Physiology and Pathology of Cerebellum

The Physiology and Pathology of the Cerebellum

The Physiology and Pathology of the Cerebellum by

ROBERT STONE DOW, M.D., Ph.D. ASSOCIATE CLINICAL PROFESSOR OF MEDICINE (NEUROLOGY) UNIVERSITY OF OREGON MEDICAL SCHOOL

and

GIUSEPPE MORUZZI, M.D. PROFESSOR AND HEAD, INSTITUTE OF PHYSIOLOGY UNIVERSITY OF PISA

The University of Minnesota Press, Minneapolis

© Copyright 1958 by the University of Minnesota. All rights reserved PRINTED IN THE UNITED STATES OF AMERICA AT THE COLWELL PRESS, MINNEAPOLIS

Library of Congress Catalog Card Number: 58-83^3 PUBLISHED IN GREAT BRITAIN, INDIA, AND PAKISTAN BY THE OXFORD UNIVERSITY PRESS, LONDON, BOMBAY, AND KARACHI AND IN CANADA BY THOMAS ALLEN, LTD., TORONTO

Preface

THE development of electrical methods of recording activity in the nervous system has greatly augmented our knowledge of the physiology of the cerebellum during the past twenty years. In no previous volume has an attempt been made to relate this new information to the facts derived from older methods of investigation. Such a summary of our present knowledge of the physiology of the cerebellum seems overdue; the present book is in response to this need. The immediate occasion for the work was that Professor Olof Larsell, after more than thirty years of research on the comparative anatomy of the cerebellum, was preparing for publication a comprehensive volume summarizing his fruitful labors on the anatomy of the cerebellum and had suggested, at first, that one of us write a chapter or two on the physiology and pathology of the cerebellum as a part of his book. Such a brief survey, however, did not seem to fill the need of a thorough review of cerebellar physiology, and with Professor Larsell's enthusiastic support we collaborated in this separate volume; the result has been an enjoyable renewal of an earlier intimate scientific association. It was our expectation that this book would be the second of a two-volume work, the first to be Professor Larsell's on the Anatomy of the Cerebellum. While this order would be the more logical, to be sure, the present work has come to completion in advance of that of Professor Larsell. Because of the frequency with which important new contributions in physiology are appearing, it seemed to all three authors unwise to delay this publication until Professor Larsell's was completed. His work is expected to appear as a companion volume in the near future. It soon became evident, once this volume was begun, that an equal division of space between physiology and pathology would result in an incomplete discussion of each phase of the subject. Because of the manifest impossibility of covering completely the pathology of the cerebellum in half of any volume, it was early decided to devote something over two thirds of our space to physiology and to deal with the clinical symptomatology and pathology in a less complete fashion. In Part II of the book, therefore, no attempt has been made to survey the entire, vast literature on pathology, even though approximately nine hundred references are included in the text. The preparation of Part I, Physiology, was a close collaboration by the authors. The chapters on stimulation, electrophysiology, correlation with other v

vi PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM nervous structures, and developmental physiology were the responsibility of G. Moruzzi. While he also contributed the major share of the other three chapters, the writing of these was a joint endeavor in the truest sense. The chapters on the history of cerebellar physiology, on ablation experiments, and on the functions of the cerebellum considered in general were selected for joint preparation because they represent a bridge between physiology and pathology. Part II, Clinical Symptomatology and Pathology, was prepared by R. S. Dow. In the first chapters an attempt has been made to approach the symptomatology of cerebellar deficiency from a physiological point of view. In the systematic review that follows of the various pathological processes affecting the cerebellum, the emphasis has been upon the clinical findings present in the various disease processes known to involve the cerebellum. Our aim has been to present in a systematic fashion all the pertinent older observations as well as the results of more recent investigations, and to point out the particularly obvious gaps in our present knowledge. The preparation of the volume has itself revealed such gaps and has stimulated some investigations by physiologists of the Pisa laboratory which are as yet partially unpublished but the results of which have been included in the present monograph. It is our hope that the volume will stimulate other studies by many of our readers. The collaboration was made possible by a grant made to one of us to travel to Italy as a Fulbright research scholar during the academic year 1953-1954. The Commission for Cultural Exchange with Italy facilitated our work in many ways, and for their many kindnesses and great help we are very grateful. We wish to express our particular appreciation to Professor Larsell, whose original stimulus provoked the effort to prepare this volume. He has read the entire manuscript and made many valuable suggestions. We are also deeply grateful to Willetta Dow, who, throughout a period of six months spent in Italy, gave all her time toward assisting in the preparation of the manuscript of the chapters on ablation experiments and pathology. The large amount of work that was accomplished during this period would have been impossible without her help. All the manuscript was read and many constructive suggestions were made by our great teacher Professor Frederic Bremer; in his laboratory in Brussels twenty years ago began the personal friendship and scientific collaboration which have culminated in this work. It is a pleasure as well to thank Professors Gilberto Rossi, Jan Jansen, Alf Brodal, and John Brookhart, who have also read all the manuscript, and Professor Ragnar Granit, who has read the chapter on the regulation of the y discharge. They all made many valuable suggestions. Dr. Ludo van Bogaert and Professor Percival Bailey both have read much of the part on Clinical Symptomatology and Pathology. Dr. van Bogaert offered valuable suggestions for the chapters dealing with developmental defects and atrophies and Professor Bailey has done likewise for the chapter on cerebellar tumors. Dr. William Lehman has read critically the chapters on pathology, for which we wish to thank him. We are greatly indebted to Doctors Franco Magni, Ottavio Pompeiano, and Alberto Zanchetti for their help in the revision of the bibliography and in the

PREFACE vii preparation of the indexes, as well as to Shiena Bergendahl, Ellen Techtman, Erma Ray, Marie Wagner, and Clarice Ashworth for technical assistance in the preparation of the manuscript and the illustrations. We are grateful to Professor Luyendijk and to Dr. Storm van Leeuwen who very kindly sent us original photographic plates of the illustrations chosen from Rademaker's monograph "Das Stehen." Finally, we wish to express our appreciation to the entire staff of the University of Minnesota Press.

R.S. D. G.M.

Table of Contents

Part I. Physiology 1. HISTORICAL INTRODUCTION

3

2. ABLATION EXPERIMENTS

8

A. Ablation experiments in submammalian forms, 10: 1. Fish, 10. 2. Amphibia, 12. 3. Reptiles, 13. 4. Birds, 13. A. TOTAL ABLATION, 13; B. UNILATERAL ABLATION, 14; c. LOCALIZED ABLATION, 15. B. Generalized ablation experiments in mammals, 21: 1. Introductory remarks, 21. 2. Total ablation, 23. A. IN SUBPRIMATES, 23, (1) Unstabilized deficiency, 24, (2) Stabilized deficiency, 30; B. IN PRIMATES, 35, (1) Unstabilized deficiency, 35, (2) Stabilized deficiency, 37. 3. Unilateral ablation, or section of the three homolateral cerebellar peduncles, 38. A. IN SUBPRIMATES, 38, (1) Unstabilized deficiency, 38, (2) Stabilized deficiency, 44; B. IN PRIMATES, 46, (1) Unstabilized deficiency, 46, (2) Stabilized deficiency, 48. 4. Bisection of the cerebellum and vermian ablation, 48. A. IN SUBPRIMATES, 48; B. IN PRIMATES, 49. C. Localized ablation experiments in mammals, 50: 1. Introductory remarks, 50. 2. Ablation of the flocculonodular lobe, 52. A. LOCALIZED ABLATION INCLUDING, BUT NOT RESTRICTED TO, THE VESTIBULAR PART OF THE CEREBELLUM, 52; B. ISOLATED ABLATION OF THE NODULUS,

LOBULE x OF LARSELL, 54, (1) In subprimates, 54, (2) In primates, 55; c. ISOLATED ABLATION OF THE FLOCCULUS, LOBULE H x OF LARSELL, 56, (1) In subprimates, 56, (2) In primates, 56. 3. Ablation of the anterior lobe of the corpus cerebelli, 56. A. TOTAL ABLATION WITH THE REST OF THE NERVOUS SYSTEM INTACT, 56, (1) In subprimates, 56, (2) In primates, 58; B. TOTAL ABLATION IN THE THALAMIC OR DECEREBRATE PREPARATION, 60; C. PARTIAL ABLATION, 61, (1) In subprimates, 61, (2) In primates, 63. 4. Ablation of the posterior lobe of the corpus cerebelli, 63. A. TOTAL ABLATION, 63; B. UNILATERAL OR BILATERAL ABLATION OF THE LOBULUS ANSOPARAMEDIANUS, 64, (1) In subprimates, 64, (2) In primates, 66; c. ISOLATED ABLATION OF SINGLE CEREBELLAR LOBULi, 67, (1) Lobulus simplex of Bolk, or lobules VI and H VI of Larsell, 67, (2) Lobulus ansiformis of Bolk, or sublobule H Vila of Larsell, 67, (3) Lobulus paramedianus of Bolk, or sublobules H Vllb and H Villa of Larsell, 69, (4) Lobulus medius medianus of Ingvar, or lobule VII of Larsell, 70, (5) Pyramis (lobule VIII), uvula (lobule IX), paraflocculus (sublobule H VHIb and lobule H IX), together constituting Larsell's paleocerebellar part of the posterior lobe, 70, (6) Errors and limitations in the experiments of isolated ablation of individual cerebellar lobules, 71. 5. "Postural asymmetries" and "asymmetrical phasic reflexes" after localized cerebellar ablations, 73.

D. Isolated destruction of the cerebellar nuclei in mammals, 77: 1. Isolated lesions of the nucleus fastigii, 77. A. WITH THE REST OF THE NERVOUS SYSTEM INTACT, 77; B. IN THE DECEREBRATE PREPARATION, 80. 2. Isolated lesions of the nucleus interpositus, 86. 3. Isolated lesions of the nucleus dentatus, 87. E. Section of the cerebellar peduncles in mammals, 88: 1. Introductory remarks, 88. 2. Inferior cerebellar peduncles, 88. A. RESTIFORM BODY PROPER, 88; B. JUXTARESTIFORM BODY, SUPRAMEDULLARY PART, 90; C. JUXTARESTIFORM BODY, INTRAMEDULLARY PART, 91. 3. Middle

cerebellar peduncle, 91. 4. Superior cerebellar peduncle, 92. F. General considerations, 95.

3. STIMULATION EXPERIMENTS

103

A. Stimulation experiments in submammalian forms, 104: 1. Fish, 104. 2. Amphibia, 105. 3. Reptiles, 105. 4. Birds, 105. B. Mechanical and chemical stimulation in mammals, 109: 1. Mechanical stimulation, 109. 2. Intracerebellar injections of curare or of nicotine, 110. 3. Local applications of strychnine or of eserine, 111. C. Electrical stimulation of the cerebellar cortex in mammals, 113: 1. Stimulation of the flocculonodular lobe, 113. 2. Stimulation of the anterior lobe of the corpus cerebelli, 113. 3. Stimulation of the posterior lobe of the corpus cerebelli, 137. D. Cortical and subcortical cerebellar stimulations in unrestrained, unanesthetized mammals, 139. E. Electrical stimulation of the cerebellar nuclei in mammals, 141. F. The efferent

pathways mediating the cerebellar response, 148.

G. General considerations, 151.

4. ELECTROPHYSIOLOGICAL EXPERIMENTS

158

A. Electrophysiological experiments in submammalian forms, 159: 1. Fish, 159. 2. Amphibia, 160. 3. Reptiles, 160. 4. Birds, 160. B. Electrical activity of the cerebellar cortex in mammals, 162: 1. Spontaneous activity led with surface macroelectrodes, 162. 2. Spontaneous activity led with microelectrodes, 164. 3. Electrical activity after transection of the brain stem and of the spinal cord at C 1, after section of the cerebellar peduncles, and after supranuclear transection, 173. 4. The effects of direct-current stimulation, 174. 5. The effects of single electrical shocks, 175. 6. The effects of repetitive stimulation, 176. 7. The effects of convulsant drugs, 178. C. Electrophysiology of the afferent cerebellar connections in mammals, 182: 1. Responses to natural stimulation, 182. A. STIMULATION OF VESTIBULAR RECEPTORS, 182; B. STIMULATION OF MUSCLE, TENDON, OR JOINT PROPRIOCEPTORS, 182; C. STIMULATION OF EXTEROCEPTORS, 185; D. STIMULATION OF VISUAL AND AUDITORY TELECEPTORS, 186; E. RESPONSES TO SPONTANEOUS CORTICOFUGAL VOLLEYS, 189. 2. Responses to single-shock stimulation of peripheral nerve fibers, 189. A. LOCALIZATION OF THE RESPONSE, 189; B. THE NATURE OF THE AFFERENT VOLLEYS YIELDING THE CEREBELLAR RESPONSE, 195; C. PATHWAYS OF TRANSMISSION, 197. 3. Stimulation of cerebellipetal pathways or of central structures projecting onto the cerebellum, 200. A. SPINOCEREBELLAR SYSTEMS, 200; B. OLIVOCEREBELLAR AND RETICULOCEREBELLAR SYSTEMS, 201; C. VESTIBULOCEREBELLAR SYSTEM, 202; D. PONTOCEREBELLAR SYSTEM, 202; E. MIDBRAIN STIMULATION, 202; F. STIMULATION OF THE CEREBRAL CORTEX, 204; G. STIMULATION OF THE CAUDATE NUCLEUS, 211; H. STIMULATION OF THE OLFACTORY BULBS, 211. 4.

General patterns of the afferent cerebellar response, 211. A. POLARITY OF THE EVOKED RE-

SPONSE, 211; B. THE EFFECTS ON SPONTANEOUS ELECTRICAL ACTIVITY, 211; C. SLOW POTENTIAL CHANGES ELICITED BY SENSORY VOLLEYS, 216; D. INTERACTIONS BETWEEN AFFERENT RESPONSES, 216.

D. Electrophysiology of the efferent cerebellar connections in mammals, 218: 1. Efferent spike discharges in the cerebellar peduncles, 218. 2. Responses of the bulbar reticular formation to cerebellar stimulation, 219. 3. Responses of the vestibular nuclei to cerebellar stimulation, 230. 4. Responses of the midbrain and diencephalon to cerebellar stimulation, 232. 5. Responses of the cerebral cortex to cerebellar stimulation, 234. 6. Intracerebellar connections, 235. E. Electrophysiological investigations on the cerebellar nuclei, 235. F. General considerations, 2^0.

5. RELATIONS BETWEEN THE CEREBELLUM AND OTHER CENTRAL STRUCTURES

254

A. Relation to the spinal cord, 255: 1. Regulation of the gamma discharge, 255. 2. Coordination of the alpha discharge, 262. 3. Interrelations between spinal inhibition and cerebellar facilitation, 265. 4. Lasting effects of asymmetrical cerebellar innervation upon motor units and extrafusal muscle fibers, 268. B. Relation to the labyrinthine system, 271: 1. Introductory remarks, 271. 2. Cerebellar influence on static labyrinthine reflexes, 273. A. THE RELEASE OF TONIC LABYRINTHINE REFLEXES FOLLOWING ACUTE CEREBELLECTOMY, 273; B. THE EFFECTS OF CHRONIC CEREBELLECTOMY ON TONIC LABYRINTHINE REFLEXES, 280; C. THE EFFECTS OF ACUTE OR CHRONIC CEREBELLECTOMY ON THE RIGHTING REFLEXES, 282; D. FASTIGIAL INFLUENCES ON LABYRINTHINE TONUS AND THE CONFLICT OF CEREBELLAR FACILITATION WITH VESTIBULAR INHIBITION, 283; E. VESTIBULAR COMPONENTS IN THE RELEASE SYMPTOMS ELICITED BY ACUTE CEREBELLECTOMY

AND THEIR COMPENSATION BY SPINAL INHIBITORY MECHANISMS, 283. 3. Cerebellar influence on kinetic labyrinthine reflexes, 287. A. THE EFFECT OF CEREBELLAR ABLATION ON POSTROTATORY NYSTAGMUS, 287; B. THE EFFECT OF CEREBELLAR ABLATION ON GALVANIC NYSTAGMUS, 287; C. SPONTANEOUS NYSTAGMUS AFTER CEREBELLAR ABLATION, 288; D. CEREBELLAR INFLUENCE IN THE HABITUATION OF POSTROTATORY NYSTAGMUS, 289; E. THE EFFECT OF CEREBELLAR ABLATION ON THE REFLEX RESPONSES TO LINEAR ACCELERATION, 290.

C. Relation to the vegetative junctions, 290: 1. Introductory remarks, 290. 2. Effects on circulation, 291. 3. Effects on respiration, 299. 4. Effects on the endocrine glands, 300. 5. Effects on thermoregulation, 302. 6. Effects on the general metabolism, 303. 7. Autonomic effects on the eyes, 303. 8. Effects on the digestive tract, 305. 9. Effects on bladder functions, 305. 10. Effects on the sexual organs, 308. 11. Trophic influences on the muscles and skin, 308. 12. Effect on the galvanic skin reflex, 309. 13. Cerebellipetal projections of visceral afferent fibers, 309. D. Relation to the cerebral cortex, 311: 1. The effects of cerebellar stimulation on the cerebral cortex, 311. A. EFFECTS ON THE EXCITABILITY OF THE MOTOR AREA, 311; B. EFFECTS ON CORTICALLY INDUCED MOVEMENTS, 311; C. EFFECTS ON THE ELECTROCORTICOGRAM, 323. 2. The

effects of cerebellar ablation on the cerebral cortex, 327. A. EFFECTS ON THE EXCITABILITY OF THE MOTOR CORTEX, 327; B. EFFECTS ON THE MOTOR AND ON THE INHIBITORY RESPONSES OF THE CEREBRAL CORTEX, 329; C. ELECTROPHYSIOLOGICAL INVESTIGATIONS, 330. 3. The effects

of combined cerebellar and cerebral ablations, 330. A. COMPENSATION OF THE CEREBELLAR SYNDROME BY THE CEREBRAL CORTEX, 330; B. INFLUENCE OF CEREBELLAR ABLATION ON THE PRECENTRAL MOTOR CORTEX, 332; C. SUMMATION OF THE TONIC INHIBITORY INFLUENCES EXERTED BY THE CEREBRAL CORTEX AND BY THE CEREBELLUM ON THE POSTURAL EXTENSOR

TONUS, 335. 4. The cerebellum and conditioned reflexes, 338.

E. Relation to sensory functions, 344: 1. Conclusions drawn from reflex responses to sensory stimulations, 344. 2. Effects on sensory receptors and on primary sensory neurons, 346. 3. Effects on postprimary sensory neurons, 347. 4. Effects on the ascending reticular system, 348. F, General considerations, 350.

6. DEVELOPMENTAL PHYSIOLOGY

359

7. GENERAL CONSIDERATIONS ON THE FUNCTION OF THE CEREBELLUM

368

Part II. Clinical Symptomatology and Pathology 8. THE CLINICAL SYMPTOMATOLOGY OF CEREBELLAR DISORDERS

377

A. Neurological abnormalities in cerebeUar lesions and their relative frequency, 379. B. A classification of cerebeUar symptoms on the basis of a functional division of the organ, 380. C. Disturbances resulting from involvement of the flocculonodular lobe, 381: 1. Gait disturbance, 381. 2. Rotated posture of the head, 382. 3. Spontaneous nystagmus, 383. 4. Disturbance in station, 384. D. Disturbances resulting from involvement of the anterior lobe or the medial part of the corpus cerebelli, 385: 1. Gait disturbance as seen in cortical cerebeUar atrophy, 385. 2. CerebeUar catalepsy, 386. 3. Positive supporting reactions, 386. 4. CerebeUar seizures, 386. E. Symptoms resulting from involvement of the posterior lobe or the lateral parts of the corpus cerebelli, 386: 1. Reflex and postural disturbances, 388. A. HYPOTONIA, 388; B. PENDtTLAR KNEE JERK, 388; C. STATIC TREMOR, 389; D. DISTURBANCE IN STATION, 390; E. PASTPOINTING AND SPONTANEOUS DEVIATION OF THE LIMBS, 390. 2. Disturbances in voluntary movements, 390. A. ASTHENIA, 390; B. DELAY IN STARTING AND STOPPING MUSCULAR CONTRACTIONS, 390; C. DISTURBANCES IN THE RATE OF VOLUNTARY MOVEMENTS, 392; D. DISTURBANCES IN COMPOUND MOVEMENTS, 392, (1) Dysmetria, 392, (2) Adiadochokinesis, 392, (3) Speech disturbances, 394, (4) Disturbances in writing, 394, (5) Gait disturbances, 395, (6) Tremor of voluntary movement, 395; E. LOSS OF ASSOCIATED MOVEMENTS, 395. 3. Symptoms of doubtful occurrence, 395. A. PROPRIOCEPTIVE LOSS (?), 395; B. ANISOSTHENIA (?), 395; C. CLINICAL EVIDENCE OF VEGETATIVE FUNCTION, 396.

F. Clinical evidence for somatotopic localization in the cerebellum, 396. G. Special diagnostic tests useful in cerebeUar disorders, 398. Summary, 398.

9. THE "CEREBELLAR" SYMPTOMATOLOGY OF EXTRACEREBELLAR LESIONS

399

A. Lesions below the tentorium cerebelli, 399: 1. Acoustic neurinomas and pontine gliomas, 399. 2. Lesions of the inferior cerebeUar peduncle, 400. 3. Lesions of the superior cerebeUar peduncle, 401. 4. Lesions within the fourth ventricle, 402. B. Lesions above the tentorium, 403: 1. Suprasellar lesions, 403. 2. Lesions of the cerebral

cortex, 404. A. FRONTAL ATAXIA, 404; B. "CEREBELLAR" SIGNS FROM PARIETAL, TEMPORAL, AND OCCIPITAL LESIONS, 406.

Summary, 406.

10. CONVULSIVE AND HYPERKINETIC DISORDERS OF THE CEREBELLUM

408

A. Jackson's "cerebdlar fits," 4.08. B. Cerebellar coma, 411. C. The cerebellum and myoclonic epilepsy, 411D. Palatal myoclonus, 413. Summary, 415.

11. DEVELOPMENTAL ANOMALIES OF THE CEREBELLUM A. Malformations of the skull affecting

416

the cerebellum (BasUar impression), 418.

B. Abnormalities in the position of the cerebellum in relation to the skull (Arnold-Chiari malformation), 4@0. C. Complete or nearly complete agenesis of the cerebellum (Aplasia), 4%4D. Agenesis limited to specific parts of the cerebellum (Partial aplasia), 4%9: 1. Complete and incomplete loss of the cerebellar vermis, 429. 2. Loss of one hemisphere, 434. E. Underdevelopment of the cerebellum (Hypoplasia), 436: 1. Bilateral, 436. 2. Unilateral, 440.

A. CROSSED CEREBELLAR HYPOPLASIA, 440;

B. NEOCEREBELLAR HYPOPLASIA, 440.

F. Malformations of individual folia (Dysplasia), 441G. Effects on the development of the cerebellum produced by specific congenital disorders, 441: 1. Mongolian idiocy, 441. 2. Congenital syphilis, 442. 3. Cretinism, 442. H. Pneumoencephalography as an aid in the diagnosis of cerebellar maldevelopment, 44%Summary, 443.

12. ATROPHIC CHANGES OF THE CEREBELLUM AND ITS CONNECTING PATHWAYS

445

A. Cortical cerebellar atrophies, 446:1. Familial or hereditary, 446. A. OCCURRING IN ADULTS, 446; B. OCCURRING IN INFANTS, 449. 2. Nonfamilial or acquired cortical cerebellar atrophy, 451. A. LOCALIZED, 451, (1) Circumscribed panatrophy, 451, (2) Predominant in the anterior lobe, 452; B. GENERALIZED, 454, (1) Chronic, 454, (2) Subacute, 455, (3) Acute, 458. B. Olivopontocerebellar atrophies, 459. C. Cerebellar nuclear atrophies, 463. D. Crossed cerebellar atrophy, 464E. Hereditary spinal ataxias, 466: 1. Friedreich's ataxia, 467. 2. Spastic ataxia (Marie's cerebellar ataxia), 469. F. Cerebellar changes of a degenerative type associated with specific neurological conditions, 4^4'- 1. Amaurotic familial idiocy, 474. 2. Pick's disease, 475. 3. Alzheimer's disease, 475. 4. Progressive lenticular degeneration (Wilson's disease), 476. 5. Degeneration of the cerebral gray matter of Alpers, 477. 6. Multiple sclerosis, 477. 7. Symmetrical calcification of the dentate nuclei, 477. 8. Tuberous sclerosis, 478. Summary, 479.

13. ACUTE INFLAMMATORY AND TOXIC DISORDERS OF THE CEREBELLUM

480

A. Infections, 480: 1. Malaria, 480. 2. Whooping cough, 482. 3. Louping ill, 482. 4. Epidemic parotitis, 484. 5. Poliomyelitis, 484. 6. Cerebellitis of unknown cause, 484. B. Systemic diseases, 485. C. Exogenous toxins, 485: 1. Alcohol, 485. 2. Lead, 486. 3. Manganese, 486. 4. Hydrocyanic acid, 486. 5. Thiophene, 486. 6. DDT (dichlorodiphenyltrichloroethane), 487. 7. Ethyl acetate, 487. 8. Trichloroethylene, 487. 9. Carbon tetrachloride, 487. 10. Mercury, 488. 11. Eosinophilic leukocyte toxin, 488. D. Anoxia and hypoglycemia, 489. E. Vitamin deficiency, 490. F. Physical agents, 491: 1. Heat stroke, 491. 2. Fatigue, 492. Summary, 493.

14. CHRONIC INFECTIONS OF THE CEREBELLUM AND CEREBELLAR ABSCESS

494

A. Tuberculosis, 494B. Syphilis, 497. C. Cerebellar abscess, 498: 1. Historical summary and introduction, 498. 2. Incidence, 499. 3. Pathogenesis and morbid anatomy, 499. 4. Symptomatology, 505. 5. Differential diagnosis, 506. 6. Treatment, 506. 7. Nonotogenic abscesses, 507. D. Fungicitic infections, 507. E. Parasitic involvement of the cerebellum, 508: 1. Amebiasis, 508. 2. Cysticercosis, 508. Summary, 508.

15. VASCULAR DISEASES OF THE CEREBELLUM

510

A. Occlusion, 511: 1. Posterior inferior cerebellar artery, 511. A. INCIDENCE, 511; B. ETIOLOGY, 512; c. PATHOLOGICAL CHANGES, 512, (1) Variations in the extent of the lesion and gross cerebellar findings, 512, (2) Histological changes in the cerebellum, 512; D. SYMPTOMS, 513; E. TREATMENT, 514. 2. Anterior inferior cerebellar artery, 514. 3. Anterior superior cerebellar artery, 514. A. INCIDENCE, 514; B. ETIOLOGY, 514; c. PATHOLOGICAL CHANGES, 515, (1) Variations in the extent of the lesion and gross cerebellar findings, 515, (2) Histological changes in the cerebellum, 515; D. SYMPTOMS, 515; E. TREATMENT, 517. B. Hemorrhage, 517: 1. Incidence, 517. 2. Etiology, 517. 3. Pathological changes, 517. 4. Symptoms, 519. 5. Treatment, 520. Summary, 520.

16. CEREBELLAR TRAUMA

521

A. Cerebellar laceration, 521. B. Extradural cerebellar hematoma, 523: 1. Incidence, 523. 2. Etiology, 523. 3. Symptoms, 523. 4. Treatment, 525. C. Traumatic hemorrhage of the cerebellum, 525. Summary, 525.

17. CEREBELLAR TUMORS

526

A. General considerations, 527: 1. Classification, 527. 2. General symptomatology, 528. 3. Neurological deficiency symptoms, 530. A. CEREBELLAR, 530; B. EXTRACEREBELLAR, 531, (1) Visual defects, 531, (2) Mental symptoms, 531, (3) Direct pressure effects, 532. 4. Roentgenographic findings, 532. A. SKULL FILMS, 532; B. PNEUMOENCEPHALOGRAMS, 532; c. VENTRICULOGRAMS, 533. 5. Electroencephalographic findings, 534. 6. Arteriographic findings, 536. B. Astrocytoma, 536: 1. Incidence, 537. 2. Location, 537. 3. Symptoms, 537. 4. Gross appearance, 538. 5. Microscopic appearance, 538. 6. Treatment, 541. C. Medulloblastoma, 541: 1. Incidence, 542. 2. Location, 542. 3. Symptoms, 543. 4. Gross appearance, 543. 5. Microscopic appearance, 545. 6. Cell type and origin of the tumor, 546. 7. Treatment, 547. D. Astroblastoma, 548. E. Glioblastoma multiforme, 549. F. Oligodendroglioma, 550. G. Ganglioneuroma, 551. H. Spongioblastoma polare, 552. I. Neuroepithelioma, 552. J. Vascular tumors, 552: 1. Angiomatous malformations, 552. 2. Hemangioblastoma, 553. A. INCIDENCE, CLASSIFICATION, AND HEREDITARY TENDENCIES, 553; B. SYMPTOMS AND DIAGNOSIS, 555; c. GROSS APPEARANCE, 555; D. MICROSCOPIC APPEARANCE, 556; E. TREATMENT, 556.

K. Dysembryomas, 557. L. Metastatic tumors, 559. M. Extracerebellar gliomas and ependymomas, 559. N. Meningiomas, 560. 0. Sarcomas, 560. P. Acoustic neurinoma, 561. Summary, 562.

BIBLIOGRAPHICAL INDEX OF AUTHORS

567

SUBJECT INDEX

637

Part I Physiology

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1 Historical Introduction

THE history of cerebellar physiology begins with the seventeenth century, when Du Verny (1673) reported that he had been able to keep pigeons alive whose cerebrum and cerebellum had been extirpated. From Galen to Thomas Willis (1664) no experiments were performed; writers indulged only in theoretical speculations, which were generally based upon gross anatomical observations. Readers interested in the pre-experimental phase of biology should consult the monographs of Neuburger (1897) and the article by Rawson (1932). Only the outlines vill be given here. Galen thought the hard, firm consistency of the cerebellum suggested that its mnction was one to impart strength to the motor nerves, whereas Poseidon believed that the cerebellum was a center for memory. Arabian and medieval scholars simply elaborated upon these concepts, which were still common among the great anatomists of the Renaissance. Hence Varolio believed that the cerebellum controlled movements through animal spirits descending along the posterior columns, but also sensory functions (such as hearing, taste, and unconscious sensibility) were performed by this part of the encephalon. Thomas Willis's views (1664) are more frequently quoted, although it is only fair to say that he did not bring any evidence supporting his opinions: "Intus in Cerebro imaginatio, memoria, discursus, aliique superiores functionis animalis actus peraguntur . . . Cerebelli autem omcium esse videtur, spiritus animales nervis quibusdam suppeditare; quibus actiones involuntariae (cuiusmodi sunt cordis pulsatio, respiratio d/^'aoTog, alimenti concoctio, chyli protusio, et multae aliae) quae nobis insciis aut invitis constanti ritu fiunt, peraguntur" (pp. 139-140).* Willis's speculations had at least the merit of promoting scientific investigation. No useful data can be gathered from the crude experiments performed by Du Verny, Boerhaave, von Haller, Zinn, Chirac, Lorry, Pourfour du Petit, Saucerotte, and Mehee de la Touche; nor are we interested any more in knowing * "Within the cerebrum imagination, memory, speech and the other superior activities of the animal functions are performed . . . But the cerebellar function seems to be one of supplying animal spirits to some nerves, through which are performed involuntary activities (such as heart beatings, spontaneous respiration, concoction of the aliment, the protrusion of the chyle, and many others), which occur constantly and independently from our knowledge or will."—Thomas Willis (16211675) was Professor of Natural Philosophy at Oxford University (1660-1666) and later a leading physician in London.

3

4 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM if the heart beat or life itself comes to an end when the cerebellum is ablated. But the works of these investigators were suffused with a new spirit, since at least they did recognize that only experiments—and never speculations or gross anatomical observations—were likely to uncover the functions of the hindbrain. The reader is referred to the first and fourth volumes (1757, 1766) of the monumental work of A. von Haller, Elementa physiologiae, for a contemporary report on these endeavors, as well as to the previously cited works of Neuburger (1897) and Rawson (1932).* Rolando's first edition of the Saggio sopra la vera struttura del cervello dell'uomo e degli animali e sopra le junzioni del sistema nervoso was published in Sassari in 1809,f and a French translation of the most significant part of it was published by Magendie in his Journal de physiologic experimentale et pathologique in 1823. As we have seen, Rolando was not the first to perform experiments on the cerebellum, and actually his naive comparison between Volta's pile and the disposition of the lamellae within the arbor vitae obviously represented the old tendency to draw physiological conclusions from gross anatomical observations. But there is no doubt that some of the results obtained from the Italian anatomist still represent a foundation stone of cerebellar physiology. Following ablation experiments on goats, rabbits, guinea pigs, turtles, and different types of birds, he made the important observation that cerebellar deficiency was concerned with motor activity as differentiated from (a) sensory function, (b) a function vital to the life of the animal, or (c) the intellectual functions of the brain. His further contribution was the determination that the cerebellum exerted its motor function in a homolateral relation to the parts of the body— i.e., lesions of the right half of the cerebellum affected the right side of the body. His experiments were all acute, and his greatest misconception, as Magendie (1823) rightly pointed out, was in the conclusion that the cerebellum was responsible for motor function rather than exercising some regulatory influence on motor activity. The concept of a regulatory influence was brought forward by Flourens (1824, 1842), who investigated the cerebellum by making ablation experiments chiefly on birds.$ From his first experiments, which were reported to the Academic Royale des Sciences on March 31 and April 27 of 1822, and from those reported in his book (1824, 1842), Flourens concluded that the cerebellum was not responsible for motor functions. He assigned this responsibility to the spinal cord and the nerves going to the muscles. Nor was the cerebellum responsible for the volition of motor activity; this he assigned to the cerebral hemispheres. After distinguishing these essential divisions of motor activity, he said that "dans le cervelet reside une propriete dont rien ne donnait encore 1'idee en physiologie et qui consiste a coordonner les mouvements" (1842, p. xii). And in another place he said that after cerebellar ablation "la possibilite d'executer des mouvements d'en*Albrecht von Haller (1708-1777) was Professor of Anatomy at Gottingen from 1736 to 1753. fLuigi Eolando (1773-1831) was Professor of Anatomy at Sassari (1804-1814) and at Turin (1814-1831). $ Marie-Jean-Pierre Flourens (1794-1867) was Professor of Comparative Anatomy at the University of Paris.

HISTORICAL INTRODUCTION 5 semble persistait; mais la coordination de ces mouvements eri mouvements de locomotion, regies et determines, etait perdue" (1842, p. 38). His experiments were of further value in that he observed the great facility for compensation which the cerebellum possesses. He observed that if he removed in successive layers the superior one half of the cerebellum in a young cock, four days later the state of equilibrium was less troubled and the gait was stronger and more certain. Fifteen days later the equilibrium was totally re-established. However, he noted that if he removed the entire cerebellum from a hen, it did not recover even though it lived four months after the operation. He assigned a contralateral function to the cerebellum. This was not actually an error, as has been maintained up to our times, but was rather an incomplete description of the symptoms of cerebellar deficiency in birds. Flourens's findings will be further discussed in another section of this monograph (p. 74). He stated: "Le cervelet d'un pigeon etant mis a nu, j'ai soumis a des piqures superficielles * tout le cote droit de ce cervelet. II a paru sur le champ une faiblesse assez marquee du cote gauche. J'ai retranche, par couches successives, tout le cote gauche du cervelet d'un second pigeon. La faiblesse du cote droit s'est accrue visiblement comme s'aggravaient les mutilations" (1842, p. 115). The release phenomena following cerebellar ablation, however, were missed altogether by Flourens, and it remained for Fodera (1823) to discover that extensor hypertonia follows acute cerebellectomy in birds and in mammals.* A few months after the first communications of Flourens, on December 31, 1822, Fodera reported to the Academie Royale des Sciences his acute ablation experiments. Following the destruction of the medial and superior part of the cerebellum in the guinea pig and in the rabbit, he observed that "1'animal porte la tete en arriere, les pattes posterieures s'ecartent, les extremites anterieures sont droites et tendues" (p. 193, italics ours). The ablations performed on mammals were admittedly incomplete, but they are extremely interesting, since for the first time the paleocerebellar syndrome was described. Fodera performed total ablation of the cerebellum in the pigeon and immediately thereafter the animal "ne pouvait plus se tenir sur ses pattes, qui sont dans un etat d'extension force; sa nlarche etait tout-a-fait desordonnee; nous le soutinmes par les extremites de ses ailes, il marcha sans plier les jambes; nous le jetames en 1'air et il agita ses ailes avec regularite, mais apres la chute, il se pencha en arriere, ses jambes tendues et sa tete dans un etat d'opisthotonos" (pp. 211-212, italics ours). In this really fundamental paper, which was surprisingly forgotten or undervalued by later investigators, the absence of any paralysis was clearly stated almost simultaneously with Flourens; moreover, the release of postural mechanisms which occurs following acute ablations in both mammals and birds was described seventy years before Luciani and Lange. Magendie (1824) also made many observations on the cerebellum, particularly on the results of sectioning its peduncles.f The contributions of this great *Michele Fodera (1793—1848) performed his experiments on the cerebellum in Magendie's laboratory, while holding a scholarship of the government of Naples. He was later appointed Professor of Physiology at the University of Palermo. f Francois Magendie (1783—1855) was from 1836 Professor of Physiology in the College de France.

6 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM French physiologist, however, were not outstanding in this field when compared with his other achievements. He observed rolling movements toward the side of the lesion, which were due to concomitant vestibular damage. He is responsible (1825) for the notion that the cerebellum might be the center for the nervous mechanism of equilibrium, an idea which was to influence thought about the cerebellum for many years. It is hard to believe that Gall's hypothesis regarding the cerebellum as a center for sexual activity could have been published in 1825, when the works of Rolando, Flourens, Fodera, and Magendie were already available. The experiments dealing with this unscientific theory now are only an historical curiosity. They were reviewed and buried by Longet (1850). There were many others who experimented on the cerebellum during the remainder of the nineteenth century, but their contributions were not outstanding. Only a paper by Wagner (1861) will be cited, not because of new facts he discovered—his ablation experiments on pigeons essentially confirmed Fodera's conclusions—but in view of the fact that for the first time, although diluted in a mass of purely hypothetical speculations, the concept of an inhibitory function of the cerebellum was clearly stated.* Commenting upon the extensor hypertonus of a decerebellate pigeon, he suggested that the spinal motoneurons innervating the extensor muscles might be released from cerebellar inhibition. The modern period of cerebellar physiology begins with Luciani, who was the first to perform chronic ablation experiments on mammals.f In his 1891 monograph Luciani wrote a detailed and penetrating review of the development of cerebellar studies during the nineteenth century. This review and the one written by Andre-Thomas (1897) a few years later should be consulted by anyone interested in the history of cerebellar physiology. Among the various hypotheses on cerebellar function suggested from Rolando's times to his own, Luciani discerned three lines of thought, originating respectively in the works of Rolando, Flourens, and Magendie. Rolando's idea of a diffuse cerebellar influence on all motor activities was the germ of Luciani's hypothesis of a tonic facilitating influence ("un'azione continua di rinforzo"), exercised by the cerebellum on the central structures connected with the activity of the striated muscles. Flourens's suggestion that the cerebellum might be concerned with the coordination of movements was developed by Lussana (1862, 1885,1886) and by Lewandowski (1903) in an attempt to correlate cerebellar functions with deep sensibility. Finally the hypothesis put forward by Magendie was further elaborated by Ferrier (1876), von Bechterew (1884, 1896), Stefani (1877, 1903), and Andre-Thomas (1897) in different attempts to correlate the cerebellum with the nervous mechanisms regulating equilibrium and above all (Stefani 1877, 1903) with the vestibular apparatus. The physiologists of the nineteenth century were mainly concerned with ablation experiments. Just at the end of the past century the discovery was *The inhibitory hypothesis of Budge (1841) was later (1862) abandoned by the author. — R. Wagner (1805-1864) was, after 1840, Professor of Physiology at the University of Gottingen. fLuigi Luciani (1840-1919) was Professor of General Pathology at Parma (1875-1880) and of Physiology at Siena (1880-1882), Florence (1882-1893), and Rome (1893-1917).

HISTORICAL INTRODUCTION 7 made almost simultaneously by Lowenthal and Horsley (1897) and by Sherrington (1897) that decerebrate rigidity could be inhibited by stimulating the anterior lobe of the cerebellum. This epoch-making observation can be regarded as the beginning of a new line of approach, in which the cerebellum was investigated by stimulation experiments. The third line of approach is still younger, since it is concerned with recording the bioelectric potentials from the cerebellum or related structures. Although some early attempts were made with the string galvanometer (Beck and Bikeles, 1912a, b; Camis, 1919), it is only with a short preliminary note written by Adrian in 1935 that modern cerebellar electrophysiology begins. In twenty years outstanding progress has been made. There is a natural tendency, which is perhaps stronger in our time, to stress the importance of new approaches and to forget experiments made with older techniques. We believe that it would be particularly dangerous to indulge in this trend in a monograph on the cerebellum. The historical perspective of the reader would first of all be seriously distorted. Moreover, all the refinements in stimulating and recording techniques will never supplant ablation experiments. In fact, it is only through extirpation experiments that we may hope to know the main features of cerebellar function and to evaluate, more or less quantitatively, the relative importance of the different types of functional activity of this organ. Furthermore, if the results of animal experiments are to be compared with the findings of those physiologists and clinicians who study the effects of cerebellar destruction and disease in order to learn the function of the human cerebellum, it is through a careful analysis of the ablation experiments in lower animals that this correlation can be made. Stimulation experiments and electrophysiological studies can direct and suggest points for attack by ablation experiments, but can never take their place. Aside from the physiological importance of experimental ablation studies, there is a practical clinical value in the study of the effects of well-controlled ablation experiments: they are of aid in understanding the cerebellar deficiencies which occur in the patient suffering from disease or injury of the cerebellum. For these reasons we shall initiate our review with a detailed analysis of the ablation experiments, even though some of these observations were made and in some cases forgotten many years ago. Reports of the investigations performed by other methods will be considered in later chapters of Part I of this monograph.

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Ablation Experiments

A. Ablation experiments in submammalian forms 1. Fish 2. Amphibia 3. Reptiles 4. Birds a. Total ablation b. Unilateral ablation c. Localized ablation B. Generalized ablation experiments in mammals 1. Introductory remarks 2. Total ablation a. In subprimates (1) Unstabilized deficiency (2) Stabilized deficiency b. In primates (1) Unstabilized deficiency (2) Stabilized deficiency 3. Unilateral ablation, or section of the three homolateral cerebellar peduncles a. In subprimates (1) Unstabilized deficiency (2) Stabilized deficiency b. In primates (1) Unstabilized deficiency (2) Stabilized deficiency 4. Bisection of the cerebellum and vermian ablation a. In subprimates b. In primates C. Localized ablation experiments in mammals 1. Introductory remarks 2. Ablation of the flocculonodular lobe a. Localized ablation including, but not restricted to, the vestibular part of the cerebellum b. Isolated ablation of the nodulus, lobule X of Larsell (1) In subprimates (2) In primates c. Isolated ablation of the flocculus, lobule H X of Larsell 8

10 10 12 13 13 13 14 15 21 21 23 23 24 30 35 35 37 38 38 38 44 46 46 48 48 48 49 50 50 52 52 54 54 55 56

ABLATION EXPERIMENTS (1) In subprimates (2) In primates 3. Ablation of the anterior lobe of the corpus cerebelli a. Total ablation with the rest of the nervous system intact (1) In subprimates (2) In primates b. Total ablation in the thalamic or decerebrate preparation c. Partial ablation (1) In subprimates (2) In primates 4. Ablation of the posterior lobe of the corpus cerebelli a. Total ablation b. Unilateral or bilateral ablation of the lobulus ansoparamedianus (1) In subprimates (2) In primates c. Isolated ablation of single cerebellar lobuli (1) Lobulus simplex of Bolk, or lobules VI and H VI of Larsell (2) Lobulus ansiformis of Bolk, or sublobule H Vila of Larsell (3) Lobulus paramedianus of Bolk, or sublobules H Vllb and H Villa of Larsell. (4) Lobulus medius medianus of Ingvar, or lobule VII of Larsell (5) Pyramis (lobule VIII), uvula (lobule IX), paraflocculus (sublobule H VHIb and lobule H IX), together constituting Larsell's paleocerebellar part of the posterior lobe (6) Errors and limitations in the experiments of isolated ablation of individual cerebellar lobules 5. "Postural asymmetries" and "asymmetrical phasic reflexes" after localized cerebellar ablations D. Isolated destruction of the cerebellar nuclei in mammals 1. Isolated lesions of the nucleus fastigii a. With the rest of the nervous system intact b. In the decerebrate preparation 2. Isolated lesions of the nucleus interpositus 3. Isolated lesions of the nucleus dentatus E. Section of the cerebellar peduncles in mammals 1. Introductory remarks 2. Inferior cerebellar peduncles a. Restiform body proper b. Juxtarestiform body, supramedullary part c. Juxtarestiform body, intramedullary part 3. Middle cerebellar peduncle 4. Superior cerebellar peduncle F. General considerations

9 56 56 56 56 56 58 60 61 61 63 63 63 64 64 66 67 67 67 69 70 70 71 73 77 77 77 80 86 87 88 88 88 88 90 91 91 92 95

The most obvious and, historically, the first approach to a study of the function of an organ is to observe an animal after the organ is removed in whole or in part. Experiments of this type were applied to the cerebellum, as to most other bodily structures, in the preliminary efforts to evaluate its functional significance. There have been three principal sources of error throughout the entire history

10 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM of cerebellar investigation. The first one is the failure to recognize differences between species, with the result that effects seen after cerebellar ablation in subprimate forms were mistakenly expected to be found also in primates and to be comparable to the effects of cerebellar deficiencies in man. The second, which has caused much confusion, is the failure to appreciate which symptoms are the result of acute loss of cerebellar influence on the rest of the nervous system and which are due to other centers correcting or compensating for this loss of cerebellar activity. The third source of error, particularly evident in the older papers, is the lack of histological controls, with the consequence that sometimes it is difficult to see which symptoms are due to the intentional destruction of a given cerebellar area and which are in fact the result of damage produced to other cerebellar or brain stem structures. We shall attempt in the following section to make this distinction clear in each instance, at least whenever the description of the individual ablation allows us to do so. The object of most of the older experiments was simply to observe or record, in an otherwise intact animal, the changes in posture or motor activity resulting from cerebellar extirpation. In more recent times, however, as other parts of the central nervous system became more fully understood, ablation experiments were performed to put this or that hypothesis to an experimental test and to seek a specific answer about cerebellar function in relation to some other nervous mechanism with which it was known to be anatomically connected. These experiments will be reviewed in another section, which will be devoted to the relations of the cerebellum to other nervous structures. In presenting the results of ablation experiments, we hope that a systematic description following the outline above will be more enlightening to the reader than simply a chronological record of previous work in which ablation experiments were done. Such a chronological record would serve only to reiterate all the misconceptions and confusions that have retarded progress toward a clear conception of how the cerebellum actually accomplishes its functions. This, even at the present time, is still obscure in spite of the vast amount of work that has been done on this part of the brain during the last several decades. By attempting to fit the data, now available in the literature, into the complete outline of cerebellar physiology as it has been investigated by ablation experiments, it also will be possible to indicate where there are gaps in our present knowledge. A. ABLATION EXPERIMENTS IN SUBMAMMALIAN FORMS 1. FISH The nineteenth-century literature on the fish cerebellum has been reviewed by ten Gate (1935). Only Rolando (1809), Lussana (1863), Renzi (1863-1864), Dickinson (1865), and Pugliatti (1885) reported alterations in swimming movements following cerebellectomy. Baudelot (1864), Vulpian (1866), TraubeMengarini (1884), Steiner (1888), Loeb (1891, 1905), Corso (1895), and Bethe (1899) got negative results. Because of lack of anatomical controls it would be difficult to evaluate these old findings. The experiments of Corso (1895) deserve to be mentioned because of the ingenuity of the technique he utilized to gauge

ABLATION EXPERIMENTS 11 muscular strength in fishes. By an elastic band he secured a cork to the animal's body and then stimulated the fish with a rod. To escape from the surface to the bottom of the aquarium, the fish had to overcome the resistance provided by the buoyancy of the cork. Normal fishes did not differ from the cerebellectomized ones in their ability to overcome this impediment. Polimanti (1911, 1912) made the first attempt to utilize cinematographic methods in order to analyze movements in fishes. He got negative results from cerebellectomized teleosts, whereas swimming was found to be slightly abnormal in the decerebellate selachians. Reisinger (1915, 1919, 1926) found that only minor changes in motility were elicited by ablating the corpus cerebelli in teleosts, whereas the equilibrium remained normal. In these fishes, however, the anterior part of the cerebellum (valvula cerebelli) is situated below the optic lobes; hence its ablation had been neglected by previous investigators. Reisinger reported that whenever the midbrain and the underlying valvula cerebelli were damaged or destroyed, a loss of equilibration occurred. The fish swam on one side or upside down, with its abdomen up. Tilney (1923) and Rizzolo (1929) observed no alterations in equilibrium after destroying the corpus cerebelli in selachians. According to Tilney, however, the coordination of the intersegmental movements of the body was lost and the animals swam with their tails only. Ten Gate (1929, 1930a, b, and c, 1931a and b) is responsible for the first systematic and histologically controlled ablation experiments on the selachian cerebellum. His experiments were performed on many types of sharks (Scyllium canicida, Scyllium catulus, Mustelus vulgaris) and of rays (Torpedo marmorata, Raja ondulata, Trygon pastinaca, Myliobatis aquild). In these plagiostomes the distinction between the corpus cerebelli, connected with spinocerebellar and olivocerebellar pathways, and the auriculae, connected with the vestibular apparatus, is clear-cut. Ten Gate was the first to perform the ablation of these two parts of the cerebellum separately. Following lesions of the auricles, he found alterations in muscle tone, with hypertonicity in the homolateral side, in all species studied. This resulted in a curvature of the body with the concavity toward the side of the lesion. The fish as a result swam toward the side of the lesion. This is clearly distinct from vestibular damage, for none of the rolling movements noted in fish with vestibular damage were observed. In other forms, Trygon and Myliobatis, a disturbance again due to muscular hypertonia was observed affecting the homolateral fin. The conclusion was drawn that the ablation of the auricles produced an increase in the tonus of the ipsilateral muscles, particularly those which are connected with swimming movements. The ablation of the corpus cerebelli, however, was without effect on movement, even in those fishes (like Trygon and Myliobatis) in which this structure is strongly developed. Clear-cut symptoms were observed only in specimens in which histological controls showed that the pedunculi cerebelli had been damaged; in these the results were similar to those following ablation of the auricles. Tuge (1934) in experiments on teleosts (Carassius auratus) described rapid spiral and disordered movements during the early stages following operations on the corpus cerebelli. After two or three days, however, the overactive muscles

12 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM became hypotonic. This was demonstrated on picking the fishes up and comparing the tone with that of a normal specimen. Unilateral lesions of the corpus cerebelli failed to produce any clearly defined differences on the two sides, though at times the fishes turned more to the operated side. At other times they were observed to lie on the bottom of the tank, on the side homolateral to the ablation, with the body flexed laterally, so that only the head and tail touched the bottom. According to Tuge, hyposthenia and ataxia were the main deficiency symptoms observed in his experiments. Karamjan (1949) found marked postural, motor, sensory, and trophic alterations in teleosts (Carassius carassius, Cyprinus carpio, Perca fluvialis, and Esox lucius) whose corpus cerebelli had been totally ablated. Following unilateral ablations the symptoms were localized on the ipsilateral side of the body. The cerebellar syndrome was not modified by the ablation of the forebrain. The integrity of the brain stem structures was shown by histological controls. Karamjan also performed experiments of cerebellar ablation on plagiostomes. He stressed the fact that besides postural and motor symptoms there were alterations in sensory functions, particularly those of vision.

2. AMPHIBIA Complete or unilateral cerebellar ablation was frequently performed by the old physiologists. Flourens (1824; see p. 147), Budge (1841, 1862), Goltz (1869), Onimus (1870-1871), Pugliatti (1885), and Loeser (1905) observed alterations in posture or in walking and swimming movements, whereas essentially negative results were reported by Fodera (1823), Desmoulins (1835), Renzi (1863-1864), Dickinson (1865), Vulpian (1866; see p. 639), and Steiner (1885). Both groups of investigators failed to control their results anatomically, and Eckhard (1879, p. 105) should be credited with having suggested that accidental lesions of the brain stem could possibly explain some of the symptoms which had been described in the cerebellectomized frog. Postural or motor alterations were also described, however, by modern investigators, who performed histologically controlled ablations on different kinds of anurans. Possibly because of differences between species or between methods of observation the abnormalities they reported differed in many respects. Mayer and Heldfond (1936) did not observe any abnormality following total cerebellectomy in the frog, except for the failure of the animal to terminate forward progression when confronted with an obstruction such as the end of a tank or table. In unilateral lesions the results, while less enduring than those following injury to the labyrinth or the medullary vestibular mechanism, were qualitatively the same—namely, a tilting of the head and forepart of the trunk toward the side of the lesion and extension of the limbs on the side opposite the lesion. On jumping, the animal spiraled toward the side of the lesion. Essentially negative results were obtained by Konheim (1939), while Gerebtzoff (1942) reported ipsilateral hypotonia following unilateral cerebellar ablation in Rana temporaria. The latter pointed out, however, that owing to the small dimensions of the cerebellar lamina, only in two cases were cerebellar lesions obtained without vestibular damage.

ABLATION EXPERIMENTS 13 Lutterotti (1934) performed her experiments on Hyla arborea, an anuran in which the cerebellum is better developed than in Rana, possibly related to its living in trees. With chronic and histologically well-controlled experiments she observed clear-cut postural, walking, and springing abnormalities, while swimming was altogether normal. The typical hopping walk which characterizes normal Hyla was absent following cerebellectomy, and the animal crept slowly on the ground like a toad. Karamjan (1949) performed complete cerebellectomy on frogs and on toads, and controlled histologically the integrity of the neighboring structures. Only minor postural and motor symptoms were observed. They were more evident in Rana ridibunda than in Rana temporaria and Rana esculenta. Abbie and Adey (1950) worked on the South American Bufo marinus. Following histologically controlled cerebellar ablation, they found symmetrical hypertonia of the forelimbs and neck, provided the cerebellar nuclei were mostly or wholly removed. An increased threshold of spinal reflexes was reported by Bianconi (1953) ipsilaterally to the ablation or the novocainization of the cerebellum performed on Rana temporaria.

3. REPTILES Anatomically the reptilian cerebellum is so complex (see Larsell, 1958) that it is difficult to draw physiological conclusions from the few ablation experiments which have been reported. The older literature has been reviewed by ten Gate (1937). It is likely that the severe symptoms described by Rolando (1809) and by Flourens (1824, p. 147) were due to brain stem lesions. At any rate, the results of Fano (1883, 1921), Steiner (1900), and Bickel (1901) for the main part were negative. Paul Bert (1875) alone reported that the spontaneous color changes of the chameleon were abolished by cerebellectomy, whereas the reflex color changes remained. No one has reported repeating these experiments with appropriate histological controls. Leblanc (1923) performed ablation experiments on lizards (Uromastix acanthinurus, Varanus griseus, Chamaeleon vulgaris) and found alterations in the equilibrium, with ataxia and asthenia in the limb movements. The animals walked as if they were drunk. Since in one Varanus, however, these symptoms were not observed although the cerebellectomy was complete, one wonders (van Rijnberk, 1931) whether the positive results in other specimens might not have resulted from brain stem lesions. Hacker (1931) performed her ablation experiments on twro forms of lizards, Ophisaurus apus, a snakelike animal with no legs, and Lacerta viridis. The experiments were controlled histologically. The movements of progression of 0. apus were uncoordinated, whereas the limbs of L. viridis showed tremor and dysmetria. 4. BIRDS a. TOTAL ABLATION

The older literature has been reviewed by Luciani (1891), van Rijnberk (1931), ten Gate (1936), and in the historical introduction of this monograph.

14 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM It will suffice to recall here that experiments were performed by Rolando (1809), Flourens (1822, 1824), Fodera (1823, 1826), Magendie (1825), Serres (1826), Bouillaud (1827), Longet (1842), Wagner (1861), Dalton (1861), Lussana (1862),Renzi (1863-1864), Dickinson (1865), Schiff (1866), and Weir Mitchell (1869). Modern physiological study of the avian cerebellum began with an important paper by Lange (1891). He performed chronic ablation experiments on pigeons. The ablation was not complete, since about one third of the cerebellum was left, but the anatomic controls showed that the cerebrum, the optic lobes, and the medulla oblongata had not been damaged. Lange made a distinction between acute symptoms, which were observed within the first 24 hours, and chronic symptoms. During the acute period the pigeon was unable to stand. The limbs were overextended, resulting in inability to walk. Attempts to walk were followed by spastic extension of the limbs so that the animal fell on one side. Any attempt to take food by flexing the head was followed by strong opisthotonos. This is the typical picture of spasticity, characterized mainly by strong increase in myotatic reflexes, which had been described by Fodera (1823). The animals also were unable to fly. The chronic symptoms (stationdre Symptome) were characterized by a milder degree of spasticity. The animal was able to walk, but it touched the ground with only three toes (instead of four) and actually with only their tips. The obvious reason is that the entire limb was still in a spastic condition, as reported by Lange. As a consequence, walking was "steifbeinig," i.e., characterized by rigidity of the legs. The animal was unable to perch upon a rod, attempts to do so resulting in a sudden extension of the limbs when the rod was touched by the animal with its toes. Later on a decrease of these spastic symptoms occurred and the animal was able to walk and to fly. No alterations in equilibrium were observed. After the symptomatology resulting from cerebellar ablation was stabilized, both labyrinths were destroyed, producing typical labyrinthine symptomatology. A clear-cut distinction was thus made between the effects of cerebellar and vestibular ablation. Bilateral ablations were performed by Friedlander (1898), Reisinger (1916), Martin and Rich (1918), Tilney (1923), and Talbert and Jenkins (1925), and the results were reviewed by van Rijnberk (1931) and ten Gate (1936). The spasticity observed by Fodera (1823) and by Lange (1891) in the pigeon was confirmed by Reisinger in the hen, and Trendelenburg (1910) pointed out that the extensor tonus was increased tremendously whenever the bird touched the ground with its feet. Martin and Rich (1918), using chickens, as well as all the other authors who investigated the pigeon cerebellum, emphasized the lack of coordination in the movements performed by their animals. b. UNILATERAL ABLATION

We have just seen in the historical introduction that the founders of cerebellar physiology had reached opposite conclusions about the effects of unilateral lesions of the avian cerebellum, since both ipsilateral (Rolando, 1809) and contralateral (Flourens, 1822, 1824) weakness of the pelvic limb was observed. These

ABLATION EXPERIMENTS 15 conflicting reports are to be found in the cerebellar literature up to the present time. Luciani (1891, p. 257) made a few experimental unilateral lesions in the pigeon in order to check Flourens's controversial statement (see p. 5) about the crossed influence of the cerebellum. If the unilateral destruction of the cerebellum was performed by puncture with a needle, i.e., by the old Flourens technique, a strong ipsilateral extension of the leg occurred which, according to Luciani, gave the wrong impression of contralateral weakness reported by Flourens. When unilateral ablation instead was complete, clear-cut atonia and asthenia were observed ipsilaterally. According to Luciani, the ipsilateral hyperextension was due to irritation, since the needle puncture produced a larger amount of bleeding. This interpretation by Luciani was disproved, however, by the chronic experiments of Lange (1891). Experiments of unilateral ablation were performed also by Shimazono (1912), who reported hypotonia of the ipsilateral pelvic limb. C. LOCALIZED ABLATION

Bremer (1924) was the first to show that isolated ablation of the anterior lobe in the thalamic pigeon is followed by a symptomatology of extensor rigidity and exaggeration of myotatic reflexes which is strikingly similar to that elicited by complete cerebellectomy. Ablation of Ingvar's lobus medius, however, had no effect on postural tonus. Ten Gate (1936) confirmed Bremer's findings for the anterior lobe, but claimed that some alterations were elicited also by destroying the lobus medius and the lobus posterior. He made the important observation that hypertonia follows a lesion of the cerebellum limited (as had been shown by appropriate histologic controls) to the anterior lobe. He thought that spasticity was due to irritation, an hypothesis which is clearly disproved by the experiments of chronic ablation performed by Lange (1891) and by the work of Bremer and Ley (1927). The lastnamed investigators showed that the hypertonia following total ablation of the anterior lobe in the thalamic pigeon was mainly due to an increase in the myotatic reflex (Fig. 1). These reflexes were still very strong many days after this localized cerebellar ablation, when the reflex standing posture was apparently normal. Hence there is no doubt that extensor hypertonia is due, as Bremer (1935) rightly pointed out, to a release from cerebellar inhibition; i.e., it represents a symptom of cerebellar deficiency. Bremer and Ley (1927) reported that the spastic syndrome gradually decreased in intensity also in the thalamic preparation, as had been observed by Lange in the otherwise intact pigeon. A similar observation was made later on by Rademaker (1931) in decorticate mammals and obviously suggests that cerebellar inhibition can be compensated by the vicarious activity of brain stem or diencephalic structures. Ten Gate (1926a) also performed many experiments of unilateral ablation in the otherwise intact pigeon. The histologically controlled lesions were localized sometimes within the two caudal folia of the lobus anterior and the two rostral folia of the lobus medius, sometimes confined to only one of these lobes. He reported ipsilateral extensor hypertonia, which later on decreased and finally

16

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

Figure 1. The effect of complete ablation of the anterior lobe of the corpus cerebelli in the acute thalamic pigeon. A. After ablation of the anterior lobe: when the animal is held in the air by its tail the legs are flexed. B. The same animal is now shown touching the ground with the soles of its feet. The marked increase in the postural reflexes is shown by the strong rigidity of the legs. C, D. Another acute thalamic pigeon showing extensor spasticity of the legs one hour after ablation of the anterior lobe. The animal is able to stand only when held by the tail (C). (From F. Bremer and R. Ley, 1927, Recherches sur la physiologic du cervelet chez le pigeon, Arch, internat. de physiol., 28:58-95, Figs. 5 and 10.)

faded away and occasionally was replaced by ipsilateral hypotonia. In other experiments, however, the latter syndrome occurred immediately after the operation. Ten Gate (1926a) rightly correlated ipsilateral hypertonia with the spastic phenomena occurring in the mammals during Luciani's dynamic period (see p. 24). As in mammals, the exaltation phenomena were followed, according to ten Gate, by a deficiency period, during which atonia and asthenia were observed instead in the ipsilateral extensor muscles. Hence the ipsilateral limb was more flexed when the pigeon was standing on its feet. If the animal was lifted in the air by its legs, so that the head remained down, the normal wing was kept near the body, whereas the other one drooped. Ten Gate disregarded the results obtained during the dynamic period and maintained that the avian cerebellum had a tonic and sthenic influence on the ipsilateral extensor muscles. There are, however, two facts which make it difficult to share ten Gate's opinion. First of all, ipsilateral atonia was sometimes observed immediately after the operation (Luciani, 1891; ten Gate, 1926a), whereas in other instances it occurred only after many days. One wonders if the extent of the cerebellar destruction was the same in both cases. Second, and more important, when cere-

ABLATION EXPERIMENTS 17 bellectomy is bilateral, spasticity progressively decreases in intensity (Lange, 1891) but it is never replaced by atonia. Extensor atonia occurs, as pointed out by Bremer and Ley (1927), only after unilateral ablation. In the chronic, bilaterally decerebellate pigeon, spasticity might be mild in intensity, but it is always present (Lange, 1891). Bremer and Ley (1927) also performed experiments of unilateral ablation of the anterior lobe and obtained, paradoxically, the same postural effects, i.e., ipsilateral flexor posture with contralateral extensor rigidity (Fig. 2), which were elicited by stimulating the same cerebellar area. With the exception of the contra-

Figure 2. Unilateral ablation of the anterior lobe of the corpus cerebelli in the acute thalamic pigeon. An acute thalamic pigeon (^4) shows strong extensor hypertonia of the right hindlimb (B, C) following a lesion performed on the left side of the anterior lobe (D). There is no rigidity in the ipsilateral leg, but possibly flexor hypertonia (B). (From F. Bremer and R. Ley, 1927, Recherches sur la physiologic du cervelet chez le pigeon, Arch, intcrnat. de physiol., 28:58-95, Fig. 8.)

lateral rigidity, which ten Gate (1926a, 1936) failed to detect, this symptomatology clearly corresponded to that described by the Dutch physiologist following unilateral cerebellar ablations. According to ten Gate, ipsilateral extensor atonia corresponds to the deficiency period of Luciani, whereas Bremer and Ley believed that irritation phenomena were responsible for this effect. One difficulty with this explanation is apparent, however; for all agree that complete anterior lobe lesions invariably produce bilateral spasticity, in either thalamic or intact pigeons, within minutes after the lesion is made. No effects were noted in the thalamic pigeon by Bremer and Ley (1927) following total or unilateral lesions of the "middle lobe," whereas according to ten Gate (1926a) ipsilateral alterations of the leg and wing tonus were elicited in the intact animal. Ten Gate conceded.

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM however, that the postural alterations were much lighter than those following lesions of the anterior lobe and that they disappeared sooner. With the method of tonic asymmetry, developed by Rossi (1921, 1925) and his pupils (see p. 73), Manni (1948a, 1951a) showed that lesictns involving the lateral one half of the "middle lobe" of the cerebellum, in the intact pigeon, resulted in some consistent differences in the resting posture of the legs. If more than two or three folia were destroyed (the lesion remaining confined to the cerebellar cortex) the asymmetry might also involve the wings and the tail. Following reflex stimulation of different types phasic asymmetries were observable for four or five days. These effects could be re-established by light ether anesthesia. With histologically controlled experiments performed on thalamic pigeons, Chiarugi and Pompeiano (1956a) showed that both ipsilateral hindleg extension (with contralateral flexion), which they called Flourens's posture, and ipsilateral extensor atonia (with spasticity of the contralateral hindleg), which they called Rolando's posture, should be regarded as syndromes of unilateral cerebellar deficiency. Flourens's posture is elicited by pure corticocerebellar lesions, whereas Rolando's posture occurs whenever the cerebellar nucleus is involved. Hence the different results obtained by previous investigators were attributed to differences in the extent of the lesions inflicted upon the avian cerebellum. A typical Flourens posture was produced by superficial decortication of Larsell's folia IHb, IV, V, and VI, with histologically controlled integrity of the underlying nucleus; but clear-cut results were obtained also with more restricted 18

Figure 3. Flourens's and Rolando's postures after unilateral cerebellar lesions. Two thalamic pigeons following unilateral lesions on the right side, limited to the cerebellar cortex (^4, B; see Fig. 4F~) or involving also the ipsilateral cerebellar nucleus (C, D; see Fig. 5), yielding respectively extensor spasticity of the right leg (Flourens's posture, A, B) and left leg (Rolando's posture, C, D). (From E. Chiarugi and O. Pompeiano, 1956, Effetti della distruzione unilaterale e bilaterale della corteccia e dei nuclei del cervelletto sul tono posturale del piccione talamico, Arch, di sc. biol., 40:1-23, Figs. 2, 1, 9, and 8.)

ABLATION EXPERIMENTS

19

H Figure 4. A schematic representation of unilateral lesions limited to the cerebellar cortex. Roman numerals represent Larsell's nomenclature for the cerebellar cortex. A combination of Roman numerals and letters shows subdivision of the primary folia into secondary folia. The dotted areas delimit the cerebellar nuclei. The shaded areas correspond to an extension of the secondary lesion. The primary lesion was produced by aspiration. Serial sections, alternatively stained by Weil and Nissl methods, were made, and the sagittal section, where the lesion was the most extensive, was selected for reproduction with the camera lucida. Each schema corresponds to a different experiment. E to //. Unilateral destructions limited to the cerebellar cortex of the thalamic pigeon. In each case an ipsilateral extension and a contralateral flexion of the limbs (Flourens's posture) occurred. They were observed throughout the experiment (up to the thirteenth day postoperatively in G). (From E. Chiarugi and O. Pompeiano, 1956, Effetti della distruzione unilaterale e bilaterale della corteccia e del nuclei del cervelletto sul tono posturale del piccione talamico, Arch, di sc. biol., ^0:1-23, Fig. 6.)

cortical lesions (Fig. 4), sometimes strictly limited to the anterior lobe. The release of the ipsilateral extensor mechanisms was shown by the tonic extension of the leg (Fig. 3A, B), whereas phasic labyrinthine reflexes yielding extension and elevation of the wings were strongly increased on the same side of the body. These symptoms gradually subsided, but could be easily observed when the bird was sacrificed (up to thirteen days thereafter). Rolando's posture was observed instead, first, whenever the rostral part of one cerebellar nucleus was involved in any bilateral or unilateral cortical ablation (Fig. 3C, D; Fig. 5) and, second, following pure nuclear lesions made electrolytically through a microwire. Moreover, in two cases, a Flourens syndrome which had been obtained with what was intended to be a cortical lesion was replaced by Rolando's postures three and seven days thereafter. The histological controls

Figure 5. A schematic representation of unilateral combined lesions of the cerebellar cortex and nuclei. Nos. 1 to 9 refer to one physiologically controlled lesion in a thalamic pigeon, which showed ipsilateral flexion and contralateral extension (Rolando's posture) throughout the experiment (Fig. 3(7, D). The dotted areas represent the cerebellar nuclei. The shaded area delimits the extension of a secondary lesion. The primary one was produced by aspiration. Progressive numbers orient the histological section in the cerebellum and brain stem in a rostrocaudal axis. Sections were of 20 /JL and were stained every 200 (JL. (From E. Chiarugi and O. Pompeiano, 1956, Effetti della distruzione unilaterale e bilaterale della corteccia e dei nuclei del cervelletto sul tono posturale del piccione talamico, Arch, di sc. biol., 40:1-23, Fig. 12.)

20

ABLATION EXPERIMENTS 21 showed inflammatory and degenerative changes in the rostral part of the underlying cerebellar nucleus, and it seems likely that Rolando's posture ensued when the secondary lesions spread to the nucleus. Alternative explanations of the symptom of ipsilateral extensor atonia could be dismissed. The irritation hypothesis was disproved (a) by the long duration of Rolando's posture, which was never replaced by Flourens's symptoms, and (b) by the syndrome of bilateral spasticity which occurred at the end of the operation when both nuclei had been fulgurated. The histologically controlled integrity of all brain stem structures and of the contralateral cerebellar nucleus suggested, moreover, that the ipsilateral extensor hypotonia was due to the destruction of fastigial neurons or the severance of cerebellifugal pathways exercising a facilitatory influence on the extensor mechanisms of the same side of the body. We are going to see later on that Sprague and Chambers (1953) had previously arrived at similar conclusions in their investigations on mammals (see p. 80). In the birds, moreover, an increase in the extensor tonus of the ipsilateral leg occurred when the cerebellar nucleus was stimulated (Chiarugi and Pompeiano, 1956b; see below, p. 107). The main question we are confronted with is why extensor atonia occurs only following unilateral nuclear lesions, and why bilateral extensor rigidity ensues as soon as both nuclei are symmetrically encroached upon. It should be pointed out in this connection that Chiarugi and Pompeiano (1956a) entirely confirmed the observations of Bremer (1924) and of Bremer and Ley (1927) and showed that following bilateral lesions, localized either in the cerebellar cortex or in both cerebellar nuclei, the syndrome was constantly one of generalized spasticity. Apparently Rolando's posture cannot be explained, at least exclusively, by the lack of some facilitatory influence arising in the nucleus which has been destroyed. The unilateral extensor hypotonia is the result of an asymmetrical nuclear innervation rather than of the withdrawal of nuclear facilitation. Experiments of Moruzzi and Pompeiano (1955b, c; 1957a) showing that the unilateral collapse of decerebrate rigidity elicited in mammals by fastigial lesions is related to an inhibitory influence arising in the muscle and labyrinthine receptors of the opposite side of the body will be reported in another section of this monograph (see pp. 265-268). B. GENERALIZED ABLATION EXPERIMENTS IN MAMMALS 1. INTRODUCTORY REMARKS Luciani (1891) has been criticized for his arbitrary division of the postoperative symptomatology after cerebellar ablation into three periods: Functional exaltation (dynamic phenomena), Deficiency phenomena, and Compensation. Nevertheless it is impossible to describe the results of cerebellar lesions without in some manner separating those symptoms which immediately follow the operation, and gradually fade away, from those which are permanent. Both are equally important for a balanced view of the effects of ablation and are equally significant. In his first monograph Luciani dismissed the early symptoms of functional exaltation as irritative phenomena, his work having been done before Sherrington's description (1898) of decerebrate rigidity. Andre-Thomas (1897, p. 326) was

22 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM the first to point out that the dynamic phenomena of Luciani might really be due to lack of cerebellar innervation. Sherrington (1900, pp. 907-908), in Schafer's Textbook of Physiology, interpreted them as release phenomena, similar to those occurring during decerebrate rigidity. Luciani himself conceded in his handbook (1915) that irritation alone was insufficient to explain the period of functional exaltation. While it is now recognized that the compulsory movements observed during the first twenty-four to forty-eight hours following an ablation may be the result of edema or the irritation of surrounding nervous tissue, the predominant cause of the spastic phenomena which characterize the animal after cerebellar lesions is a release of brain stem postural mechanisms from cerebellar inhibition. The evidence for this view is overwhelming and will be developed fully. If this interpretation is accepted, it naturally follows that compensation begins immediately after the lesion and continues until a plateau of deficiency is reached or until no abnormalities are detectable by the method of observation chosen by the examiner. It is therefore illogical to attempt to divide the period of functional exaltation from that of deficiency phenomena, since both are the result of loss of cerebellar control. We prefer, therefore, the term "unstabilized cerebellar deficiency" to identify the period following ablation during which the condition of the animal is subject to progressive modification. It corresponds to Luciani's periods of functional exaltation and of deficiency phenomena. The remaining portions of the nervous system, both intracerebellar and extracerebellar, begin to compensate for the deficiency produced by cerebellar ablation very soon and to the fullest extent of which they are capable. The condition of the animal steadily improves and a level of recovery is finally attained in which the functional state of the remaining part of the machinery related to the cerebellum is no longer unstable; that is, it is no longer being modified by the relatively minor effects of edema and vascular disturbance in the surrounding tissue and is no longer subject to the further progress of compensatory nervous mechanisms. We choose the term "stabilized deficiency" to indicate this later period. It would correspond to the compensation period of Luciani and to the lasting symptoms (Dauerstorung) so completely analyzed by Rademaker (1931) in his totally decerebellate dogs. After regional ablations, so far as methods of "clinical" examination of animals reveal, there is no period of stabilized deficiency, for the animal fully regains his previous faculties, either by means of remaining portions of the cerebellum or by extracerebellar nervous mechanisms. As will be developed later, the symptoms of cerebellar deficiency, however, can again be brought to light by rendering functionally inactive the intracerebellar or extracerebellar structures which have assumed the functions of the originally damaged area. Description of the abnormal movements or postural patterns following cerebellectomy through the years has developed an involved nomenclature, many of the terms having assumed different meanings to different writers. Most of the terminology of physiologists has been utilized by clinical neurologists, but frequently with different connotations. Holmes (1922), in his classic description of acute cerebellar injuries in man, attempted to redefine the terms used in describing these deficiencies. As defined by him, they were placed in physiological litera-

ABLATION EXPERIMENTS 23 ture by Walker and Botterell (1937) and have since been generally used both in clinical and in physiological writing. These terms and their respective definitions are as follows (Walker and Botterell, 1937, p. 330): "Cerebellar ataxia embraces all abnormal motor phenomena of cerebellar deficiency, including dysmetria, tremor, decomposition of movement, etc. "Dysmetria includes any disturbance in the range of voluntary movements. "Hypermetria is excessive range of movement as when the limb overshoots the desired point. "Hypometria is deficient range so that the limb stops before the goal is reached. Frequently a concomitant factor is a disturbance of the force of the movement which is not well adapted to its end. "Decomposition of movement is defined as the performance of an act so that 'its various components are not executed in their proper sequence or measure.' "Tremor is of two types namely trembling movements that occur in an extremity at rest or while maintaining a posture ('static tremor'), and those that occur during any part of active movement ('kinetic tremor'), and in any plane. Terminal tremor, i.e. the tremor occurring at the end of a movement, is usually more marked than the tremor at the start or during the course of a movement. "Tone (tonus or postural resistance) was defined by Holmes (1922) as 'the slight constant tension characteristic of healthy muscles, owing to which the limbs, when handled or moved passively, offer a definite resistance to displacement.' To the physiologists 'tone' is a reflex postural contraction most evident in antigravity muscles and depending upon the position of the body in space at the time of examination. "Hypotonia is a somewhat unsatisfactory but widely-used term denoting a diminished resistance to passive movement: the passive movement of a hypotonic limb may be carried through a range greater than normal, and on passively shaking the proximal segment of a 'hypotonic' limb there is abnormal excursion at the affected joint." Since the terminology of the old investigators was somewhat different, more attention will be paid to a description of symptoms than to the labels given them. 2. TOTAL ABLATION a. IN SUBPRIMATES

The ablation experiments performed before Luciani concerned mammals below the primates exclusively and were partly reported in the historical section of this book. A complete review was given in the monograph of Luciani (1891, 1904) and Andre-Thomas (1897). Following our practice with reference to the ablation experiments in submammalian forms, we simply recall that total or partial extirpations of the mammalian cerebellum or lesions of the cerebellar peduncles were performed by Rolando (1809), Flourens (1822, 1824), Fodera (1823), Magendie (1824), Serres (1826), Bouillaud (1827), Budge (1841,1862), Claude Bernard (1858), Schiff (1858, 1866, 1883), Leven and Ollivier (1862), Lussana (1862, 1885, 1886), Renzi (1863-1864), Dickinson (1865), Vulpian (1866), Albertoni (1875-1879), Ferrier (1876), Goltz (1881), Bianchi (1882), Baginsky (1881, 1882-1883), Pugliatti (1885), Borgherini (1888, 1891), Borgherini and Gallerani (1891, 1892), Gallerani and Borgherini (1892a, b).

24

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM The cerebellar investigations occupied Luciani from 1882 to 1891, when his monograph on the cerebellum appeared, but preliminary notes were published in 1882, 1883, and 1884. He later reviewed his experience in the light of subsequent research in his celebrated textbook on human physiology. The volume on the muscular and nervous systems was edited by Gordon Holmes in its English translation, which appeared in 1915, and it is this edition we have used for our quotations and descriptions. Luciani's advance over previous workers was due in part to technical progress, since he was the first who succeeded in keeping animals alive for a long period after cerebellar ablation. His careful analysis of the symptoms of cerebellar deficiency, however, constituted his great contribution. His experiments may be divided into four groups: first, those in which the whole cerebellum was removed; second, those in which one half of the organ was removed; third, those in which partial lesions were made, especially of the vermis; and fourth, those in which the cerebellar ablations were combined with lesions of the cerebellar cortex. The last group will be reviewed in the chapter on cerebellocerebral relations. The subprimate part of Luciani's investigations were performed on dogs. Later investigators also frequently used cats. We shall devote a few lines at the end of this section to the experiments performed on more unusual mammals, such as the guinea pig and the bat. (1) Unstabilized Deficiency We shall first discuss the symptoms which immediately follow removal of the entire cerebellum in the dog. According to Luciani (1891, 1915), if the dog is not too deeply anesthetized or enfeebled by bleeding, it is agitated, cries out, and shows other evidence of unrest. Opisthotonos, or backward curving of the vertebral axis, especially of the head and neck, is observed. There is tonic extension of both forelimbs with alternating clonic movements of the hindlimbs; bilateral convergence of the eyes and a tendency to stagger and fall backward. These symptoms, which Luciani called dynamic phenomena, he at first attributed to irritation of the severed cerebellar peduncles. The reasons which he gave for assigning these symptoms to irritation were (a) that they corresponded to the degree of operative injury—i.e., they were less marked in partial than in complete lesions—and corresponded also to the appearance of inflammatory or infective processes in the wound; (b) that they were more pronounced as the cerebellar peduncles were approached; and (c) that after a vermian lesion which allowed the peduncles to degenerate, subsequent removal of the lateral lobe produced only slight and transient symptoms of this dynamic type. In the light of Ferrier's subsequent experiments (1894) on cauterization of the cerebellum, which Luciani (1895a, b) confirmed, he withdrew from his earlier position with regard to the source of these symptoms. He stated: "The explanation of the dynamic phenomena of the first period is still a mystery; it is very doubtful how far they depend on irritation or paralysis of the cerebellar peduncles" (1915, p. 437). He still did not believe, however, that it was possible "at present to argue from these phenomena in regard to the normal functions of the cerebellum." These forced movements and hyperactivity reactions gradually abate over a

ABLATION EXPERIMENTS 25 period of about eight days. As the animal gradually begins to move about, other defects can be noticed. Luciani stated: "On the disappearance of the dynamic phenomena of the early postoperative period, the dog remains, for a certain time, incapable of standing on its feet and sustaining the weight of its own body. At each attempt to get up it falls now on one side and now on the other. Later it begins to rise on the fore-limbs only, because the hind-limbs flex at each attempt to stand up. "That this inability of the animal to assume and maintain the upright posture is due solely to asthenia, atonia, and astasia, and not to inability to coordinate its movements, nor to deficient equilibrium, is proved by the fact that during this period the animal is able to swim as well as any normal dog. "At a later period the animal manages to rise gradually, and to take a few steps, but it frequently falls to one side or the other, owing to the flexion of the limbs, particularly the hind-legs, which are always the weakest. In the upright position it is never still for a moment, and always seeks the support of a wall in its first attempts at walking. It is only later that it gradually learns to walk without support and to fall less often and less suddenly, till at last it avoids this altogether" (p. 448). The analysis of the particular behavior which brought him to the conclusion that the three cardinal symptoms of cerebellar deficiency were atonia, asthenia, and astasia was developed in large part from the results of unilateral extirpation (see p. 39). Russell (1894) removed the entire cerebellum in four dogs and confirmed the main observations of Luciani. He was unsuccessful, however, in performing this surgical feat in one operation, but did accomplish it in twro stages, two or three weeks apart. Extensor spasms of all four limbs were described. The limbs were said to be rigidly extended from the trunk, as a rule; if spasticity was not present spontaneously, it was evoked whenever the animal was disturbed. The tendon reflexes were increased bilaterally. Russell did not indicate the length of time his animals were observed, but it is likely from his description that the animals died during the dynamic period. Andre-Thomas (1897) was able to keep his totally decerebellate dogs alive for from one to two months. His description of the dynamic and deficiency period was like that of Luciani. He made, in addition, the interesting observation (p. 315) that the tendon reflexes were still increased when both rigidity and opisthotonos had faded away. Lewandowski (1903, 1907) performed his experiments mainly on dogs, but also used cats and rabbits. While his controversy with Luciani is well known (see Luciani, 1915), the protocols of his observations on a fully decerebellate dog actually differ very little from those of Luciani. Both the acute symptomatology (extensor rigidity, opisthotonos) and the chronic (atonia) were confirmed by Lewandowski; in addition he made the observation that nineteen days after the operation—i.e., during Luciani's deficiency period—the atonia might still disappear and be replaced by strong - spasticity (particularly evident in the forelimbs) whenever the animal was lifted from the ground by. grasping its dorsal skin. The tendon reflexes were considerably increased, and one month after the ablation the extreme atonia could occasionally still be replaced by extensor

26 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM spasms wnenever an attempt was made to put the animal on its feet. These occasional extensor spasms were more evident in the forelimbs (just as in the extensor rigidity observed during the dynamic period), and at times they were suddenly replaced by a relaxation of the antigravity muscles, so that an animal which a few moments before might have utilized his rigid limbs as stilts fell at once to the ground. Lewandowski was right in pointing out that these spastic phenomena, which occurred after one month, could not possibly be related to irritation. He wrongly denied, however, that the extensor spasms which occurred when the animal touched the ground had anything to do with an increase in the tendon reflexes. As we shall see later, when dealing with the experiments of Dusser de Barenne and Rademaker, some of the release effects observed during the dynamic period obviously persist during the so-called deficiency period, and there is an overlap between the deficiency effects that yield Luciani's atonia and those that are responsible for the spastic phenomena. Another of Lewandowski's observations may be noticed because of its relation to some clinical findings: his dogs were characterized by an explosive and monotonous way of barking, a symptom which continued for some months after the cerebellar ablation. It is difficult to extract the essential findings from the papers presented by Munk (1906-1908) to the Prussian Academy, since facts and speculations are inextricably mixed in them. He agrees with Luciani that the symptoms which follow complete cerebellectomy concern the motor sphere and confirms Luciani's description of the dynamic period and of many of the deficiency symptoms. Perhaps his most interesting observation is that cerebellar ataxia concerns only the muscles of the trunk and limbs. There were no alterations in the ocular, masticatory, and laryngeal muscles in his totally decerebellate dogs. He stated that he was unable to confirm Lewandowski's findings on the alterations in barking and also that some rather complex movements performed by the limbs (such as those involved in the scratch reflex) were quite normal. In 1914 there appeared a short but extremely important communication by Beritoff and Magnus concerning the influence of decerebellation on decerebrate rigidity. In his classic paper of 1898 Sherrington had made the remark that "decerebrate rigidity sometimes persists after removal of the cerebellum, if the latter ablation be performed without any serious amount of haemorrhage" (p. 327). Weed (1914), however, had come to opposite conclusions, while Edinger (1912), on purely anatomical grounds, had suggested that the cerebellum might be the center for postural tonus and therefore of decerebrate rigidity. Beritoff and Magnus gave final and clear-cut evidence that decerebellation does not abolish decerebrate rigidity. The possibility that irritation may be responsible for the persistence of decerebrate rigidity after cerebellectomy was dismissed through another experiment, performed by Beritoff in Magnus's laboratory. The Russian physiologist was able to show that rigidity was still present eight hours after decerebration and decerebellation. Hence Weed's results were disproved and shown to be due to inadequacies in his technical procedure. Bremer (1922a) confirmed and extended Magnus and Beritoff's results by decerebrating cats which had been cerebellectomized some days before. A strong extensor rigidity ensued,

ABLATION EXPERIMENTS 27 and no important differences were noticed when the animals had been hemicerebellectomized. Dusser de Barenne (1923, 1937), with experiments of total decerebellation performed on dogs and cats, confirmed that both opisthotonos and extensor rigidity of the forelimbs were the dominant symptoms during the first two or three days following the operation. In agreement with Munk (1906), he was unable to find any abnormality in the position of the eyes or ocular nystagmus during the dynamic period and suggested that these effects, when present, might be due to incidental lesions of the brain stem. He observed that tremor began very soon, while the animal was still unable to walk and the extensor rigidity of the forelimbs was very marked. The tremor was confined mainly to the head and to the muscles of the shoulders. Only after ten days was the first successful attempt at walking made. Disagreeing with both Luciani and Lewandowski, he categorically denied any existence of atonia in his animals. The ability to walk improved after the tenth day, but tremor was still the dominant symptom. He claimed that asthenia was disproved by the fact that the animal could move around in the garden for fifteen minutes, in order to get a piece of meat, without showing a sign of fatigue. Van Rijnberk (1931), however, made the pertinent remark that no fatigue tests had been made before decerebellation and that Luciani's asthenia, moreover, meant a decreased strength in the muscular contraction and not increased fatigability. Finally Dusser de Barenne extended Munk's findings that cerebellar deficiency symptoms were limited to only a few types of movements. Not only was the scratch reflex normal in the decerebellate dogs but the typical biting movements with which a dog tries to catch a fly on its body were also normal. This is not a spinal nor a brain stem reflex, since it is never observed in the decorticate dog. Also normal was the complicated movement by which a cat cleans its snout with a foreleg. Hence Dusser de Barenne concluded that the cerebellar deficiency was restricted to a few movements of locomotion. He conceded (as Munk did) that his decerebellate dog swam much better than it walked, during the deficiency period, but stated that the swimming was nevertheless abnormal. He agreed with Luciani that the difference between the abilities to swim and walk was related to the fact that the animal's body was supported by the water. A close perusal fails to reveal in the monographs of Dusser de Barenne any real factual contribution to cerebellar physiology. He confirmed or extended Lewandowski's and Munk's findings in most of the points on which they disagreed with Luciani. His opinions, however, were widely quoted, possibly because of the clear-cut and uncompromising position he took on many issues which had been taken for granted until his time, such as the existence of atonia and asthenia. According to Lewandowski, during Luciani's deficiency period spastic phenomena were intermingled with those related to Luciani's atonia, whereas Dusser de Barenne flatly denied the very existence of both atonia and asthenia. Important new facts were reported by Pollock and Davis (1923, 1927, 1930a, b). By their well-known method of anemic decerebration (high ligation of the basilar artery and of both carotids) they prepared a decerebrate cat, in which all

28 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM the nervous structures supplied by blood vessels arising cephalad to the basilar ligature (including, therefore, the anterior lobe, which is supplied by the superior cerebellar artery) were functionally inactivated. By coagulating or ligating the inferior cerebellar arteries, a completely decerebrate and decerebellate cat was obtained. The extensor rigidity and the opisthotonos were of great intensity (Fig. 6). This was a very important observation in cerebellar physiology because,

Figure 6. Opisthotonos resulting from removal of the cerebellum in a decerebrate animal. Both decerebration and decerebellation were performed by the anemic method. (From L. J. Pollock and L. Davis, 1927, The influence of the cerebellum upon the reflex activities of the decerebrate animal, Brain, 50:277-312, Fig. 21.)

together with the experiments performed almost simultaneously by Camis (1922a, 1923) on the anterior lobe (see p. 60), it completely disposed of the first hypothesis of Luciani that traumatic irritation was the cause of this type of dynamic phenomena. Pollock and Davis showed, moreover, that the rigidity decreased if the head was passively flexed and that an extreme extension of the forelegs occurred as soon as the head was released and assumed the original position of opisthotonos. Since this degree of opisthotonos was never observed in an ordinary decerebrate animal, and since it was abolished when both labyrinths were destroyed, it is apparent that some, at least, of the release phenomena observed during the dynamic period are labyrinthine in origin. The fundamental experiments performed by Rademaker (1926a, b, 1930, 1931) deserve a most careful description. They were made on cats and dogs, some of which were kept alive for six years. According to Rademaker, the period of stabilized deficiency (Stadium der Dauerstorung) did not begin until three to six months after cerebellar ablation, and therefore the period of imstabilized deficiency would correspond not only to Luciani's dynamic and deficiency periods, but also to that part of Luciani's compensation period in which recovery is still progressing. In his description of the early stages following total decerebellation, Rademaker made first of all a distinction between "rigid" and "flaccid" animals. The rigid animals were characterized by the classic release symptoms described by Luciani during the dynamic period. Rademaker confirmed Sherrington's state-

ABLATION EXPERIMENTS 29 ment (1898, 1900) about the close similarity between decerebrate rigidity and decerebellate spasticity and remarked that the latter gradually disappeared during the first week following decerebellation. The second group of animals, instead of exhibiting rigidity, were characterized by complete flaccidity, the absence of myotatic reflexes, and an inability to stand. It is important to stress that Rademaker's flaccidity does not correspond to Luciani's atonia. It is an early symptom observable as soon as the animal recovers from anesthesia. It begins to disappear within the first day, and during the second day the animal is sometimes able to bring its head and forequarters from the lateral to the normal (abdomen down) position. Rademaker (1931, p. 367) dismissed the symptoms occurring immediately after the cerebellar ablation, considering them the consequence of shock or diaschisis. As we have already pointed out, the spasticity of the dynamic period is due almost certainly to the release from cerebellar inhibition. Hence it is a genuine deficiency effect. To express an opinion about Rademaker's "flaccid" animals is more difficult. Flaccidity was either missed or neglected by previous investigators. Dusser de Barenne (1937, p. 252), who made the error of homologizing Rademaker's flaccidity with Luciani's atonia, claimed that brain stem lesions would be responsible for this effect, but this categoric statement is not substantiated by any histological controls. We believe that vasomotor collapse is a more likely explanation, since there is no doubt that decerebrate rigidity turns into flaccidity whenever circulatory changes of this kind occur. The cerebellar tremor, at any rate, was absent during these early stages, although a shivering could easily be evoked (Rademaker, 1931, p. 414). The symptoms of both the "rigid" and the "flaccid" animals as described by Rademaker became more and more similar as recovery progressed. Those related to postural tonus will be reviewed in the next section, since Rademaker made his careful analysis of the different types of postural reactions during the period of stabilized deficiency, i.e., when compensation was complete. This circumstance will help to explain, incidentally, why he denied the existence of both asthenia and atonia, although one must concede that other factors, besides the period of observation, should be taken into account. They will be discussed when all the data about postural disturbances in cerebellar ataxia have been made available to the reader. The symptoms which had been grouped by Luciani under the name of astasia, however, were fully confirmed by Rademaker (1931), and we shall briefly review his observations here. His analysis of astasia was made on his totally decerebellate dogs. Inasmuch as normal dogs also exhibit tremor, unilateral ablations are more favorable for this analysis (see p. 40). The tendency to exhibit tremor was found to be increased after decerebellation, and a tremor was observed also in those parts of the body (such as the tail) where it never occurs in the normal animal. The tremor increased as a consequence of psychical excitation, and disappeared during rest and sleep or whenever a hyperextension of the limbs occurred. It was more evident in the muscles of the neck. The large, uncontrolled oscillations (Luciani's "oscillazioni ritmiche") which are so evident when the animal is eating were confirmed (p. 416), and Rademaker emphasized that these symptoms disappeared

30 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM (as the tremor did) during sleep or whenever the animal was lying quietly on the ground. Cerebellar tremor was further investigated by Fulton, Liddell, and Rioch (1932); their important paper will be reviewed in the section on cerebellocerebral relations. The total cerebellectomies performed by Schmidt (1921) on the guinea pig and by Merzbacher (1903) and Polimanti (1909) on the bat may be mentioned here. They produced no new facts, except that the bat is unable to fly following cerebellectomy. (2) Stabilized Deficiency The symptoms Luciani observed during his period of compensation following total cerebellectomy he attributed to what he called functional compensation. They are represented by "abnormal movements directed to meeting and partially compensating for the effects of deficiency." In the dog, following total cerebellar ablation, they consist mainly of exaggerated abduction of all four limbs in walking. At the same time the swaying of the body increases; and in an attempt to control this, particularly when it changes its direction of progression, the animal will frequently cross its legs over one another, setting the left leg to the right of the right one. As it oscillates from side to side it attempts to compensate for this by exaggerated abduction or exaggerated adduction. Luciani used charts of the dog's footprints before and during the various stages of postoperative recovery to demonstrate and illustrate these abnormalities. The most detailed analysis of the lasting effects of total cerebellectomy in subprimate forms is that of Rademaker (1931). His chief contribution to cerebellar physiology is the accurate description of the modifications that cerebellectomy effects on the different types of reflexes that he and his teacher Magnus had described. In the following paragraphs the results obtained by the Dutch physiologist in his careful analysis of postural reactions will be reviewed; the effect of cerebellar ablation on labyrinthine and cortical reflexes will be dealt with in another chapter (see pp. 271, 338). Stiltzreaktion. The "supporting reaction" is an extensor reaction of the extremities designed to maintain the weight of the body against the force of gravity. It is evoked by gentle contact with the foot pads, the adequate stimulus appearing primarily to be the stretching of the small muscles of the feet when the pads become slightly separated; further pressure stretches the flexor muscles of the toes as well as the antigravity muscles of the proximal parts of the limbs, thereby giving rise to a synergistic myotatic reflex. Contact with the skin alone is of some value in eliciting the reflex; reactions induced by exteroceptive stimulation are known as magnet reactions. These cutaneous reflexes, however, are absent in the cat (Rademaker, 1931; Ingram, Ranson, and Barris, 1934), and they are generally absent also in the normal dog, if the animal is placed in a dorsal position. The supporting reaction in Rademaker's experiments was strongly increased in intensity in the chronically decerebellate dog. Hence its exteroceptive component, the magnet reaction, was constantly observed when the dog was placed in the dorsal position and was sometimes evoked simply by touching the foot

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31

Figure 1. The magnet reaction after decerebellation. The decerebellate dog is lying in the supine position, with the hindlegs flexed (1). Slight tactile stimulation of the sole of one foot (2, 4) or of both feet (3) elicits a strong extensor hypertonus. (From G. G. J. Rademaker, 1931, Das Stehen, Berlin: J. Springer, p. 41, Fig. 28.)

pads with cotton. A slight tactile stimulation of the sole evoked a very strong response which spread to the vertebral muscles as well as to the entire limb (Fig. 7). Also the proprioceptive component of the Stiitzreaktion was increased by the decerebellation. The exaltation of the most important of the mechanisms concerned with reflex standing was responsible, according to Rademaker, for the fact that spasticity and not atonia characterized his totally decerebellate dogs. He stated categorically that "Bei stehenden kleinhirnlosen Hunden ist keine Spur von Atonie zu beobachten" (p. 85). While this was regarded as the final disproof of the existence of Luciani's atonia, it must be emphasized that Rademaker was concerned with totally decerebellate dogs, examined during the compensation period; whereas Luciani's analysis was based mainly upon hemidecerebellate dogs and monkeys, examined during the intermediate deficiency period. No one would deny that the excitability of the postural reflexes is increased following chronic cerebellectomy. This is an important fact which should be correlated with the exaltation of tendon reflexes observed by Russell (1894), Luciani (1894), AndreThomas (1897), and Lewandowski (1903, 1907), as well as with the extensor spasms observed occasionally by Luciani himself (1891; see Dusser de Barenne, 1937, p. 251) and by Lewandowski (1903, 1907) during the deficiency period, following total decerebellation. Stiltztonusstdrke. Rademaker's experiments on the strength of the supporting tonus are much less widely cited, although they disclose an aspect of cerebellar

32 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM function that had been missed altogether by previous investigators. Technically they are extremely simple to perform. When a standing dog is loaded with a burden of given weight, the increased pressure on the skin of the sole of the feet and, above all, the augmented stretching of the flexors of the toes and of all the antigravity muscles will produce an increase in the postural tonus. The strength of the postural tonus will be indicated by the maximum load that the animal will bear before its knees give way.

Figure 8. The effect of complete cerebellectomy in the chronic thalamic dog. 1, 2. Thalamic dog, 3 weeks after decortication. 3, 4. The same animal 46 days after decortication and 6 days after cerebellectomy. Spasticity of the legs (3, 4), opisthotonos, and dorsal flexion of the tail (4) are observed in both the supine (3) and standing (4) positions. The strength of the supporting tonus was shown, however, to be greatly decreased by the cerebellectomy. (From G. G. J. Rademaker, 1931, Das Stehen, Berlin: J. Springer, p. 117, Fig. 79.)

A normal dog is generally able to carry on its back a load approximately equal to its own weight. According to Rademaker, the strength of the postural tonus was not decreased when it was measured a long time after total decerebellation, i.e., during the compensation period of Luciani. Data during the first month following cerebellar ablation—i.e., during Luciani's deficiency period—are not given for the cerebellectomized but otherwise intact animal, but can be found for the thalamic dog, Robbie, which lived thirty-eight days following total cerebellectomy. Six days after total cerebellectomy, the thalamic dog showed a typical picture of spasticity, both in the dorsal and in the normal positions (3 and 4 of Fig. 8). The strength of the postural tonus, measured when the animal was standing on its forefeet with the load on its shoulders, however, was about 10 Kg. in contrast to 15 Kg. supported under the same experimental conditions before decerebellation, although the posture of the thalamic animal showed then no signs of spasticity (1 and 2 of Fig. 8). If the resistance to passive flexion of the limb was tested manually, any pressure on the sole thus being avoided, it was found instead to be stronger after decerebellation. During the following days the

ABLATION EXPERIMENTS 33 spasticity, as estimated by manipulating the leg, decreased, while the strength of the postural tonus increased, a difference confirming the independence of these two effects. We shall comment further upon these experiments when the data on hemidecerebellation have been presented. Everybody would agree that following total cerebellar ablation a dog may show clear-cut signs of hypertonia if placed in a dorsal position or in a hammock or if tested by the routine procedure of manually flexing its proximal joints, even though the strength of its Stiitztonus may be definitely less than in its normal state. Let us suppose that the strength of the supporting tonus goes below the critical level required to support the animal's weight; then an otherwise spastic preparation will show in the standing position the typical sagging which characterizes atonia. Schunkelreaktion. The "swaying reaction" involves the changes in the Stiltztonus produced in one limb by an alteration in the position of the corresponding forelimb or hindlimb. It may be tested in the following way: If, to detect changes in the supporting tonus, the right forefoot of a standing animal is raised passively and allowed to rest in the observer's palm, it will be noted that on moving the trunk toward the right there will be a strong abduction and extension of the right limb. The stimulus for the reflex is the passive abduction of the left extremity, which is bearing the weight of the animal and has been allowed to rest on the table. Conversely, a movement to the left which adducts the left or standing limb will cause a readily detectable reduction of the Stiitztonus in the right limb, which is resting on the hand of the examiner. Immediately after decerebellation the Schunkelreaktion was abolished, but it reappeared within one week (Fig. 9). Rademaker, however, had the impression that in the decerebellate animal less adduction of the standing limb was required to decrease the supporting tonus of the tested limb and, on the other hand, a greater amount of abduction was required to increase the Stiitztonus reflexly. Hence this type of contralateral reflex inhibition of the Stiitztonus was more marked after cerebellectomy. When dealing with the magnet reaction in the hemidecerebellate dog, we shall see another example of increased reflex inhibition of the extensor tonus arising in the contralateral limb (see p. 45); and the significance of these findings in explaining Luciani's atonia will be discussed at the end of this chapter (see p. 98). The changes in the supporting tonus of the hindlimbs elicited by modifying the position of the forelimbs are proprioceptive reactions fundamentally similar to those of the Schunkelreaktion. If the animal is placed with the forefeet on a firm support, such as a table top, and if the hindfeet are allowed to rest on the observer's palm, movements of the trunk forward and backward will change the Stiitztonus in the hindlimbs. Thus if the trunk is moved backward so that the forelimbs slant forward from the shoulder, the hindlimbs extend toward the rear and offer increased resistance to the examiner's hands. Conversely, when the trunk is moved forward, the resistance which the hindlimbs exert to the observer's hands diminishes. These reactions, present in the normal dog, were more lively and less well controlled in the decerebellate dog (Fig. 10). Stemmbeinreaktion and Hinkebeinreaktion. The reactions of the supporting limb (Stemmbeinreaktion) and the hopping reaction (Hinkebeinreaktion) show

Figure 9. The "Schunkelreaktion" after cerebelleclomy. The animal is standing on its left forelimb. The passive adduction of this leg, elicited by a movement of the trunk toward the left side yields a strong decrease m the supporting tonus of the right forelimb (1). The opposite effect (strong extension) is produced on the right limb by a passive abduction of the left forelimb following a movement of the trunk toward the right side. (From G. G. J. Rademaker, 1931, Das Stehen, Berlin: J. Springer, p. 216, Fig. 153.)

Figure 10. The influence of the position of the forelimbs on the supporting tonus of the hindlimbs iollowing cerebellectomy. If the trunk is moved in a caudal direction, the supporting tonus of the hindhmbs is strongly increased (1, 3), whereas the opposite effect is elicited by moving the dog forward (2, 4) The dog, Piccolino, was blindfolded (S, J,). The stimulus facilitating the postural reaction is produced by modifying the position of the forelimbs in relation to the trunk

(From G. G. J. Rademaker, 1931, Das Stehen, Berlin: J. Springer, p. 235, Fig. 169.)

34

ABLATION EXPERIMENTS 35 the modifications of the Stiitztonus of an individual limb produced by changes in the position of the limb itself. Rademaker found that the position of maximum Stiitztonus was the so-called middle position, i.e., with the supporting limb almost perpendicular to the supporting surface and in such relation to the body of the animal that the weight of the trunk may be supported with the least effort. Thus when a foot which is under static tension maintaining the weight of the body in the middle position is moved out of this position by passively moving the trunk in any direction, the Stiitztonus is diminished and the foot is raised and set down again nearer its optimum or middle position. The act of raising and replacing the foot is known as the Hinkebeinreaktion. It may be demonstrated by holding the animal up in such a way that one foot alone maintains most of the weight of the trunk. The trunk is then moved passively one way or another and the limb will automatically be lifted and placed to resume the middle position more nearly perpendicular to the supporting surface on which the animal is being examined. This test lends itself to a quantitative study, for one can compare the number of these reactions occurring when moving along a given length, before and after cerebellectomy, thereby gaining a quantitative idea of the changes in a specific disability. According to Rademaker, the Hinkebeinreaktion was lacking during the first few days of the postoperative period after cerebellectomy. It then gradually returned, but never became normal. The Hinkebein step was delayed and occurred only after a considerable change in the position of the limb. When it finally did occur, the limb was lifted too high and moved an extraordinary distance before it was set down again. Since the length of each step was longer than normal, the number of steps the decerebellate animal took to move its limb along a measured distance was smaller than the number taken by the normal animal. The Stemmbeinreaktion is the increase in tone which is found in a limb as it approaches the middle position. Thus if a dog is placed on an examining table and pushed or pulled gently toward the limb being observed, there is an increase in Stiitztonus as the middle position is reached. This increase can also be demonstrated if the animal is allowed to stand on a tilt table. When the table is tilted toward the limb being tested, the animal executes a Stemmbein, or bracing, reaction, and the Stiitztonus is increased. In the decerebellate dog these reactions were easily elicited and, in fact, seemed exaggerated. They appeared more automatic and less subject to inhibition, particularly during attempts to pull the dogs backward or sideways. It was thought that this exaggeration might be due, in part, to the stance the decerebellate dog habitually assumes, that of abduction and backward extension of the hindleg. b. IN PRIMATES

(1) Unstabilized Deficiency Complete ablation of the cerebellum in the monkey was described by Luciani (1891) , Munk (1906) , Rademaker (1931), and Aring and Fulton (1936) . Extensive ablations, in which all the cerebellum save some remnants was removed, were reported by Ferrier and Turner (1894), Russell (1894), and Lewandowski (1903).

36

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM Luciani's experiments were performed on Macacus cynomolgus. The dynamic symptoms were definitely less intense than those observed in the dog. Neither opisthotonos nor extensor rigidity of the forelimbs was observed; actually a tonic flexion rather than extension was reported. The duration of the dynamic symptoms was also very short; the beginning of the deficiency period took place within a few days, by which time all the forced movements had disappeared. We read in one of Luciani's protocols (1891, p. 136) that the day following the operation one of his monkeys was found off its recovery bed and was clutching on the leg of a table for support. Although movements were accompanied by great ataxia, the cerebellectomized monkey was able to take fruits with one forelimb and to bring them to its mouth. The contrast with the acute decerebellate dogs could hardly be more striking; this observation, although Luciani did not recognize the fact, clearly disposes of all the hypotheses put forward—from Luciani to Rademaker—concerning the origin of the release symptoms in lower mammals as due to irritation, shock, or diaschisis. The deficiency symptoms, on the other hand, were much more like those observed in the dog, and are described by Luciani as follows: "During the period in which the monkeys are unable to stand upright and are compelled by the functional incapacity of their hind-limbs to drag the body along the ground, they can clamber on to the furniture by means of their forelimbs, which are always less asthenic than the hind. Even long after the operation the monkey is incapable of standing erect and of walking in the vertical position on its hind-legs only, as it not infrequently does under normal conditions. "Again the dorsal curvature of the back, due to atony of the extensor muscles of the vertebral column, is more pronounced in monkeys than in dogs, so that in the tracing of the footprints those of the hind-limbs always fall in front of those of the fore-limbs. The animal deviates from side to side in walking, making an undulating line, and if it falls to right or left this is always due to the giving way of one or both hind-limbs, in which atony is predominant. In comparison with a normal monkey, it moves more slowly, and from time to time feels obliged to rest, sitting on its buttocks. "The astasia is most prominent in the neck, but spreads more or less to all the other muscles, as shown by the slight trembling of the limbs each time they are used for isolated movements, such as to carry fruit to the mouth, to catch the insects in the hair, etc. "In monkeys, too, the limbs are raised unduly in walking (dysmetria), owing to disturbed functions of the organs charged with the compensatory processes. This dysmetria is certainly not sensory in origin, because cutaneous and muscular sensibility are not found, with the various methods of investigation which can be employed on animals, to be appreciably disturbed" (1915, pp. 450-451). Ferrier and Turner (1894), who succeeded in keeping one monkey (Macacus rhesus) alive for two months and seventeen days, in their description of the results of cerebellar ablation fully confirmed the observations of Luciani. They commented on the animal's ability to localize the slightest touch on any part of its body the second postoperative day and they reported forcible grasp of the hands and feet within a short time after the ablation and great difficulty in dislodging the monkey from whatever it clung to. Russell (1894) also, in his monkey

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37

experiments, confirmed Luciani's observations and emphasized that "there was an absence of the extensor spasm of the fore-limbs so characteristic of cerebellar lesions in dogs" (p. 857). Lewandowski's description (1903) mainly concerned unilateral ablations (see p. 47). Munk (1906) performed complete cerebellar ablations in his monkeys. He stated that only the flocculus was left, in order to avoid damaging the eighth nerve, but that the floccular pedunculus had been cut. He confirmed most of Luciani's findings, but emphasized that not every movement was abnormal. Actually, according to Munk, the ways in which the monkey utilized its hands for picking up food and bringing it to the mouth, for scratching the different parts of its body, or for catching a fly, were normal. Only when the food was far away, so that the animal had to stretch its arm in order to get it, were Luciani's observations confirmed. This, in our opinion, is an important observation, since it showed that the severity of the cerebellar syndrome is not correlated with the accuracy of the movements performed. Actually the proximal muscles which were impaired are those mainly concerned with posture and with comparatively coarse movements. These findings were the main foundation of Munk's doctrine that the cerebellum is concerned mainly with generalized movements (G&meinschaftsbewegungen), which occur during standing or walking; according to Munk, skilled isolated movements (Einzelbewegungen) would be normal after cerebellectomy. Munk's observations were frequently confirmed and commented upon in clinical works (Murri, 1908, 1915; Holmes, 1917, 1922). While there is no doubt that various voluntary movements are differently affected by cerebellar ataxia, far-reaching physiological conclusions from these findings should be drawn with caution. One should not forget that movements which require the animal to reach out for a faraway object necessarily involve several joints and all the muscles acting on them simultaneously. These are the compound movements of Holmes's analysis (1917, 1922) of cerebellar deficiency in man. The defect will also be compounded so that each component part will show its own error of rate, force, and range of movement; when the individual movements are fused, they will fail to occur in smooth succession. Obviously "the error of the whole movement is relatively greater than the sum of those of its parts." This is what Holmes called decomposition of movement, and movements of this type are the most obviously affected in cerebellar disorders. Rademaker (1931) was mainly interested in cerebellar ablations in dogs, and in his book there is no detailed description of the results of the single complete cerebellar ablation he performed in the monkey. The important paper of Aring and Fulton (1936) will be reviewed in the chapter on cerebellocerebral relations. No complete cerebellar ablations have been described in animals higher in the primate scale than the macaque, though (as will be pointed out) partial lesions have been made in baboons and chimpanzees. (2) Stabilized Deficiency No systematic study of postural reflexes in the totally decerebellate monkey has been reported corresponding to Rademaker's description of these reflexes in

38 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM the dog. The primate does not show the reflexes to the same degree as does the dog; monkeys, moreover, are usually not so amenable as dogs to this type of analysis because of their tendency to resist efforts to test reflex activities. The effect upon the hopping and placing reactions will be considered in a later chapter (p. 338). It was noted that no detectable change in the manifestations of cerebellar ataxia occurred in the monkey during the period from three to six months after cerebellectomy. It is doubtful whether any appreciable change would occur if such a preparation were maintained for a longer period. 3. UNILATERAL ABLATION, OR SECTION OF THE THREE HOMOLATERAL CEREBELLAR PEDUNCLES a. IN SUBPRIMATES

(1) Unstabilized Deficiency Among physiologists who conducted ablation experiments, common practice was to emphasize the effects of unilateral cerebellar ablation. Actually Luciani's doctrine was mainly constructed on the results of unilateral cerebellectomy, since it was believed that a comparison between the postural tonus or the movements of the two sides was equivalent to comparing "two animals of the same breed, age and constitution, one characterized by an almost normal cerebellar innervation and the other one being almost devoid of such innervation" (Luciani, 1891, p. 54). The obvious implication of this concept, which was silently accepted by later investigators, is that the difference between total and unilateral cerebellectomy merely concerns the extent of the muscles involved, not the intensity nor the type of the deficiency symptoms. This is not altogether true, as we shall see later on, and many misconceptions arose from neglecting the fact (see p. 98). Only in von Bechterew's reviews (1909, p. 910) and Bremer's (1935, p. 70) on cerebellar physiology was this important point properly emphasized. There is no doubt, however, that very important observations were made on unilaterally cerebellectomized animals and that cerebellar innervation concerns mainly homolateral muscles. Unilateral cerebellectomy can be performed in three ways: (a) by splitting the corpus cerebelli and the flocculonodular lobe and removing one half; (b) by destroying one cerebellar hemisphere; and (c) by severing unilaterally the three cerebellar peduncles. The results should not be expected to be the same. Simonelli and Di Giorgio (1926, especially pp. 494-511) showed that following chronic unilateral cerebellectomy, performed according to the first procedure, the Purkinje cells of the so-called normal side were actually abnormal throughout the lobus anterior, in the lobus medianus posterior, and also in the lobulus paramedianus, whereas in the cerebellar regions next to the transection the Purkinje neurons were completely absent. The contralateral fastigial nucleus was destroyed. Of course the extent of the lesion was not altogether constant, but these cerebellar ablations cannot be expected to be strictly unilateral. For this reason Dusser de Barenne (1937, p. 241) suggested that hemispheral ablation be performed. With this procedure, however, the extent of the vermian lesion indirectly produced by the surgical operation was still uncertain. Neither will section of the three cerebellar peduncles strictly reproduce the effects of unilateral cerebellectomy, be-

ABLATION EXPERIMENTS 39 cause of the crossing of the ventral spinocerebellar tract and the uncinate bundle of Russell. The lack of histological controls in most of the older experiments, however, makes it impossible to review separately the results obtained with these procedures. They will be considered together in this chapter. Luciani (1891, 1915) stated that the dog, immediately after complete removal of one half of the cerebellum, showed "pleurothotonos, or curvature of the vertebral axis to the side operated on, tonic extension of the anterior limb on the same side with clonic movements of the three other limbs" (1915, p. 432). There was rotation of the head, the eyes, and the whole body around the longitudinal axis from the side operated on to the healthy side. This rotation was the first and the pleurothotonos was the last of the dynamic symptoms to disappear, as they did eight to ten days after the operation, to be followed by the deficiency period. During the deficiency period the dog "is so weak in the muscles of the limbs on the operated side, particularly the hind-limbs, that at first sight they appear paralyzed. In order to move from one place to any other, it is obliged to crawl on the buttock of the operated side, the principal effort being made with the muscles of the healthy side. This inability to stand upright and walk may last four weeks. During this time, however, if the animal can lean the flank of the operated side against a wall it is able to stand upright and make regular steps. Further, if thrown into the water, it keeps itself quite well on the surface, maintains its equilibrium, and swims with perfect coordination." The swimming, however, was not exactly like that of a normal dog: the trunk was not horizontal, the operated side being deeper in the water than the normal side, and the animal tended to swim in a circle toward the sound side. When it was able to walk, it fell constantly to the side operated, owing to the giving way of the limbs on that side. In time this tendency was overcome, mainly by what Luciani again called functional compensation. This consisted of abduction of the homolateral limbs, which made it more difficult passively to flex the joints on the affected side, and of a tendency of the vertebral axis to curve toward the operated side in swimming, which he claimed acted as a rudder overcoming the tendency to swim in a circle. This was the third stage of Luciani's syndrome, the compensation period. Luciani's doctrine was based mainly upon the observation of hemidecerebellate animals during the deficiency period. He believed that all symptoms could be explained by a deficiency of muscular tone (atonia), by a decreased strength of the phasic contractions (asthenia), and by a peculiar kind of tremor and oscillatory movements (astasia). In order to give a faithful account of his results and interpretations, the symptoms he described will be reviewed in the same sequence. Atonia was shown (a) by the lower resistance of the legs of the operated side to passive flexion, the flexion being also more complete than on the normal side, and (b) by the slow, spontaneous flexions of the legs ipsilateral to the cerebellectomized side which occurred when the animal ate while standing, its attention being fully devoted to the food. Its falling toward the operated side was avoided by voluntary movements resulting in the re-establishment of normal posture. The atonia was, of course, much more pronounced during the first few days of the deficiency period, when the animal was unable to stand because its legs

40 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM were unable "to bear the weight of the body on the operated side." Luciani attributed to atonia another symptom, which he called dysmetria and which later was frequently compared with the ataxic gait of the tabetic patient (andatura di gallo, Hahnentntt, cock gait, or goose step). It consisted in lifting the involved legs too high and in their being placed down on the floor unduly hard, so that a characteristic type of walking occurred. He assigned this symptom to atonia, stating that it was due to too rapid a relaxation of the antagonistic muscles because of their lack of tone. This was to become one of the most controversial points in cerebellar physiology, and Luciani (1915) himself conceded that dysmetria might be regarded as an independent fourth symptom of cerebellar ablation. Among the symptoms which Luciani assigned to asthenia, the most important was the tendency of the limbs to give way in walking. This persisted in one animal, which had been trained to stand up on its hindlegs and beg for food, for fourteen months after unilateral ablation of the cerebellum. Luciani also noted that the dog would not attempt to dislodge a clamp fastened to the ear of the operated side with the involved forepaw, while it readily did so with the normal extremity on the unoperated side. Broadly speaking, asthenia, in Luciani's terminology, was a deficiency of strength in the voluntary movements, whereas atonia represented the corresponding deficiency in the postural sphere. Astasia, as defined by Luciani, is a symptom of quite a different order. To quote directly from this author: "In normal limbs the contractions of the muscles are gradual and sustained in character, that is without interruption of continuity, without trembling or oscillation, and with perfect fusion of their elementary impulses. When lying down in its kennel the animal, after removal of half its cerebellum, differs only from the normal animal by a slight and almost constant trembling of the head, which in this posture is the only unsupported part of the body, its position being maintained by the active contraction of the muscles of the neck. When the animal stands it can be seen that the tremor is not limited to the head, but involves the whole body, which oscillates slightly either in the transverse, oblique, or diagonal direction. When it moves slowly this tremor is exaggerated; the movements of the limbs on the operated side and of the vertebral column show a characteristic defect in continuity and stability, owing to the intermittent nature of the contractions, as though the summation of single impulses were imperfect. This defective coordination and unsteadiness is known to clinicians as titubation, since it gives the impression that the patient hesitates to decide, or has difficulty in transmitting the voluntary impulses to the muscles. . . . "The tremor increases and assumes the character of marked rhythmical oscillations when the animal eats some favorite food. . . . The animal is unable to check or arrest them, so that its nose may hit the bottom of the dish or the floor on which the food is placed. "To this group of phenomena, which includes tremor, titubation and rhythmical oscillating movements, we gave the name of astasia for the sake of brevity and owing to their probable common origin" (1915, pp. 443-444). Luciani attempted to determine whether cerebellar symptoms occurred in the sensory sphere, but his conclusions were that cerebellectomy does not affect sen-

ABLATION EXPERIMENTS

41

sation. He noted, to be sure, that soon after operation, when the animal was unable to stand or to walk, tactile responses were absent on both sides, and slightly painful stimuli might evoke no reaction at all, particularly on the operated side. If the dog was tested, however, three or four weeks later, when the cerebellar ataxia was at its maximum, the reactions to contact never failed; they were only slightly delayed on the operated side. Eventually this difference was no longer seen during the compensation period. Luciani also analyzed proprioceptive sensibility. During the earlier period of recovery a tendency for the limbs on the involved side to assume or maintain unnatural positions for a longer period than on the normal side was observed. Because these effects eventually disappeared, he stated that they were not dependent upon the integrity of the cerebellum. This cannot be regarded as satisfactory evidence by modern physiologists, since by this reasoning dynamic symptoms could likewise be dismissed as symptoms of cerebellar deficiency. Russell (1893,1894) made important observations on the effects of unilateral ablations of the cerebellum in the dog. He removed first one lateral lobe, an operation which, while not defined in modern terms of cerebellar anatomy and not subjected to histological control, appears to have been equivalent to an ablation of the lobulus ansoparamedianus of Bolk (lobule H Vila, b, and H VIII of Larsell) plus some lateral portions of the lobulus simplex (lobule H VI) and culmen lobules (H IV and H V) and the flocculus (H X). It is quite likely, however, that lesions, only detectable by histological study, had been inflicted upon the more medial parts of the anterior lobe as well (see also Simonelli and Di Giorgio, 1926). Russell's description of the dynamic period confirmed Luciani's findings. During the first few days the animal was unable to stand. This symptom was due chiefly to "a paresis of the posterior extremities and, to a slighter degree, of the anterior extremity of the same side as the lesion." The paresed limbs were "unable to support the weight of the animal" so that it fell to the same side as the lesion. The description here corresponds very closely to that of Luciani. The British physiologist's observations on the animal's recovery and resumption of walking deserve special attention. He stated: "The animal walks on a wide basis as if the joints were stiff on that side, the extremities being moved like rigid pins, as if they were inflexible and only the pointed digits appear to touch the ground" (1894, p. 833; italics ours). As Dusser de Barenne (1937, p. 251) pointed out, similar observations clearly showing the existence of spasticity were also recorded occasionally in Luciani's protocols. Twenty-six days after a complete decerebellation—i.e., during the typical deficiency period—Luciani's dog Z walked "with stiff limbs, as if they were made of a single piece" (Luciani, 1891, p. 122). These facts were, however, disregarded by Luciani in formulating his theory of cerebellar functions. We believe that they can be simply stated by saying that during Luciani's deficiency period symptoms of spasticity may be intermingled with those of atonia. The occasional spasticity observed during the deficiency period should be correlated with the hyperexcitability of the tendon reflexes, which Russell was the first to describe. On the same side as the lesion, the knee jerk was always

42 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM exaggerated and continued so throughout the period of observation. That on the opposite side, which at first was depressed, changed within one to two days and then also became exaggerated. In the anterior limbs, however, the asymmetries of the tendon reflexes on the two sides persisted, the homolateral being increased and the contralateral remaining approximately normal. These important observations were confirmed by Luciani (1894), who stated that the ipsilateral increase in tendon reflexes was very marked ten days after unilateral cerebellectomy and that this effect slowly faded away. Hence there is no doubt that myotatic reflexes still are hyperexcitable during the deficiency period. This fact provides a further evidence of the mixture of release and hypotonic symptoms which occurs following cerebellectomy. Russell (1894) contrasted the effects of hemispheral lesions with the symptoms resulting from complete midline splitting of the vermis and removal of one half of the cerebellum. The symptoms in the two cases were, in his words, "with one or two exceptions, identical with those which resulted after extirpation of one lateral lobe, except in degree of intensity. With the removal of an increased quantity of the organ there was an intensification of all the symptoms which had been observed after the less severe lesion, and a persistence of them for a greater length of time. So closely did the symptoms agree with those that have already been enumerated, that enumeration of them here would be needless repetition. One point is worthy of note, however, and that is, that the intensification of the symptoms was out of proportion to the increased amount of the organ which was removed, that is, the increased portion of nervous matter removed was small compared to the great intensification of the symptoms. In other words, the larger mass of the lateral lobe of the cerebellum appears to be of less functional importance than the smaller central lobe" (p. 837; italics ours). It is apparent, though not appreciated, that the spastic symptoms which follow cerebellectomy are mainly related to ablation of the vermis. Andre-Thomas's experiments (1897) were performed on dogs, cats, guinea pigs, and rabbits, his results fully confirming those of Luciani. He should be credited with the interpretation that Luciani's dynamic phenomena were actually due to deficiency or lack of cerebellar innervation. This interpretation certainly holds true for the spastic component of the dynamic period (see p. 98); the compulsive movements are probably due to brain stem lesions. Lewandowski (1903, 1907) confirmed, in his hemidecerebellate dogs, Luciani's description of the dynamic symptoms as well as the atonia and astasia occurring ipsilaterally during the deficiency period. He denied, however, the existence of a generalized asthenia, since, he said, the cock gait actually showed an excessive expenditure of muscular energy during voluntary contractions (1903); he conceded, however, that asthenia might occur as a consequence of a defective coordination of the muscles performing a given movement. His well-known controversy with Luciani (1915) was mainly one of a theoretical nature and was centered upon the significance of the deficiency symptoms. Lewandowski thought, with Lussana (1862, 1863, 1885, 1886), that those symptoms were due to an alteration of what he called muscular sense. He was careful to point out, however, that he did not mean necessarily that conscious proprioceptive sensibility

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43

was affected (1903, p. 160), and he conceded that in most clinical cases there was actually no evidence of this (1907, p. 190). The deficiency was due, therefore, to the absence of the unconscious cerebellar elaboration of the proprioceptive messages coming from the muscular or tendon receptors. The best evidence for the alteration of what he called "muscular sense" was provided, according to Lewandowski, by the cock gait and by the failure to correct the abnormal postures which occurred on the cerebellectomized side. To these symptoms Lewandowski ascribed the greatest importance, and he held that astasia, atonia, and asthenia were nothing but the consequence of sensory ataxia (1903, p. 172). Actually, as Sherrington (1900, p. 910) pointed out, "the tabetic is without sensations which the decerebellate possesses," and according to Lewandowski himself, only the unconscious elaboration of the proprioceptive messages by the cerebellum was lacking. Lewandowski's doctrine simply emphasized, therefore, as Bremer (1935, p. 69) pointed out, the obvious hypothesis that the cerebellar regulation of postural tonus and of phasic movements might be driven, reflexly, by proprioceptive impulses. This is indeed a likely assumption and was embodied in the famous Sherringtonian statement (1906, p. 348) that the cerebellum might be regarded as "the chief co-ordinative centre or rather group of centres of the reflex system of proprioception." It is misleading, however, as Luciani rightly pointed out, to call cerebellar ataxia a sensory ataxia. A sensory component may eventually be present in the symptoms of cerebellar deficiency (see p. 344), but no evidence of its existence was provided by Lewandowski. Ducceschi and Sergi (1904), in Luciani's laboratory, and Patrizi (1905) devoted their attention to the "muscular sense" in the hemidecerebellate dog. According to Ducceschi and Sergi (1904), the correction of malpositions is simply delayed, not abolished, on the decerebellate side; abolition was observed only during the first few days, when the animal was unable to stand or to walk. Abolition and delay would simply be the consequence of the disorder of the motor mechanisms. Patrizi (1905) pointed out instead that the tension of muscle spindles might be modified, eventually, by the atonia of the main striate fibers, secondary disturbances of the muscular sense thereby arising. Dusser de Barenne's experiments (1923, 1937) on unilateral cerebellectomy in cats and dogs added no new facts or ideas to those dealt with in the section on total ablation. It is surprising, however, in view of his flat denial of the very existence of atonia, to find that when the animal is able to stand and to walk, "ofters knicken diese Gliedmassen, besonders das Hinterbein, plotzlich ein" (1937, p. 242). The giving way of the knees was actually, according to Luciani, the main symptom of atonia. Dusser de Barenne claimed, moreover, that during the compensation period there was no atonia, whereas the cock gait was still present and actually could be regarded as a permanent symptom. This fact might simply indicate that atonia is compensated earlier than dysmetria and that Luciani's first explanation of the cock gait was eventually inadequate. It does not disprove, however, the existence of Luciani's atonia during the deficiency period. Rademaker (1931) fully confirmed Luciani's description of the release phenomena occurring ipsilaterally during the dynamic period. As Russell (1894) had pointed out, the ipsilateral spasticity decreased and eventually disappeared dur-

44

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

ing the period of stabilized deficiency. It was still present, however, during the phase corresponding to Luciani's deficiency period. That spasticity and atonia are paradoxically intermingled on the cerebellectomized side was shown in Hademaker's dog Fox two weeks after unilateral cerebellectomy had been performed on the right side (1931, p. 87). When the animal was lying supine, the legs of the same side as the lesion were clearly extended. Spasticity and not atonia obviously was the result of cerebellar deficiency in this position. If, however, the Stiitzreaktion was elicited in the normal hindlimb, which showed a very strong extensor response, the spasticity of the cerebellectomized hindlimb suddenly decreased. This inhibition from the receptors of the contralateral hindlimb will, of course, give atonia on the cerebellectomized side when the animal is standing on its feet. This is actually the observation reported by Luciani, and also by Dusser de Barenne (see above, p. 43). Rademaker (1931, p. 87) stated that "wenn die Tiere in diesem Stadium auf beide Hinter- oder auf beide Vorderpfoten oder auf alle Viere gestellt werden, knicken die homolateralen Pfoten ein und die Tiere fallen auf die Exstirpationsseite." Simonelli (1930) recorded a similar observation when he stated that the tonus of the ipsilateral limbs, in the hemidecerebellate dog, immediately faded away as soon as they were confronted with the task of supporting the animal's body. Rademaker's observations brought to light a new fact, which is completely missing in Luciani's work. According to our interpretation of the results of the Dutch physiologist, ipsilateral atonia may be due also to an inhibition from the contralateral, normal side. Herein both the difficulty in detecting atonia after complete decerebellation in lower mammals and the observations that atonia and spasticity may actually coexist during the deficiency period find an easy explanation. Rademaker apparently did not realize the implications of his important findings, for he stated that the existence of Luciani's atonia was disproved by his experiments. Cook and Stavraky (1952) performed unilateral surgical ablations of the cat's cerebellum. Histologically controlled lesions of the left cerebellar nuclei were also made with the Horsley-Clarke technique. These combined lesions amounted to almost complete unilateral cerebellar ablation, only the flocculonodular lobe, the Purkinje cells of which project directly to the brain stem, being spared. Only a few lines were devoted to the description of the symptoms, and most of the abnormalities which were reported are concerned with the tendency to fall toward the normal side during the first week, an observation which may be correlated with rotation, hypertonia, and pleurothotonos described by Luciani during the dynamic period. The data of these authors fully supported the statements of Dusser de Barenne (1923, 1937) and Camis (1928) about the vestibular nature of the rolling movements observed in the dynamic period. The movements were altogether absent when the vestibular nuclei had been spared. (2) Stabilized Deficiency Luciani kept many of his animals for more than a year and found that the symptoms elicited by the unilateral ablation gradually decreased until a background of stabilized deficiency was attained. He made a distinction between organic compensation, which was responsible for the actual disappearance of

ABLATION EXPERIMENTS 45 some of the effects of the cerebellectomy (through the vicarious action of other nervous structures, particularly the remaining portions of the cerebellum), and what he called functional compensation, i.e., the voluntary or instinctive movements that made it possible for the animal to overcome its deficiency in the postural or motor spheres. He attributed to functional compensation the abduction of the homolateral limb and the curvature of the trunk to the side of the lesion, the assumption of which position he believed due to the animal's adjusting itself so that its weight was supported by the normal extremity. He apparently noted increased resistance to passive flexion in the stabilized deficiency state, but he attributed this to the position of abduction which the limbs assumed. The various symptoms which he grouped under the term astasia also persisted to some degree. He made the remarkable observation that during the compensation period it was possible to reproduce clear-cut deficiency effects on the hemicerebellectomized side by injections of morphine. His experiments on the compensatory influence of the motor cortex will be dealt with elsewhere (p. 331). Rademaker (1931) is responsible for the careful analysis of the postural reflexes during the period of stabilized deficiency that follows unilateral cerebellectomy. His observations deserve careful attention mainly because they show how dangerous it is to assume that the symptoms elicited by unilateral cerebellectomy are qualitatively the same (although restricted to one side of the body) as those which follow total ablation. As we saw in the last section, Rademaker himself was not fully aware of this fact, and he denied the existence of Luciani's atonia partly because he overemphasized the results of total cerebellectomy. Luciani, on the other hand, was particularly impressed by atonia because his theory was mainly developed from the results of unilateral cerebellectomy. We have already stated (p. 30) that the supporting reaction and its exteroceptive component, the magnet reaction, are greatly increased following total cerebellectomy. These augmentative effects obviously were responsible for an increase in the postural extensor tonus, or at least in the excitability of the myotatic reflexes, an effect which could not easily be reconciled with Luciani's atonia. Actually Rademaker denied the existence of atonia. Its analysis, following unilateral cerebellectomy, is important, however, because it may help to explain the ipsilateral giving way of the knee described during the deficiency period by Luciani and confirmed by all later investigators. A light touch to the sole of one foot, in addition to yielding a strong ipsilateral increase in the extensor tonus (magnet reaction), decreased the postural tonus in the contralateral limb. This decrease was particularly marked ("besonders deutlich"—Rademaker, 1931, p. 45) on the hemicerebellectomized side (Fig. 11). This reaction obviously occurs when the animal is supporting its own weight, but not when the animal is lying in the dorsal position. Hence the different results found in these conditions are explained. It is interesting, moreover, to note that the modifications of the magnet reaction after cerebellectomy were described by Rademaker in the hindlimbs, in which Luciani's ipsilateral atonia was particularly marked. Another reason for Rademaker's inability to detect Luciani's atonia is the fact that most of his observations were made within the compensation period. That the time factor must be carefully considered is obvious from the following

4C

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

Figure 11. The inhibition of the supporting tonus of the cerebellectomized side elicited by a contralateral magnet reaction. This dog lived more than three years after unilateral cerebellectomy on the right side. The interval after the operation was not stated, but the experiment probably was made during the compensation period. The magnet reaction had an inhibitory effect on the supporting tonus of the contralateral, cerebellectomized limb. The inhibitory response was present also on the normal side, but it was particularly marked on the cerebellectomized side. (From G. G. J. Rademaker, 1931, Das Stehen, Berlin: J. Springer, p. 4,5, Fig. 34.)

observations made by Rademaker. When the knees of the animal gave way, ipsilaterally to the cerebellar ablation, the strength of the supporting tonus also was decreased. This symptom was limited, however, to what Luciani called the deficiency period. During the compensation period a remarkable recovery occurred, and the strength of the supporting tonus was equalized on both sides. Rademaker's results on the dog Fox are reported in tabular form below in order to support this statement. It is apparent that the strength of the postural tonus, which was still slightly decreased one month after ablation—i.e., approximately at the end of Luciani's deficiency period—was normal eight months thereafter. Strength of the Supporting Tonus (Standing Position) in the Dog Fox (Weight Kg. 7.3) Following Right Cerebellectomy Length of Time after Ablation 1 month . 8 months

Kilograms Left Hindlimb

Right Hindlimb

8i/2 10%

ioy2

7

b. IN PRIMATES

(1) Unstabilized Deficiency In Luciani's experiments (1915) the forced movements and postures in the monkey after unilateral ablations were similar to those in the dog. They differed

ABLATION EXPERIMENTS 47 in that there was tonic flexion of the forelimb rather than extension and in that these dynamic phenomena were less intense and of shorter duration. As a result the animal began to move about sooner and demonstrated its deficiencies more quickly, usually within a few days. The monkey avoided falling by strong abduction of the limbs on the affected side and usually assumed an upright posture by grasping onto some object. It prevented the swaying of the head and trunk by resting the head against the wall or the floor. According to Luciani: "The asthenia of the limbs on the injured side is expressed, in addition to the signs already described in dogs, in the less use which the animal makes of them; when a favourite fruit is offered, the monkey always grasps it with the hand of the sound side. "This is not due to paresis of the limbs on the operated side, for when the animal is suspended in the air by a sling round its trunk, and one of the feet is brought near a small table, the latter is strongly grasped with both hands. By pulling gradually on a dynamometer which is fixed to the sling, while the ape is fastened in this way to the leg of the table, it is possible to measure the force by which the animal holds the table; also it will be noticed that first the hand of the operated side and then that of the sound side gives way. "The atonia is shown by the fact that when the monkey is on all fours on the ground, in the horizontal position, the affected side hangs lower, owing to the defective tone in the muscles of the limbs on that side. Sometimes there is slight ptosis of the upper eyelid of the injured side, and a drawing over of the mouth towards the healthy side, when the animal shows its teeth in biting its food. "Finally, the astasia that is expressed in tremor, titubation and rhythmical oscillation is more marked in the monkey than in the dog. Monkeys show tremor not only of the head, but unmistakably in both the fore- and hind-limb of the operated side, whenever these are employed" (1915, p. 445). Ferrier and Turner (1894) ablated one cerebellar hemisphere in Macacus rhesus. They confirmed Luciani's astasia, but stated that they were unable to detect any difference between the two sides with respect to muscular strength as tested "by the force required to detach the monkey from its hold on any object" (p. 730). Hence they denied the existence of asthenia. Luciani's experiments on asthenia in the monkey were confirmed, however, by Lewandowski (1903, p. 158). Ferrier and Turner, moreover, were unable to find atonia "as far as this may be indicated by the state of the knee-jerk on the side of the lesion." This, however, was an unwarranted conclusion, as we have seen in discussion of the modifications of the knee jerk in subprimates (see p. 42). The histological controls in Ferrier and Turner's ablations showed occasional ipsilateral lesions of the nucleus of Deiters. It remained for Botterell and Fulton (1938a, c) to perform unilateral section of the cerebellar peduncles and radical ablation of a cerebellar hemisphere on baboons (Papio papio) and monkeys (Macaca mulatto). These operations were well controlled histologically. The symptoms presented by one baboon, which lived 88 days, and by another one, which was observed for 111 days (but was never reported on in detail), led these authors to the following conclusions with reference to the effects of unilateral section of the three cerebellar peduncles in

48 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM the baboon: "1. ataxia with conspicuous dysmetria, tremor and decomposition of movement on the side of the lesion, i.e., in ordinary movements there were conspicuous errors of rate and range as well as of force and direction; 2. unmistakable hypotonia, more marked than in the macaque, but less marked than in chimpanzee (Botterell and Fulton, unpublished); 3. far more rapid compensation on the affected side than would occur on either side if the whole cerebellum were removed. The compensation was less rapid, however, and ultimately less complete than in the macaque" (1938a, p. 40). Botterell and Fulton (1938a) also give a complete protocol of radical ablation of the left cerebellar hemisphere in a macaque put under observation for thirtythree days, when it was sacrificed for histological study. This study showed that these lesions did not involve the medial portion of the anterior lobe appreciably and that the fastigial nucleus was intact; the ipsilateral vestibular nucleus also was intact. The authors (p. 41) fully confirmed the results which had been reported on the same species of primates by Luciani. Astasia ("extreme degree of tremor"), atonia (on the seventh and seventeenth days "the animal repeatedly fell to the left"), and dysmetria (on the twenty-fifth day "the gait was of an irregular high-stepping, slapping type") were observed. The same operation has not been reported in detail in the chimpanzee but, as indicated above and as will be discussed later, there is progressive hypotonia as one approaches man through the higher primates (Botterell and Fulton, 1938d). (2) Stabilized Deficiency Luciani observed one monkey (Macacus cynomolgus) for as long as ten months after operation. He noted functional improvement during the first two months, but the animal's condition remained stabilized during the following eight months. Abduction of the ipsilateral hindleg and a tendency to utilize the normal foreleg for taking food were the most relevant of the permanent symptoms. According to Botterell and Fulton (1938a), using Macacus rhesus, the hypotonia had already disappeared on the twenty-fifth day. As already stated, Botterell and Fulton's baboons were kept alive for approximately three months. Progressive improvement was noted for about two months, but notes on the sixty-fourth and eighty-second days indicated no improvement as compared with the conditions described on the fifty-fourth day, at which time some improvement had apparently occurred. Neither of these two animals is adequate for the estimation of the chronic effects, since the survival period was too short. 4. BISECTION OF THE CEREBELLUM AND VERMIAN ABLATION a. IN SUBPRIMATES

In the dogs operated by Luciani (1891), complete ablation of the vermis resulted in dynamic symptoms which, as he rightly pointed out (p. 51), were quite similar to those observed following total cerebellectomy. Strong rigidity of the forelimbs and marked opisthotonos were observed. These symptoms lasted seven to eight days. Since spasticity was definitely less marked and lasted only two or three days following hemispheral ablation, the conclusion appears in-

ABLATION EXPERIMENTS 49 escapable that the spastic phenomena observed after complete cerebellectomy are mainly vermian in origin, or at least are related in some way to the surgical ablation of the vermis. Luciani, however, did not take this view, probably because of his misconception regarding the irritative origin of the dynamic syndrome. According to him the symptoms of the deficiency period were of greater importance; they were characterized by asthenia and atonia in the hindlimbs and by astasia in the forelimbs. The functional and the organic compensation was very rapid and brought the animal almost to complete recovery. Following a median vertical section, separating the two lateral halves of the cerebellum from each other, Luciani (1891) found that the symptoms were instead surprisingly small. The dynamic effects were altogether absent, whereas those of the deficiency period were slight and eventually disappeared when the animal walked with all its energy. Trendelenburg confirmed Luciani's results with experiments performed on rabbits (1907) and dogs (1908) and showed that opisthotonos and extensor rigidity occurred only when the neighboring regions of the vermis had been damaged. If forelimb rigidity and opisthotonos are release symptoms, as is now generally believed, the obvious conclusion from these experiments is that the tonic inhibitory influence of the vermis is mediated mainly through direct cerebellifugal pathways or at least that it is not abolished by severing Russell's crossed fastigiobulbar tract. Bremer's stimulation experiments (1922a) fully support this conclusion. Luciani's experiments were confirmed by Russell (1894) on the dog and by Andre-Thomas (1897) on the dog and the cat. The French neurologist was the first to recognize that hyperextension and opisthotonos are due "au defaut ou au manque d'innervation cerebelleuse." b. IN PRIMATES

Ablation experiments of the vermis were reported by Luciani (1891) in Macacus cynomolgus. The animals were observed for more than one year. The important observation was made that the dynamic symptoms were slight and extremely labile, and that they were characterized by tonic flexion of the limbs. Again the correlation between these findings and the paucity of dynamic symptoms following total cerebellar ablation in primates (Luciani, 1891; see above, p. 36) should be stressed. On the third day the flexor hypertonus had already faded away. Astasia was the first deficiency symptom to appear, whereas atonia and asthenia were observed only after fifteen days. Luciani commented upon the fact that in primates, whose dynamic symptoms were slight, the deficiency period was clear-cut, whereas the reverse was true in the dog. The penetrating comparison he drew between subprimates and primates might be considered a forerunner of Bremer's concepts (1935) of the paleocerebellum and neocerebellum, which are discussed on p. 99. But, here again, his undervaluation of the dynamic symptoms and the scanty knowledge prevailing in his time upon the inhibitory portion of the cerebellum prevented him from drawing many important physiological conclusions from facts which he methodically recorded. Luciani's experiments were confirmed by Ferrier and Turner (1894), who performed both vermian ablation and division of the cerebellum in the midline in

50 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM different species of monkeys (Macacus rhesus, Macacus sinicus, and Cercopithecus). The experiments performed by Botterell and Fulton (1938b) represent considerable progress because of the careful histological controls that made it possible to separate the experiments of longitudinal splitting of the cerebellum in which the deep nuclei were seriously involved from those in which the cerebellar nuclei (with the exception of the fastigial nuclei) were not seriously affected. The authors state: "Midline splitting of the cerebellum from anterior to posterior vermis gives rise to extreme swaying and titubation affecting head and trunk but . . . only a relatively slight degree of tremor of the extremities was detected" if only the fastigial nuclei were involved in the lesion (p. 60). When the "interpositus nuclei as well as the superomedial part of the superior peduncles are involved, a more enduring tremor results, in addition to slight equilibratory disturbance. The tremor, however, is not as intense as that which occurs when the dentate nuclei are also involved in the lesion." C. LOCALIZED ABLATION EXPERIMENTS IN MAMMALS 1. INTRODUCTORY REMARKS In 1891 Luciani made some partial ablations of the cerebellum in both dogs and monkeys. He did not systematically investigate the problem of functional localization, but was impressed by the difference between the speed of recovery from these lesions and that from lesions of the entire cerebellum or one half of the organ. Later, referring to his experiments on cerebellar localization, he stated: "Our studies on the cerebellum aimed specially at formulating the general junction of this organ on an experimental basis, and were confined to analysis of the components of the ataxy consequent on more or less complete extirpation of one half, or of the so-called vermis, or of the entire cerebellum. 'From our researches as a whole,' we wrote in 1891, 'it is plain that the different segments of the cerebellum all have the same function. In fact, the loss of the median lobe may in great measure be repaired, i.e. organically compensated, by the lateral lobes; and, generally speaking, whatever the cerebellar mutilation, symmetrical or asymmetrical, circumscribed or extensive, the defect phenomena do not differ intrinsically, but only in intensity, extent, and duration, and in their more or less greater incidence on one or the other side of the body. . . . We cannot, therefore, regard the cerebellum as a collection of functionally distinct or different centres in the sense that each of its segments is in more or less intimate or direct relation with a special group of muscles, or is designed for functions of different character.' "Nevertheless, our investigations resulted in one definite fact which paves the way to the theory of cerebellar localization, viz. that in dogs and monkeys the influence of each lateral half of the cerebellum is mainly direct, that is, is exerted principally on the muscles of the same side" (1915, p. 478). Luciani's work preceded the comparative anatomical investigations of Bolk (1902a, b, 1904, 1906), which paved the way for many investigators who subsequently made regional ablation experiments. During the first decade of this century cerebellar physiology was dominated by Bolk's concepts, and experiments were essentially devoted to finding out somatotopic localization within the

ABLATION EXPERIMENTS 51 cerebellar cortex. The problem was believed to be essentially the same as that of the representation of the different muscular districts within the Rolandic area. Van Rijnberk, who worked for many years in Luciani's laboratory in Rome, provided a great stimulus to these endeavors, both with his experimental contributions as well as with four excellent reviews of cerebellar physiology (1908a, b, 1912, 1925a, b, 1931). Edinger (1910) and Comolli (1910) suggested an entirely new approach to the problem of cerebellar localization. The distinction between paleocerebellum (vermis and flocculus) and neocerebellum (the rest of the cerebellum), notwithstanding the criticisms raised on both anatomical and physiological grounds, had tremendous historical importance, since the suggestion that the paleocerebellum was concerned with regulating the postural tonus and the neocerebellum with influencing cerebrocortical activities meant, as Bremer (1935) rightly pointed out, that "la localization . . . n'est plus musculo-regionale, c'est une localization de fonctions" (1935, p. 115). We may add that in Bolk's approach the efferent aspect of cerebellar localization was emphasized, whereas the afferent aspect was stressed by those who followed the lead of Edinger and Comolli. Actually the first clear-cut evidence of localization of different functions within the cerebellar cortex was implicit in the discovery made by Lowenthal and Horsley (1897) and by Sherrington (1898) that stimulation of a limited area of the cerebellum inhibits decerebrate rigidity (see p. 113). The same concept was stressed a few years later by Pagano (1902, 1904) following his experiment of local curarization (see p. 110). Only after the work of Edinger and Comolli, however, was the anatomical background of such localization laid. It was supplemented by Ingvar's concept (1918, 1928a) of the three divisions of the cerebellum dominated respectively by vestibular, spinal, and corticopontocerebellar fibers. It remained for Bremer to give the conclusive experimental demonstration (1922a) that the area yielding inhibition of extensor tonus coincided with the spinal story of the cerebellum. Bremer also formulated a physiological doctrine (1935) based upon the distinction between paleocerebellum and neocerebellum. Subsequently Herrick (1924) and particularly Larsell (1937), carrying forward the comparative anatomical approach of Edinger and Comolli, developed our present concepts of cerebellar morphology. Modern localization theories are based mainly upon the concept of the localization of different functions, although a somatotopic localization within limited areas of the cerebellar cortex (anterior lobe and lobulus paramedianus) may now be regarded as established, if some restrictions are accepted. There is little doubt, at present, that different functions are represented within the histologically homogeneous cerebellar cortex; modern investigators have given up attempts to find a single formula to synthetize the function of the cerebellum as a whole. There are few fields of neurology in which different approaches have been so beautifully integrated as in investigations on the cerebellum. Morphology (comparative anatomy, embryology, fiber connections), physiology (ablation and stimulation experiments, electrophysiology), and pathology (morbid anatomy and clinical symptomatology)—each has contributed in different ways to the development of present concepts of cerebellar localizations. We refer to Larsell's

52 PHYSIOLOGYANDPATHOLOGYOFTHE CEREBELLUM forthcoming monograph (1958) for all anatomical data, and in the following section only the ablation experiments will be reviewed.

2. ABLATION OF THE FLOCCULONODULAR LOBE Although, historically, the flocculonodular lobe was the last to be studied by isolated ablation experiments, it is discussed first because of its phylogenic relations. Following the comparative analysis of Larsell, presented in final form in the companion volume of this work, it was demonstrated that the posterolateral sulcus was the fundamental landmark in cerebellar morphology in mammals as well as in lower forms (Larsell, 1934, 1937; Larsell and Dow, 1935). In 1936 it was shown that this subdivision has significance so far as the fiber connections from the posterior parts of the mammalian cerebellum are concerned (Dow, 1936). It then became apparent that ablation experiments restricted to this area should be made since it is dominated by vestibular connections both afferent and efferent. a. LOCALIZED ABLATION INCLUDING, BUT NOT RESTRICTED TO, THE VESTIBULAR PART OF THE CEREBELLUM

Ablation experiments performed on the posterior vermis prior to the work of Larsell will first be described briefly, since the symptoms reported obviously are not related alone to the vestibular area of the cerebellum. A detailed account would be mainly of historical interest and can be found in van Rijnberk's monographs (1908a, b, 1912, 1925a, b, 1931). Ferrier (1876) and Ferrier and Turner (1894) reported that following ablation of the posterior vermis in the monkey the animal was seen on several occasions to "fall over on its back" (1894, p. 733), and Russell (1894) confirmed their observations. The ablation experiments of Adamkiewicz (1904, 1905) and Pagano (1904) were performed respectively on rabbits and dogs, but because of the lack of anatomical controls were of no value for a study of functional localization. Rothmann (1913a) was the first to perform, on dogs, a complete and isolated ablation of Bolk's lobulus medianus posterior, including therefore the uvula (lobule IX) and the nodulus (lobule X). Most of the symptoms he reported (inability to walk, opisthotonos) disappeared within a few days; weakness and ataxia of the hindlimbs were the only long-lasting effects. They were observed also following isolated ablation of the uvula (lobule IX) and of the pyramis (lobule VIII). Andre-Thomas and Durupt (1914, pp. 47-52) performed on the dog Rip an incomplete ablation of Bolk's lobulus medianus posterior; the anatomical controls showed that the white matter underlying the uvula and nodulus had been severely damaged. The main symptoms were opisthotonos and a tendency for the animal to fall over on its back. The same symptoms were reported by Ingvar (1918), who destroyed the pyramis, the uvula, and, in one instance, also the nodulus in rabbits. Here again the animals showed a marked tendency to fall over on their backs. This symptom impressed Ingvar so much that he regarded the lobulus posterior medianus as the center of the muscular activities that prevent the animal from falling backward. This naive conception was severely criticized by Simonelli (1921), who performed similar experiments on dogs, cats, and rabbits. Following destruction of

ABLATION EXPERIMENTS 53 Ingvar's lobulus posterior medianus (pyramis, uvula, nodulus: lobules VIII to X) he observed, during the dynamic period, many tonic fits characterized by opisthotonos with extension of the forelegs and a tendency to fall backward. He made, however, the important observation that these symptoms depended upon the tonic extension of the neck and could be prevented if the head was passively flexed. Hence Ingvar's symptoms were nothing but the consequence of the opisthotonos, a symptom produced (as Pollock and Davis (1923) showed two years later) by a release of tonic labyrinthine reflexes. The structures which had been destroyed were not directly related, therefore, to the muscles of the trunk or of the limbs. Simonelli (1921) criticized Ingvar's experiments for the lack of histological controls and Ingvar's theory for having been founded upon dynamic symptoms, i.e., on effects which eventually disappeared during the deficiency period. The first criticism undoubtedly was well founded, and it is important to emphasize that no histological controls were made in most of the experiments reported so far. Simonelli (1924) was the first to perform accurate histological controls with cell stains, and his results were indeed both striking and unexpected. He showed that following lesions of the lobulus posterior medianus, the fastigial nuclei were almost completely destroyed and also that the dentate nuclei had been damaged, possibly because of circulatory disturbances. Apparently most of the cerebellum and certainly the fastigial neurons relaying impulses arising in the anterior lobe had been destroyed both in the experiments of Ingvar (1918) and in Simonelli's own earlier experiments (1921), and both opisthotonos and hyperextension of the forelegs could easily be explained by these collateral lesions. Accordingly Ingvar's physiological theory (1918, 1923) crumbled, but crumbled because of its faulty experimental basis, which was disproved by Simonelli (1924), and not—a point that should be clearly understood—for having been built upon the symptoms of the dynamic period. Actually opisthotonos and rigidity of the forelimbs are the most important signs of cerebellar deficiency localized in the anterior lobe (see p. 56). Botterell and Fulton (1938b) described monkey experiments in which the posterior vermis was involved, but since there was also involvement of other posterior cerebellar structures, the deep nuclei, and of a part of the superior cerebellar peduncle, this experiment is not of great value in analyzing the effects of injury to the flocculonodular lobe. The symptoms resulting from ablation of the nodulus were inextricably mixed, in all the aforementioned experiments, with those produced by excision of nonvestibular parts of the posterior vermis. The same difficulty is met with in any attempt at reviewing the older literature on the flocculus. Rothmann (1913b), Andre-Thomas and Durupt (1914), Troell and Hesser (1922), Kuzume (1926), and Mussen (1927), who were interested in this lobulus, reported experiments on the "formatio vermicularis," on the rabbit's "lobulus petrosus," or simply on what they called the "flocculus." It is sometimes obvious and always very probable that other structures, and above all the paraflocculus, were encroached upon; and in many instances the lesions said to involve the flocculus (lobule H X) actually were limited to the paraflocculus (lobules H VIII, H IX).

54

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

b. ISOLATED ABLATION OF THE NODULUS, LOBULE X OF LARSELL

(1) In Subprimates Ablation of the entire nodulus was performed by Bard, Woolsey, Snider, Mountcastle, and Bromiley (1947) in experiments devoted to investigating the nervous mechanisms of motion sickness. They observed that the dog still was easily susceptible to the emetic effect of motion after removal of both temporal lobes, of both frontal poles (including the somatic motor and sensory areas), or of all the neocortex except one or both frontal poles. One animal was kept alive for fifty-three days after decerebration by the removal of a wedge of tissue just rostral to a plane between the anterior colliculi. During the interval between the twenty-sixth and fifty-third days the dog vomited when subjected to motion in the swing after three to nine minutes, a result indicating slightly more susceptibility than before decerebration. Complete cerebellectomy was then performed on another dog that had been previously shown to be highly susceptible to the emetic effect of motion: the animal was kept alive for seventeen months after the operation, and no vomiting was elicited even after sixty minutes of revolving in the swing, on fifteen different tests. Further restriction of the areas of ablation by extirpation of various portions of the vermis behind the primary fissure demonstrated that the nodulus and the lower part of the uvula include the essential cerebellar mechanism involved. The experiments were finally controlled by giving the animal apomorphine, after it had been made immune to motion sickness; this drug readily induced vomiting. These experiments were reviewed by Tyler and Bard (1949) and confirmed by Wang and Chinn (1952, 1953, 1956). They confirm other evidence of the intimate relation between the nodulus and adjacent part of the uvula to the vestibular apparatus. Manni (1950b) made unilateral and histologically well-controlled lesions of the nodulus and found alterations in or sometimes abolition of the otolithic reflexes on the ipsilateral eye. Compulsive circling and rolling movements, nystagmus, and abnormal positions of the head or the trunk also were observed after the operation, but these dynamic symptoms lasted for a short time only; they remained, moreover, after bilateral labyrinthectomy. The alteration in the otolithic reflexes lasted, instead, for a longer period; after two weeks they had disappeared, but could still be observed under slight ether anesthesia. This technique of demonstrating permanent effects which are hidden by compensation mechanisms is one which was used by many of the older cerebellar physiologists. It could be used to advantage more often in present-day experimentation. Disturbances similar to those mediated by the nodulus were elicited by unilateral lesions of the lingula, but not by unilateral destructions of the lower part of the uvula. Cook and Stavraky (1952) performed unilateral ablations of the nodulus and of the lower part of the uvula in four cats, in two of which the ipsilateral flocculus also was removed. They stated that the effects were "essentially similar to those seen after the ablation of the cerebellar nuclei" (p. 79), i.e., that "the cats were ataxic on the side of the lesion but leaned and staggered to the opposite side for one to three weeks." This is a surprising statement since its obvious correlate

ABLATION EXPERIMENTS 55 would be that the Purkinje neurons of the corpus cerebelli, which project upon the nuclei which had been destroyed, have no important functions to perform. Chambers and Sprague (1955a and b) have not performed ablations limited to the vestibular parts of the cat cerebellum, but following observations of the behavior of animals with lesions of the pyramis, uvula, and nodulus (lobules VIII, IX, and X of Larsell) plus secondary fastigial nuclear damage, have noted a marked resemblance to the effects of anterior lobe lesions. They have claimed, therefore, that there is little justification for a differentiation of the various parts of the vermis—a point of view which is incompatible with the findings in the primate cerebellum. Their own protocols, so far as the differences between lesions in the folium and tuber vermis (lobules VI and VII of Larsell) and the anterior and posterior parts are concerned, contradict their conclusions as to the physiological unity of the vermis. (2) In Primates Dow (1938b) showed that ablation of the nodulus and lower part of the uvula in the monkey, baboon, and chimpanzee resulted in a syndrome of disequilibration consisting of oscillations of the head and neck, falling, and a titubating ataxic gait which lasted for over a month. During the first days the animals were reluctant to move and preferred to cling to the cage, generally in a corner. Despite the grave disturbance in movements of the body as a whole, there was no tremor in the extremities, no disturbances of reflexes, and no hypotonia. The excision of much larger portions of the cerebellar cortex elsewhere failed to produce this syndrome. These excisions included the pyramis in three animals, the folium and tuber vermis (lobule Vila of Larsell) in another, and these lobules plus a portion of lobules VI and V (the upper culmen) in another. In two monkeys the operative procedure, including an opening into the fourth ventricle, failed to precipitate the syndrome. The syndrome as described was transient, and within five to eight weeks the animals could not be distinguished from normal monkeys so far as cage activities and various clinical tests were concerned. This may be explained by the fact that in no case was a complete destruction of all the lobules that receive vestibular fibers accomplished. Dow's results were confirmed by Carrea and Mettler (1947). Their monkeys presented typical patterns of disequilibrium and were unable to stand or to walk within the first forty-eight hours after operation; they became permanently unable to run. Asymmetrical lesions or ablations purposely designed to involve the lateral one half of the nodulus and lower part of the uvula caused a less-enduring disturbance of equilibrium than did the removal of the same areas bilaterally (Dow, 1938b). In addition, however, such preparations showed a disturbance of posture and movement which was the reverse of that following unilateral labyrinthectomy in the primate (Dow, 1938a, and others) or following damage of the intramedullary portion of the juxtarestiform body (Ferraro and Barrera, 1936a, b, 1938). After these asymmetrical lesions of the vestibular part of the cerebellum there was rotation of the head with the occiput to the opposite side of the lesion;

56 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM moreover, the animal in climbing tended to rotate around the longitudinal axis of its body away from the side of the lesion. While the disequilibration syndrome was not seen if either symmetrical or asymmetrical cerebellar ablations of this type were performed after the monkey had recovered from a bilateral labyrinthectomy, the rotated position of the head and the spiraling in climbing were still present (Dow, 1938b). The rotation of the head continued about four weeks after these unilateral uvulonodular lesions were made. Complete unilateral ablation of the nodulus and uvula, combined with a unilateral destruction of the flocculus of the same side, has never been performed. C. ISOLATED ABLATION OF THE FLOCCULUS, LOBULE H X OF LARSELL

(1) In Subprimates Acute unilateral ablations of the flocculus were performed by Manni (1950b) in the decerebrate or thalamic guinea pig. Histological controls showed that the neighboring eighth nerves and the brain stem nuclei were undamaged. With the exception of compulsive circling movements and rolling movements, which were not observed, the symptoms were similar to those elicited by unilateral lesions of the nodulus in the same animal. The most important effects were the alterations in the otolithic reflexes of the eyes, a symptom which apparently characterizes any lesion of the floeculonodular lobe and which was never observed following excisions within the corpus cerebelli (Manni, 1950b). (2) In Primates Carrea and Mettler (1947) succeeded in damaging the flocculus alone in the monkey. Bilateral lesions produced disorders of posture and a syndrome of disequilibration not unlike the effects of the symmetrical uvulonodular lesions described by Dow (1938b). The patterns of disequilibrium were less pronounced, however, and more transient in the monkeys with floccular lesions than in those with uvulonodular ablations; significant differences in the manner of sitting, standing, and walking were nevertheless reported. No unilateral lesions of the flocculus have been made in primates. 3. ABLATION OF THE ANTERIOR LOBE OF THE CORPUS CEREBELLI a. TOTAL ABLATION WITH THE REST OF THE NERVOUS SYSTEM INTACT (1) In Subprimates Rothmann (1913a) was the first completely to remove the anterior lobe in the dog. He showed in well-documented chronic experiments that immediately after extirpation of the lobe a strong opisthotonos of the head and trunk occurred, with a marked extensor hypertonus of the limbs. The symptoms, therefore, were the same as the release effects described by Luciani during the dynamic period following total cerebellectomy (see p. 24) or complete vermian ablation (see p. 48). It is likely that this part of Luciani's dynamic syndrome was in some way correlated with the extirpation of the anterior lobe. After about three days, only occasional fits of opisthotonos, with a tendency to fall backward, were observed by Rothmann; they occurred during strong

ABLATION EXPERIMENTS 57 voluntary movements, such as those performed when the animal made an attempt to stand or to eat. They disappeared altogether one or two days later, and about one week after the operation the animal was again able to walk; it stood, however, hunch-shouldered ("Der Kopf sitzt in den Schultern"—p. 393), a position which was rightly regarded by Bremer (1935, p. 85) as a cerebral reaction aimed at counteracting a latent tendency to opisthotonos and to falling backward. The gait was ataxic, and clear-cut tremor as well as strong oscillations of the head and of the trunk occurred. Rothmann (1913a) was able to keep his dogs with anterior lobe ablation for as long as five months. In one of them he subsequently removed Bolk's lobulus medianus posterior, corresponding to Larsell's lobules VII to X, twenty-seven days after having excised the cerebellar cortex of the anterior lobe. Immediately thereafter he again observed strong opisthotonos and tonic extension of the forelimbs. The evolution of the symptoms was approximately the same as that observed after the first operation, although the recovery was somewhat delayed. Two years later (1915) he reported the results of his histological controls, which showed clear-cut atrophy of both fastigial nuclei. The German physiologist was right when he emphasized that the extensor rigidity of the forelimbs occurring after ablation of the anterior lobe was possibly strengthened, through Magnus reflexes, by the opisthotonos. This, indeed, was proved to be true by Simonelli (1921) and by Pollock and Davis (1923). But he was almost certainly wrong when he claimed that his experiments confirmed Bolk's suggestion that the anterior lobe was connected only with the head. Actually the atonia of the masticatory muscles, on which he so strongly insisted, was disproved by Connor (1941), and his ideas about a laryngeal center were not accepted by later investigators (see p. 61). It is now easier to understand the great significance of the symptoms Rothmann obtained after the second ablation, which removed the vermian part of the posterior lobe of the corpus cerebelli and the nodulus. The symptoms resulting from a total destruction of the posterior vermis have been reported several times (see above, pp. 52-55), and have been analyzed recently by Chambers and Sprague (1955b). The syndrome is strikingly similar to that produced by ablation of the anterior lobe. When the ablation of the posterior vermis was performed on an otherwise intact animal, however, it might be objected that the opisthotonos and the extensor rigidity could be related to the anatomical or functional lesion of the efferent pathways arising from the vermal cortex of the anterior lobe or to the destruction of their rostrofastigial relays. This explanation obviously cannot account for the symptoms observed by Rothmann following the second operation. His experiment beautifully showed, (a) that the spastic symptoms characterizing the dynamic period could not be exclusively explained by the ablation of the anterior lobe, and (b) that some recovery of the inhibitory functions of other cerebellar structures occurred between the two operations, a finding which might be regarded as a good example of Luciani's organic compensation. Snider and Woolsey (1941) investigated the influence of simultaneous ablation of the anterior lobe of the cerebellum and of the pericruciate areas of both

58 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM cerebral hemispheres in the cat; they reported that in their preparations the releases from cortical and cerebellar inhibition were "summated, to produce an intensively exaggerated antigravity attitude." The attitude persisted "with little diminution in intensity for several days," an interesting observation which showed that the earlier recovery of Rothmann's dogs was due also to cerebrocortical compensation. Their results were confirmed by the electromyographic investigations performed on cats by Lindsley, Schreiner, and Magoun (1949). Rothmann's results were confirmed by Connor (1941) and by Bickers, Peterson, and Scherrer (1949). Connor, however, disproved Rothmann's statement about the atonia of masticatory muscles. The description of Connor's results is quoted by Fulton (1949), in whose laboratory the experiments were made: "When the entire anterior lobe, including the culmen, centralis, and lingula, is removed . . . the animal passes into extreme opisthotonos, the pattern of reaction corresponding closely to that of the anterior lobe pigeons. The jaws are tightly closed, and during the first week the animal has periodic seizures of extreme head retraction. When supported by the abdomen, positive supporting reactions identical to those described in Rademaker's dogs are strongly developed. Such a lesion incapacitates an animal for one to two months, but when gradually he regains his feet there is no sign of swaying or disturbed equilibrium, such as one encountered with lesions of the flocculonodular lobe, and voluntary movements were performed without tremor" (p. 118). Chambers and Sprague (1955b) recently described the results obtained on cats following total destruction of the anterior lobe "back to the primary fissure and including the rostral one-third of both fastigial nuclei and the rostral poles of the interpositus nuclei" (p. 657). Rothmann's results were fully confirmed. The opisthotonos disappeared by the seventeenth postoperative day, and even on the seventy-sixth to the eightieth days "walking was hesitant, in a low crouch with marked ataxia, accomplished with great difficulty and then only for a few steps" (p. 658). (2) In Primates Fulton and Connor (1939) were the first to extirpate the anterior lobe in primates. Following total ablation (lingula, lobulus centralis, and culmen, i.e., lobules I to V of Larsell) in the macaque, they observed disturbances in the postural sphere, with an increase in the tendon reflexes, pronounced and enduring lengthening and shortening reactions, and exaggerated positive supporting reactions. Gross disturbances in coordination also were reported, with wide errors in range and direction in all four extremities and in head movements, severe nodding and weaving of the head in all planes, and a pronounced static tremor in all four extremities. They also described a disturbance of equilibration, with inability to maintain balance on a horizontal bar while blindfolded. The syndrome of disequilibration was found by more restricted ablations to be due to the lingula alone (Larsell's lobule I), while the other symptoms were the results of ablation of the lobulus centralis (lobules II and III) and of the culmen (lobules IV and V). Connor and German (1941) again described the effects of anterior lobe abla-

ABLATION EXPERIMENTS 59 tion in monkeys and also in cats and dogs. They reported "extreme opisthotonos, strongly hyperactive reflex of stance." The validity of this statement for primate and man was challenged in the discussion of the paper by Ferraro, who stated that he never had seen a release of extensor mechanisms following ablation of the anterior lobe in monkeys; Penfield emphasized that no extensor rigidity occurs in man when the anterior lobe has been damaged or destroyed by a tumor or by surgical operation. Connor conceded in his reply that "the syndrome in the monkey is distinctly less intense and of much shorter duration," although "qualitatively identical with that in the dog." Fulton (1949), however, reviewing the results of Soriano and Fulton (see below, p. 63), stated that "unlike the dog, the monkey does not exhibit strongly developed positive supporting reaction when the entire lobe is removed." None of the papers dealing with total anterior lobe ablation in primates has been published to date in more than abstract form. It would appear that further clarification is still needed on what the results of complete anterior lobe ablation in the monkey are. Rigid histological control of the possible damage to the underlying deep nuclei is extremely important. Simonelli (1914a, b, 1922, 1924) found histological evidence of nuclear damage in some of his corticocerebellar ablations, even though the lesion was well separated from these structures on gross inspection, and his results were confirmed by Luna (1918). The atrophic changes were attributed by Simonelli to secondary vascular changes. This may be a factor of considerable significance in explaining the divergent results in the reports of the effect of ablation of the anterior lobe in the monkey. There are no reports of the operation in the chimpanzee. Carrea and Mettler (1947) made lesions in the anterior lobe in the monkey, but no complete ablations were reported. They did not find any manifestations of extensor hypertonus or opisthotonos after ablations of the anterior lobe or of the "hemispheral cortex" of the anterior lobe and the lobulus simplex (lobules H III, H IV, H V, and H VI). Although there may be uncertainty whether some release of the postural mechanisms or none at all occurs following total ablation of the anterior lobe in primates, tonic inhibition from this cerebellar area appears to be definitely less strong in the monkey than in lower mammals. This observation deserves a comment. It may be true that the function of the anterior lobe is basically different in the primates; i.e., it may facilitate instead of inhibit postural extensor tonus. The stimulation experiments of Snider and Magoun (1949), discussed on p. 126, actually may support this point of view. Another interpretation is supported, however, by the following experiment of Soriano and Fulton (1947). They stated: "In the rhesus macaque, unlike dog and cat, complete ablation of the anterior lobe of the cerebellum fails to cause marked augmentation of the positive supporting reactions with spasticity. If, however, ablation of the anterior lobe is combined with an extirpation of areas 4 and 6 of the cerebral cortex, conspicuous and enduring spasticity ensues in the extremities opposite to the precentral lesion" (italics ours). These striking differences between lower mammals and primates in the results obtained from ablation experiments should be correlated Avith differences in the

60 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM effects of total cerebellectomy upon them. In the monkey the dynamic symptoms which occur following total cerebellectomy or vermian ablation are of lower intensity and shorter duration (Luciani, 1891; see above, p. 36). These differences between species are good evidence, although indirect, that the postural release observed during the dynamic period is actually a deficiency symptom, related to the sudden interruption of the tonic inhibitory influence of the anterior lobe. b. TOTAL ABLATION IN THE THALAMIC OR DECEREBRATE PREPARATION

Thiele (1905) and Weed (1914) reported that ablation of the anterior lobe in the midbrain cat yielded a strong increase in decerebrate rigidity, but their necessarily acute experiments were open to many criticisms on technical grounds. During the years 1922 and 1923 three fundamental papers were published on these problems, by Bremer (1922a), Camis (1922a, 1923), and Pollock and Davis (1923). These contributions, and the paper published by Bremer and Ley (1927), provide the bulk of our present knowledge on the tonic influence of the anterior lobe. Bremer (1922a) found that the rigidity of the decerebrate cat strongly increased following ablation of the anterior lobe. In collaboration with Ley (1927) he described what he later (1932) called "rigidite de decerebration sans decerebration." Following ablation of the anterior lobe in the acute thalamic cat, Bremer and Ley found the typical patterns of extensor rigidity in a preparation showing the pseudoaffective and righting reflexes which are normally abolished following decerebration (Fig. 12). Their histological controls showed that the brain stem and particularly the red nuclei were intact. Bremer and Ley's experiments were confirmed by Simonelli (1930, p. 310) in one of his thalamic cats and later by Pancratoff (1938). They are fundamental in the physiology of the anterior lobe. The presence of the righting reflexes clearly showed that the rigidity was not due to a diaschisis of structures belonging to the upper brain stem, whereas the histological controls disposed of the hypothesis that occasional midbrain lesions might have been the real origin of the extensor rigidity. It is surprising to note that in 1931 Rademaker (p. 367) still insisted on these causes of error. The other possible objection was that the irritation of cerebellar fibers facilitated the extensor tonus. This was disproved by Camis (1922a, 1923), who showed that cooling of the anterior lobe elicited a strong increase in extensor rigidity in the decerebrate cat or dog. A movement of progression (stepping reflex) occurred during the increase in decerebrate rigidity. Camis's results were confirmed by Moruzzi (1949). The same increase in extensor rigidity was obtained by the injection (Magoun, Hare, and Ranson, 1937) or local application (Dow, 1938c) of cocaine. Hence the irritation hypothesis may be ruled out, and the observation made by Pollock and Davis (1923) that the extensor rigidity after anemic decerebration is stronger than that following intercollicular transection is easily explained by the fact that the anterior lobe was included in the anemic area. The increase in decerebrate rigidity following anterior lobe ablation was con-

ABLATION EXPERIMENTS

61

Figure 12. Extensor rigidity elicited, by ablation of the anterior lobe of the corpus cerebeUi in the acute thalamic cat. Extreme extensor rigidity after destruction of the anterior lobe, with conservation of the righting and pseudoaffective reflexes. The red nuclei were shown to be histologically normal. (Photograph reproduced by the kind permission of Professor F. Bremer. See F. Bremer and B. Ley, 1927, Recherches sur la physiologic du cervelet chez le pigeon, Arch, internat. de physiol., 25:58-95, Fig. 9.)

firmed by Moruzzi (1935b), Stella (1944a and b, 1946), Terzuolo and Terzian (1951a and b), Sprague and Chambers (1953), Terzian and Terzuolo (1954), and Granit, Holmgren, and Merton (1955). Their results will be reviewed elsewhere in this monograph. C. PARTIAL ABLATION

(1) In Subprimates Rothmann (1913a) found that both isolated ablation of the culmen (Larsell's lobules IV and V) and of the lobulus centralis (lobules II and III) were followed in the dog by a slight tendency toward opisthotonos. After ablation of the lobulus centralis he also reported that there were atonia of the masticatory muscles, abnormalities of the vocal cords, and an absence of barking during the first six to eight weeks. The same observation had been reported by Lourie (1910) after ablation of the superior vermis and by Katzenstein and Rothmann (1911, 1912). Following Bolk's ideas, Rothmann thought that the culmen was a center for the muscles of the neck, whereas the masticatory and laryngeal muscles would have been represented within the lobulus centralis. These speculations were ill founded, since after total cerebellectomy barking is not abolished (Lewandowski, 1903; Munk, 1906), and no alterations were observed by Grabower (1912) and Bender (1927, 1928) in the laryngeal movements after ablation of Rothmann's "barking" center as well as of other cerebellar structures. Bremer (1922a) and Bremer and Ley (1927) stated that the unilateral ablation of the anterior lobe in the decerebrate cat produced an ipsilateral increase

62 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM in the extensor tonus of the same side. Camis (1923) confirmed Bremer's results by cooling unilaterally the anterior lobe of decerebrate cats or dogs. Ferraro and Davidoff (1931) performed localized ablations of the culmen in the cat. The acute symptoms were not reported; the lasting effects, which were present as long as one year after the operation, were dysmetria of the ipsilateral foreleg and a certain amount of shaking of the head. Manni (1950a) performed, in the intact guinea pig, unilateral and very superficial ablation of the culmen (i.e., of the caudal part of the anterior lobe, lobules IV and V of Larsell) and of the declive (i.e., the vermian part of the lobulus simplex, lobule VI). He was unable to find clear-cut postural asymmetries. Chambers and Sprague (1955a) aspirated unilaterally the medial (vermian) part of the anterior lobe in two cats and observed them respectively for 14 and 42 days. These authors observed "extension and abduction of the ipsilateral limbs and flexion and adduction of the contralateral legs with concavity of the head and neck toward the side opposite to the lesion" (p. 116). Rothmann's release syndrome was reproduced in another cat (survival 12 days) by destroying totally and bilaterally only the vermal cortex of the anterior lobe, including the rostral one half of both fastigial nuclei. "The animal could stand alone on the fifth and sixth postoperative days and take a few steps with a broad base, high in forequarters, low in hind, tail dorsiflexed" (Chambers and Sprague, 1955b). With further experiments on cats, Chambers and Sprague (1955a) showed a striking difference between the effects of ablation of the medial (vermian) portion of the anterior lobe and of ablation of the intermediate portion which projects to the nucleus interpositus.* It is, according to Sprague and Chambers (1953) and Chambers and Sprague (1955a), only the medial part of the anterior lobe which is responsible for the release of the ipsilateral extensor tonus. The caudal 1 to 4 folia of the hemispheral part of the anterior lobe (Larsell's lobule H V) were chronically destroyed in four cats. Chambers and Sprague (1955a) stated that during the first days the ipsilateral foreleg "was frequently held flexed, and in the stepping sequence it was placed gingerly and lifted suddenly again as if the bars were hot" (p. 117). These symptoms were transient, but the animals showed throughout the survival period (up to 159 days) "a persistent impairment of the ipsilateral foreleg, indicated by overstepping while walking on the elevated bars" (p. 117). Chambers and Sprague (1955b) reported also the symptoms elicited by a more discrete lesion of the cerebellar cortex of the anterior lobe and summarized their results as follows: "The vermal zone consists of two contiguous but independent halves, consisting of cortex and fastigial nucleus, each of which controls the posture, tone, locomotion and equilibrium of the entire body and functionally closely resembles the extrapyramidal portion of the cerebrum. . . . Somatotopic localization is present in the vermal cortex with maximal involvement of tail in the lingula, hindlegs and pelvic girdle in the centralis and rostral culmen, forelegs, pectoral girdle, head and neck in the caudal culmen, head, neck, and forelegs in the simplex, and *Jansen and Brodal (1940, 1942, 1954; see Larsell, 1958) have shown that the hemispheral part of the anterior lobe in the cat is homologous to the intermediate part of the anterior lobe in the rabbit and monkey. It projects entirely onto the nucleus interpositus.

ABLATION EXPERIMENTS 63 head, neck and eyes in the tuber and folium. However, the entire body was involved, to a lesser extent, in each lesion. . . . Each paravermal, intermediate zona, consisting of paravermal cortex and interpositus nucleus, controls the postural placing and hopping reflexes, tone and individual movements of the ipsilateral limbs, and functionally resembles the pyramidal part of the cerebrum. . . . Somatotopic localization in the cerebellum reaches its greatest discreteness in the paravermal cortex, especially that in the anterior lobe" (p. 678). (2) In Primates Subtotal ablations in the region of the anterior lobe in the macaque have been performed by several workers in Fulton's laboratory. A unilateral cortical lesion of the anterior lobe in a macaque was performed by Walker and Botterell (1937) as a control for their section of the superior cerebellar peduncle. This animal failed to show symptoms other than high stepping of the homolateral extremities, a slight fumbling with these extremities, and a slight tendency to fall to that side. All these symptoms subsided in a week. Dow (1938b) also, as a control procedure for the ablations of the flocculonodular lobe series, removed the medial part of the culmen (lobules IV and V) and of the lobulus simplex (lobule VI) and the folium and tuber vermis (lobule VII) in one animal, without seeing any striking abnormality in gait or posture. Connor (1941) and Connor and German (1941) performed local ablation experiments on monkeys and also on cats and dogs. They reported a release of postural tonus, less developed in monkeys than in lower mammals, which was localized in the hindlegs when the culmen was ablated and in the forelegs and neck respectively when the posterior and anterior parts of the lobulus centralis were ablated; when the lingula (lobule I) was ablated, the tonic labyrinthine reflexes were released. Almost simultaneously, however, Adrian (1941) arrived at opposite results with electrophysiological experiments; the results of his investigations were confirmed by ablation experiments performed on the macaque by Soriano and Fulton (1947), who stated: "Primary ablations of culmen or centralis on the macaque have given equivocal results so far as localization is concerned, but when carried out following unilateral ablation of areas 4 and 6, the upper extremity opposite the cerebral lesion becomes predominantly spastic when the cerebellar lesion is limited to the culmen, and the lower extremities when the lesion is limited to the centralis." The full report of this work has not appeared, so that the long-time chronic effects are not known. 4. ABLATION OF THE POSTERIOR LOBE OF THE CORPUS CEREBELLI a. TOTAL ABLATION

No ablations which have completely removed the posterior lobe of the corpus cerebelli and at the same time spared the anterior lobe and the flocculonodular lobe have been reported. The nearest approach to such an operation is the destruction of the "middle lobe" of the cerebellum (lunate, tuber, ansiformis, and paramedian lobules, and in addition the paraflocculus lobules), described by Keller, Roy, and Chase (1937) in dogs and monkeys. Although the small effect

64 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM these authors ascribe to this lesion is remarkable when compared to the dramatic disability that follows lesions of the flocculonodular lobe and anterior lobe, to deny, as they do, that any disabilities result from such extensive ablations is nevertheless so at variance with the findings of so many competent observers, that it is difficult to evaluate their contribution. Their suggestion that "neocerebellum is not essential for any of the functions that have been attributed to cerebellum" and that the cerebellar signs would be due to derangement of the brain stem is refuted by too much evidence, both clinical and experimental, to be accepted. b. UNILATERAL OR BILATERAL ABLATION OF THE LOBULUS ANSOPARAMEDIANUS

Ingvar's lobus medius corresponds to what Larsell (1937) called the "neocerebellar part of the posterior lobe of the corpus cerebelli." The lobulus simplex of Bolk, the lobulus medianus of Ingvar, and the lobulus ansoparamedianus of Bolk are included in it. In the more recent terminology of Larsell it includes lobules VI and VII of the vermis and lobules H VI, H Vila, and H Vllb. No one has reported an attempt to perform a unilateral destruction of Ingvar's lobus medius, and in view of Simonelli and Di Giorgio's findings (1926) on the vermian lesions following hemicerebellectomy (see above, p. 38) this seems an almost impossible task. Hence unilateral cerebellar ablations have generally been restricted to the lobulus ansoparamedianus. (1) In Subprimates Marrassini (1905, 1906, 1907) performed many isolated, unilateral ablations of the lobulus ansoparamedianus in the dog. The autopsies showed that the extirpations usually were not quite complete. Ipsilateral atonia and oscillations of the head were the conspicuous symptoms he reported. Bremer (1935) gave a most complete description of the effect of ablation of the "neocerebellum" in the dog and in the cat. He pointed out most clearly that it is necessary strictly to limit the extirpation to the lobulus ansoparamedianus, and not to involve the whole one half of the cerebellum, if one wishes to observe only the effects of ablation of that portion of the cerebellum which is completely dominated by corticopontocerebellar fibers. The failure to observe this precaution is the mistake so many physiologists had made previously, including Luciani (1891), Russell (1894), Lewandowski (1907), Andre-Thomas (1911), Munk (1906), and Dusser de Barenne (1923, 1937). Bremer emphasized that the effects of "neocerebellar" ablation are presented only when the ansoparamedian lobule alone is extirpated, so that the picture is not obscured by the release of extensor postural reflexes which invariably occurs if the homolateral half of the anterior lobe also is damaged. The release phenomena observed immediately after complete cerebellectomy (Luciani, 1891) or total ablation of the vermis (Luciani, 1891; Andre-Thomas, 1897) or of the anterior lobe (Rothmann, 1913a) were entirely absent following the destruction of the lobulus ansoparamedianus. This is further evidence of the paleocerebellar origin of opisthotonos and of the extensor rigidity observed dur-

ABLATION EXPERIMENTS 65 ing Luciani's dynamic period. It is only after the animal was again able to stand and to walk that the typical symptoms of ansoparamedian destruction were observed. They were strictly ipsilateral and surprisingly similar to those occurring during Luciani's. deficiency period. The effects of extirpation of the ansoparamedian lobule, as Bremer (1935) described them, are as follows: 1. Clear-cut hypotonia, which is demonstrable in many ways other than the ipsilateral sagging of the body under its weight described by Luciani (1891) or the lessened resistance to passive movements and manipulations, routinely used in clinical work. The hypotonia may be gauged by having the dog standing on one leg only: on the hypotonic side the resistance to a pressure applied along the axis of the leg is definitely low. Graphically the hypotonia may be shown by the absence of the myotatic appendage on the tendon reflex in the homolateral extremity (Fig. 13). What Andre-Thomas (1897) called the pendular character of the knee jerk is due to the absence of the shortening reaction, which normally slows down the decontraction of the extensor muscle.

Figure 13. Myograms of the cat's knee- jerks on the normal and on the cerebellectomized side. Three days after unilateral cerebellectomy on the left side, the knee jerk was recorded isotonically from the left (G) and from the right (D) limbs. The excursion of the reflex response was definitely greater on the cerebellectomized side (G), but the decontraction was not interrupted, as it was in D, by the myotatic appendage. The myograms should be read from right to left. Time: 1/100 sec. (From F. Bremer, 1935, Le cervelet. In G. H. Roger and L. Binet, Traite de physiologic normale et pathologique, Paris: Masson, 10:39-134, p. 100, Fig. 24 bis.)

2. The gait is characterized by uncertainty and hypermetria in the movements of the homolateral extremities. These symptoms are particularly evident in the anterior extremity, during the flexion stage of the step (demarche de cog). On the other hand, there is an absence of gross titubation in walking. 3. Oscillation and tremor of the head and of the ipsilateral legs. 4. Weakness of cortical reflexes, which might be responsible for the slow correction of malpositions of the limbs. These symptoms were also observed following unilateral cerebellectomy and will be again dealt with in the chapter on cerebellocortical relations. The typical deficiency symptoms described by Luciani were observed by Bremer following neocerebellar ablations limited to the lobulus ansoparamedianus. He stressed, however, that the neocerebellar effects were weaker and "d'une surprenante fugacite: une hypermetrie se manifestant par la demarche de coq la plus demonstrative, 1'hypotonie d'un membre la plus nette, peuvent avoir totalement disparu au bout de quelques jours" (p. 101). He attributed his findings to the recovery of neighboring areas, which had been reversibly damaged immediately after the operation, and to Luciani's organic compensation.

66

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

(2) In Primates According to Bremer (1935) the syndrome as seen in the macaque is essentially similar to that in the dog and cat. The hypermetria and the intention tremors are particularly manifest in primates. The experiments of Botterell and Fulton (1936, 1938c and d) were performed on six monkeys (Macaca mulatto) and on one baboon (Papio papio). The results of unpublished experiments on the chimpanzee were also mentioned. Histological controls showed, in most cases, that the midline structures and the flocculus and the paraflocculus had been spared. The hemispheral parts of the anterior lobe (lobules H III, H IV, and H V) and of the lobulus simplex (lobule H VI) were not mentioned in their protocols, but probably were extirpated. Possibly only experiment 7, performed on the baboon, corresponded strictly to the ablation of the lobuli ansoparamediani, since the autopsy showed "bilateral removal of the posterior half of each cerebellar hemisphere. The paraflocculi were intact . . . slight damage to right dentate nucleus" (1938c, p. 82). It is apparent from the photograph published by the authors that the hemispheral part of the anterior lobe had been spared. Their results are summarized as follows by Fulton and Dow (1937): "In monkeys, ablation of the neocerebellum gives rise to a syndrome similar in most respects to that seen in cats and dogs, but there is more grave disturbance of skilled movements and in the baboon a more conspicuous and enduring hypotonia. Tremor, however, is practically absent so long as the dentate nuclei are not involved. . . . (1) Unilateral ablation restricted to the cortex causes homolateral awkwardness, hypotonia, and disturbance of gait, the effects being equally marked in the upper and lower extremities, but all symptoms are transient, lasting at most about two weeks, the disturbance of gait being the most enduring. (2) When the ablation involves the dentate nuclei all disturbances just mentioned are more enduring and conspicuous and they are associated in addition with noticeable tremor in voluntary movements. (3) Simultaneous bilateral ablations restricted to the cortex cause more marked symptoms than does a unilateral lesion, and they are associated with a gross disturbance of gait characterized by leaping and an inability to arrest forward progression when an obstruction is in view. No evidence was found in these experiments of functional localization of individual muscles of limbs within discrete areas of the neocerebellum. All symptoms were more marked in the baboon than in the monkey" (p. 105). Botterell and Fulton have never presented their experiments on the chimpanzee (1938d) in complete form, but did publish a preliminary note (1936); and Fulton and Dow (1937) in a review on cerebellar localization included a summary. Here we read, concerning the chimpanzee: "Lesions restricted to the cerebellar hemispheres have been found to produce the picture just described for monkeys, but in a more enduring form with conspicuous slowness in the initiation of movements, and associated with a degree of hypotonia that far overshadowed that seen in monkeys or baboons. Indeed, the hypotonia from a neocerebellar lesion in the chimpanzee coincided in all details with the hypotonia seen in man following gunshot injury" (p. 105). Carrea and Mettler (1947) performed their neocerebellar ablations on Macacus rhesus. Bilateral extirpation of the ansiform lobules and paramedian lobules,

ABLATION EXPERIMENTS 67 complicated, however, by destruction of the pyramis, yielded "slight unsteadiness, with falling to either side, and a decreased motor performance, with diminished resistance to passive movements in the lower limbs, which improve rapidly and disappear within two weeks" (p. 227). Hence the main results of Botterell and Fulton's experiments were confirmed by Carrea and Mettler. C. ISOLATED ABLATION OF SINGLE CEREBELLAR LOBULI

(1) Lobulus simplex of Bolk, or Lobules VI and H VI of Larsell Following ablation of the median one third of the lobulus simplex (corresponding to lobule VI of Larsell) in the dog, van Rijnberk (1904, 1905, 1906) reported continuous weaving of the head in a transverse plane. These movements were compared to those of a man saying "no"; they lasted a long time (up to two months) and the cervical astasia was the only symptom observed after such localized ablations. Van Rijnberk believed that his findings substantiated Bolk's localization within the lobulus simplex of the cerebellar centers controlling cervical musculature. Following ablation of the lobulus simplex (lobule VI and H VI) in the dog, opisthotonos, with a tendency to fall backward, was observed by Luna (1906) during the acute period. His findings could not be regarded as invalidating those of van Rijnberk, who was concerned with more chronic effects. Moreover we have seen (p. 57) that opisthotonos was observed by Rothmann (1913a) following ablation of the anterior lobe and by Ingvar (1918) in experiments which were shown by Simonelli (1924) to involve the nucleus fastigii. It is likely, therefore, that the culmen or the fastigial nuclei had been damaged in Luna's operations. Van Rijnberk's isolated cervical astasia was confirmed by Lourie (1910) in dogs, but with anatomically poorly controlled ablation experiments; by Rothmann (1913a), who combined the ablation of the lobulus simplex in the dog with the destruction of Ingvar's lobulus medius medianus (Bolk's sublobulus C2; Larsell's lobule VII); and by Luna (1918) in experiments on monkeys. The experiments performed by Marrassini (1905, 1906, 1907) on dogs and by Andre-Thomas and Durupt on monkeys and dogs (1914) cannot be utilized, because the lesions of the lobulus simplex were associated with damage to other cerebellar areas. In the experiment of Grey (1916d), the ablations of the lobulus simplex in the dogs yielded ataxia of the trunk and of the legs, besides the wellknown cervical astasia; however, no anatomical controls were reported. Negative results were obtained by Ferraro and Davidoff (1931) in the cat. (2) Lobulus ansiformis of Bolk, or Sublobule H Vila of Larsell Isolated ablation of crus I was performed by van Rijnberk (1904, 1905) in the dog. Immediately after the operation the animal presented symptoms which he named "military salute": any acoustic or mechanical stimulation evoked a sudden flexion of the foreleg, so that the foot was brought near the ear. This symptom was ascribed to irritation. Later on the dysmetric gait described by Luciani ("goose step," "cock gait") appeared; it was localized in the ipsilateral foreleg. All symptoms, including dysmetria, disappeared within three to five days.

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According to van Rijnberk, these findings substantiated Bolk's scheme of localization, since the movements of the foreleg appeared to be controlled by the ipsilateral crus I. In a later paper (1906) van Rijnberk reported dysmetria of the ipsilateral hindleg following ablation of crus II in the dog. In Marrassini's works (1905, 1906, 1907) no experiment of isolated ablation of the lobulus ansiformis was reported. Using dogs, Luna (1906, 1908), Ossokin (1912), and Rothmann (1913b) confirmed van Rijnberk's results. Andre-Thomas and Durupt (1914) showed that dysmetria and postural alterations in the forelegs followed the destruction of crus I in both dogs and monkeys, whereas the hindlegs were represented in an area localized on the border between crus I and crus II. A further development of Bolk's doctrine is seen in the observation of the French investigators that the locus for abduction of the ipsilateral forelimb was the medial half, and that for adduction the lateral half, of crus I. Grey (1916d) reported dysmetria in the ipsilateral foreleg and weakness in the ipsilateral hindleg of the dog following destructions localized respectively in crus I and crus II. Bolk's localization was also confirmed in the experiments performed by Luna (1918) on crura I and II in one cat and many monkeys. These apparently clear-cut localizations were not entirely confirmed by other investigators, whose results may be summarized by the statement that a given part of the body is mainly, but not exclusively, represented in a given area of the lobulus ansiformis. Rossi (1921, 1922), Ferraro and Davidoff (1931), and Di Giorgio (1942a) emphasized that some alterations could be found also in the hindlimb following ablation of crus I in dogs and cats. Vice versa, the muscles of the forelimbs as well as those of the hindlimbs are represented in crus II, according to Troell and Hesser (1922), Ferraro and Davidoff (1931), and Di Giorgio (1942a). According to Manni (1950a), the trunk also is affected by lesions of the lobulus ansiformis in the guinea pig. Recent investigations performed by Carrea and Mettler (1947) on monkeys and by Chambers and Sprague (1955b) on cats led to the conclusion that purely cortical lesions of the lobulus ansiformis or of any part of it would be asymptomatic. Chambers and Sprague (1955b) suggested that the foreleg effects elicited by lesions of crus I might occur only when the neighboring intermediate part of the anterior lobe or the nucleus interpositus were encroached upon, while the hindleg symptoms yielded by lesions of crus II would result from infringement on the paramedial cortex or that part of the interpositus nucleus onto which it projects. It should not be forgotten, however, that Carrea and Mettler (1947) performed bilateral ablations of the lobulus ansiformis in monkeys whose central nervous system was otherwise intact. It is at least likely that many symptoms were missed owing to lack of asymmetrical innervation (see p. 73), or because the spontaneous movements and the refractoriness to examination of the intact monkey prevented the observation of phenomena which are more easily observed in tame animals, such as the dog or the rabbit (see p. 74). Clear-cut postural asymmetries were reported by Rossi and Di Giorgio (1942) following unilateral ablation of either crus I or crus II in midbrain monkeys. A purely cortical lesion of crus I was performed by Chambers and Sprague (1955b) on one cat only. The

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infringement on the neighboring cortex or deep nuclei is undoubtedly a serious objection, and one which has been approached experimentally many times (see pp. 71-72). We feel, however, that other experiments are required before we may accept the conclusion that no tonic influence is exerted by the cerebellar cortex of the lobulus ansiformis on either posture or movements. Rossi's technique of postural asymmetries (see pp. 73-77), combined with careful histological and physiological controls of the integrity of neighboring structures, might turn out to be of great value for this kind of investigation. (3) Lobidtis paramediamts of Bolk, or Sublobules H VHb and H Villa of Larsell The paramedian lobule of Bolk consists of a pars anterior, connected medially with sublobule Vllb, and a pars posterior, which is connected with lobule VIII, the pyramis (Larsell). Scholten (1946) found similar subdivisions. It appears probable that these subdivisions may differ from each other to some extent in functional significance. In the present section the results of experimentation before the recognition of the anatomical subdivisions of the paramedian lobule will be reviewed. The most discrete ablation performed by Marrassini (1905, 1906, 1907) on the dog's lobulus paramedianus included also the neighboring lamellae of crus II (1906, p. 44). No dynamic effect resulted, only atonia of the ipsilateral limbs (particularly evident, however, in the hindlegs) being reported. Typical dynamic effects on the muscles of the trunk (pleurothotonos) were observed by van Rijnberk (1906), Hulshoff Pol (1909), and Grey (1916d) in their studies on the dog. On the other hand, the experiments of Troell and Hesser (1922) on the lobulus paramedianus, in dogs and cats, agreed for the most part with those of Marrassini, since the conclusion was reached that the lobulus paramedianus was related to the muscles of the neck and of the limbs (particularly those of the forelegs). During more recent years the correlations between the lobulus paramedianus and the musculature of the extremities have been further elucidated. Mussen (1930, 1931) observed ataxia in the ipsilateral forelimb following lesions of the rostral lamellae of the cat's lobulus paramedianus. Ferraro and Davidoff (1931) reported dysmetria of the foreleg and ataxia of the ipsilateral hindleg following destructions localized, respectively, within the rostral and the caudal parts of the lobulus paramedianus of the cat. Bagnoli (1942), in the rabbit, and Manni (1950a), in the guinea pig, observed postural asymmetries which were mainly localized in the forelegs if the rostral lamellae of the lobulus paramedianus had been destroyed, in the hindlegs whenever the caudal part of the lobulus had been damaged. Dynamic phenomena were never observed, nor were abnormalities in the muscles of the trunk and of the eyes reported. Finally Chambers and Sprague (1955b) reported that the symptoms elicited by total removal of one paramedian lobule in two cats were (though much milder) similar to those following ablation of the entire intermediate part of the anterior lobe. The relation of the rostral and caudal folia respectively to the ipsilateral foreleg and hindleg was confirmed. To sum up, the results of the somatotopic localization within the paramedian lobe are quite consistent, and accord very nicely, moreover, with

70 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM electrophysiological findings which will be reported in another section of this book (see pp. 186, 210). (4) Lobitlus medius medianus of Ingvar, or Lobule VII of Larsell The isolated ablation of Bolk's sublobulus C2 (folium and tuber; van Rijnberk's lobulus S, lobule VII of Larsell) was performed by van Rijnberk (1906) on dogs, with no obvious results. This lobule, however, is little developed in dogs; it is much larger in sheep. Van Rijnberk (1907) and Vincenzoni (1908) performed ablation experiments in the latter species. No eifect was obtained after superficial or unilateral ablation, but transient inability to walk and later an ataxic gait were reported following deeper destructions. After these early papers, the lobulus medius medianus (lobule VII Larsell) was surprisingly neglected, and lesions in it were frequently associated with injury to the lobulus simplex, lobulus ansiformis, or sublobulus Cl (pyramis). Manni (1950a) performed isolated and unilateral ablations of Ingvar's lobulus medius medianus in the guinea pig. He stated that the somatotopic relationships were the same as those of the corresponding lamellae of the lobulus ansoparamedianus. Following chronic ablation of lobule VII in one cat, Chambers and Sprague (1955b) observed symptoms both in the somatic sphere (increase of extensor tone in all legs, goose step in foreleg, resting head tremor) and in the sensory (poor attention to light and especially to sound). After one week the animal was almost normal, but the defect in the response to various sounds remained striking throughout the survival period (40 days). These sensory disturbances should be related to electrophysiological findings to be reported in another section of this book. (5) Pyramis (Lobule VIII), Uvula (Lobule IX), and Paraflocculus (Sublobule H VHIb and Lobule H IX), Together Constituting Larsell's Paleocerebellar Part of the Posterior Lobe There is little information on the effects of the isolated ablation of these lobules; the pyramis and the uvula have been included generally in wider destructions of the posterior vermis, and parafloccular ablations have often been associated with lesions of the flocculus. Rothmann (1913a), was the first to perform isolated ablations of both the pyramis and the uvula in the dog. During the first two days the animal could not stand; later it began to creep and finally was able to walk, but marked weakness and ataxia of the hindquarters were reported. Chambers and Sprague (1955a) with chronic experiments performed on cats found that "results essentially similar to those obtained from the anterior lobe cortex followed ablation in the cortex of pyramis and uvula." Moruzzi and Pompeiano (1955a; 1956b) analyzed the influence of unilateral lesions of lobules VIII and IX on the extensor rigidity of the decerebrate cat. Their results will be reviewed together with other experiments on the caudal part of fastigial nucleus and on the hook bundle (see pp. 80-85). Lesions restricted to the pyramis (lobule VIII) alone were made in monkeys by Dow (1938b) in the process of differentiating this portion of the "posterior

ABLATION EXPERIMENTS 71 lobe" of the vermis from the flocculonodular lobe. Following ablation of the pyramis in monkeys he could detect no significant disturbance of equilibrium or muscle tone. No other abnormality was seen except that, for about three days after the lesion, on running down a long corridor the animal would crash headlong into the wall as if unable to arrest its progression quickly enough to avoid the obstruction. Ten Gate (1925, 1926b) made histologically controlled ablations of the paraflocculus in the cat. After destruction of the anterior part he found weakness and atonia of the ipsilateral legs, the forelegs being most severely affected. The same effects, but more evident in the hindlegs, were elicited by destroying the posterior part of the paraflocculus. Scholten (1946) carried out a major anatomical and physiological investigation concerning the paraflocculus. He found, following its ablation in the rat, changes which conformed to the results previously described by ten Gate (1926b) in the cat. The animals walked with a sudden sagging of the homolateral legs, followed by an immediate return to normal. He attributed these disturbances, as did ten Gate, to reduced muscle tone in the homolateral limbs. According to Carrea and Mettler (1947) ablation of the paraflocculus is physiologically silent in monkeys. No clear-cut effects and, particularly, no postural abnormalities were found by Manni (1950a) during the ablation experiments he performed on the paraflocculus of the guinea pig. (6) Errors and Limitations in the Experiments of Isolated Ablation of Individual Cerebellar Lobules We shall see in a later section of this monograph that stimulation experiments as well as those devoted to recording bioelectric responses can hardly be reconciled with most of the results of localized ablation which have been reviewed in the preceding pages. Actually, as far as Larsell's posterior lobe of the corpus cerebelli is concerned, the agreement between the results obtained by different methods in the lobulus paramedianus appears to be the exception rather than the rule. There naturally has arisen a widespread skepticism about the results obtained with ablation techniques. We believe that the time has come for a general appraisal of the results so far reviewed. It does not appear to us that the experiments performed by the older techniques should be abandoned simply because they do not agree with, or are not substantiated by, the results of newer methods. Techniques should not be classified by age; all that should be considered is their adequacy or inadequacy for solving a given problem. Hence we are only interested in determining whether the deficiencies in cerebellar function which followed ablation, localized or massive, were properly produced and adequately analyzed. The first and major drawback in the work of the older students of physiology is anatomical, and the warning came as soon as the first histological controls were made. In 1908 Binnerts, in Winkler's laboratory, examined histologically the cerebella which had been operated by van Rijnberk in Luciani's laboratory in Rome from 1904 to 1907. He showed that the extent of the lesions was far greater than one might have expected from gross inspection and that the symptoms

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described by van Rijnberk (cervical asthasia for lobulus simplex, ipsilateral forelimb dysmetria for crus I, alteration in the musculature of the trunk for lobulus paramedianus) occurred only whenever deep lesions had been made. Moreover, Rossi (1921) found that when superficial cortical lesions had been applied to crus I, van Rijnberk's symptoms were completely absent, although postural asymmetries in the forelimbs showed that some cerebellar function was lacking on the operated side. Finally Simonelli (1914a, b, 1922, 1924), Rothmann (1915), and Luna (1918) showed that alterations of the deep nuclei occurred following supposedly cortical lesions. Undeniably the complete lack of histological controls which characterizes most of the earlier experiments on cerebellar ablation casts serious doubt on their validity for localizing purposes. It is indeed likely that after fairly deep cortical destructions, secondary atrophy of the cerebellar nuclei or (as Simonelli, 1922, rightly pointed out) undercutting of the projection fibers from other folia might give a picture unrelated to the structures which had been intentionally removed. But we feel that a skeptical attitude toward all localized ablations would be entirely unjustified. There is no doubt that nuclear alterations can be avoided. This statement is supported by the well-known anatomical data of Horsley and Clarke (1905), showing that no degenerated fibers could be traced in the peduncles following localized corticocerebellar ablations. The validity of the findings has remained unchallenged, at least as far as Larsell's lobus posterior is concerned (Jansen and Brodal, 1940, 1942). But we have more direct physiological evidence. Simonelli (1922) controlled both histological structure (by the Nissl method) and the vascular supply (by carminium injection) of the cerebellar nuclei of dogs whose crus I had been destroyed up to six months before their death. Nuclear cells and vascular supply both were normal, not only following superficial lesions which yielded only the postural asymmetries described by Rossi, but also after somewhat deeper destructions. This shows that nuclear atrophy is simply a surgical accident, due possibly to circulatory damage (thrombosis?); it should be controlled routinely, but must not discourage future investigators from performing other experiments of localized ablation. They will take advantage of the works of Shellshear (1922) and Fazzari (1924, 1931) on cerebellar circulation, as well as of the method of localized destruction with chloroform introduced by Rossi (1921, 1923a). With this procedure superficial cortical lesions can be produced, their depth can be properly modified, and the boundaries between normal and abnormal areas are clear-cut (Di Giorgio, 1923). Moreover the so frequently raised objection of irritative phenomena is easily eliminated by Rossi's technique. The second drawback was emphasized by an experiment performed by Ferri (1925) in Rossi's laboratory. He found postural asymmetries in dogs whose cerebellar lobules had not been extirpated but simply exposed to the air for a few minutes after the dura had been cut. The animals were killed from one day to two weeks after the operation and clear-cut histological damage was observed. According to Ferri (1925) the main causes of error were (a) failure to sew the dura, with consequent herniation of the cerebellar folia; and (b) compression or venous thrombosis produced by the hemostatic wax. It is quite likely that these

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causes of error were neglected by previous investigators. With respect to the effects of localized compression on cerebellar lobules, the works of Greggio (1914, 1922) should be consulted. A third drawback, of particular importance for the experiments regarded as negative by their authors, is the lack of adequate tests of cerebellar deficiency. Obviously only large and deep lesions will yield visible alterations of either standing or gait. It is only by comparing the normal side with that operated upon, the animal being fastened in the dorsal or vertical position, that minor differences, obviously related to an asymmetrical cerebellar innervation, will be detected. The same animal, examined when standing or walking, may present no visible sign of cerebellar deficiency. Rossi (1921) is responsible for having introduced this procedure, and the next section will be fully devoted to postural and reflex asymmetries. It should be stressed at this point that whenever an asymmetrical cerebellar innervation is not elicited (as after bilateral, symmetrical lesions of the lobulus ansiformis in the guinea pig: Manni, 1951b) or not appropriately looked for, small and superficial cerebellar ablations are likely to appear physiologically silent. Manni (1950a) was right, in our opinion, when he pointed out that for this reason the negative results obtained from experiments of bilateral ablation of the lobulus ansiformis (Carrea and Mettler, 1947) could hardly be regarded as conclusive. The importance of an adequate method of examination is illustrated by the experiments of Meyers (1916, 1919a, b). He attempted to demonstrate, by graphic methods, the effect of isolated lesions of the posterior lobe in the dog. His animals were trained to walk in a harness, pulling a small wagon on which a recording kymograph was placed. After studying the normal gait as recorded by tambours fastened to the pads of all four feet, he performed ablations limited to crus I in one dog and to right crus II in a second dog. There were no further observations, and he used no histological controls. He did describe changes, observable on the records, indicating a modification in the rhythm of the affected limbs; the homolateral forelimb and contralateral hindlimb were affected in lesions of crus I, and the homolateral hindlimb and contralateral forelimb in lesions of crus II. His paper is mentioned here because by his graphic method effects were observed for 10 days in the first animal and 19 days in the second whereas by simple observation no evidence of defect could be seen in either animal after the first few postoperative days. This suggests that with trained animals and modern recording methods, including electromyographic apparatus, abnormalities of muscular movement might be detected, after localized cerebellar ablation, that would not be evident from ordinary visual observation and manual handling of the limbs and muscles.

5. "POSTURAL ASYMMETRIES" AND "ASYMMETRICAL PHASIC REFLEXES" AFTER LOCALIZED CEREBELLAR ABLATIONS We shall review in this section the results obtained by Rossi and his associates (Simonelli, Di Giorgio) on the problem of so-called asymmetrical cerebellar innervation. Although, technically, these experiments consisted in localized destructions of small and superficial parts of the cerebellar cortex, the problem of

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cerebellar localization represented only a collateral aspect of their investigations, which aimed at a close analysis of the basic mechanisms of neocerebellar function. In order to avoid repetition, the postural asymmetries obtained with the strychnine stimulations and the experiments dealing with corticocerebellar, vestibulocerebellar, and spinocerebellar relations will be dealt with separately in other chapters (see pp. 112, 268, 287, 327). If a dog is secured with its back on the animal board, the head and the trunk lying symmetrically along the sagittal line, the position of the four legs will be symmetrical as soon as the typical passive attitude is assumed. The symmetry will be present whether the animal is lying supine (horizontal position) or propped in a vertical position. If then a small lesion of crus I is made, the symmetry will be lost and the ipsilateral foreleg will generally appear more flexed (Fig. 14)' This phenomenon was called by Rossi (1921) "postural asymmetry," and its appearance was correlated with an asymmetrical innervation brought about by the localized cerebellar excision.

Figure U. Postural asymmetry following unilateral ablation oj crus I The time is 28 days after superficial ablation of the left crus I. The dog is lying supine and shows clear-cut flexion ipsilaterally to the cerebellar lesion. (From G. Rossi, 1921, Sulle localizzazioni cerebellari corticali e sul loro significato in rapporto alia tunzione del cervelletto, Arch, fisiol., 19:391-445, Fig. 19, p. 432.)

The problem then arose of localizing the central structures which were asymmetrically innervated by the cerebellum. Bilateral topectomy of the motor cortex, bilateral decortication, and thalamic transection neither prevented nor abolished the postural asymmetry; it disappeared, however, following intercollicular decerebration (Rossi, 1921). These observations are of great importance, since they showed that the tonic outflow from a typical neocerebellar structure remained after the cerebral cortex had been destroyed. Rossi suggested that the red nuclei might be concerned in relaying the efferent outflow which is affected by an asymmetrical cerebellar lesion. On the afferent side these experiments showed that a tonic discharge from

ABLATION EXPERIMENTS 75 neurons in the lobulus ansiformis was still present when the inflow of cerebral impulses descending through the corticopontocerebellar paths had been interrupted. The problem then arose as to whether other afferent impulses, besides those arriving from corticopontine structures, could be held responsible for the neocerebellar discharge. According to Brodal and Jansen (1946), the neocerebellum is characterized "not only positively by receiving pontine fibers predominantly, but also negatively by the absence of spino-cerebellar and vestibulocerebellar fibers as well." Vestibular impulses are certainly not essential for this type of neocerebellar activity, since the postural asymmetries were not abolished by acute or chronic labyrinthectomy (followed by local cocainization), nor did they disappear when thalamic decerebration was later performed. They were, moreover, still present if a functional ablation of crus I was performed with Rossi's chloroform method or by local cooling. Both groups of experiments were performed by Simonelli (1923), and his work disposed of the possible objections of irritative impulses arising in the vestibular apparatus or in the wounded cerebellar area. We know now that impulses arriving through olivocerebellar fibers (Dow, 1939; Brodal, 1940) or, possibly, some kind of automatic activity of the cerebellar neurons (Snider and Eldred, 1949; Brookhart, Moruzzi, and Snider, 1950; Crepax and Infantellina, 1955, 1957) may well explain the persistence of a tonic neocerebellar activity after the interruption of the corticopontine paths. Following ablation of crus I in the dog or in the thalamic cat, phasic reflex responses to faradization of the nasal septum also were found by Rossi (1925) to be performed asymmetrically. These "motor asymmetries" were confirmed by Di Giorgio (1927) in the rabbits in which crus II had been removed unilaterally. Here the symmetry of the reflex responses of the hindlegs to faradic stimulations applied on the genital area was lost as a consequence of the imbalance in the bilateral cerebellar innervation. Both "tonic" and "motor" asymmetries disappeared, simultaneously, with the same dose of curare (Rossi, 1923b, 1927). This important observation shows, incidentally, that when the animal is standing on its feet, postural tone is maintained by neural and muscular mechanisms that are not necessarily the same as those responsible for the muscle tone of the same legs when they are not supporting the weight of the body. The difference between antigravity tonus and the mechanisms underlying Rossi's postural asymmetries should be stressed here. Antigravity tonus (a) concerns exclusively or at least mainly the extensor muscles and, above all, the motor units innervating the "red" fibers (Denny-Brown, 1929a and b, Bremer, 1932, for references); (b) is driven, reflexly, mainly by stretch and labyrinthine receptors (see p. 273) and (c) is selectively abolished by subparalytic doses of curare (Bremer, Titeca, and van der Meiren, 1927; Bremer, 1932—see especially his Fig. 23; Moruzzi, 1934a, 1935a, b). What we call tonus in Rossi's experiments (a) concerns both extensor and flexor muscles; (b) is comparatively independent of exteroceptive, myotatic (Di Giorgio and Menzio, 1946a-d; Manni, 1949a) and labyrinthine (Simonelli, 1922) influences; and (c) is not selectively blocked by subparalytic doses of curare (Rossi, 1923b). The failure to appreciate this distinction is partly responsible for the controversy about tone among cerebellar physiologists and clinicians (see Holmes's definition of tone

76 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM above, p. 23). It was after a penetrating analysis of his results that Rossi (1927) came to the hypothesis of the central regulation of intrafusal muscle fibers. This field of investigation, which through the experiments performed by Granit and his colleagues is now one of the high spots in modern cerebellar physiology, will be dealt with in the chapter on cerebello-spinal relations. The more recent contributions on postural and motor asymmetries will be reviewed briefly. Asymmetric walking and swimming movements were observed by Simonelli (1930) in the thalamic cat, following acute ablation of crus I. Rossi and Di Giorgio (1933) investigated the influence of unilateral lesions within crus I, crus II, and the lobulus paramedianus on Rademaker's reflexes (see p. 30) in the dog. No asymmetric responses were noted after superficial lesions had been made, albeit typical postural asymmetries occurred; Rademaker's asymmetric reflexes were reported, however, when the deeper portion of the cerebellar folia, but not the cerebellar nuclei (as shown by Nissl controls), had been damaged. Di Giorgio (1942a) found that postural asymmetries were abolished by intercollicular decerebration simply because the "asymmetrical innervation" was concealed by decerebrate rigidity. With experiments performed on dogs, rabbits, and guinea pigs she showed that localized ablations of crus I, crus II, or the lobulus paramedianus yielded postural asymmetries also if they were followed (within 40 minutes) by a postcollicular decerebration, provided, however, the extensor rigidity was originally not too strong or, if so, that it was decreased by such experimental procedures as Magnus reflexes or cooling of the preparation. Whether or not her postcollicular decerebrations spared the descending collaterals which, as Ramon y Cajal (1909) showed, are given off from the fibers of the brachium conjunctivum, was not determined, although this is an important factor in the critical interpretation of the results of her experiments. Anatomically, the neocerebellar outflow occurs entirely through the superior cerebellar peduncles (Jansen and Brodal, 1940, 1942; Jansen and Jansen, 1955). Accordingly, if the brachium conjunctivum was completely interrupted in Di Giorgio's experiments, it is likely that the asymmetries were mediated to the brain stem through intracerebellar connections and the efferent fibers descending along the inferior cerebellar peduncles. Di Giorgio and Menzio (1946a-d) showed that the postural asymmetries elicited by localized ablations of crus I, crus II, or the lobulus paramedianus in the dog were still present after acute (1946a, c) or chronic (1946c) deafferentation, eventually combined with intercollicular decerebration (1946d). The asymmetries actually were increased in the guinea pig, if the limbs had been skinned bilaterally and the wounded surface had been cocainized (Manni, 1949a). It would be interesting to combine the experiments of Di Giorgio and Menzio (1946a-d) with those of Simonelli (1923) to determine whether asymmetries can still be produced after bilateral labyrinthectomy and deafferentation, followed by decerebration. Rossi's cerebellar experiments (19£3b, 1927) with curare were resumed by Manni (1946). Confirming Bremer and Titeca (1927, 1931, 1935), he found that extensor rigidity was blocked much earlier than the postural asymmetries of Rossi, which disappeared only when all motor activity had been paralyzed. It is

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apparent, therefore, that Rossi's postural asymmetries involve neural mechanisms different from those underlying antigravity postural tonus. Using the method of postural asymmetries, Manni (1951b) undertook to investigate the problem of multiple representation within the cerebellar cortex of a given muscular district (see p. 138). He found that bilateral ablation of the forelimb area of crus I in the guinea pig did not evoke postural asymmetries in the foreleg. These did appear, however, when a unilateral lesion of the forelimb area of the lobulus paramedianus was made. The reverse experiment also was performed. It was observed, moreover, that the asymmetry evoked by a unilateral lesion of the hindleg area of the lobulus ansiformis was not abolished by a bilateral lesion of the hindleg area of the lobulus paramedianus. The obvious implications of these interesting findings is that two cerebellar areas regulating the same muscular district project independently onto the cerebellar nuclei, so that the tonic influence of the lobulus ansiformis is not mediated, through associational fibers, by the lobulus paramedianus but occurs through its own efferent projections. D. ISOLATED DESTRUCTION OF THE CEREBELLAR NUCLEI IN MAMMALS 1. ISOLATED LESIONS OF THE NUCLEUS FASTIGII

a. WITH THE REST OF THE NERVOUS SYSTEM INTACT Reports of isolated destruction of the fastigial nuclei are few, since the vermis generally was more or less severely damaged in the operations intended to produce lesions in them. In Botterell and Fulton's primate experiments (1938b) the destruction of the fastigial nuclei was associated with injury to the pyramis (lobule VIII), uvula (lobule IX), and nodulus (lobule X), or with longitudinal splitting of the vermis. In Snider's experiments (1940a), which were performed on rabbits, the unilateral lesion of the nucleus fastigii was complicated by subtotal or complete splitting of the vermis, so that Russell's tract arising in the contralateral fastigius was severed and the lesion could not be regarded as strictly ipsilateral. Carrea and Mettler (1947) performed complete or partial ablations of the fastigial nuclei, but their lesions also involved various lobules of the vermis. Lindsley, Schreiner, and Magoun (1949) were the first to analyze, on cats, the influence of stereotaxically oriented bilateral destructions of the nucleus fastigii. They recorded electromyographically the stretch reflexes of the extensor muscles and found a clear-cut increase of these reflexes two weeks after the operation. Two weeks later, the stretch reflexes were only slightly increased, "but the positive supporting reaction was still definitely augmented" (p. 202). Sprague and Chambers (1953) destroyed stereotaxically one fastigial nucleus in the cat. They stated: "These animals were unable to right themselves or walk for the first four days; the limbs were held in a persistent spasticity—extensor in the contralateral and flexor in the homolateral limbs. Standing was achieved on the sixth day, but was often terminated by jailing to the side of the lesion. . . . Walking improved somewhat in the last postoperative days, but the marked leaning to the lesion side was retained and the animal sought to support this side" (pp. 454-455; italics ours). These late symptoms recall Luciani's description

78 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM of atonia following unilateral cerebellectomy. The cats were observed up to twenty-two days, and then a decerebration was performed. The completeness of the lesion as well as the integrity of the contralateral fastigial nucleus was shown physiologically by the fact that after decerebration "stimulation of the medial cortex overlying the destroyed fastigial nucleus gave no discernible tonic effects, although the opposite medial cortex was fully excitable" (p. 455). Sprague and Chambers also carried out histological controls by Weil and Nissl methods. Entirely opposite effects—i.e., ipsilateral extension (with abduction) and contralateral flexion (with adduction)—were elicited by unilateral decortication of the vermian part of the anterior lobe. Fourteen days after the operation the animal still showed a tendency to fall "to the side opposite the lesion" (italics ours). Hence Sprague and Chambers obtained the unexpected result that a fastigial lesion did not reproduce, but actually reversed, the postural patterns obtained after ablation of the overlying cerebellar cortex. Sperti and Zatti (1953c) aspirated the nucleus fastigii of dogs with a 3-millimeter glass pipette. The animals were killed after four to ten weeks, and the extent of the lesion was controlled by Nissl-stained sections. When the unilateral lesion was complete or limited to the rostral part of the nucleus, the results of Sprague and Chambers (1953) were occasionally confirmed (ipsilateral flexor spasticity), but less frequently the opposite effect occurred (ipsilateral extensor spasticity). A difference in technique, rather than in species, probably is responsible for the discrepancies, since histological alterations were found by Sperti and Zatti (1953b) in both the dentate and the interposite nucleus when one fastigial nucleus had been partially or totally destroyed. Negative results were reported by Rand (1954) in an anatomical work in which the caudal end of one fastigial nucleus had been stereotaxically destroyed in only one monkey. Batini and Pompeiano (1955a, b, 1957) analyzed in ninety-five cats unilateral and bilateral fastigial lesions involving either the whole nucleus or only its rostral or caudal parts. The extent of the electrolytic destruction, which was performed with the Horsley-Clarke apparatus, and the integrity of the other cerebellar nuclei and of brain stem structures were controlled histologically on serial Weil and Nissl slides. The symptoms were also recorded cinematographically. Only the results in those animals in which the fastigial lesions were not complicated by other destructions will be reported. Exception is made for the degeneration of the caudal pole of one fastigial nucleus that follows the total lesion of the other fastigial nucleus (Batini and Pompeiano, 1955a, 1957). Such a lesion is due to postdecussational interruption of Russell's hook bundle and cannot be avoided, on purely anatomical grounds (see Rasmussen, 1933; Jansen and Jansen, 1955). Hence a total, and even simply a rostral, fastigial lesion cannot be really unilateral, a fact which had been neglected by the previous investigators. Confirming the results of acute fastigial lesions made on decerebrate cats (Moruzzi and Pompeiano, 1955a; 1956b; see below, pp. 81-85), Batini and Pompeiano reported that chronic lesions of the rostral part of one fastigial nucleus were followed by a syndrome which was opposite in laterality to the syndrome produced by destruction of the caudal part of the nucleus.

ABLATION EXPERIMENTS 79 The unilateral lesions, involving the whole fastigial nucleus or only its rostral part, were followed by an asymmetrical posture similar to that reported by Sprague and Chambers (1953). For about three or four days the animal made no attempt to walk. The ipsilateral limbs were flexed, while the contralateral ones were extended and abducted. It was only after about ten days that the animal was again able to stand and to walk. The hypotonia of the ipsilateral extensor muscles was then shown by symptoms quite similar to those characterizing Luciani's atonia, namely, (a) ipsilateral sagging of the body under its weight, (b) fall of the animal toward the operated side, (c) a tendency to lean this side of the body against the wall, and (d) a lower resistance of the ipsilateral limbs to passive flexion. There were also oscillations of the head and of the trunk, which remained for about three weeks, and it was only after thirty to thirty-five days that the compensation of the postural disturbances and of the motor disability of the limbs was practically complete. A lesion of the caudal pole or of the caudal one half of one fastigial nucleus yielded the same results, but on the opposite side of the body. The syndrome was, however, slightly milder, as shown by the fact that the first attempt to walk occurred after one to two days, and practically complete compensation occurred in from fourteen to twenty-two days. Both the ipsilateral and contralateral extensor atonia disappeared, and the limbs of both sides were equalized in a strong extensor tonus, when the homotopic structures were destroyed on the opposite side of the body. Batini and Pompeiano (1957) also investigated the influence of total and bilateral destruction of roof nuclei in the otherwise intact cat. Histological controls showed the integrity of the nucleus interpositus and nucleus dentatus and of all brain stem structures of both sides of the body. The roof nuclei and the white matter interposed between them were, however, entirely destroyed. During the first three days a strong extensor hypertonus was present in all limbs, but was more pronounced in the forequarters, possibly as a consequence of the opisthotonos. The animal was unable to stand and to walk and its posture was similar to that of the decerebrate preparation. The first attempt to stand was limited to the forequarters, and occurred toward the fourth day. The attempts were generally unsuccessful, because of the retropulsion that occurred as a consequence of the exaggerated supporting reaction. After about eight days the animal was able to stand, but the legs were stiff and abducted, and a marked swaying of the head and of the body occurred during the progression movements. After fifteen days both standing and walking movements were normal, but the myotatic reflexes were still somewhat exaggerated. The animals were followed for thirty days. Neither hypotonia nor nystagmus was observed. Summing up, following bilateral fastigial lesions, only the release symptoms of Luciani's dynamic period were observed, but not extensor atonia. Vice versa, unilateral fastigial lesions yielded a syndrome strikingly similar to that characterizing Luciani's extensor atonia, although it occurred on the same side of the body only after a rostral or total fastigial lesion, and was localized on the opposite side when the caudal pole had been encroached upon. Neither crossed nor direct fastigial atonia was preceded by release symptoms. These puzzling results will

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM be explained by the experiments of Moruzzi and Pompeiano (1955b, 1957a) to be reviewed in other sections of this book (see pp. 265, 283). Chambers and Sprague (1955b), simultaneously and independently, carried on experiments of unilateral selective destruction of the fastigial nucleus. Their results following unilateral lesions confined to the rostral one half of the fastigial nucleus were in full agreement with those of Batini and Pompeiano (1955a). They missed, however, the syndrome of crossed extensor atonia that follows the destruction of the caudal one third of the fastigial nucleus on one side, since they stated that "the distribution of tone was similar to the other partial nuclear lesions" (p. 661). Their experiment was limited, however, to only one cat, which survived four days and showed lethargy. It is likely that a deterioration of the cat's general condition prevented the occurrence of a syndrome which is as constant as the ipsilateral extensor atonia that follows any unilateral rostrofastigial lesion. 80

Figure 15. A diagrammatic representation of the effects on the postural tone of the forelimbs produced by isolated lesions of the cortex of the medial part of the anterior lobe of the corpus cerebelli and of the fastigial nuclei. The lesions are marked in cross-hatch. MC = medial cortex of the anterior lobe; F — fastigial nuclei; R = reticular formation. CFT = corticofastigial tract; FBI = fastigiobulbar tract; RST — reticulospinal tract; PG = pectoral girdle and brachial spinal cord. A. Orientation diagram showing bilateral moderate extensor tone of the decerebrate cat. B. Ipsilateral increase in the extensor tone and contralateral decrease after unilateral ablation of the cerebellar cortex. C. Reversal of the tonic effect, with ipsilateral flexor rigidity and contralateral extensor rigidity, when the fastigial nucleus is destroyed on the same side as the cortical ablation. D. Marked accentuation of the postural asymmetries of C produced by ablation of the remaining portion of the medial anterior lobe cortex. E. Strong bilateral extensor accentuation produced by bilateral ablation of the medial part of the cortex of the anterior lobe and both fastigial nuclei. (From J. M. Sprague and W. W. Chambers, 1953, Regulation of posture in intact and decerebrate cat. I. Cerebellum, reticular formation, vestibular nuclei, J. Neurophysiol., 16:451-463, Fig. 4, publ. Charles C. Thomas.) b. IN THE DECEREBRATE PREPARATION

Chambers and Sprague (1951) and Sprague and Chambers (1953) found that decortication of the anterior lobe, in the decerebrate cat, yielded ipsilateral extensor spasticity and contralateral flexion (Fig. 155). These effects were generally more marked in the forelegs, and were reversed as soon as the underlying nucleus fastigii was totally aspirated (Fig. 15C). The marked extensor hypertonus then shifted to the side contralateral to the fastigial ablation, whereas a flexor hypertonus appeared ipsilaterally. Since the same patterns were elicited when the decerebration was performed on a cat in which one nucleus fastigii had been destroyed twenty-two days earlier, the effects of fastigial ablation could

ABLATION EXPERIMENTS 81 not be regarded as irritative in nature. According to the American investigators, the strengthening influence exerted by each fastigial nucleus on the ipsilateral extensor tonus was not related to impulses going from the pyramis (lobule VIII) and the uvula (lobule IX) to the caudal part of the roof nuclei, since the nuclear effect was "still obtained after previous chronic ablation of all the cerebellum except anterior lobe, simplex lobule and*rostral fastigial nucleus" (p. 459). They stressed the fact that exactly the same patterns were obtained if the decerebration was performed following unilateral ablation of Deiters' nucleus, whereas both extensor and flexor tonus were absent, ipsilaterally, if the decerebration was performed in a cat whose nucleus fastigii and Deiters' nucleus had been destroyed. They stated: "Our results cause us to postulate a functional division of the fastigial nucleus: one part is primarily activated by the cortex of the anterior lobe, simplex lobule and pyramis, which facilitates flexor and inhibits extensors ipsilaterally; the other part, largely independent of the cortex and activated by extracortical afferents, facilitates extensors and inhibits flexors ipsilaterally. . . . These observations, analyzed singly and in combination, indicate that the part of the reticular formation concerned with postural tonus is not intrinsically active as was previously assumed, but is dependent on outside sources for its activation in the decerebrate animal, a large part of this activation coming from the fastigial nuclei and probably Deiters' nuclei as well" (Sprague and Chambers, 1953, pp. 459-460). Since the well-known work of Beritoff and Magnus (1914) (see p. 26), it had been universally agreed that extensor rigidity was purely extracerebellar in origin. If Sprague and Chambers' challenging conclusions were now to be found correct, extensor rigidity would be conditioned by the released tonic discharge of both brain stem (Deiters' nucleus) and cerebellar (nucleus fastigii) structures. A serious objection to this view arises, in our opinion, from an important observation actually made (but not explained) by Sprague and Chambers themselves (Fig. 15E). They reported that the complete destruction of the other fastigial nucleus was followed by the reappearance of decerebrate rigidity in the atonic limbs, and actually it "equalized all legs in extreme extensor spasticity" (p. 455). If decerebrate rigidity and the extreme extensor spasticity which occurs after decortication of the anterior lobe had been the result of the release of fastigial activity, they should have been abolished, or at least strongly decreased, after bilateral destruction of the roof nuclei. This prediction, however, was falsified by the experiment. The results of Sprague and Chambers (1953) were confirmed by Moruzzi and Pompeiano (1955a, 1956b) and by Stella, Zatti, and Sperti (1955), who reported, simultaneously and independently, that extensor rigidity was strongly reduced when only the rostral part of the ipsilateral fastigial nucleus had been acutely or chronically destroyed (Fig. 16). This syndrome was called "ipsilateral fastigial atonia" by Moruzzi and Pompeiano (1955a, 1956b). These authors found, moreover, that the postural asymmetry was opposite in laterality when the lesion was limited to the caudal pole of the fastigial nucleus (Fig. 17). When this operation was performed, acutely, on decerebrate cats, the extensor rigidity increased in

Figure 16. A schematic reconstruction of a fastigial lesion yielding an ipsilateral disappearance of extensor rigidity. The scheme was made on serial slides 30 ft, thick. The intervals between one drawing and the following is 450 JJL. The drawings are numbered in a rostrocaudal direction from 1 to 8. The rostral half of the right fastigial nucleus had been destroyed while the caudal portion had been spared. The shaded area represents the lesion. F, I, D = fastigial, interposite, and dentate nuclei. (From G. Moruzzi and O. Pompeiano, 1956, Crossed fastigial influence on decerebrate rigidity, J. Comp. Neural., 106:371-392, Fig. 6.)

82

Figure 17. Schematic reconstructions of a unilateral jastigial lesion yielding crossed disappearance oj extensor rigidity. Details as in Fig. 16. The striking postural imbalance was obtained when the caudal half of the left roof nucleus had been encroached upon, while the rostral half was thoroughly intact. (From G. Moruzzi and O. Pompeiano, 1956, Crossed fastigial influence on decerebrate rigidity, J. Comp. Neurol., 106:371-392, Fig. 5.)

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Figure 18. The effect of a lesion of the caudal pole of the left fastigial nucleus after precollicular decerebration. Cat in the prone (A) and supine (5) position. Disappearance of extensor rigidity and mild flexor tonus of the right legs. (From G. Moruzzi and 0. Pompeiano, 1956, Crossed fastigial influence on decerebrate rigidity, J. Comp. Neurol., 106:371-392; from the original of Fig. 2.)

Figure 19. Effects of symmetrical lesions of the caudal poles of both roof nuclei. The same cat as in Fig. 18 in the prone (A) and supine (B) position, following lesion of the caudal part of the other (right) fastigial nucleus. Extensor rigidity is again present in the right legs, and the body posture is now symmetrical. (From G. Moruzzi and O. Pompeiano, 1956, Crossed fastigial influence on decerebrate rigidity, J. Comp. Neurol., 106:371-392; from the original of Fig. 3.)

