Cognition and Recognition: On the Origin of Movement: Rademaker (1887-1957) (History of Science and Medicine Library)

Cognition and Recognition: On the Origin of Movement

History of Science and Medicine Library VOLUME 6

Cognition and Recognition: On the Origin of Movement Rademaker (1887–1957) A Biography

By

L.A.H. Hogenhuis

LEIDEN • BOSTON 2009

Cover illustration: Painting of Prof. Rademaker. This portrait, which hung on the walls of the department of Neurology at Leiden University for more than 30 years, shows Rademaker at his desk with a characteristic look of dreamlike absorption on his face as he listens to the exposition of some clinical insight or problem by a student or colleague. This book is printed on acid-free paper. Library of Congress Cataloging-in-Publication Data Hogenhuis, Leon A. H., 1927Cognition and recognition : on the origin of movement : Rademaker (1887-1957), a biography / by L.A.H. Hogenhuis. p.; cm. — (History of science and medicine library, ISSN 1872-0684; v. 6) Includes bibliographical references. ISBN 978-90-04-16836-7 (hardback : alk. paper) 1. Rademaker, G. G. J. (Gijsbertus Godefriedus Johannes), 1887-1957. 2. Neurophysiologists—Netherlands—Biography. I. Title. II. Series. [DNLM: 1. Rademaker, G. G. J. (Gijsbertus Godefriedus Johannes), 1887-1957. 2. Neurophysiology—Netherlands—Biography. 3. Physicians—Netherlands—Biography. 4. Biomedical Research—history—Netherlands. 5. History, 20th Century—Netherlands. 6. Movement—Netherlands. 7. Neurophysiology—history—Netherlands. WZ 100 R1268H 2008] QP353.4.R33H64 2008 612.8092—dc22 [B]

2008014325

ISSN 1872-0684 ISBN 978 90 04 16836 7 Copyright 2009 by Koninklijke Brill NV, Leiden, The Netherlands. Koninklijke Brill NV incorporates the imprints Brill, Hotei Publishing, IDC Publishers, Martinus Nijhoff Publishers and VSP. All rights reserved. No part of this publication may be reproduced, translated, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without prior written permission from the publisher. Koninklijke Brill NV has made all reasonable efforts to trace all rights holders to any copyrighted material used in this work. In cases where these efforts have not been successful the publisher welcomes communications from copyright holders, so that the appropriate acknowledgements can be made in future editions, and to settle other permission matters. Authorization to photocopy items for internal or personal use is granted by Koninklijke Brill NV provided that the appropriate fees are paid directly to The Copyright Clearance Center, 222 Rosewood Drive, Suite 910, Danvers, MA 01923, USA. Fees are subject to change. printed in the netherlands

Dedicated to my parents who taught me the meaning of courage and to Jan Mulders, National President of the Dutch Student Resistance in Leiden

CONTENTS Foreword ...................................................................................... Michel D. Ferrari, Leiden University Medical Centre How to Use this Book ................................................................. List of Illustrations .......................................................................

ix xi xiii

BOOK I Account of the Biographical Approach and Sources Used. Definition ......................................................... 1.1. ‘The Son of the Minister’. Prodromes ........................... 1.2. Parents and Family .......................................................... 1.3. Initial Steps and Training ................................................ 1.4. G.P. and Surgeon in Surabaya (1916–1922) .................... Endnote ............................................................................

1 10 12 14 16 19

BOOK II Experimental Physiology. Work in Magnus’ Laboratory—‘Körperstellung’. The Facts ............................... 21 2.1. The Development of Rademaker’s Working Method. ‘The Husband-and-Wife Team’ ...................................... 34 2.2. Thesis ‘cum laude’ (1924) ................................................ 57 2.3. The nucleus ruber. The ‘King of the Red Nucleus’. The Red Nucleus meets Stereotaxis ............................... 59 2.4. Experimental Physiology of French (Magendie, Claude Bernard)—Russian (Sechenov, Pavlov, De Cyon) and Anglosaxon (Sherrington) Origin. History ...................... 67 2.5. ‘Das Stehen’. Why Translating? ......................................... 85 2.6. The Fall Reflex and ‘Mathematical Biology’ .................. 125 2.7. Infant Development as a Mirror of the Evolutionary Process .............................................................................. 142 Endnotes .......................................................................... 148 BOOK III Physiology Leiden after Einthoven ........................ 3.1. Blink Reflex ...................................................................... 3.2. The RaGa Story in Paris ................................................ 3.2.1. The Results: The Three Eponyms ....................... 3.3. ‘Réactions labyrinthiques et équilibre’—The Study of Labyrinthine Function ................................................

167 170 182 185 190

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BOOK IV Wartime. The Philosophy Behind Resistance. In Memoriam Jan Mulders. Development of the Idea of Civitas Academica ........................................................................ 4.1. Theses Prepared under Rademaker’s Supervision at the Neurophysiology Laboratory, Leiden (1932–1946) ... 4.2. Professor of Neurology (1944–1957) ............................... 4.3. ‘The Lengthening and Shortening Reactions’ ................ Endnotes ..........................................................................

203 214 251 254 258

BOOK V Rademaker the Man ............................................... 259 5.1. Rademaker the Physician, the Surgeon, the Neurologist ....................................................................... 267 BOOK VI The End of Postural Research. A Short Summary with Chronology ...................................................................... 271 6.1. Walshe’s Account of a Visit to Magnus’s Laboratory .... 275 BOOK VII The Intellectual Climate in the Netherlands ....... 7.1. Bibliography ..................................................................... 7.2. The Triptych .................................................................... 7.3. Honours ...........................................................................

279 282 296 298

BOOK VIII ‘On the Origin of Movement’. History ............. 301 8.1. Rademaker’s Axioms and Postulates ............................... 302 BOOK IX Geometrical—Trigonometrical Clue ..................... 323 9.1. The Shadow of Movement ............................................. 325 9.2. Mathematics Research with Rondot’s Summary, Geometrical and Trigonometrical Model by the Author .............................................................................. 329 Death ............................................................................................ Rademaker’s Legacy . . . ............................................................... Epilogue: Four Epiphanies .......................................................... L’anecdote est le pretexte . . . et l’histoire de l’intimité ................ Acknowledgments ........................................................................ Conclusion on the Model of Cognition Presented ....................

331 335 337 341 345 349

Index ............................................................................................ 351

FOREWORD The author of this book, Dr. Leon Hogenhuis, one of Rademaker’s former students, throws an unusually penetrating light on Rademaker’s creative genius against a background of clinical research in the Netherlands of the early twentieth century, and makes him truly come alive. He paints a fascinating literally picture of a captivating hero in a highly original style. This brilliantly crafted historical study is based on decades of meticulous investigation, interviews with Rademaker’s former research associates and prolonged study of archives in many countries in search of the repercussions of Rademaker’s scientific achievements in the ‘Golden Age of Dutch experimental Physiology’. It truly provides meaningful insights into his philosophy of science. It is much more than a biography pure and simple. It takes us behind the scenes of medical research, and shows us a genius at work. As Lawrence G. Hrebiniak, Associate Professor of Managament at Wharton University of Pennsylvania, put it so aptly in another context,1 “Here’s a model of execution derived from real data. Here are the steps. And the author leads people through it. . . .” But the book goes further. From a thought-provoking tale, it extends its range to challenge our perception of the past and open up future vistas. This new-style biography offers a compelling synthesis of the history, philosophy and ethics of medical and physiological practice and research, mathematics, health care and university management, throwing up challenging ideas about the education and training of physicians, medical researchers and other health-care workers. Programmes for a new-style Master’s degree in health care—and research with—considerable emphasis on the history and philosophy of medicine, based on an Anglo-Saxon model developed at Harvard and Pennsylvania in the United States, have recently been introduced at Dutch universities. Large parts of this book read as if they had been written specifically for such a forward-looking degree course. 1 Cited from an introduction to a Master’s degree course in health care at Wharton University of Pennsylvania.

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foreword

It is a fitting memorial to a man who, though somewhat neglected in his own land, was recognized as a genius by his peers worldwide. Michel D. Ferrari, MD, PhD Professor of Neurology Leiden University Medical Centre Leiden, The Netherlands

HOW TO USE THIS BOOK The structure of this book is simple, if somewhat unusual. It is woven out of alternating strands of history and biography on the one hand, and facts from the fields of experimental physiology and neurology on the other. The experimental data may be somewhat heavy going for readers who are not acquainted with this subject matter, and can be skipped if so desired. However, readers who would like to be introduced to some basic physiology and new terms and symbols introduced by Magnus and Rademaker to describe key concepts in the fields of posture and the physiology of standing which they had made their own, alongside the experimental methods they had developed, will find the necessary information in these passages. It goes without saying that such a neat dichotomy between biography and science cannot be fully maintained throughout a book dealing with such a large, complex subject. Here and there the material overlaps, gaps are left elsewhere and sometimes parallel vistas are presented in different sections. But the basic approach is maintained and I believe that the twin strands give the book a strength and unity which it would not otherwise have had.

LIST OF ILLUSTRATIONS Frontispiece Fig. 1-1. Fig. 1-2. Fig. 1-3. Figs. 1-4 & 1-5. Fig. 1-6. Fig. 1-7. Fig. 2-1.

Fig. 2-2.

Fig. 2-3.

Fig. 2-4. Figs. 2-5 & 2-6. Fig. 2-7.

Painting of Prof. Rademaker as can be seen at Leiden University for over 30 years. Prof. Derek E. Denny-Brown (1901–1981). Ds. G.A. Rademaker, Minister of the Dutch Reformed Church in The Hague. Prof. Raymond Garcin, Professor of clinical neurology at the hospital la Salpêtrière in Paris (1897–1971). G.G.J. Rademaker on the wards of the teaching clinic during his training in surgery and orthopaedics at the Zuidwal Hospital. Announcement in local newspapers spreading the news that Rademaker’s brother Geurt Arend had to give up his practice. House in the Palmenlaan, Surabaya, occupied by Rademaker during the period 1916–1922. Frontispiece of the classic ‘Die Körperstellung’ (‘Posture’) published in 1924 by Magnus which summarized his work and reviewed Rademaker’s work on the red nucleus. Photo of the research group led by Professor R. Magnus taken on 3 November 1926, on the occasion of a visit by the Russian physiologist Professor A. Samojloff. Title page of a publication by A. Samojloff and W. Wassiljewa from 1925, with a handwritten dedication to “my dear friend and respected colleague Einthoven from A. Samojloff ”. Magnus, de Kleyn en Rademaker seated at a table in the Physiology laboratory in Utrecht. Mrs. Rademaker in the laboratory during observations on decerebellate dog Erik. ‘Untersuchungen über das Gehirn. Abhandlungen physiologischen und pathologischen Inhalts’, Berlin, Hisrschwald, 1874–1904.

xiv Fig. 2-8.

list of illustrations

John Farquhar Fulton (1899–1960), Yale University, Physiologist and writer on American medical history. Fig. 2-9. Caricature of Rademaker on rotary table with experimental animal. Fig. 2-10. Frontispiece thesis Rademaker. Fig. 2-11. The critical line (red) indicating the localization of the coronal intercollicular section through the mesencephalon of a rabbit. Fig. 2-12. The first caricature of Rademaker in the attitude of the attentively listening ‘scientist’ during a discussion of progress in a research project, drawn by his pupil and assistant Pol Dom (1940). Fig. 2-13. Rademaker, with bowler hat, as seen by a student caricaturist while watching a boat race. Figs. 2-14 & 2-15. Caricatures of Prof. Barge and Prof. J. Mulder. Fig. 2-16. Prof. C.S. Sherrington (1857–1952). Fig. 2-17. Frontispiece of thesis of P.C. Kraan, 1939. Fig. 2-18. Schematic illustration of the Horsley-Clarke stereotaxic apparatus as modified by Kraan and Rademaker. Fig. 2-19. The position of the three planes of the Horsley Clarke stereotaxic apparatus in the cat. Fig. 2-20. Sechenov, Ivan Michailovich (1829–1905), Physiologist, St. Petersburg. Fig. 2-21. Sechenov’s sketch of his experiment showing levels of the frog’s brain at which he made cuts. Fig. 2-22. Frontispiece of ‘The Physiology of Standing’ (‘Das Stehen’). Figs. 2-23 a, b, c, & d. The magnet reaction (exteroceptive supporting reaction) of the hindlimbs. Figs. 2-24 a & b. A totally (for more than a year) decerebellate, right-sided decorticate dog, showed the same increased extensor tonus and reduced supporting tonus in the left legs that followed extirpation of the right half of the cerebrum alone. In this animal also, the abnormal extensor tonus of the right hindleg disappeared

list of illustrations

Figs. 2-25 a & b. Figs. 2-26 a & b. Fig. 2-27. Fig. Fig. Fig. Fig.

2-28. 2-29. 2-30. 2-31.

Fig. 2-32. Figs. 2-33 a & b. Fig. 2-34. Fig. 2-35. Fig. 2-36. Fig. 2-37.

Figs. 3-1 a & b.

Fig. 3-2.

xv

with static stress on the left hindleg. In this figure in dorsal position of this animal the left hindlimb showed initially extended posture with increased extensor tonus, which disappeared on touching (1) and static stress (2) on the sole of the right hindlimb. Rocking (displacement) reactions of the forelegs in the decerebellate dog. Strength of supporting tonus in the unilaterally decorticate totally decerebellate dog. Decerebellate, right side decorticate dog. “Das Kleinhirn”. Frontispiece of the classic by Luciani. German translation of “Il cerveletto” (1891). Decerebrated animal (cat). Frontispiece ‘Acta-Laryngologica’. Dr. J.W.G. Ter Braak (1903–1971). High-speed film frames of cat turning over in free fall. Drawing of a falling cat by G.G.J. Rademaker and J.W.G. Ter Braak. The Physiology Laboratory on the Zonneveldstraat in the centre of Leiden. Mathematical drawing of a falling cat by G.G.J. Rademaker and J.W.G. Ter Braak. Print of a 2-cylinder animation. Press cutting from the Dutch NRC (Nieuwe Rotterdamsche Courant): a summary of an article that appeared in Nature on 14 April (1960 or 1970?). “A walk”. Observations by the author of the combined elements of the step sign as demonstrated (exhibited) while walking with his 12 months old grandson. Aerial photos of the University Hospital, Rijnsburgerweg 10, (now LUMC, Albinusdreef 2), Leiden, in course of construction in 1928 and as seen from the east in 1934. A dinner of the medical debating society “Boerhaave”, with Rademaker seated second from the right.

xvi Fig. 3-3. Fig. 3-4. Fig. 3-5. Fig. 3-6. Fig. 3-7. Fig. 3-8. Fig. 4-1. Fig. 4-2. Fig. 4-3. Fig. 4-4. Fig. 4-5. Figs. 4-6 a & b. Fig. 4-7. Fig. 4-8. Figs. 5-1 a & b.

Fig. 5-2. Fig. 5-3. Fig. 5-4.

list of illustrations Schematic representation of the reflex arcs for the blink reflex in response to menacing movements, after Rademaker and Garcin (1933). Forebrain of the dog, after Campbell (1908). Reflex arc of the blink reflex elicited by a menacing movement in the left half of the field of vision, after Campbell (1908). Prof. Raymond Garcin with his staff and visiting assistants (assistants étrangers). “Réactions labyrinthiques et équilibre. L’ataxie labyrinthique”, published in 1935. Tilt test (Rademaker and Garcin). Prof. J.A.J. Barge (1884–1952). Photocopy of the letter Rademaker wrote on 24 August 1942 to Barge. Prof. Rademaker entering the physiology laboratory in the morning during the war years. Student J.H.A. Mulders, Med.Drs. (13 Sept. 1919–5 Sept. 1944). Photograph of the Horsley-Clarke apparatus used by Kraan, taken from his thesis. The newly built Magnus-Rademaker Physiology Laboratory in Utrecht. Patient demonstration by Professor Rademaker (1945) during a lecture for students in the Department of Neurology, Academic Hospital. ‘Decerebrate rigidity’ and postural reflexes. Diagram illustrating differences in man between decorticate rigidity and true ‘decerebrate rigidity’. Photos of the houses where Rademaker and his wife Blanche lived during the early years of their marriage, while he was engaged in scientific research under Magnus at the Institute of Pharmacology in Utrecht. Mrs. M.J.W. Rademaker-Stoltz (‘Blanche’), born 28-09-1894, whom Rademaker married on 27-051922 in Auteuil. Brain 81, 284–289, 1938. The house at Prins Hendriklaan 2 in Oegstgeest, where the Rademakers lived from 1928 till his death in 1957.

list of illustrations Fig. 6-1. Fig. 7-1. Figs. 7-2 a & b. Fig. 7-3. Figs. 7-4 a & b.

Fig. 8-1. Figs. 8-2 a & b.

Fig. 8-3. Fig. 8-4. Fig. 8-5. Fig. 8-6. Fig. 8-7. Fig. 9-1. Fig. A.

xvii

One of Rademaker’s experiments: a silk thread was passed through the brainstem of a rabbit in vivo to permit ligation of Forel’s decussation. Prof. W. Einthoven (second from the right) and staff members Ir. W.F. Einthoven, F. Hugenholtz, Dr. Waar, Dr. Flohil, Dr. F.L. Bergansius, Dr. J. Bijtel. Rademaker’s bound handwritten lecture notes with drawings. G.G.J. Rademaker, 1935. Courtesy: Deutsche Akademie der Naturforscher LEOPOLDINA, Halle (Germany). The medal for the 11th World Congress of Neurology in September 1977 in Amsterdam, on which Rademaker and Winkler are portrayed. Design: Ger Zijlstra, Amsterdam The triangle of movement, showing the connections between movement, posture and muscle tone. These two paintings by the avant-garde Russian artist Varvara Stepanova (1894–1958) give a lively impression of the disjointed movements she saw as symbolic of the times she lived in. They also bear an uncanny resemblance to the “mouvements décomposées” observed by physicians in patients with neurological disorders (dyskinesias) known under the general name of chorea, which is derived from the Greek χορεία (a kind of dance). Stepanova adds anatomical exactitude by using different colours for muscle groups that are in extension and contraction. Giovanni Alfonso Borelli (1608–1679). Frontispiece drawing. Frontispiece of “De motu animalium” by Giovanni Alfonso Borelli. Frontispiece of thesis on muscular contraction written in 1694 by Johann Bernoulli (1705–1748). Table V of “De motu animalium”, showing elements of animal movements. The triangle movement at a given moment in time and stage of development. Trigonometric model of some locomotor functions with relevant EMG data. Ophidiaster Ophidianus (Lamarck).

xviii Figs. B & C. Fig. D. Fig. E. Fig. F. Fig. G. Fig. H.

list of illustrations The student A.W. van ’t Hoff, Leiden, february 1924, in his comment on the frontpage on Von Uexküll’s monograph ‘Umwelt und Innenwelt der Tiere’. Frontispiece of “The integrative action of the nervous system” by Sir Charles Sherrington, as it appeared in London in 1906. Prof. J. Mulder. The Rademaker family grave in the “Oud Eik en Duinen” cemetery in The Hague. Frontispiece of Herschel’s Traité d’Astronomie. Jeltje, the daughter of Rademaker’s butler, with her dog.

BOOK I

ACCOUNT OF THE BIOGRAPHICAL APPROACH AND SOURCES USED. DEFINITION Introduction Just as the first part of the twentieth century saw enormous advances in physics, the second part of that century in biology and the start of the twenty-first century in our knowledge of genetics and ‘brain-mind’ science, the period from the end of the nineteenth century to the middle of twentieth was that in which experimental (neuro)physiology particularly flourished. This book is conceived as a biography of an experimental physiologist who became a neurologist during this period. Definition Biography is defined as a model of the dynamics of cognition leading to a dual account of the life and scientific endeavours of G.G.J. Rademaker. Biographical approach In this biography of the life and scientific endeavours of Gysbertus Godefriedus Johannes Rademaker (1887–1957), much more attention is paid to how his scientific ideas developed over time—about which a great deal has been rediscovered of recent years—than about the details of his private life. Rademaker himself took great care to keep his private life separate from his professional work, so that even his friends knew little about his professional preoccupations while outsiders knew even less. On the other hand, most of his scientific colleagues knew little about his private life. His wishes on this matter will be respected here. It is only recently that the opening of certain archives at Leiden University have revealed Rademaker’s ideas about giving physiology a central place in the medical curriculum, about a new neurophysiology-based

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neurology and about the extent to which psychiatry should or should not be kept separate from neurology, long a vexed question to which his great objectivity allowed him to give an authoritative answer. Rademaker’s ideas developed by degrees, starting from his education at home as the son of a clergyman in The Hague and passing through the successive stages of his time as a general surgeon in a prestigious teaching hospital, a GP and surgeon in a flourishing private practice in the tropics and ultimately, after his return to the Netherlands and a major career switch from medical practice to scientific research at the age of 35, turning to his life-long passion for the analysis of movement, muscle tone and posture as his way of studying nature, citing Galileo’s dictum, “to be ignorant of motion is to be ignorant of Nature”. His life, which was full of surprises, led to national and international recognition of his scientific work. Following the method originally developed by Plutarch in his Lives, written in the first century AD, this biography explores a number of parallel biographical themes. First, it focuses on the lives and works of Rademaker and his teacher Rudolf Magnus at Utrecht. The second ‘double life’ considered here is that of Rademaker and Raymond Garcin from Paris, whose intellectual rapport was so immediate and complete that their application of the analysis of Rademaker’s experimental data in the clinical field produced gems of scientific research and a life-long friendship.1 The period covered in this book was shaped by the ideas of a whole series of eminent researchers in the golden age of Dutch experimental physiology, including the 1924 Nobel laureate Einthoven (1860–1927), Magnus (1873–1927), whose nomination for the Nobel Prize in 1927 was annulled by his untimely death, and De Kleyn (1883–1949) who was also nominated for the Nobel Prize in 1927, Wertheim Salomonson (1861–1922) from Amsterdam, Winkler (1885–1924), Rademaker’s close friend Dusser de Barenne (1885–1940)2 who was active first in Utrecht and then at Yale, and Rademaker himself (1887–1957) in Utrecht and later in Leiden.

1 L.A.H. Hogenhuis, “Rademaker à la Salpêtrière”, and P. Rondot, “Garcin avec un passion”, papers read at a symposium on Franco-Dutch cultural relations organized by the Institut Néerlandais in Paris, 07.11.2001. 2 L.A.H. Hogenhuis, “Rademaker and Dusser de Barenne” in “History of Neurology in the Netherlands”, Boom ed. Amsterdam, 2002, pp. 309–317; 353–360.

account of the biographical approach and sources used

3

A third important aspect of this biography may be introduced by the following dictum of Rademaker’s: “involvement with the factual results of experimental research, even when such data are not easily accessible to the layman or the uninitiated, is essential,” to which it may be added that scientific research played such an important part in his life that no description of his life would be complete if it did not include in-depth coverage of his scientific work. While care has been taken not to overemphasise his work at the expense of more conventional biographical details, excerpts from the various monographs he produced have been included to throw light on the major aspects of his scientific observations and thinking. He was a major scientist, who changed our perception of the nature of neurology and our approach to posture, muscle tone and motricity—in his opinion, the key points in any examination of a patient with possible neurological problems. He trained a whole generation of Dutch neurologists. He was a great teacher, developed a whole series of innovative experimental methods, and his publications remain relevant today. Pivotal themes The major influences determining the complex course of Rademaker’s journey through life were often hidden, even to Rademaker himself, as he often gallantly admitted in his own, highly personal modest manner. To give structure to this story of the development of Rademaker’s work and thinking, the following four pivotal themes have been distinguished. • His personal struggle. Starting out in life with great confidence (perhaps even over-confidence), well aware of his intellectual baggage and social ethos, with a strong interest (alongside his backbreaking, adventurous medical work in the romantic tropical environment in which he found himself ), in motor function, muscle tone, posture and behaviour in animals, with the racetrack of Surabaya as his first physiology laboratory. We see here a struggle between the physician and healer on the one hand and the scientist in statu nascendi on the other. This heroic period of his life was brought to an end by an eye disease, which forced his return to the Netherlands for medical treatment not available in the tropics. After a brief period of indecision

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as to the form his further career should take on his return home, he chose to follow the path of scientific research. Despite his initial determination not to take a job as a surgeon in a big hospital, his clinical concerns remained with him all his life, and indeed strengthened towards the end. • The development of his character as a scientist. His initial talents—great (micro-)surgical skills, powers of observation and the ability to record his findings objectively—were clearly recognised by Magnus. The honesty with which he recorded his observations was also recognised by others (such as Denny-Brown). In his struggle to establish himself, he developed a strong logical line in his work (clearly shown e.g.. in his monograph on the Physiology of Standing) and a conviction of the importance of discussion in scientific work. He wished to test the validity of his theoretical conclusions against clinical findings, but his ability to do so was limited by the restricted amount of clinical data available to him (mainly case histories of brainstem pathology due to miliary tuberculosis or metastases of luetic gummata; seldom solitary lesions). • His desire and ability to innovate. One interesting way in which he did this was by combining the results of his researches in the fields of experimental physiology, pathology and clinical applications, e.g. with the aid of symbolic mathematics. This approach was particularly successful in the case of the fall reflex he investigated in co-operation with Ter Braak. There would still seem to be scope for the development of similar methods of representation for the complex association of posture, muscle tone and motor function and the ontogenesis of this complex in the newborn and infants. • His ability to turn setbacks into opportunities. On several occasions, episodes of (serious) sickness in himself or close members of his family served as a spur to research or triggered a new phase in his life. For example, when he went to the Dutch East Indies to take over his brother’s medical practice in Surabaya when the latter fell ill, or his return from Surabaya because of an eye complaint that led indirectly to the start of his research career. His interest in thyroid disease and exophthalmus arose from concern on two fronts: the appearance of the early signs of Grave’s disease (exophthalmic goitre) in his wife Blanche in the late 1930s, and the chance observation in 1930 that the puppies in a litter born at the Physiology laboratory were suffering from enlarged thyroid of unknown origin. This condition was rarely seen among dogs, at least

account of the biographical approach and sources used

5

in the Netherlands, at this time. (As appears from the penultimate section of Book II, Part 2.1—Rademaker’s attitude towards his experimental animals—both Rademaker and Blanche were unusually devoted to the care of his experimental animals and could be said without too much exaggeration to regard them almost as members of the family!) Blanche’s condition, signs of which are clearly visible in the photo later in this book, was considered not to require operation. However, Rademaker’s concern about it doubtless led, at least in part, to his work on the pathophysiology of ephedrine-induced exophthalmus in cats and dogs together with C. Kuypers3 and to his long-term interest in endocrinology, which continued till the end of his life.4 Rademaker’s intellectual contributions to the therapy of this disorder was only minimal, however, a fact which he regretted immensely. Another example of this ability to turn problems into solutions concerns the case of two of Rademaker’s experimental animals, the decerebrate dogs Vos and Miesel. After the operation, Vos never ate spontaneously: all the food he needed to keep alive had to be placed in his mouth by his carers. Miesel, on the other hand, had a healthy appetite once he had got over the operation. Rademaker wanted to know the reason for this difference, and when the dogs died he sent their remains to his old friend the renowned neuroanatomist C. Winkler and asked him whether he could clear up the puzzle. The result was an elegant little paper5 entitled (in translation) “The LuysEdinger sniffer organ, Jacobson’s vomero-nasal organ and the ability of animals with muzzles to distinguish between useful and harmful food”, in which Winkler showed that as a result of the operation Vos had lost the part of the brain responsible for his highly developed

3 C. Kuypers, “Untersuchungen über den Mechanismus der Exophthalmus”, Arch. Néerl. de Physiologie de l’homme et des animaux 25, 323–335, 1941. 4 Rademaker lectured to his students on the physiology of the endocrine system. A well preserved copy of his lecture notes is kept in the Boerhaave Museum in Leiden. This handwritten, illustrated manuscript is a vivid proof of his lively interest in this topic. The content of these lectures is not discussed in this book. Ganong, writing on the state of the art and the interface between neurology and endocrinology, stated: “Actually, there are few, if any endocrine glands in the body that are not affected by the nervous system”. (Ganong P.: “The brain and the endocrine system: a memoir”, in J. Meites, B.T. Donovan and S.M. McCann (eds.), Pioneers in Neuroendocrinology II, pp. 187–200 New York: Plenum, 1978). 5 C. Winkler, “Het snuffelorgaan van Luys-Edinger, het organon vomero-nasale jacobsonii en het vermogen om schadelijk en bruikbaar eten van elkander te onderscheiden bij de snuitdragende dieren”, Tschr. Ned.-Ind. 76 (feestbundel), 348–352, 1936.

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book i sense of smell, while in Miesel this organ was still intact. It is noteworthy that in this article, Winkler has taken over Rademaker’s habit of referring to his experimental animals by name—a practice not normally followed by experimental physiologists (see Book II, Part 2.1, ‘Rademaker’s attitude towards his experimental animals’). The finding of thyroid disease in his experimental animals, on the other hand, did lead to more concrete results. One of the doctoral investigations carried out under Rademaker’s supervision, by H.H. Maas, involved a pioneering, extensive study of the diet given to experimental animals held in the Physiology Laboratory and elsewhere, and came up with recommendations which led to changes in the diet that these animals received.6 Sources

Some explanation also needs to be given of the sources and investigative methods used in the collection of the material for this biography. As a former pupil and latterly chief clinical assistant to Rademaker (one of the requirements for which was residence in-house . . .), I had for several years in the late 1940s and early 1950s full access to his notes and publications, became acquainted with his views and opinions during clinical rounds, lectures and discussions, and had the opportunity of meeting many of his distinguished scientific visitors. Much later, I was able to study the impact of Rademaker’s work abroad in various ways. A generous grant from the Wellcome Institute for the History of Medicine in London in the period 2000–2001 allowed me to explore the Institute’s own archives and those of the departments of Physiology in Liverpool (where Magnus had worked under Sherrington), London (where Sharpey Schäfer was active) and Oxford (where Sherrington was professor of Neurology during the latter part of his career). During a visit to the USA in 2001, I was able to visit the Fulton Library in New Haven and to study the archives of the Yale School of Medicine and of the Massachusetts General Hospital in Boston, where the cor-

6 Maas, originally a pupil of C. Winkler, moved to Leiden for the purposes of this investigation. His thesis was published under the title ‘Onvolwaardig voedsel en krop’ (Dietary deficiencies and struma) was published by N.V. Boek- en Steendrukkerij Eduard Ydo, Leiden and defended in public on 11 October 1933. For a summary of its content, see Book IV—Part 4.1.

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respondence of Derek Denny-Brown is housed. In Paris I was able to study relevant documents in the Charcot Library and the Garcin archives at the Salpêtrière. The department of Metamedica of the University of Leiden (Prof. Harm Beukers) kindly allowed me to study the proceedings of the Medical Faculty from their archives, for the years when Rademaker was professor of Physiology and later of Neurology, and secretary and later chairman of the faculty. I have also reviewed the seven (Dutch-language) dissertations produced under Rademaker’s supervision while he was professor of Physiology.7 Research was done in the Leopoldino archives in Halle, Germany and in the Pavlov archives in St. Petersburg, Russia. The Boerhaave Museum of the History of Medicine in Leiden likewise contained valuable material for this biography, including the Rademaker and Einthoven files and photo collections, and the display of instruments used in the Physiology laboratory at the time (1928) when Rademaker took over from Einthoven as professor—many of which were actually used by Rademaker and his co-workers. Rademaker’s extensive private collection of photo and film material, containing a wealth of information about his work, was most unfortunately destroyed in toto before it could be studied in detail, after transfer to the new Physiology laboratory which forms part of the modern University Hospital campus.8 A small collection of Rademaker’s pictures and films retained by the Audiovisual Department at Leiden University is still in use for teaching purposes. Other Dutch university libraries, in particular the Walaeus Library in Leiden, contributed to the wealth of publications cited in this work. I would like to convey my hearty thanks to the staff of all the above-mentioned institutes for their invaluable help in giving me access to the relevant material. Valuable information was also derived from the many conversations and interviews I have had over the years with Rademaker’s former colleagues and students, many of whom were still alive when I started to write this biography.9 They provided me with published and unpublished documents (including books), photographs and objects, encouraged me

7 For summaries of the contents of these dissertations, not previously available in English, see Book IV—Part 4.1. 8 Personal communication by G.J. Tammeling, emeritus professor of Physiology at Leiden University (2001). 9 Physiology lecture notes by prof. Em. Dr. E. Noach, one of Rademaker’s former students.

