a small laminotomy, which can be performed using local anesthesia, supplemented by conscious sedation, general anesthesia or spinal anesthesia. The choice of anesthesia is largely driven by the surgeon’s experience, his or her comfort level, and patient choice. Spinal anesthesia, however, cannot be used for electrode implants above the mid-thoracic level, for obvious reasons. Our patients are placed in the prone position on an operative table, with the torso well padded. A 3–4 cm incision is made in the midline at the desired level of the proposed laminotomy. The most common level at which the laminotomy is done is either T10–11 or T11–12. The spinous process and the lamina of the vertebrae are exposed. A small portion of the lamina and the ligament of flavum is removed (laminotomy) to expose the epidural space. Under fluoroscopic control and after the exposed epidural space is developed/dilated by the introduction of Medtronic inc.

(C)

FIGURE 86.1 A display of different percutaneous and surgical leads from various manufacturers. (A) Advanced Neuromodulation Systems leads; (B) Boston Scientific Neurological leads; (C) Medtronic leads (Reproduced courtesy of ANS, Inc., Boston Scientific, and Medtronic, Inc.)

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manufacturer-provided “hockey-stick” configured dilator/dissector and the manufacturer-provided “dummy” lead, the permanent surgical lead is inserted into the epidural space. Once the lead is in the desired anatomical position, intraoperative testing for concordancy of paresthesia to the patient’s pain is performed. This is done by attaching the lead to an external stimulator outside of the sterile field. Intraoperative testing to ensure concordancy of paresthesia is only possible if the patient is awake and is able to give conscious feedback to the implanter. For this to occur, the procedure must be performed under either local or spinal anesthesia. If negative feedback is provided by the patient that paresthesia is not acceptable, the position of the lead is adjusted within the epidural space until the patient is satisfied that stimulation-induced paresthesia is concordant to their pain, or at least covers 80–90% of the painful area (see Figure 86.2). If local anesthesia is used, when repositioning of the lead takes place, patients may complain of discomfort along the chest wall. If general anesthesia is used, the surgeon will be obliged to rely on the x-ray position

or somatosensory evoked potentials (SSEP)1 to ascertain proper placement. The final position of the lead is then assessed by postero-anterior x-ray or fluoroscopy to ensure that lead deviation, to either side of the midline, has not occurred. Lead deviation may cause root irritation at a later period. The present recommendation (Henderson et al., 2006) is that no anchor be used. Instead, a strain relief loop should be placed in the epifascial plane. If an extension is used, the connector should be placed near the lead, in order to prevent a third point of fixation within the system. The extension can either be externalized for trial stimulation or connected to the implantable pulse generator (IPG). The wound is then closed. It should be noted that placement of the IPG in the buttock region can produce up to a fivefold increase in tensile loading compared to placement in the abdominal wall (Henderson et al., 2006). Therefore, placement of the IPG in the buttock region should be reserved for special clinical situations.

ANESTHETIC TECHNIQUES Local Anesthesia Our drug of choice for local anesthesia is 0.5–1% lidocaine with epinephrine, injected in the skin, the subcutaneous soft tissue, and the paravertebral muscles. To prevent the “burning sensation” caused by the local infiltration of local anesthetic within the dermis and epidermis, we add 5 ml of sodium bicarbonate 7.5%

FIGURE 86.2 Schematic drawing of the surgical procedure for implantation of a surgical lead. Most often, only part of a spinous process, a small part of the lamina and ligament of flavum need to be removed to gain access to the epidural space (Reproduced with permission from Lind et al. (2003). Lippincott, Williams & Wilkins; www.lww.com)

1 Somatosensory evoked potentials (SSEPs) are used in neuromonitoring to asses the function of a patient’s spinal cord during surgery. They are recorded by stimulating peripheral nerves, most commonly the posterior tibial nerve, median nerve or ulnar nerve, typically with an electrical stimulus. The stimulus is then recorded from the patient’s scalp. Because of the low amplitude of the signal once it reaches the patient’s scalp and the relatively high amount of electrical noise caused by background EEG, scalp muscle EMG or electrical devices in the room, the signal must be averaged. The use of averaging improves the signal-to-noise ratio. Typically, in the operating room, over 100 and up to 1000 averages must be used to adequately resolve the evoked potential. The two most looked at aspects of an SSEP are the amplitude and latency of the peaks. The most predominant peaks have been studied and named in labs. Each peak is given a letter and a number in its name. For example, N20 refers to a negative peak (N) at 20 ms. This peak is recorded from the cortex when the median nerve is stimulated. It most likely corresponds to the signal reaching the somatosensory cortex. When used in intraoperative monitoring, the latency and amplitude of the peak relative to the patient’s post-intubation baseline is a crucial piece of information. Dramatic increases in latency or decreases in amplitude are indicators of neurological dysfunction.

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to 80 ml of 0.5% lidocaine. The amount of the anesthetic agent that can be safely used is governed by the patient’s body mass. The anesthesiologist dictates the selection of the drugs used for conscious sedation. In Regina, Canada, propofol (10 mg/ml) 25–50 μg/kg/min is being used for light to moderate sedation. Local anesthesia enables test stimulation for paresthesia during surgery for proper lead placement. However, in our experience the downside of local anesthesia is that the procedure is quite stressful, causes discomfort, and is generally poorly tolerated by many patients.

SCS paddle lead Motor nerve tract

General Anesthesia As an alternative, general anesthesia can be used. The agents administered are at the discretion of the anesthesiologist in attendance. Unfortunately the use of general anesthetic eliminates the opportunity for intraoperative test stimulation and feedback from the patient. In order to overcome this drawback, SSEP can be used to guide proper placement. To the best of our knowledge, the use of SSEP to guide SCS lead placement is not a routine practice. We provide the following synopsis in order to be comprehensive. EMG/SSEP during SCS Implant Surgery* During surgery to implant SCS paddle leads, SSEP data are gathered by stimulating dorsal pathways and recording the resulting signals through electrodes on the scalp. The signals are averaged to distinguish them from sources of electrical noise such as background EEG, EMG, or nearby electrical devices. Changes in the latency or amplitude of the signals can indicate neurological impairment, such as pressure on the spinal cord or nerve roots. High levels of anesthetic gases, such as halogenated agents or nitrous oxide, may affect SSEP signals. EMG signals are produced using needle electrodes placed into muscle tissue within dermatomes targeted for stimulation. After an SCS paddle lead is implanted into the dural space, it is turned on and tested briefly. The resulting stimulation of sensory fibers in the dorsal spinal cord elicits a reflexive motor response, and therefore EMG signals, in specific dermatomes. The signals are considered in light of the active electrodes on the lead and are used to position the lead on the physiological midline of the spinal cord to produce optimal paresthesia coverage.

*

This section was provided by Dr Kenneth Alo’.

Electrode

EMG

FIGURE 86.3 Common sites for EMG electrodes when used to implant an SCS lead to treat low back and legs (Reproduced by permission of Dr Kenneth Alo’)

EMG/SSEP signals are analyzed by computer and displayed as waveforms on a screen. The EMG/SSEP waves may be observed concurrently in separate screen areas, with the EMG waves further divided by dermatome. The shape, height, and length of the waves indicate the strength of their underlying signals and are interpreted by a technician or trained member of the surgical team (Figure 86.3). It must be noted that although a considerable body of literature exists supporting the use of SSEP in other areas of neurosurgery, there is minimal evidence supporting its use to aid the placement of SCS leads. Hallstrom and colleagues (1989, 1991) examined the use of SSEP in awake patients to determine their use in the guidance of proper lead placement during general anesthesia. However, this approach proved impractical, since antidromic responses were extremely sensitive to bodily movement and were also contaminated by simultaneously evoked motor potentials. As a result, SSEP is not a totally reliable means of predicting the postoperative paresthesia coverage. Besides being unreliable, another downside of using of SSEP is

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that it prolongs the procedure and requires the assistance of an electromyographer.

TABLE 86.1 Distribution of patients by diagnosis Diagnoses

No. of patients

Failed back surgery syndrome (FBSS)

7

Spinal Anesthesia

Complex regional pain syndrome (CRPS)

5

Following the publication of Lind and colleagues (2003) of the Karolinska University Hospital, Stockholm, our interest in performing this procedure under spinal anesthesia was aroused. While some colleagues today still remain skeptical, we at the Regina General Hospital have adopted this technique for the past 5 years. The spinal anesthetic agent that is generally used in our institution is bupivacaine, 0.5–0.75%. The dose is dependent upon the body mass of the patient, with a dose range of 12–20 mg. For this procedure, it is our preference to achieve anesthesia up to the T6 level. Typically, the higher the level required, the larger the dose necessary. To provide anesthesia with a prolonged effect, intrathecal fentanyl can be added. It must be noted that when using spinal anesthesia it is still possible to produce stimulation-induced paresthesia to painful areas for proper placement of the lead. Occasionally, supplementary local anesthesia, 1% lidocaine with adrenaline, may be needed in the skin and subcutaneous soft tissue, if the patient complains of pain during skin incision. At both of our institutions, the Regina General Hospital, Regina, Canada, and the Karolinska University Hospital, Stockholm, Sweden, we have found spinal anesthesia to be the preferred method when implanting surgical leads. We present our combined case series data here to demonstrate that this approach is feasible, reliable and is favored by both the surgeon and the patient.

Ilioinguinal neuralgia

3

Diabetic neuropathy

2

Phantom limb pain

1

Ischemic limb pain

1

Spinal cord injury pain

5

Miscellaneous neuropathies

29

LAMINOTOMY-PLACED LEADS UNDER SPINAL ANESTHESIA: THE RESULTS From our combined database, we present data from 53 patients who have undergone an implantation of a surgical lead under spinal anesthesia, supplemented by conscious sedation. The study group consisted of 24 men (45%) and 29 women (55%), with the mean age of 48.4 years (range 14–79 years). Three patients required two procedures to achieve the desired level of pain control, thus 53 patients underwent 56 procedures. The type of lead selected was as follows: 34 Resume (Medtronic, Inc., Minneapolis, MN), 8 Specify (2 4 contacts) (Medtronic, Inc.), 5 Symmix (Medtronic, Inc.), 4 Specify 5-6-5 (16 contacts arranged in three rows) (Medtronic, Inc.), and 1 Artisan (16 contacts arranged in two rows) (Boston Scientific Neurological, Valencia, CA).

The distribution of diagnoses is presented in Table 86.1. FBSS is reported to be the most common indication for SCS, which reflects the findings in this series (Kumar et al., 2006). In 21 of these patients, a surgical lead was used as a primary procedure due to the nature and distribution of the pain or the preference of the surgeon. The other 34 patients had previous percutaneous cable electrodes implanted that had either fractured or required frequent repositioning. The most common level at which laminotomy was done in this series was either T10–11 or T11–12, the highest level being T8–9. The average time taken to do the procedure was 117 minutes (range 44–210 minutes). The spinal anesthetic agent used in our institutions was bupivacaine 0.5–0.75% in all cases. The mean dose was 15.75 mg (range 12–20 mg). In two patients the spinal anesthesia achieved was not high enough to proceed with implantation, therefore a second dose of 7.5 mg of bupivacaine, 0.75%, was administered, which increased the anesthesia to the desired level of T6. To prolong postoperative analgesia, intrathecal fentanyl was added to the spinal anesthesia in 12 of the 56 procedures (Regina Hospital), with a mean dose of 19 μg (range 10–50 μg). In three cases supplementary local anesthesia in the skin and the subcutaneous tissues, using 1% lidocaine with adrenaline, was necessary. The average intraoperative voltage used to obtain stimulation, producing paresthesia which overlapped the painful area, was 3.56 V (range 0.9–6.5 V). The day following implantation, when the stimulation was repeated with the patient in a prone position, the same stimulation-induced paresthesia was reproduced and required a mean of 2.07 V (range 0.4–3.5 V). The pulse width and the frequency of stimulation remained the same intraoperatively and postoperatively. The mean difference in voltage between the intraoperative and postoperative testing was 1.49 V. All patients who underwent implantation using spinal anesthesia were asked to report their satisfaction

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and discomfort (if any) that they might have experienced during the operation. All patients, except one, expressed satisfaction with the procedure. Another patient also complained of minor discomfort around his rib cage during the procedure. The operating surgeon was specifically asked about ease of technique, the time spent, and his/her comparative analysis of the procedure done under spinal versus local or general anesthesia. All of the implanting surgeons reported satisfaction and felt that performing the procedure using spinal anesthesia was a safer and more comfortable technique for both the patient and themselves. Surgeons found that it was possible to alter the position of the electrode, to achieve optimal paresthesia, without producing any discomfort or pain to the patient. There were no complications reported as a direct consequence of the procedure itself, although in one case effective stimulation-induced paresthesia could not be obtained, therefore pain relief was unsatisfactory and the system was removed. We have not attempted the procedure in upper thoracic areas because safety of the anesthetic technique is limited to T6 and below.

DISCUSSION Contrary to popular belief that spinal anesthesia produces complete motor and sensory block, we found that it does not block all sensory transmission in the superficial layers of the spinal dorsal columns, thus permitting intraoperative testing and proper lead positioning. Lind et al. (2003) concluded that subarachnoid anesthetic agents act mostly on spinal rootlets and perhaps the ganglia, but the spinal afferent pathways remain unaffected. The authors found their conclusions to be supported by others’ observations that during epidural anesthesia, somatosensory evoked responses could be produced from segments below the anesthetized levels (Lang et al., 1990; Zaric et al., 1996). In our study, the voltages required to achieve stimulation-induced paresthesia were only moderately higher (mean 1.49 V) intraoperatively when compared to postoperative voltages. This study demonstrates that surgical leads can be safely implanted and proper placement can be assured by stimulation-induced paresthesia, which is not abolished under spinal anesthesia. Patients report that the procedure is relatively pain free. The operating surgeons echo the same sentiment and feel that it is much easier and less stressful, both on them and their patients, when compared to when the procedure is performed under local anesthesia. Similarly, spinal

anesthesia has the added benefit of not requiring the need to do somatosensory evoked potentials for proper placement.

CONCLUSION The placement of surgical leads via laminotomy is a safe and effective procedure and is gaining popularity amongst implanters of SCS. There is approximately only 1.5 V difference when comparing the intraoperative and postoperative testing. Spinal anesthesia allows proper placement with the guidance of stimulation-induced paresthesia and eliminates the need for somatosensory evoked potentials. It is technically easy on the patient and the surgeon when compared with local anesthesia.

ACKNOWLEDGMENT The authors wish to acknowledge and thank Kenneth Alo’, MD, of Houston, Texas, for providing the script for the section “EMG/SSEP during SCS implant surgery.”

References Barolat, G., Oakley, J.C., Law, J.D., North, R.B., Ketcik, B. and Sharan, A. (2001) Epidural spinal cord stimulation with a multiple electrode paddle lead is effective in treating intractable low back pain. Neuromodulation 4: 59–66. Hallstrom, Y.T., Lindblom, U. and Meyerson, B.A. (1991) Distribution of lumbar spinal evoked potentials and their correlation with stimulation-induced paresthesia. Electroencephalogr. Clin. Neurophysiol. 80: 126–39. Hallstrom, Y.T., Lindblom, U., Meyerson, B.A. and Prevec, T.S. (1989) Epidurally recorded cervical spinal activity evoked by electrical and mechanical stimulation in pain patients. Electroencephalogr. Clin. Neurophysiol. 74 (3): 175–85. Henderson, J.M., Schade, C.M., Sasaki, J., Caraway, D.L. and Oakley, J.C. (2006) Prevention of mechanical failures in implanted spinal cord stimulation systems. Neuromodulation 9 (3): 183–91. Holsheimer, J., Nuttin, B., King, G.W., Wesselink, W.A., Gybels, J.M. and de Sutter, P. (1998) Clinical evaluation of paresthesia steering with a new system for spinal cord stimulation. Neurosurgery 42: 541–9. Krames, E.S. (2001) Mechanisms of action of spinal cord stimulation. In: S.D. Waldman (ed.), Interventional Pain Management, 2nd edn. W.B. Saunders: Philadelphia, pp. 561–5. Kumar, K., Hunter, G. and Demeria, D. (2006) Spinal cord stimulation in treatment of chronic benign pain: challenges in treatment planning and present status, a 22-year experience. Neurosurgery 58: 481–96. Kumar, K., Toth, C., Nath, R.K. and Laing, P. (1998) Epidural spinal cord stimulation for treatment of chronic pain-some predictors of success. A 15-year experience. Surg. Neurol. 50: 110–21.

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Lang, E., Erdmann, K. and Gerbershagen, H.U. (1990) High spinal anesthesia does not depress central nervous system function as measured by central conduction time and somatosensory evoked potentials. Anesth. Analg. 71: 176–80. Lind, G., Meyerson, B.A., Winter, J. and Linderoth, B. (2003) Implantation of laminotomy electrodes for spinal cord stimulation in spinal anesthesia with intra-operative dorsal column activation. Neurosurgery 53: 1150–4. Melzack, R. and Wall, P.D. (1965) Pain mechanism – a new theory. Science 150: 971–9. Meyerson, B.A. and Linderoth, B. (2000) Mechanisms of spinal cord stimulation in neuropathic pain. Neurol. Res. 22: 285–92. North, R.B., Kidd, D.H., Olin, J.C. and Sieracki, J.M. (2002) Spinal cord stimulation electrode design: Prospective, randomized, controlled trial comparing percutaneous and laminectomy electrodes – Part I. Technical outcomes. Neurosurgery 51: 381–90.

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Sharan, A., Cameron, T. and Barolat, G. (2002) Evolving patterns of spinal cord stimulation in patients implanted for intractable low back and leg pain. Neuromodulation 5: 167–79. Shealy, S., Mortimer, J.T. and Reswick, J.B. (1967) Electrical inhibition of pain by stimulation of the dorsal columns: preliminary clinical report. Anesth. Analg. 46: 489–91. Villavicencio, A.T., Leveque, J.C., Rubin, L., Bulsara, K. and Gorecki, J.P. (2000) Laminectomy versus percutaneous electrode placement for spinal cord stimulation. Neurosurgery 46: 399–406. Zaric, D., Hallgren, S., Leissner, L., Nydahl, P.A., Adel, S.O., Philipson, L. et al. (1996) Evaluation of epidural sensory block by thermal stimulation, and recording of somatosensory evoked potentials. Reg. Anesth. 21: 124–38.

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87 Techniques for Peripheral Nerve Stimulation Implantation Michael Stanton-Hicks

O U T L I N E Introduction

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INTRODUCTION At the present time surgery for peripheral nerve stimulation (PNS), the direct placement of electrodes surgically on or near to an exposed nerve, is limited to the use of the one electrode that has been approved by the FDA for this purpose. The On-Point electrode (Medtronic, Inc., Minneapolis, MN) is a quadrapolar electrode originally designed for spinal cord stimulation (SCS) to which a Gor-Tex skirt has been added to allow fixation around a particular nerve. Because of its design and size, this electrode is limited to radial, median, and ulnar nerves in the upper extremity, and to the sciatic, common peroneal, and posterior tibial and femoral nerves in the lower extremity.

SURGICAL TECHNIQUE FOR MEDIAN AND ULNAR NERVES After induction of general or regional anesthesia is complete, the patient is placed supine with the arm

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extended on an arm board. Following preparation and draping of the chest wall and ipsilateral extremity, an incision is made approximately 5 cm proximal to the elbow and medial to the biceps muscle. Dissection is carried down to the median nerve, taking care to identify the medial antebrachial cutaneous nerve, and associated blood vessels. Likewise any cutaneous nerves are identified and protected. The median nerve is identified deep to the vein and adjacent to the brachial artery. After protecting these structures, a length of nerve, sufficient to accommodate the On-Point electrode, is dissected free, taking care to preserve any anastomotic vascular supply to the nerve. The electrode is placed adjacent to the nerve and secured in place with Nurolon (Nylon) sutures through the Gor-Tex skirt and epineurium (Figure 87.1). The ulnar nerve is identified medial to the median nerve and posterior to the intermuscular septum. Dissection is carried through this structure to where the ulnar nerve is found, in a manner similar to that for the median nerve. It is dissected free for a length sufficient to allow placement of the On-Point electrode.

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Ulnar nerve Median nerve

FIGURE 87.1 Site in arm for median nerve PNS implant

FIGURE 87.2 Site in arm for implant of an ulnar nerve PNS

Care is taken to preserve its anastomotic blood supply. The On-Point electrode is attached in a similar manner using several 4-0 Nurolon sutures through the Gor-Tex skirt and epineurium. The radial nerve is located at a similar distance from the lateral epicondyle, lateral to the brachialis muscle where it is found in the spiral groove or penetrating the intermuscular septum. Because of its course through the lateral intermuscular septum and entry into the anterior compartment, it is preferable to divide the septum and dissect free a length of the radial nerve sufficient to accommodate the On-Point electrode. Taking care to preserve any motor branches and anastomotic vessels, it is easier to place the electrode between the nerve and humerus. 4-0 Nurolon sutures are used to retain the electrode in situ. The radiofrequency receiver (RF) or implanted pulse generator (IPG) can be located beneath the clavicle. Depending on the depth of the subcutaneous tissue fascia, the IPG can be attached to the deep fascia overlaying the pectoralis muscle, or in thin individuals, for cosmetic reasons, the pectoris muscle can be divided allowing a pocket to be made on the anterior

chest wall where the IPG is sutured to the fascia overlying the intercostal muscles. The extension from the electrode site is passed through a tunnel made from the wound in the arm to the pocket site and attached to the IPG (Figure 87.2).

