Handbook of Clinical Neurophysiology Series Editors
Jasper R. Daube Managed Care Department, Mayo Clinic, 200 First Street SW; Rochester, MN 55905, USA and
Francois Mauguiere Functional Neurology and Epilepsy Department, Htipital Neurologique Pierre Wertheimer, 59 Boulevard Pinel, F-69394 Lyon Cedex 03, France
Volume 1 Movement Disorders Volume Editor
Mark Hallett Human Motor Control Section, NIH, Building 10, Room 5N226, 10 Center Drive, MSC 1428, Bethesda, MD 20892-1428, USA
2003
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Foreword
Clinical neurophysiology encompasses the application of a wide variety of electrophysiologic methods to the analysis of normal function and the diagnosis and treatment of diseases involving the central nervous system, peripheral nervous system and muscles. A small number of these methods are applied to a single category disease, but most are useful in multiple clinical settings. Previous editions of the Handbook of Clinical Neurophysiology have focused on categories of testing and the many ways they can be applied. The steady increase in growth of subspecialties in neurology and the study of disorders of the nervous system have led to a need for a compilation of the application of the whole range of physiologic methods used for the major categories of neurologic disease. Each volume will be designed to serve as the ultimate reference source for academic clinical neurophysiologists, and as a reference that will provide subspecialists in an area, they will need to fully understand, assess and treat disorders in their patients. As such these volumes will also serve as a major teaching text for trainees in that subspecialty. Subsequent volumes will include all of the clinical disorders served by clinical neurophysiology: the epilepsies, autonomic dysfunction, peripheral nerve disease, muscle disease, motor system disorders, somatosensory system disorders, behavioral disorders, visual and auditory system disorders, and monitoring neural function. Each will focus on the advances in one of these major areas of clinical neurophysiology. Each volume will include critical discussion of new knowledge in basic neurophysiology, approaches to characterization of disease type, localization, severity and prognosis with detailed discussion of advances in techniques to accomplish these. It is recognized that some techniques will be discussed in more than one volume, but with different focuses in each of them. Each volume will include an overview of the field, followed by a section that includes a detailed description of each of the CNP techniques used in the category of disorders, and a third section discussing specific diseases. The latter will include how to evaluate each and comparison of relative contribution of each of the methods of evaluation. A final section will discuss ongoing research studies and anticipated future advances. Selection of movement disorders as the first volume is particularly appropriate in view of the many advances in the application of clinical neurophysiology in these disorders. We are privileged to have one of the world's leaders in the clinical neurophysiology of movement disorders as the volume editor. He has done a superb job of assembling the world leaders in the description of the methods and in their application to particular categories of disease. Jasper R. Daube Francois Mauguiere
Series Editors
List of Contributors
M.Aramideh
Department of Neurology/Clinical Neurophysiology, Medical Center Alkmaar, P.O. Box 501, 1800 AM Alkmaar, The Netherlands.
C.Ardouin
INSERM 318, Joseph Fourier University, Centre Hospitalier Universitaire, Pavillon B, BP 217,38043 Grenoble Cedex 9, France.
J.U.J. Allum
Department of ORL, University Hospital, Basel, Switzerland.
P.G. Bain
Imperial College School of Medicine, Charing Cross Hospital Campus, Pulham Palace Road, London W6 8RF, UK.
A.L. Benabid
INSERM 318, Joseph Fourier University, Centre Hospitalier Universitaire, Pavillon B, BP 217,38043 Grenoble Cedex 9, France.
A. Benazzouz
INSERM 318, Joseph Fourier University, Centre Hospitalier Universitaire, Pavillon B, BP 217,38043 Grenoble Cedex 9, France.
R. Benecke
Department of Neurology, University of Rostock, Gehlsheimer Strasse 20, D-18147 Rostock, Germany.
A. Berardelli
Dipartimento di Scienze Neurologiche, Universita di Roma "La Sapienza", Viale Universita 30,00185 Rome, Italy.
B.R.Bloem
Department of Neurology, 326, University Medical Center St. Radboud, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
C. Braun
MEG Center, Eberhard-Karls University Tubingen, Hoppe-Seyler Strasse 3, D-72076 Tubingen, Germany.
P. Brown
Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, Queen Square, London WC1N 3BG, UK.
D. Burke
College of Health Sciences, The University of Sydney, Sydney, Australia.
J.N. Caviness
Department of Neurology, Mayo Clinic Scottsdale, 13400 East Shea Blvd., Scottsdale, AZ 85259, USA.
S. Chabardes
INSERM 318, Joseph Fourier University, Centre Hospitalier Universitaire, Pavillon B, BP 217,38043 Grenoble Cedex 9, France.
S. Chokroverty
Department of Neurology/Cronin 466, St. Vincents Hospital, 153 W 11th Street, New York, NY 10011, USA.
G. Croccu
Department of Neurological Sciences, University of Rome "La Sapienza", 00185 Rome, Italy.
viii
LIST OF CONTRIBUTORS
A. Curra
Istituto Neurologico Mediterraneo "Neuromed", Via Atinense 18, 86077 Pozzilli, IS, Italy.
G. Deuschl
Department of Neurology, Christian-Albrechts-Universitat Kiel, Niemannsweg 147, D-24lO5 Kiel, Germany.
C. Dohle
Department of Neurology, University Hospital Diisseldorf, Moorenstrasse 5, D-40225 Diisseldorf, Germany.
J.O. Dostrovsky
Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S lA8, Canada.
R.J. Elble
Department of Neurology, Southern Illinois University School of Medicine, P.O. Box 19643, Springfield, IL 62794-9643, USA.
U. Fietzek
Department of Neurology, Christian-Albrechts-Universitat Kiel, Niemannsweg 147, D-24lO5 Kiel, Germany.
M.K. Floeter
Electromyography Section, National Institute of Neurological Disorders and Stroke, NIH, 10 Center Drive, MSC 1404, Bethesda, MD 20892-1404, USA.
V. Fraix
INSERM 318, Joseph Fourier University, Centre Hospitalier Universitaire, Pavillon B, BP 217,38043 Grenoble Cedex 9, France.
H.-J. Freund
Department of Neurology, University Hospital Diisseldorf, Moorenstrasse 5, D-40225 Diisseldorf, Germany.
S.C. Gandevia
Spinal Injuries Research Centre, Prince of Wales Medical Research Institute, University of New South Wales, Sydney, Australia.
C. Gerloff
Cortical Physiology Research Group, Department of General Neurology, Eberhard-Karls University Tiibingen, Hoppe-Seyler Strasse 3, D-72076 Tiibingen, Germany.
J.-M. Grades
Department of Neurology, Mount Sinai Medical Center, 1 Gustave L. Levy Place, Annenberg 2/Box 1052, New York, NY 10029-6574, USA.
S.T. Grafton
Center for Cognitive Neuroscience, 6162 Moore Hall, Dartmouth College, Hanover, NH 03755, USA.
M. Hallett
Human Motor Control Section, National Institute of Neurological Disorders and Stroke, NIH, Building lO, Room 5N226, 10 Center Drive, MSC 1428, Bethesda, MD 20892-1428, USA.
M. Hayes
Department of Neurology, Concord Repatriation Hospital, Sydney, Australia.
B. Hellwig
Neurologische Universitatsklinik, Neurozentrum, Breisacher Strasse 64, D-79106 Freiburg, Germany.
W.Hening
Johns Hopkins Center for Restless Legs Syndrome, 5th Floor, Room 5B71C, Asthma & Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224, USA.
W.D. Hutchison
Department of Surgery, Division of Neurosurgery, Toronto Western HospitallMC 2-433, 399 Bathurst Street, East Wing 6-528, Toronto, ON M5T 2S8, Canada.
A. Ikeda
Department of Neurology, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
ix
LIST OF CONTRIBUTORS
M. Jahanshahi
Sobell Research Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, Queen Square, London WCIN 3BG, UK.
R. Kaji
Department of Clinical Neuroscience, Hospital of the University of Tokushima, 2-Chome 5-1, Kuramotocho, Tokushima City, Tokushima 770-8503, Japan.
K.R. Kaufman
Biomechanics Laboratory, Charlton North L-IION, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
S.Klebe
Department of Neurology, Christian-Albrechts-Universitat Kiel, Niemannsweg 147, D-24105 Kiel, Germany.
A. Koudsie
INSERM 318, Joseph Fourier University, Centre Hospitalier Universitaire, Pavillon B, BP 217,38043 Grenoble Cedex 9, France.
P. Krack
INSERM 318, Joseph Fourier University, Centre Hospitalier Universitaire, Pavillon B, BP 217,38043 Grenoble Cedex 9, France.
A.M. Lozano
Department of Surgery, Division of Neurosurgery, Toronto Western HospitallMC 2-433, 399 Bathurst Street, East Wing 6-528, Toronto, ON M5T 2S8, Canada.
C.H. Liicking
Neurologische Universitatsklinik, Neurozentrum, Breisacher Strasse 64, D-79106 Freiburg, Germany.
V.G. Macefield
Spinal Injuries Research Centre, Prince of Wales Medical Research Institute, University of New South Wales, Sydney, Australia.
M.-UManto
Charge de Recherches FNRS, Neurologie, 808 Route de Lennik, 1070 Brussels, Belgium.
F. Maugulere
Department of Functional Neurology and Epileptology, Neurological Hospital, 59 Boulevard Pinel, 69330 Lyon, France.
T.Mima
Department of Brain Pathophysiology, Human Brain Research Center, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
T. Nagamine
Human Brain Research Center, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
F. Pauri
AFaR, Dip. Neuroscienze, Osdpedale Fatebenefratelli, Isola Tiberina 39, 00186 Rome, Italy.
P.Poliak
INSERM 318, Joseph Fourier University, Centre Hospitalier Universitaire, Pavillon B, BP 217, 38043 Grenoble Cedex 9, France.
B.W. Ongerboer de Visser Department of Neurology/Clinical Neurophysiology Unit, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands. P.M. Rossini
Direzione Scientifica AFaR, Associazione Fatebenefratelli per la Ricerca, Lungotevere degli Anguillara 12,00186 Rome, Italy.
J.C. Rothwell
Sobell Department, Institute of Neurology, Queen Square, London WCIN 3BG, UK.
H. Shibasaki
Human Brain Research Center and Department of Neurology, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
x
LIST OF CONTRIBUTORS
D.M. Simpson
Clinical Neurophysiology Laboratories, Mount Sinai Medical Center, 1 Gustave L. Levy Place, New York, NY 10029, USA.
L. Sudarsky
Department of Neurology, ASB 1-2, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.
P.O. Thompson
Department of Neurology and University Department of Medicine, Royal Adelaide Hospital and University of Adelaide, Adelaide, SA 5000, Australia.
F.Valldeoriola
Unitat d'EMG, Servei de Neurologia, Hospital Clinic, Villarroel 170, Barcelona 08036, Spain.
J. Valls·Soh~
Unitat d'EMG, Servei de Neurologia, Hospital Clinic, Villarroel 170, Barcelona 08036, Spain.
J.E. Visser
Department of Neurology, 326, University Medical Center St. Radboud, P.O. Box 9101,6500 HB Nijmegen, The Netherlands.
J. Volkmann
Department of Neurology, Christian-Albrechts-Universitat Kiel, Niemannsweg 147, D-24105 Kiel, Germany.
U. Ziemann
Clinic of Neurology, Johann Wolfgang Goethe University of Frankfurt, TheodorStem-Kai 7, D-60590 Frankfurt am Main, Germany.
Movement Disorders Handbook of Clinical Neurophysiology, Vol. I M. Hallett (Ed.) © 2003 Elsevier B.V. All rights reserved
3 CHAPTER I
Movement disorders: overview Why have a book devoted to the Clinical Neurophysiology of movement disorders? A primary consideration is the growth of the field of movement disorders. Movement disorders is a relatively new field that grew out of an original interest in Parkinson's disease. The interest in Parkinson's disease itself blossomed after the finding that it could be well treated with levodopa. The field soon expanded to other disorders involving the basal ganglia, including dystonia and Huntington's disease. Myoclonus was added shortly after the finding that many cases were treatable with 5-hydroxytryptophan. Then other disorders were included where the motor system was impaired, and the field expanded to include the ataxias, spasticity and even paresis. The field got its name from Stan Fahn and C. David Marsden who helped popularize this way of organizing neurological disorders. The field has now been codified with the formation of an international society and journal. The common theme of movement disorders is the motor system and its diseases. A good deal of emphasis in the field has been placed on pharmacology as the mainline method of treatment. Recently, genetics and cell biology have been giving insights into the nature of the disease processes that cause movement disorders. Another critical area of interest has always been in the physiology and pathophysiology of the motor system, and this is the entry point for clinical neurophysiology. How is movement normally generated? What are the abnormalities underlying manifestations such as bradykinesia, tremor, chorea, tics, and myoclonus? Not only are these questions of interest by themselves, but the answers may point toward new therapeutic options. The first intersection of clinical neurophysiology and movement disorders is this research issue about the nature of motor disturbances. Clinical neurophysiology has always been a field that has contributed to the diagnosis of neurological disorders. As has been said often, it is an extension of the neurological examination. The second intersection of clinical neurophysiology and movement disorders is diagnosis. Clinical neurophysiologists
have traditionally been trained largely in EEG and EMG, focused largely on epilepsy and neuromuscular disorders, respectively. However, it is clear that clinical neurophysiology can contribute in other areas. In addition to movement disorders, for example, clinical neurophysiology can contribute to the fields of autonomic nervous system disorders, sleep disorders, and central nervous system monitoring during operations on the brain or spine. In movement disorders that look superficially similar, it is critical to make the right diagnosis because therapies might differ. Is a quick movement a tic, a myoclonic jerk or a voluntary movement? Studies of the surface EMG and the correlative EEG can give a definitive answer. Small differences in timing, easily measured with simple techniques, can be impossible to tell by eye. What is the burst duration of EMG underlying an involuntary movement? For example, is a myoclonic jerk due to a fragment of epilepsy or a fragment of a basal ganglia movement disorder? The EMG burst length is shorter in the former than the latter. What is the latency of a muscle jerk after a stimulus? Is it shorter than possible reaction time? If so, it cannot be voluntary or psychogenic. What is the frequency of tremor and how does it change with an intervention? Exaggerated physiological tremor should reduce in frequency with weighting of the limb by 1 or 2 Hz. This cannot be appreciated by visual inspection. Might there be two components of a tremor? Again, only physiological measurements will reveal this finding. Quantification of movement disorders is often useful for monitoring change over time including assessment of therapy. There are clinical scales that can be useful, but these are largely subjective and subtle changes over months or years might be missed. Physiological techniques can be valuable in this regard and can be used, for example, to monitor the amplitude of tremor or the magnitude of spastic tone. A new intersection of movement disorders and clinical neurophysiology is therapy. EMG guidance
4
improves the delivery of botulinum toxin to muscles with unwanted spasms. Neurophysiological monitoring is valuable in locating targets for deep brain stimulation. Transcranial magnetic stimulation is being explored for its utility in several movement disorders. This should be a valuable text for clinical neurophysiologists. The topic of movement disorders is usually treated superficially in even large textbooks of clinical neurophysiology. Useful clinical methods and research techniques are covered extensively. The book anticipates that the reader will have some basic knowledge of clinical neurophysiology, but then can be useful for the novice who wants an introduction and by the expert who is looking for details.
M. HALLETT
The book is arranged in two main parts. The first part deals with techniques. Here is where the reader can find exactly how to do a specific test and how to interpret the results. The application of the techniques to movement disorders is only briefly discussed. In the second part, individual movement disorders are the topics. Each chapter describes the disorder and its physiology, concentrating on the research and clinical methods that can be useful. It might be necessary when reading these chapters to refer back to the detailed technique in the first part of the book. At the end, there is a short look to the future with some guesses as to the direction of the field. Mark Hallett Bethesda, MD, USA June 2003
Movement Disorders Handbook of Clinical Neurophysiology, Vol. 1 M. Hallett (Ed.) © 2003 Elsevier B.V. All rights reserved
7 CHAPTER 2
Electromyography Mark Hallett* Human Motor Control Section. National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892-/428. USA
Electromyography (EMG) is an important tool for the analysis of movement disorders (Hallett, 1999, 2000). Muscles are responsible for movements, and EMG is a direct measurement of the activity of muscle and a fairly direct measure of alpha motoneuron activity. EMG is most commonly used in clinical neurophysiology for the analysis of peripheral neuromuscular disease, answering the questions of whether there is a neuropathy, myopathy or neuromuscular junction disorder. In general, when dealing with movement disorders, it is assumed that all those aspects are normal, and the questions are different. In this context the questions asked include what muscles are active and what is the pattern of activation. The term kinesiological EMG is sometimes applied, and it is often apt, since the issue is what is the EMG responsible for the movement. Since numerous muscles act on any joint, it is typically necessary to record from at least two muscles with antagonist actions. The main information that can be extracted is the amplitude and the timing. EMG data can be measured with surface, needle, or wire electrodes (Hallett et al., 1994). Surface electrodes have the advantages that they are not painful and they record from a relatively large volume of muscle producing a good average of its activity. For these reasons, pairs of surface electrodes are ordinarily used for the analysis of movement disorders. The two surface electrodes are typically placed near the middle of the muscle belly about 2 or 3 em apart. Belly-tendon recording is often not optimal since recording volume would be too extensive and pickup would include unintended
* Dr. Mark Hallett, M.D., Human Motor Control Section, NIH, Building 10, Room 5N226, 10 Center Dr., MSC 1428, Bethesda, MD 20892-1428, USA. E-mail address:
[email protected] Tel.: 3011496-9526; fax: 3011480-2286.
nearby muscles. Needle electrodes have the advantage that they are more selective, sometimes a necessity when recording from small or deep muscles. Traditional needle electrodes are stiff, however, and it is best to use them when recording from muscles during movements that are close to isometric. If there is substantial movement, needles will be very painful, in part because of the relative movement of the skin and muscle belly. Pairs of fine wire electrodes have the advantage of selectivity similar to that of needle electrodes and are flexible, permitting free movement with only minimal pain. There is slight movement of the wires with movement, but they do provide a reasonably stable recording. Regardless of the electrodes used, it is important to avoid movement artifact, which can contaminate the EMG signal. Wire movement should be limited. Low-frequency content of the EMG signal can be restricted with filtering, and this can remove much of the movement artifact. Movement artifact is largely in the range of DC to 10 or 20 Hz. Surface EMG has significant power in this range as well, but the peak power is at about 100 Hz, so the filtering of power below 20 Hz still leaves most of the EMG power. When surface electrodes are used, their impedance should be reduced to 10 kO or less. This will reduce electrogenesis at the electrode-skin interface caused by slight movements. In order to reduce the impedance sufficiently, it is usually necessary to abrade the skin (Fig. 1). If there is a question about the possible peripheral origin of the movement disorder, then needle EMG may be very helpful. For peripheral disorders, typically there are characteristic findings. For example, there might be fasciculations, myokymia, neuromyotonia or other high frequency bursts. The amplitude of EMG conveys information about the magnitude of the central nervous system output. For this purpose it is generally not useful to
M.HALLETT
8
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.
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4
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.
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/,t\~
... r· .«. 500 juv 50.1. 5
,J~
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.
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. Off
Fig. 1. Surface EMG recordings in a normal volunteer simulating a tremor. Muscles, from top down, are biceps, triceps, flexor carpi radialis and extensor carpi radialis. (A) The recordings are contaminated with movement artifact because the surface electrodes had high impedance. (B) The recordings here are much better after the skin was abraded and the impedance was reduced to less than 10 kD.
note the magnitude in mV. Since the electrodes are not in a "standard" position and there will be varying relationships between the skin surface and the muscle belly, the absolute measurement has ambiguous meaning. There are two ways of standardizing the measurements. One is in relation to maximal voluntary EMG output, and the other is with respect to a maximum compound muscle action potential (CMAP) produced by nerve stimulation. The former is more commonly used, and in many circumstances nerve stimulation would not be easy to do anyway.
EMG is occasionally used as a measure of force, but this should only be considered approximate since the relationship between EMG amplitude and force is not exact, may change in different circumstances and is often not linear (Perry and Bekey, 1981; Solomonow et al., 1986; Hof, 1997). In processing the EMG for amplitude it is often useful to rectify and smooth the recording (Fig. 2). This process yields an "envelope" of the EMG signal. The amplitude of the envelope can be used as the magnitude of the EMG, and for a burst of EMG,
ELECTROMYOGRAPHY
9
B
8
Off
Fig. 1. Continued.
the integrated area of the envelope is a good measure. If a tremor is being recorded, then the successive envelopes of EMG form a curve like a sinusoid, and the record can be subjected to frequency analysis to get information about the frequency content of the signals driving the tremor. The EMG patterns underlying voluntary movement are characteristic and vary with the speed of movement (Berardelli et al., 1996; Hallett, 1999, 2000) (Fig. 3). A slow, smooth movement is characterized chiefly by continuous activity in the agonist. A movement made as rapidly as possible, a so-called ballistic movement, has a triphasic pattern with a burst of activity in the agonist lasting 50-100
ms, a burst of activity in the antagonist lasting 50-100 ms, and return of activity in the agonist often in the form of a burst. In different disorders of voluntary movement, there are characteristic abnormalities. With cerebellar lesions, there is prolongation of the first agonist and/or antagonist EMG bursts. The prolongations can be marked, and there is a good correlation of the acceleration time of the movement with the duration of the first agonist burst. Unwanted prolongation of acceleration time should predispose to hypermetria. The antagonist burst can be delayed as well. With parkinsonian bradykinesia, there is abnormal patterning, with multiple bursts having the
10
M.HALLETT
A
500
IJ-V
Amp 2
B
100 IJ-V
Fig. 2. Surface EMG recordings in a normal volunteer simulating a tremor. (A) The top trace is the raw EMG from biceps and the bottom is the same trace rectified. (B) This is a record similar to that in (A), but the EMG has been smoothed as well as rectified.
Table I EMG appearance in different types of involuntary movements. Disorder
EMGpattem Reflex
Myoclonus
x
Examples/comment Ballistic
x
x
Tic Dystonia Chorea
X
X
(Modified from Hallett, 1999, with pennission.)
Tonic
x
Epileptic myoclonus Ballistic movement overflow myoclonus Dystonic myoclonus
x
Not fully involuntary
X
Also athetosis
X
Also dyskinesia, ballism
ELECTROMYOGRAPHY
A
BICEPS
TRIClPS
ARM
STEP POSITION
B BICEPS
TRICEPS
SUP
II
different types of movements. Specification of duration in the range of 30-300 ms merely by clinical inspection is virtually impossible due to the relative slowness of the mechanical events compared with the electrical events. Finally, antagonist muscle relationships can be specified as synchronous or asynchronous (reciprocal) by inspection of the EMG signal. In a tremor, asynchronous activity would be described as alternating (Fig. 4). There are three EMG patterns that may underlie involuntary movements (Figs. 5 and 6) (Hallett et al., 1987, 1994; Hallett, 1997, 1999,2000). One pattern, which can be called "reflex", resembles the burst occurring in many reflexes, including H-reflexes and stretch reflexes. The EMG burst duration is 10-30 ms, and EMG activity in the antagonist muscle is virtually always synchronous. Another pattern, which can be called "ballistic", resembles voluntary ballistic movements with a triphasic pattern; there is
AIlM POSITION
Fig. 3. EMG activity in biceps and triceps during (A) fast flexion of the elbow and (B) slow, smooth flexion. STEP indicates the target to be tracked and ARM POSITION is the actual elbow angle; reaction time and movement time information can be obtained from these records. The vertical calibration line corresponds to 500 mV for A and 20 mV for B. Modified from Hallett et al., 1975, with permission.
appearance of repetitrve cycles of the triphasic pattern to complete the movement. With dystonia and athetosis, there is excessive activity, including cocontraction activity, in the antagonist. Excessive activity also overflows into muscles not needed for the action. EMG burst length can be prolonged. In athetosis particularly, there are a variety of abnormal patterns of antagonist activity that appear to block the movement from occurring. Inspection of the EMG signal of an involuntary movement reveals, first, whether the movement is regular (usually a tremor) or irregular. There are sometimes surprises in such an analysis. Rhythmic EMG activity can appear irregular clinically if the amplitude varies; irregular EMG activity will sometimes appear rhythmic clinically if it is rapid. The duration of the EMG burst associated with an involuntary movement can also be measured; specific ranges of duration are associated with
A
EXT INn
B TIB ANT
GASTROC
Fig. 4. Recordings from pairs of antagonist muscles in different tremors. (A) Needle EMG recordings from the first lumbrical and the extensor indicis in a patient with essential tremor showing synchronous activation. (B) Surface EMG recordings in a patient with Parkinson's disease showing alternating activity in tibialis anteriorand gastrocnemius. From Sabra and Hallett, 1984, with permission.
12
Fig. 5. Comparison of (A) "reflex" and (B) "ballistic" EMG appearance underlying different types of myoclonus. Part A is from a patient with reticular reflex myoclonus, and part B is from a patient with ballistic movement overflow myoclonus. Vertical calibration is 1 mV for part A and 0.5 mV for part B. From Chadwick et al., 1977, with permission.
a burst of activity in the agonist muscle lasting 50-100 ms, a burst of activity in the antagonist muscle lasting 50-100 ms, and then return of activity in the agonist, often in the form of another burst. The third pattern, which can be called "tonic", resembles slow voluntary movements and is characterized by continuous or almost continuous EMG activity lasting for the duration of the movement, from 200-1000 ms or longer. Activity can be solely in the agonist muscle, or there can be some cocontraction of the antagonist muscle with the agonist.
M.HALLETT
Different types of myoclonus show one of the three types of patterns, and the EMG can be very helpful in making a diagnosis. Dystonia and athetosis show largely tonic patterns. Chorea is characterized by a wide variation of EMG burst durations encompassing all three patterns. In tic, there can be ballistic or tonic patterns. These data are summarized in Table 1. There can also be a brief lapse in tonic innervation that is clinically called asterixis or negative myoclonus (Shibasaki, 1995). Clinically, it appears as an involuntary jerk superimposed on a postural or intentional movement. Careful observation often reveals that the jerk is in the direction of gravity, but this can be difficult since the lapse is frequently followed by a quick compensatory antigravity movement to restore limb position. The involuntary movement is usually irregular, but when asterixis comes rapidly there may be the appearance of tremor. EMG analysis shows characteristic synchronous pauses in antagonist muscles (Fig. 7). In clinical practice, it is of course valuable to couple EMG studies with either kinesiologic or EEG observations or both. Nevertheless, the simple application of EMG can be extremely helpful as a first step.
Acknowledgment This review includes sections updated from earlier chapters (Hallett, 1999, 2000). Work of the U.S. government, it has no copyright.
Fig. 6. EMG recordings from a patient with focal hand dystonia when attempting hand writing. Recordings are from 4 muscles in the right arm during motor performance. From Cohen and Hallett, 1988, with permission.
ELECTROMYOGRAPHY
13
Fig. 7. EMG and accelerometric recording of asterixis. EMG is from flexors and extensors of the wrist and accelerometer was on the dorsum of the hand. From Hallett, 1999, with permission.
References Berardelli, A, Hallett, M, Rothwell, JC, Agostino, R, Manfredi, M and Thompson, PD et al. (1996) Review Article. Single-joint rapid arm movements in normal subjects and in patients with motor disorders. Brain, 119: 661-674. Chadwick, D, Hallett, M, Harris, R, Jenner, P, Reynolds, EH and Marsden, CD (1977) Clinical, biochemical, and physiological features distinguishing myoclonus responsive to 5-hydroxytryptophan, tryptophan with a monoamine oxidase inhibitor, and clonazepam. Brain, 100: 455-487. Cohen, LG and Hallett, M (1988) Hand cramps: clinical features and electromyographic patterns in a focal dystonia. Neurology, 38: 1005-1012. Hallett, M (1997) Myoclonus and myoclonic syndromes. In: JJ Engel and TA Pedley (Eds.), Epilepsy: A Comprehensive Textbook. Lippincott-Raven, Philadelphia, pp. 2717-2723. Hallett, M (1999) Electrophysiologic evaluation of movement disorders. In: MJ Arninoff (Ed.), Electrodiagnosis in Clinical Neurology. Churchill Livingstone, New York,pp.365-380. Hallett, M (2000) Electrodiagnosis in movement disorders. In: KH Levin and HO Liiders (Eds.), Comprehensive Clinical Neurophysiology. W.B. Saunders Company, Philadelphia, pp. 281-294.
Hallett, M, Shahani, BT and Young, RR (1975) EMG analysis of stereotyped voluntary movements in man. J. Neurol. Neurosurg. Psychiatry, 38: 1154-1162. Hallett, M, Marsden, CD and Fahn, S (1987) Myoclonus (Chapter 37). In: PJ Vinken, GW Bruyn and HL Klawans (Eds.), Handbook of Clinical Neurology. Elsevier Science Publishers, Amsterdam, pp. 609-625. Hallett, M, Berardelli, A, Delwaide, P, Freund, H-J, Kimura, J and Lucking, C et al. (1994) Central EMG and tests of motor control. Report of an IFCN Committee. Electroencephalogr. Clin. Neurophysiol., 90, 404-432. Hof, AL (1997) The relationship between electromyogram and muscle force. Sportverletz Sportschaden, 11, 79-86. Perry, J and Bekey, GA (1981) EMG-force relationships in skeletal muscle. Crit. Rev. Biomed. Eng., 7: 1-22. Sabra, AF and Hallett, M (1984) Action tremor with alternating activity in antagonist muscles. Neurology, 34: 151-156. Shibasaki, H (1995) Pathophysiology of negative myoclonus and asterixis. In: S Fahn, M Hallett, HO Luders and CD Marsden (Eds.), Negative Motor Phenomena. Lippincott-Raven Publishers, Philadelphia, pp. 199209. Solomonow, M, Baratta, R, Zhou, BH, Shoji, H and D'Ambrosia, R (1986) Historical update and new developments on the EMG-force relationships of skeletal muscles. Orthopedics, 9: 1541-1543.
Movement Disorders Handbook of Clinical Neurophysiology, Vol. I
M. Hallett (Ed.) © ZOO3 Elsevier B.V. All rights reserved
15 CHAPTER 3
EEG (MEG)/EMG correlation Hiroshi Shibasaki'<" and Takashi Nagamine" a
Human Brain Research Center and b Department of Neurology, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
3.1. Introduction The cerebral cortex is involved in the control of voluntary movements to various extent depending on the kind of movement. In involuntary movements such as myoclonus and dystonia, the sensori-motor cortex in particular is involved either directly or indirectly in the pathophysiology. The functional relation between the cortical activities and the movements, whether voluntary or involuntary, can be studied non-invasively by using the functional neuroimaging techniques such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), and with various electrophysiological methods. Among the latter techniques, the simultaneous recording of electroencephalogram (EEG) or magnetoencephalogram (MEG) with electromyograms (EMG) provides useful information about the temporal and spatial relation between the cortical activities and those movements (Shibasaki and Rothwell, 1999). Subcortical structures, especially basal ganglia and cerebellum, are extremely important for the control of voluntary motor execution and also in relation to the pathogenesis of certain involuntary movements. By using EEG or MEG, however, the functional states of these subcortical structures can only be estimated by measuring the cortical activities that might be influenced by the functional abnormalities of these subcortical structures. This is in strong contrast with neuroimaging techniques which enable us to visualize the activated areas, if any, also in these deep structures.
* Dr. Hiroshi Shibasaki, M.D., Ph.D., Department of Neurology, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. E-mail address:
[email protected] Tel.: +81-75-751-3770; fax: +81-75-761-9780.
Three kinds of electrophysiological methods can be used for analyzing the relation between the cortical electric activities and the movements: (1) recording of electric or magnetic fields associated with the movement; (2) analysis of change of cortical rhythmic oscillations related to the movement; and (3) coherence analysis between EEG or MEG and EMG. As the cortico-muscular coherence is dealt with in another chapter in this book, the first two techniques are described in this chapter.
3.2. EEG versus MEG With EEG and MEG, essentially the same neuronal activities can be recorded, namely the post-synaptic potentials of apical dendrites of large pyramidal neurons in the cerebral cortex. Theoretically EEG is formed by electric potential fields resulting from extra-cellular current of the apical dendrites whereas MEG is a magnetic field formed by the intra-cellular current generating the magnetic flow occurring around the apical dendrite. As the majority of those apical dendrites are oriented at a right angle to the cortical surface, and as the conventional MEG machine adopts sensors oriented parallel to the skull surface, only the current flow of apical dendrites tangentially oriented with respect to the head surface can be recorded by MEG. In other words, MEG is much more sensitive to the activities arising from the cortical sulci as compared to those arising from the crown of cortical gyri. This is in strong contrast with EEG that is derived from a summation of both tangentially and radially oriented current flows. Although both EEG and MEG have to depend on the estimation of the current sources by solving the inverse problem, the biggest advantage of MEG is its high spatial resolution. This is mainly because MEG is not affected by the 'shunt effect' caused by different electrical conductivity of the structures surrounding the brain surface such as
16
spinal fluid, skull and subcutaneous tissues whereas the EEG field is strongly influenced by the 'shunt effect'. Therefore, MEG provides more accurate information about the source of cortical electric activities as compared with EEG. 3.3. Electric or magnetic fields associated with movements 3.3.1. Self-initiated movements 3.3.1.1. Principle Among various methods used for the investigation of self-initiated movements, the EEG (MEG)/EMG correlation is studied mainly for understanding the cortical mechanisms underlying the central motor control and its disorders. Since the movementrelated cortical potentials (MRCP) (signal) are usually much smaller as compared to the background EEG or MEG activities (noise in this case), they cannot be identified just by visual inspection of the raw record, even if they might occur in close time relation to the movement. Therefore, the method for averaging the EEG or MEG with respect to the time of each movement is employed for increasing the signal-to-noise ratio. In contrast to the study of sensory or perceptive mechanisms, an emphasis is often placed on the epoch before the movement onset, which makes it necessary to average the data backward with respect to the actual fiducial time point; the movement onset in most cases. 3.3.1.2. Method of recording For recording MRCP, EEG and/or MEG and EMG are simultaneously recorded while the subject repeats a voluntary movement at a self-paced rate of once every 5 s or longer (Shibasaki, 1993). Any kind of movement can be studied, but simple movements such as finger extension, wrist extension, tongue protrusion and foot extension are commonly employed. MRCP can also be recorded in association with more natural movements such as gait initiation (Vidailhet et al., 1993) and chewing (Yoshida et al., 2000). Magnitude and distribution of MRCP is slightly different depending on the kind of movements. Usually a complex movement is associated with a larger pre-movement negative slope than a simple one (Kitamura et al., 1993b), and a discrete movement of an isolated finger produces a larger slope than the simultaneous movement of two fingers (Kitamura et al., 1993a).
H. SHIBASAKI AND T. NAGAMINE
EEG electrodes should be placed at least over the central areas, approximately C3 and C4 for hand movement and Cz for foot movement according to the International 10-20 system. Use of additional electrodes, if possible, is helpful not only for studying the distribution of potentials over the head, but also, perhaps more importantly, for identifying each subcomponent of MRCP. Linked ear electrodes are commonly used as the reference for common referential derivation. Electrode impedance must be kept below 5 ko. It is important to use a long time constant for recording the slow components, and thus the filter setting of amplifiers commonly used is 0.05-120 Hz (-3 dB). EMG is recorded by a pair of disk electrodes placed over the contracting muscle with a filter setting of 30-120 Hz, and rectified. Accordingly, sampling rate of 400 Hz or higher is preferable. A fiducial point for averaging is determined when the rectified EMG exceeds a preset threshold for an on-line analysis, but an off-line analysis by visually determining the precise onset of each EMG discharge as well as by excluding the trials containing various artifacts gives rise to better waveforms (Barrett et al., 1985). The analysis window should preferably cover 3.0 s before and 0.5 s after the movement onset. For monitoring blink artifacts, electro-oculograms (EOGs) should be simultaneously recorded and averaged by using the same method as used for processing the EEG. Two or more sessions should be repeated for each kind of movement in order to confirm reproducibility of the waveform, and each session commonly consists of about 50 trials. 3.3.1.3. Normalfindings In normal subjects, self-initiated finger movement is preceded by a slow negative potential shift starting at about 2.0 s before the movement onset (Fig. 1). This early component called either Bereitschaftspotential (BP), or the early component of readiness potential (RP) or NS1, is maximal at the midline central region and distributed widely and symmetrically over the scalp whatever movement is employed as the task (Shibasaki et al., 1980). Approximately 400 ms before the movement onset, a sharper negative slope, called Negative Slope (NS'), the late component of RP or NS2, appears over the central region contralateral to the movement (Cl for the right and C2 for the left hand movement). Immediately before the movement, a small negative
17
EEG (MEG)/EMG CORRELATION
Vol. Lt Wrist Extension Ref:A1A2
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Fig. 1. Movement-related cortical potentials (MRCP) recorded from a normal subject and schematic illustration of the scalp distribution of Bereitschaftspotential (BP) and negative slope (NS'). MP: motor potential. Self-paced, voluntary (Vol.) left (Lt) wrist extension. Average of 98 trials.
potential is identified in some subjects, which is localized to the contralateral central electrode (motor potential, MP). This potential continues to increase in negativity and moves anteriorly and to the midline where it peaks about 100 ms after the movement onset. According to the results of direct cortical recording of these potentials with subdurally implanted electrodes, the BP preceding unilateral hand movement mainly arises from activities in the hand area of the primary sensori-motor cortex (S1M!) and the supplementary motor areas (SMAs) both bilaterally, and the NS' reflects activities arising from the same areas but with much more contralateral predominance (Ikeda and Shibasaki, 1992; Ikeda et al., 1992). During the early pre-movement period, the averaged magnetic field is rather silent while BP is observed on the averaged EEG, and in the later period while NS' is seen bilaterally with the
contralateral predominance, the magnetic field is seen almost exclusively at the contralateral central region (Nagamine et al., 1996). In view of the fact that MEG is almost exclusively composed of tangentially oriented current sources (see 3.2), it can be postulated that initially the crown of the precentral gyrus (probably the premotor area for hand movements) is activated bilaterally, and the anterior bank of the contralateral central sulcus (area 4) is activated closer to the movement onset. How much the activities of SMA contribute to the scalprecorded BPINS' has not yet been clarified. In the recent subdural recording in epilepsy patients, it has been shown that not only the SMA proper but also the rostral part of SMA, probably corresponding to the pre-SMA of monkey, produces BPINS' (Kunieda et al., 2000). The SMA, especially the pre-SMA, was significantly less active with the rapid rate of movement repetition (2 Hz) than with the slower rate
18
while the Sl-MI remained active regardless of the movement rate (Kunieda et al., 2000). 3.3.1.4. Muscle relaxation MRCP is usually recorded by employing the movements caused by muscle contraction, but the negative movement caused by voluntary termination of muscle contraction, or muscle relaxation, can be also subjected to the MRCP recording. For this purpose, the onset of the negative movement can be identified by visual inspection of the silent period of EMG discharges or by an accelerometer and is used as a fiducial point for averaging the simultaneously recorded EEG or MEG. BPINS' preceding the movement induced by muscle relaxation appears quite similar to the one preceding the muscle contraction (Terada et al., 1995, 1999). In isometric muscle relaxation, however, a smaller BPINS' was observed in the lateral central area as compared with muscle contraction (Rothwell et al., 1998). Ikeda et al. (2000) reported, based on the presurgical study of medically intractable epilepsy patients, that stimulation of some parts of the SI-Ml with a single electric shock produced a silent period in the on-going EMG discharges without any preceding motor evoked potential (MEP). In these areas, the stronger the stimulus intensity, the longer was the induced silent period. This finding suggests the presence of inhibitory areas in human SI-Ml. By contrast, Liiders et al. (1995) proposed two distinct negative motor areas in human also based on the study of epilepsy patients; one rostral to the face area of Ml at the lateral frontal convexity (primary negative motor area, PNMA) and the other rostral to SMA (supplementary negative motor area, SNMA). Stimulation of these areas with high frequency (50 Hz) pulses was found to interfere with repetitive finger movements and sustained muscle contraction. BPINS' can be recorded from the SNMA not just before self-paced muscle relaxation but also before muscle contraction (Yazawa et aI., 1998). Furthermore, the SNMA was found to generate BP regardless of the site of movement (Yazawa et aI., 2000). Thus, the mechanism of voluntary motor inhibition remains to be elucidated further. 3.3.1.5. Clinical application MRCP can be applied to the investigation of pathophysiology of primary as well as non-primary motor cortices in various kinds of movement dis-
H. SHIBASAKI AND T. NAGAMINE
orders. For example, BPINS' is often absent in patients with cerebellar lesions, especially those involving the dentate nucleus and its efferent pathway or the dentato-thalamo-cortical pathway (Shibasaki et al., 1986; Ikeda et al., 1994; Kitamura et aI., 1999). BP was reported to be smaller in patients with Parkinson's disease than in agematched control subjects while NS' was normal or even larger in the patient group, and administration of L-DOPA to these patients was shown to increase the amplitude of BP along with the clinical improvement (Dick et aI., 1989). NS' was reported to be smaller than normal at the contralateral central region in patients with writer's cramp; a kind of focal dystonia (Deuschl et aI., 1995). Yazawa et aI. (1999) found that, in patients with writer's cramp, the BPINS' preceding self-initiated muscle relaxation of the right hand was smaller at the left central area whereas that preceding muscle contraction did not show significant difference from the normal control. It was interpreted to indicate dysfunction of the inhibitory system in the motor cortex in focal hand dystonia. MRCP can also be applied to the clinical study of the mechanism underlying motor recovery of a paralyzed limb. Investigating two patients, who recovered from hemiparesis due to stroke, by using the blood flow activation study with PET and by recording MRCP both associated with hand movement, Honda et aI. (1997) showed evidence suggesting a participation of the ipsilateral hemisphere to motor recovery. 3.3.1.6. Steady-state movement-related fields Recording of MRCP or movement-related magnetic fields with long inter-trial intervals requires strong motivation and cooperation of the subjects, which makes it difficult to apply this technique to patients with various movement disorders. In such cases, fast repetitive movements, at a rate of 2 Hz for example, will provide enough information at least as to the location of the precentral and postcentral gyrus (Fig. 2) (Gerloff et aI., 1998). 3.3.2. Cued movements
In a reaction time paradigm in which a pair of stimuli (S1 and S2) are presented with a fixed interstimulus interval of, for example, 2.0 s, and the subject is asked to make a motor task soon after S2,
19
EEG (MEG)/EMG CORRELATION
2 Hz movement
Fig. 2. (a) Steady-state movement-related magnetic fields associated with self-paced abduction of the right thumb in a normal subject. The first component (motor field, MF; asterisk) peaks immediately after the EMG onset (vertical line), and the second component (post-movement field, post-MF; closed circle) peaks after the EMG peak. The analysis window covers 300 ms before and 200 ms after the EMG onset. (b) Co-registration of equivalent current dipole (ECD) solutions with anatomical MRls of two subjects. Self-paced abduction of the right thumb. The ECD for the MF (red) is located in the precentral gyrus and that for the post-MF (yellow) is in the postcentral gyrus. White arrows indicate the left central sulcus. (Cited from Gerloff et a\., 1998 with permission).
a slowly rising negative potential shift called contingent negative variation (CNV) is recorded between the two stimuli. By subdural recording, the late component of CNV was found to be generated, in addition to the SMA and SI-Ml, in many cortical areas including the prefrontal cortex (Ikeda et aI., 1996; Hamano et aI., 1997). The late CNV was
found to be abnormal especially in patients with basal ganglia disorders such as Parkinson's disease and focal dystonia while it was well preserved in patients with cerebellar disorders (Ikeda et aI., 1994; Kaji et aI., 1995; Ikeda et aI., 1997). CNV can be also applied to the investigation of daily movement like gait initiation. In this case, gait initiation is
20
subject 1
H. SHIBASAKI AND T. NAGAMINE
subject 5
Fig. 2. Continued.
employed as the motor task immediately after the S2. By this method, Yazawa et al. (1997) found a larger amplitude of the late CNV in gait initiation compared with simple foot dorsiflexion employed as a control task. This observation probably suggests a greater participation of SMA in gait initiation than in the simple foot movement.
3.3.3. Involuntary movements 3.3.3.1. EEG (MEG)/EMG polygraphic recording The use of EEG (MEG)/EMG correlation for the study of involuntary movements serves as a supplement to clinical diagnosis as well as a method for clarifying the physiological mechanism underlying
EEG (MEG)/EMG CORRELATION
the generation of each involuntary movement. The most fundamental method for studying EMG-EEG correlation in spontaneous involuntary movements like myoclonus is a polygraphic recording of surface EMG and EEG, by using either an electroencephalograph or a cathode ray oscillograph. The same electrode placement as used for the recording of MRCP is applicable to this study. Filter setting of amplifiers used for recording EEG is usually 1-300 Hz, and that for EMG is 30-300 Hz. By contrast to MRCP, higher sampling rate such as 1000 Hz is preferable. Large EEG activities like periodic synchronous discharges seen in association with periodic myoclonus in patients with CreutzfeldtJakob disease or subacute sclerosing panencephalitis are easily identified on the conventional polygraphic records without averaging (Oga et aI., 2000). 3.3.3.2. Jerk-locked back averaging On the conventional polygraph, however, it is usually difficult to study a precise relation between the EMG and EEG activities. In such cases, EEG or MEG can be back averaged with respect to the onset of the EMG discharge associated with involuntary movements by adopting the same principle as used for recording the MRCP (jerk-locked back averaging) (Shibasaki and Kuroiwa, 1975; Shibasaki, 1993, 2000). The analysis window commonly used for the investigation of myoclonus is from 400 ms before to 200 ms after the myoclonus onset. By this method, the temporal and spatial relation between myoclonus and the EEG or MEG activity can be studied more precisely. In cases of cortical reflex myoclonus, a myoclonic jerk of the hand is preceded by a positivenegative cortical spike by about 20 ms and the latter is localized to the hand area of the contralateral central region. As for the generator site of the myoclonus-related cortical activity, the jerk-locked averaging of MEG confirmed the source in the contralateral precentral gyrus corresponding to the involved muscle (Figs. 3 and 4) (Mirna et aI., 1998a). Even in cases where the conventional polygraph fails to show EEG spikes in association with myoclonus, this technique may disclose a spike preceding the myoclonus if that is of cortical origin. Furthermore, in some cases the jerk-locked averaging of MEG may detect the myoclonus-related cortical activity that is not detectable on the jerklocked average of EEG (Mirna et al., I998a).
21
Furthermore, if the aim of the study is to distinguish psychogenic movement disorders such as psychogenic myoclonus from "organic" involuntary movements, the use of low frequency filter of approximately 0.05 Hz is necessary, so that slow activity like BPINS' could be recorded to see if there was any such activity preceding the movement in question (Terada et aI., 1995).
Fig. 3. Myoclonus-related magnetic fields obtained by jerk-locked back averaging in a patient with cortical myoclonus. (a) Waveforms from two different blocks of averages are superimposed. The vertical line corresponds to the onset of myoclonic EMG discharge recorded from the left wrist extensor muscle. Biphasic activity preceding the myoclonus is localized to the right central area. (b) Magnified waveform from a selected channel (rectangle in a). (c) Contour map of the earliest peak preceding the myoclonus onset. The white arrow indicates the site of the ECD and its direction. (Cited from Mirna T et al., 1998a with permission).
22
H. SHIBASAKI AND T. NAGAMINE
Fig. 4. ECDs of myoclonus-related cortical activities superimposed on the axial MRI in a patient with cortical reflex myoclonus. Yellow spot shows ECD of the initial negative peak (N20m) of somatosensory evoked magnetic field in response to electric stimulation of the left median nerve at wrist, and the blue spot the following peak that is abnormally large (P25m). The ECD of the main peak of the pre-myoclonus activity demonstrated by jerk-locked back averaging with respect to the spontaneous myoclonus of the left hand is shown in red. Green arrowhead indicates the right central sulcus. (Recorded by Mirna T).
3.3.3.3. Cortical reflex myoclonus Some involuntary movements, especially myoclonus, are often induced by external stimuli, thus called stimulus-sensitive or reflex myoclonus. Stimulus-sensitive myoclonus can be studied by the
simultaneous recording of the short latency cortical evoked potentials and the transcortical long loop reflexes. Cortical reflex myoclonus is the best clinical indication for this study. The most appropriate modality of stimulus should be chosen
EEG (MEG)/EMG CORRELATION
depending on the specificity of stimulus sensitivity in each individual case, but electric stimulation of the peripheral nerve is most commonly used for recording the somatosensory evoked potentials (SEP) and the long loop reflex simultaneously. EMG is recorded from a pair of electrodes placed over the corresponding muscles of the stimulated or other extremities, and rectified. Then the rectified EMG and the simultaneously recorded EEG or MEG are averaged by using the stimulus onset as a trigger. In cortical reflex myoclonus, the EMG response of a hand muscle at a latency of about 45 ms is extremely enhanced (C reflex), which corresponds to an evoked myoclonic jerk itself. Cortical reflex myoclonus often shows a rapid spread of the reflex myoclonus from the proximal to distal muscles within the stimulated limb and also to the muscles of the contralateral limb, the latter most likely being mediated by transcallosal conduction (Brown et aI., 1991). In most cases of cortical reflex myoclonus, early cortical components of SEP, except for the initial peak (N20), are extremely enhanced (giant SEP). By using somatosensory evoked magnetic fields, Mima et al. (I 998b ) identified the source of the enhanced P25 component in the precentral gyrus, just near the area where the cortical activity preceding the spontaneous myoclonus occurred (Fig. 4). 3.3.3.4. Negative myoclonus Negative myoclonus (asterixis) of cortical origin can be studied also by using the back averaging method. In this case, the onset of the EMG silent period is used as the fiducial point for averaging (silent period-locked averaging) (Ugawa et aI., 1989). The precise origin of the cortical negative myoclonus has not been determined, but some of them are sensitive to the somatosensory stimulus just like cortical reflex positive myoclonus (cortical reflex negative myoclonus) (Shibasaki et aI., 1994).
3.4. Event-related desynchronization and synchronization 3.4.1. Background EEG and MEG signals are composed of activities belonging to several frequency bands, and some of
23 them contain strong rhythmic oscillations. Oscillations of different frequencies are thought to be produced by activities arising from different physiological circuits within the brain. Oscillation of brain activity, such as the mu rhythm, has been estimated to have functional significance from its topographical distribution and its characteristic response to external stimuli. However, temporal profile of the change in response to external stimuli or in association with internal drive for action cannot be obtained by the mere inspection of the raw activity. In order to detect relations between discrete EMG events and alteration of oscillatory activities in the EEG/MEG, the technique of event-related desynchronization/synchronization (ERD/ERS) can be used. For extracting the desired activity embedded in the background activity, the averaging technique has been widely adopted, in which a specific event such as EMG onset is used as the fiducial point for averaging. However, this technique is applicable only when the desired activity (signal) is timelocked as well as phase-locked to each event. Since the palarity of oscillatory activity is not necessarily phase-locked among different epochs, it has to be expressed as the change of net power of the activity (event-induced activity) (Lopes da Silva and Pfurtscheller, 1999). During the resting state, electric activity within a local area shares a common phase of oscillation, like a resonance, which is called an idling state. Once the local area becomes activated, each electric activity within the restricted area becomes detached from the resonant state and behaves out of phase to various extents. Due to the phase cancellation of the electrical activity within the local area in spite of the maintenance of the frequency range, the net power of the electric events within the local area is reduced (desynchronization). When the activation ceases, oscillation of the circuit is reinforced, sometimes resulting in transient hyperactivity (hypersynchronization), and finally returns to the original state. Alteration of oscillatory activity partly reflects a non-specific general reaction, but it also reflects a more specific function of the restricted cortical area. Among them, ERD/ERS in the sensorimotor area has been shown to have distinct functional relevance with motor preparation and execution.
24
H. SHIBASAKl AND T. NAGAMINE
3.4.2. Method of recording
3.4.3. Normal findings
For investigating ERDIERS in relation to voluntary movements, EEG/MEG and EMG signals are usually recorded continuously and stored on a computer while the subject repeats a voluntary movement similar to the recording of the movementrelated slow potentials. An interval of 4 s or longer is preferable to detect pre-movement dampening. These signals are bandpass filtered depending on the frequency range of interest by digital filtering, and then squared (Pfurtscheller and Aranibar, 1977) or rectified (Salmelin and Hari, 1994) in order to avoid phase cancellation at the time of averaging across epochs. Manual or automatic methods are then used to identify particular events in the EMG that can be used as fiducial points about which averaging can be performed with certain duration of time window. Instead of squaring or rectification, the envelope of the signal can also be used (Ciochon et aI., 1996). In order to normalize the different power of the resting activity, averaged responses are often expressed as the relative magnitude to that of the initial segment of the analysis time window. As for motor function, since 10Hz and 20 Hz frequency ranges are considered to reflect different functions, most analyses utilize bandpass filters centering around each of these two frequency ranges (Pfurtscheller and Klimesch, 1991). In some special conditions, 40 Hz activity also depicts the motor related modulation. Digital methods are used to filter the EEG. In addition to the center frequency of bandpass filter, the filter width is another concern. Since a narrower frequency width requires a longer analysis window, frequency resolution and temporal resolution have reciprocal interaction. Derived from the compromise between these two factors, 2 to 4 Hz are recommended as the filter width for motor function (Salmelin and Hamalainen, 1995; Pfurtscheller and Lopes da Silva, 1999). Pfurtscheller and Lopes da Silva (1999) recommend dividing the alpha frequency range into two, low alpha and high alpha. Another way to delineate the temporal evolution of oscillations is the use of the power spectrum of short-time periods. In this case, since four dimensional data of time, frequency, power and location is obtained, the conventional display reduces the results into three dimension by selecting a certain location and shows power by color coding (Baker et aI., 1997).
A typical use of ERDIERS techniques is to demonstrate the attenuation of the 10Hz rhythm (mu or alpha rhythm) preceding and accompanying voluntary movement, which is commonly followed by the rebound of the 20 Hz rhythm (beta rhythm). Usually the 10 Hz rhythm starts dampening (ERD) around 2 s prior to the movement onset over the sensorimotor area contralateral to the movement. The ERD continues during the ongoing muscle contraction and recovers to the original resting state I s after the cessation of the movement. The ipsilateral sensorimotor area also demonstrates 10Hz ERD with later initiation compared to the contralateral side. The 20 Hz rhythm shows later initiation of dampening compared to the 10Hz ERD, actually starting around 1 s prior to the movement onset. It also shows rebound peaking around 1 s after the cessation of movement (ERS). As for the spatial distribution, the 10 Hz ERD has bilateral sensorimotor foci around the movement onset. In contrast, the 20 Hz ERD is usually more localized and located anterior to that of the 10Hz ERD with contralateral predominance. The focus of 20 Hz ERD corresponds to the respective cortical representation of the movements (Salmelin et al., 1995; Pfurtscheller et aI., 1997). This distribution is in good conformity with the results of subdural recording of ERDIERS, which is restricted to the contralateral side and located anterior to that of the 10 Hz ERD (Crone et al., 1998; Ohara et aI., 2000). In MEG studies, similar reactivity patterns of 10 Hz and 20 Hz rhythms are observed (Fig. 5). Contralateral predominance of 20 Hz ERDIERS of MEG is more conspicuous compared to that of EEG (Nagamine et al., 1996). The 20 Hz ERDIERS also discloses somatotopic representation and anterior localization compared to the 10Hz ERD (Salmelin et aI., 1995). The 10Hz ERD in MEG starts as early as 3 to 4 s prior to the movement onset, whereas the readiness field of MEG starts around 1 s before the movement initiation (Fig. 5). This is in clear contrast to the relation of MRCP with ERDIERS in EEG (Nagamine et aI., 1996). The 20 Hz ERD in MEG is seen a few seconds before the actual event in both muscle contraction and muscle relaxation, which suggests participation of similar preparatory mechanisms in these two kinds of movements (Toma et al., 2000).
25
EEG (MEG)/EMG CORRELATION
Somatomotor area
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Fig. 5. Event-related desynchronization (ERD) and eventrelated synchronization (ERS) in association with self-initiated movement in comparison with slow magnetic fields (movement-related cortical magnetic fields) in a normal subject. Channels corresponding to the sensorimotor areas from each hemisphere are shown. Magnetic fields were recorded by a first-order planar gradiometer that detects the largest signal just above the generator currents. Average of 74 trials of right index finger extension.
Comparison between the slow potential and ERD was performed in contingent negative variation task (Filipovic et al., 200 I). Contrary to the almost zero reaction in the no-go condition during the preparatory phase between S I (go/no-go) and S2, alphaERD in no-go condition showed dampening to similar degree to that in the go condition.
3.4.4. Clinical application Since ERDIERS cannot provide high spatial resolution comparable to multichannel recording of slow potential fields due to methodological limitations, it is mainly applied for the investigation of pathophysiology of abnormal motor function. Focusing on akinesia in patients with Parkinson's disease, self-initiated unilateral hand movement has been analyzed, mainly focusing on pre-movement ERD of the mu rhythm. Comparison between the age-matched controls and chronic Parkinson patients
under medication demonstrated several differences. Delayed initiation of contralateral ERD of the mu rhythm, increased ipsilateral ERD of the mu rhythm with similar onset latency, and delayed bilateralization were the main features seen in Parkinson patients (Defebvre et al., 1993, 1994). Further studies evaluated untreated akinetic Parkinson patients and the influence of chronic administration of L-DOPA. The delayed contralateral ERD of the mu rhythm was also noted in patients of early stages, and ERD occurred earlier after chronic administration of L-DOPA (Defebvre et al., 1998). A similar effect was also noted after acute administration of LDOPA in patients under chronic L-DOPA treatment (Magnani et aI., 1999). ERS of the beta rhythm induced by simple voluntary movement was investigated in patients with Parkinson's disease, and the ERS was found to be reduced compared to normal subjects. Another study also showed higher peak frequency of ERS in patients with Parkinson's disease compared to that in normal subjects (Pfurtscheller et al., 1998). Another experiment using contingent negative variation (CNV) has focused on the preparatory period. Similar to the ERD associated with simple self-initiated movement, contralateral alpha band ERD started around 1.5 s prior to the movement triggered by the go signal. In Parkinson patients, this contralateral ERD of the alpha band started later, similar to the latency of the self-initiated movement. This indicates that an external cue does not ameliorate the late onset ERD of the alpha band in Parkinson's disease (Magnani et al., 1998). Investigation of ERD of the mu rhythm in patients with progressive supranuclear palsy (PSP) suggested more severely affected motor programming than in patients with Parkinson's disease. In case of selfinitiated movement, initiation of ERD of the mu rhythm over the contralateral sensorimotor area was delayed (around 0.4 s) in PSP patients compared to Parkinson patients (I s) and normals (1.7 s). Bilateralization of ERD was similar to that of Parkinson patients (Defebvre et al., 1999). In patients with focal dystonia, Toro et aI. (2000) found reduced 20-30 Hz ERD over the contralateral motor area in movements of both affected and unaffected hands. This reduction was prominent both before and after the movement. This finding supports the notion of abnormal command at the cortical level in dystonic patients.
26
Reorganization of the motor cortex was investigated in patients with ischemic supratentorial stroke during self-initiated movement (Platz et al., 2000). There was increased beta-ERD in patients suffering from central arm paresis and reduced alpha-ERD and beta-ERD in patients with somatosensory deficits. Patients with ideomotor apraxia showed reduced beta-ERD during movement preparation. Abnormal ERD was also demonstrated in patients with focal motor seizures (Derambure et al., 1997). Contralateral ERD of the mu rhythm accompanying self-initiated movement was delayed in patients with frequent motor seizures compared to normals and patients with temporal lobe seizures, indicating functional alterations of the motor areas in those patients. Related to the development of implicit and explicit learning, Zhuang et aI. (1997) investigated alpha-ERD during a variation of the serial reaction time task. During the initial learning, maximal alpha-ERD over the sensorimotor area contralateral to the hand movement was gradually enhanced and reached its peak when the subjects acquired full knowledge of the sequence explicitly. Thereafter, alpha-ERD became smaller. This finding also supports the concept of modulation of motor area activation over the course of learning.
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Honda, M, Nagamine, T, Fukuyama, H, Yonekura, Y, Kimura, J and Shibasaki, H (1997) Movement-related cortical potentials and regional cerebral blood flow change in patients with stroke after motor recovery. J. Neurol. Sci., 146: 117-126. Ikeda, A and Shibasaki, H (1992) Invasive recording of movement-related cortical potentials in humans. J. Clin. Neurophysiol., 9: 509-520. Ikeda, A, Luders, HO, Burgess, RC and Shibasaki, H (1992) Movement-related potentials recorded from supplementary motor area and primary motor area. Role of supplementary motor area in voluntary movements. Brain, 115: 1017-1043. Ikeda, A, Shibasaki, H, Nagamine, T, Terada, K, Kaji, R, Fukuyama, H and Kimura, J (1994) Dissociation between contingent negative variation and Bereitschaftspotential in a patient with cerebellar efferent lesion. Electroencephalogr. Clin. Neurophysiol., 90: 359-364. Ikeda, A, Luders, HO, Collura, T, Burgess, RC, Morris, HH, Hamano, T and Shibasaki, H (1996) Subdural potentials at orbitofrontal and mesial prefrontal areas accompanying anticipation and decision making in humans: a comparison with Bereitschaftspotential. Electroencephalogr. Clin. Neurophysiol., 98, 206-212. Ikeda, A, Shibasaki, H, Kaji, R, Terada, K, Nagamine, T, Honda, M and Kimura, J (1997) Dissociation between contingent negative variation (CNV) and Bereitschaftspotential (BP) in patients with parkinsonism. Electroencephalogr. Clin. Neurophysiol., 102: 142-151. Ikeda, A, Ohara, S, Matsumoto, R, Kunieda, T, Nagamine, T, Miyamoto, S, Kohara, N, Taki, W, Hashimoto, N and Shibasaki, H (2000) Role of primary sensorimotor cortices in generating inhibitory motor response in humans. Brain, 123: 1710-1721. Kaji, R, Ikeda, A, Ikeda, T, Kubori, T, Mezaki, T, Kohara, N, Kanda, M, Nagamine, T, Honda, M, Rothwell, JC, Shibasaki, H and Kimura, J (1995) Physiological study of cervical dystonia. Task-specific abnormality in contingent negative variation. Brain, 118: 511-522. Kitamura, J, Shibasaki, H and Kondo, T (1993a) A cortical slow potential is larger before an isolated movement of a single finger than simultaneous movement of two fingers. Electroencephalogr. Clin. Neurophysiol., 86: 252-258. Kitamura, J, Shibasaki, H, Takagi, A, Nabeshima, Hand Yamaguchi, A (1993b) Enhanced negative slope of cortical potentials before sequential as compared with simultaneous extensions of two fingers. Electroencephalogr. Clin. Neurophysiol., 86: 176-182. Kitamura, J, Shibasaki, H, Terashi, A and Tashima, K (1999) Cortical potentials preceding voluntary finger
27 movement in patients with focal cerebellar lesion. Clin. Neurophysiol., 110: 126-132. Kunieda, T, Ikeda, A, Ohara, S, Yazawa, S, Nagamine, T, Taki, W, Hashimoto, Nand Shibasaki, H (2000) Different activation of pre-supplementary motor area, supplementary motor area proper, and primary sensorimotor area, depending on the movement repetition rate in humans. Exp. Brain Res., 135: 163-172. Lopes da Silva, FH and Pfurtscheller, G (1999) Basic concepts on EEG synchronization and desynchronization. In: G Pfurtscheller and FH Lopes da Silva (Eds.), Event-Related Desynchronization. Handbook of Electroencephalography and Clinical Neurophysiology., Elsevier, Amsterdam, revised series, Vol. 6, pp. 3-11. Ltiders, HO, Dinner, DS, Morris, HH, Wyllie, E and Comair, YG (1995) Cortical electrical stimulation in humans. The negative motor areas. Adv. Neurol., 67: 115-129. Magnani, G, Cursi, M, Leocani, L, Volonte, MA, Locatelli, T, Elia, A and Comi, G (1998) Event-related desynchronization to contingent negative variation and self-paced movement paradigms in Parkinson's disease. Mov. Disord., 13: 653-660. Magnani, G, Leocani, L, Cursi, M and Comi, G (1999) ERD of the mu rhythm in self-paced and externally triggered movements in idiopathic Parkinson's disease and effect of a single dose of L-DOPA on self-paced movement. In: G Pfurtscheller and FH Lopes da Silva (Eds.), Event-Related Desynchronization. Handbook of Electroencephalography and Clinical Neurophysiology. Elsevier, Amsterdam, revised series, Vol. 6, pp.371-382. Mirna, T, Nagamine, T, Ikeda, A, Yazawa, S, Kimura, J and Shibasaki, H (l998a) Pathogenesis of cortical myoclonus studied by magnetoencephalography. Ann. Neurol., 43: 598-607. Mirna, T, Nagamine, T, Nishitani, N, Mikuni, N, Ikeda, A, Fukuyama, H, Takigawa, T, Kimura, J and Shibasaki, H (I 998b) Cortical myoclonus. Sensorimotor hyperexcitability. Neurology, 50: 933-942. Nagamine, T, Kajola, M, Salmelin, R, Shibasaki, Hand Hari, R (1996) Movement-related slow cortical magnetic fields and changes of spontaneous MEG- and EEG-brain rhythms. Electroencephalogr. Clin. Neurophysiol., 99, 274-286. / Oga, T, Ikeda, A, Nagamine, T, Sumi, E, Matsumoto, R, Akiguchi, I, Kimura, J and Shibasaki, H (2000) Implication of sensorimotor integration in the generation of periodic dystonic myoclonus in subacute sclerosing panencephalitis (SSPE). Mov. Disord., 15: 1173-1183. Ohara, S, Ikeda, A, Kunieda, T, Yazawa, S, Baba, K, Nagamine, T, Taki, W, Hashimoto, N, Mihara, T and Shibasaki, H (2000) Movement-related change of
28 electrocorticographic activity in human supplementary motor area proper. Brain, 123: 1203-1215. Pfurtscheller, G and Aranibar, A (1977) Event-related cortical desynchronization detected by power measurements of scalp EEG. Electroencephalogr. Clin. Neurophysiol., 42: 817-826. Pfurtscheller, G and Klimesch, W (1991) Event-related desynchronisation during motor behaviour and visual information processing. Electroencephalogr. Clin. Neurophysiol., Suppl. 42: 58-65. Pfurtscheller, G, Neuper, C, Andrew, C and Edlinger, G (1997) Foot and hand area mu rhythms. Int. J. Psychophysiol.,26: 121-135. Pfurtscheller, G, Pichler-Zalaudek, K, Ortmayr, B, Diez, J and Reisecker, F (1998) Postmovement beta synchronization in patients with Parkinson's disease. J. Clin. Neurophysiol., 15: 243-250. Pfurtscheller, G and Lopes da Silva, FH (1999) Functional meaning of event-related desynchronization (ERD) and synchronization (ERS). In: G Pfurtscheller and FH Lopes da Silva (Eds.), Event-Related Desynchronization. Handbook of Electroencephalography and Clinical Neurophysiology. Elsevier, Amsterdam, revised series, Vol. 6, pp. 51-63. Platz, T, Kim, IH, Pintschovius, H, Winter, T, Kieselbach, A, Villringer, K, Kurth, R and Mauritz, KH (2000) Multimodal EEG analysis in man suggests impairmentspecific changes in movement-related electric brain activity after stroke. Brain, 123: 2475-2490. Rothwell, JC, Higuchi, K and Obeso, JA (1998) The offset cortical potential: an electrical correlate of movement initiation in man. Mov. Disord., 13: 330-335. Salmelin, Rand Hari, R (1994) Spatiotemporal characteristics of sensorimotor neuromagnetic rhythms related to thumb movement. Neuroscience, 60: 537-550. Salmelin, RH and Harnalainen, MS (1995a) Dipole modelling of MEG rhythms in time and frequency domains. Brain Topogr., 7: 251-257. Salmelin, R, Hamalainen, M, Kajola, M and Hari, R (1995b) Functional segregation of movement-related rhythmic activity in the human brain. Neuroimage, 2: 237-243. Shibasaki, H (1993) Movement-related cortical potentials. In: A Halliday (Ed.), Evoked Potentials in Clinical Testing. Churchill Livingstone, Edinburgh, 2nd ed., pp.523-537. Shibasaki, H (2000) Electrophysiological studies of myoclonus. Muse. Nerve, 23: 321-335. Shibasaki, H and Kuroiwa, Y (1975) Electroencephalographic correlates of myoclonus. Electroencephalogr. Clin. Neurophysiol., 39: 455-463. Shibasaki, H and Rothwell, JC (1999) EMG-EEG correlation. In: G Deuschl and A Eisen (Eds.), Recommendations for the Practice of Clinical Neurophysiology:
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Guidelines of the International Federation of Clinical Neurophysiology. Electroencephalogr. Clin. Neurophysiol., Suppl, 52, pp. 269-274. Shibasaki, H, Barrett, G, Halliday, E and Halliday, A (1980) Components of the movement-related cortical potential and their scalp topography. Electroencephalogr. Clin. Neurophysiol., 49: 213-226. Shibasaki, H, Barrett, G, Neshige, R, Hirata, I and Tomoda, H (1986) Volitional movement is not preceded by cortical slow negativity in cerebellar dentate lesion in man. Brain Res., 368: 361-365. Shibasaki, H, Ikeda, A, Nagamine, T, Mirna, T, Terada, K, Nishitani, N, Kanda, M, Takano, S, Hanazono, T, Kohara, N, Kaji, R and Kimura, J (1994) Cortical reflex negative myoclonus. Brain, 117: 477-486. Terada, K, Ikeda, A, Nagamine, T and Shibasaki, H (1995a) Movement-related cortical potentials associated with voluntary muscle relaxation. Electroencephalogr. Clin. Neurophysiol., 95: 335-345. Terada, K, Ikeda, A, Van Ness, PC, Nagarnine, T, Kaji, R, Kimura, J and Shibasaki, H (1995b) Presence of Bereitschaftspotential preceding psychogenic myoclonus: clinical application of jerk-locked back averaging. J. Neurol. Neurosurg. Psychiatry, 58: 745-747. Terada, K, Ikeda, A, Yazawa, S, Nagamine, T and Shibasaki, H (1999) Movement-related cortical potentials associated with voluntary relaxation of foot muscles. Clin. Neurophysiol., 110: 397-403. Toma, K, Nagamine, T, Yazawa, S, Terada, K, Ikeda, A, Honda, M, Oga, T and Shibasaki, H (2000) Desynchronization and synchronization of central 20 Hz rhythms associated with voluntary muscle relaxation: a magnetoencepha1ographic study. Exp. Brain Res., 134: 417-425. Toro, C, Deusch1, G and Hallett, M (2000) Movementrelated electroencephalographic desynchronization in patients with hand cramps: evidence for motor cortical involvement in focal dystonia. Ann. Neurol., 47: 456461. Ugawa, Y, Shimpo, T and Mannen, T (1989) Physiological analysis of asterixis: silent period locked averaging. J. Neurol. Neurosurg. Psychiatry, 52: 89-93. Vidailhet, M, Stocchi, F, Rothwell, JC, Thompson, PD, Day, BL, Brooks, DJ and Marsden, CD (1993) The Bereitschaftspotential preceding simple foot movement and initiation of gait in Parkinson's disease. Neurology, 43: 1784-1788. Yazawa, S, Shibasaki, H, Ikeda, A, Terada, K, Nagamine, T and Honda, M (1997) Cortical mechanism underlying externally cued gait initiation studied by contingent negative variation. Electroencephalogr. Clin. Neurophysiol., 105: 390-399. Yazawa, S, Ikeda, A, Kunieda, T, Mirna, T, Nagamine, T, Ohara, S, Terada, K, Taki, W, Kimura, J and Shibasaki,
EEG (MEG)/EMG CORRELATION
H (1998) Human supplementary motor area is active in preparation for both voluntary muscle relaxaion and contraction: subdural recording of Bereitschaftspotential. Neurosci. Lett., 244: 145-148. Yazawa, S, Ikeda, A, Kaji, R, Terada, K, Nagamine, T, Toma, K, Kubori, T, Kimura, J and Shibasaki, H (1999) Abnormal cortical processing of voluntary muscle relaxation in patients with focal hand dystonia studied by movement-related potentials. Brain, 122: 13571366. Yazawa, S, Ikeda, A, Kunieda, T, Ohara, S, Mirna, T, Nagamine, T, Taki, W, Kimura, J, Hori, T and Shibasaki, H (2000) Human supplementary motor area
29 is active before voluntary movement: subdural recording of Bereitschaftspotential from medial frontal cortex. Exp. Brain Res., 131: 165-177. Yoshida, K, Kaji, R, Hamano, T, Kohara, N, Kimura, J, Shibasaki, H and Iizuka, T (2000) Cortical potentials associated with voluntary mandibular movements. J. Dent. Res., 79: 1514-1518. Zhuang, P, Toro, C, Grafman, J, Manganotti, P, Leocani, L and Hallett, M (1997) Event-related desynchronization (ERD) in the alpha frequency during development of implicit and explicit learning. Electroencephalogr. Clin. Neurophysiol., 102: 374-38 I.
Movement Disorders Handbook of Clinical Neurophysiology, Vol. 1 M. Hallett (Ed.) © 2003 Elsevier B.v. All rights reserved
31 CHAPTER 4
Electrocorticography in motor control and movement disorders Akio Ikeda* Department of Neurology. Kyoto University Graduate School of Medicine. Shogoin, Sakyo-ku, Kyoto 606, Japan
4.1. Introduction
Direct recording from the brain surface in humans is not a routine part of clinical EEG. It was initially performed in the 1940s intraoperatively by using electrodes placed on the cortical surface (electrocorticography or ECoG) (Penfield and Jasper, 1954). Chronic intracranial recordings were subsequently obtained by using flexible strips of electrodes inserted into the epidural or subdural space through a burr hole (Penfield and Jasper, 1954). Stereotactic implantation of rigid electrodes (depth electrodes) directly into specific intracerebral structures was later developed in order to obtain more anatomically precise localization of epileptiform discharges (stereotactic EEG or SEEG) (Talairach and Bancaud, 1974). On the other hand, since the 1970s, chronic implantation of large multi-electrode grids over a wide surface of the cerebral cortex exposed by craniotomy has enabled us to obtain well organized cortical activity almost continuously in awake patients without much restriction for up to several weeks (chronic subdural EEG). These invasive recording techniques had been developed exclusively for epilepsy surgery, but recently chronic subdural EEG has also been applied for functional surgery other than epilepsy, for example, when a brain tumor is located at or very close to the functional cortices such as motor, sensory, visual and language areas (Morris et aI., 1986). Chronic subdural EEG recorded by electrode grids provides us with the following two advantages to SEEG: (1) The cortical surface is widely covered
* Dr. Akio Ikeda, M.D., Ph.D., Department of Neurology, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto 606, Japan. E-mail address:
[email protected] Tel.: +81-75-751-3772; fax: +81-75-751-9416.
by electrode grids spaced 1 em apart. These grids are able to localize the recorded activity such as epileptiform discharges, mu rhythm, evoked cortical potentials to peripheral sensory stimulation and so on. (2) Electric currents applied on each grid electrode can be used for functional cortical mapping. In studies of normal motor control or in patients with movement disorders of central origin, the Bereitschaftspotential (BP) or readiness potential, the slow brain potential occurring before voluntary movements, may provide important clues to the understanding of preparatory cortical functions in association with voluntary movements in normal subjects and in patients with movement disorders like dystonia, parkinsonism, and psychogenic movement disorders. Since the initial report of BP in scalp recording (Komhuber and Deecke, 1965), its complicated scalp distribution has impeded the understanding of its cortical generators. Invasive studies in animals have partly revealed the cortical generators of the BP (Sasaki and Gemba, 1991), but because the BP reflects preparatory brain functions in voluntary movements, animal studies are limited. Recent study by means of magnetoencephaIography with whole head coverage has revealed the cortical generators partly, but deeper sources like in the mesial frontal surface could not be completely investigated, and furthermore, sources producing radial dipoles are poorly recorded (Erdler et aI., 2000). Chronic subdural EEG recording in epilepsy surgery provides the opportunity to investigate cortical generators of the BP to clarify the central cortical mechanism of voluntary movements (Ikeda et aI., 1992; Shibasaki and Ikeda, 1997; Yazawa et aI.,2000). Because subdural EEG recording is an invasive, diagnostic technique to localize cortical functions
32
and abnormal cortical areas prior to surgical intervention (Ltiders et al., 1987; Ajmone-Marsan, 1990), there is little indication in patients with movement disorders. However, if noninvasive techniques fail to differentiate severe movement disorders like paroxysmal dyskinesias from intractable, focal epilepsy, then chronic subdural EEG would be clinically useful as previously reported (Lombroso, 1995, 2000). 4.2. Recording technique In chronic implantation for several days to weeks, commercially available subdural electrodes are used consisting of electrode grids or strips with multiple contacts embedded at uniform intervals (such as 1 em) in a silicon rubber sheet. Electrodes are made of platinum-iridium or stainless steel. 4.2.1. Electrodes The size and shape of grids used clinically depend on where they are placed over the cortical surface. Large grids (8 x 8, 6 x 5 or 5 x 4 electrode contacts) are usually placed over the lateral convexity where a large functional area is expected to be covered such as the perirolandic area or perisylvian area (Fig. 1). Small grids (8 x 2, 5 x 2) or strips (1 x 4, 1x 5, 1 x 8) are prepared for investigating the interhemispheric zone (supplementary motor area (SMA), cingulate motor area or mesial occipital area), basal temporal area or basal frontal area. Bidirectional electrode grids (two identical sheets of silicon rubber containing 2 x 5 set of electrodes glued together back to back so that the recording surface of each set of 10 electrodes faces in opposite directions) are often used to investigate the bilateral mesial frontal areas simultaneously by inserting only one in one side of the interhemispheric fissure (Fig. 2). It records subdural EEG from one side, and epidural EEG from the opposite side through the falx cerebri. Electrodes are typically 3 mm in diameter, and commonly the center-to-center electrode distance is set to 1 em. Depth electrodes have much smaller recording surfaces. When an electrode is attached on the scalp or brain surface, it can be represented by a resistance (R) and capacitance (C) in series (R-C circuit). Therefore, it has the property of a low frequency filter (LFF), and acts together with the input impedance of the amplifier (Tyner et al., 1983). Since the capacitance is proportional to the surface
A. IKEDA
area of an electrode, an electrode of large surface such as the subdural contact with a diameter of 3 mm, attenuates slow potentials minimally. Depth electrodes with small contact surfaces can not record slow potentials well, and thus, subdural electrodes should record the BP much better than depth electrodes. However, in published reports, depth electrodes inserted in patients with intractable partial epilepsy recorded the BP at the primary motor area (MI) as nicely as subdural electrodes did (Rector et al., 1994, 1998). The effects of electrode size on slow subdural EEG were also compared between electrode contacts of 3 mm diameter and 5 mm diameter, and no significant difference was observed between the two (Ikeda et al., 1999a). This was probably because modem amplifiers with large input impedance more than 50 megaohm can overcome the negative effects of recording surface size. It is difficult to decide optimal inter-electrode distance, but in the clinical situation decreasing electrode interval below 5 mm usually yields little improvement or difference in the information obtained (Ajmone-Marsan, 1990). This can be explained by the experimental results that two epileptic spike foci separated by 4 mm on the same gyrus produced by penicillin solution were consistently dependent whereas spike foci separated by 6 mm were always independent (Lueders et al., 1981). "Cross-talk" between cortical columns is limited to columns 1 to 2 mm apart, and the largest horizontal branches extend approximately 2.5 mm in the superficial cortical layer (Szentagothai, 1969). An interelectrode interval of 5 to 10 mm, mostly 10 mm, is clinically used. On special occasions, an interelectrode distance of 5 mm has been used to map the detailed topography of short latency, cortical components of somatosensory evoked potentials (Allison et al., 1990). Metals for invasive electrodes should not be toxic to brain tissue, and thus stainless steel or platinum are widely used. Electrodes made of stainless steel produce baseline fluctuations large enough to obscure slow potentials. These large electrode potentials arise because stainless steel electrodes are polarized, and thus they also theoretically have problems recording slow EEG components (Cooper, 1963, 1980). However there are several factors that may compensate: (i) a large input impedance would reduce voltage "loading" at the electrode level, resulting in less electrode potentials; (ii) subdural
33
ELECTROCORTICOGRAPHY IN MOTOR CONTROL AND MOVEMENT DISORDERS
;J\.
A1
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;
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04
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Fig. 1. Movement-related cortical potentials in association with self-paced tongue protrusion recorded from the subdural electrodes placed across the left lower central sulcus in an epilepsy patient. Large negative BP, NS' and MP are seen in the tongue motor area (maximum at Al and B1), defined by high frequency electric cortical stimulation. Symbols in the figure show the results of electric cortical stimulation (AI, A2, B3, B4 and C4=positive motor response of the right mouth and tongue; Bland C3 = positive motor and sensory responses of the right mouth and tongue; B2 and C2=positive sensory responses of the right mouth and tongue; D4, E3 and E4= sensory language function). (From Ikeda et aI., 1995a with permission.)
electrodes fixed on the brain surface nunmuze baseline fluctuations of electrode potentials arising from unstable contact between electrode and recording surface; and (iii) subdural EEG potentials are recorded with the amplifier sensitivity of 70 to 100 f1 V/mm in contrast with that of 10 f1 V/mm in usual scalp recording. Therefore subdural recording lessens the effect of electrode potentials by 1/7 to 1/10 times. Taking these three factors into account, it is most likely that slow brain potentials such as BP, contingent negative variation (CNV) or ictal DC
shifts are well recorded by using subdural electrodes made even of stainless steel (Ikeda et al., 1992, 1996c, 1998). Since platinum can record slow potentials better than stainless steel (Cooper, 1963), subdural electrodes made of platinum are more effective. 4.2.2. Amplifier and recording conditions
Currently available amplifiers have a large input impedance of 50-200 Mf], and thus, as discussed
A. IKEDA
34
seizure discharges or significant slow activity. Alternately, one of the scalp electrodes placed on the mastoid process or earlobe contralateral to the side of craniotomy can also be used. Since all the EEG signal from the brain surface is recorded with the sensitivity of 70 I-lVImm, small artifacts from the scalp electrode used as the reference is usually negligible. 4.2.3. Electrode placement Fig. 2. Schematic representation of the coronal view of an interhemispheric electrode plate. Two of 2 x 5 electrode grids are attached to each other and face in opposite direction, so as to record subdural potentials directly from one side and epidural potentials from the other side through the falx cerebri. (From Ikeda et aI., 1992 with permission.)
above, they minimize the adverse effects of electrode potentials on slow potential recording. In conventional chronic subdural EEG monitoring for several days, LFF and high frequency filter (HFF) are set to the same condition as that of scalp EEG recording, but opening of LFF down to 0.03 or even 0.01 Hz can record very slow subdural EEG potentials satisfactorily without artifacts as opposed to the scalp EEG even though the patients do not necessarily stay still on the bed. EEG signals are continuously recorded with the sampling rate of at least 200 Hz, preferentially 500 Hz. When fast activity is to be analyzed, larger sampling rates such as 1000 Hz are recommended. Scalp EEG reflects the brain activity occurring simultaneously at the cortical surface of at least 6 em', and the brain activity smaller than that is little recorded because of general attenuation of EEG signal mainly caused by the bone (Cooper et aI., 1965). On the other hand, sensitivity for subdural EEG is usually set to 70 I-lVImm, one-seventh of that of scalp EEG. Fast activity more than 15 Hz is obviously better recorded as compared with scalp EEG, because the scalp and the bone also act as an HFF so as to attenuate further selectively faster frequencies in scalp EEG (Pfurtscheller and Cooper, 1975). A referential montage is better than a bipolar montage to map any focal cortical activity within the area of the grid. As a reference electrode, a subdural electrode contact is chosen which on cortical stimulation does not elicit any symptom or sign, and from which subdural EEG does not show spikes,
Electrode grids of appropriate size are placed during a first craniotomy and removed during a second craniotomy. Detailed surgical techniques are beyond this chapter. When targeting a functional area for mapping, it is important to cover the whole functional area as much as possible because the information of the accurate boundary of the functional area is clinically required. Therefore, in addition to the anatomical landmarks, intraoperative recording of short latency evoked potentials or the mu rhythm immediately before implantation is clinically useful to decide which area should be mainly covered by the electrode grids. 4.2.4. Patient condition for recording and safety
Recording can be started soon after the patients recover from the first craniotomy to place the subdural electrode grids. During the initial several days, intermittent focal or widely distributed slow or transient spikes are observed, but they usually disappear or become less. Conventional subdural EEG can record fast activity more than scalp EEG as already discussed. Surface EMG and EOG are sometimes recorded simultaneously as done in a scalp EEG study. In a scalp EEG study, EOG is monitored in order to exclude the possibility of EOG artifacts on the scalp EEG. Subdural EEG is almost free from artifacts of extracranial origin such as EMG or EOG. Therefore, EOG is not necessarily monitored in this respect (Ikeda et al., 1996a). For obtaining a BP, voluntary movements of any part of the body can be examined as long as fiducial points can be accurately identified with the movement onset. Each movement should be identical and self-paced at intervals of 5-10 s. Subdural EEGs are finally averaged backward and forward time-locked to the trigger pulse, for which the onset of surface EMG discharge is usually used. Subdural EEG has a
35
ELECTROCORTICOGRAPHY IN MOTOR CONTROL AND MOVEMENT DISORDERS
Precentral (A1)
--100 msec. (BP, NS')
Postcentral (C2)
-+50 msec. (MP)
-+250 msec. (RAP)
Fig. 3. Subdurally recorded movement-related cortical potentials across the central sulcus in tongue protrusion, and assumed cortical generator in an epilepsy patient shown in Fig. I. Surface-negative BP at the precentral and positive BP at the postcentral area are seen. (From Ikeda et aI., 1995a with permission.)
better SIN ratio than scalp EEG, but at least 50 trials should be averaged for one session. A rapid-rate movement task (1-2 Hz) is also possible to locate the cortical generator corresponding to MI (Gerloff et aI., 1997; Kunieda et aI., 2000). Patients with intracranial electrodes should be considered in the high risk category for safety. Current leakage of any devise attached to the intracranial electrodes should be less than 10 fLA (Engel et aI., 1986). When patients suffer from intractable epilepsy and antiepileptic medication is also reduced during invasive recording to catch habitual seizures, precautions against accidental head trauma by falling with seizures should be taken. Attenuation of the amplitude of all frequencies or selective attenuation of the fast activity suggests certain pathological conditions like development of acute subdural hematoma or increased intracranial pressure leading to compressing of the brain surface by the grid and causing dysfunction of the cortex.
4.2.5. Data analysis and interpretation
Besides BP, any kind of study done by scalp EEG (sensory evoked potentials, CNV, event-related potentials, event-related desynchronization, EEGEMG coherence and EEG-EEG coherence, etc.) are all possible. Since a large grid can delineate the distribution of the potentials, application of the current source density method is more accurate than for scalp EEG (Nagamine et al., 1992). Subdural electrodes placed on the cortical surface theoretically record both tangential and radial dipole components, arising from the crown of a gyrus and from the sulcus, respectively (Fig. 3), according to solid angle theory (Gloor, 1985). However, since an electrode records potentials from both the components simultaneously, it is usually difficult to decompose the two. Partial coherence analysis methods can differentiate the two using phase analysis (Towle et aI., 1999).
36
A. IKEDA
4.2.6. Intraoperative ECoG This refers to acute recording of epicortical EEG during the exposure of the cortical surface in the course of surgical treatment. If the patient's cooperation is needed, recording is done without general anesthesia, but the time of recording and patient cooperation is limited because of a less comfortable situation. Otherwise, all the recording equipment and settings are the same as that of chronic subdural EEG.
4.3. Cortical generators of BP 4.3.1. Scalp-recorded SP It is well accepted, regardless of movement sites of the body, that pre-movement potentials consist of
three components; BP or readiness potential (Komhuber and Deecke, 1965), negative slope (NS') (Shibasaki et al., 1980), and motor potential (MP) (Komhuber and Deecke, 1965) (Fig. 4). They are followed by post-movement potentials called Reafferente Potentiale (RAP) (Kornhuber and Deecke, 1965). In the case of simple limb movements, the BP starts as early as 1.5-2 s before movement onset. It is maximal at the central midline and is symmetrically and widely distributed over the scalp irrespective of the side of the movements. At 300-400 ms before movement onset, the slow negative shift becomes steeper (NS'), especially at the centroparietal region contralateral to the movement side. The negative slope becomes much steeper immediately before movement onset and then peaks at or just after the movement onset (MP), followed by large, mainly positive transients (RAP). BPINS' is strongly related to voluntary movements, because it is not recorded before passive movements or involuntary movements such as simple tics, myoclonus and chorea in Huntington's disease (Shibasaki and Ikeda, 1996). BPINS' becomes smaller in patients with Parkinson's disease and with focal dystonia associated with a lesion of the basal ganglia.
4.3.2. Multiple cortical generators of SP EMG
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@~ Fig. 4. Scalp-recorded wave forms of BP, NS', MP and RAP with voluntary, self-paced extensions of the right hand(upperhalf), and schematic scalptopography of each component (BP, NS' and MP) with right hand voluntary movements viewed from the top (lower half). LHM=left hand motor area, RHM=right hand motor area. (Upper half was modified from Fig. 4 of Shibasaki et aI., 1980 with permission: lower half modified from Fig. 5 of Neshige et al., 1988 with permission.)
Based on the distribution of each component on the scalp, the BP was originally thought to be represented by the bilateral SMA activities, and the NS' and MP were mainly represented by the contralateral primary motor and sensory cortices (MI-SI). So far, subdural EEG studies have revealed that MI-SI, SMA proper and pre-SMA are cortical generators of pre-movement potentials (BP, NS' and MP) (Fig. 5) (Ikeda and Shibasaki, 2002).
4.3.2.1. Precentral gyrus (positive motor area) A somatotopy of the positive motor area in the precentral gyrus as revealed by electric cortical stimulation is also consistent with that by BP (Fig. 6) (Neshige et al., 1988; Ikeda et al., 1992), but it seems that BPs for each task are often distributed wider than the motor mapping made by cortical stimulation. It may be partly because BP is generated not only by the anterior bank but also by the crown part of the precentral gyrus (Ikeda et al., 1995a), from both of which corticospinal pathways originate.
ELECTROCORTICOGRAPHY IN MOTOR CONTROL AND MOVEMENT DISORDERS
Contralateral
37
Ipsilateral
Fig. 5. Schematic representation of the cortical generators of BP, NS' and MP for hand movements viewed from the top. The degree of darkness of the shading in the pre-SMA, SMA proper and MI-SI is approximately proportional to the amplitude of the corresponding potentials. MI=primary motor area, Sl eprimary sensory area. (Modified from Fig. 14 of Ikeda et al., 1992 with permission.)
4.3.2.2. Supplementary motor area (SMA) SMA is subdivided into caudal (SMA proper) and rostral (pre-SMA) parts in humans as well as in monkeys at the level of the VAC line (Picard and Strick, 1996); both SMA proper and pre-SMA are generators of the BP. SMA proper, like the precentral gyrus, has a somatotopic organization demonstrated by both electric cortical stimulation and BP (Fig. 7) (Ikeda et al., 1992, 1993, 1995b). Pre-SMA generates a similar BP invariably regardless of the sites of the voluntary movements in the body (Fig. 8) (Yazawa et al., 2000). Furthermore, the following findings may aid in differentiating the motor cortices located in the mesial frontal area.
proper could not be defined only by anatomical information. (2) The pre-SMA and SMA proper both generate a clear BP with slow-rate repetition of voluntary movements, but little BP in the rapid-rate repetition of movements, whereas MI generates a clear BP for slow- and rapid-rate repetition of movements (Kunieda et al., 2000). In the rapidrate repetition of movements, voluntary movements may be conducted as so called "automatic" movements, while in the slow-rate repetition of movements each movement is regarded as a discrete, individual execution, each of which may involve different motor control mechanisms.
(1) Onset time of BP between the foot MI and foot
4.4. Motor mapping by BP in functional neurosurgery
area at the SMA proper has no significant difference, but movement-related desynchronization before movement onset starts earlier at the SMA proper than at MI (Ohara et al., 2000). The foot area of the SMA proper generates BP not only for contralateral but also for ipsilateral movements whereas the foot MI generates BP exclusively for contralateral foot movements. Additionally, the latter generates a clear RAP immediately after movement onset whereas the former does not (Ikeda et al., 1992) (Fig. 9). Since the SMA proper is also often found in the lower half of the paracentral lobule by both electric cortical stimulation (Lim et al., 1996) and the BP (Ikeda et al., 1992), the boundary between the foot MI and foot area at the SMA
For mapping SI, SEPs and high frequency cortical stimulation are equally useful. The central sulcus can be delineated by SEPs. However, it does not directly represent the location of MI, but either the radial or tangential dipole arising from the postcentral gyrus. Like SEPs to define postcentral gyrus, the BP is clinically useful to localize the motor cortices. With regard to the mesial frontal cortices, functional delineation between the foot MI and the foot area at the SMA proper, or between the SMA proper and the pre-SMA, is made exclusively by high frequency cortical stimulation or just by anatomical approach. The BP can also be clinically useful to differentiate the mesial motor cortices, at least by complementing
38
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Fig. 6. Movement-related cortical potentials in association with self-paced extension of the right middle finger recorded from the subdural electrodes placed across the left central sulcus in an epilepsy patient. BP, NS' and MP are well localized to the finger motor area, and to a lesser degree, to the sensory area. Me motor, S=sensory. (From Neshige et al., 1988 with permission.)
the result of cortical stimulation (Ikeda and Shibasaki, 1992; Allison et aI., 1996; Yazawa et al., 1997). Motor mapping by BP has the following four advantages: (1) it reflects the activity of the motor cortices which are actually involved in preparation for and execution of voluntary movements; (2) it is present for voluntary movements of all parts of the body; (3) cortical activity in the bank of the sulcus (like the anterior bank of the central sulcus) may be recorded as a tangential dipole; (4) it is not associated with the risk of seizure induction in contrast with high frequency cortical electric stimulation. The BP method has the following two
disadvantages as compared with cortical electric stimulation: (1) voluntary movements of one kind need to be repeated at least 50 times to obtain averaged wave forms; (2) the patient's cooperation is needed to conduct the task of voluntary movements and to obtain satisfactory results (Ikeda et al., 2002). 4.5. Contingent negative variation (CNV) CNV is one of the event-related potentials initially reported by Walter et al. (1964). It is a slow negative brain potential occurring between two successive
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Fig. 7. Movement-related cortical potentials in association with self-paced movements of the right finger, right foot and tongue recorded from the left SMA in an epilepsy patient. The figure illustrates the somatotopic distribution of the BP within the SMA proper, consistent with the results of cortical stimulation. The broken line shows the boundary between the foot MI posteriorly (lower part in the right figure) and the SMA proper anteriorly (middle part in the right figure). Symbols in the figure show the results of electric cortical stimulation (A5 and B5 =positive motor response in the face and negative motor response of the bilateral hands; A6=rhythmic vocalization; B6=tonic motor response of the right hand; A7 and B7=positive motor response of the right hand and foot; A8, B8, A9 and B9=clonic motor response of the right foot). (From Ikeda et al., 1992 with permission.)
stimuli only when the two stimuli are associated with or contingent to each other, but not when the two are merely a simple pairing of stimuli. The basic paradigm of CNV recording is a constant foreperiod, reaction-time paradigm. In general, the first stimulus (SI) serves as a preparatory "warning" signal for the "imperative" stimulus (S2), to which a motor response is usually made. From the viewpoint of motor control and movement disorders, the CNV should represent the neuronal activity necessary for sensorimotor integration or association, and, there-
39
fore, it is related to planning or execution of externally-paced, voluntary movements. On the other hand, BPs represent the neuronal activity prior to self-paced voluntary movement (Tecce and Cattanach, 1993). The CNV is a composite wave form consisting of at least two components when the interval between S1 and S2 is set to 1.5 s or longer (Rohrbaugh et al., 1976). These are: (i) an early CNV (initial epoch of 300-500ms); and (ii) a late CNV (final epoch of 300-500 ms). The early CNV is thought to represent a reactive, arousal process associated with S1 and partly an anticipatory process for S2, and the late CNV is thought to represent an anticipatory process for S2 and attention to the motor response (Simson et al., 1977). The early CNV shows a frontal dominant distribution maximal at the midline. The late CNV is centrally dominant with little or no laterality, as opposed to the later part of the BP which is larger contralateral to the movement side (Grunewald et al., 1979). The late CNV is diminished in patients with focal dystonia, suggesting impairment of sensorimotor integration in a reaction-time paradigm (Kaji et al., 1995; Ikeda et al., 1996b; Hamano et al., 1999). Subdural EEG recording has revealed the cortical generators of CNV. The late CNV originates at nonprimary motor cortices (pre-SMA, SMA proper, lateral premotor area), prefrontal area (mesial and orbitofrontal areas) and MI (Lamarche et al., 1995; Ikeda et al., 1996a, d, 1999b; Hamano et al., 1997). The early CNV, if related to discrimination of external dichotic stimuli and selection of the movement, was observed principally at the pre-SMA, and its onset and peak latencies were 200 and 600 ms, respectively, after S1 in an "S l-choice of GolNoGo and S2-reaction-time" paradigm (Ikeda et al., 1999b). It represents the characteristic function of pre-SMA in cognitive motor control. 4.6. Electrocorticography in patients with movement disorders Paroxysmal dyskinesias are a heterogeneous group of movement disorders whose main features are intermittent attacks of dystonic, choreoathetotic and ballistic movements, and the clinical semiology is often indistinguishable from seizures arising from the SMA. Nocturnal paroxysmal dystonia has clin-
40
A. IKEDA
Fig. 8. Movement-related cortical potentials in association with self-paced extension of the left middle finger (B) and the right middle finger (C), and dorsiflexion of the left foot (D) and the right foot (E), recorded from the right mesial frontal cortex in an epileptic patient. In all tasks, negative BP is observed at F4, located anterior to the VAC line, being most likely pre-SMA. F2 just on the paracentral lobule (most likely foot MI area) generates BP only in association with the left foot movements. VAC=a line on the anterior commissure perpendicular to AC-PC line, VPC =a line on the posterior commissure perpendicular to AC-PC line. (From Yazawa et al., 2000 with permission.)
ical semiology suggesting paroxysmal dysfunction of the basal ganglia, but it is also indistinguishable from epileptic seizures arising from SMA or other frontal lobe structure. Based on the assumption that those movement disorders are caused by paroxysmal activity at either frontal lobe or basal ganglia following noninvasive EEG and SPECT studies, Lombroso and colleague decided to implant subdural electrode grids chronically over the mesial and lateral frontal cortices and depth electrodes at the caudate and amygdala nuclei in 3 patients (Lombroso, 1995, 2000; Lombroso and Fischman, 1999). Among 3 patients, 1 patient had ictal onset activity at the SMA, rapidly spreading to the basal ganglia; 1 patient had ictal onset at the orbitofrontal area, rapidly spreading selectively to the SMA; and 1 patient showed sustained 7-12 Hz discharges only at the caudate nucleus during habitual attacks. Invasive recording techniques can provide important informa-
tion with regard to pathogenesis in patients with movement disorders, and indications should be clarified based on the results of noninvasive, comprehensive investigations done beforehand. 4.7. Future consideration
Multiple cortical generators of BP and eNV have been revealed by invasive studies, but it is not certain which are the most important generators, or how they are functionally related to each other. Inter-areal functional coupling among the areas is essential for studying more sophisticated higher cortical functions. Furthermore, the presence of multiple cortical areas does not necessarily mean that surgical resection of any participating area causes dysfunction, and thus a future study combined with transcranial magnetic stimulation (TMS) which
ELECTROCORTICOGRAPHY IN MOTOR CONTROL AND MOVEMENT DISORDERS
41
Acknowledgments This study was supported by Grants-in-Aid for Scientific Research on Priority area (C)-Advanced Brain Science Project 12210012 from the Japan Ministry of Education, Culture, Sports, Science and Technology (MEXT); Research Grants (B2)13470134 and (C2)-13670460 from the Japan Society for Promotion of Sciences; Research Grant from Brain Science Foundation.
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References
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Fig. 9. Movement-related cortical potentials associated with voluntary, self-paced foot dorsiflexion of the left (upper halt) and the right (lower halt) side recorded from the left mesial brain surface subdurally in the same patient as Fig. 7. Positive BPs are of approximately equal amplitude at both SMA proper (A7) and in the contralateral foot MI (A8). A negative transient at + 145 ms was seen only at the contralateral foot MI (A8, A9), but not in the SMA proper (A7). The broken line shown the boundary between the foot MI posteriorly (lower part in the figure) and the SMA proper anteriorly (upper part in the figure). Symbols in the figure are explained in Fig. 7. (From Ikeda et aI., 1992 with permission.) produces transient dysfunction may be helpful. "Functional plasticity" associated with pathological conditions such as epilepsy or intraparenchymal tumor could produce a large variability in the functional mapping, and thus a careful investigation and interpretation of the results is needed for each patient. How well cortical mapping by BP or CNV reflects "functional plasticity" as compared with mapping by high frequency electric cortical stimulation should also be studied.
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accompanying anticipation and decision making in humans: a comparison with Bereitschaftspotential. Elecroencephalogr. Clin. Neurophysiol., 98: 206212. Ikeda, A, Shibasaki, H, Kaji, R, Terada, K, Nagarnine, T, Honda, M, Hamano, T and Kimura, J (1996b) Abnormal sensorimotor integration in writer's cramp: study of contingent negative variation. Mov. Disord., 11: 691-700. Ikeda, A, Terada, K, Mikuni, N, Burgess, R, Comair, Y, Taki, W, Hamano, T, Kimura, J, Liiders, HO and Shibasaki, H (1996c) Subdural recording of ictal DC shifts in neocortical seizures in human. Epilepsia, 37: 662-674. Ikeda, A, Liiders, HO and Shibasaki, H (1996d) Generation of contingent negative variation (CNV) in the supplementary sensorimotor area. In: HO Ltiders (Ed.), Supplementary Sensorimotor Area. Advances in Neurology. Lippincott-Raven, New York, Vol. 70, pp. 153159. Ikeda, A, Nagarnine, T, Yarita, M, Terada, K, Kimura, J and Shibasaki, H (1998) Reappraisal of the effects of electrode property on recording slow potentials. Elecroencephalogr. Clin. Neurophysiol., 107: 59-63. Ikeda, A, Taki, W, Kunieda, T, Terada, K, Mikuni, N, Nagamine, T, Yazawa, S, Ohara, S, Hori, T, Kaji, R, Kimura, J and Shibasaki, H (1999a) Focal ictal DC shifts in human epilepsy as studied by subdural and scalp recording. Brain, 122: 827-838. Ikeda, A, Yazawa, S, Kunieda, T, Ohara, S, Terada, K, Mikuni, N, Nagarnine, T, Taki, W, Kimura, J and Shibasaki, H (1999b) Cognitive motor control in human pre-supplementary motor area studied by subdural recording of discrimination! selection-related cortical potentials. Brain, 122: 915-931. Ikeda, A, Miyamoto, Sand Shibasaki, H (2002) Cortical motor mapping in epilepsy patients: information from subdural electrodes in presurgical evaluation. Epilepsia, 43 (Suppl. 9): 56-60. Kaji, R, Ikeda, A, Ikeda, T, Kubori, T, Mezaki, T, Kohara, N, Kanda, M, Nagarnine, T, Honda, M, Rothwell, J, Shibasaki, H and Kimura, J (1995) Physiological study of cervical dystonia: task-specific abnormality in contingent negative variation. Brain, 118: 511-522. Kornhuber, HH and Deecke, L (1965) Hirnpotentialanderungen bei Willkiirbewegungen und passiven Bewegungen des Menschen: Bereitschaftspotential und reafferente Potentiale. Pfiugers Archiv., 284: 1-17. Kunieda, T, Ikeda, A, Ohara, S, Yazawa, S, Nagarnine, T, Taki, W, Hashimoto, Nand Shibasaki, H (2000) Different activation of pre-supplementary motor area (pre-SMA), SMA-proper and primary sensorimotor area depending on the movement repetition rate in humans. Exp. Brain Res., 135: 163-172.
ELECTROCORTICOGRAPHY IN MOTOR CONTROL AND MOVEMENT DISORDERS
Lamarche, M, Louvel, J, Buser, P and Rector, I (1995) Intracerebral recording of slow potentials in a contingent negative variation paradigm: an exploration in epileptic patients. Elecroencephalogr. Clin. Neurophysiol., 95: 268-276. Lim, SH, Dinner, DS and Liiders, HO (1996) Cortical stimulation of the supplementary sensorimotor area. In: H Liiders (Ed.), Advances in Neurology. Supplementary sensorimotor Area. Lippincott-Raven, Philadelphia, Vol. 70, pp. 187-197. Lombroso, CT (1995) Paroxysmal kinesigenic choreoathetosis: an epileptic or non-epileptic disorder? Ital. J. Neurosci., 16: 271-277. Lombroso, CT (2000) Nocturnal paroxysmal dystonia due to a subfrontal cortical dysplasia. Epileptic Disord., 2: 15-20. Lombroso, CT and Fischman A (1999) Paroxysmal nonkinesigenic dyskinesia: pathophysiological investigation. Epileptic Disord., 2: 187-193. Lueders, H, Bustamante, L, Zablow, Land Goldensohn, ES (1981) The independence of closely spaced discere experimental spike foci. Neurology, 31: 846-851. Liiders, H, Lesser, RP, Dinner, DS, Morris, HH, Hahn, JF, Friedman, L, Skipper, G, Wyllie, E and Friedman, D (1987) Commentary: Chronic intracranial recording and stimulation with subdural electrodes. In: J Engel Jr (Ed.), Surgical Treatment of the Epilepsies. Raven Press, New York, pp. 297-321. Morris, HH III, Liiders, H, Hahn, JF, Lesser, RP, Dinner, DS and Estes, ML (1986) Neurophysiological techniques as an aid to surgical treatment of primary brain tumors. Ann. Neurol., 19: 559-567. Nagamine, T, Kaji, R, Suwazono, S, Hamano, T, Shibasaki, H and Kimura, J (1992) Current source density mapping of somatosensory evoked responses following median and tibial nerve stimulation. Elecroencephalogr. Clin. Neurophysiol., 84: 248-256. Neshige, R, Liiders, H and Shibasaki, H (1988) Recording of movement-related potentials from scalp and cortex in man. Brain, 111: 719-736. Ohara, S, Ikeda, A, Kunieda, T, Yazawa, S, Baba, K, Nagamine, T, Taki, W, Hashimoto, N, Mihara, T and Shibasaki, H (2000) Movement-related change of electrocorticographic activity in human SMA proper. Brain, 123: 1203-1215. Penfield, Wand Jasper, H (1954) Epilepsy and functional anatomy of the human brain. Little, Brown and Company, Boston, 896 pp. Pfurtscheller, G and Cooper, R (1975) Frequency dependence of the transmission of the EEG from cortex to scalp. Elecroencephalogr. Clin. Neurophysiol., 38: 93-96.
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Picard, N and Strick, P (1996) Motor area of the mesial wall: a review of their location and functional activation. Cerebr. Cortex, 6: 342-353. Rector, I, Feve, A, Buser, N, Bathien, N and Lamarche, M (1994) Intracranial recording of movement-related readiness potentials: an exploration in epileptic patients. Elecroencephalogr. Clin. Neurophysiol., 90: 273-283. Rector, I, Louvel, J and Lamarche, M (1998) Intracranial recording of potentials accompanying simple limb movements: a SEEG in epileptic patients. Elecroencephalogr. Clin. Neurophysiol., 107: 277-286. Rohrbaugh, JW, Syndulko, K and Lindsley, DB (1976) Brain wave components of the contingent negative variation in human. Science, 191: 1055-1057. Sasaki, K and Gemba, H (1991) Cortical potentials associated with voluntary movements in monkeys. Elecroencephalogr. Clin. Neurophysiol., Suppl. 42: 80-96. Shibasaki, H, Barrett, G, Halliday, E and Halliday, AM (1980) Components of the movement-related cortical potentials and their scalp topography. Elecroencephalogr. Clin. Neurophysiol., 49: 213-226. Shibasaki, H and Ikeda, A (1996) Generation of movement-related potentials in the supplementary sensorimotor area. In: HO Liiders (Ed.), Supplementary SensorImotor Area. Advances in Neurology. Lippincott-Raven, New York, Vol. 70, pp. 117-125. Simson, R, Vaughn, HG Jr and Ritter, W (1977) The scalp topography of potentials in auditory and visual go/nogo tasks. Elecroencephalogr. Clin. Neurophysiol., 43: 864-875. Szentagothai, J (1969) Architecture of the cerebral cortex. In: HH Jasper, AA Ward and A Pope (Eds.), Basic Mechanisms of the Epilepsies. Little, Brown, Boston, pp.13-28. Talairach, J and Bancaud, J (1974) Stereotactic exploration and therapy in epilepsy. In: PJ Vinken and GW Bruyer (Eds.), Handbook of Clinical Neurology. NorthHolland, Amsterdam, Vol. 15, pp. 758-782. Tecce, 11 and Cattanach, L (1993) Contingent negative variation. In: E Niedermeyer and F Lopes da Silva (Eds.), Electroencephalography. Basic Principles, Clinical Applications and Related Fields. Wiliams & Wilkins, Baltimore, pp. 887-910. Towle, VL, Carder, RK, Khorasani, L and Lindberg, D (1999) Electrocorticographic coherence pattern. J. Clin. Neurpohysiol., 16: 528-547. Tyner, FS, Knott, JR and Mayer, WB Jr (1983) Electrodes. In: Fundamentals of EEG Technology. Basic Concepts and Methods. Raven Press, New York, Vol. 1, pp. 126-135. Walter, WG, Cooper, R, Aldridge, VJ, McCallum, WC and Winter, AL (1964) Contingent negative variation: an
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electrical sign of sensorimotor association and expectancy in the human. Nature, 203: 380-384. Yazawa, S, Ikeda, A, Terada, K, Mirna, T, Mikuni, N, Kunieda, T, Taki, W, Kimura, J and Shibasaki, H (1997) Subdural recording of Bereitschaftspotential is useful for functional mapping of the epileptogenic motor area: a case report. Epilepsia, 38: 245-248.
A. IKEDA
Yazawa, S, Ikeda, A, Kunieda, T, Ohara, S, Mirna, T, Nagamine, T, Taki, W, Hori, T and Shibasaki, H (2000) Human pre-supplementary motor area is active before voluntary movement: subdural recording of Bereitschaftspotentials from mesial frontal cortex. Exp. Brain Res., 131: 165-177.
Movement Disorders Handbook of Clinical Neurophysiology, Vol. 1 M. Hallett (Ed.) © 2003 Elsevier B. V. All rights reserved
45 CHAPTER 5
Somatosensory evoked responses Francois Mauguiere" Department of Functional Neurology and Epileptology, Neurological Hospital, 59 Boulevard Pinel, 69330 Lyon, France
Modem history of clinical somatosensory evoked potentials (SEPs) testing began fifty years ago with George Dawson's recordings, in patients with myoclonus, of what is known today as a 'giant' somatosensory cortical response (Dawson, 1947). Thus, the first clinical application of SEP was to elucidate the mechanism of a movement disorder. Cortical SEPs were the first studied in normal subjects and patients, while spinal and sub-cortical far-field potentials were identified in the seventies and early eighties. The most recent advances in our knowledge of cortical responses to somatosensory stimulation are issued from development of multichannel recordings of SEPs and somatosensory evoked magnetic fields (SEFs) coupled with source localization in the 3D images of brain volume, as provided by magnetic resonance imaging (MRI). Studies based on electro-clinical correlations in patients with focal lesions have identified a single generator for each SEP component, a view compatible with the concept that the processing of somatosensory inputs by the nervous system is based on a sequential activation of fibers and synaptic relays. Source localization studies rather suggest that the evoked field recorded on the scalp surface at a given moment often results from activities of multiple distributed sources overlapping in time (Mauguiere et aI., 1997). This model fits better with the parallel activation and feedback loops characterizing the process of sensory inputs at the cortical level. In this chapter, we will focus on the early SEP components that can be helpful for analyzing the somatosensory control of movement in normal subjects. Similarly we will consider only SEPs' abnormalities observed in patients presenting with movement disorders.
* E-mail address:
[email protected]
Tel.: 33 (0) 472 35 7106; fax: 33 (0) 472 35 7105.