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to continue my researches and repeatedly confirmed the need for a biography of Rademaker. While a list of all contributors is included in the book, I would like to pick out four of them here for special mention here because of the importance of the contribution they made. Prof. Henk Verbiest (doubtless the first neurosurgeon appointed in the Netherlands) had a wealth of first-hand information on Rademaker’s first hours as professor of Physiology, his lectures, talks with him that went on ‘until deep in the night’, and his demonstrations as professor of Clinical Neurology. Prof. Verbiest gave perhaps the most penetrating insights into the character of “the only man to teach me anything worth knowing about the essentials of neuroscience,” as he put it, “with his unique teaching methods, who has provided inspiration which will endure until my last day as a physiologist and neurosurgeon”. Prof. W. Storm van Leeuwen Jr., the clinical neurophysiologist who gave form to this discipline in the Netherlands, was one of Rademaker’s close friends. He had a lot to tell about Rademaker’s ‘patriarchal attitude’ to his pupils. Rademaker advised him to complete his training in Lord Adrian’s laboratory in the UK, which he did after the Second World War to return as one of the first professors of clinical neurophysiology in the Netherlands. His lucid approach to his world-famous teacher, whose influence he so greatly appreciated, was refreshing. “He sent me abroad,” he explained, “because he had no interest in electricity.” Prof. Raymond Garcin was a case apart and unique in his admiration for Rademaker as a personal friend and scientific collaborator. He explained, with a wealth of clinical examples, the relevance of Rademaker’s experimental findings to a wide variety of clinical conditions. Finally, Prof. Derek Denny-Brown (see figure), himself a former pupil of Sherrington’s. When, as a young medical graduate continuing my medical training in London, I first saw him on his clinical rounds in the National Hospital, Queen Square, and listened to his talks on Rademaker’s work, I was struck by his close personal resemblance to Rademaker. With his slender posture and introvert air, he could have been the latter’s twin brother. The audience was reduced to silence when he told them of Rademaker’s pioneering work on muscle tone and involuntary movement and the philosophy that lay behind it. Years later, I encountered Denny-Brown again at a meeting held in the National Institutes of Health, Bethesda, Maryland. On hearing of my acquaintance with Rademaker, he stressed the honesty with which the latter had recorded his original findings of cerebellar dysfunction and vestibular function, later confirmed by Denny-Brown and other American physiologists. Later still, he produced the English translation

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Fig. 1-1. Prof. Derek E. Denny-Brown (1901–1981). (Source: users.ipfw.edu/vilensk/dbwebintro.htm)

of Rademaker’s monumental Das Stehen (On the Physiology of Standing) (1981)—an invaluable addition to medical literature since as DennyBrown put it in his Introduction, “few in the English-speaking world would have been able to read in detail the 476 pages of heavy German in the original monograph, which is a mine of carefully documented information defining precisely the part played by the many cutaneous, proprioceptive and labyrinthine reactions that are the fundamental features of regulation of posture and equilibrium.” Acknowledgments Finally, I would like to mention the two main motives that led me to write this lengthy account of the life, scientific work and philosophy of a man whom I regard as one of the great Dutch academics of the 20th century. On the one hand, my personal gratitude to Rademaker himself as my teacher and my admiration for his pioneering investigations, the contributions he made to the restructuring of the medical faculty at Leiden after the Second World War together with his colleagues Barge, Gorter and Mulder and his personal courage during that war which was an example to a whole generation of students. On the other, the encouragement and help I have received from Prof. Beukers of the department of Metamedica at Leiden University who, recognising the need for an English-language account of the life and times of

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Rademaker, initiated this project, inspired me to write this biography and opened the archives of the Medical Faculty, revealing a wealth of hitherto inaccessible and almost forgotten publications which made an enormous contribution to our knowledge of a world which seems almost to have disappeared but which still provides the essential foundation for the scientific and medical endeavours and advances of today. 1.1. ‘The Son of the Minister’. Prodromes Let us go back to the beginning and consider the influence of his parents. Young Gijs10 was very fond of both his parents, and they of him. They presented him with patterns of behaviour, which he would follow—of his own free will, not from any compulsion on their part—in later life. His father, the minister of a large congregation of the Dutch Reformed Church in The Hague, gave him as it were a theological training. Studying the words of Holy Scripture in the old family Bible with his father in the evening, the father carefully recording special events inside its front cover, Gijs gave his parents evidence of his intellectual gifts. The religious motto credo ut intelligam seemed eminently applicable to him during most of his adolescence and guided his development. His father had many of his sermons published in book form and also wrote other theological works, which his son read with interest. Rademaker’s theological training was so thorough that later, when he was professor of Physiology in Leiden, he could impress the professors of Theology by the accuracy of his Biblical quotations and could point out slips in their own quotations and theological arguments. His father was convinced that he was destined to study for the ministry, but fate determined otherwise. Like four of his brothers out of a large family of thirteen (from his father’s two marriages), he ultimately chose to study medicine—a choice that his father could respect. When he later made the big jump from medical practice to scientific research, he was supported in this decision by his mother.11 10 Rademaker received the baptismal names Gysbertus Godefriedus Johannes, but in common with many others in the Netherlands was known in the circle of family and friends—at least in his youth—by the highly abbreviated form of his first name, Gijs (the ‘G’ being pronounced like the ‘ch’ in the Scottish ‘loch’ and the ‘ij’ something like the ‘ie’ in ‘pie’. 11 This may be seen from the dedication of his doctoral thesis: “To my mother, whose wish it was that I should write this thesis”.

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Fig. 1-2. Ds. G.A. Rademaker. Minister of the Dutch Reformed Church in The Hague (06-12-1834–10-05-1908).

The involvement of his father in Rademaker’s upbringing and studies up to his adolescence is known from various sources, in particular his friends W. Storm van Leeuwen Jr. and J.W.G. Ter Braak as well as Rademaker himself. Rademaker was 21 years old when his father died. Scientific confirmation of the value of being the son of a clergyman A recent study of the origins of genius (see endnotei), pointed out that the sons of clergymen, along with other classes of individuals, are statistically more than usually likely to possess certain characteristics that one might expect to find in geniuses or highly gifted persons such as creativity, persistence (the ability to become completely absorbed in a problem, forgetting the distinction between day and night or the need for meals or sleep for long periods) and wide-ranging talents and interests enabling them to excel in several careers or disciplines. This characterization would seem to apply to Rademaker as well as for example to Magnus (who while a professor of Pharmacology pioneered the experimental study of the physiology of posture in what he described himself as his ‘hobby’) and Albert Schweitzer (theologian, philosopher, organist and mission doctor in equatorial Africa), to name but two. One of the many ways in which Rademaker gave expression

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Fig. 1-3. Prof. Raymond Garcin. Professor of clinical neurology at the hospital la Salpêtrière in Paris (1897–1971).

to his ability to cross the boundary between various disciplines was in his fruitful cooperation with the French clinical neurologist Raymond Garcin.12 1.2. Parents and Family The parents of G.G.J. Rademaker were:13 – Geurt Arend Rademaker (1834–1908), minister of religion, and – Iefke Maria Louisa Dorothea Notten (1844–1921). It is stated in the death certificate of G.A. Rademaker that he was the widower of Anneke Hakkert (1832–. . . ., they married in 1858).

See Book III—part 3.2. I am indebted to Mrs. S.L. Atema, archivist of the Municipality of The Hague, for providing much of the information given here. 12 13

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Geurt Arend Rademaker had the following children: 1. Jacob Arend Rademaker (1859–. . . .), lieutenant commander and physician 2. Dania Helena Rademaker (1861–1921), spinster 3. Adriana Johanna Rademaker (1863–. . . .), went to Batavia (Dutch East Indies) 4. Helena Geertruida/Geurtruida (1864–. . . .) 5. T(h)esselina Ardina Rademaker (1866–1927), spinster 6. Lennard/Leonard Albert Rademaker (1872–1956), minister of religion and journalist, editor of the daily newspaper “Het Vaderland” in The Hague 7. Arend Hendrik Gerard Rademaker (1874–. . . .) 8. Diederik Theodorus Rademaker (1877–1892) 9. Anna Wilhelmina Rademaker (1879–. . . .) 10. Geurt Arend Rademaker (1881–1971), physician, had general practice in Surabaya (Dutch East Indies); after his return to the Netherlands, he established himself as an internist and specialist in tropical diseases in The Hague 11. Rinkiena Artiena Dania Rademaker (1883–. . . .) 12. Gysbertus Godefriedus Johannes Rademaker (1887–1957) 13. Aart Cornelis Arnold Rademaker (11 March 1890–1964), physician, worked for some time as assistant to Prof. W. Einthoven in Leiden,14 later physician at the psychiatric hospital Oud-Rosenburg in Loosduinen on the outskirts of The Hague. The first six children listed above were issue of the marriage between Geurt Arend Rademaker and Anneke Hakkert, while the remaining seven were issue of the marriage between Geurt Arend Rademaker and Iefke Notten. It would take us too far to give extensive details of the family history. However, the bare bones presented above give some impression of the responsibilities of the paterfamilias, who had to raise seven sons and six daughters on a clergyman’s modest income. It requires a stretch of

14 The period with Einthoven produced the publication W. Einthoven and A.C.A. Rademaker, “Über die angebliche positive Stromschwankung in der Schildkrötenvorkammer bei Vagusreizung nebst Bemerkungen über den Zusammenhang zwischen Kontraktion und Aktionström (Gaskelleffect)”, Pflüger’s Archiv. f.d.ges. Physiologie des Menschen u.d. Tiere, 166, 109–143, 1913.

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the imagination for us living in a modern economy to grasp the sheer difficulty of finding a job at the turn of the twentieth century. Four of the six sons studied medicine, and one theology. The only respectable employment for woman was governess or nurse. Two of Gijs’s sisters chose the former course, and two the latter. The Hague, the centre of Dutch government and of colonial administration for the Dutch East Indies and home to a large community of ex-colonials, was also the centre of Gijs’s emotional world. His father died when Gijs was 21 years old. 1.3. Initial Steps and Training During his time at the gymnasium (grammar school), Rademaker showed particular interest in mathematics, mechanics, biology and chemistry and scored high marks in these subjects. His medical studies at Leiden— where he attended the courses in physiology given by Einthoven (the later Nobel laureate, whose chair he was to take over in 1927) and those in neuro anatomy given by Jelgersma (1859–1942), among others—were equally successful. His interest in motor development in the new-born, statics and mechanics, neurophysiological aspects of behaviour in animals and pathology were striking, and were indicate of the subsequent development of his career. He sometimes referred to this later, mentioning his conviction of the need for further explanation of human posture during work and under pathological conditions (such as diseases affecting the muscles). He read Duchenne’s classical work, and later Von Monakow, Sherrington and Pavlov.15 These were the cognitive stimuli, that led him to decide to undergo further training in 15 List of the most frequently cited ‘classics’ in Rademaker’s own library: • G.B. Duchenne de Boulogne, “Physiologie des mouvements”, démontrée a l’aide de l’expérimentation electrique et de l’observation clinique et applicable à l’étude des paralyses et des déformations”, Première édition, J.-B. Baillière et Fils, 1867, pp. 873. • G.B. Duchenne de Boulogne, “De l’electrisation localisée et de son applications à la pathologie et à la therapeutique par courants induits et par courants galvanique interrompus et continus”, Troisième édition, Paris, J.-B. Baillière et Fils, 1872, pp. 1120. • C. von Monakow, “Die Lokalisation im Grosshirn und der Abbau der Funktion durch Kortikale Herde”, Verlag von J.F. Bergmann, 1914, pp. 1033. • C.S. Sherrington, “The integrative action of the nervous system”, London Archibald Constable & Co, 1906, pp. 411. • I.P. Pavlov, “Conditioned reflexes, an investigation of the physiological activity of the cerebral cortex”, Translated and edited by G.V. Enrep MD, DSc, Oxford University Press: Humphrey Milford, 1926, pp. 426.

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general surgery and orthopaedics—a discipline in which he proved to have a marked talent (see figure). At the same time, his determination to continue his training for general practice strengthened. During his period as houseman at a big teaching clinic (see figures) which formed part of the requirements for this training (and involved regular periods when he was on call day and night), he was exposed to other aspects of medical practice. His main interest was in pain control, and this remained one of his primary concerns throughout his career.

Figs. 1-4 & 1-5. G.G.J. Rademaker on the wards of the teaching clinic, During his training in surgery and orthopaedics at the Zuidwal Hospital. Courtesy Haags Gemeentearchief.

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book i 1.4. G.P. and Surgeon in Surabaya (1916–1922)

Shortly before Rademaker completed his medical studies and surgical training in The Hague, news reached the family that his elder brother Geurt Arend, a GP and specialist in tropical medicine in Surabaya, was ill—possibly burnt out after six years in the tropics. Rademaker went out to Surabaya to replace him (see figure)—an unexpected turn of events. He too was to stay there for six years (1916–1922). Rademaker had read his brother’s letters home, in which he sketched what life in the tropics was like. But in practical terms, both tropical medicine and life in the tropics were terra incognita to Rademaker when he set foot in Surabaya.

Fig. 1-6. The above announcement in local newspapers spread the news that Rademaker’s brother Geurt Arend had to give up his practice. Courtesy Kon. Ned. Tropenmuseum archive.

The translation of the announcement is as follows: Dr. G.A. RADEMAKER is leaving Java for six months due to family circumstances. His practice will be temporarily taken over by Dr. G.G.J. RADEMAKER Telephone No. and surgery hours remain unchanged. Power of attorney has been granted to Messrs. EICHHOLTZ (solicitor) and G.G.J. RADEMAKER

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When he started on his new phase in his life, Rademaker was a healthy, good-looking, well-built man of nearly thirty, energetic and enterprising and looking forward to the adventure that awaited him. He took charge of his brother’s general medical and surgical practice, and built it up to the biggest in the Dutch East Indies by unremitting hard work and keen interest in his work and the problems that faced him. Rademaker rode the valleys of the colony on horseback or was transported by carriage—which he preferred. He developed considerable skills in general tropical medicine, but also as an independently operating general surgeon supported by a small staff whom he had instructed and trained in the safe administration of limited anaesthesia. When he was called out on emergencies, the whole team would accompany Rademaker as he travelled to some distant village by horse and carriage. Rademaker’s above-mentioned interest in motor functions of man and animal bore unexpected fruit during his stay in Surabaya, as illustrated by the following quotation from a letter written during this period: “One of Rademaker’s less well known interests was in horse-breeding and horse-racing. Equine physiology was his first ‘hobby’—eccentricity or extracurricular interest?” As Rademaker said himself later, “A horse is both a racer and a labourer; these two aspects of the animal explain its morphology.” He became especially interested in work going on on a particular breed of horses in an island in the Strait of Madura. He developed a marked talent for observation and exact recording of his results, which stood him in good stead later in his clinical and experimental work. He was a much sought-after advisor on the selection and scouting of horses, and a fortiori on the selection of horses for the races held in the neighbourhood, which had a long history.16 In this way, Rademaker was able to develop a talent (hidden, even from himself ) for the observation of the morphology and movement patterns of the horse, and as an afficionado of horse racing he turned the racetrack into his first physiological laboratory. On the basis of this knowledge, he was able to amass a small fortune from successful betting on horses—a topic he did not discuss on his return to the Netherlands, from a Calvinist sense of shame about any form of gambling. In fact, no one in his

16 Organized horse-racing is known to have taken place in Surabya since 1874. Since 1925, it was under the auspices of the Sourabiaanse Harddraverij en Renvereniging (Surabayan Trotting and Horse-Racing Association), which owned a modern race track to the west of Sawaän, about 3 km from the house at Palmenlaan 10, Surabaya, where Rademaker lived and exercised his medical practice.

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Fig. 1-7. House in the Palmenlaan, Surabaya, occupied by Rademaker during the period 1916–1922.

family knew anything about these ‘extra earnings’ of his.17 It is known, however, that he sent money home to help pay for the education of brothers and sisters. He returned to the Netherlands in 1922.

I am indebted for this information to two (emeritus) professors (De Beaufort and Querido) who had known Rademaker well, and who told me independently about his winnings on the horses and were even able to put a figure on the fortune built up in this way. 17

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Endnote Endnote i In his study of the origins of genius (L’origine des genies, Ed. du Seuil, 2003), the sociologist of science Claude Thélot pointed out that the sons of clergymen are well represented among the ranks of geniuses. Thélot compiled a list of 350 persons generally recognized to have been geniuses—people like Leonardo da Vinci, Bach and Shakespeare—and subjected their individual characteristics to various kinds of analysis. He noted that 5% of this group were the sons of clergy, in particular Protestant ministers. Thélot distinguished 11 different groups of geniuses (composers, writers, mathematicians etc.), and found sons of the clergy in 10 of them. They are particularly well represented among the philosophers (Hobbes, Nietzsche) and those whose genius lay in the field of social thought—and action—like Martin Luther King and Albert Schweitzer, but surprisingly enough the largest cohort is to be found among the mathematicians. Their names included Euler (1707–1783), Colin Maclaurin (1698–1746), Niels Henrik Abel (1802–1829), G.F.B. Riemann (1826–1866) (see also Derbyshire J., “Prime obsession; Bernhard Riemann and the Greatest Unsolved Problem in Mathematics”, Joseph Henry Press, Washington DC, 2003) and Emil Borel (1871–1956). One of Abel’s notebooks contained, in between all the scribbled numbers and equations, a prayer composed by this mathematical genius: “Our Father who art in Heaven, give me bread and beer. Listen for once” [original in Norwegian, cited in “Abel’s Proof: An Essay on the Sources and Meaning of Mathematical Unsolvability”, by Peter Pesic, MIT Press 2004]. Thélot suggested that the reason why so many Protestant ministers’ sons were geniuses lay in the importance Protestants attach to reading, starting with reading of the Bible. Martin Luther in Germany produced the first complete translation of the Bible from the original Greek and Hebrew into a modern European language, so that every believer could read the Scriptures himself. Protestants believe that each individual can gain access to the truth that makes us free by independent study of the Bible—unlike Catholics, who place at least equal weight on the transmission of faith via the priesthood. Hence the great importance Protestants attached to the mastery of the text of the Bible to such an extent that one can back up one’s opinions by citing the appropriate Biblical quotation, with chapter and verse. Their motto was ‘read, mark, learn and inwardly digest’. Each Protestant family would have Bible readings every evening where the whole family, and servants, were supposed to listen attentively while the paterfamilias read from the Good Book. It is understandable that these influences were particularly marked in the minister’s son, and it is known that this also applied to Rademaker. Of course, other influences to be expected in the family environment—the religious atmosphere, the importance attached to moral commandments such as “Thou shalt not kill” and “Love thy neighbour as thyself ” and hence to the performance of charitable works, the spirit of equality arising from the idea that we are all God’s children—made a lasting impression on Rademaker. His father (see Fig. 1–2 on page 11) wrote sermons on these themes, some of which are preserved (my thanks to Ms S.L. Atema of the Municipal Archives in The Hague for giving me access to these). These few details will help to explain the intellectual and social development of Rademaker and his siblings (six brothers and six sisters: three of his brothers were physicians too, one working as an assistant in experimental physiology under Einthoven; his youngest brother was a Protestant minister like their father and a journalist, who made a name for himself as an active champion of the cause of “the oppressed, the hopeless, the broken”; and two sisters were nurses.

BOOK II

EXPERIMENTAL PHYSIOLOGY. WORK IN MAGNUS’ LABORATORY—‘KÖRPERSTELLUNG’. THE FACTS Three factors determined his ultimate choice of career: 1) his study trips to important clinical centres in London, Paris and Berlin, 2) the awakening of his interest in scientific work and 3) the advances in neurophysiology introduced by Sherrington and Rademaker’s acquaintance with Magnus, Professor of Pharmacology and Physiology at Utrecht. He joined the group at Utrecht working to develop Magnus’ concept of ‘Körperstellung’ [bodily posture]—a neurophysiological theory of the activities of walking and standing. Rademaker proved to be highly skilled in operating on experimental animals; so much so that—unlike others, including Magnus—he could carry out ablation operations at the level of the mesencephalon and cerebellum which would guarantee the animals concerned a long postoperative life. Experimental work under R. Magnus Sr. at Utrecht (1922–1927; elaboration of the concept of posture (‘Körperstellung’) Back in the Netherlands after six years as a GP in the Dutch East Indies, and “with the firm determination not to seek a surgical practice in a general hospital” (Verbiest), Rademaker decided to start by visiting clinical centres in Berlin, Paris and London to see what had been going on in the medical world in his absence. He was struck by the new developments in the field of neurophysiology, and made a decision which would prove to be crucial in shaping the whole of his future career. He asked professor Magnus in Utrecht—a major figure in European medical research at the time—for permission to undertake a research project in his laboratory. Who was this Magnus under whose guidance Rademaker began his scientific work? Though born and largely educated in Germany, Rudolf Magnus (1873–1927) was the first professor of Pharmacology (or strictly speaking, of Pharmacodynamics) in the Netherlands, being appointed to this position at the University of Utrecht in 1908. Before that he

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had worked in Heidelberg, where he had produced a number of highly original publications on such matters as the action of digitalis, water balance in tissues, renal function and oedema, blood-pressure measurements in exposed arteries and the diuretic effect of pituitary extracts. He had also worked at the Stazione zoological Anton Dohrn in Naples, where he wrote a paper on the pupillary reaction of the octopoda—a most elegant investigation he had carried out there under the inspiration of Von Uexküll in 1902 (Magnus R., “Die Pupillarreaction der Octopoden”, Archiv. F.d. ges. Physiol. 92, 623–643, 1902). At Gottlieb’s Institute of Pharmacology in Heidelberg, he had developed a new technique for studying the automatic rhythm and local reflexes of the intestinal wall. As a student, Magnus had already been deeply impressed by the work of the physiologist W. Kühne (1837–1900), and had attended lectures by the neurologist W. Erb (1840–1921). He had worked under eminent scientists at various laboratories abroad, such as Von Uexküll in Naples as mentioned above (1902), Schäfer (1850–1935) in Edinburgh (1900), Langley (1852–1925) in Cambridge (1905) and Sherrington (1859–1952) in Liverpool in 1908. It was at Sherrington’s institute that he became interested in experimental work on postural reflexes. His appointment to the chair at Utrecht and his visit to Sherrington, both in 1908, were of crucial importance for the development of his scientific career. For further details of Magnus’ life and work, the reader is referred to the biography by his son, Otto Magnus. Rudolf Magnus, physiologist and pharmacologist, 1873–1927, ed. Louis M. Schoonhooven. Amsterdam: Koninklijke Nederlandse Akademie van Wetenschappen: Dordrecht: Kluwer Academic Publishers. 2002, p. xii, 350, illus., (hardback 90-6984-327-7). Though it was not very common for foreigners to be appointed to chairs at Dutch universities, Magnus was certainly not the only one. In fact, several distinguished foreign academics have contributed to the development of the university of Utrecht. In 1924, Magnus received a request to return to Germany as professor at Heidelberg. He told the university of Utrecht that he would stay—provided they built a new laboratory for him. This requirement was met, and Magnus led the building work with care and devotion. A grant from the Rockefeller Foundation was needed to complete the work, since the funds provided by the Dutch authorities were inadequate. Sadly, Magnus never taught in the new laboratory: he died suddenly while on holiday in Ponteresina in 1927. His students—including Rademaker—had to supervise

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its completion. Rademaker mentioned the sense of obligation they felt in this respect in his inaugural lecture as professor of Physiology at Leiden in 1928. The zoologist Von Uexküll and the physiologist Sherrington (1858– 1952) have both left their mark on current views of the development of the motor system of living organisms (Von Uexküll with special reference to the lower organisms and Sherrington with reference to mammals and through them to man). They also helped to guide Magnus towards his postural research. Pride of place in this context goes to Sherrington, who was one of the first to observe the phenomenon of decerebrate rigidity and who analysed this phenomenon in his laboratory in Liverpool at the end of the 19th and the beginning of the 20th century. The role played by Von Uexküll is sketched in the endnotesi.

Fig. 2-1. Frontispiece of the classic ‘Die Körperstellung’ (‘Posture’) published in 1924 by Magnus which summarized his work and reviewed Rademaker’s work on the red nucleus. The text included a non-standard nomenclature for the names of the reflexes identified by Magnus and de Kleyn. This nomenclature was later followed by Rademaker in his monograph ‘Das Stehen’ (‘On standing’) and by other investigators referring to these investigations.

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Fig. 2-2. Photo of the research group led by Professor R. Magnus taken on 3 November 1926, on the occasion of a visit by the Russian physiologist Professor A. Samojloff. This was 2½ years after Rademaker had gained his doctorate in Utrecht, and one year before the sudden death of Magnus in 1927. The persons to be seen on this photo are Dusser de Barenne (1), van Esveld (2), de Kleyn (3), Rademaker (4), Samojloff (5), Le Heux (6), Magnus (7), de Haes (8) and de Lindt van Wijngaarden (9).

Fig. 2-3. Title page of a publication by A. Samojloff and W. Wassiljewa from 1925, with a handwritten dedication to “my dear friend and respected colleague Einthoven from A. Samojloff ”. The Nobel Prize-winner Einthoven was Rademaker’s predecessor as professor of Physiology at Leiden.

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De Kleyn, who had been Magnus’s main assistant, and Rademaker the newest addition to the team were the two Magnus relied upon to continue his work. Since de Kleyn wanted to concentrate on the problems of labyrinthine physiology, it fell to Rademaker to work on the further development of Magnus’ brilliant neurophysiological concept of “Körperstellung” (posture). This should not be taken to imply that Rademaker had already decided at this stage in his career that neurophysiological research was what he really wanted to do. No one knows what topic he had originally suggested he should work on under Magnus’ supervision. As so often happens, his written proposal seems to have disappeared in the professor’s desk. This sudden change in Rademaker’s career, from overworked GP in the tropics to scientific researcher, came as a complete surprise to his surroundings. This was not the first, nor the last time he took such unexpected decisions which turned out so well. His marriage may be cited as one striking example, as may his acceptance in 1945 of the chair of clinical neurology offered to him after his many years of devotion to experimental neurophysiology. In view of Rademaker’s surgical skills, it seemed appropriate to assign him a research project involving animal experiments. He joined the group1 that had been carrying out animal experiments on postural reflexes since 1912, and whose teamwork seemed about to be crowned with success. Magnus was world-famous in this field. Alongside Sherrington (1858–1952) and Pavlov (1849–1936), Magnus (1873–1927) was one of the great proponents of the mechanistic concept of the function of the central nervous system. He had come to the conclusion that the “normal” posture of the body is based on a balance of reflex muscle tones, and he had set himself and his team the task of identifying and analysing the individual reflexes contributing to this balance, and of identifying the receptors and the CNS pathways which played a role in this connection. The great importance of the midbrain (mesencephalon) in this context had become apparent in the course of these investigations. Rademaker, the newcomer to the team,

Magnus named the following as his research staff in this period: J.G. Dusser de Barenne, U.G. Bijlsma, J.H. de Haas, J. v.d. Hoeve, J.M. Hoffmann, D.J. Jonkhof, J.J. Koster, G. Liljenstrand, H. Dort, Ch. Soein, H. Stenvers, W. Storm van Leeuwen Sr., C.R.J. Versteegh, W. Weiland, C.G.L. Wolff and A. de Kleyn. 1

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was given the task of identifying its role more precisely.2 There were three factors which made him ‘the right man at the right spot’ for this job. Firstly, there was his striking talent for impartial observation and analysis of the behaviour of the experimental animals in which CNS lesions had been induced—his clinical gifts, in other words. Secondly, the remarkable microsurgical skills he had acquired. And finally, the great talents his wife proved to have for taking care of the experimental animals. Rademaker took the experimental animals (dogs, cats or rabbits) home at the end of each working day, to be looked after by his wife. The distance to be covered was not great, since he lived across the road from the laboratory. Nevertheless, the logistic problems involved were not inconsiderable. Rademaker picked up this line of investigation when he joined the team of researchers at Magnus’s laboratory in 1922. He had noticed the uncertainty concerning the level at which the cut was made to bring about decerebrate rigidity in the experimental animal, had also noted the differences between the various experimental animals studied when the cut was made at different levels and had finally shown how consideration of the function of the nucleus ruber explained this phenomenon. Sherrington had been aware of this effect, but had been unable to produce an explanation for it. In order to understand Rademaker’s later scientific work properly, we need to pause here to review Magnus’s work and sketch the state of affairs in the laboratory where he and his research team were active at the time when Rademaker started his research there. 2 The introduction to the first paper that Rademaker wrote together with Magnus on “Die Bedeutung des Roten Kernes für die Körperstellung” [The significance of the nucleus ruber for bodily posture] (published as a ‘Vorläufige Mitteilung’ in Schweiz. Arch. f. Neurologie und Psychiatrie 13, 408–411, 1923) contained the following passage (which we translate from the original German) cited from “Der Rote Kern, die Haube und die Regio Hypothalamica bei einigen Säugetieren und beim Menschen” (Wiesbaden, Verlag von J.F. Bergmann, 1910, p. 387), by the neuro-anatomist Von Monakow (1853–1930) (reviewed in Arbeiten a.d. Hirnanatom. Institut Zurich 3, 51–267, 1909): “What the rolandic region, the pyramidal tract and the various spinal centres subordinated to them do for the finer functional details of purposive movements, the nucleus ruber together with the sites representing it in the frontal lobes and the cerebellum (the nucleus dentatus) do for other motor or regulatory tasks—tasks probably very cloesly related to the unconscious orientation of one’s body and the corresponding adjustments in space e.g. the maintenance of the body’s upright posture, which humans (and indeed primates in general) have to struggle to do every time they execute a locomotor motion”.

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What ideas were circulating, and what goals were set, at the time when Rademaker joined the team? The best way to answer this question is to take a look at Magnus’s monograph “Körperstellung” (Posture), which appeared in 1924. This magnum opus of 730 pages3 summarizes the activities of Magnus and his team—including the later experimental work by Rademaker.4 The book, which became a physiological classic, was initially published only in German in 1924. It was later translated into other languages, including Russian. In the preface to this book, Magnus told about the chance occurrences which led him to perform the experiments which form the subject of this monograph, and which added one of the most fascinating chapters of its history to the physiology of the nervous system. In the fifteen years that had passed since the first description of that ‘observation privilegiée’, Magnus and his co-workers (among whom de Kleyn took pride of place) had published the results of their experimental investigation of the problems relating to the neural regulation of posture in a series of more than thirty papers. Walshe (an admirer of Magnus; see Book VI, Part 6.1) and other contemporaries said that the physiological literature had seldom seen more lucid, impressive reports of ingenious experiments, of the problems to be overcome in performing them and of the exact information obtained. The English school of physiology may be justly proud that the thirty years of work by Sir Charles Sherrington provided the foundation for the masterly edifice of scholarship built on it by the Utrecht school. Rademaker was well aware of the spiritual affinities between himself and his Dutch colleagues on the one hand and English neurophysiology on the other. He often mentioned it in the spoken and written word, e.g. in the obituary of Sherrington that he wrote for the Yearbook of the Royal Dutch Society of Sciences in 1954. (G.G.J. Rademaker, “Levensbericht van Sir Charles Scott Sherrington (28 Nov. 1855–1 Maart 1952)” Jaarboek der Koninklijke Nederlandse Akademie van Wetenschappen, 1–8, 1953/1954)

3 Despite the pessimistic statement by Callimachus (305–240 BC, Head Librarian at the great library of Alexandria) that “a big book is a big nuisance”, Magnus’s monograph makes fascinating reading! 4 See in particular pp. 614–643, where the experiments performed by Rademaker on “Die Stellreflexe (Labyrinthstellreflexe; Körperstellreflexe auf den Kopf; Körperstellreflexe auf den Körper; Halsstellreflexe)” [The righting reflexes [Labyrinthine righting reflexes acting on the body, the head and the neck] and “Die Bedeutung des roten Kernes, für die normale Tonusverteilung und die Stellreflexe” [The significance of the nucleus ruber for the normal distribution of muscle tone and righting reflexes] are summarized.