SURGICAL TECHNIQUE FOR SCIATIC NERVE In the lower extremity, peripheral nerve stimulation is most commonly directed to the sciatic nerve, less frequently to the common peroneal, post-tibial or femoral nerves. While both posterior and lateral approaches to the sciatic nerve may be used, the lateral approach is more comfortable for the patient and obviates the discomfort that sometimes attends a posterior approach to the sciatic nerve. An incision is made (Figure 87.3) in the mid-thigh that allows dissection down to the tensor fascia lata (iliotibial band) which is divided along its posterior edge. Dissection is carried down between short and long

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Sciatic nerve

Tibial nerve

FIGURE 87.3

Site in thigh posterior to the iliotibial band for implant of a sciatic nerve PNS

heads of the biceps to the sciatic nerve. This is identified between the long head of biceps and hamstring muscles. The nerve is mobilized circumferentially, taking care to preserve any motor branches and its vascular anastomoses. Two On-Point electrodes are sutured together using 4-0 Nurolon at their margins. This allows the two electrodes to be placed as a “sandwich” in apposition to the tibial and common peroneal divisions of the nerve. While it has been common practice to place the IPG in the region overlying the gluteus medius muscle using an extension passed from the pocket to the electrodes in the thigh, it is now considered preferable to place the IPG behind the iliotibial band. It can be retained at this site using 2-0 Nurolon, Nylon or silk sutures. This approach avoids a long extension and passage around a joint.

FIGURE 87.4 Site in leg above medial malleolus for implant of a tibial nerve PNS

SURGICAL TECHNIQUE FOR COMMON PERONEAL NERVE For this nerve, an incision is made posterior to the termination of the iliotibial band and proximal to the popliteal fossa. The dissection is carried down to the common peroneal nerve where it lies over the lateral head of the gastrocnemius muscle. A length of nerve sufficient to accommodate the On-Point electrode is dissected free taking care to preserve any vascular anastomoses. The electrode is placed under the nerve and sutured in place using 4-0 Nurolon sutures between the Gor-Tex skirt and the epineurium. As with the sciatic nerve, the IPG can be placed at mid thigh behind the iliotibial band where a pocket is made and is connected to the electrode by the extension cable.

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SURGICAL TECHNIQUE FOR POSTERIOR TIBIAL NERVE

Femoral nerve

The posterior tibial nerve is gained by making an incision anterior to the tendo Achilles and approximately 6 cm above the medial malleolus (Figure 87.4). The dissection is carried down to the flexor hallucis longus muscle where the tibial nerve and accompanying vessels are found. The nerve is dissected free for a length sufficient for placement of the On-Point electrode behind where it is retained in situ using 4-0 Nurolon sutures. The IPG can be placed lateral and under the fascia of the gastrocnemius muscle.

SURGICAL TECHNIQUE FOR FEMORAL NERVE Exposure for the femoral nerve is made via a transverse lower abdominal incision. Exploration is carried out by a retroperitoneal approach to the iliopsoas muscle where the femoral nerve is located (Figure 87.5). The electrode is sutured to the iliopsoas fascia stabilizing its relationship to the nerve using 4-0 Nurolon sutures to the perineurium. The extension cable can be passed retroperitoneal to a pocket, for the IPG in the subcutaneous tissue of the lower hypogastrium.

TRIALING

FIGURE 87.5 psoas fascia

Site for implant of a femoral nerve PNS on the ilio-

If appropriate, and in circumstances where some doubt may exist as to the likely outcome effectiveness of peripheral nerve stimulation, an inpatient trial of the PNS may be undertaken. For this purpose, an externalized extension can be tunneled (10–15 cm) from the wound site.

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88 Techniques for Subcutaneous Peripheral Nerve Field Stimulation for Intractable Pain Giancarlo Barolat

Subcutaneous peripheral nerve field (PNfS) stimulation is a technique where the lead(s) stimulates not a main nerve trunk, but the small nervous endings of the distribution of the nerve within the subcutaneous tissue. The subcutaneous tissue lies just underneath the dermis (see Figure 88.1). Entry in the subcutaneous tissue is usually characterized by a “pop” feeling due to the loss of resistance once the needle has penetrated through the epidermis/ dermis. This technique has determined a revolutionary change in the paradigm of classical neurostimulation. In the classical stimulation the goal is to stimulate some major nervous sensory structures upstream from the painful area to convey paresthesiae in that area. With PNfS we actually place the lead in or near the area of the pain (or the area of the projection of the pain). This technique was developed in order to be able to direct stimulation to areas that are notoriously impossible or difficult to reach from the spinal cord or major nerve trunk level. While originally developed for these difficult situations, PNfS is becoming utilized sometimes as a first, minimally invasive, neurostimulation procedure if the pain is limited to a relatively small and well-defined area. PNfS is best accomplished with percutaneous cylindrical leads and not with paddle leads. The reason lies in the target of the stimulation. When performing dorsal column, nerve root or large peripheral nerve stimulation, the target is well defined and the lead is placed on top of it. The current is therefore unidirectional and best delivered by a paddle lead. With PNfS, instead, the lead is placed within the target, which is made of all the small sensory nerve endings within

Neuromodulation

the subcutaneous tissues. The best electrical field is therefore one that is circumferential, as the one delivered by a percutaneously placed cylindrical lead. The principle of PNfS is that the lead should be placed within or as near as possible to the painful area. Each electrical contact spreads a circumferential electrical field which is about 2 cm in diameter (personal observation). The number, spacing, and distribution of the electrical contacts should therefore be carefully planned according to the size and shape of the painful area (see Figures 88.2, 88.3, and 88.4). Larger areas might require several leads placed strategically. The author has placed up to four widely spaced percutaneous leads in an effort to cover larger areas of the body. If there is allodynia, the above principles might have to be modified. If the allodynia is mild, more of a hypersensitivity, the lead(s) may still be placed within the painful area. In case of severe allodynia, however, placement within the painful area might be contraindicated, since it could generate a severe flare-up of the pain. The stimulation is also often perceived as painful. The best strategy in this case is to insert the leads on each side of the allodynic area, in order to “bracket” it. By using this strategy, the author has been able to substantially reduce severe allodynia. It is crucial to carefully map the transition zone between the allodynic and non-allodynic area and place the lead exactly in that zone. A centimeter difference could substantially impact the success or failure of the modality. Occasionally, lead placement in the center of an allodynic area will have positive effects on reduction of the allodynia.

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Epidermis

Lead placement for scapular/trapezius pain

Dermis

Horizontal lead placement for lumbar pain

Subcutaneous tissue

Subcutaneous nerves and blood vessels

Pain area

Leads

FIGURE 88.2 Schematic representation of different electrode placement strategies for different pain areas

FIGURE 88.1

Schematic drawing of the human skin and subcu-

taneous layers

Almost any area of the body can be reached with this technique. The most commonly addressed ones include the lumbar area, the posterior thoracic area, the scapular area, the inguinal area as well as various regions of the head and face. The trial is performed without an incision by inserting the leads in the subcutaneous tissue through the needle provided in the kit or some other inserting device. Even though the procedure is simple, it has to be done with heavy (albeit short) intravenous sedation. The reason for the heavy sedation is two-fold. Inserting a large bore needle in the subcutaneous tissue parallel to the skin is very painful, particularly if the tissues are taught. Secondly, the tract cannot be infiltrated with local anesthetic, since that would hide the correct plane and would not allow an immediate feedback to be obtained from the stimulation. Once the leads are inserted, the trial is undertaken just like a regular spinal cord stimulation trial. If the trial is successful in reducing the pain, the whole system is implanted at a second sitting. It is possible to perform a trial with permanent electrodes, but that entails an incision and the use of one or more extension cables.

Lead placement for posterior cervical and shoulder pain

Vertical lead placement for lumbar pain

FIGURE 88.3 Schematic representation of different electrode placement strategies for different pain areas

XI. NEUROMODULATION DEVICE IMPLANT TECHNIQUES

TECHNIQUES FOR SUBCUTANEOUS PERIPHERAL NERVE FIELD STIMULATION FOR INTRACTABLE PAIN

AP X-ray of the lumbar spine. Patient with unilateral low back pain IPG

Painful area

Subcutaneous leads

FIGURE 88.4

X-ray of electrodes and pulse generator placement for unilateral lumbar pain

transcutaneous stimulation through a TENS unit is a good indicator of success with PNfS. Of course, if the TENS unit is effective and the patient finds it a suitable modality, then there is no need to proceed with PNfS. A negative response to the TENS unit does not necessarily mean that PNfS will not be successful. The author does not withhold a PNfS trial in case of a negative response to the TENS unit treatment. PNfS can also be utilized in conjunction with intraspinal stimulation and/or large peripheral nerve stimulation. The author has several patients where both modalities were successfully implemented jointly, either as separate procedures or as part of a single implant procedure. Even though the technique is not very invasive, utmost care must be placed in the surgical planning and execution. The leads must be placed exactly in the painful area(s), and this requires careful assessment of the topography of the pain. The author usually presents the patient with two key questions: (1) Where is the area of your worst pain? (2) Where is the area from which your pain originates (if there is one)? In the author’s practice, the most common indications include: ●

●

The author has performed several hundred implants of PNfS. Indications include, in the author’s experience, instances of both nociceptive and/or neuropathic pain. In the author’s experience, a good response to

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● ● ● ●

Intractable axial lumbar pain (whether the patient has received surgical intervention or not) Intractable posterior thoracic pain Intractable scapular pain Inguinal pain Thoracic wall pain Shoulder pain

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C H A P T E R

89 Surgical Placement of Leads for Occipital Nerve Stimulation Richard L. Weiner

O U T L I N E Introduction

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Permanent Implant – Paddle Electrode

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Trial Stimulation

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References

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Permanent Implant – Percutaneous Wire Electrodes

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INTRODUCTION

TRIAL STIMULATION

Occipital lead placement into the subcutaneous tissues innervated by the C2, C3 posterior primary rami which comprise the greater and lesser occipital nerves has been an evolving methodology for the treatment of intractable occipital headache syndromes since the first implant in 1993. The first reported cases in the literature (Weiner and Reed, 1999) described a percutaneous method of wire electrode lead placement, which will be amplified and clarified with text and pictures in this chapter. Since that first report, there have been numerous reports of the use of neuromodulation for occipital neuralgia and headache (Weiner, 2000; Weiner et al., 2000, 2001; Alo’ and Holsheimer, 2002; Popeney and Alo’, 2003; Alo’ and Popeney, 2004; Oh et al., 2004). Paddle electrode placement has also been developed in an effort to reduce electrode migration and improve tissue contact and conduction.

Almost all potential candidates for ONS implant undergo a percutaneous trial electrode placement of up to one week or more to demonstrate initial efficacy and pain control to both the patient and the implanter. This procedure can be done in an office or other outpatient setting with minimal or no sedation via a Tuohy needle puncture on either side of the midline at approximately C1 below the area of localized pain with the needle directed across the midline to the opposite site (Figure 89.1). The needle is placed in the subcutaneous space lateral or slightly superior to the insertion point above (superficial) to the cervical muscular fascia extending a centimeter or so beyond the point of maximal pain complaint in the occipital region so that it can be pulled back if necessary during polarity and voltage testing. The electrodes are then sutured to the skin, covered with generous

Neuromodulation

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89. SURGICAL PLACEMENT OF LEADS FOR OCCIPITAL NERVE STIMULATION

FIGURE 89.2 Lateral positioning with suboccipital head shave

FIGURE 89.1 Temporary electrode fixation with transverse subcutaneous placement on either side of midline extending towards the opposite side

dressings for the trial period, and connected to the supplied transmitter. Following the trial period, the electrodes are removed, the patient interviewed, and a decision reached regarding permanent implantation. The wounds should be given at least a couple of weeks to heal before an incision is made in the area for permanent implantation to minimize risks of infection. Alternatively, permanent electrodes can be placed and tunneled with extension wires for a trial period, then converted to a total implant with generator placement (IPG).

PERMANENT IMPLANT – PERCUTANEOUS WIRE ELECTRODES Most implants are bilateral lead placements at or near the level of C1 with trajectories ranging from zero (straight lateral) to almost 90 degrees toward the vertex of the occipital scalp. Patient positioning

FIGURE 89.3 Prone position with midline incision and maximal pain areas marked

is usually lateral or prone with the head resting on a suitable horseshoe or donut head holder. The issue of airway protection under sedation in some patients will require the lateral position though generator placement in the lower lumbar/upper buttock region with linear tunneling is most attractive, with the patient prone. A stepwise implant method with percutaneous electrode placement is as follows: 1. Informed consent with patient knowledge of offlabel indication (as of this writing) 2. Suboccipital head shave to avoid hair contamination 3. Nasal O2, IV 4. Lateral or prone position with patient awake, arms tucked at sides (Figures 89.2, 89.3)

XI. NEUROMODULATION DEVICE IMPLANT TECHNIQUES

PERMANENT IMPLANT – PERCUTANEOUS WIRE ELECTRODES

FIGURE 89.4 Antibacterial draping before placing standard drapes

FIGURE 89.6

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Curved Tuohy needle aimed from midline inci-

sion laterally

FIGURE 89.5

Local anesthetic injection into incision area only

5. Scrub and paint prep all involved skin areas and cover with antibacterial sticky drapes followed by normal draping (Figure 89.4) 6. Marker pen drawing of incision sites: 2–3 cm vertical midline at level of C1 (Figure 89.3), transverse incision upper buttock or abdomen 7. Small dose of propofol, midazolam, or other shortacting anesthetic agent prior to local anesthetic injection of incision site only (Figure 89.5). (Do not inject the entire proposed needle track away from the incision in the neck as this will distort the subcutaneous anatomy and might produce a hematoma and failure to adequately stimulate the area in question)

FIGURE 89.7 Gentle subcutaneous needle insertion while using left index finger to monitor needle tip to avoid placing too superficially or too deep into the fascia

8. Incision through skin and subcutaneous tissue to level of cervical fascia, obtain hemostasis with electrocautery or bipolar cautery 9. Create small subcutaneous pockets on either side of the incision with Metz scissors to allow seating of electrode loops created at end of case to help avoid migration 10. Gently curve supplied Tuohy needle, be sure stylet can be removed (Figure 89.6) 11. Place needle subcutaneously in midline incision aimed laterally or angled somewhat superiorly staying superficial to the fascia at all times. Extend the needle beyond the point of maximal occipital tenderness or pain as reported by the patient to

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89. SURGICAL PLACEMENT OF LEADS FOR OCCIPITAL NERVE STIMULATION

FIGURE 89.8 C-arm fluoroscopic confirmation of needle position

FIGURE 89.10 External cable connection for on the table stimulation to confirm electrode position

FIGURE 89.9 C-arm fluoroscopic confirmation of electrode

FIGURE 89.11 Repeat procedure for second side

placement at level of C1

allow for some proximal electrode repositioning if necessary during on the table stimulation with C-arm fluoroscopic guidance (Figures 89.7, 89.8) 12. Remove stylet and place multicontact electrode through the needle to its tip. Gently pull back on needle while keeping mild forward pressure on the electrode to remove needle totally (Figure 89.9) 13. Connect distal end of electrode to lead extension wire for intraoperative stimulation testing with patient awake to report response (Figure 89.10) 14. With successful stimulation, affix the electrode to the underlying fascia with supplied anchors using 2-0 silk or other non absorbable strong suture with multiple sutures per anchor (two or three is sufficient)

15. Repeat procedure on other side (Figure 89.11) 16. Patient is usually sedated at this point with short-acting anesthetic agents in preparation for tunneling and generator pocket dissection and placement. LMA intubation, if possible, is recommended. Alternatively, ketamine and midazolam have been used in the prone position without significant airway alteration 17. Prior to wound closure, electrode tension relieving loops are created within the cervical incision and secured to the fascia gently with absorbable suture to maintain the loop and reduce migration as well as avoid electrode twisting which could result in local electrode erosion through the dermis

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PERMANENT IMPLANT – PADDLE ELECTRODE

FIGURE 89.12 Position and marking for paddle electrode placement. Marks depict two distinct pain areas

FIGURE 89.14 Paddle placement with electrodes facing towards subcutaneous tissue

FIGURE 89.13 Incision to left of midline with markings to right of midline. Vertex to right, body to left

pocket

FIGURE 89.15

Plastic or metal dissector to complete paddle

PERMANENT IMPLANT – PADDLE ELECTRODE 1. Lateral or prone position with markings of pain site (Figure 89.12) 2. Incision medial to pain site even if to one side of midline (Figure 89.13) 3. Requires sharp subcutaneous dissection to accommodate paddle electrode face down with contacts towards the fascia in the fat layer (Figure 89.14) 4. Create pocket with plastic or metal dissector to accept paddle (Figure 89.15) 5. Meticulous attention to hemostasis with cautery 6. Test, anchor, tunnel, IPG connect, fluoroscopic verification (Figure 89.16)

FIGURE 89.16 C-arm fluoroscopic verification. Slight electrode angle was able to capture both pain areas using each contact array selectively into two-channel IPG

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89. SURGICAL PLACEMENT OF LEADS FOR OCCIPITAL NERVE STIMULATION

These techniques will continue to evolve to accommodate the changing hardware landscape from the traditional wired percutaneous and paddle electrode systems to more refined total local implants and wireless products which will, hopefully, continue to provide effective subcutaneous neurostimulation while solving some of the current complication issues including electrode migration and erosion.

References Alo’, K.M. and Holsheimer, J. (2002) New trends in neuromodulation for the management of neuropathic pain. Neurosurgery 50 (4): 690–704. Alo’, K.M. and Popeney, C.A. (2004) Peripheral nerve stimulation (PNS) relieves the symptoms of transformed migraine and reduces associated disability. Neurocontact (Newsletter/Articles from the Editorial Board – Summarial Abstract from Headache 2003; 43: 369-73) Summer 2004; Medicus International, pp.1–4.

Oh, M.Y., Ortega, J., Bellotte, J.B., Whiting, D.M. and Alo’, K. (2004) Peripheral nerve stimulation for the treatment of occipital neuralgia and transformed migraine using a C1-2-3 subcutaneous paddle style electrode: a technical report. Neuromodulation 7 (2): 103–12. Popeney, C.A. and Alo’, K.M. (2003) C1-2-3 peripheral nerve stimulation (PNS) for the treatment of disability associated with transformed migraine. Headache 43: 369–73. Weiner, R.L. (2000) The future of peripheral nerve neurostimulation. Neurol. Res. 22: 299–304. Weiner, R.L. and Reed, K.L. (1999) Peripheral neurostimulation for the control of intractable occipital neuralgia. Neuromodulation 2: 369–75. Weiner, R.L., Alo’, K.M. and Reed, K. (2000) Peripheral neurostimulation for control of intractable occipital headaches. In: Abstracts of the World Pain Meeting 2000, President Elliot Krames, San Francisco, CA, July 2000. Weiner, R.L., Alo’, K.M., Reed, K.L. and Fuller, M.L. (2001) Subcutaneous neurostimulation for intractable C2 mediated headaches. In: Abstracts from the American Association of Neurological Surgeons, Pain Section Newsletter. 3, 2001, Toronto, Canada.

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C H A P T E R

90 Surgical Technique for Intrathecal Medication Delivery System Implantation Joshua M. Rosenow

O U T L I N E Surgical Planning/Preoperative Considerations

Pump Preparation and Insertion

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Closure

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Positioning and Surgical Preparation

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Postoperative Considerations

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Catheter Insertion

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References

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SURGICAL PLANNING/PREOPERATIVE CONSIDERATIONS Planning for the implantation of an intrathecal medication delivery system requires considerations for the prevention of hardware infection, ergonomics of system function and comfort of the patient, prevention of pump pocket and catheter complications, and prevention of cerebrospinal fluid (CSF) leak. An implanted system for the delivery of intrathecal medication consists of an intrathecal segment of catheter, a subcutaneous segment of catheter, and an implanted pump. The intrathecal and subcutaneous catheter segments may be either part of the same catheter (1-piece catheter) or separate catheters joined with a connecting pin (2-piece catheter system). The choice of either a 1-piece catheter or 2-piece catheter system is determined by the preference of the implanter. A 1-piece catheter eliminates the need for connecting pins and the related considerations that go with connecting

Neuromodulation

two catheters together including assuring that the two catheters will not pull apart, etc. A 1-piece catheter is also longer in total length than the intrathecal segment of the 2-piece system and thus can be used to reach higher vertebral levels (upper thoracic or cervical) that may be difficult to reach with a 2-piece catheter system. Conversely, a 2-piece catheter system may be easier to handle when revising the intrathecal catheter because the intrathecal portion may be disconnected and interrogated in the back, unlike the 1-piece system, which must be cut and then connected with a new connecting pin following open interrogation or replacement of part, unless an entirely new 1-piece catheter is implanted. Given that the pump itself is somewhat large, the placement location of the pump is not a small consideration both technically and, to the patient, cosmetically. The most common programmable pump for implantation in the USA is the Synchromed II (Medtronic, Inc., Minneapolis, MN), which comes in two sizes and holds either 20 ml or 40 ml of medication.