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the ipsilateral limbs and disappeared or was strongly reduced on the opposite side of the body. This syndrome was called "crossed fastigial atonia" (Fig. 18). The experiments of Moruzzi and Pompeiano were made on sixty decerebrate cats. The melting of extensor rigidity in the limbs of the opposite side of the body was shown to be a symptom of fastigial deficiency by the following histological controls and experiments: (a) Serial Nissl and Weil slides showed that the other cerebellar nuclei and all brain stem structures were normal, and that clearcut effects were obtained when the lesion was strictly localized in the caudal pole of one fastigial nucleus, (b) Crossed fastigial atonia lasted as long as the preparation in the acute experiments (up to twenty-four hours), and no extensor rigidity ensued in the contralateral limbs even when the caudofastigial lesion had been chronically performed some time before the decerebration (Batini and Pompeiano, 1955a, b, 1957). (c) Just the opposite posture, i.e., ipsilateral flexion and crossed extension, was observed when the caudal pole of one fastigial nucleus was electrically stimulated (300/sec; 1 msec.; 0.3-0.5 volt). Since Russell's hook bundle originates in the caudal part of the fastigial nucleus (Jansen and Jansen, 1955; see also Jansen and Brodal, 1954), the hypothesis was put forward that the Russellian system would exercise a tonic facilitatory influence on the extensor mechanisms of the opposite side of the body, through crossed fastigiobulbar pathways. Crossed fastigial atonia disappeared and the symmetrical distribution of extensor rigidity was re-established when the homotopic structures of the opposite roof nucleus were encroached upon (Fig. 19). Hence it was the asymmetrical fastigial innervation, not simply the withdrawal of fastigial facilitation, that was responsible for the unilateral melting of decerebrate rigidity. This observation incidentally explains why extensor rigidity disappears ipsilaterally to a total fastigial destruction. After such a lesion both Russellian systems are inactivated, either by postdecussational severance of one hook bundle or by destruction of the somata whose axons give rise to the other Russell's tract. Hence the asymmetrical innervation concerns only the direct fastigiobulbar system, whose unilateral destruction would be mainly responsible for this type of ipsilateral fastigial atonia. The hypothesis was made that the extensor mechanisms, deprived of the support of Russellian facilitation, were overwhelmed by an inhibitory barrage arising in the opposite side of the body. Experiments to be reviewed in other sections of our monograph (see pp. 265, 283) actually showed that a crossed inhibitory barrage arising in the stretch receptors of the rigid limbs (Moruzzi and Pompeiano, 1955b, 1957a) and in vestibular receptors of the spastic side of the body (Moruzzi and Pompeiano, 1955c, 1957a) is responsible for the unilateral collapse of decerebrate rigidity. A striking reduction in the extensor rigidity of the right legs occurred also if the caudal part of the left fastigial nucleus was spared when the left half of the cortical areas of the pyramis and uvula (lobules VIII and IX) or the white matter underlying them was destroyed. These cerebellocortical areas are known to project onto the caudal pole of the ipsilateral fastigial nucleus (Jansen and Brodal, 1940, 1942, 1954), and the hypothesis was made that Russellian facilitation might be at least partially driven by corticonuclear impulses. The symmetri-

86 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM cal distribution of extensor rigidity was re-established when the remaining part of lobules VIII and IX was ablated. The ipsilateral fastigial atonia is anatomically a more complex phenomenon. Any rostrofastigial lesion will involve not only (a) an extensive destruction of the somata of the direct fastigiobulbar neurons, which are mainly located in the rostral portion of each roof nucleus (Jansen and Jansen, 1955; see also Jansen and Brodal, 1954), but also (b) the postdecussational severance of most of the fibers of Russell's tract arising in the caudal portion of the opposite fastigial nucleus (see Rasmussen, 1933). Hence a rostrofastigial lesion can never be really unilateral. To overcome this difficulty, Batini and Pompeiano (1958a and b) performed the bilateral destruction of the caudal half of the fastigial nucleus, thereby producing the symmetrical inactivation of most of the Russellian systems. The cats were decerebrated two to sixteen days thereafter, and the functional integrity of the rostral portions of the roof nuclei was tested by stimulating electrically the corticocerebellar areas projecting upon them (see Jansen and Brodal, 1954). Threshold stimulations of the culmen and of the lobulus centralis (Larsell's lobules V, IV, and III) yielded the classical melting of extensor rigidity. The unilateral destruction of the large-celled rostromedial part was then followed by a marked decrease in the ipsilateral and by an increase in the contralateral extensor rigidity, i.e., by symptoms similar to those characterizing the ipsilateral fastigial atonia. The destruction of the rostrolateral part yielded just the mirror image of this postural asymmetry, i.e., a further release of the ipsilateral extensor tonus and a reduction in the spasticity of the contralateral limbs. The latter operation was followed, moreover, by a clear-cut reversal of the classical inhibition of extensor rigidity elicited by stimulating the overlying anterior hemivermis, a previously made observation (Moruzzi and Pompeiano, 1954, 1957b) hinting that the inhibitory fastigial relays had been more or less selectively destroyed (see p. 131). The unilateral extensor atonia disappeared and the limbs of both sides showed strong and symmetrical extensor rigidity when the homotopic structures of the other nucleus were fulgurated. The conclusion was drawn that neurons exerting facilitatory and inhibitory influences upon antigravity mechanisms are located respectively within the rostromedial and the rostrolateral portions of each fastigial nucleus. 2. ISOLATED LESIONS or THE NUCLEUS INTERPOSITUS Snider (1940b) found tremor, ataxia, and slight ipsilateral hypertonia following histologically controlled lesions in the rabbit limited to one nucleus interpositus. A transient loss of tactile and abduction placing reactions was reported by Chambers (1948), following lesions limited to the interpositus and dentate nuclei in the cat. These findings were confirmed by Sperti and Zatti (1953c). With further investigations Chambers and Sprague (1955a) found a permanent ipsilateral loss of tactile placing reactions following total unilateral destruction of the nucleus interpositus. Proprioceptive placing and hopping reflexes were absent or sluggish during the first week in the ipsilateral limbs, whose extensor tonus and supporting reflexes were mildly, though clearly, increased. Both ipsilateral limbs showed goose stepping, and "during the first 7-10 days, when propriocep-

ABLATION EXPERIMENTS 87 live reflexes were absent or very poor, the animal frequently came to rest standing on the dorsum of the forefoot." These symptoms had been observed by the old physiologists following hemicerebellectomy (Lewandowski, 1903; Ducceschi and Sergi, 1904); the famous controversy about cerebellar influence on the "muscle sense" has been reviewed elsewhere in this book (p. 43). Chambers and Sprague (1955b) also described the effects of partial lesions of the interpositus nucleus: the results were essentially the same, but only transient abolition of the placing reflexes was observed. Chambers and Sprague (1955a) reported that when decerebration was carried out in a cat whose nucleus interpositus had been totally and chronically destroyed, extensor rigidity was greater in the ipsilateral foreleg. This postural asymmetry was, therefore, the reciprocal of that elicited by unilateral, total fastigial lesions. It was not abolished by retrorubral decerebration. In the primate experiments of Botterell and Fulton (1938b) and of Carrea and Mettler (1947) the destruction of the nuclei globosus and emboliformis, corresponding to the nucleus interpositus of the lower mammals, was associated with other cortical and nuclear lesions. 3. ISOLATED LESIONS OF THE NUCLEUS DENTATUS Following unilateral dentate ablation in the dog, both static and intentional tremor were reported by Sperti and Zatti (1953c). A slight static tremor was observed also following fastigial destruction, but it disappeared within ten days, whereas the dentate tremor was still present ten weeks after the operation. No hypotonia, but abolition of the placing reactions, was reported. According to Chambers and Sprague (1955b), purely cortical lesions of the lobulus ansiformis were asymptomatic in the otherwise intact cat, whereas a clear-cut syndrome ensued when the underlying dentate nucleus was almost completely encroached upon. The ipsilateral limbs showed "loss of tactile placing, impairment of visual, vestibular and proprioceptive placing, reduction of hopping and general poverty of individual limb movements. . . . There was no detectable alteration in postural tone, supporting reflex and knee jerks." These workers rightly pointed out that "the most striking symptoms—the total loss of tactile placing and the poverty of certain movements—were especially interesting because of the lack of changes in tone and deep reflexes and the absence of any abnormality of limb position or of any deficit in walking on the floor" (p. 661). Botterell and Fulton's lesions of the nucleus dentatus in primates (1938c) were associated with decortication of one cerebellar hemisphere. The monkeys were compared, however, with others in which "almost exactly the same amount of cerebellar cortex" (p. 67) had been destroyed but in which the dentate nucleus had not been encroached upon. The neocerebellar decortication elicited "ipsilateral awkwardness in volitional movements, hypotonia (also ipsilateral) and disturbance of gait," but "unilateral hemisphere ablations involving part of the dentate nucleus cause all the disturbances just mentioned and in addition transient ataxia with tremor" (p. 86). Hence tremor, according to these workers, would be mainly a symptom of dentate deficiency. These results were confirmed by Carrea and Mettler (1947), who stated that "lesions of the dentate and interposed nuclei

88 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM produce intense ataxia and ataxic tremor, occurring during voluntary and associated activity, as well as tremor which may disappear during voluntary activity" (p. 282). According to these investigators, then, both postural and intentional tremor occur following dentate lesions in primates. E. SECTION OF THE CEREBELLAR PEDUNCLES IN MAMMALS 1. INTRODUCTORY REMARKS The older experiments of isolated section of the cerebellar peduncles will not be reviewed in this book, since they were not checked histologically. The need of histological controls is particularly great when lesions so near the brain stem are performed. Most of the symptoms reported were very probably due either to irritation or to lesions of brain stem structures. Moreover, the effect of pain from the wound should not be neglected, since Di Giorgio (1925) found that the rolling movements elicited by unilateral section of the cerebellar peduncles were abolished following cocainization of both skin and muscles in the wounded area. The reader interested in the history of early experiments on peduncular section is referred to Longet (1850), Luciani (1891), and von Bechterew (1909). The older investigators were mainly interested in the neural mechanisms of the rolling movements, the discovery of which is attributed to Pourfour du Petit (1766) and which attracted the attention of such prominent physiologists as Magendie (1824) and Schiff (1845). It is likely that these effects were due to lesions of the vestibular nuclei; and it is certain, at least, that no satisfactory evidence of their cerebellar origin was obtained by the nineteenth-century physiologists. These experiments accordingly will be ignored. In the following pages we shall review only those experiments which included histological controls and which resulted in conclusions that make it likely that major brain stem lesions had been avoided.

2. INFERIOR CEREBELLAR PEDUNCLES Ferrier and Turner (1894), in experiments performed on the macaque, failed to differentiate the restiform body proper from the juxtarestiform body and made no attempt to separate the various components of the restiform body proper. Moreover, many of the effects they described probably were due to injury of the intramedullary portion of the juxtarestiform body, as shown by the results obtained by Ferraro and Barrera (1936a, b, 1938) in the same species. a. RESTIFORM BODY PROPER

Marburg (1904) was the first to attempt to section separately the various components of the inferior peduncle. He severed the dorsal spinocerebellar tract at the second cervical segment in dogs, but his lesions were complicated by simultaneous involvement of the underlying corticospinal tract. Bing (1906, 1907) confined his lesions, which he also made at the second cervical segment in dogs, to the spinocerebellar tracts (Flechsig's and Gowers'); with Marchi controls he showed that no descending degeneration had been produced. Both his anatomical and physiological results were confirmed by Moruzzi (1934a) with experiments performed on dogs.

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Following a unilateral section, Bing noted abduction of the ipsilateral legs, with slow correction of malpositions, ataxic gait, and hypotonia. The animals' disabilities were accentuated when they were blindfolded. If the dogs were made to jump, they often fell to the operated side. Improvement occurred rapidly and after four weeks the only difficulty was in turning toward the operated side in search of food. When the ventral spinocerebellar tract was spared, the syndrome was qualitatively the same, but the intensity was definitely lower and the recovery occurred very quickly; two weeks after the operations it was impossible to perceive any difference between operated and normal sides. Bing confirmed these findings by experiments of bilateral spinocerebellar transection. He thought that the function of the spinocerebellar tract was to conduct proprioceptive impulses to the vermis. The main difference which he found between section of the spinocerebellar tract and ablation of its projection areas within the cerebellar cortex was that hypotonia, not hypertonia, was elicited by severing the afferent pathways. These results may eventually be explained if more anatomical information becomes available on the relations of the spinocerebellar system to brain stem and fastigial structures. Ferraro and Barrera (1935, 1936a, 1938) were the first to differentiate lesions of the restiform body proper from lesions of the juxtarestiform body; they also made observations on the selective damage of some of these components of the restiform body. To differentiate these components, they described (1935) the results of sectioning (a) the dorsal spinocerebellar tract at the third or fourth cervical segment, (b) the restiform body at the level of the middle one third of the cuneate nucleus, and (c) the restiform body at the level of its passage under the eighth cranial nerve. This last lesion severed all of the afferent fibers of the restiform body proper, except a few olivary fibers; the second spared many olivary fibers and some of those from the other medullary nuclei. All these lesions, however, were confined to the restiform body proper. A comparison between the deficiencies in monkeys having one or the other of these three lesions at different levels showed entirely quantitative differences; i.e., the effects were more intense and lasted longer the higher the level of the section, the higher levels involving a larger number of fibers than the lower. No new or different symptoms were noted as a consequence of involvement of additional afferent systems. After section of the dorsal spinocerebellar tract, Ferraro and Barrera found some ipsilateral weakness, some hypotonia, and slight dysmetria. There were a very transitory diminution of the placing and hopping reactions and a slight diminution of tendon reflexes on the homolateral side. For a few days the animals occasionally fell toward the side of the lesion and the limbs were used in abduction. The disturbances were all transient and had practically disappeared within one to two weeks. Subsequently it was "difficult to distinguish one of these animals from a normal monkey" (1935, p. 199). After lesions at higher levels the tendency to fall was greater; there was more hypotonia, and the defect was still obvious at the end of a week. Save for minor defects which could still be noted when the monkeys were tested on a swinging bar or when landing from a high jump, even those animals whose spinocerebellar lesion had been complete could hardly be distinguished from normal ones at the

90 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM end of a period of two weeks, at which time they were sacrificed for anatomical studies. Relatively mild effects also were noted in the monkey after bilateral section of the restiform body proper at the level of the cuneate nuclei. Animals so operated fell easily for the first few days, but were able to walk and even to run within twenty-four hours. The authors described the behavior of one monkey within a week of the operation as follows: "It appears perfectly at home in the cage, although it manifests a very marked fear reaction. On the floor it still shows a tendency to fall suddenly, and in running there is still undue flexion of the forelimbs with drooping of the chest and head toward the floor. The ataxia and dysmetria are still present. The deep reflexes and muscle tone now appear normal throughout." After one month practically no abnormalities were observed except a tendency, when jumping, to land hard on the floor and occasionally to fall from a swinging bar. After two months it was practically a normal monkey (1935, p. 193). Histological controls revealed that all the afferent fibers had been severed on both sides, except the vestibulocerebellar connections of the juxtarestiform body, which were completely spared, and most of the olivary fibers coming from the more rostral parts of the inferior olive. b. JUXTARESTIFORM BODY, SUPRAMEDULLARY PART

Ferraro and Barrera (1936a, 1938) made an extensive study of the effects of section of the juxtarestiform body in the monkey. The symptoms they reported were identical, so far as we can tell from their description, with those elicited by unilateral ablation of the nodulus (Dow, 1938b) or of the flocculus (Carrea and Mettler, 1947). As already pointed out (see p. 55), ablation of the vestibular part of the cerebellum results in a syndrome of disequilibration plus abnormalities of posture and movement which are the reverse in laterality of those produced by section of the eighth nerve or by intramedullary section of the juxtarestiform body. It is likely, therefore, that the symptoms Ferraro and Barerra (1936a, 1938) described were due to the interruption of efferent fibers arising in the flocculonodular lobe and, possibly, in the lingula. They believed, however, that the effects they reported were related to section of the fastigiobulbar tract. This opinion might easily have been substantiated if the postural effects elicited (see p. 113) by stimulating the vermian part of the anterior lobe or the nucleus fastigii, after postcollicular transection and median splitting of the vermis, had been shown to be absent in the operated monkey. Unfortunately they did not undertake this control (1938) before sacrificing their animals. It is therefore impossible to determine whether the minor disturbances of postural tone they reported ("occasional slight ipsilateral hypotonia"), which contrast so markedly with the striking effects of isolated fastigial destruction in lower mammals (see p. 77), may be explained by the differences between species, by the presence of a fastigial outflow through the brachium conjunctivum (Jansen and Jansen, 1955), or, more simply, by the fact that the lesions which they performed were incomplete.

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C. JUXTARESTIFORM BODY, INTRAMEDULLARY PART

Ferraro and Barrera (1936a, 1938) also described the symptoms following intramedullary section of the juxtarestiform body in the monkey. These symptoms were the reverse of those resulting from extramedullary section and similar to those observed after unilateral labyrinthectomy. These experiments will not be reviewed here, but one thing may be mentioned. The fact that lesions only a few millimeters apart cause opposite effects on the position of the head explains some of the difficulties in interpreting this sign in the clinic, as will be pointed out in that part of our book dealing with clinical symptomatology (see pp. 382-383). 3. MIDDLE CEREBELLAR PEDUNCLE No studies have appeared of the effects of pure middle cerebellar peduncle section in subprimates. The symptoms reported as resulting from sections were most certainly caused by involvement of the adjacent vestibular complex and other brain stem structures. In the monkey experiment of Ferrier and Turner (1894) the lesion of the tegmentum pontis included the fifth nerve and also the descending corticospinal tract, as shown both from histological controls and the symptoms they reported. Turner and German (1941) described the results of unilateral section of the middle peduncle in three monkeys, all of which had been trained in psychobiological tests (problem boxes). They stated: "Unilateral section of the brachium pontis was followed by curvature of the head and spine, spiralling and circus movements toward the side of the lesion; awkwardness of the lower extremities in locomotion, with incoordination between the hindlimbs and forelimbs; slight hypotonia of both lower extremities. These symptoms disappeared within three to four weeks. A decrement in activity sometimes endured for a somewhat longer time. Transient dysmetria and nystagmus were present for a few days after operation. No tremors in either voluntary or associated movements were noted at any time" (p. 204). No chronic effects, accordingly, were observed and the experimenters failed to find the typical signs of cerebellar deficiency in their animals. In the light of the analysis made by Ferraro and Barrera (1936a, 1938) and by Dow (1938b) of vestibular and cerebellar symptoms in the monkey, some of the temporary findings they reported should be regarded as due to transient interference with brain stem vestibular centers. The fact that no permanent changes were found after unilateral lesions is in line with the well-known capacity for compensation and with the existence of a bilateral pontocerebellar projection (see pp. 202, 204). Turner and German succeeded in sectioning both middle peduncles in only one specimen, a trained mangabey monkey. There was an interval of four months between the two operations, the animal having shown no abnormalities of any kind after the first postoperative month. After the second side was operated upon, symptoms of the same vestibular type mentioned above were observed on the side of the more recent section. These persisted for two months. Four months later, according to the authors' description: "The animal's walking now differs only subtly from the normal . . . yet its gait is obviously not the easy, rhythmic gait of the normal animal. One gets the impression that the animal must con-

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stantly 'watch its step,' and this may be borne out by the fact that when forced to run, the incoordination between the hindlimbs and the forelimbs becomes more marked, with the result that it loses its balance and falls" (p. 197). Six months later, i.e., about one year after the second operation, the monkey showed a progressive deterioration in its coordinating abilities. This also was noted in another animal which had been subjected to section of one peduncle after a previous unilateral cerebellar ablation. The early symptoms appeared to be "increased greatly in severity" (p. 199), an observation which can be related to that of Luciani upon the effect of destroying the motor cortex in animals with a chronic cerebellar syndrome (see below, p. 331). Apparently certain centers that had been concerned with compensating the cerebellar deficiency were undergoing progressive deterioration. A postmortem examination showed bilateral lesions of the brachium pontis, which were complete except for some "dubious strands" intermingled with the inferior peduncle on one side. The authors offered no explanation for the late deterioration in the symptomatology. They stated that they had evidence of progressive widespread atrophy of the Purkinje cells after lesions of the brachium pontis, to be described in another paper, which apparently has not yet been published. Summing up their results, they stated that the syndrome following bilateral section of the middle peduncle was characterized by "incoordination between the lower and the upper extremities in locomotion, disequilibrium, and sluggishness of general behaviour." We may add that this syndrome was soon compensated for and that it came to light again when other cerebellar or extracerebellar structures deteriorated, six months after the operation. These experiments might have been of the greatest importance if they had been performed on more animals and if there had been a more detailed histological investigation of the monkey sacrificed during the compensation period as well as of those killed during the last decompensatory phase.

4. SUPERIOR CEREBELLAR PEDUNCLE Ferrier and Turner (1894) sectioned the superior cerebellar peduncle in the monkey, but the histological controls they reported showed quite clearly that brain stem structures also had been encroached upon in their experiments. It is likely that extracerebellar lesions were made in a section of this peduncle by Ferraro and Barrera (1936b), who also used monkeys. Keller and Hare (1934) and Keller, Roy, and Chase (1937) obtained negative results on monkeys and dogs respectively, possibly owing to incomplete lesion of the superior cerebellar peduncle. Carrea and Mettler (1955) rightly remarked that "it is almost impossible to cut all of the brachium conjunctivum without injuring neighborhood structures. If the lesion is not large enough to overcome the law of physiologic safety (i.e., if much of the brachium escapes damage) we may fail to detect the true consequences of brachial section. If the lesions are too large and consistently involve the same neighborhood structures damage of these may introduce spurious deficits" (p. 163). Our review will be restricted to those papers in which a deliberate attempt

ABLATION EXPERIMENTS 93 was made to correlate physiological findings with the results of the histological controls. Walker and Botterell (1937) performed the chronic section of one or both superior cerebellar peduncles on nineteen primates, three of them baboons (Papio papio), and sixteen of them macaques (Macaco, mulatta). In serial sections of the pons, cerebellum, and caudal part of the mesencephalon they showed that the syndrome was not due to coincidental damage of adjacent structures, but chiefly to interruption of efferent cerebellar pathways. On the first postoperative day following unilateral section, "when the animal attempted to walk or run about, it staggered and fell, usually to the side of the lesion. . . . The hind limb on the side of the lesion frequently gave way beneath the weight of the animal. . . . Usually the ipsilateral limbs were less resistant to passive movements at all joints" (pp. 335-336, italics ours). These are obviously the patterns of atonia, as described by Luciani in the monkey (see above, p. 47), and the lack of release symptoms in the acute stage is typical of primate behavior after unilateral cerebellectomy (see p. 36). Astasia (intentional tremor), but no asthenia ("no motor weakness could be detected on examination," p. 335), was observed. The compensation was very efficient but never complete, since within a few weeks of the operation the acute signs subsided and after a period of six weeks there was but little change from day to day (p. 337). During the chronic period the intentional tremor in the ipsilateral upper extremity was minimal and there was no hypotonia. Some dysmetria still was present, and Luciani's functional compensation was shown by the observation that the animal's base was widened on the side of the lesion. After a few months the animal became almost normal, but if it became excited, fatigued, or was forced to use its affected extremities for delicate movements, the cerebellar deficiency was again manifested. Walker and Botterell (1937) also gave a detailed description of the effects of bilateral section of the brachium conjunctivum. Both sides were sectioned in a one-stage operation in two monkeys, and in two other animals in two stages. Very accurate histologic controls were performed. The disturbance in volitional movements was "severe and persisting." It was "more than the arithmetic sum of the disability produced by two unilateral sections of the superior cerebellar peduncle" (p. 350). This was shown by the fact that "within a few weeks the animal with a unilateral section of the superior cerebellar peduncle is able to walk around without falling, whereas a monkey with both superior cerebellar peduncles cut staggers and falls even after four months" (p. 350). Tremor also was definitely stronger and more persistent, and the authors made the important observation that an accentuation of the contralateral signs occurred following section of the second cerebellar peduncle. They suggested that the superior cerebellar peduncle might also have a contralateral influence. We believe that their results fully support Luciani's ideas of organic compensation from remaining cerebellar structures. According to Walker and Botterell, there was no hypotonia on the third day, since "no abnormality in the resistance to passive movements on the two sides" was observed (p. 345). But the fact that "at first the gait consisted of pulling the

94 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM body forward by forelimbs, the buttocks and the flexed hind limbs scraping the floor," and that "later the hind limbs were slightly extended so that the buttocks were just raised from the floor" (p. 344, italics ours) could easily be explained, we think, by a severe atonia of the antigravity muscles of the legs supporting the weight of the body. These symptoms were observed when the animal began to walk, i.e., two or three weeks after the operation. Asthasia ("any attempt to lift the head resulted in extreme swaying of the head and trunk"; "the kinetic tremor of the extremities became less marked in the course of a few weeks, but was present and definite as long as the animals were observed") and dysmetria ("error of range and rate of movement") were also reported (p. 344). Peterson, Magoun, McCulloch, and Lindsley (1949) observed action tremor and dyssynergia following chronic interruption, in monkeys, of the superior cerebellar peduncles at their crossing. There was also some spasticity, which they referred to adjacent tegmental involvement, but no postural tremor. Carrea and Mettler (1955) came to different conclusions with experiments performed on forty-three monkeys (Macacus rhesus} and one baboon (Papio papio). They maintained that postural tremor was elicited not only by dentate lesions (Carrea and Mettler, 1947), but also when the ventral component of the crossed ascending limb of the brachium conjunctivum was damaged. These fibers project rostrally toward the thalamus and globus pallidus, and their isolated lesion brought about postural tremor without ataxia. The latter occurred when the brachial lesion interrupted efferent pathways projecting caudally to segmental levels, namely, when the severance of the crossed descending limb of the brachium conjunctivum was associated "with interruption of the conduction circuit mediated successively through dorsal and intermediate components of the crossed ascending limb, the magnocellular part of the red nucleus and the rubro-spinal tract" (1955, p. 300). However, in a recent preliminary note, Mettler and Orioli (1955) reported that a combined lesion of the rubrospinal tract and of the crossed descending limb of the brachium conjunctivum was not followed by ataxia, which, they maintained, "cannot be produced by any non-cerebellar lesion short of total abolition of the outflow through the brachium conjunctivum." Biirgi (1943a and b) destroyed the superior cerebellar peduncle in twelve cats, using high-frequency currents introduced through Hess electrodes. Histological controls were performed using Marchi's and Donaggio's degeneration techniques and the methods of Nissl and Heidenhain. Some of the symptoms Biirgi reported might have been related to Luciani's atonia ("Einknicken der Extremitaten, Abweichen und manchmal Fall nach der Herdseite," 1943a, p. 379), although he denied (1943b) the existence of this symptom. But the fact that the tendon reflexes were sometimes increased (1943b) does not preclude atonia (see above, p. 42). Astasia was found to be entirely absent, a finding not in accord with the marked tremor found after dentate ablation in the dog (see p. 87). Rademaker's reflexes were carefully investigated. If the hands were applied to the back of the animal, only a small amount of pressure was necessary to roll it over toward the side of the lesion. On the other hand, a strong push was required to accomplish this in the other direction, toward the uninvolved side. The animal did not modify a passive abduction of the ipsilateral limbs as on the normal side

ABLATION EXPERIMENTS 95 and sometimes remained in a peculiar position for several minutes. This was interpreted as some kind of cataleptic symptom. There were no symptoms which did not completely disappear in two to three weeks. It is clear from these experiments that section of the superior cerebellar peduncles reproduced most of the signs of Luciani's deficiency, at least in primates, where the effect of the operation was particularly severe and less easily compensated for. F. GENERAL CONSIDERATIONS That cerebellar physiology has been approached predominantly from a medical point of view none would deny. It is no wonder, therefore, that the vast majority of modern experiments have been performed on mammals. A fair number have been performed on birds, but disproportionally little is known of the cerebellar physiology of the lower vertebrates. Comparative physiology has not been entirely neglected, and the results of the experiments performed on lower vertebrates are cited in different sections of this volume. It has not been systematically explored, however, so that it is impossible to write a monograph on the physiology of the cerebellum from the comparative point of view. Hence our discussion is limited to birds (pigeon), lower mammals (cat and dog), and primates (monkey and ape), since these are the animals on which most of the experimental studies have been made. We have pointed out that differences between species often have not been given the weight they deserve in analyses of the deficiencies seen after ablation experiments. There appears to be a cleavage between the birds, the subprimate mammals (dog and cat), and the primates in this respect. In the avian cerebellum we are dealing with an organ predominantly concerned with the regulation of spinal and brain stem mechanisms. In the dog and cat cerebellar control is more or less equally devoted to spino-brain stem and to cerebrocortical mechanisms. In the primates, on the other hand, the cerebellum is chiefly related to voluntary movements, to the distinct subordination of the spino-brain stem mechanisms. As Bremer (1935) rightly pointed out, much controversy on the nature of cerebellar function might have been avoided if investigators had not overlooked or underrated the importance of differences between species. There is no doubt that the symptoms reported by the authors who performed ablation experiments concerned mainly—often indeed exclusively—the somatic motor system. A relation to sensory functions or to the autonomic nervous system is possible and indeed has been suggested, chiefly as a result of stimulation or of electrophysiological experiments (see p. 350). Obviously, however, the regulation of the contraction of the somatic muscles is the principal result of cerebellar activity. Possibly a more refined analysis of the symptoms presented by completely or partially cerebellectomized animals may eventually uncover deficiencies also in the sensory or automatic spheres. But the very fact that most physiologists have so frequently missed or at least disregarded such deficiencies, being impressed instead by the severity of the postural and motor symptoms, is in itself conclusive evidence that the regulation of somatic movements is at least more essential, or less easily compensated for, than any influence the cerebellum may

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exercise on the conscious elaboration of sensory messages or on the regulation of the autonomic nervous system. Hence our discussion will be limited, intentionally, to the effects of cerebellar ablation in the somatic motor sphere. The contraction of skeletal muscles may be postural or phasic. Sherrington (1906) remarked that skeletal muscles might be regarded as structures "concerned with the maintenance of attitude" (postural tonus) and as "organs of motion" (phasic movements) (p. 340). He added that "the body and other levers of the body are maintained in certain attitudes both in regard to horizon, to the vertical and to one another," and concluded that "evidently the greater part of the skeletal muscles is all the time steadily active, antagonizing gravity." Although the antigravity tonus of the extensor muscles represents by far the most important part of the postural activities of quadruped mammals, at least when they are standing on their feet, it should be emphasized—and was conceded by Sherrington himself—that other muscles may also be concerned in the maintenance of posture. Postural tonus and antigravity tonus are not synonyms, as was silently assumed by many physiologists. When the significance of Rossi's postural asymmetries was discussed (see p. 73), we pointed out that the tonic activity of the cerebellum is not uniquely concerned with the neural control of reflex standing. Phasic contractions were defined by Sherrington as "short-lived events" whose aim is to alter a posture, therefore bringing about a movement of the whole body or of only its parts. Phasic contractions may be reflex or voluntary in origin. An analysis of cerebellar influence in the somatic motor sphere should be concerned with three topics: (a) postural tonus, (b) reflex phasic contractions, and (c) voluntary phasic contractions. The present discussion will be devoted almost entirely to the first of these. Cerebellar influence on phasic reflexes will be dealt with in the chapter on stimulation experiments, and the problem of cerebellar regulation of voluntary movements and conditioned reflexes will be discussed at the end of the fifth chapter, when the data on cerebellocortical relations have been made available to the reader. Only a few remarks on the nonpostural symptoms of cerebellar deficiency will be made at this time. The problem of somatotopic and functional localizations will be left until later, since the data we have reported so far are too scanty to be discussed. Cerebellar influence on postural tonus has been the subject of so much controversy that it is both surprising and gratifying to note that on the facts, at least, there is fundamental agreement between the authors who performed complete or unilateral ablation experiments. Our discussion may well begin with the classic works of Lange (1891) and Luciani (1891), who were the first to perform chronic ablations on birds and mammals respectively. Lange's experiments were made on pigeons, and his results were confirmed by Bremer (1924), ten Gate (1926a), Bremer and Ley (1927), and Chiarugi and Pompeiano (1956a). There is no doubt that extensor hypertonia results from either acute or chronic ablation of the avian cerebellum and even from lesions restricted to its anterior lobe. These release symptoms suggest that the tonic activity of the avian cerebellum is mainly inhibitory in nature, at least as far as the regulation of the antigravity tonus is concerned. It should not be forgotten, however, that

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Chiarugi and Pompeiano (1956a) found in the thalamic pigeon a striking ipsilateral decrease in the extensor tonus of the pelvic limbs when the deep nuclei had been asymmetrically encroached upon. The ipsilateral extensor hypotonia is, moreover, a deficiency symptom, and it disappears altogether when the other nucleus is destroyed. Hence there is a puzzling discrepancy between the results of unilateral and bilateral lesions of the avian cerebellum. The same difficulty (which will be discussed later) is met with when the fastigial nuclei are either unilaterally or bilaterally destroyed in lower mammals. Luciani's experiments were performed on dogs and on monkeys. In order to avoid any misconception, it will be helpful to define what Luciani meant by the term he coined to describe the postural deficiencies of the cerebellectomized mammal. Luciani's atonia is essentially represented by a decrease of the supporting tonus, which is observed (a) during the deficiency period, (b) in the standing animal, (c) when the rest of the nervous system is intact. For the time being we are not concerned with Luciani's doctrine, but simply with the facts he presented. We believe that the following conclusions can be drawn: (a) Extensor hypotonia has been confirmed by all investigators who made total or unilateral ablations in primates, (b) In the sense previously stated, extensor hypotonia was constantly found also (although often not labeled as such) after unilateral cerebellectomy in lower mammals. It is important to stress, in view of the flat denial of the very existence of atonia repeatedly made by Dusser de Barenne (1923, 1937) and by Rademaker (1931), that actually their own negative experiments concerned exclusively the effects of total cerebellectomy in lower mammals. We have pointed out (see p. 44) that atonia, in Luciani's sense, was undoubtedly present in their unilaterally cerebellectomized dogs. The negative results obtained by Rademaker with his totally decerebellate dogs cannot be neglected, however, and the careful experiments performed by the Dutch investigator deserve a detailed discussion. His observations were often, but not exclusively, made during Luciani's compensation period. This may be an important reason, but hardly the only one, for his failure to detect atonia. Many misconceptions about cerebellar regulation of the supporting tonus arose (a) from the lack of a clear-cut distinction between the reflex excitability and the strength of the postural mechanisms, and (b) from the unjustified assumption that the intensity and the type of the deficiency symptoms should be essentially the same following either total or unilateral cerebellectomy. These distinctions are so important, in our opinion, that they require detailed discussion. The difference between reflex excitability and the over-all strength of the postural extensor mechanism has not been adequately recognized by cerebellar physiologists. When the tendon reflexes (Russell, 1894; Luciani, 1894; AndreThomas, 1897; Lewandowski, 1903), the magnet reaction (Rademaker, 1931), or the labyrinthine reflexes (Pollock and Davis, 1927) are found to be increased following cerebellectomy, this simply means that a lower intensity of myotatic, tactile, and vestibular stimulation is required for eliciting the response of the extensor motoneurons. We are then entitled to say that the reflex excitability of the postural mechanisms is increased. We are not justified, however, if we state— as Ferrier (1894) and von Monakow (1897) were the first to do—that these find-

98 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM ings disprove Luciani's atonia. Atonia is essentially represented by a decreased strength of the supporting tonus, as shown by the sagging of the limbs under the weight of the body. Actually Rademaker himself showed quite clearly, although he did not draw the obvious conclusions from his findings (see p. 32), that after cerebellectomy the legs may show clear-cut spasticity when the animal is lying supine and yet the strength of the supporting tonus may be greatly decreased. This decreased strength of the extensor tonus is not necessarily and exclusively due to lack of cerebellar facilitation, as Luciani believed. It may be explained, at least as concerns fastigial atonia, but possibly also as concerns other types of cerebellar atonia, by an inhibitory influence arising in muscle and labyrinthine receptors. The experiments of Moruzzi and Pompeiano (1955b and c, 1957a) dealing with the conflict between cerebellar facilitation and bulbospinal inhibition will be reviewed elsewhere (see pp. 265, 283). In the second place, the difference between the results of unilateral and total cerebellectomy in lower mammals is another important fact, surprisingly neglected both by physiologists who supported Luciani's views and by those who contended against them. Following unilateral ablation, extensor tonus is certainly strongly inhibited, on the cerebellectomized side, when a Stutzreaktion or a Magnetreaktion is elicited in the contralateral, "normal" limb (Rademaker, 1931; see above, p. 45 and Fig. 11). This might be explained by Luciani's concept of atonia, since a decrease in the background of tonic excitation would make the centers for the extensor tonus more easily inhibited on the cerebellectomized side. We have also emphasized the fact that decerebrate rigidity vanishes in the ipsilateral limbs following total unilateral fastigial destruction, whereas bilaterally strong extensor spasticity occurs when both fastigial nuclei or homotopic portions of them are symmetrically destroyed (Sprague and Chambers, 1953; Moruzzi and Pompeiano, 1955a, 1956b). Hence fastigial atonia results from asymmetrical cerebellar innervation rather than from withdrawal of a facilitatory influence arising in the roof nuclei. The postural mechanisms of the "atonic" side of the body are probably overwhelmed by the inhibitory influence arising in the stretch receptors of the opposite limb (Moruzzi and Pompeiano, 1955b, 1957a; see below, p. 265). This inhibitory influence is likely to increase when, as in Rademaker's experiments (1931), a Stutzreaktion is made in the "normal" limbs or simply when their extensor muscles are stretched by the weight of the body, as they certainly are in any standing position. Undoubtedly atonia is not the unique consequence of cerebellar deficiency in the postural sphere. The release symptoms, so evident in birds, are observable also in the lower mammals during Luciani's dynamic period, whereas they are practically absent in primates. There is no doubt, in our opinion, that the extensor rigidity of the forelimbs and the opisthotonos observed by Luciani in the dog during the first week following total cerebellectomy are due to a release from cerebellar inhibition of both myotatic and labyrinthine reflexes. The evidence for this is overwhelming, and has been fully reviewed above (see p. 60). It should be emphasized again that the release symptoms occurring during the dynamic period are nothing but the result of a type of cerebellar deficiency which simply lasts for a shorter period than the deficiency which is responsible for Luciani's

ABLATION EXPERIMENTS 99 atonia, possibly because it is more easily compensated for by other nervous structures. Actually, during the deficiency period the symptoms of hypertonia and those of atonia coexist in the same animal (see p. 41). This observation, which Luciani (1891) himself made and which was particularly stressed later on by Lewandowski (1903), was a major source of controversy in the discussions which arose among cerebellar physiologists. The finding seemed indeed to be paradoxical, since the cerebellum was believed by these investigators to be a functionally homogeneous structure, and it was difficult for them to understand how such antagonistic influences might be exercised by the same center on the same neurons. But the observation is less surprising in our time. We are now coming to grips with what may be regarded as one of the most controversial problems in cerebellar physiology. It is certainly disturbing to realize that the antigravity muscles, so obviously hypotonic for some time after cerebellar ablation (Luciani's atonia), are those responsible for decerebrate rigidity; and to learn, moreover, that the latter is not abolished (Sherrington, 1898; Beritoff and Magnus, 1914), but actually strengthened, by anterior lobe topectomy (Bremer, 1922a) or even by total cerebellectomy (Pollock and Davis, 1927). The answer to this problem may be searched for in two different directions. The first is represented by Bremer's comparative approach to cerebellar physiology; the second is provided by recent investigations on fastigial physiology. Bremer (1935) is responsible for a lucid interpretation of the evolution of the cerebellar regulation of postural tonus. He held that postural extensor mechanisms are tonically inhibited, through bulbospinal relays, by the paleocerebellum, whereas a tonic facilitating influence is exercised by the neocerebellum on the cerebral cortex. This may explain why hypertonia results from total cerebellar ablation in birds, whose cerebellar regulation is mainly paleocerebellar in origin, whereas clear-cut atonia is present in monkeys and appears to be particularly marked in the ape and in man, in which the cerebral cortex and the neocerebellum have such an overwhelming importance. In lower mammals atonia would be less striking, as Miller (1926b) had already suggested, because of the algebraic summation of the release symptoms with those which are due to the withdrawal of cerebellar facilitation. Clear-cut atonia occurs also in lower mammals, according to Bremer (1935), when the ablation is localized in the neocerebellum (see p. 65). Bremer's views on cerebellar control of postural tonus in monkeys were confirmed by the experiments of Botterell and Fulton (1936, 1938c). They were also indirectly supported by the observation that a tonic discharge could be led from the pyramidal tract (Adrian and Moruzzi, 1939), as well as by the similarity between the symptoms of hypotonia following cerebellectomy and those elicited by medullary pyramidotomy in primates (Tower, 1940). As far as primates are concerned, Bremer's hypothesis (1935) that "I'hypotonie cerebelleuse, au meme titre que 1'asthenie volontaire qui I'accompagne, est 1'expression de I'insuffisance fonctionnelle des activites reflexes cortico-spinales et cortico-bulbaires resultant de la suppression de 1'action facilitatrice (sthenique) qu'exerce sur ces activites le neocervelet" (p. 124) is likely to account in a large measure for the postural syndrome that characterizes cerebellar deficiency.

100 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM In lower mammals, however, the neocerebellar explanation of the extensor hypotonia meets with some difficulty. First of all, the importance of the cerebral cortex for the maintenance and even for the regulation of the antigravity tonus is greatly reduced in the carnivores. Second, Rademaker (1931) has clearly shown that a striking decrease in the supporting tonus occurs even when the hemicerebellectomy is performed in a chronically decorticate dog. Third and finally, recent investigations on fastigial physiology (Sprague and Chambers, 1953; Moruzzi and Pompeiano, 1955a, 1956b; Stella, Zatti, and Sperti, 1955) have demonstrated that decerebrate rigidity disappears on one side of the body whenever the roof nuclei are asymmetrically encroached upon. Hence the same bulbopontine mechanisms released by decerebration or by the topectomy of the anterior lobe apparently require the strengthening influence of some fastigial neurons, at least when the homotopic elements of the opposite side are intact. This kind of cerebellar atonia has been shown by histological controls to be entirely independent of both neocerebellar and vestibular lesions. It occurs on the ipsilateral or contralateral side of the body, when the rostral or the caudal parts respectively of one fastigial nucleus are encroached upon (Moruzzi and Pompeiano, 1955a, 1956b). A syndrome strikingly similar to Luciani's atonia ensues, moreover, when the whole (Sprague and Chambers, 1953) or the rostral part (Batini and Pompeiano, 1955a, 1957) of one fastigial nucleus is chronically destroyed in the otherwise intact cat. When the chronic lesion concerns the caudal portion of the roof nucleus, the symptoms of extensor atonia are localized on the opposite side of the body (Batini and Pompeiano, 1955a, 1957). Dusser de Barenne's suggestion that Luciani's atonia was due to lesions of the vestibular nuclei and that this symptom occurred simply as a surgical accident is well known. This opinion was never proved and can be safely dismissed, even as regards the lower mammals. Obviously no one would be prepared to maintain that in the older ablation experiments the vestibular nuclei were never encroached upon. But there is no doubt that a striking syndrome of ipsilateral extensor atonia occurs whenever a comparatively small part of the cerebellum, such as the roof nuclei, is unilaterally destroyed, with histologically controlled integrity of the other cerebellar structures and of the brain stem. That brain stem lesions are more likely to occur following large cerebellar ablations is conceded, but we are at a loss to understand why neighborhood lesions should have been elicited constantly (since ipsilateral atonia is a constant phenomenon) after unilateral ablation and never after total cerebellar ablation, at least in the experiments performed by Dusser de Barenne and by Rademaker. Although the unilateral interruption of fastigial innervation is followed, in lower mammals, by a postural syndrome strikingly similar to Luciani's atonia, there is no reason to believe that the hemispheres and the neocerebellar nuclei do not contribute to the regulation of the postural extensor tonus even in the carnivores. The evidence is undoubtedly negative for the dentate nuclei, but Chambers and Sprague (1955b) have recently shown that posture is affected in opposite directions by a destruction of either the intermediate part of the anterior lobe or the nucleus interpositus to which it projects. Vice versa, a fastigial component is likely to be present in the extensor hypotonia resulting from hemicere-

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bellectomy in primates. We have yet no experimental evidence, but since this syndrome is present in birds and in lower mammals following asymmetrical nuclear lesions, that it will be entirely absent in primates is unlikely. In surnmary, the difference between lower mammals and primates would be mainly related to the greater importance in primates of the lateral nuclei and of cerebellocerebral relations in the maintenance of the supporting tonus. In consequence, extensor hypotonia would occur even after bilateral cerebellar lesions. Finally, a few words about the nonpostural symptoms of cerebellar deficiency. 1. With the exception of atonia, Luciani's deficiency symptoms (as well as those described by clinical neurologists) concern the sphere of voluntary movements or at least rather complex supraspinal activities, such as those which occur during walking. 2. Astasia, asthenia, and dysmetria are primary signs of cerebellar deficiency, which cannot be regarded as the consequence of alteration occurring in the postural sphere. The evidence for this is overwhelming and will be developed in another chapter (p. 353). At this point it is sufficient to remember that both astasia and dysmetria are clearly present when compensation for atonia is already practically complete (see p. 43). Walshe's statement (1927) that "there is no such phenomenon as cerebellar ataxy in the reflex preparation" and that "solely voluntary movement . . . is dependent upon cerebellar activity" (p. 380) is certainly too extreme to be accepted, even if its scope is limited to primates and man. We have repeatedly emphasized that brain stem activities are controlled by the cerebellum both in birds and lower mammals. It would be surprising if this regulatory influence were lost in primates and in man. It is easier to think—and it has been proved for the flocculonodular lobe—that in primates the paleocerebellar deficiencies are simply more or less concealed by the severity of the neocerebellar syndrome. Walshe's statement, however, cannot be entirely dismissed, since there is no doubt that voluntary movements are more severely affected by decerebellation than phasic reflexes. For the reflexes occurring in the spinal preparation (such as the scratch reflex) the observation is too obvious to be discussed further; our attention should be directed toward more complex reflexes involving the whole of the brain stem. Because of limited space, the discussion will be centered upon swimming and walking movements. Swimming appears to be purely reflex in nature, at least in the lower mammals, since it was observed in the guinea pig after intercollicular decerebration (Di Giorgio, 1938) and in puppies which were still unable to stand and to walk (Murri, 1915). Although it cannot be regarded as normal in the cerebellectomized dog (Luciani, 1891; Dusser de Barenne, 1937), it is certainly definitely less affected during the deficiency period than is gait (see p. 39). This might be regarded as good evidence that rather complex reflex activities are comparatively little affected by cerebellectomy. It is more difficult to understand, however, why other reflex activities, such as those which occur during walking, are so severely affected by cerebellectomy, although they certainly are subcortical in nature, at least in lower mammals. One of the reasons was pointed out by Luciani (1916), who insisted that both the

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newly born puppy and the recently cerebellectomized dog do not walk mainly because they are unable to stand. When the animal's weight is supported by the water, a defective regulation of the postural contraction of the antigravity muscles is obviously less important, and the swimming movements (which in the dog are essentially the same as the walking movements) occur. Apparently gait is severely affected by cerebellectomy because it is the result of the integrated activity of vestibular, postural, and reflex mechanisms, so that a reciprocal potentiation of the isolated cerebellar deficiencies occurs. This point will be discussed again in the clinical part of the volume.

.3

Stimulation Experiments

A. Stimulation experiments in submammalian forms 1. Fish 2. Amphibia 3. Reptiles 4. Birds B. Mechanical and chemical stimulation in mammals 1. Mechanical stimulation 2. Intracerebellar injections of curare or of nicotine 3. Local applications of strychnine or of eserine C. Electrical stimulation of the cerebellar cortex in mammals 1. Stimulation of the flocculonodular lobe 2. Stimulation of the anterior lobe of the corpus cerebelli 3. Stimulation of the posterior lobe of the corpus cerebelli D. Cortical and subcortical cerebellar stimulations in unrestrained, unanesthetized mammals E. Electrical stimulation of the cerebellar nuclei in mammals F. The efferent pathways mediating the cerebellar response G. General considerations

104 104 105 105 105 109 109 110 Ill 113 113 113 137 139 141 148 151

THE discovery by Fritsch and Hitzig (1870) of the "electrical excitability" of the motor cortex prompted several physiologists to investigate whether movements could be elicited also by stimulating the surface of the cerebellum. Underlying these early endeavors, and indeed such recent papers as those of Mussen (1927, 1930, 1931, 1934), was the assumption that cerebellar responses should be similar in type to those obtained from the motor area of the cerebrum and that the different parts of the body were likely to be represented all over the cerebellar cortex more or less in the same way as had been so strikingly shown in the seventies for the Rolandic area. These were quite unwarranted hypotheses, as we shall see later, but motor (mostly phasic) effects were nevertheless reported by Hitzig (1874), Ferrier (1876), Russell (1894), Probst (1899, 1902), Wersiloff (1899), Prus (1901), Negro and Roasenda (1907), Lourie (1907, 1908), Greker (1909), Rothmann

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(1910), and Uffenorde (1912), and their localization on the cerebellar cortex was mapped by Mussen (1927). Most of the effects obtained with faradic and occasionally (Hitzig, 1874; Prus, 1901; Greker, 1909; Uffenorde, 1912) galvanic stimulation were due, as was sometimes conceded by the authors themselves (Lourie, 1907, 1908; Rothmann, 1910), to the spread of currents and could hardly be attributed to the cerebellum. The fact was suggested by the clonic character of the movements, by the complete lack of appropriate controls, and, last but not least, by the inability of later investigators to confirm the observations. Of course genuine cerebellar responses were also occasionally reported, such as conjugate ocular deviations (see p. 138) or ipsilateral withdrawal of the forelimb (Rothmann, 1910), but the foci yielding these effects were not exactly localized. Horsley and Clarke (1908), Beck and Bikeles (1914-1915), Bikeles and Zbyszewski (1914-1915), and Bernis and Spiegel (1925) should be credited with the demonstration that no phasic response could be elicited by stimulation of the cerebellar cortex when the spread of current to the underlying structures was avoided, and with the suggestion that many of the motor effects which had been described were probably due to actual stimulation of bulbopontine structures or at least of cerebellar nuclei. Paradoxically, however, the outstanding paper of Horsley and Clarke (1908) greatly delayed progress along these lines of investigation, since the authors experimented on anesthetized animals and wrongly concluded from their findings that the cerebellar cortex was "unexcitable," or had, at least, no influence on motor activities. Such an assumption hardly could be reconciled with the existence of inhibitory (Lowenthal and Horsley, 1897; Sherrington, 1897, 1898) and facilitating (Rossi, 1912b) cerebellar effects, but only a quarter of a century after the discovery of cerebellar inhibition was it universally accepted by investigators that the inhibitory response really arose within the cerebellar cortex (Bremer, 1922a; Miller and Banting, 1922). The following years saw a flowing tide of research devoted to stimulating the different areas of the cerebellum, so that this approach can now be regarded as one of the most fruitful in the history of cerebellar physiology. The problem of the "excitability" of the cerebellar cortex has only an historical interest, and for that reason the old papers have barely been mentioned here. More details will be found in the reviews of van Rijnberk (1908a and b, 1912, 1931), Brun (1926), Spiegel (1927) and ten Gate (1931c). The following chapters will be exclusively devoted to an analysis of those responses which can be regarded as certainly or at least probably cerebellar in character. Stimulation techniques have been utilized also in electrophysiological experiments or in order to investigate the interrelations between the cerebellum and other central structures or nervous mechanisms, such as the cerebrum or the autonomic nervous system. An account of these latter groups of investigations will be presented in other chapters of the monograph. A. STIMULATION EXPERIMENTS IN SUBMAMMALIAN FORMS 1. FISH Ten Cate (1930b) found that no movements of the trunk or of the fins were elicited by bipolar faradic stimulation of the corpus cerebelli in the ray (Trigon

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pastinaca), although the optic lobes responded clearly to the same intensities. Motor responses occurred only when current intensity was further increased, but they were fallacious in character, since ipsilateral section of the crura cerebelli did not prevent them. Before accepting ten Gate's opinion that the corpus cerebelli is not excitable in those fishes, it might be advisable to investigate whether some inhibitory or facilitatory effects can be observed when the cerebellum is stimulated at a time when spontaneous or reflexly evoked movements are occurring or when motor responses are elicited by stimulating the optic lobes. Ten Gate's experiments conclusively showed, at any rate, that the head and ocular movements reports by Ferrier (1876) in fishes were due to the spread of current. In the following year ten Gate (1931a) performed experiments of chemical stimulation on the cerebellum of sharks (Scyllium canicula, Mustelus vulgaris). No motor response was observed following the superficial application of strychnine, carbolic acid, or curare, nor after the injection of a curare solution into the subcortical matter of the corpus cerebelli. Only when a sticky powder containing curare was applied to the cut surface of one crus cerebelli, following unilateral cerebellectomy, were motor responses observed. However, a spread of the drug to the medulla occurred some time thereafter. Ten Gate pointed out quite rightly that the positive results of his experiments should be interpreted with great caution.

2. AMPHIBIA The responses of the cerebellum of Rana tempararia to bipolar faradization were recorded myographically (M. ileofibularis) by Gerebtzoff (1942). Ipsilateral shortening, followed by relaxation and finally by sustained contraction, was observed, while pure excitation was reported on the opposite side. The mixed ipsilateral effect gave way to a purely inhibitory response if the cerebellar stimulation was timed to occur during a period of reflex contraction. Gerebtzoff (1942) concluded that these effects arose in the cerebellar lamina and were mediated by cerebellobulbar fibers, since they were abolished by local cocaine (2 per cent) but persisted when the brain stem was transected behind the optic lobes. Negative results were reported by Abbie and Adey (1950) on two Australian anurans (Hyla aurea, Lymnodynastes dorsalis and tasmaniensis) and on Bufo marinus, but their stimulation experiments were performed on anesthetized preparations.

3. REPTILES The reptilian cerebellum has not been explored by means of either electrical or chemical stimulation. 4. BIRDS Negative results were reported by Weir Mitchell (1869) in the experiments he performed on pigeons. There is no evidence of the cerebellar origin of the head and ocular movements which were observed by Ferrier (1876). Shimazono (1912) was the first to perform experiments of chemical stimulation on the avian cerebellum. Following local applications of 1 per cent strychnine, an ipsilateral increase of the hindleg extensor tonus occurred, which reached

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its maximum in ten minutes and faded away ten minutes thereafter. The response could be duplicated by local applications of strychnine to the cerebellar nuclei following excision of the corresponding cortex. Shimazono's results were not confirmed by Beck and Bikeles (1914), although stronger concentrations (2 per cent) of strychnine were used; and just the opposite effect, i.e., tonic flexion of the ipsilateral pelvic limb, was reported by Manni (195la) after 1 per cent strychninization. All these experiments were performed on intact, unanesthetized pigeons, but the area which was strychninized was given only in Manni's paper as two or three folia of the lobus medius. Beck and Bikeles (1914) gave no details of their experiments. It is likely that the facilitating effects reported by Shimazono (1912) following cortical strychninization were due to a spread to the underlying cerebellar nucleus (see Chiarugi and Pompeiano, 1956b). In their fundamental papers on the cerebellum of the thalamic pigeon (already dealt with in Chapter 2), Bremer (1924) and Bremer and Ley (1927) were concerned with bipolar faradic stimulation of the two posterior lobuli (the culmen; lobules IV, V) of the anterior lobe. They reported relaxation of the extensor muscles of the ipsilateral wing only when the stimulation occurred during contraction of the extensor muscles, but as soon as the faradization was discontinued an extensor rebound was observed; repeated stimulation at short intervals showed clear-cut facilitation of the rebound with recruitment of new units. The wing rebound is one of the most striking phenomena in cerebellar physiology. A contralateral extension of both wing and leg was also observed during the stimulation. Bremer and Ley (1927) showed quite conclusively that their effects arose in the cerebellar cortex, since the effects were duplicated by mechanical stimulation and abolished by local cocainization (£ per cent). They pointed out, moreover, that the myographic responses were tonic in character, easily distinguishable, therefore, from those obtained by faradizing the optic lobes or the cranial nerves. One of the most important aspects of these experiments was the demonstration that the avian responses were quite similar to those obtained by Bremer (1922a) from the anterior lobe of decerebrate mammals (see p. 115). The observation that a contraction of the extensor muscles of the forelegs occurs in both birds and mammals during the rebound from cerebellar cortex stimulation represents an interesting problem in comparative physiology, since the functional significance of the muscles is different in the two classes, the posture of the wing being essentially flexor in character. A myographic analysis performed many years later by Bremer and Brihaye (1948) and by Brihaye (1953), on the same preparation, showed that both flexor and extensor muscles of the elbow contracted during the cerebellar rebound, although the extensor response was much stronger and characterized by a prolonged afterdischarge. During the cerebellar stimulation there was a relaxation of the extensor muscles, whereas a slight contraction sometimes occurred in the flexor ones. The strychnine reversal affected only the flexor response, but did not prevent the cerebellar inhibition of the extensor motoneurons (on strychnine reversal see p. 115). Bremer and Brihaye (1948) made, moreover, the important observation that sometimes the increased excitability of the extensor mechanisms (phenomenon of the re-

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bound facilitation) yielded extension of the wings during the stimulation. These augmentatory responses originated in the cerebellar cortex just as did the inhibitory ones (cocainization controls). Sometimes rhythmic flying movements, occurring either during the stimulation or as a rebound response, were observed following repeated stimulations. They were inhibited at once upon renewed stimulation of the same cerebellar area. Chiarugi and Pompeiano (1956b) stimulated the surface and the interior of the avian cerebellum with rectangular pulses (300/sec; pulse duration, 1 msec.), delivered through unipolar enameled steel electrodes. Thalamic pigeons were used throughout, and sometimes the optic lobes were destroyed by suction, in order to explore the underlying rostral surface of the anterior lobe. Only the most rostral folia (I and II of Larsell's nomenclature) and the caudal (IX and X) could not be stimulated. Microelectrolytic destructions (Mollica, Rossi, and Venturelli, 1954) were used for purposes of localization or for the production of small lesions in chronic experiments. Histological controls were routinely performed on serial Weil and Nissl slides. Cerebellocortical responses, very similar to those described by Bremer and his associates, were obtained from the caudal folia of the lobus anterior (III, IV, V) and occasionally from the most rostral folium of the lobus medius (Via). No clear-cut somatotopic localization was found, although the pelvic limbs were affected more strongly from folia III and IV and wing responses were more easily elicited from folium V (and occasionally Via). Chiarugi and Pompeiano showed, moreover, that the lack of a wing response during the cerebellar stimulation was simply the consequence of the flexed posture. If the ipsilateral wing was passively extended with a light weight, an active withdrawal occurred during each stimulation, followed by the well-known rebound extension when the stimulus was over. There was no doubt about the cerebellar-cortical origin of these responses, which were obtained with low voltages (0.5 to 2 volts) and disappeared when the microelectrode was slightly displaced, e.g., from folium V (or Via) to folium VIb. A slight novocainization of the stimulated area increased the threshold about three or four times. If the repetition rate of the square pulses was reduced from 300 to 10 per second (pulse duration, 3 msec.), an ipsilateral augmentatory effect occurred during the stimulation, in confirmation of the results previously obtained on mammals (Moruzzi, 1948a, b). The same parameters of electrical stimulation (300/sec; 1 msec.; 0.4 to 2 volts) gave a sustained extension of the ipsilateral wing and hindleg when the tip of the microelectrode was thrust into the interior of the cerebellum. There was no flexor rebound at the end of the stimulation. The structures which gave the augmentatory effects were mapped and found to correspond to the rostromedial part of the cerebellar nucleus and to the white matter immediately surrounding it (Figs. 20, 21). A spread of current was not a factor, for controls were made in each experiment which showed, quite consistently, that the augmentatory response was extremely localized. In the chapter dealing with ablation experiments (see p. 18) other observations by Chiarugi and Pompeiano (1956a) have been reported suggesting that the atonia following unilateral cerebellectomy in birds may be the consequence of

Figure 20. Localization of augmentatory areas within the interior of the avian cerebellum. Composite diagrams showing on sagittal (A) and transversal (5) sections the localization of structures (triangles) yielding an increase in the extensor tonus of the ipsilateral hindleg. Unipolar stimulation of the interior of the cerebellum in acute thalamic pigeons. The cerebellar folia are classified according to Larsell. The stippled areas show the location of the cerebellar nuclei. Larsell's folia I, II, Ilia and b, IVa are concealed by the optic lobes (L. 0.). (From E. Chiarugi and O. Pompeiano, 1956, Effetti della stimolazione elettrica localizzata della corteccia e dei nuclei del cervelletto nel piccione talamico, Arch. d. sc. biol, 40:25-37, Fig. 1.)

Figure 21. Localization of an augmentatory zone in the rostromedial part of the cerebellar nucleus in the pigeon. Transverse section near the rostral pole of the cerebellar nuclei. Nissl method (40 X). The point in the left fastigial nucleus yielding an increase in the extensor tonus in the ipsilateral hindleg (300/sec; 1 msec.; 0.6 V.) was localized with a microelectrolytic lesion (0.1 mA. for 30 sec.). (From E. Chiarugi and 0. Pompeiano, 1956, Effetti della stimolazione elettrica localizzata della corteccia e dei nuclei del cervelletto nel piccione talamico, Arch. d. sc. biol., 40:25-37, Fig. 2.)

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lesions inflicted upon the underlying cerebellar nucleus. The stimulation experiments support this hypothesis as well as the dual nature of the fastigial nucleus (see p. 86). The papers by Machne and Zanchetti (1949) and by Machne (1950) will be reviewed separately, since they were mainly concerned with the interrelations between the cerebellum and the optic lobes in the thalamic pigeon. Faradic stimulation (Ferrier, 1876; Bremer and Ley, 1927) and chemical stimulation (Kschischkowski, 1911; Martino, 1926; Moruzzi, 1946a, 1947a) had shown that the avian optic lobes share many of the properties of the mammalian motor cortex. Machne and Zanchetti (1949) reported that bipolar faradic stimulation of the first three folia of the lobus medius (lobule Via, b, d) facilitated the extensor clonus of the wing elicited by local strychninization of the ipsilateral optic lobe, and lowered the faradic threshold of this structure. Sometimes, however, the strychnine clonus was inhibited from the same cerebellar area. A tentative explanation of the aforementioned results was suggested by Machne in another paper (1950). She recorded isotonically the contractions of M. pectoralis secundus after slight strychninization of the optic lobe. When the myogram was silent, the first cerebellar faradization elicited clonic twitches, which were inhibited by further stimulations of the same cerebellar area. This is an example of how the cerebellar response may be reversed, depending upon the background of activity, an observation made also in mammalian experiments dealing with cerebellocerebral relations (Moruzzi, 1941a). Machne suggested that cerebellar facilitation might occur at tectal levels, whereas the spinal motoneurons would be inhibited. It would be interesting to repeat these experiments while using unipolar microelectrodes and well-controlled rectangular pulses, in order to find out whether the cerebellar areas influencing the motor responses of the optic lobe overlap or actually coincide with those yielding either the rebound following electrical stimulation (Bremer and Ley, 1927; Chiarugi and Pompeiano, 1956b) or the flexor posture during local strychninization (Manni, 1951a). B. MECHANICAL AND CHEMICAL STIMULATION IN MAMMALS 1. MECHANICAL, STIMULATION Mechanical stimulation is, of course, quite an unphysiological procedure, since the peripheral response is ultimately due to an injury discharge arising in a group of dying or severely wounded neurons. Hence the only significance of the punctures made with hot or unheated wires as well as with fine needles by Bouillaud (1827), Gratiolet and Leven (1860), Leven and Ollivier (1862), Weir Mitchell (1869), Hitzig (1874), Nothnagel (1876), Balogh (1876), Baginsky (1882-1883), Dupuy (1885), Wersiloff (1899), Lewandowski (1903), and Adamkiewicz (1905) lies in the fact that the response undoubtedly arose in the injured area. This control was utilized by Bremer and Ley (1927), Snider, McCulloch, and Magoun (1949), and Snider and Magoun (1949). Moreover Hoshino (1921) and Dusser de Barenne (1922), by mechanical stimulations of Bolk's lobulus medianus posterior (lobules VII to X), were able to duplicate the conjugate ocular deviations elicited by electrical stimulations of the same area (see p. 138). Greggio's chronic experiments (1914, 1922) of localized compression should be

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classified as ablation experiments, whereas it is likely that the movements elicited by intracerebellar injections of 1-6 molar sodium citrate (Robertson and Burnett, 1912) were due to injury discharges, not necessarily cerebellar in origin. Injury discharges arising in the cerebellar cortex probably caused the inhibition of decerebrate rigidity which occurred when a too hot pledget of wool was applied to the cat's anterior lobe (Denny-Brown, Eccles, and Liddell, 1929). With histologically well-controlled experiments, Clark (1939b) analyzed the irritation phenomena following small mechanical lesions of the cat's lobulus medius medianus (lobule VII) and lobulus ansiformis (sublobule H Vila). They resembled the effects of electrical excitation of the same areas (see p. 139), although "the phase of stimulus was certainly the least obvious after mechanical stimulation and the long after effect the most pronounced" (p. 46). The so-called "cerebellar seizure" was the most striking consequence of the irritation. This seizure differs from generalized epilepsy in that "the movements are slower and less violent; the various parts of the animal are involved in definite sequence (suggesting the 'march' of Jacksonian attacks), instead of all at once; there is little or no manifestation of visceral effects (except upon the pupils), and the animals do not appear to lose consciousness." The seizure lasted only a few minutes and could not be duplicated by electrical stimulation of the cerebellar focus immediately after the cessation of the spontaneous attack. Hence it is likely that the response arose in a group of cerebellar neurons, which became refractory at the end of the seizure, and thence spread "more or less indefinitely by so-called avalanche conduction through the cortex." 2. INTRACEREBELLAR INJECTIONS OF CURARE OR OF NICOTINE Pagano's experiments (1902, 1904) were performed on unanesthetized dogs. Following injections into the vermis (0.1-0.3 cc. of 1 per cent curare, within the anterior lobe), the animal's behavior suggested a reaction to a feeling of deep anxiety or of extreme fear (barking, mad dashing with uncontrolled attempts to escape). This effect was still present, but strongly decreased, following ablation of the acoustic and visual areas of the cerebral cortex. Injections into the cerebellar hemispheres instead resulted in ipsilateral tonic movements followed, sometimes, by a generalized epileptic seizure. Only the tonic response persisted after bilateral removal of the motor cortex, whereas the seizure was abolished. Since the local application of curare on the cerebellar surface was constantly without effect (Pagano, 1904; Ciovini, 1910; Amantea, 1912a), the main problem was one of the origin of the responses elicited by the drug. Technical details about the controversy which arose between the investigators will be found in the monographs of ten Gate (1931c) and van Rijnberk (1931). The main criticism was directed against the so-called psychical responses elicited from the anterior lobe. The evidence suggesting a diffusion of the drug to the medulla (Amantea, 1912a, b; Stern and Rothlin, 1918) is really impressive; but both Pagano (1904, 1912), who made some valuable controls, and those who criticized him, failed to perform the only experiment that might have been crucial, i.e., an intracerebellar injection following section of the cerebellar peduncles. The criticism was milder as regards the localized responses which follow the hemispheral injections,

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although Galante's confirmation (1914a, b) of Pagano's results is open to some doubt, since it is unlikely that the cerebellar cortex of the hemisphere or its underlying nuclei were responsible for the motor effects he observed in the newborn dog (see p. 366). Moreover, in all these experiments, as Clark (1939b) rightly pointed out, the effect of mechanical injury (see p. 110) was completely disregarded. Pagano's technique was certainly unsatisfactory, but it would be unwise to dismiss altogether his results without further controls. We should not forget that patterns of generalized excitation occur following electrical stimulation of the anterior lobe if the animals are made hyperexcitable by chloralosane anesthesia (Moruzzi, 1941a) or by acute decortication (Moruzzi, 1947c). Even normal cats, unanesthetized and unrestrained, occasionally "appeared frightened and sometimes attempted to escape" (McDonald, 1953, p. 80) when certain folia of the anterior lobe were electrically stimulated; similar responses were obtained by Clark (1939a) from the paramedian lobules and by Chambers (1947) from the fastigial nuclei. Moreover, mass stimulation of the neighboring structures of Ingvar's lobulus medius medianus (LarselPs lobule VII) might influence the sensory sphere (thereby eliciting seemingly psychical phenomena) by giving rise to a barrage of impulses impinging upon the visual and auditory areas of the cerebral cortex (see below, pp. 234-235). Nicotine injections within the cerebellar nuclei of cats and dogs yielded an increase in the extensor rigidity and walking movements of the four limbs in the decerebrate preparation (Camis, 1923) as well as ocular responses when the brain was intact (Camis, 1913). These effects were explained, however, by a functional ablation, since they could be duplicated by cocaine injections (Camis, 1913) or by cooling the anterior lobe (Camis, 1923). 3. LOCAL APPLICATIONS OF STRYCHNINE OR OF ESERINE Flourens (1831) was the first to perform experiments in which drugs were applied locally to the cerebellar cortex; he reported that therebentine oil and opium had exactly the opposite effects on rabbits. Weir Mitchell (1869) painted the cerebellar surface with tincture of cantharides. However, only modern investigators have been concerned over the serious objection represented by the diffusion of the drug. Magnini (1910) thought that the motor (phasic) and autonomic effects he observed following local applications (or superficial injections) of strychnine to the dog's lobulus medianus posterior (lobules VII to X), lobulus paramedianus (sublobule H VHb and lobule H VIII), and crus secundum (sublobule H Vila) were due to the diffusion of the drug to the medulla. Actually they were duplicated by bulbar strychninization, and the shorter the distance from the medulla, the greater was their intensity. Beck and Bikeles (1911, 1914), were also unable to obtain reliable cerebellar responses by strychninizing different cerebellar lobuli in the unanesthetized dog. It is likely that the early investigators missed the cerebellar effects of local strychnine because (a) their technique of observation was inadequate and (b) they did not explore the areas yielding clear-cut responses upon electrical stimulation. Positive and more reliable results were obtained, moreover, as soon as Miller

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(1920,1926a) and Simonelli (1926) suggested holding the animal on its back. This simple procedure enabled the limbs of the stimulated side to be compared more easily with the contralateral ones, and the slightest postural or reflex asymmetry could be detected. Following the local application of 1 per cent strychnine to the lobulus ansiformis (sublobule H Vila) of unanesthetized cats and rabbits, Miller (1920, 1926a) observed, ipsilaterally, a strong tremor followed by an increase of the extensor tonus when the knee jerk was elicited or when the limb was passively flexed. We should say now that the myotatic reflexes were increased ipsilaterally to the strychninized area. One wonders whether these results—like those obtained by Shimazono (1912) on the avian cerebellum (see p. 105)—might have been due to the spread of the drug to the underlying nuclei (nucleus interpositus ? see p. 150). Following strychninization of crus I (sublobule H Vila) in thalamic cats and dogs, Simonelli (1926) observed clear-cut and thoroughly reversible postural asymmetries of the forelimbs. One minute after the application of a disk of filter paper, soaked with 1 per cent strychnine sulphate, a slow ipsilateral extension of both elbow and wrist, and sometimes, a true extensor rigidity occurred. The effect lasted only two to five minutes and after ten minutes the posture was thoroughly symmetrical again. Simonelli pointed out, quite rightly, that the previous authors had failed to demonstrate the excitability of the cerebellar cortex, because they wrongly believed that the responses would necessarily be motor (phasic) in type. His results were confirmed by Rossi and Di Giorgio (1942) in decerebrate monkeys. Miller was the first to investigate the effect of the local application of strychnine nitrate (1926a) and of eserine salicylate (1937) to the anterior lobe of the decerebrate cat. Following 1 per cent strychninization, he observed a regular alternation between an extension of the head and neck (opisthotonos), together with running movements of the forelimbs, and a cervical ventroflexion which yielded a decrease in the rigidity of the forelimbs as well as an increase in the extensor tonus of the hindlimbs. The changes in limb rigidity were probably due to Magnus reflexes elicited by the head and neck movements. A rhythmic alternation between limb rigidity and relaxation was observed also after local eserine, but no cervical effects were then reported. To quote: "Two ophthalmic tablets containing together 0.22 mg eserine salicylate were now applied near the centre of the lobus anterior and almost at once the right foreleg was thrust forward, the left likewise but more slowly. The hind leg relaxed promptly, then stiffened, later relaxed and stiffened alternately" (1937, p. 214). By careful control Miller ensured that these effects should be due to "a specific local action on the cortex." The effect was certainly "local," since its muscular distribution was similar to that elicited by faradizing the same area. He pointed out (1937) that the response to the chemical stimulus was also "specific," since only an inhibition of extensor rigidity—never an alternation between flexion and extension—occurred during faradization. We know now that both facilitating and inhibitory units are contained in the anterior lobe (see p. 134), and it is likely that they were alternatively played upon by the drug. It would be interesting to investigate whether a nuclear

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component was involved in the rhythmic responses described by Miller (1926a, 1937) and by Simonelli (1926). C. ELECTRICAL STIMULATION OF THE CEREBELLAR CORTEX IN MAMMALS

1. STIMULATION OF THE FLOCCULONODULAR LOBE It is extremely unlikely that the movements of tongue, lips, and larynx which Mussen (1930) said occurred when the nodulus (lobule X) was electrically stimulated, really arose in this vestibular part of the cerebellum. Barany's experiments (1914) concerned the paraflocculus (lobules H VIII and H IX) and will be reviewed in another section (see p. 139). Rothmann (1910) himself conceded that the responses he got from the formatio vermicularis were due to a spread of current, and the same criticism holds true for the tail movements reported by Mussen. The flocculonodular lobe (lobules X and H X) is so near the medulla that its localized stimulation appears to be an extremely difficult task. 2. STIMULATION OF THE ANTERIOR LOBE OF THE CORPUS CEREBELLI The discovery that decerebrate rigidity is inhibited by faradic stimulation of a limited area of the cerebellar cortex was reported almost simultaneously by Lowenthal and Horsley (1897) and by Sherrington (1897). Although the paper of Lowenthal and Horsley is generally quoted, it should be pointed out that in the communication which was presented by them to the Royal Society in 1897, Lowenthal alone was credited with the discovery. The first preliminary note on decerebrate rigidity was presented by Sherrington to the Royal Society in 1896, but only in a short note of 1897 and in the full paper of 1898 did he report that an inhibition of the extensor hypertonus was elicited by cerebellar stimulations. Lowenthal and Horsley (1897) experimented on decerebrate cats and dogs. They stated that "the most excitable area is along the line of junction of the vermis superior with the lateral lobe" (p. 24). The inhibition of the extensor muscles (with shortening of the flexor ones) was much stronger ipsilaterally, and the same result was obtained by stimulating the underlying white matter and the cerebellar peduncles. Sherrington (1897, 1898) worked on decerebrate monkeys. He stated (1898) that "inhibition of decerebrate rigidity can be produced by excitation of the anterior (cerebral) surface of the cerebellum. Faradization of points in a large area extending from near the midline far out toward the lateral border of the cerebellar surface causes relaxation of the rigid neck and tail muscles and relaxation of the rigid limbs, especially of the uncrossed side" (p. 327). The importance of this discovery hardly needs to be stressed, since not only was the inhibitory function of the cerebellum proved for the first time, but the structures yielding these effects were localized in a limited area of the cerebellar surface. Hence the papers of Lowenthal and Horsley (1897) and of Sherrington (1897, 1898) are rightly regarded as the first works suggesting a localization of functions within the cerebellar cortex. It is surprising that their appearance aroused so little interest among contemporary physiologists, and actually the discovery was underestimated by the authors themselves. No mention can be

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found in Luciani's Fisiologia dell'uomo. The phenomenon was barely recalled by Sherrington (1900) himself in the detailed account of cerebellar physiology he prepared for Schafer's handbook. Moreover, when Horsley and Clarke (1908) wrongly concluded from their experiments on anesthetized animals that the cerebellar cortex was not excitable, they surprisingly did not discuss the previous paper by the senior author. The experiments we shall review in this chapter can be regarded as the development of the discovery made by Lowenthal and Horsley and by Sherrington toward the end of last century. To be sure, we know that the postural response is much more complex than it was first believed, since other groups of ipsilateral muscles besides the extensor ones, as well as the contralateral legs, are also involved. Moreover, a striking reversal of the postural effect generally occurs as soon as the stimulation is over (rebound phase). The old terminology of cerebellar inhibition and facilitation has been retained, nevertheless, with the proviso that these words shall simply mean that the ipsilateral extensor muscles relax or stiffen during the stimulation. This is the effect which was most frequently looked for and the one which is easiest to detect in the decerebrate preparation. Only when responses of other muscles were reported by the author are their sign and localization specified in the text. During a quarter of a century (1897 to 1922) only three groups of investigators (Thiele, 1905; Weed, 1914; Cobb, Bailey, and Holtz, 1917) approached the problem through experiments performed on decerebrate cats. Thiele (1905) suggested that the inhibition was mediated by impulses going from the cerebellar cortex to the Deiters nucleus. According to Weed (1914) the inhibitory area was "fairly well delimited to the superior vermis." Cobb, Bailey, and Holtz (1917) got instead inhibitory responses from the hemispheral part of the anterior lobe, but suggested that they were due to a spread of current to the underlying brachium conjunct!vum. The cerebellar excitability was probably depressed and the stimulation intensity was certainly too strong in their experiments. That the inhibitory response really arose from the cerebellar neurons of the stimulated area was shown almost simultaneously by Bremer (1922a) and by Miller and Banting (1922), through experiments performed on decerebrate cats. They pointed out (a) that the faradic threshold was even lower for the anterior lobe than for the sigmoid gyrus (Bremer, 1922a; Miller and Banting, 1922), and (b) that it was strongly increased by 1 per cent cocainization (Miller and Banting, 1922) and by cooling or undercutting (Bremer, 1922a) the stimulated area. Moreover the response was absent when the cerebellar cortex was pale, but came back following the local application of a hot saline solution (Bremer, 1922a). The excitable area, as mapped by Miller and Banting (1922), was probably too wide, since it included the entire surface of the anterior lobe and part of crus I (sublobule H Vila). Bremer (1922a) made instead the important observation that inhibition could be elicited only from the spinal story of the cerebellum (the vermal part of the anterior lobe, lobules I to V, and the pyramis, lobule VIII; see Fig. 22). Hence there was no doubt that inhibitory volleys really arose in the Purkinje cells of this zone of the cerebellar cortex. Many other new facts were reported by Bremer (1922a). Faradic stimulation

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of the same vermian area yielded an ipsilateral inhibition of extensor rigidity in both the forelimb and hindlimb. Hence no somatotopic localization could be detected. Contralaterally, a less intense inhibition was occasionally observed, whereas in other instances extensor rigidity was clearly increased. Besides decerebrate rigidity, both phasic and tonic (myotatic appendage) components of the crossed extensor reflex were inhibited by paleocerebellar faradization, and Bremer suggested that this inhibition might occur at both brain stem and spinal levels. The running movements were instead sometimes inhibited and sometimes facilitated by the stimulation, an effect suggesting that an optimal tonus was required for their occurrence. Myographic recordings from a couple of antagonistic muscles, isolated by Sherrington's technique, showed that the flexor motor units were either unaffected or slightly inhibited, an observation which showed that cerebellar inhibition and spinal inhibition of the extensor motoneurons were different phenomena. The same records gave the demonstration of an optimal tonus for the rhythmic running movements in the decerebrate cat. Finally, Bremer (1922a) observed that a powerful rebound, localized in the extensor muscles and facilitated when the stimulation was repeated at short intervals, occurred at the end of each cerebellar faradization (Fig. 23). The difference between cerebellar and spinal inhibition was again stressed by Bremer (1922b, 1925) in further experiments, which showed that the inhibitory response of the anterior lobe was never reversed (although the extensor rebound was increased) following subtetanizing injections (0.1 mg/Kg) of strychnine, "ce qui tient a ce qu'elles sont pures de tout element d'excitation" (Bremer, 1935, p. 82). The cerebellar effects behaved, therefore, like the inhibition elicited by natural stimulations of muscular (Liddell and Sherrington, 1925; Cooper and Creed, 1927) or lung (Creed and Hertz, 1933) stretch receptors or by labyrinthine impulses (Magnus and Wolf, 1913). It is well known that an excitatory component is concealed by the inhibition of the extensor motoneurons during the ipsilateral flexor reflex, and that this inhibition is reversed by the injection of strychnine (Owen and Sherrington, 1911). Following the publication of Bremer's paper one knew that cerebellar inhibition was a genuine cortical phenomenon, arising in the Purkinje neurons, localized in the spinal story of the cerebellum, and different from the spinal inhibition underlying reciprocal innervation. It was only natural that these findings should provide a great stimulus to later investigators. Bernis and Spiegel (1925) stressed the difference between the tonic cerebellar responses "die erst nach langerer Latenzzeit in Erscheinung treten, langsam ablaufen, in der Regel so lange anhalten, als der Reiz andauert," and the clonic twitches elicited by the spread of current to the cranial nerves. The cerebellar responses observed by Bernis and Spiegel (1925) in the decerebrate cat differed, however, from those reported by Bremer (1922a), since (a) they were obtained from the hemispheral part of the anterior lobe and (b) since sometimes a contraction of the flexor muscles occurred during the inhibition of decerebrate rigidity. The anterior lobe of the decerebrate cat was faradized by Denny-Brown, Eccles, and Liddell (1929), and its myographic and electromyographic responses were optically recorded from couples of antagonistic muscles. In the ipsilateral

Figure 22. The inhibitory areas in the cat's cerebellum. Schematic localization on the superior surface (A) and on sagittal sections (C). See the coincidence between the spinocerebellar projection areas (B, from Ingvar, 1918) and the inhibitory areas (C, lobulus centralis, culmen, pyramis). (Redrawn from F. Bremer, 1922, Contribution a 1'etude de la physiologic du cervelet. La fonction inhibitrice du paleocerebellum, Arch, internat. de Physiol., 19:189-226, Figs. 1, 2A, and 2B.)

Figure 23. Facilitation of the extensor rebound elicited by a sequence of cerebellar stimulations. Reading downward: myogranis of M. triceps (T), of M. brachialis (B), signal of faradic stimulation of the ipsilateral vermal surface of the anterior lobe, time (2 sec.). Decerebrate cat. The first stimulation (1) was made during a background of extensor atonia and no peripheral effect was observed (1,2). The extensor rebound occurred as soon as the third stimulation was over and then it gradually increased (temporal facilitation, 4 to 10). No effect was observed on the flexor muscles (B), while the background of activity elicited during each extensor rebound (T) was inhibited by the next stimulation. (From F. Bremer, 1922, Contribution a 1'etude de la physiologic du cervelet. La fonction inhibitrice du paleocerebellum, Arch, internat. de Physiol., 19:189-226, Fig. 18.)

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forelimbs (M, brachialis anticus and M. triceps brachii) and hindlimbs (M. quadriceps and M. semitendinosus) four types of response were observed, namely (a) inhibition of the extensors, (b) excitation of the flexors, (c) inhibition of the flexors, and (d) excitation of the extensors. In regard to the inhibition of the extensor motoneurons, Denny-Brown, Eccles, and Liddell (1929) reported that decerebrate rigidity, the crossed extensor reflex, and the knee jerk were clearly inhibited by cerebellar stimulation, the most excitable area being where the lateral superior cerebellar vein (paravermal vein) divides the vermal from the hemispheral part of the anterior lobe. When the cerebellar stimulation was timed to occur against a background of crossed extension, the inhibition showed clear-cut recruitment, with long latent periods. The response was entirely different, therefore, from the abrupt slackening of the quadriceps which occurred upon stimulation of the central end of the ipsilateral sciatic nerve (spinal inhibition). If the anterior lobe was stimulated when the background of extensor activity was represented by a series of knee jerks, a gradual fall in the height of each individual reflex, with progressive lengthening of the "silent period," occurred. An important observation was that the jerk reflex was less easily inhibited than decerebrate rigidity; in other words, "the kinetic stretch reflex (jerk) is less susceptible to impairing influences than the static stretch reflex (posture)" (p. 523). The same difference holds true for spinal shock, and it remained for later experiments to show that this parallel behavior is not devoid of significance (see p. 230). From a perusal of the protocols, it becomes apparent that the contraction of the flexors was elicited only by much stronger stimuli than that required for the inhibition of the extensors (2 to 3 cm. of distance between the induction coils, instead of 6 to 12 cm.) and consequently from a larger cerebellar area. Even the flexor responses which were obtained in the nondenervated preparation (sharp flexion of elbow and wrist, abduction and extension of the digits and protrusion of the claws, an attitude which recalled that of the "rampant" animals of heraldry) were brought about by rather strong stimuli. We regard it as unlikely that the recruitment of flexor motor units, which sometimes concealed an inhibitory component (as shown by the rebound contraction which occurred when the stimulus was over), arose entirely within the cerebellar cortex or at least that it involved the same group of Purkinje cells responsible for the inhibition of the antigravity muscles (see p. 115). It is more likely that the strong faradic stimulation spread to underlying nuclear elements (somata or efferent fibers) or to the neighboring medial strip of the intermediate part (Pompeiano, 1958a; see below, p. 137). An inhibition of flexors was observed when the background was represented by the reflex of ipsilateral flexion. Here again, however, the intensities which are given in the protocols were definitely higher than those which were utilized for inhibiting the crossed extensor reflex. Finally, the evidence of excitation of the extensors, according to Denny-Brown, Eccles, and Liddell (1929), was the wellknown extensor rebound, which they regarded as "the result of an excitatory process from some cortical units concurrent with an inhibitory from others" (p. 532). Moreover, the extensor muscles showed occasionally—for stimulation

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intensities of the order of those inhibiting the antigravity activity—a recruiting excitation, followed by a rebound contraction when the stimulation was over. On these occasions the inhibitory component was concealed, during the phase of stimulus, by the excitatory effect. Denny-Brown, Eccles, and Liddell (1929) believed that every point of the excitable area had "underneath it nerve units of four tendencies, inhibition and excitation of extensors and inhibition and excitation of flexors" (p. 533). That neurons of opposite function are intermingled within the vermian cortex of the anterior lobe was confirmed by later investigators and can now be regarded as a well-established fact (Moruzzi and Pompeiano, 1954, 1957b; see below, pp.131134). In view of Bremer's findings (1922a), which we have fully confirmed, and of the threshold differences reported above, we should be more inclined to think that the responses elicited by liminal vermal stimulations are mainly concerned, at least in the decerebrate preparation, with the regulation of antigravity mechanisms. We are loth, moreover, to accept another statement of Denny-Brown et cd., namely, that cerebellar inhibition "differs from spinal inhibition only in speed of onset and development" and that "the ultimate locus of its incidence is the final motor neurone" (p. 532). Actually the lack of strychnine reversal (Bremer, 1922b, 1925) and the fact that flexors and extensors sometimes relax and then rebound together (Bremer, 1922a; Denny-Brown, Eccles, and Liddell, 1929) suggest that we are dealing with somewhat different phenomena. The localization of the neurons which are impinged upon by the inhibitory volleys is indeed a most controversial problem, to which many papers were to be devoted in the following years. A first attempt to elucidate it was made by Moruzzi (1935c). Bremer, Titeca, and van der Meiren (1927) had shown that subparalyzing doses of curare abolished entirely decerebrate rigidity, while leaving the phasic reflexes intact (curare atonia). Moruzzi (1935c) found that the crossed extensor reflex, isometrically recorded from the M. vastocrureus, was strongly inhibited by faradizing the vermal surface of the anterior lobe of the decerebrate cat (Fig. 24C), when both the extensor rigidity and the tonic component (myotatic appendage or pseudoafterdischarge) of the spinal reflex itself had been entirely and selectively blocked with subparalyzing doses of curare (Fig. 241?). Hence there was no doubt that purely phasic reflexes, spinal in character, could be blocked with cerebellar stimulations. Moruzzi (1935c) thought that this type of inhibition occurred at spinal levels. This, however, was by no means the only possible explanation of his findings. Curare atonia was limited to the peripheral (muscular) component of the extensor tonus (Bremer and Titeca, 1927, 1931, 1935; Moruzzi, 1934b, 1935a, b). Hence an inhibition occurring at brain stem levels, by bringing about a sudden arrest of the tonic (facilitating) reticulospinal and Deitersian-spinal barrage, might also abolish or strongly decrease the phasic component of the crossed extensor reflex, with an indirect mechanism similar to that underlying the spinal shock. Later experiments of Bach and Magoun (1947) showed the great importance of vestibular facilitation on spinal activities. Moruzzi's suggestion (1949) to utilize as a background the ipsilateral flexor reflex, which is less influenced by supraspinal facilitation, was followed by Brihaye (1953) and by

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Figure S4-. Cerebellar inhibition of the phasic component oj the crossed extensor reflex during curare atonia. Cats following anemic (A, B) or precollicular decerebration (C), before (A) and during (B, C) curare atonia. Reading downward: isometric myogram of M. vastocrureus, signal of faradic stimulation of the contralateral sciatic nerve (A, B, C~) and of the ipsilateral vermal surface of the anterior lobe (C). The long postural afterdischarge (A) is selectively abolished during curare atonia (B), and the phasic component of the crossed extensor reflex is inhibited by the cerebellar stimulation (C). (From G. Moruzzi, 1935, Contributo allo studio del meccanismo dell'atonia curarica, Arch, fisiol., #4:455-466, Figs. 1, 2, and G. Moruzzi, 1935, Cervelletto e attivita fasica dei muscoli striati, Arch, fisiol., 34:293-339, Fig. 2.)

Ricci and Zanchetti (1953), but their evidence was inconclusive, because too high intensities of stimulation were required (Denny-Brown, Eccles, and Liddell, 1929; Ricci and Zanchetti, 1953) and only inconstant results were obtained (Brihaye, 1953; Ricci and Zanchetti, 1953). It remained for experiments performed along quite different lines (Moruzzi, 1941c; Snider, McCulloch, and Magoun, 1949; Terzuolo, 1952, 1954) to show that spinal neurons may be directly inhibited by cerebellifugal volleys. As was suggested by Bremer (1922a) and shown experimentally by Mollica, Moruzzi, and Naquet (1953) and by De Vito, Brusa, and Arduini (1956), reticular and vestibular units may also be inhibited by cerebellar stimulations. During the control experiments, which were routinely performed before injecting curare, the unexpected observation was made (Moruzzi, 1935b) that sometimes the myotatic appendage of the crossed extensor reflex (the so-called "pseudoafterdischarge") was increased and prolonged, instead of being inhibited, during a cerebellar stimulation (Fig. 25). These findings would be more easily explained now, since we know that the tension of the intrafusal muscle fibers is modified by the cerebellar stimulation (Granit and Kaada, 1952, especially pp. 139-140). The increase of the myotatic appendage by cerebellar stimulation was more frequently observed when the extensor rigidity was not very pronounced. Following this observation an attempt was made to investigate systematically the influence of background activity upon the sign of the cerebellar response, in the decerebrate cat (Moruzzi, 1936a, b, c).

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Figure 25. Cerebellar facilitation of the myotatic appendage of the crossed extensor reflex. Decerebrate cat. Reading downward: isometric myogram of M. vastocrureus, signal of faradic stimulation of the central end of the contralateral sciatic nerve, time in seconds, signal of faradic stimulation of the ipsilateral vermal surface of the anterior lobe. When the crossed extensor reflex (pseudoafterdischarge) is elicited during the cerebellar stimulation, the myotatic appendage appears to be increased and greatly prolonged, outlasting the cerebellar faradization. The latter had no clear-cut effect on the contraction occurring during the reflex stimulation. (From G. Moruzzi, 1935, Cervelletto ed attivita fasica del muscoli striati, Arch, fisiol., 5^:293339, Fig. 5.)

The responses of M. triceps or M. vastocrureus, isolated by Sherrington's technique, were compared on isometric records under the opposite conditions of strong extensor rigidity and extreme atonia, produced by Magnus's cervical and labyrinthine reflexes (Moruzzi, 1936a) or by Sherrington's shortening and lengthening reactions (Moruzzi, 1936b). The area of the anterior lobe which was stimulated (just medially to the paravermal vein) and the intensity of the bipolar faradization were kept constant throughout the experiment. When the responses of M. triceps were recorded, a postbrachial transection of the spinal cord was made, in order to increase both extensor rigidity and labyrinthine reflexes (Magnus and de Kleijn, 1912; Socin and Storm van Leeuwen, 1914). The rigidity was first increased by rotating the jaw toward the recorded side (Magnus's "mandibular" limb). Ipsilateral vermian stimulation at once abolished the extensor spasticity. The inhibition was initially "d'emblee" and later "recruitment" in type, and the recruiting phase was more marked when the intensity of the stimulation was decreased (Fig. 26). For threshold stimulations no rebound was observed (Fig. 26A). The head was then rotated toward the opposite side and a complete collapse of extensor rigidity occurred in the recorded limb (Magnus's "cranial" limb). If then the same cerebellar stimulation was repeated against this background of reflexly induced atonia, a reversal of the cerebellar inhibition was occasionally observed (Fig. 275). Contrary to expectation, however, this was by no means the most frequent event. The slight residual tonus of the "cranial" limb was more frequently inhibited, but as soon as the stimulation was over, a strong rebound occurred, which brought the extensor rigidity to its highest levels

Figure 26. Cerebellar inhibition of the extensor tonus in the "mandibular" limbs (Magnus reflexes). Precollicular cat. Reading downward: isometric myogram of M. triceps brachii, signal of faradic stimulation of the ipsilateral vermal surface of the anterior lobe, time in seconds. The rotation of the jaw (arrow) toward the side recorded from ("mandibular" limb) yields a strong extensor hypertonus in the previously flaccid, "cranial," forelimb (Magnus's labyrinthine and cervical reflexes). The new background of activity is inhibited by cerebellar stimulations of increasing intensities (coil distance in A, B, C: 14, 10, 8 cm.), but no postinhibitory rebound is observed following threshold stimuli (A). (From G. Moruzzi, 1936, Ricerche sulla fisiologia del paleocerebellum. Riflessi labirintici e cervicali, paleocerebellum e tono posturale, Arch, fisiol., 36:57-112, Figs. 1, 2, and 3.)

Figure 27. The effect of cerebellar stimulation on flaccid "cranial" limbs (Magnus reflexes). Technical details are the same as in Fig. 26. When the background of postural activity is one of extreme hypotonia ("cranial limb"), cerebellar stimulation yields either slight inhibition, followed by a strong extensor rebound (A), or a clear-cut increase in the extensor tonus (B). The hypertonia elicited in "cranial" limbs as the rebound response to cerebellar stimulation fades away only after many seconds. At its climax, the tension of the extensor muscle during the cerebellar rebound is about the same as that elicited by Magnus reflexes, when the jaw is rotated to a "maximum position" for extensor tonus ("mandibular" limb, A, arrow). (From G. Moruzzi, 1936, Ricerche sulla fisiologia del paleocerebellum. Riflessi labirintici e cervicali, paleocerebellum e tono posturale, Arch, fisiol., 36:57-112, Figs. 6 and 7.)

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for about three or four minutes. Then the extensor response gradually subsided. If the jaw was then turned toward the recorded side, the extensor rigidity increased again in the "mandibular" limb, although the muscular tension never did attain a level higher than the levels recorded during the previous rebound (Fig. 274). Summing up, Moruzzi's observations (1936a) showed that it was extremely difficult to get rid of the inhibitory component of the cerebellar response, even when the stimulation was made during a period of almost complete atonia. Obviously the sign of the response was related to some intrinsic property of the cerebellar neurons and not simply conditioned by the background of activity. It remained to explain, however, (a) why an augmentatory response was sometimes observed in the atonic limb and (b) why the rebound was so strikingly developed on the "cranial" side of the body. Moruzzi (1936a) suggested (a) that augmentatory and inhibitory neurons were intermingled in the vermal cortex and (b) that the augmentatory response was particularly strengthened by a background of extensor atonia, while the inhibitory component was paramount if a strong extensor rigidity was present. These concepts were later accepted by Brihaye (1953), and Denny-Brown's statement (1952) that the cerebellar responses had often been examined "against a very biased background" or that "in the decerebrate preparation the whole righting mechanism is, so to speak, thrown out of gear in favor of extensor reactions" followed a similar line of thought. At present we should be inclined to restrict somewhat the meaning of these experiments, by stating that the peripheral effects brought about by stimulating augmentatory cerebellar units appeared more evident when tested against a background of extensor atonia. Obviously a facilitating influence on the extensor niotoneurons is more likely to be missed if tested against a background of extreme spasticity, and the reverse holds true for the inhibitory responses. Whether a corresponding change in the response of brain stem or of spinal neurons to cerebellar stimulation (central response) really occurs, we could not say with certainty. Although true postural reversals were occasionally observed by Moruzzi (1936a), it should not be forgotten that augmentatory vermal responses were also observed, under appropriate experimental conditions, when the extensor rigidity was very strong (Moruzzi, 1948a, b; Moruzzi and Pompeiano, 1954, 1957b). Hence the background activity is only one of the elements likely to control the sign of the cerebellar response. Koella's experiments (1953) should be cited here, although they were concerned with stimulating different points within the interior of the cerebellum, in the decerebrate cat. Koella was interested in the influence of position in space (i.e., with the patterns of otolithic impulses) upon the cerebellar response to slightly suprathreshold rectangular pulses (300/sec; 0.2 msec.; less than 1 volt). He found that "the position in which rigidity was maximal coincided with the position in which cerebellar facilitatory effects were maximal and cerebellar inhibitory effects were minimal and vice versa." These positional changes were abolished by bilateral labyrinthectomy, and were observed also by stimulating folia of the anterior lobe which do not receive vestibular impulses (see Dow, 1939). Hence in these simplified conditions cerebellar and otolithic impulses were

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shown to converge on some lower structure where some kind of summation occurred. Koella's experiments were mainly concerned with the influence of the central background of brain stem activity upon the cerebellar response, whereas in Moruzzi's investigations the greater postural changes brought about by the combined effect of neck and vestibular reflexes overshadowed the central interrelations. Koella's technique is obviously simpler and more suited to this kind of neurophysiological investigations. In further experiments (Moruzzi, 1936b) the same cerebellar stimulation was applied alternately during the shortening and the lengthening reactions. A reversal of the response was again observed, and sometimes rhythmic movements appeared whenever a given level of postural tonus was attained (Fig. 28A).* However, we want to stress once more that the augmentatory response was by

Figure 28. The effect of cerebellar stimulations during the lengthening reaction. Precollicular cats, whose extensor rigidity had been strongly reduced by a lengthening reaction. Reading downward: isometric myogram of M. quadriceps, signal of faradic stimulation of the ipsilateral vermal surface of the anterior lobe, time in seconds. A. Cerebellar stimulation yields an increase in the extensor tonus (A), the hypertonia being thereafter constantly inhibited by identical stimulations applied to the same cerebellar area (B, c, D). Note that rhythmic movements occur whenever a critical intensity of tonus is reached. B, C. Another preparation, showing delayed (B) and prompt (C) augmentatory effects of vermal stimulations, followed by rebound contractions. (From G. Moruzzi, 1936, Ricerche sulla fisiologia del paleocerebellum. II. Riflessi propriocettivi somatici, paleocerebellum e tono posturale, Arch, fisiol, 56:337-364, Figs. 3, 13, and 14.) * These findings confirmed Bremer's observations (1922a) on the "tonus optimum" which is required for eliciting rhythmic responses.

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no means constant, even when the extensor muscle was thoroughly relaxed by the lengthening reaction. It was extremely difficult to get rid of the inhibitory component, and the persistent mixture of excitation and inhibition was shown by the rebound contraction occurring at the end of a cerebellar increase of the extensor tonus (Fig. 2&B, C) and by other observations reported in the paper. The main objection against the concept of an intermingling of excitatory neurons among the inhibitory ones was represented by Bremer's disclosure (1922b, 1925) that cerebellar inhibition could not be reversed by subtetanic doses of strychnine. Moruzzi (1936c) fully confirmed these findings during recordings from hyperextended "mandibular" limbs. If the head was turned toward the opposite direction, so that a sudden relaxation occurred in the "cranial" limb, the same cerebellar stimulation yielded instead clear-cut augmentatory effects. Moreover, the inhibition elicited by stimulating the central end of the ipsilateral hamstring nerve, which was regarded as "pure" because it was not reversed by strychnine (Liddell and Sherrington, 1925), could also sometimes be reversed (just like the cerebellar inhibition) depending upon the background of extensor tonus (Moruzzi, 1936c). In the experiments reviewed so far, the most reliable responses had been obtained from the anterior vermis. The hemispheral part of the anterior lobe had also been occasionally explored, but the corticocerebellar origin of these effects had not been conclusively proved. Stella (1944a) was the first to report that the responses of the hemispheral part of the anterior lobe were not abolished following acute ablation of the neighboring vermian cortex. Hence they could not be explained by a physical or neural spread to the vermis proper. According to Stella, an inhibition of decerebrate rigidity occurred, in both dogs and cat, only when the hemispheral part of the culmen (lobules H IV and H V) was stimulated, while just the opposite effect was elicited from the hemispheral part of the lobulus centralis (lobule H III). An ipsilateral increase in extensor rigidity was elicited also by Hampson, Harrison, and Woolsey (1945, 1952) with faradic or 60-cycle stimulation of the hemispheral part of the anterior lobe in decerebrate cats, dogs, and monkeys. They found that a short faradization (less than one second) of the medial three fifths of the anterior lobe yielded, in the decerebrate cat, an ipsilateral inhibition of and, occasionally, a contralateral increase in extensor rigidity. This was a typical vermal response. In some instances, however, ipsilateral contraction of the flexor muscles was also observed, but if the stimulation lasted longer (15 seconds), only inhibition of the extensor tonus occurred ipsilaterally. By stimulating the lateral two fifths of the anterior lobe, Hampson et al. found just the opposite effect, i.e., ipsilateral extension followed by flexor rebound when the stimulation lasted less than one second. Longer stimuli (15 seconds) yielded first an increase in and then an inhibition of extensor rigidity, followed by a flexor rebound when the stimulus was over. Hence the hemispheral part of the anterior lobe differed from the vermis proper in that an ipsilateral increase in decerebrate rigidity occurred upon electrical stimulation. The authors stated (1952) that "there is some overlap of these two regions and increasing the strength of the stimulus above threshold could alter the response." They pointed out that "in the

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case of the monkey there appears to be a relatively greater development of the lateral zone" and remarked quite rightly that "this suggests a possible explanation of the differences in effect of cerebellar ablation on muscle tone seen in lower and higher forms" (p. 305). Hampson, Harrison, and Woolsey reported in the same papers (1945, 1946, 1952) that the cerebellar responses of the anterior lobe were somatotopically arranged, the forelimbs being represented in the culmen (lobules IV, V), the hindlimb in the lobulus centralis (lobule IIII), aand the tail in the lingula (lobule I, Fig. 29). Their experiments were performed on cats, dogs, and monkeys which had been decerebrated under sodium pentobarbital 18 to 24 hours previously, and stimuli of a constant rate were used.

Figure 29. Patterns of somatotopic localization in the cat's cerebellum. From experiments of electrical stimulation of the cerebellar cortex in the decerebrate animal. (From J. L. Hampson, C. R. Harrison, and C. N. Woolsey, 1952, Cerebro-cerebellar projections and the somatotopic localization of motor function in the cerebellum, A. Research Nerv. & Ment. Dis., Proc., 50:299-316, Fig. 158.)

The augmentatory response of the hemispheral part of the anterior lobe was confirmed in the decerebrate cat by Moruzzi (1947b). He showed that the response arose within the stimulated area, since the faradic threshold was about the same as that of the vermal surface and was strongly increased by the local application of chloroform or cocaine (2 per cent). Other experiments were devoted by Moruzzi (1947c) to the somatic and autonomic responses elicited in the thalamic cat by faradizing, with Hess electrodes, cerebellar folia just before or behind the fissura prima. The spontaneous out-

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bursts of sham rage were inhibited by weak stimuli and were instead elicited, as a rebound response, if the cerebellar stimulation was timed to occur during an interval of quietness. An account of the autonomic component of these outbursts will be given in another chapter (see p. 295), but the somatic effects (struggling movement, lashing of the tail) were very marked, although phasic in character and entirely different from those occurring in the decerebrate cat. The inhibition of the somatic response which was observed during the stimulus phase might occur, of course, at spinal levels, but the rebound outburst of sham rage was probably due to cerebellar impulses impinging upon diencephalic centers. The experiments we have reviewed so far were performed almost exclusively with induction coils. The duration of the single faradic shock being very short, the response was obtained by increasing the intensity of the stimulation (strengthduration curve). This fact was obviously responsible for a quick deterioration of the stimulated area and sometimes for a spread of current to underlying structures, at least when the excitability of the cerebellar cortex was already depressed. Moreover, the rate of stimulation (40 to 60 per second) was kept constant, and no physical measurements of the intensity of the stimuli were taken. In the experiments we are now going to analyze, electronic stimulators were used, which gave electric pulses whose duration, amplitude, and repetition rate could be modified easily and independently. In the last years also direct-current stimulation has been used, but the results of this group of experiments will be dealt with in the next chapter. Snider, Magoun, and McCulloch (1947) and Snider, McCulloch, and Magoun (1949) first performed a group of experiments on cats, both decerebrate and under barbital anesthesia. They found that the knee jerk was inhibited by stimulating the anterior border of the culmen with condenser discharges (Goodwin stimulator; 100/sec; 2 msec.). On ten monkeys (Macaco, midatta) and two cats, under chloralosane, nembutal, or chloralosane-nembutal anesthesia, Snider and Magoun (1949) reported instead that the same stimuli yielded clear-cut facilitation of the knee jerk. The authors did not specify whether the vermal or the hemispheral part of the anterior lobe was stimulated, but from a map of the monkey cerebellum which they gave it is clear that both divisions were explored. They thought that the opposite results were mainly due to differences between species. Actually, an inhibition of rigidity had been obtained on decerebrate monkeys by Sherrington (1898), Bremer (1922a), and Hampson, Harrison, and Woolsey (1952), and it is likely that the greater extent of the hemispheral zone was responsible for the predominance of the facilitatory responses in primates. The existence of a somatotopic distribution of the efferent projections was confirmed. Moruzzi's experiments (1948a-d; see also, 1949, 1950a and b) were concerned exclusively with the vermal surface of the anterior lobe, i.e., with the cerebellar zone yielding a relaxation of ipsilateral rigidity. The main result was that either an inhibition of extensor rigidity or an increase occurred, depending upon the rate of the stimulus. In decerebrate cats, bipolar unpolarizable electrodes were placed on the culmen of the anterior lobe (lobules IV, V) just medially to the paravermal vein.

STIMULATION EXPERIMENTS 127 A relaxation of the ipsilateral limbs occurred for repetition rates ranging from 30 to 300 per second if rectangular pulses of constant duration (1 millisecond) were applied. The higher the repetition rate, the lower were the threshold voltages; and the lowest values (down to 0.4 to 0.6 volt, for the most excitable preparations) were observed with repetition rates as high as 300 per second. Rates lower than 30 per second were ineffective, at least for stimulation intensities at which the possibility of current diffusion could be safely dismissed. These results showed that the rhythm of the usual faradizations (40 to 50 per second) lay within the lowest ranges of the inhibitory spectrum (30 to 300 per second) so that it is likely that fairly high intensities had to be used by the previous experimenters in order to abolish the extensor hypertonus (Moruzzi, 1948a, b). Moreover, the localization of the response in the ipsilateral forelimb, which had been reported by Hampson, Harrison, and Woolsey (1945, 1946), was observed if square pulses of low repetition rates (50 per second) and of corresponding threshold voltages (1.3 to 1.5 volts) were used. If the repetition rate was then increased, the tension being kept constant, the ipsilateral hindlimb also relaxed (100 per second). The flaccidity of the contralateral forelimb ensued soon thereafter, whereas the contralateral hindlimb became flaccid only for repetition rates of 200 to 300 per second (Moruzzi, 1948c). Hence the somatotopic differences were canceled out by the irradiation of the inhibitory response which was brought about by increasing the rate of stimulation. With lower repetition rates (2 to 10 per second), a surprising reversal of the response occurred. It was characterized by a slow increase in the ipsilateral extensor rigidity, which lasted as long as the stimulus and slowly declined thereafter, with no sign of flexor rebound. The augmentatory effect was also observed when the extensor rigidity was quite strong, and therefore was not conditioned by the background of activity. The threshold of the augmentative effect was higher and its resistance to a deterioration of the cerebellar cortex (anemia, slight edema) was lower than that of the inhibitory response, an observation which could be explained by the less efficient temporal summation which was likely to occur when the interval between rectangular pulses was increased. Higher voltages obviously meant that deeper structures were involved. But that the augmentatory responses, like the inhibitory ones, arose within the cerebellar cortex was shown by the following evidence: (a) An inhibition of the ipsilateral extensor rigidity instead of an increase in it occurred simply by increasing the repetition rates from 10 to 30 per second, the other electrical parameters remaining unchanged; (b) the threshold voltages of the augmentative response were lowered to the same level as the inhibitory one if the pulse duration was increased, whereas (c) the threshold was greatly raised by local cocainization (Moruzzi, 1948b); (d) finally, subtetanic injections of strychnine abolished neither the augmentative nor the inhibitory effect, although the upper limit of the facilitating spectrum was increased up to about 25 per second (Moruzzi, 1948b). Two hypotheses could account for these observations (Moruzzi, 1949). 1. Inhibitory and facilitating neurons are intermingled within the stimulated cortex. Square pulses of low repetition rates would selectively activate the augmentatory system, possibly because the inhibitory fastigial and brain stem

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relays require particularly efficient mechanisms of temporal summation. Fast repetition rates would instead stimulate both systems, the inhibitory component prevailing during the stimulation and the facilitatory units yielding the extensor rebound when the stimulus is over. 2. The same cerebellar units might be inhibitory or facilitating according to their rate of discharge. A temporal summation of impulses (Setschenow's summation), occurring at lower (nuclear or brain stem) levels would be responsible for conveying the cerebellifugal volleys to either facilitating or inhibitory brain stem structures, depending upon the rate of the synchronous beatings imposed by the electrical stimuli upon the same Purkinje cells. The rebound would then represent the low-frequency afterdischarge of the same units whose high-rate stimulation yielded an inhibition of decerebrate rigidity during the stimulus phase. The latter hypothesis was supported by indirect evidence, reviewed elsewhere (Moruzzi, 1949, p. 416). However, recent findings by Moruzzi and Pompeiano (1954, 1957b), to be reported later, are more easily explained by the assumption that inhibitory and augmentatory neurons are actually intermingled within the vermal cortex. The reversal of the cerebellar response through a change in the rate of stimulation was duplicated in the decerebrate cat, and shown by recording electromy©graphically the cat's stretch reflexes (Moruzzi, 1950b). Clear-cut facilitations of the stretch reflexes were obtained not only with repetition rates (2 to 10 per second) yielding an increase in decerebrate rigidity, but also with slightly higher rates of stimulation (10 to 30 per second), which had no visible effect on the extensor hypertonus. Square pulses from 40 to 300 per second constantly inhibited the stretch reflexes. The reversal of the cerebellar inhibition, which is brought about by lowering the rate of stimulation, was confirmed by Brihaye (1953), Terzian and Terzuolo (1954), and Terzuolo (1954), in experiments to be reviewed now and at p. 260 below. The electrophysiological experiments performed by Terzuolo (1952, 1954) in Bremer's laboratory should be reviewed in this section, because they were concerned with the general mechanisms underlying cerebellar inhibition and facilitation. The convulsive waves, 10 to 20 per second, occurring in the electrospinogram of curarized, decerebrate cats after intravenous injections of tetanizing doses of strychnine (Bremer, 1941), were shown to be strongly influenced by thyratron stimulation of the anterior lobe and the reticular formation. High-rate stimulation of the anterior lobe or of Magoun's inhibitory center decreased the frequency of the strychnine waves, without reducing their amplitude (Fig. 30A, B). Actually the convulsive waves were abolished altogether if the strength of the stimulation was slightly increased (Fig. 30(7, D). The postinhibitory rebound was characterized by an increased rate of convulsive activity, again without significant changes in the amplitude of the single waves (Fig. 30). The cerebellar inhibition was strengthened by anelectrotonic and antagonized by catelectrotonic polarization of the spinal cord, a procedure which had been shown (Bremer, 1941; Ajmone-Marsan, Fuortes, and Marossero, 1951) to influence in opposite directions the strychnine., tetanus. Inasmuch as the convulsive waves are present in isolated and deafferented parts of the spinal cord (Brooks and Fuortes, 1952;

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Figure SO. Cerebellar and bulboreticular inhibition of strychnine tetanus. Convulsive waves, led from the spinal cord during strychnine tetanus (intercollicular cat, under curare), are inhibited by high-frequency (200/sec) stimulation of the anterior lobe (A, B, C: 0.5, 0.8, 1.1 V.) and of Magoun's bulboinhibitory center (D: 1.3 volts). (From C. Terzuolo, 1954, Influences supraspinales sur le tetanos strychnique de la moelle epiniere, Arch, internat. de physiol., 60:179-196, Fig. 5.)

Figure 81. Cerebellar and bulboreticular facilitation of strychnine tetanus. Technical details are the same as in Fig. 30, but the rate of the strychnine waves is increased (A) by high-frequency (200/sec; 2.5 V.) stimulation of the pontile reticular formation and by low-frequency stimulation (18/sec; 2.5 V.) of the anterior lobe (5, C). (From C. Terzuolo, 1954, Influences supraspinales sur le tetanos strychnique de la moelle epiniere, Arch, internat. de physiol., 60:179-196, Fig. 3.)

Terzuolo, 1954), their inhibition by cerebellifugal volleys could not be explained by a blockade of supraspinal facilitation (see p. 118). Moreover, the fact that the amplitude of the single wave was not decreased suggested that the shower of inhibitory impulses arising in the cerebellar cortex and impinging upon the spinal neurons was unable to disrupt their synchronous beating. The convulsive units behaved in an "all-or-none" manner, since their synchronous discharge either was blocked altogether or thoroughly escaped inhibition. Low-rate (under 20 per second) stimulation of the anterior lobe or highfrequency (200 per second) pulses applied to facilitating (pontine) reticular centers yielded just the opposite effects; i.e., the onset of the tetanus was pre

130 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM cipitated if it happened to be absent at the moment of the simulation, or the rhythm of the strychnine waves was strongly accelerated if they were already going on (Fig. 31). Summing up, in the cat injected with tetanizing doses of strychnine, three old observations were confirmed; namely (a) that cerebellar inhibition is not reversed by the drug (Bremer, 1922b, 1925; Moruzzi, 1936c, 1948b); (b) that augmentatory effects can be obtained from the so-called inhibitory area if the rate of stimulation is decreased (Moruzzi, 1948a, b); and (c) that the reversal of the response is still present after injection of strychnine (Moruzzi, 1936c, 1948b). It had been stated that for spinal inhibitory effects "strychnine supplies a test for their freedom from admixture with excitatory components, in other words for their purity" (Liddell and Sherrington, 1925, p. 282). Terzuolo's experiments gave the final evidence that paleocerebellar inhibition could not be regarded as "pure" simply because it was not reversed by strychnine. They showed, moreover, that even the convulsive activity of the spinal cord could be controlled by the cerebellum. In Brihaye's experiments (1953), the anterior lobe of decerebrate cats was stimulated with an induction coil (50 per second) or with a thyratron. Brihaye

Figure 32. Localization of the fastigial lesion yielding a reversal of the inhibitory response of the anterior lobe. The diagrams are numbered in a rostrocaudal direction from 1 to 8, with intervals of 100 /it. The dotted areas represent the fastigial (F), interpositus (7), and dentate (D) nuclei, while the shaded areas represent the region showing electrolytic destructions or histological alterations. The rostrolateral lesion begins at the anterior pole of the fastigial nucleus and stops after diagram 8, i.e., about at the junction between the rostral and middle one third of the roof nucleus.—Decerebrate

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cat. The vermal cortex of the anterior lobe (lobules III to V) was stimulated with regular pulses of 300/sec, 1 msec., 0.62 V. rectangular pulses. The threshold and spontaneous electrical activity were unchanged following the fastigial lesion, but stimulation of the overlying cortex of lobules III to V yielded an increase in instead of an inhibition of decerebrate rigidity. The classical inhibitory effect was obtained from the opposite side of the anterior vennis. (From G. Moruzzi and O. Pompeiano, 1957, Effects of vermal stimulations after fastigial lesions, Arch. ital. Biol., 95:31-55, Fig. 2.)

showed that bulbopontine activities, certainly nonpostural in type (such as reflex lowering of the jaw), were inhibited. However, the corneal reflex was constantly unaffected, and he confirmed that the most striking and constant of the cerebellar responses was the relaxation of the rigid antigravity muscles. Only inconstant and unpredictable effects were instead observed on the flexor myograms. He confirmed Moruzzi's results on the influence of low- and fast-rate stimuli on the extensor tonus, and he reported similar findings when the background of activity was represented by either extensor or flexor reflexes. However, reflex lowering of the jaw was inhibited only with high-rate stimuli (100 to 200 per second) and was not obviously modified when the repetition rate of the electric pulses was decreased. After stereotaxically oriented and histologically controlled lesions of the rostrolateral part of the nucleus fastigii (Figs. 32, 33), in the decerebrate cat, Moruzzi and Pompeiano (1954, 1956a, 1957b), found that the corresponding vermal surface of the anterior lobe (lobules III to V) yielded a clear-cut increase in extensor rigidity in the ipsilateral limbs (Fig. 34). The effect was obtained with

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high-rate pulses, lasted as long as the stimulation, and was never followed by rebound. Rectangular pulses having the same parameters (300/sec; 1 msec.; threshold voltages) yielded instead a typical inhibition of decerebrate rigidity, followed by a strong extensor rebound, if the bipolar electrodes were applied on the opposite surface of the same lobules, only a few millimeters apart. Even this inhibitory effect was constantly reversed if an acute lesion was made in the homotopic structures of the other fastigial nucleus. The reversal of the cerebellar response was brought about by destroying the same nuclear structures which yielded a withdrawal of the ipsilateral limb upon electrical stimulation (300/sec; 1 msec.). The reversal of the inhibitory response of lobules HI, IV, and V was analyzed by Moruzzi and Pompeiano on 135 decerebrate cats, whose anterior lobes were stimulated after different types of fastigial lesions. Only the results on the vermal part of the anterior lobe were reported. The specificity of the reversal of the classical inhibitory response was shown by the following evidence: (a) complete acute or chronic lesion of the caudal two thirds of the roof nuclei was thoroughly ineffective, while any response of lobules III, IV, and V was absent, when the rostral halves of the fastigial nuclei had been completely destroyed, either acutely or chronically; (b) the rostrolateral part of one fastigial nucleus had to be encroached upon and the rostromedial part had to be spared in order to obtain the reversal of the postural response; (c) the reversal of the cerebellar effect lasted as long as the preparation (up to four hours), and was present also when the cat was decerebrated following chronic rostrolateral lesion of one fastigial nucleus; (d) the spontaneous electrical activity and the electrical excitability appeared exactly the same on the inhibitory and on the augmentatory side of the vermal cortex. Hence the reversal was apparently related to the interruption of specific efferent pathways, and could not be explained by irritation or injury of the overlying cerebellar cortex. That the augmentatory vermal response really arose within the stimulated area of the cerebellar cortex was shown (a) by the marked lowering of the threshold that occurred after local application for only 30 seconds of 0.1 per cent of strychnine nitrate and its marked increase following local cocainization; (b) by the abolition of the augmentatory effect elicited by undercutting the stimulated area of the cerebellum; (c) by the fact that for threshold stimuli the electrical parameters were the same for both the augmentatory and the inhibitory vermal area, i.e., ipsilaterally and contralaterally to the fastigial lesion; (d) by the demonstration of sharp limits between the two vermal areas as well as between the excitable zone and the unresponsive folia behind the fissura prima. The augmentatory response was not relayed through the ipsilateral hemispheral part of the anterior lobe, since its inactivation by suction was without effect. Even the electrolytic destruction of the underlying nucleus interpositus, which entirely abolished the response of the intermediate part of the anterior lobe, did not influence the augmentatory response of lobules III, IV, and V. Nor was the vermal augmentatory response due to a neural or physical spread to the opposite vermis, the stimulation of which occasionally yields ipsilateral inhibition and a contralateral increase in extensor rigidity (see pp. 136ff), since (a) only

Figure S3. Microphotograph showing a rostrolateral fastigial lesion yielding a reversal of the inhibitory response of the anterior lobe. The Nissl slide corresponds to diagram no. 6 of Fig. 2 (same cat). The lesion occupies the rostrolateral, parvicellular part of the right fastigial nucleus, while the rostromedial, magnocellular part is intact. (From G. Moruzzi and 0. Pompeiano, 1957, Effects of vermal stimulations after fastigial lesions, Arch. ital. Biol., 95:31-55, Fig. 3.)

Figure 34. A scheme of the vermal areas of the anterior lobe yielding augmentatory responses after destruction of the rostrolateral part of the right fastigial nucleus. Rostral (A) and dorsocaudal (B) view of the cat's anterior lobe. Scheme and nomenckture are taken from Larsell (J. Comp. Neurol., 1953, 99:135-200). /. pr. = fissura prima; f. icul. 1, f. icul. 2 = intraculminate fissures 1 and 2; /. pc. = preculminate fissure; /. ic. 1 — intracentral fissure 1; f. prc. = precentral fissure. The vermal zone whose electrical stimulation yields an ipsilateral increase in extensor rigidity following rostrolateral lesion of the right fastigial nucleus is represented by the dotted area. The same electrical stimulation yields the classical inhibition of ipsilateral rigidity when applied to the left vermal area, a few millimeters apart. Lobules I and II were not explored. (From G. Moruzzi and O. Pompeiano, 1957, Effects of vermal stimulations after fastigial lesions, Arch. ital. Biol., 95:31-55, Fig. 1.) 133

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ipsilateral effects were obtained, at threshold, from both the inhibitory and the augmentatory sides of lobules III, IV, and V; and (b) suction of the inhibitory side of the anterior vermis or its inactivation by severing the ipsilateral cerebellar peduncles did not abolish the response of the augmentatory side. Although the inhibitory and the augmentatory pathways diverge at fastigial levels, so that the inhibitory component of the cerebellar response can be more or less selectively abolished by strictly localized nuclear lesions, their further course is more or less the same. The authors reported that both the inhibitory and the augmentatory response of lobules III, IV, and V were present after postcollicular decerebration, and pointed out that both effects disappeared when the inferior cerebellar peduncle was severed ipsilaterally. The brain stem relays were not determined, but the latent times were measured by recording electromyographically the medial head of M. triceps brachii, and the figures for the inhibitory response (10 to 15 milliseconds) were found to be constantly much lower than those for the augmentatory effects (50 to 60 milliseconds). Summing up, both the augmentatory and the inhibitory responses of lobules III, IV, and V appear to be relayed by direct fastigiobulbar neurons, whose somata are localized in the rostral part of each roof nucleus and whose axons course through the inferior cerebellar peduncle. When the lesion is localized in the rostrolateral part of one fastigial nucleus, most of the inhibitory pathways are interrupted, while most of the augmentatory relays are spared. Hence the augmentatory effect is no longer concealed below the overwhelming inhibition. A rather likely explanation of these and previous findings might be the following: (a) inhibitory and facilitating units are intermingled within the anterior vermis; (b) during the stimulation the facilitatory response is concealed below the inhibitory effect; (c) isolated facilitation may be brought about either by interrupting inhibitory nuclear relays or by selective low-frequency stimulation (Moruzzi, 1948a, b); (d) both facilitatory and inhibitory units are stimulated by high-frequency pulses at about the same threshold, whereas the facilitatory system is activated also by low-rate stimulation, at least if higher voltages are applied (Engelmann-Richet effect). These findings might incidentally explain why only facilitation of the extensor motoneurons was obtained by Hampson, Harrison, and Woolsey (1952) from the anterior lobes of decerebrate dogs which had been chronically intoxicated with methyl chloride (Smith, 1952). It is likely that the inhibitory system had been blocked somewhere, although the lesions were certainly neither selective nor exactly localized, as shown by the fact that before decerebration the animals presented not only extensor hypertonia, but also cerebellar tremor and ataxia. Sprague and Chambers (1954) stimulated the cerebellar cortex of decerebrate cats with 60-cycle sine waves or with rectangular pulses (mainly 50/sec; 1 msec.). Their vermian responses—which were obtained from the lobus anterior (lobules I to V), lobulus simplex (lobule VI), pyramis (lobule VIII), and uvula (lobule IX)—confirmed Bremer's description (1922a), since ipsilaterally the extensors were inhibited while the flexors were left unchanged. They pointed out, however, that the flexor motoneurons, when tested with the pinch-withdrawal reflex, showed subliminal facilitation. At threshold the response was limited to the ipsi-

STIMULATION EXPERIMENTS 135 lateral forelimb and was not followed by poststimulatory rebound. Gradual increase in the intensity of the stimulation caused a spread to the contralateral forelimb, whose extensor rigidity increased, and then to the hindlegs, while the rebound appeared. They stated that the vermian responses were similar to those elicited from the nucleus fastigii, restiform body, and medial reticular formation, and they made the important observation that following chronic cerebellectomy (survival period, 19 to 302 days) and acute decerebration, the poststimulatory rebound was absent when the medial reticular formation was stimulated, although the inhibition of extensor rigidity was still present. Since both inhibition and rebound were present (a) after acute cerebellectomy and (b) after bilateral chronic ablation of Deiters' vestibular nuclei, they inferred that the reticular rebound was due to stimulation of the terminations of cerebellifugal fibers impinging upon the reticular formation. This observation would seem to support the hypothesis that the cerebellar rebound is due to facilitating volleys arising in cortical or nuclear neurons (see p. 128). Sprague and Chambers (1954) stated, however, that "only a mild rigidity" followed the acute decerebration of a chronically decerebellate cat, while it is well known (and it was confirmed by the authors) that a tremendous increase in rigidity occurs if cerebellectomy is made acutely in the decerebrate animal or if decerebration is performed a few days after complete cerebellectomy (Bremer, 1922a). Since this increase is a release phenomenon (see p. 60), one wonders if chronic cerebellectomy, besides allowing time for the degeneration of cerebellifugal pathways, was followed by transneuronal or circulatory changes in the brain stem neurons. This hypothesis would also explain some of the results obtained by Stella (1947; see below, pp. £80-282). The hemispheral responses were obtained from the lobus anterior (lobules H I to H V) and the lobulus simplex (lobule H VI), lateral to the paravermal veins, and from the paramedian lobuli, and were duplicated by stimulating the nucleus interpositus, brachium conjunctivum, and lateral reticular formation (Sprague and Chambers, 1954). At threshold, they were characterized by extensor facilitation in the ipsilateral foreleg, in confirmation of the previous findings of Stella (1944a), Hampson et al. (1945, 1946, 1952), and Moruzzi (1947b). A flexor inhibition was observed only if the stimulation was timed to occur against a background of flexor rigidity, but the rebound was constantly flexor in character. If the stimulation was increased, the response became more pronounced, but it remained localized in the ipsilateral foreleg. Sprague and Chambers (1954) emphasized that cerebellar and reticular responses were often reciprocal in character, and regarded as "grossly misleading" the "reference to the cerebellum as a center of tonic inhibition." They conceded, however, that "the occurrence of generalized inhibition at threshold stimulation in the reflexly active decerebrate animal, even though infrequent, poses a question for which an answer cannot be made." The answer was given by recent experiments performed by Pompeiano (1955, 1956) on decerebrate cats. He stimulated unilaterally lobules IV and V with rectangular pulses (300/sec; 1 msec.), delivered through bipolar metallic electrodes. He confirmed that the threshold response (0.4 to 0.6 volt) was strictly confined to the ipsilateral forelimb and was represented by the classical inhibition

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of extensor rigidity. Slightly higher voltages (0.6 to 0.8 volt) yielded also, but inconstantly, a crossed increase in extensor rigidity, as reported by Sprague and Chambers (1954). A further increase in tension (above 0.8 volt) evoked, constantly, the bilateral disappearance of the extensor hypertonus described by Moruzzi (1948c). Controls showed that all these voltages were greatly below the critical values which give a significant physical spread of current, even within the anterior lobe. Pompeiano showed that these multifarious responses of the contralateral limbs were mediated by quite different neural mechanisms and that the results became constant and predictable as soon as the efferent pathways were identified. In particular he reported that contralateral inhibition was constantly abolished, and a crossed increase in extensor rigidity constantly occurred, whenever (a) the hemivermis or (b) the whole and even only the rostral part of the fastigial nucleus or (c) the three cerebellar peduncles were, respectively, destroyed by suction, stereotaxically fulgurated, or severed on the side of the body opposite to the stimulated vermal area. Moreover, even when a chronic lesion of, say, the left fastigial nucleus was followed by total midbrain section, stimulation of the right side of lobules IV and V never inhibited, but always increased, the extensor rigidity of the left legs. Ipsilaterally to the stimulated area, the classic inhibition of extensor rigidity was instead observed. These findings hint that cerebellar inhibition of the extensor rigidity of the contralateral limbs is due to activation of the cerebellofastigiobulbar mechanisms of the opposite hemivermis, possibly through intracortical association fibers. Only when this neural spread, or at least its peripheral effect, is prevented by one of the operations listed above, does the reciprocal organization of the postural response come to light; i.e., the extensor rigidity disappears ipsilaterally and increases contralaterally to the vermal stimulation. Hence bilateral inhibition is correlated with a neural spread within the cerebellum, while the reciprocal organization of the response is actually an extracerebellar phenomenon. The neural mechanisms underlying the reciprocal organization of the cerebellar responses have been investigated by Pompeiano (1956). The reciprocal effect was not abolished by suction of the midbrain followed by midline splitting of the pons. In two histologically controlled cases in which the midline section of the brain stem reached the medulla, the contralateral augmentatory effect disappeared, while the ipsilateral inhibition remained. A hemisection of the spinal cord between the fourth and fifth cervical segments abolished not only the inhibitory response of the ipsilateral vermis (a confirmation of Ingersoll, Magoun, and Ranson, 1936) but also the increase in extensor rigidity which was elicited by stimulating the contralateral side of the anterior vermis. It would appear, therefore, that the crossed pathways which underlie the reciprocal organization of the cerebellar response are localized in the medulla oblongata, but that intraspinal mechanisms are also possible. An analysis of the effects of threshold electrical stimulations (300/sec; 1 msec.; square pulses of 0.6 to 1 volt) of the intermediate part of the anterior lobe was recently performed by Pompeiano (1958a and b) on precollicular cats. In order to get rid of the possible consequences of a neural or physical spread to

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the neighboring anterior vermis, he utilized animals whose fastigial nuclei had previously been destroyed, totally, bilaterally, and chronically, with the stereotaxic apparatus. In these preparations the vermal portion of the anterior lobe gave no response to the electrical stimuli, and the excitable area was limited to the intermediate part of the anterior lobe. The response of this area was entirely unaffected by acute destruction of the caudal two thirds of the nucleus interpositus and of the whole nucleus dentatus. It was mediated or relayed by the rostral one third of the nucleus interpositus, since following the destruction of that third the intermediate part became thoroughly inexcitable. The intermediate part could be further divided into two longitudinal strips, each having its own efferent projections. The response of the medial strip was characterized by ipsilateral active flexion and by contralateral extension. This effect was abolished (a) by destroying the rostromedial part of the ipsilateral nucleus interpositus, (b) by postcollicular decerebration, (c) by midline splitting of the mesencephalon, and (d) by stereotaxic destruction of the caudal part of the contralateral red nucleus, a region whose localized stimulation yielded crossed active flexion (Pompeiano, 1957). This response was, therefore, mediated by cerebellorubrospinal relays, and the double crossing accounted for the ipsilaterality of the flexor effect. The response of the lateral strip was instead characterized by tonic extension of the ipsilateral and frequently also of the contralateral limbs, and it was abolished by destroying the rostrolateral part of the ipsilateral nucleus interpositus, but not by postcollicular decerebration. Hence this response was certainly not mediated by midbrain relays. Active flexion had been frequently reported following stimulation of the anterior lobe (Bernis and Spiegel, 1925; Denny-Brown, Eccles, and Liddell, 1929; Hampson, Harrison, and Woolsey, 1945, 1952), but this response had not been differentiated from the sheer inhibition of extensor rigidity which is brought about by threshold vermal stimuli. Actually the routes of these effects are entirely different, the vermal response being mediated by direct fastigiobulbar pathways, whereas the hemispheral effect is probably due to interpositorubrospinal mechanisms. Also the extensor response of the ipsilateral strip had been previously described (Stella, 1944a; Hampson, Harrison, and Woolsey, 1945; Moruzzi, 1947b; Sprague and Chambers, 1954), but its efferent pathways appear to be entirely different from those of the medial strip.

3. STIMULATION OF THE POSTERIOR LOBE OF THE CORPUS CEREBEI/LI Hampson, Harrison, and Woolsey (1952) observed that "neck, facial, masticatory and certain extraocular muscles were affected primarily by the Lobulus simplex (Lobules VI and H VI)" (p. 303) whereas according to Brihaye (1953) both trismus and chewing reflexes were inhibited by high-rate stimulation not only of the lobulus simplex (lobules VI and H VI) but also of the culmen (lobules IV, V) and pyramis (lobule VIII). It is likely that this discrepancy is due to different rates of stimulation (Moruzzi, 1948c; see above, p. 127). Responses similar to those reported for the anterior lobe were obtained from

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the pyramis, or lobule VIII (Bremer, 1922a; Hampson, Harrison, and Woolsey, 1945, 1946, 1952; Sprague and Chambers, 1954), from the uvula, or lobule IX (Sprague and Chambers, 1954), and from the lobulus paramedianus, or sublobules H Vllb and lobule H VIII (Hampson, Harrison, and Woolsey, 1945, 1946, 1952; Snider, McCulloch, and Magoun, 1949; Snider and Magoun, 1949; Sprague and Chambers, 1954). A somatotopic localization was found within the paramedian lobule (Fig. 29), since the upper folia "influence the facial musculature, the middle folia influence the arm, while the lowermost folia are concerned with leg and tail musculature" (Hampson et al., 1952, p. 305). Both inhibition (Snider, McCulloch, and Magoun, 1949) and facilitation (Snider and Magoun, 1949) of the knee jerk were obtained also from the contralateral paramedian lobe, although the effects were less pronounced than the ipsilateral ones. An account of the effects of stimulating the lobulus ansiformis (sublobule H Vila) on cortically induced (Rossi, 1912b) and autonomic (Hampson, 1949; Emerson et al., 1954) activities falls to another chapter (see p. 311). The conjugate ocular movements which were so frequently observed, but never exactly localized, by the earlier investigators (Hitzig, 1874; Ferrier, 1876; Balogh, 1876; Dupuy, 1885; Prevost, 1899; Probst, 1899, 1902; Wersiloff, 1899; Prus, 1901; Lourie, 1907, 1908; Greker, 1909; Rothmann, 1910; Uffenorde, 1912) are probably represented within Ingvar's lobulus medius medianus (folium and tuber, lobule VII) and also in the folia lying just rostrally (declive, lobule VI) and caudally (pyramis, lobule VIII) to this structure. This is the conclusion from the electrical stimulations performed by Hoshino (1921), Dusser de Barenne (1922), Mussen (1927), Bremer (1935), Dow (1935), Hare, Magoun, and Ranson (1937), Hampson, Harrison, and Woolsey (1945, 1946, 1952), Moruzzi (1947c, 1948e), and Cranmer (1951). Hoshino's "ophthalrnotropogene Zone" is localized near the rostral end of the sulcus paramedianus. With experiments performed on intact, unanesthetized rabbits he observed a horizontal deviation of both eyes toward the side stimulated. The response was abolished by cooling the cerebellar cortex, but not by bilateral labyrinthectomy. These results were confirmed by Dusser de Barenne (1922). Bremer (1935), by stimulating the lobulus simplex (lobules VI and H VI), and Mussen (1927) and Hampson, Harrison, and Woolsey (1945, 1946, 1952), by faradizing the lobulus medius medianus (lobule VII), also confirmed Hoshino's results in both intact (unanesthetized) and decerebrated cats. Conjugate ocular movements were reported by Hare, Magoun, and Ranson (1937) following faradizations "limited to the most medial part of the stalk of the Tuber and to the folia of the Declive" of normal cats, while Dow (1935) and Cranmer (1951) got similar responses from the pyramis (lobule VIII). Moruzzi's experiments (1948e) were performed in unanesthetized thalamic cats, in which the optic tracts (and consequently the pupillary photic reflexes) had been spared by the brain transection. Rectangular pulses applied to the lobulus simplex (lobule VI) and to the lobulus medius medianus (lobule VII) yielded conjugate ocular deviations, associated with responses of the pupils and of the nictitating membrane. The voltage thresholds were about the same as those of the anterior lobe, and for both areas they decreased when the pulse rate was increased (up to 300 per second). Some-

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times the threshold of the somatic responses was slightly lower than that of the autonomic ones, and the effects could be dissociated. As Bremer (1935) pointed out, the depth of the cerebellar folia is quite small in these cerebellar folia, so that stimulation of the underlying white matter cannot be dismissed in all these experiments. The rabbit's paraflocculus (lobules H VIII, H IX) was faradized by Barany (1914), who misnamed (as Dow pointed out) the so-called lobulus petrosus as the flocculus (lobule H X). He found ocular movements, which were more pronounced on the same side. His results, however, were not confirmed by Dow (1935) in experiments performed on rabbits under barbital anesthesia. D. CORTICAL AND SUBCORTICAL CEREBELLAR STIMULATIONS IN UNRESTRAINED, UNANESTHETIZED MAMMALS Cerebellar stimulations of conscious animals were reported for the first time by Lewandowski (1903, p. 150). Faradization of the region of the paramedian fissure, with Ewald's implanted electrodes (1898), yielded flexion of the ipsilateral forelimb in five unanesthetized dogs. The same type of experiment was performed by Mussen (1934) and by Brogden and Gantt (1937), although the latter authors were mainly concerned with the problem of "conditioning" to cerebellar stimulation. An accurate investigation was carried out by Clark (1939a), who explored the cat's cerebellar cortex with chronically implanted concentric electrodes and 50-cycle sine-wave currents. The responses were tonic and slow in character and could be divided into three phases, namely (a) the short phase of stimulus, (b) the rebound, which was more rapid in onset and opposite in direction, and (c) the long aftereffect which "involves the head, limbs, body and tail of the animal in a series of slow movements lasting for several minutes." Our attention will be concentrated on the third phase, which was called "cerebellar seizure" and never occurred in the decerebrate preparation or in the intact, slightly anesthetized cat. It was particularly evident when the vermis (just before or behind the fissura prima) and also crus I (sublobule H Vila) and the lateral part of crus II (sublobule H Vila) were stimulated, whereas only stimulus and rebound phases were brought about by stimulating the paramedian lobuli (sublobules H VTIb, H VIII), the medial part of crus II (sublobule H Vila), and the posterior vermis. The response elicited by stimulating, for example, the lateral part of the vermis just back of the primary fissure, lasted from 5 to 15 minutes and is best described in the author's own words: "With the stimulus the head turns gradually to the homolateral side, being held in this position for the duration of the stimulus. Promptly at the end of the stimulus the head turns toward the contralateral side in rebound. At the same time or within a few seconds afterward the homolateral forelimb may lift and protract; and may deviate in the direction of the head. The foot may wave slowly and even be lifted higher than the head. After about half a minute or a minute the animal returns to its normal resting posture or may go directly into the long after-effect. If the homolateral limb did not lift at first it now goes

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through the procedure. At this time the head may or may not turn tonically to the homolateral side. The forelimb gradually relaxes, while the contralateral forelimb becomes involved in a similar manner, and the head may turn to the contralateral side. By 2% to 3 min. after the stimulus these movements have subsided. There may appear a concavity of the trunk to one side then the other along with or following the forelimb involvement. About 4 to 5 min. after the stimulus the homolateral hindlimb begins to be affected, and lifts as did the foreleg showing an overaction of different groups of muscles in the extremity, so that its position gradually changes. It may be protracted awhile, then retracted, and the hocks may deviate medially then laterally. The tail at this time tends to curve tonically toward the homolateral side so that it is in a horizontal plane with tip pointing toward the head. These effects gradually give way and at about 6 or 7 min. after the stimulus the contralateral hindleg shows an effect like the homolateral; the tail hooks to the contralateral side, sometimes showing a stage where it hooks dorsalward and at other times resembling a corkscrew in the period of transition from one side to the other. As these effects gradually cease the animal returns to normal" (pp. 22-23). These findings were duplicated by either mechanical irritation (see above, p. 110; Clark, 1939b) or electrical stimulation of the interior of the cerebellum (Chambers, 1947) in conscious cats. Clark and Ward (1949, 1952) reported that the cerebellar seizure was present after bilateral ablation of the motor cortex and almost complete decortication. In the EEG records, only a generalized arousal reaction was observed, with no signs of convulsive activity (Clark and Ward, 1949). The fact that the long aftereffect did not occur in the acute decerebrate cat does not necessarily mean, we think, that the diencephalon was involved in the seizure, since Clark (1939a) showed that the latter was absent even in the normal cat, some time after the anesthesia (more than 24 hours in the case of nembutal). The somatic responses yielded by the cerebellar nuclei in conscious cats were reported by Chambers (1947) to be similar to those in the anesthetized animal. The anterior lobe was explored in conscious cats by McDonald (1953), with similar technique and results. It is apparent from his description that both type and somatotopic localization of the primary effects (stimulus and rebound phases) followed the patterns which had been reported many times in decerebrate and in normal anesthetized animals (see p. 125), although he pointed out that the hindlimb responses were elicited from the most rostral folia of the culmen (lobules IV, V). The cerebellar seizure was instead observed only in the unanesthetized preparation and occurred when stronger stimuli were used. It began in the forelimb or hindlimb which had been affected by the primary response. These observations suggested that even in Clark's experiments (1939a, b), previously referred to, the cerebellar activity spread gradually from the lobulus simplex (lobule VI and H VI) to the neighboring centers of the anterior lobe. The problem then arose of whether this Jacksonian-like march was due entirely to a slow, neural spread within the cerebellar cortex. Clark and Ward (1952) reported that the seizure was confined to the homolateral side after complete splitting of the cerebellum, but that a normal contralateral spread still occurred if a bridge of the cortex cranially and caudally had been left. A proprioceptive reverberation was dis-

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proved by the occurrence of seizures after section of the eighth cranial nerve followed by cervical and limb deafferentation (Clark and Ward, 1952). Sprague and Chambers (1954) reported on the effect of fastigial and bulboreticular stimulations in decerebrate, anesthetized, and unanesthetized cats. An account of the basic effects observed in either decerebrate or anesthetized preparations has been given in an earlier section (p. 135). Suffice it to say here that at threshold the responses were about the same in all three states. Suprathreshold stimulations yielded, however, instead complicated and well-organized movements of the conscious cat, which, "starting from a reclining position, involve righting of head and body and circling toward the side of the stimulus." Further increases in the stimulus resulted in vocalization and struggling movements. The responses were similar following fastigial and reticular stimulation, but the delayed, long-lasting cerebellar seizures were observed only when the roof nuclei were stimulated. The authors stressed the fact that a generalized inhibition was not observed in the conscious cats. This observation is certainly interesting, but should not be overestimated, since also the ascending reticular system was certainly activated by either brain stem or fastigial stimulations (Moruzzi and Magoun, 1949). Hence the inhibitory influence of the reticulospinal neurons might be complicated by the activation of rostral structures and, possibly, by the central action of adrenalin discharges (see Bonvallet, Dell, and Hiebel, 1954). Experiments of electrical stimulation of the ansiform (sublobule H Vila) and paramedian (sublobules H Vllb and H Villa) lobules (Delgado and Schulman, 1955) and of the basal cerebellum (Koella, 1955) of the cat were recently reported. The cerebellar responses were not altered by destruction of anterior and posterior sigmoid gyri (Delgado and Schulman, 1955) and were reversed in direction by changing the rate of the stimulation (Koella, 1955). E. ELECTRICAL STIMULATION OF THE CEREBELLAR NUCLEI IN MAMMALS The first experiments performed with the stereotaxic apparatus had led to the conclusion that only the cerebellar nuclei were excitable. The threshold of the cortex was so high, according to Horsley and Clarke (1908), that its responses should be attributed to current diffusion to the underlying nuclei. In the posthumous paper of Clarke (1926) the suggestion was put forward that even these "nuclear" responses were fallacious in character and depended on current diffusion to brain stem structures, since the points yielding the best responses were not exclusively concentrated within the nuclei but were distributed all over the roof of the fourth ventricle. We have already made an attempt to explain these erroneous beliefs (p. 104). We should like only to stress here that there was no reason to be surprised that the "nuclear" thresholds were so strikingly lower, since (a) with the concentric bipolar electrode only a small volume of nervous substance could be stimulated and the current impinged upon a greater wealth of perikarya or of efferent fibers when the tip was near or within the deep nuclei, and (b) the nuclear responses are much less affected by anesthesia than the cortical ones (Henneman, Cooke, and Snider, 1952). Nor was there any reason to wonder about Clarke's observa-

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tion (1926), showing that the deep responses were not strictly localized within the nuclei, since stimulation of corticonuclear paths or of the efferent fastigiobulbar tracts was also likely to yield similar effects (see p. 150). Only short preliminary accounts were presented in the following years by Sachs and Fincher (1927) and by Mussen (1927), who stimulated stereotaxically the cerebellar nuclei in monkeys and cats with faradic current, but never reported control experiments clearly dismissing the objection concerning current diffusion. Miller and Laughton, who used precollicular decerebrate cats, stimulated with faradic current the dorsal surface of the cerebellar nuclei, after these structures had been exposed by removing the overlying cortex. It was shown for the first time that the effects arose within the nuclei, since "the responsive areas were strictly limited in various directions," if unipolar stigmatic electrodes and threshold currents were used. However, neither the direct observation (1928a) nor myographic recordings from couples of antagonistic muscles (1928b) showed basic differences between the responses of different nuclei. Stimulation of the nucleus dentatus yielded active flexion of the ipsilateral forelimb and hindlimb (M. tibialis anterior and M. biceps brachii), and only slight effects were observed on the extensor myograms (M. triceps brachii and M. gastrocnemius soleus). An increase of extensor rigidity was, only inconstantly, observed in the ipsilateral hindlimb, while trunk and tail movements were reported. Stimulation of the nucleus interpositus (emboliformis and globosus) gave similar but somewhat stronger flexor responses. If the initial tone of M. triceps or of M. gastrocnemius soleus was marked, a relaxation occurred during the stimulation; otherwise the only sign of an extensor response was the subsequent rebound. Contralaterally the forelimb relaxed and the hindlimb stiffened during the stimulation. Ocular, trunk, and tail movements were observed. Finally, the nucleus fastigii yielded strong active flexion of both forelimbs and sometimes of both hindlimbs, followed by an extensor rebound. The myographic responses differed "from those previously described merely in the exaggeration of their various phases" and the postinhibitory rebound of M. triceps brachii was powerful, "rivalling or sometimes surpassing in height the excitatory contraction of biceps." The demonstration that an inhibition and a poststimulatory rebound of extensor rigidity were obtained from the nucleus fastigii, just as from the vermian surface of the anterior lobe, was an important finding; it was interesting to learn, moreover, that fastigial responses were not a sheer duplication of the corticocerebellar ones, since flexor contraction was always present during the "nuclear" effect. The bewildering aspect of these experiments was represented, however, by the essential similarity between the responses of the different nuclei. This was certainly not the result one would have expected from the anatomical data on corticonuclear relations (see Jansen and Brodal, 1954) and from the physiological experiments on electrical stimulation of the corresponding cerebellar cortical areas (see p. 135). Actually the data on the nucleus interpositus and nucleus dentatus were not (or were only partially) confirmed by Hare, Magoun, and Ranson (1936, 1937), by Sprague and Chambers (1953), and by Pompeiano, Ricci, and Zanchetti (1954). It is likely that the excitability of the cerebellar nuclei had deteriorated owing to surgical exposure, which "was attended by a

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considerable amount of bleeding" as well as by the repetitive clamping of vertebral arteries required for checking the hemorrhage. The cerebellum is certainly extremely sensitive to anemia, and the importance of avoiding the compression of vertebral arteries and the permanent clamping of the carotids will be stressed in the chapter on electrophysiological experiments. That the condition of many preparations was not entirely satisfactory is shown by the myograms of the extensor muscles reported by Miller and Laughton (1928b). Only exceptionally was a background of hypertonus present, so that the relaxation elicited by the "nuclear" stimulation was often surprisingly small (Miller and Laughton, 1928b). The Horsley-Clarke apparatus was again utilized for faradic stimulation of the interior of the cerebellum in intact, nembutalized monkeys (Magoun, Hare, and Ranson, 1935) and cats (Hare, Magoun, and Ranson, 1936) as well as in decerebrate cats (Hare, Magoun, and Ranson, 1936, 1937). In these fundamental works every cubic millimeter of cerebellar substance was explored with concentric bipolar electrodes, and the localization of each point stimulated was histologically controlled on serial slides. In the monkey experiments, the responses of the eyes, head, and trunk and tail were distinguished from those of the limbs. The first group of effects consisted of deviations from the longitudinal axis of the body. Three types of reactions were described, namely, (a) marked conjugate deviations of the eyes, and (not constantly) turning of the head, to the side stimulated (type I); (b) "movements of the eyes and usually of the head to a position of forward gaze, each from a position of contralateral deviation" (type II); and (c) diphasic responses, the first phase of which occurred during the stimulation, while the second appeared as a rebound when the stimulation was over (type III). The first and second types of response were obtained from all the cerebellar nuclei and the adjacent white matter, whereas the third one was elicited only by stimulating midline structures, and above all the region of the roof nuclei. During the period of fastigial or parafastigial stimulation "the eyes and head moved to a position of forward gaze or deviated to the side of stimulation, as before. Immediately following the cessation of the stimulus, the eyes and head briskly and actively deviated to the contralateral side" (Fig. 35A, B; 36C-F). Sometimes also the responses of the trunk and tail were observed, and then the first phase consisted "either of a relaxation of a pre-existing concavity of the body axis to the opposite side, or of the production of a concavity of the trunk and deviation of the tail to the side of cerebellar stimulus," while the rebound phase was represented by "production of a concavity of the trunk and a deviation of the tail to the side opposite the cerebellar stimulus." The postural reactions of the limbs were characterized by a relaxation from a pre-existing posture followed at the end of the stimulus by a rebound assumption of the previous posture. It should be emphasized (a) that the inhibition was not limited to the antigravity muscles but that a relaxation from any posture (extension, flexion, pronation, abduction) could be elicited, and (b) that the rebound phase was an active phenomenon and not simply the result of the fading away of inhibition. Actually the assumption of a given posture was due to the rebound

Figure §5. The effects of stimulating the interior of the cerebellum in the nembutatized monkey. Each pair of drawings shows the response to faradic stimulation of a single point within the interior of the cerebellum during the stimulation (left) and the rebound phase (right). A, B. Stimulation on the left side yields a slight turning to the left during the stimulation (A), with a rebound deviation to the right (5). Type III response. C, D. Stimulation on the left side yields a relaxation of the ipsilateral forelimb (C) followed by a flexor rebound (D). Group I response. E, F. Stimulation on the right side yields a flexion of the ipsilateral forelimb (E) followed by an extensor rebound (F). Group I response. (From H. W. Magoun, W. K. Hare, and S. W. Ranson, 1935, Electrical stimulation of the interior of the cerebellum in the monkey, Am. J. Physiol., W#: 329-339; from the original of Fig. 1.)

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Figure 36. The effects of stimulating the interior of the cerebellum in the nembutalized monkey. Drawings arranged as in Fig. 35. A, B. Stimulation on the left side yields a relaxation of all limbs (A), followed by a rebound extension of the left limbs and a rebound flexion of the right limbs (B). Group II response. C, D. Stimulation on the right side, close to the midline, evokes a retraction and flexion of both forelimbs (C), followed by a rebound extension of the right limbs and a rebound flexion of the left limbs (D). Group II response. E, F. Stimulation on the right side yields a flexion of the right limbs and an extension of the left limbs (E), followed by a rebound extension on the right side and a rebound flexion on the left side (F). Group II response. (From H. W. Magoun, \V. K. Hare, and S. W. Ranson, 1935, Electrical stimulation of the interior of the cerebellum in the monkey, Am. J. Physiol., Ii#:329-339; from the original of Fig. 2.)

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146 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM occurring at the end of the first stimulus and then "the cycle of inhibition and rebound could be continued indefinitely with repeated stimulation, the responses becoming augmented on repetition." When the stimulation was discontinued, the rebound posture was maintained for a period of minutes. Two groups of limb responses were described. In the first group the response was confined to the ipsilateral forelimb (Fig. 35C-F) and was obtained "from the buried cerebellar cortex of the anterior lobe both caudal to and overlying the fastigial, globose and emboliform nuclei," (group I). The second group of responses were similar to those obtained by Miller and Laughton (1928a, b) from the nucleus fastigii. They concerned all four limbs (Fig. 36) and sometimes "during stimulation there was a flexion of the ipsilateral limbs and an extension of the contralateral limbs, while after stimulation there followed, as before, a rebound extension of the ipsilateral limbs and a flexion of the contralateral limbs" (Fig. 36E, F). These effects (group II) were obtained from midline structures, "the buried cerebellar cortex of the anterior lobe, both caudal to and overlying the globose and fastigial nuclei." The lateral nuclei, emboliform or dentate, never yielded these responses. Summing up, stimulation of the dentate nucleus yielded no specific effect, stimulation of the emboliform and globose nucleus and of the neighboring white matter gave localized limb responses belonging to group I, whereas the generalized limb responses of group II as well as the diphasic eye, head, and trunk responses (type III) were brought about by stimulating the fastigial nucleus and the neighboring white matter. Van Rijnberk (1931, p. 819) had wondered if Miller and Laughton's results could be obtained also in intact limbs of normal animals. It was very important to show that the biased background represented by decerebrate rigidity was not essential for eliciting these effects and that a strong and long-lasting rebound posture could be elicited in the flaccid limbs of animals under barbital anesthesia. Magoun, Hare, and Ranson (1935) gave, moreover, the final demonstration that the diphasic responses really arose within the stimulated structures, since (a) the responses were reversed on crossing the midline, (b) they disappeared when the tip of the electrode was lowered, and (c) they were never duplicated by stimulating the brain stem. In the cat experiments (Hare, Magoun, and Ranson, 1936, 1937) the same results were reported, although the effects obtained in the normal nembutalized preparation were obviously less pronounced than those in the decerebrate animal. The midline responses involving the head, trunk, tail, and all four extremities were obtained from "that part of the vermis extending from the base of the folia of the lobulus centralis anteriorly to the Nodulus caudally, from the fibers which project the vermal cortex onto the roof nuclei, from the roof nuclei themselves and the medial part of the emboliform and finally from fastigio-bulbar fibers" (1937). They resembled the tegmental reaction (Ingram, Ranson, Hannett, Zeiss, and Terwilliger, 1932) and were characterized, as far as the limbs were concerned, by ipsilateral flexion and contralateral extension during stimulation, ipsilateral extension and contralateral flexion during the rebound phase. It should be recalled, however, that the rebound is absent in the tegmental effects, and actually the midbrain responses outlast the stimulus for some time. The responses from

STIMULATION EXPERIMENTS 147 more lateral structures—i.e., "paramedian lobuli, the stalk of the semilunar lobe, the folia of the culmen and from the caudal end of the emboliform nucleus"—were instead characterized by ipsilateral extension followed by rebound flexion. It is obvious from the localization data reported by Hare, Magoun, and Ranson (1937) that their deep responses were composite effects, due to stimulation of presynaptic (corticonuclear) and postsynaptic (e.g., fastigiobulbar) fibers as well as of nuclear somata. Obviously it would have been impossible to obtain pure "nuclear" effects, even if the tips of the electrodes had been localized exactly within the nuclei themselves, since electrical stimulation of the presynaptic terminations or of the "fibrae perforantes" (see Jansen and Brodal, 1954) could hardly be avoided. This would not be a serious difficulty if the nuclei were nothing but relays within the efferent cerebellar paths. That the situation is not so simple has been indicated repeatedly (pp. 80-86), and we feel that electrical stimulation of cerebellar nuclei following degeneration of the corresponding corticonuclear projections might give illuminating results. With further experiments Magoun, Hare, and Ranson (1937) showed that prolonged rebound postures could be obtained in the chronically deafferented forelimb (2 to 4 weeks before) of the decerebrate cat, after bilateral chronic labyrinthectomy (8 weeks before), acute denervation of the contralateral forelimb, and acute postbrachial transection of the spinal cord. Actually the duration of the extensor rebound of the deafferented forelimb (90 to 95 seconds) was tremendously increased (up to 3 hours) by postbrachial transection of the spinal cord (Schiff-Sherrington effect). Since the main afferent sources of postural tonus were abolished in these experiments, the rebound posture was obviously due to some kind of automatic activity, which was continuously going on either (a) within the brain stem or (b) within the cerebellum. The nature of the cerebellar rebound will be dealt with in the discussion, but its long duration as well as its tremendous intensity in the experiments previously referred to was probably related to sensitization of the spinal segments by the chronic deafferentation (Cannon's law of denervation: Bremer, 1928; Terzian and Terzuolo, 1954). The extensor rebound following fastigial stimulation was reported to be greatly affected by intracarotid injections of calcium and potassium (Gerard and Magoun, 1936). In the following years the only authors who were concerned with responses to nuclear stimulations were Chambers (1947), Sprague and Chambers (1954), Pompeiano, Ricci, and Zanchetti (1954), Moruzzi and Pompeiano (1955a; 1956b). The experiments of the American investigators have been reviewed in other sections (see p. 135). Pompeiano, Ricci, and Zanchetti stimulated stereotaxically the nucleus interpositus of decerebrate cats with rectangular pulses (1 msec.; 300/sec). They were able to duplicate the increase in the extensor rigidity of the ipsilateral foreleg reported by Hare, Magoun, and Ranson (1936, 1937) and by Sprague and Chambers (1954), but not the flexor rebound. They found, moreover, that responses similar to those elicited from fastigial areas by Hare, Magoun, and Ranson (1936, 1937) were occasionally observed from the most rostral part of the nucleus interpositus. Moruzzi and Pompeiano (1955a; 1956b) stimulated in the decerebrate cat, using the same technique, the caudal pole of the nucleus fastigii.

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where most of the hook bundle arises. They reported an inhibition of the ipsilateral and an increase in the contralateral extensor rigidity. Hence, the response was the same as that elicited from the pyramis (lobule VIII; see Bremer, 1922a). These experiments agree quite satisfactorily with the results of the localized lesion (crossed fastigial atonia; see pp. 81-86). F. THE EFFERENT PATHWAYS MEDIATING THE CEREBELLAR RESPONSE The efferent pathways of the anterior lobe have been extensively investigated from both anatomical (see Jansen and Brodal, 1954) and physiological standpoints. The experiments we are going to review can be divided into the following groups: (a) selective destruction of the deep nuclei; (b) midline splitting of the cerebellum; (c) decerebration at different levels; (d) stimulation of cerebellar peduncles; (e) section of various parts of the spinal cord; (f) parallel investigation of eerebellarcortical, "nuclear," and reticular responses. Stimulation of the cerebellar cortex of the anterior lobe after selective lesions of the deep nuclei has been performed only within the last years. According to Sprague and Chambers (1953, 1954), "the vermal effects persist and those from lateral cortex disappear after destruction of interpositus nucleus, whereas the opposite holds after destruction of the fastigial nucleus" (1954, p. 61). These results were confirmed and extended by Moruzzi and Pompeiano (1957b). These authors showed that no responses could be obtained from vermal areas of the anterior lobe (lobules III to V), in the decerebrate cat, following complete chronic lesion (three to twelve days previously) of both roof nuclei. The intermediate part of the anterior lobe was instead fully excitable. Lobules III to V were inexcitable also when only the rostral halves of both roof nuclei had been chronically fulgurated, while the unresponsiveness was limited to the overlying hemivermis of the anterior lobe when only one fastigial nucleus had been totally destroyed. An ipsilateral inhibition of extensor rigidity was obtained with almost normal voltages from lobules III, IV, or V when the chronic lesion had been limited to the caudal two thirds of both fastigial nuclei. Occasionally only the foremost one fourth of the roof nuclei had been spared bilaterally by the chronic lesion, and the excitable area was found to be limited to lobules III, IV, and the foremost folia of V. Even when all the interfastigial white matter had been destroyed and the rostromedial part of both roof nuclei had been encroached upon, were the inhibitory effects observed on decerebrate rigidity. All the experiments of Moruzzi and Pompeiano (1957b) were controlled on serial histological slides and the cerebellar cortex was regarded as unexcitable when no response could be obtained with rectangular pulses (300/sec; 1 msec.) of up to ten times threshold intensity. With the same bipolar metallic electrodes, responses could be obtained from the normal vermis or from the intermediate part, following complete fastigial lesions, with only 0.4 to 0.8 volt. Lobules I, II, H I, and H II were not explored. The experiments of Moruzzi and Pompeiano suggest that the inhibitory impulses arising from lobules III, IV, and V are mediated (a) by the ipsilateral roof nuclei and, more precisely, (b) by the rostral part of these structures. It may be inferred from this work also (c) that the long corticofugal fibers (see Jansen and

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Brodal, 1954, pp. 207-209) are not responsible for these inhibitory responses, unless the assumption is made that the long Purkinje axons course through these restricted portions of the roof nuclei; finally, it may be concluded (d) that the inhibitory impulses arising from lobules III to V are relayed by neurons that would be mainly located within the rostrolateral part of each fastigial nucleus. The first conclusion (a) is supported by the previous experiments of Sprague and Chambers (1953, 1954); the second and third (b and c) nicely fit in with the results of anatomical investigations (Jansen and Brodal, 1940, 1942, 1954); and the fourth (d) is indirectly supported by the experiments of Moruzzi and Pompeiano (1954, 1957b) reported on p. 131. Both anatomical and physiological data can hardly be reconciled with the results of Nulsen, Black, and Drake (1948; see below, p. 321), who maintained that the inhibitory influence of the anterior lobe would be mediated by the nucleus dentatus, while the augmentatory effects would be relayed by the nucleus fastigii. Midline splitting of the cerebellum of the anterior vermis, in the decerebrate cat, did not abolish the inhibitory response of the anterior lobe (Lowenthal and Horsley, 1897; Bremer, 1922a). These findings support the hypothesis of Bernis and Spiegel (1925) that the inhibition of decerebrate rigidity is mediated by the ipsilateral, uncrossed fastigiobulbar bundle. The problem of the anatomical background of the crossed postural effects elicited by vermal stimulations has been dealt with in another section of this monograph (p. 136). Decerebration at different levels is the simplest way to find out whether the postural responses of the anterior lobe are mediated by midbrain relays. Conflicting results were at first reported, since the response of the anterior lobe was found by different investigators to be absent (Cobb, Bailey, and Holtz, 1917; Dusser de Barenne, 1923), partially and inconstantly present (Bremer, 1922a), and constantly present (Bernis and Spiegel, 1925) in the postcollicular decerebrate cat. Later experiments showed, however, that inhibitory responses certainly arising within the vermal cortex of the cat's anterior lobe were not abolished (Moruzzi, 1935c; Snider, McCulloch, and Magoun, 1949), nor even was their threshold raised (Moruzzi, 1948c), by postcollicular decerebration. Actually the rigid limbs relaxed when square pulses of extremely low voltages and high rate (300/sec) were applied (Moruzzi, 1948c). These experiments definitely showed that midbrain relays were not necessary in order to elicit the cerebellar response. Bernis and Spiegel (1925) found, moreover, that no ipsilateral effect whatever was obtained following section of the inferior cerebellar peduncle in the postcollicular cat. They suggested (pp. 216-217) that in this preparation the response was mediated by the uncrossed fastigiobulbar tract and that the efferent impulses impinged upon the reticular formation, an assumption which is supported also by anatomical (Allen, 1924; Rasmussen, 1933) and electrophysiological (Snider, McCulloch, and Magoun, 1949) evidence. A serious problem is represented, however, by the tremendous increase in extensor rigidity which is brought about by any postcollicular decerebration. If this phenomenon is due to release from cerebellar inhibition, the conclusion should be drawn that either (a) important inhibitory pathways exist also in the superior cerebellar peduncle, as had been postulated by Rothmann (1910), by Cobb, Bailey, and Holtz (1917), by

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Bremer (1922a), and by Bernis and Spiegel (1925), or (b) that the tonic inhibitory discharge descending through the inferior cerebellar peduncle is abolished or strongly decreased following postcollicular decerebration. It is likely that cerebellar responses are mediated also by the superior cerebellar peduncle. Hare, Magoun, and Hanson (1936) showed that the ipsilateral foreleg extension with rebound flexion, elicited by stimulating lateral cerebellar structures (see p. 147), was abolished in the cat by postcollicular decerebration. They suggested a path "by the way of the brachium conjunctivum and the fibers which branch from it below the level of red nuclei and descend in the brain stem" (p. 265), but they pointed out that the fastigial responses, on the other hand, were unaffected by low decerebration. Pompeiano, Ricci, and Zanchetti (1954) reported that an ipsilateral increase in extensor rigidity, not followed however by a flexor rebound, was brought about by high-rate stimulation of the nucleus interpositus in the decerebrate cat. This effect was prevented, however, neither by postcollicular decerebration nor by midline splitting of the mesencephalon. Stimulation of the cerebellar peduncles was frequently performed by earlier investigators (Thiele, 1905; Cobb, Bailey, and Holtz, 1917; Miller and Banting, 1922; Kure, Shinosaki, Fujita, Hata, and Nagano, 1923); but Bernis and Spiegel (1925) were the first to show that the effect was not due to a diffusion of current to the neighboring structures of the brain stem. They reported that the response yielded by faradic stimulation of the inferior cerebellar peduncle of the decerebrate cat (flexion of the ipsilateral forelimb) was abolished by severing its fibers below, but not immediately above, the stimulated point. A similar response was obtained by Sprague and Chambers (1954), who pointed out that the ipsilateral flexion was accompanied by contralateral extension, while the opposite response was elicited by stimulating the superior cerebellar peduncle. Hence the inferior cerebellar peduncle duplicated the fastigial and vermal effects, whereas the response of the hemispheral part of the anterior lobe and of the nucleus interpositus was reproduced by stimulating the superior cerebellar peduncle. Burgi (1943a) performed his experiments, using Hess's methods, on unanesthetized, unrestrained cats. He obtained ipsilateral phasic movements by low-rate (8/sec) stimulation of the brachium conjunctivum, but his responses were only strongly decreased, not abolished consistently, by diathermocoagulation. The influence of sectioning various parts of the spinal cord on both vermian (Rothmann, 1910) and fastigial (Ingersoll, Magoun, and Ranson, 1936) responses was investigated in anesthetized dogs (Rothmann) and cats (Ingersoll et al.). Following hemisection of the first cervical segment, Ingersoll et al. observed that "the reactivity of the limbs on the side of section was consistently abolished to stimulation of either the ipsi- or the contralateral half of the cerebellum." Since the reactivity of the contralateral limbs "was retained to stimulation of either half of the cerebellum," it was obvious that the crossing of the cerebellar response occurred at prespinal levels. Isolated sections of the lateral (Ingersoll et al.) or ventral (Rothmann; Ingersoll et al.) funiculi never abolished the response, while the effect of combined lesions approached that of hemisection (Ingersoll et al.). Hence the conclusion was drawn that the efferent pathways were diffusely repre-

STIMULATION EXPERIMENTS 151 sented in both the lateral and ventral funiculi. The same results were obtained later on by Niemer and Magoun (1947) for the reticulospinal tracts. A parallel analysis of the responses of the surface of the anterior lobe, of the deep nuclei, and of the reticular formation was performed in decerebrate cats by Ricci and Zanchetti (1953) and by Sprague and Chambers (1954; see above p. 135). Both groups of investigators stated that medioreticular and vermian responses were similar in type, but Ricci and Zanchetti (1953) pointed out that cerebellar inhibition was definitely weaker and much more easily depressed by barbiturates than was the reticular inhibition. Extensor rigidity was the most easily affected by cerebellar inhibition, the crossed extensor reflex somewhat less, exceptionally (and only with very strong stimuli) the ipsilateral flexor reflex. The corneal reflex was never affected by cerebellar stimulation. On the other hand, decerebrate rigidity, crossed extension, and the corneal reflexes were affected equally by reticular inhibition, with about the same intensities of stimulation, whereas the ipsilateral flexor reflex was less strongly and less constantly blocked. Ricci and Zanchetti (1953) suggested that cerebellar inhibition was not exclusively relayed by Magoun's center, or at least that transsynaptic recruitment of reticulospinal neurons was less extensive and effective than direct electrical stimulation of their somata. Moreover, both the extensor rebound and the inhibition of crossed extensor reflexes were completely blocked by doses of barbiturates which only slightly decreased the reticular inhibition of both flexor and corneal reflexes. It should be recalled in this connection that the cerebellar inhibition of the knee jerk was found to be more depressed by myanesin than was the reticular inhibition (Henneman, Kaplan, and Unna, 1949; Kaada, 1950). The surprising results of Mnukhina (1951) and of Sigg and Weitzmann (1954) may be cited to conclude this chapter. They maintained that the effect of cerebellar stimulation was not abolished when the descending spinal pathways were interrupted by transection of the cord. G. GENERAL CONSIDERATIONS At the end of the chapter on ablation experiments (Chapter 2, Section F) it was pointed out that the disproportionate attention paid to mammalian experiments in cerebellar physiology makes almost impossible any presentation of the subject from a comparative point of view. The fact is perhaps still more evident regarding stimulation experiments, which, with a few notable exceptions, have been performed on mammals and especially on cats. It is certainly reassuring to learn, from the works of Bremer and Ley (1927) and of Chiarugi and Pompeiano (1956b), that the responses of the anterior lobe are basically the same in decerebrate cats and the thalamic pigeons, though we should not forget that these experiments were concerned only with the regulation of posture, i.e., with lowlevel activities. On the other hand, it would be unwise to underestimate the importance of the anatomical differences which obviously exist between vertebrates. Suffice it to recall here the striking development of the hemispheral part of the anterior lobe in the monkey (see p. 125), the lack of a true decerebrate rigidity in submammalian forms, the importance of background activity in determining the sign and the intensity of the cerebellar response (see p. 119), and,

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finally, the different muscles involved in postural activities (compare, for example, the wings of the birds with the forelegs of four-footed mammals; see p. 106). Although the great majority of stimulation experiments have been concerned with the anterior lobe, some data are available on the posterior lobe of the corpus cerebelli. Because the danger of the spread of current is particularly great for the flocculonodular lobe little is known of the effects of stimulation here. Actually, two main groups of effects have been obtained from the posterior lobe of the corpus cerebelli, namely, conjugate ocular movements (Ingvar's lobulus medius medianus, lobule VII, and neighboring folia) and limb responses very similar to those yielded by stimulating the anterior lobe. The ocular movements are obviously related to the problem of the visual projections to the cerebellum and will be dealt with at the end of the next chapter (p. 245). Hence the present discussion will be centered upon the mammalian anterior lobe; the nucleus fastigii and the nucleus interpositus, with occasional reference to the functionally related areas of the posterior lobe (the lobulus paramedianus, sublobule H VHb, and lobule H VIII; the uvula, lobule IX; and the pyramis, lobule VIII) will also be considered. Our first task will obviously be to correlate the results of the stimulation experiments with the anatomical data on the efferent connections of both the cerebellar cortex and the nuclei. The reader is referred to the recent monograph of Jansen and Brodal (1954) and to the forthcoming companion volume by Larsell (1958) for a detailed account of the morphological literature. Only those conclusions likely to explain physiological findings will be recalled in the present discussion. According to Jansen and Brodal (1940, 1942) three longitudinal zones should be distinguished within the anterior lobe of mammals, namely, a vermis, an intermediate part, and a lateral part. Since the lateral part is lacking in the cat, on which most of the physiological experiments were performed, it appears that the vermian and hemispheral responses reported by the physiologists arose respectively in the vermis proper and in the intermediate part of Jansen and Brodal. We shall restrict our discussion to these cortical districts and to their nuclear relays. The vermis proper of the anterior lobe projects onto the rostral part of the ipsilateral nucleus fastigii, but long corticofugal fibers going directly to the vestibular nuclei have been repeatedly described and some of them have been reported to pass through the nucleus interpositus as fibrae perforantes (see Jansen and Brodal, 1954). The classical inhibitory response of the decerebrate preparation is apparently not mediated by this group of long Purkinje axons, since it is abolished by chronic lesions restricted to the fastigial nucleus (Sprague and Chambers, 1953, 1954) or even to the rostral part of it (Moruzzi and Pompeiano, 1957b). The experiments of Moruzzi and Pompeiano (1954, 1957b) suggest, moreover, that inhibitory relays are probably localized within the rostrolateral part of this nucleus and show that a response opposite in sign (ipsilateral increase in decerebrate rigidity) occurs when this portion of the roof nuclei is selectively destroyed. Since (a) this augmentatory response is still obtainable from the vermis (lobules III to V) when the intermediate part of the anterior lobe is

STIMULATION EXPERIMENTS 153 removed by suction (Moruzzi and Pompeiano, 1954, 1957b), and since (b) the vermal cortex becomes unresponsive when the rostral poles of both roof nuclei are wholly fulgurated (Moruzzi and Pompeiano, 1957b), the conclusion seems unavoidable that the facilitating impulses arising in the Purkinje cells of the vermis proper are relayed through the rostromedial part of the nucleus fastigii. The functional significance of the long Purkinje axons, which do not synapse in the fastigial nuclei, remains therefore open. Since some of them course, as fibrae perforantes, through the nucleus interpositus, the working hypothesis might be ventured that they give off unmyelinated collaterals to this structure. As we shall see later (p. 234), stimulation of the anterior lobe yields electrical responses restricted to the sensorimotor cerebral cortex of the opposite side (Henneman, Cooke, and Snider, 1952), but the pathways mediating these effects are still unknown. While the course of the efferent fastigial pathways mediating the augmentatory effects on the extensor tonus requires further investigation, the information about the pathways concerned with the ipsilateral inhibition of decerebrate rigidity is quite satisfactory. If the first relay is localized in the rostrolateral part of the nucleus fastigii (Moruzzi and Pompeiano, 1954, 1957b), the inhibitory impulses impinging upon reticular and vestibular structures should be conducted only by uncrossed fastigiobulbar fibers (Jansen and Jansen, 1955; see Jansen and Brodal, 1954, for references) and consequently pass through the ipsilateral inferior cerebellar peduncle. This conclusion is physiologically well supported, since relaxation of the ipsilateral rigid limb still occurs after midline splitting of the vermis (Bremer, 1922a) or postcollicular decerebration (Bernis and Spiegel, 1925; Moruzzi, 1935a, 1948d). Both vermal and fastigial stimulations yield also contralateral effects (see p. 135). The experiments of Pompeiano (1956) have shown that the reciprocal organization (Sprague and Chambers, 1954) of the bilateral responses is due to extracerebellar correlations localized in the medulla oblongata and possibly in the spinal cord. The bilateral inhibition of decerebrate rigidity (Moruzzi, 1948c) that occurs with slightly greater intensities of vermal stimulation would be due instead to intracerebellar spread from the stimulated area to the vermofastigial systems of the opposite side. The reciprocal organization of the response is concealed by the generalized inhibition, whenever this intracerebellar spread of activity occurs. The observation that the responses of the intermediate part of the anterior lobe are entirely abolished by destroying the rostral portion of the ipsilateral nucleus interpositus (Pompeiano, 1958a and b) agrees nicely with the anatomical data of Jansen and Brodal (1940, 1942, 1954), who have shown that the corticonuclear fibers arising from the hemispheral portion of the cat's anterior lobe project onto the ipsilateral nucleus interpositus. The distinction of the intermediate part into two sagittal strips, each having its own efferent connections (Pompeiano, 1958a and b), might prompt anatomical investigations, just as the problem of the corticonuclear projections onto the rostromedial and the rostrolateral portions of each fastigial nucleus might also do. It is certainly more difficult to correlate anatomical findings with the responses

154 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM obtained from the posterior lobe of the corpus cerebelli. The fibers from the uvula (lobule IX) and the pyramis (lobule VIII) project onto the caudal part of the nucleus fastigii (Jansen and Brodal, 1942), the efferent projections of which go through the hook bundle to the opposite side of the medulla (Jansen and Jansen, 1955; see Jansen and Brodal, 1954). Hence the inhibitory responses of the posterior vermis, first reported by Bremer (1922a), should be abolished by midline splitting of the vermis. This control has never been made. The paramedian lobule (lobules H VHb, H VIII) projects, at least in the rabbit, "so far medial within the cerebellar nuclear mass that the intermediate as well as the fastigial nucleus seems involved" (Jansen and Brodal, 1954, p. 206). The crossed fastigial connections through the hook bundle might explain the observation of Snider, McCulloch, and Magoun (1949) and of Snider and Magoun (1949) that the contralateral knee jerk is also influenced by stimulating the paramedian lobe (lobules H Vllb, H VIII). Two types of cerebellar localization should be considered, namely (a) localization of functions and (b) somatotopic localization. There is no doubt that the vermal and fastigial responses are easily distinguishable from those elicited from the intermediate part of the anterior lobe or from the nucleus interpositus, since the latter effects are sometimes augmentatory and strictly ipsilateral in character (see p. 124). This would seem to justify a functional localization within the anterior lobe. However, neurons increasing the ipsilateral extensor rigidity are certainly intermingled with the inhibitory ones within the vermis proper (p. 131), while an inhibition of extensor rigidity with active flexion has been obtained from the medial strip of the pars intermedia (p. 137). Hence the differences between the postural effects of the vermal and of the intermediate part of the anterior lobe are mainly those of emphasis, and the distinction that might be drawn concerns the Purkinje cells which inhibit the extensor tonus and those which have the opposite effect. The former type of neurons is apparently predominant within the vermis proper. This is certainly an oversimplified distinction, and, as we have seen, the terms "inhibitory" and "facilitating" have been regarded as misleading by Sprague and Chambers (1954), since the same stimulation that inhibits the ipsilateral extensor tonus may have opposite effects on the flexor muscles or on the extensors of the opposite side. However, the fact that the cerebellar responses sometimes (see p. 135) comply with the law of reciprocal innervation does not necessarily mean, in our opinion, that the cerebellifugal volleys elicited by the stimulation are arranged in a reciprocal manner. Most of the mechanisms underlying the correlations between antagonistic muscles of the same limb or between both sides of the body are localized within the spinal cord or the brain stem, and Pompeiano (1956) has shown that the reciprocal organization of the limb responses of both sides of the body to a stimulation of lobules III, IV, and V is certainly an extracerebellar phenomenon. That the use of decerebrate preparations in the overwhelming majority of the experiments may be partially responsible for our emphasis on a cerebellar regulation of the extensor tonus, none would deny. This approach was certainly a biased one, and there is no doubt that stimuli applied to the same cerebellar loci in the thalamic cat will yield phasic

STIMULATION EXPERIMENTS 155 and autonomic responses either lacking or far less pronounced in the decerebrate preparation. It is undeniable, however, that (a) the deficiency effects elicited by anterior lobe topectomy in low mammals are characterized by a striking release of the extensor mechanisms, even in the otherwise intact animal, while (b) the response of the decerebrate preparation to threshold stimulation of the anterior lobe affects more readily and quite constantly the extensor muscles. These facts cannot be overlooked, and we are justified when we venture the hypothesis that supervision of the postural extensor mechanisms is the main (though certainly not the unique) task of the vermal part of the anterior lobe. The old hypotheses on the nature of cerebellar rebound have been reviewed at length elsewhere (Moruzzi, 1949). Our main problem is to find out why a sudden reversal of the response occurs just at the end of the stimulation. For the sake of simplicity, the present discussion will be particularly concerned with the response of the spinal extensor motoneurons to an ipsilateral vermal stimulation. Although the extensor rebound is likely to be prolonged by the play of proprioceptive reverberations (myotatic appendage), there is no doubt that the powerful discharge of the extensor motoneurons which occurs at the end of the stimulation is due to (or, at least, is initiated by) facilitating volleys descending from brain stem structures. A postinhibitory enhancement of those spinal units whose tonic discharge had been blocked during the stimulation could hardly account for the whole of the rebound response to cerebellar stimulation. Such an explanation would necessarily imply that the cerebellar and the reflex rebound are basically identical phenomena, an assumption which is disproved by the fact that in the decerebrate cat the reflex rebound of M. quadriceps is abolished simply by deafferenting at the sixth and seventh lumbar segments (CastilloNicolau and Schweitzer, 1949), whereas a powerful cerebellar rebound is constantly observed following chronic (Magoun, Hare, Hanson, 1937) and even acute (Terzuolo and Terzian, 1953) deafferentation of the forelimbs. It is most likely that the shower of brain stem augmentatory impulses which impinges upon the extensor motoneurons when the vermal stimulation is over, arises within the reticular formation and/or the vestibular nuclei, and what we want to know is whether the increased and prolonged activity of these structures is self-sustained or is driven (or at least strengthened) by facilitating volleys arising in the cerebellum. A self-sustained activity might be due either (a) to a release from tonic cerebellar inhibition (release hypothesis: Miller and Laughton, 1928a, b) or (b) to a postinhibitory superactivity of the vestibular nuclei (Bremer, 1922a) and, generally, of every structure whose activity had been blocked during the vermal stimulation (Bremer, 1952b). The augmentatory cerebellar afterdischarge might arise (a) in the vermal facilitating units, whose peripheral effect had been concealed by inhibition during the stimulation (dineuronic hypothesis: Denny-Brown, Eccles, and Liddell, 1929; Moruzzi, 1936a, b, c; Moruzzi and Pompeiano, 1954,1957b); but an increase in the extensor tonus could be elicited also (b) by units which are predominantly inhibitory in character, when the rate of their cellulifugal discharge goes below the

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critical level required for transsynaptic activation of the underlying inhibitory pathways (hypothesis of the low-frequency afterdischarge: Moruzzi, 1949). The release hypothesis is seemingly supported by Dow's observation (1938c) that during the phase of depression of cerebellar electrical activity, which sometimes occurs after stimulation of the anterior lobe, the extensor tonus rises above normal. Recent observations by Calma and Kidd (1955) and by Granit and Phillips (1957) would also support this hypothesis (see pp. 219 and 172). Dow himself pointed out, however, that "the state of activity of the anterior lobe will not explain the whole of cerebellar rebound," since the quick rebound described by Bremer (1922a) probably occurs when the electrical activity of the anterior lobe is still strong. At any rate, the release hypothesis would be obviously limited to those neural activities which are tonically inhibited by the cerebellum, so that another explanation should be suggested for the flexor rebound. The drawback to the hypothesis of the low-frequency afterdischarge is that cerebellar inhibition is tonic. Hence the individual rate of the facilitating afterdischarge should be lower than that of the spontaneous discharge of the same units. The dineuronic hypothesis and the hypothesis of postinhibitory superactivity are, in our opinion, those deserving the most careful consideration. The dineuronic hypothesis is supported by the observation that impulses arising in the vermal area being stimulated may either increase or inhibit the extensor tonus (Moruzzi, 1948a and b, 1949, 1950a and b; Terzuolo and Terzian, 1953; Brihaye, 1953), the spinal reflexes (Brihaye, 1953), and strychnine tetanus (Terzuolo, 1952, 1954), according to the rate of stimulation. The pathways diverge at least at fastigial levels, and it is likely that augmentatory and inhibitory neurons are intermingled within the vermal cortex, so that both systems are bound to be driven simultaneously by the electrical pulses (Moruzzi and Pompeiano, 1954, 1957b). It must be conceded, however, (a) that there is no evidence showing that the facilitating afterdischarge outlasts the response of the inhibitory system; (b) that, actually, a strong electrical afterdischarge has been recorded from the anterior lobe during an inhibition of decerebrate rigidity (Dow, 1938c); and (c) that a strong increase in reflex excitability is observed following electrical stimulation of the avian cerebellum when the rebound has been facilitated by repetition of the stimulation (Bremer and Brihaye, 1948; Bremer, 1952b). There is no doubt that these facts could be reconciled with the dineuronic hypothesis only if rather elaborate assumptions were accepted. The hypothesis of a postinhibitory superactivity was put forward by Sherrington (1906) to explain the successive induction and the spinal rebound, and its extension to the cerebellar rebound was vigorously supported by Bremer (1952a). In his experiments on rebound facilitation in the avian cerebellum Bremer (1952a) observed, that "pendant quelques secondes apres chaque inhibition, 1'animal reagit par une spasme a tous les stimuli reflexogenes, comme s'il etait strychninise"; he pointed out that these features were similar to those observed in the peripheral nerve fibers following anelectrotonic depression (Skoglund, 1945) and quoted Terzuolo's experiments (1952, 1954) showing that cerebellar inhibition of strychnine tetanus was increased by anelectrotonic and decreased by catelectrotonic polarization of the cat's spinal cord.

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While the difficulties confronting the dineuronic hypothesis could undoubtedly be explained if the idea of a postinhibitory superactivity of the brain stem were accepted, this idea is itself not easy to reconcile with certain facts. First of all, a rebound should be observed whenever any inhibitory barrage suddenly comes to an end. Actually, (a) for threshold stimuli, a cerebellar inhibition of extensor rigidity is not followed by an extensor rebound (Moruzzi, 1936a: see Fig. 26A, p. 121; Sprague and Chambers, 1954); (b) the diphasic responses are typical of the cerebellum, whereas there are undoubtedly other instances in which brain stem nuclei are inhibited without a similar rebound (e.g., during Magnus's labyrinthine and cervical reflexes); (c) a strong extensor rebound is observed in the acutely deafferented forelimbs of the decerebrate cat following vermal stimulations (Terzuolo and Terzian, 1953), although Magnus reflexes are absent in these experimental conditions (Liljestrand and Magnus, 1919; Stella, 1944a; Terzian and Terzuolo, 1954). Even the observation that sometimes a response quite similar to that observed in the rebound phase occurs during stimulation (Moruzzi, 1936a; Bremer and Brihaye, 1948) or at the beginning of it (Bremer, 1952a) is not easily explained by the hypothesis of postinhibitory superactivity. Summing up, we are still at loss to understand the sudden reversal of the response which occurs as soon as the vermal stimulation is over. Many difficulties would be overcome, perhaps, if we were prepared to assume that a barrage of cerebellifugal impulses is potentiated by a postinhibitory increase in the excitability of brain stem structures. But crucial evidence supporting such an eclectic borrowing from both hypotheses is still lacking. The long duration of the extensor rebound can be explained in several ways, such as by myotatic reverberations, a poststimulatory extinction of the vermal cortex, and (for chronic experiments) Cannon's sensitization. Much emphasis has been placed in the last years on the somatotopic localizations within the efferent cerebellar systems (see p. 125). While the basic facts underlying these conceptions have been repeatedly confirmed, two important limitations should be borne in mind. Anatomically "there is good evidence to the effect that at least the first link in these efferent chains, i.e. the cortico-nuclear projection, is organized in principle according to a point to point localization. As regards the following links we know that the central cerebellar nuclei are connected with a variety of brain stem nuclei. To what extent a somatotopical localization prevails within these connections remains an open question for the time being" (Jansen and Brodal, 1954, p. 383). Hence, anatomically, the brain stem nuclei offer widespread opportunities for the neural diffusion of an activity originated in a given cerebellar focus, although intracortical and intranuclear connections should not be overlooked. Physiologically, the tendency of cerebellar inhibition to spread from one limb to all extensor muscles is very marked, at least in the unanesthetized decerebrate preparation (Moruzzi, 1948c). There is no doubt, therefore, that the somatotopic arrangement is by far less pronounced on the cerebellar than on the cerebral cortex and that it would be seriously misleading to expect that the different cerebellar areas should be separated by sharp borders, as are those of the Rolandic zone.

A,

Electrophysiological Experiments

A. Electrophysiological experiments in submammalian forms 1. Fish 2. Amphibia 3. Reptiles 4. Birds B. Electrical activity of the cerebellar cortex in mammals 1. Spontaneous activity led with surface macroelectrodes 2. Spontaneous activity led with microelectrodes 3. Electrical activity after transection of the brain stem and of the spinal cord at C 1, after section of the cerebellar peduncles, and after supranuclear transection. . 4. The effects of direct-current stimulation 5. The effects of single electrical shocks 6. The effects of repetitive stimulation 7. The effects of convulsant drugs C. Electrophysiology of the afferent cerebellar connections in mammals 1. Responses to natural stimulation a. Stimulation of vestibular receptors b. Stimulation of muscle, tendon, or joint proprioceptors c. Stimulation of exteroceptors d. Stimulation of visual and auditory teleceptors e. Responses to spontaneous corticofugal volleys 2. Responses to single-shock stimulation of peripheral nerve ibers fibers a. Localization of the response b. The nature of the afferent volleys yielding the cerebellar response c. Pathways of transmission 3. Stimulation of cerebellipetal pathways or of central structures projecting onto the cerebellum a. Spinocerebellar systems b. Olivocerebellar and reticulocerebellar systems c. Vestibulocerebellar system d. Pontocerebellar system e. Midbrain stimulation f. Stimulation of the cerebral cortex g. Stimulation of the caudate nucleus h. Stimulation of the olfactory bulbs 4. General patterns of the afferent cerebellar response a. Polarity of the evoked response 158

159 159 160 160 160 162 162 164 173 174 175 176 178 182 182 182 182 185 186 189 189 189 195 197 200 200 201 202 202 202 204 211 211 211 211

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b. The effects on spontaneous electrical activity c. Slow potential changes elicited by sensory volleys d. Interactions between afferent responses D. Electrophysiology of the efferent cerebellar connections in mammals 1. Efferent spike discharges in the cerebellar peduncles 2. Responses of the bulbar reticular formation to cerebellar stimulation 3. Responses of the vestibular nuclei to cerebellar stimulation 4. Responses of the midbrain and diencephalon to cerebellar stimulation 5. Responses of the cerebral cortex to cerebellar stimulation 6. Intracerebellar connections E. Electrophysiological investigations on the cerebellar nuclei F. General considerations

211 216 216 218 218 . . . 219 230 232 234 235 235 240

ALTHOUGH the beginning of electrophysiological investigations on the cerebellum can be traced back to the pioneer works of Beck and Bikeles (1912a, b) and of Camis (1919), only within the last twenty years have investigations in this field acquired a remarkable momentum. Electrophysiological methods have been used more frequently for an anatomical than for a physiological approach. The anatomical task of mapping out the afferent and the efferent connections of the cerebellum was successfully achieved with the technique of evoked potentials through the joint work of several investigators. As will be pointed out later, most of the data gathered by neuroanatomists with Marchi, Gudden, and silver methods were confirmed with bioelectrical techniques, and striking and unexpected additions to our knowledge were obtained in certain fields, such as the relation of the cerebellum to the visual and auditory systems (Snider and Stowell, 1944). The physiological approach was slower to be taken, but is now coming more and more to the front of neurophysiological endeavor. The spontaneous electrical activity of the cerebellar cortex (Adrian, 1935) and its obvious correlations with the tonic influence of the cerebellum on brain stem and spinal structures (Dow, 1938c) represented for many years the main contributions in this field of research. The exploration with microelectrodes of precerebellar and corticocerebellar structures as well as of the efferent cerebellar pathways is likely to give most promising results if an attempt is made to localize, anatomically, and to understand, physiologically, the units from which records are taken. A. ELECTROPHYSIOLOGICAL EXPERIMENTS IN SUBMAMMALIAN FORMS 1. FISH Tzkipuridse (1947) reported that only fast waves could be led from the cerebellum of fishes, as well as of amphibia (frog) and reptiles (tortoise). Tzkipuridse and Bakuradse (1948) suggested that these results could be explained by the lack of anatomical connections between the forebrain and cerebellum in the lower vertebrates (see p. 163).

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Beritashvili and Tzkipuridse (1945) reported that the spontaneous electrical activity of the frog's cerebellum was almost abolished during hibernation. During spring and summer the spontaneous fast activity (200 to 300 per second) was particularly marked near the midline, was modified by sensory stimulations, and did not disappear (although the frequency fell to 100 to 150 per second) when the cerebellum was completely isolated.

3. REPTILES Crepax and Parmeggiani (1958a, b) recorded with wire microelectrodes the electrical activity of the cerebellum of Lacerta viridis. The records were similar to those led by the same technique from the granular and Purkinje layers of the decerebrate cat (Brookhart, Moruzzi, and Snider, 1950), since spike potentials were superimposed on a background of fast waves (300 to 350 per second). 4. BIRDS Whitlock (1952) mapped out the responses of the avian cerebellum to tactile, acoustic, and visual stimuli and to single shocks applied to peripheral nerve fibers. His experiments were performed on pentobarbital-anesthetized or decerebrated pigeons, owls, and ducks; the map he gave of the pigeon cerebellum is reproduced in Figure 37. Responses to tactile and single-shock stimulation of the uropygium were found, ipsilaterally, in Larsell's folia III (upper central lobule) and IV (lower culmen); the leg area was located in folia IV and V (culmen) and also in folium III, the representation of the ipsilateral wing was localized in folia IV and V and in folium Via (rostral declive), while the face projected onto folium VI. Auditory and visual receiving areas were found in folia Vic (caudal declive), VII (folium and tuber vermis lobule), and VIII (pyramis). Hence the afferent connections of the tactile areas were shown to be somatotopically arranged in the rostral folia of the avian cerebellum, while the auditory and visual areas appeared to be coextensive with the tactile face area. The afferent cerebellar projections were characterized by extensive overlapping. Whitlock (1952) emphasized that visual responses could be obtained only if the optic tectum was intact, and dwelt upon the long duration of their latent periods. His findings were confirmed by Buser and Rougeul (1954a, b) who showed that in the unanesthetized pigeon, the audio-visual areas of the cerebellum gave about the same response whether single shocks were applied to the optic nerve or to the optic tectum. Hence it was likely that the visual response of the cerebellum was mediated by tectal relays. That tectal or pretectal structures could not be held responsible, however, for the long latent periods (25 to 50 milliseconds) of the cerebellar effects was shown (a) by the fact that latencies were not shortened in any appreciable way when electrical shocks were applied to the optic tectum rather than to the optic nerve and, (b) by the observation that an earlier (and smaller) cerebellar response to optic nerve stimuli occurred after 5 to 10 milliseconds. Hence the cerebellar cortex alone is responsible for the long latency of the delayed response led from its surface. Intracellular recording from single Purkinje cells, with hyperfine glass microelectrodes, gave the final

28 Composite diagrams of total number of active points located in the cerebellum of pigeon as plotted on midsagittal (28A), anterior (28C) and posterior (28B) views. The stimulation of a peripheral nerve or of a tactile receptor or of various parts of the body, as well as auditory or visual receptors, are indicated as follows: NKRVl STIMULATION

Tail Leg Wing Face Auditory Visual Tectal

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T

The active points are projected to the surface of the folium from which they were recorded in the anterior and posterior views. Figure 37. Localization of the electrical responses oj the avian cerebellum to sensory stimulations. (From D. G. Whitlock, 1952, A neurohistological study of afferent fiber tracts and receptive areas of the avian cerebellum, J. Comp. Neurol., 97:567-623; from the original of Fig. 4.)

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Figure 38. Surface, intracortical, and intracellular responses oj the avian cerebellum to optic volleys, a, b. Monopolar records from the dorsal surface of the pigeon cerebellum, showing shortlatency (10 msec.) and long-latency (45 msec.) responses to single shocks applied to the optic nerve (a) and to the optic tectum (b). c. The short-latency response is particularly evident when the potentials are led from deep portions of the cerebellum, d, e. D.c. potentials are led with low-gain amplifiers, just before (d) and immediately after (e) penetration of the hyperfine pipette into the Purkinje soma (lower records). See the negative shift (upward deflection: 12 mV.) of the base line (polarization potential) when the hyperfine pipette is thrust into the Purkinje soma. Simultaneous recording with high-gain a.c. amplifiers (upper records) shows a positive shift (downward deflection: membrane depolarization) synchronous with the delayed response to visual stimulation. The spontaneous (injury?) spike discharge is blocked during this delayed response.—Time: 50 c.p.s. Gains: 1 cm. = 100 /iV. (a, b, c), 4mm. = 300 /uV. (d, e, upper records), 4 mm. = 15 mV. (d, e, lower records). (From P. Buser and A. Rougeul, 1954, Etude des reponses du cervelet du pigeon a la stimulation du nerf optique, Boll. Soc. ital. biol. sper., 50:758-760, Figs, a-e.)

evidence that the long-latency response corresponded to the reflex activation of these efferent neurons (Fig. 38). B. ELECTRICAL ACTIVITY OF THE CEREBELLAR CORTEX IN MAMMALS 1. SPONTANEOUS ACTIVITY LED WITH SURFACE MACROELECTRODES In 1935 Adrian reported that the patterns of spontaneous electrical activity were entirely different for the cerebral and for the cerebellar cortex. The latter was characterized, in the decerebrate cat, by low-voltage fast waves (150 to 250 per second), without any "sign of the slower type of oscillation found in the cerebral cortex." Adrian's results were confirmed by Dow (1938c). Dow showed, moreover, that the fast cerebellar rhythms arose within the underlying cortical layers and were associated with the tonic discharge of the corresponding Purkinje neurons, since local cocainization (2 per cent) of the anterior lobe decreased its spontaneous electrical activity and simultaneously increased extensor rigidity. Experiments performed on "encephale isole" cats gave the possibility of comparing, in the same unanesthetized preparation, the electrical activity of the cerebral and cerebellar cortices. The latter was strongly affected, though slightly less than the

ELECTROPHYSIOLOGICAL EXPERIMENTS 163 former, by asphyxia, by clamping both carotid and vertebral arteries and by ether anesthesia, and was shown to be extremely sensitive to hypotension. Dow (1938c) observed occasionally, in both the "encephale isole" and the decerebrate cat, the slow waves previously described by Foerster and Altenburger (1935) and by Spiegel (1937), but maintained that these cerebral-like rhythms (15 to 30 per second) were pathological in character, since they occurred when the general (circulatory, respiratory) or local conditions (prolonged exposure, repeated faradizations) had deteriorated. Both fast and slow rhythms were recorded from the cerebellar surface of cats under barbital anesthesia (Wiggers, 1942a; ten Gate and Wiggers, 1942; Tzkipuridse and Bakuradse, 1948) and of unanesthetized animals (Gualtierotti and Capraro, 1941; Narikashvili, 1950; Cooke and Snider, 1954). These results were confirmed on dogs by Swank and Brendler (1951), who reported also that extremely frequent potential oscillations (1,000 to 2,000 per second) were superimposed on Adrian's rhythms. All authors agreed that the cerebellar slow waves were characterized by repetition rates (8 to 12 per second) similar to those of the a waves which were led simultaneously from the cerebral cortex (Spiegel, 1937; Gualtierotti and Capraro, 1941; Wiggers, 1942; ten Gate and Wiggers, 1942; Tzkipuridse and Bakuradse, 1948; Narikashvili, 1950), and most of them stated that slow rhythms were actually abolished by decerebration (ten Gate, Walter, and Koopman, 1940; ten Gate and Wiggers, 1942; Tzkipuridse and Bakuradse, 1948; Cooke and Snider, 1954). Tzkipuridse and Bakuradse (1948) showed, moreover, that the occurrence of 8- to 12-per-second rhythms on the cerebellar cortex could not be ascribed to a physical spread of cortical potentials from the cerebral hemispheres, since the slow waves disappeared only in the cerebellum, but not in the cortex, following midbrain transection. Hence slow rhythms were due to corticofugal impulses impinging on the cerebellar cortex, possibly through corticopontocerebellar pathways. Somewhat different conclusions were reached recently by Tzkipuridse and Bakuradse (1948), by Irger, Koreisa, and Tolmasskaja (1951), and by Moruzzi (1953a, 1957). Tzkipuridse and Bakuradse (1948) led two kinds of rhythms from the cerebellar cortex of the decerebrate cat, namely (a) fast waves (350 to 400 per second) and (b) an intermediate rhythm characterized by potential oscillations of 40 to 50 per second. Irger, Koreisa and Tolmasskaja (1951) experimented on pigeons, rabbits, and dogs, and in another work (1949) led slow rhythms also from the human cerebellum. The frequency of the slow waves recorded in low mammals was reported to be lower in the neocerebellar (6 to 8 per second) than in the paleocerebellar areas (30 to 40 per second), and the rhythms of the neocerebellum were found to be synchronized with the spontaneous outbursts of the contralateral cerebral cortex. These findings obviously hinted at a neural driving by corticofugal volleys. A cortically induced synchronization of cerebellar neurons did not account entirely, however, for this type of electrical activity, as shown by the fact that its abolition by decerebration was not permanent. The slow waves came back soon thereafter, first on the vermis (30 minutes) and later (60 minutes) on the cerebellar hemispheres. Only when the middle and inferior cerebellar

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peduncles were bilaterally severed in the decerebrate animal was the slow activity permanently abolished, although Adrian's ubiquitous fast rhythms (150 to 200 per second, up to 300 per second) could still be led from any part of the cerebellar cortex. Hence the conclusion was drawn (1951) that the fast rhythms represent an intrinsic property of the cerebellar cortex (see Snider and Eldred, 1949; Brookhart, Moruzzi, and Snider, 1950; Crepax and Infantellina, 1955, 1957), while slow-rate synchronization may be induced by any type of afferent volleys impinging upon the cerebellum. Recent experiments by Mollica and Naquet (1953) and Moruzzi (1953a, 1957) showed that the fast activity led with wick electrodes from the cat's cerebellar cortex was characterized by much higher voltages (above 50 microvolts, usually 80 to 120 microvolts) if the decerebration was performed without clamping the vertebral arteries and with only temporary occlusion of the common carotids. Decerebration performed by the old techniques resulted in a permanent depression of cerebellar activity (with an enhancement of extensor rigidity), an observation that fits well Dow's findings (1938c) about the extreme sensitivity of the cerebellar cortex to ischemia. When the cerebellar cortex was in excellent condition, the precollicular preparation was characterized by moderate rigidity (possibly as a consequence of the strong tonic inhibitory influence exerted by the anterior lobe), while a collapse of forelimb rigidity could be elicited with very low intensities of bipolar stimulation of lobule V (300/sec; 1-millisecond rectangular pulses that were about 0.25 milliampere in peak intensity). The good condition of the brain stem centers was demonstrated by the following: the myosis, the briskness of the corneal reflex, and the extreme spasticity which ensued when the anterior lobe was extirpated. The bioelectrical activity of the cerebellar cortex was characterized not only by Adrian's waves (200 to 300 per second) but also by spikes similar to those led with microelectrodes (about 1 millisecond in duration). The fast activity was superimposed on slower potential oscillations lasting up to 20 milliseconds, which probably correspond to the rhythms previously described by the Russian investigators. This type of activity lasted for several hours if the anterior lobe was kept in a moist, warm chamber, constructed on the anterior portion of the skull. In contrast to the results by this technique, when the decerebration had been performed by the routine technique, or whenever the preparation had deteriorated, the extensor rigidity of the precollicular cat was greater and the threshold of stimulation of the anterior lobe was higher, and only Adrian's waves (10 to 30 microvolts in amplitude) were present. Both 1-millisecond spikes and 50-per-second waves had disappeared. The same result could be obtained if the cocainization was arrested before the complete abolition of the spontaneous activity (Fig. 39). Apparently both the spikes and the slower waves of the decerebrate preparation represent some kind of activity, possibly arising in the superficial parts of the cerebellar cortex, which is more easily abolished when either the general or local conditions have slightly deteriorated. 2. SPONTANEOUS ACTIVITY LED WITH MICROELECTRODES Brookhart, Moruzzi, and Snider (1950) utilized monopolar wire microelectrodes for leading from the cerebellar cortex of decerebrate or chloralosed cats.

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Figure 39. Spontaneous activity of the cerebellar cortex of the decerebrate cat. Precollicular cat. The decerebration was performed without clamping the vertebral arteries and with only temporary occlusion of the common carotids. Activity led with bipolar wick macroelectrodes. A. Activity led from the right part of lobule V. Fast activity and 1-msec. spikes superimposed on slower potential oscillations. B. The same, 2 min. after local application of 5 per cent cocaine chlorhydrate. C. Record taken immediately after B, from the left part of lobule V (3 mm. apart). Activity normal, showing that the cocaine depression was strictly localized. D. The same leads as in A and B, 35 min. after the end of local cocainization, show a good recovery of spontaneous activity. (From G. Moruzzi, 1957, Esperimenti e considerazione sull'elettronarcosi cerebellare, Arch, di sc. biol., 41:91-104, Fig. 3.)

Superimposed on the base line formed by the spontaneous cerebellar waves, spike potentials as large as 0.5 millivolt, lasting about 1 millisecond, and predominantly negative in sign were recorded. These spontaneous discharges could be distinguished easily from the injury effects produced by the microwire, and unchanging patterns of spontaneous activity, modified by afferent stimulations of different kinds, were occasionally recorded from a single locus for over an hour. Activity in more than one unit was generally recognizable as such, on the basis of polarity (Fig. 40A) or of voltage (Fig. 401?). Spike discharges of constant amplitude and polarity (Fig. 4
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Figure 40. Multiple- and single-unit discharges in the cerebellar cortex. Decerebrate cat. Multiple (A, B) and single (C) units led with wire (.4) and glass (B, C) microelectrodes from cms I (A, B) and the lobus anterior (C). A and B. Two units can be differentiated on the basis of the polarity (A) or voltage (B) of the spike potentials. C. Modulation of the spike amplitude produced by cardiovascular movements of the cerebellum (three cardiac cycles are shown). (From J. M. Brookhart, G. Moruzzi, and R. S. Snider, 1950, Spike discharges of single units in the cerebellar cortex, J. Neurophysiol., 13:465-486, Fig. 3, publ. Charles C. Thomas.)

Figure 41- Patterns of single-unit discharge in the cerebellar cortex. Records from the lobus anterior (A, B) and crus I (C) of the decerebrate cat (different preparations) led with glass (A) and wire (B, C) microelectrodes. A. Spontaneous, irregular, low-frequency (average, 34/sec) discharge. B. Spontaneous, irregular outbursts (frequency range in each burst, 40-100/sec). C. Regular, fast discharge (150-160/sec). (From J. M. Brookhart, G. Moruzzi, and R. S. Snider, 1950, Spike discharges of single units in the cerebellar cortex, J. Neurophysiol., IS:465-486, Figs. 1A, B, and 4>A, publ. Charles C. Thomas.)

proprioceptive barrage arising in the rigid limbs could not account entirely for these high rates of activity, since frequencies higher than 100 per second were occasionally observed in nondecerebrate preparations under chloralosane anesthesia, as well as in neocerebellar areas of the decerebrate cat (Fig. 41C). These rates of spontaneous (or at least not intentionally evoked) activity are never attained by spinal units (Adrian and Bronk, 1929) or pyramidal units (Adrian and Moruzzi, 1939); and we may wonder whether, besides asynchrony, the high

ELECTROPHYSIOLOGICAL EXPERIMENTS

167 frequency of the single-unit discharge may not be held responsible for the fast activity which is led from the surface of the cerebellum. Further microelectrode experiments by Brookhart, Moruzzi, and Snider were devoted to the problem of the relation between the 150- to 250-per-second waves, which are led from the cerebellar surface with coarse electrodes, and the spike discharges recorded with microelectrodes. When the tip of the microelectrode was placed on the pial surface, the records were indistinguishable in their general features from those obtained with coarse electrodes. Moreover, only low-voltage, fast waves were led when the microwire was in the molecular layer or in the white matter. As soon as the tip of the microelectrode was thrust into the granular or

Figure 42. Localization oj electrical activity within the cerebellar cortex. Decerebrate cat, anterior lobe. Three microelectrode positions are shown in the photomicrographs and their clarifying diagrams to the left. Records typical of derivation from each locus are shown on the right. The noise level, recorded from moist cotton on the superior colliculus, is shown in the lowest recording. Darkly stained areas of the photomicrograph and the stippled areas of the diagrams indicate the granular layer of the cortex. Time: 25 c.p.s. (From J. M. Brookhart, G. Moruzzi, and R. S. Snider, 1951, Origin of cerebellar waves, J Neurophysiol., 14:181-190, Fig. 2, publ. Charles C. Thomas.)

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Purkinje layers, typical spike discharges appeared in the record, superimposed on a base line of increased wave activity (Fig. 42). These findings suggest that with the comparatively coarse micro wires (12.5 microns in diameter) which were used in those experiments, only the soma potentials of the Purkinje cells and of the largest neurons of the granular layer were recorded, whereas the axon potentials and the soma potentials of the small cells were probably missed. The micro wire experiments of Brookhart, Moruzzi, and Snider (1951) did show, at any rate, that Purkinje and granular layers were mainly responsible for the high-voltage, spike discharges and for cerebellar waves, since "as the electrode was passed through several folia, it was possible to predict placement in the Purkinje-granular layer with a high degree of accuracy." From a comparison between the results of leading from the white matter and from the granular layer, it appears most unlikely that the spike discharges recorded in the latter structure arose in Purkinje axons or in mossy and climbing fibers. Hence they were probably "all-or-none" soma potentials, as suggested also by their large amplitude (500 microvolts) and the lack of initial positivity. The durations ranged between 0.5 and 1 millisecond. Spikes were never observed without waves, although waves were frequently observed without spikes, obviously because the spikes are strictly localized phenomena, whereas the waves gave the composite picture of multi-unit activity in a larger volume of cerebellar substance. That the large spikes were not the only origin of the waves was shown by the fact that the two electrical manifestations could easily be dissociated by temporary ischemia, the waves persisting some time after and reappearing some time before the spikes (Fig. 43). Similar results had previously been obtained on the pyramidal system (Adrian and Moruzzi, 1939). It was suggested that either smaller "all-or-none" potentials, which could not be isolated by the microwire technique, or fluctuating membrane potentials of a nonpropagating nature gave their contribution to the cerebellar waves. We have already reported (see p. 160) that the first intracellular records of cerebellar units were taken by Buser and Rougeul (1954a, b) on birds. They made the unexpected observation that sometimes the spike discharge was arrested during transient membrane depolarization. Almost simultaneously Suda and Takahira (1954) and Ushiyama (1954) published preliminary notes on the results they had obtained by leading with hyperfine micropipettes from the cerebellar cortex of mammals. It remained for Granit and Phillips (1956a, b, c, 1957) to utilize this technique for a detailed analysis of the behavior of identified Purkinje cells during natural and evoked discharges. This major work was performed on decerebrate cats. To avoid repetitions, all their experiments will be summarized below, although some results were obtained with single-shock or repetitive stimulation of the cerebellar surface, i.e., by experimental approaches which are grouped under other headings of the present book (see pp. 175-178). The identification of the unit as a Purkinje cell was based (a) on the fact that the discharge was characterized by giant spikes, which were found, moreover, only at a depth corresponding to that of the Purkinje layer; (b) on the consideration that these were the largest responses obtained from the cerebellar cortex and that the Purkinje somata are the largest cells available; (c) on the

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Figure 43. The effect of temporary ischemia on high-voltage spikes and on cerebellar waves. Decerebrate preparation. Records made with 10-msec. sweep on moving film. Time marker to left of records: 25 msec. The vertical white stripe to the right (B, C} shows occlusion of the vertebral arteries (the common carotids had been tied). A. Control record. B. 9 sec. after the beginning of occlusion; shows temporary increase in spike activity. C. At the end of 15 sec. of occlusion; shows absence of large spikes, while wave activity is reduced but not abolished. D. 13 sec. after the readmission of blood. Last two sweeps are noise-level controls. Sensitivity calibration: 250 ^V. (From J. M. Brookhart, G. Moruzzi, and R. S. Snider, 1951, Origin of cerebellar waves, J. Neurophysiol., U: 181-190, Fig. 4, publ. Charles C. Thomas.)

anatomical evidence that within the culmen (lobules IV and V) the Purkinje cells are the only cerebellar cortical neurons that are likely to be activated, both antidromically and monosynaptically, by fastigial shocks; and finally (d) on other, more indirect, lines of evidence. The experiments providing the third criterion were performed by applying single electrical shocks to the corresponding fastigial nucleus or to the underlying arbor vitae. The shortest latencies (0.35 to 0.6 milliseconds) were attributed to antidromic stimulation of the Purkinje axons, while the slightly longer latent periods (0.6 to 0.8 milliseconds) were ascribed to orthodromic stimulation via climbing fibers. The authors stated that no earlier spikes were ever led from the cerebellar cortex in response to fastigial stimulation. Granit and Phillips (1956c) reported that they had been able to obtain only a few intracellular records, since the resting and action potentials of the cerebellar units deteriorated very rapidly. As in other parts of the brain, however, quite stable resting potentials of the order of minus 60 to minus 80 millivolts were frequently encountered, but the nature of the elements responsible for them remained obscure, since neither oscillations nor spikes were superimposed on them. Most of the work was based, therefore, on extracellular records, as shown by the absence of "resting" membrane potentials in the d.c. records, but several data and above all the size of the spikes indicated that the tip of the microcapillary was very close to the cell. Two types of short-lasting events were led from the Purkinje cells, namely

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(a) the "prepotentials," brief wavelets (1 to 2 milliseconds), positive in sign, which remained positive in the few successful penetrations of the membrane and thus could not have been generated in the membrane underlying the recording site, and (b) the "giant spikes," huge potential changes, sometimes purely negative (2 to 3 millivolts), sometimes positive-negative (20 to 40 millivolts), whose main negative-going component was constantly reversed on penetration, showing that they were related to the active response of the membrane at the recording site. Since the spikes arose near the crests of the "prepotentials," the latter potential oscillations were regarded as connected in some way with the process leading to the discharge of an impulse. The "giant spikes" were regarded as the spikes of the huge soma-dendritic system of the Purkinje neurons, "invading the soma and dendrites in retrograde fashion from the axon hillock" (Granit and Phillips, 1956c, p. 543). Very frequently prepotentials failing to give rise to all-or-none spikes were seen. This observation might explain, in our opinion, the presence of cerebellar "waves" after ischemic abolition of the spikes, previously reported by Brookhart, Moruzzi, and Snider (1951); what was left of the cerebellar waves in these conditions was probably related to these "prepotentials." Confirming previous observers, Granit and Phillips (1956c) stated that the Purkinje cells of the decerebrate cat "often are silent, then suddenly start firing and again lapse into silence for no obvious reason and also in a highly random fashion. Caught fresh or in the unstimulated state by a microelectrode they have modest firing frequencies, from next to nothing up to 30 impulses per sec., more rarely 50-60" (p. 528). These authors suggested that the coarser electrodes utilized by Brookhart, Moruzzi, and Snider (1950, 1951) might have led to higher rates of firing, by producing a larger amount of destruction in the molecular layer. The latter investigators had presented evidence showing that the neurons they recorded had not been injured, but it would certainly be impossible to dismiss the hypothesis that a penetration of the microwire or of the terminal shaft of the microcapillary into neighboring regions or layers of the cerebellar cortex had produced irritative foci on structures synaptically connected with the unit led from. Anyway, Brookhart, Moruzzi, and Snider (1950) reported that low-frequency discharges in the range of 30 to 40 per second were also recorded and that, sometimes in the same preparation, frequencies ranging widely were observed from different loci. The Purkinje firing could be inhibited in two distinct ways, which were tentatively ascribed to (a) depolarization and (b) hyperpolarization of the membrane. We have seen that a blockade of the spike discharge occurring simultaneously with membrane depolarization had been reported by Buser and Rougeul (1954a). Granit and Phillips (1956c) described as "inhibition by inactivation" a sudden, short-lasting (15 to 30 milliseconds) arrest of the Purkinje firing which generally occurred spontaneously but was occasionally elicited by fastigial shocks. Intracellular records showed that the arrest of the discharge was due to cathodal inactivation, i.e., to "a depolarization going beyond the firing capacity of the membrane" (p. 532). This "inhibitory strangulation" of the Purkinje cells could not be due to activation of the collaterals of their axons, since it was only rarely

ELECTROPHYSIOLOGICAL EXPERIMENTS 171 observed when the Purkinje neurites were antidromically activated by fastigial shocks. Granit and Phillips (1956c) suggested that this effect might be due to "a depolarization beginning from the bottle-neck of the Purkinje cell where it, together with a part of its axon, is surrounded by the synapses of its own specific basket axons" (p. 532). They pointed out that "when the Purkinje cell is firing spontaneously at a high rate under intense synaptic bombardment a similar cathodal depression or inactivation may develop, during which it merely discharges fast prepotentials, too small to activate a spike" (p. 544). Hence a kind of self-strangulation elicited through the synaptic loop of the basket cells would prevent excessive firing of the Purkinje neurons. A mechanism similar to that underlying the inactivation responses, namely excessive depolarization, would explain the gradual diminution of the spike amplitude which sometimes occurs on single-unit records. Granit and Phillips (1956c) presented tracings of fast-discharging Purkinje units, occurring during high-frequency stimulation of the fastigial nucleus, which showed a gradual decrease in the spike height at the end of the stimulation. These results are similar to those reported by Brookhart, Moruzzi, and Snider (1950) after the local application of strychnine. The last group of investigators reported (p. 472) that the spike discharges occurred in long outbursts. They stated that "during the course of the outburst there was an avalanching increase in frequency and values as high as 400—500/sec. were attained. During the avalanching period, the amplitude of the spikes decreased. The outburst terminated abruptly, was followed by a short silent period, then occurred again." It is likely that cathodic depression was responsible also for the short duration of the strychnine outbursts. The usual inhibition by hyperpolarization was also observed by Granit and Phillips (1956c). They suggested that the postexcitatory pause, which may be elicited by a pair of fastigial shocks and lasts about 30 milliseconds, might be due to this mechanism. After the postexcitatory pause the spikes do not gradually increase in size, as after the inactivation response. They start full-size. The second memoir was devoted by Granit and Phillips (1957) to the effects of surface stimulation of the cerebellar cortex on the discharge of the Purkinje cells. The anterior lobe of the cerebellum was stimulated in the decerebrate cat through a focal electrode 0.5 mm. in diameter. Owing to the small size of the electrode, an inhibition of decerebrate rigidity was never obtained with voltages below 0.8 to 1.0 volt (frequency 140/sec; duration of rectangular pulse 0.050 msec.). Since the superficial Purkinje cells responded to only 0.015 volt, it is apparent that a large number of units within the deeper folds of the cerebellar folia or on the neighboring surface must be activated in order to produce the mass discharge which will yield the first visible effect on extensor rigidity. Granit and Phillips (1957) calculated that these "liminal" shocks could hardly excite less than 20,000 Purkinje cells. Confirming the results obtained by Brookhart and Blachly (1952, 1953) and by Mollica, Moruzzi, and Naquet (1953) with d.c. stimulation, Granit and Phillips (1957) found that surface-positive pulses had lower thresholds than surfacenegative ones, provided the Purkinje cells were superficial and lying just below the focal electrode. The excitability of the neurons was lower during the periods

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of silence interrupting the spontaneous discharge. However, when deeper-lying Purkinje cells were recorded, lower thresholds were more frequently observed with surface-negative pulses, possibly owing to a different orientation of their dendrites (Brookhart and Blachly, 1952, 1953; see below, p. 174). A physiological spread of activity through the axons of the granule cells (parallel fibers) was also shown to exist, in confirmation of Dow's experiments (1949; see below, p. 175). The spike discharge of the Purkinje cell was sometimes inhibited by a single rectangular pulse. Sometimes the blockade was due to refractoriness, but occasionally true inhibition was observed. Repetitive stimulations drove the silent Purkinje cells and triggered those which were already spontaneously active. Rates of driving as high as 266 per second were observed. Although excitation was observed most frequently, inhibition was also stirred up by repetitive stimulation. The results obtained by Granit and Phillips (1956a, b, c, 1957) are of the greatest importance both from the point of view of general neurophysiology and for understanding the functional organization of the cerebellum. Only the latter aspect of the problem will be considered here. One knew from the experiments of Adrian and Moruzzi (1939) and of Phillips (1956) that a so-called subliminal stimulation of the motor cortex might indeed represent a strong stimulus for many Betz cells, at least in the anesthetized cat. We now learn from the results of Granit and Phillips (1957) that the same conclusion applies also to the cerebellar cortex in the wholly unanesthetized animal. Stimuli which may be regarded as subliminal if relaxation of the stiff legs is taken as the indicator response, may excite, indeed quite intensively, the Purkinje cells immediately underlying the electrode. Liminal effects at the periphery involve the mass discharge of a fairly large number of Purkinje neurons. There is a good correspondence, moreover, between the highest rates at which a Purkinje cell may be driven by a surface stimulation of the cerebellum and the optimum frequency at which repetitive pulses yield an inhibition of decerebrate rigidity. The natural rates of Purkinje firing are much lower, at least in the vermal cortex of the decerebrate cat, and the discharges are apparently asynchronous, as shown also by the fact that many cells are silent when no stimuli are applied. The integration of all these natural unitary activities is, nevertheless, a tonic inhibition of the antigravity tonus. Granit and Phillips (1957) suggest that the poststimulatory inactivation of this natural discharge might be responsible for the extensor rebound, a phenomenon which has been extensively analyzed in another section of this monograph (see pp. 155-157). The work of Granit and Phillips emphasized a point that could have been predicted from anatomical data but so far had been rather neglected by physiologists, namely, that every electrical stimulation of the cerebellar nuclei is necessarily polluted by antidromic backfiring and by orthodromic activation of the Purkinje neurons of the overlying cortex. Recent experiments by Arduini and Pompeiano (1956, 1957), to be reviewed later (p. 237), have shown that units located within the rostromedial part of each fastigial nucleus are quite frequently inhibited by polarizing the overlying cerebellar vermis. These results they regard as evidence that some kind of

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inhibitory influence is exerted by the cerebellar cortex on those fastigial neurons which are not concerned with relaying the corticofugal inhibitory volleys to the antigravity mechanisms of the brain stem. The experiments of Granit and Phillips (1956a, b, c, 1957) suggest that elements exerting an inhibitory influence on some Purkinje cells are present within the cerebellar cortex. If the corresponding fastigial relays are driven exclusively by the corticofugal volleys, their tonic discharge will be inhibited as well. Hence the blockade of fastigial firing does not imply necessarily that the process of inhibition occurs within the roof nuclei. One of the first aims of microphysiological investigation is obviously an analysis of this inhibitory element of the cerebellar cortex. It might start with the basket cells of the molecular layer.

3. ELECTRICAL, ACTIVITY AFTER TRANSECTION OF THE BRAIN STEM AND OF THE SPINAL CORD AT C 1, AFTER SECTION OF THE CEREBELLAR PEDUNCLES, AND AFTER SuPRANUCLEAR TRANSECTION

The inflow of spinocerebellar and corticocerebellar impulses was interrupted by Dow (1938c) by two sections performed at midbrain and cervical (C 1) levels. No consistent changes in the spontaneous electrical activity of the cerebellar cortex were observed, provided the circulation was not altered, locally or generally. Complete neural isolation of the cerebellum might be obtained, obviously, only by severing all peduncles, without damaging the cerebellar vessels. On anatomical grounds this would represent, however, an extremely difficult task, and all the peduncular transections reported so far were probably more or less incomplete. At any rate, after this severe operation neither the cerebellar fast waves (Spiegel, 1937; Dow, 1938c; Snider and Eldred, 1949) nor the spike discharges (Brookhart, Moruzzi, and Snider, 1950) were abolished. It might be inferred from these studies that the electrical activity of the cerebellum is basically different from that of the cerebral cortex, at least insofar as the former appears to be completely independent of underlying nervous structures. Three main objections could be raised against this point of view, namely (a) that in acute experiments impulses might arise from the cut surface of the afferent fibers; (b) that spontaneous activity might be driven by remnants of the afferent projections; and (c) that intrinsic cerebellar activity might be related to corticonuclear reverberations. The irritation hypothesis can safely be dismissed, since both waves (Snider and Eldred, 1949) and spike discharges (Brookhart, Moruzzi, and Snider, 1950) were recorded following chronic section of the cerebellar peduncles (Fig. 445). The second objection cannot be laid aside with the same certainty, since no evidence of the completeness of the chronic transection of the cerebellar peduncles has been reported so far. It is true that physiological controls, such as the absence of any evoked response to tactile stimulation and of the inhibition of decerebrate rigidity following electrical stimulation, showed that most of the efferent and afferent connections of the anterior lobe had been severed (Brookhart, Moruzzi, and Snider, 1950), but no evidence of the completeness of the isolation was given. The hypothesis involving corticonuclear reverberations was disproved by the fact that three days after the interruption of the corticonuclear

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Figure kk- Spontaneous activity of the isolated cerebellum. A. Decerebrate cat 3 days after supranuclear transaction of the cerebellar white matter. Micropipette in anterior lobe. Cortex deafferented but some efferent fibers persist. B. Decerebrate cat 44 days after section of all six peduncles. Wire microelectrode in the anterior lobe. The absence of evoked potentials and of responses to electrical stimulation indicates severance of afferent and efferent paths. (From J. M. Brookhart, G. Moruzzi, and R. S. Snider, 1950, Spike discharges of single units in the cerebellar cortex, J. Neurophysiol., 13:465-486, Fig. 7, publ. Charles C. Thomas.)

pathways a strong spike discharge was recorded from the anterior lobe of a decerebrate cat (Fig. 44A) (Brookhart, Moruzzi, and Snider, 1950). It must be conceded, however, that the last two groups of experiments merely suggest that spontaneous fast activity may arise within the corticocerebellar network. The effects of histologically controlled transections, isolating Larsell's lobule V from its neural but not its circulatory connections with the rest of the body, were recently described by Crepax and Infantellina (1955, 1957). Unanesthetized, decerebrated cats were used throughout. Fast spontaneous activity, normal in voltage (100 to 200 microvolts) but slightly lower (about 20 per cent) in frequency, was led with macroelectrodes from the isolated slab of cerebellum. The electrical waves lasted many hours (4 to 6), but were abolished within a few minutes by local cocainization (5 per cent) or by severing the arterial bridge. A spike activity could be recorded by leading through a wire microelectrode from the isolated slab, and its intensity waxed and waned with the potential oscillations led simultaneously from the cerebellar surface. Summing up, neurological isolation had very little effect on the spontaneous activity of the cerebellar cortex, an observation that strikingly contrasts with the results obtained by Burns (1950, 1951) and by Infantellina (1955) on the isolated slab of the cat's cerebral cortex. 4. THE EFFECTS OF DIRECT-CURRENT STIMULATION Brookhart and Blachly (1952, 1953) reported that the spike discharge of spontaneously active units in the Purkinje-granular layer of the decerebrate cat was altered by d.c. polarization (0.1 to 1.0 milliamperes). The strongest effects were observed when the current flow was in the direction of the dendrito-axonal axis of the Purkinje cell, the spontaneous activity being increased by dendritic

ELECTROPHYSIOLOGICAL EXPERIMENTS 175 positivity and decreased by dendritic negativity. A current flow perpendicular to the plane of the dendritic tree had no effect upon the spontaneous spike discharge. The response to d.c. polarization was immediate in onset and nonadaptative, and recovery was prompt. D.c. polarization of the cerebellum was used by Mollica, Moruzzi, and Naquet (1953), by von Baumgarten, Mollica, and Moruzzi (1954), by Scheibel, Scheibel, Mollica, and Moruzzi (1955), and by Gauthier, Mollica, and Moruzzi (1956) for driving reticular units with cerebellifugal impulses. These experiments will be reviewed elsewhere (see pp. 219-230). 5. THE EFFECTS OF SINGLE ELECTRICAL SHOCKS Single condenser discharges were applied by Dow (1949) to the dissected surface of a cerebellar folium, in the decerebrate cat. Surface-negative responses were led when the unipolar recording needle (60 microns) was placed on the same folium, laterally to the stimulating electrode. No response was obtained (a) when the distance between the stimulating electrodes and the leading wire was more than 5 millimeters; (b) when a section deep enough to sever the fibers of the molecular layer was made between stimulating and recording electrodes; and (c) when the lead was applied in another folium (Fig. 45). Latency measurement indicated a very slow rate (up to 0.5 meters per second) of conduction, and Dow (1949) pointed out that these physiological specifications could be fulfilled only by neural transmission through the fibers of the molecular layer, whose position, orientation, and size could easily account for the effects he observed. The sign of the potential changed from negative to positive when the recording needle was pushed deeper than the cell bodies of the Purkinje cells. This deep response was believed to be due to their transsynaptic activation, since (a) tem-

Figure !&. Response to single-shock stimulation of the surface of a cerebellar folium. Unipolar recording electrode on the culmen of the decerebrate cat. a. Small response when the lead is 3 mm. anterior to the stimulating electrodes, b. Large surface-negative response when the lead is 3 mm. lateral to the stimulating electrodes, c and d. Lead electrode same as in b, with stimulating electrodes thrust 0.5 (c) and 1 mm. (d) below the surface of the folium. Calibration: 200 (j.V and 5 msec. (From R. S. Dow, 1949, Action potentials of cerebellar cortex in response to local electrical stimulation, J. Neurophysiol., 1%: 245-256, Fig. 1, publ. Charles C. Thomas.)

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poral facilitation, (b) augmentation by local picrotoxin, and (c) quick abolition by asphyxia were reported. Both surface and deep responses had the same origin, as shown by comparing the facilitation curves, and were probably due to soma potentials of the Purkinje neurons. Since the duration of the response to electrical shocks was much longer than that of the spikes led from single elements during spontaneous activity (Brookhart, Moruzzi, and Snider, 1950, 1951), it seems likely that it represented the composite response of many Purkinje neurons, which were probably activated in quick succession by the volley of impulses coursing in the molecular layer.

6. THE EFFECTS OF REPETITIVE STIMULATION Adrian (1935) reported that faradic stimulation of the cat's cerebellum was followed by a regular series of high-frequency waves (150 to 250 per second), which were "evidently due to a number of neurones pulsating in phase." Dow (1938c) confirmed Adrian's observation and showed that the epileptiform afterdischarge of the cerebellar cortex was followed "by a period of decreased activity which lasted for 1 or 2 min. before it returned to its previous level of activity." If the stimuli were shorter or weaker, "instead of the increase in activity, there was apparently a primary depression," probably because, as Dow pointed out, the epileptiform afterdischarge stopped before the amplifiers became stabilized. The epileptiform cerebellar afterdischarge differed from that of the cerebral cortex not only in its much higher rate (Adrian, 1935; Dow, 1938c) but also in being confined to the site of stimulation, an observation which was explained (Dow, 1938c) by the absence of long association tracts in the cerebellar cortex (Dow, 1936). A simultaneous recording in decerebrate cats of electrical activity in the anterior lobe (probably lobules IV and V) and of tension in the extensor muscles (Dow, 1938c) showed that decerebrate rigidity markedly fell during the epileptiform afterdischarge and strongly increased during the poststimulatory depression (Fig. 46). These findings provided crucial evidence (a) that spontaneous electrical activity was correlated with the tonic influence of the cerebellum, and (b) that the cerebellifugal barrage of inhibitory impulses increased during the epileptiform afterdischarge. Gualtierotti, Martini, and Marzorati (1942, 1949) reported that the spontaneous electrical activity of the cat's cerebellar cortex was completely silenced following prolonged (30 seconds), repetitive (1-millisecond rectangular pulses at 280/sec), and very intense (up to 200 volts, 40-milliampere peak) stimulation of the cortex itself or of the brain stem. They claimed that this poststimulatory inactivation, which they called electronarcosis, was due to reverberating cerebellomesencephalo-cerebellar circuits (see Martini, Gualtierotti, and Marzorati, 1951). However, Arduini, Moruzzi, and Terzuolo (1951) and Moruzzi (1953a, 1957) were unable to support these conclusions. Moruzzi (1953a, 1957) pointed out, moreover, that the intensity of the stimulation utilized in the experiments on cerebellar electronarcosis was about fifty times greater than that which gave complete inhibition of decerebrate rigidity and about five times greater than that which was followed by the epileptiform afterdischarge described above. These

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Figure b&. Correlations between the extensor tonus and the epileptic after'discharge and poststimulatory depression of the anterior lobe. The extensor tonus (M. plantaris) was recorded with an isometric myograph while the electrical activity of the stimulated area of the anterior lobe was led simultaneously with bipolar macroelectrodes. During faradic stimulation (B, signals at bottom of record and between G and H) the amplifiers were shunted, and only the myogram was recorded. Decerebrate cat. A. Before stimulation. B. Extensor rebound and its inhibition by a second stimulation. Four stimulations of 1 sec. each (only two shown on the published record) resulted in a poststimulatory depression and in a strong increase in extensor rigidity. C to F. The progressive recovery of the electrical activity 19 (C), 31 (D), 40 (E), and 77 (F) sec. after the stimulation parallels the return of the extensor tonus to its prestimulatory level. G. Before stimulation. H. 4 sec. after the end of continuous faradization for 20 sec. at the same strength as in B. The long-lasting stimulation resulted in an epileptiform afterdischarge, while the inhibition of rigidity depressed the myogram below the recording paper. /. Poststimulatory depression and increase in extensor tonus 7 sec. later. J. Stabilization of the extensor tonus and of electrical activity 60 sec. later. (From R. S. Dow, 1938, The electrical activity of the cerebellum and its functional significance, J. Physiol., 9-4:67-86, Fig. 8.)

currents spread, in a purely physical way, to the cranial nerves and to all the brain stem. The hypothesis that midbrain mechanisms were involved in the poststimulatory inactivation of the cerebellar cortex was upheld also in two papers recently published by Gualtierotti and Martini (1952) and by Gualtierotti (1954). Suffice it to say that the authors maintained that the midbrain had a tonic inhibitory influence on the spontaneous rhythms of the cerebellum. Pursuing the same line of thought, Gualtierotti and Margaria (1956) stated that the usual patterns of fast and slow waves, 80 to 120 microvolts in amplitude, which had been recorded by several investigators from the cerebellar cortex of the decerebrate preparation (see pp. 162-164), were actually present only after postcollicular transection

178 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM or whenever the brain stem of the mesencephalic animal had deteriorated. They maintained that a good precollicular preparation was characterized only by fast waves (150-300 per second) of extremely low voltages (15 microvolts). Here again Moruzzi (1957) was unable to confirm these findings. He reported that the patterns of "spontaneous" electrical activity in the cerebellar cortex were essentially the same whether in the precollicular cat, with physiologically controlled integrity of the midbrain, or in the postcollicular preparation. The patterns of spontaneous electrical activity which, according to Gualtierotti and Margaria (1956), would characterize the precollicular preparation were indeed occasionally recorded, both in precollicular and in postcollicular decerebrate cats, but only when the general (mainly vasomotor collapse) or local conditions of the preparation were severely depressed. The results of these experiments, during which the blood pressure was controlled, have already been reported (p. 164). The effects of localized electrical stimulation on the spontaneous activity of the anterior lobe were investigated recently by Mollica and Naquet (1953), in unanesthetized postcollicular cats. An epileptiform afterdischarge could be obtained with rectangular pulses (300/sec; 1 msec.) only when their amplitude rose to voltages (20 to 30 volts) about ten times higher than those which were required for inhibiting extensor rigidity. An electrical silence, probably due to postconvulsive exhaustion, followed these synchronous, high-frequency (150 to 250 per second) outbursts. When these intense stimuli were prolonged for as much as 15 to 20 seconds, the exhaustion occurred during the stimulation, as shown by the cessation of the inhibition of extensor rigidity. In these experimental conditions only the electrical silence could be recorded. The experiments of Mollica and Naquet (1953) provide a convincing explanation of the nature of the poststimulatory silence of the cerebellar cortex and show that this effect may occur independently of the midbrain.

7. THE EFFECTS OF CONVULSANT DRUGS Kornmiiller (1935) reported that the strychnine spikes which are so easily led from the surface of the cerebrum did not occur following a local application of the drug to the rabbit's cerebellar cortex. His results were confirmed on the cat's cerebellum by Dow (1938c) and by all later investigators. That cerebellar neurons are nevertheless stimulated by the drug is shown (a) by the postural and motor effects repetitively reported following local strychninization of the cerebellar lobuli (Miller, 1920, 1926a; Simonelli, 1926; Rossi and Di Giorgio, 1942; Manni, 1951a; see above, p. 112); (b) by the clear-cut changes in the electrical response to afferent volleys elicited by the local strychninization of tactile or auditory projection areas (Bonnet and Bremer, 1951; Bremer and Bonnet, 1953; Bremer and Gernandt, 1954; see below, p. 211); and (c) by the convulsive outbursts of all-or-none potentials led with microelectrodes from any strychninized area of the cerebellar cortex (Brookhart, Moruzzi, and Snider, 1950, 1951). Hence the conclusion appears unavoidable that local strychnine may excite cerebellar neurons without eliciting the hypersynchronous paroxysms so typical of the convulsive behavior of the cerebral cortex. Brookhart, Moruzzi, and Snider (1950) and Bremer and Bonnet (1953) sug-

ELECTROPHYSIOLOGICAL EXPERIMENTS 179 gested that the inherently asynchronous nature of the rest activity of the corticocerebellar neurons might account for their lack of hypersynchrony following local strychninization. This hypothesis appears to be supported by two observations: (a) Even the so easily elicited cortical strychnine "spikes" are blocked whenever brain synchrony is disrupted by stimulations of different kinds (Gozzano, 1935, 1936; Kornmiiller, 1937; Dempsey, Morison, and Morison, 1941; Bremer, 1943; Gellhorn and Ballin, 1948; Gellhorn, Hyde, and Gay, 1949; Arduini and LairyBounes, 1952; Lairy-Bounes, Parma, and Zanchetti, 1952; Arduini, Magni, and Roger, 1955). (b) No strychnine "spikes" can be led from the olfactory bulb (Frankenhaeuser, 1951), a structure which is characterized (as is the cerebellum) by the presence of asynchronous fast rhythms during its rest activity (Adrian 1950; Arduini and Moruzzi, 1953). There is no doubt, therefore, that neurons of the cerebellar cortex can be stimulated by local strychnine without any sign of the hypersynchronous paroxysms which characterize the convulsive behavior of cellular masses in the cerebral cortex. The mechanisms underlying this type of chemical stimulation of the cerebellum should now be submitted to discussion. It has been pointed out (see Moruzzi, 1946b, 1950c, 1954) that the convulsive activity of the cerebrum is characterized not only (a) by mass discharges (hypersynchrony) but also (b) by high-frequency outbursts in the single units (Adrian and Moruzzi, 1939; Mollica and Rossi, 1953; Li and Jasper, 1953; Jung, 1953, 1954). The second aspect of this convulsive behavior is present, although in a somewhat modified form, in the strychninized cerebellar cortex. Brookhart, Moruzzi, and Snider (1950, 1951), in the microelectrode experiments previously referred to (see p. 164), observed that high-frequency outbursts occurred spontaneously in the cerebellar cortex following local strychninization. The discharge began at frequencies which were still in the normal ranges of 75 to 80 per second. During the course of the outburst, however, there was an avalanching increase in frequency, and values as high as 400 to 500 per second were attained. The number of impulses in each outburst was generally higher, but the critical rate of firing was lower, than in the pyramidal discharges occurring after strychninization of the motor cortex (Adrian and Moruzzi, 1939). During the avalanching period the amplitude of the spikes decreased, an observation attributed to the fact that the intervals between spikes became shorter than the relative refractory period. At any rate, the discharge frequency at the end of the avalanching period was critical for the cerebellar neurons, since it was followed by an abrupt arrest of the convulsive barrage (Fig. 47). The convulsive spike outbursts were more easily depressed by ischemia than the cerebellar waves. Although local strychnine is apparently unable to yield a convulsive synchronization of cerebellar neurons, at least if other intentional stimulations are avoided, such an effect is constantly observed following injections of tetanizing doses of the drug. In these experimental conditions, high-voltage (100 to 400 microvolts), low-frequency (10 to 30 per second) waves were led from the cerebellar cortex of curarized animals by Gualtierotti and Capraro (1941), Johnson, Browne, Markham, and Walker (1950), Markham, Browne, Johnson, and Walker (1951, 1952), Ruf (1951), Johnson, Walker, Browne, and Markham (1952),

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Figure 47. Avalanching outbursts in the cerebellar cortex following local strychninization. Decerebrate cat. Glass micropipette in right lobulus paramedianus. A. Normal multi-unit discharge which had been in progress for 7 min. B. 9 min. after application of 3 per cent strychnine locally near tip of electrode. Note long outbursts with terminal increase in frequency. C. 1 min. after B. Convulsive outbursts are shorter and more frequent, with higher initial frequency. D. Strychnine removed and area washed with a saline solution 14 min. after application. Record taken 1 hr. after application of strychnine. Convulsive outbursts have disappeared. Time and sensitivity constant throughout as indicated. (From J. M. Brookhart, G. Moruzzi, and R. S. Snider, 1950, Spike discharges of single units in the cerebellar cortex, J. Neurophysiol, 13:465-486, Fig. 5, publ. Charles C. Thomas.)