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Sherrington’s investigations in which he explained muscular tone as a purposive reflex action which forms the basis for all activities of the muscular system aimed at maintenance of bodily posture have become such an integral part of clinical neurological thinking that it is hardly necessary to refer to them any more—except in such cases as the present when we are trying to throw light on that special moment in the history of science when the work of Magnus and co-workers was taking shape in Utrecht alongside that of Sherrington et al. in Liverpool, the models that they produced forming the basis on which Rademaker could exercise his genius. The animal model that formed the basis for all of Sherrington’s experimental investigations of muscular tone and for Rademaker’s subsequent work in this field was the animal with decerebrate rigidity (the ‘decerebrate preparation’).5 This is an animal (usually a dog or cat, but 5 The phenomenon of ‘decerebrate rigidity’ was undoubtedly observed by many early students of the nervous system (including Whytt 1755/1763; Rolando 1809 and Flourens (1794–1867) and Th. Ziehen, 1890; but the significance of the exaggerated posture was not understood until Sherrington’s papers on the subject were published in 1898. – Sherrington C.S., “Decerebrate rigidity and reflex coordination of movements”, J. Physiology 22, 319–332, 1898; – Magendie (Magendie Fr., 1783–1855; French physiologist whose work was admired by Rademaker) in the observation he made in 1823 on decerebrate animals anticipated Sherrington by an accurate and detailed description of decerebrate rigidity in rabbits: Magendie Fr., Sur la siège du movement et du sentiment dans la moelle épinière”, J. Physiol. Expér. et Pathol. du Système Nerveux 3, 153–157, 1923. – This was as remarked by Brazier (1988) (Mary A.B. Brazier, “A History of Neurophysiology in the 19th Century”, Raven Press New York, 1988, p. 44) in the years before the discovery of anaesthesia (in man) by the American surgeon Morton (1819–1868) (William Thomas Greene Morton, “On the physiological Effects of Sulphuric Ether and its Superiority to Chloroform”, Clapp. Boston, 1850) in the Massachusetts General Hospital in Boston in 1846 and Magendie was severely criticized for the use of vivisection. “It was probably the reason why his observations did not get the attention which they deserved as the original observations on the phenomenon”. – Sherrington C.S., “Experiences in the examination of the peripheral distribution of the fibres of the posterior roots of some spinal nerves”, II Croonian Lectures—Philos. Trans. 1898a, 190 B, 45–186 (introduced the term ‘decerebrate rigidity’, which had been used for the first time in 1896; the manuscript was submitted on 12th November 1896, and the paragraph (pp. 128–186) where he discussed decerebrate rigidity and its inhibition by anterior cerebellar stimulation (p. 174) was presented at the Croonian Conference in April 1897) [31, 32, 103, 119, 139, 145, 163, 482]. He noted that shortly after section of the brainstem, just rostral to the cerebellum, a state of exaggerated extensor posture developed, affecting all four extremities and also the neck and tail. When Sherrington first discovered decerebrate rigidity, he asked

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sometimes a rabbit) in which the brainstem has been transected at the level of the tentorium. The upper and lower limits between which such a cut had to be made were later determined precisely by Rademaker. The headward limit was a coronal section at the level of the corpora quadrigemina posteriora, and the caudal limit the section at the level where the eighth cranial nerve joins the brainstem. After transection within these closely defined limits, all the muscles which normally maintain the body in an upright posture were found to be in a state of rigidity or hypertonus. The stimulus needed to bring this change about is generated in the proprioceptive nerve endings of the tonic muscles themselves. Sherrington and his co-worker Liddell later (in 1924) found that stretch is the adequate stimulus for this purpose. They were also able to describe the conditions required for the development and incidence of the necessary tension. It followed from their findings that integrity of the afferent nerve supply to the muscle is a fundamental condition for the development and maintenance of muscle tone. What lay behind Magnus’s work? What aspect of this investigation had inspired Rademaker so strongly? Rademaker wrote as follows about this at a later date:6 This work arose from a simple observation of an apparently unimportant phenomenon—of which, however, the penetrating gaze of the observer was able to see the fundamental importance. Analysis of this phenomenon led to an investigation which proceeded step by step, the technical problems involved being overcome at each step, until the overall result of great scientific value was attained: a knowledge of the physiology of

himself the following questions: 1) Can decerebrate rigidity be seen in all species?; 2) What are the anatomical connections essential for it?; 3) Which sensory pathways play a role in the maintenance of this rigidity?; 4) Can decerebrate rigidity be inhibited by the stimulation of other parts of the nervous system? Sherrington argued that this effect could not be due to irritation at the site of the cut, since it persisted indefinitely and must therefore be regarded as a phenomenon in which the lower brainstem is ‘freed’ from the control normally exercised by higher centres in the forebrain. He recognized furthermore that this rigidity involved primarily the antigravity muscles i.e. those which normally maintained the animal in an erect posture. His analysis of this condition is regarded as one of the classics of physiological endeavour. Fulton’s Textbook of Physiology, 17th edition 1955, Chapter 12, p. 213, W.B. Saunders, Philadelphia and London. 6 Rademaker G.G.J., “Willekeurige en onwillekeurige handelingen” [Voluntary and involuntary actions]. Inaugural lecture as professor of Physiology at the University of Leiden 10-10-1928, p. 23.

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book ii the brainstem and of the reflex maintenance of normal posture with respect to the surroundings.

Magnus tells us at the start of his book Körperstellung that on an afternoon in the Spring of 1909 (after returning from his visits to Langley and Sherrington), he happened to be handling a decerebrate dog when he noticed in passing that when he moved the animal from a lateral position (lying on its side) to a supine position (lying on its back), the tone of the extensor muscles of its legs increased noticeably. He also noticed that flexion of the animal’s head with respect to its body so that a line drawn through the mouth made an angle of 45 degrees above the horizontal plane caused a further increase in the above-mentioned tone which could be observed after a latent period of a few seconds. These changes in tone would persist for as long as the new position of the head that brought them about was maintained. Sherrington made similar observations round about the same time, independently of Magnus. He found, for example, that when the animal’s head was rotated, the limbs on the side towards which the vertex was rotated showed an inhibition of extensor tone. Extirpation of the labyrinths did not eliminate this effect, but transection of the superior cervical nerve roots did. This showed that the reaction was a reflex originating in the nerve endings of the deep structures of the throat-neck region. In the first report of the effect of the rotation of the animal’s head by Magnus and de Kleyn (1912), the authors refer to the simultaneous discovery of this effect by Sherrington as follows (we translate from the original German): During the course of these investigations, Prof. Sherrington kindly informed one of us (Magnus) that he had also observed a reduction in the muscle tone in the hind leg—on the same side as that towards which the vertex of the skull is turned [this leg is called the ‘Schädelbein’—literally ‘skull leg’—in the terminology used by Magnus; see further page 48]—less so in the front legs of the decerebrate rat in response to rotation of the head.7 Prof. Sherrington was also kind enough to send us his experimental notes. His experiments also showed that the reaction persisted when both vestibulocochlear nerves were transected or both labyrinths destroyed, and also when in addition both trigeminial nerves were transected. The reac-

7 Magnus R. and the Kleyn A., “Die Abhängigkeit des Tonus der Extremitätenmuskeln von der Kopfstellung”, Pflüger’s Archiv. f.d.ges. Physiol. des Menschen u. der T. 145, 455–548, p. 468, 1912.

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tion was however eliminated by transection of both first cervical nerves and the posterior roots of the third cervical nerve pair. The occurrence of the head-rotation reflex has thus been confirmed by independent observations in two different laboratories.

Sherrington8 confirmed this and added: In addition, the active and passive rotation of the neck about its long axis in the decerebrate preparation inhibits the tonus of the extensors in the posterior limb on the same side as the downward ear and gives rise to active flexion of the knee; the same reaction is found after section of the two Vth pairs of cranial nerves and the two VIIIth pairs. Furthermore, although the prolonged regular post-decerebration tonus is characteristically absent in the muscle in the deferent vasto-crural portion of the decerebrate preparation, nevertheless this portion does show tonic contraction from time to time for relatively short periods and this reaction can be followed all the way to the afferent sources at the root of the posterior limb.

Sherrington had used the decerebrate preparations to study the individual reflexes and their mechanisms (transfer of the relevant signals within the nervous system). As we have seen above, after Magnus had left Liverpool, Sherrington and Magnus independently discovered the effects of the rotation of the head on the posture of the decerebrate cat. When Sherrington learned that Magnus had observed this reaction, he encouraged him to follow this up and generously confirmed that he considered it fitting for Magnus to elucidate the origin of this observation. Magnus quickly understood the importance of this phenomenon, and spent most of his time for the rest of his life in its analysis. He died a year after the masterly overview of his overall findings, which he gave as the Cameron Prize lecture in Edinburgh on 19 and 20 May 1926. The work of Magnus and the experimental investigations of Rademaker, the results of which were also published in Magnus’s monograph ‘Körperstellung’, formed the basis for much subsequent research. We need to understand this basic information before we can go on to deal with Rademaker’s complicated ideas on this subject. The accompanying photo shows de Kleyn, Magnus and Rademaker at the time they were working together on this topic.

8 Sherrington C.S., “Flexion reflex of the limb, crossed extension-reflex, and reflex stepping and standing”, Journal of Physiol. 40, 28–121, 1910; see p. 112.

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Fig. 2-4. Magnus, de Kleyn en Rademaker seated at a table in the Physiology laboratory in Utrecht. Rudolf Magnus (1873–1927) became the first professor of pharmacology in the Netherlands in the University of Utrecht in 1908. Before that he worked in Heidelberg, where he had already published a number of original papers on the action of digitalis, the water-balance of the tissues, kidney function and edema, the measurements of pressure in an exposed artery, and the diuretic action of pituarity extracts. In Gottlieb’s Institute for Pharmacology at Heidelberg he had invented a new and elegant technique for the investigation of the automatic rhythm and local reflexes of the intestinal wall. As a student Magnus was deeply impressed by the physiologist Willy Kûhne (1837–1900) and by the neurologist Wilhelm Erb (1840–1921). He visited the physiology laboratories of Von Uexküll in Napels, Schäfer in Edinburgh (1900), Langley in Cambridge (1905). On this picture he is shown with his first and closest co-worker Adriaan De Kleyn (1883–1949) who was an ENT specialist by training, and Rademaker (1887–1957) who joined Magnus’ team in 1922. Courtesy: dr. O. Magnus.

It should not be forgotten that Magnus, who had trained as a pharmacologist and was a full-time professor of Pharmacology at the University of Utrecht, called his scientific work on the concept of posture a ‘hobby’ when talking about it to third parties. While it is true that this physiological hobby did incidentally have certain pharmacological aspects, this does not alter the fact that he always regarded this work on posture as “just” something he did in his “free time”. This also

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partly helps to explain the reliance he placed on others (in particular de Kleyn and Rademaker) for the performance of the enormous amount of experimental work needed as a basis for his theory—though it is of course quite normal for a professor or other leading scientist to collect around him a team of researchers to perform the investigations needed to explore a given idea, which are often beyond the powers of a single man. The above-mentioned observations formed the starting point for Magnus’s subsequent work, which is described in his book ‘Körperstellung’. This work resulted in the discovery and classification of an extremely complex series of reflex mechanisms of proprioceptive origin, which are expressed as variations in muscular tone and hence in posture. Rademaker and co-workers concluded that the otoliths, the organs of the labyrinths (not the semicircular canals), and the proprioceptive nerve endings in muscles, tendons and joints throughout the body were the sources of the tonic reactions that allow animals to assume the various postures required in the course of their highly varied motor activities. They further observed a series of reflex movements, the phasic reflexes, which are elicited by stimulation of the semicircular canals and which together with the above-mentioned tonic reactions allow the intact animal to keep its balance while moving through space. The combined investigation of Sherrington, Magnus and their co-workers elucidated the nature of the motor activities of the spinal cord, brainstem and cortex. They made it possible for the first time to subject to scientific analysis the bewildering variety of motor disorders that may be associated with diseases of the human central nervous system, which may give rise to neurological problems and were so often completely unexplained. In their investigations of decerebrate animals, Magnus and de Kleyn observed that passive changes to the position of the animals’ head or body led to reproducible changes in the tone of the muscles involved in reflex decerebrate rigidity. These changes were visible, and were expressed either as changes in limb position or as palpable modifications of the decerebrate rigidity. In order to appreciate Rademaker’s scientific work, we need to understand the vast array of reflexes observed by Magnus and de Kleyn. This is no easy reading matter, but is vital for good comprehension of the theoretical and practical foundation of the continuation of Magnus’ work.

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The two main groups of reflexes investigated by Magnus and coworkers and reported on in ‘Körperstellung’ are the tonic labyrinthine reflexes and the tonic neck reflexes. They also investigated a related set of reactions controlling the position of the eyes. An overview of these reflexes is given in endnoteii. We will now go on to discuss how Rademaker developed his working method (Part 2.1) and his discovery of the key role of the nucleus ruber in coordinating all these reflexes (Parts 2.2 and 2.3). 2.1. The Development of Rademaker’s Working Method. ‘The Husband-and-Wife Team’ “There is little doubt that the most important event in recent human evolution was the invention of the bicycle.”9 This statement applies equally to the evolution of Rademaker’s experimental style, since he did not have a car at his disposal at the start of his career and never learned to drive himself. There is also little doubt that Rademaker took the experimental animals he had operated on home in the evening, probably on the luggage carrier of his bicycle and certainly with very great care—the meticulous care he devoted to every aspect of his experimental work was one of the key factors of his success. He did not have far to go. He lived just across the road from the laboratory where he performed his experiments, so the risk involved in the transport was slight. (see endnoteiii) Once he had got the animals home, his wife Blanche assumed responsibility for their animals’ post-operative care. She did this with such skill and attention—working round the clock if necessary—that complications due to hypothermia, dehydration and the need for artificial feeding were largely avoided. As the daughter of a French tonnelier (cooper), she was not afraid of hard work (see also Book I, Part 1.1). Rademaker observed and recorded the post-operative findings. He also wrote his thesis during this period, in the remarkably short space

9 J.S. Jones, “Bicycling to Utopia”. Essays on science and technology from the Royal Institution. Edited by Peter Day and Richard Catlow, Oxford Univ. Press, 1995, pp. 9–17; see also Endnotes of this book.

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of time of two years (1923–1924), and was awarded a doctorate cum laude on its basis in 1924. One of the first discoveries Rademaker, ever the student, made was thus ‘the husband-and-wife team’ (see figures). Although it was difficult to keep these decerebrate animals alive for long because the operation caused them to lose the power of spontaneous heat regulation,10 Rademaker and Blanche proved that it was possible with the aid of hot-water baths and blankets if the lesion had been made correctly.11 They had only recently got married. They had no source of income, as during the whole period he was with Magnus he worked as an unpaid assistant (and was booked as such in the university’s records). Blanche did not work either (apart from the full-time unpaid job she had looking after the experimental animals!). The couple lived on the money he had saved during the six-year period he spent as a GP and general surgeon in Surabaya was, but in fact mainly from the money he had won betting on horse races during that time (this source of income was not generally known). Thus, Rademaker funded this first research project himself, bought the photographic material he needed himself and often even paid for the experimental animals. Nevertheless, those who knew them in these early days describe them as a happy couple, full of enthusiasm for their scientific adventure—very much, doubtless, like the Curies in the early days of their scientific career. They went to Paris, where her family lived, as often as they could. They loved the Paris nightlife and dancing, which was how they had met in the first place. After he was appointed professor of Physiology in Leiden in 1928, Rademaker used a variety of experimental animals in his research. He started off with rabbits, as he had done in his first studies of the red nucleus. However, when the existence of a species specificity

10 A.D. Keller and W.K. Hare, “Heat regulation in Medullary and Mid-brain Preparations”, Proc. Soc. Exp. Biol. and Med. 29, 1067–1068, 1932. 11 See the remarks on the need for precision in the coronary section of the midbrain in footnote J.S. Jones, “Bicycling to Utopia”. Essays on science and technology from the Royal Institution. Edited by Peter Day and Richard Catlow, Oxford Univ. Press, 1995, pp. 9–17. A.D. Keller and W.K. Hare, “Heat regulation in Medullary and Mid-brain Preparations”, Proc. Soc. Exp. Biol. and Med. 29, 1067–1068, 1932. See the remarks on the need for precision in the coronary section of the midbrain in . . . Book III, Part 6, section 6.1.

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Figs. 2-5 & 2-6. Mrs. Rademaker in the laboratory during observations on decerebellate dog Erik. (Fig. 2-5.) Observations on the decerebellate dog Erik with blindfold on a support which can be raised at the tail end. 1. The tail end of the board is lower than the head end. Head in normal posture; i.e. the muzzle at an angle of 45º below the horizontal: neck and spine form almost a straight line. The hindlegs maximally extended, the muscles of the hindlegs in strong contracteions. 2. The tail end of the board is higher than the head end. Due to the influence of labyrintine righting reflexes, the head was moved dorsally to the trunk, so that the muzzle is now also situated 45º blow the horizontal. Neck and dorsal spine form an upward abtuse angle. In agreement with the alteration of head posture and the trunk, the supporting tonus of the hindlegs has diminished and the legs have gone into a flexed position. The importance of alterations in supporting tonus on lifting and lowering of the head for adaptation to static conditions. (Fig. 2-6.) Observations on the decerebellate dog Erik with blindfold on a board which is moved up and down at the head end. 1. Head of the board is lower than the tail end. The dog keeps in muzzle ± 43º below the horizontal, neck and dorsal spine form an upward opened obtuse angle, hindlegs are fixed so that the posterior part of the body is in a sitting posture. 2. Head end of the board is above the horizontal. The muzzle now also stands at an angle of ± 45º below the horizontal due to a ventral flexion of the head, neck and dorsal spine form an almost straight line. The hindlegs are extended with a strong supporting tonus. Pictures and text after G.G.J. Rademaker in ‘On Standing’, Ed. D. Denny-Brown, published by the University of Minnesota Press, 1980, p. 202. Originally published as Monograph in General Neurology and Psychiatry No. 59 by Julius Springer, Berlin, 1931.

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was discovered12 he also used cats and later, for prolonged studies of abnormalities in posture and gait, dogs. Finally, he also found it necessary to use primates during his time at Leiden. While the financing of Magnus’s laboratory by the faculty and/or the university was sufficient to cover normal running costs, there was no room in the budget for the acquisition of primates such as monkeys. During the Depression of the ‘thirties and the war years, it was impossible to get hold of experimental animals at all. When the department had no funds for the acquisition of experimental animals, Rademaker paid for them out of his own pocket since as he put it, “at that moment he was fortunately still in a position to do so”.13 Investigation of muscle tone When Rademaker had completed his thesis on the nucleus ruber and started his great study of decerebellate and decorticate animals the results of which were to be laid down in his monograph Das Stehen (1931), one of the key issues that faced him was one that had been bothering Magnus’s research group for some time: the need to clear up the confusion in the definition of muscle tone or tonus, and to arrive at a well-based method of determining it. Tonus, the slight, continuous contraction of muscle which in skeletal muscle aids in the maintenance of posture and the return of blood to the heart, had been known since the time of Galen but was interpreted by different researchers in widely differing ways. (See further) The limbs of vertebrates are built up of bony segments interconnected by a complicated arrangement of ligaments and moved or held in a fixed position by muscles. Fasciae also play a role in this connection. The whole system can be easily moved in various directions, but can also be held more or less rigidly in a number of postures. The problem was how to explain how e.g. an extremity can sometimes be used as an instrument for various purposes such as digging, scratching or fighting, in which case all joints are freely mobile, while at other times it can

See also Book II on the neuroanatomy of the nucleus ruber in different species. Personal communication P.H.R. Burgerhoff Mulder (1913), at that time a neighbouring friend. 12 13

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serve as a sturdy support, a sort of rigid pillar capable of supporting the body’s weight. Experiments had shown that this variability in function could be achieved by means of a series of local static reflexes, which could be influenced by carefully located lesions at various points in the nervous system. This approach, passed on from Sherrington via Magnus to Rademaker, allowed much to be learnt about the mechanisms governing posture and movement in animals. Rademaker’s operative skills, combined with Blanche’s devoted care, made it possible to keep the experimental animals alive much longer than most researchers before him had achieved, and thus to study the muscle tone of these animals over a period of many months or even years. He soon realised that this was no easy task, and that the condition of the muscle tone of an extremity at a given moment depended very largely on the way in which it was investigated. If for example a dog was laid on its side and the resistance of a forelimb to passive bending was investigated “with the hand and fingers flexed, often no resistance can be felt. But if the latter are extended and pressure exerted against the pads of the foot, then the forelimbs become strongly extended and can hardly be flexed at all. . . .”. This effect could also be observed in intact animals. Rademaker devoted considerable effort to working out a consistent procedure for determining the tonus, which could be relied on to give reproducible, comparable results. Choice of experimental model The first experimental animal model applied by Rademaker was that involving decerebrate rigidity, initially only in the rabbit and the cat. In subsequent series of experiments, he used coronary sections at different levels, oral or caudal from the initial intercollicular site on the brainstem. Some experiments involved complete ablation of the cerebrum and cerebellum. Other researchers had tried to carry out similar experiments in the past, but had generally been unable to study the results of the ablation over a period of weeks or months, either because of inability to keep the experimental animals alive or because of inadequate knowledge of the anatomy involved. One important general issue here is whether to use the animal models to study movement or posture. As Magnus put it, “Movement affords many points of attack for research because by movement changes in the condition of the body or its parts occur, which attract the attention of the

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observer and can be recorded and measured”.14 In studies of posture, on the other hand, one is dealing with a constant or semi-constant condition without apparent changes so that the researcher is not motivated to look for causal relationships and there is no immediate reason to believe that active processes are at work. While older authors had speculated that posture might be based on an active process, how could experiments be of help in elucidating the basic mechanisms underlying such a process?

Investigation of righting reflexes as a baseline While Rademaker studied a wide range of reflexes in his experimental animals (see Book II, Parts 2.3 and 2.4), he tended to concentrate on the righting reflexes (those governing the organism’s ability to return to a preferred position after a departure from it, which play a part e.g. in sitting up or standing from a supine position, or in the fall reflex which governs a cat’s ability to land on all fours even when dropped from a supine position) as a general indicator of the animal’s condition. Research had shown that righting behaviour depends on the combined action of five groups of reflexes. It is impossible to study the operation of one of these groups in isolation by inactivating the sensory nerve on which it is based or by otherwise blocking the sensory perception on which this group depends: the other four groups will probably compensate for the loss of the group in question so that no overall disturbance of the righting reflex is observed. Here, as in other complex functions of the central nervous system, we cannot draw general conclusions from the results of the elimination of a single set of reflex centres. A broadly based understanding of the mechanism as a whole is only possible if the experimental results are compared with those for a null option or zero condition in which all centres playing a role in the mechanism in question are inactivated so that the experimental animal shows no trace of the function involved. In subsequent experiments, one centre or another will be left intact and the animal’s reactions compared with those for the zero condition. This procedure does make it possible to study each reflex group separately and to deduce how the general function comes about by interaction of the individual reflexes.

14 Magnus R., “Some results of studies in the physiology of posture”, Lancet iii, pp. 531–536, 1926—Cameron Prize Lecture.

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The zero condition and zero option for righting reflexes The original zero condition for righting reflexes, as developed by Magnus, is as follows: A thalamus or mid-brain animal, after extirpation of both labyrinthen, is held firmly in the air so that its paws cannot touch the ground. Under these conditions, the animal will make no active movements aimed at bringing its head into the normal position. If the animal is held by the pelvis in a lateral or supine position then the whole body, including the head, will remain in that position. It should be noted, however, that this zero condition is species-dependent. No further measures are required for rabbits and guinea pigs, whose eyes play no role in the righting reflexes. Cats, dogs and monkeys, on the other hand, must be blindfolded to produce the desired disorientation that will eliminate the righting reflexes completely. Rademaker used the procedure described above to study the labyrinthine, optical, neck and body righting reflexes; it could also be applied to other types of reflexes. Similar zero conditions for the righting reflex may also be observed in human patients. The precise nature of the zero condition depends on the nature of the patient’s complaints. For example, if a deaf and dumb subject without labyrinths is immersed in water the body righting reflex will not be operative since there are no optical aids to orientation and as mentioned the labyrinths do not work. Such patients will thus drown if there is no one at hand to help them out of the water. Magnus sketched various such examples in his Cameron Prize lecture delivered at the University of Edinburgh in May 1926. This lecture, which gave a masterly survey of the state of art in this field, turned out to be Magnus’s swan song, since he died unexpectedly the following year. Rademaker, the researcher in action The best way to gain an impression of the way a scientist works is to look over his shoulder in the laboratory or operating theatre, or failing that to read through the books and articles for scientific journals he has written or if possible to peruse his laboratory notes. There may even be pictures of the researcher in action in these publications. Rademaker’s works, in particular his monograph Réactions labyrinthiques et équilibre: l’ataxie labyrinthique (1933), are a rich source of such illustra-

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tions. They show clearly his affinity for the experimental animals and his powers of close observation: during the experiments, he holds the animals carefully in his hands, walks round with them or sits on the tilting table or chair with the animal on his lap. He shows the same personal approach and close attention to detail in the clinical application of these experiments, e.g. when using a tilting bed during the development of clinical tests for patients at La Salpêtrière in Paris together with Garcin or when trying out the support reaction on himself as discussed and illustrated below.15 The authority with which Rademaker designed and performed these experiments is impressive; the research or clinical assistants visible on some of the filmstrips he has left behind seem to be equally impressed. While, to use Denny-Brown’s words, his monographs are often ‘no easy reading matter’, the filmstrips they contain speak a very clear language. Rademaker planned his animal experiments carefully in advance, following a strictly logical scheme, and stuck to this scheme faithfully when performing the experiments. The same logical approach is to be found in the lectures he gave to students and the diagrams he used to illustrate them (see figure). Wherever possible, Rademaker used the insights he had gained in his animal experiments as the basis for clinical research in a patientbased situation. Of course, this was dependent on the availability of patients with chronic lesions of the systems he was interested in. His close friend and colleague Raymond Garcin, professor of Neurology at La Salpêtrière, was always ready to tour other Parisian clinics with him in search of suitable patient material, or to make prior appointments with patients when Rademaker announced his arrival in Paris in advance, as he often did during his summer holidays. The number of patients that Garcin in his enthusiasm was able to recruit for these fairly short visits is impressive. For example, the two of them carried out static adaptation tests using the tilting table on 80 patients for Réactions labyrinthiques et équilibre.

15

Book III, Part 3.2.

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A separate problem that Rademaker faced was getting the results of his researches accepted in clinical practice. Thanks in part to the support of Garcin and his superior at La Salpêtrière Guillain, Rademaker eventually built up a considerable reputation among French clinicians based on the results of his neurophysiological experiments—better, in fact than in the neurology clinics of the universities in his own country. Anaesthesia and postoperative care of the experimental animals The anaesthesia gave rise to specific problems in the animal experiment. The kind of problem encountered depended on the choice of the experimental animal. Like de Kleyn before him—another researcher from the Magnus stable, who had published independently on anaesthesia techniques in small experimental animals16—Rademaker realised the importance of this aspect of the experiment. The care he took in the choice of anaesthesia techniques was one of the reasons for his success. One of Rademaker’s original ideas was his recognition of the need to pay close attention to the post-operative care of his experimental animals in the long term. Few authors before him had taken this attitude. Rademaker gave due credit to those who had, such as the German physiologist Goltz, of whom he wrote “This researcher managed to keep dogs alive for months after extirpation of the cerebrum” (1928). It is known from work on different species, especially cats, that success in keeping decerebrate animals alive and in good condition depends very largely on how well the body temperature is maintained at or near the normal level. Since one of the most important characteristics of a decerebrate animal is its loss of temperature control, it is necessary to provide artificial heat regulation in such cases. This is done either by heating the surrounding medium to normal body temperature17 or, less elaborately

16 A. de Kleyn, “Zur Technik der Labyrinthextirpation und Labyrinthausschaltung bei Katzen”, Pflüger’s Arch. f.d.ges. Physiol. d. Menschen u.d. Tiere 145, 549–556, 1912.I (“On the technique of extirpation and elimination of the function of the labyrinth in cats”). 17 This was done as a matter of routine by Bazett and Penfield, as recorded in their publication Bazett H.C. and Penfield W.G., “A Study of the Sherrington Decerebrate Animal in the Chronic as well as the Acute Condition”, Brain 45, 185–265, 1922.

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but still effectively by Rademaker, by using an electric pad or hot-water bottle and blankets. Introduction of the chronic animal model in neurophysiological research Rademaker never regarded the ‘defect symptoms’ occurring during the acute postoperative phase as representative (see ‘Diaschisis as a complicating factor’ below), and preferred to observe the experimental animals patiently for weeks, months, sometimes even years after the end of this initial phase. In his opinion, the effects which only manifested themselves after a (considerable) delay or changes in the reactions that were preserved were much more worthy of consideration. This applied particularly to the observation of behavioural changes in decerebellate animals. It was in such work that Rademaker showed himself at his best. He was never daunted by the technical problems involved in ablation of the cerebrum or the cerebellum, or both. The key to his success in these experiments remained the outstanding postoperative care his animals received in his own home. An additional advantage was that Rademaker’s own impartial appraisal of these animals was complemented by observations made by his wife. All his publications show the untiring attention paid to such matters as temperature fluctuations, hypothermia (which often proved impossible to correct), incontinence, pressure ulceration (‘bed sores’), but above all the animal’s preferred position during feeding (which was often given via a tube): whether the animal was conscious at the time, whether it turned towards or away from the perceived source of nourishment, etc. All these facets were carefully noted in logbooks and protocols, making Rademaker a true pioneer in the chronic animal experiment. Apart from this long-term post-operative observation of the experimental animals, Rademaker also pioneered the cine-film recording of his experiments. All provocation tests, and the sequence of movements produced e.g. when animals held in a certain position were allowed to fall freely to the ground, were filmed in this way. The films produced valuable material for subsequent detailed analysis. Good examples, reproduced as filmstrips, are to be found in Rademaker’s publications such as the monograph Reactions labyrinthiques et equilibre from 1933. Pages full of these filmstrips give a clear impression of the movement patterns studied, and provide a lively record of Rademaker at work. They show how he developed the various tests and the equipment such a tilting or rotary tables he used for this purpose (and on which he often took place himself ). He added additional information by hand on these

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prints, such as the direction of rotation (clockwise or anticlockwise) of the table, the directions in which the animals fall and the position of their body and head at the start and end of the experiment. Diaschisis as a complicating factor The often unusual operative techniques used by Rademaker on his experimental animals could lead to complications such as shock, diaschisis (the loss of function and electrical activity caused by cerebral lesions in areas remote from the lesions but neuronally connected to them hypothesized by the Swiss neuropathologist Von Monakow) and dystrophy (described by Sherrington). The potential problems resulting from these effects were well known, and Rademaker gave them considerable thought when planning his investigations. In a contribution he wrote for the Nederlands Leerboek der Physiologie (Netherlands Manual of Physiology), p. 172,18 Rademaker draws the reader’s attention to these problems as follows: Such a major operation as the removal of the cerebellum, even if carried out as accurately as possible and without damaging other parts of the nervous system, will always cause circulatory disturbances leading to nutritional defects, oedema and extravasation resulting in loss of function and wasting of tissue in the neighbourhood of the operation wound, and this ancillary damage will lead to further disturbances in its turn. This damage is worst immediately after the operation and will gradually decrease in intensity due to resorption of the extravasated blood and the oedema and the formation of new blood vessels so that the disturbance caused by this damage, referred to in general as “shock”, will also gradually diminish. When a part of the central nervous system that more or less regularly sends impulses e.g. to the motor anterior horn cells is removed, this not only gives rise to disturbances that are a direct result of the lack of these impulses but also causes disturbances that are an indirect result of this: since the cells no longer receive these impulses, their function is disturbed so that for a certain time they no longer react at all, or react much less

18 G.G.J. Rademaker in Nederlandsch Leerboek der Physiologie (Netherlands Manual of Physiology), compiled by professors at various universities under the leadership of G. van Rijnberk, Part V: Central Nervous System, by J. ten Cate, C.U. Ariëns Kappers, G.G.J. Rademaker and G. van Rijnberk; second revised and expanded edition, with index, 1946, C.V. Swets & Zeitlinger, Amsterdam; in Dutch, p. 1972.