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It is my opinion that when using these programmable pumps, patients should be shown models of each pump so that they grasp the magnitude of the implanted device and can express their opinion as to which size they prefer, understanding that the smaller capacity pump must be refilled more often. The actual size difference between the two pumps, however, is not that great: 19.5 mm vs. 26 mm respectively. The patient should be queried as to the usual location of the waistband of their pants, as it is desirable to prevent this from rubbing on the pump and contributing to erosion of the hardware through the skin. The pump should be sited on the patient in both the supine and seated positions, to ensure that it will be placed in a comfortable location. The pump should impact neither the lower costal margin nor the iliac crest. For most patients, the pump may be comfortably placed in a paramedian location with the superior aspect near the level of the umbilicus, adjusted as needed for individual anatomy. When possible, the site of implant should be chosen so as to avoid other implanted devices such as ventriculoperitoneal shunts, gastrostomy tubes, and other implantable devices such as a neuropulse generator for spinal cord stimulation. If a pump is being reimplanted following removal of a prior one owing to infection, it is desirable to use the contralateral abdomen if possible. While pump pocket or hardware infections are rarely life-threatening, they result in interruptions in therapy, further trips to the operating room, increased healthcare costs, and frustration for all involved. It is rare to salvage an infected pump, although reports of this in the literature do exist. Patients must be free of infection at the time of implant. This includes urinary and respiratory tract infections, as well as infected decubitus or other skin ulcers. Most pump infections are due to skin contaminants, such as Staphylococcus species. Preoperative bathing for several days with a solution containing chlorhexidine gluconate may decrease skin colonization with both sensitive and antibiotic-resistant organisms (Motta et al., 2007). Intranasal mupirocin ointment twice daily may help decrease the rate of intranasal carriage of resistant Staphylococcus species (Mehtar, 1998; Sanderson, 2001). Antibiotics, such as cefazolin or oxacillin, which cover common skin organisms, are usually sufficient for prophylaxis, however some physicians recommend that all patients be given vancomycin preoperatively to cover methicillin-resistant Staphylococcus aureus (MRSA) bacteria. It is our opinion that preoperative cross-sectional imaging of the planned catheter insertion site should be obtained so that the surgeon may have advance knowledge of any anatomic variants or barriers to

catheter insertion or passage. The level of the conus should be noted.

POSITIONING AND SURGICAL PREPARATION The patient is placed on the operating table in the supine position. After the induction of general endotracheal anesthesia, the pump implant site is then marked on the abdomen (if this has not been done prior to coming to the operating room). It is important to do this before the patient is turned into the lateral position, as the abdominal skin can shift greatly, especially if the patient has a pendulous abdomen. The patient is turned into the lateral decubitus position with the planned pump implant side up. An axillary roll is placed to relieve traction and pressure on the brachial plexus. Padding is also placed under the lower knee and ankle, as well as between the legs. Both arms are placed such that they are pointing as far superiorly as is comfortably possible for the patient. This facilitates visualization of the spine and catheter with fluoroscopy. The lower arm is either placed on an arm board and the upper one typically on an airplane-type arm holder or both arms, separated by padding, are placed in the “praying mantis” position and secured in that position. Each arm is thoroughly padded to prevent pressure on the ulnar nerves. Some surgeons secure the patient in the lateral decubitus position using wide cloth tape and some secure the patient in that position using a “beanbag.” If a beanbag-type pad is used, it may be wrapped around the patient and suction applied to harden it and support the patient. Care should be taken in doing this so that neither the lumbar nor the abdominal operative site is obscured. The beanbag should not rise higher than the lumbar spinous processes or the umbilicus. Care should also be taken to ensure that sharp points do not cut into the patient. Sturdy fabric tape is applied across the patient’s hips (padded as well) to prevent rotation during the procedure. The fluoroscope is brought in and anteroposterior images are obtained. The fluoroscope should be aligned to the patient’s spinal anatomy such that the spinous processes are centered between the pedicles and the vertebral end-plates are visualized end on. In patients without prior lumbar fusion, the catheter is often inserted at the L1–2 or L2–3 interspace. For this, the incision should be centered over the skin representation of the L3 or L4 pedicle, respectively, on the side of the pump implant, so that the catheter does not cross the midline.

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CATHETER INSERTION

There are many methods to surgical preparation. This author’s preferred technique involves initial skin decontamination with isopropyl alcohol, followed by marking of the lumbar incision and remarking of the abdominal incision. The operative field is then outlined with a border of Mastisol solution (Ferndale Labs, Ferndale, MI). Plastic drapes (Number 1010, 3 M, St Paul, MN) are then placed to isolate the operative field. A typical scrub and paint preparation is then performed with povidone-iodine solutions. Once the paint has dried, the incisions are remarked with a sterile surgical marker and a layer of Duraprep (3 M, St Paul, MN) is applied. The operative field is outlined in sterile towels and an iodine-impregnated drape (Ioban, 3 M, St Paul, MN) is applied before the final draping. Double gloving is used during the procedure and outer gloves are changed following draping and before starting the procedure. After a time-out procedure, the incisions are infiltrated with generous amounts of local anesthetic. This author prefers a 1 : 1 mixture of lidocaine with epinephrine (1 : 100 000 or 1 : 200 000) and 0.5% bupivacaine due to its combination of rapid onset (due to the lidocaine) and long duration (due to the bupivacaine).

CATHETER INSERTION The low-complication catheter placement technique described here is intended to minimize catheter breakage by reducing stress on the implanted catheter. These stressors include compression by the spinous processes and acute angles of passage. It also is intended to reduce the incidence of CSF leakage along the catheter track (Follett et al., 2003). Once the lumbar incision is made, electrocautery or sharp dissection is used to expose the lumbodorsal fascia. Some authors (Albright, 2006) advocate lining the incision edges with iodine-soaked cottonoids to reduce the incidence of infection, but the author has not found this to be necessary. The catheter will be anchored to the fascia, so it should be meticulously cleaned of all loose areolar tissue and fat, as they do not provide the stability required and interfere with proper anchoring. Using fluoroscopy, the Tuohy needle is guided to a midline puncture of the thecal sac beginning from a paramedian fascial entry point over the ipsilateral pedicle. The intended level of thecal sac puncture is at least one level above the pedicular level of insertion. For example, entry into the fascia over the L4 pedicle should lead to a puncture of the thecal sac at no lower than L2–3. Either live or intermittent fluoroscopy may

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be used during this part of the procedure. This paramedian shallow approach prevents the catheter from being intermittently compressed by the spinous processes during lumbar extension and eventually fracturing. Moreover, it provides a shallow angle of catheter entry into the CSF. This not only facilitates catheter passage, but also reduces bending stress on the catheter and reduces catheter kinking and fracture. The bevel is oriented so that the opening faces laterally during the dural puncture. This allows for more of a fiber-splitting approach through the ligamentum flavum. Once tactile feedback of sac puncture has been obtained, the stylet is removed and flow of CSF is confirmed. The bevel is then rotated to face cranially for catheter passage. A common problem often encountered by physicians performing spinal placements of intrathecal catheters is inadvertent multiple dural punctures because the surgeon cannot “find” the thecal sac. Multiple punctures into the thecal sac can lead to excessive CSF leak and post dural puncture headache (Grady et al., 1999) and neural trauma, which, in turn, can lead to neuropathic pain, paresis, loss of bowel and bladder control, loss of sexual function, paresis, and even paralysis. Besides these complications of low pressure headache or neural trauma, multiple attempts and failures at “finding” the intrathecal space can lead to excessive epidural bleeding, possibly resulting in epidural hematoma (Noli et al., 2001) or installation of bacteria, resulting in either epidural infection, abscess formation or meningitis (Pray, 1941). Haddadan and Krames (2007) proposed a technique whereby the midline of the epidural space is identified using a loss of resistance technique. The dural sac is then identified in the lateral fluoroscopic position by injecting non-ionic X-ray dye into the epidural space and visualizing the dye as it layers on the thecal sac (see Figure 90.1a). The needle is then advanced slowly under fluoroscopic control until the needle tents first the dural and subdural layers and then enters the thecal sac (see Figure 90.1b). Confirmation of placement is made by further injecting dye and visualizing the dye layering on the anterior dural membrane (see Figure 90.1c). The catheter is then passed cephalad until it reaches its intended target within the thecal sac. Under fluoroscopic guidance, the catheter is then threaded through the needle to the desired spinal level. The catheter should pass easily and smoothly without obstruction, resistance, or visualized kinking. Any indication of these issues should prompt retraction of the catheter through the needle, but slowly to avoid shearing of the catheter. If the catheter as it is being retracted presents some resistance to retraction,

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(A)

(B)

(C)

FIGURE 90.1 (A) The epidural needle enters the epidural space using a loss of resistance technique and 0.5 ml of contrast dye is injected. Dye is seen layering out along the thecal sac. (B) The epidural needle is slowly advanced against the resistance of the dura mater. Dye is now seen tented along the dura mater and along the subdural membrane. (C) The needle is advanced further until there is a discernible loss of resistance or feeling of a “pop” and dye is again injected. Seen posteriorly is the tenting of the dura and subdural membranes and anteriorly is the layering of dye along the anterior thecal sac. Confirmation of placement is made by observing a free flow of CSF (From Haddadan and Krames (2007), Figs 1, 2, and 3. John Wiley & Sons Ltd. Reproduced with permission)

the needle and catheter should be removed together to avoid shearing. The needle is then reinserted and the catheter is once again advanced within the thecal sac. There is no firm rule for the preferred spinal levels for catheter tip placement. Penn has demonstrated a significant concentration gradient of intrathecal medication that may influence this decision. The author typically places the catheter tip at T10 for spastic paraparesis or intrathecal medication administration for axial low back pain. The tip is placed between C6 and T4 for spastic quadriparesis but may be threaded as high as C4 for this purpose. For those patients with dystonia, the catheter may be placed as high as C1–4 (Albright et al., 2006). Once the catheter is at the desired targeted level, the catheter stylet is removed and spontaneous CSF flow from the end of the catheter should be verified. The stylet is partially replaced and a nonabsorbable purse-string suture is placed through the fascia around the needle entry point. The needle and stylet are then removed while using fluoroscopy to ensure constant position of the catheter tip. CSF flow from the end of the catheter is once again verified when this is completed and then again after the purse-string suture is tied down. The catheter is clamped off and a manufacturer’s provided for anchor is threaded over the catheter to its fascial entry point. The anchor is secured right at the catheter entry point to provide both stability and strain relief. If a “butterfly” anchor is used, two nonabsorbable sutures are placed, one through fascia and both eyes of the wings and another through the fascia and around the necks of the wings. CSF flow is once again verified and the catheter end is clamped off to prevent further loss of CSF.

If the patient has a history of prior spinal headaches, an epidural injection of autologous blood may be performed at the level of catheter insertion (or one level below) through a separately inserted 18G or smaller spinal needle to help prevent a recurrence of this problem postoperatively.

PUMP PREPARATION AND INSERTION Once the catheter is inserted intrathecally to its intended target area of the spinal canal and anchored, an incision is made for pump pocket creation. Electrocautery and/or sharp dissection is used to expose the rectus fascia in thin or relatively thin patients. In the majority of patients, the pump pocket is created over the fascia, keeping all of the subcutaneous fat superficial to the pump. Some obese patients will need to have their pockets created in the mid flat plane and some extremely thin patients may even need their pockets to be created subfascially (Kopell et al., 2001). This reduces the size of the pump bulge and protects it against erosion through the skin. Almost all of the pocket dissection is done inferior to the incision, but the upper flap should be lifted as well to help cover the top of the pump. Ideally, the top of the pump should sit just below the incision, with none of the pump lying directly under the incision. There are often substantial vessels that penetrate the fascia and extend into the fat. These should be thoroughly coagulated, lest they result in a pocket hematoma. Once the pump pocket is created to just larger than the pump, a 1-piece intrathecal catheter is tunneled

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from the lumbar incision to the abdominal pocket. If a 2-piece catheter system is used, the tunneling tool is passed from the lumbar incision to the abdominal pocket and the proximal pump catheter, which has a connector for the pump on one end, is passed through the tunneler from the pocket to the lumbar incision, usually via a mid-flank incision. The newer 1-piece catheters made by Medtronic have no pre-attached connector on the end, but instead come with a short extension catheter with the pump connector. For this system, the tunneling tool is passed from the abdominal incision to the lumbar region. The intrathecal catheter of the 2-piece system is then trimmed appropriately. This author prefers to trim enough catheter such that there is only a single gentle bend of catheter remaining in the lumbar incision and the connection between the two catheters is located just lateral to the incision. This places this connection in an easily accessible position should it be necessary to retrieve it during a revision procedure. Some implanters always place a single or double loop within the lumbar incision after creation of a “lumbar catheter pocket.” This single or double loop provides strain relief for the catheter within the thecal sac. The 2-piece catheter system requires that the catheters be connected. Some systems have a connecting pin preset into the end of the extension catheter. A strain relief boot is placed on the intrathecal catheter and the catheters are then connected, taking care not to poke the connecting pin through the end of the intrathecal catheter. The boot is slid into place and secured with a nonabsorbable suture. The trimmed piece of catheter is saved and measured for use in the dosing of the catheter priming bolus. The pump, a Synchromed II, itself is prepared on the back table. The sterile water that comes prefilled in the pump is emptied and the desired preservative-free medication is then loaded. It is important to ensure that the pump is completely emptied before filling, as any residual sterile water will dilute the drug and result in underdosing. Extraneous catheter is then taken up at the abdominal end to allow only a single gentle bend of catheter to remain in the lumbar incision. The pump and catheter are then connected. The newer sutureless connectors simply click onto the pump. The older connectors were snapped onto the pump nozzle and then were secured with a single nonabsorbable suture tie. The pump is then placed within the pocket with an extra extension catheter coiled gently beneath it. Some surgeons prefer to trim the extension catheter before connecting it to the pump to eliminate significant coils behind the pump. This is done in the hope of preventing kinking of this length of catheter. The pump is

then secured to the fascia using nonabsorbable suture through the fascia and through at least two pump loops. It is important to inspect the sutures before tying them down to visually ensure that the pump catheter is not caught and constricted by the sutures. An alternative to this is the use of a manufacturer’s provided for Dacron sock that encases the pump and firmly scars in over time, thus reducing the likelihood of pump rotation. Patients who are obese, who have their pockets created in the mid fat plane, will need this Dacron sock encasing the pump because there is no fascia near the pocket to suture to.

CLOSURE Once hemostasis is achieved, all incisions are thoroughly irrigated with antibiotic-impregnated saline solution. The author prefers to close the incisions with two layers of absorbable sutures beneath the skin, in addition to skin closures. The deeper fat is brought together, not in an attempt to add strength to the closure, but instead to provide another closed layer of tissue between the hardware and the external environment. This reduces the risk that the pump or catheter will erode through the skin at the incision. The skin may be closed as per the surgeon’s preference. Staples, sutures, or subcuticular closure with skin adhesive are all acceptable. Before closing it is essential that all bleeding vessels are electrocauterized to avoid a pump pocket hematoma. Following closure, the pump is then programmed for the appropriate priming bolus and starting dose.

POSTOPERATIVE CONSIDERATIONS It is this author’s preference that all patients receive an abdominal binder to wear for the first postoperative week. This is intended to reduce the formation of a seroma within the pump pocket and help hold the pump in place until it firmly scars in. Patients are kept flat for 2 hours postoperatively, longer if they have a history of spinal headaches. This is not absolutely necessary, but this author has found it helpful. Antibiotics are continued for 24 hours postoperatively. X-rays of the entire pump system are obtained in both the anteroposterior and lateral views. This includes all spinal segments containing the catheter as well as the abdomen. These images provide baseline views against which any further investigations may be compared if there is a question of hardware disconnection or migration.

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References Albright, A.L., Turner, M. and Pattisapu, J.V. (2006) Best-practice surgical techniques for intrathecal baclofen therapy. J. Neurosurg. 104: 233–9. Follett, K.A., Burchiel, K., Deer, T., DuPen, S., Prager, J., Turner, M.S. and Coffey, R.J. (2003) Prevention of intrathecal drug delivery catheter-related complications. Neuromodulation 6: 32–41. Grady, R.E., Horlocker, T.T., Brown, R.D., Maxson, P.M. and Schroeder, D.R. (1999) Neurologic complications after placement of cerebrospinal fluid drainage catheters and needles in anesthetized patients: implications for regional anesthesia. Mayo Perioperative Outcomes Group. Anesth. Analg. 88 (2): 388–92. Haddadan, K. and Krames, E.S. (2007) Technique that better localizes the dura mater during intrathecal catheterization should reduce inadvertent multiple dural punctures and reduce complications. Neuromodulation 10 (2): 164–6. Kopell, B.H., Sala, D., Doyle, W.K., Feldman, D.S., Wisoff, J.H. and Weiner, H.L. (2001) Subfascial implantation of intrathecal

baclofen pumps in children: technical note. Neurosurgery 49: 753–6, discussion 756-7. Mehtar, S. (1998) New strategies for the use of mupirocin for the prevention of serious infection. J. Hosp. Infect. 40 (Suppl. B): S39–S44. Motta, F., Buonaguro, V. and Stignani, C. (2007) The use of intrathecal baclofen pump implants in children and adolescents: safety and complications in 200 consecutive cases. J. Neurosurg. 107: 32–5. Noli, M., Crispino, M., Nicosia, F., Borghi, B. and Montone, N. (2001) Diagnosis and therapy of intrathecal bleeding. Minerva Anestesiol. 67 (9 Suppl. 1): 82–91. Pray, L.G. (1941) Lumbar puncture as a factor in the pathogenesis of meningitis. Am. J. Dis. Child. 295: 62–8. Sanderson, P.J. (2001) The role of methicillin-resistant Staphylococcus aureus in orthopaedic implant surgery. J. Chemother. 13 (Spec. No. 1): 89–95.

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91 Surgical Technique for Vagus Nerve Stimulator Implantation Jeffrey W. Cozzens

O U T L I N E Surgical Anatomy

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Vagus nerve stimulation (VNS) is a treatment option for a number of disorders. The potential effectiveness of this treatment cannot be fully achieved if the device is not implanted correctly. There have been a few papers written previously that describe the technique of implantation (Amar et al., 1998, 2004; Morris and Mueller, 1999). Most of these articles were written soon after the device was approved for general use. This chapter is intended to describe this surgical technique in detail and include some ideas learned from many years of experience with this technique. It is important to note the statement from the manufacturer that accompanies the device (Cyberonics, Inc., Houston, TX). This states that the vagal nerve stimulation therapy system is indicated for use as an adjunctive therapy in reducing the frequency of seizures in adults and adolescents over 12 years of age with partial onset seizures, which are refractory to anti-epileptic medications. Use of this device is also indicated for the adjunctive long-term treatment of chronic or recurrent depression for patients 18 years

Neuromodulation

of age or older who are experiencing a major depressive episode and have not had an adequate response to four or more adequate antidepressant treatments. It cannot be used in patients after a bilateral or left cervical vagotomy.

SURGICAL ANATOMY A basic understanding of the anatomy of the neck is important for successful implantation of a vagal nerve stimulator. One should not only understand the routinely encountered structures but also the less commonly encountered structures and anatomic variants of the major structures. It is helpful to discuss these structures in the order that they are encountered during a typical surgical procedure for implantation of vagal nerve stimulator electrodes. But first one should begin with a description of the fascial planes of the neck (Figure 91.1).

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Sternocleidomastoid Sternohyoid and sternothyroid Internal carotid artery Platysma Omohyoid

Prevertebral fascia

Branch of ansa cervicalis

Esophagus

Intermediate fascia

Internal jugular vein Vagus nerve Lymph node Thyroid

Trachea

Carotid sheath Phrenic nerve Investing layer of fascia

RLN

C6

Scalenus anterior Vertebral artery

Spinal Cord

FIGURE 91.1

Diagram of the cross-section anatomy of the left neck at the level of C6 showing the relationship of the vagus nerve to the various muscles, fascial layers, and vascular structures. RLN  recurrent laryngeal nerve

An understanding of the fascial planes in the neck is very important to a successful surgical exposure. The superficial fascia is the subcutaneous tissue containing the platysma and cutaneous nerves of the cervical plexus. This most superficial layer is also called the “investing layer” because it surrounds the sternocleidomastoid and trapezius muscles. This fascia attaches in the midline posterior to the spinous process. The next layer is the intermediate layer, which envelopes the sternohyoid and sternothyroid muscles medially and the anterior and posterior bellies of the omohyoid muscle. Also included in this layer is a visceral layer that surrounds the thyroid gland, esophagus, and trachea. The deepest layer of fascia is the prevertebral fascia. The carotid sheath is a condensation of deep fascia in which is embedded the common and internal carotid arteries, internal jugular vein, and the vagus nerve. The carotid sheath blends in front with the pretracheal and investing layers of deep fascia, and behind with the prevertebral layer of the fascia. Most of the dissection for a vagal nerve stimulator electrode placement is in the anterior triangle of the neck. The anterior triangle is bounded anteriorly by the midline of the neck, posteriorly by the anterior border of the sternocleidomastoid, and superiorly by the lower margin of the body of the mandible. When one dissects in this area one first encounters the skin, the subcutaneous fat, the platysma, and the investing layer of fascia. The platysma muscle fibers usually run

vertically in the neck and are incomplete towards the midline. Branches of the transverse cutaneous nerve are found in the investing layer of cervical fascia, superficial to the sternocleidomastoid muscle. The carotid triangle is bounded superiorly by the posterior belly of the digastric, inferiorly by the superior belly of the omohyoid, and posteriorly by the anterior border of the sternocleidomastoid muscle. This triangle is important for surgical access to the carotid sheath. The carotid sheath lies just deep to the inferior corner of the carotid triangle. Within the carotid sheath lies the common carotid artery, the internal jugular vein, and the vagus nerve. Also within the carotid sheath are the nerves of the ansa cervicalis and the sympathetic plexus. The internal jugular vein is usually first encountered during a dissection into the carotid sheath at this level. Occasionally one will find a branch from the jugular vein in this region. This is usually a branch that crosses medially over the carotid artery and is a superior thyroid vein or middle thyroid vein. The common facial vein usually branches from the jugular vein at a more cephalad level, near the thyroid cartilage. The internal jugular vein is bluish in color and has a much thinner wall than the carotid artery. It is the largest structure in the carotid sheath and enlarges when the patient is in the supine position for surgery. The common carotid artery is found deep and medial to the jugular vein. The carotid artery bifurcates into the internal carotid artery and external carotid artery, usually at the level of the upper border of the thyroid cartilage. In approximately 70% of cases, the common carotid artery divides into the internal and external carotid arteries at the level of the fourth cervical vertebra (C4). In approximately 20% of cases, the division is at the C3 level, and in 10%, it is at the C5 level (Magnadottir and Harbaugh, 2000). There are usually no branches from the carotid artery inferior to the bifurcation but a descending branch of the external carotid, the superior thyroid artery, is often seen in a dissection of the common carotid. The common carotid artery is white in color and pulsates easily. It is distinguished by vasa vasorum which mark the surface of the artery. The artery was also covered with loose areolar tissue. Often the vagus nerve is adherent to the loose areolar tissue around the artery. The vagus nerve is the largest nerve in the carotid sheath. It is composed of both motor and sensory fibers. It originates in the medulla oblongata and leaves the skull through the middle of the jugular foramen in company with the IXth and XIth cranial nerves. The vagus nerve possesses two sensory ganglia: a rounded superior ganglion which is situated on the nerve within the jugular foramen, and a cylindrical