Marossero and Garrone (1952), Bremer and Bonnet (1953), and Bremer and Gernandt (1954). These data should not be regarded, however, as inconsistent with the negative findings reported following local applications of the drug, since the convulsive synchronization of cerebellar neurons is elicited by afferent volleys arising in the tetanized bulbospinal structures. This condition obviously does not occur in local strychnine experiments, if intentional stimulations are avoided. The evidence suggesting that the tetanic waves led from the cerebellar surface of decerebrate cats are induced by afferent volleys was summarized by Bremer and Bonnet (1953) as follows: (a) a striking similarity in shape between tetanic waves and responses of the same folium to sensory afferent volleys; (b) reciprocal interference between tetanic waves and cerebellar responses to sensory stimuli (Fig. 48); (c) typical tetanic waves are led only from spinocerebellar and bulbocerebellar projection areas, whereas the waves led from the cortex of the cerebellar hemisphere are by far smaller in amplitude and can possibly be explained by a physical spread of bioelectric potentials (Fig. 48). It might be maintained that these synchronous cerebellar potentials would be due simply to afferent volleys of axon potentials impinging upon the cerebellar cortex. That intrinsic corticocerebellar neurons are synchronously driven by the spinocerebellar and bulbocerebellar barrage is shown, however, (a) by the phase reversal which occurs when the tip of the recording lead reaches a critical depth (Bremer and Bonnet,

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Figure 48. Convulsive waves and responses to afferent volleys in the cerebellar cortex, during strychnine tetanus. Decerebrate and curarized cat following the injection of a tetanizing dose of strychnine. Unipolar leads from vermal surface (Aa, A2, both records; B to F, upper records) and hemispheral surface (B to F, lower records) of the cerebellum. The tetanic waves (Ai, Bi, Ci) led from the culmen show the same shape and polarity as those induced in the same cerebellar area by synchronous afferent volleys (digital electrical shocks: arrows), impinging upon the cortex in an interval between two tetanic outbursts (A2, B2, C2). Both kinds of potentials are by far greater when led from the culmen than when led from the surface of crus I (compare upper and lower records Bi to F). "When the afferent volleys (digital electrical shocks) are timed to occur during the tetanic phase (D to F: arrows) the evoked response may summate with the strychnine potentials (D) or may be either blocked (E) or increased by them (F). (From F. Bremer and V. Bonnet, 1953, Action de la strychnine sur les reponses sensorielles et sur les potentiels electriques spontanes de 1'ecorce cerebelleuse. L'activite convulsive du cervelet, Fol. Psych. Neurol. et Neurochir. Neerl., 56:438-446, Fig. 3 and part of Fig. 1.)

1953) and (b) by the fact that only the surface-positive component of the tetanic wave, which resists local injury (including thermocoagulation), is due to fiber potentials arising in the afferent pathways, whereas both the surface-negative component and the negative microelectrode potentials are selectively affected by local nembutal or by asphyxia (Bremer and Gernandt, 1954). Hence these latter electrical manifestations were regarded by Bremer and Gernandt as indicating a reflexly driven synchronous discharge of the Purkinje neurons. Since the Purkinje barrage arising in the vermal part of the anterior lobe has a tonic inhibitory influence on the convulsive activity of the spinal cord, as shown by the increase of spinal tetanus which occurs when the anterior lobe is cooled (Terzuolo, 1952), these spinocerebellar correlations would represent an example of a true negative feedback. It will be shown in another section of this monograph that Purkinje neurons can be reflexly synchronized even when general strychninization is avoided (see p. 211). Convulsive patterns have been recorded in the electrocerebellogram of intact curarized cats (Crescitelli and Gilman, 1946; Pollock and Bain, 1950) and monkeys (Crescitelli and Gilman, 1946) following administration of 2,2 bis (p-chlorophenyl), 1,1,1 trichloretane or DDT (Crescitelli and Gilman, 1946), or of

182 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM /2-chlorinated amines (Pollock and Bain, 1950). The spike activity of the cerebellar cortex was strongly intensified by local applications of prostigmine or of eserine followed by acetylcholine (Crepax, Nigro, and Parmeggiani, 1956, 1957). C. ELECTROPHYSIOLOGY OF THE AFFERENT CEREBELLAR

CONNECTIONS IN MAMMALS 1. RESPONSES TO NATURAL STIMULATION a. STIMULATION OF VESTIBULAR RECEPTORS In a pioneer work performed with the string galvanometer before the era of the vacuum tube amplifiers, Camis (1919) made the first attempt at recording cerebellar responses to natural vestibular stimulations. He reported that rotation yielded potential changes in the fastigial nuclei but not in the cerebellar cortex. Many years later this problem was approached from the same angle by Price and Spiegel (1937), who connected their string galvanometer to a three-stage amplifier. They reported that rotation increased the spontaneous activity of the vestibular part of the cerebellar cortex. They did not present records led from other parts of the cerebellar cortex, however, nor did they dismiss, by appropriate controls, the objection that the slight changes they recorded in bulbocapnine cats might be due to collateral effects on the somatic or autonomic nervous system. To continue these experiments using modern techniques and careful anatomical and physiological controls would be important. b. STIMULATION OF MUSCLE, TENDON, OR JOINT PROPRIOCEPTORS

Dow (1938c) reported that manual stretching of M. vastocrureus, in a decerebrate cat, failed to induce any detectable change in the electrical activity of the cerebellar cortex. A few years later positive results were obtained, however, by Dow and Anderson (1942) in experiments on lightly nembutalized rats. They led large positive potentials from the pyramis following a sudden tap on a taut cord which had been fastened to the tendons of either M. quadriceps femoris or M. triceps brachii (Fig. 49). These different results are not surprising, since a synchronous volley of proprioceptive impulses impinging upon the cerebellar cortex, when both muscular tonus and spontaneous cerebellar activity are depressed by barbiturates, is more likely to be detected than the effect of slowly stretching a single extensor muscle in the unanesthetized decerebrate preparation. The same authors reported, moreover, that tapping of the tendon of M. triceps brachii, never of M. quadriceps femoris, yielded surface-positive responses in the uppermost folia of the culmen, an observation which fits well with the theory of somatotopic localization. More difficult to explain, anatomically, is their observation that sometimes surface-positive responses were led from the lobulus ansiformis when the tendon of M. triceps brachii was tapped. When this effect was observed, however, it appeared after a prolonged latency. Adrian's experiments (1943) were performed on barbiturized cats and monkeys as well as on decerebrate cats. Decerebration was performed under barbiturate anesthesia, in experiments aimed at leading afferent spike discharges with a microwire. In this way the preparation was greatly simplified, since decerebrate

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Figure 49. Cerebellar responses to abrupt proprioceptive and exteroceptive stimulations. A. Lateral view of the rat's cerebellum. Nos. 1 to 8 refer to the lead points for the corresponding records. Abbreviation c.p. = cerebral peduncle; cl la=. cms I lobuli ansiformis; cr II la — crus II lobuli ansiformis; fis. p. =fissuraprima; floe. = flocculus; lo. ant. •=. lobus anterior (highest folium of culmen); lo. med. = lobus medius (folium and tuber vermis); I. simp. = lobulus simplex; /. p. med. = lobulus paramedianus; med. obi. = medulla oblongata; mes. = mesencephalon (superior and inferior colliculi); n. V = trigeminal nerve; n. VIII = acoustic nerve; p. = pons; pfl. = paraflocculus; pyr. = pyramis; uv. = uvula. B. Potentials recorded following tapping the tendon of the homolateral quadriceps femoris. A deflection downward in these and subsequent records indicates a positive potential. The instant of stimulation is not shown, but all records in each column have been mounted so that the time sequence of one is comparable to another. Note an early positive potential only in the pyramis, B*. C. Potentials recorded following tapping the tendon of the homolateral triceps brachii muscle in the same animal. Note that the largest early surface-positive potential is led from the pyramis, C*. Other surfacepositive potentials of comparable amplitude are led from the uvula, CE, and crus II, C7. They occur respectively 17 and 21 msec, later than one led from the pyramis. D. Potentials recorded following moving the hair on the back of the same animal. Note that the early surfacepositive potentials are restricted to the culmen. (From R. S. Dow and R. Anderson, 1942, Cerebellar action potentials in response to stimulation of proprioceptors and exteroceptors in the rat, J. Neurophysiol., 5:363-371, Fig. 1, publ. Charles C. Thomas.)

rigidity was abolished (thereby greatly reducing the tonic barrage from the stretch receptors), while spontaneous activity of the cerebellar cortex was markedly depressed. Decerebration was instead performed under ether, whenever the experiment was aimed at investigating the influence of afferent volleys on spontaneous cerebellocortical activity, which was then led from the surface with cotton wool electrodes. In order to decrease the barrage of afferent impulses from the stretch receptors, decerebrate rigidity was abolished with curare. This second group of experiments will be reviewed in another section (see p. 212). Natural stimulations of different kinds were used, such as pressure, joint movements, and stretching of muscles. The best results were obtained with a dorsiflexion of the digits or with a pressure on the toe and foot pads. Adrian pointed out that the

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receptors mos,t likely to be concerned in these responses were the Pacinian corpuscles, which are localized in the pads of the toe and foot and under the flexor tendons of the toes, wrist, and ankle. Stretch receptors and hair endings were stimulated as well, so that the impulses impinging upon the cerebellum were mainly but not exclusively proprioceptive in origin. The stimulation of the face receptors was mainly exteroceptive (bending or pulling the vibrissae, touching the hairs, pressure on the skin). The afferent projections for hindlimb, forelimb, and face were found respectively within the ipsilateral vermal and hemispheral parts of the lobulus centralis (Larsell's lobules III and H III), the culmen (lobules IV, V and H IV, H V), and the lobulus simplex (lobules VI and H VI). This somatotopic arrangement was found in the cat and in the monkey (Fig. 50) and was confirmed in two dogs and one goat. A segregation of the projections from different parts of the forelimb and hindlimb was also reported. When single-unit discharges were picked up with the microwire, they differed very little from the sensory messages led from peripheral nerve fibers. The frequency of the impulses increased smoothly with the stimulus over a range of 5 to 200 a second. There was often a resting discharge (about 10 a second as a rule), and the response to a constant stimulus declined gradually; a silent period occurred when the stimulus was withdrawn. Adrian (1943) thought that these single-unit discharges were led from afferent spinocerebellar or bulbo-

Figure 50. Spinocerebellar receiving areas in the cat's and the monkey's cerebellum. Projection areas for hindlimb, forelimb, and face on the anterior lobe and lobulus simplex of the cat's (A, B) and the monkey's (C, D) cerebellum. (From E. D. Adrian, 1943, Afferent areas in the cerebellum connected with the limbs, Brain, 66:289-315, Figs. 4, 5, 8, and 9.)

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cerebellar fibers, since (a) the response to a pressure on the toe pads and a dorsiflexion of the digit and wrist could be led "under almost any condition of anesthesia," and (b) there was a likeness between the afferent discharges in the cerebellum and those in the peripheral nerve fibers. He pointed out, however, that a convergence of impulses must occur at some precerebellar level, since "an axon in the cerebellum may be in touch with a receptive field much larger than that of the peripheral nerve fiber." These low-level interactions in the spinocerebellar system were also found (see p. 217) by Grundfest and Campbell (1942), Carrea and Grundfest (1954), Laporte, Lundberg, and Oscarsson (1956b), and Laporte and Lundberg (1956). C. STIMULATION OF EXTEROCEPTORS

The unexpected discovery that the cerebellum, which Sherrington (1906) had called "the head ganglion of the proprioceptive system," is heavily impinged upon by exteroceptive impulses was reported almost simultaneously by Snider and Stowell (1942b, 1944), Dow and Anderson (1942), Adrian (1943), and Snider (1943). To avoid repetition, the results will be reviewed in the chronological order of the full papers, although the first preliminary note was presented by Snider and Stowell (1942b). Dow and Anderson (1942) reported that large responses to movements of the hair could be led from the culmen (lobules IV, V), the lobulus simplex (lobules VI, H VI), and the pyramis (lobule VIII) in the nembutalized rat. The responses under nembutal anesthesia were most pronounced in the culmen and were not abolished by postcollicular decerebration. Adrian (1943) led spike discharges with wire electrodes from the lobulus simplex (lobules VI, H VI) of cats and monkeys deeply anesthetized with barbital, by bending or pulling the vibrissae and occasionally by touching the hairs inside the ear and along its margin. These effects were strictly ipsilateral. Snider and Stowell (1944) performed their experiments on cats and monkeys under different types of anesthesia. Exteroceptive volleys were evoked by a quick displacement of a few hairs or of the vibrissae while the cerebellar surface was explored with unipolar wick electrodes. Responsive areas for the forepaws were found (a) in the posterolateral part of the ipsilateral half of the anterior lobe (and occasionally in the most medial folium of crus I); (b) in a portion of the ipsilateral paramedian lobule (and occasionally in some folia of crus II); and finally (c) in a smaller portion of the contralateral paramedian lobule. A hindpaw area was localized in the ipsilateral anterior lobe, in the fifth, sixth, seventh, and eighth folia, rostral to the primary fissure. It was reported to be wholly separated from the forepaw area, whereas overlapping occurred in the paramedian projections. The trigeminal projection areas occupied four folia, two anterior and two posterior to the primary fissure (Fig. 51). Summing up, the somatotopic distribution of afferent projections within the anterior lobe and lobulus simplex coincided in the experiments performed with purely tactile stimulations (Snider and Stowell, 1942b, 1944; Snider, 1943) and in those where mixed exteroceptive and proprioceptive stimuli were applied (Adrian, 1943). Exteroceptive projections were found, moreover, on the pyramis

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Figure 51. Tactile projection areas on the cerebellar cortex. A drawing of the dorsal surface of the cat's cerebellum showing the distribution of electrical responses evoked by stimulation of the tactile receptors. Note the overlap in the forefoot and hindfoot areas of the paramedian lobules and their complete topographical separation in the anterior lobe. (From R. S. Snider and A. Stowell, 1944, Receiving areas of the tactile, auditory and visual systems in the cerebellum, J. Neurophysiol., 7:331-357, Fig. 4, publ. Charles C. Thomas.)

(Dow and Anderson, 1942), on the lobulus paramedianus, and on some folia of the lobulus ansiformis (Snider and Stowell, 1942b, 1944; Snider, 1943). d. STIMULATION OF VISUAL AND AUDITORY TELECEPTORS

Snider and Stowell (1942a, 1944) and Stowell and Snider (1942a, b) should be credited with the unexpected discovery that auditory and visual systems are represented within the cerebellar cortex, although a few occasional observations of this kind had been reported previously by Gerard, Marshall, and Saul (1936). Snider and Stowell's experiments were performed on anesthetized cats. Maximal responses to clicks were found in the lobulus simplex and tuber vermis (Larsell's lobules VI, H VI, and VII), although smaller and inconstant responses were led occasionally from neighboring areas, when chloralosane anesthesia was used. Sodium pentobarbital depressed the amplitude of the evoked potentials and reduced the total area of response to about one half (Fig. 52), but did not affect the latency (6 to 14 milliseconds). A surface-positive response could be led from the first turn of the tuber vermis even in deeply barbiturized preparations. The acoustic potentials were abolished (a) by destroying both cochleae, (b) by severing both acoustic nerves, and (c) by bilateral destruction of the inferior colliculi. They were instead unaffected (a) by severing both trigeminal nerves, (b) by inserting a nonconductive barrier between the posterior colliculi and anterior cerebellum, and (c) by chronic decerebration. These controls and the strict localization of the response showed that the response could not be attributed to a spread of bioelectrical impulses, to proprioceptive reverberation, or to occasional exteroceptive stimulation. Hence the conclusion was drawn that auditory impulses are relayed by brain stem pathways, probably through tectal neurons, to their projection areas within the* cerebellar cortex. Another important observation was that the auditory areas coincided very closely with the cerebellar zone yielding responses to a flash of light. The most common form of visual potentials was represented by a surface-positive component followed by a surface-negative wave. The visual responses differed from the auditory ones in their much longer latencies (40 to 50 milliseconds) and in their greater sensitivity to barbiturates. Practically all the experiments had to be

Figure 52. Location and extent of the auditory area of the cat's cerebellum. The distribution of responses to click stimulation (A, C), and a composite chart showing the extent and location of the auditory area (B, D) in the cat anesthetized with chloralosane (A, B) and sodium pentobarbital (C, D). (From R. S. Snider and A. Stowell, 1944, Receiving areas of the tactile, auditory and visual systems in the cerebellum, J. Neurophysiol., 7:331-857, Fig. 5, publ. Charles C. Thomas.)

Figure 53. Location and extent of the visual areas of the cat's cerebellum. The distribution of responses to photic stimulation of one eye (A}, and a composite chart (B) showing three zones of maximal responses (cross-hatching) in the chloralosed cat. (From R. S. Snider and A. Stowell, 1944, Receiving areas of the tactile, auditory and visual systems in the cerebellum, J. Neurophysiol., 7:331-357, Fig. 11, publ. Charles C. Thomas.)

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188 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM performed under chloralose anesthesia. The photic responses were unaffected (a) by bilateral sections of the trigeminal and facial nerves and (b) by chronic (eleven months) ablation of the neocortex, and could be duplicated (c) by singleshock stimulation of the dorsal surface of a superior colliculus. These controls, as well as the silent bands interposed between the responsive areas (Fig. 53), showed that the effect could not be explained by a spread of bioelectric potentials, proprioceptive reverberations, or occasional exteroceptive stimulation. Retinal impulses were relayed to the cerebellar cortex probably through tectal neurons, and the area striata as well as the lateral geniculate bodies (which degenerate following ablation of the cortical visual area) were shown to be unnecessary for the cerebellar response. Snider and Stowell (1944) had already suggested that the photic responses of the cerebellar cortex under chloralose anesthesia might be "the result of an excitatory or strychnine-like action of this anesthetic." Gastaut, Naquet, Roger, and Badier (1951) came to similar conclusions. They were able to lead photic responses from the superior colliculi, but never from the cerebellar cortex of deeply barbiturized cats. Cerebellar effects appeared on midline structures, such as the lobulus simplex, folium, tuber, and pyramis (Larsell's lobules VI, H VI, VII, VIII), as well as on the paramedian lobules (Larsell's sublobules H Vllb, H Villa) following the intravenous injection of 15 to 20 mg/Kg of cardiazol. Gastaut (1951) suggested that these cerebellar potentials were similar in nature to the subconvulsive, "irradiated" responses which appeared simultaneously on the nonvisual areas of the cerebral cortex. Inasmuch as the cerebellar effects were present in the curarized preparation, they could not be regarded as the proprioceptive reverberation of the myoclonic effect (see Gastaut, 1951). Gastaut, Naquet, Roger, and Badier (1951) suggested that retinal impulses might reach the cerebellar cortex only in abnormal conditions, i.e., when the excitability of the tectocerebellar system had been increased by injections of convulsant drugs. That the photic response of the cerebellar cortex was a normal phenomenon, although undoubtedly distorted and magnified by chloralose anesthesia, was shown by Fadiga, Pupilli, and von Berger (1956). The responses of lobules VI and VII to photic stimuli were present also in the unanesthetized cat. They were decreased by local cocainization, increased by local strychnine, and reversed in polarity when the wire electrode reached the granular layer. The amplitude of the evoked potentials increased after the injection of chloralose, and photic responses could then be led also from folia of the lobulus ansiformis (sublobule H Vila). In a few experiments Fadiga, Pupilli, and von Berger (1956) found, moreover, that visual responses to a flash of light could be led from the surface of crus I and crus II also in the unanesthetized (curarized) cat. This finding prompted new investigations. The shape, latency, and distribution of the responses evoked by single electrical shocks to the optic nerve were studied in the same type of preparation. The patterns of these evoked potentials were similar to those elicited by natural visual stimuli; they could be regularly recorded, however, also from the lobulus ansiformis. The responses led from crus II arose in the underlying cerebellar cortex, since they were increased by local applica-

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tions of dilute (0.1 per cent) strychnine. The first, surface-positive component of the evoked potential was strikingly decreased, whereas the second, surfacenegative component was abolished altogether, following the local application of nembutal (6 per cent) or of cocaine (5 per cent). Finally, the hemispheral response was not modified when the vermal effect had been abolished by cocainizing the whole area lying between the fissura prima and the fissura uvulo-nodularis, an observation suggesting that the effect observed on cms II was not due to a neural transmission from lobules VI and VII. The authors stated, however, that some components of the evoked potentials led from crus I did not arise within the cerebellar cortex underlying the pick-up electrode. The unexpectedness of the results of this second group of experiments of Fadiga, Pupilli, and von Berger (1956) inheres in the demonstration that hemispheral areas of the cerebellar cortex are also impinged upon by visual impulses, though less intensively than lobules VI and VII. At least on crus II, chloralose would simply magnify a preexisting physiological phenomenon. C. RESPONSES TO SPONTANEOUS CORTICOFUGAL VOLLEYS

Slow cerebellar rhythms have been observed after decerebration, a finding which is obviously inconsistent with the old hypothesis that they should be exclusively explained by cerebral driving (see p. 163). That corticofugal volleys arising spontaneously in the cerebral cortex influence the electrical activity of the cerebellum is clearly shown, however, by the experiments of Adrian (1943). The 8- to 12-per-second rhythm characterizing the EEG patterns in barbiturate anesthesia was led from not only the motor cortex but also the pyramidal tract after bulbar crossing (Adrian and Moruzzi, 1939) and from the cerebellar cortex (Adrian, 1943) in both cats and monkeys. Pyramidal (Adrian and Moruzzi, 1939) and cerebellar (Adrian, 1943) grouped discharges were immediately abolished in the cat by destroying the contralateral motor area. Adrian's results on the localization of corticopontocerebellar projections will be dealt with in another section (see p. 206), but there is no doubt that the cerebellum is influenced by corticofugal volleys arising "spontaneously" within the contralateral motor cortex.

2. RESPONSES TO SINGLE-SHOCK STIMULATION OF PERIPHERAL NERVE FIBERS a. LOCALIZATION OF THE RESPONSE Beck and Bikeles (1912b) were the first to report that in the curarized dog Bolk's lobulus medianus posterior (Larsell's lobules VII to X; lobule VIII is the pyramis) and (less intensively) the paramedian lobule (sublobules H Vllb, H Villa) became surface-negative following repetitive stimulation of the spinal nerves or vagi by induction shocks. They used a galvanometer, and it is likely that the slow potential drifts which were observed many years later by Arduini, Borazzo, and Brusa (1955; see below, p. 216), with d.c. amplifiers and cathode ray oscillographs, correspond to the responses recorded by the Polish investigators in their pioneer work. The fast cerebellar response evoked by single-shock stimulation of peripheral nerve fibers was first described by Dow (1939) in the decerebrate cat. The entire anterior lobe (Larsell's lobules I to V and H I to H V), lobulus simplex (lobules

Figure 54, Cerebellar responses to single-shock stimulation of the spinal nerves. Decerebrate cat. Records taken with bipolar needle electrodes, 1 mm. apart. The shaded area shows the responsive zones (anterior lobe, pyramis). Numbers of points and records correspond; taken from a single illustrative experiment. Record 2 from the pyramis shows a slight effect, considerably less than usual. (From R. S. Dow, 1939, Cerebellar action potentials in response to stimulation of various afferent connections, J. Neurophysiol., '2:543-555, Fig. 3, publ. Charles C. Thomas.)

Figure 55. The overlapping of afferent projections from various nerves of the four legs. Cat under barbiturate anesthesia. Symbols relate to cutaneous, articular, and muscular branches (for the hindlegs). Overlapping of afferent projections on the left side of the anterior lobe. (From F. Morin and B. Haddad, 1953, Afferent projections to the cerebellum and the spinal pathways involved, Am. J. Physiol., -Z72:497-510, Fig. 1.)

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ELECTROPHYSIOLOGICAL EXPERIMENTS 191 VI and H VI), pyramis (lobule VIII), and, occasionally, lobulus paramedianus (sublobules H Vllb, H Villa) showed clear-cut responses. Sciatic, saphenous, median, and ulnar nerves were stimulated, but no evidence of a somatotopic distribution of afferent projections was found within these areas, even when proprioceptive reverberation had been abolished by curare (Fig. 54). Although stronger ipsilaterally, responses to single-shock stimulation could be led from both sides. The same technique yielded similar results on nembutalized rats (Dow and Anderson, 1942) and monkeys (Dow, 1942), but in Macaco, midatta the evoked potentials of the anterior lobe were strictly limited to the vermis. Snider (1943) was also unable to find, with electrical stimulation of the major branches of the fifth nerve, the strict localization of the evoked potentials which occurs when natural stimuli are applied to the trigeminal area (see p. 185). Similar experiments performed on barbiturized cats (Morin and Haddad, 1953) and monkeys (Morin and Gardner, 1953) gave substantially identical results, as shown by the convergence of the impulses from the four limbs on the same area of the anterior lobe (Fig. 55). These conclusions did not remain unchallenged when other nerves were stimulated. Remarkably discrete projections were reported when the single shock was applied, in either barbiturized (Lam and Ogura, 1952; Haddad, 1953) or unanesthetized (Dell and Olson, 1951) cats, to a thin joint nerve (Haddad, 1953) or to laryngeal (Lam and Ogura, 1952) and vagal (Dell and Olson, 1951) fibers. Vagal responses were led from the neighborhood of the fissura prima (the lobulus simplex and caudal folia of the anterior lobe) and were correlated (Dell and Olson, 1951) with the effects upon circulatory and respiratory reflexes observed by Moruzzi (1938a, b; 1940a, b; see below, p. 291) following electrical stimulation of the anterior lobe. Stimulation of the most rapidly conducting fibers (25 to 30 meters per second) of the superior laryngeal nerve was followed by responses localized within a limited area of the lobulus ansiformis and lobulus paramedianus, at the border between the vermis and cerebellar hemispheres (Fig. 56). These findings were correlated (Lam and Ogura, 1952) with the speech disturbances observed in man as result of cerebellar deficiency (see p. 394). Summing up, the somatotopic arrangement of the evoked responses that had been observed consistently following natural stimuli of different kinds (Adrian, 1943; Snider and Stowell, 1944; see above, p. 184) was entirely missed—or at least was characterized by considerable overlapping—in most of the single-shock experiments reported above. It is true that the evoked responses were limited to discrete cerebellar areas when thin afferent nerves (Lam and Ogura, 1952; Haddad, 1953) or the vagus (Dell and Olson, 1951) was stimulated. But it cannot be denied that when many fibers projecting upon the cerebellar cortex are synchronously activated by a single electrical shock a widespread response is recorded. Undoubtedly the response evoked by cutaneous volleys is limited to the spinal projection areas of the cerebellar cortex (see Fig. 57), and the response to single-shock stimulation of afferent fibers cannot be designated as really "diffuse." A convergence of the impulses elicited by stimulation of different sensory modalities was occasionally shown, however, in the decerebrate cat under optimal functional conditions (carotids free). Acoustic impulses were then

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Figure 56. Cerebellar projections oj the superior laryngeal nerve. From experiments performed on barbiturized cats. The four stippled areas represent the loci of evoked potentials. A. Anterior lobe. B. Crus I lobuli ansiformis. C. Lobulus paramedianus. D. IV ventricle. E. Medulla. F. Crus II lobuli ansiformis. (From R. L. Lam and J. H. Ogura, 1952, An afferent representation of the larynx in the cerebellum, Laryngoscope, 62:486-495, Fig. 1.)

Figure 67. Absence of somatotopic localization within the spinal story of the cerebellar cortex. Decerebrate cat, under optimal conditions (carotids free). Monopolar recording from the cerebellar cortex. Single electrical shocks applied to one forefoot finger evoke a large response from lobule IV (upper records) and from lobule VI (A, lower record), but no effect is observed on lobule VII, only one folium behind the lobulus simplex (B, lower record). (Unpublished illustration, reproduced by courtesy of Professor F. Bremer.)

reported to reach even the tactile projection areas in lobules III, IV, and V (Bonnet and Bremer, 1951), and actually to influence the response of these areas to cutaneous stimulation (Bremer and Bonnet, 1951b; see below, pp. 216—217). Bremer and Bonnet (1951b) observed, moreover, interactions between tactile and vagal volleys (see Dell, 1952, pp. 486-487). These data obviously conflict with the hypothesis of strictly localized afferent projections onto the cerebellar cortex. Combs's work (1954) was entirely devoted to the problem of diffuse versus localized and somatotopically arranged projections of the afferent systems onto the cerebellar cortex. He confirmed that a somatotopic distribution of spinocerebellar projections was absent in the unanesthetized decerebrate cat. Responses were obtained from exactly the same area when either lumbar or thoracic

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Figure 58. Spinocerebellar projection areas in the unanesthetized decerebrate cat. The responses were elicited with dorsal root stimulation, but the same localization was found with single-shock stimulation of mixed nerves. Crossed lines indicate areas of greatest potentials. Within stippled zones small and inconstant responses were found. (From C. M. Combs, 1954, Electro-anatomical study of cerebellar localization. Stimulation of various afferents, J. Neurophysiol., 17:123-148, Fig. 2, publ. Charles C. Thomas.)

dorsal roots, hindlimb or forelimb nerves (Fig. 58), were stimulated with single electrical shocks. These findings were duplicated with natural stimuli, since the whole surface of the lobus anterior (LarselFs lobules I to V and H I to H V) and lobulus simplex (lobules VI and H VI) showed electrical changes following tactile stimulation of a limited skin area (e.g., left forepaw). As soon as the decerebrate cat was deeply anesthetized with nembutal, a somatotopic distribution was found. The response resulting from stimulation of the right saphenous nerve was then strictly limited to the posterior three folia of the lobulus centralis and the anterior two folia of the culmen on the right side (Fig. 59), whereas the potentials evoked by single-shock stimulation of the radial nerve were strictly confined to the posterolateral part of the ipsilateral culmen, namely, to a limited corner of the ipsilateral pars intermedia corresponding approximately to Larsell's lobules H IV and H V. It might be inferred from these experiments that the somatotopic distribution of cerebellipetal projections was simply concealed, in the unanesthetized preparation, by a spread of activity within the cerebellar cortex. Combs, however, felt he could dismiss this hypothesis, since the diffuse response yielded by singleshock stimulation of the left superficial radial nerve, in the unanesthetized decerebrate cat, was still present when the ipsilateral pars intermedia had been ablated to a depth of 6 millimeters, an operation which obviously destroyed the entire projection area, as mapped on the nembutalized preparation (see Fig. 60). From these experiments and from the additional fact that both the shape and the latencies of the cerebellar responses were modified by barbiturate anesthesia, Combs drew the following conclusions: "It seems probable that there is a double sensory representation in the cerebellar cortex, the more extensive one of these being made up of fibers from all parts of the body intermingling and terminating primarily in culmen, simplex and at least in the posterior folia of centralis. These are bilaterally represented with a slight preponderance for the ipsilateral projection. The second sensory projection is apparently arranged in a definite somatotopic manner with specific areas receiving, in addition to a diffuse projection, a localized afferent supply" (p. 140). Combs recalled the abundant anatomical evidence (see Jansen and Brodal, 1954, and Larsell, 1958, for references) showing that all known spinocerebellar

Figure 59. Spinocerebellar projection areas from the hindlimb in the nembutal anesthetized cat. Responses of the anterior lobe to stimulation of the right saphenous nerve. (From C. M. Combs, 1954, Electro-anatomical study of cerebellar localization. Stimulation of various afferents, J. Neurophysiol., 17:123-143, Fig. 9, publ. Charles C. Thomas.)

Figure 60. Spinocerebellar projection areas from the forelimbs in the unanesthetized cat. Responses of the anterior lobe to stimulation of the left superficial radial nerve, following ablation of the left intermediate part (cross lines). (From C. M. Combs, 1954, Electro-anatomical study of cerebellar localization. Stimulation of various afferents, J. Neurophysiol., 17:123-143, Fig. 11, publ. Charles C. Thomas.)

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ELECTROPHYSIOLOGICAL EXPERIMENTS 195 systems project diffusely onto the spinal story of the cerebellar cortex, the only exception being the ascending spinal fibers that go to the lateral reticular nucleus and thence to the cerebellar cortex (Brodal, 1943, 1949; Jansen and Brodal, 1954). "It would follow that Nembutal depresses the fibers or cells responsible for the unlocalized projection more than those which give somatotopic localization" (p. 140). Combs (1956) recently reported that he had been able to substantiate his hypothesis. He showed that the localized response to superficial radial nerve stimulation, occurring in the cat under nembutal anesthesia, was unaffected by lesions in the ventral spinocerebellar tract, external cuneate nuclei, or spinoolivocerebellar system; the evoked potential was completely eliminated, however, by destroying the ipsilateral lateral reticular nucleus. The main difficulty with Combs's explanation lies in its corollary, namely, that monosynaptic transmission through Flechsig's system should be depressed more heavily than conduction through spinoreticulocerebellar pathways. Moreover, Combs (1956) himself called attention to the fact that most of the spinoreticulocerebellar fibers project primarily to the vermian part of the anterior lobe (Brodal, 1943,1949) rather than to the intermediate part, where the localized forearm area is located. A tentative explanation of Combs's interesting observations (1954, 1956) will be given later (see p. 252). b. THE NATURE OF THE AFFERENT VOLLEYS YIELDING THE CEREBELLAR RESPONSE

Grundfest and Campbell (1942) are responsible for the first attempt to identify the origin of evoked cerebellar responses on the basis of latency measurements. From the ipsilateral rostral portion of the cat's vermis they led three responses to single-shock stimulation of the mixed tibial nerve, whose latency ranges lay respectively within 4 to 6, 8 to 10, and 13 to 17 milliseconds (Fig. 61). These were called respectively potentials I, II, and III (Carrea and Grundfest, 1954). Potential I had earlier been described by Dow (1939) and was also later described by Mountcastle, Covian, and Harrison (1952), Morin and Gardner (1953) and Carrea and Grundfest (1954), although most of these investigators reported that this short-latency response was fleeting and of low amplitude. Grundfest and Campbell (1942) pointed out that the early response was (a) absent following section of Flechsig's tract and (b) less easily depressed by cerebellar ischemia. It was regarded by all groups of investigators as due to the incoming Flechsig volley. It is difficult to relate potentials II and III to the responses described by the other investigators, since the latent times were often of a different order. Potential II was (a) absent following cutaneous nerve stimulation, (b) selectively abolished by cerebellar ischemia, and (c) only strongly reduced by severing Flechsig's tract. Grundfest and Campbell thought that it was due to an early response of the cerebellar neurons to the first proprioceptive volley. The late potential III, by far the largest wave (Fig. 61), was also abolished by cerebellar ischemia, but was present also following stimulation of a purely cutaneous nerve or section of Flechsig's tracts. Mountcastle, Covian, and Harrison (1952) confirmed, on decerebrate cats.

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Figure 61. Responses of the cerebellar cortex to single-shock stimtilation of the mixed tibialii nerve. The records were made with a needle just touching the surface of the ipsilateral rostral portion of the vermis, in the cat. The three surface-positive potentials are seen, but the dominant is the third, which occurs after 13-17 msec. (From H. Grundfest and B. Campbell, 1942, Origin, conduction and termination of impulses in the dorsal spino-cerebellar tracts of cats, J. Neurophysiol., 5:275-294, Fig. 16, publ. Charles C. Thomas.)

that potentials of short latency (4.8 to 5.8 milliseconds) were absent when a cutaneous nerve (the sural) was stimulated. They occurred instead following either (a) supramaximal stimulation of a mixed tibial nerve or (b) when single shocks of group I strength were applied to a purely muscular nerve. These earlier cerebellar potentials paralleled the large monosynaptic response led from the ventral roots. They were attributed to fast afferent volleys arising in group I fibers and activating, monosynaptically, either anterior horn cells or spinocerebellar neurons. Responses with longer latencies (18-19 and 24-26 msec.) were found only with supramaximal stimulation of both mixed and cutaneous nerves, but latencies of the order of 25 milliseconds were observed following supramaximal stimulation of a purely muscular nerve. These late potentials paralleled the polysynaptic discharge led from the ventral roots and were correlated with stimulation of group II and III fibers. Experiments performed on barbiturized cats (Morin and Haddad, 1953) and monkeys (Morin and Gardner, 1953) confirmed that no specific cerebellar areas exist for superficial and deep sensory projections. Unexpected findings reported by these investigators were (a) the lower threshold and shorter latency of the mixed and cutaneous nerves, which yielded also potentials of higher amplitude with respect to those evoked by stimulation of muscular branches, and (b) the absence of the short-latency (5 to 7 milliseconds) response following single-shock stimulation of purely muscular nerves. Morin and Gardner (1953) concluded that the cerebellar responses to deep nerve stimulation were due to activation of fibers of smaller diameter than those belonging to group I. Combs (1954) recorded identical responses following stimulation of purely muscular (deep radial) and purely cutaneous (superficial radial) nerves. Morin (1956) reported that the responses led monopolarly from the surface of the anterior lobe or of the paramedian lobule, following threshold stimulation of the radial nerve, consisted of, first, a low-amplitude, positive deflection (potential x), followed by a diphasic, plus-minus, wave (potential y). Potential x followed

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higher rates of stimulation, was less easily depressed by local cooling or by local application of anesthetics, and seemed to be related to the arrival of impulses to the granular layer. Potential y was affected by topical cooling and by local drugs, and was related to the postsynaptic activation of Purkinje neurons. Laporte, Lundberg, and Oscarsson (1956a) recorded from the dissected Flechsig's fasciculus, in the cat under nembutal anesthesia, a mass discharge yielded by single-shock stimulation of skin and muscle nerves. Both exteroceptive and proprioceptive volleys were found to be mediated, monosynaptically, by the dorsal spinocerebellar system. By leading from the surface of the rostral portion of the vermis, they were able to confirm the occurrence of the three components previously described by Grundfest and Campbell (1942). They stated that potential I was due to the stimulation of group I muscle afferents, while potentials II and III resulted from the stimulation of cutaneous nerves. After section of Flechsig's fasciculus potentials I and II disappeared, whereas potential III was not modified. C. PATHWAYS OF TRANSMISSION

The problem of the afferent pathways mediating the cerebellar response to single-shock stimulation of the peripheral nerves has been approached from two different angles, namely (a) the effects of partial transections of the spinal cord on the cerebellar response and (b) the responses of afferent cerebellar tracts and of precerebellar nuclei to nerve stimulation. While the first group of experiments remains entirely within the realm of cerebellar physiology, and therefore will be fully reviewed in this chapter, the second group of experiments involves mostly the physiology of the brain stem and hardly could be included within the narrow limits of our monograph. An exception will be made for the experiments in which leads were taken from the spinocerebellar tracts, since there is no doubt that the main task of these systems is to carry impulses to the cerebellar cortex. Grundfest and Campbell (1942) showed that stimulation of the peripheral nerve fibers evoked a complex response in Flechsig's tract. Impulses from different fibers were found to converge on the same groups of cells in Clarke's column, whose activation occurred after a synaptic delay of 0.5 to 0.9 milliseconds. The response to the hamstring nerve stimulation was blocked whenever it was timed to occur within 1 millisecond of the response to the peroneal nerve stimulation, and the reciprocal result was also observed. These conditioning effects also took the form of a summation of excitatory states and clearly indicate a high degree of complexity in the organization of Flechsig's tract. In experiments performed on decapitate or barbiturized cats Uoyd and Mclntyre (1950) showed that the large (22 to 13 microns), fast (about 110 meters per second) fibers arising in the hindlimb stretch receptors (group I fibers) conduct at much lower speeds within the dorsal columns. After giving off myotatic reflex collaterals to the motoneurons, they terminate in the upper lumbar and in the lower thoracic segments, where synaptic articulation with the cells of Clarke's column occurs. Through these spinal relays, stretch-evoked discharges would be monosynaptically transmitted to the cerebellar cortex. The authors, however,

198 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM limited to the spinal cord their analysis of the proprioceptive cerebellipetal volleys. Morin and Haddad (1953) and Haddad (1953) reported that neither the threshold nor the latency of the cerebellar response to stimulation of both the superficial and deep hindlimb nerves was modified following ipsilateral or bilateral transection of the dorsal spinocerebellar tracts and of the dorsal funiculi. These experiments were made on cats under nembutal anesthesia and showed (a) that afferent impulses could reach the anterior lobe through the ventral quadrants, and (b) that there is no basis for considering the dorsal and the ventral spinocerebellar tracts as functionally different (e.g., as either proprioceptive or exteroceptive pathways). When only one ventral quadrant was left, the ipsilateral response was not significantly altered and the contralateral one was strongly reduced but not abolished. These findings were explained by the existence in the ventral quadrants of crossed (ventral spinocerebellar and spinoolivocerebellar) and direct (spinoreticulocerebellar) fibers. That spinal crossing is followed by a second crossing at brain stem or cerebellar levels was shown by the fact that responses to stimulation of the left nerves could be led from the left anterior lobe, when only the right ventral tract remained intact. Here again the results of physiological investigations fit well with those obtained by the neuroanatomists, who showed that both ventral spinocerebellar (Beck, 1927) and spinoolivocerebellar (Brodal, Walberg, and Blackstad, 1950) tracts crossed twice. Only a few experiments were devoted to conduction from the forelimb and to transmission of impulses through the dorsal quadrants. Further experiments by Catalano (1955) showed that the cat's and the monkey's dorsal columns are available for the transmission of impulses from the skin, muscle, and joint nerves. Morin and Gardner (1953) came to similar conclusions in experiments performed on monkeys anesthetized with barbital, but showed that "the contralateral ventral quadrant is the more important part of the cord so far as the projection to the anterior lobe is concerned" (p. 158). Finally, by recording the responses of the paramedian lobule of the decerebrate cat to purely tactile stimulations, Morin and Lindner (1953) came to the same conclusions, since they were unable to find any evidence in support of the specificity of various afferent tracts. Bohm's (1953) experiments were concerned with the responses of the anterior lobe and paramedian lobules to single-shock stimulation of low-threshold cutaneous fibers. His findings confirmed those of Morin and Haddad (1953) in so far as the cerebellar response was found to be unaffected by transection of the dorsal columns. It was completely obliterated, however, by severing the anterior quadrants of the cord, and the conclusion was drawn that the cutaneous impulses ascend through the anterolateral part of the spinal cord, probably through the spinoreticulocerebellar system (Brodal, 1943, 1949; Jansen and Brodal, 1954). These conclusions are obviously at variance with those of Morin and Haddad (1953). The discrepancy might be eventually explained, since in Bohm's experiments (a) the cats were under deeper anesthesia (30 mg/Kg of nembutal intravenously instead of 20-25 mg/Kg intraperitoneally), and (b) only low-threshold cutaneous fibers were stimulated. It might be interesting to repeat Bohm's experiments in unanesthetized decerebrate cats and to check whether other types

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of responses are present when those from low-threshold cutaneous fibers are obliterated by severing the ventral quadrants. A major investigation on the ventral spinocerebellar tract was performed by Carrea and Grundfest (1954) on decerebrate cats and on monkeys under nembutal anesthesia. Stimulation of the mixed, deep, or superficial afferents from either hindlimb and either forelimb evoked responses in the ventral spinocerebellar fibers, which were led through microelectrodes at the level of the superior cerebellar peduncle. Here the tract is more concentrated and a somatotopic arrangement was found, the fibers that convey impulses from the hindlimbs being placed superficially in relation to those arising in the forelimb. When the contralateral hindlimb nerves were stimulated, the largest response began after 6 to 8 milliseconds and lasted about 30 milliseconds. Crossed forelimb responses were shorter both in latency (4 to 5 milliseconds) and duration (10 to 15 milliseconds). Afferents from different nerves were shown to converge onto the cells of origin of the ventral spinocerebellar tract, which would represent a final common path for both proprioceptive and exteroceptive impulses. Synaptic delays were longer than those occurring within the columns of Clarke (0.9 to 1.0 milliseconds). The origin and the pathways of transmission of the cerebellar response were further investigated. The evoked potentials were labeled I, II, and III according to their latent periods (see p. 195). When the electrical shock was applied to a cutaneous nerve in either forelimbs or hindlimbs, the latencies of potential I ranged respectively within 4 to 5 and 6 to 8 milliseconds. They were respectively 1 and 2 milliseconds shorter when a muscular nerve was stimulated. These latent periods were too short to be explained by a transmission through the inferior olive or the lateral reticular nuclei. Carrea and Grundfest (1954) stated that type I potentials were elicited by volleys traveling through the dorsal spinocerebellar tract when a muscular (deep) nerve was stimulated, and through the ventral spinocerebellar tract, when a cutaneous nerve was excited. Following the stimulation of superficial nerves, type I potentials were led from the whole vermis proper of the anterior lobe, with the exception of its anterior two folia, and from the ipsilateral hemispheral part of the culmen. These areas probably correspond to Larsell's lobules III, IV, V, H IV, and H V and were regarded by Carrea and Grundfest as the projection of the ventral spinocerebellar tracts. According to the authors, these projections would be somatotopically arranged even in the unanesthetized decerebrate cat (Fig. 62). The radial nerve yielded type I potentials within the whole vermian part and the ipsilateral intermediate part of the culmen (Larsell's lobules IV, V, H IV, and H V), whereas the saphenous nerve evoked early responses from the adjacent ventral folia of the culmen and the whole vermian lobulus centralis (lobules IV, III, H IV, H III). Hence "the areas for forelimb and hind-limb projections are contiguous, but do not overlap" (p. 225). The authors emphasized that a somatotopic arrangement could be found only by analyzing the distribution of the afferent impulses (potential I). Potential II was regarded by them as a relayed response initiated in the granular layer, while potential III was attributed to intrinsic cerebellar activity, which could be initiated by various cerebellipetal paths. Type III potentials, the largest of the cerebellar responses, were found over a much wider area.

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PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM Figure 62. Somatotopic localization of the early cerebellar response (potential I) to superficial nerve stimulation. Data representing four experiments on cats. Circles represent localization of type I potentials evoked by stimulation of the ipsilateral superficial radial nerve (latency 4-5 msec.). Diamonds indicate sites from which the early response was recorded, 6-8 msec, after stimulation of the ipsilateral saphenous nerve. (From R. M. E. Carrea and H. Grundfest, 1954, Electrophysiological studies of cerebellar inflow. I. Origin, conduction and termination of ventral spino-cerebellar tract in monkey and cat, J. Neurophysiol., 17:208-238, Fig. 14, publ. Charles C. Thomas.)

The discrepancy between the results obtained on unanesthetized decerebrate cats by Carrea and Grundfest (1954) and by Combs (1954) might be explained by the fact that type III potentials were utilized by the latter investigator for mapping the cerebellipetal projections. However, Carrea and Grundfest's interpretations meet with two difficulties, namely (a) that neuroanatomical investigation has shown no clear-cut evidence of somatotopic localization within the ventral spinocerebellar tract, and (b) that the early superficial responses might be mediated also by other afferent pathways. Jansen and Brodal (1954) have stressed the latter possibility: "Considering the numerous spino-cerebellar pathways available, one might, from an anatomist's point of view, feel inclined to suggest that one or more of these, in addition to the ventral spino-cerebellar tract, may be responsible for the localization observed by Carrea and Grundfest" (p. 95). Carrea and Grundfest (1954) had reported that the ventral spinocerebellar tract could be activated by single-shock stimulation of both cutaneous and muscular, ipsilateral as well as contralateral nerves. Oscarsson (1956) was unable to confirm their findings. He led the spinocerebellar discharge from the spinal cord, from the superior cerebellar peduncle, and from the anterior lobe, in cats under nembutal anesthesia. He maintained that a well-synchronized mass discharge of the ventral spinocerebellar tract occurred only on stimulation of contralateral muscle nerves. Hence he regarded the ventral spinocerebellar tract as completely or almost completely crossed. It is well known that the dorsal spinocerebellar tract is reported to be exclusively or almost exclusively uncrossed. He stated, moreover, that the ventral spinocerebellar tract conducted impulses arising mainly or exclusively from Golgi tendon organs, whereas the dorsal spinocerebellar tract had been shown by other experiments of the same group to be activated by both muscle spindles and tendon organs (see p. 218).

3. STIMULATION OF CEREBELLIPETAL PATHWAYS OR OF CENTRAL STRUCTURES PROJECTING ONTO THE CEREBELLUM a. SPINOCEREBELLAR SYSTEMS Single-shock stimulation of spinocerebellar tracts was performed in the cat by Dow (1939) and by Grundfest and Campbell (1942); the cerebellar response

ELECTROPHYSIOLOGICAL EXPERIMENTS 201 was led from the projection areas of the rostral vermis. Both groups of authors pointed out that the shortest latencies suggested extremely high conduction velocities, ranging between 100 and 140 meters per second (Grundfest and Campbell, 1942). These surprisingly high conduction rates were confirmed by Lloyd and Mclntyre (1950). Carrea and Grundfest (1954) stimulated the ventral spinocerebellar tract with single shocks at the level of the superior cerebellar peduncle, in the monkey under nembutal anesthesia. They led the orthodromic response from the cerebellar cortex and the antidromic potentials from the thoracic anterolateral column. The conduction velocity of the fastest fibers was only 74 meters per second. b. OLIVOCEREBELLAR AND RETICULOCEREBELLAR SYSTEMS

Dow (1939) recorded evoked potentials throughout the whole of the cerebellar cortex following single-shock stimulation of the inferior olive in the decerebrate cat. These bilateral but contralaterally stronger responses occurred after

Figure 68. Prolonged subnormaUty following the cerebellar response to olivary stimulation. Midsagittal section of the cat's cerebellum showing the position of reticular (Si) and olivary (82) stimuli and a folial pattern showing the position of the leads La and La. a, b, c. Stimulus Si in dorsal reticular formation and lead Li on ventral part of the culmen. Responses surface-positive, a. Conditioning alone, b. Testing alone, c. Both. Note that the inhibition of the second response is very slight. d. Stimulus Si and lead L2 on the lobulus ansiformis. Note the absence of response, e, j, g. Stimulus Sa in inferior olivary nuclei, lead Li. Responses now surface-negative, e. Conditioning alone. /. Testing alone, g. Both. Note marked reduction in the test response, h, i, j. Stimulus S2, lead La. Same experiments as in e, f, g. Note the almost complete abolition of the test response by a conditioning shock occurring 65 msec, before the test.—Decerebrate cat. Unipolar leads, with wick macroelectrodes. (From R. S. Dow, 1989, Cerebellar action potentials in response to stimulation of various afferent connections, J. Neurophysiol., #: 543-555, Fig. 7, publ. Charles C. Thomas.)

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a latency of about 5 milliseconds and were usually surface-negative, though often preceded by a surface-positive oscillation. The olivary responses could be easily separated from those elicited in the same cerebellar areas by stimulating the medulla only a few millimeters dorsally, within the reticular formation. Besides the differences in both shape and size, the olivary responses were followed by an extremely prolonged subnormality period (up to 5 seconds), which actually brought about complete suppression of the test potential when the conditioning shock had been timed to occur 65 milliseconds earlier (Fig. 63). Schoepfle's experiments (1949) were performed on dogs, and the potentials were led with unipolar microelectrodes from the different cerebellar layers. The postsynaptic responses to single-shock stimulation of olivocerebellar fibers appeared as predominantly positive when the electrode was within the molecular layer; they were predominantly negative instead when the recording electrode was in the Purkinje or granular layer. C. VESTIBULOCEREBELLAR SYSTEM

The cerebellar responses elicited by single shocks applied to the eighth nerve belong, from an anatomical standpoint, to the potentials evoked by stimulating peripheral nerve fibers. They are described in the present chapter because of the close relation between the cerebellum and the vestibular apparatus. Dow (1939) led the evoked potentials from the flocculonodular lobe, the uvula (lobule IX), the lingula (lobule I), and the fastigial nucleus (Fig. 64). The latency was of the order of 4.5 milliseconds, but in one experiment a response was led from the fastigial nucleus after only 0.6 millisecond and was ascribed to the primary vestibular fibers observed by Ingvar (1918) and by Dow (1936). The close correspondence between anatomical and physiological projections shows that these potentials were due to stimulation of the labyrinthine component of the eighth nerve. d. PONTOCEREBELLAR SYSTEM

Dow (1939) applied single condenser discharges to the pons of the decerebrate cat and led the evoked potentials from the lobulus ansiformis (sublobule H Vila), paraflocculus (lobules H Vlllb, HIX), lobulus paramedianus (sublobules H Vllb, H Villa), and the declive and tuber vermis (lobules VI, VII). Responses were led also from spinocerebellar projection areas, such as the culmen (lobules IV, V, and H IV, H V), lobulus simplex (lobules VI and H VI), and pyramis (lobule VIII), but they were of lower amplitude (Fig. 65). Moreover, the same data hinted that anterior lobe responses were obtained only from the most posterior part of the pons. These electrophysiological data accord very nicely with those obtained by anatomical methods (Brodal and Jansen, 1943, 1946; see Jansen and Brodal, 1954). C. MIDBRAIN STIMULATION

Snider (1945) reported that potentials could be led from the tuber vermis and lobulus simplex (Larsell's lobules VII, VI, and H VI) 10 to 16 milliseconds after single-shock stimulation of the dorsal surface of the superior colliculi, in the cat

Figure 64. The responses of the cat's cerebellum to stimulation of the eighth nerve. Decerebrate cat. The shaded area is that in which the responses to stimulation of the eighth nerve (single condenser discharges) were found. Oscillographic records taken with bipolar needle electrodes with bared tips, 1 mm. apart, dec. and tub. = declive and tuber vermis; 1. cent. = lobulus centralis; 1. cul. = culmen; 1. simp. = lobulus simplex; ling. = lingula; nod. = nodulus; nu. fast. = fastigial nucleus; nu. inf. ol. rz inferior olivary nuclei; pyr. = pyramis; uv. = uvula. (From R. S. Dow, 1939, Cerebellar action potentials in response to stimulation of various afferent connections, J. Neurophysiol., 2:543-555, Fig. 1, publ. Charles C. Thomas.)

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Figure 65. Cerebellar responses to pontine stimulation. A schematic diagram of the folial pattern of the cat's cerebellum. Localization of the responses to single-shock stimulation of the pons, led in the decerebrate cat with a unipolar wick electrode. The shaded area indicates the lobes responding to pontine stimulation, and the intensity of the shading furnishes a rough index of the relative amplitude of the evoked potentials. The numbers of the points and records correspond. Note that almost the whole of the exposable cortex shows a response to pontine stimulation. (From R. S. Dow, 1939, Cerebellar action potentials in response to stimulation of various afferent connections, J. Neurophysiol., 2:543-555, Fig. 5, publ. Charles C. Thomas.)

under barbital anesthesia. Snider and Stowell (1944) had previously suggested that the visual responses which are found in the same cerebellar areas (see p. 186) might be mediated by the tectocerebellar tract. f. STIMULATION OF THE CEREBRAL CORTEX

Beck and Bikeles (1912b) were the first to utilize this approach to cerebellar physiology. They reported that the surface of the lobulus paramedianus (sublobules H VHb, H VIHa) and of crus II (sublobule H Vila) of the curarized dog became surface-negative during thermal stimulation of the contralateral motor cortex. Ipsilateral effects were present but were less marked, while the potential drift of Bolk's lobulus medianus posterior (LarselPs lobules VII to X) was either

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absent or very small. Stimulations of cortical areas localized caudally to the motor cortex were ineffective. Only after about thirty years were electrophysiological investigations on cerebrocerebellar projections resumed. Curtis (1940) reported that evoked potentials could be led, in the cat under barbiturate anesthesia, from the hemispheral cortex and from the posterior part of the anterior lobe, but not from the declive and tuber (lobules VI, VII), following single-shock stimulation of many cerebrocortical areas, such as the sigmoid gyrus, medial suprasylvian and ectosylvian gyri, and gyrus marginalis. A single cortical point yielded widespread and bilateral (although contralaterally stronger) cerebellar responses. The cerebellar potentials were characterized by a surface-positive wave, with a latency of 25 milliseconds, and were followed after much longer latent periods (200 milliseconds) by a second surface-positive oscillation. The local negativity following the surfacepositive deflection was strongly increased by local picrotoxin. In the following year Gualtierotti and Capraro (1941) stated that synchronously with the strychnine waves of the motor cortex, potential oscillations could be led from both cerebellar hemispheres of the cat. The areas from which leads were taken were not reported. The effects could not be explained by exteroceptive or proprioceptive reverberations elicited by clonic twitches, at least in those experiments performed after cervical transection of the spinal cord. Dow's experiments (1942) were performed on nembutalized cats and monkeys. The cat experiments confirmed Curtis's observations about the possibility of leading responses from widely scattered parts of the cerebellar surface following stimulation of a single point on the cerebral cortex. Evoked potentials were led from "all the folia which may be exposed on the surface of the cerebellum of the cat except the uvula" (Dow, 1942, p. 122) when single condenser discharges were applied to the sigmoid, coronal, lateral, suprasylvian, ectosylvian, and sylvian gyri. The major deflection occurred after 25 milliseconds, was usually surfacepositive, and could be either extinguished or facilitated by a previous conditioning shock applied to another point of the motor area (Fig. 66). These conditioning effects were prevented by cocainizing the cortical area to which the first stimulus was applied (Fig. 66). They could not be explained, therefore, by a sheer spread of currents, but rather indicated the existence of intracortical connections or the convergence of corticofugal impulses arising in different cerebral areas on some common structure of the corticocerebellar system. The later response, occurring after 200 milliseconds (Curtis, 1940), was only inconstantly observed. A much earlier potential (3 milliseconds) was evoked when the strength of the shock was increased to several times the threshold. In the monkey a predominance of representation from certain areas to certain cerebellar lobes could be observed. Area 4 and the postcentral gyrus appeared to have their richest projections in the vermian and paravermian lobes, while areas 4s and 6 (and also 7, 18, and 22) were predominantly connected with the lobulus ansiformis. Responses could be obtained from the postcentral gyrus and the frontal association areas following acute ablation of areas 4 and 6, an important finding indicating that these regions have their own corticopontine connections. Finally "an invasion by cortico-ponto-cerebellar fibers of vermian lobes" (Dow, 1942, p. 134) was shown

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Figure 66. Conditioning effects between cerebellar responses to single-shock stimulation of two different points within the motor cortex. Nembutalized cat. The conditioning shock was applied to the hindlimb area (1) and the testing shock to the forelimb area (2) of the left cerebral hemisphere (B), while the response was led from point 1 on the right lobulus paramedianus (A). C and D. Conditioning and testing response alone. E. Almost complete elimination of the testing response 32 msec, after the conditioning shock (32 msec, interval). The cocainization of point 1 (5 per cent, 5 min.) obliterated the conditioning response (F) and abolished the conditioning effect (H), but the testing response elicited from point 2 was unaffected (G). (From R. S. Dow, 1942, Cerebellar action potentials in response to stimulation of the cerebral cortex in monkeys and cats, J. Neurophysiol., 5:121-136, Fig. 2, publ. Charles C. Thomas.)

to characterize the corticocerebellar projections in primates. These results are in full agreement with the anatomical investigations performed by Nyby and Jansen (1951). Adrian (1943) confirmed that the primate vermis is heavily impinged upon by corticofugal volleys, and pointed out that an extensive overlapping occurs between spinocerebellar and corticocerebellar projection areas, the latter extending simply more laterally in the cerebellar hemisphere. He showed that afferent volleys reached the cerebellar cortex during different types of cortical stimulation, namely (a) strong electrical stimulation of area 4 yielding an epileptiform afterdischarge or (b) local applications of strychnine or picrotoxin to the same cortical area. Adrian reported that in the monkey under barbiturate anesthesia the corticocerebellar projections showed a clear-cut somatotopic disposition (Fig. 67). "The lobulus centralis was found to be connected with the hind-limb region

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Figure 67. Somatotopic arrangement of corti-* cocerebellar projections in the barbiturized monkey. The lobulus centralis is connected with the hindlimb region of the opposite motor cortex, the culmen with the forelimb regions, and the lobulus simplex with the face region. Note that both the vermal and the hemispheral parts of the anterior lobe and of the lobulus simplex are projected upon. (From E. D. Adrian, 1943, Afferent areas in the cerebellum connected with the limbs, Brain, 66:289-315, Fig. 13.)

Figure 68. Distribution of the cerebellar potentials evoked by stimulation of the cortical auditory areas. Cat under sodium pentobarbital anesthesia. Potentials were recorded within the folium and tuber vermis following stimulation of auditory areas I (A} and II (B). (From J. L. Hampson, 1949, Relationships between cat cerebral and cerebellar cortices, J. Neurophysiol, 12:37-50, Fig. 2, publ. Charles C. Thomas.)

of the opposite motor cortex, the culmen with the forelimb region and the lobulus simplex with the face region" (p. 300). Hence the lobus anterior and lobulus simplex showed the same somatotopic arrangement when either sensory receptors or the motor cortex was stimulated. Control experiments showed that the cerebellar responses to cortical stimulation were not due to the reverberation elicited by clonic twitches, since both phenomena could be dissociated in different ways. Hampson's experiments (1948, 1949) were mainly concerned with the cere-

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bellar projections of sensory cerebrocortical areas (see also Hampson, Harrison, and Woolsey, 1952). The cerebral cortex of cats under light barbiturate anesthesia was stimulated with condenser discharges. Evoked potentials with latencies of 6 and 21 milliseconds were found, bilaterally, only in the folium and tuber vermis (lobule VII), i.e., in the cerebellar areas responding to acoustic and visual stimulations, when the single shock was applied to either auditory area I or II (Fig. 68). Somatic area I, the homologue of the postcentral gyrus of primates, was reported to project onto the anterior lobe and lobulus simplex. Monophasic or diphasic responses with latencies of the order of 8 milliseconds were found, contralaterally, (a) in both the lobulus simplex and upper culmen, (b) in the culmen, and (c) in the lower culmen and upper centralis when the stimulation was localized respectively within face, foreleg, and hindleg cortical areas (Fig. 69). Here again there was a good agreement between the somatotopic distribution within the cerebellar cortex of cerebral and sensory projections. Adrian's somatic sensory area II (1941), lying in the anterior ectosylvian gyrus, evoked potentials after 2 and 28 milliseconds in the contralateral paramedian lobule, and some-

Figure 69. Cerebellar responses to stimulation of various portions oj cerebral somatic area I. Cat under sodium pentobarbital anesthesia. Projections of somatic I areas for the face (A), forearm (B), trunk (C), and hindlimb (D) in the contralateral anterior lobe and lobulus simplex. (From J. L. Hampson, 1949, Relationships between cat cerebral and cerebellar cortices, J. Neurophysiol., 1$: 37-50, Fig. 5, publ. Charles C. Thomas.)

Figure 70. A composite drawing showing cerebellar projections of the cortical areas belonging to the medial wall. Experiments on anesthetized cat. The entire surface was explored, and these were the only areas consistently active. The anterior zone corresponds to the autonomic areas whose cerebellar projections were investigated by Hampson (1949). (From R. S. Snider and E. Eldred, 1951, Electro-anatomical studied on cerebro-cerebellar connections in the cat, J. Comp. Neurol., 95:1-16; from the original of Fig. 6.)

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times also in the tuber vermis (lobule VII) and the pyramis (lobule VIII). Somatotopic relationships were found, however, only for threshold stimuli. Finally an area on the medial wall of the cerebral cortex, yielding autonomic effects such as mydriasis, retraction of the nictating membrane, and exophthalmos (Siebens and Woolsey, 1946), was reported to project onto the lobulus ansiformis, but also onto the lateral part of the lobulus anterior and lobulus simplex and onto the most rostral folia of the lobulus paramedianus. This last group of findings was correlated with stimulation experiments suggesting an autonomic function of the cerebellar cortex (see p. 292). Snider and Eldred (1948, 1951) came to similar conclusions with experiments performed on cats, under different types of anesthesia. The only discrepancy was represented by the fact that somatic area I projected also onto the paramedian lobules, while the results of stimulating somatic area II were controversial. The authors also explored the cerebellar projections of the medial wall of the cerebral hemisphere; their results are represented in Figure 70. They emphasized that Hampson's autonomic cortical area (1949) projected mainly upon the medial folia of crus I and crus II. Snider and Eldred (1952) carried out a similar group of experiments on curarized monkeys, under local anesthesia. Area-to-area localizations were found only within the contralateral part of the lobus anterior and lobulus simplex and within both paramedian lobules, when either precentral or postcentral gyri were stimulated with single shocks. A summarizing diagram is reproduced in Figure 71, but it should be emphasized (a) that it was only with threshold stimuli that somatotopic localizations were detected; (b) that there was a considerable overlap between leg, arm, and face areas; and (c) that the response of the ipsilateral paramedian lobule was most variable. Auditory and visual cortical areas evoked responses from essentially the same cerebellar lobules (the midpart of the lobulus simplex and the folium and tuber vermis, Larsell's lobules VI and VIE). A complete chart giving the corticocerebellar projections found in these studies is given in Figure 72. Jansen, Jr., (1956) recorded the responses of the cerebellar hemispheres to single-shock stimulation of the cerebral cortex. In the cat under nembutalchloralose anesthesia two types of evoked potentials were described, namely (a) short-latency potentials (2 to 5 milliseconds), most readily elicited from somatosensory area II, and (b) long-latency potentials (12 to 25 milliseconds), most typically obtained by stimulating somatosensory area I. The long-latency responses were less resistant to asphyxia, were followed by longer "unresponsive times" (up to 150 milliseconds, whereas periods shorter than 20 milliseconds were observed after the short-latency responses), and were more strongly blocked by a conditioning shock applied to peripheral nerve fibers. The short-latency deflection had a prolonged (up to 150 milliseconds) depressing effect on the long-latency potential, whereas the short-latency activity was hardly influenced by a conditioning long-latency potential. Both responses were mediated by the pontine nuclei. The short-latency potentials were attributed to the activation of granule cells, while the long-latency potentials were suggested to involve the discharge of the Purkinje neurons.

Figure 71. A summarizing diagram, of the projections from the precentral and postcentral cerebral gyri to various cerebellar areas. Macaca mulatta under chloralose plus nembutal anesthesia. Area-toarea projections were found for the contralateral anterior lobe and lobulus simplex and for the contralateral lobulus paramedianus. Data suggesting projection from the same cortical areas onto the ipsilateral lobulus paramedianus were also found. (Redrawn from R. S. Snider and E. Eldred, 1952, Cerebro-cerebellar relationships in the monkey, J. Neurophysiol., 15:27-40, Fig. 15, publ. Charles C. Thomas.)

Figure 12. A summarizing diagram of the cerebral projections from somatic sensory, somatic motor, auditory, and visual areas to various cerebellar areas in the monkey. Note that cerebral somatic sensorimotor areas project onto the contralateral anterior lobe and lobulus simplex cerebellar areas and to paramedian lobules bilaterally, and that there are definite leg, arm, and face regions within these areas. Note also that the cerebral auditory and visual areas project onto an area of the cerebellum which is different from, but overlaps, the sensorimotor receiving areas. (Redrawn from R. S. Snider and E. Eldred, 1952, Cerebro-cerebellar relationships in the monkey, J. Neurophysiol., 15:27-40, Fig. 4, publ. Charles C. Thomas.)

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g. STIMULATION OF THE CAUDATE NUCLEUS

With single-pulse stimulation of the head and the body of the caudate nucleus, Coxe and Snider (1956) found, in curarized cats, that the best responses were led from crus I and crus II (sublobule H Vila) and from the tuber vermis (lobule VII). The evoked wave showed two peaks, one at approximately 5 milliseconds and the other at 12 to 15 milliseconds. These findings fit well the anatomical data of Walberg (1954), who showed that crus I is played upon by the caudate nucleus, through the inferior olive. h. STIMULATION OF THE OLFACTORY BULBS

Working on curarized or "encephale isole" cats, Hugelin, Bonvallet, David, and Dell (1952) recorded responses to stimulation of both olfactory bulbs near the fissura prima, i.e., in the cerebellar folia projected upon by tactile (face) and by vagal impulses (Snider and Stowell, 1944; Dell and Olson, 1951). 4. GENERAL PATTERNS OF THE AFFERENT CEREBELLAR RESPONSE a. POLARITY OF THE EVOKED RESPONSE The typical cerebellar response to an afferent stimulation is represented by a surface-positive wave followed by a surface-negative potential oscillation, which is generally slower, smaller in amplitude, and less resistant to anesthetics and every kind of depressant agent. This is apparently the reason why only surfacepositive waves were observed in most of the experiments performed under barbiturate anesthesia. The experiments of Bonnet and Bremer (1951) and Bremer and Bonnet (1951a, 1953; see Bremer, 1952a, c) were performed on unanesthetized decerebrate cats, with both common carotids undamped. Hence the general and local conditions were optimal, and the surface-negative phase of the response was constantly observed. It was strongly increased by temporal summation of two afferent volleys (Fig. 73B) and by local strychninization (0.1 per cent) (Fig. 73E) and more or less selectively depressed by general anesthesia, by anoxia, and by the local application of nembutal (6 per cent) (Fig. 737). The surface-negative potential was attributed to the synchronous efferent discharge of the Purkinje cells, while the surface-positive wave was regarded as a postsynaptic response arising in the internuncial neurons of the granular layer. Bremer and Gernandt (1954) investigated the response to click stimulation in the decerebrate cat by leading simultaneously from the same folium with a conventional wick electrode placed on the cerebellar surface and with a microelectrode introduced at different depths. Their results suggested that a synchronous discharge of the Purkinje cells occurred 4 to 8 milliseconds after "the onset of the positive deflection signalling the arrival of the fastest afferent impulse." This reflexly induced discharge was selectively increased by local strychnine and reversibly depressed by asphyxia and by depressant drugs applied locally to the surface of the explored folium. b. THE EFFECTS ON SPONTANEOUS ELECTRICAL ACTIVITY

The large potential oscillations evoked by afferent volleys are followed by marked changes in the spontaneous activity of the cerebellar cortex. They are

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Figure 73. The influence of temporal summation, of local strychnine, and local nembutal on the sensory responses of the cerebellar cortex. Deoerebrate cat. Cerebellar (upper record) and collicular (lower records) responses to acoustic clicks (arrows). The cerebellar records were led from the folium vermis (lobule VII) in A, B and D, E (different experiments) and from the lobulus simplex (lobule VI) in I, J (another experiment, no collicular record). A, B. Increase in the negative component of the cerebellar response, by temporal summation, when a sequence of two clicks (interval of 20 msec.) is applied (B). D, E. Responses to a single click before (D) and some minutes after the application of 0.1 per cent strychnine to the cerebellar cortex (E). Note that only the surface-negative component of the cerebellar response is increased. I, J. Another experiment. The strong surface-negative response of the strychninized lobule VI to a single electrical shock applied to the nose skin (/) is reversed in polarity by 1-minute application of 6 per cent nembutal to the cerebellar area led from (/). (From F. Bremer and V. Bonnet, 1953, Action de la strychnine sur les reponses sensorielles et sur les potentiels electriques spontanes de 1'ecorce cerebelleuse. L'activite convulsive du cervelet, Fol. Psych. Neurol. et Neurochir. Neerl., 56:438-146, Fig. 1. The arrangement of the original illustration has been modified by courteous permission of the authors.)

observed at their best when experiments are performed on unanesthetized preparations. Adrian (1943) reported that natural stimuli of different kinds increased both the amplitude and the frequency (from 180/sec up to 300/sec) of the fast cerebellar waves, in the unanesthetized decerebrate cat (Fig. 74). The effect was most marked when the background of spontaneous activity was not too strong, and it was easily fatigued upon repetition of the stimulus. The increase in the spontaneous electrical activity was never strictly localized, even when proprioceptive reverberation had been prevented by curare; the effect was simply more pronounced in the appropriate region, but the response became strictly localized only

Figure 74. The effect oj natural stimulations on the spontaneous activity of the cerebellar cortex. A. UnanesthetLzed decerebrate cat. Record from posterior part of the oilmen upon pressing the forefoot. The frequency rises to 240/sec. B. Another preparation. The frequency rises from 180/sec. to 220/sec. (From E. D. Adrian, 1943, Afferent areas in the cerebellum connected with the limbs, Brain, 66:289-315, Fig. 20.)

Figure 76. Extrinsic and intrinsic cerebellar responses to sensory stimulation. Microelectrode records in the decerebrate cat. A. Wire electrode in the corpus restiformis. Brief passive flexion of the left forelimb at the elbow signaled by white bars. Responses shown are the last two of a series of 27 responses hi 40 sec. B. 7-micron micropipette in the white matter of the right anterior lobe. The signal indicates touch and proprioceptive stimulation of the right forepaw. These are the seventh and eighth responses in a period of 18 sec. C. 20-micron wire in the gray matter of the right anterior lobe. The signal indicates touch and proprioceptive stimulation of the right forepaw. Shown are the eighth to twelfth responses in a period of 16 sec. D, E. 7-micron micropipette in the cortex of the right anterior lobe. Tactile and proprioceptive stimulation of the right forefoot at the signals. D is the first and E is the sixth of a series elicited in a period of 46 seconds. Note the afterdischarge and fatigability evident here as compared to the responses in A, B, and C. (From J. M. Brookhart, G. Moruzzi, and R. S. Snider, 1950, Spike discharges of single units in the cerebellar cortex, J. Neurophysiol., 13:465-486, Fig. 9, publ. Charles C. Thomas.)

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when nembutal was injected. Adrian thought that "an afferent discharge produces an increased activity in the cerebellar cortex, which is greatest at the point of arrival but spreads out some distance from it" (p. 311). Yoshii and Ito (1954) reported that the amplitude of spontaneous fast activity was markedly increased in the vermis of both the cat and rat, under urethane and cyclopropane anesthesia, when the hindlegs were flexed passively. The modification of the spontaneous electrical activity of the cerebellar cortex under the impact of afferent volleys is probably the result of many factors, namely (a) presynaptic impulses arriving through extrinsic mossy and climbing fibers; (b) postsynaptic activation of internuncial neurons of the granular and molecular layers; (c) a reflex discharge of the cerebellar final common path, the Purkinje neuron. So far microelectrode experiments have been concerned mainly with the problems of discriminating between extrinsic (presynaptic) and intrinsic (postsynaptic) spike discharges. The results of a microelectrode analysis of the spontaneous activity of the cerebellar cortex have been reported in another section (see pp. 164-173). Brookhart, Moruzzi, and Snider (1950) led with a microwire both spontaneous and reflexly evoked spike discharges from (a) the restiform body, (b) the white matter, and (c) the cortex of the cerebellum (Fig. 75). In the decerebrate cat presynaptic spike discharges were led from afferent units of the restiform body (Fig. 75A) and sometimes, probably, from the cerebellar cortex itself (Fig. 755, C). They appeared comparatively free from manifestations of fatigue and afterdischarge. Quite different patterns of evoked spike activity were led occasionally from the cerebellar cortex (Fig. 75D, E). They were characterized by a prolonged afterdischarge (Fig. 75D), which was easily fatigued upon repetitive stimulation. These afferent responses were strongly increased by local strychnine (Fig. 76) and therefore were attributed to postsynaptic activation of intrinsic cerebellar neurons. Sometimes a highly localized inhibition of the spontaneous spike discharge was elicited by strong sensory stimuli (Fig. 77). This effect was observed on the anterior lobe, but could be elicited from all limbs, without any sign of somatotopic localization; moreover a reflex blockade of spontaneous activity was found also on crus I, i.e., in an area quite outside the spinal projection area of the cerebellar cortex. That the suppression of the spontaneous discharge could not be explained by a sudden fall of the blood pressure was shown by the fact that it was missed in neighboring cerebellar areas. A displacement of the floating microwire to an inactive locus was unlikely on technical grounds and was disproved by the sudden reappearance of the same patterns of electrical activity when the stimulation was over (Fig. 77). Hence we are confronted here with the only examples of a pure inhibition of spontaneous cerebellar activity elicited by sensory stimulation. Both an increase in and a blockade of the cerebellar spike discharge were also elicited in the paramedian lobule of chloralosed cats by a single shock applied to the contralateral motor cortex. Bremer and Bonnet (1953; see also Bremer, 1952a, c) confirmed Adrian (1943) on the effects of sensory stimulation on spontaneous cerebellar activity in the decerebrate cat. Sometimes the afterdischarge lasted several seconds and

Figure 76. The effect of local strychnine on sensory-evoked cerebellar spike discharges. Decerebrate cat; microwire in the anterior lobe. A. Normal response to light tactile stimulation of the forepaw at the signal. B. Response to similar stimulation 6 min. after local strychninization. C. Response to similar stimulation 11 min. after local strychnine. See repetitive convulsive outbursts during the afterdischarge. (From J. M. Brookhart, G. Moruzzi, and R. S. Snider, 1950, Spike discharges of single units in the cerebellar cortex, J. Neurophysiol., 15:465-486, Fig. 10, publ. Charles C. Thomas.)

Figure 77. The inhibition of the spontaneous spike discharges of the cerebellar cortex elicited by sensory stimulation. Decerebrate cats. Microwire in the anterior lobe (^4); in another preparation, micropipette in two different positions of crus I. The inhibition of the spontaneous spike discharge was elicited by deep-pressure stimulation of the ipsilateral gastrocnemius muscles. (From J. M. Brookhart, G. Moruzzi, and R. S. Snider, 1950, Spike discharges of single units in the cerebellar cortex, J. Neurophysiol., 15:465-486, Fig. 12, publ. Charles C. Thomas.)

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was represented by a sequence of synchronous convulsive waves, similar to those elicited by direct electrical stimulation. Bremer and Bonnet (1953) showed that this convulsive afterdischarge was blocked by a second sensory volley, an effect which they compared to the sensory "arousal" of the cerebral cortex. C. SLOW POTENTIAL CHANGES ELICITED BY SENSORY VOLLEYS

The slow components of the cerebellar response to single-shock stimulation of peripheral nerve fibers were recorded by Arduini, Borazzo, and Brusa (1955) with d.c. amplifiers and a cathode ray oscilloscope. With unipolar wick electrodes these investigators led responses from the vermal part of the culmen (Larsell's lobules IV and V) following rectangular pulse stimulation of either a deep or superficial branch of the radial nerve. The cat was decerebrated without clamping the vertebral arteries and with only temporary occlusion (less than 10 minutes) of both common carotids. The surface-positive oscillations were similar to those recorded with a.c. amplifiers, but the late surface-negative wave appeared as a slowly decreasing negativity, which lasted from 1 to 3 seconds. Summation of these residual negatives occurred even when the test shock was delivered after an interval of less than 10 milliseconds, although the second response was reduced (for intervals of less than 200 milliseconds) and practically abolished (intervals of less than 10 milliseconds) when the records were taken with the usual a.c. amplifiers. These lasting negativities were enhanced by local strychnine and depressed by local nembutal, as was the surface-negative wave of Bonnet and Bremer (1951) and Bremer and Bonnet (1951a). After local nembutal the longlasting potential was reversed in polarity. Occasionally the fast surface-positive waves were followed by a long-lasting residual positivity, which also presented the phenomenon of temporal summation. d. INTERACTIONS BETWEEN AFFERENT RESPONSES

The occurrence of interactions between afferent cerebellipetal responses has already been reported (Dow, 1942; Grundfest and Campbell, 1942; Carrea and Grundfest, 1954), and it was pointed out that a convergence of impulses of different origin occurs at precerebellar levels (see pp. 197—200). In recent years this problem has been thoroughly investigated by Bonnet and Bremer (1951), Bremer and Bonnet (1951b; see also Bremer, 1952b, c), and Albe-Fessard and Szabo (1954). Bonnet and Bremer (1951) and Bremer and Bonnet (1951b) reported that when a conditioning volley was followed by a test volley coming from another afferent pathway, the second response could be (a) entirely blocked (zero interval: occlusion); (b) increased by temporal summation (small intervals); and (c) decreased by the subnormality period following the first volley (intervals of the order of 20 milliseconds). Working on decerebrate cats, Bremer and Bonnet showed that interactions occurred not only between the cutaneous nerves and sensory fibers from the muscles of the same limb, but also between forelimb and hindlimb cutaneous stimulations as well as between forelimb and facial stimulations. A convergence was shown, moreover, between impulses elicited by facial or forelimb cutaneous stimulations and vagal or acoustic volleys impinging upon

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the cerebellum. They pointed out that at least the interactions between cutaneous and acoustic stimulations could hardly be explained as the result of a convergence of afferent impulses upon the same group of precerebellar neurons. The most likely explanation was that tactile and acoustic volleys interacted because they converged on common or at least on closely related structures of the cerebellar cortex. Albe-Fessard and Szabo (1954) led an evoked response from the surface of the paramedian lobule of cats under light nembutal anesthesia. The single shocks were applied either (a) to forelimb and hindlimb nerves or (b) to the motor cortex and to the point of sensory cortices S I and S II giving the best response when the corresponding nerve was stimulated. In the double-shock experiments the conditioning stimulus was applied to the nerve and the test shock to the cortex, or vice versa, the same result being obtained throughout. The same type of experiment was repeated by leading, with intracellular ultramicroelectrodes, the response from single Purkinje cells. Albe-Fessard and Szabo (1955) showed that these neurons discharged during the surface-positive potential elicited by the afferent volley, thereby confirming the results of Buser and Rougeul (1954a, b; see above, p. 160). The Purkinje neurons died from a few seconds to 1 to 2 minutes following the penetration of the tip of the hyperfine (0.5 to 1 micron) micropipette within their somata, and because of the extreme lability of these cells the problem of the interrelations between different volleys impinging upon the same area of the cerebellar cortex was approached mainly by leading from the cerebellar surface. The results obtained by Szabo and Albe-Fessard (1954) by macroelectrode recording are summarized below. Szabo and Albe-Fessard (1954) reported the remarkable observation that areas responding exclusively (/? points) or predominantly (a points) to ipsilateral stimulation of either hindleg or foreleg nerves, as well as areas responding to stimulation of all four legs (y points), could be localized and isolated on the paramedian surface. The points localized within folia 1 and 2 (YI and y2) yielded stronger responses when an ipsilateral nerve was stimulated; but when the lead was taken from a y point localized in the third folium (y3), the evoked potential was about the same for all four limbs. The ipsilateral and contralateral latencies were approximately the same (13 and 20 milliseconds) everywhere. Evoked potentials could be led from the same points, after latencies of 13 to 14 milliseconds, when the cerebral cortex was stimulated. Interactions between the cortex and sensory nerves (a, (3, y points) and between couples of sensory nerves (y3 points) were reported in a second note by Albe-Fessard and Szabo (1954). Using the double-shock technique, they found either a complete blockade (intervals below 50 to 80 milliseconds) of the test response or a reduction in it (intervals between 50 to 80 and 120 to 150 milliseconds). Different results were obtained between 0 and 40 milliseconds, since in a group of experiments the second response was entirely lacking, whereas in the second group its size progressively decreased. The experiments based on single-fiber recordings from Flechsig's tract, recently reported by Laporte and Lundberg (1956) and by Laporte, Lundberg, and Oscarsson (1956b), are particularly important in that they give a direct demonstration that a very marked convergence of afferent impulses occurs already at

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precerebellar levels. Single fibers of Flechsig's tract were led intra-axonally from cats under nembutal anesthesia, and the responses to single-shock stimulation of afferent fibers (Laporte, Lundberg, and Oscarsson, 1956b) and to natural stimuli (Laporte and Lundberg, 1956) were recorded. Laporte, Lundberg, and Oscarsson (1956b) described a first group of neurons, with ascending axons in Flechsig's tract, which were monosynaptically activated by group I muscle afferents. These nerve cells, probably located in Clarke's column, were activated as well by group II muscle afferents, which also originate from the muscle spindles. A convergence of excitatory impulses from different extensor muscles (e.g., gastrocnemius and quadriceps) onto a single second-order neuron was frequently found. Stimulation of the nerves from antagonistic muscles (e.g., quadriceps- and biceps-semitendinous nerves) showed that the response of a single cell of a Clarke nucleus was usually driven in a reciprocal manner, but occasionally a convergence of excitatory impulses was found. A second group of neurons were activated only by high-threshold muscle afferents (groups II and III). These units were occasionally driven also by skin afferents, and sometimes the same nerve cell was influenced in a reciprocal manner by two skin nerves. Neurons driven by single-shock stimulation of group I afferents were frequently shown, upon adequate stimulation, to be also driven by muscle spindle receptors and not by Golgi tendon organs. In a more recent work performed with the same technique Lundberg and Oscarsson (1956) pointed out that actually the great majority of the cells of Clarke's column "subserve transmission of information only from one receptor system, either Golgi tendon organs or muscle spindles" (p. 73). They stated, however, that a convergence of excitatory impulses from Golgi tendon organs and muscle spindle afferents upon the same Clarke neuron cannot be dismissed altogether, and is actually supported by other evidence. Clarke's cells receive excitatory impulses also from interneurons, whose activity is probably mainly responsible for their resting discharge (Holmqvist, Lundberg, and Oscarsson, 1956). D. ELECTROPHYSIOLOGY OF THE EFFERENT CEREBELLAR CONNECTIONS IN MAMMALS 1. EFFERENT SPIKE DISCHARGES IN THE CEREBELLAR PEDUNCLES Cooper, Daniel, and Whitteridge (1953a, b) led spike potentials by means of steel microelectrodes from the superior cerebellar peduncle of the goat. They recorded a spontaneous discharge showing small groups recurring at a rate of 7 to 13 times a second, which was increased after a latency of 30 milliseconds when a stretch was applied to an extrinsic eye muscle. Since (a) the same long-latency responses were obtained after decerebration, and since (b) the same spontaneous rhythms were led from other cerebellar pathways and from the cerebellum itself, they suggested that the spontaneous discharge and its modulation by proprioceptive stimulation represented the activity of efferent cerebellar neurons. Calma and Kidd (1955) recorded simultaneously, in precollicular decerebrate cats, the cerebellar cortical potentials and the efferent discharge in the brachium

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conjunctivum. They led from the cerebellar cortex a complex series of waves following afferent stimulation: a 1st positive wave, latency 10-12 msec.—PI a 1st negative wave, latency 18-20 msec.—NI a 2nd positive wave, latency 25-30 msec.—P2 a 2nd negative wave, latency 25-40 msec.—N2 They reported that the P2 wave was associated with the efferent cerebellar discharge, while the N2 wave corresponded to a period of decreased efferent cerebellar activity. If a single electrical shock was applied to the cerebellar cortex, there was an efferent discharge, followed by a period of silence lasting about 50 milliseconds. They pointed out that any low-frequency stimulation of the cortex was likely to abolish the tonic cerebellar inhibition simply by breaking up the pattern of steady cerebellar discharge, whereas "frequencies above about 20/sec produce a steady efferent cerebellar discharge, as the cortex is driven to increased activity continuously." The relation between these experiments and those of Moruzzi (1949) and of Terzuolo and Terzian (1953) will be discussed elsewhere (see pp. 260-262). With bipolar macroelectrodes Goldman and Snider (1955) led the response of the brachium conjunctivum of the curarized cat to single-shock stimulation of the contralateral inferior olive, of the ipsilateral and contralateral restiform body, and of the ipsilateral brachium pontis. They recorded a short-latency (1 to 1.5 milliseconds) wave (Ci), which was interpreted as the discharge of dentate or interpositus neurons, activated monosynaptically by afferent volleys by passing the cerebellar cortex. The second wave (C2) had a longer latency (2.5 to 3.0 milliseconds) and was interpreted as a multisynaptic response, involving both cortical and nuclear cerebellar relays.

2. RESPONSES OF THE BULBAR RETICULAR FORMATION TO CEREBELLAR STIMULATION Snider, McCulloch, and Magoun (1949) with bipolar electrodes picked up the evoked response of the bulbar reticular formation in the cat under barbiturate anesthesia, following single-shock stimulation of the culmen or nucleus fastigii. The peak of the first wave occurred 1 millisecond after the shock artifact when the cerebellar cortex was stimulated, whereas the latency was much shorter (0.3 milliseconds) following nuclear stimulation. The authors suggested that cerebellar inhibition might be mediated by fastigioreticulospinal pathways. In the experiments performed by Mollica, Moruzzi, and Naquet (1953) on decerebrate or "encephale isole" cats, the cerebellar cortex was stimulated with galvanic currents, and the spike discharges of single units of the medial bulboreticular formation were led with a unipolar microwire. The best responses were obtained with 0.5 to 1.5 milliamperes when the anode was on the culmen and the cathode on the posterior vermis. Control experiments showed that the cerebellifugal volleys arose in the cortex underlying the anode. Cathode stimulation was much less effective, in confirmation of the results of Brookhart and Blachly (1952). The position of the tip of the microwire was checked at the end of the experiments, (a) physiologically, since an inhibition of extensor rigidity and of

220 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM the corneal reflex (see Magoun and Rhines, 1946) occurred only when the microwire which was used as the unipolar stimulating electrode (300/sec pulses) was localized within the medial bulboreticular formation, and (b) anatomically, by controlling on serial Nissl and Weil slides the localization of microelectrolytic lesions made through the microwire (Mollica, Rossi, and Venturelli, 1954). D.c. stimulation of the vermal cortex of the anterior lobe (a) inhibited extensor rigidity in the decerebrate preparation (Fig. 78); (b) produced an EEG arousal in the "encephale isole" cat (see p. 324), and finally (c) strongly increased the spontaneous spike discharge of some bulboreticular units (Figs. 78, 79). Only occasionally the elements led from could be identified as inhibitory reticulospinal neurons. This was done whenever their spontaneous spike discharge waxed and waned synchronously with oscillations in the intensity of decerebrate rigidity, an increase in the reticular discharge corresponding to the collapse of extensor hypertonus (Fig. 79). Cerebellar polarization then yielded a pattern marked by an increased reticular discharge and a collapse of extensor rigidity (Fig. 79.E). More frequently, however, to identify the efferent projections of the reticular neurons led from was utterly impossible. An unexpected but frequent observation was a cerebellar inhibition of the reticular discharge. The blockade of the spontaneous reticular activity could not be regarded as the consequence of the sudden decrease in the proprioceptive barrage, which is likely to occur when both a and y discharges are blocked by

Figure 78. The increase in the bulboreticular spike discharge and the inhibition of extensor rigidity elicited by galvanic stimulation of the vermal part of the anterior lobe. The effect of anode polarization of the cerebellar surface (1 mA.) on the electromyographic activity of M. triceps brachii (upper records) and on the ipsilateral bulboreticular spike discharge (lower records). Unitarian {A, B, C) and multiple (D, E, F) electromyograms and reticular discharges were recorded in two different decerebrate cats, before (A, D), during (B, E) and after (C, F) cerebellar polarization. The increase in the reticular discharge parallels the blockade of electromyographic activity in the extensor muscle. (From A. Mollica, G. Moruzzi, and R. Naquet, 1958, Decharges reticulaires induites par la polarisation du cervelet: Leurs rapports avec le tonus postural et la reaction d'eveil, Electroencephalog. & Clin. Neurophysiol., 5: 571-584, Fig. 8.)

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Figure 79. Waxing and waning bulboreticular discharge and the effects thereon of galvanic stimulation of the cerebellar cortex. Decerebrate cat, whose extensor rigidity decreased synchronously with spontaneous rhythmic outbursts of large reticular spikes (B, C). Anodic polarization (1.5 mA.) of the vermal surface of the anterior lobe began during the waning period of reticular activity (end of J5), when the extensor hypertonus was very marked. A strong increase in the rate of the large reticular spikes (E) occurred with a collapse of the extensor rigidity. Both effects remained throughout the cerebellar stimulation. (From A. Mollica, G. Moruzzi, and R. Naquet, 1953, Decharges reticulaires induites par la polarisation du cervelet: Leurs rapports avec le tonus postural et la reaction d'eveil, Electroencephalog. & Clin. Neurophysiol., 5:571-584, Fig. 1.)

the cerebellar stimulation (see p. 256), since the phenomenon was observed also on "encephale isole" and later on curarized preparations. Hence inhibition was undoubtedly due to cerebellar impulses impinging directly upon the unit led from. It was unlikely, moreover, that the blockade occurred when inhibitory reticulospinal neurons were impinged upon by impulses arising in Purkinje units facilitatory for the extensor tonus. These neurons certainly exist (Moruzzi and Pompeiano, 1954, 1957b), but it should be pointed out that once a reticular unit was inhibited by cerebellar polarization, the response could neither be changed nor reversed by displacing the stimulating electrode within the excitable area. The only assumption which can be made with some certainty is that the units inhibited by the cerebellum, during the inhibition of decerebrate rigidity, did not belong to the reticulospinal neurons which are inhibitory for the extensor tonus. The reticular units inhibited by cerebellar polarization were further investigated by von Baumgarten, Mollica, and Moruzzi (1954) and by von Baumgarten and Mollica (1954). They worked on "encephale isole" preparations or on cats whose mesencephalon, exclusive of the cerebral peduncles, had been interrupted

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Figure 80. A schema of experiments on cerebelloreticular and corticoreticular relations. A corticofugal discharge is elicited from efferent units of the motor cortex (5) by either local strychninization or electrical stimulation (anodic polarization or single shock applied through electrode 2). The Purkinje discharge of the vermal cortex of the anterior lobe is elicited through electrode 1 by anodal polarization and transmitted to the nucleus fastigii (N.f.) Pyramidal and fastigial volleys converge on reticular units, whose destination is generally unknown. If reticulospinal units are impinged upon, the spinal motoneurons (M) will be influenced by both pyramidal and cortically driven reticular discharges. Ascending reticular neurons will feed back onto the cortical cells (reticular efferents are represented by dashed lines). Reticular structures are led through microwire 3 or stimulated unipolarly, at the end of the experiment, through the same electrode or through a twin microwire (4). (From R. von Baumgarten, A. Mollica, and G. Moruzzi, 1954, Modulierung der Entladungsfrequenz einzelner Zellen der Substantia reticularis durch corticofugale und cerebellare Impulse, Arch, f. d. ges. Physiol., 259:56-78, Fig. 12.)

at the intercollicular level through high-frequency thermocoagulation. In these unanesthetized "pyramidal" preparations (Whitlock, Arduini, and Moruzzi, 1953) the cerebrum was connected with the brain stem only through peduncular fibers and above all by the pyramidal tract. A schema of these experiments is given in Figure 80. Von Baumgarten, Mollica, and Moruzzi (1954) showed that the same bulboreticular units whose spontaneous discharge was blocked by cerebellar polarization were frequently impinged upon by corticofugal volleys arising in the locally strychninized motor cortex. Sometimes the rate of the reticular discharge was increased (up to 150/sec) whenever a strychnine wave occurred on the motor area (Fig. 81d, /). The cerebellar polarization then clearly inhibited both spontaneous (Fig. 816) and (less strongly) cortically induced (Fig. 81e) reticular activity, but did not influence cortical convulsive waves (Fig. Sle). Occasionally reticular activity was instead blocked during the strychnine wave (Figs. 82, 83), the inhibitory pause being followed, sometimes, by a rebound increase in the resting discharge (Fig. 83). In these instances a summation of both cerebral and cerebellar inhibitory effects was occasionally observed (Fig. 82), while the rebound following the cortical inhibition was blocked altogether by cerebellar polarization (Fig. 83).

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Figure 81. Cerebellar inhibition of spontaneous and of cortically induced bulboreticular discharges. The spontaneous discharge of a single unit of the cat's medial bulboreticular formation (a, c) is strongly accelerated whenever strychnine waves (d, e, i, lower records) occur on the motor cortex (d, f), but is not abolished following its ablation (g, i). Anodal polarization of the anterior lobe (0.5 mA.) inhibits the spontaneous discharge before (b) and after strychninization (e) or ablation (h) of the motor cortex. Reticular discharges modulated by strychnine outbursts are strongly decreased during cerebellar polarization, while strychnine waves are unaffected (e). (From R. von Baumgarten, A. Mollica, and G. Moruzzi, 1954, Modulierung der Entladungsfrequenz einzehier Zellen der Substantia reticularis durch corticofugale und cerebellare Impulse, Arch. f. d. ges. Physiol., 259:56-78, Fig. 2.)

That the cortically induced effects really arose within the strychninized cortex was shown by their abolition following ablation of this area (Figs. 81, 82). The hypothesis that proprioceptive reverberations elicited from the strychnine clonus might be responsible for the cortically induced effects was disproved, since the latter were observed (a) in the "encephale isole" cat and (b) following complete curarization (Fig. 83). Hence the conclusion was drawn (a) that cerebellar and corticofugal impulses converge on the same reticular cells, and (b) that the cerebellum might influence motoneuron response to corticospinal volleys through the reticulospinal system. It was suggested that a pyramidal volley might drive, through collaterals given off at bulbar levels (Ramon y Cajal, 1909; Scheibel, 1955; Rossi and Brodal, 1956), inhibitory or facilitatory reticulospinal neurons. This cortically induced reticulospinal activity would be supervised by the cerebellar cortex (see Fig. 80). Other experiments by the same authors showed also that reticular units whose discharge was increased by cerebellar polarization were impinged upon by corticofugal volleys. In other experiments the reticular units were driven by single shocks applied to the motor cortex, and similar interrelations between cortical and cerebellar effects were reported. Further investigations employing the same technique were devoted by von Baumgarten and Mollica (1954) to an analysis of cerebellar influence on reflexly evoked discharges of single bulboreticular units. They found that when a spontaneous reticular discharge was blocked altogether by cerebellar polarization,

Figure 82. The convergence of inhibitory cortical and cerebellar impulses on a single bulboreticular unit. Low-voltage and highvoltage spike discharges are recorded from at least two different reticular units of the cat's medulla throughout this experiment. The large unit, easily identified as such because of the constant size and similar position of the notches, is almost selectively inhibited by cerebellar polarization (6), while both large and small units are blocked whenever a strychnine wave (lower records) occurs on the motor cortex (d, e, f), although small units escape earlier from inhibition (d, e). A summation of cortical and cerebellar inhibition occurs when strychnine waves appear during cerebellar polarization (e). The patterns of the spike discharges and of cerebellar inhibition are unaffected by ablation of the strychninized motor area

(a, h, *).

(From R. von Baumgarten, A. Mollica, and G. Moruzzi, 1954, Modulierung der Entladungsfrequenz einzelner Zellen der Substantia reticularis durch corticofugale und cerebellare Impulse, Arch. f. d. ges. Physiol., 259:56-78, Fig. 4.)

Figure 83. The postinhibitory rebound of a single bulboreticular discharge at the end of a cortical strychnine wave and its inhibition during cerebellar polarization. Microwire in the cat's medial bulboreticular formation. An inhibition of the single-unit discharge, followed by a rebound, occurs (a, 6) synchronously with the strychnine waves (lower records) of the motor cortex. Both spontaneous and rebound discharges are strongly inhibited during cerebellar polarization (c, d) and are clearly present as soon as the inhibitory cerebellar effect is over (e). The same results are obtained after complete curarization, by recording before (/), during (gr), and following (h) cerebellar polarization. (From R. von Baumgarten, A. Mollica, and G. Moruzzi, 1954, Modulierung der Entladungsfrequenz einzelner Zellen der Substantia reticularis durch corticofugale und cerebellare Impulse, Arch. f. d. ges. Physiol., 059:56-78, Fig. 8.)

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Figure 84. Cerebellar inhibition of spontaneous and reftexly evoked bulboreticular discharges. Microelectrode in the cat's medial bulboreticular formation. Single rectangular pulses applied to the cornea (black dots). A spontaneously active and reflexly driven unit (a) is inhibited by anodal polarization of the vermal part of the anterior lobe with 0.5 (6), 1.0 (c), and 1.5 (d) mA. The spontaneous discharge offers less resistance to inhibition. Record e is taken 3 min. after the end of cerebellar polarization. (From R. von Baumgarten and A. Mollica, 1954, Der Einfluss sensibler Reizung auf die Entladungsfrequenz kleinhirnabhangiger Reticulariszellen, Arch. f. d. ges. Physiol., #50:79-96, Fig. 6.)

Figure 85. Reflex and cerebellar activation of the same bulboreticular unit. The unit is led from the cat's medial bulboreticular formation. A single shock applied to the central end of the sciatic nerve yields a short-lasting increase in the rate of discharge, both against a background of spontaneous activity (a) and when the reticular firing is strongly increased by cerebellar polarization (b). (From R. von Baumgarten and A. Mollica, 1954, Der Einfluss sensibler Reizung auf die Entladungsfrequenz kleinhirnabhangiger Reticulariszellen, Arch, f. d. ges. Physiol., 259:79—96, Fig.7.)

it could still be driven by single shocks applied to peripheral nerves or by natural stimuli (Fig. 846, c). However, the rate of the reflexly evoked reticular discharge was strongly reduced. By increasing the intensity of the cerebellar polarization, a complete blockade of the reflex responses could be obtained (Fig. 84c£). Hence reflex responses were simply more resistant than spontaneous activity to cerebellar inhibition. When the spontaneous rate of the reticular discharge was increased by cerebellar polarization, a further increase could be evoked by applying single shocks to the sciatic nerve (Fig. 85). Finally, a convergence of augmentatory, sensory (from all four limbs), and corticofugal (from both motor cortices) impulses and of cerebellar inhibitory volleys on a single bulboreticular unit was shown by appropriate experiments (Fig. 86). Sometimes the sensory response was followed by a prolonged silent period (Fig. 87). The nature of the reticular units led from remained unsettled. The authors pointed out that if some of them could

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Figure 86. Cerebellar inhibition of a bulboreticular unit driven by sensory and by corticofugal impulses. Microelectrode in the cat's medial bulboreticular formation. A spontaneously active unit (a) driven by single shocks applied to the sciatic nerve (black dots), inhibited by cerebellar polarization (6), rebounds when the cerebellar stimulation is over (c) and returns to the normal pattern of discharge a few minutes thereafter (d). The same unit is then increased by anodal polarization (e) and by single shocks (black dot, g) applied to the motor cortex (/ is a control record taken immediately after the end of the motor cortex polarization). The motor cortex is then strychninized, and a frequency modulation of the discharge occurs synchronously with the strychnine waves (lower record, h). (From R. von Baumgarten and A. Mollica, 1954, Der Einfluss sensibler Reizung auf die Entladungsfrequenz kleinhirnabhangiger Reticulariszellen, Arch. f. d. ges. Physiol., 259:79-96, Fig. 8.)

Figure 87. Short-lasting increase, followed by a silent period, in the discharge of a bulboreticular unit inhibited by cerebellar polarization. Microelectrode in the cat's medial bulboreticular formation. The spontaneous discharge (a) is inhibited by cerebellar polarization (b). Single shocks (black dots) applied to the central end of the sciatic nerve yield a short-lasting increase in the discharge, followed by a silent period (c, d). (From R. von Baumgarten and A. Mollica, 1954, Der Einfluss sensibler Reizung auf die Entladungsfrequenz kleinhirnabhangiger Reticulariszellen, Arch. f. d. ges. Physiol., 259:79-96, Fig. 5.)

be ascribed to the ascending reticular system, the cerebellar sphere of influence should be extended to the input side of the central nervous system (see p. 344). The work of Scheibel, Scheibel, Mollica, and Moruzzi (1955), performed with similar techniques on decerebrate, "encephale isole," or curarized cats, was mainly devoted to problems of reticular physiology. The main result of these experiments was to show that the degree of convergence of sensory and cortical impulses upon reticular units is definitely limited and that different groups of

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functionally distinguishable elements are present within the bulbar and midbrain reticular formation. Only the experiments dealing with cerebelloreticular relations will be reviewed here. Cerebellar polarization yielded three types of reticular responses: (a) an increase in the firing rate; (b) a decrease in or a complete cessation of spike discharges; and (c) a change in the firing patterns, with development of repetitive bursts of high-frequency spikes (up to 500/sec), the bursts being separated by intervals of 10 to 50 milliseconds (Fig. 88A, B, C). The first two types of responses (a and b) had already been reported and were found respectively in about 60 per cent and 30 per cent of cases; they were duplicated by leading from the midbrain reticular formation. The burst-type discharge (c) was found only in about 10 per cent of cases, and for this reason and because of its injury-like pattern it was at first disregarded. That it deserves attention was shown by the fact that high-frequency outbursts could be elicited (Fig. 88J5) and/or modified (Fig. S8E) in a thoroughly predictable and reversible way by cerebellar polarization. An attempt to correlate these different types of responses with given reticular loci was unsuccessful, since the sites were intermingled. Actually, when two neighbor-

Figure 88. Burst-type responses led from the bulboreticular formation during cerebellar polarization. Decerebrate (A, B, C) and "encephale isole" (D, E, F) cats. A background of regular reticular discharges (A, C) yields high-frequency outbursts with intervals of complete silence (B) during cerebellar polarization (0.75 mA.). A mixed background of regular reticular discharges with occasional outbursts (D, F) shows the blockade of normal discharges and the increased occurrence and duration of high-frequency outbursts during cerebellar polarization (1 mA.). (From M. Scheibel, A. Scheibel, A. Mollica, and G. Moruzzi, 1955, Convergence and interaction of afferent impulses on single units of reticular formation, J. Neurophysiol., 15:309-331, Fig. 8, publ. Charles C. Thomas.)

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Figure 89. Cerebellar inhibition of spontaneous but not of acoustically driven bulboreticular discharges. "Encephale isole" cat. Potential oscillations of the auditory cortex (upper records, A to D, H to 7) and spike discharges of a single bulboreticular unit (lower records) are recorded simultaneously. Clicks (dark dots) yield cortical responses, but the driving of the reticular unit is almost concealed by its spontaneous discharge (A, 5). The spontaneous reticular discharge is completely abolished by cerebellar polarization, but a click still drives a single spike (C to F). The same unit is driven by a tactile stimulus to the nose (G) and is completely unaffected when strychnine waves occur spontaneously on the auditory cortex (H; last wave of 7). A click drives both the strychninized cortex (first wave of 7) and the reticular unit (7). (From M. Scheibel, A. Scheibel, A. Mollica, and G. Moruzzi, 1955, Convergence and interaction of afferent impulses on single units of reticular formation, J. Neurophysiol., 18:309-331, Fig. 4, publ. Charles C. Thomas.)

ing units were recorded with a single microwire, occasionally only one of them was affected by cerebellar polarization (see also Fig. 82). Reticular units responding to auditory stimuli (clicks) were found in the "encephale isole" preparation; their spontaneous but not their reflexly evoked discharge was blocked by anterior vermis polarization (Fig. 89). Gauthier, Mollica, and Moruzzi (1956) were mainly concerned with the localization of the cerebellar areas projecting onto the bulbar reticular formation. The vermis proper and the intermediate part of the anterior lobe (Larsell's lobules III, IV, V, H III, H IV, H V) as well as crus I of the lobulus ansiformis (sublobule H Vila) were polarized anodically with unipolar silver-silver chloride electrodes in the decerebrate cat. The best effects on bulboreticular units were obtained from the vermis proper. The threshold increased about twice when the "different" electrode was placed on the intermediate part, and a further, strong

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increase was necessary in order to get a response from crus I. At least the effects obtained from the latter structure were definitely shown to be due to a physical spread to either vermal neurons or their efferent projections. Two types of vermal effects were found, namely (a) diffuse reticular responses, which were exactly the same when any of Larsell's lobules from III to V were stimulated, either ipsilaterally or contralaterally, and (b) localized effects, which for threshold stimuli were obtained, selectively, only from the ipsilateral side of a single lamella. The diffuse responses were obtained with intensity ranges of the order of those previously reported (0.5 to 0.8 and 1.0 to 1.5 milliamperes). The localized effects were obtained instead with only 0.15 to 0.3 milliampere, and for these threshold stimuli the effect disappeared (a) when the anode was moved away only 2 mm. or (b) following aspiration of the surface of the active folium and its replacement with wet cotton or (c) following local cocainization of the excitable surface. When threshold intensities were increased by about 0.1 to 0.2 milliampere, a response could still be obtained, possibly through a localized spread to underlying efferent fibers or to neighboring folia. There was no doubt, at any rate, that the reticular responses elicited by threshold stimuli were elicited by volleys that arose from structures immediately underlying the "different" electrode. The authors pointed out that the available data did not justify a distinction between diffuse and localized cerebelloreticular projections. Diffuse effects might simply result from the fact that sometimes the recorded bulboreticular units were projected upon by Purkinje neurons lying in the deepest parts of the cerebellar folia. To stimulate these deep structures with surface polarization, the intensity of the d.c. currents had to be increased and then a physical spread to neighboring folia could hardly be avoided. Many localizations of the tip of the microelectrode happened to be within Brodal's nucleus reticularis paramedianus (1953), which had been shown by Brodal and Torvik (1954) to project onto the same vermal areas the d.c. stimulation of which yielded such striking effects on the resting discharge. Obviously there arose a question whether some, at least, of the effects might not eventually be due to antidromic stimulation of reticulocerebellar fibers. It is likely, in our opinion, that the inhibitory effects were orthodromic and transsynaptically elicited, since when the spontaneous rate of the reticular discharge was strongly decreased by cerebellar polarization, the few reticular spikes that appeared during the inhibitory period did not show, on fast sweep records, the slightest changes in either polarity or form. The same held true even for most of the augmentatory responses. Some of them, however—most frequently those presenting the outburst type of discharge—behaved in a peculiar manner, which was not easily reconciled with the hypothesis of orthodromic plurisynaptic activation of reticular neurons by cerebellofastigial volleys. The response of these units to cerebellar polarization was extremely resistant to barbiturates, since it was observed after doses of pentothal which altogether abolished decerebrate rigidity as well as the effects on the postural tonus elicited by iterative vermal stimulations. These cerebellar effects on reticular firing were either antidromic effects or orthodromic oligosynaptic responses, particularly resistant to barbital anesthesia.

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3. RESPONSES OF THE VESTIBULAR NUCLEI TO CEREBELLAR STIMULATION That the vestibular nuclei are impinged upon by cerebellar impulses is suggested by abundant anatomical and physiological evidence, which will be reviewed in another chapter (see p. 271). It has been pointed out, moreover, that the inhibition of decerebrate rigidity which occurs when the vermal part of the anterior lobe is stimulated might not be entirely due to the inhibitory barrage descending through fastigioreticulospinal pathways. Contributing to the collapse might be cerebellar inhibition of the tonic facilitatory influence of the Deitersian system as well (Moruzzi, 1950a). That the extensor hypertonus of the decerebrate cat is abolished when lesions are inflicted upon vestibular nuclei or their vestibulospinal projections is well known (Thiele, 1905; Bernis and Spiegel, 1925; Fulton, Liddell, and Rioch, 1930; Martin, 1932; Bach and Magoun, 1947). De Vito, Brusa, and Arduini (1956) are responsible for the first direct approach to the physiology of cerebellovestibular connections. Responses were led from Deitersian units in decerebrate cats with stereotactically oriented steel microelectrodes, and the effects of monopolar, monoaural galvanic stimulation of the labyrinth and of unipolar, anodic polarization of the anterior lobe were recorded. Cerebellovestibular relations turned out to be more complicated than expected. Anodal polarization of the anterior lobe resulted in an inhibition of the spontaneous discharge in 40 per cent of the Deitersian units, in an augmentation in 30 per cent, and in no modification in the remainder. These different groups of Deitersian units could not be distinguished on the basis of the resting discharge or of their response to vestibular stimulation. They were mostly (a) spontaneously active, the rate of discharge ranging from 0.5 to 100 per second and the usual frequency being 10 to 20 per second; (b) strongly and often reciprocally affected by polarizing the ipsilateral and contralateral labyrinth; and yet (c) their resting discharge was not entirely abolished by severing the eighth nerve. The last observation accords well with classic experiments showing that the abolition of decerebrate rigidity elicited by destroying the ipsilateral vestibular nuclei will not be duplicated by severing the eighth nerve (Sherrington, 1898). The fact that cerebellar polarization had no effect on a group of Deitersian units could not be regarded as an incidental finding, to be explained by the lability of cerebellar function. Other units were eventually found, in the same preparation, which were clearly affected by anodal polarization of the anterior lobe. Moreover, both the electrical activity and the electrical excitability of the anterior lobe were controlled and found to be normal in these experimental conditions. But the majority of the Deitersian units were affected by the cerebellum. This observation might have been expected, although it is doubtful whether all these units were concerned with the regulation of the extensor tonus. As just reported, spontaneous discharges of about 30 per cent of the Deitersian units led with this technical procedure were facilitated by the anodal polarization of the vermal part of the anterior lobe (Fig. 90). The intensities of the active galvanic currents ranged between 0.6 and 1.5 milliamperes and were therefore of the same order as those inhibiting decerebrate rigidity. It is most unlikely that the Deitersian facilitation of the extensor tonus was mediated by this group of

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Figure 90. Spontaneous Deitersian discharge influenced by galvanic labyrinthine stimulation and increased by cerebellar polarization. Decerebrate cat. A, C, F are controls, showing the spontaneous multiple discharge before the application of the stimulus (solid line under tracing) in subsequent strips. An increase (B) and a blockade (D) of Deitersian firing units, followed by a rebound discharge (.E), are elicited respectively by ipsilateral (B) and contralateral (D) cathode labyrinthine polarization. An increase in the spike discharge is elicited by intensities (0.6 mA.) of anodal polarization of the vermal part of the anterior lobe which inhibited ipsilateral extensor rigidity (G). (From R. V. De Vito, A. Brusa, and A. Arduini, 1956, Cerebellar and vestibular influences on Deitersian units, J. Neurophysiol., 19:241-253, Fig. 1, publ. Charles C. Thomas.)

units. Such a hypothesis could be held for that 40 per cent of the Deitersian elements whose discharge was inhibited by cerebellar polarization (Fig. 91). However, the threshold of galvanic labyrinthine stimulation which clearly influenced the resting discharge of these units was about the same as that yielding the wellknown cephalogyric responses. The effect on extensor rigidity reported by Spiegel and Scala (1943) occurred, instead, at much higher intensities of galvanic vestibular stimulation. Hence the Deitersian units inhibited by cerebellar polarization were probably concerned with phasic labyrinthine reflexes. These findings accord very well with classical ideas about the cerebellar inhibition of nystagmus and generally of phasic labyrinthine reflexes (see p. 287). But the intrinsic mechanism

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Figure 91. Facilitation by cathodal polarization of the ipsilateral labyrinth and inhibition by galvanic cerebellar stimulation of the spontaneous discharge of the same Deitersian unit. Decerebrate cat. A, C, and E are controls. Augmentation during cathodal polarization of the labyrinths (B) and inhibition during galvanic stimulation of the vermal part of anterior lobe (D). (From E. V. De Vito, A. Brusa, and A. Arduini, 1956, Cerebellar and vestibular influences on Deitersian units, J. Neurophysiol., 19:241-253, Fig. 4, publ. Charles C. Thomas.)

of both vestibular and cerebellar regulation of the postural tonus is still an open problem, which should be further investigated. Another conclusion drawn from the experiments just cited should be stressed, namely, that units anatomically belonging to Deiters' nucleus and physiologically influenced by labyrinthine stimulations are strongly affected by impulses arising within the spinal projection area of the cerebellum. The distinction between the vestibular and spinal zones of the cerebellum, established on anatomical grounds (see Larsell, 1958) and substantiated by the results of both ablation experiments and electrophysiological analysis of afferent pathways, appears to be not quite so well justified when the efferent connections are taken into account. 4. RESPONSES OF THE MIDBRAIN AND DIENCEPHALON TO CEREBELLAR STIMULATION Whiteside and Snider (1953) applied single shocks to the cerebellar surface of curarized cats and led the responses from the midbrain and diencephalon with bipolar electrodes, oriented stereotactically at intervals of 1 millimeter. The composite drawings of Figure 92 show that the evoked potentials were especially prominent in two major systems of the brain stem: (a) the mesencephalic plus diencephalic tegmentum and (b) many of the sensory relay nuclei of the thalamus. The basal ganglia and particularly the caudate nucleus were unaffected by the

Figure 92. A composite drawing showing the areas of the midbrain and diencephalon responding to cerebellar stimulation. Curarized cats. Cross-hatching denotes the responsive areas to single-shock stimulation of the paramedian lobule (I), anterior lobe (II), and combined tuber vermis and lobulus ansiformis (III) at Horsley-Clarke levels A 3-2, A 4-5, A 6-7, A 8-9, A 10-11. One set of diagonal lines indicates short (less than 1 msec.) responses; dotting indicates medium-latency responses (1-3 msec.); the diagonal lines at 90° to those indicating short latencies indicate responses of 3-12 msec, latency. (From J. A. Whiteside and R. S. Snider, 1953, Relation of cerebellum to upper brain stem, J. Neurophysiol., 16:397-413, Fig. 5, publ. Charles C. Thomas.)

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cerebellar shocks. Responses with latencies shorter than 1 millisecond were found not only in the midbrain but also in the diencephalon and were classified as "asynaptic." The authors suggested that these might be due to transmission through long corticofugal fibers, without the usual relays in the cerebellar nuclei, but it appears extremely difficult to explain these findings on the basis of our present anatomical knowledge (see Jansen and Brodal, 1954). The effects on the thalamic nuclei suggested, according to the authors, that "cerebellar action might alter threshold activity of these nuclei and thus influence sensory influx to cerebral cortex" (p. 409). 5. RESPONSES OF THE CEREBRAL CORTEX TO CEREBELLAR STIMULATION The cerebellifugal pathways projecting onto the cerebral cortex are best investigated by means of the single-shock technique. The results of such experiments will be reviewed in this chapter. Cerebellar influence on the cerebral cortex, however, is much better analyzed, physiologically, by means of any type of prolonged or repetitive stimulation. The results of this second group of experiments will be dealt with in the next chapter, in the section on cerebellocerebral relations (see p. 323). Henneman, Cooke, and Snider (1952) stimulated the cerebellar cortex and nuclei in cats under different types of anesthesia as well as in curarized or "encephale isole" preparations. Single shocks (0.5 to 1 millisecond) were delivered once per second, and the cerebral responses were recorded with a cathode ray oscilloscope. Unlike the afferent projections, the efferent systems arising in the cerebellar cortex were found to be extremely sensitive to barbiturates, while the responses elicited from the cerebellar nuclei were much less depressed. Stimulation of the anterior lobe and the lobulus simplex "elicited responses restricted to

Figure 93. Projection oj the contralateral anterior lobe and lobulus simplex onto the pericruciate region of the cerebral cortex, A. Cat cerebellum with vertical lines indicating the area stimulated (Larsell's lobules III to VI and H III to H VI). B. Vertical lines indicate the cerebral areas which are activated by cerebellar stimulation within the areas outlined in A. The lobulus centralis, culmen, and lobulus simplex project onto different parts of the sensorimotor cortex and somatic sensory area II. (Redrawn from E. Henneman, P. M. Cooke, and R. S. Snider, 1952, Cerebellar projections to the cerebral cortex, A. Research Nerv. & Ment. Dis., Proc., 50:317-333, Fig. 1624, 5.)

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somatic sensory and motor areas of the contralateral cerebral cortex" (p. 320) after 3.5 to 5 milliseconds (Fig. 93), while paramedian stimulation evoked potentials in the same areas of both cortices (Fig. 94). Stimulation of the visual and auditory areas of the cerebellum yielded a response in both auditory areas I (latency 3.5 to 4.5 milliseconds), but effects with longer latencies were found also in the neighboring ectosylvian regions (Fig. 95). No clear-cut effects were observed in the visual cortex of the cerebrum, nor were consistent responses reported following stimulation of crus I and crus II. No "point to point" relations between the cerebellar nuclei and the cerebrum were found, and responses could be led from somatic sensory and motor areas following stimulation "of any site in the cerebellar nuclei, ipsilateral and contralateral" (p. 327). The authors stressed the fact that the cerebellar areas receiving tactile and proprioceptive impulses projected onto the somatic cerebral areas, and that the same relations hold for auditory cerebral and cerebellar cortices.

6. INTRACEREBELLAR CONNECTIONS The only electrophysiological experiments on intracerebellar connections are those performed on cats by Barnard and Woolsey (1950). They are reported in this chapter, since the technique (single shock on the cerebellar cortex) is the same as that utilized for investigating the cerebellifugal pathways. Stimulation of the lobulus centralis of the anterior lobe (lobule III) yielded responses in the ipsilateral leg area of the paramedian lobule (sublobules H Vllb, H Villa) and also in the pyramis (lobule VIII); the culmen (lobules IV, V) projected to the arm area of the paramedian lobule and also to the pyramis. Conversely, electrical stimulation of the arm and leg areas in the paramedian lobule gave responses in the ipsilateral culmen and centralis respectively, a finding fitting very nicely the Marchi studies performed by Jansen (1933) in the rabbit. Antidromic mechanisms were dismissed, since the latency was about 6 milliseconds. Conduction occurred within the cerebellum, since section of the ipsilateral cerebellar peduncles did not abolish the effect. E. ELECTROPHYSIOLOGICAL INVESTIGATIONS ON THE CEREBELLAR NUCLEI Narikashvili (1950) led simultaneously, with chronically implanted silver macroelectrodes, the electric activity of the cerebellar cortex and deep nuclei in unrestrained, unanesthetized cats. He recorded from both structures the usual fast waves (250 to 300 per second), occasionally intermingled with or superimposed on slower rhythms (9 to 12 per second). The amplitude of the fast waves was much larger on the vermis (up to 200 to 250 microvolts) than on the hemispheres, whereas the opposite was true for the slow waves. The outbursts of slow waves were possibly increased by mechanical injury produced by the electrodes, since they were observed more frequently during the first days. They occurred synchronously in the cerebellar cortex and in the nuclei, but each cortical wave slightly preceded the nuclear one, and it was likely that a corticofugal discharge occurred during each outburst. Both fast rhythms and slow waves were led from

Figure 94. Projection of the contralateral paramedian lobule onto the pericruciate area of the cerebral cortex. A. Responsive area of the cat's cerebral cortex shown in stippling. It encompasses the motor area, somatic sensory areas I and II, and the ansate area. B. The four folia of the paramedian lobules shown in stippling are the most effective ones for "firing" the pericruciate area. (From E. Henneman, P. M. Cooke, and R. S. Snider, 1952, Cerebellar projections to the cerebral cortex, A. Research Nerv. & Ment. Dis., Proc., 50:317-333, Fig. 1634, B.)

Figure 95. Projection of the cerebettar auditory area onto the auditory areas of the cerebral cortex. A. Auditory receiving area of the cat's cerebellum situated in the lobulus simplex and folium and tuber vermis (LarselPs lobules VI, H VI, and VII). B. Cerebral-cortical region which responds when the cerebellar area shown in A is stimulated. Responses are limited to auditory areas I and II. C. Area of the cerebellum stimulated in a single typical experiment. D. Responses recorded from the pial surface of the cerebral cortex when one folium of the tuber vermis (see C) was stimulated. Experiments on curarized cats. (From E. Henneman, P. M. Cooke, and R. S. Snider, 1952, Cerebellar projections to the cerebral cortex, A. Research Nerv. & Ment. Dis., Proc., 50:317-333, Fig. 164.)

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the caudal part of the midbrain and from the red nuclei, but the midbrain potentials followed the cerebellar slow waves after a delay of 40 to 50 milliseconds. Arduini and Pompeiano (1956, 1957) recently carried out a microelectrode analysis of the nucleus fastigii in the decerebrate cat. The localization of the tip of the microelectrode was controlled on serial Nissl and Weil slides. So far only the rostral one third of the nucleus has been explored. The rostrofastigial units were frequently, but not constantly, affected by bipolar d.c. stimulation (0.1 to 0.8 milliampere) of the ipsilateral cortex of lobules IV and V (culmen), whereas this result was constantly missed when the units happened to be located within the caudal portion of this nucleus. These data fit very well the anatomical results of Jansen and Brodal (1940, 1942, 1954). The fastigial response was really due to excitation of the stimulated area, since (a) the d.c. threshold for the cerebellar effect was increased up to 5 to 7 times following local cocainization (5 per cent), and (b) in many experiments the fastigial response disappeared altogether when the stimulating electrodes were placed only a few millimeters laterally, on the corresponding folia of the intermediate part of the anterior lobe (lobules H IV and H V) (Fig. 96). Proprioceptive reverberations could be dismissed, because the effects were obtained after complete curarization. By changing the polarity or the position of the stimulating electrodes, it was always possible to find a cortical cerebellar area yielding the best responses with the lower intensities of current. Two types of nuclear responses were observed following stimulation of the ipsilateral vermis, namely, an increase in (Fig. 96) and an inhibition (Figs. 97, 98) of the resting fastigial discharge. The units increased and those inhibited by stimulating the ipsilateral vermal cortex were localized (chiefly, but not exclusively) within the rostrolateral and the rostromedial portions of the fastigial nucleus, i.e., within structures exercising respectively an inhibitory and an augmentatory influence on the antigravity extensor tonus (Batini and Pompeiano, 1958a and b). The same units could be driven also by galvanic (cathodal) stimulation of both labyrinths. The contralateral labyrinth occasionally inhibited the resting discharge, and sometimes no effects were observed. About half of the units which were unaffected by polarizing lobules IV and V were driven by labyrinthine stimulation. Since other units of the same region of the fastigial nucleus were clearly influenced by the usual intensities of cerebellar stimulation, the unresponsive elements might correspond (a) to neurons driven by lobules I, II, III, (b) to association neurons, or finally (c) to the intrinsic fastigial elements postulated by Sprague and Chambers (1953), which would be driven by cerebellipetal impulses but not by the cerebellar cortex (see above, p. 81). The sign of the fastigial response could be reversed by changing the polarity of the labyrinthine stimulation. The fastigial units were driven also by natural stimuli and by single shocks applied to cutaneous and muscular nerves (Fig. 98). Quite frequently a single unit was driven by sensory stimuli applied to all four limbs, but the mechanism of these diffuse, long-latency (10 to 20 milliseconds) responses was not investigated. The potential oscillation led from the surface of the culmen (lobules IV and V) and the spike discharge of ipsilateral rostrofastigial units were recorded, simul-

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Figure 96. Augmentatory effects of cerebellarcortical and labyrinthine stimulations on the resting discharge of fastigial units. Decerebrate cat. The normal resting discharge of a rostrofastigial unit (A, C, E, G) was increased by d.c. stimulation of the ipsilateral side of lobules IV and V (5), while the same intensities of current (0.6 mA.) were ineffective when the electrodes were placed a few millimeters laterally (D), on the intermediate part of the anterior lobe (lobules H IV and H V). The discharge was also increased by galvanic (cathodal) polarization of the ipsilateral labyrinth (F). (From A. Arduini and O. Pompeiano, 1957, Microelectrode analysis of units of the rostral portion of the nucleus fastigii, Arch. ital. de biol., 95:56-70, Fig. 1.)

Figure 97. The inhibition of the rostrofastigial spike discharge during cerebellar polarization and its increase by labyrinthine stimulation. Decerebrate cat. The resting discharge of rostrofastigial units (A, C, E) was inhibited (A, B) by d.c. stimulation of the ipsilateral side of lobules IV and V (0.4 mA.), and increased (D) by galvanic (cathodal) polarization of the ipsilateral labyrinth. (From A. Arduini and O. Pompeiano, 1957, Microelectrode analysis of units of the rostral portion of the nucleus fastigii, Arch. ital. de biol., 95:56-70, Fig. 2.)

taneously, following single-shock stimulation of the central end of the radial nerve (Fig. 98). The fastigial response never preceded, but always followed, the large potential oscillation occurring on the vermal cortex. This cerebellar cortical response, probably corresponding to potential III of Grundfest and Campbell (1942), has been correlated with the reflexly evoked discharge of the Purkinje neurons (see p. 199). In another group of experiments the decerebration was performed a few days after extensive, chronic ablation of the culmen (lobules IV and V). Completely to destroy the deep portion of the culmen without damaging the rostral pole of the fastigial nucleus was impossible. Anyway, the fact that a very marked fastigial response was observed following single-shock stimulation of the radial

Figure 98. Cerebellar-cortical and jastigial responses to single-shock stimulation of sensory fibers. Decerebrate cat. The responses to single-shock stimulation of the radial nerve were led from the surface of lobule V with one macroelectrode (upper record) and from the ipsilateral rostrofastigial units with a microelectrode (lower record). A fastigial resting discharge (A, C), inhibited by d.c. stimulation (0.6 mA.) of the ipsilateral side of lobule V (5), was driven by single-shock stimulation of ipsilateral (D, F) and contralateral (E, O) skin (D, E~) and muscular (F, G) nerves. In H the response to ipsilateral skin-nerve stimulation was recorded at higher speed (time, 20 msec.). (From A. Arduini and 0. Pompeiano, 1957, Microelectrode analysis of units of the rostral portion of the nucleus fastigii, Arch. ital. de biol., 95:56-70, Fig. 3.)

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nerve suggests that the sensory volleys from the forelimbs are not exclusively mediated, in somatotopic manner, by the cerebellar cortex of lobules IV and V. The fastigial discharge was always preceded by a potential oscillation occurring on the surface of lobule III (lobulus centralis), an observation confirming the results of Combs (1954) already reported and discussed (see p. 192). F. GENERAL CONSIDERATIONS Twenty years of intensive and sometimes extremely fruitful electrophysiological work have been reviewed in the preceding pages. Although we are still unable to grasp the functional significance of some of the data that have been steadily accumulating since the beginning of the electronic era, it may be rewarding to correlate the new findings with those obtained in the ablation and stimulation experiments reported in Chapters 2 and 3 of this book. The electrophysiological data may be correlated as well with the rapidly expanding knowledge of cerebellar morphology, for which the reader is referred once more to the forthcoming companion volume by Larsell and to the book by Jansen and Brodal (1954). To attempt such a correlation is the major task of the present section. Often, indeed, the task will appear easy, since many of the results we have reported could be, and sometimes actually were, predicted before the introduction of modern electronic techniques. Not infrequently, however, the results of the electrophysiological endeavor were quite unexpected; occasionally, they appeared even to conflict, or at least not readily to accord, with what already was known from neuroanatomy or from classical neurophysiology. These difficulties we shall not ignore, but on the contrary shall stress, since they are likely to prompt a fresh approach to cerebellar physiology, possibly in the not too distant future. The present discussion will center upon the problems of the cerebellar regulation of posture and of reflex or voluntary movements. We are aware, of course, that there are other data showing, or hinting, that the cerebellum may also supervise the autonomic and sensory spheres. These results and their possible significance will be dealt with in the next chapter. Here we are interested merely in finding out how electrophysiological and corresponding anatomical data may be correlated with classical ideas concerning the cerebellar regulation of posture and of movements. From this angle we shall approach the following problems: (a) the spontaneous activity of the cerebellar cortex; (b) the significance of the representation of different sensory modalities within the cerebellar cortex; (c) the localization of functions; and (d) the somatotopic distribution of afferent projections. The fast rhythms which are so easily and constantly led from the cerebellar cortex (Adrian, 1935; Dow, 1938c) represent one, at least, of the electrophysiological manifestations of what had been designed, in classical neurophysiology, as the tonic influence of the cerebellum on other central structures. This identity perhaps is not complete, since potential oscillations of internuncial neurons and even of the final common path of the cerebellar cortex, the Purkinje cell, are not necessarily associated with a tonic discharge in the efferent pathways (Brookhart, Moruzzi, and Snider, 1951). However a close correlation is suggested by

ELECTROPHYSIOLOGICAL EXPERIMENTS 241 two entirely independent findings, namely: (a) "all-or-none" signals of large amplitude (spike discharges) are led with microelectrodes from the Purkinje and granular layers together with Adrian's waves (Brookhart, Moruzzi, and Snider, 1950), and may eventually be shown to arise from intrinsic neurons of the cerebellar cortex; (b) the amplitude of the spontaneous activity led from the socalled inhibitory areas of the anterior lobe (probably lobules IV and V) shows a remarkably close inverse relation to the intensity of decerebrate rigidity (Dow, 1938c). Hence there is little doubt that the tonic barrage of efferent impulses arising in the Purkinje layers is related to the spike discharges and the fast rhythms continuously going on within the cerebellar network. It is tempting to dwell upon the similarities between the "tonus cortical" (Bremer, 1938) of the cerebrum, with its continuous outflow of efferent impulses (Adrian and Moruzzi, 1939), and the cerebellar tone. But when an attempt is made to compare the spontaneous electrical activity of the cerebral and cerebellar cortices under the same conditions—e.g., in the unanesthetized "encephale isole" or "cerveau isole" preparations—we are at once confronted with several difficulties. First and foremost, the slow synchronous rhythms which are so easily led from the cerebral cortex, in normal (a waves) as well as in pathological (strychnine waves) conditions, are never found in the cerebellum (see p. 163). It is true that a slow-rate synchronization may be induced in the cerebellar cortex, even in the decerebrate preparation (Irger, Koreisa, and Tolmasskaja, 1951), by afferent volleys "spontaneously" impinging upon it. But these slower rhythms coexist with and are superimposed on by the fast 200 to 250 waves, which are always present in the record, and actually represent its main feature. The smooth contour of the a waves and their dramatic replacement by faster rhythms during arousal have no counterpart in cerebellar electrophysiology. One would be inclined to draw the conclusion either (a) that the beating of the cerebellar neurons is less easily synchronized or (b) that there is no extrinsic synchronizing force, at least none so powerful as that which might be provided to the cerebrum by the diffuse projection system of the thalamus. These two hypotheses are not mutually exclusive, and the second one is indirectly supported by the convulsive synchronization which occurs in the cerebellar cortex during the epileptic afterdischarge that follows any strong electrical stimulation (Adrian, 1935; Dow, 1938c; Mollica and Naquet, 1953). The difference between cerebral and cerebellar cortices is not only one of synchronization but also of level of activity. Frequencies such as those characterizing Adrian's waves (150 to 250 per second) are never seen in cerebrocortical records, even during the arousal elicited by strong sensory stimulations. Moreover, individual rates of discharge higher than 100 per second are frequently led from single units of the cerebellar cortex (Brookhart, Moruzzi, and Snider, 1950). These facts might explain, incidentally, wrhy the electrical activity of the cerebellar cortex is so strikingly affected by transient anoxia or by a lowered blood pressure (Dow, 1938c). The potential oscillations led from the cerebellar cortex are called "spontaneous" in the sense that they are not conditioned by stimulation intentionally applied to any part of the animal's body, but there is no doubt

242 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM that the uninterrupted barrage of impulses arising in receptors of different modalities represents a powerful driving force. It might be interesting to cut off this continuous play of afferent impulses upon the cerebellum, as is so easily done for the cerebrum by midbrain transection followed by bilateral interruption of both the optic and olfactory tracts. Crepax and Infantellina (1955, 1957) recently attained this goal by preparing an isolated "slab" of cerebellar cortex and reported a waxing and waning of fast activity similar to that occurring in the cerebral cortex after midbrain transection. The problem now arises whether the cerebellipetal impulses simply modulate some kind of activity which we might call "autochthonous" (see Sherrington, 1946, p. 256) in the sense that it does not depend upon continuous or rhythmic afferent discharges impinging upon the cerebellar cortex. The controversy of spontaneous vs. autochthonous activity is one of the oldest in the history of physiology, as any student of the neural control of respiration knows. The experiments of Crepax and Infantellina support the hypothesis of autochthonous activity, since the rate of the fast waves was only slightly reduced (about 20 per cent) and their amplitude was practically normal in the isolated "slab" of cerebellar cortex. It is important to recall that no spontaneous activity was recorded by Burns (1950,1951) and by Infantellina (1955) in the isolated "slab" of cerebral cortex, prepared acutely by a similar technique, but contrary results have frequently been reported (see Ingvar, 1955, for references). We now come to grips with the second of our topics, namely, the functional significance of the representation of different sensory modalities in the cerebellar cortex. It is certainly puzzling to learn that such a striking change in the proprioceptive discharge as is likely to occur when strong decerebrate rigidity is altogether abolished by curare (curare atonia: Bremer and Titeca, 1927) will yield no clearcut reduction in the spontaneous activity of the spinocerebellar projection areas of the anterior lobe (Mollica and Orsini, 1956). Evoked potentials can be led from the cerebellar cortex following stimulation of the proprioceptors (Dow and Anderson, 1942) or of deep nerves (Mountcastle, Covian, and Harrison, 1952; Morin and Haddad, 1953; Morin and Gardner, 1953; Combs, 1954). There is no doubt, nevertheless, that by far the best responses are those elicited by tactile stimuli (see pp. 185-189) or by single shocks applied to superficial nerves (see pp. 195-197). These are unexpected findings. If a prediction had been ventured before the beginning of the electronic era, opinions doubtless would have been unanimous in regarding both stretch-evoked and labyrinthine volleys as the major sources of the reflex regulation of cerebellar activity. The recent discovery that striking effects on the regulation of the spindle bias are obtained by stimulating (Granit and Kaada, 1952) or by inactivating (Granit, Holmgren, and Merton, 1955) the anterior lobe would seem to support this belief, at least if some kind of servomechanism is taken to underlie these phenomena. It is certainly a stimulating hypothesis that the Purkinje neurons which influence the y discharge may be tonically controlled, in turn, by impulses arising in the nuclear bag and the Golgi receptors.

ELECTROPHYSIOLOGICAL EXPERIMENTS 243 We still hold the view that the importance of proprioceptive regulation is not disproved by modern electrophysiological results, and that both the comparatively small size of the stretch-evoked response and the wealth of afferent cutaneous projections may be accounted for, if the data available are properly evaluated. First of all, no reason for believing that the majority of the Purkinje neurons of the spinocerebellar projection area are concerned with the regulation of postural tonus is given by the simple fact that striking effects on decerebrate rigidity are produced by ablation or stimulation of the anterior lobe. The spirit of Rossi's hypothesis (1927) (see p. 255) is actually that the cerebellum, by regulating the tension of the intrafusal muscle fibers, will influence postural tonus through certain "strategic" points of the central nervous system, a large portion of the neural control being then left to purely spinal mechanisms. Hence the striking effects on extensor rigidity brought about, for example, by anterior lobe stimulation might be related to the discharge of only a fraction of the Purkinje neurons. The discharge of the units influencing, say, the cerebral cortex (Moruzzi, 1941a, b, c; Snider, McCulloch, and Magoun, 1949), the diencephalic centers (Moruzzi, 1947c; Zanchetti and Zoccolini, 1954), or the spinal phasic reflexes (Moruzzi, 1935a) would be concealed by the fact that the corresponding structures had been eliminated by decerebration or might be merely neglected for lack of a proper background. In the second place, a single shock applied to the peripheral nerve fibers is more likely to resemble a volley of impulses arising in the fastadapting tactile receptors than the prolonged iterative discharge of the slowly adapting proprioceptors. Slow stretching of a large muscle is undoubtedly a more physiological procedure, but to detect a definite increase in fast potential oscillations against a background of intense spontaneous activity (Dow, 1938c) is difficult, although slow potential drifts may clearly be observed in these experimental conditions (Arduini, 1958). Summing up, the fact that only small responses have been recorded with a.c. amplifiers following single-shock stimulation of deep nerves (Grundfest and Campbell, 1942; Morin and Haddad, 1953; Morin and Gardner, 1953) or sudden stretches applied to a muscle (Dow and Anderson, 1942) appears as after all not entirely surprising. The abundant tactile projections are likely, moreover, to make an important contribution to the cerebellar regulation of posture and of reflex movements. Our attention perhaps has been directed too much toward the proprioceptive mechanisms, and in consequence tactile reflexes may not have been stressed as much as they deserve. If the literature is closely scrutinized, we find nevertheless many observations which can fully be appreciated only when correlated with the demonstration of tactile projections onto the cerebellar cortex. Cerebellar influence on the y motoneurons innervating the intrafusal muscle fibers will be reviewed in another section of this monograph (see p. 255). Let us simply recall here (a) that the anterior lobe has a striking influence on the y discharge (Granit and Kaada, 1952; Granit, Holmgren, and Merton, 1955) and (b) that the y neurons are quite easily driven, reflexly, by skin stimulations (Hunt, 1951; Kobayashi, Oshima, and Tasaki, 1952; Granit, Job, and Kaada, 1952; Eldred and Hagbarth, 1954). We feel that in normal conditions a cerebellar

244 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM influence on the y system, and in particular on y reflexes, would be impossible, or at least meaningless, were not the anterior lobe impinged upon by exteroceptive volleys. This is actually what is shown by the electrophysiological investigation. The lower threshold of the y neurons would easily account for their leading the reflex response. Other evidence hinting that exteroceptive impulses may be important in the cerebellar regulation of the postural tonus is provided by some observations of Rademaker (1931), the significance of which was not emphasized as much as might have been deserved, possibly because they were published when the existence of cutaneous projections onto the cerebellar cortex had not been demonstrated. That the exteroceptive component of the Stutzreaktion, the magnet reaction, is strongly increased in the totally decerebellate dog has been already pointed out but has not been commented upon. Rademaker (1931) showed that the magnet reaction was absent in both the normal and decorticate dog when the animal was lying on its back, whereas the supine position did not prevent the appearance of the reaction in the cerebellectomized animal. Rademaker (1931) measured the Stutztonusstarke (see below, p. 31) in a dog which had been hemicerebellectomized on the right side one month before. The figures were approximately the same when the animal was standing on its feet (6% Kg.) and when it lay on its back (7 Kg.) if the measurements were made on the right hindleg; but the second position brought about a true collapse of the Stiitzstonusstarke (from 8 to 2% Kg.) in the hindlimb still retaining its cerebellar innervation. Rademaker showed quite convincingly that a reflex inhibitory influence arose in the receptors lying in the dorsal part of the skin (p. 288) and concluded, "Die Riickenlage bedingt also bei kleinhirnlosen Tieren eine geringere Hemmung der Magnet- und Stutzreaktion als bei grosshirnlosen und intakten" (p. 403). The most likely explanation of Rademaker's findings—and above all of his striking observations on the hemicerebellectomized dog—would be that stimulation of the dorsal skin brings about a reflex activation of the Purkinje neurons inhibiting the magnet reaction and more generally the supporting tonus. A pure hypothesis but certainly not an unlikely one is that these neurons are those whose electrical stimulation, in the decerebrate cat, inhibits the y (Granit and Kaada, 1952) as well as the a (Terzuolo and Terzian, 1953) discharge of the extensor half-centers. These inhibitory volleys would act on either the midbrain or diencephalon, since the inhibitory effect of posture is abolished, and actually reversed, by decerebration. Hence this type of reflex inhibition appears to be different from that occurring, through reciprocal mechanisms, in Hagbarth's cutaneous reflexes (1952), which are instead clearly present in the decerebrate preparation. A third reason for a close relation between cutaneous receptors and the anterior lobe is found in the cerebellar influence on the placing reactions. These reflexes, mainly exteroceptive in origin, are permanently abolished by destroying the motor cortex (see p. 340). There are many reasons to believe, as will be shown in the next chapter (see p. 339), that the cerebellum has a facilitatory influence on these mechanisms. It is certainly interesting to learn that the same cerebellar areas—namely, the anterior lobe, lobulus simplex, and lobulus para-

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medianus (Snider and Stowell, 1942b, 1944; Snider, 1943; Dow and Anderson, 1942; Adrian, 1943)—that are impinged upon by cutaneous impulses project onto the sensorimotor cortex (Henneman, Cooke, and Snider, 1952), i.e., onto the cortical structures underlying these reflex responses. Summing up, the surprising wealth of exteroceptive projections appears actually justified by the presence of important cutaneous reflexes involving postural tonus as well as spinal and cortical movements. These data do not disprove the existence of a cerebellar influence on the sensory sphere (this problem will be discussed in the next chapter), but we want simply to point out that to assume such an influence is not necessary for explaining the close relation between exteroception and the cerebellum. The discovery of visual and auditory projections onto the cerebellar cortex (Snider and Stowell, 1944) certainly represented a still more unexpected achievement of electrophysiology, and one that at first sight could not so easily be accounted for without leaving the classical position with respect to the cerebellar regulation of movements. Although the functional significance of lobules VI and VII and of their relation to the teleceptors is still largely unknown, it must be conceded that some correlation is likely to exist with the ocular movements that are obtained following stimulation of these or of neighboring cerebellar areas. Lobules VI and VII might supervise, without being necessarily responsible for, the coordination of ocular movements brought about by visual and auditory stimuli. This coordination is an extremely delicate and important task, since a fusion of the images from the two eyes is made possible only when light from an object falls upon both foveas or on corresponding points of the two retinas. It is certainly surprising that the efferent discharges of the oculomotor nuclei of both sides are so precisely regulated, although the eyes are seldom wholly quiet, and small flicker movements occur even in fixation. To the best of our knowledge, these mechanisms have not been investigated in cerebellectomized patients or in animals following ablation of lobules VI and VII. The reflex regulation of ocular movements is mainly related to the activity of subcortical structures, and therefore the hypothesis we have put forward does not account easily for the recent results of Hampson (1948, 1949), Snider and Eldred (1948, 1951, 1952), and Henneman, Cooke, and Snider (1952). As previously reported (see p. 209), these authors demonstrated that impulses from the auditory and visual cortices converge upon lobules VI and VII, while impulses arising in these cerebellar areas reach auditory area I (no clear-cut responses could be led from the visual cortex). The relation between the visual cortex and the cerebellum might perhaps be more easily accounted for if it were possible to show that the cerebellipetal volleys arose in the neurons of areas 17 and 18, whose stimulation yields conjugate deviation of the eyes to the opposite side. Lobules VI and VII would thereby be placed in a position somewhat similar to that of the anterior lobe with respect to the motor cortex. Occipitalpontine fibers have been repetitively described by the neuroanatomists (see Nyby and Jansen, 1951), and Poljak (1927) stated that they were derived from the peri- and parastriate area. It must be conceded, however, that the existence of interrelations between the auditory cortex and the cerebellum is obviously more difficult to ex-

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plain, at least if we are unwilling to leave the usual ground relating to the cerebellar regulation of movements. The labyrinthine and vagal projections will be discussed in the chapters dealing with the relation of the cerebellum to the vestibular (see p. 271) and autonomic (see p. 309) systems. We come now to the third problem defined for discussion, namely, the contribution of electrophysiology to the localization of functions within the cerebellum. Electrophysiological analysis of the afferent cerebellar connections (Dow, 1939), in full agreement with the anatomical data (Dow, 1936) and with the results of ablation experiments (Dow, 1938b; Carrea and Mettler, 1947; Manni, 1950b), shows that the flocculonodular lobe is first and foremost related to the vestibular apparatus. This is perhaps not the whole story, and there is no doubt that anatomical data such as the connections between the caudate nucleus, the rostral part of the medial accessory olive (Walberg, 1954), and the flocculonodular lobe (Brodal, 1940) should prompt physiological investigations. So far only the olivocerebellar connections have been explored electrophysiologically, and the whole of the cerebellar cortex—including the flocculonodular lobe—has been shown to be projected upon by the olivary system (Dow, 1939). An electrophysiological analysis of the efferent cerebellar connections of the flocculonodular lobe has not been attempted so far, possibly owing to technical difficulties. But in view of the anatomical data reported by Dow (1938d) it may be safely predicted that the vestibular nuclei will be heavily impinged upon by impulses arising in these areas of the cerebellar cortex. It should not be forgotten, however, that the vestibular nuclei are influenced also by areas of the corpus cerebelli such as lobules III, IV, and V, not impinged upon by direct vestibular projections. The release of labyrinthine tonus brought about by a complete or incomplete destruction of the anterior lobe (Stella, 1944c; Terzuolo and Terzian, 1953; Moruzzi and Pompeiano, 1955c, 1957a; see pp. 273-280) cannot be regarded perhaps as a clear-cut demonstration of this statement, since lobules I and II were either ablated or possibly functionally encroached upon in these investigations. Even the stimulation experiments (see pp. 120-123) of Moruzzi (1936a) and Koella (1953) do not mean necessarily that labyrinthine nuclei are directly controlled by the corpus cerebelli. Their results might be explained as well by a convergence of cerebellar and of vestibulary impulses upon some spinal structures. But no alternative explanation is left for the recent electrophysiological findings of De Vito, Brusa, and Arduini (1956). They showed that the same Deitersian units were influenced by labyrinthine stimulations and by impulses arising in lobules IV and V (see pp. 230-232). If the assumption is made, first, that this influence of the corpus cerebelli upon Deitersian activity occurs also spontaneously, and, second, that it is controlled by labyrinthine impulses, following the usual patterns of the servomechanisms, the flocculonodular lobe should not be regarded as the unique corticocerebellar area being impinged upon by vestibular receptors. The neural spread of labyrinthine signals might occur through indirect and functionally iterative pathways, which would escape any analysis that employed Marchi or single-shock techniques.

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Summing up, we feel that Larsell's distinction between the flocculonodular lobe and the corpus cerebelli is fully substantiated by anatomical and electrophysiological investigations. Obviously the fact that primary direct vestibular fibers and secondary fibers arising in the vestibular nuclei terminate preponderantly within these narrow areas of the mammalian cerebellum does not imply— and actually was never supposed to mean—that wider areas might not be activated through associational fibers (see Jansen and Brodal, 1954) or through fastigial relays (Ingvar, 1918; Dow, 1936, 1939) and the nucleocortical axons, presumably entering the cerebellar cortex as climbing fibers (Carrea, Reissig, and Mettler, 1947). The classical subdivision, on the other hand, of the corpus cerebelli into vermis and hemispheres, representing respectively the spinal and the cerebral zones of the cerebellum, has not resisted the combined assault of anatomical and electrophysiological investigations. That vermal (Moruzzi, 1941a, b, c) stimulations might influence the cerebral cortex or that corticofugal volleys might reach vermal lobules (Dow, 1942) had already been reported. It remained for Adrian (1943) to give the final electrophysiological demonstration that what had been regarded as an overlapping between neocerebellar and paleocerebellar areas was actually so extensive as to amount practically to a full invasion of the anterior lobe by the corticofugal volleys. Hampson (1948, 1949) as well as Snider and Eldred (1948, 1951, 1952) further extended the scope of Adrian's findings, when they reported that both somatomotor and somatosensory cortical areas projected onto the same cerebellar areas which had been shown by other electrophysiological investigations (Dow, 1939; Adrian, 1943; Snider and Stowell, 1944) to be impinged upon by spinocerebellar volleys, namely, the anterior lobe (lobules III, IV, V and H III, H IV, H V), the lobulus simplex (VI and H VI), the paramedian lobules (H Vllb and H Villa), and occasionally the pyramis and uvula (lobules VIII and IX). The invasion of the spinocerebellar projection area by the corticofugal projections is fully substantiated by recent neuroanatomical work. If we limit ourselves to that part of the spinocerebellar projection area which belongs to the paleocerebellum in the old sense of Edinger (1910) and Comolli (1910)—namely, Larsell's lobules III, IV, V, VI, VIII, and IX—we realize at once that there are at least three structures which may be available for relaying corticocerebellar impulses, namely, pontine nuclei (Sunderland, 1940; Brodal and Jansen, 1943, 1946; Nyby and Jansen, 1951) and paramedian reticular nuclei (Brodal, 1953; Brodal and Torvik, 1954) as well as (for lobules VIII and IX only) the olivary complex (Walberg, 1954). Vice versa, areas belonging to the neocerebellum, as originally defined by Edinger (1910) and Comolli (1910), are heavily impinged upon by spinocerebellar impulses. The intermediate part of the anterior lobe receives spinal impulses passing through Flechsig's tract or via the external cuneate nucleus and the lateral reticular nucleus (see Jansen and Brodal, 1954, pp. 301333). For the paramedian lobule, the anatomical evidence of spinocerebellar projections is not equally satisfactory, but according to Jansen and Brodal (1954, pp. 354-358), spinal paths relayed by the lateral reticular nucleus, spinopontine fibers, and a few spinocerebellar fibers may account for the neurophysiological

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observations, while the bilateral activation of paramedian lobules might be explained by association fibers (Jansen, 1933). From a careful analysis of the available anatomical evidence, Jansen and Brodal (1954, p. 384) concluded that "it seems expedient to dispose of the terms of paleo- and neocerebellum, as they are apt to confuse rather than clarify our conception of the cerebellum." Summing up, if we approach the problem of the localization of functions in the corpus cerebelli from the angle of the afferent projections, we find a wide area which is under the joint influence of corticocerebellar and of spinocerebellar impulses. It corresponds to the vermal and the intermediate parts of the lobulus centralis and culmen, the uvula, the pyramis, and the paramedian lobules—i.e., to Larsell's lobules III, IV, V, VIII, IX, H HI, H IV, H V (with the exception of the lateral part proper of the anterior lobe), and sublobules H Vllb and H Villa. This area appears to be concerned first and foremost with the regulation of a and y discharges in spinal segments. Howsoever the segmental final common paths are activated, whether through the posterior roots or through reticulospinal, vestibulospinal, and corticospinal neurons, this part of the cerebellar machinery is likely to be set in motion. Its influence will be felt, directly or indirectly, at different levels: y (Granit and Kaada, 1952) or a (Terzuolo and Terzian, 1953) neurons; reticular formation (Snider, McCulloch, and Magoun, 1949; Mollica, Moruzzi, and Naquet, 1953; von Baumgarten, Mollica, and Moruzzi, 1954; von Baumgarten and Mollica, 1954; Scheibel, Scheibel, Mollica, and Moruzzi, 1955; Gauthier, Mollica, and Moruzzi, 1956); Deiters' nuclei (De Vito, Brusa, and Arduini, 1956); and cerebral cortex (Moruzzi, 1941a, b, c; Moruzzi and Magoun, 1949). If we assume that the lobulus simplex (VI and H VI) and both tuber and declive (VII) behave toward the motoneurons of the cranial nerves in a somewhat similar manner, we might perhaps venture to give a wider development to our conclusions. From lobule III to lobule IX, from H III to H VI, and from H Vllb to H Villa, the cerebellar cortex appears to be concerned with the regulation of postural tonus, phasic reflexes, and voluntary movements, i.e., with any type of contraction of the skeletal muscles, either innervated by ventral spinal roots or by cranial nerves. As soon as reflex, brain stem, or cortical volleys converge upon the final common path, whenever the a or the y discharge is started and a contraction of skeletal or intrafusal fibers occurs, these cerebellar areas are played upon in multifarious ways by afferent impulses. From the angle of the efferent pathways these areas have an important feature in common, since their efferent projections are relayed entirely (if the long corticofugal fibers are disregarded) by either the fastigial or the interposite nucleus. Hence they might be designated as the interpositofastigial system. The reader is referred to Jansen and Brodal (1954, pp. 188-248) and to Jansen and Jansen (1955) for a description of the efferent connections of these nuclei, but there is abundant anatomical evidence that the whole of the brain stem reticular formation and the vestibular nuclei represent the main spheres of influence of the interpositofastigial system. Through the reticulospinal and vestibulospinal pathways on one side, and through the ascending reticular system on the other side, both the spinal cord and the cerebrum may be controlled by these areas of the cerebellum. The interpositofastigial

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system is also likely to play upon the upper part of the brain stem and on the cerebrum through the fibers of the ascending brachium conjunctivum. As a matter of fact, to quote from Jansen and Brodal (1954, p. 242), "in the cat approximately one-third of the fibers of the ascending brachium conjunctivum pass beyond the red nucleus. Of these fibers about two-thirds are derived from the lateral nucleus while the remaining one-third originate with approximately equal parts from the nucleus interpositus and the fastigial nucleus." The remaining parts of the corpus cerebelli are represented by the lobulus ansoparamedianus and by the paraflocculus, namely, by Larsell's sublobule H Vila and by H VHIb and H IX. Anatomically these areas present a common feature, in that their efferent projections are related entirely and exclusively to the nucleus lateralis (dentatus). This structure is extremely well developed in primates, where the nucleus dentatus represents by far the largest component of the nuclear system of the cerebellum. This corticonuclear complex will henceforth be referred to as the dentate system. A discussion of the electrophysiological investigations dealing with this system will be deferred to the end of the next chapter, after the data on cerebrocorticocerebellar relations have been fully reported. We are now confronted with the last of the problems we have selected for discussion—somatotopic localization within the cerebellum. Conceptually, one should make a distinction between genuine physiological problems (such as the regulation of the postural tone through the a or y mechanisms or the labyrinthine system) and purely morphological problems, even if the latter happen to be intensively investigated in physiological laboratories. The somatotopic arrangement in the cerebellar cortex belongs to this second group. To determine whether Purkinje neurons with the same afferent and efferent projections are grouped in different areas of the cerebellar cortex, and if so grouped, where, is essentially a morphological problem. As a matter of fact, it could be solved by purely anatomical methods if it were possible to follow, for example, the efferent fibers and their relays from each cerebellar folium to the different segments of the spinal cord. That these problems, like those of segmental innervation or of cerebral localization, have been so frequently taken over by physiologists is purely a matter of convenience and ultimately of technical approach. From a physiological standpoint any cerebellar regulation of movements would hardly be thinkable without the assumption that some Purkinje neurons are in some way related to the extrinsic muscles of the eyes and others to the skeletal musculature of the forelimbs or hindlimbs. That differentiation of anatomical constituents occurs in anatomical space may be very helpful for the experimenter, but it is by no means a physiological necessity. This digression on the lack of agreement between anatomical and electrophysiological findings will perhaps be thought the unsolicited excuse that is at the same time a selfaccusation—qui s'excuse s'accuse—and the embarrassing aspect of the situation none would deny. It will indeed be apparent from the brief account of the literature that is given below. A tentative explanation, however, will be suggested at the end of this chapter.

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For simplicity's sake, our analysis may be restricted (a) to those systems which are best known physiologically, namely, the spinocerebellar and the corticocerebellar pathways, and (b) to their termination within the anterior lobe. The results of the anatomical and electrophysiological investigations that have been reported may be summarized as follows: 1. Of the nine spinocerebellar systems which have been anatomically investigated so far—dorsal, intermediate, and ventral spinocerebellar tracts, spinal afferents relayed by the external cuneate nucleus, inferior olive, pontine nuclei, nucleus reticularis tegmenti pontis, lateral reticular nucleus, and paramedian reticular nucleus—none betrays "a somatotopical organization of the distinctness which one might expect to exist from the physiological observations" (Jansen and Brodal, 1954, p. 303), with the possible exception of the spinocerebellar pathway via the lateral reticular nucleus. Even there the sharpness of the arrangement is far from being satisfactory, since "the spinal afferents to this nucleus terminate in a somatotopical manner, although with a considerable degree of overlapping (Brodal, 1949), and there are indications that the 'forelimb' area of the cerebellum receives its fibers vnth some preponderance from the area of the lateral reticular nucleus in which the 'forelimb' fibers terminate, even if there is no sharp localization" (Jansen and Brodal, 1954, p. 303; italics ours). 2. Of the three major systems which, according to our present anatomical notions, are likely to mediate the corticocerebellar impulses—namely, the corticopontocerebellar, corticoolivocerebellar, arid corticoreticulocerebellar pathways— none appears to be somatotopically organized (Jansen and Brodal, 1954). 3. Electrophysiological investigations showed clear-cut somatotopic arrangements of the "evoked" potentials following single-shock stimulation of the cerebral cortex or of sensory nerves or after natural stimulation of different kinds when the experiments were performed on anesthetized (generally barbiturized) animals (Adrian, 1943; Snider and Stowell, 1944; Hampson, 1948, 1949; Snider and Eldred, 1948, 1951, 1952; Combs, 1954). 4. No somatotopic arrangement of the evoked responses was observed when single shocks were applied to peripheral fibers in the unanesthetized decerebrate preparation (Dow, 1939; Bremer and Bonnet, 1951b; Combs, 1954), but sometimes did not appear either in animals under barbiturate anesthesia. Even when the stimuli were electric shocks applied to cutaneous spots of the paws or of the head, a somatotopic localization was found only exceptionally, i.e., when liminal intensities were used. 5. "Diffuse" projections were occasionally reported after single-shock stimulation of peripheral fibers (Dow, 1942; Dow and Anderson, 1942) or of the cerebral cortex (Curtis, 1940; Dow, 1942). That a somatotopic organization of the afferent projections was sometimes found and occasionally missed in barbiturized animals might perhaps be explained by different intensities of stimulation and possibly also by different depths of anesthesia. Combs's experiments are particularly illuminating in this respect, inasmuch as they showed that the somatotopic localization, constantly absent in the unanesthetized decerebrate animal, appeared as soon as the preparation was injected with strong doses of nembutal. Combs (1954) is also responsi-

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ble for the clear-cut demonstration that the "diffuse" responses could not be attributed to an intracortical spread from a primary projection area. In view of the recent advances in our knowledge of the specific and diffuse sensory systems, it might be advisable to distinguish first of all between the possible patterns of afferent projections onto the cerebellum and to state clearly what is meant by such terms as "diffuse projection" or "somatotopic organization." 1. Some afferent projections may really be diffuse, a given cerebellar neuron being impinged upon by impulses arising in different parts of the body and even from receptors belonging to different modalities. This is the type of organization which prevails in the reticular formation. 2. Neurons with different afferent or efferent projections may not be differentiated in anatomical space, but rather be intermingled in the cerebellar cortex. This is another arrangement one could predict from the anatomical data on the afferent pathways (see above). 3. Different anatomical constituents may be differently grouped in the cerebellar cortex. This postulate follows if the theory of somatotopic localization is accepted. The experiments performed by Dow (1942), Grundfest and Campbell (1942), Bremer and Bonnet (1951b), Albe-Fessard and Szabo (1954), and Carrea and Grundfest (1954) with the double-shock technique (see p. 216) do not necessarily prove, in our opinion, that the first hypothesis is true, i.e., that a single neuron, located either in precerebellar nuclei or in the cerebellar cortex itself, may be impinged upon diffusely by impulses of different origin. Facilitatory or inhibitory interrelations are likely to occur between the neurons underlying the surface led from with macroelectrodes: for example, Brookhart, Moruzzi, and Snider (1950) have shown that the spontaneous activity of the cerebellar cortex was occasionally inhibited by an afferent volley. A true diffuseness of projection can be demonstrated only when single-unit discharges are recorded, as they frequently have been for the reticular formation (see, for instance, von Baumgarten, Mollica, and Moruzzi, 1954). To the best of our knowledge this type of evidence has not yet been provided for the cerebellar cortex, and the only experiments that may be cited in this connection concern the functional organization of the dorsal spinocerebellar tract. As previously reported (see p. 217), Laporte and Lundberg (1955, 1956) and Laporte, Lundberg, and Oscarsson (1956b), who led the spike potentials from single axons of Flechsig's tract, showed that the postsynaptic discharge of a given cell of Clarke's nucleus was evoked by the nuclear bag receptors of muscle spindles and was inhibited by other afferents of the same or of antagonistic muscles. Occasionally they found, moreover, that excitatory impulses from different muscles and from the skin converged upon the same Clarke unit. These results are certainly important, inasmuch as they hint that the afferent messages may be heavily manipulated, in several complex ways, at precerebellar levels. To exploit with further experiments this promising approach may be rewarding. Even if it can be demonstrated that a widespread convergence of impulses from different receptors occurs either at precerebellar sites or at the level of the cere-

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bellar cortex, these afferent projections need not be regarded only as "energizers," i.e., as systems concerned with maintaining a critical level of cerebellar activity rather than with specific regulations. As Granit (1955a) has pointed out for other parts of the nervous system, there are several ways, such as changes in the rate of firing or in the rate of spike frequency against time, in which the cerebellar cortex might, so to say, discriminate between different types of information transmitted by a single precerebellar unit. Such results as those obtained by Dow (1939) and by Combs (1954) on unanesthetized decerebrate cats, in which no evidence of somatotopic localization could be found within the spinocerebellar projection area, are exactly what one might have predicted on purely anatomical grounds. They do not mean necessarily that the spinocerebellar projections are diffuse in the physiological sense of the word, but simply that there is no differentiation in the anatomical space. In view of the overwhelming anatomical evidence against somatotopic localization, it is up to the physiologist, we feel, to explain why a somatotopic arrangement is observed under certain conditions and is absent when the experimental parameters are different. It is not up to the anatomist, whose results are both constant and consistent, to account for the occasional somatotopic distribution of the evoked potentials. Bremer (1952b) suggested that the somatotopic foci might correspond simply to those cerebellar areas that are more heavily impinged upon than some others are by the signals arising in the different parts of the body, a suggestion that confronts us with the problem of explaining, anatomically, this uneven distribution of the afferent projections to the cerebellar cortex. We have already stated the reason why we regard it as not yet proved that the burden of the somatotopic distribution of spinocerebellar projections should be placed exclusively upon the lateral reticular nucleus (see p. 195). First of all, no evidence has been reported so far that synaptic transmission occurring, for example, through the columns of Clarke should be more heavily depressed by barbiturates than that occurring within the lateral reticular nuclei. Second, in the experiment performed by Combs on an animal under nembutal anesthesia, the projection areas of the forelimbs and hindlimbs were entirely separated (see Fig. 59), whereas a large overlapping occurs even in the cerebellipetal pathways relayed by the lateral reticular nucleus. Two explanations might be offered in an attempt to account for electrophysiological findings which so far have appeared in sharp conflict with our anatomical notions. It might be suggested that what we lead from the cerebellar surface, under deep barbiturate anesthesia, is actually the potential oscillation due to the incoming afferent volley. Even with high gains, these evoked potentials might be recorded only, or at their best, from those areas of the cerebellar cortex which overlay a large and superficial group of closely packed and synchronously active afferent fibers. This hypothesis is supported by the fact that the spinocerebellar projection areas found by Combs (1954) in deep barbiturate anesthesia were located within the hemispheral part of the anterior lobe, where the white matter is rather superficial. This explanation, which might be tested by selective inactivation of the neurons of the cerebellar cortex, would eventually account for

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those of Combs's experiments in which amounts of nembutal "great enough to stop respiration" did not abolish completely the "evoked" response. There is, however, another physiological interpretation which we regard as more likely, at least when the anesthesia is not too deep. It should never be forgotten that a somatotopic organization of evoked responses was found only when single shocks or brief natural stimuli of threshold intensity were applied. It is no wonder that in those experimental conditions temporal summation was very little effective and synaptic resistances were not easily overcome within the cerebellar network. Obviously this situation became worse when the preparation was injected with barbiturates. It is likely that the postsynaptic activation of cerebellar units was then strikingly reduced, and correspondingly that the fringe of subliminal and inactive neurons was increased, so that each active spot was surrounded by silent zones. If this assumption is accepted, the foreleg or the hindleg areas found under barbiturate anesthesia would merely give us the location of the "ultimum moriens" between the evoked responses. This potential oscillation is likely to be found where an overlapping of functionally homogeneous "boutons terminaux" provides the best arrangements for overcoming synaptic resistances through spatial summation. These areas may or may not appear as more closely related to either foreleg or hindleg receptors, when Marchi or silver methods are used. If this interpretation is accepted, somatotopic localization would concern only the remnants of much wider and largely overlapping "evoked" responses. They might be, so to say, dissected and isolated in barbiturate anesthesia, simply because under these experimental conditions functional organization is extremely simplified.

,5,

Relations between the Cerebellum and Other Central Structures

A. Relation to the spinal cord 1. Regulation of the gamma discharge 2. Coordination of the alpha discharge 3. Interrelations between spinal inhibition and cerebellar facilitation 4. Lasting effects of asymmetrical cerebellar innervation upon motor units and extrafusal musclefibers fibers B. Relation to the labyrinthine system 1. Introductory remarks 2. Cerebellar influence on static labyrinthine reflexes a. The release of tonic labyrinthine reflexes following acute cerebellectomy b. The effects of chronic cerebellectomy on tonic labyrinthine reflexes c. The effects of acute or chronic cerebellectomy on the righting reflexes d. Fastigial influences on labyrinthine tonus and the conflict of cerebellar facilitation with vestibular inhibition e. Vestibular components in the release symptoms elicited by acute cerebellectomy and their compensation by spinal inhibitory mechanisms 3. Cerebellar influence on kinetic labyrinthine reflexes a. The effect of cerebellar ablation on postrotatory nystagmus b. The effect of cerebellar ablation on galvanic nystagmus c. Spontaneous nystagmus after cerebellar ablation d. Cerebellar influence in the habituation of postrotatory nystagmus e. The effect of cerebellar ablation on the reflex responses to linear acceleration. .. C. Relation to the vegetative functions 1. Introductory remarks 2. Effects on circulation 3. Effects on respiration 4. Effects on the endocrine glands 5. Effects on thermoregulation 6. Effects on the general metabolism 7. Autonomic effects on the eyes 8. Effects on the digestive tract 9. Effects on bladder functions 10. Effects on the sexual organs 11. Trophic influences on the muscles and skin

254

255 255 262 265 268 271 271 273 273 280 282 283 283 287 287 287 288 289 290 290 290 291 299 300 302 303 303 305 305 308 308

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 255 12. Effect on the galvanic skin reflex 309 fibers 13. Cerebellipetal projections of fiberseral afferent fibers 309 D. Relation to the cerebral cortex 311 1. The effects of cerebellar stimulation on the cerebral cortex 311 a. Effects on the excitability of the motor area 311 b. Effects on cortically induced movements 311 c. Effects on the electrocorticogram 323 2. The effects of cerebellar ablation on the cerebral cortex 327 a. Effects on the excitability of the motor cortex 327 b. Effects on the motor and on the inhibitory responses of the cerebral cortex .. . 329 c. Electrophysiological investigations 330 3. The effects of combined cerebellar and cerebral ablations 330 a. Compensation of the cerebellar syndrome by the cerebral cortex 330 b. Influence of cerebellar ablation on the precentral motor cortex 332 c. Summation of the tonic inhibitory influences exerted by the cerebral cortex and by the cerebellum on the postural extensor tonus 335 4. The cerebellum and conditioned reflexes 338 E. Relation to sensory functions 344 1. Conclusions drawn from reflex responses to sensory stimulations 344 2. Effects on sensory receptors and on primary sensory neurons 346 3. Effects on postprimary sensory neurons 347 4. Effects on the ascending reticular system 348 F. General considerations 350

A. RELATION TO THE SPINAL CORD 1. REGULATION OF THE GAMMA DISCHARGE ROSSI (1927) was the first to realize that the motor innervation of the muscle spindles was likely to be of major importance in the proprioceptive regulation of muscle tonus. In a paper devoted to the postural asymmetries elicited by localized cerebellar lesions, he went as far as to make the remarkable prediction that "i centri piu elevati non debbano occuparsi, per cosi dire, di inviare impulsi alle cellule motorie che innervano direttamente il muscolo, ma che sia forse sufficiente una loro azione sugli elementi contrattili degli organi di recezione" (p. 148). This statement might still be used to epitomize modern ideas about the regulation of posture and of movements through the y route. It remained for Leksell (1945) to show, in Granit's laboratory, that the efferent innervation of the muscle spindle is provided by y fibers, which constitute about one third of the axons of the ventral roots, while the a fibers represent the classical motor units, and are responsible for the contraction which is routinely recorded in any myogram. It would be beyond the scope of our monograph to review the experimental investigations made in the last ten years. They led to the important discovery that the control of the intrafusal muscle fibers is one of the major tasks of the central nervous system and showed, in particular, that the y neurons may be either facilitated or inhibited by reflex stimulations or by descending volleys arising in widespread supraspinal structures. The reader is referred to Granit's

256 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM Silliman lectures (1955a) for literature and a critical exposition of the available data. The present chapter will center upon the cerebellar control of the intrafusal muscle fibers. Most of the experiments of Granit and Kaada (1952) were made on cats under chloralose-dial anesthesia (20 and 10 nig/Kg respectively), but controls on unanesthetized decerebrate preparations were also performed. The afferent discharge of the muscle spindles was led from isolated fibers of the dorsal roots connected to A-type endings (Matthews, 1933), identified by the silent period occurring during the clonic twitch, and recorded before, during, and after cerebellar stimulation. The efferent y discharge was led from the ventral roots (SI, LI). The afferent discharge arising from the muscle spindles of M. gastrocnemius was increased during stimulation of the hemispheral part of the anterior lobe and strongly decreased, and sometimes altogether blocked, during stimulation of its vermal part (Fig. 99). Myographic records showed that these effects could be dissociated, respectively, from the increase in and the collapse of the extensor tonus yielded by electrical stimulation of the same cerebellar areas (see pp. 115 and 124). Striking changes in the firing rate of the spindles were actually observed for stimulation intensities which were completely ineffective on the tone of the extrafusal fibers. These controls were particularly important not only in demonstrating a cerebellar influence on the intrafusal fibers, but also in showing that the threshold of the response to cerebellar stimulation was lower for the y than for the a motoneurons. Actually the conventional muscular response to any reflex or supraspinal stimulation was usually heralded by a y discharge. Direct evidence of a cerebellar influence on the y neurons was provided by leading from the ventral roots: vermal stimulation inhibited the efferent y discharge. Eldred (1955) reported similar results from stimulations of the dentate and interposite cerebellar nuclei and the brachium conjunctivum.

Figure 99. Inhibition of the muscle spindle discharge from the vermal part of the anterior lobe (culmen). Decerebrate cat. Muscle spindle discharge and myogram of M. gastrocnemius. Myograph at maximum sensitivity except in 1, in which the clonic contraction to a single shock applied to the gastrocnemius nerves demonstrates the silent period. 2—If. Controls before stimulation. 5—10. During cerebellar stimulation at 140/sec. with 1-msec. shocks for 26 sec. 5-7. After 18-20 sec. 8-10. After 24-26 sec. 11-18. Immediately after cessation of stimulation. During the cerebellar stimulation the spindle frequency drops from about 20/sec. to an irregular discharge frequency of about 5/sec. (From R. Granit and B. Kaada, 1952, Influence of stimulation of central nervous structures on muscle spindles in cat, Acta physiol. Scandinav., £7:130-160, Fig. 14.)

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 257 Granit and Kaada (1952) and Granit (1955a) had shown that the muscular spindles are particularly active in the decerebrate preparation, while the experiments of Hunt (1951), of Kobayashi, Oshima, and Tasaki (1952), and of Eldred, Granit, and Merton (1953) suggested "that y hyperactivity leading to intrafusal cramp is an important feature of rigidity" (Granit, 1955a, p. 243). The part played by the y system was actually found to be of major importance in the decerebrate preparation. It is well known that extensor rigidity (Sherrington, 1898) and Magnus's tonic neck reflexes (Liljestrand and Magnus, 1919; Stella, 1944b; Terzuolo and Terzian, 1951b; Terzian and Terzuolo, 1954) disappear following acute deafferentation. Eldred, Granit, and Merton (1953) reported that reflex activation by rhythmic turning of the head in the horizontal plane occurred synchronously for both the a and y systems before dorsal radicotomy. After acute deafferentation, only the y response was present, whereas the a discharge was completely abolished. These findings were explained by Granit (1955a) as follows: "The interpretation of all these experiments is that the y system is there not only to improve the performance of the sense organ but also as an 'ignition mechanism' to initiate movement as well as to maintain tonus. When the loop through the muscle to the ventral horn cell has been interrupted on its afferent side, the y system still operates to carry out its task in the activation of the ventral horn cells, but the nuclear bag impulses are prevented from reaching the latter, and so the a reflexes do not come off. A consequence of this interpretation is that the muscles possessing spindles actually are provided with two motor systems. This being so, cc-y linkage, in which mostly y activity is leading, means that a very large number of motor acts do not at all take place the way one imagined and held to be self-evident, namely that the a contraction simply was put on by whatever circuits happened to be activated. In many if not most natural contractions hitherto studied the y loop was first started, the nuclear bag afferents then facilitated, and the appropriate a motor neurones and direct a activation came last or together with y activity. With this arrangement the sense organs in the muscle are immediately ready to 'measure' during the ensuing contraction" (p. 268). It is worth while to recall, in this connection, that Magnus reflexes are present in the chronically deafferented (Sherrington, 1913; Bremer, 1928; Terzuolo and Terzian, 1951b; Terzian and Terzuolo, 1954) and also in the acutely deafferented forelimbs, following postbrachial transection of the spinal cord (Magnus and de Kleijn, 1912; Liljestrand and Magnus, 1919). These data suggest that the a route may also be utilized by these reflexes. The experiments of Eldred, Granit, and Merton (1953) clearly show, however, that the a motoneurons are more heavily depressed than y neurons by the sudden interruption of the myotatic barrage. Recent experiments by Granit, Holmgren, and Merton (1955) have shown that the a-y linkage can be experimentally destroyed by the functional inactivation of the anterior lobe of the cerebellum. Reversible and clear-cut results were obtained simply by cooling the anterior lobe in the decerebrate cat. In the control records the spindle discharge was rapid and irregular, and any increase in rigidity was heralded by an acceleration of the proprioceptive barrage to still

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higher rates (Fig. 100A). The cooling of the cerebellar cortex increased the extensor rigidity but silenced the spindle discharge (Fig. 1005); re warming the cerebellum restored the original picture (Fig. 100C). The abolition of the spindle discharge was not always complete, but the main result of cerebellar inactivation was that "instead of anticipating and supporting a contraction the spindle behaves passively, pausing during contraction as it does in isolated muscle" (I. c.,

Figure 100. The effect on decerebrate rigidity and on the afferent spindle discharge of cooling the cerebellum. Precollicular cat. Records from the left soleus muscle. Reading downward: response of a single spindle, muscle tension, electromyogram. A. Basal activity. B. Frozen Ringer applied to left side of the cuhnen. Spindle virtually silenced, rigidity increased (tension trace lifted into and just above spindle trace). C. Cerebellum rewarmed with Ringer at 38° C. (From R. Granit, B. Holmgren, and P. A. Merton, 1955, The two routes for excitation of muscle and their subservience to the cerebellum, J. Physiol., 130:213-224, Fig. 2.)

Figure 101. The effect on the Magnus reflexes and on the afferent spindle discharge of cooling the cerebellum. Intracollicular cat. Responses to head flexion of extrafusal fibers (below, tension records) and of the afferent discharge of a single spindle (above, M. soleus), when the cuhnen is cooled by frozen Ringer (A), rewarmed to 38° C (B), and surgically ablated (C) (the lobulus medius medianus was also destroyed). Only in B did an acceleration of the spindle discharge herald and parallel the increase in tension. (From R. Granit, B. Holmgren, and P. A. Merton, 1955, The two routes for excitation of muscle and their subservience to the cerebellum, J. Physiol., ISO:213-224, Fig. 3.)

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 259 p. 216). This shift of emphasis from the y to the a mode of activation was particularly marked during the Magnus neck reflexes (Fig. 101). Surgical ablation of the anterior lobe, in cats decerebrated by the Sherringtonian technique, or its functional inactivation by Pollock and Davis's anemic decerebration yielded similar results, but the authors were careful to emphasize that the paralysis of the y system sometimes did not occur following surgical ablation of the culmen, lobulus centralis, and lobulus medius medianus and was, moreover, never complete after anemic decerebration. They suggested that the different extent of the cerebellar lesion might explain these discrepancies, and some of their data actually hint that corticocerebellar destruction might not account alone for the relative paralysis of the y system. In our opinion it might be important to follow also the recovery of the y mechanisms which is likely to occur after cerebellar ablation. Cooling the anterior lobe is possibly very effective because it involves the sudden disappearance, without irritation, of cerebellar function. While discussing the results reported in Figure 100, Granit, Holmgren, and Merton (1955) made the following pertinent remark: "Were y paralysis the only result of cooling the cerebellum, its effect on rigidity should be the same as that of cutting the dorsal roots. The fact that rigidity, on the contrary, may be intensified can only mean that the proprioceptive excitation of which the motoneurones are deprived is replaced, or even exceeded, by activity in the a pathway" (p. 217). The release of the labyrinthine component of the postural tonus from cerebellar inhibition (Stella, 1944b; see below, p. 274) is the most likely explanation of the fact that the stiffness of the limbs is so strikingly increased by topectomy of the anterior lobe in spite of the decreased myotatic activity brought about by the y paralysis. The striking increase in extensor rigidity elicited by ablation of (Bremer, 1922a) or by cooling (Camis, 1923) the anterior lobe, as well as the opisthotonos and the extreme stiffness of the limbs which occur when the anterior lobe or the whole of the cerebellum is infarcted by anemic methods (Davis and Pollock, 1926; see below, p. 274), was generally ascribed to a release of both the myotatic (Bremer, 1922a) and labyrinthine (Stella, 1944b) component of the postural tonus. It was tacitly assumed by everybody that the rigidity brought about by Sherringtonian decerebration was simply increased, but not qualitatively modified, by the cerebellar topectomy. These concepts should be revised in the light of the discovery of the y regulation of postural tonus. It appears now that decerebrate rigidity is chiefly a myotatic phenomenon, the brain stem facilitation being mainly mediated by the y route, whereas decerebellate rigidity is mainly related to the release of the labyrinthine component of the postural extensor tonus. Obviously a sharp distinction between the two types of rigidity (henceforth designated respectively as y and a rigidity) may have only a didactic value, and the difference is likely to be one of emphasis. The Sherringtonian type is probably due also to a direct release of a motoneurons, while a pure a rigidity may be observed, following cerebellectomy or anterior lobe topectomy, only on completely deafferented legs (see pp. 273-280). There is, however, an important corollary to these concepts, namely that both the a and y systems are likely to

260 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM be influenced by the cerebellifugal volleys. This conclusion is supported also by experimental evidence of a different nature, which will be summarized below. Some pharmacological observations might be more easily explained by Granit's distinction between a and y rigidity. Dordoni (1948b) reported that Sherringtonian rigidity was strongly reduced, in the decerebrate dog, by intravenous or intramuscular injections of 0.8 mg/Kg of morphine chlorhydrate, whereas a dose of even 4 mg/Kg was entirely ineffective after ablation of the cerebellar anterior lobe. Apomorphine (0.04 mg/Kg) was, on the other hand, active in both cases (Dordoni, 1948a). These effects were absent, however, in the cat (Wikler, 1944, 1950; Dordoni, 1951). Similar results were recently reported by Henatsch and Ingvar (1956). They found that the Sherrington type of extensor rigidity was completely abolished, in the decerebrate cat, by intravenous injections of chloropromazine, but stated

that this effect was lacking altogether in the Pollock and Davis preparation, i.e., after functional inactivation of the anterior lobe. They made, moreover, the interesting observation that the strong decerebrate rigidity occurring in the forelimbs after postbrachial transection of the spinal cord was blocked altogether by chloropromazine. They suggested that chloropromazine might have a depressant influence on the reticular structures controlling the y discharge (Granit and Kaada, 1952; see Granit, 1955a). The a rigidity occurring after cerebellar release (Granit, Holmgren, and Merton, 1955) would be unaffected by this centrally acting drug. It might be worth while to recall, in this connection, that curare atonia is easily obtained in the Pollock and Davis preparation or in the decerebrate and cerebellectomized cat (Moruzzi, 1935b). That also the a motoneurons may be played upon by cerebellifugal volleys directly, i.e., without involvement of the y system, was shown by Terzian and Terzuolo (1951) and by Terzuolo and Terzian (1953). They reported that Sherringtonian flaccidity of either an acutely or chronically deafferented leg was replaced, in the decerebrate cat, by a strong extensor hypertonus during lowfrequency stimulation of the ipsilateral side of the vermal cortex (lobules III, IV, and V) of the anterior lobe (Fig. 102). The cerebellar-cortical origin of these responses was shown by their enhancement after the application of 0.1 per cent strychnine and by their depression by local cocaine (Fig. 103). Hence augmentatory effects arising undoubtedly within the stimulated areas of the vermal cortex were clearly observed following experimental destruction of the a-y linkage. At least in these experimental conditions, the cerebellar effect was mediated entirely through the a route. Augmentatory responses were obtained also in the acutely deafferented foreleg of the decerebrate cat, following denervation of the contralateral limb, bilateral labyrinthectomy, and postbrachial transection of the spinal cord. Terzuolo and Terzian (1953, p. 554) pointed out that whenever both myotatic and labyrinthine deafferentations are performed acutely, decerebrate rigidity is never restored by cerebellectomy, so that in these experiments low-frequency stimulation "acts because it induces a cerebellofugal discharge of facilitatory impulses and not because it abolishes the inhibitory tonic activity" of the stimulated area. The second mechanism has been recently postulated by Calma and Kidd (1955).

ented foreleg. A, B. Decerebrate cat after acute deafferentation of one foreleg. Silent electromyogram

of M. triceps brachii, observed at the beginning of records A, B, C, and F, shows complete flaccidity of the deafferented extensor muscle (Sherrington's atonia). A. Low-frequency stimulation of the ipsilateral side of the anterior lobe (10/sec.; 1 msec, pulse duration; 5 V.) yields a strong and long-lasting rigidity. B. A few minutes thereafter, when the background of flaccidity is again present, stimulation at a higher rate of the same area (300/sec.; 1 msec.; 3 V.) is followed by a strong, long-lasting extensor rebound. C-H. Another cat, with chronic deafferentation of one foreleg and of the first three cervical segments. After decerebration, an acute deafferentation of the contralateral foreleg and an acute bilateral labyrinthectomy were performed. Although both myotatic and vestibular sources of the postural tonus were abolished, a long-lasting rigidity of the acutely deafferented muscles was elicited (C) by low-frequency stimulation of the anterior lobe (10/sec.; 1 msec.; 6 V.; records D and E were taken 90 and 150 sec. after C); rigidity, as a postinhibitory rebound (F), also followed highfrequency stimulation of same area (300/sec.; 1 msec.; 4 V.; records G and H were taken 60 and 120 sec. after F). (From C. Terzuolo and H. Terzian, 1953, Cerebellar increase of postural tonus after deafferentation and labyrinthectomy, J. Neurophysiol., 16:551-561, Fig. 1, publ. Charles C. Thomas.)

Figure 103. The increase in both the cerebellar rebound and in cerebellar facilitation fottounng local strychninization of the anterior lobe. Decerebrate cat. Electromyograms from extensor muscles of the acutely deafferented left forelimb. A-D. The facilitating effect of low-frequency stimulation (10/sec.; 1 msec.; 5 V.) of the ipsilateral side of the anterior lobe (A) is no longer observed 60 (B), 120 (C), and 150 (D) sec. after A. E-H. The rebound response (E), following high-frequency stimulation of the same area (300/sec.; 1 msec.; 4 V.), is present 30 (F) and 60 sec. (G), but is lacking 120 sec. (H) after E. I-R. After local 0.1 per cent strychninization of same area, a background of spontaneous extensor rigidity is observed (7). It is still increased 30 (L, P), 90 (M, Q), and 150 sec. (N, R~) after 7 and 0—i.e., after low-frequency (10/sec.; 1 msec.; 4 V.) and high-frequency (300/sec.; 1 msec.; 3 V.) stimulation of the strychninized area. These stimuli elicited, as before, facilitation (7) and inhibition followed by a rebound (0), but the intensity and duration of the postural response were increased. (From C. Terzuolo and H. Terzian, 1953, Cerebellar increase of postural tonus after deafferentation and labyrinthectomy, J. Neurophysiol., 16:551-561, Fig. 2, publ. Charles C. Thomas.)

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Their interesting results (see pp. 218ff) suggest that the tonic inhibitory influence of the cerebellar cortex might be interrupted during low-frequency stimulation, but there is little doubt (a) that augmentatory units are present within the vermal cortex of the anterior lobes (Terzuolo and Terzian, 1953; Moruzzi and Pompeiano, 1954, 1957b) and (b) that their strengthening influence on the extensor motoneurons may be mediated entirely through the a route (Terzuolo and Terzian, 1953). Terzuolo and Terzian's argumentation (1953), however, is weakened by the experiments of Batini, Moruzzi, and Pompeiano (1956a and b, 1957), to be reviewed on pp. 276-280 of this monograph. The same conclusion holds true for the inhibitory influence of the vermal cortex on the antigravity extensor muscles. After acute or chronic deafferentation of the forequarters, a background of extensor rigidity is at once re-established by a postbrachial transection of the spinal cord (Liljestrand and Magnus, 1919; Stella, 1944b). This nonmyotatic rigidity, whose origin will be discussed later (see pp. 273-280), was clearly inhibited by electrical stimulation of the vermal part of the anterior lobe (Stella, 1944a; Terzuolo and Terzian, 1953). Obviously these inhibitory effects were not mediated by the y route. Likewise the inhibition of the convulsive activity of the spinal cord which occurs in the decerebrate and completely curarized cat when the anterior lobe of the cerebellum is stimulated (Terzuolo, 1952, 1954; see above, pp.128-130) cannot be explained by an influence on the y neurons. Granit, Henatsch, and Steg (1956) recently showed on decerebrate cats that the a motoneurons of the extensor muscles, which might be designated as "tonic" because they went on firing for a long duration in a maintained stretch and therefore probably subserved long-lasting postural functions, were characterized by a striking posttetanic potentiation. The "phasic" cells innervating the extensor muscles, which fired only one or two spikes on the rising phase of the stretch, were very little affected by potentiation. Both types of a motoneurons were released by ablation of the anterior lobe, but the effect on the "tonic" cells in the potentiated state was of tremendous intensity. An analysis of spike size showed that the "tonic" ventral horn cells tended to fire smaller spikes than the "phasic" ones. Hence the "tonic" motoneurons "tend to group themselves among the smaller ventral horn cells" (p. 125) . Summing up, cerebellar influence on the postural extensor tonus may be mediated either by impulses impinging directly upon the a motoneurons or by the roundabout way of the y system. The sensitivity of the latter mechanism is greater, but its sphere of influence is obviously limited to the regulation of the myotatic component of the postural tonus. As we shall see (see pp. 273-282) later, the labyrinthine component is also very important, and it is clearly present, moreover, when the a-y linkage has been broken by deafferentation. A direct control of the a discharge is likely to improve the efficiency of the cerebellar regulation.

2. COORDINATION OF THE ALPHA DISCHARGE Howsoever the cerebellar influence is mediated, whether by the roundabout way of the y system or by impulses impinging directly on the a motoneurons or

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES

263

on reticular, vestibular, and cerebrocortical structures, there is no doubt about the immediate cause of the abnormal movements which occur during cerebellar deficiency. Their presence shows that the firing of motor units does not occur in the proper sequence and with the proper intensity. Hence during cerebellar deficiency the spinal keyboard is not played upon harmoniously and the a discharges are not properly coordinated in either space or time. When we were dealing with the cerebellar regulation of posture, the usual scheme of a facilitatory or an inhibitory influence on a pool of functionally homogeneous extensor motoneurons could still be regarded as a useful, though over-simplified, working hypothesis. As soon as we are confronted with the task of explaining cerebellar ataxia, however, the scheme appears utterly inadequate. From the time of Flourens to the present it has been realized that the cerebellum does not act merely as a regulator of the intensity of the postural discharge, but is likely to be concerned also with the spatial and temporal regulation of the activity of all skeletal muscles. When the papers devoted to this fundamental problem are critically reviewed, however, as we are trying to do in this chapter, it is surprising how scanty and often unconvincing are the experimental data that have been gathered so far. Leiri (1924, 1926, 1931), Camis (1926), and Lapicque (1939a) suggested that the cerebellum might be concerned with reciprocal innervation. Before discussing the experiments which were undertaken to test this hypothesis, the following points should be clearly stated. 1. The innervation of a couple of antagonistic muscles is merely one aspect of the much wider problem of cerebellar coordination. The relations between the proximal and distal muscles of the same leg and between the movements of the forelimbs and hindlimbs or of both sides of the body should as well be considered. 2. Reciprocal innervation is generally meant as the lengthening or relaxing of the antagonist that occurs when the excited muscle contracts. Actually this is only one of the varieties of intermuscular relations. Co-contraction and other types of interrelations were frequently observed even on couples of true antagonists. The reader is referred to the articles of Tilney and Pike (1926) and of Pollock and Davis (1930b) for reviews of the old literature and for reports on original experiments. The recent book of Granit (1955a) should also be consulted for a penetrating analysis of findings which were regarded as anomalous simply because it was not realized that "reciprocal action on antagonist meant something only in terms of one type of receptor" (p. 229). From our own angle it appears doubtful that an analysis of reflex or cortically induced muscular responses, influenced as they are in multifarious ways by widespread receptors, will solve the problem of the cerebellar influence on reciprocal innervation. It seems unsafe to compare different animals with and without a cerebellum, when the background to be tested is so variable and unpredictable. 3. Reciprocal innervation is mainly a spinal or brain stem phenomenon. As such, it may possibly be supervised by the cerebellum, but should not be expected to disappear following total or partial ablation of the cerebellum. De Kleijn (1925) recorded simultaneously the myograms of antagonistic ocular muscles in totally and acutely cerebellectomized rabbits. Caloric nystagmus

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was elicited either under ether anesthesia or in the unanesthetized decorticate preparation. Reciprocal innervation was found to be constantly present, since whenever one of the muscles contracted, the antagonist lengthened and relaxed. These findings clearly show that this type of spatial coordination of the a discharges is basically an extracerebellar phenomenon. Obviously a cerebellar influence on reciprocal innervation was not disproved by these experiments. Tilney and Pike (1925, 1926) came to opposite conclusions by recording myographically a couple of antagonist muscles in cats and monkeys, during spontaneous and cortically induced movements. It is doubtful whether the changes in the reciprocal innervation which they reported, following poorly localized lesions of the cerebellum, were true and predictable deficiency effects. Their conclusions were not substantiated, at any rate, by the experiments of Pollock and Davis (1930b), who reported that "co-contraction and reciprocal innervation both occurred as the result of reflex activity, depending upon the particular function to be served" (p. 402) but who emphasized that the results were the same when the background was that of Sherringtonian rigidity or when the rostral part or the whole of the cerebellum had been infarcted by the anemic method. The experiments on subordination chronaxie fall to this chapter. The two-toone ratio in the chronaxies of extensor to flexor motor units had been regarded by Lapicque as an important factor in the mechanism of reciprocal innervation (see Davis and Forbes, 1936). Rudeanu and Bonvallet (1932) reported that the chronaxies were equalized in the pigeon following acute cerebellar lesions. Bartorelli (1941) reported similar findings for the antagonistic muscles of the dog's forelimbs following acute ipsilateral lesions of crus I. These effects occurred simultaneously with Rossi's postural asymmetries (see pp. 73-77) and were abolished by postcollicular decerebration. His findings were confirmed by Sager and Kreindler (1947) in chronically cerebellectomized dogs. Lapicque (1939a) suggested that the cerebellum might coordinate movements simply by regulating subordination chronaxie. The main drawback to this theory is the fact that there is no evidence that the evolution of cerebellar ataxia is really correlated with the chronaxie alterations. The activity of antagonistic muscles has frequently been recorded during stimulation of the cerebellar cortex (Bremer, 1922a; Denny-Brown, Eccles, and Liddell, 1929; Sprague and Chambers, 1954) or of the deep nuclei (Miller and Laughton, 1928a, b; Magoun, Hare, and Ranson, 1935; Hare, Magoun and Ranson, 1936, 1937). The results have been reviewed and discussed in the chapter dealing with stimulation experiments, and it is clear that at least in many instances the responses were not reciprocally organized. Mnukhina (1951) devoted an entire paper to the influence of cerebellar faradizations on reciprocal innervation in the decerebrate cat. He recorded myographically either a couple of antagonists in the same limb or two symmetrical flexors in both hindlegs. A reciprocal organization of the muscle responses was observed when spinal reflexes were elicited by stimulating a sensory nerve, but it disappeared during cerebellar faradization. Unfortunately the localization of the stimulated areas was not given, although the author stated that the best effects were obtained "on the border

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 265 between vermis and hemispheres." It is likely that responses of different sign were obtained when either the vermal or the intermediate part of the anterior lobe was stimulated (see pp. 124-137).

3. INTERRELATIONS BETWEEN SPINAL INHIBITION AND CEREBELLAR FACILITATION The effects of unilateral fastigial lesions on decerebrate rigidity and on the supporting tonus of the otherwise intact cat have been reviewed in another section of this book (see p. 80). It was stated that decerebrate rigidity disappears, or is strongly reduced, ipsilaterally to the electrolytic lesions of the whole (Sprague and Chambers, 1953; Moruzzi and Pompeiano, 1955a, 1956b; Stella, Zatti, and Sperti, 1955) or of the rostral part (Moruzzi and Pompeiano, 1955a, 1956b; Stella, Zatti, and Sperti, 1955) of one fastigial nucleus, whereas the same effect occurs on the opposite side of the body, when the caudal pole of one roof nucleus is destroyed (Moruzzi and Pompeiano, 1955a, 1956b). Hence two syndromes opposite in laterality, henceforth referred to as ipsilateral and contralateral fastigial atonia, are observed, depending upon the localization of the fastigial lesion. Let us confine our discussion to crossed fastigial atonia, the anatomical background of which appears well established. The disappearance of extensor rigidity is probably due to the unilateral interruption of a facilitatory barrage, arising in the caudal pole of each roof nucleus and impinging upon brain stem structures of the opposite side through Russell's hook bundle (Moruzzi and Pompeiano, 1955a, 1956b). If we assume that decerebrate rigidity is conditioned by Russellian facilitation, the hypertonus should disappear bilaterally when the caudal poles of both roof nuclei are encroached upon. Actually the reverse is true. The destruction of the other caudal pole abolishes fastigial atonia and the stiffness of the limbs appears quite strong on both sides of the body. Crossed fastigial atonia cannot be explained, therefore, simply as the result of the withdrawal of Russellian facilitation. The phenomenon appears to be conditioned also by an asymmetry of fastigial innervation. The working hypothesis was made that the unilateral collapse of extensor rigidity in the "atonic" limbs was related to an inhibitory influence arising in the "spastic" side of the body. This hypothesis was substantiated by the experiments of Moruzzi and Pompeiano (1955b, 1957a) that we are now going to describe. They suggest that the postural mechanisms of the side of the body deprived of cerebellar facilitation are easily overwhelmed by a tonic inhibitory barrage arising in the stretch receptors of the "spastic" legs. The experiments were carried out on forty-six decerebrate cats. The extent of the stereotactic fastigial lesion and the integrity of the neighboring deep nuclei and of brain stem structures were controlled on serial Weil and Nissl slides. In order to give concreteness to the description that follows, we refer to one ideal experiment in which electrolytic destruction of the caudal pole of the left fastigial nucleus had been followed by a disappearance of extensor rigidity in both the foreleg and hindleg of the right side of the body (Figs. 104, 105). When a dorsal rhizotomy was performed on the left side of this preparation, say from C 5 to D 2, a strong extensor hypertonus appeared in the right foreleg, while Sherringtonian flaccidity ensued in the deafferented forelimb. The old

Figure 104. Scheme of the experiments on the myotatic inhibitory mechanisms underlying the collapse of extensor rigidity elicited by unilateral caudofastigial lesions. Decerebrate cats, in supine position. A. Sherringtonian rigidity, symmetrical on both sides and stronger in the forequarters. B. Cat A after acute lesion of the caudal pole of the left fastigial nucleus. C. Cat B after deafferentation of the left forelimb or novocaine infiltration of left M. triceps brachii. D. Cat B after deefferentation of the left hindlimb or following left spinal hemisection between D 12 and L 1. E. Cat B following left spinal hemisection between C 4 and C 5. (From G. Moruzzi and O. Pompeiano, 1957, Inhibitory mechanisms underlying the collapse of decerebrate rigidity after unilateral fastigial lesions, J. Comp. Neurol., .707:1-25, Fig. 4.)

Figure 105. Disappearance of extensor rigidity following a contralateral caudofastigial lesion and its reappearance after contralateral deaferentation. A. Rigidity disappears in the right legs following a lesion of the caudal pole of the left fastigial nucleus. B. Following deafferentation of the left forelimb (C 5 to D 2) extensor rigidity ensues in the right foreleg, while Sherringtonian flaccidity is observed in the deafferented limb. The previous fastigial asymmetry persists in the hindquarters. (From G. Moruzzi and O. Pompeiano, 1957, Inhibitory mechanisms underlying the collapse of decerebrate rigidity after unilateral fastigial lesions, J. Comp. Neurol., i07:1-25, Fig. 2.)

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THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 267 fastigial asymmetry persisted in the hindquarters (Figs. 104C; 1055). When deafferentation was limited to the left hindlimb (L 3 to S 2), the same reversal of postural asymmetry occurred, but this time it was localized to the hindquarters (Fig. 104D). The reappearance of extensor rigidity in the previously flaccid right limb was a release effect. The irritative hypothesis was dismissed since (a) the hypertonus persisted in the right limb as long as the preparation remained in good condition (several hours); (b) it was constantly observed when the central ends of the severed dorsal roots were novocainized; and (c) when the deafferentation of the forelimb had been performed chronically, i.e., three days before decerebration, the acute destruction of the caudal pole of the left fastigial nucleus was followed by a disappearance of rigidity only in the right hindleg, while in the right foreleg a good extensor hypertonus was observed. Other experiments suggested that the extensor atonia occurring on the right side of the body was due to reflex inhibition arising in the overstretched proprioceptors of the left side. A release of the extensor mechanisms of the right forelimb could actually be obtained without deafferenting the left forelimb, but occurred whenever the extensor rigidity of this leg was abolished or strongly reduced either (a) by hemisecting ipsilaterally the spinal cord between C 4 and C 5 (Fig. 104.E) (see Sherrington, 1898) or (b) by injecting small doses of novocaine (Fig. 104C) into the left triceps muscle (see Liljestrand and Magnus, 1919). A release of the extensor mechanisms of the right hindlimb was similarly obtained when the rigidity of the left hindlimb was abolished either by an ipsilateral spinal hemisection at D 12 or by severing from L 3 to S 2 the left ventral roots (Fig. 104Z)). The irritative hypothesis could be dismissed, since the results were duplicated by chronic experiments. The caudal portion of the left fastigial nucleus was destroyed chronically, and seven days thereafter the left hindleg was deefferented. When the decerebration was made, two days after the second operation, rigidity supervened at once in the opposite (right) hindlimb, while the typical crossed fastigial atonia was present in the right foreleg. The nature of the receptors that are responsible for crossed inhibition has not yet been determined. Symmetrical extensor muscles of either fore- or hindquarters behave as true antagonists, at least in the walking movements of the cat. In view of the reciprocal organization of the responses of the a motoneurons to an afferent discharge arising in a homogeneous group of receptors (see Granit, 1955a), it may be suggested that the impulses from the nuclear bag receptors of the left extensor muscles exercise an inhibitory influence on the a or y neurons of the extensor half-center of the right side. If this hypothesis is accepted, the question may be raised whether the postural imbalance which follows the left caudofastigial lesion is due either (a) to an increase in the afferent discharge arising in the spindles of the left extensor muscles, following release of the corresponding a and y neurons, or (b) to the fact that the a and possibly the y neurons corresponding to the extensor muscles of the right side collapse under the impact of the crossed inhibitory barrage, as soon as they are deprived of the support of Russellian facilitation. The two hypotheses are not mutually exclusive, but the existence of a Russellian facilitation is suggested

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indirectly by the following considerations. When total topectomy of the anterior lobe is performed in a postcollicular cat, the tonic spasm of the extrafusal fibers becomes so extreme that it can hardly be expected to increase ipsilaterally to the caudofastigial lesion. Because of the relative y paralysis produced by this cerebellar topectomy (Granit, Holmgren, and Merton, 1955), shortening of the intrafusal fibers is also unlikely to occur in the spindles of the extensor muscles of the left limbs. Hence the tonic barrage arising in the nuclear bag receptors of the left extensor muscles should not be substantially increased following an ipsilateral caudofastigial lesion. Moruzzi and Pompeiano (1955a, 1956b) showed that crossed fastigial atonia was clearly present, nevertheless, in these experimental conditions. The most likely explanation of their findings is that the extensor a and y neurons of the right side of the body collapse more easily under the impact of crossed inhibition when they are deprived of the support of Russellian facilitation. The a motoneurons innervating the extensor muscles of the right forelimb are controlled by at least three types of inhibitory reflexes arising in muscle or tendon receptors, namely (a) autogenetic inhibition, arising in Golgi tendon organs and also, probably, in the myotube endings (flower-spray endings of the muscle spindles) of the corresponding muscles (see Granit, 1955a); (b) crossed proprioceptive inhibition (Stella, 1944b; Cardin, 1946a, b, c), possibly arising in the nuclear bag receptors (anulospiral endings of the muscle spindles) of the left extensor muscles; and (c) ascending reflex inhibition, arising in the receptors of the right hindleg (Stella, 1944b, c). In the otherwise intact decerebrate preparation the symmetrical distribution of extensor rigidity is not altered, but it is probably reflexly controlled and improved by the play of the inhibitory influences which each leg exerts on the others, and particularly on its opposite counterpart. However, as soon as a postural imbalance is produced by an asymmetrical caudofastigial lesion, these delicate reflex mechanisms are likely to be disorganized. The influence of the cerebellar lesion on autogenetic inhibition has not yet been investigated. That on crossed proprioceptive inhibition has been the theme of the experiments reported in this chapter. Ascending reflex inhibition is probably unimportant in the mechanism of crossed fastigial atonia, since the extensor mechanisms of the right foreleg were never released by a postbrachial transection of the spinal cord or by deafferenting the right or left hindleg or all the hindquarters (Moruzzi and Pompeiano, 1955b, 1957a). Finally it should be stated that even the ipsilateral fastigial atonia that follows a rostrofastigial lesion in the decerebrate cat (Moruzzi and Pompeiano, 1955a, 1956b), and also all types of extensor hypotonia elicited by chronic fastigial lesions in the otherwise intact animal (Batini and Pompeiano, 1955a, 1957), were reversed when the symmetrical leg was either acutely or chronically deafferented.

4. LASTING EFFECTS OF ASYMMETRICAL CEREBELLAR INNERVATION UPON MOTOR UNITS AND EXTRAFUSAL MUSCLE FIBERS Commenting upon the muscular degenerations which had been occasionally observed following chronic cerebellar lesions, Luciani (1891, 1905) suggested that

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 269 the cerebellum might have a trophic influence on motor units. Krestovnikoff (1928) came later to similar conclusions from a group of experiments devoted to the analysis of an old observation of Patrizi. Patrizi (1905, 1906) had reported that the critical fusion rate for both flexor and extensor muscles was increased by cerebellar ablation. He recorded in the unanesthetized dog the ergogram during repetitive intramuscular stimulation. Following chronic (one to two weeks) hemicerebellectomy the same rate of faradization was found to yield a complete tetanus on the "normal" side, while ipsilaterally to the lesion the tetanus was incomplete. On this side of the body the muscles were also more easily fatigued. This asymmetrical muscular response disappeared during anesthesia, and Patrizi thought that the decrease of the critical fusion rate was simply the consequence of cerebellar atonia. The main drawback in Patrizi's experiments, which were confirmed on dogs by Castagnari (1928) and Krestovnikoff (1928), was that the asymmetrical distribution of postural tone brought about by the hemidecerebellation was obviously strongly modified by the antidromic and orthodromic impulses arising in the nerve endings of the stimulated muscles. Krestovnikoff (1928) reported, however, that following chronic hemicerebellectomy (one to two weeks) and acute severance of the brachial plexus, the myographic response of M. triceps brachii to repetitive stimulation of its motor nerve was modified in exactly the same way. An asymmetry of the peripheral muscular responses was observed also when the chronic lesion had been limited to the lobulus ansoparamedianus (lobules H VII, H VIII) or to lobulus ansiformis (sublobule H Vila). Acute cerebellar lesions were instead ineffective. Krestovnikoff made an attempt to explain his findings by Pavlov's (1922) theory of trophic innervation, and he adopted the views put forward by Camis (1913, 1922b, 1926) and by Kure, Shinosaki, Kishimoto, Fujita, and Sato (1922) about the cerebellar influence on the sympathetic nervous system. Actually his important physiological observations, which unfortunately were not controlled histologically, might suggest that some motor units (possibly those innervating the "red" muscles) were inactivated or damaged by a prolonged deficiency or absence of cerebellar innervation. Even his findings that the tetanus on the operated side became complete when the rate of the stimulation was further increased, whereas its amplitude was sometimes strikingly lower, might be easily explained in this way. As Bremer (1935) rightly pointed out, the muscle alterations might be due to the "retentissement sur la trophicite musculaire de 1'inaction relative qui est a la fois 1'expression de cette hypotonie (le tonus musculaire est un tetanos reflexe partiel des muscles) et la consequence de leur asthenie reflexe" (p. 125). It should be pointed out that a specific trophic influence of the cerebellum on skeletal muscles has not yet been proved. One wonders whether Krestovnikoff's results could be observable after unilateral chronic deafferentation, in the otherwise intact animal; if so, the observation would make obviously untenable the hypothesis of a specific trophic influence exerted by the cerebellum on skeletal muscles. Strack (1941) confirmed Krestovnikoff's data, since he showed that faradic stimulation of the peripheral end of the sciatic nerve, in either dogs or rabbits,

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yielded a smaller muscular response ipsilaterally to the hemicerebellectomy. These physiological observations might perhaps be related to the biochemical data of Martini and Torda (1938), who reported changes in the cholinesterase activity of the rat's muscles following cerebellectomy. The experiments of Di Giorgio and her collaborators showed that an asymmetrical cerebellar innervation was followed by long-lasting changes in the spatial patterns of the motoneuron discharge, which persisted when all connections between the cerebellum and spinal cord had been interrupted. The investigations dealing with Rossi's postural asymmetries, which were usually elicited by unilateral lesions in the area of the lobulus ansoparamedianus (Larsell's lobules H VII, H VIII), have been reviewed in another section of this book (see pp. 73-77). Di Giorgio reported that a postbrachial transection of the spinal cord performed on dogs or rabbits from six hours to two days after a unilateral cerebellar lesion abolished in the hindquarters—as would be expected —both the asymmetrical posture and the asymmetry of the phasic reflexes. The surprising observation was made, however, that the pre-existing asymmetry reappeared a few hours thereafter when the symptoms of spinal shock had faded away (Di Giorgio, 1929a). It reappeared even much earlier, if the spinal depression had been counteracted by pharmacological agents (strychnine, adrenaline) or by hyperventilation (Di Giorgio, 1929c). The functional asymmetry was not muscular in origin, as in Krestovnikoff's experiments (1928), since it was abolished by severing both dorsal and ventral roots or by curare (Di Giorgio, 1929b). Hence an asymmetrical distribution of spinal activity, brought about by the cerebellar lesion, could still be observed when all neural connections between the cerebellum and spinal cord had been interrupted. These unexpected findings were confirmed and extended in further experiments by Di Giorgio (1942b, 1943,1949) and by Mnukhina (1946). The persistence of Rossi's asymmetries was observed when the cerebellar lesion had been made in postcollicular rabbits and dogs (Di Giorgio, 1942b; see above, pp. 76-77) and the spinal cord had been severed after only forty to ninety minutes of asymmetrical innervation (Di Giorgio, 1943). These experiments showed that lasting effects on spinal activity were produced even when the efferent cerebellar pathways were relayed only by bulbopontine structures. When cerebellar asymmetries were elicited in the acutely deafferented forelimbs of the dog (Di Giorgio and Menzio, 1946a-d), they were increased by a postbrachial transection of the spinal cord, but not abolished by severing the spinal cord at the second cervical (Di Giorgio, 1946). Hence the "memory" of a past asymmetrical cerebellar innervation was retained in isolated and deafferented (from C 2 to D 3) segments of the spinal cord (Di Giorgio, 1947). The duration of the asymmetrical cerebellar innervation which is required for producing lasting changes in the spinal cord was determined in the pigeon by Manni (1949b). Postural asymmetries of the pelvic limbs were elicited by unilateral ablation (Manni, 1948b) or strychninization (Manni, 1949b) of the lobus medius. They were never observed when the interval between the beginning of the cerebellar response and the thoracic transection of the spinal cord was less than seven minutes. After three or four local applications of 1 per cent strychnine

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 271 for ten to eighteen minutes, or thirty to sixty minutes following a unilateral lesion, the long-lasting spinal effects were quite marked and persisted for some days (strychnine) and even for three to four weeks (surgical ablation). The duration of these long-lasting spinal effects did not increase when the interval between the cerebellar lesion and the spinal transection was prolonged from one hour to one to five days (Manni, 1949b). The bilateral ablation of the sympathetic chain corresponding to the isolated portion of the spinal cord was reported to have no effect on these cerebellar asymmetries (Giulio and Manni, 1950). B. RELATION TO THE LABYRINTHINE SYSTEM

1. INTRODUCTORY REMARKS Any review of cerebellovestibular relations must start with the classic papers by Magnus (1914) and by de Kleijn and Magnus (1920). Complete cerebellectomies were performed by the Utrecht investigators on decerebrate and on otherwise intact cats, as well as on decerebrate and on thalamic rabbits. The completeness of the ablation was controlled histologically in every experiment. Only a few folias of the flocculus turned out to be frequently spared by the lesion, but their connections with the brain stem had been, as a rule, interrupted, so that the cerebellectomy could be regarded as functionally complete. Both labyrinthine and cervical reflexes were reported to be constantly present in all these cerebellectomized animals. De Kleijn and Magnus (1920) rightly maintained (a) that the pathways mediating the main cervical and labyrinthine reflexes do not course through the cerebellum, but (p. 172) they were careful to point out (b) that their findings did not disprove the hypothesis of a cerebellar influence upon the brain stem structures underlying the reflex response to vestibular stimulation. Modern investigations are nothing but the development of these fundamental ideas. The first statement by de Kleijn and Magnus (1920) was substantiated by all the later investigators (Dusser de Barenne, 1923, 1937; Rademaker, 1931), the only exception being Bard et al. (1947) in their experiments on motion sickness (see p. 54). These investigations concerned, however, autonomic reflexes, which had not been considered by de Kleijn and Magnus (1920). Particularly important are the accurate investigations of Rademaker (1931), who reported that all the righting reflexes—namely, labyrinthine, body, neck, and optical reflexes—were present in his dogs and cats, which were examined after total chronic cerebellectomy. The second statement clearly shows that the Utrecht investigators fully realized that neither the arrival of labyrinthine impulses to the cerebellum nor the cerebellar contribution to the maintenance of equilibrium was disproved by their experiments. It should be emphasized here that the old (Magendie, 1824; Ferrier, 1876; Andre-Thomas, 1897; Ingvar, 1918) as well as the new (Dow, 1938b; Carrea and Mettler, 1947) views and experimental data on the syndrome of disequilibration brought about by cerebellectomy or by ablation of the flocculonodular lobe alone (see pp. 55-56) might be accounted for quite easily by postulating a cerebellar control of the brain stem mechanisms underlying the labyrinthine reflexes.

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PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM Actually this view was held by Simonelli and Di Giorgio (1925, 1926). They reported that the labyrinthine reflexes were strikingly modified by asymmetrical cerebellar lesions, whereas total cerebellectomy was much less effective. The importance of creating a background of asymmetrical cerebellar innervation does not inhere simply in the possibility of detecting minor differences between the two sides of the body, as was surmised by Luciani (1891); but also, and possibly still more, in the fact that any asymmetrical cerebellar lesion precipitates a major imbalance in the mutual interrelations between the vestibular nuclei of the two sides (Moruzzi and Pompeiano, 1955c, 1957a; see pp. 283-287). The results of Simonelli and Di Giorgio (1925, 1926) might of course be explained simply by the convergence of vestibular and cerebellar impulses on the final common path. That labyrinthine impulses reach the flocculonodular lobe of the cerebellum (Dow, 1939) and that Deitersian units may be influenced by cerebellifugal volleys (De Vito, Brusa, and Arduini, 1956) was shown many years later by electrophysiological experiments, which have been reported in another section of this book (see pp. 230-232). Most of the old theories on vestibulocerebellar relations and most of the experiments in support of them became of course obsolete after the publication of the results obtained by the Utrecht investigators. These old papers will now be briefly reviewed, mainly for the sake of completeness and historical interest. Nineteenth-century investigations on the physiology of the vestibular apparatus were generally performed on birds. It was from a long series of avian experiments that Ewald (1892) proposed his famous doctrine about the labyrinthine influence on postural tonus, a conception that was fully substantiated many years later by the experiments performed on pigeons by Groebbels (1927a and b, 1928a and b, 1929a, b, c) and by all the modern investigations on mammals (see the next section). Stefani (1877, 1881, 1903, 1920) suggested that the vestibular reflexes of the pigeon might course through the cerebellum and made an attempt to reconcile Ewald's and Luciani's views on vestibular and on cerebellar tonus. He supported his doctrine (a) by anatomical data showing the existence of close connections between the vestibular system and the cerebellum and (b) by the similarity between the symptoms occurring after labyrinthectomy and those following cerebellectomy. His observation that the Purkinje cells of the pigeon cerebellum occasionally degenerate following chronic labyrinthectomy (Stefani and Weiss, 1877; Deganello, 1900; Malesani, 1909) was not confirmed, however, on the adult bird (Spamer, 1880; Obersteiner and Exner, 1891; Fano and Masini, 1893; Marx, 1907; Maestrini, 1913; Groebbels, 1928a). On the other hand, the physiological investigations performed on pigeons by Groebbels (1927a and b, 1928a and b, 1929a, b, c) showed that the symptoms elicited by unilateral cerebellar and vestibular lesions were actually opposite in sign, suggesting, therefore, that a tonic inhibitory influence is exerted by the cerebellum on the vestibular nuclei. Stefani's views were embodied also in the theories of Bechterew (1909) and of Barany (1912a, b, c; 1913), which were widely accepted, mainly in the field of clinical investigation. It is sufficient to say here that the experiments on subprimate mammals and on man, which were made in order to test these views, may be easily explained in other ways (Simonelli and Di Giorgio, 1925, 1926).

THECEREBELLUMAND OTHERCENTRALSTRUCTURES 273 It is only fair to add that the experiments that were believed to disprove Stefani's views appear now equally unconvincing. The works by Wilson and Pike (1914) on the turtle, by Lowenberg (1873), Spamer (1880), and Lange (1891) on birds, and by Hogyes (1881), Beyer and Lewandowski (1906), Barany, Reich, and Rothfeld (1912), Wilson and Pike (1913), Rothfeld (1914), and Papilian and Cruceanu (1925a) on mammals were often cited as evidence of the extracerebellar course of the vestibular reflexes. These data, however, are unreliable because the cerebellar ablation was sometimes admittedly incomplete and, moreover, was never controlled histologically. Hence it might be surmised that the presence of labyrinthine reflexes after partial cerebellectomy was due to the fact that the basal cerebellum, and in particular the flocculonodular lobe, had probably been spared by the lesion. In short, there is little doubt that modern physiology on vestibulocerebellar relations starts with the experiments of Magnus (1914) and of de Kleijn and Magnus (1920). The latter authors (p. 175) rightly pointed out that their results could be easily predicted from Luciani's observation (1891) that swimming was not seriously altered following cerebellectomy. Since labyrinthectomized animals are unable to swim, it was apparent that vestibular reflexes were not destroyed by total cerebellectomy. Had this simple inference been made thirty years before, doubtless a fierce controversy, as well as many unconvincing experiments and theories, would have been avoided.

2. CEREBELLAR INFLUENCE ON STATIC LABYRINTHINE REFLEXES Vestibular reflexes elicited by a position of the head in relation to the dimension of space (Magnus's "Reflexe der Lage"), arising in macular receptors, influencing bulbopontine (Magnus's tonic reflexes) and midbrain (Magnus's "Stellreflexe": righting reflexes) structures, are directly supervised by the cerebellum. The evidence for that is overwhelming and will be reported in this section. A third group of static labyrinthine reflexes is represented by the otolithic reflexes acting upon the eyes. They are clearly affected by ablation of the flocculonodular lobe (Manni, 1950b; see above, p. 54). a. THE RELEASE OF TONIC LABYRINTHINE REFLEXES FOLLOWING ACUTE CEREBELLECTOMY

Sherrington's discovery (1898) that decerebrate rigidity is abolished by deafferentation was for a long time regarded as the best evidence of the reflex (mainly myotatic) origin of postural extensor tonus. Liljestrand and Magnus (1919) were the first to point out, however, that labyrinthine and cervical reflexes might represent an alternative source of afferent impulses. They actually made the important observation that after deafferentation of the forelimb "es ist nun moglich gewesen, durch Durchschneidung des Riickenmarkes in untersten Brustteil und durch geeignete Lagerung des Kopfes bei den Tieren hinreichen starke Starre des Triceps zu erzielen" (p. 179). At that time the importance of Schiff-Sherrington inhibition was not fully understood, and this remarkable observation was entirely forgotten. Many years later Pollock and Davis (1931)

274 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM reported that extensor rigidity was present in their anemically decerebrate cats, despite complete chronic deafferentation. It remained for Stella (1944b, c) to give a convincing explanation of the physiological meaning of all these findings. He confirmed the observation that following postbrachial transection of the spinal cord extensor rigidity ensued in the acutely deafferented forelimbs of decerebrate cats or dogs. The same result occurred also when a vermal area corresponding approximately to Larsell's lobules II, III, IV, and V was either extirpated or cooled. He rightly argued that the rigidity observed in the deafferented limbs of Pollock and Davis's cats was due to the fact that the anterior lobe had been infarcted by the anemic procedure. The main conclusion of Stella (1944b and c, 1946) was that decerebrate rigidity is abolished by deafferentation, not because the stretch reflexes are the only source of extensor tonus, but owing to the fact that the nonmyotatic component of the postural tonus is completely inhibited. The flaccidity of the deaiferented leg would result, therefore, from active inhibition arising in the cerebellum or in the lumbosacral segments of the spinal cord; it is not exclusively due, as had been previously surmised, to sheer lack of reflex excitation. The main objection that might be raised to Stella's views is that all these effects might be due to irritation. This hypothesis is disproved, however, by several observations: (a) extensor rigidity is lacking even in chronically deafferented legs if the decerebration is performed in the usual way (Sherrington, 1898; Terzian and Terzuolo, 1954), but it is at once replaced by strong spasticity when the surface of the anterior lobe is cooled (Terzian and Terzuolo, 1954); (b) a minimal amount of irritation is obviously involved in the anemic inactivation of the cerebellum (see Pollock and Davis, 1931); (c) Schiff-Sherrington release phenomena may be obtained by a cold block of the spinal cord (Ruch and Watts, 1934), and a clear-cut release of the antigravity mechanisms occurs when the surface of the anterior lobe is cooled (Camis, 1923; Stella, 1944b, c). The nonmyotatic component of decerebrate rigidity, which is so strikingly released by cerebellectomy or by postbrachial transection of the spinal cord, is represented mainly by the tonic labyrinthine reflexes. Their importance was not recognized for many years, possibly because they were overshadowed by the myotatic reflexes. As a matter of fact, most of the experimenters worked on animals decerebrated in the classical manner, whose dorsal roots had been left intact. We know that in these conditions we have a background of y rigidity (Granit, Holmgren, and Merton, 1955; see above, pp. 257-259), which obviously is predominantly driven by the afferent barrage arising in the stretch receptors. Sherrington's observation (1898, p. 326) that in a monkey, decerebrated five hours after intracranial section of the left nervus octavus, extensor rigidity "quickly set in and developed with about equal rapidity and in about equal degree on the left and on the right side" can now be easily explained in this way. Actually by perusing Magnus's protocols (1914: see, for example, p. 235) one sees that Sherrington's findings were not confirmed when the same operation was performed on a decerebrate and decerebellate cat. Magnus reported that the most intense rigidity of this preparation strongly decreased ipsilaterally to the section of the eighth nerve. We know that after decerebellation we are confronted with

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275

a rigidity of the a type (Granit, Holmgren, and Merton, 1955), which apparently is more heavily affected than y rigidity by labyrinthine deafferentation (see above, p. 259). The striking release of tonic labyrinthine reflexes that occurs following cerebellectomy was first recognized by Pollock and Davis (1927). They produced a complete functional inactivation of the cerebellum by tying the inferior cerebellar arteries in their anemically decerebrated cat. After this operation, "if the head of the decerebro-cerebellate animal was turned vertex down, the forelegs were thrust forward suddenly with great force and with unsheathing of the claws. The force of this tonic contraction was so great that often the whole body was displaced. Its sudden appearance was tetanic, startling and entirely dissimilar to anything observed in an ordinary decerebrate preparation" (p. 305, italics ours). They reported, moreover, that an extreme opisthotonos occurred in their decerebro-cerebellate animals (see Fig. 6), and pointed out that the dorsiflexion of the head was likely to increase the rigidity of the forelegs through the play of Magnus's cervical reflexes. When both labyrinths were destroyed in the decerebrocerebellate cat, the opisthotonos entirely disappeared. Such an extreme opisthotonos is never observed in the ordinary decerebrate animal, unless a postoperative hemorrhage occurs and blood is found below the tentorium (Bazett and Penfield, 1922). It is likely that in these cases the anterior lobe is partially inactivated. Pollock and Davis rightly concluded from their experiments that the "cerebellum as a whole inhibits tonic labyrinthine reflexes" (1. c., p. 306). Stella (1944b) maintained that the nonmyotatic component of extensor rigidity, which is released by complete cerebellectomy, by topectomy of the anterior lobe or by postbrachial transection of the spinal cord, is mainly labyrinthine in origin, since the rigidity of the deafferented forelegs was not abolished by bilateral dorsal radicotomy from C 1 to C 4, i.e., following the interruption of all Magnus's cervical reflexes, whereas it disappeared ipsilaterally to the acute section of the eighth nerve. Summing up the conclusions of fifty years of physiological investigations— from Sherrington (1898) to the last works of Granit and his colleagues (see p. 255)—the following statements may be made: (a) both muscle and labyrinthine receptors support reflexly the postural extensor tonus; (b) following cerebellectomy the importance of the myotatic component of extensor rigidity is reduced by y paralysis, while that of the vestibular component is on the contrary increased through a release mechanism; (c) the disappearance of extensor rigidity following deafferentation shows that the vestibular component is totally and tonically inhibited by cerebellar or spinal (Schiff-Sherrington) mechanisms. Before going on with our survey, it is perhaps advisable to emphasize that the extensor rigidity of deafferented limbs is not exclusively supported by tonic labyrinthine reflexes. There are other neural mechanisms, which also appear to be tonically inhibited by the cerebellum. They are represented by Magnus's cervical reflexes and, possibly, by other components of the postural tonus. Magnus's cervical reflexes are undoubtedly released when the anterior lobe of the cerebellum is infarcted by the anemic procedure. Pollock and Davis (1927, 1930b) reported the following results on labyrinthless cats decerebrated with their

276 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM anemic method: "When suspended, such an animal assumed a good decerebrate rigidity in the fore- and hindlegs. Shortly afterward, the head began to droop and the rigidity lessened in the forelegs. If the head was passively extended and suddenly released, it dropped into a position of flexion, and the forelegs were convulsively flexed in all joints and adducted. At the same time the hindlegs were more rigidly extended backward" (1930b, p. 391, italics ours). (See Fig. 106.) They pointed out (1930b, p. 392) that rigidity in flexion was "as great as rigidity in extension in an ordinary decerebrate animal" and stated that this posture was retained until the head was passively extended. In the classic paper of Magnus and de Kleijn (1912) the same type of experiments had been carried out, but on cats decerebrated by Sherrington's technique. From the detailed description there (pp. 480-481) one gets the impression that active flexion was inconstant and by far less evident than after anemic decerebration. The striking changes of extensor rigidity that were observed in the labyrinthless cats of Pollock and Davis (1927, 1930b), following movements of the head, were obviously due to cervical reflexes. These reflexes probably had been released from the tonic inhibitory influence of the vermal part of the anterior lobe, which is functionally inactivated by the anemic decerebration. An attempt to unravel the different components of the release phenomena occurring in the deafferented forelimbs of the decerebrate preparation, following postbrachial transection of the spinal cord and/or cerebellectomy, was recently made by Batini, Moruzzi, and Pompeiano (1956a and b, 1957). Their experiments were made on twenty-two cats, and the extent of the lesions was always controlled histologically on serial slides. They first confirmed Liljestrand and Magnus's observation (1919) that in the decerebrate cat the flaccidity of the bilaterally deafferented forelimbs (Fig. 107A) was replaced by extensor rigidity following postbrachial transection of the spinal cord; they stated, however, that

Figure 106. A suspended, anemicatty decerebrated cat following destruction of the labyrinths. Flexor spasticity of the forelegs when the head is dropped into a position of flexion. (From L. J. Pollock and L. Davis, 1930, The reflex activities of a decerebrate animal, J. Comp. Neurol., 50:377-411; from the original of Fig. 5.)

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 277 there was never opisthotonos in such a preparation (Fig. 107B). This symptom appeared only later, when both roof nuclei were destroyed electrolytically with stereotaxically oriented electrodes (Fig. 107(7). Following bilateral fastigial destruction, opisthotonos was observed throughout the animal's survival (up to thirty-six hours). Even when the forelimbs of the decerebrate cat had not been deafferented there was no opisthotonos, if only a postbrachial transection of the spinal cord had been performed. This symptom ensued immediately upon bilateral stereotaxic destruction of both roof nuclei. Hence two different types of release are brought about, in the decerebrate cat, (a) by postbrachial transection of the spinal cord and (b) by bilateral destruction of the roof nuclei. The opisthotonos was observed only after the cerebellar lesion, and the further increase in forelimb rigidity that was then noticed was probably the consequence (in part, at least) of the cervical reflexes elicited by the new position of the head. Opisthotonos and extensor rigidity of deafferented forelegs are related, moreover, to different mechanisms. A bilateral deafferentation of both forelimbs was performed during the same operation in which both fastigial nuclei were destroyed. Two to eight days thereafter the animals were decerebrated and the spinal cord was severed at thoracic levels. Both forelimb rigidity and opisthotonos were clearly present (Fig. 108A). After bilateral transection of the eighth nerve, the opisthotonos disappeared, but the extensor rigidity was still present in the deafferented forelegs (Fig. 108(7). The completeness of the vestibular deafferentation was shown by the abolition of the cephalogyric and postural responses to galvanic stimulation of the labyrinths, and was later checked anatomically. The rigidity without opisthotonos lasted as long as the preparation (up to eleven hours), and therefore could hardly be ascribed to irritation. The short interval between the two operations (down to two days) precluded also the possibility of Cannon's sensitization of the deafferented spinal segments. Hence opisthotonos appears to be a labyrinthine phenomenon which is tonically inhibited by the cerebellum. But there is still decerebrate rigidity when both the myotatic and labyrinthine sources of postural tonus have been abolished, although the tension developed by the extensor muscles is obviously reduced. It is apparent from all these findings that the rigidity ensuing in the deafferented forelegs after postbrachial transection of the spinal cord is by no means exclusively labyrinthine in origin. However, the importance of the vestibular impulses in the regulation of postural tonus is so great, and it is often so difficult to disentangle the labyrinthine from the other nonmyotatic components of extensor rigidity, that the term "labyrinthine rigidity" has been retained in this book. This will also simplify our description. For the same reasons all experiments on the mechanism of decerebrate rigidity in the deafferented legs are being reviewed in this section, which is primarily devoted to cerebellovestibular relations. The observation that the decerebrate rigidity occurring in the deafferented forelegs following cerebellectomy and/or postbrachial transection of the spinal cord is not abolished by severing both nervi octavi would seem to be in conflict with Stella's report (1944b, c) that this type of extensor hypertonus collapsed ipsilaterally to the transection of only one of these nerves. Actually Batini, Moruzzi, and Pompeiano (1956a and b, 1957) were able to confirm Stella's obser-

Figure 107. Different release effects elicited by postbrachial transection of the spinal cord and by a bilateral total fastigial lesion. Intercollicular cat, after bilateral forelimb deafferentation (A), followed by postbrachial transection of the spinal cord (B) and, later, by a bilateral total fastigial lesion (C). The release from Schiff-Sherrington inhibition yielded extensor rigidity in the deafferented forelimb (B), but opisthotonos appeared only after the bilateral fastigial lesion (C). (From G. Batini, G. Moruzzi, and O. Pompeiano, 1957, Cerebellar release phenomena, Arch. ital. de biol., 95:71-95, Fig. 1.)

Figure 108. Labyrinthine influences on the opisthotonos and on the antigravity tonus of the deafferented forelegs following a bilateral fastigial lesion, decerebration, and postbrachial transection of spinal cord. The cat was decerebrated by the trephine method 3 days after bilateral deafferentation of the forelimbs (C 5 to T 2) and bilateral, total destruction of the roof nuclei. After decerebration the spinal cord was transected at D 12. A. Opisthotonos and forelimb rigidity following postbrachial transection of the spinal cord. B. Same cat, after transection of the left VIII nerve. Collapse of extensor rigidity in the left forelimb. C. Bilateral extensor rigidity, without opisthotonos, following transection of the right VIII nerve. (From C. Batini, G. Moruzzi, and 0. Pompeiano, 1957, Cerebellar release phenomena, Arch. ital. debiol., 95:71-95, Fig. 2.)