5.1. Recording procedures Only the essential technical requirements for SEPs recording will be given here. More technical details concerning electrodes, amplifiers, stimulators, and safety can be found in several book chapters (Spehlmann, 1985; Chiappa, 1990; Halliday, 1993; Mauguiere, 1995, 1999) and in guidelines published by the International Federation of Clinical Neurophysiology (Mauguiere et aI., 1999). 5.1.1. Stimulus types and peripheral fibers involved in response
SEPs can be evoked either by electric stimulation of different categories of nerves according to their content in skin, joint, muscle afferent fibers, or by natural stimuli. Since one of the applications of SEPs in movement analysis consists in assessing somatosensory feedback control mechanisms of movement, it is of uppermost importance to know which type of fibers is involved in producing the response. Furthermore, when stimulating a nerve containing several fibers of different origins, diameters and conduction velocities, interference and occlusion phenomena may occur. Lastly the different types of somatosensory inputs will not necessarily produce all of the SEP components. This last point will be detailed in the description of the normal components of the response (see below). 5.1.1.1. Electrical stimuli Brevity and strict control in time of stimulus onset and cutoff, and thus of averaging trigger, are the major advantages of electrical stimulation over any other types of stimulus. SEPs are usually evoked by bipolar transcutaneous electrical stimulation applied on the skin over the trajectory of peripheral nerves. Monophasic electrical pulses of 100-300 u.s can
46
be delivered through rectangular, disk or needle electrodes connected respectively to the negative (cathode) or positive (anode) pole of the stimulator. Electrical stimuli thus by-pass the peripheral encoding of natural stimuli (pressure, vibrations, joint movements) by the receptors. Electric simulation of pure sensory nerves, such as digital nerves for the upper limb and sural nerve for the lower limb activates exclusively skin and joint peripheral and dorsal column fibers. It is advisable to use this type of stimulus in any attempt to correlate the quality of perception with SEP data in normal subjects as well as in patients with impaired sensation (Mauguiere et al., 1983a). At the upper limb stimulation of the finger tip (Desmedt and Osaki, 1991) or distal phalanx of fingers (Restuccia et al., 1999) activates selectively skin fibers, while stimulation of digital nerves at the level of the first or second phalanx concern both joint and skin afferents. In most clinical applications the electric stimulus is applied to mixed nerve at intensities equivalent to 3 to 4 times the sensory threshold. This type of stimulus produces a twitch in the muscles innervated by the stimulated nerve when it contains a contingent of motor fibers. At these stimulus intensities all rapidly conducting large myelinated fibers, including fibers subserving touch and joint sensation but also muscle afferents, are activated. The contribution of muscle afferents to cortical SEPs after stimulation of upper limb mixed nerves remains a matter of controversy. It is considered as negligible by Halonen et al. (1984) and Kunesch et al. (1995). However selective intrafascicular stimulation of hand muscle afferents at the wrist and motor-point stimulation were shown to produce short-latency cortical SEPs with the same waveforms (Gandevia et al., 1984; Gandevia and Burke, 1988) and modeled dipolar sources (Restuccia et al., 2002) as those obtained by stimulating the trunk of a mixed nerve. These cortical responses were obtained also after motor point stimulation of proximal upper limb muscles (Gandevia and Burke, 1988) and muscles of the trunk (Gandevia and Macefield, 1989). They are relatively small as compared with potentials evoked from the whole mixed nerve or digital nerves because only relatively few afferents are activated. Their first cortical' component peaks later than for median nerve stimulation at the wrist and at approximately the same latency as for
F. MAUGUIERE
stimulation of the digital nerves (Gandevia and Burke, 1990). Therefore the possibility remains that, when stimulating a mixed nerve of the upper limb such as the median nerve, the cortical response to muscle afferents inputs could be gated by the response to cutaneous and joint inputs. To conclude, the contribution of muscle afferents to median nerve SEPs can be considered as weak as compared to that of cutaneous afferents. The situation is quite different after electric stimulation of lower limb sensory-motor nerves such as the posterior tibial nerve for which muscle afferents have been shown to have a major contribution to cortical SEPs (Burke et al., 1981, 1982: Gandevia et al., 1984; Macefield et al., 1989). The latency of the earliest cortical response is shorter after stimulation of abductor hallucis muscular fascicle than after stimulation of the posterior tibial nerve and its amplitude is approximately half that of the tibial nerve response (Burke et al., 1981). It has been shown that, after stimulation of the tibial nerve, inputs conveyed by muscle afferents, which have the fastest conduction velocity, are able to occlude the response to cutaneous inputs (Burke et al., 1982). Because of this gating the cutaneous afferent volley may make little, or no contribution at all, to the cerebral potential evoked by electric stimulation of lower limb mixed nerves. Paired electrical stimuli delivered to the same nerve at various interstimulus intervals can be used to characterize distinct components of a given response according to their refractoriness after the response to the first stimulus of the pair (conditioning stimulus), and also to combine SEP testing with psycho-physical evaluation of time discrimination performances in detecting the second stimulus of the pair (El Kharroussi et al., 1996). The voltage of the response to the second stimulus of the pair is evaluated by subtracting the response to the test stimulus delivered alone in a separate session. The effect on SEPs of spatial interference between two electrical stimuli delivered simultaneously but at two distinct sites has been first described by Burke et al. (1982) and Gandevia et al. (1983). These authors showed that after simultaneous stimulation of both index and middle fingers of the same hand the size of the early component of the cerebral potential is less than predicted by simple addition of the potentials produced by stimulation of the fingers individually. A procedure based on this observation has been
47
SOMATOSENSORY EVOKED RESPONSES
recently applied to the study of somatosensory processing in patients with dystonia (Tinazzi et al., 2000). The interfering influences of sensory and motor events on electrically evoked SEPs have been widely used in the context of gating paradigms (see Cheron et al., 2000 for a review). In particular, models of centrifugal and centripetal SEP gating during movement programming or execution are based on the results from these studies (see below). 5.1.1.2. Natural stimuli Physiological stimuli have a higher selectivity than that of electrical stimulation of sensory nerves. SEPs and somatosensory evoked magnetic fields (SEFs) can be obtained in response to a brief mechanical impact on the finger tip (Debecker and Desmedt, 1964; Halliday and Mason, 1964; Nakanishi et al., 1973; Pratt and Starr, 1981; Kakigi and Shibasaki, 1984) or air puffs (Schieppati and Ducati, 1984; Hashimoto, 1987; Forss et al., 1994). For skin stimulation there is some difficulty in getting a consistent quick and well defined movement of the striker using an electro-mechanical device; this is why stimulators producing fast rise-time (1 ms) and short duration (4-5 ms) air puffs have been developed. However, due to the small population of excited fibers, these mechanical stimuli produce low voltage responses and are not used routinely in the clinical setting, in spite of their potential advantage over conventional electrical stimuli. Selective stimulation of joint afferent fibers using passive movements of fingers is difficult to achieve mostly because of possible interference between activations of joint, tendinous and muscle stretch receptors. Dedicated devices have been developed in order to activate selectively finger joint afferents (Desmedt and Osaki, 1991) or muscle afferents (Mirna et al., 1996). These stimulators produce a small and brisk passive flexion movement of finger II, or fingers II and III, proximal interphalangeal joint, with an amplitude 2° (Desmedt and Osaki, 1991) or 4 ° (Mirna et al., 1996) in 25 ms. In spite of close similarities between stimulation paradigms and evoked responses in these two studies, authors are diverging about the nature of afferent peripheral fibers involved in cortical response genesis, although they discard the hypothesis of a significant participation of cutaneous fibers. Desmedt and Osaki (1991) considered that the small 2° flexions they applied to
the finger with the wrist in slight extension were unlikely to activate the spindle afferents of finger extensor muscles. Mirna et a1. (1996) opposed the argument that joint afferents discharge only in extreme flexion or extension positions while a 4° flexion of the finger produces a muscle stretch in extensor muscle far larger than that needed to record evoked cortical response in monkeys (Phillips et al., 1971). Moreover they observed that responses to finger flexion were preserved after anoxic ischemia blocking the conduction of joint and cutaneous fibers from the moved finger, and concluded that muscle afferents from finger extensor muscles were responsible for cortical evoked responses. Lastly this latter observation is in partial contradiction with that of an abolition of cortical evoked responses to larger finger displacements (up to 45°) after anoxia of the hand reported earlier by Papakostopoulos et a1. (1974). Thus, although it is obviously difficult to be sure of the fibers involved during passive finger movements, this natural stimulus has the clear advantage over electrical stimulation to reproduce the physiological condition of the proprioceptive control of movement and would merit a larger utilization for exploring the pathophysiology of movement disorders. As performed routinely in Clinical Neurophysiology laboratories, SEPs do not explore the small myelinated Ao or unmyelinated C afferents to spinothalamic tracts, which subserve temperature and pain sensation. Since the report by Halliday and Wakefield (1963) it has been known that SEPs to electrical stimulation of the median nerve are normal in patients with lesions of the spino-thalamic tract and loss of pain and temperature sensation. Selective activation of Ao and C fibers can be achieved by brief heat pulses delivered by a CO 2 laser beam applied to the skin surface (Bromm and Treede, 1987). Since there is no evidence that slow conducting peripheral fibers are involved in movement control, we will not report on these potentials in this chapter. 5.1.2. Stimulus rate Stimulus rates of 1 to 10 s are commonly used in clinical neurophysiology laboratories with no significant changes in the amplitudes or latencies of subcortical or primary sensory cortex (SI) responses. These rates are considered as acceptable for clinical
48
studies in most textbooks (Chiappa, 1990; Halliday, 1993). However, lower rates are recommended to study the amplitudes of cortical potentials peaking more than 25 ms after stimulation of the upper limb. At rates over 3 s even early cortical potentials peaking after the initial SI response can be depressed, in particular the frontal N30 potential which is one of the SEPs most often reported as affected in movement disorders. The amplitudes of middle and long latency responses, in particular those generated in the SII area, reach their saturation level at stimulus rates far below 1 s (Hari et aI., 1984). The effect of stimulus rates on the amplitude of cortical SEPs can be used as a means to distinguish the components one with another, this approach has been applied to identify short latency SEPs to median nerve (Garcia-Larrea et al., 1992) and tibial nerve (Tinazzi et al., 1996a) stimulation.
5.1.3. Analysis time, sampling rate and filters
Most of the SEP components which have proved their clinical utility peak before 50 and 100 ms respectively for upper and lower limb stimulation. Consequently there is no necessity to record SEPs over analysis times longer than 100 ms in routine except for the recording of middle latency responses generated in SII (Hari et al., 1983, 1984), posterior parietal (Forss et al., 1994) and mesial cortical areas (Forss et al., 1996) Most commercially available devices can calculate 512 sampling points over analysis times in the 10-100 ms range. This gives bin widths of 97 and 195 f..LS for analysis times of 50 and 100 ms, which are appropriate to obtain far-field and short-latency cortical SEPs without aliasing, respectively (see Spehlmann, 1985). A band-pass, with a high-pass filter set at less than 3 Hz and a low pass filter set over 2000 Hz, is optimal to record without distortion all early SEP components including fast far-field potentials. A lower high cut-off frequency down to 200 Hz is acceptable for the recording of SEPs peaking later than 50 ms for upper limb stimulation. Analog filter rolls off should not exceed 12 and 24 dB/octave for low and high frequency filters respectively. Digital filtering of responses acquired with a broad band pass filter offers the possibility of selecting off-line frequencies of clinical interest.
F. MAUGUIERE
5.1.4. Gain and number of sweeps
Gains between 100,000 and 200,000 are adequate. The number of sweeps to be averaged is variable according to the signal/noise ratio of the different SEP components. In practice 500 sweeps are enough, in most instances, to obtain the responses at Erb's point, as well as to extract the main early cortical components. For the recording of spinal and scalp far-field EPs often up to 1000-2000 sweeps must be averaged. 5.1.5. Placement of the recording electrodes
When recording SEP, one usually aims to study during the same run peripheral, spinal, brainstem and early cortical SEPs. Peripheral nerve volleys of action potentials as well as conducted and segmental spinal SEPs can be recorded by placing cutaneous electrodes along the route of the fibers tracts or close to the fixed generators of segmental spinal responses (near-field recording). Electrodes placed on the scalp pick up both SEPs generated in the cortex which are picked up as near-field responses located in restricted areas and far-field positivities reflecting the evoked activity generated in peripheral, spinal and brainstem somatosensory fibers. Standard disk electrodes, well attached on the skin and scalp surface, are suitable for most types of recordings; needle electrodes can also be used. The routine four-channels montages proposed in the IFCN guidelines (Mauguiere et al., 1999) explore the afferent peripheral volley (in the supra-clavicular and popliteal fossa for upper and lower limb, respectively), the segmental spinal responses at the neck and lumbar spine levels, as well as the subcortical far-field and early cortical SEPs using scalp electrodes placed in the parietal and frontal regions for upper limb SEPs and at the vertex for lower limb SEPs. MUltiple channel recordings (24, 32, 64 or more) permit to assess the scalp topographic distribution of SEPs; they can be obtained using a cap with electrodes placed according to the modified tentwenty electrode system for SEPs, or whole-head magneto-encephalography (MEG) devices for SEFs. These multiple-channel recordings, eventually assisted by mapping based on computerized voltage or current fields interpolation, have brought invaluable information on the spatial distribution of each component of the response; moreover they are indispensable for calculating the evoked fields
49
SOMATOSENSORY EVOKED RESPONSES
sources coordinates in a spherical or MRI-based realistic model of the head. The SEP literature is full of discussions about the most appropriate site for the reference electrode to record each of the components of the response; in fact the knowledge of the field distributions and of supposed source locations and orientations is enough for a correct choice of the recording derivation. Considering the field distribution, the optimal recording condition is in theory that where the reference is not influenced by the activity under study. Most of the far-field potentials that have proved to be clinically useful are widely distributed over the scalp. Consequently they reach their maximal amplitude in referential recordings in which the reference electrode is placed in a noncephalic position and they are cancelled, or drastically reduced, when both recording electrodes are placed on the scalp. Furthermore a non-cephalic reference common to all channels is also adequate for all near-field recordings and there is no theoretical argument against the recommendation of using this type of montage in all situations. However the electrical and physiological (ECG, EMG ...) noise level may be increased by the long distance between the active and reference electrode in non-cephalic reference montages. Conversely, differential amplification between the two maxima of a dipolar potential field on the scalp produced by an identified single generator increases the signal voltage and reduces the noise level. Therefore montages proposed for routine recordings often stem from a compromise between: (i) the theoretical optimum represented by a common non-cephalic reference; and (ii) practical considerations in terms of pertinent components to be studied in a given clinical condition and electrical environment. 5.1.6. Placement of the ground electrode
To minimize the electrical artifact produced by the stimulation, the ground electrode should be placed on the stimulated limb between the stimulation site and the recording electrodes. Flexible metal strips covered with a saline-soaked cloth wrapped around the limb close to the stimulus site are recommended. Electrically isolated stimulators allow the use of a ground electrode on the head which is adequate for eliminating artifact related to the electrical main and radiofrequency interference.
5.2. Normal responses Short latency SEPs to upper limb stimulation (electrical stimulation of median, ulnar, radial or finger nerves)
The main early SEP components will be described as they appear on recordings using a non-cephalic reference electrode placed at the shoulder on the non-stimulated side after stimulation of the median nerve at the wrist (Fig. 1). When necessary we will discuss the modifications of waveform and latency related to the use of other reference electrode sites.
7
6
5
4
3
, P13 "spinal"
~ Nl-o-- N11
2_~
~ tN9
L-
~35msK
Fig. 1. Normal median nerve SEPs. This figures illustrates normal responses recorded using a non-cephalic reference montage. Note that the segmental response peaks as a negative N13 at Cv6 spinous process (channel 2) and as a positive spinal Pl3 at the anterior cervical recording site (channel 3). In this subject the four far-field scalp positive potentials P9, PH, Pl3 and Pl4 are well individualized (channels 4-7); the Nl8 potential recorded in the parietal region ipsilateral to stimulus looks biphasic because of the large diffusion of the parietal P27 potential (channel 4) ; the N24 potential is hardly visible on the ascending phase of the frontal N30 (channel 7) between the P20 and N30 peaks.
50
5.2.1. Peripheral, spinal and sub-cortical potentials 5.2.1.1. The peripheral N9 potential Stimulation of a mixed nerve such as the median nerve elicits a compound action potential (CAP) reflecting the peripheral ascending volley that can be recorded at different levels of forearm and arm. In most routine SEP recordings the peripheral ascending volley is recorded only at Erb's point in the supraclavicular fossa ipsilateral to stimulation. The CAP appears as a triphasic positive-negative-positive waveform with a negative peak culminating at about 9 ms in normal subjects (N9). The reference electrode can be placed at the contralateral Erb's point (EPc) or at Fz site in the frontal region of the scalp. With the EPc reference, only the N9 triphasic wave is recorded, with the Fz reference it is followed by a Nl4 negativity and a P30 positivity which correspond to the P14 and N30 potentials recorded at Fz, respectively (see below). When a limited number of channels is available the EPi-Fz derivation thus permits to assess the far-field P14 and frontal N30 potentials. Median nerve CAP are a mixture of motor antidromic and sensory orthodromic responses, and thus are qualitatively different from SEPs generated in the somatosensory pathways. The amplitude of peripheral CAPs are unaffected by interfering stimuli applied on the stimulated hand or when the stimulus rate is increased up to 50 Hz (Ibanez et aI., 1989). 5.2.1.2. The spinal segmental N13 potential Electrical stimulation of large diameter myelinated fibers of peripheral nerves produces a dorsal horn (DH) potential with a posterior-negative and anterior positive dipolar field perpendicular to the cord axis. This field distribution ofDH potentials has been studied by direct spinal recordings at all segmental levels of the cord. A comprehensive atlas of these responses is now avalaible (Dimitrijevic and Halter, 1995). The cervical N13 potential is recorded at the posterior neck, with a maximum voltage at the level of Cv5-Cv7 spinous processes and decreases in amplitude at more rostral or caudal electrode positions. N 13 does not show any latency shift between lower and upper cervical levels after median nerve stimulation in' normal subjects (Desmedt and Cheron, 1980a; Mauguiere, 1983; Desmedt and Nguyen, 1984). When recorded ante-
F. MAUGUIERE
rior to the cord by an electrode placed at the anterior aspect of the neck (Desmedt and Cheron, 1980a; Mauguiere and Ibanez, 1985) the cervical DH response is recorded as a spinal P13 positivity. This polarity reversal has been demonstrated with esophageal (Desmedt and Cheron, 1981a) and epidural (Cioni and Meglio, 1986) recordings and also by direct recordings from the surface of the cervical cord (Jeanmonod et aI., 1989, 1991). Both N13 and P13 spinal components are reduced in amplitude to the same degree when the stimulation rate is increased over 10 s (Ibanez et aI., 1989), both persist in brain death or in cervico-medullary lesions (Mauguiere et aI., 1983b; Buchner et aI., 1988) and both are selectively reduced or abolished in lesions of the cervical cord gray matter sparing the spinal somatosensory tracts (Restuccia and Mauguiere, 1991; Ibanez et aI., 1992). Thus, the most likely generator of the N13/P13 cervical potentials is the compound segmental post-synaptic potential triggered in the dorsal horn gray matter by the afferent volley in fast conducting myelinated fibers. A cervical transverse derivation between two electrodes located respectively over the Cv6 spinal process and at the anterior aspect of the neck (anterior cervical reference, AC) above the laryngeal cartilage is the most adapted for recording the spinal N13/P13 segmental response. Subtraction of the anterior cervical positivity from the posterior neck negativity increases the signal/noise ratio and has the advantage, over the more conventional Cv6-Fz montage, to record a segmental DH response that is not contaminated by SEP components generated above the foramen magnum (Mauguiere and Restuccia, 1991). Apart from its field distribution a second characteristic of the segmental N13 potential is that it shows amplitude reduction, rather than latency prolongation, when the dorsal afferent volley is time dispersed, or when the number of responding DH neurons is reduced. For diagnostic purposes the limitation of N13 amplitude measurements is that distribution of this parameter in a group of normal subjects does not show a Gaussian profile. Therefore, the lower limit of normal N13 amplitude values estimated by the mean minus 2 to 3 standard deviations (SD) is statistically meaningless. The best way to evaluate the N13 amplitude is to calculate the ratio between the N13 amplitude and that of the dorsal root N9/P9 deflection,which immediately
SOMATOSENSORY EVOKED RESPONSES
precedes N13 in transverse cervical montage recordings (Restuccia and Mauguiere, 1991). The distribution of the loglO(N131N9) amplitude ratio has a Gaussian profile in normals. The normal lower limit of the normal N131N9 ratio, defined as the mean value minus 2.5 SD, is of about 1.2. The N91P9 deflection shows a good test-retest and its amplitude closely reflects the incoming volley in the cervical roots. Moreover the N131P9 amplitude ratio remains stable when tested at stimulus intensities between motor threshold and twice the motor threshold. Lastly normal values of the amplitude ratio between N13 and the preceding N9-P9 have been published for median, ulnar and radial nerve stimulation (Restuccia and Mauguiere, 1991; Restuccia et aI., 1992) with this derivation. 5.2.1.3. The upper cervical NJ3 potential It has been known for many years that a negative potential peaking at a latency of about 13 ms can be recorded intraoperatively at the dorsal aspect of the cervico-medullary junction (Andersen et aI., 1964; Allison and Hume 1981; Lesser et al 1981; Meller et aI., 1986; Morioka et aI., 1991). On the skin surface however, it is uneasy after median nerve stimulation to separate this potential at upper cervical level from the segmental cervical N13, so that the former can be interpreted as a rostral spread of the latter. In particular there is no evidence of a latency increase of the median nerve N13 negativity from Cv6 to Cv2 level in non-cephalic reference recordings, although in bipolar recordings along the neck the mean N13 peak latency was found to be longer at rostral than at caudal levels (Kaji and Sumner, 1987). An elegant insight to this latency problem was provided by Zanette et al. (1995) who showed that the N13 recorded at upper cervical level peaks 0.8 ms later than the Ic-N13 after ulnar nerve stimulation, but not after median nerve stimulation, in non-cephalic reference recordings. The greater distance from the dorsal root entry zone to the cuneate nucleus for ulnar nerve than for median nerve afferent fibers was proposed to explain this latency shift. More recently Araki et al. (1997) have addressed the question of separate generators for the lower and upper cervical N13 potentials by using a conditioning-test paired stimulus paradigm. They confirmed that at interstimulus intervals of 4-18 ms the test median nerve lower cervical N13 to the second stimulus was attenuated by 2-34% when compared to the control
51
response, as previously reported by Iragui (1984) after median nerve stimulation and by EI-Kharoussi et al. (1996) after stimulation of the 2nd and 3rd fingers. More unexpected was the finding that, while the scalp P13-P14 showed the same attenuation as the lower cervical N13, the N13 recorded at the Cv2 level showed an increase of 4-25% at these lSI. The upper cervical N13 is supposed to be generated by the pre-synaptic volley in the DC fibers close to the cuneate nucleus, but the difficulty for separating it from the dorsal hom N13 lessens its clinical reliability in routine clinical recordings (see Mauguiere, 2000, for a review). 5.2.1.4. The conducted cervical N11 potential The NIl potential is recorded all along the posterior aspect of the neck, where it usually appears to encroach upon the ascending slope of N13. In non-cephalic reference recordings, its onset latency increases from Cv6 to Cv 1 spinal processes by 0.9±0.15 ms (Desmedt and Cheron, 1980a; Mauguiere, 1983). This bottom-up shift of NIl onset latency suggests that Nil is generated by the ascending volley of action potentials in the dorsal columns of the cervical spinal cord. As first reported by Cracco (1973), it is often difficult to differentiate the Nil from the following N13 component. This seriously hampers the use of NIl in clinical practice, which is limited to cervical cord lesions obliterating selectively the N13 potential. In direct recordings on the cervical cord surface during surgery, Nil appears as a fast polyphasic component which overlaps in time with the slower N13 segmental post-synaptic potential. 5.2.1.5. The far-field positive scalp potentials (P9, PlJ, PJ3, P14) On scalp non-cephalic reference recordings with a high frequency filter over 1000 Hz and a fast sampling rate (bin width ~200 us), three or four stationary positive potentials are consistently observed with a wide distribution and a mid-frontal predominance. These potentials have in common to be generated by sub-cortical structures (Craceo and Cracco, 1976; Nakanishi et aI., 1978; Anziska and Cracco, 1980; Desmedt and Cheron, 1980a; Yamada et al., 1980; Mauguiere and Courjon, 1981). In normal adults these potentials peak with mean latencies of 9, 11, 13 and 14 ms respectively and are labeled P9, P11, P13 and P14 according to the
52 polarity-latency nomenclature. There is some interindividual variation in the waveform of the two latest Pl3 and P14 potentials since either the Pl3 or P14 peaks can predominate. The amplitude of these farfield positive potentials is not affected when the stimulation rate is increased up to 50 Hz (Ibanez et al., 1989). Due to their widespread distribution on the scalp, far-field positive SEPs must be recorded with a noncephalic reference electrode. The best location for the active electrode is the medio-frontal region; however, when only a limited number of channels is available, it is recommended to place the active electrode in the parietal region contralateral to stimulation in order to record also the early parietal SEPs. The P9 potential is picked up at the neck as well as on the scalp. It reflects the afferent volley in the trunks of the brachial plexus in axilla and supra-clavicular fossa (Cracco and Cracco, 1976; Nakanishi et al., 1983). Its peaking latency varies with arm length and its onset latency, but not its peaking latency, is influenced by the respective positions of and trunk (Desmedt et al., 1983). The P11 potential reflects the ascending volley in the fibers of dorsal columns at the cervical level. Desmedt and Cheron (l980a) first reported that, after median nerve stimulation at the wrist, the P11 potential begins in synchrony with the cervical NIl potential at the Cv6 level, which is close to the dorsal root entry zone in the cervical cord. The P11 potential is not recorded in about 20% of normal controls and, thus the clinical significance of its absence in patients is questionable. Conversely its persistence when later scalp components are abnormal is a reliable indicator of preserved dorsal column function in patients with lesions located in the medulla oblongata or at the cervico-medullary junction. The P13-P14 far-field potentials are consistently recorded in normal subjects (see Restuccia, 2000, for a recent review). Both may be of similar amplitude, or either of them may be the larger of the two. In some subjects P14 is hardly visible as a notch on the ascending phase of Pl3, in others Pl3 and P14 cannot be differentiated. In the same individual the morphology of the Pl3-P14 complex can display some degree of side-to-side difference, which creates difficulties for interpreting left-right asymmetries in patients. P14, but not Pl3, always peaks
F. MAUGUIERE
later than the cervical segmental Nl3 potential (Mauguiere, 1987). Since the Pl3-P14 complex is picked up at the earlobe with a lesser amplitude than in the frontal region of the scalp, it can be recorded with a scalp-earlobe montage (Nakanishi et al., 1978). The P13-P14 complex is the only scalp far-field SEP which is reduced by interfering stimulations, such as vibrations, applied to the hand on the stimulated side (Ibanez et al., 1989). This suggests that it is generated after the synaptic relay in the nucleus cuneatus (NC). Patients with thalamic lesions usually show a normal P14 suggesting that this component originates at sub-thalamic level (Nakanishi et al., 1978; Anziska and Cracco, 1980; Mauguiere et al., 1982). Conversely in cervicomedullary lesions (Mauguiere et al., 1983b; Mauguiere and Ibanez, 1985; Yamada et al., 1986) or in brain-dead patients (Buchner et al., 1988) the P14 potential is absent. These findings suggest that the generator of P14 is situated above the level of the foramen magnum. Simultaneous scalp and naso-pharyngea1 SEP recording in deeply comatose and brain-dead patients brought some information concerning the origins of the P14 potential (Wagner, 1991). In patients with signs of upper brainstem dysfunction this author observed that the P14 recorded between scalp and naso-pharynx is lost while an earlier P13 positivity persists in scalp to shoulder traces. This observation suggests that the P14 recorded between the scalp and the naso-pharynx reflects the activity of medial lemniscus pathways at the upper part of the brainstem whereas the P13 might be generated at the cervico-medullary junction. A normal Pl3 coexisting with an abnormal P14 has been observed in patients with pontine or mesencephalic lesions (Nakanishi et al., 1983; Delestre et al., 1986; Kaji and Sumner, 1987; Mavroudakis et al., 1993), supporting the hypothesis that Pl3 and P14 potentials could be generated at different anatomical levels in the cervico-medullary and brainstem somatosensory pathways. This view is reinforced by the observation, in non-cephalic reference recordings, that the P13 positivity recorded at the naso-pharynx can be preserved while the scalp P14 is abnormal in lesions of the lower brainstem (Restuccia et al., 1995). The scalp and naso-pharynx Pl3 potential is different from the segmental spinal Pl3 recorded at the anterior aspect of the neck (see above). In spite
SOMATOSENSORY EVOKED RESPONSES
of their similar latencies and polarities, these two components have different distributions and origins and the segmental spinal Pl3 is preserved in all patients with upper cervical or cervico-medullary lesions. Thus, to our present knowledge the most probable generators of the P13-P14 potentials are: (i) the ascending volley in upper cervical DC fibers at the cervico-medullary junction or in medial lemniscus fibers in the brainstem; (ii) the post-synaptic response of NC neurons; (iii) junctional stationary potentials related with the moving action potential volley across the border between neck and posterior fossa (Kimura et al., 1983, 1984). For sake of clarity the P13-P14 complex is often labeled as "P14." It can be useful to calculate the P91 P14 amplitude ratio in patients. As the IIV amplitude ratio of Brainstem Auditory EPs the P9/P14 ratio compares the amplitude of a peripheral potential (P9) with that of a brainstem potential (PI4). In normal subjects the P9/P14 ratio is less than 1 when recorded with a broad band-pass of 1.6 to 3200 Hz, and its distribution has a Gaussian profile (GarcfaLarrea and Mauguiere, 1988). 5.2.1.6. The N18 scalp potential This potential identified by Desmedt and Cheron (1981b) is a long-lasting scalp negative shift that immediately follows P14 in non-cephalic reference scalp recordings. In normal subjects N18 can only be identified in the posterior parietal region ipsilateral to the stimulation, where there is no or minimal interference with cortical potentials. The N18 is a long lasting component (about 20 ms when recorded with a 1-3000 Hz band pass). The N18 negativity may contain several sub-components considering that several wavelets are superimposed on its plateau at fixed latencies in the same individual. In normal subjects non-cephalic reference recordings of scalp SEPs show two positive cortical potentials, which are superimposed upon N18 in the central and frontal regions contralateral to stimulation, namely central P22 and frontal P20 (see below). Thus, the early portion of N18 appears as a negativity preceding the onsets of P20 and P22 in the midfrontal and central regions respectively. These frontal and central negativities have been considered as genuine cortical responses and labeled as "NI5", "NI6", "NIT' or "NI9" components (Yamada et al., 1984; Iwayama et al., 1988). However super-
53
imposition of traces recorded in the posterior parietal region ipsilateral to stimulation, where Nl8 is not contaminated by contralateral cortical components, clearly shows that there is no scalp negativity other than N18 and N20 within the first 22 ms following stimulation. When all cortical responses are eliminated by deafferentation due to a lesion of the ventro-posterolateral (VPL) thalamic nucleus (Mauguiere et al., 1983c) or by a direct lesion of the centro-parietal cortex (Mauguiere, 1987), N18 can be recorded on the whole surface of the scalp. After hemispherectomy, which entails retrograde degeneration of the thalamo-cortical neurons, the N18 potential is most often preserved (Mauguiere and Desmedt, 1989). However it can be missing, as well as the P14 potential, long after hemispherectomy including the thalamus (Restuccia et al., 1996) in relation with retrograde degeneration of the lemniscal fibers projecting on the thalamus. These observations rule out the possibility that N18 could reflect a cortical or a thalamic response to lemniscal or extra-lemniscal inputs. Since N18 is absent, or grossly abnormal, in cervico-medullary lesions it is assumed that its generator is situated below the thalamus and above the foramen magnum. The earliest hypothesis, concerning the generation of N18, was that of a post-synaptic response of the brainstem nuclei connected with the dorsal column (DC) nuclei to ascending inputs conveyed by ancillary fibers of the medial lemniscus. This hypothesis has been supported by intra cerebral SEP recordings in man showing a stationary negativity between the upper pons and the midbrain, peaking at the same latency as the scalp N18 (Urasaki et al., 1990). However naso-pharyngeal recordings (Tomberg et al., 1991) rather suggested an N18 origin in the medulla oblongata and, more precisely in the nucleus cuneatus (NC). Potentials recorded dorsal and ventral to NC in humans (Morioka et al., 1991) show a biphasic waveform, which is very similar to that of NC responses to peripheral nerve stimulation in cats. The first phase of this response in cats represents the post-synaptic potential of NC relay neurons to the DC afferent volley, while the second one reflects the pre-synaptic inhibition of DC fibers terminals in NC (Andersen et al., 1964). This inhibition consists in a feedback depolarization of DC terminals, triggered by the afferent volley in DC fibers collaterals, and mediated by NC inter-neurons.
54
To date it is accepted that N18 reflects a similar phenomenon in the human brainstem (see Sonoo, 2000, for a review). Several arguments lend substance to this analogy: (i) The distribution and polarity are similar in cat and human recordings; (ii) The pre-synaptic inhibition of DC terminals in cats, like the human N18, lasts for several tens of milliseconds, probably because it is mediated via a poly-synaptic chain of inter-neurons; and (iii) The N18 voltage is unaffected by interfering vibrations applied on the hand on the stimulated side (Manzano et al., 1998), contrary to the P14 potential, which is attenuated (Ibanez et al., 1989); this finding fits with the inference that N18 reflects inhibitory activity upon DC terminals. 5.2.2. Early cortical potentials
These cortical SEPs are peaking in the 18-35 ms latency range and are all obtained with optimal voltage in response to stimuli delivered at a slow rate (less than 2 per second). They are recorded on the scalp in the parietal region contralateral to stimulation and in a large fronto-central area, mostly contralateral to stimulation. Though studies in normal subjects and patients converge on the conclusion that responses recorded in the parietal region originate in the somatosensory area SI, there is still some controversy as to whether some of the early cortical SEPs recorded in the frontal region might be generated in the precentral cortex. 5.2.2.1. The N20-P20 and P22 potentials Two sets of early cortical potentials are consistently recorded in normal subjects on the scalp contralateral to stimulation. The first one is made of a parietal N20 and frontal P20 dipolar field; the second is composed of a central P22 positive potential. These components are also present after finger stimulation with a latency delay of 2-3 ms, as compared with median nerve SEPs, because of finger to wrist conduction time. There is a consensus to consider that parietal N20 and frontal P20 potentials represent the earliest cortical potential elicited by median nerve stimulation and reflect the activity of a dipolar generator in Brodmann's area 3b, tangent to scalp surface and situated in the posterior bank of the rolandic fissure (Broughton, 1969; Goff et al., 1977; Allison et al., 1980). This dipolar field distribution is also observed in magnetic recordings.
F. MAUGUIERE
On scalp and some direct cortical recordings a P22 recorded in the central region was found to peak 1-2 ms later than the N20-P20 potentials (Desmedt and Cheron, 1980b, 1981b; Papakostopoulos and Crow, 1980). This has been taken as an argument to consider P22 as a genuine component generated by a source distinct from that of N20-P20 (Desmedt and Cheron, 1981b), while others denied the existence of an independent P22 (Allison, 1982). Sequential spatial maps of scalp recorded SEPs have shown that the N20-P20 dipolar field is followed in the central region contralateral to stimulation by a positive P22 field peaking 1.0-2.5 ms with little or no negative counterpart on the scalp (Deiber et al., 1986). This spatial distribution of P22 suggests that its source is radial to the scalp surface. Most studies of somatosensory evoked magnetic fields (SEFs) failed to confirm such a source in the central region probably because magnetic recordings are blind to magnetic fields produced by dipolar sources radial to scalp surface (Brenner et al., 1978; Okada et al., 1984; Wood et al., 1985). The question whether the radial source of the central P22 is located behind the central sulcus, in the primary somato-sensory area, or in front of it, in the primary motor area, is not easy to address by scalp recordings in normal subjects, even when assisted by dipole modeling techniques based on a spherical head-model (Franssen et al., 1992; Buchner et al., 1995). One argument in favor of a pre-central origin of the P22 potential is that it may be selectively lost in patients with hemispheric lesions who have normal sensations but signs of upper motor neuron dysfunction, and selectively preserved in patients with hemianesthesia or astereognosis and no motor deficit (Mauguiere et al., 1983a; Slimp et al., 1986; Tsuji et al., 1988; Mauguiere and Desmedt, 1991). However, some direct cortical recordings in monkeys and humans failed to identify a P22 in the precentral cortex (Allison et al., 1989, 1991; McCarthy et al., 1991) but individualized a surface positive potential that they labeled as P25, with a source radial to the scalp surface and located at the posterior edge of the rolandic fissure in Brodmann's area 1. Dipole modeling studies of SEPs using realistic head models and constraining the solution in the individual brain MRI volume supported the view that the P22 source is located at the crown of the post-central gyrus (Buchner et al., 1996). These data from
SOMATOSENSORY EVOKED RESPONSES
cortical recordings and modeling of scalp responses are challenged by other experimental data in monkeys; (i) short-latency unit response to finger stimulation has been recorded in the motor cortex (Lemon, 1981; Tanji and Wise, 1981); and (ii) an early median nerve potential has been recorded in the motor cortex (Brodmann's area 4) as well as in area 1 (Nicholson-Peterson et aI., 1995). According to the data of Nicholson-Peterson et al. (1995), the earliest cortical responses to upper limb stimulation are likely to result from the approximately coincident activation of at least three dipolar sources in areas 3b, 4 and 1 with orientations both opposing and orthogonal to each other. Sources in area 3b and 4 have opposite orientations tangent to the scalp surface, while the source located in area 1, at the crown of the post-central gyrus, is oriented radial to the scalp surface. Thus, even if it would be hazardous to imagine a strict homology between SEP components in monkey and man, due to the considerable anatomical differences between the two species, these experimental data support the contribution of the motor cortex to the N20-P20 and P22 scalp potentials. 5.2.2.2. The parietal P24 and P27 potentials These potentials are recorded in the parietal region contralateral to stimulation, their peaking latencies show large inter-individual variations between 24 and 27 ms. In some subjects two distinct P24 and P27 can be identified while only either of the two peaks is observed in others. This explains why, according to the polarity-latency nomenclature, the first parietal positive potential following N20 has received various labels in literature (P24, P25 or P27). These variations reflect the fact that the activities of several parietal sources overlap in time in this latency range. The P27 potential was found to be abnormal in patients with focal lesions of the parietal cortex, presenting with a astereognosis and normal N30 frontal responses (Mauguiere et aI., 1982; Mauguiere and Desmedt 1983a). No abnormality of these potentials has been specifically related to movement disorders, except their exaggeration in cortical myoclonus (see below). 5.2.2.3. Thefrontal "N30" potential (N24-N30 complex) The frontal potential, labeled as "N30" in most clinical studies, is picked up in the frontal region
55
contralateral to stimulation, however it often spreads to the mid-frontal region and to the frontal region ipsilateral to stimulus. Its waveform show two distinct components of which the earlier one, peaking at about 24 ms (N24), appears as notch on the ascending slope of the later one, which peaks at 30 ms (N30) and has the larger voltage of the two in normal young adults. There is presently some consensus on the conclusions that the frontal negativity with its two N24 and N30 peaks cannot be generated by a single source (Delberghe et aI., 1990; Garcia-Larrea et aI., 1992; Osaki et aI., 1996), and that the early part (N24) of the frontal negativity corresponds to the polarity reversal of a parietal P24 potential across the central sulcus. The latter statement is supported by several observations issued from intra-cranial and scalp recordings: (1) In the latency range of the scalp "N30" Allison et al. (1989), using intra-cranial recordings during surgery, have identified a dipolar field, frontal negative and parietal positive, and considered it as generated by a source in area 3b, tangent to the scalp surface. Probably because of anesthesia this field reached its maximum at 30 ms and was labeled N30-P30 by these authors. (2) On the scalp the field distribution is clearly dipolar at the peaking latency of the N24 with a parietal positivity and a mid-frontal negativity spreading to the fronto-central region. This dipolar potential field has been labeled N24-P24 (Garcia-Larrea et aI., 1992) or N27-P27 (Osaki et aI., 1996), it corresponds to the N30-P30 of Allison et al. (1989) and its distribution fits well with a dipolar source perpendicular to the rolandic fissure and tangent to the scalp. (3) The two negative frontal N24 and N30 components react differently to changes in stimulus rate (Delberghe et aI., 1990; Garcia-Larrea et aI., 1992; Valeriani et aI., 1998a). The early N24 remains unaffected if the stimulus frequency is increased up to 10Hz, while the later N30 decreases at stimulus rates higher than 1 per second and is virtually absent at 10 per second. (4) Source modeling studies of scalp responses converge to the conclusion that the distribution of the scalp N24-P24 can be explained by a single source in the posterior bank of the central
56
sulcus (Buchner et aI., 1995; Valeriani et aI., 1998b). (5) The administration of tiagabine, which enhances GABA inhibition, increases selectively the voltage of the N24-P24 dipolar field suggesting that it could reflect the repolarization of the neuronal population that produces the N20-P20 field in area 3b (Restuccia et aI., 2002). Conversely the origin of the main N30 negativity of the frontal N24-N30 is still a debated issue. Since it has been argued that N30 might reflect the pre-motor cortex participation in the long loop of trans-cortical reflexes, this question is of importance regarding the potential use of SEPs in movement disorders. Three early observations have supported the hypothesis that, contrary to the N241P24 dipolar field, N30 does not represent the frontal counterpart of the parietal P27: (1) N30 amplitude decreases with ageing whilst that
of P27 increases (Desmedt and Cheron, 1980b). (2) N30 can be selectively absent, or decreased, with preserved parietal P27 in focal hemispheric lesions causing pure motor symptoms with normal sensation (Mauguiere et aI., 1983a; Mauguiere and Ibanez, 1990). (3) N30 was found to be selectively reduced in Parkinson's disease with a decrease of the N30/ P27 amplitude ratio (see below). Based on these findings it has been proposed that the N30 and P27 potentials originate in the pre-central cortex and in SI (Brodmann's area I), respectively; each of these two dipolar sources being oriented perpendicular to the scalp surface. Some observations (see Cheron et aI., 2000, for a review) are compatible with the view that the N30 potential could be related with motor programming and generated in the pre-motor cortex of area 6, and more precisely in the supplementary motor area (SMA): (1) N30 was reported to be absent in a patient with a falx meningioma compressing the inner aspect of the pre-central frontal cortex (Rossini et aI., 1989). (2) Voluntary movements of the fingers on the stimulated side was shown to exert a gating effect on frontal SEPs by reducing selectively
F. MAUGUIERE
the amplitude of N30, without effect on parietal potentials (Cohen and Starr, 1985; Cheron and Borenstein, 1987, 1991; Rossini et aI., 1989; Rossi et aI., 2002). This effect, which had been observed and to a certain extent overviewed by Papakostopoulos et aI. in 1975, is less for simple than for complex fingers movements. Two mechanisms have been proposed to explain this selective gating of frontal SEPs by active movement. First, cortical motor neurons involved in fingers movements could also account for part of the frontal SEPs and would be unable to respond simultaneously to the afferent volley triggered by the electric stimulation. The second mechanism is that of a cortico-cortical inhibition by which the motor neurons active during movements would suppress the response of cortical neurons involved in the generation of the N30 potential. (3) A gating of N30, but also of N24, occurs during movement preparation in reaction time paradigms where SEPs are recorded before movement onset (Shimazu et aI., 1999). (4) The gating of N30 does not require that the intended movement be executed (Fig. 2) and also occurs when the subject mentally simulates a complex sequence of finger movements on the stimulated side (Cheron and Borenstein, 1992; Rossini et aI., 1996). When the same mental movement simulation (MMS) concerns the nonstimulated hand, or when the subject performs a mental task other than motor simulation, this gating effect does not occur. It has been known for long that this MMS task selectively increases the cerebral blood flow in the SMA (Roland et aI., 1980); this observation has been considered as indirect evidence that SMA might be the generator of the N30 potential. (5) The N30 potential, as well as the homologue M30 magnetic field, is enhanced when subject observes repetitive grasping movements or complex sequences of fingers movements performed by an examiner during stimulation. This effect is independent of the complexity of the observed movements; it has been interpreted as reflecting storage of subject's somatosensory information connected with the observed movements (Rossi et aI., 2002), and related to the SMA activation observed in PET studies when subjects observe meaningful actions (Grezes et aI., 1998).
SOMATOSENSORY EVOKED RESPONSES
.....J
~ z
o
0:::
LL
Fig. 2. Gating of frontal SEPs during mental movement simulation (MMS). These responses were obtained in two distinct normal subjects (right and left traces) before (A, D, G, J), during (B, E, H, K) and after (C, F, I, L) mental simulation of movement. The dotted areas indicate the N30 potential surface above the baseline. Note that the N24 frontal potential, labeled N23 by the authors, and the parietal responses are not affected by mental imagery of movement. (From Cheron and Borenstein, 1992, with permission.) However, if there is little doubt that the N30 amplitude is linked to motor programming, its origin in the SMA is challenged by data from direct cortical recordings, which favor an N30 dipolar source radial to the scalp surface, located in Brodmann's area 1 of the SI cortex, (Allison et al., 1989, 1991), and do not show a N30 potential in this area (Barba et aI., 2001). Moreover, after subtraction of the N24-P24 field, the maximum of the remaining scalp N30 field has the same location as that of the P22 potential in the central region (Osaki et aI., 1996). This suggests
57
that the N30 potential is generated close to the central sulcus and not in the pre-motor cortex, a view supported by most of the source modeling studies of early SEPs (Valeriani et aI., 2000). Lastly, functional magnetic resonance imaging studies have shown that all of cortical areas involved in actual movements, and not only the SMA, are activated during mental simulation of movements (Stephan et aI., 1995). To date the hypothesis that N30 could be generated in the primary motor area has not been ruled out by direct recordings, or source modeling, of SEPs or SEFs. Conversely recent source modeling studies rather supported this hypothesis (Waberski et aI., 1999). The movement related gating of N30 could therefore reflect a similar change in motor cortex excitability both during movement and mental motor imagery. Studies using transcranial magnetic stimulation (TMS) converge to the conclusion that the excitability of the motor cortex is increased during actual movement and mental movement simulation (Ridding et aI., 1995; Kasai et aI., 1997), so that N30 amplitude would reflect the level of motor cortex inhibition. However, the fact that N30 and motor cortex inhibition are decreased during movement and motor imagery does not imply that the underlying mechanisms are the same in the two conditions. A recent TMS study by Ridding and Rothwell (1999) suggests that, in spite of a similar effect of movement and motor imagery on N30 amplitude, activity in the circuits responsible for GABAergic inhibition of the motor cortex is reduced during voluntary contraction while motor imagery, which activates similar brain regions as overt movement but does not result in afferent input, does not produce significant changes in intracortical inhibition. 5.3. Short latency SEPs to lower limb stimulation (electric stimulation of tibial, sural and peroneal nerves) Electrical stimulation of the tibial nerve at the ankle is adopted by most authors for the testing of the sensory pathways of the lower limb. However the electrical stimulation can also be applied to the sural nerve at the ankle, or to the peroneal nerve at the knee without major changes in the general waveform of the spinal or scalp responses. As compared with tibial nerve SEPs only the peaking latencies are modified; they are delayed by about 3 ms, or
58
F. MAUGUrERE
shortened by about 5-6 ms, respectively for sural and peroneal nerve stimulation. In what follows tibial nerve SEPs will be taken as the reference for describing the normal waveforms (Fig. 3). 5.3.1. Peripheral, spinal and subcortical potentials
5.3.1.1. The N7 potential A compound action potential corresponding to the activation of tibial nerve fibers is recorded at the posterior aspect of the knee using a bipolar montage. The latency of this near-field potential is of about 7 ms in adults and varies with the length of the lower limb. N7 reflects a mixed response of motor and sensory fibers, which is clinically useful to assess the function of the peripheral segment of the pathway. The afferent volley in cauda equina roots can be recorded using skin electrodes placed at the L5-Sl level and a distant reference site, for instance at the knee opposite to the stimulation. 5.3.1.2. The spinal potentials A montage between an electrode situated on the spinal process of TI2 or Ll vertebrae and distal reference electrode records a spinal negative potential peaking at 21-24 ms in normal subjects. According to different authors this segmental
response has been labeled N20 (Tsuji et aI., 1984), N2l (Small and Matthews, 1984), N22 (Lastimosa et al., 1982; Riffel et aI., 1984), N23 (Yamada et al., 1982) or N24 (Desmedt and Cheron, 1983). These differences in nomenclature are mostly due to differences in the mean body height of the subjects sampled for normative studies, In what follows this response will be labeled N22. After tibial nerve stimulation the lumbar N22 originates mostly from the spinal segment receiving fibers from the S1 root (Delbeke et aI., 1978; Dimitrijevic et aI., 1978; Jones and Small, 1978; Lastimosa et aI., 1982; Desmedt and Cheron, 1983; Small and Matthews, 1984; Tsuji et al., 1984; Delwaide et aI., 1985). As all segmental dorsal hom responses (see Dimitrijevic and Halter, 1995, for a review) the N22 potential demonstrates a polarity reversal when recorded anterior to the cord, a field distribution consistent with a horizontal dipolar source reflecting the postsynaptic response of dorsal hom neurons to incoming inputs. In direct spinal cord and roots recordings the N22 amplitude is maximal close to the entry zone of the S1 root in cord surface recordings and decreases steeply without any latency shift at more rostral or caudal electrode sites (Jeanmonod et aI., 1991). The N22 potential is followed by a slow positivity, known as the "P" wave, which reverses into a negativity when recorded at the anterior aspect of the cord (Shimoji et al., 1977; Jeanmonod et al., 1989) and may reflect
Left Tibial nerve
Cz'-A2
P39!f\ Pro JW~ ~
:>
so
P~O
Fpz-Cv6 N37
Ll-Abd '--=----' l"22
Po. F
100 ms
Fig. 3. Normal tibial nerve SEPs (see text for description).
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SOMATOSENSORY EVOKED RESPONSES
the processes of pre-synaptic inhibition affecting the primary afferent fibers in the dorsal hom. In peroperative direct recording of the cord, several fast negativities are superimposed to the ascending slope of the N22, which reflect the action potentials ascending in the dorsal columns. In most skin surface recordings these negativities cannot be individualized. When the reference electrode is not situated on the axis of propagation of the peripheral ascending volley, the N22 potential is preceded by a small positivity peaking around 17 ms. This P17 potential is a far-field potential originating in lumbo-sacral plexus trunks, which can also be recorded occasionally on the scalp when the reference electrode is placed at the knee (or iliac crest) on the nonstimulated side (Yamada et al., 1982; Desmedt and Cheron, 1983).
5.3.1.3. The scalp far-field P30 potential With appropriate non-cephalic reference montages widespread far-field potentials, other than the P17 described above, can be recorded on the scalp which peak before the onset of the earliest cortical potential in the 25-32 ms latency range (Yamada et al., 1982; Desmedt and Cheron, 1983; Kakigi and Shibasaki, 1983). Only the latest of these potentials, identified by Yamada et al. (1982) as "P31", is consistently recorded in normal subjects after tibial nerve stimulation at the ankle. This observation was confirmed by several investigators who labeled this potential as P28 (Chiappa and Ropper, 1982; Kakigi et aI., 1982), P30 (Vera et al., 1983; Desmedt and Bourguet, 1985; Guerit and Opsomer, 1991; Urasaki et aI., 1993) or P31 (Desmedt and Cheron, 1983; Seyal et al., 1983). The latency of this potential varies according to body height, and will be labeled P30 in this chapter, according to the author's normative data. The utility of the P30 potential has been validated for clinical applications of tibial SEPs in patients with spinal cord and brainstern lesions (Tinazzi and Mauguiere, 1995; Tinazzi et aI., 1996b). The P30 potential is widely distributed on the scalp but predominates in the frontal region (Desmedt and Bourguet, 1985; Guerit and Opsomer, 1991, therefore it is drastically reduced in scalpreference recordings (Seyal et aI., 1983). When recorded with electrodes located in the fourth ventricle during surgery, this potential shows the same intra-cranial spatio-temporal distribution as the
Pl4 component of median nerve SEPs (Urasaki et aI., 1993). Therefore the P30 potential is likely to be generated in the lower brainstem (Yamada et al., 1982; Desmedt and Cheron, 1983) and can be viewed as the homologue, for the lower limb, of the far-field P14 recorded on the scalp after median nerve stimulation. Recording of P30 is made easier if the scalp electrode is placed in the mid-frontal region at Fz or Fpz, where P30 has its maximal amplitude with minimal contamination by subsequent cortical potentials. The most practical reference site for recording of P30 is the spinous process of the 6th cervical vertebra (Seyal et al., 1983; Tinazzi and Mauguiere, 1995). Since no segmental response is evoked by lower limb stimulation at the cervical cord level, the neck can be considered as virtually inactive at the peaking latency of P30. The ascending volley in spinal somatosensory pathways reaches the cervical level at a latency of about 27 ms but, due to the time dispersion of afferent impulses, there is no consistent potential recorded by a skin cervical electrode at this latency. In some normal subjects a scalp far-field P27 potential distinct from P30 can be recorded in the frontal region, which reflects the ascending volley in the cervical cord (Yamada et aI., 1982; Desmedt and Cheron, 1983).
5.3.1.4. The N33 scalp potential In non-cephalic reference recordings a small N33 negativity (Desmedt and Bourguet, 1985; Guerit and Opsomer, 1991) may precede the P39 potential. This negativity is widely distributed over the scalp; part of it is also picked at the earlobe so that it is drastically reduced in ear lobe reference recordings. Because some of the cortical potentials are picked up at the earlobe contralateral to stimulation, it is preferable to use the earlobe ipsilateral to stimulation as reference site for the recording of cortical tibial nerve SEPs (Tinazzi et aI., 1997a). N33 is considered as the homologue of the N18 upper limb SEP and is likely to have the same origin in the brainstem (see above). 5.3.2. Early cortical potentials 5.3.2.1. The P39 potential The earliest cortical potential elicited by the stimulation of tibial nerve at the ankle is a positive
60 potential usually labeled P37, P39, or P40 for it peaks at a mean latency of 37-40 ms in normal subjects. In what follows this potential will be labeled as P39. This potential peaks 6 to 7 ms earlier after stimulation of the tibial nerve at the popliteal fossa, and about 3 ms later after stimulation of the sural nerve at the ankle. In normal subjects P39 is recorded on the vertex and can be reliably obtained at midway between Pz and Cz using a scalp to earlobe montage (see Yamada et al., 2000, for a recent review). Frequently the maximum of P39, although close to the midline, is slightly shifted on the side of the scalp ipsilateral to the stimulation (Cruse et al., 1982). The reason for this paradoxicallateralization, documented by source modeling of SEPs (Baumgartner et al., 1998), is that the somatotopic representation of the lower limb in the somatosensory SI, and in particular that of the foot, is situated at the inner aspect of the hemisphere. This paradoxical scalp distribution of P39 is not observed when the proximal leg is stimulated for instance: after stimulation of the femoral nerve or lateral femoral cutaneous nerve (Wang et al., 1989; Yamada et al., 1996). SEP mapping in normal subjects often shows a dipolar field distribution for P39, with a maximum of positivity ipsilateral to the stimulation in the parietal region and a maximum of negativity (N39) in the contralateral fronto-central region (Cruse et al., 1982; Seyal et al., 1983; Desmedt and Bourget, 1985; Kakigi and Jones, 1986; Tinazzi et al., 1996a). Magnetic fields evoked by stimulation of the lower limb also show this type of distribution (Hari et al., 1984; Huttunen et al., 1987). The negative N39 maximum of this dipole is not consistently obtained, probably because of differences between subjects in the orientation of the leg area in SI with respect to the scalp surface, so that all intermediates are possible between a vertical radial dipole with a positive maximum on the vertex, and a nearly tangential one with a P39 and N39 culminating respectively in the ipsi- and contralateral parietal regions. As for median nerve SEPs the question is still debated whether all of these potentials reflect the activity of the lower limb area in SI, or whether some could be generated in other cortical areas. Another question is to determine whether the P39N39 dipolar field has a single source in SI tangent to the scalp (Tsumoto et al., 1972; Cruse et al., 1982;
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Seyal et al., 1983; Kakigi and Jones, 1986; Kakigi and Shibasaki, 1992), or several (Vas et al., 1981; Desmedt and Bourguet, 1985; Pelosi et al., 1988). Recent studies have rather favored the latter hypothesis by showing that: (1) N39 and P39 can show some difference in their respective latencies, the former peaking earlier than the latter, this explains why some authors have proposed to label these potentials N37 and P40, respectively (Yamada et al., 2000). (2) P39 is selectively reduced with preserved N39 in patients with motor neuron disease (Zannette et al., 1996). (3) P39 is reduced at high stimulation rates (Chiappa and Ropper, 1982; Chiappa, 1990), while the frontal N39 amplitude remains unaffected at stimulus rates up to 7.5 Hz (Tinazzi et al., 1996a). (4) Recent source modeling studies of scalp responses (Baumgartner et al., 1998) and direct intra-cerebral recordings (Valeriani et al., 2001) have suggested that two sources located in the central region are quasi-simultaneously involved in the generation of the N39-P39 field on scalp surface. One is indeed tangential to scalp surface and responsible for a dipolar field with a positive maximum in the centro-parietal region ipsilateral to stimulus, and a negative maximum in the fronto-temporal region contralateral to stimulus. The other is perpendicular to scalp surface and responsible for part of the vertex P39 potential. Recent studies of the effects of movement on cortical tibial SEPs (Fig. 4) have shown that P39, but not N39, is gated during voluntary movement of the stimulated foot (Tinazzi et al., 1997b; Valeriani et al., 1998b, 2001). During tonic contraction this effect is proportional to the level of muscle strength maintained by the subjects. These findings have been interpreted in different ways according to the different source models. Tinazzi et al. (1998) proposed that P39 could be generated in the motor cortex, while N39 could be the equivalent of the median nerve N20 and generated in area 3b in the SI area. Valeriani et al. (1998b, 2001) considered that only the radial central source of the vertex P39, possibly located rostral to the central sulcus, is sensitive to voluntary movements.
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SOMATOSENSORY EVOKED RESPONSES
with distinct orientations (Desmedt and Bourguet, 1985; Guerit and Opsomer, 1991»However, there is no clinical study demonstrating that N5Qor P60 can be selectively affected by a single focal lesion, and these two potentials show the same attenuation as P39 during active movement (Tinazzi et aI., 1997b). 5.4. Abnormal SEPs in central motor deficits and movement disorders 5.4.1. Motor deficits related with hemispheric lesions
Fig. 4. Gating of tibial nerve SEPs during movement. (Grand average waveforms in 10 normal subjects.) The vertex P37 ipsilateral to stimulus (right traces) and the contralateral frontal N37 (left traces) correspond to the P39 and N39 potentials described in the text, respectively. Note that the gating of the P37 is observed only during active isometric contraction or active movement of the foot on the stimulation side. Conversely movement of the foot contralateral to stimulus and passive foot movement on the stimulated side do not affect the P37 potential. No change in N37 potential amplitude is observed in any of the experimental conditions. (From Tinazzi et aI., I997b, modified, with permission.)
5.3.2.2. The N50 and P60 potentials The "W" profile of the cortical response recorded on the vertex and in the centro-parietal region is made of three sequential responses P39, N50 and P60. This waveform has been reported in all studies of tibial nerve SEPs (see Tinazzi et aI., 1997a, for a recent review). Electrical stimulation of the L5 and S1 dermatomes also evokes a consistent, W-shaped response on the scalp (Katifi and Sedgwick, 1986). The N50 and P60 potentials culminate at the vertex (Cz) and do not show the same clear dipolar distribution as the P39-N39 response on the scalp, thus suggesting that the W shaped P39-N50-P60 waveform could be generated by several sources
In our series of 241 patients with a focal hemispheric lesion documented by neuroimaging (Mauguiere and Ibanez, 1990), SEPs to median nerve stimulation were abnormal in more than 70% of capsulo-thalamic and in nearly 90% of posterior thalamic lesions. After stimulation of the affected side amplitude reduction or absence of both parietal N20-P27 and frontal P22-N30 potentials with preserved scalp far-field potentials, including P14 and N18, represent the most frequent SEP abnormalities in thalamic or capsular lesions interrupting the somatosensory pathways (Nakanishi et aI., 1978; Mauguiere et aI., 1982, 1983c; Stohr et aI., 1983; Graff-Radford et aI., 1985; Yamada et al., 1985; Mauguiere and Ibanez, 1990). In large cortical lesions involving the central and parietal areas SEP abnormalities are very similar to those encountered in posterior thalamic lesions. When pooling all patients (n= 109) with cortical lesions of our series, there was globally a highly significant correlation between abnormal SEPs and the presence of sensory and/or motor deficits. Astereognosis of the hand opposite to the cortical lesion, eventually combined to hypesthesia for some elementary sensory modalities, was consistently associated with abnormal N20 and/or P27 abnormality (Mauguiere et al., 1983a). Conversely precentral lesions eliminating specifically the P22 and N30 potentials were usually associated to central hemiparesis or hemiplegia. Similarly patients with a selective loss of frontal P22-N30 SEPs in relation with a sub-cortical lesion present with various types of motor deficits including; hemiplegia, ataxic hemiparesis and motor neglect. However hemiparesis, or hemiplegia, can be associated with preserved frontal P22 and N30 potentials in sub-cortical lesions interrupting selectively the efferent motor pathways.
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Less than 10% of patients with focal hemispheric lesions present with dissociated abnormalities of frontal and parietal early cortical SEPs showing either reduced or absent N20-P27 with preserved P22-N30, or the reverse (Mauguiere and Ibanez, 1990). 5.4.2. Myoclonus
Since the first description by Dawson in 1947, it has been known that giant SEPs can occur in association with the cortical reflex myoclonus observed in progressive myoclonic epilepsies (PME) and with focal motor seizures in lesions of the peri-rolandic area (Dawson, 1947; Shibasaki and Kuroiva, 1975; Mauguiere and Courjon, 1980; Rothwell et al., 1984; Obeso et al., 1985; Shibasaki et al., 1985a, b; Kakigi and Shibasaki, 1987; Seyal, 1991; Ikeda et al., 1995; Valeriani et al., 1997a, b). The giant SEP in PME was first described as a "P25-N33" complex by Shibasaki and Kuroiwa (1975), the amplitude of which, when measured from peak to peak, can reach 50 f.LV or more and is usually of more than 15 f.L V. Giant SEPs show a large degree of inter- and intra-individual variation, nevertheless most of PME patients with cortical myoclonus show a parietal positive and frontal negative dipolar field peaking at about 25 ms contralateral to median nerve stimulation. Jerklocked back averaging the EEG prior to the myoclonus shows that spontaneous myoclonus can be associated with an abnormal cortical spike in some patients with cortical myoclonus (Shibasaki and Kuroiwa, 1975). The interval between the peak of the back-averaged cortical spike and the onset of the myoclonus is in the order of 20 ms in the arm, consistent with rapid conduction from motor cortex to muscle down to a direct cortico-spinal pathway. This observation suggests that giant SEPs and myoclonus-related spikes reflect a cortical hyperexcitability to afferent impulses which is the mechanism underlying the "pyramidal myoclonus" (Halliday, 1967). When identifiable the parietal N20 potential to median nerve stimulation has normal latency and amplitude in most patients with cortical myoclonus (Mauguiere et al., 1981; Rothwell et al., 1984; Obeso et al., 1985; Shibasaki et al., 1985a). Similarly, P14 is normal in such patients (Mauguiere et al., 1981). The normal size of the N20 component
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indicates that the sensory input into the cortex as well as the primary cortical response are not grossly abnormal. It has been suggested on the basis of waveform decomposition and computerized modeling that the giant SEP results from an abnormal enhancement of certain components of the normal SEPs (Shibasaki et al., 1990). This has been confirmed by dipole modeling showing that the scalp distribution of both normal and giant SEPs can be explained by the same cortical sources and suggesting that giant SEPs mostly reflect an enhanced response of the N24-P24 generator in area 3b (Valeriani et al., 1997a). Enhanced cortical response to proprioceptive inputs can be observed in some of the PME patients with giant median nerve SEPs, in association with exaggerated EMG response to passive movements (Mima et al., 1997). Thus, cortical hyper-responses to either cutaneous inputs alone or to both cutaneous (area 3b) and proprioceptive (areas 3a or 2) inputs can occur in PME with cortical reflex myoclonus. The various combinations of these two abnormalities, in terms of amplitude, may account for the waveform variations reported in early literature on this topic. Intravenously (LV) injected benzodiazepines reduce spontaneous myoclonus and reflex muscle jerking, but their effect on giant SEPs is a matter of controversy. Both reduction (Mauguiere and Courjon, 1980; Shibasaki et al., 1985a) and paradoxical enhancement (Rothwell et al., 1984) of SEPs have been reported under the effect of benzodiazepines. Giant SEPs can be recorded in the absence of myoclonus-related spikes and vice versa. Thus, patients who apparently have similar clinical symptoms can show different SEP abnormalities (see Tassinari et al., 1998, for a review). Complete electrophysiological investigation of patients with myoclonus includes jerk-locked EEG back-averaging (Shibasaki and Kuroiwa, 1975), conventional SEP recordings to median nerve and/or finger stimulation and the recording of the long latency myogenic reflex activity (C reflex) to median nerve stimulation, which reflects the myoclonus itself. When both giant SEPs and jerk-locked spikes are absent in a patient with myoclonus, the efferent impulses generating myoclonus in response to afferent inputs is likely to be generated in subcortical reticular structures (reticular reflex myoclonus of Hallett et al., 1977).
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SOMATOSENSORY EVOKED RESPONSES
Not all of the patients with myoclonus have giant SEPs. In particular enhanced SEPs are usually not observed in benign forms of juvenile myoclonic epilepsies and in essential non-progressive isolated myoclonus. They are inconstant in CreutzfeldtJakob disease and post-hypoxic myoclonus. In the two latter conditions the existence of giant ·SEPs probably depends on the evolution stage of the disease. Conversely giant SEPs are an almost constant feature in the various forms of Progressive Myoclonic Epilepsies (PME). At the end of the evolution amplitude of SEPs may decrease and even return to normal range in PMEs (Mervaala et aI., 1984). Giant SEPs can also be observed over the damaged hemisphere in patients with supra-tentorial tumors, post-traumatic cortical atrophies or long after an ischemic or hemorrhagic stroke (Laget et al., 1967; Furlong et al., 1993; Valeriani et aI., 1997b). In these patients the enhancement of the cortical response is often less than that observed in PME patients with cortical reflex myoclonus. Loss of inhibitory control and post-lesional collateral sprouting of cortical afferents could be responsible for such SEP abnormalities. Various components of the normal cortical SEP waveform can be increased and the resulting aspect often differs from that of the giant P25-N33 observed in cortical myoclonus. A selective increase of the N20-P22 deflection strictly localized in the central region has been reported in a patient with a rolandic tumor (Valeriani et al., 1997b). The scalp topography of this abnormal response was compatible with a dipolar source radial to the scalp surface, and interpreted as an abnormal response of Brodmann's area 3a, which is known to receive proprioceptive inputs from muscle afferents. In focal lesions giant SEPs are often observed in the absence of myoclonus triggered by somatosensory stimuli, but the occurrence of focal motor seizures is frequent in the history of such patients. In some children aged 3-13 years with normal neurological status vertex and parietal EEG spikes, corresponding to high voltage SEPs (up to 400 /-LV), can be evoked by a single tactile stimulation (De Marco and Negrin, 1973). The presence of these "Extreme SEPs" might forecast the possible occurence of partial motor seizures with benign outcome (De Marco and Tassinari, 1981). Median nerve cortical SEPs in these children are usually normal up to a latency of 60 ms and then show a large central
negativity, which reaches its maximum only for low stimulation frequencies of 0.2 to 0.5 Hz (Plasmati et aI., 1989). 5.4.3. Huntington's disease Since the first study by Oepen et aI. (1981), several authors have reported abnormal early cortical N20-P27 potentials in scalp reference recordings of patients with Huntington's chorea (Bollen et aI., 1984; Ehle et aI., 1984; Noth et al., 1984). Topper et al. (1993) have shown that the frontal P22 and N30 potentials are selectively depressed in this disease. However these authors did not find any significant correlation between the severity of the movement disorder and that of the SEP abnormalities. Moreover abnormal SEPs have also been reported in clinically asymptomatic subjects at risk for the disease, as well as in symptomatic patients during sedation of the choreic movements. Thus, there is no proven link between the movement disorder and SEP abnormalities in this pathology.
5.4.4. Parkinson's disease Rossini et aI. (1989) were the first to report a reduction of the frontal N30 median nerve SEP in patients with Parkinson's disease (PD), in association with parietal SEPs of normal amplitude. These authors hypothesized that the rigidity and/or the akinesia of PD patients could be related to this SEP abnormality, which was confirmed after MPTP treatment in monkeys by the recording of the frontal N15, which is the homologue of the human N30 in monkeys (Onofrj et al., 1994). Statistical analysis of SEP topography showed that differences in temporal and power spectrum distributions of SEPs between normal subjects and PD patients are confined to frontal scalp areas (Babiloni et aI., 1994). Moreover the amplitude of the N30 potential was found to be inversely correlated with that of the second component (latency range 50-60 ms) of the long latency reflexes (LLRs) evoked by electrical stimulation of the median nerve (Rossini et aI., 1991), which are commonly increased in PD. It has also been shown by Cheron et al. (1994) that, though reduced, the N30 potential in PD shows the same amplitude decrease as in normal subjects during voluntary finger movements, and that this gating effect is not modified by apomorphine, a dopamine receptors agonist.
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There are however conflicting reports concerning attenuation of the frontal N30 potential in patients with PD. The N30 reduction was confirmed in two successive studies respectively in 69% and 71% of PD patients (Rossini et al., 1993, 1995) emphasizing the utility of evaluating the decrease of the amplitude ratio between the frontal and parietal SEPs, the latter being preserved in such patients. Conversely a reduced N30 was observed in only 32.5% of PD patients by Onofrj et al. (1995), with no clear relation between N30 amplitude and motor performances and several authors failed to confirm this N30 reduction, either when comparing PD patients with normal subjects matched for age, or when comparing the SEPs to stimulation of the most affected side with those to stimulation of the less affected side in patients with hemiparkinsonism (Huttunen and Teravainen, 1993; Mauguiere et al., 1993; Garcia et al., 1995). SEPs to median nerve stimulation have also been reported as normal in multiple system atrophy (Abbruzzese et al., 1997). Another open question is whether the amplitude of the N30 potential actually correlates with motor performances in Parkinson's disease and could be used as an objective marker of the evolution state of the disease. Motor fluctuations with "off' periods of severe parkinsonian disability alternating with "on" periods of relative mobility marked by dyskinetic involuntary movements offer the possibility to address directly this question in test-retest studies in individual patients. "On" periods can be obtained by subcutaneous (s.c) injection of apomorphine which is an agonist of D1 and D2 dopamine receptors. The effects of subcutaneous apomorphine injection on the amplitude of the frontal N30 have been studied with controversial results. Rossini et al. (1993, 1995), Cheron et al. (1994) and Stanzione et al. (1997) reported a clear-cut and selective amplitude increase of N30 in association with clinical improvement, while other authors did not observe this effect on frontal SEPs, in spite of a clear improvement of motor performances (Mauguiere et al., 1993). In line with this latter negative result, acute or chronic administration of L-DOPA and bromocriptine did not modify the SEP amplitude in PD patients, in spite of positive clinical effects in the study by Onofrj et al. (1995). Differences in the severity of the disease between patients cohorts included in these studies may account for such divergences. Pierantozzi et al. (1999) provided the most recent evidence in favor of
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a link between N30 amplitude and motor performances in PD patients treated deep brain stimulation of the internal globus pallidus or of the nucleus subthalamicus. These authors reported that during stimulation, the N30 amplitude increases in correlation with the positive effects on motor abilities, conversely after interruption of stimulation the N30 enhancement fades nearly in parallel with the clinical effects.
5.4.4.1. Dystonia Abnormal central integration of afferent somatosensory inputs is, among others, a possible causative mechanism of dystonia (Hallett, 1995). The first report on SEPs in patients with focal or generalized dystonia is that of Reilly et al. (1992). These authors reported a selective increase of the N30 potential, which could reflect hyperactivity of the striatocortical loops. However, in this study, N30 abnormalities were similar after stimulation of either the affected or unaffected side in patients with unilateral dystonia. This result has been replicated by Kanovsky et al. (1997, 1998) in patients with spasmodic tortiscollis, but a decreased N30 has also been reported in this condition (Mazzini et al., 1994) and in patients with hand dystonia (Grissom et al., 1995). More recently Tinazzi et al. (1999) reported an increase of tibial nerve P39 and N50 potentials that was unrelated to the severity of the disease and present on both sides in patients with unilateral dystonia. This finding can be interpreted as reflecting an abnormal central processing of somatosensory inputs related to increased excitability of the motor cortex and is quite coherent with the early findings of Reilly et al. (1992). This interpretation makes sense if one assumes that P39 and N50 are generated in the motor cortex, a view that is plausible (see above), and that the decreased activity in the putamen, which is the most commonly affected in secondary dystonia, increases the excitability of the motor cortex. Responses to paired interfering stimuli have been studied recently by comparing the amplitudes of SEPs to simultaneous stimulation of the median and ulnar nerve on the same side, with that of the sum of SEPs amplitudes after stimulation of each nerve, individually. In normal subjects the former are smaller than the latter for N13, P14, N20, P27 and N30 potentials, while this does not occur for the peripheral N9 potential. This gating phenomenon,
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SOMATOSENSORY EVOKED RESPONSES
which can be interpreted as reflecting a central surround inhibition of incoming volleys from neighboring territories, was found to be less efficient in dystonic patients than in normal subjects (Tinazzi et aI., 2000). This sensory overflow could playa role in the distortion of sensory and motor cortical maps of dystonic patients. Abnormal movement related gating of SEPs has been carefully investigated in patients with writer's cramp using a reaction time paradigm (Murase et aI., 2000). The main finding was that pre-movement gating of N24 and N30 frontal SEPs, usually observed in normal subjects with this paradigm is lacking, or reduced, in patients with writer's cramp (Fig. 5). This abnormality was identical in dystonic as well as in simple writer's cramp. Conversely there was no difference in SEPs gating during voluntary movements between patients and normal subjects.
These authors considered that, during movement preparation, changes in SEPs are due mainly to changes in central sensory transmission produced by the intention to move, and unrelated to a centrifugal gating produced by an efferent copy of the motor command, which is preserved in writer's cramp. Thus, dystonia could be related with some defect in a pre-motor subroutine (Kaji et aI., 1995), which includes the specification of motor commands for a forthcoming action as well as the specific setting of cortical responsiveness to afferent somatosensory inputs.
5.5. Conclusion For the past ten years there has been a revival of SEP studies in movement disorders in parallel with new concepts on motor processes, which emphasizes
Fig. 5. Pre-movement gating of frontal median nerve SEPs. Responses recorded during movement preparation are represented in thick traces and responses at rest are in thin traces. Left traces are grand average responses in 11 normal subjects. Right traces are grand average responses in 10 patients with writer's cramp. Note that the N30b corresponds to the frontal N30 potential, while the peak labeled N30a corresponds to the N24 potential described in the text. These two potentials are reduced in the pre-movement phase in normal subjects, while this gating does not occur in patients (from Murase et al., 2000, with permission.)
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the role of somatosensory information processing in the preparation and execution of movements. Most of these recent advances have no direct diagnostic application but proved useful to assess the pathophysiology of motor disorders. At the present time only a few research laboratories have developed experimental paradigms where all of the physiological parameters influencing cortical SEPs are adequately controlled. Persisting controversies concerning the source locations of cortical potentials sensitive to motor programming are another limiting factor for a routine use of SEPs in patients with motor disorders. However in clinical research, SEPs have a potential utility for monitoring the effects of medical and surgical treatments, as well as post lesion reorganization of cortical functional representations.
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Movement Disorders Handbook of Clinical Neurophysiology, Vol. I M. Hallett (Ed.) © 2003 Elsevier B.Y. All rights reserved
77 CHAPTER 6
Coherence, cortico-cortical Christian Gerloff":", Christoph Braun" and Mark Hallett" a
Cortical Physiology Research Group, Department of General Neurology, Hertie Institute for Cl~~i~'al Brain Research, and h MEG Center. Eberhard-Karls University Tlibingen, Hoppe-Seyler Strasse 3, D-72076 Tiibingen. Germany C HMCS, MNB, NINDS, National Institutes of Health, Bethesda, MD 20892, USA
6.1. Introduction Synchronization (coupling) of distant brain areas provides the basis for integration of complex information and is thus a fundamental element in the neuronal representation and control of behavior. Perceptions or actions can be represented in the brain by large numbers of distributed neurons firing in synchrony (Singer, 1994). In the visual system, this has been referred to as 'binding' (Singer and Gray, 1995). From correlated single unit discharges, the 'binding' concept has been extended to coherent oscillations of local field potentials (LFPs) (Singer, 1993) and from high-frequency (gamma) (Miltner et aI., 1999; Rodriguez et aI., 1999) to oscillatory activity in lower frequency bands (below 30 Hz; alpha, beta; (Classen et aI., 1998; Gerloff et aI., 1998; Mirna et aI., 2000a» in the surface EEG. It has been shown in laboratory animals (Bressler et aI., 1993; Singer and Gray, 1995) and in humans (Classen et aI., 1998; Miltner et aI., 1999; Rodriguez et aI., 1999) that the presence of interregionally coherent oscillations can represent relevant aspects of behavior, e.g. expectation of stimuli after associative learning, perception of faces, or coordination of motor reactions in reaction time experiments. In addition, it is thought that interregional synchronization plays an important role in any form of synaptic modulation, e.g. during learning or remodeling of neuronal representations after lesions. Disturbance of interregional coupling causes disconnection syndromes like associative object agnosia (Carlesimo et aI., 1998), left hand apraxia
* Correspondence to: Dr. Ch. Gerloff, Dept. of Neurology, University of Tiibingen, Hoppe-Seyler Strasse 3, 0-72076 Tiibingen, Germany. E-mail address:
[email protected] Tel: +497071 298 6525.
(Tanaka et aI., 1996; Marangolo et aI., 1998) or alien hand syndrome (Geschwind et aI., 1995). The clinical observations suggest that functional decoupling could be a mechanism underlying several neurological syndromes. Of note, modulation of interregional synchronization may occur in the absence of changes in mean neuronal firing rates or LFP amplitudes, and without significant alterations of other markers of regional cerebral activation (evoked potential amplitudes, local spectral power changes in EEG or MEG; regional cerebral blood flow or blood oxygenation levels in positron emission tomography or functional magnetic resonance imaging). Any mathematical model applied needs to incorporate this physiological feature. After covariance methods had been used in the context of time-averaged evoked responses in the 80s and 90s (Gevins et aI., 1987, 1989), the focus has lately shifted to methods allowing for correlation analyses in the frequency domain based on single trials. The standard approach which will be outlined in detail below is the analysis of cortico-cortical coherence. Coherence analysis has the advantage that it does not make assumptions about the phase relationship between two signals of concern. While time-domain averaging and subsequent covariance analysis requires the signals to be phase-locked to a certain event, coherence analysis in the frequency domain can determine synchronization independent of phase. Phase (tp) information, however, is also available from ordinary coherence analysis. It corresponds to the relation of imaginary (Im(x» to real part (Re(x» of the complex cross-spectrum and can be analyzed separately (in addition to coherence magnitude). Another advantage of coherence relates to the theory of frequency coding. This concept allows for a virtually unlimited number of parallel,
78
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independent encoding processes within the same neuronal assembly or inside the same distributed network in different frequency bands.
6.2. Methodology 6.2.1. The basic approach: coherence estimation
The most commonly used approach is based on discrete Fourier transforms, usually Fast Fourier Transformation (FFT). The general analytical approach can be separated in 5 steps: (1) Segmentation of raw data into epochs (2) Minimization of spectral leakage (e.g. Hamming window) (3) Computation of coherence (Coh) based on FFT (4) Computation of Task-Related (or event-related) Coherence (TRCoh or ERCoh) by comparing coherence values during a given task with coherence values during rest (for details of TRCoh and ERCoh computation see below) (5) Statistical evaluation (e.g. ANOVA) after stabilizing the variances (e.g. inverse hyperbolic tangent transformation, tanh-I) Depending on the statistical model used, steps 4 and 5 can be merged and the task dependency of coherence changes can be tested by contrast analyses, post-hoc tests or other forms of determining significance criteria (e.g. confidence intervals, statistical probability mapping based on permutation analyses as described below). The FFT approach implies that all information is collapsed within one epoch, and it is assumed that the signal is stationary within the epoch. For nonoverlapping epochs, the length (1) of the epoch is the temporal resolution (Res(t)=T [s]). If T is in seconds, the frequency resolution Res(F) =liT (Hz). For facilitation of statistical analysis, it is recommended to use non-overlapping epochs. However, if higher temporal resolution is attempted, overlapping (sliding) windows can be used. The use of overlapping windows increases the risk of broadening a temporal event, but can improve resolution of the peak. The coherence values are calculated for each frequency bin>. according to Eq. (1). 2
Coh (>.)=IR (>')12 Ifxi>') 1 xy x)' fxx(>')fvi>')
(1)
Equation (1) is the extension of Pearson's correlation coefficient to complex number pairs (Papoulis, 1984; Bronstein and Semendjajew, 1987). In this equation, f denotes the spectral estimate of two EEG signals x and y for a given frequency bin (X), The numerator contains the cross-spectrum for x and y (!xy), the denominator the respective auto-spectra for x (fxx) and y (1;)'). For each frequency, the coherence value (Cohxy) is obtained by squaring the magnitude of the complex correlation coefficient R, and is a real number between 0 and I. Some authors prefer to use the square-root of coherence, which is termed coherency.
6.2.2. Functional measures: task-related coherence and event-related coherence
With few exceptions, functional changes of cortico-cortical coherence in relation to behavioral tasks are evaluated and compared with coherence estimates during baseline or control conditions (Rappelsberger et al., 1994; Leocani et aI., 1997; Classen et aI., 1998; Gerloff et aI., 1998; Miltner et al., 1999; Mima et al., 200 I b). This reduces effects of inter-subject and inter-electrode-pair variability of absolute coherence values. If a continuous task is under study (i.e. continuous movement or force generation), task-related coherence (TRCohxy) is obtained by subtracting rest (Cohxy rest) from corresponding activation conditions (Cohxy activation), according to Eq. (2).
In this equation, coherence magnitude increments are expressed as positive values, and coherence decrements are expressed as negative values. Coherence increments or decrements between baseline and movement conditions for each pair of electrodes can be displayed as color-coded "link" plots, which permit the inspection of the magnitude and spatial patterns of TRCoh (Fig. I). This method also eliminates the bias in the absolute coherence introduced by the reference electrodes (Fein et aI., 1988; Rappelsberger and Petsche, 1988; Classen et aI., 1998; Gerloff et aI., 1998). If coherence changes are expected to occur as a phasic change, tightly bound to a single event, then it might be more appropriate to analyze event-related
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9-11 Hz
20-22 Hz
Fig. 1. Color-coded "link" plot of TRCoh during simple finger movements. EEG data. Red to yellow lines indicate taskrelated increases of coherence (positive values, "coupling"). Blue and green colors indicate task-related decreases of coherence (negative values, "decoupling"), In this example, the major network nodes lie in the bilateral central region. The links converge predominantly on electrodes C3 and CP3, known to overlie roughly the primary motor, primary somatosensory and parietal cortices.
coherence (ERCoh). There are several ways to compute ERCoh. Example I. The mathematics of ERCoh can be identical with those of TRCoh, but ERCoh is computed on shorter epochs (i.e. 256 ms), if necessary with 50% (or 75%) overlap in order to arrive at (smoothed) 128 ms (or 64 ms) temporal resolution without reducing the frequency resolution further. This procedure has the advantage of not forcing the experimenter to make a priori assumptions about reactive frequency bands. The temporal evolution of coherence is automatically available across the full frequency range. This however is achieved at the expense of frequency resolution Res(F). According to Res(F) = liT (Hz), with T=0.256 s, Res(F)=3.9 Hz. Example 2. If the frequency range of interest is clear, then an approach similar to the one of eventrelated desynchronization can be used. The raw data is band-pass filtered for the frequency range of interest (a filter without phase distortion should be used). Then covariances are computed on the basis of single trials between electrodes of interest. Correlation in the time domain is identical with the real part of coherency (the imaginary part can be expressed as the correlation of the time-lagged signals). With this approach, the covariances can be plotted for each sampling point. However, this does not correspond to a temporal resolution of ERCoh that is only determined by the sampling rate. The trade-off between temporal and spectral resolution is similar to example 1. This is due to filtering. In order
to arrive at correlation values for certain frequency ranges, filtering is mandatory before covariances are computed. A filter of specific width in the frequency domain must have a minimum length in the time domain. Therefore, the filtered data are implicitly smoothed. For example, a steep band-pass filter for 10-10.9 Hz will cause smoothing of the data over several hundred milliseconds. This makes the results of example 2 similar to using FFT-based coherences in overlapping epochs as described in example I. Because of boundary effects, however, the results of examples I and 2 will never be absolutely identical. Example 3. In addition to ordinary coherence and covariance methods, wavelet analysis has been used to determine event-related changes of interregional coupling in the frequency domain. Wavelet analysis has a number of mathematical advantages and can attenuate the dilemma of the trade-off between Res(F) vs. Res(t). However, it has the inherent problem of determining physiologically valid wavelet shapes a priori. At this point, it is not clear how much of a bias can arise from this a priori decision, and thus, we prefer ordinary coherence analysis or covariance analysis on band-pass filtered data at this point. 6.2.3. Special aspects: multiple frequencies, statistical evaluation
Coherence values have certain properties which make it necessary to transform them prior to further statistical evaluation (Rosenberg et aI., 1989;
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Farmer et a!., 1993; Halliday et a!., 1995; Amjad et al., 1997). For coherence values, which are real numbers between 0 and 1, the variance decreases for values at both ends of the range (Brockwell and Davis, 1991). For coherence estimates, the inverse hyperbolic tangent (tanh:': synonym arc-hyperbolic tangent) transformation of the square root of coherence cVCohx.P,)=RxvCA))) is typically used to normalize the underlying distribution of correlation coefficients and to stabilize the variances (var) of the distributions (Rosenberg et al., 1989; Farmer et al., 1993) (Eq. (3». A limitation of this transformation is related to its monotonically increasing slope (0--+ infinity). It stretches intervals close to 1 more than those close to O. The transformation is nearly linear when coherence is less than -0.6, so it has little effect on the interpretation or statistical analysis in this range. In the range of (non-subtracted) coherence magnitudes that are commonly observed between EEG or MEG signals, the transformed coherences have approximately constant variance. Although the transformed coherence is slightly less easily interpretable than raw coherence, it is more suitable for analyses of variance (ANOVA). 1
varitanh:'(RxvC A))) =-
.
(3)
2n
In this equation, var denotes the variance of the transformed coherence measure between two signals x and y at a frequency A, and n the number of trials entered into the coherence calculation. The tanh:' transformation is applied to each individual data set prior to subtraction of the coherence estimates in order to compute the task-related coherence TRCoh. Thus, for the statistical analysis, Eq. (2) becomes Eq. (4).
TRtanh-1Rxi A)
=tanh:' [Rxy(A)activation] -
tanh:' [Rxy(A)resl]
(4)
The TRtanh-'RxiA) values can be entered into a factorial ANOVA to assess the significance of TRCoh differences between different conditions (Gerloff et al., 1998). Alternatively, as mentioned above, the unsubtracted tanh-IRxy(A) values for each condition can be entered directly into the ANOVA including tanh-1Rxy(A)resl and significant task-related (TR) changes can be determined by contrast or posthoc analysis (Andres et al., 1999).
TRCoh is usually analyzed separately in different frequency bins. If the TRCoh properties across frequency bins are to be tested, a repeated-measures ANOVA design with frequency as a within-subjects factor is advisable. To account for violation of sphericity, the Greenhouse-Geisser or Huynh-Field correction should then be used. For appropriate statistical testing, data reduction can be necessary. With respect to the topographic distribution of coherences, a "region-of-interest" or "electrode pair/sensor pair-of-interest" (POI) approach is acceptable if clear a priori hypotheses can be formulated. Similarly, frequencies of interest can be defined a priori if the functional relevance of the respective frequency ranges can be determined on the basis of prior knowledge. Mere statistical parametric mapping, i.e. entering all possible combinations of signal pairings and frequency bins into the analysis is mostly inappropriate because of lack of statistical power and the need of corrections for multiple comparisons in the order of several thousands (e.g. 64 channels --+2,048 pairs --+ x 50 frequency bins from 1-50 Hz-e102,400 pairs). In addition to the "pair-of-interest" approach there are hypothesis-free techniques which can be used to get around this dilemma, for example, principal component analysis (PCA) (Andres et al., 1999) and "statistical probability mapping" (Lutzenberger et aI., 2002). In the PCA, the coherence values for all conditions are entered and the eigenvalues for each main component and the loading factors for each electrode pair are determined. The loading factors are ranked, plotted as a function of electrode pair, and the cut-off point is defined, for example visually determined as the first prominent change in slope when starting from the maximum value. The PCA can also be used to test the plausibility of POI that have been selected a priori on the basis of physiological and anatomical knowledge. To reduce the risk of false positives further, it should be considered to only accept electrodes with at least 2 links to other electrodes as potential nodes of a coherence network (Andres et al., 1999). We have used the PCA approach usually in order to determine the POI within selected frequency ranges. An interesting technique to select reactive frequency bins without making a priori assumptions has been referred to as "statistical probability mapping" (Lutzenberger et al., 2002). This method
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has orginally been applied to spectral power values but can be extended to coherence estimates. The statistical probability mapping approach is based on permutation tests (Blair and Karniski, 1993). It includes corrections for multiple comparisons and for possible correlations between data from neighboring frequency bins. The starting point is the observed distribution of the t values for all frequency bins x coherence estimates. To ensure that tests for two consecutive frequency bins are significant, a new distribution of the minimal t values, tm, is computed for all pairs of neighboring frequency bins (time points) i and sensors}, according to Eq. (5). (5)
The t value tm and its corresponding p value Po.os are determined for which 5% of the observed tmi,j are greater. In the case of highly correlated data, Po,os is ::;0.05, for highly independent data, Po,os is >0.05. Then the distribution of the maximal t values, tmax' is computed for each of the n rand=2n permutations across n subjects of the observed values for the two conditions for all frequency bins i x coherence estimates j, according to Eq. (6).
(6) The critical t value t erit is now defined as the value where Po.os x nrand of the obtained t max are greater. This critical t value t erit is then applied as significance criterion to the observed data. Once the frequency bins of interest are defined, broad-band coherence values across multiple frequencies can be computed. For broad-band coherence, Cohxi~), Cohxi}..) is averaged over frequency bins j = }..min to }..max (with }..min and }..max corresponding to the lower and upper frequency bins in the chosen frequency band). To average the frequency bins the concept of pooled coherence can be used as described by Amjad et aI. (1997). For all subjects, electrode pairs, and conditions, the number of frequency bins pooled should be equal (Amjad et al., 1997). 6.2.4. Advanced computations: phase analysis, partial coherence analysis, source modeling
In the coherence estimate, phase P xy is delineated from the relation of imaginary (1m(x» to real part (Retx) of the complex cross-spectrum f .ry It can also
be expressed as the argument of the cross-spectrum, according to Eq. (7). (7)
This equation provides information about the temporal relationship (phase lag) of the 2 signals of interest. However, it is not possible to decide which of the signals leads or lags. One approach to solve this dilemma is the "constant phase shift and constant time lag model" (Mirna et aI., 2000b). This model is based on regression analysis of constant or frequency-independent time lags in multiple frequencies and is described in more detail in Chapter 6 of this volume. The model has been successfully applied to EEG-EMG coherence, but its application to cortico-cortical coherence is more difficult. While EEG-EMG (or MEG-EMG) coherences are raw coherence data, cortico-cortical coherences have to be corrected for influences of volume conduction and variable inter-electrode distances. As described above, this is done by computing task-related coherence, TRCoh. Accordingly, this approach will provide us with information that resembles a "taskrelated change of the phase lag between two signals". This information cannot simply be translated into conduction times or numbers of synapses involved. This information might be helpful if during the task, zero-phase lag synchronization is present, but not during rest. However, the physiological meaning of the magnitude of task-related changes of phase lags yet needs to be determined. An alternative approach to describing the "direction of information flow" between multivariate time series is "directed coherence" (Wang and Takigawa, 1992; Baccala and Sameshima, 2001; Mirna et aI., 2001a). The principle of this method is the decomposition of multivariate partial coherences computed from multivariate autoregressive models into two directed coherences rather than into one "ordinary" coherence (Eq. (1». Directed coherence is thought to reflect a frequency-domain representation of the concept of Granger causality (Baccala and Sameshima, 2001). It stresses the "lead" or "lag" of a signal by decomposing their interactions into "feedforward" and "feedback" aspects. So far, little attention has been paid to this method in respect to the analysis of task-related modulations of corticocortical interactions, although the method has been applied sporadically in this context for already more than one decade (Wang and Takigawa, 1992).
82 Directed coherence between two time series X and Y at a given frequency (A) is usually referred to as 'Yx/A) and is similar to the estimator called "directed transfer function" (DTF) (Kaminski et al., 2001). Of note, any phase computations and interpretations in the context of cortico-cortical coherences are only valid, if "reference-free" signals are used. If two signals with a common reference are compared, "zero-phase lag synchronization" might erroneously be introduced by the relative contribution of the reference signal. Bipolar leads or source derivations (e.g. Laplacian) must be computed if phase information is to be addressed. The general question of which reference should be used for cortico-cortical coherence analyses has been much debated. For coherence magnitude, in addition to bipolar and Laplacian signals, common average or monopolar recordings can also be used. The crucial point is that the reference signal must not be modulated as a function of the behavioral task. For example, if the primary sensorimotor cortex is the region of interest and the task is visually cued, significant task-related influences of earlobe electrodes are quite unlikely. This would be very different for an auditory task. The choice of the reference must depend on the physiological paradigm under study. Recently, the method of partial coherence analysis has been introduced into EEG spectral analysis. Most importantly, regarding coherence results in the alpha band partial coherence allows for assessing potential influences of the reference electrode(s). This could be the case with false high interhemispheric coherence between sensorimotor regions because of contamination of the reference electrode signal (earlobe or mastoid electrodes) by the occipito-parietal alpha rhythm (Mima et al., 2000a). Partial coherence is computed according to Eq. (8).
In this equation, ijA), J;,/A), andlziA) are autospectra of EEG (or MEG) signals X, Y, and Z for a given frequency (A). The terms fx/A),frz(A), and Iz/A) are
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the cross-spectra between two of them for a given frequency (A). In this example, Z would be the signal corresponding to the occipito-parietal alpha rhythm, X would correspond to the signal over the left, Y over the right sensorimotor cortex. Equation (8) then provides the coherence between the two sensorimotor regions after removal of any potential linear influence of the occipito-parietal alpha rhythm. Figure 2 illustrates how task-related coherence patterns may change after eliminating the influence of the occipito-parietal alpha rhythm. The question of which sources are generating the coherence estimates can be addressed by using source models, i.e. considering brain regions, rather than raw data or digitally re-referenced or otherwise
Fig. 2. Task-related coherence (TRCoh) during a simple finger extension task. Epoch length, I s. Top, standard computation of TRCoh (movement minus baseline). Note the similar amplitudes of TRCoh between left sensorimotor region (LSM) and frontocentral midline cortex (ML) and between LSM and the right sensorimotor region (RSM). After removal of linear influences of the occipitoparietal alpha rhythm by partial coherence analysis, interhemispheric coherence (LSM-RSM) is relatively reduced as compared with intrahemispheric coherence (e.g. LSM-ML). The orange bar indicates the usual range of frequencies of interest (alpha, beta) in this type of paradigm with EEG. Atanh = tanh:', inverse hyperbolic tangent. The horizontal dotted line indicates minimum level for significant change.
COHERENCE, CORT/CO-CORT/CAL
spatially processed (e.g. Laplacian) data from multiple recording channels. The basis for coherence calculation is then the source waveform which corresponds to the (modelled) time course of oscillatory activity of the respective source (Thatcher, 1995; Gross et aI., 2001). These approaches are important extensions of the coherence method and are particularly useful, if intrasulcal activity is investigated. Electric or magnetic sources that are located inside a sulcus produce predominantly dipolar field distributions. For the primary sensorimotor region, this can result in two maxima, a frontal and a parietal one which are 180 deg out of phase but highly coherent. Source reconstructions can here be used to image the most likely origin of the signal. Naturally, a source model can only be as good as its stability and the plausibility of the assumptions that the model is based on. Spurious constraints, biases by a priori channel selections or selection of an unfortunate starting point (for a moving dipole fit), or solutions contaminated by poor signal-to-noise ratios will result in meaningless coherence data. Gross et al. (2001) have proposed a signal-to-noise ratio of 5-12 for their method of "dynamic imaging of coherent sources" (DICS). 6.2.5. Data acquisition: comments on recording technique
Beyond the usual requirements for high-quality EEG or MEG recordings (or recordings of firing rates or LFPs with invasive methods), a particular point of concern for coherence data is the number of single trials (epochs). The variance of the squareroot of coherence is solely determined by the n of epochs (see Eq. (3». There is no mathematically defined range for the number of trials necessary to produce reliable coherence values. However, in our experience one should obtain approximately n= 100 artifact-free, non-overlapping epochs, corresponding to an improvement of the signal-to-noise ratio of 10 (=Yn).
For the experimental design, it is important to decide the desired frequency resolution. For example, a standard task-related approach aimed at (hypothesis-free) I-Hz frequency resolution necessitates an epoch length of at least 1000 ms for each target condition.
83
6.3. Applications The analysis of task- and event-related coherence has advanced our knowledge of neurophysiological processes underlying the performance and learning of skilled finger movements (Rappelsberger et al., 1994; Andrew and Pfurtscheller, 1996; Leocani et al., 1997; Gerloff et al., 1998; Manganotti et al., 1998). It has become clear that various types of higher task demands are reflected by changes in the functional coupling of different cortical areas and not only by changes in regional activation (Gerloff et al., 1998; Manganotti et al., 1998). It has been demonstrated that the learning of bimanual coordination is associated with modulation of taskrelated coherence between the motor areas of both cerebral hemispheres (establishment of efficient bimanual 'motor routines') (Andres et al., 1999; Gerloff and Andres, 2002). In paradigms involving the functional interaction between visual and sensorimotor areas, corticocortical coherence has been demonstrated to be elevated specifically in situations in which signal processing in both regions needs to be integrated (Classen et al., 1998; Miltner et al., 1999; Chen et al., 2003). The amplitude of task-related coherence between visual and sensorimotor regions correlated positively with the behavioral efficacy in a visuotactile matching task (Hummel and Gerloff, 2001). In particular, the studies on visuomotor and visuotactile integration suggest that cortico-cortical coherence reflects meaningful and functionally relevant coupling of distant brain areas in large-scale networks. Cortico-cortical coherence has also been used in a number of neurocognitive paradigms, such as language processing (Weiss and Rappelsberger, 1996), associative learning (Miltner et al., 1999), processing of pain (Chen and Rappelsberger, 1996), mental rotation (Rappelsberger and Petsche, 1988), and object recognition (Neven and Aertsen, 1992; Mima et al., 200lb). Recently, the influence of the dopaminergic neurotransmitter system on task-related cortico-cortical coherence has been addressed in parkinsonian patients during a visuomotor tracking task (Cassidy and Brown, 2001). After levodopa the amplitude of broad-band interregional coherence was significantly increased (compared with off levodopa). This led the authors to the conclusion that ascending
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dopaminergic projections from the ventral mesencephalon may be important in determining the pattern and extent of corticocortical coupling during executive tasks. The relative contributions of corticocortical connectivity as self-emerging property of the neocortex and of third pacemaker structures to cortico-cortical coherence are yet to be determined. Cortico-cortical coherence of the resting EEG (not task-related) has furthermore been used to assess cortical connectivity in several neurological (e.g. multiple sclerosis (Leocani and Comi, 1999)) and psychiatric conditions (e.g. dementia (Stevens et al., 2001».
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Movement Disorders Handbook of Clinical Neurophysiology, Vol. 1 M. Hallett (Ed.) © 2003 Elsevier B.v. All rights reserved
87 CHAPTER 7
Coherence, cortico-muscular Tatsuya Mirna":", Mark Hallettb and Hiroshi Shibasaki" a
Department of Brain Pathophysiology, Human Brain Research Center, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan b HMCS, NINDS, National Institutes of Health, Bethesda, MD 20892, USA
7.1. Introduction
understanding the cortical control of muscle activity.
One of the fundamental questions in motor physiology is the relationship between cortical activity and the motor output. In some pathological conditions, the electroencephalographic (EEG) correlate of electromyographic (EMG) activity can be recognized in the conventional EEG-EMG polygraph. For example, an EMG jerk can be preceded by a positive spike at the contralateral central area in some patients with cortical myoclonus. Even a small EEG activity can be detected by applying an averaging technique with respect to the EMG onset (jerk-locked back averaging). For voluntary ballistic movements, the same back averaging technique can reveal a cortical slow negative potential preceding the movement (movement-related cortical potentials, Bereichtshaftspotential) (Komhuber and Deecke, 1965; Shibasaki et aI., 1980). In addition to this type of time-domain analysis for the EEG-EMG correlation, there have been considerable interests in cortico-muscular coherence, starting with the report using magnetoencephalography (MEG) (Conway et aI., 1995). Coherence is also a measure of correlation but in the frequency domain. Coherence computation enables us to compute the normalized magnitude of correlation as a function of frequency (coherence spectra). Since the oscillatory nature of EEG/MEG and EMG signals has been well-recognized for many years, this approach might provide us a new useful tool for
* Correspondence to: Dr. T. Mirna, Department of Brain Pathophysiology, Human Brain Research Center, Kyoto University Graduate School of Medicine, Shogoin, Sakyoku, Kyoto 606-8507, Japan. E-mail address:
[email protected] Fax: +81-75-751-3202.
At first, we will discuss the computational and statistical evaluation of EEG-EMG coherence. Secondly, we will overview the normal findings and the possible generator mechanisms of corticomuscular coherence. Thirdly, clinical applications of this method will be introduced. Finally, recent developments in computational technique will be reviewed. 7.2. Methodology
7.2.1. Coherence estimation Coherence is a measure of linear correlation in the frequency domain and defined as cross-spectra divided and normalized by auto-spectra. Some researchers prefer to use the square-root of coherence, which is termed as coherency. Mathematical formula of coherence is as follows.
In this equation, Ix/i), J;;ii) and jxy(i) are values of auto- and cross-spectra at a specific frequency i. Since the coherence is a normalized value, it distributes from 0 to 1, with 1 indicating the perfect linear correlation and 0 indicating the lack of linear association. To perform a spectral analysis of the signal, a fast Fourier transform method (FFT) is commonly used. To test whether the observed coherence value is statistically significant or not, the 95% confidence value based on the assumption of linearly independent signals is usually used. Confidence limit at X%
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Table I Confidence level of coherence as a function of sample numbers. Number of samples 95% confidence 99% confidence 0.146 0.059 0.030 0.015 0.010 0.006
20 50 100 200 300 500
0.215 0.090 0.045 0.023 0.Q15 0.009
can be approximated by the equation as follows (Rosenberg et aI., 1989):
CL(X)=I-
(
)lI(n-IJ
X I--
lOa
This is relatively a simple equation, and it should be noted that the number of independent samples (n) influences the confidence limit (Table I). Although statistically significant, the actual magnitude of cortico-muscular coherence is not very large and is usually smaller than 0.3. To compare the magnitude of coherence, the archyperbolic tangent transformation of the square root of coherence is used to normalize the data, which stabilizes the variance as a function of the number of independent samples (Rosenberg and Amjad, 1989): 1 var(tanh-I(Rxy(i)))=-
2n
Therefore, if the number of samples for the computation of coherence is approximately the same, a general linear statistical approach, such as t-test or analysis of variance can be applied to the normalized coherence. 7.2.2. Phase analysis
Since the cross-spectra are complex numbers, their argument gives us the phase information between two signals at a given frequency:
PX),(j) =arg(f.i i» Although the phase reflects the temporal relationship between two signals, it is impossible to determine whether the phase lag reflects the delay or advance
in the time domain. However, if multiple frequencies have a constant or frequency-independent time lag, a regression analysis can reveal the temporal relationship between the two signals ("constant phase shift and constant time lag model") (Mima et aI., 2000):
360 Px/i) = 1000 i.i:« where t is the frequency-independent time lag in milliseconds and K is the constant phase shift. In the case of cortico-muscular coherence, the EEG leads the EMG with a short time delay at the frequency around 20 Hz (Mima et aI., 2000). 7.2.3. Recording technique
To extract the timing information of grouped motor unit activity from the surface EMG, the EMG signal is full-wave rectified and used for further analysis. It seems that the surface EMG is better than the needle EMG for the purpose of coherence estimation (unpublished observation). Since the polarity of the recorded motor unit activity can vary depending on the location of the active electrode, it is necessary to rectify the EMG signal before coherence computation. Spectral analysis of the rectified EMG typically shows 10, 20 and 40 Hz peaks, which might partly reflect the centrally generated frequencies (McAuley et aI., 1997). If the EEG is used for recording the cortical activity, it should be noted that the magnitude and distribution of cortico-muscular coherence heavily depends on the EEG derivation type (Mima and Hallett, 1999). The best results in terms of coherence value and spatial resolution can be achieved by the current source density (CSD) estimation, including Hjorth transformation. If the earlobe electrode or common average reference is used, the measured EEG-EMG coherence is smaller compared to CSD method. Moreover, possibly artifactual EEG-EMG coherence over the medial frontal area can be observed in these EEG derivations because this coherence can be abolished by CSD computation. However, a contribution of the medial frontal area for the generation of cortico-cortical coherence has been demonstrated with subdural recording in patients with intractable seizures (Ohara et aI., 2000). Bipolar EEG might distort the phase spectra because the phase can show the pi-phase delay (polarity inversion) depending on the relative loca-
89
COHERENCE, CORTICO-MUSCULAR
tion of the active and reference electrode with respect to the coherent EEG, which might produce frequency-independent constant phase spectra (Mirna and Hallett, 1999).
tion time (Salenius et aI., 1997; Mirna et aI., 2000). It is strongly suggested that the coherence reflects the motor command from the cortex to the muscle. alphabeta
7.3. Normal findings and possible generator mechanisms Cortico-muscular coherence measured by EEG, electrocorticogram (ECoG) or MEG shows significant value over the primary sensorimotor area during a weak tonic contraction task mainly at 15-35 Hz (Conway et aI., 1995; Salenius et aI., 1996, 1997; Baker et aI., 1997; Mirna et aI., 1998; Marsden et aI., 2000; Mirna et aI., 2000). Using a whole-head MEG system coregistered with brain MRI, the generator source of the EMG-correlated cortical activity can be localized at the anterior bank of the central sulcus, that is the primary motor cortex (Salenius et aI., 1997). The spatial distribution of corticomuscular coherence over the scalp demonstrates a somatotopic pattern; the hand and arm over the contralateral lateral convexity and the foot over the midline (Salenius et aI., 1997; Brown et al., 1998; Mirna et aI., 2000). In addition to the primary sensorimotor area, subdural EEG recording in epileptic patients revealed involvement of contralateral premotor cortex, supplementary motor areas and cingulate cortex (Ohara et aI., 2000). It is possible that the coherence between the activities at those motor-related areas and muscle is associated with direct cortical projections to the spinal motoneuron (Dum and Strick, 1991; Rizzolatti et al., 1998). Not only the spatial localization but also the spectral structure can be studied by using coherence analysis. During a weak tonic contraction, corticomuscular coherence demonstrates the highest peak usually within the beta band (13-30 Hz) (Conway et aI., 1995; Baker et al., 1997; Salenius et aI., 1997; Mirna et aI., 2000). However, some normal subjects show the significant coherence in a lower frequency band (3-13 Hz) (Mirna et al., 1999; Mirna et aI., 2000; Marsden et al., 200 I). Phase analysis revealed that the generator mechanism of coherence in the beta band might be different from that in the lower frequency band. For the beta band, both phase analysis and cross-correlogram showed that the EEG leads the EMG by a short time lag which is similar or slightly shorter than the cortico-muscular conduc-
gamma
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180r------------,
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Fig. 1. (a) EEG power spectra at the left central area, showing a peak at 9 Hz. (b) EMG power spectra of a right hand muscle (abductor poIIicis brevis), showing a peak at 20 Hz. (c) EEG-EMG coherence spectra computed from the data shown in Figs. la and lb (n=280). Significant coherence can be seen at 8-33 Hz. 95% confidence limit is shown as the dotted line. (d) EEG-EMG phase spectra. Phase spectra is linear >20 Hz (modified from Mirna et aL,2000).
90
T. MIMA ET AL.
Fig. 3. EEG-EMG coherence as a function of produced force. Coherence between the EMG at the APB muscle and the EEG at C3 (thick line) and that at FC3 (thin line). During the very strong contraction (80% of the maximal force), gamma band coherence can be seen at FC3. In contrast, EEG-EMG coherence within the beta range was almost invariant for the force change from 10 to 60% of the maximal contraction (modified from Mima et a!., 1999).
Fig. 2. Scalp topography of the significant EEG-EMG coherence for the hand (abductor pollicis brevis) and foot (abductor hallucis) muscles. Topography was constructed at the peak frequency of the EEG-EMG coherence.
In contrast, cortico-muscular coherence within the lower frequency band shows the near-zero time lag (Mirna et aI., 2000). Thus, it is possible that this coherence might be associated with a subcortical rhythm generator which affects both the cortical and muscle oscillatory activities. A possible association between physiologic tremor and this coherence has been suggested (Marsden et aI., 2001). It is unlikely, however, that this coherence has relevance for the generation of physiologic tremor because the coherence in this lower frequency band is generally smaller than that in the beta band even in normal subjects with enhanced physiologic tremor (Mirna et aI., in press). Cortico-muscular coherence in the gamma band can be seen during a very strong contraction task
(Brown et aI., 1998; Mirna et aI., 1999). It has been reported that this coherence is associated with the motor unit grouping at around 40 Hz (Piper rhythm). Even when the subjects performed a gradual increase in the force level, there is no gradual shift in the coherence from the beta to the gamma band (Brown et aI., 1998; Mirna et aI., 1999). Brown and colleagues showed that the peak coherence frequency in the gamma band for the arm and foot muscle are different, which suggests different neural circuits for the generation of coherence at different somatotopic cortical areas (Brown et aI., 1998). . These findings might indicate that the corticomuscular coherence in different frequency bands reflects the different coupling mechanisms between cortex and muscle.
7.4. Factors that will affect the cortico-muscular coherence For physiological experiments or clinical application of cortico-muscular coherence, one should
COHERENCE, CORTICO-MUSCULAR
91
EEG·EMG coherence in Parkinson tremor 0.16 . , - - - - - - - - - - - - -
consider the following factors that have considerable effects on the coherence estimate: (1) Produced force level As we have discussed earlier, the corticomuscular coherence during very strong contraction (more that 60% of maximal strength) might show a peak frequency at around 40 Hz. However, for weak to moderate isometric tonic contractions, the coherence in the beta band is generally insensitive to the produced force (Brown et al., 1998; Mima et al., 1999). In a precision grip task against a spring-like load, there is a positive relationship between the coherence magnitude and the level of object compliance (Kilner et al., 1999). (2) Phasic vs. tonic movements Significant cortico-muscular coherence can be observed during continuous tonic contraction tasks or the tonic hold phase of precision grip tasks, but is absent or very small during phasic movements (Baker et al., 1997; Kilner et al., 1999). (3) EEG derivation type As we have mentioned earlier, reliable EEGEMG coherence can be computed by the current source density or its approximation (Hjorth transformation). If bipolar or ear-lobe reference EEG is used, EEG-EMG coherence might show a misleading spatial distribution and phase estimate as well as an apparently small value (Mirna and Hallett, 1999).
7.5. Cortico-muscular coherence in pathological conditions Since cortico-muscular coherence is a noninvasive measure of cortico-motoneuronal coupling as a function of frequency, this method can be applied clinically to various motor dysfunctions or movement disorders. One possible application is to investigate the cortico-spinal function in motor deficits. For example, in patients with subcortical stroke who manifested pure motor paresis and recovered well, this coherence for the affected side was significantly smaller than that for the healthy side (Mima et al., 2002). It is suggested that the clinical recovery in these patients might not be associated with the direct
~
~
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Q)
:3 \A
10
A }95% confidence L--'
20
30
40
50
Frequency (Hz) Fig. 4. EEG-EMG coherence in a Parkinson patient during a rest condition. EMG was recorded from the left extensor carpi radialis muscle. Significant coherence is observed at the resting tremor frequency (6 Hz). This observation may indicate the involvement of the primary sensorimotor cortex for the generation of tremor.
cortico-motoneuronal pathway but with an indirect one. Another challenging field of clinical application is movement disorder research. Existence of corticomuscular coherence might suggest the involvement of the primary sensorimotor area for the generation of involuntary movement. Volkmann and colleagues showed cortico-muscular coherence at the resting tremor frequency over the contralateral premotor and primary sensorimotor area in Parkinsonian patients (Volkmann et al., 1996). For essential tremor, there are conflicting results on the existence of corticomuscular coherence at tremor frequency (Halliday et al., 2000; Hellwig et al., 2000, 2001). The negative results might well be false negatives due to low amplitude tremors. These studies of tremor-related coherence indicate the possible important role of the cortex or cortico-subcortical loop for the generation of tremors. Recent study of the local field potential oscillation recorded from the nucleus ventralis intermedius of the thalamus also supports this idea (Marsden et al., 2000). Cortico-muscular coherence can be applicable for other types of movement disorders, such as cortical myoclonus and dystonia (Brown et al., 1999; Tijssen et al., 2000). 7.6. Newly developed computational techniques To measure the correlation between cortical oscillatory activity and EMG quantitatively, several
T. MIMA ET AL.
92
0.2
Coherence
r------......----~--__,
0.1
10
20
30
40
50
methods to measure phase coherence that focuses on the phase but not on the amplitude information (Tass et aI., 1998; Feige et aI., 2000; Gross et aI., 2000, 2001). Another approach is the use of directed coherence or directed transfer function (Mirna et al., 2001). Conventional coherence is a measure of correlation and does not account for the temporal relationship between two signals. By using a multivariate autoregression model for the analysis of cortical and muscle activities, it is possible to detect the normalized value of information flow from cortex to muscle and from muscle to cortex separately.
Frequency (Hz) 7.7. Conclusion
0.2
Directed transfer function
Functional coupling between the cortical oscillatory activity and EMG can be quantitatively measured by cortico-muscular coherence, using EEG, MEG or electrocorticogram. This method can be a useful tool for understanding the pathophysiology of motor deficits and movement disorders as well as normal motor control.
From EEG to EMG 0.1 From EMG to EEC\••
•• •
••
••••••••
••••••••• 0 ......._ ........_ _.........._ _""-10
20
30
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40
References
50
Frequency (Hz) Fig. 5. Coherence spectra and directed transfer function computed by the multivariate autoregressive model (n = 200). In this subject, DTF from the EEG to EMG (thick line) was larger than that from EMG to EEG within 0-30 and 40-50 Hz. This finding suggests an asymmetric information flow from the cortex to the muscle in these frequencies.
new methods other than conventional coherence have been introduced. One possible way is to measure the phase coherence. Since conventional coherence is a normalized cross-spectra, it reflects both the amplitude covariation and the phase consistency. In the case of functional coupling between cortex and muscle, the latter factor might be more physiologically important for the cortical control of muscle activity. Several groups have introduced
Baker, SN, Olivier, E and Lemon, RN (1997) Coherent oscillations in monkey motor cortex and hand muscle EMG show task-dependent modulation. J. Physiol., SOl: 225-241. Brown, P, Salenius, S, Rothwell, JC and Hari, R (1998) Cortical correlate of the Piper rhythm in humans. J. Neurophysiol., 80: 2911-2917. Brown, P, Farmer, SF, Halliday, DM, Marsden, J and Rosenberg, JR (1999) Coherent cortical and muscle discharge in cortical myoclonus. Brain, 122: 461-472. Conway, BA, Halliday, DM, Farmer, SF, Shahani, D, Maas, P, Weir, AI and Rosenberg, JR (1995) Synchronization between motor cortex and spinal motoneuronal pool during the performance of a maintained motor task in man. J. Physiol., 489: 917-924. Dum, RP and Strick, PL (1991) The origin of corticospinal projections from the premotor areas in the frontal lobe. J. Neurosci., 11: 667-689. Feige, B, Aertsen, AD and Kristeva-Feige, R (2000) Dynamic synchronization between multiple cortical motor areas and muscle activity in phasic voluntary movements. J. Neurophysiol., 84: 2622-2629.
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Gross, J, Tass, PA, Salenius, S, Hari, R, Freund, H-J and Schnitzler, A (2000) Cortico-muscular synchronization during isometric muscle contraction in humans as revealed by magnetoencephalography. J. Physiol., 527: 623-631. Gross, J, Kujala, J, Harnalainen, M, Timmermann, L, Schnitzler, A and Salmelin, R (200 I) Dynamic imaging of coherent sources: Studying neural interactions in the human brain. Proc. Nat. Acad. Sci. USA, 98: 694-699. Halliday, DM, Conway, BA, Farmer, SF, Shahani, U, Russell, AJC and Rosenberg, JR (2000) Coherence between low-frequency activation of the motor cortex and tremor in patients with essential tremor. Lancet, 355: 1149-1153. Hellwig, B, HauBler, S, Lauk, M, Guschlbauer, B, Koster, B, Kristeva-Feige, R, Timmer, J and Liicking, CH (2000) Tremor-correlated cortical activity detected by electroencephalography. Clin. Neurophysiol., 111: 806-809. Hellwig, B, Haufsler, S, Schelter, B, Lauk, M, Guschlbauer, B, Timmer, J and Liicking, CH (2001) Tremor-related cortical activity in essential tremor. Lancet, 357: 519-523. Kilner, lM, Baker, SN, Salenius, S, Jousmaki, V, Hari, R and Lemon, RN (1999) Task-dependent modulation of 15-30 Hz coherence between rectified EMGs from human hand and forearm muscles. J. Physiol., 516: 559-570. Kornhuber, HH and Deecke, L (1965) Hirnpotentialanderungen bei Willkiirbewegungen und passiven Bewegungen des Menschen: Bereitschaftspotential und reafferente Potentiale. Pfliigers. Arch. Ges. Physiol., 284: 1-17. Marsden, JF, Ashby, P, Limousin-Dowsey, P, Rothwell, JC and Brown, P (2000a) Coherence between cerebellar thalamus, cortex and muscle in man: cerebellar thalamus interactions. Brain, 123: 1459-1470. Marsden, JF, Werhahn, KJ, Ashby, P, Rothwell, JC, Noachtar, S and Bown, P (2000b) Organization of cortical activities related to movement in humans. J. Neurosci., 20: 2307-2314. Marsden, JF, Brown, P and Salenius, S (200 I) Involvement of the sensorimotor cortex in physiological force and action tremor. Neuroreport, 12: 1937-1941. McAuley, JH, Rothwell, JC and Marsden, CD (1997) Frequency peaks of tremor, muscle vibration and electromyographic activity at 10 Hz, 20 Hz and 40 Hz during human finger muscle contraction may reflect rhythmicities of central neural firing. Exp. Brain Res., 114: 525-541. Mirna, T and Hallett, M (l999a) Cortico-muscular coherence: a review. J. CUn. Neurophysiol., 16: 501-511. Mirna, T and Hallett, M (1999b) Electroencephalographic analysis of cortical-muscular coherence: reference
93 effect, volume conduction and generator mechanism. Clin. Neurophysiol., 110: 1892-1899. Mirna, T, Gerloff, C, Steger, J and Hallett, M (1998) Frequency-coding of motor control system - coherence and phase estimation between cortical rhythm and motoneuronal firing in humans. Soc. Neurosci. Abstr., 24: 1768. Mirna, T, Simpkins, N, Oluwatimilehin, T and Hallett, M (1999) Force level modulates human cortical oscillatory activities. Neurosci. Lett., 275: 77-80. Mirna, T, Steger, J, Schulman, AE, Gerloff, C and Hallett, M (2000) Electroencephalographic measurement of motor cortex control of motoneuronal firing in humans. CUn. Neurophysiol., 111: 326-337. Mirna, T, Matsuoka, T and Hallett, M (200 I) Information flow from the sensorimotor cortex to muscle in humans. CUn. Neurophysiol., 112: 122-126. Mirna, T, Toma, K, Koshy, B and Hallett, M (2002) Coherence between cortical and muscular activities following subcortical stroke. Stroke, 32: 2597-2601. Mirna, T, Ohara, Sand Nagamine, T (in press) Corticalmuscular coupling. In: H Shibasaki (Ed.), Inter-areal Functional Coupling of the Human Brain. Elesevier Co. Ohara, S, Nagamine, T, Ikeda, A, Kunieda, T, Matsumoto, R, Taki, W, Hashimoto, N, Baba, K, Mihara, T, Salenius, Sand Shibasaki, H (2000) Electrocorticogram-electromyogram coherence during isometric contraction of hand muscle in human. CUn. Neurophysiol., Ill: 2014-2024. Rizzolatti, G, Luppino, G and Matelli, M (1998) The organization of the cortical motor system: new conElectroencephalogr. CUn. cepts Review. Neurophysiol., 106: 283-296. Rosenberg, JR, Amjad, AM, Breeze, P, Brillinger, DR and Halliday, DM (1989) The Fourier approach to the identification of functional coupling between neuronal spike trains. Prog. Biophys. Molec. Biol., 53: 1-31. Salenius, S, Salmerin, R, Neuper, C, Pfurtscheller, G and Hari, R (1996) Human cortical40-Hz rhythm is closely related to EMG rhythmicity. Neurosci. Lett., 213: 75-77. Salenius, S, Portin, K, Kajola, M, Salmelin, Rand Hari, R (1997) Cortical control of human motoneuron firing during isometric contraction. J. Neurophysiol., 77: 3401-3405. Shibasaki, H, Barrett, G, Halliday, E and Halliday, AM (1980) Components of the movement-related potentials and their scalp topography. Electroencephalogr. Clin. Neurophysiol., 1980: 213-226. Tass, P, Rosenblum, MG, Weule, J, Kurths, J, Pikovsky, A, Volkmann, J, Schnitzler, A and Freund, H-J (1998) Detection of n: m phase locking from noisy data:
94 Application to magnetoencephalography. Physic. Rev. Lett., 81: 3291-3294. Tijssen, MA, Marsden, JF and Brown, P (2000) Frequency analysis of EMG activity in patients with idiopathic torticollis. Brain, 123: 677-686.