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inferior ganglion which lies on the nerve just below the foramen. Below the inferior ganglion the cranial root of the accessory nerve joints the vagus nerve and is distributed mainly in its pharyngeal and recurrent laryngeal branches. The vagus nerve passes vertically down the neck within the carotid sheath, lying at first between the internal jugular vein and the internal carotid artery and then between the vein and the common carotid artery. Its position is usually deep between the internal jugular vein and the carotid artery. The vagus nerve is separated from the sympathetic trunk by the prevertebral layer of the cervical fascia. There are several branches of the vagus nerve which are of surgical importance in the dissection in the neck. The pharyngeal branch arises from the inferior ganglion of the vagus nerve and passes between the internal and external carotid arteries to reach the pharyngeal wall. The superior laryngeal nerve arises from the inferior ganglion and runs downward and medially behind the internal carotid artery. It divides into internal and external laryngeal nerves. There are also two or three cardiac branches arising from the vagus nerve. These branches usually arise from the nerve, superior to the thyroid cartilage. On the left side, the recurrent laryngeal nerve arises from the vagus nerve as the vagus nerve crosses the arch of the aorta in the thorax. This nerve hooks around and beneath the arch behind the ligamentum arteriosum and ascends into the neck in the groove between the trachea and the esophagus. A nonrecurrent laryngeal nerve occurs in approximately 1% of patients on the right but is extremely rare on the left (Toniato et al., 2004). The ansa cervicalis is a plexus of nerves that arise from the cervical plexus, formed by the anterior rami of the first four cervical nerves. The ansa cervicalis also lies within the carotid sheath but usually is anterior to the carotid artery and jugular vein. It is important to distinguish this nerve from the vagus nerve so as to avoid placing the stimulating electrodes on the wrong nerve. The ansa cervicalis supplies the sternohyoid muscle, the sternothyroid muscle, the omohyoid muscle, and the sternocleidomastoid muscle. Deep to the carotid sheath is the prevertebral layer of fascia. This fascia covers not only the vertebral body and the longus coli muscles on the anterior vertebral bodies but also of the scalenus anterior muscle. Within the prevertebral fascia and deep to the carotid sheath is the phrenic nerve. The cervical part of the sympathetic trunk extends upward to the base of the skull and below to the neck of the first rib where it becomes continuous with the thoracic part of the sympathetic trunk. It lies directly

behind the internal and common carotid arteries (i.e., medial to the vagus) and is embedded in deep fascia between the carotid sheath and the prevertebral layer of deep fascia. There is a superior cardiac branch of the sympathetic trunk, which descends in the neck behind the common carotid artery. It ends in the cardiac plexus in the thorax. At the most inferior end of the anterior neck exposure and deep to the prevertebral fascia is the thoracic duct. In the lowest part of the neck the thoracic duct passes upward along the left margin of the esophagus. As it reaches the level of the transverse process of the 7th cervical vertebra it bends laterally behind the carotid sheath and in front of the vertebral vessels. On reaching the medial border of the scalenus anterior it turns downward in front of the left phrenic nerve and the first part of the subclavian artery.

OPERATIVE TECHNIQUE The following is a description of the surgical technique of vagus nerve stimulator implantation used at Evanston Hospital. This technique has evolved over the past ten years and about 300 implants and is still evolving as we learn better ways to do things. This description is not intended to be an authoritative and complete account, since acceptable variations occur with certain operative situations and surgeon preference. One must be sure that all of the implantable devices and materials are available before beginning the procedure. The surgeon should interrogate the generator while it is still in the sterile package using the programming device to insure the function of the device. As with all surgical implants, we usually do not open the sterile package until the implant is actually needed in surgery. Infection is a very serious complication and in most instances requires removal of the device. For this reason prophylactic antibiotics should be given to the patient before surgery. In our institution we usually give the patient an infusion of gentamicin and vancomycin before surgery (except when the patient is allergic to these medications). We also give the patient 10 days of oral antibiotics after surgery. The surgery is usually done under general anesthesia. There have been reports of this procedure being done under local anesthesia but this is not widely performed (Bernard et al., 2002). The patient should be placed on the operating table in the supine position. The anesthesiologist is usually positioned at the head of the table and the surgeon is on the left side. Sometimes the left arm is extended on an arm board.

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This is generally done if the incision for the generator is made along the anterior border of the axilla. If the incision for the generator is made in one of Langer’s lines (Wilhelmi et al., 1999), extending from the superior edge of the axilla, then the arm can be tucked at the side, taking great care to prevent any unusual pressure on the neurovascular structures in the arm including the ulnar nerve. A small roll of a towel is usually placed behind the neck to allow gentle extension of the neck. The patient’s head can usually be in the midline or turned slightly to the right (Figure 91.2). In our institution the skin is usually cleaned and prepared three times. We first clean all the skin surfaces with isopropyl alcohol. We then wash the skin with iodinated soap and then iodinated solution. This is dried and then the skin is finally prepared with a solution of iodine povacrylex (0.7% available iodine) and isopropyl alcohol (DuraPrep, 3M Health Care, St Paul, MN). This is allowed to air dry. The incisions are marked with a sterile pen. The midline is identified as well as the anterior border of the left sternocleidomastoid muscle. The cricoid cartilage is palpated and a line is drawn following a skin crease, lateral to the cricoid cartilage and centered on the anterior border of the sternocleidomastoid muscle. This usually allows the incision to be centered at about the level of C5–C6. The incision should be about 3–4 cm in length to allow for adequate vertical exposure of the vagus nerve. In the axilla, the incision line is usually marked along the anterior border of the axilla or it can follow one of Langer’s lines extending from the superior edge of the axilla. The surgical area is draped off with towels and then covered with an iodinated plastic adhesive drape. The skin at the site of incisions is then infiltrated with 1% lidocaine and 0.5% bupivacaine mixed together in a 50–50 solution. The neck incision is then made through the skin and subcutaneous fat to the platysma. The platysma was separated from the subcutaneous fat with sharp dissection so as to expose 3–4 cm of the platysma from superior to inferior. A self-retaining Wietlander retractor usually helps to expose this area. An incision is then made in the platysma, following the underlying anterior border of the sternocleidomastoid muscle. A dissection is then made through the fascia to the plane between the sternocleidomastoid and the strap muscles (sternohyoid and sternothyroid muscles). This dissection should be made in the loose areolar tissue in the fascial plane between the sternocleidomastoid muscle and the strap muscles so as to minimize bleeding. Small branches of the external jugular vein can sometimes be identified in this region and usually can be ligated and cut without consequence. There are small muscular branches of the nerves of the ansa cervicalis also seen in this region. Every effort should be

Incision line in neck

Medial border of sternocleidomastiod Incision line in axilla

FIGURE 91.2 View of the left side of a supine individual positioned on the operating table for vagal nerve stimulator implant surgery. The midline of the neck is marked with a continuous line and the medial border of the sternocleidomastoid muscle is marked with a dashed line. The neck incision is made in the natural creases in the neck and the axillary incision is made following Langer’s lines

made to preserve as many of these branches as possible, but some of them may need to be cut to allow sufficient access to the deeper structures. The omohyoid muscle is usually seen in the middle of the exposure. Its orientation is almost perpendicular to the sternocleidomastoid muscle and a small triangle containing fatty tissue is found at the superior junction of the omohyoid muscle and the sternocleidomastoid muscle. The jugular vein is usually directly underneath this triangle. Great care is taken to separate the omohyoid muscle from the sternocleidomastoid and then the omohyoid muscle is mobilized and retracted medially and inferiorly. Except for a small Wietlander self-retaining retractor for the skin, we have not found any self-retaining retractors that are reliable and safe for the deep neck dissection. We usually therefore place sutures in the fascia surrounding structures that need to be retracted. Therefore to retract the omohyoid muscle inferiorly and medially, we place a suture in the fascia surrounding the muscle and then clamp the suture to the drapes with a hemostat. This technique also works for other structures including the sternocleidomastoid muscle, which is retracted laterally. The jugular vein is then exposed by careful dissection into the fascial plane found deep to the omohyoid muscle. Dissection into this fascial plane allows entry into the carotid sheath. Inside the carotid sheath is loose areolar tissue and often several nerves are seen. If these nerves are superficial in the carotid sheath,

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they are most likely to be laryngeal branches of the vagus nerve or branches of the ansa cervicalis. These nerves are usually no larger than 1–1.5 mm in diameter and will have many branches. It is important not to confuse these nerves with the vagus nerve which is much larger and deeper in the carotid sheath. There is sometimes seen a small branch of the jugular vein (most likely a medial thyroid branch) which crosses anteriorly and medially from the anteromedial surface of the jugular vein. This vein often must be ligated and cut to allow adequate exposure of the vagus nerve. The common facial vein is rarely seen entering the jugular vein since it is usually found more cephalad to this exposure at C5–C6. If encountered, the facial vein can usually be mobilized and retracted cephalad. The common carotid artery is medial and deep to the jugular vein. Further dissection of the carotid sheath medial to the jugular vein is made with blunttipped dissecting scissors until the surface of the common carotid artery is seen. If one is at the proper level of dissection (about C5–C6) then one should not see any branches from the carotid artery. If one sees branches from the carotid artery, then the dissection is too high in the neck at the level of the external carotid artery and one therefore needs to dissect further caudal to be at the level of the common carotid artery. The jugular vein can usually be retracted laterally by carefully placing a suture in the loose adventitia surrounding the jugular vein, and clamping the suture to the drapes. The vagus nerve is found deep within the carotid sheath, between and deep to the jugular vein and common carotid artery (Figure 91.3). The vagus nerve usually cannot be found without lateral retraction of the jugular vein, but retraction of the common carotid artery is rarely necessary. The vagus nerve lies within the fascia of the carotid sheath, deep and lateral to the common carotid artery. It is adherent to the fascia and mobilization of the nerve requires careful sharp dissection. At this point, use of DeBakey forceps is very important to minimize damage to the nerve and surrounding structures. The adventitia of the nerve can usually be held by the DeBakey forceps and the nerve can be elevated from the deep fascia of the carotid sheath to allow dissection around the nerve. Great care must be taken when one is dissecting the vagus nerve since the nerve can be easily damaged by excessive retraction or manipulation. The use of vessel loops around the nerve can sometimes lead to inadvertent excessive traction on the nerve and we therefore avoid their use. One must also be careful to preserve the vasa nervosum in the adventitia around the nerve so as to preserve its function. There are usually no branches of the vagus nerve at the level of this dissection at C5–C6. If numerous

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FIGURE 91.3 Intraoperative photograph showing the left vagus nerve being dissected from the loose areolar fascia within the carotid sheath. The instrument on the right is retracting the internal jugular vein and the instrument on the left is on the common carotid artery. The vagus nerve is running horizontally in the fascia between the two instruments from caudal on the left to cephalad on the right

branches are found coming off the nerve, then either the nerve has been exposed too far caudally or too far cephalad, or the nerve is in fact not the vagus nerve. Some surgeons will place a small square cut from a surgical glove under the nerve so as to isolate the nerve from the surrounding tissue. An inspection of the nerve should be made at this time so as to judge the size of the stimulating electrode. It is important not to select an electrode that is too large since this will not allow a close fit of the electrode contacts to the nerve. An electrode that is too small will strangle the nerve and damage it over time. A dissection should be made in the space caudal to the exposed nerve which is between the omohyoid and the carotid sheath. This space will accommodate a strain relief loop of the electrode after the electrode is situated on the nerve. At this time, a second incision is then made in the chest, anterior to the axilla, for the pulse generator. A dissection is made to the fascia covering the pectoralis muscle. A pocket for the pulse generator is then made between the subcutaneous fat and the pectoralis muscle. Some surgeons have recommended implanting the pulse generator deep to the pectoralis muscle in patients with very little body fat (Bauman et al., 2006). The packages containing the tunneling tool and the electrode are then opened, and the tunneling tool and tunneling sheath are assembled. The tunneling tool is passed through the subcutaneous fat between the two incisions. The bullet tip is removed from the tunneling tool and the metal rod is removed from the sheath. The connector tip of the electrode is

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introduced into the tunneling sheath at the level of the neck incision and then the tunneling sheath and electrode together are pulled through to the incision in the axilla. The three helical electrode coils are then placed on the vagus nerve (Figure 91.4). This is best done with magnification, either using an operating microscope or loupes. The helical coils consist of a tethering (inactive) coil and two electrode coils. The tethering coil is the coil closest to the body of the electrode cable and is marked with a blue–green suture. The middle helical coil is the positive electrode as marked with a white suture. The distal helical coil is the negative electrode and is marked with a blue–green suture. The electrodes must be placed with the anchor coil being the most caudal coil and the distal negative electrode being the most cephalad coil. Microsurgery forceps are used to manipulate the coils so that they will wrap around the nerve. We found that this is accomplished best when one of the microsurgery forceps has a straight tip and the other has a curved-tip. Before placing the coils on the nerve, the surgeon should carefully inspect the helical coil in relationship to the nerve and think carefully about how the coil will wrap around the nerve. Some surgeons find success with holding the coil at a 45 degree angle to the nerve and then placing the coil around the nerve. The coil should be manipulated by using the attached sutures and not by directly handling the electrode surface. We have found that it is easiest to place the caudal tethering coil first, followed by the middle

FIGURE 91.4 Intraoperative photograph showing the process of placement of helical electrodes on the left vagus nerve. A small square cut from a sterile glove has been placed under the nerve which runs from left (caudal) to right (cephalad). The most proximal, anchoring coil is being placed on the caudal portion of the nerve. The middle and distal coils have not been placed

positive coil and finally the cephalad negative coil. This sequence allows for stabilization of the electrode on the nerve and makes placement easier. The company that manufactures the device (Cyberonics, Inc., Houston, TX) also makes a training model of the vagus nerve that surgeons can use prior to surgery to practice placing the coils on the nerve. Once the coils are placed, a 3 cm portion of the electrode cable must be looped caudally into the space previously created by a dissection deep to the omohyoid muscle. This loop allows for strain relief but also allows the distal portion of the electrode cable to be oriented cephalad, parallel to the nerve. This loop therefore minimizes the chance of the coils dislodging from the nerve resulting from normal movement of the neck. The cable is anchored to the surrounding tissue using the Silastic tie-downs supplied with the electrode and a small nonabsorbable suture. The rubber sheet under the nerve and the retracting sutures are then removed, taking great care to prevent dislodgment of the electrodes. The electrode cable is then coiled in a further strain relief loop in a pocket under the platysma and anchored to the sternocleidomastoid with another Silastic tiedown. The platysma is then closed with several small absorbable sutures. The package containing the pulse generator is then opened (Figure 91.5). Neither the pulse generator nor the lead should be immersed in any fluid before implantation. Immersion may cause the insulated portions of the connector pin to swell and become difficult to insert into the pulse generator. The holes for the electrode lead connector pin in the pulse generator should be inspected to make sure that there is no obstruction. The set screw should not be visible in this hole. If it is visible the set screw should be backed out

FIGURE 91.5 Two commonly used VNS pulse generators (Cyberonics, Inc., Houston, TX) with a US quarter for size comparison. The smaller generator (Demipulse Model 103) was introduced in 2008

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using the hex screwdriver. The hex screwdriver should then be inserted into the set screw plug to relieve back pressure. The connector pin should then be inserted into the connector port in the pulse generator. The position of the connector pin should be inspected through the clear plastic to be sure that the pin is advanced far enough into the connector port. The set screw is then tightened using the hex screwdriver. The screwdriver is a torque wrench and will click when the appropriate tightness is achieved. The programming wand should then be placed in a sterile plastic bag for use on the surgical field. These bags are usually found in an operating room for use with a laser or with an ultrasound probe. Some surgeons prefer to have both the programming wand and the small hand-held computer both inserted into the sterile plastic bag so that the surgeon can both place the programming wand on the pulse generator and do the initial diagnostic tests himself. The programming wand and computer are used then to perform the system diagnostic tests. When these are complete, the pulse generator is placed into the subcutaneous pocket. It does not matter whether the logo on the pulse generator is facing up or down. A nonabsorbable suture can be used to secure the pulse generator to the subcutaneous fat. One should avoid any sharp bends in the lead. The lead is usually coiled around the pulse generator in the subcutaneous pocket. After implantation, final system diagnostic tests should be repeated using the programming wand and computer. The final programming step is to verify that the output current is 0 milliamps. We usually closed the wounds with a small absorbable suture for the subcutaneous tissue. The skin incisions are both closed with a subcuticular technique using a small monofilament absorbable suture on a cutting needle. We then apply sterile adhesive strips over the wound in several layers. These adhesive strips protect the wound and serve as a dressing for the incisions. In our institution, most patients will be able to go home the same day as the surgery. About a third of the patients will stay overnight and be released the following day. There is usually very little pain associated with the implant procedure. As a further precaution to prevent infection, we usually send patients home with 10 days of oral antibiotics.

wires in the electrode lead. This is usually found with diagnostic tests of the pulse generator using the programming wand and hand-held computer. Breakage can also be confirmed, usually with an x-ray of the device. Surgery for replacement of the electrode lead is usually more difficult than the initial implantation (Espinosa et al., 1999; MacDonald and Couldwell, 2004). Scar tissue makes the surgery more tedious. With a second surgery the risk of damage to the structures within the carotid sheath is significantly increased. Injury to the internal jugular vein and/or the vagus nerve is more common with a second surgery. Nevertheless the presence of the old electrode lead usually will help guide the surgeon to the vagus nerve, assuming that the lead was on the vagus nerve in the first place. If there is evidence that the device had a beneficiary effect at one time, then one can usually assume that the electrode was on the vagus nerve. If the surgeon is asked to revise the electrode because it never had any effect, then the risk of unsuccessful electrode revision surgery is much greater. In both cases the surgeon must warn the patient that re-implantation might not be possible. Once the nerve is isolated, the old electrode lead can usually be removed without difficulty and the new electrode lead placed. Sometimes it is advisable to use the 3 mm diameter helical electrode coils for a revision since the nerve is usually enlarged with scar tissue.

REPLACEMENT OF THE ELECTRODE LEAD

COMPLICATIONS OF SURGERY

The surgical procedure for replacement of the electrode is indicated if there is any breakage of the

REPLACEMENT OF THE PULSE GENERATOR Depending upon the amount of stimulation, the pulse generator will last 3–5 years before battery depletion. Replacement of the pulse generator is usually performed under local anesthesia and with sedation. The pulse generator should be turned off before surgery. It is very important to be cautious about dissection around the pulse generator. One should avoid touching the metal case of the pulse generator with electrocautery. One should also be very careful to avoid cutting the electrode lead or damaging it with heat from the electrocautery. If the electrode lead is damaged, it will need to be replaced.

Infection is the most common serious complication of the surgery. Although some authors have reported resolution of infection without removing the device

XI. NEUROMODULATION DEVICE IMPLANT TECHNIQUES

1040

91. SURGICAL TECHNIQUE FOR VAGUS NERVE STIMULATOR IMPLANTATION

(Liechty et al., 2006), this is rare (Patel and Edwards, 2004). Usually infection requires removal of the entire device. There are exceptions to this rule, however. We have had one instance where the pulse generator eroded through the skin in a woman with very little body fat. We opened both the incision in the neck and the incision in the chest and removed the pulse generator and the portion of the lead in the subcutaneous fat between the two incisions. We cut the electrode at the neck incision so that the distal portion of the electrode lead remained attached to the vagus nerve. By leaving the cut electrode attached to the vagus nerve, this allowed for an easier dissection when the electrode lead was replaced several weeks later. Another complication associated with surgery is damage to the structures in and around the carotid sheath. This can include damage to the vagus nerve, the jugular vein, carotid artery, ansa cervicalis, phrenic nerve, thoracic duct, and recurrent laryngeal nerve. Reports of damage associated with vagal nerve stimulation implantation surgery to these structures are rare, however. Hoarseness due to activation of the device is common, especially in the first few weeks of stimulation. Hoarseness due to damage associated with initial vagal nerve stimulation implantation surgery to the recurrent laryngeal nerve or vagus nerve is also rare (Murphy et al., 1998; Smyth et al., 2003; Rychlicki et al., 2006; Shaw et al., 2006).

CONCLUSION A thorough understanding of the surgical anatomy of the vagus nerve and carotid sheath is essential to successful implantation of a vagal nerve stimulator device.

References Amar, A.P., Heck, C.N., Levy, M.L., Smith, T., DeGiorgio, C.M., Oviedo, S. et al. (1998) An institutional experience with cervical vagus nerve trunk stimulation for medically refractory epilepsy: rationale, technique, and outcome. Neurosurgery 43: 1265–76, discussion 1276–80.