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strongly, to impulses reaching them via other routes (this is the “diaschisis” described by Von Monakow).19

He goes on to say: The higher the animal species involved, the longer the functional disturbances will in general last. It has also been found that in higher animals cells may undergo not only functional changes but also microscopically observable changes (Sherrington’s “isolation dystrophy”). These changes also generally disappear after some time, but they may be so intense that some of the cells involved never recover but are eventually destroyed and resorbed. It has been found in monkeys, for example, that if the pyramidal tracts are cut a part of the motor anterior horn cells degenerate and disappear.

While Rademaker was aware of the existence of diaschisis, writing for example: under the influence of “diaschisis”, i.e. the failure of certain impulses to arrive, motor cells initially do not respond to stimuli, or respond much less than usual, while later, after recovery, they are still usually abnormally over- or underexcitable. And this can also contribute to abnormality of the animals’ reactions . . .,

he did not take an active part in the general discussion of diaschisis among neurologists and neuropathologists initiated by Von Monakow round about 1905. There were at that time interesting theoretical discussions of this phenomenon, which Von Monakow himself described in different ways: to sum up briefly, diaschisis would mean a transfer of the impairment of the function of one member on the entire complex of neurones;

and the recovery of activity does not result from removal of an inhibitory stimulus from the vicinity of the lesion

—as the German authority in this field Eduard Hitzig (1838–1907) (see picture: reproduction of the title page of his book Untersuchungen über das Gehirn—Investigations of the Brain—below) had assumed—

19 Von Monakow C., “Die Lokalisation im Grosshirn und der Abbau der Funktion durch kortikale Herde”, Ch. I Allgemeines über die kortikale Ausfallserscheinungen, par. 4 Die Diaschisis, pp. 26–34, Wiesbaden, Verlag von J.F. Bergmann, 1944, 1033 pp.

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Fig. 2-7. ‘Untersuchungen über das Gehirn. Abhandlungen physiologischen und pathologischen Inhalts’, Berlin, Hisrschwald, 1874–1904, 276 pp. The work includes Hitzig’s and Fritsch’s original paper on electrical stimulation of the frontal cortex as well as new research which enabled Hitzig to delineate the limits of the motor area in the cerebral cortex of the dog and the monkey. Hitzig’s epochal studies of the electrical excitability of the cerebral cortex undertaken together with the experienced G.T. Fritsch were initiated during the 1860s. Their joint paper marked the beginning of a new era in the study of brain physiology. Working subsequently without the aid of Fritsch, Hitzig defined the limits of the motor area in the cerebral cortex of dog and monkey and using this discovery as a starting point, he disproved the holistic theory of the equivalence of all parts of the cerebrum proposed in 1842 by Flourens and adopted by Goltz. Rademaker cited this experimental work from the start of his scientific career.

but rather by the reorganisation and retraining at the place of the origin of the so called remote effect i.e. by proper facilitation and extension of contact

or more simply, by: division into single components by elimination of superior centres.

As mentioned above, Rademaker did not take part in this discussion of the post-operative phenomenon referred to Von Monakow and others as diaschisis, though he recognized its existence. He preferred to call it simply “shock”—a term that Von Monakow was reluctant to use in this connection. According to the latter, such an acute phenomenon [as diaschisis], beyond doubt related to shock (but in no way identical) is a local battle for preservation of function as it were . . . .

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In this discussion, which occupied the minds of many western European neurologists, especially in Switzerland and Germany, one psychiatrist called Bleuler went so far as to suggest, with good clinical evidence to back up his argument, that schizophrenia was caused by diaschisis. Rademaker saw it above all as a post-operative phenomenon, which he tried to combat as effectively as possible. While taking this effect into account as pragmatically as he could, he preferred to keep well away from all the confusion caused by the post-operative picture in the acute phase by waiting patiently till the experimental animal’s condition had stabilized while providing all the necessary supportive measures and care in the meantime. He realised clearly that the interpretation of the effects produced after removal of part of the nervous system “is in general far from simple”. Reporting Rademaker’s reports of his experiments were always very clear. He regarded proper formulation as extremely important and was a purist in language matters, as some of his students found to their cost. When revising articles intended for publication or doctoral theses, he corrected sentences containing syntactic errors or an incorrect choice of words without mercy. After he had finished going through a manuscript it would be full of his corrections in red pencil, changing the punctuation, the word order or other aspects of composition. Some of his assistants felt that he went too far in his zeal for exact language while others, like Luyendijk, were glad to follow his example. Convinced of the difficulty of capturing pathological or other changes of the motor system precisely in words, Rademaker made cine-film records of all his experiments starting in 1926. Examination of the reflexes The testing of reflexes is one of the most common, almost obligatory means of examination in neurophysiology and neurology, allowing as it does the physician to assess the condition of the patient’s peripheral and central nervous system. Alongside the use of the stethoscope and the examination of the throat (“Say ‘Aah!’”), it is perhaps seen by the layman as one of the most stereotypical activities of any doctor. No matter how essential this technique may be, it should not be used to the

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exclusion of all others. As Rademaker’s friend and colleague Raymond Garcin put it very poetically, “Le reflex c’est l’instant du motricité, la substance du temps” (which may be freely translated “The reflex is the instant plucked out of the continuum of motion, the substance of time”). On the one hand, Rademaker stressed the importance of using the correct procedure to examine reflexes, while on the other he pointed out that the examiner must never forget that there is no such thing as an isolated reflex or reflex arc but that the stimulus must always be considered in relation to the nervous system as a whole. It was in this sense that Sherrington wrote in his book “The integrative action of the nervous system” (1906) that a simple or isolated reflex is a “fiction”, since all parts of the nervous system are interconnected and probably no single part functions separately without influencing other parts or being under the influence of yet other parts. In line with this, the reflex has been defined in German physiology as a “künstlich isolierte Funktionsbausteine”—an artificially isolated functional element (Minkowski, 1924, 1925).20 Neurological examination often involves eliciting reflexes with the aid of unphysiological stimuli. Such a procedure can only yield artificial, fragmentary results, forcibly detached from their natural context. The renowned physiologist and clinician Goldstein must have had something like this in mind when he stated, “nach dem die nervös bedingte Reaktion durch eine Erregung des ganzen Nervensystems, und nicht eines Teiles davon, zu stande komt . . .” (since a neurological reaction is brought about by excitation of the entire nervous system, not of a part of it . . .). Rademaker’s approach to physiological examination was based on a preference for the use of physiological stimuli to elicit reflexes within the experimental set-up. For example, when studying the fall reflex he would simply record and analyse the movements of an animal during free fall and when studying the labyrinthine righting reflex he would use passive rotation of the head as stimulus.

20 Minkowski M., “3. Zum gegenwärtigen Stand der Lehre von den Reflexen in entwicklungsgeschichtlicher und anatomisch-physiologischer Beziehung”, Schweiz. Arch. Neurol. 15, 239–259, 192. Minkowski M., “6. Zum gegenwärtigen Stand der Lehre von den Reflexen in entwicklungsgeschichtlicher und anatomisch physiologischer Beziehung”, Schweiz. Arch. Neurol. 16, 266–284, 1925.

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This feature of Rademaker’s experimental approach was not lost on French clinicians. For example, Guillain writes in his foreword to the monograph ‘Reactions labyrinthiques et equilibre’ in 1933: Rademaker gives a predominant place in the equilibrium mechanism to labyrinthine reactions of the extremities, since it is the extremities that are responsible for maintaining the balance. He believes that the problem of equilibrium must be studied by exploring the labyrinth not with the aid of the widely used caloric tests—which are not physiological—but only with physiological stimuli such as free fall or rotation.

This consistent preference for a physiological approach to clinical problems was one of Rademaker’s main characteristics. Definitions Before undertaking a scientific study of an organ or its functions, Rademaker would study the existing literature on it. It often happened that this review of the literature would lead him to the conclusion that no satisfactory definition of the organ or function in question had yet been given. For example, in the introduction to Reactions labyrinthiques et equilibre (1933) Rademaker takes issue with the views on the organ of balance that were current at that time. He cites a representative statement by Goltz (1870) in this connection: “Die Bogengänge bilden eine Vorrichtung, welche die Erhaltung des Gleichgewichts dient. Sie sind so zu sagen Sinnesorgane für das Gleichgewicht des Kopfes und mittelbar des ganzen Körpers” (The semicircular canals form a system that serves to maintain equilibrium. They can be regarded as sensory organs for the equilibrium of the head and hence of the body as a whole)

This view was shared by a French contemporary of Goltz, Flourens (1794–1867). Rademaker is very critical of this position: According to these publications, the essential function of the labyrinths is to maintain and re-establish the equilibrium of the body. However, one searches in vain for the methods by which the labyrinths accomplish this task, for the reactions by which they regularize balance (p. 1).

The continuation of Rademaker’s argument on this point is sketched in the description of this monograph in Book III, Part 3.3.

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book ii The use of ablation techniques in animal experiments

In an interesting discussion following the reading of a paper on the relation of the cerebrum to the cerebellum, delivered by the eminent American researchers Fulton and Rioch from Yale, and the British physiologist Liddell from Oxford, to the New York Academy of Medicine and the New York Neurological Society on 10 November 1931,21 those present exchanged views about the various methods used by physiologists to investigate the nervous system. The paper in question described a systematic attempt to study the consequences of ablation of parts of the cerebellum and cerebral hemispheres in a large series of mammals, including higher and lower primates. The investigation was based on the well-known fact22 that in the course of evolution the neocerebellum developed pari passu with the growth of the cerebrum, implying a close functional relationship between the two. The results of the investigation confirmed previous findings by Magnus,23 Pollock and Davis,24 Rademaker25 and others that the cerebellum as such did not form an essential part of the neural system involved in tonic neck, labyrinthine and righting reflexes, but that it did serve to control these mechanisms in the acute phase shortly after the operation on the experimental animals. These investigators found that the postural and righting reflexes showed clear signs of hyperactivity in the acute decorticate and decerebellate cat. It was further concluded that the cerebellum played an active role in the control of certain lower centres involved in postural reflex patterns. One of the topics covered in the discussion following the paper was the finding of tremor and ataxia after ablation. As Walshe (1927)26

21 Fulton J.F., Liddell E.G.T., Rioch D.Mc.K., “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, 1932. 22 Rossi G., “Sue rapporti funzionali del cerveletto con la zona motrice della corteccia cerebrale”, Arch. di fisiol. 11, 258, 1913—cited by Luciani L. in: ‘Das Kleinhirn’, p. 286. 23 Magnus R., “Körperstellung”, Berlin, Julius Springer Verlag, 1924. 24 Pollock L.J., Davis L., “The influence of the cerebellum upon the reflex activities of the cerebrate animal”, Brain 50, 277–323, 1927. Pollock L.J., Davis L., “The reflex activities of a Decerebrate Animal”, J. Comp. Neurol. 50, 377–411, 1930. 25 Rademaker G.G.J., “Das Stehen”, Berlin, Julius Springer Verlag, 1931. 26 Walshe F.M.R., “The significance of the voluntary element in the genesis of cerebellar ataxy”, Brain 50, 377–385, 1927.

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had shown, the ataxia was only found in connection with ‘voluntary’ movements and not e.g. in a spinal animal (dog or cat). A number of questions immediately arose in this context: which part of the nervous system is responsible for such a tremor? Can the tremor and ataxia be eliminated once they have manifested themselves by ablation of part of the brain? According to the authors, this aspect of the problem had not yet been dealt with experimentally: Rademaker’s brilliant study of a thalamic dog that survived for thirtyeight days after decerebellation did not allow him to study the point, since the cerebral hemispheres had been removed before he extirpated the cerebellum.27

Some of the most eminent American researchers in the field of the neurophysiology of the central nervous system at that moment took part in the subsequent discussion. Apart from Fulton himself, contributions were made by Henry Alsop Riley, Ramsay Hunt, Pike and Oliver Sprong. The discussion as a whole reflected the ideas that were current at the time about the pros and cons of experimental neurophysiological research involving ablation of parts of the nervous system. Riley, who had won his spurs in the field of the comparative anatomy of the cerebellum, started the ball rolling with the statement: I have a definite feeling of distrust of these major operative procedures on the highly organized central nervous system, a system that has taken millions of years to bring into being and one that has developed by the pyramiding of one level to another, each one of them actively interrelated and cooperating with the other

and went on to speak of “extensive mutilations of the nervous system” and “such enormous damage to this complicated mechanism”. The academic Ramsay Hunt countered with the comment that experimental physiology, with the use of these methods in England under the aegis of Sherrington, has made remarkable advances in the field of somatic innervation of striated muscle fibres

and recalled the results achieved by Denny-Brown with the aid of these techniques. The equally renowned physiologist F.H. Pike also spoke up in defence of the experimentalists, referring to the breakthrough 27 Rademaker G.G.J. and Winkler C., “Annotations on the physiology and the anatomy of a dog, living 38 days, without both hemispheres of the cerebrum and without the cerebellum”, Verhandelingen v.d. Kon. Akad. v. Wetenschappen Amsterdam 31, 332–337, 1928.

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in neurophysiology and clinical science brought about by the classical studies of Bell and Magendie, who had shown experimentally that the dorsal roots of the spinal nerves carried the afferent impulses to the central nervous system while the ventral roots carried the efferent motor pulses. Of course, we damage the central nervous system by experimental operation, sometimes to lesser and sometimes to greater degrees than in neurosurgery on human beings, and sometimes a little less than that which results from disease processes. I think that the experimental method is the best we can do just now. I think that all of us appreciate that the nervous system is a complex mechanism. . . .

and further The possibilities are many, and while the experimentalist cannot see how things are linked together, he can see only the complexity of the problem, which requires much work. Possibly he is no worse off than the morphologist or the clinician. . . .

Fulton, the nestor of American neurophysiology (who had a great admiration for Rademaker’s work), rounded off the discussion with an authoritative comment: “Dr. Riley, I think, said more than he really means, because if he were literally interpreted, progress in knowledge of the nervous system would be limited to chance observation. The experimental approach to the nervous system, it seems to me, is the one approach that allows one with certainty to make new knowledge—if I may use that term—but I agree that extirpations represent only one aspect of the experimental approach. The challenge to the surgeon approaching experimental neurology is the challenge that Dr. Riley has made: namely that we must do our work delicately. The improvement that we are going to make in the future will come through the development of a fastidious surgical procedure. . . . Our chief pride is to be able to make a sharply circumscribed lesion, and to operate again six months or a year later and find that the lesion is just where we made it, and not spread over half the cortex, and that the degeneration of fibres e.g. in the pyramidal pathway, originates only in the part in which the lesion was made. This is very difficult” (indeed). . . . “As one improves I think that the protest that Dr. Riley made, is to a certain extent, met”

As Rademaker’s colleagues and pupils subsequently testified (Ter Braak et al., 1953), his microsurgical skills met these very stringent requirements:

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Fig. 2-8. John Farquhar Fulton (1899–1960), Yale University. Physiologist and writer on American medical history, who combined the intuition of a clinician and physiologist with the erudition of a historian. Fulton helped to introduce Rademaker’s work to a much wider audience right from the start, e.g. in his influential book on muscular contraction ( J.F. Fulton, Muscular contraction, London: Baillière, Tindall and Cox, pp. 506–511, 1926). For example, he paid considerable attention to Rademaker’s pioneering work on the nucleus ruber described in parts 2.2 and 2.3 of the present book, and together with DennyBrown often referred to Rademaker as the ‘King of the red nucleus’. The research results obtained by Magnus, De Kleyn and Rademaker were often discussed in the “Fulton Society”—a group of leading researchers who met informally to debate current advances in the state of the art during world congresses on physiology and neurology. John Fulton became a good friend of Rademaker, visited the Netherlands and contributed to the Liber Amicorum honouring Rademaker in 1953 (see Reference list). Their collaboration has been discussed in Parts 2.1, 4.1(6) and 8.1 of the present book.

Owing to his remarkable talent to make an unprejudiced analysis of the behaviour of experimental animals as to his operative skill, Rademaker was undoubtedly the right man for such an examination.

And regarding the nucleus ruber (Ter Braak et al. 1953): His research consisted in the infliction of lesions in or near the midbrain, the analysis of the changes in reflex behavior and finally in the microscopical-anatomical elaboration of the material.

Rademaker’s attitude towards his experimental animals Rademaker was unique in his closeness to his experimental animals. This sharpened his cognitive skills to such an extent that he could observe

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and describe phenomena that other investigators were completely blind to. It was rooted in his philosophy of nature, and was perhaps the most characteristic aspect of his cognitive make-up. Retrospectively, it can perhaps first be recognized in Surabaya when he started to take an interest in the horse races at the racetrack near his surgery and later became involved in the breeding and selection of the horses for these races. As mentioned above, the considerable sums of money he won betting on the horses there, on the basis of his deep understanding of their function and capabilities, were probably a key factor in making his whole research career possible since they enabled him to work for Magnus as an unpaid assistant and thus acquire and demonstrate his great research skills. Of course, his sensitive feeling for the animals he was working with was another essential factor. He must have had to overcome an enormous inner resistance before he started betting on the horses. After all, such an activity was anathema for someone with a strict Calvinist upbringing like himself. He may have felt the ability his winnings gave him to send money home to support his parents in the financial obligations they were under in bringing up a large family was some justification—and later, perhaps, that the financial independence and physiological insights that he had gained from his involvement with the horses had been providential in helping him to success in the career to which he had been called. In fact, his involvement with horses in Surabaya was twofold: not only did he admire the grace and power of the racehorses, he was also dependent on a horse-drawn carriage for transport to distant patients. Rademaker was probably unique in giving all the experimental animals he used in Utrecht, and later in Leiden, names. These names were recorded in his laboratory notebooks and in his publications. For example, the English translation of his monograph “The physiology of Standing” Univ. of Minnesota Press, 1980) includes a list of all the experimental animals he had used in collecting the data for this book. It starts as follows: “Erik, extirpation of cerebellum: 9 Oct. 1924, still alive after 72 months; Piccolino, extirpation of cerebellum: 24 Dec. 1924, died 7 Jan. 1929, lived for 49 months”. This was pointed out to me by researcher and scientific editor Dr. R. Bathgate [personal communication], who commented “I have never known of any other cases in the literature where experimental animals are treated in such a personal way; this seems to run counter to the emotionally detached attitude generally expected of experimental scientists”. It would hardly be going too far to say that Rademaker seemed to regard his experi-

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Fig. 2-9. Caricature of Rademaker on rotary table with experimental animal.

mental animals as friends and collaborators in his attempts to unravel the secrets of animal neurophysiology. The ‘tender loving care’ provided postoperatively by his wife Blanche represents a similar approach. Magnus, following more traditional methods of scientific reporting, did not mention these details of Rademaker’s working style in the publications describing their joint researches. They did not however escape the attention of the student cartoonist (see figure below) who tellingly depicted the contrast between Rademaker’s customary formal attire (tailor-made three-piece suit and always brightly polished shoes) and the comradely attitude in which he holds an experimental animal on his lap on the rotary table. The care with which Rademaker dressed during lectures and even during experiments was seen by some as a sign of “an excessive love of precision”, as noted by O. Magnus Jr. in a biography of his father.28 The omnipresent odour of the animal room During his first experimental work in Magnus’s laboratory, but also later in Leiden, Rademaker spent most of his time apart from that devoted

28 Rudolf Magnus Sr. by O. Magnus Jr., Netherlands Acad. Sci. Amsterdam, Kluwer Acad. Publ. Dordrecht, New York, Boston, 2002, p. 307.

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to lectures and demonstrations in the animal rooms and operating theatres. He made it a full-time activity to observe the animals before and after operations, to exercise them in the inner courtyard of the laboratory and to examine their reflexes while walking, standing or falling. As mentioned above, at the beginning of his career he used to take the animals home in the evening after their operations so that they could convalesce under the care and observation of his wife. All this contact with animals inevitably meant that he continually carried a strong animal odour around with him wherever he went. His wife and colleagues often pointed this out to him. His response to this was to change his clothes more frequently and to apply very liberal doses of eau de cologne to mask the scent of the animals. As a result, he left a very distinctive ‘odour trail’ after himself wherever he went, so that his secretary and laboratory assistant could check immediately with the aid of their sense of smell whether he had arrived in the building in the morning (Mrs. H.P. Boersma, Leiden, Personal communications 1996, 1998) People who had worked with Rademaker remembered this idiosyncrasy of his many years after. One visiting American physiologist gave the following reminiscence and explanation [ersonal communication Dr. W. Kramer, 1999]: A smell can be overwhelmingly nostalgic because it triggers powerful images and emotions before we have time to edit them but there is almost no short-time memory with odours. It’s all long-term. Furthermore, smells stimulate learning and retention. We as doctors have always relied on their sense of smell, along with those of sight, feel, and hearing, to diagnose disease, especially in the days before sophisticated technology. Typhus is said to smell of mice; diabetes of sugar, the plague was said to smell of mellow apples; measles of freshly plucked feathers as we learned from Gorter the paediatrician, yellow fever of the butcher’s shop; nephritis of ammonia. The smell of acetone on a patient’s breath or blankets signals a diabetic coma (as the internist Mulder taught us while spreading the blankets of a patient before our noses). Since Rademaker frequented the stables of animals, which had been operated upon or held them for a long time on his lap while testing, he smelled strongly of the Yardley lavender toilet water he sprinkled on liberally to mask the original animal smell. There was an anecdote that the ‘Chronicle of Higher Education’ had reported that tests at the University of Cincinnati had shown how fragrances added to the atmosphere of a room could increase typing speed and work efficiency in general. . . . Since Rademaker continued to use this Yardley lavender water even when most of his work was in the neurology clinic, some of those who came into contact with him were moved to comment that he was in a

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double sense ‘een geestelijk geparfumeerd man’ (which might perhaps be freely translated as ‘a man who lives in an odour of scientific activity’). [Personal communication Dr. W. Kramer, 1999]

2.2. Thesis ‘cum laude’ (1924) Unbelievable fast: less than two years after the start of his research career. Building on the work of Magnus, Rademaker arrived at surprising conclusions concerning the role of the ‘red nuclei’ (nuclei rubri), which may be regarded as the main centres for control of the postural reflexes. He found that the reflex arcs for the labyrinthine righting reflexes and the body righting reflexes, which are indispensable for a normal distribution of muscle tone, pass through the red nuclei. His investigations also allowed many conclusions to be drawn concerning the localization of reflexes not involving the red nuclei. The results of his investigation were summarized in a thesis entitled “De beteekenis der roode kernen en van het overige mesencephalon voor muscletonus, lichaamshouding en labyrintaire reflexen” [The significance of the red nuclei and the rest of the mesencephalon for muscle tone, posture and labyrinthine reflexes], which was awarded the predicate cum laude when he defended it at a public meeting of the medical faculty in Utrecht in 1924 (see figure). Rademaker’s discovery was that for the first time in the history of physiology/neurology, on experimental evidence a function could be attributed to a group of cells (neurons)29 in the mesencephalon of the brain. The thesis was a hefty tome, written in a clear, businesslike style and giving extensive details of a large number of experiments on rabbits and cats, analysis of which led to the conclusions which he presented. The main conclusions were that when the nuclei rubri were ablated in rabbits and cats, the normal muscle tone changes to a state of enhanced extensor tone, and that these nuclei are the centres through which certain righting reflex arcs pass. As we shall see later (Book II—part 2.3), however, these conclusions were contested to a certain extent in the course of time.

29 Anatomically known as the nucleus ruber or Stillings nucleus. Benedict Stilling, German surgeon, anatomist and physiologist, 1810–1879.

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Fig. 2-10. Frontispiece thesis Rademaker. Original in Dutch, translations in German and French.

Fig. 2-11. The critical line (red) indicating the localization of the coronal intercollicular section through the mesencephalon of a rabbit.

The autopsy material from the operated animals was processed in Winkler’s laboratory. This brought Rademaker into closer contact with Winkler, and through him with neurology. Together with Winkler Rademaker scrutinized the world literature on neuropathological-clinical data on isolated nucleus ruber lesions in the mesencephalon. This evidence from mostly French, Dutch, German and English origin confirmed Rademaker’s surprising conclusions. This survey of the neuropathology in human autopsy literature search was added to the thesis. It is not discussed here because of space. Rademaker regarded Winkler as one of his most important teachers— and also, as we have mentioned above, as one of his friends.

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Fig. 2-12. The first caricature of Rademaker in the attitude of the attentively listening ‘scientist’ during a discussion of progress in a research project, drawn by his pupil and assistant Pol Dom (1940). Courtesy of Prof. Emeritus Luyendijk-Elshout.

In the introduction to his thesis, Rademaker had the following to say about Magnus: Through you, I came into contact with pure scientific research for the first time. You smoothed the path for me, a service which was all the more necessary since all my past experience lay in the more practical field.

2.3. The nucleus ruber. The ‘King of the Red Nucleus’. The Red Nucleus meets Stereotaxis After the series of publications that followed soon after the appearance of his thesis,30 Rademaker was given the title ‘the King of the red nucleus’ by American physiologists who knew him (Fulton, DennyBrown).31 Despite a certain formality that was a key part of his character, 30 See: Weisenburg T.H. and Alpers B.J., “Decerebrate rigidity following encephalitis”, Arch. Neurol. and Psychiatr. 18, 1–15, 1927. 31 America may be a country that has banned aristocratic titles from public life, but it still bestows epithets with a whiff of aristocracy on many well-known figures. They are perhaps particularly frequent in the world of jazz—think of Duke Ellington, Count Basey and Nat ‘King’ Cole—but are also to be found among neurologists. For example, Dr. W. King Engel, the successor of Milton Shy at the National Institutes of Health in Bethesda, Maryland. This man, the very image of modesty, with whom

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and that could be perceived as aloofness by those who met him for the first time, Rademaker could appreciate this playful approach. He also liked the caricatures of himself that circulated among students during the years when he taught physiology (a role which his students considered to be his ‘best performance’ (see figure)). It was not only abroad but also in his own country that some people noticed ‘something regal’ about him. His asthenic build contributed to this impression. He was regularly asked to head committees or delegations set up by the Koninklijk Instituut voor Wetenschappen (the Royal Dutch Academy of Sciences), of which he was a member.32 His contemporary Professor H.C. Rümke sketched the reasons for this as follows much later: “. . . he was the obvious candidate for many years, a man with such an air of dignity and yet so modest.” Thus, Rademaker was a legend in his own lifetime. First of all in a limited circle, nourri dans le serail of Magnus and the mutual admiration society of neurophysiologists that had grown up around the latter in Utrecht. After the sudden death of Magnus in 1927, Rademaker seemed the obvious choice to succeed him; he was certainly accepted as such by the rest of the team. As it turned out, however, he was offered a chair not in Utrecht but in Leiden as the successor of Einthoven. He never forgot his Utrecht roots, though; in particular, his friendship with the eminent Cornelis Winkler (1855–1941) there, the first professor of psychiatry and neurology in the Netherlands, lasted the rest of his life. The red nucleus meets stereotaxis During the closing decades of the nineteenth century, experimental physiologists such as Hughlings Jackson (1835–1911) in the UK and Cornelis Winkler in the Netherlands were keen to identify the anatomical basis of the functional changes they observed. The first precise localization of function in the brain had been performed by Broca (1824–1880) in 1861. Further contributions had been made in 1870 by Fritsch (1838–1891) and Hitzig (1838–1907) in Germany and later by Ferrier (1843–1928) in London. The University College in London

I had a close working relationship for many years, was often (rightly) called ‘King’ by his friends and colleagues. 32 See also Book VII—Part 7.1.

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Fig. 2-13. Rademaker was a figure who captured students’ imagination, especially in the days when he was lecturing on physiology in Leiden. Here: Rademaker, with bowler hat, as seen by a student caricaturist while watching a boat race.

Figs. 2-14 & 2-15. Two other caricatures from the period 1928–1942. Caricatures of professors—here Prof. Barge (Fig. 2-14) and Prof. J. Mulder (Fig. 2-15; drawing by Drs. L. Valk)—were not uncommon in the medical faculty in the years between 1920 and 1950, and decorated the walls of many students’ rooms in Leiden. The caricature, known as an art form since Michelangelo, is an effective means of portraying facial expressions and body language. It is often used to stress less attractive aspects of the subject’s personality. Caricatures showing professors in action, like the one of Prof. Mulder above, are less common.

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was a major centre of such research. It was here that Horsley and Clarke developed their ‘stereotaxic apparatus’—a key instrument of research in this field. Rademaker is said to have been intrigued by the work of both these authors and to have been fascinated by Horsley’s life style, which was comparable with his own. Both Rademaker and Horsley had initially trained as surgeons, were courageous pioneers and had to ‘steal’ time for research from a hectic clinical life. Sir Victor Horsley (1857–1916), the first neurosurgeon—or ‘brain surgeon’ as he was called at the time—in the UK, had a keen interest in cerebral localization and was an active experimentalist. Almost as soon as he completed his formal surgical training he plunged into a frantically busy professional life, which he managed to live at many different levels simultaneously. Though instantly successful as a consultant and as a practising surgeon, he insisted on setting aside part of each day for work in the physiology lab. Later in life, apart from writing on a variety of scientific and non-scientific subjects he took up such activities as the espousal of women’s rights and the defence of physiologists against the attacks of antivivisectionists (like Rademaker). He differed however from Rademaker—a heavy cigarette smoker—in his fierce campaign against tobacco. At the age of twenty-seven, Horsley was made a professor and superintendent of the legendary Brown Institute in London, a sort of national research institute for pathophysiology where he did famous work on rabies and thyroid disorders (myxoedema). His successor there was none other than Sherrington.

Fig. 2-16. Prof. C.S. Sherrington (1857–1952).

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He later moved on to the University College where he worked in a small room. It was here that Robert Henry Clarke, a pathologist seven years Horsley’s senior, came to work with him on problems related to the nervous system. The little we know about his life indicates that he was a very different sort of man from Horsley. He loved sports such as cricket, football and rowing in his youth, and during his student days at Cambridge he was better known as a member of the Queen’s College boat than for his achievements in science or art. Later in life he was still a good golf player. His best-known non-neurological paper was on roaring horses. It was however Clarke’s inspiration to apply inside-out geometry to the study of the brain rather than to follow the more obvious approach of taking reference points on the exterior of the skull. He had quickly realised the ‘futility’ of using the cranium as a reference surface for localizing structures deep within the brain at a time when the German physician Franz Joseph Gall (1758–1828) was creating a furore in all Europe’s fashionable salons round the end of the eighteenth century with his ‘phrenology’—the theory that one could draw conclusions about someone’s personality and mental abilities by ‘reading their bumps’ (examining the detailed external structure of their cranium).33 Clarke may be considered as the auctor intellectualis of the stereotaxic apparatus. Horsley’s major contributions to the project were his intuitive thinking, his unparalleled energy and his insatiable curiosity. Clarke might never have had an opportunity to know the full extent of his ability to deal effectively with the problems of stereotaxis had he not been working literally at the nerve centre of British physiology of his day under such inspiring leadership. Writing in 1970, Tepperman34 typified the apparatus as one of the key instruments in the history of science: Galileo’s telescope had to be invented before the heavens could be explored; Leeuwenhoek devised a system of lenses which made possible the development of microbiological sciences. Sir Victor Horsley and Robert Henry Clarke pooled their complementary insights and skills

33 See J.A.J. Barge, “Van Wetenschap tot Gezelschapsspel” (From Science to Party Game), Stenfert Kroese, Leiden, 1951, p. 38. 34 Tepperman J., “Horsley and Clarke: a biographical medallion”, Perspect. Biol. Med. 13, 295–308, 1970; cited in “Discoveries in the Human Brain” by Louise H. Marshall and Horace W. Magoun, Humana Press, Totowa New Jersey, 1998.

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book ii and invented an instrument which enabled their scientific descendants to explore the deepest recesses of the brain with great precision.