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Volkmann, J, Joliot, M, Mogilner, A, Ioannides, AA, Lado, F, Fazzini, E, Ribary, U and Llinas, R (1996) Central motor loop oscillations in parkinsonian tremor revealed by magnetoencephalography. Neurology, 46: 1359-1370.
Movement Disorders Handbook of Clinical Neurophysiology, Vol. I M. Hallett (Ed.) © 2003 Elsevier B.V. All rights reserved
95 CHAPTER 8
Transcranial magnetic stimulation Vif Ziemann* Clinic of Neurology, Johann Wolfgang Goethe University of Frankfurt, Theodor-Stem-Kai 7. D-60590 Frankfurt am Main, Germany
This chapter surveys the techniques and principles of transcranial magnetic stimulation (TMS) to study the corticospinal tract, motor cortex excitability and motor cortex connectivity. Clinical applications are usually only hinted at but will be dealt with in the disorders section of the book.
8.1. Technical principles: modes of corticospinal tract activation TMS was introduced in its contemporary form in 1985 (Barker et aI., 1985a, b; Barker, 1999). It was originally designed to assess non-invasively the human corticospinal tract and to do this with much less discomfort compared to transcranial electrical stimulation (Merton and Morton, 1980). A magnetic stimulator works by discharging a capacitance through a copper-wire stimulating coil. A large current (current peak -5000 A) flows and induces a transient magnetic field (rise time 50-200 us, maximum field strength 1-2.5 Tesla) about the coil. Because the magnetic field changes rapidly, it can induce a (much smaller) current in other conductors, such as the human brain. In contrast to electrical currents, the magnetic field passes through electrical insulators, like the scalp and skull, without significant attenuation. The depth of penetration of the magnetic field is limited to a few ems because the magnetic field strength decays rapidly as a quadratic function of the distance from the coil (Epstein et aI., 1990; Roth et aI., 1991). Magnetic pulse characteristics are either near-monophasic, biphasic or polyphasic (damped cosine). These different waveforms may have complex effects on the exact way how neural tissue is activated (Maccabee et aI., 1998; Corthout et aI., 2001; Kammer et aI., 2001). Various geometries of stimulating coils are available
* E-mail address:
[email protected] Tel.: +49696301 5739; fax: +49696301 6842.
for non-focal (circular, cap-shaped) and focal (eightshaped, double-cone) TMS (Roth et aI., 1991; Kraus et aI., 1993). How does TMS excite the corticospinal tract? A single high-intensity TMS pulse produces multiple descending corticospinal discharges (Fig. 1). The first wave is called D-wave, later waves are called I-waves (Patton and Amassian, 1954; Arnassian et aI., 1987). In humans, the D-wave very likely reflects direct excitation of the cortico-spinal axon at the initial axon segment (Day et aI., 1989). In contrast, I-waves reflect indirect (i.e. transsynaptic) excitation of corticospinal cells through excitation of tangentially oriented cortico-cortical or thaIamo-cortical axons in the deep cortical layers or in the superficial white matter at a depth of 1.5-2 em beneath the scalp surface (Day et aI., 1989; Epstein et aI., 1990; Rudiak and Marg, 1994). The I-waves follow the Dwave at regular intervals of about 1.5 ms. All waves are rapidly conducted at 60-70 rnIs (Arnassian et aI., 1987; Di Lazzaro et aI., 1999b). The first wave recruited depends on the direction of the current induced in the brain. With posterior-to-anterior direction, the lowest threshold wave usually is the 1,wave (Fig. 1), with lateral-to-medial direction the D-wave and with anterior-to-posterior direction the 13-wave (Werhahn et aI., 1994; Kaneko et aI., 1996a; Nakamura et aI., 1996; Sakai et aI., 1997; Di Lazzaro et aI., 1998a) (Fig. 1). Increase in stimulus intensity leads to the recruitment of other waves. The descending corticospinal volley is transmitted mainly or exclusively monosynaptically to the motoneurons in the spinal cord (Zidar et aI., 1987; Mills, 1991; Maertens de Noordhout et aI., 1999). Some evidence was given for the additional activation of a disynaptic pathway to forearm muscles via propriospinal-like intemeurons in the cervical spinal cord (Pierrot-Deseilligny, 1996), or for the activation of cortico-reticulospinal projections (Ziemann et aI., 1999). In adults, the motor response occurs usually
V.ZIEMANN
96
exclusively in muscles contralateral to the stimulated motor cortex. One exception are facial and axial PO
P1 P2 P3
I
AnodelSS %
Clockwise magnetic 35%
,
Antlclockwise magnetic35%
, 40
Fig. 1. Post-stimulus time histograms from a single motor unit in the first dorsal interosseous muscle studied using anodal TES (top), clockwise TMS (round coil, current in the coil view from above, middle) and anticlockwise TMS (bottom). Each histogram was constructed from the responses to 100 stimuli given 10 ms before the start of each record. Stimulus intensity is given as a percentage of the maximum output of each stimulator. The histogram peaks have been labeled PO, PI, P2 and P3 (continuous vertical lines) according to their latency after the stimulus. The discrete sub-peaks are called D-wave (PO), and I" 12 , Irwaves (PI, P2, P3). The single motor unit data suggest that all forms of cortical stimulation produce a complex corticospinal discharge with multiple peaks, but that anodal TES preferentially produces a D-wave, while TMS preferentially produces an I-wave, either an I,-wave if the induced current in the brain is directed from posterior to anterior, or an I}-wave if the induced current is directed from anterior to posterior (with kind permission, modified from Day et al., 1989).
muscles which often receive corticospinal projections from either hemisphere (Benecke and Meyer, 1991; Ferbert et al., 1992a; Hamdy et al., 1996). Another exception are ipsilateral motor responses in limb muscles which, however, are only obtainable during muscle contraction and usually much smaller and delayed by some 5-10 ms when compared to size-matched contralateral responses (Wassermann et al., 1994; Ziemann et al., 1999; Eyre et al., 2001). In summary, for neurophysiological routine purposes it can be taken that TMS assesses the motor system via trans synaptic activation of fast-conducting cortico-spinal tract fibers that project monosynaptically on alpha-motoneurons in the contralateral spinal cord. Finally, many studies used transcranial electrical stimulation (TES) in addition to TMS to sort out whether a physiological process occurs at the cortical or at a subcortical level (see below). This opportunity relies on the fact that low-intensity anodal TES activates the corticospinal tract directly (Fig. 1), probably close to the axon initial segment, and therefore does not detect changes that occur at the level of the corticospinal neuron or further upstream (Day et al., 1989; Rothwell et al., 1994; Di Lazzaro et al., 1998a).
8.2. Assessment of the cortico-spinal tract A recipe for how to perform single steps of TMS in clinical practice, including safety issues, exact placement of EMG electrodes and stimulating coil etc. is given in the IFCN recommendations for the practice of clinical neurophysiology (Rossini et al., 1999) and will not be repeated here. The following sections are devoted to details of how the integrity of the corticospinal tract can be assessed by central motor conduction time and the amplitude of the motor evoked potential.
8.2.1. Central motor conduction time 8.2.1.1. Techniques and principles The conduction time from motor cortex to alphamotoneurons in the spinal cord is referred to as the central motor conduction time (CMCT). Several methods have been proposed for measuring CMCT. All of them compute the difference between the conduction time from cortex to muscle (cortico-
TRANSCRANIAL MAGNETIC STIMULATION
muscular latency, CML) and the peripheral motor conduction time (PMCT). The CML equals the onset latency of the motor evoked potential (MEP). The PMCT can be measured by five different methods: F-wave latency (Rossini et aI., 1987; Robinson et aI., 1988), tendon reflex latency (Ofuji et aI., 1998), electrical needle stimulation of the spinal nerve roots (Evans et aI., 1990), transcutaneous electrical stimulation of the spinal nerve roots (Merton et aI., 1982; Rossini et al., 1985; Schmid et aI., 1991), and transcutaneous magnetic stimulation of the spinal nerve roots (Epstein et aI., 1991). For the F-wave method, PMCT is calculated by PMCT=(F+M -1)/2 where F is the shortest of (usually) 20 F-wave latencies, M is the M-wave latency and 1 (in ms) is the estimated delay time for antidromic activation of the spinal alpha-motoneuron. For the tendon reflex method, PMCT is calculated by PMCT=(T-1)12 where T is the tendon reflex latency and 1 (in ms) is the delay time at the spinal alpha-motoneuron. For all other methods, PMCT equals the onset latency of the compound muscle action potential (CMAP) evoked by stimulation of the spinal nerve roots. Spinal nerve root stimulation implies that the CMCT includes the proximal segment of the spinal motor nerve because excitation takes place not at the spinal alpha-motoneuron directly but in the region of the intervertebral foramen (Epstein et aI., 1991; Maccabee et al., 1991). Therefore, the CMCT obtained by the F-wave and tendon reflex methods is shorter by 0.5-1.4 ms for the cervical roots (Ugawa et aI., 1989; Britton et aI., 1990; Chokroverty et aI., 1991; Samii et aI., 1998) and by 3.~.1 ms for the lumbosacral roots (Ugawa et aI., 1989; Britton et al., 1990; Chokroverty et aI., 1993) compared to the CMCT obtained by one of the spinal nerve root stimulation methods. CMCT measured by the Fwave or stretch reflex methods comprises the conduction time from motor cortex to spinal cord plus one synaptic delay (synapse between the corticospinal axon and the spinal alpha-motoneuron) plus temporal summation time at the spinal alphamotoneuron to reach action potential threshold. This spinal delay time was estimated as 0.5 ±0.3 ms in active target muscle (Ugawa et aI., 1995a).
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It is recommended to measure CMCT in the isometrically contracting target muscle (5-20% of maximum voluntary contraction) using stimulus intensities of 120-150% above motor threshold (Rossini et aI., 1994, 1999; Rothwell et aI., 1999). The CMCT measured in active muscle is shorter by some 2-3 ms (sometimes up to 6 ms) compared to the CMCT measured in resting muscle (Hess et aI., 1986; Rothwell et aI., 1987). This is explained by elimination of the temporal summation to reach action potential threshold of some spinal alphamotoneurons at motor response onset, and by recruitment of larger, more rapidly conducting spinal alpha-motoneurons during muscle contraction. The CMCT is shorter by 0-3 ms if the current induced in the brain is directed lateral-to-medial rather than posterior-to-anterior due to the preferential activation of the D-wave with lateral-to-medial directed currents compared with preferential activation of I-waves with posterior-to-anterior directed currents (see above) (Werhahn et aI., 1994). These sources of variance underline the necessity to adhere always to a standardized protocol for CMCT measurements (e.g. Rossini et aI., 1994, 1999; Rothwell et al., 1999). Normative CMCT data in adults are available for many muscles of the upper and lower limb, axial muscles and cranial muscles (e.g. Rothwell et al., 1991). CMCT to lower but not upper limb muscles requires correction for body height (Claus, 1990). Finally, CMCT changes with maturation and aging of the corticospinal tract (Muller et al., 1991; Eyre and Miller, 1992; Kloten et aI., 1992; Caramia et aI., 1993). Conduction time measurements of the corticospinal tract can be segmented. The CMCT from motor cortex to the pyramidal tract decussation is the latency difference of the motor evoked potentials elicited by motor cortex stimulation and by either magnetic (Ugawa et aI., 1994b; Ugawa, 1999) or electrical direct stimulation (Ugawa et aI., 1991b) of the descending corticospinal tract at the level of the foramen magnum. Furthermore, the corticospinal tract can be activated by transcutaneous electrical stimulation at several levels further downstream (Ugawa et aI., 1995a). The conduction velocity is 68±5 mls along the corticospinal tract but lowers to 40±7 mls at the cauda equina (Ugawa et aI., 1995a). Conduction time within the cauda equina can be measured as the latency difference of motor evoked
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potentials elicited by magnetic stimulation with a large eight-shaped coil oriented vertically over the proximal cauda and horizontally over the distal cauda (Maccabee et al., 1996).
8.2.1.2. Applications CMCT prolongation may be caused by: (i) demyelination (and therefore slowing of conduction) of the fastest-conducting corticospinal fibers; (ii) degenerative or ischemic damage of the fastestconducting fibers; and (iii) increased dispersion of the multiple corticospinal discharge, resulting in less effective temporal summation at the spinal alphamotoneuron. Consequently, CMCT measurements are useful in central demyelinating disease (e.g. multiple sclerosis), cerebral ischemic stroke, myelopathies, neurodegenerative disease affecting the corticospinal tract (e.g. ALS, hereditary spastic paraplegia, HMSN with pyramidal signs, Friedreich's ataxia, SCA-1), some movement disorders (e.g. Wilson's disease, MSA, PSP), mitochondrial disorders, and myotonic dystrophy. 8.2.2. Motor evoked potential amplitude 8.2.2.1. Techniques and principles The amplitude of the motor evoked potential (MEP) elicited by motor cortex stimulation should be related to the amplitude of the maximum M wave obtained by supramaximal stimulation of the peripheral nerve (Rossini et al., 1994): MEP%=MEPlMmaxx 100 where MEP and M max are the peak-to-peak amplitude (Rossini et al., 1994) or area under the curve (Kiers et al., 1995) of the motor evoked potential and the maximum M wave, respectively. This ratio estimates the portion of the spinal alpha-motoneuron pool activated by TMS (Rossini et al., 1994). MEP amplitude and MEP area increase with stimulation intensity, usually in a non-linear, sigmoid fashion (Hess et al., 1987a; Rothwell et al., 1987; Kiers et al., 1995; Devanne et al., 1997). Intrinsic hand muscles show the steepest input-output relation and highest MEP% levels (Rothwell et al., 1987; Chen et al., 1998b) while proximal arm muscles, in particular the biceps (Rothwell et al., 1987; Chen et al., 1998b), trunk muscles (Chen et al., 1998b) and lower limb muscles (Rothwell et al., 1987; Chen et al., 1998b) have lower figures. These differences are
V.ZIEMANN
explained by the highest density and largest number of corticomotoneuronal fibers, and the highest excitatory descending drive onto spinal alpha-motoneurons of intrinsic hand muscles compared to other muscles (Cowan et al., 1986; Palmer and Ashby, 1992a; Maertens de Noordhout et al., 1999). MEP% increases with voluntary contraction of the target muscle (Hess et al., 1986, 1987a; Ravnborg et al., 1992; Kischka et al., 1993) or, to a lesser degree, with contraction of other muscles (Hess et al., 1986; Pereon et al., 1995; Stedman et al., 1998). Most likely, both cortical (Hess et al., 1986; Baker et al., 1995; Lemon et al., 1995; Pereon et al., 1995; Mills and Kimiskidis, 1996; Di Lazzaro et al., 1998b) and spinal mechanisms (Maertens de Noordhout et al., 1992a; Kaneko et al., 1996b; Di Lazzaro et al., 1998b) contribute this MEP facilitation induced by contraction. Measurements of MEP% suffer from two important limitations. First, MEP% shows a considerable trial-to-trial variability the causes of which are not entirely understood (Hess et al., 1987a; Rothwell et al., 1987; Kiers et al., 1993; Nielsen, 1996; Van der Kamp et al., 1996; Ellaway et al., 1998; Gugino et al., 2001). This variability can be reduced by high stimulus intensity, controlled muscle contraction, or paired stimulation (Nielsen, 1996; Van der Kamp et al., 1996; Kiers et al., 1993). Second, even with maximum stimulus intensity and strong muscle contraction, MEP% is usually considerably less than 100%. This is mainly due to phase cancellation of muscle action potentials, caused in turn by the desynchronized activation of the spinal alpha-motoneurons (Magistris et al., 1998). For intrinsic hand muscles, maximum MEP% values are, on average, around 50-60% with a large inter-individual variability (Hess et al., 1987a, b; Rothwell et al., 1987). Therefore, MEP% in hand muscles can be considered abnormal only when < 15%.
8.2.2.2. Applications MEP% reduction may be caused by: (i) increased dispersion of the multiple corticospinal discharge, resulting in increased desynchronicity of alphamotoneuron discharge and increased phase cancellation; (ii) complete or incomplete failure of conduction due to interruption or degeneration of the corticospinal tract; (iii) severe depression of excitability of the corticospinal neuron and/or the spinal motoneuron; and (iv) intracortical conduction block
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along the neural elements responsible for the generation of l-waves. MEP% measurements are useful in the same diseases given above for CMCT measurements. 8.2.3. Triple stimulation technique 8.2.3.1. Techniques and principles The problem of phase cancellation in the conventional MEP% measurement can be overcome by a recently developed triple stimulation technique (TST) (Magistris et al., 1998) which, through two collisions, suppresses MEP desynchronization. TST was first introduced and will be described here for the abductor digiti minimi muscle (Magistris et al., 1998) (Fig. 2). The first pulse is TMS applied to the hand area of the motor cortex. The second pulse is supramaximal electrical stimulation to the ulnar nerve at the wrist after Delay I (equal to the minimal latency of the MEP, rounded down to the nearest millisecond, minus the latency of the maximum M wave, rounded up to the nearest millisecond). The third pulse is supramaximal electrical stimulation of Erb's point after Delay II (equal to the CMAP Erb latency rounded down to the nearest millisecond, minus the latency of the maximum M wave, rounded up to the nearest millisecond). The first collision occurs along the peripheral nerve between the descending volley induced by TMS and the antidromically ascending volley induced by the distal ulnar nerve stimulation. The second collision occurs between the descending volley induced by stimulation of Erb's point and that part of the ascending volley produced by distal ulnar nerve stimulation which had not been collided in the first collision. Two extreme scenarios are possible. If TMS results in 0% activation of the alpha-motoneuron pool (due to, e.g. subthreshold TMS or complete cortico-spinal conduction block) then no first collision takes place because there is no descending volley. The second collision will be complete so that the resulting CMAP Erb after TST will be 0% of an unconditioned CMAPErb control response. In contrast, if TMS results in 100% activation of the alpha-motoneuron pool then the first collision will be complete. No second collision will occur because there is no remaining part of the ascending volley from the distal ulnar nerve stimulation to collide with. Therefore, CMAP Erb after TST will be 100% of the unconditioned CMAP Erb control response. The larg-
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est obtainable ratio of TST CMAPErJcontrol CMAP Erb was, on average, 99±2% in healthy subjects (Magistris et al., 1998). To achieve this, slight contraction of the target muscle was required in most instances. The intensity of TMS was on average 80% of maximum stimulator output. TST values <93% were considered abnormal (Magistris et al., 1998). TST was also validated for a foot muscle (Buhler et al., 2001). Limitations of TST are that it is more complex than MEP% measurements and cannot be applied to proximal muscles. 8.2.3.2. Applications TST shows promise to detect and quantify with greater sensitivity and reliability conduction failure along the corticospinal tract than was possible with the conventional MEP% technique (Magistris et al., 1999; Rosier et al., 2000; Truffert et al., 2000). Consequently, TST is useful in the diseases given above for CMCT and MEP%. 8.2.4. Single motor unit recordings 8.2.4.1. Techniques and principles In the routine neurophysiological setting, the motor response induced by TMS is recorded most often by surface electromyography (EMG). In addition, or alternatively, single motor units (SMU) can be recorded with needle EMG. This may reveal additional information that cannot be disclosed with surface EMG (Mills, 1991). In hand muscles of healthy subjects, peri-stimulus time histograms (PSTH) show an increased firing probability of a voluntary activated SMU 17-30 ms after the TMS pulse (Day et al., 1989; Boniface et al., 1991; Mills, 1991) (Fig. 1). The area of this 'primary peak' can be used to estimate the amplitude of the composite excitatory post-synaptic potential (EPSP) at the spinal alpha-motoneuron, and the duration of the primary peak reflects the rise time of this EPSP (Ashby and Zilm, 1982; Fetz and Gustafsson, 1983). The short duration of the primary peak of 4.6± 1.7 ms suggests that the corticospinal neurons activated by TMS project largely mono-synaptically onto the spinal alpha-motoneurons (Day et al., 1989). The primary peak is largest for intrinsic hand muscles (estimated mean EPSP for the first dorsal interosseus 2.9±0.2 mY) while forearm muscles and the biceps brachii receive weaker net facilitation (Palmer and Ashby, 1992a). Many triceps and deltoid SMU are
100
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TRANS CRANIAL MAGNETIC STIMULATION
inhibited by TMS so that there is no net facilitation (Palmer and Ashby, 1992a). SMU are recruited by TMS in the same order as by voluntary contraction, following the Henneman size principle (Hess et aI., 1987a; Awiszus and Feistner, 1994; Awiszus et aI., 1999). The primary peak is divided into subpeaks, some 1.5 ms apart (Day et aI., 1989; Mills, 1991) (Fig. 1). Very likely, these subpeaks reflect the Dand I-waves (see above). With different current directions in the motor cortex it is possible to activate selectively single subpeaks (Day et al., 1989; Sakai et aI., 1997; Terao et aI., 2001) (Fig. 1).
8.2.4.2. Applications Multiple sclerosis (Boniface et aI., 1991), ALS (e.g. Awiszus and Feistner, 1995; Weber et aI., 2000), Parkinson's disease (Kleine et aI., 2001), spinal cord injury (Smith et aI., 2000). 8.3. Motor cortex excitability 8.3.1. Motor threshold 8.3.1.1. Techniques and principles Motor threshold (MT) has been defined in different ways in the literature. According to IFCN recommendation, MT is the minimum intensity that is sufficient to produce a small MEP (> 50 IJo V) in at least half of the trials in the resting (resting MT) or contracting (active MT) target muscle (Rossini et aI., 1994, 1999). A slightly different approach deter-
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mines the maximum stimulus intensity with a probability of zero to elicit an MEP in the target muscle (lower threshold) and the minimum stimulus intensity with a probability of one (upper threshold) (Mills and Nithi, 1997b). Finally, threshold can be defined as the x-axis intercept of the peak slope tangent of the MEP intensity curve (Carroll et aI., 2001). Within-subject variability of MT is low so that longitudinal measurements are reasonable (Ziemann et aI., 1996a; Mills and Nithi, 1997b; Carroll et aI., 2001). In contrast, between-subject variability is high for a largely unexplained reason (Cicinelli et aI., 1997; Mills and Nithi, 1997b). The active MT is on average 25% lower than the resting MT. Therefore, it is important to monitor complete voluntary muscle relaxation for measurements at muscle rest. This can be done by high gain (50 IJo V/Div) EMG audiovisual feedback, and automatic trial rejection whenever significant voluntary EMG activity contaminated the pre-stimulus EMG period (Kaelin-Lang and Cohen, 2000). MT is lowest for hand muscles and higher for proximal muscles of the arm (Brouwer and Ashby, 1990; Macdonell et aI., 1991; Chen et aI., 1998b), trunk and lower limb (Chen et aI., 1998b). These differences may reflect the density of the corticomotoneuronal projection which is highest for intrinsic hand muscles. MT reflects the excitability of the most excitable corticospinal neurons (Hallett et al., 1999). Insight into the physiology of the MT and other motor cortex excitability measures (see below)
Fig. 2. The triple stimulation technique (TST) principle. On the left, a schematic diagram of the motor tract is simplified to four corticospinal axons with monosynaptic connections to four spinal motoneurons. Horizontal lines represent muscle fibers of four motor units. EMG recordings in the abductor digiti minimi muscle are shown on the right. (A) TST test, (H) TST control, (C) response to a single stimulus at wrist and (D) superimposition of recordings A-C. In this example, submaximal TMS excites 75% of the axons (three axons out of four). Desynchronization of the three action potentials is assumed to occur within the corticospinal tract (or possibly at the spinal motoneuron level). (A, 1) TMS excites three out of four axons. (A, 2) After a delay, a supra-maximal stimulus applied to the wrist evokes the first negative (upward) deflection in the TST test trace, this response is followed by that of the multiple-discharge volley of spinal motoneurons (not figured on the left scheme). (A, 3) After a delay, a supra-maximal stimulus is applied to Erb's point; (A, 4) a synchronized response from the three axons excited initially by TMS is recorded as the second large deflection of TST. (H, 1) A supra-maximal stimulus is applied to Erb's point; (H, 2) after a delay, a supra-maximal stimulus applied to the wrist evokes the first deflection of TST control trace; (H, 3) after a delay, a supra-maximal stimulus is applied to Erb's point; (H, 4) a synchronized response from the four axons is recorded as the second deflection ofTST control trace. (C) The response evoked by stimulating the wrist serves as a baseline for measurement of the amplitude and area of the second deflection of the TST curves. (D) On the superimposed traces, the smaller size of the second deflection on the TST test trace, compared with that of the TST control trace, demonstrates that not all spinal axons of the target muscle were excited by TMS (in this example both amplitude and area ratios should be 75% if the four individual motor units had identical sizes). Calibrations: 2 mV and 5 ms (with kind permission, from Magistris et al., 1998).
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was fostered by the combination of TMS and neuropharmacology. Voltage-gated sodium and calcium channel blocking drugs, such as carbamazepine or phenytoin elevate MT (Mavroudakis et al., 1994; Ziemann et al., 1996a; Chen et al., 1997b; Boroojerdi et al., 2001), whereas a single loading dose of neurotransmitter (GABA, glutamate, dopamine, serotonin, norepinephrine, acetylcholine) modulating drugs does usually not affect MT (for review, Ziemann and Hallett, 2000). These findings suggest that MT reflects primarily membrane-related ionchannel dependent excitability ofaxons excited by TMS. 8.3.1.2. Applications Increased MT may indicate significant damage of the corticospinal tract after stroke (Homberg et al., 1991; Catano et al., 1996) or spinal cord lesion (Linden and Berlit, 1994; McKay et al., 1997). Decreased MT suggests increased corticospinal tract excitability in untreated patients with idiopathic generalized epilepsy (Reutens et al., 1993a), in nonwasted muscles of patients with early ALS (Mills and Nithi, 1997a), in Alzheimer's disease (Pepin et al., 1999) and in patients with obsessive-compulsive disorder (Greenberg et al., 2000). MT is of limited use as a one-point observation in a single patient due to large between-subject variability, but longitudinal measurements are feasible due to low within-subject variability. 8.3.2. Motor evoked potential intensity curve 8.3.2.1. Techniques and principles The MEP intensity curve is defined as the increase in MEP amplitude (or MEP area) with stimulus intensity. This increase is typically non-linear (Hess et al., 1987a; Kiers et al., 1995) and described best by a sigmoid function (Devanne et al., 1997; Carroll et al., 2001)
MEP(s)=MEPrna/I +e m(S50-s) where MEP(s) is the MEP amplitude (or MEP area) at a given stimulus intensity (s), MEP max is the maximum MEP defined by the function, m is the slope parameter of the function, and S50 is the stimulus intensity at which the MEP size is 50% of MEPmax' Stimulus intensity can be set as percentage of maximum stimulator output irrespective of motor threshold. This facilitates longitudinal observations
where the primary interest is to compare MEP elicited by the same physical stimulus intensities. Another possibility is to set stimulus intensity as percentage of motor threshold. This would facilitate longitudinal observations corrected for change in threshold. Voluntary contraction of the target muscle shifts the MEP intensity curve toward lower intensities (decrease in motor threshold) and increases the slope (Devanne et al., 1997). The high-intensity part of the MEP intensity curve reflects most likely the excitability of corticospinal neurons with intrinsically high threshold (Thickbroom et al., 1998; Hallett et al., 1999). Several neurotransmitter-modulating drugs decrease (lorazepam, levetiracetam) or increase (d-amphetamine) slope and MEP max (Boroojerdi et al., 2001; Sohn et al., 2001). 8.3.2.2. Applications Movement disorders (Valls-Sole et al., 1994; Ikoma et al., 1996), reorganization of the motor cortex after limb amputation (Cohen et al., 1991a; Kew et al., 1994; Chen et al., 1998a). 8.3.3. Motor evoked potential mapping 8.3.3.1. Techniques and principles An MEP map is the area on the scalp surface from which MEPs can be elicited in a given target muscle. To obtain an MEP map, multiple scalp sites are stimulated by moving the stimulating coil (ideally a small eight-shaped coil) along a grid. The coordinates of the grid should be referenced relative to standard landmarks, such as C, according to the International 10-20 system. Mapping can be done either along grids with co-ordinates 0.5-2 em apart (Cartesian co-ordinate system) (Brasil-Neto et al., 1992; Wassermann et al., 1992; Classen et al., 1998), or grids with co-ordinates based on a latitudelongitude system, which forms a more general frame of reference by taking into account head curvature (Wilson et al., 1993b; Thickbroom et al., 1998). MEP mapping guided by online co-registered MRI shows significantly improved precision of coil placement compared with conventional 'blind' MEP mapping (Gugino et al., 2001). Mapping should be performed with a moderate stimulation intensity of 110-120% MT, as determined at the optimal site for eliciting MEP in the target muscle. To account for the considerable trial-to-trial variability in MEP amplitude which even increases with distance from
TRANS CRANIAL MAGNETIC STIMULATION
the optimal site (Brasil-Neto et aI., 1992), about 10 trials need to be applied to a given co-ordinate (Classen et aI., 1998). Mapping should be continued until effective sites are completely surrounded by non-effective sites. A restriction to those sites in proximity to the optimal site may degrade map accuracy considerably (Classen et aI., 1998). With an optimal mapping technique, good reliability (Mortifee et aI., 1994) and a spatial resolution in the order of 0.5 em (Brasil-Neto et aI., 1992) can be achieved. Any map is characterized by three features: extent, location and shape. Map extent is usually expressed by the number of effective stimulation sites (Wassermann et aI., 1992; Classen et aI., 1998). Map extent is a direct function of the excitability of the stimulated corticospinal neurons as shown by a close correlation between map extent and the slope of the MEP intensity curve (Ridding and Rothwell, 1997). Current spread and the depth of the stimulated corticospinal neurons with respect to scalp surface contribute to map extent, i.e. the map is always larger than the actual extent of the population of stimulated corticospinal neurons (Thickbroom et aI., 1998). Map location is often expressed by the site of the maximum MEP, but it is better to use the center of gravity (COG) which is the sum of all map coordinates weighted by MEP amplitude at those co-ordinates, divided by the sum of all MEP amplitudes (map volume) (Wassermann et aI., 1992). The weight at any scalp position can be interpreted as the proportion of the map volume contributed by that location. Map location corresponds to the scalp location at which the greatest number of the most excitable corticospinal neurons can be stimulated (Classen et aI., 1998; Thickbroom et aI., 1998). Map shape is given in descriptive terms. Maps are usually ellipsoid with the long axis parallel to the direction of the inducing current (Wilson et aI., 1996). MEP map reorganization is demonstrated best by changes in map location while changes in map extent are confounded by corticospinal excitability (Ridding and Rothwell, 1997). MEP mapping has confirmed a rough somatotopical order of motor representations in human motor cortex with the face, hand, upper arm, neck/trunk and leg MEP located along a lateral-to-medial axis (Wassermann et al., 1992; Metman et aI., 1993; Thompson et aI., 1997; Classen et aI., 1998; Krings et al., 1998). Maps for different muscles of the hand and arm overlap, but hand representations are more
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lateral than arm representations (Wassermann et al., 1992). MEP mapping was referred to the underlying anatomy (Levy et al., 1991; Wang et aI., 1994; Krings et aI., 1997, 1998; Singh et aI., 1997), and multi-modal approaches combined the results of MEP mapping with functional activation studies using positron emission tomography (Wassermann et aI., 1996c; Classen et aI., 1998) and functional magnetic resonance imaging (Krings et aI., 1997; Bastings et aI., 1998; Terao et aI., 1998; Boroojerdi et aI., 1999). These studies generally show that the MEP maps project onto the precentral gyrus and largely overlap with the functional activation areas.
8.3.3.2. Applications Testing motor cortex reorganization associated with cerebral stroke (e.g. (Hallett et aI., 1998; Liepert et aI., 1998; Byrnes et aI., 1999; Traversa et aI., 1999), dystonia (Byrnes et aI., 1998), facial palsy (Rijntjes et aI., 1997), hemi-facial spasm (Liepert et aI., 1999a), spinal cord injury (Levy et aI., 1990; Topka et aI., 1991; Streletz et aI., 1995), limb amputation (Cohen et aI., 1991a; Kew et al., 1994; Ridding and Rothwell, 1997; Karl et aI., 2001), motor practice and motor learning (Pascual-Leone et aI., 1994a; Pascual-Leone et al., 1995a, b; Liepert et aI., 1999b). MEP mapping may be used complementary to other techniques in pre-surgical identification of motor cortex. 8.3.4. Cortical silent period 8.3.4.1. Techniques and principles The cortical silent period (CSP) is defined as interruption of tonic voluntary EMG activity in a target muscle contralateral to the stimulated motor cortex (Cantello et al., 1992; Wilson et aI., 1993a). CSP duration is usually determined from the TMS stimulus artifact, or alternatively from MEP onset, to the resumption of sustained voluntary EMG activity. Automatic determination of CSP duration is possible by statistical procedures that compare the poststimulus EMG with the pre-stimulus EMG (Nilsson et aI., 1997; Garvey et aI., 2001). A CSP can be obtained in any muscle but is longest in the intrinsic hand muscles where it can exceed 250 ms (Cantello et al., 1992). CSP duration correlates approximately linearly with stimulus intensity (Cantello et al., 1992; Haug et aI., 1992; Inghilleri et aI., 1993; Triggs et aI., 1993; Wilson et al., 1993a). Ideally,
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stimulus intensity should be related to CSP threshold, not to MEP threshold, as MEP and CSP may be differentially affected by disease (Chistyakov et al., 2001). The level of muscle contraction either does not affect CSP duration (Haug et al., 1992; Inghilleri et al., 1993; Roick et al., 1993) or leads to slight shortening (Cantello et al., 1992; Wilson et al., 1993a; Mathis et al., 1998). CSP duration is altered by specifics of the motor instruction, e.g. to prepare for contraction, or to hold isotonic vs. isometric contraction (Mathis et al., 1998; Hoshiyama and Kakigi, 1999; Mathis et al., 1999). Between-subject variability is high, while within-subject variability and side-to-side differences between homologous muscles are low (Cicinelli et al., 1997; Fritz et al., 1997). The late part of the CSP originates mainly or exclusively at the cortical level while the early part is mainly due to inhibition of the spinal alphamotoneuron (Fuhr et al., 1991; Cantello et al., 1992; Inghilleri et al., 1993; Ziemann et al., 1993; Davey et al., 1994; Chen et al., 1999). The contributing mechanisms of the late part of the CSP are not exactly known but most likely GABA-B receptor mediated cortical inhibition plays a crucial role. Pharmacological activation of GABA-B receptors leads to significant CSP lengthening (Siebner et al., 1998a; Werhahn et al., 1999). 8.3.4.2. Applications Epilepsy (e.g. Classen et al., 1995; Cincotta et al., 1998; Inghilleri et al., 1998; Macdonell et al., 2001), cerebral stroke (e.g. Schnitzler and Benecke, 1994; VonGiesen et al., 1994; Classen et al., 1997; Ahonen et al., 1998), Parkinson's disease (for review, Cantello et al., 2002), Huntington's disease (Priori et al., 1994; Modugno et al., 2001), dystonia (Filipovic et al., 1997; Rona et al., 1998; Amadio et al., 2000), tic disorder (Ziemann et al., 1997; Moll et al., 2001), congenital mirror movement (Cincotta et al., 1996), ALS (Prout and Eisen, 1994; Siciliano et al., 1999), stiff person syndrome (Sandbrink et al., 2000), cerebellar ataxia (Oechsner and Zangemeister, 1999), tetanus (Warren et al., 1999), migraine (Aurora et al., 1999; Werhahn et al., 2000). 8.3.5. Paired-pulse excitability at long interstimulus intervals (20-200 ms) 8.3.5.1. Techniques and principles Paired-pulse excitability at long inter-stimulus intervals (20-200 ms) refers to the modulating
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effects of a supra-threshold conditioning pulse on the amplitude of the test MEP elicited by the subsequent supra-threshold test pulse. Both pulses are given through the same stimulating coil, usually at the same stimulus intensity of 110-150% of MT. The target muscle can either be at rest or voluntarily activated. The effect of the conditioning pulse is usually facilitatory at intervals of 20-40 ms, but inhibitory at intervals >50 ms (Claus et al., 1992; Valls-Sole et al., 1992). This paired-pulse facilitation and paired-pulse inhibition occur mainly through mechanisms at the level of the motor cortex (Claus and Brunholzl, 1994; Kaneko et al., 1996c; Nakamura et al., 1997; Chen et al., 1999). Paired-pulse inhibition at long inter-stimulus intervals underlies mechanisms different from those responsible for the paired-pulse inhibition at short inter-stimulus intervals (1-5 ms, see below) (Sanger et al., 2001), and does not test the same long-lasting inhibitory mechanisms as the CSP (Berardelli et al., 1996). 8.3.5.2. Applications Epilepsy (Brodtmann et al., 1999; Valzania et al., 1999; Manganotti et al., 2000), Parkinson's disease (for review, Cantello et al., 2002), Huntington's disease (Tegenthoff et al., 1996; Priori et al., 2000), dystonia (Chen et al., 1997c; Rona et al., 1998), cerebellar ataxia (Wessel et al., 1996). 8.3.6. Paired-pulse inhibition and facilitation at short inter-intervals (1-30 ms) 8.3.6.1. Techniques and principles Paired-pulse inhibition (PPI) and facilitation (PPF) at short inter-stimulus intervals (1-30 ms) refer to the modulating effects of a sub-threshold conditioning pulse on the amplitude of the test MEP elicited through the same stimulating coil by the subsequent supra-threshold test pulse (Fig. 3). The intensity of the conditioning pulse is usually set to 80% of resting MT or 90% of active MT, and the intensity of the test pulse to produce a test MEP of about 1 mV in peak-to-peak amplitude (Kujirai et al., 1993a; Ziemann et al., 1996b). PPI occurs at inter-stimulus intervals of 1-5 ms, PPF at intervals of 7-20 ms (Kujirai et al., 1993a; Ziemann et al., 1996b; Ziemann, 1999). Both originate through mechanisms at the level of the motor cortex (Di Kujirai et al., 1993a; Ziemann et al., 1996b; Nakamura et al., 1997; Lazzaro et al., 1998c). PPF is
105
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10 ms Fig. 3. Paired-pulse inhibition and facilitation at short interstimulus-intervals (PPI, PPF). MEPs by a supra-threshold magnetic cortical test stimulus in relaxed first dorsal interosseous muscle are inhibited by a prior, sub-threshold conditioning stimulus at short inter-stimulus intervals of 1-5 ms (PPI) and facilitated at longer intervals of 10--15 ms (PPF). The left panel shows examples of EMG data from one healthy subject. The first trace shows absence of any MEP to the conditioning stimulus alone. The lower two records have two superimposed traces, the MEP to the test stimulus given alone, and the MEP to the test stimulus when given 3 (middle traces) or 2 ms (lower traces) after the conditioning stimulus. The larger MEP (dotted line) is the response to the test stimulus alone. It is dramatically suppressed at these two inter-stimulus intervals. Each trace is the average of 10 trials. The right panel shows the averaged group data of 6 subjects (means ±SD). The conditioned MEP is given as a percentage of the test MEP (y-axis) and expressed as a function of the inter-stimulus interval (x-axis) (with kind permission, from Kujirai et al., 1993a).
physiologically distinct from PPI and not merely a rebound facilitation (Ziemann et aI., 1996b; Strafella and Paus, 2001). PPI and PPF are tested at muscle rest, as both measures are suppressed by even slight voluntary contraction (Ridding et aI., 1995). PPI and PPF are studied predominantly in hand muscles but can be obtained similarly in many other muscles (Chen et aI., 1998b). PPI but not PPF decreases with age (Peinemann et aI., 2001) and may be affected by personal trait, such as the level of neuroticism (Wassermann et aI., 2001) and by the menstrual cycle (Smith et aI., 1999). GABA-A receptor agonists, N-methyl-o-aspartate (NMDA) receptor blockers, dopamine receptor agonists and serotonin result in PPI increase and/or PPF decrease (for review, Ziemann and Hallett (2000». Dopamine (D2) receptor antagonists, muscarinic receptor antagonists, GABA-B auto-receptor activation and norepinephrine agonists decrease PPI and/or increase PPF (Ziemann and Hallett, 2000; Bor-
oojerdi et aI., 2001; Liepert et aI., 2001; Plewnia et aI., 2001). Recent findings indicate that the PPI consists of at least two distinct phases of inhibition with different physiological properties, one at interstimulus intervals of about I ms, and the other at intervals of around 2.5 ms (Fisher et aI., 2002). Futhermore, PPI may in fact be a net inhibition, consisting of strong inhibitory and weaker facilitatory effects (see l-wave facilitation below). In summary, it is currently believed that PPI and PPF test the integrity and excitability of inhibitory and excitatory neuronal circuits in the motor cortex which are under the control of various neurotransmitter systems and in tum control the excitability of corticospinal neurons. 8.3.6.2. Applications (for reviews, Ziemann et al., 1998a; Ziemann, 1999; Cantello et al., 2002) Epilepsy, cerebral stroke, Parkinson's disease, Huntington's disease and other dyskinetic syn-
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dromes, dystonia, cerebellar ataxia, ALS, autosomaldominant spastic paraplegia, stiff-person syndrome, restless legs syndrome, migraine, limb amputees, Alzheimer's disease, tic and other neuro-psychiatric disorders. Most of these diseases show a decrease in PPI and/or an increase in PPF. Therefore, while suggestive of a good sensitivity for the detection of abnormalities of motor cortex excitability, PPI and PPF at present do not differentiate between even very different pathological conditions. This weakness may be overcome by refined paired-pulse stimulation techniques (Fisher et al., 2002). 8.3.7. I-wave facilitation 8.3.7.1. Techniques and principles I-wave facilitation refers to the facilitatory effects of a sub-threshold second pulse on the amplitude of a test MEP elicited by a supra-threshold first stimulus given through the same stimulation coil 0.5-6.0 IDS earlier (Ziemann et al., 1998b). Alternatively, two pulses close to MT can be used (Tokimura et al., 1996). I-wave facilitation occurs at discrete inter-stimulus intervals of 1.1-1.5 ms, 2.3-2.9 ms and 4.1-4.5 ms with much less effect at intermediary intervals (Tokimura et al., 1996; Ziemann et al., 1998b). I-wave facilitation originates through mechanisms at the level of the motor cortex (Tokimura et al., 1996; Ziemann et al., 1998b; Di Lazzaro et al., 1999c; Hanajima et al., 2002). The inter-peak latency between the three facilitatory MEP peaks is approximately 1.5 ms, comparable to the succession of I-waves (see above). I-wave facilitation is reduced by GABAergic drugs (Ziemann et al., 1998c; Wischer et al., 2001). In summary, the available evidence suggests that this paired pulse technique probes the excitability of motor cortical circuits that are responsible for the generation ofl-waves. 8.3.7.2. Applications Patients with multiple sclerosis may show a reduction of l-wave facilitation or even a complete disorganization of the MEP facilitatory peaks (Ho et ai., 1999).
8.4. Motor cortex connectivity As a general principle, motor cortex connectivity is assessed by testing the effects of a conditioning
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stimulus on the amplitude of a test MEP elicited by stimulation of the motor cortex. Another possibility is to stimulate the motor cortex and assess the activation of distant target structures by functional imaging (PET, fMRI) or electrophysiological methods (EEG, SEP, MRP). 8.4.1. Connectivity between different motor representations within motor cortex 8.4.1.1. Techniques and principles Focal conditioning stimulation of the leg area of the motor cortex inhibits a test MEP elicited by a supra-threshold pulse given a few milliseconds (1-5 ms) later over the hand area, and vice versa (Kujirai et al., 1993a). This suggests that within motor cortex connectivity is largely inhibitory. 8.4.1.2. Applications Lateral spread into motor representations of the proximal arm can occur during high-frequency repetitive TMS of the hand area of the motor cortex suggesting stimulation-induced break-down of cortico-cortical inhibitory mechanisms (Pascual-Leone et al., 1994c). Similarly, propagation of epileptic activity, such as the Jacksonian march, or an overflow of movement associated with an intended focal voluntary movement, such as in dystonia, may originate from deficient cortico-cortical inhibition between different motor representations, although this has not yet been tested. 8.4.2. Connectivity ofpremotor cortex and SMA with motor cortex 8.4.2.1. Techniques and principles Conditioning focal stimulation 3-5 em anterior to the hand area of the motor cortex, or 6 em anterior to the vertex inhibits the test MEP elicited by suprathreshold stimulation over the hand area of the motor cortex (Civardi et al., 2001). This effect is maximal at sub-threshold intensity (90% of active MT) and at an inter-stimulus interval of 6 IDS. It is thought that these conditioning sites correspond to the premotor cortex and the pre-SMA or SMA proper, and that their connections to the hand area of the motor cortex are largely inhibitory (Civardi et al., 2001; Gerschlager et al., 2001).
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8.4.2.2. Applications No data available yet. Potentially useful in neurological diseases with a presumed abnormal connectivity between the pre-motor cortex or SMA and the primary motor cortex, in particular movement disorders. 8.4.3. Inter-hemispheric connectivity between the two motor cortexes 8.4.3.1. Techniques and principles The hand areas of the two motor cortexes are connected, although sparsely, by callosal fibers (Gould et al., 1986; Rouiller et al., 1994). This transcallosal connection can be tested by the ipsilateral silent period (ISP) (Wassermann et al., 1991; Ferbert et al., 1992b; Meyer et al., 1995; Meyer et al., 1998) and inter-hemispheric inhibition and facilitation measured with a paired stimulation protocol (Ferbert et al., 1992b; Ugawa et al., 1993; Netz et al., 1995; Gerloff et al., 1998; Di Lazzaro et al., 1999a; Hanajima et al., 200la). The ISP refers to the interruption of voluntary tonic EMG activity caused by TMS of the motor cortex ipsilateral to the target muscle. In hand muscles, the ISP onset is 10-15 ms later than the onset latency of the contralateral MEP. This difference corresponds to the estimated conduction time through the corpus callosum (Cracco et al., 1989). ISP duration in hand muscles is about 30 ms (Wassermann et al., 1991; Ferbert et al., 1992b; Meyer et al., 1995; Meyer et al., 1998). Children up to the age of 6 years do not show an ISP (Heinen et al., 1998), suggesting maturation of inter-hemispheric connections between the two motor cortexes later in life. Paired stimulation applies a conditioning stimulus over one motor cortex followed by a test stimulus over the other motor cortex. Inhibition of the test MEP occurs at inter-stimulus intervals of around 10 ms, if the intensities of both stimuli are clearly above MT (Ferbert et al., 1992b; Netz et al., 1995). Interhemispheric facilitation results at inter-stimulus intervals of 4-5 or 8 ms, if the intensity of the conditioning stimulus is close to MT (Ugawa, 1993 #1067; Hanajima et al., 200la ). Very likely, these inter-hemispheric interactions are mediated by transcallosal fibers (Di Lazzaro et al., 1999a), but some data point toward the contribution of other pathways
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at the subcortical or even spinal level (Gerloff et al., 1998).
8.4.3.2. Applications ISP: Surgical lesions or agenesis of the trunk of the corpus callosum (Meyer et al., 1995; Meyer et al., 1998), multiple sclerosis (Boroojerdi et al., 1998; Hoppner et al., 1999; Schmierer et al., 2000), dystonia (Niehaus et al., 2001b), hydrocephalus (Roricht et al., 1998), schizophrenia (Hoppner et al., 2001). Inter-hemispheric facilitation/inhibition in the paired TMS protocol: Cortical myoclonus (Brown et al., 1996; Hanajima et al., 2001b), cortical-subcortical cerebral stroke (Boroojerdi et al., 1996), congenital mirror movements (Mayston et al., 1999), professional musicians (Ridding et al., 2000), schizophrenia (Daskalakis et al., 2002). 8.4.4. Connectivity from cerebellum to contralateral motor cortex 8.4.4.1. Techniques and principles The cerebellar hemispheres can be activated with percutaneous electrical (Ugawa et al., 1991a) or magnetic stimulation (Saito et al., 1995; Ugawa et al., 1995b; Werhahn et al., 1996). This leads to, on average, 50% inhibition of a test MEP elicited from the motor cortex contralateral to cerebellar stimulation at inter-stimulus intervals of 5-7 ms (Ugawa et al., 1995b; Werhahn et al., 1996). It is thought that this inhibition results from activation of the cerebello-dentato-thalamo-cortical pathway. An inhibition starting at slightly longer inter-stimulus intervals of 7-8 ms is probably caused by activation of peripheral nerve afferents at the level of the brachial plexus (Werhahn et al., 1996). 8.4.4.2. Applications The inhibitory interaction between cerebellum and motor cortex is reduced or absent in patients with lesions along the cerebello-dentato-thalamocortical pathway (Di Lazzaro et al., 1994; Ugawa et al., 1994a; Ugawa et al., 1997; Matsunaga et al., 2001). 8.4.5. Connectivity from motor cortex to ipsilateral spinal alpha-motoneurons
8.4.5./. Techniques and principles Ipsilateral corticospinal projections withdraw in an activity-dependent process during the first years
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of life (Miiller et al., 1997; Eyre et aI., 2001). In adults, ipsilateral MEP in hand muscles are elicited only in a fraction of subjects, and only if strong voluntary contraction of the target muscle and high stimulus intensity are used (Wassermann et aI., 1991; Wassermann et aI., 1994; Ziemann et aI., 1999). Compared to contralateral MEP, ipsilateral MEP are much smaller, delayed by 5-10 ms, and the optimal stimulation site is slightly more lateral and anterior (Wassermann et aI., 1991; Wassermann et aI., 1994; Ziemann et aI., 1999). The ipsilateral MEP is either mediated by a weak residual uncrossed corticospinal tract (Eyre et aI., 2001) or an oligosynaptic cortico-reticulospinal projection (Ziemann et aI., 1999). 8.4.5.2. Applications Congenital/persistent mirror movements (e.g. Farmer et aI., 1990; Cohen et aI., 1991c), cerebral palsy (e.g. Farmer et aI., 1991; Carr et aI., 1993; Cincotta et al., 2000), adult cerebral stroke: ipsilateral MEP from the affected motor cortex (Fries et aI., 1991;Alagona et aI., 2001), adult cerebral stroke: ipsilateral MEP from the unaffected motor cortex (Turton et al., 1996; Netz et aI., 1997; Caramia et aI., 2000; Trompetto et aI., 2000), corticobasal ganglionic degeneration (Valls-Sole et aI., 2001). 8.4.6. Connectivity from cutaneous and muscle afferents to motor cortex 8.4.6.1. Techniques and principles Cutaneous and proprioceptive afferent information from the body can influence motor cortex excitability at short latencies. In upper limb muscles, electrical stimulation of a mixed nerve below or at motor threshold (resulting primarily in activation of Ia fibers) and muscle stretch produce MEP facilitation in the stimulated or stretched muscle at inter-stimulus intervals around 20-30 ms, usually followed by MEP inhibition at longer intervals (Troni et aI., 1988; Day et aI., 1991; Deuschl et aI., 1991; Mariorenzi et aI., 1991; Rossini et aI., 1991; Palmer and Ashby, 1992b; Baldissera and Leocani, 1995). The short-latency MEP facilitation after mixed nerve stimulation may be preceded by a shortlatency and short-lasting MEP inhibition at inter-stimulus intervals of 19-21 ms (Tokimura et al., 2000). Blockade of muscarinic receptors leads to a reduction of this inhibition (Di Lazzaro et aI.,
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2000). Non-painful conditioning stimulation of digital cutaneous nerves produce predominantly short-latency inhibition in muscle adjacent to the stimulated finger, consistent with the It inhibitory period but merging also into the E2 excitatory period of the cutaneous reflex (Troni et aI., 1988; Mariorenzi et aI., 1991; Maertens de Noordhout et aI., 1992b; Clouston et aI., 1995; Manganotti et aI., 1997; Classen et al., 2000; Kofler et aI., 2001; Tamburin et aI., 2001). Short-latency MEP inhibition after median nerve stimulation occurs in antagonistic muscles (wrist extensors) supplied by the radial nerve, suggesting that the classical reciprocal inhibition at the spinal cord level might be assisted by a similar reciprocal inhibition at the level of motor cortex (Bertolasi et al., 1998). MEP modulation by afferent input from the hand is somatotopically organized (Terao et aI., 1995; Kofler et aI., 2001; Tamburin et al., 2001). All reported modulating effects of cutaneous and proprioceptive inputs on MEP amplitude occur largely or exclusively through mechanisms at the level of motor cortex because MEP evoked by TES and spinal alpha-motoneuron excitability as tested with H-reflexes and F waves are significantly less affected. 8.4.6.2. Applications Patients with lesions of the central somatosensory pathways lack a short-latency MEP modulation after conditioning stimulation of peripheral nerves (Bertolasi et al., 1998; Terao et aI., 1999). In contrast, patients with certain forms of epilepsy, such as progressive myoclonic epilepsy (Reutens et aI., 1993b; Cantello et aI., 1997) and patients with Creutzfeldt-Jacob disease (Yokotaet aI., 1994) show markedly increased short-latency MEP facilitation, indicating enhanced motor cortex excitability timelocked to the afferent input. 8.4.7. Other inputs to motor cortex (photic, auditory, nociceptive) 8.4.7.1. Techniques and principles MEPs in hand muscles are inhibited 55-70 ms after the unexpected presentation of a flash light (Cantello et al., 2000), or 30-60 ms after an unexpected loud sound (>80 dB, >50 ms duration) (Furubayashi et al., 2000). The latter effect habituates rapidly, and therefore, may transmit through the same system as the startle response. Nociceptive
TRANSCRANIAL MAGNETIC STIMULATION
electrical stimulation of digital nerves results in MEP inhibition of hand muscles but MEP facilitation of the biceps muscle (Kofler et aI., 1998; Kofler et aI., 2001). This MEP modulation occurs irrespective of whether the test MEP is elicited by TMS or TES, and is therefore best explained by a spinal withdrawal reflex. However, if nociceptive stimulation of the hand is produced by a COz laser, this results in MEP inhibition of hand muscles and the biceps if MEP are elicited by TMS (Valeriani et aI., 2001). MEP elicited by TES remain unaffected, suggesting a global inhibition of motor cortex following nociceptive input. 8.4.7.2. Applications No data available yet. MEP modulation by photic input may be useful in photic cortical reflex myoclonus. MEP modulation by auditory input may be useful in startle disease. 8.4.8. Motor cortex output in distant target structures tested by PET, fMRI. EEG. SEP, MRP 8.4.8.1. Techniques and principles Positron emission tomography (PET) can be used to detect metabolic change in brain areas distant from the cortex stimulated by repetitive TMS (rTMS). rTMS of the human frontal eye field results in visual cortex and superior parietal and medial parieto-occipital cortex network activation (Paus et aI., 1997). rTMS of motor cortex results in variable results depending on rTMS frequency, intensity and number of stimuli, and on the PET method ('8FDG, HzI50 ) (Fox et al., 1997; Paus et aI., 1998; Siebner et aI., 1998, 2000a, b, 2001). Most studies show a network activation, including the stimulated sensory-motor cortex, SMA and motor cortex of the opposite hemisphere. The combination of rTMS with functional magnetic resonance imaging (fMRI) is technically more difficult to achieve because the TMS pulses have to be interleaved with MR image acquisition. The first available studies demonstrate local activation of the stimulated motor cortex, both in block and singletrial designs (Bohning et aI., 1998; Bohning et aI., 1999; Bohning et aI., 2000). The combination of TMS and electroencephalography (EEG) allows assessment of TMS induced changes in electrical brain activity with high temporal resolution. Transcallosal responses appear
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8.8-12.2 ms after TMS of one motor cortex at EEG electrodes over homologous areas of the opposite hemisphere (Cracco et aI., 1989). High-resolution multi-channel EEG and inversion algorithms show that TMS of the sensori-motor cortex elicits an immediate response at the stimulated site that spreads to adjacent ipsilateral motor areas within 5-10 ms and to homologous areas in the opposite hemisphere within 20 ms (Ilmoniemi et aI., 1997; Ilmoniemi et aI., 1999; Komssi et aI., 2002). Highfrequency rTMS of frontal cortex results in an increase in directed EEG coherence between the stimulated cortex and other electrode sites, mainly within the same hemisphere (ling and Takigawa, 2000). The P25 component of the median nerve somatosensory evoked potentials (SEP) is increased when conditioned by TMS over the motor cortex contralateral to median nerve stimulation (Kujirai et al., 1993b; Seyal et aI., 1993; Schiirmann et aI., 2001). This effect is maximal when TMS precedes the median nerve stimulus by 30-70 ms (Seyal et aI., 1993), by 10 ms (Kujirai et aI., 1993b), or is given simultaneously (Schiirmann et aI., 2001). This modulation of cortical components of the SEP may underlie the TMS induced degradation of sensory stimulus detection (Cohen et al., 1991b). Low-frequency (l Hz) rTMS of motor cortex given at 110% MT over a period of 15 min leads to a significant reduction in movement related potential (Bereitschaftspotential) amplitude (Rossi et aI., 2000), suggesting that rTMS interferes with movement-related brain activity, probably through influence on cortical inhibitory networks.
8.5. Repetitive transcranial magnetic stimulation 8.5.1.1. Techniques and principles RTMS refers to repeated TMS delivered to a single scalp site (Wassermann, 1998) and requires specially designed magnetic stimulators. RTMS is divided into low-frequency (~1 Hz) and highfrequency stimulation (> 1 Hz). This division is based on the different physiological effects and degrees of risk. Low-frequency rTMS results in a long-lasting depression of the excitability of the stimulated or connected cortex (Chen et aI., 1997a; Boroojerdi et aI., 2000; Maeda et al., 2000; Muellbacher et aI., 2000; Enomoto et aI., 2001;
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Gerschlager et al., 2001; Touge et al., 2001; Tsuji and Rothwell, 2002) and has a low risk for adverse effects (Wassermann, 1998). In contrast, highfrequency rTMS leads to an increase in the excitability of the stimulated cortex (Pascual-Leone et al., 1994c; Maeda et al., 2000; Peinemann et al., 2000; Wu et al., 2000) and is associated with a higher risk for adverse effects (Wassermann, 1998). The parameters of stimulation are: (1) frequency; (2) intensity; (3) train length; (4) inter-train interval; and (5) total number of pulses. High-intensity and highfrequency rTMS bears the risk for spread of stimulus effects and induction of EMG discharge beyond the duration of stimulation (Pascual-Leone et al., 1993; Pascual-Leone et al., 1994c). This may result from a breakdown of cortico-cortical inhibition, and the generation of local epileptic activity. Accidental seizures were induced in altogether six healthy subjects by this form of high-intensity and -frequency rTMS (Wassermann, 1998). As a consequence, a table of the maximum safe duration of an rTMS train at a given combination of frequency and intensity was published, based on the NINDS experience (Wassermann, 1998). This table has two shortcomings as it does not include frequencies below 1 Hz and intensities below resting MT. Knowledge about the safety of the inter-train interval is limited but it was noted that two of the accidental seizures were induced at particularly short inter-train intervals ~ 1 s (Wassermann et al., I 996a; Chen et al., 1997d). Several safety studies did not find significant acute or short-term adverse effects toward motor, neuropychological, vegetative or neuro-hormonal function (Pascual-Leone et al., 1993; Wassermann et al., 1996b; Foerster et al., 1997; Jahanshahi et al., 1997; Niehaus et al., 1998; Evers et al., 2001; Niehaus et al., 2001a). It is currently unknown whether there exists an increased risk for any long-term adverse effects, in particular in those subjects who have received a large number of stimuli.
8.5.1.2. Applications Generally, rTMS is applied for two reasons, investigation of cortex function or therapy. Investigation of cortex function relies on the idea that rTMS can temporarily inactivate the stimulated cortex or neuronal network in the sense of a transient and fully reversible 'lesion', thus interfering with sensori-motor or cognitive tasks (for reviews,
Pascual-Leone et al., 1999; Walsh and Cowey, 2000). Therefore, in conjunction with PET and fMRI, rTMS can be used to determine the functional significance of metabolic activation that were demonstrated with functional neuro-imaging during sensori-motor or cognitive tasks (Cohen et al., 1997; Rossi et al., 2001). One application of particular relevance is interference of rTMS with language and speech that potentially might be used in the future as a non-invasive means for pre-surgical determination of language laterality (Pascual-Leone et al., 1991; Jennum et al., 1994; Michelucci et al., 1994; Epstein et al., 1996, 1999; Stewart et al., 2001). The most extensively investigated application of rTMS is as a therapeutic tool in major depression (for recent critical review, Lisanby and Sackheim, 2000). Other fields of potential therapeutic application are central pain following thalamic or brainstern stroke (Lefaucheur et al., 2001a, b), epilepsy (Tergau et al., 1999; Menkes and Gruenthal, 2000), Parkinson's disease (Pascual-Leone et al., 1994b; Siebner et al., 1999a; Siebner et al., 2000b), or writer's cramp (Siebner et al., 1999b). Although this appears to be an extremely important clinical avenue of rTMS, it should be noted that all of the quoted reports have not yet been rigorously replicated, and therefore have to be considered experimental work. Blinded and sham-controlled trials on large populations of patients are needed (Wassermann and Lisanby, 2001). Furthermore, recipes need to be developed for which parameters of rTMS to use for which therapeutic application. Finally, therapeutic rTMS sometimes makes things worse rather than better (Boylan et al., 2001), as may happen with any therapeutic application.
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Walsh, V and Cowey, A (2000) Transcranial magnetic stimulation and cognitive neurosciences. Nature Rev., I: 73-79. Wang, B, Toro, C, Zeffiro, TA and Hallett, M (1994) Head surface digitization and registration: a method for mapping positions on the head onto magnetic resonance images. Brain Topogr., 6: 185-192. Warren, JD, Kimber, TE and Thompson, PD (1999) The silent period after magnetic brain stimulation in generalized tetanus. Muse. Nerve, 22: 1590-1592. Wassermann, EM (1998) Risk and safety of repetitive transcranial magnetic stimulation: Report and recommendations from the international workshop on the safety of repetitive transcranial magnetic stimulation June 5-7, 1996. Electroencephalogr. Clin. Neurophysiol., 108: 1-16. Wassermannm, EM and Lisanby, SH (2001) Therapeutic application of repetitive transcranial magnetic stimulation: a review. Clin. Neurophysiol., 112: 1367-1377. Wassermann, EM, Fuhr, P, Cohen, LG and Hallett, M (1991) Effects of transcranial magnetic stimulation on ipsilateral muscles. Neurology, 41: 1795-1799. Wassermann, EM, McShane, LM, Hallett, M and Cohen, LG (1992) Noninvasive mapping of muscle representations in human motor cortex. Electroencephalogr. Clin. Neurophysiol., 85: 1-8. Wassermann, EM, Pascual-Leone, A and Hallett, M (1994) Cortical motor representation of the ipsilateral hand and arm. Exp. Brain Res., 100: 121-132. Wassermann, EM, Cohen, LG, Flitman, SS, Chen, Rand Hallett, M (1996a) Seizures in healthy people with repeated "safe" trains of transcranial magnetic stimuli (letter). Lancet, 347: 825-826. Wassermann, EM, Grafrnan, J, Berry, C, Hollnagel, C, Wild, K, Clark, K and Hallett, M (1996b) Use and safety of a new repetitive transcranial magnetic stimulator. Electroencephalogr. Clin. Neurophysiol., 101: 412-417. Wassermann, EM, Wang, B, Zeffiro, TA, Sadato, N, Pascual-Leone, A, Toro, C and Hallett, M (1996c) Locating the motor cortex on the MRI with transcranial magnetic stimulation and PET. Neuroimage, 3: 1-9. Wassermann, EM, Greenberg, BD, Nguyen, MB and Murphy, DL (2001) Motor cortex excitability correlates with an anxiety-related personality trait. Biol. Psychiatry, 50: 377-382. Weber, M, Eisen, A and Nakajima, M (2000) Corticomotoneuronal activity in ALS: changes in the peristimulus time histogram over time. Clin. Neurophysiol., Ill: 169-177. Werhahn, KJ, Fong, JK, Meyer, BU, Priori, A, Rothwell, JC, Day, BL and Thompson, PD (1994) The effect of magnetic coil orientation on the latency of surface EMG and single motor unit responses in the first dorsal
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interosseous muscle. Electroencephalogr. CUn. Neurophysiol., 93: 138-146. Werhahn, KJ, Taylor, I, Ridding, M, Meyer, BD and Rothwell, IC (1996) Effect of transcranial magnetic stimulation over the cerebellum on the excitability of human motor cortex. Electroencephalogr. Clin. Neurophysiol., 101: 58-66. Werhahn, KJ, Kunesch, E, Noachtar, S, Benecke, R and Classen, I (1999) Differential effects on motorcortical inhibition induced by blockade of GABA uptake in humans. J. Physiol. (Lond.), 517: 591-597. Werhahn, KJ, Wiseman, K, Herzog, I, Forderreuther, S, Dichgans, M and Straube, A (2000) Motor cortex excitability in patients with migraine with aura and hemiplegic migraine. Cephalalgia, 20: 45-50. Wessel, K, Tegenthoff, M, Vorgerd, M, Otto, V, Nitschke, MF and Malin, IP (1996) Enhancement of inhibitory mechanisms in the motor cortex of patients with cerebellar degeneration: a study with transcranial magnetic brain stimulation. Electroencephalogr. CUn. Neurophysiol., 101: 273-280. Wilson, SA, Lockwood, RI, Thickbroom, GW and Mastaglia, FL (1993a) The muscle silent period following transcranial magnetic cortical stimulation. J. Neurol. Sci., 114: 216-222. Wilson, SA, Thickbroom, GW and Mastaglia, FL (1993b) Transcranial magnetic stimulation mapping of the motor cortex in normal subjects. The representation of two intrinsic hand muscles. 1. Neurol. Sci., 118: 134-144. Wilson, SA, Day, BL, Thickbroom, GW and Mastaglia, FL (1996) Spatial differences in the sites of direct and indirect activation of corticospinal neurons by magnetic stimulation. Electroencephalogr. CUn. Neurophysiol., 101: 255-261. Wischer, S, Paulus, W, Sommer, M and Tergau, F (2001) Piracetam affects facilitatory l-wave interaction in the human motor cortex. CUn. Neurophysiol., 112: 275279. Wu, T, Sommer, M, Tergau, F and Paulus, W (2000) Lasting influence of repetitive transcranial magnetic stimulation on intracortical excitability in human subjects. Neurosci. Lett., 287: 37-40. Yokota, T, Yoshino, A, Hirashima, F, Komori, T and Miyatake, T (1994) Increased central motor tract excitability in Creutzfeldt-Jakob disease. J. Neurol. Sci., 123: 33-37. Zidar, I, Trontelj, IV and Mihelin, M (1987) Percutaneous stimulation of human corticospinal tract: a single-fiber
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Movement Disorders Handbook of Clinical Neurophysiology, Vol. I M. Hallett (Ed.) © 2003 Elsevier B.V. All rights reserved
127 CHAPTER 9
Movement disorders surgery: microelectrode recording from deep brain nuclei W.D. Hutchison'v", J.O. Dostrovsky" and A.M. Lozano'" a
Department of Surgery, Division of Neurosurgery, Toronto Western Hospital, 399 Bathurst St., Toronto, ON M5T 2S8, Canada b Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S IA8, Canada
9.1. Introduction The development of imaging techniques in stereotactic brain surgery has greatly enhanced the capabilities of direct targeting of subcortical structures, but there is still a need for functional confirmation and optimization of the target. Microelectrode recordings provide the most definitive and accurate method of localization. The use of microelectrode recording for localizing subcortical targets for stereotactic brain surgery began in the 1950s with Albe-Fessard and Guiot (Guiot et aI., 1962) who used the technique to precisely delineate the motor and sensory thalamic nuclei. Microelectrode recording involves the measurement of electrical activity of brain cells with a high spatial and temporal resolution with thin probes that produce minimal mechanical disturbance of the neuropil. For this reason the technique has long remained a principal method for the analysis of the function of neurons and nuclei in the brain. Indeed, important insights into the pathophysiology of various movement disorders can be gained by investigation of the individual properties and population characteristics of neurons in the globus pallidus, thalamus and subthalamic nucleus. Microelectrode techniques are also continuing to evolve to examine simultaneous recordings from neuron pairs (Hurtado et aI., 1999; Levy et aI., 2000) and neuronal assemblies in the same and different nuclei (Nicolelis et aI., 1998).
* Correspondence to: Dr. W.D. Hutchison, Div. of Neurosurgery, Toronto Western Hospital West Wing 4-433, 399 Bathurst St., East Wing 6-528, Toronto, ON M5T 2S8, Canada. E-mail address:
[email protected] or
[email protected] Tel.: (416)-603-5800, ext. 2226; fax: (416)-603-5298.
Several reports of microelectrode recording techniques have been published with a focus on thalamus (Lenz et aI., 1988; Tasker et al., 1998), globus pallidus (Sterio et al., 1994; Lozano et aI., 1996; Hutchison 1998; Vitek et aI., 1998), and subthalamic nucleus (Hutchison et al., 1998a) and general articles on the techniques of extracellular recording in laboratory animals and humans (Millar 1992; Dostrovsky 1999; Lalley et al., 1999). The purpose ofthe present chapter is to review the current techniques used in our operating room and briefly outline the major neurophysiological landmarks that need to be identified for target determination in each case.
9.2. Microelectrode assembly Some detail is required in a discussion of microelectrodes, since most problems with recording are due to faulty or damaged electrodes rather than the electronic instrumentation used to amplify, filter and display the signals. In particular the fine tip of the electrode is susceptible to damage by mechanical or electrical forces. Electrodes with thicker shanks and blunter tips are less susceptible to bending and tip damage but produce more tissue damage and yield poorer multi-unit recordings. Completed electrodes with extensions allowing them to be used in a stereotactic guide tube are commercially available, but some may prefer to assemble their own. The main advantages of local manufacture are substantial cost savings and avoidance of the common problem of bending or curling of the fine tip during transport which may not be visible unless inspected under a microscope or loupes. Shank skewing may be less problematic as far as recording of good spikes is concerned but the electrode may track obliquely to the desired course. We fabricate our own electrodes from commercially available
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components. Microelectrode tips (Microprobe, Potomac, MD) are mounted on Kapton (polyimide, MicroML, College Point, NY, 23 gauge) insulated stainless steel tubing (Small Parts, Miami Lakes, FL) to extend the length for use in the stereotactic guide tube. Tungsten has the desirable properties of high tensile strength and stiffness as thin wire. Platinum is relatively malleable so unsuited to thin electrode construction on its own but when present in an alloy with iridium becomes suitably stiff as thin wire. Platinum itself is desirable as an electrode material since it reacts with free chloride in the tissue and forms a Pt-PtCI or platinum black tip interface which is non-polarizable and irreversible. This means it can convert excess hydrogen ions into hydrogen and hydroxyl ions instead of reducing the metal and physically eroding the tip during microstimulation. However, most medical electrical stimulators use biphasic pulses, so there is no net charge transfer to the patient. Tungsten microelectrodes can be plated with platinum to confer these desirable properties (see below). Tip exposures in the range of 15-25 urn are the most useful and give mostly single and occasionally multi-unit recordings. Larger tip sizes record from many more neurons making single unit discrimination more difficult whereas smaller tip sizes may record cells only in the immediate vicinity of the tip. The Parylene-C insulation on the portion of the electrode to be inserted into the extender tube is removed by mechanical stripping with fine emery paper or burning off by passing through a flame and the shank is crimped and inserted into 25 gauge stainless steel tubing so it is orthogonal with the extender tube. The 22 gauge Kapton tubing insulation fits over the extender and epoxy glue is used to make a continuous seal between the two insulators. The insulation can be tested by inserting just the electrode tip and then the rest of the shank into saline while observing the impedance reading, which should remain constant if there is no breech. Another method is to apply 3-10 V DC to the electrode in saline to watch electrolytic bubble formation, which should only occur at the tip. The thin coating of Parylene-C on the electrode tip is particularly sensitive to scratching so caution needs to be exercised during handling. Electrodes are plated using platinum and gold solutions of the free metal cations and cathodal current to attract those ions (Millar, 1992). The purpose of the prior gold plating is to aid in
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formation of a good bonding of the platinum on the tungsten. This is best carried out under microscopic control to monitor the amount of plating deposited, at least in the initial stages. The advantage of plating is to reduce the impedance and increase the signalto-noise but an added advantage is that it will protect the tungsten tip from oxidizing which occurs after prolonged storage (months). If electrodes are not plated they can be conditioned as described above in the bubble test to remove the tungsten oxides. Electrodes are best protected from damage by backloading them into 19 gauge shield tubing and securing them with adhesive tape. The shield tubing should be short enough and wide enough that the ethylene oxide will penetrate and sterilize the whole length of the electrode. Sometimes the tip can become curled during use and it will be noticeable that only vague small units are picked up in the background or there is background injury discharge before good single units can be seen. As a general rule, if there are no units recorded after about 5 mm of tracking down with the electrode, then probably the electrode is bad, since most targets are in cell dense areas, and even white matter regions show the occasional unit. With most commercially available recording systems, the impedance of the electrode can be measured in situ during a brief pause in the recording. Unplated 15-25 urn tip tungsten electrodes have impedances about 0.8-1.2 Mil. and the platinum-plated electrodes our group uses are typically 0.2-0.6 MO. Low values indicate a break in the insulation, and high values indicate that the tip may have been eroded by repeated high intensity stimulation. 9.3. Extracellular recording of spikes The term 'single unit' refers to extracellularly recorded potentials arising from action potentials generated by a single neuron. Typically, if the potential arises from the somatodendritic region of the cell the waveform is usually biphasic and of 1-2 ms duration with an after-potential, and this is referred to variously as a cell, spike or neuron. If the waveform of the potential is mono-phasic and short duration < I ms with no after-potential this usually means that its source is an axonal action potential. Multi-unit recording refers to a combination of potentials from many cells recorded simultaneously. While this allows several units to be sampled
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simultaneously, which may expedite the identification of movement-related activity, the firing rate of individual cells cannot be determined with any accuracy. Electrodes with smaller tip sizes will record mostly single units and the occasional axon especially in white matter regions such as the internal capsule. With larger tipped electrodes, more potentials are recorded at a further distance from the tip, so that in addition to the multi-units, the background noise in the recording is larger when in cell-dense regions.
9.4. Amplification and filtering of signals The relatively small bioelectric potentials (- 100 J..L V) must be amplified several thousand times (usually -5,000-50,000) for passing the signal to audio monitors and driving oscilloscopes and data display systems of computers. Typically, differential amplification is employed, so that what is amplified is the difference in signal intensity on the positive and negative leads so any large electromagnetic induction producing an interference will be common to the two leads and subtracted from the signal of interest - usually termed common mode rejection. Filtering of the signal is used to remove unwanted frequencies in the very low «200 Hz) range to provide a stable DC baseline for spike discrimination. Most often noise occurs from interference from AC mains (60 Hz in North America, 50 Hz in some other countries) due to additional equipment in the operating room that is in the vicinity of the electrode leads. This can be due to electric patient beds, monitoring equipment, overhead fluorescent lights or projection equipment. With most recording systems commercially available, sufficient shielding for dealing with this stray capacitance has been incorporated into the low noise features of the amplifier design, so again, the noise is often due to a faulty electrode with a very high impedance or a poor ground connection. Very high frequencies (> 10 kHz) need to be removed to allow individual spike waveforms to be discriminated. One source of high frequency noise in the operating room is due to cautery equipment which still produces interference with the noise reduction features of new amplifiers. Some recording systems use digital filtering of signals, the theory of which is complex and beyond the scope of this review, but one advantage is the original signal is retained and
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filtering can be changed by changing the software settings if other aspects are desired such as low frequencies of field potential oscillations.
9.5. Commercially available recording systems Several companies provide electronic equipment for recording extracellular action potentials during deep brain recording. The Axon Instruments Guideline System 3000 has been recently reviewed (Starr, 1999) and further information is available on their website (http://www.axon.com).This intraoperative system includes a "Clinical Micropositioner" that is mounted on either a Crossman-Roberts-Wells (CRW) or Leksell frame and allows movement in the X (anteroposterior) and Y (mediolateral) positions, without further adjustment of the frame settings. The recording system includes an ultra low-noise amplifier, combined with an electrical stimulation unit and a touch sensitive monitor which displays the spike waveforms as they occur on a millisecond time base as well as a more conventional oscilloscope-like tracing on a time base of 1-2 s. The level crossings viewed on the spike waveform window are displayed in a frequency histogram with 0.1-1 s bins "spike ratemeter" and the firing rate in Hz is displayed and refreshed every second. A useful feature of the Axon system is a hand-held module with controls for setting the intensity for stimulation through the tip of the electrode as well as changing the intensity of stimulation and measuring the impedance of the electrode with a 1 kHz sine wave. The stimulation parameters can be modified with pulse widths settings from 0.05 to 1 ms and the frequency range is from I to 300 Hz, and intensities range from 0-100 J..LA. A zero setting may be used as a control "null-stimulation" procedure to verify patient reports of non-motor effects such as phosphenes or tingling. Conventional parameters for microstimulation are 1-100 J..LA, a 1 s train of pulses at 300 Hz and pulse widths of 200 J..LS. These parameters are useful in determining visual and motor responses for the identification of optic tract and internal capsule respectively during pallidal procedures, internal capsule and medial lemniscus during STN and thalamic procedures as well as tremor arrest or reduction. In cases of mild tremor reduction often a longer train length of 5 s or 10 s can be carried out while visually inspecting the tremor to clarify any longer-lasting effects on tremor. In practice, stimula-
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tion above 100 tJ-A is not recommended since the high impedance of the electrode (l Mil) dictates high voltages in excess of safety requirements (> 100 V) (and most stimulators will not be able to deliver voltages greater than this). Train durations can be given manually for stimulation as long as the switch is depressed or fixed durations from 0.5 to 20 s. The recording amplifier is blocked briefly while the stimulation pulses are delivered to the electrode so the leads, once attached to the sterile electrode shaft or connector of the drive holding it, do not need to be switched. Radionics (www.radionics.com) has a Neuroplan system including an Accudrive and Taha-Burchiel Recording Electrode Kit for use with the CRW frame system. The electrode drive in this system has a cable instead of hydraulics, which obviates possible fluid leakage or suction of air into the hydraulic drive upon retractions. The entire drive is lightweight and can be autoclaved. Further features allow integrated use with DBS implantation and the system is primarily designed for use with the CRW stereotactic frame. The system is fairly compact with all operations in desktop style computer system. Further details are available on their website. AlphaOmega (http://www.alphaomega-eng.com) makes the Neurotrek system which has the capability to record up to 5 channels of data from the 5 electrode configuration used by Benabid's group. The system also includes a stepper-motor microdrive with computer based settings, that can be also controlled via a hand-held remote and depth data logging features. It has microstimulation, macrostimulation and impedance measuring capabilities on any of the 5 possible electrodes and will also record EMG data on up to 7 additional channels. The high powered and high capacity computer provides online template matching algorithms and tagging features to identify specific traces as the trajectory progresses. The template matching is supported by alphaSort (Matlab) and provides comparison of spike shapes as well as spike clusters. Temporal features are included in a post-processing software package that should meet most high level research needs with plots such as interval time histograms and cross-correlogram displays of the various channels. Additional software will plot and print out the results of specific trajectories along with recognized or "tagged" traces of sample recordings and print out a color hard-copy of the full stereotactic map. Other independent
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workers have developed shareware programs (Interspike) that have processing features specifically designed for detection of spikes trains with temporal properties (bursting and pauses) found in pallidal structures (Favre et al., 1999). At the time of writing, Medtronic (www.medtronic.com) is also in the process of developing a Lead Point recording system for use with the CRW or else frame system. 9.6. Surgical technique Standard stereotactic technique is used to calculate the target from the AC and PC co-ordinates on MRI. More detailed descriptions of the surgical technique are available (Burchiel et al., 1997) as are complete monographs on the subject (Krauss, 1996; Germano, 1998; Lozano, 2000) and it will only be briefly reviewed here for the sake of completeness. A Leksell model G stereotactic frame is applied to the head with screw-pins inserted under local anesthetic, and a fiducial box containing channels filled with radio-opaque copper sulphate is placed over the frame to obtain three dimensional reference points (X - mediolateral; Y - anterior/posterior, Z inferior/superior) for the various MRI sections. Various techniques can be used to target the structure of interest, including direct calculation of the coordinates from the visualized structure on MRI scans, or indirect targeting by localization of wellvisualized landmarks such as the anterior and posterior commissures (AC, PC) and use of a standard stereotactic atlas (Schaltenbrand and Wahren, 1977) to infer the target location. In the former method, it has been noted that some significant distortion of images occurs with direct targeting. In the latter method, co-ordinates of AC and PC are obtained from the MRI console software (GE-Signa 1.5 Tesla magnet), and these are entered into a computer program that modifies the standard sagittal maps to obtain a customized stereotactic map for each patient. 9.7. Recordings in electrode trajectories targeting globus pallidus Several groups have described their methods for localizing the globus pallidus and surrounding structures (Hutchison et al., 1994a; Sterio et al., 1994; Lozano et al., 1996; Taha et al., 1996; Burchiel
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et aI., 1997; Vitek et aI., 1998) and each uses slightly different techniques and places varying time and emphasis on the recording session. What follows is a description of our method. For pallidal procedures the target is generally considered to be in the ventral and lateral portion of GPi (Laitinen, 1990; Laitinen et aI., 1992), 20 mm lateral to the midline, 3-6 mm inferior to the AC-PC line and 2-3 mm anterior to the mid-commissural point. Recording starts about 15 mm from the target in an anterosuperior position, which corresponds to cells of GPe if initial targeting is correct. The objectives in localizing the target in globus pallidus are to identify: (1) characteristic cell types in GPe and GPi, and movement related activity of these cells; (2) the white matter lamina between these structures as well as border cells in the region; (3) optic tract ventral to the GPi; and (4) internal capsule posterior to GPi. The firing rates and patterns of basal ganglia neurons recorded in non-human primates are remarkably similar to those found in humans, so the terminology originally used in these studies is adopted here for the description of the cell types shown in Fig. 1. GPe cells have been described as occurring in two major types based on differences in firing rate and pattern as recorded in normal monkeys (DeLong, 1971; Filion et aI., 1988; Filion and Tremblay, 1991). These are the slow frequency discharge with pauses (SFD-P), and the low-frequency discharge with bursts (LFD-B). LFD-B neurons are not very common in GPe but are thought to be a characteristic feature of the region. The spontaneous ongoing activity is only about 5-10 Hz and the short bursts can reach about 300-500 Hz and occur at irregular time intervals. The known projection of GPe to thalamic reticular formation (Parent and Hazrati, 1995) and the high similarity in burst firing pattern between these cells suggests that LFB neurons are potential basal ganglia output neurons. SFD-P neurons have a higher spontaneous firing rate around 20-50 Hz which is sporadically interrupted by pauses in firing of duration about 150-300 ms (see Fig. 1). There are also cells in GPe with higher firing rates 50-70 Hz and these may be termed HFDP to follow the convention. Active and passive movements of limbs may modulate the firing rate of cells in GPe. Between GPe and GPi is a white matter lamina that is detectable by the absence of recorded units and relative quiet in background noise on the
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recordings. Border cells are frequently encountered at its margins with a wider spike (due to a longer after-hyperpolarization) than pallidal cells, which imparts a regular firing pattern due to the longer
Fig. 1. Examples of well-isolated single units found in typical electrode trajectories penetrating the segments of globus pallidus during microelectrode exploration. All traces are 2 s in duration except bottom trace which is 3 s. Top trace shows the low firing rate of a striatal neuron, typically 1-5 Hz. Next two traces down are typical cells of the external segment of globus pallidus (GPe). Low frequency discharge with bursts (LFD-B); slow frequency discharge with pauses (SFD-P). At the margins of the pallidal segments and the medullary laminae are found border cells (Bor). Lowest two traces show high frequency discharge neurons (HFD), and a tremor cell (TC) with the accelerometer output from the back of the contralateral hand indicated below. GPi,i - internal segment of the globus pallidus internus.
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relative refractory period (see Fig. 1). These electrophysiological characteristics indicate that the cells may be cholinergic and project to the cortical mantle (Carpenter, 1991). A sample of 17 border cells was found to have a mean firing rate of 35 Hz (Hutchison et aI., 1994a). After advancement of the electrode tip into GPi there is often an increase in background noise and multiunit recordings. Cells in GPi have relatively large amplitude spikes, irregular discharge patterns and the highest firing rates of all pallidal cells. The firing rates of GPi neurons are in the range of 60-80 Hz and the modal intervals for GPi neurons in the range of 5-7 ms. Some GPi neurons may show excitatory or inhibitory responses to passive and voluntary movements of limbs and orofacial structures. In some preliminary analyses of the data, there was no clear topographical organization of the body within GPi, as depicted in early studies by Hassler et al. (1979). In patients that have tremor, cells can be found with periodic oscillations in firing rate at the same frequency as the tremor (Hutchison et al., 1994b; Hutchison et al., 1997). These tremor cells show periods of coherent oscillation with limb tremor and appear to be located in ventral and lateral portions of the GPi (Hutchison et al., 1998b). Although each of the segments of GP has identified " signature" cell types that aid localization, there should be no misconception that a region can be immediately identified based on the firing rates and patterns of a few cells. Each pallidal segment has a range of firing rates and patterns and the population means of firing rates or pattern indices may show significant differences between segments. Normally a region is identified only after the track is completed and many well-isolated spikes have been recorded so that a comparison of all the firing rates and patterns can be integrated with the surmized position of the track based on the stereotactic anatomical map (Fig. 2). Below the GPi the cellular activity becomes sparse and background noise decreases. Upon entering the optic tract there may be some discernible increase in high frequency noise again due to axonal activity in the optic nerve. Stimulation at this site normally evokes phosphenes in the contralateral visual field at low current intensities (1-10 fLA). Patients frequently report white or yellow flashes of light, stars, sparkles or lightning-like patterns (see "Vi" in Fig. 2). This can be in a wedge-shaped
w.o. HUTCHISON ET AL. portion of the visual field which can sometimes be observed to move more ventral as one stimulates more dorsal in the optic tract, consistent with the rotation of the fibers in the tract at this level. In rare cases when patients do not report stimulation-evoked visual sensation, it is worthwhile to also carry out strobe-light evoked potentials by opening up the high pass filter and recording the slow-wave average (about 30-40 ms at this site) (see "VEP" in Fig. 2). If all of these features have been identified on the first trajectory through the pallidum, then the second trajectory is placed 3 rom posterior to attempt to identify the internal capsule. Recording again begins at 15 mm above the target and cells are usually again found at the top of the tract. In posteriorly located trajectories, cells may only be found at the initial part of the track indicating the posterior aspect of the GPi and the tip of the electrode will pass into the internal capsule. In the capsule, the recordings are usually quiet but the occasional unit or fiber is encountered. Passing electric current through the tip of the electrode, termed here microstimulation (up to 100 fLA, 0.2 ms pulse width, 300 Hz, 1 s train) will produce tetanic contraction of the contralateral body part or reduction or arrest of tremor (see "M" in Fig. 2). In a typical case, two or three electrode trajectories are required to complete a physiologic map and this includes unequivocal identification of the optic tract and internal capsule. If the targeting based on MRI co-ordinates is accurate, the physiological data should show a reasonably good spatial relation to the corresponding anatomical map. Macrostimulation using a large tipped (2-3 mm) electrode is used by some surgeons to locate the optic tract and internal capsule since the larger tip will allow a greater spread of electrical current. If no motor or visual effects are seen/reported at about 2 V, then the target can be considered safe from producing permanent adverse side effects.
9.8. Recording in electrode trajectories targeting the subthalamic nucleus (STN) In order to identify the STN with microelectrode recording the major features and landmarks to identify are: (1) anterior thalamus with bursting cells; (2) superior and inferior borders of STN; (3) dorsal border of SNr, and if possible; (4) the anterior and posterior borders of STN. Microelectrode
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RECORDING IN MOVEMENT DISORDERS SURGERY
3
1
2\ #2048
GPe mel
Target
Fig. 2. Completed functional map of globus pallidus showing the location of identified neuronal types as described in Fig. 1. A total of three separate passes through the pallidum were made with the electrode in the order shown at the top of each track. Data from the mapping session is plotted on top of the customized sagittal section from the Schaltenbrand and Wahren stereotactic atlas 20 rom from the midline. Abbreviations of cell types as in Fig. 1; AC, PC - anterior and posterior commissures; mel - mid-commissural line; MEA - movement-evoked activity, "Target" refers to the tentative location chosen from the results of MRI scans, which was at the base of the pallidum but in this case would be too close to the optic tract (OT) indicated by the visual responses of the patient to microstimulation (Vi) and internal capsule (lC) indicated by motor or tetanic responses to microstimulation (M).
recording methods for the identification of STN have been described in detail already (Hutchison et al., 1998a). The target is in the center of the nucleus at about 10-12 rom lateral to the midline, I rom posterior to the mid-commissural point and 5 rom below the AC-PC line. Recording in microelectrode tracks targeting the STN starts 10 -15 rom above target. Depending on the trajectory angle in the sagittal plane, and given that the MRI-determined tentative target is reasonably accurate, recording will usually start in
thalamic reticular nucleus or in the anterior part of the ventral tier subnuclei of the thalamus (see Fig. 3). In this region and particularly in the thalamic reticular formation there are cells with spontaneous burst discharges, which have been reported previously (Raeva et al., 1991; Raeva and Lukashev, 1993) and can be considered characteristic for the region. The identification of the ventral portion of the thalamus is a useful landmark in determining the relative anterior and posterior position of the trajectory. Also the distance between the ventral border of
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Fig. 3. Right panel shows typical examples of spike recordings during microelectrode exploration of subthalamic nucleus. Left panel shows location of the electrode track on the customized Schaltenbrand and Wahren map at 12 mm from the midline. Hpth - hypothalamus, Rt - thalamic reticular nucleus, Voa - ventralis oralis anterior, Vop - ventralis oraIis posterior, Vim - ventralis intermedius, ZI - zona incerta, H2 - H2 fields of Forel, STN - subthalamic nucleus, SNr substantia nigra pars reticulata, other abbreviations as in Fig. I.
thalamus and the dorsal border of STN may give some indication of laterality since the anteromedial portion of the STN is pitched more ventral than the dorsolateral pole. Below the thalamus the electrode tip passes into a white matter region which is "quieter" in background electrical noise, corresponding to the thalamic and lenticular fasciculi with the zona incerta in-between. The zona incerta may have sparse cells that are bursting since it is continuous with the thalamic reticular nucleus at its lateral border. Others have reported cells in zona incerta with properties similar to subthalamic nucleus neurons i.e. responses to eye movements (Ma, 1996) as well as reaching movements (Crutcher et aI., 1980) so this should be borne in mind when determining the dorsal border of the subthalamic nucleus. The entry into the subthalamic nucleus is apparent when the level of background noise in the recordings increase and high amplitude spikes with firing rates of 25-45 Hz are found (25 and 75 percentiles). A
large number of STN neurons show clear modulation in firing rate with active and passive movements of the limbs and one sample revealed 80% of the neurons had excitatory responses. Ipsilateral as well as contralateral movements could elicit responses. In patients with tremor at rest, tremor cells have also been identified in the human STN with oscillations in firing rate both at the frequency of tremor and also at high frequency around 15-25 Hz (Levy et aI., 2000). This higher frequency component imparts a "chatter" or "flutter"-like sound to the background noise on the audio monitor that appears to be characteristic for the STN and has proven a useful feature for localization, at least in those patients with tremor. STN neurons may only be recorded over a short distance if the electrode does not track through the center of the nucleus, and trajectories to be selected as sites of implantation should have a 4-5 mm segment populated by cells with STN-like properties. A tracing of a typical STN neuron is shown in Fig. 3.
RECORDING IN MOVEMENT DISORDERS SURGERY
Below the STN is the substantia nigra, which is divided into the dopaminergic pars compacta (SNpc) and the basal ganglia output portion called the pars reticulata (SNpr). The division between the two structures is not clear and one expects that there is degeneration of the SNpc in these PD cases. Based on monkey recordings where histological confirmation is possible, there is known to be differences in the firing rates of the two groups. Putative dopaminergic pars compacta cells have very low firing rates 1-5 Hz and have inflections on the initial phase of the action potential (Schultz, 1986), but are expected to be rarely encountered in PD patients. In contrast, the characteristic features of SNpr or reticulata neurons are a high (60-90 Hz) and regular firing rate but there may be another group that have lower rates around 20-30 Hz, possibly reflecting functional differences (DeLong et aI., 1983, 1985). The different firing rates in SNpr may depend on the portion of the reticulata that is explored, since motor regions are more laterally located in this nucleus (about 15 mm from the midline). In the human, SNpr neurons frequently display cardiac-induced fluctuations in spike amplitude that can make spike discrimination problematic. Microstimulation (up to 100 j.LA, 300 Hz, 1 s train, 0.3 ms p.w.) during STN cases is not as useful as with pallidal or thalamic target localization, but stimulation-induced tremor arrest or reduction from within STN has been observed. Paresthesias have been encountered in more ventral and posterior positions and may be due to current spread to medial lemniscus or pre-Iemniscal radiation. 9.9. Recording and microstimulation in the motor and sensory thalamus Movement disorders surgery may also involve targets in the ventrointermediate (V.i.m.) nucleus of the ventral tier thalamus where input from proprioceptive primary afferents (joint capsules, Golgi tendon organs and muscle spindles) as well as cerebellar afferents converge. The thalamic target in V.i.m. is 14.5 mm lateral to the midline, 2-4 mm above the AC-PC line and 6-7 mm behind the midcommissural point (see Fig. 4). Frequently the ventrocaudal nucleus (V,c.) located more posteriorly is targeted for the first trajectory since the somatotopy of Vc is an important landmark for orientation
135
and also to avoid inadvertent damage to this structure that might lead to permanent sensory loss. Thalamic subnuclei cannot be visualized directly with MRI placing increased emphasis on functional identification of the various ventral tier nuclei with microelectrodes. The objectives in the thalamic procedures are to identify: (1) kinesthetic zone; (2) deep tactile zone; (3) cutaneous tactile zone; and (4) ventral border of the tactile region. Recordings at the top of trajectories pass thorough the "motor thalamus", comprised of the ventralis oralis anterior and posterior subnuclei (V.o.a, V.o.p.) and V.i.m. and have cells somewhat similar to those already described in thalamic areas slightly more medial. Bursting cells are frequently encountered as well as non-bursting cells. Movement-related activity (kinesthetic responses) may be present and cells may be found that respond to deep pressure or deep tactile stimuli. In patients with tremor, tremor cells may be recorded in this region (* in Fig. 4), and microstimulation will produce tremor arrest (TA in Fig. 4) or reduction in tremor. Passing the electrode further ventral, the spontaneous activity will usually increase with entry into the thalamic tactile relay of Vc. Cells in this region will respond to light stroke with a brush or cotton swab. The well-known somatotopic organization within Vc may help to guide the laterality of the procedure and the best place for the lesion is just anterior to the face and thumb region of the tactile core. Laterality in Vim, therefore, is largely determined with reference to Vc somatotopy, leg indicating a more lateral location than face and hand. Microstimulation within Vc produces focal paresthesia that shows a somatotopic organization roughly corresponding to that obtained by recording the cellular responses to touch. Microstimulation in ventral Vc and below Vc in V.c.p.c (parvocellularis) may elicit painful sensation. Ventral to Vc, microstimulation may also elicit hemibody paresthesias due to lemniscal fiber stimulation and activation of large numbers of neurons in the tactile core ofVc. Usually several trajectories are made to define the anterior border of Vc and map a large enough segment of the motor thalamus to find the focus and extent of sites of effective tremor suppression from microstimulation. The target lies 2-3 mm anterior to the Vc/Vim border in regions occupied by cells with kinesthetic responses and tremor reduction or arrest from microstimulation (see Fig. 4).
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Fig. 4. Functional localization of thalamic nuclei for movement disorders surgery. Findings from 3 microelectrode trajectories are overlaid on a Schaltenbrand and Wahren sagittal map 14.5 mm from the midline. The AC-PC line is shown intersecting Pc. Thalamic nuclei are labeled as follows Vo.a., ventralis oralis anterior, V.o.p., ventralis oralis posterior, V.i.m., ventralis intermedius, v.c., ventralis caudalis.
9.10. Summary Microelectrode recording is useful to accurately delineate deep brain structures and sub-nuclei for various stereotactic targets. In addition, it yields much information on the cellular pathophysiology of movement disorders and the rational development of surgical therapy for the treatment of movement disorders.
Acknowledgements The support of both Parkinson Society of Canada and the Canadian Institute for Health ResearchINIH is gratefully acknowledged.
References Burchiel, KJ, Taha, JM and Favre, J (1997) Posteroventral pallidotomy for Parkinson's disease patients. In: 55
Rengachary and RH Wilkins (Eds.), AANS Publications Committee. Park Ridge, Illinois, pp. 13-26. Carpenter, MB (1991) Corpus striatum and related nuclei. In: TS Satterfield (Ed.). Williams and Wilkins, Baltimore, pp. 325-360. Crutcher, MD, Branch, MR, DeLong, MR and Georgopoulos, AP (1980) Activity of zona incerta neurons in the behaving primate. Soc. Neurosci. Abstr., 6: 676. DeLong, MR (1971) Activity of pallidal neurons during movement. J. Neurophysiol., 34: 414-427. DeLong, MR, Crutcher, MD and Georgopoulos, AP (1983) Relations between movement and single cell discharge in the substantia nigra of the behaving monkey. J. Neuroscience, 3: 1599-606. DeLong, MR, Crutcher, MD and Georgopoulos, AP (1985) Primate globus pallidus and subthalamic nucleus: functional organization. J. Neurophysiol., 53: 530-543. Dostrovsky, JO (1999) Invasive techniques in humans: microelectrode recordings and microstimulation. In: U Windhorst and H Johansson (Eds.), Modem Techniques in Neuroscience Research. Springer Verlag, Berlin, pp.1199-1209.
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Favre, J, Taha, JM, Baumann, T and Burchiel, KJ (1999) Computer analysis of the tonic, phasic, and kinesthetic activity of pallidal discharges in Parkinson patients. Surg. Neurol., 51: 665-672. Filion, M and Tremblay, L (1991) Abnormal spontaneous activity of globus pallidus neurons in monkeys with MPTP-induced parkinsonism. Brain Res., 547: 142151. Filion, M, Tremblay, L and Bedard, PJ (1988) Abnormal influences of passive limb movement on the activity of globus pallidus neurons in parkinsonian monkeys. Brain Res., 444: 165-176. Germano, 1M (1998) Neurosurgical treatment of movement disorders. AANS Publications Committee, Park Ridge, Illinois, 275 pp. Guiot, G, Hardy, J and Albe-Fessard, D (1962) Delimitation precise des structures sous-corticales et identification de noyaux thalamiques chez l'homme par l' electrophysiologie stereotaxique. Neurochirurgia (Stutt.), 51: 1-18. Hassler, R, Mundinger, F and Riechert, T (1979) Stereotaxis in Parkinson syndrome. Springer Verlag, Berlin, Hurtado, JM, Gray, CM, Tamas, LB and Sigvardt, KA (1999) Dynamics of tremor-related oscillations in the human globus pallidus: A single case study. Proc. Natl. Acad. Sci. USA, 96: 1674-1679. Hutchison, WD (1998) Microelectrode techniques and findings of globus pallidus. In: JK Krauss, RG Grossman and J Jankovic (Eds.). Lippincott-Raven, Philadelphia, pp. 135-152. Hutchison, WD, Lozano, CA, Davis, KD, Saint-Cyr, JA, Lang, AE and Dostrovsky, JO (1994a) Differential neuronal activity in segments of globus pallidus in Parkinson's disease patients. Neuroreport, 5: 15331537. Hutchison, WD, Lozano, AM, Kiss, ZHT, Davis, KD, Lang, AE, Tasker, RR and Dostrovsky, 10 (1994b) Tremor-related activity (TRA) in globus pallidus of Parkinson's disease (PD) patients. Soc. Neurosci. Abstr., 20: 783. Hutchison, WD, Lozano, AM, Tasker, RR, Lang, AE and Dostrovsky, JO (1997) Identification and characterisation of neurons with tremor-frequency activity in human globus pallidus. Exp. Brain Res., 113: 557563. Hutchison, WD, Allan, RJ, Opitz, H, Levy, R, Dostrovsky, JO, Lang, AE and Lozano, AM (1998a) Neurophysiological identification of the subthalamic nucleus in surgery for Parkinson's disease. Ann. Neurol., 44: 622-628. Hutchison, WD, Benko, R, Dostrovsky, JO, Lang, AE, and Lozano, AM (1998b) Coherent relation of rest tremor
and pallidal tremor cells in Parkinson's disease patients. Mov. Dis., 13 (Suppl. 2): 204. Krauss, JK, Grossman, RG and Jankovic, J (1998) Pallidal surgery for the treatment of Parkinson's disease and movement disorders. Lippincott-Raven, Philadelphia, 324 pp. Laitinen, LV (1990) Ventroposteromedial pallidotomy in Parkinsons disease. Stereotact. Funet. Neurosurg., 54+55. Laitinen, LV, Bergenheim, AT and Hariz, MI (1992) Leksell's posteroventral pallidotomy in the treatment of Parkinson's disease. J. Neurosurg., 76: 53-61. Lalley, PM, Moschovakis, AK and Windhorst, U (1999) Electrical activity of individual neurons in situ: extraand intracellular recording. In: U Windhorst and H Johansson (Eds.), Modem Techniques in Neuroscience Research. Springer, Berlin, pp. 127-172. Lenz, FA, Dostrovsky, JO, Kwan, HC, Tasker, RR, Yamashiro, K and Murphy, JT (1988) Methods for microstimulation and recording of single neurons and evoked potentials in the human central nervous system. J. Neurosurg., 68: 630-634. Levy, R, Hutchison, WD, Lozano, AM and Dostrovsky, JO (2000) High-frequency synchronization of neuronal activity in the subthalamic nucleus of parkinsonian patients with limb tremor. J. Neurosci., 20: 77667775. Lozano, AM (2000) Movement Disorder Surgery. Karger, Basel, 404 pp. Lozano, AM, Hutchison, WD, Kiss, ZHT, Davis, KD and Dostrovsky, JO (1996) Methods for microelectrodeguided posteroventral pallidotomy. J. Neurosurg., 84: 194-202. Ma, T (1996) Saccade-related omnivectoral pause neurons in the primate zona incerta. NeuroReport, 7: 27132716. Millar, J (1992) Extracellular single and multiple unit recording with microelectrodes. In: JA Stamford (Ed.), IRL Press at Oxford. New York, pp. 1-27. Nicolelis, MA, Stambaugh, CR, Brisben, A and Laubach, M (1998) Methods for simultaneous multi site neural ensemble recordings in behaving primates. In: MA Nicolelis (Ed.). CRC Press LLC, Boca Raton FLA, pp. 121-156. Parent, A and Hazrati, LN (1995) Functional anatomy of the basal ganglia. I. The cortico-basal ganglia-thalamocortical loop. Brain Res. Brain Res. Rev., 20: 91-127. Raeva, SN and Lukashev, A (1993) Unit activity in human thalamic reticularis neurons. II. Activity evoked by significant and non-significant verbal or sensory stimuli. Electroencephalogr. Clin. Neurophysiol., 86:
lID-I 22. Raeva, SN, Lukashev, A and Lashin, A (1991) Unit activity in human thalamic reticular nucleusI Spon-
138 taneous activity. Electroencephalogr. Clin. Neurophysiol.,79: 133-140. Schaltenbrand, G and Wahren, W (1977) Atlas for Stereotaxy of the Human Brain. Georg Thieme, Stuttgart, 69 plates. Schultz, W (1986) Responses of midbrain dopamine neurons to behavioural trigger stimuli in the monkey. J. Neurophysiol., 56: 1439-1461. Starr, P (1999) Instrumentation, technique, and technology. Axon Guideline System 3000. Neurosurgery, 44: 1354-1356. Sterio, D, Beric, A, Dogali, M, Fazzini, E, Alfaro, G and Devinsky, 0 (1994) Neurophysiological properties of pallidal neurons in Parkinson's disease. Ann. Neurol., 35: 586-591.
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Taha, JM, Favre, J, Baumann, TK and Burchiel, KJ (1996) Characteristics and somatotopic organization of kinesthetic cells in the globus pallidus of patients with Parkinson's disease. J. Neurosurg., 85: 1005-1012. Tasker, RR, Davis, KD, Hutchison, WD and Dostrovsky, 10 (1998) Subcortical and thalamic mapping in functional neurosurgery. In: PL Gildenberg and RR Tasker (Eds.). McGraw-Hill, New York, pp. 945-94-31. Vitek, JL, Bakay, RA, Hashimoto, T, Kaneoke, Y, Mewes, K, Zhang, JY, Rye, D, Starr, P, Baron, M, Turner, Rand DeLong, MR (1998) Microelectrode-guided pallidotomy: technical approach and its application in medically intractable Parkinson's disease. J. Neurosurg., 88: 1027-1043.
Movement Disorders Handbook of Clinical Neurophysiology, Vol. 1 M. Hallett (Ed.) © 2003 Elsevier B.V. All rights reserved
139 CHAPTER 10
Polysomnography and related procedures s. Chokroverty* Department of Neurology/Cronin 466, St. Vincents Hospital, New York, NY 10011, USA
Scientific progress in the laboratory evaluation of sleep and its disorders has been rather slow but great advances have been made in the last century. The driving forces in this understanding have been the discovery of the human electroencephalogram (EEG) by Berger (1929) and rapid eye movements (REMs) during sleep by Aserinsky and Kleitman (1953). Polysomnography (PSG) has come to be viewed as the single most important laboratory technique for assessment of sleep and its disorders as well as for diagnosis and differential diagnosis of abnormal movements during sleep at night. PSG refers to recordings of multiple physiological characteristics during sleep whereas polygraphy denotes recordings of similar characteristics during any time of the day. The first polygraphic study to record motor activities during sleep was probably reported by Oswald in 1959 under the title of "sudden bodily jerks on falling asleep". In this chapter I briefly outline PSG recording techniques, indications for PSG, simultaneous video-PSG, and pertinent PSG findings in selected sleep disorders, computerized PSG, recording artifacts and related laboratory procedures for assessment of patients with movement disorders with or without complex behavior during sleep including multiple sleep latency test (MSLT), maintenance of wakefulness test (MWT) and actigraphy.
determine the patient's perception of quality of sleep and the actual test results. In order to assess chronic daytime sleepiness, the patient is asked to fill out the Epworth Sleepiness Scale (ESS) (Johns, 1991), which contains questions relating to the likelihood of dozing off in situations such as riding as a passenger in a car and watching television (Table 1). PSG allows assessment of sleep stages and wakefulness, respiration, cardiocirculatory functions and body movements (Keenan, 1999). EEG, electrooculogram (EOG) and electromyogram (EMG) of the chin muscle are recorded to study and score sleep staging (Rechtschaffen and Kales, 1968). Respiratory recording includes measurement of airflow and respiratory effort (Parisi, 1999; Kryger, 2000). PSG Table I Epworth sleepiness scale. Eight situations
Scores*
1. Sitting and reading 2. Watching television 3. Sitting in a public place (e.g., a theater or a meeting) 4. Sitting in a car as a passenger for an hour without a break 5. Lying down to rest in the afternoon
10.1. Techniques of PSG recording
PSG records multiple simultaneous physiological characteristics during sleep at night (Keenan, 1999). A pre- and post-study sleep questionnaire helps * Correspondence to: Prof. S. Chokroverty, Dept. of Neurology/Cronin 466, St. Vincents Hospital, 153 W l lth Street, New York, NY 10011, USA. E-mail address:
[email protected] Fax: + 1 (212) 604-1555.
6. Sitting and talking to someone 7. Sitting quietly after a lunch without alcohol 8. In a car, while stopped for a few minutes in traffic
* Scale to determine total scores: 0= would never doze; I = slight chance of dozing; 2=moderate chance of dozing; 3=high chance of dozing. Source: Adapted from M.W. Johns. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep 1991; 14: 540-545.
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also records electrocardiogram (EKG), finger oxymetry, limb muscle activity, particularly EMG of the tibialis anterior muscles bilaterally, snoring and body positions. Special techniques not used routinely include measurements of intraesophageal pressure, esophageal pH and measurements of penile tumescence for assessing patients with erectile dysfunction. Equipment for recoding PSG contains AC and DC amplifiers. The AC amplifiers are used to record physiological characteristics showing high frequencies such as EEG, EOG, EMG, and EKG. A DC amplifier is typically used to record potentials with slow frequency such as for recording the output from the oxymeter, pH meter or CPAP titration pressure changes and recording of intraesophageal pressure. AC or DC amplifiers may be used to record respiratory flow and effort. Sensitivity and filter settings vary according to the physiological characteristics recorded (Table 2). The standard speed for recording traditional PSG is 10 mm1s, so that each monitor screen or page is a 30-s epoch. In patients with suspected nocturnal seizures, however, a 30 mm/s recording speed (a lO-s epoch) is used for easy identification of epileptiform activity. Analog recording using paper is currently being replaced in most of the laboratories by digital system recordings. It is important to have facility for simultaneous video recording to monitor the behavior during sleep. It is advantageous to use two cameras for sleep screen viewing covering the entire body. A low light level camera should be used to obtain good quality video in the dark and an infrared light source should be available after turning the laboratory lights
off. The monitoring station should have a remote control, which can zoom, tilt or pan the camera for adequate viewing. The camera should be mounted on the wall across from the head end of the bed. An intercom from a microphone near the patient should be available.
10.2. Technique of recording of multiple physiological characteristics 10.2.1. Electroencephalography Most laboratories using international 10-20 electrode placement system recorded from at least 4 channels (C3-A2, C4-Al, Ol-Al and 02-A2) to clearly document the onset of sleep. Some laboratories use 8-10 channels to cover the parasagittal and the temporal areas of the brain to record possible focal or diffuse EEG abnormalities as well as for epileptiform activities. Both bipolar montage and referential montage connecting the electrodes between an active and a relatively inactive site (e.g. AI, A2, Cz, pz) are recommended. The importance of multiple channel EEG recordings is to document focal or diffuse slow waves and particularly epileptiform discharges. Many patients are referred to the PSG laboratory for a possible diagnosis of nocturnal seizures. The standard recommended EEG recordings of 1-2 channels or even 4 channels of recordings will miss most of the epileptiform discharges during all night recording. Therefore, in patients suspected of nocturnal seizures, polysomnographic study should include multiple channels of EEG covering temporal and parasagittal regions and simultaneous video record-
Table 2 Filter and sensitivity settings for polysomnographic studies. Time constant (s)
Lowfrequency filter (Hz)
Sensitivity
70 or 35
0.4
0.3
5-7 u.V/mm
70 or 35
0.4
0.3
5-7 u.V/mm
90
0.04
5.0
2-3 fLV/mm
15
0.12
1.0
1 mV/cm to start; adjust
0.1
5-7 fLV/mm; adjust
Characteristics
Highfrequency filter (Hz)
Electroencephalogram Electro-oculogram Electromyogram Electrocardiogram Airflow and effort
15
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POLYSOMNOGRAPHY AND RELATED PROCEDURES
ing (video-PSG study) for correlation of the electrical activity with the actual behavior of the patients. In computerized (digital) PSG recordings that are now performed in most laboratories it is easy to change the recording speed from the standard 10 mm/s of the usual sleep recording to 30 mm/s of the standard EEG recording for proper identification of the epileptiform discharges. Special seizure montages with full complement of standard electrodes and special electrode placements (e.g. T1 and T2 electrodes) should be used. The value of videoPSG for the diagnosis of seizure disorders and parasomnias has been clearly documented by Aldrich and Jahnke (Aldrich and Jahnke, 1991). 10.2.2. Electro-oculography (EDG)
EOG records corneoretina1 (relative positivity at the cornea and a relative negativity at the retina) potential difference (Walczak and Chokroverty, 1999). A typical electrode placement is one em superior and lateral to the outer canthus of one eye with a second electrode placed 1 em inferior and lateral to the outer canthus of the opposite eye. Both these electrodes are then connected to a single reference electrode, either the same ear or the mastoid process of the temporal bone. Therefore, right outer canthus (ROC) and left outer canthus (LaC) electrodes are referred to either A1 or A2. In this arrangement, conjugate eye movements produce out-of-phase deflections in the two channels whereas the EEG slow activities contaminating the eye electrodes are in-phase. Both conjugate horizontal and vertical eye movements are detected by this placement scheme. The sensitivity and filter settings for EOG are similar to those used for EEG (see Table 2).
10.2.3. EMG recordings during standard PSG
EMG activity is an important physiological characteristic that needs to be recorded for sleep staging as well as for diagnosis and classification of a variety of sleep disorders. In a standard PSG recording, EMGs are recorded from mentalis or submental and right and left tibialis anterior muscles. Mental or submental EMG activity is monitored to record axial muscle tone, which is significantly decreased during REM sleep, and, therefore, an important physiological characteristic for identifying REM sleep. Additional electrodes over the masseter muscles
may be needed in patients with bruxism (tooth grinding) to document bursts of EMG activities associated with bruxism. For recording from tibialis anterior muscles, surface electrodes are used and the distance between the two electrodes is 2-2.5 em. Bilateral tibialis anterior EMG is important to record in patients suspected of restless legs syndrome (RLS) because the periodic limb movements in sleep (PLMS), which are noted in 80% of such patients, may alternate between the two legs. Ideally, the recording should also include one or two EMG channels from the upper limbs in patients with RLS as occasionally PLMS are noted in the upper limbs. For patients with suspected REM behavior disorder, multiple EMGs from all four limbs are essential as there is often a dissociation of the activities between upper and lower limb muscles in such patients. If the upper limb EMGs are not included in patients suspected of REM behavior disorder, REM sleep without atonia may be missed in some cases. In patients presenting with abnormal movements such as dystonic, choreoathetoid or ballismic movements as noted in patients with nocturnal paroxysmal dystonia (a type of frontal lobe seizure disorder), multiple muscle surface EMG recordings in addition to video-PSG recordings may be obtained to document such activities. Other EMG recordings include intercostal and diaphragmatic EMG to record respiratory muscle activities. EMG shows progressively decreasing tone from wakefulness through stages I-IV of NREM sleep. In REM sleep the EMG is markedly diminished or absent. In REM behavior disorder, a characteristic finding is absence of muscle atonia during REM sleep in the EMG recording and the presence of phasic muscle bursts repeatedly during REM sleep. 10.2.4. Electrocardiography
A single channel of EKG is sufficient during PSG recording by placing one electrode over the sternum and the other electrode at a lateral chest location. Gold cup surface electrodes are used to record the EKG. Table 2 lists the filter settings and sensitivities for such recording. 10.2.5. Respiratory monitoring technique
PSG recording must routinely include methods to monitor airflow and respiratory effort adequately to
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correctly classify and diagnose sleep disordered breathing (SDB). Respiratory effort can be measured by mercury-filled or piezoelectric strain gauges, inductive plethysmography, impedance pneumography, respiratory magnetometers and respiratory muscle EMG (Kryger, 20(0). Most commonly Piezoelectric strain gauges and inductive plethysmography are used to monitor respiratory effort. Airflow can be measured by thermistors, thermocouples or a nasal cannula-pressure transducer recording nasal pressure (Kryger, 2000). The best way to detect arterial O2 content (Pa02) is by invasive method using an arterial cannula. This is not viable from the practical standpoint and in any case intermittent sampling of blood through the cannula may not reflect the severity of hypoxemia during a particular disordered breathing event. Therefore, noninvasive method by finger pulse oximetry is routinely used to monitor arterial oxygen saturation (Sa02) or arterial oxyhemoglobin saturation, which reflects the percentage of hemoglobin that is oxygenated (Kryger, 2000). 10.2.6. Body position monitoring
Body position is monitored by placing sensors over one shoulder and using a DC channel. Snoring and apneas are generally worse in the supine position and therefore, CPAP titration must include observing patients in the supine position for evaluating optimal pressure for titration. 10.2.7. Snoring
This can be monitored by placing a miniature microphone on the patient's neck. There is no general accepted standardized technique to record quantitatively the intensity of snoring. 10.2.8. Beginning and ending the PSG
All important information including "lights out" and "lights on" as well as any unusual behavior and motor events should be clearly documented by the technologist before and during the recording. This must include the patient's name, age, date of study, the identification number, purpose of the recording (before referring the patient to the laboratory for PSG study, sleep clinicians should have performed complete history and physical examination formulat-
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ing a provisional diagnosis) and the name of the technician. When awakened in the morning (either spontaneously or at a set time), the patient is asked to fill out a post-study questionnaire which includes estimation of time to fall asleep, total sleep time, number of awakenings and the quality of sleep
10.3. Sleep stage scoring technique The gold standard for scoring a particular sleep stage is still that recommended in the manual by Rechtschaffen and Kales (R-K) in 1968 (Rechtschaffen and Kales, 1968) following recommendations by an ad hoc committee. This was originally devised for sleep scoring in normal adults. There are, however, serious limitations using the R-K manual for scoring sleep stages in pathological states and many investigators recommend a computerized rather than the manual scoring technique. However, computerized techniques have many pitfalls and have not been accepted as a gold standard yet. In the future, with more sophisticated development of computer technology, a computer scoring technique most likely will supercede the manual scoring technique. Sleep stage scoring is based on three physiologic criteria: EEG, EOG and EMG. For R-K scoring an EEG recorded at C3/A2 or C4/Al should be used, especially for the purpose of amplitude criteria. The recommendation is for an epoch by epoch scoring and the most commonly used epoch is 30 s. 10.3.1. Scoring ofperiodic limb movements in sleep
Periodic limb movements in sleep are involuntary movements periodically recurring during sleep and are counted from the right and left tibialis anterior EMG recordings. The scoring criteria for PLMS can be summarized as follows (Atlas Task Force of the American Sleep Disorders Association, 1993): the movements must occur as part of 4 consecutive movements; the duration of each EMG burst should be 0.5 to 5 s; the interval between bursts should be 4-90 s; the amplitude of the EMG bursts, although variable, should be more than 25% of the EMG bursts recorded during the pre-sleep calibration recording. PLMS (Fig. 1) mayor may not be associated with arousals, and they should be scored separately. To score PLMS associated with arousal
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Fig. 1. A portion of polysomnographic fragment showing periodic limb movements in sleep (PLMS). Left (LT) and right (RT) tibialis anterior (TIB) electromyography (EMG). The top 4 channels show EEG (international nomenclature). LOC: Left oculogram; ROC: Right oculogram. CHIN: Chin EMG. EKG: Electrocardiogram. ABD: Abdomen. S.02: Oxygen saturation in percent by finger oxymetry.
the arousal must occur within 3 s of onset of PLMS. PLMS is expressed as an index consisting of number of PLMS per hour of sleep. To be of pathologic significance PLMS index should be 5 or more. Leg movements may be noted occurring periodically associated with resumption of breathing following recurrent episodes of apneas or hypopneas. These respiratory related leg movements should not be counted as PLMS. PLMS are generally seen during NREM sleep but they can occur rarely during REM sleep. In patients with restless legs syndrome, however, periodic limb movements may occur during wakefulness when they are termed period limb movements in wakefulness (PLMW). 10.3.2. Indications for PSG and video-PSG
In addition to the standard indications for PSG as published in the guidelines (Indications for Poly-
somnography Task Force, 1997) by the American Academy of Sleep Medicine (e.g. suspected SDB, patients with excessive daytime sleepiness (EDS), CPAP titration in patients with obstructive sleep apnea syndrome (OSAS), prior to surgical procedures or dental appliances in patients with OSAS, suspected narcolepsy-cataplexy syndrome and atypical or violent parasomnias), video-PSG combining PSG with multiple EEG channels and simultaneous video recording is very useful in patients with abnormal movements and behavior during sleep at night. If these motor activities during sleep occur frequently, the changes of capturing these events in the video-PSG are much better than if these had been occurring infrequently. The video recording can include multiplex analog signal captured on a tape but currently many commercially available systems include digital video directly synchronizing and time-locking the abnormal behavior to the PSG
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Table 3
Classification of abnormal motor activities during sleep.