Amar, A.P., Levy, M.L. and Apuzzo, M.L. (2004) Vagus nerve stimulation for intractable epilepsy. In: H.R. Winn and J.R. Youmans (eds), Youmans Neurological Surgery, 5th edn. New York: W.B. Saunders, pp. 2643–50. Bauman, J.A., Ridgway, E.B., Devinsky, O. and Doyle, W.K. (2006) Subpectoral implantation of the vagus nerve stimulator. Neurosurgery 58: ONS-322–5; discussion ONS-325–6. Bernard, E.J., Passannante, A.N., Mann, B., Lannon, S. and Vaughn, B.V. (2002) Insertion of vagal nerve stimulator using local and regional anesthesia. Surg. Neurol. 57: 94–8. Espinosa, J., Aiello, M.T. and Naritoku, D.K. (1999) Revision and removal of stimulating electrodes following long-term therapy with the vagus nerve stimulator. Surg. Neurol. 51: 659–64. Liechty, P.G., Tubbs, R.S. and Blount, J.P. (2006) The use of a sump antibiotic irrigation system to save infected hardware in a patient with a vagal nerve stimulator: technical note. Surg. Neurol. 65: 48–9, discussion 49–50. MacDonald, J. and Couldwell, W.T. (2004) Revision of vagal nerve stimulator electrodes: technical approach. Acta Neurochir. (Wien) 146: 567–70, discussion 570. Magnadottir, H.B. and Harbaugh, K.S. (2000) Anatomic considerations in the treatment of extracranial cerebrovascular disease. Neurosurg. Clin. North Am. 11: 265–77. Morris, G.L., 3rd and Mueller, W.M. (1999) Long-term treatment with vagus nerve stimulation in patients with refractory epilepsy. The Vagus Nerve Stimulation Study Group E01-E05. Neurology 53: 1731–5. Murphy, J.V., Hornig, G.W., Schallert, G.S. and Tilton, C.L. (1998) Adverse events in children receiving intermittent left vagal nerve stimulation. Pediatr. Neurol. 19: 42–4. Patel, N.C. and Edwards, M.S. (2004) Vagal nerve stimulator pocket infections. Pediatr. Infect. Dis. J. 23: 681–3. Rychlicki, F., Zamponi, N., Cesaroni, E., Corpaci, L., Trignani, R., Ducati, A. et al. (2006) Complications of vagal nerve stimulation for epilepsy in children. Neurosurg. Rev. 29: 103–7. Shaw, G.Y., Sechtem, P., Searl, J. and Dowdy, E.S. (2006) Predictors of laryngeal complications in patients implanted with the Cyberonics vagal nerve stimulator. Ann. Otol. Rhinol. Laryngol. 115: 260–7. Smyth, M.D., Tubbs, R.S., Bebin, E.M., Grabb, P.A. and Blount, J.P. (2003) Complications of chronic vagus nerve stimulation for epilepsy in children. J. Neurosurg. 99: 500–3. Toniato, A., Mazzarotto, R., Piotto, A., Bernante, P., Pagetta, C. and Pelizzo, M.R. (2004) Identification of the nonrecurrent laryngeal nerve during thyroid surgery: 20-year experience. World J. Surg. 28: 659–61. Wilhelmi, B.J., Blackwell, S.J. and Phillips, L.G. (1999) Langer’s lines: to use or not to use. Plast. Reconstr. Surg. 104: 208–14.

XI. NEUROMODULATION DEVICE IMPLANT TECHNIQUES

A P P E N D I X

1 Advanced Neuromodulation Systems (ANS) IPG Specifications

Product Model Number

Renew 3416

Genesis 3608

Genesis XP 3609

Eon 3716

Eon Mini 3788

Eon C 3688

FDA-Approved applications

SCS in the treatment of chronic pain of the trunk and limbs, and to electrically stimulate peripheral nerves

An aid in the management of chronic intractable pain of the trunk and limbs

SCS in the treatment of chronic pain of the trunk and limbs

SCS in the treatment of chronic pain of the trunk and limbs

SCS in the treatment of chronic pain of the trunk and limbs

SCS in the treatment of chronic pain of the trunk and limbs

Number of contacts

16

8

8

16

16

16

Regulated (constant) current or voltage

Constant voltage

Constant current

Constant current

Constant current

Constant current

Constant current

Amplitude

0–12.0 V

0–25.5 mA

0–25.5 mA

0–25.5 mA

0–25.5 mA

0–25.5 mA

Frequency (Hz)

0–1500

0–200

0–200

0–1200

0–1200

0–1200

Frequency management modes

Passive

Passive

Passive

Passive, 1:2 active and 1:4 active

Passive, 1:2 active and 1:4 active

Passive, 1:2 active and 1:4 active

Pulse width (μs)

10–500

52–507

52–507

50–500

50–500

50–500

Battery chemistry:

External disposable AAA alkaline batteries or rechargeable lithium ion battery pack

Lithium thionyl chloride primary cell

Lithium thionyl chloride primary cell

Rechargeable lithium ion

Rechargeable lithium ion

Lithium thionyl chloride primary cell

Programs

24

24

24

24

24

24

Stim sets per program

8

2

2

8

8

8

Device life approval (rechargeable)

N/A

N/A

N/A

10 yr @ high settings, open-ended

10 yr @ high settings, open-ended

N/A

Primary cell battery capacity (Ahrs)

N/A

3.7

8.2

N/A

N/A

8.9

Implant depth maximum

1 cm

4 cm

4 cm

2.5 cm

2.5 cm

4 cm

Neuromodulation

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A P P E N D I X

2 Medtronic IPG Specifications

Manufacturer: Medtronic Model number: InterStim II #3058 FDA-Approved application(s): Sacral nerve stimulation (SNS). InterStim Therapy for Urinary Control is indicated for the treatment of urinary retention and the symptoms of overactive bladder, including urinary urge incontinence and significant symptoms of urgency-frequency alone or in combination, in patients who have failed or could not tolerate more conservative treatments Number of channels (electrodes): 4 Regulated (constant) current or voltage: Constant voltage Output waveform (description or drawing): Balanced biphasic stimulation protocol Range of output parameters: Voltage 08.5 V Frequency 2–130 Hz Pulse train specifications: Pulse width 60–450 μsec Power supply type: Conventional primary cell battery IPG packaging type (polymer/metal/ceramic): Neurostimulator material: custom titanium enclosure Connector type: custom polyurethane connector module Imaging: Specifications: compatible with X-ray and ultrasound per product labeling restrictions Unique safety features: Proprietary electromagnetic compatibility (EMC) protection circuits prevent cell phone and theft detector interactions Programming features: Programmed using Model 8840 Medtronic N’Vision Programmer Special features of programming: Custom patient programmer with LCD display allowing patients to adjust stimulation voltage and to switch between clinician-created therapy settings

Neuromodulation

Manufacturer: Medtronic Model Number: Prime Advanced #37702 FDA-Approved application(s): Spinal cord stimulation (SCS) Number of channels: 16 Regulated (constant) current or voltage: Constant voltage Output waveform (description or drawing): Balanced biphasic stimulation protocol Range of output parameters: Voltage 0–10.5 V Frequency 2–260 Hz Pulse train specifications: Pulsewidth 60–450 μsec Power supply type: Rechargeable lithium ion battery IPG packaging type (polymer/metal/ceramic): Neurostimulator material: custom titanium enclosure Connector type: custom polyurethane connector module Imaging: Specifications: Compatible with X-ray, ultrasound, and MRI per product labeling restrictions Unique safety features: Proprietary electromagnetic compatibility (EMC) protection circuits prevent cell phone, theft detector, and MRI interactions Programming features: Programmed using Model 8840 Medtronic N’Vision Programmer Special features of programming: Custom patient programmer with LCD display and patent pending Target MyStim capability

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MEDTRONIC IPG SPECIFICATIONS

Manufacturer: Medtronic Model number: Restore Advanced #37713 FDA-Approved application(s): Spinal cord stimulation (SCS) Number of channels: 16 Regulated (constant) current or voltage: Constant voltage Output waveform (description or drawing): Balanced biphasic stimulation protocol Range of output parameters: Voltage 0–10.5 V Frequency 2–260 Hz Pulse train specifications: Pulsewidth 60–450 μsec Power supply type: Rechargeable lithium ion battery IPG packaging type (polymer/metal/ceramic): Neurostimulator material: custom titanium enclosure and polysulfone Connector type: custom polyurethane connector module Imaging: Specifications: Compatible with X-ray, ultrasound, and MRI per product labeling restrictions Unique safety features: Proprietary electromagnetic compatibility (EMC) protection circuits prevent cell phone, theft detector, and MRI interactions Programming features: Programmed using Model 8840 Medtronic N’Vision Programmer Special features of programming: Custom patient programmer with LCD display and patent pending Target MyStim capability

1043

Manufacturer: Medtronic Model number: Restore Ultra #37712 FDA-Approved application(s): Spinal cord stimulation (SCS) Number of channels: 16 Regulated (constant) current or voltage: Constant voltage Output waveform (description or drawing): Balanced biphasic stimulation protocol Range of output parameters: Voltage 0–10.5 V Frequency 2–1200 Hz Pulse train specifications: Pulsewidth 30–1000 μsec Power supply type: Rechargeable lithium ion battery IPG packaging type (polymer/metal/ceramic): Neurostimulator material: custom titanium enclosure Connector type: custom polysulfone connector module Imaging: Specifications: Compatible with X-ray, ultrasound, and MRI per product labeling restrictions Unique safety features: Proprietary electromagnetic compatibility (EMC) protection circuits prevent cell phone, theft detector, and MRI interactions Programming features: Programmed using Model 8840 Medtronic N’Vision Programmer Special features of programming: Custom patient programmer with LCD display and patent pending Target MyStim capability

A P P E N D I X

3 Boston Scientific Neuromodulation IPG Specifications Manufacturer: Boston Scientific Neuromodulation Model number: SC1110 – Precision FDA-Approved application(s): P030017 Number of channels: 16 electrode contacts. Each electrode contact has a dedicated bidirectional constant current source Output waveforms: Passive recharge (130 pps) or symmetrical biphasic (130 pps) 100 μs

6 ms

201000 μs Passive recharge 100 μs

201000 μs

Neuromodulation

Symmetrical biphasic

Range of output parameters: Current: 0.1–12.7 mA per anode or cathode, up to 20 mA total Voltage: Up to 15 V (depends on tissue impedances) Pulse rate: 2–1200 pulses per second Pulse train specifications: Areas: Up to 4 interlaced at different pulse rates Cycle on time: 1 s–90 minutes Cycle off time: 1 s–90 minutes Ramp up time: 1 s–10 s Power supply type: Rechargeable lithium ion ZeroVolt™ cell, 200 mAh capacity IPG packaging type: Titanium Grade 5 case Epoxy header with two custom 8 contact in-line connector ports Imaging: X-ray and CAT scan OK. MRI is contraindicated. Unique safety features: ZeroVolt™ rechargeable cell can be discharged and stored without damaging cell. Stimulation pulse current regulated on all anodes and cathodes Programming features: Simulation parameters adjustable using clinician programmer or patient remote control. Stimulation current distribution on electrodes can be directionally adjusted using joystick to target stimulation field Interrogation capabilities of IPG: Stimulation program usage, impedance trends

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Index A AAV, see Adeno-associated virus Abdominal pain, see Visceral pain ACE, see Advanced combination encoder Acetylcholine, lower urinary tract neurotransmission, 909–910, 912 Action potential electrical generation, 112–114 neural interface system signaling, 233 overview, 112 recording, 194 Activation function, membrane potential, 113 Activa Tremor Control System, magnetic resonance imaging safety, 264, 265f, 266–269b 270 Addiction diagnostic criteria, 703 pain medication dependency case example, 23–24b surgical management complications, 708 deep brain stimulation programming, 707–708 indications, 705 nucleus accumbens targeting rationale, 704–705 outcomes, 708 patient selection, 705 perioperative patient management, 706–707 prospects, 708–709 technique, 705, 706f treatment goals, 704 Adeno-associated virus (AAV), gene therapy vectors, 133 Adenosine, intrathecal therapy, 477 Adenovirus, gene therapy vectors, 133

Neuromodulation

Advanced Bionics, product development case study, 36–40 Advanced combination encoder (ACE), cochlear implant, 718 Advanced Neuromodulation Systems (ANS) specifications for implantable pulse generators, 1041 spinal cord stimulation devices, 278 Advances in External Control of Humans Extremities (ECHE), meetings, 57–58 AF, see Atrial fibrillation Alzheimer’s disease cell transplantation therapy, 989, 990f nerve growth factor, 989–990 AMAT, see Arm Motor Ability Test American Society for Stereotactic and Functional Neurosurgery (ASSFN), historical perspective, 50–51 g-Aminobutyric acid (GABA) antinociception role, 295 epilepsy pathophysiology, 621–622 lower urinary tract neurotransmission, 920 spinal cord stimulation effects in analgesia, 349, 379 Amyotrophic lateral sclerosis, see Motor impairment Angina pectoris management approaches, 832, 834 pathophysiology, 831, 832f, 833f pharmacotherapy, 833t spinal cord stimulation cardiac neural control, 834, 835f complications, 839–840 cost analysis, 360–364 historical perspective, 835–836 implantation, 836–837 mechanism of action, 839f

1045

outcomes, 838–839 overview, 796–797 patient selection, 836f programming, 837, 838t prospects, 840–841 Angiotensin II, receptors in bed nucleus of the stria terminalis, 684 Anisotropic electrical conductivity, 147–149 Anode, definition, 110 ANS, see Advanced Neuromodulation Systems; Autonomic nervous system Anterior nucleus stimulation, see Epilepsy Antidepressants, pain management, 321 AP-5, pain studies, 307 Arm Motor Ability Test (AMAT), motor cortex stimulation studies in stroke, 757–758, 759f, 760, 761, 762f, 763f, 764f Arrhythmia, see Cardiac arrhythmia ASSFN, see American Society for Stereotactic and Functional Neurosurgery Assistive technologies, see Neural interface system ATP, lower urinary tract neurotransmission, 906–907, 910–914 Atrial fibrillation (AF), parasympathetic neuromodulation, 859–860 Atrioventricular block, cardiac pacing, 811, 812t Auditory nerve, see Cochlear implant Autonomic nervous system (ANS) organization, 185, 186f, 187 transcutaneous electrical nerve stimulation effects, 340

© 2008, 2009 Elsevier Ltd.

1046 Autonomic nervous system, gross anatomy, 98–99, 102f, 103f, 104f Avery, Roger, 13, 15 Axon, diameter and electrical field effects, 111

B Baaken, Earl, 42f Baclofen, see also Intrathecal baclofen properties, 475 spasticity management intrathecal baclofen, 563 oral baclofen, 562–563 outcomes, 565 patient selection, 563 prerequisites, 561–562 pump implantation and programming, 563–564 risks, 564–565 Balanced charge, biphasic pulse, 119 Barolat, Giancarlo, 54f Bartholow, Roberts, 10f, 87 Basal ganglia, gross anatomy, 95–96, 97f Battery, implantable neural stimulators, 221–222, 223t BDI, see Beck Depression Inventory BDNF, see Brain-derived neurotrophic factor Beck Depression Inventory (BDI), 70–71 Bed nucleus of the stria terminalis (BST) acetylcholinergic system, 683 angiotensin II receptor, 684 brain-derived neurotrophic factor, 684 calcium-binding proteins, 683 catecholaminergic system, 683–684 cytoarchitecture, 678, 679f, 680f divisions, 678 limbic system-associated membrane protein, 683 nerve growth factor, 684 neuropeptides cocaine-and amphetamineregulated transcript, 681 galanin, 681 granins, 682–683 luteinizing hormone-releasing hormone, 682 neuropeptide Y, 680 neurotensin, 682 opioid peptides, 681 oxytocin, 680 pituitary adenylate cyclase activating polypeptide, 681–682 somatostatin, 680–681

INDEX

tachykinins, 682 vasoactive intestinal polypeptide, 682 vasopressin, 680 sex hormone-binding globulin, 684 sexual dimorphism, 683–684 steroid receptors, 684 Benebid, Alim, 15, 16f BION microstimulator, magnetic resonance imaging safety, 259–260, 261b pudendal nerve stimulation, 940, 941f Bladder, see Lower urinary tract; Painful bladder syndrome; Sacral nerve stimulation; Urinary retention; Voiding dysfunction Blindness, see also Retinal prosthetic devices ciliary neurotrophic factor therapy, 726–727 epidemiology, 723, 724f, 725 gene therapy, 727 sensory substitution therapy, 726 stem cell therapy, 726 Blood pressure, see Hypertension; Orthostatic hypotension Body mass index, see Obesity Boston Retinal Implant Project (BRIP), see Retinal prosthetic devices BOTOX, see Botulinum toxin Botulinum toxin (BOTOX), dystonia management, 572 Brain, gross anatomy, 95, 96f, 97f, 98f, 99f Brain–computer interface, see Neural interface system Brain-derived neurotrophic factor (BDNF) antinociception role, 296, 307 bed nucleus of the stria terminalis, 684 Brain infusion therapy anatomy and physiology, 978–980 convection enhanced delivery, 981 historical perspective, 980–981 indications, 978t prospects, 981–982 rationale, 977–978 therapeutic agents, 978t BRIP, see Boston Retinal Implant Project Brophy, Brian, 52f BST, see Bed nucleus of the stria terminalis Bupivacaine, intrathecal therapy, 469–470 Burr-hole, drilling for deep brain stimulation, 999, 1000f

C Cable equations, 193–194 Calcitonin gene-related peptide (CGRP) lower urinary tract neurotransmission, 909, 913 nociception role, 100, 288 Calcium flux, central pain sensitization, 294–295 Calkins, Sherri Kae, 54f Cardiac arrhythmia neurostimulation parasympathetic neuromodulation, 859–860 sympathetic neuromodulation, 858–859 pathophysiology, 858 pharmacotherapy, 858 tachyarrhythmia and cardiac pacing, 813 Cardiac defibrillator, see Implantable cardiac defibrillator Cardiac pacemaker anatomy and physiology, 810, 811f cardiac resynchronization therapy, 805–806, 812–813 complications, 813–814 components, 801–802 endocardial pacing leads, 810 historical perspective, 801, 807–809 implantation, 802, 810 indications atrioventricular block, 811, 812t carotid sinus hypersensitivity, 813 heart failure, 805–806, 812–813 hypertrophic cardiomyopathy, 813 sinoatrial node dysfunction, 811 tachyarrhythmia, 813 vasovagal syncope, 813 mode-switch algorithms, 804–805 programming code, 802, 803t, 808t prospects, 806, 814 sensing, 810 stimulation, 809–810 strength–duration curve, 809 timing cycles, 803–804 Cardiac resynchronization therapy (CRT), 805–806, 812–813 Carotid sinus hypersensitivity, cardiac pacing, 813 Carotid sinus stimulation, hypertension management animal studies, 849 aortic arch role, 850, 851f clinical trials, 851, 852f human studies, 850f prospects, 852–863 CART, see Cocaine-and amphetamineregulated transcript

INDEX

Cathode, definition, 110 Caudate nucleus, deep brain stimulation for epilepsy, 645 CED, see Convection enhanced delivery Centromedian nucleus afferent fibers, 601–602 deep brain stimulation for epilepsy, 645 efferent fibers, 602 histology, 601 Centromedian–parafascicular complex anatomical overview, 600–601 deep brain stimulation for hyperkinetic movements data interpretation, 604–605, 609, 610f neurophysiological investigations, 608 outcomes, 609–610, 611f patient selection, 605 postoperative evaluation, 608, 609f prospects, 611–612 surgical planning and stereotactic anatomy, 605, 606f, 607f, 608 movement disorder pathophysiology, 603–604 overview of pathophysiology, 599–600 parafascicular nucleus anatomy, 602, 603f Cerebellothalamic pathway, tremor, 536, 550f Cerebellum deep brain stimulation for epilepsy clinical studies, 653–654 effects of stimulation, 653 historical perspective, 652–653 overview, 645–646 prospects, 654 surgical technique, 654 organization, 651–652 Cerebral cortex layers, 187f, 188 probes, 207, 208f vasculature, 190f, 191 CGRP, see Calcitonin gene-related peptide Chambered nerve cuff electrode, 203f Charge density, stimulus waveform, 120f Charge, stimulus waveform, 120f Charge–duration curve, electrical stimulus, 114f Chronic daily headache, see Headache Chronic pain specific conditions antinociception system, 295–296 central sensitization, 292–295 cycle, 314, 315f

definition, 23 dependency case example, 23–24b endogenous neuromodulation ascending sensory pathways, 309f descending controls, 305, 310 ON and OFF cells, 305–306 relevance to clinical pain, 306–307 epidemiology, 6 etiology, 314 gate control theory, 105f, 293f gene-based neuromodulation, 138–139 management, see also Deep brain stimulation; Intracerebroventricular opioids; Intrathecal analgesia; Motor cortex stimulation; Occipital neurostimulation; Peripheral nerve stimulation; Spinal cord stimulation; Subcutaneous targeted stimulation; Transcutaneous electrical nerve stimulation acute pain management in context of chronic pain, 316 biopsychosocial model case study, 318b, 320f goal-directed management planning, 320, 321t integrated treatment plan formulation, 318 pain assessment, 318, 319t, 320f brain stimulation therapy historical perspective, 304–305 clinical evaluation, 317–318 emotional component, 315–317 ethical challenges, 328 integrated treatment interventional medicine, 326 occupational therapy, 325–326 pain diary, 322–323, 325 pharmacotherapy, 320–321, 322t, 324b, 324f, 325b physical therapy, 325–326 psychotherapy, 326b, 327 record keeping, 327, 328b sequential tasks in pain management training, 326, 327b pathophysiological considerations, 314 prospects, 328–329 neuronal plasticity, 127–129 paradigm, 23 peripheral sensitization, 291–292 philosophical perspective, 26 sensory system, 100, 102–106, 287–291