The stereotaxic apparatus was first described by its inventors in Brain in 1908.35 Clarke was keen to see it used in neurosurgery, though others—including Horsley himself, and S.W. Ranson (see below)—were more sceptical.36 This difference of opinion between Horsley and Clarke is thought to have led to a rift between the two. While it was used to a limited extent in neurosurgery, it also proved to be a very useful research tool, being taken up energetically e.g. by Ranson and co-workers in Chicago in the early 1930s to add precision to their neurophysiological animal experiments. Muskens had introduced the instrument in the Netherlands.37 Its very precision was initially perceived as a threat by many physiologists, who feared it might put them out of work: if the various organs of the brain could be accurately localized by such a mechanical device, there might no longer be any need for their imagination and intuition, and the insights and experience they had worked so hard to build up. In the end, the invasive nature of this instrument limited its use, especially on humans. (It involved passing one or more fine electrodes through the brain to provide an accurate baseline. While Clarke has been skilful in reducing the trauma this caused to a minimum, it will be clear that this was a measure one would prefer to avoid.) However, the stereotactic principles on which it was based laid the foundation

35 V. Horsley and R.H. Clarke, “The structure and function of the cerebellum examined by a new method”, Brain 31, 45–124, 1908. 36 J.C. Hinsey, Pharos 24, 13, 1961. 37 Despite his many talents, L.J.J. Muskens (1881–1949), lecturer in Neurology and author of two monographs on epilepsy and the supravestibular system, found it difficult to make his way in the neurological world of Amsterdam. G.W. Bruyn and P.J. Koehler (in: ‘History of Neurology in the Netherlands’, J.A.M. Frederiks, G.W. Bruyn, P. Eling (eds.), Chapter 7, ‘Neurosurgery’ by H.A.M. van Alphen, p. 99, Boom Publishers, Amsterdam 2002) attribute this to the hostility of Prof. B. Brouwer, the leading figure in this world, a biographical sketch of whom is given in Book II, Part 2.9. ‘He got on the wrong side of Brouwer when he made evident his desire to work not only as a physiologist and epileptologist but also as a neurosurgeon—a sin also committed by others at that time. Muskens, who had been influenced by Cornelis Winkler (1855–1941) to devote his active years to the study of brain structure, went on to work on cardiac function in the physiology laboratory of Harvard Medical School in Boston, when he moved to become an assistant of Joseph Collins who held the chair of Neurology at New York postgraduate Medical School. Before returning to the Netherlands he also worked with Sir William Gowers (1845–1915) and Victor Alexander Haden Horsley (1857–1926) at the National Hospital for Paralytics and Epileptics in London.’

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for subsequent sophisticated techniques for the non-invasive investigation of the central nervous system such as computer assisted tomography (the CAT scan; developed in the 1970s) and nuclear magnetic resonance (NMR, a later invention). The red nucleus story was going through a period of crisis in the 1930s. The original concept put forward by Rademaker was being challenged by evidence uncovered by various researchers—in particular Ranson, Hinsey and their galaxy of co-workers at Midwestern University in Chicago. As indicated above, the Horsley-Clarke stereotaxic apparatus played a key role in the experiments carried out by this group. Ranson was especially vocal in his assaults on the functions attributed to the nucleus ruber. Rademaker recognized that he had to come to terms with these new data. He therefore had a slightly modified HorsleyClarke stereotaxic apparatus, designed in his own laboratory workshop, installed in his laboratory in 1939. It was used first for neuroanatomical purposes but was later employed in the neurophysiology laboratories and finally for neurosurgery. He persuaded his research assistant P.C. Kraan to make use of this instrument in a thorough review of this whole field, with the objective of putting the various conflicting views in context. The results of this study were presented in Kraan’s 1939 thesis, which is summarized elsewhere in this biography.38 As will be seen there, Kraan supported Rademaker in the importance he attached to the red nuclei as the centres for the body and labyrinthine righting reflexes, but concluded that Rademaker had underestimated the importance of the cerebral cortex for the regulation of muscle tension. According to Kraan, the views of Ingram, Ranson et al. were closest to the truth here. For further details of the discussion of the various issues involved, see the above-mentioned summary of Kraan’s thesis. One major obstacle to resolution of the various issues involved here was the difference in the nomenclature used by the different authors. Hinsey et al (1930) pointed to the different definitions of muscle tone to be found in the literature. Rademaker suggested that the experimental results obtained by different authors were highly dependent on such factors as the type and quantity of experimental animals used, the level of the lesion in the brainstem, the method used to appraise the muscle tone and the risk that electrical stimuli applied to one part

38

See Book IV, Part 4.1.

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Fig. 2-17. Frontispiece of thesis of P.C. Kraan, 1939.

Fig. 2-18. Schematic illustration of the Horsley-Clarke stereotaxic apparatus as modified by Kraan and Rademaker.

Fig. 2-19. The position of the three planes of the Horsley-Clarke stereotaxic apparatus in the cat. The horizontal plane H is parallel to the plane through the lines joining each auditory meatus to the lowest point of the corresponding orbit, and lies one-third of the distance from the middle of the auditory meatus and the vertex above it. The frontal plane V runs through the two lines that can be drawn through the middle of the auditory meatus and the vertex. The sagittal plane E corresponds to the median plane. From the thesis of P.C. Kraan (1939), p. 8.

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of the brain can spread to others.39 As he had pointed out in “Das Stehen” (1931, p. 417), Clarke and Horsley showed that the phenomena after electrical stimulation of the cerebellar cortex40 are due to currents spreading to the nerves of the brainstem and the nuclei and they assert that the cerebellar cortex cannot be stimulated at all electrically. Irrespective of this assertion as well as those of later investigators, show that the method of investigation can by no means be regarded as incontestable and precise for the physiology of the cerebellum.

and: How prudent one has to be in the estimation of findings in experiments with electrical stimulation is shown by a review of Ferrier’s own work; stimulation of the pyramids, for instance produced different reactions in different species of animals. . . .41

and Dusser de Barenne’s experiments neuronography with chemical strychnine.42 Acute or chronic experiment, all these aspects showed the complexity of the experimental model choosen. 2.4. Experimental physiology of French (Magendie, Claude Bernard)—Russian (Sechenov, Pavlov, De Cyon) and Anglosaxon (Sherrington) Origin. History The reflex is an independent entity, but it is also a preparation for more complicated movements, which require practice before they can 39 As Dusser de Barenne had pointed out, it is important to realise that neural circuits and the boundaries between them are not precise, neat entities (see the portrait of Dusser de Barenne and his work by L.A.H. Hogenhuis in the History of Neurology, J.A.M. Frederiks, G.W. Bruyn, P. Eling (eds.), Ch. 20, pp. 309–317, 2003). 40 Clarke R.H. and Horsley V., “On the intrinsic fibers of the cerebellum, the nuclei and its efferent tracts”, Brain 28, 13–29, 1905. 41 Ferrier D. and Turner W.A., “A record of experiments illustrative of symptomatology and degenerations following lesions of the cerebellum and its peduncles and related structures in monkeys”, Philosophic. Trans. Roy. Soc. Lond., 85, 722–760, 1984. 42 There was the omnipresent risk of implying that boundaries and circuits are precise and neat towards which Dusser de Barenne had pointed (see the contributions of Dusser de Barenne in the portrait of him and his work in L.A.H. Hogenhuis in the History of Neurology, J.A.M. Frederiks, G.W. Bruyn, P. Eling (eds.), Ch. 20, pp. 309–317, 2003). It was at this moment of his own hesitancy that Rademaker decided to repeat his experiments which had been the basis of his first experimental work that had lead to the cum laude thesis. He introduced the instrument in his lab and suggested his assistant P.C. Kraan to start with him again. It became Kraan’s thesis in 1939.

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be performed mechanically. For example, babies learn to crawl and walk with the aid of reflexes. In this chapter, we will review some of the main milestones in our thinking about reflexes before going on to discuss the contribution Rademaker has made in this field. Descartes (1596–1650) Descartes was the first to consider the concept of the reflex, or ‘reflection’ as it was first called. During the seventeenth and eighteenth centuries, reflex theory was a new chapter in the book that Nature puts before us and which according to Galileo should be written in the language of mathematics.43 Was ‘reflection’ a valid term in this language? The idea of ‘sympathies’ between different parts of the body had long preceded the processes of ‘reflection’ put forward by Descartes in 1662 to categorize such involuntary effects as a blink of the eyes in response to a menacing gesture (Denny-Brown, 1960).

Animal experiments were not used as a tool in the initial studies of reflexes (Hoff and Kellaway, 1952).44 The approach during this early period may be characterized rather as speculative or contemplative. With very few exceptions, none of the researchers thought of carrying out systematic investigations, transecting nerves or removing brain tissue.45 The speculation was not however completely without foundation, since the researchers in this period did have some knowledge of anatomy and physiology. While Descartes was the first to be active in this field, he was soon followed by the breakthrough in neurophysiology represented by

43 Galileo Galilei wrote in “Saggiatore” (1623), “Philosophy is written in this very great book which is continuously open in front of our eyes (I mean the universe), but it cannot be understood if one does not first learn the language, and know the characters in which it is written. It is written in mathematical language, and the characters are triangles, circles, and other geometrical figures . . .” 44 H.E. Hoff and P. Kellaway, “The early history of the Reflex”, Journ. of the Hist. of Med. 7, 211–249, 1952. 45 Sherrington (1900) did however cite some early experimental work in Textbook of Physiology, E.A. Schäfer (ed.), Edinburgh: Pentland 1900, vol. II, p. 782. This included a fundamental experiment performed by Stephen Hales in 1733, which demonstrated that the reactions of a decapitated frog were irreversibly eliminated by destruction of the spinal cord; the extension of the concept of reflex action by Whytt (1750), who reported that all reflex action is not immediately suppressed by decapitation; and work by Grainger (1837) which showed by means of partial destruction of the spinal cord that the white matter of this organ is essential for the functioning of a reflex.

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the Bell-Magendie46 experiment demonstrating the distinction between sensory and motor fibres in the nerve root. There can be no doubt that the phenomena such as muscle automatisms and muscular contraction which Descartes used in the first instance to illustrate and support his concept of the reflex (based on the idea that the ‘spirit’ is responsible for all movement of the human body) did include many involuntary effects which would be recognized as reflexes by present-day physiologists. These include peristalsis, described by Descartes in 1664,47 flexion of the arm or leg in response to nociceptive stimuli such as intense heat on the skin of the hand or foot,48 the accommodation of the pupil to light,49 the cough reflex,50 sneezing,51 yawning52 or the closure of the eyelids in response to a menacing gesture.53 In his book ‘Les passions de l’âme’ from 1649, concerning the emotional life of man, Descartes shows that automatic movements are not only caused by ‘natural events’ such as falling from a height, but are also as it were forced on us when others act towards us in a certain manner. For example, Descartes writes in this book, in which the concept of man as an ‘animal machine’ is formulated for the first time, that when someone makes a menacing gesture towards our eye the owner of that eye cannot stop blinking—even if he knows that the ‘attacker’ is a friend who is only pretending. Georg Prochaska (1749–1820), the

Sir Charles Bell (1774–1842), Scottish anatomist and surgeon in London. He showed in various studies caried out from 1807 onwards that nerves are not single units, but consist of separate fibres within a common sheath; that a fibre conveys either sensory or motor stimuli but not both (i.e. it transmits impulses in one direction only); and that a muscle must be supplied with both type of fibre. François Magendie (1783–1855), French physiologist; the pioneer of experimental physiology in France. He showed in 1832 that the spinal nerves have separate paths controlling movement and sensation, thus confirming and extending Bell’s work. 47 Traité de l’homme; Adam-Tannery edition, volume XI (A.-T., XI), p. 140, Bridoux, p. 822. 48 Ibid. A.-T., XI, pp. 141–142 and pp. 191–193, Bridoux, pp. 823 and 865. 49 Ibid. 50 Traité de l’homme A.-T., XI, p. 141, Bridoux, p. 822. 51 Ibid. 52 Ibid. 53 Traité des passions; art. 13. This example is described as follows at the end of this article: “Si quelqu’un avance promptement sa main contre nos yeux . . .” (if someone moves his hand brusquely towards our eyes . . .). This example has often been cited subsequently, e.g. by L. Binet in his collection of articles “Médécins, Biologistes et Chirurgiens” (S.E.G.F.P.) Paris, 1984, p. 35. 46

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Austrian-Tjechoslovakian anatomist and physiologist mentioned this phenomenon as “Si amicus digito sua appropinquat ad oculum nostrum, licet persuasi simus nihil mali nobis inferendum esse, tamen jam impressio illa per opticum nervum ad sensorium commune delata, in sensorial ita reflectitur in nervosa palpebrarum motui dicatus, ut nolentibus claudantur pelpebrae, et arceant molestum digiti ad oculum attactum” (in: ‘De functionoibus systematis nervosi commentatio’, p. 82 sq., 1784, copy in University library Strassbourg). This reaction proves that the body can carry out all kinds of useful, effective movements without the control of the person who ‘lives inside it’. In the third publication by Descartes to be mentioned here, ‘La description du corps humain’ (completed in 1648 but not published till 1684), Descartes shows what a great error we make when we assume that our body’s movements are all voluntary. In the first place, Descartes argues, this assumption is untenable from a philosophical point of view—for how can we imagine that an immaterial soul can control a material body? We all learned in our youth that will or intention is followed by movement; and this leads us to believe that the will, or soul, is the ruler of our body’s movements. It is true that the soul can invite the body to move when the latter is intact and is prepared to move. If this is the case, the body must be able to move on its own and does not need the soul to initiate such movement. Descartes repeats here the conclusion, which he had already expressed in ‘Les passions de l’âme’ (1648), that the body is a machine. He goes on to make the following statement concerning the blink reflex: “Mais c’est à cause que la machine de notre corps est tellement composée que le mouvement de cette main vers nos yeux excite un autre mouvement en notre cerveau, qui conduit les esprits animaux dans les muscles qui font abaisser les paupières”.54 [But it is because the machine of our body is composed in such a way that the movement of this hand towards our eyes excites another movement in our brain, which leads the animal spirits into the muscles which cause our eyelids to close.]

Rademaker (1887–1957), who knew the work of Descartes well, returned to the theme of the definition of these reflexes in his inau-

54 ‘Traité des passions’, end of art. 13. There is a difference between ‘un autre mouvement excité et un mouvement reflechi’ [an excited or generated movement and a reflected or reflex movement].

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gural lecture on ‘Voluntary and involuntary movements’ on the occasion of his appointment to the chair of Physiology in Leiden.55 The situation had changed since Descartes’ time, however. Pavlov had carried out his experiments, and Rademaker had carried out his in cooperation with Gelderblom.56 He was no longer dealing with speculations, but with data obtained from his own, and others’, animal experiments. A question which arose later was, if Descartes developed a general theory of involuntary movements and put such movements forward as a new concept, was it justified to bring these movements—as others57 had done before Rademaker—in relation to phenomena corresponding to the modern concept of the ‘reflex’, and did Descartes thus really deserve a place in the ranks of the natural scientists and physicians who had contributed to the naming and definition of this concept? According to Canquilhem (1977),58 the solution or redefinition of the epistemological and historical problem of the primacy in the development of the reflex concept must await the results of a meticulous critical study of Cartesian anatomy and physiology as regards the nerve pathways and muscles in question, before it can be concluded whether or not Descartes anticipated—albeit not always equally lucidly—modern views concerning the nature of the reflex. With particular reference to the blink reflex, e.g. the physiologist Minkowski59 (1927) restricted himself to the following statement: La notion de reflexe a été etablie par Descartes sur l’observation de ce fait l’orsqu’on approche rapidement un objet de l’oeil, il en resulte un clignement des paupières, involontaire et impossible à réprimer.

55 Rademaker G.G.J., “Willekeurige en onwillekeurige handelingen”, lecture delivered on the occasion of the acceptance of a chair at Leiden, NV Boek- en Steendrukkerij Edward Ydo, Leiden, 26 pp., 1928. 56 First published in 1930, see reference further on. 57 E.g. the French physician-philosopher De la Mettrie in his ‘L’homme machine’ from 1774 in Oeuvres philosophiques t. III, p. 74, and another Frenchman, the mathematician Laplace (1749–1827). 58 Canquilhem G., “La formation du concept de reflexe aux VIIe et XVIIIe siècles”, Vrin Paris, 1977, p. 30. 59 Minkowsky M., in: ‘L’état actuel de l’étude des reflexes’, translated from German by Henri Ey, 1927, p. 1.

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The first experimental investigation of reflexes by Sechenov (1829 –1905)

Fig. 2-20. Sechenov, Ivan Michailovich (1829–1905). Physiologist, St. Petersburg.

Russian neurophysiology reached such a state of development in the second half of the nineteenth century that it may be said in retrospect to have influenced all future concepts concerning the human and animal brain and behaviour. Before this period, it was common for Russian physiologists60 to gain experience by studying under top researchers at centres of excellence in Western Europe. Apart from furthering their own training, they could use the knowledge of scientific advances made abroad as a basis for lectures when they returned home. It is hardly surprising therefore that Sechenov—later known as the father of Russian neurophysiology—travelled to Western Europe at the age of 27,61 where he worked for six years under renowned neurophysiologists such as Müller, DuBois-Reymond, Ludwig, von Helmholtz, Burnsen and Claude Bernard. The influence of these researchers could be traced in Sechenov’s subsequent thought and development. As far as his neurophysiological views was concerned, DuBois-Reymond and Claude Bernard probably 60 This applied equally to aspirant physiologists and pathologists from Scandinavia, France, England and other countries. After completing his studies, it was de rigeur for a young physician to broaden his horizon and continue his studies by visiting various foreign centres of excellence. American and Japanese scientists had to do the same until 1940. 61 Sechenov, Ivan Michailovich (1829–1905), “Physiologische Studien über die Hemmungsmechanismus für die Reflextätigkeit des Rückenmarks inm Gehirne des Frosches”, Berlin: Hirschwald, p. 51, 1863a.

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made the greatest impression. Sechenov attended DuBois-Reymond’s lectures on animal electricity. He returned to St. Petersburg in 1860 with one of DuBois-Reymond’s ‘induction coil stimulators’, and a galvanometer which he had received from him, in his luggage and used this equipment to introduce electrophysiology to Russian science. Two years later he was back again in Paris, for a spell of work in Claude Bernard’s laboratory. The experiments performed there changed his ideas and gave him a clue about possible mechanisms of brain function. This work laid the foundation on which Pavlov developed his theory of conditioned reflexes, which was to dominate Russian neurophysiology for many years thereafter.62 Sechenov’s experiments (see figure), which had such a crucial influence on his subsequent thinking, concerned the effects on reflex movements of the placing of salt crystals at various levels on the transected neuraxes in a decapitated frog (Sechenov, 1863a) using the technique developed by Türck.63 In Sechenov’s experimental set-up,64 one toe of the decapitated frog was immersed in acid. Sechenov measured the interval between the stimulus and the time when the frog started to retract its leg by counting the beats of a metronome. This gave an indication of the extent to which placing the salt crystal on the brain stem influenced the retraction of the leg. Sechenov interpreted an increase in the time required before retraction was initiated as an inhibition of the reflex activity.65 The choice of a salt crystal as stimulus seems strange in the hands of a pupil of the electrophysiologist 62 According to Mary A.B. Brazier, in: “A History of Neurophysiology in the 19th Century”, Raven Press New York, 1904, pp. 215–216: “he was anything but an ivory tower scientist. On the contrary, he was a great believer in broadening education and was always trying to get more people into the fold, more people to be interested in science”. He even supported and believed—as was also Rademaker’s strong belief—in the education of women. One of Sechenov’s students became the first women doctor in Russia and she also became madame Sechenov, such as Rademaker’s fiancée and pupil became madame Rademaker. 63 Ludwig Türck (1810–1868), “Über die Haut-Sensibilität der einzelnen Rückenmarksnervenpaarek”, Denkschrift Königl. Akad. Wissensch. Wien. math.-nat. Cl. 29, 299–326, 1868. 64 Sechenov M.J., “Sur les modérateurs des mouvements réflexes dans le cerveau de la grenouille”, Comptes Rendus Acad. Sci. Paris, t.56, 50–53, 1863b (note presentée par M. Barnard); “Sur les modérateurs des mouvements réflexes dans le cerveau de la grenouille” (Suite et fin), Comptes Rendus Acad. Sci. Paris, t.56, 185–187, 1863c. 65 Sechenov M.J., “Ueber die elektrische und chemische Reizung der sensiblen Rückenmarksnerven des Frosches”, Graz Leuschner & Lubensky K.K. Univ. Buchhandlung, pp. 1–69, 1868.

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Fig. 2-21. Sechenov’s sketch of his experiment showing levels of the frog’s brain at which he made cuts. Cuts were made at A, B, C and D. The sketch indicates: A, the hemispheres; B, the optic thalamus; C, the quadrigeminae and D, the medulla oblangata. (From: I.M. Sechenov, 93,94 [Sechenov M.J., “Galvanische Erscheinungen an dem Verlängerten Marke des Frosches”, Arch. ges. Physiol. 27, 524–566, 1882].)

DuBois-Reymond.66 It is reminiscent of Marshall Hall’s use of such crystals some fifty years before in order to study the suppression or reinforcement of spinal reflexes.67 It was not until later that Sechenov made use of electrostimulation in his experiments on ‘spontaneous’ variations in spinal-cord potentials, which he regarded as exerting a central inhibitory effect on the skeletal (‘voluntary’) muscles (Sechenov, 1882).68 Although the indications obtained from the above experiments were slender, Sechenov must have considered their wider implications since a year later on his return to Russia he published, as one of a series of articles, the essay (1867), which was ultimately to exert such an influence on Russian physiology. This survey of ‘Cerebral reflexes’ (1863c;69 66 DuBois-Reymond E. (1818–1896), neurophysiologist, worked on animal electricity (discovered by Galvani) and especially on electric fishes. He introduced refined physical methods for measuring these effects and by 1849 had a sensitive multiplier for measuring nerve currents. His experimental methods dominated electrophysiology for a century. 67 Hall (Marschall), “On the reflex function of the medulla oblongata and medulla spinalis”, Philosophical Transactions of the Royal Society London 23, 635–665, 1833. 68 Sechenov M.J., “Galvanische Erscheinungen an dem Verlängerten Marke des Frosches”, Arch. ges. Physiol. 27, 524–566, 1882. 69 Sechenov M.J., “Refleksy golovnogo mozga (Cerebral reflexes), Medizinsky Vestnik, 47–48, 1863c. Sechenov M.J., “Fiziologiia nervnykh tsentrov”, (lectures), St. Petersburg, 1891.

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1866),70 was later published in book form—but not until after a stormy period during which attempts were made from various sides to prevent publication and to have the author censured. The ‘Council of the Censorial Department’ in Moscow declared that the book should be destroyed, but a highly placed friend of Sechenov’s in the Ministry of Justice managed to get the accusation and the court case planned to deal with it dismissed. There seems to have been a publications censor, whose responsibility it was to ensure that no work that expressed even the slightest suspicion of disagreement with the prevailing orthodoxy should be published. Sechenov got into trouble because of the patently materialistic nature of his book, which was forbidden by the Censorial Committee of St. Petersburg. He was obviously a brave man of independent mind, who was not prepared to hold his mouth when he was convinced he was in the right. The opposition to the book was largely in response to Sechenov’s claim that all higher functions were organically determined reflexes. He saw these reflexes as involving three sectors: sensory inflow, followed by a central process completely controlled by physical laws, and finally an efferent component resulting in muscular movement (see figure). All reactions, even those normally described in terms of emotions such as pleasure, fear, distress or the like, were essentially muscular in nature according to Sechenov. Passage of the stimulus through the central part of the reflex arc can be associated with either excitation (enhancing motor reflex activity as in ‘emotional’ states) or inhibition (reducing motor reflex activity, with ‘rationally’ controlled behaviour as a result). Sechenov believed that inhibition could be learnt, and that maturation and growth could cause the level of inhibition to increase. Thus, according to Sechenov all human behaviour is a balance between stimulus and inhibition, this balance being achieved at the level of the central part of the reflex arc mechanism. He regarded ‘voluntary’ movement as lacking the first component of the reflex arc, since the afferent ‘inflow’ in fact consisted of residual memories of past external stimuli. It was while working out this part of his theory that Sechenov approached the concept of the conditioned reflex by postulating that the residual memory of a past sensory experience could be evoked by the repetition of a fraction of this memory, no matter how insignificant or unrelated to a clear meaning this might be. This is in essence the

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Sechenov M.J., “Fiziologiia nervnoy sistemy”, St. Petersburg, 1866, 158 pp.

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principle underlying conditioned reflex theory, viz. the possibility of the existence of an indifferent external stimulus, as long as this is time-locked to the original experience on repetition. Another point should be mentioned in connection with this first attempt to link mental processes to the physiology of the brain: Sechenov believed that man had a special faculty, viz. an ability to influence the degree of inhibition at a central level, until complete blockage of the efferent discharge is achieved. He considered thinking to be an example of such a state. Although terms like ‘cerebral’ and ‘psychic’ reflexes occurred quite frequently here and there in the 19th century literature, these terms were mainly used by psychologists to refer to automatisms. There were very few scientists during this period who really tackled the problem of mental processes in physiological terms. Thomas Laycock (1812–1876), a pupil of Hughlings Jackson, was one of these.71 He claimed that consciousness was subject to the laws of reflex action. Pavlov became his most influential follower. Laycock’s work thus predated that of Sechenov and Ferrier. Pavlov (1849–1936) Many great discoveries arose from an attempt to clear up evident contradictions, such as those brought about by the changing concepts relating to reflex and instinct. (Pavlov)

According to Rademaker, a direct line could be drawn from the views and work of Pavlov and the work of Sherrington,72 to Magnus,73 whose 71 Th. Laycock (1812–1876), “On the reflex function of the brain”, Brit. & For. Med. 19, 298–311, 1845. 72 Sherrington C.S. (1858–1952); physiologist in Liverpool and Oxford. 73 Magnus R. (1873–1927), pharmacologist and physiologist in Heidelberg till 1908; moved to Utrecht, where he became the first professor of Pharmacoloy in the Netherlands. His main interests were the opium alkaloids and rhythmic action of the heart and intestines, where he thought choline played a role (the role of acetylcholine in the transmission of nerve impulses was eludicdated by Otto Loewi; he received the Nobel Prize for Physiology in 1936 for this discovery together with Sir Henry Dale, who had determined the physiological properties of acetylcholine). He studied the physiology of the postural reflexes together with De Kleyn (see Tonic labyrinthine reflexex—Part 2 of this book). In 1926 he demonstrated the function of the otoliths and the semicurcular canals. He was nominated for the Nobel Prize for Physiology or Medicine every year from 1922 to 1926—once in 1922, 6 times in 1923, 4 times in 1924, twice in 1925 and no fewer than 10 times in 1926. It seems certain that only

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pupil he was. Rademaker, as befits a good Dutchman, asked himself “what is the practical use of these investigations?”—and gave the following answer in his inaugural lecture (1928): In the first place, they are of great importance for the diagnosis of cerebral complaints. Thanks to Pavlov’s investigations, we are able to distinguish the reactions of the cerebrum from those of the spinal cord and brain stem on the basis of the differences in their behaviour. The investigations of Sherrington and Magnus have shown which parts of the spinal cord and brain stem are the sites of the various unconditional reflexes. On the basis of this knowledge, we can conclude from a disturbance in one or more of these reactions that certain specific parts of the central nervous system are affected, and can derive certain indications as to which parts may require surgical treatment.

Pavlov had discovered the nerve, which stimulates the pancreas to secretion in 1888, and received the Nobel Prize for this discovery in 1904. His later work was perhaps even more important. He was inspired by the work of his compatriot Ivan Michailovich Sechenov, whom we have discussed above. While Sechenov’s 1863 monograph ‘Reflexky golovnogo mozga’ (The cerebral reflexes) indicated that all human behaviour depended upon reflexes, another publication by Sechenov from 1870 taught Pavlov that all psychological questions could ultimately only be answered by the physiologist. Sechenov’s “Fiziologiia nervnoi sistemy” (‘Physiology of the nervous system’ from 1866) was popular among Russian intelligentsia and his books were widely discussed, especially in St. Petersburg. He is regarded as the father of Russian physiology. Psychology is physiology thus became the foundation on which Pavlov’s later work was based. Apart from this guiding principle, Pavlov’s work was determined by two other factors which did not go unnoticed by his critics. The first was the fact that all the investigations he carried out were performed on animals—in particular dogs. This gave him the lasting reputation of being an animal psychologist. Magnus and his school were not spared this criticism either. In order to avoid being tarred by the same brush, Rademaker always took care to relate his experimental his unexpected death in 1927 deprived him of this honour. The Institute of Pharmacology in Utrecht was named after him in 1968. His life and work are commemorated in Acta Physiologica et Pharmacologica Neerlandica 15, No. 2, 1969. See also the biography of Magnus by his son L.O. Magnus, “Rudolf Magnus, Physiologist and Pharmacologist, 1873–1927”, Kon. Ned. Akad. Wetenschappen, Amsterdam, 356 pp., with special reference to p. 117.

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work—right from the study of the nucleus ruber, which was the basis for this thesis in 1924—to the human situation and human pathology. In any case, the nature of Pavlov’s experimental work never stopped him from expressing far-reaching views about ‘la condition humaine’. The second factor was Pavlov’s conviction that the reflex had a simple stimulus-reaction structure. Pavlov used the term acquired reflex (conditional reflex, or conditioned response) to introduce a new view of the reflex. By this choice, he distanced himself from the old terminology of voluntary and involuntary reflexes (a step explicitly copied by Rademaker in his above-mentioned inaugural lecture). The conditional reflex was in fact initially called by other names. Pavlov first spoke of ‘psychic secretion’ (referring to the experiment, which later became a classic, in which dogs were observed to salivate when a bell or gong sounded before being offered meat, once they had become conditioned to this situation). He later used the term ‘psychic process’.74 The term ‘conditional reflex’, first used in 1903 in a publication by I.E. Tolochinov,75 one of Pavlov’s pupils, displaced the initial qualification ‘psychic’. This has been chronicled on the basis of a retrospective literature survey by Van de Berg (1973).76 According to G.W. Boguslavsky (1962),77 Pavlov’s own aversion to the word ‘psychic’ arose from a discussion between Pavlov and his pupil A.T. Snarski about the latter’s thesis, which in Pavlov’s view used too many psychological terms in writing about the dog. Be this as it may, Pavlov developed such a dislike of anything to do with the ‘psyche’ that he decreed that no one working in his laboratory should use the words ‘psyche’ and ‘psychic’ any more. His use of terms thus developed from a manifesto to a working programme. Until his death in 1936, Pavlov

The first more or less systematic description of ‘natural’ conditioned reflexes (still called ‘psychic reflexes’ at the time), was published by Wolfson in the thesis “Observations upon Salivary Secretion” (St. Petersburg, 1899). 75 Tolochinov I.E., “Contributions à l’étude de la physiologie et de la psychologie des glandes salivaires”, Forhändligar vid Nordiska Naturforskare och Läkaremötet. Helsingfors, 1903. The experiments discussed here were completed in 1901. 76 van de Berg J.H., “De Reflex”, publ. G.F. Callenbach BV Nijkerk, The Netherlands, pp. 181, 3rd impression, 1973. 77 Boguslavsky G.W., “Conditioning; A Historical Note”, in: Amer. Psychologist 17–1962. 74

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tried to explain not only animal but also human existence with an old, pre-Sherringtonian brand of pure physiological theory. In the series of lectures on conditioned reflexes Pavlov gave at the military medical academy in St. Petersburg in the spring of 1924, he discussed the extent to which psychology could be considered to be an exact science, and how it compared with physiology in this respect. He said: It is not possible here for me to enter deeply into this question, but I will stay to give one fact which strikes me very forcibly, viz. that even the advocates of psychology do not look upon their science as being in any sense exact. The eminent American psychologist William James, has in recent years referred to psychology not as a science but as a hope of science. Another striking illustration is provided by Wundt, the celebrated philosopher and psychologist, founder of the so-called experimental method in psychology and himself formerly a physiologist. Just before the War (1913), on the occasion of a discussion in Germany as to the advisability of making separate Chairs of Philosophy and Psychology, Wundt opposed the separation, one of his arguments being the impossibility of fixing a common examination schedule in psychology, since every professor had his own special ideas as to what psychology really was. Such testimony seems to show clearly that psychology cannot yet claim the status of an exact science. If this be the case there is no need for the physiologist to have recourse to psychology. It would be more natural that experimental investigation of the physiological activities of the hemispheres should lay a solid foundation for a future true science of psychology; such a course is more likely to lead to advancement of this branch of natural science.