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vation (Fig. 1085). They showed, moreover, that the striking ipsilateral melting of this type of extensor rigidity could be reproduced, in a reversible manner (ten to twelve minutes), by injecting 1 per cent novocaine into the fenestra ovalis. Hence this effect was certainly not due to irritation. When the eighth nerve was interrupted by electrolytic lesions, the completeness of the severance was controlled physiologically (galvanic test) and anatomically, and the effect was found to persist unmodified up to the moment of the second labyrinthine deafferentation (four hours). It was the section of the opposite eighth nerve that revealed the nature of the ipsilateral melting of the extensor rigidity. A clear-cut extensor hypertonus appeared in the previously flaccid forelimb, and the rigidity became symmetrical and quite evident in the forequarters (Fig. 108C). This posture persisted unmodified throughout the animal's survival (up to eleven hours). These experiments would suggest, according to Batini, Moruzzi, and Pompeiano (1956a and b, 1957), that the collapse of the nonmyotatic rigidity brought about by severing the ipsilateral eighth nerve is not only related to the abolition of the tonic inflow of labyrinthine impulses, but also to an inhibitory effect of afferent volleys arising from the vestibular receptors of the opposite side. A reciprocal response of the vestibular nuclei to the labyrinthine volleys arising on each side of the body is substantiated also (see pp. 230 and 283) by the electrophysiological experiments of De Vito, Brusa, and Arduini (1956), and by the disappearance of fastigial atonia that occurs in the deafferented forelimbs contralaterally to the section of the eighth nerve (Moruzzi and Pompeiano, 1955c, 1957a). The nonmyotatic, nonlabyrinthine extensor rigidity observed by Batini, Moruzzi, and Pompeiano (1956a and b, 1957) might be due to cervical reflexes, since in their experiments the dorsal radicotomy was started at C 5. We are now going to review other observations, which were made on labyrinthless cats whose cervical reflexes had been abolished by dorsal radicotomy from C 1 to C 4. Unfortunately, these experiments were carried out several days after forelimb deafferentation, and therefore, as Bremer (1932) pointed out, the results were likely to be influenced by Cannon's sensitization. Sherrington (1898) remarked that "rigidity develops either imperfectly or not at all when the afferent roots have been severed some time, i.e., a number of days prior to carrying out the operation which produces rigidity" (p. 323, italics ours). Hence both acutely and chronically deafferented animals behave more or less in the same manner with respect to decerebrate rigidity, provided the operation is performed by the classical methods. Anemic decerebration, as previously pointed out, acts by inactivating the anterior lobe of the cerebellum. Terzuolo and Terzian (1951a, b) and Terzian and Terzuolo (1954) confirmed that no extensor rigidity developed in chronically deafferented forelimbs when the animal was decerebrated by routine methods and the excitability of the cerebellum was good. These data obviously showed only that Cannon's sensitization of the chronically deafferented spinal segments was simply unable to compensate for the lack of myotatic innervation and to overcome the tonic inhibitory influences exerted by spinal (Schiff-Sherrington) and by cerebellar structures. There is no doubt, nevertheless, that the reflex response of chronically deafferented forelimbs to laby-

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rinthine stimuli is greatly enhanced (Bremer, 1928), and this fact is likely to influence the interpretation of the experiments which we shall now review. Cardin (1951) as well as Terzuolo and Terzian (1951a, b) and Terzian and Terzuolo (1954) showed that even if the bilateral section of the eighth nerve was supplemented by the deafferentation of the rostral cervical segments, thereby abolishing all Magnus reflexes, a clear-cut hypertonus ensued in the chronically deafferented forelegs, provided, of course, the routine decerebration was combined with either postbrachial transection of the spinal cord or with cerebellectomy (Cardin, 1951; Terzuolo and Terzian, 1951a, b; Terzian and Terzuolo, 1954). The neural origin of this nonmyotatic, nonlabyrinthine rigidity was shown by the fact that it could easily be inhibited by stimulating Magoun's bulbar inhibitory center (Terzian and Terzuolo, 1954). Whether this type of extensor rigidity is "autochthonous" in Sherrington's sense (1946, p. 256), as was suggested by Cardin (1951, 1952a, b), or reflexly supported by the remaining afferent pathways of the cranial nerves, cannot be decided at present. At any rate it is likely to be related to, or at least influenced by, Cannon's sensitization of spinal segments produced by the chronic (up to twenty-five days in Terzian and Terzuolo's cats, two months in Cardin's dogs) deafferentation. Its physiological significance is therefore unclear. We are now faced with the second aspect of our task, namely, the mechanism of the cerebellar inhibition of the labyrinthine reflexes. Stella (1944b, c) suggested that the Schiff-Sherrington phenomenon might be explained by the interruption of tonic reflexes arising in the hindlimb proprioceptors and inhibiting, through cerebellar relays, the postural mechanisms of the forelimbs. This hypothesis, however, can hardly be reconciled with the following facts: (a) augmentation of forelimb rigidity occurs when a postbrachial transection is performed following complete chronic deafferentation of the lower-lying spinal segments (Ruch, 1936), and (b) the effects of cerebellar and cord lesions are additive (Terzuolo and Terzian, 1951a, b; Terzian and Terzuolo, 1954). Hence our discussion will be limited to the mechanism of the cerebellar inhibition of labyrinthine tonus. Stella (1944c) showed that the cerebellar inhibition of labyrinthine tonus was not mediated by midbrain relays. When a postcollicular decerebration had been performed by the usual method, no extensor rigidity was observed in the deafferented leg. It appeared at once, however, when a cerebellar area corresponding to lobules III, IV, and V was extirpated. The tonic inhibitory influence of the vermal part of the anterior lobe was probably mediated by the cerebellofastigiobulbar pathways, which have been analyzed at length in the chapter on stimulation experiments (see pp. 113-137). b. THE EFFECTS OF CHRONIC CEREBELLECTOMY ON TONIC LABYRINTHINE REFLEXES

We have seen in the previous section that either acute cerebellectomy or acute topectomy of the anterior lobe releases the labyrinthine component of the extensor tonus, thereby re-establishing rigidity in the deafferented limbs of the decerebrate preparation. Whether this effect could be demonstrated also after chronic cerebellectomy was the next problem. Stella (1947) carried on experi-

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ments to find out the answer, and his results were altogether different from those one might have predicted. Decerebration of dogs which had been totally cerebellectomized one to six months before yielded clear-cut extensor rigidity, in confirmation of previous results by Bremer (1922a). The rigidity vanished, however, when the limbs were deafferented, an observation that might be explained by assuming that in the interval between the first and the second operation other neural structures had taken over the inhibitory control of the vestibular tonus. The real surprise in the results, however, was that decerebrate rigidity did not reappear in the deafferented forelimbs even when the spinal cord was transected at postbrachial levels. Furthermore, Schiff-Sherrington release of the extensor tonus of the deafferented forelimbs was absent also when the chronic cerebellar extirpation (four to ten weeks) had been limited to the lobulus centralis and the culmen (Larsell's lobules III to V), whereas it was clearly observed when the chronic ablation was limited to other cerebellar areas but spared those mentioned. Finally, when only one lateral half of lobules III to V had been chronically ablated, the postbrachial transection of the spinal cord re-established decerebrate rigidity only in the deafferented forelimb still retaining its cerebellar innervation, while flaccidity remained in the limb ipsilateral to the chronic lesion (Stella, Zatti, and Sperti, 1955). Stella, Zatti, and Sperti (1953, 1955) suggested that the fastigial nuclei might be the structures whose functional inactivation would be responsible for the absence of the Schiff-Sherrington release of the labyrinthine tonus, since (a) severe lesions of the rostral part of the nucleus fastigii were found, histologically, following chronic ablation of culmen and lobulus centralis (Sperti and Zatti, 1953a), and (b) fastigial destruction or section of one inferior cerebellar peduncle abolished, ipsilaterally, the Schiff-Sherrington effect on the extensor tonus (Stella, Zatti, and Sperti, 1953). The same result could be obtained also by destroying chronically only the rostral part of one fastigial nucleus (Stella, Zatti, and Sperti, 1955). Hence inhibitory impulses arising in the lumbosacral segment of the spinal cord would counteract the tonic facilitating influence which is exerted by the fastigial nuclei on the vestibular component of the extensor tonus. It is apparent that Stella's interpretation (1947) does not agree with his own findings about the reappearance of extensor rigidity in the deafferented limbs following complete acute cerebellectomy, an operation involving obviously the destruction of all the fastigial system (1944a). Unless we assume that the extensor hypertonus occurring in the deafferented limb immediately after complete cerebellectomy was due to irritation—a hypothesis already discussed and rejected (see p. 274)—we are at a loss to reconcile the two groups of experiments. Moruzzi (1949) suggested that the absence of the Schiff-Sherrington release of the labyrinthine tonus which is observed after chronic cerebellectomy might be related to secondary alterations of the vestibular nuclei. This hypothesis was supported by experiments recently performed by Batini, Moruzzi, and Pompeiano (1956a and b, 1957). Nineteen completely cerebellectomized cats were decerebrated when all release phenomena had been fully compensated (i.e., after fourteen to twenty-one days). Confirming Bremer's observations (1922a), decerebrate rigidity developed in the chronically cerebellectomized

282 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM animal and was actually quite strong. Both forelimbs were then acutely deafferented from C 5 to T 1, and the central ends of the severed dorsal roots were locally anesthetized with novocaine. The rigidity collapsed altogether, just as it would have done in any decerebrate preparation, a finding which is easily explained by the fact that other neural structures had taken over the inhibitory influence normally exerted by the cerebellum on the nonmyotatic component of postural extensor tonus (see pp. 283-287). A postbrachial transection of the spinal cord was finally made, under ether anesthesia. Clear-cut extensor rigidity ensued in the forequarters, and lasted as long as the preparation (up to six hours). Only when the histological controls showed that a brain stem region including the vestibular nuclei had been damaged by the cerebellectomy were Stella's results confirmed; i.e., no extensor rigidity developed following postbrachial transection of the spinal cord. In one cat extensor rigidity ensued in the left forelimb only, and the histological controls showed that the labyrinthine nuclei of the right side had been severely encroached upon. These data would suggest that Schiff-Sherrington inhibition may be clearly present also in the absence of the cerebellum. They suggest, moreover, that SchiffSherrington inhibition is actually likely to compensate for the loss of cerebellar control, an observation fully supported by other experiments, to be reviewed later (p. 286). C. THE EFFECTS OF ACUTE OR CHRONIC CEREBELLECTOMY ON THE RIGHTING REFLEXES

There is no doubt that righting labyrinthine reflexes may be present in the acutely cerebellectomized cat (de Kleijn and Magnus, 1920) and that they are most clearly observed in the chronically cerebellectomized dog (Rademaker, 1931). We are concerned here only with the problem of whether or not these reflexes are modified by cerebellectomy. Rademaker (1931) reported that as soon as the whole cerebellum had been removed in the dog, most of the righting labyrinthine reflexes were absent. Some of them reappeared within forty-eight hours, whereas other reactions, such as the ventroflexion of the head which occurs when the animal is placed in the supine position, were observed much later, generally within one week (Rademaker, 1931). Moreover, righting labyrinthine reflexes were found only exceptionally in the rabbit following complete cerebellectomy (de Kleijn and Magnus, 1920). These observations were attributed to postoperatory shock (de Kleijn and Magnus, 1920) or to the fact that opisthotonos or extensor hypertonia might counteract, peripherally, the righting reflexes (Rademaker, 1931). The importance of these factors cannot be questioned, but we should like to point out two things: (a) righting reflexes may coexist with postural patterns similar to those of decerebrate rigidity (Bremer and Ley, 1927; Pollock and Davis, 1927, 1930b); (b) it is perhaps not fully consistent to regard the release of bulbopontine centers elicited by acute cerebellectomy as evidence of an inhibitory influence exerted by the cerebellum on tonic reflexes and to deny any functional significance to the disorganization of midbrain activities that follows acute decerebellation. In our opinion the righting reflexes are likely to be controlled by the cerebel-

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lum, and it may be important to undertake their analysis after histologically controlled cerebellar lesions. d. FASTIGIAL INFLUENCES ON LABYRINTHINE TONUS AND THE CONFLICT OF CEREBELLAR FACILITATION WITH VESTIBULAR INHIBITION

Moruzzi and Pompeiano (1955c, 1957a) reported that in the acutely deafferented forelimbs of the decerebrate cat the vestibular rigidity elicited by postbrachial transection of the spinal cord disappeared on one side of the body when the roof nuclei were unilaterally encroached upon. The melting of the extensor hypertonus was limited to the ipsilateral limbs after rostrofastigial lesions, and to the contralateral limbs when the caudal part of one fastigial nucleus had been fulgurated. These effects disappeared altogether and bilaterally strong vestibular rigidity ensued when the homotopic structures of the other fastigial nucleus were destroyed (Fig. 109). In short, the results obtained on Sherringtonian rigidity (see p. 81) would be duplicated after elimination of the myotatic component of the postural tonus. Similar results were obtained when the same experiments were performed from four to twenty-four days following chronic deafferentation of the forelimb. Other observations by Moruzzi and Pompeiano (1955c, 1957a) suggested that the unilateral disappearance of vestibular rigidity brought about by the fastigial lesion was due to a tonic inhibitory influence arising in the labyrinthine receptors of the opposite side of the body. We have already reported that vestibular rigidity melted in the right forelimb when the caudal portion of the left fastigial nucleus had been destroyed. If the left eighth nerve was then severed intracranially, not only did the extensor rigidity disappear in the left foreleg (confirmation of Stella, 1944a; see p. 275), but the previously atonic forelimb of the right side became at once rigid (Fig. 110). This effect lasted as long as the preparation. Chronic sections of the eighth nerve were not performed, but in view of the reciprocal effects elicited by galvanic stimulation of the labyrinths of either side of the body on a single Deitersian unit (De Vito, Brusa, and Arduini, 1956), it is at least likely that the release from crossed labyrinthine inhibition overcame the effect of the asymmetrical fastigial innervation. Moruzzi and Pompeiano (1955b and c, 1957a) suggested that the postural mechanisms of the brain stem are overruled by inhibitory reflexes arising in crossed muscular (see pp. 265-268) and labyrinthine receptors, when they are deprived of the support of the fastigial facilitation. 6. VESTIBULAR COMPONENTS IN THE RELEASE SYMPTOMS ELICITED BY ACUTE CEREBELLECTOMY AND THEIR COMPENSATION BY SPINAL INHIBITORY MECHANISMS

Previous observations, reported elsewhere (pp. 28, 79), had shown (a) that no opisthotonos is observed when the cat is decerebrated by the routine methods (Bazett and Penfield, 1922); (b) that following anemic decerebration (Pollock and Davis, 1927), which involves also the functional inactivation of the cerebellar anterior lobe, this symptom is constantly present; and (c) that the same result is obtained in a cat decerebrated by the routine methods as soon as the roof nuclei are bilaterally destroyed (Batini, Moruzzi, and Pompeiano, 1956a and b,

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Figure 109. Scheme oj the experiments concerning jastigial influence on vestibular rigidity. Decerebrate cats, in prone position. A. Sherringtonian rigidity. B. Cat A following bilateral deafferentation of the forelimbs. C. Cat B following postbrachial transection of the spinal cord. D, Cat C following lesions of the caudal part of the left fastigial nucleus. E. Cat D following lesion of the caudal part of the right fastigial nucleus. (From G. Moruzzi and O. Pompeiano, 1957, Inhibitory mechanisms underlying the collapse of decerebrate rigidity after unilateral fastigial lesions, J. Comp. Neurol., 107:1-25, Fig. 5.)

Figure 110. Scheme of the experiments on the vestibular inhibitory mechanisms underlying the crossed extensor atonia elicited by unilateral caudofastigial lesions. Decerebrate cats, in prone position. A. Following destruction of the caudal pole of the left fastigial nucleus. B. Cat A following left foreleg deafferentation. C. Cat B following right forelimb deafferentation. D. Cat C following postbrachial transection of the spinal cord. E. Cat D following acute intracranial section of the left VIII nerve. (From G. Moruzzi and O. Pompeiano, 1957, Inhibitory mechanisms underlying the collapse of decerebrate rigidity after unilateral fastigial lesions, J. Comp. Neurol., 107:1-25, Fig. 6.)

1957). We know, on the other hand, (d) that the opisthotonos is abolished by bilateral labyrinthectomy (Pollock and Davis, 1927) or by severing both nervi octavi (Batini, Moruzzi, and Pompeiano, 1956a and b, 1957). Hence this typical symptom of the acutely cerebellectomized carnivore is due to an enhancement of the tonic labyrinthine reflexes. They are released following inactivation of the anterior lobe and/or destruction of the roof nuclei, but the inhibitory control of the cerebellum is still present after midbrain (Bazett and Penfield, 1922) or thoracospinal (Batini, Moruzzi, and Pompeiano, 1956a and b, 1957) transections.

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 285 Since opisthotonos and extensor rigidity of the forelimbs are constantly and strikingly present in the otherwise intact carnivores throughout the first week following total cerebellectomy (Luciani's dynamic period), and since these release phenomena are absent in the later stages of the cerebellar syndrome, it was felt that their experimental analysis was likely to give us some information on the inhibitory function of the cerebellum and on its mechanisms of compensation. Batini, Moruzzi, and Pompeiano (1956a and b, 1957) performed complete cerebellectomies on thirty-two cats; in a second group of twenty-two cats a release from cerebellar inhibition was obtained by total and bilateral electrolytic destruction of the roof nuclei through stereotactically oriented electrodes. These were all chronic experiments, and the extent and the location of the cerebellar lesion as well as the complete integrity of the brain stem were routinely controlled on serial Nissl and Weil slides. In a first group of nineteen cats the symptoms resulting from complete cerebellar ablation were analyzed, and the main classical findings were fully confirmed. A complete cerebellectomy was then performed on a second group of seven cats whose forelimbs had been deafferented one to four days before. Clearcut rigidity ensued at once in the forequarters while a marked opisthotonos appeared. The righting reflexes appeared two days thereafter. Four days later, when the animals made their first attempts to walk, the opisthotonos had faded away, while the forelimb rigidity disappeared altogether only nine days after the cerebellectomy. These experiments showed that the release symptoms characterizing Luciani's dynamic period, and in particular the forelimb rigidity, were present when the myotatic component of the postural extensor tonus had been abolished. When the compensation of the release symptoms had been completed in this second group of cats, i.e., ten to twelve days after cerebellectomy, the spinal cord was severed at thoracic levels. The symptoms of acute cerebellectomy, namely, forelimb extensor rigidity and opisthotonos, reappeared at once and remained throughout the survival period (two days). Postbrachial transection of the spinal cord gave the same results in a third group of six nondeafferented cats which had been totally cerebellectomized twelve to fifty-nine days before and in which the release symptoms had been fully compensated for. Control experiments on the effects of the postbrachial transections of the spinal cord were finally performed on a fourth group of three cats whose forelimbs had been bilaterally deafferented seven to fourteen days before, from C 5 to T 2. These animals were not cerebellectomized, but the interval between deafferentation and spinal transection was the same as for the first group of cats. These experiments were aimed at controlling the influence of Cannon's sensitization of the deafferented spinal segments in the mechanism of the release phenomena elicited by the postbrachial transection of the spinal cord. Clear-cut forelimb rigidity ensued also in this last group of animals, but no opisthotonos was observed. These experiments showed, according to Batini, Moruzzi, and Pompeiano (1956a and b, 1957), (a) that the neural mechanisms underlying opisthotonos are normally inhibited by the cerebellum; (b) that following cerebellectomy, this inhibitory influence may be gradually taken over (and therefore compensated for) by the spinal mechanisms underlying the Schiff-Sherrington phenomenon;

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and finally (c) that Schiff-Sherrington inhibition of the nonmyotatic component of the forelimb postural tonus may be mediated by extracerebellar relays. The group of fastigial experiments performed by Batini, Moruzzi, and Pompeiano (1956a and b, 1957) showed that Luciani's dynamic syndrome could be easily reproduced by total bilateral destruction of the roof nuclei. Seven days thereafter the opisthotonos had faded away altogether, and six days later the compensation of the release symptoms was practically complete, although the gait was still definitely abnormal. Striking release symptoms were obtained also if the bilateral destruction of the roof nuclei was made two days after deafferentation of both forelimbs. In short, the results obtained in the experiments of total cerebellectomy could be duplicated in the defastigiated animals. These data suggest that the release symptoms characterizing Luciani's dynamic syndrome are mainly due to the withdrawal of an inhibitory influence exerted by the fastigial nucleus or by the cortical cerebellar areas projecting upon them, a conclusion which is supported also by other experimental evidence (see pp. 28, 56, 79). The compensation of the release symptoms in the cat with bilateral destruction of the fastigial nuclei was shown to be mainly due to Schiff-Sherrington inhibition, just like the compensation of the dynamic syndrome in the wholly cerebellectomized animal. A postbrachial transection of the spinal cord was performed when the release symptoms of the defastigiated preparation had been fully compensated for, i.e., one to two weeks following the fastigial operation. All the acute symptoms (forelimb rigidity and opisthotonos) reappeared at once, and were clearly present even in those cats whose forelimbs had been deafferented two days before the fastigial operation. The following experiments show (a) that a strong inhibitory influence on the tonic labyrinthine reflexes is normally exerted by the fastigial nuclei, and (b) that this inhibitory control is still present when the postural mechanisms have been released by postbrachial transection of the spinal cord. In two normal cats and in three animals whose forelimbs had been deafferented seven to fourteen days before, the spinal cord was transected at D 12, under ether anesthesia; a good extensor hypertonus ensued in the forelimbs, but no opisthotonos was observed. One day later both fastigial nuclei were totally destroyed. Forelimb rigidity was markedly enhanced following this operation, while a strong opisthotonos appeared. Both symptoms lasted throughout the survival period (five to six days). Summing up, the following conclusions were drawn by Batini, Moruzzi, and Pompeiano (1956a and b, 1957): (a) opisthotonos is due to a release of the tonic labyrinthine reflexes from fastigial inhibition, and (b) compensation for the withdrawal of fastigial influence is provided mainly by the spinal mechanisms underlying Schiff-Sherrington inhibition. Luciani's dynamic period would be related, therefore, to the withdrawal of the tonic influence normally exerted by the cerebellum on postural reflexes. Thus the release symptoms occurring in the first week after cerebellectomy would simply unveil an aspect of cerebellar function, just as the symptoms which are observed later on, during the so-called deficiency period, disclose another aspect of cerebellar influence, in the somatic sphere. The release symptoms would be simply compensated for much earlier,

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 287 and with greater accuracy, than the other symptoms. This is the reason why the phenomena of the dynamic period are short-lasting, though markedly developed, in the carnivores, whereas they are much less pronounced in the primates, possibly owing to the greater efficiency of the mechanisms of cortical inhibition. At least in the carnivores the compensation of the release phenomenon appears to be mainly due to the fact that the inhibitory influence of the cerebellum is gradually taken over by the powerful brain stem-spinal mechanisms controlling Schiff-Sherrington inhibition. 3. CEREBELLAR INFLUENCE ON KINETIC LABYRINTHINE REFLEXES The phasic vestibular reflexes elicited by a movement of the head in relation to the dimensions of space (Magnus's "Bewegungsreflexe") are also directly supervised by the cerebellum. The reflexes elicited by angular acceleration arise in the ampullary receptors, while those produced by linear acceleration are probably produced by stimulation of the macular receptors. a. THE EFFECT OF CEREBELLAR ABLATION ON POSTROTATORY NYSTAGMUS

Bauer and Leidler (1912) reported that postrotatory nystagmus in the rabbit was markedly increased in both intensity and duration following ablation of the cerebellar vermis and of the roof nuclei. Neither vermal decortication alone nor hemispheral ablation yielded these results. The hyperexcitability of the vestibular nuclei lasted from five to ten days and was limited to the same side of the body when the vermal lesion was only or predominantly unilateral. Bauer and Leidler (1912) explained their findings as a release of the labyrinthine nuclei. Their observations were confirmed later by Hoshino (1921), who reported a marked increase in the duration of postrotatory nystagmus following total ablation of the vermis in the rabbit, while Chambers and Sprague (1955b) observed in the cat an "excessive post-rotatory nystagmus" following total bilateral ablation of the anterior lobe and of the rostral parts of nucleus fastigii and nucleus interpositus. This symptom was present even seventeen days after the operation, i.e., when the opisthotonos had faded away, and represented therefore one of the most persistent signs of the release of vestibular activities. The negative results obtained by Buchanan (1938) on the guinea pig were probably due to an incomplete lesion, while those reported by Rademaker (1931) on totally cerebellectomized dogs may be explained by the fact that the animals were examined only during the period of compensation (see Billia, 1952). b. THE EFFECT OF CEREBELLAR ABLATION ON GALVANIC NYSTAGMUS

Hahn (1950a and b, 1952) investigated the influence of chronic (two to three days) unilateral lesions of the flocculonodular lobe of the guinea pig on both galvanic and postrotatory nystagmus. Histologically controlled lesions of one half of the nodulus and of the uvula (Larsell's lobules X and IX) and occasionally of the lingula (lobules I and II) were followed by asymmetrical changes in the evoked nystagmus. The effects on galvanic nystagmus were confirmed by Hahn (1950b, 1952) following unilateral and histologically controlled lesions of either the flocculus or the nodulus in the bilaterally labyrinthectomized guinea pig.

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Only a transient (four to five days) lowering of the threshold, without asymmetrical changes, occurred after complete cerebellectomy (Hahn, 1951). The experiments of Hahn (1950a and b, 1951, 1952) show that a careful study of unilateral and anatomically well-localized cerebellar lesions yields many results which are missed following bilateral ablation. C. SPONTANEOUS NYSTAGMUS AFTER CEREBELLAR ABLATION

In Chapter 2, on ablation experiments, it was pointed out that spontaneous nystagmus is an acute, transient, and above all an inconstant symptom in the cerebellectomized animal. It was frequently missed after complete cerebellar (Munk, 1906; Schmidt, 1921; Dusser de Barenne, 1923, 1937; Rademaker, 1931; Di Giorgio, 1950) or vermal (Bauer and Leidler, 1912) ablations or after destruction of the flocculonodular lobe (Dow, 1938b). Dusser de Barenne (1937) suggested that the nystagmus was simply a surgical accident, elicited by lesion or irritation of the vestibular nuclei. This extreme view may be occasionally true, but there is much information suggesting that the release of the vestibular nuclei from cerebellar inhibition is likely to be an important factor in the occurrence of this so-called "spontaneous" nystagmus. First of all, "spontaneous" nystagmus occurs far more easily after hemicerebellectomy (Rademaker, 1931, p. 326; Di Giorgio, 1950) or after any unilateral lesion of the vermis and roof nuclei (Bauer and Leidler, 1912; Leidler, 1919) than after total, or any symmetrical, cerebellar ablations. It is difficult to believe that the vestibular nuclei are less easily injured when cerebellectomy is complete, or that in these operations they are as a rule encroached upon symmetrically as a consequence of surgical accidents. A more likely explanation, in our opinion, is that the nystagmus is related to a unilateral release of the vestibular nuclei and, above all, to an imbalance between the labyrinthine systems of the two sides of the body (see pp. 277, 283 on the mutual interrelations between vestibular nuclei). Leidler (1919) actually showed that the so-called "spontaneous" nystagmus following unilateral cerebellar lesions in rabbits disappeared when the small movements of the head were avoided. Second, a "spontaneous" cerebellar nystagmus may be increased (Spiegel and Scala, 1941) or actually elicited (Spiegel and Scala, 1942; Di Giorgio, 1950) by given positions of the head. Spiegel and Scala (1942) showed (a) that the positional nystagmus was more evident and prolonged following lesions of the lobulus posterior medianus (lobules VII to X) and of the roof nuclei; (b) that it could not be explained by brain stem lesions, since both the medulla oblongata and pons were shown to be normal by histological controls; and finally (c) that the positional nystagmus reached its maximum intensity and came back to the normal levels simultaneously with the labyrinthine hyperexcitability, as shown by the changes in the postrotatory nystagmus. These observations suggest that whenever the vestibular nuclei are released from cerebellar inhibition, a nystagmic response of the oculomotor neurons may occur either spontaneously or under the influence of reflex stimuli which would be definitely subliminal in normal conditions. The influence of the position of the head may be interpreted by assuming that the tonic barrage of otolithic impulses influences the ampullary reflexes. The

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 289 interrelations between cervical, macular, and ampullary reflexes have been investigated by Groebbels (1927a, b), Lorente de No (1931), Koella (1947a, b), and Hahn (1952). A third line of evidence was provided by the investigations on Bechterew's phenomenon which were undertaken by Demetriades and Spiegel (1927). Bechterew (1883) showed that the nystagmus occurring after unilateral labyrinthectomy disappeared at once if the other labyrinth was destroyed, whereas it reappeared in the opposite direction if the second labyrinthectomy was performed during the compensation period, i.e., when the original nystagmus had faded away. Bechterew's phenomenon shows that the "spontaneous" nystagmus elicited by unilateral labyrinthectomy is related to an imbalance between the vestibular nuclei of both sides. The compensation that follows unilateral labyrinthectomy is probably due to an increased excitability of the deafferented labyrinthine nuclei, and the new equilibrium is disrupted by the second labyrinthectomy. Through experiments on rabbits Spiegel and Demetriades (1925) and Demetriades and Spiegel (1927) studied the influence of the cerebellum on these ocular phenomena. They showed (a) that Bechterew's compensation also occurred in completely cerebellectomized animals (Spiegel and Demetriades, 1925), and (b) that whenever the cerebellar lesions were made during the compensatory period that follows unilateral labyrinthectomy, the nystagmus reappeared in the opposite direction, just as in the original Bechterew's phenomenon (Demetriades and Spiegel, 1927). The same cerebellar lesions were ineffective on the normal rabbit. Apparently the release from cerebellar inhibition re-established the imbalance between normal and deafferented vestibular nuclei. d. CEREBELLAR INFLUENCE IN THE HABITUATION OF POSTROTATORY NYSTAGMUS

The repetitive elicitation of postrotatory nystagmus markedly decreases its duration. The literature on this "habituation" effect has been recently reviewed by Di Giorgio and Pestellini (1948). Halstead (1935) and Halstead, Yacorzynski, and Fearing (1937) showed that pigeons with chronic cerebellar lesions did not become habituated to the repeated elicitation of after-nystagmus as readily as controls and, moreover, that they did not retain the habituation effect as long as the control animals. A marked loss of habituation was furthermore observed whenever a cerebellar lesion was inflicted after the habituation had previously been established. The two serious limitations of these papers are (a) that only partial cerebellar lesions were inflicted, and (b) that their histological localizations were not reported. These results were confirmed on the guinea pig by Di Giorgio and Pestellini (1948), with histologically controlled experiments. They showed that a marked loss of habituation occurred even when only two to three folia of the tuber and pyramis (Larsell's lobules VII and VIII) were extirpated, the complete integrity of the fastigial nuclei being maintained. Several explanations of the cerebellar influence on the habituation effect have been or might be suggested. Halstead, Yacorzynski, and Fearing (1937) thought that the habituation of the after-nystagmus involved some modification within the cerebellum. The obvious implication of this hypothesis would be that repeti-

290 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM tive rotation creates conditioned inhibitory reflexes, relayed by the cerebellum and blocking either the brain stem structures related to the nystagmus or possibly (through the reticular formation) the sensory mechanisms themselves (see Hernandez-Peon and Scherrer, 1955). Another hypothesis was suggested by Di Giorgio and Pestellini, namely, that the release of the vestibular nuclei and possibly (Di Giorgio, 1950, 1954, 1955) the change in the excitability of the final common pathway brought about by the cerebellar lesion might simply overcome, or at least modify, the consequences of habituation. The experiments of Menzio (1950) would seem to support this latter explanation. This author showed that the depression of both galvanic and postrotatory nystagmus elicited in the guinea pig by prolonged treatment with streptomycin disappeared, or was strongly reduced, following ablation of the pyramis and of the uvula (Larsell's lobules VIII and IX). The issue is one of great theoretical importance and could be solved by a study of the phenomena of habituation after complete chronic cerebellectomy, i.e., when postrotatory nystagmus has reached its normal level. C. THE EFFECT OF CEREBELLAR ABLATION ON THE REFLEX RESPONSES TO LINEAR ACCELERATION

The macular reflexes on limbs elicited by progressive movements were reported to be strongly increased following chronic dorsal rhizotomy (Bremer, 1928). They were always present, moreover, and occasionally strengthened following cerebellectomy (Di Giorgio, 1948). C. RELATION TO THE VEGETATIVE FUNCTIONS 1. INTRODUCTORY REMARKS In the twenty-third lecture which Claude Bernard (1858) gave at the College de France on the physiology of the nervous system there is a description of two experiments performed by the great physiologist in October 1849. In the course of his investigations on the glycosuria elicited by the puncture of the floor of the fourth ventricle he tried to limit the injury to the cerebellum. He stated: "J'ai pique sur le cervelet au-dessus du vague, comme pour les mammiferes, chez un pigeon encore jeune et ne mangeant pas seul. Le pigeon manifesta d'abord quelques desordres dans les mouvements. Chose curieuse, la digestion s'arreta completement. A 1'autopsie, le foie contenait du sucre et donnait une decoction a peine louche. Sur un second pigeon, a la suite de la meme piqure, il ne se manifesta pas de sucre dans les excrements, mais la digestion jut encore completement arretee en ce sens que le jabot qui etait plein des graines resta dans le meme etat jusqu'a la mort, qui eut lieu quatre jours apres" (vol. 1, p. 461; italics ours). In 1858 Wagner reported (see 1861, p. 262) that he had been unable to observe an arrest of the digestion following cerebellar lesions made on pigeons. Actually he found vomiting and diarrhea, but rightly pointed out that these symptoms occurred also following severe lesions of other parts of the central nervous system. Brown-Sequard, in a footnote in Wagner's paper (I. c.), stated that "toute excitation violente des parties sensitives des nerfs ou des centres nerveux peut etre suivie d'un arret des secretions des visceres servant a la digestion . . . J'ai souvent observe 1'arret complet de la digestion pendant

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 291 plusieurs jours chez les pigeons ayant eu une lesion de la moe'lle epiniere a la region dorsale. Mais apres quelques jours 1'etat normal se retablit." This old and entirely forgotten controversy may well introduce our section on cerebellar influence on the autonomic nervous system. Autonomic effects were often reported following cerebellar lesions or stimulation. But only a few authors made an attempt to find out whether the effects of the lesion were due to the withdrawal of a specific cerebellar influence or to the irritation of other centers; whether the responses to cerebellar stimulation were due to efferent volleys arising in the structures underlying the electrodes or to a sheer spread of current to the brain stem. Where these controls were not made, to interpret the results is indeed an almost impossible task. Moreover, when we are dealing with effects that are easily elicited by a variety of stimuli, such as mydriasis, increase in the blood sugar, or any change in the motor activities of the alimentary canal, it is particularly important, in our opinion, to know whether the responses were elicited specifically from a given part of the cerebellum and not from others. Unfortunately this aspect of the problem was also often disregarded by the authors. In the following pages a detailed account will be given of only those investigations in which an attempt was made to avoid some, at least, of these objections and to utilize appropriate controls. 2. EFFECTS ON CIRCULATION Changes in the heart rate were reported following electrical (Eckhard, 1872; Balogh, 1876), mechanical (Eckhard, 1872; Wada, Seo, and Abe, 1935), and chemical (Simkina, 1943a) stimulation of the cerebellum. Eckhard (1872) pointed out tha,t the cardiac effects elicited by mechanical stimulation of the vermis were abolished by bilateral vagotomy. Wiggers (1942b, 1943b), however, failed to find any change in the heart rate in the electrocardiographic records he made during electrical cerebellar stimulations; he worked, however, on barbiturized dogs. The increased heart rate found by Papilian and Cruceanu (1926) following unspecified vermal lesions is of doubtful significance because no controls of the blood pressure were reported. More interesting, in our opinion, are their findings on the increase in the oculocardiac reflex, since this effect could still be observed twenty days after the cerebellar lesion, i.e., when the heart rate was already almost normal. The blood pressure was reported to be unaffected following acute ablation (Owsjannikow, 1871) or partial lesion (Lewy and Shinosaki, 1926a, b) of the cerebellum, but to be modified by mechanical (Eckhard, 1872; Wada, Seo, and Abe, 1935), electrical (Eckhard, 1872; Pugliatti, 1885; Dresel and Lewy, 1924; Fuse, 1930; Simkina and Obeli, 1932; Mikhelson and Tikhalskaja, 1933; Saprokhin, 1937; Simkina and Mikhelson, 1938), and chemical (Suda, Abe, Uchiyama, and Mizuno, 1944) stimulations. Sometimes an increase and sometimes a decrease in the blood pressure were described. The coronary and the renal circulation were reported to be affected respectively by stimulating (Saprokhin, 1937, 1940, 1946) or extirpating (Skorokhod, 1941) the cerebellum. Most of these data can hardly be reconciled with those of Bechterew (1909, p. 959), who was unable to find in the dog any change in the spleen volume during

292 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM electrical stimulation of the cerebellum. It should be pointed out in this connection that the blood pressure records presented by Mikhelson and Tikhalskaja (1933) showed that the vasomotor effects elicited by faradic stimulation of the vermis and of the cerebellar hemispheres, in the precollicular cat, were quite small. The authors maintained, however, that these were genuine cerebellar responses, since they disappeared after an undercutting of the stimulated area, and were occasionally observed independently of the well-known effects in the somatic sphere. Bechterew gave no details about the experiments he performed, but if the spleen volume was simply observed and not graphically recorded, it would not be surprising, in our opinion, if he had missed minor vasomotor responses. Moruzzi (1938a, b) reported that the systemic blood pressure of the precollicular cat was frequently unaffected by faradic stimulation of the vermal part of the anterior lobe. An increase in the blood pressure was elicited only by quite strong cerebellar stimuli, yielding generalized movements through a sheer spread of currents to the brain stem. Only when the blood pressure was spontaneously rather high did a depressor response occur (Fig. 111). This was a genuine autonomic effect, however, since (a) it was occasionally elicited by intensities of induction currents that were subliminal for the postural responses and (b) it was still observed when the postural effect had been abolished by curare atonia (see Bremer, Titeca, and van der Meiren, 1927). This transient hypotensive effect, although occurring only when the blood pressure was spontaneously high, was not conditioned by the presence of a strong peripheral vasomotor tone, since it was never observed when low levels of blood pressure had been raised by injections of ephedrine. Apparently when the central vasomotor tone, namely, the background activity of a group of autonomic neurons of the brain stem, reached

Figure 111. Decrease in the blood pressure followed by a rebound increase elicited by stimulating the vermal part of the cerebellar anterior lobe. Precollicular cat. When, as a background, the systemic blood pressure is spontaneously rather high, a depressor effect may occur during repetitive cerebellar stimulation. The distance of the induction coils here was 32 cm., and the inhibition of extensor rigidity was absent even at a distance of 25 cm. (From G. Moruzzi, 1938, Azione del paleocerebellum sui riflessi vasomotori, Arch, fisiol., 38:36-78, Fig. 11.)

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 293 a critical level, the inhibitory effect of the cerebellar stimulation was more easily observed. More impressive by far were the inhibitory responses when the resting vasomotor tonus was strongly and abruptly shifted by pressor (Fig. 112A) or by depressor (Fig. 1125) reflexes. Also, the delayed component of the reflex rise of the blood pressure, which is probably due to a reflexly induced secretion of the adrenal glands, was blocked by cerebellar stimulation (Fig. 112A). Hence also the brain stem mechanisms controlling the adrenaline secretion were inhibited when their reflex activation was timed to occur during the cerebellar stimulation. These data are easily reconciled with those of Cannon and Rapport (1922), who stated that stimulation of the central end of the sciatic nerve still evoked an adrenaline secretion in the decerebrate and decerebellate dog. These nociceptive reflexes are probably extracerebellar phenomena, and they may be simply decreased by the play of the cerebellar inhibition. Moruzzi (1938a, b) reported also that so-called Mayer's waves, i.e., the periodic waxing and waning of the blood pressure which occurs occasionally in rhythms much slower than those associated with the respiratory movements,

Figure 112. The inhibition of vasomotor reflexes and of Mayer's waves yielded by stimulations of the vermal part of the cerebellar anterior lobe. Repetitive cerebellar stimulations (c) inhibit (A) the vasopressor responses yielded by faradic stimulations of the central end of the superior laryngeal nerve, (B) the vasodilator responses evoked by stimulating the central end of the vagus nerve (v.d.), and (C) the Mayer's waves. An effect (C) was still obtainable from the left hemivermis when the response of the right hemivermis had been completely abolished by the local application of 5 per cent cocaine. (From G. Moruzzi, 1938, Azione del paleocerebellum sui riflessi vasomotori, Arch, fisiol., 38:36-78, Figs. 1, 5, 9.)

294 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM were inhibited by the same cerebellar stimuli (Fig. 112C). It has been recently suggested that Mayer's waves are due to rhythmic afferent volleys impinging upon the vasomotor center from the chemoceptors (Andersson, Kenney, and Neil, 1950). If this explanation is accepted, this last group of observations will represent another example of cerebellar inhibition of the vasomotor reflexes. All these inhibitory effects on the vasomotor reflexes were abolished following local applications of 5 per cent cocaine. Through experiments performed on precollicular cats, Moruzzi (1938c, 1940a) also investigated the influence of vermal stimulations of the anterior lobe on the vasomotor carotid sinus reflexes (Fig. 113). He confirmed that only minor vasodepressor effects could be elicited against a background of normal systemic blood pressure, but he showed that the depressor response was clear-cut when the cerebellar stimulation was timed to occur against a background of released vasomotor tonus, elicited by clamping both common carotids. All these effects were present during curare atonia, but disappeared following local cocainization of the cerebellar surface.

Figure 113. Cerebellar inhibition of respiratory and vasomotor carotid sinus reflexes. Decerebrate cat. The inhibition elicited by faradic stimulation of the vermal part of the cerebellar anterior lobe was very small against a background of normal respiration and blood pressure. When the respiratory and vasomotor centers were released from tonic baroceptive inhibition by clamping the common carotids bilaterally (R.S.C.), the same cerebellar stimulations (c) yielded clear-cut effects. (From G. Moruzzi, 1940, Paleocerebellar inhibition of vasomotor and respiratory carotid sinus reflexes, J. Neurophysiol., 5:20-32, Fig. \C, publ. Charles C. Thomas.)

Simultaneously with and independently of the first paper of Moruzzi (1938a), Simkina and Mikhelson (1938) reported that stimulation of the cerebellum in the otherwise intact as well as in the decerebrate cat actually increased, in most cases, the vasomotor reflexes. When the stimulation was repeated several times, it was frequently followed by the appearance of Mayer's waves. Inhibitory effects on the vasomotor reflexes were observed only in a minority of cases. When the cerebellar stimulation was timed to occur, however, against a background of slow vasomotor oscillations, an inhibition of Mayer's waves was constantly observed. This was the only instance in which the observations of the Russian investigators fully coincided with those of Moruzzi. The discrepancy cannot be easily ac-

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 295 counted for, since no details about the experimental procedure followed by Simkina and Mikhelson can be found in the comprehensive review of Simkina (1948). She stated that Vvedenskaja and Khanutina (1941) also found either an increase or decrease in the excitability of the vasomotor centers during cerebellar stimulations. Moruzzi's observations were confirmed by Wiggers (1942b, 1943b). He inhibited Mayer's waves and the vasomotor reflexes by stimulating the cerebellar anterior lobe of the dog, and stated that he had been unable to confirm the augmentatory effects described by Simkina and Mikhelson (1938). The great importance of the background of autonomic activity for the cerebellar responses to electrical stimulation is quite evident in all the experiments performed on decerebrate preparations. The reader is referred to the classic paper of Bard (1928) for a description of the autonomic and somatic symptoms of "sham rage" which occur in the acute thalamic cat. This preparation is characterized by outbursts of mass activity closely resembling those of the infuriated animal. They occur sometimes "spontaneously" and may also easily be elicited by slight sensory stimulations. Since this instability and hyperexcitability of the autonomic centers might, it was thought, represent a favorable condition for testing cerebellar influence on the vegetative nervous system, cerebellar regions corresponding approximately to LarselPs lobules V, VI, and VII were stimulated by Moruzzi (1947c) with Hess electrodes in the acute thalamic cat. When the cerebellar stimulation was timed to occur during an outburst of sham rage, both the somatic (struggling movements, lashing of the tail) and autonomic (increase of blood pressure, mydriasis, retraction of the lid) components of the outburst were clearly inhibited. They reappeared, and were actually much stronger than before, during the rebound phase. An outburst of sham rage could be easily obtained, moreover, when the cerebellar stimulation was timed to occur in an interval of quietness. This rage fit appeared, as a rebound effect, when the stimulation was over. These were all generalized responses that could easily be obtained with minimal cerebellar stimulations, provided the preparation was highly excitable. The preparation deteriorated sooner or later, as usually occurs in these experimental conditions, and the blood pressure fell, sometimes in a remarkable manner. In this depressed preparation only localized responses of the pupils and of the nictitating membranes could be obtained by stimulating the same cerebellar areas. The objection that a spread of current might have been a factor in the results can be dismissed in all these experiments because (a) the threshold of the cerebellar effect was lower than that of the motor cortex and (b) silent areas were only 2 millimeters before or behind the active spots. Moreover, somatic and autonomic responses had different thresholds and could sometimes be dissociated. Finally, the generalized autonomic responses, as well as the struggling movements, were abolished by precollicular decerebration. These effects were attributed to cerebellifugal volleys impinging upon the released hypothalamic centers. Electrocardiographic records were made by Bartorelli (1947) in the same animals. No effect on the heart rate was obtained when only local autonomic responses of the eyes were elicited. When the cerebellar stimulation was timed to occur during an outburst of sham rage, the cardiac frequency clearly decreased; it increased

Figure lib. Outbursts of sham rage evoked during stimulation of the right fastigial nucleus. Abolition of effects following electrocoagulation of stimulated structures. Reading downward in each record: respiration, arterial pressure, signal of cerebellar stimulation. A. Spontaneous outbursts of sham rage. B. A strong outburst of rage is immediately elicited by cerebellar stimulation of 3 V., whereas it follows with some latency a weaker stimulation (2 V.); 1 V. is ineffective. Between B and C high-frequency electrocoagulation of the right fastigial nucleus and surrounding structures. C. Cerebellar stimulations of even 20 and 30 V. are now completely ineffective. The presence, between the two cerebellar stimulations, of a spontaneous outburst of sham rage shows that the hypothalamic excitability has remained unmodified. (From A. Zanchetti and A. Zoccolini, 1954, Autonomic hypothalamic outbursts elicited by cerebellar stimulation, J. Neurophysiol., ^7:475-483, Fig. 2, publ. Charles C. Thomas.)

296

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 297 from a range of 150 to 160 to a range of 200 to 220 when the outburst appeared as a rebound effect at the end of a cerebellar stimulation. Zanchetti and Zoccolini (1954) recently utilized square pulses (300/sec; 1 msec.) for stimulating, through concentric electrodes stereotactically oriented, the interior of the cerebellum in the acute thalamic cat. The stimulated areas were localized on serial histological slides. During the stimulation both the somatic and the autonomic components of a typical outburst of sham rage were obtained when the electrodes were located within the rostral and central parts of the fastigial nuclei. The same response appeared as a rebound effect when midline structures between or behind the posterior ends of the roof nuclei were

Figure 115. Localization within the cerebellum of autonomic responses to cerebellar stimulation in the thalamic cat. Black circles indicate points from which outbursts of rage were obtained during stimulation; black triangles, points from which outbursts were elicited as a rebound effect. The drawings are of five sections of cat cerebellum cut in the transverse plane of a Horsley-Clarke instrument. They are arranged in serial order and labeled in alphabetical sequence, A being the most rostral and E the most caudal. (From A. Zanchetti and A. Zoccolini, 1954, Autonomic hypothalamic outbursts elicited by cerebellar stimulation, J. Neurophysiol., 17:475-483, Fig. 1, publ. Charles C. Thomas.)

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Figure 116. Unilateral (right) cerebellar electrocoagulation, abolishing autonomic effects elicited by right jastigial stimulation. Same preparation as in Fig. 114. The lesion was made between records B and C. Microphotograph of Weil-stained section, showing the extent of the lesion. The destruction is confined to the right side of the cerebellum, the contralateral fastigial nucleus is spared, and the brain stem is completely intact. (From A. Zanchetti and A. Zoccolini, 1954, Autonomic hypothalamic outbursts elicited by cerebellar stimulation, J. Neurophysiol., 17:475-483, Fig. 5, publ. Charles C. Thomas.)

stimulated (Figs. 114, 115). These areas became unresponsive at once, following local high-frequency electrocoagulation (Fig. 116), although typical sham-rage outbursts could still be obtained by sensory stimulations. Hence these effects were not due to a spread of currents to sensory pathways coursing in the brain stem. A precollicular decerebration entirely abolished the sham-rage responses, which were therefore mediated, or at least conditioned, by the diencephalon. It might be suggested that the hypothalamic centers were activated by the proprioceptive and tactile barrage resulting from the well-known postural response to cerebellar stimulation. This hypothesis can be dismissed, since Zanchetti and Zoccolini (1954) showed (a) that structures yielding equally strong and identical postural reactions produced different autonomic effects, and (b) that sham-rage outbursts could often be dissociated from the postural response. They suggested that these mass effects might be due to ascending reticular volleys elicited by the cerebellar stimulation and impinging upon the hypothalamus. One should recall, in this connection, the so-called psychical response that Pagano (1902, 1904) obtained in his intact dogs, in experiments which have been fully reviewed elsewhere (see p. 110), as well as the observation that fastigial stimulation yields a generalized EEG arousal in the animal whose cerebrum is intact (Moruzzi and Magoun, 1949).

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 299 Ban, Inoue, Ozaki, and Kurotsu (1956) came recently to conclusions similar to those of Zanchetti and Zoccolini (1954). They reported that the electrical activity of the ventromedial hypothalamic nuclei was modified immediately after strong, prolonged (15 to 20 seconds), and repetitive (50 to 120 seconds) stimulations of the cerebellar anterior lobe. Their experiments were performed on unanesthetized rabbits with chronically implanted electrodes. They maintained, on the other hand, that the electrical activity of the lateral hypothalamic nucleus was not affected immediately after the cerebellar stimulation. The electrical stimuli they used evoked clear-cut signs of sympathetic discharge, such as exophthalmos and mydriasis. The experimental results of electrical stimulations of the anterior lobe were confirmed indirectly by Connor and German (1941). They stated that vasomotor reactions were enhanced following topectomy of this lobe, performed on cats, dogs, and monkeys. 3. EFFECTS ON RESPIRATION Changes in spontaneous breathing were reported following mechanical (Eckhard, 1872; Wada, Seo, and Abe, 1935) or electrical (Eckhard, 1872; Fuse, 1930) stimulation of the cerebellum. Moruzzi (1938c, 1940a) found that normal breathing was only slightly inhibited by faradic stimulation of the vermal part of the anterior lobe, in the unanesthetized decerebrate cat. He stated, however, that the inhibitory effect was much stronger if the stimulation was timed to occur against a background of hyperpnea, elicited by clamping the common carotids (Fig. 113) or by intracarotid injections of potassium cyanide (chemoceptive reflexes, Fig. 117). These respiratory effects were present even during curare atonia, i.e., when the postural response was absent; they were abolished, moreover, by local cocainization. Working on otherwise intact dogs, Wiggers (1942b, 1943b) was unable to find any effect of cerebellar stimuli on spontaneous breathing. His experiments were performed, however, under barbital anesthesia. Respiratory responses were found to be particularly striking during the sham-rage outbursts elicited by cerebellar stimulations in the acute thalamic cat (Moruzzi, 1947c; Zanchetti and Zoccolini, 1954; see Fig. 114). The results of the ablation experiments are often much less convincing. The increase in respiration observed by Papilian and Cruceanu (1926) following vermal lesions was not controlled by recording the systemic blood pressure. The experiments of Mansfeld and v. Tyukody (1936, 1937) and of Mansfeld and Hamori (1938) which appeared to show that the centers of the chemoceptive reflexes on respiration are located within the cerebellum probably contained technical errors. Their results were disproved, at any rate, by Stella (1937), who stated that decerebellation actually accelerated the rate of breathing and increased lung ventilation, in the decerebrate dog. He first thought that this effect was simply due to a fall of the blood pressure. In view of Moruzzi's results (1938c; see also 1940a) on the effect of cerebellar stimuli on respiration and on chemoceptive respiratory reflexes, Stella (1939) performed a new series of experiments, in which decerebrate dogs were decerebellated practically without loss of blood.

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PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

Figure 117. The effect of stimulation of the vermal part of the anterior lobe during a chemoceptive reflex on respiration. Precollicular cat. Reading downward: respiration, blood pressure (low vasomotor tone, unaffected by the stimulations), signal of faradic stimulation of the cerebellum (C). At the arrow: intracarotid injection of potassium cyanide. (From G. Moruzzi, 1940, Paleocerebellar inhibition of vasomotor and respiratory carotid sinus reflexes, J. Neurophysiol., 5:20-32, Fig. 5, publ. Charles C. Thomas.)

Although the arterial pressure was not affected by removal of the cerebellum, the respiration was definitely increased in both depth and rate. The influence of cerebellar ablation was much more marked during the inhalation of air containing 5 to 10 per cent carbon dioxide or nitrogen, since then "the respiratory excitation was often as much as one and a half times as great as before decerebellation." Stella (1939) concluded that the chemoceptive respiratory reflexes were neither abolished nor reduced following cerebellectomy, as had been maintained by Mansfeld and Tyukody (1936), but that they were actually released from some kind of tonic inhibition. Also the respiratory responses to nociceptive stimulations would be modified by cerebellectomy, according to Petrova (1939). 4. EFFECTS ON THE ENDOCRINE GLANDS There are only a few direct data suggesting a cerebellar influence on the endocrine glands. Tutaev, Litkevic, Isacenko, and Makarova (1937) and Tutaev and Makarova (1940) stated that the iodine content of the thyroid gland increased

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 301 in the rabbit following cerebellectomy, while its microscopic appearance was similar to that of a resting gland. Tutaev and Makarova (1940) maintained that the extracts of adrenal glands obtained from cerebellectomized animals had a less marked effect on the blood pressure. More relevant data may be gathered from indirect experimental evidence. Claude Bernard (1858, vol. 1, p. 457) reported that a puncture of the cerebellum was followed, in the rabbit, by glycosuria even when the medulla had not been injured. Still in the rabbit, Eckhard (1871) observed glycosuria and polyuria following mechanical and chemical injury of the uvula (Larsell's lobule IX) as well as after its galvanic or faradic stimulation. He called this part of the cerebellum "lobus hydruricus et diabeticus," and reported that no effects or only negligible ones could be elicited from other areas of the vermis. His results on cerebellar glycosuria were confirmed by Dresel and Lewy (1924), Lewy and Shinosaki (1926a, b), and Shinosaki (1926), who reported that strong and longlasting hyperglycemia occurred in these experimental conditions. Eckhard's cerebellar polyuria was confirmed by Schlayer (1913) and by Olivet (1930), and shown to be independent from the glycosuria (Eckhard, 1871; Schlayer, 1913; Olivet, 1930). It was missed only by Hug (1921), who, however, limited his punctures to the cerebellar hemispheres. Eckhard (1871) had already made the remarkable observation that the cerebellar glycosuria was prevented by severing the splanchnic nerves. It was only many years later that Shimidzu (1924) and Wada, Seo, and Abe (1935) showed that the rise of the blood sugar elicited by cerebellar injury was due to adrenaline discharges. The main reservation to be made in accepting the results of these acute experiments is that circulatory damage of the medulla may have occurred (van Rijnberk, 1931, p. 673) or there may have been unspecific irritation of fibers projecting onto the autonomic centers of the hypothalamus (Hiller, 1930). It must be conceded, on the other hand, that the negative results obtained by Wiggers (1942b, 1943c) from prolonged electrical stimulation of various areas of the cerebellum (including the uvula) cannot be regarded as a disproof of the old findings, since his experiments were performed on barbiturized cats. Eckhard's son, F. Eckhard (1880), had already pointed out that cerebellar injury was without effect in the rabbit under chloral hydrate anesthesia. Chronic experiments on the regulation of the blood sugar levels were also made. Luciani (1891, p. 75) reported that the glycosuria brought about by cerebellectomy lasted several days, while Papilian and Cruceanu (1926) and Perelmann (1927) stated that hyperglycemia could be found up to eighteen days following vermal lesions. Kaplan (1938a) maintained that the fasting levels of glycemia were not modified following ablation of the vermis and of the medial part of the cerebellar hemispheres in the dog. The blood sugar curve obtained following injections of glucose was, however, strikingly modified. Values of 250 mg. per cent were reached, against 140 mg. per cent in the control animals. Fasting levels were not yet attained after three hours, whereas the glycemia was back to its normal values within two hours in the control animals. These alterations could still be observed thirty to forty-five days following the operation. Alterman and Jankovskaja (1938) confirmed that the blood sugar levels attained in tolerance

302 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM tests were higher in the totally cerebellectomized dog, but stated that the time required for regaining the fasting values was normal. Wiggers (1943c) confirmed Kaplan's tolerance tests on dogs following removal of only the uvula (Larsell's lobule IX). He stated that removal of other parts of the cerebellum, even of the neighboring pyramis (Larsell's lobule VIII), was without effect. Histological controls showed that the fastigial and emboliform nuclei were normal after this operation, so that the alteration was related to the lesion of a quite small cortical cerebellar area. The effects on the blood sugar curve were observed for several weeks, but one to three months after the operation normal results were again obtained with tolerance tests. Wiggers (1943c) reported, moreover, that following chronic ablation of the uvula, pyramis, and paramedian lobules (Larsell's lobules IX, VIII, H Vllb, H Villa) in the cat, tolerance tests gave abnormal results even when the glucose was given intravenously. Hence these effects could not be attributed to abnormalities in the absorption from the gastrointestinal tract. Finally, he stated that subtotal removal of the cerebellum, including the uvula, was not followed, in the dog, by alterations of the normal glycemic level. He suggested that the opposite results obtained by the previous investigators might be due to secondary alterations in the medulla. Fasting blood sugar levels, however, showed marked fluctuations after subtotal cerebellar ablations, and even when lobule IX alone had been destroyed. The results of Kaplan (1938a) and of Wiggers (1943c) are certainly stimulating. They suggest that the cerebellum, and actually a small area of the cerebellar cortex, the uvula, may be concerned with the supervision of the homeostatic mechanisms regulating blood sugar levels through insulin secretion. 5. EFFECTS ON THBRMOREGULATION Changes in the rectal (Saprokhin, 1937; Simkina, 1948) and skin (Simkina, 1943a) temperatures were reported following electrical stimulations of the cerebellum, in the dog and in the rabbit. Simkina (1948) did not specify in her review the cerebellar areas that were stimulated nor the controls which were made in order to dismiss the danger represented by the spread of currents. The skin temperature effects observed by Simkina (1943a) in the rabbit following unilateral cerebellar stimulations were different in the ipsilateral and in the contralateral sides of the body. Hence they were obviously related to local vasomotor effects. No changes in the rectal temperature were observed by Shinosaki (1926) following lesions to the uvula yielding a striking increase in the blood sugar. Maevskij's experiments (1940) were made on chronically cerebellectomized dogs. He reported that when the animals were placed in a hot room, the rectal temperature increased more than in the control animals. These data suggest an impairment of the heat-dissipating mechanisms, and actually Maevskij (1940) stated that thermal panting appeared at higher body temperatures in the operated animals than in the controls. This might turn out to be a rather interesting observation if the integrity of the brain stem was controlled on serial slides. No data about histological controls are given in Simkina's review (1948). These effects may not be specifically related, in any case, to thermoregulation. Alek-

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 303 sanjan (1946) reported that the autonomic effects elicited by a reduction in the barometric pressure also were delayed in the cerebellectomized animal. 6. EFFECTS ON THE GENERAL METABOLISM Baryshnikow (1946) reported that basal metabolism was increased in the cerebellectomized animal, but rightly pointed out that this might be due to the tremor. It would be difficult to appraise the functional significance of the changes in the blood chemistry observed by Dresel and Lewy (1924), Papilian and Cruceanu (1926), Jankovskaja (1938), Markow (1941), and Adachi and Ushiyama (1950) in their cerebellectomized animals. The results of Dresel and Lewy were not confirmed by Shinosaki (1926). 7. AUTONOMIC EFFECTS ON THE EYES Changes in the pupil diameter and/or the nictitating membrane were frequently reported following electrical (Ferrier, 1876; Versilov, 1903; Mussen, 1927; Simkina and Orbeli, 1932; Mikhelson and Tikhalskaja, 1933; Clark, 1939a; Simkina, 1943a, 1945a; McDonald, 1953; Emerson, Bruhn, Foley, and Emerson, 1954), chemical (Versilov, 1903; Pagano, 1905; Camis, 1913; Suda, Abe, Ushiyama, and Mizuno, 1944; Okamoto, 1952), or mechanical (Shimidzu, 1924; Wada, Seo, and Abe, 1935) stimulation of the cerebellum, or after total (Kunstman and Orbeli, 1932) or partial (Brown-Sequard, 1862; Renzi, 1863-1864; Papilian and Cruceanu, 1925b) cerebellar ablation. Convincing controls, however, showing that these effects were exclusively related to the cerebellum, are not available. The same objection can be made also regarding the experiments of Simkina (1945b) on the permeability of the uveal tract vessels as well as the results of Hampson (1949) and of Hampson, Harrison, and Woolsey (1952), who stated that stimulation of the cerebellar hemispheres inhibited the pupillary dilatation elicited by sciatic volleys. Much more convincing, in our opinion, are the results that were obtained by stimulating the cerebellum with stereotactically oriented, concentric electrodes, since the excitation could then be limited to small regions, which were later localized on histological slides. Pupillary changes were reported by Sachs and Fincher (1927) following stimulation of the fastigial and interposite nuclei in the monkey. Hare, Magoun, and Ranson (1937) stated that they obtained in two otherwise intact cats, under barbital anesthesia, a bilateral constriction of the pupils by stimulating the white matter between the fastigial and interposite nuclei. They ruled out the possibility of a spread of currents, since these effects could not be elicited by electrical stimulation of the underlying cerebellar structures, but they were of the opinion that this cause of error was likely to occur when regions close to the medulla were stimulated. Mydriasis was the most frequent response obtained from these basal areas. Chambers (1947) explored with implanted concentric electrodes the pupillary response to stimulation of the interior of the cerebellum. He used otherwise intact cats, unanesthetized or under barbital anesthesia, and thought that both the mydriatic and the myotic responses he observed were due to excitation of the cerebellum, since they were obtained with weak stimuli and from areas far removed from the brain stem.

304 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM Pupillary and bladder responses were usually strictly related. These findings were confirmed by Emerson, Bruhn, Emerson, and Foley (1956) with stereotaxic cerebellar stimulation, in the decorticate cat. The cortical effects elicited by light faradic stimulation of the cerebellar anterior lobe in the chloralosed cat (Moruzzi, 1941a) will later be described, and controls showing that these responses arose in the stimulated area will be reported (see pp. 312-321). In the course of these experiments a pupillary dilatation was observed whenever generalized cortical movements occurred, either during the cerebellar stimulation or as a rebound response. These effects were still present when both sigmoid gyri had been destroyed, although the phasic responses of the skeletal muscles were then abolished, and also after complete decortication. When the cerebellar stimulation was timed to occur against a background of intense somatic activity, with clear-cut mydriasis, both somatic and autonomic effects were clearly inhibited (Moruzzi, 1941a). Obviously these ocular responses should not be directly related, or at least not necessarily related, to the cerebellar stimulation. It must be conceded, however, that the pupillary effects which were obtained after bilateral decortication could hardly be explained as a consequence of sensory reverberations. Moruzzi (194la) suggested that they might be due to cerebellifugal impulses impinging upon autonomic centers of the hypothalamus. The results of the stimulation experiments performed by Moruzzi (1947c), using Hess's technique, on unanesthetized thalamic cats have already been reported. Two types of autonomic responses of the eyes were observed. It is well known that retraction of the nictitating membrane, exophthalmos, and widening of the pupils occur as a part of the hypothalamic mass discharges characterizing any outburst of sham rage. These autonomic effects were inhibited during the cerebellar stimulation, but occurred as a rebound response when the excitation of the cerebellum was provoked in an interval of quietness. The ocular autonomic responses represented in these cases only one aspect of generalized phenomena. They might also be regarded, therefore, as the indirect consequence of neural or humoral (adrenaline discharge) activities elicited by the multifarious sensory stimulations that are likely to result from all violent movements. That this is not the whole story was shown, however, by the fact that clear-cut mydriatic responses were obtained also when the preparation was somewhat deteriorated, so that the struggling movements were entirely absent. The localized ocular phenomena could hardly be attributed to adrenaline discharges, since not the slightest change in the heart rate was observed on electrocardiographic records (Bartorelli, 1947). Different types of controls showed that these responses, which were elicited with minimal amounts of current from cerebellar structures surrounded by silent regions, were really due to excitation of the stimulated areas. Pupillary responses were obtained also by stimulating the interior of the cerebellar vermis in the acute thalamic cat (Moruzzi, 1948e; Zanchetti and Zoccolini, 1954) in the course of experiments that have been fully reported elsewhere (see pp. 295-298). In view of the great variety of the neural regions and types of stimulation that are related to the diameter of the pupils, the results of ablation experiments

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 305 can have a functional significance only in the following circumstances: (a) when the extent and the localization of the lesion are verified by histological controls; (b) if all irritative effects are avoided; and finally (c) if some specificity of the effects can be demonstrated. To the best of our knowledge, only the works of Chambers (1948) and of Chambers and Sprague (1955a, b) fulfill these requirements. In chronic experiments on cats they found that the pupil was larger contralaterally to the total lesion of one fastigial nucleus, whereas the same effect occurred ipsilaterally following total lesion of one nucleus interpositus or of the overlying intermediate part of the anterior lobe. No pupillary changes were noted when the lesion was limited to the rostral part of either the nucleus fastigii or the nucleus interpositus. The pupillary effects of cerebellar cortical lesions lasted about five days. Chronic destruction (twenty-two days survival) of that part of the dentate nucleus upon which the paraflocculus projects was not followed, in one cat, by any symptom except a dilatation of the contralateral pupil (Chambers and Sprague, 1955b).

8. EFFECTS ON THE DIGESTIVE TRACT Crop paralysis (Claude Bernard, 1858; Karamjan, 1941) and diarrhea (Wagner, 1858, 1861; Weir Mitchell, 1869; Lange, 1891; Karamjan, 1941) have been observed in the pigeon following injury or incomplete lesions of the cerebellum. Different results were reported on mammals, where constipation (Borgherini and Gallerani, 1891, 1892; Kunstman and Orbeli, 1932; Voronin and Simkina, 1935; Fulton, 1936; Kaplan, 1938b, c; Pancratoff, 1938; Markow, 1941; Chambers and Sprague, 1955b), disturbances of gastric motility (Kashkaj, 1938, 1940; Kaplan, 1938b, c; Kaplan and Ossetinskij, 1939), and plasticity of the intestine wall with marked reduction in tonus and peristaltic movements (Voronin, 1938) would result from cerebellectomy. Voronin's results are inconsistent, however, with his own observations (Voronin, 1938) and with those of Voronin and Simkina (1935, 1938), who reported that electrical stimulation of the cerebellum inhibited, in the great majority of cases, both the tone and the peristaltic movements of the intestine. Most of the experiments on the alimentary canal are subject to the criticisms which were outlined in the introduction to this section. The only clear-cut evidence of a close relation between autonomic reflexes on the gastrointestinal tract and well-defined areas of the cerebellum is represented by the experiments of Bard et al. (1947) on motion sickness, which were reviewed in the chapter on ablation experiments (see p. 54).

9. EFFECTS ON BLADDER FUNCTIONS Clinical cases of cerebellar deficiency characterized by disturbances of bladder functions have been reported rather frequently. We are concerned here only with the data obtained from experimental animals. Paralysis of the bladder was observed by Borgherini and Gallerani (1892) on their cerebellectomized dogs, but Dragomanov (1909) and Barrington (1921) stated that total removal of the cerebellum had no effect on reflex micturition in

306 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM the decerebrate cat. Both Barrington (1921) and Langworthy, Kolb, and Lewis (1940) reported, however, that in some cases the bladder of the decerebellate cat tolerated less distention than it did before cerebellar ablation, but Barrington (1921) thought that this effect was due to injury of the brain stem. Connor and German (1941) stated that the bladder reflexes were hyperactive following ablation of the cerebellar anterior lobe in cats, dogs and monkeys. Peretti (1951) came to opposite conclusions; marked bladder hypertonus occurred in the dog, he said, if the anterior lobe had been spared by partial ablation, whereas chronic cerebellar lesions involving the anterior lobe and the underlying nuclei were followed by marked vesical atonia. The importance of careful histological controls of the brain stem in this type of experiment hardly needs to be stressed, since the stretch reflex of the bladder will obviously be increased following secondary lesions of the inhibitory midbrain structures, whereas just the opposite effect will occur if the facilitatory center, which is located in the upper pons, is encroached upon (see Ruch, 1955, for references). Vesical responses were obtained following stimulation of the cerebellum, but the results were frequently contaminated by collateral effects on the brain stem. That these were present in the old experiments of Budge is almost certain. He first (1841) reported that bladder contractions occurred following mechanical or chemical (potassium hydrate) injury of the restiform body and (though less frequently) the cerebellar vermis. Many years later, however, he repeated his experiments (Budge, 1864a) using an induction coil for cerebellar stimulations, and this time he found that the vesical response disappeared altogether when the electrodes were displaced from the restiform body to the vermal surface of the cerebellum. The autonomic effect was again clearly present, however, if the same stimuli were applied to the cerebral peduncles and to brain stem regions lying between the cerebral and the inferior cerebellar peduncles (Budge, 1864a, b). Bechterew (1909, p. 958) also reported negative findings on the intestine and bladder following electrical stimulation of the cerebellum. Asratian (1934, 1941) and Pressman and Shitov (1940) reached similar conclusions, since no contraction of the esophagus or of the bladder resulted from mechanical or chemical stimulation of the cerebellum. Positive results, generally represented by forceful urination, were reported, however, following mechanical (Kremer, 1942), chemical (Pagano, 1905), and electrical (McDonald, 1953; Emerson, Bruhn, Foley, and Emerson, 1954) stimulations of the anterior lobe of the cerebellum, both in the dog (Pagano, 1905; Kremer, 1942) and in the unrestrained, unanesthetized cat (McDonald, 1953; Emerson, Bruhn, Foley, and Emerson, 1954). The discrepancy between these results and those reported by the Russian investigators cannot be easily accounted for, since neither in the reviews of Bechterew (1909) and Simkina (1948) nor in the paper by Pressman and Shitov (1940) are any details given about the areas of the cerebellum that were stimulated. Kremer (1942) obtained in 85 per cent of cases a strong contraction of the bladder by needle puncture of the anterior lobe. Crude as this method may be, it has at least the advantage that a spread of the physical or of the chemical stimulus can be ruled out. None of the authors cited above reported convincing controls showing that the vesical effects were really due to cerebellifugal volleys.

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 307 Kremer's paper is interesting also in another respect, since he worked on bladders which were artificially distended, so that the cerebellar stimulation occurred against a background of vesical stretch that might be regarded as a subliminal stimulus for the micturition reflex. This approach should be adopted in future experiments. We think that the effects of cerebellar stimulation on bladder function should be investigated against a background of constant micturition reflexes, just as the somatic responses are tested against a background of decerebrate rigidity or of phasic reflexes. This approach was recently adopted by Bruhn, Emerson, Emerson, and Foley (1956), who showed that in the intercollicular cat the micturition reflex was sometimes inhibited and sometimes facilitated by electrical stimulations confined with certainty to the cerebellar cortex. They pointed out that neither cerebral cortex, thalamus, nor hypothalamus is essential for these autonomic responses to cerebellar stimulation. Chambers (1947) is the only author to demonstrate with certainty the cerebellar origin of the micturition effects he obtained on otherwise intact cats. Figure 118 shows the discreteness of the localization of the points which gave micturition in his anesthetized cats. The points were in the region of the fastigial nuclei, the adjacent medullary substance and buried cortex, and were intermingled with unresponsive structures. With only two exceptions, the responsive regions were located in the rostral portion of the roof nuclei and in the neighboring areas, i.e., in the nuclei which are projected upon by the vermal part of the anterior lobe (Jansen and Brodal, 1940, 1942, 1954). Confirming Peretti's conclusions (1951), Chambers and Sprague (1955b) reported that the cat's bladder was hypotonic when the destruction of the rostral part of the roof nuclei was combined with a topectomy of the whole or of only the vermal part of the anterior lobe. These chronic experiments are very important, since they were carefully controlled on histological sections stained by the Marchi, Weil, or Nissl methods.

Figure 118. A diagrammatic representation of the cerebellar points giving micturition. Cats under light nembutal anesthesia. Responsive and unresponsive points are given on a midsaggital and on a coronal section (through the primary fissure and the ventricular fastigium). Stimulation with 60-cycle sine-wave current. The voltages shown to the right of each cat number were at threshold for the responsive points and were the maximum voltages used at the unresponsive points. The numbers of the unresponsive points are underlined. (From W. W. Chambers, 1947, Electrical stimulation of the interior of the cerebellum in the cat. Am. J. Anat., SO:55-93, Fig. 1.)

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10. EFFECTS ON THE SEXUAL ORGANS Many uncritical investigations and speculations were prompted by Gall's hypothesis (1822-1825) concerning a cerebellar influence on sexual activities. They have now only an historical interest and were reviewed by Longet (1850) and by Bechterew (1909, pp. 955-958). We shall only recall here that completely negative results were obtained with ablation (Luciani, 1891; Andre-Thomas, 1897) and stimulation (Plohinski, 1902; Pussep, 1902; Bechterew, 1909, p. 957) experiments. Pancratoff (1951) claimed that the period of gestation was increased by ten to fourteen days in the cerebellectomized cat. His experiments were performed, however, on only two animals. 11. TROPHIC INFLUENCES ON THE MUSCLES AND SKIN Permanent functional changes in the skeletal muscles belonging to the hemicerebellectomized side of the body were reported by Krestovnikoff (1928) and by Strack (1941). We have pointed out elsewhere (see pp. 269ff) that no evidence was provided (a) that these findings were really related to the withdrawal of a specific trophic influence of the cerebellum or (b) that this influence, if present, was mediated by the autonomic nervous system. Simkina's attempts (1948) to correlate with the Orbeli effect some observations she made with different kinds of cerebellar stimulations appear to us not altogether convincing. The problem of the sympathetic innervation of the skeletal muscles cannot be dealt with in this book, and the reader is referred to the mainly negative conclusions which Bremer (1932, pp. 735-739) and Tiegs (1953, pp. 118-122) reached in their critical reviews. We simply want to cite here the results of pigeon experiments recently performed by Giulio and Manni (1950). They confirmed (a) that postural asymmetries of the hindlegs followed unilateral cerebellar lesions and were not abolished by thoracic transection of the spinal cord (see pp. 270-271), and showed, moreover (b) that these long lasting effects of asymmetrical cerebellar innervation were not modified by total bilateral sympathectomy. To the best of our knowledge, nobody has attempted, so far, to find out whether Krestovnikoff's findings (1928) can be duplicated in the bilaterally sympathectomized animal. This might turn out to be a crucial test for the doctrine of the mediation by autonomic fibers of the so-called trophic influence which would be exerted by the cerebellum on the skeletal muscles. It would be interesting, moreover, to correlate these functional changes with careful histologic controls of the striated muscles. Working in Luciani's laboratory, Marchi found a partial degeneration of the muscle fibers following chronic cerebellectomy (Luciani, 1891, p. 207), and his results were confirmed by von Monakow (1897). These old observations should, however, be verified by modern methods, and the effects of the cerebellar ablation should be controlled, histologically, at brain stem and spinal levels. Trophic alterations of the skin were observed after cerebellectomy on pigeons by Wagner (1861, p. 263) and on mammals by Luciani (1891, pp. 206-207), Papilian and Cruceanu (1926), and Lisitza (1932). These phenomena are lacking, however, when the animal is well kept and nourished (Russell, 1894; see also Orbeli, in Simkina, 1948). Movements of tail hairs were occasionally observed following cerebellar stimulations in unrestrained, unanesthetized cats (Clark,

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 309 1939a, p. 30; McDonald, 1953, p. 75), but no proof that these effects were of a genuinely cerebellar origin was given.

12. EFFECT ON THE GALVANIC SKIN REFLEX Wang and Borison (1956) pointed out that the galvanic skin reflex is an excellent indicator in the study of central inhibition of autonomic reflexes, since the sweat glands are innervated only by the sympathetic system, do not respond to the systemic administration of epinephrin, and show no spontaneous activity. The galvanic skin reflex was evoked by stimulation of afferent fibers with single induction shocks, in the cat under chloralose-urethane anesthesia. It was clearly inhibited by stimulating with high-frequency pulses the anterior lobe of the cerebellum and also the bulbar ventromedial reticular formation.

13. CEREBELLIPETAL PROJECTIONS OF VISCERAL AFFERENT FIBERS This problem may be investigated (a) by anatomical methods and (b) by means of the electrophysiological technique of evoked potentials. The reader is referred to the companion volume of Larsell (1958) for a review of the anatomical data, and particularly for an appraisal of the significance of the nucleus visceralis secundus, anatomically belonging to the cerebellum. This interesting formation was shown, on frog material, to receive visceral fibers from the nucleus tracti solitarii and to project onto the hypothalamic region (Larsell, 1923). These anatomical findings should prompt comparative electrophysiological investigations. Allen (1923) was unable to find visceral connections with any of the deep cerebellar nuclei of mammals, and the positive results obtained by Krause (1930) on the connections between the sensory nuclei of the glossopharingeal nerves and the cerebellar vermis of the cat have recently been criticized (Jansen and Brodal, 1954, p. 174). Hence there is so far no clear anatomical counterpart for the electrophysiological investigations we are going to review. Slow potential changes (Beck and Bikeles, 1912a) and fast evoked responses (Bremer and Bonnet, 1951b; Dell and Olson, 1951) were led from the surface of the vermis following stimulation of the afferent fibers of the vagus nerve (see pp. 189—192). The remarkable finding was reported by Bremer and Bonnet (1951b) that vagal and exteroceptive volleys converge on the same neurons (see p. 216). Brookhart, Moruzzi, and Snider (1950) led occasionally from crus I or crus II (sublobule H Vila) of the decerebrate cat single units which discharged synchronously with the inspiration. These were unexpected and unpredictable findings, and unfortunately the authors did not investigate the influence of bilateral vagotomy or of stimulation of the central end of the vagus nerve on these discharges. They showed nevertheless that this respiratory periodicity was a genuine effect, probably related to rhythmic proprioceptive discharges impinging upon the cerebellar cortex during each inspiration. Widen (1955) recently devoted a detailed study to the cerebellar cortical responses elicited by single-shock stimulation of the central cut end of the splanchnic nerve. He worked on cats under barbital anesthesia, and reported that in these experimental conditions no response was elicited from the large beta fibers coming from the Pacinian corpuscles of the mesentery. Stimulation of the

310 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM thin-myelinated fibers of the delta type, usually responding to nociceptive stimulation of the viscera, yielded, however, a clear-cut surface-positive response, lasting about 20 milliseconds and followed by a surface-negative oscillation of lower amplitude and of longer duration. The responses of lobules IV, V and H IV, H V (culmen; the lobulus centralis was not explored) were characterized by slightly shorter latent periods (20 milliseconds, instead of about 25 milliseconds) and were more resistant to the anesthetic agent than those led from the paramedian lobules (sublobules H Vllb, H Villa) and from the lobulus simplex and lobulus medius medianus (lobules VI, VII). The map which was obtained on the lightly anesthetized animal (Fig. 119) showed marked overlapping with the tactile and vagal projections areas (see pp. 185-192). Controls of different kinds demonstrated that the evoked potentials were due to afferent splanchnic volleys, coursing through delta fibers at a speed of 15 to 24 m/sec, and reaching the cerebellar cortex via the anterior quadrants of the spinal cord and the restiform bodies. Simultaneous stimulation of somatic and visceral afferents showed a high degree of occlusion and of blocking interaction, partially occurring at spinal levels.

Figure 119. Cerebellar cortical localization of the evoked responses to single-shock stimulation of the central end of the splanchnic nerve. Cat under light (25-30 mg/Kg) nembutal anesthesia. Responses were led from the entire culmen (lobules IV, V, and H IV, H V), from the lobulus simplex (lobules VI and H VI), from the lobulus medius medianus (lobule VII), and from both paramedian lobules (sublobules H Vllb, H Villa). The lobulus centralis (lobules III and H III, H IV) was not explored. (From L. Widen, 1955, Cerebellar representation of high threshold afferents in the splanchnic nerve, with observations on the Cerebellar projection of high threshold somatic afferent fibers, Acta physiol. Scandinav., 33:1-69 (suppl. 117), Fig. 2.)

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D. RELATION TO THE CEREBRAL CORTEX 1. THE EFFECTS OF CEREBELLAR STIMULATION ON THE CEREBRAL CORTEX a. EFFECTS ON THE EXCITABILITY OF THE MOTOR AREA Rossi's discovery (1912b) that stimulation of the cerebellum increases the excitability of the motor cortex has repeatedly been confirmed (Bremer, 1935; Dusser de Barenne, 1937), and it is now regarded (Bremer, 1935; Holmes, 1939) as direct evidence of the facilitatory influence exerted by the cerebellum on the cerebrum. Rossi (1912b) reported that the faradic threshold for cortically induced movements was strongly lowered by stimulating the cerebellar cortex. The facilitatory response was obtained by stimulating the cerebellar hemispheres (crus I, crus II, lobulus paramedianus: Larsell's sublobules H Vila, H Vllb, H Villa) and even the posterior vermis (Bolk's lobulus medianus posterior: lobules VII to X) with 10- to 80-per-second induction shocks, whose intensity was about the same as that required for threshold stimulation of the motor cortex in the same animal. Local strychninization (1 per cent) of the cerebellar surface yielded similar results. Rossi's effect showed no somatotopic arrangement, could not be detected ipsilaterally to the stimulated cerebellar area, and was abolished by deep ether anesthesia (see Rossi, 1940). Rizzolo (1930) reported that the chronaxie of the dog's motor cortex decreased following faradic stimulation of the contralateral but also of the ipsilateral cerebellar hemisphere. The significance of his findings, however, appears doubtful for two reasons: (a) the measurements were made not during but after a very prolonged (60 seconds) cerebellar stimulation, whose intensity, moreover, was not controlled by physical and physiological tests; (b) cortically induced movements were taken as a test of the chronaxie measurement. The second objection may be raised also against the experiments of Saprokhin (1949), who reported either an increase or decrease in the chronaxie of the motor cortex following cerebellar stimulation. The fallacy of these chronaxie measurements is obvious, but the problem deserves reinvestigation. As a test of the cortical effect either the pyramidal response to single-shock stimulation of the motor cortex (Zanchetti and Brookhart, 1955) or the spontaneous discharge of single pyramidal units (Adrian and Moruzzi, 1939) should be used. If clear-cut results were to be obtained in this way on a curarized preparation, evidence would be provided that excitability changes really occur within the cereberal cortex, possibly under the impact of cerebellifugal volleys. b. EFFECTS ON CORTICALLY INDUCED MOVEMENTS

Lowenthal and Horsley (1897) were the first to investigate, in cats and dogs, the influence of cerebellar stimulations on cortically induced movements. Faradic stimuli were applied to the cerebral and the cerebellar cortices. "Synchronous excitation of the cerebral area for the forelimb and the cerebellar foci," the authors said, "has given so far, in cases where the cerebellum is definitely excitable, an addition to the tonus elicited previously from the cortex cerebri" (p. 25). Since they stimulated a region on the border between the anterior vermis and the cerebellar hemispheres, it is obviously impossible to tell whether the

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vermis proper or the intermediate part was responsible for what might be designated a facilitatory effect. Almost half a century later Moruzzi (1941a, b, c) recorded myographically, in the chloralosed cat, the influence of cerebellar stimulations on the motor area of the cerebral cortex. Most of his experiments were performed on cerebellar areas (Larsell's lobules IV and V) belonging to the vermal part of the anterior lobe, but the results were occasionally reproduced also by stimulating the pyramis (lobule VIII) and the lobulus ansiformis (sublobule H Vila). However, a higher excitability of the cerebral cortex was required to obtain an effect by stimulating these cerebellar areas. It is well known that chloralose anesthesia is characterized by a surprising increase in reflex excitability: a light tap on one foot or even on the table near the animal evokes a sudden, convulsive jerk, often involving all the animal's body. Adrian and Moruzzi (1939) showed (a) "that whenever a chloralose jerk occurred, there is an abrupt potential wave in the motor area and a corresponding discharge of impulses in the pyramidal tract" (p. 170), and (b) that the destruction of both motor areas abolished the response, leaving only some increase in the limb reflexes. This background of increased cortical excitability was utilized in the hope of getting some information on cerebellocerebral relations. The first result obtained in these experimental conditions was that cerebellar stimulation yielded a corticofugal discharge of the motor area, which was responsible for the appearance of phasic movements in the opposite side of the body. Stimulation of the vermal part of the anterior lobe evoked, first of all, the well-known inhibition of the antigravity tonus of the ipsilateral limbs, which was followed by a strong extensor rebound. Hence the postural response was present, and did not differ substantially from that observed in any decerebrate preparation. In the lightly chloralosed cat, however, strongly clonic movements were superimposed on these postural responses (Fig. 120A). In many instances, during the cerebellar stimulation there was a decrease in the extensor tonus,while clonic twitches appeared in the flexor muscles. This type of response was not related to the reciprocal organization of the corresponding half-centers of the spinal cord, since (a) clonic twitches were recorded, occasionally, also from extensor muscles, and (b) the brain structures underlying the clonic discharge were shown to be altogether different from those responsible for the postural effects. The postural response is, of course, related to the activity of brain stem centers, but the following evidence showed that the clonic twitches were due to corticofugal discharges arising from the sigmoid gyrus. The clonic effect was selectively abolished (a) by decerebration (Fig. 1205) and (b) by bilateral destruction of the motor cortex (Fig. 121), and was reversibly blocked or strongly decreased whenever the cortical excitability was depressed (c) by eliciting many outbursts at short intervals (Fig. 122) or (d) by clamping the common carotids (Fig. 123). Finally when the clonic effect had faded away, as generally happened toward the end of the experiment, it could be re-established by subliminal strychninization of the motor area (Fig. 123). When the motor cortex was strychninized for too short a period or with too

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Figure 120. Inhibition of the postural tonus and facilitation of chloralose movements produced by stimulation of the vermal part of the anterior lobe. Cat under very light chloralose anesthesia (21 mg/Kg). Reading downward: isometric record of the postural extensor tonus (elbow, extension upward) of the ipsilateral forelimb, isotonic record of phasic activity of the ipsilateral hindlimb (ankle, flexion downward), and signal of cerebellar stimulation. Inhibition of the extensor tonus and clonic twitches appear during each stimulation (A). Following decerebration only the postural effect occurs, even when the strength of the cerebellar stimulation is strongly increased (B). (From G. Moruzzi, 1941, Sui rapporti fra cervelletto e corteccia cerebrale. I. Azione d'impulsi cerebellari sulle attivita corticali motrici dell'animale in narcosi cloralosica, Arch, fisiol., 41:87-139, Fig. 12.)

Figure Wl. Chloralose movements elicited by stimulating crus I. Preparation and records as in Fig. 120. Chloralose, jerky movements, but no postural responses, are evoked during light stimulation of crus I (A). The clonic effect is abolished by destroying both motor areas, and no effect is obtained even when the intensity of the cerebellar stimulation is greatly increased (B). (From G. Moruzzi, 1941, Sui rapporti fra cervelletto e corteccia cerebrale. I. Azione d'impulsi cerebellari sulle attivita corticali motrici delPanimale in narcosi cloralosica, Arch, fisiol., 4* =87-139, Fig. 10.)

low concentrations of the drug, the myograms of a couple of antagonistic muscles of the opposite hindleg were silent. This was called subliminal strychninization, and it should be emphasized that when the hindlimb was silent, the forelimb was already twitching, i.e., the cortical strychninization was supraliminal for the response of other motoneurons. It was then possible to evoke a typical strychnine clonus of the silent hindleg by applying extremely weak faradic stimulations to the cerebellar cortex. The clonic response was ruled by Sherrington's law of reciprocal innervation. To exemplify, if the strychnine clonus was confined to the

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Figure 122. Selective fatigue of the clonic response. Preparation and records as in Fig. 120. Cerebellar stimulation was repeated at short intervals. The clonic effect was easily fatigued (c, d), while the inhibition of the postural extensor tonus was not modified. (From G. Moruzzi, 1941, Sui rapporti fra cervelletto e corteccia cerebrale. I. Azione d'impulsi cerebellari sulle attivita corticali motrici dell'animale in narcosi cloralosica, Arch, fisiol., £1: 87-139, Fig. 15.)

Figure 123. A cortical strychnine clonus evoked by cerebellar stimulation and the effect thereon of clamping both the common carotids. Cat under moderately light chloralose anesthesia (35 mg/Kg); isotonic records of M. tibialis anticus. Chloralose jerks were not evoked by the cerebellar stimulation, and in order to increase the cortical excitability the motor area was strychninized. The spontaneous strychnine clonus was absent, but twitches were evoked by light stimulation of the vermal part of the anterior lobe (A, C). The effect was reversibly abolished by clamping both the common carotids (B). It was permanently abolished later by destroying the strychninized area (record not shown). (From G. Moruzzi, 1941, Sui rapporti fra cervelletto e corteccia cerebrale. II. Azione d'impulsi cerebellari sulle attivita motrici provocate dalla stimolazione faradica o chimica del giro sigmoideo nel gatto, Arch, fisiol., 41:157-182, Fig. 5.)

extensor muscle, the flexor myogram was silent during the cerebellar stimulation; at the end of it, the clonic twitching suddenly stopped in the extensor muscle and was then observed in the flexor myogram. A new stimulation reversed the situation once more (Fig. 124). The most obvious explanation of all these findings is that the neurons of the motor area were easily driven by the cerebellar stimulation because of their subconvulsive state, a condition which characterized chloralosane anesthesia and was reproduced in some way by the local subliminal strychninization. The intensity of the electrical stimulation yielding the clonic response of the motor area was so low that the possibility of a spread of current to brain stem

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 315

Figure 1S4. Reciprocal innervation during the cerebellar driving of a strychnine clonus. Cat under moderately light chloralose anesthesia (35 mg/Kg), after local strychninization of the motor cortex. Reading downward: isotonic records of M. tibialis anticus, of M. gastrocnemius soleus, signal of stimulation of the vermal part of the anterior lobe. Only M. gastrocnemius soleus was recorded in C. A. Light cerebellar stimulation evokes a strychnine clonus in M. gastrocnemius soleus (lower record), contralaterally to the strychninized motor area; at the end of the stimulation a rebound clonus is observed in the antagonistic M. tibialis anticus. B. Same as A, but a flexor strychnine clonus is spontaneously present, and it is inhibited during the cerebellar stimulation. C. Strychnine twitching of the extensor muscle elicited by cerebellar stimulation. (From G. Moruzzi, 1941, Sui rapporti fra cervelletto e corteccia cerebrale. III. Meccanismi e localizzazione delle azioni inibitrici e dinamogene del cervellelto, Arch, fisiol., 41:183-206, Fig. 10.)

Figure 125. Dissociation between postural and clonic effects of cerebellar stimulation. Preparation and records as in Fig. 120. Threshold stimulations inhibited the postural extensor tonus, but were not followed by an extensor rebound nor did they yield a clonic response. Both these effects appeared simultaneously when the intensity of the cerebellar stimulation was slightly increased. (From G. Moruzzi, 1941, Sui rapporti fra cervelletto e corteccia cerebrale. I. Azione d'impulsi cerebellari sulle attivita corticali motrici delPanimale in narcosi cloralosica, Arch, fisiol., 41:87-139, Fig. 8.)

structures could safely be dismissed. Nor were the cortical outbursts elicited indirectly by the proprioceptive barrage brought about by the postural response, since the clonic effect was obtained also from crus I or crus II, whose stimulation never yielded postural effects. Finally, when the stimulation was confined to the vermal cortex of the anterior lobe, clonic effects were obtained for all the intensities of stimulation which yielded inhibition of the antigravity tonus followed by an extensor rebound. When the intensity of stimulation was just enough to inhibit the extensor tonus, neither clonic effects during stimulation nor postinhibitory extensor rebounds were observed (Fig. 125). Hence the facilitatory influence

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on the phasic activity of the motor area was related in some way to the cerebellar mechanisms responsible for the postinhibitory rebound (see p. 155). In short, a volley of facilitatory cerebellar impulses impinging upon the motor area of the cerebral cortex will evoke its supraliminal discharge when the cortical neurons are already in a subconvulsive state. In normal conditions only a lowering of the threshold, i.e., Rossi's effect, is likely to occur. Since a spontaneous pyramidal discharge is present even under barbital anesthesia (Adrian and Moruzzi, 1939), the hypothesis might be ventured that Rossi's effect is characterized by an increase in the spontaneous corticofugal discharge which is simply not strong enough to yield a motor response. According to this hypothesis "chloralose experiments give only a magnification, with some distortion, of Rossi's effect" (Moruzzi, 1950a, p. 53). The subconvulsive activity of the motor cortex simply made it possible to record myographically the effects of cerebellar stimulations on the motor cortex, but the peculiar action of chloralose should not be forgotten when the results of these investigations are utilized for understanding the mechanism of cerebellocerebral relations in physiological conditions. An unexpected observation was that the best facilitatory effects on the motor cortex were obtained by stimulating the vermal portion of the anterior lobe, an area which was believed at that time to influence only bulbospinal activities through fastigial relays. This result, which was then rather difficult to account for, is now easily explained. Electrophysiological investigation showed later (a) that the whole surface of the anterior lobe is closely related to the motor cortex (see pp. £04, 234), and (b) that the EEG patterns may also be strikingly influenced by stimulating the vermal cortex of the anterior lobe (Mollica, Moruzzi, and Naquet, 1953) as well as the fastigial nuclei and the medial bulboreticular formation (Moruzzi and Magoun, 1949). Stimulation of the same cerebellar structures also evoked a marked inhibition of cortically induced movements when it was timed to occur against a background of supraliminal activity of the motor area. This background was easily obtained by supraliminal faradization (Fig. 126) or by local strychninization (Fig. 127) of the sigmoid gyrus. The cortical movements were then inhibited during the stimulation of the vermal part of the anterior lobe, and markedly increased during the rebound phase. Sometimes a rebound effect on cortical movements was found when no inhibition had been observed during the stimulation period, because the motor cortex was not active at that particular moment. The clonic rebound was immediately inhibited if the same cerebellar stimulation was timed to occur while the phasic rebound was still going on, and the sequence of clonic rebounds and of inhibitory phases could be prolonged at will by repeating at proper intervals the cerebellar stimulation. Control experiments showed (a) that the inhibitory effect was really due to cerebellar stimulation, since it was obtained with faradic stimuli which were subliminal when applied to the motor cortex, and (b) that the phasic movements were elicited by corticofugal volleys, since they were abolished by destroying the motor area (Fig. 127(7). Hence the main task ahead was to localize the neural structures that were impinged upon by the cerebellar inhibitory volleys. Following bilateral ablation of the motor cortex, a background of phasic

Figure 126. Cerebellar inhibition of cortically induced movements. Cat under moderately light chloralose anesthesia (35 mg/ Kg). Reading downward: isotonic records of movement of the ankle (flexion downward), faradic stimulation of the vermal part of the anterior lobe, faradic stimulation of the contralateral motor cortex. The arrows indicate the end of the cortical stimulation and the beginning of a clonic (epileptiform) afterdischarge, which was also strongly inhibited, both in intensity and duration, by the cerebellar stimulation. (From G. Moruzzi, 1941, Sui rapporti fra cervelletto e corteccia cerebrale. II. Azione d'impulsi cerebellari sulle attivita motrici provocate dalla stimolazione faradica o chimica del giro sigmoideo nel gatto, Arch, fisiol., 41:157-182, Fig. 1.)

Figure 127. Cerebellar inhibition of a cortical strychnine clonus. Cat under moderately light chloralose anesthesia (35 mg/Kg). Reading downward: isometric record of the left forelimb extensor tonus (elbow, extension upward), isotonic record of the left M. gastrocnemius soleus, signals of faradic stimulation of the vermal part of the anterior lobe. Clonus elicited by application of 1 per cent strychnine nitrate on the right motor cortex. The extensor tonus collapses while clonic twitches markedly decrease in the forelimb and disappear altogether in the hindlimb during cerebellar stimulation (A, B). A rebound increase in the extensor tonus and in clonic activity follows each stimulation (^4, B). The clonic twitching is then abolished by destroying the strychninized motor area, while the postural responses to cerebellar stimulation are unaffected (C). (From G. Moruzzi, 1941, Sui rapporti fra cervelletto e corteccia cerebrale. II. Azione d'impulsi cerebellari sulle attivita motrici provocate dalla stimolazione faradica o chimica del giro sigmoideo nel gatto, Arch, fisiol., U: 157-182, Fig. 2.)

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Figure 128. Cerebellar inhibition of phasic movements yielded by jaradizing the white matter underlying the motor cortex. Cat under moderately light (35 mg/Kg) chloralose anesthesia, its right sigmoid gyrus having been previously extirpated. Reading downward: isometric myograms of the left M. triceps brachii, signal of faradic stimulation of the white matter underlying the right sigmoid gyrus, signal of faradic stimulation of the vermal part of the anterior lobe. Cerebellar inhibition of phasic activity (A, b; C, p), and postinhibitory extensor rebound (C). (From G. Moruzzi, 1941, Sui rapporti fra cervelletto e corteccia cerebrale. III. Meccanismi e localizzazione delle azioni inibitrici e dinamogene del cervelletto, Arch, fisiol., 41 '• 183—206, Fig. 3.)

activity could still be routinely elicited in two ways: (a) by stimulating electrically the white matter underlying the sigmoid gyrus (Fig. 128) or (b) by utilizing the combined effect of chloralose and strychnine (Fig. 129). Moruzzi (1944-1945) had reported that a generalized clonic seizure occurred when a chloralosed cat was given a dose of strychnine sulfate (0.05 mg/Kg) definitely below the minimal amount required for producing the typical spinal tetanus in the unanesthetized preparation. These clonic convulsions were abolished by precollicular decerebration, were first intensified and then reversibly blocked by clamping the common carotids following a ligature of the basilar artery (reversible anemic decerebration), but were entirely unaffected by bilateral destruction of the motor area (Moruzzi, 1944-1945). For threshold doses of the drug the convulsive twitches were limited to the flexor muscles, whereas for higher doses both groups of antagonistic half-centers were active. In short, during chloralose anesthesia intravenous injections of small doses of strychnine evoked generalized convulsions involving mainly extrapyramidal and subcortical structures. Both types of phasic activity were found to be strikingly blocked by stimulation of the vermal part of the anterior lobe (Figs. 128, 130). Moruzzi (1941c) suggested that the cerebellar inhibition of these extrapyramidal convulsive movements might occur at spinal levels. This is not the unique explanation, however, and the observation of von Baumgarten, Mollica, and Moruzzi (1954) that cortically driven bulboreticular discharges are blocked by cerebellar stimulation suggests that subcortical relays

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 319

Figure 129. Extrapyramidal clonic seizure elicited by strychnine in the chloralosed cat. Cat under moderately light chloralose anesthesia (35 mg/Kg). Reading downward: isotonic records of M. tibialis anticus and of M. gastrocnemius soleus, signal of stimulation of the central end of the ipsilateral saphenous nerve. A clonic seizure confined to the flexor muscles follows an intravenous injection of 0.05 mg/Kg of strychnine sulphate (A), is present after bilateral ablation of the motor cortex (B) and abolished after decerebration (D; the arrow indicates a new injection of 0.05 mg/Kg of strychnine, two hours after decerebration). C was taken a few minutes before D, and shows good reflex excitability of the decerebrate preparation, with abolition of reciprocal innervation (the intensities of the faradic stimuli are given in Kronecker units). (From G. Moruzzi, 1944-1945, Convulsion! extrapiramidali da stricnina, Arch, fisiol., 44:109—162, Fig. 4.)

of the extrapyramidal pathways may also be directly inhibited by cerebellifugal volleys. To state that cerebellar stimulations may inhibit cortically induced movements by acting at brain stem or spinal levels obviously does not exclude the hypothesis that cortical neurons may also be impinged upon by inhibitory cerebellifugal volleys. An inhibition at the cortical level was suggested, though not directly proved, by the following occasional observations (Moruzzi, 1941c). When the strychninization of the motor cortex was just enough to elicit clonic twitches of a given muscle, say M. tibialis anticus, it turned out that the inhibitory effect outlasted the cerebellar stimulation sometimes for more than one minute (Fig. 131). If the cortical clonus were blocked at spinal levels, this result could be

Figure 130. Cerebellar inhibition of an extrapyramidal strychnine clonus. Cat under light chloralose anesthesia (24 mg/Kg). Reading downward: movement of the forelimb (elbow, extension upward), myograms of M. gastrocnemius soleus and tibialis anticus, signal of faradic stimulation of the vermal part of the anterior lobe (the intensity of stimulation was higher in A). Generalized clonic convulsions had been produced, following bilateral ablation of the motor cortex, by an intravenous injection of 0.09 mg/Kg. of strychnine nitrate. The dose of the convulsant was higher than in Fig. 129 and yielded clonic activity in both flexor and extensor muscles. The convulsive activity of the antagonistic half-centers was blocked (A) or partially inhibited (B) by the cerebellar stimulation. (From G. Moruzzi, 1941, Sui rapporti fra cervelletto e corteccia cerebrale. III. Meccanismi e localizzazione delle azioni inibitrici e dinamogene del cervelletto, Arch, fisiol, 41:183-206, Fig. 1.)

Figure 131. The long duration of the abolition of a cortical strychnine clonus after the end of cerebellar stimulation. Cat under moderately light chloralose anesthesia (35 mg/Kg). An isotonic twitching of the left M. tibialis anticus had been elicited by the local application of 1 per cent strychnine nitrate to the right motor cortex. Strychninization had been stopped just at the beginning of clonic twitching in the left hindleg. Weak and short-lasting (B; C, b) faradic stimulation of the vermal part of the anterior lobe (signals) is not followed by an inhibitory aftereffect (B; C, b). The inhibition lasts more than 1 min. after the end of the stimulus if the duration (A) or the intensity (C, a) of the cerebellar faradization is increased. (From G. Moruzzi, 1941, Sui rapporti fra cervelletto e corteccia cerebrale. III. Meccanismi e localizzazione delle azioni inibitrici e dinamogene del cervelletto, Arch, fisiol., 41 '• 183-206, Fig. 4.)

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THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 321 accounted for only by postulating an unusually long inhibitory afterdischarge, such as has never been observed after cerebellar stimulations. A more likely assumption is that the convulsive synchronization was in some way disrupted by the vermal stimulation. This hypothesis was actually put forward by Moruzzi (1941c), but only many years later was it proved by electrophysiological investigations. Arduini and Lairy-Bounes (1952) showed that the strychnine spikes elicited by local applications of dilute solutions of the drug could be blocked for just a comparable length of time by stimulating the medial bulboreticular formation, a structure which is projected upon by the cerebellifugal volleys arising from the vermal part of the anterior lobe (see pp. 219-229). A few years later the influence of cerebellar stimulations on cortically induced movements was further investigated by Snider, Magoun, and McCulloch (1947), Snider, McCulloch, and Magoun (1949) and by Snider and Magoun (1949). The first group of authors experimented on cats placed under surgical levels of dial or nembutal anesthesia. The movements yielded by electrical stimulation of the pericruciate area were inhibited by applying high-rate (200 to 300 per second) condenser discharges to the culmen (lobules IV and V), to both paramedian lobules (sublobules H Vllb, H Villa), and to the roof nuclei. Because of the deep barbital anesthesia high voltages were required for the cerebellar stimulation. Similar experiments were performed by Snider and Magoun (1949) on monkeys under chloralose, nembutal, or chloralose-nembutal anesthesia. The authors obtained this time facilitatory effects, with some evidence of somatotopic localization, by applying high-rate (200 to 300 per second) pulses to the paramedian lobules or to the anterior lobe. It is apparent from the drawing they presented (Fig. 132) that the facilitatory responses were obtained mostly from the intermediate and the lateral parts of the anterior lobe, i.e., from areas projecting onto the interposite and dentate nuclei (Jansen and Brodal, 1940, 1942). Facilitatory effects were obtained occasionally on two cats. Nulsen, Black, and Drake (1948) stimulated the anterior lobe-lobulus simplex complex in the cat, dog, monkey, and chimpanzee under dial anesthesia and found that the cortically or pyramidally induced movements were either inhibited or facilitated, depending upon the frequency of the stimulus. They maintained that in each animal, except the cat, increasing the frequency of the cerebellar

Figure 132. The location of jacilitatory areas in the monkey's cerebellum. Ant. L. = anterior lobe; pyr. — pyramis; paramed. — paramedian lobule. Facilitatory areas (represented by cross-hatching) are found on the ipsilateral side of the anterior lobe (the lobulus simplex) and on both paramedian lobules. (From R. S. Snider and H. W. Magoun, 1949, Facilitation produced by cerebellar stimulation, J. Neurophysiol., 1^:335-345, Fig. 6, publ. Charles C. Thomas.)

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stimulation resulted in "facilitation of the existing cortical movement." These results are opposite to those which were reported simultaneously by Moruzzi (1948a, b; see also 1949, 1950a, b), who, however, limited his study to the effects of the stimulation of the vermal part of the anterior lobe on the extensor hypertonus of the unanesthetized decerebrate cat. In the preliminary note which so far represents the only publication, Nulsen, Black, and Drake (1948) did not specify the area of the anterior lobe which was stimulated (vermis proper, intermediate, or lateral parts) nor the frequency ranges of the electrical pulses (see also Fulton, 1949). Their statement that the "dentate nucleus (probably the dorsomedial portion) is involved in inhibition since its bilateral destruction allows only facilitation on surface stimulation" can hardly be reconciled with the anatomical (Jansen and Brodal, 1940, 1942, 1954) and physiological (Moruzzi and Pompeiano, 1954,1957b) evidence on the efferent projections of the vermis proper, whose inhibitory influence on the extensor tonus is entirely mediated by the rostral part of the roof nuclei (see pp. 131-133). Jansen and Brodal (1954, pp. 321-322) had the impression, from the illustrations reported by Fulton (1949), that the lesions of Nulsen, Black, and Drake were actually not in the dentate nucleus but in the nucleus interpositus. Nulsen, Black, and Drake stated finally that the cerebellocortical relations were arranged somatotopically in the manner previously described for the efferent cerebellar projections.

Figure 133. Cerebellar influence on the electrocorticogram. "Encephale isole" cat. Faradic stimulation of the right ansiform lobe (signal) increased both the amplitude and the frequency of the waves led from the left cruciate sulcus (upper record) and from the left coronal sulcus (lower record). This effect (A) was absent 5 min. after the application of ice to the cerebellar cortex (B), and the response was present again 8 min. later (C). (From A. E. Walker, 1988, An oscillographic study of the cerebro-cerebellar relationships, J. Neurophysiol., 1:16-23, Fig. 2, publ. Charles C. Thomas.)

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES

323

C. EFFECTS ON THE ELECTROCORTICOGRAM

A pioneer attempt to influence the electrical activity of the cerebral cortex by cerebellar stimulation was made before the electronic era by Beck and Bikeles (1912b). With a galvanometer they led slow electrical changes from the dog's motor cortex during thermal stimulation of crus I or crus II. Only inconstant results, however, were reported. Walker (1938) observed an increase in both the frequency and the amplitude of the cortical waves during faradic stimulation of the surface of the cerebellar hemispheres in the unanesthetized "encephale isole" cat (Figs. 13SA, C; 134A, C). Vermal stimulations were less active and the hemispheral effect was abolished or strikingly reduced following the local application of ice (Fig. 1331?) or novocaine to the cerebellar surface or after transection of the ipsilateral brachium conjunctivum. The increase in electrocortical activity was more easily found on the motor than on the parietal and temporal areas, was absent on the occipital lobe, and was reversibly blocked by asphyxiation (Fig. 1345). Walker suggested that these responses might be due to facilitating cerebellorubrothalamic volleys and should be regarded as the electrophysiological correlate of Rossi's effect. Rosenblueth and Cannon (1941) were unable to detect any change in the electrical activity of the precentral motor cortex (areas 4, 6, 8) and areas 1, 2, and 9 during stimulation of the cerebellum. Their negative results, however, are easily explained by the fact that monkeys under deep chloralosane anesthesia were used in these experiments (see below). A flattening of the EEG record, quite similar to that occurring during electro-

Figure 13k- The reversible abolition by asphyxia of the cerebellar effects on the electrocorticogram. Same type of experiment as in Fig. 133. The records were taken before (A) and after (B) 3 min. of asphyxia, and (C) 2 min. after the resumption of artificial respiration. (From A. E. Walker, 1938, An oscillographic study of the cerebro-cerebellar relationships, J. Neurophysiol., 1:16-23, Fig. 3, publ. Charles C. Thomas.)

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Figure 135. Generalized EEG arousal elicited by surface-positive polarization of the vermal areas of the anterior lobe (lobules IV and V). "Encephale isole" cat. Bipolar records with Grass ink-writer from left and right frontotemporal (1-3; 2-4) and temporooccipital (3-5; 4-6) areas. Signals: surfacepositive polarization of lobules IV and V (intensity given). Spindles occurring during spontaneous sleep (A) are abolished by cerebellar polarization (£), reappear only 150 sec. thereafter (C), and are back to poststimulatory levels 30 sec. later (D). The cerebellar (F) but not the sensory effect (G, whistling) on the EEG arousal is abolished by an intravenous injection (before E) of only 1.75 mg/Kg of chloralose. (From A. Mollica, G. Moruzzi, and R. Naquet, 1953, Decharges reticulaires induites par la polarisation du cervelet: Leurs rapports avec le tonus postural et la reaction d'eveil, Electroencephalog. & Clin. Neurophysiol., 5:571-584, Fig. 6.)

cortical arousal, was observed in "encephale isole" cats during repetitive stimulation of the fastigial nuclei (Moruzzi and Magoun, 1949), and also as a consequence of galvanic (Mollica, Moruzzi, and Naquet, 1953) or repetitive (Crepax, 1956) stimulation of the vermal areas of the anterior lobe (lobules IV and V). The cerebellar-cortical effects were selectively abolished (Fig. 135) by intravenous injections of chloralose in doses so small as to be completely without effect on sensory and reticular arousal (Mollica, Moruzzi, and Naquet, 1953; Crepax, 1956). A simultaneous recording of the brain waves and of the spike discharges of single units of the bulboreticular formation showed (Mollica, Moruzzi, and Naquet, 1953) that the firing rate of the reticular units increased when the brain rhythms were disrupted by cerebellar stimulation. However, the EEG effect outlasted the increase in the single-unit discharge (Fig. 136). Although it is likely that the generalized EEG changes were mediated by the ascending reticular system, Mollica, Moruzzi, and Naquet (1953) pointed out that there was no crucial evidence showing that the units they recorded belonged to the ascending reticular system. The neurons might be simply coactivated during the process of general-

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 325 ized brain stem activation which was probably responsible for the alteration in the brain rhythms. The work of Cooke and Snider (1953) was concerned with the aftereffects of strong repetitive stimulation of the cerebellar cortex on the electrocorticogram of curarized cats. Many cerebellar lobules were stimulated, and typical activation patterns were observed thereafter on the electrocorticogram. However, localized areas of the cerebellum were found to influence localized cerebral areas, an observation that hardly could be reconciled with the hypothesis of a mass activation of the ascending reticular system by cerebellifugal volleys. Snider and Cooke (1953) reported, moreover, that an electrically induced cerebral seizure was blocked by stimulation of the cerebellar cortex or of the fastigial nuclei. Dondey and Snider (1955) devoted another paper to an analysis of the slow potential changes occurring in the cerebral cortex following repetitive stimulation of the cerebellum in the curarized cat. The electrocortical arousal, with suppression of the spindles, paralleled a prolonged surface-positive shift which lasted as long as 60 seconds and was as large as 5 millivolts. It was elicited by high-rate (200 to 300 per second) stimulations. Low-rate (10 to 20 per second) stimuli evoked a surface-negative shift which might last as long as 70 seconds and be as large as 4 millivolts. Throughout this group of experiments rather high voltages were applied, so that (in our opinion) the spread of currents to the brain stem cannot be dismissed with certainty. For the same reason it is likely that the aftereffects of the cerebellar stimulations were related to the epileptiform activity of the cerebellar neurons previously described by Adrian (1935) and Dow (1938c). Canestrari, Crepax, and Machne (1955) reported that local application (2 to 7 minutes) of 1 per cent strychnine nitrate to the lobulus ansiformis (sublobule H Vila) of the dog's and cat's cerebellum markedly increased the amplitude of the cortical waves of the opposite sigmoid gyrus (Fig. 137). A smaller effect was observed on the ipsilateral motor cortex, whereas the other cortical areas were not affected. Local applications of this drug to the posterior vermis were thoroughly ineffective. These experiments were performed on otherwise intact animals, under morphine and chloralose (dogs) or under slight ether anesthesia (cats). The cortical effect was still more localized than that observed by Walker (1938) during electrical stimulation of the same lobule. Both types of responses were characterized by an increased amplitude of the cortical waves, but the acceleration of the brain rhythms, previously reported by Walker (1938), was frequently missed in the strychnine experiments. Further experiments by Crepax and Fadiga (1956) showed that the amplitude of the brain waves increased, in the unanesthetized dog, following local application of picrotoxin (0.1 per cent), prostigmin (0.25 per cent), cardiazol (1 per cent), and diisopropyl fluorophosphate (1 per cent) to the lobulus ansiformis. An opposite result, flattening of the EEG record, was obtained when picrotoxin or prostigmin was applied to the vermal surface of the anterior lobe. Summing up the results which have been obtained so far, one remains with the impression that two different types of electrocortical responses can be obtained by stimulating the cerebellar cortex, namely (a) diffuse responses, characterized by an abolition of spindle bursts and flattening of the EEG record, elicited by

Figure 136. The blockade of cortical spindles and the increase in bulboreticular firing elicited by surface-positive polarization of the vermal areas of the anterior lobe (lobules IV and V). "Encephale isole" cat. C.R.O. records of electrocortical activity (upper record: bipolar leads from frontotemporal areas) and of the spike discharge of a unit in the medial bulboreticular formation led through a unipolar microwire. A. Spindle during spontaneous sleep. B. Blockade of spindles and evoked unit discharge during cerebellar stimulation (1.5 mA.). C. 25 sec. after the end of cerebellar polarization. Reticular discharge strongly decreased, but EEG arousal present. D. 3 min. thereafter. The spindles are as in the control (.4), while the reticular unit is again silent. (From A. Mollica, G. Moruzzi, and K. Naquet, 1953, Decharges reticulaires induites par la polarisation du cervelet: Leurs rapports avec le tonus postural et la reaction d'eveil, Electroencephalog. & Clin. Neurophysiol., 5:571-584, Fig. 4.)

Figure 137. Increased amplitude of the cortical waves led from the right sigmoid gyrus following local strychninization of the left lobulus ansiformis (sublobule H Vila). Dog injected with morphine chlorohydrate (10 mg/Kg). Electrical activity led with ink-writer before (A), at the time of (B), and 5 min. after (C) the beginning of local strychninization (1 per cent). (From R. Canestrari, P. Crepax, and X. Machne, 1955, Modifications de 1'activite electrique du gyrus sygmoi'dien du chien et du chat par application de strychnine sur le cortex neocerebelleux, Arch., psicol., neurol. e psichiat., 16:19-31, Fig. 3.)

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327

stimulating vermal areas of the anterior lobe or the fastigial nuclei, and probably relayed by the ascending reticular system (Moruzzi and Magoun, 1949; Mollica, Moruzzi, and Naquet, 1953; Crepax and Fadiga, 1956; Crepax, 1956), and (b) responses mainly or exclusively confined to the sigmoid gyrus and to the neighboring cortical areas, characterized by a marked increase in the amplitude of the cortical waves, elicited by stimulating the lobulus ansiformis, and probably relayed by cerebellorubrothalamic pathways (Walker, 1938; Canestrari, Crepax, and Machne, 1955; Crepax and Fadiga, 1956). Both types of responses were recorded by Crepax and Fadiga (1956) in the same preparation (unanesthetized dog) following local applications of drugs respectively to the vermal cortex of the anterior lobe and to the lobulus ansiformis. The only objection to this scheme is represented by an observation of the same authors, who reported that the increased amplitude of the brain waves was observed on the frontal, parietal, and temporal areas of both cerebral hemispheres when prostigmin and cardiazol had been applied to the lobulus ansiformis. The same effect was, however, localized when drugs like strychnine or picrotoxin had been applied to the same lobule. Hence in given experimental conditions diffuse EEG effects would be obtained also from a cerebellar area projecting onto the nucleus dentatus.

2. THE EFFECTS OF CEREBELLAR ABLATION ON THE CEREBRAL CORTEX a. EFFECTS ON THE EXCITABILITY OF THE MOTOR CORTEX Luciani (1883, 1884a and b, 1891, 1894) obtained inconstant results by comparing the excitability of the ipsilateral with that of the contralateral motor cortex in hemicerebellectomized dogs (1883, 1884a and b, 1891, 1894) and monkeys (1894). Russell (1894) maintained that the excitability of the dog's motor cortex to faradic stimulation was increased contralaterally to the ablation of one cerebellar hemisphere, and his results were confirmed later by Versilov (1903). As Rossi (1912a) rightly pointed out, the deficiency period was missed in Russell's experiments, since the dogs were examined either a few hours or three months (Fig. 138) after the cerebellar hemispherectomy. The chronic experiments Russell made were nevertheless important, and he rightly suggested that "this increased activity of the cells of the opposite hemisphere, after unilateral destruction of the cerebellum, is a provision for compensation, and accounts for the rapid and almost complete recovery which takes place after such a lesion" (1894, p. 861). As we shall see later (p. 331), Luciani's experiments on the cerebral compensation of cerebellar deficiency fit very well Russell's hypothesis. Rossi (1912a) performed his experiments on hemicerebellectomized dogs. He confirmed that the faradic threshold of the contralateral motor area was lowered during the compensation period, but pointed out that the threshold was actually increased during the deficiency period. The latter effect was obviously the mirror image of that elicited by cerebellar stimulation (Rossi, 1912b). It might be related to the withdrawal of a facilitatory influence tonically exerted on the corticospinal system, although Rossi (1912a) was careful to emphasize that no evidence was provided by his experiments that the cerebellar facilitation occurred at cortical levels. He reported (1912a) that the faradic threshold of the motor cortex was increased also when the measurement was made in the acute

328 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM period following a contralateral hemicerebellectomy, and pointed out that the opposite results of Russell (1894) had been obtained following ablations limited to one cerebellar hemisphere. The unilateral encroachment on vermal structures, and particularly on the fastigial nuclei, might turn out to be the right explanation of Rossi's results. Syndromes of fastigial atonia have already been described (see pp. 77-80), and it is likely that the response of the spinal motoneurons to the corticofugal volleys will be depressed on the side of the body which is deprived of the facilitatory influence of the roof nuclei. At any rate no changes in cortical

Figure 138. Increased excitability of the contralateral motor cortex 3 months after ablation of a cerebellar hemisphere. The contraction of the left (L) and right (R) extensor muscles of the wrist was recorded myographically in the dog 3 months after ablation of the left cerebellar hemisphere. Faradic stimuli of threshold intensity for the left motor cortex (400 Kronecker units) yielded a strong response when applied to the right motor area (myogram L). (From J. S. R. Russell, 1894, Experimental researches into the functions of the cerebellum, Philos. Tr. Roy. Soc., London, s. B, 185:819-861, Fig. 3.) Figure 139. Preponderance of the absinth convulsions ipsilaterally to the chronic ablation of one cerebellar hemisphere. Extensor myograms of the left (L) and right (R) forelimbs of the dog 4 weeks after ablation of the left cerebellar hemisphere. (From J. S. R. Russell, 1894, Experimental researches into the functions of the cerebellum, Philos. Tr. Roy. Soc., London, s. B, 185:819-861, Fig. 4.)

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 329 threshold were elicited by cooling (Rossi, 1912b) or by destroying (Rossi, 1913) localized areas of the cerebellar hemispheres, and Rossi (1913) concluded that only large cerebellar lesions, possibly involving the deep nuclei, were able to influence the excitability of the motor area. Di Giorgio (1942b) confirmed Rossi's findings on the acutely hemicerebellectomized guinea pig and reported that the threshold of the motor cortices was not equalized by the ablation of the remaining part of the cerebellum. b. EFFECTS ON THE MOTOR AND ON THE INHIBITORY RESPONSES OF THE CEREBRAL CORTEX

That cortically induced movements are not grossly modified by cerebellectomy was shown by Bianchi (1882) in the dog, and has been recently confirmed by Delgado and Schulman (1955) on the unrestrained, unanesthetized cat. Only a detailed cinematographic or electromyographic analysis performed on the hemicerebellectomized animal might uncover, however, the differences that are likely to occur in the functional organization of both motor cortices. Such an investigation has not been carried out to the best of our knowledge, and it would not be advisable to rely on direct observations for detecting what might turn out to be minor effects of cerebellar deficiency. Russell (1894) investigated the effects of cerebellar ablations on the generalized clonic convulsions elicited by absinth injections. He recorded the myograms of the extensor muscles from both forelimbs in the hemicerebellectomized dog, and reported that the convulsive movements were much stronger on the same side as that from which the cerebellar hemisphere had been removed, either acutely or from one to five months before (Figs. 138, 139). His acute experiments were not confirmed, however, by Boyce (1895) on the cat. Russell (1894) recalled Gowers's hypothesis (1890) about the inhibitory influence which would be exerted by the cerebellum on the opposite cerebral cortex. One must recall, however, that Gowers (1890) did not support his views by experiments, nor was any evidence provided by Russell (1894) or others (a) that the absinth convulsions arose exclusively within the motor cortex or (b) that the release from cerebellar inhibition occurred at cortical levels; finally (c) no experiment was carried out by Russell (1894) during the deficiency period. The first two criticisms apply also to the experiments of Meyers (1916), who confirmed Russell's findings seven to twelve days after the ablation of isolated lobules of one cerebellar hemisphere. His statement that the release effects elicited by the lesion of either crus I or crus II in the cat were localized respectively in the ipsilateral forelimb and hindlimb is certainly surprising in view of the fact that the background of activity was represented by generalized absinth convulsions. These old experiments, however, should not be dismissed without further investigations. Some of the results were really striking and might contribute, if confirmed, to an analysis of cerebellar function, though not necessarily of cerebellocerebral relations. It is well known that inhibitory effects are obtained by stimulating the frontal areas of the cerebral cortex in lower mammals (Bubnoff and Heidenhain, 1881; Exner, 1882; Fano, 1895; Rioch and Rosenblueth, 1935; Tower, 1936; Garol, 1942), in subhuman primates (Hering and Sherrington, 1897; Brown and Sherring-

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ton, 1912; Cooper and Denny-Brown, 1927; Tower and Hines, 1935; see Hines, 1943,1947, 1949), and in man (Bucy, 1949). Some of these inhibitory effects were related to reciprocal innervation (Hering and Sherrington, 1897; Brown and Sherrington, 1912), but the fact that frontopontocerebellar pathways arise just in the same areas (see Jansen and Brodal, 1954; Larsell, 1958) prompted some investigators to surmise the existence of cerebellar relays for the efferent pathways mediating cortical inhibition. Weed (1914) reported that electrical stimulation of the mesial one fifth or one sixth of the cerebral peduncle, on the cut surface of the decerebrate cat, inhibited the ipsilateral extensor hypertonus. This effect was abolished by acute cerebellectomy or by severing the contralateral middle cerebellar peduncle, and Weed suggested that the cortical inhibition of extensor mechanisms was mediated by frontopontocerebellar pathways. His findings were confirmed by Warner and Olmsted (1923), but not by Rioch and Rosenblueth (1935). The electrophysiological investigations of McCulloch, Graf, and Magoun (1946) and of McCulloch, Ward, and Magoun (1946) support the conclusions of Rioch and Rosenblueth (1935), since the inhibitory areas of the cerebral cortex appear to be connected with the brain stem reticular formation through descending pathways, not necessarily involving cerebellar relays. The origin and the termination of the corticofugal fibers going to the brain stem reticular formation have been recently investigated by Rossi and Brodal (1956), using methods of terminal degeneration. C. ELECTROPHYSIOLOGICAL INVESTIGATIONS

For obvious technical reasons the experiments that were carried on by Meyers (1915) have now mainly an historical value. He reported that the central ends of either the sciatic or the ulnar nerve were negative in respect to their opposite counterparts, following chronic (one to three weeks) ipsilateral ablation of one cerebellar hemisphere. Since these effects were absent after bilateral ablation of the motor cortex, he surmised that each cerebellar hemisphere exerted a tonic inhibitory influence on the opposite motor area. Walker (1938) maintained that the electrocortical activity of the "encephale isole" cat was not modified by local applications of ice or of novocaine to the cerebellar hemispheres. Sager and Kreindler (1945-1947) stated that the spontaneous electrical activity led from the cerebral cortex of the cat and of the dog, under evipal anesthesia, was modified by acute destruction of one cerebellar hemisphere or of the vermis and also by dentate lesions. Their records, however, are quite unconvincing, and they made no controls for dismissing the possibility of irritation or of other collateral phenomena. Gonzalo Sanz (1954) recently reported that the stereotaxic interruption of the brachium conjunctivum in the cat decreased the electrical activity of the contralateral ventral thalamic nuclei, but was not followed by constant and clear-cut changes in the EEG.

3. THE EFFECTS OF COMBINED CEREBELLAR AND CEREBRAL ABLATIONS a. COMPENSATION OF THE CEREBELLAR SYNDROME BY THE CEREBRAL CORTEX Bianchi (1882) was the first to suggest that the functional compensation of the cerebellar symptoms might be due to the motor area of the cerebral cortex.

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 331 He gave, however, only scanty and indirect evidence supporting his hypothesis, and it remained for Luciani (1891) to show that the deficiency symptoms of the hemicerebellectomized dog reappeared, during the compensation period, when both motor areas of the cerebral cortex had been extirpated. From this fundamental group of experiments and from other data Luciani drew the conclusion that the motor cortex of the cerebrum was mainly responsible for the compensation of the cerebellar deficiency symptoms. He stated: "i movimenti compensatori mediante i quali gli animali scerebellati diventano capaci di mantenere 1'equilibrio nella stazione eretta, nella deambulazione e nel nuoto, dipendono dalle sfere sensorio-motrici del cervello, e possono quindi essere soppressi e separati dalla sindrome delle deficienze cerebellari, merce la semplice abolizione dei giri sigmoidei, che rappresentano il segmento piu importante di dette sfere" (1891, p. 163). The technique of abolishing the functional compensation of the cerebellar syndrome by extirpating bilaterally the cortical motor area was widely adopted by later investigators. Luciani's discovery was confirmed on chronically hemicerebellectomized dogs by Sergi (1903) and by Fulle (1913). Less consistent results were obtained, however, when the asymmetrical lesion had been confined to a small area of the cerebellar cortex. No effects were reported by Fulle (1913), whereas Grey (1916d) stated that the symptoms yielded in the dog by the ablation of the lobulus simplex (lobules VI and H VI) or of crus II (sublobule H Vila) reappeared, during the compensation period, when both motor areas were destroyed. Other experiments of combined cortical and cerebellar ablation, which were widely cited in the past, now appear less convincing. It is obviously difficult to disentangle cerebellar from cerebral symptoms when the ablation of one cerebellar hemisphere is followed by the destruction of the contralateral motor cortex. Luciani (1891) reported that the cerebellar symptoms were strikingly strengthened by extirpating the opposite motor area, but an obvious drawback inhered in this experimental approach, since the effects of the asymmetrical cerebellar lesion were polluted by the independent asymmetry of the cerebral influence. Luciani (1884a and b, 1891) stated also that no compensation of the cerebellar syndrome was observed in a bitch whose motor area had been bilaterally, though asymmetrically, extirpated seven months before the total cerebellectomy. Eleven months after the last operation the animal was killed, and the extent of the lesion was grossly anatomically controlled by Golgi and Pallacani, who, however, did not perform histological examinations. Histological controls were made many years later by Simonelli and Di Giorgio (1931) on a dog that had not recovered from the effects of a total cerebellectomy performed five and a half months before. Deiters's and Bechterew's nuclei had been severely encroached upon, although the cerebral cortex and the pyramidal tracts were normal. The complete lack of compensation presented by Luciani's bitch might possibly, though not necessarily, be explained in this way. The problem of the brain stem lesions which sometimes occur after unilateral or total cerebellectomy was dealt with at length in the chapter on ablation experiments (see pp. 27, 100). There is no doubt that these lesions may occur

332 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM and also that they can be avoided. Obviously it is impossible to know whether the brain stem was sometimes encroached upon in the experiments performed by Luciani or by other nineteenth-century physiologists, since histological controls were never, or only exceptionally, made by them. What matters is that with unilateral fastigial lesions, surely sparing all brain stem structures, Luciani's deficiency syndrome can be easily reproduced in the cat (see pp. 77-80). The experiments of Batini and Pompeiano (1955b, 1957) clearly confirmed the existence of a compensatory influence of the motor cortex on these symptoms of localized cerebellar deficiency. Both ipsilateral and crossed fastigial atonia, following chronic lesions confined respectively to the rostral and to the caudal part of one fastigial nucleus (see pp. 81-86), were studied by Batini and Pompeiano (1955a and b, 1957). They reported that compensation was almost complete thirty to thirty-five days following a rostral lesion, and fourteen to twenty-two days following a caudal one. When compensation was practically complete, and the animals could hardly be distinguished from normal ones, it could be abolished by a bilateral cortical ablation. Bilateral symmetrical removal of the cortex of the anterior and posterior sigmoid gyri, extending not beyond the sulcus coronalis on either side, precipitated a striking cerebellar syndrome, quite similar to that observed within the first days following the fastigial lesion. The newly established cerebellar syndrome lasted about two weeks, and after an average interval of sixteen to seventeen days from the cortical operation, the posture was again symmetrical, and the gait was normal. This second compensation might be attributed to premesencephalic structures, since precollicular decerebration was followed by a typical asymmetrical distribution of decerebrate rigidity. Hence the effects brought about by acute lesions confined respectively to the rostral and to the caudal part of one fastigial nucleus (Moruzzi and Pompeiano, 1955a, 1956b) could be reproduced when decerebration was performed on fully compensated animals. In a second group of experiments Batini and Pompeiano (1955b, 1957) attempted to localize the area of the cerebral cortex which is mainly responsible for the compensation of fastigial atonia. Decompensation was obtained by limiting the bilateral cortical ablation to the area giganto pyramidalis of the gyrus sigmoideus (see Brodmann, 1905-1906, p. 381). The histological controls showed the integrity of the neighboring cortical areas and of the underlying head of the nucleus caudatus. The effect was about the same as that elicited by the complete bilateral ablation of the gyri sigmoideus and proreus. b. INFLUENCE OF CEREBELLAR ABLATION ON THE PRECENTRAL MOTOR CORTEX

The precentral motor cortex belongs to the frontal lobes and in subhuman primates engages Brodmann's areas 4, 6, and 8 (see Fulton, 1949). Its influence on brain stem and spinal motoneurons is exerted through extrapyramidal and pyramidal pathways. Rostrally to the precentral motor cortex are found the socalled "prefrontal areas," or frontal areas (Fulton, 1949), sensu strictiori (areas 9, 10, 11, 12). Although they contribute to the frontopontine tract (see Nyby and Jansen, 1951), their physiological relations to the cerebellum are little known and will not be dealt with here.

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 333 The close interrelation between the precentral motor area and the cerebellum is shown anatomically by the following facts: (a) both motor (area 4) and premotor (area 6) cortical regions project onto the pontine gray matter and thence onto the cerebellar cortex (see Levin, 1949; Nyby and Jansen, 1951), and (b) cerebellothalamocortical pathways project onto areas 4 and 6 (see Brodal, 1948, and Walker, 1949). According to observations on human brains by Papez (1940) and Hassler (1950), cerebellar impulses would be relayed primarily to area 4. Both anatomical (see Nyby and Jansen, 1951) and electrophysiological (see pp. 208ff and 235ff) investigations suggest that cerebellocerebral interrelations are by no means limited to the frontal lobes and in particular to the precentral motor areas. These structures, however, are those whose relations to the cerebellum have been most extensively investigated, and in the present section we shall deal exclusively with the influence of cerebellar ablations on the motor activities arising from areas 4 and 6. It is an almost impossible task to separate physiologically the motor (4) from the premotor (6) area in the small cerebral cortex of the carnivores. In the cat "area 4 lies adjacent to area 6 in the depths of the cruciate sulcus and these areas appear on the medial aspect of the hemisphere on the superior and inferior lips of that sulcus respectively" (Garol, 1942, p. 143). Hence what is called the "motor cortex" in either the dog or the cat corresponds to a combination of the motor (4) and the premotor (6) areas of the primates. There is abundant anatomical (see Jansen and Brodal, 1954; Larsell, 1958) and physiological (Mingazzini and Polimanti, 1906; Polimanti, 1906, 1908; Delmas-Marsalet, 1932) evidence showing that the cerebellum and "motor cortex" are closely related structures also in low mammals, but the old physiological experiments appear now unsatisfactory mainly because no histological controls were made on the extent of the cortical areas that had been spared and of those that had been encroached upon. Mingazzini and Polimanti (1906) performed, in two stages, the ablation of one cerebellar hemisphere and of all the cerebral cortex lying rostrally to the sulcus cruciatus (regio praecruciata). The symptoms of cerebellar deficiency presented by their dogs were similar to, and reinforced by, those occurring following the cortical ablation, and the same results were observed when the sequence of the operations was reversed. Their cortical lesion, however, was rather complex, since it involved the gyrus sigmoideus anterior and the gyrus proreus, i.e., part of areas 4 and 6 and all of areas 9, 10, 11, 12 (see Winkler and Potter, 1914). Polimanti (1906, 1908) extirpated also a cortical area (Munk's area I; see Munk, 1892) corresponding more or less to the gyrus proreus alone, but unfortunately no cerebellar ablations were performed in this group of experiments. Only in one dog an ablation of Munk's area was performed following complete cerebellectomy. This last type of experiment might still represent an interesting approach in order to dissociate the cerebral influences that are mediated by the corticopontocerebellar pathways from those that are mediated by purely extracerebellar relays. In short, the main result of the physiological investigations of Mingazzini and Polimanti (1906) and of Polimanti (1906, 1908) was the demonstration that in a region of the dog's cerebral cortex corresponding to the precentral motor cortex (4, 6) and to the frontal area (9, 10, 11, 12) of the primates, a group of neurons is

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located whose function appears to be similar in certain aspects to that of the cerebellum, but whose corticofugal discharges are not mediated (at least exclusively) by pontocerebellar relays. The similarity between cerebellar and frontal syndromes was confirmed also by Delmas-Marsalet (1932) in experiments performed on dogs. All these experiments should obviously be correlated with the old observations of Luciani previously referred to, inasmuch as they showed that cerebellar symptoms could be compensated by the motor area of the cerebral cortex. Apparently the cortical neurons whose ablation is followed by a syndrome similar to that characterizing cerebellar ataxia are likely to make the greatest contribution to the compensation of cerebellar deficiency. An entirely new approach was discovered when it was realized that a major symptom of the cerebellar syndrome, far from being strengthened, was abolished by cerebral ablations. Reporting the symptoms presented by a dog which had been decorticated some months before complete cerebellectomy, Rademaker stated incidentally, "Das Tier zeigte keine Tremor, ebensowenig die typischen unbeherrschten Wackelbewegungen von Kopf und Pfoten, auch nicht wenn es auf alle Viere gesetzt wurde" (1931, p. 446). It remained for Fulton, Liddell, and Rioch (1932) to undertake the first systematic study of the origin of cerebellar tremor on thirty-six decerebellate cats. Fulton, Liddell, and Rioch (1932) rightly dwelt upon the fact that tremor was lacking during the first days following cerebellectomy, i.e., when the cerebellar syndrome of the carnivores is mainly represented by the release symptoms characterizing Luciani's dynamic period. Tremor of the extremities did not appear until the animals made "active attempt to walk, usually on the seventh or eighth day." They stated, furthermore, that "tremor as such does not come on until the animal begins voluntarily to use its extremities" (p. 544). These data obviously suggested the cortical origin of tremor. Actually when the cerebellectomized cat was hemidecorticated, the spontaneous movements on the hemiplegic side were "invariably free from ataxic tremor." Five fully cerebellectomized cats were later decorticated bilaterally in two stages. The constant result was "complete absence of tremor" following the third operation (p. 558). The experiments of Fulton, Liddell, and Rioch (1932) clearly showed that there are some neurons in the cat's cerebral cortex whose activity affecting the motor sphere requires the tonic support of the cerebellum. Tremor would result from the withdrawal of the cerebellar influence on these cortical structures, the localization of which obviously could be determined only by experiments performed on the large cerebral cortex of the primates. This was the aim of the important investigations which were carried out by Aring and Fulton (1936) on two baboons (Papio papio) and fourteen monkeys (Macaco, mulatto). The cerebellar tremor appeared in the monkey much earlier than in the dog, i.e., within forty-eight hours from the complete ablation. It was completely abolished by extirpating the motor (4) and the premotor (6) areas on both sides of the body. "Lesions sharply restricted to the premotor area (6), on the other hand, caused a dramatic accentuation of previously established cerebellar signs" (p. 455). This was the effect that had been observed on the dog by Luciani (1891), and Aring and Fulton drew from their observations the important

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 335 conclusion that "compensation for cerebellar deficit would appear, therefore, to be a particular function of the premotor area" (p. 458). No changes in the cerebellar syndromes, on the other hand, were elicited by destroying the so-called prefrontal areas (9, 10, 11, 12). It might be surmised from these findings that cerebellar tremor arises from the motor (4), not from the premotor (6) areas, since this symptom was actually markedly increased by ablation of area 6. This prediction, however, was not confirmed by the experiments of Aring and Fulton (1936), who showed that tremor was not abolished by the isolated ablation of the motor area (4). Summing up, the withdrawal of the influence exerted by the cerebellum on the whole precentral motor area is responsible for the appearance of cerebellar tremor. Hassler's hypothesis (1950, p. 661) that the cerebellar influence is exerted on area 4, but not on area 6, is not supported by the experiments of Aring and Fulton (1936). Both pyramidal and "extrapyramidal" systems belong to the sphere of the cerebellar influence. The "extrapyramidal" system, which is mainly (though not exclusively) concentrated on area 6, appears to be endowed, however, with another function, which is mainly responsible for the cortical compensation of cerebellar deficiency (Luciani's effect). It is likely that the cortical neurons which give rise to the cerebellar tremor are different from those which compensate the syndrome of cerebellar deficiency. In short, most of the experiments that were performed on carnivores concerned Luciani's effect, i.e., the compensation of the cerebellar deficiency by a descending influence of the extrapyramidal neurons connecting the cerebral cortex with the brain stem and particularly with the pontine gray matter. The cerebellar tremor, on the other hand, is correlated with an entirely different phenomenon, namely, with the interruption of the ascending influence exerted by the cerebellum on the precentral motor area. According to Carrea and Mettler (1955) this ascending influence would be mediated by the ventral component of the crossed ascending limb of the brachium conjunctivum (see above, p. 94). C. SUMMATION OF THE TONIC INHIBITORY INFLUENCES EXERTED BY THE CEREBRAL CORTEX AND BY THE CEREBELLUM ON THE POSTURAL EXTENSOR TONUS

The release symptoms occurring within the first week following total cerebellar ablation (opisthotonos, extensor rigidity) are mainly related to the withdrawal of a tonic inhibitory influence arising within the vermal cortex and mediated by the fastigial nuclei (see pp. 56, 77). A similar release of the antigravity tonus has been reported following ablations of frontal areas of the cerebral cortex in subprimate mammals (Warner and Olmsted, 1923; Olmsted and Logan, 1925; Bernis and Spiegel, 1925; Langworthy, 1928; McKibben and Wheelis, 1932; De Lisi and Pintus, 1936; Morin, Gastaut, and Duplay, 1947), in subhuman primates (Fulton and Kennard, 1932; see Fulton, 1936, 1949), and in man (see Bucy, 1949). Whether this tonic inhibitory influence is exerted only by the extrapyramidal system (Fulton and Kennard, 1932; Tower, 1940) or whether the Betz cell-bearing cortex (Denny-Brown and Botterell, 1947) and the pyramidal tract are involved is still a matter of controversy. So far extensor spasticity following isolated bulbar pyramidotomy has been observed only in cats (Ranson, 1932; Marshall, 1934; Liddell and Phillips, 1944) and in dogs (Morin, Donnet, and Zwirn, 1949; Morin,

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Pom-sines, Donnet, and Maifre, 1951), but not in subhuman primates (Tower, 1940). In subprimate mammals a tonic inhibitory influence on the extensor mechanisms is exerted by the sigmoid gyri (Bard, 1933), and in particular by the Betz cell-bearing area (Morin, Poursines, Donnet, and Maffre, 1951), but this effect is only partially mediated by the corticospinal tract (Marshall, 1935; Morin Donnet, and Maffre, 1951). The inhibitory corticofugal (McCulloch, Graf, and Magoun, 1946; McCulloch, Ward, and Magoun, 1946) and cerebellifugal (Snider, McCulloch, and Magoun,' 1949) impulses converge on the inhibitory part of the brain stem reticular formation. Hence the prediction might be ventured (a) that the release of the antigravity mechanisms elicited by cerebellectomy and by cortical ablation will

Figure 140. The effect of total cerebellectomy and of the ablation of the right cerebral hemisphere JLhe dog Vici survived 18 months after these operations, which were performed on the same day. During the period of stabilized cerebellar deficiency, a striking extensor hypertonus was present in the left limbs (1, ®). It increased respectively in the hindlimb and in the forelimb when the head was flexed (3} or extended (4). (From G. G. J. Rademaker, 1931, Das Stehen, Berlin: J. Springer, Fig. 273.)

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337

Figure 1^1. Disappearance of the extensor hypertonus of the left hindlimb and extension of the left forelimb during the magnet reaction of the right hindlimb. The dog Vici (see Fig. 140) with the head extended (1) and flexed (2, 8). A reversal of the postural syndrome of the left legs was elicited by touching the sole of the right hindfoot. (From G. G. J. Rademaker, 1931, Das Stehen, Berlin: J. Springer, Fig. 278.)

summate, and (b) that the frontal areas of the cerebral cortex will compensate the release symptoms occurring after cerebellectomy. This is actually the result of the experiments of combined cerebral and cerebellar ablations performed in lower mammals (Rademaker, 1931; Fulton, Liddell, and Rioch, 1932) as well as on subhuman primates (Aring and Fulton, 1936; Soriano and Fulton, 1947), although the compensation of the cerebellar release does not appear to be exclusively related to cortical structures (Rademaker, 1931; Batini, Moruzzi, and Pompeiano, 1956a and b, 1957). Rademaker (1931) described carefully the symptoms presented by two dogs and one cat whose right cerebral hemisphere had been ablated simultaneously with the entire cerebellum. Immediately after the end of the operation the release symptoms characterizing Luciani's dynamic period were observed, and the posture was similar to that of any decerebrate animal. The extensor rigidity disappeared first, however, in the right limbs, while the left legs remained stiff and their postural tonus was strikingly affected by the movements of the head (Fig. 140). A clear-cut postural asymmetry was observed throughout the period of stabilized deficiency (Stadium der Dauerstorung; see p. 22), i.e., even during Luciani's compensation period. It was probably related to the combined effects of the withdrawal of cerebellar and cerebral inhibition. These results were confirmed by Fulton, Liddell, and Rioch (1932) on the cat. Rademaker (1931) reported, moreover, that when the previously flexed right hindlimb was actively hyperextended, as the result of a magnet reaction, the antigravity tonus of the spastic left hindleg collapsed, while a clear-cut increase occurred in the left forelimb (Fig. 141). This is a good example of the reflex influences exerted by the posture of one limb on the extensor tonus of the other legs. Their relations with the cerebellar symptoms have been dealt with in another part of this book (see pp. 265-268).

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A summation of cortical and cerebellar release symptoms is shown also by experiments performed on subhuman primates. It is well known that the release of the antigravity mechanisms following total cerebellectomy or complete topectomy of the anterior lobe is extremely marked in the carnivores, but absent or quite slight in subhuman primates (see pp. 36, 58). Brown (1913, p. 155) reported, however, that in precollicular monkeys complete removal of the cerebellum was followed by "marked extensor tonus." He did not comment upon his observation, which obviously suggests that in the otherwise intact monkey the cerebellar release is concealed by premesencephalic structures. Many years later, Aring and Fulton (1936) severed the right cerebellar peduncles in one monkey and later extirpated in three stages the precentral motor area on both sides of the body. They reported that the right lower extremity was held rigidly extended throughout the survival period following the last operation. Soriano and Fulton (1947) also reported "marked augmentation of the positive supporting reaction with spasticity" when ablation of the anterior lobe was combined with extirpation of areas 4 and 6 of the cerebral cortex. That the release symptoms were not entirely due to the ablation of the precentral motor area was shown by the fact that the upper extremity opposite the cortical lesion became predominantly spastic when the cerebellar ablation was limited to the culmen (lobules IV and V), while the symptoms were more marked in the opposite hindlimb when the cerebellar lesion was located within the lobulus centralis (lobule III). At least in the carnivores, however, compensation of the release symptoms of cerebellar ablation may occur also independently of the cerebral cortex. Rademaker (1931) gave a detailed report of the symptoms presented by a dog that had been totally cerebellectomized following complete chronic decortication. The cerebellar ablation was followed by a striking release syndrome, quite similar to that occurring in any decerebrate preparation. The animal was unable to stand and to walk throughout the survival period (thirty-eight days), but the extensor rigidity gradually subsided and appeared strongly reduced during the fourth and the fifth week after the last operation and when the animal was sacrificed. Rademaker fully understood the importance of his findings, since he insisted upon the fact "(1) dass die Kleinhirnextirpation auch bei grosshirnlosen Hunden eine Streckstarre mit typischer Plastizitat, wie nach einer Decerebrierung, hervorzurufen vermag, und dass diese Starre in volliger Ausbildung nahe zu einer Woche andauern kann, (2) dass die durch die Kleinhirnextirpation bedingte Starre auch beim grosshirnlosen Hunde allmahlich abnimmt und fast ganz verschwinden kann" (1931, pp. 446-447, italics ours). The mechanisms of the extracortical compensation of the cerebellar release symptoms were not investigated, however, by Rademaker. This was the aim of the experiments carried on by Batini, Moruzzi, and Pompeiano (1956a and b, 1957) on totally cerebellectomized cats and on cats with bilateral destruction of the fastigial nuclei (see pp. 283-287).

4. THE CEREBELLUM AND CONDITIONED REFLEXES The relation between the cerebellum and conditioned reflexes may be conceived in two different ways. First of all, a perfectly admissible assumption

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 339 would be that cerebellar neurons are inserted in the route of the unconditioned or of the conditioning afferent impulses. Consequently, electrical stimulation of the cerebellum might be substituted for either the unconditioned or the conditioning stimulus in the establishment of some types, at least, of conditioned reflexes. This was the approach of Brogden and Gantt (1942). Other hypotheses, however, are possible and, in our opinion, appear more likely. It may be maintained that the afferent and the efferent routes of the conditioned reflexes as well as the neural locus of conditioning are located outside the cerebellum, which simply exerts some kind of facilitatory or inhibitory influence on the neural mechanisms underlying conditioning. If we assume that cortical reflexes and the motor area of the cerebral cortex are essential in carrying out a given conditioned response, complete or partial cerebellectomy may disorganize conditioned patterns or the process of conditioning itself through a mechanism recalling von Monakow's diaschisis (1902). Couched in modern terms, this amounts to saying that cerebellar facilitation of the cerebral cortex is essential or at least very important for the acquisition or the retention of a conditioned response. This is, in our opinion, the most likely explanation of the old findings of Lewandowski (1903), Bremer (1922a, 1935), and Rademaker (1931) as well as of the more recent findings in investigations on the effect of nuclear lesions which will be reported later. In the experiments of intraneural conditioning performed on dogs by Brogden and Gantt (1942), electrical stimulation of the lobulus ansiformis was substituted for the usual unconditioned shock to the foot. Unfortunately, of the three types of movements they described, at least two (contraction of the ipsilateral neck and shoulder muscles and sharp closure of the ipsilateral eyelid with wigwagging of the ipsilateral pinna) are likely, in our opinion, to have been related to a spread of current to cranial nerves. At any rate, no control of the cerebellar origin of the motor effect nor any measurement of the intensity of the stimulation was reported by the authors. We feel that before their concept of "cerebellar conditioned reflexes" is accepted, some evidence should be provided that stimulation, through a spread of current, of peripheral or central sensory fibers did not represent the real unconditioned stimulus in their experiments. The second approach is by far more convincing. Most of the experiments to be reported concern the placing reactions, which were regarded as conditioned reflexes by Rademaker (1931). Bard (1933) fully confirmed the evidence with which Rademaker supported his view, but stated that further experiments were required in order to come to a final decision on this point (p. 72). Since the placing reactions are undoubtedly cortical reflexes, it seems at any rate justified to deal with them in the present section. Lewandowski (1903, p. 182) reported that Munk's Beruhrungsreflex, i.e., the flexion of the limb that occurs in an animal suspended by the neck when a light touch is applied to the dorsum of the foot, was temporarily abolished in the cerebellectomized dog. It came back later on, but the recovery was never complete. Although Munk (1892) had previously shown that the Beruhrungsreflex was altogether abolished in the dog following extirpation of the contralateral motor cortex, Lewandowski failed to realize the great importance of his obser-

340 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM vation—which was later confirmed by Rademaker (1931), Bremer (1935), and Dusser de Barenne (1937)—for a functional analysis of cerebellocerebral relations. Many years later Bremer (1922a) reported the following observation in the cat, after ablation of one cerebellar hemisphere: "Si, en le tenant suspendu, on le rapproche du sol, les membres du cote opere ne font pas la moindre tentative d'appui, bien qu'ils ne soient nullement paralyses" (p. 201). He pointed out later (1935, p. 99) that this response, which had been so greatly impaired by unilateral cerebellectomy, was a conditioned placing reaction to visual stimulation. We owe to Rademaker (1931) a beautiful analysis of all these phenomena. He carefully described, in the dog, the different types of placing reactions (pp. 20-38); he showed that these responses were absent in the newborn animal and when developed, were abolished by decortication; finally he pointed out that these cortical reactions could be subjected to the process of "experimental extinction" (see Pavlov, 1927) and should be regarded as conditioned reflexes. He confirmed, moreover (p. 29), Munk's findings (1892) about the Beruhrungsreflex and showed that this was merely a manifestation of the Stehbereitschaft, i.e., a placing reaction. The placing reactions were thoroughly investigated by Bard in cats (1933) and in monkeys (1938). He showed quite conclusively that the cortical representation of the placing reactions was strictly localized, in the cat, in the sigmoid gyri, and was functionally independent of all other cortical areas. These results were confirmed and greatly extended on the large cerebral cortex of the monkey, concerning which he stated: "When a unilateral precentral ablation has produced a complete loss of the placing reactions of the opposite limb it is still possible (in a blindfolded animal) to obtain placing of the sound (the ipsilateral) hand or foot by bringing the deficient (the contralateral) members into slight contact with the edge of a table" (1938, p. 591). A complete disappearance of the placing reaction to tactile stimuli was obtained, in the monkey, only by removing the contralateral postcentral gyrus. The other cortical areas appeared to be of little value for the placing reactions. As a matter of fact Bard remarked that "ablation of all cortex of the frontal lobe lying rostral to area 4 or extirpation of occipital and temporal lobes together has no permanent effect on the hopping reactions and the non-visual placing reactions. When both removals were carried out in the same hemisphere, the remnant, consisting of areas 4, 3, 1, 2, 5 and 7, was able normally to control the reactions of the opposite legs" (1938, p. 593). Rademaker (1931) was the first to undertake a systematic analysis of the effects of cerebellectomy on the placing reactions. He reported that the placing reactions to tactile stimulation were abolished by cerebellectomy, but stated that they reappeared from a few days to a few weeks thereafter (Fig. 142). He felt, however, that his observations had no real importance for cerebellar physiology and supported his point of view by the following considerations: (a) Abolition of the placing reactions was in his experiments only a transient phenomenon. It was not surprising, he maintained, that labile neural activities such as the conditioned reflexes should be abolished as a consequence of a major operation like cerebellectomy. (b) Following hemicerebellectomy the placing reactions disappeared on

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 341

Figure H2. Transient disappearance of the placing reactions following cerebellectomy. Twelve days following complete cerebellectomy the placing reactions to tactile and visual stimulations (eyes open) were altogether absent (1), but they reappeared later (2, 8). (From G. G. J. Rademaker, 1931, Das Stehen, Berlin: J. Springer, Fig. 14.)

both sides of the body, although he conceded that they reappeared first on the contralateral limb, (c) He rightly pointed out that the defective correction of malpositions was related to the alterations in the Stehbereitschaft, but recalled the observations of Ducceschi and Sergi (1904) showing that hemicerebellectomy yielded these symptoms on both sides of the body. Also these authors had pointed out, however, that recovery occurred earlier in the limbs of the opposite side of the body, (d) He stressed that these transient effects of cerebellectomy were not due to a deficiency in the sensory sphere, as had been surmised by Lewandowski (1903) and by Dusser de Barenne (1923). That they could not be was shown by the fact, for example, that cerebellectomy transiently abolished the placing reactions to visual stimuli but did not interfere with other conditioned responses to retinal impulses. Rademaker's conclusions are best expressed in his own words: "Die Storungen des Korrektionsvermogens und der Stehbereitschaft nach Kleinhirnextirpation beruhen also sehr wahrscheinlich nicht auf einem Reizausfall, sondern vermutlich auf einer durch die Operation verursachten allgemeinen Hemmung oder Shockwirung, da bei fast jeder schweren, besonders fieberhaften Krankheit eine ahnliche Stoning dieser Reaktion zu beobachten ist" (1931, p. 34). In our opinion the following objections may be raised to Rademaker's point of view. (a) There are many symptoms which either disappear or are greatly reduced a few days or weeks after cerebellectomy, and yet it is generally conceded that they

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really express the effect of withdrawal of a tonic influence exerted by the cerebellum on other neural structures (see, for example, the spasticity and the opisthotonos of the dynamic period and some manifestations of the cerebellar ataxia). (b) Bard's experiment (1933) in which both cerebral cortices of the cat had been entirely removed in three stages, with the exception of the frontal areas of both sigmoid gyri and of the neighboring cortex of the right hemisphere, represented undoubtedly a series of major surgical operations. And yet the small cortical remnant carried out all the placing reactions, since "except for a few days following the second and third operations, the placing and hopping reactions of the left legs were wholly normal" (p. 62). This observation is, moreover, fully consistent with those of Pavlov (1927), who remarked that "the first change which follows the extirpation of some part of the cortex is the almost invariable disappearance of conditioned reflexes; but in the majority of cases it is only the 'artificial' conditioned reflexes which disappear, i.e. those which were established in the laboratory, being therefore relatively recent and little practised" (p. 322). (c) The electrophysiological experiments of Walker (1938) and of Canestrari, Crepax, and Machne (1955) show that the effects of stimulation of the lobulus ansiformis are not strictly unilateral, "a weak response being present in the ipsilateral motor cortex" (Walker, 1938, p. 20). (d) Rademaker (1931, p. 33) was certainly right when, disagreeing with Lewandowski (1903) and Dusser de Barenne (1923), he pointed out that the deficient correction of malpositions did not mean necessarily an alteration within the sphere of proprioception. Everybody would agree, moreover, with Munk (1906-1908) and with Dusser de Barenne (1923, 1937), who both maintained that the abolition of the Beruhrungsreflex need not be regarded as an index of alterations in the tactile sphere. But the abolition of the placing reactions might be due to the withdrawal of a facilitatory influence exerted by the cerebellum on the neural loci where conditioning occurred in the infant animal, or on the efferent side of the reflex arc underlying the conditioned response (pyramidal and extrapyramidal pathways; see Marshall, 1934). The main objection to the traumatic shock hypothesis is that the placing reactions are affected, and sometimes abolished, by small cerebellar lesions, involving only a minor surgical operation. Rossi and Di Giorgio (1933) performed histologically controlled lesions of the lobulus ansiformis in the dog. Serial Nissl slides showed complete integrity of the lateral cerebellar nuclei in three animals, while only slight alterations were found in the ipsilateral nucleus of another dog. The placing reactions to nonvisual stimuli were always delayed and sometimes absent ipsilaterally to the lesion, but the cortical reflexes were again symmetrical two to three weeks after the operation. In one dog, in which only the superficial part of crus I had been extirpated, the placing reactions were normal, although Rossi's postural asymmetries (see p. 73) were present. This observation may suggest that the alteration in the placing reactions is not related to the asymmetrical posture, which is essentially a brain stem phenomenon. A loss of the tactile placing reactions was reported by Chambers (1948), Austin, Chambers, and Windle (1949), and Sprague and Chambers (1953) following cortical cerebellar lesions within the anterior lobe, but the

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 343 last group of authors stated that the transient abolition of the response was related to the involvement of the underlying rostral part of the interposite nucleus. The effects of lesions of the cerebellar nuclei on the placing reactions have been thoroughly investigated in later years. Snider (1940b) had reported that the tactile placing reactions were transiently abolished, in the rabbit, following a lesion of the nucleus interpositus, and Chambers (1948) had obtained similar results in the cat following lesions limited to the ipsilateral interpositus and dentate nuclei. No loss of placing reactions occurred following an extensive lesion of the fastigial nuclei. Chambers (1953), Sprague and Chambers (1953), and Chambers and Sprague (1955a, b) stated later that permanent (two years) loss of the tactile placing reactions occurred in the cat following a lesion of the most rostral part of the ipsilateral nucleus interpositus. The placing reactions were increased following destruction of the fastigial nuclei or of the vermal cortex projecting upon them, whereas a transient loss (twenty days) of the placing reactions occurred when deep extirpation of the intermediate part of the anterior lobe was followed by slight gliosis of the rostral nucleus interpositus. When the lesion of the intermediate part was more superficial and the nucleus interpositus had been spared, the ipsilateral placing reactions were actually enhanced. Threshold electrical stimulations of the nucleus interpositus or of the intermediate part of the anterior lobe projecting upon it, in the otherwise intact cat, resulted in an enhancement followed by a poststimulatory extinction of the tactile placing reactions. The results of the ablation experiments on the fastigial, interposite, and dentate nuclei were confirmed on dogs by Sperti and Zatti (1953a, b). The experiments of the American investigators clearly show that within the nucleus interpositus are located neural structures that have a critical importance for the placing reactions. Localized cortical cerebellar extirpations yield only temporary inactivation or impairment of the placing reactions, and it is likely that these effects occur only when the deep nuclei are encroached upon anatomically, or at least functionally. Chambers and Sprague (1955b) showed, moreover, that a loss of the tactile placing reactions occurred also following near-total destruction of one dentate nucleus and most of the white matter of crura I and II. Cortical destruction of crus I "extending deeper into the white matter of the interpositus and dentate nuclei with subsequent gliosis of those nuclei" reduced temporarily, but did not abolish, the tactile placing reactions of the ipsilateral foreleg. These effects were lacking when the dentate nuclei had been spared. Hence also the dentate system, though not necessarily the overlying cerebellar cortex, appears to have a critical importance for the placing reactions. It is not easy to understand why a permanent loss of the tactile placing reactions should be elicited by a lesion localized to the rostral part of the nucleus interpositus in the cat (Chambers, 1953; Chambers and Sprague, 1955a, b), whereas only transient effects are obtained following hemicerebellectomy in the dog (Rademaker, 1931). A clue is perhaps provided by the enhancement of the placing reactions that occurs following destruction of the vermal part of the

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anterior lobe or of the fastigial nuclei (Chambers, 1953; Chambers and Sprague, 1955a, b). The influence of cerebellar ablations on conditioned reflexes artificially established in the laboratory has been much less intensively investigated. Orbeli (1940) briefly recalled experiments by Livshitz, who showed that salivary conditioned reflexes were modified by cerebellectomy. To the best of our knowledge, the only experiments performed on lower vertebrates are those of Karamjan (1949). He found it very difficult to establish conditioned reflexes to light in cerebellectomized fishes; reflexes which were elicited after 6 to 9 associations in normal animals, were not obtained even after 33 to 47 associations in the cerebellectomized fishes. In the decerebellate frogs and toads, however, the establishment of the conditioned reflexes was still possible, and those previously established were only slightly modified. E. RELATION TO SENSORY FUNCTIONS

1. CONCLUSIONS DRAWN FROM REFLEX RESPONSES TO SENSORY STIMULATIONS Holmes's statement (1939, p. 7) that "in man even extensive lesions of the cerebellum involve no form of conscious sensations" may be taken as a condensed account of the conclusion reached by most of the leading physiologists and clinicians from Luciani (1891) to our times. The authority of their wide experience and our tendency to rely upon their keen spirit of observation should not, however, prevent us from attempting a critical appraisal of the few investigations that led to opposite conclusions. In the experiments performed before the electronic era obviously only indirect and often quite controversial data could be gathered from the analysis of behavior and of reflexes in the cerebellectomized animal. The main results are summarized below. Renzi (1863, vol. 1, pp. 219-245) reported that the fear reactions to visual stimuli were strongly reduced, in birds, contralaterally to a cerebellar lesion. He was aware of the danger represented by collateral lesions and stated that he had discarded all the experiments in which the optic lobes had been encroached upon (1864, vol. 3, p. 28). He maintained, moreover, that it was more difficult to arouse a bird with tactile stimuli applied to the contralateral side of the body. He claimed, finally, that these observations could be reproduced in the guinea pig, whose reactions to auditory stimuli were decreased after a cerebellar lesion. These were all acute experiments; the extent of the cerebellar lesion was not given and, what is worse, the integrity of the brain stem was never controlled, either anatomically or physiologically. Renzi's views, moreover, were so unusual up to a few years ago, that we can understand why the three volumes he devoted to the neurophysiology of the vertebrates are now entirely forgotten. The cerebellum, he stated, was the organ of the "innervazione centrifuga dei sensi" (1863, vol. 1, p. 265), an expression that might be regarded with some reason as meaningless from the standpoint of experimental physiology, before the discovery of the cerebellar influence on the gamma neurons (see pp. 255-262). The centrifugal innervation, he said further, was connected with the phenomenon of sensory

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 345 attention, a function that has been recently ascribed to the brain stem reticular formation (see pp. 347-348). It would be difficult to tell whether all the results he reported (1863-1864) were really due to the withdrawal of a cerebellar influence, but some of them have recently been confirmed by Chambers and Sprague (1955a, b). The American investigators found in cats a "great reduction in startle response to loud noises, lack of attention to noises which had preoperatively aroused quick investigation, following bilateral cortical ablation of tuber and folium." Thirty years after Renzi, Russell (1894), while describing the results of the ablation of one cerebellar hemisphere in the dog, stated that in the first few days "the animal may take notice of cold water dropped onto all the other extremities, or to the painful clip applied to any of these, and yet take no notice of either of these stimuli when they were directed to the posterior extremity on the same side as the lesion" (p. 835). He was unable to find any affection of the hearing, sight, or smell, and stated that the recovery of normal responsiveness to nociceptive or thermal stimulations was complete one week after the operation. These symptoms were bilateral when both hemispheres had been ablated, and cleared up on the anterior extremities before they did on the posterior. Here again one should recall the recent experiments of Chambers and Sprague (1955a, b), who observed a "marked increase in threshold to nociceptive stimuli of ipsilateral limbs and trunk following dentate destruction." When discussing the experiments performed by Lewandowski (1903) and by Ducceschi and Sergi (1904) on cerebellar influence upon the so-called "musclesense" (pp. 42—43) and when reviewing more recent investigations on the effect of cerebellar lesions upon the placing reactions (pp. 339-344), we pointed out that these data did not prove, necessarily, that the transmission of sensory messages or their conscious elaboration was supervised by the cerebellum. The withdrawal of a tonic facilitatory influence exerted by the cerebellum on the motor cortex might bring about the disappearance of a conditioned response without affecting, necessarily, conscious sensation. Rademaker's observations (1931, pp. 437-448) concerned the effects of cerebellectomy (thirty-eight days survival) on a fully decorticate dog. He reported that the motor responses of his dog to meaningful noises were actually increased following total cerebellectomy, and made the following comment: "Diese Beobachtung ist aus zweierlei Griinden merkwiirdig. Erstens weil das Tier gerade auf dieses Gerausch, mit dem man gewohnlich intakte Hunde anruft, so stark reagiert, wahrend es auf andere, sogar sehr laute Gerausche, wie z. B. auf das durch einen kraftigen Schlag mit der Hand auf eine Tischplatte ausgeloste Gerausch, nicht oder fast nicht reagierte. Und zweitens, weil die Reaktionen auf das Pfiffgerdusch viel starker hervortrdten als vor der Kleinhirnextirpation" (p. 446, italics ours). Hence, according to Rademaker (1931), the response to meaningful noises was actually released by chronic cerebellectomy, at least in one decorticate dog. These effects are not necessarily exerted on the neurons of the cochlear nuclei, but might be related to an inhibitory influence of the cerebellum on the pseudoaffective reflexes, which are localized in the brain stem (Forbes and Sherrington,

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1914; Bazett and Penfield, 1922, especially p. 224). Also the marked instability of the motor responses to different types of sensory stimulations which was observed after cerebellectomy by several Russian physiologists (Tetjaeva and Jankovskaja, 1940; Markow, 1941, 1947; Mnukhina, 1946; see Orbeli, 1938 and 1940 and Simkina, 1948), and which was designated by Orbeli (1940) as "sensory ataxia," is not necessarily related to the withdrawal of a cerebellar influence on sensory neurons. These symptoms might also result from the disorganization of all reflex activities that is brought about by the cerebellectomy. Simkina (1948) reviewed recently several experiments on the effects of highfrequency irradiation (Livshitz, 1946, 1947; Alekseenko, 1946; Sagorulko, 1947) or of traumatic wound (Aleksanjan, 1946) of the human cerebellum on different types of visual sensations. This approach may turn out to be interesting, but more information about the technical procedure used and the controls made is needed before expressing an opinion about these experiments.

2. EFFECTS ON SENSORY RECEPTORS AND ON PRIMARY SENSORY NEURONS The discovery of a cerebellar influence on the y neurons innervating the intrafusal muscle fibers (see pp. 255-262) prompts a reappraisal of the whole problem of cerebellar influence on the so-called "muscle sense." Granit (1955a, p. 273) suggested that cerebellar dysmetria might be related to the fact that the "internal measuring instruments" in the spindles cannot be utilized in the normal way. Hence dysmetria might indeed result from a sensory disturbance and would be related to an abnormality of the centrifugal innervation of the muscle spindles. This does not imply, as Granit (1955a, pp. 275-276) has rightly pointed out, a sensory disturbance (sensu strictiori), i.e., an alteration in the conscious proprioceptive sensations. Granit recalled that Mountcastle, Covian, and Harrison (1952) as well as Mclntyre (1953) showed, with the technique of evoked potentials, that the nuclear bag afferents (anulospiral endings) project onto the cerebellum only. The proprioceptive information reaching the highest levels of the central nervous system might be sent by Golgi tendon organs, which of course escape cerebellar control, and by the so-called group II afferents, probably arising (flower-spray endings) from the myotubes of the muscle spindles (see Granit, 1955a). This last group of afferent fibers was actually shown by Mclntyre (1953) to be represented in the cerebrum. This background of electrophysiological information should be kept in mind in any attempt to appraise the interesting results obtained on monkeys and chimpanzees by Sjoqvist and Weinstein (1942). They reported (a) that section of the medial lemniscus "did not produce an enduring loss of proprioceptive skill in the ability of trained animals to discriminate weight" and (b) that "no significant alteration in weight discrimination" was obtained by severing the superior cerebellar peduncle. However, when the two lesions were combined "there was a marked permanent loss in general proprioceptive function and the ability to discriminate weight" (italics ours). These results might explain why Holmes (1922d, p. 112) found no disturbance in the ability of cerebellar patients to discriminate between two weights placed successively on the limb, although he conceded that they generally overestimated the weight on the abnormal side. The experimental

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 347 findings of Sjoqvist and Weinstein (1942) suggest, moreover, that cerebellothalamic pathways may contribute to the recovery of proprioceptive functions after the interruption of the medial lemniscus. We think it would be interesting to investi* gate the contribution of the cerebellum to the recovery from lemniscal deficiency when the outflow through the superior cerebellar peduncles is not interrupted but the y regulation of the muscle spindles is disorganized by a fastigial lesion.

3. EFFECTS ON POSTPRIMARY SENSORY NEURONS A blockade of the synaptic activation of the second sensory neurons was recently shown by Hagbarth and Kerr (1954) in experiments performed on curarized cats. They found that the transsynaptic response of the ventral column of the spinal cord to single-shock stimulation of the contralateral dorsal root L 7 was blocked by stimulating the ventral part of the anterior vermis. The response of the sensory cortex was also blocked—it recovered, indeed, later than the response of the ventral column (Fig. 143)—a result suggesting that sensory conduction had been probably interfered with "not only in the spinal cord but also in higher centers." These effects were reproduced by iterative stimulation of the bulbar or midbrain reticular formation, of several regions of the cerebral cortex, but not of other cerebellar areas, such as the posterior vermis or the ansiform and paramedian lobules.

Figure US. The effects of electrical stimulation of the ventral part of the anterior vermis on spinal and cortical sensory responses. Responses were led from the left ventral column (upper beam) and left sensory cortex (lower beam) in the curarized cat. Following single-shock stimulation of the right dorsal root L7, records were taken before (1), during (#), 1 sec. (3), and 4 sec. (|) after cerebellar stimulation. Note the blockade of both responses (#> 3) and the earlier recovery of the evoked potential of the ventral column (4). (From K. E. Hagbarth and D. I. B. Kerr, 1954, Central influences on spinal afferent conduction, J. Neurophysiol., 17:295-307, Fig. 4, publ. Charles C. Thomas.)

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The inhibition of the postsynaptic response of the sensory pathways was absent under chloralosane or nembutal anesthesia, which actually greatly enhanced the evoked response of the ventral column. Since a similar enhancement was obtained by transecting the spinal cord rostrally to the point led from, Hagbarth and Kerr (1954) suggested that this effect of anesthesia might be due to the "removal of tonic, descending influences capable of depressing afferent conduction in the cord." It should be recalled in this connection that Moruzzi and Magoun (1949), working on cats under very light chloralose anesthesia, found that the cortical responses evoked by single-shock stimulation of the sciatic nerves were partially blocked during the EEG arousal elicited by reticular stimulations. An inhibition of the second-order sensory neurons of the spinal cord (Hagbarth and Kerr, 1954; Lindblom and Ottoson, 1956), of the evoked responses led from the trigeminal (Hernandez-Peon and Hagbarth, 1955), gracilis (Scherrer and Hernandez-Peon, 1955), and cochlear (Jouvet, Berkowitz, and Hernandez-Peon, 1956) nuclei, as well as of the cortical responses to sensory volleys (Morin and Green, 1955) was observed following reticular stimulations. Granit (1955b) reported that retinal units were more frequently excited, and sometimes inhibited, by stimulating the midbrain reticular formation. He stated, however, that these effects, which were obtained only with high voltages (5 to 10 volts), were elicited less easily than the EEG arousal and that vascular changes occurred simultaneously in the retina. It might be interesting to compare, in threshold and predictability, the effects of reticular stimulation on the motor responses, on electrocortical activities, and on sensory neurons. Hernandez-Peon, Scherrer, and Jouvet (1956) recently suggested that the reticular system might be involved in the process of attention, since it would block the afferent impulses which are not the object of conscious sensation at that particular moment. If this stimulating hypothesis is proved correct by direct experimental evidence, the problem of identifying the reticular units which are influenced by cerebellar polarization (see pp. £19—229) will become one of major physiological interest. We are still far from being in a position to give an answer to these questions, and nobody would venture to predict the final conclusions of the experiments that are being actively pursued in many laboratories. It should not be forgotten, at any rate, that direct corticofugal fibers go to the principal and spinal trigeminal nuclei and to the nucleus of the solitary tract (Brodal, Szabo, Torvik, 1956) as well as to the nuclei of the dorsal column (Walberg, 1957). Hence regulation of the responses of the sensory neurons does not occur, necessarily, through the reticular formation. From the point of view of neurophysiological history, it is certainly interesting that the thoroughly forgotten views of Renzi (1863-1864), which were never accepted by contemporary physiologists, may be regarded, one century later, as worthy of discussion.

4. EFFECTS ON THE ASCENDING RETICULAR SYSTEM Since a generalized EEG arousal may be elicited by stimulating the cerebellar cortex of the anterior lobe (Mollica, Moruzzi, and Naquet, 1953) or the fastigial nuclei (Moruzzi and Magoun, 1949), the question should be raised whether the ascending reticular system is impinged upon by cerebellifugal impulses. There is

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 349 anatomical evidence supporting an affirmative answer, since cerebellifugal fibers do reach those areas of the reticular formation (Brodal, 1957) in which the long ascending fibers have their origin (Brodal and Rossi, 1955); physiologically the hypothesis is supported by the results of stimulation experiments (see pp. 219229) and by the observation that units located in the pontine districts of the reticular formation that give rise to the long ascending fibers may be influenced by cerebellar stimulations (Palestini, Rossi, and Zanchetti, 1957). It must be conceded that these data represent only indirect evidence, since ascending reticular neurons are predominantly, but not exclusively, represented in those brain stem regions. In any event, the assumption, if accepted, would necessarily offer for consideration the problem of the relation between the cerebellum and sleep, a problem that has not been satisfactorily investigated. To the best of our knowledge only Borgherini (1891) and Borgherini and Gallerani (1892) approached this problem through ablation experiments on dogs. They stated: "Lorsqu'on bande les yeux aux animaux en experience, c'est a dire quand on les prive de tous les secours qui peuvent leur servir pour la connaissance exacte de leur position dans 1'espace, apres quelques tentatives de locomotion encore plus desordonnees, Us s'etendent lentement sur le sol et y restent immobiles, bien qu'on les secoue. Les masses muscidaires apparaissent dans un etat de complete atonie. En soulevant 1'animal en 1'air, on voit le cou et la tete, les membres, la queue et les oreilles pendre verticalement, inertes et en resolution complete. Tout cela ne s'obtient pas chez les animaux sains. Le chien fait la meme impression que s'il se trouvait dans un etat lethargique, par ex. dans le sommeil naturel ou sous la narcose chloroformique" (p. 68). This technique of blindfolding the animal, reducing in any manner its sensory inflow, should certainly disclose a latent tendency to fall asleep, and the differential diagnosis between sleep and animal hypnosis would now be a simple matter with the EEG techniques. To ascertain, however, whether the brain stem had been injured by chronic cerebellectomy would be necessary, and unfortunately neither Borgherini (1891) nor Borgherini and Gallerani (1892) reported any control of this kind. Moreover, no report of sleeping behavior can be found in a paper by Roncali (1899b), who analyzed the effects of vermal topectomy on two sightless dogs (ablation of both eyes). He simply claimed that recovery was much delayed, but his evidence is far from being convincing (Roncali, 1899a, b). It must be stated, on the other hand, that a tonic cerebellar facilitation of the ascending reticular system is not disproved either by the observations of the physiologists (in the great majority) who found their animals fully alert and awake in the first few days after cerebellectomy. At least in the carnivores, the barrage of exteroceptive and proprioceptive impulses elicited by the striking release phenomena that characterize Luciani's dynamic period (opisthotonos, extensor spasticity) is likely to overcompensate the withdrawal of the facilitatory influence exerted by the cerebellum on the ascending reticular system, if any effect of this kind is present under normal conditions. Moreover, this type of cerebellar deficiency, if it does exist, is likely to be soon compensated by the tremendous convergence of afferent and corticofugal impulses upon the brain stem reticular formation.

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Simkina (1946) recently devoted a full paper to an analysis of the effects of faradic stimulation of the cerebellum in the unrestrained, unanesthetized cat. She stimulated with chronically implanted Hess electrodes, for unusually long periods (two to four minutes), sometimes the hemispheres and sometimes the vermis of the cerebellum; the induction currents, she stated, were so low that no motor effects occurred. The experiments were performed on seven cats, but only in three of them did a state of drowsiness or sleep definitely appear during the stimulation. The animal was at once aroused when the stimulus was over, and behavioral arousal could be elicited by strong noises while the animal was asleep, i.e., during the cerebellar stimulation. One wonders, however, if the effects elicited by these prolonged stimulations might not be due to functional inactivation of the stimulated structures (see Adrian and Moruzzi, 1939; Moruzzi, 1939). From a perusal of Simkina's article, this important point appears to have been entirely neglected. Controls could be easily made by applying the same electrical stimuli, for two to four minutes, to Larsell's lobules III, IV, or V. Their functional extinction would be evidenced by a striking release of the postural antigravity mechanisms. Another limitation of this paper is that the cerebellar stimulations were not adequately localized. According to Simkina (1948) similar results had been previously obtained by Saprokhin (1938, 1939) and by Simkina herself (1943b) on the rabbit. Simkina and Orbeli (1932) reported that cerebellar stimulation aroused the animal if it was asleep and made it fall asleep if it was awake. It would be important to repeat these experiments with localized stimuli, and possibly also to record the electrocorticogram and, at the very end of the stimulation, the electrical activity of the cerebellar cortex. F. GENERAL CONSIDERATIONS In the previous chapters of this book we have been chiefly concerned with cerebellar regulation of the postural tonus, less frequently with the control of phasic movements, and only exceptionally with experiments suggesting an influence of the cerebellum in the sensory or in the autonomic sphere. Markedly different as all these functions are in their mechanisms, and above all in the extent and continuity of the control exerted by the cerebellum, they appear to share at least one feature, namely, that none of the nervous centers involved appears to be exclusively related to the cerebellum. In other words, the structures of the spinal cord, the brain stem, and the cerebrum which are impinged upon by the cerebellifugal volleys may ultimately work independently of the cerebellum. The brain stem reticular formation (von Baumgarten, Mollica, and Moruzzi, 1954) and the vestibular nuclei (De Vito, Brusa, and Arduini, 1956) are good examples of this type of interrelations. In the unanesthetized preparation their neurons are frequently "spontaneously" active, and their discharges are influenced, in multifarious ways, by sensory receptors and sometimes by the cerebral cortex. All these "spontaneous" and driven activities are influenced, in turn, by the cerebellum (see pp. 219-229). However, the very existence of righting reflexes in the cerebellectomized animals (p. 271) or the early compensation of the release symptoms that follow the cerebellectomy (see pp. 283-287) shows that the brain

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 351 stem structures may also work independently of the cerebellum. It is unlikely that all these brain stem activities are performed only by those reticular units which were found, on microelectrode records, to be unaffected by cerebellar stimulation (Mancia, Mechelse, and Mollica, 1957; Palestini, Rossi, and Zanchetti, 1957). Far more probable is it that the brain stem neurons that are within the sphere of influence of the cerebellum may also be driven by extracerebellar sources and may influence, in turn, other parts of the nervous system without the cerebellum's being involved. This statement is true a fortiori for the spinal cord and the cerebrum. There is abundant electrophysiological evidence, on the other hand, showing that cerebellar neurons are driven by sensory volleys and by the cerebrum (see pp. 182-211). This intense mutual exchange of information points to a close cooperation between the cerebellum and other central structures. The study of these reciprocal influences is likely to give us a better understanding of what we may, so to speak, call the "foreign policy" of the cerebellum. In this chapter an attempt has been made to review all the experimental data likely to contribute to our knowledge of this aspect of cerebellar physiology. It is time now to discuss the physiological experiments and the clinical observations from this point of view. For simplicity's sake only three topics will be selected for discussion: (a) cerebellar regulation of the postural extensor tonus; (b) cerebellar regulation of voluntary movements; (c) cerebellar influence on sensory functions. The relation of the cerebellum to the autonomic nervous system will be discussed in Chapter 7. Cerebellar regulation of the postural extensor tonus. The problem of the regulation of the postural extensor tonus is closely connected with that of the relation of the cerebellum to the spinal cord, its relation to the vestibular system, and also—particularly in primates—its relation to the cerebral cortex. The data which have been reviewed in this chapter are likely to throw some light on three groups of phenomena which are routinely observed in ablation experiments, namely (a) the release phenomena characterizing the so-called dynamic period, (b) Luciani's atonia, and (c) the mechanisms of compensation of the release symptoms and of Luciani's atonia by other neural structures. The discussion of the experimental data will follow this order. We have already pointed out (p. 98) that the dynamic phenomena which are so conspicuous in the carnivores during the first week following cerebellectomy are mainly release effects. This is well established for the two most prominent symptoms, namely, opisthotonos and extensor rigidity of the forelimbs. The experiments reported in this chapter (pp. 273-280) fully confirm this assumption. They show, moreover (a) that the inhibitory structures are mainly localized within the fastigial nuclei and the cerebellar cortical areas projecting upon them; (b) that the extensor hypertonus occurs even when both forelimbs have been chronically deafferented; and (c) that the opisthotonos is due to a release of the tonic labyrinthine reflexes from an inhibitory influence arising mainly, though not exclusively, within the fastigial nuclei. These findings deserve some comment. They show (a) that cerebellar control of the postural tonus is not exclusively mediated by the y neurons, a conclusion

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fitting the result of stimulation experiments (pp. 260-262), and (b) that control over the vestibular reflexes is exerted also by the fastigial nuclei and by the cerebellar cortical areas projecting upon their rostral portions, i.e., by structures which are outside the flocculonodular lobe. That a close relation exists between the fastigial neurons and the vestibular system is supported also by the results of anatomical (Dow, 1936) and electrophysiological (Arduini and Pompeiano, 1956, 1957) investigations (see pp. 237-240). We are now coming to grips with a controversial problem in cerebellar physiology, namely, Luciani's atonia (see p. 97). That hypotonia is a prominent symptom of cerebellar deficiency in subhuman primates and in man is recognized almost universally, but Dusser de Barenne (1923, 1937) and Rademaker (1931) flatly denied its existence in the carnivores. The evidence in disproof of their opinion has been reviewed at length (pp. 97-98), but recent experiments have clearly shown that symptoms strikingly similar to those characterizing Luciani's atonia occur after unilateral fastigial lesions, with histologically controlled integrity of the remaining part of the cerebellum and of the brain stem (pp. 77-80). Although the observations of Luciani have been fully confirmed, his explanation of atonia should be somewhat revised and completed. We shall first discuss the mechanism of atonia in the carnivores and afterward make a few comments on the postural disorder occurring in subhuman primates and in man. The withdrawal of a facilitatory influence does not account entirely for fastigial atonia in the carnivores nor probably for any type of atonia occurring after unilateral cerebellar lesions. The experiments of Moruzzi and Pompeiano (1955b and c, 1957a) and of Batini and Pompeiano (1955a, 1957), which have been fully reviewed in this chapter (see pp. 265-268), suggest that unilateral atonia is also due to reflex inhibition arising from muscular and labyrinthine proprioceptors of the opposite side of the body. A reciprocal control between the two sides of the body, through crossed tonic reflexes arising from limb (Stella, 1944b; Cardin, 1946a, b, c) and labyrinthine (Moruzzi and Pompeiano, 1955c, 1957a; De Vito, Brusa, Arduini, 1956) proprioceptors, is probably always at work, under the supervision of the cerebellum. It might be suggested, actually, that these reciprocal influences are mainly responsible for the symmetrical posture of the limbs, a phenomenon which appears particularly striking when the animal is lying in a supine position. This fine regulation will obviously be entirely disrupted by any asymmetrical fastigial lesion. The structures which are deprived of the support of cerebellar facilitation are likely to be more easily overwhelmed by reflex inhibition. Also, the flow of afferent impulses arising, for example, from the muscle spindles will obviously increase on the side of the body whose a and y neurons are released from cerebellar inhibition. Hence the play of the spinal and brain stem reflexes will greatly amplify the effect of even a slight imbalance in cerebellar innervation. All these factors are probably present also in the subhuman primates and in man. It is likely, however, that primate atonia is related also to the withdrawal of cerebellar facilitation on the cerebral cortex (see Bremer, 1935), whereas in the carnivores the disturbance is mainly the consequence of a disorder in the interrelations between the cerebellum and brain stem. The problem of the compensation of the cerebellar symptoms is one of major

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 353 importance from the point of view also of clinical neurology. First of all, a distinction should be made between compensation of the release symptoms, which is extremely efficient and appears to be almost complete at the end of the first week, and compensation of Luciani's atonia. The experiments of Batini, Moruzzi, and Pompeiano (1956a, b, 1957) suggest that the stream of ascending impulses from the lower segments of the spinal cord (Schiff-Sherrington inhibition) is mainly responsible for taking over the inhibitory functions normally exerted by the cerebellum on the postural tonus of the forelimbs and neck. Hence the early disappearance of the release phenomena after complete cerebellectomy or bilateral fastigial destruction should be ascribed mainly to the vicarious activity of spinal and brain stem mechanisms (see pp. 283-287). This is not the sole cause of the compensation of the release symptoms. Experiments by Batini and Pompeiano (1955a and b, 1957) suggest that the cerebral cortex is also likely to play a role, probably a more important one in primates than in carnivores. The high efficiency of the cerebral cortical mechanism controlling the tonus of the antigravity muscles is actually responsible, to a large extent at least, for the fact that release symptoms are absent or poorly developed when the entire cerebellum or the anterior lobe is extirpated in subhuman primates and in man (see pp. 36, 58, 338). Luciani's discovery that the compensation of cerebellar atonia is mainly due to the motor area of the cerebral cortex has been repeatedly confirmed (see pp. 330-332). The experiments of Batini and Pompeiano (1955a and b, 1957) show, moreover, that even fastigial atonia—i.e., a syndrome which is certainly present in the decerebrate cat (see pp. 80-86)—may be compensated for by the area gygantopyramidalis of the cerebral cortex, in the otherwise intact animal. When both motor cortices are chronically ablated, a new compensation gradually supervenes, probably through subcortical mechanisms. This subcortical compensation does not occur, however, at brain stem levels, since precollicular decerebration of fully compensated animals is constantly followed by a typical asymmetrical distribution of decerebrate rigidity. The compensation of Luciani's postural syndrome by the cerebral cortex might be explained by a rearrangement of the tonic influence exerted by the motor area on the brain stem and on the spinal cord (see Adrian and Moruzzi, 1939). Granit and Kaada (1952) have shown that electrical stimulation of the motor cortex or of the pyramidal tract evokes an acceleration of the afferent spindle discharges without any motor contraction. One wonders if an increase in the tonic facilitation exerted by the motor cortex on the neurons of the efferent gamma system (see pp. 255-262) might contribute to the compensation of cerebellar atonia. Cerebellar regulation of voluntary movements. The physiological data on cerebellocerebral relations should now be utilized in an attempt to understand the striking alteration in voluntary movements that occurs in the cerebellectomized animal and above all in human patients. The reader is referred to Part II of this book and to the reviews of Holmes (1922, 1939), Goldstein (1927), and Bremer (1935) for a detailed account of the disorders of voluntary movements occurring after cerebellar lesions as well as for a review of the clinical literature.

354 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM In his Hughlings Jackson lecture Holmes (1939, p. 24) regarded the following cerebellar symptoms as primary or fundamental, in the sense that they could not be attributed to other causes: (a) postural hypotonia and impairment of certain reactions of the toneless muscles; (b) a mild degree of asthenia and fatigability of the muscles; (c) abnormalities in the rate, regularity, and force of voluntary movements; and (d) the failure of certain associated movements. He thought that "all the other symptoms included in 'cerebellar ataxia,' 'incoordination' and 'asynergy' are partly due to these elementary defects, in part the result of attempts of other portions of the nervous system to compensate the functions which are lost." We shall restrict our discussion to the primary alterations in the voluntary contraction. After unilateral cerebellar lesions, the following disorders are observed in the simple voluntary movements of the affected side: (a) they are initiated more slowly (Holmes, 1917, 1922, 1939), a symptom conspicuous also in the chimpanzee (Fulton and Dow, 1937) and well-evidenced in man by the striking increase in the reaction time (Goldstein and Reichmann, 1916; see Goldstein, 1927, and Bremer, 1935); (b) "their speed varies, being sometimes slower, sometimes faster than in the normal limb" (Holmes, 1939, p. 11); (c) they are usually less forceful, the strength being sometimes reduced (after acute lesions) to half that of the normal limb, and the exertion of force is also jerky or intermittent (Holmes, 1917, 1939); finally (d) there is, as a rule, also a marked slowness in beginning and effecting relaxation (Holmes, 1917, 1939; Goldstein, 1927; Bremer, 1935). Actually only the third group of these disorders of voluntary movements corresponds to Luciani's asthenia, but Bremer (1935, p. 125) pointed out that all these symptoms might be explained by the withdrawal of the facilitatory influence exerted by the cerebellum on the cerebral cortex. Because of the deficiency of cerebellar facilitation the "tonus central" of the cerebral cortex would be lowered; consequently the cortical neurons would be recruited less easily, and the general strength of corticospinal innervation would be reduced. Finally, Bremer (1935) suggested that asthenia of the inhibitory mechanisms of the cerebral cortex might also explain the failure to arrest at the right moment the voluntary movement. Summing up, according to Bremer's interpretation (1935) the disorders of the elementary voluntary movement would represent the clinical correlate of the physiological findings of Rossi (1912a), who showed that the cerebellum exerts a facilitatory influence on the motor area of the cerebral cortex (see above, pp. 311—322). Commenting upon the functional significance of muscular tonus, Sherrington (1946) wrote that "the nerve and muscle are like a tuned string, always ready to be played on" (p. 253). Bremer's views on the "tonus central" of the cerebral cortex would provide a similar interpretation of the significance of the cerebellar control exerted on the elementary voluntary contraction. The same explanation might well be extended to the results of some clinical tests which Holmes (1939) regarded as the consequence of cerebellar hypotonia. To quote: "If, for instance, the outstretched arms rest lightly on a bar the normal limb keeps its position or sags but little when the bar is suddenly removed, but the hypotonic arm falls through a greater angle and may fail to maintain its new posture. This is more striking if the hand carries even a moderate weight; when

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 355 its support is released it falls more abruptly, sways about and regains stability slowly" (p. 3). It would be interesting to make measurements of the latent times of the muscle responses which normally prevent the arms or the weighted hand from falling when the support is suddenly withdrawn. They are not necessarily postural, at least in the sense in which we so define the mechanisms underlying the regulation of the reflex standing. If the cerebral cortex is involved, the failure of the cerebellar patient might be attributed simply to the slowness and the asthenia of the voluntary contraction of the skeletal muscles. Many disorders of the compound movements could also be explained, in part at least, by the slowness and the inertia of the unitary voluntary contraction. The latter hypothesis was actually suggested by Bremer (1935) and by Holmes (1939). There are other data, however, showing that the integration between the cerebellum and cortically induced movements does not occur solely within the cerebral cortex. Some symptoms, like the jerky or intermittent character of the voluntary contraction on the affected side of the cerebellar patient, the fact that the speed of the contraction may be sometimes faster than in the normal limbs, or the slowness of relaxation, cannot be easily explained by the lack of facilitation of the cortical neurons, at least without introducing additional hypotheses. Many experiments suggest other explanations of these findings. We have seen in this chapter (see pp. 311-322) that (a) cortically induced movements may be inhibited by cerebellar stimulations at spinal levels (Moruzzi, 1941c) and that (b) inhibitory impulses arising in the vermal areas of the anterior lobe are also likely to impinge upon the motor cortex itself (Moruzzi, 1941c). In the chapter on electrophysiological experiments (see pp. 204-210) we reviewed several works showing that evoked potentials may be led from the cerebellar anterior lobe following stimulation of the motor cortex, and it is not without significance that the same area is also impinged upon by proprioceptive and exteroceptive impulses (see pp. 182-186). We think that the neurons of the anterior lobe are likely to be driven by the motor cortex and also by the sensory volleys elicited by the voluntary movement; they will in turn regulate the movement itself through cerebellifugal volleys impinging not only on the cerebral cortex but also on the brain stem and on the spinal cord. Hansen and Rech (1925) reported that when a resistance to a voluntary contraction was abruptly released in a cerebellar patient, the latent time of the relaxation of the agonist muscles was about two to three times greater on the affected side of the body. These were not voluntary relaxations, since their latent periods were always far shorter than the reaction times (see Hoffmann, 1934, p. 90). In fact, Hansen and Rech (1925) attributed to impairment of the "Entspannungsreflexe" of the agonist muscles even the rebound phenomenon of Stewart and Holmes. The experiments of Hansen and Rech (1925) should be controlled and extended, and in analyzing the mechanism of the reflex relaxation account should be taken of the recent views and data on the importance of the y innervation of the intrafusal muscle fibers in the mechanism of the voluntary contraction (Roberts, 1952; Merton, 1953). If the observations of Hansen and Rech are confirmed, we should conclude at least that a voluntary contraction may be stopped at subcortical levels by neural mechanisms involving in some way the cerebellum.

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The failure of prompt arrest of a voluntary movement described by Holmes (1917,1939) is due, first, to a delay in commencing relaxation and, second, to a slowness in effecting relaxation. Although we are dealing here with a voluntary relaxation, it is unlikely that the influence exerted on it by the cerebellum occurs exclusively at cortical levels. We have seen that the efferent discharge of the neurons of the anterior lobe may be influenced by the cerebral cortex through pontine, paramedian reticular, and olivary relays (see pp. 201-202), and there is little doubt (see pp. 316-319) that cortically induced movements may be blocked by the anterior lobe at spinal or brain stem levels (Moruzzi, 1941c). Since augmentatory and inhibitory influences of several kinds are exerted on the brain stem and on the spinal cord by the vermal (see pp. 114-124) and the intermediate (see pp. 124, 136) parts of the anterior lobe, we might venture to predict that during any voluntary contraction the response of the a and y motoneurons to the corticofugal volleys will be continuously regulated by what we called (see pp. 248-249) the interpositofastigial system of the cerebellum. Obviously a subcortical regulation of voluntary movement would not contradict the hypothesis that the cerebral cortex itself is regulated (a) by the interpositofastigial system, through ascending reticular pathways (see pp. 248-249), and (b) by the dentate system (see p. 249), via the classical cerebellorubrothalamocortical pathways. Finally, the inhibition and the facilitation of units of the reticular formation, elicited by stimulating the motor cortex, and the marked influence thereon of cerebellar stimulations (von Baumgarten, Mollica, and Moruzzi, 1954) provide other possibilities of integration, at brain stem levels, between cerebral and cerebellar functions. The cerebellar mechanisms controlling the onset and the arrest of the voluntary contraction appear particularly important when alternating movement must be rapidly and regularly executed, a consideration accounting satisfactorily for Babinski's adiadochokinesis. The new concepts introduced into neurophysiology by the discovery of the y regulation of the muscle spindles (see p. 255) throw a new light on many symptoms which had been noticed, but not satisfactorily explained, by the old experimenters and clinicians. Granit, Holmgren, and Merton (1955) suggested that the symptoms of dysmetria occurring in cerebellar patients might be due to a lack of proper cooperation between the a and y systems, a functional disorder depriving "the muscle of the services of its private length measuring instruments." Another indication comes from the experiments of Granit and Kaada (1952), showing that the y neurons may be activated by stimulating the motor cortex or the pyramidal tract. These effects are not necessarily mediated directly, i.e., through corticospinal pathways, since many units of the bulbar reticular formation, whose stimulation so strikingly influences the y discharge (Granit and Kaada, 1952), are easily driven by the pyramidal volleys (von Baumgarten, Mollica, and Moruzzi, 1954). Rossi (1927) suggested that the regulation of the intrafusal fibers might ultimately place upon lower centers much of the burden of regulating, and of sustaining, the activity of the main muscle fibers. This concept is not necessarily limited to the postural tonus, and actually Roberts (1952) and Merton (1953) suggested that the activation of the y motoneurons by the precentral motor area was likely to play a major role in any voluntary contraction. Pursuing this idea,

THE CEREBELLUM AND OTHER CENTRAL STRUCTURES 357 we may wonder if cerebellar symptoms, such as failure to maintain the final position at the end of a voluntary movement or the terminal tremor occurring at the end of a voluntary contraction, whenever an attempt is made to reach a precise objective, might not be related to the lack of proper cooperation between the a and y systems. Let us first recall the clinical observations. In his first Croonian lecture Holmes (1922) stated: "If a patient with a unilateral lesion holds both arms extended horizontally in front of him, or raises his lower extremities from the couch on which he lies, the limb of the affected side may at first maintain its attitude as steadily as its fellow . . . But as the muscles holding the limb begin to tire an irregular tremor develops" (pp. 11811182). He reported further: "On holding his finger near to, but not in contact with, the tip of the nose or some other point, or his heel above, but not actually touching, his opposite knee, a tremor may develop" (p. 1182). He finally stated that these effects were "probably due to the loss of postural tone, the failure of fixation by muscles that move the joint in one direction allowing their contracting antagonists to displace it in the opposite sense, and as these do not immediately adapt their length to the fixation of the limb in its new posture, it is again moved by the opposing muscles toward and beyond its original position. Consequently, the part oscillates around the position it should occupy." We think that to hold a finger or the arm in a given position involves the voluntary contraction of opposing groups of muscles, i.e., neurophysiological mechanisms quite different from those underlying the unconscious regulation of reflex standing. It might be misleading, in our opinion, to regard cerebellar hypotonia as responsible for symptoms which concern primarily a disorder in the sphere of the voluntary contraction of skeletal muscles. A lack of or an incomplete integration between cerebellar and cerebral functions is obviously mainly responsible for these alterations, and the fact that cerebellar tremor is abolished by ablation of the precentral motor cortex (Aring and Fulton, 1936) confirms this assumption (see p. 334). But brain stem and cerebellar activities may be "appended" to a cortically induced motor discharge, just as the shortening reaction represents the myotatic appendage of some spinal reflexes. Any corticospinal discharge would thus be prepared, assisted, and continued by the driven activity of brain stem and cerebellar structures. Any voluntary contraction would be blended with a postural response. The possibility of regulating the contraction of the intrafusal muscle fibers would thus greatly improve the precision of the voluntary movements, at the same time relieving the cerebral cortex of a large part of the burden involved in the execution and fine control of the movements themselves. When the servomechanisms of the spindle loops are impaired by a cerebellar lesion, the precision of the voluntary contraction will be greatly decreased. Fatigue, moreover, will ensue much sooner. Obviously these disorders in the sphere of voluntary movements will be evidenced by any attempt of the patient to employ tools that require delicacy and precision, as Holmes (1922) had pointed out, or whenever he is confronted with the task of holding not fully supported parts of the body in a given position for a fairly long time. To conclude, the tremor, fatigability, and many of the other alterations observed during the performance of voluntary movements are likely to be the consequence not only of

358 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM a withdrawal of the facilitatory influence exerted by the cerebellum on the cerebral cortex, but also of defective cerebellocerebral cooperation at spinal and brain stem levels. Cerebellar influence on sensory junctions. Earlier in this chapter, at the beginning of the section on the relation of the cerebellum to sensory functions (Section E, 1), we recalled Holmes's negative conclusion on the existence of sensory disturbances in cerebellar patients. His views, however, were not shared by all clinicians. Lotmar (1908), Maas (1913), Goldstein (1913, 1927), Goldstein and Reichmann (1916), Reichmann (1917), and Panzel (1925) observed a disturbance in the appreciation of weights. Holmes (1917, p. 512) himself conceded that when "identical weights were placed in his two hands, his eyes being closed, the patient frequently did not recognize that they were equal, and in almost every case stated that the heavier was in the affected hand." Holmes was unable, however, to find any difference in the accuracy of discrimination between two weights, and in his fourth Croonian lecture (1922) he suggested that the tendency to overestimate weight on the affected side might be explained (a) by the asthenia of the limbs and (b) by the toneless state of the muscles "owing to which the proprioceptive nerve endings within them may be less easily excited when they contract or are subjected to strain by the resistance of raising the weighted limb" (pp. 112-113). This explanation does not account, however, for those clinical cases in which weights were underestimated (Lotmar, 1908; Maas, 1913; Goldstein, 1913). Goldstein (1927) reported, moreover, that the threshold for perceiving difference was less accurate on the affected side. We feel that the problem of discriminating weights should be investigated anew in the light of the discovery of the cerebellar influence on the y neurons. From a clinical standpoint it would be advisable to restrict future investigations to the first weeks following neurosurgical ablation of one half of the cerebellum or of one cerebellar hemisphere: the alteration in the messages sent by the spindle receptors is likely soon to be compensated by extracerebellar structures, since unbiased information may reach the brain from exteroceptors and other proprioceptors. Physiologically, much can be learned by recording, in the decerebrate preparation, the response to natural stimulation of single spindle receptors before and after fastigial lesions producing the typical unilateral disappearance of extensor rigidity (see pp. 80-86). Goldstein (1927) was unable to find in his cerebellar patients any alteration in the sense of touch or in tactile sensitivity to pain or to differences in temperature, but stated that the localization of the tactile stimuli was often wrong on the affected side. He claimed, moreover, that slow, passive movements were properly evaluated in the affected limbs only when the excursion was greater than on the normal side. He finally observed abnormal responses to visual and auditory stimuli. These findings should be subjected to carefully controlled studies of patients; their significance is likely to be clarified by animal experiments employing electrophysiological techniques.

6

Developmental Physiology

THE development of the cerebellum has been extensively investigated by the anatomists (see Larsell, 1958), but there are only a few works on the physiological side of the problem. Two main lines of approach have been followed: first, the histogenesis of the cerebellar cortex has been compared with the development of postural and motor functions in the newborn animal; second, ablation, stimulation, and electrophysiological experiments have been performed at different intervals from birth. The reader is referred to Ramon y CajaPs book (1909-1911, vol. 2, pp. 81-106) and to the volume by Larsell (1958) that will be a companion to the present work for a review of the anatomical papers on the histogenesis of the cerebellar cortex. The main feature considered by physiologists was the disappearance of the outer granular layer, which is largely due to the migration of cells toward the inner granular layer. This migration does not occur in different species at the same period in the ontogenesis nor at the same time in different cortical areas of the same animal. Lui (1894, 1896) was the first to attempt a comparative analysis of the development of the cerebellar cortex of animals which are born immature (pigeon, sparrow, rabbit, cat, dog, man) and of those (chick, guinea pig) which at birth are fully able to stand and walk. He came to the conclusion that the species having a less-developed cerebellum at birth possess to a lesser degree the control of posture and of locomotion. He stated, moreover, that the time when the definitive form of the cerebellar cortex is reached coincides with the time of the attainment of the faculty of standing and walking. While Lui's first conclusions were fully confirmed by all later investigators, the second statement should be somewhat modified, as we shall see below. Lui (1894, 1896) gave no details about the cerebellar areas which he utilized in his comparative investigations. This omission was quite common in nineteenth-century papers, but the later discovery (see van Rijnberk, 1931, p. 741) that the histogenesis follows quite different temporal patterns in the various areas of the cerebellar cortex of the same animal should prompt further and more detailed comparative investigations. Lui's conclusions were confirmed on mammals and on birds by Lowy (1910). Addison (1911) worked on the albino rat, an animal born in a helpless condition, with the eyes shut. At the end of the first week the rat is able to crawl, at the 359

360 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM second week it is more active and surer in its movements, and on the fourteenth to fifteenth days the eyes open and the animal becomes alert and can run about. Addison reported that there was no reduction in the rows of the outer granular layer of the vermis during the first ten days but that actually the number of the outer granular cells showed a definite increase. A rapid diminution in the cell rows occurred soon thereafter. On the eighteenth day there were still two cell rows, although the animal was quite able to walk. Only on the twentieth day, as a rule, had all cells migrated from the outer granular layer (Fig. 144). Addison thought that his experiments confirmed Lui's conclusions and stated that "the development of the motor activities of the young rat is closely correlated with that of the cerebellum, and the animal is in full possession of its motor powers when the cerebellum has attained its mature arrangement" (p. 479). Chiarugi and Pompeiano (1954), working on the kitten, which is also helpless at birth, found that not until 63 days after birth was the outer granular layer reduced to one row of cells in the midline of the vermis. After 18 days—i.e., when the kitten was beginning to walk—there were still four to six rows of cells, as against ten to twelve at birth (Fig. USA, B). By 28 days—i.e., when the walking ability was already fairly good—three or four rows of cells remained in the outer granular layer. There were two or three rows of cells even after 37 days, when the kitten was able to run (Fig. 145C). Hence the correlation between the development of the cerebellar cortex and that of motor ability is not so close as was at first surmised. This fact had been realized by Ramon y Cajal (1926), who stated, "Centre la croyance presque generate, 1'architecture cerebelleuse n'a pas atteint

Figure 1U- Cortical areas of the cerebella of albino rats at different ages. Drawing (X 400) from medial sagittal sections at the level of the fissura prima. Outer granular (a), molecular (6), Purkinje (c), and inner granular (d) layers at birth and at 3, 8, 14, and 20 days. The outer granular layer is

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at its maximum thickness on the 8th day, but not until the 20th day have all the outer granular cells migrated. (From W. H. F. Addison, 1911, The development of the Purkinje cells and of the cortical layers in the cerebellum of the albino rat, J. Comp. Neurol., 21:459-488; from the original of Plate S.)

toute sa perfection avec 1'instauration de la faculte locomotrice et de 1'equilibre, mais bien quand 1'animal est arrive a la plenitude de ses forces" (p. 78). That the disappearance of the outer granular layer is correlated with the tonic inflow of afferent impulses is suggested by the experiments of Roncato (1913). He reported that the development of the cerebellar cortex was greatly reduced, in the newborn pigeon, following bilateral ablation of two semicircular canals. Unilateral ablation was ineffective. Unfortunately he did not report the areas of the cerebellar cortex which were studied in his slides, but his experimental approach deserves to be controlled and extended in further experiments that will take advantage of our present detailed knowledge of the afferent projections to the cerebellar cortex. Asratian (1938) investigated the effect of complete cerebellectomy in puppies. He reported that up to 12 to 15 days almost no effects could be observed in the motor sphere. Only mild symptoms occurred between 15 and 30 days, and compensation occurred much earlier than in the adult animal. It was only after a month to a month and a half from birth that the typical release symptoms of the

Figure 145. The outer granular layer in the newborn kitten. Microphotographs of medial sagittal sections of the culmen (X 80) at birth (A) and on the 18th (2?) and 37th (C) days. Feulgen reaction. Note the reduction in the number of cell rows from 8-10 (A) to 4-6 (B) by the 18th day, when the first signs of a tonic influence are observed. On the 37th day, when the kitten is fully able to walk

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36S

and can run about, the outer granular layer is still present in the vermal cortex, though the number of cell rows is reduced to 2-3 (C). (From E. Chiarugi and O. Pompeiano, 1954, Sui rapporti fra istogenesi ed eccitabilita del lobua anterior nel gatto neonato, Arch. d. sc. biol., 58:493-531, Figs. 2, 5, 7.)

dynamic syndrome could be observed. Asratian's results suggest that in animals born immature most of the cerebellar functions are absent at birth. His conclusions have been confirmed by means of experimental (partial, unilateral) cerebellar lesions, which will be reported below. Localized ablations of the cerebellar cortex (Di Giorgio, 1944; De Renzi and Pompeiano, 1956) and of the deep nuclei (De Renzi and Pompeiano, 1956) were performed on newborn animals. The idea was that after unilateral lesions a postural asymmetry should ensue only if a tonic influence had been exerted by the cerebellar area destroyed. It was surmised that failure to detect postural asymmetries following unilateral lesions, which would have been fully effective in the adult animal, would mean that the corresponding cerebellar structures exerted no tonic influence on the postural sphere at the moment of the operation. Di Giorgio's experiments (1942b) were performed on newborn guinea pigs, rabbits, and kittens, which had been decerebrated or were otherwise intact. In the guinea pig, which is born mature, postural asymmetries were already observable at birth following small lesions localized to the cerebellar hemispheres, whereas the same experiment gave positive results only at 8 to 10 days in the rabbit and in the kitten. The experiments of De Renzi and Pompeiano (1956) were exclusively performed on decerebrated kittens. A symmetrical extensor hypertonus was always present in the forelimbs, even when the animal had been decerebrated shortly after birth. The lesions were obtained by suction through a very thin glass

364 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM pipette; their extent and localization were routinely controlled on serial Nissl and Weil slides. No postural asymmetry was obtained between 1 and 18 days from birth in 42 kittens presenting strictly unilateral localized lesions of LarselPs lobules III, IV, and V with complete integrity of the fastigial nuclei. However, the same lesions yielded the typical increase in the ipsilateral extensor tonus in a group of 21 kittens operated on between 18 and 40 days from birth. Also the reflex responses to nociceptive stimulations were asymmetrical in these experimental conditions. When the vermal lesion was deeper and the rostral part of the underlying fastigial nuclei had been unilaterally encroached upon, the postural asymmetry was opposite in laterality, just as in the ipsilateral fastigial atonia of the adult animal (see p. 77). This syndrome was observed in a group of 40 kittens which had been operated on between 13 and 40 days from birth, but it was constantly missed in 14 kittens on which the experiment had been made at between 1 and 13 days. The integrity of the other cerebellar nuclei and of the brain stem was proved by histological controls. De Renzi and Pompeiano (1956) drew the following conclusions from their experiments: First, that the tonic influence exerted by the vermal cortex of the anterior lobe on the postural mechanisms begins on the seventeenth to eighteenth day, i.e., almost simultaneously with the appearance of postural responses to electrical stimulation (Chiarugi and Pompeiano, 1954; see below). Second, that the tonic influence of the underlying roof nuclei begins slightly earlier, namely, on the thirteenth day, showing that fastigial neurons may be already firing when they are not yet driven by stimulating the overlying vermal cortex of the anterior lobe. Third, that from birth to the twelfth day there is no tonic cerebellar activity, although the brain stem mechanisms are already functionally developed, as shown by the forelimb extensor rigidity that ensues following decerebration. The first group of observations shows that the cerebellar cortex is functionally active when the animal is beginning to walk, although the disappearance of the cells of the outer granular layer is far from being complete. The second group of findings supports the view that fastigial neurons are not merely relays in the corticofugal pathways but may be driven by afferent impulses without the involvement of the cerebellar cortex (see pp. 80-86). The third group of findings shows that vermal lesions are symptomless in the first twelve days of life because the fastigial neurons or their efferent projections are not properly developed and not because a background of activity is lacking in the postural centers of the brain stem. De Renzi and Pompeiano (1956) undertook a histological analysis of the structural development of the fastigial nuclei. The only factor which they were able to correlate with the appearance of a tonic fastigial activity on the thirteenth day was the myelinization. It commenced at the same period within and around the fastigial nuclei and in the inferior cerebellar peduncles (Fig. 146A, B). When a tonic activity appeared in the overlying vermal cortex, on the eighteenth day, the white matter of the arbor vitae was full of myelinated fibers. It was not until the thirtieth day, however, that myelinization was complete in the fastigial area (Fig. 146C). We come now to the results of the stimulation experiments. The objections made to the experiments performed on adult dogs by Pagano (1902, 1904), which

Figure H6. Myelinization oj the area of the fastigial nuclei in the kitten. Transverse sections (Weil) of the cerebellum at the level of the fastigial nucleus in the kitten at birth (A} and on the 13th (B) and (see next page) the 30th (C) days. There are no myelinated fibers at birth (A). A few myelinate fibers appear in the fastigial area, in the neighboring white matter, and in the inferior cerebellar peduncles by the 13th day (B), while myelinization has extensively progressed by the 30th day (C). (From C. De Renzi and O. Pompeiano, 1956, La comparsa dell'attivita tonica della corteccia e dei nuclei del cervelletto nel gatto neonato, Arch. d. sc., biol., .^0:523-534, Figs. 6, 7, 8.)

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have already been reviewed (p. 110), may be extended to the results of Galante (1914a, b), who injected 1 to 2 drops of curare into the cerebellum of puppies. His conclusion that responses can be obtained from the lobulus ansiformis soon after birth is unlikely to be true, in view of the results obtained by Chiarugi and Pompeiano (1954) on the vermis (see below). Aleksanjan (1948) reported likewise that electrical stimulation of the cerebellum of kittens and puppies yielded cardiac and vasomotor effects only one day after birth. Kobakova (1952) came to similar conclusions by stimulating with faradic currents the cerebellar hemispheres of puppies and of newborn rabbits under urethane anesthesia. He stated that the intestine movements could be increased or inhibited not only immediately after birth but also during the last two or three days of embryonic life. The results obtained by the Russian investigators can hardly be reconciled with those of Chiarugi and Pompeiano (1954) unless we make the unlikely assumption that autonomic functions of the cerebellum develop much earlier than its influence in the somatic sphere. Kobakova (1952) apparently failed in his experiments to control the spread of currents to the brain stem, witness his statement, for example, that inhibition of the intestinal movements occurred at the highest intensities of currents and was accompanied by responses of the whiskers, an observation which in our experience is a constant and reliable sign of spread of current to the brain stem. Chiarugi and Pompeiano (1954) stimulated with square pulses (1 msec.; 300/sec) the vermal cortex of the anterior lobe in 30 decerebrate kittens. They were unable to find any effect on the extensor tonus and on spontaneous walking movements from birth to the eighteenth day. From the eighteenth to the twentysecond day the extensor rigidity could be inhibited by stimulating lobules V and

DEVELOPMENTAL PHYSIOLOGY 367 IV, though only with fairly high voltages. De Renzi and Pompeiano (1956) felt, however, that these effects might arise within the stimulated area, since (a) their appearance coincided with that of the tonic influence exerted by the cerebellum on postural mechanisms and since (b) a spread of current to the underlying fastigial nuclei should be observed also from 13 to 17 days, these structures being then already active. The threshold decreased later on, and controls made by cooling or by applying locally 1 per cent novocaine definitely showed that the responses to electrical stimulation arose within the stimulated cortex. It was only after 74 days, however, that the normal threshold of the adult cat was reached; the postinhibitory rebound was observed only after 43 days from birth. Hence even when walking ability was well developed and the kittens were able to run about (i.e., at from 37 to 43 days), the electrical response of the anterior lobe was still different from that observed in the adult animal. Hence the excitability of the vermal cortex corresponds to that of the adult animal only when the outer granular layer has disappeared altogether. An electrophysiological approach to the developmental physiology of the cerebellum was adopted for the first time in the experiments of Ulett, Dow, and Larsell (1944). Under nembutal anesthesia they stimulated the frontal cerebral areas of newborn rabbits with single condenser discharges and led the evoked responses from the folium and tuber vermis (lobule VII), from the pyramis (lobule VIII), and from the contralateral lobulus paramedianus (lobules H VHb, H VIII). Vermal responses were obtained on the second day in only 1 out of 12 rabbits. On the third day positive effects were obtained in 3 out of 8 animals. Five out of 10 animals responded on the fourth day, and 5 out of 6 on the fifth day. No paramedian response could be detected on the second day, while on the third day 3 out of 11 tested animals showed evoked potentials. On the fourth day 5 animals of 11 tested, and on the fifth day 6 rabbits of 6 tested, showed a response from this lobule. The evoked potentials were characterized by lability of sign and by very long latencies (a mean of 77 milliseconds for the paramedian responses and of 108 milliseconds for the vermal effects). Ulett, Dow, and Larsell (1944) stressed the fact that no myelinated fibers could be found in the corticopontocerebellar connections in the brain of the one- to five-day-old rabbit and concluded that myelinization of the corticopontocerebellar tracts is not essential for the conduction of nerve impulses. These conclusions do not conflict with those of De Renzi and Pompeiano (1956), since in the electrophysiological experiments the response of the cerebellar cortex to a single afferent volley was studied, whereas in the ablation experiments the concern was with the existence of an efferent, tonic, and probably repetitive discharge arising in the cerebellar cortex. Effects of this second group are likely to develop later. We have only a short preliminary note by Snider and Jacobs (1949) on the development of spontaneous electrical activity in the cerebellar cortex. They stated that spontaneous fast waves (10 to 60 microvolts; 150 to 250 per second) appeared at 12 days in the rat, whereas they were already present in the newborn guinea pig. Whether or not the spontaneous electrical activity appeared simultaneously in the different cerebellar areas was not stated. At any rate these preliminary data fit the old conclusions of Lui (1894, 1896).

7

General Considerations on the Function of the Cerebellum

AS FAR as we know, all communication between the cerebellum and other neural structures must be carried out by means of all-or-none impulses, coursing along the afferent and efferent fibers of the cerebellar peduncles. An impressive amount of detailed information on the manifold variety of incoming and outgoing signals has been gathered in the last twenty years. This is mainly the result of the stimulation experiments and bioelectric recordings that became possible upon the introduction of electronic instruments. Some of these new findings hardly could have been predicted from the results of the ablation experiments performed at the end of the last century. For example, we know that the cerebellum is impinged upon not only by proprioceptive volleys, as had been surmised from its influence on the postural tonus, but also by tactile, visual, auditory, and even by visceral impulses. We know that cerebellifugal volleys reach not only the postural centers of the brain stem and the motor cortex, a fact predictable from anatomical findings and from the disorders of posture and of voluntary movements obviously following upon experimental ablations, but that the volleys also project upon cerebral cortical areas not strictly related to the motor functions as well as upon several somatic and autonomic structures of the diencephalon and brain stem. Finally, we have learned, quite recently, that even the spindle receptors and possibly many sensory neurons may be influenced by the cerebellum. Summing up, recent investigations have provided us with an inventory of functions ascribable to the cerebellum that is far more extensive than any available in Luciani's time. One cannot help thinking that the arrival of splanchnic or vagal volleys and of auditory or visual impulses to the cerebellar cortex, and the possible modification of the reflex activity of the vasomotor centers by cerebellifugal volleys, justify the hypothesis that a hitherto unknown control may be exerted by the cerebellum in the sensory sphere and on autonomic functions. One might perhaps state, somewhat more cautiously, that recent findings on the afferent and efferent connections of the cerebellum constitute the prerequisite for such an hypothesis, which, however, should be tested by experiments performed along different lines. We have already seen how scanty and unsatis368

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factory is the evidence for such an influence provided by ablation experiments and by clinical observations. It is not enough to know that afferent and efferent pathways are available for a given function: one must find out how intensively and for what purposes they are utilized. The main task ahead for the physiologist is to investigate to what extent and in what manner the somatic and autonomic functions of the central nervous system are supervised by the cerebellum and how the cerebellar control is regulated by incoming signals; in short, what the position of the cerebellum is in the "integrative function of the central nervous system." We need to learn about the events occurring in the felt work of the cerebellar cortex between the arrival of the incoming signals and the emission of outgoing impulses, and what the essential contribution made by the cerebellum to the function of the other portions of the central nervous system is. Much work and possibly a fresh experimental approach are required before this aim may be attained. In the six chapters devoted to cerebellar physiology in this book, an attempt has been made to give a complete account of all the relevant experimental data that have been gathered from Rolando's time to our own, but we have purposively refrained from reporting and from discussing the theoretical speculations so frequently indulged in by experimenters and clinicians. Not infrequently we have found in quite old papers experimental material that still deserves to be known and discussed, but rarely can the same be said of the authors' interpretations. These certainly become antiquated at a much faster rate and are now mainly of historical interest. The reader is referred to Luciani's book (1891) and to van Rijnberk's (1931) monograph for an expose of this aspect of the history of cerebellar physiology. Purely or mainly speculative are also the recent contributions by Lapicque (1939a, b) and Ectors (1946). Critical reviews of data, with a few theoretical considerations, are to be found in the works of Rossi (1922), Goldstein (1927), van Rijnberk (1931), Bremer (1935), Fulton and Dow (1937), Larsell and Dow (1939), Moruzzi (1949, 1950a, 1953b), Snider (1950), Ruch (1951), and Feremutsch (1952). On the whole our feeling is that the time is not yet ripe for any attempt to formulate a new concept of cerebellar functions. The last years have seen a truly remarkable but nevertheless ill-proportioned growth in our knowledge of the cerebellum. The functional anatomy of the afferent and efferent projections has been the field most advantaged by the introduction of electronic methods. The results obtained so far, however, should be subjected to control experiments performed along different lines. Important facts were probably missed in previous ablation experiments and in the routine clinical observations because the observers were not looking for these unexpected functional relationships and, therefore, no adequate tests were developed to bring them out. At this stage of our knowledge of the cerebellum, to describe briefly the fields where a fresh approach and new experiments are most urgently required is, in our opinion, more advisable than to attempt to assess the importance of any of these new functional and anatomical relationships. First of all, we think that at least a rough attempt should be made to estimate, quantitatively, the relative intensity and continuity of the control exerted

370 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM by the cerebellum on posture, on voluntary movements, and possibly also on sensory and autonomic functions. There is disagreement between the results of ablation experiments, which emphasize the importance of the control exerted by the cerebellum on the skeletal muscles, and the results obtained from electrical stimulations or bioelectric recording, which are mainly responsible for the modern tendency to expand the sphere of influence of the cerebellum. Second, we need to know what the general patterns of cerebellar control are and to learn whether they are basically the same whatever the nature and functional significance of the neural centers played upon by the cerebellifugal volleys. Third, we are as yet very poorly informed about the intracerebellar interrelations that must exist in order to harmonize the control exerted by the cerebellum on the various extracerebellar mechanisms with which it is anatomically connected. Let us start with the first problem. If we assume that the cerebellum supervises motor, sensory, and autonomic functions, we may be tempted to regard these effects as due to entirely different groups of cerebellar neurons, possibly localized in different "centers," as has been found for the cerebral cortex and the diencephalon. This segregation hypothesis is, however, not congruous with the uniform structure of the cerebellar cortex; to postulate such a segregation appears unnecessary also on physiological grounds. Let us look at a few examples. The cerebellar regulation of the y discharge is likely to influence not only the posture and the voluntary contraction of the skeletal muscles, but also, to some extent at least, the sensory functions in the proprioceptive sphere. We know, moreover, that any voluntary contraction or phasic reflex is blended with posture, and it appears likely that the same Purkinje cells of the anterior lobe will supervise the execution by the spinal cord of both postural activities and of voluntary movements. Actually, the concept of a rigid segregation of different functions within the cerebellum appears to be disharmonious with what is possibly one of its main features: anatomical studies on the afferent and efferent projections and what we know about the histology of the cerebellar cortex point to almost unlimited facilities for the exchange of information and for close interneuronal cooperation. It hardly needs to be stressed that this approach does not by any means imply a necessity to go back to the time-honored idea of the cerebellum acting "as a whole." The Purkinje cells which project onto the cerebral cortex, for example, are likely to be different from those which control the activity of the vestibular nuclei or the reticular formation. Sometimes they may be located differently in anatomical space, as shown by the distinction between the dentate and the interpositofastigial systems (see pp. 248-249); sometimes they may be intermingled in the same area, but they will be able, nevertheless, to work independently from a physiological standpoint. What matters is that the final common path from the cerebellar cortex, the Purkinje cell, has its definite and precise efferent projections; it is likely to possess, therefore, a functional orientation. To exemplify, the same group of Purkinje neurons of the anterior lobe is likely to be involved in the y regulation of the contraction of the quadriceps muscle however this contraction is produced. But the rate of firing of these Purkinje cells and the spatial distribution of their activation are likely to be different when such a contraction occurs during the knee jerk, or in the reflex standing, or during a voluntary extension of the knee joint. The same Purkinje

THE FUNCTION OF THE CEREBELLUM 371 cell may be driven through different afferent channels and by different interneurons. The cerebellar-cortical areas projecting onto the fastigial nuclei may or may not be activated along with those projecting onto the nucleus interpositus and nucleus dentatus. In short, the same anatomical tools may be utilized, alone or in combination, for quite different purposes. In discussing the significance of the effects of cerebellar stimulations on vasomotor reflexes, Moruzzi (1940b) remarked that the common idea that ablation experiments should provide the negative image of the responses elicited by electrical stimuli was in fact not justified. He pointed out that an extremely efficient control of the systemic blood pressure is provided by the carotid sinus and cardio-aortic reflexes, through purely brain stem mechanisms. Hence cerebellar supervision is unlikely to be frequently required for the control of these autonomic functions. The effects of cerebellectomy are consequently more easily and rapidly compensated for. An autogenetic reflex inhibition is at work also in the regulation of the postural tonus (see Granit, 1955a), but the efficiency of the brain stem machinery is far less satisfactory, as shown by the extreme extensor spasticity that characterizes any decerebrate and decerebellate preparation. Hence the servomechanisms of the cerebellar anterior lobe, which are involved in the control of the postural extensor tonus, are likely to be always at work, under the impact of the afferent volleys arising in the overstretched proprioceptors. The effects of cerebellectomy will therefore be much more pronounced in the sphere of regulation of the postural tonus than in the sphere of neural control of the blood pressure or of respiration. Summing up, the intensity and continuity of the control exerted by the cerebellum on the different provinces which constitute its sphere of influence are probably determined by the spatial and temporal patterns of the incoming signals. From using the technique of evoked potentials we simply know what the response of the cerebellum is when a group of afferent fibers are synchronously activated by an electrical shock, but the traffic along the roads converging upon the cerebellar cortex is likely to be unevenly distributed. Here lies, we think, the main explanation of the marked discrepancy between the results of ablation experiments and those obtained by stimulation or electrophysiological methods. We come now to the second problem, that of the basic mechanisms involved in cerebellar control of the spinal cord, brain stem, and cerebrum. A distinction should be drawn between the control of the firing rate of individual neurons and the spatial and temporal coordination of their discharges. The rate of the unitary discharge is probably controlled through the usual mechanisms of facilitation and inhibition. Let us take as an example the influence exerted by the cerebellum on the units of the reticular formation and of Deiters' nuclei that are mainly related to the regulation of the postural tonus. Their spontaneous or driven discharges may be either increased or reduced (sometimes indeed they are blocked altogether) by stimulating the anterior lobe of the cerebellum (see pp. 219-229). Facilitatory or inhibitory effects on the postural extensor tonus are elicited from different areas of the anterior lobe (see pp. 113137) or from different portions of the fastigial nuclei (see pp. 80-86). In short, there is little doubt that the cerebellum is not exclusively concerned with exerting a strengthening influence on the muscle tonus, as surmised by Luciani

372 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM (1891), but is concerned rather with its precise regulation. The tonus of the antigravity muscles will be either increased or facilitated, depending upon the postural and motor problems the animal is confronted with in every moment of its life. The idea that the cerebellum might strive to maintain an "optimum" level of postural tonus had already been put forward by Bremer (19£2a, 1935), Rossi (1925), and van Rijnberk (1931). But the basic principle of Rolando's and Luciani's doctrine is still inherent in these modern views on cerebellar regulation of the postural tonus. The fundamental idea is that the cerebellum acts as an "energizer," keeping up a certain level of activity (Bremer's central tone) in the spinal cord, in the brain stem, and in the cerebrum. It would remain for extracerebellar mechanisms to modulate this background discharge according to the needs of the body. The over-all activity of the cerebellum would be simply the sum of the individual performances of its neurons, each acting similarly to the other. It may be interesting, from the point of view of the history of science, to point out how similar these concepts are to those which have been recently put forward to explain the tonic influence exerted on the cerebrum by the ascending reticular system. But this is certainly not the whole story. Such notions as "antigravity tonus" or "elementary voluntary movement," useful as they may be for simplifying our concepts, should not obscure the more complex reality. It is not enough to keep up a certain level of activity in the postural centers of the brain stem; the posture of the limbs and indeed of the whole body will be symmetrical only if the tonic contraction of homonymous muscles is the same on both sides of the body. Nor is it enough to provide that the elementary voluntary contraction of the agonist muscle be executed with the proper speed and strength. First of all, we know that any voluntary movement is conditioned by the precise coordination of several antagonist and synergic muscles. Second, any phasic activity starts from a posture and ends as a posture, and it often requires the tonic fixation of other joints. In short, even the simplest posture and the most elementary voluntary movement implies a proper coordination, in both space and time, of the discharges of a tremendous number of a and y neurons. If Rolando and Luciani may be regarded as laying the foundation for all concepts emphasizing the importance of cerebellar influence in the control of the individual discharge of the motor units, Flourens was certainly the first who called attention to the importance of a proper coordination of these individual discharges. Nobody, of course, would now support Flourens's statement that the coordination of movements is localized exclusively in the cerebellum. To say that the reciprocal innervation or the coordination of movements is still possible in the cerebellectomized animal, however, does not mean that the distribution in either space or time of the firing of the motor units or the coordination between the a and y discharges is normal in these conditions. We have seen (see pp. 311, 353) that even the simplest voluntary movements may be controlled by the cerebellum at spinal, brain stem, and cerebral levels, the activity of several areas of the cerebellum thus being involved. We know, moreover, that walking and running movements are conditioned by the coordination between the phasic activity of the muscles involved in the movement itself and by the postural activity of

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the muscles concerned with the fixation of other, more proximal, joints. Any cerebellar control would bring chaos instead of order into the execution of voluntary movement in the absence of a proper coordination of the discharges of the Purkinje cells which are involved in its supervision. It would be hard to understand, moreover, the immense wealth of afferent projections impinging upon the cerebellum if this structure were simply concerned with keeping up an "optimum" level of activity in the underlying nervous centers. We are brought in this way to the third and last of our problems, which concerns the intrinsic aspects of the organization of cerebellar activity. Intracerebellar relations have been surprisingly neglected. All we know about the structure of the cerebellar cortex, however, suggests that any firing of a group of Purkinje neurons is likely to drive or to inhibit the discharge of other cerebellar units. Interrelations may be affected also at the level of the cerebellar nuclei and of the brain stem, but the multiplicity of the afferent channels converging upon the same areas of the cerebellar cortex (see pp. 182-211) and the manifold variety of its synaptology suggest that it is mainly at the level of the Purkinje neurons that the spatial coordination of cerebellar control takes place. The simple anatomical consideration that in mammals the afferent fibers greatly outnumber the efferent ones, as well as the obvious disproportion between the mass occupied by the cerebellar cortex and the volume of the cerebellar nuclei, suggests that only a comparatively small amount of energy and a limited number of cerebellar neurons are devoted to transmitting information or to sending orders to other portions of the central nervous system. Much energy is probably spent in the preliminary but essential task of exchanging the pieces of information which reach the cerebellar cortex through multiple afferent pathways. We must concede that we know practically nothing about the events that take place between the arrival of the afferent signals and the response of the Purkinje neurons or the modulation of their discharge. Moreover, not every Purkinje cell projects, necessarily, onto the cerebellar nuclei. Some of them, and possibly all the Golgi type-I cells of the granular layer, are likely to give rise to association fibers connecting different areas of the cerebellum with each other. Together with the small nerve cells of the molecular and granular layers, they represent a huge mass of interneurons whose functions are yet completely unknown. Most of our unsolved problems, such as the mutual relations between the different aspects of cerebellar functions or the relation of the cerebellum to the autonomic and sensory spheres, might be understood if we could gather more information about these neglected aspects of cerebellar physiology. It is, therefore, with no apologies that in concluding this portion of our monograph we admit that we are unable to state precisely how the cerebellum performs its function. Yet we are by no means inclined to belittle the physiological significance of the results that have been gathered from the early eighties to our own times. Our aim is simply to point out the essential gaps in our present knowledge and thereby to stimulate further research. It was obviously extremely important to possess a refined analysis of the symptoms of cerebellar deficiency in the carnivores, in the subhuman primates, and in man, since posture and voluntary movements, we now know, are closely supervised by the cerebellum. But other aspects also of cerebellar function might

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PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

be unveiled if the effects of experimental or clinical lesions were analyzed by means of adequate physiological and psychological tests. The detailed information gathered during the last twenty years of intense and most fruitful electrophysiological investigation is likely to represent the foundation stone for all our future work. If we are now really in a position to delimit the "sphere of influence" of the cerebellum, it is the result of these experiments. A precise knowledge of the input and the output of any neural structure is a prerequisite for understanding its function. We are yet unable, however, to tell what is going on within the cerebellar cortex or the deep nuclei during the reflex standing, during the performance of a simple voluntary movement, or during any attempt to discriminate between two weights. Nor are we better informed about the functional significance of the visceral impulses impinging upon the cerebellar cortex or on the firing patterns of the Purkinje neurons which are possibly involved in any outburst of sham rage or during vasomotor and respiratory reflexes. We are thoroughly ignorant, moreover, about the interrelations likely to exist between the different cerebellar areas, the deep nuclei, or the neurons of a single nucleus. To realize how limited is our present knowledge is important, since we are in some danger of being deceived by our own terminology. Such words as "regulation," "control," or "supervision," useful as they may be in any attempt to give a tentative explanation of our results, may create the wrong impression that we know what is going on within the cerebellum. It is tempting to suggest that the cerebellum "regulates" the postural tonus or the motor activities of the cerebral cortex. It is only too easy to surmise that the firing rate of spinal, brain stem, or cerebral neurons is likely to be modulated by the cerebellum through the usual mechanisms of facilitation and inhibition. Though these hypotheses are likely to be true, and though they are substantiated, we have seen (pp. 219-232), by many experiments of microelectrode recording, the trouble is that the same explanations are suggested and about the same words are utilized whenever an attempt is made to account for the influence exerted by the reticular formation on the spinal cord or on the cerebrum. Moreover, the same reticular neurons which are inhibited or facilitated by cerebellar stimulation may be inhibited or facilitated as well by sensory or by corticofugal volleys. These simple considerations remind us that we are still far from understanding what characterizes the influence exerted by the cerebellum on other neural structures. Everyone feels that this mass of neurons is not merely a duplicate of the inferior olive, of the vestibular nuclei, or of the reticular formation. The main problem of cerebellar physiology is to learn how so many different functions are integrated within the framework of the cerebellar cortex or of the underlying deep nuclei. We want to know, for example, how the control of the a neurons is coordinated with that of the y units, how a voluntary movement may be controlled, simultaneously, at cortical, brain stem, and spinal levels, how the autonomic functions are correlated with those of the somatic nervous system. The prediction may be ventured that the unitary analysis of the neurons of the cerebellar cortex or of the deep nuclei will advance far more rapidly than will our knowledge of the integrative functions of this part of the central nervous system.