Continued.
Motor parasomnias
Drug-induced nocturnal dyskinesias
1. Sleep-wake transition disorders a. Rhythmic movement disorder b. Sleep talking (somniloquy) c. Nocturnal leg cramps d. Propriospinal myoclonus at the transition from wakefulness to drowsiness 2. NREM sleep parasomnias a. Confusional arousals b. Sleepwalking c. Sleep terror 3. REM sleep parasomnias a. Nightmares b. REM sleep behavior disorder 4. Diffuse parasomnias (no stage preference) a. Bruxism b. Neonatal sleep myoclonus
1. Levodopa-induced myoclonus in Parkinson's disease 2. Medication-induced (e.g. tricyclic antidepressants, levodopa, lithium) periodic limb movements in sleep (PLMS)
Restless legs syndrome (RLS) - Periodic limb movements A. Nocturnal jerks and body movements in obstructive sleep apnea syndrome B. Excessive fragmentary myoclonus seen in a variety of sleep disorders C. Sleep-related panic attacks D. Dissociative disorders E. Fatal familial insomnia F. Post-traumatic stress disorder G. Narcolepsy-cataplexy-sleep paralysis syndrome
Nocturnal seizures 1. True nocturnal seizures a. Tonic seizure b. Benign rolandic seizure c. Autosomal dominant nocturnal frontal lobe seizure d. Nocturnal frontal lobe epilepsy (Nocturnal paroxysmal dystonia) e. Paroxysmal arousals and awakenings f. Episodic nocturnal wanderings g. Electrical status epilepticus in sleep 2. True nocturnal and diurnal seizures (diffuse seizures) a. Generalized tonic-clonic seizure b. Myoclonic seizure c. Infantile spasms (West's syndrome) d. Partial complex seizure e. Frontal lobe seizure f. Epilepsia partialis continua 3. Pseudoseizure (psychogenic non-epileptic seizure)
Involuntary movement disorder 1. Always persisting during sleep: a. Palatal myoclonus or palatal tremor 2. Frequently persisting during sleep a. Spinal and propriospinal myoclonus b. Tics in Tourette's syndrome c. Hemifacial spasms d. Hyperekplexia or exaggerated startle syndrome 3. Sometimes persisting during sleep a. Tremor b. Chorea c. Dystonia d. Hemiballisms
signals. Depending on the availability of the channels and the electrode inputs in the equipment multiple channels of EEGs (e.g. for suspected nocturnal seizure disorder) and EMGs to include additional muscles (e.g. to record from forearm flexor and extension muscles, masseter and other muscles for patients with suspected rapid eye movement behavior disorder (RBD) and bruxism) are recommended. Video-PSG may help characterize the movements, differentiate one jerk from another, identify a specific entity and most importantly differentiate abnormal motor activities from nocturnal seizures. Video-PSG may aid in the diagnosis of other co-existing sleep disorder, e.g. OSAS, RBD, narcolepsy. Video-PSG thus helps us classify abnormal motor activities during sleep into several identifiable entities (Table 3), e.g. motor parasomnias, noctural seizures, involuntary diurnal movements persisting during sleep, PLMS, excessive fragmentary myoclonus seen in a variety of sleep disorders, dissociative disorders, nocturnal jerks and body movements seen in patients with OSAS. Many parasomnias (defined as abnormal movements and behavior introducing into sleep without necessarily disrupting sleep architecture) may be mistaken for nocturnal seizures. For example, confusional arousals, sleep walking, sleep terror, sleep talking, bruxism, rhythmic movement disorder, RBD, nightmares and dissociative
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Table 4 Indications for video PSG. • Unusual and complex arousal disorders • Complex behaviors suspicious of RBD but not absolutely certain based on the history • Behavior and motor events at night suggesting possible nocturnal seizure disorder • EDS in patients with epilepsy to determine if excessive sleepiness is due to repeated nocturnal seizures, an undesirable side effect of antiepiieptic medications or due to an associated sleep disorder (e.g. sleep apnea) • Suspected psychogenic dissociative disorder • Other motor parasomnias (e.g. rhythmic movement disorder, bruxism) which may be mistaken for nocturnal seizures • Involuntary diurnal movement disorder persisting during sleep • Coexisting second sleep disorder (e.g. narcolepsy and RBD, OSAS and sleep walking, narcolepsy and sleep apnea) • For medicolegal purpose when the patient presents with violent behavior during sleep, video-PSG studies are mandatory to evaluate such patients for correct diagnosis of parasomnias or seizure disorders
disorders may be mistaken for seizures. RBD and nightmares occur during REM sleep. These conditions can be diagnosed and differentiated from one another based on characteristic clinical features combined with EEG and video-PSG findings. Table 4 lists indications for video-PSG. There is some controversy regarding the diagnosis of periodic limb movement disorder (PLMD) causing sleep fragmentation, arousals and excessive daytime sleepiness. Periodic limb movements in sleep (PLMS) have been noted in a number of sleep disorders as well as in normal individuals, particularly in patients over 60-65. Although the specificity of PLMS is not defined, at least 80% of patients with RLS show PLMS on PSG recordings. Therefore to document PLMS in RLS, PSG may be indicated. However, the diagnosis of RLS is a clinical one and has been based on international study group criteria (Allen et aI., 2003). PLMS as well as a sleep disturbance are not part of the essential criteria for the diagnosis of RLS. PSG indications, therefore, for RLS-PLMS remain somewhat dubious and contentious. Some investigators do not believe in the existence of PLMD as a
separate sleep disorder causing sleep dysfunction and EDS (Mahowald, 2002). The indications for pure PLMS or PLMD currently remain undetermined and further investigations including outcome studies are needed to document that PLMS or PLMD may cause sleep disturbance and EDS. Usually if one spends sufficient time in history taking and examining the patient it is possible to make a clinical diagnosis. However, even in clinically obvious cases it is important to confirm the clinical diagnosis by laboratory tests before instituting therapy because inappropriate or incorrect treatment may cause adverse side effects without necessarily helping the patient. On many occasions, however, the spells are atypical, unusual and often violent requiring video-PSG confirmation of the events. Correlation of the events with the time of the night and a particular sleep staging is important for correct diagnosis. For example, arousal disorder occurs during slow wave sleep in the first third of the night and RBD occurs during REM sleep usually in the last half to last third of the night. Rhythmic movement disorder (head banging, head rolling, body rocking) occurs during sleep stage transition from any stage of sleep whereas during psychogenic dissociated disorder EEG shows a wakeful pattern. The distinct disadvantage of video-PSG is additional expense and technologist time to place additional electrodes for extended EEG montage for suspected nocturnal seizure disorder and extended EMG montage to record multiple additional muscles for suspected RBD and bruxism. 10.4. Characteristic PSG findings in nocturnal movement disorders
There are no distinctive PSG patterns noted in most nocturnal movement disorders except characteristic epileptiform EEG patterns in nocturnal seizures. PSG findings are diagnostically nonspecific but video-PSG findings may help in the diagnosis, differential diagnosis, and in understanding pathophysiology. 1004.1. PSG findings in RLS-PLMS
These patients may show delayed sleep onset, fragmented sleep with repeated arousals and PLMS, which are noted in at least 80% of RLS patients. PLMS index (number of PLMS per hour of sleep)
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below 5 is considered normal. Based on the PLMS index the severity of PLMS may be classified into mild (index of 5-25), moderate (index of more than 25-50) and severe (index of more than 50). 10.4.2. PSG findings in parasomnias and dissociative disorders
In NREM parasomnias (e.g. sleep walking, sleep terror and confusional arousals), spells arise out of slow wave sleep and are not stereotyped but are prolonged lasting for minutes and may be up to 10 min in contrast to patients with seizure disorders who may show stereotyped behavior lasting for a few seconds to a minute or two. Furthermore, EEG shows no evolving pattern in the arousal disorders, thus, differentiating from ictal EEG with rhythmically evolving pattern of slow waves, sharp waves or
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spikes. High voltage delta waves, non-reactive alpha, stage I sleep and movement artifacts in the EEG are the other features found in patients with arousal disorders. In patients with REM behavior disorder (RBD) the behavior occurs out of REM sleep and, therefore, the EEG shows the characteristic REM sleep pattern of desynchronized EEG containing a mixture of alpha, beta and theta activities often associated with characteristic "saw-tooth" waves and rapid eye movements. The EMG shows absence of muscle atonia, phasic muscle bursts and the video may document excessive limb movements, which may be rhythmic or arrhythmic. Figure 2 is a representative sample from a patient with RBD. Psychogenic dissociative disorders may present with a variety of abnormal movements resembling those noted in frontal lobe seizures. However, in
Fig. 2. A fragment of polysomnographic tracing from a patient REM sleep behavior disorder. Note sustained muscle tone and phasic EMG bursts in the electromyograms from chin, left (L) and right (R) arms, left and right tibialis anterior muscles during REM sleep. EDGs (top two channels) show rapid eye movements and EEG (channels 3-6 from the top) is in stage 1 with a mixture of theta, alpha and beta rhythms. (Reproduced with permission from Drs. Carlos Schenck and Mark Mahowald.)
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dissociative disorders the movements are nonstereotyped and the EEG shows wakeful patterns both during and after the spells. Rhythmic movement disorder can arise during sleep-wake state transition or rarely during sleep stage transition. This condition may mimic the behavior pattern of partial complex seizure but EEG shows no ictal pattern, thus, differentiating rhythmic movement disorder from patients with partial complex seizure. Orofacial movements in patients with bruxism sometimes resemble orofacial automatisms of partial complex seizure. However, EEG in bruxism shows no ictal pattern in contrast to patients with partial complex seizure. EMG in bruxism shows characteristic rhythmic bursts in the masseter muscles and these myeogenic artifacts are also reflected in the EEG electrodes.
10.4.3. PSG findings in diurnal movement disorders There has been a growing awareness amongst both movement disorder and sleep specialists about an interaction between sleep and the movement disorders. There is increasing understanding about the effects of diurnal movements on sleep and the effect of sleep on a variety of diurnal movement disorders, and how sleep-wake states modulate the daytime and night-time abnormal movements. A case in point is the recent controversy about "sleep attacks" in Parkinson's disease (PD) patients on newer dopamine agonists. Whether these agents or the disease itself are responsible for excessive sleepiness or unpredictable "sleep attacks" remain controversial but this controversy has re-emphasized the presence of sleep dysfunction which may be seen in up to 70% to 90% of PD patients. Overnight PSG findings in PD include decreased slow wave and REM sleep, reduced sleep spindles, decreased sleep efficiency, disruption of NREM-REM sleep cycling, rapid blinking at sleep onset, sleep fragmentation, and REM-onset blepharospasm. In those presenting with RBD the EMG shows absence of muscle atonia and increased phasic EMG bursts during REM sleep. In addition, some PD patients may document SDB and PLMS. Parkinsonian tremor may persist during NREM stages I and II, is absent in slow wave and REM sleep but may reappear during sleep stage transition.
PSG findings in progressive supranuclear palsy include increased sleep latency, repeated arousals and awakenings, decreased NREM stage I and REM sleep, decreased sleep spindles, in some patients, reduced REM latency and occasionally sleep apnea. In Tourette's syndrome, PSG recordings shows increased body movements and motor tics during all stages of sleep. An increased number of awakenings and mild reduction of REM sleep may also be seen. There is an increased prevalence of sleep walking and sleep terror in these patients. PSG findings in Huntington's chorea include sleep fragmentation with progressive deterioration as the disease progresses. Other findings include decreased sleep efficiency in 48%-80% of cases and a mild reduction of REM sleep. Persistence of the involuntary movements in NREM stages I and II and reemergence during REM sleep may also be seen. Sleep spindles are increased in amplified and density. PSG findings in torsion dystonia consist of prolonged sleep latency, repeated awakenings, reduced sleep efficiency and decreased REM sleep. Dystonic movements decrease during NREM stages I and II, and are absent during slow wave and REM sleep.
10.4.4. Computerized PSG The advantages of computerized PSG include easy data acquisition, display and storage (Hirshkowitz and Moore, 1994; Hasan, 1996; Kubicki and Hermann, 1996; Hirshkowitz and Moore, 1999; Penzel and Conradt, 2000; Agarwal and Gotman, 2002). It is easy to review the record on-line (i.e, the ability to look back at early tracing during progression of recording). The other advantages include the ability to manipulate large quantity of data for review and storage for permanent record keeping. It is also easy to review using a variety of filter settings, sensitivities, monitor speeds and reformatted montages (i.e, new montages may be created retrospectively from the electrode derivations used during actual recording). In a particular segment with a question of potential epileptiform event (e.g. spikes, sharp waves, spike and waves and sharp and slow waves) the standard PSG speed of 10 mm/s can be quickly changed to the usual EEG speed of 30 mm/s for recognizing the evolving pattern of activation for a correct diagnosis. These capabilities help
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identify an abnormal EEG pattern and distinguish artifacts from true cerebral events. Computerized PSG makes it easy to document all events, to edit and report. The computerized PSG can store the raw data on relatively inexpensive CD-ROM or other suitable media making it easy to keep database and access raw data. European data format (EDF) is the most common format for exchange of digital PSGs between different laboratories in different countries. Simultaneous video monitoring during PSG recording is essential to obtain patient's behavior and motor manifestations, particularly in patients with parasomnias and nocturnal seizures. Recently introduced digital video incorporated into the computerized PSG system is an important advance over the traditional video tape recording. Digital video recordings, however, use a lot of space on the hard disk and one way to handle this problem is to save only small segments of digital video. The latest digital versatile disk (DVD) may solve the storage problems in the future. In order to overcome the limitations and fallacies of the R-K system and to reduce the time for scoring, automatic computer-assisted scoring techniques have been proposed (Hasan, 1996; Kubicki and Hermann, 1996; Hirshkowitz and Moore, 1999; Penzel and Conradt, 2000) and are commercially available. Some of the later methods are still evolving but none of the techniques have received wide popularity because of serious limitations in obtaining an acceptable scoring and because of lack of standardization, validation and precision in the methods. Some of the problems in computer-assisted scoring include artifact recognition, differentiating stage I NREM sleep from REM sleep, discriminating different sleep stages, inability to differentiate eye movements from high amplitude delta waves and failure to detect upper airway resistance. Attempts have also been made to develop computer methods to identify obstructive, central and mixed apneas and hypopneas as well as arousals and PLMS but the methods remain ambiguous, imprecise, and variable resulting in lack of universal acceptance yet. Computerized scoring has no real gold standard to compare the data. Another disadvantage of computer scoring is that there is no standardized procedure for scoring of various physiological characteristics. Furthermore, for comparison between visual and computerized scoring sampling remains a problem.
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R-K manual scoring still remains today the gold standard in clinical practice.
10.5. Artifacts during PSG recording Artifacts refer to extraneous electrical activities not recorded from the regions of interest (e.g. the brain, muscles, eyes and heart). These extraneous electrical activities may obscure the biological signals of interest and, therefore, recognition and correction of these artifacts is an important task for the polysomnographic technologist. The artifacts can be divided into three categories: physiological, environmental and instrumental (Keenan, 1999; Walczak and Chokroverty, 1999). 10.5.1. Physiological artifacts
These include myogenic potentials, artifacts resulting from movements of the head, eyes, tongue, mouth and other body parts, sweating, pulse and EKG artifacts as well as rhythmic tremorogenic artifacts. 10.5.2. Environmental sources of electrical signals
These may simulate electrocerebral activity or may obscure the EEG activities and include 60 Hz (or 50 Hz), artifacts resulting from the telephone or the pager systems. Electrostatic artifacts result from movements of the subjects in the environment. Most important is keeping the impedance of recording electrodes below 5 K. 10.5.3. Instrumental artifacts
These arise from faulty electrodes, electrode wires, switches and the polygraph machine itself. A very common artifact is electrode "pops" which are transient sharp waves or slow waves limited to one electrode. These artifacts result from faulty electrode placement or insufficient electrode gel causing abrupt changes in impedance. The electrode should be reset and gel applied. If this persists then electrodes need to be changed. Other sources of artifacts are the electrode wires, cables and the switches. In the PSG machine random fluctuations of charges result in some instrumental noise artifacts. If the sensitivity is greater than 2 microvolts per mm, which are not generally used in PSG recordings, then these instrument artifacts may
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interfere with the recording. Loose contacts in switches or wires may also cause sudden changes in voltage or loss of signal. 10.6. Pitfalls of PSG
Polysomnography is the single most important laboratory test for assessment of sleep disorders, particularly in patients presenting with excessive daytime somnolence and those suspected of nocturnal seizures, parasomnias or other abnormal motor activities. However, PSG has considerable limitations (Hinmanen and Hasan, 2000; Hirshkowitz, 2000). There is no standardized uniform protocol used in all sleep laboratories and this may make the comparison of the data from one laboratory to another somewhat misleading. The most serious limitation is that the ovemight in-laboratory PSG is labor intensive, time consuming and expensive. A single night's PSG may miss the diagnosis of mild OSAS, PLMS, parasomnias or nocturnal seizures. PSG data and patient's clinical findings may not be concordant. PSG data may be confounded by the first night effects (e.g. increased wakefulness and stage I NREM sleep and decreased slow wave and REM sleep). 10.7. Multiple sleep latency test
The most common indication for referring a patient for multiple sleep latency test (MSLT) is excessive daytime sleepiness (EDS), although sleep onset and sleep maintenance insomnia is the most common complaint in the general population. The initial step in assessment of the patient with EDS is a detailed sleep history and other history and physical examination. For assessment of persistent sleepiness the Epworth Sleepiness Scale (ESS) (Johns, 1991) is often used to assess a general level of sleepiness. This is a subjective propensity to sleepiness assessed by the patient under eight situations on a scale of 0-3, with three indicating a situation when chances of dozing off are highest. The maximum score is 24 and a score of 10 suggests the presence of EDS. This test has been weakly correlated with MSLT scores. The ESS and MSLT, however, test different types of sleepiness. MSLT tests the propensity to sleepiness objectively, and ESS the general feeling of sleepiness or subjective propensity to sleepiness. The Stanford Sleepiness
Scale (SSS) (Keenan, 1999) is a 7 point scale to measure subjective sleepiness but it does not measure persistent sleepiness. Visual Analog Scale (Keenan, 1999) is the other scale used to assess alertness and wellbeing in which subjects indicate their feelings of alertness at an arbitrary point on a line of 0-100 mm scale with 100 being the maximum sleepiness and 0 being the most alertness. 10.7.1. Technique of MSLT
The MSLT has been standardized and includes several general and specific procedures (Carskadon et al., 1986; Cherbin, 2003). The test is preceded by an overnight polysomnographic study and is scheduled about 2-3 hours after the conclusion of the overnight PSG study. The actual test consists of 4-5 opportunities for napping at 2 hour intervals and each recording session lasts for a maximum of 20 min. Between tests subjects must remain awake. The measurements include average sleep onset latency and the presence of sleep onset rapid eye movements (SOREMs). If no sleep occurs then the test is concluded 20 min after lights out. Fifteen minutes after the first 30-s epoch of any stage of sleep the test is terminated. If the finding is indefinite then it is better to continue the test than to end it prematurely. Mean sleep latency is calculated as the average of the latencies to sleep onset for each of the 4-5 naps. Mean sleep latency of less than 5 min is consistent with pathologic sleepiness. A mean sleep latency of 10-15 min is considered normal; and a mean sleep latency of up to 5-10 min is consistent with mild sleepiness. The occurrence of REM sleep within 15 min of sleep onset is defined as SOREMs. 10.7.2. Indications for MSLT
Narcolepsy is the single most important indication for performing the MSLT (Thorpy, 1992). A mean sleep latency of less than 5 min combined with SOREMs in 2 or more of the 4-5 recordings during MSLT is strongly suggestive of narcolepsy, although REM sleep dysregulation and circadian rhythm sleep disorders may also lead to such findings. In patients with upper airway obstructive sleep apnea syndrome (OSAS) the MSLT is indicated to assess the degree of severity of daytime sleepiness. Sometimes the patients underestimate the presence
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of sleepiness and often deny daytime symptoms. In such patients it is important to assess the daytime sleepiness so that the appropriate advice regarding the driving and avoidance of dangerous situations during the daytime can be given to the patient to prevent disastrous consequences. Patients with excessive daytime sleepiness with no easily ascertainable cause should also have an MSLT to document objectively EDS and findings suggesting REM sleep dysregulation. In idiopathic hypersomnia the MSLT findings will be consistent with pathologic sleepiness without SOREMs.
10.7.3. Reliability, validity and limitation of the MSLT The sensitivity and specificity of the MSLT in detecting sleepiness have not been clearly determined (Cherbin, 2003). The test-retest reliability of the MSLT, however, has been documented in both normal subjects and patients with narcolepsy. In subjects with sleepiness caused by circadian rhythm sleep disorders, sleep deprivation and ingestion of hypnotics and alcohol pathologic sleepiness has been validated by MSLT. However, there is poor correlation between the MSLT and ESS. The patient's psychological and behavioral state also interferes with the MSLT results. MSLT objectively measures tendency to sleep rather than the likelihood of falling asleep. If the patient suffers from severe anxiety or psychological disturbances causing behavioral stimulation, MSLT may not show sleepiness even in a patient complaining of EDS.
10.8. Maintenance of wakefulness test The MWT is a variant of the MSLT to measure a patient's ability to stay awake (Doghramji et al., 1997). Sleep latency is defined as in MSLT from lights out to the first epoch of any stage of sleep. It has generally been accepted that if the mean sleep latency is less than 11 min there is impairment of wake tendency. The MWT is useful in differentiating groups with normal daytime alertness from those with EDS. The MWT is more sensitive than MSLT in assessing the effects of treatments (e.g. CPAP titration in OSAS and the stimulant treatment for narcolepsy). It is less useful and less sensitive than the MSLT as a diagnostic test for narcolepsy. The MSLT and the MWT do have separate functions: the MSLT
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unmasks physiologic sleepiness, which depends on both circadian and homeostatic factors whereas the MWT is a reflection of the individual's capability to resist sleep and is influenced by physiologic sleepiness.
10.8.1. Actigraphy Monitoring of body movements and other activities can be performed continuously for days, weeks or even months by using an actigraph, also known as actometer or actimeter (Standards of Practice Committee of the American Sleep Disorders Association, 1995). This can be worn on the wrist or alternatively on the ankle for recording arm, leg and body movements. The actigraph uses piezoelectric sensors, which function as accelerometers to record acceleration or deceleration of movements rather than the actual movement. The principle of analysis is based on the fact that increased movements are seen during wakefulness in contrast to markedly decreased movements or no movements during sleep. Several actigraph models are in developing stage to carefully regulate the sampling frequencies and duration, filters, sensitivities and the dynamic range in order to detect and quantify PLMS but no generally accepted standardized technique of quantifying and identifying PLMS discriminating from other movements (e.g. those resulting from parasomnias, nocturnal seizures and other dyskinesias) is currently available. Currently the role of actigraphy in detecting, quantifying and differientiating abnormal motor activities remains controversial but there is immense potential in the future for such applications with the development of sophisticated models and techniques.
10.9. Conclusion Patients presenting with abnormal movements during sleep constitute a group of the most challenging sleep disorders. Many such patients remain undiagnosed or misdiagnosed for years and are often subjected to inappropriate treatment. We must make an effort to correctly diagnose and classify such disorders. In this chapter, I briefly summarized an important laboratory procedure (e.g. PSG) which might be helpful in assessment of patients presenting with abnormal motor activities during sleep. I must, however, emphasize that any laboratory procedure
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must act as facilitator and be subservient to the clinical approach to such patients. References Agarwal, Rand Gotman, J (2002) Digital tools in polysomnography. J. Clin. Neurophysiol., 19: 136143. Aldrich, M and Jahnke, B (1991) Diagnostic value of video-EEG polysomnography. Neurology, 41: 1060. Allen, RP, Piechietti, D and Hening, WA et al., and the International Restless Legs Syndrome Study Group (2003) Restless Legs Syndrome: diagnostic criteria, special considerations and epidemiology. Sleep Med., 4(2): 101-119. Aserinsky, E and Kleitman, N (1953) Regularly occurring periods of eye motility and concomitant phenomena during sleep. Science, 118: 273. Atlas Task Force of the American Sleep Disorders Association (1993) Recording and scoring leg movements. Sleep, 16: 748. Berger, H (1929) Uber das Elektroencephalogramm des Menschen. Arch. Psychiatr. Nervenkr., 87: 527-570. Carskadon, MA, Dement, WC and Mitler, M et al. (1986) Guidelines for the Multiple Sleep Latency Test (MSLT): a standard measure of sleepiness. Sleep, 9: 519. Cherbin, R (2003) Assessment of sleepiness. In: S Chokroverty, WA Hening and AS Walters (Eds.), Sleep and Movement Disorders. Butterworth-Heinemann; Boston. Doghramji, K, Mitler, M and Sangal, RB et al. (1997) A normative study of the maintenance of wakefulness test (MWT). Electroencephalogr. Clin. Neurophysiol., 103: 554. Hasan, J (1996) Past and future of computer-assisted sleep analysis and drowsiness assessment. J. Clin. Neurophysiol., 13: 295-313. Hirshkowitz, M (2000) Standing on the shoulders of giants: The standardized sleep manual after 30 years. Commentary. Sleep Med. Rev., 4: 169-179. Hirshkowitz, M and Moore, CA (1994) Issues in computerized polysomnography. Sleep, 17: 105. Hirshkowitz, M and Moore, CA (1999) Computerized and portable sleep recording. In: S Chokroverty (Ed.), Sleep Disorders Medicine. Butterworth-Heinemann: Boston, pp. 237-244.
151 Hinmanen, S-L and Hasan, J (2000) Limitations of Rechtschaffen and Kales. Sleep Med. Rev., 4: 149-167. Indications for Polysomnography Task Force, American Sleep Disorders Association Standards of Practice Committee (1997) Practice parameters for the indications for polysomnography and related procedures. Sleep, 20: 406-422. Johns, MW (1991) A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep, 14: 540. Keenan, SA (1999) Polysomnographic technique: An overview: In: S Chokroverty (Ed.), Sleep Disorders Medicine. Butterworth-Heinemann: Boston, pp. 151174. Kryger, MH (2000) Monitoring respiratory and cardiac function. In: MH Kryger, T Roth and WC Dement (Eds.), Principles and Practice of Sleep Medicine. WB Saunders Company: Philadelphia, pp. 1217-1230. Kubicki, S and Hermann, WM (1996) The future of computer-assisted investigation of the polysomnogram: Sleep microstructure. J. Clin. Neurophysiol., 13: 285294. Mahowald, M (2002) Hope for the PLMS quagmire: Editorial. Sleep Med., 3: 463-464. Oswald, I (1959) Sudden body jerks on falling asleep. Brain, 82: 92. Parisi, RA (1999) Respiration and respiratory function: Technique of recording and evaluation. In: S Chokroverty (Ed.). Butterworth-Heinemann: Boston, pp. 215221. Penzel, T and Conradt, R (2000) Computer based sleep recording and analysis. Sleep Med. Rev., 4: 131-J48. Rechtschaffen, A and Kales, A (1968) A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects. Washington, D.C.: U.S. Govemment Prinitng Office. Standards of Practice Committee of the American Sleep Disorders Association (1995) Practice parameters for the use of actigraphy in the clinical assessment of sleep disorders. Sleep, 18: 285-228. Thorpy, M (1992) The clinical use of the multiple sleep latency test. Sleep, 15: 268-276. Walczak, T and Chokroverty, S (1999) Electroencephalography, electromyography, and electro-oculography: General principles and basic technology. In: S Chokroverty (Ed.), Sleep Disorders Medicine. Butterworth-Heinemann: Boston, pp. 175-203.
Movement Disorders Handbook of Clinical Neurophysiology, Vol. 1 M. Hallett (Ed.) © 2003 Elsevier B.Y. All rights reserved
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CHAPTER II
Microneurography and motor disorders David Burke?", Simon C. Gandevia'' and Vaughan G. Macefield" "College of Health Sciences, The University of Sydney and h Spinal Injuries Research Centre, Prince of Wales Medical Research Institute, University of New South Wales, Sydney, Australia
The technique of microneurography was developed by Vallbo and Hagbarth (1968) and Hagbarth and Vallbo (1968), and has since been used to shed light on motor control mechanisms, cutaneous tactile sensations, pain and disturbances to sympathetic efferent function. This chapter addresses the technique and some of the contributions made using it to understanding the role of the 'Y efferent system in the control of movement and motor disorders.
11.1. Technique In microneurography, the experimenter inserts a sterilized microelectrode manually through the skin into an underlying nerve trunk and then guides the electrode tip into the desired nerve fascicle. The electrodes are usually monopolar tungsten electrodes with a shaft diameter of - 200 urn, tapered to a tip of 1-5 p.m and insulated to the tip (Fig. 1). To obtain good single unit recordings from large myelinated axons, the electrode impedance measured at 1 kHz is usually of the order of 100-300 kil. A special concentric needle electrode has also been used by some investigators (Hallin and Wiesenfeld, 1981). Different authorities use or eschew stimulation through the microelectrode to guide insertion, but all rely on auditory feedback when close to or within a fascicle. Figure 1 illustrates the recording technique, but there is a size distortion that belies the fact that the microelectrode is much larger (shaft 200 urn) than the largest axons «20 urn), Nevertheless, manipulating the position of recording tip within the fascicle is relatively easy for experienced experi-
* Correspondence to: David Burke, MD, DSc, College of Health Sciences, Medical Foundation Building - K25, University of Sydney, NSW 2006, Australia. E-mail address:
[email protected]
Tel.: lnt +61.2.9036.3091; fax: lnt +61.2.9036.3092.
menters, and it is possible to focus on different types of activity - multi-unit activity, single unit activity and the activity in unmyelinated axons, afferent or efferent. Axons with background activity are preferentially detected, merely because their discharge can be heard and the recording can be focused on this activity. Single unit recordings are those in which the activity of a single unit stands out from background activity and noise, with a sufficiently large spike that it can be heard and seen reliably, and are usually from the largest axons because the amplitude of the action potential is a function of the square of axon diameter.
11.2. Fusimotor involvement in control of reflex function, muscle tone and voluntary movement Traditionally, muscle spindle afferents have held pride of place among muscle afferents, largely because their discharge can be directly modulated by 'Y efferent (fusimotor) drive, an unusual property for a sensory receptor. Recordings from muscle spindle endings have been used as measures of 'Y efferent activity. However, this practice is safe only if all other influences on spindle discharge are measured and controlled, and this is rarely possible in human experiments. Accordingly, there are conflicting data and conclusions in the literature and, inevitably, this review reflects the experience and biases of the authors.
11.2.1. Effects of immediate history on spindle discharge It is now well documented that the discharge of muscle spindle endings is affected by previous stretch (Edin and Vallbo, 1988) and by previous fusimotor activation (Ribot-Ciscar et al., 1991; Proske et al., 1993; Wilson et al., 1995), such that, for example, the discharge of muscle spindle endings
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Fig. 1. Unitary recording from a human muscle spindle. For the recording on the right, the tungsten rnicroelectrode was inserted percutaneously into a motor fascicle of the ulnar nerve at the wrist and the target muscle identified by the responses to intraneural electrical stimulation and the responses to passive and active movements of the digits. The recording was made from a spontaneously-active (presumed secondary) spindle ending in the 4th dorsal interosseous. The spindle ending increased its discharge during extension (right panel) and passive abduction (not shown) at the 4th metacarpophalangeal joint, the responses to stretch and shortening being essentially static. A sketch of the technique is on the left. The rnicroelectrode is introduced manually and, when in situ, it is supported without rigid fixation at one end by its connecting lead and at the other by the skin and subcutaneous tissue. Its position is adjusted within the nerve until the tip penetrates the desired nerve fascicle. Minor adjustments are made to bring the desired neural activity into focus. Note that the rnicroelectrode has a shaft diameter of - 200 urn and that the largest axons have a diameter of - 20 urn,
may remain elevated for long after a voluntary contraction, as in Fig. 2 (Macefield et al., 1991; Wilson et al., 1995). This is not due to on-going fusimotor drive but to the persistence of actinmyosin bonds formed in intrafusal fibers by 'Y efferent -activity that accompanied the contraction but ceased with it. The resulting distortions of spindle responsiveness could account for some of the discrepancies between different studies. The effects of intrafusal thixotropy can be quite prominent, sufficient to produce changes in reflex function and distortions of proprioceptive sensations which depend on perception of muscle spindle discharge (e.g. Wise et al., 1998). 11.2.2. 'Y drive to resting muscle
In human subjects who are at rest, there is a very low, possibly negligible level of fusimotor drive, particularly in static 'Y efferents (Vallbo et al., 1979; Burke, 1981; Gandevia and Burke, 1992), such that
muscle spindle discharge and the response to stretch do not change appreciably following complete nerve block (Burke et al., 1976, 1981a). There may be some activity in dynamic 'Y efferents, and this may be altered by the reflex action of cutaneous afferents (Aniss et al., 1990; Gandevia et al., 1994) and, possibly, by reinforcement maneuvers (see below, Ribot-Ciscar et al., 2000). In normal subjects who are at rest, muscle tone and the tendon jerk are therefore not dependent on the level of fusimotor drive, and hypotonia and hyporeflexia cannot be due to the withdrawal of background v activity (for reviews, see Burke, 1983, 1988). 11.2.3. Reflex reinforcement
The potentiation of spinal reflexes by reinforcement maneuvers (such as the Jendrassik maneuver) is largely due to effects on reflex transmission within
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Fig. 2. Activation of a muscle spindle ending in tibialis anterior (TA) during a 60 s contraction. Panel A shows the first 20 s of the contraction, and panel B the last 10 s, the traces being the nerve recording, ankle dorsiflexion force and integrated EMG of TA. The axon had no background discharge at rest but was activated during the contraction, discharging at - 12 Hz. On cessation of the contraction, there was a high-frequency burst of impulses from the afferent as the spindle was stretched, but the discharge then continued despite the complete subsidence of EMG and force. Panel C shows the "twitch test" used to identify the afferent as of spindle origin (upper trace: discharge of the afferent in five supramaximal trials; second trace: corresponding twitch contractions). The lowest trace shows superimposed action potentials of the afferent. From Macefield et al. (1991), with permission.
the spinal cord, not to activation of the 'Y efferent system. It was believed that selective activation of dynamic 'Y efferents would potentiate the muscle spindle response to percussion sufficiently to enhance the tendon jerk (Paillard, 1955), but some authorities question whether dynamic 'Y activation could do so (Morgan et al., 1984; Wood et al., 1994), and there is evidence that it does not (Gregory et al., 2001). Some studies using microneurography have demonstrated that effective reinforcement maneuvers produce no enhancement of the background discharge or the response to stretch of muscle spindle afferents in EMG-silent muscles at constant length (Vallbo and Hagbarth, 1966; Hagbarth et al., 1975c; Burke, 1981; Burke et al., 1981b; Ribot et al., 1986), or their ease of activation in voluntary contractions (Burke et aI., 1980a). Others have reported that reinforcement maneuvers produce an increased background spindle discharge (Burg et al., 1974; Szumski et al., 1974; Ribot-Ciscar et aI., 2000), or an increased discharge of presumed dynamic 'Y efferent axons though, parodoxically, without an increase in group Ia activity (Ribot et al.,
1986). However, these maneuvers may also increase the discharge of at least some (X motoneurons (Ribot et al., 1986), raising questions about the selectivity claimed for the 'Y activation (Hagbarth et aI., 1975c; see also Ribot-Ciscar et al., 2000). If reinforcement increased the background spindle discharge, this should depress reflex transmission from the active afferents (through the mechanism known as "homosynaptic" depression). This would depress rather than enhance the tendon jerk and the H-reflex (Hultbom et al., 1996; Wood et aI., 1996), unless the spindle response to percussion could be enhanced sufficiently to overcome the "homosynaptic" depression due to increased background spindle activity. The available evidence suggests that it cannot (Gregory et al., 2001). If reflex reinforcement occurs within spinal cord circuitry, as is suggested by Fig. 3, one would expect the H-reflex to be potentiated, as indeed it is (Landau and Clare, 1964; Bussel et al., 1978; Burke et al., 1981b; Dowman and Wolpaw, 1988; Zehr and Stein, 1999; Gregory et al., 2001). Potentiation of the H-reflex is difficult to explain on a fusimotor mechanism. Similarly, when subjects are warned of the need to contract a muscle (anticipation), train on a task or mentally rehearse a movement, there is no evidence for selective activation of 'Y motoneurons although, in each instance, spinal reflex excitability is increased (Burke et al., 1980b; Gandevia and Burke, 1985; Gandevia et al., 1997). In addition, fusimotor drive does not contribute to the reflex enhancement accompanying a motor adaptation task (Al-Falahe et al., 1990). These studies indicate that there are effective mechanisms for controlling reflex "gain" independent of the fusimotor system. 11.2.4. Voluntary contractions
During a nerve block that affects (X motor axons preferentially, the effort to contract the paralyzed muscle increases the discharge of spindle endings, presumably because it activates 'Y efferents directed to the paralyzed muscle (Burke et aI., 1979a). This finding provided support for the view that, when normal subjects contract a muscle voluntarily (or unintentionally), static 'Y motoneurons innervating the contracting muscle (but not its inactive synergists) are activated (Vallbo and Hagbarth, 1966; Vallbo, 1971, 1974; Vallbo et al., 1979). When the contraction is isometric, the 'Y activation is usually
156
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Fig. 3. Effects of the Jendrassik maneuver. Panel A shows the relationship between the intensity of tendon percussion to the Achilles tendon (in arbitrary units) and the amplitude of the integrated multi-unit afferent response from the nerve fascicle innervating soleus (in arbitrary units) for one subject. Circles: subject relaxed. Triangles: subject performing the Jendrassik maneuver. Filled symbols: percussion that produced a tendon jerk. Open symbols: no reflex response. The "threshold" for the tendon jerk was equivalent to 15 units of afferent activity (or 12 units of percussion) when relaxed but 9 units of afferent activity (4-5 units of percussion) when performing the Jendrassik maneuver. Panel B shows for the same data, using the same symbols, the relationship between the afferent volley and the reflex EMG. During the Jendrassik maneuver (triangles), the same afferent volley produced a significantly greater reflex response than at rest (circles). From Burke et aI. (l98Ib), with permission.
sufficient to enhance the background discharge of spindle endings (Fig. 2), increase their discharge variability, increase their static response to stretch, and diminish the pause in discharge that occurs on muscle shortening (Vallbo, 1971, 1973, 1974; Burke et al., 1979b). There is evidence that voluntary effort also activates dynamic 'Y efferents (Kakuda and Nagaoka, 1998), and that f3 (skeletofusimotor) efferents can be activated by both voluntary effort (Aniss et al., 1988; Kakuda et al., 1998) and transcranial stimulation of the motor cortex (Rothwell et aI., 1990). When voluntary contractions produce muscle shortening, the enhanced fusimotor drive can be sufficient to maintain or even increase spindle discharge (Vallbo, 1973), but this occurs only if the movement is slow or the muscle is contracting against a load (Burke et al., 1978a, b; Hulliger et al., 1985). The increase in spindle discharge usually occurs after the onset of EMG activity in the contracting muscle, at some 20-50 ms when the contractions are rapid and phasic (Vallbo, 1971; Hagbarth et al., 1975a). However, while there has been clear evidence of a-'Y co-activation in all
voluntary acts so far tested, the balance between the a and 'Y drives can be varied (Burke et al., 1980a;
Vallbo and Hulliger, 1981; Wessberg and Vallbo, 1995). This would be expected given that different descending pathways have quantitatively different effects on a and 'Y motoneurons, and that many peripheral afferent inputs have different reflex effects on a and 'Y motoneurons (Aniss et al., 1990; Gandevia et al., 1994). Nevertheless, the evidence for disproportionate activation of 'Y motoneurons during motor learning and precision finger movements is, at best, quite modest (Vallbo and AI-Falahe, 1990; Wessberg and Vallbo, 1995; Kakuda et al., 1996). In fatiguing submaximal isometric contractions the enhancement of muscle spindle discharge is maximal initially and then decreases by about onethird (Macefield et al., 1991), a finding that implies that feedback support to the contraction is maximal initially but subsequently wanes. A further implication is that, contrary to classical views (Merton, 1953), the 'Y efferent system is not mobilized to compensate for fatigue, at least under isometric conditions. When a motor nerve is blocked distal to
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the recording site, recordings can be made from the axons of ex motoneurons deprived of feedback support from endings in the now-paralyzed muscle (Gandevia et aI., 1990, 1993; Macefield et aI., 1993). The discharge rates of motor axons reach only about two-thirds of those of normally intact motor units, a finding that suggests significant feedback support to the contracting motoneuron pool. It is more difficult to maintain motor unit firing in the absence of this feedback, but subjects can still recruit and de-recruit motoneurons and modulate motoneuron firing rates, given only knowledge of the effort that they are sending to the muscle. 11.4. Cutaneous atTerents and motor control
The traditional view that cutaneous afferents play little role in motor control is just as fallacious as the view that muscle afferents play no role in sensation. In the control of hand function, cutaneous afferents are at least as important as muscle spindle afferents and, for some motor acts, they are arguably more important sources of afferent feedback, capable of reflexly modifying the command for movement at multiple levels - segmental, suprasegmental and cerebral. There are extensive data on the response patterns of different cutaneous mechanoreceptors to tactile stimuli, to skin stretch and to passive movement of the hand (for review see Macefield, 1998), yet there has been relatively little work on the roles of tactile afferents in motor control. Most of this work has dealt with the sensorimotor specializations of the hand which, given its high density of tactile afferents (particularly in the finger pads), is perhaps not surprising. At the very least, receptors in the skin provide facilitation of the motoneuron pool: electrical or mechanical stimulation of cutaneous afferents causes short-latency (spinal) and long-latency increases in the EMG of muscles acting on the digits (Darton et aI., 1982; Evans et aI., 1986; Macefield et aI., 1996b) and, in the absence of muscle afferent feedback (anesthetic block ofthe ulnar nerve), tactile afferents traveling in the median nerve have been shown to increase the size of a volitionaIly generated motor output (Gandevia et aI., 1990). Moreover, the input from a single cutaneous afferent is sufficiently strong that it can modulate the ongoing EMG of muscles acting on the receptor-bearing digit, at
spinal latencies (McNulty et aI., 1999); conversely, the synaptic input of a single muscle spindle afferent is weak, at least for muscle spindles in the leg (Gandevia et aI., 1986). However, more than this simple facilitation of motoneurons, tactile afferents are actively engaged in fine motor control of the hand. Because of their location at the skin/object interface, cutaneous mechanoreceptors are ideally placed to monitor the loads applied by or to the finger pads during manipulation of a gripped object. Indeed, anesthesia of the digits seriously compromises the capacity to perform a precision grip and to adjust the grip force automatically as a function of the load and surface conditions (Johansson et aI., 1992c; Hager-Ross and Johansson, 1996). Tactile afferents also provide information on the frictional conditions of the object, information that is incorporated automatically into grading the grip force required to hold an object (Cole and Johansson, 1993). Unpredictable pulling forces applied to an object held between finger and thumb evoke automatic increases in grip force that serve to prevent escape of the object from the grasp (Cole and Abbs, 1988; Johansson et al., 1992a, b, c; Macefield et aI., 1996a; Macefield and Johansson, 1996), and rnicroneurographic studies have shown that tactile afferents in the glabrous skin of the digits are the only receptors capable of triggering these increases in grip force (Macefield et aI., 1996a); muscle and joint afferents respond only during the resultant increases in grip force (Macefield and Johansson, 1996). 11.5. Studies in patients
11.5.1. Spasticity There are relatively few reports of muscle spindle activity in spastic patients (Hagbarth et aI., 1973, 1975b; Szumski et aI., 1974; Wilson et aI., 1999).All are from hemiplegic patients; there are no published studies from patients with spinal cord injury. The studies of Szumski et al. (1974) and Hagbarth et al. (1975b) involved discharge patterns during clonus (described below with Parkinsonian tremor). Hagbarth et aI. (1973) reported that the responses to controlled stretch of 9 endings in triceps surae of hemiplegic patients were not greater than those of 12 spindle endings in normal subjects. Wilson et al.
D. BURKEET AL.
158
Instantaneous frequency
Fig. 4. Muscle spindle afferent innervating extensor carpi radialis (ECR) during deliberate isometric wrist extension in a patient suffering from hemiplegic spasticity (extensor strength 68% of that of the contralateral side). The afferent did not maintain a background discharge when truly at rest. During voluntary efforts to contract the muscle ("Extension"), the spindle ending was activated together with the EMG of ECR. Between the deliberate contractions, the ending was activated unintentionally during inadvertent contractions, but again with EMG. The ending in ECR was not activated during an unintentional contraction of the forearm flexors that occurred when the patient was told to relax ECR. The insert (top right) shows action potential morphology (multiple superimposed discharges). From Wilson et a1. (1999), with permission.
(1999) documented the properties of 26 endings in the forearm extensors. Background spindle discharge rates were the same as in healthy volunteers, reinforcement and other maneuvers did not enhance spindle discharge selectively, cutaneo-fusimotor reflexes could not be demonstrated, and spindles in the paretic muscles were no more difficult to activate in voluntary attempts to contract the weak muscles than in normal subjects (Fig. 4). These studies lead to the conclusion that there is no primary defect of fusirnotor function in hemiplegic spasticity - the hyper-reflexia is not due to enhanced 'Y efferent drive, and the loss of dexterity is not due to inability to activate 'Y motoneurons appropriately for the degree of a activation. Whether the same holds true for patients with spinal spasticity remains to be demonstrated. It is not unreasonable to speculate that cutaneo-fusimotor reflexes could be disinhibited in spinal patients, much as are cutaneomuscular reflexes, and it is conceivable that "normal" peripheral afferent inputs from skin, joints,
etc. may produce a background discharge in 'Y efferents. 11.5.2. Parkinson's disease The only published data from parkinsonian patients are those of Hagbarth et a1. (1975b) on parkinsonian tremor and of Wallin et al. (1973) on multi-unit muscle afferent responses to muscle stretch, together with a re-analysis of some of these data (Burke et al., 1977). In parkinsonian tremor muscle spindle endings tended to discharge twice, during the shortening phase of the test muscle (with the EMG of that muscle) and during the lengthening phase (which would subject muscle spindles to stretch). There was a similar biphasic pattern in healthy subjects who made rapid alternating movements to mimic tremor (Hagbarth et al., 1975a) whereas, in the reflex-sustained movements of clonus in spastic patients, spindle discharge occurred only during the stretching phase of the oscillating
159
MICRONEUROGRAPHY AND MOTOR DISORDERS
movement (Szumski et al., 1973; Hagbarth et al., 1975b). In multi-unit recordings, it was noted that spontaneous or evoked fluctuations in rigidity involved parallel fluctuations in afferent activity and EMG and that there was more background afferent activity in rigid muscles than in normal subjects who were relaxed. The shortening reaction is a phenomenon characteristic of Parkinson's disease and other basal ganglia disturbances, but may also occur in normal human subjects. There is one recording of a shortening reaction in a normal subject: passive dorsiflexion produced an involuntary contraction of tibialis anterior, and this was associated with a muscle spindle discharge, much as was recorded when the subject made a voluntary dorsiflexion movement (Burke et aI., 1978b). The above data suggest that there is no primary defect of fusimotor function in parkinsonian rigidity. Parkinsonian rigidity seems to behave more as if there were a defect of supraspinal drives onto relatively normal spinal mechanisms, those drives affecting a and 'Y motoneurons much as would volitional drives. However, these conclusions are based on qualitative impressions rather than quantitative recordings, and more extensive studies are required before the views can be accepted as definitive. 11.5.3. Dystonia There have been no published microneurographic studies in dystonia, but there is literature suggesting that different forms of dystonia are due to or associated with a disturbance of sensory processing, affecting particularly the input from muscle spindle endings (Kaji et al., 1995; Grunewald et aI., 1997; Yoshida et al., 1998). In addition, some of the beneficial effects of botulinum toxin in dystonic syndromes may be due to effects on the neuromuscular junction of 'Y efferents on intrafusal fibers. 11.6. Clinical value
With microneurography, the findings depend on the site of the microelectrode within a fascicle. A recording from a single afferent axon is rarely representative of the population response, whether the afferent is of cutaneous or muscle origin. Multiunit recordings can provide a representative picture
of large-fiber activity within the fascicle, but are difficult to quantify. Accordingly, when one considers the data for an individual patient, microneurography currently has no place as a diagnostic procedure, even if insights into pathophysiology come when the data from a number of patients are pooled. Evoked compound action potentials to electrical stimulation have been recorded using microneurography, and the full range of afferent axons from large-myelinated to unmyelinated can be discriminated. However, the diagnostic value of such recordings is debatable, and similar data can be obtained with near-nerve needle electrodes. The clinical value of microneurography comes from the unique insights that it can provide into pathophysiology. References Al-Falahe, NA, Nagaoka, M and Vallbo, AB (1990) Lack of fusimotor modulation in a motor adaptation task. Acta Physiol. Scand., 140: 23-30. Aniss, AM, Gandevia, SC and Burke, D (1988) Reflex changes in muscle spindle discharge during a voluntary contraction. J. Neurophysiol., 59: 908-921. Aniss, AM, Diener, H-C, Hore, J, Burke, D and Gandevia, SC (1990) Reflex activation of muscle spindles in human pretibial muscles during standing. J. Neurophysiol., 64: 671-679. Burg, D, Szumski, AJ, Struppler, A and Velho, F (1974) Assessment of fusimotor contribution to reflex reinforcement in humans. J. Neurol. Neurosurg. Psychiatry, 37: 1012-1021. Burke, D (1981) The activity of human muscle spindle endings in normal motor behavior. In: R Porter (Ed.), International Review of Physiology, Vol. 25, Neurophysiology IV. University Park Press, Baltimore, pp.91-126. Burke, D (1983) Critical examination of the case for or against fusimotor involvement in disorders of muscle tone. In: JE Desmedt (Ed.), Motor Control Mechanisms in Health and Disease, Advances in Neurology, Vol. 39. Raven Press, New York, pp. 133-150. Burke, D (1988) Spasticity as an adaptation to pyramidal tract injury. In: SG Waxman (Ed.) Functional Recovery in Neurological Disease, Advances in Neurology, Vol. 47. Raven Press, New York, pp. 401-423. Burke, D, Hagbarth, K-E, Lofstedt, L and Wallin, BG (1976) The responses of human muscle spindle endings to vibration during isometric contraction. J. Physiol. (Lond.), 261: 695-711.
160 Burke, D, Hagbarth, K-E and Wallin, BG (1977) Reflex mechanisms in Parkinsonian rigidity. Scand. J. Rehab. Med., 9: 15-23. Burke, D, Hagbarth, K-E and Lofstedt, L (1978a) Muscle spindle responses in man to changes in load during accurate position maintenance. J. Physiol. (Lond.), 276: 159-164. Burke, D, Hagbarth, K-E and Lofstedt, L (1978b) Muscle spindle activity in man during shortening and lengthening contractions. J. Physiol. (Lond.), 277: 131-142. Burke, D, Hagbarth, K-E and Skuse, NF (1979a) Voluntary activation of spindle endings in human muscles temporarily paralysed by nerve pressure. J. Physiol. (Lond.), 287: 329-336. Burke, D, Skuse, NF and Stuart, DG (1979b) The regularity of muscle spindle discharge in man. J. Physiol. (Lond.), 291: 277-290. Burke, D, McKeon, B and Westerman, RA (1980a) Induced changes in the thresholds for voluntary activation of human spindle endings. J. Physiol. (Lond.),302: 171-181. Burke, D, McKeon, B, Skuse, NF and Westerman, RA (1980b) Anticipation and fusimotor activity in preparation for a voluntary contraction. J. Physiol. (Lond.), 306: 337-348. Burke, D, McKeon, B and Skuse, NF (198Ia) The irrelevance of fusimotor activity to the Achilles tendon jerk of relaxed humans. Ann. Neurol., 10: 547-550. Burke, D, McKeon, B and Skuse, NF (1981 b) Dependence of the Achilles tendon reflex on the excitability of spinal reflex pathways. Ann. Neurol., 10: 551-556. Bussel, B, Morin, C and Pierrot-Deseilligny, E (1978) Mechanism of monosynaptic reflex reinforcement during Jendrassik maneuver in man. J. Neurol. Neurosurg. Psychiatry, 41: 40-44. Cole, KJ and Abbs, JH (1988) Grip force adjustments evoked by load force perturbations of a grasped object. J. Neurophysiol., 60: 1513-1522. Cole, KJ and Johansson, RS (1993) Friction at the digitobject interface scales the sensorimotor transformation for grip responses to pulling loads. Exp. Brain Res., 95: 523-532. Darton, K, Lippold, OC, Shahani, M and Shahani, U (1985) Long-latency spinal reflexes in humans. J. Neurophysiol., 53: 1604-1618. Edin, BB and Vallbo, AB (1988) Stretch sensitization of human muscle spindles. J. Physiol. (Lond.), 400: 101-111. Evans, AL, Harrison, LM and Stephens, JA (1989) Taskdependent changes in cutaneous reflexes recorded from various muscles controlling finger movement in man. J. Physiol. (Lond.), 418: 1-12.
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Gandevia, SC and Burke, D (1985) Effect of training on voluntary activation of human fusimotor neurons. J. Neurophysiol., 54: 1422-1429. Gandevia, SC and Burke, D (1992) Does the nervous system depend on kinesthetic information to control natural limb movements? Behav. Brain Sci., 15: 614632. Gandevia, SC, Burke, D and McKeon, B (1986) Coupling between human muscle spindle endings and motor units assessed using spike-triggered averaging. Neurosci. Lett., 71: 181-186. Gandevia, SC, Macefield, G, Burke, D and McKenzie, DK (1990) Voluntary activation of human motor axons in the absence of muscle afferent feedback. The control of the deafferented hand. J. Physiol. (Lond.), 113: 15631581. Gandevia, SC, Macefield, VG, Bigland-Ritchie, B, Gorman, RB and Burke, D (1993) Motoneuronal output and gradation of effort in attempts to contract acutely paralysed leg muscles in man. J. Physiol. (Lond.), 471: 411-427. Gandevia, SC, Wilson, L, Cordo, PJ and Burke, D (1994) Fusimotor reflexes in relaxed forearm muscles produced by cutaneous afferents from the human hand. J. Physiol. (Lond.), 479: 499-508. Gandevia, SC, Wilson, LR, Inglis, JT and Burke, D (1997) Mental rehearsal of motor tasks recruits alpha-motoneurons but fails to recruit human fusimotor neurons selectively. J. Physiol. (Lond.), 505: 259-266. Gregory, JE, Wood, SA and Proske, U (2001) An investigation into mechanisms of reflex reinforcement by the Jendrassik maneuver. Exp. Brain Res., 138: 366-374. Grunewald, RA, Yoneda, Y, Shipman, JM and Sagar, HJ (1997) Idiopathic focal dystonia: a disorder of muscle spindle afferent processing? Brain, 120: 2179-2185. Hagbarth, K-E and Vallbo, AB (1968) Discharge characteristics of human muscle afferents during muscle stretch and contraction. Exp. Neurol., 22: 674-694. Hagbarth, K-E, Wallin, G and Lofstedt, L (1973) Muscle spindle responses to stretch in normal and spastic subjects. Scand. J. Rehab. Med., 5: 156-159. Hagbarth, K-E, Wallin, G and Lofstedt, L (1975a) Muscle spindle activity in man during voluntary fast alternating movements. J. Neurol. Neurosurg. Psychiatry, 38: 625635. Hagbarth, K-E, Wallin, G, Lofstedt, L and Aquiionius, SM (1975b) Muscle spindle activity in alternating tremor of Parkinsonism and in clonus. J. Neurol. Neurosurg. Psychiatry, 38: 636-641. Hagbarth, K-E, Wallin, G, Burke, D and Lofstedt, L (1975c) Effects of the Jendrassik maneuver on muscle spindle activity in man. J. Neurol. Neurosurg. Psychiatry, 38: 1143-1153.
MICRONEUROGRAPHY AND MOTOR DISORDERS
Hager-Ross, C and Johansson, RS (1996) Non-digital afferent input in reactive control of fingertip forces during precision grip. Exp. Brain Res., 110: 131-141. Hallin, RG and Wiesenfeld, Z (1981) A standardized electrode for percutaneous recording of A and C fiber units in conscious man. Acta Physiol. Scand., 113: 561-563 Hulliger, M, Nordh, E and Vallbo, AB (1985) Discharge in muscle spindle afferents related to direction of slow precision movements in man. J. Physiol. (Lond.), 362: 437-453. Hultborn, H, Illert, M, Nielsen, J, Paul, A, Ballegaard, M and Wiese, H (1996) On the mechanism of the postactivation depression of the H-reflex in human subjects. Exp. Brain Res., 108: 450-462. Johansson, RS, Riso, R, Hager, C and Backstrom, L (1992a) Somatosensory control of precision grip during unpredictable pulling loads. I. Changes in load force amplitude. Exp. Brain Res., 89: 181-191. Johansson, RS, Hager, C and Riso, R (1992b) Somatosensory control of precision grip during unpredictable pulling loads. II. Changes in load force rate. Exp. Brain Res., 89: 192-203. Johansson, RS, Hager, C and Backstrom, L (1992c) Somatosensory control of precision grip during unpredictable pulling loads. III. Impairments during digital anesthesia. Exp. Brain Res., 89: 204-213. Kaji, R, Rothwell, JC, Katayama, M, Ikeda, T, Kubori, T, Kohara, N, Mezaki, T, Shibasaki, H and Kimura, J (1995) Tonic vibration reflex and muscle afferent block in writer's cramp. Ann. Neurol., 38: 155-162. Kakuda, N, Vallbo, AB and Wessberg, J (1996) Fusimotor and skeletomotor activities are increased with precision finger movement in man. J. Physiol. (Lond.), 492: 921-929. Kakuda, N, Miwa, T and Nagaoka, M (1998) Coupling between single muscle spindle afferent and EMG in human wrist extensor muscles: physiological evidence of skeletofusimotor (beta) innervation. Electroencephalogr. Clin. Neurophysiol., 109: 360-363. Kakuda, N and Nagaoka, M (1998) Dynamic response of human muscle spindle afferents to stretch during voluntary contraction. J. Physiol. (Lond.), 513: 621628. Landau, WM and Clare, MH (1964) Fusimotor function. Part IV. Reinforcement of the H-reflex in normal subjects. Arch. Neurol., 10: 117-122. Macefield, VG (1998) The signalling of touch, finger movements and manipulation forces by mechanoreceptors in human skin. In: JW Morley (Ed.), Neural Aspects of Tactile Sensation. Elsevier, Amsterdam, pp 89-130. Macefield, VG, Rothwell, JC and Day, BL (1996b) The contribution of transcortical pathways to long-latency
161 stretch and tactile reflexes in human hand muscles. Exp. Brain Res., 108: 172-184. Macefield, G, Hagbarth, K-E, Gorman, R, Gandevia, SC and Burke, D (1991) Decline in spindle support to alpha-motoneurons during sustained voluntary efforts. J. Physiol. (Lond.), 440: 497-512. Macefield, VG, Gandevia, SC, Bigland-Ritchie, B, Gorman, RB and Burke, D (1993) The firing rates of human motoneurons voluntarily activated in the absence of muscle afferent feedback. J. Physiol. (Lond.), 471: 429-443. Macefield, VG, Hager-Ross, C and Johansson, RS (1996a) Control of grip force during restraint of an object held between finger and thumb: responses of cutaneous afferents from the digits. Exp. Brain Res., 108: 155171. Macefield, VG and Johansson, RS (1996) Control of grip force during restraint of an object held between finger and thumb: responses of muscle and joint afferents from the digits. Exp. Brain Res., 108: 172-184. Merton, PA (1953) Speculations on the servo control of movement. In: JL Malcolm and JAB Gray (Eds.), The Spinal Cord. Ciba Foundation Symposium, Churchill, London, pp. 84-91. McNulty, PA, Tnrker, KS and Macefield, VG (1999) Evidence for strong synaptic coupling between single tactile afferents and motoneurons supplying the human hand. J. Physiol. (Lond.), 518: 883-893. Morgan, DL, Prochazka, A and Proske, U (1984) Can fusimotor activity potentiate the responses of muscle spindles to a tendon tap? Neurosci. Lett., 50: 209-215. Paillard, J (1955) Reflexes et Regulations d'Origine Proprioceptive Chez l'Homme. Arnette, Paris. Proske, U, Morgan, DL and Gregory, IE (1993) Thixotropy in skeletal muscle and in muscle spindles: a review. Prog. Neurobiol., 41: 705-721. Ribot, E, Roll, JP and Vedel, JP (1986) Efferent discharges recorded from single skeletomotor and fusimotor fibers in man. J. Physiol. (Lond.), 375: 2251-2268. Ribot-Ciscar, E, Tardy-Gervet, MF, Vedel, JP and Roll, JP (1991) Post-contraction changes in human muscle spindle resting discharge and stretch sensitivity. Exp. Brain Res., 86: 673-678. Ribot-Ciscar, E, Rossi-Durand, C and Roll, JP (2000) Increased muscle spindle sensitivity to movement during reinforcement maneuvers in relaxed human subjects. J. Physiol. (Lond.), 523: 271-282. Rothwell, JC, Gandevia, SC and Burke, D (1990) Activation of fusimotor neurons by motor cortical stimulation in human subjects. J. Physiol. (Lond.), 431: 743-756. Szumski, AJ, Burg, D, Struppler, A and Velho, F (1974) Activity of muscle spindles during muscle twitch and
162 clonus in normal and spastic human subjects. Electroencephalogr. Clin. Neurophysiol., 37: 589-597. Vallbo, AB (1971) Muscle spindle response at the onset of isometric voluntary contractions in man. Time difference between fusimotor and skeletornotor effects. J. Physiol. (Lond.), 218: 405-431. Vallbo, AB (1973) Muscle spindle afferent discharge from resting and contracting muscles in nonnal human subjects. In: JE Desmedt (Ed.), New Developments in Electromyography and Clinical Neurophysiology, Vol. 3. Karger, Basel, pp. 251-262. Vallbo, AB (1974) Human muscle spindle discharge during isometric voluntary contractions. Amplitude relations between spindle frequency and torque. Acta Physiol. Scand., 90: 319-336. Vallbo, AB and Hagbarth, K-E (1968) Activity from skin mechanoreceptors recorded percutaneously in awake human subjects. Exp. Neurol., 21: 270-289. Vallbo, AB and Hulliger, M (1981) Independence of skeletomotor and fusimotor activity in man? Brain Res., 223: 176-180. Vallbo, AB and Al-Falahe, NA (1990) Human muscle spindle response in a motor learning task. J. Physiol. (Lond.), 421: 553-568. Vallbo, AB, Hagbarth, K-E, Torebjork, HE and Wallin, BG (1979) Somatosensory, proprioceptive, and sympathetic activity in human peripheral nerves. Physiol. Rev., 59: 919-957. Wallin, BG, Hongell, A and Hagbarth, K-E (1973) Recordings from muscle afferents in Parkinsonian
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rigidity. In: JE Desmedt (Ed.), New Developments in Electromyography and Clinical Neurophysiology, Vol. 3. Karger, Basel, pp. 263-272. Wessberg, J and Vallbo, AB (1995) Human muscle spindle afferent activity in relation to visual control in precision finger movements. J. Physiol. (Lond.), 482: 225-233. Wilson, LR, Gandevia, SC and Burke, D (1995) Increased resting discharge of human spindle afferents following voluntary contractions. J. Physiol. (Lond.), 488: 833840. Wilson, LR, Gandevia, SC, Inglis, IT, Gracies, J-M and Burke, D (1999) Muscle spindle activity in the affected upper limb after a unilateral stroke. Brain, 122: 20792088. Wise, AK, Gregory, JE and Proske, U (1998) Detection of movements of the human forearm during and after cocontraction of muscles acting at the elbow joint. J. Physiol. (Lond.), 508: 325-330. Wood, SA, Morgan, DL, Gregory, JE and Proske, U (1994) Fusimotor activity and the tendon jerk in the anaesthetized cat. Exp. Brain Res., 98: 101-109. Wood, SA, Gregory, JE and Proske, U (1996) The influence of muscle spindle discharge on the human Hreflex and the monosynaptic reflex in the cat. J. Physiol. (Lond.), 497: 279-290. Yoshida, K, Kaji, R, Kubori, T, Kohara, N, Iizuka, T and Kimura, J (1998) Muscle afferent block for the treatment of oromandibular dystonia. Movement Dis., 13: 699-705.
Movement Disorders Handbook of Clinical Neurophysiology, Vol. 1 M. Hallett (Ed.) © 200] Elsevier B.V. All rights reserved
163 CHAPTER 12
Imaging Scott T. Grafton * Center for Cognitive Neuroscience, Dartmouth College, Hanover; NH 03755, USA
12.1. Introduction Brain imaging plays an important role in the evaluation of patients with movement disorders. Anatomic imaging is essential for ruling out structurallesions in subcortical nuclei and cortex, and for identifying regional atrophic changes. Imaging of brain metabolism and neurotransmitter function is an important adjunct to the clinical examination in patients with atypical akinetic-rigid syndromes that might not be secondary to idiopathic Parkinson's disease. Functional activation studies provide unique insight into normal motor control as well as the pathophysiologic basis of abnormal motor control. These imaging methods encompass techniques based on conventional x-rays, magnetic resonance and radionuclide tomography. In this chapter these techniques are reviewed and related to clinical applications, basic research and assessment of pharmacological and surgical therapy for movement disorders.
12.2. Structural imaging Although conventional x-rays of the skull are no longer used diagnostically in movement disorders, they are important historically for lesion localization and premorbid clinical-radiological correlation. In a classic 1917 study of injured soldiers, Holmes used conventional x-rays to relate the location of bullets lodged in the cerebellar hemispheres to cardinal signs of cerebellar damage including unilateral ataxia, hypotonia and dysiadochokinesia (Holmes,
* Correspondence to: Dr. Scott T. Grafton, M.D., Director, Dartmouth Brain Imaging Center, Center for Cognitive Neuroscience, 6162 Moore Hall, Dartmouth College, Hanover, NH 03755, USA. E-mail address:
[email protected] Tel.: + I (603) 646-0038; fax: + I (603) 646-1181.
1917). With the development of computer assisted tomographic imaging (CT) in the 1970s it became possible to identify supratentorial structural lesions that could cause secondary movement disorders. This early imaging work revealed that the most common structural lesion leading to parkinsonian symptoms was a large cortical or glial tumor with deformation of the basal ganglia. It is extremely rare for tumors located directly within the basal ganglia to cause parkinsonism (Waters, 1993). Other lesions, occasionally associated with parkinsonism are listed in Table 1. The advent of CT also brought attention to the incidental finding of basal ganglia calcification, i.e. Fahr's disease. The incidence of basal ganglia calcification in a general adult population is approximately 0.7%. Of these persons, less than 7% have any motor symptoms (Murphy, 1979; Brannan et aI., 1980). However, if the patient presents with hypoparathyroidism there is a 70% chance of basal ganglia calcification. This increases to almost 100% for patients with pseudohypoparathyroidism. The likelihood of motor symptoms also increases (Muenter and Whisnant, 1968; Sachs et aI., 1982; Illum and Dupont, 1985). With CT it also became possible to identify white matter changes consistent with subTable I Structura11esions associated with an akinesis or rigidity. Cortical tumors Glioma Meningioma Other Subdural hematoma Striatal abscess Midbrain tuberculoma Ventriculomegally Posterior fossa cyst Normal pressure hyodrocephalus Vascular parkinsonism
164
cortical infarction and associated arteriosclerotic parkinsonism (Critchley, 1929), i.e. subcortical arteriosclerotic encephalopathy (Binswanger's disease) (Thompson and Marsden, 1987; Bennett et al., 1990). CT was the first method to generate reliable volumetric measurements of brain anatomy in vivo. Striatal atrophy in advanced Huntington's disease was readily measured and it became possible to correlate clinical severity with tissue loss in the head of the caudate nucleus (Grafton et aI., 1992). With the introduction of magnetic resonance imaging in the early 1980s, image resolution and tissue contrast improved dramatically. The primary use of anatomic MR imaging in movement disorders is to exclude vascular disease or neoplasm causing symptoms that could mimic a neurodegenerative disease (Waters, 1993). Infratentoriallesions such as cerebellar atrophy in the hereditary ataxias can also be screened reliably. MRI changes in the basal ganglia can be seen in a variety of systemic diseases, as listed in Table 2. Most of these can be readily diagnosed clinically. Structural imaging with MRI allows for unprecedented accuracy in volumetric measurements of complete nuclei, such as the putamen or caudate. Large databases of normal and pathologic brain anatomy are currently being generated for probabilistic assessment of structure, form and volume (Mazziotta et al., 2001; Toga and Thompson, 2001). These measures can be correlated with clinical progression in Huntington's disease and possibly used to detect presymptomatic gene-positive persons at risk for the disease (Aylward et aI., 2000). Using special acquisition parameters, it may be possible to identify subtle changes in other neurodegenerative disorders including Parkinson's disease (Hu et aI., 2001).
12.3. Functional imaging 12.3.1. Radionuclide imaging The advent of single photon emission tomographic (SPECT) imaging provided early measurements of brain cerebral blood flow. With this method patients are injected with a radioactive agent that binds to cerebral tissue in proportion to local cerebral blood flow, a receptor or some other biologic marker (Podreka et aI., 1987). Injections and images are acquired with the subject at rest. Gamma-ray energy is detected with a set of
S.T. GRAFTON
Table 2 Diseases with MRI signal changes in basal ganglia. Hypointensity Wilson's diease Leigh's disease CO intoxication Anoxia Hallervorden-Spatz disease Cyanide poisoning Methanol intoxication GM2-gangliosidosis Hemolytic uremic disease Hyperintensity Wilson's disease Creutzfeldt-Jakob disease Manganese toxicity Hepatic encephalopathy AIDS Normal aging Calcified basal ganglia Hypo- and pseudohypoparathyroidism Fahrs syndrome CO intoxication Birth anoxia Tuberous sclerosis Mitochondrial encephalopathies Radiation and methotrexate therapy AIDS Congenital folate deficiency, dihydropteridine reductase deficiency Japanese B encephalitis, herpes simplex encephalitis Down syndrome Cockayne's syndrome MRI, magnetic resonance imaging; CO, carbon monoxide; AIDS, acquired immune deficiency syndrome.
collimated detectors rotating slowly around the head. Images are of low resolution (> 1.5 em) and nonuniform. Deep brain structures such as basal ganglia are of low image intensity due to attenuation of the radioactive emitter by overlying tissue. SPECT studies using blood flow tracers provided early evidence for changes in basal ganglia with Huntington's disease and temporo-parietal hypoperfusion in Alzheimer's disease. More recently, the cocaine analog 213-carbomethoxy-313-4-iodophenyl-tropane (beta-CIT) labeled with 1231 and related compounds have played an essential role in the assessment of the presynaptic striatal dopamine transporter uptake site (Brucke et al., 1993).
IMAGING
Development of positron emission tomography (PET) imaging in the early 1980s resolved many of the technical limitations of SPECT (better resolution, no attenuation artifacts) (Phelps et al., 1975). The range of biologic radiotracers that could be created with cyclotron produced radioisotopes was greatly expanded. Dominating these new compounds was "F-fluorodeoxyglucose (FDG) (Reivich et aI., 1979). The tracer is trapped within cells in proportion to glucose transport and utilization. Imaging of regional radioactivity within the brain provided a direct, simple assessment of relative glucose metabolism. Glucose metabolism is strongly correlated with local neuronal activity (Jueptner and Weiller, 1995). In particular, lesions and physiologic studies in rodents and non-human primates have established that regional metabolism reflects both excitatory and inhibitory neuronal activity and this activity is predominantly a reflection of pre-synaptic function (Nudo and Masterton, 1986). Under pathologic conditions glucose metabolism is altered when there is a change of neuronal density. Importantly, this measure was observed to be highly sensitive to underlying pathologic conditions and more reliable than other imaging methods such as blood flow imaging with SPECT or PET agents. Early clinical studies identified marked metabolic changes in temporoparietal cortex in both early and advanced Alzheimer's disease and mesial temporal hypometabolism in complex partial epilepsies. Thus, one might hope to identify subtle alterations of function circuits in movement disorders using metabolic rather than structural imaging. However, glucose metabolism also shows large changes in association with normal neuronal activation (Sokoloff, 1977). Thus, the behavioral state of the human or animal during the 20-30 min uptake period of FDG after intravenous injection will have a strong impact on the regional metabolism measured by PET imaging. In disorders with involuntary movement neural systems associated with movement production could have increased metabolic activity (Colebatch et aI., 1990; Brooks et aI., 1992b). This can potentially blur the distinction between metabolic abnormalities due to a disease (trait) with those due to a symptom (state).
12.3.1.1. Hypokinetic movement disorders A variety of cortical and subcortical metabolic changes are observed in the hypokinetic movement
165
disorders, i.e, disorders where there is a reduction of volitional movement. In Parkinson's disease the characteristic finding on PET imaging is elevated glucose metabolism in the striatum and mild to moderate reductions of cortical metabolism (Kuhl et aI., 1984; Eidelberg et aI., 1994). The hyperactivity in striatum is consistent with autoradiographic studies of non-human primates with parkinsonian symptoms secondary to the neurotoxin N-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) (Crossman et aI., 1985). Using this pattern of striatal hypermetabolism of PD as a benchmark, it was apparent that atypical parkinsonian syndromes, including multiple systems atrophy, striatonigral degeneration and olivopontocerebellar atrophy had different metabolic signatures as listed in Table 3 (Rosenthal et aI., 1988; De VoIder et aI., 1989; Fulham et aI., 1991; Otsuka et aI., 1991; Eidelberg et aI., 1993; Gilman et al., 1994; Otsuka et aI., 1994). An important generality is that all of the atypical syndromes are likely demonstrate striatal hypometabolism with variable involvement of cortical or cerebellar hypometabolism. Large clinical series have not yet been performed to establish the sensitivity and specificity of PET imaging. Nevertheless, the available evidence from smaller studies supports the utility of PET glucose metabolic imaging as an adjunct for diagnosing patients with clinically atypical akinetic-rigid movement disorders. Approximately 15% of PD patients will develop a significant dementia. With dementia there is a reduction of temporal-parietal cortical metabolism in the same areas as seen in Alzheimer's disease (Kuhl et aI., 1985). Whether this dementia and metabolic finding represents PD+AD, a special form of PD, or diffuse Lewy body disease with dementia is unknown. The neuropharmacology of movement disorders can be evaluated with PET radioisotopes that reflect presynaptic doparninergic function C8F-DOPA), post-synaptic DIID2 dopamine receptor binding (Spiperone, Raclopride) and non-specific opiod receptor binding (Garnett et aI., 1983). In Parkinson's disease there is an approximately 30% loss of F-DOPA uptake in striatum compared to normal subjects at symptom onset, progressing to a 60% reduction with advanced disease (Garnett et aI., 1984; Leenders et al., 1984; Leenders et aI., 1986; Martin et aI., 1987). There is a greater loss of FDOPA in the putamen than the caudate, whereas in
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S.T. GRAFTON
Table 3 Imaging in hypokinetic movement disorders.
Metabolism
PD
PD-Dementia
Atypical PD
PSP
CBGD
Inc striatum
Inc striatum
Dec striatum
Dec frontal
Mild dec frontal
Mild dec frontal
Dec frontal
Dec striatum, cerebellum, thalamus
Dec thalamus, parietal, temporal Asymmetric!
Dec Dec cerebellar (ataxic) temperoparietal Presynaptic dopamine Postsynaptic D2
Dec putamen
Dec putamen
Dec putament
Dec putamen
Dec putamen
Mild dec caudate
Mild dec caudate
Dec caudate
Dec caudate
Dec caudate
Dec striatum
Dec striatum
Dec striatum
Dec striatum
Dec striatum
Nl-mild inc striatum (untreated) Nl-mild dec striatum (treated)
Opioid receptors Normal PMRS
Normal striatum?
Normal striatum?
Dec NANcreatine Dec NANcreatine Dec NANcreatine
Pl): Parkinson's disease; PSP: Progressive supranuclear palsy; CBGO: Corticobasal ganglionic degeneration; Atypical PO includes striatonigral degeneration, olivopontocerebellar degeneration, and multiple systems atrophy; PMRS: Proton magnetic resonance spectroscopy.
the atypical parkinsonian syndromes both caudate and putamen are typically involved (Table 3) (Brooks et aI., 1990a, b; Laihinen et al., 1995; Brucke et aI., 1997). The reliability of using these findings for radiologic diagnosis in an individual patient depends on the experience of the imaging center performing F-DOPA imaging. Individual subject diagnosis requires the study of a large normative population with low measurement variability that patient data can be compared to. Post-synaptic dopamine receptors are normal or mildly increased in untreated early Parkinson's disease, suggestive for receptor upregulation (Rinne et al., 1990a, b). With long standing treatment with L-DOPA the postsynaptic binding is normal or reduced, consistent with mild receptor down regulation (Brooks et aI., 1992a; Turjanski et al., 1997). 12.3.1.2. Hyperkinetic movement disorders The prototypic hyperkinetic movement disorder is Huntington's disease (HD), in which the loss of
medium aspiny neurons in the striatum is accompanied by profound hypometabolism and reductions of dopaminergic, opioid and GABA associated benzodiazepine binding. All of these changes can be observed in vivo with PET imaging (Myers et al., 1988; Kuwert et aI., 1990). Reductions of metabolism likely precede clinical onset and then parallel disease progression (Mazziotta et aI., 1985b; Young et al., 1986; Mazziotta et al., 1987; Young et aI., 1987; Grafton et al., 1990; Grafton et aI., 1992). The development of a direct genetic test for Huntington's disease obviates the use of functional brain imaging as a diagnostic aid for this disease (Gusella et aI., 1983, 1993). It is interesting to note that different causes of chorea can have opposing changes of striatal metabolism as listed in Table 4. There is a common pattern of striatal hypometabolism in HD, benign familial chorea and neuroacanthocytosis (Suchowersky et aI., 1986; Hosokawa et aI., 1987; Dubinsky et aI., 1989). Hypermetabolism is observed in Sydenham's chorea, lupus and tardive
167
IMAGING
NL
PO
F-OOPA
FECNT
Fig. 1. Functional neurochemistry of the basal ganglia. Integrity of pre-synaptic dopamine synthesis can be assessed with fluoro-dopa (F-DOPA). In Parkinson's disease (PD) there is a marked reduction of uptake and decarboxylation of this compound compared to normal controls (NL), particularly in the putamen. Integrity of presynaptic dopamine terminals can also be assessed by labeling the dopamine transporter protein with compounds such as 213-carbomethoxy-313-(4-chlorophenyl)8-(2-C HF)fluoroethyl)nortropane (FECNT). This proteinis normally involved in reuptake of synaptic dopamine and is a marker of dopamine terminal density. Note the marked reduction in Parkinson's disease. Images provided by Mark Goodman and Margaret Davisof Emory University, AtlantaGA. dyskinesia (Guttman et al., 1987; Weind1 et al., 1993; Pahl et al., 1995). No changes in post-synaptic dopamine receptor function have been observed in TD, suggesting the clinical symptoms may be a result of GABA related disinhibition of motor circuits rather than upregulation of the dopaminergic pathways (Blin et al., 1989; Andersson et al., 1990). The other important set of hyperkinetic movement disorders are the dystonias. The etiology of focal, segmental, hemi- or generalized dystonia, irrespective of the distribution of symptoms is remarkably diverse. MRI has been useful in identifying focal lesions within the spine, brainstem, striatum, thalamus and white matter resulting in acquired dystonia (Grafton et al., 1988; Gille et al., 1996; Kostic et al., 1996; Lehericy et al., 1996; Karsidag et al., 1998; Kurita et al., 1998). This diversity of lesion location makes it difficult to generate a unifying pathophysio-
logic model that predicts the occurrence of dystonic movements. Functional imaging is an important alternative approach for characterizing the pathophysiology of dystonia. By definition, there is forceful and prolonged simultaneous co-contraction of agonist and antagonist muscles which distort the affected extremities into stereotypic postures (Oppenheim, 1911). Thus, imaging studies examining neural substrates of the dystonias can potentially be complicated by movement related activation. Using fluorodeoxyglucose (FDG), brain glucose metabolism has been measured in both focal and generalized dystonia (Stoessl et al., 1986; Martin et al., 1988; Karbe et al., 1992; Hirato et al., 1993; Eidelberg et al., 1995; Galardi et al., 1996; Dethy et al., 1998; Mazziotta et al., 1998). Experimental strategies to avoid movement-related activation include scanning subjects in their sleep or scanning presymptomatic subjects who test positive for the dystonia gene DYTl (Eidelberg et al., 1998; Mazziotta et al., 1998). The main finding in DYTl patients was an increased covariance of metabolism within the lentiform nucleus, cerebellum and supplementary motor area, suggesting disregulated control between cortical and subcortical motor areas.
12.3.2. Proton magnetic resonance spectroscopy Given appropriate technical modifications, conventional MRI scanners can be used to perform proton magnetic resonance spectroscopy (PMRS) of brain metabolites. The most commonly detected signals are related to N-acetylaspartate (NAA) a relative marker of neuronal density, choline-containing compounds (Cho) and creatine-phosphocreatine (Cr). Absolute quantification is difficult and most studies investigate altered ratios of these metabolites with each other. Comparative studies of PD, MSA, PSP and CBGD have been performed (Federico et al., 1999; Abe et al., 2000). Single volume assays, localized to the lentiform nucleus as well as frontal cortex assays, usually demonstrate reductions of the NAA/Cho and NANCr peak ratio in all of the atypical parkinsonian syndrome patients compared to controls. Reductions of NAA/Cho or NAA/Cr are less dramatic and inconsistently observed in the frontal lobe or striatum of PD, in part due to measurement error secondary to inorganic paramagnetic substances within the basal ganglia (Clarke and Lowry, 2000). When a reduction is observed it
168
S.T. GRAFTON
Table 4 Imaging in hyperkinetic movement disorders. Huntington's disease
Neuroacanthocystosis
Benign familial chorea
DRPLA
SLE
Sydenham's chorea
Tardive dyskinesia
Metabolism
Dec dorsal striatum Dec frontal (advanced)
Dec dorsal striatum
Dec dorsal striatum
Dec dorsal striatum
Inc striatum
Inc striatum
Inc striatum
Postsynaptic D2
Dec striatum
Dec striatum
()pioidreceptors
Dec striatum
Central benzodiazepine
Dec striatum
Normal
Normal
DRPLA: Dentatorubropallidoluysian atrophy SLE: Systemic lupus erythematosis PMRS: Proton magnetic resonance spectroscopy
can correlate with disease severity (Abe et al., 2000). Recent studies show reductions of NANCr ratios in both motor cortex and temporo-parietal cortex compared to healthy controls, suggesting alterations of thalamocortical projection areas in PD (Lucetti et al., 2001). Animal models of Parkinson's disease reveal an increase of striatal glutamate activity. However, several proton magnetic resonance spectroscopy studies of striatal glutamate + glutamine relative to Cr have been normal in PD patients who are dyskinetic, non-dyskinetic and there has been no change with acute dopaminergic treatment by apomorphine (Clarke et al., 1997; Taylor-Robinson et al., 1999). This suggests the changes observed in animal models are currently too subtle to be detected byPMRS.
such as PET as well as magnetic resonance imaging (Mazziotta et al., 1985a; Belliveau et al., 1991).
12.3.3. Functional brain mapping
12.3.3.1. PET CBF The PET blood flow method requires injections of radioactive water or inhalation of radioactive CO 2 (which is converted to water in the lungs by carbonic anhydrase). The amount of radioactivity appearing in the brain is proportional to local blood flow. The temporal resolution is limited to the time it takes to acquire sufficient radioactive counts, typically on the order of 45-90 s. Spatial resolution is nominally 5 mm and more realistically 10-15 mm after image processing. Only 10-15 scans are acquired per subject due to limits on human exposure to radioactivity. Subject motion leads to image blurring, rather than signal dropout, thus the technique can be useful in patients with abnormal movements.
Over a century ago Sherrington and Roy noticed the relationship of brain blood flow and regional activity (Roy and Sherrington, 1890). It is a remarkable fact that increases of neuronal activity, down to the columnar level of spatial resolution will lead to corresponding changes of local blood flow across a slightly larger volume of tissue and with a delay of approximately 4 s (Malonek and Grinvald, 1996; Logothetis et al., 2001). This change of blood flow can be measured with radionuclide techniques
12.3.3.2. FMR1 BOLD imaging The most commonly used functional magnetic resonance imaging technique is the blood oxygen level dependent method (BOLD) (Ogawa et al., 1990). The method detects change in the contrast of T2* weighted images by varying levels of oxygen saturation. As blood flow to an area increases, so does the delivery of oxygenated blood. The method is enhanced with MRI gradients that are capable of
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rapid acquisition using echo planar imaging (EPI) techniques (Cohen and Weisskoff, 1991). A typical commercial 1.5 Tesla scanner is capable of acquiring 10-12 slices per second with EPI imaging. Signal detection is improved with surface coils, stronger magnetic fields and acquisition at lower sampling densities (64 x 64 matrix). The method is very sensitive to head movement (signal dropout rather than signal blurring), artifacts from motion in the magnetic field (from eye or limb movements) and susceptibility artifacts maximal at air tissue interfaces such as near the sinuses. Run to run and across session variance in tMRI can be significant and create challenges for across session experimental designs (Aguirre et aI., 1998; Glover, 1999; Waldvogel et al., 2000). The tight confines of an MRI scanner have also set limits on the types of movements and behavior that can be examined in this restrictive environment. Nevertheless, tMRI has replaced PET as the most commonly used method for investigating functional anatomy in normal subjects. 12.3.3.3. Functional imaging of normal motor control Nearly two decades of experiments have mapped the functional anatomy of normal human motor behavior while subjects performed a broad range of motor tasks during brain imaging. The scope of this work is beyond the capacity of this chapter. Core observations include: (l) the delineation of the somatotopic organization of motor cortex, SMA and premotor areas (Colebatch et aI., 1991; Grafton et aI., 1991; Walter et aI., 1992; Grafton et aI., 1993; Sanes et aI., 1995); (2) the identification of premotor and parietal areas for movement selection, preparation, and on-line control (Deiber et aI., 1991, 1996; Honda et aI., 1998b; Desmurget et aI., 1999); (3) the involvement of cerebellum in movement timing and coordinated motor control (Jueptner et aI., 1996; Jueptner and Weiller, 1998; Wolpert et aI., 1998; Miall et aI., 2001); (4) the involvement of motor cortex and SMA in procedural and sequential learning (Jenkins et aI., 1994; Grafton et aI., 1995a; Karni et aI., 1995; Sadato et aI., 1996; Doyon et aI., 1997; Hazeltine et aI., 1997; Boecker et aI., 1998; Honda et aI., 1998a; Toni et aI., 1998; Grafton et aI., 2001); (5) modulation of activity in motor cortex and cerebellum as a function of force and velocity (Dettmers et aI., 1995, 1996a, b; Turner et aI., 1998).
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These experiments form a critical background for interpreting changes of functional circuits in patients with movement disorders. 12.3.3.4. Functional brain mapping of movement disorders Functional brain imaging has been used most intensively to understanding the pathophysiologic basis of Parkinson's disease. This work forms an essential benchmark for interpreting future investigations of the functional topography of other movement disorders. The goal in PD imaging research has been to determine how altered basal ganglia (BG) information processing due to dopamine deficiency leads to altered control of movements at both the cortical and subcortical levels. A key advance was developing reliable methods that could detect movement-related activity throughout cortical and subcortical circuits. For example, PET and tMRI studies of simple movement can detect activation in almost all of the nuclei of the cortico-subcortical motor circuit (Bucher et aI., 1995; Winstein et aI., 1997; Turner et aI., 1998). A related goal asks if patterns of activity observed by imaging studies correspond to specific parkinsonian signs such as bradykinesia or akinesia. Most published imaging studies of PD have focused on the hypothesis that SMA underactivity is a cause of akinesia. In this model BG dysfunction culminates in an inadequate recruitment of SMA neurons resulting in impaired movement initiation. In principal, this is a reasonable approach as the SMA is one of the main cortical receiving areas of the BG motor circuit (Schell and Strick, 1984) and the SMA has been linked to a variety of motor behaviors that are impaired in PD, including, most notably, the selection and generation of internallyguided movements. Thus, tasks that require repeated internal selection and initiation of discrete movements should provide a good substrate for testing the association between parkinsonian akinesia and SMA activity. As predicted, PD patients show a smallerthan-normal increase in CBF in the SMA during movement tasks that require selection and execution of unidirectional ballistic joystick movements (Playford et al., 1992). In a critical follow-up experiment, a more carefully designed movement task was used to compare internally and externally generated movements in normal subjects and PD patients (Jahanshahi et aI., 1995). Subjects were trained to
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make simple index finger extensions every 3 s by self initiation or external triggering, yoked to the same rate. The tasks required minimal working memory or other cognitive demands. PD patients had a smaller-than-normal activation of SMA for self-initiated movements. It is noteworthy that no differences in brain activity between normal subjects and PD patients were found in this study when they performed similar movements under an externally triggered condition. When PD patients performing the internal generation task are treated with dopamine agonists (apomorphine) there is a "normalization" of the movement-related activation of SMA accompanied by a reduction in reaction times (Jahanshahi et al., 1995). A similar effect of dopamine replacement therapy was observed by Rascol et aI. in PD patients performing a sequential movement task which requires frequent initiation of self-generated discrete finger-to-thumb movements (Rasco1 et al., 1992). They showed with single photon emission tomography (SPECT), that the SMA is under-activated in PD patients during this task (i.e. that that SMA had a smaller-than-normal task-related increase in CBF) and that the SMA defect normalized with apomorphine therapy. These results provide additional evidence that SMA activation is modulated by the BG motor circuit and that dopamine replacement therapy can ameliorate the inadequate thalamocortical facilitation of the SMA. Dopamine replacement therapy, by releasing thalamocortical facilitation, restores normal SMA activation patterns and movement initiation improves. Alternative models are emerging from imaging experiments to understand the symptoms of PD. One of these models is task specific compensation. Imaging studies have detected patterns of CBF in PD patients that may reflect adaptive changes, some of which may be closely linked to the particular motor task being performed. Using SPECT, Rascol et al. (1997) found that untreated PD patients demonstrated an abnormally high activation of the cerebellum ipsilateral to the moving arm when they performed sequential finger-to-thumb movements. Coincident with the cerebellar overactivation was a smaller-than-normal activation of the SMA, as predicted by the akinesia model. The increased activity in cerebellum was not seen in a separate group of PD subjects who were studied when on their normal dopamine replacement therapy. Cer-
S.T. GRAFrON
ebellar overactivation in untreated PD patients may be part of a compensatory recruitment of alternate motor circuits in the parkinsonian brain (including the visually driven cortico-ponto-cerebellar loop (Glickstein and Stein, 1991» in an attempt to overcome impaired function of the mesial frontal cortical circuits. Other studies also provide evidence of abnormal increased cerebral activity (CBF) in PD patients and indicate, additionally, that the specific patterns of under- and over-activation hinge on what behavioral task is used. Using PET, Samuel et al. found a bilateral task-related increase in CBF in dorsolateral premotor and inferior parietal cortices in untreated PD subjects performing a sequential finger tapping task (Samuel et al., 1997a). These areas were not activated in normal subjects performing the same task. Samuel et al. also found a task-related underactivation of mesial frontal and prefrontal areas in the PD subjects. These observations have been confirmed and extended recently by Catalan et aI. (Catalan et aI., 1999) in a PET study of PD and normal subjects performing either sequential finger movements of increasing complexity or an internal generation task (similar to the internal generation task first used by Playford et al. (1992). During sequential finger movements, they found a relative overactivation (i.e. a greater task-related increase in CBF than observed in normals) of bilateral parietal cortices, lateral premotor areas, and precuneus. Interestingly, Catalan et aI. observed that mesial frontal areas (anterior SMA/cingulate cortex) were activated during motor sequence performance in both PD and normal subjects, but that CBF increased progressively with more complex sequences only in the PD subjects. In contrast, when the same PD subjects performed the internal generation task, no parietal or premotor overactivations were observed and the mesial frontal areas, including SMA, were under-active, as previous studies predicted. Although some of the results described thus far can be interpreted within the model for parkinsonian akinesia, other results call for a revised or expanded model. The contrasting results for sequential movement and internal generation tasks in the Catalan et aI. study, for instance, indicate that the specific differences in brain activity between PD and normal subjects depend critically on the nature of the behavioral task being performed. The use of tasks that accentuate different facets of parkinsonian
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motor impairment may expand our understanding of the functional substrates of parkinsonian symptoms other than akinesia. 12.4. Imaging therapy in movement disorders 12.4.1. Ablative surgical therapy
The current model of PO pathophysiology provides a clear rationale for surgical treatment of PO by stereotaxic ablation of the posteroventral GPi (pallidotomy). Both in PO patients and in primate models of PO, pallidotomy can reduce significantly the cardinal symptoms of PO while producing no overt side-effects (Laitinen et aI., 1992; Dogali et aI., 1995; Baron et al., 1996). The presumed mechanism of action for pallidotomy is an elimination of excessive pallidothalamic inhibition and a subsequent recovery of function in the previously under-excited frontal cortical areas. The efficacy of pallidotomy as a treatment for PO points clearly to the conclusion that most of the symptoms of PO arise from the impaired function of cortical motor areas secondary to excessive inhibitory outflow from the pallidum and not, as might be assumed, from impaired BG function per se (Wichmann and DeLong, 1996). Functional imaging studies of pallidotomy have provided results consistent with the akinesia model of PO pathophysiology (Ceballos-Baumann et aI., 1994; Grafton et al., 1994, 1995b; Samuel et aI., 1997b). A consistent finding across studies has been that following pallidotomy, there is a movement
related increase of activity in the SMA compared to rest conditions. 12.4.2. Deep brain stimulation
A relative drawback of surgical pallidotomy is the potential morbidity (acute and chronic) resulting from a permanent brain lesion. The introduction of high frequency deep brain stimulation (DBS) is an important alternative to ablation because the electrode can be introduced without producing significant brain damage and, by adjusting stimulation sites and parameters, the optimal response can be obtained. Reports of clinical response to DBS are promising (Siegfried and Lippitz, 1994; Limousin et aI., 1997; Krack et aI., 1998; DBS study group, 2001). The stimulating electrode can be positioned at several nodes of the subcortical motor circuit, including the GPi, subthalamic nucleus (STN) and the motor thalamus. Evidence to date in unblinded, non-randomized trials suggest similar maximal benefit for placement in the STN and pallidum, although patients with STN stimulators may require lower amounts of supplemental L-DOPA therapy (DBS study group, 2001). The mechanism by which DBS achieves therapeutic results remains speculative. PET has been used to examine the effects of therapeutic DBS on CBF. In the first report, Limousin et aI. explored the effects on cerebral blood flow of DBS in GPi and STN (Limousin et al., 1997). Clinically effective levels of stimulation in STN led to a greater task-related increase in CBF in
Fig. 2. Functional adaptation in Parkinson's disease. PET blood flow imaging was used to assess motor system activity during visually guided tracking at different velocities. Areas in white represent sites where PD patients show a greater increase of activity as movements become faster relative to controls. These sites include bilateral premotor cortex, motor cortex, globus pallidus and cerebellum. In PD these areas are recruited to a greater degree than normal subjects to achieve the same level of performance. Images provided by Robert Turner, DC San Francisco, California.
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the SMA and dorsolateral prefrontal cortex compared to ineffective stimulation. Of concern, however, clinically effective stimulation of the GPi produced no significant changes in CBF. In a second study, Davis et. al., examined the effect of GPi DBS on brain activity during a "rest" condition (Davis et al., 1997). Clinically beneficial stimulation in the GPi was associated with a CBF increase in mesial frontal cortex anterior to the SMA. This result suggests that DBS altered the inhibitory GPi output in a manner analogous to ablation and thereby disinhibited the frontal thalamocortical circuit. The authors proposed that the increased CBF in the mesial cortical areas, although observed under a "resting" condition, could be responsible for a reduction of akinesia. In a more recent study, patients were examined while they performed simple paced sequential reaching movements. Concurrent regional cerebral blood flow recordings revealed a significant enhancement of motor activation responses in the left sensorimotor cortex and bilateral supplementary motor area. Significant correlations were evident between the improvement in motor performance and the regional cerebral blood flow changes mediated by stimulation (Fukuda et al., 2001). The combined results of these different imaging studies can be taken as further evidence that surgical therapeutic interventions for PD lead to increased cerebral activity in areas that are targets from pallido-thalamic connections. 12.4.3. Fetal transplantation
Functional imaging of dopaminergic function is extremely useful for assessing the in vivo viability and growth of transplants of fetal substantia nigra tissue in patients with advanced Parkinson's disease (Lindvall et al., 1989; Lindvall et al., 1994). Fluorodopa imaging can be used as an independent measure of tissue viability (Freed et al., 1990; Lindvall et al., 1990). In a recent large randomized trial there was significant evidence for increased fluorodopa uptake in the patients treated by transplantation therapy suggesting dopamine producing fiber outgrowth of transplanted tissue (Freed et al., 2001). An interesting observation emerging from the randomized clinical trials of PD using fetal transplantation has been a potent placebo effect in the patients receiving sham surgery. A functional imaging study helps to explain this puzzling response. PD
S.T. GRAFTON
patients who were told they were to get a new medical therapy for their disease were scanned and the availability of post-synaptic dopamine receptors was assessed with PET (de la Fuente-Fernandez et al., 2001). Patients given a placebo showed reduced receptor availability, suggesting they were releasing endogenous dopamine in the setting of increased reward expectancy (a new therapy). This measurable increase of endogenous dopamine could also improve parkinsonian symptoms. This finding is consistent with recent studies in non-human primates establishing the importance of the BG for facilitating reward expectancy and learning (Schultz, 2001). Acknowledgments
Supported NS33504.
by
PHS
Grants
NS37470
and
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Movement Disorders Handbook of Clinical Neurophysiology, Vol. I M. Hallett (Ed.) © 2003 Elsevier B.V. All rights reserved
181 CHAPTER 13
Accelerometry Rodger J. Elble* Department of Neurology, Southern Illinois University School of Medicine, P.O. Box 19643, Springfield, IL 62794-9643, USA
Accelerometers are small lightweight motion transducers that are capable of measuring accelerations less than 0.02 G (G=9.807 m/s', the static acceleration of gravity). The use of accelerometers in human motion analysis is the focus of this chapter. The Internet is a rich source of additional information pertaining to basic technology and manufacturers, and Table 1 contains an incomplete list of useful sites.
13.1. Common types of accelerometers Several types of accelerometers are now commercially available, but piezoresistive, piezoelectric and capacitance accelerometers are employed most commonly in human applications. These accelerometers are based on Newton's law of mass acceleration (Force=massxacceleration) and Hooke's law of spring action (Force=spring constant x change in length of a spring). Therefore, for a known mass attached to an elastic material, one can relate acceleration to the extent that the elastic material is stretched or compressed. Piezoresistive accelerometers consist of a small mass attached to a semiconductor beam that behaves like a spring. Deflection of the beam is measured with strain gauges that are connected in a Wheatstone bridge. The output voltage of the Wheatstone bridge is proportional to acceleration. Piezoelectric accelerometers contain a mass that is attached to a piezoelectric crystal, which behaves as a spring. Deformation of the crystal produces a small voltage (- millivolts) that is proportional to acceleration. Capacitance accelerometers contain a variable
* Correspondence to: Dr. R.I. Elb1e, Department of Neurology, Southern lllinois University School of Medicine, P.O. Box 19643, Springfield, IL 62794-9643, USA. E-mail address:
[email protected] Tel.: 217-524-7881 (ext. 3002); fax: 217-524-1903.
capacitor, in which the gap between the capacitor plates changes in proportion to acceleration.
13.2. Technical specifications and considerations In selecting an accelerometer, one must consider the required size, weight, durability, frequency range, linear amplitude range, sensitivity, transverse sensitivity, and resolution. These specifications for accelerometers are provided on the Internet web sites of most manufacturers (Table 1). Miniature accelerometers are now so small and lightweight that many are suitable for most human applications. Triaxial accelerometers with an approximate weight and volume of 10-20 g and 1-2 em' are common. Accelerometers ofthis size are necessary when recording from small body parts, such as the finger and when multiple accelerometers are used. Durability is specified in terms of the maximum acceleration that the device can experience without damage. Accelerometers are frequently constructed with mechanical stops that prevent damage by excessive sudden acceleration (i.e. shock), as may occur if the accelerometer is dropped or struck against a hard object. Sufficiently durable accelerometers can withstand shock accelerations of at least ±2000 G. Shock accelerations of this magnitude may be achieved when an accelerometer is dropped onto a hard surface, so these devices must be handled with care. The frequency range (i.e. frequency response) of most accelerometers is flat from approximately 0 Hz to 500 Hz or greater. The upper limit of the frequency range should be more than 4 times the highest frequency of movement that will be encountered. Most accelerometers easily satisfy this requirement for human applications, in which the frequency content of motion is 0-30 Hz. Accelerometers usually contain some form of damping to
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R.J. ELBLE
Table I Accelerometers and gyroscopes for human motion analysis. Manufacturer
Internet web site
Entran Devices, Inc.
www.entran.com
Piezoelectric
Kistler Instrument Corp.
www.kistler.com
Piezoresistive
Endevco U.K., Ltd.
www.endevco.co.uk
Accelerometers Type
Piezoresistive
Piezoelectric Capacitance Capacitance
Analog Devices
www.analog.com
Capacitance
Silicon Designs, Inc.
www.silicondesigns.com
Piezoelectric
Cambridge Neurotechnology
www.camntech.co.uk
Piezoelectric
1M Systems
www.imsystems.net
Motus Bioengineering, Inc.
www.motusbioengineering.com
Activity monitors (accelerometers)
Gyroscopes
Gyroscope
prevent resonant oscillation at the accelerometer's natural frequency, which resides just beyond the upper limit of the frequency range. The frequency response of piezoresistive and capacitance accelerometers extends down to 0 Hz, making them sensitive to the static acceleration of gravity and providing a useful means of static calibration. The low-frequency limit of piezoelectric devices is 0.1 Hz or higher. The sensitivity (mV/G) of an accelerometer is inversely proportional to its amplitude range. Therefore, accelerometers with excessively large ranges should be avoided. The amplitude range should have a linear sensitivity ± 1%. An amplitude range of ± lOG is suitable for most human applications, and a typical sensitivity for this range is 5-10 mV/G (Verplaetse, 1996). An amplitude range of ±20 G may be needed for accelerometers mounted on the feet or ankles during walking and running (Bouten et al., 1997). The transverse axis (cross) sensitivity is the degree to which an accelerometer erroneously detects Decelerations perpendicular to the axis of sensitivity. The transverse sensitivity should be 3% or less. The resolution of an accelerometer is the lowest acceleration that can be measured. Resolution is
determined mainly by the level of transducer noise and is 0.02 G or less for most accelerometers used in human applications. Intrinsic sources of accelerometer error and noise are: (1) electronic device noise (e.g. due to fluctuations in the power source); (2) transverse axis sensitivity; and (3) thermal drift in de response (piezoresistive devices). Ambient sources of noise are: (1) electrical interference (e.g. 60 Hz noise); (2) ambient vibrations (e.g. as when riding a car or bike); (3) inadvertent bumping or jarring with another physical object (e.g. striking the accelerometer against a table or door frame); and (4) loose or faulty attachment of the accelerometer to a body part, resulting in extraneous mechanical resonance (Bouten et al., 1997). These sources of noise have a cumulative effect when acceleration is numerically integrated over long periods of time to obtain velocity and position estimates, and this problem is a major impediment to the use of accelerometers in motion analysis of complex movements such as walking and reaching.
13.3. Signal conditioning Most accelerometers require a power source, and the power source should be stable and free of noise
ACCELEROMETRY
in order to avoid power fluctuations that cause measurement error. The output of the accelerometer is filtered and amplified before being sampled into a computer with an analog-digital converter. Highpass filters and AC-coupled amplifiers do not eliminate the sensitivity of accelerometers to gravity but are useful when the DC component of acceleration is of no interest. Low-pass filters are needed to attenuate noise at frequencies greater than the maximum frequency of biological interest. The sampling frequency of the analog-digital converter should be greater than twice the cutoff frequency of the low-pass filter, in order to avoid aliasing. 13.4. Measuring motion in 3-dimensional space
The output of accelerometers must be integrated once to obtain velocity and twice to obtain position. For a sinusoidal displacement of amplitude A (onehalf peak-to-peak amplitude), the velocity and acceleration are the first and second derivatives of displacement: displacement=A sin (wt) velocity=Aw cos(wt) accelerationw-Ass' sin(wt)
where w is the frequency of oscillation in radians per second (l cycle/s= 1 Hz=2'lT radians/s) and t is time. Thus, for two oscillations (e.g. tremors) of identical displacement amplitude but different frequencies, the oscillation with the higher frequency will have a larger velocity and acceleration. A corollary to this rule is that high-frequency low-amplitude noise will be more evident in accelerometric measurements than in position measurements, as obtained with a photogrammetric motion analysis system. Another corollary is that for a sinusoidal movement like tremor, displacement and velocity can be estimated with accelerometry by dividing the measured acceleration by w2 and to, respectively. Motion of a limb or other body part rarely occurs in a single direction. In general, a body part may exhibit translational motion in any of three orthogonal (X, Y, Z) directions, and it may rotate about any of these axes. An accelerometer will record translational and rotational inertial accelerations to the extent that these acceleration vectors are in line with the accelerometer's axis of sensitivity. In addition, gravitational acceleration is recorded to the extent
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that the axis of sensitivity is in the vertical direction of earth's gravity. Gravitational acceleration may contribute significantly to the total acceleration detected by the axis of an accelerometer and thereby limits the ability of accelerometry to reflect translational and rotational motion (i.e. inertial acceleration) of a body part. The task of separating the gravitational and inertial components of acceleration is impossible unless multiple accelerometers are used, and even with multiple accelerometers, measurement error may preclude the accurate separation of gravitational and inertial accelerations. Consider the situation in Fig. 1 in which a rodshaped body part (e.g. the index finger) rotates vertically about a fixed axis (e.g. the metacarpophalangeal joint), such that there is no translational motion. A biaxial accelerometer is attached to the body part at distance R from the axis of rotation. When the body part is perfectly horizontal, gravity is parallel to the t-axis and perpendicular to the r-axis, and the effect of gravity is reflected only in the t-axis of the accelerometer. However, the influence of gravity on the t-axis decreases as the body part rotates up and down, and the influence of gravity on the r-axis increases. The gravitational components in the t and r axes are G cos
and G sin <1>. Therefore, for fluctuations in of ± 10 degrees (20 degrees peak to peak), the gravitational component of t-axis acceleration will fluctuate between 1.0 G and 0.985 G, and the gravitational component of r-axis acceleration will be ±0.174 G. Thus, gravitational fluctuations in the r-axis of the accelerometer are substantially greater than in the t-axis, and the influence of gravity on the t-axis is nearly constant (i.e. varies less than 0.015 G). The differences in t-axis and r-axis gravitational fluctuations are significant in situations such as the one depicted in Fig. 1 because the inertial acceleration in the t-axis is much greater than the inertial acceleration in the r-axis. For example, a 6-Hz tremor producing vertical accelerometer movements of ± 1.22 em (0.0244 m peak-to-peak) produces joint rotations of ± sin:' ( 1.2217) = ±0.175 radians = ± 10 degrees, assuming the accelerometer is mounted 7 ern from the joint (i.e, R=0.07 m in Fig. 1). For sinusoidal joint rotations of this magnitude, the t-axis inertial acceleration is R times the angular acceleration, which equals ±0.07· 0.175(2'lT6)2/ 9.807=±1.77 G. These fluctuations in inertial acceleration are much larger than the 0.015 G
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fluctuations in t-axis gravitational acceleration, so the output of the t-axis of the accelerometer will reflect the fluctuations in inertial acceleration plus the nearly constant effect of gravity, which is easily removed with a highpass filter or by numerically subtracting 1.0 G. By contrast, the r-axis inertial acceleration would fluctuate between zero and R times the angular velocity squared, which equals 0.07(0.175· 2'lT6)2/9.807 =0.311 G. These fluctuations in inertial acceleration are comparable to the ±0.174 G fluctuations r-axis gravitational acceleration, so the output of the r-axis of the accelerometer will reflect significant contributions from inertial acceleration and gravity. The gravitational component will tend to obscure the inertial component, which is the measure of body motion.
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Angular acceleration (a=d 24>/dr) cannot be computed from a, and a, in Fig. 1 because 4> is not known, and hence the contributions of gravity to a, and a, cannot be computed. However, angular acceleration can be computed if a second accelerometer is mounted between the joint and the first accelerometer. Both accelerometers will have the same gravitational influence if they are mounted with the same orientation (i.e. their t-axes are parallel; Fig. 2), and the equations for angular acceleration are R,a=a1t+G cos(4)(t)) and R2a= a 2t+G cos(4)(t)), where the subscripts 1 and 2 refer to accelerometers 1 and 2. Subtracting these two equations gives the following equation for angular acceleration: a=(a't - a2t)/(R, - R2). This approach can be extended to 3-dimensional space using at least six uniaxial accelerometers that are strategically positioned on the body segment (Padgaonkar et al., 1975). The computed angular acceleration can be integrated to obtain angular velocity and rotation (4)), and having computed 4>, the r-axis and t-axis gravitational accelerations could be computed at any time t. Note that this approach assumes the precise strategic alignment of the pairs of accelerometers, and malalignment will produce error in computing a. This error and any noise in a, will have a cumulative effect when a is integrated to obtain 4>. Consequently, accelerometers are not suitable for measuring absolute translational position and rotation in space over extended periods of time because
a, = Rd 2c'P/dt2-Gcosc'P(t) For c'P(t) = c'P o sin(2JZji),
at = -R[ c'P o(2JZff sin(2JZ"fi)]-Gcos[c'Po sin(2JZ"fi)]
a, =-R(dc'P/dt)2-Gsin(c'P(t» For c'P(t) = c'P o sin(2JZji),
a, = -R[c'P o2JZfcos(2JZ"fi)f - Gsin(c'Po sin(2JZji» =-O.5R(c'Po2JZf)2[cos(4trft) + 1]-Gsin(c'Po sin(2trft» Fig. 1. Schematic diagram of a rigid body rotating about a fixed axis. A biaxial accelerometer (shaded box) is attached to the rigid body at a distance R from the axis of rotation. The X-Y reference axes are fixed to the axis of rotation. The t and r axes are the accelerometer axes of sensitivity. The equations for acceleration in the t and r axes (a, and a,) are given for a sinusoidally varying angle of rotation <1>, with amplitude c'P o and frequency f (Hz). G is the acceleration of gravity.
Fig. 2. Same as Fig. I but for two biaxial accelerometers, mounted in parallel for the measurement of angular acceleration a=d 2c'P/df
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ACCELEROMETRY
accelerometer error and noise accumulate in proportion to f. Commercially available electromagnetic and photogrammetric motion analysis systems are better suited for measuring position and rotation (Ladin et aI., 1989). Accelerometers are best suited for measuring relative motions (e.g. tremor and other involuntary movements) and short-duration changes in position and rotation. In Fig. 1, the frequency of oscillation in the inertial component of a,. is twice the frequency of sinusoidal oscillation in because of the trigonometric relationship cos 2wt= 2 cos' wt - 1. Similarly, the oscillation in the t-axis gravitational component occurs at 2w because cos(. Thus, rhythmic oscillation in will produce t-axis and r-axis acceleration signals with a mixture of oscillations at frequencies wand 2w. The 2w oscillations in the contribution of gravity to the t-axis acceleration will be negligible for angular rotations of ± 10 degrees or less, but these 2w oscillations in gravitational acceleration will assume an increasing proportion of the t-axis acceleration for larger angular rotations. For the r-axis acceleration, the 2w oscillations in centrifugal acceleration will be comparable to the w oscillations in gravitational acceleration for angular rotations of approximately ± 10 degrees, and these 2w oscillations assume an increasing proportion of the r-axis acceleration as the angular rotations exceed ± 10 degrees. Therefore, 2w oscillations in taxis and r-axis accelerations become more apparent as the amplitude of oscillation increases, and this mixture of harmonic oscillations could be misinterpreted as neurogenic when they are, in fact, purely mechanical phenomena. The resultant acceleration (=y'(a~+a~+a~)) of a single triaxial accelerometer is not a complete measure of motion in space, and the error will increase in proportion to the amount of rotational motion. At least six one-dimensional linear accelerometers must be strategically mounted on a body part to record the translational and rotational movement about three orthogonal axes (X, Y, Z), and in most instances, one triaxial and three biaxial accelerometers are needed (Padgaonkar et aI., 1975). Alternatively, accelerometers can be used in combination with gyroscopic transducers to completely record the translational and rotational motion of a body part. Gyroscopic transducers measure angular velocity, from which angular rotation and accelera-
tion can be computed by numerical integration and differentiation, respectively (Verplaetse, 1996). Gyroscopic sensors are not sensitive to gravity. Their main disadvantages are their relatively large weight and bulk.