1047 supraspinal and descending systems, 296–298 Chronic pelvic pain syndrome, see Painful bladder syndrome Chung, Sang Sup, 52f CI, see Cochlear implant Ciliary neurotrophic factor (CNTF) Huntington’s disease management, 989 vision loss management, 726–727 Cingulate cortex deep brain stimulation of subgenual cingulate cortex for depression, 696 pain processing, 105–106, 291 CIS, see Continuous interleaved sampling Clinical trial design clinical objective, 62–63 data analysis, 64–65 hierarchy, 61, 62b intervention and setting, 63–64 literature quality in neuromodulation, 65 outcome measures, 64 prospects in neuromodulation, 65, 66b randomized controlled trial advantages, 63 study population, 63 Clonidine, intrathecal therapy, 471, 472t Closed-loop stimulation, see Epilepsy CNTF, see Ciliary neurotrophic factor Cocaine-and amphetamine-regulated transcript (CART), bed nucleus of the stria terminalis, 681 Cochlea, electrodes, 201, 202f Cochlear implant (CI) anatomy and physiology, 714, 715f auditory nerve stimulation, 714, 715f, 716 bilateral implants, 719–720 combined electric and acoustic stimulation, 719–720 components, 716 historical perspective, 714 microphone input transformation into stimuli, 717–718 performance of unilateral implants, 718, 719f prospects, 720–721 Cognitive neuromodulation, deep brain stimulation, 985, 986f, 987f, 988 Colon, see Intestinal electrical stimulation; Irritable bowel syndrome

1048 Common peroneal nerve, implantation technique for peripheral nerve stimulation, 1015 Complex regional pain syndrome (CRPS) clinical features, 385, 386b peripheral nerve stimulation, 403–405 spinal cord stimulation benefits, 388b, 389 cost analysis, 361–362, 393 cost-effectiveness analysis, 393 dysautonomia, 349–350 efficacy, 386–388 indications and contraindications, 391b multidisciplinary treatment role, 390–391, 392f patient management, 392, 393f prospects, 393–394 risks, 389–390 screening trial conducting, 391–392 patient selection, 390 Compounding, see Intrathecal drug compounding Conductivity central nervous system tissues, 146t tissues at neural interface, 191, 192t Conflict of interest, 86–87 Congestive heart failure, see Heart failure Continuous interleaved sampling (CIS), cochlear implant, 717f, 718f Convection enhanced delivery (CED), 981 Coronary artery disease, spinal cord stimulation, 795f, 796f Cost analysis economics of neuromodulation resource allocation, 24–26 intrathecal analgesia, 460, 461t, 462t peripheral nerve stimulation, 404–406 spinal cord stimulation angina, 360–364 Belgium costs versus Netherlands, 366 complex regional pain syndrome, 361–362 continuous quality improvement linking with reimbursement, 365–366 cost studies cost–utility analysis, 358 general considerations, 356–357 historical perspective, 357–358 failed back surgery syndrome patients, 358–359, 365, 367f, 369f, 370f, 371f

INDEX

literature review, 364–365 long-term prospective multi-site cost-effectiveness analysis, 363–374 optimization of cost-effectiveness complication minimization, 373 equipment improvements, 373 patient selection, 372–373 peripheral vascular disease, 359–361 positioning in treatment algorithms, 373 rechargeable batteries, 371–372 retrospective cost–benefit analysis, 363–364 screening trial cost impact, 373–374 spasticity, 359 terminology, 357b CRPS, see Complex regional pain syndrome CRT, see Cardiac resynchronization therapy Current definition, 110 pulses, 120–121 Current-controlled stimulator, 219 Current density electrode versus tissue, 153f, 154 equation, 146 Current steering, 221 Cushing, Harvey, 87 CV, see Cyclic voltammogram Cyclic voltammogram (CV), electrode characterization, 116f, 117

D Data Safety Monitoring Board (DSMB), 82 Davis, Ross, 60f DBS, see Deep brain stimulation Deafness, see Cochlear implant Deep brain stimulation (DBS) barriers to clinical implementation, 171–172 blood pressure control and periaqueductal gray stimulation outcomes, 967, 968f, 969f prospects, 969 rationale, 967 centromedian–parafascicular complex stimulation for hyperkinetic movements data interpretation, 604–605, 609, 610f neurophysiological investigations, 608 outcomes, 609–610, 611f

patient selection, 605 postoperative evaluation, 608, 609f prospects, 611–612 surgical planning and stereotactic anatomy, 605, 606f, 607f, 608 cognitive neuromodulation, 985, 986f, 987f, 988 computer models clinical application of models, 175, 176f deep brain stimulation modeling, 173, 174f neurostimulation modeling, 172, 173f dystonia management complications, 576 devices, 572, 573f macroelectrode stimulation, 573, 574f magnetic resonance imaging, 573, 574f, 575f microelectrode recording, 573 outcomes, 575–576 pallidal stimulation for secondary dystonia, 576 programming, 575 prospects, 575–577 pulse generator implantation, 575 electrodes, 208, 209f epilepsy management animal studies, 640 caudate nucleus, 645 centromedian nucleus, 645 cerebellum stimulation clinical studies, 653–654 effects of stimulation, 653 historical perspective, 652–653 overview, 645–646 prospects, 654 surgical technique, 654 closed-loop stimulation with RNS device detection algorithms, 659 electrocorticography storage, 658–659 electrodes, 658 external responsive neurostimulation, 658 implantable pulse generator, 658, 659f implantation technique, 659, 660f, 661 outcomes, 661, 662t patient selection, 658 programmer, 658 prospects, 661–662 therapeutic stimulation, 659 hippocampus, 646

INDEX

mechanism of action, 640 open- versus closed-loop systems, 646 subthalamic nucleus, 645 thalamus anterior nucleus stimulation complications, 644 indications, 640 pilot studies, 643, 644t rationale, 640 surgical technique, 641–642 targeting, 640, 641f ethics conflicts of interest, 86–87 device development, 83 historical determinants, 87–89 informed consent decisional capacity, 83–84 decisional incapacity, 84–86 exceptionalism in deep brain stimulation, 86 historical perspective, 15–17, 42 hypothalamus lesioning and stimulation for obesity, 963–964 indications, 171 magnetic resonance imaging safety of systems Active Tremor Control System, 264, 265f, 266–269b 270 case studies of injuries, 272, 273f Libra DBS system, 270–272b overview, 263–264 mechanisms of action depolarization block hypothesis, 158–159 neural jamming/modulation hypothesis, 161–162 overview, 157–158 prospects for study, 165–166 synaptic depression hypothesis, 161 synaptic facilitation hypothesis, 162, 163f, 164f, 165 synaptic modulation hypothesis, 159–160 Meige syndrome management outcomes and complications, 593, 595t prospects, 595 technique, 593, 594f neuropsychiatry utilization affect and mood effects of stimulation, 693 customization, 695 depression adverse effects, 698–699 ethics, 699

follow-up, 699 mechanism of action, 697–698 targets, 695–697 historical perspective, 691–692 implantation, 694 obsessive-compulsive disorder, 693–694 research protocols, 699–700 stimulation technique, 694–695 nucleus accumbens surgical targeting in addiction complications, 708 deep brain stimulation programming, 707–708 indications, 705 outcomes, 708 patient selection, 705 perioperative patient management, 706–707 prospects, 708–709 rationale, 704–705 technique, 705, 706f pain management chronic cluster headache chronic stimulation parameters, 511 macrostimulation, 511f microelectrode recording, 510–522 outcomes, 511–512 patient characteristics, 509–510 posterior hypothalamus stimulation, 509 surgical technique, 510 efficacy, 501f, 503, 504t indications, 500t overview, 499–500 patient selection, 500–501 prospects, 503, 505 safety, 503 surgical technique, 501, 502f, 502t, 503 Parkinson’s disease contraindications, 541 device programming, 545 indications, 541 mechanism of action, 531–532, 533f, 540 outcomes Class I outcome studies, 545, 546t complications, 546–547 subthalamic nucleus targeting outcomes, 546 subthalamic nucleus versus globus pallidus targeting, 545–546 preoperative screening, 540–541

1049 prospects, 547 rate model, 533, 534f technique anesthesia, 543 coordinate systems and target selection, 542–543 exposure, 543 frame placement, 541–542 imaging, 542f implantation of pulse generator and lead extenders, 544–545 lead insertion and test stimulation, 544 microelectrode recording, 543, 544f patient positioning, 543 target localization, 541f psychological factors in outcomes, 72 surgical technique burr-hole drilling, 999, 1000f complications, 1001–1002 electrode implantation and fixation, 1000 frameless guidance, 996 implantable pulse generator implantation, 1001 microelectrode recordings, 999 overview, 995–996 preoperative imaging, 996, 997f programming, 1002 stereotactic frame, 996f target localization, 997, 998f Tourette’s syndrome management historical perspective, 580–581 mechanism of action, 583 patient selection, 583–584 perioperative evaluation, 584 postoperative evaluation, 584 programming, 584–585 prospects, 585 surgical technique, 584 targets globus pallidus, 583 medial thalamus, 583 nucleus accumbens, 583 overview, 581, 582f, 583 tremor management adverse events, 556t, 557 indications, 554 outcomes, 555–556 patient selection, 554 programming, 555 prospects, 557 rationale, 553–554 surgical technique, 554–555 Defibrillator, see Implantable cardiac defibrillator DeJongste, Mike, 54f

1050 Dependency, see Addiction Depolarization block hypothesis of deep brain stimulation, 158–159 definition, 111 Depression deep brain stimulation overview, 695 adverse effects, 698–699 ethics, 699 follow-up, 699 mechanism of action, 697–698 targets inferior thalamic peduncle, 695 subgenual cingulate cortex, 696 ventral capsule/ventral striatum, 696 electroconvulsive therapy cognitive effects, 667 efficacy, 666 principles, 666, 691 relapse rates, 666–667 epidemiology, 689 medications failure rate, 665 refractory patient management, 690–691 types, 690 morbidity, 689–690 pathogenesis, 690 transcranial magnetic stimulation adverse events, 670 efficacy, 669–670 mechanism of action, 668 motor threshold, 668 principles, 667–668, 691 prospects, 669–670 vagus nerve stimulation efficacy, 672–673 mechanism of action, 670–671 overview, 670 safety, 672 Device development, see Implantable medical device development Diabetic neuropathy assessment, 381 epidemiology, 380–381 medical management, 381 spinal cord stimulation, 381–382 DLF, see Dorsal lateral funiculus Dobelle, Bill, 13, 15 Dorsal genital nerve stimulation, voiding dysfunction management, 952–953 Dorsal lateral funiculus (DLF), antinociception role, 304 Dorsal root ganglia (DRG), nociception, 287–288

INDEX

DRG, see Dorsal root ganglia Drug abuse, see Addiction Drug compounding, see Intrathecal drug compounding DSMB, see Data Safety Monitoring Board Dystonia, see also Torsion dystonia deep brain stimulation complications, 576 devices, 572, 573f macroelectrode stimulation, 573, 574f magnetic resonance imaging, 573, 574f, 575f microelectrode recording, 573 outcomes, 575–576 pallidal stimulation for secondary dystonia, 576 programming, 575 prospects, 575–577 pulse generator implantation, 575 diagnosis and classification, 571–572 medical therapy, 572 pathophysiology, 535 surgical interventions, 572 torsion dystonia clinical features, 571

E EBM, see Evidence-based medicine ECHE, see Advances in External Control of Humans Extremities Economics, see Cost analysis ECT, see Electroconvulsive therapy Ejaculation, see Sex organs Electreat, 11f, 13 Electrical conductivity anisotropic electrical conductivity, 147–149 central nervous system tissues, 146t inhomogeneous electrical conductivity, 149–150 tissues at neural interface, 191, 192t Electric field electrode design blocking, 197 recording, 197–198 stimulation, 196–197 electrode geometry effects current density on electrode versus tissue, 153f, 154 electrode–tissue interface, 151, 152f extracellular voltage effects on neurons, 154 regulated voltage and regulated current stimulation, 152–153 voltage versus distance, 151f

equation, 147 generation principles, 145–150 Electroconvulsive therapy (ECT), depression management cognitive effects, 667 efficacy, 666 principles, 666, 691 relapse rates, 666–667 Electrode, see also Implantable neural stimulator behavior under pulsed conditions balanced charge, 119 biphasic pulses, 119 imbalanced charge, 119 monophasic pulses, 118f overview, 117 bipolar electrode electric field generation, 150, 151f characteristics, 111 computer models of stimulation clinical application of models, 175, 176f deep brain stimulation modeling, 173, 174f neurostimulation modeling, 172, 173f deep brain stimulation implantation and fixation, 1000 design principles electric field blocking, 197 recording, 197–198 stimulation, 196–197 implant procedure considerations, 199 location selection functional complexity, 195–196 material and processing technology, 195 neuron proximity, 194–195 risk–benefit ratio, 195, 196f removability, 199 tissue response, 198–199 device development, see Implantable medical device development electrochemistry, 115–117 geometry effects on electric field generation current density on electrode versus tissue, 153f, 154 electrode–tissue interface, 151, 152f extracellular voltage effects on neurons, 154 regulated voltage and regulated current stimulation, 152–153 voltage versus distance, 151f intestinal electrical stimulation placement

1051

INDEX

mucosal electrodes, 895 serosal electrodes, 895 potentials generated by point source electrode, 146, 147f, 148f retinal prosthetic devices, 733, 734f types of neural interface electrodes central nervous system electrodes cortical probes, 207, 208f deep brain stimulation, 208, 209f spinal cord electrodes, 207, 208f superficial/distal interfaces, 206, 207f cochlear electrodes, 201, 202f muscle electrodes, 201f peripheral nervous system electrodes extraneural electrodes, 202, 203f, 204f interfascicular electrodes, 204, 205f intrafascicular electrodes, 205f placement, 206 regeneration arrays, 206f retinal electrodes, 202, 203f surface electrodes, 200f Electromyography (EMG amplitude of activity, 194 hemifacial spasm intraoperative monitoring, 591 neuromuscular electrical stimulation triggering, 744–745 spinal cord stimulation lead placement monitoring, 1008f, 1009 voiding dysfunction patients, 948 Electron energy, electrode, 115f EMG, see Electromyography Endoneurium conductivity, 192t mechanical properties, 192 Enkephalin, nociception, 100, 288 Epidural analgesia anatomy, 437–438 catheter and needle issues, 434 overview, 433–434 vacuum effect, 436–437 Epilepsy clinical features, 619–620 deep brain stimulation animal studies, 640 caudate nucleus, 645 centromedian nucleus, 645 cerebellum stimulation clinical studies, 653–654 effects of stimulation, 653 historical perspective, 652–653 overview, 645–646 prospects, 654

surgical technique, 654 closed-loop stimulation with RNS device detection algorithms, 659 electrocorticography storage, 658–659 electrodes, 658 external responsive neurostimulation, 658 implantable pulse generator, 658, 659f implantation technique, 659, 660f, 661 outcomes, 661, 662t patient selection, 658 programmer, 658 prospects, 661–662 therapeutic stimulation, 659 hippocampus, 646 mechanism of action, 640 open- versus closed-loop systems, 646 subthalamic nucleus, 645 thalamus anterior nucleus stimulation complications, 644 indications, 640 pilot studies, 643, 644t rationale, 640 surgical technique, 641–642 targeting, 640, 641f epidemiology, 617, 651 gene-based neuromodulation, 137, 138f interictal to ictal transition, 622 medication failure rate, 639 pathophysiology, 620–622 vagus nerve stimulation advantages, 630–631 adverse events, 629–630 clinical trials, 629 complication avoidance and management, 635–636 lead removal or revision, 635 mechanism of action, 627–629 Neurocybernetic Prosthesis device, 625, 626f, 627f, 632 patient selection, 631 surgical technique anatomy, 633–634 general considerations, 632–633 implantation and testing, 634–635 incisions, 634 nerve dissection, 634 Erection, see Sex organs Essential tremor (ET), see also Tremor pathophysiology, 536

transcranial magnetic stimulation studies, 536 ET, see Essential tremor Ethics deep brain stimulation, 83–86 deep brain stimulation in psychiatric illness, 699 neuromodulation resource allocation, 24–26 pain management, 328 research and therapy demarcation, 81–83 Evidence-based medicine (EBM), clinical trial design, 61, 65 External neuromodulation, 418, 419f

F Failed back surgery syndrome (FBSS), spinal cord stimulation cost analysis, 358–359, 365, 367f, 368f, 369f, 370f FBSS, see Failed back surgery syndrome Femoral nerve, implantation technique for peripheral nerve stimulation, 1016 Fentanyl, intrathecal therapy, 447, 452t FES, see Functional electrical stimulation Field potential (FP), neural interface system decoding, 239–240 signaling, 233–234 FINE, see Flat interface nerve electrode Flat interface nerve electrode (FINE), 204f fMRI, see Functional magnetic resonance imaging Foreman, Robert, 54f FP, see Field potential Functional electrical stimulation (FES) see also specific indications benefits, 7 definition, 5 Functional magnetic resonance imaging (fMRI) motor cortex stimulation studies in stroke, 757f, 758 neuronal plasticity studies, 124, 127–129

G GABA, see g-Aminobutyric acid Gabapentin, intrathecal therapy, 476–477 Galanin, bed nucleus of the stria terminalis, 681 Gastric bypass surgery, complications, 961t

1052 Gastric stimulation complications, 887 contraindications, 887 gastroparesis management etiology, 883 historical perspective, 881 implantation, 884, 885f indications, 884 magnetic resonance imaging safety of electrical stimulation systems, 278–279 mechanisms of action, 886–887 obesity management etiology, 883 historical perspective, 882 outcomes, 886 patient selection, 884 programming and stimulation parameters, 885, 886f prospects, 887–888 rationale, 883–884 stomach anatomy and gastric propulsion mechanisms, 882f, 883f Gastroparesis, see Gastric stimulation Gate control theory, pain, 105f, 293f GDNF, see Glial-derived neurotrophic factor Gene-based neuromodulation direct delivery of vectors, 134 indications chronic pain, 138–139 epilepsy, 137, 138f Parkinson’s disease, 136–137 spasticity, 139–140 overview, 131, 132f prospects, 140 remote delivery of vectors, 135f transgene expression regulation, 133–134 viral vectors adeno-associated virus, 133 adenovirus, 133 herpes simplex virus, 133 lentivirus, 133 ex vivo gene therapy, 135–136 in vivo gene therapy, 132–135 Gildenberg, Philip, 52f Glial-derived neurotrophic factor (GDNF) biological activity and properties, 566 central nervous system delivery, 982 gene therapy for neurodegenerative disease, 989 Parkinson’s disease infusion therapy Amgen Phase II clinical trial, 567 preliminary studies, 566–567 prerequisites, 561–562

INDEX

prospects, 567–568 Globus pallidus deep brain stimulation for Parkinson’s disease contraindications, 541 device programming, 545 indications, 541 mechanism of action, 531–532, 533f, 540 outcomes Class I outcome studies, 545, 546t complications, 546–547 subthalamic nucleus targeting outcomes, 546 subthalamic nucleus versus globus pallidus targeting, 545–546 preoperative screening, 540–541 prospects, 547 rate model, 533, 534f technique anesthesia, 543 coordinate systems and target selection, 542–543 exposure, 543 frame placement, 541–542 imaging, 542f implantation of pulse generator and lead extenders, 544–545 lead insertion and test stimulation, 544 microelectrode recording, 543, 544f patient positioning, 543 target localization, 541f dystonia pathophysiology, 535 Meige syndrome and deep brain stimulation outcomes and complications, 593, 595t prospects, 595 technique, 593, 594f Parkinson’s disease firing rate, 533, 534f pathophysiology, 530, 531f Tourette’s syndrome and deep brain stimulation, 583–584 Glutamate receptors, central pain sensitization, 293–294

H Headache, see also Occipital neurostimulation deep brain stimulation for chronic cluster headache chronic stimulation parameters, 511

macrostimulation, 511f microelectrode recording, 510–522 outcomes, 511–512 patient characteristics, 509–510 posterior hypothalamus stimulation, 509 surgical technique, 510 epidemiology, 409–410 epilepsy pathophysiology, 620 migraine treatment options, 410 occipital neurostimulation complications, 414 literature review, 410–411, 413t mechanism of action, 414 prospects, 414–415 stimulation parameters, 413 surgical technique curved needle placement, 411f, 412 electrode fixation and tunneling, 412 intraoperative stimulation testing, 412 positioning and sedation, 414 pulse generator implantation, 412 Hearing loss, see Cochlear implant Heart failure acute heart failure neurostimulation, 856–858 cardiac pacing, 805–806, 812–813 chronic heart failure neuromodulation, 856 etiology, 855 pathophysiology, 855–856 Hemifacial spasm (HFS) clinical features, 588 differential diagnosis, 588 neurodiagnostic evaluation, 588, 589f pathophysiology, 588 surgical intervention complications, 592 historical perspective, 587–588 outcomes, 591, 592t prospects, 592 technique closure, 591 dural excision and exposure, 590 intraoperative monitoring, 591 microvascular decompression, 590–591 offending vessels, 590t patient positioning, 589 scalp incision and drill hole, 590 Henderson–Hasselbach equation, 469f Herpes simplex virus (HSV), gene therapy vectors, 133 HFS, see Hemifacial spasm

INDEX

Hill equation, 114 Hippocampus deep brain stimulation for epilepsy, 646 epilepsy pathophysiology, 621 Hodgkin–Huxley equations, 193–194 Horsley, Victor, 10f HSV, see Herpes simplex virus Huntington’s disease cell transplantation therapy, 989, 990f ciliary neurotrophic factor therapy, 989 RNA interference studies, 990 Hydromorphone, intrathecal therapy, 446–447, 452t Hyperpolarization, definition, 111 Hypertension carotid sinus stimulation animal studies, 849 aortic arch role, 850, 851f clinical trials, 851, 852f human studies, 850f prospects, 852–863 epidemiology, 845, 967 periaqueductal gray stimulation outcomes, 967, 968f, 969f prospects, 969 rationale, 967 pharmacologic neuromodulation, 848–849 physiology autonomic nervous system, 846f, 847f baroreflex, 847, 848f Hypertrophic cardiomyopathy, cardiac pacing, 813 Hypothalamus deep brain stimulation for chronic cluster headache, 509 obesity anatomy and physiology, 961, 962f human studies of lesioning and stimulation, 963–964