Part II Clinical Symptomatology and Pathology

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8 The Clinical Symptomatology of Cerebellar Disorders

A. Neurological abnormalities in cerebellar lesions and their relative frequency B. A classification of cerebellar symptoms on the basis of a functional division of the organ C. Disturbances resulting from involvement of the flocculonodular lobe (Archiocerebellar Syndrome) 1. Gait disturbance 2. Rotated posture of the head 3. Spontaneous nystagmus 4. Disturbance in station D. Disturbances resulting from involvement of the anterior lobe or the medial part of the corpus cerebelli (Paleocerebellar Syndrome) 1. Gait disturbance as seen in cortical cerebellar atrophy 2. Cerebellar catalepsy 3. Positive supporting reactions 4. Cerebellar seizures E. Symptoms resulting from involvement of the posterior lobe or the lateral parts of the corpus cerebelli (Neocerebellar Syndrome) 1. Reflex and postural disturbances a. Hypotonia b. Pendular knee jerk c. Static tremor d. Disturbance in station e. Past-pointing and spontaneous deviation of the limbs 2. Disturbances in voluntary movements a. Asthenia b. Delay in starting and stopping muscular contractions c. Disturbances in the rate of voluntary movements d. Disturbances in compound movements (1) Dysmetria (2) Adiadochokinesis (3) Speech disturbances (4) Disturbances in writing (5) Gait disturbances (6) Tremor of voluntary movement e. Loss of associated movements 377

379 380 381 381 382 383 384 385 385 386 386 386 386 388 388 388 389 390 390 390 390 390 392 392 392 392 394 394 395 395 395

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3. Symptoms of doubtful occurrence a. Proprioceptive loss (?) b. Anisothenia (?) c. Clinical evidence of vegetative function F. Clinical evidence for somatotopic localization in the cerebellum G. Special diagnostic tests useful in cerebellar disorders Summary

395 395 395 396 396 398 398

THE preceding portion of this book has been concerned with the cerebellum of animals as studied through ablation, stimulation, and electrophysiological experiments. This portion is devoted to the cerebellum as studied in the clinic. Some of the most significant facts about this part of the brain have come from clinicians who studied their patients carefully, and these data are of primary importance for an understanding of the function of the cerebellum in man. But anatomical and physiological observations are also of importance in the light that they may shed upon clinical observations that have thus far been obscure. While no pathological lesion limits itself to a selected area of the cerebellum as exactly as a well-executed cerebellar ablation does, there are three syndromes of cerebellar dysfunction that we believe can be separated on purely clinical grounds. These have been described under several different names. Symptoms and signs that are the result of injury or disease of the flocculonodular lobe were called the Archiocerebellar Syndrome by Bailey (1942, 1944) and Wyke (1947), and the Syndrome of the Vestibular Complex by Brown (1949). Those due to damage to the anterior lobe of the corpus cerebelli or, perhaps more properly, to the medial part of the corpus cerebelli were called the Paleocerebellar Syndrome by Bailey (1942, 1944) and Wyke (1947), a term that had earlier been applied by Bremer (1922a, 1985) to include the effects of damage to both areas (see above, p. 51). The most common syndrome of all in man is that resulting from lesions in the lateral parts of the corpus cerebelli, which in man are chiefly the posterior lobe of the corpus cerebelli; when unilateral, Brown (1949) called it the Syndrome of the Cerebellar Hemisphere, and Bremer (1922a, 1935), Bailey (1942, 1944), and Wyke (1947) designated it as the Neocerebellar Syndrome. While the corpus cerebelli can be divided morphologically into an anterior and a posterior lobe, there is considerable physiological evidence (amply presented in Part I of this monograph) that a division into medial, intermediate, and lateral parts may be of greater physiological significance. This concept has not as yet permeated the clinical literature, and when attempts have been made to correlate clinical entities to the anterior lobe of the corpus cerebelli, the authors have more specifically been speaking of the medial part of the corpus cerebelli, of which the anterior portion has been the more intensively studied to date. Likewise, the clinical descriptions of the "Neocerebellar Syndrome" or the "Syndrome of the Cerebellar Hemisphere," while these symptoms do result chiefly from damage to the posterior lobe of the corpus cerebelli, may actually prove to include symptoms which result from damage to the lateral and intermediate parts of the anterior lobe as well and probably do not include symptoms from damage

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to those parts of the posterior lobe which project to the fastigial nuclei. The three distinct clinical syndromes will be discussed separately after a brief review of the signs of cerebellar dysfunction as they are elicited in a routine neurological examination. A. NEUROLOGICAL ABNORMALITIES IN CEREBELLAR LESIONS AND THEIR RELATIVE FREQUENCY To review the historical development of the various tests that have been and are employed in the routine clinical examination of a patient with cerebellar disease will not be attempted here. The following references, each a major contribution of its author, should be consulted by those interested: Andre-Thomas, 1897, 1911; Babinski and Tournay, 1913; Bolk, 1906; Bremer, 1935; Brouwer and Biemond, 1938; Brun, 1925; Dusser de Barenne, 1923, 1937; Goldstein, 1927; Grant, Webster, and Weinberger, 1941; Grey, 1915a and b, 1916a, b, c; Holmes, 1917, 1922, 1939; Ingvar, 1918, 1923, 1928a, b; Keschner and Grossman, 1928; Luciani, 1891; Marburg, 1924, 1936; Mills and Weisenburg, 1914; van Rijnberk, 1908a, b, 1925b, 1931; Stewart and Holmes, 1904; Walshe, 1921; Weisenburg, 1927. Keschner and Grossman (1928) reported the neurological signs of cerebellar deficiency as they were observed in a series of 29 unselected cases of intracerebellar disease. In the order of their frequency these symptoms were: Number of Patients 1. Disturbance in gait 27 2. Ataxia of isolated movements of the upper extremity 25 3. Spontaneous nystagmus 23 4. Adiadochokinesis 21 5. Ataxia of the lower extremity 17 6. Abnormal head posture 16 7. Hypotonia 15 8. Disturbances in station 15 9. Past-pointing and spontaneous deviation of the limbs 9 10. Stewart-Holmes phenomenon 5 11. Dysmetria 7 12. Tremor 7 13. Cerebellar speech disturbance 5 14. Pendular knee jerk 4 3 15. "Cer 16. Cerebellar catalepsy 2 It is at once apparent that though such a list gives a clue to the likelihood of encountering a particular symptom of cerebellar deficiency in a given case, it tells nothing about the pathophysiology of cerebellar disease and does not in any way correlate the clinical findings with what has been learned about cerebellar physiology from the laboratory. To attempt to do this, we shall classify these symptoms, together with a few others thought to result from cerebellar lesions, according to the three functional divisions of the cerebellum which we believe to have clinical as well as other physiological importance.

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B. A CLASSIFICATION OF CEREBELLAR SYMPTOMS ON THE BASIS OF A FUNCTIONAL DIVISION OF THE ORGAN Some of the symptoms of cerebellar deficiency defy limitation to any one division of the cerebellum. The best example is the disturbance in gait. That this was the most commonly encountered symptom in the group of 29 patients with intracerebellar disease mentioned above is a significant observation. Gait may be disturbed as a part of the equilibratory dysfunction encountered in disorders involving the flocculonodular lobe; the disturbance may result from the loss of cerebellar control of the spinal and brain stem reflexes which are important for the maintenance of a standing posture when the anterior lobe is damaged; and finally the gait is affected by loss of the influence on the tone and voluntary movement of the lower extremities which is normally exerted by the posterior lobe of the corpus cerebelli. Gait disturbance is, therefore, a symptom which might well be expected to be the most commonly encountered in unselected cases representing all types of cerebellar diseases or injuries. Ataxia of isolated movements of the upper extremity is a common symptom in man. This term refers to the total of all the disturbances of movement seen following cerebellar lesions (see p. 23). Human beings have developed a motor control of the upper limb which is beyond that found in any lower animal. Many clinical tests of upper extremity dexterity will therefore pick up cerebellar deficiencies from early lesions, particularly when they involve the lateral portions of the corpus cerebelli. It is obvious from Table I that the syndrome of cerebellar deficiency in man is due primarily to the involvement of the posterior lobe, or perhaps more correctly the lateral parts of the whole corpus cerebelli. Table I. The Most Common Symptoms of Cerebellar Deficiency, Classified according to the Division of the Cerebellum Thought Primarily Responsible for the Symptom When Diseased or Damaged

Symptoms, in Order of Frequency 1. Disturbance in gait 2. Ataxia of isolated movements of upper extremity 3. Spontaneous nystagmus 4 Adiadochokinesis 5. Ataxia of lower extremity 6. Abnormal head posture 7. Hypotonia 8. Disturbance in station 9. Past-pointing and spontaneous deviation of the limbs 10. Stewart-Holmes phenomenon 11. Dysmetria 12. Tremor 13. Cerebellar speech disturbance 14. Pendular knee jerk 15. Cerebellar "fits" 16. Cerebellar catalepsy 17. Positive supporting reaction

Division of the Cerebellum Responsible for Symptom Anterior Lobe of Posterior Lobe of Corpus Cerebelli or Corpus Cerebelli or Flocculonodular Lateral Parts of Medial Part of Corpus Cerebelli Lobe Corpus Cerebelli x x x x x? x

x

X

x X

x

x

X X? X X X X X

X? X? X?

SYMPTOMATOLOGY OF CEREBELLAR DISORDERS

381

C. DISTURBANCES RESULTING FROM INVOLVEMENT OF THE FLOCCULONODULAR LOBE

1. GAIT DISTURBANCE The pathological condition which in man is most often seen to produce the syndrome of the flocculonodular lobe (Fulton and Dow, 1937), called the Archiocerebellar Syndrome by Bailey (1942, 1944) and Wyke (1947), is a midline cerebellar tumor, the medulloblastoma. This tumor most commonly occurs in children and arises from cell-rests in the posterior medullary velum at the base of the nodulus (Ostertag, 1936; Raaf and Kernohan, 1944). The pathological findings in these cases will be discussed in greater detail in a later chapter (p. 541). When neurological symptoms first appear, they are characterized by unsteadiness in balance without appreciable "ataxia" in the movements of individual extremities (Bailey, 1933, 1942; and others). It is common in clinical experience to see a child with a medulloblastoma walk and maintain balance very poorly and yet when recumbent, so that the position of the body in space is maintained, or when the body is well braced, fail to show any definite evidence of the usual signs of cerebellar deficiency in the arms, legs, or trunk. As Fulton and Dow (1937) stated: "It has long been taught in clinical neurology that the posterior vermis controls the trunk muscles and that when the posterior vermis is damaged the trunk muscles show 'ataxia.' This indeed is a curious form of reasoning, for careful analysis of these cases indicates that the equilibrium of the body as a whole is disturbed; we are dealing with a physiological function and not an anatomical part. The patient or the animal is not able to progress and any movements of the body through space precipitate the symptom. When the body as a whole is at rest, individual movements, especially of the hand, can be carried out without evidence of locomotor disturbance, the heel-to-knee test can be performed without tremor, etc. Only when the body is propelled through space are difficulties encountered. The symptom therefore is one of disturbed coordination of the body in space" (p. 111). Miller-Guerra (1954) emphasized the fact that not all medulloblastomas are located in the posterior vermis and that much of the dysequilibration exhibited is on the basis of involvement of the anterior lobe of the corpus cerebelli and the vestibular brain stem centers as well. With this one must agree, but the fact remains that the appearance of animals with lesions of the nodulus closely resembles the clinical state found in many patients with lesions which usually arise at this site. Other types of cerebellar tumors, vascular lesions, traumatic lesions and cerebellar atrophies usually do not selectively damage this area. In the literature a few isolated instances are found in which lesions of the flocculonodular lobe produced the forced movements of the whole body (Leri, 1916) which occur in animals following removal of the posterior vermis (p. 52). In Gordon Holmes's cases of war wounds of the cerebellum it is unlikely that this part of the brain was selectively injured, so that this syndrome will probably not have been covered by his analysis of cerebellar function, which will be discussed in detail below.

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2. ROTATED POSTURE OF THE HEAD While a rotated posture of the head as a sign of cerebellar disease has been the subject of considerable difference of opinion both as to its mechanism and clinical significance, it is true that it is not uncommonly seen in patients with cerebellar tumors (Fig. 147). Batten (1903) first discussed this subject when he described a case of tuberculoma of the right side of the cerebellum in which the head was rotated with the occiput directed to the left and also flexed so that the mastoid approached the left shoulder. Later Stewart and Holmes (1904) stated that this head position in patients with cerebellar tumors usually involved rotation of the occiput toward the lesion, and that it was not of diagnostic importance as it also occurred with tumors of the pons, midbrain, and forebrain. However, Grey (1916a) found in a comparative statistical study that in 60 patients with subtentorial new growths, 23, or 40 per cent, exhibited a rotated or tilted position of the head, whereas in a group of 43 patients with tumor above the tentorium, only 3, or 7 per cent, showed such an abnormal position of the head. Holmes (1917) at first considered rotation of the head a sign of acute cerebellar injury but later (1922) dismissed it as of no importance; in his most recent review (1939) he fails to mention this sign. Starr (1910) and Gushing (1917) both noted the head position with the occiput toward the side of the lesion, the reverse of Batten's original description, in patients with acoustic nerve tumors. Wilson

Figure 147A. A child with a tuberculoma of the right side of the cerebellum, showing a rotation of the head with the occiput to the left. Compare with Fig. 148^4. Figure 147B. A man with a rotated posture of the head with the occiput to the right, as a result of chronic nonsuppurative otitis interna on the right, with diminished hearing on the right of a perceptive type. Compare with Fig. 148B. (A from F. E. Batten, 1903, On the diagnostic value of the position of the head in cases of cerebellar disease, Brain 26:71-80, Fig. 1. B from W. R. Brain, 1926, On the rotated or "cerebellar" posture of the head, Brain, 49:61-76, Fig. 1.)

SYMPTOMATOLOGY OF CEREBELLAR DISORDERS 383 (1920) held that the sign was part of decerebrate rigidity and decided the lesion responsible for its appearance was in the mesencephalon. Horsley (1909) believed it was due to vestibular involvement. Brain (1926), who devoted a paper to this subject including a complete review of the literature up to that time, denied that the sign was ever due to cerebellar disease. He believed that in every case there was damage to either the eighth nerve, if rotation of the occiput was toward the side of the lesion, or to the brain stem, if the reverse was true. More recently clinical interest in this sign has been less evident. The only reference in recent years is the discussion of the Bruns Syndrome by Alpers and Yaskins (1944), to which syndrome they add the sign of head posturing; they state: "It is essential to recognize, however, that the degree of rotation or lateral flexion is never as great as in tumors of the cerebellar hemispheres or the cerebellopontine angle. The neck muscles are contracted firmly, the head being splinted so that head movement loses its normal freedom and the head moves en masse with the body" (p. 126). This type of head posturing, as well as that described by Stenvers (1925), therefore seems quite different from the rotated position of the head which may occur from purely cerebellar lesions in monkeys and which we believe to result from an asymmetrical involvement of the flocculonodular lobe. A comparison between the head postures in the primate after labyrinthectomy and after unilateral nodulus ablation was entirely consistent with this interpretation and may serve to clarify this clinical problem (Fig. 148). As pointed out in Part I (pp. 52-56, 90), an asymmetrical lesion of the flocculonodular lobe or the supramedullary portion of the juxtarestiform body, which severs the efferent fibers from the flocculonodular lobe, produces rotation of the head with the occiput to the opposite side, while a lesion of the labyrinth, the vestibular nerve, or the intramedullary portion of the juxtarestiform body produces a rotation of the head with the occiput toward the side of the lesion. With such widely divergent effects produced from damage to such closely related areas of the brain, it is not surprising that the direction of rotation would differ in individual clinical cases or might reverse itself as a pathological process advanced from one area to another. There is nothing in the clinical literature which corresponds to the demonstration by Bard, Woolsey, Snider, Mountcastle, and Bromiley (1947) that in the dog the nodulus is essential to the nervous mechanism responsible for motion sickness. 3. SPONTANEOUS NYSTAGMUS Horizontal nystagmus is seen transitorily after unilateral nodular ablation. It is horizontal but in the opposite direction to that seen in vestibular lesions. In experimental animals it is not seen following lesions of the corpus cerebelli (Botterell and Fulton, 1938a, b, c), though vertical nystagmus may be induced by certain head postures (Spiegel and Scala, 1941, 1942) after lesions of the posterior vermis. Nystagmus from acute cerebellar injuries to the cerebellum in man (Holmes, 1917, 1922) differs in many respects from that resulting from labyrinthine disorders. Like that seen from unilateral nodular lesions, its quick component is

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Figure 148A. A monkey after removal of the right half of the nodulus and lower part of the uvula, showing rotated position of head with occiput to the left. Compare with Fig. 1474. Figure 148B. A baboon after destruction of the right labyrinth. Note the rotation of the head with the occiput to the right. Compare with Fig. 147.B. (A from R. S. Dow, 1938, Effect of lesions in the vestibular part of the cerebellum in primates, Arch. Neurol. & Psychiat., 40:500-520, Fig. 45. B from R. S. Dow, 1938, The effects of unilateral and bilateral labyrinthectomy in monkey, baboon and chimpanzee, Am. J. Physiol., 121:392-399, Fig. 2o.)

toward the side of the lesion. The deviation is toward the side opposite the lesion. It is brought out by fixation and is slower and more irregular in its excursion than is true of labyrinthine nystagmus. Usually it is horizontal but rarely may be vertical. Compensation occurs rather readily, and with small and superficial lesions little nystagmus is noted. This may account for the infrequency of its being observed in slowly developing lesions. In many of the cases described by Keschner and Grossman (1928), who found it in 23 out of 29 patients, it was probably produced by extracerebellar involvement of the vestibular system, for even in this group of intracerebellar lesions, 24 showed pyramidal tract involvement and 19 supranuclear seventh nerve weakness. 4. DISTURBANCE IN STATION Disturbance in station is a tendency to fall to one side or the other or forward or backward when standing with the feet close together. Closing the eyes does not materially influence the tendency in cerebellar disease as it does in a positive Romberg test. The symptom may be due to involvement of any or all three of the principal functional divisions of the cerebellum. While the tendency usually is to fall toward the side of the lesion, this is not invariable. There may be another mechanism which causes the more unusual falling away from the side of

SYMPTOMATOLOGY OF CEREBELLAR DISORDERS 385 the lesion, since in experimental cortical lesions of one side of the nodulus and in lesions of the medial portion of the anterior lobe of the corpus cerebelli, the animal may fall toward the normal side. D. DISTURBANCES RESULTING FROM INVOLVEMENT OF THE ANTERIOR LOBE OR THE MEDIAL PART OF THE CORPUS CEREBELLI

1. GAIT DISTURBANCE AS SEEN IN CORTICAL CEREBELLAR ATROPHY The clinical manifestations of lesions restricted to the anterior lobe of the corpus cerebelli in man are less well known than those of lesions of the posterior lobe or the flocculonodular lobe. While a great deal of investigative work has been done on the physiology of the anterior lobe of the cerebellum, the cases in which destructive processes have been limited to this area in men are very rare. There must be significant differences in the function of the anterior lobe as one goes from subprimate to primate and to man, especially with respect to the large lateral outgrowths of the human culmen known by the B.N.A. terminology as the pars anterior of the lobulus quadrangularis (lobule H IV of Larsell). Though we believe, therefore, from some clinical evidence, that a different symptomatology results from injury to the anterior and the posterior lobes of the corpus cerebelli respectively, it is true that in man these differences appear only with respect to isolated symptoms such as hypotonia. The symptomatology of this part of the cerebellum has been discussed by Bailey (1942) as the Paleocerebellar Syndrome and by Brown (1949) as the Syndrome of the Anterior Lobe. Each of these authors describes a cerebellar tumor in this area. Another patient in whom a tumor was found in this area is described by Kononova (1925). In this instance there must have been severe compression of the brain stem, as evidenced by cranial nerve involvement. The patient described by Bailey appears to have had the most circumscribed lesion, but the symptomatology which might have been expected from an isolated lesion here was not actually found. Brown (1949), in discussing a group of cerebellar syndromes, gives a brief resume of a case of anterior lobe tumor, though the exact limitations of the growth are not given in morphological terms. He says: "The syndrome of the anterior lobe consists of disturbed postural reflexes and walking synergies. These patients walk with a wide base and stagger or deviate to both sides. The gait tends to be stiff-legged due to exaggerated positive supporting reaction. On occasion it is possible to demonstrate an extensor thrust reflex." The clinical condition which affects the anterior lobe with greatest frequency is the cerebellar atrophy classically described by Marie, Foix, and Alajouanine (1922) as "1'atrophie cerebelleuse tardive a predominance corticale." This form of cerebellar atrophy, discussed in detail in later chapters, is most marked in the anterior lobe. While there is no strict limitation to this lobe, the atrophy is sufficiently limited to produce a symptomatology which we believe illustrates that of the anterior lobe of the corpus cerebelli. The authors cited above emphasize the differences found between patients with such atrophy and those in which the lateral expansion of the posterior lobe (hemisphere) is the site of maximal involvement. In a postscript to their original paper they recognize the relationship be-

386 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM tween their clinical observations and the classical physiological studies on the anterior lobe (paleocerebellum) by Bremer (also published in 1922). In their excellent description of this disease, Marie, Foix, and Alajouanine emphasize that the patient shows a marked disturbance of gait with very mild cerebellar disturbance of the upper extremities, and that hypotonia is absent (Fig. 149). They also note the absence of nystagmus, some trembling of the head and neck, and some manifestations of cerebellar catalepsy (Babinski, 1902b). An absence of the pendular reflex is a characteristic feature, even though the disorder produced more pronounced effects on the legs than on the arms. The outstanding symptom was a disturbance in the legs which made walking impossible. 2. CEREBELLAR CATALEPSY Cerebellar catalepsy is an abnormality first described by Babinski (1902b) and is brought out by having the patient, lying on his back, flex his lower extremities at both hip and knee. The lower extremities are lifted from the bed and the feet are separated. Oscillations of the trunk and limbs occur at first, but later they become abnormally fixed. This is a relatively rare sign in cerebellar diseases and is seldom looked for in routine examinations. The physiological basis is obscure. 3. POSITIVE SUPPORTING REACTIONS Rademaker (1931) claims to have demonstrated exaggerated positive supporting reactions in man in cases of cerebellar disease. Schwab (1927), however, was unable to demonstrate them in cerebellar disease. As pointed out by Bailey (1942), they should be searched for in cases of suspected anterior lobe involvement. They are elicited easily in decerebellate dogs (see p. 30) and in man at times are observable as an increase in tone resulting from a passive stretching of the antigravity muscles. 4. CEREBELLAR SEIZURES Attacks of tetanus-like opisthotonos occur in the terminal stages of midline cerebellar tumors. While the release of anterior lobe inhibitory mechanisms may be a factor in their production, they are now generally regarded as being an acute manifestation of decerebrate rigidity or functional decortication and do not occur unless brain stem as well as cerebellar involvement is present. (For a more detailed analysis, see Chapter 10.) E. SYMPTOMS RESULTING FROM INVOLVEMENT OF THE POSTERIOR LOBE OR THE LATERAL PARTS OF THE CORPUS CEREBELLI The posterior lobe of the mammalian cerebellum reaches its greatest size and complexity in man, owing to the increased size in him of the corticopontocerebellar connections. Wounds of the cerebellum, if they involve the flocculonodular lobe or the medial part of the corpus cerebelli, would in most instances be fatal. The study of a series of cases which survived gunshot wounds would, for the most part, be an analysis of the function of the posterior lobe. As has been pointed out, total ablations in subprimate forms are in many respects not to be compared with the effects of wounds of the cerebellum in man, in which the

Figure 149. Typical gait disturbance seen in a case of late cerebellar atrophy. (From I. Rossi, 1907, Atrophie primitive parenchymateuse du cervelet a localisation corticale, Nouv. iconog. de la Salpetriere, #0:66-83.)

387

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lesions will chiefly involve the posterior lobe or the lateral parts of the corpus cerebelli. Only since ablation experiments have been performed involving this part of the cerebellum in the chimpanzee have the striking differences between species been generally appreciated. In our discussion of the clinical symptomatology of the posterior lobe of the corpus cerebelli, it seems desirable to adhere to the description furnished by Gordon Holmes (1917, 1922, 1927, 1939) in his classical studies of injuries of the cerebellum. Not only is his description the clearest which has ever been presented, but it conforms to our own experience in the examination of patients suffering from disease or injury of this dominant part of the cerebellum in man. This syndrome has been termed the Neocerebellar Syndrome (Bremer, 1935; Botterell and Fulton, 1936; Fulton and Dow, 1937; and Bailey, 1942, 1944).

a. HYPOTONIA

1. REFLEX AND POSTURAL DISTURBANCES

Cerebellar lesions of the posterior lobe produce first a loss or diminution of muscle tone. This term has been previously defined (p. 23). In unilateral lesions, which are best suited for an analysis of deficiencies of this type, hypotonia involves the homolateral extremities and, in some degree, also the trunk. It diminishes as the weeks pass after acute injuries but can persist for many months or years. Loss of tone may be demonstrated by many methods. The arms may be held vertically and the hands allowed to fall loosely. On the affected side the hand falls passively into a position of greater flexion than on the normal side (Fig. 150A). A limb showing hypotonia from such a lesion will show a greater range of motion when shaken passively after grasping it either near the body or at the hand or foot. Also, if the arms are held outstretched and gently tapped, the affected arm moves in decidedly wider excursions. In early and severe cases definite flabbiness can be palpated, and the muscles will allow greater stretch without discomfort, a circumstance accounting, in Holmes's opinion, for the disordered positions in which many of these patients allow the limb to rest. There is deficient muscular elasticity, so that frequently the heel can be pressed tightly against the buttock without the usual sensation of strain when this is done by passive flexion of the hip and knee (Fig. 150J5). The onset of hypotonia occurs almost immediately after the injury but increases to some degree in the course of a week to ten days. Pendular reflexes are a clinical manifestation of hypotonia. Holmes believes that static tremor and the rebound phenomenon, first described by Stewart and Holmes (1904), are also manifestations of hypotonia. b. PENDULAR KNEE JERK

The pendular knee jerk is due to hypotonia and the lack of contraction in the antagonists to the prime movers in this reflex and to a loss of the myotatic appendage normally observed. As a result the extremity goes through several pendulum-like oscillations after the reflex is elicited. Wartenberg (1951) has pointed out that the same phenomenon may be more readily demonstrated if the patient sits on the edge of a table with the limbs hanging freely and they are simply lifted to a horizontal position and suddenly released. The involved extremity will swing to a greater degree than the normal one.

SYMPTOMATOLOGY OF CEREBELLAR DISORDERS

889

Figure 150. Cerebellar hypotonia. A. Demonstrated by holding the forearms vertically; the left flexes more than the right under the influence of gravity. Extensive injury to the left side of the cerebellum one week previously. Compare with Fig. 14, from Rossi, showing tonic asymmetry in the dog. B. Demonstrated by passive flexion of the affected limb ten weeks after severe injury to the right half of the cerebellum. (From G. Holmes, 1917, The symptoms of acute cerebellar injuries due to gunshot injuries, Brain, 40:461-535, Figs. 1 and 2.) C. STATIC TREMOR

Hypotonia and poor fixation of the proximal segments of the extremity play a role in static tremor. Static tremors and chorea-like states are sometimes associated with lesions of the dentate nucleus and its efferent pathways in the brain

390 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM stem. The myoclonias may be in some way related to cerebellar disturbances (p. 413), but are not usually regarded as a sign of cerebellar deficiency. d. DISTURBANCE IN STATION

This symptom has been discussed above (p. 384) under disturbances resulting from involvement of the flocculonodular lobe. It may also result, however, from posterior lobe involvement, and this may be its usual cause in man. C. PAST-POINTING AND SPONTANEOUS DEVIATION OF THE LIMBS

This abnormality is demonstrated by having the patient, with his eyes closed, repeatedly attempt to touch the examiner's hand from a position above the head. In cerebellar disorders the arms tend to deviate, usually outward. This same tendency can be seen if the patient is asked to hold the extremities in front of the trunk in a horizontal position with the eyes closed. The cause of this abnormality is obscure. 2. DISTURBANCES IN VOLUNTARY MOVEMENTS Most of the terms which are customarily employed to designate cerebellar deficit in man can best be analyzed under the general heading of disturbances in voluntary movements. These include the so-called cerebellar asynergia, cerebellar ataxia and cerebellar incoordination, dysmetria, hypermetria, and adiadochokinesis. Holmes (1917, 1922, 1939) describes these disturbances in voluntary movements by first analyzing the disturbances which can be observed in simple movements involving only one joint and in a single direction. a. ASTHENIA One of the disturbances in voluntary movements which cannot be explained simply by a lack of tone is muscular weakness, or asthenia. Holmes prefers the term asthenia to 'paresis. The weakness is subjective and the patient occasionally describes the limb as simply "more useless," a description indicating the peculiar character of this loss of strength. If the arm is tested by having the patient set his muscles and the examiner attempt to displace the limb, the weakness cannot easily be detected. That weakness is present seems clear from the dynamometric readings taken in these cases (see Table II). The muscles have half to two-thirds the strength of the normal side in the upper extremity, but considerably less difference could be shown in the lower extremity. With this asthenia goes an easy fatigability, which may be striking. The contraction is not only weak but irregular in force. This irregularity can be detected if the patient is asked to grasp the examiner's hand; instead of being steady in its pressure, the grip is discontinuous. Holmes identifies this clinically demonstrable defect in muscular contraction with Luciani's astasia. It can be readily demonstrated graphically when a patient is asked to flex the forearm slowly against the resistance of a spring. b. DELAY IN STARTING AND STOPPING MUSCULAR CONTRACTIONS

There is a readily discernible delay in starting any movement. This disturbance is easily demonstrable by graphic methods (Fig. 151).

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391

Table II. The Averages of Several Dynamometric Measurements Obtained from Two Patients with Gunshot Wounds of One Side of the Cerebellum (from G. Holmes, 1939, The cerebellum of man, Brain, 6£:1-30, p. 8.)

Grasp Flexion of elbow Extension of elbow Supination Pronation Depression of arm . . . Flexion of ankle Extension of ankle Depression of leg

Case 1 (thirty days) Unaffected Affected Side (R) Side (L) ..124 5.8 26.2 15.3 11.8 5.2 10 5.2 20 14.5 17

15

Case 2 (sixty-eight days) Unaffected Affected Side (L) Side (R) 10 17 7 10 4.6 7

10.4 12.5 18 10.5

6.5 10.5 15 9

There is also a slowness in stopping the movement which frequently results in hypermetria. That this is not due to lack of tone in the antagonists is demonstrated by the fact that the symptom still occurs even with movements against resistance. There is a delay in their reaching the full extent of contraction and of relaxation which is also clearly demonstrable graphically. Though Holmes (1922) attributes the Stewart-Holmes phenomenon to hypotonia, it seems to be principally a defect in voluntary movement and to be related to the delays in starting and stopping muscular contractions. It is brought out by having the patient pull against the resistance of the examiner, who suddenly releases his hold. In cere-

Figure 151. From a case of injury to the right lateral lobe of moderate severity, ten days after the injury. Record to demonstrate graphically the delays in starting and stopping muscular contraction. The patient was asked to grasp simultaneously with his two hands against two springs of equal strength. 1 and 1' represent the simultaneous ordinates; A and A', the lines traced on a rapidly revolving drum. The drum was allowed to complete one revolution and a signal to relax was then given; 2 and 2' represent the simultaneous ordinates, and B and B' the tracings of relaxation. Time by tuning fork of 128 vibrations per second. (From G. Holmes, 1917, The symptoms of acute cerebellar injuries due to gunshot injuries, Brain, 40:461-535, Fig. 3, and G. Holmes, 1939, The cerebellum of man, Brain, 62:1-30, Fig. 4.)

392 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM bellar disease the patient is unable to change quickly the pattern of contraction and may frequently strike himself before he can halt the flexion. The so-called rhythmic stabilization test described by Kabat (1955) he believes to be an important clinical test in the identification of cerebellar deficiencies, especially when they are combined with corticospinal lesions. This procedure consists of having the patient hold a limb rigid by co-contraction of the antagonists while the examiner applies resistance rhythmically and alternately in an attempt to move the joint. It is probable that this defect is related to the delay in starting and stopping a muscular contraction. C. DISTURBANCES IN THE RATE OF VOLUNTARY MOVEMENTS

One can also note, particularly with the use of a flashing light on photographic films, disorders in the rate of movements, at times too slow, at other times abnormally rapid, particularly when the movement is unopposed by gravity. d. DISTURBANCES IN COMPOUND MOVEMENTS

(1) Dysmetria When a movement requires muscle action at two or more joints, the disorders demonstrable in cerebellar dysfunction in the simple one-joint movements, which are described above, are compounded. Such movements are the finger-to-nose and heel-to-knee tests commonly employed in routine examinations. Each component part shows its own errors of force and rate of movement, and when fused the components fail to occur in smooth succession. These errors "combine as it were in geometric progression so that the error of the whole movement is relatively greater than the sum of those of its parts." As a result there occurs the phenomenon of decomposition of movement. In a compound movement, such as touching the nose with the finger from a position above the head, the patient may drop the arm before the forearm is completely flexed. Part of this decomposition is attributed to lack of proper fixation of the proximal joints, the result of hypotonia, but most of it is due to disorders in the rate, regularity, and force of the individual parts of the compound movement. When a movement requires a change in direction, the difficulties show a further geometric progression (Fig. 152). As a result, the clinical tests demonstrate dysmetria or, in the case of the finger-to-nose test, a failure accurately to touch the finger to the nose. The finger may overshoot its goal, hypermetria, or fail to reach it, hypometria. (2) Adiadochokinesis This sign, first described by Babinski (1902a), is a disturbance in the patient's ability to perform rapid alternate movements. It is usually demonstrated by having the patient supinate and pronate the forearms and slap the palms and then the dorsum of the hands on the knees. As the movement gains speed, differences between the normal and the affected extremity become more and more apparent (Fig. 153). The affected limb moves more and more irregularly, and the arm deviates widely from its normal position. Finally, the affected extremity becomes entirely unable to keep up with the normal extremity. A further elaboration of this test is the disturbance present in cerebellar

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393

Figure 152. Records obtained by photographing points of light attached to the tips of the forefingers. A patient with a lesion of the left side of the cerebellum was asked to outline the square of a room with each upper extremity in succession. Each flash of light represents the distance covered by the moving finger in 0.04 seconds. Note the irregular distance between the points of light, indicating lack of uniformity of speed of the movement, and the compounded disturbance when there is a change in the direction of the movement. (From G. Holmes, 1939, The cerebellum of man, Brain, 62:1-30, Fig. 13.)

Figure 153. A. Tracing of alternating pronation and supination of the normal (above) and the ataxic arm of a patient with a right-sided lesion of the cerebellum. Time in seconds. B. The same with the movements done more rapidly, showing the greater contrast between the normal (below) and the affected side (above). (From G. Holmes, 1939, The cerebellum of man, Brain, 62:1-30, Figs. 14 and 16.)

disease which has been described by Wertham (1929) as arrhythmokinesis. Here, instead of being asked to perform alternate movements as rapidly as possible, the patient is asked to tap out a definite rhythmic pattern of varying complexity with the uninvolved extremity, the involved one, and with both sides simultaneously. The disturbance in his ability to follow accurately a rhythmic pattern can best be observed by making a graphic record of the sequence of the taps on moving paper. Allowance must be made for individual variation in ability to sense and execute a particular rhythm.

394 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM This author believes that disturbances in this sphere are distinct from adiadochokinesis and that arrhythmokinesis is more specific for a cerebellar disorder, being absent in Parkinsonism and spastic states in which the rate but not the rhythm of the alternate movements is impaired. He also found that when the tapping was done simultaneously with the involved and uninvolved sides, the ability was improved in the cases of Parkinsonism but actually aggravated in the cerebellar cases. An electromyographic analysis of arrhythmokinesis (Wertham and Lyman, 1926) showed that there was an "irregularity in amplitude of action currents, their continuation long after the mechanical movement has apparently stopped, and considerable lack of synchronous relations between flexor and extensor action currents." (3) Speech Disturbances Speech is affected early in patients with severe unilateral lesions but clears rather rapidly. Holmes (1917) describes the speech disturbance as follows: "Speech is abnormal in most cases in which the lesions are recent and severe; it is usually slow, drawling and monotonous, but at the same time tends to be staccato and scanning. This gives it an almost typical 'singsong' character and makes it indistinct and often difficult to understand. In a few patients speech was in fact quite unintelligible for a time. In many cases the utterance is remarkably irregular and jerky, and many syllables, especially, as Marie has pointed out, of those that end a sentence, tend to be explosive. "Phonation is as a rule more affected than articulation, though both vowels and consonants are slurred and uttered unequally and irregularly. All classes of consonants, too, are affected but articulation sometimes has a special nasal character and the labials particularly tend to be explosive. "Another striking feature is the apparent effort necessary to utter a series of syllables or a sentence; the attempt is associated with excessive facial grimacing and speech has consequently a laboured character that often recalls a pseudobulbar paresis" (p. 505). Bonhoeffer (1908) and Ottonello (1941, 1943) have written on the character of the speech disturbance in cerebellar diseases, and Hiller (1929) has studied the disturbance in Friedreich's ataxia. Hiller has emphasized the influence of poor coordination of respiration and has demonstrated this graphically. Zentay (1937) has classified the disturbances in speech seen in cerebellar disorders as follows: (a) ataxic speech, in which articulation, respiration, and phonation may each be interfered with in varying degrees; (b) adiadochokinesis of speech, which he feels expresses itself in the slowness characteristic of the cerebellar speech disturbance; (c) explosive-hesitant speech, which he feels is due to a disturbance in the "inhibitory or braking" function of the cerebellum; and (d) scanning speech, in which there is a stretching of syllables, which are also sharply cut off from one another. (4) Disturbances in Writing Irregularities in compound movements can be demonstrated by means of handwriting, in which the affected part shows graphically the disturbances in rate, force, and rhythm noted above.

SYMPTOMATOLOGY OF CEREBELLAR DISORDERS 395 (5) Gait Disturbances Holmes remarks that the difficulties encountered in walking, consisting of a tendency to deviate and fall to the side of the lesion, were in all his cases secondary to the defective control of the affected leg. In these patients balance was often surprisingly well maintained considering the defect in the compound movements of the leg. This is in striking distinction to the flocculonodular syndrome, as described above. (6) Tremor of Voluntary Movement Tremor in cerebellar disease does not occur at rest. During movement or at the termination of a movement, it is the result of the same factors which have been described before plus the conscious effort to correct the abnormality on the part of the patient. C. LOSS OF ASSOCIATED MOVEMENTS

Loss of some of the associated movements, such as swinging of the arms in walking, was noted. Holmes feels this is a separate deficiency, distinct from the other defects described above. Its basis is obscure. 3. SYMPTOMS or DOUBTFUL OCCURRENCE a. PROPRIOCEPTIVE LOSS (?)

Defects in the patient's ability to detect minor differences in weights has been noted by some clinical observers and denied by others. This disability, plus the well-known tendency for the involved limbs to be maintained in awkward positions and for the experimental animal to walk on the dorsum of the foot at times, has led some workers to believe that the cerebellum may be involved in the mechanism underlying proprioceptive sensation (see p. 42). Holmes (1917, 1922), on the other hand, though he admits that equal weights when tested on an involved and on a normal limb are uniformly felt by patients to be heavier on the involved side, attributes this to asthenia and states categorically that even in such cases the patient is still able to detect small differences in weights tested in the involved hand and that there are no clinically detectable disturbances in any modality of the sensation in cerebellar deficiency. He says: "All the evidence available from the careful investigation of sensibility in cases of cerebellar lesions in man, in whom alone it can be properly tested, shows conclusively that this organ is not concerned in the transmission, or in any modification or elaboration of these afferent impulses which give rise to conscious sensations" (1917, p. 514). b. ANISOTHENIA (?)

Andre-Thomas (1911) described as a cerebellar symptom a lack of balance between groups of muscles so far as their tone was concerned. It was on the basis of this theory that the deviations and centers for different movements described by Barany (1912b) were explained. Holmes (1922), however, states he has never found such a condition to exist, and inasmuch as the proposal of Barany for

396 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM cerebellar localization is now discarded by all clinicians, this symptom need not be given further consideration. C. CLINICAL EVIDENCE OF VEGETATIVE FUNCTION

An extensive review of the clinical literature on the cerebellum has failed to disclose any good evidence of vegetative function in the cerebellum obtained from the study of diseases of this part of the brain in man. In the purely speculative stage of ideas about its function, from Thomas Willis (1664) on, there was much written about its role in the regulation of vital functions. Experimental studies during the last twenty years, as discussed in the chapters of Part I, have indicated a possible role as a regulator of some autonomic reflex activities of the brain stem. For a review of the clinical evidence for a cerebellar control of vegetative function, the reader is referred to Wiggers (1943a, b, c). F. CLINICAL EVIDENCE FOR SOMATOTOPIC LOCALIZATION IN THE CEREBELLUM There is general agreement that there is a homolateral relation between the lateral portions of the cerebellum and the corresponding extremities. Holmes (1927) stated in conclusion: "No local lesion affects only or exclusively one limb or portion of a limb" (p. 388). Opposed to this point of view have been a great number of other workers who, following Bolk's comparative studies (1906), have attempted to locate specific topographical regions or parts of the body in specific areas or subdivisions of the cerebellum (see below, pp. 50-73). Both animal experiments and clinical pathological studies (Ingvar, 1928b; and others) were used in support of the general ideas of functional localization suggested by Bolk's studies. Some workers went so far as to claim that specific movements had their special location in the subdivisions of the areas selected to represent the various parts of the body and used experimental data in support of Barany's method (1912b, 1924) for localizing cerebellar lesions, which consisted of alterations in the particular direction of the deviation of the arms in response to his tests for labyrinthine function. Weisenburg (1927), one of the clinical neurologists who believed in this localization, has described his parcellation of the cerebellum as follows: "There is a functional localization in the cerebellum. In the vermis are represented the synergistic activities of the trunk; in the superior vermis the movements of the shoulder girdle or the upper trunk; in the inferior vermis the pelvic girdle or the lower trunk. Synergistic activities concerned in talking and movements of the eyes are located in the vermis, in all probability the superior vermis. Synergistic control of the limbs is in the lateral hemispheres, for the upper limbs in the superior portion, for the lower in the inferior" (p. 376). During the past ten years there has been a resurgence of support for the concept of topographical localization in the cerebellum. However, this new pattern bears little resemblance to the schemata proposed during the earlier period. It seems quite obvious that ablation experiments based upon this new evidence for topographical localization, which are the experiments which simulate most closely the effects of injury and disease of the cerebellum in man, will have to be repeated if this new information is to be correlated with what is observed

SYMPTOMATOLOGY OF CEREBELLAR DISORDERS 397 by the clinician who examines a patient with cerebellar disease. Snider (1950) has recognized the difficulties here. Although it may be possible to demonstrate by ablation experiments cerebellar disturbances confined to the parts assigned to specific lobules by these newer anatomical studies (see p. 185), it is not likely that this would occur in pathological processes as they are found clinically. It must be recognized that folia related to a particular part of the body have been found in three different areas, one contralateral and the others homolateral, but in the anterior and posterior lobes. No conceivable pathological process could be expected to destroy all three of these areas and fail at the same time to affect other areas thought to be responsible for the cerebellar control of the movements of the other parts of the body. It should also be emphasized, so far as any inferences that may be drawn from these electrophysiological data in terms of cerebellar function are concerned, that these facts are essentially anatomical facts. They have been determined, to be sure, by physiologists, and by methods technically different from those used by the older anatomists. Nevertheless, to draw conclusions about the function of these connections is as dangerous now as to come to physiological conclusions on the basis of comparative anatomical or any other type of anatomical information in the nervous system has proved to be in the past. That this new information derived from electrophysiological studies calls for anatomical verification and further physiological and clinical pathological studies goes without saying. Experimental work demonstrating the widespread interrelations that exist between specific localities within the cerebellum conforms better to what has been learned about it from a study of its diseases in man than do studies designed to isolate topographical areas within the three major divisions which do have, as we have indicated, a clinical as well as an anatomical and physiological basis. The clinical neurologist can still contribute to a knowledge of the physiology of the cerebellum by the study of patients with cerebellar disorders. If he is to make a contribution which will give clinical significance to the new information, he must study his patients with more intensity than is customary in the usual clinical examination. Possibly, with the advance in electronic instruments, techniques can be developed which will throw more light on the disorders following cerebellar damage. Electromyographic and electroencephalographic techniques, with a few exceptions, have not been applied to the study of cerebellar diseases in man. A more general use of the graphic methods so successfully used by Holmes would also be worth while. In view of the projection onto the cerebellum of afferent connections which may be activated by auditory and visual stimulation, perhaps the type of intensive study by a team of specially trained investigators, such as the combined work of neurologist and psychologist in the illuminating work in the cerebral cortex by Bender and his associates, might be of value in the study of cerebellar disease. The fact will always remain incontestable that the best place to study the cerebellum of man is man, and such study is possible only to the neurologist alert to grasp his unique opportunity in his daily contact with cerebellar dysfunction in man.

398 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM G. SPECIAL DIAGNOSTIC TESTS USEFUL IN CEREBELLAR DISORDERS Special procedures have been used to assist in the diagnosis of cerebellar disorders for many years. One of the first to be applied was the labyrinthine tests of Barany (1912b, 1924). While these are still widely used and are of great value in the diagnosis of labyrinthine and eighth-nerve difficulties, they have been abandoned by many neurologists and neurosurgeons in the diagnosis of intrinsic cerebellar disease. In the opinion of these neurologists the results originally claimed for the tests have not proved consistent enough for routine clinical use. Grey (1916b) and many others found the results to be misleading and ambiguous, often leading to false interpretations. An evaluation of these procedures in a large series of cases has been made by Brunner (1924), Grant and Fisher (1926), Kobrak (1930), Grahe (1932), Maybaum and Gossman (1935), Shuster (1936), Coates, Shuster, and Slotkin (1936), Nylen (1939), and others. These workers have shown that while there are exceptions, usually when the results of the tests are correlated with the actual pathology observed, a differentiation between supra- and infratentorial lesions is found to be possible to approximately the same degree of accuracy as in localizing cerebral lesions with the electroencephalogram. Lesions in the cerebellopontine angle can be identified with even greater accuracy. Since neither electroencephalography nor arteriography, two special methods of investigation presently in vogue in the localization of intracranial pathological process, is well adapted to investigate the posterior fossa, it is possible that these tests should be used more frequently than they are in the study of cerebellar disorders. Caloric stimulation is the method of choice for the purpose of investigating these responses and has quite largely supplanted rotation tests and galvanic stimulation. Other procedures, such as clinical electroencephalography, pneumoencephalography, ventriculography, and arteriography, each of which may be employed to some advantage in specific pathological processes, will be discussed in the appropriate sections in later chapters. SUMMARY An attempt to organize the various symptoms and signs of cerebellar dysfunction in relation to the three functional divisions of the cerebellum has been made. Some, such as disturbances of gait, are affected severely from lesions in all three divisions, the flocculonodular, the anterior, and the posterior lobes of the corpus cerebelli. Others, such as ataxia of voluntary movement of the upper extremity, are probably chiefly or exclusively disturbances resulting from lesions of the posterior lobe or the lateral parts of the corpus cerebelli. Each symptom and sign can be classified as to the mechanism of its production. In man defects in the rate, range, and force of voluntary movements play a predominant role in cerebellar dysfunction. It is through the careful clinical investigations of Gordon Holmes that these symptoms can be best understood. Further extension of his graphic methods and the employment of newer techniques of investigation will be necessary if the newer laboratory data about the cerebellum are to have clinical application.

9

The "Cerebellar" Symptomatology of Extracerebellar Lesions

A. Lesions below the tentorium oerebelli 1. Acoustic neurinomas and pontine gliomas 2. Lesions of the inferior cerebellar peduncle 3. Lesions of the superior cerebellar peduncle 4. Lesions within the fourth ventricle B. Lesions above the tentorium 1. Suprasellar lesions 2. Lesions of the cerebral cortex a. Frontal ataxia b. "Cerebellar" signs from parietal, temporal, and occipital lesions Summary

399 399 400 401 402 403 403 404 404 406 406

A. LESIONS BELOW THE TENTORIUM CEREBELLI 1. ACOUSTIC NEURINOMAS AND PONTINE GLIOMAS There is no essential difference between the disorders of muscular movement that result from lesions of the cerebellar peduncles and those that result from damage to the cerebellum proper. This also applies to involvement of these tracts within the brain stem. Clinically the differentiation between intracerebellar and extracerebellar lesions is made on the basis of the chronological sequence in the development of the total clinical picture. If the lesion is in the brain stem, the early development of signs resulting from the involvement of the corticospinal tracts, the ascending sensory pathways, and the cranial nerves is the feature distinguishing it from an intracerebellar lesion. If the pathology is in the cerebellopontine angle, it is the early appearance of deafness and vestibular abnormalities and other cranial nerve palsies rather than any peculiarity of the cerebellar signs that allows one to make the correct clinical diagnosis. Keschner and Grossman (1928), in their tabulation of the symptoms and signs encountered in cerebellar disease, also recorded vestibular signs and evidences of 399

400 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM cranial nerve involvement. In addition to the 29 cases of intracerebellar lesions, they studied 13 pontine angle tumors and 6 brain stem gliomas. They found disturbances of gait, cerebellar ataxia of the extremities, and adiadochokinesis to be the most frequent cerebellar symptoms in all three groups. The lower extremity was more frequently ataxic than the upper extremity in the group with pontine lesions, whereas the reverse was true in the other two groups. Spontaneous nystagmus, while it occurred in 23 out of 29 patients in the intracerebellar group, occurred in all the cases of cerebellopontine angle tumors and in 5 of the 6 cases of brain stem lesions. Cranial nerve involvement was significantly more frequent in the group with extracerebellar lesions, but all cranial nerves except the olfactory were occasionally involved in the intracerebellar group. Once increased intracranial pressure becomes marked, however, it is well recognized that olfactory loss may also occur. Pyramidal tract signs were about as frequent in one group as in another. Headaches, vomiting, vertigo, and dimness of vision were common symptoms in all the groups. Keschner and Grossman concluded: "Diagnosis must be made, not on the nature and distribution of the cerebellar symptoms, but oh their association with other symptoms due to involvement of the pons and medulla, and on the history and chronological appearance of each symptom." Alpers and Yaskin (1939), as well as others, noted that in pontine gliomas cerebellar signs and long-tract motor signs were very frequent and cranial nerve involvement was universal. Only 1 of the 11 patients in their series had an involvement of the ascending sensory pathways, an unusual finding, however, for, as the authors point out, most series analyzed have shown such sensory long-tract involvement in about half the cases. Except for brain stem tumors, all expanding lesions of the posterior fossa are characterized by an early obstruction of the circulation of the cerebrospinal fluid, which results in many remote neurological findings. Such findings may include almost any symptom or sign capable also of being produced by direct involvement of supratentorial structures. A knowledge of these false localizing signs, which may be produced by increased intracranial pressure, is of utmost importance in the evaluation of any expanding intracranial lesion. 2. LESIONS OF THE INFERIOR CEREBELLAR PEDUNCLE While thrombosis of the posterior cerebellar artery is a fairly common occurrence, the signs of cerebellar involvement may be minimal unless the softening involves the restiform body. The symptoms and signs resulting from this lesion are cerebellar ataxia of the extremities on the side of the lesion, falling to the side of the lesion, marked nystagmus with the quick component toward the opposite side, and marked vertigo with vomiting. There is a disturbance of cutaneous sensation involving the face on the same side, as a result of damage to the spinal fifth nucleus, and there is also a loss of the sense of pain and of temperature on the opposite side of the body from the cervical level down, as a result of interruption of the lateral spinothalamic tract. There may be difficulties with swallowing and phonation, owing to involvement of the nucleus ambiguus, and very occasionally weakness of the tongue on the side of the lesion. There may be hemiplegia, to a greater or lesser degree, on the opposite side, owing to involvement of the corticospinal tract before its decussation. When this occurs it is indicative of involve-

SYMPTOMATOLOGY OF EXTRACEREBELLAR LESIONS 401 ment of the vertebral artery. Myosis and narrowing of the palpebral fissure (partial Horner's syndrome) is also seen. As the distribution of the artery is very variable, the individual patient frequently exhibits only a part of the full syndrome. Here, as in other extracerebellar lesions, the diagnosis rests upon the symptoms produced by the involvement of neighboring structures, for the cerebellar symptomatology is the same in every case. There are many reports of lesions here, and they will be discussed in greater detail in a later chapter (pp. 511-514). A rather unusual lesion in this region is that described by Guillain, Alajouanine, Bertrand, and Garcin (1929), of a patient who had a softening practically limited to the middle and inferior peduncles, without the usual involvement of other brain stem tracts and nuclei. This lesion, which completely severed these two afferent pathways to the cerebellum on one side, resulted in comparatively few symptoms shortly after the vascular accident in 1925. The patient showed only a slight ataxia in the homolateral arm plus peripheral facial paralysis and a minimal sixth nerve weakness, both on the same side. There was a pendular reflex on the same side of the lesion, but he was able to walk without difficulty, and there were none of the severe equilibratory difficulties usually seen. However, instead of showing improvement after the initial insult, the patient suffered a progressive increase in his symptoms of cerebellar deficiency during a period of two years. At the end of this period he could hardly walk, needed support at all times, and tended to fall to the right. This progression of symptomatology is similar to the findings of Turner and German (1941), who also noted increasing symptoms in monkeys after section of the middle cerebellar peduncle. Both groups of authors would attribute the progression of symptomatology to a progressive degeneration of cellular elements of the cerebellum in a transneuronic fashion. 3. LESIONS or THE SUPERIOR CEREBELLAR PEDUNCLE The most frequent cause of a lesion of the superior cerebellar peduncle is an occlusion of the superior cerebellar artery or its branches. The syndrome resulting from this vascular disorder has been described by many authors and will be discussed later (pp. 514-517). The symptoms of cerebellar deficiency consist of homolateral hypotonia of the arm and leg, marked cerebellar ataxia, with all the disorders of voluntary movement discussed in the preceding chapter. These include asthenia and disorders in the rate, range, and speed of muscular contractions. There is always severe difficulty in walking, and when the ability is regained, the homolateral lower extremity is placed uncertainly and in abduction. Though improvement continues for several months, compensation is never complete. In some cases there is damage to the adjacent cerebellar cortex, but in one of the cases of Davison, Goodhart, and Savitsky (1935) and in one of those of Luhan and Pollock (1953), the lesion damaged the brachium conjunctivum exclusively in the brain stem. In the resulting cerebellar signs and symptoms, however, no essential differences were apparent. As with other extracerebellar lesions which cause cerebellar ataxia, the location of the lesion is determined by the signs produced by the involvement of

402 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM neighboring structures and not by any peculiarity of cerebellar deficiency. In occlusions of the superior cerebellar artery, the associated findings include a loss of the sensation of pain and temperature over the contralateral one half of the body including the head. At times, owing to variation in the collateral circulation, this involvement may be very minimal, and in one case resulted in paresthesia and spontaneous pain (Girard, Bonamour, Garde, and Etienne, 1950). There is frequently a homolateral Horner's syndrome. Loss of hearing contralateral to the lesion is occasionally found. A loss of emotional facial expression on the contralateral side with a preservation of voluntary facial movement has been described. In a few patients fourth and sixth nerve paralysis has been noted, the former being contralateral, owing to nuclear involvement. Nystagmus also has been noted in a few patients when the median longitudinal fasciculus is involved in the lesion. One patient in whom the damage was predominantly in the brain stem showed a palatal myoclonus. Hemichorea and other hyperkinetic syndromes may be associated with lesions of this efferent pathway. Biirgi (1943a and b, 1945, 1950), on the basis of stimulation experiments, believes that these may be the effects of an irritation of these pathways rather than of their destruction. The mechanism for the production of these hyperkinetic phenomena is unknown. Why only a relatively few of the patients with such lesions develop such symptoms remains a mystery. Some clinical and pathological studies point to a connection between the superior cerebellar peduncle or the dentate nucleus and various hyperkinetic syndromes of unusual type—those of Bonhoeifer (1897), Muratow (1899), Bremme (1919), Leiri (1923), Tsiminakis (1933), Guillain, Bertrand, and Lereboullet (1934), Dow and van Bogaert (1938), and others. Birnbaum (1941) described two cases of chronic progressive chorea with cerebellar cortical atrophy. Wohlfart and Hook (1951) have emphasized the clinical similarity of myoclonic epilepsy (Unverricht-Lundborg), myoclonic cerebellar dyssynergia (Hunt), and hepatolenticular degeneration (Wilson). 4. LESIONS WITHIN THE FOURTH VENTRICLE When a lesion involves the fourth ventricle, particularly an expanding lesion such as a cyst or tumor, a group of symptoms may result called the Bruns syndrome. The original description of Bruns (1902, 1906) involved a freely movable cysticercus cyst within the fourth ventricle. Bruns attributed the symptom to mechanical obstruction from this movable structure, but as an identical symptomatology can occur with fixed lesions, the mechanism does not now seem so simple. The syndrome as originally defined was the occurrence of periodic attacks of violent vertigo, vomiting, and headache, precipitated by movement of the head, with complete freedom from symptoms between attacks. To these subjective symptoms Alpers and Yaskin (1944) have added an objective sign, an abnormal head posture in which the head is held rigidly in anterior flexion and at times slightly rotated and laterally flexed but not to the degree seen in cerebellar lesions. In addition to headache, vomiting, and vertigo some patients report disturb-

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ances of vision, either amauroses or flashes of light, tachycardia, irregularity of respiration, and even syncope with apnea. Originally this syndrome was thought to be characteristic only of cysticercus cysts, as all the early reports concerned such cases: Bruns (1902, 1906), Osterwald (1906), Henneberg (1906), and Stern (1907). Later, Gordon (1908), Stenvers (1925), Davis and Gushing (1925), van Bogaert and Martin (1928) all found an identical syndrome with a variety of lesions, mostly tumors, which involved the fourth ventricle. Weisenburg (1910) and Dandy (1933, 1934) reported similar subjective symptoms from intraventricular tumors in the lateral and third ventricles, but there the objective sign of head posturing was significantly lacking. Not all the lesions are neoplastic or surgical, as Alpers and Yaskin (1944) report one instance in which a diagnosis of multiple sclerosis was made because of other findings. During a subsequent remission the patient showed a clearing of this syndrome. Alpers and Yaskin feel that the mechanical theory originally proposed by Bruns (1902) and supported by Oppenheim (1923) and van Bogaert and Martin (1928) will not explain the presence of the symptoms in the cases of fixed tumors. Dandy (1933, 1934) speculated that changes in the blood supply of the tumors were responsible for the transient disturbances which are set off by changes in the position of the head. Alpers and Yaskin (1944) suggest, on the basis of microscopic changes in the vestibular nuclei noted upon pathological examination of two of their cases, that the episodes were due to some central vestibular derangement, the attacks being due to mechanical stimulation of the central pathways when the head moved. The experimental observations of Spiegel and Scala (1941, 1942) suggest that after lesions in this area, movements of the head may reflexly precipitate a vertiginous episode. This explanation, however, will hardly account for the severe headache which is an accompaniment of the attacks in many of the patients. In conclusion, the Bruns syndrome consists of two subjective components, attacks of vertigo and vomiting, headache, and visual disturbances produced by movement of the head, together with freedom from these symptoms between attacks. As defined by Alpers and Yaskin, the syndrome has a third, objective component, consisting of a posturing of the head, which is fixed as if splinted, usually in anterior flexion, and which the patient has a marked disinclination to move. The syndrome occurs chiefly with tumors and cysts of the fourth ventricle, many of which may arise from the cerebellum. It may occur with intra ventricular tumors in the third and lateral ventricle, but here the head posturing is not seen. While tumors of the cerebellum may involve the fourth ventricle and vice versa, the cerebellum itself is not involved in the pathogenesis of this symptom complex. B. LESIONS ABOVE THE TENTORIUM 1. SlJPRASELLAR LESIONS

Bailey (1924a) has discussed cerebellar symptoms in suprasellar tumors and feels that the main source of difficulty in differentiating these lesions is the equilibratory disturbances each may cause. Cerebellar symptoms may result from a direct extension of the tumor into the posterior fossa or from increased intracranial pressure. While tumors of the cerebral hemispheres may easily be differen-

404 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM tiated from cerebellar tumors by ventriculography, differentiation may be quite difficult at times in cases of suprasellar lesions (Peterson and Baker, 1941). One still must depend on a careful history of the chronological development of the symptomatology. With suprasellar lesions visual disturbances, such as bitemporal hemianopsia and primary optic atrophy, and evidence of hypogonodal function, come first. Equilibratory signs and disorders of voluntary movement appear later. If the tumor is a craniopharyngioma, suprasellar calcification will be present in 85 per cent of the cases, and when present is of great diagnostic significance. With cerebellar lesions, while symptoms of pituitary dysfunction, visual disturbances, and destruction of the sella turcica may appear, these manifestations are due to pressure from a dilated third ventricle and appear late in the chronological development of the total clinical picture.

2. LESIONS OF THE CEREBRAL CORTEX a. FRONTAL ATAXIA

The problem of frontal ataxia has been the object of considerable investigation and a great deal of clinical pathological study during the past sixty years. This work has been concerned (a) with a demonstration that lesions of the cerebrum and particularly of the frontal lobe can be confused with cerebellar disorders, (b) with the clinical differential features, and (c) with the mechanism of the difficulty. Bruns (1908) first called attention to an ataxia, somewhat similar to that found in cerebellar disorders, which occurred in 4 patients with tumors of the frontal lobe. Taking advantage of the knowledge of "crossed cerebrocerebellar atrophy," which had been described much earlier, and what knowledge there was at the time concerning the connections between the cerebrum and the cerebellum, he considered the cerebellar symptom complex which he saw in his patients to be some interference with this nervous mechanism. With the development of neurosurgery in the years following, the matter assumed considerable practical importance, and it was not uncommon for the neurosurgeon to explore the posterior fossa expecting to find a cerebellar tumor only to discover, frequently at the autopsy, that the patient actually had a cerebral neoplasm, usually frontal in location. In clinical material as carefully studied as that of Gushing, there were £7 instances of posterior fossa exploration for supratentorial tumors among the first 575 posterior fossa explorations in his series (Grant, 1928). There are many other isolated case reports of similar mistakes. This had a very real importance, for in the Gushing material reported by Grant there was an operative mortality of 50 per cent among patients explored for a posterior fossa lesion who actually had a supratentorial tumor, whereas in posterior fossa explorations the operative mortality was 12 per cent when the correct preoperative diagnosis had been made. While the preoperative diagnosis is now frequently assisted by ventriculograms, electroencephalograms, and arteriograms, even these are at times interpreted with difficulty, and the clinical findings still remain of great importance. Clinical symptoms and signs which are recorded, some with surprising frequency, in cases of frontal lobe tumors include nystagmus, unsteadiness in posture

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and gait with a positive Romberg test, Babinski's trunkal asynergia, hypermetria, hypotonia, and dysdiadochokinesis. There were some who attributed these manifestations entirely to the presence of increased intracranial pressure. Among those who took this view were Ikutaro (1927), Vincent (1911, 1928), Grant (1928), and others. On the other hand, Gordon (1917, 1934), Riggs (1929), Hare (1931), Frazier (1936), Ferrero (1948), and others attributed the findings to involvement of the nervous mechanisms in the frontal lobe and particularly the frontopontocerebellar system. Hare (1931) presented a series of 50 patients with frontal lobe tumors of which 5 had such fairly definite cerebellar signs that the diagnosis of cerebellar tumor was seriously considered, and in almost every instance there was involvement of both hemispheres. He concluded that it was the bilaterality of the lesions that was responsible for the production of cerebellar signs. Frazier (1936), however, in analyzing 105 patients with frontal lobe tumors found a high percentage of "cerebellar" symptoms and signs. Out of the 105, 24 had staggering gait, 23 a positive Romberg test, 20 dyssynergia, 17 dysdiadochokinesis, 11 dysmetria, and 9 nystagmus. Of 15 instances of meningiomata located over the superior lateral surface of the brain, in 13 there was ataxia as compared to only 1 out of 21 instances of similar tumors arising from the sphenoidal ridge. He concluded that not only was ataxia frequent with tumors of the frontal lobe, but it was most apt to occur not with a central lesion but with one located just anterior to the precentral motor area. Some authors, particularly Gordon (1917, 1934) and Engerth and Hoff (1930), presented definite criteria for differentiating the two conditions and for determining whether the "cerebellar" signs were due to a cerebellar or a cerebral lesion. Gordon used what he called "dissociated phenomena," claiming that with the frontal lobe lesions some of the signs were contralateral to others, and that they never could be fitted into one or the other cerebellar hemispheral syndrome. Engerth and Hoff (1930) claimed that if patients were observed walking on all fours, they could be differentiated, for the patient with frontal lobe ataxia could progress in this fashion while the patient with cerebellar disease could not. Most felt, as did Keschner and Grossman (1928), that the differentiation could not be made at the bedside, and as a result neurosurgeons have come to depend more and more on roentgenographic methods of diagnosis. Observations that after compensation from cerebellar injury cortical ablation on the opposite side caused a return of symptoms (Luciani, 1891; Aring and Fulton, 1936) were used to support the hypothesis of a neurological mechanism for frontal ataxia as opposed to a simple pressure mechanism. These experimental observations, however, are more applicable, as pointed out by Demole (1927), to clinical observations of cases of congenital cerebellar lesions in which there were no symptoms until a later acquired cerebral cortical lesion produced cerebellar signs. Those who hold that nervous mechanisms are responsible for the false localizing cerebellar signs have cited in support of their position such experimental studies as those of Delmas-Marsalet in dogs (1932), who found that animals show circling movements and other disturbances thought to be equilibratory in nature after frontal lesions. Kennard and Ectors (1938) quite adequately demonstrated,

406 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM however, that these symptoms are related to area 8 (Brodmann) and are concerned with visual rather than with cerebellar or vestibular systems. It would seem that Brun (1932) is correct in his position that there are two syndromes. One is severe in type, is bilateral from its onset, and appears in the terminal stages of frontal lobe tumors. It is due to massive pressure in the anterior posterior direction on the posterior cranial fossa. The other type of frontal ataxia appears early, is unilateral and often contralateral, and results from involvement, according to Brun, of the frontopontine pathways. While nervous mechanisms may play a role in some instances of frontal ataxia, to attribute it exclusively to one afferent pathway is difficult to harmonize with the observation of Meyers (1951) that complete surgical section of the frontopontine tract does not result in any appreciable motor or coordination deficit, and of Andre-Thomas, Martel, and Guillaume (1936), who describe a patient having complete posttraumatic ablation of one frontal lobe without demonstrating any sign of frontal ataxia. Smyth (1941) attributes these cerebellar signs in cases of frontal ataxia not to an involvement of the afferent connections to the cerebellum but to a retrograde transneuronic degeneration of the dentate nucleus itself. In addition to 4 personally observed cases of frontal lobe lesions, 3 tumors and 1 tuberculoma, which resulted in pathological changes in the contralateral dentate nucleus, he cites the observations of Bertrand and Smith (1933), Demole (1927), and Kononova (1912) in support of this point of view. b. "CEREBELLAR" SIGNS FROM PARIETAL, TEMPORAL, AND OCCIPITAL LESIONS While much more has been written about the effects of frontal lobe lesions on cerebellar symptomatology, cerebral tumors in other lobes have also been associated with disorders which appear to be cerebellar. Bruns (1909), Rothmann (1914), Meyers (1928), Gordon (1935), and Thiebaut (1948) have all described such cases. Ayers, in the discussion of Meyers' paper in 1928, certainly voiced the more usual and expected situation when he reminded the speaker that in his experience with cases of otogenic brain abscesses the presence or absence of cerebellar symptomatology was the essential differentia in deciding whether the site was the posterior fossa or the temporal lobe. He remarked that he had never seen a temporal lobe abscess which showed any cerebellar-like symptoms. It was recognized by Gushing and many others that careful examinations of the visual field were of great importance in differentiating these lesions from those which are in the posterior fossa. Possibly the reason these lesions have not attracted so much attention as those in the frontal area is that the differential diagnosis was easier because of this clinical observation. The mechanism in these cases is usually considered to be due to pressure on the cerebellum or its efferent pathways either at the foramen magnum or, probably more frequently, at the tentorial level, where herniation may frequently occur. SUMMARY Disease processes outside the cerebellum proper may give rise to symptoms and signs which are indistinguishable from those due to disease or injury to the cerebellum proper. Such may be the case with lesions of the pontine angle, the

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pons, and the inferior and superior cerebellar peduncles. In these instances, while the lesion is extracerebellar, the symptomatology is due to the damage to connecting pathways to or from the cerebellum. The differentiation is based entirely on the character of the concomitant involvement of brain stem structures and on the order of their development as compared with the cerebellar deficiency symptoms. The fact that supratentorial lesions, quite remote from the cerebellum, may give rise to symptoms and signs resembling those of cerebellar deficiency is discussed. Evidence pointing to a nervous mechanism for frontal ataxia is presented, even though in many instances the increased intracranial pressure is the offending agent, producing cerebellar signs by direct pressure on the cerebellum or its peduncles.

10

Convulsive and Hyperkinetic Disorders of the Cerebellum

A. Jackson's "cerebellar fits" 408

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B. Cerebellar coma C. The cerebellum and myoclonic epilepsy D. Palatal myoclonus Summary

411 411 413 415

A. JACKSON'S "CEREBELLAR FITS" Convulsive seizures in association with cerebellar lesions have been rather infrequently referred to in the literature. Fulton in 1929 published a translation of the earliest report on record, written by Wurffbain in 1691. The attack of head retraction and opisthotonos described is very similar to the attacks subsequently described by Stephen Mackenzie and published by Hughlings Jackson in 1906, now commonly called "cerebellar fits" (Fig. 154). Jackson's report is as follows (p. 429): "Sometimes but not always, the seizure was preceded by a loud cry. There was no twitching of the face nor any special deviation of the eyeballs. His hands were clenched; his forearms were flexed on the upper arms, which were generally kept to the sides. The head was drawn back and the back was curved. His legs were always extended to the fullest possible degree, the feet being arched backwards. Sometimes he passed urine and faeces in the attack. The seizures generally lasted 3 or 4 minutes, and when passing off, they returned if he moved about." These attacks were associated with a persistent posture, which resembled the position of the body during the seizure, though with less violent head retraction and rigidity, and which Jackson called the "cerebellar attitude." Cerebellar seizures were described by Stewart and Holmes (1904). These were observed in a nine-year-old boy operated on for a large tumor on the under surface of the vermis. In this case the asymmetrical nature and the reciprocal effects seen in the direction of the rotation of the homolateral and contralateral limbs are somewhat similar to the type of seizures described by Clark (1939b) in cats 408

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Figure 154. An outline drawing of a child with a midline cerebellar tumor, showing the tetanus-like seizure described by Jackson and now commonly known as the "cerebellar fit." (From J. H. Jackson, 1906, Case of tumor of the middle lobe of the cerebellum—cerebellar paralysis with rigidity (cerebellar attitude—occasional tetanus-like seizures, Brain, 59:425-440, Fig. 1.)

with superficial lesions of the cerebellar cortex (Fig. 155). Stewart and Holmes (1904) state: "Summarizing from these descriptions it will be seen that each fit consisted of rotation of the head, trunk and limbs on the longitudinal axes from the side of the lesion to the healthy side and deviation of the eyes in the same direction. The homolateral limbs were also adducted, and the contralateral abducted. There were no clonic movements at any stage of the many seizures observed. Their onset was abrupt, but the relaxation of the spasm gradual. In many of the fits the tonic spasm was greatest in the muscles of the trunk and in all of them it was more pronounced in the homolateral limbs than in the opposite. "We have also had the opportunity of observing a few seizures which affected

Figure 155. Microscopic section of a small abscess which developed beneath the electrode on the posterior vermis of the cat in which the seizures were described. The right margin of the picture is the posterior wall of the primary fissure. (From S. L. Clark, 1939, Motor seizures accompanying small cerebellar lesions in cats, J. Comp. Neurol., 7^:41-57, Fig. 5.)

410 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM the trunk and limbs in an exactly similar manner in the case of a girl where a large tumour infiltrated the pons and one lateral lobe of the cerebellum" (p. 545). Stewart and Holmes (1904) have also described a different type of attack: "A few of our patients have given accounts of jerking movements of the homolateral arm, often associated with attacks of vertigo. In one case of extracerebellar tumor (No. 18) in which such involuntary movements were observed, they preceded the vertigo and consisted of an isolated jerk, or a short series of jerks, of a sudden shock-like character of any part of the homolateral arm, lasting over a period of two to three minutes. The movements were irregular in distribution and sequence, and according to the patient occasionally affected the contralateral arm simultaneously, but always in slighter degree" (p. 545). Dana (1905) has discussed "cerebellar seizures," but the attacks he describes appear to have been severe labyrinthine vertigo with falling. MacRobert and Feinier (1921) analyzed 45 cases of cerebellar tumors in one of which a tonic spasm similar to that published by Hughlings Jackson was observed. Four cases showed at some time or other homolateral rigidity of an extremity with irregular jerking movements. Many others since have described these tonic fits, and they are known to occur in a wide variety of clinical conditions not all cerebellar by any means. Wilson (1920), Walshe (1922, 1923a), and others believe these attacks to be the result of transient vascular insufficiency in the brain stem and therefore a transient decerebration. Webster and Weinberger (1940) in their review of convulsive disorders occurring in association with tumors of the cerebellum express the opinion that these tonic seizures are the result of transient functional decortication rather than decerebration. They attributed this to "temporary cortical ischemia resulting from transient alterations in intracranial pressure." Not all seizures which occur in association with cerebellar tumors are of this variety. These authors, in a survey of 34 instances of seizures in 158 cases of cerebellar tumor, found 7 segmental clonic, 3 generalized clonic, 11 generalized tonic, and 13 syncopal attacks. Any of these attacks could occur during any part of the clinical course of the disease and, as had been pointed out by Collier (1904), once increased intracranial pressure is present, such seizures have no localizing value. The tonic seizures which were seen usually were not of the classical "cerebellar fit" variety, but consisted for the most part of bizarre atypical tonic seizures which in some instances somewhat resembled hysterical attacks. There was no significant correlation between the location of the tumor and the type of seizure or the occurrence of the seizure. Neither did the age or sex of the patient or the type of tumor seem to be related to the seizures. The only factor of apparent relevance was the increased intracranial pressure. Lazell (1938) has described a case of status epilepticus of cerebellar type occurring in insulin shock treatment. Here we have no evidence that the process which he observed had its source in the cerebellum, although the attacks bore some resemblance to the tonic spasms of Hughlings Jackson. The best opportunity to investigate this problem, it appears, would be to extend Pool's observations (1943) on the effect of electrical stimulation of the human cerebellum in unanesthetized patients, recording both the subjective and

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objective results. This method has proved of great value in the understanding of cerebral epilepsy in the hands of Penfield and his associates, but it has never been attempted in a systematic way on the cerebellum. B. CEREBELLAR COMA Gordon (1938), under the title "cerebellar coma," described two patients who suggested to Clark (1939a) that "cerebellar coma" might be the clinical counterpart of what he had observed in unanesthetized cats following electrical stimulation (see p. 139). Gordon's patients had a cerebellar lesion and had "sudden unconsciousness, which would last about 10 to 15 minutes. They would occur without aura or any other motor phenomena. The eyes would be closed. Upon awakening the patient presented no sign of special fatigue, somnolence or drowsiness." Both patients died in one of their comatose attacks. In one, a superficial cerebellar abscess was found, and in the other, a local vascular lesion. While these peculiar attacks do not seem to us to resemble in any sense the cerebellar motor seizures produced in cats by electrical or mechanical stimulation, their periodicity and brief duration are suggestive of some kind of akinetic seizure. However, the fact that in each case death occurred in an attack suggests some more profound disturbance than any type of epileptic phenomenon. The psychodynamic mechanism offered by Gordon as a possible explanation for these peculiar episodes does not seem plausible. To speculate further on the nature and mechanisms of this condition of so-called "cerebellar coma" seems useless. C. THE CEREBELLUM AND MYOCLONIC EPILEPSY The relation between cerebellar lesions and myoclonic epilepsy should also be considered. The clinical and pathological studies of Hodskins and Yakovlev (1930) showed that in a neurological survey of 300 patients with epilepsy 83 per cent yielded either pyramidal, extrapyramidal, or cerebellar manifestations, or a combination of these. While only 10 per cent of the patients with evidence of organic neurological disease had evidences of cerebellar disease, two thirds of this 10 per cent had a myoclonic form of epilepsy, whereas this type of epilepsy was found in only 15 per cent of the whole group of 300 chronic epileptics. Conversely, when all the 45 patients who had myoclonic seizures were analyzed for evidences of cerebellar deficiency, it was found that about 1 in 3 had such symptoms as compared with only 1 in 12 for the whole group. The signs of cerebellar deficiency which they found were disturbances in the rate, range, and force of muscular contraction, with intention tremor, ataxia of individual extremities, nystagmus, adiadochokinesis, etc. The cases ranged in severity from those presenting a fullblown Ramsey-Hunt syndrome of dyssynergia-cerebellaris-myoclonica to those with relatively minor evidence of cerebellar deficiency. Hodskins and Yakovlev pointed out that Hammond (1867), one of the first to describe the symptom of myoclonus, suspected, because of the incoordination he saw in his patient, that the condition was related to a cerebellar disease. About fifty years later Hunt (1914) described the syndrome which bears his name and which he called "dyssynergia-cerebellaris-myoclonica." He found in patients with this syndrome a striking association of myoclonus and the symp-

412 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM toms of cerebellar deficiency. A histological examination of the brain of one such case (Hunt, 1921) showed a marked atrophy of the dentate nucleus, the remainder of the cerebellum apparently being quite normal. This patient also yielded clinical and pathological findings characteristic of Friedreich's ataxia. Hodskins and Yakovlev (1930) also made a systematic review of the pathological findings in 18 cases of myoclonic epilepsy which had been described in the literature up to that time and which had been fairly extensively analyzed from the standpoint of histopathological changes in the nervous system. These included the patients of Volland (1911), Lafora and Glueck (1911), Sioli (1913), Jacquin and Marchand (1913), Hanel and Bielschowski (1915), Westphal and Sioli (1920), Frigerio (1922), Bellavitis (1923), Schou (1925), Ostertag (1925a), Catalano (1926), Liebers (1927), Hunt (1921), Pilotti (1921), and Precechtel (1927). While the histological study was not always complete, it was noted that in 12 adequately studied cases there was a lesion in the dentate nucleus or its efferent pathway, the brachium conjunctivum. In those cases where, in addition to the myoclonic attacks there had also been severe tonic clonic convulsions, there were also neurological symptoms and pathological findings indicating damage to the extrapyramidal system. Some authors have linked myoclonus to changes in the inferior olive. In the case described by Precechtel (1927) some changes were noted in the olivary nuclei, the arcuate nuclei, and the flocculus, as well as in the dentate nucleus. His patient was thought to have hypoplasia of these structures. A number of clinical contributions are reviewed by Roge and Farfor (1938). These authors state that because of the rarity of the syndrome and the diversity of its manifestations, they question the advisability of regarding the RamseyHunt syndrome as a clinical and pathological entity. Louis-Bar and van Bogaert (1947) have described a case in point which, in addition to extensive degenerative changes in the spinal cord and medulla, showed severe cell loss and gliosis of all the deep cerebellar nuclei. These authors state that while degeneration in these areas is not uncommon in all forms of hereditary spinal ataxia, myoclonic epilepsy of the Ramsey-Hunt type is never seen except in association with some atrophy of the nucleus dentatus. Greenfield (1954) states that in his experience cases of myoclonic epilepsy may have extensive loss of Purkinje cells without any lesion of the dentate, and in other cases basophilic inclusions of the Lafora type have been found predominantly in the dentate nucleus. Christophe and Remond (1951) found the spike and wave pattern characteristic of the myoclonic epilepsies in a case of dyssynergia-cerebellaris of RamseyHunt; the patient had been so diagnosed and under observation for many years. Lennox and Robinson (1951), on the assumption that the cingulate gyrus is concerned with the brain stem mechanism which on stimulation may produce the spike and wave pattern, found that they could produce an afterdischarge in the cerebellum on stimulation of the cingulate gyrus. Btirgi (1943a and b, 1945), on experimental and clinical grounds, contends that it is the irritative quality of certain lesions of the dentate system which is responsible for the so-called chorea of the superior cerebellar peduncle. It is conceivable that this represents a more or less continuous form of a myoclonic disorder occurring unilaterally. Up to now no electroencephalographic studies have been reported on these peculiar hyperkinetic

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disturbances which are at times associated with damage to the superior cerebellar peduncle, and which have been discussed in a preceding chapter (p. 402). D. PALATAL MYOCLONUS Rhythmic myoclonus of the palate, pharynx, larynx, etc., has been described for many years. Although most credit Spencer (1886) or Oppenheim and Siemerling (1885) with being the first to describe this condition, Guillain and Mollaret (1932) state that Kiipper gave a precise description of the syndrome in 1873. It was first called nystagmus of the palate, but this term is not commonly used now. The number of reported cases is now over a hundred, but the nervous mechanism responsible is still unknown. The movements of the palate may be unilateral or bilateral; they are rapid, rhythmic, single twitch-like movements which vary in rate from about 100 to 150 per minute. In addition to the palate, they may involve the extraocular muscles, the facial muscles, the larynx, the pharynx, the diaphragm, the neck, and even at times the upper extremity and very rarely other muscles. When the muscles around the auditory tube are involved, there may be a sound which may bring the patient to the physician. The movements are not stopped by sleep. There is no interference with speaking, chewing, or swallowing; in fact, voluntary movement seems to inhibit myoclonic twitches. It was not until the pathological studies of Klein (1919), Foix and Hillemand (1924), Foix, Chavany, and Hillemand (1926), and van Bogaert (1926) that it was definitely recognized that the inferior olive was concerned in this symptom complex; Other important contributions to this subject were made by Gallet (1927), van Bogaert and Bertrand (1928), Leshin and Stone (1931), Guillain and Mollaret (1931, 1932, 1935), Garcin, Bertrand, and Frumason (1933), Riley and Brock (1933), Freeman (1933), Guillain, Thurel, and Bertrand (1933a, b), Alajouanine, Thurel, and Hornet (1935), Lhermitte, Levy, and Trelles (1933, 1935), Davison, Riley, and Brock (1936), de Savitsch and Ley (1937), Guillain (1938), Nicolesco, Sager, and Hornet (1938), Kreindler (1939), Dobson and Riley (1941), Jacobson and Gorman (1949), Bender, Nathanson, and Gordon (1952), Erickson and Ablin (1953), Nathanson (1956), and others. In the majority of the cases the vascular lesion is in the central tegmental tract, with the olivary changes being interpreted as a transneuronic effect. The condition may also result from a lesion near the hilus of the opposite dentate nucleus, in which case the condition is looked upon as the result of a retrograde degeneration. In both cases it would appear that the presence of a peculiar hypertrophic degenerative process in the olive is the essential for the development of the clinical picture (Fig. 156). Alajouanine, Thurel, and Hornet (1935), after presenting one of the most completely studied cases from a pathological viewpoint, conclude: "The lesion of the inferior olive constitutes the anatomical basis for the myoclonic syndrome and when the myoclonia is unilateral it is the opposite olive which is affected. This change is usually from a lesion of the central tegmental tract but may be from a lesion in the dentate nucleus on the opposite side. The olivary lesion is a special type manifested microscopically by a hypertrophy more or less massive and histologically by a hypertrophic degeneration of the olivary cells and a maximal proliferation of neuroglia." Not all lesions of the central tegmental tract produce a pseudohypertrophy of

Figure 156. A. Myelin sheath stain of a case showing pseudohypertrophy of the right inferior olive with marked degeneration of the olivo-cerebellar fibers of the opposite restiform body. Note beginning change on the left. B. Examples of the cellular changes of the inferior olives as shown by silver stains. The small cell in the center of the lower four represents a normal olivary cell for comparison. (From J. Lhermitte and M. J. O. Trelles, 1933, L'hypertrophie des olives bulbaires Encephale 28:588-600, Figs. 15 and 12.)

Figure 157. A diagram indicating the triangular interconnected structures, the interruption of which in certain cases has resulted in the appearance of palatal myoclonus. (From G. Guillain and P. Mollaret, 1931, Deux cas de myoclonies synchrones et rhythmees velo-pharyngo-laryngo-oculo-diaphragmatiques. Le probleme anatomique et physiopathologique de ce syndrome, Rev. neurol., 2:545-566, Fig. 5.)

414

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the ipsilateral olive, and not all patients with pseudohypertrophy have a palatal myoclonia. Why certain cases show this change is completely unknown. Several papers have been devoted primarily to pseudohypertrophy of the inferior olive. Marie and Foix (1913), Lhermitte and Trelles (1933), and others believe that something besides the retrograde or transneuronic degeneration is responsible for the change in the nerve cells. They would lay the blame on the vascular supply of the nucleus and look upon the change in the nerve cells as a peculiar reaction to the vascular pathology or to an inflammatory process. However, Davison, Riley, and Brock (1936) found no vascular or inflammatory lesions which could be considered the cause of the typical pseudohypertrophic change they describe. Not all the cases are associated with vascular occlusions in the dentate or the central tegmental tract. Myoclonic phenomena have been associated with inflammatory processes, traumatic lesions, and tumors. Guillain, in his many papers on the subject, says this syndrome may result from a lesion anywhere in the triangular nervous pathway formed by the olive, the contralateral dentate nucleus and the ipsilateral red nucleus and their connections the rubroolivary tract, the olivocerebellar tract, or the dentorubral pathway (Fig. 157). There is very little experimental work which throws any light on this relatively rare but interesting clinical and pathological problem. Wilson and Magoun (1945) in the cat removed the inferior olive by aspiration by a direct approach through the parapharyngeal region. In addition to a syndrome of cerebellar deficiency on the opposite side, they noted a nonrhythmical myoclonus of the ipsilateral vocal fold at a rate of 130 to 300 per minute. They considered this to be the feline counterpart of palatal myoclonus in the human being. This seems hardly likely, for the condition they observed was not rhythmical and was on the wrong side to correspond to what has been observed in the human cases. Weinstein and Bender (1943), using a Horsley-Clark apparatus, did produce some synchronous movements of the palate and face by electrical stimulation near the inferior olivary nucleus, and Bender in the discussion of Erickson and Ablin's report (1953) mentions an enduring myoclonus following electrolytic lesions near the inferior olive. SUMMARY The tonic seizures which are at times associated with cerebellar tumors and have long been designated as Jackson's "cerebellar fits" depend for their production on transient ischemia of the higher centers of the brain stem and cerebral cortex and are not due to activation of cerebellar nervous elements in the same way as convulsive disorders of the cerebrum are. The peculiar tonic movements elicited in experimental animals by cerebellar stimulation have no counterparts in clinical experience. The cerebellum has a role, still incompletely understood, in myoclonic epilepsy. Many peculiar hyperkinetic syndromes are associated with lesions of the dentate nucleus and the brachium conjunctivum, but the exact mechanism of the cerebellar role is not fully understood. While lesions of the cerebellum may result in palatal myoclonus, the production by some such lesions of a pseudohypertrophy of the inferior olive appears to be the pathological condition essential to this interesting condition.

11 Developmental Anomalies of the Cerebellum

A. Malformations of the skull affecting the cerebellum (Basilar impression) 418 B. Abnormalities in the position of the cerebellum in relation to the skull (Arnold-Chiari malformation) 420 C. Complete or nearly complete agenesis of the cerebellum (Aplasia) 424 D. Agenesis limited to specific parts of the cerebellum (Partial aplasia) 429 1. Complete and incomplete loss of the cerebellar vermis 429 2. Loss of one hemisphere 434 E. Underdevelopment of the cerebellum (Hypoplasia) 436 1. Bilateral .. 436 2. Unilateral 440 a. Crossed cerebellar hypoplasia 440 b. Neocerebellar hypoplasia 440 F. Malformations of individual folia (Dysplasia) 441 G. Effects oh the development of the cerebellum produced by specific congenital disorders 441 1. Mongolian idiocy 441 2. Congenital syphilis 442 3. Cretinism 442 H. Pneumoencephalography as an aid in the diagnosis of cerebellar maldevelopment. . . 442 Summary 443

THIS chapter will be concerned with the abnormalities of the cerebellum resulting from defects in its development as opposed to degenerative changes occurring to portions of the organ which have already formed. To distinguish between the two is not so easy as might at first appear, for atrophy may occur along with anomalous development, and to make the distinction often becomes possible only after careful study of the histological material from many parts of the brain to determine which changes represent agenesis and which secondary atrophy. For purposes of description some classification is necessary, and it is important to attempt to differentiate which processes are primary developmental defects and which are degenerative changes. Some true malformations will be a part of a skeletal malformation and will be 416

DEVELOPMENTAL ANOMALIES 417 discussed separately. Classifications of these anomalies present great difficulties, and previous workers have not reached any agreement. It was early recognized that the congenital absence of a major part of the cerebellum could occur without the clinical symptoms which result from destruction of the organ or its degeneration being apparent. Nothnagel (1879), who first attempted to make such a classification, collected 13 cases and found that they fell into two groups, those with symptoms and those without symptoms or with very little clinical evidence of disease. He recognized that those with symptoms had an involvement of the vermis and hemisphere and that the tissue of the defective cerebellum was hard and sclerotic. Subsequently many others have attempted a classification, including Andre-Thomas (1897), Warrington and Monsarrat (1902), Ferrier (1900), Dejerine and Andre-Thomas (1900), Raymond (1905), Holmes (1907b), and Lejonne and Lhermitte (1909). Most of them agree on a classification which separates abnormalities presumed to be present at birth from those due to a degenerative process. Vogt and Astwazaturow (1912), in a work devoted to congenital cerebellar disorders, attempted to utilize the comparative anatomical studies of Edinger (1910) and Comolli (1910) and made a classification of congenital atrophies based upon the concept of the neocerebellum and paleocerebellum. Benda (1952) has devoted a chapter to developmental disorders of the cerebellum. To arrive at an entirely satisfactory classification either on a clinical or on a pathological basis is impossible. The etiology is almost always obscure. The difficulty, in addition to the areas of incomplete knowledge about the subject, lies in the fact that the nervous system is not static, and if damage to it occurs from any cause and in any part, this damage in itself results in secondary changes in connecting nuclei and fiber tracts both afferent and efferent to the site of the maldevelopment or intrauterine pathology. Actually, as Lichtenstein (1945) pointed out, each case must be analyzed from every possible point of view if one is to gain any understanding of this relatively rare but interesting group of neurological diseases. Another complication which has to be taken into consideration is the exact time in the development at which the damage actually occurs. Brun (1917-1918, 1925) recognized this factor in his differentiation between primary and secondary correlative checking changes, the former operating when the subcerebellar structure had already reached a measure of full development and was then affected simultaneously by the same noxious agent which disturbed the development of the cerebellum. The secondary correlative checking changes were those which occurred in a nucleus or tract not yet developed at the time of the application of the noxious effect. According to this idea, this nucleus would fail to develop because it did not receive the stimulus normally exercised by the damaged or poorly developed part. Brodal (1946), on the basis of his observations on developmental changes in the cerebellar vermis of a strain of white mice afflicted with a defect in this part of the brain (see p. 431), suggested that if the defect occurred before the nucleus reached sufficient maturity to have sent fibers to the part of the cerebellum destroyed, that nucleus might go on to apparently full development under the inherent stimulus to growth which it possesses plus the stimulus that the remaining undamaged portions of the cerebellum might be able to exert toward its

418 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM normal development. While this is a very logical explanation for the observed fact that in many congenital cerebellar defects portions of the subcerebellar nuclei that are known to be severely affected by lesions of the cerebellum near birth or even in adult life are perfectly normal, when the hypothesis was tested experimentally by Harkmark (1956) it could not be supported (see p. 433). The problem is further complicated by the fact that defects of development are frequently multiple. Thus, as we shall see below, there is frequent association of skeletal and nervous system malformations, and it is difficult to know how each relates to the other and to concomitant change in more remote parts of the nervous system. For example, does the Arnold-Chiari malformation result as the mechanical effect of a meningomyelocele which may be present, or is it due to an anomalous development of the brain stem occurring along with but not caused by the defect in closure of the neural tube? A. MALFORMATIONS OF THE SKULL AFFECTING THE CEREBELLUM (BASILAR IMPRESSION) The basal portion of the occipital bone and the first four cervical vertebrae are formed by a complicated series of developmental steps from three or four occipital sclerotomes and the first four cervical sclerotomes into the structures which are normally present in the adult. List (1941) has outlined the essential information on the developmental process gleaned from the embryological literature. Anomalies are frequently found to occur in this area, and while only those which result in basilar impression of the occipital bone, or as it is sometimes called "platybasia," directly involve the cerebellum, other anomalies may be associated with disturbances of the position of the cerebellum (Arnold-Chiari malformation). These skeletal anomalies may be at the upper cervical level or may be found in the dorsal or lumbar levels. The more common anomalies are those in which the most caudal occipital sclerotome takes on characteristics of the atlas (manifestations of occipital vertebrae) or in which the first cervical sclerotome may fuse with the occipital bone (assimilation). With these may be associated spina bifida, fusion of cervical vertebrae, and absence of various portions of these structures. Most of the bony abnormalities do not in themselves cause any neurological symptoms, but in a few cases the maldevelopment causes bony or ligamentous structures to be so weak that displacement occurs. The one which most commonly produces cerebellar compression occurs when the occipital bone is thin or absent to a greater or lesser degree so that in time the bone around the foramen magnum and the uppermost cervical vertebra protrudes into the posterior fossa, presumably under the weight of the head. The deformity was first adequately described by Boogard (1865), Virchow (1877), and Grawitz (1880). It was first diagnosed by roentgenograms by Schuller (1911). Many clinical pathological studies have been reported. Among these should be mentioned Homen (1901), Kecht (1932), Sinz (1933), Merio and Risak (1934), Ebenius (1934), de Morsier and Junet (1936), Chamberlain (who was the first to call the condition to the attention of the American neurosurgeons; 1939), Gustafson and Oldberg (1940), List (1941), Walsh, Camp, and Craig (1941), Ray (whose

DEVELOPMENTAL ANOMALIES 419 cases occurred not as a developmental anomaly but as a part of the picture of osteitis deformans in one instance and osteogenesis imperiecta in another; 1942), Stephens (1942), Custis and Verbrugghen (1944), Bagley and Smith (1951), and Phillips (1955). Symptoms of the condition may occur in childhood (List, 1941), but usually are first manifest in the third or fourth decade. Some have carried the malformation until over 50 years of age without showing any symptoms (Custis and Verbrugghen, 1944). The cause of the relatively late appearance of symptoms from what is usually a congenital anomaly is not known. Many theories have been suggested. Craig, Walsh, and Camp (1942) thought the formation of adhesions might play a role, and injuries at times appear to play a part (Chamberlain, 1939). The patients have a characteristic appearance. The hair line is abnormally low. Their necks are short, and the head appears to be resting on the shoulders. There is often limitation of motion of the neck. There may be palsies of the lower (ninth to twelfth) cranial nerves and usually involvement of the ventrally placed pyramidal tracts. The cerebellar signs are not in any way different from those encountered with other lesions and are due partly to direct compression and partly to foraminal obstruction. If the bony deformity is more marked on one side, ipsilateral lesions of cranial nerves may be combined with ipsilateral or contralateral signs of involvement of the pyramidal tract. In some instances pressure on the anterolateral tracts leads to a dissociated sensory disturbance of a syringomyelic type. Hydrocephalus may be marked, and the patient may exhibit all the manifestations of increased intracranial pressure. This usually indicates an advanced case. There may be an associated anomaly of the hindbrain, either one of the Arnold-Chiari type or a dysraphic process (Ostertag, 1925b; Bremer, 1927), i.e., a disturbance of the closure of the medullary tube. Syringomyelia may occur either as an independent process or as a result of pressure on the upper region of the cervical cord. Treatment of the condition is surgical, and numerous recent reports deal with this phase of the problem primarily. Wide decompression with removal of the occipital bone adjacent to the foramen magnum and the atlas is recommended. In addition, stress is laid upon the necessity of removing any constricting adhesions or strands of dura or arachnoid. Mortality is high, owing to respiratory failure. A secondary fusion has been tried but is not usual as it appears to add to the risks and those who survive the operation are usually relieved adequately by the decompression alone. The importance of adequate roentgenographic examination is emphasized by all writers on the subject, and the techniques of this examination are outlined by Chamberlain (1939) (Fig. 158). If the odontoid process is located above a line drawn between the hard palate and the posterior rim of the foramen magnum, basilar impression may be said to be present. McGregor (1948) and Bull, Nixon, and Pratt (1955) have modified these criteria. Poppel, Jacobson, Duff, and Gottlieb (1953) consider platybasia to be different from basilar impression. Platybasia, is present when there is abnormal obtuseness of the basal angle of the skull. Basilar impression is frequently seen in Paget's disease whereas platybasia is not,

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PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

Figure 158. A. Right lateral projection of the upper cervical spine and base of the skull in a typical case of platybasia, and tracing from same. Note the cephalic bulge at the clivus, the displacement of the odontoid process of the axis and most of the atlas to a level cephalad of the indicated base line (from the hard palate to the dorsal margin of the foramen magnum). B. Lateral view and tracing of the same view of a normal, for comparison. Note the caudal position of all parts of the axis and atlas to the "base line." (From W. E. Chamberlain, 1939, Basilar impression (Platybasia). A bizarre developmental anomaly of the occipital bone and upper cervical spine with striking and misleading neurological manifestations, Yale J. Biol. & Med., 11:487-496, Fig. 1.)

according to these authors. At times laminograms are necessary accurately to locate these landmarks, but in many instances a good lateral view is all that is required. Others have stressed the advisability of the use of ventriculography and myelography when each is indicated in the preoperative evaluation of the problem. B. ABNORMALITIES IN THE POSITION OF THE CEREBELLUM IN RELATION TO THE SKULL (ARNOLD-CHIARI MALFORMATION) The deformity of the hindbrain, now known as the Arnold-Chiari malformation, was first mentioned by Chiari in 1891. Arnold independently described the

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421

malformation in 1894 as it occurred in a newborn human monster with a very large myelomeningocele and gross deformities of the lower extremities and viscera. He described the cerebellum as extending down into the spinal canal as a tail-like projection which was attached to the spinal cord. Chiari again published on the subject in 1896 when he collected 7 cases and classified them into groups depending upon the degree of deformity present. Most people use the double eponym to describe the malformation, which was suggested by Schwalbe and Gredig in 1907, but some prefer to refer to the cerebellar projection as Arnold's malformation and a dorsal folding of the elongated hindbrain on the upper cervical cord as Chiari's malformation (List, 1941; Lichtenstein, 1942). The first surgical attack on the malformation was that of van Houweninge in 1932. Russell and Donald (1935) described the condition in 10 cases of lumbosacral or dorsolumbar meningomyelocele among infants stillborn or under four weeks. In all of these the malformation was described as a toilgue of tissue of variable length consisting of cerebellar substance and a greatly elongated medulla oblongata which protruded into the spinal canal and overlapped and compressed the spinal cord. The dura was distended and the foramen magnum obstructed. The underlying cords were small and the lower cranial nerves and upper cervical nerves took a cephalic course to find their foramina of exit. The cerebella were deformed and hypoplastic and often degenerated. Hydrocephalus was present in 9 of the 10 cases. Since this report a number of similar cases have been described in which the patient reached maturity only to have the malformation produce symptoms of cord compression, hydrocephalus, and cerebellar ataxia. As in cases of basilar impression, the symptoms tend to make their appearance in the third and fourth decade of life. Penfield and Coburn (1938) described such a patient, who at the age of three years had had a lower dorsal meningocele repaired. No further difficulty was noted until the age of sixteen years, when the patient noted a loss of hearing, which progressed over a period of nine years. At the age of twenty-six she noted some dimness of vision in the right eye and occasionally had double vision on looking to either side. Her friends had remarked upon the weakness of the right side of her face for some time, and she had noted a tendency for the right eye to tear easily. Finally, shortly before she was examined, she had noted a tendency to stumble easily and to fall forward. Neurological examination at the age of twenty-nine revealed a slight temporal pallor of both optic discs with some filling of the physiological cups. There was nystagmus on looking to the right and a vertical nystagmus on looking upward. There was bilateral weakness of the medial recti bilaterally, suggesting a paresis of both occulomotor nerves. The corneal reflex was absent on the right, and there were a right peripheral facial weakness and a bilateral perceptive deafness. There was some decrease in the deep tendon reflexes and a "trunkal" ataxia. A preoperative diagnosis of bilateral acoustic neuroma was made, and on exploring the posterior fossa, a typical protrusion of the Arnold-Chiari type was found (Fig. 159). A decompression was performed, but the patient died two months later without regaining consciousness. Others who discussed the problem at about the same period are McConnell

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Figure 159. A. A photograph of the appearance of an Arnold-Chiari malformation at the time of surgery. An instrument has been placed under the tail of the cerebellum, which is still attached by its tip to the leptomeninges of the cervical cord. B. A schematic representation of the deformity which was thought by Penfield and Coburn (1938) to result from traction from adhesions at the site of the repaired myelo-meningocele at T 4. Note the dilated ventricular system and the downward displacement of the pons, Po; the medulla oblongata, MO; and the decussation of the pyramis, Py. (From W. Penfield and D. F. Coburn, 1938, Arnold-Chiari malformation and its operative treatment, Arch. Neurol. & Psychiat., -40:328-336, Figs. 3a and 4.)

and Parker (1938) and D'Errico (1939), the latter being particularly interested in the condition as one of the causes of hydrocephalus. Aring (1938) also described a patient whose history and findings illustrate many of the features of this condition. His patient had a syndrome of cerebellar dysfunction with a markedly staggering gait, slowness of speech, nystagmus, dysdiadochokinesis, and ataxia in the finger-to-nose and heel-to-knee tests. He had increased reflexes, a bilateral ankle clonus, and a bilateral extensor plantar reflex. He also had dysphagia, bouts of sneezing, and on examination, a right-sided palatal weakness, right-sided weakness of the sternomastoid and trapezius muscles, and fasciculations of the tongue. A spinal puncture revealed a strongly positive globulin and 220 milligrams per cent of total protein. At first this patient was considered to have a cerebellar degenerative disease of some type, but later a diagnosis of cystic tumor of the cerebellum was considered and he was subjected to a suboccipital exploration. Again the same tonguelike protrusion of cerebellar tissue was found, and although a decompression was performed, the patient died eighteen hours postoperatively of respiratory failure.

DEVELOPMENTAL ANOMALIES 423 Since these pioneer experiences with this condition, many neurosurgeons have encountered these cases and have reported their results. Important reports of a series of such cases have been made by Adams, Schatzki, and Scoville (1941) and Ingraham and Scott (1943). Benda (1952) considers that these defects can be subdivided into three groups. The first are associated with spinal abnormalities, with or without hydrocephalus; the second are the result of the chronic displacement from pressure from above of a hydrocephalic cerebrum; and in the third the displacement has occurred without a spinal defect but a secondary hydrocephalus has developed as a result of the obstruction to the cerebrospinal circu: lation in the posterior fossa. On the whole, the results have been better than with the cases of basilar impression, and over fifty operations for this condition have been reported, according to Malis, Cohen, and Gross (1951), who have recently summarized the problem and added their own experience. As indicated above, this condition may frequently be associated with basilar impression and other anomalies of the cervical spine. The early reports of List (1941), Krayenbiihl (1941), Craig, Walsh, and Camp (1942), Lichtenstein (1942, 1943a), and Custis and Verbrugghen (1944) contain such examples. A fairly complete pathological report of the findings in the case reported by Aring (1938) was summarized as follows: "There were adhesions between the elongated cerebellar tonsils both of which were adherent to the medulla. The medulla was small and deformed chiefly because of 'wasting' in the region of the olives and of the olives themselves in the rostral half of the medulla. The caudal part of the pons was shrunken and there was a loss of transverse fibers in the pons. The pyramidal tracts and spinocerebellar tracts in the cord were somewhat degenerated in the lower levels and approximated to the normal in the higher sections of the cervical cord and medulla. There was moderate degeneration in the columns of Goll." In the cerebellum no histological abnormalities were found aside from a peculiar bulbous swelling on the axis cylinders of many of the Purkinje cells. The author also describes some of the fibers of the enveloping baskets coming down to envelop these localized swellings, which are called "torpedoes." Previous workers had cast doubt on the significance of these bodies seen only with silver stain (Bielschowsky, 1920; Spielmeyer, 1922), but in a small series Aring was unable to find these peculiar formations nearly so frequently as in this patient, though they were occasionally encountered in other conditions. Lichtenstein (1942) has found marked cerebellar dysplasias in many of his cases; this was also the experience of Jacob (1939) and Brun (1917—1918) in instances of meningocele. The mechanism of the Arnold-Chiari malformation has been the subject of considerable attention. Penfield and Coburn (1938) looked upon the condition as a mechanical traction produced by adhesions at the site of a meningomyelocele which pulls the hindbrain structures out of their normal position when skeletal growth and growth of the spinal cord fail to keep pace with each other. Lichtenstein (1942) believes the mechanical theory explains the cerebellar abnormality. List, however, does not feel that such a simple explanation will account for the complicated kinking which is frequently found in these cases. Malis, Cohen, and

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Gross (1951), after reviewing the fairly large number of cases which had been reported up to that time, were also of the opinion that a simple traction mechanism would hardly explain the developmental defect. Feigin (1956) reports autopsy findings on three infants, two of whom had the Arnold-Chiari malformation and all of whom had a deformity of the caudal portion of the midbrain tectum, which pointed back over the cerebellum and pons. This deformity, he feels, cannot be explained solely by mechanical factors but may be a form of developmental arrest. Most workers are agreed that cases of Arnold-Chiari malformation will gen% erally respond to wide decompression and the freeing of adhesions and any constricting bands of dura and arachnoid membrane. Lichtenstein (1942) emphasized the importance of an associated atresia of the aqueduct of Sylvius, which of course is not affected by suboccipital decompression. It is obvious from the clinical findings in these cases how frequently they may be mistaken for nonsurgical disorders of the brain stem and spinal cord. Alertness and care to rule out these possibilities by appropriate roentgenographic studies are necessary when dealing with any patient who has a high cervical or medullary syndrome. C. COMPLETE OR NEARLY COMPLETE AGENESIS OF THE CEREBELLUM (APLASIA) Combettes (1831) is credited with the first description of the rather rare anomaly consisting of complete absence of the cerebellum, and Andre-Thomas (1897) provides a complete account of what information is available in this case. The child in whom the condition was found was small, dentition was delayed, and she did not speak until she was three. She was unable to walk until five years of age. These symptoms of weakness were accompanied by gross mental deficiency. She was finally admitted to an institution in January 1830, where she remained for over a year. She was able to walk but fell frequently. She was subject to seizures and masturbated almost continually. She seemed indifferent to her surroundings. Finally, at the age of eleven, she died of intercurrent infection. During the last two or three months of her life she lay in a semistupor obviously deteriorated from the time of her admission. She was able to move her legs, and they had normal sensation. She readily used her hands. She never spoke unless spoken to and only yes and no. She died in a severe generalized convulsion. The postmortem examination revealed, so far as the nervous system was concerned, that in place of the cerebellum there was a gelatinous membrane of semicircular shape attached to the medulla oblongata by two membranous peduncles. Attached to this were two small separate pea-sized masses of white matter. Above one of these could be found the trochlear nerves. The quadrigeminal bodies were intact. Behind and below these was a depression, in the middle of which was the orifice of the aqueduct of Sylvius. There was no fourth ventricle nor any trace of the pons varolii. No histological study was made. However, a very similar patient was described by Anton in 1903, and a complete, excellently illustrated pathological study, with serial sections through the brain stem, was published by Anton and Zingerle in 1914. This child was also weak and frail. She walked and talked late and was not

Figure 160. A. Base of the brain of a child with a complete failure of development of the cerebellum except for a tiny remnant of the flocculus (Fl). B. Same brain seen from above after separating the brain stem and exposing the floor of the fourth ventricle. (From G. Anton and H. Zingerle, 1914, Genaue Beschreibung eines Falles von beiderseitigem Kleinhirnmangel, Arch. f. Psychiat., 54:8-75, Figs. 2 and 1.)

425

426 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM normal in motor performance or intelligence. No convulsions are mentioned. The cause of death was not determined. There is no gross evidence of the cerebellum in this case (Fig. 160). Serial sections reveal that there was a remnant of the left flocculus. There were no pontine cells. The cerebellar nuclei were represented by a tiny cell mass, believed to represent the left dentate nucleus. There were two small cellular accumulations, thought to represent the inferior olivary nuclei (Fig. 161).

Figure 161. Myelin stain of a section of the brain stem of the case illustrated in Fig. 1604 and B. The only structure which was thought to be cerebellar is labelled Cbll. (From G. Anton and H. Zingerle, 1914, Genaue Beschreibung eines Falles von beiderseitigem Kleinhirnmangel, Arch. f. Psychiat., 54:8-75, Fig. 9.)

Priestly (1920) has a brief note concerning a four-month-old child who entered the hospital too ill to be carefully examined and who died a few days later of bronchopneumonia. The child had a spina bifida and meningocele in the lumbar area. The brain was not examined microscopically, but there was no visible evidence of either cerebellum or pons. Ferrier (1876) refers to the brain of a feeble-minded girl fifteen years of age whose cerebellum was represented by a nodule, the pons and peduncles being absent. Flechsig (1883) and Sternberg (1912) are credited with the observation that the complete absence of the cerebellum is always accompanied by definite signs and symptoms of cerebellar deficiency, while incomplete and partial agenesis may at times be found in people in whom there is no clinical evidence of any serious structural anomaly in the cerebellum. Freeman (1929) and Rubinstein and Freeman (1940a) present such a case report and have furnished a detailed pathological report. Their patient had an

DEVELOPMENTAL ANOMALIES 427 almost complete absence of the cerebellum except for two small lateral portions which the authors interpret as being flocculi but which, from their appearance in the illustrations and the connections which the authors describe, most probably were remnants of both the flocculus and corpus cerebelli. It is quite likely that both this case and the one described by Fusari (1892) should be considered examples of lesions of the vermis, as the portions of the cerebellum that were present can be seen to represent fragments of the lateral portions of the cerebellum (see p. 429). It seems, however, because of the very small bits of tissue that were present, that they should be discussed in the present section as instances of almost complete loss of the cerebellum. The patient described by Fusari (1892) was described clinically by the following brief note: "While she was at the institution she demonstrated psychic symptoms of a grave imbecility. Physically she did not present any phenomenon of scientific interest to warrant an objective examination. There was no obvious incoordination of voluntary movement in her walking. Many times she was observed taking her food and drinking and she did this with precision. There was never any difficulty in her station and her gait was with perfect equilibrium." In this case the cerebellum consisted of two lateral parts which were found to be on the right 28 x 9 x 11 millimeters, and on the left 30 x 14 x 14 millimeters. There was no gross evidence of an inferior olivary nucleus. The pons was grossly shrunken. Histological study revealed a rudimentary corpus restiforme, dentate nucleus, pons, and inferior olive. The patient described by Rubinstein and Freeman (1940a), in spite of the limited amount of cerebellar cortical tissue, was able to carry on surprisingly well with this defect, plus other rather extensive defects of development involving other portions of the central nervous system, until generalized cerebral arteriosclerosis overtook him at about the age of seventy years. He had always been subnormal mentally, had never gone to school, but according to his brother walked and talked at the usual age. He was able to run and play quite normally as a child, though one leg was shorter than the other. Since adolescence he had been self-supporting, working as a gardener. He knew the value of money and had made a good adjustment, living with his brother his whole life. He had never married. It was only when he became elderly, three years before his admission to the hospital at seventy-two years, that he began to show a tendency to fall forward and to the left and to show some deviations to the left in standing and walking. This tendency progressed, along with defects in memory and delusions. When admitted to the hospital he had gross defects in memory and vague and poorly systematized delusions of a religious nature. His speech was jerky and slurred, and he walked with his trunk bent forward and to the left and frequently fell when not supported. His pupillary reactions were sluggish. There were a coarse intention tremor of all four extremities and some spontaneous "athetoid" movements of the hands. He eventually became bedridden, had to be fed, and died of tuberculosis. The postmortem examination, in addition to revealing tuberculosis and arteriosclerosis, revealed both cerebellar and extracerebellar congenital defects in the

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central nervous system. The extracerebellar lesions were extensive in the brain stem on the right side. The details of the extracerebellar defects are described in another paper by Rubinstein and Freeman (1940b). The cerebellum (Rubinstein and Freeman, 1940a) consisted of two bits of convoluted tissue situated in the region of the flocculi, that on the left measuring 8 x 7 x 5 millimeters, that on the right 8 x 6 x 6 millimeters. On the ventral aspect of the specimen the pons was represented by a thin sheet of tissue barely concealing the underlying pyramidal tracts (Fig. 162). Cerebellar tissue extended from the levels lying between the caudalmost fibers of the fifth and the eighth nerves, a distance of 11.7 millimeters. These small bits of tissue consisted of eight fairly well formed folia on the left and fewer on the right. Occasional microgyri were present, but otherwise those folia which were present were of normal histological structure. Between these more or less healthy areas were gray masses of glial tissue practically devoid of myelin sheaths and ganglion cells. The dentate nuclei were very rudimentary, lying in the most ventral part of the lateral wall of the fourth ventricle. The left was larger than the right, and a minute representation of the nucleus emboliformis was found on the left. The restiform bodies were very small, but the hook fasciculus of Russell could not be identified. The pontine nuclei were merely scattered cells ranging in number from ten to fifteen per cross section. The transverse fibers were grouped for the most part medially to the entrance of the fifth nerve and were somewhat more numerous on the left side than on the right. The superior cerebellar peduncle began as a capsule of fibers mainly along the

Figure 162. Myelin stain through the lower part of the pons and cerebellum of the patient described by Rubinstein and Freeman (1940). Contrast this section with Fig. 161. The difference in the amount of cerebellar tissue between the two cases appears to indicate the minimum necessary to allow one to go through most of life without showing definite signs of cerebellar deficiency. Note the dilated fourth ventricle and the dentate nucleus and its fibrous capsule larger on the left than on the right. (From H. S. Rubinstein and W. Freeman, 1940, Cerebellar agenesis, J. Nerv. & Ment. Dis., 92:489-502, Fig. 2.)

DEVELOPMENTAL ANOMALIES 429 medial aspect of the dentate nucleus. This tract could be followed easily on both sides to its decussation, where it appeared to become larger and more heavily myelinated. It was seen to enter the red nucleus. The inferior olive was very simple in formation, consisting of a single folded lamella, although the characteristic cells bearing large quantities of pigment were readily visible. The median accessory olive was visible on each side, but its nerve cells were few and far between. No dorsal accessory olive was noted. Baker and Graves (1931) furnish a gross description of the brain of a boy whose cerebellum consisted of two lateral masses corresponding, so we are told, to what is seen in a 24-millimeter embryo on the left and a 13-millimeter embryo on the right. All connections with the brain stem were much reduced in size. There was a bilateral absence of the inferior olives. There was very poor development of the pons. There was no hydrocephalus. Cohen (1942) found an agenesis at operation, and Pintos, Celle, and Frugoni (1943) have briefly described a case of agenesis of the cerebellum. It has been assumed that in cases of agenesis of the cerebellum compensation takes place if the intelligence is normal (Batten, 1905; Brouwer and Biemond, 1938). From these observations there would appear to be a critical amount of cerebellar tissue which must be present to allow the patient to compensate. Though all the patients described were mentally handicapped and most had a very low level of intelligence, they differed greatly in their capacity for coordinated movement. The rudimentary cerebellum of the Rubinstein-Freeman case probably represents the absolute minimum which is necessary to allow for adequate compensation to occur so far as coordination is concerned. That the cerebral cortex is responsible for this compensation is also suggested by this most instructive case, for it was coincident with the diffuse damage to the cerebrum caused by the arteriosclerosis that the patient's latent cerebellar deficiency became manifest. These patients also illustrate how much greater is the degree of potential compensation by the cerebral cortex possessed by man than by the dog. Dogs with less extensive defects than in either the Rubinstein-Freeman or the Fusari (1892) case are never able to overcome their congenital cerebellar deficit. Furthermore, human beings having defects of the vermis comparable in extent to those reported in lower animals are often free of all signs of cerebellar deficiency. It is perhaps of some interest that although the total quantity of cerebellar tissue functioning in the case of Rubinstein and Freeman (1940a) was very small, all three major divisions of the cerebellum were present in some measure and functioning to some degree if it is granted that what these authors called the flocculus does in fact include rudiments of the corpus cerebelli as well as the flocculonodular lobe. D. AGENESIS LIMITED TO SPECIFIC PARTS OF THE CEREBELLUM (PARTIAL APLASIA) 1. COMPLETE AND INCOMPLETE Loss OF THE CEREBELLAR VERMIS Agenesis of the vermis is a peculiar developmental anomaly of the cerebellum that has been known for a considerable period of time. The first description on

430 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM record included no histological study (Rossi, 1891). The brain described by Fusari (1892), which has been considered in the preceding section (see p. 427), may represent an extremely severe degree of the anomaly and was so considered by Brodal, Bonne vie, and Harkmark (1944), who give a complete review of the literature. Numerous examples of this defect have been found in human beings (Fig. 163); the most frequently quoted are the descriptions of Woskressenski (1911), Obersteiner (1916), Lyssenkow (1931), Pines and Surabaschwili (1932), Castrillon (1933), Sahs (1941), Lichtenstein (1943b, case II), Brodal (1945), Sidenberg, Kessler, and Wolpaw (1946), and Svaty and Masek (1950). The same defect has been found in several other mammals: in a calf (Lesbre and Forgeot, 1905); in the dog (Baker and Graves, 1936; Bertrand, Medynski, and Salles, 1936; and Dow, 1940); and in the goat (Verhaart, 1942). In the particularly important series of studies by Clark (1932), Bonnevie (1943, 1944), Brodal, Bonnevie, and Harkmark (1944) and Bonnevie and Brodal (1946), the condition has been found in association with hydrocephalus as a mutation in a strain of house mice. The degree of involvement of the vermis may vary. The whole vermis may be lacking or represented by only microscopic remnants laterally, and this defect may be associated with symmetrical or asymmetrical involvement of the lateral portions of the cerebellum. The condition may involve only a part of the vermis. If any part is intact, it is always the most basal folia of the anterior lobe. Less extensive lesions will spare, as well as the anterior lobe, the nodulus and occasionally

Figure 163. An example of the partial defect of the cerebellar vermis in man. Note the presence of the flocculus, which has been sectioned along with the cerebellum and the medulla just caudal to the pons. Within the dilated fourth ventricle can be seen the anterior portion of the vermis, which is quite intact. (From H. A. Castrillon, 1933, Ueber palaocerebellare Aplasie des Kleinhirns, Ztschr. f. d. ges. Neurol. u. Psychiat., 144'-113-134, Fig. 3.)

DEVELOPMENTAL ANOMALIES 431 the lower part of the uvula. The most likely portion to be lacking is the portion of the posterior lobe of the corpus cerebelli made up of the lobulus simplex, declive and tuber vermis, and pyramis. While some authors have considered this condition a failure of development of the "paleocerebellum," this is not an acceptable concept (Dow, 1940). The defect involves areas which differ in phylogenetic development, fiber connections, and functional relations. Furthermore, because of the preservation of the flocculus in all cases, the defect does not conform to what has been described as the paleocerebellum. That the condition can be harmonized, however, with the morphological facts, developed in detail in the companion volume of this monograph, has been pointed out (Dow, 1940, p. 583) in the following discussion of this anomaly in dogs: "In complete agenesis of the vermis it is possible that some factor interfering with normal development, about the nature of which we have no information, had prevented completion of the cerebellar commissure, along which the corpus cerebelli is formed, and the lateral commissure, along which the flocculonodular lobe is formed. The separate lateral parts, not being dependent upon the commissural development, might be capable of forming to some extent their own structures, namely, hemispheres, paraflocculi and flocculi. "In partial agenesis of the vermis, of which condition these dogs are examples, the formation of the cerebellum was possibly arrested at a slightly later stage after the cerebellar commissure had begun to form. This would allow a greater or less number of folia in the anterior lobe, beginning with the most anterior, to form across the midline in a fairly normal manner. The formation of the lateral commissure apparently is somehow retarded. In amphibia this commissure appears at a later stage of development than the commissura-cerebelli. In reptiles and mammals it is certain that the fusion of the cerebellar elements, which migrate along the lateral commissure to form the nodulus or its reptilian forerunner, occurs significantly later than does the fusion of elements which form the corpus cerebelli about the cerebellar commissure. Failure in development at this stage would prevent the formation of the nodulus, the uvula, pyramis, declive and tuber vermis and the lobulus simplex. The parts which could go on to relatively normal development would be the hemispheres, the paraflocculi, the flocculi and the more anterior folia of the anterior lobe. "This particular defect is found not only in these two animals but in every case of partial agenesis of the cerebellar vermis thus far reported in both man and lower animals. The constancy of this defect in all the reported cases of partial agenesis of the cerebellar vermis is of particular significance. Not only does it thereby allow one to offer a reasonable suggestion as to the mechanism responsible for this otherwise meaningless anomaly but nature has thereby presented us with 'experimental' demonstrations of the order of development of the cerebellar vermis. We have no information, however, as to what might be responsible for the inadequate formation of the cerebellar commissure." In important studies Brodal, Bonne vie, and Harkmark (1944) demonstrated what the probable cause was for this failure of formation of the commissure and the migration of the cellular elements along them. They found in studying the instance of hereditary hydrocephalus in the mouse, first described by Clark (1932) and then studied genetically by Bonnevie (1943, 1944), that the defect in the

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cerebellum was due to hydrocephalus which was present at a critical time in the development of the cerebellum and which interfered mechanically with the formation of the commissure and the subsequent cellular migration. In their mouse material all degrees of severity of this defect have been found. The slightest defect consists of a failure of development of lobulus C (pyramis, declive and tuber vermis, and lobulus simplex) and an incomplete fusion of the culmen, the uvula, and the nodulus, the lobulus centralis and lingula being normal. The most extreme form which these authors illustrate is summarized as follows (Brodal, Bonnevie, and Harkmark, 1944, p. 23): "The cerebellum in this specimen is completely split in two halves. The left half is considerably reduced in size, as practically the entire lobulus ansoparamedianus is absent. On the right side all folia of this lobule can be identified. Of the lobulus anterior only the lobuli 3 and 4 are found, apparently somewhat smaller than normal on both sides. The lobuli a and b are present only on the right side, both abnormally drawn out and split at the ventral (lateral) extremity. The paraflocculus appears to be grossly normal on both sides, whereas the flocculus is smaller than normal on the left side. "The intracerebellar nuclei are approximately of normal size on the right side, whereas on the left side their total mass is clearly reduced." Marburg (1914) had stressed the importance of hydrocephalus as a factor in the production of cerebellar anomalies, but this concept had been largely ignored. Coexisting hydrocephalus is mentioned by Castrillon (1933), Dow (1940), and Sahs (1941), but no particular attention was paid to their observation until the studies were reported on the mouse material. Brodal (1945) described an instance of this anomaly in a human being who had a clinically evident hydrocephalus; the brains described by Verhaart (1942), Sidenberg, Kessler, and Wolpaw (1946), and Svaty and Masek (1950) also showed some hydrocephalus, the last authors reporting an associate absence of the corpus callosum as well. Taggart and Walker (1942) and Walker (1944) found at operation this type of defect associated with an atresia of the foramina of Luschka and Magendie. These authors believe that most if not all of these midline defects are the result of the failure of these openings to the fourth ventricle to form. In the patient Walker described in 1944 the presenting symptom was headache of such severity as to be disabling, and the roentgenographic study revealed a marked enlargement of the posterior cranial fossa with upward displacement of the transverse and confluent sinuses. An internal hydrocephalus was also demonstrated. Operative interference revealed, in addition to the cyst-like enlargement of the fourth ventricle, the defect of the posterior vermis which has been described above. Wide ventriculostomy of the fourth ventricle resulted in complete relief of her headaches. Schwarzkopf (1950) has also more recently described a similar condition, and Benda (1952), who has recognized the importance of this defect, has reported six cases. The patient described by Brodal (1945) was also operated upon because of an obstructive hydrocephalus and cyst-like enlargement of the fourth ventricle. This child died on the second postoperative day. Brodal has analyzed this defect in the human being in the light of his rich anatomical background in cerebellar mor-

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phology and his experience with the development of the defect as observed in the mouse, and his description of this condition is the finest available in the literature. He concludes that his and all the human cases previously reported probably belong to the same type of cerebellar malformation as in the hydrocephalic mice "and that they form a distinct group of malformation with its own developmental mechanism" (1945, p. 39). The work of Brodal, Bonnevie, and Harkmark (1944) and particularly of Bonne vie and Brodal (1946), in which study the fetal states of these abnormal mice are described, has demonstrated the importance of a fetal hydrocephalus as the essential cause of this developmental defect, and the timing of the occurrence of stretching of the developing cerebellar plate adequately explains the variations of this defect. In the first of these studies the authors stated: "We are led to the conclusion that in this mouse strain the internal hydrocephalus is responsible for the anomaly of the cerebellum by causing a mechanical distention of the cerebellar plate. The different degrees of the vermal maldevelopment are probably caused by a slightly different time of realization of the hydrocephalus" (1944, p. 35). In the second study, after a detailed description of the developmental states of these mice cerebelli, they state: "In the abnormal embryos the development of the hydrocephalus starts at the twelfth day stage. The degree of the hydrocephalus varies within wide ranges, but the changes taking place are principally of the same type. The increased pressure of the intracerebral fluid results in an abnormal stretching primarily of the thin area anterior which for this reason is not, as in the normal embryo, incorporated in the plexus. However, the cerebellar plate is also affected, the normally thin median part being broader than usual. This attenuation is most pronounced in the caudal part of the plate, whereas the normally thicker rostral part is less attenuated. At later states the persistence of the area anterior will have as its consequence that the median part of the plexus choroideus of the fourth ventricle will be separated by a certain distance from the caudal end of the cerebellum and likewise this part of the plexus will not reach its full development. "The attenuation of the cerebellar plate interferes apparently also with the normal development of the cerebellar cortex. The inner granular layer is often more uneven than usual and the embryonic granular layer as well as the inner layer becomes gradually thinner as they approach the median part of the cerebellum. This itself, in more extremely affected specimens, is attenuated to a thin membrane, eventually containing some fibers (presumably commissural) and a single layer of more or less flattened ependymal cells on its ventricular surface" (Bonnevie and Brodal, 1946, p. 57). Brodal (1946) has used the example of this study to illustrate certain principles of development particularly in relation to the presence or absence of secondary changes in the subcerebellar nuclei. His ideas gain their support from these observations on the developmental stage of this particular anomaly in the mouse. Brodal's concept that secondary changes in the subcerebellar nuclei failed to develop when the cerebellar lesion occurred before the growth of the neurites into the cerebellum was put to an experimental test by Harkmark (1956). This worker made lesions in the cerebellum in the developing chick embryo and found that

434 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM the development of the inferior olive and the pons was affected by lesions at all stages of development. He felt that the location and size of the cerebellar lesion was of chief importance in determining the presence or absence of these olivary and pontine changes. He states in conclusion, "The earlier hypothesis that nerve fibers must be present in the cerebellum at the time of injury to result in secondary degeneration in the brain stem can now definitely be disproved." Clinical symptoms of agenesis of the vermis are often lacking in human beings. When clinical symptoms become evident, they are those of increased intracranial pressure due to obstruction of the ventricular system at the site of the malformation (see p. 432). In the lower animals, in which lesions of this part of the cerebellum seem to be capable of producing more symptomatology than in primates, a very definite syndrome of cerebellar deficiency has been observed. The syndrome as described by Dow (1940) is not unlike that resulting from total cerebellectomy in the same species. Heterotopias of the cortex in association with this defect have been described by many of those who have studied developmental errors of the cortex. As Brodal, Bonnevie, and Harkmark (1944) have pointed out, this association is not unexpected, for Brun (1917-1918) has interpreted heterotopias as being due to a delay in the migration of neuroblasts. It is natural to assume that the mechanical stretching would distort the normal architecture of the cerebellar cortex even when it was not sufficient to interrupt completely the cortical development. Not every case of vermian defect can be explained by this mechanism, for in cases VI, VII, and IX of Brun (1917-1918) the vermian cleft was in the anterior lobe; but in these, as Brodal said in 1946, the many additional abnormalities present in the nervous and skeletal systems suggest that these three cases were entirely different from the more frequently encountered anomaly of the cerebellar vermis which we have been discussing.

2. Loss OF ONE HEMISPHERE Agenesis of a lateral part of the cerebellum has been described by several authors. These include Salter (1852), Hitzig (1884), Neubeuger and Edinger (1898), Mackiewicz (1935), and Erskine (1950). The cases reported vary in the completeness of the defect, ranging from complete loss of the entire lateral half of the cerebellum, including the flocculus and portions of the vermis (Mackiewicz, 1935) (Fig. 164), to a situation in which there is a considerable part of the hemisphere remaining. Some of these, such as case II of Baker and Graves (1931), may properly be considered examples of asymmetrical lesions of the vermis, and this one was so considered by Brodal, Bonnevie, and Harkmark (1944). The loss of subcerebellar structures varies in proportion to the amount of involvement of the aplastic hemisphere. These specimens have been used for the purpose of making anatomical observations on the connections to the cerebellum, but, as has been pointed out by Brodal (1946), such observations may be quite inaccurate because of differences in the stage of development of the embryo when the primary damage actually occurred. No information is available concerning the cause of these developmental errors except for those which may possibly represent an asymmetrical vermis defect. Where the whole lateral portion is missing,

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Figure 16k- A drawing of a case of unilateral agenesis of the cerebellum. (From S. Mackiewicz, 1935, Ueber einen Fall von halbseitiger Aplasie des Kleinhirns, Schweiz. Arch. f. Neurol. u. Psychiat., 36:81-111, Fig. 1.)

including the choroid plexus, one naturally thinks of a vascular lesion occurring sometime in the prenatal period. The clinical symptomatology is variable. Some patients had no evidence of cerebellar deficit, and the condition was discovered by accident during the autopsy. Such are the two cases described by Erskine (1950). Other patients, such as the one described by Strong (1915), were obviously defective, but in this case no careful neurological examination was made. The only patient who has been at all adequately examined neurologically is the one described by Neubeuger and Edinger (1898). The clinical findings in this case revealed that the patient had consulted a physician before his fatal illness because of fainting attacks which were probably of cardiac origin. His neurological examination showed that he was steady in his gait and there was no abnormality of posture, no weakness of the lower limbs, no alteration in speech or intelligence. The tendon reflexes were equal on both sides. He died after a nine-day illness characterized by loss of consciousness and an extremely slow pulse. The description given by Neubeuger and Edinger of this patient's brain may be summarized by stating that the greater part of the right half of the cerebellum was absent. The left hemisphere was normal in shape, size, and foliations. The right hemisphere was represented by a nodule of the size of a hazelnut which projected from the vermis. All three cerebellar peduncles were present on this side but greatly reduced in size, especially the brachium conjunctivum, which was formed by a narrow band of fibers. The olive on the right side was normal, while that on the left opposite the agenetic hemisphere was represented by a tiny area of gray matter. The left pontine nucleus was absent and the left red nucleus was greatly reduced in size.

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The case described completely by Strong was that of a three-year-old child who was obviously defective but of whom no neurological examination was made. Here the findings are similar, but there was almost complete unilateral agenesis, with grave reduction in the contralateral corpus restiforme and middle cerebellar peduncle. There was marked attenuation of the contralateral olivary nucleus, the contralateral pes pedunculus and substantia nigra and red nucleus. An extremely well studied case that should be mentioned also is that of Mackiewicz (1935). E. UNDERDEVELOPMENT OF THE CEREBELLUM (HYPOPLASIA)

1. BILATERAL No attempt will be made to review completely the extensive literature on the subject of bilateral cerebellar hypoplasia. The most important articles dealing in whole or in part with this particular defect of development as encountered in man are those of Vogt and Astwazaturow (1912), Brun (1917-1918), Koster (1926), and Krause (1929). The defect in man allows for a certain degree of development of the cerebellum; in most instances the vermis and flocculus are spared to a greater or lesser degree and the maximum involvement is in the cerebellar hemispheres. In some instances this contrast is extremely striking, as, for example, in the first case of Brun (1917-1918). In others it would appear that the whole cerebellum was more or less equally hypoplastic. Such an example is the first case described by Vogt and Astwazaturow (1912). Almost without exception these cases exhibited other central nervous system defects, and in all instances in which adult life was attained, the patients were grossly mentally defective. Many of the cases were in infants who succumbed during the first few months of life. Cerebellar deficiency was frequently observed, but in most cases either no adequate examination was performed or there were other severe defects of the central nervous system which obscured the signs of cerebellar deficiency. The pathological changes, while varying in minor details, are for the most part differences in degree of involvement only. The cases described by Koster (1926) are used as examples of this type of developmental defect and his description may be summarized as follows: The hemispheres were very poorly developed in contrast to the vermis, which showed a nearly normal development (Fig. 165). Among the parts which were nearly normal also were the flocculus, paraflocculus, and tonsilla. The lobules which showed the greatest change were the lobulus quadrangularis, particularly its lateral part, the lobuli lunatus, semilunaris, and gracilis. These parts correspond to the lateral parts of the culmen, lobulus simplex, and crus I and II of the lobulus ansiformis (Larsell H IV, H V, H VI, and H Vila and b). Microscopically the three layers of the cortex were distinguished in all areas. The cells showed no abnormalities aside from some smallness and thinness of the Purkinje cells in the lateral parts of the lobulus simplex and the culmen. There was an abnormal thinning and undulation in the thickness of the molecular layer, beginning in the lateral part of the vermis and becoming maximal in the intermediate zones between hemisphere and vermis. The granular layer corresponded

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Figure 165. A. Section through the brain stem and cerebellum of a case of bilateral hypoplasia. Note the well preserved myelin-stained fibers of the flocculus and posterior part of the vermis, with marked hypoplasia of the hemispheres. B. Section through the cerebellum and brain stem at the level of the pons. Note the absence of normally stained fibers of the pontocerebellar fibers, the marked hypoplasia of the lateral cerebellar parts, and the preservation of the basal folia of the anterior lobe of the corpus cerebelli. (From S. Koster, 1926, Two cases of hypoplasia ponto-cerebellaris, Acta Psychiat. et Neurol., 1:47-83, Figs. 2 and 80.)

to these changes and was in places only one-half to one-third its normal thickness. In these areas of maximal change there was some sparseness of the Purkinje cells also. Heterotopias were noted. There was a marked decrease in the central white matter and the nucleus dentatus was almost touching the thin cortex. The radiation from the middle cerebellar peduncle was almost absent. In the tonsils and vermis, by contrast, the radiation of myelin fibers was quite normal. There was also a very prominent bundle of association fibers between the tonsil and the vermis (probably uvula). The dentate nucleus was too small, and instead of forming the normal bandlike shape, the cells were grouped into small clusters of about ten cells surrounded by a clear zone very poor in fibers. Most of the normal-appearing cells lay in the dorsomedial or paleocerebellar part of the nucleus dentatus. The nucleus emboliformis was much better, but smaller than normal, and the caudal part could not be distinguished from the caput of the dentate nucleus. The fastigial nucleus was too small, but the globosus had a normal appearance. The restiform body was much too small; the middle peduncle was represented by a few thin fiber bundles, and the superior peduncle was about one-tenth its normal diameter. The following structures of the hindbrain appeared quite normal: the nuclei of the dorsal funiculi, the nucleus of the restiform body, the internal arcuate fibers, the ventral and dorsal external arcuate fibers, the vestibular nuclei, the striae acusticae profundae, the tapezoid body, the posterior longitudinal bundle, the medial lemniscus, the taenia pontis, the cranial nerves and their nuclei, and the pyramidal tracts. Aside from a reduction in the size of the red nucleus (the num-

438 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM her of cells in its pars magnocellularis being reduced and its fibrous mantle being almost lacking) no abnormalities were seen in the midbrain, diencephalon, or forebrain. There were minor defects noted in the nucleus interquinto-cuneatus externus, in the retrotrigeminal gray matter, and the lateral part of the juxtarestiform body. There was complete absence of the striae medullares (Piccolomini), the arcuate nuclei were too thin, and the cells were poorly developed and stained poorly. The same could be said for the corpus pontobulbare, which was barely distinguishable. In the pons, while the frontopontine and temperopontine fibers were relatively normal, the pontine nuclei themselves were grossly deficient, being represented by only a few cells located chiefly in the dorsal and rostral position. The inferior olives were better developed but were clearly abnormal, with a thickening of the foliations of the nucleus and a general thinness of the olivocerebellar fibers. Cellular changes in the nuclei were maximal in the principal olivary nucleus and relatively little affected in the medial nuclei of the olivary complex. Other less well systematized examples of cerebellar hypoplasia are the cases described by Marburg (1914), Zimmerman and Finley (1932), and Norman (1940a), as well as some of those included in the reports of Vogt and Astwazaturow (1912) and Brun (1917-1918). These atypical examples of cerebellar hypoplasia blend, without sharp demarcation, into the cases which are clearly cerebellar atrophies, which will be discussed in the next chapter, and with the malformations of individual lobes or folia which will be considered in other sections of this chapter. Cerebellar hypoplasia has also been described in the cat by a number of different authors. The reports of Langelaan (1907), Jelgersma (1918), Cobb (1928), Brouwer (1934, 1936), Finley (1935), and Verhaart (1948) should be mentioned. The cats described by Herringham and Andrews (1888)) appear to have been examples of atrophy rather than hypoplasia. While there are some variations here from one case to another, all the above descriptions appear to fall into a definite pattern. This defect is familial, two or three animals in the same litter frequently being affected. In the instance described by Verhaart (1948) a similar cerebellar syndrome was noted in one kitten in the second generation. The cats exhibit from birth the typical manifestations of cerebellar deficiency found in grown cats subjected to cerebellar ablation. The pathological studies, while varying somewhat so far as the extracerebellar lesions are concerned, are fairly constant so far as the cerebellar hypoplasia and the related changes in the inferior olivary and pontine nuclei are concerned. Brouwer (1934) and Verhaart (1948) have reviewed the literature. The character of the cerebellar disorder in two litter mates was most completely described by Brouwer after a period of seven months of observation. He found the defect restricted to cerebellar deficiency, the animals being normal in growth and general cage behavior. The ataxia they exhibited had all the characteristics of cerebellar deficiency. Rademaker, who examined the cats, found the same exaggerated supporting reactions as seen in cats subjected to cerebellar ablations. While "magnet reactions" were not elicited, "hopping reactions" were present but were retarded in all directions.

DEVELOPMENTAL ANOMALIES 439 The clinical condition of the animals did not change materially throughout their life, one animal being observed for twenty-two months. Finley (1935) gives the most complete description of the brain in this animal, again emphasizing the marked cerebellar ataxia and the absence of asthenia and hypotonia. There were gross pathological changes in the cerebellum, but the spinal cord, midbrain, and forebrain were normal. The cerebellum was smaller in its entirety, but the difference from the normal cat cerebellum was most striking in the lobulus ansiformis in which, in addition to each folium's being smaller, there was a marked decrease in the number and complexity of the folia as well. Microscopic study revealed that there was a decrease in the cells of the cerebellar cortex in all areas, but again most evident in the hemispheres. As nearly as can be made out from the diagrams furnished, this change was maximal in the lobulus ansiformis. Here no Purkinje cells could be found, and there was a marked thinning of the molecular and granular layer together with an absence of tangential fibers in the molecular layer when stained by the Bielschowsky technique. The next most severe changes were in the lobulus simplex, folium and tuber vermis, pyramis, lobulus paramedianus, and what appears to be the paraflocculus. Slight and minimal changes were seen in the anterior lobe, uvula, nodulus, and the medial portion of the flocculus. In these areas some Purkinje cells were found, and there were a few tangential fibers in the molecular layer which took the silver stain. The deep cerebellar nuclei were entirely normal, so far as cells are concerned, though there was some pallor in the myelin stains in the surrounding white matter. The only nucleus affected in the spinal cord and medulla was the inferior olive. Here there was a bilateral symmetrical loss of the cell bodies which was maximal in the principal olivary nucleus and least in the dorsal accessory olivary nucleus. The medioventral accessory olive showed intermediate changes of a similar character. In the pons the hypoplasia was also evident, more at oral than at caudal levels. There was some diminution of the brachium pontis, but the other two peduncles were normal. All the structures of the midbrain, thalamus, striate body, and pallium appeared normal under microscopic study. When the diagrams of the olivary nuclei in the two litter mates are compared, it appears that the changes were less extensive in the younger animal described by Brouwer (1934). Otherwise the two animals were similarly affected in all ways. The authors of these studies on cats do not speculate on the possible mechanism of this familial and congenital hypoplasia. They do, in the papers cited, call the condition hypoplasia, but Brouwer and Biemond in 1938 refer to the same condition as a familial olivopontocerebellar atrophy occurring in the cat. This is an example of the confusion of terms which one finds throughout the literature in this area of neuropathology. Certainly these cases bear no resemblance to the olivopontocerebellar atrophy which is well recognized pathologically in the human being. The condition found in these cats should rightly be designated by the term hypoplasia. Innes, Russell, and Wilsdon (1940) have reported on the hereditary, clinical, and pathological findings in cases of familial cerebellar hypoplasia in purebred

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Hereford calves. They link these cases to the cats described by Herringham and Andrews (1888) and by Brouwer (1934); the former we believe to be a case of degeneration and the latter of hypoplasia. In the calves there are findings, principally gliosis, which indicate that some secondary degenerative changes in the hypoplastic cerebellum have occurred. The condition is present at birth and should be considered a hypoplasia corresponding to the cats described by Brouwer and his associates and many others. Unless there is a true heterotopia, it may be impossible to determine whether these congenital lesions are developmental defects or prenatal degenerative processes. 2. UNILATERAL a. CROSSED CEREBELLAR HYPOPLASIA Unilateral hypoplasia or atrophy of the cerebellum is commonly seen in human beings in association with a lesion of the opposite cerebral cortex. This condition is difficult to place with certainty. It has many aspects of a hypoplasia. It is well known that the degree of hypoplasia or atrophy will depend upon the age at which the cerebral insult occurred. Furthermore, Ellis (1920) has shown by his own investigations and from the results of previous studies that the cerebellum does not reach its full size until about the fifteenth year. However, some degenerative changes have been described in these cases, and similar degenerative changes have been described even in adult life (Kononova, 1912). We are adhering to the accepted classifications and considering these processes as atrophies rather than hypoplasia (Lichtenstein, 1943b). They will be discussed, therefore, in the next chapter (see p. 464). b. NEOCEREBELLAR HYPOPLASIA

Unilateral hypoplasia without any primary involvement of the cerebral cortex has apparently been reported only occasionally: Cramer (1891), Brouwer (1913), Jakob (1928), and Lichtenstein (1943b, case I). Cramer's case had minor changes in the opposite cerebral hemisphere (Cramer, 1891). The hypoplasia is usually discovered at the postmortem examination. Brouwer's patient had showed no neurological illness aside from the history of two attacks of headache of a rather severe kind. A cerebellar lesion was not suspected. The autopsy revealed normal cerebral hemispheres, but a marked hypoplasia of the left half of the cerebellum. The tissue of the involved lobes was hard and firm. The hypoplasia was limited to the left hemisphere and spared the vermis and flocculus; in addition, atrophy was found on the same side in the corpus restiforme, the brachium pontis, the "Bodenstriae," and the stria archiformis externa. Some of these cases might better be placed in the category of acquired atrophies, but Brouwer and Biemond in 1938 insisted, because of the lack of symptoms, that Brouwer's case should be considered a disorder of development. Certainly bilateral lesions, of a type that appears to be similar to the one just described, would seem to be able to occur as a development disorder (see p. 436). Russell (1895) has described a case of unilateral hypoplasia in a cat which exhibited homolateral signs of cerebellar deficiency not unlike those he described after unilateral ablations in the dog.

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F. MALFORMATIONS OF INDIVIDUAL FOLIA (DYSPLASIA) Brim has given a complete classification of malformations of individual folia. Many of the grosser types of developmental changes outlined above will contain gross and microscopic changes that fall into these various categories. In addition, studies on microgyria of the brain, such as that of Lowy (1916), contain descriptions of these peculiar but for the most part clinically insignificant abnormalities. In these cases there are usually malformations of the rest of the nervous system which are responsible for mental changes and other defects, and if only the cerebellum is involved in such a minor process, the abnormality is simply discovered by chance at the autopsy. Brun's morphological classification of these defects is as follows: /. Lobar dysplasias. In these, while the gross form of the cerebellum is preserved to some degree, individual lobes are malformed. II. Lobidar dysplasias. Here the defect is less severe and only sublobules show some degree of anomalous structure. Naturally these morphological types may coexist in the same cases. 777. Intracortical dysplasias. Some of these changes are discovered only on microscopic examination and have been further classified by Brun (1917-1918) as: A. Dysplasias of the outer structure 1. Abnormalities of configuration of the folial pattern (Allogyria) 2. Abnormally small but with excessive numbers of foldings (Microgyria and Polygyria) 3. Abnormally large but with few numbers of foldings (Macrogyria) 4. Loss of a number of folia (Agyria) Peculiar growth disturbances of the cerebellum which bear some likeness to tumors and some attributes of developmental anomalies are described in the reports of Barten (1934), Heinlein and Falkenberg (1939), Duncan and Snodgrass (1943), Alajouanine, Bertrand, and Sabouraud (1951), and others. Weil (1933) also described a very rare condition in which the cerebellum shared in a diffuse hypertrophy of glial tissue. This poorly understood condition was not a developmental abnormality, for the child appeared to be normal until his sixth year. G. EFFECTS ON THE DEVELOPMENT OF THE CEREBELLUM PRODUCED BY SPECIFIC CONGENITAL DISORDERS

1. MONGOLIAN IDIOCY The literature dealing with the pathology of Mongolian idiocy indicates that the cerebellum shares to some degree in the maldevelopment of the central nervous system in these cases. The only intensive study of this problem which has been found is the work of de Villaverde (1931). He studied material which he recognizes was inadequate in quantity, and studied it exclusively by reduced silver methods. His material was such that he did not know the age of the patient or the time elapsed before fixation. Certain histological changes he describes may represent pathological alterations, but confirmation by other methods and in a larger, better-controlled series of pathological studies would be needed before any specific cerebellar changes could be assigned to this condition. He gives an inten-

442 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM sive review of the literature on the pathology of Mongolian idiocy, and particularly of the neuropathological studies which have been made. It is generally agreed that the cerebellum is hypoplastic. More investigation is necessary to determine the specific changes which are present. Villaverde was of the opinion that there were changes in this condition which differed in their histological characteristics from those he found in 1925 in a similar study on the cerebellum in a non-Mongolian idiot (Villaverde, 1925). 2. CONGENITAL SYPHILIS While congenital lues has been incriminated in a number of instances of cerebellar maldevelopment, it is very difficult to prove its influence in a given case. In addition, histological changes may occur as a part of the pathological process of juvenile general paresis in the cerebellum which will be difficult to differentiate from developmental defect. Rondoni (1909) includes the cerebellum along with the rest of the central nervous system in his discussion of developmental abnormalities associated with congenital syphilis. No recent study of this problem is available. Probably syphilis shares with many other prenatal infectious processes responsibility as a cause of developmental defects. In recent years the effects of certain specific viruses and toxoplasmosis have been more frequently studied than has syphilis. No specific changes in the cerebellum have been attributed to these prenatal inflammatory processes. It is quite likely that many cerebellar developmental anomalies have as their basis some such unrecognized prenatal inflammatory condition; of the rest of the nervous system, however, the same is true. 3. CRETINISM Lotmar (1931) has devoted special study to the problem of defects in the cerebellar cortex in cretins. He gives an extensive review of the literature. His study is based on 8 patients whose ages varied from nineteen to seventy-seven years. His findings concern abnormalities in the Purkinje cells, which are hypoplastic and are frequently displaced toward the surface of the cerebellum. H. PNEUMOENCEPHALOGRAPHY AS AN AID IN THE DIAGNOSIS OF CEREBELLAR MALDEVELOPMENT The advent of pneumoencephalography has increased the ability of the clinician to verify the presence of cerebellar atrophy and malformations, though it does not enable a differential diagnosis between the two (Dyke and Davidoff, 1934). "In the posterior fossa in the normal in the anterioposterior view, gas in the subarachnoid space outlines the cerebellum in the form of an inverted V, the limbs of which are supported by the quadrangular lobes of the hemispheres and the apex of which covers the culmen of the vermis. The upper portion of the fourth ventricle is usually visualized as a triangle. In the lateral view, virtually the entire cerebellum may be seen in profile, surrounded by the cisterna ambiens anteriorly, subtentorial air dorsally and caudally, and the cisterna magna posterioinferiorly. The superior vermis and its individual components (lingula, lobulus centralis, culmen and declive) may be identified. Posteriorly, the quadrangular

DEVELOPMENTAL ANOMALIES 443 lobules of the hemispheres can sometimes be recognized in the normal. Air is often seen as thin lines between contiguous folia" (Davidoff and Dyke, 1946). In a paper devoted exclusively to the diagnosis of cerebellar atrophy by pneumoencephalography by Murphy and Arana (1947) 15 cases are reported in which the pneumograms either confirmed a clinical impression of cerebellar atrophy of some type or revealed an unexpected hypogenesis or agenesis. The authors summarize their results as follows: "Cerebellar atrophy may appear as an enlargement of the cisterna magna and fourth ventricle, or as widening and deepening of interfolial sulci and fissures, or as a combination of these abnormalities. Scalloping and deep fissuring of the surface of the hemispheres and nodulation of the vermis are especially evident in cerebellar degeneration of the parenchymatous cortical or olivopontocerebellar types of Friedreich's disease. Increase in size of the cisterna magna as compared with the normal is a feature of cerebellar hypoplasia. This may be related to initiation of the pathological process at the start of the developmental period or to the immature form of cerebellum in infancy." Mussio-Fournier and Rawak (1936) had previously described a patient with a clinically evident cerebellar disorder in whom subtentorial air was interpreted as confirming the clinical diagnosis of cerebellar atrophy. However, as Dyke and Davidoff (1934), Lemere and Barnacle (1936), and others have pointed out, this is not an adequate finding in itself. Lemere and Barnacle, after reviewing 800 pneumoencephalograms, found subtentorial air in 16 cases. This air when seen is interpreted as being in the subdural space and bears no relation to atrophy of the cerebellum. The finding which they believe to be indicative of cerebellar atrophy or hypogenesis is air lying posterior to the cerebellum and seen best in the lateral view. Ellerman (1943) in one case and Uzman (1948) in five others have also used pneumoencephalography successfully to confirm a diagnosis of cerebellar atrophy or maldevelopment. Davidoff and Epstein (1955) also discuss this problem. SUMMARY To classify the developmental anomalies of the cerebellum is not easy because of the difficulty in separating the changes which are a part of the primary defect of development from those which are secondary atrophies resulting from the original process. Even primary cerebellar atrophies are at times difficult to distinguish from anomalies. The skeletal deformity which results in cerebellar involvement is known as platybasia, or basilar impression. While this is usually congenital, a few cases are described in which the condition results from bony disease. In either circumstance there is a protrusion of the upper cervical vertebra into the posterior cranial fossa, with resulting pressure effects on the brain stem, the cranial nerves, and the cerebellum. At times a chronic, internal hydrocephalus is found. Frequently the neurological signs do not develop until early adult life. At times associated with skeletal defects either locally or at other segmental levels is the condition known as the Arnold-Chiari malformation. The neurologi-

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cal signs may be very similar to those of platybasia. In both, surgical decompression and freeing of secondary adhesions are the treatment applied. The cases of cerebellar aplasia are very rare. If there is absolutely no remnant of the organ, cerebellar deficiency can be noted, usually along with gross mental deficiency and often convulsive seizures. If even tiny portions are present, however, remarkable freedom from the usual signs of cerebellar deficiency is found. Partial agenesis of the cerebellar vermis is a common defect which has been described in several species. It appears to result from a hydrocephalus occurring during embryonic development which mechanically interferes with the formation of the commissures of the cerebellum and the later migration of neuroblasts along the commissural fibers. Though symptoms of cerebellar deficiency with these lesions are the rule in subprimates, they are usually not found in human beings. In man the condition is discovered during life as a result of increased intracranial pressure occurring from secondary obstruction of the outlet of the fourth ventricle. The anomaly is then noted at the time of surgical relief of this obstruction. Agenesis of one hemisphere is less common and is likewise unassociated with cerebellar deficiency in human beings. Hypoplasias of the cerebellum occur in both man and subprimates. In the latter, definite signs of cerebellar deficiency occur. Detailed histopathological studies of examples of this condition are available and are summarized. In these cases the border line between malformation and atrophy may become difficult to define. This is particularly true of so-called crossed cerebellar hypoplasia, cases of which are regarded as examples of cerebellar atrophy and are discussed in Chapter 12. Hypoplasias may be bilateral or unilateral but usually involve so-called neocerebellar parts. Defects of cerebellar development associated with Mongolian idiocy, congenital syphilis, and cretinism are discussed. The pneumoencephalogram properly interpreted is a valuable diagnostic tool in the identification of these lesions, though it will not differentiate them from atrophies of the cerebellum.

12

Atrophic Changes of the Cerebellum and Its Connecting Pathways

A. Cortical cerebellar atrophies 1. Familial or hereditary a. Occurring in adults b. Occurring in infants 2. Nonfamilial or acquired cortical cerebellar atrophy a. Localized (1) Circumscribed panatrophy (2) Predominant in the anterior lobe b. Generalized (1) Chronic (2) Subacute (3) Acute B. Olivopontocerebellar atrophies C. Cerebellar nuclear atrophies D. Crossed cerebellar atrophy E. Hereditary spinal ataxias 1. Friedreich's ataxia 2. Spastic ataxia (Marie's cerebellar ataxia) F. Cerebellar changes of a degenerative type associated with specific neurological conditions 1. Amaurotic familial idiocy 2. Pick's disease 3. Alzheimer's disease 4. Progressive lenticular degeneration (Wilson's disease) 5. Degeneration of the cerebral gray matter of Alpers 6. Multiple sclerosis 7. Symmetrical calcification of the dentate nuclei 8. Tuberous sclerosis Summary

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446 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM THE neurological diseases which are associated with atrophic changes in the cerebellum remain one of the most confused chapters in the whole field of clinical neurological literature. This is not surprising in view of the difficulties of clinical differential diagnosis between the various pathological types, the lack of general agreement on the pathology, the confusion of terminology, and finally the almost complete ignorance of the etiology of any of the pathologically recognizable varieties within this group of diseases. Even to suggest a logical classification for these diseases is difficult. The variety of classifications proposed is evidence that none of them is satisfactory. The outline we have devised above (see p. 445) will at least serve to indicate the order in which the subject will be discussed, and there does seem to be some basis for considering atrophic changes under these headings. A. CORTICAL CEREBELLAR ATROPHIES 1. FAMILIAL OR HEREDITARY a. OCCURRING IN ADULTS Holmes (1907a) first reported a familial disease which fits the category of a familial cortical cerebellar atrophy. The family described consisted of eight children, five males and three females. One male child died in infancy and of the remaining four males, three were afflicted with the disease as was one of the females. All the members of the family who had the condition followed an identical course, characterized by the gradual onset of a disturbance of gait coming on between the ages of thirty-three and forty. After a gradual progression of this symptom, in four or five years uncertainty in the movements of the upper extremities and a typically cerebellar speech disturbance were added. The speech was described as hesitant, scanning, and explosive. Eventually cerebellar tremor and nystagmus were also noted. The tendon reflexes were slightly exaggerated, but there was no ankle clonus. The one brother who lived thirty-five years with the disease before he died in his seventies had a grossly atrophic cerebellum. The weight of the cerebellum and brain stem was only 58 grams, about a third of the normal. The most marked changes were in the cortex, the Purkinje cells being totally absent in most areas, a few remaining in the uvula, nodulus, and the cerebellar tonsils. There was atrophy of the other cellular elements of the cortex. There was considerable involvement of the central white matter, and these changes were maximal in the culmen, the pyramis, and the anterior and posterior quadrilateral lobes (lobules IV, V, IX, H IV, H V, and H VI, Larsell). There was marked atrophy of the inferior olivary nuclei, which Holmes interpreted as being secondary to the cerebellar cortical degeneration. The cerebellar nuclei were not involved, and no changes were seen in the rest of the nervous system. Since Holmes presented his description, there have been a number of similar reports of familial disease of this type. Stone (1933) and Huard (1935) presented a clinical report. Another report, including a pathological study, is that of Thorpe (1935), whose patients, two brothers, in addition to having the progressive cerebellar syndrome, had had epilepsy from childhood. His pathological study of one of the two brothers showed a more uniform loss of the Purkinje cells than has

ATROPHIC CHANGES 447 usually been found in these cases, but the gross atrophy was chiefly evident in the superior aspect of the vermis. Clinically the ataxia of arms and legs appeared simultaneously. Another distinction between his and Holmes's family is the lack of significant changes he found in the inferior olive. He attributed this difference to the greater duration of the disease in Holmes's case and considered his family to be of the same group as that of Holmes. Richter (1938, 1940) reported another family with the same condition. He found no gross atrophy and no olivary changes. He felt that this family, as well as another family reported in 1950, corresponded to the one described by Thorpe. He was inclined to place the family of Holmes in a different category. In this position he is supported by Hassin and Harris (1936). Most subsequent students have not made this fine distinction and look upon the cases of Holmes as of unusually long duration and severity but of a similar type (Weber and Greenfield, 1942; Greenfield, 1954). The next such family to be reported was that of Akelaitis (1938), who reported a family illustrating both familial and hereditary features, the disease appearing in three generations. Stone had previously reported an hereditary trait in his family, but this group has never been identified histologically as an example of this condition. Akelaitis's family was different from those heretofore described in showing, in addition to the progressive cerebellar disturbance, a terminal dementia and a more rapid course. One of the patients (case I) (Fig. 166), who was examined post mortem, was described four months after the onset of the disease as follows: "The gait was markedly ataxic; the patient walked with a broad base, lunging and lurching forward. He showed no ataxia in the finger-to-nose test, and when lying down there was no ataxia in the heel-to-knee test" (p. 1119). Three months later examination revealed that the arms were involved, ataxia and tremor being described, and he died the following month a few hours after a surgical exploration of the posterior fossa. In this case the pathological changes were definitely most marked in the anterior lobe and were associated with pathological changes in the frontal and parietal cerebral cortex, accounting for the terminal mental changes from which not only this patient but his brother suffered. The medial part of the dorsal lamella of the inferior olive was involved, and there was a loss of cells here as well as a reactive gliosis. The Purkinje cells were very much diminished in number in the lingula, lobulus centralis, culm en, and declive (lobules I, II, III, IV, V, and VI, Larsell). Here most of the remaining cells were shrunken. There was a proliferation of Bergman's astrocytes, and the Purkinje cells were absent. Empty baskets were present in Bielschowsky-stained sections (Fig. 167). From this area of the most intense damage, the changes gradually decreased but were well marked in the vincula lingulae, the alea lobuli centralis, and the anterior quadrate lobule (lobules H II, H III, H IV, and H V). The superior semilunar lobule and posterior quadrate lobule (lobules H Vila and H VI) were less severely affected. The lobuli semilunaris inferior, the lobuli biventer, the tonsillae, the flocculi, tuber vermis.

Figure 166 A schematic drawing of the superior surface of the cerebellum, showing by the density of the stippling the intensity of the atrophic change in the various lobules of the cerebellum in a case of hereditary cortical cerebellar atrophy. That on the left is from case 1, and that on the right from case 2. (From A. J. Akelaitis, 1938, Hereditary form of primary parenchymatous atrophy of the cerebellar cortex associated with mental deterioration, Am. J. Psychiat., 94:1115-1140, Fig. 2.)

Figure 167. Cerebellar cortex from the ala lobulus centralis stained by the Bielschowsky method in a case of hereditary cortical cerebellar atrophy. Note the absence of Purkinje cells and the preservation of baskets and parallel fibers. (From A. J. Akelaitis, 1938, Hereditary form of primary parenchymatous atrophy of the cerebellar cortex associated with mental deterioration, Am. J. Psychiat., 94:1115-1140, Fig. 4.)

448

ATROPHIC CHANGES 449 pyramis, uvula, and nodulus (lobules H Vllb, H VIII, H IX, H X, VII, VIII, IX, and X) were apparently normal. The deep cerebellar nuclei were all normal except that a few pyknotic and shrunken cells were found in the anteromedial part of the left dentate nucleus. The brother had a similar though more acute course, and his mental symptoms were somewhat more prominent. He did show marked ataxia, inability to stand with eyes open or closed, and a gross disturbance of speech. The cerebellar changes were more acute and restricted to the lobulus centralis (lobules II and III), though involving the culmen (lobules IV and V) to a degree. Very early changes were seen in the lateral expansions of these lobules. The olivary changes were more intense, as was the cerebral cortical involvement. Since then Hall, Noad, and Latham (1941, 1945) have reported on a large family group in Australia, and pathological reports have been made by Weber and Greenfield (1942), van Bogaert (1947), and others. One of Richter's patients (1950) showed changes in the basal ganglia and before death developed a Parkinsonian syndrome. Van Bogaert's patient likewise had a lesion in the globus pallidus, but it was not productive of any symptoms of a Parkinsonian nature. Richter (1950) discusses the hereditary characteristics of the various families which have been reported and feels that the hereditary mechanism is related to a dominant Mendelian characteristic. Greenfield (1954) gives in tabular form the essential clinical and pathological findings in this condition, which he classifies as group B (Holmes) of hereditary cerebellar ataxia. He recognizes the more homogeneous character of this group as compared to his group A (Menzel), the latter of which we prefer to consider a variety of the much more common hereditary spinal ataxias that we shall discuss below. b. OCCURRING IN INFANTS

Jervis (1950) has described a familial disease under the title "Early familial cerebellar degeneration." This report is based upon the postmortem findings in an imbecilic infant of two years of age who died suddenly of an "acute septic infection." She had two older sisters who were similarly affected. Mental deficiency was marked in all three children; symptoms were first noticed during the first year in each and may have been present at birth. The cerebellar signs were said to be "inconspicuous and nonprogressive" in the child who came to autopsy. In the other two siblings the signs of cerebellar deficiency are definite from the descriptions of their neurological status. The older and less seriously affected was showing some improvement in walking and talking at the time of the publication of the report. While these patients clinically might be considered examples of defects of development, the pathological changes found in the one child seem definitely those of an atrophy rather than a hypoplasia, justifying their consideration here. This case illustrates well the necessity of taking into consideration all the facts available in these difficult problems to identify them properly. The cerebellum was very grossly shrunken, including all major divisions,

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though the vermis somewhat less than the hemispheres. While the pathological study revealed the cerebellar cortex to be the site of the primary involvement, the cells affected were chiefly the granular cells rather than the Purkinje cells. There was some loss of Purkinje cells and those present were abnormal, with "torpedoes" on their axons and peculiar "cactus-like formations" on their dendritic trees. Basket cells and the empty baskets were frequently seen in silver stains. Climbing fibers were present, but only a few mossy fibers were noted. There were some pyknosis and chromatolysis in the dentate nucleus. There was a considerable outfall of nerve cells in the inferior olive, most noticeable in the dorsolateral region of the nuclei; the cells of the remainder were pyknotic. The remainder of the nervous system appeared to be normal. The author identifies the changes in this case with those in the two patients described by Norman (1940b), in which a cortical atrophy, most marked in the granular layer, was also described. Lichtenstein (1945), however, has stated that these patients were cases of amaurotic familial idiocy, mistakenly identified as cases of primary cerebellar cortical atrophy. This criticism hardly seems justified as there were no alterations in the basket cells, and none of the lipoid deposits characteristic of amaurotic idiocy were found. Santha (1930) described a patient with similar clinical and histological findings, but there was no family incidence. The findings are similar, as Jervis points out, to cases 2, 3, and 4 described by Scherer (1933a), but in Scherer's reports the clinical information is meager. We do know that cases 3 and 4 of Scherer were siblings and both were idiots. Jervis also points out the resemblance between his patient and those reported by Schob (1921), case 2, and Vogt and Astwazaturow (1912), case 2. In most of these cases the disease occurred at birth, and the abnormalities as a group might be called congenital atrophies. They could hardly be correctly considered defects in development (hypoplasias) in view of the marked gliosis, the preservation of pericellular baskets together with an absence of the Purkinje cells, and the "degenerative" changes in those Purkinje cells that were present. A prenatal or early infantile toxic or inflammatory process might be considered, but the strong familial tendency can hardly be explained on this basis. Van Bogaert (1947) classed the cases in the very early report of Fraser (1880) as an example of familial cortical cerebellar atrophy. The histological study was not sufficiently detailed to be certain whether they fit in the above group or not. The children described by Fraser had the onset of their disease at four and seven years, respectively. While the cases as a group are much less clearly defined clinically and pathologically than the familial cortical cerebellar atrophies of adult life, they may represent a part of the large group of cases described in clinical terms by Batten (1905) as "ataxia of childhood," by Beyerman (1917) as "cerebello-ataxic mental deficiency," and most recently by Mutrux, Martin, and Chesni (1953). More pathological studies are needed in all cases of mental deficiency and ataxia of early childhood and infancy. Instances of a familial and hereditary congenital cerebellar disorder occurring in young lambs is reported by Innes, Rowlands, and Parry (1949) and by van Bogaert and Innes (1950). The latter authors interpret their findings as indicat-

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ing two separate conditions: one—the more frequent, the so-called "daft lambs" —being a toxic or metabolic defect of hereditary type which results in a vacuolar and lytic disintegration of the Purkinje and Golgi cells occurring before birth; the other, a true abiatrophy, affecting all cortical elements, with replacement gliosis, and corresponding to a true cerebellar atrophy as seen in man. The latter condition occurred in an isolated specimen, and its exact counterpart in human neuropathology was undetermined. 2. NONFAMILIAL OR ACQUIRED CORTICAL CEREBELLAR ATROPHY

The pathological changes encountered in this group of diseases can be classified as either localized or general atrophy, depending upon whether the degenerative changes are distributed uniformly over the whole cerebellar cortex or whether they are more or less restricted to a particular part of the cerebellum. The generalized atrophies, in turn, fall rather logically into three groups: chronic, subacute, and acute. We will include in the chronic group those patients whose disease has run a course of five or more years. Those cases in which the disease takes a more rapid course, terminating within a period of months after the onset of symptoms of cerebellar deficiency, will be regarded as subacute cortical cerebellar atrophy. The acute cases will only be mentioned in passing and will be discussed more completely in the next chapter, on toxic and inflammatory disorders of the cerebellum, in which will also be discussed the effects of anoxemia and thermal changes on the cerebellum. It is a fact that the Purkinje cells of the cerebellar cortex are among the most vulnerable cellular elements of the nervous system with respect to a large group of noxious influences. The end results of acute injury to the Purkinje cell by such toxic influences may, after many months or years, be indistinguishable from some chronic, slowly progressive process. It is therefore obvious that this division into acute, subacute, and chronic is necessarily arbitrary. The localized atrophies are all chronic. They seem to form a more or less distinct group and will be dealt with first. a. LOCALIZED

(1) Circumscribed Panatrophy Circumscribed panatrophy is the name given by Lichtenstein and Levinson (1946) to an atrophic process which involves the cerebellar cortex, including all the cortical elements, in a sharply circumscribed fashion. The condition is not associated with any evidence of cerebellar deficiency, since the atrophic process is limited, as a rule, to a very small area. It has been discovered in routine postmortem examinations in which the cerebellum was carefully and systematically investigated. Its histological characteristics suggest that it is a chronic process in which active pathological processes have occurred a long time previously. No vascular or inflammatory processes are present to account for the peculiar local changes. In the areas of cell loss a very intense gliosis is found, and in some cases (Hassin, 1934) the process may involve a rather large area of certain lobes of the cerebellum. No clue has been found as to a possible cause. Scherer (1931), in describing a large number of such lesions, lists thirty pathological conditions with which they have been associated, many of which are fortuitous only. Hanon

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(1928) and many others have described such lesions. Hassin used the term "sclerotic atrophy" to identify his cases, but the term suggested by Lichtenstein seems more descriptive. It is probable that such changes are more common than these reports indicate, but inasmuch as the lesion is asymptomatic it is not looked for frequently and probably not often reported when found. At the present time these lesions are little more than pathological curiosities. Their true significance remains for further study. (2) Predominant in the Anterior Lobe This atrophic condition has been described under a great many different names. First by Andre-Thomas (1905) as "atrophie lamellaire des cellules de Purkinje," then by I. Rossi (1907) as "atrophie primitive parenchymateuse du cervelet a localisation corticale," next by Archambault (1918) as "parenchymatous atrophy of the cerebellum," by Lhermitte (1922) as "1'astasie-abasie cerebelleuse par atrophie vermienne chez le vieillard," and finally and most completely by Marie, Foix, and Alajouanine (1922) under the title "1'atrophie cerebelleuse tardive a predominance corticale." Most subsequent authors have continued to use the last term (van Bogaert and Bertrand, 1932; Maas and Scherer, 1933; Moyano, 1937; de Haene, 1937). Courville and Friedman (1940) prefer to stress the tendency for localization in the anterior lobe, and have called the condition "chronic progressive degeneration of the superior cerebellar cortex." Because of the tendency toward secondary degeneration of the inferior olives, others have called the condition "cerebelloolivary atrophy" (Weber and Greenfield, 1942; Critchley and Greenfield, 1948; Brain, Daniel, and Greenfield, 1951). Greenfield and his associates did not feel that it was necessary to differentiate between the localized and generalized form of cerebelloolivary atrophy but only to divide the cases into purely cortical and corticoolivary types. Greenfield (1954) in his monograph, however, has recognized the importance of differentiating the diffuse from the localized cortical atrophies and now refers to this condition by the more generally used term "late cortical cerebellar atrophy". Hassin and Harris (1936) have gone so far as to look upon these cases as "formes frustes" of olivopontocerebellar atrophy, with which point of view Greenfield and his associates are not in accord. The condition usually involves a very chronic process, in a few instances beginning in youth but usually making its appearance during the fifth or sixth decade. The cases referred to above are not familial, though Richter (1938, 1940, 1950) contends that there is no basis for differentiating between those that are familial and those that are not. It must be admitted that the anatomopathological changes are very similar in the familial and nonfamilial groups. The disease manifests itself by ataxia, always beginning in the lower extremities. It is noted first as an unsteadiness in walking with a marked titubating gait. As the disease progresses, the legs show evidence of ataxia in the heel-to-knee test, and later a generalized ataxia of the upper extremities and a disturbance of speech develop. Lhermitte (1935), discussing this condition, says: "One characteristic is striking. The legs are always much more seriously affected than the arms, even at the terminal stage. Three patients of mine were totally unable to

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stand or walk without help, but they could perform many of the necessary little occupations of everyday life such as shaving, eating and dressing, but not handwriting which, as a rule, showed a trace of incoordination and tremor, even when these phenomena were not very noticeable" (p. 382). Deep tendon reflexes may be markedly accentuated, and in some cases rigidity of a Parkinsonian character has been noted. Ley (1924) describes such a case, which, however, has some characteristics of olivopontocerebellar atrophy. Pathologically the most striking feature in these cases is a grossly apparent atrophy of the cerebellum, which is marked in the superior surface of the vermis and its lateral extension (Fig. 168). The anterior lobe of the corpus cerebelli is the part chiefly involved, though there is eventually involvement of the remainder of the cerebellum in a progressively severe fashion laterally and posteriorly. In a few instances folia situated posteriorly bore the brunt of the involvement (van Bogaert and Bertrand, 1932; Kirschbaum and Eicholz, 1932). Histologically the most characteristic lesion is an outfalling of Purkinje cells, maximally in the areas of gross atrophy and gradually decreasing in severity laterally and posteriorly. Where the cells are still present, they are usually pyknotic, and in those areas showing minimal or no involvement they may be entirely normal. The other elements of the cortex may be affected to a greater or lesser degree. Thus in the case of Courville and Friedman (1940) there was a marked involvement of the granular layer, with narrowing and loss of cells, while basket cells and empty baskets were still to be seen and myelin sheath stains showed a sharply demarcated thinning in the involved folia. Characteristically

Figure 168. A photograph of a sagittal section of the cerebellum from a case of cerebellar cortical atrophy predominant in the anterior lobe. Note the striking difference between the gross atrophy of the folia on the superior surface lying under the tentorium and the intact folia in the caudal and inferior part of the cerebellum. (From H. J. Scherer, 1933, Beitrage zur pathologischen Anatomic des Kleinhirns. Genuine Kleinhirnatrophien, Ztschr. f. d. ges. Neurol. u. Psychiat., 145:335-405, Fig. 18.)

454 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM only a slight proliferation of glial tissue is found in the atrophic areas. In other cases the myelin sheath stain will show little or no changes, but the basket cells will be entirely gone (de Haene, 1937). In almost every case of this group there are lesions of the inferior olivary nuclei which correspond to the site of the maximal involvement of the cerebellar cortex corresponding to the well-known localized olivocerebellar projection. This aspect of the condition has been particularly well discussed by de Haene; in his case there was a complete disappearance of the olivary cells in the dorsal and medioventral paraolivary bodies and in the oral, dorsal, and medial part of the principal olivary nucleus. These changes gradually decreased in prominence throughout the rest of the nucleus; in the caudal, ventral part of the principal nucleus the cells appeared quite normal. No other abnormalities are found in most of the cases but because of the advanced years of the persons affected, it is not uncommon to find described unrelated vascular lesions. In a few instances vascular changes have been thought to be related to the atrophic anterior lobe (Archambault, 1918). Courville and Friedman (1940) described a meningeal change over the site of major involvement, but this is quite exceptional. The etiology of this condition is unknown. It is of interest that Ellis (1920), in counting the number of Purkinje cells in various portions of the cerebellar cortex at different ages, found that the percentage of decrease was greater in the area anterior to the primary fissure as compared to another area located more posteriorly. This would suggest that even in the normal progress of senescence the Purkinje cells of the anterior lobe are more vulnerable than those located more posteriorly. Courville and Friedman (1940), after a full discussion of the various theories which have been advanced, make the following comment: "In conclusion it may be stated that chronic progressive atrophy of the superior cerebellar cortex is not a disease entity but rather a condition due to a rare combination of factors of diverse character which lead to a lowering of the oxygen supply to this region. Whether the Purkinje cells are weakened by precedent infectious disease, are subjected to prolonged hypoxemia (chronic alcoholism) or whether their blood supply is limited by chronic arachnoidal thickening, the peculiar localization of the process to the superior surface of the cerebellum seems to be due to the close proximity of this surface in life to the under surface of the tentorium, possibly interfering with blood flow through the superior cerebellar arteries" (p. 181). b. GENERALIZED

(1) Chronic An example of chronic generalized cortical atrophy is the case described by Jelgersma (1919). In such patients the onset is at varying ages, and the disease progresses slowly for many years. The symptoms of gait disturbance and ataxia of the individual movements of the extremities come on simultaneously. Corresponding with this uniform dysfunction of the anterior and posterior lobes of the corpus cerebelli is a more nearly uniform distribution of the atrophy throughout the whole of the cerebellar cortex. Pathologically a gross atrophy of the whole cerebellum may be found, vermis

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and hemisphere both being affected. All the Purkinje cells may be lost and, if so, there is a marked disturbance of the granular layer as well. The molecular layer is thin, and only the Golgi cells can be identified. There is little gliosis. The dentate nucleus may be affected in its microgyric portion, and there is an atrophy of the paraolivary nuclei and the dorsal part of the main olivary nucleus, particularly in its oral part. Occasionally there is a slight change in the internal group of pontine nuclei. No other abnormalities are seen, and the fiber tracts of the brain stem and spinal cord were all normal in the cases described. Another patient who might fit this category is the unusual example described by Bertrand and Godet-Guillain (1942a). This patient had a rather sudden onset of her disorder at the age of thirty-three years. Her symptoms were pain in the back and extremities, swelling of the joints, elevation of temperature, and delirium. One month after the onset of this acute illness there appeared a typically cerebellar disorder of gait and speech, with incoordination, vertigo, and intention tremor. There was a gradual improvement for a few years, after which the condition remained stationary until her death from carcinoma of the ovary twentytwo years later. A generalized cortical cerebellar atrophy was evident at the autopsy. There was no change in the severity of her neurological disease during her last illness. This is of special interest in view of the frequent association of carcinoma, particularly of the ovary, with subacute generalized cortical cerebellar atrophy. If this patient had died within a year or two of the onset of her illness, in all likelihood the cerebellar damage would have been as extensive then as it was found to be twenty-two years later, though the changes in the subcerebellar nuclei might not have made their appearance if they are, as we believe them to be, secondary to the cerebellar cortical damage. (S) Subacute Subacute cortical cerebellar degeneration has been fully discussed by Brain, Daniel, and Greenfield (1951). These authors have added to the medical literature 4 new cases which fall in this category. They review the essential clinical and pathological findings in 12 more patients, 2 of which had already been reported on by Greenfield in 1934. These patients show a more rapid development of their cerebellar syndrome. Unsteadiness is usually the first or a very early symptom and is followed by signs of cerebellar deficiency in the upper extremities. This sequence of events may be very striking, as in the cases of Brouwer (1919), Kennard (1935), and Parker and Kernohan (1935), but in other cases ataxia of the upper extremities appears simultaneously with the drunken reeling gait. In all the patients who died from the natural progression of their disease the cerebellar syndrome became complete before death, including cerebellar speech disturbance as well. Diplopia was complained of by about one half of the patients (Brain, Daniel, and Greenfield, 1951; Casper, 1929; Kennard, 1935; and others). Nystagmus was also frequently seen, and is considerably more common than in the chronic forms of cortical cerebellar degeneration. The patient frequently may complain of pains in the legs as an early symp-

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torn; mental deterioration also is not uncommon. These findings correlate with the fact that extracerebellar lesions are more frequently seen in many of these cases than in some of the other types of cortical cerebellar degeneration. Upon examination, the cerebrospinal fluid reflects the more rapid degenerative process going on in the brain, for at times a considerable lymphocytic pleocytosis has been reported (Brain, Daniel, and Greenfield, 1951; Greenfield, 1934; and Munch-Peterson, 1947). A paretic zone Lange curve has been found several times, and an excess of total protein is frequent (Parker and Kernohan, 1933; Kennard, 1935; Brouwer and Schlesinger, 1947). As emphasized by Brain, Daniel, and Greenfield (1951), the association of carcinoma with these cases has been most remarkable. Eleven of the 16 patients reviewed by these authors had malignant growths. In 3 the tumor was of the lung, but even more striking is the fact that ovarian carcinoma was found in 5 cases, as also in the most recent case reported, that by Barraquer-Nordas and Lowenthal (1953) (Parker and Kernohan, 1933; Kennard, 1935; Zulch, 1936; Brouwer and Schlesinger, 1947; and Brain, Daniel and Greenfield, 1951). The other sites of malignant growths were the uterus (Alessi, 1940) and breast (Casper, 1929; Greenfield, 1934). The condition cannot always be attributed to carcinoma, for the patients reported by Parker and Kernohan (1935), Dimitri and Victoria (1934), Murri (1900), and Schroeder and Kirschbaum (1928), all of whom would fit into the subacute group, had no carcinoma; and in the case reported by Bertrand and Godet-Guillain (1942a) the patient, from her clinical findings, must have had a severely damaged cerebellum before she developed her terminal carcinoma of the ovary. The presence of the carcinoma did not serve to aggravate her pre-existing cerebellar disease; neither are cerebellar lesions found in the great majority of cases of malignant growths. That carcinoma may have a damaging effect on the nervous system is well known, and the association of polyneuritis with carcinomatosis is frequently observed (Denny-Brown, 1948; Lennox and Prichard, 1950). Probably it is only one of many toxic influences capable of damaging the Purkinje cells. Infections (Murri, 1900; Parker and Kernohan, 1935) have been incriminated, as has alcohol (Stender and Liithy, 1931; Ohmori, 1926; Skillicorn, 1955). Pathologically the group has usually shown "widespread degeneration and disappearance of Purkinje cells with a lesser degree of degeneration of the neurons of the granular layer and little or no damage to the basket cells and tangential fibres. This degeneration is diffuse affecting the vermis at least as much as the hemispheres" (Brain, Daniel, and Greenfield, 1951, pp. 71-72) (Fig. 169). The predilection for the anterior lobe of the cerebellum is not at all evident in this group; in fact, in the case reported by Parker and Kernohan (1935), the only Purkinje cells to be found were in this part of the cerebellum. The observation that disturbance of gait is also an early and constant symptom of this group makes one have some doubt about the validity of the conclusions that have been drawn from the cases of cortical atrophy predominant in the anterior lobe. In these conclusions concerning the syndrome of the anterior lobe of the cerebellum

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Figure 169. A. Cerebellar cortex of a case of subacute cortical cerebellar atrophy, stained with hematoxylin. Note the absence of Purkinje cells and the lymphocytic infiltration of the meninges. B. Cortex of the cerebellar vermis from the same case, stained by Bielschowsky's method, showing the loss of Purkinje cells and the preservation of baskets and tangential fibers. (From W. R. Brain, P. M. Daniel, and J. G. Greenfield, 1951, Subacute cortical cerebellar degeneration and its relation to carcinoma, J. Neurol., Neurosurg. & Psychiat., 1J^: 59-75, Figs. 2 and 1.)

in man, the early gait disturbances have been interpreted as evidence of the effect on postural mechanisms of lesions in this area. It should be borne in mind, however, that even when gait disturbance does occur early in the subacute cases, it is uniformly followed by a full-blown, generalized syndrome of cerebellar deficiency within a few months. In the more chronic forms of the disease death may overtake the patient before the whole cerebellum is involved. In the cases with lesions restricted to the anterior lobe there may be a considerable disproportion between the ataxia in the movements of individual extremities and the use of the legs in maintaining posture throughout the course of the disease. By the use of quantitative methods of recording the spread of the ataxia involving the various parts of the body during the development of a case of cortical cerebellar atrophy, possibly considerable light could be shed on this problem. Certainly with such information one could more easily compare different cases than is possible from the use of the reports of different observers. Such reports are subject to a great many differences of interpretation. The dentate nucleus is more frequently involved in the subacute than in the chronic group; likewise, the spinal cord is the site of degenerative changes in 7 out of the 16 cases reviewed by Brain, Daniel, and Greenfield (1951).

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The cellular reaction in the spinal fluid is mirrored in a meningeal and perivascular lymphocytic infiltration. This may be very marked, but even when so, it has been interpreted as simply a nonspecific reaction to the rapid evolution of the degeneration rather than as evidence of an inflammation. Secondary degeneration of the inferior olives is much less common in this group than in the more chronic cases. De Haene (1937) has paid considerable attention to this contrasting feature between the subacute form as exemplified by Kennard's case (1935) and his own. Both were studied in Brouwer's laboratory. De Haene attempted to draw some inferences relative to the anatomical connections to the cortex on the basis of the presence of climbing fibers in Kennard's case, in which there was no degeneration of the inferior olive, and their absence in his own case, where there was a marked secondary atrophy of the olive connected with the involved cerebellar folia. One would have expected the reverse to have been the situation with respect to the climbing fibers, if they actually come from the deep cerebellar nuclei, as is suggested by the anatomical work of Carrea, Reissig, and Mettler (1947); for in Kennard's case there were degenerative changes in the deep nuclei but none in the olive, while in the case reported by de Haene (1937), in which the climbing fibers were missing and the olive was degenerated, the deep nuclei were perfectly normal. Brain, Daniel, and Greenfield (1951) suggest that this peculiar toxic effect may be related to the so-called "Gordon phenomenon," in which the Purkinje cells are known to suffer following injections of lymphoma, bone marrow, and particularly eosinophiles. They state: "It is well known that a high eosinophilia may appear in the blood in cases of carcinoma, especially of the ovary, but there is no record of such an association in any of the reported cases of subacute cerebellar degeneration, nor is it known whether, or to what extent, there was carcinomatous invasion of the bone marrow in these cases" (p. 73). Meyer and Foley (1953) found that extracts of bone marrow largely replaced by metastatic lung cancer were ineffective in producing Purkinje cell loss. (3) Acute The acute cerebellar cortical "atrophies" will be discussed in detail in the next chapter. They are simply mentioned here to place them in some relation to the chronic and subacute forms of cortical cerebellar atrophy. It is well known that the Purkinje cells are vulnerable to a large number of noxious agents which may affect the nervous system in an acute fashion. Degeneration of these elements has been reported following heat stroke, exposure to various exogenous toxic substances, the intracerebral injection of certain lymphomas, bone marrow, and eosinophiles, anoxemia, and the toxins of typhus fever, scarlatina, tuberculosis, syphilis, and enteritis of unknown cause. What the interrelation between these various noxious agents is one cannot say. The observations to be discussed in the next chapter have, of course, a very important bearing on the problem of cerebellar atrophy, although it is impossible to state at this time whether any one of the acute noxious agents plays a role in any of the recognized types of chronic cortical cerebellar atrophy we have discussed above.

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The study of these acute conditions may eventually throw some light on the problem of cerebellar cortical atrophy and on the problem of cellular neuropathology in general. The Purkinje cell, because of its size, regular geometric arrangement, and the ease with which it can be damaged, offers a favorable cell type for an experimental approach to the problems of cellular neuropathology. To this unit of the nervous system quantitative studies can be applied that would not be so easy to apply to a more diffusely organized cell mass. As we shall see in the next chapter, only a beginning has been made along these lines in a field which offers much to our understanding of the fundamentals of cellular pathology as it applies to the nervous system. B. OLIVOPONTOCEREBELLAR ATROPHIES It has been apparent that any attempt to subdivide cortical cerebellar atrophies is necessarily somewhat arbitrary. Certain cases are assigned to certain categories when features may exist that tend to link the condition to another category; and when the etiology is more fully known, some cases now classed together will logically be separated. Certain cases have been reported, moreover, which tend to link the cortical atrophies to the olivopontocerebellar atrophies. Such, for example, are the patients described by Guillain, Bertrand, and Thurel (1933) and one of those described by Schroeder and Kirschbaum (1928). The olivopontocerebellar atrophies also find a point of union with hereditary spinocerebellar ataxias (Andre-Thomas, 1897; Schroeder and Kirschbaum, 1928; Hassin and Harris, 1936; Ley, 1947; and others). The same overlap between olivopontocerebellar atrophies and degenerative diseases of the basal ganglia exists (Scherer, 1933b; Titeca and van Bogaert, 1946; Critchley and Greenfield, 1948; and others). Hassin and Harris (1936) took the extreme position that olivopontocerebellar atrophy and heredocerebellar atrophy are one and the same disease process. They state: "Careful analysis of the cases recorded as instances of heredocerebellar atrophy of Marie forces one to the conclusion that practically all such cases may be considered cases of olivopontocerebellar atrophy." The situation is not simplified by the appearance of such papers as the one by Davison and Wechsler (1938) which describes, under the title of olivopontocerebellar atrophy, a patient in whom some atrophic and demyelinating process was evident, but it was unilateral and involved simultaneously the cerebellum, tegmentum, and cranial nerves on one side. Also, one might question the advisability of presenting as a case of olivopontocerebellar atrophy the patient so presented by Noica, Nicolesco, and Banu (1936)—a patient who had changes in the pons, olive, and cerebellum rather characteristic of this condition but who showed, in addition, pathological changes in the spinal cord including Clarke's column and the dorsal root ganglia, the substantia nigra, the thalamus, and the frontal and parietal lobes of the cerebral cortex. It is at once evident that though one can find and describe a patient with a relatively pure degeneration limited to the olive, the pons, and the cerebellum, there are other cases in which this disease process is associated with atrophic changes in both related and remote areas of the nervous system in a most

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bizarre and bewildering fashion. Marburg and Riese (1947) have attempted to relate some of these widespread changes to the vascular supply. Although earlier reports exist of cerebellar degenerative processes which may have been examples of this condition, the first one presented in proper detail pathologically and with an adequate clinical description is that of Dejerine and Andre-Thomas (1900) (Fig. 170). It is to these workers that the credit for the first description of this disease is usually given. In the summary of their paper is the following statement, which expresses about all that is known even now about this condition: "There exists a cerebellar disorder characterized anatomically by atrophy of the cortex, the inferior olives and the grey matter of the pons, by the complete degeneration of the middle peduncle and by partial atrophy of the restiform body, by the relative intactness of the central grey nuclei; it is a primary systematic degenerative atrophy, neither sclerotic nor inflammatory. Clinically it is less well characterized for it is manifested by the cerebellar syndrome common to all the atrophies. It is neither hereditary, nor familial, nor congenital and it begins at an advanced age. Its etiology is obscure. It belongs to the category of primary cerebellar atrophies. We designate it olivopontocerebellar atrophy" (p. 360). Since this description was made, others have published examples of this condition. Among them are the reports of von Stauffenberg (1918), who gave a fairly complete description of fourteen earlier cases, some of which were probably examples of olivopontocerebellar atrophy. Among them, however, were the cases described by Holmes which we consider to be examples of familial cerebellar cortical atrophy.

Figure 170. Myelin stain of the original case of olivopontocerebellar atrophy, showing the marked contrast between the degenerated hemispheres and the well-preserved white matter of the vermis and about the dentate nucleus. (From J. Dejerine and Andre-Thomas, 1900, L'atrophie olivo-ponto-cerebelleuse, Nouv. iconog. de la Salpetriere, 15:330-370, Fig. D.)

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Besides the numerous case reports which serve to illustrate the linkages between this condition and other degenerative diseases in the nervous system, there have been several clinicopathological reports of relatively pure forms of this disease. Among such reports should be mentioned those by Hoeneveld (1923) and of Winkler (1923), each of whom described one of two brothers; Parodi and Ricca (1925); van Bogaert and Bertrand (1929); and Bakker (1924). Critchley and Greenfield (1948) have reported two cases, one a pure case of olivopontocerebellar atrophy, and the other showing in addition some pallidal degeneration. They have outlined the clinical manifestations associated with this striking pathological change and discuss at length the general problems of cerebellar degeneration and the interrelations among the various subtypes with which we are now concerned. Geary, Earle, and Rose (1956) have described a pure form of this disease most completely, in admirable detail both clinically and pathologically. Most neurologists are agreed that it is not possible to differentiate clinically between olivopontocerebellar atrophy and the chronic cortical degenerations which appear in later life. Olivopontocerebellar atrophy begins in late middle life. The instances of familial involvement in typical cases are very unusual, and when a familial history is present it is a point favoring a diagnosis of either a familial form of cortical cerebellar atrophy or of spinohereditary ataxia. In the family described by Keiller (1926) definite spinal cord changes were noted in the original report, but one brain from this family was later described by Hassin and Harris (1936) as a typical case of olivopontocerebellar atrophy. According to Critchley and Greenfield (1948), the findings on which this classification was made were "far from convincing." Aring's patient (1940) likewise, while familial to be sure, had more clinical and pathological features suggesting Wilson's disease than features suggesting olivopontocerebellar atrophy. Chandler and Bebin (1956) have described a hereditary form of cerebellar ataxia which, in the one patient examined post mortem, showed pathological features resembling those of olivopontocerebellar atrophy but showed as unusual features an almost complete loss of the Purkinje cells and rather marked changes in the cerebral cortex. The disease shows unremitting progression, terminating fatally in four to six years. The first symptom complained of in most instances is difficulty in walking. The two patients described by Critchley and Greenfield (1948) complained of their legs giving way, a symptom reminiscent of the behavior of experimental animals after cerebellar lesions involving the portion of the cerebellum dominated by pontine connections. It is possible that the gait disturbance seen early in the disease differs qualitatively from the titubating gait which is seen in the cortical cerebellar atrophies of anterior lobe predominance and which is, in our opinion, the clinical manifestation of lesions of the anterior lobe. Impaired articulation, tremor of the hands, and awkwardness in fine finger movements are soon noticed as the disease progresses. Later on, possibly owing to the progressive involvement of extracerebellar pathways and nuclei, one observes weakness, rigidity of the legs, mental impairment, sphincter disturbances, first of the bladder and then of the bowel, and finally a state in which even chewing and swallowing are disturbed. Negative symptoms which should be mentioned are the absence of sensory changes, visual symptoms, muscular wasting, and cranial nerve lesions.

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The essential features of the pathological findings are first, a grossly evident atrophy of the pons and of the inferior olivary nuclei bilaterally, together with a cerebellar atrophy which is generalized but maximal in those lobules which receive the bulk of their afferent connections from the pontine and olivary nuclei. Microscopically there is noted a very striking and usually complete loss of cells in the olivary and pontine nuclei, with a completely pale brachium pontis and middle peduncle. This shows in sharp contrast to the normal pyramidal fibers and cranial nerve rootlets. The cerebellar sections show the fiber degeneration extending into the lateral portions of the anterior and posterior lobes of the corpus cerebelli. The flocculonodular lobe and those parts of the vermis which have their sources of afferent fibers in the spinal cord are spared and stand out in bold relief, as do the dentate and roof nuclei, the superior cerebellar peduncle, and the vestibulocerebellar and spinocerebellar pathways. The most acceptable conception of the nature of this process is to look upon it as a true abiotrophy of those nerve cells which are known to grow out from the rhomboid lip to form the pontine, the arcuate, the lateral, and the olivary nuclei. There has been some disagreement as to where the pathological process begins. Some say in the fibers (von Stauffenberg, 1918); others, in the nuclei (van Bogaert and Bertrand, 1929); and Scherer (1933b) described the degeneration as beginning in the distal parts of the fibers and gradually extending back toward the cell body. The atrophy of the Purkinje cells is variable, and usually the degree of cortical cellular loss is not so complete as in the cortical atrophies, unless one is dealing with a borderline type such as the one reported by Guillain, Bertrand, and Thurel (1933). When observed, this cellular degeneration is usually most marked in the hemispheres and is looked upon by most authorities as a transneuronic lesion. The explanation for the rather frequent involvement of the remote parts of the nervous system is not easy. The vascular supply has been suggested as playing a role here (Marburg and Riese, 1947). It may be that Hassin and Harris (1936) are correct in their assumption that the hereditary ataxia and olivopontocerebellar atrophy are indistinguishable and represent different aspects of the same disease process. It is true that clinical differentiation between individual cases of cortical cerebellar atrophy, olivopontocerebellar atrophy, and some of the hereditary spinal ataxias is impossible, but unless one is to take the position that the whole group of primary degenerative diseases of the cerebellum are one and the same condition, a point of view few will be willing to accept, it seems best to consider them now as separate entities. Until we have knowledge of the etiology of these so-called degenerative diseases, the confusion in regard to the classification will remain. That the outlook for a successful treatment will remain in the same hopeless state until such knowledge is available goes without saying. Schut (1946) has described in a cat a condition which, from the pathological appearances, resembled olivopontocerebellar atrophy. No information is available concerning any symptoms the cat may have exhibited.

ATROPHIC CHANGES 463 C. CEREBELLAR NUCLEAR ATROPHIES For purposes of completeness in discussing the primary atrophies of the cerebellum, a category of nuclear atrophy should be considered. The evidence for the existence of an isolated atrophy of the cerebellar nuclei is not very great. The dentate nucleus is sometimes involved in cortical cerebellar atrophy, particularly of the subacute form (Kennard, 1935). Changes here are seen in certain cases of dystonia musculorum deformans, and Davison and Goodhart (1938) have given a report of this literature. The evidence that dentate nuclear changes are essential for this syndrome is not good, and in every case there were extensive lesions of the extrapyramidal system. However, Bostroem and Spatz (1928) have claimed that in a case of athetosis reported by them the only pathological finding was an atrophy of the dentate nucleus and brachium conjunctivum. Van Bogaert, David, Ajuriaguerra, Hecaen, and Talairach (1951) have most recently discussed the relation between the dentate nucleus, the superior cerebellar peduncle, and athetosis. The condition which might be considered to fall into a category of primary atrophy of the cerebellar nuclei is the so-called atrophie olivo-rubro-cerebelleuse of Lejonne and Lhermitte (1909). As has been pointed out by Critchley and Greenfield (1948), no similar case has appeared in medical literature since the original report, and probably the importance of this case has been overrated. The report contains practically no clinical data. The patient was never seen by the authors. She had a small thrombosis of the left cerebral peduncle, verified at the autopsy, which involved to a minimal degree the decussation of the brachium conjunctivum. It seems quite probable that the case was one of ordinary chronic cortical cerebellar degeneration with secondary olivary changes, complicated by a vascular lesion of the brachium conjunctivum with retrograde degeneration of the dentate nucleus. This is one category of cerebellar atrophy, it would seem, that could profitably be dropped from an already over-complex group of diseases. The syndrome of Ramsey-Hunt, dyssynergia-cerebellaris-myoclonica, has been discussed in the chapter on convulsive disorders (p. 441). It will suffice to recall here that in the one case examined pathologically, an atrophy of the dentate nucleus of the cerebellum was observed, but there were also findings of Friedreich's ataxia both clinically and pathologically. Scherer (1932) has given a complete discussion of the types of cellular changes which can be expected in the dentate nucleus in association with a large variety of pathological conditions, but his work does not suggest that there is a primary cerebellar nuclear atrophy which should be considered a clinical or pathological entity. Dentate-rubral atrophy is the term used by Andre-van Leeuwen, Babel, van Bogaert, Franceschetti, Klein, and Montandon (1948) to denote the atrophies of the cerebellar nuclear system. Most of the cases they have assembled, however, have had associated lesions in other parts of the brain stem. One of the few cases which appear to be a pure form of this condition is that reported by Grinker (Grinker and Bucy, 1949), with the pathological study credited to Ford. The case report is presented briefly and the pathological study does not specifically mention the spinal cord, though so far as the cerebellum and the brain stem are concerned,

464 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM the degeneration was limited to the dentate nucleus and the superior cerebellar peduncles. D. CROSSED CEREBELLAR ATROPHY Unilateral atrophy or hypoplasia of the cerebellum is usually seen in association with a lesion of the opposite cerebral hemisphere. This condition has been given the name of crossed cerebellar atrophy (Fig. 171). It is not considered a disorder of development, for the atrophy is at times seen in adults after cerebral lesions. The most striking changes are seen when the cerebral insult occurs before birth or in early infancy. In fact, in a certain sense the condition can be considered an example of hypoplasia if the cerebral damage occurs any time before the fifteenth year, when the cerebellum reaches its adult size (Ellis, 1920).

Figure 171. A photograph of the base of the brain of a typical case of crossed cerebrocerebellar atrophy. (From W. Boyd, 1912, A case of cerebral and crossed cerebellar hemiatrophy, Rev. Neurol. & Psychiat., 10:318-325, Fig. 1.)

Regressive changes are also observed, however, and it is on the basis of these changes, which occur hand in hand with retardation in development, that the condition is categorized as an atrophy rather than a hypoplasia. Credit for the first description of this condition is difficult to assign. Some very early references to it occur in the older literature, according to Andre-Thomas and Cornelius (1907). The first record we have actually found is that of Charcot and Turner (1852). Turner then wrote a thesis on the subject (1856). There then follow a number of reports of cerebral lesions with atrophy of the opposite side of the body, including the opposite lobe of the cerebellum. These include the descriptions of Schroeder Van der Kolk (1861), which was translated into English from an essay originally written in 1852. This contains some information concerning even earlier reports. Later papers devoted to the subject are those of Howden (1875), Poullain (1876), Major (1879), Mosse and Guibert (1888), von Monakow (1895), De Jong (1896), Mott and Tredgold (1900), Reitsema (1904),

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Cornelius (1907), Andre-Thomas and Cornelius (1907), Lhermitte and Klarfield (1911), Andre-Thomas and Kononova (1912), Claude and Loyez (1912), Boyd (1912), Kononova (1912), Mingazzini and Gianulli (1924), Tschernyscheff (1925), Miskolszy and Dancz (1934), Hassin (1935), Juba (1936), Schenk (1937), Moore (1943), Verhaart and van Wieringen-Rauws (1950), and many others. Some authors have stated that in order to obtain this crossed atrophy of the cerebellum, the lesion must involve the thalamic area as well as the cortex of the cerebral hemisphere (Mott and Tredgold, 1900; Boyd, 1912; Moore, 1943; and others). Brouwer and Biemond (1938) maintain that it may occur after a purely cortical lesion. Verhaart and van Wieringen-Rauws (1950), who tabulated the essential pathological findings in 38 cases of crossed cerebellar atrophy, found no absolutely predictable relation between any of the factors which have been thought to be important in determining the occurrence or the site of the cerebellar atrophy. Andre-Thomas and Kononova (1912), and others later, had pointed out the three ways in which this influence could be brought out theoretically. One is by connections via the cerebral peduncle, the pontine nuclei, and the middle peduncle to the opposite half of the cerebellum; a second is by descending connections from the brain stem via the central tegmental tract and the inferior olive to the opposite half of the cerebellum. Both these ways would involve some type of transneuronic influence of a trophic nature on the opposite half of the cerebellum. The third pathway, a retrograde one, would be via the thalamus and the superior cerebellar peduncle to the deep cerebellar nuclei of the opposite side. In the cases analyzed by Verhaart and van Wieringen-Rauws (1950) the crossed atrophy appeared to result from any one or any combination of these various pathways, but the route was quite unpredictable in any given case. They pointed out a fact that has been overlooked, namely, that there are undoubtedly many cases of severe cerebral damage occurring even in early life in which no cerebellar atrophy can be detected on the contralateral half of the cerebellum. Such cases are probably quite frequent but are usually not reported. They furnished two such instances and also some equivalent negative results in monkeys after surgical lesions. Von Monakow (1895) had previously reported a crossed cerebellar atrophy after a cerebral lesion of the motor cortex in two newborn puppies. His results were later confirmed by Demole (1927), also in the dog. Winkler had also reported extensive degenerative changes in the cerebellum of an adult dog whose cerebral hemispheres had been removed one and a half years previously. Verhaart and van Wieringen-Rauws (1950) reported no effect on the cerebellum almost two years after severing the superior cerebellar peduncle in an adult monkey and almost three years after section of the central tegmental tract in another adult monkey. They also reported that in a three-day-old monkey the whole frontal lobe was removed, and at sacrifice three years later no atrophic changes in the contralateral cerebellar hemisphere could be detected. After reviewing a large number of cases, they concluded that there is no tendency for the atrophy to be limited to the "neo-cerebellum" when the frontal lobe is injured nor any tendency for it to include the vermis as well when the

Bogaert, 1942, 1949; Louis-Bar and van Bogaert, 1947; Andre-van Leeuwen, Babel, van Bogaert, Franceschetti, Klein, and Montandon, 1948; Myle and van Bogaert, 1949) should particularly be mentioned. The publications of Schut (1950, 1951), Schut and Haymaker (1951), and Schut and Book (1953) are representative of the most recent on this subject. Finallv. Greenfield's monoerar>h (1954) is the most effective presentation to

466 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM temporal and parietal lobes are injured. This is contrary to the claim of Tschernyscheff (1925). Verhaart and van Wieringen-Rauws (1950) could find no consistent or predictable relation between the part of the cerebrum damaged and the part of the cerebellum which was atrophic. The conditions which seemed to favor the development of atrophy of this type were extensive cerebral damage occurring in early life and survival for a number of years. On occasion, however, atrophy might follow limited lesions or lesions occurring in adult life, even if the survival period was relatively short. Conversely, as the negative cases which they cited illustrate, all the conditions felt to be favorable for the development of a crossed cerebeHar atrophy might be present and no atrophy occur. Furthermore, the atrophic cases might show an intermingling of atrophic and normal folia in an apparently random fashion. The conclusion seems obvious that some unknown factor of susceptibility to atrophy is inherently present in the cerebelli of those cases which show the atrophic change which allows the trophic influence to become effective. Verhaart and van Wieringen-Rauws (1950) spoke of a barrier to the effects of the cerebral lesion which must be passed before the cerebellar effect can manifest itself. They wrote in conclusion: "The size, situation and type of the cerebellar atrophy therefore may depend more on the character of the cerebellum involved than on the cerebral lesion eliciting it" (p. 499). Isolated observations by many of the authors listed above which were interpreted as indicating one or another mechanism to explain this phenomenon seem unimportant in the light of this analysis. The pathological changes may be maximal in the nuclei, and may involve to a greater or lesser degree the corresponding cortical elements. There is usually a corresponding atrophy of pontine nuclei and the inferior olivary nucleus ipsilateral to the cerebral lesion and contralateral to the cerebellar involvement. Cerebellar symptomatology is completely lacking in these cases, the cerebral cortex being nonfunctioning. This observation agrees with the effect of cerebral cortical ablation on the symptoms of cerebellar deficiency in experimental animals as reported by Fulton, Liddell, and Rioch (19S2) and Aring and Fulton (1936). E. HEREDITARY SPINAL ATAXIAS

The literature concerning hereditary spinal ataxias is so voluminous that no attempt can be made to cover it in this volume. In our discussion of familial cortical cerebellar atrophy and of olivopontocerebellar atrophy we have already referred to the close relation between these primarily cerebellar atrophies and the hereditary spinal ataxias. The latter are not only related to the cerebellar atrophies but are associated also with degenerations of the extrapyramidal system, with degenerations of practically all the cranial nerves, with spinal motoneuron degeneration, and with retinitis pigmentosa. Indeed, Fricdreich's ataxia has been associated not only with the skeletal abnormalities which are characteristic of its group but also with cardiac disorders (van Bogaert and van Bogaert, 1936; Evans and Wright, 1942; Russell, 1946; Nadas, Alimuring, and Sieracki, 1951; and others). No agreement has been reached on how these cases should be classified nor on

ATROPHIC CHANGES 467 whether any classification is feasible. A few look upon hereditary spinal ataxia and the cerebellar atrophies proper as a single entity, varying only in the location of the disease process. While the literature is too extensive to be reviewed completely here, the papers of Hallervorden (1936), Waggoner, Lowenberg, and Speicher (1938), and Welte (1939) should be consulted. The monographs of Bell and Carmichael (1939) and of Sjogren (1943) are devoted exclusively to this problem and deal with virtually all the cases in England and Sweden, respectively. The important papers of van Bogaert and his many associates (van Bogaert, 1947, 1950b, 1951a, b; Nyssen and van Bogaert, 1934; van Bogaert and Scherer, 1936; Andre-van Leeuwen and van Bogaert, 1942, 1949; Louis-Bar and van Bogaert, 1947; Andre-van Leeuwen, Babel, van Bogaert, Franceschetti, Klein, and Montandon, 1948; Myle and van Bogaert, 1949) should particularly be mentioned. The publications of Schut (1950, 1951), Schut and Haymaker (1951), and Schut and Book (1953) are representative of the most recent on this subject. Finally, Greenfield's monograph (1954) is the most effective presentation to date of the whole problem of spinocerebellar degenerations. Not only has it brought some order out of the confusion but surveys the subject clearly from a historical point of view. Because of the greater incidence of spinal ataxias than of purely cerebellar heredofamilial degenerations, a solution to the fundamental problems of etiology, pathogenesis, and therapy will probably first be found for the former group. If by the time such a solution is reached it has been established that spinocerebellar degenerations are in truth all related to a single genetic factor, the knowledge gained about one form of this complex group may readily be applied to all its varied manifestations. 1. FRIEDREICH'S ATAXIA The relatively well-defined entity known as Friedreich's ataxia was first described clinically and pathologically by Friedreich in 1863—the first detailed description of any familial form of ataxia. Through the years, as more and more cases have been added to the medical literature, it has come to be recognized clinically as a familial and hereditary disease, beginning before the age of twenty, in which a progressive ataxia is associated with a loss of reflexes and with the presence of pes cavus and kyphoscoliosis. Pathologically, the condition constantly exhibits a severe degeneration of the posterior column. But it does not limit itself to rigid pathological boundaries, even though it is more clearly defined both clinically and pathologically than the condition we choose to call hereditary spastic ataxia, after Bell and Carmichael (1939). Instances of Friedreich's ataxia are regularly associated with clinical manifestations and pathological changes involving the dorsal spinocerebellar and pyramidal tracts. That in these cases the cerebellum may also be involved is shown by the cases reported by Mott (1907), Guillain, Bertrand, and Mollaret (1932), Lhermitte, Mollaret, and Trelles (1933), Pfeiffer (1922), Hunt (1921), Trelles (1934), Schut and Haymaker (1951), van Bogaert (1951b), and others. One cannot agree with Hassin (1938) that Friedreich's ataxia is never associated with

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cerebellar degeneration. The degree of cerebellar change may be minimal, as in the case of Pfeiffer (1922), who found only minor changes in the cerebellar cortex; or it may be extremely severe, as in the cases described by Trelles (1934) and Schut and Haymaker (1951). The latter authors state: "Demyelination of the inferior and middle cerebellar peduncles and medullary center of the cerebellum was severe and some Purkinje cells were lost, but posterior and anterior midline structures were spared. These changes are characteristic of olivopontocerebellar atrophy" (p. 194). (Fig. 172.) The cerebellar changes associated with Friedreich's ataxia may be in the dentate nucleus and superior peduncle (Hunt, 1921). Van Bogaert (1951a), after

Figure 172. A Myelm stam of the cerebellar folia of case 1, of the family described by Schut and Haymaker (1951), which is classified clinically and pathologically as a case of Friedreich's ataxia Note the demyelmation of the folia in the lobulus ansiformis. B. Bodian stain of the cortex in the same area to show involvement of both the Purkinje cells and the granular layer. C. Myelin stain of the brain stem of the same case. Note the severe demyelination of the brachium pontis and the transverse fibers of the pons. There is also involvement of the brachium conjunctivum (From J. W. Schut and W. Haymaker, 1951, Hereditary ataxia: pathological study of 5 cases of common ancestry, J. Neuropath. & Clin. NeuroL, 1:18S-213, Fig. 2.)

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commenting on the pyramidal amyotrophic and cerebellar changes seen in Friedreich's ataxia, has said: "The degree of development of certain signs depends on the period of the illness when the patient is observed. It is quite apparent that paralysis, obvious amyotrophy with fibrillary twitching are not at all exceptional in an advanced phase of the illness and it is superfluous to consider such cases atypical or intermediary forms" (p. 622).

2. SPASTIC ATAXIA (MARIE'S CEREBELLAR ATAXIA) Spastic ataxia has not achieved the same degree of recognition as a clinical entity that Friedreich's ataxia has. First described by Marie in 1893 as hereditary cerebellar ataxia, its actual position has been the source of considerable discussion ever since. Clinically, as originally defined by Marie and his pupil Londe (1895), the disease begins with a cerebellar ataxia after the age of twenty and follows a milder course than does Friedreich's ataxia. The deep reflexes are normal or exaggerated and there are frequent ocular disorders of various types, extrapyramidal changes, mental difficulties, and cranial nerve lesions. As pointed out by Holmes (1907b), subsequent pathological studies of the cases on which this description was based demonstrated that it was a heterogeneous group; Holmes denied that the condition should be considered either a clinical or pathological entity. It has, however, gradually come to be regarded as a clinical entity, essentially as described by Marie. Exaggerated tendon reflexes rather than decreased tendon reflexes is the feature which clearly separates spastic ataxia from Friedreich's ataxia. Spasticity may so dominate the picture that at times it is difficult to differentiate certain cases of spastic ataxia from cases of hereditary spastic paraplegia, first described by von Striimpell in 1893. Greenfield (1954) credits Menzel (1891) with having first clearly defined a hereditary cerebellar ataxia, Menzel having observed it in three generations and having made a complete postmortem examination of one of six patients affected. There is no agreement among pathologists concerning spastic ataxia. The French school (Marie and Foix, 1914; Foix and Tretiakoff, 1920; Guillain, Bertrand, and Godet-Guillain, 1941) has emphasized the importance of the degeneration in the ventral portion of the spinal cord and especially the ventral spinocerebellar tract. Hassin and Harris (1936), as we have indicated above, have insisted that the pathological condition which forms the basis of Marie's ataxia is olivopontocerebellar atrophy. In this they are supported by Welte (1939). Waggoner, Lowenberg, and Speicher (1938) contended that the postmortem findings were so variable from case to case that no specific patho-anatomical picture could be assigned to hereditary cerebellar ataxia. Most recently Schut and his associates in an important study have collected data on the largest group of cases of this condition known to stem from a single ataxic individual. This was a male who migrated from the Netherlands to the United States in 1866. Ataxia has been determined to have been present in 41 of his 343 descendants, who have been followed through six generations. Schut has personally made complete neurological examinations of 13 of these patients, and has had access to the records of an additional 9 examined at various clinics near where this family has lived.

C E N C A L O G I C C H A R T OF A FAMILY D I S P L A Y I N G H E R E D I T A R Y A T A X I A

Arabic numerals abort symbols are assigned on// to mtmbers born of an atonic parent. Children of non-atoxic members are indicated collectively by a number within the symbol. A Roman numeral denotes the generation and whin followed by on Arabic figure is the individual's geneologic number serving as identification. Numbered members and their children who have not reached the age of 35 may yet become atoxic (gen. IS -22, 23, 25,29, 34,37,38,47 and all numbered members of generations' except 1,3,4,8 and IO i

Figure 173. The genealogic chart of a family displaying hereditary ataxia. (From J. W. Schut and W. Haymaker, 1951, Hereditary ataxia: pathological study of 5 cases of common ancestry, J. Neuropath. & Clin. Neurol., 1:183-213, Chart I.)

Table III. The Clinical Types of Hereditary Ataxia, with Their Pathological Counterparts, from a Family with a Common Ancestor. (From J. W. Schut and W. Haymaker, 1951, Hereditary ataxia: pathological study of 5 cases of common ancestry, J. Neuropath. & Clin. Neurol., 1:183-213, Table 2.)

Type

Individuals Affected

Cases Studied Pathologically in Present Report

Clinical Criteria Employed

Main Pathologic Findings

Friedreich's ataxia

V-5* V-ll?

V-5 (Case 1) a. 17 yearsf b. 25 yearsf

(1) onset before 20th year. (2) deep reflexes absent. (3) some skeletal deformity.

Severe posterior column degeneration; severe olivopontocerebellar atrophy; severe gross cerebellar atrophy; severe degeneration of bulbar cranial nerve nuclei.

Hereditary cerebellar ataxia, Subgroup A

III-7 IV-2 IV-4

IV-6 (Case 2) a. 29-30 years b. 42 years

(1) normal or hypoactive deep reflexes. (2) prominent co-ordinative disturbances.

Moderate posterior column degeneration; severe cortical cerebellar atrophy combined with olivopontocerebellar atrophy; moderate gross cerebellar atrophy; severe anterior horn cell degeneration; minimal degeneration bulbar nuclei.

IV-9 (Case 8) a. 25 years b. 47 years IV-26 (Case 4) a. 25 years b. 37 years IV-27 (Case 5) a. 20 years b. 30 years

(1) hyperactive deep reflexes. (2) moderate co-ordinative disturbances.

In all 3, cerebellum only slightly atrophied, nuclei pontis preserved, and olivary atrophy severe. Posterior column & spinocerebellar tract atrophy was severe in Case 3, moderate in Case 4, absent in Case 5. Bulbar nuclear degeneration conspicuous in Case 4; moderate in Cases 3 & 5. Muscular atrophy in Case 4.

None

(1) early prominent pyramidal disorder in lower limbs. (2) minimal co-ordinative disorder.

No pathologic studies done.

rv-e*

V-2 V-7

Hereditary cerebellar ataxia, Subgroup B

III-8, IV-9 IV-15, IV-16

rv-2i, rv-26

IV-27, IV-28 IV-30,IV.S2* IV-35, IV-36

Hereditary spastic paraplegia

IV-43* IV-48

*These cases were described clinically in a previous publication, fo, age at onset; b, age at death.

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These 22 cases fell into four clinical groups classified on the basis of the status of the deep reflexes and the degree of coordination defect. The four groups are Friedreich's ataxia, 1 case; hereditary cerebellar ataxia, 19 cases, which were further subdivided into subgroups A and B of 7 and 12 respectively; hereditary spastic paraplegia, 2 cases, so considered clinically and placed in this group because of their clinical findings. The genealogic chart of this important family is shown in Figure 173, and the summary of the pathological findings in three of the four clinical types is shown in Table III. Case 1 was considered a case of Friedreich's ataxia, and the pathological findings so far as the cerebellum are concerned have already been mentioned (p. 468). Case 2 is an example of subgroup A, and cases 3, 4, and 5 of subgroup B. No pathological studies have as yet been reported from the fourth group. Schut and Haymaker (1951) summarize their results as follows: "The essential differences in the three members of subgroup B of hereditary cerebellar ataxia (Cases 3, 4 and 5), when compared to the other two groups (Cases 1 and 2) consisted of 1) minimal gross cerebellar atrophy, 2) minimal pontile changes, and 3) minimal posterior column degeneration early in the course of the disease. As to posterior column degeneration, it occurred earlier in Case 1 than in any member of subgroup B, and in Cases 4 and 5 was insignificant. The severe posterior column degeneration in Case 3, a member of subgroup B, is ascribed to the prolonged course of the disease (twenty-two years) when comparison is made with Cases 4 and 5 in which the duration was half as long (twelve and ten years); this patient had not manifested any disorder of the posterior columns clinically eleven years after the onset of his disorder. Thus, pathologic changes varied with the stage of the illness; and taking this point into consideration it would seem likely that the different clinical groups have real pathologic counterparts. "Bulbar palsy, considered a significant factor in duration of the disease in our cases, occurred in all three groups, being relatively severe both clinically and pathoanatomically in all instances except Case 3, in which, however, some fibers of the IXth and Xth nerves were degenerated. The duration of the illness in this case was twenty-two years, which is in contrast to the others, in which it varied from eight to twelve years. Involvement of the bulbar cranial nerve nuclei in this family was conspicuous when comparison is made with the average run of cases reported in the literature" (p. 208). Individual families, as reported by Bell and Carmichael (1939) and others, have shown a considerable difference in the amount of bulbar palsy present. The cerebellum was reduced in size in all the cases studied by Schut and Haymaker (1951), and in all but case 4, the molecular layer, Purkinje cells, granular and medullary layers, and the dentate nucleus were all involved in the degenerative process. Even in case 4 there was severe degeneration of the inferior olive and corpus restiforme. This case had been studied by Hassin, who considered it an incomplete form of olivopontocerebellar atrophy. Schut and Haymaker (1951) state in conclusion: "In explanation of the variability of expression manifested by members of this series, it is postulated that in addition to the mutant gene which determines the existence of the disease, there are certain unidentified factors (genetic modifiers) which govern the localization of the disease, and that other separate specific

ATROPHIC CHANGES 473 factors may control the extent of the degeneration and the rapidity with which given lesions progress" (p. 210). In a special study devoted to the genetic factors in the family, Schut (1951) assembled additional data by studying other known inherited characteristics, namely, the blood groups and the ability to taste phenylthiocarbamide. From the clinical and pathological study it had been apparent that not only was there considerable variation in the site of the degenerative process but that the patients with similar clinical findings, based upon a distinctive pathological change, were all closely related. Thus the progeny of III-l—namely, IV-2, 4, and 6 and V-2 and 5—all showed clinical evidence of early posterior column degeneration without involvement of the pyramidal system. On the other hand, the progeny of 111-15, a cousin of III-l on her mother's side—namely, IV-43, 45, 46 and 48— all had early signs referable to the pyramidal signs. Schut was unable to demonstrate a tight linkage between the dominant gene for the hereditary ataxia in his family group and the four known genes for human blood groups or the genes for the inherited ability to taste phenylthiocarbamide. He states in conclusion: "The disease appeared as a dominant trait in forty-five members. There was a suggestion that the disease was determined by a partially sex-linked gene, but conclusive evidence for this type of inheritance must await the time when certain members reach the upper limit of the age of the onset. "Complete penetrance of the gene was apparent. The age of onset was recorded in thirty-two instances of the ataxia, usually within a range of years. With one exception, the disease made its appearance before the age of thirty-five, with an overall average of 26.5 years. There exist fifty-one individuals in the fourth, fifth and sixth generations who by virtue of their parentage may yet exhibit ataxia before the age of thirty-five years" (p. 109). No investigation of the possible environmental factors which may be of some importance in the variations of this large family group has been attempted. Evidence collected on the mode of inheritance of this disease has been reviewed by Schut. Most believe that both dominant and recessive forms of the disease exist. Brain (1925), Bell and Carmichael (1939), and Sjogren (1943) had previously attempted to explain the hereditary manifestations by postulating two characteristics, one recessive and widely distributed in the population, the other a dominant, appearing as a mutation only rarely. It would appear that family groups differ and that Friedreich's ataxia tends to be recessive and spastic ataxia dominant. Greenfield (1954) has presented in tabular form all the essential clinical and pathological findings of the cases in the thirteen families reported to date of hereditary cerebellar ataxia which he identifies as the type A (Menzel) form of the disease. As he points out, it is not possible to differentiate clinically the different forms of cerebellar and spinocerebellar disease. Sjogren's study included 26 cases, in six families, which clinically were thought to correspond to Marie's clinical description of hereditary cerebellar ataxia. These cases probably are, however, like those of Marie's original description, a heterogeneous group, belonging in the general category of spastic ataxias but relatively few of the cases having as a predominant feature cerebellar degeneration.

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F. CEREBELLAR CHANGES OF A DEGENERATIVE TYPE ASSOCIATED WITH SPECIFIC NEUROLOGICAL CONDITIONS

1. AMAUROTIC FAMILIAL IDIOCY Amaurotic familial idiocy is a heredodegenerative disease, usually of a recessive type. It was first described by Tay (1881, 1884) on the basis of changes in the macula, and by Sachs (1887, 1892, 1896), who emphasized the cerebral changes of what is now known as Tay-Sachs disease. These authors described the infantile type, the usual onset of which is during the first year of life. It is the most common form of this condition. The characteristic cellular pathology is degeneration of the nerve cells and secondary atrophy of fiber tracts, associated with the accumulation of a characteristic lipoid substance in the cytoplasm. While these changes are generalized throughout the brain and spinal cord in many patients, the degeneration seems to show a predilection for certain areas in some. As a rule the cerebellum is little affected as compared to the thalamus, the cerebral cortex, and the retina (Hassin, 1924). That cerebellar degeneration can occur is borne out by the reports of Westphal (1917), Dollinger (1919), Globus (1923), Ostertag (1925c), and Steegman and Karnosh (1936). When it occurs it is quite similar to the pathological change seen in the late infantile form. In this type cerebellar degeneration is so regularly seen that Jansky (1910), who first described this variety, considered it to represent a cerebellar form of the disease. The late infantile form has been studied by Jansky (1910), Bielschowsky (1914,1920), Hassin (1926), and others. The type which appears in older children, the so-called juvenile type, may also be associated with gross cerebellar atrophy (Sjogren, 1931; and others). Because of the vagaries of the site of maximum involvement, classifications which tend to differentiate the cases on the basis of the site of maximum pathology have tended to be disregarded at the present time. In general it is true that the older the child, the less fulminating the course, and the cherry red spot in the retina diagnostic of the disease in the infant period is not seen in the older cases. Also, the predilection for Jewish families noted in the infantile cases is not found in the cases coming on later in life. As a rule blindness and mental deterioration, leading in time to a vegetative existence and even to decerebrate rigidity, are more prominent clinical manifestations than are the signs and symptoms of cerebellar deficiency. However, in the case described by Steegman and Karnosh (1936), the infant which had been normal to the age of six months began to have difficulty sitting up and showed other signs of arrested development. There was such a marked hypotonia that a diagnosis of injury to the cerebellum at birth was at first entertained. As the disease progressed, the cerebral and ocular symptoms became predominant. The case of Steegman and Karnosh (1936) and that of Hassin (1926) are similar to each other and to the majority of reported cases so far as the cerebellar pathology is concerned. The organ is grossly atrophic, with widening of the sutures and gross shrinkage of the middle peduncle. Microscopically the cells of the granular layer suffer most greatly, consisting of only a single row of cells at times. The Purkinje cells show some loss, but many are preserved, exhibiting the customary enlargement of their cell body by the fat-staining inclusion body. The

ATROPHIC CHANGES

475

dendrites are distorted and the neurofibrils pushed aside. There is marked degeneration of the medullary substance, which shows increased vascularization. The nuclei and their axons are somewhat less affected, though all parts share in the pathological process. Mossy fibers and the baskets about the Purkinje cells are strikingly absent. This is characteristic of the so-called centripetal type of cerebellar cortical atrophy. In Hassin's case the degree of demyelination was considerably less in the cerebrum and brain stem than in the case described by Steegman and Karnosh.

2. PICK'S DISEASE The combination of Pick's disease and cerebellar atrophy has been recorded a few times, though the relation between the two conditions is obscure. The earlier reports were those of Verhaart (1930) and Lowenberg (1936); in describing such a case of Pick's disease they recorded the presence of cerebellar atrophy, but in neither instance could the cerebellar atrophy be said to be characteristic of any of the recognized forms. Verhaart's case might be considered an example of circumscribed cortical panatrophy (see p. 451). That of Lowenberg, while its anterior lobe location was such as one usually sees in the localized cortical cerebellar atrophy, did not show typical histological changes, and it was not considered by Lowenberg to be typical of this group. Buchanan, Overholt, and Neubuerger (1947) have described a case which is typical clinically of the localized form of cortical cerebellar atrophy (see p. 452). In this case there were changes in the cerebrum more on the right than on the left, involving the island of Reil and the hippocampal gyri, and in the convolutions of the temporal lobe. There was a marked falling out of nerve cells in the involved areas, with gliosis. There was no sharp line of demarcation at the borders of the atrophic areas. There were some argentophile plaques, but they were small and not entirely limited to the atrophic areas. These authors quote Hassin (1934), who states: "The only morbid condition of the central nervous system which is analogous to cerebellar cortical atrophy macroscopically and microscopically is Pick's disease." However, the case described by Hassin in the 1934 paper was like those which Lichtenstein and Levinson (1946) called circumscribed panatrophy. No clear basis for the association of these two conditions was evident, and while both familial and nonfamilial forms of both conditions are known to occur, there was only a very indefinite family history obtained in the case described by Buchanan, Overholt, and Neubuerger (1947). Neubuerger, in commenting upon their possible relationship, stated in the discussion of this paper: "We are dealing with two well-defined, different diseases of the brain that commenced at different times and showed the characteristic pathological lesions usually associated with either of them; if they are to be considered as a unity this can be done only on the ground of their belonging to the group of heredofamilial degeneration" (p. 163).

3. ALZHEIMER'S DISEASE The only instance of an associated cerebellar atrophy and Alzheimer's disease is the one reported by Hemphill and Stengel (1941). In this case a crossed cerebrocerebellar atrophy was present. It would seem that the second possibility pre-

476

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

sented by the authors to explain this unusual combination is the most likely one, namely, that the crossed cerebrocerebellar atrophy was the result of an asymptomatic cerebral affection which damaged the right hemisphere sufficiently to produce the asymmetry noted at death. Alzheimer's disease appeared later and was responsible for all the clinical manifestations. As the authors point out, it is not unusual for cerebral lesions to occur at or before birth and to cause no detectable neurological deficit. As we have indicated in the section on crossed cerebellar atrophy, there is very little relation in many instances between the degree of the cerebral injury and the development of the crossed cerebellar atrophy. It would therefore appear that on the basis of this single case one could not suppose any real connection between Alzheimer's disease and cerebellar atrophy.

4. PROGRESSIVE LENTICULAR DEGENERATION (WILSON'S DISEASE) In previous sections of this chapter we have called attention to the association between cerebellar atrophy and changes in the basal ganglia. Such changes are particularly prone to occur in the hereditary ataxias and in olivopontocerebellar atrophy. They may also occur in the cortical cerebellar atrophies. The converse of this association is also possible, and the case reported by Aring (1940) is an example. Extrapyramidal symptomatology of a hyperkinetic type dominated the picture throughout the patient's life, and there was no clue from the clinical findings that the cerebellum or its pathways were involved. The autopsy showed a marked cavitation in the basal ganglia with smaller similar excavations lower down in the brain stem. This seemed to represent the oldest part of the pathological process. It is well known that such cavitation can occur in long-standing cases. Probably also due to its long duration, the pathological process had extended into the lower brain stem and cerebellum. Here the marked gliosis and glial cellular reaction usually seen in the lenticular nucleus was seen instead in the dentate nuclei and the inferior olives. This was interpreted as indicating activity of the pathological process in these areas at the time of death. The cerebellar atrophy was mixed. There was an almost complete disappearance of the Purkinje cells, with diminution of the granular cells and proliferation, in a spotty manner, of the small blood vessels throughout the medullary layer. In addition to this diffuse change, which was the least advanced in the anterior lobe, there was a recent softening in the right hemisphere, thought to be unrelated to the basic pathology. The title of Aring's paper is somewhat misleading, for in the discussion the author clearly points out the basis for his belief that the disease did not represent an olivopontocerebellar atrophy but rather an extension into the cerebellum and subcerebellar nuclei of a disease originating in the basal ganglia, a disease which, if it was not Wilson's disease, closely resembled it. It is of interest that cerebellar atrophies, which, during their long course, may secondarily develop basal ganglion pathology, usually show late in the disease process the rigidity and non-intention tremor that are the clinical evidence of basal ganglion pathology (see pp. 449, 453, 459). In this case, in which the pathology started in the basal ganglia, "extrapyramidal" symptomatology completely

ATROPHIC CHANGES

477

dominated the clinical picture throughout, and there was no clue, even at the time of the patient's death, that cerebellar findings of this severity would be found. 5. DEGENERATION OF THE CEREBRAL GRAY MATTER OF ALPERS Ford, Livingston, and Pryles (1951) have again called attention to an illdefined and rare condition, striking during infancy or during early childhood, in which there is a diffuse degeneration of the gray matter of the central nervous system. First described by Alpers in 1931, the condition has been identified by Christensen and Krabbe (1949) and others. While the cellular degeneration always involves the cerebral cortex, it may or may not involve the cerebellum. When it does, the cortex or nuclei or both may be involved. While cerebellar symptoms may in a few instances be early manifestations, they are overshadowed by the symptoms of mental deterioration, convulsions, myoclonus, spasticity, and choreoathetosis. The etiology and pathogenesis are completely unknown, although the condition may at times be familial.

6. MULTIPLE SCLEROSIS That the cerebellum is involved in multiple sclerosis is well known. The lesions may involve any part of the organ and are in no way different from the lesions of multiple sclerosis in any other part of the central nervous system. The wellknown predilection for the paraventricular areas makes the cerebellar nuclei and the peduncles particularly vulnerable to the demyelinating process. Many of the symptoms of multiple sclerosis are dependent upon the involvement by the disease of these parts of the nervous system. Several writers have called attention to the frequency with which cerebellar atrophies have been mistakenly identified as multiple sclerosis. Many have pointed out that in cases of so-called familial multiple sclerosis, the condition is often an example of hereditary ataxia or one of the familial forms of cerebellar atrophy. Under these circumstances a diagnosis of familial multiple sclerosis is justified only when there is a clear history of typical remissions. Jermulowicz (1934) and Ammerbacker (1938) have each devoted a paper to the pathological changes in the cerebellum in multiple sclerosis.

7. SYMMETRICAL CALCIFICATION OF THE DENTATE NUCLEI Calcification and iron deposition in minute pericapillary and vascular colloid substance has been recognized to occur in the basal ganglia, particularly the globus pallidus, and in the dentate nucleus. The literature on this subject has been reviewed by Eaton, Camp, and Love (1939). Microscopic amounts of this deposition at these sites is so common in routine examinations of the brain as to be without pathological significance. When depositions are of such density as to be visible in roentgenograms of the skull, they may or may not cause clinical symptoms (King and Gould, 1952) (Fig. 174). The calcifications are frequently associated with evidences of parathyroid deficiency, as has been particularly emphasized by the numerous publications on this subject from the Mayo Clinic. Vascular occlusion may occur in the advanced stages. Frequently, however, the

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PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

Figure 174. A. roentgenogram of the skull, occipital view, retouched. Note the coarse symmetrical masses of calcification in the posterior fossa. (From A. B. King and D. M. Gould, 1952, Symmetrical calcification in the cerebellum; report of 2 cases, Am. J. Roentgenol., 67:562-568, Fig. 8, publ. Charles C. Thomas.)

cellular structure is relatively little damaged and presumably functioning normally. Usually when the dentate is involved sufficiently to show in the roentgenograms, there is even greater calcification in the basal ganglia (Rand, Olsen, and Courville, 1943), but in the two cases reported by King and Gould the process was restricted to the dentate nuclei alone. This is the only report in which the dentate nuclei were involved alone, and in these cases no sign of cerebellar deficiency was noted. Because of the frequent association of this condition with parathyroid deficiency, the latter should be ruled out in every case. 8. TUBEROUS SCLEROSIS Only isolated instances of cerebellar involvement with tuberous sclerosis can be found in the literature. Stevenson and McGowan reported such a medical curiosity in 1937, and Liber (1940) another. The latter author gives a review of the literature, collecting only seven instances of the lesion. In the case described by Stevenson and McGowan (1937) a cerebellar tumor was the clinical diagnosis, but the cause of the increased intracranial pressure was actually an internal hydrocephalus due to a gliosis and obstruction in the aqueduct of Sylvius. The glial proliferation in the cerebellum was very extensive, and the right hemisphere and vermis were involved. In the others cerebellar lesions were found incidental to a more widespread involvement. Calcification may be particularly dense in the patches seen in the cerebellum.

ATROPHIC CHANGES 479 SUMMARY One of the more homogeneous varieties of hereditary cerebellar ataxias is that first described by Holmes and now identified by a number of workers as a cortical cerebellar atrophy occurring in the middle adult years, with permanent secondary olivary degeneration in some instances. Less well defined is a familial form of cerebellar atrophy coming on in infancy, but a few reports indicate there is such a condition. Whether a disorder occurring in newborn sheep, known as "daft lambs," is a comparable condition cannot be determined at this time. The so-called late cortical cerebellar atrophies represent a rather distinct group in which the lesion is predominantly in the anterior surface of the cerebellum, located here possibly because of the relation to the overlying tentorium. Of physiological interest is the fact that some features of this syndrome suggest an early involvement of those cerebellar lobules of the anterior lobe which are primarily concerned in the postural reflexes of standing and walking. While generalized cortical cerebellar atrophy may be arbitrarily classified into chronic, subacute, and acute forms, the subacute variety is that most frequently encountered. It is of special interest in being associated very frequently with carcinomatosis. Olivopontocerebellar atrophy is believed to be a true abiotrophy involving those nerve cells which are known to grow out from the rhomboid lip to form the pontine, arcuate, lateral, and olivary nuclei. It is a degeneration primarily of the white matter of the cerebellum formed by the axons of these cells. This group is not very homogeneous, and associated involvement of the extrapyramidal system is not uncommon. Other cases link the condition to the heredocerebellar ataxias and heredospinal ataxias, though the condition seems to occur as a distinct entity. It cannot be differentiated clinically from the more common corticocerebellar atrophies. Cerebellar nuclear atrophies are so rare that their very existence is open to some question. Crossed cerebellar atrophy occurs following a lesion of the opposite cerebral hemisphere, usually during infancy. This trophic disturbance may be mediated either as a transneuronic effect via the pons or inferior olive or retrograde by way of the efferent cerebellar connections to the cerebral cortex. Because the effect is by no means universal, there is some inherent cerebellar factor necessary for the development of this atrophy. The hereditary spinal ataxias frequently have cerebellar degeneration as part of their pathology. This is true of Friedreich's ataxia and spastic ataxia. That these are all interrelated conditions is proved by the fact that examples can be found in the descendants of a single ataxic individual. The duration of the illness is an important factor in assigning a given case to one or the other groups. Pathological changes in the cerebellum may be found as a part of a large number of neuropathological conditions which are not confined in any sense to the cerebellum. Several of these are discussed briefly, including amaurotic family idiocy, Pick's disease, Alzheimer's disease, Wilson's disease, degeneration of the cerebral gray matter of Alpers, multiple sclerosis, symmetrical calcification of the dentate nucleus, and tuberous sclerosis.