13.5. Applications Resolving complex translational and rotational motion of a single body segment (e.g. the thigh) with 6 or more uniaxial accelerometers is a difficult task, and capturing complex motion of multiple body segments, as in walking and throwing, requires too many accelerometers and complicated mathematical algorithms to be practical. Consequently, accelerometers are used far less than photogrammetric systems in the motion analysis of walking and other complex movements involving multiple body segments. Accelerometers are occasionally used in combination with photogrammetric methods when there is a need to measure as accurately as possible the acceleration of a particular site on the body. Accelerometers are also used in isolation when only a rough or representative measure of body motion is needed during a particular motor act (Bussmann et aI., 2000; Sekine et aI., 2000). Even then, the user must remain mindful of the limitations of accelerometry discussed in Section 13.4 of this chapter. Accelerometers have been used extensively in the study of tremor and are ideally suited for this purpose. Tremor is easily distinguished from most other movements because tremor is a rhythmic movement at a particular frequency. This is particularly true of pathologic tremors, which produce a narrow (i.e. finely tuned) Fourier spectral peak at the tremor frequency. These finely tuned spectra are typical of tremor and are not produced by other forms of voluntary or involuntary movement, except for rhythmic voluntary movements, such as chewing and cursive writing (Hoff et aI., 2001). Most voluntary and involuntary movements are not rhythmic, and their frequency content is primarily 0-3 Hz (Manson et aI., 2000; Hoff et aI., 2001). Very abrupt transient movements (e.g. myoclonus and chorea) produce Fourier spectra with broader frequency content, ranging from a to more than 30 Hz. Accelerometry and Fourier analysis cannot distinguish dyskinesias from voluntary movements but are useful in the quantification of dyskinesias when patients are relatively sedentary
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Coherence Spectrum
EMG
Rectification Low-pass Filtering
Phase Spectrum
Fig. 3. Flow diagram summarizing the steps in performing auto- and cross-spectral analyses of two signals such as accelerometry and EMG. Filtering and rectification can be performed with analog devices before digitization with an analog-to-digital (AID) converter, as shown in this figure, or these procedures could be performed with computer software after digitization of the acceleration and EMG signals. Rectification of the EMG is performed before low-pass filtering to produce the envelope of amplitude fluctuations in EMG over time. The cut-off frequency of the low-pass filter is typically set to 40 Hz or less, depending upon the frequency range of biological interest. The fluctuations in rectified-filtered EMG are proportional to muscle force (Journee et al., 1983). Signals such as acceleration, EEG and neuronal spike trains do not require rectification (Elble and Randall, 1976).
(e.g. seated in a chair) (Manson et al., 2000; Hoff et al., 2001). The optimum sites for mounting the accelerometer(s) have not been determined. Most commercially available activity monitors contain one or more piezoresistive or piezoelectric accelerometers (Table 1). Digitized data are stored within these devices and later downloaded to a personal computer for analysis. They are often worn on the wrist but may be worn elsewhere. Acceleration can be recorded continuously, or accelerations above a specified threshold can be summed over time to give a measure of activity. These "actigraph" devices have been used extensively in sleep analysis and assessment of daytime activity levels. Polysomnography is a more accurate method of sleep assessment because actigraphs tend to overestimate sleep when people lie awake and motionless in bed and underestimate sleep when there is increased motor activity during sleep (Jean-Louis et al., 2000; Verbeek et al., 2001). Nevertheless, actigraphy has been used successfully in the quantification of periodic leg movements during sleep because the pseudoperiodicity of these movements distinguishes them from other motor activity when the patient is in bed (Kazenwadel et al., 1995).
13.6. Frequency (spectral) analysis of accelerometry and EMG 13.6.1. Spectral analysis
Tremor consists of one or more oscillations that are superimposed on a background of broad-frequency activity, which is often regarded as noise.
Consequently, tremor and other rhythmic signals (e.g. EEG) are ideally suited for analysis in the frequency domain, using spectral techniques. A detailed description of spectral analysis is beyond the scope of this chapter. There is an extensive literature on this subject, and the principles and mathematical methods have been reviewed in the context of tremor (Elble and Koller, 1990; Timmer et al., 1996). Spectral methods have been applied extensively to the analysis of tremor, EMG, EEG and neuronal spike trains recorded from muscle (Elble and Randall, 1976; Halliday et al., 1999), peripheral nerve, and central nervous system (Elble et al., 1984; Hua et al., 1998; Zirh et al., 1998; Lemstra et al., 1999). Here, an overview of these methods is provided, and the steps in performing auto- and cross-spectral analyses of two signals such as EMG and accelerometry are summarized in Fig. 3. Spectral analysis of a signal is a mathematical process that decomposes the digitized signal into its frequency components. The most popular method of spectral analysis is Fourier transformation, which produces series of sine and cosine waves that in sum provide an approximation of the recorded signal. The frequencies of the sine and cosine waves reflect the frequency content of the signal, and the amplitudes of the sine and cosine waves reflect the amplitude of the signal at each frequency. The sum of the squared sine and cosine amplitudes at each frequency plotted vs. frequency is called an autospectrum (power spectrum). For a signal x(t) that is digitized to produce a continuous time series x( i) (i= 1,2,3, ... ,N), the Fourier transform X(w p ) is
187
ACCELEROMETRY
given by the following three equations, where p=O, 1,2, ... , N/2): X(wp)=Ax(w p) - jBx(wp)
2
Ai wp ) = ( N) ~N
Blwp) =
2
(
N ~
N
)
27Tpi
IV
xU) cos ( )
27Tpi
IV
xU) sin ( )
The autospectrum (power spectrum) is A;( wp ) + B .~( wp ) .
Gl wp ) =
The coefficient of the sine and cosine components varies among authors and programmers. Therefore, the user of any program should "calibrate" the program by computing the autospectrum of an artificial sinusoidal signal of known amplitude and frequency. The coefficient can then be adjusted so that the autospectrum yields the mean squared, baseline-to-peak squared, or peak-to-peak squared amplitude vs. frequency. A continuous time series is the realization of a continuous signal (e.g. accelerometry, rectifiedfiltered EMG, EEG) observed and sampled in time, at repeated intervals of Llt. The sampling frequency 1/Llt must be greater than twice the highest frequency contained in the signal. Violation of this requirement is called undersampling and will cause aliasing. Aliasing is a phenomenon in which frequencies greater than the Nyquist folding frequency, /N= 1/(2Llt), appear to be frequencies less than/N0 In other words, for any frequency / in the range 0~f5fN' the frequencies (2nfN±f), n= 1,2, ... are indistinguishable from f Thus, if the sampling frequency is 70 samples per second lfN=35 Hz), 60-Hz and 80-Hz noise in digitized recording will be mistaken for lO-Hz oscillations. The truncated ends of a data segment produce artificial side lobes or peaks in the autospectrum, surrounding the true or biological spectral peak. To reduce this spectral leakage, the ends of a data segment can be tapered to zero by multiplying the segment by an appropriate "window" of the same length. Several data windows are available, each with unique merits and limitations (Harris, 1978). The Hamming and Hanning cosine windows are commonly used in tremor and EEG analyses. These windows suppress the side lobes (leakage) but have
the adverse effect of broadening the true spectral peak. This is a problem only when one is trying to resolve two closely-spaced frequency components. Prior to windowing, the mean and any linear trend must be removed from the data segment. Neuronal spike trains are examples of a stochastic point process. A stochastic point process is a series of N identical events, occurring at times t; where i= 1,2, ... N. Only the times of occurrence of the action potentials are of interest. Therefore, the spike train is represented by a series of impulses (Dirac delta functions) at i, For a neuronal spike train y(t) of total duration T, the Fourier transform Y(wp ) is given by the following three equations, where p=O, 1,2, ... ,N12 and W p =27Tp/T: Y(wp)=A/w p) - jB,{wp)
The autospectrum (power spectrum) is G/wp ) = A;(wp)+B;(wp) (Bartlett, 1963; Lewis, 1970). For a
totally aperiodic spike train with Poisson distributed interspike intervals, the autospectrum is statistically flat, with a value of 2 at all frequencies (Bartlett, 1963; Lewis, 1970). Here again, the coefficient of the sine and cosine FFT components varies among authors and programmers, and the user of any program is advised to "calibrate" the program by computing the autospectrum of an artificial spike train with various values of N and T. This approach to computing the auto spectrum of a spike train entails two special problems: the fast Fourier transform algorithm cannot be used, and there is spectral leakage from the non-zero mean of the point process (French and Holden, 1971). Consequently, alternative approaches in which the point process is converted to a continuous time series by low-pass filtering have been developed (French and Holden, 1971; Lago and Jones, 1982). G(wp ) is merely a statistical estimate of the true spectral power at each frequency wp- G(w p ) is proportional to a chi square random variable with 2 degrees of freedom. To reduce the variance of the spectral estimates, the time series is divided into L
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non-overlapping segments, and the spectra of these segments are averaged. This reduces the variance of the spectral estimates by a factor of L, and G( wp ) becomes a chi square random variable with 2L degrees of freedom. This method of averaging is limited by the length of the time series and by the required frequency resolution of the final spectrum. For the entire time series, resolution of the spectrum is liT or lI(Nt1t), where Ilt is the sampling interval used in digitization. For a spectrum that is the average of L segments of the total time series, the frequency resolution is reduced by a factor of L. This can be a problem when dealing with short time series. An alternative method of reducing the variance of spectral estimates is to smooth the spectrum with a smoothing window, such as a moving average. The width of the window must be large enough to produce adequate statistical reliability but not so large that the spectral peaks are excessively attenuated. Timmer and colleagues described an approach in which the width of the smoothing window is adjusted to a preliminary estimate of the bandwidth of the spectral peak (Timmer et al., 1996; Lauk et al., 1999). Regardless of the approach used, there is obviously an unavoidable element of subjectivity in spectral estimation. The problem of leakage is increased when short time series are analyzed. The shorter the data segment, the greater the effect of the truncated ends of the segment. Therefore, an autoregressive (AR) method of spectral analysis has been developed for short data segments. This method first fits the time series to an autoregressive equation of order k, and the spectrum is computed from this equation. This approach is described and contrasted with the fast Fourier transform (FFT) in three recent papers (Cappello et al., 1997; Muthuswamy and Thakor, 1998; Spyers-Ashby et al., 1998). The FFT and AR methods are used with the assumption that the signal is statistically stationary or very slowly varying (Muthuswamy and Thakor, 1998). A stationary signal has first, second and higher order statistical properties (i.e. mean, variance) that do not change with time. The FFT and AR methods of spectral analysis are performed easily with Matlab and the Matlab signal processing toolbox (The MathWorks, Inc., Natick, MA). The FFT method is mathematically efficient and is familiar to most clinical and basic neuro-
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physiologists. It is well suited for the typical tremor, EEG or EMG recording of a minute or so. The AR method is better suited for short recordings of several seconds, as may occur in the recording of intention tremor during a reaching task (Morgan et al., 1975).
13.6.2. Cross-spectral, coherence and phase analyses Given the auto spectra Gx(wp) and Giwp) of two signals x(t) and y(t), the cross-spectrum Gxy(wp) between the two signals is Gxiwp)=X (wp)Y*(wp)=Axy(wp)+jB,i wp)
where Y*(wp) is the complex conjugate of Y(wp). The cross-spectrum is commonly normalized by the product of the two auto spectra to produce the coherence spectrum K~(wp).
K~( w
p)
Gxiwp)G ~(wp) Giwp)Giwp)
The coherence spectrum is the squared linear correlation between two signals (time series) at frequency w p (Benignus, 1969). The coherence spectrum is bounded by values ranging from zero (no linear relationship) to 1 (perfect linear relationship). Note that low coherence (i.e. < 1.0) can be caused by a lack of linear correlation between two signals or by a nonlinear relationship between two signals. The confidence limit for coherence is 1(l - a)I/(L-I), where a is the confidence level (e.g. 0.95) and L is the number of non-overlapping segments for which the auto- and cross-spectra are computed and averaged in the computation of coherence. Coherence values less than this limit are not statistically different from zero. Amjad and coworkers (Amjad et al., 1997) described a method for computing the coherence of data from two or more experimental trials. The phase spectrum Pxy(wp) between x(t) and y(t) is
and the 95% confidence interval for a phase estimate is
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ACCELEROMETRY
[l( 1
±1.96 - - 2- - 1 )]112 . L K xy(Wp ) The coherence spectrum must be calculated with smoothed auto- and cross-spectral estimates, and the phase spectrum must be calculated with smoothed cross-spectral estimates.
an analog-to-digital converter at a sampling rate of at least twice the highest frequency content of the signal, to avoid frequency aliasing. Acknowledgments
This work was supported by the Spastic Paralysis Research Foundation of Kiwanis International, Illinois-Eastern Iowa District.
13.7. Summary References
Accelerometry is ideal for measuring low-amplitude rapid movements. However, accelerometers are sensitive to earth's gravity, so their rotation in space produces a time-varying gravitational signal that tends to obscure the inertial acceleration of the body part to which the accelerometer is attached. The magnitude of fluctuations in gravitational acceleration relative to changes in inertial acceleration depends upon the orientation of the accelerometer's axis of sensitivity to earth's gravity and to the direction(s) of body motion. This limitation of accelerometry must be considered when using an accelerometer to quantify body motion, which is typically translational and rotational. The task of separating the gravitational and inertial components of acceleration is impossible unless multiple accelerometers are used, and even with multiple accelerometers, measurement error may preclude the accurate separation of gravitational and inertial accelerations. A three-dimensional accelerometer is not sufficient to record three-dimensional movement in space if there is rotation of the body part. At least six one-dimensional linear accelerometers must be strategically mounted on a body part to record the translational and rotational movement about three orthogonal axes (X, Y, Z), and in most instances, one triaxial and three biaxial accelerometers are needed. Spectral analysis is best suited for detecting rhythmic activity in signals such as tremor, EEG, EMG and neuronal spike trains. Coherence and phase analyses are useful for quantifying the linear relationship between rhythmic activity in two signals (e.g. accelerometry and rectified-filtered EMG), recorded simultaneously. These methods can also be applied to neuronal spike trains, which are treated as stochastic point processes. A continuous signal (e.g. accelerometry, EEG, EMG) must be digitized with
Amjad, AM, Halliday, DM, Rosenberg, JR and Conway, BA (1997) An extended difference of coherence test for comparing and combining several independent coherence estimates: theory and application to the study of motor units and physiologic tremor. J. Neurosci. Methods, 73: 69-79. Bartlett, MS (1963) The spectral analysis of point processes. J. Roy. Stat. Soc. B, 25: 264-281. Benignus, VA (1969) Estimation of the coherence spectrum and its confidence intervals using the fast Fourier transform. IEEE Trans. Audio and Electroacoustics, 17: 145-150. Bouten, CV, Koekkoek, KT, Verduin, M, Kodde, R and Janssen, JD (1997) A triaxial accelerometer and portable data processing unit for the assessment of daily physical activity. IEEE Trans. Biomed. Eng., 44: 136-147. Bussmann, JB, Damen, Land Stam, HJ (2000) Analysis and decomposition of signals obtained by thigh-fixed uni-axial accelerometry during normal walking. Med. Bioi. Eng. Comput., 38: 632-8. Cappello, A, Leardini, A, Benedetti, MG, Liguori, R and Bertani, A (1997) Application of stereophotogrammetry to total body three-dimensional analysis of human tremor. IEEE Trans. Rehabil. Eng., 5: 388-393. Elble, RJ and Koller, WC (1990) Tremor. The Johns Hopkins University Press, Baltimore. Elble, RJ and Randall, JE (1976) Motor-unit activity responsible for 8- to 12-Hz component of human physiological finger tremor. J. Neurophysiol., 39: 370383. Elble, RJ, Schieber, MH and Thach, WT, Jr. (1984) Activity of muscle spindles, motor cortex and cerebellar nuclei during action tremor. Brain Res., 323: 330-4. French, AS and Holden, AV (1971) Alias-free sampling of neuronal spike trains. Kybemetic, 8: 165-171. Halliday, DM, Conway, BA, Farmer, SF and Rosenberg, JR (1999) Load-independent contributions from motor-
190 unit synchronization to human physiological tremor. J. Neurophysiol., 82: 664-675. Harris, FJ (1978) On the use of windows for harmonic analysis with the discrete Fourier transform. Proc. IEEE, 66: 51-83. Hoff, Jl, Van den Plas, AA, Wagemans, EA and Van Hilten, JJ (2001) Accelerometric assessment of levodopa-induced dyskinesias in Parkinson's disease. Mov. Disord., 16: 58-61. Hua, SE, Lenz, FA, Zirh, TA, Reich, SG and Dougherty, PM (1998) Thalamic neuronal activity correlated with essential tremor. J. Neurol. Neurosurg. Psychiatry, 64: 273-276. Jean-Louis, G, Mendlowicz, MV, Gillin, JC, Rapaport, MH, Kelsoe, JR, Zizi, F, Landolt, H and Von Gizycki, H (2000) Sleep estimation from wrist activity in patients with major depression. Physiol. Behav., 70: 49-53. Joumee, HL, Van Manen, J and Van der Meer, JJ (1983) Demodulation of e.m.g.s of pathological tremours. Development and testing of a demodulator for clinical use. Med. BioI. Eng. Comput., 21: 172-175. Kazenwadel, J, Pollmacher, T, Trenkwalder, C, Oertel, WH, Kohnen, R, Kunzel, M and Kruger, HP (1995) New actigraphic assessment method for periodic leg movements (PLM). Sleep, 18: 689-697. Ladin, Z, Flowers, WC and Messner, W (1989) A quantitative comparison of a position measurement system and accelerometry. J. Biomechanics, 22: 295308. Lago, PJA and Jones, NB (1982) Note on the spectral analysis of neural spike trains. Med. BioI. Eng. Comput., 20, 44-48. Lauk, M, Timmer, J, LUcking, CH, Honerkamp, J and Deuschl, G (1999) A software for recording and analysis of human tremor. Comput. Meth. Prog. Biomed., 60: 65-77. Lemstra, AW, Verhagen Metman, L, Lee, Jl, Dougherty, PM and Lenz, FA (1999) Tremor-frequency (3-6 Hz) activity in the sensorimotor arm representation of the
R.J. ELBLE internal segment of the globus pallidus in patients with Parkinson's disease. Neurosci. Lett., 267, 129-132. Lewis, PAW (1970) Remarks on the theory, computation and application of the spectral analysis of series of events. J. Sound Vihr., 12: 353-375. Manson, AJ, Brown, P, O'Sullivan, JD, Asselman, P, Buckwell, D and Lees, AJ (2000) An ambulatory dyskinesia monitor. J. Neurol. Neurosurg. Psychiatry, 68: 196-201. Morgan, MH, Hewer, RL and Cooper, R (1975) Intention tremor - a method of measurement. J. Neurol. Neurosurg. Psychiatry, 38: 253-258. Muthuswamy, J and Thakor, NY (1998) Spectral analysis methods for neurological signals. J. Neurosci. Methods, 83: 1-14. Padgaonkar, AJ, Krieger, KW and King, AI (1975) Measurement of angular acceleration of a rigid body using linear accelerometers. J. Appl. Mech. (Trans. ASME), 42: 552-556. Sekine, M, Tamura, T, Togawa, T and Fukui, Y (2000) Classification of waist-acceleration signals in a continuous walking record. Med. Eng. Phys., 22: 285291. Spyers-Ashby, lM, Bain, PG and Roberts, SJ (1998) A comparison of fast fourier transform (FFT) and autoregressive (AR) spectral estimation techniques for the analysis of tremor data. J. Neurosci. Methods, 83: 35-43. Timmer, J, Lauk, M and Deuschl, G (1996) Quantitative analysis of tremor time series. Electroencephalogr. Clin. Neurophysiol., 101: 461-468. Verbeek, I, Klip, EC and Declerck, AC (2001) The use of actigraphy revised: the value for clinical practice in insomnia. Percept. Mot. Skills, 92: 852-6. Verplaetse, C (1996) Inertial proprioceptive devices: selfmotion-sensing toys and tools. IBM Syst. J., 35: 639-650. Zirh, TA, Lenz, FA, Reich, SG and Dougherty, PM (1998) Patterns of bursting occurring in thalamic cells during parkinsonian tremor. Neuroscience, 83: 107-121.
Movement Disorders Handbook of Clinical Neurophysiology, Vol. I M. Hallett (Ed.) © 2003 Elsevier S.v. All rights reserved
191 CHAPTER 14
Kinesiology Christian Dohle* and Hans-Joachim Freund Department ofNeurology, University Hospital Dusseldorf, D-40225 Dusseldorf, Germany
14.1. Overview In motor control studies, recordings of the kinematics and dynamics of movement can be employed at a high level of sophistication. These techniques have been applied for research, for the study of pathophysiology and for diagnostic purposes. In clinical settings, their use is still restricted because they are expensive, time consuming and require skilled technical personnel. Another reason is that better insights into movement kinematics are often not critical for differential diagnosis or therapeutic decisions. The situation is going to change as rehabilitative strategies and procedures become more specific. The previously used qualitative or semiquantitative scores are increasingly complemented by electrophysiological and kinematic recordings. Kinematic techniques will therefore be required for both the study of normal motor behavior and for restorative neurology. Neuroimaging techniques are providing new insights into brain function. They produce high resolution, spatial information about brain structure and functional activation states during a broad range of cognitive and sensorimotor behaviors. In contrast to the highly sophisticated imaging techniques the assessment of behavior is often poorly controlled. For motor control, this is partly due to the restricted mechanical conditions for measurement in the scanners or to interference with the magnetic devices. This situation is just about to change as more recording techniques are available for application in neurofunctional studies. This article gives an outline of the most commonly used kinematic recording techniques and their
* Correspondence to: Dr. C. Dohle, Neurologische Klinik, Universitatsklinikum Dusseldorf, MoorenstraBe 5, D-40225 Dusseldorf, Germany. E-mail address:[email protected] Tel.: +49-211-81 18678; fax: +49-211-81 18485.
methodical backgrounds. The major emphasis is put on the analysis of upper limb movements, as gait analysis is dealt with in a separate chapter.
14.2. Technical principles Depending on the purpose of the movement study, different movement recording systems can be used. One-dimensional systems, such as goniometers or lever constructions can record only one degree of freedom - usually unidirectional limb movements. In contrast, three-dimensional recording systems allow the recording of the entire movement of a limb in three-dimensional space. Both systems have specific advantages. One-dimensional techniques are simpler and cheaper and often serve the desired purpose. Three-dimensional movement recording systems are usually marker-based: the position of (active or passive) markers that are fixed to certain body parts is recorded by detectors. Their position in three-dimensional space has to be calibrated before the measurement. In principle, two different types of systems can be distinguished: (a) Active systems with markers emitting a signal (usually infrared light) in well-defined time intervals which is recorded by CCD cameras (e.g. Optotrak, Selspot (now out of business». (b) Passive systems with markers consisting of colorful or light-reflecting material. Their position is recorded by video- or infrared-based camera systems (e.g. Elite, MacReflex, Vicon). Usually, the recording procedure is based on infrared light. Active systems make use of infrared emitting diodes (LEOs) that are recorded by sensitive cameras. In passive systems the camera is coupled with an array of infrared emitting diodes, and the light is reflected by the markers. The most prominent problem of both systems is noise due to reflections from extraneous shiny surfaces. Other systems can detect markers directly from video recordings with-
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out any additional technical setup. In principle, these systems are very versatile as they do not require any extensive technical set-up. On the other hand, they require considerable manual post-processing and assignment of the markers at the beginning of each recording session. These systems are also much more viable to optical interferences. A completely different technique is based on ultrasound (ZEBRIS). The markers consist of small ultra-sound emitting sources and the signals are recorded by an array of three microphones fixed on a rack at well-defined distances to each other. Although these markers make use of small piezo elements to generate ultrasound, they barely emit electromagnetic waves, so that they can also be used in environments that are sensitive to electromagnetic 'noise' such as magnetoencephalography or magnetic resonance tomography. On the other hand, the system has only a limited range and is very liable to acoustic noise. Common to all these systems is the limitation that one camera can only detect positions in two dimensions. Thus, at least two cameras are necessary in order to obtain a three-dimensional position. Other systems are available that make use of different technologies. Gained from developments for the market of virtual reality techniques, electromagnetic tracking devices are partly employed for movement analysis (mainly Polhemus, Flock of Birds). In these systems, one emitter generates a static electromagnetic field of a certain dimension. The sensor consists of a coil that indicates position and orientation of the moving part relative to the emitter. In principle, these systems are rather cheap, very accurate and can provide both position and orientation of a marker in real-time. On the other hand, they are very liable to any type of metal within the range of the emitter as well as electromagnetic 'noise', e.g. of nearby located large computer monitors. All systems have specific advantages and disadvantages. Active systems are usually more expensive. For measurements, it is necessary to 'wire' the subjects, i.e. to connect the marker and the control unit. This ensures that every marker is always uniquely defined, even if it is occluded during certain measurement epochs. Passive measurement systems are usually cheaper and the measurement is easier to realize, because they do not require direct connections of the markers
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and the control unit. The major drawback of these systems is the ambiguity of marker identification. Consequently, the analysis of every trial has to be preceded by a manual assignment of markers that are then tracked further by the analysis software. Depending on the type of movement, marker trajectories can cross - at least in the field of view of one of the cameras. In this case, the marker assignment has to be corrected manually. In summary, passive systems are cheaper and easier in the initial acquisition of data. This advantage, however, has to be counterbalanced against a much higher demand in manual post-processing. All measurement systems of this type deliver time series of X-, Y: and z-coordinates as a result, that are sampled at certain frequencies. The further analysis of these data is poorly standardized, so that not many commercial programs are available. Usually, different laboratories make use of different, custom-made software packages. A good (and still valid) overview of the general principles of human movement analysis can be found in Winter (1990). Since this review is mostly restricted to applications in neurophysiology and sports medicine, we will mainly concentrate on the analysis of patients. Such recordings offer two advantages: They can quantify certain aspects of motor behavior and disclose qualitative features that cannot be detected otherwise.
14.3. Coordinate systems As outlined above, the majority of three-dimensional movement measurement systems provide (Cartesian) X-, y- and z-coordinates in time. The point of origin and the orientation of these coordinates is defined by a calibration procedure that has to be performed prior to the measurement. The calibration should be adjusted to match the coordinate axes to the main axes of the movement task to be recorded. Generally, the x- and y-axis define the floor or table plane with the z-axis pointing upwards. Although it is clear that the brain does not use cartesian coordinates for its computations, it is less clear what type of coordinates are used instead. In their pioneering studies on goal-directed movements, Soechting and Flanders (Soechting and Terzuolo, 1988; Soechting and Flanders, 1989a, b; Flanders et al., 1992) analyzed the variability of upper-limb pointing movements directed at targets in
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three-dimensional space. From their analysis, they proposed that arm movements are organized in a polar system based at the respective shoulder, having two angles (yaw and elevation) and one length (distance) as coordinate values. This proposal was theoretically based and inferred solely from kinematic measurements. Recent cell recordings in the awake monkey, however, demonstrated different cell populations responding specifically to the variation of one of the three values (Lacquaniti et al., 1995). On the other hand, a study of sensorimotor transformation errors in patients with lesions of the inferior parietal lobule showed dissociations of distance and direction errors, supporting the idea of different central processing modules for these two variables (Darling et al., 2001). 14.4. Levels of observation When subjects are required to write their signature either on a sheet of paper with a fine pen or on a blackboard with a piece of chalk attached to a broomstick, the individual features of their signature remain basically preserved - even when the writing is performed with the foot or a pen between their teeth. This phenomenon is called motor equivalence and neatly demonstrates that the brain is capable to transfer a given movement blueprint into a distinct kinematic pattern, irrespective of the biomechanical requirements. This is accomplished by converting the movement scheme into joint torques and muscle activation patterns specific for the limb that is actually performing the movement (inverse dynamics). For the analysis of human movements, this implies that movement analysis can be performed at different levels of observation: (1) Examination of (one-dimensional) limb angles.
This is particularly useful in the consideration of intra- and inter-limb coupling. When trajectories are recorded in using threedimensional measuring systems, more information is available about the position of the entire limb in space. Thus, additional levels of observation can be analyzed. (2) Examination of trajectories in three-dimensional space (kinematics). (3) Examination of multi-joint angles (limb configuration)
(4) Examination of joint torques (dynamics) Obviously, these considerations mainly apply to whole limb movements, i.e. the analysis of arm movements or gait. As gait analysis is covered in a separate chapter of this volume, the following analysis will focus on upper limb movements. Especially, we will demonstrate how the different levels of observation have been used to determine features of normal and pathological movements in patients with neurological disorders. 14.5. Analysis of patient populations The optimum strategy for the different applications depends whether the kinematic analysis should either elaborate previously defined patient's profiles or to allow the identification of different subpopulations of patients based on the kinematic data. In the first case, the mean values of pre-assigned kinematic parameters are determined for certain, apparently homogenous patient groups. These data can then be referenced either to those of normal subjects, or - if the type of disturbance only affects one side of the body - to the 'unaffected' body side. This procedure can only be applied if the patient groups are well defined and homogenous, such as hemiparkinsonism or hemiparesis. Conversely, kinematic data can be used to identify subgroups of patients with similar kinematic abnormalities and then to examine a possible correlation with distinct lesion localizations. This approach is more demanding, because the identification of the respective kinematic measures that are suitable to differentiate 'affected' from 'not affected' patients requires extensive prior research. 14.6. Temporal kinematics The kinematic analysis of recorded movements is exclusively based upon the trajectory of the recorded body segment, e.g. the hand or the fingertip. As the movement recording is usually performed at sampling frequencies around 100 Hz, it produces a large number of data points. In order to compare the trajectories of one person under different experimental conditions or trajectories of different patient populations it is necessary to decrease the dimensions of the trajectory, i.e. to parameterize the movement. One way to parameterize movements is the determination of fixed temporal 'landmarks'. This approach was extensively used in the analysis of
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grasping movements by Jeannerod and his coworkers (Jeannerod, 1981, 1984, 1988). He focused on hand velocity as a measure for the (proximal) reach component of the arm and grip aperture as a measure for the (distal) grasp component of the fingers. This work demonstrated the independence of these two components, by studying the times of maximum values of the two measures as representatives of the two components of the prehension movement (for review, see Paulignan and Jeannerod, 1996). The independence of these two components was the focus of many subsequent studies in normal subjects. In a typical paradigm in normal subjects, a determinant of one of the two components was varied (e.g. object size) and its effect on the second component (e.g. time of maximum hand velocity) was studied. Further support for the independent organization of these two components came from patients with focal cerebral lesions, especially of the posterior parietal cortex. Single case reports confirmed the role of the posterior parietal cortex for these types of sensorimotor transformations (Jeannerod, 1986a, b; Pause et al., 1989; Jakobson et al., 1991). In a first systematic study in patients with lesions of the parietal cortex, presenting the clinical picture of optic ataxia, Perenin and Vighetto showed deficits in the transport component of both arms in the left visual field following right parietal lesions ('field effect'). On the other hand, the transport component of patients with optic ataxia due to left parietal lesions was not only found to be impaired in the right visual field, but additionally also with all movements of the right arm in the left visual field and with central fixation ('hand effect'). The grasping component was tested for by adjustment of hand orientation in the frontal plane, following the paradigm of Haaxma and co-workers (Haaxma and Kuypers, 1974). Deficits in hand orientation showed the same distribution as deficits in the transport component, so that in this condition no dissociation between the two components could be demonstrated. It should be noted, however, that hand orientation is a kind of intermediate task that has to be accomplished in a synergy of proximal and distal joint angles (Dohle et al., 1995; Desmurget et aI., 1996). A kinematic study of prehension movements in patients with parietal lesions (Binkofski et al., 1998b) demonstrated an impairment of the grasp task but not of the reach component, supporting the
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concept of two independent visuomotor channels. This finding is of special interest as it corresponds to experimental inactivation studies in monkeys where the transport and the grasp component could be impaired independently (Gallese et aI., 1994). In an attempt to identify measures for disturbances of apraxic arm movements, Poizner and co-workers applied the approach of comparing temporal landmarks on repetitive movements. In the analysis of the times of maximum hand velocity and minimum hand path curvature during each stroke of a cyclical arm movement, the decoupling of these two measures was proposed to indicate a specific deficit in apraxic movements (Fig. 1, Poizner et al., 1990). Such interpretations have to be met with caution by two reasons. First, the underlying mathematics is not clear. Based on basic differential geometry (Morasso, 1983; Bartsch, 1986), the absolute value of hand path curvature c(t) at a given point of the three-dimensional trajectory r(t) (with its temporal derivatives velocity r'(t)=v(t) and acceleration r'(t)=a(t)) is calculated as: c(t)
=1(r' (r) x r'(t))/I r' (t) 131 =1(v(t) x a(t))/I v(t) 131
In other words, the value of curvature is calculated as a derivative of hand velocity. This fact on its own makes it highly unlikely that the two measures can be varied by the central commands independently. Second, Poizner's analysis was based mainly on the consideration of maximums and minimums of the time course of velocity and curvature. In normal subjects' movements, no significant time delay was observed between the timing of these extreme values. In apraxic patients, however, their occurrence did not correlate at all. Inspection of the raw data clearly shows that the movements were fragmented and consisted of several movement segments. It is clear, that this type of noisy data produce more extreme values that do not match each other. This leaves the reader wondering what is the phenomenom of decoupling of tangential velocity and hand path curvature. 14.7. Temporal aspects of movement organization
Quantitative measurements can provide insights in new principles of organization. An example are recordings from hand and finger movements that
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Fig. I. Velocity - curvature coupling during carving movements in an apraxic patient (right) in comparison to a normal subject (left). Upper panels: tangential velocity (mis, broken lines) and radius of curvature (m, continuous lines). Lower panels: time correspondences between velocity minima and radius of curvature minima (from Poizner et aI., 1990).
provided evidence for a clear cut functional dichotomy of manipulative hand and finger movements. On a qualitative basis, movements of the hand as a whole used for writing, shading and hammering had been previously classified as extrinsic and movements of the fingers against each other or the palm as intrinsic hand movements. Quantitatively, it has been demonstrated that these two types of hand movements are performed at distinctly different preferred frequencies. Extrinsic hand movement are usually performed at 4-7 Hz (type I) and intrinsic hand movements at 1-1.5 Hz (type II; Kunesch et aI., 1989). Surprisingly, there is no overlap between the two ranges (Fig. 2). Since the difference in their characteristic frequencies cannot be explained by mechanical reasons it has been concluded (Kunesch et aI., 1989) that the grouping into distinct frequency ranges represents different types of sensorimotor interactions. The slower type I movements require a continuous sensory guidance for their execution and must be carried out slowly in order to meet the time requirements for the detailed sensory analysis. The faster type II movements are rapid automated subroutines that are largely predictive and require only some crude sensory monitoring.
The observed grouping at preferred frequencies fits well into the more general scheme that most of our repetitive motor behaviors such as speaking, eyemovements during reading, chewing, walking, swimming or dancing is performed at characteristic frequencies. Central pattern generators in the brainstem play an important role for their generation. Therefore, the assessment of the temporal aspects of motor organization is only possible on the basis of quantitative movement analysis.
14.8. Spatial kinematics Apart from determining the timing of certain landmarks during the movement, the spatial position of some body part at the time is of interest as well. For prehension movements, this approach was first proposed by Haggard and co-workers (Haggard et aI., 1994). In their study, it could be demonstrated that the aperture during a prehension movement was not only scaled on the basis of the temporal pattern of the prehension movement, but also depending on the spatial position of the hand in the entire trajectory. In a patient with cerebellar damage, the strategic trial-to-trial coordination seemed to be
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Fig. 2. Distribution of the frequencies at which finger movements are performed during four tactile exploratory tasks (left) and of hand movements during execution of three normal skills (right) (from Kunesch et aI., 1989).
preserved in spite of gross abnormalities of the arm trajectory (Haggard et al., 1994). Another spatial feature of arm trajectories is preservation of the movement plane, which was presented by Poizner and colleagues as a typical feature of movements in apraxic patients (Poizner et al., 1990). In their study, it could be shown that the plane of motion in cyclical arm movements shows a high inter-trial variability when compared to those of normal subjects. These findings convincingly characterize the deranged movements. However, similar deficits were later shown to occur in deafferented patients (Sainburg et al., 1993), raising the question of specificity of this finding. 14.9. Limb and body configuration
The analysis methods presented so far were only focused on the hand and the finger. However, the three-dimensional recording systems also offer the possibility to catch the movement of the entire limb,
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namely the upper arm and forearm. By adding two further markers at the shoulder and at the elbow, three further limb angles can be calculated: upper arm elevation, upper arm yaw and elbow angle (Soechting and Lacquaniti, 1981). This method does not take into account forearm pronation or supination, which can simply be regarded as a radial segment rotating around an ulnar segment (Reich and Daunicht, 2000). Its calculation out of recorded kinematic data requires a further marker on the forearm defining the transversal axis of the hand joint in space. Soechting and Lacquaniti's pilot studies in normal subjects demonstrated that upper arm elevation (usually referred to as shoulder elevation) and elbow angle are tightly coupled during a pointing (or grasping) task (Soechting and Lacquaniti, 1981). Subsequently, this relationship was found to be disturbed in a variety of neurological disorders, such as deafferentation (Sainburg et al., 1993; Ghez and Sainburg, 1995) (Fig. 3), apraxia (Poizner et al., 1995), in patients with parietal lesions with and without apraxia (Binkofski et al., 1998a), cerebellar ataxia (Bastian et al., 1996; Massaquoi and Hallett, 1996), hemiparesis (Levin, 1996; Beer et al., 2000; Cirstea and Levin, 2000) or Parkinson's disease (Seidler et al., 2001). The authors of these studies noted the similarities of their findings, but it remains unclear if the loss of interjoint coupling is a specific pathological phenomenon, or rather some epiphenomenon that is to be found in different types of deranged arm movements. 14.10. Dynamics
When both information about the joint angles and estimates about the inertial mass of the body segments (e.g. Winter, 1990) are available, inverse dynamics equations can be applied to calculate the joint torques that are necessary to produce the observed movements. Different authors have used different terminologies (Soechting and Lacquaniti, 1981; Hollerbach and Flash, 1982; Bastian et al., 1996), but in general, one has to distinguish (according to the terminology used by Bastian and co-workers): • Net torque: sum of all the torques acting at a joint.
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Control 2
Fig. 3. Coupling of elbow and shoulder motions in two patients with deafferentation (middle and bottom) in comparison to a normal subject (top). The elbow flexion! extension angle has been plotted against the upper arm elevation (top) and yaw (bottom) angles for individual cycles of a four cycle movement (from Sainburg et al., 1993).
According to the formulas presented in Soechting and Lacquaniti (1981) and Bastian et al. (1996), this consists from the sum of:
• muscle torques: sum of all muscle and passive tissue forces that are necessary to generate the observed movement; • gravitational torque: torque produced by the force of gravity acting on the limb segments of the arm; • interaction torques: motion-dependent torques that occur at any joint due to movements that are linked. In normal subjects, it could be demonstrated that phasic EMG activity occurs in muscles solely acting at adjacent joints, even if those joints are mechanically immobilized (Gribble and Ostry, 1999). This was interpreted as experimental support for the theoretical proposal that central control signals to muscles are adjusted, in a predictive manner, to compensate for interaction torques. In only a very limited number of studies have these analysis techniques been applied to patient movements. In studies on patients with deafferentation (Sainburg et al., 1993, 1995), cerebellar ataxia (Bastian et al., 1996) and Parkinson's disease (Seidler et al., 2001) these interaction torques were found to be inadequately adjusted in order to generate smooth, straight movements. It remains unclear, however, if this deficit can be pinpointed to the abnormal control of interaction torques as result of a deficient processing of somatosensory information or whether this disturbance is the pure description of a lack of joint coordination at a different level of observation. Further studies are necessary to clarify this point. In a later study, Bastian and co-workers (Bastian et al., 2000) tried to exclude that this inaccurate adjustment of interaction torques in cerebellar patients was solely due to a general inability to generate sufficient levels of phasic torque. For this purpose, they studied practically identical upper-arm pointing movements in cerebellar patients, either with their shoulder free or their shoulder fixed (Bastian et al., 2000). Cerebellar patients changed the pattern of muscle activity fundamentally when changing between these two conditions, producing inadequately scaled interaction torques, due to deficits in coordination of multi-joint movements. 14.11. Manipulative hand movements
Apart from whole-limb movements of either arm, manipulative movements, such as those during exploration of small objects, can be recorded and
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analyzed quantitatively. In this case, movements of the fingertips of the thumb and the forefinger have to be recorded. Although movement paths are restricted to a narrow workspace, the same trajectory in space is never repeated (Kunesch et al., 1989). The temporal profile, however, shows a regular, periodic pattern (Fig. 4). Spectral analysis typically exhibits a single peak in the frequency spectrum between 1 and 2 Hz, showing high variability across, but not within different subjects (Kunesch et al., 1989). This is typically impaired in subjects with lesions of the posterior parietal cortex, showing deficits in the recognition of objects by haptic exploration (astereognosis). In these patients, the space of exploration is grossly enlarged and the mean frequency and the regularity of the movement is reduced (Kunesch et al., 1995; Binkofski et al., 2001). A more detailed analysis of subgroups of 3D-trajectories
these patients show that astereognosis is correlated with grossly enlarged space of exploration, but not with slower or more irregular movements per se (Binkofski et al., 2001).
14.12. Bilateral synergies The last paragraphs lead to another question: To which extent can different limb segments be controlled independently, especially between both sides of the body? The most basic model of coupled limb movements is that of rhythmic flexion and extension movements of the index fingers or hands of both arms, that are moving either in-phase or anti-phase. This paradigm was extensively studied by Kelso and co-workers who noted that in-phase movements are much more stable than anti-phase movements (Kelso, 1981, Movement<:haraeteflslics of thumb andindex finger
Movement characteristics of lhumb and indexfinger
Frequency spectrum
OIlhumb movemems
Frequencyspectrum 01 thumb movements
Fig. 4. Exploratory finger movements in two patients with focal cerebral lesions (middle and bottom) in comparison to a normal subject (top). Left panels: 3-D reconstruction of thumb (T) and index finger (FF) movement trajectories. Middle panels: scan paths of thumb and index finger. Right panels: frequency distribution of the thumb movements (from Binkofski et aI.,
2001).
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1984; Kelso and Tuller, 1984). Furthermore, if subjects perform externally paced anti-phase movements with increasing movement frequency, a sudden transition to in-phase movements occurs. These observations led to the Haken-Kelso-Bunz model, explaining the superior stability of the inphase pattern by a theoretical model of coupled oscillators (Haken et al., 1985). Although this model has been extensively studied and refined since then (Kay et al., 1987; Forrester and Whitall, 2000; Beek et al., 2002), it is only recently that the perceptual component of this phenomenon has come into the focus of attention. For example, it could be shown that the same stability of the in-phase pattern when compared to the anti-phase holds true when two people have to
synchronize their movements (Bingham et al., 1999). Finally, in a recent study Mechsner and coworkers studied bimanual finger movements when one hand was either pronated or supinated (Mechsner et al., 2001). Surprisingly, in this setup, the symmetrical movements of the fingers were also more stable than parallel movements when one of the two hands was pronated and the other supinated. In other words, the superior stability of the in-phase pattern only depended on the actual movement direction of the fingers, but not on the finger muscles involved. In a second experiment, the subjects had to synchronize two circular-moving handles. In one handle, however, the ratio of transmission was altered in such a way that three rotations of the hand resulted in four rotations of the handle (Mechsner et
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Fig. 5. Bilateral synchronous movements of shoulder (top), elbow (middle) and wrist (bottom) in a patient with right sided hemispherectomy. Left panels: movement cycles (right side: upper trace). Right panels: bilateral correlation (from Miiller et aI., 1991).
200 al., 2001). In this set-up, stability of in-phase circular movements was achieved flawlessly, further supporting the idea that it is the perception of in-phase pattern that is controlled rather than the implementation in the subjects' biomechanical system. All these experiments were performed with movements of distal parts of the arm (hand or finger movements) and synchrony was usually assessed by comparison of the inter-tap-times of each hand. In this analysis procedure, the actual movement trajectory is not considered, but only the final 'goal' (Wiesendanger et al., 1994). Analysis of phase diagrams comparing right- and left sided movements and calculating correlation coefficients between the entire trajectory of either side might help to understand the mechanisms of bilateral coordination in more detail. In a study on bilateral prehension movements using this approach, Dohle and coworkers could demonstrate different coupling mechanisms for the reach and the grasp component respectively (Dohle et al., 2000). Whereas the grasp (thus distal) component shows only little coordination during the movement, suggesting largely independent movement organization mechanisms of either side, the reach (thus proximal) component seems to be 'hard-wired' connected between both sides. This is compatible with a study in a patient with right-sided hemispherectomy, showing preserved coordination between proximal arm movements of either side, but largely independent, fractionated movements of more distal parts of the body (Muller et al., 1991) (Fig. 5).
14.14. Summary In this chapter, we have presented an overview about the different techniques and methods in kinesiology, especially with respect to their application in the movement analysis of neurological patients. A number of different disturbance patterns provide useful information about the characteristic changes in a particular pathological condition. Some of them are specific, while others reflect more general abnormalities.
References Bartsch, H-I (1986) Mathematische Formeln, 21. Auflage. Leipzig:VEB Fachbuchverlag. Bastian, AJ, Martin, TA, Keating, JG and Thach, WT (1996) Cerebellar Ataxia: Abnormal control of inter-
C. DOHLEAND H.-J. FREUND
action torques across multiple joints. J. Neurophysiol., 76: 492-509. Bastian, AJ, Zackowski, KM and Thach, WT (2000) Cerebellar Ataxia: Torque deficiency or torque mismatch between joints? J. Neurophysiol. 83: 30193030. Beek, PI, Peper,CE and Daffertshofer, A (2002) Modeling rhythmic interlimb coordination: beyond the Hakenkelso-Bunz model. Brain Cogn., 48: 149-165. Beer, RF, Dewald,IPA and Rymer, WZ (2000) Deficits in the coordination of multijoint arm movements in patients with hemiparesis: evidence for disturbed control of limb dynamics. Exp. Brain Res., 131: 305319. Bingham, GP, Schmidt, RC and Zaal, FT (1999) Visual perception of the relative phasing of human limb movements. Percept. Psychophys., 61: 246--258. Binkofski, F, Dohle, C, Hefter, H, Schmitt, M, Kuhlen, T, Seitz, R and Freund, H-I (1998a) Deficits in ThreeDimensional Limb Coordination in Parietal Patients With and WithoutApraxia. In: M Fetter,T Haslwanter, H Misslisch and D Tweed (Eds.), 3-D Kinematic Principles of Eye, Head and Limb Movements in Health and Disease. Amsterdam: Harwood Publishers.
Binkofski,F, Dohle, C, Posse, S, Stephan, KM, Hefter, H, Seitz, RJ and Freund, HI (1998b) Human anterior intraparietal area subserves prehension: a combined lesion and functional MRI activation study. Neurology, 50: 1253-1259. Binkofski,F, Kunesch, E, Classen, J, Seitz, RJ and Freund, HI (2001) Tactile apraxia: unimodal apractic disorder of tactile object exploration associated with parietal lobe lesions. Brain, 124: 132-144. Cirstea, MC and Levin, MF (2000) Compensatory strategies for reaching in stroke. Brain, 123: 940--953. Darling, WG, Rizzo, M and Butler, AJ (2001) Disordered sensorimotor transformations for reaching following posterior cortical lesions. Neuropsychologia, 39: 237254. Desmurget, M, Prablanc, C, Arzi, M, Rossetti, Y, Paulignan, Y and Urquizar, C (1996) Integrated control of hand transport and orientation during prehension movements. Exp. Brain Res., 110: 265-278. Dohle, C, Hefter, H, Meermagen, S, Nies, A and Freund, H-J (1995) Disturbances in orienting finger-thumb opposition space in patients with parietal lesions. In: Parietal Lobe Contributions to Orientation in 3-D space. Ttibingen.
Dohle, C, Ostermann, G, Hefter, H and Freund, H-I (2000) Different coupling for the reach and the grasp components in bimanual prehension movements. NeuroReport, 11: 3787-3791.
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Flanders, M, Helms Tillery, SI and Soechting, JF (1992) Early Stages in a sensorimotor transformation. Behav. Brain Sci., 15: 309-362. Forrester, Land Whitall, J (2000) Bimanual finger tapping: effects of frequency and auditory information on timing consistency and coordination. J. Mot. Behav., 32: 176-191. Gallese, V, Murata, A, Kaseda, M, Niki, N and Sakata, H (1994) Deficit of hand preshaping after muscimol injection in monkey parietal cortex. NeuroReport, 5: 1525-1529. Ghez, C and Sainburg, R (1995) Proprioceptive control of interjoint coordination. Can. 1. Physiol. Pharmacol., 73: 273-284. Gribble, PL and Ostry, OJ (1999) Compensation for interaction torques during single- and multijoint limb movements. J. Neurophysiol., 82: 2310-2326. Haaxma, Rand Kuypers, H (1974) Role of occipitofrontal cortico-cortical connections in visual guidance of reatively independent hand and finger movements in rhesus monkey. Brain Res., 71: 361-366. Haggard, P, Jenner, J and Wing, A (1994) Coordination of aimed movements in a case of unilateral cerebellar damage. Neuropsychologia, 32: 827-846. Haken, H, Kelso, JA and Bunz, H (1985) A theoretical model of phase transitions in human hand movements. BioI. Cybem., 51: 347-356. Hollerbach, JM and Flash, T (1982) Dynamic interactions between limb segments during planar movements. Bioi. Cybem., 44: 67-77. Jakobson, LS, Archibald, YM, Carey, DP and Goodale, MA (1991) A kinematic analysis of reaching and grasping movements in a patient recovering from optic ataxia. Neuropsychologia, 29: 803-809. Jeannerod, M (1981) Intersegmental coordination during reaching at natural visual objects. In: J Long and A Baddeley (Eds.), Attention and Performance IX. Hillsdale, NJ: Lawrence, pp. 153-169. Jeannerod, M (1984) The timing of natural prehension movements. 1. Mot. Behav., 16: 235-254. Jeannerod, M (1986a) The formation of finger grip during prehension. A cortically mediated visuomotor pattern. Behav. Brain Res., 19: 99-116. Jeannerod, M (1986b) Mechanisms of visuomotor coordination: a study in normal and brain-damaged subjects. Neuropsychologia, 24: 41-78. Jeannerod, M (1988) The neural and behavioural organization of goal-directed movements. Oxford: Oxford University Press. Kay, BA, Kelso, JA, Saltzman, EL and Schoner, G (1987) Space-time behavior of single and bimanual rhythmical movements: data and limit cycle model. J. Exp. Psychol. Hum. Percept. Perform., 13: 178-192.
201 Kelso, JAS (1981) On the oscillatory basis of movement. Bull. Psychon. Soc., 18. Kelso, JAS (1984) Phase transitions and critical behavior in human bimanual coordination. Am. J. Physiol., 246: R 1000-1 004. Kelso, JAS and Tuller, B (1984) A dynamical basis for action systems. In: MS Gazzaniga (Ed.), Handbook of Cognitive Neuroscience. New York: Plenum, pp. 321356. Kunesch, E, Binkofski, F and Freund, HJ (1989) Invariant temporal characteristics of manipulative hand movements. Exp. Brain Res., 78: 539-546. Kunesch, E, Binkoski, F, Steinmetz, H and Freund, H-J (1995) The pattern of motor deficits in relation to the site of stroke lesion. Eur. Neurol., 35: 20-26. Lacquaniti, F, Guigon, E, Bianchi, L, Ferraina, S and Caminiti, R (1995) Representing spatial information for limb movement: role of area 5 in the monkey. Cereb. Cortex, 5: 391-409. Levin, MF (1996) Interjoint coordination during pointing movements is disrupted in spastic hemiparesis. Brain, 119: 281-293. Massaquoi, S and Hallett, M (1996) Kinematics of initiating a two-joint arm movement in patients with cerebellar ataxia. Can. J. Neurol. Sci., 23: 3-14. Mechsner, F, Kerzel, D, Knoblich, G and Prinz, W (2001) Perceptual basis of bimanual coordination. Nature, 414: 69-73. Morasso, P (1983) Three dimensional arm trajectories. Bioi. Cybem., 48: 187-194. Muller, F, Kunesch, E, Binkofski, F and Freund, H-J (1991) Residual sensorimotor functions in a patient after right-sided hemispherectomy. Neuropsychologia, 29: 125-145. Paulignan, Y and Jeannerod, M (1996) Prehension Movements. The Visuomotor Channels Hypothesis Revisited. In: AM Wing, P Haggard and R Flanagan (Eds.), Hand and Brain. San Diego: Academic Press, pp. 265-282. Pause, M, Kunesch, E, Binkofski, F and Freund, HJ (1989) Sensorimotor disturbances in patients with lesions of the parietal cortex. Brain, 112: 1599-1625. Poizner, H, Mack, L, Verfaellie, M, Rothi, LJG and Heilman, KM (1990) Three-dimensional computergraphic analysis of apraxia. Brain, 113: 85-101. Poizner, H, Clark, MA, Merians, AS, Macauley, B, Rothi, LJG and Heilman, KM (1995) Joint coordination deficits in limb apraxia. Brain, 118: 227-242. Reich, J and Daunicht, WJ (2000) A rigid body model of the forearm. J. Biomech., 33: 1159-1168. Sainburg, RL, Poizner, H and Ghez, C (1993) Loss of proprioception produces deficits in interjoint coordination.1. Neurophysiol., 70: 2136-2147.
202 Sainburg, RL, Ghilardi, MF, Poizner, H and Ghez, C (1995) Control of limb dynamics in normal subjects and patients without proprioception. J. Neurophysiol., 73: 820-835. Seidler, RD, Alberts, JL and Stelmach, GE (2001) Multijoint movement control in Parkinson's disease. Exp. Brain Res., 140: 335-344. Soechting, JF and Lacquaniti, F (1981) Invariant characteristics of a pointing movement in man. J. Neurosci., 1: 710-720. Soechting, JF and Terzuolo, CA (1988) Sensorimotor transformations underlying the organization of arm
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movements in three-dimensional space. Can. J. Physiol. Pharmacol., 66: 502-507. Soechting, JF and Flanders, M (1989a) Sensorimotor representations for pointing to targets in threedimensional space. J. Neurophysiol., 62: 582-594. Soechting, JF and Flanders, M (1989b) Errors in pointing are due to approximations in sensorimotor transformation. J. Neurophysiol., 62: 595-608. Wiesendanger, M, Kaluzny, P, Kazennikov, 0, Palmeri, A and Perrig, S (1994) Temporal coordination in bimanual actions. Can. J. Physiol. Pharmacol., 72: 591-594. Winter, DA (1990) Biomechanics and motor control of human movement. New York: Wiley.
Movement Disorders Handbook of Clinical Neurophysiology, Vol. 1 M. Hallett (Ed.) © 2003 Elsevier B.v. All rights reserved
203 CHAPTER 15
Reaction time as an index of motor preparation/programming and speed of response initiation Marj an Jahanshahi * Sobell Research Department ofMotor Neuroscience and Movement Disorders, Institute ofNeurology, Queen Square, London WCIN 3BG, UK
15.1. Introduction
15.2. Historical background of the study of RTs
Measuring the accuracy and speed of responding have been two key methods for quantifying a subject's performance under a variety of experimental conditions. The speed of responding to a stimulus, the so-called 'reaction time' RT has been widely used to measure the speed of information processing in a diversity of tasks and paradigms such as covert orienting of attention (Posner, 1980) or memory scanning (Sternberg, 1966). Reaction times have also been employed as an index of movement preparation and programming. The main focus of this chapter will be on the latter use of RT, that is as an index of motor preparation and movement initiation. Following a brief historical overview, I will describe the common types of RT tasks used to study motor preparation and programming, and then outline the factors known to influence RT. I will then consider the functional anatomy of RT tasks based on evidence from imaging studies. The important issue of parallel vs. serial information processing will be a good starting point for discussion of the advantages and disadvantages of RT measurement and the value of complementary use of other techniques such as recording of event-related potentials. Finally, I will consider the application of RT measurement to a range of movement disorders.
The measurement of the time of mental processes has a long history that goes back to the work of Donders and Sternberg. Donders (1968/1969) made a distinction between A, B and C type RT tasks, respectively requiring responses to a single stimulus (type A), a particular response to each of several stimuli (type B) and a response to only one of several stimuli (type C). These respectively correspond to what is now known as simple, choice and 'go/no go' RT tasks (see below for description). With himself as the experimental subject and using vowel sounds as stimuli, Donders reported average RTs which were fastest for A task, intermediate for C task and slowest for B task. He noted that the difference between the C and A tasks, was approximately half (39 ms) of the difference between the B and A tasks (75 ms). The former difference was considered to reflect 'the time required for conception of a certain sound' or in modem parlance the time for stimulus discritnination necessary in the 'go/no go' RT task (type C) but not the simple RT task (type A). Donders considered the difference between the B and A tasks to reflect the time required "for that same conception combined with the corresponding expression of the will" (p. 424). In the language of modem neuroscience, the 'expression of the will' refers to the process of response selection, or (choosing the particular response associated with the particular stimulus presented) involved in choice RT (type B) but not simple RT (type A). Donders' logic for the 'substraction method' illustrated above, was based on his idea that a number of successive processes or stages intervene between stimulus presentation and response production and that each process or stage only begins when the preceding stage has ended. As discussed in a
* Correspondence to: M. Jahanshahi, Sobell Research Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, Queen Square, London WCIN 3BG, UK. E-mail address:[email protected] Tel.: 44 20 7837 3611 (ext. 3055); fax: 44 20 7278 9836.
204
later section, the latter assumption has been questioned. In addition, Donders' 'substraction method' has been criticized since it is based on the assumption of 'pure insertion', that is, it suggests that it is possible to add or remove one of the processing stages without altering other stages of processing that intervene between the stimulus and response. In practice, it is difficult to devise experimental tasks that only differ in a key stage of processing. To overcome the problems associated with Donders' substraction method, Sternberg (1969) proposed an 'additive factor model' for stage analysis of RTs. According to this model, if two experimentally manipulated variables or factors have an additive effect on RT such that the combined effect of the two factors is equal to the sum of the effect of each factor assessed independently, then it is assumed that each factor is affecting a different stage of processing. In contrast, if the two factors interact, that is the combined effect of the two factors is either greater or smaller than the effect of each factor assessed independently, then it is assumed that the two factors are influencing at least one common stage of processing. The additive factors model, similar to Donders' subtraction method, is based on the assumption of serial and independent stages of processing between a stimulus and a response, and has been widely criticized (e.g. Sanders, 1980). Nevertheless, even its critics (Sanders, 1980) have considered the Sternberg model a valuable heuristic tool for studying reaction processes.
15.3. Measurement of RT and MT RT refers to the time interval between the presentation of a stimulus and the initiation of a response, usually involving some form of movement. Movement time (MT) is the time taken to execute a movement from its moment of initiation. A variety of mechanical and electronic techniques have been used to measure RTs and MTs. Whatever method is used for quantification of RT and MT, it should allow accuracy in the millisecond range. A distinction has been made between premotor vs. motor RTs. Premotor RTs are measured as the time between the presentation of a stimulus and the start of electromyographic (EMG) activity in the muscles acting as the prime movers in initiating and executing the response. Motor RTs refer to the interval
M. JAHANSHAHI
between the onset of EMG activity and start of the behavioral response such as lifting the finger from a microswitch. Premotor and motor RTs respectively reflect central and peripheral processes. Tomberg et al. (1991) compared different methods for recording RTs such as onset of EMG responses, pressing microswitches or photoelectric detection of finger extension or flexion. They concluded that RTs based on EMG onset or photoelectric detection of finger extension provided the most reliable RT recordings. For reliable RTs, measurements have to be obtained across a number of trials. This allows development of an attentional or response 'set' and ensures that the values are not unduly affected by lapses in attention that may occur on some trials. To ensure that subjects have understood task instructions and to familiarize them with the task requirements, it is also customary to provide a number of practice trials before the actual measurement of RTs. The optimal number of trials for reliable measurement of RTs will vary depending on the precise nature of the RT task, but while too few trials render the measurements unreliable because of inadequate sampling, too many trials may be affected by fatigue, given the need to maintain focused attention throughout the task. A much replicated finding in the RT and MT literature is the 'speed-accuracy trade-off' (for review see Meyer et aI., 1988). This refers to the finding that with faster RTs and MTs, subjects make more errors. Thus, when speed of responding improves this seems to be at the expense of poorer accuracy of performance. Trial by trial analysis of response times has also shown that following an error RTs are slower on the next trial and then gradually become faster (Rabbitt, 1966). Keyobservations relating to the speed-accuracy trade-off were made by Woodworth (1938) and Fitts (1954). In Fitts' paradigm, subjects were required to move a metal-tipped stylus between two metallic target plates as quickly and accurately as possible. The width of the target plates (0.25, 0.5, 1 and 2 inches) and the distance between them (2, 4, 8, and 16 inches) were experimentally manipulated. Fitts defined an 'index of difficulty' as a function of the distance between (D) and the width of the target plates (W). This index of difficulty, log, (2DIW) is known as Fitts' law. Fitts' results showed that MTs are a linear function of the index of difficulty. With the distance between the targets kept constant, when
REACTION TIME AS AN INDEX OF MOTOR PREPARATIONIPROGRAMMING
the target width is reduced, subjects have to slow down their movements as otherwise they will make more errors. Therefore, these results showed that an inverse relationship exists between the spatial accuracy and speed of rapid aimed movements (Fitts, 1954). While in Fitts' paradigm, spatial accuracy of the aimed movements was of interest, in other RT paradigms, the precise nature of the errors depend on the type of task used. Anticipations or premature responses are errors in timing of release of the response: the response is made before presentation of the stimulus. Such anticipatory errors usually occur in RT tasks where the subject builds up high levels of preparedness or readiness to respond such as in simple or primed choice RT tasks. Incorrect response selection is an error encountered in choice RT tasks, particularly those with a large number of stimulus(S)-response(R) alternatives or with low SR compatibility such as with poorly learned or arbitrary S-R associations. Long RTs which are two or more standard deviations outside the mean RTs for the individual subject are another type of error that can occur. Errors of omission (failure to respond) or commission (making a response when none required) are other types of errors that can be respectively encountered on 'go' and 'no go' trials of go/no go RTs. In most studies, the mean and standard deviation of RTs are reported. However, typically, RT distributions have a positively skewed shape. The presence of a skewed distribution means that the mean and standard deviation of the sample's RT, the two parameters most frequently used to quantify RT data, do not convey precise information about the performance of the sample. Use of median RTs and providing information about the fastest and the slowest responses may also be of value. Heathcote et al. (1991) recommend that "distributional analysis should not be treated as a supplementary technique. Rather, we contend that RT measures should always be analyzed using a distributional analysis." 15.4. Motor programs Complex movements such as those involved in playing the piano occur too quickly to be influenced by peripheral feedback. For performance of even the simplest movements, the motor system has to generate and process a great deal of information very
205
quickly. One way of achieving this is for movements to be prepared in detail or 'programmed' before their execution. This central programming model of motor control dates back to the pioneering observations of Lashley (1917). The basic component of this model is a motor program, defined as "a set of muscle commands that are structured before a movement sequence begins and that allows the entire sequence to be carried out" (Keele, 1968). An important piece of evidence in support of the central programming model was the observation, first reported by Henry and Rogers (1960), that the time to initiate rapid responses increased as a function of the number of components in the response. Henry and Rogers (1960) suggested that this 'sequence length effect' (SLE) was due to programming of the response, with more complex responses requiring longer programs and longer compilation times. A similar finding was reported by Sternberg et al. (1978) who found that the RT to initiate the first response in a string of typewritten or spoken responses became longer with the increase in the number of elements in a string. They proposed that the SLE reflected the longer time required for search of a motor buffer and subprogram retrieval in the case of more complex responses. The infinite number and permutations of movements that are possible raise the problem of storage of the motor programs that would be required. This storage problem is overcome by the concept of 'generalized motor programs' (Schmidt, 1975). These are abstract representations which are modified to meet current demands by setting the appropriate motor parameters. Such generalized motor programs ensure storage 'economy' while allowing infinite variability and novelty in motor performance. A second line of evidence supporting the central programming model is the existence of invariant motor patterns. For example, a person's signature retains a number of constant features whether produced using a pen on paper or a brush on a canvas or with a piece of chalk on a board. This invariance and constancy of performance has been considered to derive from the use of the same generalized motor program in the different situations. While feedforward control and lack of reliance on feedback are the key components of the central programming model, nevertheless it is clear that sensory feedback is also used by the motor system.
206 This is, for example, evident in the case of aimed movements which deteriorate in the absence of visual feedback (Keele and Posner, 1968). In fact, when describing aimed movements, Woodworth (1938) considered these to consist of two phases, an 'initial impulse' at the start of movement and a terminal phase involving 'current control', respectively corresponding to centrally programmed and feedback-dependent components.
15.5. Some common types of RT tasks A variety of RT tasks or paradigms have been used to measure specific aspects of perceptual and cognitive processing and learning. These RT paradigms are too numerous to consider individually here. Instead, given the focus of this volume on Movement Disorders, I will consider some of the most common types of RT task that have been used to study speed of processing in these disorders. These include Simple, Choice (uncued and precued), and Go/no go RT tasks, which have been employed to investigate the processes of motor preparation and programming and response initiation and inhibition. If programming of the movement occurs before the onset of a stimulus, this so-called preprogramming of a response, confers a speed advantage to RT over the conditions in which the subject engages in motor programming after the onset of the stimulus. 15.5.1. Simple, uncued and precued choice RTs In its classic form, Simple RT (SRT) is defined as the time taken to initiate a single invariant response to a single invariant stimulus. As the precise nature of the response is known in advance, it can be preprogrammed, i.e. the response can be selected and fully specified before stimulus presentation (Klapp et al., 1979). Furthermore, as the nature of the stimulus is also invariant, registering the occurrence of the stimulus is sufficient for initiation of the preprogrammed response (Fig. la). However, preprogramming of the response before onset of the stimulus, which is essential for conferring its speed advantage to SRT, is optional. As noted by Klapp (1977) "Such advance programming would not be obligatory when the SRT paradigm is used since subjects could merely ignore the advance information and postpone programming until the onset of the 'go' signal" (pp. 234-235).
M. JAHANSHAHI
A Choice RT (CRT) task involves more than one stimulus each with its associated response. CRT is the time taken to initiate one of a set of possible responses to one of a set of stimuli. On any particular trial, as the stimulus and its associated response varies, the response cannot be preprogrammed. On each trial, the subject has to identify the particular stimulus presented, refer to the stimulus-response (S-R) codes in order to select the appropriate response, and then to program, initiate and execute that response (Fig. lb). So, in CRT conditions programming of a response does occur, but unlike SRT, it is performed after stimulus presentation, rather than before. In CRT, additional processes intervene between presentation of the stimulus and execution of the response. The relative prolongation of CRT compared to SRT, or the so-called "central delay", is considered to reflect central information processing operations such as stimulus evaluation and identification, S-R decoding, response selection, and motor preparation/programming which occur following the onset of the stimulus. In situations where the stimuli and responses are highly compatible or have a "natural" or a priori relationship such as in some cases of tactile CRT, reference to S-R mapping rules or matching lists (Hasbroucq et al., 1990) for response selection may not be necessary. In such conditions, preparation of the response can proceed following identification of the stimulus. Besides the "classical" SRT and CRT paradigms depicted in Figs la and b, other RT tasks have also been used in the study of motor programming. One of the most frequently employed tasks has been the precued CRT paradigm originally devised by Rosenbaum (1980). In this task (Fig. lc), a precue presented at some fixed or variable interval prior to the imperative stimulus provides the subject with partial or complete advance information about the nature of the required response. This advance information can be potentially used by the subject to partially or fully preprogram the response. Precued CRTs are faster than uncued CRTs, since the stages of processing that in a standard CRT (Fig. 1b) would normally occur after presentation of the imperative stimulus can take place before it (Fig. lc). SRT and precued CRT tasks are similar in-so-far as in both preprogramming of the response prior to the imperative stimulus is possible. However, given that the response to be preprogrammed remains constant in
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8.
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SRT but varies from trial to trial in precued CRT, the exact nature of the attentional processing and extent of volitional control involved in the preprogramming of the response is likely to differ in the two tasks. For example, in SRT, because of the constant nature of the response across trials, development of a motor set is possible, which is not the case in precued CRT where a degree of S-R uncertainty remains since a different set of stimuli requiring different responses are presented across trials. The use of SRT and CRT paradigms in the study of motor programming is based on the fundamental fact that the time to initiate a response in a SRT task is less than the time taken in a CRT task. The faster speed of response initiation in SRT tasks results from two sources. First, in SRT tasks but not in CRT, the subject has the opportunity to prepare or preprogram the response in advance of the go signal. Second, after stimulus onset, additional processing stages are involved in CRT that are not necessary in SRT, partly as a result of preprogramming in the latter case. The extra stages increase the time between presentation of the stimulus to initiation of the response. Given that in precued CRT, preprogramming of the response on the basis of the information provided by the precue is also possible, the speed advantage of precued CRT relative to uncued CRT has been used as another index of motor programming. Frith and Done (1986) have distinguished three routes to action. They refer to a 'fast' route used in SRT conditions, a 'direct' route used in CRT tasks with high S-R compatibility, and a 'slow' route underlying responses in CRT conditions where S-R compatibility is low. They further proposed that the degree of volitional control necessary is different in the three routes. Volitional control is minimally involved in the 'direct' route (compatible CRT) in which response preparation and initiation is entirely ruled by the onset of the stimulus. In contrast, the stimulus plays a minimal role in the 'fast' route (SRT), where preprogramming of the response depends on an act of will. In the 'slow' route, volitional control is necessary to some extent for decoding of the arbitrary S-R codes. On the basis of the results of a study examining the degree of interference produced by a secondary task on the performance of SRT and CRT tasks, Frith and Done (1986) proposed that focused attention is not needed for the direct route whereas it is required for the fast
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route. In summary, in Frith and Done's terminology, in SRT the response is preprograrnmed through an act of will, a process which requires focused attention, whereas in CRT, programming of a response is triggered by the onset of the stimulus and requires less volitional control and makes fewer demands on attentional resources. 15.5.2. Tasks to study the sequence length effect
Another way in which RT tasks have been used to examine motor programming has been by experimental investigation of the sequence length effect (SLE). To study the SLE, sequential finger tapping is commonly incorporated in RT paradigms, although more complex hand movements have also been studied by some (e.g. Haadland et al., 1987). In SRT, the same movement of a fixed sequence length is repeated throughout a block of trials. Therefore, the subject knows the number of required components in advance and can preprogram the movement sequence prior to the go stimulus. In an uncued CRT task, the sequence length randomly varies across trials in a block. The subject knows which sequence length to perform only after the go signal appears. In a variation of the precued CRT, on each trial a precue provides information about the number of components in a sequence before the go stimulus. This allows subjects to preprogram the movement during the precue-go signal interval of each trial. In such tasks, the effect of sequence length on measures of movement execution such as movement time (Hulstijn and Van Galen, 1983), inter-tap-intervals (Rafal et al., 1987; Stelmach et al., 1987) and mean duration (Sternberg et al., 1978) have also been examined. Since the initial observations and experiments of Henry and Rogers (1960) and Sternberg et al. (1978) showing that the RT to initiate the first movement in a sequence increased with the complexity and the number of components in the sequence, the study of SLE using finger tapping tasks has yielded inconsistent results in relation to the linearity of the SLE (Garcia-Colera and Semjen, 1987; Rafal et al., 1987; Stelmach et al., 1987; Balfour et al., 1991; Franks and Donkelaar, 1991). This inconsistency of the SLE may reflect methodological differences across studies. The precise type of movement used (tapping with single finger or 2 or 3 fingers), the nature of the RT task (SRT, uncued or precued CRT), the length of the sequence (3 to 8
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components), and the amount of practice are some of the variables that vary across studies.
15.5.3. Go/no go RTs Go/no go tasks allow measurement of the participants' ability to discriminate between 'go' and 'no go' stimuli and to differentially initiate and execute a response on 'go' trials and inhibit or withhold responses on 'no go' trials. A two-stimulus (51-S2) paradigm is commonly used to study go/no go RTs. Variations of the SI-S2 paradigm have been employed in the literature depending on whether S1 or S2 are the informative stimulus providing go/no go information. In the most basic form of the go/no go RT task, S1 is a warning signal which is followed after a preparatory interval by S2 which indicates that a response should be initiated (e.g. green circle or 1000 Hz tone) or withheld (e.g. red circle or 2000 Hz tone) on that trial. In Donders' original formulation, the go/no go RT or type C task required the subject to make a response to only one of several stimuli. Such go/no go RTs involved preparation of a single response which was then either initiated on go and withheld on no go trials. Therefore, compared to a simple RT with an invariant stimulus across trials, in a go/go RT task the main requirement was for the subject to discriminate go from no go stimuli and then release the preprograrnmed response. More
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recently 'hybrid' choice go/no go RT tasks have been devised which also require more than one type of response to be prepared; In these hybrid tasks, go/ no go and movement parameter information (e.g. go to left or right button) are respectively provided by SI and S2 (Hackley and Miller, 1995) or both sets of information are communicated by different features of S2, and S1 simply acts as a warning signal (Osman et al., 1992). In go no RT tasks, a key factor affecting the strategies adopted by subjects and the latency of their RTs on go trials and their success in withholding responding on no go trials is the percentage of go to no go trials in a block. A higher percentage of no go trials increases action uncertainty. Conversely, a higher percentage of go trials increases the likelihood and extent of advance preparation by subjects which will in tum increase the probability of errors of commission on no go trials. RTs get faster when the percentage of go trials increase from 25% to 50% to 75% (Van der Molen et al., 1989).
15.6. Factors that influence RT Some of the most widely investigated factors that have been shown to influence RTs are listed in Table 1. These factors can be broadly divided into two classes: subject/operator-related and procedural.
Table I Some of the most widely investigated factors shown to influence RTs. Subject/operator-related factors
Age Handedness Arousal/attentional state of subject: attentional and motor 'set', alcohol, drug, sleep deprivation effects Instructions to subjects: emphasizing speed or accuracy Practice/fatigue effects Motivational influences Procedural factors Nature of stimuli, modality of presentation, discriminability, probability Nature of responses Extent of S-R compatibility Number of S-R alternatives Presence/absence and nature of advance information (warning signal, temporal cue, precue) Timing of presentation of stimuli: interval between warning signal/precue and go stimulus, duration of the responsestimulus interval, inter-stimulus interval
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Detailed consideration of the influence of these factors on RT is beyond the scope of the present chapter, and I will only briefly consider the ways in which RTs are altered by some of these factors. 15.6.1. Subject/operator-related factors
The speed of processing and reacting to external stimuli changes with age. The function relating RTs to age is U-shaped. During infancy RTs are slow but with maturation of the central nervous system and particularly the motor system, RTs become faster up to the age of about 30 and from then on gradually become slower (Wilkinson and Allison, 1989). RTs are generally faster with the dominant than the nondominant hand, and the latency of responses are effector-dependent with RTs with the hand, for example, being faster than those with the foot (Boff and Lincoln, 1988). The arousal/attentional state of the subject has a major impact on RTs which is the reason why alcohol and drugs that alter the arousaV attentional state of the individual such as benzodiazepines and barbiturates affect RTs (Maylor and Rabbitt, 1973; Borland and Nicholson, 1975). For similar reasons, factors such as sleep deprivation or fatigue also prolong RTs and reduce accuracy (Boff and Lincoln, 1988). Practice has been shown to generally improve RTs and confers a differentially greater advantage on CRTs than SRTs (Mowbray and Rhoades, 1959). Practice has been shown to interact with procedural factors such as the number of S-R alternatives or S-R compatibility, such that practice results in a greater speeding of RTs under conditions with a larger number of S-R alternatives and higher S-R incompatibility (Techner and Krebs, 1974). The motivational state of the subject plays a fundamental role, with RTs being faster when success, gain or reward is anticipated (e.g. Shankweiler, 1959). Response selection has been shown to be sensitive to reward expectancy even at the neuronal level. For example, in the monkey, in a cued saccade task, evidence from single cell recordings has shown that not only target selection behavior but also the extent of neuronal activity in the lateral intra-parietal area are determined by the expected gain and outcome probability (Platt and Glimcher, 1999). The specific instructions to subjects, whether emphasizing speed or accuracy of performance, is another factor that can influence RTs (Fitts, 1966).
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15.6.2. Procedural factors
The precise nature of the stimuli and responses and how stimuli and responses are related are key determinants of the speed and accuracy of responding (Keele, 1986). Simple, Choice and go/no go RTs are influenced by a set of common factors, for example, all variables that influence the subject's performance as well as a number of procedural variables such as stimulus discriminability. However, there are also factors that specifically prolong or speed up only SRTs, CRTs or go/no go RTs. Under optimal conditions, RTs to tactile stimuli are fastest and those to visual stimuli slowest, with reactions to auditory stimuli being intermediate (Postman and Egan, 1949). Stimuli that are difficult to discriminate or of low intensity are associated with longer RTs (Woodworth, 1938; Postman and Egan, 1949). In CRT, two factors that can influence response selection are response uncertainty (the number of SR alternatives) and S-R compatibility (Sanders, 1980). The interaction of these two factors in CRT tasks (e.g. Broadbent and Gregory, 1965) suggests that they affect a common stage of processing. A reliable finding in RT studies is that an increase in the number of S-R alternatives results in an increase in RT. This association is represented by the HickHyman law: RT=a+b log, N, where a and b are constants and N is the number of alternatives (Hick, 1952; Hyman, 1953). In the process of response selection, the subject must perform a sensory-motor transformation to retrieve the appropriate response representation from the response set based on the stimulus presented on each trial (Hasbroucq et aI., 1990). In conditions where the relationship between the stimuli and responses are not natural or highly compatible, decoding of S-R relations becomes a significant factor in response selection. The nature of the relationship between the stimuli and responses and the degree of S-R compatibility determines the amount and type of decoding necessary for response selection. RTs are faster when stimuli and responses are highly compatible (Fitts and Seeger, 1953; Fitts and Deiginger, 1954). The nature of the S-R pairing may be spatial (e.g. left stimulus indicating a left response) or symbolic (e.g. the number 12 indicating a response to the top position of a circular clock-like array of buttons). In conditions of low S-R compatibility, the S-R relationship may be based on some
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arbitrary association (e.g. red stimulus indicates left response), or on some transformational rule (e.g. a stimulus on the left indicates a right response). The S-R compatibilty effect has been discussed in terms of the strategies that subjects use in performing the S-R transformation. For S-R decoding in CRT tasks with low S-R compatibility, Hasbroucq et al. (1990) have distinguished between the subjects' use of strategies involving rule implementation (when a common concept links the stimuli and responses) and memory list scanning (when stimuli and responses cannot be represented in terms of a common concept). When independently investigated, higher S-R compatibility results in faster RTs and a greater number of S-R alternatives prolong RTs. When manipulated concurrently, S-R compatibility interacts with the number of S-R alternatives and high S-R compatibility can reduce the effect of having a larger number of S-R alternatives on RTs (Boff and Lincoln, 1988). Related to S-R compatibility, is the so-called 'Simon' effect (Simon, 1969). This is the prolongation of RTs due to a taskirrelevant feature. For example, right and left hand RTs to arrows pointing to the left or right are prolonged when the task relevant information (direction of arrow) is incongruent with the task irrelevant information such as the spatial location of arrow presentation relative to a central fixation point (e.g. left pointing arrow presented to the right of central fixation cross). The presence/absence, the precise nature of the advance information provided by preparatory stimuli (warning signal or precue) and their timing relative to the go stimulus also influence RTs. In general, RTs are faster with than without a preparatory stimulus. A preparatory stimulus can act as a warning signal and/or temporal cue and/or a movement parameter precue. A warning signal informs the subject that an imperative stimulus is about to be presented. It allows the subject to increase his/her readiness to respond. A temporal cue is a preparatory signal which allows the subject to prepare to respond at a particular time. For example, a warning signal presented at a fixed interval prior to an imperative stimulus across trials can act as a temporal cue as it will allow the subject to develop an anticipatory set or temporal expectancy for the occurrence of the imperative stimulus. A movement parameter cue provides information about the precise character-
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istics of the response, such that it allows the subject to select and prepare a specific response in advance of the imperative stimulus. The interval between the preparatory and imperative stimuli, the so-called S1S2 interval also affects RTs. RTs initially become faster with longer intervals of up to 200 ms (which is the optimal foreperiod resulting in the fastest RTs) and then gradually level out and then become slower with S1-S2 intervals in the 4-8 s range (Posner et al., 1973; Posner and Snyder, 1975; Van der Molen et al., 1989). Thus RTs have a U-shaped relation to the duration of the warning signal interval in the 0 (unwarned) to 800 ms range. In contrast, the function relating percent of errors to the warning signal interval has an inverted U shape, with the highest percent of errors observed for foreperiods of 100 ms (Ponser et al., 1973). RTs are prolonged when intervals between the response and presentation of the next stimulus are short and become faster when the R-S intervals are increased from 20 to 200 ms (Rabbitt, 1980). Another timing-related factor of importance is the inter-stimulus interval. The socalled 'psychological refractory period' refers to the finding that if the interval between two stimuli both of which require responses is shorter than the time required to produce a response to the first stimulus, the RT to the second stimulus is delayed (Boff and Lincoln, 1988). The probability/frequency of presentation of a stimulus across trials also determines the latency of responses to it. RTs are faster to more frequent stimuli (Fitts et al., 1963; Hawkins and Underhill, 1971). Evidence suggests that it takes less time to perceive a highly probable stimulus than a less probable stimulus (Miller and Pachella, 1973). So faster perceptual processing times could partly explain the faster RTs with higher probability stimuli. For disjunctive RTs, the percentage of go and no go stimuli are altered across blocks in some studies, for example, from 75, to 50 to 25%. RTs to the go stimuli are faster in blocks with higher go to no go probabilities (Low and Miller, 1999). In these circumstances, it is also possible that the changes in go probability alters the usefulness of motor preparation across trials (Low and Miller, 1999). Related to such probability effects is the 'repetition effect' . This refers to the finding that RTs are faster on trials when the same stimulus is repeated as on the preceding trial (Berthelson, 1961).
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15.7. Functional anatomy of RT tasks A hierarchical model of action representation has been proposed by Requin (1992), with each level of the hierarchy considered to be associated with activity in specific brain areas. At the most abstract level, are 'action goals', non-motoric and symbolic representations of what the goal is. It is suggested that the representation of action goals is mediated by the frontal and parietal association cortices. At the next level, are motor programs which are also nonmotoric representations involved in setting the best parameters for movement based on past experience and current environmental constraints and associated with activity in the lateral and medial premotor cortices. Finally, there are the basic motor units involved in production of the motor output, namely the primary motor cortex and cortico-spinal pathways. Animal studies, investigations of patients with focal brain lesions, functional imaging, and studies using transcranial magnetic stimulation (TMS) have provided evidence for the involvement of these brain regions in the preparation, initiation and execution of movements. Animal studies have established that motor preparatory signals can be recorded from the motor, lateral and medial premotor, posterior parietal, and prefrontal cortices as well as from the striatum and cerebellum (Fuster and Alexander, 1971; Evarts and Tanji, 1974; Tanji et al., 1980; Alexander, 1987; Crarnmond and Kalaska, 1989; Muschiake and Strick, 1995; Wise et al., 1997). In one of the first studies of this kind, Evarts and Tanji (1974) used a delayed CRT task, in which monkeys were trained to pull a handle when a red light was presented and to push the handle when a green light was presented. Neuronal activity in the motor cortex started with presentation of the stimulus and continued until movement execution. It has been unclear whether delay related neuronal activity in the prefrontal cortex reflects motor preparation or the role of this area in working memory. There is now evidence from animal lesion (Quintana and Fuster, 1993) and imaging (D'Espositio et al., 2000) studies that the prefrontal cortex is involved in both delayed response tasks that involve working memory or motor preparation. Patients with unilateral lesions of the prefrontal cortex (Alivisatos and Milner, 1989) or the medial frontal lobe including the SMA (Verfaellie and
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Heilman, 1987) do not benefit from advance movement parameter information provided by precues, suggesting a failure of motor preparation. Functional imaging with PET or fMRI has confirmed the role played by the prefrontal, premotor and parietal cortices in response selection and preparation. Compared to rest, a SRT involving performance of a simple movement (right index finger extension) on presentation of a tone with irregular inter-stimulus intervals of 2-7 s across trials, significantly activated the sensorimotor cortex, caudal SMA, parietal area 40, insular cortex and the putamen (Jenkins et al., 2000). The same movement, when performed with regular inter-stimulus intervals, which allows stimulus anticipation and motor preparation, also activated the lateral premotor cortex, the rostral SMA and the anterior cingulate (Jahanshahi et al., 1995), suggesting that the activation of these additional areas related to the motor preparation possible with regular but not irregularly timed SRTs. Naito et al. (2000) also found that relative to a rest condition, visual, auditory and somatosensory SRTs were associated with activation of the sensorimotor cortex, dorsal premotor cortex, SMA and anterior cingulate, and that there were no modality-specific activations in motor areas. They also found that greater activation in the anterior cingulate was associated with faster RTs. The lack of differential effects of stimulus modality on activation of motor areas has been confirmed by some (Weeks et al., 2001) but not others (Sugiura et al., 2001). Nevertheless, all three studies (Naito et al., 2000; Suguira et al., 2001; Weeks et al., 2001) underline the activation of sensorimotor, dorsal and medial premotor areas with RT tasks. When response selection is required, the prefrontal cortex is also activated. For example, compared to a 'fixed' control condition, during which subjects moved a joystick in a predetermined direction, performance of joystick movements in one of four possible directions which necessitates response selection on each trial was found to significantly activate the dorsolateral prefrontal cortex (BA 46, 9), premotor cortex, SMA and the superior parietal cortex (Deiber et al., 1991). CRTs require response selection on every trial which is not the case in SRT, where a pre-selected response is initiated on presentation of the stimulus. Comparison of CRTs and SRTs has also revealed greater activation of the inferior and middle frontal areas, dorsal premotor cortex and intraparietal sulcus
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associated with response selection (Shulter et al., 2001). Use of precued RT tasks providing full or partial information about movement parameters or the time of presentation of the imperative stimulus with PET have been found to be associated with greater activation of the left parietal cortex compared to CRTs providing no advance information (Deiber et al., 1991; Coull and Nobre, 1998), thus indicating the importance of this area in motor preparation. This has been confirmed in an event-related fMRI study (Toni et al., 1999) which revealed that with a precued CRT task sustained activity during the precue-imperative stimulus was observed in the dorsal premotor cortex and the posterior parietal cortex. Compared to control conditions, RT tasks with low S-R compatibility are associated with greater activation of the superior parietal cortices (Deiber et al., 1991; Iacoboni et al., 1996) and the dorsolateral prefrontal cortex (BA 46,9) (Deiber et al., 1991). The Simon effect on RTs is also associated with greater activation of the parietal cortices relative to the Stroop interference task (Petersen et al., 2002). Functional imaging has been useful in identifying the brain regions activated during performance of a variety of RT tasks. However, from these data it is difficult to establish the areas that are essential for preparation, initiation or execution of a response. Such information which previously was only available from studies of patients with focal brain lesions or animal lesion studies, can now be also obtained by using TMS to create a temporary 'virtua11esion' in specific areas under the coil and examine whether or not and at what point performance is disrupted. In an SRT task, magnetic stimulation of the motor cortex in the interval between the onset of the imperative stimulus and execution of the response, was shown to delay the motor response for up to 150 ms (Day et al., 1989). The pattern of agonist/antagonist EMG activation was unaffected, which was interpreted as indicating that the motor program for the movement was held unaltered in a motor buffer and was released after the inhibitory process had subsided. In a precued RT task, Hasbroucq et al. (1997) used TMS to demonstrate that corticospinal excitability was reduced prior to and then increased following presentation of the response signal. Using TMS with go/no go RTs, it has also been demonstrated that while MEPs in the agonist muscle increased 100-200 after the go signal they decreased after the
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no go signal; respectively reflecting the activation and inhibition of the corticocospina1 pathway (Hoshiyama et al., 1996, 1997; Leocani et al., 2000). Shulter et al. (1999) delivered TMS over three sites at different times after the presentation of the visual cue. They found that TMS over the anterior premotor cortex slowed movements when applied 140 ms after the visual signal; whereas TMS over the posterior motor cortex slowed movements when applied 180 ms after the cue; and movements were delayed with TMS over the sensorimotor cortex when this was delivered 220 ms after the cue. The results were considered to reflect the change of activity from signal to movement-related processing from the premotor to motor cortex. Shulter et al. (1999) also used a precued RT task with the precue and the 'go' signal respectively informing subjects which movement to make and when to initiate it. TMS over the anterior premotor cortex or the sensorimotor cortex during the interval between the precue and the 'go' signals both slowed the movement, indicating the involvement of both areas in motor 'set'. Using repetitive TMS, Praamstra et al. (1999) found that stimulation over the premotor cortex increased interference effects due to the Simon effect. Evidence for the role of the dorsolateral prefrontal cortex in response selection as distinct from working memory was provided by Hadland et al. (2001) who showed that repetitive TMS disrupted performance in a task requiring response selection but without any working memory demands. Several lines of evidence suggest that performance of go/no go RTs depends on the integrity of the prefrontal cortex. A female patient with a meningioma in the medial aspects of the prefrontal cortex bilaterally had impaired go/no go RTs, with a large number of errors of commission on go trials. Following surgical excision of the tumor, the go/no go performance of the patient became normal (Leimkuhler and Mesulam, 1985). In a group study of patients with frontal or posterior regions, Godefroy et ai. (1996) found that responses to irrelevant stimuli on bimodal go/no go RT tasks were more frequent with lesions of the dorsolateral prefrontal cortex and the caudate nucleus. In a study by Ikeda et al. (1996), field potentials associated with a warned choice go/no go RT task were recorded from subdural electrodes over the prefrontal, SMA and primary motor cortex in 5 patients with epilepsy. Both go and no go trials elicited a slowly rising
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potential between SI and S2, with part of the potential at least corresponding to the late CNV. This was seen not only at electrodes over the SMA, but also over orbitofrontal and mesial prefrontal areas. This potential was considered to be related to decision making upon S2 in both go and no go conditions. There is now also mounting evidence from imaging studies (e.g. Humberstone et aI., 1997; Konisihi et aI., 1999, Rubia et aI., 2000) for the involvement of various prefrontal areas in go/no go RTs. For example, using fMRI, Humberstone et al. (1997) reported that the SMA proper was activated only on the go trials associated with motor execution, while the pre-SMA was activated in both go and the go go trials, representing the process of decision making about whether to initiate or inhibit a response. 15.8. Parallel vs. serial information processing
While the above section has been concerned with where in the brain the processing required for performance of RT tasks takes place, there is also the issue of the time course of information processing that precedes the production of a response to a stimulus. In much of the foregoing account and in Fig. 1, a discrete serial or stage model of RTs has been adopted. According to such a model, the stages of processing intervening between presentation of a stimulus and production of an appropriate response occur one after another in a serial fashion. In the "classical" versions of stage models (Donders, 1969; Sternberg, 1969), processing in anyone stage does not begin until processing in preceding stage has been completed. In contrast, alternative conceptualizations of RT, the so-called "parallel" processing models, for example, the "continuous flow model" (Grice et aI., 1977, 1982; Eriksen and Schultz, 1979; McClelland, 1979), maintains that the processes necessary for production of an appropriate response can be activated with presentation of the stimulus and operate simultaneously and in parallel rather than sequentially. A third type of model, the "asynchronous discrete" model of Miller (1982), combines features of the discrete serial and parallel models. It suggests that transfer occurs between the processing elements only when an element has completely processed a "grain" of information. While information represented by a single grain is transferred discretely, various processing elements
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can work in parallel when more than one grain of information is involved. A number of studies have addressed the question of whether processes that intervene between presentation of a stimulus and production of a response occur in series or in parallel. Recording of eventrelated potentials, particularly the lateralized readiness potential (Coles et aI., 1986; Smid et aI., 1987) has proven of value in investigation of the 'serial vs. parallel' processing issue, since it has supplied an index of covert processing to supplement the measure of overt responses provided by RTs. Two paradigms have been commonly used, the conflict paradigm or a modified 'hybrid' go/no go RT task. In the conflict paradigm, the subject has to respond with either the left or right hand to target stimuli presented in the center of a VDU. On compatible trials, the target stimulus is flanked by stimuli indicating the same response as the target, for example, a central arrow pointing to the right, flanked by other arrows also pointing to the right. In contrast, on incompatible trials, the target and flanking stimuli indicate different responses, for example, a central arrow pointing to the right, flanked by arrows pointing to the left. The critical issue in relation to the 'serial vs. parallel' processing question is what happens on the incompatible trials when the target and flanking stimuli provide conflicting information. If partial information transmission occurs, then information about the incompatible flankers may also reach the response system and result in preparation of the incorrect response in parallel with preparation of the correct response. In the hybrid go/no go RT task, one feature of the stimulus provides information about hand selection while another feature indicates whether to initiate or withhold a response on that trial. In this task, the critical result is what happens on the no go trials, and presence of an initial LRP on no go trials would provide evidence in favor of partial transmission of information. Recording of the LRP has shown that the incorrect response is in fact covertly prepared on incompatible trials in the conflict paradigm (Gratton et al., 1988; Smid et aI., 1991) and that partial information about the responding hand does result in preparation of a response on no go as well as go trials (Miller and Hackley, 1992; Osman et aI., 1992; Smid et aI., 1992). This evidence favors partial transmission of information as suggested by the continuous flow (Grice et al., 1977, 1982; Eriksen
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and Schultz, 1979; McClelland, 1979) and asynchronous discrete (Miller, 1982) models rather than the serial models (Donders, 1969; Sternberg, 1969) of RT. 15.9. RT and MT in movement disorders In the study of movement disorders, the measurement of RTs and MTs to quantify the deficits in movement initiation and execution has a long history. In Parkinson's disease, the first "formal" study of RT was by Wilson (1925), who obtained an average RT of 360 ms for patients compared to the mean RT of 240 ms for normal controls. A report in 1959 by King provided no quantitative data but made a number of observations on the RT of four patients with Parkinson's disease compared to sexand age-matched normal controls. The first quantitative SRT and CRT data in Parkinson's disease were provided by Talland (1963) who assessed SRT and CRT in 25 patients and 25 age- and sex-matched normals. The eight most severely affected patients were noted to be significantly slower under all conditions than the controls and the rest of the patient sample. The more recent work on RTs in Parkinson's disease and other movement disorders has been partly driven by attempts to test the hypothesis that the basal ganglia are normally responsible for "the automatic execution of learned motor plans" (Marsden, 1982), a corollary of which is the proposal that motor symptoms such as bradykinesia and akinesia are problems with programming of movements. Below, a brief overview of the RT literature in movement disorders will be provided, starting with Parkinson's disease which has been most extensively studied with RT paradigms. 15.9.1. RT in Parkinson's disease
Several approaches have been used to study motor programming with RT paradigms in Parkinson's disease. As SRT provides the possibility for preprogramming of motor responses, the first approach has been through a comparison of SRT in patients with Parkinson's disease and normals. The second approach has involved a comparison of SRT and CRT in patients with Parkinson's disease relative to normals. A selective impairment of SRT and normality of CRT in Parkinson's disease has been considered to indicate deficits in preprogramming of
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movements. The third approach has examined whether advance information about the required response can be used by patients with Parkinson's disease to preprogram movements and hence speed up their RT. The fourth approach has investigated the sequence length effect in Parkinson's disease to determine whether the time to initiate the first response in a sequence increases linearly as a function of the length of the sequence or not. As a result, there is now a sizeable literature on RTs in Parkinson's disease. For each of these four RT approaches to study motor programming in Parkinson's disease, the results of the existing studies are inconsistent. With regard to the first approach, while most studies have found slower SRTs in Parkinson's disease relative to normals (e.g. Bloxham et al., 1984; Sheridan et aI., 1987; Pullman et aI., 1988; Goodrich et aI., 1989; Daum and Quinn, 1991; Jahanshahi et aI., 1992a; Brown et al., 1993; Harrison et aI., 1995; Kutukcu et aI., 1999; Henderson et al, 2001), some have not found such a deficit (Talland, 1963; Wiesendanger et aI., 1969; Girotti et aI., 1986; Heitanen and Teravainen, 1986; Kerr et aI., 1988). Nevertheless, of all the findings relating to RTs in Parkinson's disease, the most consistent is a deficit in SRT (Jahanshahi et al., 1992a; Gauntlett-Gilbert and Brown, 1998). However, in SRT preprogramming of the response before onset of the stimulus is optional. Therefore, in isolation the results of these studies do not allow an unequivocal attribution of the prolongation of SRT in Parkinson's disease to deficits in motor programming, which could be due to slowness of the other two stages of processing that precede execution of the response (Fig. la), i.e. stimulus registration or response initiation. In fact, Klapp (1977) recommended that "research on response programming should be based on choice rather than simple reaction time and, furthermore, that effects appearing in simple reaction time may not necessarily be given a programming interpretation." In relation to the second approach comparing SRT and CRT in Parkinson's disease and normals, a selective slowing of SRT in patients relative to normals has only been found in some (Evarts et aI., 1981; Bloxham et aI., 1984; Sheridan et al., 1987; Pullman et al., 1988; Goodrich et aI., 1989; Henderson et aI., 2001) but not other studies (Talland, 1963; Wiesendangeret al., 1969; Girotti et aI., 1986; Heitanen and Teravainen, 1986; Stelmach et aI.,
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General slowing
SRT
No slowing
CRT
CRT
Selective slowing of SRT
Selective slowing of CRT
SRT
SRT
CRT
SRT
CRT
Fig. 2. The four patterns of SRT vs. CRT found in Parkinson's disease (filled symbols) relative to normal controls (white symbols) in the literature.
1986; Mayeux et al., 1987; Lichter et al., 1988; Reid et al., 1989; Pullman et al., 1990; Jahanshahi et aI., 1992a; Brown et al., 1993; Kutukcu et al., 1999). In fact, as discussed elsewhere (Jahanshahi et al., 1993b), when comparing Parkinson's disease patients and controls, the literature suggests that the relationship between SRT and CRT can be described by one of 4 possible patterns. These 4 patterns are shown in Fig. 2a-d. These patterns which can be respectively labeled "no deficit" (Talland 1963; Wiesendanger et al., 1969; Girotti et aI., 1986; Heitanen and Teravainen, 1986; Kerr et aI., 1988), "general slowing" (Stelmach et aI., 1986; Mayeux et aI., 1987; Dubois et aI., 1988; Rafal et aI., 1989; Yanagisawa et aI., 1989; Pullman et al 1990; Daum and Quinn, 1991; Jahanshahi et aI., 1992a), "selective slowing of SRT" (Evarts et aI., 1981; Bloxham et al., 1984; Sheridan et aI., 1987; Pullman et aI.,
1988; Goodrich et al., 1989) and "selective slowing of CRT" (Wiesendanger et al., 1969; Lichter et aI., 1988; Reid et al., 1989; Brown, Jahanshahi and Marsden; 1993; Kutukcu et aI., 1999) are each supported by evidence from a number of studies. The third approach has examined whether advance information about the required response provided by a precue can be used by patients with Parkinson's disease to preprogram movements and hence speed up their RTs. The studies which have used this approach have shown that the use of advance movement parameter or temporal information provided by precues is qualitatively normal in Parkinson's disease (e.g. Stelmach et al., 1986; Jahanshahi et aI., 1992a; Labutta et aI., 1994), but that patients only take full advantage of such advance information with longer intervals between precues and go stimuli (Jahanshahi et al., 1992a).
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From a quantitative meta-analysis of the results of the studies which have examined use of advance information in Parkinson's disease, Gauntlett-Gilbert and Brown (1998) concluded that there is no evidence of motor programming deficits from these results. The fourth approach based on the sequence length effect has produced inconsistent results with some evidence suggesting deficits in motor programming in Parkinson's disease (e.g. Harrington et aI., 1991) and others finding no such deficits (e.g. Rafal et al., 1987; Stelmach et aI., 1987). From the existing evidence, the most parsimonious conclusion is that patients with Parkinson's disease have a deficit in response initiation, which is a stage of processing common to both SRT and CRT (J ahanshahi et al., 1992a). Regardless of the approach that has been used to study RTs in Parkinson's disease, it is clear that the literature is inconsistent about the existence and the nature of deficits in RTs in this disorder. One possible reason for this inconsistency may be the heterogeneous nature of Parkinson's disease, whereby the presentation may vary from a pure motor disorder to one accompanied by depression, cognitive (frontal) dysfunction or even dementia. Berry et al. (1999) examined the influence of 'frontal lobe impairment' as one factor that could influence presence or absence of motor slowness in Parkinson's disease. They divided their sample into two groups: those who were impaired on a test of frontal lobe function, the Wisconsin Card Sorting test, and those who were not. Only the 'frontally impaired' subgroup had significantly slower RTs on visual search tasks than controls and the 'non-frontal' subgroup had RTs that were similar to those of normals. This suggests that RT deficits may only be present for those patients with Parkinson's disease, for whom the pathophysiology affects the frontal lobes. This issue of heterogeneity is clearly worth further investigation with regards to other features of the disorder. 15.9.2. MT in Parkinson's disease
In addition to slowness in initiating movements, patients with Parkinson's disease have problems in execution of movement. This problem is evident for execution of all forms of movement from simple ballistic movements aimed at targets, to simultaneous or sequential and continuous movements (Brown and Jahanshahi, 1996).
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Performance of fast ballistic movements aimed at a target depend on a characteristic pattern of preprogrammed agonist/antagonist EMG activity. In patients with Parkinson's disease the size of the first agonist burst is reduced (Hallett et al., 1977; Hallett and Khoshbin, 1980), and although patients can modulate the size of the first agonist burst as a function of amplitude of movement (Berardelli et aI., 1986); movements are hypometric, requiring additional bursts of agonist activity to reach the target. Besides the step-wise manner in which targets are achieved during aimed ballistic movements, patients with Parkinson's disease are shown to be dependent on visual feedback to a greater extent than normals during performance of fast movements (Cooke et al., 1977). Execution of pointing movements by patients with Parkinson's disease are particularly slow and hypometric when performed without vision of the moving hand (Klockgether and Dichgans, 1994). In fact, patients are described as executing ballistic movements in a 'closed loop' fashion, requiring online feedback control, instead of in an 'open-loop', fast and pre-programmed way (Flowers, 1976). For aimed movements, movement time is a function of difficulty defined by factors such as target size or distance (Fitts, 1954). With distance kept constant, when the target width is reduced, even normal subjects have to slow down their movements or rely on visual guidance to ensure end-point accuracy, otherwise they will make more errors. In two experiments where participants were required to make rapid or slow movements to targets at different distances or widths, Sheridan et al. (1987, 1990), found that like normals, patients with Parkinson's disease can produce fast ballistic movements but these had disproportionately lower end-point accuracy than in normals. In real-life situations, for example, when reaching for a cup of tea, underreaching has less drastic consequences than over-reaching. While the latter may result in spilling the contents of the cup, under-reaching could be corrected by one or more additional movements. Thus, in Parkinson's disease, the fact that movements are hypometric and dependent on visual feedback may represent a strategic adaptation to a 'noisy' motor control system which has a basic deficit in force generation (Sheridan et aI., 1987; Brown and Jahanshahi, 1996). More complex movements requiring bimanual coordination and simultaneous and sequential move-
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ments are also impaired in Parkinson's disease. Early studies showed that simultaneous performance of movements such as pressing a tally counter and picking up beads with a tweezer (Talland and Schwab, 1964) are impaired in Parkinson's disease. Relative to controls, patients with Parkinson's disease show greater decline in bimanual index finger tapping, bimanual peg insertion and simultaneous tapping with one hand and peg insertion with the other hand compared to when performing these tasks unimanually (Brown et al., 1993). In the study of Benecke et al. (1986), two movements, a rapid forearm flexion and a 30N isometric contraction of the hand were performed either alone or simultaneously. When executed alone, patients with Parkinson's disease were slow in performing each movement relative to controls. When the two movements were performed simultaneously, the patients were even more dramatically slower than normals. Similar problems with performance of simultaneous eye and hand movements (Warabi et al., 1988) or reach and grasp movements (Castiello et al., 1993) have been reported in Parkinson's disease. The patients' problems with simultaneous movements are less pronounced if the tasks performed with the two hands are discrete and involve a common timing element (Stelmach and Worringham, 1988). In another study, Benecke et al. (1987) required subjects to perform a set of movements sequentially. Patients with Parkinson's disease showed an increased inter-onset-latency between sequential movements. Marked hesitations between movement segments in Parkinson's disease relative to controls has also been documented by others (e.g. Agostino et al., 1992). In Parkinson's disease, reduction of visual guidance impairs performance of sequential movements further (Georgiou et al., 1993). These problems with sequential movements have been interpreted as reflecting difficulty in rapid switching between motor programs, particularly when this has to be internally driven rather than externally triggered. The ability to make continuous and predictive movements required for accurately tracking a moving target have also been investigated in Parkinson's disease. The results are inconsistent, with some studies suggesting that patients with Parkinson's disease show impaired learning of manual pursuit tracking (e.g. Frith et al., 1986) and others finding no such deficits in non-demented and medicated
M. JAHANSHAHI
patients (e.g. Bloxham et al., 1984; Soliveri et al., 1997). Such predictive movements require development of an 'internal representation' incorporating the spatial and temporal characteristics of the moving target. Day et al. (1984) found that when subjects were explicitly told that the target track was repetitive, patients with Parkinson's disease similar to the controls showed predictive tracking and were able to reduce their phase lag. Nevertheless, patients are more dependent on visual feedback, and tracking which is quite normal with visual feedback, deteriorates when visual feedback is not available (Cooke et al., 1978; Flowers, 1978).
15.9.3. Effect of Levodopa on RT and MT in Parkinson's disease In idiopathic Parkinson's disease, the motor symptoms improve with levodopa. This clinical benefit of levodopa would lead one to expect that RTs and MTs would also be significantly faster following such medication. This is not borne out by the evidence which has shown that levodopa medication does not consistently improve RTs or MTs across studies. Several methodological approaches have been used to study the effect of medication on RTs and MTs in PD (Gauntlett-Gilbert and Brown, 1998), including: (i) assessing de novo patients before and after starting therapy or comparing de novo and medicated patients (e.g. Velasco and Velasco, 1973; Jordan et al., 1992; Van Hilten et al., 1998); (ii) examining the effect of withdrawal of medication on performance (e.g. Bloxham et al., 1987; Starkstein et al., 1989; Jahanshahi et al., 1992b; Zappia et al., 1994); (iii) investigating the effect of spontaneous on-off fluctuations of motor symptoms on RT and MT (e.g. Rafal et al., 1984; Girotti et al., 1986); and (iv) measuring the effects of intravenous injections of levodopa (Pullman et al., 1988, 1990; Van Hilten et al., 1997). Regardless of the approach used, the majority of studies have shown that while patients with Parkinson's disease have faster RTs and MTs on compared to off medication, the benefits of levodopa on RT are often small and non-significant (Velasco and Velasco, 1973; Heilman et al., 1976; Girotti et al., 1986; Bloxham et al., 1987; Pullman et al., 1990; Jahanshahi et al., 1992b; Jordan et al., 1992; Starkstein et al., 1992; Van Hilten et al., 1997, 1998). Other studies have found SRT (Trevainen and Calne,
REACTION TIME AS AN INDEX OF MOTOR PREPARATIONIPROGRAMMING
1980; Rafal et aI., 1984; Viallet et aI., 1987; Montgomery and Nuessen, 1990; Harrison et aI., 1995) or CRT (Pullman et aI., 1988; Brown et al., 1993; Zappia et aI., 1994; Harrison et aI., 1995) to be significantly faster following levodopa medication. This inconsistent effect of levodopa on RT is also mirrored in the association of RT with ratings of severity of various symptoms. While some studies (e.g. Yanagisawa et aI., 1989) have found positive associations between RT and ratings of bradykinesia and rigidity, others (e.g. Dubois et aI., 1988) have found no such associations or have found RT to be more closely related to rigidity and tremor than to bradykinesia (e.g. Lichter et aI., 1988). Some investigators (Zappia et aI., 1994) have proposed that MT is of greater value in the assessment of Parkinson's disease than RT, since levodopa has a greater effect on MT which is also more strongly related to the severity of symptoms, particularly bradykinesia than RT. Similar suggestions have been made in favor of tapping rate, due to its greater responsiveness to dopaminergic manipulation than MT or RT (Van Hilten et aI., 1997). However, as noted by Harrison et aI. (1995) RT should not be considered as a laboratory test for akinesia or bradykinesia, but rather as a task involving a specific set of cognitive and motor processes. A number of explanations have been proposed for the inconsistent effect of levodopa on RT. First, it is possible that in Parkinson's disease RT deficits result from deficiency of a neurotransmitter other than dopamine. In fact, CSF levels of a noradrenaline metabolite significantly correlate with SRT and CRT in Parkinson's disease (Stem et al., 1984). Second, Jahanshahi et al. (1992b) suggested that it is possible that some form of threshold effect is operational such that the clinical symptoms of Parkinson's disease, RT and MT deficits appear at different levels of dopamine depletion, with clinical symptoms appearing first, followed by slowing of MT and then RT slowing. This proposal that the effects of levodopa may be threshold related, with differentially greater effects with increasing complexity of movement, is supported by the results of studies showing greater improvement of complex than simple movements with levodopa (e.g. Benecke et aI., 1987). Third, as discussed in more detail below and elsewhere (Jahanshahi et aI., 1993a, b), it is possible that RT slowness is a non-specific feature of brain damage and impaired not only in Parkinson's disease but also
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other disorders involving striato-frontal dysfunction as well as other forms of neurological illness. 15.9.4. RT and MT in other movement disorders
Although less extensively studied, RT and MT have also been assessed in other movement disorders such as Huntington's disease, dystonia and other parkinsonian syndromes such as progressive Supranuclear Palsy (PSP), Multiple System Atrophy (MSA) and Cortico-basal degeneration (CBD). Slowness of RT and MT has been documented in patients with Huntington's disease. Girotti et al. (1988) found that the CRTs of 20 non-demented patients with Huntington's disease were significantly longer than those of 44 hospital controls and 67 patients with Parkinson's disease. Halsband et aI. (1990) compared the performance of 14 patients with Huntington's disease, nine Parkinson's disease sufferers and 20 normal controls on two tasks. On the first task requiring precise aiming movements, the patients with Huntington's and Parkinson's disease showed similar increases in MT as a function of task difficulty relative to normals. On the second writing task, the patients with Huntington's disease showed disproportionate increases in writing time when letter size was increased. Viallet et aI. (1987b) reported that the SRTs of six patients with PSP were significantly longer than those of 13 Parkinson's disease patients. Similarly, in the study of Dubois et aI. (1988) 10 patients with PSP had significantly longer RTs on a SRT and three go-no go CRT tasks compared to 33 patients with Parkinson's disease and 20 normal controls. In addition, they found that while 'decision time' (RT difference between go/no go CRT and SRT) and 'analysis time' (RT difference between two go/no go CRTs with increased complexity of stimulus discrimination) were significantly longer for patients with PSP than controls, these measures did not differ significantly for the Parkinson's disease patients and controls. More recently, Pirtosek et aI. (2001) compared RTs and cognitive event-related potentials in patients with Parkinson's disease without dementia, PSP, MSA and CBD and matched groups of younger and older controls. Only the patients with PSP and CBD showed ERP abnormalities in the auditory oddball P300 paradigm. In the auditory and visual selective attention tasks, all patient groups showed ERP abnormalities to varying degrees, with
220 the changes in PSP being most prevalent and those in Parkinson's disease and MSA being minimal. The patients with CBD had the longest RTs which were significantly different from those of controls and patients with Parkinson's disease in all tasks. The patients with PSP had also significantly longer RTs than controls across all tasks. The RTs of the patients with MSA were longer than those with Parkinson's disease, and significantly so in the auditory selective attention task. Inzelberg et aI. (1995) found no differences in RTs between dystonia patients and normals and concluded that motor preparation is normal in this disorder. The latter conclusion was supported by the results of Jahanshahi et aI. (2001) who examined SRT, uncued and precued CRTs in 12 patients with dystonia and 12 age-matched controls and suggested that while response initiation and execution are significantly slower in patients with dystonia than normals, movement preparation is not quantitatively or qualitatively different. Curra et aI. (2000) used kinematic analysis and compared self-initiated and externally-triggered sequences of arm movements in patients with generalized or focal dystonia relative to age-matched controls. From the results it was concluded that "patients with dystonia have a general impairment of sequential movements" and that dystonia impairs internal cueing more than external cueing of movements. In summary, there is evidence that deficits in RT are present in other forms of striatal pathology and not just in Parkinson's disease and that the slowing of RT may be even more prominent in other movement disorders than in idiopathic Parkinson's disease. Most of the existing literature has addressed the question of "normality" of RTs in Parkinson's disease, by comparing the performance of the patients with that of matched normals on various RT tasks. With regard to interpreting the significance of the RT deficits found in Parkinson's disease, a major issue is whether such impairments are "specific" to patients with this disorder. 15.10. RT as a measure sensitive to brain injury/ insult The first aspect of the "specificity" question is whether RT deficits are specific to Parkinson's disease or are also present in other disorders involving striatal pathology. Given that a role in
M. JAHANSHAHI
motor preparation has been attributed to the lateral cerebellum (Allen and Tasakuhara, 1978) and the SMA (Evarts and Wise, 1984) as well as the basal ganglia (Marsden, 1982), the second aspect of the "specificity" question is whether the impairment of RT is specific to disorders of the basal ganglia or is also a feature of other movement disorders involving damage to the cerebellum or SMA. Finally, given that RTs measure a host of cognitive and motor processes that precede the production of a response to a stimulus, it is also possible that brain injury of any form affects RTs. Relatively few comparative studies of RTIMT in Parkinson's disease relative to other disorders involving striatal pathology such as Huntington's disease (Girotti et al., 1988; Halsband et al., 1990; Jahanshahi et al., 1993a) or Progressive Supranuclear Palsy (PSP) (Viallet et al., 1987b; Dubois et al., 1988) or extra-striate pathology (e.g. cerebellar disease; Nakamura and Taniguchi; 1980; Jahanshahi et al., 1993a) have been carried out. In one such comparative study, Nakamura and Taniguchi (1980) studied premotor SRT following a warning signal in 13 patients with Parkinson's disease, 10 with cerebellar degeneration and 14 controls. The RTs of the patients with Parkinson's disease were not different from those of controls. The patients with cerebellar disease, however, had RTs which were significantly slower than those of the Parkinson's disease sufferers and the controls. Verfaellie and Heilman (1987) examined preprogramming of motor responses in two patients with unilateral lesions of the medial frontal lobe. The patient with a left-sided lesion used the advance information about the required response to speed up RT, whereas the case with a right-sided lesion did not. On the basis of the results a role in motor preparation was attributed to the medial frontal lobe which includes the SMA, and it was further suggested that the right hemisphere may have a dominant role in mediating these processes. In another comparative study, Jahanshahi et aI. (1993a), the SRT and CRTs of eight patients with Parkinson's disease tested after withdrawal of dopaminergic medication, eight non-demented patients with Huntington's disease and nine patients with cerebellar disease were compared. The SRTs of the patients with Huntington's disease were slower than those of the other two groups, and the patients with cerebellar disease had the slowest CRTs. However, none of the group differences were
REACTION TIME AS AN INDEX OF MOTOR PREPARATIONIPROGRAMMING
significant. The CRTs of all patients were speeded up by presentation of a warning signal prior to the imperative stimulus. In a precued CRT task, advance movement parameter information was used to speed up RTs relative to an uncued condition by patients in all three groups. Thus, behavioral slowness as indexed by RT was observed in all three patient groups and there were no major differences between the groups with regard to the beneficial effects of a warning signal or in terms of the use of advance information. Montgomery et aI. (2000) compared the RTs of patients with Parkinson's disease or essential tremor. Both groups of patients had longer RTs and slower movement velocities than the normal controls. From the results of these studies, it is evident that RT deficits are not limited to patients with Parkinson's disease, as they are present in patients with other disorders involving the basal ganglia such as those with Huntington's disease, dystonia, PSP or MSA as well as in patients with movement disorders in which the basal ganglia are spared such as those with cerebellar disease or SMA lesions. Furthermore, from the available evidence it appears that prolongation of SRT and/or CRT is a feature of other neurological illnesses. Significant prolongation of SRT and/or CRT relative to normals has been reported for patients with epilepsy (Bruhn and Parsons, 1977), head injury (Miller, 1976; Van Zomeron and Deelman, 1978; MacFlynn et aI., 1984) or Alzheimer's disease (Ferris et aI., 1976; Pirozzolo et aI., 1981; Gordon and Carson, 1990). The impairment of RT with brain damage of any type was illustrated by the results of Elsass and Hartelius (1985) who found that 485 patients with various forms of cerebral dysfunction had prolonged RTs compared to 60 hospitalized controls and that the RT deficit was not influenced by etiology or chronicity of the disorder, although RTs were more impaired by progressive than non-progressive disease. As noted by Milner (1986) it appears that brain damage of any kind results in slower reactions, which is also observed in psychiatric disorders such as depression and schizophrenia (King, 1954; Fuller and Jahanshahi, 1999), as well as in normal ageing (Hicks and Birren, 1970). What would be of value would be the demonstration that specific types of RT such as SRT or CRT are selectively impaired or that the various stages of processing in these tasks are differentially or selec-
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tively affected by different types of brain damage (Milner, 1986). The demonstration of such differential effects has been attempted in some investigations (e.g. Ferris et aI., 1976; Miller, 1976; Van Zomeren and Deelman, 1978; Pirozzolo et al., 1981). The general picture that emerges from this evidence is that RT is a measure sensitive to injury! insult to various cortical and subcortical regions of the brain, which has been particularly of value in quantifying the motor deficits of patients with movement disorders.