I IBS, see Irritable bowel syndrome ICD, see Implantable cardiac defibrillator IDE, see Investigational Device Exemption IES, see Intestinal electrical stimulation IFESS, see International Functional Electrical Stimulation Society Imbalanced charge, biphasic pulse, 119 Implantable cardiac defibrillator (ICD) components, 818 historical perspective, 817–818 implantation, 818–819

indications, 820 patient selection, 820–821 programming, 819–820 prospects, 821 Implantable medical device development, see also Electrode Advanced Bionics case study, 36–40 cardiac device comparison with neuromodulation devices, 46–47 competitive landscape, 46 design phase clinical study, 36 manufacturing acceptance, 36 module design, 35 process development, 35 process validation, 35–36 system integration, 35 verification and validation of design, 35 historical perspective of neuromodulation devices early devices, 41–43 2001, 43 2002, 43–44 2003, 44 2004, 44 2005, 44–45 2006, 45 2007, 45–46 novel product categories, 47 overview of process, 33 planning phase feasibility study, 34 marketing requirements, 34 product definition, 34–35 product identification and market analysis, 34 regulation, 33 research and therapy demarcation ethics, 81–83 transfer/acceptance phase, 36 Implantable neural stimulator circuitry, 219–221 communication and telemetry, 223–224 components, 216 design, 216–217 electrodes and leads, 218–219, 220f functional overview, 215–216 materials, 217–218 multiplexed stimulation systems, 221 power system, 221–222, 223t prospects, 225–226 sensors for device command and closed-loop control, 224–225

1053 size, 216 waveforms, 220f Implantable pulse generator (IPG) deep brain stimulation implantation, 1001 specifications Advanced Neuromodulation Systems devices, 1041 Medtronic devices, 1042 Inferior colliculus, gross anatomy, 98f Inferior thalamic peduncle (ITP), deep brain stimulation for depression, 695 Informed consent decisional capacity, 83–84 decisional incapacity, 84–86 exceptionalism in deep brain stimulation, 86 Infusion pumps, see Programmable infusion pumps Inhomogeneous electrical conductivity, 149–150 INS, see International Neuromodulation Society Institutional Review Board (IRB), 82 Insula, pain processing, 106 Insulin, adiposity signal, 962 Intellectual property (IP), 32 International Functional Electrical Stimulation Society (IFESS) Advances in External Control of Humans Extremities meetings, 57–58 executive board, 59t, 60f historical perspective, 55–57 International Neuromodulation Society collaboration, 53 workshops and conferences, 56t, 58, 59t, 60 International Neuromodulation Society (INS) chapters, 53, 54t executive officers, 54f, 55f, 55t historical perspective, 52–53 membership, 54 mission statement, 54–55 neuromodulation definition, 1, 3 International Society for Research in Stereoencephalotomy, historical perspective, 50 Interstitial cystitis, see Painful bladder syndrome Intestinal electrical stimulation (IES) dual pulses, 894f, 895 dysmotility disorders, 894 electrode placement mucosal electrodes, 895 serosal electrodes, 895

1054 Intestinal electrical stimulation (IES) (Continued) gastric effects, 896 historical perspective, 891–892 intestinal effects motility effects, 896, 897f slow wave, 895, 896f transit and absorption, 897f, 898 long-pulse stimulation, 894 migrating motor complex, 892, 893f obesity management, 898, 899f pulse rain, 894 short-pulse stimulation, 894f small intestinal myoelectrical activity, 892–893 synchronized stimulation, 895 Intracerebroventricular opioids administration techniques, 493–494 adverse effects, 494, 495t chronic pain of non-malignant origin management, 495 clinical trials, 494t historical perspective, 491–492 indications, 492–493 mechanisms of action, 491, 492f patient selection, 492–493 reservoir types, 493f surgical technique, 493 Intrathecal analgesia compounding of drugs, see Intrathecal drug compounding cost efficacy, 460, 461t, 462t drug distribution factors, 438, 439f, 440 implantable systems AccuRx, 459, 460f Arrow 3000, 459f complications, 462, 463t, 464 Medtronic Isomed, 459f Medtronic Synchromed, 458f outcome data, 464 overview, 444, 457 programmable versus constant flow pumps, 464t, 465 implantation of delivery systems catheter insertion, 1029, 1030f closure, 1031 patient positioning, 1028 postoperative considerations, 1031 preoperative considerations and planning, 1027–1028 pump preparation and insertion, 1030–1031 surgical preparation, 1028–1029 intrathecal placement catheter placement, 433

INDEX

confirmation of catheter placement, 434 fluoroscopy, 433 needle placement, 433 needle removal, 433 patient positioning, 432–433 non-opioid analgesics adenosine, 477 baclofen, 474–475, 476t clonidine, 471, 472t gabapentin, 476–477 ketamine, 474 local anesthetics bupivacaine, 469–470 lidocaine, 469f mechanism of action, 467–468 ropivacaine, 470–471 midazolam, 476 overview, 467, 468t polyanalgesic algorithm, 450, 451f, 452, 469f prospects, 477–478 ziconotide, 472–474 opioids dosing, 452t examples, 468t fentanyl, 447, 452t hydromorphone, 446–447, 452t indications, 441, 442f, 443f meperidine, 449–450 methadone, 448–449 morphine, 444–446, 452t polyanalgesic algorithm, 450, 451f, 452, 469f sufentanil, 447–448, 452t trial therapy, 443–444 painful bladder syndrome, 941–942 spine anatomy dura innervation, 438 epidural space, 436–438 ligaments, 434–435, 436f lower thoracic spine, 432f nerve root, 434, 438 spinal cord, 434, 435f spinal tract mapping, 438, 439f vasculature, 435–436, 437f Intrathecal baclofen adverse events, 475, 476t baclofen properties, 475 cost efficacy, 461, 462t implantable systems AccuRx, 459, 460f Arrow 3000, 459f complications, 462, 463t, 464 Medtronic Isomed, 459f Medtronic Synchromed, 458f overview, 444, 457

spasticity management outcomes, 565 overview, 563 patient selection, 563 pump implantation and programming, 563–564 risks, 564–565 Intrathecal drug compounding Food and Drug Administration regulation, 484–486, 487b, 488 historical perspective, 484 overview, 483–484 polyanalgesia consensus guidelines, 489–490 pump considerations, 488–489 risk levels, 486 United States Pharmacopoeia guidelines, 485–486, 489 Investigational Device Exemption (IDE), 82 IP, see Intellectual property IPG, see Implantable pulse generator IRB, see Institutional Review Board Irritable bowel syndrome (IBS) clinical features, 865 colon neural control, 865, 866f pathophysiology, 865–866 spinal cord stimulation animal studies, 866–867, 868f clinical studies, 868 pain management, see Visceral pain prospects for study, 868–869 Ischemic pain, spinal cord stimulation for management, 350–351 ITP, see Inferior thalamic peduncle

J Justice, neuromodulation resource allocation, 25–26

K Ketamine, intrathecal therapy, 474 Krames, Elliot, 54f

L Laminotomy, see Spinal cord stimulation Laparoscopic implantation of neuroprosthesis (LION), sacral nerve stimulation, 939 Lentivirus, gene therapy vectors, 133 Leptin, adiposity signal, 962 LHRH, see Luteinizing hormonereleasing hormone Libra DBS system, magnetic resonance imaging safety, 270–272b Lidocaine, structure, 469f

INDEX

Limbic system-associated membrane protein, bed nucleus of the stria terminalis, 683 Linderoth, Bengt, 54f LION, see Laparoscopic implantation of neuroprosthesis Long, Charles, 109–110 Lower urinary tract anatomy, 907f, 908f, 909 bladder dysfunction, see Urinary retention; Voiding dysfunction central nervous system pathways brain pathways, 917 spinal cord pathways afferent projections, 916 anatomy, 916 efferent pathways, 916 interneurons, 916–917 tracing, 915–916 innervation afferent pathways, 912–913 neural modulatory mechanisms, 911–912 parasympthetic pathways, 909f, 910f, 911t somatic pathways, 912 sympathetic pathways, 911 urothelial-afferent interactions, 913–914 neural pathways in cats, 906f neurotransmitters in micturition reflex pathways excitatory neurotransmitters, 919–920 inhibitory neurotransmitters, 920 pain management, see Painful bladder syndrome; Sacral nerve stimulation reflex mechanisms, 914t, 915f spinal cord injury and neurogenic dysfunction, 920–922 urine storage and voiding reflex organization pontine micturition center, 918–919 somatic pathways to urethral sphincter, 917–918 spinobulbospinal micturition reflex pathway, 916f suprapontine control, 919f sympathetic pathways, 917 Luteinizing hormone-releasing hormone (LHRH), bed nucleus of the stria terminalis, 682

M Magnetic resonance imaging (MRI), see also Functional magnetic resonance imaging

anterior nucleus of thalamus, 640, 641f bioeffects of magnetic fields gradient fields acoustic noise, 245–246 human studies, 245 static fields, 244–245 deep brain stimulation patients chronic pain patients, 501, 502f, 510f preoperative imaging, 996, 997f surgical technique, 573, 574f, 575f target localization, 997, 998f excessive heating and burn prevention, 248, 249b implants and devices artifacts, 253 classification terminology for safety, 253–254 evaluation for safety, 250–251, 252f, 253 heating issues, 251, 252f, 253 motor cortex stimulation patients, 516–517, 518f, 519f neuromodulation system safety BION microstimulator, 259–260, 261b deep brain stimulation systems Active Tremor Control System, 264, 265f, 266–269b 270 case studies of injuries, 272, 273f Libra DBS system, 270–272b overview, 263–264 gastric electrical stimulation systems, 278–279 heating-related factors, 255b overview, 254–255 phrenic nerve stimulation systems, 278 programmable infusion pumps IsoMed pump, 258–259b MedStream pump and catheter, 259f, 260b SynchroMed pumps, 255, 256–258b Renova Cortical Stimulation System, 278 sacral nerve stimulation systems, 278 spinal cord stimulation systems Advanced Neuromodulation Systems devices, 278 Medtronic systems, 274–277b Precision Spinal Cord Stimulation System, 278 VNS Therapy System, 262f, 263b, 264f nucleus accumbens, 75, 706f

1055 pregnancy precautions, 248–250 radiofrequency radiation human studies of thermal responses, 247 specific absorption rate, 246 thermophysiological response, 246–247 very-high field systems, 247 screening for magnetic environment individuals, 248 patients, 247–248 Magnetoencephalography (MEG), neuronal plasticity studies, 124, 125f, 128f Major depression, see Depression Mann, Alfred E., 36–40 Market, see Neurostimulation market McGill Pain Questionnaire (MPQ), 70 MCS, see Minimally conscious state; Motor cortex stimulation Meadows, Paul, 60f Median nerve, implantation technique for peripheral nerve stimulation, 1013, 1014f Medical Implant Communications Service (MICS), 224 Medtronic intrathecal analgesia devices Isomed, 459f Synchromed, 458f specifications for implantable pulse generators, 1042 spinal cord stimulation systems, 274–277b Medulla, gross anatomy, 98, 99f MEG, see Magnetoencephalography Meige syndrome clinical features, 593 deep brain stimulation of globus pallidus outcomes and complications, 593, 595t prospects, 595 technique, 593, 594f history of study, 592 pathophysiology, 593 Melzack–Wall gate, 13f Membrane potential activation function, 113 resting membrane potential, 111 Meperidine, intrathecal therapy, 449–450 Methadone, intrathecal therapy, 448–449 N-Methyl-D-aspartate (NMDA) receptor, antagonists in pain management, 307–308

1056 Microvascular decompression (MVD) hemifacial spasm surgical intervention complications, 592 historical perspective, 587–588 outcomes, 591, 592t prospects, 592 technique closure, 591 dural excision and exposure, 590 intraoperative monitoring, 591 microvascular decompression, 590–591 offending vessels, 590t patient positioning, 589 scalp incision and drill hole, 590 tinnitus management, 973 MICS, see Medical Implant Communications Service Micturition, see Lower urinary tract Midazolam, intrathecal therapy, 476 Migraine, see Headache Migrating motor complex (MMC), small intestinal motility, 892, 893f Minnesota Multiphasic Personality Inventory (MMPI), 69–70 Minimally conscious state (MCS), deep brain stimulation, 986–987 MMC, see Migrating motor complex MMPI, see Minnesota Multiphasic Personality Inventory Mobility, see Motor impairment Morphine intracerebroventricular administration, 494t intrathecal therapy, 444–446, 452t Mortimer, Thomas, 13–14, 42f Motor cortex stimulation (MCS) complications, 521 historical perspective, 515–516 mechanism of action, 524 outcomes central pain, 520f literature review, 521, 522–523t neuropathic facial pain, 520f peripheral pain, 520–521 spinal cord lesion, 521 prospects, 524–525 stroke animal studies, 754f, 755f, 756f human studies, 756, 757f, 758, 759f, 760f, 761, 762f, 763f, 764f prospects, 764–765 rationale, 753–754 technique craniotomy, 517 intraoperative electrophysiology, 517–519

INDEX

motor cortex preoperative localization, 516–517, 518f, 519f stimulation parameters, 519–520 Motor impairment etiology, 231 neural interface systems for mobility restoration control signals action potentials, 233 field potentials, 233–234 movement signal sources, 234–236 system demands, 232–233 decoding field potentials, 239 limitations, 239–240 principles, 238–239 spiking patterns, 239 goals, 231 muscle control, 240–241 overview, 229, 230f prospects, 241 sensing and decoding overview, 232 sensors, 235f, 236–237, 238f terminology, 231 Movement disorders, see also Dystonia; Hemifacial spasm; Meige syndrome; Motor impairment; Parkinson’s disease; Spasticity; Tourette’s syndrome; Tremor centromedian–parafascicular complex anatomical overview, 600–601 centromedian nucleus afferent fibers, 601–602 efferent fibers, 602 histology, 601 deep brain stimulation for hyperkinetic movements data interpretation, 604–605, 609, 610f neurophysiological investigations, 608 outcomes, 609–610, 611f patient selection, 605 postoperative evaluation, 608, 609f prospects, 611–612 surgical planning and stereotactic anatomy, 605, 606f, 607f, 608 movement disorder pathophysiology, 603–604 parafascicular nucleus anatomy, 602, 603f

pathophysiology overview, 599–600 functional neurosurgery historical perspective, 529–530 infusion therapy, see Baclofen; Glialderived neurotrophic factor thalamocortical dysrhythmia, 534–535 MPQ, see McGill Pain Questionnaire MRI, see Magnetic resonance imaging MS, see Multiple sclerosis Multiple sclerosis (MS), voiding dysfunction and neuromodulation therapy, 948–949 Muscle, electrodes, 201f MVD, see Microvascular decompression Myocardial ischemia, see Angina pectoris

N NAcc, see Nucleus accumbens Nerve fiber anatomy, 398f, 399 blood supply, 399, 400f conduction properties, 399f fascicular structure, 400f functional mapping, 401f trunks, 400 Nerve growth factor (NGF) Alzheimer’s disease management, 989–990 bed nucleus of the stria terminalis, 684 peripheral pain sensitization, 292 Nervous system major divisions, 182, 183f, 184 size scales, 184 Neural interface system (NIS) control signals action potentials, 233 field potentials, 233–234 movement signal sources, 234–236 system demands, 232–233 decoding field potentials, 239 limitations, 239–240 principles, 238–239 spiking patterns, 239 goals, 231 muscle control, 240–241 overview, 229, 230f prospects, 241 sensing and decoding overview, 232 sensors, 235f, 236–237, 238f terminology, 231 Neuroaugmentation, definition, 5 Neurocybernetic Prosthesis, see Vagus nerve stimulation

INDEX

Neuromodulation definition, 1, 3–5 historical perspective, 9–17, 41–46 market growth, 3, 4f popularity by indication, 3, 4f, 22t, 25t Neuromotor prosthesis, see Neural interface system Neuromuscular electrical stimulation (NMES), see also Functional electrical stimulation contraindications, 744 lower limb applications, 745 motor relearning, 744 prospects, 749 shoulder pain in stroke intramuscular neuromuscular electrical stimulation, 746f, 747 surface neuromuscular electrical stimulation, 745–746 theoretical framework, 745, 746f upper limb applications, 744–745 Neuronal plasticity chronic pain, 125–127 history of study, 123–125, 127, 129 movement disorders, 127 neurostimulation effects, 127, 128f Neuropeptide FF, antinociception role, 296 Neuropeptide Y (NPY) bed nucleus of the stria terminalis, 680 lower urinary tract neurotransmission, 909–910, 912 Neuroprosthetics, definition, 5 Neurostimulation market Advanced Bionics case study, 36–40 device development, see Implantable medical device development growth, 3, 4f intellectual property, 32 patient population, 30–31 reimbursement, 33 technologies, 31–32 Neurotensin, bed nucleus of the stria terminalis, 682 NGF, see Nerve growth factor NIS, see Neural interface system Nitric oxide (NO) gastric stimulation effects, 886–887 lower urinary tract neurotransmission, 906–907, 909, 911, 913 peripheral pain sensitization, 292 sexual function, 926 NMDA receptor, see N-Methyl-Daspartate receptor

NMES, see Neuromuscular electrical stimulation NNT, see Number needed to treat NO, see Nitric oxide Nociception, see Chronic pain Nodes of Ranvier, current flow, 113f, 193 North, Richard, 54f NPY, see Neuropeptide Y NRM, see Nucleus raphe magnus Nucleus accumbens (NAcc) deep brain stimulation for Tourette’s syndrome, 584 surgical targeting in addiction complications, 708 deep brain stimulation programming, 707–708 indications, 705 outcomes, 708 patient selection, 705 perioperative patient management, 706–707 prospects, 708–709 rationale, 704–705 technique, 705, 706f Nucleus raphe magnus (NRM), antinociception role, 297–298 Number needed to treat (NNT), 64

O Oakley, John, 54f Obesity body mass index table, 960t classification, 959, 960t definition, 959 economic impact, 960 epidemiology, 959 etiology, 883 gastric bypass surgery complications, 961t gastric stimulation complications, 887 contraindications, 887 historical perspective, 882 implantation, 884, 885f indications, 884 mechanisms of action, 886–887 outcomes, 886 patient selection, 884 programming and stimulation parameters, 885, 886f prospects, 887–888 rationale, 883–884 stomach anatomy and gastric propulsion mechanisms, 882f, 883f hypothalamus anatomy and physiology, 961, 962f

1057 animal studies of stimulation, 962–963 human studies of lesioning and stimulation, 963–964 intestinal electrical stimulation, 898, 899f mortality, 960 treatment approaches, 960–961 Obsessive-compulsive disorder (OCD) anterior capsulotomy management, 678, 691 bed nucleus of the stria terminalis stimulation, see Bed nucleus of the stria terminalis deep brain stimulation, 693–694 epidemiology, 678 Obstructive sleep apnea (OSA) anatomy, 777, 778f, 779f epidemiology, 777 management approaches, 778 neuroprosthesis airway patency control through tongue muscles, 778, 779f, 780 design overview, 780f, 781 prospects, 784–785 selective stimulation, 782, 783f, 784f single electrode closed loop design, 781, 782f risk factors, 778 Occipital neurostimulation (ONS) complications, 414 literature review of headache management, 410–411, 413t mechanism of action, 414 overview, 1021 permanent implantation technique paddle electrodes, 1035f, 1026 percutaneous wire electrodes, 1022, 1023f, 1024f prospects, 414–415 stimulation parameters, 413 surgical technique curved needle placement, 411f, 412 electrode fixation and tunneling, 412 intraoperative stimulation testing, 412 positioning and sedation, 414 pulse generator implantation, 412 trial stimulation, 1021, 1022f Occupational therapy, pain management, 325–326 OCD, see Obsessive-compulsive disorder OFF cell, pain neuromodulation, 305–307

1058 Ohm’s Law, 146–147 Ohye, Chihiro, 52f ON cell, pain neuromodulation, 305–307 ONS, see Occipital neurostimulation Opioids intracerebroventricular administration, see Intracerebroventricular opioids intrathecal analgesia, see Intrathecal analgesia mechanisms of action, 491 receptors and antinociception role, 295–296 Orthostatic hypotension epidemiology, 967 periaqueductal gray stimulation outcomes, 967, 968f, 969f prospects, 969 rationale, 967 OSA, see Obstructive sleep apnea Overactive bladder, see Voiding dysfunction Oxytocin, bed nucleus of the stria terminalis, 680

P PACAP, see Pituitary adenylate cyclase activating polypeptide Pacemaker, see Cardiac pacemaker PAD, see Peripheral arterial disease PAG, see Periaqueductal gray Pain, see Chronic pain Painful bladder syndrome (PBS) Bion device for pudendal nerve stimulation, 940, 941f clinical features, 931–934 diagnosis, 933–934 epidemiology, 932 intrathecal analgesia, 941–942 pathophysiology, 932–933 percutaneous tibial nerve stimulation, 941f sacral nerve stimulation complications, 940 outcomes, 940 programming, 940 rationale, 935 technique anterograde approach, 939f laparoscopic implantation of neuroprosthesis, 939 retrograde approach, 937, 938f, 939 retrograde laminotomy, 939 sacral transforaminal approach, 937