13

Acute Inflammatory and Toxic Disorders of the Cerebellum

A. Infections 1. Malaria 2. Whooping cough 3. Louping ill 4. Epidemic parotitis 5. Poliomyelitis 6. Cerebellitis of unknown cause B. Systemic diseases C. Exogenous toxins 1. Alcohol 2. Lead 3. Manganese 4. Hydrocyanic acid 5. Thiophene 6. DDT (dichlorodiphenyltrichloroethane) 7. Ethyl acetate 8. Trichloroethylene 9. Carbon tetrachloride 10. Mercury 11. Eosinophilic leukocyte toxin D. Anoxia and hypoglycemia E. Vitamin deficiency F. Physical agents 1. Heat stroke 2. Fatigue Summary

480 480 482 482 484 484 484 485 485 485 486 486 486 486 487 487 487 487 488 488 489 490 491 491 492 493

A. INFECTIONS

1. MALARIA MALARIA involves the cerebellum along with the rest of the central nervous system. Brill and Pellicano (1943), in classifying the clinical types of cerebral malaria, list ataxic and cerebellar types along with nine other types. Clinical syn480

ACUTE INFLAMMATORY AND TOXIC DISORDERS 481 dromes of cerebellar type have been described in cases of malaria by Irish (1946), Russo (1947), Danaraj (1949a), and many others. While signs of cerebellar deficiency are completely reversible in many patients, they are not always so. In the case described in detail by Irish (1946) the onset of the malaria occurred in the South Pacific in mid-January. The patient was stuporous on arrival at the hospital, but returned to duty without symptoms on February 15, 1944. After three days he was rehospitalized with a diagnosis of arthralgia and with a chief complaint of weakness in the knees. Neurological examination at this time revealed a "broad base, lurching gait." He had papilledema on the right side. Diagnosis was then made of an acute cerebellar tumor. It was at this time that he was transferred to a station hospital where, in addition to the gait disturbance, it was noted that he had difficulty in pronouncing words, trouble in writing, and loss of his previous skill in playing the accordion. His deep tendon reflexes were hyperactive, and there were bilateral positive Babinski signs. Malarial parasites were found, and the diagnosis was again changed, to "ataxia, cerebellar, acute, postcerebral malaria." His condition improved under treatment for the first three or four months, but nine months after the original attack he admitted no further improvement. At this time his gait and fine coordination were still impaired. It is of interest that the same delay between the acute infection and the appearance of cerebellar ataxia has been described by Fletcher and Rigdon (1946) in experimental malaria in the duck. Danaraj (1949a) divides cerebral malaria into two categories: one, the prolonged type in which symptoms persist for several months after the malarial fever, and the other, a transient type which is present only during the fever. Pathological studies have been made by Rigdon (1944), who reviewed the literature, Kean and Smith (1944), Rigdon and Fletcher (1945), Arieti (1946), and others. Arieti (1946) also reviewed the literature and described the histopathological changes in complete fashion in three cases. His findings showed that the main pathological changes occur in the capillaries of the central nervous system. In the most intense infections the whole capillary plexus may be so filled with malarial pigment that the angio-architecture may be visible in thick, unstained sections which have been cleared and mounted in balsam. About these occluded vessels small hemorrhages occur. Two of the sites most commonly observed are the subcortical white matter of the cerebrum and the molecular layer of the cerebellum. After this pericapillary hemorrhage occurs, the central portion clears, owing to the disappearance of the central core of red cells and the development of a central area of demyelinization and at times, in severe lesions, to a central necrosis. Surrounding this is a glial proliferation which may be so intense as to simulate a granulomatous formation, though Arieti (1946) insists the cells are not inflammatory and should not be called granulomas. In addition, endothelial proliferation and adventitial thickening occur, which add to the occlusive process. Principally as a result of ischemia, according to Arieti, but also from the fever and the toxic effects on the cell, nerve cell changes may be seen which have long been associated with ischemia (Spielmeyer, 1922; Gildea and Cobb, 1930; and many others). In addition, in the most severely involved cases, cellular changes of

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swelling, central chromatolysis, and dislocation of the nucleus usually thought to indicate a process of retrograde degeneration are seen. These arise presumably from the multiple areas of focal necrosis which we have pointed out as being most evident in the white matter. While no specific mention is made of cell changes in the cerebellar cortex by Arieti, in view of the clinical findings in many cases and the well-known susceptibility of the Purkinje cell to both anoxia and hyperthermia, these cells probably often suffer severely. Rigdon and Fletcher (1945) found severe damage to the Purkinje cells in the young child dying of malaria on whom they reported. Fletcher and Rigdon (1946), in an experimental study in the duck, found that the cerebellum and its pathways seemed to bear the brunt of the pathological changes in this species. They also observed that the neurological manifestations of cerebellar deficiency might come on two to six weeks after the onset of the infection and after the animal had apparently recovered from the febrile part of the illness. They considered the neurohistological changes in malaria to be of the ischemic type, but attributed them to "anoxia which results first, from anemia produced by the rapid destruction of red blood cells by the parasites and, second, from vasomotor instability and circulatory failure." Kean and Smith (1944) did not feel that capillary plugging was closely related to the occurrence of symptoms of cerebral malaria in their analysis of 100 fatal cases of malaria. The detailed pathological studies of Arieti (1946) are very convincing, however, and indicate that in some cases, at least, this plays a significant role.

2. WHOOPING COUGH Besedovsky and Turner (1947) have described a cerebellar syndrome following whooping cough. Though this is a rare complication, in view of considerable evidence that cerebral damage and behavior disorders follow this disease in young children, cerebellar damage may also be expected in some instances. The cerebral changes are thought to be the result of anoxic episodes, and the Purkinje cell is also vulnerable to oxygen lack.

3. LOUPING ILL Louping ill is a natural disease of sheep which is endemic in northern England and Scotland. It was first described by Duncan in 1807, and the extensive literature on the condition has been reviewed by Pool (1931). In sheep the symptoms consist of tremors, hyperesthesia, ataxia, paresis, and paralysis. The nerve cells which are particularly affected by this neurotropic virus are the Purkinje cells of the cerebellum and the anterior horn cells of the spinal cord. The condition is known to be caused by a filterable virus and has been transmitted experimentally into monkeys, mice, swine, and rats (Hurst, 1931; Schwentker, Rivers, and Finkelstein, 1933; and others). In monkeys ataxia is the outstanding neurological sign and is believed to be due to the widespread disintegration of the Purkinje cells found in this species. In mice, tremor, hyperesthesia, incoordination, weakness, and paralysis are found, and in this experimental host the cerebrum and spinal cord show the major change.

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Four laboratory workers are believed to have been infected with this virus (Rivers and Schwentker, 1934). Each had a systemic, influenza-like illness, followed in three out of the four by a more severe illness with headache and some central nervous system manifestations, but there was no ataxia observed in any of them. A diagnosis of encephalitis was made in all three, all recovered without sequelae, and all had definite serological evidence of having had an infection caused by this virus or having been in contact with it. Wiebel (1937) has described a girl of fourteen years who developed an acute encephalitis, characterized chiefly by severe ataxia, from which she recovered without sequelae. Reactions in mice injected with material from the patient led the author to conclude that this represented a case of louping ill in a human being. Japanese B encephalitis can result in complete destruction of Purkinje cells along with a more generalized involvement of the central nervous system (Zimmerman, 1946). These changes resemble those seen in cases of louping ill. A close serological relationship between the virus of louping ill and that of Russian Far East encephalitis was demonstrated by Casals in 1944. Russian observers have reported louping ill in White Russia in both sheep and man (Sergeev, 1944; Silber and Shubladze, 1945; Olitsky and Casals, 1948). There have been two clinical reports which, in an attempt to explain the selective damage to the Purkinje cells, have suggested that the cases described were a human counterpart of this disease. One is the report of Parker and Kernohan (1935) on a case of subacute cerebellar cortical degeneration. Few have accepted their theory, however, and an acute virus disease can hardly have been responsible for the progressive illness they describe. The case reported by Johnston and Goodpasture (1936) seems a more likely possibility, though the authors were unable to infect rabbits, mice, or monkeys with injections of the brain of this patient, and the serum of close relatives did not contain any antibodies for the louping ill virus. The patient described in this report was a four-year-old Negro boy who had suffered a superficial burn on the thigh ten days before admission to the hospital. He seemed to be recovering well from the burn when suddenly the night before admission to the hospital he was found unable to speak and having generalized convulsive twitchings. These continued after admission for eight hours, until controlled by chloral hydrate administered via the rectum. He remained comatose until his death, fifty-two hours after the first convulsion. Upon examination the brain showed a generalized, perivascular, mononuclear cellular infiltration throughout the central nervous system except in the spinal cord. There was shrinkage of many nerve cells of the cortex and brain stem. Marked necrosis and cell loss with neuronophagia had occurred, limited to the cerebellum. Here the Purkinje cells were chiefly affected. The meningeal reaction was also most severe over the cerebellum. The authors concluded: "A case of acute diffuse nonsuppurative encephalitis is reported. There were marked destructive changes in the cerebellum, with neuronophagia of the Purkinje cells and mononuclear infiltration of the molecular layer and meninges. Such cerebellar changes have not, to our knowledge, been described in cases of encephalitis in man, but they are analogous to the cerebellar lesions of louping ill in animals. Although in no known case of encephalitis in man due to the virus of louping ill

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has autopsy been performed, it seems likely that in the case reported here the disease was due to a filterable virus which induces lesions similar to those brought about by the louping ill virus in monkeys."

4. EPIDEMIC PAROTITIS A meningeal reaction with spinal fluid pleocytosis is extremely common in epidemic parotitis. De Massary, Tockman, and Luce (1917) have claimed that it occurred at some time in the course of the disease in all of 56 patients with epidemic parotitis on whom they performed repeated spinal punctures. The neurological complications are varied, but when they occur, most authorities agree they are usually completely reversible. McKaig and Woltman (1934), who reviewed the voluminous literature up to the time of their article, reported that in those cases in which encephalitis was associated with the disease, ataxia might sometimes be the predominant symptom. This is no more than might be expected from a disease which can strike at any part of the central nervous system. The only clinical report of such a case which has come to our attention is that of Gliick (1939), on a man of twenty-one years who developed an acute neurological disorder during his recovery from mumps, with coma followed by a syndrome of cerebellar deficiency. No pathological studies were rnade, since he slowly recovered, with a residual speech defect as his chief permanent difficulty. The pathological changes are not very well established in this disease, for deaths are infrequent, and when patients are examined one cannot be certain that the neurological disorder is actually due to the mumps. There is both clinical and pathological evidence that some of the neurological complications are the result of a vascular process presumably secondary to the inflammation. A pathological report which has appeared since the review of McKaig and Woltman is that of Wegelin (1935).

5. POLIOMYELITIS There is considerable evidence that the virus of poliomyelitis does affect the cerebellum, though clinical evidence of cerebellar deficiency in poliomyelitis is uncommon. Baker and Cornwell (1954) have recently reviewed the literature on this subject and have analyzed the extent of cerebellar involvement in 75 fatal cases in which the cerebellum was studied pathologically in great detail. They found that some degree of inflammatory and/or neuronal change had occurred in 77 per cent of the cases. Inflammatory changes within the meninges were observed in 40 per cent and were most frequently encountered over the vermis. Neuronal changes had occurred within all nuclear groups of the cerebellum but were most frequent and severest in the dentate nucleus and the Purkinje layer of the vermis.

6. CEREBELLITIS OF UNKNOWN CAUSE Van Bogaert (1950a) has described a cerebellar lesion in two kittens, litter mates, in which the disease had a clinical course entirely different from that of the cats described by Brouwer and his associates (see p. 438). Van Bogaert believes his animals to have had an encephalitis of unknown cause which predomi-

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nantly affected the cerebellum, resulting in severe damage to the Purkinje cells. In these animals there was also involvement of the deep nuclei of the cerebellum, the vestibular nuclei, the mesencephalic fifth nucleus, and the pontobulbar reticular formation. Clinical reports of encephalitis with predominantly cerebellar manifestations have been given by Lhermitte and de Massary (1931) and de Gispert Cruz (1942). Of the postexanthematous encephalitides it is commonly held that the one following chickenpox is the most frequently associated with signs of cerebellar deficiency. Cerebellar deficiency may be seen in any of the cases of postinfectious encephalitis, but there is no particular predilection for the cerebellum or its pathways, nor are there any peculiarities in the pathological picture so far as the cerebellum is concerned. B. SYSTEMIC DISEASES Several subacute cortical cerebellar atrophies have been associated with systemic diseases (see p. 456). Ziilch (1948) has collected four acute and subacute cases, some of which have been mentioned above. Van Bogaert (1934) has noted that cerebellar deficiency can be associated with angioneurotic edema, but no pathological reports are available. Spielmeyer (1922) has commented upon the effects of the toxins of scarlatina on the cerebellum. As originally shown by Scherer (1932) and as recently pointed out by Brain, Daniel, and Greenfield (1951), the cells of the dentate nucleus are notoriously prone to show cytological changes in a great variety of clinical conditions, and degenerative changes here are probably not of clinical importance unless there is an associated degeneration of the fibers of the superior cerebellar peduncle. Another pathological change of even less clinical importance is the peculiar appearance of the granular layer which was described by Bertrand and GodetGuillain (1942b) in cases of carcinoma and diabetic coma. This change was felt by Brain, Daniel, and Greenfield to be partly agonal and partly due to postmortem autolysis. Autolytic changes of the granular layer have also been emphasized by Krainer (1949). C. EXOGENOUS TOXINS

1. ALCOHOL Alcohol has been incriminated by a number of authors as an agent responsible for cerebellar damage. Ziilch (1948) in his review collected five such cases with postmortem findings, though most of them fall into the subacute classification. Romano, Michael, and Merritt (1940) have presented several clinical cases of chronic, subacute, and acute syndromes of cerebellar deficiency which were believed to be associated with the toxic effects of alcohol. From the time of Flourens the site of the action of alcohol has been suggested to be the cerebellum. Through the methods of electrophysiology possibly the susceptibility of the cerebellum to alcohol could be compared to that of the rest of the nervous system. It is well known that the cerebellum is physiologically very sensitive to most anesthetic agents, particularly the barbital derivatives, but no observations on the effect of alcohol on the electrical activity of the cerebellum have been reported.

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Dosuzkov, Kocka, and Uttl (1931) have written on the acute effects of alcohol, describing a case of acute alcoholism with coma; on recovering consciousness the patient demonstrated a full-blown cerebellar syndrome ten days later. Ohmori (1926) described a similar case.

2. LEAD Bucy and Buchanan (1935) reported on the similarity between lead encephalitis and midline cerebellar tumors in children. Both conditions produce increased intracranial pressure. Staggering gait is frequent in both, and this may be due, in the cases of lead poisoning, to the damage to the Purkinje cells described by Ferraro and Hernandez (1932), Freifeld (1933), Villaverde (1936), and others. The residual symptoms of lead encephalopathy are chiefly those of cerebral damage. McKhann and Vogt (1933) have listed convulsions, cerebral atrophy, blindness, mental retardation, tremor, speech defects, and muscular weakness as the residual symptoms of lead poisoning. These symptoms, none of which, with the possible exception of tremor, are suggestive of cerebellar involvement, are thought by these authors, as well as by Bucy and Buchanan, to be the result of the increased intracranial pressure which accompanies the lead encephalopathy. Bucy and Buchanan (1935) have also pointed out that the clinical course of these cases can be favorably influenced by appropriate surgical methods designed to control this pressure. Biemond and van Creveld (1939a, b) described a clinical case of lead poisoning in a two-year-old child in whom the only symptoms were those of cerebellar deficiency. No increased intracranial pressure was found, and the child recovered without evident residual symptoms.

3. MANGANESE Van Bogaert and Dallemague (1943) have described a cerebellar cortical atrophy in a monkey following intoxication with air-borne manganese. The symptoms of cerebellar deficiency developed some months later, and proof of a causative relationship must await further experiments. Another monkey given manganese by mouth failed to develop any neurological symptoms, and no histopathological changes were noted in this animal. To date no human cases have been reported.

4. HYDROCYANIC ACID Fiessinger, Duvoir, and Boudin (1936) have described symptoms of spasticity and cerebellar deficiency which persisted for eighteen months after recovery from a period of coma resulting from hydrocyanic acid poisoning.

5. THIOPHENE D'Antona (1935) reported on the effect of inhalation of thiophene in various experimental animals. In some, cerebellar symptoms as well as convulsions were seen, and on postmortem examination a degeneration of the granular layer of the cerebellum was observed.

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6. DDT (DICHLORODIPHENYLTRICHLOROETHANE) Several investigations, reviewed by Haymaker, Ginzler, and Ferguson (1946), had indicated that symptoms of incoordination, muscular twitching, and flaccidity occurred in a variety of animal species given DDT to test its toxicity. Wigglesworth (1945) reported similar symptoms in a man who applied the drug in an acetone solution to the skin. Bing, McNamara, and Hopkins (1946) determined that dogs given DDT in daily doses of more than 250 mg/Kg over a period of two to four weeks developed a syndrome which was believed to be due to cerebellar damage. This consisted of hypermetria, the animals walking with a highstepping gait, and increased extensor tone with strong positive supporting reactions. In standing the animals held the legs rigid, hyperextended, and abnormally abducted, and they walked in a zigzag fashion. These symptoms were associated with severe weight loss, dehydration, and evidence of some liver damage. In keeping with this neurological picture, Haymaker, Ginzler, and Ferguson (1946) reported cellular changes in the Purkinje cells and in the deep cerebellar nuclei which were not observed in some normal controls. Previous work had shown pathological changes in the anterior horn cells but none in the brain. Crescitelli and Gilman (1946) reported on the electrical activity of the cerebrum and cerebellum after intravenous administration of the drug. Their records were taken with an ink-writing electroencephalograph, so that no information could be noted on the effect of the drug on the rapid activity which is characteristic of the cerebellum. The convulsive-like waves were undoubtedly projected activity from other areas, presumably the brain stem, as is true of the convulsant activity of strychnine (see pp. 179-182). Globus (1948) found that a number of animals in a large series of monkeys, dogs, cats, and rats exposed to DDT showed neurological symptomatology. The histopathological findings in the nervous system, however, werfe very meager. 7. ETHYL ACETATE Baker and Tichy (1953) reported swelling and pallor of the Purkinje cells in dogs after the intravenous injection of ethyl acetate. 8. TRICHLOROETHYLENE Baker and Tichy (1953) described striking alterations in the Purkinje cells of the cerebellar cortex in both acute and chronic intoxication with trichloroethylene in dogs. Ataxia was a prominent neurological symptom in these animals. This has also been an important symptom in those patients using an excessive amount for the treatment of trifacial neuralgia (Cotter, 1950; Rickles, 1945).

9. CARBON TETRACHLORIDE Carbon tetrachloride, the common household article used widely as a cleaning solvent, produces, in addition to its more commonly recognized liver and kidney damage (Moon, 1950), symptoms of a neurological nature. The pathological examinations indicate the cerebellum and particularly the Purkinje cells to be the

488 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM site of extensive damage. There is a marked potentiation of this toxicity in chronic alcoholics or in animals or patients acutely intoxicated with alcohol at the time of ingestion or exposure to the fumes of this volatile substance. Stevens and Forster (1953) have reviewed this subject completely. They have shown extensive changes in the cerebellar cortex in one patient. The molecular layer was strikingly disorganized, with loss of neurons, and the Purkinje cells were pyknotic and decreased in number. They quote the experimental studies of Tanohata and Tagawa (1932), who found similar neuronal changes as well as fresh hemorrhages in the cerebellar cortex in dogs fatally poisoned with carbon tetrachloride. These animals showed incoordination along with other neurologic and metabolic symptoms before they died. Stevens and Forster (1953) however, state that, although the cerebellar cortex is involved, "We have found no persistent cerebellum signs in our patients who survived, nor is there any description of a cerebellar degeneration clinically evident in the other reports in the literature. It may well be that cerebellar damage occurs only in those patients so severely intoxicated that they are unable to recover" (p. 641). Cohen (1957) describes two fatal cases, in neither of which were there definite symptoms of cerebellar deficiency during the relatively short hospital course. Pathological changes in the cerebellum were found in one case, consisting of two patterns of hemorrhagic lesions in addition to the degenerative changes in the Purkinje cells. The concept of Stevens and Forster that some vascular changes in the nervous system in this condition might be from fat emboli was not confirmed by the pathological studies of Cohen (1957), although he lists this as one of several possible factors responsible for the pathological changes.

10. MERCURY Hunter, Bomford, and Russell (1940) described human cases of poisoning with methyl mercury compounds in which ataxia of a sensory type was a very pronounced part of the clinical picture. All the patients recovered, but had varying degrees of neurological residual symptoms. In experimental intoxications of rats designed to throw some additional light on these cases, some of the animals showed a degeneration of the granular layer of the cerebellar cortex in addition to other widespread involvement of the nervous system. The authors speculate upon the possibility that similar lesions in their clinical cases could have contributed to the gross ataxia, which was undoubtedly chiefly due to a peripheral neuropathy and posterior column degeneration.

11. EOSINOPHILIC LEUKOCYTE TOXIN Gordon (1932) reported the development of a neurological syndrome in rabbits following the intracerebral injection of lymph node suspensions from cases of Hodgkin's disease. From the work of Friedmann and Elkeles (1933), Kelser and King (1936), Edward (1938), Turner, Jackson, and Parker (1938), and others, it was evident that this material is found in greatest amount in eosinophilic leukocytes and that the cell most susceptible to its action is the Purkinje cell. Meyer and Foley (1953) have reviewed this earlier work in detail and have confirmed its

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main essentials besides adding important facts to what was previously known. At present it can be stated that damage to the Purkinje cells can be identified when there are no clinical symptoms. The agent can be effective when given subcutaneously as well as intracerebrally and cysternally, and cats as well as rabbits, guinea pigs, and chickens are susceptible. The extract has been obtained from man, Macacus rhesus, chicken, and mouse. The agent is inactivated by heating, is resistant to freezing, desiccation, x-ray, weak phenol, and formalin. It is filterable and readily soluble at pK 7.4. The agent has a point of minimum solubility at pH 4.2, is destroyed by pepsin, may be precipitated with ammonium sulphate, and is nondialyzable. This indicates the probable protein nature of the material. The essential nature of the encephalopathy is a neuronal degeneration of the Purkinje cells. There is some lymphocytic infiltration of the meninges, and in severe cases some authors have found neuronal damage to cells of the brain stem though to a lesser degree than to the Purkinje cells. D. ANOXIA AND HYPOGLYCEMIA Gildea and Cobb (1930) have reviewed the literature and described in great detail the histological changes in nerve cells which are associated with asphyxia, particularly confirming the work of Spielmeyer (1922). They added information concerning the time it takes to develop some of the classical cellular changes which are well known to result from anoxia of any type. They confined their observations to the cerebral cortex. The cerebellar cortex is one of the most susceptible parts of the nervous system to oxygen deficiency. This is shown by the symptoms which result in animals when the circulation to the brain is shut off (Kabat, Dennis, and Baker, 1941), by the rapidity with which the electrical activity of the cerebellar cortex is affected by anoxia (Sugar and Gerard, 1938; Dow, 1938a), by the high oxygen demands of the cerebellar tissue as compared to other parts of the brain (Dixon and Meyer, 1936), and by pathological evidence which will be pointed out below. Kabat, Dennis, and Baker (1941), in a systematic study of the recovery after the arrest of cerebral circulation, found that ataxia was the most persistent neurological symptom in dogs that eventually recovered from this circulatory arrest. As these authors point out, it is possible that if conditioned reflex studies had been used, even more long-lasting effects could have been demonstrated. In animals who barely survived and were rendered permanently and grossly neurologically deficient, virtually no nerve cells were found in the neocortex, corpus striatum, and parts of the thalamus, and there were no Purkinje cells in the cerebellum. The rest of the nervous system was normal. This known susceptibility of the Purkinje cell to anoxia has been used by Courville and Friedman (1940) in their explanation of the frequent localization of cortical cerebellar atrophy to the anterior surface (see p. 454). Courville (1936) has described extensive damage to the Purkinje cells in cases of brain damage resulting from the anoxia at times associated with nitrous oxide anesthesia. The cerebellar damage from malaria is thought by many to result from anoxia (see p. 481). On the other hand, Titrud and Haymaker (1947), in their pathological investigation of an aviator exposed to severe oxygen deprivation who died after

490 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM three weeks of complete mental incapacity, reported that there were severe degeneration of the lower lamina of the cerebral cortex, massive necrosis of the striatum, focal necrosis of the globus pallidus, and "only moderate involvement" of the cerebellum, limited to the Purkinje cells. Malamud, Haymaker, and Custer (1946) used this observation and the differences between this case and the cases they had observed of heat stroke to deny the previous assertions that brain damage in cases of heat stroke was the result of shock and anoxia. It is well established that the cerebral damage from insulin shock is related to the oxygen requirements of nerve cells. Gellhorn and Kessler (1942) have shown that the electroencephalographic slowing produced by hypoglycemia can be offset by the inhalation of pure oxygen and that the slow waves caused by anoxia can be aggravated by insulin hypoglycemia. Himwich (1951) and many others have pointed out the parallelism between the symptoms of hypoglycemia and anoxia. It is not unexpected, therefore, that Hedon, Loubatieres, and Broussy (1938) should have found cerebellar lesions in pancreatectomized dogs treated with protamine zinc insulin. The clinical and pathological reports of Layne and Baker (1939), Gardner and Reyersbach (1951), and many others deal mostly with the effects of this central nervous system damage in the cerebral cortex. Bodechtel (1933) did point out involvement of the cerebellum in man; so also did Lawrence, Meyer, and Nevin (1942), who offer a complete review of the literature. Weil, Liebert, and Heilbrunn (1938) have shown cerebellar damage in experimental studies in the rabbit after repeated hypoglycemic episodes. Loss of the Purkinje cells in restricted areas is a common finding in all types of epilepsy. Spielmeyer (1922) has emphasized these lesions as well as those in the hippocampus and has used these to support the idea that vasospasms might be an important factor in the pathogenesis of the convulsive state. Most workers are of the opinion at present that changes of this character at these sites are the result of anoxic damage to susceptible parts of the nervous system reproduced by the tonic phase of the seizure itself, and are not of importance so far as the etiology of the seizure is concerned. Scholz (1933), who also wrote on this subject, pointed out that lesions are by no means limited to these sites in patients with severe epilepsy. Zimmerman (1938) describes frequent involvement of the cerebellum in children dying following illnesses associated with severe convulsions. He attributes these degenerative changes to cerebral anoxemia resulting in part from these convulsions. E. VITAMIN DEFICIENCY The fact that the cerebellum and its pathways share in the nervous disorders which are the result of nutritional defects is chiefly indicated by the reports of those who have had experience with these conditions in the Far East. Stannus (1944), Ransome (1944), and Danaraj (1949b) have been among those who have pointed out the cerebellar symptoms of vitamin deficiency. Ransome and Monteiro, as reported briefly by Ransome (1944), used cinematographic and flash bulb photographic tracings to demonstrate an ataxia that was out of proportion to any loss of posterior column or peripheral nerve function that was found. He

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felt that the basis of the ataxia was a degeneration of the cells of Clarke's column, in view of the marked changes discovered there at the autopsy of one of his patients. The case was just in process of investigation at the time of the fall of Singapore, and there was no histological study of the cerebellum. There are no other cases which have been studied post mortem and which include an adequate neurohistological investigation. In the case reported by Danaraj (1949b) the ataxia was so typically cerebellar and the patient was so free of other neurological findings that one examiner, unaware of the nutritional nervous diseases present in this area, made a diagnosis of primary cerebellar atrophy. Stannus (1944) felt the difficulty was due to a lack of riboflavin which interfered with capillary function, damaging selectively those parts of the nervous system having the greatest number of capillaries, of which the cerebellar cortex and the deep cerebellar nuclei are among the highest. F. PHYSICAL AGENTS 1. HEAT STROKE The first demonstration of the lability of the Purkinje cells to excessive temperature is credited to Weisenburg in 1912. The patient he describes did not die but did show, after being admitted to the hospital with a temperature of 107° F. as a result of heat stroke, a severe ataxia of cerebellar type. He had as well bilateral ankle clonus and a bilateral positive Babinski's sign, with a loss of bowel control. He also exhibited periods of severe manic behavior. Since then reports of a similar syndrome have appeared: by Stewart (1918), Freeman and Dumoff (1944), and Krainer (1949) as the result of heat stroke; by Cruickshank (1951) during acute rheumatic fever with temperatures as high as 110° F.; and by Silverman and Wilson (1950) as a complication of subtotal thyroidectomy with temperatures as high as 108.4° F. Freedman and Schenthal (1953) furnish clinical reports of two patients, one with heat stroke and the other with a prolonged high temperature presumably from an infection, both of whom developed a severe and permanent syndrome of cerebellar deficiency. Malamud, Haymaker, and Custer (1946), in reviewing 125 cases of fatal heat stroke, reported that "changes in the cerebellum were more striking, more consistent and more rapid in development than in any other part of the brain." In these cases there was a marked loss of the Purkinje cells (Fig. 175). They were almost completely gone if the patient survived more than twenty-four hours. If several days elapsed before death, there was also glial proliferation in the molecular and granular layers, eventually with rarefication of the granular cells. The damage was equally distributed over the vermis and hemisphere, and the dentate nucleus was also involved. The pathological changes so far as the nervous system is concerned were summarized by the authors as follows: "Pathological changes in the central nervous system were most conspicuous, and consisted of 1) progressive degeneration of neurons and replacement by glia, especially in the cerebellum, cerebral cortex, and basal ganglia, but not in the hypothalamus or the rest of the brain stem, the severity of the changes corresponding to the length of survival after the occurrence of hyperthermia; 2) congestion, edema, and

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Figure 175, A degenerating Purkinje cell and its apical dentrite surrounded by glial elements, from a case of heat stroke in which the duration of illness was 276 hours. (From N. Malamud, W. Haymaker, and R. P. Custer, 1946, Heat stroke; a clinico-pathologic study of 125 fatal cases, Mil. Surgeon, 99:397-449, Fig. 14. The original of this photograph was made available through the courtesy of the Armed Forces Institute of Pathology, Walter Reed Army Medical Center, Picture #86499.)

petechial hemorrhages, most commonly in the region of the third ventricle, all of which were inconstant and regarded as terminal. In our opinion the cellular changes were caused by excessive heat, and the hemorrhages by shock" (p. 445). 2. FATIGUE An enormous amount of time and effort was spent for almost fifty years by a large number of investigators on the effects of fatigue on the cytological characteristics of nerve cells. It was early recognized that the Purkinje cells of the cerebellum were ideal nerve cells for such a study because of their large size and the ease with which, owing to their geometric arrangement, they could be counted. Those who believed they could find cytological changes to result from fatigue were attracted to this cell because it is subject to a great deal of variation. No attempt will be made to review this subject or to outline the complicated classifications and stages which were identified by some of the more enthusiastic workers. There can be no doubt that the changes first described were in error, for as the methods of staining and the control of experiments improved, it became apparent that the changes first described were due to many other factors than the state of fatigue which had been induced in the animal. One of the last workers in this field was Andrew, who in 1937 reviewed much of the previous literature

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and made some important observations. He found that while there were changes which he could detect, they were not obvious and were never so great as those seen to result from aging of the animal. Some accentuation of some of the changes characteristic of senile animals was seen in the exhausted older animals when compared to normal animals of the same age. SUMMARY Malaria is among the infectious diseases which damage the cerebellum. Here the changes are not exclusively in the cerebellum and are believed by some to be secondary to the vascular damage associated with malaria. The cerebellar damage in whooping cough may be related to anoxic episodes. Louping ill, on the other hand, is a viral disease in sheep in which the cell which is primarily attacked is the Purkinje cell. Human cases are very rare, authentic ones having occurred only in laboratory workers, and in these no permanent cerebellar deficiencies were noted. The cerebellum may be involved in both mumps and poliomyelitis, even though it is not the predominant site for the infectious agent to strike. Postexanthematous encephalitis may also result in cerebellar deficiency symptoms in some cases. Exogenous toxins that may have a more or less specific effect upon the cerebellum are alcohol, lead, manganese, hydrocyanic acid, thiophene, DDT (dichlorodiphenyltrichloroethane), ethyl acetate, trichloroethylene, carbon tetrachloride, mercury, and a toxic material of protein nature derived from eosinophilic leukocytes. The cerebellum, particularly the Purkinje cell, shares with other elements of the cerebral nervous system a rather marked susceptibility to anoxia and hypoglycemia. The effect on the cerebellum is comparable to but perhaps not so great as that upon the cerebral cortex, the caudate nucleus, and the putamen. Ataxia is a prominent part of the neurological manifestations of severe vitamin deficiency as seen in the Far East. While there is some clinical evidence that cerebellar deficiency may be responsible for a part of this ataxia, there are as yet no studies providing pathological demonstration of cerebellar damage in these cases. There is abundant clinical and pathological evidence to show that the Purkinje cell is the most highly susceptible of all neurons to damage from excessive body temperature, though cells of the cerebral cortex and the basal ganglia also suffer severely. The effects of fatigue on the Purkinje cell were the subject of much study over twenty years ago. It is now recognized that most of the putative changes were artifacts of fixation and staining or the unrecognized effects of aging on these neurons.

14

Chronic Infections of the Cerebellum and Cerebellar Abscess

A. Tuberculosis B. Syphilis C. Cerebellar abscess 1. Historical summary and introduction 2. Incidence 3. Pathogenesis and morbid anatomy 4. Symptomatology 5. Differential diagnosis 6. Treatment 7. Nonotogenic abscesses D. Fungicitic infections E. Parasitic involvement of the cerebellum 1. Amebiasis 2. Cysticercosis Summary

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A. TUBERCULOSIS TUBERCULOSIS of the central nervous system may involve the epidural space, the dura mater, or the leptomeninges, either as a chronic localized variety or as a diffuse tuberculous meningitis. Isolated parenchymatous lesions or tuberculomas are also found, and these may be combined with the leptomeningitis, the symptoms of the meningitis predominating over those resulting from the tuberculoma. Scott and Groves by 1933 had collected 815 cases of tuberculoma of the brain since the first report of this condition, which is credited to Ford in 1790. Asenjo, Valladares, and Fierro (1951) have presented a recent review of the literature and an analysis of 159 cases occurring in the people of Chile, many of whom have little resistance to the disease compared to European populations. Statistics concerning the incidence of these lesions published half a century or more ago indicate that tuberculomas represented about one half the expanding intracranial lesions encountered at that time in patients under nineteen years of 494

CHRONIC INFECTIONS 495 age (Starr, 1890). However, van Wagenen (1927) found that among 1,000 verified brain tumors in Cushing's material there were only 14 tuberculomas. When this group was broken down by age, it was found that there were 5 among 140 verified tumors in patients under nineteen years of age, or an incidence of 3.5 per cent as compared to Starr's 50.8 per cent. In both series the incidence of tuberculomas among patients with brain tumors under nineteen years of age was about four times that among those over this age (Starr, 1893). Tooth in 1912, analyzing a group of 258 verified brain tumors, found 5.4 per cent to be tuberculomas. Rasdolsky (1935) has given in tabular form the incidence of these cases found at autopsies performed at general hospitals; the incidence varies from 1.5 per cent to 0.2 per cent. The percentage of tuberculomas to the total number of brain tumors in a large general hospital varied from 6 to 45 per cent, and the percentage of tuberculomas among brain tumors in a neurological clinic varied from 1.4 to 2.8. It is to be expected that statistics taken from autopsy material in a large general hospital would show percentages quite different from those obtained from a neurosurgical clinic. Many of the cases derived from the postmortem examinations involved only small tuberculomas, and the clinical picture was completely dominated by the associated tuberculous meningitis. Such patients would never find their way into a neurosurgical clinic in most circumstances. Furthermore, the variations among countries and periods in the practice of segregating tuberculous patients into separate institutions make statistical comparisons difficult. The differences between the older and the later groups of statistics have been explained by the over-all reduction in tuberculosis during the last fifty to seventy-five years, a reduction reflected in the smaller number of cerebral tuberculomas. For some reason, possibly owing to the reputedly greater prevalence of bovine tuberculosis in some European countries than in the United States, though no studies have been made on this point, the incidence of isolated tuberculomas found among the total number of patients dying from intracranial tuberculosis varies widely, from the 28.9 per cent reported by Trevelyan (1903) from the Leeds General Infirmary to the 9.1 per cent from the Children's and Infants' Hospital in Boston for the years 1915 to 1925 (van Wagenen, 1927). A survey of the percentage of intracerebral tuberculomas found within the cerebellum indicates that aside from Starr's series, in which slightly less than a third were in the cerebellum, and van Wagenen's, in which 11 out of 14 were in or involved the cerebellum, the incidence of cerebellar tuberculomas has been about 15 to 20 per cent of all those which were intracranial. As might be expected in view of the hematogenous source of these lesions, a large number are multiple, often involving several remote areas of the nervous system simultaneously (Ferris, 1929). No explanation for the unusually high incidence of cerebellar tuberculomas in van Wagenen's series is apparent or has been suggested. Asenjo, Valladares, and Fierro (1951) found in a statistical analysis of the age of the patients and the location of these lesions that a cerebellar location was relatively more frequent in the younger patients. Aubin (1941) has published a thesis dealing exclusively with tuberculomas of the cerebellum. The symptoms of the tuberculomas are frequently masked by those of tuber-

496 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM culous meningitis (Anderson, 1928). When the tuberculomas present themselves as isolated lesions, they may exhibit the symptoms and signs of any other progressive, expanding lesion. Their average course has been variously estimated as from two to six months. Headache, vomiting, and choked discs are common with cerebellar tuberculomas as they are with cerebellar tumors. In addition, signs of cerebellar deficiency of a progressive nature and associated cranial paralysis are encountered. The lesions have simulated acoustic neurinomas in the clinical picture they present (Elkins and Rack, 1951). Nystagmus is frequent. While a lowgrade fever, systemic tuberculosis, a history of contact, and a positive tuberculin test in a small child may lead one to suspect the presence of a tuberculoma as opposed to a tumor, the diagnosis is usually not made until the expanding lesion is explored. Considering the great rarity of the lesion at the present time, this is understandable. The spinal fluid may be normal or show a lymphocytic pleocytosis. Buchstein and Adson (1940) state that cerebellar tuberculomas are more apt to show more marked spinal fluid changes than those of other areas. They point out that because of the deep fissures in the cerebellum, the inflammatory mass, which is usually a fusion of several fibrocaseous nodules with relatively little fibrotic reaction, will involve the subarachnoid spaces at several points, allowing the inflammation to spread more widely than in other situations. This, in addition to the naturally increased hazards of posterior fossa lesions, makes the cerebellar cases more difficult to treat surgically than the cerebral lesions, of which those situated about the central sulcus offer the most favorable prognosis. Roentgenograms of the skull show intracerebral calcifications in 5 per cent of tuberculomas, according to Mudd, Perlmutter, and Strain (1955). Orley (1949) states that a dense, irregular shadow with crevated, angular, or indented margins is usually seen. When the tuberculoma is markedly deformed, specular, angular plates or strands of calcification may be broken off the periphery of its calcified shell. The tuberculoma is well demarcated from the brain tissue and is a hard, firm mass as a rule; the center may be necrotic. Microscopically it consists of the same accumulations of cells found in the tuberculous lesions elsewhere in the body. Giant cells and central caseation is present, and there may be a coalescence of several tubercles, as with these lesions elsewhere. Calcification may or may not be present microscopically, and the degree of fibrosis will depend upon the rapidity of the growth and the resistance of the body to the infection. In general, fibrosis is of a limited degree in cerebellar lesions. Tubercle bacilli can be demonstrated in the pathological sections. Guillain, Christophe, and Bertrand (1929) have described a staining method. The prospects for successful surgical treatment at the time of van Wagenen's report (1927) seemed very dismal, as they had been from the time of the first report of the removal of one of these lesions by Hahn in 1882 (Wernicke and Hahn, 1882). His patient died fourteen days postoperatively of systemic tuberculosis and tuberculous meningitis. In van Wagenen's report, only in 1 out of the 6 cases where extirpation was tried did the patient fail to succumb to a tuberculous meningitis within a few weeks. Van Wagenen felt that decompression as a palliative measure and medical

CHRONIC INFECTIONS 497 treatment offered the most for these patients. Buchstein and Adson (1940) collected isolated case reports of 21 patients in whom extirpation of the tuberculoma had been attempted. Of these, 1 died after operation, 6 died shortly afterward of tuberculosis, systemic or meningitic, and 14 were reported as alive for one to nine years. As the authors point out, such a survey will produce an unduly optimistic impression, for it is the isolated successful cases that tend to be reported. The results of surgical treatment of the 12 cases which they collected from the Mayo Clinic were as disappointing as were those earlier reported by van Wagenen. They also recommended palliative measures rather than extirpation, as had Grinker and Lifvendahl (1928). Kwan (1929) reported cases of recovery after operation with survivals up to eleven years. Dott and Levin (1939) reported only 2 deaths from tuberculous meningitis out of 18 operated cases which they treated personally. They compiled statistics on 94 cases taken from the records of the members of the Society of British Neurological Surgeons; in this group the total deaths numbered 51, of which 16 were from tuberculous meningitis, 11 were operative fatalities, 4 from pre-existing meningitis, 4 from multiple tuberculomas, 12 from systemic tuberculosis, and 4 from unverified cause. These authors conclude: "We believe the prevailing pessimism is not justified and that the risk of a fatal postoperative meningitis has been grossly exaggerated." Recently a new factor must be given consideration, as has been pointed out by Obrador and Urquiza (1948), Ivey, Phillips, and Meirowsky (1950), Asenjo, Valladares, and Fierro (1951), Descuns, Garre, and Pheline (1954), and others. This is the beneficial effect of streptomycin therapy in tuberculous meningitis. It would appear that this treatment will prevent the tuberculous meningitis from occurring following the surgical extirpation of the lesion. The issue of the proper handling of these cases is not yet settled. While further trial of surgical and streptomycin therapy is indicated, the results of surgery should be compared to the results of streptomycin alone. Surgery should be reserved for those cases in which pressure symptoms or neurological deficit make exploration and decompression essential, at which time complete extirpation should be attempted if surgically feasible and the lesion is not multiple. B. SYPHILIS We have already noted (p. 442) that cerebellar maldevelopment has at times been attributed to syphilis with very little evidence that syphilis was responsible. Thiers (1934) has written concerning cerebellar syphilis. There are a few reports available concerning instances of meningovascular lues affecting the cerebellum. Urechia, Kernbach, and Elekes (1933) and Camauer (1940) each reported isolated cases of cerebellar hemorrhage which they believed to be due to a syphilitic arteritis, the latter being a clinical report only. Syphilitic gummata have involved the cerebellum, but these are extremely rare lesions, Bagdasar (1929) having found only 8 cases among 1,500 verified brain tumors in Cushing's material, and none of these were in the cerebellum. What has been said concerning the decreasing frequency of tuberculomata is even more true of this syphilitic lesion.

498 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM Dufour (1913) described a case of an idiot dying at the age of twenty-five years who had a lesion which he interpreted as a cerebellar gumma associated with chronic syphilitic meningitis. No details of the histological studies are given, and apparently the only finding on which the diagnosis was made was the positive blood Wasserman. Urechia and Elekes (1933) reported a case where the clinical diagnosis of a cerebellar tumor was made and seemed well justified, but at surgery granulomatous tissue was found with miliary gumma formation. No other syphilitic lesions were demonstrable. Bodart (1935) described a patient with a gumma of the cerebellum in whom the signs of an expanding lesion appeared too late to allow surgical treatment. Buttaro (1946) reported a case of syphilitic meningoencephalomyelitis which also simulated a tumor. As has been pointed out by Bagdasar (1929), when there are the symptoms and signs of a brain tumor, the presence of a positive serology itself should not deter the neurosurgeon from operating. The likelihood of a gumma is extremely remote, and even if one is uncovered it may be removed with impunity, or a decompression can be provided and the case treated medically. This course of action is better than taking the chance that the patient's brain tumor findings are based on syphilis. Out of 1,000 patients with brain tumors Moersh (1928) cited 18 who had a falsely positive serological test, which, because of its frequency, he believed was due to the presence of the tumor. Furthermore, among the 8 cases of gumma of the brain a positive serology was found in only about half of his cases. C. CEREBELLAR ABSCESS 1. HISTORICAL SUMMARY AND INTRODUCTION The first report of the clinical symptomatology and gross pathological findings in a case of cerebellar abscess is that of Abercrombie (1828). He described two patients; one was a child of nine years whom he saw in 1810, who had a chronic otitis and then developed headache and vomiting and died. The second was a girl of eighteen years who, after an acute otitis media, developed headache and a strabismus and died. The description of the gross changes in the cerebellum in the first patient was as follows: "A considerable quantity of colorless fluid was found in the ventricles of the brain. In the left lobe of the cerebellum there was an abscess of considerable extent containing purulent matter of intolerable foetor. The dura mater, where it covered this part of the cerebellum, was thickened and spongy, and the bone corresponding to this portion was soft and slightly carious on its inner surface; but there was no communication with the cavity of the ear." The first attempt at surgical drainage of a cerebral abscess, following a correct preoperative diagnosis with accurate localization of the lesion, is credited to Gowers and Barker in 1886, according to Davidoff (1935). Asherson (1942) credits Macewen with having accomplished the same feat for a cerebellar abscess in 1889. Cerebellar abscess, occurring from one-half to one-tenth as frequently as the otogenic cerebral abscess, depending on the series reported, has been characterized by a much higher mortality rate than the cerebral abscess. Aside from the experience of Macewen (1893), who was singularly successful in his handling of these cases, no series of cases in substantial numbers had been reported with a better than about 80 per cent mortality until twenty years ago.

CHRONIC INFECTIONS 499 Considering the relative infrequency of these lesions, the literature on this subject is very great, but many of the publications are isolated case reports. There have been a number of monographs and other papers of similar proportion written on the subject. No attempt will be made to review all this literature. Monographs and other sources of information of importance include those of Neumann (1907), Friesner and Braun (1916), and Asherson (1942), dealing with cerebellar abscesses. Those of Okada (1900), Hegener (1909), Eagleton (1922), Atkinson (1934), Alexander (1929), Brunner (1936, 1946), and others deal with either the broader subject of brain abscess in general or intracranial complications of ear disease, which, as we shall see, is responsible for the vast majority of the cerebellar abscesses. There are many other important contributions to this subject, some of which we shall mention later. 2. INCIDENCE Some idea of the frequency of these lesions is given by the statement by Courville and Nielsen (1937) that in Los Angeles they encountered only 21 cases of cerebellar abscess in 15,000 autopsies, of which all but one were of otogenic origin. In a survey made by a group of continental otologists, neurologists, and opthalmologists. and reported by Ramadier et al. (1935), it was concluded that practically every case was secondary to suppuration of the ear, but that these abscesses constituted only 30 per cent of all brain abscesses. Stuart, O'Brien, and McNally (1955) report 20 cerebellar abscesses out of 125 brain abscesses, or 16 per cent. That it is a rare complication of serious infectious disease of the ear is borne out by the fact that out of 4,961 mastoid operations performed in the period 19211931 at the Massachusetts Eye and Ear Infirmary there were only 10 otogenic brain abscesses, of which 2 were cerebellar (Meltzer, 1935). Considering these statistics, it is understandable why the usual otological or neurosurgical specialist sees only a few of these cases in a lifetime of practice. With the reduction in chronic complications of middle ear disease which has resulted from the use of antibiotics and better attention by the otologist and the pediatrician to the prevention of these chronic lesions, the incidence of this serious and often fatal condition will probably be even less. Atkinson (1938) says that 80 per cent of otitic cerebellar abscesses result from chronic otitis and only 20 per cent from acute inflammatory processes of the ear. Neumann (1907) gave 88 per cent and 12 per cent as his estimate of the same relationship. Males are affected about twice as frequently as females. According to some authors, most patients are affected during their childhood, and this is borne out by Wilkins' experience (1940). On the other hand, in the statistics compiled by Atkinson the highest incidence was in the second and third decade, as Courville and Nielsen (1937) find also. 3. PATHOGENESIS AND MORBID ANATOMY The analysis of the routes of infection through the skull to reach the cerebellum has resulted in several classifications being proposed. Courville and Nielsen (1937) divide these, first, into preformed paths by which the infection may pass (Fig. 176). These are the internal auditory meatus, the facial canal, aqueductus vestibuli containing the endolymphatic duct, aqueductus cochleae, the petroso-

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Figure 176. Diagrams showing possible pathways of infection through the temporal bone to the cerebellum in otogenic cerebellar abscess. 1. Through petrous angle (Trautmann's triangle). £. Posterior semicircular canal. §. Vestibule of labyrinth (ductus endolymphaticus). ^. Perilabyrinthine cells. 5. Through lateral sinus. 6. Along lateral sinus and cerebellar veins. 7. From exudate in the lateral pontine cistern. 8. Through posteriorly placed mastoid cells. (From C. B. Courville and J. M. Nielsen, 1937, The pathogenesis of otogenous cerebellar abscess; a study of 16 cases verified at autopsy, California & West. Med., 47:29-36, Fig. 1.)

squamosal suture in children, and the hiatus subarcuatus. These authors agree with many others that these are the most common routes of extension of the infection to the posterior fossa. When these channels are used, however, meningitis rather than cerebellar abscess is more likely. The frequency of meningitis is attributed to the large subarachnoid cysterna in this part of the intracranial cavity. Courville and Nielsen (1937) next consider the entrance of the infection through intermediate cell groups, depending on the degree of pneumatization of the various parts of the temporal bone. These are the cells in the petrous angle, with extension through Trautmann's triangle, those about the sigmoid sinus and the posteriorly placed mastoid cells, the perilabyrinthine and the apical petrosal cells. The authors state that the apical petrosal cells never, to their knowledge, have actually transmitted the infection to form a brain abscess. Of all these various routes the first through Trautmann's triangle is the shortest and one of the most common. In Eagleton's series (1922) this route was used in 22 instances, or 17.6 per cent of the total. These abscesses are said to be poorly encapsulated. This was the route found to have been used in 7 of 16 cases in which Courville and Nielsen (1937) felt certain about the route of entrance of the infection. While extension through the lateral sinus itself is common where there is a vascular involvement, the infection less commonly goes through the air cells about the sinus. The spread through the posterior mastoid cells is even less common, as these cases are treated before the cerebellum would ordinarily be reached. As for the perilabyrinthine cells it is difficult to distinguish these from the labyrinth itself, and the critical histological studies that would do so have not been made. Most authorities, as has been pointed out by Courville and Nielsen (1937), have found that 40 to 50 per cent of cerebellar abscesses result from extension of the process from a suppurative labyrinthitis. Of the various divisions (Eagleton, 1922), out of 125 cases listed, there were 19 in which the labyrinth proper was responsible; 6, the semicircular canals; 11, the vestibular aqueduct; 1 in which there was a retrograde thrombosis of the vein of the vestibular aqueduct; and 5 in which the ductus endolymphaticus was incriminated. The fourth, or venous, route results from the spread of a retrograde thrombosis back to the cerebellar veins either from the lateral, the inferior, or the

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501 superior petrosal sinus. Authors who have studied large groups of cases attribute anywhere from approximately 30 to 50 per cent to this mechanism. Courville and Nielsen (1937) point out that once the venous channels are involved, it is possible to find the abscesses spreading to secondary areas and causing further damage. Subdural abscess, subdural hemorrhage, and red softening of the cerebellar tissue may also follow thrombosis of the lateral sinus. Finally, these authors point out that in reading the records of some of these cases, it is impossible to escape the conclusion that the infecting organism has at times been introduced by the surgeon in probing for an abscess through an infected mastoid wound. They state that this was not true in any of the cases which they personally examined. Atkinson (1934) was more interested in studying the pathogenesis of these lesions than in describing the method by which the organism actually enters the cerebellar tissue. He did illustrate the most probable site for the abscesses to form, from the three principal routes of entrance (Fig. 177), the lesions produced by way of the labyrinth being the most medial and the smallest, those in which the organism enters through Trautmann's triangle being slightly more accessible and lying laterally and more superficially, and those of lateral sinus origin being the most satisfactory of all to deal with, being found still farther posteriorly and laterally. Aubry (1939) also emphasized the diiferent positions depending on the route of infection, though he undoubtedly oversimplified the problem.

Figure 177. A diagram to show the usual position in the posterior fossa of otogenic cerebellar abscesses which result from extension of the infection. 1. Through the labyrinth. 2. Through Trautmann's triangle. 3. Through the lateral sinus. IA .M. = internal auditory meatus; E.A. = eminetia arcuata; J.F. = jugular foramen; F.M. = foramen magnum; L.S. = lateral sinus; M.P. = mastoid process. (From E. M. Atkinson, 1938, Otogenous cerebellar abscess, Ann. Otol., Rhin. & Laryng., 47:1020-1034, Fig. 6.)

Atkinson (1934) insisted that the site of penetration through the dura is of macroscopic size, refuting Eagleton's claim (19£2) that grossly visible evidence of the route could only be found in 4 per cent of the cases. In discussing the mode of entry of the organism into the cerebellar tissue, Atkinson stated that his histological investigations showed that the infection reaching the meninges produces a localized meningitis and from there enters the cerebellum along the perivascular spaces surrounding the cortical vessel. Again he disagreed with Eagleton on the importance of retrograde thrombosis. From the perivascular space the infection penetrates into the medullary substance, which is a zone of relative avascularity.

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Figure 178. Section through the site of beginning of a cerebellar abscess in the white matter of the cerebellar folium. The infection in this instance has come by way of the perivascular spaces, which show inflammation, as does the overlying cortex. Tissue necrosis begins in the relatively avascular zone of the white matter. (From E. M. Atkinson, 1938, Otogenous cerebellar abscess, Ann. Otol., Rhin & Laryng 47:1020-1034, Fig. 4.)

Here the abscess starts. He summarized the main points of distinction between the three ways by which the infection enters the brain substance. These are given in the order of their frequency. (1) In the perivascular group, the vessels are patent and there is a gross mononuclear perivasculitis. The perivascular sheath is adherent to a cortex which is much thickened and altered by inflammatory changes but is not actually involved in a suppurative process until a late stage (Fig. 178). (2) In the venous group there are thrombosed veins and there is only a minor degree of perivasculitis. The reaction which is present is polymorphonuclear. The vascular sheath is loosely adherent to the cortex, which is comparatively normal early except for engorged veins and patches of hemorrhage. (3) In the arterial group changes similar to the above are found except that the arteries instead of the veins are thrombosed. In this instance there is an absence of engorgement and hemorrhage. He insists the abscess tends to remain confined to a single folium, assuming an ovoid shape with smooth walls and a thickened capsule if the virulence of the organism is such as to allow the tissues to build this defense against further spread. The cavity tends to be limited by the central core of white matter which surrounds the nuclei, and this limitation, in his opinion, accounts for the late appearance or lack of cerebellar deficiency so often commented upon in these cases (Fig. 179). It is well known, as has been pointed out in Part I of this monograph, that the signs of cerebellar deficiency from a local lesion of the cerebellar hemisphere may be very transient unless the deep nuclei are involved.

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Figure 179. Sections of a cerebellar hemisphere, showing the extent of an otogenic cerebellar abscess. Note its separation from the dentate nucleus, the smooth outline of the cavity, and the unilobular involvement. (From E. M. Atkinson, 1938, Otogenous cerebellar abscess, Ann. Otol., Rhin. & Laryng., 47:10201034, Fig. 5.)

Courville and Nielsen (1937), on the other hand, speak of the abscess spreading between the folia, and Fremel (1923a, 1926) and Eagleton (1922) stated that its shape is irregular, with fingerlike processes projecting in various ways. Atkinson said that in serial section of seventeen specimens he had never observed such a condition. One commonly speaks of the capsule about an abscess, but this is perhaps a misnomer, for only in the very chronic cases which have been dormant for months can one properly consider the abscess to be surrounded by a truly limiting membrane of fibrous tissue (Atkinson, 1934). The histological structure of the wall of the abscess will depend upon the duration of the process and the virulence of the invading organism. The abscess may be best described in terms of acute, subacute, and chronic, although it must be recognized that there is no sharp demarcation between these three types (Atkinson, 1934). By the acute abscess is meant a pyogenic infection of the brain in which there is no trace of a limiting membrane. The necrotic brain tissue occupies the center of what might be called an acute suppurative encephalitis and is simply in contact with surrounding tissue, which

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can be seen to be rapidly degenerating. There may be some polymorphonuclear cells present both in the necrotic tissue and in the brain immediately surrounding. The cells stain poorly, and there is no proliferation of the endothelial cells nor any mobilization of glial cells in an effort to form a limiting membrane. The majority of cases coming to surgery or postmortem examination would fall into what is called the subacute class. Here sufficient time has elapsed for a limiting membrane to form, consisting of three layers. The innermost is composed of necrotic tissue with thrombosed veins and leukocytic infiltration. Outside of this is a layer of granulation tissue. The third and outermost layer contains the above inflammatory cells plus neuroglial hyperplasia and a greater or lesser degree of fibrosis, depending upon the age of the lesion and the virulence of the invading organism. The chronic stage is reached only rarely. Here a fibrous wall forms which can truly be said to represent a capsule. It can be penetrated only with a knife. The necrotic layer and the granulation layer are thinned and much less prominent. This abscess is the type which can be treated successfully only by excision. The effects of antibiotic medication on the stages of development deserve some comment, for it is unusual at this time to see a patient with an otogenic brain abscess who has not had more or less adequate antibiotic and chemotherapeutic treatment. These drugs have greatly reduced the frequency of such lesions. If the administration of antibiotics can be begun during the very early stages of the condition when there may only be a localized cerebritis, a resolution may occur without a liquefaction state ever being reached, and in these instances the abscess may require no surgery. In other cases it is possible to carry a patient for a longer time with safety than without these measures, the antibiotics allowing the body to mobilize its defense so that a greater proportion of cases will eventually reach the late subacute and chronic stages when they can most successfully be treated surgically. However, there are a few cases in which the drugs are a mixed blessing. They can lull the unwary into a false sense of security unless it is recognized that the patient must be followed very carefully for weeks and that eventually surgery may be necessary no matter how favorable the outcome appears soon after the beginning of treatment. Furthermore, when the infection is not controlled and the condition continues to progress despite the use of antibiotics, the case is very difficult to handle surgically. Here the inflammation is diffuse without a definite limiting membrane, there is much edema and swelling, and if an opening is made, necrotic and inflamed tissue tends to fungate without much if any drainage of pus. While it can be argued that such patients would never have been saved in the pre-antibiotic era, they can be a source of a great deal of therapeutic difficulty. The organisms which may be responsible for cerebellar abscesses are usually streptococci, both hemolytic and nonhemolytic, Staphylococcits aureus, the pneumococcus, colon bacilli, and, rarely, usually reported as isolated cases, Proteus bacillus (Atav, 1948; Chambers and Clark, 1951) and Pasteurella multocida (Harris, Veazie and Lehman, 1953). The importance of determining the organism and its sensitivity is obvious in these days of antibiotics and chemotherapy. With the common use of penicillin it is to be expected that those cases of ear disease

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which do go on to develop cerebellar abscesses may frequently be cases in which there is an infection with a less common organism than the usual gram-positive cocci.

4. SYMPTOMATOLOGY The symptomatology has been particularly well described by Atkinson (1938). Fever, malaise, and drowsiness are recognized as the early symptoms of the invasion stage. In cases of abscess within the posterior fossa the signs of increased intracranial pressure are earlier in onset and more severe than in cases of cerebral abscess. Headache is the most constant finding, with nausea very frequent but replaced by vomiting only during the acute stages of the condition or when terminal pressure signs appear. Asherson (1942) stresses the importance of nuchal rigidity without the presence of a positive Kernig and the other signs of meningitis. Headache has been the object of particular analysis in cerebral and cerebellar abscess by Portman and Retrouvey (1929). They find it is usually occipital in location and of only moderate intensity unless meningitis supervenes. Focal signs of cerebellar deficiency are of great diagnostic importance when they occur. All authors agree that these may be late in appearing; the patient may die in coma or of respiratory failure before these signs appear unless they are looked for carefully and repeatedly throughout the course of a suspicious case. They may include any or all of the manifestations of cerebellar deficiency discusssed in previous sections. Nystagmus is one of the most important signs, occurring in 14 out of 16 cases, according to Fremel (1923b). It may be confusing because of its frequent occurrence in labyrinthine disease, which may be present along with the cerebellar abscess. Atkinson (1938) distinguishes between the two as follows: "Cerebellar nystagmus is slow, coarse and horizontal, in contrast to the rapid, fine, rotatory nytagmus of labyrinthine disease, and is characteristically to the side of the lesion, though it may be accompanied by a rapid, fine, irregular nystagmus to the opposite side which may cause confusion" (p. 1026). Where there is cerebellar involvement, past-pointing is limited to the homolateral limbs, whereas in the labyrinthine affection it is bilateral, and rather than being uniformly outward it is in the direction of the slow component of the nystagmus. Bucy and Weaver (1941) have devoted special attention to the paralysis of conjugate movements of the eyes in cerebellar abscess. The paralysis is to the side of the lesion and may be associated with spontaneous deviation to the normal side. It is by no means a constant manifestation. This sign has been emphasized also by others, whose reports are reviewed by these authors. Piquet (1948) has most recently described it in some of his cases, and believes it to be a grave prognostic sign when present. Both agree that it should be looked upon as a sign of medullary compression. As the case becomes more chronic, the signs present during invasion will subside. The temperature will fall and may even become subnormal. The pulse will slow, particularly if increased pressure becomes marked. Choked discs, while more common with cerebellar than with cerebral abscesses, are not invariable and may never appear even in fatal cases. Terminal symptoms are coma, if obstructive

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hydrocephalus occurs, and in other cases rather rapid respiratory paralysis. While rupture of the abscess and meningitis may occur, it is usually a small leak and rarely the dramatic intraventricular rupture so commonly the terminal event in the cerebral otogenic abscess. Most authorities rightfully warn against the dangers of spinal puncture in these cases, but Asherson (1942) not only claims the danger is overemphasized but lays great stress on the spinal fluid findings. However, he does not advise spinal puncture in the face of papilledema. The expected spinal fluid findings are a mild pleocytosis of less than 100 cells, with normal chloride levels. Some neurosurgeons advise ventriculograms, though most feel these should be reserved for doubtful cases. The value of ventricular taps, either at the time of surgery or in preparing the patient for the operation while the systemic reaction is being controlled and the abscess is being allowed to form a capsule, is stressed by several. Kahn (1939) has injected thorium into brain abscesses for visualization of their location and to observe changes in their size, but this practice is not general at this time. Electroencephalography and arteriography have not been applied to this problem, and pneumoencephalography is definitely contraindicated.

5. DIFFERENTIAL DIAGNOSIS Atkinson (1934, 1938), in discussing the differential diagnosis, mentions acute suppurative labyrinthitis and extradural abscess in the lateral part of the posterior fossa. The nystagmus, the pointing tests which have been mentioned, and the direction of falling are the most useful differential signs to observe. The falling in labyrinthitis is always toward the slow component of the nystagmus and will vary with the position of the head. One should also mention frontal lobe abscess in the opposite frontal lobe, a problem which has been discussed in a previous chapter (p. 404), cystic serous meningitis (Jenkins, 1926), tuberculous meningitis, and cerebellar tumor.

6. TREATMENT We cannot discuss treatment with any fullness. The subject is handled in detail in the articles of Asherson (1942), Wilkins (1940), and Pennybacker (1948). While there is no disagreement that the abscess must be treated surgically, there is no general agreement on when or how the abscess is to be drained or whether excision is the method of choice. Otologists, as exemplified by Asherson (1942, 1948), insist on the advantages of drainage along the "path of infection" particularly, so they say, because the local pathological condition must be cared for as well. Wilkins (1940) has reported very good success with tube drainage through an occipital "clean" exposure. Schreiber (1941) had 8 recoveries out of 9 cases in which repeated puncture drainage and antibiotics were employed, and Pennybacker (1948) and Medwick, Uihlein, and Hallberg (1949) advocate complete excision with antibiotics. The patient will receive the best which medical science has to offer only if both the otologist and the neurosurgeon, whose fields are separated only by the dural membrane, cooperate wholeheartedly in the care of these patients.

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7. NONOTOGENIC ABSCESSES

While the description given in section 3 will suffice for the pathology and pathogenesis of about 95 per cent of cerebellar abscesses, there are rare instances in which the abscess arises in some other way. Wilkins (1940) had an unusually large percentage of metastatic abscesses of the cerebellum. While their diagnosis is more difficult because of their rarity and because one is more apt to be on guard for cerebellar abscesses in cases of chronic otitis, they are not different in any other respect. They all arise from some source outside the cranial cavity whether near or remote. The blood-borne ones are apt to be multiple. The clinical diagnosis is not really justifiable without some infection being present, usually in the lungs or involving the heart (Rabinowitz, Weinstein, and Marcus, 1932). A most unusual case is the one reported by Antognoli (1936), where the abscess followed a nasopharyngeal malignant growth, the infection spreading via the venous plexus at the base of the brain. D. FUNGICITIC INFECTIONS A few reports are in the literature of cerebellar abscesses caused by various molds. They cause a chronic, low-grade, indolent-type of inflammation which may at times be confused with a pyogenic abscess but more often with a tumor. Peet (1946) reported a patient briefly who had such a lesion from Aspergillus fumigatus, which resulted from chronic otitis. The seven-and-a-half-year-old child improved after surgery, though the type of procedure is not described. Sabrazes (1921) has given a brief description of a cerebellar abscess caused by streptothrix. This occurred in a veteran who had a severe infection in wounds of the lower extremities, eventually requiring amputation. Some time later he developed a cerebellar abscess which the author assumed to be blood-borne from the old infection. No other lesions aside from the cerebellar abscess were found. The mycosis was identified by cultural characteristics. List, Williams, Beeman, and Payne (1954) report a case of multilocular cerebellar abscess due to Nocardia asteroides which was successfully treated by surgical excision and intensive and prolonged antibiotic and chemotherapeutic treatment. This mold has been designated in the past under the synonyms Cladothrix asteroides, Streptothrix eppingeri, Oospora asteroides, and Actinomyces asteroides according to these authors. Stevens (1953) has presented a recent review of the problem of infections of the nervous system with these organisms. He feels that while infections due to Actinomyces bovis and Nocardia asteroides cannot be ordinarily differentiated clinically, it is important to distinguish between them by their different cultural and staining characteristics. Most previous reviews had not differentiated them. These are now the preferred terms for the two distinguishable organisms, infection with which is commonly referred to as "actinomycosis." In cases of infection with both molds the intracranial involvement is metastatic, usually from the lung. Most abscesses are cerebral and meningitis may also occur. The cerebellar symptomatology is that of a chronic expanding lesion whose granulomatous nature could only be suspected by systemic evidence of the disease. The central nervous system symptoms may develop very rapidly after a long history of chronic systemic disease at times lasting many years.

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PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

There are several reports in the recent South American literature of cerebellar abscesses caused by Torula and Coccidioides infections and having the characteristics of tumors rather than of infectious processes. While these organisms are occasionally encountered as the cause of a chronic meningitis, the reports of localized cerebellar lesions are very rare. Some of these reports are those of Dickman, Veppo, and Negri (1942), Prado, Insausti, and Matera (1946), and Sammartino (1947). Craig and Carmichael (1938) reported a case of blastomycosis of the cerebellum. The patient had a lesion of the elbow which they suspected was a granulomatous lesion caused by blastomycosis. He developed headache, choked disc, and some signs of cerebellar deficiency, and after the presence of a posterior fossa lesion had been proved, operation disclosed a granulomatous lesion, and the organism was identified. The mass, which they call a blastomycoma, was removed completely, but the patient died a few months later of fulminating meningitis, according to the clinical diagnosis. E. PARASITIC INVOLVEMENT OF THE CEREBELLUM

1. AMEBIASIS Spellberg and Zivin (1948) have reported one patient who died of a cerebellar abscess caused by Entamoeba histolytica. Craig (1944) mentions 52 cases of brain abscess due to E. histolytica, all but one of which were in the cerebrum. Up to this time the condition has been 100 per cent fatal. It is always secondary to a liver abscess and is thought to follow traumatization of the diseased liver.

2. CYSTICERCOSIS As has been pointed out above, cysticercus cysts of the fourth ventricle were once considered to be the sole pathological condition associated with Bruns' syndrome. At that time a number of cases were reported in this connection, particularly the reports of Bruns (1902, 1906), Henneberg (1906), Stern (1907), and Osterwald (1906). Of recent years a number of reports concerning such lesions affecting the cerebellum and fourth ventricle have appeared, chiefly from the neurosurgical clinics of South America. The reports are by Bernales and Encinas (1943), Arana and Asenjo (1945), Dickman (1946), and others. Clinically these lesions show only manifestations of increased intracranial pressure, consisting of headache, vomiting, choked discs, and, at times, staggering gait. On ventriculographic examination the aqueduct of Sylvius is usually seen to be partially filled and dilated, and there is some gas in the fourth ventricle and about the cerebellum, which may be atrophic. This, combined with a symmetrical dilatation of the lateral and third ventricles, is characteristic of these lesions, while tumors in the same sites usually produce obliteration of the fourth ventricle and displacement of the aqueduct and complete obstruction of gas into the cysterna magna. SUMMARY Tuberculosis of the central nervous system may involve the cerebellum as an isolated lesion. The incidence has fallen greatly in the last fifty years, and now these rare lesions are usually discovered only at the time of surgical operation for

CHRONIC INFECTIONS

509

what was thought to be a cerebellar tumor. While extirpation has been looked upon as extremely dangerous, with the use of chemotherapy and streptomycin it is now becoming the treatment of choice. Syphilitic gumma are even rarer and when found are best removed surgically. Little has been published concerning the changes in the cerebellum occurring in general paresis, though undoubtedly lesions occur. Cerebellar abscess is much less frequent than cerebral abscess, but when it does occur, it results from middle ear disease, usually chronic. The various routes through which the infection may pass into the intracranial cavity are pointed out. The pathological changes associated with an abscess vary with its age, and they may be arbitrarily divided into acute, subacute, and chronic. Antibiotic therapy modifies the natural progression of these lesions. The symptomatology of cerebellar abscess consists of an initial febrile period followed by symptoms and signs of increased intracranial pressure, particularly important being headache. Focal signs of cerebellar deficiency may be late in appearing. While treatment is primarily surgical, it is modified by antibiotic drugs, and these have enabled extirpation rather than drainage to be oftener employed. Fungicitic infections rarely involve the cerebellum, and when they do, they are differentiated from tumor with difficulty. The parasitic diseases in which the cerebellum may be involved include, rarely, amebiasis and, more commonly, especially in South American countries, cysticercosis. In the latter the symptomatology is that of an expanding posterior fossa lesion.

15

Vascular Diseases of the Cerebellum

A. Occlusion 1. Posterior inferior cerebellar artery a. Incidence b. Etiology c. Pathological changes

511 511 511 512 512 gs findings512 (1) Variations in the extent of the lesion and gross cerebellar 512 (2) Histological changes in the cerebellum 512 d. Symptoms 513 e. Treatment 514 2. Anterior inferior cerebellar artery 514 3. Anterior superior cerebellar artery 514 a. Incidence 514 b. Etiology 514 c. Pathological changes 515

(1) Variations in the extent of the lesion and gross cerebellar findings 515

(2) Histological changes in the cerebellum d. Symptoms e. Treatment B. Hemorrhage 1. Incidence 2. Etiology 3. Pathological changes 4. Symptoms 5. Treatment Summary

515 515 517 517 517 517 517 519 520 520

THE cerebellum is supplied by three arteries, the posterior inferior cerebellar from the vertebral, the anterior inferior cerebellar and the anterior superior cerebellar from the basilar. The first and last contribute to the blood supply of the deep nuclei (Shellshear, 1922; Fazzari, 1933). Except for these deep branches, there are no end arteries but a plexus of anastomotic channels formed between the branches of the three arteries and the corresponding ones of the other side. There is a great deal of variation in these arteries. Stopford (1916-1917) has not only 510

VASCULAR DISEASES

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described the arterial anatomy in great detail but has interested himself in the clinical correlations, particularly as far as the associated brain stem is concerned. A study of the capillary network has been made by Aby (1899) and Craige (1920, 1924). Craige has compared in a quantitative way the relative vascularity of the molecular layer, the granular layer, and the dentate nucleus. He has found that in the adult rat the relative vascularity, according to his arbitrary quantitative scale, varies from 1,250 in the fasciculus cuneatus, which was the least vascular, to 10,500 in the dorsal cochlear nucleus, which was the most vascular. These may be compared with the relatively richly supplied cerebellum, which, according to the same quantitative scale, was 7,100 in the molecular layer, 8,750 in the granular layer, and 9,000 in the dentate nucleus. The period of development of this cerebellar capillarity is somewhat later than that of most parts of the brain stem, which reach their adult richness between the fifth and tenth day. In the cerebellum the adult level is not reached until after the twentieth day. The venous drainage from the cerebellum is so highly variable that one can only say that it occurs into the lateral, straight, superior, and inferior petrosal sinuses. Our discussion in this chapter will concern itself with arterial occlusion, thrombosis and embolism, and with cerebellar hemorrhage. A. OCCLUSION

1. POSTERIOR INFERIOR CEREBELLAR ARTERY a. INCIDENCE

Although Wallenberg's name has been attached to the syndrome resulting from occlusion of the posterior inferior cerebellar artery, Spiller (1908), who furnishes a complete review of the early literature, lists at least three cases which were described before the one by Wallenberg (1895). As was first pointed out by Breuer and Marburg (1902) and as has been emphasized by many since, it is impossible to determine clinically in individual cases whether the occlusion is confined to the posterior inferior cerebellar artery or involves the vertebral as well. The reason for this is twofold; first, there is frequent variation in the course and distribution of these arteries, a circumstance considered by Wallenberg (1895) and completely reviewed by Stopford (1916-1917), and second, because of the tendency of the clots to propagate themselves, it is impossible to say whether the occlusion found at the time of death was actually the extent of the vascular obstruction present when the stroke and its symptomatology were first described. As has been pointed out by Sheehan and Smyth (1937) and many others, if there are signs of a crossed hemiplegia one can be quite certain that the vertebral artery itself is involved. The absence of these signs by no means allows one to say that the occlusion is limited to the posterior inferior cerebellar artery. The two syndromes are therefore treated as one, though it is recognized that many variations in the extent of the lesion will necessarily be found. No figures on the actual incidence of occlusion of this artery have been found. Nor has any one recently totaled the number of cases which have been reported. It must be many times more frequent than occlusion of the other cerebellar arteries. Many of these cases recover, and only a small fraction are ever reported.

512

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

b. ETIOLOGY

The vast majority of these cases occur in the late years of life and are the result of atherosclerotic changes in the affected vessels. Thrombosis can occur in the course of syphilitic vascular disease, diabetes, and any other of the less common causes of cerebral vascular damage. Suechting and French (1955) reported an occlusion following skeletal traction for a fractured cervical vertebra. Tatlow and Bammer (1957) have recently reviewed the subject of vertebral occlusion produced by neck movement. Emboli usually arise from mural cardiac thrombi or from the vegetations of the heart valves in subacute bacterial endocarditis. C. PATHOLOGICAL CHANGES

(1) Variations in the Extent of the Lesion and Gross Cerebellar Findings It is rare that the pathological changes in the cerebellum are described in detail. Indeed, because of the rich anastomoses provided to the vessel once it reaches the cerebellum by the other cerebellar arteries, it often happens that the cerebellum is entirely spared. Such was the situation in the pathological descriptions of Wallenberg (1895), Spiller (1908), Wilson and Winkelman (1927), Merritt and Finland (1930), Hall and Eaves (1934), Goodhart and Davison, cases 1 and 3 (1936), Sheehan and Smyth (1937), and others. In the cases reported by Foix, Hillemand, and Schalit (1925) the cerebellum was spared by the thrombosis, which involved only a medullary branch of the posterior inferior cerebellar artery, which they call the artery of the lateral fossa of the bulb. The major anatomical work, however, has indicated that this is only one of a number of such penetrating arteries and that the variations in the extent of the lesion depend upon the size of these end arteries and the extent of the field supplied by them. The cerebellum may be involved along with the medulla, as is shown by the cases of Vulpian (cited by Tschernyscheff and Grigorowsky, 1930a, b), Hun (1897), Schwarz (1912), Richter (1924), Winther (1927), Goodhart and Davison, case 2 (1936), Spillane (1937), Fattovich (1950), and others. In a few instances the cerebellum may be involved without the usual associated brain stem lesions; for example, the cases reported by Guillain, Alajouanine, Bertrand, and Garcin (1929), Goodhart and Davison, cases 4 and 5 (1936), and others. Fattovich (1938) has described a cerebellar softening in the portion of the cerebellum supplied by this artery, i.e., the posterior and inferior surface of the hemisphere, which was unassociated with any detectable sign of cerebellar deficiency and was discovered by accident at the autopsy. When the cerebellum is grossly affected, as in the case of Spillane (1937), the dentate nucleus may be involved. Unfortunately, in none of the reported cases was the exact identity of the portions of the cerebellum destroyed determined. (2) Histological Changes in the Cerebellum The characteristic changes in the cerebellum produced by vascular obstruction are outlined by Goodhart and Davison (1936). Cresyl violet stains demonstrated the cerebellar convolutions to be filled with compound granular corpuscles, and the Purkinje cells showed pathological changes. The same authors

VASCULAR DISEASES

513

described destruction of both the molecular and granular layers in the area of softening. d. SYMPTOMS The symptoms of this condition which may be attributed to the cerebellum are homolateral cerebellar ataxia and hypotonia. In general these symptoms show a marked tendency to improve. This is true even where there is gross atrophy of the corresponding cerebellar hemisphere, as in the case of Spillane (1937). Here, however, in spite of the cerebellar changes, the inferior peduncle was spared. Damage to this structure is the usual source of the cerebellar symptomatology in these cases. It may be quite marked, with gross ataxia of the involved extremities. The nystagmus and falling to the side of the lesion can usually best be explained on the basis of damage to the vestibular complex of the medulla. More attention has been paid to the other manifestations of brain stem involvement than the cerebellar signs, and as a matter of fact these are the more constant parts of the syndrome of occlusion here. In the majority of cases the cerebellar deficiency is less enduring than in cases of lesions of the anterior superior cerebellar artery. While at first glance this difference might seem to be correlated with the difference between the durations of the disability noted after section of the inferior and after section of the superior cerebellar peduncle in the monkey (see pp. 85-95), it may also be a result of less complete involvement of the cerebellar structures in the occlusions of the posterior inferior cerebellar arteries. The lack of adequate histological study of the cerebellum in the majority of cases makes any definite opinion impossible. The additional symptoms of disturbances of cutaneous sensation in the face on the side of the lesion and occasionally on the opposite side as well, the loss of sensitivity to pain and temperature on the opposite side of the body at times sparing a variable part of the cervical segments, have been the object of special study. Workers in this area have made important deductions concerning the course and distribution of the sensory pathways in the human being. Among such studies are those of Sheehan and Smyth (1937) and several publications of Stopford. There may be difficulties in swallowing and phonation, with homolateral palatal weakness, and at times changes in cardiac rate, owing to involvement of the vagal nuclei. Myosis and narrowing of the palpebral fissure, at times associated with a diminution of sweating on the homolateral side, are found, due to involvement of the descending autonomic pathways in the reticular formation. If crossed hemiplegia or homolateral weakness of the tongue occurs, the vertebral artery is also involved. Loss of taste on the posterior one third of the tongue is, as a rule, due to damage to the glossopharyngeal nerve and nuclei, although Gerard (1923) states this loss is on the anterior two thirds of the tongue. The onset may be sudden or the condition may gradually progress during a few hours. Improvement varies, as with cerebral vascular accidents elsewhere. There may or may not be premonitory signs and symptoms. The more rapid onset favors embolism, but in this condition the younger age of the patient and the existence of a cause of the embolic process, usually in the heart, are the important factors in differential diagnosis.

514

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

C. TREATMENT

The usual measures of general supportive therapy are indicated here, as well as prophylactic therapy to avoid aspiration pneumonia. In some instances tube feedings will be necessary for some time. Rarely will a tracheotomy be necessary, though, as in all cases of bulbar paralysis, the operation is commoner now than formerly. Stellate ganglion blocks and other methods of vasodilatation, as well as anticoagulants, are still in the experimental stage. The use of Dramamine, by rectum if necessary, can help to control the nausea and vomiting which may be distressing during the initial stages of the stroke. Sometimes the occlusion is the first manifestation of the underlying vascular or cardiac pathological condition, which will need to be treated appropriately.

2. ANTERIOR INFERIOR CEREBELLAR ARTERY Only one example of occlusion of the anterior inferior cerebellar artery has been found in the literature. This is case 6 reported by Goodhart and Davison (1936). This patient had had hypertensive cardiovascular disease for at least eight years before her hospital admission in 1934. She had had several cerebrovascular episodes during this time, and her signs and symptoms were those of multiple lesions. There was some ataxia of the right arm and to a lesser degree of the right leg. At the postmortem examination an occlusion of the right anterior inferior cerebellar artery was found, with an area of softening involving the right cerebellar hemisphere limited to the upper third and inferior surface of the "paramedian lobule and the right Crus II of the lobulus ansiformis." Microscopic study confirmed the gross findings. The authors attributed the "weakness of the right arm and leg and the clumsiness in dressing and feeding, as well as the slight tremor and ataxia on the right side" to this lesion. There were, however, other vascular lesions, and this case cannot be said to indicate definitely the symptoms which would result from such a lesion.

3. ANTERIOR SUPERIOR CEREBELLAR ARTERY a. INCIDENCE There are no figures available on the incidence of occlusion of the anterior superior cerebellar artery. It is generally conceded that it occurs less frequently than does occlusion of the posterior inferior cerebellar artery. Certainly its recognition as a diagnostic entity came later, for it was only about twenty-five years ago that the syndrome was recognized as anything but a clinical curiosity. It may be more frequent than is usually believed in view of the fact that Luhan and Pollock (1953) were able to identify six cases, three of which included postmortem examinations, in a four-year period in a single large general hospital. b. ETIOLOGY

Nothing can be added to the etiology of occlusion here which has not already been said in the discussion of the causes of occlusion of the posterior inferior cerebellar artery. It has been assumed that embolism occurs most frequently in arteries which are formed in the direct continuity of the trunk from which they are the branches. This explains the frequency with which the middle cerebral

VASCULAR DISEASES 515 artery is involved in cerebral embolism. On this basis Stopford (1916-1917) states: "Owing to their origin being at right angles to the basilar, these vessels are rarely obstructed by embolism" (p. 363). Thompson (1944) has been able to collect, in a pathological study, five instances of embolic obstruction of this artery. He believes the anterior superior cerebellar artery is more susceptible to embolism than is either of the other cerebellar arteries because it is directed only at right angles to the parent vessel while the other two actually are directed posteriorly and in a reverse direction to the blood flow in the vertebral and basilar arteries. C. PATHOLOGICAL CHANGES

(1) Variations in the Extent of the Lesion and Gross Cerebellar Findings The anterior superior cerebellar artery has a more important role to play in the nutrition of the cerebellum than does either of the others, if one may judge from the frequency with which occlusion produces gross damage to the cerebellum (Fig. 180). As pointed out above, the posterior inferior cerebellar artery is not infrequently occluded without any visible damage to the cerebellum. In the anterior superior cerebellar artery, on the contrary, only two instances are recorded in which occlusion failed to produce a grossly evident softening of the cerebellum. These instances are one of the cases described by Luhan and Pollock (1953) and one described by Davison, Goodhart, and Savitsky (1935). The fact that in these two cases the symptoms of cerebellar deficiency were still present has been used by the first-named authors rightly to attribute the cerebellar deficiency to the constant damage to the superior cerebellar peduncle (see p. 401) whether this occurs in the cerebellum, as is the usual case, or entirely in the midbrain. The cerebellar damage may not be extensive. In one of the cases described by Luhan and Pollock it consisted of a slightly depressed, brownish area on the dorsal surface of the right hemisphere about 1 centimeter in diameter. In another case an extensive, yet superficial, dirty-brownish-colored softening in the dorsal surface of the right cerebellar hemisphere was seen. (2) Histological Changes in the Cerebellum Only fragmentary descriptions of the changes in the structure of the cerebellum are reported by Luhan and Pollock. Of one case they state that the cerebellar folia were completely demyelinated and shriveled near the area of necrosis in the rostral part of the pons. In another they mention the presence of "incomplete softening of the dentate nucleus." The third case, in which there was no gross evidence of cerebellar lesion, revealed on histological study "ischemic ganglion cell disease and diffuse polymorphonuclear infiltration, as in beginning softening." All of these cases showed a crossed pseudohypertrophy of the inferior olivary nucleus (Fig. 156, p. 414). d. SYMPTOMS

The symptoms of occlusion of the anterior superior cerebellar artery have been discussed in detail in connection with our discussion of the effects of lesions of the superior cerebellar peduncle (p. 401). This syndrome has been describedlE^

516

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

Figure 180. Section through the cerebellum of a case of occlusion of the anterior superior cerebellar artery. Note the complete destruction of the dentate nucleus. (From M. Critchley and P. Schuster, 1933, Beitrage zur Anatomic und Pathologic der Arteria cerebelli superior, Ztschr. f. d. ges. Neurol. u. Psychiat., 141:681-741, Fig. 24.)

Porot (1906), Mills (1908, 1912), Guillain, Bertrand, and Peron (1928), Russell (1931), Critchley and Schuster (1933), Davison, Goodhart, and Savitsky (1935), Freeman and Jaffe (1941), Thompson (1944), Girard, Bonamour, Garde, and Etienne (1950), and Luhan and Pollock (1953). The syndrome includes, briefly reviewed, homolateral hypotonia, asthenia, and disorders in the rate, range, and speed of muscular contraction involving the ipsilateral upper and lower extremities. There is always severe difficulty in walking, and after a time, when the ability is regained, the limb is placed uncertainly in abduction. The associated findings, which allow one to determine the level of the lesion in the brain stem and serve to distinguish this condition from occlusion of the posterior inferior cerebellar artery, are the loss of sensibility to pain and temperature in the contralateral half of the body, including the head, occasionally a loss of hearing contralateral to the lesion, and in a few patients a loss of emotional expression in the lower face on the contralateral side with preservation of voluntary movements. Hyperkinetic movements, and in one patient palatal myoclonus, have been described, and in a few, weakness of the fourth and sixth nerves has been seen. The condition is sudden in onset in all cases, but without loss of consciousness. As with occlusion of the posterior inferior cerebellar artery, nystagmus, pain, and paresthesia may occasionally be seen. No swallowing difficulties, palatal weakness, anesthesia in the glossopharyngeal distribution, aphonia, nor pyramidal tract signs are encountered. Homer's syndrome, however, observed in the more caudal lesions, may be seen here as well.

VASCULAR DISEASES

517

6. TREATMENT

The treatment in cases of this kind is not so difficult during the acute stages, since interference with swallowing is not a problem. Muscle training, occupational therapy, walking training, and other exercises to overcome the cerebellar deficiency are of primary importance. B. HEMORRHAGE

1. INCIDENCE The often expressed opinion that cerebellar hemorrhage is an exceedingly rare occurrence is probably the result of the study reported by Michael in 1932, who found that among 17,257 autopsies there were 1,112 cases of cerebral hemorrhage and only 10 cases of cerebellar hemorrhage. This report indicated that the ratio between the two was about 1 to 111. This very low incidence has not been found by other workers, and the prevailing notion that cerebellar hemorrhage is exceedingly rare needs to be corrected. Kron and Mintz (1927), Zannoni (1933), Mitchell and Angrist (1942), and others have demonstrated that hemorrhages of the cerebellum approach the number which might be expected on the basis of its weight relative to that of the rest of the central nervous system, which is about 10 per cent. None of these figures includes traumatic hemorrhage, nor do we propose to discuss this subject here. Mitchell and Angrist (1942) have reviewed 109 cases previously reported, in which group there were 16 males and 46 females. The highest incidence occurred in the sixth, seventh, and eighth decades. Cerebellar hemorrhage can occur at any age, and Wessels (1942) found the condition to be present at the ages of 16, 26, and 29 years; only 1 of his 4 cases occurred in the older, more common age group. One of the patients reported by Michael (1932) was only one month old.

2. ETIOLOGY The associated pathology of .cerebellar hemorrhage, which has a bearing also on its etiology, does not differ from that of cerebral hemorrhage. All authors agree that most cerebellar hemorrhages occur in association with hypertensive cardiovascular disease and atherosclerosis. Some are found in cases of blood dyscrasia, and an occasional one is due to vascular syphilis or a miliary aneurysm. There are also a fairly large number of cases in which no cause for the hemorrhage can be determined, the patient being in the younger age group and without any evidence of cardiac or vascular disease. Hyland and Levy (1954) found 8 out of 32 cases to result from angiomatous malformation.

3. PATHOLOGICAL CHANGES The vessel which appears to be the site of the hemorrhage is usually a branch of the anterior superior cerebellar artery which supplies the dentate nucleus. In the 122 cases analyzed from the standpoint of location by Mitchell and Angrist (1942), 47 of the hemorrhages occurred in the left hemisphere, 57 in the right, and 18 in the vennis. All of them extended into the subarachnoid space, and 43 resulted in intraventricular bleeding. Inasmuch as in many of the older case reports the extent was not specifically mentioned, it is possible that an even larger por-

518

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

tion ended fatally from intraventricular extension of the hemorrhage. In 119 cases in which the size of the hemorrhage was determined, 95 were larger than 5 centimeters in diameter. There is nothing distinctive about the gross and microscopic pathological changes produced by cerebellar hemorrhage as compared to hemorrhages in other parts of the central nervous system. When the lesions are examined early there is an associated softening about the hemorrhage and a cellular infiltration with leukocytes (Fig. 181). As a result of the damage to the nervous tissue demyelimzation and gliosis, with secondary scarring from fibrous tissue, mark the old lesion. Blood pigments still may be evident in the old lesion, and occasionally the whole mass is enclosed in a firm capsule (Michael, 1932, case 1). Such a lesion could become the site of calcification.

Figure 181. A. Massive hemorrhage of the right lobe of the cerebellum, extending into the vermis occurring as the terminal event in chronic myelogenous leukemia. B. A low-power photomicrograph of the cerebellum in the same case, showing leukemic infiltration and hemorrhage in the white matter adjacent to the molecular layer of the cortex. A

(]?T ?' Mitche11 and A' Angnst, 1942, Spontaneous cerebellar hemorrhage; report of 15

Am. J. Path., 15:935-953, Plate 142, Figs. 1 and 2.)

VASCULAR DISEASES 4. SYMPTOMS

519

Mitchell and Angrist (1942) concluded that there was no characteristic clinical picture which could be associated with cerebellar hemorrhage. However, in some instances it has been possible to make the diagnosis and remove the clot with good results; therefore, it is well to analyze those symptoms which could be used in some cases to arrive at a correct diagnosis. Michael (1932) has divided the cases into three groups. He recognizes that in many cases death will be so sudden that no diagnosis is possible, and these make up about 10 per cent of the total number he reports. The patient is often found dead or dies within a few minutes or an hour after the attack. This group is classified as fulminating. The only sign may be a sudden cry and a grasping of the head or neck indicating the severe pain which ushers in the attack. The next group, which Michael considers the grave hemorrhages, are the most common of the three types. Here the onset, less abrupt, allows time for a complaint to be expressed of severe headache, usually occipital in location, vertigo, nausea, vomiting, and inability to stand or walk. Eventually there is a loss of consciousness, which may supervene in minutes or hours; at this time manifestations of increased intracranial pressure may be evident, and death may occur from medullary compression and respiratory paralysis. If the course is slow enough, the patient may exhibit signs of cerebellar deficiency maximal on the side of the hemorrhage, which, as we have already seen, is located usually in one or the other hemisphere. Tonic spasms may occur, but paralysis and signs of hemiplegia are absent. There may be a divergent strabismus and nystagmus. This chain of events proceeds so rapidly that in over half the cases coming to autopsy, the patient is dead in less than twenty-four hours. This was true in 64 out of 113 cases analyzed for this feature of their illness by Mitchell and Angrist (1942). Most of those in this category had intraventricular extension of the hemorrhage. There are a number who may live for days or weeks, and it is in this group that a diagnosis might reasonably be expected to be made and perhaps successful evacuation of the clot performed. The differential diagnosis between these hemorrhages and spontaneous subarachnoid may be quite difficult. The presence of definite cerebellar signs, when they can be demonstrated, would be the principal differential point. If coma gradually deepened with the gradual development of increasing intracranial pressure, a ventriculogram localizing a posterior fossa lesion might be necessary before the patient could justifiably be explored. The benign group are those cases in which the hemorrhage arrests itself, and the patient recovers to die of some other condition. Most of these cases are discovered at the postmortem table, not having been suspected. If the lesion is big enough to cause symptoms of cerebellar deficiency or coma, the patient dies usually of his expanding posterior fossa lesion. A few cases are reported, such as that of Schaller (1921), where serious and permanent cerebellar deficiency followed what was probably a cerebellar hemorrhage, although the author was apparently not certain whether the condition was a hemorrhage or a thrombosis. Certainly the first case reported by Michael (1932) would represent such a patient.

520

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM 5. TREATMENT

From the pathology of these lesions it is apparent that there will be a small number of patients whose condition will allow sufficient time for a diagnosis and will require that surgical interference be seriously considered. The results, mostly of isolated cases, which have thus far been reported, appear to justify the attempt, particularly if the patient is not already an invalid from other manifestations of hypertension or arteriosclerosis. The report of Kron and Mintz (1927) represents the first successful surgical attack. Although the patient was followed for only two weeks, there was already complete return of cerebellar control and the patient was symptom-free on discharge. Since then successfully treated cases have been reported by Torkildsen (1937), Pilcher (1941), Guillaume and Sigwald (1943), LeBeau and Feld (1947), Guillaume, Roge, and Janny (1949), Ferey (1950), Werden (1951), Hyland and Levy (1954), and others. Aside from what hope surgery has to offer, the supportive and physical therapeutic measures outlined in our discussions of occlusion of the cerebellar arteries is the only therapy available in these cases. SUMMARY Syndromes of vascular disease of the cerebellum include those which follow occlusion of the posterior inferior cerebellar artery and the anterior superior cerebellar artery. Embolism as a cause of occlusion is generally believed to be less common than thrombosis, and relatively less so in the cerebellum than in the cerebrum. Cerebellar hemorrhage is usually a rapidly fatal condition in which the signs or symptoms of fulminating increased intracranial pressure with medullary compression usually overshadow evidences of cerebellar deficiency. Recently a few isolated instances of successful surgical evacuation of the clot have been reported.

16

Cerebellar Trauma

A. Cerebellar laceration B. Extradural cerebellar hematoma 1. Incidence 2. Etiology 3. Symptoms 4. Treatment C. Traumatic hemorrhage of the cerebellum Summary

521 523 523 523 523 525 525 525

TRAUMA to the cerebellum, like cerebral trauma, may be classified into concussion, contusion, laceration, and traumatic hemorrhage. Cerebellar concussion, if it occurs, is so overshadowed by the effects of concussion on the rest of the nervous system that it has no practical significance and it does not manifest its presence in any clinically observable way. Contusion, while it does occur, does not in itself usually result in any clinically evident manifestations or any sequelae such as the focal convulsive disorders that may result after cerebral contusion. Lecount and Apfelbach (1920) found cerebellar contusion in 30.89 per cent of fatal fractures of the posterior cranial fossa, in 6.02 per cent of fractures in the middle cranial fossa, and in 18.03 per cent of those in the anterior fossa. Pratt-Thomas and Berger (1947) reported two fatalities due to thrombosis of the basilar artery following chiropractic manipulations; they believed the thrombosis to have resulted from a contusion of the cerebellum produced by the treatment. However, Ford and Clark (1956) and Tatlow and Bammer (1957) attribute these sequelae to compression of the vertebral artery and subsequent thrombosis of the basilar artery. Andre (1947) described a syndrome of cerebellar deficiency following a head injury in a boy of four years. The child was unconscious for ten days, and the cerebellar syndrome, though it gradually cleared to a degree, was still clearly evident seven months after the injury. A. CEREBELLAR LACERATION Laceration of the cerebellum of sufficient severity to produce symptoms of cerebellar deficiency is seen practically exclusively following gunshot wounds or 521

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other penetrating wounds of a similar kind. Many patients with such wounds involving the posterior fossa die as a result of hemorrhage into the posterior fossa and/or concomitant injury to the vital centers of the medulla and pons. Patients who recover but who have severe enough involvement of the cerebellum to result in definite symptoms of cerebellar deficiency are rare. About the only time wounds such as this are found in any number is in time of war. Holmes (1917) originally based his classical analysis of cerebellar dysfunction in man on a group of 40 patients of whom 21 lived long enough or had symptoms of sufficient severity and duration to investigate. These symptoms have been described in detail in an earlier chapter (p. 388), and as pointed out, in most of these cases, if the patient survived, the principal damage was necessarily in the lateral portions of the cerebellum and most particularly in the posterior lobe of the corpus cerebelli. Some of these cases were followed for several years, and in 1922, at the time of his second report on this material, Holmes had increased the total number to 75. We may say from the results of his studies that after mild injuries in man no permanent symptoms or signs may result, but after severe injuries the deficiencies, which he has so well described, are permanent, though a degree of compensation can always be seen. The process of recovery can be accelerated by appropriate physical and occupational therapeutic measures. The treatment of the acute effects of these injuries is beyond the scope of this monograph and will not be discussed. Andre-Thomas (1915, 1918, 1932) has also reported 3 cases of cerebellar dysfunction following war-inflicted wounds of this organ. He describes findings which he felt supported his concept of localization of function on a somatotopic basis and his so-called anisothenia (see p. 395). We have already referred to Leri's interesting case report (1916) of a wound which was thought to have involved the posterior vermis exclusively. Aside from these reports, which do not compare with Holmes's well-known investigations, no other publications have appeared, and no studies of a similar type have been reported from military casualties in more recent conflicts. Hellenthal (1933), in discussing the incidence of cerebellar injuries following closed head injuries and particularly of contrecoup effects, reported that out of 137 contrecoup brain injuries 12 were located in the cerebellum. At times head injuries may produce the symptomatology of pre-existent tumors, or tumors of the cerebellum may follow a history of trauma which may have involved this part of the brain (Forster, 1943), but there is no good evidence that there is any causative relation between cerebellar trauma and neoplasia. A great deal has been written on the relation between the vertiginous element of the postconcussion syndrome and the function of the vestibular system. A few such studies are those of Linthincum and Rand (1931), Grove (1931), Marinesco and Facon (1932), de Morsier and Barbey (1937), Ruf (1939), Zacks (1939), and Brunner (1940). Some have attempted to implicate the cerebellum in this syndrome (Grant, 1944), but the subjective sensations of light-headedness, the difficulty with balance on looking up or on changing position, the fear and at times actual unsteadiness in climbing and working on high scaffoldings which are fre-

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quently seen after head injury, are not associated with any real clinical evidence of cerebellar deficiency, and there is no pathological evidence that trauma to the cerebellum could be the actual cause of this part of the postconcussion syndrome B. EXTRADURAL CEREBELLAR HEMATOMA

1. INCIDENCE Extradural cerebellar hematoma as a complication of head injury has attracted considerable attention during the past fifteen years. Since the original description by Wharton (1901) there have been over twenty reports of cases, most of which have been published during the past five or ten years. Lecount and Apfelbach (1920) among 504 cases of skull fracture found 104 extradural hematomas large enough to compress the brain appreciably. Of these, 8 were the result of fracture in the posterior fossa with hemorrhage from one of the transverse sinuses. In no case was a hematoma actually described as being confined to the posterior fossa. Vance (1927) in 512 cases of skull fracture found 61 extradural hematomas, of which 4 were in the posterior fossa. In spite of these figures taken from postmortem studies, Anderson (1949), in reporting an isolated case, stated that no examples of this lesion had been encountered among more than 25,000 patients with head injury admitted to the Los Angeles County Hospital during the preceding fourteen years. In view of the increasing frequency of the reports, it is quite likely that, while rare, it occurs more commonly than is recognized.

2. ETIOLOGY The blow which is responsible for the extradural hematoma is usually to the occipital region, and, as was stressed by Gordy (1948), the external evidence of such a blow is an important diagnostic finding. Of 19 cases summarized by Beller and Peyser (1952) all but 4 had external signs of injury over the posterior fossa. The lesion which is responsible is a tearing of the transverse sinus or the torcula Herophiles. While the progression of the hematoma is somewhat slower than is the case where the source of bleeding is the arterial supply of the meninges, the site is more confining, and generalized increased intracranial pressure is as rapid. The skull is usually fractured in the occipital region, but this is not universally so. While most cases occur after major head injuries from falls and blows to the occiput, Campbell and Cohen (1951) reported the successful surgical evacuation of a hematoma in a two-weeks-old infant who had been injured by obstetrical forceps applied to the head in a breech delivery. The fracture was occipital, and the hematoma spread from the posterior fossa over the occipital and parietal lobes.

3. SYMPTOMS Several authors have summarized the symptoms and signs which may be found. Among these are McKenzie (1938), Coleman and Thomson (1941), Kessel (1942), Gurdijian and Webster (1942), Grant and Austin (1949), Bacon (1949), Herren and Zeller (1950), Schneider, Kahn, and Crosby (1951), Munslow (1951), and Lemmen and Schneider (1952).

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Turnbull (1944) reported a most unusual instance in which a nine-month interval elapsed between the original injury and his successful operative interference. This is the only example of what might be called a chronic extradural hematoma. This patient suffered a blow of moderate severity over the left eye with a laceration when she fell on some ice. She did not lose consciousness. Headaches began at that time but were not incapacitating. They continued for nine months, when, following a very minor head trauma, she first noticed pronounced blurring of vision in the left eye, increasingly severe headaches, and some drowsiness. About this time unsteadiness of gait was also noted. Neurological examinations at this time revealed a slight stiffness of the neck, a marked choked disc on the left, with hemorrhages and severe loss of vision, and a mild elevation of the nerve head on the right. There was slight ataxia on the right, with diminished deep reflexes and a tendency to stagger to the left. The spinal fluid, aside from an elevated pressure noted soon after the second injury, and roentgenograms of the skull yielded normal findings. A tentative diagnosis of cerebellar tumor was made, but as the signs were not conclusive, a ventriculogram was done; it showed a uniform internal hydrocephalus without proper filling of the fourth ventricle. At operation an extradural hematoma the size of a golf ball was removed over the cerebellar hemisphere on the right side, after which the patient made an uneventful recovery. Turnbull postulates, in view of the nonexistence of truly chronic cerebral extradural clots, that the original injury may have caused bleeding which was largely reabsorbed, leaving a vascular pseudomembrane which bled again on the occasion of the second injury. In the remaining cases which have been reported, operation or death occurred within hours or days of the original injury. Immediate loss of consciousness occurred in about half the cases, after which a lucid interval might or might not have been present. Coma or impending coma have been almost universally present, occurring in 8 out of 9 cases reviewed by Herren and Zeller (1950). Contrary to one's expectation, hemiparesis or lateralizing reflex changes of a noncerebellar type were present in about two thirds of the cases reviewed by Seller and Peyser (1952), while cerebellar localizing signs were found in slightly less than one half of them. Increase in the spinal fluid pressure occurred in about half the cases, as did bloody or xanthochromic spinal fluid. These authors rightly warn against spinal puncture, and in one of their cases death occurred immediately after one was performed. Roentgenographic findings rarely may be normal and usually show a linear fracture of a compound depressed fracture. Headache, drowsiness, nausea, and vomiting are common symptoms. Stiff neck is a frequent sign. If the duration of the symptoms is longer than three days, choked disc may be found, but never before three days. Kessel (1942) emphasized the importance of "cerebellar fits" as of diagnostic importance. Though they are a grave sign demanding surgical interference, given a suggestive history and other findings, these seizures cannot be considered of great localizing value. In any case of head injury the important thing is to recall the possibility of an extradural lesion at this site, particularly where the blow is occipital and a fracture has been found in this region of the skull.

CEREBELLAR TRAUMA 525 4. TREATMENT The treatment is surgical, consisting of burr hole exploration and direct control of the hemorrhage, and as with all extradural hemorrhages, the condition constitutes a surgical emergency. Without surgery death can be expected in all cases. Of the 19 reviewed by Seller and Peyser (1952), there was successful evacuation in 12, with complete recovery and no residual disability. All the failures were instances in which the diagnosis was not made before death or was too late. C. TRAUMATIC HEMORRHAGE OF THE CEREBELLUM If hemorrhage within the substance of the brain follows closed head injury, it almost invariably results in intracerebral rather than intracerebellar hemorrhage (Courville and Blomquist, 1940). A few cases of such hemorrhages are recorded, those described by Mackenzie (1934) and Tavania (1939) ending fatally. Tavania's patient had both a posttraumatic pneumococcic meningitis and a traumatic cerebellar hemorrhage, the latter discovered unexpectedly at the autopsy. Echols (1937) in a very brief note described a patient with a cerebellar hemorrhage the symptoms of which appeared during a wrestling bout. After a six-weeks' illness, characterized by headache and vomiting but without definite signs of cerebellar deficiency or definite evidence of increased intracranial pressure, he died during the night, after the administration of nine grains of sodium amytal. Evans, Friedman, and Courville (1940) reported two patients who showed evidence of intravascular calcification similar to that discussed above (p. 477). and who were found to have intracerebellar hemorrhages after being struck by an automobile. The authors concluded that these hemorrhages were predisposed by the calcification of the cerebellar blood vessels. SUMMARY Trauma to the cerebellum, though it can occur in closed head injuries, is usually an insignificant part of the total clinical picture in such cases. Penetrating wounds occur in large numbers only in a military situation, and the study of these cases by Holmes has contributed immeasurably to our knowledge of cerebellar physiology in man. Recently posttraumatic extradural hematoma of the posterior fossa has received considerable attention by neurosurgeons. These lesions result from a tearing of the transverse sinus or torcula Herophiles. While the bleeding is of venous origin because of its location, a fulminating syndrome of increased intracranial pressure results. This occurs following trauma, usually with fracture, in the occipital region. Signs of cerebellar deficiency are present in less than half the cases. Prompt recognition and surgical evacuation are essential if these patients are to be saved. A few traumatic intracerebellar hemorrhages have been reported.

17,

Cerebellar Tumors

A. General considerations 1. Classification 2. General symptomatology 3. Neurological deficiency symptoms a. Cerebellar b. Extracerebellar (1) Visual defects (2) Mental symptoms (3) Direct pressure effects 4. Roentgenographic findings 532 a. Skull films 532 b. Pneumoencephalograms c. Ventriculograms 5. Electroencephalographic findings 534 6. Arteriographic findings 536 B. Astrocytoma 1. Incidence 2. Location 3. Symptoms 4. Gross appearance 5. Microscopic appearance 6. Treatment C. Medulloblastoma 1. Incidence 2. Location 3. Symptoms 4. Gross appearance 5. Microscopic appearance 6. Cell type and origin of the tumor 7. Treatment D. Astroblastoma E. Glioblastoma multiforme F. Oligodendroglioma G. Ganglioneuroma H. Spongioblastoma polare I. Neuroepithelioma

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CEREBELLAR TUMORS J. Vascular tumors 1. Angiomatous malformations 2. Hemangioblastoma a. Incidence, classification, and hereditary tendencies b. Symptoms and diagnosis c. Gross appearance d. Microscopic appearance e. Treatment K. Dysembryomas L. Metastatic tumors M. Extracerebellar gliomas and ependymomas N. Meningiomas O. Sarcomas P. Acoustic neurinoma Summary

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THE number of monographs dealing with intracranial tumors or some aspect of the subject is in itself testimony to the importance of it. Worthy of particular mention is the study of Bailey and Gushing (1926), which first introduced some order into the pathology of intracranial tumors. Puusepp (1927-1929), PurvesStewart (1927), Gushing (1932), Dandy (1932), Bailey (1933), McLean (1937), and many others have also dealt with the problems of intracranial neoplasms as a whole. Other monographs published since 1926 specifically concerning the cerebellum have been confined to a discussion of neoplasms of the posterior fossa (Martel and Guillaume, 1934), to the tumors of the fourth ventricle (Lereboullet, 1932), or to a particular age group, such as, for example, children, in which tumors of this part of the nervous system are especially common. Among the last are the monographs by Loisel (1935) and Bailey, Buchanan, and Bucy (1939). In addition to these valuable sources of information there are a number of monographic works that confine themselves to a single tumor which may or may not have a definite predilection for the cerebellum. These will be referred to when the specific neoplasms they concern are discussed. A. GENERAL CONSIDERATIONS 1. CLASSIFICATION A logical classification of cerebellar tumors is to divide those which are found within the substance of the organ from those which originate outside the confines of the cerebellum but as they grow may compress or invade the cerebellar structures. The first category may be further subdivided into the neoplasms originating (a) in the glial elements, (b) in the nerve cells themselves, and (c) in the blood vessels. In the first group, in the order of their frequency, we find the astrocytoma and the medulloblastoma, which are common gliomata of the cerebellum, and the astroblastoma and glioblastoma multiforme, which are relatively rare in this

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location but are closely related to the astrocytoma and may arise within the latter by a malignant degeneration of the slower growing neoplasm. Less common tumors in this location, but still of glial origin, are the oligodendroglioma and neuroepithelioma. The tumors of nerve cell origin, the second group, are very rare here as they are in all other parts of the nervous system. The tumors of vascular origin, the third group, are of two types: those which are more properly considered angiomatous malformations but by some are considered neoplastic, and the so-called hemangioblastomas, which are definitely neoplastic in every respect. These tumors are apt to be present simultaneously in other organs, and are the only examples of neoplasia in the cerebellum which may follow a definite familial and hereditary pattern. The second major category is that of the more heterogeneous tumors which arise from extracerebellar structures but may secondarily involve the cerebellum. These include the dysembryomas, the metastatic tumors, the extracerebellar glial tumors, such as the ependymomas, which usually grow from the floor of the fourth ventricle, and finally the pontine gliomas. Any of these may come to involve the cerebellum or its peduncles. Other extracerebellar tumors include those which arise from the covering tissue of the nervous parenchyma. Those from the meninges and the dural sinuses are the meningiomas and rare sarcomas. Those from the sheath cells are the acoustic neurinomas. This classification is presented in tabular form below. It does not consider the malignant or nonmalignant character of the various growths, since in this location all tumors are fatal if not removed, and they very rarely if ever metastasize widely throughout the body (Nelson, 1936). Intracerebellar Tumors 1. Gliomas a. Astrocytoma b. Medulloblastoma c. Astroblastoma d. Glioblastoma multiforme e. Oligodendroglioma 2. Ganglioneuroma 3. Vascular tumors a. Angiomatous malformations b. Hemangioblastomas

Extracerebellar Tumors 1. Dysembryomas a. Dermoids b. Teratoid cysts c. Chordomas 2. Metastatic tumors 3. Extracerebellar gliomatous tumors a. Ependymoma b. Pontine gliomas 4. Tumors of the covering cells a. Meningeal tumors (1) Meningioma (2) Sarcoma b. Sheath tumors (1) Acoustic neurinoma

2. GENERAL SYMPTOMATOLOGY Cerebellar tumors frequently first show themselves by the production of the symptoms of increased intracranial pressure. The reason is twofold: first, the cerebellum may frequently be involved at a slow enough rate so that compensation can keep pace with the destruction of the organ, particularly if the lesion does not involve the deep nuclei or the efferent outflow from them; second, because of the proximity to the fourth ventricle and the passageways into and out

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of this cavity, a block of the cerebrospinal fluid pathways can occur early, with a resulting increased intracranial pressure due to internal hydrocephalus. The triad of headache, vomiting, and choked disc can precede any sign or symptom of cerebellar deficiency or any other localizing neurological sign. The headache is usually occipital and is present in the great majority of cases. It is not noted in children so frequently as in adults, possibly because of the ability of the skull in the young child to enlarge. Even in small children, however, it was a presenting symptom in 63.1 per cent of 38 cases analyzed by Rand and van Wagenen (1935), and was the initial symptom in 45 out of 100 children with brain tumor in the series studied by Smith and Fincher (1942). Stewart and Holmes (1904) found headache to be an early and almost constant complaint of patients having either intracerebellar or extracerebellar tumors. The headaches were mope severe and invariable with the intracerebellar lesions. They were usually occipital in location and accompanied by radiating pain down the back of the neck. The pain might extend to the region between the shoulders, often some stiffness of the neck and a disinclination to move it being encountered. Many have remarked upon the tenderness of the suboccipital muscles in these cases. In some patients the headache is initially in the frontal and retrobulbar area. Bailey, Buchanan, and Bucy (1939) state that in the majority it is located in the frontal region. The headaches were never unilateral in the experience of Stewart and Holmes (1904), a circumstance that would differentiate this headache from the much more frequent occipital neuralgia, which is usually unilateral. The headache in cerebellar tumors is usually very severe, and as the disease progresses and the cerebellar tonsils come to project down to the upper part of the cervical canal, it becomes excruciating and unbearable. This pain, when combined with extreme reluctance to move the neck and marked muscle spasm, is followed by a medullary compression that may be extremely rapid in its development, particularly if one is injudicious enough to do a spinal puncture. A symptom of cerebellar tumor rivaling headache in frequency and surpassing it in children is vomiting. In Helmholz's review (1931) of 277 children with malignant growth of the brain, 84 per cent showed nausea and vomiting and 81 per cent headache. Smith and Fincher (1942) found that 94 of their 100 children with intracranial tumors eventually were subject to vomiting, and they state that the importance of this symptom in children cannot be overemphasized. Every person of experience who has ever written on this subject has dwelt on the importance of this symptom, yet children are sometimes still subjected to intraabdominal surgery for persistent vomiting when the cause is intracranial. Indeed, cerebellar tumor can result in retention of a barium meal for over twenty-four hours in the case reported by Mallows (1947). In the vast majority of cases, even if there are no neurological evidences of central nervous system involvement, an inspection of the eyegrounds will identify the cause of the persistent vomiting caused by a cerebellar tumor. Vomiting, while it may occur in the early morning and may be sudden, forceful, and unassociated with nausea, may occur at any time, may be associated with nausea, and is not necessarily forceful. Most mistakes are made because brain tumor is not thought of in any child who continues to vomit over any period of time. In adults also the symptom is almost

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invariable at some stage of the disease. The tendency to attribute the symptom to extracerebral causes is not so great in adults because by the time vomiting is a principal complaint, there are usually other symptoms pointing unmistakably to the central nervous system. Brain tumors arising outside the posterior fossa frequently do not cause the changes in the optic fundus which are characteristic of increased intracranial pressure. It is rare, however, for any of the tumors we are to discuss here, except the pontine gliomas, not to do so. While the diagnosis may frequently be made before the appearance of choked disc, visual symptoms may be the first manifestation of a tumor's presence. This was true in 6 out of the 100 patients analyzed by Smith and Fincher (1942), and is even more constant in adult patients. Stewart and Holmes (1904) state concerning papilledema in cerebellar tumors: "It seems to be one of the earliest signs, to be remarkably intense, and often out of proportion to the general symptoms. Its onset is as a rule acute, so much so that vision may be considerably impaired early in the illness. Attacks of transient blindness may occur during any state of the illness, and often herald the approach of permanent loss of vision" (p. 525). It should be emphasized that in choked disc or any of the other general symptoms there is nothing that specifically separates the cerebellar from the supratentorial tumors. It is only the relative constancy of the symptoms, their intensity, and the earliness of their appearance that do so. The eyeground changes begin with a loss of normal venous pulsation, followed by engorgement of the veins of the retina. Edema follows, with some blurring of the medial border of the nerve head, then a filling up of the physiological cup, and then measurable elevation of the nerve head. As the condition becomes more severe, flame-shaped hemorrhages appear about the discs. By this time complaints of blurring of vision or attacks of dimness of vision will usually be noted, but always to a much lesser degree than is found in a true neuritis of the optic nerve. Examination of the visual field on a tangent screen reveals, first, some enlargement of the physiological blind spot and, second, a generalized constriction of the field. Every effort should be made to prevent such severe changes. If there has been severe visual loss due to damage to the optic nerve, usually little useful vision is regained even though an operation is otherwise successful.

3. NEUROLOGICAL DEFICIENCY SYMPTOMS a.CEREBELLAR

The symptoms of cerebellar deficiency have been described at length in Chapter 8. The differences in cerebellar symptomatology between medulloblastomas, which arise at the base of the nodulus, and the astrocytomas of the lateral portion of the corpus cerebelli, give us one of the best clinical examples of the differences between these two divisions of the cerebellum so far as the clinical manifestations of cerebellar deficiency are concerned. There is, however, nothing to prevent an astrocytoma from being located in the basal portions of the vermis, and it is not uncommon for the medulloblastoma, as it grows, to involve the superior cerebellar peduncle or the dentate nucleus. When this occurs the disorders of voluntary movement which we have come to group together as cerebel-

CEREBELLAR TUMORS 531 lar ataxia, the hypotonia and asthenia of the involvement of the corpus cerebelli in man, are readily apparent. While it is possible to make an intelligent guess at the pathological diagnosis, the differentiation is not certain enough to justify treating the patient on the assumption that a medulloblastoma is the tumor present without first verifying the diagnosis by surgical exploration. b. EXTRACEREBELLAR

(1) Visual Dejects In addition to the blurring of vision which may result from papilledema, as mentioned above, double vision and external strabismus due to abducens paralysis are common in cases of cerebellar tumors. Weinberger and Webster (1941) have pointed out that these tumors, as a result of their tendency to produce an internal hydrocephalus with dilatation of the third ventricle, can result in various difficulties in the visual fields besides the generalized constriction which customarily follows long-continued papilledema. In a review of 158 patients, these authors found 8 in whom various types of visual field defects were found which confused the total diagnostic picture. In 4 there was a homonymous field defect, and in 2 of these it consisted of a fairly complete hemianopsia. In 1 a bitemporal defect was found and in the other 3 bizarre abnormalities were seen, one of which was associated with the appearance of a "primary" optic atrophy. In all but 1 of the 8 cases the diagnosis was confused by the visual field changes, and ventriculography was necessary to clarify the picture. Gushing and Walker (1912) had previously reported an instance of a binasal field defect which was the result of a cerebellar tumor. Visual hallucinations have likewise been associated with cerebellar tumors rather infrequently. Some of the patients with mental symptoms described by Keschner, Bender, and Strauss (1937) had such symptoms as a part of their mental disturbance, and Deery (1931) has described 2 patients with such complaints, both of whom had severe increased intracranial pressure, as evidenced by choked discs. (2) Mental Symptoms Keschner, Bender, and Strauss (1937) have discussed the question of mental symptoms associated with subtentorial tumors and have reviewed the literature on the subject. The number of patients with mental symptoms was somewhat greater in their series of 120 patients than had been found earlier by Southerland (1932) and Minski (1933). Keschner, Bender, and Strauss (1937) had found some degree of mental disturbance in 56 of their 120 patients (47 per cent). Symptoms were observed early in the disease in 14 (12 per cent) and were the first manifestation of disease of the central nervous system in 3. This incidence was about one-half that which the same authors had found in cases of tumors in the frontal and temporal lobes. They conclude: "There was no significant difference in the incidence, nature and severity of the mental symptoms in adults as regards the nature and location of the tumor. The mental symptoms were milder and less complex, in children than in adults. . . . Mental symptoms in cases of subtentorial tumor were much milder and less complex than those in cases of supratentorial tumor."

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There is no evidence that these symptoms when they occur are anything more than false localizing signs, usually the result of an associated increase in the intracranial pressure. In fact, Davidoff (1930) stated that psychotic manifestations other than apathy or drowsiness were unusual in association with tumors of the posterior fossa. The same author observed in 1945 that children with tumors of the cerebellum appeared to be "unusually alert, cooperative and of sweet disposition." Langford and Klingman (1942) have stressed the importance of personality and environmental factors when mental and behavioral symptoms occur in the patients with brain tumors, particularly those in the posterior fossa. (3) Direct Pressure Effects The involvement of the brain stem in cerebellar tumors is always a possibility, and has already been discussed in an earlier chapter (p. 400). The neurological signs, which are explained by direct pressure on the brain stem, are cranial nerve palsies of all kinds and the long-tract signs, giving rise to sensory deficits and corticospinal motor involvement. 4. ROENTGENOGRAPHIC FINDINGS a. SKULL FILMS

Plain skull films have their chief usefulness in the positive identification of increased intracranial pressure in very young children in whom choked discs may be absent. The tumors to be discussed in this chapter in detail, at least those of frequent occurrence, do not, as a rule, calcify. As we shall see, there are some acoustic neurinomas in which an enlargement of the internal auditory meatus may be found, but asymmetries are so frequent normally that in most instances they are of relatively little use. The manifestations of increased intracranial pressure are, if the child is under five years of age, spreading of the sutures. Unless of a most extreme degree, digital markings in young people are not reliable evidence of increased intracranial pressure. Helmholz (1931) found roentgenographic evidence of increased intracranial pressure in 67 per cent of children with intracranial tumors. He does not report the percentage in cases of cerebellar tumors, nor what the criteria were which indicated elevated intracranial pressure. Bailey, Buchanan, and Bucy (1939) state that 95 per cent of children with intracerebellar tumors show separation of the sutures and conclude: "With malignant tumors of the cerebellum, th'e sella turcica is usually unaltered; with benign tumors of the cerebellum, the sella turcica is often enlarged, and the clinoid processes eroded" (p. 561). In adults plain skull x-rays occasionally may give some evidence of chronic increased intracranial pressure in cerebellar tumors, such as enlargement of the sella turcica, erosion and flattening of the posterior clinoid processes, and perhaps some increase in digital markings. These changes, however, do not, as a rule, have time to make their appearance in patients with cerebellar tumors. b. PNEUMOENCEPHALOGRAMS

Though McConnell and Childe (1937) have discussed the localization of brain tumors by pneumoencephalography, this procedure is contraindicated where in-

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creased intracranial pressure is present and is to be avoided in any case in which a posterior fossa tumor is a seriously considered possibility. Filling would not be obtained to a satisfactory degree in most cases even if the risks of the procedure were not prohibitive. Pneumoencephalography has nothing to recommend it and much to condemn it as an aid in the diagnosis of cerebellar tumors (Gardner and Nosik, 1942). C. VENTRICULOGRAMS

Any lesion in the posterior cranial fossa of an expanding nature will give rise to an internal hydrocephalus involving the two lateral ventricles and the third ventricle. Theoretically it should be easy to differentiate the posterior fossa lesions from those which arise in the region of the aqueduct and posterior part of the third ventricle by the preservation of the contour of the third ventricle and the beginning of the aqueduct of Sylvius. As a practical matter, however, usually because filling of these structures is often imperfect, the differentiation by ventriculography alone is not so simple as it would appear. This point has been emphasized by Peterson and Baker (1941). Walker and Hopple (1949) also cite 2 cerebellar tumors out of 45 in which the diagnosis was missed because of the presence of air in the fourth ventricle on ventriculography. It is well to review the distinguishing features of intracerebellar tumors that can be noted in films technically ideal. These are well illustrated by Twining (1939), Johnson and List (1940), Lysholm (1935, 1939, 1946), LeBeau (1944), and many others. With midline cerebellar tumors there is no air in the fourth ventricle if the tumor occupies the superior portion of the vermis. The aqueduct may be compressed at its beginning, the effect thus simulating the appearance of a true neoplasm of the aqueduct. There may also be visualized an upward displacement of the inferior margin of the third ventricle. When the lesion is in the posterior vermis, the aqueduct and at times even the upper part of the fourth ventricle may be fillecl. The triangular roof portion of the fourth ventricle is flattened and may be visible only as a thin line of translucency which is anterior to the normal position of the floor of the fourth ventricle. Along with the anterior displacement of the floor of the fourth ventricle, there is a reduction in the angle formed by the aqueduct and the floor of the ventricle (Johnson and List, 1940). Tumors which occupy the lateral portions of the cerebellum or compress the cerebellum from the side either obliterate the fourth ventricle or, if it is partially or wholly visualized, cause it to be pushed to the opposite side. Tumors which arise within the fourth ventricle tend to obstruct its outlet. In these the entire ventricular system including the aqueduct and the first part of the fourth ventricle is enlarged. Indeed, the tumor itself can occasionally be outlined within the enlarged fourth ventricle. It should be emphasized, as Johnson and List (1940) point out, that the exact localization of posterior fossa tumors is only possible in "technically perfect" ventriculograms. Davidoif and Epstein (1955) have outlined certain measurements which may be applied to the fourth ventricle and some surrounding bony landmarks. They emphasize the value of laminography in visualizing the fourth ventricle. They were able to obtain what they considered adequate outline of the fourth ventricle

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in 24 out of 56 cases. They summarize their observation as follows: "In conclusion, one may say that the characteristic ventriculographic changes present in patients with cerebellar tumors are dilatation of the lateral and third ventricles with no displacement from the midline. The aqueduct of Sylvius is usually dilated and in an appreciable number of patients, may be displaced cephalad and to a lesser degree may be displaced either to the right or left. When the aqueduct is displaced cephalad and presents an increased convexity at the junction of its proximal and mesial thirds in an adult, the possibility of a hemangioblastoma should be considered. Visualization of the fourth ventricle is extremely important and displacement in any direction may indicate the site of the tumor. Narrowing of the cisterna pontis is significant in identifying the posterior fossa localization of a tumor" (p. 288). (See Fig. 182.)

5. ELECTROENCEPHALOGRAPHIC FINDINGS In the first attempts at electroencephalographic intracranial tumor localization it was generally conceded that the changes seen in cerebellar tumors were

Figure 182. A cerebellar hemangioblastoma, showing the symmetrical dilatation of the lateral ventricles, dilatation of the third ventricle, dilatation of the anterior portion of the aqueduct of Sylvius, with the forward bending so characteristic of cerebellar tumors (arrow), particularly hemangioblastomas

TJv (From L.M. Davidoff and B.S. EpStein, 1955, The Abnormal Pneumoencephalogram, ed. 2i^Ti,.1- TM< P*™* ^ B S' EpSt6in' 1955' The Abnormal Pneumoencephalogram, ed2

Philadelphia: Lea & Febiger, Fig. 150.)

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too variable to be of practical value. In 1940, however, Smith, Walter, and Laidlow reported that in all of 8 children, aged four to nine years, a focus of slow activity could be identified in the mastoid area which was related to the side of the lesion and which disappeared after the surgical relief of then* symptoms. These authors attributed this to the age of their patients and the fact that the tentorium was sufficiently mobile to allow direct pressure of the growing tumor to affect the occipital lobe. Similar results were reported by Holland (1941) in 2 patients, and Walter (1938) also had previously noted a few instances of such abnormality. Rheinberger and Davidoff (1942) analyzed their results in 23 patients with posterior fossa tumors, all but one of whom were adults. They were unable to find any consistent pattern of abnormality, although in a few cases such a focal abnormality was seen. But they felt foci at remote areas of the brain were sufficiently numerous to justify an expression of warning: "We conclude that there is no pattern or distribution of electrical abnormality specifically indicative of posterior fossa disturbance. We are also impressed with the possibility that the bilateral inequality of cortical changes arising in association with some posterior fossa lesions may be sufficiently suggestive of primary cortical abnormality to be so interpreted by the unwary." During the next ten years there were some incidental observations on the subject, which are completely reviewed by Bagchi, Lam, Kooi, and Bassett (1952). These authors, in a study of 37 patients with surgically confirmed posterior fossa lesions, found that in 25 out of 28 cases of cerebellar hemisphere lesions the maximal changes were in the opposite cerebral hemisphere. The changes observed were not specific for posterior fossa tumors. They stated that one could justifiably conclude from the electroencephalogram alone that a patient had a posterior fossa tumor only when it could be established that he did not have (1) idiopathic epilepsy, (2) temporal lobe seizures, (3) generalized cortical atrophy, (4) "degeneration," (5) cerebral arteriosclerosis, (6) hypertension, and (7) acute vascular and traumatic conditions, for all these conditions could give rise to the same electrical abnormalities recorded in the cases of posterior fossa tumors which they studied. The next year Daly, Whelan, Bickford, and McCarty (1953) demonstrated that indistinguishable abnormalities could be found as the result of third ventricle tumors, obstructive hydrocephalus, and posterior fossa tumors. They analyzed 66 cases of posterior fossa tumors, 12 cases of tumors of the third ventricle, and 9 cases of obstructive hydrocephalus. They found the principal abnormality to consist of rhythmic, bilaterally synchronous slow waves and, less often, of irregular arhythmic waves. The degree of abnormality was greater where the lesions were rapidly advancing and in younger age groups. They found no lateralization in cerebellar hemisphere tumors, and they could not confirm the earlier observations of occipital foci. They proposed the theory that the abnormality was due to an effect on the thalamic nuclei which in turn caused an effect on the cortical activity. This was most probably brought about, in their opinion, by a dilatation and hypertension within the third ventricle. They agreed with previous workers that similar changes in the cerebral activity may be seen

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in a variety of diffuse toxic, degenerative, and inflammatory processes as well as in epilepsy and trauma. However, given a patient with a suspected brain tumor, it is rare to find such EEG changes from a cortical lesion, and when found such changes would be a point in favor of a deep-seated lesion in the region of the third or fourth ventricles. Dow (1956) analyzed the electroencephalographic findings in 51 patients with posterior fossa tumors and came to similar conclusions. There is no indication from any of this work on clinical electroencephalography that the activity observed is related in any way to either the spontaneous or induced electrical activity of the cerebellum which has been discussed in a previous section of this monograph (pp. 159-253).

6. ARTERIOGRAPHIC FINDINGS Vertebral arteriography has lagged behind carotid studies. This can be accounted for by the greater difficulty of the procedure and the fact that aneurysms of the vertebral circulation, the condition for which arteriography is most widely employed, usually do not lend themselves to surgical attack even if discovered by angiography. The percutaneous method has been reported successful in experienced hands in over 90 per cent of the cases investigated (Sjogren, 1953). It is usually employed in preference to the method of arterial catheterization introduced by Radner (1951), which in his hands proved very successful. Although the vascular tree within the posterior fossa may be distorted by a tumor, the method has less practical use in posterior fossa tumors than ventriculography. In some instances, however, characteristic changes have been reported in posterior fossa meningioma and hemangioblastoma which have allowed investigators experienced in the method to make a preoperative diagnosis of both the type and the location of the tumor (Sutton, 1955). Cerebellopontine angle tumors may also be shown by vertebral arteriography (Sutton and Hoare, 1951; Olsson, 1953). The most promising use of this technique is in cases of vascular lesions of the posterior fossa, where the method offers the only preoperative or pre-autopsy method of diagnosing such lesions (Sutton, 1951, 1955; Logue and Monckton, 1954). Others who have contributed to this subject are Sugar, Holden, and Powell (1949), Lindgren (1950), Sjogren (1953), and Ecker and Riemenschneider (1955). B. ASTROCYTOMA Gliomas, of which the astrocytoma is the most frequently occurring example, were first recognized by Abernathy in 1804, who designated them as "medullary sarcoma," according to Scherer (1940a). They were identified by the terms encephaloides by the early French writers and as fungos medidlar by the Germans. Virchow first used the term glioma and divided these tumors into myxoglioma and fibroglioma, or glioma durum. It is among this latter group that most astrocytomas of the cerebellum belong. Bailey (1932) credits Golgi in 1875 with being the first to insist that gliomas contain star-shaped cells. Of all the types of gliomas that have since been differentiated, the cerebellar astrocytoma

CEREBELLAR TUMORS 537 contains these mature cells in purest culture. Not until the accumulation of sufficient material in the hands of one clinical group could the differences in the age incidence, growth characteristics, histological structure, proper treatment, and prognosis be determined. This differentiation was in large part accomplished by the clinical data of Harvey Gushing and the pathological studies by Percival Bailey.

1. INCIDENCE According to Cushing's statistics (1932) cerebellar astrocytomas make up about 4.5 per cent of all intracranial tumors. They are equally divided between the sexes and are definitely a tumor of children and young people. The mean age among Cushing's 91 cases was 13 years. In the series of Mabon, Svien, Adson, and Kernohan (1950) it was 13.6 years; Ringertz and Nordenstam (1951) reported a mean age of 14.8 years, and Bucy and Gustafson (1939), 8.9 years.

2. LOCATION The location, according to Cushing's description in 1931, is mostly midline, the cyst with which the astrocytoma is so frequently associated occupying one or the other hemisphere. Bailey (1933) in his book uses this tumor as the typical example of a hemispheral lesion. Mabon and associates (1950) found that of 130 astrocytomas, the location of which was known, 67, or 51.5 per cent, were in the midline, 40 occupied the right hemisphere, and 23 the left hemisphere. Elvidge, Penfield, and Cone (1937) had found that in their cases the hemisphere lesions were found in patients older than those in whom the midline tumors appeared, an observation also made by Ringertz and Nordenstam (1951). This observation was not confirmed by either Bucy and Gustafson (1939) or by Mabon and his associates. The latter workers did find that the solid tumors were more apt to be located in a midline position and the cystic in the hemispheres. They attribute this to the shorter time probably necessary for the tumor to show itself symptomatically in the midline lesions.

3. SYMPTOMS The symptoms of the astrocytoma will depend on its location and its rate of development. While in general this tumor is slower in its growth than the medulloblastoma, when it occupies a midline position it may be indistinguishable from the latter (Ingraham and Campbell, 1941). They are both characterized by the early appearance of generalized symptoms of brain tumor (see p. 528) and by the neurological findings characteristic of lesions of the flocculonodular lobe, i.e., unsteadiness in walking without appreciable ataxia in the movements of the individual extremities. When the astrocytoma is located in the cerebellar hemisphere, on the other hand, the neurological manifestations are quite different. In these cases we find the homolateral hypotonia, asthenia, and disorders in the rate, regularity, and force of muscular contraction that have been discussed under the heading of the syndrome of the posterior lobe of the corpus cerebelli (pp. 386-396). It should be stressed that because of the tumor's slow development, compensation may occur along with its growth, and the symptoms of cerebellar

538 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM deficiency may be very minimal. Apparently the signs of deficiency are brought to light by the hydrocephalus and the increased intracranial pressure interfering with the compensatory mechanisms. When the pressure is relieved, the patient may show practically no evidence of cerebellar deficiency, and the neurosurgeon cannot help being astounded at the paucity of the findings compared to the extensiveness of the destruction of the cerebellum (Gushing, 1931). Visual disturbances may be the first symptom to bring the child to the physician, and if the patient is neglected irreparable damage to the optic nerves may result. 4. GROSS APPEARANCE The gross appearance of the astrocytoma is chiefly characterized by the presence of a cyst or by multiple cysts. The cyst may be lined with tumor cells, or the tumor may occupy a certain part of the wall as a raised, grayish-pink nodule. The latter phenomenon has been stressed by Gushing (1931), Bailey (1933), Bailey, Buchanan, and Bucy (1939), and Bucy and Gustafson (1939). Mabon, Svien, Adson, and Kernohan (1950) state that although the surgeons at the Mayo Clinic were impressed with the necessity of finding this mural nodule, it frequently happened that none could be identified grossly, and when biopsies were taken from various parts of the wall, they were all found to be composed of tumor tissue. The inner wall of the cyst is glistening white, and the fluid is xanthochromic and has a high protein content, which causes it to coagulate as soon as it is exposed to the air. The source of the cystic fluid has been the subject of some controversy. Gushing (1931) attributed it to the exudation of fluid from the surface of the tumor. Elvidge, Penfield, and Cone (1937) felt that these tumors, as well as the cysts formed in the more rapidly growing gliomas of the cerebrum, were formed by the liquefaction of the tumor cells. This opinion was attacked by Bucy and Gustafson (1939) on several arguments; the chief was that fluid accumulates too rapidly after simple tapping of the cyst to account for its reformation by the growth of the tumor and subsequent liquefaction. Mabon and his associates take the middle view that probably both mechanisms may operate to a greater or lesser degree in individual cases. The tumor may present itself on the surface at the time of operation or it may reveal itself by a widening of individual folia of the vermis or hemisphere. Needling of the hemisphere may locate the cyst, but if this is unavailing, Gushing (1931) recommends complete midline section of the vermis in cases where the tumor cannot be found by less radical methods. It is well known that this procedure in man is not followed by any appreciable sign of cerebellar deficit. The solid tumors in this group are grayish in color, usually firm and avascular, though at times even in this location they may be mushy and soft in consistency and readily removed by suction apparatus. 5. MICROSCOPIC APPEARANCE The proper classification of these tumors and their relation to the astrocytomas of the rest of the brain has been the subject of a good deal of argument among neuropathologists. As soon as considerable experience with these lesions

CEREBELLAR TUMORS 539 had been accumulated, it became apparent that there were important differences between the astrocytoma of the cerebellum and that of the cerebrum. All workers agree that they differ with respect to the age of incidence, the frequency of permanent cures after surgical removal, and in those which do recur, with respect to the time when an obviously incompletely removed tumor causes either focal neurological symptoms or generalized symptoms of increased intracranial pressure. Whether one is justified in separating the two completely is not settled. Gushing, Bailey, Bucy and their associates thought not. Scherer (1940a) was more impressed with their differences than with their similarities and would have preferred to consider them distinct entities. Mabon, Svien, Adson, and Kernohan (1950) simply take the position that, for some reason which they cannot identify, the percentage of these cerebellar astrocytomas that are of what they call grade I malignancy is higher than the same percentage for astrocytomas of the cerebrum (Kernohan, Mabon, Svien and Adson, 1949; Svien, Mabon, Kernohan, and Adson, 1949a, b). The survival time in cases of tumors that are of what they call grade II and grade III malignancy is not appreciably different from that in the much larger group where the tumors are of so-called grade I malignancy. The authors do state that if they had excluded from the grade III category two patients with tumors which were entirely removed surgically and which to date have not recurred, the postoperative recovery period with that grade would drop down to only 3 months as compared to 78 months and 74 months with grades I and II respectively. What these authors call an astrocytoma of grade III malignancy, however, would be classified by Bailey and his followers as a glioblastoma multiforme, a lesion quite distinguishable from an astrocytoma in either the cerebrum or cerebellum. As Bucy and Gustafson (1939) have stated, unless a new classification or terminology is based upon evidence that the older established one is erroneous, it only further confuses an already complicated subject. For the identification of gliomatous tumors the abandoning of well-established terms in favor of a scheme of numbers which then in turn have to be defined by arbitrary criteria does not seem to have sufficient merit to justify the confusion entailed. Time alone will tell whether the substitution of numeral grades of malignancy for the terms which have been in use for twenty-five years will become generally accepted by neuropathologists. Bucy and Gustafson (1939) and Bailey, Buchanan, and Bucy (1939) adequately disposed of the conception that cerebellar astrocytomas were in reality developmental defects (Bergstrand, 1932, 1937), and this subject will not be discussed further. Ringertz and Nordenstam (1951) believe that the majority of the cells are unipolar or bipolar spongioblasts which in their degeneration provide some specific characteristics of this tumor. These authors claim to have found ten tumors of the cerebral hemisphere which have such distinguishing features, and in these cases survival periods comparable to those in cases of cerebellar astrocytomas, or "spongioblastomas," as these authors would prefer to call them, were found. The great majority of the cells of this tumor are the typical stellate astrocytes (Fig. 183). They may be predominantly fibrillary, in which case a fine

540 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM matrix characteristic of these tumors is the predominant structure, the cellular density being rather sparse. In the protoplasmatic type many of the cells have a larger body, with fewer, shorter, and blunter processes. The distinction, while interesting histologically, does not appear to have any significance in conjunction with the other features of these tumors, and Gushing (1932) tends to minimize these differences. As is true of all tumors of the spongioblastic series, there are some cells identifiable as spongioblasts, astroblasts, and oligodendroglia, but these are found in less than 1 per cent. In isolated areas of certain tumors there are exceptions, but fewer than with cerebral or brain stem astrocytomas. The nuclei of the astrocytes are small, round, or oval, without a nucleolus and with moderate amounts of chromatin granules. While atypical nuclei may be seen which are larger and contain nucleoli, they are not common in these tumors. Mitotic figures are not seen. Degenerative changes are found, commonly consisting of a complete disappearance of recognizable cells in places, various stages of cellular pathology with fragmentation of protoplasmic processes, swollen eosinophilic cytoplasm, and displacement of the nucleus. Vacuolization and at times liquefaction of the intercellular matrix with fat formation, which may or may not be engulfed by phagocytes, are also seen at times. Calcification is found

Figure 183. Microscopic appearance of a cerebellar astrocytoma, showing numerous well-developed astrocytes. A. Formalin; frozen; hematoxylin-eosin; X 300. B. Formalin-bromide; frozen; goldsublimate; X 300. (From P. Bailey, D. C. Buchanan, and P. C. Bucy, 1939, Intracranial Tumors of Infancy and Childhood, Chicago: Univ. of Chicago Press, Fig. 26.)

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microscopically in about 20 per cent of the tumors, in about half of which it is of sufficient density to be seen in skull films. In tumor tissue not showing these degenerative changes the blood vessels are few and small. They are very thin-walled, and there is rarely any additional supportive connective tissue outside of the very thin adventitia of the vessels. When degeneration takes place, the vessels proliferate and become distended and, as the degenerative process proceeds, may be transformed into hyalized structures without a lumen. These changes are neither limited to nor characteristic of the vessels of cerebellar astrocytomas, but are found with other tumors and in many other non-neoplastic states. With this vascular change occasional coarse connective tissue bands may be noted. Near the periphery of the tumor occasional nerve cells and fibers may be encountered, but in numbers never approaching those found in diffuse fibrillary astrocytomas in other areas of the nervous system. There is no capsule, and no sharp boundary can be made out between the tumor and the cerebellar tissue. There may be some glial changes in the surrounding cerebellar folia, which, according to Bucy and Gustafson, have been misinterpreted by Bergstrand (1932, 1937). The Purkinje cells and the granular cells are reduced in number or show evidence of degeneration. The pia may become thickened over the tumor, and occasionally a spread of the tumor cells into the subarachnoid space is seen. Such a spread is not common, and only a very few instances of seeding of this tumor have ever been recorded (Cairns and Russell, 1931). Walker (1941) has reported a case of von Recklinghausen's disease in which the subarachnoid extension of an astrocytoma was very considerable.

6. TREATMENT Of all the gliomas, cerebellar astrocytomas offer the best prognosis for surgical removal, according to most observers. Even with nothing more than evacuation of the cyst, some extraordinary intervals of good health have been reported. Hausman and Stevenson (1933) describe one patient who survived for 45 years without an operation, and Robinson (1955) reported a case with a preoperative course of 21 years. There is no evidence that roentgen therapy is of any value in these tumors. In 1932 Gushing reported an over-all case mortality of 16.6 per cent and an operative mortality of 11.2 per cent. More remarkable are his results with 29 cases, from July 1928 to July 1931, in which group he had only 1 operative death among 34 operations, the operative mortality therefore being 2.9 per cent and the case mortality 3.4 per cent. The most recent reports have not bettered these figures (Ringertz and Nordenstam, 1951). C. MEDULLOBLASTOMA The malignant invasive character of tumors originating near the fourth ventricle has been described, according to Bailey and Gushing (1925), in a large number of reports, the earliest being that of Ollivier in 1827. Until 1925 most of these reports indicated that the tumors were sarcomas, because of the appearance of the cells in conventional stains and the remarkable tendency of the tumors to spread throughout the central nervous system by way of the sub-

542 PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM arachnoid spaces. Since the report of Bailey and Gushing, their ectodermal origin has not been seriously questioned. The principal points for discussion have concerned whether the tumors are of glial origin, related to the neuroblastic cells, or whether they arise from a bipotential cell capable of forming both glial cells and nerve cells. Besides their clinical manifestation, the feature that has occupied the attention of a considerable number of workers has been the proper methods of treatment. These are among the most unsatisfactory of all brain tumors to attack surgically. 1. INCIDENCE Gushing (1932) reported 68 cases of cerebellar medulloblastoma among 2,023 intracranial tumors, or an incidence of a little over 3.5 per cent. They make up, according to the same series, about 8 per cent of the gliomatous tumors. Ringertz and Tola (1950) found 6.5 per cent of 1,571 gliomas to be medulloblastomas. These figures establish them as the second most common intracerebellar tumor, and after the acoustic neurinoma and the cerebellar astrocytoma, the third most frequent neoplasm encountered in the posterior fossa. Isolated cases have been reported in infants so young that the tumor was evidently present during the prenatal period (King, 1953) and in persons as old as fifty-five (Spitz, Shenkin, and Grant, 1947) and sixty-five years (Ingraham, Bailey, and Barker, 1948). The tumor is predominantly one of childhood, the average age of incidence being ten to eleven years in Cushing's material and the peak incidence around five years (Bailey, Buchanan, and Bucy, 1939). In the original description of this condition (Bailey and Gushing, 1925) the incidence in males was almost two to one. Gushing (1930) reported three to one, and Bailey, Buchanan, and Bucy (1939) found about the same predominance of males. 2. LOCATION The origin is most frequently the roof of the fourth ventricle (Bailey and Gushing, 1925) and, more specifically, probably the cell rests located at the base of the nodulus (Ostertag, 1936; Raaf and Kernohan, 1944). The medulloblastoma is not confined to the midline area of the cerebellum but can invade the cerebellar hemisphere and the cerebellopontine angle. Gushing (1930) thought that these laterally placed tumors were more common among older patients, in whom the chances of a longer postoperative period of freedom from symptoms is somewhat greater. Spitz, Shenkin, and Grant (1947) have supported this opinion in their statistical analysis of cerebellar medulloblastomas in adults. While Ingraham, Bailey, and Barker (1948) felt the location in the pons and cerebellopontine angle was more common in the older group, they could see no relation between the location and the course of the disease. The problem of the cerebral medulloblastoma is a debatable one and need not concern us here. It seems doubtful that what have been called medulloblastomas of the cerebral hemispheres are the same tumors that we are now discussing, even though resembling them in histological appearance. Ringertz and Tola (1950) deny the existence of cerebral medulloblastomas. If there are actually two tumors with entirely different growth characteristics but indistinguishable histologically,

CEREBELLAR TUMORS 543 possibly the occasionally noted cases of posterior fossa tumors of this appearance with a very benign course are actually related to the "cerebral medulloblastoma" rather than to the more common cerebellar type, which is a childhood lesion of high malignancy. Such might be the rare and atypical cases described by Ingraham and Bailey (1944) and by Penfield and Feindel (1947). To speculate about the nosological position of these rare neoplasms is useless, for it is readily apparent that no one knows how to classify them accurately. 3. SYMPTOMS The difference between the symptoms of cerebellar medulloblastomas and cerebellar astrocytomas is in the more abrupt onset and the more steadily progressive downhill course of the former, with death or operative treatment usually within a few months of the first symptom. An average of three months for the preoperative period is commonly observed, though in rare instances symptoms may be present for two years. Headache and vomiting are the earliest signs in the vast majority of cases; in adults 80 per cent of the lesions that are of hemispheral location and 75 per cent of those in the midline begin in this way according to Spitz, Shenkin, and Grant (1947), and in children the percentage is even higher. The cerebellar signs, when they appear are usually those of a midline lesion, as described in Chapter 8 under the syndrome of the flocculonodular lobe. If the tumor involves only the hemisphere, the neurological symptoms are those described in Chapter 8 under the syndrome of the posterior lobe of the corpus cerebelli, and disturbances in the regulation of movements of the homolateral extremities result (see pp. 386-396). It cannot be stressed enough that in all cases the signs and symptoms of increased intracranial pressure are predominant. In young children spreading of the cranial sutures, with the so-called "cracked pot note" on percussion of the skull (McEwen's sign) as well as roentgenographic evidence of this skull change and at times obvious enlargement of the head, is important. As in cases of cerebellar astrocytomas the observation of choked discs is important, though the more fulminating course does not make residual secondary optic atrophy as frequent as in the slower-developing tumors. The symptoms of nerve root compression, spinal cord involvement, and cerebral destruction secondary to implantation of this tumor may arise during the terminal postoperative period. Double vision may occur (Grant, 1929). Cerebellar tonic fits are common in the late states of these lesions. Death in untreated cases results from increased intracranial pressure and respiratory paralysis, and in some of the treated cases it can result from the widespread seeding which may occur as a terminal manifestation of this condition. The operative mortality is high and will be discussed further in the section on the treatment of these cases. 4. GROSS APPEARANCE The tumor is of a reddish-gray color, and as it separates the cerebellar tonsils which may be herniated down the cervical canal, it is usually visible at the time of exposure at operation. If it is not visible, it may be seen by separating the tonsils or at times by midsagittal section of the vermis. Its position may be

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betrayed by an enlargement of the folia over the posterior aspect of the vermis. The tumor is soft and friable, and bleeds readily from its base when it is removed by suction. At times there is enough connective tissue stroma to give it some consistency, but it is always definitely grossly invasive. At times small, flat, reddish and gray plaques of seeded tumor are seen over the surface of the cerebellum at the time of original exposure. This is so unusual with any other tumor occurring in this location that it is an important gross characteristic when present. When the brain is sectioned the cut surface is uniform in appearance and consistency (Fig. 184). Rarely are any of the cysts, hemorrhages, or degenerated areas so frequent in the other malignant gliomas found. The tumor fills the fourth ventricle but does not invade its walls. The posterior vermis is invaded, and the anterior folia are compressed against the tentorium. At times the tumor is im-

Figure 184. A medulloblastoma, showing the typical location in the posterior vermis (Z?) and the common occurrence of spread throughout the leptomeninges over the spinal cord (A). (From P. Bailey, D. C. Buchanan, and P. C. Bucy, 1939, Intracranial Tumors of Infancy and Childhood, Chicago: Univ. of Chicago Press, Plate IX, Figs. 4 and 5.)

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planted in the third ventricle and has even been found completely filling the other ventricles, with enormous enlargement of the fourth (Winkelman and Eckel, 1936). The implants in the spinal canal may invade the spinal cord or be attached to the cauda equinae as multiple tiny nodules along many of the nerve roots. The spread may be over the base of the brain and throughout the cisterna, to involve the medial and tentorial surface of the occipital lobe. In two very exceptional cases there is a possibility that extracranial metastases to the sternum (Sachs, Rubinstein and Arneson, 1936) and to the bone marrow (Nelson, 1936) occurred. The cerebral convolutions are flattened, and there is a herniation of the cerebellar tonsils along with the tumor. The residual changes from deep x-ray treatment of these tumors and implants show a tendency to dense scar-tissue formation, which in some instances seems to be responsible for the terminal symptoms.

5. MICROSCOPIC APPEARANCE The tumor is very cellular, consisting of densely packed cells with very little cytoplasm. The nuclei are oval and are characterized by a heavy chroma tin network (Fig. 185). The nuclei have a tendency to be grouped, with a clear area filled with cytoplasm. These are called pseudorosettes. The vessels are thin-walled and

Figure 185. Microscopic appearance of a cerebellar medulloblastoma. A. Formalin; celloidin; iron hematoxylin; X 230. B. Formalin; frozen; hematoxylin-eosin; X 300. (From P. Bailey, D. C. Buchanan, and P. C. Bucy, 1939, Intracranial Tumors of Infancy and Childhood, Chicago: Univ. of Chicago Press, Fig. 14.)

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appear as sinuses. The stroma is sparse except where the tumor has invaded the pia mater, where the excess of connective tissue has resulted in the erroneous diagnosis of sarcoma, according to Bailey (1933). Special staining methods, which were used in great numbers in the original description of these tumors by Bailey and Gushing (1925), reveal cells which are identified as various developmental stages of the immature spongioblast. Also in most instances much rarer cell types can be seen, having large spherical nuclei, prominent nuclei, and very little chromatin material. These are identified as neuroblasts in various stages of development by Bailey and Gushing (1925); it is chiefly the occurrence of cells of both the spongioblastic series and the neuroblastic series in the tumor that resulted in Bailey's naming it as he did and in his concept of its histogenesis from the undifferentiated cell of development first described by Schaper (1897).

6. CELL TYPE AND ORIGIN OF THE TUMOR The theoretical concept on which the histogenesis of the medulloblastoma has been based has been the subject of considerable controversy since the first description presented by Bailey and Gushing before the American Neurological Association in 1924. As Gushing said in the discussion of this paper, the first name chosen was spongioblastoma, and it was only after their original manuscript had been prepared that they became aware that Globus had already used this term in relation to quite another rapidly growing invasive glioma of the cerebral hemispheres. In order to avoid confusion and because they visualized this tumor as arising from an indifferent cell which was capable of formation of both neurons and glial elements, they named it the medulloblast. The embryological basis for this concept was derived from the publications of Schaper (1894, 1895, 1897), who described such cells as being found throughout the nervous system; he had called them indifferente Zellen. After Schaper's publications there arose a considerable controversy among embryologists of the nervous system concerning the identification of such a cell. The literature concerning this has been discussed in considerable detail by Kershman (1938), who points out that this theory was thought by Schaper to have been confirmed by Lugaro (1894) and Popoff (1895, 1896), who found in Golgi preparations such cells in the external granular layer of the cerebellum. This was denied by Ramon y Cajal (1890,1906,1909-1911), as well as earlier by His (1889). His had said that the cells destined to produce the glial elements of the nervous system were all derived from the columnar epithelium lining the internal limiting membrane of the primitive central canal—His called them primitive spongioblasts—and that all nerve cells were derived from the germinal cells which were differentiated from the time of the earliest formation of the medullary canal. Thus the two opposing views were set up, and the controversy was continued for many years. The details need not concern us here. It was finally determined through the important work of Del Rio-Hortega (1932) that many of the undifferentiated wandering cells which Schaper had originally described were oligodendroglia cells. This, according to Kershman (1938), cast doubt upon the whole concept of the existence of the medulloblast, and he set himself the task of reexamining the

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problem in human embryos by more modern methods than were available to the older histologists of Schaper's period. After an important study he concluded that although there were no such indifferent cells capable of forming both glial and nerve cells in the spinal cord or the cerebrum, they were present in the external granular layer of the cerebellum, where they had originally been found by Schaper (1894, 1895, 1897), Lugaro (1894), and Popoff (1895, 1896). This seemed to conform to the clinical observation that most if not all medulloblastomas are also found in the cerebellum, and Kershman (1938) quotes Bailey to the effect that they all arose in the cerebellum and that those which had been described by himself and others as occurring in the cerebral hemispheres were actually some other tumor similar in histological appearance. These observations directed neuropathologists to a closer look at the external granular layer of the cerebellum. This transitory structure of the cerebellar cortex has been discussed in detail in the forthcoming companion volume to this monograph by Larsell. Suffice it to say here that Raaf and Kernohan (1944) in their study of this layer found that abnormal collections of cells occurred in the posterior medullary velum near the base of the nodulus in almost one fourth of the 104 fetuses and young infants examined. This was not a new observation, as Pfleger (1880) had found similar changes in 75 out of 400 cerebelli, not including some that were visible grossly and not checked histologically. These heterotopias have been described by many others (Kuhlenbeck, 1950). Abbott and Kernohan (1943a) questioned the uniform malignancy of these tumors and suggested the possibility that they could be graded histologically, as carcinomas commonly are. Grading has not been attempted by Kernohan and his associates at the Mayo Clinic, and in 1949 it was indicated that these tumors were too uniform histologically to allow such a gradation (Kernohan, Mabon, Svien and Adson, 1949; Svien, Mabon, Kernohan and Adson, 1949b).

7. TREATMENT The first effort at treatment of the medulloblastoma was that of surgical extirpation, and although it was hoped at one time that with early recognition and wide excision the tumor could be completely removed (Bailey and Gushing, 1926), this point of view was definitely abandoned by Bailey in 1930, and now all are agreed that radiological treatment offers more prospect for cures than surgery ever will. There is not general agreement on exactly the technique which should be employed. Most neurosurgeons remove enough tumor tissue to ensure temporary relief of the symptoms of obstruction until the radiation treatment can be effective. There have been some who advocated only an exposure and decompression, with biopsy of the tumor, in order to make less likely a wide dissemination of the tumor (Elsberg and Gotten, 1933). Prolonging the operation unduly in an attempt at complete extirpation seems definitely an error in surgical judgment. Cutler, Sosman, and Vaughn (1936), because of the high operative mortality, advocated a therapeutic trial of roentgen therapy, and if there was response in a week to ten days, to proceed with the full course of treatment. This program has not been generally accepted even among radiologists, and with a conserva-

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tive surgical attack on the tumor the early high operative mortality may not be present. Given the well-known tendency of astrocytomas to be intermittent in their clinical course, particularly when the child is under hospital management, it may be very difficult to differentiate between these and medulloblastomas, with disastrous results so far as vision is concerned (Ingraham and Campbell, 1941). The whole cranial cavity and the spinal canal must be treated if the best results are to be expected. The reports of Pendergrass, Hodes, and Godfrey (1942), Lampe and Maclntyre (1949, 1954), and others give details of technique and dosage. The literature is also covered by these authors. Lampe and Maclntyre took the least pessimistic view of the outlook in these cases. Their conclusions in 1949 were as follows: "The results in 25 patients with medulloblastoma of the cerebellum treated by surgical removal followed with vigorous postoperative irradiation are reported. Eighteen patients were dead (17 at thirty-eight months or less, and 1 at sixty-eight months, after treatment). Seven (28 percent) were alive, without evidence of neoplasm, thirty-three, forty-seven, fifty, seventy, seventy-two, eighty-three and ninety-two months after treatment. Six of the seven patients were in good clinical condition. "In 1 patient the only surgical procedure performed was biopsy; the patient was living and well forty-seven months after treatment. "The evidence suggests that medulloblastoma of the cerebellum may be a curable disease and that cure is possible only with irradiation." When these same 7 cases had been followed for a longer time, Lampe and Maclntyre (1954) became less optimistic, and they have modified the treatment technique employed in the earlier series. Their reason is the development of definite manifestations of brain damage in 3 and possibly in a fourth patient. In 1 this was not evident until seven and one-half years after treatment, when convulsions first appeared. Only 3 are living now and symptom-free, but as the authors point out, even these may yet develop seizures from central gliosis. They still feel that the neoplasm is radiocurable. None of the other workers has been able to prolong life so long in such a large percentage of cases, survival of the patient beyond three or four years being very rare. In the experience of Bailey and Gushing (1925), for example, among those who survived the operation and were not irradiated, there was an average survival of only seven months. D. ASTROBLASTOMA Astroblastomas are cerebral tumors which Bailey (1933) states "are a poorly defined group of tumors which occur in the cerebral hemispheres of adults. They have many of the characteristics of glioblastoma multiforme but grow more slowly; their average clinical course extends over a period of more than twentyeight months. Microscopically they are composed mainly of astroblasts. Transitional forms are found to be glioblastoma multiforme on the one hand and astrocytoma on the other. There is a characteristic overgrowth of connective tissue around the numerous blood vessels." It is on the basis of the intermediate position of these tumors that Kernohan, Mabon, Svien, and Adson (1949) proposed to substitute their classification on a

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numerical basis for the classification introduced by Bailey. Bailey and Bucy (1930) found no astroblastomas, but Bailey, Buchanan, and Bucy (1939) and Grotts (1949) each reported one of these tumors arising in the cerebellum. Clinically these tumors could not be differentiated from the slower-growing astrocytomas. The results of surgery were disappointing in both of these cases. E. GLIOBLASTOMA MULTIFORME Glioblastoma multiforme has finally won acceptance as the name for a particular type of glioma. It has had a long historical background, which has been briefly reviewed by Powell (1947). Virchow (1864), who first used the term glioma, was referring to what we now speak of as an astrocytoma. The more malignant forms of these tumors he considered to be sarcomas. Stroebe (1895) felt that both gliomatous and sarcomatous elements made up the tumors and called them gliosarcomas. As information accumulated about the development of the body, such a term was soon recognized as inept. Strauss and Globus (1918) first described its major histological features, its infiltrative character, and its rapid growth. In 1925 Globus and Strauss reported 16 cases of this one tumor, which they named spongioblastoma multiforme. This term was adopted by Bailey and Gushing (1926), but later, in order to avoid confusion with the "polar spongioblasts," they used the term glioblastoma mvltijorme in their collective and separate writings after 1932. Since then the term has had wide acceptance, though the tumor has been named differently by Del Rio-Hortega (1932) in his classification, and the term has been abandoned by Kernohan in his classification, his astrocytoma of grade III and IV malignancy corresponding to this tumor (Mabon, Svien, Adson, and Kernohan, 1950). Regardless of what this tumor is called, it has certain well-recognized characteristics that both link it to the astrocytic series and differentiate it from such less rapidly growing forms as the astrocytoma or the astroblastoma. It is predominantly a tumor of adult life and is found generally in the cerebral hemispheres, where it seems to arise in the white matter, spreading through the corpus callosum in 75 per cent of the cases, according to Maxwell (1946). It is frequently seen as a zone of rapid-growing neoplastic tissue in one or multiple areas of an otherwise more benign-appearing lesion—a feature recognized by Bailey and his pupils but emphasized particularly by Scherer (1940b) and others. Metastasis outside the nervous system has been reported only once, and there have been some who have not accepted this tumor as a glioblastoma multiforme. Its occurrence in the pons and mesencephalon is occasional, but its isolated appearance in the cerebellum except as an invasion from a pontine tumor is for some unknown reason very rare. Powell (1947) reviewed in tabular form the previous cases of cerebellar glioblastoma multiforme that had been diagnosed as such and reported up to the time of his writing, of which there were 13 all told, including one of his own. Of those previously reported all except those of Carmichael (1928), Davidoff and Ferraro (1929), and Baker (1940) were considered to be uncertain examples for one reason or another, mostly because of incomplete description by the authors. The great rarity of this tumor is apparent not only from the small number of

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cases that have been reported but from the fact that each of the accepted cases has been an isolated instance from neurological and neurosurgical centers of considerable size and from the fact that 208 of these tumors tabulated by Gushing in 1932 "occurred without exception in the cerebral hemisphere of adults." Mabon, Svien, Adson, and Kernohan (1950) had 8 out of 131 astrocytomas of the cerebellum which they classified as of grade III malignancy and which, along with their grade IV group, made up what has been called by most neuropathologists glioblastoma multiforme. However, 2 out of the 8 were presumably completely extirpated, a result so unusual for this tumor that it is doubtful whether these would be accepted by all neuropathologists. Nothing in the clinical findings in these cases enables the differential diagnosis from the other gliomatous tumors of the cerebellum except their rapid course and the fact that all of them accepted as reasonably certain instances of this tumor occurred in adults. Powell's case was that of a seventy-year-old man who had only a three weeks' history of headache, vomiting, and intention tremor of the left extremities, with only haziness of the medial border of the discs on admission and no elevation of spinal fluid pressure. Extreme dizziness and nausea accompanied any movement. The patient resisted any effort to move him from a recumbent position on the right side because of these symptoms. A brain tumor was considered, but the clinical diagnosis was a vascular lesion of the brain stem, and he died less than three weeks after admission, or not quite six weeks after the sudden onset of his illness. Kampmeier (1936) describes a case of cerebellar tumor occurring in a Negro with hemiatrophy of the body. The tumor found appeared to have arisen from the cerebellum and is said to have been a "spongioblastoma multiformis," but no adequate description is given and its intraventricular location makes this diagnosis unlikely. Pathologically these lesions when they occur in the cerebellum do not differ from what they are in their more common locations. To summarize briefly, they show on cut section a variegated color, with numerous areas of degeneration, hemorrhage, and frequent small cysts. The tumors are obviously invasive and destructive, producing great distortion of the part of the brain which is their location. Their histological features are well summarized by Elvidge, Penfield, and Cone (1937) as constant findings: (1) cell type spongioblast; (2) plump astrocytes (gemastete Zetteii); (3) tumor giant cells; (4) areas of necrosis; (5) proliferation of vascular endothelium; (6) mitosis; (7) fibroblastic overgrowth. As probably constant findings these authors list: (1) increased vascularity; (2) adventitial proliferation. Cyst formations of small size, with neighboring glial reactions, are frequently observed. The treatment is surgical; the procedure is palliative, and after being carried to its usual extent, it is followed by roentgen therapy in most cases, but with no anticipation that the results will be as effective as in cases of medulloblastoma. F. OLIGODENDROGLIOMA Oligodendrogliomas are not common at any site, comprising only 1.33 per cent of the 2,023 cases of intracranial tumors reported by Gushing in 1932. The

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first complete description of a fairly large group of these lesions was that of Bailey and Bucy in 1929, after the tumor had been identified by Bailey and reported in his original classification of tumors (Bailey and Gushing, 1926). At first believed to be practically restricted to the cerebral hemispheres, these lesions, as the years have gone by, have been found in practically every part of the central nervous system (Lowenberg and Waggoner, 1939). Only a few instances of the tumors involving the cerebellum have been recorded. Some case reports are those of Wertheimer, Dechaume, Croizat, and Romand-Monnier (1935), Juhasz (1942), and Wycis (1948). The histological description is very brief in the last-mentioned of these, and the tumor might have been confused with a medulloblastoma without the use of specific stains. Grossly this tumor did not suggest the medulloblastoma, as it was a large cystic tumor which could be teased out of its bed in the depths of the left cerebellar hemisphere. It had not recurred at the time of the report two years after operation. These growths show a considerable tendency to involve the meninges, and one instance of involvement of the cerebellum through such diffuse spread from the cerebral hemisphere is recorded by Lorentzen (1950). The symptoms in Wycis's case were typically those of a tumor of the left cerebellar hemisphere, which was the clinical diagnosis. Some of these tumors show some evidence of a more rapid growth, and for these the term oligodendroblastoma has been suggested in contradistinction to oligodendrocytoma for the usual slower-growing type, which in the cerebral hemisphere shows a well-known, marked tendency toward calcification. Kernohan and his associates (1949) have expressed themselves as expecting eventually to be able to grade these tumors according to malignancy, on the basis of their grades I to IV, but as yet the cases are too few in number for such an attempt at classification. Prognosis and treatment are difficult to judge in view of the rarity of the lesion, a statement particularly applicable to the few isolated instances of cerebellar involvement. G. GANGLIONEUROMA Aside from the confusion which may have arisen in the literature over what the proper name should be to identify the medulloblastoma, there is very little to be found concerning tumors derived from nerve cells in the cerebellum. Courville (1930) reviewed the literature and reported two cases of tumors derived from nerve cells. Neither of them was in the cerebellum. The occasional references to granuloblastoma which can be found—for example, Saccone and Epstein (1948)—hark back to the suggestion of Stevenson and Echlin (1934) and some others that this name be substituted for medtdloblastoma, which for some reason they found objectionable. It would seem that Kershman's demonstration that the cells of the external granular layer are bipotential and may correctly be called medullocytes, in the original sense in which the word was used, should be sufficient warrant for avoiding the confusion which necessarily arises from the substitution of an unfamiliar for a well-established term. In our discussion of malformation of the cerebellum, we mentioned that heterotopias and hypertrophy of individual folia or, in rare instances, of an

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entire hemisphere can simulate a cerebellar tumor (see p. 441). The problem of whether to regard these as malformations or as tumors has been faced by all writers on this subject. For practical purposes they are tumors, and their symptomatology is that of a slow-growing cerebellar or brain stem tumor. They may be attacked surgically (Barten, 1934). Alajouanine, Bertrand, and Sabouraud (1951) have reviewed the six cases previously reported and have added one of their own. They discuss the biological implications of a tumor which preserves such unusual growth characteristics, forming definite layers of cerebellar cortex of large and distorted size. Kernohan, Mabon, Svien, and Adson (1949) have suggested that to simplify the terminology, all the terms which have been used to describe these rare tumors be abandoned and the one they prefer be used. They propose that neuroastrocytoma be substituted for the following list of names, under any one of which one may find these tumors referred to: neurocytoma, ganglioneuroma, gangliocytoma, ganglioglioma, neuroblastoma, spongioneuroblastoma, and glioneuroblastoma. H. SPONGIOBLASTOMA POLARE The spongioblastoma polare, here included for the sake of completeness, is not considered by most investigators to be sufficiently different from the astrocytoma to justify a separate category. Ringertz and Nordenstam (1951) consider most of the cerebellar astrocytomas examples of this tumor (see p. 539). Tumors so diagnosed were found in the cerebellum in 7 of Cushing's 2,023 cases. They were frequently cystic and slow-growing, and did not recur when completely removed. I. NEUROEPITHELIOMA The neuroepithelioma, like the spongioblastoma polare, can probably be grouped with the ependymomas, as Kernohan, Mabon, Svien, and Adson (1949) have grouped it in their classification. Since this is a relatively invasive tumor, it may involve the cerebellum, as in the case reported by Bucy and Muncie (1929). J. VASCULAR TUMORS 1. ANGIOMATOTJS MALFORMATIONS We shall follow Gushing and Bailey's classification (1928a) of vascular tumors, dividing them into the angiomatous malformations, which are considered to be defects of development, and the true neoplasms, or hemangioblastomas. Dandy (1932) was of the opinion that no such distinction could be made. Gushing and Bailey differentiate between the two by the character of the tissue between the vascular channels. If the tissue was glial, it was assumed that no active cellular proliferation was occurring. If it consisted of mesenchymal tissue with reticular fibers, endothelial cells, and fat-ingested cells, the lesion was considered to be a hemangioblastoma. The angiomatous malformations are further subdivided into capillary, venous, and arterial, depending on which is the predominant vascular channel found. The differentiation between the last two is best made on the basis of the presence

CEREBELLAR TUMORS 553 or absence of pulsation of the vascular malformation when it is seen at the time of surgery. These large vascular channels may not easily be distinguished simply by the histological character of their wall. The capillary angiomatous malformations, or telangiectases, are asymptomatic lesions so far as the nervous system is concerned. They are at times associated with similar multiple lesions of the skin and, according to Bailey (1933), as many as thirty such lesions have been scattered about through the brain, spinal cord, and retina. Usually they are single, occupying a site near the upper part of the pons. No specific description of such lesions in the cerebellum has as yet been located in the literature, though there is no reason to believe that they should spare this part of the central nervous system. The venous and arterial malformations are usually either cerebral or located in the spinal cord. In the former they are frequently associated with focal and generalized seizures, and in the latter they are the cause of a group of bizarre paralytic manifestations which may lead eventually to paraplegia. Gushing and Bailey (1928a) found two cerebellar lesions of this type, compared to fourteen cerebral, and gave a detailed description of a case of Olivecrona's. Lindau (1931) mentioned such a case as well. It is possible that with the greater utilization of vertebral arteriography, these lesions will be discovered more frequently in the cerebellum in the future. 2. HEMANGIOBLASTOMA a. INCIDENCE, CLASSIFICATION, AND HEREDITARY TENDENCIES Unlike the malformations of the blood vessels, the true neoplasms of vascular elements affecting the cerebellum are common. They are responsible for about 7 per cent of the verified neoplastic lesions of the posterior fossa, according to Olivecrona (1952), and if one considers only such lesions in patients over twenty years of age, the percentage will be about 10 per cent, according to the same statistics, they being the fourth most common lesion, trailing acoustic neurinomas, gliomas, and meningiomas in that order. Bergstrand, Olivecrona, and Tonnis (1936) chose the term angioreticulomas to refer to these tumors, as do many continental writers, and Silver and Hennigor (1952) prefer the term hemangioma. The lesions may be either cystic or solid, and in Olivecrona's material, consisting of 70 cerebellar hemangioblastomas, 15 were solid and 55 were cystic. In some of these latter the cysts were so small as to be surgically insignificant, so that for practical purposes the tumors, he stated, had to be handled surgically as solid tumors in one third to one fourth of the cases. These figures conform quite closely to the proportions found in other large series, though the cystic nature of the lesions has been emphasized because of their early confusion with cystic astrocytomas. Silver and Hennigor (1952) have suggested a histological classification of these tumors into a juvenile type, found during the first three decades of life, a transitional type, and a clear-cell type, the last two looked upon as progressive changes in the histological structure of the tumor as the years pass. As indicated above, the hemangioblastoma is a tumor of adult life, the average age in practically all reports of large series being in the middle thirties. Olive-

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crona (1952) found only 6 cases out of 70 in which the patient was under twentyone years, and he found no case before puberty. This is remarkable when one considers that this lesion is hereditary and familial in many instances and is looked upon as related to a disorder of development occurring at the third month of fetal Jife. The group of cases reported by Olivecrona (1952) consisted of 41 males and 29 females. A familial incidence can be detected in some of these cases, and there have been many reports specifically dealing with the hereditary and familial features of this condition (Gushing and Bailey, 1928b; Moller, 1929, 1944; Vincent and Rappoport, 1931; Hartmann and Sourdille, 1931; Martin and van Bogaert, 1933; Levin, 1936; Porta, 1936; MacDonald, 1940; Patterson and Anderson, 1940; Craig, Wagener, and Kernohan, 1941; Norlen, 1941; Grossman and Kesert, 1944; Bradford, 1948; Craig and Horrax, 1949; Moller, 1952; Tonning, Warren and Barrie, 1952; Adams, 1953). Reports of larger groups of cases, such as those of Lindau (1927), Perlmutter, Horrax, and Poppen (1950), Cramer and Kimsey (1952), Olivecrona (1952), and Silver and Hennigor (1952), as well as the monographs of Lindau (1926), Gushing and Bailey (1928a), and Bergstrand, Olivecrona, and Tonnis (1936), have included certain cases which are familial. It had been recognized among ophthalmologists for many years that the retinal manifestation of this disease, the so-called angiomatosis of the retinae, or von Hippel's disease (1904), at times was an hereditary condition. It remained for Lindau in 1926 to discover that the retinal and the central nervous system hemangioblastomas were a part of the same pathological process and that these lesions were frequently associated with cystic changes in the pancreas, kidney, and lungs and occasionally with angiomatosis of the liver, hypernephromas, and tumors of the epididymis. It has been assumed that the pathological process is related to some defect in the mesenchymal formation at the third fetal month; that the difficulty is a dynamic one, however, is evidenced by the fact that the tumors grow and that even new ones can become clinically evident while the patient is under observation. Lindau attributed the difficulty to failure in the integration between mesodermal and epithelial components. Tonning, Warren, and Barrie (1952) have expressed their concept of this disease as follows: "We may accept the fact therefore that some of the lesions in Lindau's Syndrome are not the results of an isolated antenatal developmental abnormality but that they represent a fundamental persistent lack of integration between blood vessels and parenchyma. One of the results is a proliferation of epithelial cells and one a proliferation of endothelial cells so that we cannot say that the main fault lies predominantly with either. "The condition must be due to an hereditary but persistent abnormality in which there is lack of integration between blood vessels and their field of supply. In the phase of foetal development this leads to cysts, in later life to neoplasms (p. 131). The cysts are usually asymptomatic, but a considerable number of these patients die of carcinoma of the kidney (Lindau, 1926; Tonning, Warren, and Barrie, 1952). The hereditary studies show the condition to be a non-Sex-linked dominant characteristic which, as in many hereditary conditions, has been noted

CEREBELLAR TUMORS 555 to affect successive generations at a progressively younger age (Norlen, 1941; Adams, 1953). b. SYMPTOMS AND DIAGNOSIS

The symptomatology is like that of any other cerebellar lesion. Unless a family history is obtained or a retinal lesion observed, the pathological nature of the lesion cannot be determined before operation. It was at one time hoped that careful ophthalmoscopic examination would allow the diagnosis to be made before surgery in a large proportion of cases, but most of the cerebellar lesions are isolated. Perlmutter, Horrax, and Poppen (1950) found 4 retinal angiomas among 25 cases of cerebellar hemangioblastomas. Olivecrona (1952) believes this to be exceptional, as he has encountered only 1 in his 70 cases. Headache is the initial and most constant symptom. Vertigo is common and may be precipitated by movement. Eventually vomiting, choked discs, and signs of cerebellar deficiency are to be expected. Because of their slow growth and the frequent lateral and superficial location of the lesion the signs of cerebellar involvement may be masked by the more severe symptoms of intracranial pressure by the time the patient comes to the hospital. Cranial nerve palsies occur about as frequently as they do in patients having any other intracerebellar expanding lesions. Most cases will require air studies. Dyke and Davidoff (1940) and Davidoff and Epstein (1955) have outlined the features which are to be expected in the ventriculograms in these cases (see p. 534). Olivecrona (1952) found that some type of contrast roentgenographic study was necessary for accurate diagnosis in all but three of his cases which came to surgery. He points out the distinct advantages to be obtained from vertebral angiography in dealing with these lesions and states that in any case in which there is a positive family history such studies are definitely indicated in order to pick up possible multiple tumors that in all likelihood would be missed by ventriculography. C. GROSS APPEARANCE

As has been stated above, hemangioblastomas are more commonly cystic than solid. The cyst may be small and within the solid tumor, or it may represent the bulk of the lesion, the tumor being found only as a nodule of pea to walnut size on the wall. Rarely the tumor may even be microscopic in size (Gushing, 1932). It is frequently red from the many blood channels it contains, or it may have a yellowish appearance, owing to the fat contained in the cells of the tumor. It bleeds profusely when injured at operation. The surface is irregularly nodular and is well demarcated from the cerebellar tissue. It is attached at some point to the surface of the cerebellum, but is at times located far anterior on the tentorial surface of the cerebellum. If there is a mural nodule, it is usually located at the point of attachment to the pia mater. The cystic fluid is yellow and coagulates on exposure. There is a characteristic enlargement of the supplying vessels on the neighboring surface of the cerebellum. It is this vascularity which serves to identify the lesion by arteriography. The location is usually in the cerebellar hemisphere, this being the site in 56 cases analyzed by Olivecrona (1952) as compared to 9 in the vermis and 5 in the region of the fourth ventricle.

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d. MICROSCOPIC APPEARANCE

The tumors are formed largely of blood vessel elements which may be very large and thin-walled. The cells between the vessels are typically elongated, are endothelial in type, and may be laden with fat. At times these cells may be the predominant feature, capable of being compared to a hypernephroma or a xanthoma. At times the vessels are so large and so dominate the histological picture that the lesion might be interpreted as a vascular malformation. Bailey (1933) did not feel these variations were of importance, since they were present in different parts of the same tumor. Silver and Hennigor (1952), on the other hand, used such variations as the basis for a classification, in the belief that they represented evolutionary stages in the tumor. The younger tumors, called by these authors "juvenile," have predominantly vascular channels and endothelial cells. In the transitional stage there is a response on the part of the endothelial cells to hemorrhage, resulting in degenerative changes which are found throughout the tumors. There may be some giant cells noted in these lesions. In the third, or clear-cell stage, the cells are almost entirely those of the lipid-containing elements. Lindau (1926) attributed this lipoid to a disturbance of circulation in the tumor, with a stagnation of lymph from which the cells phagocytize the fat. Others have looked upon these as degenerative changes. No matter how varied the picture in the cellular arrangement, the most distinctive feature is the presence of a rich reticulum which, when stained with specific stains such as that of Perdrau, shows the clearly mesenchymal nature of the tumor. C. TREATMENT

The treatment of these cases is surgical. Because of the tumor's great tendency to bleed, surgery may be very difficult, and mortality rates have continued to be considerable in these cases. Recurrences are attributed to failure to remove the cystic nodule in most instances. Sometimes it is felt that recurrence is due to the growth of a second tumor, as hemangioblastomas are known to be at times multiple. Dyke and Davidoff (1940) speak of "migration" of the tumors to a more favorable posterior position after decompression from their original site high under the tentorium. Olivecrona (1952) has on one occasion successfully removed one such tumor by approdching it through a large occipital parietal flap and splitting the tentorium. The new method of intracranial surgery, which controls the blood pressure either chemically or by high spinal anesthesia, may prove to be of advantage chiefly in the surgical treatment of these lesions as well as in the attack on the angiomatous malformations. Gushing (1932) was able to operate on 24 of his 25 cases, with 6 operative deaths in 44 total operations, or a case mortality of 25 per cent and an operative mortality of 13.6 per cent. Olivecrona (1952) was able to operate on 64 patients. Of these, 42 were considered to show good long-term results; 11 were operative fatalities. The 11 other patients consist of 6 who died later, 3 possibly as a result of their disease, and of 5 who are invalids from residuals of their disease. Although roentgen therapy is used with some success in cases of angiomatous malformations, it is considered of very limited value in treating with the hemangioblastomas.

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K. DYSEMBRYOMAS Dysembryomas form a small percentage of all intracranial tumors. Gushing (1932) reports only 15 of these lesions among 2,023 intracranial tumors. When they do occur, the cerebellum is involved in approximately one half the cases. Of 39 cases of intracranial dermoids collected from the literature by Brock and Klenke (1931), 15 were cerebellar or midline posterior fossa; of 10 intracranial complications of dermal sinus formation reported by Matson and Ingraham (1951), 9 were related to the posterior fossa as compared to 1 supratentorial lesion. Several different names have been applied to these lesions, such as pearly tumors and cholesteatomas, but since Bostroem's classic pathological study in 1897, the lesions have been regarded as resulting from the enlargement of buried remnants of ectodermal tissue, which is due to imperfect closure of the neural tube. The term tumeurs perlees was applied to these cerebellar tumors by Cruveilhier in 1829. Subsequently Miiller in 1838, because of the frequent demonstrations of cholesterol in the amorphous contents of these often cystic lesions, gave the tumor the name cholesteatoma. This proved to be unfortunate, for chronic inflammatory lesions resulting from epidermal accumulations from middle ear disease were also called cholesteatomas. Furthermore, as was pointed out by Munro and Wegner (1937), who also give a complete historical discussion of the shifting pathological conception of these lesions during the eighteenth century, some of these tumors do not have cholesterol in them, and other totally unrelated tumors can contain this fatty substance as a result of degenerative changes. Besides the reports specifically mentioned in the discussion, the reader is referred to those of Bailey (1920, 1924b), Critchley and Ferguson (1928), Davidoff and von Deesten (1935), Divry and Lecomte (1936), Askenasy, Arsenic, and Georgiade (1939), and Paulian, Bistriceanu, and Tudor (1940). These tumors are usually classified as follows: 1. Epidermoids. In these only the epidermal tissue is found, and these are usually the type which have the characteristic pearly-white appearance which resulted in the descriptive name applied by Cruveilhier. These may be intracerebral, with pial or dural attachment, or they may find sufficient blood supply to enlarge to enormous size within the cranial bones themselves. 2. Dermoids. Here the tissue involves not just the epidermis but the mesenchymal structures of the skin, with hair follicles, sweat glands, and sebaceous glands; the only really distinguishing feature grossly is the hair contained in the dermoids. 3. Teratomata. When these are solid, they contain fetal tissue but not organs, and when cystic they contain fetal organs as well. Records of the third type of dysembryomas have been found involving the cerebellum on very rare occasions (Hosoi, 1930). The clinical manifestations of the first two are quite similar. The dermoids may be present at any age or even at birth, while the epidermoids are almost always discovered in the third or fourth decade. They may involve the cerebellum either in the cerebellopontine angle (Olivecrona, 1949) or in the midline region of the posterior fossa, where they may be attached to the dura of the tentorium. They occupy the fourth ventricle or, more commonly, the cisterna

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magna, where they push the cerebellar vermis forward and separate the cerebellar hemispheres. The midline lesions produce signs of increased intracranial pressure, with headache, vomiting, and choked disc, before any evidence of cerebellar deficiency can be detected. When they are located laterally, cranial nerves are first involved, and the lesion is usually not distinguishable from other expanding lesions at this site. One differential feature which has been pointed out by Hodes, Pendergrass, and Dennis (1951) is the longer average duration of symptoms in this condition than in cases of other cerebellopontine angle tumors. In "cholesteatomas" these authors found this average duration to be 5% years as compared to 15 months for gliomas, 18 months for acoustic nerve tumors, and 3 years for meningiomas. Unlike acoustic neurinomas, by far the most common lesion at the cerebellopontine angle, dysembryomas do not commonly affect auditory and vestibular function. Gonzalez (1948) found that in 10 out of IS cases of "cholesteatomata" there was normal hearing, and in 9 there was normal labyrinthine function; and Olivecrona (1949) found the same to be true in 5 out of 7 cases in his study. Lewis and Echols (1951) report a patient with some eighth nerve involvement in whom the auditory and vestibular function returned to normal after the successful evacuation of a tumor of this type. Hodes, Pendergrass, and Dennis (1951) reported some erosion of the petrous tip in 3 out of 6 cases examined with satisfactory radiographs of the petrous bone. They also pointed out a minimal distortion and decalcification of the sphenoidal ridge in 2 of their 7 patients. Olivecrona (1949), on the other hand, stated there were no positive roentgenological findings in these cases. The epidermoid is usually glistening white when exposed, its outer layers being tough and easily separated from the surrounding brain substance, which it compresses before it as it enlarges in an irregular manner, forcing its way between the structures near to it. The contents of the tumor, which is surrounded by a fibrous capsule, is of a mushy, cheesy consistency, at times containing pieces of calcified material and almost always a fatty material which contains cholesterol crystals. The contents of the dermoid are similar, though less uniform in texture and color, and always contain hair, for this is the essential difference between the two types. The wall of the epidermoid consists of an outer thin, fibrous layer with a flattened layer of epidermal cells of varying thickness. At times only a single layer is found, and at other times all the successive layers of normal skin are seen, including the protoplasmic bridges. The dermoids have a thicker wall, which includes the deeper layers of the skin. Here one may find hair follicles, sebaceous glands, and sweat glands. The hair usually grows from a mural nodule located at the point of attachment, which is the only place any blood vessels can be found entering the otherwise avascular mass. The treatment is surgical. When dysembryomas are accessible, they can be removed, and they do not recur. If they have become infected, which frequently happens when a tract remains to the outside surface, the surgical treatment becomes much more complicated. Matson and Ingraham (1951) show this to be

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strikingly true in their cases. In those cases which were not removed before infection had taken place, the treatment was very unsatisfactory. Two of four cases died, one still living is in a decerebrate state, and the other developed such a postoperative hydrocephalus from a dense adhesive arachnoiditis that a ventriculo-ureteral shunt was necessary. Of the six children operated on in whom the lesion was not infected, all survived and are symptom-free. These authors stress the external manifestation of this lesion. It consists of a tiny dimple or subcutaneous mass which may be detectable only after shaving the head. It should always be sought for carefully in any unexplained meningitis, and can sometimes be found to be associated with a very small underlying skull defect, which can be demonstrated roentgenologically. L. METASTATIC TUMORS Metastatic tumors will be considered only briefly. There are a number of scattered reports of isolated metastatic lesions of the cerebellum. Those of Musa (1936) and of Edelman (1941) may be mentioned. When the cerebellum is involved, if it is recognized that there is a primary site, the lesions will naturally be expected to be multiple, and in such circumstances, as Bailey (1933) has pointed out, the wisest policy is to do nothing with surgery or roentgen therapy. Occasionally such a lesion will be found unexpectedly. For this reason, when any adult patient is suspected of having a brain tumor, a chest film should always be obtained before any surgery is contemplated. The lung, as is well known, is the source of more intracranial metastases than any other organ. They are found frequently in the terminal stage of breast cancer, in hypernephroma, in melanosarcoma, in cancers of the prostate and thyroid. Carcinomas of the nasopharynx and sarcomas of the skull and dura usually invade the brain directly or may spread over the surface if they reach the subarachnoid spaces. There is nothing distinctive about the cerebellar or posterior fossa location of any of these malignant lesions, and they will not be discussed further. M. EXTRACEREBELLAR GLIOMAS AND EPENDYMOMAS The gliomas of the pons and the ependymomas of the fourth ventricle may involve the cerebellum. The differential diagnosis of these lesions has already been discussed in Chapter 9. It is usually possible to differentiate the glioma of the pons from an intracerebellar lesion, but if there is any doubt the patient is entitled to an exploration of the posterior fossa. The differential diagnosis between cerebellar and pontine tumors is usually difficult only in those few instances when evidences of increased intracranial pressure are present in the pontine gliomas. In these cases exploration and decompression do give some palliative relief, further justifying surgery in most doubtful cases. Ependymomas are frequently indistinguishable from intracerebellar lesions which obstruct the fourth ventricle. The diagnosis cannot be made until surgery, at which time the tumor is usually quite readily differentiated grossly. As these are not strictly cerebellar tumors, the limitations of space require that we mention them only in passing.

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N. MENINGIOMAS Meningiomas are rarely truly cerebellar in location. They may arise in a portion of the meninges which allows them to replace the cerebellar hemispheres, and in extremely unusual circumstances, as is shown by the case reported by Freiman and Ficarra (1943), they may attain enormous size without producing either evidence of increased intracranial pressure or signs of cerebellar deficiency. In this case even a pneumoencephalogram showed air in the fourth ventricle and was itself misleading. Another isolated case report of a meningioma which was purely cerebellar is that of Christophe and Divry (1937). Michon and Rousseaux (1939) reported a meningioma of the tentorium which compressed the cerebellum and the brain stem, but the symptomatology was that of a midbrain tumor. The monograph of Gushing and Eisenhardt (1938), which is an analysis of 313 cases of this tumor, reported only 25 single tumors in the posterior fossa, and of these only 16 could be truly said to involve the cerebellum. Other important series studied are those of Campbell and Whitfield (1948), D'Errico (1950), Castellano and Ruggiero (1953), Russell and Bucy (1953), and Markham, Fager, Horrax, and Poppen (1955). Gushing and Eisenhardt (1938) classify meningiomas, which arise from the dura, usually along the sinuses, and from tissues forming the arachnoid villa, into nine different subgroups; the complex histological characteristics cannot be adequately discussed here. Meningiomas of the posterior fossa arise usually from the lateral sinus or sigmoid sinus or, less commonly, from the undersurface of the tentorium, without definite relation to the dural sinuses. The symptomatology is not unlike that of other tumors at this site: headache followed by signs of increased intracranial pressure, symptoms and signs of cerebellar deficiency, and cranial nerve palsies. Gushing was able to remove successfully 12 of these lesions, several operations being required. The longest survival was over twenty-four years, and of the first 7 patients, 5 had been well and active fourteen years or more when the cases were reported in 1938. Markham, Fager, Horrax, and Poppen (1955) report complete removal in 76 per cent of their series of 29 cases of posterior fossa meningiomas, with an immediate operative mortality of 31.2 per cent in the 22 cases operated during the first ten years studied and 15.4 per cent mortality in the second ten-year period. 0. SARCOMAS Primary intracranial sarcomas are rare tumors. Before the term was restricted to include only malignant tumors of mesenchymal origin, and before the true nature of the gliomatous tumors was recognized, many gliomas were called sarcomas of the brain in the older literature. While most of these old reports do not concern sarcomas as we now use the term, truly malignant tumors taking origin from the mesenchymal elements which enter into the formation of the meninges and of the perivascular tissues are occasionally encountered. They have been classified by Hsu (1940) into sarcomatosis, perithelial sarcoma, alveolar sarcoma, and fibrosarcoma. All these tumors tend to spread widely throughout the subarachnoid spaces and then only occasionally invade the

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brain in any area, including the cerebellum. In the first group this meningeal spread is most marked. In the others varying degrees of local invasion may occur. In the last group this is definitely perivascular. The second and third groups form invasive destructive masses in the cerebellum. Such cases are very rare but have been described in detail by Foerster and Gagel (1939), Hsu (1940), Marquardt (1941), Bailey (1942), and Neubuerger and Greene (1946). Other important papers which should be mentioned dealing with intracranial sarcomas are those of Abbott and Kernohan (1943b) and Globus, Levin, and Sheps (1944). There is no symptom which would differentiate these tumors from any other rapidly growing intracranial tumors. Those which involve the cerebellum may or may not give rise to symptoms recognizable as cerebellar. The case described by Bailey (1942), which has already been mentioned in an earlier chapter (p. 385), gave clinically no definite evidence of cerebellar involvement. The patient described by Neubuerger and Greene (1946) had all the manifestations expected from a rapidly advancing cerebellar tumor, though she was not operated upon, and we are not told what the clinical diagnosis was. The patient reported by Hsu (1940) was recognized as having a cerebellar tumor, and a posterior fossa exploration was performed, but the pathological nature of the lesion was not recognized until after histological study. In one of the three cases reported by Foerster and Gagel (1939), the patient was operated on and well two months after surgery, this being the only case recorded where a tumor of this type appears to have been grossly removed. The pathological findings in the case reported by Neubuerger and Greene (1946) suggested to these authors that the lesion could have been removed without too great difficulty but that, from the microscopic appearance, the probabilities were that there would be an early recurrence. Grossly this tumor was located on the dorsal aspect of the right cerebellar hemisphere, covering about one third of its surface and extending across the midline. It resembled a mushroom in shape, was moderately firm, and on section was homogeneously grayishwhite. It could be shelled out completely except for a small extension to the left hemisphere, where it merged with cerebellar tissue to a depth of 2 to 2.5 centimeters. Microscopically it was a poorly vascularized, highly cellular structure, made up of irregularly interwoven cords of cells with dark, slender, and fusiform nuclei. Perdrau's stain, which is essential to the proper identification of these tumors, showed a delicate network of fibrils obviously of mesenchymal type. Special stains for nerve and glial tissue failed to disclose any in the tumor itself. This tumor would probably have been classified by Hsu as a fibrosarcoma. P. ACOUSTIC NEURINOMA While the acoustic neurinoma is one of the most frequent growths encountered in the posterior fossa and is often associated with cerebellar signs, particularly at the later period of its clinical course, it is not to be considered in this monograph in any detail because it is pathologically always extracerebellar in its origin. We have already discussed the differential features of these tumors and intracerebellar tumors in Chapter 9. The clinical picture of these lesions is well known; it was the subject of an extensive monographic report by Gushing in 1917, and

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was again reviewed by him in his monograph on intracranial tumors in 1932. Other reports are those of Eraser (1920), Walshe (1923b), Parker (1928), Bailey (1933) and Edwards and Paterson (1951); there is also the work of Gonzalez (1948) and Hodes, Pendergrass, and Dennis (1951) which has been mentioned earlier. Ecker (1948) has paid particular attention to the upward herniation of the brain stem in these tumors as well as in cerebellar tumors, and to the resulting distortions of the positions of the third ventricle and other supratentorial structures. SUMMARY Cerebellar tumors, in common with most posterior fossa expanding lesions, result in early, constant, intense manifestations of increased intracranial pressure. The symptoms resulting from this—namely, headache, vomiting, and visual disturbances—and the choked disc and other signs of increased intracranial pressure may precede the evidences of cerebellar deficiency, and the increased intracranial pressure may give rise to many false localizing signs. Roentgenograms of the skull are useful in demonstrating increased intracranial pressure. In the diagnosis of these lesions ventriculograms are the most valuable aid, and electroencephalograms and arteriograms are of relatively little value. Astrocytomas of the cerebellum are chiefly distinguished by the fact that of all gliomatous tumors they offer the most favorable prognosis following surgical removal. Whether because of this fact they are properly to be set apart from cerebral astrocytomas is questionable. Medulloblastomas are believed to originate from cell rests of the external granular layer of the cerebellum, located in the posterior medullar velum at the base of the floccular nodular lobe. They are chiefly noted for the remarkable tendency for implantation throughout the subarachnoid circulation, particularly in the spinal canal. Radiological treatment is effective in retarding the growth of these tumors, but if doses capable of producing "cures" are used, grave danger of brain damage results. Other less common cerebellar tumors discussed are the astroblastoma, glioblastoma multiforme, oligodendroglioma, ganglioneuroma, spongioblastoma polare, and neuroepithelioma. Vascular tumors are subdivided into hemangiomatous malformations and hemangioblastomas. The latter are also known as angioreticulomas and hemangiomas. These lesions are at times familial and hereditary and occasionally are found associated with similar lesions in the retina (von Hippel's disease). The tumors appear to be the result of a defect in the development of the mesenchymal formation at the third fetal month, and with the cerebellar lesions one can find cystic changes in the pancreas, lungs, and kidneys. That other than a developmental factor plays a role is evidenced by the fact that these are actively neoplastic and that new tumors are known to form in adult life, at which time the tumors almost always are clinically manifest. The symptoms and signs are not different from those of other cerebellar tumors, and most of these vascular tumors arise in the hemispheres. The identification of the mesenchymal origin of the tissue by appropriate stains differentiates the lesions from gliomatous

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tumors. The treatment is surgical. The difficulties of control of hemorrhage may be eased by the application of the newer techniques in the control of blood pressure. The various dysembryomas—epidermoids, dermoids, and teratomas—are rare intracranial lesions, but when they do occur about one half are found in the cerebellum. Metastatic tumors may involve the cerebellum, but when they do they are usually multiple, with several cerebral lesions. Tumors of extracerebellar origin may give rise to symptoms of cerebellar deficiency, but space permits only a brief mention of them. They include the gliomas of the pons, ependymomas, and acoustic neurinomas. Meningiomas are relatively rare in the posterior fossa, and a truly cerebellar location is almost a medical curiosity. Primary intracranial sarcomas are rare, but when they do occur, the cerebellum may be involved. They may spread throughout the subarachnoid space to a remarkable degree.

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Bibliographical Index of Authors

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Bibliographical Index of Authors

THE italicized numbers in parentheses at the end of each entry indicate the pages where the reference either is specifically cited or relates to the discussion. The long dash at the beginning of a bibliographic entry indicates that the author or authors are exactly the same as in the immediately preceding entry; a dash plus other names means that the author or authors are the same, with the addition of the further-named collaborators. The abbreviations employed for periodicals are those of the Quarterly Cumulative Index Medicus. Abbie, A. A., and W. R. Adey, 1950. Motor mechanisms in the anuran brain. J. Comp. Neurol., 92:241-292. (13,105) Abbott, K. H., and J. W. Kernohan, 1943a. Medulloblastomas; concerning the problems of spinal metastasis and malignancy: A report of 6 cases and discussion of problems involved. Bull. Los Angeles Neurol. Soc., 8:1-10. (547) — , 1943b. Primary sarcomas of the brain: Review of the literature and report of twelve cases. Arch. Neurol. & Psychiat., 50:43-66. (561) Abercrombie, J., 1828. Pathological and Practical Researches on Diseases of the Brain and Spinal Cord. Edinburgh: A. Balfour & Co. (498) Aby, Fr., 1899. Observations on the blood capillaries in the cerebellar cortex of normal young adult domestic cats. J. Comp. Neurol., 9:26-34. (511) Adachi, C., and J. Ushiyama, 1950. Effect of chemical stimulation of the cerebellum on the blood and intestinal movements. (In Japanese.) J. Physiol. Soc. Japan., 12:67. (303) Adamkiewicz, A., 1904. Die wahren Zentren der Bewegung. Neurol. Zentralbl., 23:546-548. (52, 109) , 1905. Die wahren Zentren der Bewegung und der Akt des Willens. Wien: W. Braumiiller. (52) Adams, J. E., 1953. Familial hemangioblastoma of the cerebellum. Pedigree of two families. J. Neurosurg., 10:421-423. (554, 555) Adams, R. D., R. Schatzki, and W. B. Scoville, 1941. Arnold-Chiari malformation; diagnosis, demonstration by intraspinal lipiodol and successful surgical treatment. New England J. Med., 225:125181, July 24. (423) Addison, W. H. F., 1911. The development of the Purkinje cells and of the cortical layers in the cerebellum of the albino rat. J. Comp. Neurol., 21:459-488. (359-361) Adrian, E. D., 1935. Discharge frequencies in the cerebral and cerebellar cortex. J. Physiol., 83:P32-33. (7,159,162,176, 240, 241, 325) , 1941. Afferent discharges to the cerebral cortex from peripheral sense organs. Ibid., 100:159191. (63, 208) , 1943. Afferent areas in the cerebellum connected with the limbs. Brain, 66:289-315. (182-185, 189, 191, 206-207, 212-214, ®45, 247, 250) , 1950. The electrical activity of mammalian olfactory bulb. Electroencephalog. & Clin. Neurophysiol., 2:377-388. (179) and D. W. Bronk, 1929. The discharge of impulses in motor nerve fibers. II. The frequency of discharge in reflex and voluntary contraction. J. Physiol., 67:119-151. (166) Adrian, E. D., and G. Moruzzi, 1939. Impulses in the pyramidal tract. J. Physiol., 97:153-199. (99,166, 168, 172, 179, 189, 2^1, 311, 312, 316, 350, 353) Ajmone-Marsan, C., M. G. F. Fuortes, and F. Marossero, 1951. Effects of direct currents on electrical activity of spinal cord. J. Physiol., 113:316-321. (128) 567

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Akelaitis, A. J., 1938. Hereditary form of primary parenchymatous atrophy of the cerebellar cortex associated with mental deterioration. Am. J. Psychiat., 94:1115-1140. (447-449) Alajouanine, T., I. Bertrand, and C. Sabouraud, 1951. Ganglioneurome myelinique diffus de 1'ecorce cerebelleuse. Rev. neurol., 84:3-13. (Ml, 562) Alajouanine, T., R. Thurel, and T. Hornet, 1935. Un cas anatomoclinique de myoclonies velopharyngees et oculaires. Rev. neurol., 64:853-872. (413) Albe-Fessard, D., and Th. Szabo, 1954. Observations sur 1'interaction des afferences d'origines peripherique et corticale destinees a 1'ecorce cerebelleuse du chat. J. Physiol., Paris, 46:225-229. (216, 217, 251) , 1955. Activites enregistrees au niveau des cellules de Purkinje dans le cortex cerebelleux du chat. Compt. rend. Soc. de biol., 149:1090-1093. (217) Albertoni, P., 1875-1879. Protocols of unpublished experiments performed in Padova between 1875 and 1879. Cited by Lussana, 1885, pp. 22-29. (23) Aleksanjan, A. M., 1946. On cerebellar functions. A thesis. Cited by Simkina, 1948. (303, 346) , 1948. On the functions of the cerebellum. Quoted by Kobakova, 1952. (366) Alekseenko, N. Iv., 1946. Perception of sound direction during simultaneous non-acoustic excitation. A thesis. Cited by Simkina, 1948. (346) Alexander, G., 1929. Der otogene Kleinhirnabscess (Komplikation dritter Ordnung). In G. Alexander, 0. Marburg, and H. Brunner, Handbuch der Neurologic des Ohres, vol. 2/2, pp. 1427-1484. Berlin: Urban u. Schwarzenberg. (499) Allen, W. F., 1923. Origin and destination of the secondary visceral fibers in the guinea-pig. J. Comp. Neurol., 35:275-311. (309) , 1924. Distribution of the fibers originating from the different basal cerebellar nuclei. Ibid., 86:399-439. (149) Alpers, B. J., 1931. Diffuse progressive degeneration of gray matter of cerebrum. Arch. Neurol. & Psychiat., 25:469-505. (477) and J. C. Yaskin, 1939. Gliomas of the pons: Clinical and pathologic characteristics. Ibid., 41:435-459. (400) Alpers, B. J., and H. E. Yaskin, 1944. The Bruns syndrome. J. Nerv. & Ment. Dis., 100:115-134. (383, 402, 403) Alterman, G. L., and C. L. Jankovskaja, 1938. On the cerebellar influence on blood chemistry. II. Influence of cerebellectomy on the content of blood sugar. (In Russian, with English summary.) Izv. naucn. Inst. Lesgafta, 21:95-98. Abstracted in Ber. ges. Physiol., 114:116 (1939), and Wiggers, 1943a. (301) Amantea, G., 1912a. Sull'azione del curaro applicato direttamente sui centri nervosi. Arch, di farmacol. sper., 14:41-74. (110) , 1912b. A proposito dell'azione del curaro applicato direttamente sui centri nervosi. Riv. di pat. nerv., 17:696-700. (110) Ammerbacker, W., 1938. TJeber Kleinhirnveranderungen bei multipler Sklerose. Arch. f. Psychiat., 107:675-687. (477) Anderson, F. M., 1949. Extradural cerebellar hemorrhage; review of the subject and report of a case. J. Neurosurg., 6:191-196. (523) Anderson, F. N., 1928. Tuberculoma of the central nervous system. Arch. Neurol. & Psychiat., 20:354-365.(496) Andersson, B., R. A. Kenney, and E. Neil, 1950. The role of the chemoceptors of the carotid and aortic regions in the production of the Mayer waves. Acta physiol. Scandinav., 20:203-220. (294) Andre, M. J., 1947. Ataxie cerebelleuse generalised regressive sans hemorragie meningee apres un traumatisme ferme. J. beige de neurol. et de psychiat., 47:511-516. (521) Andre-Thomas, 1897. Le cervelet: Etude anatomique, clinique et physiologique. Paris: G. Steinheil.

(6, 21, 23, 25, 31, 42, 49, 64, 65, 97, 271, 308, 379, 417, 424, 459)

, 1905. Atrophie lamellaire des cellules de Purkinje. Rev. neurol., 13:917-924. (452) , 1911. La fonction cerebelleuse. In Encyclopedic scientifique. Paris: 0. Doin et Fils. (64, 379, 395) , 1915. Contribution a 1'etude semiologique des destructions partielles du cervelet par blessures de guerre. Rev. neurol., 28:1256-1264. (522) , 1918. Etudes sur les blessures du cervelet. Paris: Vigot Freres. (522) , 1932. Syndrome cerebelleux residuel a la suite d'une blessure remontant a 17 ans: Persistence de la passivite. Rev. neurol., 2:500-507. (522) and R. Cornelius, 1907. Un cas d'atrophie croisee du cervelet. Rev. neurol., 15:197-205. (464,465) Andre-Thomas and A. Durupt, 1914. Localisations cerebelleuses. Paris: Vigot Freres. (52, 53, 67, 68)

BIBLIOGRAPHICAL INDEX OF AUTHORS

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Andre-Thomas and Kononova, 1912. L'atrophie croisee du cervelet chez 1'adulte. Rev. neurol., 23: 321-327.(466) Andre-Thomas, Th. de Martel, and J. M. Guillaume, 1936. A propos d'un traumatisme du lobe frontal: Absence de symptomes cerebelleux et vestibulaires. Rev. neurol., 65:111-119. (406) Andre-van Leeuwen, M., J. Babel, L. van Bogaert, A. Franceschetti, D. Klein, and A. Montandon, 1948. Heredo-ataxies par degenerescence spino-ponto-cerebelleuse: Leurs manifestations retiniennes, optiques et cochleaires. Rapport du 14th Congres d'O. N. O. a Toulouse. Rev. d'otoneuro-opht., 20:1-230. (463, 467) Andre-van Leeuwen, M., and L. van Bogaert, 1942. Sur 1'atrophie optique heredo-familiale compliquee (Behr), forme de passage de 1'atrophie de Leber aux heredo-ataxies (premiere observation anatomique). Monatschr. f. Psychiat. u. Neurol., 105:314-350. (467) , 1949. Hereditary ataxia with optic atrophy of the retrobulbar neuritis type, and latent degeneration. Brain, 72:340-363. (467) Andrew, W., 1937. Effects of fatigue due to muscular exercise on Purkinje cells of mouse, with special reference to factor of age. Ztschr. f. Zellforsch. u. Mikr. Anat., 27:534-554. (492) Antognoli, G. C., 1936. Ascesso cerebellare d'origine naso-faringea (sindrome di Collet-Sicard). Riv. oto-neuro-oftal., 13:37-52. (507) Anton, G., 1903. Ueber einen Fall von beiderseitigen Kleinhirnmangel mit kompensatorischer Vergrosserung anderer Systeme. Wien. klin. Wchnschr., 16:1349-1354. (424) and H. Zingerle, 1914. Genaue Beschreibung eines Falles von beiderseitigem Kleinhirnmangel. Arch. f. Psychiat., 54:8-75. (424, 425, 426) Arana, R., and A. Asenjo, 1945. Ventriculographic diagnosis of cysticercosis of the posterior fossa. J. Neurosurg., 2:181-190. (508) Archambault, L., 1918. Parenchymatous atrophy of the cerebellum. J. Nerv. & Ment. Dis., 48:273312.(468, 454) Arduini, A., 1958. Unpublished experiments. , A. Borazzo, and A. Brusa, 1955. Potenziali evocati lenti nella corteccia cerebellare. Boll. Soc. ital. biol. sper., 31:815-816. (189, 216) Arduini, A., and G. C. Lairy-Bounes, 1952. Action de la stimulation electrique de la formation reticulaire du bulbe et des stimulations sensorielles sur les ondes strychniques corticales chez le chat "encephale isole." Electroencephalog. & Clin. Neurophysiol., 4:503-512. (179, 321) Arduini, A., F. Magni, and A. Roger, 1955. Effet de la stimulation iterative du nerf optique sur les ondes strychniques de 1'ecorce cerebrale. J. Physiol., Paris, 47:849-856. (179) Arduini, A., and G. Moruzzi, 1953. Sensory and thalamic synchronization in the olfactory bulb. Electroencephalog. & Clin. Neurophysiol., 5:235-242. (179) and C. Terzuolo, 1951. Elettronarcosi e cervelletto. Arch, fisiol, 50:328-348. (176) Arduini, A., and O. Pompeiano, 1956. Modificazioni delPattrivita di unita fastigiali prodotte da stimolazioni cortico-cerebellari sensitive. Boll. Soc. ital. biol. sper., 32:947-948. (172, 237, 352) , 1957. Microelectrode analysis of units of the rostral portion of the nucleus fastigii. Arch. ital. de biol., 95:56-70. (172, 238, 237-240, 352) Arieti, S., 1946. Histopathologic changes in cerebral malaria and their relation to psychotic sequels. Arch. Neurol. & Psychiat., 56:79-104. (481-482) Aring, C. D., 1938. Cerebellar syndrome in adult with malformation of the cerebellum and brain stem (Arnold-Chiari deformity), with note on the occurrence of "torpedoes" in the cerebellum. J. Neurol. & Psychiat., 1:100-109. (422, 423) , 1940. Degeneration of the basal ganglia associated with olivo-ponto-cerebellar atrophy. J. Nerv. & Ment. Dis., 92:448-470. (461, 476) and J. F. Fulton, 1936. Relation of the cerebrum to the cerebellum. II. Cerebellar tremor in the monkey and its absence after removal of the principal excitable areas of the cerebral cortex (area 4 and 6 a, upper part). III. Accentuation of cerebellar tremor following lesions of the premotor area (area 6 a, upper part). Arch. Neurol. & Psychiat., 35:439-466. (35, 37, 334-335, 337, 338, 357, 405, 466) Arnold, J., 1894. Myelocyste, Transposition von Gewebskeimen und Sympodie. Beitr. z. path. Anat. u. z. allg. Path., 16:1-28. (480-481) Asenjo, A., H. Valladares, and J. Fierro, 1951. Tuberculomas of the brain: Report of one hundred and fifty-nine cases. Arch. Neurol. & Psychiat., 65:146-160. (494, 495, 497) Asherson, N., 1942. The otogenic cerebellar abscess, with special reference to the posterior fossa cerebrospinal fluid syndrome. J. Laryng. and Otol., 57:129-156. II. Cerebellar abscess: Some case records. Ibid., pp. 225-249. III. The Otogenic cerebellar abscess: Its operative treatment and postoperative care. Ibid., pp. 281-310. (498, 499, 505, 506) , 1948. Cerebellar abscess, acute, otogenic: Note on early diagnosis and drainage with some case records. Ibid., 62:278-307. (506)

570

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

Askenasy, H., C. Arsenie, and M. Georgiade, 1939. Tumeur perlee du IVe ventricule: Intervention; guerison. Rev. neurol., 71:746-753. (557) Asratian, E. A., 1934. Zur Frage der autonomen Zentren im Gross- und Kleinhirn. (In German.) Proc. VI Caucasus Congress of Physiologists, Pharmacologists and Biochemists, October 11 to 17. 1934, pp. 23-25. Cited by Wiggers, 1943a. (806) , 1938. Beitrage zur Alterscharakteristik des Kleinhirns. (In Russian, with German summary.) Fiziol. zhur., 19:448-453. (361-363) , 1941. Influence of cerebellum and of cerebral cortex on the autonomic functions. (In Russian.) Nevropat. i. psikh., 10:35-39. Abstracted in Ber. ges. Physiol., 132:462, 1943. (306) Atav, N., 1948. Case of otogenous cerebellar abscess due to Proteus vulgaris. Acta med. turc., 1:3-6. (SOU Atkinson, E. M., 1934. Abscess of the Brain: Its Pathology, Diagnosis and Treatment. London: Med. Pub. Ltd. (499, 501-502, 503, 506) , 1938. Otogenous cerebellar abscess. Ann. OtoL, Rhin. & Laryng., 47:1020-1034. (499, 501, 502, 503, 505, 506) Aubin, Helene, 1941. Les tubercules du cervelet: Etude anatomo-clinique, prognostique et therapeutique. These #361, Paris. Paris: Libraire Le Francois. (495) Aubry, M., 1939. Un cas d'abces du cervelet de variete posterieure. Ann. d'oto-laryng., pp. 485-489. (501) Austin, G. M., W. W. Chambers, and W. F. Windle, 1949. Localization in anterior lobe of cerebellum of dog, with special reference to the placing reactions. Am. J. Physiol., 159:561. (31$) Babinski, J., 1902a. Sur le role du cervelet dans les actes volitionnels necessitants une succession rapide de mouvements. (Diadococinesie). Rev. neurol., 10:1013-1015. (392) , 1902b. De 1'equilibre volitionnel statique et de 1'equilibre volitionnel cinetique. Ibid., pp. 470-474.(386) and A. Tournay, 1913. Les symptomes des maladies du cervelet et leur signification. 17th Internat. Congress of Med., London, 11:1-58; see also Rev. neurol., 26:306-322. (379) Bach, L. M. N., and H. W. Magoun, 1947. The vestibular nuclei as an excitatory mechanism for the cord. J. Neurophysiol., 10:331-337. (118, 230) Bacon, A., 1949. Cerebellar extradural hematoma: Report of a case. J. Neurosurg., 6:78-81. (523) Bagchi, B. K., R. L. Lam, K. A. Kooi, and R. C. Bassett, 1952. EEG findings in posterior fossa tumors. Electroencephalog. & Clin. Neurophysiol., 1:23-40. (535) Bagdasar, D., 1929. Le traitement chirurgical des gommes cerebrales. Rev. neurol., 2:1-30. (497, 498) Baginsky, B., 1881. Ueber Untersuchungen des Kleinhirns. Arch. f. Anat. u. Physiol., Physiol. Abt., pp. 560-566.(23) , 1882-1883. Ueber die Funktionen des Kleinhirns. Biol. Centralbl., 2:725-734. (23, 109) Bagley, C., Jr., and G. W. Smith, 1951. Unilateral cervical displacement of cerebellum associated with basilar impression, producing signs of high cervical cord tumor. Ann. Surg., 133:874-885. (419) Bagnoli, E., 1942. Ricerche sulle localizzazioni cortical! cerebellari nel coniglio. Boll. Soc. ital. biol. sper., 17:539-540. (69) Bailey, P., 1920. Cruveilhier's "Tumeurs perlees." Surg. Gynec. & Obst., 31:390-401. (557) , 1924a. Concerning the cerebellar symptoms produced by suprasellar tumors. Arch. Neurol. & Psychiat., 11:137-150. (403) , 1924b. Further observations on pearly tumors. Arch. Surg., 8:524-534. (557) , 1930. Further notes on cerebellar medulloblastomas: The effect of roentgen radiation. Am. J. Path., 6:125-136. (547) , 1932. Cellular types in primary tumors of the brain. In W. Penfield, Cytology and Cellular Pathology of the Nervous System, chap. 8, pp. 905-951. New York: Paul B. Hoeber, Inc. (536) , 1933. Intracranial Tumors. Springfield, 111.: Charles C. Thomas. (381, 527, 537, 538, 546, 548, 553, 556, 559, 562) , 1942. Reflections aroused by an unusual tumor of the cerebellum. J. Mt. Sinai Hosp., 9:299310. (378, 381, 385, 386, 388, 561) •, 1944. The relationship to the cerebellum. In P. C. Bucy, The Precentral Motor Cortex, chap. 10, pp. 279-291. Urbana: Univ. of Illinois Press. (378, 381, 388) , D. C. Buchanan, and P. C. Bucy, 1939. Intracranial Tumors of Infancy and Childhood. Chicago: Univ. of Chicago Press. (527, 529, 532, 538, 539, 540, 542, 544, $45, 549) Bailey, P., and P. C. Bucy, 1929. Oligodendrogliomas of the brain. J. Path, and Bact., 32:735-751.