The sentiments expressed in the above passage are in line with Pavlov’s appreciation of the work of Magnus, which he knew well and which he regarded as confirming his own views. To quote once again from the same series of lectures (p. 4), The physiologist must thus take his own path, where a trail has allready been blazed for him. Three hundred years ago Descartes evolved the idea of the reflex. Starting from the assumption that animals behaved simply as machines, he regarded every activity of the organism as a necessary reaction to some external stimulation, the connection between the stimulus and the response being made through a definite nervous path: and this connection, he stated, was the fundamental purpose of the nervous structures in the animal body. This was the basis on which the study of the nervous system was firmly established. In the eighteenth, nineteenth and twentieth centuries the conception of the reflex was used to the full by the physiologists. Working at first only on the lower parts of the central nervous system, they came gradually to study more highly

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Pavlov went on to cite one example taken from Magnus’s work, viz. the phenomenon of the chain reflex (p. 10): We are familiar with numerous reflexes which most certainly fuse into chains . . . and may take one of the chain reflexes recently established by Magnus.78 A cat even when deprived of its cerebral hemispheres, will in most cases land on its feet when thrown from a height. How is this managed? When the position of the otolithic organ in space is altered a definite reflex is evoked which brings about a contraction of the muscles in the neck, restoring the animal’s head to the normal position. This is the first reflex. With the righting of the head a fresh reflex is evoked, and certain muscles of the trunk and limbs are brought into play, restoring the animal to the standing posture. This is the second reflex.

And finally (p. 10): Last of all, it is sometimes held that whereas reflexes determine only the activities of single organs and tissues, instincts involve the activity of the organism as a whole. We now know, however, from the recent investigations of Magnus and de Kleyn, that standing, walking and the maintenance of postural balance in general, are all nothing but reflexes . . . .

Rademaker The above passages illustrate the prevailing view at the moment when Rademaker drew his conclusions from his first experimental work. By and large, he clearly followed Pavlov’s views and, like him, referred on several occasions to the history of speculation and research in this field, going right back to Descartes. One important occasion of this kind was Rademaker’s inaugural lecture in 1928 (pp. 6, 7). As we shall see, however, he does add his own touches to the story. He starts by saying, R. Magnus, “Wie sich die fallende Kätze in der Luft umdreht”, Arch. Néerlandaises de Physiol. de l’homme et des animaux 7, 218–222, 1922; Volume jubilaire H. Zwaardemaker. R. Magnus, “Die Körperstellung”, p. 228, Julius Springer Verlag Berlin, 1924. 78

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Three hundred years ago, Descartes developed the idea of the reflex. He assumed that animals performed their functions like machines, and regarded each action of the animal organism as a necessary reaction to external stimuli, the relation between these stimuli and the responses being determined by the nervous system. According to Descartes, a given reflex must have been preceded by a specific stimulus and a given stimulus can only be associated with one particular response. A reflex is thus an involuntary action, strictly determined by cause and effect.

He continues with some critical reflections on previous definitions of reflexes (p. 6): It is remarkable that the concept of the reflex, as opposed to psychic or voluntary reactions, has found such general acceptance. The remarkable thing about it is that every action is ultimately linked to certain causes and can be traced to events, which took place in the immediate or more distant past. There is thus no essential difference between the processes by which these various reactions arise, at most a difference in degree, in the more or less constant, more or less complicated nature of the link between cause and effect. The introduction of the concept of the reflex, characterized by a constant relationship between cause and effect mediated by the nervous system, has nevertheless yielded great scientific benefits. It has stimulated systematic attempts to trace the causes of the various reactions and to determine which parts of the central nervous system are involved in processing the incoming stimuli and producing the resulting reactions.

Rademaker also stressed the importance of clinical thinking in relation to these concepts, as the following passage (p. 7 of the text of the inaugural lecture) makes clear: these investigations showed that all typical reflexes, all typical involuntary actions bypassing the cerebrum, are mediated by the spinal cord and its prolongation or by the brain stem. This is true in the first place of functions of the internal organs which are normally exercised unconsciously, e.g. also during sleep, of the action of the heart and circulatory system, and of the organs of digestion and respiration. It has been found that the action of these organs is regulated by centres situated in the brain stem, and that removal of the cerebrum does not put an end to these functions. Another group of functions is mediated by centres in the spinal cord. Observations on patients in whom the spinal cord has been completely interrupted as a result of tumours, inflammation processes or wounds have shown that these patients had completely lost all feeling in or control over the parts of their body situated below the point where the spinal cord was interrupted. Thus, when their eyes were closed these patients had lost all awareness of the position or stance of these parts of their body. Nevertheless, these ‘lost’ parts of the body could still exhibit an appreciable number of reflex actions.

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Rademaker, who had been greatly influenced by Sherrington right from the start of his experimental work,79 then went on to refer to the contributions made by Sherrington who had not only determined the various reflexes which could occur in the hind extremities after section of the spinal cord, but also taught us which stimuli brought these reflexes about, and the significance of these reflexes.

Finally, Rademaker had the following to say about the history of reflex theory: Under the influence of these and other data, a classification of the reactions on the basis of their anatomical mechanism was gradually created. The reactions mediated by spinal cord and brain stem were considered to be typical reflexes, typical involuntary actions, while the reactions of the cerebrum were regarded as psychic, voluntary actions”. “It is true that this distinction was rarely formulated so sharply, but it was drawn in countless publications.

and gave a brief introduction to his own subsequent experimental work: The first problem crying out for solution now was which actions were beyond the control of the cerebrum and could thus still be carried out e.g. after removal of that organ, thus deserving the name of real reflexes.

Rademaker went on to give an analysis of the main literature on the reactions which were still possible after extirpation of the cerebrum, citing work from classical researchers such as Magendie (1783–1855; 1825), Longet (1811–1871), Vulpian (1826–1877; 1860), Goltz (1834–1902; 1892), Munk (1839–1912; 1896, 1907, 1908, 1909), Christiani (1885), Zeliony (1913) and the Dutch workers Dusser de Barenne (1885–1940) and Magnus (1873–1927). It goes without saying that Goltz occupied a pre-eminent place here. Rademaker’s admiration for the latter’s technical skills was expressed in the following analysis: This researcher managed to keep dogs alive for months after extirpation of the cerebrum.80 These dogs were still able to walk, step over obstacles, bark and whine, maintain their equilibrium by performing the right cor79 G.G.J. Rademaker, “Levensbericht van Sir Charles Scott Sherrington (28 Nov. 1858–1 Maart 1952)”, [Life of Sir Charles Scott Sherrington (28 Nov. 1858–1 March 1952) Jaarbook der Koninklijke Nederlandse Akademie van Wetenschappen, 1–8, 1953/1954. 80 A ‘Guiness Book of Records’ could be compiled with data from the literature on the number of months or years animals survived after extirpation of the cerebrum

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rective actions when they were pulled to and fro, and perform many other very complicated actions.81 The animals were able not only to remain upright, but to get up from a supine position or from lying on their side. Magnus had analysed these phenomena and reported on them in various publications, summarized in his book ‘Körperstellung’ [Posture] (1924). In Magnus’s opinion, the ability to get up from a supine position or from lying on one’s side was due to a number of reflexes, the stimuli for which came from the labyrinths, the surface of the body and the deeper parts of the neck and were processed in centres situated in the midbrain and the spinal cord.” “And”

Rademaker pointed out further in this connection, “Magnus’s investigations revealed another important fact, viz. that there was no one-to-one relationship between stimulus and effect in these reflexes, as Descartes had supposed. A given stimulus need not always lead to the same reflex under all circumstances. A dog whose spinal cord has been transected will react quite differently when its hind leg is bent than when it is straight. The stimulus can thus go to quite different motor centres, depending on the position of the leg (a phenomenon referred to as “Schaltung”—switching—by Von Uexküll and Magnus)”. (see endnotei)

Rademaker continues (as cited in “On Standing”), “Walshe reports a case in which the positive Babinski reflex could be transformed into a negative one by means of the tonic cervical reflexes by passive or active rotation of the head, the distribution of the tonus was changed in the paralysed extremity. Guillain and Barré, Boveri, Bychowski and others observed the transition of the positive Babinski reflex into a plantar flexion when the patients were turned from a dorsal into a ventral position, which was similarly observed by Mankowski and Beder, when they passively flexed the knee and hipjoints. Even after the transverse lesion of the spinal cord either a plantar flexion or a dorsal movement of the big toe could be observed at different times in the same patient (Riddoch Lhermitte). It is thus natural to assume that the negative and positive Babinski reflex can be brought about spinally without participation of higher centers. These observations further prove that the same stimulation

or the cerebellum. Rademaker and Luciani would be found to be top scorers in this champions’ league. 81 Goltz F., “Der Hund ohne Grosshirn”, Pflügers Arch. f.d. ges. Physiol. 51, 570–614, 1892; Pavlov also cited the following publications in this connection: Rothmann M., “Der Hund ohne Grosshirn”, Neurologisches Centralblatt V, xxviii, 1045–1046, 1909; Rothmann M., “Demonstration des Sektionsbefundes des grosshirnlosen Hundes”, Neurologisches Centralblatt 31, 867–868, 1912. The dog described by Rothmann displayed the same neurological signs as Goltz’s dog, but survived longer after the operation.

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book ii can also sometimes cause a flexor, and sometimes an extensor reflex in the spinal man. Following Von Uexküll and Jordan’s findings in invertebrate animals, in which the centres of stretched muscles can be “engaged ”, (i.e. a stimulation in a network of nerves always flows towards the stretched muscles), Magnus observed that also in spinal animals, a certain stimulus as for instance, the tapping of the patellar tendon, sometimes causes an extensor reaction and sometimes a flexor reaction according to whether the extensor or flexor muscle was previously stretched (“reflex inversion”, “reversal”.

These and other observations by Magnus thus prove according to Rademaker that even in the case of spinal-cord reflexes, the effect depends not only on the nature of the stimulus but also on other circumstances. Close as Élie de Cyon (1842–1912), a brilliant intuitive and imaginative Russian physiologist was to Sechenov, he had major disagreement with him (M.A.B. Brazier, 1988)82 when Sechenov developed his idea of ‘reflexes in the brain’, De Cyon maintained that they did not occur above the spinal level. Rademaker became interested in his work, which he published in later years, expanding his interests in such subjects as perception of space and the role the vestibular system plays. De Cyon’s views on the role of the labyrinth raised both dissent (from Bechterew) and an agreement (from Ukhtomsky) and later in 1959 from Beritoff, once one of Magnus’ collaborators. Rademaker cited his work, regarding the function of the semicircular canals, in his monograph on ‘Réactions labirinthiques’ and agreed with his views. He dissented on his views on the physiological action of thyreoid extracts.83 Neurophysiology had been developing as a science on its own rights in France (Magendie and Claude Bernard), United Kingdom (Sherrington) and Germany (Muller). An excellent survey of the comparative neurophysiology of this period has been given by Stella V.F. Butler in her (unpublished) thesis84 on “Science and Education of Doctors in the 82 “A history of neurophysiology in the 19th century”, Raven Press, pp. 218–220, 1988. 83 E.F. de Cyon and Adolf Oswald, “Über die physiologischen Wirkungen einiger aus der Schildrüse gewonnener Produkte”, Pflüger’s Arch. f.d. ges. Physiol., 83, 1901 (On the physiological effects of some products extracted from the thyreoid gland). 84 Stella V.F. Butler, “Science and Education of Doctors in the Nineteenth Century: A Study of British Medical Schools with Particular Reference to the Use and Development of Physiology”, Thesis Manchester December 1981, 338 pp. (courtesy Miss Nicole Grimaud, Paris).

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Nineteenth Century” in which she demonstrated the various intellectual styles of British physiology in the nineteenth century relating concepts of the body to the institutional organisation of medical research and ‘the major paradigma shifts away from a reductionist mechanistic approach towards a holistic view of the body’. Starling’s institutional ambitions could be compared to Rademaker’s views. Rademaker hold the same opinions and advised his students to read Starling’s textbooks. Russian neurophysiology and its origins in: “History of neurophysiology in the 19th century” has been discussed by Mary A.B. Brazier (Dpt. of Anatomy and Physiology USLA School of Medicine; Raven Press, New York, 1988, pp. 212–248) (part 3.1). The only conditioned reflex which has achieved significance for neurological diagnosis in human adults is the blink reflex in response to threats. It was discovered by Rademaker and co-workers. The reflex is discussed in Book III. 2.5. ‘Das Stehen’. Why Translating? Rademaker’s monograph ‘Das Stehen’, originally written in German and published in 1931 by Springer Verlag in Berlin, was finally translated into English in 1980, under the title ‘The physiology of Standing; Postural Reactions and Equilibrium with Special Reference to the Behavior of Decerebellate Animals, Edited with a foreword by D. Denny-Brown, Univ. of Minnesota Press, Minneapolis.’85 After a brief discussion of the motives for publishing a translation of this monograph nearly 50 years after the appearance of the original, the content of Das Stehen is summarized at some length and key elements of Rademaker’s findings are explained. The German terms for the different reactions involved are retained for the sake of interest but are translated or paraphrased for the convenience of the Englishspeaking reader.

85 A lengthy summary of ‘Das Stehen’ in English was published by A.T. Mussen in ‘Arch. Neurol. and Psychiatry, 28, 679–701, 1932. The author commented, “The enormous amount of material presented, the numerous and important tests described, the changing symptoms in the same animal following the different operations were all so significant that a brief summary was clearly impossible.”

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Fig. 2-22. Frontispiece of ‘The Physiology of Standing’ (‘Das Stehen’).

Why translate Das Stehen? It is worth asking why Denny-Brown went to the trouble of persuading the University of Minnesota Press to publish an English translation of Das Stehen nearly 50 years after its original appearance and took upon himself the task of editing this voluminous monograph—no mean enterprise in itself. This question has already been posed e.g. by the physiologist Van Hof (1992)86 and the natural philosopher Prof. RobVisser (2003). While no records have been preserved of the correspondence between Denny-Brown and the publishers, he was clearly capable of undertaking such a momumental job since he had already published the collected works of Sherrington.87 Moreover, it is clear from his Foreword to the translation that he was convinced that the monograph contained a wealth of information that was still highly relevant to researchers in this field. He added, “The complete objectivity Rademaker achieved gives them [his results] a timeless quality . . . Nevertheless, few in the English-speaking world have been able to read in detail the 476 pages of heavy German in the original monograph.” The 1980 version filled this gap. It was not a simple translation, however, since Denny-Brown 86 van Hof M.W., “Het zenuwstelsel: een netwerk van neuronen, een doolhof van gedachtengangen” (The nervous system: a network of neurons, a maze of ideas). Valedictory lecture as professor of Physiology at Erasmus University Rotterdam, 25 June 1992. 87 Denny-Brown D., “Selected Writings of Sir Charles Sherrington”, Hamish Hamilton Medical Books, London, 1939, p. 532.

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added ample editorial comment in the form of footnotes, explained the context in which Rademaker did his experimental work and even added reports of his own experiments, including confirmation of Rademaker’s own findings. All this made the translation even bulkier than the original—almost 200 pages more. To make the work more accessible to an Anglo-Saxon readership, Denny-Brown adopted a more concise style, and rewrote the somewhat cumbersome definitions of the key German concepts such as Sprungbereitschaft introduced by Magnus and Rademaker. Finally, and perhaps most importantly, the English version presented its readers not only with ample insights but also with a challenge: on the basis of the unanswered questions that Rademaker had listed at the end of the book, after his description of the most remarkable experiments (such as the combined ablation of both cerebrum and cerebellum) he formulated axioms and postulates to be worked out by the reader. It was clear that Denny-Brown hoped, and expected, that this line of research would be continued. Summary of ‘Das Stehen’ In his opening comments Rademaker points out that it is the tone in the muscle that makes standing possible and that this tone is regulated by the central nervous system; the connection of the muscles with the spinal cord is not in itself sufficient, for if the spinal cord is separated from the brain the ability to stand is lost, and lesions of the midbrain and cerebellum destroy this power to a greater or lesser degree. The object of the research was to find an answer to the following questions: How is standing achieved, and what reactions take part in the normal standing reflex? What part of the central nervous system must be present in order that these reactions may arise? To answer these questions, the following operations were performed. In fifteen animals the entire cerebellum was removed; in five, half of the cerebellum; in three, the whole cerebellum and half of the cerebrum; in two, the cerebellum and the cerebrum; in the five, the entire cerebrum; in one, the cerebellum and both labyrinths, and in one, both labyrinths and half of the cerebrum. In a general review of the question of standing and the static reactions, attention is drawn to the observations of Duchenne in 1867, who first pointed out that maintenance of the different positions involved in standing required continual activity of the flexor and extensor

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muscles. Sherrington showed the influence of the muscle reflexes. He also reported that the rigidity, which developed after section of the mesencephalon, disappeared when the posterior roots of the spinal cord pertaining to the feet were cut. Magendie, Longet, Shiff, Vulpian, Christiani, Munk and Goltz demonstrated that animals without a cerebrum could stand, but that the reaction was purely reflex in nature, without any voluntary element. Luciani observed that animals without a cerebellum showed astasia. Edinger held that the cerebellum was the organ that controlled ‘statotonus’. Von Bechterew stated that the cerebellum is the centre for static coordination, that the essential preliminary requirement for execution of these reflex muscular activities is that they give rise to a sensation that permits exact determination of the position of the body and the head in relation to the vertical plane, so that at any given moment the effects of a disturbed centre of gravity can be overcome. Against these interesting theories Rademaker points to the fact that after extirpation of the cerebellum, both the labyrinthine reactions and the postural reactions are still present. The effect of spinal-cord injuries on the standing reflexes is carefully considered, as is the manner in which these reflexes are influenced by the division of the posterior roots. An interesting case of Sherrington’s is reported which indicates that proprioceptive irritation may arise in the muscles themselves. The question of whether the tendon reflexes are spinal or have their origin in the midbrain is discussed. Bastian held the opinion that flaccid paraplegia with anaesthesia and absence of all reflexes indicated absolutely that the cord had been completely divided. Gradually, however, cases were observed that disproved this. Kausch reported the case of a patient with the spinal cord completely divided, in whom a distinct patellar reflex persisted. Head, Riddock and Lhermitte found in their examinations of men wounded in the war, with total transverse section of the spinal cord, that muscle tone could sometimes still be observed, as well as spinal and skin reflexes (e.g. the Achilles, periosteal, homolateral flexion and crossed extension reflexes). Riddock and Lhermitte emphasized that there is an absolute agreement between the observations in man and the results obtained in experimental animals. What was the situation when Rademaker started his experimental work? The study of righting reflexes in man was still in its infancy at the end of the Magnus era, though it was known that these reflexes were present in man as well as in animals. The animal experiments that

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had been performed had not been subjected to thoroughgoing logical analysis, and little was known about the way in which the different reflexes worked together in the maintenance of the erect posture. Landau (1925), Schaltenbrand (1925), Isbert and Peiper (1927) and others had just begun their studies of children during the initial stages of development, where they learn how to stand and walk.88 Magnus stated at the end of his monograph: “Only when this pioneer work has been accomplished will an understanding of pathological conditions be possible”. Labyrinthine righting reflexes could be demonstrated in children who were blindfolded and held by the pelvis in the air in different positions: under these circumstances, the children could be seen to move their head towards the normal position (Schaltenbrand, 1925). Neck righting reflexes were found to be very active in man. In children they were studied by Landau (1925) who showed that babies in the prone position usually brought the head into the normal position by dorsiflexion and that this was followed by strong lordosis of the vertebral column with extension of the limbs. Passive ventroflexion of the head caused disappearance of the lordosis so that the whole body became ventrally concave.89 Schaltenbrand had published photographs and films of babies in which rotation of the head had caused the body to roll from the supine into the lateral position, a reflex that according to Zingerle (1925, 1926)90 could be demonstrated in many patients. Cerebellar patients showed particularly strong neck righting reflexes on passive rotation of the head (in several of these patients, rotation of the trunk and head appeared on a passive outward rotation of a leg). Textbook photographs of gymnasts gave ample evidence of the presence of similar neck righting reflexes in normal adults. Magnus’ school had paid relatively little attention to the optic reactions (Ter Braak et al., 1953).91 Rademaker had insisted that the optical See Book II, Part 2.7. For references see Book II, Part 2.7. 90 Zingerle H., “Über Stellreflexe und automatische Lageveränderungen des Körpers beim Menschen”, Klin. Wschr. 3, 41–.., 1924. Cited by Rademaker in “Das Stehen”. Zingerle H., “Klinische Studie über Haltungs- und Stellreflexe, sowie andere automatische Körperbewegungen beim Menschen”, J.f. Psychiatr. 31, 330–418, 1925. 91 J.W.G. ter Braak, W. Storm van Leeuwen en H. Verbiest, “Professor Rademaker, the man and his work”, Folia Neurol. Neurochirurg. Neerlandica 56, 393–563, 1953 (Festschrift). 88 89

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righting reflexes in man could play a very important role of which many examples could be given (one of which he presented in his monograph “Réactions labyrinthiques et équilibre”, 1935). It was well known that aeroplane pilots (in the early days before radarbased navigational aids were available) found it practically impossible to know which way up they were when flying through mist or clouds, where visual cues were unavailable. On emerging from the clouds, they would often discover that they had been completely disoriented with respect to the earth. One important concept in this context is the null option or ‘zero condition’, in which all reflexes playing a role in the mechanism in question are inactivated. This is found in the case of righting reflexes in humans, for example, if deaf-mutes in whom the labyrinths are lacking or inoperative are submerged under water. Since optical orientation is impossible under these circumstances and the labyrinths do not function, no body righting reflexes can be evoked and such patients will drown if no one is there to help them out of the water. Experiments by Garten and his pupils92 on an inclining chair had clearly demonstrated the great influence of the body righting reflexes evoked by the contacts with the surface of the seat. Even when labyrinth impulses were made as ineffective as possible and the eyes were closed, there was a very precise estimation of the smallest deviations from the horizontal plane. These experimental subjects were never placed under the above-mentioned zero conditions. As to the relative effect of the different sensory organs on orientation, it could be stated at that time that optical and tactile influences played a very important role in man, whereas the part played by the labyrinths was ‘probably less than in rabbits and Guinea pigs’. The concept of Körperstellung (posture) introduced by Magnus and his school was preceded by intuitive ideas about muscle tone and postural reflexes held by previous researchers. Since a basic grasp of the development of thinking in this field is essential for proper understanding of Rademaker’s Das Stehen, the history of these ideas will be briefly sketched below. 92 Also cited by – Peiper in “Die Hirntätigkeit des Sauglings”, Berlin Springer Verlag, 1928, and in Jahrbuch f. Kinderheilk. 134, 149, 1932; – Zador J., “Les réactions d’equilibre chez l’homme”, Masson et Cie., 1938, pp. 255.

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The postural reflexes as such took a long time to be recognized. Magendie had an experimental observation in 1823.93 Robert Whytt, the distinguished Edinburgh neurologist (1714–1766),94 was probably the first to distinguish the phenomenon of decerebrate rigidity, as indicated in his “Essay on the vital and other involuntary motions of animals”. However, it was not unambiguously described until Sherrington’s paper in 1898.95 When the effect of rotation of the head on the posture of the decerebrate cat became clear, Magnus and de Kleyn were quick to appreciate the importance of the phenomenon. Magnus and Rademaker focused their research on analysis of the effects of decerebrate rigidity, and developed a new vocabulary to explain their findings. This ‘new physiological language’ was not only explanatory but also instrumental, as it guided the direction taken by the investigations. Rademaker took over the vocabulary initially coined by Magnus, de Kleyn and other members of the Utrecht school and developed it further over the years. Sherrington had observed ‘standing reflexes’ and ‘static tonus’ of the extensor muscles of the extremities in decerebrate animals, but Magnus and later Rademaker stressed that the way these animals stood was a caricature of normal standing and that the relationship between the tone of the various muscles involved differed totally from that in normal standing.96 As Rademaker stated,97 Duchenne98 was the first to perceive in 1867 that the ligaments alone could not possibly explain the fixation of the bones in the various positions observed in standing, but that rather

93 M. Magendie, “Note sur le siege du mouvement et du sentiment dans la moeffe épinière”, J. Physiol. Exp. Pathol., 3, 153–157, 1823. 94 R. Whytt, “Physiological essays”, Edinburgh, Hamilton, Balfour and Neill, 1755, XV, 223 pp. 95 Sherrington C.S., “Decerebrate rigidity, and reflex coordination of movements”, J. Of Physiol. 22, 319–322, 1897/1898. 96 Magnus R. in: Cameron Prize Lectures on some results of studies in physiology of posture, May 19th and 20th 1926; Lancet ii, 531–536; 585–588, 1926. Rademaker G.G.J., “Physiologie en pathologie van het staan”, Ned. Tijdschr. v. Gen. 71, 1641–1645, 1927. 97 G.G.J. Rademaker, “Over de physiologie van het staan”, Verslag van de gewone vergadering afdeeling Natuurkunde van de Akad. v. Wetenschappen; In Verhandelingen en Bijdragen van de Ned. Akad. v. Wet. 36, 635–649, 1927. See also ‘The physiology of Standing’ (1980), p. 6. 98 Duchenne (de Boulogne) G.B., “Physiologie des mouvements”, Paris, J.-B. Baillière et fils, 1867; Duchenne (de Boulogne) G.B., “Physiologie der Bewegungen”, Cassel u. Berlin: Theodor Fischer, 1885.

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continuous muscular contraction was necessary to keep an animal in an erect position. He drew attention to the fact that a standing animal’s muscles can be felt to be tensed, and that extensors as well as flexors participate in the process of fixation of the legs. He further pointed out the fact that animals with muscular atrophy may experience considerable difficulty in standing. In this context, Rademaker often commented in his lectures to students that “there is more nerve than muscle in muscle . . .” (See endnotes: iv and v) Key concepts from ‘Das Stehen’ The conditions associated with standing in decerebrate animals Sherrington showed that a transverse section through the mesencephalon produces an extensor rigidity; that the rigid legs have a static tonus and that they can, through the standing reflexes, support the weight of the body; that this rigidity is so marked that the animal stands on its toes, with head retracted, back arched and tail extended. On the other hand, Magnus had demonstrated that the rigidity may be less severe, the elbows and wrist joints showing some flexion, the head not retracted and the tail drooping. In some cases the tonic labyrinthine reflexes exert so strong an influence that when the animal is placed on its back there is a well-developed rigidity in the legs. In others, when the head and neck are stretched backward the tonic neck reflex is so great that the hindlegs show a flexor tonus. These animals can stand only with the aid of their forelegs. “Stehbereitschaft” (Preparation for standing)99 Normal standing is made possible through the ability of the animal to place the extremities in the correct position to maintain equilibrium; if the supporting tone is sufficient, the weight of the body will then be borne by the extremities. To demonstrate this reaction, a normal animal, which has been blindfolded, is held over a table with its head down, and is then lowered till its muzzle touches the table. As soon as the animal feels the surface, it will place its forelegs on it and extend

99

“The physiology of Standing”, Chapter IV, pp. 31–35.

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the legs, the shoulders being raised. A similar reaction occurs when the backs of the feet touch the edge of the table. And when the animal is held head up and the body is moved about so that the tail or hindlegs touch the surface, it will immediately place its hindfeet on it and extend its legs. The correction of an abnormal position of the paws is shown to be influenced by exteroceptive stimuli and the stroking reflex of Munk. Visual impressions alone will give rise to the reaction. Decerebrate, spinal and thalamic animals, as well as those without a cerebrum, lose the capacity to stand. After the removal of the cerebellum, this capacity disappears in a few days. In puppies it is not present for from three to six weeks. That the cerebrum is largely responsible for the reaction in the forefeet is indicated by the fact that this reaction is absent after complete extirpation of the cerebrum. After half of the cerebrum is removed, the reaction is present only in the homolateral forefoot. If the cerebellum is also removed in this animal, the character of the disturbance is not altered. Animals with half a cerebellum or with no cerebellum can place their feet in the proper position for standing through the influence of the visual impressions. By virtue of these and other reactions, the preparation for standing is considered to be a cerebral reflex. “Stützereaktionen” (Support reactions)100 For normal standing, in addition to the correct position of the limbs, a sufficient supporting tone is necessary. This tone is released through the pressure of the underlying surface on the soles of the feet. When a normal dog or one without a cerebellum is held in the back position, the limbs are flexed. If passive movements are made, one feels some resistance to extension, but hardly any against flexion; a distinct extensor tone is absent. The position of the joints and the tension of the muscles are incapable of supporting any weight. On holding the animal in the air, in the ventral position, the feet are either drawn up against the body or hang partly extended. Passive movements show some resistance to flexion, though not sufficient to bear the weight of the body. But as soon as the animal is placed on a supporting surface, the limbs at once become firm, owing to the development of a strong extensor tone. The investigation of these phenomena shows that three

100

In: “The physiology of Standing”, Chapter V-A, pp. 56–58.

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factors are concerned in the release and maintenance of this supporting reaction: (1) contact with the soles, i.e., the magnet or exteroceptive supporting reaction, (2) the position of the terminal joints and (3) the pressure on the soles. The Magnetreaktion of the hindfeet101 Extroceptive impulses originating through contact with the soles of the hindfeet produce extension with fixation of the limbs. This is most clearly observed in dogs without a cerebellum. The extension holds as long as the pressure lasts, whether the eyes are open or closed, and is present in the back and ventral positions as well as when hanging with the head up. If a dog is held in the ventral position by the head and tail, the back is concavely flexed. As soon as the soles of the hindfeet are touched, the hindlegs are extended, and the tone in the back increases. Dogs without a cerebellum show marked reactions even when the back is weighted. These and other tests indicate that by ouching the soles of the feet, exteroceptive impulses are released, giving rise to a strengthening of all the muscles in the leg under examination, which are stretched and fixed in extension. There is a strengthening in the pelvis, breasts, neck and spinal muscles, a lessening in the extensor tone of the opposite hindleg, as well as changes in the tension of the muscles of the forefeet. The Magnetreaktion of the forefeet102 Contrary to the hindfeet, the forefeet of an intact dog, or one without a cerebellum, do not show any reaction in the dorsal position. This difference depends on the wrist joint, which shows a maximal flexion. If the joint is passively extended to 90 or 100 degrees and the sole of the foot is touched, the reaction will appear promptly. When held in the ventral position, the legs are more or less extended. On touching the sole of one foot, it is fully extended and becomes rigid. The appearance of the Magnetreaktion depends on the position of the pelvis to the spinal column, and of neck and trunk, the position of the pelvis to the spinal column, and of the feet to the body. The reaction is permanently lost after the complete removal of the cerebrum in decerebrated animals, after extirpation of both labyrinths and after section of the posterior

101 102

In: “The physiology of standing”, Chapter V-B, pp. 73–79. In: “The physiology of standing”, Chapter V-B, pp. 73–79.

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Figs. 2-23 a, b, c, & d. The magnet reaction (exteroceptive supporting reaction) of the hindlimbs. The exteroceptive stimulations induced by touching of the sole of the foot may cause an extension of the hindlegs with fixation in extended position. This influence of exteroceptive stimulation can best be observed in decerebellate dogs in dorsal (supine) posture. Such an animal in a dorsal position with the muzzle pointing vertically upwards keeps its four limbs flexed. ‘Magnet reaction’ of the hindlimb: 1. Decerebellate dog in dorsal position with the muzzle pointing vertically upwards. The hindlimbs are totally flexed. 2. On the slightest touch of the sole maximum extension of the right hindlimb. 3. On touching the soles of both hindlimbs extension of both. 4. Decerebellate dog: magnet reaction of the right hindleg. With the slightest touch on the ball of the toe, an extension of the limb occurs by which the touching finger is pushed away. If one slowly withdraws the finger the hindlimb will follow, as if attracted by a magnetic force until it is maximally extended. Rademaker is shown performing this magnet reaction. (Reproduced from the original glass-negatives, in: G.G.J. Rademaker, “On the Physiology of Standing”, pp. 58–59.)

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Figs. 2-24 a & b. A totally (for more than a year) decerebellate, right-sided decorticate dog, showed the same increased extensor tonus and reduced supporting tonus in the left legs that followed extirpation of the right half of the cerebrum alone. In this animal also, the abnormal extensor tonus of the right hindleg disappeared with static stress on the left hindleg. In this figure in dorsal position of this animal the left hindlimb showed initially extended posture with increased extensor tonus, which disappeared on touching (1) and static stress (2) on the sole of the right hindlimb. (Reproduced from the original glassnegatives, in: G.G.J. Rademaker, “On the Physiology of Standing”, pp. 128–129.)