15.11. Conclusions Regardless of whether a serial or parallel model of information processing is adopted, RT paradigms provide behavioral data which reflect the total time taken for the various processes which intervene between presentation of a stimulus and execution of a response. On the basis of such RT data it is not possible to differentiate the time taken up by each of the processes intervening between the stimulus and response, such as those depicted in Figure 1. In fact, in 1938, Woodworth stated that "Since we cannot break up the reaction time into successive acts and obtain the time of each act, of what use is the reaction time?" (p. 83). Nevertheless, the major advantage of RTs is that they are non-invasive techniques for measuring the speed of processing. As noted by Jahanshahi et aI. (1993b), examination of the processes involved in the preparation and execution of movement can be greatly enhanced through the use of other techniques to supplement RT data. Three techniques that are particularly relevant for investigating the brain structures involved in motor preparation and movement initiation and execution and the time course of their activation are recording of event-related potentials (ERPs) both cognitive and motor, TMS, and functional imaging using PET or fMRI. Adoption of a multidimensional approach to the study of motor preparation, initiation and execution through the simultaneous use of different techniques, for example, RTs and ERPs or TMS and imaging; would overcome some of the shortcomings of the individual procedures when used in isolation.
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Movement Disorders Handbook of Clinical Neurophysiology, Vol. 1 M. Hallett (Ed.) © 2003 Elsevier B.Y. All rights reserved
231 CHAPTER 16
Spinal reflexes Mary Kay Floeter* Electromyography Section, National Institutes of Neurologic Disorders and Stroke. National Institutes of Health, Bethesda, MD 20892-1404. USA
16.1. Introduction Reflexes are stereotyped motor actions evoked by specific sensory stimuli. The clinical usefulness of reflexes is well established (Kimura et al., 1994). Reflexes are important in the study of movement disorders for several reasons. First, reflexes play a normal role in adjusting movements in response to changes in sensory feedback. Muscle, joint and skin afferents will each be activated in a quite distinct way during a movement, signaling displacement of individual joints, pressure on particular regions of the skin, or stretch of certain muscles. These multisensory signals feed back to the motor system and reinforce the expected movement. Should perturbations occur as the movement proceeds, the sensory signal relayed back to the nervous system will evoke a reflex response that changes the motor output. Abnormal reflex responses are a characteristic of many movement disorders. Reflexes are also important in the study of movement disorders because they can provide a non-invasive means for assessing the central nervous system and exploring changes in the strength of the connections of spinal intemeurons. Simple reflexes, such as the stretch reflex, can be used as a tool to assess the excitability of motor neurons in patients with movement disorders. Spinal reflexes, defined as those whose circuitry lies within the spinal cord, can be categorized as either excitatory or inhibitory. Excitatory spinal reflexes produce movement or activation of motor neurons. Inhibitory reflexes are those in which the
* Correspondence to: Dr. Mary Kay Floeter, EMG Section, NINDS, NIH, 10 Center Drive, MSC 1404, Bethesda, MD 20892-1404, USA. E-mail address: [email protected] Tel.: + 1-(301)-496-7428; fax: + 1-(301)-402-8796.
sensory stimulus either terminates ongoing motor activity or suppresses a motor response. Inhibitory reflexes can produce either postsynaptic inhibition of motor neurons, which will reduce the motor neuron's excitability to all inputs, or pre-motor inhibition, which reduces the response to either a selected set of afferents (presynaptic inhibition) or to the intemeurons that relay inputs to motor neurons. Most spinal reflexes involve more than one muscle. Generally speaking, reflexes will affect muscles that have synergistic actions in the same manner. But reflexes can be complex, and in some, such as the flexor reflex, one group of muscles may be excited (the flexors) whereas another group of muscles (the extensors) is inhibited.
16.2. Stretch reflexes: T-waves and H-reflexes The stretch reflex, assessed clinically by tapping on the muscle tendon of a relaxed, slightly stretched muscle, is the simplest spinal reflex. The tap causes a brief stretch which activates the muscle spindle: the spindle's primary (la) afferents respond with a burst of spikes that may be repeated as the muscle oscillates until stopping (Burke et al., 1983). Ia afferents synapse monosynaptically on homonymous motor neurons and, less potently, on heteronymous motor neurons such as those that innervate synergist muscles. Ia afferents have later effects on motor neurons through non-monosynaptic pathways. The latency of a stretch reflex can be measured using a tendon hammer with a contact-activated switch to trigger a sweep of surface EMG activity from the muscle being stretched. The response, called the Twave has relatively constant latency upon repeated tapping, but the amplitude will vary, reflecting changes in the number of motor neurons responding with each tap. The latency of the T-wave is
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proportional to the proximal-distal location of the muscle. T-waves can be elicited from any superficial muscle in which a tendon reflex can be obtained (Fig. 1). T-waves are useful for assessment of proximal sensory function and for estimating peripheral conduction time, but are less useful in studies of motor control than the H-reflex. The H-reflex is an electrically elicited homologue of the T-wave that shares the same efferent pathway but has a slightly different afferent origin (Magladery and McDougal, 1951; Burke et al., 1984). H-reflexes are evoked by electrical stimulation of the muscle nerve with long stimulus pulses (0.5 ms-l ms duration). Unlike mechanical taps, electrical stimulation is not selective for the activation of muscle spindles, although it selectively activates larger diameter sensory axons at a lower intensity than the motor axons in many nerves because of differences in their strength-
duration properties (Panizza et al., 1994; Kiernan et al., 1996; Mogyoros et al., 1996; Panizza et al., 1998). An electrical stimulus activates the Ia fibers, as well as other large diameter sensory fibers and some motor axons, in a synchronous volley. Because the nerve is stimulated proximal to the spindle, the H-reflex is independent of spindle properties, such as thixotropy, as well as the level of activity in the gamma motor neurons. The latency of the H-reflex in a given muscle is shorter than its T-wave latency because electrical stimulation is given at a more proximal site (Fig. 1B vs. l C). T-waves and Hreflexes amplitudes both vary with stimulus intensity and with moment-to-moment changes in the excitability of the motor neuron pool. H-reflexes can be easily elicited in only a few muscles at rest, most notably the calf muscles and the forearm flexor muscles. H-reflexes can be obtained in many other muscles, however, during slight muscle contraction.
A +
'22.5 rns
B
c
~
36.0 ms
••
.+
31.4 illS Fig. 1. Stretch reflexes - T-waves and H-reflexes. (A) T-wave elicited from the quadriceps muscle. The patellar tendon tap was delivered at the beginning of the trace. (B) T-wave elicited from the soleus muscle in the same subject. The latency is slightly longer. The Achilles tendon tap was delivered at the beginning of the trace. (C) H-reflex elicited from the soleus muscle in the same subject, stimulating the tibial nerve in the popliteal fossa.
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16.3. H-reflexes: methodological considerations
16.3.1. Recruitment curves The amplitude of the H-reflex has a If-shaped relationship to the stimulus intensity. A plot of the Hreflex amplitude and the amplitude of the compound muscle action potential (M-wave) against the stimulus intensity is called a recruitment curve. As stimulus intensity increases, the H-reflex amplitude increases to a maximum amplitude, then declines with further increases in intensity (Fig. 2). The Hreflex amplitude increases on the ascending limb of the recruitment curve because progressively more Ia fibers are activated. The H-reflex amplitude declines when the stimulus intensity begins to activate progressively more motor axons, as demonstrated by the growing amplitude of the M-wave in the same trace. There are several proposed mechanisms for the decline in H-reflex amplitude. Collision between the antidromically and orthodromically propagated action potentials within the motor axon will prevent reflex volleys from reaching the muscle, and is one of the proposed mechanisms. Another mechanism is that the antidromic invasion of the motor neuron cell
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body produces a short period of refractoriness, that prevents Ia impulses from activating the motor neuron. There has been some debate whether recurrent inhibition, activated by antidromic impulses traveling in motor axon collaterals, contributes significantly to the decline of the H-reflex amplitude. The participation of recurrent inhibition depends on the timing - whether the recurrent inhibitory synaptic potentials, relayed through Renshaw intemeurons (Eccles et al., 1954), arrive at the motor neuron before the arrival of the Ia volley. In most circumstances, the slightly faster conduction velocities of sensory afferents (Macefield et al., 1989) coupled with the additional synaptic delay in the recurrent circuit, will tend to produce maximal recurrent inhibition after the peak of the Ia volley has arrived at the motor neuron. Construction of the H-reflex recruitment curve provides several experimental parameters useful for describing H-reflexes. The ratio of the maximum Hreflex amplitude to the maximum M-wave amplitude (Hma/Mma,) provides a rough measure of the number of motor neurons in the pool that are excitable to peripheral stimuli (Koelman et al., 1993; Hilgevoord et al., 1994). Hma/Mma, ratios are altered in periph-
Fig. 2. H-reflex recruitment curve. The amplitude of the H-reflex initially increases as the stimulus intensity is increased until a maximum amplitude (Hma, ) is reached, shown in waveforms on the left and in the ascending limb of the recruitment curve (shading) in the plot on the right. The amplitude of the H-reflex declines as the stimulus intensity increases further and the M-wave amplitude increases.
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eral neuropathies as well as in central disorders, particularly those producing spasticity. Expression of the amplitude of an H-reflex as a percentage of the maximal M-wave normalizes for individual differences in M-wave size, thus allowing comparison between different persons. 16.3.2. Techniques for evoking H-reflexes
Soleus: The H-reflex is easily obtained in the soleus muscle and gastrocnemius muscles at rest. Surface EMG recordings from the soleus muscle can be made by placing the active recording electrode a few em distal to the gastrocnemii muscles with a reference electrode on the Achilles tendon or 3-4 em distal to the active electrode (Fig. 3A). The tibial nerve is stimulated in the popliteal fossa either using monopolar stimulation, with a remote anode on the patella, or using bipolar stimulation with the cathode facing proximal. After eliciting an If-reflex, the
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amplitude of a subsequent H-reflex is initially depressed, taking as long as 10 s to recover fully. A stimulus rate no faster than every 3-5 s is recommended for routine clinical evaluation, and slower rates may be preferable for experimental paradigms. The criteria for recognizing an H-reflex includes: appropriate latency, elicited by stimulus intensities below those needed to evoke an M-wave, and enhancement by voluntary contraction. Forearm flexors: In many, but not all, normal subjects an H-reflex can be elicited from the median innervated forearm muscles at rest (Fig. 3B). The active recording electrode is placed over the belly of the flexor carpi radialis (FeR), and the reference electrode is positioned either 3 em distally or on the ulnar styloid. Although the longer inter-electrode distance produces a higher amplitude waveform, the larger pick-up area often contains volume conducted responses from muscles outside the forearm that may interfere with observation of the H-reflex in
Fig. 3. H-reflexes. (A) Locations for stimulating the tibial nerve in the popliteal fossa and recording from the soleus muscle to elicit an H-reflex. (B) Locations for stimulating the median nerve at the elbow and recording from the forearm (FeR) muscles to elicit an H-reflex
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some experimental paradigms. To elicit the H-reflex, the median nerve is stimulated at the elbow, usually using bipolar stimulation with the cathode facing proximal, or less frequently, using monopolar stimulation with a remote anode near the elbow. Like the soleus H-reflex, the FCR H-reflex increases in amplitude with increasing stimulus intensity. In some individuals the FCR M-wave duration exceeds the latency of the H-reflex, such that the maximal Hreflex response may be obscured by the M-wave. When this occurs it may also be difficult to verify that the H-reflex amplitude declines with increasing stimulus intensities. The identification of an H-reflex is supported by an appropriate latency (15-20 ms), appearance at stimulus intensities below those needed to evoke an M-wave, and enhancement by voluntary contraction (Kimura et al., 1994). Other muscles: Techniques for measuring Hreflexes in resting quadriceps (Sabbahi and Khalil, 1990; Valls-Sole et al., 1998) and biceps (Miller et al., 1995) muscles have been described. For muscles in which H-reflexes are not readily elicited at rest, voluntary contraction can be used to visualize the reflex (Burke et al., 1989). The muscle nerve is stimulated using low intensity, long duration (0.5 to 1 ms) stimuli while the subject maintains a slight, steady contraction. If the H-reflex is small, it may not be detected unless the EMG signal is rectified and averaged. Identification of the resulting waveform as an H-reflex requires that it is reproducibly time-locked to the stimulus, that it has an appropriate latency for the muscle (similar to the F-wave obtained by supramaximal nerve stimulation), that it increases in amplitude with increasing stimulus intensity and disappears with stimulation supramaximal for the M-wave. 16.3.3. H-reflexes as a probe for motor neuron excitability
The H-reflex is commonly used to assess how stimuli affect the excitability of motor neurons using a conditioning-test paradigm (Pierrot-Deseilligny and Mazevet, 2000). Conditioning-test paradigms compare the amplitudes of H-reflexes evoked by a fixed intensity "test" stimulus with those evoked when the test stimulus is paired with a "conditioning" stimulus. Changes in the H-reflex amplitude during conditioning stimulus trials are used to infer changes in the excitability of the motor neuron pool.
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Because there is normally trial-to-trial variability in H-reflex amplitude, it is important to average a number of trials with each type of stimulus. There are several important methodological considerations when the H-reflex is used to test motor neuron excitability. (1) The intensity of the "test" stimulus must remain constant throughout the experiment. When the paradigm involves testing H-reflexes only in relaxed muscles, it may be sufficient to firmly fasten the stimulator to the skin and use constant current stimulation. However, if the H-reflex is being elicited during movement, minor displacements of the stimulator with respect to the underlying nerve will change the stimulation intensity delivered. To monitor for stimulator movement, an accepted practice is to use an intensity that evokes a small M-wave (Capaday, 1997). The M-wave is generated by motor axons that are activated directly by the stimulus, and these respond in an all-or-none fashion. A constant amplitude of the M-wave indicates that the stimulus intensity remains constant. Trials with changes in the M-wave amplitude should be discarded. (2) The size of the test H-reflex influences the magnitude of the conditioning effect (Crone et al., 1990). Small H-reflexes, consisting of a few early-recruited motor units, may show disproportionately large effects since many inputs to motor neurons have more potent effects on the first-recruited motor units. On the other hand, large H-reflexes which approach the maximal Hreflex amplitude will be relatively insensitive to weak inhibitory inputs and may exhibit occlusion with excitatory conditioning inputs. An optimal test H-reflex size allows facilatatory and inhibitory actions to be observed. One common practice is to use a test H-reflex that is 50% Hmax• Another practice is to use a test H-reflex that is 15-25% of the maximal M-wave amplitude. The latter practice allows comparison across subjects and ensures that a similar portion of the motor neuron pool will be assessed. (3) Fluctuations in the excitability of the motor neuron pool are unavoidable, but the paradigm should be designed to ensure that they are distributed across conditioning and test trials. To avoid systematic effects of long term trends in
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excitability, conditioning and test trials should be interleaved, rather than delivered as separate blocks of trials. Randomization or psuedorandom balanced designs are preferable to performing a strict alternation between conditioning and test trials, to avoid systematic effects of long-lasting changes induced by the conditioning stimulation. (4) If the H-reflex is used to assess motor neuron excitability during movement, the level of muscle contraction must be controlled (Capaday, 1997). The amplitude of the H-reflex increases approximately linearly with the background rectified EMG activity, although the slope of that increase depends on the amplitude of the Hreflex (Capaday and Stein, 1986). Muscle contraction can be a significant problem when studying patients with movement disorders. In patients with rigidity or stiffness, complete muscle relaxation may not be possible. A compromise is to assess the H-reflex at the same level of voluntary background contraction in control subjects as involuntary contraction in patients. The strategy of matching levels of muscle contraction, however, is not practical when H-reflexes are used to assess motor neuron excitability in different phases of a complex movement - walking for example - in which EMG activity varies throughout the task. A further source of H-reflex variability is the movement-induced central modulation of the H-reflex by presynaptic mechanisms. The investigator must devise control conditions for each task that address the possible confounding influences of the movement itself. (5) The H-reflex is affected by its recent history of activation (Crone and Nielsen, 1989a). The recovery cycle of the soleus H-reflex has been explored using paired stimulation pulses (Koelman et aI., 1993). When a second stimulus is given at a delay of 30-75 ms after an H-reflex occurs, the amplitude of the second H-reflex is depressed. At a slightly longer delay of around 200 ms, the H-reflex is potentiated. At later intervals, the amplitude is again depressed, with recovery occurring over several seconds, taking as long as 10 s for complete recovery. The depression of the H-reflex has several causes. The depression at short delays has been attributed to post-spike after hyperpolarization, and to
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postsynaptic inhibition through recurrent inhibition and Ib-activated inhibition. Presynaptic inhibition, mediated by GABAergic interneurons, persists up to several hundred ms (Hultborn et aI., 1996) but cannot explain the very long phase of recovery lasting for several seconds. The prolonged recovery is best explained by an activity-dependent process intrinsic to the presynaptic terminal (Capek and Esplin, 1977; Hultborn et aI., 1996; Kohn et al., 1997) that has been termed homosynaptic depression or postactivation depression (Hultborn and Nielson, 1998). Unlike classic presynaptic inhibition, post-activation depression is not mediated through interneurons, and is likely to be related to presynaptic autoreceptors or mechanisms controlling transmitter turnover and release. Most studies of post-activation depression have focused on the soleus If-reflex, but differences in H-reflex recovery between upper and lower limb muscles have been reported (Rossi-Durand et aI., 1999). 16.4. Methods using single motor units 16.4.1. Peristimulus time histograms
The reflex effects of a conditioning stimulus on a motor neuron pool can be assessed by sampling its effects on single motor units. Normally a motor unit fires at a fairly regular rate during steady contraction. Variations produced by a conditioning stimulus can be quantified by constructing a peristimulus time histogram (PSTH) of motor unit firing (Fig. 4). Excitatory stimuli produce time-locked peaks above baseline in the PSTH, whereas inhibitory stimuli produce troughs. An advantage of single motor unit analysis is that it can be applied to any voluntary muscle, unlike an H-reflex. Furthermore, additional analysis of the timing and synchrony of the peaks can be used to infer whether the connection is likely to be monosynaptic. The disadvantages of the technique include the requirement that a patient can produce a steady contraction for several minutes, and that a number of single units may need to be sampled to understand effects across the motor neuron pool, since the method preferentially samples early recruited units. In addition, the tonic contraction required to observe the motor unit could alter the excitability of the reflex pathway being studied.
SPINAL REFLEXES
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Fig. 4. Peristimulus time histogram of firing of a tibialis anterior motor unit with stimulation of the peroneal nerve below motor threshold. The peak of firing in the PSTH at a latency of 45 ms after the stimulus corresponds to the reflex response to stimulation of Ia afferents. Bin size 1 ms. y-axis indicates the counts per bin.
16.4.2. Unitary H-reflex
An alternative method to assessing variations in firing patterns is a technique described by Shindo et al. (1994), in which the threshold for single motor unit firing in response to stimulation of the muscle nerve is assessed. Like the H-reflex, firing of the motor unit is elicited using electrical stimulation of the muscle nerve, but the stimulus intensity is continually adjusted to produce a 50% probability of motor unit firing, using a computer controller. When a conditioning stimulus produces excitatory effects, the current required to maintain firing declines, whereas inhibitory stimuli increase the current required. This method can be used at rest or during contraction. 16.5. Vibration-induced inhibition of H-reflexes
Muscle or tendon vibration is a handy way to deliver small, repeated stretches to activate primary muscle spindle afferents, which can follow at
frequencies of 20-200 cycles per second (Burke et aI., 1976). When muscle vibration is applied continuously for several seconds or longer, the excitability of motor neurons innervating the vibrated muscle increases, as demonstrated either by the appearance of a tonic vibration reflex or by an increase in the probability of F-wave firing. In contrast, the H-reflex amplitude declines after a short train of vibration, a dissociation that has been called the "vibration paradox" (Desmedt, 1983). The vibration-induced increase in motor neuron excitability has been attributed to the induction of plateau potentials, self sustaining states of membrane depolarization, by the barrage of spindle volleys (Kiehn and Eken, 1997; Gorassini et aI., 1998). Although it is clear that the vibration-induced inhibition of Hreflexes has a presynaptic origin, the relative contributions of different presynaptic mechanisms has not been well delineated (Katz, 1999). Repeated activation of the Ia afferent leads to post-activation depression (Crone and Nielsen, 1989a; Hultbom and
238 Nielson, 1998), but the vibration probably also activates classic GABAergic mediated presynaptic inhibition by the spread of vibration to antagonist muscles. With prolonged vibration, depletion of transmitter or mobilization of synaptic vesicles may be a limiting consideration. Nevertheless, impairment of vibration-induced inhibition of If-reflexes is one of the most consistent physiological findings in patients with spasticity (Ashby et al., 1980; Pierrot-Deseilligny, 1990; Calancie et al., 1993; Delwaide and Pennisi, 1994). Several methods for quantifying vibration-induced inhibition of H-reflexes have been described (Bour et al., 1991; Koelman et al., 1993). One method is to measure the H-reflex recruitment curve, interleaving trials with and without a preceding vibration stimulus at each intensity. Vibration-induced inhibition of the H-reflex amplitude is dependent on the size of the control reflex, with smaller H-reflexes showing the greatest inhibition. For this reason, it is best assessed over a range of intensities on the ascending limb of the recruitment curve. The amplitude of the vibrated H-reflex will be smaller than the control Hreflex elicited at the same intensity, whereas the amplitude of the M-wave remains unchanged.
16.6. Flexorand cutaneomuscular reflexes A flexor reflex is a limb response that occurs upon activation of several different types of afferents cutaneous, joint, and some muscle afferents - often in combination. The movement generally produces a mass movement of the limb that tends to move it away from the stimulus, and thus flexor reflexes are often viewed as protective reflexes. The afferents that produce flexor reflexes are commonly grouped as "flexor reflex afferents" or FRAs. Animal studies have shown that FRAs activate multiple circuits, such that the final movement represents the combination of a number of alternative reflex pathways whose state of excitability varies with respect to ongoing movement (Lundberg et al., 1987). Subtle differences occur in the flexor reflex with differences in the afferents stimulated and the site of stimulation. Most electrophysiological studies of flexor reflexes in people have used electrical stimulation of the skin or skin nerves to evoke the movement. The discussion below will describe several reflexes evoked by cutaneous stimulation which can be viewed as belonging to the family of flexor reflexes.
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16.6.1. Cutaneomuscular reflexes
Stimulation of the skin produces a mixture of excitatory and inhibitory reflex actions. The combined actions can be observed by assessing the effect of skin stimulation upon tonic EMG activity. The response, termed the cutaneomuscular reflex, is the summation of the action of several reflex circuits, each with different latencies, time course and sign. The pattern and timing of excitatory and inhibitory peaks is specific to the muscle and the stimulation site (Meinck et al., 1983). Electrical stimulation of one of the fingers during a tonic contraction of the first dorsal interosseus muscle, for example, produces a sequence of changes as shown in Fig. 5, an average of 250 traces. The earliest excitatory peak, E1, has a peak latency of about 40 ms. E1 is followed by transient suppression of EMG, and this inhibitory period, 11, has a peak latency of about 50 ms. E1 and 11 are spinal reflexes. A second excitatory peak, E2, occurs at a latency of 60-66 ms. The magnitude of E2 is reduced in patients with dorsal column lesions and is enhanced by cortical stimulation (De Noordhout et al., 1992), suggesting a supraspinal contribution to its generation. The cutaneomuscular reflex as described above is elicited using electrical stimulation of moderate intensity, 2-4 times the perceptual sensory threshold (Fuhr and Friedli, 1987), below the threshold for producing pain. A short train of stimuli is typically more effective than a single shock (Meinck et al., 1983). The amplitude, but not the latency, of the peaks varies with stimulus strength. Muscle contraction strength also influences the magnitude of the excitatory and inhibitory peaks. Moderate contractions, e.g. 20% maximum force, are commonly used. Strong contractions can lead to occlusion of excitatory peaks. The surface EMG signal is rectified and averaged, triggering each sweep from the electrical stimulus in such a way as to include a baseline period prior to the stimuli. After averaging, the rectified signal peaks are identified using a predetermined criterion, for example an amplitude change of 50% from the mean baseline EMG. 16.6.2. Cutaneous silent period
Shocks ofrelative1y high intensity, in the range of ten to fifteen times higher than the perceptual threshold (Shefner and Logigian, 1993), produce a
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El
E2
• •
12.0mA 500 uV N: 251
20ms
t
11 Fig. 5. Cutaneomuscular reflex in the FDI, stimulating the index finger at an intensity of four times perceptual threshold. Average of 251 traces.
strong inhibition of tonic EMG activity, termed the cutaneous silent period (Leis et al., 1995; Inghilleri et al., 1997; Manconi et al., 1998). The cutaneous silent period is very pronounced in the intrinsic hand muscles with stimulation of the digits, but can also be observed in some arm and leg muscles (Uncini et al., 1991) (Fig. 6B). In hand muscles it has a latency approximately 70-80 ms, and a duration of approximately 50 ms. It exhibits little habituation, even with intervals as short as 100 ms between pulses (Inghilleri et al., 1997). Leis (1998) has suggested that the cutaneous silent period is a protective reflex that allows the grasp to open before withdrawing the hand. Several lines of evidence suggest that small diameter afferents are primarily responsible for evoking the cutaneous silent period, including estimates of afferent conduction velocity (Inghilleri et al., 1997), relative sparing in large fiber neuropathy (Leis et al., 1992), and reduction in small fiber neuropathy (Syed et al., 2000). Cutaneous inhibition consistent with the cutaneous silent period has been demonstrated in patients after spinal injury, indicating a spinal localization of the reflex circuitry (Logigian et al., 1999). Although there has been debate whether the inhibition is presynaptic or postsynaptic (Leis et al., 1995), studies using magnetic stimulation favor a postsynaptic inhibition of motor neurons, mediated through spinal interneurons (Kaneko et al., 1998; Manconi et al., 1998).
16.6.3. Flexor reflexes Flexor reflexes of the leg occur when a moderately strong stimulation is applied to the sole of the foot. The predominant movement is flexion of the hip, knee, and ankle that produces a withdrawal of the foot. However, on closer examination, relaxation of the extensor muscles is observed to occur simultaneously (Sherrington, 1910; Hagbarth, 1960). With electrical stimulation of the posterior tibial nerve at the ankle, the flexor reflex is seen to be widely distributed across the leg flexor muscles, and the EMG signal reveals two separate components (Shahani and Young, 1971). The EMG response in the tibialis anterior muscle consists of two relatively short latency bursts (Fig. 7). The first component (Rl) has a latency < 100 ms, and the second component (R2) has a latency of about 150 ms. The Rl component has a slightly lower threshold than the R2 component. The flexor reflex is present in normal subjects, but the R2 component, which corresponds to the flexor movement itself, is enhanced in patients with pyramidal tract lesions (Shahani and Young, 1971; Fisher et al., 1979; Roby-Brami et al., 1989). Different subgroups of interneurons are thought to produce the early and late components of the flexor reflex, which can be differentially inhibited by contralateral stimulation (Bussel et al., 1989). The flexor reflex can be elicited in muscles at rest or during muscle contraction.
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Inhibitory effects are observed in antagonist extensor muscles when the flexor reflex is elicited while extensors are active. 16.7. Mixed nerve silent periods
Supramaximal stimulation of a mixed nerve during ongoing contraction of the muscle it innervates produces an interrupted inhibition of the EMG called the mixed nerve silent period (Shahani and Young, 1973). The first segment of the silent period follows the M-wave and lasts until the F-wave, approximately 30 ms in the intrinsic hand muscles. This period of silence is caused by collision between the (volitional) orthodromic motor action potentials and the antidromic action potentials evoked by nerve stimulation. The silence which follows the F-wave has a more complex origin. Originally it was attributed to the pause in the Ia afferent firing that occurs when the spindle is unloaded following a
M.K. FLOETER
muscle twitch (Shahani and Young, 1973). However, the demonstration that this portion of the silent period also occurs in heteronymous muscles and shifts its latency in proportion to the site of afferent stimulation (Leis et al., 1991) focused attention on contributions from inhibitory spinal reflex circuits activated by nerve stimulation. Recurrent inhibition activated by the antidromic volleys in motor axons contributes to the second period of inhibition (Shefner et al., 1993) as do inhibitory reflexes produced by activation of Ia and Ib (Golgi tendon organ) afferents. Contributions from cutaneous inhibition occur after 50 ms. The second period of silence in the hand muscles is often interrupted by the long latency response around 60-70 ms. When this response is absent there is no clear distinction between a second and third segment of the silent period. The end of the mixed nerve silent period has been attributed to cutaneous inputs, since it corresponds fairly well to the end of the cutaneous silent period (Fig. 6A).
Fig. 6. Silent periods in the Abductor pollicis brevis muscle. (A) Mixed nerve silent period, stimulating the median nerve at the wrist with supramaximal stimulation (arrow) and recording from the APB during moderate contraction. Four traces are superimposed, and there is a 20 ms period of baseline EMG prior to the stimulus. The first portion of the silent period lies between the M-wave and the F-wave. The second (SP2) and third (SP3) portions are indicated (see text). (B) Cutaneous silent period (CSP) in the same subject, stimulating the index finger at 13 times perceptual threshold (arrow) and recording from the APB muscle during moderate contraction. Four traces are superimposed.
241
SPINAL REFLEXES
j~l
Vastus Lateralis
~O.5mv SOms
j~~~i\~:::f' A
Rl
R2
Fig. 7. Flexor reflex elicited in the leg by stimulation of the sole of the foot with a train of 4 pulses at 300 Hz at an intensity 1.75 times twitch threshold (arrowhead). Single traces, rectified EMG. The lower two traces show a two-component response (Rl and R2) in the tibialis anterior and hamstring, two flexor muscles. In this subject, activation of the vastus lateralis muscle, an extensor muscle (top trace) occurred at a slight delay with a timing appropriate for alternation.
16.8. Reciprocal inhibition
Contraction of a muscle is normally accompanied by inhibition of its antagonist muscle, a phenomenon called reciprocal inhibition. The effectiveness of reciprocal inhibition in curbing co-contraction depends on its strength and the duration of its action. Because a number of movement disorders exhibit abnormal co-contraction, the modulation of circuits producing reciprocal inhibition has been extensively studied in people. Spinal and supraspinal mechanisms both contribute to reciprocal inhibition. Descending systems exert many of their effects through the interneurons in spinal reflex circuits that effect reciprocal inhibition. Separate spinal reflex circuits produce postsynaptic inhibition of antagonist motor neurons and presynaptic inhibition of la afferents from antagonist muscles. The shortest latency reflex for reciprocal inhibition is disynaptic, mediated through the glycinergic la inhibitory interneuron (laIN) which has been well characterized in animals (Hultborn et al., 1976a, b). The laiN produces a brief inhibitory postsynaptic potential in motor neurons, transiently reducing the response to all excitatory inputs. lalNs are activated reflexively by la afferents from the antagonist muscle, and also by descending corticospinal, rubro-
spinal and vestibulospinal inputs and by various segmental inputs (Hultborn et al., 1976b). The pattern of connections to lalNs follows the principle that inputs which excite a motor neuron pool will also excite the lalNs that inhibit the antagonist motor neuron pool. The convergence of inputs upon the laiN allows the strength of laiN reciprocal inhibition to be dynamically modulated (Crone and Nielsen, 1994). For example, reciprocal inhibition can be suppressed when the planned movement requires cocontraction and can be facilitated in movements with alternating activation of antagonists, such as in stepping. Descending modulation of laIN reciprocal inhibition can be impaired in movement disorders even when the reflex reciprocal inhibition is normal (Meunier et al., 2000). A final point is that the strength of reciprocal inhibition at rest varies considerably for different pairs of antagonistic muscles, and that normative ranges must be established for the muscles under study. At a slightly longer delay, the reciprocal inhibition produced by lalNs is reinforced by presynaptic inhibition of the la afferents from the antagonist muscle. Presynaptic inhibition reduces the likelihood that passive lengthening of the antagonist muscle during the movement will induce a counteracting stretch reflex, but permits the motor neuron to
242
remain responsive to other inputs. Presynaptic inhibition is generated through polysynaptic circuits, with a GABAergic interneuron serving as the final interneuron (Rudomin, 1990). Like the laIN, the interneurons in the reflex circuit producing presynaptic inhibition are subject to modulation through supraspinal and segmental inputs. Several techniques have been described for measuring the strength of reciprocal inhibition in people. One method uses the H-reflex in a conditioning-test paradigm in which the conditioning stimulus consists of stimulating the antagonist nerve at different delays. In the arm, stimulation of the radial nerve in the spiral groove with long duration stimuli (0.5-1 ms) at an intensity below the motor threshold produces two periods of inhibition of the FCR Hreflex at short latencies (Day et aI., 1984) (Fig. 8) and a longer latency third period of inhibition. The
M.K. FLOETER
first period occurs when the radial and median nerve stimulation are delivered nearly simultaneously. The reduction in the H-reflex represents postsynaptic inhibition, thought to be mediated by the laIN. During the second period of inhibition, occurring at delays from 7-50 ms, motor neurons remain excitable to corticospinal activation by TMS, supporting a presynaptic origin of inhibition (Berardelli et al., 1987). The late phase of inhibition, from 50-500 ms is not well understood, and is likely to involve supraspinal mechanisms. Reversal of the third period of inhibition has been reported in dystonia and Parkinson disease (Panizza et aI., 1990; Tsai et al., 1997). Conditioning-test paradigms also have been used to demonstrate reciprocal inhibition between ankle flexor and extensor muscles, measuring the effects of common peroneal nerve stimulation near the fibular
Fig. 8. Reciprocal inhibition between forearm flexor and extensor muscles. (A) FCR H-reflexes in response to median nerve stimulation alone (test condition). Gray box highlights the FCR H-reflex, several traces superimposed. (B) A radial nerve conditioning stimulus reduced the amplitude of the test FCR H-reflexes when both nerves were simultaneously stimulated. (C) Plot of the ratio of the conditioned/test FCR H-reflex amplitude (mean±SD) in 10 normal subjects with different conditioning-test interstimulus intervals. Two periods of inhibition occur, as described in text.
243
SPINAL REFLEXES
head on the amplitude of the soleus H-reflex (Crone and Nielsen, 1994). At the shortest delay, 2-4 ms, a small inhibitory effect is observed in the resting soleus muscle although there is marked variability in the magnitude of inhibition among individuals. This phase of inhibition is enhanced at the onset of antagonist contraction, reflecting the activation of supraspinal inputs that converge upon the underlying interneurons (Crone and Nielsen, 1989b; Nielsen et al., 1992; Shindo et al., 1995). A later period of inhibition, from delays of 7-50 ms was first demonstrated by assessing changes in tonic soleus EMG following peroneal nerve stimulation at intensities near motor threshold (Mizuno et al., 1971). This period of inhibition, termed D1, is maximal at about a 20 ms delay, and is thought to be mediated through presynaptic inhibition. An even later period of depression, D2, beginning about 130 ms after the stimulus, is caused by passive stretch of the calf muscles and can be reduced by fixation of the foot. Reciprocal inhibition in the opposite direction from ankle extensor afferents upon flexor motor neurons - has also been demonstrated in healthy subjects. Stimulation of the tibial nerve produces a sharp trough in the PSTH of tibialis anterior motor unit firing at a latency of about 35 ms (Ashby and Wiens, 1989), an effect that can be presumed to represent disynaptic inhibition from IaINs by its timing. Patients with spasticity and weakness of the tibialis anterior were found to have increased reciprocal inhibition from ankle extensors with this method (Ashby and Wiens, 1989); the same finding was reported in spastic patients who had H-reflexes in their tibialis anterior muscles using a conditioning-test paradigm (Yanagisawa et al., 1976). In contrast, when reciprocal inhibition was assessed in the same patients in the opposite direction -- i.e. inhibition of soleus H-reflexes by peroneal nerve stimulation -- reciprocal inhibition was markedly reduced or, in some patients, peroneal stimulation even produced facilitation (Yanagisawa et al., 1976; Crone et al., 1994). Both changes were in a direction to cause increased excitability of ankle extensor reflexes and inhibition of ankle dorsiflexors. This example highlights the point that reciprocal inhibition is not a unitary process modulated in the same way for every muscle pair. When assessing reciprocal inhibition, or other spinal reflexes, it is important to consider the actions produced by the muscles
under study, and the normal function of the reflex during movement.
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Hultborn, H, Illert, M and Santini, M (1976a) Convergence on interneurons mediating the reciprocal Ia inhibition of motoneurons 1. Disynaptic Ia inhibition of Ia inhibitory interneurons. Acta. Physiol. Scand., 96: 193-201. Hultborn, H, mert, M and Santini, M (1976b) Convergence on interneurons mediating the reciprocal Ia inhibition of motoneurons III. Effects from supraspinal pathways. Acta. Physiol. Scand., 96: 368-391. Hultborn, H, mert, M, Nielsen, J, Paul, A, Ballengard, M and Wiese, H (1996) On the mechanism of the post-activation depression of the H-reflex in human subjects. Exp. Brain Res., 108: 450-462. Hultborn, H and Nielson, J (1998) Modulation of transmitter release from Ia afferents by their preceding activity - a "postactivation depression." In: P Rudomin, R Romo and L Mendell (Eds.), Presynaptic Inhibition and Neural Control. New York: Oxford University Press, pp. 178-191. Inghilleri, M, Cruccu, G, Argenta, M, Polidori, Land Manfredi, M (1997) Silent period in upper limb muscles after noxious cutaneous stimulation in man. Electroencephalogr. Clin. Neurophysiol., 105: 109115. Kaneko, K, Kawai, S, Taguchi, T, Fuchigami, Y, Yonemura, H and Fujimoto, H (1998) Cortical motor neuron excitability during cutaneous silent period. Electroencephalogr. Clin. Neurophysiol.; 109: 364-368. Katz, R (1999) Presynaptic inhibition in humans: a comparison between normal and spastic patients. J. Physiol. Paris, 93: 379-385. Kiehn, a and Eken, T (1997) Prolonged firing in motor units: evidence of plateau potentials in human motoneurons? 1. Neurophysiol., 78: 3061-3068. Kiernan, MC, Mogyoros, I and Burke, D (1996) Differences in the recovery of excitability in sensory and motor axons of human median nerve. Brain, 119: 1099-1105. Kimura, J, Daube, J, Burke, D, Hallett, M, Cruccu, G, Ongerboer de Visser, BW, Yanagisawa, N, Shimamura, M and Rothwell, J (1994) Human reflexes and late responses. Report of an IFCN committee. Electroencephalogr. Clin. Neurophysiol., 90: 393-403. Koelman, JH, Bour, LJ, Hilgevoord, AA, Van Bruggen, OJ and Ongerboer de Visser, BW (1993) Soleus H-reflex tests and clinical signs of the upper motor neuron syndrome. J. Neurol. Neurosurg. Psychiatry, 56: 776781. Kohn, AF, Floeter, MK and Hallett, M (1997) Presynaptic inhibition compared with homosynaptic inhibition as an explanation for low frequency depression. Exp. Brain Res., 116: 375-380. Leis, AA, Ross, MA, Emori, T, Matsue, Y and Saito, T (1991) The silent period produced by electrical stim-
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ulation of mixed peripheral nerves. Muscle Nerve, 14: 1202-1208. Leis, AA, Kofler, M and Ross, MA (1992) The silent period in pure sensory neuronopathy. Muscle Nerve, 15: 1345-1348. Leis, AA, Stetkarova, I, Beric, A and Stokic, DS (1995) Spinal motor neuron excitability during the cutaneous silent period. Muscle Nerve, 18: 1464-1470. Logigian, EL, Plotkin, GM and Shefner, JM (1999) The cutaneous silent period is mediated by a spinal inhibitory reflex. Muscle Nerve, 22: 467-472. Lundberg, A, Malmgrem, K and Schomburg, ED (1987) Reflex pathways from group II muscle afferents. 3. Secondary spindle afferents and the FRA: a new hypothesis. Exp. Brain Res., 65: 294-306. Macefield, G, Gandevia, SC and Burke, D (1989) Conduction velocities of muscle and cutaneous afferents in the upper and lower limbs of human subjects. Brain, 112: 1519-1532. Magladery, JW and McDougal, DB (1951) Electrophysiological studies of nerve and reflex activity in normal man. Bull. Johns Hopkins Hosp., 86: 265-290. Manconi, FM, Syed, NA and Floeter, MK (1998) Mechanisms underlying spinal motor neuron excitability during the cutaneous silent period in humans. Muscle Nerve, 21: 1256-1264. Meinck, HM, Benecke, R, Kuster, S and Conrad, B (1983) Cutaneomuscular (Flexor) reflex organization in normal man and in patients with motor disorders. In: JE Desmedt (Ed.), Motor Control Mechanisms in Health and Disease. New York: Raven Press, pp. 787-796. Meunier, S, Pol, S, Houeto, JL and Vidailhet, M (2000) Abnormal reciprocal inhibition between antagonist muscles in Parkinson's disease. Brain, 123: 10171026. Miller, TA, Mogyoros, I and Burke, D (1995) Homonymous and heteronymous monosynaptic reflexes in biceps brachii. Muscle Nerve, 18: 585-592. Mizuno, Y, Tanaka, Rand Yanagisawa, N (1971) Reciprocal group I inhibition on triceps surae motoneurons in man. J. Neurophysiol., 34: 1010-1017. Mogyoros, I, Kiernan, MC and Burke, D (1996) Strengthduration properties of human peripheral nerve. Brain, 119: 439-447. Nielsen, J, Kagarnihara, Y, Crone, C and Hultborn, H (1992) Central facilitation of Ia inhibition during tonic ankle dorsiflexion revealed after blockade of peripheral feedback. Exp. Brain Res., 88: 651-656. Panizza, M, Lelli, S, Nilsson, J and Hallett, M (1990) Hreflex recovery curve and reciprocal inhibition of H-reflex in different kinds of dystonia. Neurology, 40: 824-828. Panizza, M, Nilsson, J, Roth, BJ, Rothwell, J and Hallett, M (1994) The time constants of motor and sensory
245 peripheral nerve fibers measured with the method of latent addition. Electroencephalogr. Clin. Neurophysiol., 93: 147-154. Panizza, M, Nilsson, J, Roth, BJ, Grill, SE, Demirci, M and Hallett, M (1998) Differences between the time constant of sensory and motor peripheral nerve fibers: further studies and considerations. Muscle Nerve, 21: 48-54. Pierrot-Deseilligny, E (1990) Electrophysiological assessment of the spinal mechanisms underlying spasticity. In: PM Rossini and F Mauguieres (Eds.), New Trends and Advanced Techniques in Clinical Neurophysiology. Amsterdam: Elsevier, pp. 364-373. Pierrot-Deseilligny, E and Mazevet, D (2000) The monosynaptic reflex: a tool to investigate motor control in humans. Interest and limits. Neurophysiol. CUn., 30: 67-80. Roby-Brami, A, Ghenassia, J and Bussel, B (1989) Electrophysiologic study of the Babinski sing in paraplegic patients. J. Neurol. Neurosurg. Psychiatry, 52: 1390-1397. Rossi-Durand, C, Jones, KE, Adams, Sand Bawa, P (1999) Comparison of the depression of H-reflexes following previous activation in upper and lower limb muscles in human subjects. Exp. Brain Res., 126: 117-127. Rudomin, P (1990) Presynaptic inhibition of muscle and tendon organ afferents in the mammalian spinal cord. Trends Neurosci., 13: 499-505. Sabbahi, M and Khalil, M (1990) Segmental H-reflex studies in upper and lower limbs of healthy subjects. Arch. Phys. Med. Rehabil., 71: 216-222. Shahani, B and Young, R (1971) Human flexor reflexes. J. Neurol. Neurosurg. Psychiatry, 34: 616-627. Shahani, BT and Young, RR (1973) Studies of the normal human silent period. In: JE Desmedt (Ed.), New Developments in Electromyography and Clinical Neurophysiology. Basel: Karger, pp. 589-602. Shefner, JM and Logigian, EL (1993) Relationship between stimulus strength and the cutaneous silent period. Muscle Nerve, 16: 278-282. Shefner, JM, Berman, SA and Young, RR (1993) The effect of nicotine on recurrent inhibition in the spinal cord. Neurology, 43: 2647-2651. Sherrington, CS (1910) Flexion-reflex of the limb, crossed extension-reflex, and reflex stepping and standing. J. Physiol., 40: 28-121. Shindo, M, Yanagawa, S, Morita, H and Yanagisawa, N (1994) Conditioning effect in single human motoneurons: a new method using the unitary H-reflex. J. Physiol., 481: 469-477. Shindo, M, Yanagawa, S, Morita, Hand Yanagisawa, N (1995) Increase in reciprocal Ia inhibition during
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Movement Disorders Handbook of Clinical Neurophysiology, Vol. I
M. Hallett (Ed.) © 2003 Elsevier B.Y.All rights reserved
247 CHAPTER 17
Cranial nerve reflexes: anatomical pathways, recording techniques and normative data M. Aramidehv'<, G. Cruccu" and B.W. Ongerboer de Visser b b
a Department ofNeurology/Clinical Neurophysiology, Medical Center Alkmaar, Alkmaar, The Netherlands Department ,of Neurology/Clinical Neurophysiology Unit, Academic Medical Center, Amsterdam, The Netherlands Department of Neurological Sciences, University of Rome, "La Sapienza ", Rome, Italy
17.1. Introduction Recording of the brainstem reflexes enables us to assess the functional integrity of these reflexes within the brainstem and their afferent and efferent connections. Many structural abnormalities, such as tumors or infarctions at the level of the brainstem may abolish reflexes. Recording of different brainstem reflexes may enable us to exclude structural lesions or, on the other hand, to localize more accurately the lesion within the brainstem. In the latter case a more tailored MR imaging examination of this region may be sufficient. Recording of the brainstem reflexes also plays an important role in the pre-selection of patients for additional MR imaging examination and in objectively assessing the functional abnormality of the cranial nerves by elucidating subtle changes in one or more variables of the reflex features in terms of amplitude or latency of the responses (Majoie et al., 1999). The studies of different reflex responses also provide relevant information about the physiology and pathophysiology of segmental and suprasegmental control mechanisms upon the brain stem reflexes and help to differentiate between segmental or suprasegmental origin of an abnormality. In this chapter, we describe the recording techniques, physiology, central pathways and normative data of different brainstem reflexes. As it is impossible to discuss all different aspects of the brainstem reflexes and functions in a chapter of a text book, only those neurophysiological tests that we believe
* Correspondence to : Dr. Majid Aramideh MD PhD Department of Neurology/Clinical Neur;physiology: Medical Center Alkmaar, P.O. Box 501, 1800 AM Alkmaar, The Netherlands. E-mail address:[email protected]
to be relevant in the assessment of patients with movement disorders are selected. 17.2. Orbicularis oculi reflexes 17.2.1. Blink reflex responses
The British physician Overend first elicited the blink reflex by tapping one side of the forehead (Overend, 1896). Kugelberg (1952) analyzed the blink reflex electromyographically by electrically stimulating the supraorbital nerve. When interpreting the findings, one should realize that supratentorial lesions may change corneal and blink reflex features. Reflex changes produced by lesions at different anatomical levels must therefore be analyzed with caution. In hemispheric disorders, blink reflex and corneal reflex responses may be abnormal when the affected side of the face is stimulated. In patients with extrapyramidal disorders, such as Parkinson's disease, parkinsonism, and in patients with idiopathic dystonic disorders, such as blepharospasm, Meige's syndrome and spasmodic torticollis, the orbicularis oculi reflexes should be normal. This indicates that afferent, efferent and central pathways involved in the generation of these reflexes are intact in these patients. However, recovery curves of these reflexes may be affected (vide infra). 17.2.1.1. Technique of recording During recording of the electrical blink reflex the subject lies supine on a bed with the eyes open. The supraorbital nerve is stimulated transcutaneously. The cathode is placed over the supraorbital notch on one side; the anode is placed about 2 em higher and rotated laterally at an oblique angle to avoid spread of current to the contralateral supraorbital nerve
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Fig. 1. Electrode placements for recording responses to supraorbital nerve and corneal stimulations. GI: active electrode; G2: reference electrode.
(Fig. 1). If the second trigeminal division is to be examined, the infraorbital nerve is stimulated by placing the cathode over the nerve as it exits through the infraorbital foramen at the inferior rim of the orbit. The anode is then placed about 2 em below the cathode. Reflex responses from the inferior portion of both orbicularis oculi muscles are recorded simultaneously by surface or needle electrodes. The active surface electrode is placed on the mid-third of the inferior orbital rim and the reference electrode on the lateral surface of the nose or the temple. A ground electrode is taped under the chin or placed around the upper arm. The optimal time to stimulate is between spontaneous blinks. To minimize habituation, stimuli should be delivered at intervals of 7 s or longer, while the subject is kept alert (Boelhouwer and Brunia, 1977). Low-intensity shocks are used initially and the intensity is gradually increased until maximum and nearly stable responses are obtained with repeated trials. 17.2.1.2. Physiology and normative data The common afferent limb of the reflex components is mediated via ophthalmic division of the trigeminal nerve. The facial nerve is the common efferent limb. The electrical stimulation of the supraorbital nerve elicits two responses (Fig. 2); the first or early reflex, RI, is a brief unilateral response that occurs at about 10 ms latency in the orbicularis oculi muscle ipsilateral to the side of stimulation. The second or late response, R2, has a latency of about 30 ms. The second response is longer in duration and occurs bilaterally. RI is not visible clinically. R2 responses of the blink reflex correlate with closure of the eyelids. A contralateral RI response may sometimes occur in healthy subjects.
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RI response is delayed, if it exceeds 13.0 ms and R2 is delayed if it exceeds 41 ms. (Kimura and Powers, 1969; Ongerboer de Visser and Goor, 1974). A difference between the two sides greater than 1.5 ms for RI and 8.0 ms for R2 is also considered abnormal. In addition, the difference between the ipsilateral and contralateral R2 should not exceed 5 ms (Kimura and Powers, 1969) or 8 ms (Ongerboer de Visser and Goor, 1974). Amplitudes vary considerably from one subject to the next. The normal values (mean±SD) are 0.38±0.23 mV for RI, 0.53±0.24 mV for ipsilateral R2, and 0.49±0.24 mV for contralateral R2 (Kimura et aI., 1969). Stimulation of the infraorbital nerve always evokes an R2 response, but not necessarily an RI. When R1 is not present, it is difficult to evaluate R2, because of the wide range of latency times. An absent R2, however, is certainly abnormal. While recording blink reflexes it is important to keep the subject alert. In a state of diminished consciousness or sleep, R2 and to a lesser extent RI, shows a prolonged latency and decreased response amplitude. 17.2.1.3. Central pathways The central pathways, through which the blink reflex responses are mediated, are still incompletely understood. It seems that the impulses for the RI response are conducted through the pons and are relayed via an oligosynaptic arc, probably consisting of one or two intemeurons, located in the vicinity of the main sensory nucleus of the trigeminal nerve (Fig. 2) (Shahani and Young, 1972; Kimura, 1975; Ongerboer de Visser, 1983). For the R2 responses, it has been established that afferent impulses are conducted through the descending spinal tract of the trigeminal nerve in the pons and medulla oblongata before they reach the caudal spinal trigeminal nucleus (Kimura and Lyon, 1972; Ongerboer de Visser and Kuypers, 1978). From there, impulses are relayed via medullary pathway that ascends bilaterally to reach the facial nuclei in the pons. These trigemino-facial connections are thought to pass through the lateral tegmental field, that lies medial to the spinal trigeminal nucleus (Ongerboer de Visser and Kuypers, 1978 in the human; Holstege et aI., 1986 in the cat). The observations of Aramideh et al. (1997) established that the uncrossed, ascending trigeminofacial pathway originates at the level of the lower
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Fig. 2. (A) Normal early (R I) and bilateral late (R2) responses of the blink reflex. The responses are shown from the right (r) and left (I) orbicularis oculi muscles after stimulation of the right (r*) and (1*) supraorbital nerves. (B) Diagram showing the presumed location of the bulbar intemeurons subserving the two components of the blink reflex. (Vll e facial nucleus; Vle abducens nucleus; Vpre principal trigeminal nucleus; Vm etrigeminal motor nucleus; Med. Tegm. Field=medial tegmental field).
medulla oblongata and that the contralateral R2 response is established by way of an ascending trigemino-facial connection that crosses the midline at the level of the lower third of the medulla oblongata. The blink reflex is influenced by many suprasegmental structures, including the motor cortex, the postcentral area of the cortex and the basal ganglia (see Esteban, 1999, for a review). 17.2.2. Corneal reflex responses 17.2.2.1. Technique of recording During recording of the corneal reflex responses, the subject lies supine on a bed or sits in a reclining
chair. Responses are recorded simultaneously with surface electrodes positioned as for recording blink reflex responses (Fig. 1). The optimal time to stimulate the cornea is between spontaneous blinks. The cornea can be stimulated mechanically or electrically. With mechanical stimulation, orbicularis oculi responses are evoked by successive manual application of a small metal sphere, 2 rom in diameter, to the cornea (Ongerboer de Visser et al., 1977). The examiner holds the upper eyelid open with one finger. When the sphere touches the cornea, contact is made between the subject and an electronic trigger circuit; which delivers a pulse. When the corneal reflex is studied by electrical stimulation, the cornea is touched lightly with a thin saline-
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soaked cotton thread connected to the cathode of a constant-current stimulator. The anode is placed on the earlobe or forearm (Accornero et al., 1980). Square pulses, 1 ms duration, 0.1 to 3 rnA are delivered manually and the oscilloscope is triggered by the stimulus. Electrical shocks excite the A-delta nerve fibers directly. 17.2.2.2. Physiology and normative data The corneal reflex is typically nociceptive and serves to protect the eye. The cornea is innervated by unmyelinated (C) and small myelinated (A-delta) fibers (Lele and Wedell, 1959). After penetrating the cornea, the myelinated axons lose myelin and both types ofaxons terminate in the stroma and epithelium as free nerve endings. The mechanical or electrical stimulation of the cornea gives rise to a bilateral contraction of the orbicularis oculi, leading to closure of the eyelids. Three pairs of latency times should be assessed from stimulus artifact to onset of the EMG response (Fig. 3). In contrast to the blink reflex, the corneal reflex does not evoke the early R1 response. When cornea is touched mechanically, the latency time of the direct (ipsilateral) response should not exceed the consensual (contralateral) response latency by more than 8 ms. The latencies of the direct responses, evoked by stimulation of both corneas separately, should never differ by more than 10 ms. This also applies to the consensual response latencies (Ongerboer de Visser et al., 1977). With an electrical stimulus, the difference between the direct and consensual responses never exceeds 5 ms. The difference between the direct responses should never exceed 8 ms. The reflex threshold in normal subjects rarely exceeds 0.5 rnA (Accornero et al., 1980). Mechanical and electrical stimuli elicit reflex responses with similar latency times. Absolute latency values range from 36 ms to 64 ms with mechanical stimulation and from 35 ms to 50 ms with electrical stimulation. This wide range of latencies narrows if control subjects are divided into age groups, to account for the influence of age. 17.2.2.3. Central pathway The reflex afferents are A-delta fibers (Cruccu et al., 1987) passing through the long ciliary nerves and the ophthalmic division of the trigeminal sensory root, to reach the pons (Dengler et al., 1982;
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Ongerboer de Visser, 1983). The central circuit is grossly similar to that of the R2 responses of the blink reflex (Fig. 3). The corneal reflex differs from R2, however, because it is a purely nociceptive reflex. The corneal reflex is relayed through different and fewer interneurons than R2 (Ongerboer de Visser and Moffie, 1979) and it is far more resistant to suprasegmental influences (Cruccu et al., 1997b).
Fig. 3. (A) Normal corneal reflex. The responses are shown from the right (r) and left (I) orbicularis oculi muscles after mechanical stimulation of the right (r*) and (1*) cornea. (B) Diagram showing the presumed central pathways subserving the corneal reflex. (For key abbreviations, see legend to Fig. 2).
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Afferent impulses descend along the spinal trigeminal tract, reach below the obex at the level of the trigeminal subnucleus caudalis and ascend along a multisynaptic chain of intemeurons in the lateral tegmental field before impinging on the facial motoneurons. 17.2.3. Blink reflexes responses evoked by non-trigeminal inputs 17.2.3.1. Somatosensory blink reflex An electrical stimulus to peripheral nerves, specifically the median nerve at the wrist, may induce responses in the orbicularis oculi muscles (VallsSole et aI., 1994). The circuits involved in those responses are not fully comprehended. However, the somatosensory induced blink reflex can be part of a generalized activation of the startle circuit (Karpukhina et aI., 1986), or the expression of a release phenomenon (Miwa et aI., 1998). Electrical stimulation of the median nerve may also induce responses in lower facial muscles, as an electrophysiological equivalent of the palmomental reflex (Dehen et al., 1975). 17.2.3.2. Acoustic blink reflex Sound induces a response in the orbicularis oculi muscle, which can be limited to this muscle, or involve neck and extremity muscles as in the generalized auditory startle reaction. When the response is limited to the orbicularis oculi, it is known as the auditory blink reflex (ABR). Some authors consider the ABR as the least expression of the generalized startle response (Wilkins et aI., 1986). In practical terms, however, if two different responses are generated by sound stimulation in the orbicularis oculi muscles, they cannot be easily differentiated in single individuals in routine practice. The latency of the orbicularis oculi response to sound is usually between 40 and 60 ms. 17.2.3.3. Photic blink reflex Yates and Brown (1981a) thoroughly studied orbicularis oculi reflex responses evoked by light stimuli using a photic stimulator. In a control group they obtained the optimal response and the shortest latency (50.0 ms±4.5 ms), with the stimulator held at a distance of 200 mm in front of the eyes. Afferent optic fibers probably enter the brainstem in the pretectum and impulses are then conveyed to the
facial nuclei in the pons (Tavy et al., 1984). It seems that the cerebral cortex is not involved in the generation of the photic blink reflex, since experimental ablation of occipital cortex does not influence the reflex (Weiskrantz et aI., 1974). As mentioned earlier, similar to the orbicularis oculi reflexes, the above mentioned reflexes should be normal in patients with extrapyramidal disorders such as Parkinson's disease, Parkinsonism or dystonic disorders. 17.3. Levator palpebrae inhibitory reflex The levator palpebrae superioris (LP) muscle and the orbicularis oculi (00) muscle act antagonistically during various movements of the eyelids (see subsection recording of movements). The LP muscle is innervated by the third cranial nerve. The inhibitory reflex of the LP can be examined together with the 00 reflex (Aramideh et aI., 1998). The reflex is normal in patients with cranial dystonia such as blepharospasm and oromandibular dystonia (Aramideh et aI., 1998), and whether it is altered in patients with the so-called apraxia of eyelid opening, also known as involuntary levator palpebrae inhibition, should yet be examined. 17.3.1. Technique of recording
The EMG recordings from the LP and the 00 muscles can be obtained with the subject supine. To record from the LP, a bipolar needle electrode should be inserted through the skin in the middle portion of the upper eyelid and directed toward the LP, while the subject looks downward and keeps the eyelids gently closed. The subject is then asked to open the eyes. This maneuver results in an EMG activity of the LP, which can be verified on the monitor and by the sound signal. To record from the 00, a bipolar needle electrode is inserted into the upper or lower eyelids. The position of the needles can be adjusted by asking the subject to blink or to close the eyes gently. The supraorbital nerve stimulation is similar to that for the electrical blink reflex. The stimulation should be given in the absence of spontaneous blinking, while the subject keeps the eyes voluntarily open. 17.3.2. Physiology and normative data
Stimulation of the supraorbital nerve evokes two silent periods in the LP muscle (Fig. 4) (Aramideh et
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Fig. 4. Left panel: superimposition of three traces of the right levator palpebrae muscle (upper traces) and the right orbicularis oculi muscle (lower traces) after stimulation of the ipsilateral right supraorbital nerve (R*). The ipsilateral stimulation causes an ipsilateral early (SPl = first silent period) and late (SP2=second silent period) in the levator palpebrae and an ipsilateral RI and R2 in the orbicularis oculi. Right panel: the same superimposition of three traces, but after stimulation of the contralateral left supraorbital nerve (L*). In contrast to Rl response, regardless of the stimulation site, the first silent period, SPI, could still be evoked.
aI., 1998). The first or early silent period (SPI), and the second or late period (SP2). In contrast to Rl response of the 00 muscle, the SPI occurs bilaterally regardless of the stimulation site. The latency of the SPI varied from 9 to 13 ms and is slightly shorter than the latency of the corresponding R1 response after the ipsilateral stimulation. The SPI has a duration of 12 to 15 ms. Previous experimental works, including tracing studies, have shown that a small percentage of the LP motoneurons have axon collaterals to both LP muscles (Vanderwerf et al., 1997). Whether these motoneurons are involved in the generation of the first silent period is unclear. The majority of LP motoneurons project to one LP muscle. The latency of the SP2 varies from 27 to 35 ms and is again slightly shorter than that of the corresponding R2 responses. The SP2 has a duration of 32 to 50 ms. There is a slight variability in the features of the LP inhibitory reflex, depending on the pre-stimulus
contraction level of the LP muscle and the stimulus intensity; when the pre-stimulus contraction of the levator is weak, SPI and SP2 may form a one large inhibitory period. At lower stimulus intensities, SP2 appears sooner than SPl, Rl and R2 responses, shows a longer latency and has a shorter duration. The SP2 latency decreases and its duration increases following supramaximal stimulation of the supraorbital nerve. Preliminary data indicate that the inhibition responses of the LP muscle are probably relayed through other central pathways than those involved in Rl and R2 responses of the 00 muscle.
17.4. Jaw reflexes 17.4.1. Jaw jerk
The jaw-jerk induced by a tap on the chin was first described by De Watteville (1886). It is also called jaw reflex, mandibular reflex or masseter reflex. Without EMG recording, the clinical value of the
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mandibular tendon jerk is generally confined to the distinction between normal and brisk reactions, because in healthy subjects the movement of the mandible is often undetectable. Furthermore, on clinical examination alone, a unilateral interruption of the reflex arc can never be disclosed. The jaw-jerk is unaltered in patients with extrapyramidal disorders. In patients with hemirnasticatory spasm, a rare condition characterized by painful involuntary contractions of the masseter or temporal muscles on one side, often associated with hemifacial atrophy, the jaw-jerk is absent on the affected side. A bilaterally absent reflex at advanced ages has no definite clinical significance because this may also occur in healthy subjects. 17.4.1.1. Technique of recording To elicit the jaw-jerk, the examiner puts one finger on the subject's chin and taps it with a reflex hammer provided with a microswitch that triggers with a microswitch the sweep of the oscilloscope (Goodwill and O'Tuama, 1969; Ongerboer de Visser and Goor, 1974 and 1976). Electromyographic responses are recorded simultaneously from the two sides by surface electrodes. The active electrode is placed on the masseter muscle belly, in the lower third of the
--G1
-02
/ /
/ I
II
stimulus Fig. 5. Electrode placement for recording the jaw-jerk and masseter inhibitory reflex with electrode placements for stimulating the mental nerve.
distance between the zygoma and the lower edge of the mandible, and the reference electrode is placed below the mandibular angle (Fig. 5). Reflex responses can also be picked up by a small diameter concentric needle electrode inserted into each masseter muscle. In this case, a ground electrode is taped onto the forehead, neck or upper arm. To ensure a constant latency time taps should be delivered at intervals of 5 s or more. 17.4.1.2. Physiology and normative data
The latency time, which provides the most useful parameter, should be evaluated in several trials or measured on the averaged signal (Ongerboer de Visser and Goor, 1976; Yates and Brown, 1981b). The mean latency in healthy subjects is 6.8 ms (SD 0.8 ms) and a range of 5 to 10 ms (Fig. 6) (Cruccu and Ongerboer de Visser, 1999). Comparison of the latency time of the jaw-jerk responses, recorded simultaneously on both sides in one subject is of great value. A difference of more than 0.5 ms or a consistent unilateral absence of the reflex is an abnormal finding. The masseter reflex is strongly influenced by dental occlusion and can be asymmetrical or even absent in patients with temporomandibular disorders (Cruccu et aI., 1997a). Therefore, whenever the jaw-jerk is the only abnormal trigeminal reflex, it should be tested not only in the postural position but also in intercuspal occlusion or during clenching. Changing the position of the mandible or the level of pre-innervation may strongly reduce or worsen the asymmetry in patients with dental problems, but not in patients with a lesion along the reflex arc. 17.4.1.3. Central pathway Whether the afferent fibers travel in the trigeminal motor root (McIntyre and Robinson, 1959; Pennisi et aI., 1991) or the trigeminal sensory root (Goor and Ongerboer de Visser, 1976; Ferguson, 1978; Ongerboer de Visser, 1982) is still controversial (Fig. 6). Unique among the primary sensory neurons, these afferents have their cell body within the central nervous system, in the trigeminal mesencephalic nucleus, rather than in the ganglion. Collaterals from the trigeminal mesencephalic nucleus descend to the midpons to activate monosynaptically jaw-closing motoneurons of the ipsilateral side only.
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The MIR should generally be normal in patients with extrapyramidal disorders. In patients with hemimasticatory spasm, study of the MIR during the spasm, shows an efferent block, i.e. SPI and SP2 are completely absent in the affected muscle, regardless of the side of stimulation. The silent periods are absent probably because the motor potentials are ectopically generated along the nerve, and cannot be suppressed by the reflex inhibitory input on the motoneurons (Cruccu et al., 1991).
Fig. 6. (A) Normal jaw-jerk responses from the right (R) and left (L) masseter muscles. The lower traces are made by averaging, and arrows mark the latency times. (B) Diagram showing the presumed central pathways subserving the jaw-jerk responses. (Ncl Mes N V =mesencephalic nucleus of the trigeminal nerve; Ncl Mot N V=motor nucleus of the trigeminal nerve; Ncl Prine N V= principal sensory nucleus of the trigeminal nerve; Ncl Tract Spin N V =nucleus of the trigeminal spinal tract; Nill= oculomotor nerve; Ophth=ophthalmic trigeminal root; Max =maxillary trigeminal root; Mand=mandibular trigeminal root; Mot Root N V =trigeminal motor root; N Vle abducens nerve.
17.4.2. Masseter inhibitory reflex
The masseter inhibitory reflex (MIR), also called the cutaneous silent period or exteroceptive suppression reflex, was first described by Hoffman and Tonnies (1948), as the inhibitory component of the tongue-jaw reflex seen after electrical stimulation of the tongue. The EMG silent period (SP) refers to a transitory relative or absolute decrease in EMG activity evoked in the midst of an otherwise sustained contraction (Shahani and Young, 1973).
17.4.2.1. Technique of recording The masseter inhibitory reflex is recorded bilaterally with the same position for electrodes as described for the jaw-jerk (Fig. 5). Subject is sitting upright, and instructed to clench the teeth as hard as possible, for a period of 2-3 s, with the aid of auditory feedback. The reflex can only be measured properly if the subject is able to clench the teeth in intercuspal occlusion and to produce an interferential EMG pattern. It may be necessary to use a concentric needle electrode, instead of surface electrodes, particularly if the signal is contaminated by facial muscle activity. Single electrical shocks 0.2 ms in duration are delivered to the mentalis or infraorbital nerves, through surface electrodes placed over the homonymous foramina. A stimulus intensity of about 2-3 times of the reflex threshold (usually 20-50 rnA) yields the best results. It is always necessary to examine several trials, usually 8-16, allowing 10-30 s of rest between the contractions. Some authors measure the latency at the last EMG peak, some at the last crossing of the isoelectric line, and others at the beginning of the electric silence. Each of these methods is clinically satisfactory if the same criterion is maintained and intra-individual differences between right and left stimulations are examined. 17.4.2.2. Physiology and normative data Mechanical or electrical stimulation, applied anywhere within the mouth or on the facial skin of the maxillary and mandibular trigeminal divisions, evokes a reflex inhibition in the jaw-closing muscles. These reflexes probably play a role in the reflex control of mastication, by preventing intraoral damage that could occur with uncontrolled contraction of jaw closing muscles, and in jaw movements during speech.
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The MIR consists of two electrical silent periods, interrupting the voluntary EMG activity in the ipsilateral and contralateral masseter muscles (Shahani and Young, 1973; Godeaux and Desmedt, 1975; Ongerboer de Visser and Goor, 1976) (Fig. 7). The early silent period, SP1, has a latency of 10-15 ms. The late silent period, SP2, has a latency of 40-50 ms. A latency difference between the ipsilateral and contralateral responses greater than 2 ms for SP1 or 6 ms for SP2 is abnormal (Cruccu, 1987). In a few subjects, little or no EMG activity occurs between the two SPs, i.e. SPI and SP2 merge in a single long-lasting SP, even when the strength of contraction is maximum. In this case, the latency of the recurrence of EMG activity is taken as a measure of SP2. The latency difference between right and left stimulations following recording from one muscle should not exceed 8 ms. If full-wave rectification is available, 8-16 trials should be averaged. The latency and duration of SPs can be measured from the intersection of the rectified and averaged signal and a line indicating 80% of the background EMG level (Cruccu et aI., 1987). In 100 normal subjects, aged 15-80 years, the mean latency of SP1 was 11.8 ms (SD 0.8) and that of SP2 was 45 ms (SD 5.2). The duration of SP1 was 20 ms (SD 4) and the duration of SP2 was 40 ms (SD 15) (Cruccu and Ongerboer de Visser, 1999). Probably because electrical stimuli yield a mixed nociceptive and non-nociceptive input, whether the SP1 or the SP2, or both components, are nociceptive reflexes remains controversial (Miles and Turker, 1987; Ellrich et aI., 1997). Both inhibitory responses can nevertheless be elicited with innocuous mechanical stimuli, and indirect evidence supports the view that the afferents belong to the intermediately myelinated A beta group (Shahani, 1970, Cruccu et al., 1989). 17.4.2.3. Central pathway After stimulation of the mental or infraorbital nerve, impulses reach the pons via the sensory mandibular or maxillary root of the trigeminal nerve, respectively (Fig. 7) (Ongerboer de Visser and Goor, 1976). The SP1 response is probably mediated by one inhibitory interneuron, located close to the ipsilateral trigeminal motor nucleus. The inhibitory interneuron projects onto jaw-closing motoneurons bilaterally. The whole circuit lies in the mid-pons (Ongerboer de
A. stimulus
*-
Fig. 7. (A) Normal early (SPI = first silent period) and late (SP2=second silent period) phase of the masseter inhibitory reflex. The responses are shown from the right (upper trace) and left (lower trace) masseter muscles after stimulation of the right (r*) mental nerve. (B) Diagram presenting the presumed location of the bulbar interneurons subserving (I) the early (SP!) and (2) the late (SP2) phase of the masseter inhibitory reflex. (For key abbreviations, see legend to Fig. 25.6).
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Visser et al., 1990). The afferents for SP2 descend in the spinal trigeminal tract and connect with a polysynaptic chain of excitatory interneurons, probably located in the lateral reticular formation, at the level of the pontomedullary junction. The last interneuron of the chain is inhibitory and gives rise to ipsilateral and contralateral collaterals that ascend medial to the right and left spinal trigeminal complexes, to reach the trigeminal motoneurons (Ongerboer de Visser et al., 1990). 17.5. Assessment of cranial nerves motor function
17.5.1. Cranial nerves conduction examination
Of the cranial nerves, only the facial nerve and the spinal accessory nerve are commonly studied by stimulating the nerve along its course and recording the direct motor response of the muscle, because stimulation of the other nerves, lying for most of their course in the depth of craniofacial structures is difficult. By means of magnetic transcranial stimulation, however, the motor cortex and the intracranial root of most cranial motor nerves can be excited painlessly, and the potential can be recorded from the target muscles. Measurement of the latency and amplitude of the muscle potential provides quantitative information on nerve function. 17.5.1.1. Facial nerve Electrical stimuli are delivered to the facial nerve through surface electrodes placed near the stylomastoid foramen, i.e. just below and anterior to the mastoid bone. Selective stimulation of the upper (zygomatic) or lower (mandibular) branches of the nerve can also be applied. Surface recording electrodes are placed over the orbicularis oculi, nasalis, orbicularis oris, or mentalis muscles, and the direct muscle potential (M-wave) can be recorded by surface electrodes. The reference electrode is placed either over the nasal bone or over the same muscle on the opposite side. The position of the ground electrode is not critical and it is often placed on the lip, chin, or wrist. The main problem with surface recordings from facial muscles is that signals from nearby muscles may be picked-up by volume conduction. This often alters the M wave, which makes the measurement of the onset latency and amplitude difficult. In order to obtain an M wave starting with a negative deflection
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of maximum amplitude, it is sometimes necessary to move the active and reference electrodes, since the optimal position varies slightly between subjects. Some investigators prefer recording by concentric needle-electrode placed at the comer of the mouth or the lateral epicanthus of the eye. In needle recordings, contamination by nearby muscles is avoided because the signal is only picked up from the target muscle. On the other hand, only a proportion of motor units contribute to the signal. Measurement of latency and amplitude is, therefore, less accurate with needle electrode than it is with surface electrode. Normal latency values, as measured by surface electrodes, vary between 2.5 and 5 ms, with a mean of 3.2 ms (SD 0.7). The amplitude varies widely among muscles and individuals and is only examined by side-to-side comparison. 17.5.1.2. Spinal accessory nerve The spinal accessory nerve has two principal components; the larger and more important component is the spinal portion and the smaller branch is the accessory nerve, so called because of its function as accessory to the vagus nerve. The spinal accessory nerve can be stimulated percutaneously in the posterior triangle of the neck at the midportion of the posterior edge of the sternocleidomastoid muscle. Evoked potentials can be recorded over the trapezius muscle at the angle of neck and shoulder. Normal latencies vary between 1.8 and 3.0 ms in healthy subjects, aged 10-60 years (Cherington, 1968; Berry et al., 1991). 17.5.1.3. Hypoglossal nerve Hypoglossal nerve provides motor innervation to the extrinsic and intrinsic muscles of the tongue. The hypoglossal nucleus contains afferent fibers, which appear to be largely spindle afferents (Thomas and Mattias, 1992). Hypoglossal nerve conduction can be accomplished by placing surface electrodes on the top of the tongue and stimulating in the submandibular region, just medial to the angle of the mandible (Redmond and Di Benedetto, 1988). 17.5.2. Recording of movements
Electromyographic recording of spontaneous movements occurring normally in muscles of the
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with a search coil, Bour et al. (2000) also showed that during the electrical blink reflex an early ipsilateral response and late bilateral responses can be identified in the upper eyelid movement (Fig. 11). Based on the coordinated movements of the eyelids and eyes during different types of blinking, it may be suggested that within the brainstem there is a premotor neural structure acting as a generator to
Fig. 8. Schematic drawing of the three components of the orbicularis oculi muscle.
face is of some utility for understanding physiological and pathophysiological aspects of the brainstem and suprasegmental structures. Eyelid kinematics can be investigated using electromagnetic recordings (Evinger et al., 1984; Bour et al., 2000). Furthermore, needle EMG recordings simultaneously from the levator palpebrae and the orbicularis oculi muscles provide information on the normal reciprocal activity between these two muscles (Gordon, 1951; Bjork and Kugelberg, 1953; Aramideh et al., 1994b, 2001). Needle electrodes can be inserted into different portions of the orbicularis oculi (Fig. 8); the pretarsal portion is involved particularly in different types of blinks. The orbital portion is involved in forceful closure of the eyelids and the preseptal portion is more or less activated during both movements. A needle electrode can be inserted into the levator palpebrae as discussed earlier (see levator palpebrae inhibitory reflex). In physiological conditions, during a blink the levator relaxes, followed by the contraction of the orbicularis. As soon as the orbicularis returns to its quiescent state, the levator resumes its tonic activity and raises the eyelid to its previous position. The same reciprocal activity can be observed during voluntary closure and opening of the eyelids (Fig. 9) (Aramideh et al., 1994b, 1995b, 2001). By using double magnetic induction technique or the search coil technique, it is also possible to record the eye movements during different movements of the eyelids (Collewijn et al., 1985; Riggs et al., 1987; Bour et al., 2000). During all types of blinking, Aramideh et al. (l994a) and Bour et al. (2000) demonstrated a downward and nasalward displacement ofthe eyes (Fig. 10). By recording of the eyelid
Fig. 9. Electromyograms from the levator palpebrae superioris (LP) and the orbicularis oculi (00) muscles, showing the reciprocal inhibition between these two muscles in a healthy subject. When the subject is asked to close the eyes gently, LP activity ceases abruptly, followed by contraction of 00 (upper two traces at black arrow). Note the occurrence of dense bursts of action potentials with high amplitude preceding the return of LP activity on the order "open eyes", following the inhibition of 00 (lower third trace at open arrow). The lowest two traces show the total inhibition of the LP muscle activity and a brief contraction of the 00 during the act of spontaneous blinking (two times).
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Horizonta' 00(°)
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~Oj
A Horizontal 00 (0)
0.0
~j
Horizontal OS (0)
0.0
(0)
~Oj
Vergence
0.0
(0)
-10.0
Vertical 00(°)
Vertical
~Oj
Vertical 00 (0)
0.0
(0)
~l
Vertical 05(°)
0.0
0.0
~Oj 00
~Oj
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~Oj
Vertical Vergence
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-10.0
~Oj
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-10.0
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-10.
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-10.0 Horizontal OS (0)
~Oj
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(0)
15
~Oj
0.0
----v-.
-
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-10.0
15
Fig. 10. The features of eye movement during spontaneous blinking (A) and gentle closing and opening of the eyelids (B), recorded in two healthy subjects. Positive changes denote right gaze, divergence, or upward gaze. For vertical vergence, positive changes denote that the right eye (00) is higher than the left eye (OS).
coordinate the incoming impulses to different subnuclei of the ocular motor system as well as the facial motoneurons. Swallowing is another natural spontaneous movement that occurs repeatedly in awake humans. Although muscles involved in swallowing are not readily accessible to electromyographic recordings, they can be studied with combined EMG and mechanical methods (Ertekin et aI., 1995). A simple approach to the functional assessment of superficial muscles involved in mastication and swallowing can be performed by surface electrodes placed on the masseter and orbicularis oris muscles. These are activated in a well-defined alternating pattern while chewing that becomes synchronous when swallowing (Fig. 12).
17.6. Recovery curves to paired stimuli Because of passive mechanisms (e.g. after-hyperpolarization potential) or the intervention of negative feedback circuits, the excitability of a reflex circuit is depressed after the passage of an earlier impulse. With the double-shock technique it is possible to draw the recovery curve (or excitability cycle) of a given reflex and thus obtain a measure of the excitability of the reflex circuit (Kimura, 1973). Stimulus intensity and position of the stimulating and recording electrodes are the same as those used in a standard reflex study. Electrical stimuli of equal intensity are delivered in pairs, at varying interstimuli time-intervals. The response to the first shock
259
CRANIAL NERVE REFLEXES
OS(20mA)
Time(ms)
OD(20mA)
Time(ms)
Fig. 11. Two components of eyelid movement during evoked blink reflex. From top to bottom: horizontal (Eh(OD», and vertical (Ev(OD» movements of the right eye, upper eyelid movement (lid(OD» and upper eyelid velocity (lidve,(OD» for the right eye and EMG of the right orbicularis oculi muscle (OOEMO(OD» and the left orbicularis oculi (OOEMO(OS». Several responses after electrical stimulation of the left (A) and right (B) supraorbital nerves with an 8-mA current are superimposed. Upward deflections relate to rightward eye movement for the horizontal component, upward eye movement for the vertical component and upward movement or upward velocity of the upper eyelid. Arrows in B indicate the start of the early component.
is called "conditioning" and the response to the second shock is called "test" response. The size (amplitude, duration or area) of the two responses is measured, and that of the test response is expressed as a percentage of the conditioning response. The recovery curve is drawn by plotting the size of the test response, as a percentage of the conditioning response, on the Y-axis and the time-interval on the
X-axis (see Chapter Aramideh, Valls-Sole, Ongerboer, Fig. 8) (Kimura 1973). The studies on the recovery curves of different cranial nerve reflexes have been performed in various movement disorders, particularly in patients with dystonic disorders, Parkinson's disease and parkinsonism disorders. The recording of the recovery curve enables us to examine the excitability of
260
M. ARAMIDEH ET AL.
Fig. 12. Normal alternating masseter and orbicularis oris muscle activation patterns during chewing, and synchronous activation during swallowing.
the interneuronal circuits and the integrity of the suprasegmental structures. Patients with blepharospasm have an abnormal brain stem interneuronal excitability enhancement, as investigated with the recovery curves of R2 response of the orbicularis oculi reflex, similar to that found in patients with parkinsonism (Berardelli et al., 1985; Tolosa et al., 1988; Cruccu et al., 1991; Aramideh et al., 1995a). In a group of 33 patients with involuntary eyelid closure, based on EMG patterns, Aramideh et al. (1995a) showed that recovery of R2 was enhanced in all patients with pure blepharospasm, but it was normal in all patients with pure involuntary levator palpebrae inhibition and in 75% of patients with a combination of both disorders. Nakashima et al. (1990), Pauletti et al. (1993) and Eekhof et al. (1996) found that the abnormalities of the recovery curve are also present in patients with cervical and generalized dystonia, even in those without blepharospasm. Normal recovery curves are usually seen in focal arm dystonia only (Tolosa et al., 1988; Nakashima et al., 1990). The recovery curves of the SP2 component of the masseter inhibitory reflex may be enhanced in dystonic patients, with or without facial dystonia (Cruccu et al., 1991). It is interesting that the
recovery of SP2 was also facilitated in dystonic patients not exhibiting jaw closing dystonia (Pauletti et al., 1993), as was the recovery of the R2 component of the blink reflex, which was facilitated in patients without blepharospasm (Nakashima et al., 1990). In Parkinson's disease, the enhanced excitability of brain stem interneurons leads to a rapid recovery of the responses (Kimura, 1973). Similar abnormalities have been described in the excitability recovery curve of the MIR (Cruccu et al., 1991). The blink reflex excitability recovery curve has also been studied in other parkinsonian disorders such as progressive supranuclear palsy and multiple system atrophy, with abnormalities that were similar to those found in patients with Parkinson's disease.
17.6.1. Recovery of orbicularis oculi reflexes A complete excitability cycle of the orbicularis oculi reflex can be examined with the time-intervals between 10 ms and 100 ms every 10 ms, and those between 100 ms and 1500 ms every 100 ms. However, it is not clinically indispensable to check all these time-intervals. The test R1 summates with the conditioning R1 or R2 at short interstimuli time-intervals, up to 60-70
261
CRANIAL NERVE REFLEXES
ms. The apparent facilitation may reach 250% at 30-40 ms intervals. With longer intervals, Rl is affected little by the conditioning shock. It may be very slightly reduced (80% at the 100 ms interval) and slowly recovers to 90-100% of the conditioning response at the intervals of 200-500 ms (Kimura, 1973). The test R2 is usually completely abolished at interstimuli time intervals shorter than 200, it then very slowly recovers, reaching about 40-50% at the 500 ms interval and 70-90% at the 1500 ms interval (see Chapter Aramideh, Valls-Sole, Ongerboer, Fig. 8) (Aramideh et al., 1995a; Eekhof et al., 1996). The recovery of the corneal reflex parallels but is more rapid than that of R2. The test corneal reflex already measures about 30% at the 200 ms interval, while R2 of the blink reflex is still abolished, and reaches 90-100% at the 1500 ms interval (Kimura, 1973; Cruccu et al., 1986). Since the same motoneurons are shared by the various orbicularis oculi reflexes, the difference in recovery times (progressively longer for R1, corneal reflex, and R2) is commonly attributed to the difference in the interneuronal net. The R2 of the blink reflex response is most susceptible to changes in excitability, and the R2 recovery curve has provided valuable information in research and clinical settings. It may also be valuable to measure the recovery index (Aramideh et al., 1995a; Eekhof et al., 1996).
80
E Q)
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60 40
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17.6.2. Recovery of levator palpebrae inhibitory reflex
With the same needle position as for the recording of the levator palpebrae EMG activity and the inhibition reflex (see earlier), the recovery of the inhibition periods of the levator palpebrae muscle can be examined with the recovery curve of the orbicularis oculi responses (Fig. 13) (Aramideh et al., 1998). The durations of the two silent periods are measured, and that of the test response is expressed as a percentage of the conditioning response. The recovery curve is drawn by plotting the size of the test response, as a percentage of the conditioning response, on the Y-axis and the time interval on the X-axis. At interstimuli time-intervals higher than 500 ms, the percentage of inhibition recovery of the second
0
Ql
II:
40
~ 0
20 00
200
400 600 Stimulus Interval
800
1000
Fig. 13. The recovery curve of the second silent period (SP2) of the levator palpebrae (L. Palpebrae) and the recovery curve of the R2 response of the orbicularis oculi (0. Oculi). The lowest panel shows the recovery curves of both muscles together. At higher stimulus intervals, for instance 1 s and 0.5 s, the percentage of inhibition recovery of the SP2 was similar to that of the excitability recovery of the R2 response. At lower stimulus intervals, the recovery curve of inhibition responses were shifted upward, i.e. SP2 recovered faster than corresponding R2 response. For example, at 200 ms where R2 response did not show any recovery, the SP2 could still be recruited for about 20-30%. The SPI is not examined systematically.
262
M. ARAMIDEH ET AL.
silent period (SP2) was similar to that of the excitability recovery of the R2 response (Fig. 13). At lower intervals, the recovery curve of SP2 was shifted upward, i.e. SP2 recovered faster than corresponding R2 response. For example, at 200 ms where R2 response was completely abolished, the SP2 could still be recruited for about 20-30%. These findings are in agreement with our earlier observation (see earlier) and indicate that responses are relayed on different central pathways.
I I I I
~
17.6.3. Recovery of masseter inhibitory reflex
L!¥; I
o
100
me
250
c
100
20 100
250
500
Fig. 14. Recovery curvesof the masseterinhibitoryreflex. (A) Eight rectified and averaged signals, recorded in a healthy subject after stimulation of the mental nerve. The first (conditioning) shock is indicated by the dashed line. The second(test) shock is indicated by the arrows. After a secondshockwith an interstimulus interval of 100 ms, the test SP2 is almostabolished(AI) and partly recovers with an interval of 250 ms (A2). (B) The same as in (A) but in a patient with Parkinson's disease. The test SP2 is only slightlysuppressed at the interstimulus intervalof 100 ms (B1) and completely recovers at the interval of 250 ms (B2). (C) Recovery curve of the SP2 component of the masseter inhibitory reflex. X-axis: interstimulus interval (ms); Y-axis: area of the test response expressed as percentage of the conditioning response. The two curves are ± standard errors of the estimate in 20 healthy subjects. The two squares indicate the recovery value for the 100 ms and 250 ms intervals in (B). Note that the recovery of SP2 is enhanced in the patient with Parkinson's disease.
The recovery cycle of the masseter inhibitory reflex is studied by delivering paired stimuli at interstimulus time-intervals of 100 ms, 150 ms, 250 ms, and 500 ms, with the same low-rate stimulation and alternation of "clench" and "rest" phases described for the assessment of the reflex values. The recovery curve is drawn by plotting the timeintervals on the X-axis and the size (area or duration) of the test response as a percentage of the size of the conditioning response on the Y-axis (Fig. 14). The recovery of SP1 in normal subjects varies from about 85% at 100 ms interval to approximately 96% at 500 ms (Fig. 14). The recovery of SP2 varies from 24% at 100 ms to 79% at 500 ms. The function of correlation between time interval (milliseconds) and size of the test response (percent) is linear for SP1 (Y=0.02 X+85) and logarithmic in base 10 for SP2 (Y =75 log X - 120) (Cruccu et al., 1991). Recovery can also be evaluated however by simply measuring the duration of SP1 and SP2 in non-rectified recordings, and for clinical use, it may be sufficient to measure the recovery of SP2 at the 250 ms interval (Cruccu et al., 1997a; Cruccu and Ongerboer de Visser, 1999).
References Accornero, N, Berardelli, A, Bini, G, Cruccu, G and Manfredi, M (1980) Corneal reflex elicited by electrical stimulation of the human cornea. Neurology, 30: 782-785. Aramideh, M, Bour, LJ, Koelman, JHTM, Speelman, JD and Ongerboer de Visser, BW (1994a) Abnormal eye movements in blepharospasm and involuntary levator palpebrae inhibition: clinical and pathophysiological considerations. Brain, 117: 1457-1474. Aramideh, M, Ongerboer de Visser, BW, Devriese, PP, Bour, LJ and Speelman, JD (1994b) Electromyo-
CRANIAL NERVE REFLEXES
graphic features of levator palpebrae superioris and orbicularis oculi muscles in blepharospasm. Brain, 117: 27-38. Aramideh, M, Eekhof, JLA, Bour, U, Koelman, JHTM, Speelman, JD and Ongerboer de Visser, BW (1995a) Electromyography and blink reflex recovery in involuntary eyelid closure: A comparative study. J. Neurol. Neurosurg. Psychiatry, 58: 692-698. Aramideh, M, Ongerboer de Visser, BW, Koelman, JHTM and Speelman, JD (1995b) Motor persistence of orbicularis oculi muscle in eyelid opening disorders. Neurology, 45: 897-902. Aramideh, M, Ongerboer de Visser, BW, Koelman, JHTM, Majoie, CB and Holstege, G (1997) The late blink reflex abnormality due to lesions of the lateral tegmental field. Brain, 120: 1685-1692. Aramideh, M, Ongerboer de Visser, BW and Van der Werf, F (1998) The inhibitory response of levator palpebrae muscle to evoked blink reflexes. In: J Valls-Sole and E Tolosa (Eds.), Brainstem Reflexes and Functions. ENE Publicidad, Madrid, pp. 89-98. Aramideh, M, Koelman, JHTM, Speelman, JD and Ongerboer de Visser, BW (2001) Eyelid movement disorders and electromyography. Lancet, 357: 805806. Berry, H, MacDonald, EA and Mrazeh, AC (1991) Accessory nerve palsy: a review of 23 cases. Can. J. Neural. Sci., 18: 337-341. Bjork, A and Kugelberg, E (1953) The electrical activity of the muscles of the eyes and eyelids in various positions and during movement. Electroencephalogr. cu« Neurophysiol., 5 : 595-602. Boelhouwer, AJW and Brunia, CHM (1977) Blink reflexes and the state of arousal. J. Neural. Neurosurg. Psychiatry, 40: 58-63. Bour, U, Aramideh, M and Ongerboer de Visser, BW (2000) Neurophysiological aspects of eye and eyelid movements during blinking in man. J. Neurophysiol., 83: 166--176. Collewijn, H, Van Der Steen, J and Steinman, RM (1985) Human eye movements associated with blinks and prolonged eyelid closure. J. Neurophysiol., 54: 11-27. Cruccu, G and Ongerboer de Visser, BW (1999) The jaw reflexes. In: G Deuschl and A Eisen (Eds.), Recommendations for the Practice of Clinical Neurophysiology: Guidlines of the International Federation of Clinical Neurophysiology. Elsevier Science Publisher B.Y., pp. 243-247. Cruccu, G, Agostino, R, Berardelli, A and Manfredi, M (1986) Excitability of the corneal reflex in man. Neurosci. Lett., 63: 320-324. Cruccu, G, Inghilleri, M, Fraioli, B, Guidetti, B and Manfredi, M (1987) Neurophysiological assessment of
263 trigeminal function after surgery for trigeminal neuralgia. Neurology, 37: 631-638. Cruccu, G, Agostino, Rand Inghilleri, M (1989) The masseter inhibitory reflex is evoked by innocuous stimuli and mediated by A beta afferent fibers. Exp. Brain Res., 77: 447-450. Cruccu, G, Pauletti, G, Agostino, R, Berardelli, A and Manfredi, M (1991) Masseter inhibitory reflex in movement disorders. Huntington's chorea, Parkinson's disease, dystonia, and unilateral masticatory spasm. Electroencephalogr. Clin. Neurophysiol., 81: 24--30. Cruccu, G, Frisardi, G, Pauletti, G, Romaniello, A and Manfredi, M (1997a) Excitability of the central masticatory pathways in patients with painful temporomandibular disorders. Pain, 73: 447-454. Cruccu, G, Leandri, MG, Ferracuti, S and Manfredi, M (1997b) Corneal reflex responses to mechanical and electrical stimuli in coma and narcotic analgesia in humans. Neurosci. Lett., 222: 33-36. Dengler, R, Rechl, F and Struppler, A (1982) Recruitment of single units in human blink reflex. Neurosci. Lett., 34: 301-305. Dehen, H, Bathien, N and Cambier, J (1975) The palmomental reflex. An electrophysiological study. Eur. Neurol., 13: 395-404. De Watteville, A (1886) Note on the jaw-jerk, or masseteric tendon reaction, in health and disease. Brain, 8: 518-519. Eekhof, JLA, Aramideh, M, Bour, LJ, Hilgevoord, AAJ, Speelman, JD and Ongerboer de Visser, BW (1996) Blink reflex recovery curves in blepharospasm, torticollis spasmodica and hemifacial spasm. Muscle Nerve, 19: 10-15. Ellrich, J, Hopf, HC and Treede, RD (1997) Nociceptive masseter inhibitory reflexes evoked by laser radiant heat and electrical stimuli. Brain Res., 764: 214--220. Ertekin, C, Pehlivan, M, Aydogdu, I, Ertas, M, Uludag, B, Celebi, G, Colakoglu, Z, Sagduyu, A and Yuceyar, N (1995) An electrophysiological investigation of deglutition in man. Muscle Nerve, 18: 1177-1186. Esteban, A (1999) A neurophysiological approach to brainstem reflexes. Blink reflex. Neurophysiol. Clin., 29: 7-38. Evinger, C, Shaw, MD, Peck, CK, Manning, KA and Baker, R (1984) Blinking and associated eye movements in humans, guinea pigs and rabbits. J. Neurophysiol., 52: 323-339. Ferguson, IT (1978) Electrical study of jaw and orbicularis oculi reflexes after trigeminal nerve surgery. J. Neurol. Neurosurg. Psychiatry, 41: 819-823. Godeaux, E and Desmedt, JE (1975) Exteroceptive suppression and motor control of the masseter and temporalis muscles in normal man. Brain Res., 85: 447-458.
264 Goodwill, CJ and O'Tuama, L (1969) Electromyographic recording of the jaw reflex in multiple sclerosis. J. Neural. Neurosurg. Psychiatry, 32: 6--10. Goor, C and Ongerboer de Visser, BW (1976) Jaw and blink reflexes in trigeminal nerve lesions. Neurology, 26: 95-97. Gordon, G (1951) Observation upon the movement of the eyelids. Br. J. Ophthalmol., 35: 339-351. Hoffman, P and Tonnies, JF (1948) Nachweis des vollig konstanten verkommens des zungen-kiefer-reflexes bei menschen. Pfliigers Archiv., 250: 103-108. Holstege, G, Tan, J, Van Ham, 11 and Graveland, GA (1986) Anatomical observations on the afferent projections to the retractor bulb motoneuronal cell group and other pathways possibly related to the blink reflex in the cat. Brain Res., 374: 321-334. Karpukhina, MY, Gokin, AP and Limanskii, yP (1986) Activation of pontine and bulbar reticulo-spinal neurons in the cat by somatosensory stimuli of different modalities. Neurophysiology, 18: 329-336. Kimura, J (1973) Disorder of interneurons in parkinsonism. The orbicularis oculi reflex to paired stimuli. Brain, 96: 87-96. Kimura, J (1975) Electrical elicited blink reflex in diagnosis of multiple sclerosis. Review of 260 patients over a seven-year period. Brain, 98: 413-426. Kimura, J (1982) Conduction abnormalities of the facial and trigeminal nerves in polyneuropathy. Muscle Nerve, 5: 149-144. Kimura, J and Lyon, LW (1972) Orbicularis oculi reflex in Wallenberg syndrome: alteration of the late reflex by lesion of the spinal tract and nucleus of the trigeminal nerve. J. Neural. Neurosurg. Psychiatry, 35: 228-233. Kimura, J, Powers, 1M and Van Allen, MW (1969) Reflex response of orbicularis oculi muscles to supraorbital nerve stimulation. Study in normal subjects and in peripheral facial paresis. Arch. Neurol., 21: 193-199. Kugelberg, E (1952) Facial reflexes. Brain, 75: 385-396. Lele, PP and Wedell, G (1959) Sensory nerves of the cornea and cutaneous sensibility. Exp. Neurol., 1: 334-359. McIntyre, AK and Robinson, RG (1959) Pathway for the jaw jerk in man. Brain, 75: 385-396. Miles, TS and Turker, KS (1987) Decomposition of the human electromyogramme in an inhibitory reflex. Exp. Brain Res., 65: 337-342. Miwa, H, Nohara, C, Hotta, M, Shimo, Y and Amemiya, K (1998) Somatosensory-evoked blink reflex response: investigation of the pathophysiological mechanism. Brain, 121: 281-291. Nakashima, K, Rothwell, JC, Thompson, PD et al. (1990) The blink reflex in patients with idiopathic torsion dystonia. Arch. Neurol., 47: 413-416.
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Ongerboer de Visser, BW (1982) Afferent limb of the human jaw reflex: electrophysiologic and anatomic study. Neurology, 32: 536--546. Ongerboer de Visser, BW (1983) Anatomical and functional organization of reflexes involving the trigeminal system in man: jaw reflex, blink reflex, corneal reflex and exteroceptive suppression. Adv. Neurol., 39: 729-738. Ongerboer de Visser, BW (1986) The recorded corneomandibular reflex. Electroencephalogr. CUn. Neurophysiol., 63: 25-31. Ongerboer de Visser, BW and Goor, C (1974) Electromyographic and reflex study in idiopathic and symptomatic trigeminal neuralgias: Latency of the jaw and blink reflexes. 1. Neurol. Neurosurg. Psychiatry, 37: 12251230. Ongerboer de Visser, BW and Goor, C (1976) Jaw reflexes and masseteric electromyograms in mesencephalic and pontine lesions. An electrophysiologic study. J. Neural. Neurosurg. Psychiatry, 39: 90-92 Ongerboer de Visser, BW and Kuypers, HGJM (1978) Late blink reflex changes in lateral medullary lesions. An electrophysiological and neuroanatomical study of Wallenberg's syndrome. Brain, 101: 285-294. Ongerboer de Visser, BW and Moffie, D (1979) Effects of brainstem and thalamic lesions on the corneal reflex. An electrophysiological and anatomical study. Brain, 102: 595-608. Ongerboer de Visser, BW, Mechelse, K and Megens, PHA (1977) Corneal reflex latency in trigeminal nerve lesions. Neurology, 27: 1164-1167. Ongerboer de Visser, BW, Cruccu, G, Manfredi, M and Koelman, JHTM (1990) Effects of brainstem lesions on the masseter inhibitory reflex. Functional mechanisms of reflex pathways. Brain, 113: 781-792. Overend, W (1986) Preliminary note on a new cranial reflex. Lancet, I: 619. Pauletti, G, Berardelli, A, Cruccu, G, Agostino, R and Manfredi, M (1993) Blink reflex and masseter inhibitory reflex in patients with dystonia. Mov. Disord., 8: 495-500. Pennisi, E, Cruccu, G, Manfredi, M and Palladini, G (1991) Histometiric study of myelinated fibers in the human trigeminal nerve. J. Neural. Sci., 105: 22-28. Redmond, MD and Di Benedetto, M (1988) Hypoglossal nerve conduction in normal subjects. Muscle Nerve, 11: 447-452. Riggs, LA, Kelly, JP, Manning, KA and Moore, RK (1987) Blink-related eye movements. lnv. Ophthalmol. Vis. Sci., 28: 334-342. Shahani, BT (1970) The human blink reflex. J. Neurol. Neurosurg. Psychiatry, 33: 792-800. Shahani, BT and Young, RR (1972) Human orbicularis oculi reflexes. Neurology, 22: 149-154.
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Tavy, DL, Van Woerkom, TCAM, Bots, GTAM and Endtz, U (1984) Persistence of the blink reflex to sudden illumination in a comatose patient. Arch. Neurol., 42: 323-324. Thomas, PK and Mattias, CJ (1992) Diseases of the ninth, tenth and eleventh and twelfth cranial nerves. In: PJ Dyck and PK Thomas (Eds.), Peripheral Neuropathy (3rd ed). Philadelphia, Saunders, pp. 869-883. Tolosa, E, Montserrat, L and Bayes, A (1988) Blink reflex studies in focal dystonias. Enhanced excitability of brain stem intemeurons in cranial dystonia and spasmodic torticollis. Mov. Disord., 3: 61-69. Valls-Solt\ J, Cammarota, A, Alvarez, R and Hallett, M (1994) Orbicularis oculi responses to stimulation of nerve afferents from upper and lower limbs in normal humans. Neurosci. Lett., 650: 313-316. Van der Werf, F, Aramideh, M, Ongerboer de Visser, BW, Baljet, B, Speelman, JD and Otto, JA (1997) A
265 retrograde double fluorescent tracing study of the levator palpebrae superioris muscle in the cynomolgous monkey. Exp. Brain Res., 113: 174-179. Weiskrantz, L, Wanington, EK, Sanders, MD and Marshall, J (1974) Visual capacity in the hemianoptic field following a restricted occipital ablation. Brain, 97: 700-728. Wilkins, DE, Hallett, M and Wess, MM (1986) Audiogenic startle reflex of man and its relationship to startle syndromes: a review. Brain, 109: 561-573. Yates, SK and Brown, WF (198Ia) Light-stimulus-evoked blink reflex: methods, normal values, reaction to other blink reflexes, and observation in multiple sclerosis. Neurology, 32: 272-281. Yates, SK and Brown, WF (198Ib) The human jaw-jerk: electrophysiologic methods to measure the latency, normal values, and changes in multiple sclerosis. Neurology, 31: 632-634.
Movement Disorders Handbook of Clinical Neurophysiology, Vol. I M. Hallett (Ed.) © 2003 Elsevier B. V. All rights reserved
267 CHAPTER 18
Startle and prepulse effects Josep Valls-Sole" Unitat d'EMG, Servei de Neurologia, Departament de Medicina, Hospital Clinic, /nstitut d'Investigacio Biomedica August Pi i Sunyer (ID/BAPS), Universitat de Barcelona, Villarroel /70, Barcelona 08036, Spain
18.1. Introduction The startle reaction (SR) is an involuntary, reflex, behavioral reaction, generated in the brainstem reticular formation by unexpected external stimuli. It serves the purpose of protecting the organism from the effects of a presumed danger. Usually, the SR is induced by loud acoustic stimuli (auditory SR), although visual (Stitt et al., 1976; McManis et aI., 2001), somatosensory (Gokin and Karpukhina, 1985; Matsumoto et aI., 1992), and vestibular stimuli (Bisdorff et aI., 1994) have also been employed. The most apparent component of the auditory SR is its short latency motor response (Wilkins et al., 1986; Brown et aI., 1991a), which consists of the activation of many muscles, in a pattern that follows a rostrocaudal progression, in accordance to the spread of the excitatory volley presumably initiated in the caudal brainstem (Fig. 1A). A startle gives rise also to changes in autonomic function (Gogan, 1970; Gautier and Cook, 1997), neuroendocrine indices (Campeau et aI., 1997), and electroencephalographic activity (Andermann and Andermann, 1986) that have been less thoroughly investigated. These longlatency effects may be part of the so-called 'orienting' reaction (Turpin, 1986). Being a behavioral response, the SR is modified according to the emotional state, and hence has been used as a probe for such emotions as fear, aversion, pleasure, etc. (Lang et aI., 1990; Grillon et aI., 1991). The excitability of the SR is modulated not only by inputs from many central nervous system structures (Ho et al., 1987; Liegois-Chauvel et aI., 1989), but also by preceding stimuli, called 'prepulse'
* Correspondence to: Dr. Josep Valls-Sole, Unitat d'EMG, Servei de Neurologia, Hospital Clinic, Villarroel, 170, Barcelona 08036, Spain. E-mail address:[email protected] Tel.: 34-93-2275413; fax: 34-93-2275783.
stimuli. A prepulse stimulus is typically a stimulus of an intensity so weak that is incapable of inducing a response by itself. However it causes inhibition of the response to an incoming startling stimulus (Fig. 1B). Prepulse inhibition (PI), known also as 'reflex modification' (Hoffman and Ison, 1980; Ison and Hoffman, 1983), 'stimulus anticipation' (Ison et aI., 1990), or 'sensorimotor gating' (Rossi and Scarpini, 1992; Swerdlow et aI., 1992), does not depend on learning or on previous experiences with the same kind of stimuli. The effect might be due to the attentional shift required to process the information carried by the afferent volley generated by the prepulse stimulus (Graham, 1975; Blumenthal and Gescheider, 1987). PI may also be regarded as a method to assess sensorimotor integration at a subcortical level and, as a consequence, the technique is being increasingly used in the study of physiological mechanisms of behavior, and of the pathophysiology underlying certain diseases, in experimentation animals and in humans. In the following paragraphs, we will deal with some physiological aspects of SR and PI, emphasizing the utility of both as neurophysiological tools to examine and quantify functional aspects of the brainstem that are not readily available using other means of evaluation.
18.2. Startle 18.2.1. Circuits of the SR Research in animals has provided basic information on the circuits involved in the motor component of the auditory SR (Davis et aI., 1982, Lingenhohl and Friauf, 1994; Yeomans and Frankland, 1996). The response persists in experimental animals after intercollicular decerebration (Davis and Gendelman, 1977), and, therefore, it should depend on structures of the lower brainstem. Davis and co-workers (Davis
1. VALLS-SOLE
268
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Acoustic stimulus
Fig. 1. Startle reaction (A) and prepulse inhibition (B) in a healthy volunteer. (A) An auditory stimulus of an intensity of 130 dB is given at the vertical line. (B) The same stimulus is given 100 ms after a weak electrical stimulus to the 3rd finger (prepulse). Note the absence of the startle reaction in B.
et al., 1982) reported that, in the rat, the SR could be generated by electrical stimulation of the nucleus reticularis pontis caudalis (nRPC), but not of the nucleus reticularis gigantocellularis (Davis et al.,
1982), and proposed a circuit consisting of the cochlear nucleus, the nucleus of the lateral lemniscus, the nRPC, and the brainstem and spinal motoneurons. Later, Lee et al. (1996) found that the cochlear nucleus and the nRPC, but not the nucleus of the lateral lemniscus, were required for the response, and Lingenhohl and Friauf (1994) described that the nRPC received direct inputs from the cochlear nuclei. The nRPC projects to the brainstem and spinal cord alpha motoneurons via the medial reticulospinal tract. In present days, the simplest circuit of the auditory SR is believed to involve the cochlear nuclei, the nRPC, and the alpha motoneurons (Davis, 1996; Yeomans and Frankland, 1996; Koch, 1999). The giant neurons of the nRPC are not modality specific (Wu et al., 1988), likely responding to inputs other than those generated by acoustic stimuli. It is conceivable that somatosensory, visual and vestibular inputs induce startle responses through activation of the same efferent circuit. There is no reason to suggest that the SR in humans uses other circuits. Instead, there are several lines of evidence in favor of the origin of the human SR at the lower brainstem: It is present in anencephalic newborns (Brown et al., 1991a); the pattern of muscle recruitment is consistent with a brainstem origin (Wilkins et al., 1986; Brown et al., 1991a), and symptomatic lesions causing enhanced or depressed SR involve the caudal brainstem reticular formation (Brown et al., 1991b; Vidailhet et al., 1992). In humans, the muscle activated with the shortest latency is the orbicularis oculi, followed by the sternocleidomastoid, masseter, and the muscles of the upper and lower limb (Table 1). Some authors believe that the earliest part of the orbicularis oculi response (beginning at about 40 ms) is actually an auditory blink reflex (ABR), separated from the SR, while the true startle reaction starts at a relatively longer latency, and overlaps with the ABR (Brown et al., 1991a). These authors suggest that the physiological mechanisms of the ABR differ from those of the auditory SR. This theory is supported by the anatomic description of a specific circuitry for the ABR, involving the inferior colliculus and the mesencephalic reticular formation (Hori et al., 1986). The possibility of physiological differences between the ABR and the auditory SR is an important point because of the large amount of
269
STARTLE AND PREPULSE EFFECTS
Table 1 Latencies in ms of the auditory startle reaction measured in 15 healthy volunteers, aged 31 to 56 y.o. Mean
SD
Orbicularis oculi
48.3
6.9
Sternocleidomastoid
53.9
10.4
Masseter
54.1
9.2
Wrist flexors
74.3
8.6
Wrist extensors
75.1
9.5
Tibialis anterior
123.5
19.4
literature published in which the SR was identified with just the responses recorded in the orbicularis oculi (Graham, 1975; Lang et aI., 1990; Boelhouwer et al., 1991; Swerdlow et al., 1995). In theory, the findings reported in studies exploring only the responses of the orbicularis oculi could be related to the ABR but not necessarily to the auditory SR. However, the idea that the ABR and the auditory SR have separate anatomic pathways and physiological mechanisms is not universally accepted. From the anatomical point of view, Koch (1999) reported that, in animals, the same nRPC neurons mediate facial and limb muscle responses, suggesting that the cranial nerve and spinal alpha motoneurons respond to inputs from the same source. From the physiological point of view, Valls-Sole et aI. (1999a) reported that responses to auditory stimuli limited to the orbicularis oculi (and, therefore, considered to be ABRs) were modulated by prepulse stimuli in the same way as those involving also the masseter and the sternocleidomastoid muscles (and, therefore, considered to be auditory SRs). An alternative view to the understanding of the SR as the result of single or multiple excitatory volleys spreading from the nRPC was given by Bisdorff et aI. (1994) on the basis of their analysis of the SR generated through vestibular inputs. These authors hypothesized that the differences between onset of EMG activity in various muscles are not simply governed by the respective distance from the brainstem nuclei but that the SR is the expression of a patterned response, built in the reticular formation with a temporo-spatial distribution. This pattern would be specifically modulated by sensory inputs, according to the examination conditions, and by the
biological weight of certain muscle components. A similar reasoning was put forward by Matsumoto et aI. (1992) in their explanation of the results obtained in patients with hyperekplexia. If this is the case, the different behavior of the blink component of the SR could be explained by it being relatively hard-wired in the reticular formation (Jenny and Saper, 1987), reflecting the predominant role of the mechanisms protecting the eye during potentially harmful stimuli. 18.2.2. Long latency motor and non-motor aspects of the SR
A startling stimulus generates not only the short latency SR, but other effects occurring at a longer latency (Gogan, 1970). The orienting reaction (OR) is an ill-defined behavioral response that depends on psychological factors and may contain effects related to the subject's curiosity, fear, annoyance, etc. The motor component of the OR can account for complex movements, and may involve defense reactions and the 'flight or fight' response (Turpin, 1986). In some of our subjects, we observed an OR consisting in the turning of the head towards the source of the loud noise, a relatively long lasting activity of cranial nerve innervated muscles (Fig. 2), the articulation of a few words of surprise, or expressions of emotion such as laughing or guttural noises. It is difficult to know at present whether there is any relationship between the long-latency motor phenomena induced by a startling stimulus in normal subjects and the tonic spasms observed in patients with hyperekplexia (Saenz-Lope et al., 1984; Brown et al., 1991b) or startle epilepsy (Anderman and Anderman, 1986; Brown et aI., 1991b). The EEG correlates of the normal human startle reflex are not clear. Most descriptions report that the unavoidable artifact related to blinking is followed by a brief desynchronization of the background EEG activity (Wilkins et aI., 1986). The same findings have been reported in patients with hyperekplexia, although some of them might actually have enhanced excitability of the motor cortex manifesting with enhanced amplitude of somatosensory evoked potentials (Markand et al., 1984). In startle epilepsy, ictal activity is delayed with respect to the changes related to the initial startle reflex (Bancaud et al., 1975). Autonomic changes induced by a startling stimulus can be part of the OR, and include the
270
J. VALLS-SOLl~,
Fig, 2. Two motor components of the startle reaction. The short latency component (shown as the bursts close to the stimulus, applied at the vertical line) is followed by a long latency reaction that may be part of the orienting reaction (underlined),
elicitation of the galvanic cutaneous sudomotor response, and a relatively long-lasting modulation of blood pressure and heart rate (Dimberg, 1990; Gautier and Cook, 1997; Holand et al., 1999; VallsSole et al., 2002). 18.2.3. Other features related to the external activation of the startle pathways
Apart from the generation of an overt short latency motor response, and other long latency changes, the auditory SR has other features of physiological interest such as the generation of the PI potential, the interindividual variability and habituation rate, the effects induced on voluntary motor reactions, and the modulation of segmental
reflexes. Table 2 summarizes the motor and nonmotor effects that can be induced by an auditory startling stimulus. 18.2.3.1. The P1 potential Any auditory stimulus generates auditory evoked potentials of short, medium and long latency.Among these responses, the one that has been thought to be generated in startle-related structures is the PI potential (Reese et al., 1995). This potential is recorded in the vertex at a latency of about 50 ms and is preceded by another potential known as the Pa potential (Buchwald et al., 1991). In contrast to the Pa potential, the PI potential amplitude decreases significantly as the stimulus rates exceed l/s. Also, intravenous injection of cholinergic antagonists
271
STARTLE AND PREPULSE EFFECTS
Table 2 Some effects of an auditory startling stimulus. Auditory blink reflex
Fox, 1979; Hori et al., 1986
Short latency startle reaction
Davis et al., 1982; Wilkins et al., 1986; Brown et aI., 1991
Reflex habituation and sensitization
Davis et aI., 1982; Rimpel et al., 1982
Reflex modification
Hoffmann and Ison, 1980; Ison et al., 1990
Orienting reaction
Gogan, 1980
Autonomic reactions
Turpin, 1986
PI potential
Reese et al., 1995
Acceleration of reaction time
Valls-Sole et aI., 1995; Valldeoriola et al., 1998
Audiospinal reflex
Rossignol and Melvill-Jones, 1976; Delwaide et aI., 1993
resulted in a decrease of the PI potential. These characteristics were considered as indicating that the PI potential is generated in the reticular ascending system, and likely in the pedunculopontine tegmental nucleus (PPTn) (Reese et aI., 1995). An evoked potential with characteristics similar to those of the PI potential was recorded in the rat, near the PPTn and the mesencephalic locomotor region, Ebert and Ostwald (1991). Ninomiya et aI. (1997) suggested that the PI potential is the result of overlapping of temporally coincident evoked potentials, and that part of the potential might relate to a motor response process. 18.2.3.2. 1nterindividual variability and habituation The magnitude of the startle reaction varies from subject to subject, making it difficult to draw normative values (Chokroverty et aI., 1992). However, one can reasonably expect that the first time a loud auditory stimulus is applied, it causes short latency responses seen as EMG bursts in at least several cranial and neck muscles. Apart from interindividual differences, groups of normal subjects have been identified to respond differently to a startling stimulus. Variables such as age, gender, smoking habits, and body mass might be important (Kumari et aI., 1996; Faraday et aI., 1999; Lehmann et al., 1999; Kofler et aI., 200la, b). The size of the responses can be potentiated or inhibited depending in part on the subject's posture (Brown et aI., 1991c). However, in any given posture, the short latency SR fades away quite fast with repeated stimuli in normal subjects (Wilkins et
aI., 1986; Brown et aI., 1991a; Chokroverty et al., 1992; Matsumoto et aI., 1992). Habituation may be indeed inconvenient for clinical applicability of the startle reaction, because the examiner may not have the opportunity to replicate the results obtained from the first stimulus. In a study of habituation rate of SR in different environmental and behavioral conditions, Valls-Sole et aI. (1997) found significantly reduced habituation rate when subjects were prepared to execute a ballistic movement in a reaction time task paradigm, in comparison to other conditions (Fig. 3). This observation suggests that preparation for execution of a voluntary movement causes an increase in the excitability of the circuits conveying the SR. At the same time, the voluntary
Fig. 3. Comparison of habituation rate in the responses recorded in the orbicularis oculi and the sternocleidomastoid muscles in two different conditions: Quiet environment and preparedness to perform a ballistic movement. Histograms represent the mean size of the responses of 15 healthy volunteers to startling stimuli delivered every 3Q-.45 s in each condition, in percentage of the size of the response to the first stimulus. Note the reduced habituation of the response recorded in the sternocleidomastoid in the condition of preparedness.
J. VALLS-SOLl~
272
reaction was speeded up but not otherwise modified by the startling stimulus (Valls-Sole et al., 1995, 1999b), suggesting that the circuits of the SR might have been used in the execution of the voluntary ballistic movement. 18.2.3.3. The effects of a startle on reaction time The execution of ballistic movements in a reaction time task paradigm involves activation of many descending motor tracts, but the relative role of each one of them in the accurate performance of fast movements is mostly unknown (Porter and Lemon, 1993). That the corticospinal tract is involved in the execution of fast ballistic movements in humans is assumed in part from the observations of an increase in the excitability of the motor pathway to transcranial electrical and magnetic stimulation, beginning at about 80 ms before onset of the EMG activity in the agonist muscle (Starr et aI., 1988; Pascual-Leone et aI., 1992). When testing such an effect, Pascual-Leone et aI. (1992) observed also that subthreshold transcranial magnetic stimulation (TMS) induced acceleration of the voluntary reaction. Reaction time shortening by subthreshold TMS was interpreted as the consequence of an externally induced acceleration in the process of motor cortex energization to reach the level of excitability appropriate for activation of the execution channel. However, alternative explanations were given such as the possibility to activate subcortical motor structures. We found out later that a startling stimulus, which is supposed to directly activate subcortical motor structures, induced even more acceleration of the reaction time than TMS (Valls-
Sole et al., 1995). Furthermore, the shortening effect involved the whole three-burst pattern constituting the motor program for ballistic movements (Hallett et aI., 1975). In such a study, we asked healthy volunteers to perform a ballistic wrist movement. They were trained to produce the triphasic agonistantagonist-agonist EMG pattern by vigorous activation of the wrist extensors and wrist flexors. In test trials, a startling stimulus was delivered together with the imperative signal. The mean results for all subjects as a group are summarized in Table 3, and individual mean data are shown in Fig. 4. In test trials, the latency of the first agonist EMG burst was significantly shorter than in control trials, but the configuration of the triphasic pattern did not change between control and test trials. These results indicate that the whole programmed three bursts pattern of the ballistic movement was moved to a shorter latency, as if it was triggered by the startle itself. Our interpretation is that the excitability of the pathways involved in the startle reaction was modulated according to the patterned three burst response during preparation for the execution of the ballistic movement. If this were not the case, one should have expected a significant change in the configuration of the three burst pattern. These observations suggest that the reticulospinal tract is actively involved and plays a most important role in the execution of ballistic movements (Valls-Sole et aI., 1999b). Startle-induced reaction time shortening offers an interesting question to the physiologist: Is there enough time for cortical sensory processing before execution of the 'voluntary' task? Preparation for the
Table 3 Acceleration of reaction time by a startle. Test
Control Movement of the hand
203.6
(74.5)
104.3
(17.6)*
Latency of 1st agonist burst
171.4 (50.9)
77.3
(10.7)*
72.9
(11.2)
35.6
(10.4)
Duration of 1st agonist burst Interval agonist-antagonist
76.6
(15.6)
36.2
(11.9)
Interval 1st-2nd agonist bursts
143.2 (34.6)
138.4 (24.8)
Duration of antagonist burst
121.5 (47.0)
109.3 (21.3)
Measures of wrist movement and the electromyographic three bursts pattern in control condition (control) and when the 'go' signal was accompanied by a startling stimulus (test). * Statistically significant differences with respect to control.