(651)

, 1930. Astroblastoma of the brain. Acta psych, et neurol. Scandinav., 5:439-461. (549) Bailey, P., and H. Gushing, 1925. Medulloblastoma cerebelli: A common type of midcerebellar glioma of childhood. Arch. Neurol. & Psychiat., 14:192-224. ($41, 543, 546, 548)

BIBLIOGRAPHICAL INDEX OF AUTHORS

571

, 1926. A Classification of the Tumors of the Glioma Group on a Histogenic Basis with a Correlated Study of Prognosis. Philadelphia: J. B. Lippincott Co. (527, 547, 51*9, 551) Baker, A. B., 1940. Intracranial tumors: A study of 467 histological verified cases. Minnesota Med., 23:696-703.(549) and S. Corn well, 1954. Poliomyelitis. X. The cerebellum. Arch. Neurol. & Psychiat., 71:455465.(484) Baker, A. B., and F. Y. Tichy, 1953. The effects of the organic solvents and industrial poisonings on the central nervous system. A. Research Nerv. & Ment. Dis., Proc., 32:475-505. (487) Baker, R. C., and G. O. Graves, 1931. Cerebellar agenesis. Arch. Neurol. & Psychiat., 25:548-555. (429, 430, 434) , 1936. Partial cerebellar agenesis in dog. Ibid., 36:593-600. (430) Bakker, S. P., 1924. Atrophia olivo-pontocerebellaris. Ztschr. f. d. ges. Neurol. u. Psychiat., 89:213246.(461) Balogh, K., 1876a. Untersuchungen iiber die Funktionen der Grosshirnhemispharen u. des kleinen Hirns. (In Hungarian.) Sitzungsb. d.k. ungar. Akad. der Wissensch., vol. 8. Cited by Hermann, 1876. (109,138, 291) , 1876b. Untersuchungen iiber den Einfluss des Gehirns auf die Herzbewegungen. (In Hungarian.) Ibid., VII, vol. 8. German summary in Jahresb. u.d. Fortschr. d. Anat. u. Physiol., 5:38-39. (109,138, 291) Ban, T., K. Inoue, S. Ozaki, and T. Kurotsu, 1956. Interrelation between anterior lobe of cerebellum and hypothalamus in rabbit. Med. J. Osaka Univ., 7:101-115. (299) Barany, R., 1912a. Beziehungen zwischen Bau und Funktion des Kleinhirns nach Untersuchungen am Menschen. Wien. klin. Wchnschr., 25:1737-1739. (272) , 1912b. Lokalisation in der Rinde der Kleinhirnhemispharen des Menschen. Ibid., pp. 20332038. (272, 395, 396, 398) , 1912c. Weitere Untersuchungen und Erfahrungen iiber die Beziehungen zwischen Vestibularapparat und Zentralnervensystem. Wien. med. Wchnschr., 62:3209-3213, 3282-3287. (272-) , 1913. Lokalisation in der Rinde der Kleinhirnhemispharen. Deutsche med. Wchnschr., 39:637642.(272) , 1914. Untersuchungen iiber die Funktion des Flocculus am Kaninchen. Jahrb. f. Psychiatr. u. Neurol., 26:631-651. (113,139) , 1924. Localisations dans 1'ecorce de 1'hemisphere du cervelet humain. Rev. d'oto-neuro-ocul., 2:23-40. (396, 398) , Z. Reich, and J. Rothfeld, 1912. Experimented Untersuchungen iiber die vestibularen Reaktionsbewegungen an Tieren, insbesondere im Zustande der decerebrate rigidity. Neurol. ZentraM, 31:1139-1146. (273) Bard, P., 1928. A diencephalic mechanism for the expression of rage with special reference to the sympathetic nervous system. Am. J. Physiol., 84:490-515. (295) , 1933. Studies on the cerebral cortex. I. Localized control of placing and hopping reactions in the cat and their normal management by small cortical remnants. Arch. Neurol. & Psychiat., 30:40-74. (336, 339, 340, 342) , 1938. Studies on the cortical representation of somatic sensibility. Bull. New York Acad. Med., 14:585-607. (340) , C. N. Woolsey, R. S. Snider, V. B. Mountcastle, and R. B. Bromiley, 1947. Delimitation of central nervous mechanisms involved in motion sickness. Federation Proc., 6:72. (54, 271, 805, QQQ \ <8o3)

Barnard, J. W., and C. N. Woolsey, 1950. Interconnections between the anterior lobe and the paramedian lobule of the cerebellum. Anat. Rec., 106:173-174. (235) Barraquer-Nordas, L., and A. Lowenthal, 1953. Le syndrome cerebelleux preterminal des carcinoses. Monatschr. f. Psychiat. u. Neurol., 125:239-260. (456) Barrington, F. J. F., 1921. The relation of the hind-brain to micturition. Brain, 44:23-53. (305306) Barten, H., 1934. Eine seltene Fehlbildung des Kleinhirns. Beitr. z. path. Anat. u. z. allg. Path., 93:219-237. (441, 552) Bartorelli, C., 1941. Localizzazioni cerebellari e cronassia di subordinazione. Arch, fisiol., 41:362410.(264) , 1947. Recherches electrocardiographiques sur 1'allure de la frequence cardiaque pendant et apres la stimulation du cervelet chez le chat thalamique. Proc. XVII Internat. Congress Physiol., Oxford, pp. 105-107. (896, 304) Baryshnikow, I. A., 1946. Influence of extirpation of the cerebellum on the basal metabolism. (In Russian, with English summary.) Fiziol. zhur., 32:213-221. (303)

572

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

Batini, C., G. Moruzzi, and O. Pompeiano, 1956a. Origine e meccanismi di compensazione dei fenomeni dinamici di Luciani. R. C. Accad. Lincei, 21:474-479. (£68, 276, 277, 279, 281-282, 283, 284, 286-287, 337, 338, S5S) , 1956b. Component! labirintiche ed estralabirintiche nelle manifestazioni spastiche del gatto decerebrato e decerebellato. Ibid., 21:328-332. (262, 276, 277, 279, 281-282, 283, 284, 285-287, 337, 338, 353) , 1957. Cerebellar release phenomena. Arch. ital. de biol, 95:71-95. (262, 276-279, 281-282, £83, 28^, 285-287,337, 338, 353) Batini, C., and O. Pompeiano, 1955a. Sugli effetti di distruzioni croniche, parziali o totali, del nucleo del tetto nel gatto. Boll. Soc. ital. biol. sper., 31:805-807. (78, 80, 85, 100, 268, 332, 352, 353) , 1955b. Meccanismi corticali e sottocorticali nella compensazione funzionale dell'atonia fastigiale cronica. Ibid., pp. 1223-1225. (78, 85, 332, 353) , 1957. Chronic fastigial lesions and their compensation in the cat. Arch. ital. de biol., 95:147165. (78, 79, 85,100, 268, SS2, 362, 353) , 1958a. Opposte influenze esercitate sul tono posturale dalle porzioni rostro-mediali e rostrolateral! del nucleo del tetto. R. C. Accad. Lincei, in press. (86, 237) , 1958b. Effects on decerebrate rigidity of rostro-medial and rostro-lateral fastigial lesions. To be published in Arch. ital. de biol. (86, 237) Batten, F. E., 1903. On the diagnostic value of the position of the head in cases of cerebellar disease. Brain, 26:71-80. (38£) , 1905. Ataxia in childhood. Ibid., 28:484-505. (429, 460) Baudelot, M. E., 1864. Recherches experimentales sur les fonctions de 1'encephale chez les poissons. Ann. d. sc. nat., 1:105-112. (10) Bauer, J., and R. Leidler, 1912. Ueber den Einfluss der Ausschaltung verschiedener Hirnabschnitte auf die vestibularen Augenreflexe. Arb. a. d. neurol. Inst. a. d. Wien. Univ., 19:155-226. (287, 288) Baumgarten, R. von, and A. Mollica, 1954. Der Einfluss sensibler Reizung auf die Entladungsfrequenz kleinhirnabhangiger Reticulariszellen. Arch. f. d. ges. Physiol., 259:79-96. (221, 223, 225-226, 248) and G. Moruzzi, 1954. Modulierung der Entladungsfrequenz einzelner Zellen der Substantia reticularis durch corticofugale und cerebellare Impulse. Arch. f. d. ges. Physiol., 259:56-78. (175, 221-224, 248, 251, 318, 350, 356) Bazett, H. C., and W. G. Penfield, 1922. A study of the Sherrington decerebrate animal in the chronic as well as the acute condition. Brain, 45:185-265. (275, 283, 284, 346) Bechterew, W. von, 1883. Ergebnisse der Durchschneidung des N. acusticus, nebst Erorterung der Bedeutung der semicircularen Canale fur das Korpergleichgewicht. Arch. f. d. ges. Physiol., 30:312-347. (289) , 1884. Ueber die Verbindung der sogenannten peripheren Gleichgewichtsorgane mit dem Kleinhirn. Ibid., 34:362-388. (6) , 1896. Ueber die Empfindungen, welche mittels der sogenannten Gleichgewichtsorgane wahrgenommen werden, und iiber die Bedeutung dieser Empfindungen in Bezug auf die Entwickelung unserer Raumvorstellungen. Arch. f. Anat. u. Physiol., Physiol. Abt., pp. 105-141. (6) , 1909. Die Funktionen der Nervencentra. Vol. 3, pp. 816-995. Jena: Fischer. (38, 88, 272, 291292, 306, 308) Beck, A., and G. Bikeles, 1911. Zur Frage der Erregbarkeit der Kleinhirnrinde. Zentralbl. f. Physiol., 25:1066-1067.(Ill) , 1912a. Versuche iiber die gegenseitige funktionelle Beeinflussung von Gross- und Kleinhirn. Arch. f. d. ges. Physiol., 143:283-295. (7, 159, 309) , 1912b. Versuche iiber die sensorische Funktion des Kleinhirnmittelstucks (Vermis). Ibid., pp. 296-302. (7,159,189, 204, 323) , 1914. Zur Erregbarkeit der Kleinhirnrinde vermittels Strychnins nach Baglioni. Zentralbl. f. Physiol., 28:195-196. (106, 111) , 1914-1915. Ueber den Einfluss der Kuhlung auf die Erregbarkeit der Grosshirnrinde einerseits und der Kleinhirnrinde anderseits. Ibid., 29:1-2. (104) Beck, G. M., 1927. The cerebellar terminations of the spinocerebellar fibers of the lower lumbar and sacral segments of the cat. Brain, 50:60-98. (198) Bell, J., and E. A. Carmichael, 1939. On hereditary ataxia and spastic paraplegia. In The Treasury of Human Inheritance, vol. 4, pt. 3. London: Cambridge Univ. Press. (467, 472, 473) Bellavitis, C., 1923. Contribute alTanatomia patologica della sindrome di Unverricht. (Policlonia ed Epilessia.) Note e riv. di psichiat., 11:459-478. (41%) Seller, A. J., and E. Peyser, 1952. Extradural cerebellar hematoma. Report of three cases with re- • view of the literature. J. Neurosurg., 9:291-298. (523, 524, 525) Benda, C. E., 1952. Developmental Disorders of Mentation and Cerebral Palsies. New York: Grune & Stratton. (417, 4$3,4SS)

BIBLIOGRAPHICAL INDEX OF AUTHORS

573

Bender, L., 1927. An experimental study of the cerebellar control of the vocal organs. Proc. Akad. Wetensch., Amsterdam, 30:715-723. (61) , 1928. The cerebellar control of the vocal organs. Arch. Neurol. & Psychiat., 19:796-833. (61) Bender, M. B., M. Nathanson, and G. G. Gordon, 1952. Myoclonus of muscles of the eye, face, and throat. Arch. Neurol. & Psychiat., 67:44-58. (413) Bergstrand, H., 1932. Ueber das sog. Astrocytom im Kleinhirn. Virchows Arch. f. path. Anat., 287:538-548. (539, 541) , 1937. Weiteres iiber sogenannte Kleinhirnastrocytome. Ibid., 299:725-739. (639, 541) , H. Olivecrona, and W. Tonnis, 1936. Gefassmissbildungen und Gefassgeschwiilste des Gehirns. Leipzig: G. Thieme. (553, 554) Beritashvili, I., and L. Tzkipuridse, 1945. The bioelectric activity of the cerebellum and its alteration under the influence of various external stimulations. Bull. Georg. Acad. Sci., SSSR. Cited by von Buddenbrock, 1953, p. 317. (160) Beritoff, J. S., and R. Magnus, 1914. Zusatz bei der Korrektur. Arch. f. d. ges. Physiol., 159:249-250. See also Magnus, 1914. (26-27, 81, 99) Bernales, S. E., and E. Encinas, 1943. Cistercosis cerebral con sintomatologia de tumor con localization a predominio ponto-cerebelosa. Rev. neuro-psiquiat., 6:1-57. (508) Bernard, C., 1858. Lecons sur la physiologic et la pathologic du systeme nerveux. Vols. 1, 2. Paris: J. B. Bailliere. (23, 290, 301, 305) Bernis, W. J., and E. A. Spiegel, 1925. Die Zentren der statischen Innervation und ihre Beeinflussung durch Klein- und Grosshirn. Arb. a. d. neurol. Inst. a. d. Wien. Univ., 27:197-224. (104, US, 137, 149,150,153, 230, 335) Bert, P., 1875. Sur le mecanisme et les causes des changements de couleur chez le cameleon. Comp. rend. Acad. d. sc., 81:938-991. (13) Bertrand, I., and J. Godet-Guillain, 1942a. Etude anatomo-clinique d'un cas d'atrophie lamellaire cerebelleuse. Rev. neurol., 74:287. (455, 456) , 1942b. Degenerescences cerebelleuses latentes chez les cancereux. Compt. rend. Soc. de biol., 136:664-665. (485) Bertrand, I., C. Medynski, and P. Salles, 1936. Etude d'un cas d'agenesie du vermis cerebelleux chez le chien. Rev. neurol., 66:716-733. (430) Bertrand, I., and F. Smith, 1933. Sur une type speciale d'atrophie croisee du cervelet. Rev. neurol., 2:554-565.(406) Besedovsky, Y., and M. Turner, 1947. Sindrome cerebeloso post-coqueluchoso. Rev. Soc. pediat. d. literal, 12:9-14. (488) Bethe, A., 1899. Die lokomotion des Haifisches (Scyllium) und ihre Beziehungen zu den einzelnen Gehirntheilen und zum Labyrinth. Arch. f. d. ges. Physiol., 76:470-493. (10) Beyer, H., and M. Lewandowski, 1906. Experimentelle Untersuchungen am Vestibularapparat von Saugetieren. Arch. f. Anat. u. Physiol., Physiol. Abt., pp. 451-464. (273) Beyerman, W., 1917. Ueber angeborene Kleinhirnstorungen. Arch. f. Psychiat., 57:610-658. (450) Bianchi, L., 1882. Contribuzione sperimentale alle compensazioni funzionali cortical! del cervello. Riv. sper. di freniat., 8:431-440. (23, 329, 330) Bianconi, R., 1953. Effetti dell'estirpazione del cervelletto sulla attivita spinale riflessa nella rana. Boll. Soc. ital. biol. sper., 29:235-236. (13) Bickel, A., 1901. Beitrage zur Gehirnphysiologie der Schildkrote. Arch. f. Anat. u. Physiol., Physiol. Abt., pp. 52-80. (13) Bickers, D. S., E. W. Peterson, and J. Scherrer, 1949. Observations on progressively reduced nervous system in cats. Am. J. Physiol., 159:562. (58) Bielschowsky, M., 1914. Ueber spatinfantile familiare amaurotische Idiotic mit Kleinhirnsymptomen. Deutsche Ztschr. f. Nervenh., 1:7-29. (474) , 1920. Zur Histopathologie und Pathogenese der amaurotischen Idiotie mit besonderer Beriicksichtigung der zerebellaren Veranderungen. J. f. Psychol. u. Neurol., 26:123-199. (423, 474) Biemond, A., and S. van Creveld, 1939a. Cerebellar form of encephalopathy due to lead poisoning. Nederl. tijdschr. v. geneesk., 83:16-23. (486) , 1939b. On the cerebellar form of saturnine encephalopathy. Acta paediat., 27:51-62. (486) Bikeles, G., and L. Zbyszewski, 1914-1915. Ueber den Einfluss von Kocain auf die Erregbarkeit der psychomotorischen Region einerseits und der Kleinhirnrinde anderseits. Zentralbl. f. Physiol., 29:3-4. (104) Billia, P., 1952. Importanza dell'intensita dell'eccitamento vestibolare nei riguardi dei riflessi labirintici dopo lesione cerebellare. Boll. Soc. ital. biol. sper., 28:1385-1386. (287) Bing, R., 1906. Experimentelles zur Physiologic der Tractus spino-cerebellares. Arch. f. Anat. u. Physiol., Physiol. Abt., pp. 250-270. (88-89)

574

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

, 1907. Die Bedeutung der spino-cerebellaren Systeme. Wiesbaden: J. F. Bergmann. (88-89) Bing, R. L., B. McNamara, and F. H. Hopkins, 1946. Studies on pharmacology of DDT (2,2,bispara-chlorophenyl-1,1,1 trichloroethane) chronic toxicity of DDT in dog. Bull. Johns Hopkins Hosp., 78:308-315. (487) Binnerts, A., 1908. Over localisatie van functies in het cerebellum. Acad. prefschr., Amsterdam, 8:153. Cited by van Rijnberk, 1912. (71) Birnbaum, G., 1941. Chronisch-progressive chorea mit Kleinhirnatrophie. Arch. f. Psychiat., 114:160182.(402) Bodart, A., 1935. Gomme intracerebelleuse caseifiee a symptomatologie dementielle et tumorale. J. beige de neurol. et de psychiat., 35:33-41. (498) Bodechtel, G., 1933. Der hypoglykamische Shock und seine Wirkung auf das Zentralnervensystem, zugleich ein Beitrag zu seiner Pathogenese. Deutsches Arch. f. klin. Med., 175:188-201. (490) Bogaert, A. van, and L. van Bogaert, 1936. A propos des alterations de 1'electrocardiogramme dans la maladie de Friedreich. Arch. d. mal. du coeur, 29:630-642. (466) Bogaert, L. van, 1926. Syndrome de la calotte protuberantielle avec myoclonie localisee et troubles du sommeil. Rev. neurol., 1:977-988. (413) , 1934. Symptomes oculaires et cerebellovestibulaires dans 1'oedeme angioneurotique de Quincke. Rev. d'oto-neuro-opht., 12:321-327. (485) , 1947. Sur une atrophie cerebelleuse tardive du type Marie-Foix-Alajouanine hereditaire et familiale avec une atrophie pallidale partielle cliniquement muette. J. beige de neurol. et de psychiat., 47:268-286. (449, 460, 467) , 1950a. Sur une encephalite cerebelleuse chez deux jeunes chats. Folia psychiat., neurol. et neurochir. neerl., 53:167-171. (484-485) , 1950b. Situation de certains tremblements, syndromes dystoniques et cerebelleux heredofamiliaux, a 1'egard des processus abiotrophiques et vasculaires de 1'involution. Medicina clinica, 15:209-220. (467) , 1951a. Les heredodegenerescences spino-cerebelleuses. Acta neurol. et psychiat. belg., 51:621647. (467, 468-469) , 1951b. Sur ces formes d'heredoataxie de 1'enfant et de 1'adolescent qui comportent une atteinte grave des noyaux moteurs spino-bulbo-mesencephaliques. Rev. neurol., 84:121-130. (467) and I. Bertrand, 1928. Sur les myoclonies associees synchrones et rythmiques par lesions en foyer du tronc cerebral. Rev. neurol., 1:203-214. (413) , 1929. Une variete d'atrophie olivo-pontine a evolution subaigue avec troubles dementiels. Ibid., 1:165-178. (461, 462) , 1932. Sur une forme hyperspasmodique de 1'atrophie cerebelleuse tardive. Ibid., 2:55-65. (458, 453) Bogaert, L. van, and M. Dallemague, 1943. Sur une atrophie cerebelleuse corticale observee chez le singe dans 1'intoxication par aerosols manganeux. (Note preliminaire.) Bull. Acad. roy. de med. de Belgique, 8:99-121. (486) Bogaert, L. van, M. David, J. de Ajuriaguerra, H. Hecaen, and R. Talairach, 1951. D'un syndrome degeneratif du groupe de la dystonie a debut cerebelleux correspondent a une abiotrophie spino-striee avec degenerescence du systeme olfactif. Monatschr. f. Psychiat. u. Neurol., 121: 143-162. (468) Bogaert, L. van, and J. R. M. Innes, 1950. Cerebellar disorders in lambs; a study in animal neuropathology with some comments on ovine neuroanatomy. Arch. Path., 50:36-62. (450-451) Bogaert, L. van, and P. Martin, 1928. Les tumeurs du quatrieme ventricule et le syndrome cerebelleux de la ligne mediane. (Etudes cliniques, histopathologiques et chirurgicales.) Rev. neurol., 2:431-483. (403) Bogaert, L. van, and H. J. Scherer, 1936. Zur Frage der Beziehungen von Pallidum- und Kleinhirnlasionen zum Syndrom der Drehbewegungen um die Korperachse. Monatschr. f. Psychiat. u. Neurol., 93:140-165. (467) Bohm, E., 1953. An electro-physiological study of the ascending spinal anterolateral fibre system connected to coarse cutaneous afferents: A spino-bulbo-cerebellar system. Acta physiol. Scandinav., 29, suppl. 106:106-137. (198-199) Bolk, L., 1902a. Hauptziige der vergleichenden Anatomic des Cerebellums der Saugetiere mit besonderer Beriicksichtigung des menschlichen Kleinhirns. Monatschr. f. Psychiat. & Neurol., 12:432-467. (50) , 1902b. Hoofdlynen der vergelykende anatomie van het cerebellum der zoogdieren, voornamelyk in verband met den bouw van de kleine hersenen van den mensch. Psychiat. en neurol. bl., 6:175-217. (50) , 1904-1906. Das Cerebellum der Saugetiere: Eine vergleichende anatomische Untersuchung. Nederl. bydragen anat. 3:1-136, 137-250 (1904); 4:251-330 (1906). (50)

BIBLIOGRAPHICAL INDEX OF AUTHORS

575

, 1906. Das Cerebellum der Saugetiere: Eine vergleichende anatomische Untersuchung. Haarlem: Fisher. (50, 379, 396) Bonhoeffer, K., 1897. Ein Beitrag zur Lokalisation der choreatischen Bewegungen. Monatschr. f. Psychiat. u. Neurol., 1:6-41. (402) , 1908. Ueber den Einfluss des Cerebellums auf die Sprache. Monatschr. f. Psychiat. u. Neurol., 24:379-382. (394) Bonnet, V., and F. Bremer, 1951. Auditory responses of the cerebellum. J. Physiol., 114:P54-55. (178,198,811,816) Bonnevie, Kristine, 1943. Hereditary hydrocephalus in the House Mouse. I. Manifestation of the hy-mutation after birth in embryos 12 days old or more. Norske Vid. Akad. Oslo, Skr. I, Mat. Naturv. Kl., no. 4. (430, 431) , 1944. Hereditary hydrocephalus in the House Mouse. III. Manifestation of the hy-mutation in embryos 9-11 days old, and younger. Ibid., no. 10. (430, 431) and A. Brodal, 1946. Hereditary hydrocephalus in the house mouse. IV. The development of the cerebellar anomalies during foetal life with notes on the normal development of the mouse cerebellum. Norske Vid. Akad. Oslo, Skr. I, Mat. Naturv. KL, no. 4. (430, 433) Bonvallet, M., P. Dell, and G. Hiebel, 1954. Tonus sympathique et activite electrique corticale. Electroencephalog. & Clin. Neurophysiol., 6:119-144. (141) Boogard, J. A., 1865. Basilar impression: Its causes and consequences. Nederl. tijdschr. v. geneesk., 1:81. (418) Borgherini, A., 1888. Contributo alia fisiopatologia del cervelletto. Riv. sper. di freniat., 14:81-110. (23) , 1891. Schlafahnlicher Zustand bei Thieren, denen das Kleinhirn entfernt wurde. Neurol. Zentralbl, 10:649-653. (23, 349) and G. Gallerani, 1891. Contribuzione allo studio dell'attivita funzionale del cervelletto: Lavoro sperimentale. Riv. sper. di freniat., 17:231-262. (23, 305) 1892. Contribution a 1'etude de 1'activite fonctionnelle du cervelet. Arch. ital. de biol., 17:64-70. (23, 305, 349) Bostroem, A., and H. Spatz, 1928. Bindearmatrophie bei idiopathischer Athetose. Zentralbl. f. d. ges. Neurol. u. Psychiat., 48:560-561. (463) Bostroem, E., 1897. Ueber die pialen Epidermoide, Dermoide und Lipome und duralen Dermoide. Centralbl. f. allg. Path. u. path. Anat., 8:1-98. (557) Botterell, E. H., and J. F. Fulton, 1936. Relations of the cerebrum to the cerebellum. IV. Functions of the paleo and neocerebellum in chimpanzees and monkeys. Tr. Am. Neurol. A., 62:172. (66, 99, 388) , 1938a. Functional localization in the cerebellum of primates. I. Unilateral section of the peduncles. J. Comp. Neurol., 69:31-46. (47-48, 383) , 1938b. Functional localization in the cerebellum of primates. II. Lesions of the midline structures (vermis) and deep nuclei. Ibid., pp. 47-61. (50, 53, 77, 87, 383) , 1938c. Functional localization in the cerebellum of primates. III. Lesions of hemispheres (neocerebellum). Ibid., pp. 63-87. (47, 66, 87, 99, 383) -, 1938d. Functional localization in the cerebellum of primates. IV. "Hypotonia" and "ataxia" following lesions of the cerebellum in the chimpanzee. Unpublished observations; see Fulton and Dow, 1937, and Fulton, 1949. (48, 66) Bouillaud, J., 1827. Recherches experimentales tendant a prouver que le cervelet preside aux actes de la station et la progression et non a 1'instinct de la propagation. Arch. gen. de med., 15:64-91. (14, 23,109) Boyce, R., 1895. A contribution to the study of descending degenerations in the brain and spinal cord, and of the seat of origin and paths of conduction of the fits in absinthe epilepsy. Philos. Tr., Roy. Soc., s. B, 186:321-382. (329) Boyd, W., 1912. A case of cerebral and crossed cerebellar hemiatrophy. Rev. Neurol. & Psychiat., 10:318-325. (464, 465) Bradford, F. K., 1948. Hemangioblastoma of posterior fossa (Lindau's disease): Report of two cases with familial history. J. Neurosurg., 5:196-201. (554) Brain, W. R., 1925. The mode of inheritance of hereditary ataxia. Quart. J. Med., 18:351-358. (473) , 1926. On the rotated or "cerebellar" posture of the head. Brain, 49:61-76. (882, 383) Brain, W. R., P. M. Daniel, and J. G. Greenfield, 1951. Subacute cortical cerebellar degeneration and its relation to carcinoma. J. Neurol., Neurosurg. & Psychiat., 14:59-75. (452, 455, 456, 457, 458, 485) Bremer, F., 1922a. Contribution a 1'etude de la physiologic du cervelet: La fonction inhibitrice du paleocerebellum. Arch, internat. de physiol., 19:189-226. (26-27, 49, 51, 60, 61, 99, 104, 106, 114116, 118, 119, 123, 126, 134, 135, 138, 148, 149, 150, 153, 154, 155, 156, 259, 264, 281, 339, 340, S72, 378, 386)

576

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM , 1922b. La strychnine et les phenomenes d'inhibition. Compt. rend. Soc. de biol., 87:10551057. (115,118, 124, ISO) , 1924. Recherches sur la physiologic du cervelet chez le pigeon. Ibid., 90:381-384. (15, 21, 96, 106) , 1925. Recherches sur le mecanisme de Faction de la strychnine sur le systeme nerveux. I. La strychnine et les phenomenes d'inhibition. Arch, internat. de physiol., 25:131-152. (115, 118,

124, iso)

, 1928. De Fexageration des reflexes, consecutives a la section des racines posterieures. Ann. de physiol., 4:750-752. (147, 257, 280, 290) , 1932. Le tonus musculaire. Ergebn. d. Physiol., 34:678-740. (60, 75, 279, 308) , 1935. Le cervelet. In G. H. Roger and L. Binet, Traite de physiologic normale et pathologique, vol. 10, pt. 1-2. Paris: Masson. (W, 38,43, 49, 51, 57, 64, 65, 66, 95, 99, 115, 138, 139, 269, 311, 339, 340 352, 363, 354, 355, 369, 372, 378, 379, 388) , 1938. L'activite electrique de Fecorce cerebrale et le probleme physiologique du sommeil. Boll. Soc. ital. biol. sper., 13:271-290. (241) , 1941. Le tetanos strychnique et le mecanisme de la synchronisation neuronique. Arch, internat. de physiol., 51:211-260. (128) , 1943. Etude oscillographique des reponses sensorielles de 1'aire acoustique corticale chez le chat. Arch, internat. de physiol., 53:53-103. (179) , 1952a. Analyse oscillographique des reponses sensorielles des ecorces cerebrale et cerebelleuse. Rev. neurol., 87:65-92. (156, 157, 211, 2U, 216) 1952b. Considerations sur le probleme de 1'inhibition centrale. Schweiz. med. Wchnschr., 82:974-977. (166,156, 252) , 1952c. Les reponses sensorielles de 1'ecorce cerebelleuse: Essai d'intepretation physiologique. Colloquio cientifico international de Madrid. (Cajal's symposium held November 14 to 20, 1952.). To be published. (211, 214, 216) and V. Bonnet, 1951a. Caracteres generaux de la reponse du cervelet a une voice d'influx afferents. J. Physiol., Paris, 43:662-665. (211, 216) , 1951b. Convergence et interaction des influx afferents dans 1'ecorce cerebelleuse, principe fonctionnel du cervelet. Ibid., pp. 665-667. (192, 216-217, 250, 251, 309) , 1953. Action de la strychnine sur les reponses sensorielles et sur les potentiels electriques spontanes de 1'ecorce cerebelleuse: L'activite convulsive du cervelet. Folia psychiat., neurol. et neurochir. neerl., 56:438-446. (178-179, 180-181, 211, 212, 214, 216) Bremer, F., and J. Brihaye, 1948. Etude des effets de 1'excitation du cervelet de 1'oiseau. Comp. rend. Soc. de biol., 142:1445-1446. (106, 156, 157) Bremer, F., and B. E. Gernandt, 1954. A micro-electrode analysis of the acoustic response and the strychnine convulsive patterns of the cerebellum. Acta physiol. Scandinav., 30:120-136. (178, 180,181, 211) Bremer, F., and R. Ley, 1927. Recherches sur la physiologie du cervelet chez le pigeon. Arch, internat. de physiol., 28:58-95, and Bull. Acad. roy. de med. de Belgique, 7:60-101. (15, 16, 17, 21, 60, 61, 96, 106, 109, 151, 282) Bremer, F., and J. Titeca, 1927. Mecanisme de Faction elective du curare sur le tonus postural et les hypertonies. Compt. rend. Soc. de biol., 97:1407-1411. (76, 118, 242) , 1931. Nouvelles recherches sur le mecanisme de Fatonie curarique. Ibid., 107:253-257. (76, 118) , 1935. Atonic curarique et inhibition de Wedensky. Arch, internat. de physiol., 42:223-250. (76,118) and L. van der Meiren, 1927. Action elective du curare a faibles doses sur le tonus musculaire. Compt. rend. Soc. de biol., 96:704-707. (75, 118, 292) Bremer, F. W., 1927. Die pathologisch-anatomische Begriindung des Status dysraphicus. Deutsche Ztschr. f. Nervenh., 99:104-123. (419) Bremme, H., 1919. Ein Beitrag zur Bindearmchorea. Monatschr. f. Psychiat. u. Neurol., 45:107120.(402) Breuer, R., and O. Marburg, 1902. Zur Klinik und Pathologic der apoplectiformen Bulbar-paralyse. Arb. a. d. neurol. Inst. a. d. Wien. Univ., 9:181-250. (511) Brihaye, J., 1953. Contribution a Fetude de la double action, inhibitrice et dynamogene, du cortex paleocerebelleux. Arch, internat. de physiol., 61:145-184. (106, 118, 119, 122, 128, 130-131, 137, 156) Brill, N. Q., and V. L. Pellicano, 1943. Estivoautumnal malaria with frontal lobe syndrome. J.A.M.A., 121:1150-1152. (480) Brock, S., and D. A. Klenke, 1931. Case of dermoid overlying the cerebellar vermis, with a review of literature on intracranial dermoids. Bull. Neurol. Inst. New York, 1:328-342. (557)

BIBLIOGRAPHICAL INDEX OF AUTHORS

577

Brodal, A., 1940. Experimentelle Untersuchungen iiber die olivocerebellare Lokalisation. Ztschr. f. ges. Neurol. u. Psychiat., 169:1-153. (75, 246) ; 1943. The cerebellar connections of the nucleus reticularis lateralis (nucleus funiculi lateralis) in rabbit and cat. Experimental investigations. Acta psychiat. et neurol., 18:171-233. (195, 198) , 1945. Partial defective development of the cerebellar vermis (partial agenesis) in a child. Norske Vid. Akad. Oslo, Skr. I, Mat. Naturv. Kl., no. 3, pp. 1-40. (430, 432-433)

•

, 1946. Correlated changes in nervous tissues in malformations of central nervous system. J. Anat., 80:88-93. (433, 434) , 1948. Neurological Anatomy in Relation to Clinical Medicine. Oxford: Clarendon Press. (333) , 1949. Spinal afferents to the lateral reticular nucleus of the medulla oblongata in the cat: An experimental study. J. Comp. Neurol., 91:259-295. (195, 198, 250) , 1953. Reticulo-cerebellar connections in the cat: An experimental study. Ibid., 98:113-153. (829, 247) , 1957. Personal communication. (349)

, Kristine Bonnevie, and W. Harkmark, 1944. Hereditary hydrocephalus in the house mouse. II. The anomalies of the cerebellum: Partial defective development of the vermis. Norske Vid. Akad. Oslo, Skr. I, Mat. Naturv. KL, no. 8, pp. 1-42. (430, 431, 432, 433, 434) Brodal, A., and J. Jansen, 1943. Ekxperimentelle unders0kelser over de ponto-cerebellaren forbindelser hos Katt og Kanin. Norske Vid. Akad., Avh. I, Mat. Naturv. KL, no. 10, pp. 1-27. Cited by Jansen and Brodal, 1954. (202,247) , 1946. The ponto-cerebellar projection in the rabbit and the cat: Experimental investigations. J. Comp. Neurol., 84:31-118. (75, 202, 247, 417) Brodal, A., and G. F. Rossi, 1955. Ascending fibers in brain stem reticular formation of cat. Arch. Neurol. & Psychiat., 74:68-87. (349) Brodal, A., Th. Szabo, and A. Torvik, 1956. Corticofugal fibers to sensory trigeminal nuclei and nucleus of solitary tract: An experimental study in the cat. J. Comp. Neurol., 106:527-555. (348) Brodal, A., and A. Torvik, 1954. The cerebellar projection of the paramedian reticular nucleus of the medulla oblongata in the cat. J. NeurophysioL, 17:484-495. (229, 247) Brodal, A., F. Walberg, and T. Blackstad, 1950. Termination of spinal afferents to the inferior olive in cat. J. Neurophysiol., 13:431-454. (198) Brodmann, K., 1905-1906. Beitrage zur histologischen Lokalisation der Grosshirnrinde: Ueber den allgemeinen Bauplan des Cortex pallii bei den Mammaliern und zwei homologe Rindenfelder in besonderen. Zugleich ein Beitrag zur Furchenlehre. J. f. Psychol. u. Neurol., 6:275-400. (332) Brogden, W. J., and W. H. Gantt, 1937. Cerebellar conditioned reflexes. Am. J. PhysioL, 119:277278. (139) , 1942. Intraneural conditioning: Cerebellar conditioned reflexes. Arch. Neurol. & Psychiat., 48:437-455. (339) Brookhart, J. M., and P. H. Blachly, 1952. Cerebellar unit response to DC polarization. Am. J. PhysioL, 171:711. (171,172,174, 219) , 1953. The influence of DC potential fields on cerebellar unit activity. Proc. XIX Internat. Congress PhysioL, Montreal, pp. 236-237. (171, 172, 174) Brookhart, J. M., G. Moruzzi, and R. S. Snider, 1950. Spike discharges of single units in the cerebellar cortex. J. NeurophysioL, 13:465-486. (75, 160, 164-166, 169, 170, 171, 173-174, 176, 178179,180, 213, 214, '215, 240, 241, 251, 309) , 1951. Origin of cerebellar waves. Ibid., 14:181-190. (167-168, 170, 176, 178, 179) Brooks, C. McC., and M. G. F. Fuortes, 1952. Potential changes in spinal cord following administration of strychnine. J. NeurophysioL, 15:257-267. (128) Brouwer, B., 1913. Ueber Hemiatrophia neocerebellaris. Arch. f. Psychiat., 51:539-577. (440) , 1919. Beitrag zur Kenntnis der chronischen diffusen Kleinhirnerkrankungen. Neurol. CentralbL, 38:674-682. (455) , 1934. Familial olivo-ponto-cerebellar hypoplasia in cats. Psychiat. en neurol. bl., 38:352-367. (438,439,440) , 1936. Cerebellar hypoplasia in cats without muscular hypotonia. Folia neuropath, eston., 15-16:236-242. (438) and A. Biemond, 1938. Les affections parenchymateuses du cervelet et leur signification du point de vue de 1'anatomie et de la physiologic de cet organe. J. beige de neurol. et de psychiat., 38:691-757. (379, 429, 439, 440, 465) Brouwer, B., and F. G. Schlesinger, 1947. Carcinoma ovarii and cerebellar degeneration. Proc. Konig. Akad. van Wetensch., Amsterdam, 50:1329. Cited by Greenfield, 1954, p. 90. (456) Brown, J. R., 1949. Localizing cerebellar syndromes. J.A.M.A., 141:518-521. (378, 385)

578

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

Brown, T. G., 1913. On postural and non-postural activities of mid-brain. Proc. Roy. Soc., London, s. B, 87:145-163. (338) and C. S. Sherrington, 1912. On the instability of a cortical point. Proc. Roy. Soc., London, s. B, 85:250-277. (329-330) Brown-Sequard, C. E., 1862. Remarques sur la physiologic du cervelet et du nerf auditif. J. de la physiol. de 1'homme, 5:484-492. (303) Bruhn, J. M., J. D. Emerson, G. M. Emerson, and J. 0. Foley, 1956. Autonomic responses to cerebellar stimulation in the intracollicular decerebrate cat. Proc. XX Internat. Congress Physiol., Brussels, pp. 135-136. (307) Brun, R., 1917-1918. Zur Kenntnis der Bildungsfehler des Kleinhirns. Schweiz. Arch. f. Neurol. u. Psychiat., 1:61-123; 2:48-105; 3:13-88. (417, 423, 434, 436, 43$, 441) , 1925. Das Kleinhirn: Anatomie, Physiologic und Entwickelungsgeschichte. Ibid., 16:183-197. (379, 417) , 1926. Das Kleinhirn: Anatomie, Physiologic und Entwickelungsgeschichte. III. Physiologic des Kleinhirns. Ibid., 19:323-362. (104) , 1932. Zur Frage der Stirnhirnataxia: Ein neues Stirnhirnssyrnptom. Ztschr. f. d. ges. Neurol. u. Psychiat., 138:122-130. (406) Brunner, H., 1924. Allgemeine Symptomatologie der Erkrankungen des Nervus Vestibularis. In G. Alexander and O. Marburg, Handbuch der Neurologic des Ohres, vol. 6, pp. 940-1088. Berlin: Urban u. Schwarzenberg. (398) • , 1936. Otogene endokranielle Erkrankungen. In O. Bumke and O. Foerster, Handbuch der Neurologic, vol. 10, pp. 194-267. Berlin: J. Springer. (499) , 1940. Disturbances of the function of the ear after concussion of the brain. Laryngoscope, 50:921-949.(522) •— , 1946. Intracranial Complications of Ear, Nose and Throat Infections. Chicago: The Yearbook Publishers, Inc. (499) Bruns, L., 1902. Neuropathologische Demonstrationen. Neurol. Centralbl, 21:561-567. (402, 403, 508)

, 1906. Neuropathologische Demonstrationen. Ibid., 25:540-544. (402, 403, 508) , 1908. Die Geschwiilste des Nervensystems. Berlin: S. Karger. (404) , 1909. Zwei weiteren Hirntumorfallen, bei denen seine Lokaldiagnose falsch war. Neurol. Centralbl., 28:665-666. (406) Bubnoff, N., and R. Heidenhain, 1881. Ueber Erregungs- und Hemmungsvorgange innerhalb der motorischen Hirncentren. Arch. f. d. ges. Physiol., 26:137-200. (329) Buchanan, A. R., 1938. Post-rotatory nystagmus following decerebration in guinea pigs with unilateral cerebellar lesions. Proc. Soc. Exper. Biol. & Med., 37:713-715. (287) , L. C. Overholt, and K. T. Neubuerger, 1947. Parenchymatous cortical cerebellar atrophy associated with Pick's disease. J. Neuropath. & Exper. Neurol., 6:152-165. (475) Buchstein, H. F., and A. W. Adson, 1940. Tuberculoma of the brain. Arch. Neurol. & Psychiat., 43:635-648.(496, 497) Bucy, P. C., 1949. Effects of extirpation in man. In P. C. Bucy, The Precentral Motor Cortex, chap. 14, pp. 353-394. Urbana: Univ. of Illinois Press. (330, 335) and D. N. Buchanan, 1935. The stimulation of intracranial tumor by lead encephalopathy in children, with remarks concerning the surgical treatment of the latter. J.A.M.A., 105:244-250. (486) Bucy, P. C., and W. A. Gustafson, 1939. Structure, nature and classification of the cerebellar astrocytomas. Am. J. Cancer, 35:327-353. (537, 538, 539) Bucy, P. C., and W. S. Muncie, 1929. Neuroepithelioma of the cerebellum. Am. J. Path., 5:157-170. (552) Bucy, P. C., and T. A. Weaver, Jr., 1941. Paralysis of conjugate lateral movement of the eyes in association with cerebellar abscess. Arch. Surg., 42:839-849. (505) Buddenbrock, W. von, 1953. Vergleichende Physiologic. Vol. 2, Nervenphysiologie. Basel: Birkhauser. (See Beritashvili and Tzkipuridse, 1945.) Budge, J., 1841. Untersuchungen uber das Nervensystems. Cited by L. W. Bischoff, 1842, Bericht iiber die Fortschritte der Physiologic im Jahre 1841, Arch. f. Anat., Physiol. u. wissensch. Med., Q-fil 133 (IP VQ uUDJ QHR] S7.O1—Loo. [-*•&, &o,

, 1862. Lehrbuch der speciellen Physiologic des Menschen. Leipzig: Voigt u. Gunther. (12, 23) , 1864a, b. Ueber den Einfluss des Nervensystems auf die Bewegung der Blase. Ztschr. f. rat. Med. 21:1-16, 174-191. (306) Bull, J. W., W. L. Nixon, and R. T. Pratt, 1955. The radiological criteria and familial occurrence of primary basilar impression. Brain, 78:229-247. (419)

BIBLIOGRAPHICAL INDEX OF AUTHORS

579

Biirgi, S., 1943a. Reizung und Ausschaltung des Brachium conjunctivum. I. Experimenteller Teil. Helvet. physiol. et pharmacol. acta, 1:359-380. (94, 150, 402, 412) , 1943b. Reizung und Ausschaltung des Brachium conjunctivum. II. Bindearme und Kleinhirnfunktion. Ibid., 1:467-487. (94, 402, 412) , 1945. Die Bindearm-Chorea im Lichte der experimentellen Forschung. Schweiz. med. Wchnschr., 75:1036-1038. (402, 412) , 1950. Zur Frage der Bindearmchorea. Nervenarzt, 21:255-256. (402) Burns, B. D., 1950. Some properties of the cat's isolated cerebral cortex. J. Physiol., 111:50-68. (174,242) —, 1951. Some properties of the isolated cerebral cortex in the unanesthetized cat. J. Physiol., 112:156-175. (174, 242) Buser, P., and A. Rougeul, 1954a. La reponse electrique du cervelet de Pigeon a la stimulation de la voie optique et son analyse par microelectrodes. J. Physiol., Paris, 46:287-291. (160, 168, 170) , 1954b. Etude des reponses du cervelet du pigeon a la stimulation du nerf optique. Boll. Soc. ital. biol. sper., 30:758-760. (160, 162, 168) Buttaro, C. A., 1946. Su di un caso di meningo-encefalomielite luetica. Rassegna internaz. clin. e terap., 26:297-303. (498) Cairns, H., and D. S. Russell, 1931. Intracranial and spinal metastases in gliomas of the brain. Brain, 54:377-420. (541) Calma, I., and G. L. Kidd, 1955. Observations on the cerebellar response to afferent and cerebellar cortical stimulation. J. Physiol., 129:P57-58. (156, 218, 260) Camauer, A., 1940. Sindrome Cerebeloso por hemorragia medica a nivel del vermis del cerebelo por arteritis ectasiante luetica. Dia med., 12:464-467. (497) Camis, M., 1913. Contributi alia fisiologia del labirinto. Nota VIII. Intorno agli effetti di iniezioni di nicotina nel cervelletto. Folia neuro-biol., 7, summer suppl.: 157-174. (Ill, 269, 303) , 1919. Le correnti d'azione nel cervelletto per eccitamento del labirinto. Arch, di sc. biol., 1:92-119. (7,159,182) , 1922a. Nuove osservazioni sui movimenti deambulatori: L'azione delle basse temperature sul cervelletto. Boll. Soc. Med. di Parma, 15:54-56. (28, 60) , 1922b. Das Kleinhirn, als Regulationszentrum des sympatischen Muskeltonus. Arch. f. d. ges. Physiol., 197:441-442. (269) , 1923. Recherches sur le mecanisme central des mouvements de deambulation. Arch, internat. de physiol., 20:340-370. (28, 60, 62, 111, 259, 274) , 1926. II cervelletto e il labirinto in rapporto col tono muscolare. Boll. Soc. ital. biol. sper., 1:649-677. (263, 269) , 1928. La fisiologia delPapparato vestibolare. Bologna: Zanichelli. Translated by R. S. Creed, 1930, Oxford: Clarendon Press. (44) Campbell, E., and R. D. Whitfield, 1948. Posterior fossa meningiomas. J. Neurosurg., 5:131-153. (660) Campbell, J. B., and J. Cohen, 1951. Epidural hemorrhage and the skull of children. Surg. Gynec. & Obst., 92:257-280. (623) Canestrari, R., P. Crepax, and X. Machne, 1955. Modifications de 1'activite electrique du gyrus sygmoi'dien du chien et du chat par application de strychnine sur le cortex neocerebelleux. Arch. psicol., neurol. e psichiat., 16:19-31. (325, 326, 327, 342) Cannon, W. B., and D. Rapport, 1922. Studies on the conditions of activity in endocrine glands. VII. The reflex center for adrenal secretion and its response to excitatory and inhibitory influences. Am. J. Physiol., 58:338-352. (293) Cardin, A., 1946a. Rigidita da decerebrazione negli arti posteriori deafferentati. Boll. Soc. ital. biol. sper., 22:81-83. (268, 352) , 1946b. Meccanismo della inibizione reciproca degli arti posteriori dell'animale decerebrato. Ibid., 22:607-608. (268, 352) , 1946c. Influenza della deafferentazione di uno o piu arti sul tono posturale degli altri arti nell'animale normale. Ibid., 22:609-611. (268, 352) , 1951. II tono muscolare non e di natura riflessa. Ibid., 27:1178-1181. (280) , 1952a. II tono muscolare non e di natura riflessa. II. Attivita del midollo spinale deafferentato. Ibid., 28:368-369. (280) , 1952b. II tono muscolare non e di natura riflessa. III. Attivita del midollo spinale. Ibid., 28:371-373.(280) Carmichael, E. A., 1928. Cerebral gliomata. J. Path. & Bact., 31:493-510. (649) Carrea, R. M. E., and H. Grundfest, 1954. Electrophysiological studies of cerebellar inflow. I. Origin, conduction and termination of ventral spino-cerebellar tract in monkey and cat. J. Neurophysiol., 17:208-238. (185, 195, 200, 201, 216, 251)

580

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

Carrea, R. M. E., and F. A. Mettler, 1947. Physiologic consequences following extensive removal of the cerebellar cortex and deep cerebellar nuclei and effect of secondary cerebral ablations in the primate. J. Comp. Neurol., 87:169-288. (55, 36, 59, 66-67, 68, 71, 73, 77, 87, 90, 94, 246, 271) , 1955. Function of the primate brachium conjunctivum and related structures. Ibid., 102:151322. (92, 94, 835) Carrea, R. M. E., M. Reissig, and F. A. Mettler, 1947. The climbing fibers of the simian and feline cerebellum; experimental inquiry into their origin by lesions of the inferior olives and deep cerebellar nuclei. J. Comp. Neurol., 87:321-365. (247, 458) Casals, J., 1944. Immunological relationship among central nervous system diseases. J. Exper. Med., 78:341-359. (483) Casper, J., 1929. Toxische Kleinhirnatrophie bei Brustkrebs. Zentralbl. f. d. ges. Neurol. u. Psychiat., 53:854-856. (455, 456) Castagnari, G., 1928. Nuova conferma col metodo Patrizi dell'atonia omolaterale del muscoli nel cane emiscerebellato. Boll. Soc. ital. biol. sper., 3:1316-1318. (269) Castellano, F., and G. Ruggiero, 1953. Meningiomas of the posterior fossa. Acta radiol., suppl. 104. (560) Castillo-Nicolau, J. del, and A. Schweitzer, 1949. Reflex rebound in extensor muscles. Quart. J. Exper. Physiol., 35:1-10. (155) Castrillon, H. A., 1933. Ueber palaocerebellare Aplasie des Kleinhirns. Ztschr. f. d. ges. Neurol. u. Psychiat., 144:113-134. (430,432) Catalano, A., 1926. Per la mioclono-epilessia: Studio clinico ed istopatologico. Riv. sper. di freniat., 50:39-49. (418) Catalano, J. V., 1955. Spinal pathways from the forelimbs to the cerebellum. Anat. Rec., 121:391392. (198) Gate, J. ten, 1925. Contribution a la localisation fonctionnelle dans le cervelet: Le paraflocculus. Arch, neerl. de physiol., 10:24-53. (71) , 1926a. Contribution a la physiologic comparee du cervelet. I. Le cervelet du pigeon. Ibid., 11:1-82. (15-17, 96) , 1926b. Contribution a la localisation fonctionelle dans le paraflocculus du cervelet chez le chat: Examen microscopique des cervelets. Ibid., 11:223-233. (71) , 1929. De la fonction du cervelet des requins. Ibid., 14:234-236. (11) , 1930a. Contribution a la physiologic comparee du cervelet. II. Le cervelet des plagiostomes. Ibid., 15:479-528. (11) , 1930b. Contribution a la physiologie comparee du cervelet. III. Le cervelet des raies. Bull. Stat. biol. d'Arcachon, 27:1-30. (11, 104-105) , 1930c. Contribution a la physiologie comparee du cervelet. Ibid., 27:147-174. (11) , 1931a. Beitrage zur vergleichenden Physiologie des Kleinhirns. IV. Die chemische Reizung des Kleinhirns der Selachier. Arch, neerl. de physiol., 16:6-20. (11, 105) , 1931b. Beitrage zur vergleichenden Physiologie des Kleinhirns. V. Weitere Versuche am Kleinhirn der Haifische. Ibid., pp. 21-32. (11) , 1931c. Methoden zur Erforschung der Funktionen des Kleinhirns. In E. Abderhalden, Handbuch der biologischen Arbeitsmethoden, sec. 5, pt. 5, pp. 693-788. Berlin: Urban u. Schwarzenberg. (104,110) , 1935. Physiologie des Zentralnervensystems der Fische. Ergebn. d. Biol., 11:335-409. (10) , 1936. Physiologie des Zentralnervensystems der Vogel. Ibid,., 13:93-173. (IS, 14, 15, 17) , 1937. Physiologie des Zentralnervensystems der Reptilien. Ibid., 14:225-279. (13) , W. G. Walter, and L. J. Koopman, 1940. Note on electroencephalography of the brain stem and cerebellum of cats. Arch, neerl. de physiol., 25:51-56. (163) Gate, J. ten, and K. Wiggers, 1942. On the occurrence of slow waves in the electrocerebellogram. Arch, neerl. de physiol., 26:423-425. (163) Chamberlain, W. E., 1939. Basilar impression (Platybasia): A bizarre developmental anomaly of the occipital bone and upper cervical spine with striking and misleading neurological manifestations. Yale J. Biol. & Med., 11:487-496. (418, 419, 420) Chambers, W. R., and W. Clark, 1951. Bacillus proteus abscess of cerebellar lobe of otogenic origin: Report of case with recovery. Arch. Otolaryng., 54:179—182. (504) Chambers, W. W., 1947. Electrical stimulation of the interior of the cerebellum in the cat. Am. J. Anat., 80:55-93. (Ill, lj-0,147, 303, 307) , 1948. Loss of placing reactions and occurrence of pupillary dilatation following cerebellar lesions. Anat. Rec., 100:649. (86, 305, 342, 343) , 1953. Role of cerebellum in placing reactions of cat. Federation Proc., 12:25. (343, 344) and J. M. Sprague, 1951. Differential effects of cerebellar anterior lobe cortex and fastigial nuclei on postural tonus in the cat. Science, 114:324-325. (80)

BIBLIOGRAPHICAL INDEX OF AUTHORS

581

, 1955a. Functional localization in the cerebellum. I. Organization in longitudinal corticonuclear zones and their contribution to the control of posture, both extrapyramidal and pyramidal. J. Comp. Neurol., 103:105-129. (55, 62, 70, 86, 87, 305, 343, 344, 345) , 1955b. Functional localization in the Cerebellum. II. Somatotopic organization in cortex and nuclei. Arch. Neurol. & Psychiat., 74:653-680. (55, 57, 58, 62-63, 68, 69, 70, 80, 87, 100, 287, 305, 307, 343, 344, 345) Chandler, J. H., and J. Bebin, 1956. Hereditary cerebellar ataxia: Olivopontocerebellar type. Neurology, 6:187-195.(461) Charcot, J. M., and T. E. Turner, 1852. Example d'atrophie cerebrale avec atrophie et deformations dans un moitie du corps. Comp. rend. Soc. de biol., 4:191. (464) Chiari, H., 1891. Ueber Veranderungen des Kleinhirns infolge von Hydrocephalie des Grosshirns. Deutsche med. Wchnschr., 17:1172-1175. (420) , 1896. Ueber Veranderungen des Kleinhirns, der Pons und der Medulla oblongata infolge von congenitaler Hydrocephalie des Grosshirns. Denkschr. Akad. Wissensch. "Wien., 63:71-116. (421) Chiarugi, E., and O. Pompeiano, 1954. Sui rapporti fra istogenesi ed eccitabilita del lobus anterior nel gatto neonato. Arch, di sc. biol., 38:493-531. (360-364, 366) , 1956a. Effetti della distruzione unilaterale e bilaterale della corteccia e dei nuclei del cervelletto sul tono posturale del piccione talamico. Ibid., 40:1-23. (18-21, 96, 97, 107) , 1956b. Effetti della stimolazione elettrica localizzata della corteccia e dei nuclei del cervelletto nel piccione talamico, Ibid., 40:25-37. (21, 106,107-108, 109, 151) Christensen, E., and K. H. Krabbe, 1949. Poliodystrophia cerebri progressiva: Report of a case. Arch. Neurol. & Psychiat., 61:28-43. (477) Christophe, J., and A. Remond, 1951. Dyssynergia cerebellaris myoclonica de Ramsay Hunt: Etude clinique et electroencephalographique. Rev. neurol., 84:256-262. (412) Christophe, L., and P. Divry, 1937. Meningiome intracerebelleux. J. beige de neurol. et de psychiat., 37:575-582. (560) Ciovini, M., 1910. Remarques physiologiques sur le cervelet et sur les lobes occipitaux du chien sous 1'action de certaines substances chimiques et particulierement du curare. J. de physiol. et de path, gen., 12:891-894. (110) Clark, F. H., 1932. Hydrocephalus, a hereditary character in the house mouse. Proc. Nat. Acad. Sc., 18:654-656. (430, 431) Clark, S. L., 1939a. Responses following electrical stimulation of the cerebellar cortex in the normal cat. J. Neurophysiol., 2:19-35. (Ill, 139-140, 303, 308, 411) , 1939b. Motor seizures accompanying small cerebellar lesions in cats. J. Comp. Neurol., 71:4157. (110, 111, 140, 408, 409) and J. W. Ward, 1949. The electroencephalogram in cerebellar seizures. Electroencephalog. & Clin. Neurophysiol., 1:299-304. (140) , 1952. Observations on the mechanism of experimental cerebellar seizures. J. Neurophysiol., 15:221-234.(140-141) Clarke, R. H., 1926. Experimental stimulation of the cerebellum. Brain, 49:557-569. (141, 142) Claude, H., and M. Loyez, 1912. Atrophie croisee du cervelet par lesion traumatique de la capsule interne. Encephale, 7:345-354. (465) Coates, G. M., B. H. Shuster, and H. B. Slotkin, 1936. Vestibular (Barany) tests in the diagnosis and localization of intracranial lesions: Report of 16 proved cases. J.A.M.A., 107:412-419. (398) Cobb, S., 1928. A case of cerebellar aplasia in a cat. Arch. Neurol. & Psychiat., 19:931-932. (438) , A. A. Bailey, and P. R. Holtz, 1917. On the genesis and inhibition of extensor rigidity. Am. J. Physiol., 44:239-258. (114, 149, 150) Cohen, I., 1942. Agenesis of cerebellum (verified by operation). J. Mt. Sinai Hosp., 8:441-446. (429) Cohen, M. M., 1957. Central nervous system in carbon tetrachloride intoxication. Neurology, 7:238244. (488) Coleman, C. C., and J. L. Thomson, 1941. Extradural hemorrhage in the posterior fossa. Surgery, 10:985-990. (523) Collier, J., 1904. The false localising signs of intracranial tumor. Brain, 27:490-508. (410) Combettes, 1831. Absence complete du cervelet, des pedoncules posterieurs et la protuberance cerebrale chez une jeune fille morte dans sa onzieme annee. Bull. Soc. anat. de Paris, 5:148-157. (MS) Combs, C. M., 1954. Electro-anatomical study of cerebellar localization: Stimulation of various afferents. J. Neurophysiol., 17:123-143. (192-195, 196, 200, 240, 242, 250, V52-253) , 1956. Bulbar regions related to localized cerebellar afferent impulses. J. Neurophysiol., 19: 285-300. (195) Comolli, A., 1910. Per una nuova divisione del cervelletto dei mammiferi. Arch. ital. di anat., 9:247273. (51, 247, 417)

582

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

Connor, G. J., 1941. Functional localization within the anterior cerebellum. Proc. Soc. Exper. Biol., 47:205-207. (57, 58, 63) and W. J. German, 1941. Functional localization within the anterior cerebellar lobe. Tr. Am. Neurol., 67:181-186. (58-59, 63, 299, S06) Cook, W. H., and G. W. Stavraky, 1952. A cerebellar component of convulsive manifestations. Arch. Neurol. & Psychiat., 68:741-754. (44, 54) Cooke, P. M., and R. S. Snider, 1953. Some cerebellar effects on the electrocorticogram. Electroencephalog. & Clin. Neurophysiol., 5:563-569. (325) , 1954. The electrocerebellogram as modified by afferent impulses. Ibid., 6:415-423. (163) Cooper, S., and R. S. Creed, 1927. More reflex effects of active muscular contractions. J. Physiol., 64:199-214. (115) Cooper, S., and D. Denny-Brown, 1927. Responses to stimulation of the motor area of the cerebral cortex. Proc. Roy. Soc., London, s. B, 102:222-236. (330) Cooper, S., P. M. Daniel, and D. Whitteridge, 1953a. Nerve impulses in the brain stem of the goat: Responses with long latencies obtained by stretching the extrinsic eye muscles. J. Physiol., 120:491-513. (218) , 1953b. Nerve impulses in the brain stem and cortex of the goat. Spontaneous discharges and responses to visual and other afferent stimuli. Ibid., pp. 514-527. (218) Cornelius, R., 1907. Les atrophies croisees du cervelet. These, Paris. (465) Corso, F., 1895. Quelques experiences sur le cervelet des poissons. Arch. ital. de biol., 22:xciv. (10-11) Cotter, L. H., 1950. Trichloroethylene poisoning. Arch. Indust. Hyg., 1:319-322. (487) Courville, C. B., 1930. Ganglioglioma; tumor of the central nervous system: Review of the litera* ture and report of two cases. Arch. Neurol. & Psychiat., 24:439-491. (551) , 1936. Asphyxia as a consequence of nitrous oxide anesthesia. Medicine, 15:129-245. (489) and O. Blomquist, 1940. Traumatic intracerebral hemorrhage, with particular reference to its pathogenesis and its relation to "delayed traumatic apoplexy." Arch. Surg., 41:1-28. (525) Courville, C. B., and A. P. Friedman, 1940. Chronic progressive degeneration of superior cerebellar cortex (parenchymatous cortical cerebellar atrophy), with particular reference to its pathogenesis and pathology. Bull. Los Angeles Neurol. Soc., 5:171-183. (452, 453, 454, 489) Courville, C. B., and J. M. Nielsen, 1937. The pathogenesis of otogenous cerebellar abscess: A study of 16 cases verified at autopsy. California & "West. Med., 47:29-36. (499-500, 501, 503) Coxe, W. S., and R. S. Snider, 1956. Some relationships of caudate nucleus to cerebellum. Federation Proc., 15:42. (211) Craig, C. F., 1944. Etiology, Diagnosis and Treatment of Amebiasis. Baltimore: Williams & Wilkins Co. {508) Craig, W. M., and F. A. Carmichael, Jr., 1938. Blastomycoma of cerebellum: Report of case. Proc. Staff Meet., Mayo Clinic, 13:347-351. (508) Craig, W. M., and G. Horrax, 1949. Occurrence of hemangioblastomas (two cerebellar and one spinal) in three members of family. J. Neurosurg., 6:518-529. (554) Craig, W. M., H. P. Wagener, and J. W. Kernohan, 1941. Lindau-von Hippel disease: Report of 4 cases. Arch. Neurol. & Psychiat., 46:35-54. (554) Craig, W. M., M. N. Walsh, and J. D. Camp, 1942. Basilar invagination of skull, so-called platybasia: Report of 3 cases in which operation was done. Surg., Gynec. & Obst., 74:751-754. (419, 423) Craige, E. H., 1920. On the relative vascularity of various parts of the central nervous system of the albino rat. J. Comp. Neurol., 31:429-464. (511) , 1924. Changes in vascularity in the brain stem and cerebellum of the albino rat between birth and maturity. Ibid., 38:27-48. (511) Cramer, A., 1891. Einseitige Kleinhirnatrophie mit leichter Atrophie der gekreuzten Grosshirnhemisphare, nebst einem Beitrage zur Anatomic der Kleinhirnstiele. Beitr. z. path. Anat. u. z. allg. Path., 11:39-58. (440) Cramer, F., and W. Kimsey, 1952. Cerebellar hemangioblastomas: Review of 53 cases, with special reference to cerebellar cysts and association of polycythemia. Arch. Neurol. & Psychiat., 67:237252.(554) Cranmer, R., 1951. Nystagmus related to lesions of the central vestibular apparatus and the cerebellum. Ann. Otol., Rhin. & Laryng., 60:186-196. (138) Creed, R. S., and D. Hertz, 1933. The action of strychnine on Hering-Breuer reflexes. J. Physiol., 78:85-95. (115) Crepax, P., 1956. Effetti della stimolazione del lobus anterior del cervelletto sull'attivita elettrica della corteccia cerebrale. Atti Accad. Naz. Lincei, cl. sc. fis. mat. e nat., 20:95-101. (324, 327) and E. Fadiga, 1956. La stimolazione chimica della corteccia cerebellare. Arch, di sc. biol., 40:66-80. (325, 327)

BIBLIOGRAPHICAL INDEX OF AUTHORS

583

Crepax, P., and F. Infantellina, 1955. L'attivita elettrica del lembo isolate di corteccia cerebellare di gatto. Boll. Soc. ital. biol. sper., 31:1229-1231. (75, 164, 174, %4%) , 1957. II preparato di lembo isolato di corteccia cerebellare di gatto. Arch, di sc. biol., 41:5773. (75,164,174,242) Crepax, P., A. Nigro, and P. L. Parmeggiani, 1956. Modifications de 1'activite electrique unitaire de 1'ecorce cerebelleuse provoquees par 1'acetylcholine et par 1'eserine. Proc. XX Internat. Congress Physiol., Brussels, pp. 200-201. (182) , 1957. Fattori che regolano 1'attivita unitaria corticocerebellare e modificazioni dell'attivita medesima per effetto di stimoli chimici. Arch, di sc. biol., 41:163-190. (182) Crepax, P., and P. L. Parmeggiani, 1958a. L'attivita elettrica spontanea del cervelletto di Lacerta viridis e le sue modificazioni per effetto di impulsi aft'erenti. Arch, di sc. biol., in press. (160) -— -, 1958b. Efletto degli stimoli fotici sull'attivita elettrica del cervelletto e del tetto ottico di Lucertola. Ibid., in press. (160) Crescitelli, F., and A. Gilman, 1946. Electrical manifestations of the cerebellum and cerebral cortex following DDT administration in cats and monkeys. Am. J. Physiol., 147:127-137. (181, 487) Critchley, M., and F. R. Ferguson, 1928. Cerebrospinal epidermoids (cholesteatomata). Brain, 51: 334-384.(557J Critchley, M., and J. G. Greenfield, 1948. Olivo-ponto-cerebellar atrophy. Brain, 71:343-364. (452, 459, 461, 463) Critchley, M., and P. Schuster, 1933. Beitrage zur Anatomic und Pathologic der Arteria cerebelli superior. Ztschr. f. d. ges. Neurol. u. Psychiat., 144:681-741. (516) Cruickshank, E. K., 1951. Hyperpyrexia with cerebellar damage in acute rheumatism. Lancet, 1: 1052-1053. (491) Cruveilhier, J., 1829. Anatomic pathologique du corps humain. Paris: J. B. Bailliere. (557) Curtis, H. J., 1940. Cerebellar action potentials in response to stimulation of cerebral cortex. Proc. Soc. Exper. Biol. & Med., 44:664-668. (205, 250) Gushing, H., 1917. Tumors of the Nervus Acusticus and the Syndrome of the Cerebellopontile Angle. Philadelphia: W. B. Saunders Co. (382, 561) , 1930. Experiences with the cerebellar medulloblastomas: Critical review. Acta path, et microbiol. Scandinav., 7:1-86. (542) , 1931. Experiences with cerebellar astrocytomas: Critical review of 76 cases. Surg., Gynec. & Obst., 52:129-204. (537, 538) , 1932. Intracranial Tumors. Springfield, 111.: Charles C. Thomas. (406, 527, 537, 540, 541, 542, 550,555, 556, 557) and P. Bailey, 1928a. Tumors Arising from the Blood Vessels of the Brain; Angiomatous Malformations and Hemangioblastomas. Springfield, 111.: Charles C. Thomas. (552, 653, 554) —, 1928b. Hemangiomas of cerebellum and retina (Lindau's disease): With report of a case. Arch. Ophth., 57:447-463. (554) Gushing, H., and Louise Eisenhardt, 1938. Meningiomas. Springfield, 111.: Charles C. Thomas. (560) Gushing, H., and C. B. Walker, 1912. Distortions of the visual fields in cases of brain tumor. Arch. Ophth., 41:559-598. (406, 531) Custis, D. L., and A. Verbrugghen, 1944. Basilar impression resembling cerebellar tumor: Report of a case. Arch. Neurol. & Psychiat., 52:412-415. (419, 423) Cutler, E. C., M. C. Sosman, and W. W. Vaughn, 1936. Place of radiation in treatment of medulloblastoma: Report of 20 cases. Am. J. Roentgenol., 35:429-453. (547) Dalton, C., 1861. On the cerebellum, as the centre of coordination of the voluntary movements. Am. J. M. Sc., 41:83-88. (14) Daly, D., J. L. Whelan, R. G. Bickford, and C. S. McCarty, 1953. The electroencephalogram in cases of tumors of the posterior fossa and third ventricle. Electroencephalog. & Clin. Neurophysiol., 5:203-216. (535) Dana, C. L., 1905. The cerebellar seizure (cerebellar fits): A syndrome characteristic of cerebellar tumors. New York Med., 81:270-272. (410) Danaraj, T. J., 1949a. Cerebellar syndrome following malaria. Proc. Alumni A. King Edward VII Coll. Med., 2:227-228. (481) , 1949b. The cerebellar aspect of nutritional spinal ataxia. Tr. Roy. Soc. Trop. Med. & Hyg., 43:343-344.(490, 491) Dandy, W. E., 1932. Brain tumors: General diagnosis and treatment. In Lewis, Practice of Surgery, pp. 443-774. Hagerstown, Md.: W. E. Prior. (527, 552) , 1933. Benign Tumors in the Third Ventricle of the Brain. Springfield, 111.: Charles C. Thomas. (403) , 1934. Benign Encapsulated Tumors in the Lateral Ventricles of the Brain. Baltimore: Williams & Wilkins Co. (403)

584

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

D'Antona, S., 1935. Sulla intossicazione da tiafene veleno epilettogeno ad azione predilettiva sullo strato granuloso del cervelletto. Fisiol. e med., 6:753-764. (486) Davidoff, L. M., 1930. Mental symptoms among brain tumor patients, and brain tumors among the insane. New York State J. Med., 30:1205-1209. (582) , 1935. The history of the surgical treatment of otogenic abscess of the brain. Laryngoscope, 45:295-306. (498) , 1945. Difference in mental reaction between children suffering from cerebral and cerebellar tumors. Psychosom. Med., 7:38-41. (532) and H. T. von Deesten, 1935. Epidermoid cyst compressing the vermis of the cerebellum. J.A.M.A., 105:873-874. (557) Davidoff, L. M., and C. G. Dyke, 1946. The Normal Encephalogram. Philadelphia: Lea & Febiger. (442-443) Davidoff, L. M., and B. S. Epstein, 1955. The Abnormal Pneumoencephalogram. Philadelphia: Lea & Febiger. (443, 533-534, 555) Davidoff, L. M., and A. Ferraro, 1929. Intracranial tumors among mental hospital patients: Histopathological report with special attention to tumors of the glioma series. Am. J. Psychiat., 8:599-645.(549) Davis, H., and A. Forbes, 1936. Chronaxie. Physiol. Rev., 16:407-441. (264) Davis, L., and H. Gushing, 1925. Papillomas of the choroid plexus. Arch. Neurol. & Psychiat., 13:681-710.(403) Davis, L., and L. J. Pollock, 1926. Studies in decerebration. III. The labyrinth. Arch. Neurol. & Psychiat., 16:555-565. (259) Davison, C., and S. B. Goodhart, 1938. Dystonia musculorum deformans: A clinicopathologic study. Arch. Neurol. & Psychiat., 39:939-972. (463) and N. Savitsky, 1935. The syndrome of the superior cerebellar artery and its branches. Arch. Neurol. & Psychiat., 33:1143-1174. (401, 515, 516) Davison, C., H. A. Riley, and S. Brock, 1936. Rhythmic myoclonus of the muscles of the palate, larynx and other regions: A histopathologic study. Bull. Neurol. Inst. New York, 5:94-126. (413, 415) Davison, C., and I. S. Wechsler, 1938. Olivo-ponto-cerebellar atrophy and unilateral involvement of cranial nerve nuclei. J. Nerv. & Ment. Dis., 88:569-588. (459) Deery, E., 1931. Two cases of tumor of the posterior cranial fossa causing visual hallucinations. Bull. Neurol. Inst. New York, 1:97-104. (531) Deganello, U., 1900. Asportazione del canali semicircolari: Alterazioni consecutive nelle cellule dei nuclei bulbari e del cervelletto. Arch. sc. med., 24:337-356. (272) Dejerine, J., and Andre-Thomas, 1900. L'atrophie olivo-ponto-cerebelleuse. Nouv. iconog. de la Salpetriere, 13:330-370. (417, 460) De Jong, J. V., 1896. Beschreibung eines Falles von Hemiatrophia cerebri mit Atrophie der gekreuzten Kleinhirn-Hemisphare. Dissertation, Freiburg. Utrecht: J. Nikerk. (464) Delgado, J. M. R., and A. Schulman, 1955. Cerebro-cerebellar correlations in the awake cat. Federation Proc., 14:36-37. (141, S29) De Lisi, L., and G. Pintus, 1936. Alterazione della postura provocate nel gatto dalla separazione del cervello frontale. Arch. gen. neurol. psichiat. e psicoanal., 17:5-45. (335) Dell, P., 1952. Correlations entre le systeme vegetatif et le systeme de la vie de relation. Mesencephale, diencephale et cortex cerebral. J. Physiol., Paris, 44:471-558. (192) and R. Olson, 1951. Projections thalamiques, corticales et cerebelleuses des afferences viscerales vagales. Comp. rend. Soc. de biol., 145:1084-1088. (191, 211, 309) Delmas-Marsalet, P., 1932. Etudes sur le lobe frontal et les voies centrales de 1'equilibre. Signes des desequilibre d'origine frontal. Le syndrome experimental du carrefour frontal anterior; sa nature cerebello-vestibulaire; son equivalent clinique. Rev. neurol., 2:617-651. (33S, 334, 405) Del Rio-Hortega, P., 1932. Estructura y sistematizacion de los gliomas y paragliomas. Arch, espan. d. oncol., 2:411-677. (546, 549) Demetriades, Th. D., and E. A. Spiegel, 1927. Zur Frage der Bedeutung des Kleinhirns fiir die Entwicklung von Spontannystagmus. Ztschr. Hals-, Nasen u. Ohrenheilk., 19:250-257. (£89) Demole, V., 1927. Structure et connexions des noyaux denteles du cervelet. Schweiz. Arch. f. Neurol. u. Psychiat., 20:271-294; 21:73-110. (405, 406, 465) Dempsey, E. W., R. S. Morison, and B. R. Morison, 1941. Some afferent diencephalic pathways related to cortical potentials in the cat. Am. J. Physiol., 131:718-731. (179) Denny-Brown, D., 1929a. On the nature of postural reflexes. Proc. Roy. Soc., London, s. B. 104:252301.(75) , 1929b. The histological features of striped muscle in relation to its functional activity. Ibid., 104:371-411.(75)

BIBLIOGRAPHICAL INDEX OF AUTHORS

585

, 1948. Primary sensory neuropathy with muscular changes associated with carcinoma. J. Neurol., Neurosurg. & Psychiat., 11:73-87. (456) , 1952. Discussion of Hampson, Harrison, and Woolsey, 1952. A. Research Nerv. & Ment. Dis., Proc., 30:314. (122) and E. H. Botterell, 1947. The motor functions of the agranular frontal cortex. A. Research Nerv. & Ment. Dis., Proc., 27:235-345. (335) Denny-Brown, D., J. C. Eccles, and E. G. T. Liddell, 1929. Observations on electrical stimulation of the cerebellar cortex. Proc. Roy. Soc., London, s. B, 104:518-536. (110, 115, 117-118, 119, 1S7, 155, 264) De Renzi, C., and O. Pompeiano, 1955. Sull'epoca d'insorgenza nel gatto neonato decerebrato degli effetti posturali di lesioni cortico- e nucleo-cerebellari. Boll. Soc. ital. biol. sper., 31:807-808. , 1956. La comparsa dell'attivita tonica della corteccia e del nuclei del cervelletto nel gatto neonato. Arch, di sc. biol., 40:523-534. (363, 364-366, 367) D'Errico, A., 1939. The surgical treatment of hydrocephalus associated with spina bifida. Yale J. Biol. & Med., 11:425-430. (422) , 1950. Meningiomas of the cerebellar fossa. J. Neurosurg., 7:227-232. (560) Descuns, P., H. Garre, and C. Pheline, 1954. Tuberculomas of the brain and cerebellum. J. Neurosurg., 11:243-250. (497) Desmoulins, 1835. Anatomie des systemes nerveux. Cited by Eckhard, 1879, p. 105. (12) De Vito, R. V., A. Brusa, and A. Arduini, 1956. Cerebellar and vestibular influences on Deitersian units. J. Neurophysiol., 19:241-253. (119, 230-232, 246, 248, %72, 279, 283, 350, 352) Dickinson, W. H., 1865. On the functions of the cerebellum. Brit. & For. M.-Chir. Rev., 36:455-480. (10,12,14, 23) Dickman, G. H., 1946. Cysticercus of post cranial fossa. Cisticercosis de la fosa craneana posterior (4 cases). Rev. neurol. de Buenos Aires, 11:160-179. (508) , A. A. Veppo, and T. Negri, 1942. Torulopsis del sistema nervioso central (cerebelo) de forma tumoral. Rev. neurol. de Buenos Aires, 7:347-360. (508) Di Giorgio, A. M., 1923. Lesioni cerebellari ottenute col metodo del cloroformio. Arch, fisiol., 21:217230. (72) , 1925. Sul determinismo di alcuni fenomeni dinamici consecutivi a lesioni del labirinto e del cervelletto. Ibid., 23:193-207. (88) , 1927. Asimmetrie motorie degli arti posteriori da lesioni asimmetriche del cervelletto. Boll. Soc. ital. biol. sper., 2:601-603. (75) , 1929a. Persistenza, nell'animale spinale, di asimmetrie posturali e motorie di origine cerebellare. Arch, fisiol., 27:519-542. (270) , 1929b. Persistenza, nell'animale spinale, di asimmetrie posturali e motorie di origine cerebellare. II. Ricerche intorno al meccanismo funzionale di tali asimmetrie. Ibid., pp. 543-557. (270) , 1929c. Persistenza, nell'animale spinale, di asimmetrie posturali e motorie di origine cerebellare. III. Sulla possibilita di evocare tali asimmetrie durante lo shock spinale, mediante la stricnina, 1'adrenalina e 1'iperventilazione. Ibid., pp. 558-580. (270) , 1938. Ricerche intorno alle strutture del tronco encefalico che, nelle cavie, regolano la flessione dorsale del capo nel nuoto. Boll. Soc. ital. biol. sper., 13:789-791. (101) , 1942a. Azione del cervelletto—neocerebellum — sul tono posturale degli arti e localizzazioni cerebellari nell'animale rombencefalico. Arch, fisiol., 42:25-79. (68, 76) , 1942b. Persistenza di effetti cerebellari nella corteccia cerebrale. Boll. Soc. ital. biol. sper., 17:101-103. (270, 329, 364) , 1943. Ricerche sulla persistenza dei fenomeni cerebellari nell'animale spinale. Arch, fisiol., 43:47-63. (270) • , 1944. Sulla organizzazione della attivita cerebellare nei mammiferi neonati. Ibid., 44:1-25. (363) , 1946. Sui rapporti cerebello-spinali: Asimmetrie cerebellari dopo deafferentazione e sezione del midollo spinale. Arch, neerl. de physiol., 28:466-474. (270) , 1947. Modificazione funzionali del midollo spinale per effetto di impulsi asimmetrici cerebral! o cerebellari. Arch, fisiol., 47:254-261. (270) , 1948. Rapporti fra le attivita del cervelletto ed i riflessi vestibolari. Riv. med. aero., 11:523530. (290) , 1949. Midollo spinale e manifestazioni toniche di origine centrale. Boll. Accad. svizzera sc. med., 5:132-146. (270) , 1950. Reflexes vestibulaires et cervelet. Acta oto-rhino-laryng. belg., 4:282-294. (288, 290) , 1954. Estinzione della influenza del cervelletto sulla motilita oculare nella ipotermia progressiva. Ibid., 80:1401-1402. (290)

586

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

, 1955. Significato della "via finale comune" nel determinismo delle reazioni asimmetriche vestibolari da lesioni del cervelletto. Ibid., 31:31-32. (290) and P. Menzio, 1946a. Azione tonica del cervelletto neU'animale deafferentato (arti anteriori). Boll. Soc. ital. biol. sper., 22:824-825. (75, 76, 270) , 1946b. Effetti della emidecerebellazione neU'animale deafferentato. Ibid., pp. 826-827. (75, 76, 270) , 1946c. Comportamento degli arti posteriori dopo deafferentazione e lesione unilaterale del cervelletto. Ibid., pp. 827-828. (75, 76, 270) , 1946d. Azione cerebellare neU'animale deafferentato: Effetti della decerebrazione. Ibid., pp. 828-829. (75, 76, 270) Di Giorgio, A. M., and G. Pestellini, 1948. Inibizione acquisita dei riflessi vestibolari: Significato degli emisferi cerebrali e del cervelletto. Arch, fisiol., 48:86-110. (289) Dimitri, V., and M. Victoria, 1934. Zum Studium der spaten Kleinhirnatrophie mit Starrheit. Zentralbl. f. d. ges. Neurol. u. Psychiat., 72:229. (466) Divry, P., and Lecomte, 1936. Volumineux cholesteatoma du cervelet chez un sujet atteint de maladie de Klippel-Feid. J. beige de neurol. et de psychiat., 36:343-353. (557) Dixon, T. F., and A. Meyer, 1936. Respiration of brain. Biochem. J., 30:1577-1582. (489) Dobson, J. P., and H. A. Riley, 1941. Rhythmic myoclonus: Clinical report of 6 cases. Arch. Neurol. & Psychiat., 45:145-150. (413) Dollinger, A., 1919. Zur Klinik der infantilen Form der familiaren amaurotischen Idiotie (Tay-Sachs). Ztschr. f. Kinderh., 22:167-194. (474) Dondey, M., and R. S. Snider, 1955. Slow potential shifts following cerebellar stimulation. Electroencephalog. & Clin. Neurophysiol., 7:265-272. (325) Dordoni, F., 1948a. Sugli effetti dell'associazione morfina-apomorfina nel cane. II. L'apomorfina e 1'ipertono da decerebrazione. Boll. Soc. ital. biol. sper., 24:231-233. (260) , 1948b. Sugli effetti dell'associazione morfina-apomorfina nel cane. III. La morfina ed i centri rombencefalici del tono muscolare. Ibid., 24:233-234. (260) , 1951. L'apomorfina e 1'ipertono da decerebrazione nel gatto. Ibid., 27:1107-1108. (260) Dosuzkov, Th., Z. Kocka, and K. Uttl, 1931. Kleinhirnstorung und erhohte Vestibularisreizbarkeit nach akuter Alkoholvergiftung. Zentralbl. f. d. ges. Neurol. u. Psychiat., 61:112. (486) Dott, N. M., and E. Levin, 1939. Intracranial tuberculoma. Edinburgh M. J., 46:36-41. (497) Dow, R. S., 1935. The relation of the paraflocculus to movements of the eyes. Am. J. Physiol., 113:296-298. (138,139) , 1936. The fiber connections of the posterior parts of the cerebellum in the rat and cat. J. Comp. Neurol., 63:527-548. (52, 176, 202, 246, 247, 352) • , 1938a. The effects of unilateral and bilateral labyrinthectomy in monkey, baboon and chimpanzee. Am. J. Physiol., 121:392-399. (55, 384, 489) • , 1938b. Effect of lesions in the vestibular part of the cerebellum in primates. Arch. Neurol. & Psychiat., 40:500-520. (55, 56, 63, 70-71, 90, 91, 246, 271, 288, 384) • , 1938c. The electrical activity of the cerebellum and its functional significance. J. Physiol., 94:67-86. (60, 156, 159, 162-163, 164, 173, 176, 177, 178, 182, 240, 241, 243, 325) , 1938d. The efferent connections of the flocculonodular lobe in Macaca mulatta. J. Comp. Neurol., 48:297-306. (846) • , 1939. Cerebellar action potentials in response to stimulation of various afferent connections. J. Neurophysiol., 2:543-555. (75, 122, 189-191,195, 200, 201-204, 246, 247, 250, 252, 272) —, 1940. Partial agenesis of the cerebellum in dogs. J. Comp. Neurol., 72:569-586. (430, 431, 432, 434) • , 1942. Cerebellar action potentials in response to stimulation of the cerebral cortex in monkeys and cats. J. Neurophysiol., 5:121-136. (191, 205-206, 216, 247, 250, 251) , 1949. Action potentials of cerebellar cortex in response to local electrical stimulation. Ibid., 12:245-256. (172,175) , 1956. Electroencephalographic findings in cerebellar tumors: A review of current and old concepts. Electroencephalog. & Clin. Neurophysiol., 8:165. (536) , and R. Anderson, 1942. Cerebellar action potentials in response to stimulation of proprioceptors and exteroceptors in the rat. J. Neurophysiol., 5:363-371. (182, 183, 185, 186, 191, 242, 243, 245, 250) Dow, R. S., and L. van Bogaert, 1938. On complex involuntary movements appearing late following the resection of a cerebellar hemisphere. J. beige de neurol. et de psychiat., 38:803-807. (402) Dragomanov, 1909. Cited by von Bechterew, 1909, p. 959. (305) Dresel, K., and F. H. Lewy, 1924. Die Lokalisation vegetativer Zentren im Kleinhirn. Deutsche Ztschr. f. Nervenh., 81:82-83. (291, 301, 303)

BIBLIOGRAPHICAL INDEX OF AUTHORS

587

Ducceschi, V., and S. Sergi, 1904. II senso muscolare nelle lesion! del cervelletto. Arch, fisiol., 1:233240. (43, 87, 341, 345) Dufour, H., 1913. Gomme du cervelet et meningite chronique syphilitique ayant provoque une hydrocephalie compliquee d'autres troubles chez un individu idiot depuis 1'age de 3 ans et mort a 25 ans. Rev. neurol., 25:355. (498) Duncan, D., and S. R. Snodgrass, 1943. Diffuse hypertrophy of the cerebellar cortex (myelinated neurocytoma): Report of case. Arch. Neurol. & Psychiat., 50:677-684. (441) Duncan, H., 1807. Tr. Highland Soc. Scotland, 3:339. Cited by Pool, 1931. (482) Dupuy, E., 1885. Sensibilite du cervelet a la douleur. Compt. rend. Soc. de biol., 37:711. (109, 138) Dusser de Barenne, J. G., 1922. Sur 1'excitation artificielle du cervelet. Arch, neerl. de physiol., 7:112115. (109,138) , 1923. Die Funktionen des Kleinhirns: Physiologic und allgemeine Neuropathologie. In G. Alexander and O. Marburg, Handbuch der Neurologic des Ohres, vol. 1, pp. 589-672. Berlin: Urban u. Schwarzenberg. (27, 43, 44, 64, 97,149, 271, 287, 341, 342, S52, 379) , 1937. Experimented Physiologic des Kleinhirns. In O. Bumke and O. Foerster, Handbuch der Neurologic, vol. 2, pp. 235-267. Berlin: J. Springer. (27, 29, 31, 38, 41, 43, 44, 64, 97, 101, 271, 287, 311, 340, 342, 352, 379) Du Verny, 1673. Experiments reported, without quotation, by Preston, 1697. (3) Dyke, C. G., and L. M. Davidoff, 1934. Significance of abnormally shaped subarachnoid cisterns as seen in the encephalogram. Am. J. Roentgenol., 32:743-756. (442, 443) , 1940. Pneumo-encephalographic appearance of hemangioblastoma of the cerebellum. Ibid., 44:1-8. (555, 556) Eagleton, W. B., 1922. Brain Abscess: Its Surgical Pathology and Operative Technique. New York: Macmillan & Co. (499, 500, 501, 503) Eaton, L. M., J. D. Camp, and J. G. Love, 1939. Symmetric cerebral calcification, particularly of the basal ganglia, demonstrable roentgenographically; calcification of the finer cerebral blood vessels. Arch. Neurol. & Psychiat., 41:921-942. (477) Ebenius, B., 1934. The roentgen appearance in four cases of basilar impression. Acta radiol., 15:652656.(418) Echols, D. H., 1937. Hematoma of the cerebellum: A report of a case. Univ. Hosp. Bull., Ann Arbor, 3:10-11. (525,) Ecker, A., 1948. Upward transtentorial herniation of brain stem and cerebellum due to tumor of posterior fossa, with special note on tumors of acoustic nerve. J. Neurosurg., 5:51-61. (562) and P. A. Riemenschneider, 1955. Angiographic Localization of Intracranial Masses. Springfield, 111.: Charles C. Thomas. (536) Eckhard, C., 1871. Untersuchungen iiber Hydrurie (Fortsetzung). Beitr. z. Anat. u. Physiol. (Giessen), 6:51-115. (301) , 1872. Ueber den Einfluss des kleinen Gehirns auf die Herz- und Atembewegungen sowie auf die Urinsekretion nach Versuchen an Hunde. Ibid., 6:175-192. (291, 299) , 1879. Physiologic des Riickenmarks und des Gehirns mit Ausschluss der Grosshirnrinde. In Hermann, Handbuch der Physiologic, vol. 2, pt. 2, pp. 1-191. Leipzig: F. C. Vogel. (12) Eckhard, F., 1880. Ueber den Einfluss des Chloralhydrats auf gewisse experimentell zu erzeugenden Diabetesformen. Arch. f. exper. Path. u. Pharmakol, 12:276-282. (301) Ectors, L., 1946. Le cecrvelet freine 1'inertie des muscles immobiles et en mouvement. Rev. neurol., 78:14-23.(369) Edelman, L., 1941. Hypernephroma of the kidney, with solitary metastasis to the cerebellum. J. Mt. Sinai Hosp., 7:343-348. (559) Edinger, L., 1910. Ueber die Einteilung des Cerebellums. Anat. Anz., 35:319-323. (51, 247, 417) , 1912. Ueber das Kleinhirn und den Statotonus. Zentralbl. f. Physiol., 26:618-623. (26) Edward, D. G., 1938. Observations on the cerebellar basis of the Gordon test for lymphadenoma. Lancet, 1:936-938. (488) Edwards, C. H., and J. H. Paterson, 1951. A review of the symptoms and signs of acoustic neurofibromata. Brain, 74:144-190. (562) Eldred, E., 1955. Some brain structures which influence muscle spindles. Federation Proc., 14:43. (256) • , R. Granit, and P. A. Merton, 1953. Supraspinal control of the muscle spindles and its significance. J. Physiol., 122:498-523. (257) Eldred, E., and K. E. Hagbarth, 1954. Facilitation and inhibition of gamma afferents by stimulation of certain skin areas. J. Neurophysiol., 17:59-65. (243) Elkins, C. W., and F. J. Rack, 1951. Tuberculoma of cerebellopontine angle simulating acoustic neuroma. Am. Rev. Tuberc., 63:227-229. (496)

588

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

Ellerman, M., 1943. A case of cerebellar atrophy. J. Nerv. & Ment. Dis., 97:389-396. (US) Ellis, R. S., 1920. Norms for some structural changes in the human cerebellum from birth to old age. J. Comp. Neurol., 32:1-33. (UO, 454, 464) Elsberg, C. A., and N. Gotten, 1933. The results of conservative compared with radical operations in the cerebellar medulloblastomas: Analysis of 23 cases. Bull. Neurol. Inst. New York, 3:3352.(547) Elvidge, A., W. Penfield, and W. Cone, 1937. The gliomas of the central nervous system: A study of 210 verified cases. A. Research Nerv. & Ment. Dis., Proc., 16:107-181. (637, 538, 550) Emerson, J. D., J. M. Bruhn, J. O. Foley, and G. M. Emerson, 1954. Autonomic responses to cerebellar stimulation in unanesthetized cat. Federation Proc., 13:41. (138, 303, 306) Emerson, J. D., J. M. Bruhn, G. M. Emerson, and J. O. Foley, 1956. Autonomic responses to cerebellar stimulation in the suprathalamic decerebrate (decorticate) cat. Federation Proc., 15:58. (304) Engerth, G., and H. Hoff, 1930. Ein weiterer Beitrag zur Lehre von der Stirnhirnfunktion. Ztschr. f. d. ges. Neurol. u. Psychiat., 129:332-341. (405) Erickson, T. C., and G. Ablin, 1953. Palatal myoclonus in association with posterior fossa neoplasma: Two cases. Tr. Am. Neurol. A., 78:201-206. (413, 415) Erskine, C. A., 1950. A symptomatic unilateral agenesis of the cerebellum. Monatschr. f. Psychiat. u. Neurol., 119:321-339. (434, 435) Evans, H. S., A. P. Friedman, and C. B. Courville, 1940. Calcification of small vessels of cerebellum: Report of 2 cases with traumatic hemorrhage. Bull. Los Angeles Neurol. Soc., 5:18-30. (525) Evans, W., and G. Wright, 1942. The electrocardiogram in Friedreich disease. Brit. Heart J., 4:91102.(466) Ewald, J. R., 1892. Physiologische Untersuchungen iiber das Endorgan des Nervus octavus. Wiesbaden: J. F. Bergmann. (272) , 1898. Ueber kiinstliche Reizung der Grosshirnrinde. Deutsche med. Wchnschr. (VereinsBeilage), 24:180-181. (139) Exner, S., 1882. Zur Kenntniss von der Wechselwirkung der Erregungen im Centralnervensystem. Arch. f. d. ges. Physiol., 28:487-506. (329) Fadiga, E., G. C. Pupilli, and G. P. von Berger, 1956. Risposte della corteccia cerebellare a impulsi trasmessi per le vie ottiche. Arch, di sc., biol., 40:541-601. (188-189) Fano, G., 1883. Recherches experimentales sur un nouveau centre automatique dans le tractus bulbospinal. Arch. ital. de biol., 3:365-368. (13) , 1895. Contribution a la localisation corticale des pouvoirs inhibiteurs. Ibid., 24:444-446. (329) , 1921. Nouvelles recherches sur les fonctions de 1'encephale de 1'Emys europaea. Arch, internat. de physiol., 18:535-548. (13) and G. Masini, 1893. Intorno agli effetti delle lesioni portate sull'organo dell'udito: Ricerche sperimentali. Sperimentale, 47:353-405. (272) Fattovich, G., 1938. Contribute allo studio delle lesioni vascolari del cervelletto. Gior. di clin. med., 19:883-893. (512) , 1950. Sui rammollimenti cerebellari (contributo clinico ed anatomo-patologico). Cervello, 26:48-64. (512) Fava, F. J., H. G. Foss, and E. A. Phillip, 1954. Transabdominal encephalocentesis in a case of congenital hydrocephalus. Am. J. Obst. & Gynec., 67:158-160. Fazzari, I., 1924. La circolazione arteriosa della corteccia cerebellare. Riv. di pat. nerv., 29:425-459. (72) , 1931. Le arterie del cervelletto. Mem. R. Accad. Naz. Lincei, cl. sc. fis. mat. e nat., 4:333418.(72) , 1933. L'irrorazione arteriosa dei nuclei cerebellari nell'uomo. Riv. di pat. nerv., 41:558-586. (510) Feigin, I., 1956. Arnold-Chiari malformation with associated analogous malformation of the midbrain. Neurology, 6:22-31. (424) Feremutsch, K, 1952. Das Kleinhirn. Fortschr. d. Neurol., Psychiat., 20:24-41. (369) Ferey, M. D., 1950. Le traitement chirurgical des hematomes intracerebraux et intra-cerebelleux: A propos de trente-trois cas operes. Rev. neurol., 83:368-370. (520) Ferraro, A., and S. E. Barrera, 1935. The effects of lesions of the dorsal spino-cerebellar tract and corpus restiforme in the Macacus rhesus monkey. Brain, 58:174-202. (89-90) , 1936a. Effects of lesions of the juxtarestiform body (I.A.K. bundle) in Macacus rhesus monkeys. Arch. Neurol. & Psychiat., 35:13-29. (65, 88, 89, 90, 91) , 1936b. The effects of lesions of the superior cerebellar peduncle in the Macacus rhesus monkey. Bull. Neurol. Inst. New York, 5:165-179. (55, 88, 92)

BIBLIOGRAPHICAL INDEX OF AUTHORS

589

, 1938. Differential features of "cerebellar" and "vestibular" phenomena in Macacus rhesus: Preliminary report based on experiments on 300 monkeys. Arch. Neurol. & Psychiat., 39:902918. (55, 89, 90, 91)

Ferraro, A., and L. M. Davidoff, 1931. Effects of fragmentary and complete extirpation of the cerebellum of the cat: A preliminary report on cerebellar localization. Arch. Neurol. & Psychiat., 26:1-22. (62, 67, 68, 69)

Ferraro, A., and R. Hernandez, 1932. Lead poisoning. Psychiatric Quart., 6:121-146, 319-350. (486) Ferrero, C., 1948. Syndrome cerebelleux d'origine frontale: Observation anatomo-clinique. Encephale, 37:147-161. (405) Ferri, G., 1925. Qualche osservazione relativa alia tecnica degli interventi operatori sperimentali sul cervelletto. Arch, fisiol., 23:183-191. (72) Ferrier, D., 1876. The Functions of the Brain. London: Smith-Elder & Co. (6, 23, 52, 103, 105, 109, 138, 271, 303, 426)

, 1894. Recent work on the cerebellum and its relations: With remarks on the central connexions, and trophic influence of the fifth nerve. Brain, 17:1-26. (24, 35, 36, 4.7, 97) , 1900. The regional diagnosis of cerebral disease. In Allbutt's System of Medicine, vol. 7, pp. 271-394. (417) and W. A. Turner, 1894. A record of experiments illustrative of the symptomatology and degenerations following lesions of the cerebellum and its peduncles and related structures in monkeys. Philos. Tr. Roy. Soc., s. B, 185:719-778. (49, 52, 88, 91, 92) Ferris, H. W., 1929. Eight cases of tuberculoma of the brain found at necropsy. J.A.M.A., 92:16701674.(495) Fiessinger, N., M. Duvoir, and G. Boudin, 1936. Syndrome cerebello-spasmodique durable survenu apres un coma apparement du a une intoxication cyandydrique. Bull, et mem. Soc. med. d. hop. de Paris, 52:1365-1373. (486) Finley, K., 1935. An anatomical study in familial olivo-ponto-cerebellar hypoplasia in cats. Koninklijke Akademie van Wetenschappen te Amsterdam, Proceedings, 38:1-10. (438, 439) Flechsig, P. E., 1883. Plan des menschlichen Gehirns. Leipzig: Veit & Co. (426) Fletcher, D. E., and R. H. Rigdon, 1946. Neurologic manifestations associated with malaria in ducks: Clinico-pathological study. Arch. Neurol. & Psychiat., 55:35-42. (481, 482) Flourens, P., 1822. Determination des proprietes du systeme nerveux. Memoires lus a 1'Academie des Sciences de 1'Institut dans les seances du 31 mars et 27 avril 1822. Rapport par M. le baron Cuvier, secretaire perpetuel de 1'Academie. J. de physiol. exper. et pathol., 2:327-384. (See also Flourens, 1824, 1842, pp. 26-59.) (14, 23) —, 1824, 1842. Recherches experimentales sur les proprietes et les fonctions du systeme nerveux dans les animaux vertebras. Ed. 1, Paris: Crevot, 1824; ed. 2, Paris: Bailliere, 1842. (4, 5, 12, 13, U, 23) , 1831. Action exercee par certaines substances immediatement appliquees sur les differentes parties du cerveau. Memoire lu a 1'Academie Royale des Sciences, 7 Fevrier. (See Flourens, 1842, pp. 405-411.) (Ill) Fodera, M., 1823. Recherches experimentales sur le systeme nerveux. J. de physiol. exper. et pathol., 3:191-217. (5,12,14, 23) • , 1826. Lettre au redacteur general. J. compl. d. sc. med., 26:101-110. (14) Foerster, O., and H. Altenburger, 1935. Elektrobiologische Vorgange an der menschlichen Hirnrinde. Deutsche Ztschr. f. Nervenh., 135:277-288. (163) Foerster, O., and 0. Gagel, 1939. Das umschriebene Arachnoidealsarkom des Kleinhirns. Ztschr. f. d. ges. Neurol. u. Psychiat., 164:565-580. (561) Foix, C., J. A. Chavany, and P. Hillemand, 1926. Le syndrome myoclonique de la calotte: Etude anatomo-clinique du nystagmus du voile et des myoclonies rythmiques associees, oculaires, faciales, etc. Rev. neurol., 1:942-956. (413) Foix, C., and P. Hillemand, 1924. Nystagmus du voile du palais associe a un nystagmus oculaire synchrone et a des secousses myocloniques de la face, synchrones egalement. Rev. neurol., 1:588— 592.(413) Foix, C., P. Hillemand, and I. Schalit, 1925. Sur le syndrome lateral du bulbe et 1'irrigation du bulbe superieur. Rev. neurol., 1:160-179. (512) Foix, C., and Tretiakoff, 1920. Les lesions medullaires au cours de 1'heredoataxie cerebelleuse de la maladie de Friedreich et de la paraplegic spastique familiale. Bull, et mem. Soc. med. d. hop. de Paris, 44:1140-1151. (469) Forbes, A., and C. S. Sherrington, 1914. Acoustic reflexes in the decerebrate cat. Am. J. Physiol., 35:367-376.(346) Ford, E., 1790. Some remarks on hydrocephalus internus. London M. J., pp. 56-67. (See Scott and Groves, 1933.) (494)

590

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

Ford, F. R., and D. Clark, 1956. Thrombosis of the basilar artery with softenings in the cerebellum and brain stem due to manipulations of the neck; a report of two cases with one post-mortem examination, reasons are given to prove that damage of the vertebral arteries is responsible. Bull. Johns Hopkins Hosp., 98:37-42. (521) Ford, F. R., S. Livingston, and C. V. Pryles, 1951. Familial degeneration of the cerebral gray matter in childhood, with convulsions, myoclonus, spasticity, cerebellar ataxia, choreoathetosis, dementia, and death in status epilepticus; differentiation of infantile and juvenile types. J. Pediat., 39:3343. (477) Forster, A., 1943. Cerebrale Spatfolgen und ein Astrocytoma cerebelli nach Trauma. Deutsche Ztschr. f. d. ges. geritchtl. Med., 37:105-117. (522) Frankenhaeuser, B., 1951. Limitations of method of strychnine neuronography. J. Neurophysiol., 14:73-79. (179) Fraser, D., 1880. Defect of cerebellum occurring in a brother and sister. Glasgow M. J., 13:199-210. (450) Fraser, J. S., 1920. Tumors of the eighth nerve. Proc. Roy. Soc. Med. (sec. Otol.), 13:109-161. (562) Frazier, C. H., 1936. Tumor involving the frontal lobe alone: A symptomatic survey of one hundred and five verified cases. Arch. Neurol. & Psychiat., 35:525-571. (405) Freedman, D. A., and J. E. Schenthal, 1953. A parenchymatous cerebellar syndrome following protracted high body temperature. Neurology, 3:513-516. (491) Freeman, W., 1929. Cerebellar agenesis: Preliminary report of an extreme case. Arch. Neurol. & Psychiat., 22:858-859. (426) , 1933. Palatal myoclonus. Ibid., 29:743-755. (413) and E. Dumoff, 1944. Cerebral syndrome following heat stroke. Arch. Neurol. & Psychiat., 51:67-72. (491) Freeman, W., and D. Jaffe, 1941. Occlusion of the superior cerebellar artery: Report of a case with necroscopy. Arch. Neurol. & Psychiat., 46:115-126. (516) Freifeld, H., 1933. Veranderungen des Nervensystems bei Bleivergiftung: Entstehung der Bleikolik. Virchows Arch. f. path. Anat., 287:549-554. (486) Freiman, I. S., and B. J. Ficarra, 1943. Osteochondroblastic meningioma of left cerebellar hemisphere. Arch. Path., 35:900-905. (560) Fremel, F., 1923a. Morphologic und Wachstum des Kleinhirnabscesses. Monatschr. f. Ohrenheilk., 57:517-547. (503) , 1923b. Der Nystagmus als Symptom bei otogenen intrakraniellen Erkrankungen. Ibid., 57: 930-946.(505) , 1926. Zur Frage der Morphologic und des Wachstums der Kleinhirnabscesse. ZentralbL Hals-, Nasen u. Ohrenh., 16:68-76. (503) Friedlander, A., 1898. Untersuchungen iiber das Riickenniark und das Kleinhirn der Vogel. Neurol. ZentralbL, 17:351-359, 397-409. (U) Friedmann, U., and A. Elkeles, 1933. Studies on the aetiology of blood diseases: A pathogenic agent in normal human bone marrow. Brit. Med., 2:1110-1112. (488) Friedreich, N., 1863. Ueber degenerative Atrophie der spinalen Hinterstrange. Virchows Arch. f. path. Anat., 26:391-419, 433-459; 27:1-26. (467) Friesner, I., and A. Braun, 1916. Cerebellar Abscess. New York: Paul Hoeber. (499) Frigerio, A., 1922. Sull'istopatologia della mioclonoepilessia. Note e riv. di psichiat., 10:319-338. (JUS)

Fritsch, G., and E. Hitzig, 1870. Ueber die elektrische Erregbarkeit des Grosshirns. Arch. f. Anat., Physiol. u. wissensch. med., 37:300-332. (103) Fulle, C., 1913. Sulle compensazioni organiche e funzionali delle deficienze cerebellari. Arch, fisiol., 11:379-385. (331) Fulton, J. F., 1929. A case of cerebellar tumor with seizures of head retraction described by Wurffbain in 1691. J. Nerv. & Ment. Dis., 70:577-583. (408) , 1936. The interrelation of cerebrum and cerebellum in the regulation of somatic and autonomic functions. Medicine, 15:247-306; also Harvey Lect., 31:135-182. (305, 335) , 1949. Functional localization in the frontal lobes and cerebellum. Oxford: Clarendon Press. (Z&

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ZQ

OU,

Q®& OO%, 339 3I3I/J) O<Jl}/

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and G. Connor, 1939. The physiological basis of three major cerebellar syndromes. Tr. Am. Neurol. A., 65:53-57. (58) Fulton, J. F., and R. S. Dow, 1937. The cerebellum: A summary of functional localization. Yale J. Biol. & Med., 10:89-119. (66, 354, 369, 381, 388) Fulton, J. F., and M. A. Kennard, 1932. A study of flaccid and spastic paralyses produced by lesions of the cerebral cortex in primates. A. Research Nerv. & Ment. Dis., Proc., 13:158-210. (335)

BIBLIOGRAPHICAL INDEX OF AUTHORS

591

Fulton, J. F., E. G. T. Liddell, and D. McK. Rioch, 1930. The influence of unilateral destruction of the vestibular nuclei upon posture and the knee-jerk. Brain, 53:327-343. (230, 334, 337) , 1932. Relation of the cerebrum to the cerebellum. I. Cerebellar tremor in the cat and its absence after removal of the cerebral hemispheres. Arch. Neurol. & Psychiat., 28:542-570. (30, 466) Fusari, R., 1892. Caso di mancanza quasi totale del cervelletto. Atti Accad. Sc. Bologna, series 5, 2:177-192; also Mem. R. Accad. d. 1st. di Bologna, 2:643-658. (427, 430) Fuse, G., 1930. Sinkeikagaku Zassi, 32:120. Cited by Wiggers, 1942b, 1943a, and Simkina, 1948. (291, 299) Galante, E., 1914a. L'eccitabilita del cervelletto nei cani neonati. Riv. di pat. nerv., 19:129-136. (Ill, 366) , 1914b. L'excitabilite du cervelet chez les chiens nouveau-nes. Arch. ital. de biol., 62:203-208. (Ill, 366) Gall, F. J., 1822-1825. Sur les fonctions du cerveau et sur celles de chacune de ses parties, avec des observations sur la possibilite de reconnoitre les instincts, les penchants, les talents ou les dispositions morales et intellectuelles des hommes et des animaux, par la configuration de leur cerveau et de leur tete. 6 vols. Paris: Bailliere. (6, 308) Gallerani, G., and A. Borgherini, 1892a. Sezione mediana antero-posteriore del verme del cervelletto: Contributo allo studio della fisiologia del cervelletto. Riv. sper. di freniat., 18:369-380. (See Luciani, 1892.) (23) , 1892b. Risposta [to Luciani's observations, 1892]. Ibid., p. 388. (23) Gallet, J., 1927. Le nystagmus du voile et les myoclonies associees oculaires, faciales, subhyoidiennes, diaphragmatiques, le syndrome myoclonique de la calotte protuberantielle. These, Paris. Soc. fr. impr. Poitiers. (413) Garcin, R., I. Bertrand, and P. Frumason, 1933. Etude anatomoclinique d'un cas de syndrome de Parinaud et de myoclonies rythmiques du voile du palais. Rev. neurol., 2:812-820. (413) Gardner, L. I., and G. C. Reyersbach, 1951. Brain damage in a juvenile diabetic patient associated with insulin hypoglycemia. Pediatrics, 7:210-214. (490) Gardner, W. J., and W. A. Nosik, 1942. Experience with encephalography in cerebellar tumor. Am. J. Roentgenol., 47:691-698. (583) Garol, H. W., 1942. The "motor" cortex of the cat. J. Neuropath. & Exper. Neurol., 1:139-145. (329, 333) Gastaut, H., 1951. Manifestations electrographiques de 1'activite des voies optiques. Riv. neurol., 21:261-287. (188) , R. Naquet, A. Roger, and M. Badier, 1951. Reponse irradiee cerebelleuse a la stimulation lumineuse chez le chat soumis a Faction du cardiazol. Compt. rend. Soc. de biol., 145:916-917. (188) Gauthier, C., A. Mollica, and G. Moruzzi, 1956. Physiological evidence of localized cortico-cerebellar projections onto the bulbar reticular formation. J. Neurophysiol., 19:468-483. (175, 228-229, 248) Geary, J. R., K. M. Earle, and A. S. Rose, 1956. Olivopontocerebellar atrophy. Neurology, 6:218-224. (461) Gellhorn, E., and H. M. Ballin, 1948. Role of afferent impulses in experimental convulsions. Arch. Neurol. & Psychiat., 59:718-733. (179) Gellhorn, E., J. Hyde, and J. Gay, 1949. Proprioception and convulsions. Arch, internat. de pharmacodyn., 80:110-118. (179) Gellhorn, E., and M. Kessler, 1942. The effect of hypoglycemia on the electroencephalogram at varying degrees of oxygenation of the blood. Am. J. Physiol., 136:1-6. (490) Gerard, M. W., 1923. Afferent impulses of the trigeminal nerve: The intramedullary course of the painful, thermal and tactile fibers. Arch. Neurol. & Psychiat., 9:306-338. (513) Gerard, R. W., and H. W. Magoun, 1936. Influence of potassium and calcium in motor discharges. Proc. Soc. Exper. Biol., 34:755-756. (147) Gerard, R. W., W. H. Marshall, and L. J. Saul, 1936. Electrical activity of the cat's brain. Arch. Neurol. & Psychiat., 36:675-738. (186) Gerebtzoff, M. A., 1942. Contribution a la physiologic comparee du cervelet: Le cervelet des anoures. Arch, internat. de physiol., 52:249-260. (12, 105) Gildea, E. F., and S. Cobb, 1930. The effects of anemia on the cerebral cortex of the cat. Arch. Neurol. & Psychiat., 23:876-903. (481, 489) Girard, P. F., G. Bonamour, A. Garde, and R. Etienne, 1950. Les syndromes de 1'obliteration de 1'artere cerebelleuse superieure et du ramollissement global de la calotte protuberantielle dans son tiers superieur: Participation du pathetique. Rev. neurol., 83:199-201. (402, 516) Gispert Cruz, I. de, 1942. Cerebelitis agudas primitivas. Rev. clin. espan., 7:272-274. (485)

592

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

Giulio, L., and E. Manni, 1950. Simpatico lombare e tono degli arti nel piccione spinale. Boll. Soc. ital. biol. sper., 26:1080-1081. (271, 308) Globus, J. H., 1923. Ein Beitrag zur Histopathologie der amaurotischen Idiotic. Ztschr. f. d. ges. Neurol. u. Psychiat., 85:424-466. (474) , 1948. DDT (2,2bis[jj-chlorophenyl] 1,1,1-trichloroethane) poisoning: Histopathologie observations on the central nervous system in so-treated monkeys, dogs, cats and rats. J. Neuropath. & Exper. Neurol., 7:418-431. (487) , S. Levin, and J. G. Sheps, 1944. Primary sarcomatous meningioma (Primary sarcoma of the brain). J. Neuropath. & Exper. Neurol., 3:311-343. (561) Globus, J. H., and I. Strauss, 1925. Spongioblastoma multiforme. Arch. Neurol. & Psychiat., 14:139191.(549) Gliick, G., 1939. Cerebellite da parotite epidemica. Biv. neurol., 12:309-316. (484) Goldman, M. A., and R. S. Snider, 1955. Mono- and multisynaptic arcs of cerebellum. J. Neurophysiol., 18:536-546. (219) Goldstein, K., 1913. Ueber Storungen der Schwereempfindung bei gleichseitiger Kleinhirnaffektion. Neurol. Centralbl, 32:1082-1087. (358) •, 1927. Das Kleinhirn. In A. Bethe, G. von Bergmann, G. Embden, and A. Ellinger, Handbuch der normalen und pathologischen Physiologic, vol. 10, pp. 222-317. Berlin: J. Springer. (353, 354, 358, 369, 379) and F. Reichmann, 1916. Beitrage zur Kasuistik und Symptomatologie der Kleinhirnerkrankungen. Arch. f. Psychiat., 56:466-521. (354, 358) Golgi, C., 1875. Sui gliomi del cervello. Rev. spir. di freniat., 1:66-78. (536) Goltz, F., 1869. Beitrage zur Lehre von den Funktionen der Nervenzentren des Frosches. Berlin: A. Hirschwald. (12) , 1881. Ueber die Verrichtungen des Grosshirns. Arch. f. d. ges. Physiol., 26:1-49. (23) Gonzales, R. A., 1948. Differential diagnosis of tumors at the cerebellopontile recess. Bull. Johns Hopkins Hosp., 83:178-212. (558, 562) Gonzalo Sanz, L. M., 1954. Aportaciones al estudio de la influencia cerebelosa en la actividad bioelectrica del encefalo. An. de anat., 3:275-296. (330) Goodhart, S. P., and C. Davison, 1936. Syndrome of the posterior inferior and anterior inferior cerebellar arteries and their branches. Arch. Neurol. & Psychiat., 35:501-524. (512, 514) Gordon, A., 1908. A special diagnostic phenomenon in cerebellar disease. J. A. M. A., 51:461-463. (403) , 1917. Lesions of the frontal lobe simulating cerebellar involvement: Differential diagnosis. J. Nerv. & Ment. Dis., 46:261-275. (406) • , 1934. Frontal lobe lesions with cerebellar manifestations: Contribution to the frontal lobe as a center of equilibrium. Ibid., 79:411-422. (405) , 1935. Visual field defects as a deciding diagnostic factor in lesions of temporal lobe simulating cerebellar involvement. Ibid., 82:394-399. (406) , 1938. Cerebellar coma. Ibid., 88:193-199. (411) Gordon, M. H., 1932. In T. Border, M. H. Gordon, K. Stone, L. P. Garrod, E. R. Cullinan, and B. D. Pullinger, Rose Research on Lymphadenoma. Bristol: John Wright & Sons, Ltd. (458, 488) Gordy, P. G., 1948. Extradural hemorrhage of the anterior and posterior fossae. J. Neurosurg., 5:294298.(523) Gowers, W. R., 1890. Notes on the function of the nervous system. Lancet, 68(l):955-956. (389) • and A. E, Barker, 1886. On a case of abscess of the temporo-sphenoidal lobe of the brain, due to otitis media, successfully treated by trephining and drainage. Brit. M. J., 2:1154-1156. Cited by Davidoff, 1935. (498) Gozzano, M., 1935. Ricerche sui fenomeni elettrici della corteccia cerebellare. Riv. neurol., 8:212265.(179) • , 1936. Bioelektrische Erscheinungen bei der Reflexepilepsie. J. Psychol. u. Neurol., 47:24-39. (179) Grabower, 1912. Zur Frage eines Kehlkopfzentrums in der Kleinhirnrinde. Arch. f. Laryng., 26:17-28. (61) Grahe, K., 1932. Him und Ohr. Leipzig: George Thieme. (398) Granit, R., 1950a. Reflex self-regulation of muscle contraction and autogenetic inhibition. J. Neurophysiol., 13:351-372. , 1950b. Autogenetic inhibition. Electroencephalog. & Clin. Neurophysiol., 2:417-424. , 1955a. Receptors and Sensory Perception. New Haven: Yale Univ. Press. (252, 256, 257, 260, 263, 267, 268, 346, 371) , 1955b. Centrifugal and antidromic effects on ganglion cells of retina. J. Neurophysiol., 18: 388-411.(348)

BIBLIOGRAPHICAL INDEX OF AUTHORS

593

, H. D. Henatsch, and G. Steg, 1956. Tonic and phasic ventral horn cells differentiated by post-tetanic potentiation in cat extensors. Acta physiol. Scandinav., 37:114-126. (262) Granit, R., B. Holmgren, and P. A. Merton, 1955. The two routes for excitation of muscle and their subservience to the cerebellum. J. Physiol., 130:213-224. (61, 242, 243, 257-259, 260, 268, 274, 275, 356) Granit, R., C. Job, and B. Kaada, 1952. Activation of muscle spindles in pinna reflex. Acta physiol. Scandinav., 27:161-168. (243) Granit, R., and B. Kaada, 1952. Influence of stimulation of central nervous structures on muscle spindles in cat. Acta physiol. Scandinav., 27:130-160. (119, 242, 243, 244, 248, 256, 257, 260, 353, 356) Granit, R., and C. G. Phillips, 1956a. Two types of inhibition of cerebellar Purkinje cells. J. Physiol., 132:58P-59P. (168,172,173) , 1956b. Excitation and inhibition of cerebellar Purkinje cells. Proc. XX Internat. Congress Physiol., Brussels, pp. 364-365. (168, 172,173) — , 1956c. Excitatory and inhibitory processes acting upon individual Purkinje cells of the cerebellum in cats. J. Physiol., 133:520-547. (168, 169-170, 171, 172, 173) — , 1957. Effect on Purkinje cells of surface stimulation of the cerebellum. J. Physiol., 135:73-92. (156,168,171,172,173) Grant, F. C., 1928. Cerebellar symptoms produced by supratentorial tumors: Further report. Arch. Neurol. & Psychiat., 20:292-308. (404, 405) , 1929. A clinical study of midline cerebellar tumors in children. Clin. North America, 9:11551168. (543) and G. M. Austin, Jr., 1949. Evacuation of the traumatic extradural hemorrhage from the posterior fossa. Ann. Surg., 130:963-966. (523) Grant, F. C., and L. Fisher, 1926. One hundred and sixteen verified intracranial lesions with report of vestibular test findings: Their value in localization. J. f. Psychol. u. Neurol., 34:113-185. (398) Grant, F. C., J. E. Webster, and L. M. Weinberger, 1941. Unusual symptomatology with tumors of the cerebellum based on 158 verified cases. Am. J. M. Sc., 202:313-329. (379) Grant, W. T., 1944. Clinical diagnosis of cerebellar injuries. California & West. Med., 60:204-209. (522) Gratiolet, P., and M. Leven, 1860. Sur les mouvements de rotation sur 1'axe que determinent les lesions du cervelet. Compt. rend. Acad. d. sc., 51:917-921. (109) Grawitz, P., 1880. Beitrag zur Lehre von der basilaren Impression des Schadels. Virchows Arch. f. path. Anat., 80:449-474. (418) Greenfield, J. G., 1934. Subacute spino-cerebellar degeneration occurring in elderly patients. Brain, 57:161-176. (455, 456) • , 1954. The Spino-Cerebellar Degenerations. Springfield, 111.: Charles C. Thomas. (412, 447, 449, 452, 467, 469, 473) Greggio, E., 1914. Contribute sperimentale allo studio delle localizzazioni cerebellari. Folia neurobiol., 8:157-185. (73,109) —, 1922. Sulla patogenesi di alcuni fenomeni di lesioni cerebellari. Ibid., 12:189-209. (73, 109) Greker, 1909. Quoted by Bechterew, 1909, vol. 2, pp. 877-878. (103, 104, 138) Grey, E. G., 1915a. Studies on the localization of the cerebellar tumors. I. Significance of staggering gait, limb ataxia, the Romberg test, and adiadochokinesis. J. Nerv. & Ment. Dis., 42:670-679. (379) —, 1915b. Studies on the localization of cerebellar tumors. III. Posterior new growths without nystagmus. J. A. M. A., 65:1341-1345. (379) , 1916a. Studies on the localization of cerebellar tumors: The position of the head and suboccipital discomforts. Ann. Surg., 63:129-139. (379, 382) , 1916b. Studies on the localization of cerebellar tumors. II. Pointing reaction and caloric test. Am. J. M. Sc., 151:693-705. (379, 398) , 1916c. Studies on the localization of cerebellar tumors. V. The cranial nerves. Bull. Johns Hopkins Hosp., 27:251-262. (379) , 1916d. On localization of function in the canine cerebellum. J. Nerv. & Ment. Dis., 43:105120. (67, 68, 69, 331) Grinker, R., and P. C. Bucy, 1949. Neurology. Springfield, 111.: Charles C. Thomas. (463) Grinker, R., and R. A. Lifvendahl, 1928. A study of cerebral tuberculomas. Arch. Neurol. & Psychiat., 20:415-416. (497) Groebbels, F., 1927a. Zur feineren Analyse der Beziehungen zwischen Labyrinth und Kleinhirn. Klin. Wchnschr., 6:1806-1807. (272, 289)

594

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

, 1927b. Die Lage- und Bewegungsreflexe der Vogel. V Mitt. Die physiologische Gruppierung der Lage- und Bewegungsreflexe der Haustaube und ihre weitere Analyse durch Labyrinthentfernung und galvanische Reizung nach Entfernung des Labyrinths und seiner Teile. Arch. f. d. ges. Physiol, 217:631-654. (272, 289) , 1928a. Die Lage- und Bewegungsreflexe der Vogel. VI Mitt. Degenerationsbefunde am Zentralnervensystem der Taube nach Entfernung des Labyrinths und seiner Teile. Ibid., 218:8997. (272) , 1928b. Anatomisch-physiologische Untersuchungen iiber die Beziehungen zwischen Labyrinth und Kleinhirn. Deutsche Ztschr. f. Nervenh., 107:154-160. (272) , 1929a. Die Lage- und Bewegungsreflexe der Vogel. IX Mitt. Die Wirkung von Kleinhirnlasionen und ihre anatomisch-physiologische Analyse. Arch. f. d. ges. Physiol., 221:15-40. (272) , 1929b. Die Lage- und Bewegungsreflexe der Vogel. X Mitt. Die Analyse der Beziehungen zwischen Labyrinth und Kleinhirn. Ibid., pp. 41-49. (272) , 1929c. Die Lage- und Bewegungsreflexe der Vogel. XI Mitt. Die Analyse der Stiitzreaktion. Ibid., pp. 50-65. (272) Grossman, M. O., and B. H. Kesert, 1944. Familial incidence of tumors of the brain: Cerebellar hemangioblastoma. Arch. Neurol. & Psychiat., 52:327-328. (55k) Grotts, B. F., 1949. Astroblastoma of the cerebellum in an infant: Report of a case. Arch. Pediat., 66:283-288. (549) Grove, W. E., 1931. The ear in head injuries: Practical considerations. Ann. Otol., Rhino. & Laryng., 40:222-241.(522) Grundfest, H., and B. Campbell, 1942. Origin, conduction and termination of impulses in the dorsal spino-cerebellar tracts of cats. J. Neurophysiol., 5:275-294. (185, 195, 196, 197, 200, 201, 216, 238,243, 251) Gualtierotti, T., 1954. Ulteriori osservazioni sulla cosidetta elettronarcosi cerebellare e cerebrale. Arch, fisiol., 54:81-91. (177; and V. Capraro, 1941. Influenza degli stimoli periferici e central! sulle variazioni dei potenziali d'azione del cervelletto. Arch. di. sc. biol., 27:247-262. (163, 179, 205) Gualtierotti, T., and R. Margaria, 1956. Electrical activity of the cerebellum in the intact and decerebrated cat: The role of the pontine structures. Yale J. Biol. & Med., 28:298-307. (177, 178) Gualierotti, T., and E. Martini, 1952. Sulla cosidetta elettronarcosi cerebellare. Arch, fisiol., 52:189204.(177) , and A. Marzorati, 1943. Untersuchungen liber die Elektronarkose: Mit besonderer Beriicksichtigung der aktiven elektrischen Erscheinungen des zentralen Nervensystems. Arch. f. d. ges. Physiol., 246:359-371. (176) , 1949. Electronarcosis. I. Inhibition of electrical activity of the cerebellum. J. Neurophysiol., 12:363-369. (176) Guillain, G., 1938. The syndrome of synchronous and rhythmic palato-pharyngo-laryngo-oculodiaphragmatic myoclonus. Proc. Roy. Soc. Med., London, 31:1031-1038. (413) •———, Th. Alajouanine, I. Bertrand, and R. Garcin, 1929. Etude anatomo-clinique d'un ramollissement cerebelleux frappant electivement les pedoncules moyen et inferieur d'un cote: Du role des arterites aigues dans certain ramollissements des atheromateux. Rev. neurol., 1:12631272. (401, 512) Guillain, G., I. Bertrand, and J. Godet-Guillain, 1941. Etude anatomique d'un cas d'heredo-ataxie cerebelleuse. Rev. neurol., 73:609-611. (469) Guillain, G., I. Bertrand, and J. Lereboullet, 1934. Myoclonies arythmiques unilaterales des membres par lesion du noyau dentele du cervelet. Rev. neurol., 2:73-78. (402) Guillain, G., I. Bertrand, and P. Mollaret, 1932. Les lesions sus-medullaires dans la maladie de Friedreich. Compt. rend. Soc. de biol., 111:965-967. (467) Guillain, G., I. Bertrand, and W. Peron, 1928. Le syndrome de 1'artere cerebelleuse superieure. Rev. neurol., 2:222-227. (516) Guillain, G., I. Bertrand, and R. Thurel, 1933. Etude anatomo-clinique d'un cas d'atrophie olivoponto-cerebelleuse avec symptomes pseudo-bulbaires. Rev. neurol., 2:138-154. (459, 462) Guillain, G., J. Christophe, and I. Bertrand, 1929. Abces tuberculeux du cervelet: Sur la coloration des bacilles de Koch dans le nevraxe. Bull, et mem. Soc. med. d. hop. de Paris, 45:1031-1037. _ (496) Guillain, G., and P. Mollaret, 1931. Deux cas de myoclonies synchrones et rythmees velo-pharyngolaryngo-oculo-diaphragmatiques: Le probleme anatomique et physio-pathologique de ce syndrome. Rev. neurol., 2:545-566. (413, 414, 415) , 1932. Nouvelle contribution a 1'etude des myoclonies velo-pharyngo-laryngo-oculo-diaphragmatiques. Ibid., 2:249-264. (413)

BIBLIOGRAPHICAL INDEX OF AUTHORS

595

, 1935. Le syndrome myoclonique. Synchrone et rythme. Velo-pharyngo-laryngo-oculo-diaphragmatique. Presse med., 45:57-60. (4-13) Guillain, G., R. Thurel, and I. Bertrand, 1933a. Sur la lesion responsable du syndrome myoclonique du tronc cerebral: Etude anatomique d'un cas demonstratif sans lesions focales. Rev. neurol., 2:666-674.(41S) , 1933b. Examen anatomo-pathologique d'un cas de myoclonies velo-pharyngo-oculo-diaphragmatiques associes a des myoclonies squeletiques synchrones. Ibid., 2:801-812. (4-13) Guillaume, J., R. Roge, and P. Janny, 1949. Les hematomes spontanes du cervelet: Etude clinique et therapeutique. Presse med., 57:567. (520) Guillaume, J., and J. Sigwald, 1943. Hematomes intracerebelleux operes. Rev. neurol., 75:246. (520) Gurdijian, E. S., and J. E. Webster, 1942. Extradural hemorrhage: Collective review of literature and report of 30 cases of middle meningeal hemorrhage and 4 cases of dural sinus hemorrhage treated surgically. Internat. Abstr. Surg., 75:206-220. (523) Gustafson, W. A., and E. Oldberg, 1940. Neurologic significance of platybasia. Arch. Neurol. & Psychiat., 44:1184-1198. (£18) Hacker, A., 1931. Zur Physiologic des Reptilienkleinhirns. Ztschr. vergl. Physiol., 15:679-692. (IS) Haddad, B., 1953. Projection of afferent fibers from the knee joint to the cerebellum of the cat. Am. J. Physiol., 172:511-514. (191,198) Haene, A. de, 1937. Contribution a 1'etude clinique et anatomique de "Patrophie cerebelleuse tardive a predominance corticale." J. beige de neurol. et de psychiat., 37:427-454. (452, 454, 458) Hagbarth, K. E., 1952. Excitatory and inhibitory skin areas for flexor and extensor motoneurones. Acta physiol. Scandinav., 26, suppl. 94:1-58. (244) and D. I. B. Kerr, 1954. Central influences on spinal afferent conduction. J. Neurophysiol., 17:295-307. (347, 348) Halm, R., 1950a. Eccitamento galvanico del labirinto nelle lesioni limitate della corteccia cerebellare. Boll. Soc. ital. biol. sper., 26:43-45. (287, 288) , 1950b. Soglia vestibolare galvanica dopo lesione flocculo-nodulare del cervelletto in animali a labirinti integri e slabirintati. Ibid., 26:934-935. (287, 288) , 1951. Eccitabilita vestibolare (stimolazione galvanica) dopo emidecerebellazione e decerebellazione totale. Ibid., 27:27-28. (288) , 1952. Influenza delle posizioni compensatorie oculari da riflessi otolitici e del collo sull'attivita fasica da stimolazione vestibolare galvanica. Arch, fisiol., 52:20-29. (287, 288, 289) Hall, A. J., and E. C. Eaves, 1934. Posterior inferior cerebellar thrombosis with unusual features. Lancet, 2:975-979. (512) Hall, B., K. B. Noad, and 0. Latham, 1941. Familial cortical cerebellar atrophy. Brain, 64:178194.(449) , 1945. Familial cortical cerebellar atrophy: A contribution to the study of heredo-familial cerebellar disease in Australia. M. J. Australia, 1:101-108. (449) Haller, A. von, 1757-1766. Elementa physiologiae corporis humani. 8 vols. See Vol. 1, Fibra, Vasa, Circuitus sanguinis, Cor. (Lausanne: Michael Bousquet, 1757), pp. 474-479; and Vol. 4, Cerebrum, Nervi, Musculi (Lausanne: Francisci Grasset, 1766), pp. 345-351. (S, 4) Haliervorden, J., 1936. Die hereditare Ataxie. In O. Bumke and O. Foerster, Handbuch der Neurologie, vol. 16, pp. 657-660. Berlin: J. Springer. (467) Halstead, W. C., 1935. The effects of cerebellar lesions upon the habituation of post-rotatory nystagmus. Comp. Psychol. Monogr., 12:1-130. (289) , G. Yacorzynski, and F. Fearing, 1937. Further evidence of cerebellar influence in the habituation of after-nystagmus in pigeons. Am. J. Physiol., 120:350-355. (289) Hammond, W. A., 1867. On convulsive tremor. New York M. J., 5:185-198. (411) Hampson, J. L., 1948. Relationships between the cerebral and cerebellar cortices in the cat. Federation Proc., 7:50. (207-208, 245, 247, 250) , 1949. Relationships between cat cerebral and cerebellar cortices. J. Neurophysiol., 12:37-50. (138, 207-208, 245, 247, 250, 303) , C. R. Harrison, and C. N. Woolsey, 1945. Somatotopic localization in anterior lobe and lobulus simplex of cerebellum in cat and dog. Federation Proc., 4:31. (124, 125, 127, 135, 137, 138) , 1946. Somatotopic localization in the cerebellum. Ibid., 5:41. (125, 127, 135, 138) , 1952. Cerebro-cerebellar projections and the Somatotopic localization of motor function in the cerebellum. A. Research Nerv. & Ment. Dis., Proc., 30:299-316. (See also Denny-Brown, 1952.) (184-125, 126, 134, 135, 137, 138, 208, 303) Hanel, H., and M. Bielschowsky, 1915. Olivo-cerebellare Atrophie unter dem Bilde des familiaren Paromyoclonus. J. f. Psychol. u. Neurol., 21:285. (412) Hanon, J. L., 1928. La esclerosis laminillar del cerebelo. Semana med., 1:143-155. (451)

596

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

Hansen, K., and W. Rech, 1925. Beziehungen des Kleinhirns zu den Eigenreflexen. Deutsche Ztschr. f. Nervenh., 87:207-222. (355) Hare, C. C., 1931. The frequency and significance of cerebellar symptoms in tumors of the frontal lobes. Bull. Neurol. Inst. New York, 1:532-562. (405) Hare, W. K., H. W. Magoun, and S. W. Ranson, 1936. Electrical stimulation of the interior of the cerebellum in the decerebrate cat. Am. J. Physiol., 117:261-266. (1!&, US, 146, 147, 150, 264) , 1937. Localization within the cerebellum of reactions to faradic cerebellar stimulation. J. Comp. Neurol., 67:145-182. (138, 142, 11$, 146-147, 264, 303) Harkmark, W., 1956. The influence of the cerebellum on development and maintenance of the inferior olive and the pons: An experimental investigation on chick embryos. J. Exper. Zool., 131:333-372. (418, 433-444) Harris, Barbara, L. Veazie, and W. L. Lehman, 1953. Fatal cerebral abscess caused by Pasteurella multocida. West. J. Surg., 61:237-238. (604) Hartmann, E., and G. Sourdille, 1931. Un cas de maladie de Lindau a deux; angiome du cervelet chez la mere, maladie de von Hippel chez le fils. Ann. d'ocul., 168:881-890. (554) Hassin, G. B., 1924. A study of the histopathology of amaurotic family idiocy (infantile type of TaySachs). Arch. Neurol. & Psychiat., 12:640-662. (474) , 1926. A case of amaurotic family idiocy: Late infantile type (Bielschowsky) with clinical picture of decerebrate rigidity. Ibid., 16:708-727. (474-475) , 1934. Sclerotic atrophy of the cerebellum: Report of two cases. Ibid., 31:1205-1221. (451, 452, 475) —, 1935. Crossed atrophy of the cerebellum: Pathological study of a case. Ibid., 33:917-928. (465)

, 1938. Friedreich's ataxia: A histopathologic study. Ibid., 39:116-130. (467) •— and T. H. Harris, 1936. Olivopontocerebellar atrophy. Arch. Neurol. & Psychiat., 35:43-63. (447, 452, 459, 461, 462, 469) Hassler, R., 1950. Ueber Kleinhirnprojektionen zum Mittelhirn und Thalamus beim Menschen. Deutsche Ztschr. f. Nervenh., 163:629-671. (333, 335) Hausman, L., and L. Stevenson, 1933. Astrocytoma: Survival period of 45 years without operation. Arch. Neurol. & Psychiat., 30:1100-1110. (541) Haymaker, W., A. M. Ginzler, and R. L. Ferguson, 1946. The toxic effects of prolonged ingestion of DDT on dogs with special reference to lesions in the brain. Am. J. M. Sc., 212:423-431. (487) Hedon, L., A. Loubatieres, and J. Broussy, 1938. Lesions cerebelleuses consecutive a des accidents hypoglycemiques chez un chien depancreate traite par 1'insuline-protamine-zinc. Compt. rend. Soc. de biol, 128:1009-1011. (490) Hegener, J., 1909. Labyrinthitis und Hirnabscess. Beit. z. Anat., Physiol. Path. u. Therap. d. Ohres, 2:359-462. (499) Heinlein, H., and Falkenberg, 1939. Beitrag zur Kasuistik der Ganglionneurome des Kleinhirns. Ztschr. f. d. ges. Neurol. u. Psychiat., 166:128-135. (441) Hellenthal, E., 1933. Ueber das Zustandekommen, die Haufigkeit und die Lokalisation der Contrecoup-Verletzungen des Gross- und Kleinhirns: Eine kritisch-statistische Studie. Deutsche Ztschr. f. d. ges. gerichtl. Med., 21:231-251. (522) Helmholz, H. F., 1931. Malignant neoplasma in childhood. Proc. Staff Meet., Mayo Clin., 6:721-724. (529,532) Hemphill, R. E., and E. Stengel, 1941. Alzheimer's disease with predominating crossed cerebrocerebellar hemiatrophy. J. Neurol. & Psychiat., 4:97-106. (475-476) Henatsch, H. D., and D. H. Ingvar, 1956. Chloropromazin und Spastizitat: Eine experimentelle elektrophysiologische Untersuchung. Arch. f. Psychiat. u. Zeitsch. Neurol., 195:77-93. (260) Henneberg, R., 1906. Ueber den Rautengruben-Cysticerkus. Monatsch. f. Psychiat. u. Neurol., 20: 28-66.(403, 508) Henneman, E., P. M. Cooke, and R. S. Snider, 1952. Cerebellar projections to the cerebral cortex. A. Research Nerv. & Ment. Dis., Proc., 30:317-333. (141, 153, 234-235, 236, 245) Henneman, E., A. Kaplan, and K. Unna, 1949. A neuropharmacological study on the effects of myanesin (tolserol) on motor systems. J. Pharmacol. & Exper. Therap., 97:331-341. (151) Hering, H. E., and C. S. Sherrington, 1897. Ueber Hemmung der Contraction willkiirlicher Muskeln bei elektrischer Reizung der Grosshirnrinde. Arch. f. d. ges. Physiol., 68:222-228. (329, 330) Hermann, L., 1876. Riickenmark, Gehirn. Jahresb. v. d. Fortschr. d. Anat. u. Physiol., 5(111 Abt.): 22-42. (See Balogh, 1876a.) Hernandez-Peon, R., and K. E. Hagbarth, 1955. Interactions between afferent and cortically induced reticular responses. J. NeurophysioL, 18:44-55. (348) Hernandez-Peon, R., and H. Scherrer, 1955. "Habituation" to acoustic stimuli in cochlear nucleus. Federation Proc., 14:71. (290)

BIBLIOGRAPHICAL INDEX OF AUTHORS

597

and M. Jouvet, 1956. Modification of electric activity in cochlear nucleus during "attention" in unanesthetized cats. Science, 123:331-332. (348) Herren, R. Y., and W. E. Zeller, 1950. Extradural hematomas of the posterior fossa. Arch. Surg., 60:953-956. (523, 524)_ Herrick, C. J., 1924. Origin and evolution of the cerebellum. Arch. Neurol. & Psychiat., 11:621-652. (51) Herringham, W. P., and F. W. Andrews, 1888. Two cases of cerebellar disease in cats with staggering. St. Earth. Hosp. Reports, 24:241-248. (438, 440) Hiller, F., 1929. A study of speech disorders in Friedreich's ataxia. Arch. Neurol. & Psychiat., 22:7590. (394) , 1930. Zur Frage des Zuckerzentrums in der Medulla Oblongata. Miinchen. med. Wchnschr., 77:836-839. (301) Himwich, E., 1951. Brain Metabolism and Cerebral Disorders. Baltimore: Williams & Wilkins Co. (490) Hines, M., 1943. Control of movements by the cerebral cortex in primates. Biol. Rev., 18:1-31. (330) , 1947. The motor areas. Federation Proc., 6:441-447. (330) — , 1949. Significance of the precentral motor cortex. In P. C. Bucy, The Precentral Motor Cortex, chap. 18, pp. 459-499. Urbana: Univ. of Illinois Press. (330) Hippel, E. von, 1904. Ueber eine sehr seltene Erkrankung der Netzhaut. V. Graefes Arch. f. Ophth., 59:83-106.(554) His, W., 1889. Die Neuroblasten und deren Entstehung in embryonalen Mark. Arch. f. Anat. u. physiol., Anat. Abt., pp. 249-300. (546) Hitzig, E., 1874. Physiologische und klinische Untersuchungen iiber das Gehirn. Ed. 1, Berlin: A. Hirschwald; see also ed. 2, 1904. (103, 104, 109, 138) , 1884. Ueber einen Fall von halbseitigem Defekt des Kleinhirns. Arch. f. Psychiat., 15:266268.(434) Hodes, P. J., E. P. Pendergrass, and J. M. Dennis, 1951. Cerebellopontine angle tumors: Their roentgenologic manifestations. Radiology, 57:395-406. (558, 562) Hodskins, M. B., and P. I. Yakovlev, 1930. Anatomico-clinical observations on myoclonus in epileptics and on related symptom complexes. Am. J. Psychiat., 9:827-848. (411, 412) Hoeneveld, G., 1923. De beteekenis der olivo-pontine atrophie voor de kennis van palaeo- en neocerebellum. Dissertatie, Utrecht. See Rijnberk, 1931. (461) Hoffmann, P., 1934. Die physiologischen Eigenschaften der Eigenreflexe. Ergebn. Physiol., 36:15108. (555; Hogyes, A., 1881. Der Nervenmechanismus der associirten Augenbewegungen. (In Hungarian.) Mitt. Math, naturwissensch. Kl. d. ungar. Akad. der Wissensch., 10:1-62; 11:1-100. German summary by F. Klug in Biol. Zentralbl., 1:216-220 (1881-1882). (273) Holland, C. G., 1941. Changes caused by cerebellar neoplasms in the electroencephalogram. Virginia M. Monthly, 68:459-462. (535) Holmes, G., 1907a. A form of familial degeneration of the cerebellum. Brain, 30:466-488. (446, 447) , 1907b. An attempt to classify cerebellar disease with a note on Marie's hereditary cerebellar ataxia. Ibid., 30:545-567. (417, 469) • , 1917. The symptoms of acute cerebellar injuries due to gunshot injuries. Ibid., 40:461—535. (37, 354, 356, 358, 379, 381, S82, 383, 388, 389,390, 391, 394, 395, 522) , 1922a-d. The Croonian lectures on the clinical symptoms of cerebellar disease and their interpretation. Lancet, 100(1):1177-1182, 1231-1237; 100(2):59-65, 111-115. (22, 37, 346, 353, 354, 367, 358, 379, 382, 383, 388, 390, 391-392, 395) , 1927. Discussion of papers in a symposium on the cerebellum. Brain, 50:385-388. (388, 396) , 1939. The cerebellum of man (Hughlings Jackson memorial lecture). Ibid., 62:1-30. (311, 344, 353, 354-355, 356, 379, 382, 388, 390, 391, 393) Holmqvist, B., A. Lundberg, and O. Oscarsson, 1956. Functional organization of the dorsal spinocerebellar tract in the cat. V. Further experiments on convergence of excitatory and inhibitory actions. Acta physiol. Scandinav., 38:76-90. (218) Homen, E. A., 1901. Zur Kenntnis der rachitischen Deformationen der Schadelbasis und der basalen Schadelhyperostosen. Deutsche Ztschr. f. Nervenh., 20:3-15. (418) Horsley, V., 1909. The cerebellum (The Cavendish lecture). West. London M. J., 14:149-158. (383) and R. H. Clarke, 1905. On the intrinsic fibers of the cerebellum, its nuclei and its efferent tracts. Brain, 28:13-29. (72) , 1908. The structure and functions of the cerebellum examined by a new method. Ibid.,

31:45-124. (104, H4, UD Hoshino, T., 1921. Beitrage zur Funktion des Kleinhirnwurmes beim Kaninchen. Acta oto-laryng., suppl., 2:1-72. (109,138, 287)

598

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

Hosoi, K., 1930. Teratoma and teratoid tumors of the brain. Arch. Path., 9:1207-1219. (557) Houweninge Graftdijk, C. J. van, 1932. Occurrence of hydrocephalus in spina bifida. Maandschr. v. kindergeneesk, 2:93-116. (4.8!) Howden, J. C., 1875. Case of atrophy of right hemisphere of cerebrum and left side of cerebellum. J. Anat. & Physiol., 9:288-296. (461) Hsu, Y. K., 1940. Primary intracranial sarcomas. Arch. Neurol. & Psychiat., 43:901-924. (560, 561) Huard, J. A., 1935. Atrophie cerebelleuse probable a caractere familial. Bull. Soc. med. d. hop. universitaires de Quebec, 5:206-210. (446) Hug, E., 1921. Influence des lesions cerebrales et cerebelleuses sur la diurese. Compt. rend. Soc. de biol, 85:594-595.(301) Hugelin, A., M. Bonvallet, R. David, and P. Dell, 1952. Topographic des projections centrales du systeme nerveux olfactif. Rev. neurol., 87:459-463. (211) Hulshoff Pol, D. J., 1909. Cerebellaire ataxie. Psychiat. en neurol. bl, 13:273-315. (69) Hun, H., 1897. Analgesia, thermic anesthesia and ataxia, resulting from foci of softening in medulla oblongata and cerebellum due to occlusion of the left posterior inferior cerebellar artery: A study of the course of the sensory and coordinating tracts in the medulla oblongata. New York M. J., 65:513-518, 581-584, 613-620.(512) Hunt, C. C., 1951. The reflex activity of mammalian small nerve fibers. J. Physiol., 115:456-469. /£>/,•? \ K/qO , PWY\ &Q t )

Hunt, J. R., 1914. Dyssynergia cerebellaris progressiva: A chronic progressive form of cerebellar tremor. Brain, 37:247-268. (411) , 1921. Dyssynergia cerebellaris myoclonica. Primary atrophy of the dentate system: A contribution to the pathology and symptomatology of the cerebellum. Ibid., 44:490-538. (4-12, 467, 468) Hunter, D., R. R. Bomford, and D. S. Russell, 1940. Poisoning by methyl mercury compounds. Quart. J. Med., 9:193-213. (488) Hurst, E. W., 1931. Transmission of louping-ill to the mouse and the monkey: Histology of the experimental disease. J. Comp. Path. & Therap., 44:231-245. (482) Hyland, H. H., and D. Levy, 1954. Spontaneous cerebellar hemorrhage. Canadian M. J., 71:315323. (517,520) Dcutaro, T., 1927. Frontalpoltumoren. Arb. a. d. neurol. Inst. a. d. Wien. Univ., 29:280-314. (405) Infantellina, F., 1955. Azione dell'acetilcolina, dell'eserina e dell'atropina sul lembo isolato di corteccia cerebrale di gatto. Arch, di sc. biol., 39:209-232. (174, 2^2) Ingersoll, E. H., H. W. Magoun, and S. W. Ranson, 1936. The spinal path for responses to cerebellar stimulation. Am. J. Physiol., 117:267-270. (136, 150) Ingraham, F. D., and O. T. Bailey, 1944. Cerebellar medulloblastoma with verification 19 years after onset of symptoms. J. Neurosurg., 1:252-257. (543) and W. F. Barker, 1948. Medulloblastoma cerebelli: Diagnosis, treatment and survivals, with report of 56 cases. New England J. Med., 238:171-174. (542) Ingraham, F. D., and J. B. Campbell, 1941. Dangers of radiation without biopsy in brain tumors in children: report of case. New England J. Med., 224:925-927. (537, 548) Ingraham, F. D., and H. W. Scott, Jr., 1943. Spina bifida and cranium bifidum; Arnold-Chiari malformation: study of 20 cases. New England J. Med., 229:108-114. (423) Ingram, W. R., S. W. Ranson, and R. W. Barris, 1934. The red nucleus: Its relation to postural tonus and righting reactions. Arch. Neurol. & Psych., 31:768-786. (30) Ingram, W. R., S. W. Ranson, F. I. Hannett, F. R. Zeiss, and E. H. Terwilliger, 1932. Results of stimulation of the tegmentum with the Horsley-Clarke stereotaxic apparatus. Arch. Neurol. & Psychiat., 28:513-541. (146) Ingvar, D. H., 1955. Electrical activity of isolated cortex in the unanesthetized cat with intact brain stem. Acta physiol. Scandinav., 33:151-168. (242) Ingvar, S., 1918. Zur Phylo- und Ontogenese des Kleinhirns. Folia neuro-biol., 11:205-495. (51, 5253, 67, 202, 247, 271, 379) , 1923. On cerebellar localization. Brain, 46:301-335. (53, 379) , 1928a. Studies in Neurology. I. The phylogenetic continuity of the central nervous system. Bull. Johns Hopkins Hosp., 43:315-337. (51, 379) , 1928b. Studies in Neurology. II. On cerebellar function. Ibid., pp. 338-362. (379, 396)

Innes, J. R. M., W. T. Rowlands, and H. B. Parry, 1949. An inherited form of cortical cerebellar atrophy in ("daft") lambs in Great Britain. Veterinary Record, 61:225-228. (450) Innes, J. R. M., D. S. Russell, and A. J. Wilsdon, 1940. Familial cerebellar hypoplasia and degeneration in Hereford calves. J. Path. & Bact., 50:455-461. (439) Irger, I. M., L. A. Koreisa, and E. S. Tolmasskaja, 1949. Biull. eksper. biolog. i. med., 27:4; Voprosy nejrokhirurgii, n°5, 34. Cited by Irger et al., 1951. (163)

BIBLIOGRAPHICAL INDEX OF AUTHORS

599

, 1951. Investigations on the electrical activity of phylogenetically differentiated part of the cerebellum in man and in the animals. Fiziol. zhur., 37:273-282. (163, 21*1) Irish, C. W., 1946. Cerebral malaria: Review of literature and report of case with residual symptoms indicative of cerebellar involvement. Bull. Los Angeles Neurol. Soc., 11:111-123. (481) Ivey, D., S. Phillips, and A. M. Meirowsky, 1950. Fibrocaseous cerebellar tuberculoma: Surgical resection in conjunction with streptomycin therapy. J. Neurosurg., 7:370-373. (4-97) Jackson, J. H., 1906. Case of tumor of the middle lobe of the cerebellum: Cerebellar paralysis with rigidity (cerebellar attitude), occasional tetanus-like seizures (1871). Brain, 29:425-440. (£08, 409) Jacob, H., 1939. Ueber die Fehlentwicklungen des Kleinhirns, der Briicke, und des verlangerten Markes (Arnold-Chiarische Entwicklungsstorung) bei kongenitaler Hydrocephalie und Spaltbildung des Ruckenmarkes. Ztschr. f. d. ges. Neurol. u. Psychiat., 164:229-258. (423) Jacobson, M. B., and W. F. Gorman, 1949. Palatal myoclonus and primary nystagmus following trauma: Report of case. Arch. Neurol. & Psychiat., 62:798-801. (413) Jacquin, G., and L. Marchand, 1913. Myoclonie epileptique progressive (type Unverricht-Lundborg). Encephale, pp. 205-218. (1>12) Jakob, A., 1928. Das Kleinhirn. In W. von Mollendorf, Handbuch der mikroskopischen Anatomie des Menschen, vol. 4, pp. 674-916. Berlin: J. Springer. (440) Jankovskaja, C. L., 1938. On the influence of cerebellectomy on blood chemistry. I. Influence of cerebellectomy on Ca, K and Cl concentration of the blood. (In Russian, with English summary.) Izv. naucn. Inst. Lesgafta., 21:87-93. Abstracted in Ber. ges. Physiol., 112:279 (1939). (303) Jansen, J., 1933. Experimental studies on the intrinsic fibers of the cerebellum. I. The arcuate fibers. J. Comp. Neurol., 57:369-399. (235, 248) — and A. Brodal, 1940. Experimental studies on the intrinsic fibers of the cerebellum. II. The cortico-nuclear projection. J. Comp. Neurol., 73:267-321. (62n, 72, 76, 85, 149, 152, 153, 237, 307, 321, 322) , 1942. Experimental studies on the intrinsic fibers of the cerebellum: The cortico-nuclear projection in the rabbit and in the monkey. (Macacus rhesus). Norske Vid. Akad. Oslo, Avh. I, Mat. Naturv. Kl., no. 3, pp. 1-50. (62n, 72, 76, 85,149, 152, 153, 154, 237, 307, 321, 322)

, 1954. Aspects of Cerebellar Anatomy. Oslo: Johan Grundt Tanum Vorlag. (62n, 85, 86, 142, 147, 148, 149, 152, 153, 154, 157, 193, 195, 198, 200, 202, 234, 237, 240, 247, 248, 249, 250, 307, 309, 322, 330,333) Jansen, J., and J. Jansen, Jr., 1955. On the efferent fibers of the cerebellar nuclei in the cat. J. Comp. Neurol., 102:607-632. (76, 78, 85, 86, 90, 153, 154, 248) Jansen, J., Jr., 1956. Some observations of cerebro-cerebellar action potentials. Proc. XX Internal. Congress Physiol., Brussels, pp. 471-472. (209) Jansky, J., 1910. Ueber einen noch nicht beschriebenen Fall der familiaren amaurotischen Idiotic mit Hypoplasia des Kleinhirns. Ztschr. f. d. Erforsch. u. Behandl. d. jugendl. Schwachsinns, 3:86-88. (474) Jelgersma, G., 1918. Drei Falle von Cerebellaratrophie bei der Katze; nebst Bemerkungen iiber das cerebro-cerebellare Verbindungssystem. J. f. Psychol. u. Neurol., 23:105-136. (438) , 1919. Eine Systemerkrankung im Kleinhirn. Ibid., 25:42-46. (454) Jenkins, G. J., 1926. Cystic serous meningitis. J. Laryng., 41:781-784. (506) Jermulowicz, W., 1934. Untersuchung liber das Kleinhirn bei multipler Sklerose. Deutsche Ztschr. f. Nervenh., 135:1-10. (477) Jervis, G. A., 1950. Early familial cerebellar degeneration (report of three cases in one family). J. Nerv. & Ment. Dis., 111:398-407. (449-450) Johnson, H. C., K. M. Browne, J. W. Markham, and A. E. Walker, 1950. Effect of strychnine on the cat's electrocerebellogram. Proc. Soc. Exper. Biol. & Med., 73:97-99. (179) Johnson, H. C., A. E. Walker, K. M. Browne, and J. W. Markham, 1952. Experimental cerebellar seizures. Arch. Neurol. & Psychiat., 67:473-482. (179) Johnson, V. C., and C. F. List, 1940. Ventriculographic localization of intracranial tumors; tumors of cerebellum and fourth ventricle. Am. J. Roentgenol., 43:346-355. (533) Johnston, L. M., and E. W. Goodpasture, 1936. Acute encephalitis in child with cerebellar lesions like those of louping-ill in monkeys. Am. J. Dis. Child., 52:1415-1426.

(483-484)

Jouvet, M., E. Berkowitz, and R. Hernandez-Peon, 1956. Unpublished experiments. Cited by Hernandez-Peon, Scherrer, and Jouvet, 1956. (348) Juba, A., 1936. Ueber gekreuzte halbseitige Kleinhirnatrophie. Arch. f. Psychiat., 105:504-513. (-465) Juhasz, P., 1942. Ueber ein diffuses Kleinhirnoligodendrogliom und das Oligodendrogliom der hinteren Schadelgrube. Ztschr. f. d. ges. Neurol. u. Psychiat., 174:701-714. (551) Jung, R., 1953. Allgemeine Neurophysiologie. In G. von Bergman, W. Frey, and H. Schwiegk, Handbuch der inneren Medizin, vol. 5(1), pp. 1-181. Berlin: J. Springer. (179)

600

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

, 1954. Neuronal discharge. Electroencephalog. & Clin. Neurophysiol., 6(suppl. 4):57-71. (179) Kaada, B., 1950. Site of action of myanesin (mephenesin, tolserol) in the central nervous system. J. Neurophysiol., 13:89-104. (151) Kabat, H., 1955. Analysis and therapy of cerebellar ataxia and asynergia. Arch. Neurol. & Psychiat., 74:375-382. (392) — , C. Dennis, and A. B. Baker, 1941. Recovery of function following arrest of the brain circulation. Am. J. Physiol., 132:737-747. (489) Kahn, E. A., 1939. Treatment of encapsulated abscess of the brain: Visualization by colloidal thorium dioxide. Arch. Neurol. & Psychiat., 41:158-165. (506) Kampmeier, R. H., 1936. Total hemiatrophy and cerebellar tumor. J. Nerv. & Ment. Dis., 84:187192.(550) Kaplan, P. M., 1938a. Cerebellum and carbohydrate metabolism. (In Russian, with French summary.) Fiziol. zhur., 25:322-328. (301, 302) , 1938b. The cerebellum and the emptying of the stomach. (In Russian, with French summary.) Ibid., pp. 315-321. Abstracted in Ber. ges. Physiol., 111:614 (1939). (305) •, 1938c. The cerebellum and the evacuation of the stomach. Bull. biol. et med. exper. URSS, 5:428-436. Abstracted in Ber. ges. Physiol., 111:578 (1939). (305) and T. G. Ossetinskij, 1939. The cerebellum and the motor functions of the stomach. (In Ukrainian, with French summary.) Eksper. med. Kharkov, 1:31-35. Abstracted in Ber. ges. Physiol., 114:283 (1939) and cited by Simkina, 1948. (305) Karamjan, A. I., 1941. Sovet. nevropsikh., 6:479. Cited by Simkina, 1948. (305) , 1949. Evolution of the functional interrelations between cerebellum and cerebral hemispheres. I. Functional interrelations between cerebellum and forebrain in the teleosts. (In Russian.) Fiziol. zhur., 35:167-181. II. Functional interrelations between cerebellum and forebrain in the amphibia. (In Russian.) Ibid., pp. 653-667. (12, 13, 344) Kashkaj, D. Cited by Orbeli, 1938, 1940. (305) Katzenstein, J., and M. Rothmann, 1911, 1912. Zur Lokalisation der Kehlkopfinnervation in der Kleinhirnrinde. Neurol. Zentralbl., 30:1146-1147, and Beitr. Anat. Physiol. Path. Ther. Ohres, 5:380-389.(61) Kean, B. H., and J. A. Smith, 1944. Death due to estivo-autumnal malaria: Resume of 100 autopsy cases, 1925-1942. Am. J. Trop. Med., 24:317-322. (481, 482) Kecht, B., 1932. Zur Kenntnis der Klinik eines Falles von basilarer Impression des Schadels. Ztsch. f. d. ges. Neurol. u. Psychiat., 141:132-140. (418) Keiller, W., 1926. Four cases of olivo-ponto-cerebellar atrophy giving a history of heredity with three autopsies. South. M. J., 19:518-522. (461) Keller, A. D., and W. K. Hare, 1934. The rubrospinal tracts in the monkey. Arch. Neurol. & Psychiat., 32:1253-1272. (92) Keller, A. D., R. S. Roy, and W. P. Chase, 1937. Extirpation of the neo-cerebellar cortex without eliciting so-called cerebellar signs. Am. J. Physiol., 118:720-733. (63, 92) Kelser, R. A., and L. S. King, 1936. Studies of a paralysis syndrome produced in rabbits and guinea pigs by extracts of normal primate bone marrow. Am. J. Path., 12:317-332. (488) Kennard, Margaret A., 1935. Clinical and histological observations on a case of primary cortical degeneration of the cerebellum. Proc. Konig. Akad. van Wetensch., Amsterdam, 38:544-552. (455, 456, 458, 463) and L. Ectors, 1938. Forced circling in monkeys following lesions of the frontal lobes. J. Neurophysiol., 1:45-54. (405) Kernohan, J. W., R. F. Mabon, H. J. Svien, and A. W. Adson, 1949. A simplified classification of the gliomas. Proc. Staff Meet., Mayo Clin., 24:71-75. (689, 547, 548, 551, 552) Kershman, J., 1938. The medulloblast and the medulloblastoma: A study of human embryos. Arch. Neurol. & Psychiat., 40:937-967. (546, 547, 551) Keschner, M., M. B. Bender, and I. Strauss, 1937. Mental symptoms in cases of subtentorial tumor. Arch. Neurol. & Psychiat., 37:1-18. (531) Keschner, M., and M. Grossman, 1928. Cerebellar symptomology evaluation on the basis of intracerebellar and extracerebellar lesions. Arch. Neurol. & Psychiat., 19:78-94. (379, 384, 399-400, 405) Kessel, F. K., 1942. Cerebellar extradural hematoma. J. Neurol. & Psychiat., 5:96-100. (523, 524) King, A. B., 1953. Medulloblastoma with onset during the neonatal period. J. Neurosurg., 10:75-81. (542) • and D. M. Gould, 1952. Symmetrical calcification in the cerebellum: Report of 2 cases. Am. J. Roentgenol., 67:562-568. (477-478) Kirschbaum, W., and A. Eicholz, 1932. Ueber primare Kleinhirnrinden-atrophie. Deutsche Ztschr. f. Nervenh., 125:21-44. (453)

BIBLIOGRAPHICAL INDEX OF AUTHORS

601

Kleijn, A. de, 1925. Die reciproke Innervation des Augenmuskeln des Kaninchens bei kalorischer Reizung nach totaler Cerebellumextirpation. Acta otolaryng., 8:195-198. (263) and R. Magnus, 1920. Ueber die Unabhangigkeit der Labyrinthreflexe vom Kleinhirn und iiber die Lage der Zentren fur die Labyrinthreflexe im Hirnstamm. Arch. f. d. ges. Physiol., 178:124-178. (271, 273, 282) Klein, H., 1919. Beitrag zur anatomischen Grundlage und zur Physiopathologie der kontinuierlichen rhythmischen Krampfe nach Herderkrankungen des Kleinhirns nebst Bemerkungen iiber einige Fragen der Kleinhimfaserung. Monatschr. f. Psychiat. u. Neurol., 45:1-46. (413) Kobakova, E. M., 1952. Influence of the electrical stimulation of the cerebellum on the movements of the small intestine during the ontogenesis. Fiziol. zhur., 38:53-59. (366) Kobayashi, Y., K. Oshima, and I. Tasaki, 1952. Analysis of afferent and efferent systems in the muscle nerves of the toad and cat. J. Physiol., 117:152-171. (21$, 257) Kobrak, F., 1930. Aus Theorie und Praxis oto-neurologischer Diagnostik. Monatschr. f. Ohrenh., 64:947-969.(398) Koella, W., 1947a. Experimentell-physiologischer Beitrag zum Nystagmusproblem. Helvet. physiol. Acta, 5:154-168. (289) , 1947b. Die Beeinflussbarkeit des postrotatorischen Augennystagmus durch propriozeptive Halsreflexe beim Kaninchen. Ibid., pp. 430-440. (289) , 1953. Influence of position in space on cerebellar inhibitory and facilitatory effects in the cat. Am. J. Physiol., 173:443-448. (122-123, 2tf) , 1955. Motor effects from electrical stimulation of basal cerebellum in the unrestrained cat. J. Neurophysiol., 18:559-573. (Ul) Konheim, B. G., 1939. A study of the functional significance of the cerebellar and decussating medullary pathways of the frog. Am. J. Physiol., 127:232-242. (12) Kononova, E., 1912. L'atrophie croisee du cervelet consecutive aux lesions cerebrales chez 1'adulte. Paris: Steinheil. (406, 440, 465) , 1925. Die Lokalisation der Funktion des Kleinhirns. Fortschr. f. Rossolimo, 10:117-124. See also Zentralbl. f. d. ges. NeuroL u. Psychiat., 44:597, 1926. (385) Kornmuller, A. E., 1935. Der Mechanismus des epileptischen Anfalles auf Grund bioelektrischer Untersuchungen am Zentralnervensystem. Fortschr. d. Neurol., Psychiat., 7:1-30. (178) , 1937. Die bioelektrischen Erscheinungen der Hirnrindenfelder. Leipzig: G. Thieme. (179) Koster, S., 1926. Two cases of hypoplasia ponto-cerebellaris. Acta psychiat. et neurol., 1:47-83. (436-438) Krainer, L., 1949. Lamellar atrophy of the Purkinje cells following heat stroke: Report of a case. Arch. Neurol. & Psychiat., 61:441-444. (485, 491) Krause, F., 1929. Ueber einen Bildungsfehler des Kleinhirns und einige faseranatomische Beziehungen des Organs. Ztschr. f. d. ges. Neurol. u. Psychiat., 119:788-815. (436) •, 1930. Ueber erne Verbindung des sensiblen Vagus und Glossopharyngeus mit dem Cerebellum. Proc. Konig. Akad. van Wetensch., Amsterdam, Sect. Sc., 33:1082-1089. (309) Krayenbiihl, H., 1941. Chronischer Hydrocephalus internus infolge einer der Arnold-Chiarischen Entwickelungsstorung nahestehenden Fehlbildung des Kleinhirns. Schweiz. med. Wchnschr., 71:414-416. {483) Kremer, F., 1942. The influence of cerebellum on vegetative functions. Acta brevia Neerl., 12:95-96. (306-307) Kreindler, A., 1939. Die rhythmischen und synchronen Myoklonien der Rachenhohle und des Kehlkopfes: Physiopathologische Untersuchungen. Schweiz. Arch. f. Neurol. u. Psychiat., 43:79-88. (W) . Krestovnikoff, A. N., 1928. De 1'influence de 1'ablation d'une partie de cervelet sur certaines proprietes de la musculature striee. Arch, neerl. de physiol., 12:368-402. (See also Russk. phyziol. zhur., 11:43-76 (1928), Russian with German summary.) (269, 270, 308) Kron, I., and W. Mintz, 1927. Kleinhirnblutung, geheilt durch Operation. Deutsche med. Wchnschr., 53:1054.(517, 520) Kschischkowski, C., 1911. Chemische Reizung des Zweihiigels bei Tauben. Zentralbl. f. Physiol., 25:557-566. (109) Kuhlenbeck, H., 1950. Transitory superficial granular layer of cerebellar cortex: Its relationship to certain cerebellar neoplasms. J. Am. M. Women's A., 5:347-351. (547) Kunstman, K. I., and L. Orbeli, 1932. On the problem of the alteration of movements following cerebellectomy in the dog. (In Russian, with German summary.) Fiziol. zhur., 15:549-556. Abstracted in Ber. ges. Physiol., 72:343, 1933, and cited by Simkina, 1948. (303, 305) Kiipper, 1873. Ueber klonische Krampfe der Schlingmuskeln. Arch. f. Ohrenh., 1:296-297. (413) Kure, K., T. Shinosaki, U. Fujita, Y. Hata, and T. Nagano, 1923. Elektromyographisches Studium

602

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

der durch Reizung des Kleinhirns und des roten Kernes hervorgerufenen Kontraktion des willkiirlichen Muskels. Ztschr. f. d. ges. exper. Med., 38:302-325. (150) Kure, K., T. Shinosaki, M. Kishimoto, U. Fujita, and M. Sato, 1922. Das Kleinhirn als Regulationszentrum des sympatischen Muskeltonus. Arch. f. d. ges. Physiol., 195:525-526. (869) Kuzume, G., 1926. Experimentell-anatomische Untersuchungen iiber die inneren und ausseren Verbindungen des Flocculus und der Kleinhirnkerne (hauptsachlich des Dachkerns). Folia Anat. Japan, 4:75-110. (53) Kwan, S. T., 1929. Tuberculoma of the brain, with report of cases eleven years after operation. Arch. Neurol. & Psychiat., 22:1093-1094. (497) Lafora, G. R., and B. Glueck, 1911. Beitrag zur Histopathologie der myoklonischen Epilepsie. Ztschr. f. d. ges. Neurol. u. Psychiat., 6:1-14. (412) Lairy-Bounes, G. C., M. Parma, and A. Zanchetti, 1952. Modifications pendant la reaction d'arret de Berger de 1'activite convulsive produite par 1'application locale de strychnine sur le cortex cerebral du lapin. Electroencephalog. & Clin. Neurophysiol., 4:495-502. (179) Lam, R. L., and J. H. Ogura, 1952. An afferent representation of the larynx in the cerebellum. Laryngoscope, 62:486-495. (191,192) Lampe, I., and R. S. Maclntyre, 1949. Medulloblastoma of the cerebellum. Arch. Neurol. & Psychiat., 62:322-329.(548) , 1954. Experiences in the radiation therapy of medulloblastoma of the cerebellum. Am. J. Roentgenol, 71:659-668. (548) Lange, B., 1891. Inwieweit sind die Symptome, welche nach Zerstorung des Kleinhirns beobachtet werden, auf Verletzungen des Acusticus zuriickzufuhren? Arch. f. d. ges. Physiol., 50:615-625. (14,15,17, 96, 273, 305) Langelaan, J. W., 1907. On Congenital Ataxia in a Cat. Amsterdam: J. Muller. Also Konig. Akad. van Wetensch. Amsterdam, Verhandelingen, 13:#3. (438) Langford, W. S., and W. O. Klingman, 1942. Behavior disorders associated with intracranial tumors in childhood: Report of cases. Am. J. Dis. Child., 63:433-452. (532) Langworthy, O. R., 1928. The area frontalis of the cerebral cortex of the cat, its minute structure and physiological evidence of its control of the postural reflex. Bull. Johns Hopkins Hosp., 42:20-65.(335) , L. C. Kolb, and L. G. Lewis, 1940. Physiology of Micturition. Baltimore: Williams & Wilkins Co. (306) Lapicque, L., 1939a. Sur le role du cervelet. Compt. rend. Soc. de biol., 131:556-559. (263, 364, 369) , 1939b. Esquisse anatomo-physiologique de la voie cerebello-spinale. Ibid., pp. 851-854. (369) Laporte, Y., and A. Lundberg, 1955. Analysis of dorsal spino-cerebellar tract with intra-axonal microelectrodes. Colloque international sur la microphysiologie comparee des elements excitables, Gif-sur-Yvette, 19-23 juillet 1955. To be published. (251) , 1956. Functional organization of the dorsal spino-cerebellar tract in the cat. III. Single fibre recording in Flechsig's fasciculus on adequate stimulation of primary afferent neurones. Acta physiol. Scandinav., 36:204-218. (185, 217-218, 251) and 0. Oscarsson, 1956a. Functional organization of the dorsal spino-cerebellar tract in the cat. I. Recording of mass discharge in dissected Flechsig's fasciculus. Acta physiol. Scandinav., 36:175-187. (197) , 1956b. Functional organization of the dorsal spino-cerebellar tract in the cat. II. Single fibre recording in Flechsig's fasciculus on electrical stimulation of various peripheral nerves. Ibid., pp. 188-203. (186, 217-218, 251) Larsell, 0., 1923. The cerebellum of the frog. J. Comp. Neurol., 36:89-112. (309) , 1934. Morphogenesis and evolution of the cerebellum. Arch. Neurol. & Psychiat., 31:373395.(52) , 1937. The cerebellum: A review and interpretation. Ibid., 38:580-607. (51, 52, 64) , 1958. The Cerebellum from Myxinoids to Man. Anticipated publication in 1958 or 1959. Minneapolis: Univ. of Minnesota Press. (13, 152, 193, 232, 240, 309, 330, 333, 359, 547) • and R. S. Dow, 1935. The development of the cerebellum in the bat (Corynorhinus sp.) and certain other mammals. J. Comp. Neurol., 62:443-468. (52) , 1939. The cerebellum: A new interpretation. West. J. Surg., 47:256-262. (369) Lawrence, R. D., A. Meyer, and S. Nevin, 1942. The pathological changes in the brain in fatal hypoglycaemia. Quart. J. Med., 11:181-201. (490) Layne, J., and A. B. Baker, 1939. Hypoglycemic cerebral damage in diabetic patients. Minnesota Med., 22:771-776. (490) Lazell, E. W., 1938. Status epilepticus of cerebellar type occurring in insulin shock treatment of schizophrenia, with recovery. M. Bull. Vet. Admin., 14:365-372. (410)

BIBLIOGRAPHICAL INDEX OF AUTHORS

603

LeBeau, J., 1944. La hernie du cervelet au-dessus du tentorium. Diagnostic ventriculographique entre les tumeurs de la partie haute du cervelet et les tumeurs de la partie posterieure du troisieme ventricule. Leur voie d'abord chirurgical. Union med. du Canada., 73:243-252. (533) and M. Feld, 1947. Hematomes spontanes chroniques du cervelet operes et gueris. Rev. neural., 79:42-44. (520) Leblanc, E., 1923. L'acerebellation experimentale chez les lezards. Compt. rend. Acad. d. sc. Paris, 76:1182-1184. (13) Lecount, E. R., and C. "W. Apfelbach, 1920. Pathologic anatomy of traumatic fractures of cranial bones and concomitant brain injuries. J. A. M. A., 74:501-511. (521, 523) Leidler, R., 1919. Kann von der Substanz des Kleinhirns direkt rhythmischer Nystagmus erzeugt werden? Klin. Beitr. Ohrenheilk. Festschrift fur v. Urbantschitsch, Wien, pp. 403-412. (288) Leiri, F., 1923. Ueber Tremor bei Kleinhirnaffektionen. J. Psychol. u. NeuroL, 29:429-433. (402) , 1924. Le cervelet, un organe servant a 1'innervation des antagonistes dans 1'activite musculaire. Acta oto-laryng., 6:516-542. (263) , 1926. Bemerkungen zur Arbeit von A. de Kleyn: Die reciproke Innervation der Augenmuskeln des Kaninchens bei kalorischer Reizung nach totaler Cerebellumextirpation. Ibid., 9:390-393.(263) • , 1931. Das Kleinhirn und die Innervation der antagonistischen und posturalen Muskeltatigkeiten. Ztschr. f. d. ges. Neural, u. Psychiat., 137:259-316. (263) Lejonne, P., and J. Lhermitte, 1909. Atrophie olivo-rubro-cerebelleuse. Nouv. iconog. de la Salpetriere, 22:605-619.(417, 463) Leksell, L., 1945. The action potential and excitatory effects of the small ventral root fibers to skeletal muscle. Acta physiol. Scandinav., vol. 10, suppl. 31. (255) Lemere, F., and C. H. Barnacle, 1936. Encephalography: Review of 800 encephalograms with special reference to subdural air. Arch. Neurol. & Psychiat., 35:990-1001. (443) Lemmen, L. J., and R. C. Schneider, 1952. Extradural hematomas of the posterior fossa. J. Neurosurg., 9:245-253.(523) Lennox, B., and S. Prichard, 1950. The association of bronchial carcinoma and peripheral neuritis. Quart. J. Med., 19:97-109. (456) Lennox, Margaret A., and F. Robinson, 1951. Cingulate-cerebellar mechanisms in the physiological pathogenesis of epilepsy. Electroencephalog. & Clin. Neurophysiol., 3:197-205. (412) Lereboullet, J., 1932. Les tumeurs du quatrieme ventricule. Paris: Bailliere. (527) Leri, A., 1916. Contribution a 1'etude des localisations cerebelleuses chez 1'homme: Parasyndrome cerebelleux par blessure du vermis inferieur (syndromes de Duchenne et syndrome de Babinski, associes et limites aux membres inferieurs). Bull. Acad. de med., Paris, 57:596-598. (381, 522) Lesbre and Forgeot, 1905. Anomalies multiples chez un veau. Rev. gen. de med. veterinaire., 6:198207. Cited by Bertrand, Medynski, and Salles, 1936. (430) Leshin, N., and T. T. Stone, 1931. Continuous rhythmic movements of the palate, pharynx and larynx. Arch. Neurol. & Psychiat., 26:1236-1250. (413) Leven, M., and A. Ollivier, 1862. Recherches sur la physiologic et pathologic du cervelet. Arch. gen. de med., 20:513-525. (23,109)

Levin, P. M., 1936. Multiple hereditary hemangioblastomas of the nervous system. Arch. Neurol. & Psychiat., 36:384-391. (664) , 1949. Efferent fibers . In P. C. Bucy, The Precentral Motor Cortex, chap. 5, p. 133. Urbana: Univ. of Illinois Press. (6,333) Lewandowski, M., 1903. Ueber die Verrichtungen des Kleinhirns. Arch. f. Anat. u. Physiol., Physiol. Abt., 27:129-191. (25-26, 31, 35, 37, 42-43, 47, 61, 87, 97, 99, 109, 139, 339, 341, 342, 345) , 1907. Die Funktion des zentralen Nervensystems, pp. 164-196. Jena: G. Fischer. (25-26, 31, 42-43, 64) Lewis, M. L., and D. H. Echols, 1951. Pearly tumor of the cerebellopontine angle: Report of a case with reversible deafness. Laryngoscope, 61:1123-1125. (558) Lewy, F. H., and T. Shinosaki, 1926a. Die Bede^tung des Kleinhirnwurms fur den Blutzuckerspiegel. Skandinav. Arch. f. Physiol., 49:169-170. (291, 801) , 1926b. Die Bedeutung des Kleinhirnwurms fur den Blutzuckerspiegel. Klin. Wchnschr., 5:2312-2313. (291, 301) Ley, R. A., 1924. Forme atypique d'atrophie cerebelleuse ayant evolue en syndrome rigide. J. beige de neural, et de psychiat., 25:92-108. See also Arch, internat. de med. exper., 1:277-299. (453) , 1947. Sur 1'atrophie olivo-ponto-cerebelleuse familiale. J. beige de neural, et de psychiat., 47:287-297.(459) Lhermitte, J., 1922. L'astasie-abase cerebelleuse par atrophie vermienne chez le vieillard. Rev. neural., 38:313-317.(452) , 1935. Cortical cerebellar degeneration. Proc. Roy. Soc. Med., 28:379-390. (452-453)

604

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

and B. Klarfield, 1911. Etude anatomique d'un cas d'atrophie croisee du cervelet. Rev. neurol., 22:73-74. (466) Lhermitte, J., M. G. Levy, and M. J. 0. Trelles, 1933. Un cas de nystagmus du voile avec myoclonies cervicales synchrones. Rev. neurol., 1:492-495. (413) , 1935. Un nouveau cas de myoclonies velo-palatines et laryngees avec etude hystologique. Rev. neurol., 63:238-247. (413) Lhermitte, J., and J. de Massary, 1931. Un cas d'encephalite aigue a forme cerebelleuse pure. Rev. neurol., 2:796-798. (486) Lhermitte, J., P. Mollaret, and J. Trelles, 1933. Sur les alterations cerebelleuses et ganglionaires de la maladie de Friedreich. Rev. neurol., 2:795-801. (467) Lhermitte, J., and M. J. 0. Trelles, 1933. L'hypertrophie des olives bulbaires. Encephale, 28:588-

• 600. (414,416)

Li, C. L., and H. H. Jasper, 1953. Microelectrode studies of the electrical activity of the cerebral cortex in the cat. J. Physiol., 121:117-140. (179) Liber, A. F., 1940. Tuberous sclerosis with cerebellar involvement. Am. J. Clin. Path., 10:483-492. W8) Lichtenstein, B. W., 1942. Distant neuroanatomic complications of spina bifida (spinal dysraphism); hydrocephalus, Arnold-Chiari deformity, stenosis of aqueduct of Sylvius, etc.; pathogenesis and pathology. Arch. Neurol. & Psychiat., 47:195-214. (421, 423, 424) , 1943a. Cervical syringomyelia and syringomyelia-like states associated with Arnold-Chiari deformity and platybasia. Ibid., 49:881-894. (423) , 1943b. Maldevelopments of the cerebellum: A pathologic study with remarks on the associated degeneration of olivary bodies and the pontine and dentate nuclei. J. Neuropath. & Exper. Neurol., 2:164-177. (430, 440) , 1945. Cerebellar atrophy: An analysis of the various forms and an analytic scheme for their study (review). Ibid., 4:379-392. (417, 450) and S. A. Levinson, 1946. Cortical cerebellar atrophy without ataxia; primary circumscribed variety. J. Neuropath. & Exper. Neurol., 5:29-42. (451, 45®, 475) Liddell, E. G. T., and C. G. Phillips, 1944. Pyramidal section in the cat. Brain, 67:1-9. (336) Liddell, E. G. T., and C. S. Sherrington, 1925. Further observations on myotatic reflexes. Proc. Roy. Soc. London, s. B, 97:267-283. (116, 124, ISO) Liebers, Max, 1927. Zur Histopathologie der amaurotischen Idiotie und Myoclonusepilepsie. Ztschr. f. d. ges. Neurol. u. Psychiat., 111:464-484. (412) Liljestrand, G., and R. Magnus, 1919. Ueber die Wirkung des Novokains auf den normalen und den tetanusstarren Skelettmuskel und iiber die Entstehung der lokalen Muskelstarre beim Wundstarrkrampf. Arch. f. d. ges. Physiol., 176:168-208. (167, 257, 262, 267, 273, 276) Lindau, A., 1926. Studien iiber Kleinhirncysten: Bau, Pathogenese und Beziehungen zur Angiomatosis retinae. Acta path, et microbiol. Scandinav., suppl. 1:1—128. (554, 556) , 1927. Zur Frage der Angiomatosis retinae und ihrer Hirnkomplikation. Acta ophth., 4:193226.(654) , 1931. Discussion on vascular tumours of the brain and spinal cord. Proc. Roy. Soc. Med. (Sect. Neurol. & Sect. Ophth.), 24:363-370. (563) Lindblom, U. F., and J. O. Ottoson, 1956. Bulbar influence on spinal cord dorsum potentials and ventral root reflexes. Acta physiol. Scandinav., 35:203-214. (348) Lindgren, E., 1950. Percutaneous angiography of the vertebral artery. Acta radiol., 33:389-404. (536) Lindsley, D. B., L. H. Schreiner, and H. W. Magoun, 1949. An electromyographic study of spasticity. J. Neurophysiol., 12:197-205. (68, 77) Linthincum, F. H., and C. W. Rand, 1931. Neuro-otological observations in concussion of the brain. Arch. Otolaryng., 13:785-821. (522) Lisitza, F. M., 1932. Nevropat. it., 6:159-170. Cited by Wiggers, 1943a, and Simkina, 1948. (308) List, C. F., 1941. Neurological syndromes accompanying developmental anomalies of occipital bone, atlas and axis. Arch. Neurol. & Psychiat., 45:577-616, (418, 419, 421, 423) List, C. F., J. R. Williams, C. B. Beeman, and C. A. Payne, 1954. Nocardiosis with multilocular cerebellar abscess: Report of a cured case. J. Neurosurg., 11:394-398. (507) Livshitz, N. N., 1946. Cited by Simkina, 1948. (346) -, 1947. Cited by Simkina, 1948. (346) Lloyd, D. P. C., and A. K. Mclntyre, 1950. Dorsal column conduction of Group I muscle afferent impulses and their relay through Clarke's column. J. Neurophysiol., 13:39-54. (197, 201) Loeb, J., 1891. Ueber den Anteil des Hb'rnerven an den nach Gehirnverletzung auftretenden Zwangsbewegungen, Zwangslagen und associierten Stellungsanderungen der Bulbi und Extremitaten. Arch. f. d. ges. Physiol., 50:66-83. (10)

BIBLIOGRAPHICAL INDEX OF AUTHORS

605

, 1905. Experiments on the cerebellum. In Comparative Physiology of the Brain and Comparative Psychology, chap. 13, pp. 171-176. London: Murray. (10) Loeser, W., 1905. A study of the functions of different parts of the frog's brain. J. Comp. Neurol., 15:355-373. (12) Logue, V., and G. Monckton, 1954. Posterior fossa angiomas: A clinical presentation of nine cases. Brain, 77:252-273. (536) Loisel, G., 1935. Les astrocytomes du cervelet de 1'enfant. Paris: Arnette. (527) Londe, P., 1895. Maladies familiales du systeme nerveux. De 1'heredo-ataxie cerebelleuse. These, Paris. Paris: Battaille et Cie. (See Greenfield, 1954.) (469) Longet, F. A., 1842. Anatomic et Physiologic du systeme nerveux de 1'homme et des animaux vertebres. 2 vols. Paris: Fortin, Masson et Cie. (14) , 1850. Traite de Physiologie. 2 vols. Paris: Masson et Cie. (6, 88, 308) Lorente de No, R., 1931. Ausgewahlte Kapitel aus der vergleichenden Physiologie des Labyrinthes: Die Augenmuskelreflexe beim Kaninchen und ihre Grundlagen. Ergebn. Physiol., 32:73-242. (289) Lorentzen, K. A., 1950. Histologic report on a case of oligodendroglioma malignum in cerebral hemisphere with metastatic extension to the cerebellum. Acta psychiat. et neurol., 25:241-250. (551) Lotmar, F., 1908. Ein Beitrag zur Pathologic des Kleinhirns. Monatschr. f. Psychiat. u. Neurol., 24:217-238. (368) , 1931. Entwickelungsstorungen in der Kleinhirnrinde beim endemischen Kretinismus. Ztschr. f. d. ges. Neurol. u. Psychiat., 136:412-435. (442) Louis-Bar, D., and L. van Bogaert, 1947. Sur la dyssynergie cerebelleuse myoclonique (Hunt). Monatschr. f. Psychiat. u. Neurol., 113:215-247. (412, 467) Lourie, A., 1907. Ueber Reizungen des Kleinhirns. Neurol. Centralbl., 26:652-662. (103, 104, 138) , 1908. Ueber die Augenbewegungen bei Kleinhirnreizung. Ibid., 27:102-107. (103, 104, 138) , 1910. Beitrag zur Lokalisation der Funktionen des Kleinhirns. Arch. f. d. ges. Physiol., 133: 282-286.(61, 67) Lowenberg, 1873. Ueber die nach Durchschneidung der Bogengange des Ohrlabyrinthes auftretenden Bewegungsstorungen. Arch f. Augen- u. Ohrenh., 3:1-12. (273) Lowenberg, K., 1936. Pick's disease: A clinicopathologic contribution. Arch. Neurol. & Psychiat., 36:768. (476) and R. W. Waggoner, 1939. Gross pathology of the oligodendrogliomas. Arch. Neurol. & Psychiat., 42:842-861. (551) Lowenthal, M., and V. Horsley, 1897. On the relations between the cerebellar and other centers (namely cerebral and spinal) with special reference to the action of antagonistic muscles. Proc. Roy. Soc. London, 61:20-25. (Received February 8, read February 25, 1897.) (7, 51, 104, 113, 149, 311) Lowy, R., 1910. Zur Frage der superfiziellen Kornerschichten und Markscheidenbildung des Kleinhirns: Ihre Beziehungen zum Lokalisationproblem und zur Gehfahigkeit. Arb. a. d. neurol. Inst. a. d. Wien. Univ., 18:253-293. (359) , 1916. Zur Frage der Mikrogyrie: Ein Beitrag zur Theorie der Windungsbildungen. Ibid., 21:1-40.(441) Luciani, L., 1882. Comunicazione nella adunanza pubblica del 2 Luglio 1882. Atti Soc. med.-fis. fiorentina, Anni 1880, 1881, 1881-82, pp. 85-89. Firenze: Tipografia Cenniniana. (24) >, 1883. Sulle funzioni del cervelletto. Atti del IV Congresso della Societa Freniatrica italiana tenutosi in Voghera dal 16 al 22 Settembre 1883. Supplemento al Fasc. VI, 1883 de 1'Archivio italiano per le malattie nervose e le alterazioni mentali, pp. 215-230. Milano: Rechiedei. (24, 327) , 1884a. Linee generali della fisiologia del cervelletto. Prima memoria. Pubblicazioni del R. Institute di Studi Superiori in Firenze, Sezione di Scienze fisiche e natural!, p. 26. Firenze: Lemonnier. (24, 327, 331) , 1884b. Comunicazione nell'adunanza pubblica del 17 Giugno 1883. Atti Soc. med.-fis. fiorentina, Anno 1882-83, pp. 42-46, 48-51 (Discussione). Firenze: Tipografia Cenniniana. (24, 327, 331) , 1891. II cervelletto: Nuovi studi di fisiologia normale e patologica. Firenze: Le Monnier. German translation, Leipzig: E. Besold, 1893. (6, 13, 15, 16, 17, 21, 23, 24, 31, 35-36, 38, 39, 41, 48-49, 50, 60, 64-65, 88, 96, 99, 101, 268, 272, 273, 301, 308, 327, 331, 334, 344, 369, 371-372, 379, 405) , 1892. Nota critica alia precedente memoria [of Gallerani and Borgherini, 1892a]. Riv. sper. di freniat., 18:381-387. , 1894. De 1'influence qu'exercent les mutilations cerebelleuses sur 1'excitabilite de 1'ecorce cerebrale et sur les reflexes spinaux. Arch. ital. de biol., 21:190-194. (31, 42, 97, 327)

606

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

, 1895a. Ueber Ferrier's neue Studien zur Physiologic des Kleinhirns. Biol. Centralbl., 15:355372, 403-408.(24) , 1895b. Les recentes recherches sur la physiologic du cervelet suivant le prof. David Ferrier, Rectifications et rcpliques. Arch. ital. de biol., 23:217-242. (24) , 1901-1911. Fisiologia dell'uomo. Ed. 1 & 2, 4 vols. Milano: Societa editrice libraria. (Ed. 3 & 4, 5 vols., 1908-1913.) (114) , 1904. Das Kleinhirn. Ergebn. Physiol. 3(11 Abt.):259-338. (23) , 1905-1911. Physiologic des Menschen. 4 vols. Jena: G. Fischer. (268) , 1915. Muscular and Nervous System. Vol. 3 of Human Physiology, 5 vols., London: McMillan & Co., 1911-1917. (24-25, 36, 39-47, 50) , 1916. La questione del nuoto e del cammino in ordine alia dottrina del cervelletto. Arch. fisiol., 14:147-156. (101) Lugaro, E., 1894. Ueber die Histogenese der Korner der Kleinhirnrinde. Anat. Anz., 9:710-713. (546, 547) Luhan, J. A., and S. L. Pollock, 1953. Occlusion of the superior cerebellar artery. Neurology, 3:7789. (401, 514, 515, 516) Lui, A., 1894, 1896. Osservazioni sullo sviluppo istologico della corteccia cerebellare in rapporto alia facolta della locomozione. Riv. sper. di freniat., 20:218-224; 22:27-40. (359, 367) Luna, E., 1906. Localizzazioni cerebellari: Contributo sperimentale anatomofisiologico. Ricerche lab. di Anat. norm. R. Univ. di Roma, 12:199-223. (67, 68) , 1908. Einige Beobachtungen iiber die Lokalisationen des Kleinhirns. Anat. Anz., 32:617— 623. (68) • , 1918. Studio sulle localizzazioni cerebellari. Riv. di pat. nerv., 23:193-312. (59, 67, 68, 72) Lundberg, A., and O. Oscarsson, 1956. Functional organization of the dorsal spinocerebellar tract in the cat. IV. Synaptic connections of afferents from Golgi tendon organs and muscle spindles. Acta physiol. Scandinav., 38:53-75. (218) Lussana, F., 1862. Lecons sur les fonctions du cervelet. J. de la physiol. de 1'homme, 5:418-441. (6,14, 23, 42) , 1863. Nouvelles observations en reponse aux remarques de M. le docteur Brown-Sequard sur la physiologic du cervelet et du nerf auditif. Ibid., 6:169-193. (10, 42) , 1885. Fisiologia e patologia del cervelletto, p. 241. Verona e Padova: Drucker e Tedeschi. (6, 23, 42) —, 1886. Physio-pathologie du cervelet. Arch. ital. de biol., 7:145-157. (6, 23', 42) , and A. Lemoigne, 1871. Fisiologia dei centri nervosi encefalici. 2 vols. Padova: Prosperini. Lutterotti, M., 1934. Kleinhirnextirpation bei Hyla arborea. Z. wissensch. Zool., 145:66-78. (13) Lysholm, E., 1935. Das Ventrikulogram. III. Dritter und vierter Ventrikel. Acta radiol., vol. 26, suppl, 124 pp. (533) —, 1939. Ventriculography of the fourth ventricle. Am. J. Roentgenol., 41:18-24. (533) • , 1946. Experiences in ventriculography of tumours below the tentorium (Mackinzie Davidson memorial lecture). Brit. J. Radiol., 19:437-452. (533) Lyssenkow, N. K., 1931. Ueber Aplasia palaeocerebellaris. Virchows Arch. f. path. Anat., 280:611625. (430) Maas, O., 1913. Storung der Schwerempfmdung bei Kleinhirnerkrankung. Neurol. Centralbl., 32:405409. (358) and H. J. Scherer, 1933. Zur Klinik und Anatomic einiger seltener Kleinhirnerkrankungen. Ztschr. f. d. ges. Neurol. u. Psychiat., 145:420-444. (452) Mabon, R. F., H. J. Svien, A. W. Adson, and J. W. Kernohan, 1950. Astrocytomas of the cerebellum. Arch. Neurol. & Psychiat., 64:74-88. (337, 538, 539, 549, 550) McConnell, A. A., and H. L. Parker, 1938. A deformity of the hindbrain formation associated with internal hydrocephalus: Its relation to the Arnold-Chiari malformation. Brain, 61:415-429. (422) McConnell, I. H., and A. E. Childe, 1937. Pneumographic localization of tumors of the brain. I. Tumors of the lobes of the cerebellum. Arch. Neurol. & Psychiat., 37:33-55. (532) McCulloch, W. S., C. Graf, and H. W. Magoun, 1946. A cortico-bulbo-reticular pathway from area 4-S. J. Neurophysiol., 9:127-132. (330, 336) McCulloch, W. S., A. Ward, Jr., and H. W. Magoun, 1946. One component of the extrapyramidal system. Tr. Am. Neurol. A., 71:93-96. (330, 336) MacDonald, A. E., 1940. Lindau's disease: Report of 6 cases with surgical verification in 4 living patients. Arch. Ophth., 23:564-576. (554) McDonald, J. V., 1953. Responses following electrical stimulation of anterior lobe of cerebellum in cat. J. Neurophysiol., 16:69-84. (Ill, 140, 303, 306, 309) Macewen, W., 1893. Pyogenic infective disease of the brain and spinal cord, meningitis, abscess of brain, infective signs, sinus thrombosis. Glasgow: J. Maclehose & Sons. (498)

BIBLIOGRAPHICAL INDEX OF AUTHORS

607

McGregor, M., 1948. The significance of certain measurements of the skull in the diagnosis of basilar impression. Brit. J. Radiol., 21:171-181. (419) Machne, X., 1950. Localizzazione di effetti cerebellari nel piccione talamico. Arch, di sc. biol., 34:8997. (109) • and A. Zanchetti, 1949. Sui rapporti fra cervelletto e lobi ottici nel piccione talamico. Arch. di sc. biol., 33:77-83. (109; Mclntyre, A. K., 1953. Cortical projection of afferent impulses in muscle nerves. Proc. Univ. Otago Med. School, 31:5-6. (346) McKaig, C. B., and H. W. Woltman, 1934. Neurologic complications of epidemic parotitis. Report of a case of parotitic myelitis. Arch. Neurol. & Psychiat., 31:794-808. (484) Mackenzie, G. M., 1934. Traumatic hemorrhage into cerebellum without fracture of skull; comment on status thymicolymphaticus as possible contributory cause of death. Clin. Misc., Mary I. Bassett Hosp., 1:98-103. (525) McKenzie, K. G., 1938. Extradural haemorrhage. Brit. J. Surg., 26:346-365. (523) McKhann, C. F., and E. C. Vogt, 1933. Lead poisoning in children. J.A.M.A., 101:1130-1135. (486) McKibben, P. S., and D. R. Wheelis, 1932. Experiments on the motor cortex of the cat. J. Comp. Neurol., 56:373-389. (335) Mackiewicz, S., 1935. Ueber einen Fall von halbseitiger Aplasie des Kleinhirns Schweiz. Arch. f. Neurol. u. Psychiat., 36:81-111. (434, 435, 436) McLean, A. J., 1937. Intracranial tumors. In O. Bumke and O. Foerster, Handbuch der Neurologic, vol. 14, pp. 131-241. Berlin: J. Springer. (527) MacRobert, R. G., and L. Feinier, 1921. Cerebellar fits. Arch. Neurol. & Psychiat., 5:296-304. (410) Maestrini, D., 1913. Sulle pretese alterazioni cerebellari in seguito alia asportazione totale o parziale uni- e bilaterale dei canali semicircolari nei colombi. Ann. Fac. med. Univ. Perugia, Ser. IV, 3:25-27. (272) Maevskij, W. E., 1940. Alterations of thermoregulation in the dog following cerebellectomy. (In Russian, with German summary.) Fiziol. zhur., 28:247-254. Abstracted in Ber. ges. Physiol., 122:99 (1941). (302) Magendie, F., 1823. Footnote at pp. 113-114 of Rolando, 1823. (4, 5, 14, 23) , 1824. Memoires sur les fonctions de quelques parties du systeme nerveux. J. de physiol. exper., 4:399-407.(88, 271) , 1825. Precis elementaire de physiologic. 2 vols. Paris: Mequiguon-Marvis. (6; Magnini, M., 1910. Effetti dell'applicazione locale di stricnina e di fenolo sulla corteccia cerebellare del cane. Arch, fisiol., 8:166-170. (Ill) Magnus, R., 1914. Welche Teile des Zentralnervensystems miissen fur das Zustandekommen der tonischen Hals- und Labyrinthreflexe auf die Korpermuskulatur vorhanden sein? Arch. f. d. ges. Physiol., 159:224-249. (271, 273, 274) and A. de Kleijn, 1912. Die Abhangigkeit des Tonus der Extremitatenmuskeln von der Kopfstellung. Arch. f. d. ges. Physiol., 145:455-548. (120, 257, 276) Magnus, R., and C. G. L. Wolf, 1913. Weitere Mitteilungen iiber den Einfluss der Kopfstellung auf den Gliedertonus. Arch. f. d. ges. Physiol., 149:447-461. (115) Magoun, H. W., W. K. Hare, and S. W. Ranson, 1935. Electrical stimulation of the interior of the cerebellum in the monkey. Am. J. Physiol., 112:329-339. (143-146, 147, 264) , 1937. Role of the cerebellum in postural contractions. Arch. Neurol. & Psychiat., 37:12371250.(60,155) Magoun, H. W., and R. Rhines, 1946. An inhibitory mechanism in the bulbar reticular formation. J. Neurophysiol., 9:165-171. (220) Major, H. C., 1879. Case of paralytic idiocy with right sided hemiplegia; epilepsy; atrophy with sclerosis of left hemisphere of the cerebrum and of the right lobe of the cerebellum. J. Ment. Sc., 25:161-165. (464) Malamud, N., W. Haymaker, and R. P. Custer, 1946. Heat stroke: A clinico-pathologic study of 125 fatal cases. Mil. Surgeon, 99:397-449. (490, 491-492) Malesani, A., 1909. Sulle degenerazioni dei centri nervosi nei colombi consecutive all'estirpazione dei canali semicircolari. Nevraxe, 10:341-347. (272) Malis, L. I., I. Cohen, and S. W. Gross, 1951. Arnold-Chiari malformation. Arch. Surg., 63:783798. (483, 424) Mallows, H. R., 1947. A case of cerebellar tumour simulating pyloric obstruction. Brit. M. J., 2:999. (629) Mancia, M., K. Mechelse, and A. Mollica, 1957. Microelectrode recording from midbrain reticular formation in the decerebrate cat. Arch. ital. de biol., 95:110-119. (351) Manni, E., 1946. Azione del curaro sulla ipertonia estensoria e sulle asimmetrie cerebellari in animali deafferentati. Boll. Soc. ital. biol. sper., 22:1182-1183. (76)

608

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

, 1948a. Azione del cervelletto sul tono degli arti e delle ali nei piccioni. Ibid., 24:1328-1329. (18) , 1948b. Persistenza nel piccione spinale di asimmetrie degli arti da lesioni cerebellari. Ibid., 24:785-786.(270) , 1949a. Asimmetrie toniche e motorie d'origine cerebellare e loro comportamento dopo parziale ablazione della cute. Sistema Nervoso, 1:30-37 (l.II). (75, 76) , 1949b. Fenomeni di eccitamento stricnico della corteccia cerebellare e loro persistenza dopo taglio del midollo spinale nel piccione. Boll. Soc. ital. biol. sper., 25:440-442. (270, 271) ———, 1950a. Localizzazioni cerebellari corticali nella cavia. I. II corpus cerebelli. Arch, fisiol., 49:213-237. (62, 68, 69, 70, 71, 73) , 1950b. Localizzazioni cerebellari corticali nella cavia. II. Effetti di lesioni delle parti vestibolari del cervelletto. Ibid., 50:110-123. (54, 56, 24-6, 273) , 1951a. Sulla funzione del lobo medio cerebellare degli uccelli. Arch. d. sc. biol., 35:504-510. (18,106,109,178) , 1951b. Azione tonica esplicata su uno stesso territorio muscolare da aree cerebellari differenti. Arch, fisiol., 50:407-415. (73, 77) Mansfeld, G., and A. Hamori, 1938. TJntersuchungen iiber die zentrale Regulierung der Atmung. Arch, internat. de pharmacodyn., 60:179-194. (299) Mansfeld, G., and Fr. v. Tyukody, 1936. Atemzentrum und Narkose. Arch, internat. de pharmacodyn., 54:219-246. (299, 300) , 1937. Ueber periodische Atmung. Ibid., 57:334-341. (299) Marburg, O., 1904. Die physiologische Funktion der Kleinhirnseitenstrangbahn (Tractus spinocerebellaris dorsalis) nach Experimenten am Hunde. Arch. f. Anat. u. Physiol., Physiol. Abt., pp. 457-482. (88) , 1914. Das Kleinhirn beim angeborenen Hydrocephalus: Ein Beitrag zur Pathogenese der angeborenen Kleinhirnerkrankungen. Arb. a. d. neurol. Inst. a. d. Wien. Univ., 21:213-256. (438) , 1924. Entwicklungsgeschichte, makroskopische und mikroscopische Anatomic des Nervus cochlearis, vestibularis und Kleinhirns sowie der zugehorigen Abschnitte des centralen Nervensystems (Centren und Bahnen). In G. Alexander and 0. Marburg, Handbuch der Neurologic des Ohres, vol. 1, pp. 175-336. Berlin: Urban u. Schwarzenberg. (379) , 1936. Symptomatologie der Erkrankungen des Kleinhirns. In O. Bumke and O. Foerster, Handbuch der Neurologie, vol. 5, pp. 555-607. Berlin: J. Springer. (379) and W. Riese, 1947. Chronic progressive spino-cerebello-cortical lipodystrophy affecting certain arterial supply areas. J. Neuropath. & Exper. Neurol., 6:61-77. (460, 462) Marie, P., 1893. Sur 1'heredo-ataxie cerebelleuse. Semaine med., 13:444-447. (469) and C. Foix, 1913. Sur la degeneration pseudo-hypertrophique de 1'olive bulbaire. Rev. neurol., 26:48-52.(415) —, 1914. Lesions medullaires dans quatre cas d'heredo-ataxie cerebelleuse. Ibid., 27:797-798. (469) and T. Alajouanine, 1922. De 1'atrophie cerebelleuse tardive a predominance corticale. Rev. neurol., 38:849-885, 1082-1111. (385, 386, 452) Marinesco, G., and E. Facon, 1932. Les troubles cerebello vestibulaires apres les traumatismes craniens. Rev. d'oto-neuro-opht., 10:645-646. (522) Markham, J. W., K. M. Browne, H. C. Johnson, and A. E. Walker, 1951. Rhombencephalic convulsive activity. Bull. Johns Hopkins Hosp., 89:442-467. (179) , 1952. Convulsive patterns in cerebellum and brain stem. A. Research Nerv. & Ment. Dis., Proc., 30:282-298. (179) Markham, J. W., C. A. Fager, G. Horrax, and J. L. Poppen, 1955. Meningiomas of the posterior fossa: Their diagnosis, clinical features, and surgical treatment. Arch. Neurol. & Psychiat., 74:163-170.(560) Markow, D. A., 1941. Med. zhur., Kiev 2, 3, 1941. Cited by Simkina, 1948. (303, 305, 346) , 1947. Cited by Simkina, 1948. (346) Marossero, F., and M. Garrone, 1952. Convulsive activity in the cerebellar cortex. Electroencephalog. & Clin. Neurophysiol., 4:230. (180) Marquardt, B., 1941. Ueber ein umschriebenes Arachnoidealsarkom des Kleinhirns. Ztschr. f. d. ges. Neurol. u. Psychiat., 171:117-127. (561) Marrassini, A., 1905. Sopra gli effetti delle demolizioni parziali del cervelletto. Arch, fisiol., 2:327336. (64, 67, 68, 69) , 1906. Contribute sperimentale allo studio della fisiopatologia del cervelletto. Pisa: A. Valenti. (64, 67, 68, 69) , 1907. Sur les phenomenes consecutifs aux extirpations partielles du cervelet. Arch. ital. de biol., 47:135-176. (64, 67, 68, 69)

BIBLIOGRAPHICAL INDEX OF AUTHORS

609

Marshall, C., 1934. Experimental lesions of the pyramidal tract. Arch. Neurol. & Psychiat., 32:778796. (335, 342) , 1935. Further experimental lesions on the pyramidal tracts. Proc. Soc. Exper. Biol. & Med., 32:745-747.(336) Martel, Th. de, and J. Guillaume, 1934. Les tumeurs de la loge cerebelleuse. Paris: 0. Doin et Fils. (527) Martin, E. G., and W. H. Rich, 1918. The activities of decerebrate and decerebellate chicks. Am. J. Physiol., 46:396-411. (14) Martin, P., 1932. Etude de 1'influence des noyaux vestibulaires et en particulier des noyaux de Deiters sur la reflectivite tendineuse. Arch, internat. de med. exper., 7:1-39. (230) and L. van Bogaert, 1933. Deux cas d'hemangiome du cervelet chez deux soeurs. J. beige de neurol. et de psychiat., 33:809-812. (554) Martini, E., T. Gualtierotti, and A. Marzorati, 1951. Precisazione sull'elettronarcosi cerebellare. Riv. neurol., 21:426-427. (176) Martini, E., and C. Torda, 1938. Die cholinesterasische Aktivitat einiger Rattenmuskeln nach Zerstorung des Kleinhirns. Klin. Wchnschr., 17:889. (270) Martino, G., 1926. Contributo alia conoscenza della funzione dei lobi ottici nel Colombo. Arch, fisiol., 24:282-292. (109) Marx, H., 1907. Untersuchungen iiber Kleinhirnveranderungen nach Zerstorung der hautigen Bogengange des Ohrlabyrinths. Arch. f. d. ges. Physiol., 120:166-180. (27%) Massary, E. de, Tockman, and Luce, 1917. Meningite lymphocytique et syndromes nerveux dans les oreillons. Bull, et mem. Soc. med. d. hop. de Paris, 41:847-853. (484) Matson, D. D., and F. D. Ingraham, 1951. Intracranial complications of congenital dermal sinuses. Pediatrics, 8:463-474. (557, 558-559) Matthews, B. H. C., 1933. Nerve endings in mammalian muscle. J. Physiol., 78:1-53. (256) Maxwell, H. P., 1946. The incidence of interhemispheric extension of glioblastoma multiforme through the corpus callosum. J. Neurosurg., 3:54-57. (549) Maybaum, J. L., and M. Gossman, 1935. Evaluation of caloric tests in localization of lesions of posterior fossa: Study of 40 verified cases. Arch. Otolaryng., 22:565-584. (398) Mayer, S., and A. Heldfond, 1936. The function of the cerebellum in frogs as shown by extirpation experiments. J. Comp. Neurol., 64:523-527. (12) Medwick, J. X., A. Uihlein, and O. E. Hallberg, 1949. Abscess of cerebellar lobe of otogenic origin; combined otolaryngologic and neurosurgical treatment in 6 cases. Arch. Otolaryng., 50:429-439. (506) Meltzer, P. E., 1935. Treatment of thrombosis of lateral sinus: A summary of results obtained during 12 years at Mass. Eye and Ear Infirmary. Arch. Otolaryng., 22:131-142. (499) Menzel, P., 1891. Beitrage zur Kenntnis der hereditaren Ataxie und Kleinhirnatrophie. Arch. f. Psychiat. u. Nervenkr., 22:160-190. (469) Menzio, P., 1950. Riflessi labirintici in animali trattati con streptomicina e significato delle lesioni cerebellari. Boll. Soc. ital. biol. sper., 26:39-41. (290) Merio, P., and E. Risak, 1934. Klippel-Feilsches Syndrom, basilare Impression und endokrine Erkrankungen. Ztschr. f. klin. Med., 126:455-468. (418) Merritt, H., and M. Finland, 1930. Vascular lesions of the hind brain (lateral medullary syndrome). Brain, 53:290-305. (512) Merton, P. A., 1953. Speculations on the servo-control of movement. In Ciba Foundation Symposium: The spinal cord, pp. 247-260. London: J. A. Churchill. (Boston: Little Brown & Co.) (355, 356) Merzbacher, L., 1903. Untersuchungen iiber die Funktion des Centralnervensystems des Fledermaus. Arch. f. d. ges. Physiol., 96:572-600. (30) Mettler, F. A., and F. L. Orioli, 1955. Analysis of cerebellar ataxia. Federation Proc., 14:101. (94) Meyer, J. S., and J. M. Foley, 1953. The encephalopathy produced by extracts of eosinophils and bone marrow. J. Neuropath. & Exper. Neurol., 12:349-362. (458, 488) Meyers, L, 1915. Galvanometric studies on the cerebellar function. J. A. M. A., 65:1348-1355. (330) , 1916. Cerebellar localization: An experimental study by a new method. J. A. M. A., 67:17451751. (73,329) , 1919a. The cerebellar gait: A pedegraphic study. J. Nerv. & Ment. Dis., 49:14-34. (73) , 1919b. Locomotor disturbances in disease of the cerebellum: A graphic study. Arch. Neurol. & Psychiat., 2:376-388. (73) , 1928. Cerebellar phenomena in lesions of the temporal lobe. Ibid., 19:1014-1025. (406) Meyers, R., 1951. Human frontocorticopontine tract: Functional inconsequence of its surgical interruption. Neurology, 1:341-356. (406) Michael, J. C., 1932. Cerebellar apoplexy. Am. J. M. Sc., 183:687-695. (517, 518, 519)

610

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

Michon, P., and R. Rousseaux, 1939. Meningiome de la tente du cervelet. Bull, et mem. Soc. med. d. hop. de Paris, 55:291-296. (Reviewed in Rev. neurol., 71:663 [1939].) (560) Mikhelson, A. A., and V. V. Tikhalskaja, 1933. Effect of the electrical stimulation of the cerebellum on blood pressure. (In Russian, with German summary.) Fiziol. zhur., 16:469—471. (291, 292, 303) Miller, F. R., 1920. Cerebellar localization by application of strychnine. Science, 51:413-414. (112, 178) , 1926a. Action of strychnine on the cerebellar cortex. Tr. Roy. Soc. Canada, 20:239-240. (112,113,178) , 1926b. The physiology of the cerebellum. Physiol. Rev., 6:124-159. (99) , 1937. The local action of eserine on the central nervous system. J. Physiol., 91:212-221. (112,113) and F. G. Banting, 1922. Observations on cerebellar stimulations. Brain, 45:104-112. (104, 114, 150) Miller, F. R., and N. B. Laughton, 1928a. The function of the cerebellar nuclei as determined by faradic stimulation. Arch. Neurol. & Psychiat., 19:47-72. (142, 146, 155, 264) , 1928b. Myograms yielded by faradic stimulation of the cerebellar nuclei. Proc. Roy. Soc. London, 103:575-598. (U2,143,146,155, 264) Miller-Guerra, 1954. Le syndrome cerebelleux et le syndrome vestibulaire. Paris: Masson. (381) Mills, C. K., 1908. Hemianesthesia to pain and temperature and loss of emotional expression on the right side, with ataxia of the upper limb on the left. The symptoms probably due to a lesion of the thalamus or superior peduncles. J. Nerv. & Ment. Dis., 35:331-332. (516) , 1912. Preliminary note on a new symptom complex due to lesion of the cerebellum and cerebello-rubro-thalamic system, the main symptoms being ataxia of the upper and lower extremities of one side and on the other side deafness, paralysis of emotional expression in the face, and loss of the sense of pain, heat and cold over the entire half of the body. Ibid., 39:73-76. (516 ) and T. H. Weisenburg, 1914. Cerebellar symptoms and cerebellar localization. J. A. M. A., 63: 1813-1818.(379) Mingazzini, G., and F. Gianulli, 1924. Klinischer und pathologische-anatomischer Beitrag zum Studium der Aplasie cerebro-cerebello-spinalis. Ztschr. f. d. ges. Neurol. u. Psychiat., 90:521572. (465) Mingazzini, G., and O. Polimanti, 1906. Ueber die physiologischen Folgen von successiven Extirpationen eines Stirnlappens (Regio praecruciata) und einer Kleinhirnhalfte. Monatschr. f. Psychiat. u. Neurol., 20:403-424. (333) Minski, L., 1933. Mental symptoms associated with 58 cases of cerebral tumor. J. Neurol. & Psychopath., 13:330-343. (531) Miskolszy, D., and M. Dancz, 1934. Atrophia cerebro-cerebellaris cruciata. Arch. f. Psychiat., 101: 637-656. (465) Mitchell, N., and A. Angrist, 1942. Spontaneous cerebellar hemorrhage; report of 15 cases. Am. J. Path., 18:935-953. (517, 518, 519) Mitchell, S. Weir, 1869. Researches on the physiology of the cerebellum. Am. J. M. Sc., 57:320-338. (14,105,109, 111, 305) Mnukhina, R. S., 1946. Effects of cerebellar ablations and stimulation on the reflexes of the spinal cord. Thesis presented at the VIII Conf. URSS Acad. Sc. (In Russian.) Cited by Simkina, 1948. (870, 346) , 1951. On the participation of the cerebellum to the coordination of the reflexes of the spinal cord. Fiziol. zhur., 37:52-58. (151, 264) Moersch, F. P., 1928. Tumors of the brain and syphilis. Am. J. M. Sc., 175:12-18. (498) Moller, H. U., 1929. Familial angiomatosis retinae et cerebelli (Lindau's disease). Acta ophth., 7:244260. (554) , 1944. Ophthalmic symptoms and heredity in cerebellar angioreticuloma. Acta psychiat. et neurol., 19:275-292. (554) Moller, P. M., 1952. Another family with von Hippel Lindau's disease. Acta ophth., 30:155-165. (554) Mollica, A., G. Moruzzi, and R. Naquet, 1953. Decharges reticulaires induites par la polarisation du cervelet: Leurs rapports avec le tonus postural et la reaction d'eveil. Electroencephalog. & Clin. Neurophysiol., 5:571-584. (119, 171,175, 219-221, 248, 316, 324, 326, 327, 348) Mollica, A., and R. Naquet, 1953. Activite convulsive et silence electrique dans 1'ecorce cerebelleuse. Electroencephalog. & Clin. Neurophysiol., 5:585-587. (164, 178, 241) Mollica, A., and M. Orsini, 1956. Differenze nell'attivita elettrica spontanea fra diverse aree della corteccia cerebellare. Boll. Soc. ital. biol. sper., 32:953-954. (242)

BIBLIOGRAPHICAL INDEX OF AUTHORS

611

Mollica, A., and G. F. Rossi, 1953. Sulla natura assonica degli impulsi nervosi registrati in corrispondenza della decussatio pyramidum e della piramidi bulbari. Arch, fisiol., 53:233-246. (179) — and E. Venturelli, 1954. Sopra un metodo di localizzazione di microelettrodi metallici nel tessuto nervoso (microelettrolisi). Boll. Soc. ital. biol. sper., 30:272-273. (107, 220) Monakow, C. von, 1895. Experimentelle und Pathologische-anatomische Untersuchungen tiber die Haubenregion, den Sehhiigel und die Regio subthalamica, nebst Beitragen zur Kenntnis friih erworbener Gross- und Kleinhirndefecte. Arch. f. Psychiat. u. Neurol, 27:1-128, 386-478. (308, 464, 466) , 1897. Gehirnpathologie. In Nothnagel's Specielle Pathologie und Therapie, Vol. 9, pt. 1, p. 623. Wien: A. Holder. (97) , 1902. Ueber den gegenwartigen Stand der Frage nach der Lokalisation im Grosshirn. Ergbn. Physiol., 1(11 Abt.):534-665. (339) Moon, H. D., 1950. The pathology of fatal carbon tetrachloride poisoning with special reference to the histogenesis of the hepatic and renal lesions. Am. J. Path., 26:1041-1057. (487) Moore, J., 1943. Hemiatrophy of brain with contralateral cerebellar atrophy; case presentation with histopathologic findings. J. Nerv. & Ment. Dis., 98:31-41. (465) Morin, F., 1956. Activation of cerebellar cortex by afferent impulses. Federation Proc., 15:133. (196-197) and E. D. Gardner, 1953. Spinal pathways for cerebellar projections in the monkey (Macaca mulatta). Am. J. Physiol., 174:155-161. (191, 195, 196, 198, 242, 243) Morin, F., and B. Haddad, 1953. Afferent projections to the cerebellum and the spinal pathways involved. Am. J. Physiol., 172:497-510. (190, 191, 196, 198, 242, 243) Morin, F., and D. Lindner, 1953. Pathways for conduction of tactile impulses to the paramedian lobule of the cerebellum of the cat. Am. J. Physiol., 175:247-250. (198) Morin, F. A., and J. D. Green, 1955. Influence of brain stem activation on sensory messages. J. Michigan M. Soc., 54:480. (348) Morin, G., V. Donnet, and S. Maffre, 1951. Nouveaux documents relatifs a 1'interpretation de la rigidite de decortication. Compt. rend. Soc. de biol., 145:1700-1701. (336) Morin, G., V. Donnet, and P. Zwirn, 1949. Nature et evolution des troubles consecutifs a la section d'une pyramide bulbaire chez le chien. Compt. rend. Soc. de biol., 143:710-712. (335) Morin, G., H. Gastaut, and J. Duplay, 1947. Liberation des reflexes posturaux en extension chez le chien decortique (pseudo-rigidite de decerebration). Rev. neurol., 79:207-213. (335) Morin, G., Y. Poursines, V. Donnet, and S. Maffre, 1950. Sur les phenomenes de spasticite consecutifs a la section du faisceau pyramidal dans le bulbe chez le chien. Compt. rend. Soc. de biol., 144:1083-1084. (336) , 1951. Topographic des lesions susceptibles de provoquer la "rigidite de decortication." Ibid., pp. 410-412. (336) Morsier, G. de, and E. Barbey, 1937. La predominance unilaterale du nystagmus provoque. Son importance dans 1'etude des voies vestibulaires centrales en particulier dans les etats vertigineux post-commotionels. Rev. d'oto-neuro-opht., 15:654-665. (522) Morsier, G. de, and R. Junet, 1936. L'aplasie de la lame basilaire de 1'os occipital avec syndrome clinique de tumeur de la fosse posterieure. Rev. neurol., 65:1483-1492. (418) Moruzzi, G., 1934a. Ricerche sperimentali sulle degenerazioni transneuroniche. Ateneo parmense, 6:513-559. (75, 88) , 1934b. Sulle proprieta curarisimili di alcuni sali di onio negli omeotermi; azione sul tono posturale. Ibid., 336-370. (118) , 1935a. Sur les proprietes curariformes de quelques sels d'onium dans les homeothermes. Action sur le tonus postural. Arch. ital. de biol., 93:107-111. (75, 118, 153, 243) , 1935b. Contribute allo studio del meccanismo dell'atonia curarica. Arch, fisiol., 34:455—466. (61, 75,118,119, 260)

, 1935c. Cervelletto ed attivita fasica dei muscoli striati. Ibid., 34:293-339. (118, 119, 120, 149) , 1936a. Ricerche sulla fisiologia del paleocerebellum. I. Riflessi labirintici e cervicali, paleocerebellum e tono posturale. Ibid., 36:57-112. (119, 120, 121, 122, 155, 157, 246) , 1936b. Ricerche sulla fisiologia del paleocerebellum. II. Riflessi propriocettivi somatici, paleocerebellum e tono posturale. Ibid., 36:337-364. (119, 120, 121, 123, 124, 155) , 1936c. Ricerche sulla fisiologia del paleocerebellum. III. Sulla natura e sul meccanismo dell'inversione dell'inibizione paleocerebellare. Ibid., 36:408-427. (119, 124, 130, 155) , 1938a. Azione del paleocerebellum sui riflessi vasomotori. Ibid., 38:36-78. (191, 292-294) , 1938b. Sur les rapports entre le paleocervelet et les reflexes vasomoteurs. Ann. physiol.. 14:605-612. (191, 292-294)

612

—

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

, 1938c. Action inhibitrice du paleocervelet sur les reflexes circulatoires et respiratoires d'origine sino-carotidienne. Compt. rend. Soc. de biol., 128:533-539. (294, 299) , 1939. Contribution a 1'electrophysiologie du cortex moteur: Facilitation, afterdischarge et epilepsie corticales. Arch, internat. de physiol., 49:33-100. (350) , 1940a. Paleocerebellar inhibition of vasomotor and respiratory carotid sinus reflexes. J. Neurophysiol., 3:20-32. (190, 294, 299, 300) , 1940b. Sulle funzioni vegetative del cervelletto. Relazioni XXVIII riunione Soc. ital. progresso scienze, Pisa, 11-15 Ottobre 1939, vol. 4, pp. 155-159. (190, 371) , 1941a. Sui rapporti fra cervelletto e corteccia cerebrale. I. Azione d'impulsi cerebellari sulle attivita cortical! motrici deH'animale in narcosi cloralosica. Arch, fisiol., 41:87-139. (109, 111, 24-3, gtf, 248, 304, 312-315) , 1941b. Sui rapporti fra cervelletto e corteccia cerebrale. II. Azione d'impulsi cerebellari sulle attivita motrici provocate dalla stimolazione faradica o chimica del giro sigmoideo nel gatto. Ibid., 41:157-182. (243, 247, 248, 312-317) , 1941c. Sui rapporti fra cervelletto e corteccia cerebrale. III. Meccanismi e localizzazione delle azioni inibitrici e dinamogene del cervelletto. Ibid., 41:183-206. (119, 243, 247, 248, 312-321, 355, 356) , 1943. Contribute alia fisiologia generale dei centri nervosi. I. Azione dell'aneniia acuta sull'attivita dei neuroni encefalici, inibitori ed eccitatori. Ibid., 43:1-21. , 1944-1945. Convulsion! extrapiramidali da stricnina. Ibid., 44:109-162. (318-319) , 1946a. Sulle funzioni motorie dei lobi ottici negli uccelli. Ibid., 45:110-140. (109) , 1946b. L'epilessia sperimentale. Bologna: Zanichelli. (179) , 1947a. Tectal and bulbopontine eyelid reflexes and mechanism of the sleeping attitude of the acute thalamic pigeon. J. Neurophysiol., 10:415-424. (109) , 1947b. Le aree cerebellari aumentatrici del tono posturale. Rassegna biol. urn., 2:100-105. (125,135,137) , 1947c. Sham rage and localized autonomic responses elicited by cerebellar stimulation in the acute thalamic cat. Proc. XVII Internat. Congress Physiol., Oxford, pp. 114-115. (Ill, 125, 138, 243, 295, 299, 304) , 1948a. Ricerche sperimentali e una nuova ipotesi sulla natura del rimbalzo cerebellare. Boll. Soc. ital. biol. sper., 24:397-398. (107, 122, 126, 127, 130, 134, 156, 322) , 1948b. Nuove ricerche sugli effetti paleocerebellari aumentatori del tono. Ibid., pp. 753-755. (107,122,126,127,130,134,156, 322) , 1948c. L'irradiazione degli effetti paleocerebellari inibitori del tono. Ibid., pp. 755-756. (126,127,136,137,149,153,157)

, 1948d. Le vie efferent! per 1'inibizione paleocerebellare del tono. Ibid., pp. 756-757. (126, 153) , 1948e. Nuove osservazioni intorno agli effetti della stimolazione del cervelletto sul sistema nervoso autonomo. Ibid., pp. 752-753. (138, 304) , 1949. L'action du paleocervelet sur le tonus postural. J. Physiol., Paris, 41:371-420. (60, 118, 126, 127, 128,155, 156, 219, 281, 322, 369) , 1950a. Problems in Cerebellar Physiology. Springfield, 111.: Charles C. Thomas. (126, 156, 230, 316, 322, 369) , 1950b. Effects at different frequencies of cerebellar stimulation upon postural tonus and myotatic reflexes. Electroencephalog. & Clin. Neurophysiol., 2:463-469. (126, 128, 156, 322) , 1950c. L'epilepsie experimentale. Paris: Hermann. (179) , 1953a. Nuove ricerche sull'elettronarcosi cerebellare. Arch, fisiol., 53:299-325. (163, 164, 176) , 1953b. Cerebellar and cerebral mechanisms. Proc. XIX Internat. Congress Physiol., Montreal, pp. 89-98. (369) , 1954. General mechanisms of seizure discharges. Electroencephalog. & Clin. Neurophysiol., 6, suppl. 4:221-232. (179) , 1957. Esperimenti e considerazioni sull'elettronarcosi cerebellare. Arch, di sc. biol., 41:91-104. (163,164,165,176,178) and H. W. Magoun, 1949. Brain stem reticular formation and activation of the EEG. Electroencephalog. & Clin. Neurophysiol., 1:455-473. (141, 248, 298, 316, 324, 327, 348) Moruzzi, G., and O. Pompeiano, 1954. Inversione dell'inibizione paleocerebellare prodotta dalla distruzione parziale del nucleo del tetto. Boll. Soc. ital. biol. sper., 30:493-494. (86, 118, 122, 128, 131,149,152,153,155,156, 221, 262, 322) , 1955a. Influenze cerebellari crociate sul tono posturale. R. C. Accad. Lincei, 18:420-424. (70, 78, 81, 98,100,147,265, 268, 332) , 1955b. La inibizione propriocettiva riflessa come causa dell'atonia fastigiale. Ibid., 19:326-330. (21, 80, 85, 98, 265, 268, 283, 352)

BIBLIOGRAPHICAL INDEX OF AUTHORS

613

, 1955c. Soppressione dell'atonia fastigiale del gatto decerebrato mediante sezione del N. VIII contralaterale. Ibid., 19:471-475. (81, 85, 98, 246, 272, 279, 283, 352) , 1956a. Effetti di lesioni croniche del nucleo del tetto sulle risposte alia stimolazione elettrica della corteccia cerebellare vermiana del lobus anterior. Ibid., 21:333. (131) , 1956b. Crossed fastigial influence on decerebrate rigidity. J. Comp. Neurol., 106:371-392. (70, 78, 81-85, 98,100, U7, 265, 268, 332) , 1957a. Inhibitory mechanisms underlying the collapse of decerebrate rigidity after unilateral fastigial lesions. Ibid., 107:1-25. (21, 80, 85, 98, 265-267, 268, 272, 279, 283, 384, 352) •——•—•, 1957b. Effects of vermal stimulation after fastigial lesions. Arch. ital. de biol., 95:31-55. (86, 118,122,128,131-134,148-149,152,153,155,156, 221, 262, 322) Mosse and Guibert, 1888. Note sur un cas d'atrophie cerebrale; atrophie croisee du cerveau et du cervelet. Gaz. hebd. d. sc. med. de Montpel., 10:341-344. (464) Mott, F. W., 1907. A case of Friedreich's disease with autopsy and systemic microscopical examination of the nervous system. Arch. Neurol. Path. Lab. London County Asyl., Claybury, London, 3:180-200. (467) and A. F. Tredgold, 1900. Hemiatrophy of brain and its results on the cerebellum, medulla and spinal cord. Brain, 23:239-263. (464, 465) Mountcastle, V. B., M. R. Covian, and C. R. Harrison, 1952. The central representation of some forms of deep sensibility. A. Research Nerv. & Ment. Dis., Proc., 30:339-370. (195-196, $42, 346) Moyano, B. A., 1937. Atrofia senil del cerebelo: Sobre la persistencia de los nidos o cestas despues de la desaparicion de las celulas de Purkinje. Arch, argent, de neurol., 17:23-34. Abstracted in Arch. Neurol. & Psychiat., 41:187 (1939). (462) Mudd, R., I. Perlmutter, and R. E. Strain, 1955. Calcified intracranial tuberculoma. Am. J. Roentgenol., 73:19. (496) Miiller, J., 1838. Ueber den weineren Bau und die Formen der krankhaften Geschwiilste. Berlin: G. Reimer. (557) Munch-Peterson, C. J., 1947. Ataxia subacuta; atrophia cerebelli primaria. Acta psychiat. et neurol. suppl., 46:213-225. (456) Munk, H., 1892. Ueber die Fiihlsphaeren der Grosshirnrinde. Sitzungsb. d. kon. preuss. Akad. d. Wissensch., pp. 679-723. (333, 339) —, 1906-1908. Ueber die Funktionen des Kleinhirns. Ibid., 1906, pp. 443-480; 1907, pp. 16-32; 1908, pp. 294-396. (26, 27, 35, 37, 61, 64, 288, 342) Munro, D., and W. Wegner, 1937. Primary cranial and intracranial epidermoids and dermoids. New England J. Med., 216:273-279. (557) Munslow, R. A., 1951. Extradural cerebellar hematomas: Report of two cases. J. Neurosurg., 8:542545.(523) Muratow, W., 1899. Zur Pathogenese der Hemichorea postapoplectica. Monatschr. f. Psychiat. u. Neurol., 5:180-192. (402) Murphy, J. P., and R. Arana, 1947. Pneumoencephalogram of cerebellar atrophy. Am. J. Roentgenol., 57:545-555. (443) Murri, A., 1900. Degenerazione cerebellare da intossicazione enterogena. Riv. crit. di clin. med., 1:593-598, 609-616.(456) , 1908. Sui tumori del cervelletto. In Lezioni di Clinica Medica, pp. 561—750. Milano: Societa editrice libraria. (37) , 1915. L'atassia nel cammino e nel nuoto. Riforma med., 31:1009-1019. (37, 101) Musa, A. B., 1936. Metastatic carcinoma of the cerebellum with primary focus in the lung. Me. Bull. Vet. Admin., 13:176-180. (559) Mussen, A. T., 1927. Experimental investigations on the cerebellum. Brain, 50:313-349. (53, 103, 104, 138,142, 303) , 1930. The cerebellum: A new classification of the lobes based on their reactions to stimulation. Arch. Neurol. & Psychiat., 23:411-459. (69, 103, 113) , 1931. The cerebellum: Comparison of symptoms resulting from lesions of individual lobes with reactions of the same lobes to stimulation: A preliminary report. Ibid., 25:702-722. (69, 103) , 1934. Cerebellum and red nucleus: A preliminary report on a new method of physiological investigation. Ibid., 31:110-126. (103, 139) Mussio-Fournier, J. C., and F. Rawak, 1936. Encephalographie dans un cas d'atrophie cerebelleuse. Rev. neurol., 65:662-668. (443) Mutrux, S., F. Martin, and Y. Chesni, 1953. Ataxie congenitale et familiale associee a des malformations somatiques, a des troubles oculaires et a des troubles mentaux. J. de genetique humaine, 2:103-116. (450)

614

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

Myle, G., and L. van Bogaert, 1949. Sur une heredoataxie avec demence, epilepsie, myoclonie et arachnodactylie (sa situation vis-a-vis de la dyssynergie cerebelleuse myoclonique de Hunt). Monatschr. f. Psychiat. u. Neurol, 118:364-378. (467) Nadas, A. S., M. M. Alimuring, and L. A. Sieracki, 1951. Cardiac manifestations of Friedreich's ataxia. New England J. Med., 244:239-244. (466) Narikashvili, S. P., 1950. Electrical activity of brain stem, cerebral cortex and cerebellum in the unanesthetized cat. (In Russian.) Publications of the Institute of Physiology "I. Beritashvili" of the Academy of Sciences of Georgia, 8:135-182. Tbilisi. (163, 235) Nathanson, M., 1956. Palatal myoclonus. Arch. Neurol. & Psychiat., 75:285-296. (413) Negro, C., and G. Roasenda, 1907. Risultati di esperienze relative alia localizzazione di centri motori nel cervelletto, per mezzo di eccitamenti con correnti indotte unipolari. Gior. d. r. Accad. di Med. di Torino, 13:76-79. (103) Nelson, A. A., 1936. Metastases of intracranial tumors. Am. J. Cancer, 28:1-12. (528, 545) Neubeuger, T., and L. Edinger, 1898. Einseitiger fast totaler Mangel des Cerebellums: Varix oblongatae. Herztod durch Accessoriusreizung. Berl. klin. Wchnschr., 35:69-72, 100-103. (434, 435) Neubuerger, K. T., and L. W. Greene, Jr., 1946. Circumscribed arachnoidal sarcoma of cerebellum: Report of a case. J. Neuropath. & Exper. Neurol., 5:233-239. (561) Neuburger, M., 1897. Die historische Entwickelung der experimentellen Gehirn- und Riickenmarksphysiologie von Flourens, p. 36. Stuttgart: Enke. (3, 4) Neumann, H., 1907. Der otitische Kleinhirnabcess. Leipzig: Frank Deuticke. (499) Nicolesco, J., O. Sager, and T. Hornet, 1938. Reflexions a propos d'un cas de myoclonies velopalatines consecutives a une lesion cerebelleuse droite avec hypertrophie des cellules nerveuses de 1'olive bulbaire gauche. Rev. neurol, 70:301-317. (413) Niemer, W. T., and H. W. Magoun, 1947. Reticulo-spinal tracts influencing motor activity. J. Comp. Neurol., 87:367-379. (161) Noica, D., J. Nicolesco, and E. Banu, 1936. Contribution a 1'etude de 1'atrophie olivo-ponto-cerebelleuse. Rev. neurol., 66:285-306. (459) Norlen, G., 1941. Familial occurrence of cerebellar angioma. Acta chir. Scandinav., 85:198-202.

(554, 555)

Norman, R. M., 1940a. Cerebellar atrophy associated with etat marbre of the basal ganglia. J. Neurol. & Psychiat., 3:311-318. (438) , 1940b. Primary degeneration of granular layer of the cerebellum: An unusual form of familial cerebellar atrophy occurring in early life. Brain, 63:365-378. (450) Nothnagel, H., 1876. Experimentelle Untersuchungen iiber die Funktionen des Gehirns. V. Das Kleinhirn. Virchows Arch. f. path. Anat., 68:33-58. (109) , 1879. Topische Diagnostik der Gehirnkrankheiten: Eine klinische Studie. Berlin: A. Hirschwald. (417) Nulsen, F. E., S. P. W. Black, and C. G. Drake, 1948. Inhibition and facilitation of motor activity by the anterior cerebellum. Federation Proc., 7:86-87. (149, 321-322) Nyby, O., and J. Jansen, 1951. An experimental investigation of the cortico-pontine projection in Macaca mulatta. Norske Vid. Akad. Oslo, Avh. I, Mat. Naturv. Kl., no. 3, pp. 1-47. (206, 245,

247, 332, 333)

Nylen, C. O., 1939. Oto-neurologic diagnosis of tumours of the brain. Acta oto-laryngol., suppl., 33:1-151. (398) Nyssen, R., and L. van Bogaert, 1934. La degenerescence systematisee optico-cochleo-dentelee. Rev. neurol., 2:321-345. (467) Obersteiner, H., 1916. Ein Kleinhirn ohne Wurm. Arb. a. d. neurol. Inst. a. d. Wien. Univ., 21:124— 136.(430) and S. Exner, 1891. Experiments cited by Breuer, 1891, p. 254. (272) Obrador, S., and P. Urquiza, 1948. Two cases of cerebral abscess of unusual nature; tuberculous abscess and suppurated hydatid cyst. J. Neurosurg., 5:572-576. (497) Ohmori, S., 1926. Ueber einen Fall der die cerebellare Ataxia begleitenden akuten Alkoholamaurose. (In Japanese.) Zentralbl. Neurol., 43:77. (456, 486) Okada, W., 1900. Diagnose und Chirurgie des otogenen Kleinhirnabscesses. Klin. Vortr. a. d. Geb. d. Otol. u. Pharyngo-Rhinologie, 10:313-450. (499) Okamoto, U., 1952. Studies on pupillary dilatation elicited by chemical stimulation of cerebellum and reflex pupillary dilatation. (In Japanese.) Brain Research, 15:358-367. (303) Olitsky, P. K., and J. Casals, 1948. Viral Encephalitides from Viral and Rickettsial Infections of Man, pp. 163-212. T. M. Rivers, ed. Philadelphia: J. B. Lippincott Co. (483) Olivecrona, H., 1949. Cholesteatomas of the cerebello-pontine angle. Acta psychiat. et neurol., 24:639-643. (557, 558) , 1952. The cerebellar angioreticulomas. J. Neurosurg., 9:317-330. (553, 554, 555, 556)

BIBLIOGRAPHICAL INDEX OF AUTHORS

615

Olivet, J., 1930. Die diuretischen Hormone des Gehirns. Miinchen. med. Wchnschr., 77:58-59. (301) Olmsted, J. M. D., and H. P. Logan, 1925. Lesions in the cerebral cortex and extension rigidity in cats. Am. J. Physiol., 72:570-582. (335) Olsson, O., 1953. Vertebral angiography in the diagnosis of acoustic nerve tumours. Acta radiol., 39:265-272.(536) Onimus, E., 1870-1871. Recherches experimentales sur les phenomenes consecutifs a 1'ablation du cerveau et sur les mouvements des rotation. J. de 1'anat. et de physiol., 7:633-677. (12) Oppenheim, H., 1923. Lehrbuch der Nervenkrankheiten fur Aerzte und Studierende, vol. 2, p. 1503. Berlin: Karger. (403) and E. Siemerling, 1885. Die acute Bulbarparalyse und die Pseudobulbarparalyse. ChariteAnn., 12:331-395. (412) Orbeli, L. A., 1938. Lectures on the physiology of the nervous system. (In Russian.) Moscow: Medghiz. (846) , 1940. New conceptions on the functions of the cerebellum. (In Russian.) Uspekhi Sovrem j. biol., 13:207-220. (344, 346) Orley, A., 1949. Neuroradiology. Springfield, 111.: Charles C. Thomas. (496) Oscarsson, D., 1956. Functional organization of the ventral spinocerebellar tract in the cat. I. Electrophysiological identification of the tract. Acta physiol. Scandinav., 38:145-165. (200) Ossokin, N., 1912. Zur Frage iiber die motorischen Zentren des Kleinhirns. Ann. Ksl. Nicolaus, Univ. Saratow. Cited by Rijnberk, 1931. (68) Ostertag, B., 1925a. Zur Histopathologie der Myoklonusepilepsie: Eine weitere Studie iiber die intraganglio-cellularen, corpuscularen Einlagerungen. Arch. f. Psychiat., 73:633-656. (41®) , 1925b. Zur Frage der dysrhaphischen Storungen des Riickenmarks und der von ihnen abzuleitenden Geschwultsbildungen. Ibid., 75:89-143. (419) , 1925c. Entwickelungsstorungen des Gehirns und zur Histologie und Pathogenese, besonders der degenerativen Markerkrankung, bei der amaurotischen Idiotic. Ibid., 75:355-391. (4?4) , 1936. Einteilung und Charakteristik der Hirngewachse. Jena: G. Fischer. (381, 54%) Osterwald, K., 1906. Beitrag zur Diagnose des Cysticercus Ventriculi Quarti. Neurol. Centralbl., 25:265-270. (403, 508) Ottonello, P., 1941. Singolari alterazioni della loquela (incoordinazione verbo-mimico-emotiva) rilevate nel decorso del processi morbosi endocranici con interessamento dell'apparato cerebellare. Riv. di pat. nerv., 57:131-161. (394) , 1943. L'incoordinazione verbo-mimico-emotiva nelle atrofie primitive nel cervelletto. Ibid., 62:108-126.(394) Owen, A. G. W., and C. S. Sherrington, 1911. Observations on strychnine reversal. J. Physiol., 43: 232-241. (115) Owsjannikow, Ph., 1871. Die tonischen und reflektorischen Centren der Gefassnerven. Ber. ii. d. Verandl. d. konigl. sachs. Gesellsch. d. Wiss. zu Leipzig. 2-3:135-147. (291) Pagano, G., 1902. Studi sulla funzione del cervelletto. Riv. di pat. nerv., 7:145-152. (51, 110-111, 298,

364) , 1904. Saggio di localizzazione cerebellare. Ibid., 9:209-228. (51, 52, 110-111, 298, 364) —

, 1905. Essai de localisations cerebelleuses. Arch. ital. de biol., 43:139-159. (SOS, 306)

, 1912. A proposito dell'azione del curaro applicato direttamente sui centri nervosi. Riv. di pat. nerv., 17:513-517. (110-111) Palestini, M., G. F. Rossi, and A. Zanchetti, 1957. An electrophysiological analysis of pontine reticular regions showing different anatomical organization. Arch. ital. de biol., 95:97-109. (349, 351) Pancratoff, M. A., 1938. Observations on cats without cerebral hemispheres and cerebellum. (In Russian, with English summary.) Izv. nauch. Inst. Lesgafta, 21:269-278. Abstracted in Ber. ges. Physiol., 114:282, 1939. (60, 305) —, 1951. Influence of the cerebellum on the course of gestation in the cat. (In Russian.) Fiziol. zhur., 37:59-63. Abstracted in Ber. ges. Physiol., 151:299, 1952. (308) Panzel, A., 1925. Untersuchungen iiber das Vergleichen von Gewichten bei Gesunden und Kranken. Deutsch. Ztschr. f. Nervenh., 87:161-206. (358) Papez, J. W., 1940. Unpublished results. Cited by Walker, 1949, p. 116. (333) Papilian, V., and H. Cruceanu, 1925a. Rapports entre le tonus musculaire des extremites et la position de la tete, chez les animaux apres lesion du cervelet. Compt. rend. Soc. de biol., 92:1075-1076. (273) , 1925b. L'influence du cervelet sur les fonctions organo-vegetatives de 1'oeil. Ibid., 92:10811082.(303) , 1926. Recherches experimentales sur les fonctions organo-vegetatives du cervelet. J. de physiol. et de pathol. gen., 24:47-53. (291, 299, 301, 303, 308)

616

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

Parker, H. L., 1928. Tumors of the nervous acusticus: Signs of involvement of the fifth cranial nerve. Arch. Neurol. & Psychiat., 20:309-318. (562) and J. W. Kernohan, 1933. Parenchymatous cortical cerebellar atrophy (chronic atrophy of Purkinje cells). Brain, 56:191-212. (456) , 1935. Parenchymatous cortical cerebellar atrophy. (Subacute cerebellar encephalitis.) Arch. Neurol. & Psychiat., 33:959-975. (455, 456, 483) Parodi, U., and S. Ricca, 1925. Contribute alia conoscenza della atrofia olivo-ponto-cerebellare. Riv. di pat. nerv., 30:273-303. (461) Patrizi, M. L., 1905. Su qualche punto controverso della fisiologia del cervelletto. Mem. d. r. Accad. d. sc., lett., arti, Modena, serie III, 6:84-135. (43, £69) , 1906. Sur quelques points controverses de la physiologic du cervelet. Arch. ital. de biol., 45:18-57. (269) Patterson, G. H., and F. M. Anderson, 1940. Intracranial tumors occurring in 3 members of family. Bull. Los Angeles Neurol. Soc., 5:218-223. (554) Paulian, D., I. Bistriceanu, and M. Tudor, 1940. Tumeur de la fosse posterieure (cholesteatome de I'hemisphere cerebelleux gauche) a symptomatologie atypique. Arch, de neurol., 4:209-213. (557) Pavlov, I. P., 1922. L'innervation trophique. Livre jubilaire en 1'honneur de A. A. Netschaeff. Leningrad. (269) , 1927. Conditioned Reflexes: An Investigation of the Physiological Activity of the Cerebral Cortex. London: Oxford Univ. Press. (340, 342) Peet, M. M., 1946. Aspergillus fumigatus infection of cerebellum. Tr. Am. Neurol. A., 71:165. (507) Pendergrass, E. P., P. J. Hodes, and E. W. Godfrey, 1942. The radiation treatment of cerebellar medulloblastoma: Report of 31 cases. Am. J. Roentgenol., 48:476-490. (548) Penfield, W., and D. F. Coburn, 1938. Arnold-Chiari malformation and its operative treatment. Arch. Neurol. & Psychiat., 40:328-336. (421, 422, 423) Penfield, W., and W. Feindel, 1947. Medulloblastoma of cerebellum, with survival for 17 years. Arch. Neurol. & Psychiat., 57:481-484. (543) Pennybacker, J., 1948. Cerebellar abscess; treatment by excision with the aid of antibiotics. J. Neurol., Neurosurg. & Psychiat., 11:1-12. (506) Perelmann, L. R., 1927. Med. biol., Z., 3:37; Zbl. Neur., 47:617. Cited by Wiggers, 1943a, p. 292. (301) Peretti, G., 1951. Ricerche sul tono posturale della vescica urinaria e sulla sua regolazione nervosa: Prime osservazioni sopra 1'influenza del cervelletto sul tono posturale del muscolo detrusore vescicale. Arch, fisiol., 51:46-53. (306, 307) Perlmutter, I., G. Horrax, and J. L. Poppen, 1950. Cystic hemangioblastomas of cerebellum; end results in 25 verified cases. Surg., Gynec. & Obst., 91:89-99. (554, 555) Peterson, E. W., H. W. Magoun, W. S. McCulloch, and D. B. Lindsley, 1949. Production of postural tremor. J. Neurophysiol., 12:371-384. (94) Peterson, H. O., and A. B. Baker, 1941. Difficulties in differentiating midbrain lesions from cerebellar lesions. Am. J. Roentgenol., 46:37-51. (404, 533) Petrova, N. G., 1939. Influence of cerebellar ablation on respiration. (In Russian.) Eksper. Med. Kharkov, 3:51-56. Abstracted in Ber. ges. Physiol., 116:620 (1940). (300) Pfeiffer, J. A. F., 1922. A case of hereditary ataxia (Friedreich) with anatomical findings. Arch. Neurol. & Psychiat., 7:341-348. (467, 468) Pfleger, L., 1880. Beobachtungen iiber Heteropie grauer Substanz im Marke des Kleinhirns. Centralbl. f. d. med. Wissensch., 18:468-470. (547) Phillips, C. G., 1956. Cortical motor threshold and the thresholds and distribution of excited Betz cells in the cat. Quart. J. Exper. Physiol., 41:70-84. (172) Phillips, D. G., 1955. Basilar impression. J. Neurol., Neurosurg. & Psychiat., 18:58-67. (419) Pilcher, C., 1941. Subcortical hematoma: Surgical treatment, with report of eight cases. Arch. Neurol. & Psychiat., 46:416-430. (520) Pilotti, G., 1921. Sulle Mioclonie: Contributo clinico ed anatomo-patologico. Policlinico (sez. med.), 28:137-173. (412) Pines, L., and A. Surabaschwili, 1932. Ein seltener Fall von partieller Agenesie des Kleinhirnwurmes. Arch. f. Psychiat., 96:718-728. (430) Pintos, C. M., R. A. Celle, and E. A. Frugoni, 1943. Encefalopatia congenita por agenesia del cerbelo en un prematuro. Arch, de pediat. de Uruguay, 14:728-730. (429) Piquet, J., 1948. Symptomes peu connus de 1'abces cerebelleux otogene. Presse med., 56:270-271.

(505)

Plohinski, 1902. Obozren. psikhiat., Petrograd. Cited by Bechterew, 1909, p. 957. (308) Polimanti, O., 1906. Contributi alia fisiologia ed alPanatomia dei lobi frontali. Rome: G. Bertero.