Figs. 2-25 a & b. Rocking (displacement) reactions of the forelegs in the decerebellate dog. Right foreleg and posterior part of body lifted from the ground so that the animal stands only on the left foreleg. On passive movement of the trunk to the right by which the left foreleg is passively pulled into abduction posture, the right foreleg was actively and vigorously extended and abducted and offers resistance against passive, static and non-static flexion. By a movement of the trunk towards the left, the left foreleg is passively adducted and the support tonus of the right leg has relaxed and can now easily be flexed, returning it to position 1. (Reproduced from partly damaged glass-negatives, in: G.G.J. Rademaker, “On the Physiology of Standing”, p. 311.)

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Figs. 2-26 a & b. Strength of supporting tonus in the unilaterally decorticate totally decerebellate dog. Decerebellate, right side decorticate dog. In a dorsal position on a supporting surface with ventrally directed muzzle (1) the left hindlimb is rigidly extended in the air. When the muzzle is held below the horizontal (2) the left foreleg goes into an extended position with increased extensor tonus. (Reproduced from the original glass-negatives, in: G.G.J. Rademaker, “On the Physiology of Standing”, p. 172.)

roots connected with the foot under examination. It is temporarily absent following the removal of the cerebellum. It has been observed on both sides when only half of the cerebrum is present. Influence of the position of the terminal joints on the “Stütztonus”103 The position of the terminal joints of the feet is as important as the touching of the soles for the release of the supporting reaction. If an intact dog or one without a cerebellum is held in the back position and the wrist joint is passively extended without touching the sole, the elbow joint will also be involved and the leg will assume a position of partial extension. In explanation of this close relationship of the joints to one another, it is suggested that the stretching of the flexors, through the passive extension of the joint, gives rise to impulses which evoke a contraction not only in the extended muscles but also in the remaining muscles, and so determines the position and fixation of the elbouw and shoulder joints.

103 In: The physiology of standing”, Chapter V, The supporting reactions C, pp. 79–87.

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Pressure on the sole104 If an intact dog or one without a cerebellum is laid on its back and the toes and wrist joints are brought into the standing position without touching the sole, then the feet will be stretched out and fixed in the extended position. This fixation is increased when pressure is applied to the sole. Pressure like touch gives rise to exterocetive stimuli, but the intensity is much stronger. The three factors—touching the sole, the position of the terminal joints and pressure against the sole—constitute the positive supporting reactions. They make it possible for the limbs of intact animals and those without a cerebellum to become so rigid that they are able to support not only the trunk but twice the weight of the body.105 Complementary posture dependence of the proximal joints106 The fourth factor, which takes part in the origin of the supporting tone, is the complementary posture dependence of the proximal joints. Passive extension of these joints induces extension and fixation of the terminal joints, while passive flexion is accompanied by flexion and relaxation. This complementary reaction explains the alteration in the tone of the forelimbs and hindlimbs of a standing animal when the hindpart or forepart of the body is raised or lowered. It is through these changes in the supporting tone that the position of the legs is brought into proper relation with the actual position of the underlying surface. The correction of abnormal positions of the feet is also due to this associated reaction. If a dog without a cerebrum is stood on a table in such a manner that the forefeet rest on the back of the paws, the position will be immediately corrected as soon as the animal begins to walk. For, as the shoulder joints move forward the wrist joints and the fingers are extended so that the feet are correctly placed on the soles. The supporting tone is absent in newborn dogs, cats and rabbits. After section of the posterior roots to the feet, all reactions belonging to the standing reflexes are lost. Following transection of the cord the 104 In: “The physiology of standing”, Chapter V, The supporting reactions D, pp. 87–91. 105 The clinical relevance of these data are discussed by the authors. Vide: G.G.J. Rademaker et R. Garcin, “Sur une variété d’astasie-abasie conditionnée par l’exagération des réactions de soutien (Stützreaktion). Leur extéeriosation dans le decubitus”, Revue Neurologique (Paris) 1, 186; 384–391, 1933. 106 In: “The physiology of standing”, Chapter V, The supporting reactions E, pp. 91–147.

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Magnetreaktion is absent. On testing the standing reflex of the flexed legs, there is no extension, and if the legs are extended, there is no fixation. The supporting reaction is present in all four legs after the removal of the whole or the half of the cerebrum. In dogs without a cerebellum the reaction is at first lost, but returns during the first week. On standing the legs are overextended; when the animal runs the legs are raised too high and too stiffly. In pigeons from which the cerebrum and, an hour later, the anterior lobe of the cerebellum have been removed, the legs hang partly flexed when held in the air, but they become extended and rigid as soon as the feet touch the table. Injury of the cerebellar nuclei increases the tone. A dog with half of the cerebrum and both labyrinths extirpated shows the same reactions in the supporting tone as is found in dogs with but half of the cerebrum. The removal of the entire cerebellum and the right half of the cerebrum produces the same results as when only the right half of the cerebrum has been extirpated. There is an interesting review of the literature dealing with these reactions in man. Though the question has not been systematically investigated, a number of pertinent observations have been made which indicate that the positive and negative supporting reactions are present. Finally, the question of how the central mechanism of these proprioceptive supporting reactions is to be explained is carefully considered. The strength of the supporting tone and its adaptability to the load107 If a sand bag is laid slowly on the back of a standing dog, the legs do not bend, but if it is dropped suddenly the legs are first flexed, then extended, showing that the supporting tone was not at first sufficient. This adaptability is accomplished through the increased pressure of the animal against the supporting surface, which intensifies the exteroceptive impulses arising in the soles. After a careful examination of the strength of the supporting tone in intact animals and those without a cerebellum, in animals with one half of the cerebellum removed, with the complete cerebrum extirpated, in thalamic animals without a cerebellum, in animals without a cerebellum and with only half of the cerebrum present, in decerebrate animals and those without labyrinths, the following conclusions are arrived at:

107

In: “The physiology of standing”, Chapter VI, pp. 147–149.

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The tone varies greatly under different circumstances. For example, intact dogs can bear a load equal to the body weight; dogs without a cerebellum can carry a load greater than the body weight; in dogs with half a cerebellum, the tone in the homolateral limbs is at first weakened, later normal; with the cerebrum removed, the supporting tone is reduced; with both the cerebrum and the cerebellum removed, the supporting tone is weaker than when only the cerebrum was extirpated; with half of the cerebrum removed, the tone in the opposite limbs is lessened; with half of the cerebrum and the entire cerebellum removed, the tone in the limbs contralateral to the extirpated half of the cerebrum is strongly and permanently diminished. Decerebrate animals in the standing position usually show a distinct reduction in tone on pressure against the soles. Extirpation of both labyrinths has no effect on the supporting tone. In intact dogs the supporting tone is less in the back position than when standing. In thalamic animals and those without a cerebellum the supporting tone is the same as in intact animals. Decerebrate animals in the back position show a stronger supporting tone than when standing. In human beings with disease of the central nervous system no definite results have been obtained. Changes in the supporting tone on raising and lowering the head. The supporting tone and the vertebra-prominens reflex108 The adaptation of the supporting tone to static conditions is dependent on the coordination of numerous reflexes having their origin in different parts of the body. Raising and lowering of the head in intact animals produces distinct changes in the supporting tone and position of the limbs. In the standing position, with the head well back, the tone in the hindlimbs is diminished. With the head flexed ventrally, the tone is increased. In the back position the changes in the tone are inconstant. Dogs with half a cerebellum removed, in the standing position, show changes in the supporting tone equally strong on both sides, but in the back position, on moving the head ventrally, the increase in the supporting tone is generally stronger in the homolateral hindfoot. With the removal of the entire cerebellum, the alterations in the supporting tone and the position changes in the limbs appear a long time after the operation in both the standing and the back position. In the standing position,

108

In: “The physiology of standing”, Chapter VII, pp. 201–204.

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with the head ventrally flexed, the increase in the supporting tone in the hindlegs is less than in intact animals. In the back position the tone is almost completely lost. The importance of the changes in the supporting tone on raising and lowering the head is to enable the animal to adapt itself to its static surroundings. When an animal is stood on a support, which is raised at the tail end, the head in sinking will be passively moved forward. Through these position changes of the head resumes its original position. Both the labyrinth reflexes and the tonic neck reflexes are responsible for the changes in the supporting tone and the position of the extremities. The vertebra-prominens reflex observed by Magnus and De Kleyn in decerebrate animals109 is released either through the ventral displacement of the neck in the lower cervical joints, or through pressure on the spinous processes of the lower cervical and upper dorsal vertebrae. It produces a diminution in the extensor tone of the forelimbs and hindlimbs. The reaction can be obtained in intact dogs, as well as in those without a cerebellum or cerebrum.110 Changes in the supporting tone on turning or rotating the head111 When the head of a decerebrated animal is passively turned, there is a diminution in the rigidity of the extremities on the side to which the vault of the cranium is directed, and an increase in the extensor tone of the limbs on the side toward which the jaw points. These are due to tonic neck and labyrinth reflexes.112

109 De Kleyn A. and R. Magnus, “Die Abhängigkeit der Tonus der Extremitätenmuskeln von der Kopfstellung”, Pflüger’s Archiv. f.d. ges. Physiologie der Menschen u. der Tiere, 145, 455–458, 1912. 110 Rademaker G.G.J. in “The physiology of standing”, Chapter VIII Alteration of supporting tonus by raising and lowering of the head. The supporting tonus and the vertebra prominens reflex. A The importance of alteration supporting tonus on lifting and lowering of the head for adaptation to static conditions, pp. 184–201. 111 In: “The physiology of standing”, Chapter VIII, pp. 204–224. 112 De Kleyn en Magnus (1912) observed, on rotation of the head of the decerebrate animal, a decrease in extensor rigidity in the so-called ‘cranial legs’ (the extremities of the side towards which the vertex of the cranium is turned) and an increase of extensor tonus in the ‘mandibular legs’ (the extremities of the side towards which the lower jaw is turned). Denny-Brown D. in an editorial note, in the translation (1980) of the book by Rademaker “The Physiology of Standing”, pp. 204–205, notes quite correctly: Magnus and de Kleyn’s term rotation of the head is a movement around the muzzle-occipital foramen

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In a number of interesting experiments the following points are demonstrated: If an animal with half or the entire cerebellum removed or with half or the whole cerebrum extirpated, is stood on one foot, the turning of the head produces no definite changes in the supporting tone. On the contrary, distinct changes in the supporting tone appear when the head is turned in animals without a cerebellum, when they again begin to stand. In the cerebellar animals the tonal changes occur in the limbs on the side of the operation; in the cerebral animals the changes appear in the contralateral extremitities. In the back position, dogs with half or the entire cerebellum removed show, sometime after the operation, on turning the head, distinct changes in the strength of the supporting tone in the hindfeet. Intact animals or those with half or the whole cerebrum removed show no changes. These alterations in the supporting tone produced by turning the head are of importance in adapting the animal to static conditions. If one places an intact animal or one without a cerebellum, with the eyes closed, on a horizontal surface and then raises the left side, the right side will sink so that the animal passively in the long axis is turned to

axis, or a rotation in the atlanto-epistropheal joint around the process of epistropheus as an axis. By turning the head, they mean a movement round a dorsoventral axis. These definitions, however, are not quite correct, because when the animal holds the neck vertically upwards and the muzzle horiizontally, then a movement of the head round a dorsoventral axis comes about by a rotation in the atlanto-epistropheal joint with the process of epistropheus as an axis. The reactions on rotating and turning of the head also appear in labyrinthectomized animals; therefore, the tonic neck reflexes must play role. The alteriations are always the same. When the animal holds its head horizontally and it is turned round the muzzle-occipital foramen axis, a spiral torsion is produced. This is also the case when the muzzle and neck are directed upwards. When, however, the neck is directed upwards and the muzzle is horizontal, the movement of the head round the muzzle-occipital foramen axis, for instance towards the right, will produce a concave curvature of the neck towards this side. Also, in the dorsal position when the neck is flat on the ground and the muzzle is directed upwards, this movement of the head will cause a curvature of the neck. Thus, the movement of the head round the muzzle-occipital foramen axis will sometimes produce a spiral torsion and sometimes a lateral curvature of the neck. Likewise, a movement of the head round the dorsoventral axis will sometimes produce a curvature and sometimes a spiral torsion of the neck, according to muzzle and neck forming a more or less straight line or standing almost cortically to one another. From this we see that it is absolutely necessary, for avoiding any misunderstanding, to state exactly each time what is meant by rotating and tuning and from which initial posture of the head and neck is the alteration of head posture carried out. When in the following a relating and turning of the head is mentioned, we mean the rotation of the head by a movement in the atlanto-epistropheal joint with the proces of epistropheus as axis, followed by a spiral torsion of the neck, while with turning, we mean a movement of the head round a dorsoventral axis of the neck followed by a lateral curvature of the neck.

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the right. The head is then rotated to the left; the left limbs are flexed and the right extended. This adaptability of the position of the feet to a surface, which is raised sideways, does not definitely mean that the changed position of the head is responsible. The reaction probably originates as a labyrinth reflex. These reflexes in their various forms, and combined with the “lift” and Sprungbereitschaft reactions are carefully considered and well illustrated. It has been shown in decerebrate animals that moving the head effects tonal changes in the extremitities. Turning the head to the right, i.e., bringing the right ear toward the right shoulder, the right limbs show an increase in the extensor tone, the left a diminution. Ventral and horizontal positions produce other changes. Contrary to these reactions, intact animals and those without a cerebrum, in the back position, do not show any distinct changes on turning the head; the limbs remained flexed. But when standing on all four feet, the turning of the head has a distinct influence. With the head turned to the right, the center of gravity is shifted to the right and there is a distinct increase in the tone of the right foreleg and a diminution in the left. Influence of the position of the spnal column and pelvis on the supporting tone113 Another factor that influences the position of the spinal column is the relation of the limbs to the trunk. If an intact animal or one without a cerebrum is placed in a standing position and the hindlegs are moved backward, the back will be observed to sink. On moving the feet forward, the opposite condition appears. In animals without a cerebellum the dorsal convexity is increased, while in intact animals the hollow back is straightened or convexed. These various reactions have been carefully observed; the anatomy of the muscles concerned is shown, and the tonal changes are reported. Influence of the position of the back on the supporting tone114 If a dog is held firmly by head and shoulders with the hindfeet resting on one hand, when the feet are lowered the convexity of the back increases, the legs are stretched out and show a strong supporting tone. On moving the feet upward the back becomes concave, the limbs are flexed and the tone is reduced. Dogs without a cerebrum show the same

113 114

In: “On the physiology of standing”, Chapter X, pp. 284–301. In: “On the physiology of standing”, Chapter X-B, pp. 298–300.

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reactions. In those without a cerebellum the supporting tone appears later. The curvature of the back also affects the adaptability of the limbs to the underlying support. Placing the forefeet and hindfeet on different surfaces and changing their position demonstrate this. Influence of the position of the pelvis on the supporting tone of the hindfeet115 When the pelvis is moved ventrally or dorsally on the lower joints of the lumbar vertebrae, changes in the supporting tone of the hindlimbs appear. If an intact dog is placed on a board in the ‘chest position’ so that the pelvis and hindlegs hang over the end, on moving the pelvis dorsally a stronger supporting tone will be observed in the statically tested leg than is found when the pelvis is moved ventrally. Dogs without a cerebellum show the same reaction in the back position. Lay a dog on a table in the dorsal position, the pelvis resting on a board, the forepart of the body firmly fixed and the muzzle at an angle of plus or minus 45 degrees. Then move the board upward till the spine shows a convexity between the thoracic and lumbar regions. If pressure is now applied to the sole of the hindfoot, the limb will be immediately extended and the tone increased. In man the influence of the curvature of the spine and the position of the pelvis on the supporting tone in the limbs has not been fully investigated. As interesting discussion of certain cases reported in the literature is included in which the abnormal synergic reactions are carefully compared with similar disturbances in animals. Rademaker concluded at that moment of his research with the following five points: – “The dorsal movement of the head in the atlanto-occipital joint produces: a decrease in supporting tone of the hindlegs, increase in supporting tone in the forelegs. – The dorsal movement of neck relative to the thorax produces: a decrease of supporting tone in the hindlegs, increase of supporting tone in the forelegs. – The dorsoconvex curvature of the back produces: an increase of supporting tone in the hindlegs.

115

In: “On the physiology of standing”, Chapter X-D, pp. 301–310.

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– The dorsal movement of the pelvis produces: an increase of supporting tone in the hindlegs. – While alterations of position in a reverse direction produces opposite changes in supporting tonus.” Rademaker gives an illustration:116 These synergic reactions as mentioned above indicate a conformity with conditions in man and animal. Every wrestler knows that the legs of the opponent are easily brought into flexion by pressure under the lower jaw from behind the shoulder as soon as he succeeds in bending the spinal column at the point of junction of the thoracic and lumbar part of the spine.

Shoulder reactions The manner in which the position of one limb affects the supporting tone in the opposite limb is demonstrated by passively lifting the right foot of a standing dog and gently pushing the trunk to the right. A strong extension and abduction is then felt in the elevated leg. This reaction does not depend either on the optic impulses, the labyrinths or the neck reflexes, for it is also present when the head is fixed and the eyes bandaged. It is due to changes in the position of the opposite leg. The shoulder reaction is lost after section of the posterior roots. Extirpation of the cerebellum inhibits it for a week. With half of the cerebellum removed, it is at first lost and later returns. In dogs without a cerebrum, the reaction returns on the second day. In total extirpation of the cerebrum and cerebellum there is no reaction. With the cerebellum and right half of the cerebrum removed, the left limbs show an exaggerated shoulder reaction. In decerebrate animals and after transection of the cord, the reactions on both sides are lost. In man the shoulder reaction is absent until standing and walking appear. A patient with a gunshot wound in the right cerebellar hemisphere, on passively moving the body to one side of the other, showed that he could raise the rigt leg from the floor but not the left.

Rademaker G.G.J., “The physiology of standing”, Chapter X, Supporting Tonus affected by the posture of the spinal column and pelvis. D Influence of the position of the pelvis on the supporting tonus of the hindlegs, pp. 302–303; and in: “The physiology of standing”, Chapter IX-!, pp. 310–320. 116

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Importance of the shoulder reactions in the preservation of equilibrium If a running dog is suddenly pushed to the left while the left forefoot is raised, the passive abduction of the right leg releases a shoulder reaction in the left leg. The effect of this is to produce a strong extension and abduction of the left foot, which prevents the animal from falling. If the animal is stood on a board, which during the lifting of the left foot is moved to the left, then the center of gravity will be drawn to the left, and the right leg brought into a position of abduction. This again induces an active extension and abduction of the raised left foot, which then assumes a correct position to the underlying surface. Reactions on strong abduction of the contralateral limb If a dog is held in such a position that the right hindleg rests firmly on a surface, fixed by the hand so that it cannot move, and is then slowly abducted, the left hindfoot will be raised, extended and abducted to be placed beside the right foot. When an intact animal standing on all four feet is drawn to the right, the right feet will be placed more to the right and the left feet will be abducted and placed beside them. Animals with the left half of the cerebrum removed, or with the whole of the cerebrum extirpated, when drawn to the left side show the same reactions as a normal animal. These and the reactions in animals without a cerebellum are carefully observed and described. Changes in the supporting tone of one foot on moving the contralateral foot forward and backward If a dog is placed on a support with one forefoot exactly in the middle position, the other on being passively raised is found easy to flex and no attempt is made to extend it when the hand supporting the sole is moved. But on shifting the body forward a strong extensor movement develops and the limb is difficult to flex. A similar reaction occurs when the body is moved backward. The important factor is the change in the position of the supporting leg to the body. These reactions are present in intact animals as well as those, in which the labyrinths have been removed, or the cerebrum or cerebellum extirpated. They are absent in decerebrate animals.

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Influence of the position of the forefeet on the supporting tone of the hindfeet117 In a number of well-illustrated tests the movements of one or both forefeet forward showed an increase in the supporting tone in both hindlegs. The tone in the hindlegs is diminished when the forefeet are moved backward. When the hindfeet are moved forward the supporting tone in the forelegs is diminished. On moving them backward the tone is increased. Slight adduction of one foot decreases the supporting tone in the opposite foot and increases the tone in the moved foot. With strong adduction the reaction is reversed. Slight abduction of one foot increases the tone in the opposite limb while strong abduction decreases it. Effect of the position of the foot on the supporting tone of the leg118 A. The Stemmbein reaction: If a dog is stood on one foot the strength of the supporting tone depends on its position. In strong abduction it is weak, the elbow joint giving to slight pressure on the shoulder. When the leg is brought into the middle position the tone is increased. Forward and backward positions show a diminished tone. This reaction plays an important role in the adaptation of the position of the legs to the supporting surface. It is present in intact animals, as well as those without cerebellum or cerebrum. It is absent in decerebrate and spinal animals. B. The Hinkebein reaction: When a leg is passively moved more and more from its middle position, the supporting tone becomes less and less, and the leg is shifted into a better position to support the strain. The reaction is present in intact dogs with eyes bandaged, and in dogs without a cerebrum. With half of the cerebrum removed, the reaction is present in the contralateral leg. With half or the entire cerebellum extirpated, the reaction is at first lost but later returns. It is also demonstrable in animals without a cerebellum and with only half of the cerebrum present, as well as in animals after extirpation of the labyrinths. In decerebrate and spinal animals and in those in which the posterior roots have been cut, it is lost. In the adaptation of the relation of the legs to the changed position of the underlying surface, the following factors take part: labyrinth

117 118

In: “The physiology of standing”, Chapter XII, pp. 338–349. In: “The physiology of standing”, Chapter XIII, pp. 349–406.

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rotating reactions; labyrinth progressive reactions; the position reflexes; the influence of the position of the distal joints on the proximal; the influence of the curvature of the back on the supporting tone; the shoulder reactions; the influence of the position changes in one foot on the supporting tone in the opposite foot, and the Stemmbein and Hinkebein reactions. In man with multiple sclerosis the reactions are absent. C. The proprioceptive correction movements: Attention has already been called to the fact that dogs without a cerebrum, in spite of the absence of the Stehbereitschaft reactions, optic and body impulses, do not show any abnormal position of the feet either standing or running. Contrary to those animals in which the posterior roots from the feet have been cut, and spinal animals which allow the dorsal side of the feet to drag on the floor, the animal without a cerebrum places the soles of the feet correctly on the underlying support. These reactions are present in intact animals as well as in those without cerebrum, cerebellum or labyrinths. They are aabsent in decerebrate and spinal animals and those in which the posterior roots have been cut. In man no definite conclusions have been arrived at. The manner in which stimuli from the surface of the body, the acoustic and optic apparatus influence the supporting tone119 The importance of stimuli arising in one part of the body surface, viz., the soles of the feet, has already been spoken of. Further, it has been mentioned that intact dogs and those without a cerebrum, when held in the air in the ventral position, show a strong extensor tone in the limbs when pressure is made against the soles of the feet, while with the back resting on a supporting surface the extensor tone is weak, and in the hindlegs is sometimes quite lost. These observations deserve special attention because, according to Magnus and De Kleyn, they are found in dogs when placed in the maximum position for the tonic labyrinth reflexes. In consequence of these reflexes decerebrate dogs in the back position with the muzzle above the horizontal show extensor rigidity in all four legs, which is distinctly stronger than in the ventral position or on

119

In: “The physiology of standing”, Chapter XIV, pp. 406–415.

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standing, if the muzzle is held 45 degrees below the horizontal. Dogs without a cerebellum also pass through a stage of prolonged diminution in the supporting tone when in the back position. These reactions may be explained by the fact that in intact animals and those without a cerebrum in the back position the stimuli arising from pressure on the surface of the back induce a diminution in the supporting tone. If the animal is raised by the hands under the neck and pelvis, the supporting tone is found to be immediately increased as soon as the pressure against the back is removed. Animals without a cerebrum in the standing position show so strong a reduction in the supporting tone when a fold of the skin of the back is gripped that the limbs collapse under the weight of the trunk. In a normal man lying on his back the legs can be easily flexed by pressure against the soles of the feet, but on standing it is hardly possible to bend the legs by pressure on the shoulders. This makes it possible for dock laborers to carry loads of 100 Kg. or more. Acoustic stimuli: Intact dogs and those without a cerebrum lying quietly in the side position react to certain noises by pointing the ears, raising the head and stretching the paws. Also, if a table is struck sharply by the hand a standing animal will be observed to crouch. These changes are the result of subcortical reactions. Optic stimuli: These can also release conditional changes in the supporting tone in dogs with intact cerebrum. This was particularly well shown in animal without a cerebellum when placed on a floor covered with Holzgranit. The dog would not stand up but crept about. When straw was thrown in a corner he crawled over to it and when a few paces away stood up straight, took a few quick steps and fell on it. Later he stood up on the straw. General consideration of the center of gravity reactions and their retention in animals without a cerebellum120 This chapter includes an interesting discussion on the question, and the views of some of the leading authorities for and against the opinion that the cerebellum is the main organ of equilibrium are carefully considered.

120

In: “The physiology of standing”, Chapter XV, pp. 415–445.

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Rademaker points to the difficulty of reaching any satisfactory conclusion until it has been definitely settled just what an organ of equilibrium really means. According to him, an equilibrium organ is a center through the intervention of wich one or more equilibrium reactions are brought into play. Such a reaction is a complex of movements by which equilibrium is maintained, or if lost is again set up, i.e., through the influence of which the center of gravity of the body is maintained within the supporting surface, or will be brought back to this. Rademaker cited as an illustration G.K. Ariens Kappers, a neuroanatomist from Amsterdam:121 “In the turtle, the cerebellum was a more highly developed shape than that of snakes and frogs”—and nevertheless—“The turtle is not able to turn over its carapace when lying on its back and must wait for death in this posture. When a turtle is dropped from the air in a dorsal position, it will touch the ground with its back and not turn around in the air. It seems to me that these examples speak against the theory of balance with the same justifications as, according to Ingvar,122 the strong development of the cerebellum in the massive elephant and crocodile speaks for the support of this theory (the development of the cerebellum and related to its balance mechanism)”

Retention of the position reflexes in animals without a cerebellum Labyrinth reflexes: These are necessary for the maintenance and readjustment of the head in a normal position. They are present without exception in all animals without a cerebellum, as well as in animals with half of the cerebellum removed. Neck position reflexes: By turning the head, stimuli are released in the deeper parts of the neck which affect the position of the neck and chest. In intact animals and those without a cerebellum, the return of the head to the normal position is followed by the trunk and pelvis. In falling sideways, the labyrinth reflexes bring the head back to the normal position, and after that through the neck reflexes the equilibrium

121 Quoted from G.K. Ariens Kappers: “Die vergleichende Anatomie der Nervensystems der Wirbeltiere und Menschen” (Comparative anatomy of the nervous sytem of vertebrates and men), 2, p. 682, Haarlem, De Erven Bohn, 1921. 122 Ingvar S., “Zur Phylo- and Ontogenese des Kleinhirns nebst eine Versuche zu einheitlicher Erklärung der zerebellaren Funktion und Lokalisation”, Haarlem, De Erven F. Bohn, 1918.

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of the body is resumed.123 The neck reflexes are present in all animals without a cerebellum. The influence of the body-position reflexes on the head can only be determined in animals without labyrinths and with the eyes closed. In the cat (Peggy), both labyrinths were removed and the body-position reflexes were lost. Three weeks later, the cerebellum was extirpated and two days after the operation the reflexes reappeared. This cat also showed a more marked ataxia than animals without a cerebellum with both labyrinths intact. If the cerebellum were the central apparatus of the labyrinth reflexes, then extirpation of the labyrinths in animals without a cerebellum would not produce any symptoms. But Magnus has shown that unilateral labyrinthectomy in an animal without a cerebellum produces the same symptoms as in intact animals. Rademaker claims that these observations are against the idea that the cerebellum is the central apparatus of the labyrinth reflexes.124 Raising and supporting reactions of the forefeet (the pulling-up and propping-up reactions of the forelegs):125 If a normal cat is walking along the edge of a roof and the hindfeet fall off it will hold tight with the forepaws, raise itself until the center of gravity is anterior to the shoulders, and then place the hindfeet beside the forefeet. Cats without a cerebellum, with or without the eyes bandaged, can recover their center of gravity when hanging on the edge of a table. Cats without a cerebrum can also draw the body up, but owing to the failure of the Stehbereitschaft reaction (preparation for standing-placing) the hindfeet are not set on the underlying surface. This supporting reaction is developed through the activity of the flexors following passive extension of elbow and shoulder joints; also through the ventral flexion of the head and neck as a result of the labyrinth reflexes induced by the backward passive movement of the animal. “Thus, the pulling up of the trunk is brought about purely as a reflex” (Rademaker).

123 in an editorial note in “The physiology of standing” (p. 435) by Denny-Brown (1980): “Moreover, the labyrinthine reactions also participate due to a rotation around the longitudinal axis” 124 Italics are mine (L.H.). 125 In: “The physiology of standing”, Chapter XV-C, pp. 461–471.

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Retention and the restoration of the center of gravity in animals without a cerebellum through the Schunkel, Stemmbein and Hinkebein reactions.126 The facts of these investigations show that in cats and dogs without a cerebellum no definite lasting loss of a single reaction of equilibrium position reflex, or labyrinth reflex can be pointed to. From this one can conclude that thus far no ground exists for the assumption that the cerebellum is to be considered as the central apparatus for the regulation of equilibrium and the labyrinth reflexes, and that these reflexes must therefore have convenient centers in the neighborhood of the cerebellum to which the afferent and efferent tracts run. Thomas has suggested (and many agree with him) that the restoration of the capacity to maintain equilibrium in an animal without a cerebellum is due to the compensation of the cerebrum.127 Opposing this view, Rademaker cites the thalamic animal, Robbie, in which the cerebellum was also removed, which showed five weeks after the extirpation a return of the labyrinth reflexes from the side position of the Hinkebein reaction in the hindfeet, to demonstrate that equilibrium reactions can appear without the compensatory influence of the cerebrum. There is also a careful investigation of the manner in which equilibrium is preserved in animals without a cerebellum when on a turntable, as well as of the reactions of the spinal column and pelvis in maintaining the center of gravity. “In summing up” states Rademaker “one can say that the ‘hopping reactions’ as well as ‘legbracing’ and ‘leg-slackening reactions’ in the

In: “The physiology of standing”, Chapter XV-C, pp. 461–471. in een “note of the editor” door Denny-Brown (1980) (p. 471): “According to Thomas and Ingvar, a falling to the right side, in addition to rotation of the vertebral column and inclination of the head towards the other, left side, is prevented by raising and adducting the right legs. After the unilateral extirpation of the cerebellum, according to their opinion, the adducting reaction of the extremities ipsilateral to the extirpation are absent, which promotes the falling towards the side of extirpation. According to Ingvar, the centers for adduction are situated in the most lateral section of the equilateral lobulus ansiformis, the centers for abduction in the median part of crura lobuli ansiformis, and he asserts that lesions of the lateral part of crura, therefore, cause a falling towards the side of the lesion and destruction of the median part, falling to the opposite side. However, as we have seen, falling towards the side of extirpation is nearly always prevented by a bracing outwards, or transferring outwards i.e. by abduction of the legs ipsilateral to extirpation and only in rare cases, as for instance in slipping by abduction. The absence of centers of abduction of the ipsilateral legs would thus promote falling towards the side of the operation, in opposition to Ingvar’s assertion. Besides the statement is also wrong that, after unilateral extirpation of the cerebellum, the adducting reactions in the ipsilateral legs are absent”. 126 127

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decerebellated animal are carried out in the most appropriate manner for the maintenance of balance.” “With regard to these observations, André-Thomas findings (1897; 1925)128 are noteworthy in that patients with cerebellar atrophy, in spite of a high of cerebellar atrophy, are able to offer a good resistance in pulling and pushing while running so that visually neither falling nor propulsion, retropulsion or lateropulsion occurs.” General comment on muscle tone, especially in relation to animals without a cerebellum129 Leven and Olliver,130 from their observations on seventy-six cases of cerebellar disease, claimed that the disturbances in movement depended on muscle weakness. Luys131 came to the same conclusion. Weir Mitchell132 considered the cerebellum as a source of energy for the spinal centers influencing voluntary and involuntary movements. According to Luciani,133 the cerebellum does not possess any individual fi eld of action that is not influenced through the centers of the cerebrospinal system. He considered that its function is a strengthening one, and its disturbance is indicated by asthenia, astasia and atonia. He defines tone as the active tension of a muscle in its different voluntary, automatic and reflex activities. In the present discussion muscle tone is understood to mean the tension with which the muscle resists a passive change of position, and muscle strength the maximal power with which a muscle can perform a movement, which is determined by measuring the power necessary to prevent the 128 André-Thomas, “Le cervelet, étude anatomique, clinique et physiologique”, Paris: Steinhill, Éditeur, 1897. André-Thomas, “Pathologie du cervelet”, Nouveau Traité de Méd., G.H. Roger, F. Widal et P.J. Teissier, Vol. 39, p. 755, Masson et Cie, 1925. 129 In: “The physiology of standing”, Chapter XVI, pp. 486–528. 130 Leven et Olliver, “Recherches sur la physiologie du cervelet”, Arch.gén.Méd. 20, 513–525; 696–716, 1862/1863. 131 Luys I., “Etudes sur l’anatomie, la physiologie et la pathologie du cervelet”, Arch. gén.Méd. 22, 385–412; 580–590; 698–710, 1884. 132 Weir Mitchell S., “Researches on the physiology of the cerebellum”, Amer.J.Med. Sci..., 320–338, 1869. 133 Luciani L. (1840–1919), “Il cerveletto. Nuovi Studi di Fisiologia normale e pathologica”, Le Monnier Ed., Firenze, 1891. Luciani L., “Das Kleinhirn”, translated into German by M.O. Fraenkel, Leipzig. Verlag E. Bezold (Arthur Georgi), 1893. Luciani L., “Fisiologia dell’uomo; traitato didattico”, Milano, 1901–1911, Societa Editrice Libraria, Via Disciplini 15, Milano. Luciani L., “Human Physiology”, translated from the German by F.A. Welby, edited by M. Camis, London, Mac Millan Company, 1915, Vol. 3.