INDEX

treatment approaches, 934 types, 932–933 Parafascicular nucleus, see Centromedian–parafascicular complex Parkinson’s disease (PD), see also Deep brain stimulation cell transplantation therapy, 989, 990f centromedian–parafascicular complex, see Centromedian– parafascicular complex deep brain stimulation contraindications, 541 device programming, 545 indications, 541 mechanism of action, 531–532, 533f, 540 outcomes Class I outcome studies, 545, 546t complications, 546–547 subthalamic nucleus targeting outcomes, 546 subthalamic nucleus versus globus pallidus targeting, 545–546 preoperative screening, 540–541 prospects, 547 rate model, 533, 534f technique anesthesia, 543 coordinate systems and target selection, 542–543 exposure, 543 frame placement, 541–542 imaging, 542f implantation of pulse generator and lead extenders, 544–545 lead insertion and test stimulation, 544 microelectrode recording, 543, 544f patient positioning, 543 target localization, 541f gene-based neuromodulation, 136–137 glial-derived neurotrophic factor infusion therapy Amgen Phase II clinical trial, 567 preliminary studies, 566–567 prerequisites, 561–562 prospects, 567–568 infusion therapy, see Glial-derived neurotrophic factor medical therapy limitations, 540 pathophysiology, 530, 531f, 534, 535f surgical intervention historical perspective, 539–540

thalamocortical dysrhythmia, 534–535 treatment approaches, 565–566 tremor, see Tremor Patient, definition, 21 PBS, see Painful bladder syndrome PD, see Parkinson’s disease Penis, see Sex organs Percutaneous tibial nerve stimulation (PTNS) painful bladder syndrome, 941f voiding dysfunction, 953 Periaqueductal gray (PAG) antinociception role, 297, 309f, 310f deep brain stimulation for blood pressure control outcomes, 967, 968f, 969f prospects, 969 rationale, 967 deep brain stimulation for pain management, 499–501, 502t, 503, 504t, 505 micturition control, 919f Perineurium conductivity, 192t mechanical properties, 192–193 Peripheral arterial disease (PAD) epidemiology, 823 management approaches, 823–824 spinal cord stimulation clinical trials, 824t, 827 complications, 827 cost analysis, 359–361 historical perspective, 824–825 implantation, 826 indications, 825, 826t outcomes, 827–828 patient selection, 825–826 programming, 826 prospects, 828 Peripheral nerve stimulation (PNS), see also Transcutaneous electrical nerve stimulation cost-effectiveness analysis, 404–406 historical perspective, 397–398, 417 implantation techniques common peroneal nerve, 1015 femoral nerve, 1016 median nerve, 1013, 1014f posterior tibial nerve, 1015f, 1016 sciatic nerve, 1014, 1015f trialing, 1015 ulnar nerve, 1013, 1014f indications, 400–402 literature review of outcomes, 403–404 nerves anatomy, 399–400 types for neuropathic pain management, 400b

1059

INDEX

patient selection, 403b staging, 418 stimulation parameters, 403 subcutaneous peripheral nerve field stimulation for intractable pain, 1017, 1018f, 1019f surgical technique, 402–403 Peripheral nervous system (PNS) electrodes extraneural electrodes, 202, 203f, 204f interfascicular electrodes, 204, 205f intrafascicular electrodes, 205f placement, 206 regeneration arrays, 206f peripheral nerve structure, 185f size scales, 184 somatotopic organization, 185, 186f structure and organization, 184–185 vasculature, 189f, 190 Periventricular gray (PVG), deep brain stimulation for pain management, 499–501, 502t, 503, 504t, 505 PET, see Positron emission tomography PHN, see Post-herpetic neuralgia Phrenic nerve stimulation, magnetic resonance imaging safety of systems, 278 Physical therapy, pain management, 325–326 Pituitary adenylate cyclase activating polypeptide (PACAP), bed nucleus of the stria terminalis, 681–682 Plasticity, see Neuronal plasticity PMC., see Pontine micturition center PNfS, see Subcutaneous peripheral nerve field stimulation PNS, see Peripheral nerve stimulation; Peripheral nervous system Pons, gross anatomy, 97, 98f Pontine micturition center (PMC), 918–919 Positron emission tomography (PET) micturition control studies, 919f sexual central reflex pathways, 925 Posterior tibial nerve, implantation technique for peripheral nerve stimulation, 1015f, 1016 Post-herpetic neuralgia (PHN) epidemiology, 382 spinal cord stimulation, 382–383 Precision Spinal Cord Stimulation System, magnetic resonance imaging safety, 278 Programmable infusion pumps, magnetic resonance imaging safety

IsoMed pump, 258–259b MedStream pump and catheter, 259f, 260b SynchroMed pumps, 255, 256–258b Pseudorabies virus, neural tracing, 915–916 Psychiatric morbidity, disease states, 24 Psychological evaluation, implantation patients instruments, 74–76 optimization of neuromodulation therapy, 76 outcome-influencing factors, 71, 72t, 73–74 overview, 69–70 personality disorders, 74–75 prospects for study, 77 review of studies, 70–71 Psychosurgery, historical perspective and ethics, 88–89 Pudendal nerve stimulation painful bladder syndrome, 940, 941f voiding dysfunction, 952 PVG, see Periventricular gray Pyramidal motor system, gross anatomy, 106

R Radiofrequency coupling, implantable neural stimulator power, 223 Regeneration arrays, peripheral nervous system electrodes, 206f Rehabilitation Engineering Society of North America (RESNA), 58 Renova Cortical Stimulation System, magnetic resonance imaging safety, 278 Resistance, Ohm’s Law, 146 RESNA, see Rehabilitation Engineering Society of North America Resting membrane potential, overview, 111 Retina, electrodes, 202, 203f Retinal prosthetic devices Boston Retinal Implant Project device biocompatibility, 736f electronics, 730, 741f encapsulation of implant, 731, 732f feedthrough channels, 733 implantation technique, 735f, 736 iridium oxide electrodes, 734f microfabrication of circuits, 730–731 overview, 728 performance in humans, 736, 737f, 738–739

stimulating electrode array design and fabrication, 733–734 titanium case, 732–733 conceptual development, 724, 725f design criteria, 727, 728f neural interface, 727, 728f prospects, 739–740 research programs, 728, 729–730t Rexed’s laminae, 104f, 106, 287, 288f RNA interference, Huntington’s disease studies, 990 Ropivacaine, intrathecal therapy, 470–471 Rostral ventral medulla (RVM), pain modulation, 304–305, 307–308, 310f RVM, see Rostral ventral medulla

S Sacral nerve stimulation (SNS) historical perspective, 934–935 indications and contraindications, 935–936 magnetic resonance imaging safety of systems, 278 pelvic neuroanatomy, 936–937 preoperative assessment, 936 voiding dysfunction management bilateral neuromodulation, 951 complications, 952 contraindications, 949 dorsal genital nerve stimulation, 952–953 mechanisms of action, 947f outcomes, 951–952 patient selection, 947–948 percutaneous tibial nerve stimulation, 953 pudendal nerve stimulation, 952 special populations multiple sclerosis, 948–949 spinal cord injury, 949 success predictors, 948 surgical technique, 949, 950f, 951 SAR, see Specific absorption rate SCC, see Subgenual cingulate cortex SCI, see Spinal cord injury Sciatic nerve, implantation technique for peripheral nerve stimulation, 1014, 1015f SCS, see Spinal cord stimulation Self-sizing electrode, 204f Sensory substitution therapy, vision loss, 726 Serotonin, nociception, 100, 288 Sex hormone-binding globulin (SHBG), bed nucleus of the stria terminalis, 684

1060 Sex organs central reflex pathways, 925–926 innervation parasympathetic pathways, 922 somatic pathways, 923 sympathetic pathways, 922–923 male sexual reflexes emission–ejaculation, 925 erection central mechanisms, 924 peripheral mechanisms, 923–924 glandular secretion, 924–925 overview, 922t SHBG, see Sex hormone-binding globulin Shealy, Norm, 13 Shoulder pain, see Neuromuscular electrical stimulation Sindou, Marc, 52f Single photon emission computed tomography (SPECT), vagus nerve stimulation effects on brain, 671 Sinoatrial node dysfunction (SND), cardiac pacing, 811 Sleep apnea, see Obstructive sleep apnea Small intestine, see Intestinal electrical stimulation SND, see Sinoatrial node dysfunction SNS, see Sacral nerve stimulation Somatosensory evoked potential (SSEP), spinal cord stimulation lead placement monitoring, 1008 Somatostatin, bed nucleus of the stria terminalis, 680–681 SP, see Substance P Spasticity baclofen therapy intrathecal baclofen, 563 oral baclofen, 562–563 outcomes, 565 patient selection, 563 prerequisites, 561–562 pump implantation and programming, 563–564 risks, 564–565 gene-based neuromodulation, 139–140 spinal cord stimulation cost analysis, 359 treatment approaches, 562 SPEAK, see Spectral peak Specific absorption rate (SAR), radiofrequency radiation in magnetic resonance imaging, 246, 253

INDEX

SPECT, see Single photon emission computed tomography Spectral peak (SPEAK), cochlear implant, 718 Spiegel, Ernest, 11–12, 50f, 51 Spinal cord electrodes, 207, 208f gross anatomy, 98, 100f, 101f intrathecal therapy, see Intrathecal analgesia organization, 188f, 189 vasculature, 191f Spinal cord injury (SCI), see also Motor impairment history of neuromodulation therapy, 767–768 lower urinary tract neurogenic dysfunction, 920–922 neurological level of injury, 768 pathophysiology, 768 spinal cord stimulation indications, 769 neuroprosthesis complications, 773 components, 768f implantation, 769 lower extremity outcomes, 772f, 773 programming, 769, 770f prospects, 773–774 upper extremity outcomes, 770, 771f, 772 patient selection, 769 target selection, 768–769 voiding dysfunction and neuromodulation therapy, 949 Spinal cord stimulation (SCS) angina pectoris management cardiac neural control, 834, 835f complications, 839–840 historical perspective, 835–836 implantation, 836–837 mechanism of action, 839f outcomes, 838–839 overview, 796–797 patient selection, 836f programming, 837, 838t prospects, 840–841 cardiac control, 794, 795f, 796f, 797f, 798 complex regional pain syndrome management benefits, 388b, 389 cost analysis, 361–362 cost-effectiveness analysis, 393 dysautonomia, 349–350 efficacy, 386–388

indications and contraindications, 391b multidisciplinary treatment role, 390–391, 392f patient management, 392, 393f prospects, 393–394 risks, 389–390 screening trial conducting, 391–392 patient selection, 390 economic analysis angina, 360–364 Belgium costs versus Netherlands, 366 complex regional pain syndrome, 361–362 continuous quality improvement linking with reimbursement, 365–366 cost studies cost–utility analysis, 358 general considerations, 356–357 historical perspective, 357–358 failed back surgery syndrome patients, 358–359, 365, 367f, 368f, 369f, 370f literature review, 364–365 long-term prospective multi-site cost-effectiveness analysis, 363–374 optimization of cost-effectiveness complication minimization, 373 equipment improvements, 373 patient selection, 372–373 peripheral vascular disease, 359–361 positioning in treatment algorithms, 373 rechargeable batteries, 371–372 retrospective cost–benefit analysis, 363–364 screening trial cost impact, 373–374 spasticity, 359 terminology, 357b historical perspective, 14–15, 42, 335–336, 345 irritable bowel syndrome animal studies, 866–867, 868f clinical studies, 868 pain management, see Visceral pain prospects for study, 868–869 lead placement by laminotomy anesthesia general anesthesia, 1008–1009 local anesthesia, 1007–1008 spinal anesthesia, 1009 outcomes, 1009t, 1010

1061

INDEX

rationale, 1005–1006 surgical technique, 1006, 1007f lead types, 1006f location and effects, 346f magnetic resonance imaging safety of systems Advanced Neuromodulation Systems devices, 278 Medtronic systems, 274–277b Precision Spinal Cord Stimulation System, 278 pain management animal models, 346–347 dorsal horn and spinal circuitry, 347–348 dysautonomia and clinical pain states, 349–350 ischemic pain management, 350–351 neurotransmitter mechanisms, 348–349, 350f prospects, 351–352 peripheral arterial disease clinical trials, 824t, 827 complications, 827 historical perspective, 824–825 implantation, 826 indications, 825, 826t outcomes, 827–828 patient selection, 825–826 programming, 826 prospects, 828 peripheral neuropathic pain management diabetic neuropathy, 380–382 general clinical series, 379–380 mechanism of action, 378–379 post-herpetic neuralgia, 382–383 psychological factors in outcomes, 72–73 spinal cord injury patients indications, 769 neuroprosthesis complications, 773 components, 768f implantation, 769 lower extremity outcomes, 772f, 773 programming, 769, 770f prospects, 773–774 upper extremity outcomes, 770, 771f, 772 patient selection, 769 target selection, 768–769 visceral pain animal studies, 875, 876f devices, 877f human studies, 876–878

indications, 877t mechanisms of action, 876 outcomes, 878f prospects, 878 Spinothalamic tract (STT), nociception, 100, 104, 288–289, 309f SSEP, see Somatosensory evoked potential STAI, see State Trait Anxiety Inventory Stanic, Uros, 60f State Trait Anxiety Inventory (STAI), 70 Stimulus waveform, tissue impact, 119, 120f STN, see Subthalamic nucleus Stomach motility, see Gastric stimulation Strength–duration relationship, electrical stimulus, 114f Stroke, see also Neuromuscular electrical stimulation epidemiology, 743, 753 motor cortex stimulation animal studies, 754f, 755f, 756f human studies, 756, 757f, 758, 759f, 760f, 761, 762f, 763f, 764f prospects, 764–765 rationale, 753–754 motor relearning, 744 neuroprosthesis lower limb applications, 748f, 749f upper limb applications, 747f, 748 STT, see Spinothalamic tract Subcutaneous peripheral nerve field stimulation (PNfS), techniques for intractable pain management, 1017, 1018f, 1019f Subcutaneous targeted stimulation (TS) anatomy and physiology, 420 complications, 424 contraindications, 424 definition, 418 external neuromodulation, 418, 419f historical perspective, 417–418 implantation technique, 421–422 indications, 420 outcomes in pain management, 422, 423f, 424 patient selection, 421 programming, 422 prospects, 425 rationale for selection, 420–421 terminology, 420 Subgenual cingulate cortex (SCC), deep brain stimulation for depression, 696 Substance abuse, see Addiction Substance P (SP)

lower urinary tract neurotransmission, 909 nociception, 100, 288 Substantia nigra, Parkinson’s disease pathophysiology, 530, 531f, 534, 535f Subthalamic nucleus (STN) deep brain stimulation for Parkinson’s disease contraindications, 541 device programming, 545 firing rate, 533, 534f indications, 541 mechanism of action, 531–532, 533f, 540 outcomes Class I outcome studies, 545, 546t complications, 546–547 subthalamic nucleus targeting outcomes, 546 subthalamic nucleus versus globus pallidus targeting, 545–546 pathophysiology, 530, 531f, 534, 535f preoperative screening, 540–541 prospects, 547 rate model, 533, 534f technique anesthesia, 543 coordinate systems and target selection, 542–543 exposure, 543 frame placement, 541–542 imaging, 542f implantation of pulse generator and lead extenders, 544–545 lead insertion and test stimulation, 544 microelectrode recording, 543, 544f patient positioning, 543 target localization, 541f epilepsy and deep brain stimulation, 645 stimulation, see Deep brain stimulation Sufentanil, intrathecal therapy, 447–448, 452t Superior colliculus, gross anatomy, 98f

T Tachyarrhythmia, see Cardiac arrhythmia Telemetry, implantable neural stimulators, 223–224 TENS, see Transcutaneous electrical nerve stimulation

1062 Tetanus toxin, light chain gene therapy for epilepsy, 137, 138f Thalamocortical dysrhythmia, movement disorders, 534–535 Tinnitus epidemiology, 971 neuromodulation therapy, 973, 974f pathophysiology, 971, 972f surgical therapy, 973 treatment approaches, 972–973 TMS, see Transcranial magnetic stimulation Torsion dystonia, see Dystonia Tourette’s syndrome (TS) clinical features, 579–580 comorbidity, 580 deep brain stimulation historical perspective, 580–581 mechanism of action, 583 patient selection, 583–584 perioperative evaluation, 584 postoperative evaluation, 584 programming, 584–585 prospects, 585 surgical technique, 584 targets globus pallidus, 583 medial thalamus, 583 nucleus accumbens, 583 overview, 581, 582f, 583 epidemiology, 580 treatment approaches, 580 Transcranial magnetic stimulation (TMS) depression management adverse events, 670 efficacy, 669–670 mechanism of action, 668 motor threshold, 668 principles, 667–668, 691 prospects, 669–670 essential tremor studies, 536 Transcutaneous electrical nerve stimulation (TENS) historical perspective, 11f, 13, 335 modes of stimulation, 337f pain management analgesia mechanisms animal models, 338 high-frequency stimulation, 338, 339f, 340 low-frequency stimulation, 339f, 340 clinical application, 340–341 efficacy, 341, 342t principles, 336–338 psychological factors in outcomes, 73 terminology, 336

INDEX

Transcutaneous electrical nerve stimulation, see also Peripheral nerve stimulation cardiac control, 793, 798 Transdermal drug delivery, limitations, 432 Tremor, see also Essential tremor deep brain stimulation adverse events, 556t, 557 indications, 554 outcomes, 555–556 patient selection, 554 programming, 555 prospects, 557 rationale, 553–554 surgical technique, 554–555 etiology, 549 pathophysiology, 550f, 551f, 552f surgical intervention historical perspective, 549–550 Trigeminothalamic tract (TTT), 104 TS, see Subcutaneous targeted stimulation TS, see Tourette’s syndrome TTT, see Trigeminothalamic tract

U UEFM, see Upper extremity subscale of the Fugl-Myer scale Ulnar nerve, implantation technique for peripheral nerve stimulation, 1013, 1014f United States Pharmacopoeia (USP), compounding guidelines, 485–486, 489 Upper extremity subscale of the FuglMyer scale (UEFM), motor cortex stimulation studies in stroke, 757, 758f, 759f, 760, 761f, 762, 763f Urinary retention etiology, 953 stimulation therapy bladder and spinal cord, 953 nerve root sacral neuromodulation, 954 USP, see United States Pharmacopoeia

V Vagina, see Sex organs Vagus nerve stimulation (VNS) depression management efficacy, 672–673 mechanism of action, 670–671 overview, 632, 670 safety, 672 epilepsy management advantages, 630–631

adverse events, 629–630 clinical trials, 629 complication avoidance and management, 635–636 lead removal or revision, 635 mechanism of action, 627–629 Neurocybernetic Prosthesis device, 625, 626f, 627f, 632 patient selection, 631 surgical technique anatomy, 633–634 general considerations, 632–633 implantation and testing, 634–635 incisions, 634 nerve dissection, 634 historical perspective, 17 implantation of devices complications, 1039–1040 electrode lead replacement, 1039 operative technique, 1035, 1036f, 1037f, 1038f, 1039 pulse generator replacement, 1039 surgical anatomy, 1033, 1034f, 1035 indications, 630, 632–633 magnetic resonance imaging safety of VNS Therapy System, 262f, 263b, 264f memory effects, 632 Vasculature cerebral cortex, 190f, 191 peripheral nervous system, 189f, 190 spinal cord, 191f Vasoactive intestinal polypeptide (VIP), bed nucleus of the stria terminalis, 682 Vasopressin, bed nucleus of the stria terminalis, 680 Vasovagal syncope, cardiac pacing, 813 VC, see Ventral capsule Vegetative state, deep brain stimulation, 985–987 Ventral capsule (VC), deep brain stimulation for depression, 696 Ventral posterior lateral nucleus (VPL), deep brain stimulation for pain management, 499–501, 502t, 503, 504t, 505 Ventral posterior medial nucleus (VPM), deep brain stimulation for pain management, 499–501, 502t, 503, 504t, 505 Ventral striatum (VS), deep brain stimulation for depression, 696 Ventralis intermedius nucleus (Vim) deep brain stimulation

1063

INDEX

adverse events, 556t, 557 indications, 554 outcomes, 555–556 patient selection, 554 programming, 555 prospects, 557 rationale, 553–554 surgical technique, 554–555 tremor pathophysiology, 549–550 Vim, see Ventralis intermedius nucleus VIP, see Vasoactive intestinal polypeptide Visceral pain dorsal column pathways in nociception, 874f, 875 epidemiology, 873 hyperalgesia, 875 pain transmission in abdomen, 873–874 spinal cord stimulation animal studies, 875, 876f devices, 877f human studies, 876–878 indications, 877t mechanisms of action, 876 outcomes, 878f prospects, 878 Vision, see Blindness; Retinal prosthetic devices

VNS, see Vagus nerve stimulation Vodovnik, Lojze, 109–110 Voiding dysfunction clinical features, 945 neuromodulation therapy bilateral neuromodulation, 951 complications, 952 contraindications, 949 dorsal genital nerve stimulation, 952–953 historical perspective, 946 outcomes, 951–952 patient selection, 947–948 percutaneous tibial nerve stimulation, 953 pudendal nerve stimulation, 952 sacral neuromodulation mechanisms, 947f special populations multiple sclerosis, 948–949 spinal cord injury, 949 success predictors, 948 surgical technique, 949, 950f, 951 overactive bladder syndrome epidemiology, 7 treatment approaches, 946t Voiding reflex, see Lower urinary tract Voltage bipolar electrode, 150–151 definition, 110

electric field, 147 pulses, 120–121 Voltage-controlled stimulator, 219 Voltage-gated ion channel, 111–112 VPL, see Ventral posterior lateral nucleus VPM, see Ventral posterior medial nucleus VS, see Ventral striatum

W WDR cells, see Wide dynamic range cells Weight loss, see Obesity Wide dynamic range (WDR) cells, nociception, 289–290 World Society for Stereotactic and Functional Neurosurgery (WSSFN), historical perspective, 50–51, 52f WSSFN, see World Society for Stereotactic and Functional Neurosurgery Wycics, Henry T., 50f

Z Ziconotide, intrathecal therapy, 472–474