(333)

BIBLIOGRAPHICAL INDEX OF AUTHORS

617

, 1908. Neue physiologische Beitrage iiber die Beziehungen zwischen dem Stirnlappen und dem Kleinhirn. Arch. f. Anat. u. Physiol., Physiol. Abt., 81:102. (333) , 1909. Contributions a la physiologic du cervelet des chauves souris. Arch, internal, de physiol., 7:257-276. (30) , 1911, 1912. Contributi alia fisiologia del sistema nervoso centrale e del movimento del pesci. Zool. Jahrb., 30:477-716; 32:311-584. (11) Poljak, S., 1927. An experimental study of the association callosal and projection fibers of the cerebral cortex of the cat. J. Comp. Neurol., 44:197-258. (245) Pollock, G. H., and J. A. Bain, 1950. Convulsions in cerebellum and cerebrum induced by B-chlorinated amines. Am. J. Physiol., 160:195-202. (181, 182) Pollock, L. J., and L. Davis, 1923. Studies in decerebration. I. A method of decerebration. Arch. Neurol. & Psychiat., 10:391-398. (27-28, 53, 57, 60) , 1927. The influence of the cerebellum upon the reflex activities of the decerebrate animal. Brain, 50:277-312. (87-48, 97, 99, 275-276, 282, 283, 284) , 1930a. Studies in decerebration. V. The tonic activities of a decerebrate animal exclusive of the neck and labyrinthine reflexes. Am. J. Physiol., 92:625-629. (27-28) , 1930b. The reflex activities of a decerebrate animal. J. Comp. Neurol., 50:377-411. (27-28, 263, 264, 275-276, 282) •— , 1931. Studies in decerebration. VI. The effect of deafferentation upon decerebrate rigidity. Am. J. Physiol., 98:47-49. (273, 274) Pompeiano, O., 1955. Sulle risposte crociate degli arti a stimolazione della corteccia vermiana del lobus anterior nel gatto decerebrato. Boll. Soc. ital. biol. sper., 31:808-810. (135-136) , 1956. Sul meccanismo delle risposte posturali crociate alia stimolazione d'un emiverme del lobus anterior nel gatto decerebrato. Arch, di sc. biol., 40:513-522. (135-136, 153, 154) •— •, 1957. Analisi degli effetti di stimolazione elettrica del nucleo rosso nel gatto decerebrato. R. C. Accad. Lincei, in press. (137) —, 1958a. Analisi delle risposte posturali alia stimolazione elettrica della parte intermedia del lobus anterior del cervelletto. Ibid., in press. (117, 136-137, 153) — , 1958b. Responses to electrical stimulation of the intermediate part of the cerebellar anterior lobe in the decerebrate cat. To be published in Arch. ital. de biol. (136-137, 153) •———, G. F. Ricci, and A. Zanchetti, 1954. Cervelletto e aumento del tono estensorio. Arch. d. sc. biol., 38:125-131. (142,148,150) Pool, J. L., 1943. Effects of electrical stimulation of the human cerebellar cortex: Preliminary note. J. Neuropath. & Exper. Neurol., 2:203-204. (410) Pool, W. A., 1931. Etiology of "louping-ill." Vet. J., 87:177-200, 222-239. (482) Popoff, S., 1895. Zur Frage iiber die Histogenese der Kleinhirnrinde. Biol. Zentralbl., 15:745-752. (546, 547) — •, 1896. Weitere Beitrage zur Frage iiber die Histogenese der Kleinhirnrinde. Ibid., 16:462-466. (546, 547) Poppel, M. H., H. G. Jacobson, B. K. Duff, and C. Gottlieb, 1953. Basilar impression and platybasia in Paget's disease. Radiology, 61:639-644. (419) Porot, A., 1906. Destruction isolee per hemorragie d'un pedoncule cerebelleux superieur. Rev. neurol., 14:1097-1101. (516) Porta, V., 1936. Considerazioni su un caso di morbo di Lindau (angioblastoma reticolare del cervelletto). Riv. neurol., 9:88-114. (554) Portman, G., and H. Retrouvey, 1929. La cephalee dans 1'abces cerebral et cerebelleux d'origine otique. Rev. de laryng., 50:537-540. (505) Poullain, M., 1876. Hemiplegie spasmodique de 1'enfant. Atrophie de I'hemisphere gauche du cerveau; atrophie du lobe droit du cervelet; atrophie du bulbe (pyramide anterieure et olive du cote gauche). Bull. Soc. anat. de Paris., 51:38-39. (464) Pourfour du Petit, 1766. Nouveau systeme du cerveau. Recueil d'observ. d'anat. et de chir., p. 121. Paris: Louis. Cited by Longet, 1842, vol. 2/2, p. 215. (3, 88) Powell, C. B., 1947. Primary glioblastoma multiforme of the cerebellum: Report of a case. J. Neuropath. & Exper. Neurol., 6:279-285. (549, 550) Prado, J. M., T. Insausti, and R. F. Matera, 1946. Contribution al estudio de las coccicio y paracoccidiomicosis del sistema nervioso. Arch, neurocir., Buenos Aires, 3:90-106. (508) Pratt-Thomas, H. R., and K. E. Berger, 1947. Cerebellar and spinal injuries after chiropractic manipulations. J. A. M. A., 133:600-603. (521) Precechtel, A., 1927. Hypoplasia of the cerebellum and of the inferior olivary system in myoclonus. Psychiat. en neurol. bl., 31:147-174. (412)

618

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

Pressman, Y. M., and F. M. Shitov, 1940. On the relationship between the cerebellum and the centres of the autonomous nervous system. (In English.) Bull. biol. et med. exper. URSS, 9:43-47. (306) Preston, C., 1697. An account of a child born alive without a brain, and the observables in it on dissection. Phil. Tr. Roy. Soc., London, 19:457-467. (See Du Verny, 1673.) Prevost, J. L., 1899. De la deviation conjuguee des yeux et de la rotation de la tete en cas de lesions unilaterales de 1'encephale. Cinquantenaire de la Societe de Biologie, volume jubilaire public par la Societe, pp. 99-119. Paris: Masson et Cie. (138) Price, J. B., and E. A. Spiegel, 1937. Vestibulocerebral pathways: A contribution to the central mechanism of vertigo. Arch. Otolaryngol., 26:658-667. (182) Priestly, D. P., 1920. A case of complete absence of the cerebellum. Lancet, 2:1302. (426) Probst, M., 1899. Zur Kenntnis der Pyramidenbahn (normale und anormale Pyramidenbiindel und Reizversuche der Kleinhirnrinde). Monatschr. f. Psychiat. u. Neurol., 6:91-113. (103, 138) , 1902. Zur Anatomic und Physiologic des Kleinhirns. Arch. f. Psychiat., 35:1-86. (103, 138) Prus, J., 1901. Sur la localisation des centres moteurs dans 1'ecorce du cervelet. Arch, polon. de sc. biol. et med., 1:1-15. (103,104,138) Pugliatti, G., 1885. Alcune ricerche sopra la fisiologia del cervelletto, p. 139. Messina: G. Capra. (10, 12, 23, 291) Purves-Stewart, 1927. Intracranial tumors and some errors in their diagnosis. New York: Oxford Univ. Press. (687) Pussep, L. M., 1902. Dissertation, St. Petersburg. Cited by von Bechterew, 1909, p. 957. (308) Puusepp, L., 1927-1929. Die Tumoren des Gehirns, pt. 1-3. Tartu-Dorpat: J. Hallo. (527) Raaf, J., and J. W. Kernohan, 1944. Relation of abnormal collections of cells in posterior medullary velum of cerebellum to origin of medulloblastoma. Arch. Neurol. & Psychiat., 52:163-169. (381, 54^, 547) Rabinowitz, M. A., J. Weinstein, and I. H. Marcus, 1932. Brain abscess (paradoxical) in congenital heart disease. Am. Heart J., 7:790-795. (507) Rademaker, G. G. J., 1926a. Demonstration des deux chats decerebelles, de deux chiens decerebelles, et d'un chien ayant subi Pablation, outre du cervelet, de la moitie droite du cerveau. Arch neerl. de physiol., 11:445-450. (28-30) , 1926b. I. Korperstellung und Statik kleinhirnloser Tiere sechs oder mehr Monate nach der Operation (mit kinematographischer Vorfiihrung). II. Motilitatsstorungen kleinhirnloser Tiere. Abstracts of Com. to XII Internal. Physiol. Congress, Stockholm, 3-6 August, 1926. Skandinav. Arch. f. Physiol., 49:212. (28-30) , 1930. Experiences sur la physiologic du cervelet. Rev. neurol., 1:337-367. (28-30) , 1931. Das Stehen: Statische Reaktionen, Gleichgewichtsreaktionen und Muskeltonus unter besonderer Beriicksichtigung ihres Verhaltens bei kleinhirnlosen Tieren. Berlin: J. Springer. (15, 22, 28-35, 37, 43, 44, 45-46, 60, 97-98, 100, 110, 244, 271, 282, 287, 288, 334, 336, 337, 338, 339, 340-342, 343, 346, 352, 386) Radner, S., 1951. Vertebral angiography by catheterization. Acta radiol., suppl. 87. (536) Ramadier, J., R. Causse, Andre-Thomas, and J. A. Barre, 1935. Les abces du cervelet. Rev. d'otoneuro-opht., 13:1 (Jan.), 85 (Feb.). (499) Ramon y Cajal, S., 1890. Sur les fibres nerveuses de la couche granuleuse du cervelet et sur 1'evolution des elements cerebelleux. Internat. Monatschr. f. Anat. u. Physiol., 7:12—31. (546) , 1906. Genesis de las fibras nerviosas del embryon y observaciones a la teoria catenaria. Trav. du lab. d. recherches biol. de 1'Univ. de Madrid, 4:227-294. (546) , 1909-1911. Histologie du systeme nerveux de 1'homme et des vertebres. Ed. francaise; traduite de 1'espagnol par Dr. L. Azoulay. 2 vols. Paris: A. Maloine. (76, 223, 359, 546) , 1926. Sur les fibres mousseuses et quelques points douteux de la texture de 1'ecorce cerebelleuse. Studi neurologici dedicati a Eugenio Tanzi nel suo LXX compleanno, pp. 63-82. Torino: Tip. Soc. Torinese. (360) Rand, C. W., C. W. Olsen, and C. B. Courville, 1943. Gross calcareous deposits in corpora striata and dentate nuclei: Report of two cases with comments on certain etiologic factors. Bull. Los Angeles Neurol. Soc., 8:118-128. (478) Rand, C. W., and R. J. van Wagenen, 1935. Brain tumors in childhood: Review of thirty-eight cases. *?3Q X CUldU., R-%99 U.OA/4—OOtJ. J . Pprlint

/^Q) \ ijf-j*j J

Rand, R. W., 1954. An anatomical and experimental study of the cerebellar nuclei and their efferent pathways in the monkey. J. Comp. Neurol., 101:167-224. (78) Ransome, G. A., 1944. Neurological signs in riboflavin and allied deficiencies. Brit. M. J., 2:637. (490-491) Ranson, S. W., 1932. Rigidity caused by pyramidal lesions in the cat. J. Comp. Neurol., 55:91-97. (336)

BIBLIOGRAPHICAL INDEX OF AUTHORS

619

Rasdolsky, I., 1935. Tuberkulome des Gehirns. Ztschr. f. d. ges. Neurol. u. Psychiat., 154:18-31. (£95) Rasmussen, A. T., 1933. Origin and course of the fasciculus uncinatus (Russell) in the cat, with observations on other fiber tracts arising from the cerebellar nuclei. J. Comp. Neurol., 57:165-184. (78, 86,149) Rawson, N. R., 1932. The story of the cerebellum. Canad. M. A. J., 26:220-225. (S, 4) Ray, B. S., 1942. Platybasia with involvement of central nervous system. Ann. Surg., 116:231-250. (418) Raymond, F., 1905. Maladie de Friedreich et heredo-ataxie cerebelleuse. Nouv. iconog. de la Saltpetriere, 18:5-16. (417) Reichmann, F., 1917. Zur neurologischen Kasuistik der Kleinhirnverletzungen. Arch. f. Psychiat., 57:61-72. (358) Reisinger, L., 1915. Die zentrale Lokalisation des Gleichgewichtssinnes der Fische. Biol. Zentralbl., 35:472-475.(11) , 1916. Das Kleinhirn der Hausvogel. Zool. Anz., 47:189-198. (14) , 1919. Beitrag zur Physiologic des Kleinhirns der Teleostier. Naturwissensch. Wchnschr., pp. 145-149.(11) , 1926. Noch einmal das Kleinhirn der Fische. Biol. Zentralbl., 46:436-440. (11) Reitsema, J. M., 1904. De indirecte atrophie der kleine hersenen. Psychiat. en neurol. bl., 8:347-366. (464) Renzi, P., 1863-1864. Saggio di fisiologia sperimentale sui centri nervosi della vita psichica nelle quattro classi degli animali vertebrati. 3 vols. Milano: Societa per la pubblicazione degli Annali Universal! delle Scienze e dell'Industria. (10, 12, 14, 23, 303, 344-345, 348) Rheinberger, M. B., and L. M. Davidoff, 1942. Posterior fossa tumors and the electroencephalogram. J. Mt. Sinai Hosp., 9:734-754. (535) Ricci, G. F., and A. Zanchetti, 1953. Rapporti tra le azioni inibitrici del cervelletto e della sostanza reticolare mediale del bulbo. Arch, fisiol., 53:162-170. (119, 151) Richter, H., 1924. Anatomische Veranderungen nach Verschluss der arteria cerebelli inf. post, mit retroolivarem Erweichungsherd. Arch. f. Psychiat., 71:272-281. (512) Richter, R. B., 1938. Clinicopathologic study of parenchymatous cortical cerebellar atrophy: Report of a familial case. Tr. Am. Neurol. A., 64:21-23. (447, 453) , 1940. A clinicopathologic study of parenchymatous cortical cerebellar atrophy: Report of a familial case. J. Nerv. & Ment. Dis., 91:37-46. (447, 452) , 1950. Late cortical cerebellar atrophy: A form of hereditary cerebellar atrophy. Am. J. of Human Genetics, 2:1-29. (449, 452) Rickles, N. K., 1945. Cerebral intoxication the result of trichloroethylene. Northwest Med., 44:286287. (487) Rigdon, R. H., 1944. The pathological lesions in the brain in malaria. South. M. J., 37:687-694. (481) and D. E. Fletcher, 1945. Lesions in the brain associated with malaria: Pathologic study on man and on experimental animals. Arch. Neurol. & Psychiat., 53:191-198. (481, 482) Riggs, Helen E., 1929. Cerebellar symptoms in tumor of the frontal lobe. Arch. Neurol. & Psychiat., 22:1088-1089.(405) Rijnberk, G. van, 1904. Tentativi di localizzazioni funzionali nel cervelletto. I. II lobulo semplice. Arch, fisiol., 1:569-574. (67) —, 1905. Tentativi di localizzazioni funzionali nel cervelletto. II. II centre per gli arti anterior!. Ibid., 2:18-25. (67) , 1906. Over functioneele localisatie in het cerebellum: Experimenteele en kritische bijdrage. Nieuwe verhandelingen v. h. Bataafsch Genootschap der proefondervindelijke Wijsbegeerte te Rotterdam, II s., 611:1-56. (67, 68, 69, 70) , 1907. Le probleme de la localisation dans le cervelet. Arch, internat. de physiol., 5:[127—128]. (70) , 1908a. Das Lokalisationsproblem im Kleinhirn. Ergebn. Physiol., 7:653-698. (51, 52, 104, 379) , 1908b. Die neueren Beitrage zur Anatomic und Physiologic des Kleinhirns der Sauger. I. Zui Physiologic. II. Die neueren anatomischen Arbeiten iiber das Cerebellum. III. Das Lokalisationsproblem im Cerebellum. Folia neurobiol., 1:46-62, 403-419, 535-551. (51, 52, 104, 379) , 1912. Weitere Beitrage zum Lokalisationsproblem im Kleinhirn. Ergebn. Physiol., 12:533563. (51, 52,104) , 1925a. Idees actuelles et derniers travaux concernant les fonctions du cervelet. Arch, neerl. de physiol., 10:155-182. (51, 52) , 1925b. Les dernieres recherches relatives a la question de la localisation dans le cervelet: Anatomic, physiologic, clinique. Ibid., pp. 183-301. (51, 52, 379)

620

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

, 1931. Das Kleinhirn. Ergebn. Physiol., 31:592-843. (IS, 14, 27, 51, 52, 104, 146, SOI, 359, 369, 371, 379) Riley, H. A., and S. Brock, 1933. Rhythmic myoclonus of the muscles of the palate, pharynx, larynx and other regions. Arch. Neurol. & Psychiat., 29:726-741. (413) Ringertz, N., and H. Nordenstam, 1951. Cerebellar astrocytoma. J. Neuropath. & Exper. Neurol., 10:343-367. (537, 539, 541, 552) Ringertz, N., and J. H. Tola, 1950. Medulloblastoma. J. Neuropath. & Exper. Neurol., 9:354-372. (542) Rioch, D. McK., and A. Rosenblueth, 1935. Inhibition from the cerebral cortex. Am. J. Physiol., 113:663-676. (329, 330) Rivers, T. M., and F. F. Schwentker, 1934. Louping ill in man. J. Exper. Med., 59:669-685. (483) Rizzolo, A., 1929. A study of equilibrium in the smooth dogfish (Galeus Canis Mitchill) after removal of different parts of the brain. Biol. Bull. Med. Biol. Lab. Wood's Hole, 57:245-249. (11) , 1930. Electrical stimulation of a lateral lobe of the cerebellum in relation to the excitability of the cerebral cortex. Arch, fisiol., 29:219-233. (311) Roberts, T. D. M., 1952. The inclusion of the muscle-spindle afferent in "the final common path." J. Physiol., 118:8P-9P. (355, 356) Robertson, T. B., and T. C. Burnett, 1912. On the action of sodium citrate upon mammalia, with especial reference to acquired tolerance and to its action upon the cerebellum. J. PharmacoL, 3:635-648.(110) Robinson, R. G., 1955. Two cerebellar tumours with unusual features: 1. Cystic astrocytoma. 2. Papilloma of the choroid plexus. J. Neurosurg., 12:183-186. (541) Roge, R., and J. A. Farfor, 1938. Sur un cas de dyssynergie cerebelleuse myoclonique progressive: La place en nosologie du syndrome de Ramsay-Hunt. Rev. neurol., 70:49-55. (412) Rolando, L., 1809. Saggio sopra la vera struttura del cervello dell'uomo e degli animali e sopra le funzioni del sistema nervoso. Sassari: Stampeia da S.S.R.M. Privilegiata. (4, 10, 13, 14, 23) • , 1823. Experiences sur les fonctions du systeme nerveux. J. de physiol. exper., 3:95-113, with a footnote at pp. 113-114 by F. Magendie. (4) Romano, J., M. Michael, Jr., and H. H. Merritt, 1940. Alcoholic cerebellar degeneration. Arch. Neurol. & Psychiat., 44:1230-1236. (485) Roncali, D. B., 1899a. Intorno alle estirpazioni parziali e totali del cervelletto. Policlinico (sez. chir.), 6:11-30. (349) , 1899b. Intorno alPinfluenza della vista nel ripristinarsi della funzione deambulatoria negli animali privati parzialmente o totalmente del cervelletto. Ibid., pp. 477-495. (349) Roncato, A., 1913. Influenza del labirinto non acustico sullo sviluppo della corteccia cerebellare. Nevraxe, 14:141-160. (361) Rondoni, P., 1909. Beitrage zum Studium der Entwickelungskrankheiten des Gehirns. Arch. f. Psychiat., 45:1004-1096. (442) Rosenblueth, A., and W. B. Cannon, 1941. Cortical responses to electrical stimulation. Am. J. Physiol., 135:690-741.(323) Rossi, G., 1912a. Ricerche sulla eccitabilita della corteccia cerebrale in cani sottoposti ad emiestirpazione cerebellare. Arch, fisiol., 10:257-260. (327-329, 354) , 1912b. Sugli effetti conseguenti alia stimolazione contemporanea della corteccia cerebrale e di quella cerebellare. Ibid., 10:389-399. (104, 138, 311, 327-329) , 1913. Sui rapporti funzionali del cervelletto con la zona motrice della corteccia cerebrale. Ibid., 11:258-264. (329) , 1921. Sulle localizzazioni cerebellari corticali e sul loro significato in rapporto alia funzione del cervelletto. Ibid., 19:391-445. (18, 68, 72, 73, 74, 389) • , 1922. Effetti delle ablazioni corticali cerebellari eseguite dopo la interruzione del circolo saguigno. Ibid., 20:191-204. (68, 369) , 1923a. Del modo di produrre lesioni circoscritte in region! profonde dell'asse cerebro-spinale. Ibid., 21:205-216. (72) , 1923b. Qualche osservazione sperimentale intorno al tono muscolare. Ibid., 21:275-282. (75, 76) , 1925. Sui rapporti fra le asimmetrie toniche e le asimmetrie motorie provocate da lesioni cerebellari unilateral!. Ibid., 23:1-25. (IS, 75, 372) , 1927. Asimmetrie toniche posturali ed asimmetrie motorie. Ibid., 25:146-157. (76-7-6, 243, 255, 356) — , 1940. Azione del cervelletto sulla corteccia cerebrale. Arch, fisiol., 40:419-437. (311) and A. M. Di Giorgio, 1933. Riflessi motori nei cani sottoposti a lesioni di alcuni lobuli cerebellari. Arch, fisiol., 32:99-132. (76, 342)

BIBLIOGRAPHICAL INDEX OF AUTHORS

621

, 1942. Sulla stimolazione stricnica del cervelletto nella scimmia. Boll. Soc. ital. biol. sper., 17:546-548. (68,112,178) Rossi, G. F., and A. Brodal, 1956. Corticofugal fibers to the brain stem reticular formation: An experimental study in the cat. J. Anat., 90:42-62. (223, 330) Rossi, I., 1907. Atrophie primitive parenchymateuse du cervelet a localisation corticale. Nouv. iconog. de la Salpetriere, 20:66-83. (387, 452) Rossi, U., 1891. Un caso di mancanza del lobo mediano del cervelletto con presenza della fossetta occipitale media. Sperimentale, 45:518-528. (430) Rothfeld, J., 1914. Ueber die Beeinflussung der vestibularen Reaktionsbewegungen durch experimentelle Verletzungen der Medulla Oblongata. Bull, de 1'Acad. des sciences, Krakau. Cited by de Kleijn and Magnus, 1920, p. 174. (273) Rothmann, M., 1910. Ueber die elektrische Erregbarkeit des Kleinhirns und ihre Leitung zum Riickenmark. Neurol. Centralbl., 29:1084-1100. (103, 104, US, 138, 149, 150) , 1913a. Die Funktion des Mittellappens des Kleinhirns. Monatschr. f. Psychiat. u. Neurol., 34:389-415. (52, 56-58, 61, 64, 67, 70) , 1913b. Zur Kleinhirnlokalisation. Berl. klin. Wchnschr., 50:336-339. Cited by van Rijnberk, 1931, pp. 782-783. (53, 68) , 1914. Die Symptome der Kleinhirnkrankheiten und ihre Bedeutung. Monatschr. f. Psychiat. u. Neurol., 35:43-70. (406) , 1915. Demonstration zur Ausschaltung der Rinde des Mittellappens des Kleinhirns. Folia neuro-biol., 9:792-793. (57, 72) Rubinstein, H. S., and W. Freeman, 1940a. Cerebellar agenesis. J. Nerv. & Ment. Dis., 92:489-502. (486-487, 428, 429) , 1940b. Defective closure of the neural tube: A case of involvement of central olfactory, trigeminal mesencephalic, visual reflex, auditory and cerebellar systems. Arch. Neurol. & Psychiat., 44:636-646. (428-429) Ruch, T. C., 1936. Evidence of the non-segmental character of spinal reflexes from an analysis of the cephalad effects of spinal transection (Schiff-Sherrington phenomenon). Am. J. Physiol., 114:457467.(280) , 1951. Motor systems. In S. S. Stevens, Handbook of Experimental Psychology, chap. 5, pp. 154-208. New York: Wiley & Sons. (369) , 1955. The urinary bladder. In J. F. Fulton, Textbook of Physiology, chap. 46, pp. 943-949. Philadelphia: W. B. Saunders Co. (306) and J. W. Watts, 1934. Reciprocal changes in reflex activity of the forelimbs induced by post-brachial "cold-block" of the spinal cord. Am. J. Physiol., 110:362-375. (274) Rudeanu, A., and M. Bonvallet, 1932. Role du cervelet dans la regulation des cronaxies motrices peripheriques: Relation avec la coordination. Compt. rend. Soc. de biol., 111:962-964. (264) Ruf, H., 1939. Der traumatische retrolabyrinthare Symptomenkomplex. Ztschr. f. Hals-, Nasen- u. Ohrenheilk., 46:291-297. (522) , 1951. Ueber die Beeinflussung experimenteller epileptischer Anfalle. Nervenarzt. 22:437-439. (179) Russell, C. K., 1931. The syndrome of the brachium conjunctivum and the tractus spinothalamicus. Arch. Neurol. & Psychiat., 25:1003-1010. (516) Russell, Dorothy S., 1946. Myocarditis in Friedreich's ataxia. J. Path. & Bact., 58:739-748. (466) and C. Donald, 1935. The mechanism of internal hydrocephalus in spina bifida. Brain, 58:203-215.(421) Russell, J. R., and P. C. Bucy, 1953. Meningiomas of the posterior fossa. Surg., Gyn. & Obst., 96:183-192.(560) Russell, J. S. R., 1893. On some circumstances under which the normal state of the knee jerk is altered. Proc. Roy. Soc., London, s. B, 53:430-458. (41) , 1894. Experimental researches into the functions of the cerebellum. Philos. Tr. Roy. Soc., London, s. B, 185:819-861. (25, 31, 35, 36, 41-42, 43, 49, 52, 64, 97, 103, 308, 327, 328, 329, 345) >, 1895. Defective development of the central nervous system in a cat. Brain, 18:37-53. (440) Russo, G., 1947. Sindrome cerebellare con disartria da malaria (sindrome di Pansini): Considerazioni su sette casi clinici. Riforma med., 61:330-336. (481) Sabrazes, J., 1921. Abces a streptothrix du cervelet. Compt. rend. Soc. de biol., 84:312-314. (507) Saccone, A., and J. A. Epstein, 1948. Granuloblastoma, a primary neuroectodermal tumor of the cerebellum. J. Neuropath. & Exper. Neurol., 7:287-298. (551) Sachs, B., 1887. An arrested cerebral development with special reference to cortical pathology. J. Nerv. & Ment. Dis., 14:541-553. (474) , 1892. A further contribution to the pathology of arrested cerebral development. Ibid., 19' 603-607.(474)

Wchnschr., 61:2593-2599. (418) Schut, J. W., 1946. Olivopontocerebellar atrophy in a cat. J. Neuropath. & Exper. Neurol 5-77-81 (468) , 1950. Hereditary ataxia: Clinical study through 6 generations. Arch. Neurol. & Psychiat., 63:535-568. (467) , 1951. Hereditary ataxia: Survey of certain clinical, pathological and genetic features with linkage data on 5 additional hereditary factors. Am. J. Human Genetics, 3:93-110. (473) and J. A. Book, 1953. Hereditary ataxia. Arch. Neurol. & Psychiat., 70:169-179. (467) -*•

-*--,-. •D~*T,~l«™;,,ol oturUr nf K nasps nf common

PHYSIOLOGY AND PATHOLOGY OF THE CEEEBELLUM

§m —

, 189U. A family form of idiocy (Amaurotic Family Idiory), New Vork M, J , 63:691-703.

unt

Sachs, E., and E. F, Finches 1(H7. Anatomical and physiological observations on lesions in the

eerebdlar nuclei in Macaeus rhesus. Brain, 50:350-356. (142, JtiJ'i Stchs, E., J, E. Rubinstein, and A. K". Amesnn, 1938. Results of roentgen treatment of a sewes of one hundred and nineteen gllotnas. Arch. Xewwl & Psychial., 33:5*7-610. (545; Sager, O.j and A. Kreindlw, 1945-1947. Etudes elfrtreneephalograpbiques am les relations fanctionnelies entre 1'txorte cerebrate et le eetvelet. Atvh. roum, pathol. esper., 14:582-336, (330) — , 1947. L'exctatbiiite s, A, L,, 1941. Congenital anomaly of the eerebellnr vermU. Arch. Path,, S'i-M-SS. (430, 4S2) Salter, H., 1S.)3. Congenital absence of the middle portions and left hemisphere of the cerebellum, in

a case of chrotiic hydroeephalus. Tr. Path. Soc, London, 4:31-34. (4,34) Sammartino, B., 2917. Abj-eeso wrebeio«.t por Faracoccidioides bwsiliensii. Arch, Soc. argent, tie

anat, norm, y pat., 9:S«fO-367. f JOS) Switha, K,, 1930, Ueber dus Verhalten des Kleinhiras in einetn Falle vcm endogen-afamiliarer Idiotie.

(Znr 0if?erentialdiagi5ose der Martesehen and der son^tigen endogencn KWnhiineikrajjkangec neBst Beitrag Kur Leiae der Diplomyelie.) Ztschr. f. d. ges. Ncnrol, u. Psycftiat,, 123:717-733. (450) S&prokhin. M. J,, 1937. On the relationships beltxgen eetrbelluin and sympathetic nervous system, (In Russian, with English summary.) Fiziol. zhur, 23:648-655. (»?W, SO?) ——, 1988. Tr. Voenno-med. Akad, 17. Cited by Simkina, 1946. f,i'50> — , 1939 VI Conference Euasian Academy of Sciences on pmblems of physwlogy. Cited by Simkina, 1848, (SS&j ——, 1040. Cite] by Simlina, 194S. (S91) , 1916. Cited by Simkina, 1948. <3Mj __—_ % ISMS. E!fc«s of ctrebeUar stimnlatioms on Ihe excitabiiity (riieobase a.id caronaxia) of the cerebral cortex. Isvestija Akadfroi Nauk SSSB—Serija biologhieeskaja, 5.384-389, (311) Savitsch. E, de, and R. A. Ley, 19S7. ilyorlonies palato-pharyngo-kiryngees an cours d'un neurinome

de k region Eutcrobulbaine. Rev. neurul., 07:585-604. (US) Sctialler, W- F., 19S1. A clinical and anatomic study of a vascular lesion of both cetebellar hemi-

spheres. Arch. Neurul. & Psychiat,, 5:1-19, (SIS) Schaper, A., 1894. Die morphologiiscfie und histolopsche Entm'ickelung des Kleinhims der T«leostief, Anat. Anz., 8:48&-o01. t&*S, S|7) ——, 1898. Einige kritische Benicrkungen ssu Lugato's Aufsatz: "Unber die Hislogeneae der Korner der Kleinhirnwnde." Ibid., IO:4->W-436. (346 5^7) — , 1897. Die friiheslen Diffewnzitrurgsvorgaog* ira Ccntralnert-ensysteio: kritischp Studic und Versuoh einer Geschirlite der EntwiekelMng ncrviisec Substanz. Arch. I. Entwifkelungsraeehri., 0:81-183. (546, 547) Schcibel, A., 1955. Axonal afferent patterns in the hulbar retfci'kr Fnrmattnn. Anat. Her., 141:361—

382. (333) Scheibel, M., A. Scheibel, A. ilollicn, and G. Monizzi, 1955. Convergence and interaction of afferent impulses on single units of retietilar formation, J. NetiTOphysiol, 18:;I09-381, (17.5, £S6-S2fit $48 > Schenk, V, W. D., 1R37. <JekreiiJ!te thalanio-cerehelliire Atrophie. Psychiat. en neurul. bl.. 41rfl8-^a6. (ifi5J Severer, H. J . 1931. Beitrage zur pathologiscl;en Anstomie des Eleinhtrns: Die bfcalen VeTandetungen —

der Kleinhirnnnde. Ztschr. f. d, ges. Nenrol. u. Psychial, 186:5fl9-59S. (451) , 1983. Beitrage zur pathologischen Anatomie des Kleinhirns. Die Erlcrankungen des Klein-

hinimarkes unrf seiner Kerne, insbescradere des nucleus cUtitatm. Ibid., 139.-337-368 (463, &$5) , 19S3a, BeitriigR jtm pathologiseheit Anatomie des Kleinhirns. Genuine Kleinhirnatrophien. Ibid., 145:335-405. fi,5(). 453) —• , 1933b. Extrapyratnidale Sturungen bei der oHvopontoucrebellBreri Atrophie. Ibid., 14S-406419. (459, ^m) — -, 1940a. A critical renew: The pathology of cerebral gliomas J. Neurol. & Psychiat., 3:147\17.fSSS, 5,19) —.-..-. t 194Bb. The forms nf gro»tb in glioraas and their practical significance. Brain, 83:1-35. —

(54S) Solierrer. H., and R, Hernandra-Pe<5n, 1955. Inhibitory influence of re titular formation upon synaptic

transmission in gntcilis nucleus. Federation Proc., 14:138. f.?|S)

BIBLIOGRAPHICAL INDEX OF AUTHORS

628

Schifl', J. M., 184J. De vi motonae baseos pncepliali inquibitiones experlmentails. Frankfurt a M,; BiH,-k«tlieiir, (Sfy • —- 1858. Lelirbueh der Physiologic ties Menschen. I. Musk*!- uri>l NervenphysiolQgii?, Lahr. Schauenburg and Co. I ,'JJ — -, IBfifi. Lt,aoni ill Kisiologui .•»perini u >• Sohlayw, C, R,, 191 J. \Vrfi. J. dhi-hr. Kuugr. f. urn Mc<3, Cited b^ Oiivrt, l'J3r>. ( . W t ; Schmidt. M , litil. I ntcrauf-lmngfin uber \o)lstandit;e Enttf-rniing ties Kleiuliirns beim Meersc.hwe'i.tliw. p. s!il Tlw=e dc Graev*- No. 3?S. \Fac, tl« Mrri.i, G>-rf \e {'*>V>, yj'V 'N'linenler, K (.' , E. A. Katm, aur lir h d. ges. Neural. u. 1'f.M-hiat.. ]4.i-4n-51S. f iSO^ Schou H. I , 1!K5. Mioclraius-Epiiepsic mit ciReii'umiiciivii GchirnvTeramlctujigcn. 2fsclir, t' d. ge* Nrarol. u. Psjt-hiat,, 95;li>-i!(». f41S) Schreib" r, F,, S94L CnreWllar fthscease? «t otdic origin in t» children; H rei'O-vpries after ca.ntiula.tion Atir. Sarfc, 114:330-SSr.f.T*. Schroetlw, A. It,, and W. Kirtrlibaum, 19=!5. I ij Schulfcr, A, 1911. Zur Koiilgiit t dec basaieu ImTwvsiion des Scli,»deL AVicn. i&cd, l^t-hnschr,. 01:il93-^599. !^M Schut, J. IV 114.6 Olivfipontocefebellar atrophy in a L-at. J. Neuropath. & Exper. Xeurol., 5:77-81 ««' — -. 1950. Kfteditftry alaxia; Clinir^l study Uiiough 6 graewlions \ivli. Neurol. & P&ychiat,. 63 ,)3.>-5eS. ( {C71 — , 1851. HiMttlitary fltexis: Survey of certain cliniial, pathoiogieal and ^euriic features with linhaw? data on j -179, {W Schul, J, W.. and \V Haymaker. 1951. Hereditary ataxia: Pathulopral study of S cases of common ai.vi"tfiy J »iirop"~. ^'j?, 4§9-4Trj " SchMab, O,, 1W7. IVhrr Stut^reakIioncn (REatfnus) bfitn Mt-nochcn. t,7!uglcieh ein Bfitraf" zuc Ayfiassung dtT sog^naniilen Gelenkreflcxe.) Ztschr. f. d. ges. Neurol, u. Fsyohiat, 108:5*5-593, (Mf) Schwalbe, E., sn<j M. Gredig, 1907. Ueber EntwSckeh«igsstSrunK«ft des Kletnhhns, Hirnstani»s »rad Halsmarks bei spins bifida. (Arnold'iche und Chiari'idie Missbildung). Beitr, path. Anat. Jena, 40:182-194. (431) Schwanc, E,, J91S. Ucber cten anatomisclien mid kliiiisefceo Befund bei Veradiluss Jer Arteria cerebtli posterior inferior. Monatschr. f. Psychiat. u. Xcurol., 32:18^-139, (-51.?) Schwarzkopf, II,. 1850. 'V«ntrikulare Matrix- mtd KindcnenUvinkelung bal mediaaeiiL Kleinhimverbildungen Arch, f- Psyclilat., 185:84-94. (432) Sdi-wcntker, F. F,, T. M. Rivers, ant! M, H. FinMslein, 19S3, Observ»ltons on the imrannotogtcal idation of poliomyelitis to louping ill. J. Esper. Med., 57:933-965. (488) Scolt, E.,aadG. O- Groves, 1933, Tuberculoraa of Ihe brain: With a. report of four cases. Am. Bev. Tubetc., 97:171-198. (494) Sergccv, J. S., 19**. Clinical aspect of tick-borne encephalitis in the northwest provinces of the Soviet Union, (In Russian,} Neiiropatologiya i psykhialry'a, IS, no, i:54~57, Cited by Olitsky and Casals, 1948. (483) Sergi, S,, 1903, Rotazione intorno all'asw longitudinale negli animali con lesion! ttnikterali del cervclletto. Hiv. sper, di freniat., 39:125-150. (331)

6«4

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

S«res, A , 1836. Anatamie compare* du rervean, clans tes qoatte classes «fes animatix vtrtrbres, Appliqu« a IR pbysiologie el 4 la pathologte du systems norveux -i vols. Pari* Gmboti & Cie. Ui.-W Sfeeeh«», D, and G. E, Smyth, 1937. A stoidv «f the anatomy of lerlebral thrombosis. Lancet *: 6J+-G18. (511,,-iW, 5131 Sbeliste-ar, J, L., tfla>2. Blood supply of the drniate nucleus of the cerebellum. Lancel, 1:1046^1047. {fi\ 510) Shemngbm, C. S,, 1896, On reciprocal innervalkm of antagonistic muscle*. Third Note. Proe. Ray. Soc., London, s. B, 00:414-417. '"IIJ/ —; _ 189*. Double (antirtroBie) conduction in t!« central nervous systeiB, Piw. K*y, Soc., LonJon, s, B, t)il:243-346, (Received February 15. read April 8, I89T-M7, JOk, US) •——-. 1S98, Dectrebrate rigidity and relfex coordination of movements. 3, Physiol., 2fi:81ft-3SS, fW, £6, ,?P, 51, 39, 104 1W, 1^6, 2Jfl. 257. £G7, &~y, F?4, ^75, S7PJ • —, 1900. The cerebellum. Jn E. A. SthSfnr, Textbook of Physiofogy. vol. 8, pp. 89S--910. Edinburgh and London: Young J. Pentland. (24, 39, 43, 114) —. 1906. The Integrative Action of Uw: Nrrvous System. New \fork: Charles Scribner's Sons. fi.?. &\ 156, ISili ———, 1313, Further observations on the production of reflex stepping by combination of teflcx excitation with reflex inhibition. J. Physiol, 47:196-314. ("57) ——, 13i«, Matt on His Nature. Cambridge: TFnlv. Press, (£$, 2SO. 3H) Sbimaxnno. J., 191S. Das Kfeir.hira ckr Vogtti Arch. f. raUcr. Anal., 80:897-K9. (IJ, .'05-IWJ IJ^) Sh«i«iJzu, K., 19<4. Quantitative Messutigen dl« Adcenaiinsetcretion nach dew Zuckrrstich «n«l n»cli \crpiftuugen. Areli. L c-xper, Path, w, Pbixrmukol., 10S:5-J-72. {SD1. 30U) Shitu>>aki, T., 1936. Die Bedeutung des Kleinhtmwurms {ur die Zuckerr^gulation. Ztwhr. f. d. ges. Xeurol. u. Psyelsiat, l«e:483-510. (301, $&£t SOS) Sinister, B, It., 1936, Vestibular tests- Their practical application. Arch. Ololarj-ng,, -JSieiB-fliia. (MftS.i Siclenberg, S. S. M. M, "Kcssler and R, Wolpaw, 1140. A case cif tetralogy of Fallot with absence of cerebMlar vcrmis; tertBtnation by brain abscess. J. Pediat,, 3P:?t 9-748. f^SO, l&l) Swtens, A. A., JMW| C. N. Woolsey, 1948. Cortical &uto»omk center for the *ycs on the mMiat -surS'at'c of the fntntai lob* in the «t Federation PK>C., 75:8,5. ($(&} Sipsr. E B,. and K. D. Wettzmann. 1854, Influence of the a«ioi»tn;e .jervous system on the p^tellar «»flc\- \m. J. Physiol. 179.674. (J5J I Silter, L. A., and A. K. Shuhladze, 1945. Lrmping-ill in the USSR. Am. Rev. Soviet Sled., 2:«S9S41. Cited by Olitsky and Casals, 1848. ($S3) Silver, M. L., and G. Heunignr. 19H. CetchfHstr hesnanginma (hemangioblaUoma): A clinicopatholopicaS review of +0 cases, J. Neurnsiirg., 9:484-494. (553j SS|, '&!) Sitvrrman. J, J., a,iul J. E. Wilson, 1050, ttnusual compliratifn following tbyroiffcetoto); k^ftt sltoke with ptman«nt wrebellar daraage Ann. Int. Met!., 85:1636-1041 (iSJi Sunkina. A. M , VJtta, Jstv ats &SSB, i:ttl biol. n«ifc.. 8:152. Cited by Sitnkma, 19*8. f*91, 9t«f, Sd'i'i ___ ( ]94Sl), Autonomic fanetlons of the cprebeilum. Cited by Sirakma. JStfi. (350) ——, 3945a. flit effect produceJ on the sizv of the pupil by stimulating the (.TTcbelllim. (In Russian, with English summary.) Fiaiol. zhar,, 31:151-156, (SOS) .—— -, 19Ub. The effect produced on the permeability of the uveal tract vessels by sttmuktfons of thi» cerebellum. (In Kussian. with English summary,1) Ibid., 31:99^^07. (SOS) ———, TiMS. Cererbellum and sleep. (In Russian, with English summary.) /bid., 83:907-*Jie, (.iS6) — , 1048. Present views on the cerebellar influencp on the autonomic and sensory functions. (In RuSikn.1 Usptkhi Sovwm. Biol. -3S:S4S-S70, f395. 30?, S06, SOS, 346, #50) — and A. A. Mtkiielson, 1838. Influenvc <J>f cercbellar stimulations on vascular rcfcses in normal ami ttecewbrate <*als, {In Husstan, with English traiislalwn.t I^v naucit Tnst. tesgaftA at:ISS-H?. AUsltaeted in Her. gea. Pii.vsJol., 112:635 (1939), Cited by Wigacm, 13«l>, lS48a, widSimkiiut 1918. (091, $94, 393} Sinikina, A. M.. and L. A. Orbeli. 193t. Eff of the stimulation ot tie cetcbrUam. {In Russian, •with Gcnoan suramaty.) Fiziol zhar,, 15:357-571. Cited by Simians, 1946. (291, 363, SSO) Simonelli, G., 19l4a. Studio anatomico su c?rvell**tti apciati iji cstirpaziimp dei "Crus prinium lobull anstfonais.'* Atdt. fisiol,, 19:378-375. f,5S, 7f) —, 1914b. Contributo a(!a conoscenza ttetie lacaltzzazioni cwrbelhr:, Riv. <J; put new., 19:31785fi. (£8, 7S) —-—. 1941. Swlk fun»Q(» dei lobi medi del cerwllrtta. I. II bbo pnntMtore (Pyramid Uvula, Noiluliis, ?erond« Ingvar), Aich. fisiol,. 19:*47-4?9. (52-&S, 5?') „_—> jflsa, Lrtoali«wzio7>5 eereWlari cortical). Ibid.. 20:405-436. f,W, 7*,} —---. 7933. Fenciroem dj Iof-«tliz2fl2ione cerebtllnrf in animali slabirintBtu Ibid., 91:343-874. (75, 76}

BIBLIOGRAPHICAL INDEX OF AUTHORS

625

, 1924. Verification anatomique de cervelets operes de destruction du lobus posterieur (Pyramis, Uvula, Nodulus) et considerations sur la doctrine cerebelleuse de Ingvar. Rev. neurol., 1:432-439. (53, 59, 67, 72) , 1926. L'eccitabilita chimica della corteccia cerebellare. Studi neurologici dedicati a E. Tanzi, pp. 109-112. Torino: Tip. Soc. torinese. (112, 113, 178) , 1930. Su alcuni recenti studi di fisiologia cerebellare e sui rapporti del cervelletto con i sottostanti centri degli automatismi motori e posturali. Arch, fisiol., 28:289-323. (44, 60, 76) and A. M. Di Giorgio, 1925. De la facon de se comporter des reflexes toniques et de quelques reflexes par excitation thermique du iabyrinthe dans les lesions asymmetriques du cervelet. Arch. ital. de biol., 75:91-96. (272) , 1926. I rapporti dell'azione cerebellare con alcuni riflessi concernenti I'orientamento e 1'equilibrio del corpo. Arch, fisiol., 24:461-535. (38, 41, 64, 272) , 1931. Osservazioni intorno ai meccanismi di compensazione delle deficienze cerebellari. Boll. Soc. ital. biol. sper., 6:146-149. (331) Sinz, P., 1933. Unterentwickelung des Hinterhaupt- und Keilbeinkorpers mit gleichzeitiger knocherner Verbindung zwischen Atlas und Schadel als Todesursache. Virchows Arch. f. path. Anat., 287:641-650.(418) Sioli, F., 1913. Ueber histologischen Befund bei familiarer Myoklonus-Epilepsie. Arch. f. Psychiat., 51:30-39. (412) Sjogren, S. E., 1953. Percutaneous vertebral angiography: A review of 250 cases. Acta radiol., 40:113-127.(536) Sjogren, T., 1931. Die juvenile amaurotische Idiotic: Klinische und erblichkeitsmedizinische Untersuchungen. Hereditas, 14:197-426. (474) , 1943. Klinische und erbbiologische Untersuchungen iiber die Heredoataxien. Acta psychiat. et neurol., suppl. 27. (467, 473) Sjoqvist, O., and E. A. Weinstein, 1942. The effect of section of the medial lemniscus on proprioceptive functions in chimpanzees and monkeys. J. Neurophysiol., 5:69-74. (346, 347) Skillicorn, S. A., 1955. Presenile cerebellar ataxia in chronic alcoholics. Neurology, 5:527-534. (456) Skoglund, C. R., 1945. The electrotonic changes of excitability in nerve and their relation to accomodation. Kgl. Svenska Vetenschapsakad. Handl., 21:1-48. (156) Skorokhod, V., 1941. Fiziol. zhur., 30:4. Cited by Simkina, 1948. (291) Smith, J. R., C. W. P. Walter, and R. W. Laidlow, 1940. The electroencephalogram in cases of neoplasms of the posterior fossa. Arch. Neurol. & Psychiat., 43:472-487. (535) Smith, W. A., and E. F. Fincher, 1942. Intracranial tumors in children: Preliminary study of 100 cases. South. M. J., 35:547-554. (529, 530) Smith, W. K.. 1952. Unpublished experiments. Cited by Hampson, Harrison, and Woolsey, 1952. (134) Smyth, G. E., 1941. The significance of lesions in dentate nuclei apparently consecutive to disease of frontal lobes. Brain, 64:63-72. (406) Snider, R. S., 1940a. Functional studies following lesions of the cerebellar vermis involving the nucleus fastigii. Bull. Johns Hopkins Hosp., 67:125-138. (77; , 1940b. Functional studies following lesions of the nucleus interpositus in the rabbit. Bull. Johns Hopkins Hosp., 67:139-153. (86, 343) , 1943. A fifth cranial nerve projection to the cerebellum. Federation Proc., 2:46. (185, 186, 191, 245) , 1945. Electro-anatomical studies on a tecto-cerebellar pathway. Anat. Rec., 91:299. (202) , 1950. Recent contributions to the anatomy and physiology of the cerebellum. Arch. Neurol. & Psychiat., 64:196-219. (369, 397) and P. M. Cooke, 1953. Cerebellar activity in relation to the electrocorticogram before, during and after seizure states. Electroencephalog. & Clin. Neurophysiol., 5, suppl. 3:78. (325) Snider, R. S., and E. Eldred, 1948. Cerebral projections to the tactile, auditory and visual areas of the cerebellum. Anat. Rec., 100:714. (209, 245, 247, 250) • , 1949. Maintenance of spontaneous activity within the cerebellum. Proc. Soc. Exper. Biol. & Med., 72:124-127. (75,164,173) , 1951. Electro-anatomical studies on cerebro-cerebellar connections in the cat. J. Comp. Neurol., 95:1-16. (208, 209, 245, 247, 250) , 1952. Cerebro-cerebellar relationships in the monkey. J. Neurophysiol., 15:27-40. (209-210, 245, 247, 250) Snider, R. S., and J. Jacobs, 1949. Correlation of histogenetic changes in the cerebellum with the appearance of electrical activity. Anat. Rec., 103:559. (367) Snider, R. S., and H. W. Magoun, 1949. Facilitation produced by cerebellar stimulation. J. Neurophysiol.. 12:335-345. (59, 109, 126, 138, 154, 321)

626

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

and W. S. McCulloch, 1947. A suppressor cerebello-bulbo-reticular pathway from anterior lobe and paramedian lobuli. Federation Proc., 6:207. (126, 321) Snider, R. S., W. S. McCulloch, and H. W. Magoun, 1949. A cerebello-bulbo-reticular pathway for suppression. J. Neurophysiol, 12:325-334. (109, 119, 1-26, 138, 149, 154-, 219, 24-3, 248, 321, 336) Snider, R. S., and A. Stowell, 1942a. Evidence of a projection of the optic system to the cerebellum. Anat. Rec., 82:448-449. (1S6) , 1942b. Evidence of a representation of tactile sensibility in the cerebellum of the cat. Federation Proc., 1:82. (185,186, 245) , 1944. Receiving areas of the tactile, auditory and visual systems in the cerebellum. J. Neurophysiol., 7:331-357. (159, 185, 186-188, 191, 204, 211, 245, 247, 250) Snider, R. S., and C. N. Woolsey, 1941. Extensor rigidity in cats produced by simultaneous ablation of the anterior lobe of the cerebellum and the pericruciate areas of the cerebral hemispheres. Am. J. Physiol, 133:454. (57) Socin, Ch., and W. Storm van Leeuwen, 1914. Ueber den Einfluss der Kopfstellung auf phasische Extremitatenreflexe. Arch. f. d. ges. Physiol., 159:251-275. (120) Soriano, V., and J. F. Fulton, 1947. Interrelation between anterior lobe of cerebellum and motor area. Federation Proc., 6:207-208. (59, 63, 337, 338) Southerland, R. W., 1932. Three cases of tumor in the posterior fossa with mental symptoms. Bull. Neurol. Inst. New York, 2:144-156. (531) Spamer, C., 1880. Experimenteller und kritischer Beitrag zur Physiologic der halbkreisformigen Kanale. Arch. f. d. ges. Physiol., 21:479-590. (272, 273) Spellberg, M. A., and S. Zivin, 1948. Amebiasis in veterans of World War II with special emphasis on extra-intestinal complications, including case of amebic cerebellar abscess. Gastroenterology, 10:452-473. (508) Spencer, H. R., 1886. Pharyngeal and laryngeal "nystagmus." Lancet, 2:70£. (413) Sperti, L., and P. Zatti, 1953a. Osservazioni sulla struttura dei nuclei cerebellari in cervelletti con lesioni croniche circoscritte della corteccia. Atti Soc. med. chir., Padova, 31:437-440. (281, 343) , 1953b. Osservazioni sulla struttura dei nuclei cerebellari in cervelletti con lesioni croniche di uno o piii nuclei. Ibid., pp. 441-442. (78, 343) , 1953c. Osservazioni sul comportamento di cani con lesione cronica di uno o piu nuclei cerebellari. Ibid., pp. 537-541. (78, 86, 87) Spiegel, E. A., 1927. Der Tonus der Skelettmuskulatur. Berlin: J. Springer. (104) , 1937. Comparative study of the thalamic, cerebral and cerebellar potentials. Am. J. Physiol., 118:569-579. (163,173) and Th. D. Demetriades, 1925. Die zentrale Kompensation des Labyrinthverlustes. Arch. f. d. ges. Physiol., 210:215-222. (289) Spiegel, E. A., and N. P. Scala, 1941. Vertical nystagmus following lesions of the cerebellar vermis. Arch. Ophth., 26:661-669. (288, 383, 403) , 1942. Positional nystagmus in cerebellar lesions. J. Neurophysiol., 5:247-260. (288, 383, 403) , 1943. Response of the labyrinthine apparatus to electrical stimulation. Arch. Otolaryng., 38:131-138. (231) Spielmeyer, W., 1922. Histopathologie des Nervensystems. Berlin: J. Springer. (423, 481, 485, 489,

. 490) Spillane, J. D., 1937. Posterior inferior cerebellar artery thrombosis. Bull. Neurol. Inst. New York, 6:529-539. (512, 513) Spiller, W. G., 1908. The symptom-complex of occlusion of the posterior inferior cerebellar artery: Two cases with necropsy. J. Nerv. & Ment. Dis., 35:365-387. (511, 512) Spitz, E. B., H. A. Shenkin, and F. C. Grant, 1947. Cerebellar medulloblastoma in adults. Arch. Neurol. & Psychiat., 57:417-422. (642, 543) Sprague, J. M., and W. W. Chambers, 1953. Regulation of posture in intact and decerebrate cat. I. Cerebellum, reticular formation, vestibular nuclei. J. Neurophysiol., 16:451-463. (21, 61, 62, 7778, 79, 80-81, 98, 100, 142, 148, 149, 152, 237, 265, 342, 343) , 1954. Control of posture by reticular formation and cerebellum in the intact, anesthetized and unanesthetized and in the decerebrate cat. Am. J. Physiol., 176:52-64. (134-135, 136, 137, 138,141,147, 148, 149, 150, 151, 15®, 153, 154, 157, 264) Stannus, H. S., 1944. Some problems in riboflavin and allied deficiencies (Lumleian lectures, abridged). Brit. M. J., 2:103-105, 140-144. (490, 491) Starr, M. A., 1890. Intracranial tumors. In J. M. Keating, ed., Cyclopaedia of Diseases of Children, vol. 4, pp. 551-589. Philadelphia: J. B. Lippincott Go. (495) , 1893. Brain Surgery. New York: William Wood & Co. (495) , 1910. Tumors of the acoustic nerve, their symptoms and surgical treatment. Am. J. M. Sc., 139:551-581. (382)

BIBLIOGRAPHICAL INDEX OF AUTHORS

627

Stauffenberg, von, 1918. Zur Kenntnis des extrapyramidalen motorischen Systems und Mitteilung eines Falles von sogenannter "Atrophie olivopontocerebelleuse." Ztschr. f. d. ges. Neurol. u. Psychiat., 39:1-53. (460, 462) Steegman, A. T., and L. J. Karnosh, 1936. Infantile amaurotic family idiocy, with megalocephaly and cerebellar atrophy. Am. J. Psychiat., 92:1413-1424. (474-475) Stefani, A., 1876. Studi sulla funzione dei canali semicircolari e relazioni di esperimenti fatti per ricercare i rapporti funzionali dei medesimi col cervelletto. Atti Accad. d. sc. med. e nat. in Ferrara, 9:137-171. (276) , 1877. Contribuzione alia fisiologia del cervelletto (Studi). Ibid., 12:193-211. (6, 272) , 1881. Ulteriore contribuzione alia fisiologia del cervelletto e dei canali semicircolari. Arch, di sc. med., 4:183-189. (878) , 1903. Delia funzipne non acustica o di orientamento del labirinto dell'orecchio. I. Studio critico. II. Movimento di torsione del capo e rapporti del labirinto non acustico coi centri nervosi encefalici. Atti d. r. 1st. Veneto di sc., lett. ed arti, 62:937-1019, 1121-1151. (6, 272) , 1920. Rapporto funzionale fra cervelletto e labirinto non acustico. Mem. R. Accad. Naz. Lincei, cl. sc. fis. mat. e nat., Anno CCCXVII, ser. V, 13:323-356. (272) and G. Weiss, 1877. Ricerche anatomiche intorno al cervelletto di colombi sani e di colombi operati nei canali semicircolari. Atti Accad. d. sc. med. e nat. in Ferrara, 13:215-232. (272) Steiner, I., 1885. Untersuchungen iiber die Physiologic des Froschhirns. Braunschweig: F. Vieweg u. Sohn. (12) —, 1888. Die Funktionen des Centralnervensystems und ihre Phylogenese. II Abt. Die Fische. Braunschweig: F. Vieweg u. Sohn. (10) , 1900. Die Funktionen des Centralnervensystems und ihre Phylogenese. IV Abt. Reptilien, Riickenmarksreflexe, Vermischtes. Braunschweig: F. Vieweg u. Sohn. (13) Stella, G., 1937. On the site of the respiratory centers. Arch, internat. de pharmacodyn., 57:349356.(899) , 1939. The effect of cerebellum on respiration. J. Physiol., 96:26 P. (899, 300) , 1944a. Nuove osservazioni sugli effetti della stimolazione del paleocerebello nell'animale decerebrato. Atti Soc. med. chir., Padova, 23:22-24. (61, 124, 135, 137, 157, 262, 281, 283) , 1944b. Sul meccanismo della rigidita da decerebrazione in arti deafferentati. Ibid., pp. 5-16. (61, 257, 259, 262, 268, 274, 275, 277, 280, 352) —-, 1944c. Influenza del cervelletto sulla rigidita da decerebrazione. Ibid., pp. 17-21. (246, 268, 274, 277, 280) , 1946. Nuove osservazioni sull'attivita riflessa tonica del cervelletto nell'animale decerebrato. Boll. Soc. ital. biol. sper., 22:78-80. (60, 274) . 1947. On the mechanism of Luciani's cerebellar "atonia." Proc. XVII Internat. Congress Physiol., Oxford, pp. 97-98. (135, 280, 281) Stella, G., P. Zatti, and L. Sperti, 1953. Decerebrate rigidity in forelimbs after deafferentation and spinal transection in dogs with chronic lesions in different parts of the cerebellum. Proc. XIX Internat. Congress Physiol., Montreal, pp. 799-800. (881) . 1955. Decerebrate rigidity in forelegs after deafferentation and spinal transection in dogs with chronic lesions in different parts of the cerebellum. Am. J. Physiol., 181:230-234. (81, 100, 265, 281) Stender, A., and F. Liithy, 1931. Ueber Spatatrophie der Kleinhirnrinde bei chronischem Alkoholismus. Deutsche Ztschr. f. Nervenh., 117-119:604-622. (456) Stenvers, H. W., 1925. Position of the head in cerebral tumors above and below the tentorium. Arch. Neurol. & Psychiat., 13:711-723. (383, 403) Stephens, R. H., 1942. Platybasia: A report of a case treated surgically with improvement. Surgery, 12:943-951. (419) Stern, A., 1907. Ueber Cysticerken im Vierten Ventrikel. Ztschr. f. klin. Med., 61:64-120. (403, 508) Stern, L., and E. Rothlin, 1918. Effets de 1'application directe du curare sur les differentes parties du cervelet. Schweiz. Arch. f. Neurol. u. psychiat., 3:234-254. (110) Sternberg, C., 1912. Ueber vollstandigen Defekt des Kleinhirns. Verhandl. d. deutsch. path. Gesellsch., 15:353-359. (486) Stevens, H., 1953. Actinomycosis of the nervous system. Neurology, 3:761-772. (507) , and F. M. Forster, 1953. Effect of carbon tetrachloride on the nervous system. Arch. Neurol. & Psychiat., 70:635-649. (488) Stevenson, L., and F. Echlin, 1934. Nature and origin of some tumors of cerebellum, medulloblastoma. Arch. Neurol. & Psychiat., 31:93-109. (651) Stevenson, L. D., and L. E. McGowan, 1937. A case of tuberous sclerosis involving chiefly the cerebellum and simulating an expanding lesion of the quadrigeminal plate. Tr. Am. Neurol A., 63:26-31.(478)

628

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

Stewart, R. M., 1918. On the occurrence of a cerebellar syndrome following heat stroke. Rev. Neurol. & Psychiat., 16:78-93. (491) Stewart, T. G., and G. Holmes, 1904. Symptomatology of cerebellar tumours: A study of forty cases. Brain, 27:522-591. (379, 382, 388, 408, 409, 410, 529, 530) Stone, T. T., 1933. Primary familial degeneration of the cerebellum: A report of two cases. J. Nerv. & Ment. Dis., 78:131-136. (446, W) Stopford, J. S. B., 1916-1917. The arteries of the pons and medulla oblongata. Part I, J. Anat., 50:131-164; Part II, ibid., 50:255-280; Part III, ibid., 51:251-277. (510, 511, 513, 515) Stowell, A., and R. S. Snider, 1942a. Projection of an auditory pathway to the cerebellum of the cat. Anat. Rec., 82-99. (186) , 1942b. Evidence of a representation of auditory sensibility in the cerebellum of the cat. Federation Proc., 1:84. (186) Strack, I. S., 1941. The effect of partial extirpation of the cerebellum on the working capacity of the neuromuscular apparatus. Fiziol. zhur., 30:523-524. (269, 308) Strauss, I., and J. H. Globus, 1918. Spongioblastoma with unusually rapid growth following decompression. Bull. Neurol. Inst. New York, 1:273-281. (549) Stroebe, H., 1895. Ueber Entstehung und Bau der Gehirngliome. Beitr. z. path. Anat. u. z. allg. Path., 18:405-486. (549) Strong, 0. S., 1915. A case of unilateral cerebellar agenesia. J. Comp. Neurol., 25:361-391. (435, 436) Striimpell, A. von, 1893. Ueber die hereditare spastiche Spinalparalyse. Deutsche Ztschr. f. Nervenh., 4:173-188. (469) Stuart, E. A., F. H. O'Brien, and W. J. McNally, 1955. Some observations on brain abscess. Arch. Otolaryng., 61:212-216. (499) Suda, I., U. Abe, S. Uchiyama, and S. Mizuno, 1944. Experiments on the cerebellum. I. Changes in pupillary diameter, blood pressure and respiration following chemical stimulation of the cerebellum. Japan. J. Brain Physiol., 11-12:49-57. (291) Suda, I., and E. Takahira, 1954. Studies on the laminar structure of the central nervous system by means of microelectrodes. I, II. Cerebellar cortex. (In Japanese.) J. Physiol. Soc. Japan., 16:303 and 17:144. (168) Suechting, R. L., and L. A. French, 1955. Posterior inferior cerebellar artery syndrome following a fracture of the cervical vertebra. J. Neurosurg., 12:187-189. (512) Sugar, 0., and R. W. Gerard, 1938. Anoxia and brain potentials. J. Neurophysiol., 1:558-572. (489) Sugar, O., L. B. Holden, and C. B. Powell, 1949. Vertebral angiography. Am. J. Roentgenol., 61:166182. (536) Sunderland, S., 1940. The projection of the cerebral cortex on the pons and cerebellum in the macaque monkey. J. Anat., 74:201-226. ($47) Sutton, D., 1951. The diagnosis of intracranial vascular lesions by percutaneous vertebral angiography. Arch. Middlesex Hosp., 1:228-238. (536) , 1955. Neuroradiology. In W. R. Brain and E. B. Strauss, Recent Advances in Neurology and Neuropsychiatry, chap. 13, pp. 232-289. Boston: Little, Brown & Co.; London: Churchill. (536) and R. D. Hoare, 1951. Percutaneous vertebral arteriography. Brit. J. Radiol., 24:589-597. (556J Svaty, J., and R. Masek, 1950. Agenesia of corpus callosum and septum pellucidum with porencephaly of cerebellum. Casop. lek. cesk., 89:1171-1177. (430, 432) Svien, H. J., R. F. Mabon, J. W. Kernohan, and A. W. Adson, 1949a. Symposium on new and simplified concept of gliomas; astrocytomas. Proc. Staff Meet., Mayo Clin., 24:54-64. (539) , 1949b. A simplified classification of the gliomas, based on the concept of anaplasia. Clin. North America, 29:1169-1187. (539, 547) Swank, R. L., and S. J. Brendler, 1951. The cerebellar electrogram: Effects of anesthesia, analeptics and local novocaine. Electroencephalog. & Clin. Neurophysiol., 3:207-212. (163) Szabo, Th., and D. Albe-Fessard, 1954. Repartition et caracteres des afferences somesthesiques et d'origine corticale sur le lobe paramedian du cervelet du chat. J. Physiol., Paris, 46:528-531. (217) Taggart, J. K., Jr., and A. E. Walker, 1942. Congenital atresia of the foramens of Luschka and Magendie. Arch. Neurol. & Psychiat., 48:583-612. (432) Talbert, G. A., and F. L. Jenkins, 1925. A comparative study of equilibrium in pigeon on the ablation of cerebellum and severance of semicircular canals. Am. J. Physiol., 72:209. (14) Tanohata, K., and D. Tagawa, 1932. Histopathological study of the central nervous system in experimental carbon tetrachloride poisoning. Nagasaki Igakkai Zassi, 10:1505-1506. Cited by Stevens and Forster, 1953. (488) Tatlow, W. F. T., and H. G. Bammer, 1957. Syndrome of vertebral artery compression. Neurology, 7:331-340. (512, 521)

BIBLIOGRAPHICAL INDEX OF AUTHORS

629

Tavania, E., 1939. Emorragia cerebellare da trauma cranico chiuso: leptomeningite diplococcica finale. (Osservazione clinica ed anatomo-patologica.) Valsalva, 15:127-133. (529) Tay, W., 1881. Symmetrical changes in the region of the yellow spot in each eye of an infant. Tr. Ophth. Soc. U. Kingdom, 1:55-57. (174) , 1884. A third instance in the same family of symmetrical changes in the region of the yellow spot in each eye of an infant closely resembling those of embolism. Ibid., 4:158-159. (474) Terzian, H., and C. Terzuolo, 1951. Produzione d'ipertono estensorio in arti deafferentati mediante stimolazione a bassa cadenza del lobus anterior del cervelletto. Boll. Soc. ital. biol. sper., 27:11881189.(260) , 1954. Le component! automatiche e riflesse del tono posturale. Arch, fisiol., 54:37-61. (61,128, 147,157, 257, £74, 279, 880) Terzuolo, C., 1952. Excitation et inhibition du tetanos strychnique chez le chat curarise. Arch. internat. de physiol., 60:225-228. (119, 128, 156, 181, 262) , 1954. Influences supraspinales sur le tetanos strychnique de la moelle epiniere. Ibid., 62:179196. (119,128-130,156, 262) , and H. Terzian, 1951a. Sul meccanismo della rigidita da decerebrazione in arti anterior! cronicamente deafferentati. Boll. Soc. ital. biol. sper., 27:1317-1318. (61, 279, 280) , 1951b. Riflessi di Magnus e tono posturale in arti sottoposti a deafferentazione acuta o cronica. Ibid., pp. 1319-1320. (61, 257,279, 280) , 1953. Cerebellar increase of postural tonus after deafferentation and labyrinthectomy. J. Neurophysiol., 16:551-561. (155, 156, 157, 219, 244, 246, 248, 260-262) Tetjaeva, M. B., and Z. L. Jankovskaja, 1940. Cited by Simkina, 1948. (346) Thiebaut, F., 1948. Diagnostic entre tumeur parietale et tumeur de la fossa posterieure. Presse med., 56:394-395.(406) Thiele, F. H., 1905. On the efferent relationship of the optic thalamus and Deiter's nucleus to the spinal cord, with special reference to the cerebellar influx of Dr. Hughlings Jackson and the genesis of the decerebrate rigidity of Ord and Sherrington. J. Physiol., 32:358-384. (60, 114, 150, 230) Thiers, J., 1934. La syphilis du cervelet et des connexions cerebelleuses. Paris: 0. Doin et Fils. (497) Thompson, G. N., 1944. Cerebellar embolism. Bull. Los Angeles Neurol. Soc., 9:140-155. (515, 516) Thorpe, F. T., 1935. Familial degeneration in association with epilepsy; Report of two cases, one with pathological findings. Brain, 58:97-114. (446-447) Tiegs, O. W., 1953. Innervation of voluntary muscles. Physiol. Rev., 33:90-144. (308) Tilney, F., 1923. Genesis of cerebellar functions. Arch. Neurol. & Psychiat., 9:137-169. (11, 14) and F. H. Pike, 1925. Muscular coordination experimentally studied in its relation to the cerebellum. Arch. Neurol. & Psychiat., 13:289-334. (264) , 1926. Etude experimentale de la coordination musculaire dans son rapport avec le cervelet. Encephale, 21:305-351. (263, 264) Titeca, J., and L. van Bogaert, 1946. Heredo-degenerative hemiballismus: A contribution to the question of primary atrophy of the Corpus Luysii. Brain, 69:251-263. (459) Titrud, L. A., and W. Haymaker, 1947. Cerebral anoxia from high altitude asphyxiation: Clinicopathologic study of 2 fatal cases with unusually long survival and clinical report of non-fatal case. Arch. Neurol. & Psychiat., 57:397-416. (489-490) Tonning, H. O., R. F. Warren, and H. J. Barrie, 1952. Familial haemangiomata of the cerebellum: Report of three cases in a family of four. J. Neurosurg., 9:124-132. (554) Tooth, H. H., 1912-1913. Some observations on the growth and survival-period of intracranial tumours, based on the records of 500 cases, with special reference to the pathology of the gliomata. Brain, 35:61-108. (495) Torkildsen, A., 1937. Spontan blodning i cerebellum behandlet med operasjon. Zentralbl. f. Neurochir., 2:242-246; also Norskkmag. f. laegevidensk., 98:968-975. (520) Tower, S. S., 1936. Extrapyramidal action from the cat's cerebral cortex: Motor and inhibitory. Brain, 59:408-444. (329) , 1940. Pyramidal lesion in the monkey. Ibid., 63:36-90. (99, 335, 336) and M. Hines, 1935. Dissociation of the pyramidal and extrapyramidal functions of the frontal lobe. Science, 82:376. (330) Traube-Mengarini, M., 1884. Experimentelle Beitrage zur Physiologic des Fischgehirns. Arch. f. Anat. u. Physiol., Physiol. Abt., pp. 553-565. (10) Trelles, J. O., 1934. A propos d'un cas anatomo-clinique de Maladie de Friedreich avec troubles mentaux. Ann. med-psychol. (pt. 2), 92:760-786. (467, 468) Trendelenburg, W., 1907. Studien zur Operationstechnik am Zentralnervensystem. I. Das Myelotom, ein Apparat zur Ausfiihrung genau begrenzter Durchschneidungen. II. Medianspaltung des Kleinhirns am Kaninchen. Arch. f. Anat. u. Physiol., Physiol. Abt., pp. 83-103. (49)

630

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

, 1908. Die Folgen der Langsdurchschneidung des Kleinhirns am Hunde. Ibid., pp. 120-132. (49) , 1910. Vergleichende Physiologic des Riickenmarks. Ergebn. Physiol., 10:454-530. (14) Trevelyan, E. F., 1903. Some observations on tuberculosis of the nervous system. Lancet, 2:12761280.(495) Troell, A., and C. Hesser, 1922. Ueber das cerebellare Lokalisationsproblem: Experimentelle Untersuchung. Acta chir. Scandinav., 54:211-281. (53, 68, 69) Tschernyscheff, A., 1925. Zur Frage der pathologischen Anatomie und der Leitungsbahnen des Kleinhirns bei Hirnaffektionen. Arch. f. Psychiat., 75:301-354. (465, 466) •— and J. Grigorowsky, 1930a. Ueber die arterielle Versorgung des Kleinhirns: Anatomischmorphologisches Studium. Arch. f. Psychiat., 89:482-569. (512) , 1930b. Ueber die arterielle Versorgung des Kleinhirns; pathologisch-anatomisches Studium beim Menschen. Ibid., 92:8-85. (612) Tsiminakis, Y., 1933. Zur Lokalisation der Hemichorea. Arb. a. d. neurol. Inst. a. d. Wien. Univ., 35:57-75. (402) Tuge, H., 1934. Studies on cerebellar function in the teleost. I. Reactions resulting from cerebellar ablation. J. Comp. Neurol., 60:201-224. (11-12) Turnbull, F., 1944. Extradural cerebellar hematoma: Case report. J. Neurosurg., 1:321-324. (524) Turner, J. C., H. Jackson, and F. Parker, 1938. The etiologic relation of the eosinophil to the Gordon phenomenon of Hodgkin's disease. Am. J. M. Sc., 195:27-32. (488) Turner, R. S., and W. J. German, 1941. Functional anatomy of the brachium pontis. J. Neurophysiol., 4:196-206.(91-92, 401) Turner, T. E., 1856. De 1'atrophie partielle ou unilaterale du cervelet, de la moe'lle allongee et de la moe'lle epiniere, consecutive aux destructions avec atrophie d'un des hemispheres du cerveau. These de Paris, no. 4, v. 597. (464) Tutaev, G. V., E. V. Litkevic, N. A. Isacenko, and S. A. Makarova, 1937. Sborn. dokl. VI Vsesojusn. s'eda fisiol. biolhimik. i. farmakol. Cited by Simkina, 1948. (300) Tutaev, G. V., and S. A. Makarova, 1940. Probl. endokrinologh., 4:45. Cited by Simkina, 1948. (300, 301) Twining, E. W., 1939. Radiology of the third and fourth ventricles. Brit. J. Radiol., n. s., 12:385418, 569-598.(533) Tyler, D. B., and P. Bard, 1949. Motion sickness. Physiol. Rev., 29:311-369. (54) Tzkipuridse, L. R., 1947. Tr. VII Bsesjuzn. s'ezda fiziologov, Medgiz, 1947, 220. Cited by Irger et al., 1951. (159) and A. N. Bakuradse, 1948. Interrelations between slow potential oscillations of cerebral and cerebellar cortices. (In Russian.) Publications of the Institute of Physiology "I. Beritashvili" of the Academy of Sciences of Georgia, 7:201-214. Tbilisi. (159, 163) Uffenorde, W., 1912. Zur Bewertung der Augenmuskelreaktionen bei Labyrinthreizung und der Reaktionen bei elektrischen Kleinhirnreizungen nach experimentellen Untersuchungen am Affen. Munchen. med. Wchnschr., 59:1213-1216, 1277-1280. (104, 138) Ulett, G., R. S. Dow, and O. Larsell, 1944. The inception of conductivity in the corpus callosum and the cortico-ponto-cerebellar pathway of young rabbits with reference to myelinization. J. Comp. Neurol., 80:1-10. (367) Urechia, C. I., and N. Elekes, 1933. Syphilis cerebelleuse: Difficulte de diagnostic. Bull, et mem. Soc. med. d'hop. de Paris, 49:695-696. (498) Urechia, C. I., M. Kernbach, and N. Elekes, 1933. Hemorragie du cervelet chez un jeune syphilitique. Bull, et mem. Soc. med. d'hop. de Paris, 49:503-505. (497) Ushiyama, J., 1954. Action potentials led from the cerebellum by means of microelectrodes. (In Japanese.) J. Physiol. Soc. Japan., 16:303. (168) Uzman, L., 1948. Pneumoencephalography in the diagnosis of cerebellar atrophies: Report of 5 cases. Am. J. Roentgenol., 60:293-302. (443) Vance, B. M., 1927. Fractures of the skull. Complications and causes of death: A review of 512 necropsies and of 61 cases studied clinically. Arch. Surg., 14:1023-1092. (523) Verhaart, W. J. C., 1930. Pick's disease (Over de ziekte van Pick.) Nederl. tijdschr. v. geneesk., 74:5586-5598. (475) —, 1942. Partial agenesis of the cerebellum and medulla and total agenesis of the corpus callosum in a goat. J. Comp. Neurol., 77:49-60. (430, 432) , 1948. Cerebellar and cerebral cortical hypoplasia in a cat. Acta neerlandica morphologiae normalis et pathologiae, 6:169-174. (438) and G. A. van Wieringen-Rauws, 1950. On cerebro-cerebellar atrophy. Folia psychiat. neerl., 53:481-501. (465-466) Versilov, N. M., 1903. Z. neuropat. i. Psichiatr., 3:39-67. Cited by von Bechterew, 1909, vol. 2, pp. 852-853, and by Simkina, 1948. (303, 327)

BIBLIOGRAPHICAL INDEX OF AUTHORS

631

Villaverde, J. M. de, 1925. Les lesions cerebelleuses dans un cas d'idiotie. Trav. du lab. d. recherches biol. de 1'Univ. de Madrid, 23:101-134. (442) , 1931. Les lesions cerebelleuses dans 1'idiotie mongoloi'de et quelques considerations sur la pathologic du cervelet. Ibid., 27:111-149. (441-44®) , 1936. Les effets tardifs de 1'action des sels de plomb sur le cervelet. Arch, internat. de neurol., 55:3-10; also in Zentralbl. f. d. ges. Neurol. u. Psychiat., 81:247. (486) Vincent, C., 1911. De quelques causes d'erreur dans le diagnostic des syndromes d'hypertension intracranienne et dans celui de la localisation des tumeurs cerebrales. Rev. neurol., 21:209-217. (405) ———, 1928. Diagnostic des tumeurs comprimant le lobe frontal. Ibid., 1:801-884. (405) and F. Rappoport, 1931. Deux cas d'hemangioblastome du cervelet dont 1'un familial. Sur la valeur de 1'attitude de la tele pour le diagnostic des tumeurs de la fossa posterieure. Rev. neurol., 1:32-44. (654) Vincenzoni, G., 1908. Ricerche sperimentali sulle localizzazioni funzionali nel cervelletto della pecora. Arch, farmacol. sper., 7:119-161. (70) Virchow, R., 1864. Die krankhaften Geschwiilste. Berlin: A. Hirschwald. (549) , 1877. Beitrage zur physischen Anthropologie der Deutschen, mit besonderer Beriicksichtigung der Friesen. Berlin: F. Dummler. (418) Vogt, H., and M. Astwazaturow, 1912. Ueber angeborene Kleinhirnerkrankungen mit Beitragen zur Entwickelungsgeschichte des Kleinhirns. Arch. f. Psychiat., 49:75-203. (417, 436, 438, 450) Volland, 1911. Bericht iiber vier Falle mit der Kombination Epilepsie-Paramyoclonus multiplex. Ztschr. f. d. ges. Neurol. u. Psychiat., 7:180-206. (412) Voronin, L. G., 1938. New data on the motor activity of the intestine and its mechanisms of regulation. (In Russian, with English summary.) Izv. naucn. Inst. Lesgafta, 21:3-74. Abstracted in Ber. ges. Physiol., 114:242-243 (1939). (305) and A. M. Simkina, 1935. L'influence de 1'excitation faradique du cervelet sur la fonction motrice des intestins. Proc. XV Internat. Congress Physiol., Moscow, p. 107. (305) , 1938. Action of electrical stimulation of the cerebellum on the motor functions of the intestines. (In Russian, with English text.) Izv. naucn. Inst. Lesgafta, 21:75-86. Abstracted in Ber. ges. Physiol., 112:278 (1939). (305) Vulpian, A., 1866. Lecons sur la physiologic generate et comparee du systeme nerveux faites au museum d'histoire naturelle. Paris: Bailliere. (10, IS, 23) , 1875. Lecons sur 1'appareil vasomoteur. 2 vols. Paris: Bailliere. Vvedenskaja, I. V., and D. I. Khanutina, 1941. Sovet. psikh., 6:485. Cited by Simkina, 1948. (295) Wada, M., M. Seo, and K. Abe, 1935. Effect of the injury of the lobulus posterior medianus (Ingvar) of the cerebellum upon the blood pressure, the blood sugar content and the epinephrin secretion in non-anesthetized, non-fastened dogs. Tohoku J. Exper. Med., 27:218-244. (891, 299, 301, 303) Wagenen, W. P. van, 1927. Tuberculoma of the brain: Its incidence among intracranial tumors and its surgical aspects. Arch. Neurol. & Psychiat., 17:57-92. (495, 496) Waggoner, R. W., K. Lowenberg, and K. G. Speicher, 1938. Hereditary cerebellar ataxia: Report of a case and genetic study. Arch. Neurol. & Psychiat., 39:571-586. (467, 469) "Wagner, R., 1858-1860. Kritische und experimentelle Untersuchungen iiber die Hirnfunktionen des Gehirns. Nachrichten von der Georgia Augusta Universitat und der koniglichen Gesellschaft der Wissenschaften zu Gottingen. In Gb'ttingische gelehrte Anzeigen. Erste Reihe: Die Methoden, 2:249-264 (1858). Zweite Reihe: Ergebnisse der Experimente am kleinen Him, 2:297-311 (1858). Dritte Reihe: Vergleichung der pathologischen Erfahrungen bei Affektionen des kleinen Gehirns am Menschen mit den Ergebnissen der Experimente an Thieren, 2:321-336 (1858). Vierte Reihe: Fortsetzung der Untersuchungen iiber das kleine Gehirn mit besonderer Riicksicht auf die Funktionen der Schenkel des kleinen Gehims und der Elementar-Organisation der grauen Rinde, 3:67-82 (1859). Fiinfte Reihe: Vorlaufige Schlussbetrachtungen liber Bau und Funktion des kleinen Gehirns, 4:25-40 (1860). (305) , 1861. Recherches critiques et experimentales sur les fonctions du cerveau. J. de la physiol. de 1'homme, 4:242-266, 384-413, 546-564. (French translation of a paper published in Nachrichten von der Universitat und der koniglichen Gesellschaft der Wissenschaften zu Gottingen, 18581860, with footnotes by Brown-Sequard.) (6, 14, 290, 305, 308) Walberg, F., 1954. Descending connections to the inferior olive. In J. Jansen and A. Brodal, Aspects of Cerebellar Anatomy, pp. 249-263. Oslo: Johan Grundt Tanum Vorlag. (211, 246, 247) , 1957. Corticofugal fibers to the nuclei of the dorsal columns: An experimental study in the cat. Brain, 80:273-287. (348) Walker, A. E., 1938. An oscillographic study of the cerebro-cerebellar relationships. J. Neurophysiol., 1:16-23. (322, 323,327, 330, 342)

632

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

, 1941. Astrocytosis arachnoidae cerebelli: Rare manifestation of von Recklinghausen's neurofibromatosis. Arch. Neurol. & Psychiat., 45:520-532. (541) , 1944. Case of congenital atresia of the foramina of Luschka and Magendie: Surgical care. J. Neuropath. & Exper. Neurol., 3:368-373. (432) , 1949. Afferent connections. In P. C. Bucy, The Precentral Motor Cortex, chap. 4, p. 111. Urbana: Univ. of Illinois Press. (333) and E. H. Botterell, 1937. The syndrome of the superior cerebellar peduncle in the monkey. Brain, 60:329-353. (VS, 63, 93-94) Walker, A. E., and T. L. Hopple, 1949. Brain tumors in children: General considerations. J. Pediat., 35:671-687. (533) Wallenberg, A., 1895. Acute Bulbaraffection. Arch. f. Psychiat., 27:504-540. (511, 51%) Walsh, M. N., J. D. Camp, and W. McK. Craig, 1941. Basilar invagination of skull (so called platybasia). Proc. Staff Meet., Mayo Clin., 16:449-452. (418) Walshe, F. M. R., 1921. On disorders of movement resulting from loss of postural tone, with special reference to cerebellar ataxy. Brain, 44:539-556. (379) , 1922. Decerebrate rigidity in animals and its recognition in man. Proc. Roy. Soc. Med., 15:41-52.(410) , 1923a. A case of complete decerebrate rigidity in man, with observations on various reflex reactions. Lancet, 2:644-647. (410) , 1923b. Acusticus tumours. J. Laryng. & Otol., 38:419-426. (562) , 1927. Discussion on "The significance of the voluntary element in the genesis of cerebellar ataxy." Brain, 50:377-385. (101) Walter, W. G., 1938. Critical review: The technique and application of electroencephalography. J. Neurol. & Psychiat., 1:359-385. (535) Wang, G. H., and V. W. Borison, 1956. Suprasegmental inhibition of an automatic reflex. J. Neurophysiol., 19:564-572. (309) Wang, S. C., and H. I. Chinn, 1952. Emetic trigger zone and motion sickness in dogs. Federation Proc., 11:400. (54) , 1953. Vestibular reflex pathway in experimental motion sickness in dogs. Proc. XIX Internat. Congress Physiol., Montreal, pp. 868-869. (54) , 1956. Experimental motion sickness in dogs: Importance of labyrinth and vestibular cerebellum. Am. J. Physiol., 185:614-623. (54) Warner, W. P., and J. M. D. Olmsted, 1923. The influence of the cerebrum and cerebellum on extensor rigidity. Brain, 46:189-199. (330, 335) Warrington, W. B., and K. Monsarrat, 1902. A case of arrested development of the cerebellum and its peduncles with spina bifida and other developmental peculiarities in the cord. Brain, 25:444478.(417) Wartenberg, R., 1951. Pendulousness of the legs as a diagnostic test. Neurology, 1:18-24. (388) Weber, F. P., and J. G. Greenfield, 1942. Cerebello-olivary degeneration: An example of heredofamilial incidence. Brain, 65:220-231. (447, 449, 452) Webster, J. E., and L. M. Weinberger, 1940. Convulsions associated with tumors of the cerebellum: Clinical and patho-physiologic features. Arch. Neurol. & Psychiat., 43:1163-1184. (410) Weed, L. H, 1914. Observations upon decerebrate rigidity. J. Physiol., 48:205-227. (26, 60, 114, 330) Wegelin, C., 1935. Ueber Meningoencephalitis bei Mumps. Schweiz. med. Wchnschr., 65:249-252. (484) Weil, A., 1933. Megalencephaly with diffuse glioblastomatosis of brain stem and cerebellum. Arch. Neurol. & Psychiat., 30:795-809. (441) , E. Liebert, and G. Heilbrunn, 1938. Histopathologic changes in the brain in experimental hyperinsulinism. Arch. Neurol. & Psychiat., 39:467-481. (490) Weinberger, L. M., and J. E. Webster, 1941. Visual field defects associated with cerebellar tumor. Arch. Ophth., 25:128-138. (531) Weinstein, E. A., and M. B. Bender, 1943. Integrated facial patterns elicited by stimulations of the brain stem. Arch. Neurol. & Psychiat., 50:34-42. (415) Weisenburg, T. H., 1910. Tumours of the third ventricle with the establishment of a symptom complex. Brain, 33:236-260. (403) , 1912. Nervous symptoms following sunstroke. J.A.M.A., 58:2015-2017. (490) , 1927. Cerebellar localization and its symptomatology. Brain, 50:357-377. (379, 396) Welte, E., 1939. Die Atrophie des Systems des Briickenfusses und der unteren Oliven. Arch. f. Psychiat., 109:649-698. (467, 469) Werden, D. H., 1951. Spontaneous intracerebral and cerebellar hematoma: Report of 6 cases with operative treatment. Bull. Los Angeles Neurol. Soc., 16:174-184. (520)

BIBLIOGRAPHICAL INDEX OF AUTHORS

633

Wernicke, C., and E. Hahn, 1882. Idiopathischer Abscess des Occipitallappens durch Trepanation entleert. Virchows Arch. f. path. Anat., 87:335-344. (496) Wersiloff, N. M., 1899. Ueber die Funktionen des Kleinhirns. Neurol. Centralbl., 18:328-330. (103, 109,138) Wertham, F. I., 1929. A new sign of cerebellar disease. J. Nerv. & Ment. Dis., 69:486-493. (393) and R. S. Lyman, 1926. Disturbance of voluntary rhythmic movements in cerebellar disease: The Cerebellum. A. Research Nerv. & Ment. Dis., Proc., 6:520-529. (394) Wertheimer, J., J. Dechaume, Croizat, and Romand-Monnier, 1935. Oligodendrogliome cystique du cervelet. Lyon med., 155:681-686. (551) Wessels, R. R., 1942. Cerebellar apoplexy. Harper Hosp. Bull., 1:125-128. (517) Westphal, A., 1917. Beitrag zur Lehre von der amaurotischen Idiotie. Arch. f. Psychiat., 58:248-283. (m)

and F. Sioli, 1920. Weitere Mitteilung iiber den durch eigenartige Einschliisse in den Ganglienzellen (Corpora Amylacea) ausgezeichneten Fall von Myoklonus Epilepsie. Arch. f. Psychiat., 62:1-36. (±18) Wharton, H. R., 1901. Wounds of the venous sinuses of the brain: An analysis of seventy cases, Ann. Surg., 34:81-108. (523) Whiteside, J. A., and R. S. Snider, 1953. Relation of cerebellum to upper brain stem. J. Neurophysiol., 16:397-413.($32-234) Whitlock, D. G., 1952. A neurohistological and neurophysiological study of afferent fiber tracts and receptive areas of the avian cerebellum. J. Comp. Neurol., 97:567-623. (160, 161) , A. Arduini, and G. Moruzzi, 1953. Microelectrode analysis of pyramidal system during transition from sleep to wakefulness. J. Neurophysiol., 16:414-429. (222) Widen, L., 1955. Cerebellar representation of high threshold afferents in the splanchnic nerve, with observations on the cerebellar projection of high threshold somatic afferent fibers. Acta physiol. Scandinav. 33, suppl. 117:1-69. (309-310) Wiebel, H., 1937. Ueber louping ill beim Menschen. Klin. Wchnschr., 16:632-634. (483) Wiggers, K., 1942a. On the slow waves in the electrocerebellogram. Acta brev. neerl., 12:44-45. (163) , 1942b. De invloed van het cerebellum op de vegetatieve functies. Kampen: J. H. Kok N. V. (291, 295, 299, 301) , 1943a. The influence of the cerebellum on the vegetative functions. I. A review. Arch, neerl. de physiol., 27:286-300. (396) , 1943b. The influence of the cerebellum on the heart and the circulation of the blood. II. Ibid., pp. 301-303. (291, 295, 299, 396) , 1943c. The influence of the cerebellum on the sugar content of the blood. III. Ibid., pp. 304-331. (301,302,396) Wigglesworth, V. B., 1945. A case of DDT poisoning in man. Brit. M. J., 1:517. (487) Wikler, A., 1944. Studies on the action of morphine on the central nervous system of the cat. J. Pharmacol., 80:176-187. (260) , 1950. Sites and mechanisms of action of morphine and related drugs in the central nervous system. Pharmacol. Rev., 2:435-506. (260) Wilkins, H., 1940. Cerebellar abscess: Review of cases. South. M. J., 33:605-613. (499, 506, 507) Willis, T., 1664. Cerebri anatome; cui accessit nervorum descriptio et usus. Amsterdam: Schagen. (3, 396) Wilson, G., and N. W. Winkelman, 1927. Occlusion of the posterior inferior cerebellar artery. J. Nerv. & Ment. Dis., 65:125-130. (512) Wilson, J. G., and F. H. Pike, 1913. The effect of stimulation and extirpation of the labyrinth of the ear and their relation to the motor system. Philos. Tr. Roy. Soc., s. B, 203:127-160. (273) , 1914. A comparison of the effects of labyrinthine and cerebellar lesions in the turtle. Proc. Soc. Exper. Biol. & Med., 11:129-130. (878) Wilson, S. A. K., 1920. On decerebrate rigidity in man and the occurrence of tonic fits. Brain. 43:220-268. (383, 410) Wilson, W. C., and H. W. Magoun, 1945. The functional significance of the inferior olive in the cat. J. Comp. Neurol., 83:69-77. (416) Winkelman, N. W., and J. L. Eckel, 1936. Midline cerebellar tumors ("medulloblastoma"): A clinico pathologic report of cases showing diffuse dissemination throughout the central nervous system. Surg., Gynec. & Obst., 63:372-381. (545) Winkler, C., 1923. A case of olivo-pontine cerebellar atrophy and our conceptions of neo- and paleocerebellum. Schweiz. Arch. Neurol., 13:684-702. (461) Winkler, C., and A. Potter, 1914. An anatomical guide to experimental researches on the cat's brain. In C. Winkler, Opera omnia, suppl. II. Amsterdam: W. Versluys. (333)

634

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

Winther, K., 1927. Un cas d'occlusion (par embolie) de 1'artere cerebelleuse posterieure inferieure verifie a 1'autopsie, avec des douleurs et de 1'hyperalgesie au froid. Acta psychiat. et neurol., 2:399-416.(512) Wohlfart, G., and 0. Hook, 1951. Clinical analysis of myoclonus epilepsy (Unverricht-Lundborg), myoclonic cerebellar dyssynergy (Hunt) and hepatolenticular degeneration (Wilson). Acta psychiat. et neurol. Scandinav., 26:219-245. (402) Woskressenski, S., 1911. Ein Fall von eigenartiger Missbildung des Kleinhirns nebst anderen Anomalien neben einer chronischen Erkrankung des Zentralnervensystems. Ztschr. f. d. ges. Neurol. u. Psychiat., 6:38-59. (430) Wycis, H. T., 1948. Oligodendroglioma of cerebellum. Arch. Neurol. & Psychiat., 59:404-407. (551) Wyke, B. D., 1947. Clinical physiology of the cerebellum. M. J. Australia, 2:533-540. (378, 381) Yoshii, N., and K. Ito, 1954. Studies on the areas of response in the cerebellum. Folia psychiat. neurol., Japan., 8:158-159. (214) Zacks, M., 1939. Importance of vestibular findings following injury to the head. Arch. Otolaryng., 30:601-604.(522) Zanchetti, A., and J. M. Brookhart, 1955. Measurement of electrical responsiveness of cortico-spinal efferents in cat and monkey. J. Neurophysiol., 18:288-298. (311) Zanchetti, A., and A. Zoccolini, 1954. Autonomic hypothalamic outbursts elicited by cerebellar stimulation. J. Neurophysiol., 17:475-483. (243, 296-298, 299, 304) Zannoni, A., 1933. Morte improvvisa da emorragia cerebellare spontanea in giovani. Arch, di antropol. crim., 53:1721-1734. (517) Zentay, P. J., 1937. Motor disorders of the central nervous system and their significance for speech. Part I. Cerebral and cerebellar dysarthrias. Laryngoscope, 47:147-156. (394) Zimmerman, H. M., 1938. The histopathology of convulsive disorders in children. J. Pediat., 13:859890. (490) , 1946. The pathology of Japanese B encephalitis. Am. J. Path., 22:965-991. (483) and K. H. Finley, 19S2. Congenital hypoplasia of the olivo-ponto-cerebellar tracts. Arch. Neurol. & Psychiat., 27:1402-1420. (438) Ziilch, K. J., 1936. Ueber die primare Kleinhirnrindenatrophie. Ztschr. f. d. ges. Neurol. u. Psychiat., 156:493-573. (456) , 1948. Ueber die anatomische Stellung der Kleinhirnrindenatrophie und ihre Beziehung zur Nonne-Marieschen Krankheit. Deutsche Ztschr. f. Nervenh., 159:501-513. (485)

Subject Index

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Subject Index

Ablation, cerebellar in cats, effect of, compared to deficiency syndrome in cerebellar hypoplasia, 438 total, in subprimates, not to be compared with cerebellar gunshot wounds in man, 386388 Ablation experiments and cerebellar injuries in man, 378, 396 discrepancies with stimulation and electrophysiological experiments, 371 practical clinical value of, 7 Abscess, cerebellar; see Cerebellar abscess Absinth convulsions, effect on of ablation of crus I or crus II, 329 of hemicerebellectomy, 329 Acoustic neurinoma, 399-400, 561-562 enlargement of internal auditory meatus in, 532 and intracerebellar tumors, differential features, 399-400 most frequent neoplasm in posterior fossa, 542, 553 simulated clinically by tuberculoma, 496 Acoustic nerve tumors, rotated head posture in, 382 Actinomycosis, and cerebellar abscess, 507 importance of distinguishing two organisms causing, 507 Acute inflammatory and toxic disorders, 451, 480493; see also Malaria, Whooping cough, etc.; Alcohol, Lead, etc.; Anoxia Adiadochokinesis, 392-394 cerebellar division responsible, 380 described, 392 in extracerebellar lesions, 400 in myoclonic epilepsy, 411 relative frequency as symptom, 379 tests for, 392-393 Adrenaline discharges hyperglycemia elicited by, after mechanical stimulation of cerebellum, 301 during vasomotor reflexes, inhibited by cerebellar stimulations, 293 Agenesis, cerebellar, 424-436; see also Vermis, cerebellar

attempts at classification, anatomical, 417 complete (aplasia) case reports and histopathological studies, 424429 rarity of, 424, 444 imbecility as frequent accompaniment, 424, 426 partial, 429-436 agenesis of vermis, 429-434 loss of one hemisphere, 434-436 unaccompanied by cerebellar signs, 417, 426, 434, 435 and secondary atrophy, difficulty of distinguishing, 416, 443 Agyria, 441 Alcohol cerebellar damage from, 485-486 in potentiation of carbon tetrachloride poisoning, 488 Allogyria, 441 Alpha discharge alteration in spatial and temporal patterns of, after cerebellectomy, 262-265 coordination of, cerebellar influence on, 262-265 Alpha efferent fibers, innervation of extrafusal muscle fibers by, 255 Alpha-gamma linkage, effect on of acute topectomy of anterior lobe, 259 of anemic inactivation of anterior lobe, 259 of cooling of anterior lobe, 257, 258 Alpha motoneurons phasic, little affected by posttetanic potentiation, 262 still under cerebellar influence after abolition of gamma loop, 260 tonic striking release of, after anterior lobe topectomy, 262 strongly affected by posttetanic potentiation, 262 Alpha rigidity defined, 259 relation to decerebellate rigidity, 259-260 discrepancies between experiments on release of, 281-282

637

638

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

effect on, of: contralateral section of eighth nerve, 279, 283 ipsilateral section of eighth nerve, 279 unilateral fastigial lesion, 283 following decerebration and cerebellectomy, relation to tonic labyrinthine impulses, 274275 functional significance of experiments on release of, 274, 281, 283-287 in deafferented forelimbs elicited by low-rate stimulation of vermian part of anterior lobe in decerebrate cat, 260-262 inhibited by high-rate stimulation of vermian part of anterior lobe in decerebrate cat. 262 in deafferented limbs following anemic decerebration, 273-274 reduced but still present after bilateral section of eighth nerve in decerebrate cat, 277 relation to extralabyrinthine mechanisms, 277 release of, in deafferented forelimbs of decerebrate preparation absent: after postcollicular transection, 280 after chronic cerebellectomy, 281, 282 after postbrachial transection of spinal cord, 262, 273, 274; see also Schiff-Sherrington inhibition after total cerebellectomy or anterior lobe ablation, 259, 274 present after chronic cerebellectomy followed by postbrachial transection of spinal cord, 281, 282 tonic inhibition of, in deafferented forelimbs of decerebrate preparation cerebellar mechanism of, 259, 274 Schiff-Sherrington mechanism of, 274, 282 unaffected by chloropromazine, 260 Alzheimer's disease, and cerebellar atrophy, 475—476 Amaurotic familial idiocy cerebellar degeneration in, 474—475 primary cerebellar cortical atrophy wrongly diagnosed as, 450 Amebiasis, cerebellar involvement in, 508 Amphibia cerebellar stimulation in, 105 cerebellectomy in, 12-13 conditioned reflexes after cerebellectomy, 344 electrophysiological recording from cerebellum in, 160 Ampullary receptors; see Labyrinthine reflexes Amyotrophy, in Friedreich's ataxia, 469 Anesthetic agents, sensitivity of cerebellum to, 485 nitrous oxide, cases of cerebellar damage from use of, 489 Angiomatosis of retina (von Hippel's disease), 554 Angiomatous malformations, 552-553 as defect of development, 552 vertebral arteriography in diagnosis of, 553 Angioneurotic edema, cerebellar involvement in, 485 Anisothenia, as cerebellar symptom, 395-396, 522 Anoxia, 489-490

effects of, on Purkinje cells, 458 in malaria, 482 experimental, 489 as explanation of predilection of cortical cerebellar atrophy for the anterior lobe, 454, 489 role in pathogenesis of convulsive states, 490 severe case of, described, 489-490 susceptibility of cerebellar cortex to, 489, 493 Anterior lobe, experiments on (see also Culmen, Lingula, Lobulus centralis) ablation of combined with ablation: of areas 4 and 6 in primates, 59 of pericruciate areas in cat, 57, 58 in birds, 15-17 in decerebrate cat, 60, 61, 260 in mammals, 56-63 in primates, 58-60, 259 in subprimates, 56-58 in thalamic cat, 60 in thalamic pigeon, 15, 17, 18-21 on vasomotor reflexes, 299 ablation of intermediate part of, in otherwise intact cat, 62, 343 ablation of vermian part of in decerebrate cat, 80 in otherwise intact cat, 62, 78, 343 chemical stimulation of, in mammals, 110-113 chemical stimulation of vermian part of, effect on electrocorticogram, 325-327 cooling of, in decerebrate cat, 60, 62, 258, 259, 274 decortication of, with and without involvement of deep nuclei, in thalamic pigeon, 18-21 electrical stimulation of, effect in decerebrate cat, 113-125, 126-137 in decerebrate monkey, 113 in intact anesthetized cat, 126, 311-321 in intact anesthetized monkey, 126, 321, 322 in intact conscious cat, 140—141; see also Cerebellar seizure in mammals, 113-137 in thalamic cat, 125, 126, 295, 296, 297, 299 in thalamic pigeon, 106-109 on cortically induced movements, 311-316 on galvanic skin reflexes, 309 electrical stimulation of intermediate part of effect on decerebrate rigidity, 124-126, 135-137 postural effects elicited from lateral strip, 137 postural effects elicited from medial strip, 137 electrical stimulation of vermian part of, effect on chloralose clonic movements, 312-316 on cortical strychnine clonus, 312-314, 316-317 on decerebrate rigidity, 113-124, 126-135 on Deitersian spike discharge, 230-232 on extensor rigidity in newborn decerebrate kitten, 366-367 on extrapyramidal movements, 318-320 on Mayer's waves, 293 on postsynaptic activation of second sensory neurons, 347-348 on reflexly evoked adrenaline discharge, 293

SUBJECT INDEX on on on on effect

respiratory carotid sinus reflexes, 294, 299 reticular spike discharge, 219-229 vasomotor carotid sinus reflexes, 294 vasomotor reflexes, 293 on extensor rigidity of electrical stimulation of vermian part of abolished: by destruction of fastigial nuclei, 148 by ipsilateral section of inferior cerebellar peduncle, 134 present after postcollicular decerebration, 134, 149 evoked potentials from elicited: by natural proprioceptive stimulations, 184, 185 by natural tactile stimulations, 185, 186 following: single-shock nerve stimulation, 189195 single-shock pontine stimulation, 202 single-shock stimulation of cerebral cortex, 205-210 single-shock stimulation of spinocerebellar tract, 200-201 in mammals, 182-211 high-rate stimulation of vermian part of inhibition of alpha rigidity in ipsilateral deafferented forelimb elicited by, 260-262 ipsilateral increase of extensor rigidity elicited by, after lesion of rostrolateral part of underlying fastigial nucleus, 131-134 ipsilateral inhibition of extensor rigidity elicited by, 126, 127 inactivation of, during anemic decerebration, 27, 28, 60, 259, 274, 276, 283 low-rate stimulation of vermian part of alpha rigidity in deafferented limbs elicited by, 260-262 facilitation of spinal strychnine waves during, 128-130 ipsilateral increase of extensor rigidity during, 126-128 overlapping of corticocerebellar and of spinocerebellar projection areas in, 206 partial ablation of in primates, 63 in subprimates, 61—63 single-shock stimulation of evoked potentials following: from cerebral cortex, 234-235 from paramedian lobule and pyramis, 235 slow potential changes elicited by afferent volleys on, 216 spontaneous electrical activity of, relation to extensor rigidity in decerebrate cat, 164, 176, 177 Anterior lobe of cerebellar cortex chronic progressive degeneration of, 452-454 role of anoxia in, 489 Anterior lobe of corpus cerebelli differences in function, between subprimates, primates, and man, 385 disturbances resulting from involvement of, 378, 385-386

639

fewness of clinical cases of lesions restricted to, 385 and medulloblastomas, 381 Antibiotics, in control of otogenic brain abscess, 504 Antigravity tonus, and tonic muscular activities not concerned with reflex standing, 75, 96 Anulospinal endings, in muscle spindles, 268 Apathy, symptom, in tumors of posterior fossa, 532 Aplasia (see also Agenesis, cerebellar) complete, 424-429 partial, 429-436 Apomorphine, abolition of gamma and alpha rigidities by, 260 Applicability of physiological data to clinic, 397, 398; see also Correlations between clinical and laboratory data Archicerebellar Syndrome, 378, 381-385; see also Flocculonodular lobe of corpus cerebelli Area gygantopyramidalis, decompensation of fastigial atonia in cat after bilateral ablation of, 332; see also Compensation, Motor cortex Area 4 cerebellar tremor not abolished in primates by isolated ablation of, 335 projections of, to vermal and paravermal lobules in primates, 205 somatotopic arrangement of cortico-cerebellar projections from, 206, 207 Area 6 and cortical compensation of cerebellar deficiency in primates, 334-335; see also Tremor cerebellar tremor enhanced by isolated ablation of, 335 projections of, to lobulus ansiformis in primates. 205 Areas 4 and 6, cerebellar tremor abolished in primates by combined ablation of, 334 Arnold-Chiari malformation, 418, 420-424 cases of, described, 421, 422 defects in, classified, 423 as form of developmental arrest, 424 mechanism of, 423-424 operative treatment, 421, 422 results, 423 pathology of, case report, 423 Arnold's malformation, 421 Arrhythmokinesis, 393 distinguished from adiadochokinesis, 394 Arteries, cerebellar anterior superior role of, in nutrition of cerebellum, 515 as usual site of cerebellar hemorrhage, 517 occlusion of, 510—517 anterior inferior, rare case of, 514 anterior superior, 401—402, 514-517 frequency, 514 histological changes in, 515 susceptibility to embolism, 515, 520 symptoms, 401, 515—516 treatment, 517 posterior inferior, 400-401, 511-514

640

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

deficiency syndrome, less enduring character of, 513 extent of lesion, difficulty of determining, 511,512 etiology, 512 treatment, 514 Arteriography in differential diagnosis of cerebral and cerebellar lesions, 404 vertebral, in diagnosis of angiomatous malformations, 553 cerebellar tumors, 398, 536, 555, 562 vascular lesions of posterior fossa, 536 Ascending reticular system, relation to cerebellum, 323-326, 348-350; see also Sleep Asphyxia, effect of on cerebellar waves, 162-163; see also Ischemia on nerve cells, 489 Associated movements, loss of, in cerebellar disease, 395 Astasia (see also Tremor) after section of superior cerebellar peduncle, 9394 after total cerebellectomy: in carnivores, 25 in primates, 36 after unilateral cerebellectomy: in carnivores, 40 in primates, 47-48 in clinical patients, 357-358 Luciani's, identified by Holmes with irregularities of force of contraction, 390 Luciani's definition of, 40 Asthenia, in experimental animals after section of superior cerebellar peduncles, 93-94 after total cerebellectomy: in carnivores, 25 in primates, 36 after unilateral cerebellectomy: in carnivores, 40 in primates, 47 decreased strength of voluntary movements in Luciani's, 40, 354 Luciani's definition of, 40 Asthenia, as symptom of cerebellar deficit in man, 354 described, 390 dynamometric demonstration of, 391 as explanation of apparent loss of proprioception, 395 in lesions of superior cerebellar peduncle, 401 due to occlusion of anterior superior cerebellar artery, 516 due to destruction by medulloblastoma, 531 Asymmetrical cerebellar lesions, effects of long-lasting: on spinal cord, 270-271 on striated muscles, 268-270 on phasic reflexes, 75 on postural tonus, 73—77 Astroblastoma and astrocytoma and glioblastoma multiforme, difficulty of distinguishing, 549 cellular characteristics, 548 Astrocytoma, cerebellar, 536-541 appearance, gross, 538

cellular characteristics, 539-541 microscopic appearance, 540 and cerebral astrocytoma, questioned as distinct entities, 539, 562 classification, 528, 536 by numeral grades of malignancy, 539 difficulty of distinguishing clinically from medulloblastoma, 537, 543, 548 difficulty of distinguishing pathologically from astroblastoma, 549 identified with spongioblastoma polare, 539, 552 incidence, 537, 542, 553 location, usual, 530, 537 neurological symptoms, syndromes of both the flocculonodular and posterior lobes, 537 not a developmental defect, 539 roentgen therapy in, of no value, 541 surgical removal of, good prognosis for, 541 Asynergia cerebellar, 390 in cerebral tumors of the frontal lobe, 405 Ataxia, cerebellar (see also Cerebellar deficiency, Symptomatology of cerebellar disorders) after experimental section of superior cerebellar peduncle, 94 in cases of Arnold-Chiari malformation, 421, 422 familial cortical cerebellar atrophy, 446, 447, 449 generalized cortical cerebellar atrophies, 454, 455 heat stroke, 491 late cortical cerebellar atrophy, 452 medulloblastoma, 531 myoclonic epilepsy, 411 trichloroethylene intoxication, 487 vitamin deficiency, 490-491, 493 defined, 23 delayed appearance of, after malaria, 481 in duck, 482 in extracerebellar lesions, 400, 404 frequency in tumors of frontal lobe, 405 homolateral, in occlusion of posterior inferior cerebellar artery, 513 of isolated movements of extremities relative frequency as symptom, 379 cerebellar division responsible, 380, 398 Ataxia, Friedreich's; see Friedreich's ataxia Ataxia, frontal and cerebellar ataxia, importance of distinguishing, 404 frequency, 405 mechanism responsible, 405-406, 407 Ataxia, hereditary spinal; see Spinal ataxia, hereditary Ataxia, spastic (Marie's cerebellar ataxia); see Spastic ataxia "Ataxia of childhood," need of more pathological studies of, 450 Ataxic gait, after section of spinocerebellar tracts, 89 Atherosclerosis, role in cerebellar hemorrhage, 517

SUBJECT INDEX Athelosis, atrophy of cerebellar nuclei in pathology of, 463 Atonia (see also Antigravity tonus, Hypotonia) after section of superior cerebellar peduncle, 9394 after total cerebellectomy: in carnivores, 25 in primates, 36 after unilateral cerebellectomy: in carnivores, 3940 in primates, 47, 48 relation to crossed reflex inhibition arising from opposite side of body, 44, 45, 352 after unilateral lesions of avian cerebellum involving deep nuclei, 16-21 constantly absent after bilateral lesions of avian cerebellum, 17 Luciani's decrease of supporting tonus in, main symptom, 97 denned, 97 different mechanisms underlying, in primates and subprimates, 99, 100 existence of: denied in carnivores, 27, 31, 43, 45 experiments supporting, 32, 33, 44, 45, 46 functional significance of, 352-353 reasons for controversy concerning, 43-46, 97101 Atrophic changes of the cerebellum, 445-479; see also Cerebellar nuclei; Cortical cerebellar atrophy; Crossed cerebellar atrophy; Degenerative diseases, specific; Olivopontocerebellar atrophy; Spinal ataxia, hereditary classification, difficulties in, 446, 459 nuclear atrophies, as unnecessary category, 463 crossed cerebellar hypoplasia, 464 etiology, ignorance of, 446, 454, 462 treatment, hopeless outlook for, 462 Atrophie olivo-rubro-cerebelleuse, 463 Atrophy, olivopontocerebellar; see Olivopontocerebellar atrophy Atrophy of cerebellar nuclei; see Cerebellar nuclei Auditory cortical areas evoked potentials from folium and tuber vermis after single-shock stimulation of, 208, 209 evoked potentials on, after single-shock stimulation of folium and tuber vermis, 235 Auditory projections onto cerebellar cortex, functional significance of, 245—246 in birds, 160 in mammals, 186 Auditory stimuli, behavioral responses to after ablation of tuber and folium vermis, 345 after complete chronic cerebellectomy, 345 Autonomic functions, Willis's hypothesis on cerebellar regulation of, 1 Autonomic nervous system, and cerebellum, 290299, 300-307, 309 Autonomic ocular phenomena, effect of cerebellar stimulations on, 304 Autonomic reflexes, effect on of cerebellar ablation, 299

641

of cerebellar stimulations, 293-297, 306-307, 309 Background rigidity, influence of, on patterns and sign of postural response to cerebellar stimulation, 119-124 Barbiturate anesthesia cerebellar and bulboreticular inhibition during, 151 evoked potentials from cerebral cortex after single-shock stimulation of cerebellar cortex and nuclei during, 234 modulation of reticular single discharge by cerebellifugal volleys during, 229 Barking after ablation of lobulus centralis in dog, 61 in cerebellectomized dog, 26 Basal ganglia, damage to, from hyperthermia, 491 Basal ganglia, degenerative diseases of calcification, 477, 478 links with cerebellar atrophy, 476 familial cortical cerebellar, 449 olivopontocerebellar, 459 rigidity and non-intention tremor as clinical symptoms, 453, 476 Basilar impression of the occipital bone (platybasia), 418-420 associated with Arnold-Chiari malformation, 423 clinicopathological studies, listed, 418-419 distinguished by some from platybasia, 419 symptoms and signs, 419 treatment, 419, 443 Basket cells, possible influence of, on Purkinje firing, 171 Bat, flying ability after cerebellectomy, 30 Bechterew's phenomenon, after cerebellectomy, 289; see also Nystagmus Beriihrungsreflex; see Munk's Beriihrungsreflex Bilateral hypoplasia; see Hypoplasia Birds bilateral cerebellectomy in, 13—14 electrophysiological recording from cerebellar cortex in, 160-162 intracellular recording from cerebellar cortex in, 160-162 localized cerebellar ablations in, 15-21 stimulation of cerebellum in chemical, 105-106 electrical, 105-109 unilateral cerebellectomy in, 14-15 Bladder function disturbances of, in clinical cases of cerebellar deficiency, 305, 461 effects on, experimental of cerebellar ablation, 305-306 of cerebellar stimulations, 306-308 Blastomycosis of the cerebellum, 508 Blindness in amaurotic familial idiocy, 474 attacks of, in cerebellar tumors, 530 Blood pressure, effect on of cerebellar stimulations, 292-299 of total cerebellectomy or partial cerebellar le-

642

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

sions, 291, 292 Blood supply; see Cerebellar vascularity Bone marrow, effects of intracerebral injection of, on Purkinje cells, 458 Bony abnormalities; see Malformations, skeletal Brachium conjunctivum (see also Cerebellar peduncle, superior) atrophy of, in case of athetosis, 463 changes in, in Friedreich's ataxia, 468 crossed ascending limb of, in animals cerebellar influence on precentral motor area through, 335 relation to cerebellar tremor, 335 role of, in certain hyperkinetic syndromes. 412, 415 Brachium pontis, section of, 91—92 Brain stem involvement of, in cerebellar tumors, 400, 532 lesions in, symptomatology, 400 and pontine and intracerebellar lesions, differential diagnosis of, 399-400 nonsurgical disorders of, confused with ArnoldChiari malformation, 424 role: in palatal myoclonus, 402, 413 in static tremor and myoclonia, 389—390, 415 Bruns syndrome associated with cysticercus cysts, 508 described, 402-403 head posturing as sign in, 383 Bulbar palsy, in hereditary spinal ataxia, 471, 472; see also Cranial nerves, involvement of Burr hole exploration, as surgical treatment in extradural hematomas, 525 Calcification in cerebellar tumors, relatively infrequent, 532 astrocytoma, 540-541 oligodendroglioma, 551 of hemorrhagic lesions, 518 intracerebral, in tuberculomas, 496 intravascular, as predisposing factor in intracerebellar hemorrhages, 525 symmetrical, of the dentate nuclei, 477-478 Caloric stimulation, as test for cerebellar disorders. 398 Cannon's law of denervation, in chronically deafferented limbs, 147, 277, 279, 280, 285 Carbon tetrachloride, cerebellar damage from, in man and dogs, 487-488 role of alcohol in potentiating, 488 Carcinoma (see also Tumors, cerebellar) associated with subacute cortical cerebellar atrophy, 455, 456, 458, 479 changes in granular layer in, 485 of kidney, and hemangioblastoma, 554 nasopharyngeal, in a case of cerebellar abscess. 507 Cardiac disorders, linked with Friedreich's ataxia, 466 Cardiovascular pathology associated with cerebellar hemorrhage, 517 as underlying condition in cerebellar vascular oc-

clusions, 514 Carotid sinus reflexes, effect of cerebellar stimulations on respiratory, 294, 299 vasomotor, 294 Catalepsy, cerebellar, 386 cerebellar division responsible, 380 relative frequency as symptom, 379 Caudate nucleus, evoked potentials from crus I, crus II, and tuber vermis after singlepulse stimulation of, 211 Cellular neuropathology, Purkinje cell favored for experimental approach to problems of, 459, 492 Cerebellar abscess, 498—507 classified, on basis of morbid anatomy, 503 differential diagnosis, 505-506 frequency of, 498, 499 mortality in, 498 organism responsible. 504 origin fungicitic, 507-508 nonotogenic, 507 otogenic, 498, 509 routes of infection, 499-503 symptomatology, 505-506 treatment antibiotic medication, 504, 507, 509 excision, 504, 506, 507 surgical drainage, 498, 506 Cerebellar asynergia, 390 Cerebellar ataxia; see Ataxia, cerebellar; Ataxic gait Cerebellar cortex (see also Granular layer, Molecular layer, Purkinje neurons, etc.) acute inflammatory and toxic disorders of, 451, 480-493; see also Malaria, Whooping cough, etc.; Alcohol, Lead, etc.; Anoxia atrophy of, 446, 459; see also Cortical cerebellar atrophy chemical stimulation of, 111-113 electrical activity of, 162—182; see also Electrical activity, Spike discharges electrical excitability of, 104 electrical stimulation of, 113-139 histogenesis and functional development, interrelations between, 359-367 isolated slab of, spontaneous electrical activity in, 174 mechanical stimulation of, 109, 110 Cerebellar deficiency (syndrome of cerebellar dysfunction), 378, 379 absence of symptoms in partial agenesis of cerebellar vermis in man, in contrast to subprimates, 444 analysis of, by Holmes, in man, 388, 390, 522 in case of Amold-Chiari malformation, 422 effect on voluntary movements in animals, 37 danger of drawing conclusions for man from laboratory data, 37 focal signs of, importance, in diagnosis of cerebellar abscess. 505 in malaria

SUBJECT INDEX delayed appearance of ataxia, 481, 482 reversibility of signs, 481 permanence of, after cerebellar hemorrhage, 519 in postexanthematous encephalatides, 485 progressive, with tuberculomas, 496 signs of in complete agenesis of cerebellum, 426 in myoclonic epilepsy, 411-412 symptoms, classified according to functional division of cerebellum, 379, 381, 398 syndrome of after hydrocyanic acid poisoning, 486 in acute alcoholism, 486 permanent, from hyperthermia, 481 transiency of signs of after occlusion of posterior inferior cerebellar artery, 513 contrasted with constancy of damage after occlusion of superior artery, 515 in local lesions of hemisphere, 502 unstabilized and stabilized, 22 Cerebellar function general considerations, 368-374 in man applicability of ablation experiments to, 7, 378. 396 inferences regarding, from electrophysiological data, dangers in, 397 Cerebellar growth, full size at 15 years, 440, 464 Cerebellar Hemisphere, Syndrome of, 378 Cerebellar inhibition not reversed by strychnine, 115, 124 of postural extensor tonus alpha route for, 260-262, 273-280; see also Alpha discharge, Alpha rigidity gamma route for, 243-244, 255-260; see also Anterior lobe, experiments on: Gamma discharge; Gamma rigidity, Muscle spindles Cerebellar lesions (see also Anterior lobe of corpus cerebelli, Flocculonodular lobe. Posterior lobe) confused with cerebral neoplasms, 404 importance of differential diagnosis, 404 extent of, not exactly delimited, 378 as simulated by ablations, 378. 396 motor seizures accompanying in cats, 409 in man, 408, 410 neurological abnormalities resulting from, 379398 Cerebellar localization as localization of functions, 51, 154 clinical evidence for, 378-379, 380 as somatotopic localization, 51, 157 anatomical and physiological approaches to. 50-52, 185, 249, 396 clinical evidence for, 396-397, 522 Cerebellar nuclei electrical excitability of, 104, 141-142 in mammals (see also Nucleus dentatus, Nucleus fastigii, Nucleus interpositus) electrical recording from, 235-240

643

electrical stimulation of, 141-148 isolated lesion of, 77-88, 304-305 in man atrophy of, 479 questionableness of. as clinicopathological entity, 463-464 vulnerability in multiple sclerosis, 477 in thalamic pigeon electrical stimulation of, 107 lesion of, 19-21 Cerebellar nutrition, role of anterior superior cerebellar artery in, 515 Cerebellar peduncle, inferior (see also Juxtarestiform body) electrical stimulation of, 150 lesions of, in man, 400-401 syndrome, 400 unusual case, 401 section of, in animals, 88-91 transiency of disability after, 89 compared to symptomatology after occlusion of posterior inferior cerebellar artery in man, 513 as source of symptomatology in occlusion of posterior inferior cerebellar artery in man, 513 unilateral section of, effect on postural responses to stimulation of vermian part of anterior lobe, 134, 149 vulnerability in multiple sclerosis, 477 Cerebellar peduncle, middle involvement of, in Friedreich's ataxia, 468 section of, in monkeys, 91-92 vulnerability in multiple sclerosis, 477 Cerebellar peduncle, superior (see also Brachium conjunctivum) electrical recording from, 218-219 electrical stimulation of, 150 involvement of in Friedreich's ataxia, 468 in medulloblastoma, 530-531 lesions of, in man, 401—402 constancy of deficiency after, 401, 515 compared to symptomatology after occlusion of superior cerebellar artery, 515 differential diagnosis, 401—402 hyperkinetic disturbances with, 412-413 section of, in animals, 92—95 weight discrimination after, 346 Cerebellar peduncles (see also Cerebellar peduncle, inferior; middle; superior) complete bilateral section, effect on spontaneous electrical activity of cerebellar cortex. 173, 174 unilateral section of the three combined with bilateral ablation of precentral motor areas in primates, effect of, 338; see also Release phenomena differences in effect from hemicerebellectomy, 38-39 effect on inhibitory response elicited by electrical stimulation of contralateral vermian

644

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

cortex of anterior lobe, 136 in primates, 47-48 Cerebellar seizures, 386, 408-410 accompanying cerebellar tumors, 410 in animals after bilateral ablation of motor area or decortication, 140 after electrical stimulation of mammalian cerebellum, 139-141 after mechanical irritation of mammalian cerebellum, 110 EEG during, 140 atypical, 410 cerebellar division responsible, 380 common, in late stages of medulloblastoma, 543 described, in man, 408-409 mechanism, 410. 415 relative frequency as symptom, 379 as sign, grave, in extradural cerebellar hematomas, 524 Cerebellar signs in non-cerebellar disease; see Extracerebellar lesions, cerebellar symptomatology of Cerebellar vascularity, arterial anatomy, 510, 511 capillarity, richness of, 511 Cerebellectomy combined with decerebration in carnivores. 26. "27, 28. 135. 274-275, 280, 281, 282 in primates, 338 complete in amphibia, 12-13 in birds, 13-14 in fish, 10-17 in primates, 35-38 in reptiles, 13 in subprimates, 23-35 increased response to meaningful noises after, 345 opposite effects on excitability of postural reflexes and on strength of supporting tonus, 97 partial in amphibia, 13 in birds, 14-21 in fish, 11-12 in primates, 46-48, 49-50 in subprimates, 38-46, 48-49 Cerebelloolivary atrophy, 452 Cerebellopontine angle tumors acoustic neurinoma, most common of, 558, 561 differential diagnosis of, 399 dysembryomas, 557 medulloblastoma, 542 shown by vertebral arteriography, 536 symptomatology, 400, 406 Cerebral cortex ascending reticular system and influence exerted by vermian or fastigial structures on, 325, 327; see also EEG arousal cerebellorubrothalamic paths and influence exert-

ed by lobulus ansiformis on, 325, 327 in compensation of cerebellar agenesis, role of, 429 compared in man and dog, 429 damage to, without crossed cerebellar atrophy, in man and monkeys, 465 importance of unknown factor of susceptibility, 466 effect of cerebellar stimulations on electrical activity of, 323-327 evoked potentials from cerebellum after singleshock stimulation of, 204-211 evoked potentials on, yielded by single-shock stimulation of cerebellar cortex and nuclei, 234-336 lesions of, in man, 404-406 in unilateral cerebellar atrophy, 440, 464 relation to cerebellar and reticular control of antigravity tonus, 239-330, 335-338 to cerebellum, 311-344; see also Motor cortex susceptibility of, to anoxia, 493 vulnerability of, to hyperthermia, 491, 493 Cerebrocerebellar relations and alterations of voluntary movements in cerebellar patients, 353-358 in the control of voluntary movements, 353-358 Cervical reflexes (see also Magnus's reflexes) not abolished by Cerebellectomy, 271 released following anemic inactivation of anterior lobe, 275-276 Cervical spine, anomalies of, in association with cerebellar disease Arnold-Chiari malformation, 418, 420-424 basilar impression, 418-419 Chameleon, color changes after Cerebellectomy, 13 Chemical stimulation of avian cerebellum, 105-106 of fish cerebellum, 105 of mammalian cerebellum in adult animals, 110-113, 181-182; see also Curare, Strychnine in newborn animals, 366 Chemoceptive reflexes, respiratory, effect of cerebellar stimulation on, 299-300 Chiari's malformation, 421 Chickenpox, cerebellar deficiency after, 485 Children (see also Infants) "ataxia of childhood," need of more pathological studies of, 450 cerebellar aplasia in, cases of, described, 424-426, 429 electroencephalograms of, abnormalities, in cases of cerebellar tumors, 535 extradural cerebellar hematoma, case of, 523 head injury, case of cerebellar deficiency syndrome after. 521 increased intracranial pressure in, how evidenced, 532 mental symptoms in, with cerebellar tumors, 531, 532 tumors common in

SUBJECT INDEX astrocytoma, 537 medulloblastoma, 542 vomiting, importance of, as symptom of cerebellar tumor in, 529-530 unilateral agenesis of cerebellum, case of, 436 Chiropractic manipulation, case of cerebellar contusion after, 521 Chloralose anesthesia effect on visual responses of cerebellar cortex, 188 electrical stimulation of cerebellum during, 312319 extrapyramidal clonic seizure elicited by strychnine during, 318 Chlorinated amines, effect on cerebellar cortical activity, 182 Chloropromazine, selective abolition of gamma rigidity by, 260 Choked discs; see Ocular disturbances Chorea, chronic progressive, connection with chronic cerebellar atrophy, 402 Chronaxie alterations after total or partial cerebellectomy, 264 subordination, and cerebellum, 264 Chronic infections of cerebellum, 494-498, 507-509; see also Fungicitic infections, Tuberculoma, Tuberculosis, Syphilis Cingulate gyrus, stimulation of, effect on human cerebellum, 412 Circumscribed cortical cerebellar panatrophy, 451452, 475 Clarke's column, patterns of afferent response, 218 Classification (see also Terminology) of atrophic changes, difficulties in, 446, 459, 463 atrophy vs. hypoplasia, 440, 449 cerebellar hypoplasia or degeneration, in cats and calves, difficulty of distinguishing, 440 of cerebellar symptoms, based on functional division of the organ, 380 of cerebellar tumors, 527-528 by numeral grades of malignancy, 539, 548549 of developmental anomalies, difficulties in, 416, 417 anatomical approaches to, 417 importance of time factor in, 417 heredocerebellar atrophy, identified with olivopontocerebellar atrophy, 459 hereditary spinal ataxia and cerebellar atrophies, as single entity, 467 Climbing fibers, orthodromic monosynaptic excitation of Purkinje neurons via, 169 Clinical and physiological data, correlations; see Correlations between clinical and laboratory data Clinical syndromes of cerebellar dysfunction, 378379; see also Anterior lobe of corpus cerebelli, Flocculonodular lobe, Posterior lobe of corpus cerebelli Clinical tests, in diagnosis of cerebellar deficiency for adiadochokinesis, 392

645

for arrhythmokinesis, 393 value in differential diagnosis of Parkinsonism, 394 caloric stimulation, 398 finger-to-nose and heel-to-knee, 392 in a case of Arnold-Chiari malformation, 422 for hypotonia, discussion of, 354-355, 357-358 labyrinthine tests of Barany, 398 for rate of voluntary movements, 393 rhythmic stabilization test, 392 of upper extremity dexterity, 380 Closed head injuries, cerebellar trauma in, 522, 525 Cock gait after hemicerebellectomy, 40, 42, 43; see also Dysmetria after lesions of lobulus ansiformis or of 1. ansoparamedianus, involving cerebellar nuclei, 65, 67, 71-72 after unilateral lesion of nucleus interpositus, 86 functional significance of, 40, 42, 43 present in hemicerebellectomized dog after compensation of atonia, 43 Coma, cerebellar, 411 in extradural hematomas, 524 as terminal sign in cerebellar abscess, 505 Comparative anatomical studies of developmental defects in cerebellar vermis in dogs, 431 in white mice, 417, 431, 433 Comparisons, clinical and physiological; see Correlations between clinical and laboratory data Compensation after bilateral section of middle cerebellar peduncles, 92 after section of superior cerebellar peduncles, 93-94 capacity of cerebral cortex for, compared in men and dogs, 429 of cerebellar release phenomena after ablation of anterior lobe in dog, 57 by cerebral cortex, 335-338, 353 by Schiff-Sherrington inhibition, 283-287, 353 in thalamic pigeon, 15 occurring earlier than compensation of Luciani's atonia, 98, 99, 286 of cerebellar symptoms, importance of, for clinical neurology, 353 clinical phenomena of, 417 after lesions of superior cerebellar peduncle in man, 401, 515 after severe cerebellar laceration, 522 in cerebellar agenesis, 427 minimum amount of cerebellar tissue necessary for, 429 in slow-growing cerebellar tumors, 528 astrocytoma, 537 Flourens's demonstration of, following partial cerebellar lesions, 5 Luciani's distinction between organic and functional, 30, 44-45

646

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

Luciani's period of, 30, 44-46 of unilateral atonia following hemicerebellectomy by motor cortex, 330-332 occurring before compensation of dysmetria, 43

following asymmetrical cerebellar lesion, 353 following asymmetrical fastigial lesion by motor cortex, 332 by premesencephalic structures, 332 Compound muscular movements, voluntary, disturbances in, 37, 392-395 Conditioned reflexes, relation to cerebellum, 338344 Congenital atrophies distinguished from hypoplasias, 450 in infants, familial, 449-451 in lambs ("daft lambs"), 449-450, 479 Congenital cerebellar defects; see Agenesis, cerebellar Congenital disorders, specific, effects of, on development of cerebellum cretinism, 442 Mongolian idiocy, 441-442 syphilis, 442 Congenital hypoplasia in cats, 438-439 in calves, 440 Contrecoup brain injuries, percentage located in cerebellum, 522 Contusions of the cerebellum, 521 Convergence of afferent impulses on cerebellar cortex, 216-217 on fastigial units, 237-240 on precerebellar units, 185, 199, 217-218, 251252 on single reticular units, 226 of cerebellar cortical and labyrinthine impulses on single rostrofastigial units, 237 of corticofugal and cerebellifugal impulses on single reticular units, 222-226 of sensory and cerebellifugal impulses on single reticular units, 223-226 of sensory and of corticofugal impulses on cerebellar cortex, 217 of sensory, corticofugal, and cerebellifugal impulses on single reticular units, 223-226 Convulsions associated with cerebellar tumors, 410 role of anoxia in lesions associated with, 490 Convulsive discharges, after local strychninization of cerebellar cortex, 179 Convulsive disorders, 408-415; see also Cerebellar seizures, Myoclonic epilepsy Coordination of movements, influence of cerebellum on, Flourens's views, 4 Corneal reflex, different results of cerebellar and reticular stimulation on, 131, 151 Corpus cerebelli, divisions of, 378; see also Anterior lobe of corpus cerebelli, Flocculonodular

lobe, Posterior lobe of corpus cerebelli Corpus juxtarestiforme; see Juxtarestiform body Corpus restiforme; see Restiform body Correlations between clinical and laboratory data, 378, 379, 398' agenesis of vermis, symptoms of, in lower animals compared to man, 434 capacity of cerebral cortex for compensation of cerebellar deficit, in man and dog, 429 carbon tetrachloride, cerebellar damage from, in dogs and man, 488 cerebellar cortex, susceptibility to anoxia, in experimental animals, 489 cerebellar seizures, in cats and man, 110, 139, 408-409, 411 cerebral cortex, damage to, in man, monkeys, and dogs, with and without crossed cerebellar atrophy, 465 cortical ablation in animals not applicable to frontal ataxia in man, 405 cortical cerebellar atrophy and physiological studies of Bremer, 386 DDT, administered to dogs, 487 encephalitis in cats, 485-486 eosinophilic leukocyte toxin, cerebellar damage from, in man and experimental animals, 488-489 experimental malaria, in duck, delayed appearance of ataxia after, 481-482 experimental cerebellar lesions compared to olivopontocerebellar atrophy, as they affect walking, 461 hereditary cortical cerebellar atrophy in man and lambs, 450-451, 479 hypoglycemia, experimental, cerebellar damage from, 490 lesion of middle cerebellar peduncle in man, case of, and sectioned monkey, 401 lesions of posterior vermis, experimental and in man, 381 mercury compounds, cerebellar damage from, in rats, 488 "olivopontocerebellar atrophy" in cat, 462 palatal myoclonus, laboratory counterparts of, 415 rotated head posture, clinical and laboratory problem of, 91, 383, 384 somatotopic localization in cerebellum, laboratory and clinical support for, 396-397 transiency of disability syndrome after occlusion of posterior inferior cerebellar artery in man, 513, 515 after section of inferior cerebellar peduncle in monkey, 89 trichloroethylene, experimental intoxication of dogs with, 487 weight discrimination, in monkeys after section of superior cerebellar peduncle, and in cerebellar patients, 346, 358 Cortical cerebellar atrophy (see also next two entries) as clinical entity, 385-386, 387, 449

SUBJECT INDEX heredocerebellar atrophy, identified with olivopontocerebellar atrophy, 459, 462 mistakenly identified as multiple sclerosis, 477 in monkey, after manganese intoxication, 486 and physiological studies of Bremer, 386 and Pick's disease, 475 pneumoencephalography in diagnosis of, 442-443 predilection for anterior lobe, 385, 454, 489 so-called atrophie olivo-rubro-cerebelleuse as case of, 463 Cortical cerebellar atrophy, familial or hereditary identified with olivopontocerebellar atrophy, 459 in adults, 446-449 case reports, 446—449 hereditary mechanism, 449 pathology illustrated, 448 secondary olivary degeneration, 446, 447, 449 syndrome described, 446 in amaurotic familial idiocy, 474 in infants, 449-451 less clearly defined as group, 450 in lambs ("daft lambs"), 449-450 mistakenly identified as multiple sclerosis, 477 and Wilson's disease, 476 Cortical cerebellar atrophy, nonfamilial or acquired, 451-459; see also Acute toxic and inflammatory disorders generalized, acute, 458 relation to general problem of cellular neuropathology, 459 generalized, chronic, case reports of, 454-455 generalized, subacute, 455-458 association: of carcinoma with, 455, 456, 458, 479 of extracerebellar lesions with, 456 of secondary olivary degeneration with, anatomical inferences, 458 disturbance of gait as early symptom, significance discussed, 456-457 identified with louping ill, 483 localized (chronic), 451-454, 475 circumscribed panatrophy, asymptomatic, 451452 predominant in the anterior lobe, 452 ataxia, more marked in lower extremities, 452-453 histopathology, 453 tendency toward secondary olivary degeneration in, 452, 454 pathological changes in, classified, 451 Cranial nerves, involvement of in basilar impression, 419 in cerebellar tumors, 532 dysembryomas, 558 hemangioblastomas, 555 meningiomas, 560 in extracerebellar lesions, 399, 400 in hereditary spinal ataxia, 466, 469, 471, 472 Craniopharyngioma, 404 Cretinism, and defects in cerebellar cortex, 442

647

Crossed cerebellar atrophy, 404, 440, 464-466 absence of, in some cases of severe cerebral damage, 465 importance of unknown factor of susceptibility, 466, 479 and Alzheimer's disease, 475 cerebellar symptomatology, absence of, 466 agreement with experimental observations, 466 difficulty of distinguishing from hypoplasia, 444, 464 involvement of thalamic area as well as cortex of cerebral hemisphere, 465 mechanism in, 465, 466, 479 Crossed cerebellar hypoplasia; see Crossed cerebellar atrophy Crossed extensor reflex cerebellar inhibition of phasic component of, during curare atonia, 118 effect of electrical stimulation of vermian part of anterior lobe on myotatic appendage of, 119 inhibited by electrical stimulation of vermian part of anterior lobe, 115, 117, 151 Crus I (see also Lobulus ansiformis) ablation of, effect on absinth convulsions, 329 on posture and phasic movements, 67-69, 7173, 73-77 on subordination chronaxie, 264 electrical stimulation of, effect on cortical chloralose movements, 313, 315 on electrical excitability of motor cortex, 311 evoked potentials from after single-shock stimulation of autonomic areas of cerebral cortex, 209 after single-shock stimulation of nucleus caudatus, 211 after visual stimulation, 188 Crus II (see also Lobulus ansiformis) ablation of, effect on absinth convulsions, 329 on posture and phasic movements, 67-69, 71— 73, 73-77 electrical stimulation of, effect on electrical excitability of motor cortex, 311 evoked potentials from after single-shock stimulation of autonomic areas of cerebral cortex, 209 after single-shock stimulation of nucleus caudatus, 211 after visual stimulation, 188 Culmen (see also Anterior Lobe, experiments on) ablation of combined with ablation of areas 4 and 6 in primates, 63 effect on driven discharge of rostrofastigial units elicited by single shocks applied to radial nerve, 238-240 followed by release of alpha rigidity in deafferented limbs: of the decerebrate carnivore, 274 of the postcollicular preparation, 280

648

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

in mammals, 61-63 in primates, 63 in subprimates, 61—63 electrical stimulation of in birds, 106 in mammals, 125-127, 131-137 response of ipsilateral forelimb after, 125 spread of inhibitory response obtained by increasing rate of, 126-127 evoked potentials from after single-shock stimulation: of forelimb region of area 4 in primates, 207 of splanchnic nerve, 310 during natural stimulation of forelimbs, 184— 186 galvanic stimulation of, effect on cortically induced reticular discharges, 223224 on decerebrate rigidity, 219-221 on EEG patterns, 220, 323-325 on reticular spike discharge, 219-230 on spontaneous discharge of rostrofastigial units, 237 Curare injection of, into cerebellum, 110-111, 366 technique criticized, 110, 111 selective abolition of decerebrate rigidity with low doses of, 75, 76-77 simultaneous abolition of postural and phasic cerebellar asymmetries by, 75 Curare atonia abolition: of both gamma and alpha rigidities during, 260 of decerebrate rigidity with conservation of phasic reflexes during, 75 cerebellar inhibition during, 118 Cutaneous projections onto cerebellar cortex functional significance of, 242—£45 investigated: by natural stimulations, 185-186 by single-shock stimulation of superficial nerves, 195-197 onto fastigial nuclei, results of single-shock stimulation of superficial nerves, 237 Cutaneous sensation; see Sensory functions, disturbances of Cyst, cysticercus, in fourth ventricle, and Bruns syndrome, 402-403, 508 Cystic serous meningitis and otogenic cerebellar abscess, differential diagnosis of, 506 Cysticercosis, cerebellar involvement in, 402-403, 508 "Daft lambs," 449-450, 479 DDT cerebellar damage from, 487 effect of, on cerebellar cortical activity, 181, 487 compared to strychnine, 487 Deafferentation cerebellar rebound following, 147 extensor rigidity following, 273-282; see also Alpha rigidity

reflex rebound abolished by deafferentation, 155 release phenomena of Luciani's dynamic period following, 285 reversal of fastigial atonia following contralateral, 265-268 Decerebellate rigidity, relation to alpha rigidity, 259-260 Decerebrate rigidity bilateral increase of after anterior lobe topectomy, 60-61 after symmetrical fastigial destruction, 81 decreased (see also Fastigial atonia) contralaterally to lesion of caudal part^ of fastigial nucleus, 81-85, 265-268 ipsilaterally to lesion: of fastigial nucleus, 8081 of rostral part of fastigial nucleus, 82, 86 of rostromedial part of fastigial nucleus, 86 effect on of acute cerebellectomy, 26-27 of electrical stimulation of anterior lobe, 6, 51, 113-137 of unilateral decortication of vermian part of anterior lobe, 364 of unilateral fastigial lesion, 364 elicited by midbrain transection in chronically cerebellectomized cat, 280-282 increase of, during poststimulatory inactivation of cerebellar anterior lobe, 156, 176-177; see also Rebound increased ipsilaterally to lesion of rostrolateral part of fastigial nucleus, 86 inhibition of, elicited by cerebellar stimulations alpha mechanisms of, 262 gamma mechanisms of, 243-244, 255-256 ipsilateral increase of after acute decortication of vermian part of anterior lobe, 80 after lesion of nucleus interpositus, 87 ipsilateral increase of, during electrical stimulation of intermediate part of anterior lobe, 124-126, 135-137 of lateral strip of intermediate part of anterior lobe, 137 of nucleus interpositus, 135-147 in man in amaurotic familial idiocy, 474 cerebellar seizures as a manifestation, 386 present in newborn kitten, 363 Decerebration anemic combined with functional cerebellectomy after occlusion of cerebellar arteries, 27-28 differences from Sherringtonian decerebration in gamma control of postural tonus, 259 inactivation by infarction of cerebellar anterior lobe during, 28, 60, 274 pharmacological differences from extensor rigidity elicited by Sherringtonian decerebration, 260 release phenomena after, 27-28, 60, 259, 274-

SUBJECT INDEX 276, 283 Sherringtonian differences from decerebellate rigidity elicited by anterior lobe topectomy or anemic decerebration, 257-260 pharmacological dissociation from decerebellate rigidity, 260 relation to gamma activity leading to intrafusal cramp, 257-259 Decompensation of cerebellar deficiency by ablation of motor cortex, 330-332 spontaneous, 92 Decomposition of movement, as symptom of cerebellar deficiency defined, 23 described, 392 Holmes's analysis of, in relation to physiological data, 37 Decompression, as surgical technique in Arnold-Chiari malformation, 421, 422, 424 in medulloblastoma, 547 as palliative measure: in pontine gliomas, 559 in tuberculomas, 496-497 in platybasia, 419 Deficiency period, Luciani's relation to fastigial atonia, 79-80, 99-101 symptoms of: after total cerebellectomy, 25 after unilateral cerebellectomy, 39-41; see also Compensation Degeneration of the cerebral gray matter of Alpers, 477 Degenerative diseases, specific, cerebellar changes in, 474-478 Alzheimer's disease, 475-476 amaurotic familial idiocy, 474 degeneration of gray matter of Alpers, 477 multiple sclerosis, 477 Pick's disease, 475 symmetrical calcification of dentate nuclei, 477 tuberous sclerosis, 478 Wilson's disease, 476-477 Deiters' nucleus; see Vestibular nuclei Deitersian units; see Vestibular nuclei Delayed muscular contractions, as symptom of cerebellar deficit, 390-392 Delta fibers, afferent, in splanchnic nerve projecting onto anterior lobe, 310 Dentate nucleus; see Nucleus dentatus Dentate-rubral atrophy, 463 Dentate system, defined, 249 Developmental anomalies of the cerebellum, 416444; see also Agenesis, cerebellar; ArnoldChiari malformation; Basilar impression of the occipital bone; Dysplasia, cerebellar; Hypoplasia angiomatous malformations, as developmental defects, 552 astrocytomas, cerebellar, not developmental defects, 539 and changes in subcerebellar nuclei, 433, 434 classification of anatomical approaches to, 417

649

difficulties in, 416, 443 difficulty of distinguishing from degenerative changes, 416, 440, 442 genetic studies, 430, 431-432, 433 and hemangioblastomas, related to antenatal defect, 554 and heterotopias of cerebellar cortex, 434, 547 mechanism of production, 431-434 morphological considerations, 431, 433 multiple character of, 418 pneumoencephalography in diagnosis of, 442-443, 444 specific congenital disorders, role in, 441-442 time factor, importance of, 417, 434 Diabetes associated vascular damage, 512 diabetic coma, changes in granular layer in, 485 Diagnostic tests; see Clinical tests, Electroencephalography, Pneumoencephalography, etc. Dichlorodiphenyltrichloroethane; see DDT Diencephalon, evoked potentials from, after singleshock stimulation of cerebellar cortex, 232-234 Digestive tract, effect on of cerebellar ablations, 54, 290-291, 305 of cerebellar stimulations, 305 Disequilibration, syndrome of, after ablation of nodulus and uvula in primates, 55-56 Disturbances in gait, in speech, in station; see Gait disturbance, Speech disturbance, etc. Divisions of cerebellum, 51, 378 clinical basis functional, 379 as seen in different symptomatology of astrocytomas and medulloblastomas, 530 somatotopic, 396-397 Double vision; see Ocular disturbances Drowsiness, symptom in extradural cerebellar hematomas, 524 in tumors of posterior fossa, 532 Dynamic phenomena diaschisis hypothesis on, 29 irritation hypothesis on, 24 less developed in primates than in carnivores, 36-37, 49, 98

Luciani's, in carnivores; see also Compensation, Release phenomena, Schiff-Sherr:ngton inhibition absent after vermian bisection, 49 after total cerebellectomy, 24 after unilateral cerebellectomy, 39 relation to ablation of anterior lobe, 56 relation to vermian ablation, 42, 48—49 release hypothesis on, 22, 28, 42, 60, 98, 283-287 Dysdiadochokinesis (see also Adiadochokinesis) in Arnold-Chiari malformation, 422 in frontal lobe cerebral tumors, 405 Dysembryomas, 557-559 classification, 528, 557 different names for, 557 ectodermal tissue as origin of, 557 gross appearance, 558

650

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

location, 557-558 surgical treatment, 558-559 symptoms and signs, 557-558 auditory and vestibular function not usually affected, 558 external manifestation, importance of, 559 Dysmetria, 390, 391, 392, 398 after localized cerebellar cortical lesions involving underlying nuclei, 71-72 after section: of spino-cerebellar tracts, 89 of superior cerebellar peduncles, 93-94 after total cerebellectomy in primates, 36 after unilateral ablation: of lobulus ansiformis, 67-68 of lobulus ansoparamedianus, 65 after unilateral cerebellectomy: in carnivores, 40 in primates, 48 cerebellar, re'ation to abnormalities in centrifugal innervation of muscle spindles, 346, 356357 cerebellar division responsible, 380 defined, 23 described, 392 in lesions of cerebral frontal lobe, 405 of superior cerebellar peduncle, 401, 516 in myoclonic epilepsy, 411 relative frequency as symptom, 379 Dysphagia, in Arnold-Chiari malformation, 422 Dysplasia, cerebellar (malformations of individual folia), 441, 551 in Arnold-Chiari malformation, 423 difficulty of distinguishing from tumors, 552 morphological classification of, 441 Dyssynergia in frontal lobe cerebral tumors, 405 in myoclonic epilepsy, 411-412 Dyssynergia-cerebellaris-myoclonica; see RamseyHunt syndrome Dystonia musculorum deformans, involvement of dentate nucleus in, 463 Ear (see also Hearing, disturbances of) disturbances of, and postconcussion syndrome, 522-523 infections of, role in cerebellar abscess, 498, 499 otitis interna, chronic nonsuppurative, rotated head posture in, 382 Edema, angioneurotic, cerebellar involvement in, 485 EEG, not related to electrical activity of cerebellum in clinical cerebellar disorders, 536; see also Electroencephalography, clinical EEG arousal during cerebellar seizure, 140 elicited: by cerebellar stimulations via ascending reticular system, 324-327, 348 by galvanic stimulation of vermal areas of anterior lobe, 220, 323-327 by repetitive electrical stimulation: of culmen, QOQ Ozo

of fastigial nuclei, 323-324

Eighth nerve bilateral section of, abolition of opisthotonos but not of alpha rigidity of deafferented forelimbs after, 277-279 unilateral section of ipsilateral decrease of extensor rigidity in decerebrate and decerebellate cat after, 274275 ipsilateral disappearance of alpha rigidity in deafferented limbs of decerebrate cat after, 275, 277-279 no effect on extensor rigidity in decerebrate cat, 274 release of alpha rigidity in contralateral limbs of decerebrate cat, 277-279, 283 Electrical activity of cerebellar cortex after decerebration, 163-164 appearing at 12 days from birth in rat, 367 before decerebration, 163 effect of sensory stimulation on, 212-216 functional significance of, 240-242 led with macroelectrodes, 162—164 led with microelectrodes, 164-173 modulation by slow cerebral rhythms, 163, 189 present at birth in guinea pig, 367 reflex vs. autochthonous mechanisms of, 173174, 242 relation to tonic activity of cerebellum, 176, 240-241 unaffected after abolition of decerebrate rigidity by curare, 242 of cerebellar nuclei led with macroelectrodes, 235, 237 led with microelectrodes, 237-240 spontaneous, present in cerebellar cortex after chronic section of cerebellar peduncles, 173, 174 after supranuclear transection, 173, 174 in isolated slab of, 174 Electrical silence, after strong stimulation of cerebellar cortex, 176-178 Electrical stimulation of cerebellar cortex in adult mammals, 113-141 in birds, 106-109 in newborn mammals, 366-367 of cerebellar nuclei in birds, 107 in mammals, 141-148 of human cerebellum, for study of convulsive disorders, 411 Electrocorticogram, effect on of cerebellar ablations, 330 of cerebellar stimulations: chemical, 325-327 electrical, 323-327 Electroencephalography, clinical in diagnosis of cerebellar tumors, 535-536, 562 in differential diagnosis of cerebral and cerebellar lesions, 404 and electrical activity of cerebellum seen in laboratory, absence of any relation, 536

SUBJECT INDEX little applied in study of cerebellar disease, 397 in localizing cerebral lesions, 398 not adapted to investigate posterior fossa, 398 in study of dyssynergia-cerebellaris-myoclonica, 412 Electrophysiology data of, applicability to cerebellar disorders, 397 methods of, for study of cerebellar effects of alcohol, 485 Encephalitis associated with epidemic parotitis, 484 as human counterpart of louping ill, 483 with predominantly cerebellar manifestations, 485, 493

of unknown cause, in cats, 484 Endocrine glands, influence of cerebellum on, 300— 302

Enteritis, toxic effects on Purkinje cells, 458 Eosinophilic leukocyte toxin, 488-489 probably protein nature of, 489, 493 susceptibility of Purkinje cells to damage by, 458, 488-489 Ependymomas of the fourth ventricle, 559 and intracerebellar lesions, differential diagnosis of, 559 Epidemic parotitis, cerebellar damage in, 484, 493 permanent residual speech defect, case of, 484 Epilepsy (see also Myoclonic epilepsy) cerebral, electrical stimulation for study of, 411 loss of Purkinje cells in, 490 percentage showing myoclonic form, 411 Epileptiform afterdischarge after strong electrical stimulation of cerebellar cortex, 176 electrical silence in cerebellar cortex following, 176, 178 patterns of, led from cerebellar cortex, 176 Equilibration, disturbances in in involvement of flocculonodular lobe, 381 in suprasellar lesions, 402, 403 Equilibrium influence of flocculonodular lobe on, 55-56 Magendie's theory of cerebellar influence on, 6 Eserine, effect of application to cerebellar cortex on local electrical activity, 182 motor responses elicited by, 112-113 Ethyl acetate, cerebellar damage in dogs after injection of, 487 Evoked potentials from avian cerebellar cortex, after sensory stimulations, 160-162 from bulbar reticular formation, after singleshock stimulation of culmen or fastigial nucleus, 219 from dorsal spinocerebellar tract, 197 from fastigial nucleus, after single-shock stimulation of eighth nerve, 202 from mammalian cerebellar cortex after auditory stimulations, 186 after exteroceptive stimulation, 185 after local application of single electrical shocks, 175

651

after proprioceptive stimulation of limbs, 182— 185 after single-shock stimulation: of auditory cortical areas, 208 of cerebral cortex, 205-210 of cerebral cortex in newborn rabbit, 367 of eighth nerve, 202 of inferior olive, 201-203 of motor cortex, 206-207 of nucleus caudatus, 211 of olfactory bulb, 211 of peripheral sensory fibers, 189-200 of pons, 202 of reticular formation, 202 of somatosensory cortical area I, 208 of somatosensory cortical area II, 208—209 of spinocerebellar tract, 200—201 of superior colliculi, 202-203 after strychnine stimulation of motor cortex, 205, 206 after thermal stimulation of cerebral cortex, 204 after vestibular stimulations, 182 after visual stimulations, 186-189 differences between single-shock stimulation of cutaneous and of muscular nerves, 196 different components in response to singleshock stimulation of a mixed nerve, 195197 general patterns of, 211-218 occlusion between two sensory volleys, 216, 217 somatotopic distribution of, 184-186, 189-195, 206-207 surface-negative component of: abolished by local nembutal, 211 decreased by general anesthesia, 211 and driven discharge of Purkinje neurons, 211, 217 increased by local strychnine, 211 surface positive component of: and postsynaptic response of internuncial neurons of granular layer, 211 more resistant to local nembutal and general anesthesia, 211 temporal summation of, elicited by two sensory volleys, 216 from ventral spinocerebellar tract, 199 Exogenous toxins, and cerebellar damage, 485-489 Experimental observations, clinical applicability of; see Correlations between clinical and laboratory data Extensor rigidity; see Decerebrate rigidity labyrinthine component of; see Alpha rigidity myotatic component of; see Gamma rigidity Extracerebellar lesions in man (see also Cerebellar peduncle, inferior; superior; Cerebellopontine angle tumors; Fourth ventricle; Frontal lobe of cerebrum, tumors of) in association with subacute cortical cerebellar atrophies, 456 cerebellar symptomatology of, 399-407, 563

652

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

in acoustic neurinomas, 400, 561 false localizing signs, 405 mechanism responsible, 406 in pontine gliomas, 400, 559 in tumors of fourth ventricle, 402, 403, 559 and clonic seizures, 410 how differentiated clinically from intracerebellar, 399, 407 Extradural abscess and otogenic cerebellar abscess, differential diagnosis of, 506 Extradural hematoma, cerebellar, 523-525 chronic, unusual case of, 524 injury responsible, 523, 525 as surgical emergency, 525 symptoms, 524 Extrapyramidal clonic seizure, inhibited by electrical stimulation of vermian part of anterior lobe, 318-320 Extrapyramidal system in hereditary spastic ataxia, 469 involved in olivopontocerebellar atrophy, 459, 462, 479 linked: with hereditary spinal ataxia, 466 with myoclonic epilepsy, 412 symptomatology of, in a case of basal ganglion pathology, 476 Eyes; see Ocular disturbances Facial expression, emotional, loss of, in occlusions of superior cerebellar artery, 402 Familial cortical cerebellar atrophy; see Cortical cerebellar atrophy, familial or hereditary Familial hypoplasia in calves, 439-440 in cats, 438-439 Fasciculus uncinatus; see Hook bundle Fastigial atonia as consequence of asymmetrical fastigial innervation, 79, 81, 84-85 crossed, after destruction of caudal part of one fastigial nucleus, 79-86, 100 in cat first compensation of, by motor cortex, 332 first decompensation of, after bilateral ablation of motor cortex, 332 second compensation of, by premesencephalic structures, 332 second decompensation of, after premesencephalic decerebration, 332 in decerebrate cat, 80-86 crossed reflex inhibition arising from proprioceptors of spastic side of body as cause of, 265-268 forelimb asymmetry of, unaffected: by hindlimb deafferentation, 268 by postbrachial transection of spinal cord, 268 replaced by extensor rigidity: after contralateral hemisection of spinal cord, 266-267 after deafferentation of contralateral limb, 265-267 after deefferentation of contralateral limb.

266, 267 after lesion of homotopic structures in opposite fastigial nucleus, 81, 85, 265 during novocaine atonia of contralateral limb, 267 replaced in deafferented foreleg by alpha rigidity after section of contralateral eighth nerve, 283 effect on background of alpha rigidity, 283 ipsilateral after destruction of rostral part of one fastigial nucleus, 79-86, 100 after total destruction of one fastigial nucleus, 77-81, 100 similarities with Luciani's atonia, 79, 100, 331332 with the rest of nervous system intact, 77-80 compensation of, by motor cortex, 332 postural asymmetry of, reversed by deafferentation of contralateral limb, 268 Fastigial lesion, never strictly unilateral when rostral part of nucleus is involved, 86 Fastigial nucleus; see Nucleus fastigii Fastigial spasticity, after lesion of both roof nuclei, similarity to Luciani's dynamic phenomena, 79 Fastigiobulbar pathways, uncrossed, as mediator of augmentatory influence of vermal cortex of anterior lobe, 137 inhibitory influence of vermal cortex of anterior lobe, 134, 137, 149, 153 Feeble-mindedness; see Imbecility Fish ablation: of auricles in, 11-12 of corpus cerebelli in, 11, 12 cerebellectomy in, 10-12 chemical stimulation: of cerebellum in, 105 of corpus cerebelli in, 104 conditioned reflexes after cerebellectomy in, 344 electrical stimulation: of cerebellum in, 104-105 of corpus cerebelli in, 104—105 electrophysiological recording from cerebellum in, 159 Fits, cerebellar; see Cerebellar seizures Flechsig's tract, 197, 218 Flexor muscles, contraction of elicited by stimulating: anterior lobe, 113, 117 cerebellar nuclei, 142 intermediate part of anterior lobe, 115 medial strip of intermediate part of anterior lobe, 137 responses relayed by interpositorubrospinal paths, 137 Flexor reflex inhibition of, during strong electrical stimulation of anterior lobe, 117 subliminar facilitation of, during cerebellar inhibition of decerebrate rigidity, 134 Flocculonodular lobe ablation of, 52-56 developmental anomalies affecting agenesis of cerebellar vermis, 431

SUBJECT INDEX unilateral agenesis, 434 disturbances resulting from involvement of, 378, 381-385 distinguished from syndrome of posterior lobe, 395 electrical stimulation of, 113 fatality of wounds in, 386 relation to vestibular apparatus, 246 responses to single-shock stimulation of eighth nerve, 202 syndrome of: in astrocytoma, 537 in medulloblastoma, 381, 543 Flocculus, ablation of in primates, 56 in subprimates, 56 Flourens's posture, after unilateral corticocerebellar lesion in pigeon, 18-19 Flower-spray endings of muscle spindles, and autogenetic inhibition, 268 Flying ability in cerebellectomized bat, 36 in cerebellectomized pigeon, 14 Flying movements, elicited by cerebellar stimulation in thalamic pigeon, 107 Folium vermis evoked potentials from: after single-shock stimulation of auditory areas I and II of cerebral cortex, 208-209 after visual and auditory stimulations, 186189 evoked potentials led from auditory cerebral cortex after single-shock stimulation of, 235, 236 Fourth ventricle ependymomas of, 559 involvement of: in agenesis of cerebellar vermis, 432, 444 in dysembryomas, 557 in medulloblastoma, 544 lesions in, 402, 403 roof of, as origin of medulloblastoma, 542 Friedreich's ataxia, 467-469 cerebellar changes in, 467-469 as clinicopathological entity, 467 case of, 470, 471 disturbance of speech in, 394 in dyssynergia-cerebellaris-myoclonica, 412, 463 linked with cardiac disorders, 466 Frontal lobe of cerebrum, tumors of, 404-406 and cerebellar lesions criteria for distinguishing, 405 importance of differential diagnosis, 404, 506 cerebellar symptoms and signs, 404-405 possible nervous mechanism involved, 406, 407 statistics on, 405 Functional decortication, cerebellar seizures as manifestation, 386 Fungicitic infections of the cerebellum, 507-508 actinomycosis, importance of distinguishing organisms causing, 507 blastomycosis, 508 easily confused with tumors. 507, 509

653

Gait, after cerebellectomy in birds, 14 in mammals, 30, 60; see also Cock gait, Dysmetria more severely affected than swimming, 25, 27, 101-102 Gait disturbance as sign of cerebellar deficiency in man in Arnold-Chiari malformation, 422 in cortical cerebellar atrophy, 385-386 familial, 446, 447 generalized, 454, 455 late, 452, 457 titubating gait, clinical manifestation of lesions of anterior lobe, 461 difficulty of localizing source, 380, 398 in extracerebellar lesions, 400 in frontal lobe tumors, 404 in lead poisoning, 486 in malaria, 481 in olivopontocerebellar atrophy, 461 physiological significance of, in relation to conclusions drawn from cortical atrophy predominant in anterior lobe, 456-457, 479 relative frequency as symptom, 379 in syndrome: of anterior lobe of corpus cerebelli, 885 of flocculonodular lobe, 381, 395 of posterior lobe of corpus cerebelli, 395 Galvanic skin reflexes, effect of cerebellar stimulation on, 309 Galvanic stimulation of anterior lobe, effect on Deitersian spike discharge, 230-232 of culmen, effect on cortically induced reticular spike discharges, 223-225 on decerebrate rigidity, 219-221 on EEG patterns, 220, 323-325 on single-unit firing in reticular formation, 219-230 on spike discharge of rostrofastigial units, 237 effect on spike discharge of cerebellar cortex, 174-175 of labyrinth effect on Deitersian spike discharge, 230-232 effect on spike discharge of rostrofastigial units, 237 yielding cephalogyric responses, 231 Gamma discharge effect of cerebellar stimulation on, 243—245, 255262; see also Muscle spindles effect of cutaneous stimulations on, 243-245 from ventral root, inhibited by stimulation of vermal part of anterior lobe, 256 Gamma fibers, innervation of intrafusal muscular fibers by, 255 Gamma loop, functional significance of, 257 Gamma motoneurons, affected by lower intensities of cerebellar stimulation than alpha motoneurons. 256

654

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

Gamma paralysis, rigidity still present after, 259; see also Alpha rigidity Gamma rigidity (see also Alpha rigidity, Decerebrate rigidity) abolished by myotatic deafferentation, 274-275 defined, 259 pharmacological influences on, 260 unaffected by labyrinthine deafferentation, 274275 Ganglioneuroma, 551-552 confusion of terminology regarding, 551 unusual growth characteristics, 552 Genetic studies of familial hypoplasia: in cats, 438-439 in calves, 439—440 of hereditary spinal ataxia, 469-472 mode of transmission, 473 of hydrocephalus in mice, 430, 431-432, 433 and spinocerebellar degenerations, 467 Glioblastoma multiforme, 549—550 cellular characteristics, 550 rarity of in cerebellum, 550 terminological confusion, 539 treatment, 559 as tumor of adulthood, 549, 550 Gliomas (see also Pontine gliomas) classification of, 528, 536 extracerebellar, 559 frequency of, 542, 553 termed sarcomas in older literature, 560 Glucose, tolerance test of after extensive cerebellar lesions, 301-302 after uvula ablation, 302 Glycosuria after cerebellectomy or partial cerebellar lesions, 301 elicited by mechanical stimulation of cerebellum, 301 Golgi tendon organs and autogenetic inhibition, 268 transmission of impulses to cerebellum through specialized units of dorsal spinocerebellar tract, 218 Gordon phenomenon, 458, 488 Granular layer inner, in histogenesis of cerebellar cortex, 359— 367 outer disappearance delayed in newborn pigeon by bilateral ablation of semicircular canals, 361 in histogenesis of cerebellar cortex, 359-367 still present in kitten: when kitten is able to walk, 360-361 when cerebellar cortex exerts tonic influence on extensor tonus, 364 when cerebellar cortex is electrically excitable, 367 Guinea pig newborn, earlier appearance of cerebellar influence on tonus than in rabbit and kitten, 363

total cerebellectomy in, 30 Gunshot wounds; see Laceration, cerebellar Habituation of postrotatory nystagmus, effect of cerebellar lesions on, 289-290 Head injuries, 521-525; see also Extradural hematoma, cerebellar; Laceration, cerebellar Head posture, abnormal in Bruns syndrome, 402, 403 cerebellar division responsible, 380 relative frequency as symptom, 379 retraction of head, in "cerebellar fits," 408 in primates, after labyrinthectomy and unilateral nodulus ablation, 55-56, 90, 383, 384 rotated, 382-383 in "cerebellar fits," 409 clinical significance of, disagreement discussed, 91, 382-383, 384 Headache, as symptom in agenesis of vermis, 432 in Bruns syndrome, 402, 403 in cerebellar abscess, 498, 505, 509 in extradural hematomas, 524 in intra- and extracerebellar lesions, 400 in tumors, cerebellar, importance of as presenting symptom, 529 glioblastoma multiforme, 550 hemangioblastoma, 555 medulloblastoma, 543 meningioma, 560 tuberculomas, 496 in unilateral hypoplasia, 440 Hearing, disturbances of loss of: in case of Arnold-Chiari malformation, 421 in lesions of superior cerebellar peduncle, 402 in occlusion of anterior superior cerebellar artery, 516 Heart rate effect of cerebellar stimulations on, 291, 295, 297 during outbursts of sham rage, 295, 297 reflex influences on, affected by vermal lesions, 291 Heat stroke, cerebellar changes resulting from, 491-492 in Purkinje cells, 458, 491, 492 Hemangioblastoma, 553-556 appearance: gross, 555 microscopic, 556 associated cystic changes in lungs, pancreas, and kidney, 554, 563 classification, 528, 553 diagnosis vertebral arteriography as an aid in, 555 ventriculograms in, features of, described, .534 heredofamilial aspects of, 554, 562 incidence of, high, 553 mesenchymal origin of tissue, 556, 562 pathological changes in, 554, 562 related to antenatal developmental defect, 554 retinal involvement in, 554-555 surgical treatment, difficulties in, 556. 562

SUBJECT INDEX symptoms, 555 Hemichorea, in lesions of superior cerebellar peduncle, 402 Hemicerebellectomy decompensation of deficiency symptoms elicited by, after bilateral ablation of motor cortex (Luciani effect), 331 effect of: on absinth convulsions, 328-329 on excitability of contralateral motor cortex, 327-329 * in primates, 46-48 in subprimates, 38-46 never strictly unilateral, 38-39 Hemiplegia, in lesions of posterior inferior cerebellar artery, 400, 513 Hemisphere, cerebellar, unilateral loss of, in man, 434-436 Hemorrhage, cerebellar, 517—520; see also Extradural hematoma, cerebellar benign, 519 and cardiovascular disease, role of, 517 fatality of, 520 incidence of, 517 pathology, 517-518 surgical attack upon, 520 symptomatology, 519 traumatic, 525 Hepatolenticular degeneration, clinical similarity to myoclonic epilepsy and Ramsey-Hunt syndrome, 402 Hereditary cerebellar ataxia; see Spastic ataxia Hereditary cortical cerebellar atrophy; see Cortical cerebellar atrophy, familial or hereditary Hereditary spinal ataxia; see Spinal ataxia, hereditary Hereditary spastic paraplegia, 471, 472 Heredofamilial diseases; see Spinal ataxia, hereditary; Cortical cerebellar atrophy, familial or hereditary; Genetic studies Heterotopias of cerebellar cortex associated: with agenesis of vermis, 434 with bilateral cerebellar hypoplasia, 437 classified by Brun, 441 in posterior medullary velum, 547 simulating cerebellar tumors, 551-552 Histogenesis of cerebellar cortex, differences between animals born immature and those able to stand and walk at birth, 359-361 History of cerebellar physiology, 3-7 Hodgkin's disease, lymph node suspensions from, cerebellar effects, 488 Hook bundle relation to crossed fastigial atonia, 85; see also Nucleus fastigii, caudal part Russell's facilitatory influence of, on antigravity tonus of contralateral limbs, 85 retrograde degeneration of caudal pole of fastigial nucleus after postdecussational interruption of, 78 Hopping reaction

655

abnormal after chronic cerebellectomy, 35 affected by lesion of nucleus dentatus, 87 after section of spinocerebellar tracts, 89 lacking immediately after cerebellectomy, 35 transiently affected by ipsilateral lesion of interpositus nucleus, 86 Horner's syndrome in lesions of superior cerebellar peduncle, 402 in occlusion of anterior superior cerebellar artery, 516 partial, in lesions of inferior cerebellar peduncle, 401 Hunt syndrome; see Ramsey-Hunt syndrome Hydrocephalus and agenesis of vermis co-existing with, in man, 432-433 hereditary, in mice, 430, 431-432, 433 in Arnold-Chiari malformation, 421, 422, 423 in basilar impression, 419 fetal, role in production of cerebellar anomalies, 432, 433 internal frequency of, in cerebellar tumors, 531, 533 role of, in production of increased intracranial pressure, 529 Hydrocyanic acid poisoning, cerebellar deficiency after, 486 Hyperglycemia adrenalin discharges responsible for, elicited by mechanical stimulation of cerebellum, 301 after cerebellectomy or partial cerebellar lesions, 301 elicited by mechanical stimulation of cerebellum, 301 Hyperkinetic disorders, 413-415; see also Myoclonus, palatal and degeneration of basal ganglia, 476 in lesions of superior cerebellar peduncle, 402, 412, 413, 516 Hypermetria, 390, 391, 392; see also Dysmetria defined, 23 in frontal lobe tumors of cerebrum, 405 Hyperthermia, susceptibility of Purkinje cells to, 492, 493 heat stroke, 458, 491-492 malaria, 482 rheumatic fever, 491 Hypertonus (see also Alpha rigidity, Decerebrate rigidity, Dynamic phenomena, Release phenomena) extensor: after ablation of vermian part of the anterior lobe, 62 after bilateral fastigial lesion, 77-79 after complete ablation of anterior lobe in carnivores, 56—58 after complete cerebellectomy in carnivores, 24 after subtotal cerebellectomy in pigeon, 5, 14, 96 ipsilateral extensor, after cerebellar cortical lesions in pigeon, 16, 18-19 ipsilateral extensor and contralateral flexor, after unilateral decortication of vermian part of

656

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

anterior lobe, 78 ipsilateral flexor and contralateral extensor, after destruction of one fastigial nucleus, 77-79 Hypertrophy, cerebellar, simulating cerebellar tumor, 441, 551-552 Hypoglycemia and anoxia, parallelism of symptoms, 490 cerebral-cerebellar damage from, 490 Hypogonadal function, in suprasellar lesions, 404 Hypometria, 392; see also Dysmetria defined, 23 Hypoplasia, 436-440, 444 bilateral, in man associated with other central nervous system defects, 436 atypical examples, cited, 438 difficulty of distinguishing from atrophies, 438, 444, 449 histopathology summarized, 436-438 familial in cats, 438-439 cerebellar deficiency syndrome, similarity to that after cerebellar ablation, 438 pathological changes in, 439 in calves, 439-440 unilateral, 440, 464; see also Crossed cerebellar atrophy in cat, compared to effect of unilateral ablation in dog, 440 unusual without involvement of cerebral cortex, 440 Hypotension, arterial, effect on electrical activity of cerebellar cortex, 162 Hypothalamus electrical activity of, influenced by stimulation of anterior lobe, 299 indirect evidence of functional relations with cerebellum, 295, 298 Hypotonia (see also Atonia, Fastigial atonia) after lesion of nucleus dentatus, 87 after section of spinocerebellar tracts, 89 after unilateral ablation of lobulus ansoparamedianus, 65—66 cerebellar division responsible, in man, 380 as clinical symptom of damage to posterior lobe, described, 388-389 clinical tests for, discussed, 354-355, 357-358 defined, 23 fastigial mechanisms of, in carnivores, 100-101 in frontal lobe cerebral tumors, 405 hypothesis of neocerebellar origin of, in primates, 99; see also Neocerebellum and paleocerebellum ipsilateral extensor, after unilateral lesions of avian cerebellum involving deep nuclei, 19,97 in lesions of superior cerebellar peduncle, 401 due to medulloblastoma, 531 due to occlusion of anterior superior cerebellar artery, 516 in occlusion of posterior inferior cerebellar artery, 513

relation to disorders in sphere of voluntary movements, 353-358 relative frequency of symptom, 379 role in decomposition of movement, 392 role in static tremor, 389 Imbecility in cerebellar agenesis, 424, 426, 427 in cortical cerebellar atrophy in infants, 449 Implanted electrodes, cerebellar stimulation with, 139-141 Incoordination, cerebellar; see Ataxia, cerebellar Infants Arnold-Chiari malformation in, case of, 421 cerebellar aplasia in, case of, 426 cerebellar hypoplasia in, case of, 436 extradural cerebellar hematoma in, case of successful evacuation of, 523 heredofamilial cortical cerebellar atrophy in, 449-451 medulloblastoma in, case of, 542 Infections, cerebellar involvement in (see also specific infections) acute, 480-485 chronic, 494-498 Inferior olive; see Olive, inferior Infratentorial extracerebellar lesions, 390-403 distinguished from supratentorial, by labyrinthine tests, 398 Inhibition crossed proprioceptive, as reflex mechanism contributing to Luciani's atonia after unilateral cerebellar lesions, 98 underlying fastigial atonia, 265-268 of Purkinje firing by excessive membrane depolarization (inhibition by inactivation), 170—171 by membrane hyperpolarization, 170, 171 Inhibitory area coinciding with spinal story of cerebellum, 114 map of, in cat's cerebellum, 116 Inhibitory function of cerebellum, Wagner's hypothesis on, 6 Inhibitory response crossed, elicited by electrical stimulation of vermal part of anterior lobe, neural mechanisms responsible for, 136 elicited by cerebellar stimulation arising from vermian part of anterior lobe and from pyramis, 114 contralateral spread of, obtained by increasing rate or intensity of stimulus, 127, 136 on background of decerebrate rigidity, 113-117 predominantly ipsilateral, 113—117 present: after midline splitting of vermis, 149 after postcollicular decerebration, 149 reversed after ipsilateral lesion of rostrolateral fastigial nucleus, 131-134 Insulin shock cerebral damage from, 490 status epilepticus, cerebellar type, seen in, 410

SUBJECT INDEX Integration between alpha and gamma mechanism, cerebellar influence on, 356 between cerebral and cerebellar mechanisms, 357 Interposite nucleus; see Nucleus interpositus Interpositofastigial system, 248-249 Interpositorubrospinal paths, 137 Intracellular recording from avian cerebellar cortex, 160, 162 from mammalian cerebellar cortex, 168-171, 217 Intracerebellar connections between culmen and paramedian lobule, 235 between culmen and pyramis, 235 between lobulus centralis and paramedian lobule, 235 between lobulus centralis and pyramis, 235 Intracortical dysplasias, 441 Intracranial pressure, increased in cerebellar abscess, 505 due to suprasellar lesions, cerebellar symptoms resulting from, 403 false localizing symptoms due to, 400 "frontal ataxia" due to, 405, 406, 407 fulminating syndrome of, in extradural cerebellar hematoma, 523 importance of, as chief manifestation of cerebellar tumors, 528-529, 538, 543, 560, 562 resulting from atresia of foramina of Luschka and Magendie, 432 role of, in production of symptoms in lead poisoning, 486 seizures related to, 410 skull films in identification of, 532, 543, 562 Intraventricular tumors; see Tumors, intraventricular Ipsilateral flexor reflex, effects of electrical stimulation of anterior lobe on, 117-119, 131, 151 Ischemia, differential effects of, on waves and spike discharges of cerebellar cortex, 168 Jackson's "cerebellar fits," 408—411, 415; see also Cerebellar seizures Juxtarestiform body, section of (see also Cerebellar peduncle, inferior) effect on head position, difficulties in interpreting, 91, 382-383 intramedullary part of, 91 supramedullary part of, 90 Knee jerk (see also Reflexes) increased ipsilaterally after hemicerebellectomy, 41-42, 65 inhibited by electrical stimulation of anterior lobe, 117, 126 less easily inhibited than decerebrate rigidity by cerebellar stimulation, 117 pendular character of, after ablation of lobulus ansoparamedianus, 64 silent period of, increased by electrical stimulation of anterior lobe, 117 Kyphoscoliosis, in Friedreich's ataxia, 467

657

Laboratory counterparts of clinical conditions; see Correlations between clinical and laboratory data Labyrinth, galvanic stimulation of affecting in reciprocal fashion spike discharge of ipsilateral and contralateral Deiters' nucleus, 230 effect on rostrofastigial spike discharge, 237-238 Labyrinthectomy in adult pigeon, conflicting statements on alteration of Purkinje cells after, 272-273 bilateral abolition of opisthotonos in cerebellectomized animal after, 28, 275; see also Eighth nerve effects of lesions of flocculonodular lobe after recovery from, 56 and deafferentation, rebound posture after cerebellar stimulation not abolished by, 147 partial, in newborn pigeon, disappearance of outer granular layer delayed by, 361 unilateral rotated head posture after, 383, 384 similarity to section of Juxtarestiform body, 91 Labyrinthine reflexes kinetic, relation to cerebellum, 287-290 modified by unilateral cerebellar lesions, 272 present after cerebellectomy, 271, 273 static effect of, on postural responses to cerebellar stimulation, 122-123 relation to cerebellum, 273-287 and swimming, in cerebellectomized animal, 273 tonic, 273-282 crossed inhibitory influence of, effect on alpha rigidity, 279 importance of, in maintenance of extensor rigidity in decerebro-cerebellate preparation, 275 not essential in maintenance of extensor rigidity of decerebrate preparation, 275 release of, after cerebellectomy yielding opisthotonos, 28, 275 Labyrinthine system, relation of to anterior lobe, 246 to cerebellum, 271-290 old experiments and theories on, 271-273 to flocculonodular lobe, 52-56, 246 Labyrinthine tests (Barany's), reliability of, 398 Labyrinthine tonus, Ewald's doctrine of, 272 Labyrinthitis, acute suppurative, and otogenic cerebellar abscess, differential diagnosis, 505, 506 Laceration, cerebellar after gunshot wounds, 381, 521-522 posterior lobe as principal site of injury, 386 symptomatology, Holmes's classification, 388396

and closed head injuries, 522, 525 of posterior vermis, case of selective damage, 381, 522

658

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

severe, permanence of deficiency after, 522 and vertigo, 522-523 Laryngeal movements, after cerebellar lesions, 61; see also Laryngeal nerve normal in cerebellectomized dog, 26, 27 Laryngeal nerve, single-shock stimulation of, evoked cerebellar potentials after, 191 Larynx, rhythmic myoclonus of, 413-414 Late cortical cerebellar atrophy, 452-454 Latent period of augmentatory response to cerebellar stimulation, 134 of inhibitory response to cerebellar stimulation, 134 Lateral parts of corpus cerebelli (see also Posterior lobe of corpus cerebelli) involved in agenesis of the vermis, 430 lesions of, 378, 386-396, 522 and cerebellar deficiency syndrome in man, 380 and upper extremity dexterity, 380 as site of astrocytoma, 530 Lead poisoning, symptomatology of, 486 Lengthening reaction, effect of, on sign and intensity of postural response to cerebellar stimulation, 123-124 Lesions; see Cerebellar lesions, Extracerebellar lesions, etc. Lingula ablation of, in primates, 63 electrical stimulation of in decerebrate cat, 125 tail responses to, 125 evoked potentials from, after single-shock stimulation of eighth nerve, 202 Lobar dysplasias, 441 Lobular dysplasias, 441 Lobules I, II; see Lingula Lobule III; see Lobulus centralis Lobules I-V; see Anterior lobe, experiments on (entries involving vermian part) Lobules I-V. H I-H V; see Anterior lobe, experiments on Lobules IV, V; see Culmen Lobules H I-H V; see Anterior lobe, experiments on (entries involving intermediate part) Lobules VI, H VI; see Lobulus simplex Lobule VII; see Folium vermis, Lobulus medius medianus, Tuber vermis Lobule H Vila; see Lobulus ansiformis Lobules H Vila & b, H Villa; see Lobulus ansoparamedianus Lobules H Vllb, H Villa; see Paramedian lobule Lobule VIII; see Pyramis Lobule IX; see Uvula Lobules H Vlllb, H IX; see Paraflocculus Lobules X, H X; see Flocculonodular lobe Lobule X; see Nodulus Lobule H X; see Flocculus Lobulus ansiformis (see also Crus I. Crus II) ablation of, 67-69

effect on tactile placing reactions, 342-344 chemical stimulation of, effect on electrocorticogram, 325 evoked potentials from after single-shock stimulation of pons, 202 after visual stimulation, 188-189 relation to autonomic areas of cerebral cortex, 209 Lobulus ansoparamedianus, ablation of in primates, 66-67 in subprimates, 64-65 Lobulus centralis ablation of combined with ablation of areas 4 and 6 in primates, 63 in subprimates, 61 release of alpha rigidity after, in deafferented limbs of decerebrate carnivore, 274 of postcollicular preparation, 280 electrical stimulation of in decerebrate cat, 125 in mammals, 125-127, 131-134 response of ipsilateral hindlimb to, 125 evoked potentials from: after hindlimb stimulation, 184 after single-shock stimulation of hindlimb region of primate area 4, 206-207 inhibition of alpha rigidity by, through cerebellofastigiobulbar paths, 280 Lobulus medianus posterior ablation of, 52-53, 57 Bolk's; see Lobule VII-Lobule X electrical stimulation of, effect on electrical excitability of motor cortex, 311, 316 Lobulus medius medianus ablation of, 70 electrical stimulation of, 1S8 Ingvar's; see Lobule VII Lobulus paramedianus; see Paramedian lobule Lobulus petrosus; see Paraflocculus Lobulus posterior medianus ablation of, 53 Ingvar's; see Lobule VIII—Lobule X Lobulus simplex ablation of, 67 electrical stimulation of, 137 effect on cortically induced movements, 321322 evoked potentials from: after auditory stimulation, 186 after face stimulation, 184 after single-shock stimulation: of face region of primate area 4, 207 of nerves, 189-191 of pons, 202 of somatotopic area I, 208 after visual stimulation, 186 responses of cerebral cortex to single-shock stimulation of, 234 Lobus anterior; see Anterior lobe, experiments on Lobus flocculonodularis; see Flocculonodular lobe

SUBJECT INDEX Localization, somatotopic; see Somatotopic localization Localization of function, cerebellar, 51, 154 clinical evidence for, 378-379, 380 Looping ill, 482-484 disease of sheep, 482 human counterparts of, 483 induced in monkeys, 482, 484 selective damage to Purkinje cells in, 482, 483, 493 Luciani effect; see Motor cortex Lues, congenital; see Syphilis, congenital Lymphomas, effect of intracerebral injection of, on Purkinje cells, 458 Macrogyria, 441 Macular receptors, function of, 273 Macular reflexes, response to linear acceleration, effect of cerebellectomy on, 290 Magnet reaction absent when dog is placed in dorsal position, 30 as exteroceptive component of supporting reaction, 30 described, 30-31 increased in chronically decerebellate dog, 30-31 inhibition of, by dorsal skin reflexes, decreased following cerebellectomy, 244 Magnus's reflexes (see also Cervical reflexes, Labyrinthine reflexes) absent in acutely deafferented forelimbs, 257 alpha and gamma motoneurons affected by, 257 effects of, on sign and intensity of postural response to cerebellar stimulation, 120-122 present: in chronically deafferented forelimbs, 257 in forelimbs after acute deafferentation and postbrachial transection of spinal cord, 257 released following cerebellectomy, 28, 275-276 response of alpha motoneurons to, selectively abolished by acute deafferentation of limb, 257 Malaria, cerebellar involvement in, 480-482 delayed appearance of ataxia in, 480 pathological changes, capillary, 481, 482, 493 reversibility of signs, 481 role of anoxia in, 489 Malformations, angiomatous, 552-553 Malformations, cerebellar; see Arnold-Chiari malformation; Basilar impression of the occipital bone; Developmental anomalies of the cerebellum; Dysplasia, cerebellar; Hypoplasia Malpositions, correction of after hemicerebellectomy, 43 after unilateral lesion of nucleus interpositus, 86 after unilateral section of spinocerebellar tracts, 89 and problem of "muscle sense" alterations after cerebellectomy, 42-43, 345 Manganese, intoxication with, in monkey, 486 Map of evoked potentials

659

in avian cerebellum, 161 in cerebral cortex, after single-shock stimulation of cerebellar cortex, 234, 236 in mammalian cerebellum after single-shock stimulation: of cerebral cortex, 207-208, 210 of sensory nerves, 190, 193-194 elicited: by auditory volleys, 187 by proprioceptive volleys, 184 by tactile volleys, 186 by visual volleys, 187 Marie's cerebellar ataxia; see Spastic ataxia Masticatory movements, normal in cerebellectomized dog, 26, 27 Mayer's waves, effect of cerebellar stimulations on, 293-295 Mechanical stimulation of avian cerebellum, 106 of mammalian cerebellum, 109-110, 140 Medial part of corpus cerebelli disturbances resulting from involvement of, 385386 fatality of wounds involving, 386 responsibility for symptoms of cerebellar deficiency, 380 Medulloblast, embryological basis for identification of, 546-547 Medulloblastoma, cerebellar, 541-548 and "cerebral medulloblastoma," distinguished, 542 gross appearance, 543-545 importance of seeded plaques as a characteristic, 544 histogenesis, question of, 542, 546-547, 562 incidence, by age and sex, 542 location, 381, 530, 541, 542 microscopic appearance, 545-546 operative mortality, high, 543, 547 posterior fossa tumors of similar appearance but benign course, 543 radiology in treatment of, 547, 562 tendency to spread via subarachnoid spaces, 541, 562 two syndromes of flocculonodular lobe, 381 difficulty of distinguishing from astrocytoma, 537 of posterior lobe, 543 Meningioma, cerebral, cerebellar symptoms in, 405 Meningiomas classification, 528 frequency, 553 location, rarely cerebellar, 560, 563 symptomatology, 560 Meningomyelocele; see Myelomeningocele Mental symptoms as false localizing signs, 532 in familial cortical cerebellar atrophy, 447, 449 in hereditary spastic ataxia, 469 in olivopontocerebellar atrophy, 461 in subacute cortical cerebellar degeneration, 456 in subtentorial tumor, 531

660

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

Mercury poisoning, cerebellar symptomatology of, in men and rats, 488 Metabolism, effect of cerebellar ablations on, 303 Metastasis of cerebellar tumors extracranial, unusual cases of medulloblastoma, 545 glioblastoma multiforme, 549 rarity of. 528 Metastatic tumors, intracranial, 559 Methyl chloride intoxication, reversal of inhibitory cerebellar response after, 134 Microgyria, 441 Micturition reflex, effect on of cerebellar ablation, 306 of cerebellar stimulation, 307 Midbrain evoked potentials from, after single-shock stimulation of cerebellar cortex, 232-234 response elicited from medial strip of intermediate part of anterior lobe abolished after midline splitting of, 137 Midbrain relays, not essential for cerebellar inhibition of extensor rigidity, 134, 149-150, 280 Molecular layer microelectrode recording from, 167 neural spread of activity through fibers of, 175 Mongolian idiocy, cerebellar changes in, 441—442 Morphine, selective abolition of gamma rigidity by, 260 Morphology of cerebellum, 431; see also Divisions of cerebellum Mortality, operative in Arnold-Chiari malformation, 423 in basilar impression, 419 in posterior fossa explorations, 404 Motion sickness abolished by ablation of nodulus, 54 relation to cerebellar areas, 54, 305 Motor activities, ipsilateral, Rolando's views on cerebellar regulation of, 4 Motor asymmetries, after localized cerebellar lesions, 73-77; see also Phasic asymmetries Motor cortex bilateral ablation of decompensation: of cerebellar deficiency (Luciani's effect) after, 331 of fastigial atonia after, 332 inhibition of induced movements after, elicited by electrical stimulation of vermian part of anterior lobe, 316-318 chloralose movements from, facilitated by electrical stimulation: of crus I or crus II, 313-315 of vermian part of anterior lobe, 312-316 chronaxic measurements of, effect of cerebellar cortical stimulations on, 311 clonic movements after local strychninization of experiments suggesting cerebellar inhibition at cortical levels, 319-321 facilitated during electrical stimulation of vermian part of anterior lobe, 312-314 inhibited by stimulation of vermian part of

anterior lobe, 316-319 reciprocal innervation during cerebellar stimulation, 313-315 evoked potentials from, after single-shock stimulation of anterior lobe and lobulus simplex, 235 movements elicited by electrical stimulation of facilitated by cerebellar stimulation, 321-322 inhibited by cerebellar stimulation, 316-317, «J01_QOO *J£tAi

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not grossly modified by cerebellectomy, 329 subliminal strychninization of, facilitation of convulsive corticofugal discharge elicited by, during electrical stimulation of vermian part of anterior lobe, 313-314 threshold of, to electrical stimulation decreased during stimulation of contralateral cerebellar hemisphere (Rossi effect), 311, 316 effect on: of contralateral hemicerebellectomy on, 327-329 of localized cerebellar cortical ablations, 328-329 Motor seizures; see Cerebellar seizures Motor unit; see Alpha motoneurons Movements generalized, in cerebellectomized monkey, 37 isolated, skilled, in cerebellectomized monkey, 37 voluntary compound, in clinical cases of cerebellar deficiency, 37 Multiple representation of muscular districts in cerebellar cortex, 77 Multiple sclerosis Bruns syndrome in, 403 cerebellar changes in, 477 Mumps, cerebellar damage in, 484, 493 Munk's Beriihrungsreflex abolished: after ablation of contralateral motor cortex, 339 temporarily, after cerebellectomy, 339 as manifestation of placing reaction, 339 Muscle spindles abnormal gamma regulation of, and cerebellar dysmetria, 346 afferent discharge from criteria for identifying, 256 influenced by cerebellar cortical stimulations independently of conventional postural responses, 256 transmission of, to cerebellum, through specialized units of dorsal spinocerebellar tract, 218 behaving passively after anatomical lesion or functional inactivation of cerebellum, 257259 gamma regulation of, influenced by cerebellum, 255-262 Muscle tetanus, after chronic hemicerebellectomy decreased amplitude of, 269, 270 increase of fusion rate in, 269

SUBJECT INDEX Muscular sense, theories on cerebellar influence of, 42-43 Muscular weakness; see Asthenia, as symptom of cerebellar deficit Myanesin, different effects of, on cerebellar and reticular inhibition, 151 Mycosis; see Fungicitic infections of the cerebellum Myelinization, relation of to appearance of evoked cerebellar responses to single-shock stimulation of cerebral cortex, 367 to development of tonic activity of fastigial nucleus. 363-366 Myelography, in diagnosis of platybasia, 420 Myelomeningocele and developmental anomalies of cerebellum, 426 role in Arnold-Chiari malformation, 418, 421, 422, 423 Myoclonic cerebellar dyssynergia; see RamseyHunt syndrome Myoclonic epilepsy histopathological findings, reviewed, 412 and Ramsey-Hunt syndrome, 402, 411 relation to cerebellar disease, 411-413 Myoclonus, palatal, 413-415 and brain stem damage, 412, 413 involvement of other muscles in, 413 laboratory counterparts of, 415 and lesions of superior cerebellar peduncle, 402, 516 mechanism, 413, 415 and pseudohypertrophy of inferior olive, 413415 Myosis; see Ocular disturbances Nembutal, local application of, on mammalian cerebellar cortex surface-negative component of evoked response after, 211 surface-negative potential shift elicited by sensory stimulation after, 216 Neocerebellar Syndrome, 388; see also Posterior lobe of corpus cerebelli Neocerebellum and paleocerebellum Bremer's hypothesis on functional role of neocerebellum, 99, 100 classification of developmental anomalies based upon concept of, 417, 431 Edinger and Comolli's distinction between, 51 experimental findings in conflict with, 204—207, 234-235, 247-249, 316, 323-325 Neoplasms; .tee Tumors, cerebellar Nicotine, effect of injections of, into cerebellum, 111 Nictitating membrane, response of, to cerebellar stimulations, 138, 303-304 Nociceptive stimulation, behavioral response to, decreased after ipsilateral ablation of one cerebellar hemisphere or ipsilateral destruction of one dentate nucleus, 345 Nodulus evoked potential from, following single-shock

661

stimulation of eighth nerve, 202 resemblance between animals and patients with lesions of, 381 role of, in mechanism responsible for motion sickness in dogs, 54, 383 as site of medulloblastoma, 530, 542 total ablation of in dog, and motion sickness, 54, 383 in guinea pig, effect on otolithic reflexes, 54 in primates, 55-56 in subprimates, 54-55 unilateral ablation of effect on head posture in monkey, 383, 384 horizontal nystagmus after, 383 Nomenclature; see Terminology Novocaine atonia, reversal of fastigial atonia of contralateral limb elicited by, 267 Nuclear atrophy, cerebellar; see Cerebellar nuclei Nuclei, cerebellar; see Cerebellar nuclei, Nucleus dentatus Nuclei, deep cerebellar, secondary alterations in, after corticocerebellar lesions, 53, 72 Nuclei, subcerebellar, secondary degeneration of, in relation to developmental concepts, 433-434 Nucleus dentatus destruction of, complete, in occlusion of anterior superior cerebellar artery, 516 electrical stimulation of, in decerebrate cat, 142146 involvement of in frontal ataxia, role in producing cerebellar signs, 406 in hereditary spinal ataxia, 468, 472 in medulloblastoma, 530 more frequent in subacute than chronic cortical cerebellar atrophy, 457, 463 isolated atrophy of, little evidence for, 463 proneness of, to cell changes, in many clinical diseases, 485 role in certain hyperkinetic syndromes, 402, 415 in myoclonic epilepsy, 412 in palatal myoclonus, 413, 415 role in static tremor and myoclonia, 389-390 symmetrical calcification of, 477-478 unilateral lesion of effect on placing and hopping reactions, 87, 343 in primates, 87-89 in subprimates, 87 Nucleus fastigii bilateral acute lesion of, in decerebrate cat, 81 bilateral chronic lesion of enhancement of tactile placing reaction after, 343 with the rest of nervous system intact, 77-79, 343 caudal part chronic destruction of, with rest of nervous system intact, 79 collapse of decerebrate rigidity in contralateral limbs after lesion of, 81

662

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

ipsilateral inhibition and contralateral increase of decerebrate rigidity yielded by electrical stimulation of, 147-148 projected upon by uvula and pyramis, 85-86, 154 retrograde degeneration of, after postdecussational interruption of Russell's hook bundle, 78 symmetrical distribution of decerebrate rigidity after bilateral lesion of, 85 chronic bilateral lesion followed by decerebration, postural responses to electrical stimulation of anterior lobe after, 137 electrical stimulation of autonomic effects in thalamic cat, 297-298 in conscious cats, 141 in decerebrate cat, 142, 143, 147 EEG arousal elicited by, 323-324 in kitten functionally active before overlying vermal cortex of anterior lobe, 364 relation between functional development and myelinization, 364-366 postural responses to electrical stimulation of vermian part of anterior lobe abolished by bilateral destruction of, 137, 148 responses from: to single-shock stimulation of eighth nerve, 202 to vestibular stimulation, 182 rostral part chronic destruction of, with rest of nervous system intact, 79-80 ipsilateral decrease of decerebrate rigidity elicited by lesion of, 81 postural responses to electrical stimulation of vermian part of anterior lobe abolished by destruction of, 148 units of: affected by galvanic stimulation of labyrinth, 237 affected by single-shock stimulation of nerves, 237 facilitated by galvanic stimulation of culmen, 237 inhibited by galvanic stimulation of culmen, 237 unaffected by galvanic stimulation of culmen, 237 rostrolateral part ipsilateral release of decerebrate rigidity elicited by lesion of, after chronic destruction of caudal halves of both roof nuclei, 86 relays for inhibitory volleys arising from ipsilateral vermian cortex of anterior lobe localized in, 86, 132, 152 reversal of cerebellar cortical inhibition after lesion of, 131-134 rostromedial part ipsilateral decrease of decerebrate rigidity elicited by lesion of, after chronic destruction of caudal halves of both roof nuclei, 86 relays for facilitatory volleys arising from

vermian cortex of anterior lobe localized in, 86, 132-134, 153 unilateral acute lesion of, in decerebrate cat, 80 unilateral chronic lesion of, with rest of nervous system intact, 77-79 Nucleus interpositus acute lesion of, after decerebration responses from intermediate part of anterior lobe abolished by, 137, 148 responses from vermian part of anterior lobe not affected by, 132, 148 electrical stimulation of enhancement followed by poststimulatory extinction of tactile placing reactions during, 343 in decerebrate cat, 142, 146—147 ipsilateral increase of extensor rigidity elicited by stimulation of, still present after postcollicular decerebration, 150 rostral part permanent abolition of ipsilateral tactile placing reactions after chronic lesion of, 343 postural responses to electrical stimulation of ipsilateral intermediate part of anterior lobe abolished by lesion of, 137, 153 rostrolateral part, postural response to electrical stimulation of lateral strip of intermediate part of anterior lobe abolished by lesion of, 137 rostromedial part, postural response to electrical stimulation of medial strip of intermediate part of anterior lobe abolished by lesion of, 137 unilateral chronic lesion of effect on hopping reactions, postural tonus and gait, 86 followed by decerebration, 87 permanent abolition of ipsilateral placing reactions after, 86 Nutritional defects, cerebellar symptoms from, 490491 Nystagmus after acute cerebellar injuries in man, distinguished from labyrinthine nystagmus, 383, 505 cerebellar division responsible, 380 in extracerebellar lesions, 400, 402 frontal lobe tumors, 404, 405 frequency as clinical symptom. 379 galvanic changes after asymmetrical flocculonodular lesions, 287 changes after cerebellectomy, 287-288 horizontal, after unilateral nodular ablation, 383 not seen after lesions of corpus cerebelli, 383 positional, during labyrinthine hyperexcitability elicited by cerebellar ablations, 288-289 postrotatory increased after cerebellar lesions, 287 loss of habituation of, elicited by cerebellar lesions, 289-290 as sign of cerebellar dysfunction

SUBJECT INDEX in Arnold-Chiari malformation, 422 in cortical cerebellar atrophy familial, 446 subacute, 455 frequent, in tuberculoma, 496 important, in cerebellar abscess, 505 in myoclonic epilepsy, 411 spontaneous absent after total cerebellectomy, 27, 288 more frequent after asymmetrical cerebellar lesions, 288 relation to imbalance between vestibular nuclei elicited by asymmetrical cerebellar lesions, 288, 289 in syndrome of flocculonodular lobe in man, 383-384 in syndrome of occlusion of cerebellar arteries, 513, 516 vertical, after lesions of posterior vermis, 383 Nystagmus, labyrinthine, distinguished from cerebellar, 383, 505 Nystagmus of the palate; see Myoclonus, palatal Occipital bone, basilar impression of, 418-420 Occipital lobe of cerebrum, cerebellar symptomatology in lesions of, 406 Occlusion of cerebellar arteries; see Arteries, cerebellar, occlusion of of cerebellipetal volleys arising from different cutaneous areas, 216-217 belonging to different sensory modalities, 217 elicited by single-shock stimulation of nerves and of sensory cortex, 217 of evoked potentials, functional significance of, 251 Ocular disturbances (see also Nystagmus. Pupils, Visual field) in Arnold-Chiari malformation, 421 in Bruns syndrome, 403 choked disc, as symptom in cerebellar tumors, 529, 530 hemangioblastoma, 555 medulloblastoma, 543 tuberculoma, 496 in extradural cerebellar hematomas, 524 not invariable, in cerebellar abscess, 505 deviation of eyes, in "cerebellar fits," 409 double vision, in cerebellar tumors, 531, 543 external strabismus, in cerebellar tumors, 531 in generalized subacute cortical cerebellar atrophy, 455 in hereditary spastic ataxia, 469 importance of, in astrocytoma, 538, 548 in intra- and extracerebellar lesions, 400 myosis after occlusion of posterior inferior cerebellar artery, 513 in lesions of inferior cerebellar peduncle, 401 papilledema, as early sign in cerebellar tumors, 530, 531 paralysis of conjugate movements of eyes in cere-

663

bellar abscess, 505 retinal in amaurotic familial idiocy, 474 in hemangioblastoma (angiomatosis of retina), 554 retinitis pigmentosa, involved in hereditary spinal ataxia, 466 in suprasellar lesions, 404 Ocular movements (see also Nystagmus) cerebellar cortical areas yielding, overlapping with visual projection areas, 152, 245 conjugate, elicited: by cerebellar cortical stimulations, 138 by stimulation of cerebellar nuclei, 143 normal in cerebellectomized dog, 26, 27 Oculocardiac reflex, effect of vermian ablation on, 291 Olfactory loss, as cerebellar symptom, 400 Oligodendroglioma, 550—551 cerebral, marked tendency toward calcification, 551 rarity of, 551 Olive, inferior damage to concomitant with cortical cerebellar atrophy, 446, 447, 449, 452, 454, 458 laboratory counterparts of, 415, 439, 462 linked with myoclonus, 412 pseudohypertrophy of in occlusion of anterior superior cerebellar artery, 515 role in palatal myoclonus, 413-415 single-shock stimulation of, cerebellar cortical responses to, 201-202 Olivopontocerebellar atrophy, 459-462 in cat, 439, 462 as clinicopathological entity, 460-461, 479 pathology, 462 symptoms, 461 frequent involvement of other parts of nervous system, 459, 462 of basal ganglia, 476 and hereditary cerebellar ataxia, 468, 469, 472 links with cortical atrophy, 446, 447, 449, 452, 453, 454, 458, 459 and Wilson's disease, 476 Operative mortality; see Mortality, operative Opisthotonos abolished: by bilateral labyrinthectomy, 28 by bilateral section of eighth nerve, 277-278 absent: after bisection of cerebellum in subprimates, 49 after Sherringtonian decerebration, 275, 283 after Sherringtonian decerebration combined with postbrachial transection of spinal cord, 276-277 after ablation: of anterior lobe in primates, 5859 of anterior lobe in subprimates, 56-58 of Bolk's lobulus medianus posterior, 52, 53, 57 after subtotal cerebellectomy in birds, 5, 14

664

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

after total cerebellectomy in subprimates, 24-27 after vermian ablation in subprimates, 48 in "cerebellar fits," 408 compensation of: after ablation of anterior lobe, 56, 57 after chronic bilateral fastigial destruction, 285 after total cerebellectomy, 285 decompensation of cerebellar, after postbrachial transection of spinal cord, 285 extreme, after decerebration and cerebellectomy performed with anemic methods, 27—28, 275 present: after anemic decerebration, 283 after Sherringtonian decerebration combined with bilateral destruction of fastigial nucleus, 276-277 Optic lobes, in birds effect of cerebellar stimulation on clonic movements elicited by local strychninization of, 109 in transmission of visual impulses to cerebellum, 160 Oscillations, uncontrolled, in totally cerebellectomized dog, 29 Osteitis deformans, and basilar impression, 419 Osteogenesis imperfecta, and basilar impression, 419 Otitis, chronic suppurative, role in cerebellar abscess, 498, 499-503, 507 Otitis interna, chronic nonsuppurative, rotated head posture in, 382 Otogenic brain abscesses (see also Cerebellar abscess) cerebral and cerebellar abscess frequency of, compared, 498, 499 signs of, time of onset compared, 505 criterion for distinguishing site, 406 headache as symptom, 505 Otolithic reflexes, altered by nodulus ablation in guinea pig, 54; see also Labyrinthine reflexes Paget's disease, 419 Pain, sense of; see Sense of pain, loss of Palatal myoclonus; see Myoclonus, palatal Palatal weakness, after occlusion of posterior inferior cerebellar artery, 513 Paleocerebellar Syndrome, 378, 385; see also Anterior lobe of corpus cerebelli first described, 5 Paleocerebellum; see Neocerebellum and paleocerebellum Papilledema, as early sign of cerebellar tumor, 530, 531 Paraflocculus ablation of, 71 electrical stimulation of, 139 evoked responses from, after single-shock stimulation of pons, 202 Paramedian lobule ablation of, 69

electrical stimulation of, 138 effect: on electrical excitability of motor cortex, 311, 316 on cortically induced movements, 321 evoked potentials from after single-shock stimulation: of nerves, 191, 217 of pons, 202 of somatosensory cerebral cortex, 208-209, 217 after visual stimulation, 188 occlusion phenomena between, 217 responses of cerebral cortex to single-shock stimulation of, 235, 236 Parasitic involvement of the cerebellum, 508 and Bruns syndrome, 402-403 Paresthesia, in lesions of superior cerebellar peduncle, 402, 516 Parietal lobe of cerebrum, cerebellar symptomatology in lesions of, 406 Parkinsonism, 476 arrhythmokinesis, role of, in differential diagnosis, 394 in familial cortical cerebellar atrophy, 448, 476 overlap with olivopontocerebellar atrophy, 459 Parkinsonian rigidity, in case of late cortical cerebellar atrophy, 453, 476 Past-pointing, as symptom of cerebellar disorder cerebellar division responsible, 380 in differential diagnosis of cerebellar abscess and labyrinthine disease, 505 how demonstrated, 390 relative frequency as symptom, 379 Peduncles; see Cerebellar peduncle, inferior; middle; superior; Cerebellar peduncles Pendular knee jerk after ablation of lobulus ansoparamedianus, 64 cerebellar division responsible, 380 as clinical symptom of damage to posterior lobe, described, 388 relative frequency as symptom, 379 Penicillin, in control of otogenic brain abscess, 504 Pes cavus, in Friedreich's ataxia, 467 Phasic asymmetries after localized cerebellar lesions in mammals, 7377 after unilateral lesions in birds, 18 cerebellar inhibition of, during curare atonia, 118-119 Phonation; see Speech, disturbances of Phylogenesis, cerebellar, 431 Physiological and clinical data, correlations; see Correlations between clinical and laboratory data Pick's disease, and cerebellar atrophy, 475 Placing reactions abolished by decortication, 340 absent in newborn animal, 340 and conditioned reflexes, 339-340 effect on, of ipsilateral destruction: of nucleus dentatus, 87

SUBJECT INDEX of nucleus interpositus, 86 effect of section of spinocerebellar tracts on, 89 tactile abolished: in carnivores by contralateral ablation of sigmoid gyrus, 340 in primates by contralateral ablation of postcentral gyrus, 340 effect of unilateral lesions of lobulus ansiformis on, 343-344 enhanced after ablation of vermian or intermediate cortices of anterior lobe or after destruction of fastigial nucleus, 343 permanently abolished after lesion of rostral part of ipsilateral interpositus nucleus or of dentate nucleus, 86-87, 343 temporarily abolished by cerebellectomy, 340342 visual, impaired by cerebellectomy, 340 Platybasia; see Basilar impression of the occipital bone Pleurothotonos, after unilateral cerebellectomy, 39 Pneumoencephalography as aid in diagnosis of cerebellar maldevelopment, 442-443 in study of cerebellar disease, 398 contraindicated: in cases of otogenic cerebellar abscess, 506 in cases of increased intracranial pressure, 532 not recommended, in diagnosis of cerebellar tumors, 533 Poliomyelitis, cerebellar damage in, 484 Polygyria, 441 Pons, cerebellar cortical responses to single-shock stimulation of, 202 Pontine gliomas, 399-400 and intracerebellar and brain stem lesions, differential diagnosis of, 400, 407, 559 Position of cerebellum, abnormalities in; see ArnoldChiari malformation Positive supporting reaction; see Supporting reaction, exaggerated Postbrachial transection of spinal cord appearance of alpha rigidity in deafferented forelegs of decerebrate cat after, 262, 273-274, 276 decompensation of cerebellar release symptoms after, 285-287 reappearance of Magnus's reflexes in acutely deafferented forelimbs of decerebrate cat after, 257 without effect on forelimb fastigial atonia, 268 Postcollicular decerebration augmentatory and inhibitory responses to electrical stimulation of vermian part of anterior lobe present after, 134, 149 increase of extensor rigidity after, 149-150 ipsilstteral active flexion elicited by stimulation of medial strip of intermediate part of anterior lobe abolished by, 137 ipsilateral increase of extensor rigidity elicited by stimulation of lateral strip of inter-

665

mediate part of anterior lobe present after, 137 ipsilateral increase of extensor rigidity elicited by stimulation of nucleus interpositus present after, 150 tonic cerebellar inhibition of alpha rigidity present after, 280 Posterior lobe of corpus cerebelli (see also Folium vermis, Lateral parts of corpus cerebelli, Lobulus ansiformis, Paraflocculus, Paramedian lobule, Tuber vermis, Pyramis, Uvula) disturbances resulting from involvement of, 378, 386-396 clinical symptomatology, 388-396 Holmes's classification, 388, 390 involved in agenesis of vermis, 431 role in cerebellar deficiency syndrome, 380 site of involvement in surviving cases of gunshot wounds, 386, 522 size and complexity in man, 386 syndrome of: in astrocytoma, 537 in medulloblastoma, 543 Postexanthematous encephalitides, cerebellar deficiency in, 485, 493 Postural asymmetries after partial unilateral hemispheral lesions absent at birth in rabbit and kitten, 363 present at birth in guinea pig, 363 after unilateral cerebellar lesions abolished: by curare, 75-77, 270 by denervation, 270 concealed by decerebrate rigidity, 74, 76 not abolished: by decerebration combined with deafferentation, 76 by decortication, 74 by labyrinthectomy, 74 relation to chronaxic alterations, 264 after unilateral lesions: of avian cerebellum, 18 of mammalian cerebellum, 73-77 after unilateral strychninization: of avian cerebellum, 270, 271 of mammalian cerebellum, 112 elicited by prolonged local strychninization, present in avian pelvic legs after thoracic transection of spinal cord, 270-271 elicited by unilateral chronic cerebellar lesions, present in mammalian hindquarters after postbrachial transection of spinal cord, 270-271 Postural reflexes, increased excitability of, after cerebellectomy, 31, 97 Postural tonus and antigravity tonus, 96 autochthonous vs. reflex origin of, 279-280 defined, 96 Precentral motor area and compensation of cerebellar deficiency, 333334 relation to cerebellum, 332-335 Prenatal inflammatory process, effect on cerebellar maldevelopment, 442

666

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

Primates bisection of cerebellum in, 49-50 cerebellar release phenomena little developed in, 36, 49, 59 cerebellectomy in: total, 35-38 unilateral, 46-48 vermal ablation in, 49-50 Progressive lenticular degeneration, 476 Proprioception; see Sensory functions Proprioceptive projections onto cerebellar cortex, functional significance of, 242 Prostigmine, and acetylcholine, cerebellar cortical activity after local application of, 182 Psychical responses, so-called, elicited by stimulating anterior lobe, 110-111 Psychotic manifestations; see Mental symptoms Pupils changes in, after cerebellar ablations, 303 responses to cerebellar stimulations, 138, 303304 Purkinje neurons activated by volleys coursing in molecular layer, 176 of anterior lobe, greater vulnerability than posterior to normal senescence, 454 antidromic excitation of, 169 cathodal inactivation of, 171 criteria for identification of, 168-169 d.c. stimulation of, 171 driven discharge of depressed by asphyxia, 211 highest rates attained, 172 increased by local strychnine, 211 relation to evoked potentials, 211 effect of fatigue on, 492-493 extracellular recording from, 169-170, 217 favored for experimental approach to cellular pathology, 459, 492 final common path of cerebellar cortex, 240 giant spikes from, 170 hypothesis of inhibitory influence of basket cells on, 171 inhibition by hyperpolarization of, 170 intracellular recording from, 168-171, 217 number of, involved in liminal electrical stimulation of cerebellar cortex, 171 orthodromic monosynaptic excitation of, via climbing fibers, 169 prepotentials from, 170 selective damage to, in louping ill, 482, 493 spontaneous discharge of functional significance, 240-242 patterns, 170 relation to cerebellar waves, 240-242 susceptibility: to anoxia and hypoglycemia, 493 to hyperthermia, 491, 492, 493 to noxious influences, 451, 456 bearing on problem of cortical cerebellar atrophy, 458-459 Gordon phenomenon, 458, 488, 489 vulnerability: in encephalitis, 483 in malaria, 482

"Pyramidal" preparation, 222 Pyramidal tract, involvement of in basilar impression, 419 in Friedreich's ataxia, 467, 469 signs of, in extra- and intracerebellar disease, 400 Pyramis electrical stimulation of, 114, 116, 138, 148 evoked potentials from after proprioceptive limb stimulations. 182184 after single-shock stimulation: of nerves, 191 of pons, 202 isolated ablation of, 70-71 relation of, to fastigial neurons and hook bundle, 85-86 and uvula, combined ablation of, 70-71, 85-86 Quantitative approach to cellular neuropathology, favorableness of Purkinje cells for, 459 Ramsey-Hunt syndrome, 411, 463 clinical similarity to myoclonic epilepsy and hepatolenticular degeneration, 402 questioned as clinicopathological entity, 412 Range of voluntary movements, disturbances in; see Dysmetria Rate of voluntary movements, disturbances in in lesions of superior cerebellar peduncle, 401 as part of phenomenon of decomposition of movement, 392 tests for, 393, 398 Reaction time, increase of, in cerebellar patients, 354-355 Rebound after stimulation of cerebellar nuclei, 147 increased by postbrachial transection of spinal cord, 147 not abolished: by bilateral labyrinthectomy, 147

by deafferentation, 147 cerebellar during barbiturate anesthesia, 143-146 release hypothesis on, 156, 172, 176 in decerebrate cat at end of electrical stimulation of vermian part of anterior lobe, 115 at end of fastigial stimulation, 142, 146, 147 temporal facilitation of, 115-116 different effects of deafferentation on cerebellar and spinal rebounds, 155 dineuronic hypothesis on, 117, 155-157 hypothesis of low-frequency afterdischarge, 156 hypothesis of postinhibitory superactivity, 156157 postinhibitory extensor, absent: at end of liminal stimulation of vermian part of anterior lobe, 120-121 at end of medial bulboreticular stimulation in chronically cerebellectomized decerebrate cat, 135 of reticular spike discharge after cortically induced inhibition, 222-224

SUBJECT INDEX at end of galvanic stimulation of culmen, 226 occurring after cortically induced inhibition, effect of galvanic stimulation of culmen on, 222, 224 in thalamic pigeon at end of electrical stimulation of culmen, 106 temporal facilitation of, 106 Reciprocal innervation defined, 263 of cortical strychnine clonus during cerebellar stimulation, 313-315; see also Motor cortex effect of cerebellar stimulation on, 263-265 of postural response to cerebellar stimulation concealed by neural spread within vermian cortex, 136, 153 controversial data on, 115, 135—136 intraspinal mechanisms of, 135—136, 153 present after total cerebellectomy, 263-264 in reflex labyrinthine control of alpha rigidity, 279 Recruitment, of inhibitory response to cerebellar stimulation, 117, 120-121 Red nucleus lesion of caudal part of contralateral, and abolition of effect on decerebrate rigidity elicited from medial strip of intermediate part of anterior lobe, 137 relays for cerebellifugal volleys arising from intermediate part of anterior lobe localized in contralateral, 137 Reflex inhibition ascending, 268 autogenetic, 268 crossed, in mechanism of unilateral cerebellar atonia, 45, 98, 265-268, 352 crossed proprioceptive, 268 in postural imbalance elicited by asymmetrical fastigial lesions, 265-268 Reflexes deep tendon differences in, as basis of classification of hereditary spinal ataxias, 472 lost or decreased in Friedreich's ataxia, 467, 469, 471 increased in spastic ataxia, 469, 471 increased: in Arriold-Chiari malformation, 422 in familial cortical cerebellar atrophy, 446 in late cortical cerebellar atrophy, 453 pendular knee jerk cerebellar division responsible, 380 as clinical symptom of damage to posterior lobe, 380, 388 relative frequency as symptom, 379 Relaxation, in cerebellar patients delayed muscle relaxation, causes of, 356 reflex, slowed, 355 voluntary, delayed, 356 Release of antigravity tonus after cerebellar lesions in carnivores; see Dynamic phenomena, Release phenomena

667

in pigeon, 5, 6, 14—15, 96 after combined cerebral and cerebellar ablations, 59, 63, 338 cerebellar and Schiff-Sherrington, differences between, in decerebrate cat, 276 Release phenomena after anterior lobe topectomy, compensation of in subprimates, 56-67 in thalamic pigeon, 15 after bilateral fastigial lesion, decompensation after postbrachial transection of spinal cord, 286 after cerebellectomy compensated earlier than symptoms of Luciani's deficiency period, 286-287 compensation of: by cerebral cortex, 336-338 by subcortical mechanisms, 338 in decorticate dog, 338 decompensation of, after postbrachial transection of spinal cord, 285 overlapping with symptoms of deficiency period, 26, 41-43, 98-99 after complete cerebellectomy absent in puppies 15—30 days after birth, 361363 present in puppies 30-45 days after birth, 361363 after symmetrical fastigial lesions; see Nucleus fastigii Fodera's discovery of, after cerebellar ablation, 5 relation to Luciani's dynamic phenomena, 60, 98-99, 351-352 Reptiles cerebellectomy in, 13 electrophysiological recording from cerebellum of, 160 stimulation of cerebellum of, 105 Respiration after cerebellectomy, 299-300 disturbances of, in Bruns syndrome, 403 effect on, of cerebellar stimulation in decerebrate cat, 294, 299 in thalamic cat, 296, 299 poor coordination of, related to speech disturbances in cerebellar disorders, 394 Restiform body, section of, 88-90; see also Cerebellar peduncle, inferior Reticular formation cerebellar cortical response to single-shock stimulation of, 202 electrical stimulation of medial bulbar compared to stimulation of vermian part of anterior lobe, 151 in chronically cerebellectomized, decerebrate cat, 135 evoked potentials from, after single-shock stimulation: of culmen, 219 of fastigial nucleus, 219 spike discharge from driven by corticofugal outbursts arising from strychninized motor cortex, effect on, of galvanic stimulation of culmen, 223

668

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

driven by single shocks applied to motor cort*»Y LCA| 003 AAiiJ

effect on, of galvanic stimulation of culmen, 225 high-frequency outbursts of single units of, during galvanic stimulation of culmen, 227 identification of inhibitory reticulospinal units, effect on, of cerebellar stimulations, 220221 increase of firing rate paralleling EEG arousal during galvanic stimulation of culmen, 324-326 inhibited by corticofugal outbursts arising from strychninized motor cortex, effect on, of galvanic stimulation of culmen, 228224 single units of: critically affected by galvanic stimulation of one cerebellar lamella, 229 driven by corticofugal, cerebellifugal, and sensory volleys, 225-226 units of: facilitated by galvanic stimulation of culmen, 220-229 inhibited by galvanic stimulation of culmen, 220-229 unaffected by galvanic stimulation of culmen, 219-230 waxing and waning of, effect on, of cerebellar stimulation, 220-221 Retina angiomatosis of, and hemangioblastoma, 553 in diagnosis of amaurotic familial idiocy, 474 Retinitis pigmentosa, involved in hereditary spinal ataxia, 466 Reversal of cerebellar inhibition after lesion of rostrolateral part of nucleus fastigii, 131-134 elicited: by decreasing stimulus rate, 127-130 by lengthening reaction, 123-124 by Magnus's reflexes, 120-122 by reducing rate of electrical stimulation, hypotheses on, 127 strychnine, absent for cerebellar inhibition, 115, 124, 127-130 Rheumatic fever, acute, effect on cerebellum of hyperthermia in, 491 Rhythmic movements; see Running movements Rhythmic stabilization test, in identification of cerebellar disease, 392 Righting reflexes cerebellar control of, 282-283 present: after cerebellectomy, 271, 282 after anterior lobe topectomy in thalamic cat, 60 Rigidity, extensor (see also Alpha rigidity, Gamma rigidity) after anterior lobe topectomy, 56—58 after bilateral fastigial lesion, decompensation of, by postbrachial transection of spinal cord, 286 after cerebellectomy, decompensation of, by post-

brachial transection of spinal cord, 285 after total cerebellectomy, 24-25, 27 in deafferented forelimbs, 285 Rigidity, Parkinsonian, 453, 476; see also Parkinsonism Roentgen therapy, in treatment of cerebellar tumors astrocytoma, of no value, 541 glioblastoma multiforme, 550 medulloblastoma, 540-541 vascular, 556 Roentgenography (see also Arteriography, Pneumoencephalography, Ventriculography) in calcification of dentate nuclei, 477-478 chest x-rays, as important preliminary in suspected brain tumor, 559 in diagnosis: of Arnold-Chiari malformation, 424 of basilar impression, 419 in differential diagnosis of cerebellar and cerebral lesions, 404, 405 skull films, useful in demonstrating increased intracranial pressure, 532, 543, 562 Rolando's posture, after unilateral nuclear lesion in pigeon, 19-21 Rolling movements, occurring during dynamic period, vestibular origin of, 44 Romberg test, positive, in frontal lobe tumors, 405 Roof nucleus; see Nucleus fastigii Rossi effect, 311, 316 Rotated head posture; see Head posture, abnormal Running movements, elicited by cooling anterior lobe in decerebrate cat, 60 by electrical stimulation of inhibitory cerebellar area, 115, 123 Russellian system (see also Nucleus fastigii, caudal part) bilateral inactivation of, after destruction of caudal fastigial structures giving rise to hook bundles, 86 unilateral inactivation of; see Fastigial atonia, crossed; Hook bundle Sarcomas, 560-561 gross and microscopic appearance, 561 medulloblastomas, erroneously diagnosed as, 541, 546 mesenchymal origin of, 560 old term: for glioblastoma multiforme, 549 for gliomas, 560 rarity of cerebellar involvement, 561 Scarlatina, degeneration of Purkinje cells after, 458, 485 Schiff-Sherrington inhibition (see also Alpha rigidity, Postbrachial transection of spinal cord) compensation of cerebellar release phenomena by, 285, 286 increase of rebound posture a manifestation of, 147 of alpha rigidity extracerebellar mechanisms of, 280, 282 present in chronically cerebellectomized, decerebrate preparation, 282

SUBJECT INDEX Scratch reflex, normal in cerebellectomized dog, 26, 27 Seeding of tumors of astrocytoma, rarity of, 541 of medulloblastoma, 543 importance of seeded plaques as gross characteristic, 544 Seizures, cerebellar; see Cerebellar seizures Sense of pain, loss of; see Sensory functions Sense of temperature, loss of; see Sensory functions Sensory ataxia, differences from cerebellar ataxia, 43 Sensory attention and reticular formation, 345 old theories and new data on relation of cerebellum to, 344-345 Sensory functions cutaneous sensation, loss of, 358 in face, after occlusion of posterior inferior cerebellar artery, 513 sense of pain and temperature after occlusion of cerebellar arteries, 513, 515, 516 in lesions: of inferior cerebellar peduncle, 400 of superior cerebellar peduncle, 402 disturbances of, in patients with cerebellar deficiency, 358 proprioception, loss of, discussed, 42, 43, 358, 395 relation of cerebellum to, 344-350, 358 Sensory long-tract involvement, in extracerebellar lesions, 400 Sensory neurons effect of cerebellar stimulations on postsynaptic activation of second, 347-348 responses of, influence of reticular formation and cerebellum on, 348 Sensory organs, centrifugal innervation of, and cerebellum, 344-346 Renzi's hypothesis on, 344-345 Sensory pathways, course and distribution of in man, deductions from disturbances after occlusion of posterior inferior cerebellar artery, 513 Sensory representation, double, within cerebellar cortex, hypothesis on, 193 Sensory sphere, alterations in, after unilateral cerebellectomy, 41-42 Servomechanisms in cerebellar regulation of gamma motoneurons, 242 Sexual activity and cerebellum, 308 Gall's hypothesis of cerebellum as center for, 6 Sham rage, effect of cerebellar stimulations on, in thalamic cat, 295-299 Sherrington's atonia, cerebellar and Schiff-Sherrington inhibition of alpha rigidity responsible for, in deafferented limb of decerebrate cat, 273-274 Shortening reaction, effect of, on sign and inten-

669

sity of postural response to cerebellar stimulation, 123 Skeletal deformities, cerebellar involvement in and Arnold-Chiari malformation, 418, 443 basilar impression, 418-420 and frequent association with nervous system malformations, 418 Sleep abolition of tremor during, in totally cerebellectomized dog, 29 ascending reticular system and cerebellum, 348350 Slow potential changes, elicited in cerebellar cortex by repetitive stimulation of sensory nerves, 216 Somatosensory cortical area, evoked potentials from, after single-shock stimulation of anterior lobe and lobulus simplex, 234-235 Somatosensory cortical area I, responses of anterior lobe and lobulus simplex to singleshock stimulation of, 208 Somatosensory cortical area II, responses of contralateral paramedian lobule, tuber vermis, and pyramis to single-shock stimulation of, 208-209 Somatotopic arrangement appraisal of anatomical and physiological data on, 250-253 controversial data on, of postural and phasic responses to electrical cerebellar stimulations, 115, 125, 127, 138, 140, 321 of cerebellar potentials evoked by sensory volleys absent in unanesthetized preparation, 191, 195 controversial data in mammals, 184, 186, 191, 192, 195, 199 effect of anesthesia on, 192 in birds, 160-161 of evoked cerebellar potentials after single-shock stimulation of cat's Somatosensory area I, 208 after stimulation of primate area 4, 206-207 Somatotopic localization, cerebellar anatomical and physiological approaches to problem of, 50-52, 185, 249, 396 clinical evidence for, 396-397, 522 disagreement concerning, and tentative explanation of discrepancies between unanesthetized and anesthetized preparations, 252253 Spasms, tonic; see Cerebellar seizures Spastic ataxia (Marie's cerebellar ataxia), 469-473 as clinical entity, 469 genetic study of, 469-472 clinical groups and pathologic counterparts, 471-472 mode of transmission, 473 Spasticity; see Dynamic phenomena, Release phenomena, Rigidity Speech disturbances, 191; see also Laryngeal movements

670

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

cerebellar division responsible, 380 classified, 394 phonation, difficulties with after occlusion of posterior inferior cerebellar artery, 513 in lesions of inferior cerebellar peduncle, 400 as symptom after mumps, 484 in Arnold-Chiari malformation, 422 in cortical cerebellar atrophy familial, 446, 449 generalized, 455 late, 452 in malaria, 481 in olivopontocerebellar atrophy, 461 relative frequency, 379 Sphincter disturbances, in syndrome of olivopontocerebellar atrophy, 305, 461 Spike discharges from brachium conjunctivum after single shocks applied: to brachium pontis, 219 to cerebellar cortex, 218 to inferior olive, 219 to restiform body, 219 relation to cerebellar cortical waves, 218 from cerebellar cortex abolished by ischemia before cerebellar waves, 168-169 after local strychnine, 179, 214-215 during afferent stimulation, 184, 213-214 effect of local galvanic stimulation on, 174175 evoked by sensory stimulations after local strychnine, 214-215 inhibited by sensory stimulations, 214-215 localization within Purkinje and granular layers, 167-168 occasional findings of respiratory periodicity, 309

presynaptic and postsynaptic, evoked by sensory stimulations, 214 relation to cerebellar cortical waves, 168 rate of firing during spontaneous activity, 165166, 170 from fastigial nucleus after natural sensory stimulation, 237-238 after single-shock stimulation of nerves, 237238 during galvanic stimulation: of culmen, 237238 of labyrinths, 237-238 evoked by single-shock stimulation of radial nerve after chronic ablation of culmen, 238-240 relation to evoked response of culmen, 237— 240 from isolated slab of cerebellar cortex, 174 from restiform body, 213-215 from reticular formation, during galvanic stimulation of culmen, 219-230; see also Reticu-

lar formation from vestibular nuclei, during galvanic stimulation of culmen, 230-232; see also Vestibular nuclei Spina bifida, and developmental anomalies of cerebellum, 418, 426 Spinal ataxia, hereditary, 449, 466-473 Friedreich's ataxia (q. v.), 467-469 genealogic studies of, 469-472, 473 clinical groups and pathologic counterparts, 471-472 genetic factor in, 467 links: with familial cortical cerebellar atrophy, 449, 466 with olivopontocerebellar atrophy, 459, 461, 462 , with other degenerative changes, 466 Marie's cerebellar ataxia, 469-473 denied as clinicopathologic entity, 469 and Wilson's disease, 476 Spinal cord effect of hemisection of, on postural responses to electrical stimulation: of fastigial nuclei, 150 of vermal cortex of anterior lobe, 136, 150 involvement of, in subacute cortical cerebellar atrophy, 457 nonsurgical disorders of, frequently confused with Arnold-Chiari malformation, 424 partial transection of, effect on responses of cerebellar cortex to single-shock stimulation of nerves, 198 relation to cerebellum, 255—271 Spinal inhibition, and cerebellar facilitation, 265268 Spinal pathways, course of, mediating conduction of afferent impulses to cerebellar cortex, 198 Spinal puncture, warned against in cerebellar tumors, 529 in extradural cerebellar hematomas, 524 in otogenic brain abscesses, 506 Spinocerebellar projections, overlapping with corticocerebellar projections, 247 Spinocerebellar tract dorsal evoked potentials from, 197 intra-axonal recording from, 217, 218 ventral evoked potentials from, 199-200 relation: to Golgi tendon organs, 200, 217-218 to muscle spindles, 200, 217-218 responses to single-shock stimulation of, 201 Spinoreticulocerebellar paths, and somatotopic arrangement of evoked cerebellar potentials, 195 Splanchnic nerve, evoked cerebellar potentials after single-shock stimulation of, 309 Spongioblastoma polare, identifiable with cerebellar astrocytoma, 552 Spontaneous deviation of limbs, as symptom of

SUBJECT INDEX cerebellar disorder, 390 Station disturbances, 384-385 cerebellar division responsible, 380, 390 relative frequency as symptom, 379 Stemmbein reaction, exaggerated in decerebellate dog, 33-35 Stewart-Holmes phenomenon cerebellar division responsible, 380 as defect in voluntary movement, 391 relative frequency as symptom, 379 Stiff neck, as sign, in extradural cerebellar hematomas, 524 Stimulus rate effect on cerebellar influence: upon cortically induced movements, 321-322 upon decerebrate rigidity, 126-128, 130-131 upon spinal strychnine waves, 128-130 optimum, for cerebellar inhibition of decerebrate rigidity, 127 Stretch reflexes after bilateral destruction of fastigial nucleus, 77 effect on, of electrical stimulation of vermian part of anterior lobe at different rates, 128 Strychnine, local application of to avian cerebellar cortex, postural effects of, 105 to mammalian cerebellar cortex convulsive waves absent after, 178 effect: on surface-negative component of evoked response, 211 on surface-negative potential shift elicited by sensory stimulation, 216 on visual responses, 189 extensor rebound occurring at end of high-rate cerebellar stimulation enhanced by, 261 postural and motor effects of, 111-112 response to low-rate cerebellar stimulation enhanced by, 260-261 single-unit discharge after, 179, 214-218 Strychnine convulsive waves, potential oscillations evoked on both cerebellar hemispheres synchronously by, effect on motor cortex, 205 Strychnine reversal; see Reversal, strychnine Strychnine tetanus convulsive potentials led from cerebellar cortex during, 179-181 compared to effect of DDT, 487 spinal convulsive waves during, effect on, of electrical stimulation of vermian part of anterior lobe at different rates, 128 Subprimates bisection of cerebellum in, 48-49 total cerebellectomy in, 23-35 unilateral cerebellectomy in, 38—46 vermal ablation in, 48-49 Subtentorial lesions, cerebellar symptomatology of, 399-403; see also Cerebellar peduncle, inferior; superior; Fourth ventricle; Pontine gliomas

671

mental symptoms in, 531 Superior colliculi, cerebellar cortical response to single-shock stimulation of, 202, 204 Supporting reaction, exaggerated after cerebellar ablation and in cerebellar hypoplasia in cats, 438 cerebellar division responsible for, 380 in chronically cerebellectomized dog, 30-31 studied in man, 386 in tumor of anterior lobe, 385 Supporting tonus crossed reflex inhibition of, increased in chronically cerebellectomized dog, 33, 44 decreased during Luciani's atonia, 97 strength of and Luciani's atonia, 31-33 decreased in chronically cerebellectomized dog during deficiency period, 32, 46 decreased inhibition of, by dorsal skin reflexes after cerebellectomy, 244 normal in chronically cerebellectomized dog during compensation period, 46 Suprasellar lesions, cerebellar symptoms in, 403, 404 Supratentorial lesions (see also Frontal lobe of cerebrum, tumors of) cerebellar symptomatology of, 403-406, 407 and cerebellar tumors, differential diagnosis of, 530 mental symptoms in, 531 posterior fossa explorations for, fatal, 404 Swallowing, difficulties with after occlusion of posterior inferior cerebellar artery, 513 in lesions of inferior cerebellar peduncle, 400 in olivopontocerebellar atrophy, 461 Swaying reaction, after cerebellectomy, 33 Sweat glands, effect of cerebellar stimulation on reflex responses of, 309 Swimming after total cerebellectomy, 25, 27, 101 after unilateral cerebellectomy, 39 and labyrinthectomy, 273 reflex mechanisms of, 101 Symmetrical calcification of dentate nuclei, 477478 frequent association with parathyroid deficiency, 478 Symptomatology of cerebellar disorders, 376-398; see also specific symptoms classified according to functional division of cerebellum, 379, 380, 398 Synchronization, tendency toward, differences between cerebellar cortical and cerebral cortical neurons in, 241 Syncope, in Bruns syndrome, 403 Syphilis, 497-498 associated vascular damage, 512 cerebellar gummata, rarity of, 497-498 surgical removal, recommended, 498, 509 congenital, effect on cerebellar maldevelopment, 442, 497

67£

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

toxic effects of, on Purkinje cells, 458 Syringomyelia, in basilar impression, 419 Systemic diseases, cerebellar involvement in, 456, 458, 480-485 Tachycardia, in Bruns syndrome, 403 Tactile projection areas onto cerebellar cortex avian, 160 mammalian, 185-186 Tay-Sachs disease, 474 Tegmental reaction, 146 Tegmental tract, central, lesions of, role in palatal myoclonus, 413, 415 Temperature, changes of cutaneous and rectal, after cerebellar stimulations, 302-303 Temperature, sense of; see Sensory functions Temporal lobe of cerebrum, lesions of, cerebellar symtomatology, 406 Tendon reflexes (see also Knee jerk, Reflexes) changes in, after unilateral ablation of lobulus ansoparamedianus, 65 hyperexcitability of: after complete cerebellectomy, 25, 31 after unilateral cerebellectomy, 41-42 Terminology, neuropathological, confusions in, 446, 551 astrocytoma, numeral grades of malignancy in classification of, as substitute for established terms, 539, 549 different names: for dysembryoma, 557 for ganglioneuroma, 552 for glioblastoma multiforme, 539, 549 for medulloblastoma, 546 gliomas, called sarcomas in older literature, 560 olivopontocerebellar atrophy (rightly hypoplasia) in cat, 439 Tests, clinical; see Clinical tests, in diagnosis of cerebellar deficiency Tests of cerebellar deficiency, laboratory, 73 Thalamic cat anterior lobe topectomy in, 60 autonomic ocular responses after cerebellar stimulations in, 304 effect of cerebellar stimulation in: on circulation and respiration, 296-299 on phasic movements, 125—126 sham rage outbursts and cerebellar stimulations in, 295 Thermal changes, effects of, on Purkinje cells, 458, 491, 492, 493 Thermal panting, after cerebellectomy, 302-303 Thermoregulation, influence of cerebellum on, 302303 Thiophene, inhalation of, experimental effects on cerebellum, 486 Thrombosis, of basilar artery, after chiropractic manipulation, 521; see also Arteries, cerebellar, occlusion of Thyroid gland, iodine content after cerebellectomy, 300-301 Titubation, as clinical manifestation of lesions of anterior lobe, 452, 457, 461; see also Gait

disturbance Tone (tonus), defined, 23 Tongue, weakness of in lesions of inferior cerebellar peduncle, 400 after occlusion of posterior inferior cerebellar artery, 513 Tonus, extensor (see also Atonia, Hypotonia, Hypertonia, Rigidity) facilitated by nuclear stimulations in thalamic pigeon, 107 inhibited by cerebellar cortical stimulations in thalamic pigeon, 106, 107 inhibitory influence of avian cerebellum on, 96 Toxic substances, exogenous, effects of, on Purkinje cells, 458 Tracheotomy, in occlusion of posterior inferior cerebellar artery, 514 Trauma, cerebellar, 521-525; see also Extradural hematoma, cerebellar; Laceration, cerebellar classified, 521 relation to cerebellar tumors, 522 Traumatic hemorrhage, cerebellar, 525 Tremor defined, 23 kinetic, defined, 23 in laboratory animals after lesion: of nucleus dentatus, 50, 66, 87-88 of nucleus interpositus, 50 after section of superior cerebellar peduncle, 94 after total cerebellectomy in mammals, 27 after unilateral ablation of lobulus ansoparamedianus, 65 after unilateral cerebellectomy in mammals, 40, 47 in totally decerebellate dog abolished by decortication, 334 absent during dynamic period, 334 disappearance of, during rest and sleep, 29 more evident in neck, 29 relation to voluntary movements, 334 in totally decerebellate primate abolished by ablation of areas 4 and 6, 334 increased by ablation of area 6, 334-335 not abolished by isolated ablation of area 4, 334 lack of proper integration between cerebral and cerebellar functions responsible for, 334335, 357-358 non-intention tremor, as clinical evidence of basal ganglion pathology, 476 static, 389-390 after damage to dentate nucleus and brain stem in man, 389-390 defined, 23 as symptom, clinical cerebellar division responsible, 380 a disorder of voluntary movement, 395 in familial cortical cerebellar atrophy, 446, 447 functional significance of, 357-358 in olivopontocerebellar atrophy, 461

SUBJECT INDEX relative frequency, 379 role of hypotonia in, 389-390 Trichloroethylene, effects of, in man and dogs, 487 Trigeminal nerve, evoked cerebellar potentials after single-shock stimulation of skin areas innervated by, 191 Trophic influence of cerebellum, experiments and hypotheses on, 268-271 Tuber and folium vermis, ablation of, decreased behavioral response to startling noises after, 345 Tuber vermis evoked potentials from after auditory stimulation, 186 after single-shock stimulation: of auditory areas I and II, 208, 209 of nucleus caudatus, 211 of pons, 202 of somatosensory area II, 208-209 after visual stimulation, 186 response of auditory cerebral cortex to singleshock stimulation of, 235, 236 Tuberculomas, 494-497 cerebellar, symptoms and signs, 496 rotated head posture, 382 decreasing incidence of, 495 percentage of, among brain tumors, 494, 495 streptomycin therapy, beneficial effect of, 497 surgical treatment, outlook for, 496, 497, 509 tuberculous meningitis as a complication, 494, 495 Tuberculosis, 494-497; see also Tuberculomas toxic effect on Purkinje cells, 458 Tuberculous meningitis as complication of tuberculoma, 494, 495 and otogenic cerebellar abscess, differential diagnosis of, 506 Tuberous sclerosis, cerebellar changes in, 478 Tumors, cerebellar, 526-563; see also Astrocytoma, cerebellar; Medulloblastoma, cerebellar; Hemangioblastonia; Tuberculomas arteriographic findings, 536 attacks of opisthotonos in, 386 and cerebellar trauma, no causative relation between, 522 classified, 527-528 by numeral grades of malignancy, 539, 548549, 551 EEG or electroencephalographic abnormalities in, not specific, 535 enlargement of sella turcica in, 532 extracerebellar symptoms, 531-532 heredofamilial pattern in vascular, 528, 554 increased intracranial pressure as first manifestation, 528-530 skull films, useful in identification of, 532, 562 metastases of, 545, 549 metastatic, 559 and otogenic cerebellar abscess, differential diagnosis of, 506 pneumoencephalography in, not recommended, 533

673

primarily of adults, 549, 553 primarily of children, 537, 542 seeding of, 541, 543, 544 specific astroblastoma, 548-549 astrocytoma, 536-541 dysembryoma, 557—559 ganglioneuroma, 551—552 glioblastoma multiforme, 549-550 medulloblastoma, 541-548 meningioma, 560 oligodendroglioma, 550—551 sarcoma, 560 spongioblastoma polare, 552 vascular tumors, 552—556 symptoms of cerebellar deficiency in, 530-531 ventriculograms, as chief diagnostic aid, 533— 534, 562 Tumors, cerebral (see also Frontal lobe of cerebrum, tumors of) astrocytoma, and cerebellar astrocytoma, questioned as distinct entities, 539, 562 and cerebellar symptomatology, difficulty of differential diagnosis, 405 medulloblastoma, and cerebellar medulloblastoma, distinguished, 542 Tumors, extracerebellar, classified, 528 Tumors, intraventricular in fourth ventricle, 402-403 in lateral and third ventricles, cerebellar symptoms of, 403 Tumors, suprasellar, cerebellar symptoms of, 403 Typhus fever, degeneration of Purkinje cells after, 458 Underdevelopment of cerebellum; see Hypoplasia Unilateral hypoplasia; see Crossed cerebellar atrophy, Hypoplasia Upper extremity dexterity, effect on, of lesions of posterior lobe, 380 Uvula ablation of, effect on glucose tolerance tests, 302 electrical stimulation of, 138 evoked potentials from, after single-shock stimulation of eighth nerve, 201-202 mechanical stimulation of, effect: on adrenaline discharges, 301 on glycemia, 301 and pyramis, combined ablation of, 70, 85-86 Vagus nerve, evoked cerebellar potentials after single-shock stimulation of, 191, 309 Vascular damage, role of in cerebellar manifestations from other diseases, 481, 482, 488, 493 in pseudohypertrophy of inferior olive, 415 Vascular diseases of cerebellum, 510-520; see also Arteries, cerebellar, occlusion of; Hemorrhage, cerebellar Vascular tumors, 552—556; see also Hemangioblastonia

674

PHYSIOLOGY AND PATHOLOGY OF THE CEREBELLUM

classified, 528, 552 in posterior fossa, vertebral arteriography in diagnosis of, 536 Vasomotor reflexes, effect on of anterior lobe topectomy, 299 of cerebellar stimulations, 292-295 Vasomotor tonus, central, effect of cerebellar stimulations on, 292-293 Vegetative functions, role of cerebellum in control of, 290-310, 396 Ventriculography, as diagnostic aid in cysticercus cyst, 508 in differential diagnosis of cerebellar hemorrhages and spontaneous subarachnoid, 519 of cerebral and cerebellar tumors, 404 of intracerebellar tumors, 531, 533, 536, 562 hemangioblastoma, 555 distinguishing features as seen in technically ideal films, described, 533-534 in extradural cerebellar hematoma, 524 in otogenic cerebellar abscess, 506 in platybasia, 420 Vermis, cerebellar agenesis of, in man, 429-434 case study, 427 compensation by cerebral cortex, greater capacity for in man than in dog, 429 unaccompanied by clinical symptoms, 434, 444 agenesis of, in mammals other than man, 430 definite syndrome resulting, 434 in dogs, 431 in mice, 417, 431, 433 damage to, and convulsive seizures in cats, 409 in man, 408 mechanism of production of congenital defects, 431-434, 444 posterior ablation of, 52-53, 57 effect, compared with effect of lesions of flocculonodular lobe in man, 381 and control of trunk muscles, 381 invaded by medulloblastoma, 544 Vertigo in Bruns syndrome, 402, 403 in hemangioblastoma, 555 in intra- and extracerebellar lesions, 400, 410 Vestibular apparatus; see Labyrinthine system Vestibular Complex, Syndrome of, 378 Vestibular nuclei lesion of, effect on decerebrate rigidity, 230-232 spike discharges from during galvanic stimulation: of anterior lobe, 230-232 of labyrinth, 230-232 reciprocally affected by galvanic stimulation of ipsilateral and contralateral labyrinth, 230-232 spontaneous firing not abolished by severing eighth nerve, 230-232 Vestibular system

derangement of, role in Bruns syndrome, 403 function of, in relation to vertiginous element of postconcussion syndrome, 522 Virus diseases, cerebellar damage in, 482, 483 epidemic parotitis (mumps), 484 poliomyelitis, 484 relation between louping ill and encephalitis, 483 Vision, disturbances of; see Ocular disturbances Visual field defects of, in cerebellar tumors, confusion of diagnosis by, 531 importance of examination of in diagnosis of cerebellar tumors, 529, 530 in differentiating cerebellar lesions from those of parietal, temporal, and occipital lobes, 406 Visual projection areas functional significance of cerebellar cortical, 245246 onto cerebellar cortex: avian, 160 mammalian, 186-189 Vitamin deficiency, cerebellar symptoms from, 490491 Voluntary contraction, alteration in cerebellar patients, 354-356 Voluntary movements disorders of, in man, as sign of cerebellar deficit, 353-358, 390-395, 398 classified, 390 of compound movements, 392—395 in lesions of superior cerebellar peduncle, 401 in medulloblastoma, 531 of simple movements, 390-392 in suprasellar lesions, 404 integration of cerebellar and cerebral functions in regulation of, 356-358 Voluntary relaxation, slower in cerebellar patients, 354-356 Vomiting, as symptom in Bruns syndrome, 402, 403 in cerebellar abscess, 498, 505 in extra- and intracerebellar lesions, 400 in extradural cerebellar hematomas, 524 importance of, especially in children, as symptom of cerebellar tumor, 529-530 glioblastoma multiforme, 550 hemangioblastoma, 555 medulloblastoma, 543 tuberculoma, 496 Walking (see also Gait disturbance) difficulty in: in late cortical cerebellar atrophy, 452 in lesions of superior cerebellar peduncle, 401 in occlusion of anterior superior cerebellar artery, 516 in olivopontocerebellar atrophy, 461 disorders of, following cerebellectomy in laboratory animals, discussed, 101—10-2 less affected than swimming by cerebellectomy, 39, 101 Weight discrimination

SUBJECT INDEX after combined section of medial lemniscus and superior cerebellar peduncles in primates, 346 after section of medial lemniscus in primates, 346 after section of superior cerebellar peduncles in primates, 346 in cerebellar patients, 346, 358

675

Whooping cough, cerebellar damage in, 482, 493 Wilson's disease, and cerebellar atrophy, 476 Writing, disturbances in in cerebellar disorders, 394 in malaria, 481 X-r;iy; see Roentgen therapy, Roentgenography