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voluntary reaction to a sensory stimulus of a specific modality might block the input from other sensory modalities in their pathway to the cognitive centers, while the excitability of the motor pathway may be enhanced to prepare for the execution of a voluntary reaction (Brunia, 1993). In these conditions, the startling stimulus may trigger the whole reaction, before all sensory information processing has been completed. 18.2.3.4. Audiospinal reflex An auditory stimulus causes changes in the excitability of some reflex circuits. The effect on the H-reflex was first documented by Rossignol and Melvill Jones (1976), and later confirmed and further explored by Delwaide and coworkers, who applied the technique to the study of pathophysiological mechanisms of rigidity in parkinsonian patients (Delwaide et aI., 1993, 2000; Delwaide and Schepens, 1995). The audiospinal reflex consists of the facilitation of the H-reflex, beginning 50 to 60 ms after a sound stimulus, and lasting about 200 ms. It has been found to be of similar size and resolution in both tibialis anterior and soleus, which is taken as a proof that the audiospinal reflex is not a flexor reflex (Delwaide and Schepens, 1995). Similar long-latency effects on the soleus H-reflex have been found using TMS rather than auditory stimuli (Wolfe et aI., 1996; Goulart et aI., 2000). TMS induces two excitatory phases on the H-reflex, the first one being likely due to the generation of a motoneuronal EPSP from activation of the corticospinal tract (Goulart et aI., 2000). The second facilitatory phase peaks at about 70 ms, and is of approximately the same size as the first phase. Its origin is not clear, but, because of its similarity with the audiospinal reflex (Fig. 5), it has been suggested to arise from activation of the reticulospinal tract through converging sources of inputs. These would include somatosensory inputs to the trigeminal nerve from the TMS induced contraction of scalp muscles, auditory inputs from the acoustic stimulus generated by the magnetic coil, and descending inputs from activation of cortico-reticular connections (Goulart et aI., 2000).
18.3. Prepulse 18.3.1. Prepulseeffects on the startle reaction
The size of the auditory SR is reduced when the auditory stimulus is preceded by a stimulus of an
J. VALLS-SOLE
intensity so weak that is unable to elicit a response by itself. This effect, presently known as prepulse inhibition (PI), was first described as the phenomenon of 'reflex modification' more than 30 years ago by Hoffman and coworkers (see the reviews published by Graham, 1975; Hoffman and Ison, 1980; Ison and Hoffman, 1983). Table 4 shows a list of the different observations found in the literature with regard to the effects of a weak stimulus on the response to a subsequent strong stimulus. PI is a very robust phenomenon that occurs with stimuli of the same or different modality as the one eliciting the SR, is similar with stimulus onset and offset, and does not require learning, being present from the first time the prepulse stimulus is applied (Graham, 1975). Most studies of PI have been carried out in the domain of psychophysiology and behavioral psychology, where PI has been found to be abnormally reduced in psychosis prone and schizophrenic subjects (Braff and Geyer, 1990; Simons and Giardina, 1992; Bradley et aI., 1993). The cause of this abnormality can be the attentional deficit and information processing abnormalities exhibited by these patients, who, according to Braff and Geyer (1990), have 'normal sensory registration but defective acute directed attention'. The impairment of internal screening causes failure of information selection, with the consequence of a continuous bombardment of undifferentiated and involuntary data. Actually, normal subjects are probably able to integrate at a subcortical level inputs generated by environmental conditions of our daily life, such as visual, acoustic, somatosensory or others. In certain conditions, these punctiform environmental inputs may play the role of prepulse stimuli, causing inhibition of the reaction to unwanted interfering stimuli. Hoffman and Fleschler (1963) reported the observation of significantly reduced SRs in rats in an environment containing pulsed noise with respect to another in which there was a steady background noise. In our experience, the SRs in humans are largest when uncontrolled environmental punctiform stimuli are limited by steady background noise (Valls-Sole et aI., 1997). 18.3.2. Prepulse effects on the blink reflex and on other facial reflexes
The blink reflex is a very useful tool for the study of some integrative functions taking place in the brain stem. Most of the methods allowing for such a
Fig. 5. Modulation of the soleus If-reflex by auditory stimuli (A and C), corresponding to the audiospinal reflex, and by transcranial magnetic stimulation (B and D). A and B show the superimposition of 12 traces in which the H-reflex was elicited by a posterior tibial nerve stimulus delivered at the interval marked in the horizontal axis with respect to the conditioning stimulus, either the auditory stimulus (A) or the transcranial magnetic stimulus (B), given always at onset of the trace. C and D show the mean and one standard deviation of the soleus H-reflex amplitude in test trials with respect to control trials, marked with the letter 'C', in a group of 15 healthy subjects. The bars under C and D unerline the intervals at which the amplitude of the Il-reflex was statistically significantly larger than in the control condition. Note the similarities in the long latency facilitation by each of the two stimuli.
tv
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en
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~
tIl
en
~
~
s;? ~ ~
en
276
J. VALLS-SOLl~
Table 4 Some effects seen with a pair of stimuli. Effect
Reference
Reflex modification
Hoffmann and Ison, 1980; Ison et al., 1990
Gating of reflexes
Rossi and Scarpini, 1992
Prepulse effects
Graham, 1975; Boelhouwer et aI., 1991; Swerdlow et aI., 1995
Postpulse effects
Valls-Sole et aI., 1996
Classical conditioning
Gormezano, 1966
study make use of the collision between inputs of different sensory modalities. Orbicularis oculi responses to stimuli of a certain modality are modulated by inputs from other sensory modalities within a certain time period (Rimpel et al., 1982). When the conditioning stimulus is of suprathreshold intensity and induces a response in the orbicularis oculi muscle itself, the effects on the response to a stimulus of another sensory modality can be explained by suggesting refractoriness in a common polysensory interneuronal circuit (Rimpel et al., 1982). However, the same effect may also be obtained when using a prepulse stimulus (i.e. a stimulus of an intensity sub-threshold for elicitation of a response). The effects of prepulse stimuli were originally investigated on the blink reflex generated by auditory stimuli (Graham, 1975). However, similar observations have been reported with the blink reflex responses elicited by supraorbital nerve stimulation (Ison et al., 1990), and using other prepulse modalities (Rossi and Scarpini, 1992; Valls-Sole et al., 1994). Investigation of the prepulse effects through the electrically induced blink reflex brings the possibility to study separately the effects occurring on the Rl and on the R2. In most studies, a prepulse causes facilitation of the R1 at intervals between 40 and 100 ms, and inhibition of R2 (and of R2c) at intervals beyond 70 ms (Ison et al., 1990; Boelhouwer et al., 1991; Boulu et al., 1991; Rossi and Scarpini, 1992; Valls-Sole et al., 1994). The dissociation between the effects of a prepulse on the Rl and R2 responses suggest that the effects occur at a presynaptic level (Ison et al., 1990; Rossi and Scarpini, 1992). Prepulse effects can also be induced by activation of small myelinated fibers with laser stimuli (Valls-Sole et al., 2000a). In these instances,
the inhibitory effect occurs between 200 and 300 ms after the prepulse, the delay being related to the slow conduction of the afferent pathway. Prepulse stimuli are not only effective on the blink reflex but also on other facial reflexes. We investigated the effects of somatosensory prepulses on the masseteric silent period (Gomez-Wong and VallsSole, 1996), and saw that the second phase of the masseteric silent period to mentalis nerve stimulation (SP2) is significantly reduced with respect to control conditions when a weak electrical stimulus is applied to the 3rd finger 100 ms before. The percentage reduction of SP2 habituation was not different from the percentage reduction of the R2 during voluntary facilitation. These observations suggest that the effects of a prepulse take place at the trigeminal nerve afferents themselves, before synapsing with facial or trigeminal motoneurons. This is in keeping with the effects of inputs from peripheral nerves reported in experimental animals (Baldissera et al., 1967). 18.3.3. The physiological mechanisms of the PI
The circuit of prepulse inhibition has been delineated in animal studies (Koch et al., 1993; Swerdlow and Geyer, 1993; Inglis and Winn, 1995). Among the structures involved, the subthalamic and pallidal projections to the pedunculo-pontine tegmental nucleus (PPTn), and the cholinergic neurons that project from the PPTn to the nucleus reticularis pontis caudalis (nRPC), playa major role. Prepulse inhibition is preserved in decerebrate animals (Fox, 1979). Therefore, inputs generated by prepulse stimuli should access a group of neurons with capability of sensori-motor integration in the prepulse circuit by way of subcortical pathways. One possible structure that conforms with these require-
277
STARTLE AND PREPULSE EFFECTS
ments is the caudal pontine or pontomedullary reticular formation, and more specifically, the nRPC itself, which would activate the PPTn through reciprocal pathways (Swerdlow and Geyer, 1993) and initiate an inhibitory response. If this is the case, it should be expected that the prepulse causes subthreshold activation of the pontomedullary reticular formation before actually exerting its inhibitory action. The expected facilitation is actually found with short interval somatosensory prepulses on acoustically induced blink reflexes. To analyze better the differences between prepulse effects over the blink reflex and over the ABR, we studied the effects of auditory and somatosensory prepulses on the auditory and electrically induced blink reflexes (Valls-Sole et aI., 1999a). The modulatory effects of somatosensory prepulses on the ABR were facilitatory with interstimuli intervals of up to 50 ms, and inhibitory with interstimuli intervals of 60 ms or beyond. Regarding the electrically induced blink reflex, both somatosensory and auditory prepulses facilitated the R1 between 40 and 80 ms, and inhibited the R2 between 70 and 150 ms. We did not observe any facilitation of the electrically induced R2, which is in contrast with the facilitation observed in the auditory blink reflex by somatosensory stimuli. Therefore, although PI is indeed a cross-modality phenomenon, subtle differences can be seen between modalities. Some differences between auditory and somatosensory prepulses can be explained according to the differences in the relative length of the circuit for somatosensory and auditory inputs and, consequently, in the arrival time of the afferent volley to the brainstem centers (Fig. 6). Both stimuli cause a
Prepulse
Stimul:.~~~~~~= Responseeliciting stimulus
Second modality '--,------,."-" pathway Integrative polysensory system
Fig. 6. Diagram of the prepulse inhibition of a startle reaction. A prepulse stimulus reaches first the brainstem centers causing moderate facilitation of the efferent structures and, at the same time, engage in a prepulse circuit with inhibitory effects over the startle reaction.
window of facilitation followed by a long-lasting inhibition. Because of the different distance, afferents from auditory stimuli arrive earlier to the brainstem than those generated by somatosensory stimuli. Therefore, the window of facilitation involves only the Rl response, because of its shorter latency. On the contrary, since the ABR has a fairly short latency compared to the time at which the afferents from somatosensory prepulses will reach the brainstem, the whole ABR falls into the window of facilitation at short inter-stimulus intervals.
18.3.4. The relationship between PI and blink reflex excitability
In PI, the blink reflex is used as a probe. For this reason, it has been proposed that the results obtained with examining prepulse modulation would in part depend on the excitability of the blink reflex circuit (Schicattano et aI., 2000). However, although reduced PI goes together with enhanced blink reflex excitability recovery in patients with Parkinson's disease as well as in patients with cranial dystonia (Nakashima et aI., 1993; Gomez-Wong et al., 1998; Schicatano et aI., 2000), such coincidence does not occur in other groups of patients. One example is found in patients with Huntington's disease (HD). In these patients, several authors (Esteban and Gimenez-Roldan, 1975; Agostino et aI., 1988) have reported an abnormal decrease in blink reflex excitability, while others have reported reduced PI (Swerdlow et al., 1995). We investigated this aspect as part of a larger study of patients with HD, and confirmed that some patients might indeed have abnormally depressed blink reflex excitability together with an abnormally reduced PI (Valls-Sole, 2000). Thus, the results of prepulse studies could not be predicted from the observations made when studying blink reflex excitability in patients with HD. Why patients with Parkinson's disease and patients with Huntington's disease might have similarly reduced prepulse inhibition but opposite abnormalities in blink reflex excitability recovery is presently an unexplained observation. It is known that the reticular formation has reciprocal connections with nuclei of the basal ganglia. These connections use mainly two different pathways. One
278
might be implicated in the regulation of blink reflex excitability. and involves the internal globus pallidus (GPi) and the substantia nigra pars reticulata (SNr), which send inhibitory inputs to the superior collicuIus. The superior colliculus sends excitatory inputs to the nucleus raphe magnus, which inhibits the excitability of trigeminal neurons (Basso et al., 1996a, b). Since the GPi/SNr complex is hyperactive in Parkinson's disease and hypoactive in Huntington's disease, the effects on blink reflex should be opposite in the two diseases (Kimura, 1973; Esteban and Gimenez-Roldan, 1975). Another link between the basal ganglia and the brains tern reticular formation is established through the PPTn, which is reciprocally connected mainly to the GPi/SNr complex and the subthalamic nucleus (STn), and could have some role in the regulation of prepulse modulation of the startle reaction (Koch et al., 1993; Inglis and Winn, 1995). In Parkinson's disease, all output connections from the basal ganglia to the PPTn are hyperactive, the output of the STn being excitatory and those from the GPi and the SNr being inhibitory. According to current concepts on how the basal ganglia are interconnected, the hyperfunctioning STn will cause even more hyperactivity of the GPi, probably resulting in a net inhibitory output to the PPTn. In Huntington's disease, both the STn and the GPi/SNr are hypofunctioning. However, this is not exactly the opposite behavior with respect to PD. The reduced excitatory input from the STn to the GPi could cause this nucleus to be more dependent on the inputs from the direct pathway, which is also the one more likely implicated in dopamine-related influences on prepulse inhibition (Swerdlow et al., 1992). The decreased inhibition that the GPi receives from the direct pathway could oppose or even overcome the increased inhibition from the indirect pathway and the resulting output from the GPi could be negligible or even turn to more inhibition than normal. Whatever the case, the reduced excitatory output from the STn would cause reduced activation of the PPTn, resulting in an effect similar to the one occurring in PD patients. Therefore, even if the same prepulse effects are seen in PD and HD patients, the mechanisms inducing these effects could be different. They could involve excess inhibition from the GPi to the PPTn in PD, and reduced excitation from the STn to the PPTn in HD (Fig. 7).
J. VALLS-SOLl~
APD
B:HD
Fig. 7. Circuits of the basal ganglia suggested to control the activity in the pedunculopontine tegmental nucleus in relation to prepulse inhibition in Parkinson's disease (A) and in Huntington's disease (B).
18.3.5. Postpulse effects In a paired stimulation paradigm the effects are not limited to the response induced by the second stimulus. Repeated presentation of a trigeminal nerve stimulus generates excitability enhancement in neurons in or near the facial nerve nucleus that may contribute in part to the generation of the conditioned response (Matsumura and Woody, 1986).
STARTLE AND PREPULSE EFFECTS
279
Fig. 8. Postpulse effect in a series of 5 traces combining mechanical taps to the forearm and electrical stimuli to the supraorbital nerve. In all columns, the series of 5 stimuli begin at the bottom of the trace and go upwards. Recordings are always done in the O. oculi of both sides (the right side is the top trace of each pair). In A, supraorbital nerve electrical stimuli were given at the vertical line. The R1, R2 and R2c responses show some tendency to diminish their size with successive trials. In B, a tap is applied to the forearm at onset of the traces, and responses are present in the O. oculi to just the first and the second stimuli. In C, forearm taps and supraorbital nerve electrical stimuli are applied synchronously, separated by an interval of 100 ms. See that the R2 and R2c responses to the supraorbital nerve electrical stimulus are inhibited (prepulse inhibition), and that the O. oculi responses to the tap remain present up to the 5th trial, indicating reduced habituation (postpulse effect).
We investigated the effects of repeated presentations of paired low intensity (prepulse) auditory stimuli and supraorbital nerve stimuli of an intensity leading to the known blink reflex responses. Apart from the expected prepulse inhibition of the R2 response, we observed that the small responses induced occasionally by the low intensity auditory stimuli were larger and showed less habituation when given paired to the supraorbital nerve stimulus than when given on their own (Fig. 8). This effect, described as the 'postpulse' effect, might have physiological bases akin to those underlying pavlovian conditioning (Woodruff-Pak and Thompson, 1988; Solomon et aI., 1989) but differs from it in two important respects (Valls-Sole et al., 1996): (l) The postpulse effect occurs earlier than the acquisition of the conditioned response; and (2) While postpulse enhancement relates to the response time locked to the first stimulus of a pair, the conditioned response is time locked to the presentation of the second stimulus.
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Movement Disorders Handbook of Clinical Neurophysiology, Vol. 1 M. Hallett (Ed.) © 2003 Elsevier B.Y. All rights reserved
285 CHAPTER 19
Long-latency reflexes following stretch and nerve stimulation G. Deuschl* Neurologische Klinik, Christian-Albrechts-Universitiit Kiel, D-24/05 Kiel, Germany
19.1. Introduction Long-latency reflexes are a group of reflexes of which the stretch reflexes of hand and arm muscles and the electrically elicited hand muscle reflexes have been most extensively studied. Stretch reflexes need more sophisticated equipment and have been used mainly to assess physiological questions. Reflexes in hand muscles following nerve stimulation can be elicited and recorded with routine EMG equipment and are therefore more suited for diagnostic questions. They can be a useful tool to assess sensorimotor functions of the central nervous system. They are known to exhibit distinct patterns of abnormality in various diseases, including movement disorders or focal lesions within the spinal cord, brainstem and brain. If a reflex is to function normally not only must its afferent and efferent pathways be intact but all central processing must be normal. Reflex tests and tests using evoked potentials or transcranial stimulation therefore provide distinctly different information. Lesions along the afferent, central, or efferent pathways suppress the reflex. Central lesions involving suprasegmental areas that facilitate or inhibit the reflex circuit may suppress or enhance the response but may leave the conduction times unaffected. Stretch reflexes and electrically elicited hand-muscle reflexes are such examples (Cruccu and Deuschl, 2000). Reflexes in hand and arm muscles can be elicited with various kinds of stimuli: muscle stretch (Marsden et al., 1976; Noth et al., 1985), cutaneous stimulation with air-puffs (Deuschl et al., 1995), or
* Correspondence to: Prof. Dr. G. Deuschl, Department of Neurology, Christian-Albrechts-Universitat Kiel, Niemannsweg 147,0-24105 Kiel, Germany. E-mail address:[email protected] Tel.: 0431-597-2610; fax: 0431-597-2712.
electrical stimulation of mixed or pure cutaneous nerves (Caccia et al., 1973; Deuschl et al., 1985; Meinck et al., 1987; Deuschl and Lucking 1990). Arm and hand muscles exhibit a variety of reflex responses that are probably transmitted through distinct pathways. On account of these variant reflex pathways, attempts to generalize the findings obtained in one muscle to other muscles are both inappropriate and confusing (Marsden et al., 1981). The present chapter will focus on hand muscle reflexes that have been studied most extensively, the physiology of these reflexes is sufficiently understood and the clinical applications have proven reliable in several neurological diseases. The stretch reflexes will be mentioned whenever special results have been obtained.
19.2. The pattern and physiology of stretch reflexes and electrically elicited reflexes The reflex pattern depends on the mode of stimulation and the nomenclature for the different reflex components may vary from author to author and muscle to muscle (see Table 1). After muscle stretch the pattern consists of the so-called Ml, M2 and M3 responses (Marsden et al., 1981; Noth et al., 1985). The Ml-response is equivalent to the monosynaptic reflex response elicited by la-afferents. The long-latency response M2 of hand muscles is most likely secondary to the activation of low-threshold muscle and cutaneous afferents (Deuschl et al., 1985). Like the circuit for responses to cutaneous stimulation, the central circuit for M2 includes a transcortical loop. Recently a pure cutaneous loop has been proposed for M2 of finger muscles (Corden et al., 2000), but a long-latency reflex (LLR) mediated by la-afferents has been convincingly demonstrated earlier (Deuschl et al., 1985; Noth et al., 1985). In proximal arm muscles (m. biceps and m. brachioradialis) the short-latency Ml-response is also transmitted through the la-monosynaptic reflex
G.DEUSCHL
286 Table I
Nomenclature of long-latency, long loop and stretch reflexes in the literature and possible correspondence between the different reflexes. Long-latency excitatory (medium)
Long-latency excitatory (late)
Reference
B
M3
(Marsden et al., 1976)
M2
M3
(Noth et al., 1985)
C-reflex
C-reflex
C-reflex
(Conrad and Aschoff, 1977)
LLRI
LLRll
LLR III
(Deuschl and Liicking, 1990)
Radial superficial nerve stimulation
cLLRI
cLLRll
cLLR III
(Caccia et al., 1973; Deuschl et al., 1985)
Finger stimulation
E1
E2
E3
(Caccia et al., 1973; Jenner and Stephens, 1982)
Spinal monosynaptic
Long-latency excitatory (early)
Stretch reflexes of the thumb
MI
A
Stretch reflexes of the thumb
MI
Median nerve stimulation
HR
Median nerve stimulation
HR
Long-latency inhibitory
II
Stretch reflexes of the hand
M1
M2
M3
(Marsden et aI., 1976)
Stretch reflexes of the biceps/ triceps
M1
M2
M3
(Marsden et al., 1976)
Stretch reflexes of the triceps surae
M1
M2
M3
(Berardelli et al., 1982)
pathway. But the M2-response in arm muscles is probably a spinal response mediated by group II afferents (Thilmann et al., 1991; Fellows et al., 1993; Fellows et al., 1996). For the triceps surae and the tibial anterior muscle, the situation is less clear. But a group II-afferent spinal pathway seems to be more likely (Berardelli et al., 1982, 1983a, b) than a generation by repetitive discharges of Ia-afferents (Hagbarth et al., 1981; Bongiovanni and Hagbarth, 1990). This is also true for more complex ways of eliciting reflexes like sudden slips of the surface during standing (Dietz, 1993). The reflex pattern elicited by adequate cutaneous stimulation (air-puffs) to the tip of the finger has
been assessed only in hand muscles and is characterized by an early excitation (cLLR I), an early inhibition (11), and a late excitation (cLLR II) (Deuschl et al., 1995), comparable to the reflex pattern elicited by electric stimulation of finger nerves (Jenner and Stephens, 1982). The responses to electric stimulation have been characterized in several studies (Deuschl et al., 1985; Claus and Jakob, 1986; Claus et al., 1986; Eisen, 1987; Eisen et al., 1989; Eisen and Deuschl, 1994; Friedli and Deuschl, 1994). After mixed-nerve stimulation the first response is the M-wave due to direct excitation of the motor axons. It has a latency of about 3-10 ms depending on the site of stimula-
287
LONG-LATENCY REFLEXES FOLLOWING STRETCH AND NERVE STIMULATION
tion. The reflex pattern consists of the Hoffmann reflex (HR), followed by up to three long latency reflexes (LLR), termed LLR I, II, and III. We prefer to use the term long-latency instead of long-loop reflexes because the central pathways for LLR I and LLR III remain unclear. These reflexes have been assessed in thenar muscles after median nerve stimulation at the wrist (Deuschl and Lucking, 1990) and in the first dorsal interosseus after ulnar nerve stimulation at the wrist (Noth et al., 1985; Claus and Jakob, 1986; Claus et aI., 1986). The reflex pattern after stimulation of purely cutaneous nerves, such as the finger nerves (Caccia et aI., 1973; Jenner and Stephens, 1982) or the radial superficial nerve (Caccia et al., 1973; Deuschl et aI., 1988, 1989), consists of an early excitatory component (El, cLLR I), an inhibitory component (11), and a second excitatory component (E2, cLLR II) (Jenner and Stephens, 1982). Similarly cutaneous reflexes of leg muscles have been described (Gibbs et aI., 1999). The reflex pathway for the HR is well-known: afferent impulses are conducted along la-fibers and relayed monosynaptically to the homonymous motoneurons. The H-reflex is usually easily evoked in normal subjects; in elderly subjects it can occasionally be difficult to record without a sizable M-wave. The only other reflex response present in all normal subjects is the LLR II. The afferents for the LLR II are fast-conducting cutaneous fibers and la-fibers (Deuschl et al., 1985); afferent impulses are transmitted along the dorsal columns to the nucleus cuneatus and along the lemniscal pathway to the sensory cortex. It is assumed that the excitatory volley is then relayed to the motor cortex, which in tum activates the spinal motoneurons via the corticospinal tract (Fig. 1 top). Evidence in favor of this pathway comes from animal experiments (Bawa et aI., 1979; Bawa and McKenzie, 1981; Evarts and Fromm, 1981; Cheney, 1985) as well as from several studies in normal subjects (Bawa and McKenzie, 1981; Bawa et aI., 1983; Noth et aI., 1983, 1985; Deuschl et aI., 1985) and patients (Noth 1986; Deuschl et aI., 1988, 1989; Podivinsky et al., 1992; Michels et aI., 1993; Naumann and Reiners 1997). The pathways for the LLR I and the LLR III are much less clear. The LLR I is also considered a transcortical reflex, mainly because under pathologic conditions (patients with cortical myoclonus and giant SEPs) reflexes of similar latency (C-reflexes) can occur at the same latency as the LLR I
Primarysonsorv cortex
Thalamus
Net cuneatus
Spinal cord
s~
MU'iCle
H-ref1ex A
B
c
~
~-;-.-----'---
~
~II o
100
~
:
_I
~~
~
200 (msl
Fig. I. Reflex pathways of the hand muscle reflexes (top) and normal patterns of reflexes elicited by median nerve (left) and radial superficial nerve (right) stimulation in three normal subjects (A, B, C) (bottom). From Cruccu and Deuschl (2000).
(Shibasaki, 1995). The C-reflex could therefore be an enhanced LLR I. Because electrical stimulation of the median nerve in some patients elicits reflex myoclonic jerks at the same latency as the LLR III (Deuschl and Lucking, 1990; Deuschl, 1992), LLR III could in theory be a transcortical reflex, with a similar argument as for the LLR I. Current evidence, however, suggests that the LLR III has a more complex pathway, possibly including a transcerebellar loop (Claus et aI., 1986). Even for the hand muscles it is difficult to match the various responses evoked by stretch, cutaneous or electric nerve stimulations. Ml corresponds to the H-reflex and M2 to the LLR II/cLLR lIfE 2 responses (see below). But the other responses (Ell cLLR I/LLR I and LLR IIIIcLLR IIIIM3) of the hand muscles are more difficult to compare. Whether
288 they are equivalent across the different modalities of stimulation also remains unclear. For proximal arm and leg muscles the situation is even more complex and further studies are necessary to compare them with the hand muscle reflexes.
19.2.1. Methods Hand muscle reflexes are studied with routine EMG-equipment, using surface electrodes for stimulation and recording. Either the median nerve or the radial superficial nerve are stimulated at the wrist. The stimulus intensity for the electrical stimulus is kept at motor threshold for mixed nerves and at 2.5 x sensory threshold for sensory nerves (squarewave pulse, 200 p.s, 3 Hz repetition rate). EMG signals are recorded from the abductor pollicis brevis, filtered (5 Hz-3000 Hz), full-wave rectified and averaged (256-512 sweeps). Some commercial EMG-machines have specially implemented filters (integrators) for the rectified EMG. Because these devices sometimes alter the shape of the reflex pattern they should be turned off. It has been shown that rectified and non-rectified responses have different latencies (Kurusu and Kitamura, 1999; Sartucci et al., 1999). The latencies are measured at the onset. Reflexes preceded by a pronounced inhibitory component sometimes have a questionable onset. If the precise onset remains in doubt, the latency can be taken at the point where EMG responses and background activity cross. The amplitude depends on the number and size of subliminal fringe motoneurons and hence on the amount of background activation. But because the rectified background EMG and the reflex size are roughly linearly related (Berkefeld et al., 1986; Meinck et al., 1987; Deuschl and LUcking, 1990) the reflex size can be defined as a fraction of baseline EMG. The duration is simply defined as the difference between the onset-latency and endlatency of the reflex. Mixed reflexes can also be elicited by stimulating the median or ulnar nerve at the wrist and recording from the first dorsal interosseus muscle (Claus and Jakob, 1986; Claus et al., 1986). Cutaneous reflexes can also be elicited by stimulation of finger nerves, e.g. the second finger and recording from the first dorsal interosseus muscle (Jenner and Stephens, 1982). However, far more sweeps are necessary to get clear responses compared with radial superficial nerve stimulation.
G.DEUSCHL
We refer to the original publications for stretch reflexes of the hand muscles (Marsden et aI., 1976; Noth et al., 1985), wrist muscles (Marsden et al., 1976; Rothwell et al., 1980), cutaneous reflexes of handmuscles elicited with airpuffs (Deuschl et al., 1995) or stretch reflexes of the legs elicited with stretch (Berardelli et aI., 1982) or gait disturbances (Dietz, 1993).
19.2.2. Normal values and abnormal patterns of thenar reflexes Median nerve stimulation elicits the H-reflex (HR) at 25-34 ms in the thenar muscle followed by the LLR I in about 30%, LLR II in 100%, and LLR III in about 20% of normal subjects. The latency of these reflexes depends on the height of the subject. Adult ranges are 35-46 ms for LLR I, 45-58 ms for LLR II, and >68 ms for LLR III (Fig. 1). For normal values see Table 2. Radial superficial nerve stimulation elicits an early cLLR I (35-43 ms) in 35% and a cLLR II (43-59 ms) in 100% of normal subjects (Fig. 1). The cLLR I is never preceded by HR-like responses and is seldom followed by a discernible inhibitory period. The cLLR I corresponds to the E1 after finger nerve stimulation. Stimulation of the superficial radial nerve stimulation only occasionally elicits a cLLR III 00-82 ms). The latency of the hand-muscle reflexes depends critically on the time spent along the peripheral pathways and therefore on the individual subjects' arm-length and conduction velocity. Variance induced by these factors can be reduced in two ways. The first is to use the difference between the LLR and the median nerve HR latency as a measure to assess the central conduction time. The second is to express the LLR-Iatencies as a function of the HR-Iatency according to the following formulas (Deuschl et al., 1985): LLR II-latency =19.3 ms+1.07xHR-latency, LLR I-latency =12.6 ms+0.981 x HR-Iatency. Both approaches permit assessment of the reflexlatency even in patients with peripheral neuropathies. In some of these patients the peripheral conduction velocity is prolonged but the afferent volley remains sufficiently synchronized to elicit the full pattern of LLR.
LONG-LATENCY REFLEXES FOLLOWING STRETCH AND NERVE STIMULATION
289
Table 2 Normal values of the hand muscle reflexes after median nerve stimulation (HR and LLR) or radial superficial nerve stimulation (cLLR) in 102 normal subjects (age: 18-85 years). Mean
SD
SE
Count
Minimum
Maximum
Latency (ms) HR
28.9
2.4
0.2
102
24.1
35.4
LLRI
40.6
2.5
0.5
26
36.8
47.2
LLRII
50.3
3.2
0.3
102
43.1
59.3
LLRill
76.0
4.6
1.0
20
70.3
92.1
cLLRI
37.6
2.6
1.0
7
35.0
43.0
cLLR II
50.2
3.0
0.3
100
43.0
60.0
cLLRill
75.9
3.6
0.7
31
70.0
82.0
Amplitude (mV) HR
1.9
1.1
0.1
102
0.3
4.8
LLRI
0.4
0.1
0.0
25
0.2
0.8
LLRII
1.2
0.6
0.1
102
0.3
3.0
LLRill
0.8
0.5
0.1
20
0.3
2.3
cLLRI
0.4
0.2
0.1
7
0.1
0.6
cLLR II
1.2
0.5
0.0
100
0.3
2.5
cLLRill
0.8
0.5
0.1
31
0.3
2.4
Duration (ms) HR
10.4
2.5
0.2
102
6.0
17.0
LLR I
8.9
7.8
1.5
26
3.0
46.0
LLR II
22.3
5.4
0.5
101
12.0
40.0
LLRill
27.6
8.7
2.0
20
9.0
44.0
cLLRI
10.0
3.7
1.4
7
7.0
17.0
cLLR II
24.0
6.6
0.7
100
9.0
50.0
cLLRill
27.7
6.2
1.1
31
15.0
40.0
Hand-muscle reflexes vary little with age. In adults, the amplitude of the HR, LLR II, and cLLR II show a negative correlation with age. This decrease is small and clinically irrelevant. The maturation of the pattern of cutaneous reflexes has been studied in detail for the reflexes elicited by index finger stimulation (Issler and Stephens 1983; Evans et al., 1990). Up to the age of 8 years, the El can be larger than the E2. Later in life, the E2 predominates. Thenar reflexes in response to median nerve or radial superficial nerve stimulation can show five
distinct types of abnormality: an absent HR, an enhanced HR, an absent LLR II, a delayed LLR II, and an enhanced LLR I. (Table 3, Fig. 2). 19.3. Clinical applications 19.3.1. Intra-axial focal and multifocal lesions
The pathways of the hand-muscle long-latency reflexes cover the larger area of the cervical cord, brainstem, and brain along a narrow pathway. Focal lesions within this pathway lead to abnormal reflex
G.DEUSCHL
290 Table 3 Most typical abnormalities of hand-muscle reflexes and their diagnostic indications. Reflex abnormality
Involved pathway
Typical lesions/diseases
Absent HR
Peripheral reflex pathways
Peripheral neuropathy. radiculopathy
Enhanced HR
Suprasegmental descending projections
Various lesions along the corticospinal or bulbospinal tracts
Absent LLR II
Central reflex arc
Various lesions of the lemniscal pathways. cortex or cortico-spinal tracts; Huntington's disease
Delayed LLR II
Central reflex arc
Mostly demyelinating lesions in multiple sclerosis
Enhanced LLR I
Unknown
Myoclonus of various origin (cortical. subcortical); corticobasal degeneration; Parkinson's disease; essential tremor
patterns (Jenner and Stephens, 1982; Deuschl and Lucking, 1990; Rothwell, 1990). Especially reduced or absent LLR II are found in lesions affecting the afferent pathway to the motor cortex (dorsal columns, lemniscus medialis, thalamus, thalamocortical pathway). An enhanced HR strongly implies damage to the corticospinal tract. radial superficial nerve
·L"", ,~ D
o
100
Almost all the abnormal reflex patterns can be found in multiple sclerosis. The precise abnormality depends on the type of central lesion. The most common findings are an enlarged HR and absent LLR II. The most specific finding, found in up to 50% of patients with multiple sclerosis, is a delayed LLR II (Deuschi et al., 1988; Michels et al., 1993; lovichich, 1994). The LLR seems to yield abnormal findings more often than SEP-testing. It also sometimes provides useful diagnostic information not obtainable by SEPs and transcranial magnetic stimulation (Michels et al., 1993; lovichich, 1994). A similar delay of the LLR II has been found in two patients with adrenomyeloneuropathy (Liao et al., 2001).
19.3.2. Spasticity
~
200 0
'00
200 ems]
Fig. 2. Abnormal reflex patterns in various diseases. (A) shows a normal reflex pattern for comparison with HR and LLR II after median nerve stimulation and a cLLR II after radial superficial nerve stimulation. (B) shows the typical pattern for spasticity: an enlarged HR and an absent LLR II and cLLR II. (C) shows a delayed LLR II and cLLR II with an enlarged HR in Multiple Sclerosis. (D) shows a pattern with an enlarged LLR I and normal HR and normal cutaneous reflexes inessential tremor or Parkinson's disease. From Deuschl and Lucking (1990).
The typical pattern of hand reflexes in disorders associated with spasticity is the enhanced HR with relative amplitudes (multiples of baseline amplitude) of more than 4.5 and an absent or reduced LLR II. It is sometimes hard to decide if an LLR II is still present or not because the statistically defined lower limit for its amplitude is near zero (Table 1). We assume an LLR II to be present (and normal), if its latency is within the normal range (see Table 3) and if it has a discernible amplitude. When the HR is very large, the amplitude of the LLR II following stimulation of the median nerve can be indiscernible probably because the motoneurons are refractory. If the median-nerve LLR II is hard to discern then it is
LONG-LATENCY REFLEXES FOLLOWING STRETCH AND NERVE STIMULATION
especially helpful to test the cutaneous LLR after superficial radial nerve stimulation. 19.3.3. Huntington's disease In Huntington's disease the LLR II-amplitude is reduced or the LLR II (and cLLR II) is absent (Noth et aI., 1985; Deuschl et aI., 1989; Eisen et aI., 1989; Siedenberg et aI., 1999). In contrast to the findings in spasticity, the HR-amplitude is only slightly increased. Choreatic hyperkinesias can occur in a variety of conditions other than Huntington's disease, commonly labeled as symptomatic chorea (Durr et aI., 1995; Sinard and Hedreen, 1995). The available evidence indicates that LLR II is absent only in Huntington's disease, not in symptomatic chorea (Deuschl et aI., 1989; Eisen et aI., 1989). 19.3.4. Parkinson's disease and parkinsonian syndromes The M21M3 reflexes have been found to be increased in PD (Lee et aI., 1983; Lee, 1989; Johnson et aI., 1991). A recent study has shown that this component is decreasing after Pallidotomy (Hayashi et aI., 2001). The same reduction has been found earlier after thalamotomy (Struppler, 1983; Struppler et aI., 1984). Cutaneous reflexes have been studied and the cutaneous inhibitory period (11) after digital nerve stimulation in Parkinson's disease was found to be decreased which is probably related to Parkinsonian rigidity (Fuhr et al., 1992). Median nerve stimulation often elicits an enhanced LLR I. How this finding is related to the symptoms of Parkinson's disease remains unclear. No correlation has been found with rigidity, some correlation with the occurrence of an action tremor. Interestingly, the cutaneous reflexes do not always show this enhanced LLR I component. The enhanced LLR I is usually much larger in Parkinsonian syndromes with reflex myoclonus, e.g. corticobasal degeneration, than in idiopathic Parkinson's disease and is always accompanied by an increased cutaneous LLR I (radial superficial or finger nerve stimulation). In these syndromes the combination of an akinetic-rigid syndrome with apraxia or alien limb syndrome and reflex myoclonus is itself suggestive for corticobasal degeneration (Chen et aI., 1992; Feifel et aI., 1994; Thompson et aI., 1994; Thompson, 1995). Although reflex myo-
291
clonus and especially an enhanced LLR are almost always found in corticobasal degeneration, in the very early stages of disease both may still be normal (Lu et aI., 1998). An open question is whether the abnormal LLR I is found only in corticobasal degeneration or also in other non-idiopathic Parkinsonian syndromes. A recent study found also an increased LLR I in patients with MSA and myoclonus (Salazar et aI., 2000).
19.3.5. Dystonia Earlier investigations of LLR in dystonia showed an increased amplitude of the LLR following stretch of the wrist muscles (Rothwell, 1990). More recent investigations (Naumann and Reiners, 1997) of the electrically-elicited hand muscle reflexes have shown an increased incidence of abnormally enlarged LLR I and reduced amplitudes of the LLR II. Botulinum toxin injections lead to even smaller LLR II.
19.3.6. Cerebellar disease and Friedreich's disease Patients with Friedreich's disease whose HR and LLR-responses are preserved may have an LLR-II latency delay, compatible with delayed conduction within the dorsal columns (Alfonsi et aI., 1992). The enhanced LLR III-response seen in various cerebellar degenerations (Claus et aI., 1986; Alfonsi et aI., 1992) suggests a major role of the cerebellum in the generation of the LLR III.
19.3.7. Essential tremor About 40% of patients with essential tremor have an enhanced LLR I. Only the LLR I to median nerve stimulation is usually enhanced whereas the LLR I to radial superficial nerve stimulation is not (Deuschl et aI., 1987a). A statistical association has been found between reciprocal alternating activity in antagonistic muscles of the tremor bursts and enhanced LLR I amplitude but the pathophysiological significance of this finding remains unknown in essential tremor.
19.3.8. Myoclonus One of the most important clinical applications of hand-muscle reflex testing is the diagnosis and classification of myoclonus.
292
The various forms of myoclonus can be separated by means of clinical and electrophysiological criteria (Shibasaki, 2000). The electrophysiological criteria include LLR-testing, the measurement of the cortical SEP following median nerve stimulation and backaveraging of the ongoing EEG triggered by spontaneous myoclonic jerks. All forms of reflex myoclonus have abnormal LLR, no matter whether their origin is cortical or subcortical (Deuschl and LUcking, 1990). The most common abnormality is an enhanced LLR I. It can occur with or without a giant-SEP or a spike preceding the spontaneous myoclonic jerks by about 15-25 ms. This is mostly interpreted as indicating enhanced excitability of the primary sensory cortex when the SEP is enlarged or of the primary motor cortex when the backaveraging is positive. In some patients the LLR III is enhanced while the LLR I is not (Deuschl et al., 1987b). The LLR enhancement is often associated with an increased amplitude of the later SEP components (N2-P2-N3). Rarely, also the LLR II can be enlarged (Shibasaki, 1995). Some forms of myoclonus are notably difficult to separate from tremors. These cases have been labeled as cortical myoclonic tremor (Ikeda et al., 1990; Toro et al., 1993; Terada et al., 1997). Most of them have enhanced LLRs.
Acknowledgments GD was supported by the Deutsche Bundesministerium fur Bildung und Forschung (Kompetenznetz Parkinson).
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Movement Disorders Handbook of Clinical Neurophysiology, Vol. 1
M. Hallett (Ed.)
© 2003 Elsevier B.Y. All rights reserved
295
CHAPTER 20
Posturography Bastiaan R. Bloem":", Jasper E. Visser" and John H.J. Allum" a
Department of Neurology, University Medical Center St. Radboud, Nijmegen, The Netherlands h Department ofORL, University Hospital. Basel. Switzerland
20.1. Introduction The term posturography literally means "description of posture". The various techniques that are bundled under this term actually have a much wider perspective. First of all, most techniques aim to describe not only posture - that is, the position of various body parts during quiet stance or while being seated - but also the active and passive regulation of balance. Secondly, many posturography techniques provide much more than mere descriptions of posture or balance under unperturbed conditions. Indeed, many posturography techniques actively manipulate posture or balance, thus hoping to learn more about how healthy persons respond to such interventions, and why the underlying regulatory processes fail in patients with postural instability. Finally, although this is not made explicit by the term posturography itself, an inherent component of posturography is an objective assessment using quantitative outcome measures. Thus, simply inspecting subjects with the naked clinical eye is not a posturography technique owing to its qualitative nature. 20.1.1. Why posturography?
Regulation of normal posture and balance is very complex. The central nervous system must be informed continuously about internally or externally generated postural perturbations. To achieve this, different sources of afferent information - visual, vestibular and proprioceptive - need to be gathered,
* Correspondence to: Dr. Bastiaan R. Bloem, MD, PhD, Department of Neurology, 326, University Medical Center St. Radboud, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail address:[email protected] Tel.: 31-24-3615202; fax: 31-24-3541122.
weighted and centrally integrated. Humans require knowledge about the position of the various body segments relative to each other, relative to gravity, and relative to the surroundings - body and earthfixed coordinates - in order to regulate their posture. They also need information about the specific environmental circumstances, such as the nature or stability of the supporting surface on which they stand. This information must be combined with the plans and intentions of the subject, and weighed against the expectations based upon prior experience or specific instructions. If balance is jeopardized, humans can choose from a wide repertoire of different balance reactions, ranging from purely passive postural responses to voluntarily initiated movements. The complex physiological mechanisms underlying these reactions can only be unraveled under carefully controlled experimental conditions, with calibrated control of the environment, standardized bodily perturbations and use of quantitative outcome measures (Table 1). Apart from its use in normal physiology, posturography is essential to disentangle the complex pathophysiology of balance disorders in patients. The "disease focused" eye of an experienced clinician may remain superior in detecting that something is wrong, but has relatively limited accuracy when deciding how balance regulation is affected. For most fallers, multiple factors can be Table 1 Advantages of posturography. • • • •
Standardized and reproducible postural perturbations Quantitative and objective outcome measures Simultaneous recording of multiple variables Ability to selectively manipulate elements of postural control
296 identified that might be causally involved, but it remains difficult to determine their relative importance during a clinical examination. To complicate matters further, clinicians observe the net result of primary pathological processes and secondary compensatory strategies; separating these two aspects often calls for careful experimental manipulation. Posturography can help with this separation, thereby providing a detailed insight into pathophysiological processes. This knowledge is required for optimal development of therapeutic and fall-prevention strategies. Another potential advantage of posturography is its use as a supplement or even surrogate to clinical tests of posture and balance. A drawback of most clinical balance tests is the inherent difficulty in standardizing performance, and the subjective scoring of the outcome. For these reasons, clinical tests of posture and balance have been of limited use for early detection of subjects prone to falls, and as objective outcome measure in intervention studies. Posturography offers interesting perspectives in these fields (Table 1). Important advantages include the delivery of highly standardized postural perturbations, and the ability to quantify balance performance in an objective manner. 20.1.2. Static vs. dynamic posturography
The literature contains descriptions of a wide range of different posturography techniques. Many are custom made and can be found only in selected laboratories, but a few are commercially available. It is common practice to allocate a particular technique to one of two major categories: static posturography and dynamic posturography (Furman et aI., 1993). Although these terms are commonly used, their definitions are surprisingly poor. At first sight, the term static posturography would suggest that only stationary body positions or spontaneous sway oscillations are studied in persons who are quietly standing on a fixed support surface with imbedded strain gauges to measure surface reaction forces. In contrast, the term dynamic posturography is usually equated with experimental settings where standing subjects are actively being perturbed by a moving support surface (Furman et aI., 1993). But how does one classify an experiment where subjects standing on a fixed support surface are being perturbed by external perturbations applied directly to the trunk?
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Or studies where a person's gait is perturbed by a dynamic posturography system hidden in the walkway? And what about studies where subjects are required to balance on an unstable support surface, thereby perturbing themselves? To our mind, static posturography refers to all those techniques that measure quiet standing, with or without an instrumented fixed support surface, and without any physical body perturbation. In contrast, dynamic posturography techniques employ physical perturbations of stance, using either an unstable or motorized support surface, or an external force applied to one or more body parts. A further distinction should be made between these stance techniques and those where a gait task forms the basis of the experiment. These definitions ignore whether or not balance and gait are being manipulated in any other way, for example by eye closure or specific prior instructions. After all, such manipulations can be used with either technique. These definitions also leave aside how posture or balance is measured, again because this is not unique to one particular technique. Note that the initial body position is not specified by these definitions. Although posturography has been used widely to study upright standing persons, interesting information can also be obtained from studies in jumping, seated and even recumbent subjects (Martin, 1965; Forssberg and Hirschfeld, 1994; Perennou et aI., 1997; Bisdorff et aI., 1999; McDonagh and Duncan, 2002). This discussion of definitions sets the stage for the remainder of this chapter. We will first describe the general principles of static posturography. This is followed by an overview of the different types of physical body perturbations, as these determine the difference between the various types of dynamic posturography. The next section deals with the recording equipment that can be used to quantify posture and balance. Use of these outcome measures will be illustrated for various static or dynamic posturography experiments. The subsequent section reviews several options to manipulate posture and balance. We conclude with paragraphs on the shortcomings and possible future developments of posturography. The emphasis of this chapter is on methodology, and outcomes of studies are only mentioned when they serve to illustrate the merits or shortcomings of a particular approach. Given the rapid pace at which new techniques appear, readers
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should not expect a comprehensive summary of posturography variants, but rather an illustration of the rich spectrum of possibilities. 20.2. Static posturography
Static posturography aims to measure quiet standing while subjects maintain stance in a relatively unperturbed state (Overstall et al., 1977; Fernie et aI., 1982; Lord et al., 1991; Collins and De Luca, 1994; Riley et aI., 1997; Winter et al., 1998). Because no external perturbations are used, a relatively long trial duration is required to capture the entire range of spontaneously occurring balance responses. Depending on the type of experiment, trial duration may vary between several seconds up to 30 minutes. Subjects are often instructed to simply stand quietly on a fixed support surface, with eyes opened or closed. More recent approaches involved the use of different types of manipulations to make the balancing task more challenging; these manipulations are outlined in more detail in Section 20.5. Examples include changing the size or texture of the support surface and controlled variations in stance width - ranging from wide to tandem stance (Day et al., 1993; Baloh et aI., 1995; Gatev et al., 1999; Lord et aI., 1999; Rogers et aI., 2001). Somewhere in between static and dynamic posturography are the techniques where self-inflicted body perturbations are used - for example voluntary weight shifts while standing on a stable underground (Beckley et aI., 1995; Ondo et aI., 2000) - or where subjects actively balance on an unstable support surface (Begbie, 1967; Dietz et aI., 1980; Fitzpatrick et aI., 1992; Perennou et al., 1997). An important difference between the various static posturography studies is based on the choice of the outcome measures and the analytical approach of the obtained data, for example whether one assumes a closed or open loop control strategy of balance during quiet standing. Illustrations of actual static posturography experiments will be presented below in the section on recording equipment. 20.3. Dynamic posturography 20.3.1. Moving platforms
Dynamic posturography is best known for its use of moving platforms. In the 1920s and 1930s,
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platforms were introduced that could be rotated relative to the horizontal plane by the manual force of an experimenter (Rademaker and Garcin, 1932). This rotating platform technique gained more widespread recognition by Martin's seminal studies in the 1960s on tilting reactions in man (Martin, 1965). Horizontal "translational" perturbations have also been used since the 1930s, for example by pulling a cord attached to a waggonette upon which subjects were standing (Jongkees and Groen, 1942). Other movable platforms consisted of an unstable support surface (Begbie, 1967), hence the subject's own continuous movements caused the perturbations (Fig. 1A). In the 1970s and 1980s, important new developments took place that were stimulated to a large extent by medical engineering scientists with an interest in balance control among patients (Allum and Budingen, 1979; Nashner et al., 1982; Diener et aI., 1983; Dietz et aI., 1984). One significant improvement was the introduction of powerful torque motors that assured delivery of rapid perturbations (Figs 1B and 1C). These perturbations could be highly standardized across subjects of different height and weight owing to development of servocontrolled motors. An additional new feature was the presence of a visual enclosure that could move along with, or independent from, the movements of the support surface (Fig. 1B). Also, posturography became increasingly computerized, allowing for automatic delivery of sophisticated test protocols with randomly mixed variations of perturbations (Nashner, 1982; Diener et aI., 1983). Such motorized and computerized platforms were among the first devices to be marketed commercially, leading to more widespread use of dynamic posturography in scientific and clinical settings. For many years, the movable platforms were capable of delivering postural perturbations in only one direction, usually the pitch (anterior-posterior) plane. However, in the 1990s physiologists began to develop a new interest in the control of roll (mediallateral) stability (Day et aI., 1993; Maki et aI., 1996). At the same time, epidemiological surveys highlighted the fact that falls in daily life could occur in any possible direction, and that lateral instability could be particularly relevant for understanding the genesis of hip fractures (Nevitt and Cummings, 1993; Greenspan et al., 1998; Lord et aI., ,1999). These new insights formed the basis for the de-
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Fig. 1. Several developments in the field of moving platform posturography. A: An early example of a movable platform. The support surface is attached to two crossed struts and is in equilibrium by itself; subjects standing on the platform render the system unstable - within predefined limits, as determined by physical stops. 1\\10 of the pivots were equipped with potentiometers, thus providing one of the earliest forceplates. Modified after Begbie (1967), with permission. B: Example of a movable platform - manufactured by NeuroCom International, Clackamas, Oregon - where a servo-controlled torque motor delivers highly reproducible postural perturbations (Nashner et al., 1982). This platform has only one axis, hence postural perturbations are restricted to a single direction. The platform movements consist of rotations, co-linear with the ankle joints, or horizontal translations. The visual enclosure can also move, along with or independent from the movements of the support surface. Redrawn after a figure provided courtesy of NeuroCom. C: Example of a dual-axis movable platform that allows for multidirectional postural perturbations: purely forward or backward, purely sideways, and combinations thereof (Carpenter et al., 1999; Allum et al., 2002). 0: Example of a multidirectional movable platform that is driven by gravity. The platform drops when the supporting magnets on three of the four sides of the platform are released, leaving one side attached. The perturbation size can be varied by changing the amount of slack in the suspending cables (controlled by a simple motor). Note the large support surface - 1 m 2 - that permits study of protective stepping responses. Modified after Comrnissaris et al. (2002), with permission.
velopment of multidirectional platforms that could deliver postural perturbations in either the pitch plane, the roll plane, or combinations thereof (Maki et al., 1996; Henry et al., 1998;Allum et al., 2002)see Fig. l C and D. Another interesting area was the
shift in attention from "feet-in-place" reactions where subjects are forced to deal with postural perturbations without moving the feet - to the analysis of compensatory stepping responses. This calls for a large supporting surface, such as the one
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illustrated in Fig. lD. This particular platform, which is driven by the force of gravity, has another useful feature because it can deliver highly destabilizing postural perturbations with a very large rotation angle; an alternative would be to deliver very rapid perturbations by a torque motor. Hence, subjects can be tested around their limits of stability, and this might be necessary to understand the physiological mechanisms associated with actual falling incidents.
missaris et al., 2002; McDonagh and Duncan, 2002). Commonly used stimuli are toes-up rotational perturbations or forward translations, both types leading to a backward displacement of the center of mass (COM). Their counterparts are the toes-down rotations and the backward translations, which both induce a forward body displacement. There are several relevant differences between rotations and translations. First, rotational perturbations more consistently elicit stretch reflexes than horizontal translations because it is easier to drive the rotating platform faster. Second, rotations are subjectively more destabilizing than translations, and this may explain why postural responses habituate less rapidly following rotations. Third, the postural strategies used to restore balance are very different for both perturbation types. For example, hip and knee movements following backward translations are different from those following toe-up rotations, despite a similar amount of ankle joint rotation (Allum et al., 1989). Also, vertical head displacements are differently directed, and often more pronounced following rotational perturbations. A possible theoretical advantage to translations is the similarity to some daily life situations, such as standing in an accelerating bus or train. However, use of "unfamiliar" types of perturbations, such as rotations, may have different benefits to study falling mechanisms, because falls are almost by definition unexpected and unpractised events.
20.3.2. Types ofplatform movements
Movable platforms can deliver various types of postural perturbations (Fig. 2). As mentioned earlier, most platforms can move in only one direction, but more recent versions allow for perturbations in multiple directions (Henry et al., 1998; Rogers et al., 2001; Allum et al., 2002). The platform movements can be divided into: (a) rotations - "toes-up" or "toes-down" - usually around an axis co-linear with the ankle joints, (b) horizontal translations - forward or backward - or (c) purely vertical displacements. A specific variant involves the combined use of rotations and translations, in order to manipulate the amount of ankle rotation (Bloem et al., 2000). Most perturbation types are intended to induce a controlled mini-fall. The purely vertical displacements can be used to elicit startle-like responses or to study landing mechanisms (Bisdorff et al., 1999; Com-
A
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Fig. 2. Different types of platform movements. A: Baseline position. B: Rotational movements of the support surface, usually about the ankle axis as shown here. C: Horizontal translations of the support surface, shown here for the anteriorposterior direction, but medial-lateral or diagonal translations are used as well. D: Combinations of simultaneously occurring rotations and translations (explained in more detail in Fig. 15). E: Purely vertical displacements.
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It is possible to vary the magnitude, velocity and displacement profile of the platform movements. Most investigators use rapid and brief perturbations in order to study defensive postural reactions, in particular a "ramp" perturbation profile as this is optimal for evoking postural responses. Rotational perturbations usually have an amplitude of anywhere between 2 and 10 degrees, and the displacement velocity usually varies between 20 and 150 deg/s; the stimulus duration is always less than 200 ms. A rotation velocity of around 20 deg/s is approximately the lowest threshold to elicit stretch responses, at least in soleus muscles. Horizontal displacements usually have an amplitude of anywhere between 1 and 15 em, and the velocity of displacement usually varies between 5 and 100 cm/s. It must be realized that only the largest and most rapid platform movements are destabilizing for most healthy subjects, and even patients with moderate balance impairment can correct for most perturbations without much difficulty. This is an important drawback when it comes to studying the mechanisms associated with actual falls. For this reason, several investigators have begun to use more destabilizing stimuli, in order to study healthy subjects and unstable patients at the limits of their stability (Schieppati et aI., 1994; Hsiao and Robinovitch, 1998). An alternative to these rapid perturbations is the use of a platform that "oscillates" continuously back and forth at a much lower velocity; the oscillation frequency can be predictable or random (Diener et al., 1982; Maki et aI., 1990; Dietz et aI., 1993; Baloh et aI., 1995; Coma et al., 1999). Such predictable perturbations can be used to study stimulus anticipation and feed-forward postural control mechanisms.
20.3.3. Other types ofpostural perturbations Although dynamic posturography is often equated with moving platforms (Furman et aI., 1993), various other types of stimuli can be used to perturb posture (Table 2). One possibility is the use of external forces applied directly to one or more body segments, such as the trunk, shoulders or waist (Wolfson et aI., 1986; Cresswell et aI., 1994; Gilles et aI., 1999; Rietdyk et aI., 1999). A widely used example is the "postural stress test", where a weight is attached via a cable to a belt worn around the waist (Fig. 3A). Sudden release of this weight
Table 2 Types of physical perturbations, as used in dynamic posturography. External perturbations • Moving support surface o Translation, rotation or vertical displacement o Unidirectional vs. multidirectional o Abrupt vs. continuous (e.g. sinusoidal) o Predictable vs. non-predictable stimuli
• Stimuli applied to upper body parts o Hips o Trunk o Head Self-inflicted perturbations • Voluntary weight shifts • Anticipatory postural responses • Balancing on unstable support surface
induces a rapid postural perturbation which, depending on the direction of the pull, leads to a fall forwards, backwards or sideways. Subjects can compensate for such perturbations in different ways, for example flexion of the hips with forward flexion of the arms - when pulled backwards - or a stepping response (Wolfson et aI., 1986). A drawback here is the difficulty in standardizing the stimulus for subjects of different height and weight, but this can be partially overcome when servo-controlled torque motors deliver the pull. A promising new development involves the use of such motors to deliver perturbations in multiple directions (Matjacic, 2000). Alternatively, subjects can be placed in a forward or backward reclining position, while being supported by a firmly attached cable. Release of this cable then induces a fall forwards or backwards (Do et aI., 1988). Another variant uses an external push applied directly to the pelvis or the trunk (Fig. 3B). An advantage of all these upper body perturbation techniques is the possible relevance for daily life, where subjects are frequently being pushed or pulled aside, for example while walking in a busy crowd. Another advantage of upper body perturbations is the ability to study how afferent sensory information from the pelvis and trunk - "proximal triggers" helps to shape balance corrections. Another possibility is the use of self-inflicted postural perturbations. While such perturbations are "dynamic", the border between static and dynamic
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Fig. 3. Other types of postural perturbations. A: The "postural stress test", where the stimulus is applied at waist level. Note the different types of normal balance reactions, and the absence of postural corrections on the far right. Redrawn from Wolfson et al. (1986), with permission. B: An example of physical stimuli applied directly to upper body segments, in this case the pelvis or shoulders (four different types of perturbations are possible). This set-up was used by Rietdyk et al. (1999).
posturography is hazy because the tests are usually performed while balancing on a static platform. One example is the analysis of voluntary weight shifts in an anterior-posterior or medial-lateral direction (Fig. 4A). These weight shifts can be guided externally, for example by a continuously moving visual stimulus (Beckley et al., 1995), or by fixed visual targets towards which the subject has to move (Ondo et al., 2000). Alternatively, subjects can be asked to shift their weight as far as possible. Such experiments provide valuable insights into the actual and perceived limits of stability under normal and pathological conditions. A second example of selfinflicted postural perturbations involves the use of voluntary upper body movements, such as weight lifting or raising the arms (Fig. 4B). This type of experiment is well suited for the study of anticipatory postural responses (Cordo and Nashner, 1982; Paulignan et al., 1989; Aruin and Latash, 1996; Benvenuti et al., 1997). A third option is to use an unstable rocking support surface, so that subjects
perturb themselves by their continuous shifts in the COM (Figs. lA and 4C). A final possibility formally beyond the range of posturography as we have defined it - is to study posture and balance in freely moving subjects, for example while walking or climbing stairs. Such gait assessment techniques are common to those of posturography and are described in Chapter 2.20. 20.4. Recording equipment 20.4.1. General principles
Inherent to all posturography measurement techniques is the ability to quantify posture or balance in an objective manner. This can be achieved in various different ways (Table 3). One widely applied option is the use of biomechanical outcome measures, which can be separated into kinematics - analysis of how body parts move - and kinetics - analysis of forces and joint moments. Another possibility is the
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Fig. 4. Various types of "self-inflicted" postural perturbations. A: Voluntary weight shifts, in this example guided by two visual targets and display of the person's own center of foot pressure. B: Lifting of a weight. C: Balancing on an unstable support surface.
use of electromyography (EMG) to describe muscle activation patterns. We will first describe these different techniques separately. This is followed by an illustration of the combined use of different modalities ("multimodal posturography").
20.4.2. Kinematics
The body's kinematics can be recorded in different ways. An early application in this area involved the use of cinematography (Martin, 1965), but this
Table 3 Recording equipment and outcome measures. Equipment
Outcome measures
Kinetics
Forceplates
Center of foot pressure Torques Shear forces and moments
Kinematics
Motion sensors • Linear or angular • Displacement, velocity or acceleration
Center of gravity Segment motion
Optical motion analysis
3-D spatial representation of body (parts) in time
Surface electrodes Needle electrodes Inserted wire electrodes
Background muscle activity Individual postural responses Postural synergies
Electromyography
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technique was hampered by low sampling frequency. Another possibility is the use of lightweight position or motion sensors that can be attached to different body segments in order to record their position and, provided the sampling rate was fast enough, velocity or acceleration (Fig. SA). Ideally, such sensors should not interfere with the subject's natural movements. Linear or angular accelerometers may also be used to record acceleration directly. The information derived includes absolute changes in joint angles, and changes in the position of body segments relative to each other or with respect to an earth fixed joint. This approach has been used to quantify movements of the head, trunk, arms and upper or lower legs. Recordings from multiple body segments can also be used to arrive at an estimate of the COM (Peterka and Black, 1990). As such, kinematic studies can provide insight into postural strategies: fixed movement patterns of different body segments with respect to each other that are used to restore balance in response to specific postural perturbations. Examples of such postural strategies include the ankle strategy - where small support surface translations lead to movements that occur predominantly about the ankle joint - and the more complex "multi-link" strategy - where rapid translations or rotations of the support surface induce multisegmental movements, involving the ankles, knees and hips (Allum et aI., 1989; Allum and Honegger, 1992). One use of motion sensors is illustrated in Fig. SA, and more detailed in Fig. 6, which shows two lightweight angular velocity transducers that are mounted orthogonally in a portable box attached to a waist-worn belt (Allum et aI., 2001; Gill et aI., 2001; De Roon et aI., 2003). Depending on their orientation with respect to upright, these sensors can measure the angular velocity of the lower trunk in two different directions - usually the pitch and roll plane. This device can be used to quantify the kinematics of the trunk for both stance and gait tasks of posturography, for example during quiet stance, while climbing stairs or while undergoing a sudden pull at the shoulders from behind (Fig. 6C, D and E). Using mathematical integration or differentiation, the angular velocity signals can be converted into angular displacements or accelerations. Note that upper body movements in freely moving subjects have also been measured using linear accelerometers, but here one must
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correct the sensor output for the subject's body inclination (Moe-Nilssen, 1998). A drawback of motion sensors is that these only provide information on the body segments on which they are mounted. A more attractive, but also more expensive and complex possibility involves the use of optical motion analysis systems for stance and gait tasks, which can visualize overall body movements (Fig. SB). Such systems use multiple - up to six - cameras that are aimed at the subject from different angles. These cameras monitor signals derived from markers that are generally attached to standard anatomical landmarks, such as the acromion or lateral malleolus. Other systems use passive reflective markers that reflect the light of a centrally positioned source. Further variants use diodes that actively emit infra-red light. Use of multiple markers - usually about 20 - assures that body segment motion can be viewed in multiple planes. Use of many cameras assures that each marker is "seen" throughout its full range of movement, and permits calculation of marker position in three-dimensional space. The resultant coordinates can subsequently be connected to generate a "stick figure" representation of the human body moving in three-dimensional space (Fig. SC). 20.4.3. Kinetics
Measurement of kinetics provides a net estimate of active and passive contributions to joint torques comprising the postural neuromuscular response. This offers a clear advantage over kinematic measures and EMG, because active muscle forces as well as the viscoelastic properties of stretched tissues can be estimated. In early experiments, only reactive forces at the ankle joints were assessed in a simple manner, for example by placing subjects with one foot on each of two scales and recording the difference in pressure from both feet. Nowadays researchers use forceplates equipped with multiple strain gauges that are embedded into a supporting platform (Fig. 7A). These strain gauges measure the postural reaction forces exerted by the feet onto the platform during standing. From this information, the center of foot pressure (COP) and the reactive torques can be calculated. Most forceplates record only the vertical reaction forces - from which the anterior-posterior and medial-lateral directed torques can be calculated - but some also measure the
Fig. 5. Outcome measures used in posturography; similar systems are also used for gait analysis. A: Different types of motion sensors. These sensors can be linear or angular. B: Optical motion analysis systems. Note the two different types of markers. C: Example of a three-dimensional "stick figure" representation of a healthy person while balancing on a tilting platform, as derived from an optical motion analysis system.
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Fig. 6. Illustration of the use of motion sensors. A: Two orthogonally mounted angular velocity transducers are attached to a waist-worn belt (SwayStar, manufactured by Balance Int. Innovations, Switzerland). The recorded angular velocities are transmitted to a PC interface via a long cable (Gill et aI., 2001; Allum et aI., 2001; De Hoon et aI., 2003). This permits measurement of trunk sway in freely-moving subjects, for example while climbing stairs (A). or while responding to external perturbations. B: Angular velocities of the trunk in the roll and pitch plane are illustrated for a young healthy subject while standing quietly (C), while climbing stairs (D) and while receiving a sudden shoulder pull from behind (E).
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horizontal (shear) forces and moments. The COP deviations are estimated from the torques, assuming the body can be modeled as an inverted pendulum, with control of equilibrium originating in the lower extremities. With a multi-joint model of posture, torques at each joint can be estimated from recordings of segment inertias and angular deviations of the segments (Rietdyk et al., 1999). We will illustrate the use of COP recordings for a static posturography experiment. The spontaneous sway oscillations of the human body while standing upright are difficult to detect with the naked eye, but cause measurable movements of the COP. These movements can be plotted as a function of time (Fig. 7B). Alternatively, displacements of the COP in one direction can be plotted as a function of displacement in another direction, creating so-called "spaghetti plots" within a horizontal plane (Fig. 7C). Various summary derivations can be obtained from the COP recordings (Table 4). Stabilogram-diffusion analysis is an interesting approach to analyze
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whether COP trajectories behave as random walks (Collins and De Luca, 1994; Mitchell et al., 1995). This provides physiological information about the underlying balance control mechanisms, and is sensitive to changes that occur with balance disorders such as Parkinson's disease. However, there are various other approaches to analyze the changes in COP, particularly in relation to changes in the COM and EMG (Fitzpatrick et al., 1992; Winter et al., 1998; Gatev et al., 1999). Note that COP recordings are often equated with "body sway", but this is only correct if the body moves as a rigid pendulum - which is often not the case - and only when sway angles and the inertial forces are small. Sway can refer to the movements of the body's COM in three-dimensional space. It can also be used to describe how certain parts of the body "sway", for example the trunk. During balance control, we try to keep our "sway" within certain safety limits. The vertical projections of reaction forces onto the platform are not always a good
Fig. 7. Analysis of the center of foot pressure (COP). A: Illustration of strain gauges imbedded into the support surface. As shown here, most forceplates have strain gauges in all four comers. This particular forceplate can record both the vertical and horizontal reaction forces - indicated by x, y and z. B: Plotting of the COP in the medial-lateral (x) and anteriorposterior (y) directions, as a function of time. C: Plotting of the COP in one direction as a function of displacement in another direction. Figures Band C were redrawn from Collins et al. (1994), with permission,
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Table 4
20.4.4. Electromyography
Derivatives of static posturography measurements.
Another commonly used outcome measure is EMG. Inserted needle studies are anatomically more focal than surface EMG, but are rarely used because these might interfere with the subject's natural movements and because they present small health risks. Inserted wire electrodes hardly interfere with movement, but record only from a small portion of the muscle and produce comparable interindividual variability as surface electrodes (Horstmann et al., 1988). Surface EMG is therefore most used widely. Here, drawbacks to consider include the problem of crosstalk, the variable impedance - both across and within subjects, even during a particular experiment - and the need to normalize EMG responses for intra- and interindividual comparisons. No normalization procedure is generally accepted as the best, but one possibility is to relate EMG response amplitudes to an independent measure of maximal muscle contraction, achieved either voluntarily or by a supramaximal nerve shock (Bloem et al., 1996). Surface EMG can be used for various purposes. First, it can be used in a quantitative manner, for example to provide an estimate of background muscle activity (BGA) levels in "resting" muscles when standing quietly. This BGA depends on many variables, such as the specific posture of the person and the anticipated balance threats. For example, recordings during quiet stance suggest that BGA in the tibialis anterior muscle rarely exceeds 5% of maximal voluntary contraction (Panzer et al., 1995). Considerably higher activity can be noted in persons who actively assume a stooped "parkinsonian" posture (Bloem et al., 1999). Online visual or auditory feedback of BGA could be used as a feedback mechanism to assure a consistent posture over time within a given individual, or across different subjects. Levels of BGA are often abnormal - usually increased - in patients with balance disorders. This can be caused by the underlying disease process, e.g. rigidity in Parkinson's disease, a fear of falling, an abnormal stance, e.g. a stooped posture, or a combination of these factors (Bloem et al., 1993; Horak et al., 1996; Carpenter et al., 2001). During dynamic posturography experiments, surface EMG can be used to measure active balance reactions in individual muscles. These postural responses can be characterized in terms of onset
• Summary statistics (Furman et aI., 1993) o Anterior-posterior displacement of center of foot pressure (COP) o Medial-lateral displacement of COP o Displacement area o Displacement path o Power spectrum • Stabilogram-diffusion analysis (study of random walks) (Collins and De Luca, 1994) o Diffusion coefficients o Scaling exponents o Critical point coordinates • Stiffness measures (Fitzpatrick et aI., 1992; Winter et aI., 1998; Lauk et aI., 1999; Loram et aI., 2001) • Torques
description of sway. In fact, the COP is a reflection of the controlling elements, that is, of the passive and active forces that try to prevent sway from becoming excessive. COP recordings are therefore more dynamic than sway recordings, particularly when the subject's sway is relatively fast. These differences are illustrated in Fig. 8 for both static and dynamic conditions. Calculations of such timing differences error signals - between the COP and COM have been used to estimate stiffness (Winter et al., 1998; Loram et al., 2001). Measurements of COP can be used in an attempt to standardize each individual's baseline posture prior to every trial within a given experiment. For example, the COP can be sampled at the beginning of an experiment while the subject assumes a preferred stance position. During the experiment, subjects can be confronted with on-line visual feedback of their actual COP, relative to their own "preferred-stance" reference values. Using this visual feedback, subjects can be asked to maintain their COP within a predefined range. This helps to prevent subjects from gradually changing their initial position, either due to fatigue or due to stimulus anticipation (Bloem et al., 1999).
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Fig. 8. A: Recordings of the center of foot pressure (COP) and center of mass (COM) for a single subject under static conditions - quiet stance on a stable platform. Note that the COP moves more rapidly and with a greater amplitude than the COM. This figure was redrawn from Winter (1990), with permission. B: Similar recordings under dynamic conditions in a single upright standing subject, whose balance was perturbed by a sudden toe-up rotational movement of the support surface. Note again the difference in dynamics between the COP and COM.
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latency, duration and amplitude - the latter can be calculated as the area under the curve, or as the peak amplitude. Such calculations are essential to evaluate the modifiability of postural responses according to functional demands, and to determine whether and how such postural responses are pathologically changed in patients with balance disorders. Onset latencies are usually defined by the moment when the response amplitude consistently exceeds a predetermined level of prestimulus BGA, typically by
Individually determined onset and offset of response
more than two standard deviations. More difficulty arises when the response amplitude and duration from this onset need to be determined. This problem is illustrated schematically in Fig. 9. Some responses, in particular the early occurring stretch reflexes, have a clear onset and offset. In this case, response amplitudes can easily be calculated, and comparisons between differently sized and differently timed responses are straightforward (Fig. 9A). However, for many other responses the precise offset
Fixed time windows
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Fig. 9. Calculation of EMG response amplitudes. A: Determining the exact onset and offset of each individual response provides accurate estimates of response duration (d), and distinguishes between similarly shaped responses with a different amplitude (a) - response types 1 and 2. However, this technique cannot distinguish between differently shaped responses with a similar area under the curve, such as response types 1 and 3. Additional problems arise when the response offset is unclear, for example due to blending with later occurring responses (response type 4). B: Calculation of net EMG activity over a fixed time window - irrespective of any identified response onsets - is functionally informative as it reveals how much balance correcting activity is present at a given stage of the postural reaction (Carpenter et al., 1999; Allum et al., 2002). Delayed onsets are thus "translated" into a low level of EMG activity - compare response types 1 and 2. A drawback is the lack of insight into actual reflex behavior, for example delayed onsets or changes in waveform. C: Calculation of response amplitudes over a fixed time window following response onset avoids contamination by later occurring responses (Hansen et al., 1988; Beckley et al., 199Ib). A disadvantage is the differential outcome for responses with a different waveform. Thus, amplitudes for response types I or 2, which rapidly reach their peak amplitude following onset, are relatively overestimated relative to response type 3. D: A final possibility is to determine the peak amplitude of each postural response and to calculate the response area over a fixed time interval on each side of this peak (Grey et al., 2002). This method gives a good estimate of the maximal response size. Problems are the difficulty in identifying the peak - certainly in single subject traces - and the need to have variable intervals for differently shaped responses.
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and onset latency remain unclear due to blending with a subsequent other response, or with tonic bursts of voluntary muscle activity.This problem can be addressed in three different ways. First, response amplitudes can be expressed as the average magnitude of the EMG signal within a predetermined and fixed time window (Fig. 9B). Based upon prior knowledge of postural control in healthy subjects, such time windows can be rationally determined in order to "capture" the expected appearance of relevant postural activity (Carpenter et aI., 1999). Examples of such predetermined time intervals are 40-100 ms from stimulus onset - to capture stretch reflex activity - or 120-220 ms - to capture balance correcting responses. An advantage is the direct functional relevance to postural control: is there little or much activity in a particular muscle during important stabilizing periods? A disadvantage is the obscured insight into merely delayed responses. For example, lack of EMG activity within a given time window could be caused by either complete absence or a mere delay of the normal response; in the latter case, the delayed response would show up in a later window, giving rise to increased activity that could be falsely interpreted as "compensatory". The second approach accommodates this drawback by means of a fixed time window that starts at the measured onset of the postural response (Fig. 9C). For example, amplitudes can be calculated over a fixed 75 ms window following onset of the response (Hansen et al., 1988). Although this technique does not always encapsulate the entire response duration, it effectively avoids contamination with later response activity without blurring physiological insights. However, this approach still assumes that onset latencies can be defined correctly. A third approach is to avoid determining the onset of a response and seek its maximum amplitude (Grey. et aI., 2002). Once this is done, the area is calculated over a fixed interval, usually about 50 ms to either side of the maximum. Further interpretation of the response size depends on knowledge of BGA levels, because these show a strong positive correlation to the amplitude of postural responses evoked in stretched and, to a lesser extent, shortened muscles (Bloem et al.• 1993, 1999). It is therefore necessary to take prestimulus BGA into account if valid interpretations of changes in "pure" response amplitudes are to be made.
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Ideally, investigators should aim at keeping the amount of BGA constant within and across subjects, for example by supplying muscles with a constant pre-loading force - standing on a slightly tilted support surface - or by instructing subjects to relax completely. However, a disadvantage is that small differences in BGA, which are likely to persist, may still considerably change reflex amplitudes. Furthermore, this approach may fail in patients with neurological disorders due to their inability to relax or inability to maintain a constant pre-loading force throughout the period of examination. An alternative approach, which consists of an "after-the-fact" mathematical correction for differences in BGA, is therefore often needed. For this purpose, it is common practice in dynamic posturography experiments to record the level of prestimulus BGA, usually over a period of 50-100 ms prior to the stimulus. A common correction technique consists of subtracting this amount of BGA from the average response amplitude. This "difference method" is reasonably effective in correcting for BGA in most subjects, but cannot be used routinely since BGA continues to exert a strong influence on corrected reflex amplitudes in some individuals (Bloem et al., 1993). Covariance analysis is a more flexible correction technique that can be applied routinely to every subject, irrespective of the magnitude of the relation between BGA and response amplitudes (Fig. 10). Covariance analysis is a common statistical procedure designed to remove the influence of a confounding variable by estimating its relation to the dependent variable and providing post-hoc statistical control for this influence, leaving all other sources of variability intact. Once determined reliably, onset latencies and modifiability of response amplitudes can be used as criteria to distinguish between pure reflexes, automatic postural responses and voluntarily initiated movements. Pure reflexes are at one end of this spectrum. These are stereotyped responses to sudden muscle stretch, with an early and fixed onset latency, and a response amplitude that cannot be modified easily. Voluntary postural corrections are at the other end of the spectrum. They can be activated reactively following external postural perturbations, or in a feedforward manner, for example while making selfinitiated weight shifts. Their onset latencies are much later and more variable than those of stretch reflexes, and the magnitude depends on conscious
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decision making. Most balance reactions reside somewhere between the two ends of this spectrum. Their onset latency is rather fixed and too early or invariable to be voluntary, yet factors such as prior instruction or expectation can markedly influence the response amplitude (Horak et al., 1989; Bloem et al., 1995) - see Section 20.6.3 for more details on response modification. For this reason, the term "automatic postural responses" is best used for those balance reactions that are neither pure stretch reflexes nor strictly voluntary movements. The terminology for responses within the category of automatic postural responses is inconsistent and sometimes confusing (Table 5). One approach emphasizes the timing relative to stimulus onset.
Here all automatic postural responses are labeled "long latency", this to distinguish them from the preceding "short latency" stretch reflexes. This proved helpful to describe balance reactions in lower leg muscles following translational perturbations of posture, because most long latency responses occurred in the same stretched muscle (Nashner, 1976). However, rotational platform movements evoke distinct automatic postural responses in antagonist muscles of the lower legs (Diener et al., 1983). This led to the introduction of the term "medium latency" for balance reactions that occurred in stretched muscles; the term "long latency" response was now reserved for the slightly later occurring response in the shortened antagonist
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Table 5 Terminology of automatic postural responses. Named after timing relative to stimulus onset
• Short latency • Medium latency • Long latency Named after presumed postural function
• Simple stretch reflexes • Functional stretch reflex • Balance correcting responses (primary or secondary) Named after supposed underlying circuitry
• Monosynaptic spinal responses • Polysynaptic spinal responses • "Longloop" postural responses
muscle (Fig. 11). The problem with this approach is that medium latency responses, although of shorter duration than long-latency responses in antagonistic muscles, have similar onset latencies. Another approach tries to reflect the presumed function for postural control in its terminology. Thus, some investigators refer to automatic postural responses as "functional stretch reflexes" or "balance correcting responses", thus separating them from the functionally less effective stretch reflexes that occur shortly after the perturbation (Nashner, 1976; Carpenter et al., 1999). Depending on the onset latency relative to stimulus onset, balance-correcting responses can be subdivided into primary or secondary. Recognition of physiological differences among these functionally important responses formed the basis for the parsing algorithms described in Fig. 9B. A third possibility is to name postural responses after their supposed underlying circuitry. Commonly used terms are monosynaptic spinal responses - a synonym for the early stretch reflexes - and polysynaptic spinal responses - to describe the majority of . automatic postural responses in leg muscles. The older literature also contains descriptions of "long loop" postural responses, as a reflection of assumptions that neural pathways involving the brainstem or cortex might be involved in their generation. This term is best avoided for postural responses in the legs, trunk and upper arms, as there is no conclusive
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evidence to support the existence of such long loop pathways in humans. Examples of actual EMG responses during a dynamic posturography experiment are shown in Fig. 12. Most initial studies focused on lower leg responses (Fig. 12A), but later studies went on to analyze more proximal muscles of the upper leg, pelvis, trunk, neck and arms (Fig. 12B). These figures also illustrate how quantitative analyses of individual EMG responses can be used to detect differences in patients with balance disorders, and to study the pathophysiological mechanisms leading to postural instability and falls. For example, recordings from lower leg muscles of patients with a severe polyneuropathy usually show absence of stretch reflexes, as well as a delayed onset and diminished amplitude of balance correcting responses (Fig. 12A). In contrast, patients with Parkinson's disease typically have enlarged amplitudes of medium latency and balance correcting amplitudes in all muscles involved in postural control illustrated for the gluteus medius and paraspinals in Fig. 12B. Apart from providing quantitative measures of individual postural responses, surface EMG can also be used in a qualitative manner to describe the fixed and pre-programmed spatiotemporal activation patterns of automatic postural responses; these are termed postural synergies. For this purpose, it is best to record from multiple muscles spanning different body segments, including the limbs and trunk, because recording from only a few muscles can provide a distorted view of the synergy. An example of this is the frequently mentioned "distal-toproximal" strategy that is induced by horizontal translations of a supporting surface. Here postural responses seem to appear first in ankle muscles, while subsequent responses can be observed in muscles of respectively the thigh and trunk (Nashner and McCollum, 1985). However, later studies showed that responses appeared in neck and arm muscles even earlier than in the leg muscles (Keshner et al., 1988; Allum et al., 1993; McIlroy and Maki, 1995). Other types of postural perturbations - for example, rotational movements of a supporting surface or forces applied primarily to the trunk - can elicit different postural synergies, with prominent stretch and balance correcting responses appearing first in proximal muscles spanning the hips and trunk (Do et al., 1988; Allum et al., 2002).
Fig. II. Terminology of automatic postural responses, illustrated for the commonly used toe-up rotations which induce a rapid ankle dorsiflexion. Stretched soleus: I = short latency response or monosynaptic spinal stretch reflex; 2=medium latency response, polysynaptic spinal response or functional stretch reflex. Shortened tibialis anterior muscle: 3 = long latency response, balance correcting response or shortening reaction. These automatic postural responses are followed by more voluntary balance reactions (labeled 4) which, although shown here as clearly separate responses, usually blend with preceding balance reactions.
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Fig. 12. Illustration of actual EMG responses, recorded with surface electrodes. A: An example of timing differences, shown for postural reactions to toe-up rotations of a supporting platform in a single patient with dorsal root ganglionopathy. Note the absence of stretch reflexes and clearly delayed balance corrections in the patient. Redrawn and modified from Bloem et a1. (2002), with permission. B: An example of amplitude differences in patients with Parkinson's disease, shown for postural reactions to a sudden tilt of a supporting dual-axis platform (simultaneously to the left and backwards - 2250 in the annotation illustrated in Fig. Ie). Note the increased response amplitudes in patients, as well as their high level of prestimulus background muscle activity. Redrawn and modified from Bloem et a1. (2001), with permission.
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20.4.5. Multimodal posturography
A comprehensive view of postural control is obtained when multiple domains are measured simultaneously, including the kinetics, kinematics and surface EMG. An example is illustrated in Fig. 13 for a dynamic posturography experiment, where young healthy persons were exposed to sudden rotational movements of a supporting platform. The stimulus consisted of a combined movement of a dual-axis platform in both the pitch plane (toes-up) and roll plane (to the left). We will illustrate how the kinematics can help to interpret particular EMG findings. Surface EMG is illustrated for six different muscles, two with bilateral recordings. For example, the stretched soleus shows a clear stretch reflex with an onset at about 50 ms after the onset of first platform movement; this is followed by a prominent burst of activity in the shortened tibialis anterior muscle. In this case, tibialis anterior activity would theoretically help to regain balance control because the COM is forced backwards by the platform movement. Conversely, soleus activity would act to propel the body even further backwards (Dichgans and Diener, 1987). The net influence of these muscle responses on postural control cannot be retrieved from EMG alone. For this, one needs to examine the simultaneously recorded kinetics. The anterior-posterior ankle torque trace first shows a positive deflection shortly after stimulus onset, reflecting the passively increased pressure on the forefeet due to the upward moving platform that stretched triceps surae muscles. This will have been aggravated by the destabilizing plantar flexion force of the stretch reflex in soleus muscle. This is followed by a negative deflection of the anteriorposterior ankle torque, reflecting build-up of active stabilizing forces. Simultaneous inspection of the EMG and torque traces suggests that the tibialis anterior activity would be appropriately timed to generate such stabilizing activity, certainly when a 25 to 30 ms electromechanical coupling delay is taken into account (Allum and Mauritz, 1984). The overall "impact" of the postural perturbation, as well as the result of the stabilizing muscle forces, can be derived from various kinematic parameters. In this experiment, trunk angular velocity in the pitch and roll planes was collected using motion sensors mounted to a metal plate that hung at the level of the sternum (Fig. 13). The trunk initially
pitches forward and rolls towards the right - that is, opposite to the stimulus direction in both planes and is then gradually returned to its initial position, indicating successful restoration of upright balance. Interestingly, these kinematic parameters are nicely paralleled by corresponding muscle activation patterns in proximal muscles. For example, the rightward roll of the trunk is reflected by an early stretch reflex in the right paraspinals, as well as brief release of the left paraspinals. The subsequent bursts of balance correcting activity in both paraspinals help to keep the trunk from falling towards the direction of platform movement. Furthermore, prominent balance correcting activity can be seen in the left gluteus medius, with much less activity occurring in the right gluteus medius. This activity serves to stabilize the pelvis which rotates in the opposite direction to that of the trunk.
20.5. Manipulations 20.5.1. General aspects
A key element of posturography is the ability to selectively manipulate elements of postural control. Two elements are particularly suitable for experimental manipulation: afferent feedback signals stemming from proprioceptive, vestibular and visual sources - and cognitive or postural set. 20.5.2. Afferentfeedback signals
All afferent feedback systems can be manipulated experimentally. This can be achieved in various ways, during both static and dynamic posturography experiments. Broadly speaking, there are three different approaches: (a) reducing or entirely eliminating the feedback signal; (b) distorting the feedback signal, thereby providing false information to the central nervous system; or (c) providing subjects with more (correct) feedback than under normal circumstances. The essence lies in a selective interference with one particular feedback signal, without altering the others. However, this is not always straightforward, as we shall discuss below. 20.5.2.1. Visualfeedback Visual feedback can simply be removed by asking subjects to close their eyes or to provide them with blindfolds. A more elegant manner is to distort visual feedback by providing subjects with faulty or conflicting visual information. Early experiments in
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Fig. 13. Multimodal posturography, showing simultaneous recordings of EMG (multiple distal and proximal muscles), kinematics (ankle torque) and kinetics (trunk velocities), relative to the actual platform movement (a sudden tilt of a dualaxis platform to the left and backwards - 225 0 in the annotation illustrated in Fig. IC). Redrawn and modified from Allum et al. (2002), with permission.
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this field indicated that a moving visual scene could be used to examine a subject's spatial orientation, in particular the perception of subjective and postural verticality (Dichgans et aI., 1972). This technique can also be used to search for causes of postural instability in patients with vestibular or neurological
disorders (Bronstein et aI., 1996). In the example shown in Fig. 14A, seated subjects faced a visual background that was either stationary or continuously rotating at different velocities to the left or right. The visual roll-motion stimuli provided disorienting visual information and created an illusion
Visual roll stimuli Fig. 14. An example of visual feedback manipulation. A: Subjects are asked to align a straight line with perceived verticality while facing a rotating visual scene. B: Perceived visual vertical, as a function of visual roll. Patients with defectivelabyrinthsare more sensitive to visual roll stimuli than healthy controls. STAT =static condition;CW =clockwise rotation at 15, 30 and 60 CCW= counterclockwise rotation at 15, 30 and 600/s. Redrawn and modified from Bronstein et al. (1996), with permission. 0/s;
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of self-rotation. This could be quantified by asking subjects to set a straight indicator line - displayed in the center of the visual scene - in what they presumed to be a pure vertical position. Clockwise rotation of the visual background induced a placement of the indicator line to the right, counterclockwise rotation to the left (Fig. l4B). Patients with a bilateral vestibular deficit showed much larger deviations, suggesting a role for the vestibular system in processing visual biases for the perception of verticality. More recent studies have distorted visual feedback by immersing subjects into a virtual reality environment (Cobb and Nichols, 1998; Owen et al., 1998; Tossavainen et al., 2001). Visual feedback can be enhanced by providing extra "cues", for example stripes on the floor to reduce freezing during walking (Nieuwboer et al., 1997). 20.5.2.2. Proprioceptive feedback Proprioceptive feedback can be reduced through cooling, anesthesia or ischemia of the legs (Dietz et al., 1980; Diener et al., 1984; Schieppati and Nardone, 1997; Grey et al., 2001). These interventions all lead to greater excursions of the COP, suggesting an increase in body sway. Note that neither of these techniques is a purely selective proprioceptive manipulation. For example, limb ischemia or anesthesia reduces proprioceptive feedback, typically only for a short period of time, but may also affect muscle strength which in turn impairs balance control (Wolfson et al., 1995). A better way to eliminate proprioceptive feedback from the lower legs is use of an "ankle nulling" procedure. This can be achieved by fixating the ankle joints, thus preventing proprioceptive feedback originating from joint receptors or stretched lower leg muscles (Gurfinkel et al., 1979). Alternatively, ankle inputs can be nulled by matching the platform movements to the measured movements of the subject (Allum and Honegger, 1998; Bloem et al., 2000). For example, computer-controlled delivery of a simultaneous rearward translation and toes-down rotation of a supporting platform results in negligible ankle movement over the first 250 ms (Fig. 15A). Indeed, ankle motion remains restricted to less than 10 rotation over this period, which indicates that the "ankle nulling" procedure had been successful (Fig. 15B). This is an effective way of eliminating lower leg proprioceptive drive of automatic postural responses. Indeed, short latency
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stretch reflexes are virtually eliminated by this ankle nulling procedure (Fig. 15C). Proprioceptive feedback can be distorted by placing subjects on a thick foam mattress (Baloh et al., 1995; Gill et al., 2001; Rogers et al., 2001). The problem here is that standing on foam may lead to instability simply because the balance reactions are less effective on a compliant surface. Another possibility is applying high-frequency vibration directly over tendons or muscles. This causes massive stimulation of type Ia afferents and thus produces a false impression of muscle stretch. Commonly targeted muscles include the triceps surae, tibialis anterior, gluteus maximus and dorsal neck muscles (Gurfinkel et al., 1988; Pyykko et al., 1991; Lekhel et al., 1997). When vibration is delivered during upright stance with eyes shut, the perceived muscle stretch creates an illusory body tilt and altered perception of body position. Healthy subjects compensate for this kinesthetic illusion by actively moving in the opposite direction of presumed body inclination. Figure 17A illustrates this for blindfolded young subjects who underwent vibration of both Achilles tendons (frequency 70 Hz, amplitude 0.5 mm, duration 25 s). The subjects perceived this as stretch of the triceps surae caused by dynamic forward leaning, and actively compensated by leaning backwards. This is reflected by the COP recordings in the anterior-posterior direction, which show a rapid backward displacement that stabilized after about 3 s of vibration when presumably vestibular and residual proprioceptive signals indicated the body was "vertical" (Fig. 17B). Proprioceptive feedback from the lower legs can be increased using sudden support-surface movements of variable size or speed (Diener et al., 1988; Beckley et al., 1991a). An example is shown in Fig. 15A, where the movements of a supporting platform consist of a simultaneous rearward translation and toes-up rotation. This combined movement induces a greater ankle dorsiflexion than a simple translation (Fig. 15B), thereby leading to an enhanced proprioceptive drive of postural responses. This is confirmed by surface EMG recordings from the soleus muscle, which shows brisk and early stretch reflexes during enhanced ankle input trials (Fig. 15C). A problem with this type of manipulation is that variable support-surface movements not only manipulate lower leg proprioceptive input, but also induce different movements of other body segments.
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Fig. 15. Manipulation of ankle proprioception. A: A rearward platform translation causes ankle dorsiflexion (angle a), but this can be cancelled out by a simultaneous toes-down rotation of the platform which - on its own - would cause ankle plantarflexion. The net result is a "nulled" ankle angle (angle 13). Conversely, the combination of rearward translation and toes-up rotation of the platform - both of which cause ankle dorsiflexion - enhances the overall change in ankle angle (angle 'Y), thus producing "enhanced" ankle proprioceptive drive. B: The net effect ofthese manipulations is reflected by the ankle angle trace, which remains constant within ± 1 over the first 250 ms during ankle nulling trials, but rapidly reaches a large dorsiflexion angle during enhanced ankle input trials. C: Surface EMG recorded from the soleus muscles is consistent with the kinematics, because stretch reflexes (solid arrow) are minimally present during ankle nulling trials, but are brisk and early during enhanced ankle input trials. Note that the subsequent balance correcting responses (open arrow) are hardly affected by these manipulations, suggesting that lower leg proprioception is not required to drive these postural responses. Traces in B and C represent the population average of 15 healthy subjects. Data modified after Bloem et al. (2000), with permission.
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This is by itself enough reason to expect difference balance reactions. Another way of providing increased somatosensory feedback is passive or active touch (Jeka and Lackner, 1995; Riley et al., 1997; Rogers et al., 2001). In the experiment shown in Fig. 16, subjects were instructed to stand on a thick foam mattress during some trials, and on a normal floor during others; this was done with and without visual feedback. To provide subjects with additional somatosensory feedback, subjects were gently touched from behind at the level of either the knees or the shoulders. The results showed a reduction of postural sway with either tactile cue, and simultaneous touch at both levels gave the greatest sway reduction. Furthermore, the effects of touch were most pronounced when baseline sway was greatest, i.e. with foam support, absence of vision, or both.
20.5.2.3. Vestibular feedback An elegant way to reduce the influence of vestibular feedback, along with proximal proprioceptive feedback, was developed by Fitzpatrick et al. (1992). Their subjects were strapped at the head and waist to a rigid post. By rotating their ankle joints, they had to balance a load that was matched to the subjects' own load stiffness - as measured in a separate experiment while normally standing. In this way, an "equivalent body" swayed at the ankles without affecting other sensory inputs. Low intensity electrical (galvanic) stimulation of the labyrinth is a commonly used technique to distort vestibular feedback, presumably by stimulating distal vestibular nerve afferents, particularly those with an irregular discharge (Lund and Broberg, 1983; Goldberg et al., 1984). The central nervous system apparently interprets the galvanic input as roll-tilt of the support surface. Thus, with a positive stimulating current polarity, the body sways in the direction of the mastoid under stimulation. With a negative polarity, the body sways in the opposite direction. These effects depend on the spatial orientation of the head: body sway is in the frontal plane when the head is held in the normal position, and in the sagittal plane when the head is rotated sideways. Vestibular information processing can also be distorted by changing the orientation of the head, for example to a hyperextended position (Brandt et al., 1986). Vestibular feedback can be enhanced using isolated head perturbations (Horak et al., 2001).
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Interpretation of the resultant responses can be difficult because head perturbations also stimulate afferents from the neck and, sometimes, from lower body segments.
20.5.2.4. Weightlessness The effects of weightlessness have been studied by analyzing adaptation of postural control in astronauts during or after space flights (Clement et al., 1984; Speers et al., 1998). Because such unique experimental conditions are rarely available, Dietz et al. (1989) developed an interesting alternative by immersing a movable platform into a large bath. This underwater paradigm reduces the natural force of gravity and permits study of loading mechanisms by providing subjects with a range of different weights, but of course increases the amount of tactile feedback. Such experiments provided valuable new insights into the physiology of load receptors, and their role in the pathophysiology of balance disorders. 20.5.2.5. Combined manipulations It is possible to systematically manipulate multiple sources of afferent information during a given experiment. One example was presented earlier (Fig. 16). However, the most widely used technique is the so-called "sensory organization test" (SOT), which selectively disrupts the subject's somatosensory feedback, visual feedback, or both (Nashner et al., 1982). The SOT uses a movable platform that is equipped with a movable visual surround (Fig. lB). Subjects stand quietly for 20 s during six different conditions, while the platform continuously records displacements of the vertical reaction forces (Fig. 18). An interesting aspect is that afferent feedback is not only eliminated during some conditions - for example eye closure - but also distorted during other conditions with "sway-referencing". Here the platform, the visual surround, or both, move after a small delay in the same direction as, and proportional to, a filtered version of the anteriorposterior displacement of the on-line recorded COP. This creates a false impression of the visual environment or of ankle movements, and forces subjects to rely more upon vestibular sensations and proprioceptive input from joints other than from the ankle to remain standing. A problem is that the SOT assumes that posture behaves as an inverted pendu-
Fig. 16. Influence of external touch on postural sway, assessed using an optical motion analysis system. A: Somatosensory feedback was enhanced by providing an external tactile cue to the knees, the shoulders, or both. Additional manipulations included eye closure - yes or no - and alterations in support surface - firm floor or foam mattress. B: Touch of the shoulders and, to lesser extent, the knees reduces static sway. Combined touch was most effective in reducing sway, particularly when visual and lower leg proprioceptive feedback was reduced. Data redrawn and modified from Rogers et al. (2001), with permission.
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Fig. 18. The six different test conditions of the Sensory Organization Test (Nashner et al., 1982). Condition I: all sensory inputs available. Condition 2: absent visual feedback. Condition 3: distorted visual feedback because visual surround is "center of pressure referenced" (movements are proportional to the anterior-posterior displacement of the COP). Condition 4: distorted somatosensory feedback because supporting platform is "center of pressure referenced". Condition 5: same as condition 4, but now with eyes closed. Condition 6: distorted visual and somatosensory feedback because both visual surround and supporting platform are "center of pressure referenced". Redrawn after a figure provided courtesy of NeuroCom.
lum, but this is not always the case. For example, head movements appear to precede, rather than follow, the movements of the visual surround, suggesting a "top-down" control of posture with the head as the primary target for postural correction (Di Fabio et al., 1998).
20.5.3. Postural and cognitive set
A popular area of research focuses on "postural set": manipulating the functional demands of the ongoing postural task. This rather vaguely defined term covers a widespread array of conditions
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Table 6 Manipulations of postural or cognitive set. Actual changes in environmental situation • Stimulus characteristics o Direction o Size o Velocity o Acceleration o Duration
• Nature of support surface o Size o Friction • Handrails o Present yes or no o Distance to subject • Touch o Active (e.g. holding on to frame) vs. passive' o Gentle vs. stabilizing force • Physical restraints o Ankle straps o Immobilization (e.g. corset, fixing the trunk to a post) o Supporting harness Changes in environmental perception' • Amount of predictability" o Based upon experience o From prior information - Correct vs. incorrect - Complete vs. partial • Fear of falling • Specific prior instructions (e.g. yield to the perturbation) Changes in initial body position • Sitting vs. standing" • Amount of preleaning'' Multiple tasking • Secondary cognitive task • Secondary motor task • Combinations of cognitive and motor tasks a Under these circumstances, an increased feeling of security (a form of "cognitive set") contributes, possibly together with the fact that additional somatosensory feedback is provided; b changes in postural responses which merely depend upon altered perceptions of the environmental context (and not upon actual changes in the environment) could be referred to as changes in "cognitive set"; C this includes both the functional attenuation of postural reflexes if perturbations become predictable through repetition, and the development of fixed, "default" responses if the nature of upcoming perturbations is unpredictable; d under these circumstances, postural reflexes are altered not only because the functional demands are changed (for example, stabilizing reflexes are not required while sitting), but also because the amount of preloading, and therefore the amount of BGA, is altered.
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(Table 6). Changes in postural responses which merely depend upon altered expectations or perceptions of the environmental context - and not upon actual changes in the environment - are a form of postural set which could be referred to as changes in "cognitive set". The distinction between postural and cognitive set is somewhat arbitrary, because changes in postural set often lead to concurrent changes in cognitive set. For example, allowing subjects to hold on to a manipulandum is quoted as a change in postural set as this provides an additional frame of reference (Schieppati and Nardone, 1991). However, cognitive set is also affected through an increased feeling of security - reduced risk of falls by being able to grasp for support. The opposite can be said about standing on a narrow beam or a slippery support surface (Horak and Nashner, 1986). Interesting perspectives are offered by the ability to vary the amount of prior information about upcoming perturbations; this can be complete, partial - for example only the stimulus size but not its direction or absent, and the information given can be correct or incorrect (Diener et al., 1991; Maki and Whitelaw, 1993). Leaving subjects without prior information provides opportunities to study automatic habituation of postural responses through learning processes (Nashner, 1976; Hansen et al., 1988; Bloem et al., 1998). Another possibility is to evaluate the effects of specific prior instructions, for example to either use compensatory stepping responses or not. Healthy subjects who are specifically instructed not to resist a postural perturbation show a surprising ability to almost completely suppress certain automatic postural responses (Bloem et al., 1995). Two areas have received considerable attention in recent years. One of them is fear of falling, which is a common feature among subjects with balance impairment and prior falls. Recent posturography studies led to growing recognition that this fear may cause secondary deterioration of postural performance (Maki et al., 1991; Carpenter et al., 2001). For example, assessments of stiffness - derived from COM and COP measures - revealed that subjects standing at an elevated stable forceplate resort to a stiffening strategy that is not seen while standing at a much lower height (Fig. 19). In this illustration, stiffness is appropriately seen in the anteriorposterior, but not the medial-lateral plane. The amount of threat can be experimentally varied by altering the height of the platform or the subject's
distance with respect to the edge of the platform, thus modulating the perceived threat. Joint stiffening could have certain advantages, particularly to maximize stability under relatively static, unperturbed conditions such as standing at the edge of a cliff. However, posturography studies using movable platforms showed that under more dynamic conditions, subjects pay a price for their stiffness because the loss of joint flexibility makes them fall like a pushed toy soldier (Horak et al., 1992; Allum et al., 2002). Such all-or-nothing strategies are adopted by unstable patients with very different causes for their balance disorder, apparently in an attempt to control upright stance by standing relatively motionless when unperturbed, but at the expense of inflexibility in case of sudden postural perturbations. Another interesting area focuses on the effects of multiple tasking on postural performance. In daily life, many falls are related to simultaneous execution of a balance task such as walking and another usually unrelated - task, for example talking to someone or carrying an object. Following a fascinating report that inability to walk and talk at the same time accurately predicted falls in frail elderly persons (Lundin-Olsson et al., 1997), many investigators rushed to examine why dual tasking had such deleterious effects on postural control. Posturography experiments and gait studies proved helpful in quantifying the effects of different secondary tasks (Geurts et al., 1991; Shumway-Cook et al., 1997; Morris et al., 2000; Maki et al., 2001; Yardley et al., 2001). 20.6. Safety All platforms are equipped with safety measures to prevent actual falls. In many laboratories, persons are instructed to wear a safety harness that is secured with straps to an overhead ceiling. The amount of slack in the straps permits natural body movements within safe limits. Another possibility is the use of safety bars, so subjects can grasp for support in case of an imminent fall. This feature actually offers interesting research perspectives, because protective arm movements are an important element of the normal balance repertoire. Some groups have taken this to their advantage and performed interesting experiments where the distance to the safety bars was experimentally manipulated; this provided interesting insights in the automatic and cognitive
326
B.R. BLOEM ET AL.
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Fig. 19. Illustration of cognitive set manipulation. A: The amount of perceived postural threat ("fear") can be altered by placing subjects at either ground level or at an elevation. B: Standing on the elevated platform is associated with increased stiffness in the anterior-posterior direction, but not in the medial-lateral direction. Redrawn and modified from Carpenter et al. (2001), with permission.
regulation of protective ann responses (McIlroy and MaId, 1995; Maki and McIlroy, 1997). Some groups use a movable platform with a relatively small surface. To prevent subjects from stepping of the platform, the subject's feet can be lightly strapped into heel guides fixed to the top surface off the platform (Carpenter et al., 1999; Allum et al., 2002). An additional advantage is that these heel guides - which are adjustable in the anterior-posterior direction - can be used to ensure that the ankle joint axis is always aligned with the
axis of the rotating platform. An obvious drawback is that compensatory stepping responses cannot be investigated, and this creates a "bias" towards use of compensatory trunk and ann movements. In the few studies where actual falls were induced, the support surface consisted of a thick mattress in order to cushion the impact of the fall (Hsiao and Robinovitch, 1998). Apart from these safety measures, most research groups ensure that at least one experimenter is standing next to the subject, to provide additional support if needed.
POSTUROGRAPHY
When these safety measures are adhered to, posturography is a safe procedure (Furman et al., 1993). The authors have never seen accidental falls in their own experiments - involving hundreds of healthy subjects and patients with range of balance disorders - and are not aware of such incidents in other laboratories. Patients may be fatigued after the experiments, but this can be reduced by providing sufficient seated rests in between trials. For some patients, participation in a posturography experiment can be a painful confrontation with their physical handicaps, and this occasionally leads to emotional reactions. Nausea and anxiety reactions are rare. 20.7. Limitations Several important drawbacks - mainly to dynamic posturography - are listed in Table 7. The ecological validity of posturography remains uncertain. Subjects are tested in a high-tech laboratory setting where they are mounted with various recording devices, all this after having given prior informed consent. Hence, subjects are much "prepared" to sustain physical perturbations and are more consciously aware of their equilibrium. Furthermore, balancing on a moving support surface is unusual in daily life, except for standing in accelerating buses or trains. Some feel that this "unusualness" of moving platforms could actually be seen as advantageous, because falls themselves are unusual and unpracticed events. In this respect, a potentially greater drawback is the need to average the results of Table 7 Shortcomings of dynamic posturography. • Poor ecological validity a Use of unnatural stimuli a Need for a safety measures (harness or handrails) a Laboratory setting with prior informed consent a Averaging required to separate signal from noise a Aspecific compensatory strategies • • • •
Test-retest reliability largely unknown High intra- and intersubject variability Responsiveness largely unknown Feasibility problems a Complex instrumentation a Labor intensive data analysis a Expensive
327
multiple trials to separate true signals from the noise. Stimulus repetition leads to habituation of postural responses (Nashner, 1976; Hansen et al., 1988; Bloem et al., 1998), and this obscures a direct comparison to falls in daily life which are typically single, unexpected events. The need to employ safety measures also creates problems, as this may potentially affect postural performance in various ways. For example, the safety harness may create a feeling of safety in patients who are normally fearful of falling, thereby concealing secondary changes in postural control. In addition, the harness may supply persons with additional somatosensory feedback about the position of proximal body segments. One study found no major effects of the safety harness on dynamic postural control (Hill et al., 1994), but this issue must be examined in more detail under different experimental conditions. A further disadvantage of dynamic posturography is the general emphasis on how postural control looks, rather than functional ability (Tinetti, 1986). For example, patients with chronic disease can have a markedly impaired posture when tested in the laboratory, yet maneuver safely and effectively in daily life due to development of compensatory strategies. Such compensatory strategies markedly hamper the interpretation of findings in patients with longstanding balance disorders. Most dynamic posturography tests correlate poorly to accepted clinical tests of balance control (Bloem et al., 1998; Evans and Krebs, 1999). A general problem that hampers validity studies in this field is the lack of a golden standard for postural control. Thus, in face-to-face comparisons to medical judgment, a poor sensitivity of a particular posturography test can equally be interpreted as a false positivity in the clinical assessment. Some of the observed "differences" between patients and control populations may be artifacts of variations in initial posture. For example, many patients with balance disorders tend to adopt a stooped posture - even while seated! - and often this gradually increases over time during the experiment (Hirschfeld, 1998; Bloem et al., 1999). Such changes in baseline stance lead to different movement patterns following external perturbations, and may induce changes in pre- and post-stimulus muscle activity. Investigators should therefore not rely on EMG analyses alone, but use kinetics and kinematics to control for changes in baseline body position.
328 Other basic performance measures of posturography also remain largely unknown. For example, the test-retest reliability has rarely been examined and - if available - applies only to the specific experimental conditions and populations for which it was studied (Goldie et aI., 1989; Ishizaki et aI., 1991; Hill et aI., 1994; Ford-Smith et aI., 1995; Clark et aI., 1997; Tarantola et aI., 1997; Benvenuti et aI., 1999; Corriveau et al., 2000). Various studies reported a considerable inter- and intra-individual variability (Nashner, 1976; Geurts et aI., 1993; Takala et aI., 1997; Cobb and Nichols, 1998). Such reliability measures are required to interpret findings in patients with fluctuating clinical symptoms, and are essential if posturography is to be used as an objective outcome measure during intervention studies. Many outcome measures merely provide a "keyhole view" of postural performance. For example, measurement of sway in only the sagittal plane negates the importance of roll instability. Similarly, EMG can only be recorded from a limited number of muscles at a time, hence any inferences must be restricted to these measurements alone. Also, EMG alone provides little functional information because it is difficult to derive forces from muscular activation during dynamic contractions. An occasional problem with outcome measures is the uncertainty about data interpretation. More sway is usually equated with poorer performance, but this is not necessarily so: subjects standing with eyes shut may purposely resort to larger sway oscillations because this enhances afferent feedback about postural poorer performance from other sources, such as the vestibular system (Coma et al., 1999). A more general drawback relates to the high costs and technical complexity of dynamic posturography. This prevents more widespread clinical use in clinical settings. 20.8. Physiological and clinical utility 20.8.1 Insights into normal postural control
The greatest utility of posturography remains undoubtedly in studies of normal postural control in humans. Posturography studies have been instrumental in clarifying the role of isolated afferent feedback systems, and how different afferent signals are centrally integrated and "translated" into correc-
B.R. BLOEM ET AL.
tive balance responses. Using batteries of objective and quantitative outcome measures, posturography has helped to delineate the different types of balance corrections, ranging from purely passive factors body inertia, viscoelastic properties of stretched ligaments or muscles - to complex and preprograrnmed postural strategies. In addition, posturography studies have shed new light on the interactions between cognitive processes, voluntary intent and "automatic" postural responses. 20.8.2. Patients with balance disorders
In 1993, a specialist panel agreed that static posturography was unlikely to become an efficacious diagnostic test for patients with balance disorders (Furman et al., 1993). At the same time, this panel regarded dynamic posturography as a "promising" technique for the assessment and, possibly, the management of patients with balance disorders. A decade later, the overall utility of dynamic posturography in this field remains unconvincing, mainly because of the difficulties outlined in Section 20.7. Only few studies have produced convincing results with a potential to change the diagnostic approach or management of patients with balance disorders. One example of a practically relevant result came from a study that examined the real-life accelerations of trains and buses; when elderly persons were subsequently exposed to such linear accelerations during a posturography experiment, many lost their balance (De Graaf and Van Weperen, 1995). Such findings could influence policy makers to set a legal upper limit to accelerations in public transport vehicles. However, most studies thus far produced results that, although scientifically interesting, had little bearings on everyday clinical practice. 20.8.2.1. Selective lesion studies Perhaps the greatest utility for posturography lies in studies of patients with balance disorders caused by "selective" lesions of the central or peripheral nervous system. According to classical neurological teaching, normal functions of the nervous system can be estimated from studies on patients with selective lesions in areas that normally supply a particular function. Lesion studies could therefore provide insight into normal balance control. This approach has been applied widely and produced
329
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neuropathy is often used as a model of selective proprioceptive loss, but in fact such patients often show at least some degree of paresis upon careful examination.
interesting insights into the effects of selective lesions in, for example, the vestibular system or specific parts of the basal ganglia. However, such "lesioning studies" must be interpreted with caution, particularly if chronic patients with long-lasting balance impairment are used to attribute functions to the nervous system for postural control. Various factors obscure the interpretation of balance abnormalities in any study of chronically unstable patients, in particular the ability of such persons to develop striking compensatory strategies to cope with their longstanding balance disorder. Examples include a stooped posture - to protect against backward falls - and a stiffening strategy to minimize static sway. Such compensatory mechanisms seem more or less "generic" as they are used by patients with very different causes for their balance disorder. Other confounders include secondary physical changes due to immobility, for example contractures, and the ability of the nervous system for neuronal reorganization (plasticity). In addition, the question remains how selective a particular lesion is. For example, a diabetic sensory 0.6
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20.8.2.2. (Early) diagnosis Dynamic posturography can reveal clear abnormalities in groups of patients with balance impairment, as compared to control groups of healthy subjects. For this reason, dynamic posturography has been advocated as a potential screening tool for mild balance abnormalities, thus providing an objective and early marker for subjects at risk of falls. However, not one study has convincingly shown that posturography is superior to the clinical opinion of experienced physicians when patients with mild dysfunction must be detected. For example, at a group level, medium latency stretch responses to sudden toe-up rotational movements of a supporting forceplate are increased in patients with Parkinson's disease (Fig. 20A). Individual analysis reveals that only a few patients with the most advanced disease are responsible for this group difference, rendering
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Fig. 20. Early detection of postural abnormalities in individual patients, as illustrated for medium latency (ML) stretch responses evoked by sudden toe-up rotations of a support surface. A: There is a clear increase in ML-amplitudes for patients with Parkinson's disease as a group (N=23) compared to the control group (N=24). *=P<0.OO05. B: Individual analysis of ML-amplitudes shows that only few patients are responsible for the observed group difference. Most of these patients had advanced Parkinson's disease, indicating that ML responses cannot be used for individual analyses. Abbreviations: H&Y = Hoehn and Yahr stages; PD=Parkinson's disease. Redrawn from Bloem et al. (1992), with permission.
330
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this abnormality completely unsuitable for early detection purposes (Fig. 20B). Even among patients with clinically overt disease, posturography cannot be used to make a reliable diagnosis in individuals, nor can it be used to localize a specific lesion in the central nervous system. Indeed, most postural abnormalities reported thus far are not specific for a particular disease. This lack of overall individual diagnostic utility can be ascribed in part to the shortcomings of posturography - see Section 20.9. The presence of aspecific compensatory strategies is also responsible for the overlap across different types of balance disorders. For example, instability under conditions 5 and 6 of the SOT (Fig. 18) is often interpreted as evidence for vestibular loss (Nashner et al., 1982; Furman, 1994). However, most unstable patients - irrespective of the cause of their postural deficit - have greatest difficulty with these two test conditions, simply because they are most demanding. Therefore, posturography cannot be used for the differential diagnosis of balance disorders. There are perhaps two exceptions. One is primary orthostatic tremor, where power spectrum analysis of body sway during quiet stance may reveal the characteristic 16 Hz oscillation that is invisible to the naked eye (Yarrow et al., 2001). Psychogenic balance disorders represent the second exception, because bizarre performance on moving platforms cannot be reconciled with known organic patterns (Allum et al., 1996).
improve the ecological validity of dynamic posturography. Postural perturbations should be sufficiently destabilizing to test subjects around their stability limits, as this will presumably lead to better insights into actual falling mechanisms. Concurrent use of multiple outcome measures - "multimodal posturography" - is needed to fully understand postural control, and to determine which elements best separate patients from controls. Recent studies have begun to show that innovative computerassisted analyses of "ordinary" outcome measures such as the COP can lead to new fundamental insights into postural regulation. Such data can be entered into models of postural control (neural networks) which, in tum, can generate new questions for posturography experiments. A true challenge for the future will be to combine posturography techniques with imaging modalities, such as functional resonance imaging, single photon emission tomography and near-infrared spectroscopy (Bloem et al., 2003). Basic performance measures such as testretest reliability and responsiveness to change can be addressed fairly easily. Care must be taken to include carefully defined and homogenous patient groups, and to distinguish primary (disease-related) postural abnormalities from aspecific secondary compensation. Such experiments may be time-consuming, but they should eventually form a knowledge basis from which simple and inexpensive experiments can be distilled for use in daily clinical practice.
20.8.2.3. Patient management In light of the aforementioned shortcomings, it is understandable that dynamic posturography presently plays a negligible role in the management of individual patients. For example, it remains unclear what to do when abnormal posturography is an isolated finding. Advocates have suggested that dynamic posturography might be used to design rehabilitation programs for patients with balance disorders, for example in the field of physiotherapy (Furman et al., 1993). This remains to be demonstrated convincingly.
20.10. Acknowledgments
20.9. Recommendations for the future The ideal posturography tool addresses the concerns outlined in Table 7. Application of multidirectional perturbations and analyses of freely moving subjects are promising developments to
We thank Dr M.G. Carpenter and L. Oude Nijhuis for their critical comments. B.R. Bloem and J.E. Visser were supported by the Prinses Beatrix Fonds and de Stichting de Drie Lichten. J.H,J. Allum was supported by a grant from the Swiss National Research Foundation (31-59'319.99).
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Movement Disorders Handbook of Clinical Neurophysiology, Vol. 1 M. Hallett (Ed.) © 2003 Elsevier B.V. All rights reserved
337 CHAPTER 21
Gait analysis Kenton R. Kaufman * Biomechanics Laboratory. Mayo Clinic/Mayo Foundation, Rochester, MN 55905. USA
21.1. Introduction
21.2. Historical perspective
Every health professional must evaluate and treat the patient based on data and assumptions about the relative function of the central nervous system, selective motor control, weak or spastic muscles, joint contracture and bony deformities. The usual methods for clinical assessment include physical examination, manual muscle testing and visual observation. Most of this data is qualitative and subjective. Medical professionals apply an evolving knowledge base. A treatment plan is formed based on algorithms passed on by others and modified by experience gained from personal observations. Clinical tests are useful for diagnosis but are often not sensitive enough or objective for quantitative evaluation of treatment. However, many centers now have laboratories and skilled personnel to perform objective measurements rather than rely upon intuition and assumptions. Motion analysis laboratories provide quantitative information which can be used as a basis for appropriate therapeutic intervention as well as to objectively evaluate the effectiveness and efficacy of treatment methods. The focus of this chapter is on the methods for objective assessment of persons with movement impairment. The chapter will provide a brief overview of the gait cycle, a discussion of available measurement technology, and application of this technology for treatment planning and assessment.
Motion analysis can be described as the objective, systematic analysis of movement. The concept of depicting and recording human motion began during the Renaissance Period. Giovanni Alphonso Borelli, a student of Galileo, was among the first scientists to analyze motion while developing his theory of muscle action based upon mechanical principles (Borelli, 1685). Duchenne conducted the first scientific systematic evaluation of muscle function. His findings were published in the monumental work, Physiologie des Mouvements, published in 1857 (Basmajian and De Luca, 1985). Eadweard Muybridge first performed photographic recording of human motion. Muybridge was asked to settle a bet by Governor Leeland Stanford of California regarding whether a trotting horse had all four feet off the ground at any instant in time. Muybridge placed cameras at regular intervals along a race track. Thin threads stretched across the track triggered the shutters. The horse's hooves triggered cameras in order, and a series of photographs clearly depicted the gait sequence. Muybridge subsequently compiled a detailed photographic atlas of human and animal locomotion, which was published in three volumes (Muybridge, 1979 (original work published in 1887)). At the tum of the 20th century in Germany, Braune and Fischer became interested in measuring the motion of human body segments. They placed Geissler tubes, containing a rarified nitrogen gas, on various limb segments of a human subject dressed in black. Electrical circuits connected to the tubes created incandescence and the illuminated tubes were recorded by cameras as the subject walked. Experiments were carried out at night because there was no means to darken the room in which studies were performed. It took 10 to 12 hours to put this apparatus on the subject, whereas data collection
* Correspondence to: Dr. Kenton R. Kaufman, Ph.D., P.E., Biomechanics Laboratory, Charlton North L-llON, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. E-mail address: [email protected] Tel.: + I (507) 284-2262; fax: + I (507) 266-2227.
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was completed in minutes using four cameras. The images were digitized using a precision optical device. Coordinate geometry was used to extract three-dimensional coordinates. Equations needed to calculate resultant forces and moments at the joints of a 12-segment rigid body model were formulated. Although their quantitative results were published in 1895 (Braune and Fischer, 1895), their findings are still valid today. Inman and colleagues combined rudimentary motion recordings with electromyography (EMG) in the mid-1900s. Their pioneering work in limb prosthetic research laid the foundation for modem gait analysis. Their text, Human Walking, was published in 1981 and represents the seminal text in the field (Inman et aI., 1981). Since this pioneering work, much effort has been put into developing the needed technology for human movement analysis. Automated movement tracking systems have replaced hand digitization. Advances in the aerospace industry have been utilized for the development of force plates for kinetic analysis. Computerized electromyography systems have replaced hand palpation. Currently, the technology and knowledge for gait analysis has advanced to a level that permits rapid analysis. 21.3. Gait cycle Human walking is a unique form of movement that is bipedal. While there are animal examples of bipedal locomotion (bears, primates, marsupials), the bipedal gait in man is uniquely efficient and functional. During gait, a repetitive cyclic activity of limb motion is used to move the body forward while simultaneously maintaining stance stability. Movement of the body from one point to another is accomplished in a smooth, well-coordinated fashion by the reciprocal activity of two multi-segmented lower limbs and the total body mass. Lettre and Contini (Lettre and Contini, 1967) have described locomotion in three distinct stages: (1) development phase (from rest to constant velocity); (2) rhythmic phase (constant forward velocity); and (3) decay phase (coming back to rest) (Fig. 1). Most descriptions of gait have concentrated on the rhythmic stage (Stage II) of free-speed walking. Observations have confirmed that the rhythmic stage of human walking is very consistent and is directly related to the
K.R. KAUFMAN
I..
1
!
!
Developmenl phc~e
~I
Rhylhmk ~I
phau!!
i
..
O-ecay
phase
I
Speed
Fig. 1. Three phases of walking. (From: Sutherland, Kaufman, Moitoza, "Kinematics of Normal Human Walking", Chapter 2, Human Walking Eds. Rose and Gamble, Williams and Wilkins, 1994.)
optimal energy efficiency for an individual. The patterns of movement during free-speed walking are remarkably consistent between individuals and have been given a common nomenclature defined as the events and phases of the gait cycle (Sutherland and Cooper, 1981; Perry, 1992). This series of events is repeated by each limb in a reciprocal manner as the person moves from one point to another. Gait can be defined in terms of an interval of time during which one sequence of regularly recurring events occur (Fig. 2). During free-speed (self selected) walking this cycle of repeated events is called the gait cycle. Each gait cycle can be divided into two phases: stance and swing. The stance phase is defined by the period of time when the foot is in contact with the ground. The swing phase is the time when the foot is in the air for limb advancement. The two phases (stance and swing) can be described in terms of two repeated events: foot strike and toe off. The gait cycle starts when contact is first made with the ground. This instant of time can be called foot strike, heel strike, or initial contact. This mix of terminology is used because initial contact may not occur in the heel in patients with pathological gait patterns. As the foot leaves the ground at the end of stance phase, it is usual for the toe to be the last point of contact and this time is called toe off. However, just like foot strike, the toe may not be the last portion of the foot to leave the ground, so the term foot off may also be used. Since there are two extremities during normal locomotion, there are four events: foot strike (FS), opposite toe off (OTO), opposite foot strike (OFS), and toe off (TO). The entire cycle then repeats itself with the second foot strike.
339
GAIT ANALYSIS
Fig. 2. Typical normal walk cycle illustrating the events of gait. (From: Sutherland, Kaufman and Moitoza, "Kinematics of Normal Human Walking", Chapter 2, Human Walking, Eds. Rose and Gamble, Williams and Wilkins, 1994.)
The major subdivisions of the gait cycle (Table 1 and Fig. 2) describe the transitions that have to occur while the body's center of mass moves over the oscillating limbs. Stance phase is commonly divided into three periods: (1) initial double support (foot strike to opposite toe off); (2) single limb support (opposite toe off to opposite foot strike); and (3)
second double limb support (opposite foot strike to toe off). Swing phase can also be divided into three periods: (1) initial swing (toe off to foot clearance); (2) midswing (foot clearance to tibia vertical); and (3) terminal swing (limb deceleration). Initial double support (Table 2) is characterized by rapid loading onto the forward limb with shock absorption and
Table 1 Gait cycle: events, periods, and phases. Event Foot strike
% Gait cycle
Period
Phase
a Initial double limb support
Opposite toe-off
12
Opposite foot strike
50
Toe off
62
Foot clearance
75
Tibia vertical
85
Single limb support
Stance, 62% of cycle
Second double limb support Initial swing Mid Swing
Swing, 38% of cycle
Terminal swing Second foot strike
100
From: Sutherland, Kaufman and Moitoza, "Kinematics of Normal Human Walking", Chapter 2, Human Walking, Eds. Rose and Gamble, Williams and Wilkins, 1994.
340
K.R. KAUFMAN
Table 2 Gait cycle: periods and function. Period 1. Initial double limb support
% Cycle
0-12
Function
Contralateral limb
Loading, weight transfer
Unloading and preparing for swing (pres wing)
2. Single limb support
12-50
Support of entire body weight; center of mass moving forward
Swing
3. Second double limb support
50-62
Unloading and preparing for swing (preswing)
Loading, weight transfer
4. Initial swing
62-75 75-85 85-100
5. Mid swing 6. Terminal swing
Foot clearance
Single limb support
Limb advances in front of body
Single limb support
Limb deceleration, preparation for weight transfer
Single limb support
From: Sutherland, Kaufman and Moitoza, "Kinematics of Normal Human Walking", Chapter 2, Human Walking, Eds. Rose and Gamble, Williams and Wilkins, 1994.
slowing of the body's forward momentum. The foot usually progresses to foot flat and the knee acts as a shock absorber. After opposite toe off, the opposite limb is in swing and the weight bearing limb is in single limb stance. As the body passes over the fixed foot, the center of mass rises to its peak while both forward and vertical velocity decrease. During the single limb support interval the body's entire weight is resting on one extremity. The duration of single limb stance is the best index of the limb's support capability. During this time the anterior/posterior ground reaction force reverses from forward shear to aft shear, the center of mass falls, and the forward and vertical velocity increase. This transition from forward to aft shear occurs around 30% of the cycle, which is midstance in normal subjects. It is very difficult to determine this transition point precisely in the walking cycle without laboratory measurements. Once this peak in the elevation of the center of mass is achieved, the center of mass falls until the end of single limb stance at opposite foot strike (50% of the gait cycle). Second double limb support begins with floor contact by the other foot (opposite foot strike) and continues until the original stance limb is lifted for swing (toe off). This period of time can also be defined as preswing. As weight is transferred rapidly to the forward limb, the trailing limb is beginning its preparation to swing in front of the body.
The swing phase can be split into three phases. The subdivision of the swing phase can best be understood by comparing the leg to a compound pendulum. A compound pendulum can change its swing period by changing its configuration in space. The first phase involves the foot leaving the ground and accelerating forward. This is called initial swing (toe off to foot clearance). The critical event of foot clearance occurs around 75% of the gait cycle when a swinging limb passes the standing limb. As the swing limb passes the stance limb, this period is called mid swing (foot clearance the vertical tibia). Vertical tibia occurs when the tibia becomes vertical to the floor heralding the beginning of limb deceleration. Thereafter, the limb undergoes deceleration and the foot is controlled to get ready for the next foot strike. This final phase is called terminal swing (vertical tibia to foot strike). Although swing phase does not involve the large forces associated with ground contact, two important goals must be achieved for foot clearance during swing. First, the limb must be shortened in length so that the foot can clear the ground during the forward movement. This is accomplished by flexing the hip and knee and dorsiflexing the ankle. Secondly, during the swing phase, the masses of the lower limb are subjected to accelerations and decelerations which require muscular efforts at the joints. As the swing phase is shortened with increased walking velocity, the
341
GAlT ANALYSIS
Fig. 3. Important temporal distance parameters defined and measured in gait analysis.
acceleration becomes larger and this requires greater demands from the musculature. The gait cycle is defined in terms of percentages, rather than elapsed time, since the events occur in a repeatable sequence and are independent of time (Table 1). Therefore, initial foot strike is defined as 0% and the second foot strike completes the gait cycle at 100%. In normal subjects, the opposite limb repeats the same sequence of events but is 1800 out of phase so opposite foot strike occurs at 50% of the gait cycle. The average gait cycle consists of 62% stance phase and 38% swing phase. Stance phase can be further broken down into two subdivisions of double limb support, each lasting about 12% of the gait cycle. Therefore, timing for the stance phase consists of 12% for initial double-limb support, 38% for single limb stance, and 12% for second double limb support. Note that single limb stance for one limb occurs at the same time as swing in the opposite limb. Terminology has been developed to describe the linear measurements of the gait cycle (Fig. 3). Cadence is the number of steps taken in a standard time frame. The usual units are steps per minute. Stride length is defined by the distance (in ems) between two successive foot strikes of the same foot.
There are two steps in each stride (or gait cycle). Step length is defined by the distance between the same point on each foot (usually the heel) during double limb support. Right step length is the distance of the step when supported by the right leg. Similarly, left step length is the step distance while on the left limb. Walking speed or walking velocity is the average distance covered by the whole body in a given time in a particular direction (expressed in ems per second or meters per minute). The instantaneous velocity varies from moment to moment during the gait cycle, but the average velocity is a combination of the cadence and the stride length. The step width is the side to side distance between the two feet, usually measured at midpoint of the heel but sometimes at the center of the ankle joint. The step width also defines the walking base of support.
21.4. Equipment and methods 21.4.1. Observation The simplest form of gait analysis is observational gait analysis. A systematic approach for observational gait analysis was developed at the Rancho Los
342
Amigos Medical Center in Downey, California (Perry, 1992). An experienced observer can detect many gait deviations during both stance and swing phases. However, an obvious limitation of observation in gait analysis is the difficulty of observing multiple events and multiple body segments interacting concurrently. Further, it is not possible to visualize the location of force vectors in space or electromyographic activity of muscles. Events happening faster than 1/12 of a second (83 ms) cannot be perceived by the human eye (Gage and Ounpuu, 1989). More consistent observations are obtained when motion videotapes are reviewed in slow motion (Krebs et al., 1985). Three expert observers rated video footage of fifteen children who had lower limb disability and wore braces (Krebs et al., 1985). Pearson's Correlation coefficient was 0.6 within observers and less between observers. Thus, observational gait analysis is a convenient, but only moderately reliable technique. Saleh and Murdoch (Saleh and Murdoch, 1985) utilized experienced observers to study the gait of transtibial amputees. The prosthetic limbs of the amputees were intentionally misaligned in the sagittal plane. The agreement of experienced observers with a biomechanical model was 22%. In a similar study, 54 licensed physical therapists with varying amounts of clinical experience rated three patients with rheumatoid arthritis (Eastlack et al., 1991). Generalized Kappa coefficients ranged from 0.11 to 0.52 indicating that clinician assessments are only slightly to moderately reliable. Thus, it is easy to see that limitations in observational gait analysis can lead to misinterpretation of the patient's locomotion capabilities. Hence, it is important to utilize advances in gait analysis techniques to more precisely quantify the patient's functional status. Extensive instrumentation has been developed for recording the various parameters used to describe gait.
21.4.2. Movement measurement In the biomechanical analysis of motion, skeletal segments are studied as rigid links moving through space. These rigid links are assumed to be interconnected through a series of frictionless joints. Measurement systems that are aimed at capturing the spatial trajectories of body segments usually involve a camera system or an electromagnetic system that tracks a series of body-fixed markers.
K.R. KAUFMAN
With a camera, either passively reflective or actively illuminated markers are used (Fig. 4a). These markers are commonly attached to the subjects as either discrete points or rigid clusters with multiple markers on each cluster. Placement of these external markers on the surface of the body segments are aligned with particular bony landmarks. Using stereophotogrammetric principles, the planar projections of markers viewed by each camera are used to reconstruct the 3-dimensional instantaneous position of the markers relative to an inertially fixed laboratory coordinate system. If the position of at least three non-colinear points fixed to the body segment can be obtained (and the body segment is assumed to be rigid) then the six degrees-of-freedom associated with the position and orientation of each segment can be obtained. Initially, a body-fixed coordinate system is computed for each body segment (Fig. 4b). For instance, consider the markers on the shank at an instant in time. A vector, STZ' can be formed from the lateral malleolus (B) to the lateral knee marker (A). Another vector can be formed from the lateral malleolus to the marker on the shank wand (C). The vector cross product of these two vectors is a vector STX, that is perpendicular to the plane containing all three markers. The unit vector, STY' may be determined as the vector cross-product of STZ and STX' Thus, the vectors STX' Sn" and STZ form an orthogonal body fixed coordinate system, called a technical coordinate system. In a similar manner, the marker based, or technical coordinate system may be calculated for the thigh, i.e, TTX, TTY' and TTZ' Once the position of adjacent limb segments has been determined, it is possible to determine the relative angle between adjacent limb segments in three dimensions. This assumes that the technical coordinate systems reasonably approximate the anatomical axes of the body segments, e.g. TTZ approximates along axis of the thigh and STZ approximates the long axis of the shank. A more rigorous approach adapts a subject calibration procedure to relate the technical coordinate systems with pertinent anatomical landmarks (Cappozzo et al., 1995). Additional data can be collected that relates the technical coordinate system to the underlying anatomical coordinate system. The subject calibration is performed as a static trial with the subject standing. Additional markers are typically added to the medial femoral condyle and the medial maleolli during the static
343
GAIT ANALYSIS
(a)
x (b)
Fig. 4. Body-fixed reflective markers used for establishing anatomical coordinate systems. (a) Video camera motion measurement systems calculate the location of external markers placed on the body segments and aligned with specific bony landmarks. (b) A body-fixed external coordinate system is then computed from three or more markers on each body segment. (c) Subsequently, a subject calibration relates the external coordinate system with an anatomical coordinate system through the identification of anatomical landmarks, e.g. the medial and lateral femoral condyles and medial lateral malleoli.
calibration trial. These markers serve as anatomical references for the knee axis and ankle axis. The hip center location is estimated from markers placed on the pelvis (Bell et al., 1989). The technical coordinate system is then transformed into alignment with the anatomical coordinate system for each limb segment, e.g. SAX' SAY' SAZ (Fig. 4c). The marker system is coupled to a biomechanical model (Kadaba et al. 1990; Kaufman et al., 1995). Once the position of adjacent limb segments has been determined (and each body segment is assumed to be
rigid), it is possible to determine the relative angle between adjacent limb segments in 3-dimensions. The Euler system is the most commonly used method for describing 3-dimensional motion (Chao, 1980; Grood and Suntay, 1983) (Fig. 5). Recently, advances have been made in the animation industry that will have future applications in the biomechanics field. Computerized motion analysis systems have been developed that provide marker trajectory data in real time. These systems are now available for applications in biomechanics. These
344
K.R. KAUFMAN
Determination of Joint Motion
Fig. 5. Description of knee joint motion using Eulerian angle system. An axis fixed to the distal femur defines flexion! extension motion, <1>. An axis fixed to proximal tibia along its anatomical axis defines internal-external rotation, '1'. A floating axis is orthogonal to the other two axes and used to measure abduction-adduction, (3 (Reproduced with permission from Chao, 1980).
applications make it possible to obtain results of gait analysis studies much faster and will make gait analysis much more clinically available. The most recent development to be used for quantifying human motion is an electromagnetic tracking system (An et aI., 1988). Electromagnetic systems detect the motion of sensors placed on each segment using an electromagnetic field. A three-axis magnet dipole source and a three-axis magnetic sensor are used (Raab et al., 1979) (Fig. 6). The excitation of the source and the resulting sensor output are represented as vectors. The source excitation pattern is composed of three sequential excitation states, each of which produces an excitation vector that is linearly independent of the other two. The sensor is connected to a system controller through a cable. The sensor outputs are preamplified, multiplexed and transmitted to a system electronics unit. The resultant set of three sensor output vectors contains information sufficient to determine both the position and orientation of the sensor relative to the source. Thus, these systems can provide real-time six degree-of-freedom movement
data. The use of this equipment is growing in areas of human motion analysis. The instrumentation is simple to use and is insensitive to limb interference. The limitations are the cabling necessary to connect the sensors, the sampling frequency, and the sensitivity to magnetic interference from nearby ferromagnetic metallic structures such as a total joint replacement. Nonetheless, as these electromagnetic system capabilities increase, it is expected that these devices will be used more frequently for movement analysis. 21.4.3. Force measurement
Gait analysis is also concerned with the forces that cause the observed movement and the assessment of their effect on locomotion (kinetic analysis). Forces acting on the human body can be divided into internal and external forces. The external forces represent all physical interactions between the body and the environment. These forces include gravitational, ground reaction forces and inertial forces. The internal forces are those transmitted by body
345
GAIT ANALYSIS
Electromagnetic Tracking Technology
Position and Orientation Measurements
Fig. 6. System block diagram of an electromagnetic tracking system. The 3-axis magnetic source emits three sequential excitation states that are picked up by the 3-axis magnetic sensor. The resultant set of sensor excitation vectors is used to calculate the position and orientation of the sensor relative to the source.
tissues that include muscular forces, ligament forces, and forces transmitted through joint contact. Generally, only the ground reaction forces can be measured using a force plate. Current force plates typically use strain gauge or piezoelectric transducers. Force platforms can be used to define the magnitude and direction of the resultant ground reaction force (GRF) applied to the foot by the ground (Fig. 7). The GRF vector is three dimensional and consists of a vertical component plus two shear components acting along the force plate surface. The shear forces are applied parallel to the ground and require friction. These shear forces are usually resolved in the anterior-posterior and mediallateral directions. An additional variable, the center of pressure, is needed to define the location of this GRF vector. The center of pressure is defined as the point about which the distributed force has zero moment when applied to the foot. It is found by determining the line of action of the forces measured by the platform and calculating where that line intersects the surface of the force platform. This force data is combined with kinematic data using Newton's Second Law to calculate the intersegmental forces and moments causing motion (Fig. 8). The process of proceeding from known kinematic
data and external forces to obtain intersegmental joint forces and moments is called the inverse dynamics approach (Chao, 1971). The gravitational forces acting on each body segment can be determined from the relevant mass and location of the center of mass for each segment. These quantities can be calculated together with the segmental mass moments of inertia using prediction techniques from anthropometric dimensions. The inertial forces can be obtained from calculations of angular and linear position, as well as velocity and acceleration of the body segments with respect to either a fixed laboratory coordinate system or referenced to another body segment using kinematic data. This information can be combined to solve the inverse dynamics problem (Fig. 9). Joint power can also be calculated (Winter, 1990). These data provide understanding of the subtle musculoskeletal adaptations which are utilized by patients to maintain dynamic balance during gait. Kinetic data are available at the hip, knee and ankle joint. When the position of this force line with respect to joint center has been established by combining force and movement data, the extrinsic joint moment, which is the product of lever arm and the ground reaction force, plus gravity and inertia can be calculated. This moment is of
346
K.R. KAUFMAN
Fig. 7. A force plate is used to measure the location and magnitude of the ground reaction force. Transducers are located in the four corners of the plate. The ground reaction force is divided into three force (Fxe F)' F,) and three moment (M.. M)' Mz) components. F, and F, are shear forces. F, is the vertical force. Some force plates only measure the moment around the vertical axis, i.e. M, This assumes that no tensile forces are imposed on the force plate, i.e. the foot does not stick to the plate. Under this assumption, the other moments are zero.
mg
T~
F CP1035086B-4
Fig. 8. The joint dynamics, which includes the intersegmental forces and moments, is computed through the use of Newtonian mechanics. The computation accounts for the external loads applied at the foot, e.g. the ground reaction forces, F and T, the weight of the limb segment, mg, and the inertial loads, rna and R., in order to calculate the intersegmental force, F, and moment, M.
great importance because in the case of lower extremity muscles acting during load bearing, it determines the requirements for intrinsic (muscle) force. For example, when the force line falls behind the knee joint center, quadriceps muscle action is required to prevent knee collapse, and when the force line falls in front of the knee, extensor muscle force is not needed. At each joint, a state of equilibrium exists where the external joint forces are balanced by the internal joint forces. The measurement of internal forces requires sophisticated techniques which are invasive. Analytical procedures have been developed for estimating internal joint forces. These analytical approaches use classical mechanics and mathematical optimization routines (Kaufman et al., 1991). These analytical approaches require the use of simplifying assumptions about the mechanical structure and knowledge of muscle physiology principles. Thus, the accuracy of the analytical predictions depends not only on the quality of the input data but also on the validity of the assumptions. In general, it is necessary to evaluate the estimated quantities by comparing them with experimental observations. Typically, electromyographic data are obtained to provide information regarding muscle activation patterns.
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GAIT ANALYSIS
INVERSE DYNAMIC PROBLEM Measured Displacement x y z
¢ B l/f
d dt
Velocity
Acceleration
d
~
~
~
X
Y
dt
z
¢ iJ if!
~
x ji Z ¢ (j Iii
Equations of Motion:
Lf=rnr
c
LAfc =iJc -'-"d'('ai)-~'a[:¢~" dt 8qi
........
8qi
Fig. 9. Solution process for inverse dynamics problem. Displacement information must be differentiated twice to yield acceleration. Either Newtonian or Lagrangian formulations can be used to formulate the equations of motion.
21.4.4. Electromyog raphy
Neuromuscular coordination is required to adjust the varying muscular and ligamentous forces interacting with the abundant degrees of freedom in the joints and other parts of passive locomotive system to obtain dynamic balance during gait. Electromyographic data are useful to provide information about the timing of muscle activity and the relative intensity of muscle activity. Both surface and finewire electrodes have been used for gait kinesiological electromyographic (EMG) analysis. Each type of electrode has its advantages and disadvantages. Surface electrodes are convenient, easy to apply to the skin, and do not cause pain, irritation, or discomfort to the subject. However, they pick up signals from other active muscles in the general area of application. This feature makes surface electrodes the ideal choice for analysis of global activity in superficial muscles or muscle groups. However, surface electrodes are sensitive to movement of the skin under the electrodes and have poor specificity. They are influenced by significant muscle "crosstalk," in which the electrode signals of one muscle interfere with the signals from another (Zuniga and Simons, 1969). Thus, the activity of adjacent muscle groups can interfere and lead to false results.
However, a double differential technique has been shown to reduce cross-talk in surface EMGs (Koh and Grabiner, 1992). The major advantage of finewire electrodes is selectivity to measure the activity of specific muscles. The influence of electrical activity of nearby muscles is greatly reduced. Nonetheless, a number of disadvantages are associated with fine-wire electrodes. Pain on insertion, the difficulty of accurate placement, wire movement with muscle contraction, and the need for licensure to utilize wire electrodes are some of the drawbacks. Furthermore, subjects with in-dwelling electrodes walk more slowly after insertion of the electrodes (Young et aI., 1989). Because they are to be inserted transcutaneously, needle electrodes must be sterilized and sufficiently strong to resist breakage. Commonsense considerations, such as time, expense, pain experienced during a long study, the tolerance of the subject to multiple needle insertions, and the influence of indwelling electrodes on walking, necessitate a selection of the muscles most relevant to the specific movement abnormalities. Large muscles near the surface can be studied well with surface electrodes, whereas small muscles and those surrounded by other muscles require insertion of fine-wire electrodes. Electrical stimuli are usually given to confirm the accuracy of placement. EMG
348
systems are available in either hardwired or telemetry versions. The hardwired versions now send multiple signals on a single cable. These systems are reliable and less expensive than telemetry. Telemetry systems do not encumber the subject with cables but are susceptible to electromagnetic interference. Once the EMG data are acquired, they must be processed further to provide information about the timing of muscle activity and the relative intensity of the muscle activity. The EMG data are recorded throughout the gait cycle. The gait cycle is indicated either with synchronization of the kinematic data, foot-switch information, or force plate data to indicate each foot strike and toe-off. Analysis of the EMG is done by a phase-time plot of the activity of the muscle against events of the gait cycle. The raw EMG signal can be analyzed or processed further. The most common methods of EMG signal processing are full wave rectification, linear envelope, and integration of the rectified EMG. The linear envelope in created by low-pass filtering the full wave rectified signal. Integrated processing of the rectified signal is usually performed over short duration, i.e. 2% gait cycle, and then the integration is reset and accumulated again. The electromyogram provides a means for studying muscle activity. The signals that result from action potentials and muscle fibers are stochastic and non-stationary adding to uncertainty in interpretation. While the ultimate source of locomotor activity is muscle force, no study has established that electromyographic signals represent muscle force (Perry and Becky, 1981). The EMG signal is a measure of the bioelectric events that occur in conjunction with contraction of the muscle fibers. Thus, it is a phenomenon related to the initiation of muscle contraction rather than an effect of the muscles mechanical action. There are many difficulties in correlating the EMG signal amplitude with muscle force magnitude. Both linear and nonlinear relationships between the force level of skeletal muscles and the EMG signal have been reported (Lippold, 1952; Messier et al., 1971; Komi and Buskirk, 1972; Zuniga et al., 1972; Maton and Bouisset, 1977; Matral and Casser, 1977; Moritani and de Vries, 1978; Bigland-Ritchie et al., 1980; Woods and Bigland-Ritchie, 1983) Consequently, the EMG is commonly used in clinical gait analysis to determine phasic patterns for individual muscles or muscle groups. It is possible to examine simple
K.R. KAUFMAN
on/off patterns (Sutherland et al., 1988), or the EMG can be processed to find a graduation of signal level, after which EMG patterns are examined as defined by the level of activity over the gait cycle (Shiavi and Green, 1983; Limbird et al., 1988; Wooten et al., 1990). In the latter process, it is common to normalize the signal as a percentage of voluntary maximum muscle contraction. The process of detecting when a muscle is "turned on or off" is usually one of testing whether the average level of the signal is above some predefined limit. Normalization schemes may be used to aid in analysis. The limit is often defined as a percentage of the maximum voluntary muscle contraction or maximum EMG signal during gait. The determination of on/off time is often done by calculating the EMG level and then testing for occasions when the level exceeds some threshold value. The muscle is considered to be activated when at least 5% of the maximum electrical activity obtained during a manual muscle test is present for 5% of the gait cycle (Bogey et al., 1992). EMG on/off times are generally more variable from step to step than either kinematic or kinetic gait measurements. Problems occur in dynamic situations when using electromyographic activity as a measure of muscle functional capability. A dynamic force produced by a muscle is not proportional to the degree of muscular activity. Other factors may affect the muscle force, such as a change of the muscle length, change of the contraction velocity, the rate and type of muscle contraction, joint position, and muscle fatigue. It is desirable to find an alternative measurable mechanical parameter related to muscle force. The electromyographic signal does not assess the tension produced by a muscle, because the tension reflects the sum of both the active contraction and the passive stretch. A technique which may provide information about muscle force is measurement of intramuscular pressure. Intramuscular pressure (IMP) is a mechanical variable that is proportional to muscle tension. It is possible to obtain IMP measurements during gait and relate these measurements to the timing and intensity of muscle contraction. IMP has been used to quantify muscle function during dynamic activities (Kaufman and Sutherland, 1995). Intramuscular pressure measurements obtained during walking parallel the electromyographic activity, and also account for passive stretch of the muscle (Kaufman and Sutherland, 1995) (Fig. 10).
349
GAIT ANALYSIS
FS OTO
TO OFS I I I
EMG Right Gastrocnemius (volts)
FS
TO
OTO OFS J
I I
TO
FS TO
FS
OFS I
I I
+0.5-
+0.5
IMP Right Gastrocnemius so(mm HG) 0-
Fig. 10. Raw data for a single subject during gait. Both EMG and intramuscular pressure are being recorded from the gastrocnemius muscle. The stance phase of gait occurs from FS to TO. The swing phase of gait occurs from TO to FS. Single limb stance occurs from OTO to OFS. Peaks in intramuscular pressure during gait can be correlated with peaks of active contraction and passive stretch of the gastrocnemius. (Reproduced with permission from Kaufman and Sutherland, 1995.)
21.5. Interpretation of gait data
Once the data that describe the biomechanics of the patient's gait has been collected, the most crucial step of interpreting the data remains to be performed. Based on the clinical examination and measurements performed, the data must be synthesized and integrated in order to supply clinically relevant information. Human locomotion is very complex and multifaceted. The clinical interpretation of pathological gait disorders involves holding in human memory a large number of graphs, numbers, and clinical tests from data presented on hard copy, charts, x-rays, video, and computer generated 3-D graphics from multiple trials of a subject walking. Further, comparisons must be made to data from an able-bodied normal population in order to identify the potential movement problems for a given individual. The referring clinician, who may not be an expert in gait analysis, is commonly overwhelmed by the magnitude of the number of measurements included in a typical gait report. The
person interpreting the data must integrate this information. While data collection techniques for gait analysis have continually evolved over the last 50 years, the method of data presentation has not changed over this time. The data are still reported in 2-D charts with the abscissa usually defined as a percentage of the gait cycle and the ordinate displaying the gait parameter. Recent developments in computer animation may make it possible to apply advanced methods to visualize human movements. The large volume of variables currently found in a typical clinical report could be replaced with a few graphic images that succinctly provide the needed information. It is difficult to appreciate and fully understand the relationships between motion dynamics and biomechanical variables without scientific graphic visualization. Presently, computer software packages have advanced to the stage where it is possible to provide a gait analysis report using animation of fully 3-D, realistic graphical depictions of human locomotion. The format used for reporting test
350
K.R. KAUFMAN
results is a matter of considerable importance. The data must be presented in an accurate, clear, and concise format. If the results are not communicated in an effective format, they will be of little use to the clinician regardless of quality.
21.6. Treatment planning and assessment When treatment is being planned, the main objective is to differentiate between the primary causes and compensations for the patient's functional problems. If the treatment is directed at a compensation, the patient will lose their ability to compensate and their movement problems will worsen. The patient will display adaptations in their gait pattern due to their pain, injury, deformity, instability, and/or inappropriate muscle activation patterns. The ramifications of these problems cannot be fully assessed without an instrumented gait study. Patients can undergo dynamic adaptation related to the biomechanics of walking which must be factored into the treatment algorithm. For example, it has been shown that when planning corrective osteot-
omy knee surgery, patients with the same bony deformity will have differing knee loading due to dynamic adaptations (Prodromos et al., 1985). These dynamic adaptations will have a direct effect on surgical outcome. The patients who dynamically compensated for their malalignment had a better long-term outcome (Prodromos et al., 1985; Wang et al., 1990). For patients with progressive disorders, these dynamic adaptations will also change with time as the disease progresses. It is possible to use motion analysis studies to quantify these dynamic changes in locomotor patterns.
21.7. illustrative case We are currently conducting a study to quantify gait changes in patients with progressive multiple sclerosis. Using gait analysis techniques, it is possible to show changes in joint motion which can be attributed to disease progression. An example of changes in knee motion is shown in Fig. 11. The patient had an EDSS (Kurtzke) rating of 3.0 when
KNEE FLEXION
60
~
40
>< w
20
C)
-oz ..J La.
__
.,....----------~---
Time (Weeks) --Owk 1 wk - - 26wk 52wk ... 78wk - - Normal
W W
~
0
o
20
40
60
80
100
GAIT CYCLE (%) Fig. II. Changes in knee motion over an 18-month period in a patient with primary progressive multiple sclerosis. A normal knee motion curve is given for comparison. The patient lacks knee flexion during early stance and goes into hyperextension during midstance. The knee flexion during swing is less than normal at the initial study and progressively declines over the 18-month study period. The results for the initial visit (0 weeks) and a second study done a week later (l week) demonstrate excellent measurement repeatability.
351
GAIT ANALYSIS
first studied, and progressed to an EDSS score of 5.5 at the end of the 18 months study period, thus requiring a cane for ambulation. Comparing the data from the initial (0 week) and second visit (l week), it can be seen that the data are very repeatable. The motion curves for these two timepoints differed by less than three degrees on average throughout the entire gait cycle. The data also demonstrated that the patient lacked the normal knee flexion (shock absorption) wave during early stance. Further, the patient's knee went into hyperextension in midstance. These gait characteristics were consistent for all visits during the study period. The knee flexion during swing was less than normal at the initial visit and declined further over the 18 month study period. This example clearly illustrates the objective nature of instrumented gait analysis and the ability to document subtle changes which may not be remembered over time if only clinical observation is used.
21.8. Rationale In this era of government reimbursement for medical services, the ability to document the need and effectiveness of a particular treatment will assume an increasingly important role. Managed care will require validation for many types of therapeutic interventions. Pre- and post-treatment measurement will become mandatory. Outcomes will have to be compared. Practitioners and facilities
will be rated on their outcomes. Maximizing anticipated outcomes will be required to document that a treatment plan is worthwhile. Objective gait analysis is an essential tool to meet these demands. The technology is at a level where it is both feasible and affordable to provide an objective form of patient assessment. In all areas of medical care, a need exists for instrumentation and procedures to aid in a differential diagnosis and treatment of patients. Further, information is required to document patient response to treatment objectively. The ability to diagnose, prescribe treatment, and document results is common to all areas of medical care. However, the technology available in different medical specialties varies widely. This is particularly evident when the current medical technology for treating patients with cardiovascular conditions is compared to the technology for treating patients with neuromuscular conditions (Table 3). For both types of patients the technology can be divided into three levels: static examinations, dynamic examinations, and invasive procedures. When a patient reports to a physician that they are experiencing chest pain and the risk factors for a myocardial infarction exist, the patient is monitored with an electrocardiogram. In some centers, a computed tomography (CT) scan is obtained to assess the amount of arteriosclerosis in the vessels of the heart muscle. These tests are obtained while the patient is either sitting or lying down. Hence, these
Table 3 Current medical technology. Treatment modality Level
Exam
Cardiovascular patients
Neuromuscular patients
Static
ECG EBCT
X-ray CT
MRI
MRI
II
Dynamic
III
Invasive
PET Ultrasound Nuclear imaging Stress test Echocardiography Angiography
Nuclear imaging
Motionanalysis Diagnostic EMG Kinesiological EMG
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constitute static exams. Other static modalities include MRI, PET, ultrasound, and nuclear imaging. If the physician has a high index of suspicion, dynamic tests may be undertaken. These include a stress test or echocardiography. Finally, angiography may be utilized as an invasive procedure to further examine the heart. In stark contrast, most of the modalities for a patient with neuromuscular dysfunction are static modalities. Current modalities include x-ray, CT, MRI, nuclear imaging and diagnostic electromyography (EMG). However, all of these examinations are static and non-weight bearing. Dynamic assessment of patients with neuromuscular dysfunction can only be obtained using motion analysis techniques along with acquisition of kinesiological EMG. An objection sometimes raised is that these studies are too costly. However, this objection is unfounded. In terms of cost-benefit ratio, the most compelling consideration is the high cost of inappropriate treatment. It is important to remember that unsuccessful treatment will result in unfavorable changes in function and may require subsequent procedures to deal with the original problem. There is, of course, no assurance that gait studies performed prior to treatment planning will always ensure favorable outcome, but careful planning, based on objective data, will provide a solid foundation for decision making. Post-treatment studies will give the information required for objective evaluation of treatment results. The rate at which gait analysis technologies will become more common will depend on the market, the manufacturers, and managed care requirement. Objective patient assessment using gait analysis techniques will facilitate the identification of optimal treatment regimens, and provide a solid foundation for clinical decision making. 21.9. Summary Human function cannot be fully understood without studies of movement. The modem motion analysis laboratory that has evolved with technological advances has the potential for opening new opportunities for progress in the treatment of patients with movement disorders. Current gait analysis systems offer sophisticated automatic track-
K.R. KAUFMAN
ing systems, force platforms, and electromyographic activity measurements. When coupled with a biomechanical model, this equipment is able to provide a complete, three-dimensional, dynamic description of the patient's gait along with information on the timing and intensity of muscle activity. The function of a motion analysis laboratory is to objectively measure the dynamic aspects of an individual patient's performance that cannot be quantitatively assessed in the clinical setting. Interpretation of this data makes it possible to integrate morphology and functional adaptations in order to understand and treat the pathophysiology of movement disorders. Acknowledgment The author thanks Barbara Iverson-Literski for her careful manuscript preparation. References An, K-N, Jacobsen, MC et al. (1988) Application of a
magnetic tracking device to kinesiologic studies. J. Biomech., 21(7): 613-620.
Basmajian, JV and De Luca CL (1985) Muscles alive: their functions revealed by electromyography (5th ed.). Baltimore, MD, Williams & Wilkins. Bell, AL, Pederson, DR et al. (1989) Prediction of hip joint center location from external landmarks. Hum. Move. Sci., 8: 3-16. Bigland-Ritchie, B, Kukulka, CJ et al. (1980) Surface EMG-force relationships in human muscles of different fiber composition. J. Physiol. (Lond.), 308: 103P. Bogey, RA, Barnes, LA et al. (1992) Computer algorithms to characterize individual subject EMG profiles during gait. Arch. Phys. Med. Rehab., 73: 835-841. Borelli, GA (1685) De motor animalium. Batavis: Lugduni. Braune, Wand Fischer 0 (1895) Der Gang des Menschen (The human gait). Leipzig: BG Teubner. Cappozzo, A, Catani, F et al. (1995) Position and orientation in space of bones during movement: anatomical frame definition and determination. Clin. Biomech., 10(4): 171-178. Chao, EYS (1971) Determination of applied forces in linking systems with known displacements: with special application to biomechanics. Iowa City, Iowa, University of Iowa. Chao, EYS (1980) Justification of Triaxial Goniometer for the measurement of joint rotation. J. Biomech., 13: 989-1006.
GAIT ANALYSIS
Eastlack, ME, Arvidson, J et al. (1991) Interrater reliability of videotaped observation of gait-analysis assessments. Phys. Ther., 71(6): 465-472. Gage, JR and Ounpuu S (1989) Gait analysis in clinical practice. Sem. Orthopaed., 2: 72-87. Grood, ES and Suntay WJ (1983) A joint coordinate system for the clinical discussion of 3-dimensional motions: applications to the knee. J. Biomech. Engineer., 105: 136-144. Inman, VT, Ralston, HJ et al. (1981) Human walking. Baltimore, MD, Williams & Wilkins. Kadaba, MP, Ramakrishnan, HK et al. (1990) Measurement of lower extremity kinematics during level walking. J. Orthopaed. Res., 8: 383-392. Kaufman, KR and Sutherland DH (1995) Dynamic intramuscular pressure measurement during gait. Oper. Tech. Sports Med., 3(4): 250-255. Kaufman, K, An, K et al. (1991) Physiological prediction of muscle forces - I. Theoretical formulation. Neurosci., 40(3): 781-792. Kaufman, KR, An, KN et al. (1995) A comparison of intersegmental joint dynamics to isokinetic dynamometer measurements. J. Biomech., 28(10): 1243-1265. Koh, TJ and Grabiner MD (1992) Cross-talk in surface electromyograms of human hamstring muscles. J. Orthopaed. Res., 10: 701-709. Komi, PV and Buskirk ER (1972) Effect of eccentric and concentric muscle conditioning on tension and electrical activity of human muscle. Ergonomics, 15: 417. Krebs, DE, Edelstein, JE et al. (1985) Reliability of observational kinematic gait analysis. Phys. Ther., 65: 1027-2033. Lettre, C and Contini R (1967) Accelerographic analysis of pathologtical gait. New York, New York University School of Engineering and Science Technical Report 1368-01. Limbird, TJ, Shiavi, Ret al. (1988) EMG profiles of knee joint musclature during walking: Changes induced by anterior cruciate ligament deficiency. 1. Orthopaed. Res., 6: 630. Lippold, OCJ (1952) The relation between integrated action potentials in a human muscle and its isometric tension. J. Physiol. (Lond.), 117: 492. Maron, Band Bouisset S (1977) The distribution of activity among the muscles of a single group during isometric contraction. Eur. 1. Appl. Physiol., 37: 101-109. Matral, Sand Casser G (1977) Relationship between force and integrated EMG activity during voluntary isometric and isotonic contraction. Eur: J. Appl. Physiol., 46: 185.
353 Messier, RH, Duffy, Jet al. (1971) The electromyogram as a measure of tension in the human biceps and triceps muscles. Inter. J. Mech. Sci., 13: 585-598. Moritani, T and de Vries HA (1978) Re-examination of the relationship between the surface integrated electromyogram (IEMG) and force of isometric contraction. Am. J. Phys. Med., 57: 263-277. Muybridge, E (1979 (original work published in 1887)) Human and animal locomotion. New York, Dover. Perry, J (1992) Gait analysis: normal and pathological function. Thorofare, NJ, Slack. Prodromos, CC, Andriacchi, TP et al. (1985) A relationship between gait and clinical changes following high tibial osteotomy. J. Bone Joint Surg. (American Vol.), 67A: 1188-1194. Raab, FH, Blood, EB et al. (1979) Magnetic position and orientation tracking system. IEEE Trans. Aerospace Electron. Sys., AES-15(5): 709-718. Saleh, M and Murdoch G (1985) In defense of gait analysis. J. Bone Joint Surg., 67B: 237-241. Shiavi, R and Green N (1983) Ensemble averaging of locomotor electromyographic patterns using interpolation. Med. BioI. Eng. Comput., 21: 573. Sutherland, DH and Cooper L (1981) The events of gait. Bull. Prosthet. Res., 10-35: 281-282. Sutherland, DH, Olshen, RA et al. (1988) The development of mature walking. Oxford, England, Mac Keith Press. Wang, JW, Kuo, NN et al. (1990) The influence of walking mechanics and time on the results of proximal tibial osteotomy. J. Bone Joint Surg., 6: 905-909. Winter, DA (1990) Biomechics and Motor Control of Human Movement (2nd ed.). New York, Wiley & Sons. Woods, JJ and Bigland-Ritchie B (1983) Linear and nonlinear surface EMG/force relationships in human muscles. Am. 1. Phys. Med., 62(6): 287-299. Wooten, ME, Kadaba, MP et al. (1990) Dynamic electromyography. n. Normal patterns during gait. J. Orthopaed. Res., 8: 259. Young, CC, Rose, SE et al. (1989) The effect of surface and internal electrodes on the gait of children with cerebral palsy, spastic diplegia type. 1. Orthopaed. Res., 7(5): 732-737. Zuniga, EN and Simons DG (1969) Nonlinear relationship between averaged electromyogram potential and muscle tension in normal subjects. Arch. Phys. Med. Rehab., 50: 613. Zuniga, EN, Leavitt, LA et al. (1972) Gait patterns in the above-knee amputees. Arch. Phys. Med. Rehab., 53(8): 373-382.
Movement Disorders Handbook of Clinical Neurophysiology, Vol. I M. Hallett (Ed.) © 2003 Elsevier B.V. All rights reserved
357 CHAPTER 22
Physiologic and enhanced physiologic tremor Rodger J. Elble* Department of Neurology, Southern Illinois University School of Medicine, P.O. Box 19643, Springfield, 1L 62794-9643, USA
Healthy people exhibit rhythmic oscillations in body position and muscle contraction, and these oscillations are called physiologic tremor. The mechanisms of physiologic tremor are reviewed in this chapter.
22.1. Passive mechanical oscillation The friction and viscous damping in most joints are not sufficient to prevent passive mechanical oscillation in response to a perturbation. Skeletal muscle behaves as a low-pass filter in response to motor-unit excitation, and this filtering effect limits the fluctuations in muscle force caused by irregularities in motor unit firing (Stein and Oguztoreli, 1976). However, these irregularities are not filtered completely, and they continuously perturb associated joints into oscillation. Muscle-spindle and tendonorgan reflex loops lack the sensitivity to attenuate these small oscillations, and the underdamped mechanical properties of most joints are conducive to oscillation (Hagbarth and Young, 1979; Stiles and Hahs, 1991). Consequently, irregularities in muscle force keep most body parts in a constant state of oscillation that is barely visible to the unaided eye. This oscillation is the mechanical component of physiologic tremor. The mechanical component of physiologic tremor has a frequency w that depends upon the inertia I and stiffness K of the joint, according to the equation w =VKii (Lakie et al., 1986). Therefore, tremor frequency is increased by added stiffness and decreased by added inertia. Furthermore, the frequency of this passive mechanical oscillation will
* Correspondence to: Dr. RJ. Elble, Department of Neurology, Southern Illinois University School of Medicine, P.O. Box 19643, Springfield, IL 62794-9643, USA. E-mail address: [email protected] Tel.: 217-524-7881 (ext. 3002); fax: 217-524-1903.
vary from joint to joint, depending upon the natural inertia and stiffness. Consequently, the frequency of passive mechanical oscillation at the metacarpophalangeal joint is higher (20-30 Hz) than at the wrist (7-10 Hz) and elbow (3-5 Hz) (Stiles and Randall, 1967; Fox and Randall, 1970; Elble and Randall, 1978). The mechanical component of physiologic tremor exists during complete relaxation (rest tremor), active steady posture (postural tremor), and voluntary movement (kinetic tremor). Rest tremor occurs because the mechanical shock of cardiac systole perturbs the body into oscillation (Brumlik and Yap, 1970). These cardioballistic oscillations also contribute to physiologic action tremor (Elble and Randall, 1978), but the relative magnitude of this contribution depends upon the level of voluntary motor activity and varies with the site of recording. Postural head tremor is largely cardioballistic (Fig. 1), while cardioballistics play a minor role in postural hand tremor (Marsden et aI., 1969; Elble and Randall, 1978). The contribution of cardioballistics to physiologic tremor has been studied extensively by looking for mathematical correlation or coherence between the tremor and the timing of cardiac systole, as measured with the electrocardiogram (Marsden et aI., 1969; Elble and Randall, 1978). However, the contribution of cardioballistics is not routinely quantified in measurements of physiologic tremor. Physiologic tremor is barely visible to the unaided eye. Hand tremor is most visible in the extended fingers and may not be visible at the wrist. Physiologic hand tremor is only symptomatic during fine motor tasks requiring great precision, as in microvascular surgery (Harwell and Ferguson, 1983). Normal postural hand tremor recorded 10 em from the wrist contains rhythmic oscillations with a mean peak-to-peak amplitude of 0.009-0.153 mm displacement and 3-33 cm/s' acceleration (Elble, 1986). These mean amplitudes overlap somewhat
358
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Fig. 1. Five-second recordings of head tremor and electrocardiogram (EKG) were obtained from a healthy 80-year-old woman while she sat quietly in a chair. Tremor was measured with a triaxial accelerometer attached to her forehead. Lateral (side-to-side) acceleration is shown in the upper graph. Note the transient increase in acceleration (arrows) following each QRS complex of the EKG, typical of cardioballistic oscillation.
with the lower range of mild essential tremor (Elble, 1986). 22.2. Neurogenic oscillation
Motor unit firing is largely asynchronous during steady muscle contractions. Consequently, the Fourier power spectrum of the rectified-filtered EMG is statistically flat (Fig. 2). Two or more motor units may discharge synchronously (within a few milliseconds) during steady voluntary contractions, but this short-term synchronization occurs intermittently for a few milliseconds and affects only 8% of motor unit discharges (Dietz et al., 1976; Dengler et al., 1984; Datta et al., 1991; De Luca et al., 1993; Semmler and Nordstrom, 1998). The degree to which short-term synchronization contributes to physiologic tremor has not been quantified, and the mechanism of short-term synchronization is uncertain. Some authors believe that this synchronization is due to the joint occurrence of excitatory postsynaptic potentials evoked in multiple motoneurons by branches of a corticospinal fiber (Sears and Stagg, 1976; Datta and Stephens, 1990; Datta et al., 1991; Farmer et al., 1997), while others favor a role
for central oscillatory drive to the motoneuron pool (De Luca et al., 1993). Sensory feedback is not necessary for short-term synchronization (Farmer et al., 1993; Farmer et al., 1997). Rhythmic oscillations in volitional muscle contraction were observed more than 100 years ago by Schafer et al. (1886). The 8-12 Hz component of physiologic tremor is produced by bursts of motorunit discharge at 8-12 Hz. These bursts are produced by synchronous 8-12 Hz modulation of motor unit firing, such that double (paired) discharges, with interspike intervals of 10-40 ms, tend to occur during a cycle of tremor (Elble and Randall, 1976; Kakuda et al., 1999; Wessberg and Kakuda, 1999). The mean firing frequency of participating motor units ranges from 8 to 25 spikes/so Short-term synchronization of motor units does not contribute significantly (Farmer et al., 1993). The frequency of 8-12 Hz entrainment is independent of reflex arc length and is not reduced by increased limb inertia (Fox and Randall, 1970; Stephens and Taylor, 1974; Elble and Randall, 1976; Elble and Randall, 1978). Furthermore, the stretch reflex response to joint perturbation is too weak and too delayed to account for this entrainment (Wessberg and Vallbo, 1996). Therefore, this tremor is believed to emerge from a central source of oscillation. The inferior olive is the most frequently hypothesized source of 8-12 Hz tremor, but this hypothesis is largely conjectural, based on the similarities between this tremor and the 8-12 Hz harmaline tremor in laboratory primates (Elble, 1998a). Other sources of rhythmicity (e.g. thalamus and cortex) are also possible. Koster et al. (1998) found that the 8-12 Hz tremor, enhanced by salbutamol, was coherent between the two forearms in three patients with the syndrome of persistent mirror movements. As these patients are believed to have ipsilateral and contralateral corticospinal projections, Koster's data suggest that that enhanced physiologic tremor is conducted through corticospinal pathways. Corticospinal involvement is supported by the recent finding of coherence between the 8-12 Hz tremor and EEG (Raethjen et al., 2000a). However, the primary source of oscillation is still uncertain. Elble (2003) quantified hand tremor and forearm EMG in 100 healthy adults, aged 20-40, and 100 older adults, aged 70-90, and Raethjen et al. (2000b) quantified hand tremor and finger tremor in 117 normal people, aged 20-94 years. All of these
359
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Fig. 2. Autospectra of hand tremor and rectified-filtered extensor carpi radialis brevis EMG recorded with (thin lines) and without (thick lines) a 500-gram load on the hand. Tremor was recorded with an accelerometer and skin electrodes during horizontal extension of the hand, with forearm supported. The frequency of physiologic tremor (left column graphs) decreased with 500-gram loading, and there was no associated peak in the EMG spectrum (i.e. no evidence of motor-unit entrainment). The frequency of enhanced physiologic tremor in a patient with thyrotoxicosis (right column graphs) also decreased with mass loading, but this tremor was associated with a significant peak in the EMG spectrum (arrows).
normal controls exhibited the mechanical component of physiologic tremor, usually with no evidence of associated motor unit entrainment. Only about 10% of these controls exhibited 8-12 Hz motor unit entrainment that was strong enough to produce Fourier spectral peaks in the acceleration and rectified-filtered EMG spectra (Fig. 3). The frequency of this neurogenic tremor may be as low as 6-8 Hz in people older than 65 years. This motor unit entrainment is indistinguishable from mild essential tremor, but its relationship to essential tremor is unclear (Elble, 1986). Most, if not all, people exhibit 8-12 Hz bursts of EMG during slow voluntary movements, particularly in the wrist and finger extensors during slow wrist or finger flexion (Wessberg and Vallbo, 1996; Kakuda et al., 1999).
Thus, there is a tendency for 8-12 Hz motor unit entrainment to occur in everyone, but this tendency is too weak in most healthy adults to produce an EMG spectral peak during voluntary horizontal extension of the hand or finger. In a study of finger tremor, Halliday et al. demonstrated the presence of 15-30 Hz motor unit entrainment that was estimated to explain about 20% of finger tremor in this frequency band (Halliday et al., 1999). The contribution of 15-30 Hz motor unit entrainment to tremor in body parts with greater inertia (e.g. hand, forearm) is much smaller and usually not measurable, even with accelerometry. This component of physiologic tremor is believed to emerge from cortical rhythmicity, as detected with EEG and MEG (Conway et al., 1995; Baker et al.,
360
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Frequency (Hz) Fig. 3. Autospectra of hand tremor and rectified-filtered extensor carpi radialis brevis EMG recorded with (thin lines; right vertical axes) and without (thick lines; left vertical axes) a 300-grarn load were obtained from a neurologically-normal 32-year-old woman. Tremor was recorded with an accelerometer and skin electrodes during horizontal extension of the hand, with forearm supported. With no mass loading, a single peak is found in the acceleration and rectified-filtered EMG spectra. Mass loading reduced the amplitude and frequency of the mechanical resonance oscillation, which disclosed the second oscillation with motor-unit entrainment at 8-12 Hz (arrows). With no mass loading, the two sources of oscillation seemed to resonate at the same frequency.
1997; Salenius et al., 1997; Halliday et al., 1998; Baker et al., 1999). Normal vocal tremor has a frequency of 6-13 Hz and is due to a combination of rhythmic neural drive and mechanical resonance of the larynx (Ludlow et al., 1986; Winholtz and Ramig, 1992). Ocular microtremor has a peak frequency of approximately 80 Hz, reflecting the high-frequency motoneuron entrainment and extraocular muscle dynamics (Bolger et al., 1999; Spauschus et al., 1999). Additional ocular microtremor at 4 and 10Hz may
Enhanced physiologic tremor occurs during fatigue, anxiety and voluntary movement and in response to beta-adrenergic drugs (Stiles, 1976; Logigian et al., 1988; Stiles and Hahs, 1991). Under these circumstances, the amplitude of tremor may increase by a factor of 5 to 20, and the EMG exhibits bursts of motor unit activity at the frequency of tremor (Hagbarth and Young, 1979; Stiles, 1980). These bursts are produced by entrainment of motor units with mean firing frequencies of 8 to 25 spikes/s, and the modulation of individual motor units is such that double (paired) discharges, with interspike intervals of 10-40 ms, tend to occur during a cycle of tremor (Logigian et al., 1988). Enhanced participation of spinal and possibly longloop stretch reflex pathways plays an important role in the entrainment of motor units. In most people, this enhanced physiologic tremor consists of a single rhythmic oscillation that decreases in frequency with inertial loading (Fig. 2). Thus, enhanced physiologic tremor is typically a mechanical-reflex oscillation in which the inertia and stiffness of the joint play a pivotal role determining tremor frequency. However, the 8-12 Hz component of physiologic tremor is also increased by fatigue, anxiety, voluntary movement (e.g. wrist extension-flexion), beta-adrenergic drugs and central nervous system stimulants (Raethjen et al., 2001), and this component of physiologic tremor may be more evident in people with enhanced tremor. The stiffness and damping of the wrist and other joints are not constant; rather they are a function of displacement and velocity. The effective damping ratio of the wrist and other joints of the limbs is less than one (underdamped), making these joints prone to oscillation. Stiffness and damping increase as the displacement and velocity of oscillation decrease (Milner and Cloutier, 1998). These nonlinear mechanical properties tend to attenuate and control oscillation at low magnitudes to which the stretch reflex is relatively insensitive. Stiffness and damping also increase with increased muscle activation (Milner and Cloutier, 1998), which explains the common
PHYSIOLOGIC AND ENHANCED PHYSIOLOGIC TREMOR
361
strategy of antagonistic muscle co-contraction when stability is threatened. The frequency of enhanced mechanical-reflex tremor decreases as the amplitude increases, and this can be explained, at least partially, by a reduction in the mechanical stiffness that occurs when the amplitude of joint oscillation increases (Gottlieb and Agarwal, 1977; Agarwal and Gottlieb, 1984; Lakie et aI., 1984; Zahalak and Pramod, 1985; Milner and Cloutier, 1998). The reduction in tremor frequency with increased amplitude produces a greater phase advance of sensory feedback on tremor, and this results in greater reflex damping, which is beneficial in the control of tremor (Stiles and Hahs, 1991). Stretch-reflex responses can destabilize the wrist and similar joints at frequencies of 7 Hz or greater (Milner and Cloutier, 1998). People with deafferented limbs exhibit irregular broad-band errors in limb position that exceed the amplitude of physiologic and enhanced physiologic tremor, but they do not exhibit the increased tremor with rhythmic motor unit entrainment seen in patients with enhanced mechanical-reflex tremor (Sanes, 1985). Thus, the presence of sensory feedback is not deleterious in terms of the overall amplitude of positional error, rather sensory feedback seems to entrain or concentrate error at a particular frequency, resulting in rhythmic oscillation. The stretch reflex probably contributes to most, if not all, pathologic tremors in this manner, even when a tremor emerges from a central source of oscillation. With greater involvement of segmental and longloop reflexes, the reflex stiffness, damping and loop time play an increasingly important role in determining tremor frequency, while the influence of limb mechanics on tremor frequency diminishes. Consequently, enhanced mechanical-reflex tremor has a frequency that is less dependent upon limb mechanics and more dependent upon reflex loop properties than normal mechanical tremor (Stiles, 1980). This is nicely illustrated in mathematical models of mechanical-reflex tremor (Stein and Oguztoreli, 1976; Bock and Wenderoth, 1999). In these models, the frequency of mechanical-reflex tremor is nearly independent of limb stiffness and inertia when mechanical damping and stiffness are very small relative to stretch-reflex damping and stiffness. Therefore, in the situation of large reflex gain, a mechanical-reflex oscillation may be difficult to
distinguish from a central oscillation on the basis of the frequency response to mechanical loading. However, the mechanical-reflex tremor frequency is still a function of reflex arc length (latency) (Bock and Wenderoth, 1999) and thereby differs from the 8-12 Hz component of physiologic tremor and from essential and Parkinson tremors (Deuschl et al., 1996). 22.4. Clinical guidelines The EMG and mechanical-loading properties of physiologic tremor are of value in the electrophysiologic analysis of action tremor of uncertain etiology. However, the following guidelines and caveats are noteworthy: (1) A tremor whose frequency varies predictably
with mechanical load or reflex arc length is produced, at least in part, by mechanical-reflex mechanisms. A tremor whose frequency is independent of mechanical load and reflex arc length most likely emerges from a central source of oscillation. (2) Tremor with the EMG, amplitude and frequency properties of physiologic tremor or enhanced mechanical-reflex tremor may be recorded from patients with intermittent or very mild action tremor of central origin (e.g. essential tremor, Parkinson tremor) (Deuschl et al., 1996; Deuschl and Elble, 2000). The motor-unit entrainment in a mild pathologic tremor of central origin can be so irregular or intermittent that the bursts of motor-unit activity simply perturb the limb, producing an enhanced mechanical-reflex oscillation (Elble, 1991). A sustained rhythmic motor-unit entrainment is needed to produce an EMG spectral peak that is frequency-invariant with mechanical loading. (3) The significance of a prominent unenhanced 8-12 Hz tremor is unclear. Identical tremor can be recorded from patients with mild essential tremor (Elble, 1986) and Parkinson disease (Lance et al., 1963), and many ostensibly normal older people (age >70) may exhibit a slightly lower tremor frequency of 6--8Hz (Elble, 1998b), making this tremor virtually indistinguishable from mild essential tremor. Since a prominent 8-12 Hz tremor is found in about 10% of controls, its presence should raise the clinical suspicion of an underlying neurologic disorder.
362
(4) Some pathologic tremors exhibit the electrophysiologic characteristics of a mechanicalreflex oscillation (e.g. cerebellar outflow tract tremors) (Elble et aI., 1984; Qureshi et aI., 1996). 22.5. Summary Normal action tremor in the upper extremity consists primarily of two rhythmic oscillations, mechanical-reflex and 8-12 Hz (Elble and Randall, 1978; Timmer et aI., 1998). The 8-12 Hz component of physiologic tremor is produced by rhythmic motor-unit entrainment at 8-12 Hz although seemingly normal elderly people exhibit frequencies as low as 6-8 Hz. The frequency of this component is not affected by changes in limb mechanics (inertia and stiffness) or reflex arc length, and it is therefore believed to emerge from a central source of oscillation, the identity of which is unknown. The mechanical-reflex component is so named because its frequency is a function of the inertia and stiffness of the limb and its reflex arc, and when the stretch reflex is enhanced, the frequency of tremor is also a function of reflex arc length. Irregularities in motor unit firing and cardioballistics provide a broadfrequency forcing to the limb, resulting in mechanical-reflex oscillation. The mechanical-reflex oscillation is associated with motor-unit entrainment when its amplitude becomes large enough to induce reflex modulation of motor-unit discharge or when the sensitivity of the reflex arc is increased by such factors as drugs, fatigue, and anxiety. This enhanced mechanical-reflex oscillation is the primary source of enhanced physiologic tremor although the 8-12 Hz component is also enhanced by these factors.
Acknowledgment This work was supported by the Spastic Paralysis Research Foundation of Kiwanis International, Illinois-Eastern Iowa District.
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R.I. ELBLE
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Elble, RJ (1998b) Tremor in ostensibly normal elderly people. Mov. Disord., 13: 457-464. Elble, RJ (2003) Characteristics of physiologic tremor in young and elderly adults. Clin. Neurophysiol., 114: 624-635. Elble, RJ and Randall, JE (1976) Motor-unit activity responsible for 8- to 12-Hz component of human physiological finger tremor. J. Neurophysiol., 39: 370383. Elble, RJ and Randall, JE (1978) Mechanistic components of normal hand tremor. Electroencephalogr. Clin. Neurophysiol., 44: 72-82. Elble, RJ, Schieber, MH and Thach, WT, Jr (1984) Activity of muscle spindles, motor cortex and cerebellar nuclei during action tremor. Brain Res., 323: 330-334. Farmer, SF, Bremner, PD, Halliday, DM, Rosenberg, JR and Stephens, JA (1993) The frequency content of common synaptic inputs to motoneurons studied during voluntary isometric contraction in man. J. Physiol. (Lond.), 470: 127-155. Farmer, SF, Halliday, DM, Conway, BA, Stephens, JA and Rosenberg, JR (1997) A review of recent applications of cross-correlation methodologies to human motor unit recording. J. Neurosci. Meth., 74: 175-187. Fox, JR and Randall, JE (1970) Relationship between forearm tremor and the biceps electromyogram. J. Appl. Physiol., 29: 103-108. Gottlieb, GL and Agarwal, GC (1977) Physiological clonus in man. Exp. Neurol., 54: 616-621. Hagbarth, K-E and Young, RR (1979) Participation of the stretch reflex in human physiological tremor. Brain, 102: 509-526. Halliday, DM, Conway, BA, Farmer, SF and Rosenberg, JR (1998) Using electroencephalography to study functional coupling between cortical activity and electromyograms during voluntary contractions in humans. Neurosci. Lett., 241: 5-8. Halliday, DM, Conway, BA, Farmer, SF and Rosenberg, JR (1999) Load-independent contributions from motorunit synchronization to human physiological tremor. J. Neurophysiol., 82: 664-675. Harwell, RC and Ferguson, RL (1983) Physiologic tremor and microsurgery. Microsurgery, 4: 187-192. Kakuda, N, Nagaoka, M and Wessberg, J (1999) Common modulation of motor unit pairs during slow wrist movement in man. J. Physiol. (Lond.), 520: 929-940. Koster, B, Lauk, M, Timmer, J, Winter, T, Guschlbauer, B, Glocker, FX, Danek, A, Deuschl, G and Lucking, CH (1998) Central mechanisms in human enhanced physiological tremor. Neurosci. Lett., 241: 135-138. Lakie, M, Walsh, EG and Wright, GW (1984) Resonance at the wrist demonstrated by the use of a torque motor:
an instrumental analysis of muscle tone in man. J. Physiol. (Lond.), 353: 265-285. Lakie, M, Walsh, EG and Wright, GW (1986) Passive mechanical properties of the wrist and physiological tremor. J. Neurol. Neurosurg. Psychiatry, 49, 669-676. Lance, JW, Schwab, RS and Peterson, EA (1963) Action tremor and the cogwheel phenomenon in Parkinson's disease. Brain, 86: 95-110. Logigian, EL, Wierzbicka, MM, Bruyninckx, F, Wiegner, AW, Shahani, BT and Young, RR (1988) Motor unit synchronization in physiologic, enhanced physiologic and voluntary tremor in man. Ann. Neurol., 23: 242250. Ludlow, CL, Bassich, CJ, Connor, NP and Coulter, DC (1986) Phonatory characteristics of vocal fold tremor. J. Phonetics, 14: 509-515. Marsden, CD, Meadows, JC, Lange, GW and Watson, RS (1969) The role of the ballistocardiac impulse in the genesis of physiological tremor. Brain, 92: 647-662. McAuley, JH, Farmer, SF, Rothwell, JC and Marsden, CD (1999a) Common 3 and 10 Hz oscillations modulate human eye and finger movements while they simultaneously track a visual target. J. Physiol. (Lond.), 515: 905-917. McAuley, JH, Rothwell, JC and Marsden, CD (1999b) Human anticipatory eye movements may reflect rhythmic central nervous system activity. Neuroscience, 94: 339-350. Milner, TE and Cloutier, C (1998) Damping of the wrist joint during voluntary movement. Exp. Brain Res., 122: 309-317. Qureshi, F, Morales, A and Elble, RJ (1996) Tremor due to infarction in the ventrolateral thalamus. Mov. Disord., 11: 440-444. Raethjen, J, Lindemann, M, Dumpelmann, M, Stolze, H, Wenzelburger, R, Pfister, G, Elger, CE, Timmer, J and Deuschl, G (2000a) Cortical correlates of physiologic tremor. Mov. Disord., 15 (Suppl, 3): 90-91. Raethjen, J, Pawlas, F, Lindemann, M, Wenzelburger, R and Deuschl, G (200Gb) Determinants of physiologic tremor in a large normal population. Clin. Neurophysiol., Ill: 1825-1837. Raethjen, J, Lemke, MR, Lindemann, M, Wenzelburger, R, Krack, P and Deuschl, G (2001) Amitriptyline enhances the central component of physiological tremor. J. Neurol. Neurosurg. Psychiatry, 70: 78-82. Salenius, S, Portin, K, Kajola, M, Salmelin, R and Hari, R (1997) Cortical control of human motoneuron firing during isometric contraction. J. Neurophysiol., 77: 3401-3405. Sanes, IN (1985) Absence of enhanced physiological tremor in patients without muscle or cutaneous afferents. J. Neurol. Neurosurg. Psychiatry, 48: 645-649.
364 Schafer, EA, Canney, EL and Thnstall, JO (1886) On the rhythm of muscular response to volitional impulses in man. J. Physiol. (Lond.), 7: 1I1-117. Sears, TA and Stagg, D (1976) Short-term synchronization of intercostal motoneuron activity. 1. Physiol. (Lond.), 263: 357-381. Semmler, JG and Nordstrom, MA (1998) Motor unit discharge and force tremor in skill- and strengthtrained individuals. Exp. Brain Res., 119: 27-38. Spauschus, A, Marsden, J, Halliday, DM, Rosenberg, JR and Brown, P (1999) The origin of ocular microtremor in man. Exp. Brain Res., 126: 556-562. Stein, RB and Oguztoreli, MN (1976) Tremor and other oscillations in neuromuscular systems. Biol. Cybem., 22: 147-157. Stephens, JA and Taylor, A (1974) The effect of visual feedback on physiological muscle tremor. Electroencephalogr. Clin. Neurophysiol., 36: 457-464. Stiles, RN (1976) Frequency and displacement amplitude relations for normal hand tremor. J. Appl. Physiol., 40: 44-54. Stiles, RN (1980) Mechanical and neural feedback factors in postural hand tremor of normal subjects. J. Neurophysiol., 44: 40--59.
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Stiles, RN and Hahs, DW (1991) Muscle-load oscillations: detection, analysis and models. In: DL Wise (Ed.), Bioinstrumentation and Biosensors. Marcel Dekker, Inc., New York, pp. 75-119. Stiles, RN and Randall, JE (1967) Mechanical factors in human tremor frequency. 1. Appl. Physiol., 23: 324-330. Timmer, J, Lauk, M, Pfleger, W and Deuschl, G (1998) Cross-spectral analysis of physiologic tremor and muscle activity. I. Theory and application to unsynchronized electromyogram. Biol. Cybern., 78: 349-357. Wessberg, J and Vallbo, AB (1996) Pulsatile motor output in human finger movements is not dependent on the stretch reflex. J. Physiol. (Lond.), 493: 895-908. Wessberg, J and Kakuda, N (1999) Single motor unit activity in relation to pulsatile motor output in human finger movements. J. Physiol. (Lond.), 517: 273-285. Winholtz, WS and Ramig, LO (1992) Vocal tremor analysis with the vocal demodulator. J. Speech Hear. Res., 35: 562-573. Zahalak, GI and Pramod, R (1985) Myoelectric response of human triceps brachii to displacement-controlled oscillations of the forearm. Exp. Brain Res., 58: 305317.
Movement Disorders Handbook of Clinical Neurophysiology, Vol. I M. Hallett (Ed.) © 2003 Elsevier B.V. All rights reserved
365
CHAPTER 23
Essential tremor and primary writing tremor Peter G. Bain* Imperial College School ofMedicine. Charing Cross Hospital Campus, Fulham Palace Road, London W68RF, UK
23.1. Essential tremor
23.1.2, Clinical features
23.1.1. Definition
Essential tremor is classified as being either hereditary or sporadic. Different studies have given the overall population prevalence of essential tremor to be between 0.08 and 220 cases per 1000 people (Louis et al., 1998). The wide variations in these figures are largely the result of differences in the observed populations and the diagnostic criteria deployed in each study. If these are standardized the prevalence estimates vary from 4.1 to 39.2 cases per 1000 (Louis et al., 1998). However, two significant diagnostic difficulties remain: firstly, distinguishing between an enhanced physiological tremor and the early stages of essential tremor, as currently there is no accepted way of making this distinction; and secondly, dissecting out essential tremor from other causes of action tremor that can mimic the condition. Essential tremor has a bimodally distributed age of onset with a median age of about 15 years. The sexes are affected with equal frequency and severity. Tremor provoked disability typically begins in the second decade and increases with age and tremor duration (Koller et al., 1986; Bain et al., 1994). The upper limbs are affected first and then in a proportion of cases tremor can spread to affect the legs, head, facial muscles, voice and tongue (Bain et aI.,1994).
In a consensus statement of the Movement Disorder Society on Tremor (Deuschl et al., 1998) the following clinical criteria were developed to make the diagnosis of classical essential tremor: Inclusion criteria: (i) Bilateral, largely symmetrical postural or kinetic
tremor involving hands and forearms that is visible and persistent. (ii) Additional or isolated tremor of the head may occur but in the absence of abnormal posturing. (This item of the inclusion criteria is controversial). Exclusion criteria: (i) Other abnormal neurologic signs, especially
dystonia. (ii) The presence of known causes of enhanced
(iii) (iv) (v) (vi) (vii) (viii) (ix)
physiological tremor, including current or recent exposure to tremorgenic drugs or the presence of a drug withdrawal state. Historic or clinical evidence of psychogenic tremor. Convincing evidence of sudden onset or evidence of stepwise deterioration of tremor. Primary orthostatic tremor. Isolated voice tremor. Isolated position-specific or task-specific tremors, including occupational tremors and primary writing tremor. Isolated tongue or chin tremor. Isolated leg tremor.
* Correspondence to: Dr. Peter G. Bain, Imperial College School of Medicine, Charing Cross Hospital Campus, Fulham Palace Road, London W6 8RF, UK. E-mail address:[email protected] Tel.: 020-8846-1182; fax: 020-8846-7487.
23.1.3. Response to alcohol and other treatments
About 50% of people with essential tremor respond to alcoholic drinks. However, the tremor invariably rebounds about 3-4 hours later in a temporarily exacerbated form (Critchley, 1949; Bain et al., 1994). Even so moderate use of alcohol can facilitate feeding and social interaction. Several controlled trials have established propranolol and primidone or a combination of both as the mainstays of treatment of essential tremor, as these drugs
366
reduce the amplitude of essential tremor. However, some disability remains and patients are often troubled by side effects (Bain, 1997). Several other medications have been advocated as treatments for essential tremor, including other ~-receptor blockers, clonazepam, alprazolam, acetazolamide, amantadine, benzhexol, trazadone, phenoxybenzamine, progabide, theophylline, clozapine, verapamil, nifedipine, nicardipine and botulinum toxin, but of these only clonazepam is widely deployed as a second line treatment, particularly for the predominantly kinetic form of essential tremor (Biary and Koller, 1987; Bain, 1997). Stereotactic surgery can be an effective treatment for patients with severe essential tremor but has inherent risks (Bain, 1997). The conventional cerebral target for alleviating contralateral essential tremor is the ventralis intermedius nucleus of the thalamus (Pahwa et al., 2000), although recently ventralis oralis posterior and zona incerta have been targeted to good effect (Aziz and Bain, personal communication). The issues of the comparative safety and efficacy of unilateral thalamotomy vs. chronic thalamic stimulation were addressed in a randomized controlled trial conducted by Schuurman et al. (2000). The results of this study showed that, six months after surgery, both techniques were equally effective at suppressing essential tremor but stimulation caused a significantly greater improvement in the patients' capacities to perform their activities of daily living and was associated with fewer adverse events. The efficacy of thalamic stimulation over a one to two-year period has also been established (Koller et aI., 1997; Limousin et al., 1999). Bilateral deep brain stimulation is considered to be preferable to bilateral thalamotomies because of the high incidence of dysarthria associated with the latter (Koller et al., 2000). The short term results obtained by gamma knife thalamotomy, which has been performed on a small number of essential tremor patients who could not undergo invasive surgery, indicate that essential tremor can be alleviated by this technique. However, serious concerns about the long term consequences of this treatment remain (Niranjan et al., 2000). 23.1.4. Genetics
The gene or genes responsible for hereditary essential tremor have not been isolated. Two studies
P.G. BAIN
have excluded linkage between familial essential tremor and the DYTI dystonia locus (Conway et aI., 1993; Durr et al., 1993). Linkage with a locus ('FETl') on chromosome 3q13 has been obtained, with a LaD score of 3.71, in an Icelandic study (Gulcher et aI., 1997) and Higgins et aI. (1997) obtained linkage with a locus ('ETM') on chromosome 2p22-25 (LaD score: 5.92). These results indicate that essential tremor may have heterogeneous genetic causes. 23.1.5. Pathophysiology
Standard neuropathological techniques have failed to demonstrate any consistent physical or biochemical changes in brains obtained from patients in whom essential tremor had been present (Rajput et aI., 1991). However, it has been reported that lesions in the nucleus ventralis intermedius of the thalamus, internal capsule, and pons abolished contralateral and a cerebellar lesion abolished ipsilateral essential tremor (Hirai et aI., 1983; Larsen and Calne, 1983; Young, 1986; Duncan et al., 1988; Dupuis et aI., 1989; Nagaratnam and Kalasabail, 1997). Spectral analysis of moderate-severe essential tremor shows a clear spectral peak in both accelerometric and EMG records, although multiple peaks may be present in the spectra obtained from patients with mild essential tremor (Bain et al., 1993). However, the frequency band of essential tremor (::=4-12 Hz) is not diagnostic, as it overlaps with that of many other types of tremor (Deuschl et al., 1998) and like normal physiologic tremor, decreases with advancing age (Marshall, 1962). It has no relationship with the length of the reflex arc (Elble, 1995). The amplitude of essential tremor, recorded at the wrist, has a logarithmic relationship with the tremor frequency (Elble, 1986). Although, changes in the amplitude and frequency of essential tremor have been detected during the performance of different tasks, for example whilst holding a cupful of water and during a joy-stick controlled tracking test, compared to a maintained posture (Bain et al., 1993). Studies involving spring and peripheral mass loading have demonstrated that essential tremor consists of two components, namely a mechanical reflex and a stable frequency component, the latter being associated with abnormal entrainment of motor unit discharges (Elble, 1986, 1995). The
ESSENTIAL TREMOR AND PRIMARY WRITING TREMOR
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Fig. 1. Wrist tremor measured by accelerometry and extensor carpi radialis brevis EMG autospectra recorded from a patient with essential tremor before and during 500 g mass loading. Upper figure: Note that the 8 Hz essential tremor is associated with a prominent spectral peak in the carpi radialis brevis EMG spectrum, indicating motor unit entrainment. Lower figure: Adding 500 mg causes a mechanical reflex frequency component (at about 4.1 Hz) to separate from a frequency stable component (at about 8 Hz). It is this stable-frequency component that distinguishes essential tremor from normal physiological tremor (reproduced from Elble RJ, 1986).
mechanical reflex component of essential tremor is similar to that detected in normal physiological tremor (Elble, 1986). Bursts of EMG activity separated by relative silence occur in ail types of pathological and enhanced physiological tremor but not in normal, low amplitude, physiological tremor (Rothwell et al.,
367
1987). The relationship of the EMG bursts in agonist/antagonist muscle pairs is variable in patients with essential tremor and recordings from the same muscle pair may even vary within an individual patient. The following patterns have all been recorded from the forearm flexor and extensor muscle pairs: co-contraction, alternating, switching from alternating to co-contraction and agonist (antigravity activation alone) as well as other more diffuse patterns (Shahani and Young, 1976; Deuschl et aI., 1987; Rothwell et aI., 1987; Koller et al., 1992; Spieker et aI., 1998). Single motor unit discharges recorded from muscles of normal subjects show that a moderate tonic contraction produces motor unit discharge rates of about 10-15 Hz. In patients with essential tremor the motor units fire in bursts of up to 50 Hz, which are grouped into the active period of each tremor cycle and there is also another tendency for discharges from separate motor units to synchronize over a shorter time period. Single motor unit studies have shown that the recruitment order of units within each tremor cycle is disrupted in essential tremor (Rothwell et al., 1987). Two studies of simple voluntary ballistic wrist movements show conflicting results in patients with essential tremor: in one (Britton et aI., 1994) a delayed second agonist burst was found in the triphasic angonist-antagonist-agonist EMG pattern but this aberration was not detected in another study (Elble et al., 1994). Subsequently Deuschl et al. (2000) used an infra-red camera system to make quantitative assessments of a grasping movement, which was performed by: (a) two subgroups of essential tremor patients, one with predominant postural tremor and the other with predominant intention tremor; (b) healthy control subjects; and (c) patients with cerebellar disease. Analysis of the resulting data indicated that the amplitude of intention tremor was similar in essential tremor to that detected in cerebellar disease. Moreover, hypermetria and a slowed deceleration phase were found in the kinematic profiles of the intention-essential tremor subgroup as well as the patients with cerebellar disease, suggesting that there is an abnormality of cerebellar function in essential tremor (Deuschl et al., 2000). Essential tremor can be distinguished from the action tremor resulting from benign IgM paraproteinemic neuropathy as peripheral nerve con-
368
duction velocities are normal in the former but are markedly reduced 00-30 mls) in the latter (Smith et al., 1984; Bain et al., 1996). Various peripheral stimuli have been used to alter the phase of ongoing essential tremor activity relative to the tremor's phase prior to the disturbance. Initially developed as a method of determining how susceptible a tremor generator is to peripheral inputs (mechanical wrist perturbations or median nerve shocks) the technique has stumbled on methodological problems that have led to conflicting reports (Lee and Stein, 1981; Marsden, 1984; E1ble et al., 1987; Britton et al., 1992). One reason for this is that mechanical perturbations of the wrist produce transient mechanico-reflex oscillations that can be mistaken for the underlying essential tremor rhythm. Attempts to overcome this flaw by using sinusoidal forcings applied to the wrist showed that essential tremor could be entrained within a narrow frequency band (Elble et al., 1992). This approach has been further developed using magnetic cortical or electrical stimulation; the former but not the latter reset essential tremor (Britton et al., 1993; Pascual-Leone et al., 1994). Normal cortical excitability, motor latencies and thresholds were detected in essential tremor using the double pulse transcranial magnetic stimulation technique (Romeo et al., 1998). The forearm short and long latency stretch reflexes are of normal size, latency and duration in patients with essential tremor but afterwards rebound oscillations occur which are said to be underdamped (Rothwell et al., 1987). These rebound oscillations were thought to be characteristic of essential tremor but have since been observed in other types of action tremor (Bain, 1993). No abnormalities have been found in studies of reciprocal inhibition of the forearm H-reflex in patients with essential tremor (Panizza et al., 1990). Coherence analysis has been deployed for studying the pathophysiology of essential tremor by examining the relationship between brain activity, recorded using magnetoencephalopathy (MEG) or electroencephalopathy (EEG), and tremorgenic muscle bursts detected by electromyography (EMG) (Halliday et al., 2000; Hellwig et al., 2001). However, the results have been conflicting as Halliday et al. (2000) failed to find a relationship between MEG and EMG, whilst Hellwig et al. (2001) detected significant corticomuscular coherences between EEG and EMG signals at tremor
P.G. BAIN
frequency, with maximum coherences being located over the contralateral sensorimotor cortex. Coherence analysis has also been used to examine the relationship between tremorgenic muscle activities in different muscles within the same limb and also muscles in different limbs (Raethjen et al., 2000). Coherence between tremor-related activity in different muscles within the same limb was found but not from signals derived from muscles from different extremities; indicating that essential tremor is driven by multiple oscillators. Single cell recordings obtained from patients with essential tremor whilst stereotactic thalamic surgery was performed revealed coherent activity between thalamic cell bursts and tremor signals obtained from patients' limbs (Hua et al., 1998).
23.1.6. Functional imaging Positron emission tomography (PET) studies have demonstrated that the rate of 18F-DOPA uptake by the basal ganglia is in the low normal range in hereditary essential tremor patients and usually normal in sporadic cases, whereas in Parkinson's disease the rate of 18F_DOPA uptake by the putamen is asymmetrically diminished (Leenders et al., 1989; Brooks et al., 1992a). Furthermore, striatal dopamine transporter function was found to be normal using 123I-I3-CIT-SPECT in essential tremor, indicating that dopamine dysfunction is not relevant to the majority of essential tremor cases (Asenbaum et al., 1996). A PET study examining resting cerebral 18F_ 2-deoxyglucose utilization in essential tremor showed medullary hypermetabolism which was thought to be indicative of over-activity of the inferior olive (Dubinsky and Hallett, 1987), but these data await confirmation. Studies of regional cerebral blood flow (rCBF) in essential tremor patient cohorts demonstrated that there is overactivity of bilateral cerebellar circuitry whilst tremor is occurring and even during rest in essential tremor patients compared to normal subjects (Colebatch et al., 1990; Brooks et al., 1992b; Zeffiro et al., 1992; Jenkins et al., 1993; Wills et al., 1994, 1995; Boecker et al., 1996). The results of these studies also suggest that the bilateral cerebellar activation evident in essential tremor was not caused by peripheral sensory feedback and that bilateral red nucleus and thalamic activation is associated with essential tremor (Wills
ESSENTIAL TREMOR AND PRIMARY WRITING TREMOR
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et al., 1994; Boecker et aI., 1996). No excess olivary activity was found in these studies, possibly because the inferior olive has few interneurons and thus synaptic activity (Boecker and Brooks, 1998). A study using functional magnetic resonance imaging and single-subject analysis confirmed that rubral activation was increased in essential tremor (Bucher et aI., 1997). As drugs that potentiate GABA transmission can alleviate essential tremor the finding of increased bilateral ventrolateral thalamic [11C]flumazenil binding to central GABAA-receptors using PET in essential tremor is interesting (Boecker and Brooks, 1998). Furthermore, ethanol, which potentiates GABA transmission, reduced cerebellar overactivity in patients with alcohol responsive essential tremor but not in alcohol unresponsive cases (Boecker et aI., 1996; Boecker and Brooks, 1998).
concerned a young man who presented with difficulty writing, that resulted from bursts of tremor that were evoked whenever his right forearm was pronated. Tendon taps to the volar aspect of the patient's forearm would also induce tremor bursts. The authors concluded that the patient's tremor resulted from an abnormal response to the spindle input arising from pronator teres because his writing difficulty and tremor were temporarily abolished by partial motor point anesthesia of this muscle. Subsequently a number of patients with similar symptoms have been documented (Klawans et al., 1982; Ohye et aI., 1982; Kachi et al., 1985; Ravits et aI., 1985; Koller and Martyn, 1986; Cohen et aI., 1987; Rosenbaum and Jankovic, 1988; Elble et al., 1990; Kim and Lee, 1994; Bain et aI., 1995; Jimenez-Jimenez et aI., 1998; Minguez-Castellanos et aI., 1999; Rotella et al., 1999; Berg et aI., 2000; Racette et al., 2001).
231.7. Conclusion Presently the gene and physiological fault responsible for essential tremor have not been precisely determined, although evidence from physiological and functional imaging experiments implicate the cerebellum in the genesis of this form of action tremor. However, the cerebellum may not be the origin of essential tremor, which clearly involves more diffuse circuitry in its expression. f3-receptor blocking and GABA transmission facilitating drugs (namely alcohol and primidone) reduce the severity of essential tremor, whilst lesions or high frequency stimulation of the ventralis intermedius or ventralis oralis posterior nuclei of the thalamus or the zona incerta can abolish or greatly attenuate this common condition.
23.2. Primary writing tremor 23.2.1. Definition In a consensus statement of the Movement Disorder Society on Tremor (Deuschi et al., 1998) primary writing tremor was defined as 'being present when tremor occurs only or predominantly during writing but not during other tasks in the active hand'.
23.2.2. Introduction Primary writing tremor was first described by Rothwell et aI. in 1979. The initial description
23.2.3. Clinical features Bain et aI. (1995) studied the clinical and neurophysiological features of 21 patients (20 males and 1 female) with primary writing tremor and found a degree of non-specific action tremor of the upper limbs in most cases, which was of smaller magnitude than the writing tremor. In "" 20% of cases a preceding history of trauma to the dominant arm was obtained, although there was a delay between trauma and the appearance of tremor that varied from 18 months to 12 years. Patients with primary writing tremor were found to have significantly reduced dominant hand writing speeds (letters per minute) compared to those of healthy control subjects but their speed of writing with the non-dominant hand was within normal limits. Primary writing tremor may occur sporadically or be inherited as an autosomal dominant trait and a family history of primary writing tremor can be obtained from about one third of the patients (Rothwell et aI., 1979; Klawans et al., 1982; Ohye et al., 1982; Kachi et aI., 1985; Ravits et aI., 1985; Koller and Martyn, 1986; Cohen et aI., 1987; Rosenbaum and Jankovic, 1988; Elble et aI., 1990; Bain et aI., 1995). The mean age at primary writing tremor onset is 50.1 years (Bain et aI., 1995), which is between 15 and 20 years later than that reported for writer's cramp (Sheehy and Marsden, 1982; Sheehy et al.,
370
1988; Nakashima et aI., 1989; Waddy et al., 1991), which is also a task-specific disorder of handwriting. It is also significantly older than the mean age of onset of hereditary idiopathic torsion dystonia (Fletcher et aI., 1990) and hereditary essential tremor (Bain et al., 1994). Patients with primary writing tremor have been classified into two types depending on whether tremor appeared during writing (type A: task induced tremor) or whilst writing and also on adopting the hand position normally used for writing (type B: positionally sensitive tremor). However, no significant differences between these two primary writing tremor sub-groups with regard to age, age at tremor onset or duration of tremor was found and the condition is usually non-progressive (Bain et al., 1995). Primary writing tremor produces sufficient difficulty with writing that in most instances (voluntary) adaptive techniques are employed. However, only ::05% of patients give up trying to write and in ::0 10% employment status is affected. Curiously, only few patients switch themselves to writing with the nondominant hand (Bain et al., 1995). 23.2.4. Etiology
The etiology of primary writing tremor is controversial (Fahn, 1984; Sheehy et al., 1988; Elble and Koller, 1990; Bain et al., 1995) and opinion is divided into two main schools of thought: (i) that primary writing tremor is a variant of essential tremor (Ohye et al., 1982; Kachi et al., 1985; Koller and Martyn, 1986); or (ii) that it is a type of focal dystonia, a variant of writer's cramp (Ravits et al., 1985; Cohen et aI., 1987; Elble et al., 1990). However, it is possible that primary writing tremor is a different entity from both focal dystonia and essential tremor (Bain et al., 1995; Berg et aI., 2000). Sheehy et aI. (1988) and Rosenbaum and Jankovic (1988) have suggested a scheme in which some cases of primary writing tremor were related to essential tremor and others to torsion dystonia. The evidence supporting the hypothesis that primary writing tremor is a variant of essential tremor is that both types of tremor have similar frequencies (between 4 and 8 Hz) and can be relieved (in about 30% and 50% of cases respectively) by moderate amounts of alcohol (Ohye et al., 1982; Kachi et aI., 1985; Koller and Martyn, 1986; Bain et aI., 1994, 1995). However, the unilateral
P.G. BAIN
nature of primary writing tremor, its tendency to remain focal and to appear rather than suppress during skilled manual tasks argue strongly against primary writing tremor being a variant of hereditary essential tremor; as the latter typically affects both hands, becomes increasingly severe with time, often spreads to other parts of the body, and can usually be suppressed to some extent during skilled tasks (Bain et al., 1993). Furthermore, not one example of primary writing tremor was detected in a detailed observational study of 20 families with essential tremor (Bain et al., 1994). The view that PWT is a type of writer's cramp is supported by the observation that both conditions are task specific. Furthermore, in some cases of primary writing tremor both tremor and abnormal posturing are apparent (Sheehy and Marsden, 1982; Sheehy et aI., 1988; Elble et aI., 1990). In addition tremor without any other movement disorder can be one of the manifestations of idiopathic torsion dystonia (Bundey et al., 1975; Fletcher et al., 1990, 1991) and one family has been described in which cases of writer's cramp, writing tremor and non-task specific tremor were all noted (Cohen et aI., 1987). However, this family were subsequently found to have a spinocerebellar atrophy (SCA) mutation (Hallett, personal communication). Furthermore, classification difficulties arise because some tremulous patients voluntarily employ unusual postures and excessive force to control the pen and thus appear to be dystonic. In addition, not one case of primary writing tremor was documented in several genetic studies of focal or other forms of idiopathic torsion dystonia (Bundey et aI., 1975; Forsgren et al., 1988; Fletcher et al., 1990; Waddy et al., 1991). Kim and Lee (1994) described the development of writing tremor in a 67 year old man after a discrete left frontal infarct. The patient had mild essential tremor preceeding the stroke and developed writing tremor after recovering from a right hemiparesis. 23.2.5. Effect of alcohol and other treatments
There have been no formal therapeutic trials involving patients with primary writing tremor. However, alcohol greatly improves or abolishes writing tremor in ::033% of patients but ::0 15% express concern about their own excessive alcohol consumption (Bain et aI., 1995). Anecdotal evidence suggests that ::0 80% of patients with PWT obtain
ESSENTIAL TREMOR AND PRIMARY WRITING TREMOR
371
some benefit from treatment: propranolol, primidone and anti-cholinergic drugs being the most commonly prescribed (Bain et aI., 1995). Intramuscular botulinum toxin injected into the forearm flexor and extensor muscles has also been reported to benefit some cases (Bain et aI., 1995). In appropriate cases contralateral stereotactic ventralis intermedius thalamotomy and thalamic stimulation can alleviate primary writing tremor (Ohye et al., 1982; MinguezCastellanos et aI., 1999; Racette et aI., 2001).
primary writing tremor (Kachi et aI., 1985; Ravits et aI., 1985; Elble et aI., 1990; Bain et., 1995), although skipping between an alternating and a co-contracting pattern or alternating and extensor activation only, extensor only activation and co-contraction have also been observed (Kachi et aI., 1985; Bain et aI., 1995). Bain et aI. (1995) could not detect any rhythmic EMG activity from any of their type A primary writing tremor patients when the arms were at rest, held outstretched or placed in a writing posture. Rhythmic segmentation of the EMG could be recorded from all the type B patients when the dominant hand was placed in a writing posture or partially pronated to a critical angle (positionally sensitive tremor), but in these postures the tremor frequency was usually similar to that of their standard postural tremor (i.e. above that of their writing tremor). The only other differences between these two groups were that a co-contracting EMG pattern and tremor induced by tendon taps to the volar aspect of the wrist were present in type B but not type A cases. The amplitude and latencies of the forearm stretch reflexes were normal in five patients with primary writing tremor described by Kachi et aI. (1985) but the authors had difficulty reconciling this observation with the fact that tendon taps and muscle stretches caused tremor to appear in two and six of their nine patients, respectively. Ravits et al. (1985) recorded 5-20 I-LV cerebral potentials, which could be elicited by stretching pronator teres, and also noted that C-reflexes were absent. The time course of reciprocal inhibition of the forearm median nerve H-reflex has been clearly defined for normal individuals (Day et aI., 1984) and is known to be abnormal in patients with writer's cramp (Nakashima et aI., 1989). In normal subjects, it has been shown that the time course of inhibition of the median nerve H-reflex produced by radial nerve shocks has three distinct inhibitory phases, at conditioning-test intervals of about -3 to 1, 5 to 50 (maximal at 15-20) and 50 to at least 100 ms respectively. The first (-3 to 1 ms) of these is compatible with Ia disynaptic inhibition of flexor motomeurons produced by activation of large diameter afferents from extensor muscles. The second (5 to 50 ms) is thought to reflect presynaptic inhibition of the terminals of flexor Ia afferent fibers whilst the cause of the third inhibitory period (50 to at least 100
23.2.6. Pathophysiology In normal handwriting epochs of rhythmic EMG activity (at about 4-7.7 Hz) are seen in the intrinsic hand muscles and wrist extensors of the dominant arm and can also be evident in the biceps and triceps muscles (Bain et aI., 1995). Tremor frequencies of 5-7 Hz have consistently been found in patients with primary writing tremor (Ohye et aI., 1982; Kachi et aI., 1985; Ravits et aI., 1985; Elble et aI., 1990; Bain et aI., 1995), the only exception being the original patient described by Rothwell et al. in 1979 in whom a 4-6 Hz tremor occurred in biceps, supinator and pronator teres whilst triceps fired at about 10 Hz. Accelerometric studies show that the magnitudes of the standard postural tremors in either hand or the writing tremor/oscillation in the dominant hand were similar for a group of PWT patients compared to those of healthy control subjects (Bain et aI., 1995). The frequencies of the dominant hand writing tremor/oscillation or non-dominant standard postural tremor were also found to be similar. The frequency of primary writing tremor patients' postural tremor on the dominant side was significantly lower than that of the control group. In three primary writing tremor patients, tremor appeared solely in the dominant hand when writing with the non-dominant hand (Bain et aI., 1995). A similar phenomenon, called mirror dystonia, has been described in writer's cramp (Sheehy and Marsden, 1982). During writing with the dominant hand, rhythmic EMG is present in comparable muscle groups of PWT patients and control subjects; indicating that there is no excessive "overflow" of this rhythmic EMG activity in primary writing tremor, although this activity is more sustained in this condition (Bain et aI., 1995). EMG bursts that alternate between the forearm agonist/antagonist muscles is typical of
372
P.G. BAIN
RECIPROCAL INHIBITION
w
C/)
Z
o
a..
C/)
~ ...J o a::
IZ
o o LL o W o ~
Z W
o a:: w
a..
Fig. 2. Inhibition of the forearm flexor H-reflex when tested at different times after a single motor threshold conditioning stimulus (at t=O ms) given to the radial nerve in the spiral groove. Negative timings indicate that the median nerve test shock (used to elicit flexor H-reflexes) was given before the conditioning (radial nerve) shock. Mean (+ I SEM) values of the size of the flexor H-reflex, expressed as a percentage of the control If-reflexes, are plotted. The results from 10 normal control subjects, 13 patients with PWT and 16 patients with writer's cramp (We) are shown (reproduced from Bain et al.,
1995).
ms) is not presently understood (Day et al., 1984; Berardelli et al., 1987; Nakashima et al., 1989). The reciprocal inhibition curve for 13 patients with primary writing tremor was found to be normal in every respect and no significant differences between the curves obtained from type A and B primary writing tremor patients were detected (Bain et al., 1995). However, it should be noted that patients with tremulous writers' cramp were not included in this study. In 1982 Ohye et al. recorded a very high incidence of irregular burst discharges within the thalamus and showed that contralateral stereotactic ventralis intermedius thalamotomy could successfully abolish primary writing tremor. 23.2.7. Functional imaging studies
A single PET study demonstrated increased bilateral cerebellar regional cerebral blood flow in
six patients with primary writing tremor, whilst the patients held pen to paper but did not actually write (Wills et al., 1995). In addition three patients with primary writing tremor were examined using functional MRI involving a paradigm that consisted of alternating 30-s periods of rest or writing; the results were compared to those of healthy control subjects (Berg et al., 2000). Both primary writing tremor patients and healthy control subjects were found to have significant activation of the contralateral primary sensorimotor cortex, supplementary motor area and area 44. In addition, patients with primary writing tremor were found to have activation of the contralateral premotor area and ipsilateral prefrontal area, bilateral parietal lobule and bilateral cerebellum, the latter being more pronounced on the ipsilateral side. Consequently, the view that primary writing tremor is distinct from both essential tremor and writer's cramp is supported by these findings, as the cerebral activation patterns found in primary writing tremor integrate hallmarks
ESSENTIAL TREMOR AND PRIMARY WRITING TREMOR
373
of those found in the latter two conditions (Berg et al., 2000).
CD (1996) Tremor associated with benign IgM paraproteinaemic neuropathy. Brain, 119: 789-799. Berg, 0, Preibisch, C, Hofmann, E and Naumann, M (2000) Cerebral activation pattern in primary writing tremor. J. Neurol. Neurosurg. Psychiatry, 69: 780786. Berardelli, A, Day, BL, Marsden, CD and Rothwell, JC (1987) Evidence favouring presynaptic inhibition between antagonist muscle afferents in the human forearm. J. Physiol., 391: 71-83. Biary, N and Koller, WC (1987) Kinetic predominant essential tremor: successful treatment with clonazepam. Neurology, 37: 471-474. Boecker, H and Brooks, OJ (1998) Functional imaging of tremor. Mov. Disord., 13 (Suppl. 3): 64-72. Boecker, H, Wills, AJ, Ceballos-Baumann,A et al. (1996) The effect of ethanol on alcohol-responsive essential tremor: a positron emission tomography study. Ann. Neurol., 39: 650-658. Britton, TC, Thompson, PO, Day, BL, Rothwell, JC and Findley, U (1992) "Resetting" of postural tremors at the wrist with mechanical stretches in Parkinson's disease, essential tremor and normal subjects mimicking tremor. Ann. Neurol., 31: 507-514. Britton, TC, Thompson, PO, Day, BL, Rothwell, JC, Findley, U and Marsden, CD (1993) Modulation of postural wrist tremors by magnetic stimulation of the motor cortex in patients with Parkinson's disease, essential tremor, and in normal subjects mimicking tremor. Ann. Neural., 33: 473-479. Britton, TC, Thompson, PO, Day, BL et al. (1994) Rapid wrist movements in patients with essential tremor. The critical role of the second agonist burst. Brain, 117: 39-47. Brooks, OJ, Playford, ED, Ibanez, V, Sawle, GV, Thompson, PO, Findley,U and Marsden, CD (1992a) Isolated tremor and disruption of the nigrostriatal doparninergic system: an 18F-DOPA PET study. Neurology, 42: 1554-1560. Brooks, OJ, Jenkins, IH, Bain, PG, Colebatch, JG, Thompson, PD, Findley, U and Marsden, CD (1992b) A comparison of the abnormal pattern of cerebral activation associated with neuropathic and essential tremor. Neurology, 42 (Suppl. 3): 423. Bucher, SF, Seelos, KC, Dodel, RC, Reiser, M and Oertel, WH (1997) Activation mapping in essential tremor with functional magnetic resonance imaging. Arch. Neural., 52: 299-305. Bundey, S, Harrison, MJG and Marsden, CD (1975) A genetic study of torsion dystonia. J. Med. Genetics, 12: 12-19. Cohen, LG and Hallett, MD (1988). Hand cramps: clinical features and electromyographic patterns in a focal dystonia. Neurology, 38: 1005-1011.
23.2.8. Conclusion In conclusion, there are clinical, physiological and functional imaging differences between primary writing tremor and both writer's cramp and essential tremor. The results of physiological studies have demonstrated two specific differences between primary writing tremor and writer's cramp: Firstly, during writing in PWT there is no evidence of excessive overflow of EMG activity into the proximal musculature (Bain et al., 1995), whereas overflow is characteristic of writer's cramp (Cohen and Hallett, 1988; Hughes and Mclellan, 1989). Secondly, reciprocal inhibition is entirely normal in primary writing tremor, whereas in writer's cramp the inhibitory effect of ipsilateral radial nerve stimulation on the median nerve H-reflex is diminished when the radial nerve is stimulated between 5 and 50 ms before the median nerve (Nakashima et al., 1989; Panizza et al., 1990). There have been no post-mortem studies involving patients with PWT.
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375 Nakashima, K, Rothwell, JC, Day, BL, Thompson, PD, Shannon, K and Marsden, CD (1989) Reciprocal inhibition between forearm muscles in patients with writer's cramp and other occupational cramps, symptomatic hemidystonia and hemiparesis due to stroke. Brain, 112: 681-697. Niranjan, A, Kondziolka, D, Baser, S, Heyman, R and Lunsford, LD (2000) Functional outcomes after gamma knife thalamotomy for essential tremor and MS-related tremor. Neurology, 55: 443-446. Ohye, C, Miyazaki, M, Hirai, T, Shibazaki, T, Nakajima, Hand Nagaseki, Y (1982) Primary writing tremor treated by stereotactic selective thalmotomy. J. Neurol. Neurosurg. Psychiatry, 45: 988-997. Pahwa, R, Lyons, K and Koller, WC (2000) Surgical treatment of essential tremor. Neurology, 54 (Supp!. 4): 39-44. Panizza, M, Lelli, S, Nilsson, J and Hallett, M (1990) Hreflex recovery curve and reciprocal inhibition of H-reflex in different kinds of dystonia. Neurology, 40: 824-828. Pascual-Leone, A, Valls-Sole, J, Toro, C, Wasserman, EM and Hallett, M (1994) Resetting of essential tremor and postural tremor in Parkinson's disease with transcranial magnetic stimulation. Muscle Nerve, 17: 800-817. Racette, BA, Dowling, J, Randle, J and Mink, JW (2001) Thalamic stimulation for primary writing tremor. J. Neurol., 248: 380-382. Raethjen, J, Lindermann, M, Schmaljohann, H, Wenzelburger, R, Pfister, G and Deuschl, G (2000) Multiple oscillators are causing parkinsonian and essential tremor. Mov. Disord., 15: 84-94. Rajput, AH, Rozdilsky, B, Ang, L and Rajput, A (1991) Clinicopathologic observations in essential tremor: report of six cases. Neurology, 41: 1422-1424. Ravits, J, Hallett, M, Baker, M and Wilkins, D (1985). Primary writing tremor and myoclonic writer's cramp. Neurology, 35: 1387-1391. Romeo, S, Beradelli, A, Pedace, F, Inghilleri, M, Giovanelli, M and Manfredi, M (1998) Cortical excitability in patients with essential tremor. Muscle Nerve, 21: 1304-1308. Rosenbaum, F and Jankovic, J (1988) Focal task-specific tremor and dystonia: categorization of occupational movement disorders. Neurology, 38: 522-527. Rotella, DL, Darling, WG and Rizzo, M (1999) Effect of hand posture on the temporal and kinematic properties of pointing and drawing by healthy subjects and by a patient with primary writing tremor. J. Mot. Behav., 31: 190-198. Rothwell, JC, Traub, MM and Marsden, CD (1979) Primary writing tremor. J. Neurol. Neurosurg. Psychiatry, 42: 1106-1114.
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Movement Disorders Handbook of Clinical Neurophysiology, Vol. 1 M. Hallett (Ed.) © 2003 Elsevier B. V. All rights reserved
377 CHAPTER 24
Clinical neurophysiology and pathophysiology of Parkinsonian tremor Giinther Deuschl*, Urban Fietzek, Stephan Klebe and Jens Volkmann Department of Neurology, Christian-Albrechts-Universitdt Kiel, Niemannsweg 147. D-24105 Kiel, Germany
24.1. Introduction The pathophysiological understanding of akinesia is advanced compared with the one of tremor. The detection of the anatomy and physiology of the basal ganglia loop (Alexander et al., 1986, 1990) has been a critical step towards this aim. The ultimate confirmation of a pathophysiological mechanism may be to design a therapeutic approach. In case of akinesia this was the destruction of the subthalamic nucleus which proved to cure akinesia in monkeys (Bergman et aI., 1990) and the reversible inactivation of the subthalamic nucleus through deep-brain stimulation has meanwhile become the accepted therapy for advanced akinesia (Limousin et aI., 1995, 1998). Akinesia and tremor in Parkinson's disease seem to share some pathophysiological principles but they are by no means directly related. Thus, conclusions drawn from the explanation of akinesia should not airily be applied to tremor. The present review will summarize the clinical and paraclinical findings which are considered to be relevant for the understanding of tremor and the most recent hypothesis will be summarized. The present review is based on earlier reviews (Deuschl et aI., 2000, 2001; Bergman and Deuschl, 2002; Deuschl and Bergman, 2002). 24.2. Clinical aspects of parkinsonian tremor The clinical presentation of tremor in PO is not uniform and although rest tremor is the classical form there are other manifestations which present mainly with postural and action tremors. Because of
* Correspondence to: Prof. Dr. G. Deuschl, Department of Neurology, Christian-Albrechts-Universitat Kiel, Niemannsweg 147,0-24105 Kiel, Germany. E-mail address:[email protected] Tel.: +49(431)597-2610: fax: +49(431)-597-2712.
these variants, tremor in Parkinson's disease (PO) has been defined (Deuschl et al., 1998) to be present if: (1) the patient has Parkinson's disease according to
the brain bank criteria (Hughes et aI., 1993), i.e. bradykinesia and one of the symptoms of rest tremor, rigidity or postural instability; (2) the patient has any form of pathological tremor. Classical parkinsonian tremor is defined as a rest tremor or rest and posturallkinetic tremor with the same frequency. Mostly this tremor is inhibited during movement and may reoccur with the same frequency when adopting a posture or even when moving. There is typically a reduction of tremor amplitude during the transition from rest to posture (Deuschl et aI., 1998; Jankovic et aI., 1999). The frequency of rest tremor is mostly above 4 Hz but the upper frequency limit is not well defined. Especially in the early stages higher rest tremor frequencies of up to 9 Hz can be found (Deuschl and Lucking, 1989; Koller et al., 1989). The clinical observations fit with the hypothesis that this form of postural! kinetic tremor (with similar frequencies for both the rest and posturallkinetic tremors) is a continuation of the rest tremor under postural and or kinetic conditions. Some patients exhibit a rest and/or postural tremor without signs of bradykinesia or rigidity being significant enough to diagnose Parkinson's disease. Thus, the clinical findings are not sufficient to diagnose Parkinson's disease, although there is PET evidence, that these patients have a dopaminergic deficit (Brooks et aI., 1992). When such a syndrome persists more than two years it is labeled as monosymptomatic tremor at rest (Deuschl et al., 1998). The clinical features of this tremor form are mostly identical with classical parkinsonian tremor
378
and it is assumed that the pathophysiological basis is similar as for classical parkinsonian tremor. Some patients have rest and postural/kinetic tremors of different frequencies, with the postural/ kinetic tremor displaying a higher (> 1.5 Hz) and non-harmonically related frequency to the rest tremor (Deuschl et aI., 1998). This form has often been considered to be a combination of an essential tremor with Parkinson's disease (Lance et aI., 1963; Findley et aI., 1981; Deuschl and Lucking, 1989) and is rare « 10% of patients with Parkinson's disease) according to our experience. In these patients the tremor can be extremely disabling. Some of these patients have had their postural tremor much longer than their Parkinson's disease. A low amplitude and high frequency (8-12 Hz) kinetic tremor is present in many parkinsonian patients. This can be detected easily by analyzing slow flexion/extension movements. This tremor is not disabling by itself but the patients are disabled by akinesia and rigidity. Isolated postural and kinetic tremors do occur in PD. The tremor frequency may vary between 4 and 9 Hz. Postural tremors are quite common in the akinetic rigid variant of Parkinson's disease. Severe postural and even intention tremor are rare in Parkinson's disease. These tremors have often been considered as essential tremor variants or have been found to be indistinguishable from enhanced physiologic tremor. In the following we will mainly deal with classical parkinsonian tremor including monosymptomatic rest tremor. Rest tremor is a unique clinical feature and should not be confused with the continuation of some postural tremors when the subject is not completely relaxed. Rest tremor should be diagnosed only when it shows an increasing amplitude during mental stress and at least a diminution of its amplitude when the extremity is voluntarily activated (Deuschl et al., 1998; Jankovic et aI., 1999). If this strict definition is applied, rest tremor is almost limited to parkinsonian tremor (or tremor in nonidiopathic parkinsonian syndromes) and Holmes' tremor, a rest and intention tremor of low frequency mostly secondary to a midbrain lesion. Both of these patient groups show a dopaminergic deficit in the striatum on positron emission tomography (Remy et al., 1995; Brooks 1999). This is another strong argument favoring rest tremor as a consequence of a nigro-striatal dopamine deficit no matter if it occurs
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in PD, non-idiopathic parkinsonian syndromes or in Holmes' tremor. Rest tremor in PD is the most specific sign for idiopathic PD among the other cardinal symptoms as the presence of classical rest tremor has a more than 95% probability to indicate idiopathic Parkinson's disease (Deuschl and Koester, 1996). But the severity of rest tremor is not correlated with the disease severity of PD or its duration nor with the striatal depletion of dopamine measured with positron emission tomography (Brucke et aI., 2000; Leenders and Oertel, 2001). The pathologic hallmark of Parkinson's disease is the degeneration of dopaminergic cells within the substantia nigra and the subsequent dopamine depletion of the striatum. The question arises if the pathology of tremor-dominant PD differs from the one of akinesia/rigidity-dominant PD. The medial substantia nigra, especially the retrorubral area A8 is more severely affected by dopaminergic cell degeneration in the tremor dominant form in contrast to more severe damage of the lateral substantia nigra (A9) in the akinetic rigid variant (Paulus and Jellinger, 1991; Hirsch et aI., 1992; Jellinger, 1999). Hence parkinsonian tremor is likely to be associated with cell loss of the retrorubral substantia nigra. Other nuclei like the locus ceruleus, however, are also more affected in the akinetic rigid variant. Patients with tremor-dominant PD have a better prognosis concerning disease progression than those with the akinetic rigid variant (Jankovic et al., 1990; LeWitt et aI., 1997; Louis et al., 1999). Thus, it cannot be excluded that these pathologic findings are related to other features of the tremor-dominant variant of PD, but these findings are a first hint at specific pathologic abnormalities of rest tremor.
24.3. Clinical neurophysiology of parkinsonian tremor in humans 24.3.1. Recording of tremor Recording of tremor is an important tool for clinical neurophysiology. The features of PD tremor can be quantified with electromyography or accelerometry. Such studies have shown that the frequency of classical rest tremor is between 4 and 7 Hz (Zimmermann et aI., 1994; Deuschl et aI., 1996), but during the early stages of the disease higher resting tremor frequencies up to 9 Hz may occur (Deuschl and Lucking, 1989; Koller et aI., 1989). However, as reflected in the clinical definition of PD
CLINICAL NEUROPHYSIOLOGY AND PATHOPHYSIOLOGY OF PARKINSONIAN TREMOR
tremor, the spectrum is much broader. Some patients have tremor frequencies which differ for resting and postural tremor by more than 1.5 Hz (Deuschl et al., 1996; Deuschl, 1999). Especially in rigid patients slow movements are accompanied by a highfrequency oscillation at 7-12 Hz which has been called "rippling" and which can occur without any resting tremor (Findley et al., 1981). More complicated forms of action tremor have long been recognized (lung, 1941; Lance et al., 1963). The tremor frequency or amplitude are only poor criteria for separating PD tremor from other tremors (Deuschl et al., 1996). The pattern of activation in antagonistic muscles is mostly reciprocal alternating in rest tremors (Fig. 1) but this is not a reliable discriminator between PD and other tremors (Spieker et al., 1995; Boose et al., 1996; Spieker et aI., 1997). Methods of non-linear time series analysis have separated PD
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from essential tremor on the basis of the regularity and other more complex features of the tremor movement (Timmer et aI., 1993; Deuschl et al., 1995), but in prospective studies of larger series of patients, this distinction became much less clear (Timmer et al., 2000). Usually the cases which are most difficult to diagnose on clinical grounds are also difficult to diagnose on the basis of such electrophysiological tests. Thus, we conclude that although a variety of tests show statistically highly significant differences between PD and other tremors, no fully reliable electrophysiological tool is available to separate tremor in PD from other tremors unequivocally. 24.3.2. The contribution of reflex pathways Tremors may be caused by mechanical oscillations of a limb, enhanced reflexes, central oscilla-
Clinical Neurophysiology and Pathophysiology of Parkinsonian Tremor
Fig. 1. Electromyogram of muscles involved in tremor. Upper pair shows a classical reciprocal alternating pattern of antagonists, the pattern most frequently found in classical PD tremor, and the lower pair a synchronous pattern of antagonists.
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tions or abnormally functioning feedback-loops within the CNS. Mechanical factors do always contribute to the generation of tremor but their contribution is almost negligible for large amplitude central tremors. The contribution of reflex factors to parkinsonian tremor has been assessed in different ways. On the one hand some clinical observations demonstrate that reflexes play only a minor role for the generation of parkinsonian tremor. The removal of the dorsal roots in a patient with parkinsonian tremor did reduce the tremor amplitude but only slightly changed the frequency and did not stop the tremor (Pollock and Davis, 1930). Neurosurgeons have shown early that the section of the pyramidal tract or removal of the motor cortex abolishes parkinsonian tremor (Bucy, 1940; Putnam, 1940) indicating that reflexes could only be involved if they follow a transcortical route. On the other hand attempts have been made to analyze the contribution of reflexes with different electrophysiological and pharmacological tests. The first was to infiltrate the muscles with novocaine until rigidity and stretch reflexes were absent but force was still present (Walshe, 1924). Walshe found no significant influence of this intervention on tremor. Another attempt was to look at changes of the frequency when loads or springs were attached to the trembling limb (Rack and Ross, 1986). With these procedures the resonance frequency is changed and thus might change the tremor frequency. Later larger studies demonstrated a lack of frequency reduction following loading of the trembling limb in parkinsonian patients (Hamberg et aI., 1987; Deuschl et aI., 1996) (Fig. 2). If reflexes would play a significant role for the generation of tremor the reduced resonance frequency should be accompanied by a decrease of the EMG frequency. However, this negative result has to be interpreted with reservations as for large-amplitude tremors because the mass of the trembling limb