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movement. This resistance comes normally into action through the stretching of the muscle substance, through reflex stretching, and the stretching due to the influence of the cerebrum. These stretching reflexes and their influence on muscle tone receive particular attention, each of the six orders being carefully considered. Extirpation of the cerebellum, both in otherwise intact animals and those without a cerebrum, results in a rigidity, which has the characteristics of decerebrate rigidity. This rigidity is explained by some as being due to the falling out of the red nucleus, by others as due to shock, diaschisis or inhibition. The question is not settled. Animals without a cerebellum show distint and important changes due to disturbances in muscle tone through interference with exteroceptive and proprioceptive stimuli. With half the cerebellum removed there is often as much rigidity as after total extirpation. This is opposed to the observations of Luciani and others who maintained that with half the cerebellum removed there is hypotonus of the homolateral muscles. The contradictory opinions about cerebellar function were resolved somewhat by the work of Luigi Luciani (1849–1919), a physiologist from Rome whose expertly decerebellated dogs and apes lived for as long as a year. With such success, Luciani could see the longterm effects and proposed (1891) the theory of cerebellar regulation of tonic and static motor activity, a theory that later was criticized by Rademaker. From his experimental results he assigned a generalized (unitary) refining role (“facilitating effect” in Clarke and Jacyna, 1987, p. 302134) to the cerebellum that acts on voluntary movement initiated by higher centers. Luciani dedicated his treatise ‘Il cerveletto to Rolando, aligning himself with the foes of parcellation of cerebellar function (Marshall and Magoen135). Investigations of standing, the regulation of muscle tone and the motility of animals without a cerebrum136 In dogs without a cerebrum, all of the position reflexes, labyrinth, neck and body, are present. The optic alone is absent. These animals can 134 Clarke E. and L.S. Jacyna, “Nineteenth-Century Origens of Neuroscience Concepts”, Berkeley (Los Angeles: University of California Press), 1987. 135 Louise H. Marshall and Horace W. Magoen, in; “Discoveries in the Human Brai”, Chapter 9, The Cerebellum, p. 185, Humana Press, Totowa, New Jersey. 136 In: “The physiology of standing”, Chapter XVII, pp. 528–542.

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Fig. 2-27. “Das Kleinhirn”. Frontispiece of the classic by Luciani. German translation of “Il cerveletto” (1891). ‘Nuovi studi di fisiologia normale e pathologica’. Florence: Successori le Monnier.

stand and walk in apparently a normal manner and with seemingly a normal distribution of muscle tone. But investigation of the different reactions reveals the following disturbances: The Stehbereitschaft reaction fails, owing to the loss of impulses from vision and the body surface. There is also a distinct disturbance in correcting the abnormal position of the feet, indicating that this reaction passes through the cerebrum. The Magnetreaktion is lost. The proprioceptive Stützreaktion has disappeared. In the Hinkebein reaction the leg is raised too high and set down too broadly, the step is abnormally wide and less brisk than in animals without a cerebellum. The manner in which the distribution of muscle tone is influenced by the position of the head, through the tonic nek and labyrinth reflexes has only been in part determined. In the standing animal, raising and lowering the head, in intact dogs as well as those without a cerebrum, show a definite increase and decrease in the supporting tone. While in the back position the four legs remain more less strongly flexed in all positions of the head, even when the soles of the feet are pressed against. Animals without a cerebrum differ from normal animals in that the following reactions are destroyed: (1) reactions due to stimuli arising from the body surface—the preparedness to stand, and the correction of abnormal position of the feet are lost; the Magnetreaktion is weakened or has disappeared; gripping the skin of the back causes flexion of the

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legs; stroking the back against the hair causes extension of the legs; (2) reactions to proprioceptive stimuli released through the muscles—the supporting tone in the hindlegs is weak; the Hinkebein reaction is delayed, as are also the correction movements, the Stemmbein reactions, and the reactions due to stimuli arising from the labyrinths. A decerebrate animal can be distinguished from a decorticate one as follows: 1. by the exaggerated extensor posture, the stiffness of the neck and of the back in the periods of manifest rigidity 2. by the fact that in the decerebrate animal in a standing posture the stretch-reflex tonus gradually diminishes so that the legs give way after sometime, usually after 10 minutes, while in the decorticate animal the legs under static stress can carry the trunk for hours 3. by the incomplete supporting reactions 4. by the absence of labyrinthine and body righting reflexes 5. by the absence of hopping reactions, leg-slackening reactions, legbracing reactions, pulling-up and propping-up reactions 6. by the absence of the inhibiting influence of the supine posture on the reactions of muscles of the extremities

Finally adding to his summary: While in decorticate animals in a dorsal position almost no supporting tonus can be produced, the extremities of decerebrate animals in a dorsal position are particularly rigid due to the influence of tonic labyrinthine

Fig. 2-28. Decerebrated animal (cat). A cat in decerebrate rigidity. Note the hyperextended position of the neck, the arching of the back (opisthotonus), and extension of tail. Sherrington has designated the total pattern as “an exaggerated caricature of reflex standing”. (From: Pollock and Davis, J. Comp. Neurol., 50, 384, 1930.)

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reflexes and the stretch reflexes (myotatic reflexes of Liddell and Sherrington137) are especially rigorous

The disturbances observed in the function of standing and position after one half of the cerebellum has been removed138 The symptoms immediately following the operation differ in almost every experiment, but in no case has an animal been able to right itself or stand unsupported. Later in the stage of permanent disturbances, the symptoms are practically always the same; the animals can right themselves, stand freely and run about. Some show rolling movements to the side of the operation, possibly due to injury of the vestibular apparatus. In the first stage one usually observes on the homolateral side that the distribution of tone is abnormal; that the Stehbereitschaft and Magnet reactions fail; that the Stütz reactions, as well as the Körperstell reflexes are lost. Inconstant symptoms are the turning of the head with the vault of the cranium toward the side of extirpation and disturbances in the labyrinth position reflexes, also in the body position reflexes when lying on the intact side; on the contralateral side the Magent, Stütz, Hinkebein, Stemmbein and Schunkel reactions are abnormal. In the stage of permanent disturbances the animal is again able to stand and run. It can carry a sand bag almost equal to its body weight. Moving toward the side of extirpation, the hindfeet make running steps, toward the intact side, the hindfeet show the Hinkebein reaction. On drawing the animal toward the intact side, the hindfeet on this side are placed normally. In walking, the homolateral legs are flexed too strongly. The Stehbereitschaft, Magnet and Stütz reactions reappear. The disturbances frequently found in the contralateral limbs are possibly due to injury of the remaining half of the cerebellum at the time of operation. It is also possible that the function of the remaining half of the cerebellum may be interfered with through the loss of stimuli which normally arise in the removed half.

137 Liddell E.G.T. and C.S. Sherrington, “A comparison between certain features of the spinal flexor reflex and of the decerebrate extensor reflex respectively”, Proc. Roy. Soc. London, 95, 299, 1923. C.S. Sherrington, “Reflexes in response to stretch (myotatic reflexes), Ebenda, 96, 212, 1924. C.S. Sherrington, “Further observations on myotatic reflexes”, Ebenda, 97, 267, 1925. 138 In: “The physiology of standing”, Chapter XVIII, pp. 542–549.

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Disturbances and so-called cerebellar ataxia in animals without a cerebellum139 In complete extirpation of the cerebellum, some animals show rigidity, and others, a well-marked flaccidity. When rigidity is present the Stütz reactions, the distribution of muscle tone and the suspension of the Stell functions are similar to those found in decerebration. And in spite of the fact that these animals can see and react to optical impulses with eye movements and wagging of the tail, they nevertheless lie permanently in the side position, cannot raise the head, and the Stehbereitschaft reaction is destroyed. Stood on its feet, such an animal can carry the weight of its body. Passive movements of the head show the presence of neck and labyrinth reflexes, though these may be observed only after several days when the rigidity has somewhat lessened. The flaccid animal, on the other hand, lies with the limbs flexed. The neck muscles are also weak, and the head cannot be held upright. Nevertheless, even on the day of operation the head may be turned into a normal position, though the jaw will be resting on the floor. The raising of the head from the side position when the animal is lifted shows the presence of the labyrinth reflexes. The activity of the neck reflex is also indicated by the forepart of the body being brought into the breast position when the head is turned. The fact that the hindpart of the body remains on its side shows that the body righting reflexes arising from the body are absent. The tone of the limbs is only slightly increased by pressure against the soles, and when the animal is brought into a standing position the limbs are unable to support the weight of the body. In both the rigid and the flaccid animals the body reflexes arising from the body, The Magnet, Stemmbein, Hinkebein, Stehbereitschaft and Schunkel reactions are lost. The first of these to reappear are the Magnet and Stehbereitschaft reactions. In the flaccid animal these may be observed during the first week, but will not be present in the rigid animal till the second to fourth week. As the reactions return the animal begins to creep about with its forefeet, the hindfeet being still in the side position as the body position reflexes are still absent. On trying to raise itself it falls, owing to the absence of the Stemmbein and Hinkebein reactions. With the return of the Körperstell reflexes, the hindpart of the body is brought into the ventral position, but as these reflexes are still weak and the Stemmbein reactions have not returned, the neck position reflexes

139

In: “The physiology of standing”, Chapter XIX, pp. 559–602.

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are unopposed and each strong turning or rotation of the head results in a fall. It is considered that the inhibiting action of the cerebrum is responsible for this, for if a limping animal is taken hold of by a fold of the skin and so prevented from falling, it will raise itself, the limbs becoming extended and fixed; as soon as the skin is released the flexion in the limbs reappears. Eventually, as these reactions become stronger, the disturbed center of gravity is corrected and the animial is able to walk straight. In from three to six months, the stage of permanent disturbances is reached and the animal shows the typical appearances, which in man are usually considered under the name of cerebellar ataxia. Contrary to the conditions previously observed, the symptoms in the stage of permanent disturbances in dogs and cats are general exactly the same. Animals now show a prompt Stehbereitschaft reaction to both optic impulses as well as to those arising from the body surface. And the ability to correct abnormal positions of the feet to exteroceptive stimuli is also present. On the other hand, a number of distinct reactions are lost, e.g. the Magnet, Stütz, Stehbereitschaft and Hinkebein reactions. Disturbances are also to be observed following changes in the position of the head. Uncontrolled reactions in animals without a cerebellum consist of tremor and simple uncontrolled movements. Tremor is not always present, but as a rule these animals cannot stand quietly, there is a continuous motor unrest. The tremor continues after extirpation of the cerebrum and after transverse section of the midbrain with injury of the red nucleus. Tremor ceases when the paws are touched or pressed against, when the animal lies quietly in the side position and during sleep. In these animals division of the midbrain caudal to the red nucleus will also cause the tremor to disappear. These disturbances may be qualified by the inhibiting influences of the back position, by the delayed appearance of the Hinkebein reactions, and by the abnormal muscular activity to different stimuli. The symptoms observed after the extirpation of the cerebellum have had the result of raising a strong controversy over the question whether the cerebellum should be considered as an organ of coordination.140

140 The view that the cerebellum was an organ of coordination was first expressed by Flourens, ‘27, and later again by Bechterew, Bolk, Jelgersma ‘28, Hulshof Pol, Bárány and Dusser de Barenne. This view was strongly opposed by Luciani, Rynberk and others.

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Flourens141 observed that animals without a cerebellum were able to contract their muscles and perform certain complicated movements, though they were unable to stand unsupported nor could they run or spring. He came to the conclusion that the ability to incite or combine muscular contractions centered in the spinal cord, while the power to coordinate movements such as walking, springing, etc., arose exclusively in the cerebellum, and that the cerebellum was therefore an organ of coordination. Luciani drew attention to the fact that animals without a cerebellum could swim. This he considered a crucial test showing that the coordination was not destroyed, and that therefore the cerebellum was not an organ of coordination. According to his view an organ of coordination is one which, otherwise than through the tonic, asthenic and static effects, regulates the normal course of movements. Such an organ would exercise and influence on all actions, and the observation that a single action could be carried out in a normal manner would prove that coordination had not been suspended. According to Jelgersma,142 the cerebellum coordinated only the acquired higher forms of associated movements such as speaking, running, springing, climbing, etc., which come into being through the cerebrum under the influence of the optic, acoustic and skin stimuli, as von Bechterew W., “Die Funktionen der Nervenzentra”, H. II 763, Kleinhirn und übrige Organe der statische Koördination, Jena: Gustav Fischer Verlag, 1909. Franse vertaling ‘les fonctions nerveuses: les fonctions bulbo-médullaires’, Octave Doin et fils, éditeurs, 1910. Bolk L., “Over de physiologische beteekenis van het cerebellum”, Haarlem, De Erven Bohn, 1903. Bolk L., “Das Cerebellum der Säugetiere, eine vergleichend-anatomische Untersuchung”, Jena, Gustav Fischer Verlag, 1907. Bolk L., “Over functielocalisatie in de kleine hersenen”, Ned. Tijdschr. v. Gen. 52, 1969–1982, 1908. Hulshof Pol D.J., “Cerebellaire ataxie”, Psychiatr.Bladen 13, 273, 1909. Bárány R., “Beziehungen zwischen Bau und Funktion des Kleinhirns nach Untersuchungen am Menschen”, Wiener Klin.Wchschr., 1912. Bárány R., “Kleinhirncyste mit Ausfall der vestibulären Zeigereaktion bei den oberen Extremitäten nach abwärts”, Wiener Klin.Wchschr., 1912. Bárány R., “Lokalisation in der Rinde des Kleinhirnhemisphäre des Menschen”, Wiener Klin.Wchschr., 2033, 1912. 141 Flourens M.J.P., “Recherches expérimentales sur les proprietes et les functions du système nerveux dans les animaux vertebras”, p. 516, Parix, Chez J.-B. Baillière, 1842. 142 G. Jelgersma (1859–1942), neuroanatomist and later professor of Psychiatry at Leiden. His tenure of this chair partly overlapped with that of Rademaker as professor of Physiology at Leiden.

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well as from the impulses arising from the muscles, joints and labyrinths. In this connection it must be mentioned that dogs without a cerebellum have been heard to bark, growl and whine; and cats to purr, hiss and mew. Nevertheless, this does not mean that in man the cerebellum has no influence over speech. Munk143 has mentioned that in animals without a cerebellum there are certain movements that at times are hardly noticeable which under other conditions are definitely abnormal. In the free standing position there are a number of awkward actions, such as scratching without touching the skin, which are almost normally performed if the animal is leaning against a wall or lying down. Rademaker does not take any position in this controversy because he considers that the physiology of the cerebellum has not been sufficiently advanced to form an opinion. Also because the dispute largely depends on the unsettled question of what is meant by an organ of coordination, and what is the definition of an uncoordinated movement, for animals show disturbances not only in their actions but also standing—incoordinate standing. A comparison of the disturbances found in animals without a cerebellum with the symptoms observed in cerebellar disease144 Asynergia—In the first stages after the operation certain associated movements are abnormal. If the head of an animal in the ventral position is rotated to the right, the whole body turns over to the right side. In intact animals and those without a cerebellum in the stage of permanent disturbances, the pelvis is turned to the left. During the first days the trunk obeys the neck position reflexes on the body and the Stemmbein reactions. That is, through the loss of some reactions and the unrestricted activity of others, the animal shows a certain degree of asynergia. Later, on rotating the head the same synergic reactions are observed as in the intact animal, i.e., a spinal rotation of the trunk and a typical reaction of the feet, which prevent falling. Adiodokokinesia—This condition cannot be satisfactory examined. Cerebellar catalepsy—According to Babinski, if a patient with cerebellar disease is laid on his back and the hip and knee joints are flexed to Munk H., “Über die Funktionen der Kleinhirns”, Sitzungsberichte d. preusz. Akad. f. Wissenschaften 26 April 1896, pp. 443–480; 17 Jan. 1907, pp. 16–32 (zweite Mitteilung); 12 März, pp. 294–326 (dritte Mitteilung und Schluss). 144 In: “The physiology of standing”, Chapter XX, pp. 602–625. 143

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an angle of 90 degrees, the leg will not show any trembling. On the contrary, in a normal person as soon as the leg becomes tired a coarse tremor will be observed. Though it is not possible to reproduce the same test in animals, nevertheless some conditions have been noticed which appear important in respect to cerebellar catalepsy. If an animal with the cerebellum removed is laid on its back with the muzzle directed upward, the limbs will be held in a stretched-up position. They will not tire for some time and no trembling will be observed. With half the cerebellum removed, the limbs on the same side as the extirpation will show the same symptoms. Hypermetria—When a patient with cerebellar disease attempts to take a glass of water, the hand is too widely opened. In the monkey (Carrie), without a cerebellum, the same reaction has been observed. In other animals hypermetria has been found in the movements of running, and in the Hinkebein and Schunkel reactions. Rebound phenomenon—This feature, observed in man with cerebellar disease, also has its counterpart in animals without a cerebellum. This may be tested by gripping the tail and pulling backward. As the animal naturally pulls forward before stopping than a normal animal. Passivity—According to André Thomas,145 this is the lowering of resistance to passive movement through hyposthenia of the antagonists. This passivity is observed in the abnormal swinging movements of the arms when the trunk is passively turned to the left and right, in the swinging movement of the hand at the wrist joint and in the pendulum reaction of the patellar reflex. The presence of this reaction in animals without a cerebellum is clearly indicated in the abnormal swinging of the hindlegs when the animal is held in the air and swung to and fro. Astasia—Animals without a cerebellum show distinct ungoverned movements, which make it impossible to stand still. Nystagmus—The spontaneous form is not found. Past pointing—These and similar conditions are difficult to prove, but in the monkey (Carrie), without a cerebellum, a distinct failure to grip was sometimes observed, during the first stge. Atonia and asthenia—These are absent in animals without a cerebellum. Hypotonia is also often missed. Occasionally a well-marked hypertonia with rigidity is observed.

145 André Thomas, “Le cervelet, etude anatomique, clinique et physiologique”, Paris, Steinheil ed., 1897.

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The phenomena following the combined extirpation of the cerebellum and cerebrum146 The animal without a cerebellum and with the right half of the cerebrum removed at the same time showed at the conclusion of the operation an extensor rigidity exactly like an atypical decerebration. Gradually the conditon changed. The rigidity disappeared from the right leg, while the left remained stiff even in the back position in the stage of permanent disturbance. Later, an asymmetric distribution of muscle tone in the neck was observed. In the stage of permanent disturbances a typical combination of symptoms was noticed. It has been seen that when the cerebrum or the cerebellum has been extirpated, the Hinkebein reaction was delayed, and only appreared when the positions were definitely changed. In the present instance, with the cerebellum and right half of the cerebrum removed, the Hinkebein reaction in the left leg was more strongly disturbed than in the right. The delay of the reaction was so marked that it was unsuitable to maintain and readjust the center of gravity. As a result, the animal never learned to stand free or to run. The usual position of the animal was with the hindpart of the body in the right side position and the forepart in the ventral position, with the head raised and generally turned to the left. The most important symptoms are: (1) Hemianopia. (2) Failure of the Stehbereitschaft reaction owing to the loss of optic impulses as well as the stimuli arising from the body surface. On touching the lower jaw against the edge of the table, only the right forefoot was placed on the table, while the left remained hanging, with extended elbow and wrist joint. Laid on a latticed table with the legs drawn through the openings, only the right legs were withdrawn and the soles of the feet placed on the framework. (3) Lowering of the strength of the supporting tone in the left leg. Although the left leg showed an increased inclination for the extended position, with a distinct extensor tonus, the supporting tone was nevertheless not so strong as in the right. If the animal was placed so that only the right foreleg rested on a supporting surfice, it did not give way under a weight of 5 Kg. placed on the shoulders, while the left leg bent under a weight of 1 Kg. (4) Greater disturbance of the

146 In: “The physiology of standing”, Chapter XX—Phenomena after combined extirpation of the cerebellum and the cerebrum. A. The decerebellate and unilaterally decorticate animal (dog Vinci), pp. 602–610.

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Hinkebein reactions and the proprioceptive corrective movements in the left legs than in the right. It is considered dthat this result is only partially associated with the removal of the cerebellum, and is due principally to the extirpation of the right half of the cerebrum, because a similar difference was observed in an animal with the cerebellum intact and with only one half of the cerebrum removed. Symptoms following removal of the left half of the cerebrum147 The Stehbereitschaft reaction is disturbed on the right side. Hemianopia is present. The animal runs in circles to the left. The Hinkebein reactions in the right feet are disturbed, and the strength of the supporting tone is reduced in the right limbs. Symptoms following removal of the remaining, or right half of the cerebrum The running in circles to the left disappeared. This was all the more extraordinary because in the standing position the head was always turned to the right. The optic and acoustic reflexes were absent, as well as the Stehbereitschaft and the stimuli from the body surface. The animal could walk well and did not show abnormal extension of the limbs. Correction of the limbs to proprioceptive stimuli was present. The supporting tone in the forelimbs was plus, in the hindlimbs minus. The Hinkebein reactions were prompt, and the coordination of the feet in walking was normal. Extirpation of the cerebellum in an animal without a cerebrum, as in intact animals, is followed by decerebrate rigidity. Following the extirpation the animal lies rigidly on its side, the neck drawn backward, the back arched and the tail extended dorsally. Labyrinth and Körperstell reflexes are absent, and there is no attempt of the animal to right itself. Pressure against the soles increases the stiffness. If stood on its feet there is well-marked extension of the limbs and retraction of the head. The limbs are not flexed by the weight of the body. In the back position the limbs are also stiff. Absent reflexes include the Schunkel, Stemmbein and Hinkebein reactions, as well as the corrective movements to proprioceptive stimuli. Ear muscle, sneezing, the corneal and eyelid reflexes are present. Meat

147 In: “The physiology of standing”, Chapter XX—Phenomena after combined extirpation of the cerebellum and the cerebrum. B. The dog without cerebrum and cerebellum, pp. 610–625 and scheme in appendix.

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was swallowed from the third day on. Urination and defecation were spontaneous. Rigidity had mostly disappeared by the end of the week. The strength of the supporting tone was now less than that before the extirpation of the cerebellum. During the second and third weeks, with the further reduction of the rigidity, the labyrinth reflexes returned. In the fourth and fifth weeks the extensor tone was still further reduced and the animal showed positive and negative supporting reactions. Some conclusions regarding combined extirpation of cerebrum and cerebellum From a comparison of the reactions observed in animals in which both the cerebrum and the cerebellum have been removed with those found in animals with intact cerebellum but with the cerebrum extirpated, one is not able to conclude that the difference depends exclusively on the loss of the cerebellum. Although in the dog (Robbie), the investigations did not yield the desired results, they have nevertheless given certain definite reactions: 1. The extirpation of the cerebellum, even in dogs without a cerebrum, permits the development of the same rigidity with plasticity that is found after decerebration, and the rigidity in the fully developed state can last a week. 2. The rigidity gradually diminishes and almost disappears. 3. The diminishing rigidiy is accompanied by a return to the Stütz reaction. Through this the statically tested hindlegs can carry a heavier load than the stiffly extended hindlegs of animals in the rigid tage in the standing position. 4. The Stütztonus strength after the removal of the cerebellum is indeed at first diminished, notwithstanding that in animals without a cerebrum the same power is again attained as before the extirpation of the cerebellum. 5. Even in dogs without a cerebrum some of the reflexes, such as the labyrinth position reflexes and the Hinkebein reactions, which in the first days after the extirpation of the cerebellum are completely lost, gradually return. Consequently, the reappearance of equilibrium afther the removal of the cerebellum does not depend entirely on the compensation of the cerebrum, as has been maintained by some authors. 2.6. The Fall Reflex and ‘Mathematical Biology’ 1. Small and seemingly insignificant observations can sow the seed of major discoveries, but the nature of the discovery can vary widely depending on what was in the observer’s mind at the time. Every

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schoolboy knows the story (which may be apocryphal) of Newton and the apple: how the chance observation of an apple falling from a tree led Isaac Newton to formulate his world-shaking theory of gravitation that applied not only to objects falling on earth but also to the movement of the heavenly bodies, the earth, the moon and the planets, the sun and the stars. He was the first to prove that the motion of these heavenly bodies was not due to the influence of divine forces, but was governed by objective physical laws. Observation of the way cats fall to land on their feet led the physiologist Rademaker and his co-worker W. Ter Braak in quite another direction, to the important discovery of the fall reflex as described below. But before going on to discuss this, it may be interesting to make a slight digression to show how other scientists, thinking about very similar phenomena, came to strikingly different conclusions. Albert Einstein was a genius of the same stature as Newton, and often regarded as his successor. In his book “Euclid’s Window”,148 Leonard Mlodinow tells a story of the birth of Einstein’s theory of relativity which forms a telling parallel to that of Newton and the apple. I cite from the beginning of Chapter 26 of the book, Einstein’s Apple: As Einstein later told it, in November 1907, I was sitting in a chair in the patent office in Bern when all of a sudden a thought occurred to me: “if a person falls freely, he will not feel his own weight.” And as Einstein told it: “It was the happiest thought of my life”

Mlodinow goes on to describe in elegant, entertaining prose how this simple idea led Einstein to revolutionary conclusions about the nature of space and time undermined the mechanistic certainty of Newton’s Laws and have deeply influenced the way we think about the world and the universe today.

148 Euclid’s Window: The story of Geometry from Parallel Lines to Hyperspace”, Leonard Mlodinow, Simon and Schuster, Touchstone Books, ISBN 0-684-86524-6; new edition published by Penguin Books, 2003, ISBN-13 978-01410009094.

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A couple of decades later, J.B.S. Haldane149 looked at the phenomon of falling animals in quite a different way in his essay “On Being the Right Size” (1927):150 You can drop a mouse down a thousand-yard mine shaft; and on arriving at the bottom, it gets a slight shock and walks away; a rat is killed, a man is broken, a horse splashes . . .

Though his main emphasis in this quotation is on the biological advantage of (small) size, and in particular the protection small animals enjoy when falling thanks to the disproportionately large air resistance they experience, Haldane seems to be reflecting here on the pioneering work done by his father, the respiration physiologist J.S. Haldane, on the physical and chemical dangers faced by mineworkers in the English coal mines. 2. A less extreme example of the ability of small animals to escape injury after a fall is the well-known fact that cats can land on their feet when falling from a relatively great height. Rademaker and Ter Braak made a significant contribution to the elucidation of the “fall reflex” or “righting reflex” underlying this effect. The important paper describing the results of their researches which they published in 1935, discussed at length below, failed to attract the attention of the scientific community until recently, however.

149 J.B.S. ( John Burdon Sanderson) Haldane (1892–1964), British geneticist, founder of population genetics (with R.A. Fisher) and author of brilliant publications on a wide range of scientific and social themes who inspired a whole generation of British intellectuals, was the brother of the famous writer and peace activist Naomi Mitchison (1897–1999) and the son of the noted British respiration physiologist J.S. ( John Scott) Haldane (1860–1936). After teaching physiology at the universities of Dundee and Oxford, the father became director (in 1913) of a mining research laboratory that was affiliated with the university of Birmingham from 1921. His important discoveries in the field of respiration physiology did much to improve the working conditions of coal miners, industrial workers and deep-sea divers. Both father and son were active and well known when Ter Braak started his research career. He was particularly well acquainted with the father’s work on the nervous regulation of respiratory phenomena, which was the subject of Ter Braak’s thesis. 150 J.B.S. Haldane, “On Being the Right Size”, in “Possible Worlds and Other Essays” (London: Chatto & Windus (1927) pp. 18–26). This well-known essay has been reprinted many times, e.g. in “From Eros to Gaia” by Freeman Dyson, Penguin Books, pp. 8–10, 1992.

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Fig. 2-29. Frontispiece ‘Acta-Laryngologica’. Article by G.G.J. Rademaker and J.W.G. Ter Braak, The fall reflex, 1935.

3. W. ter Braak (1903–1971) first came into contact with Rademaker around 1929, when he was working on his doctoral thesis in Prof. Brouwer’s laboratory in Amsterdam. Rademaker had assisted him in his experimental work on respiratory complaints of neurological origin in cats, which involved making selective lesions in the Goll and Burdach tracts of the spinal cord. After completion of his thesis towards the end of 1932,151 Ter Braak moved to Leiden in 1934 and worked as an assistant to Rademaker (who had been appointed professor of Physiology there in 1928). He was made curator of the Physiology laboratory, and joined Rademaker in the experimental work on the fall reflex. Ter Braak’s attention had moved from respiratory neurophysiology to the study of the cortical optic reactions and their functional disorders. He had chosen the optokinetic nystagmus function as the via regia to the central nervous system (CNS), which in his opinion had too long been disregarded as the coordinator of the peripheral Magnus-de Kleyn reflexes for posture and gait. The cooperation between Rademaker and Ter Braak in the period 1934–1939 generated three important joint papers in Brain and their 1935 article on the fall reflex in cats which included a two-cylinder ergometric model of the fall mechanism and mathematical analysis

151 W. Ter Braak conducted the public defence of his thesis, entitled “Klinisch anatomisch onderzoek over neurologische ademhalingsstoornissen” (Clinical-anatomical investigation of neurological respiration disorders), at the University of Amsterdam on 2 November 1932.

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Fig. 2-30. Dr. J.W.G. Ter Braak (1903–1971). Courtesy: Mrs. Ter Braak-Faber.

of this process.152 Ter Braak helped to supervise the doctoral students in the Physiology laboratory, and lectured on neurology together with Rademaker during a prolonged absence of the reader due to a chronic illness. Just before the war, Ter Braak took up a post as neurologist at a teaching hospital in The Hague, where he had the responsibility for the neurology and psychiatry wards. When the occupying forces started putting bedridden Jewish patients from the big teaching hospital De Zuidwal in The Hague on transport in the annus horibilis 1942, Ter Braak (the neurologist in charge at the time) refused any form of cooperation. He was arrested, remanded in custody in the notorious Oranje Hotel prison in Scheveningen and sentenced to six months at the concentration camp in Vught, after which he was released.153 After the war, he was appointed professor of Neurology at University Hospital Rotterdam (see figure). Rademaker and his highly principled, brilliant pupil Ter Braak remained ‘congenial friends’ and continued to take an interest in one another’s scientific pursuits, which in Ter Braak’s case centred round optokinetic nystagmus and other optical functions. During the war, both had been the conscience of Dutch neurology while after the war both were given functions in the collaboration assessment commissions set up by professional organizations and the government, and both were praised for their courageous stance in the Resistance. 152 G.G.J. Rademaker and J.W.G. ter Braak, “Das Umdrehen der fallende Katz in der Luft”, Acta Laryngologica (Stockholm) 23, 313–343, 1935. 153 From O. Magnus’s portrait of Ter Braak in “Drie Neurologen”.

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Fig. 2-31. High-speed film frames of cat turning over in free fall. Drawing by Etienne-Jules Marey, Collège de France, 1894. Etienne-Jules Marey (1830–1904), the leader of the research group at the Collège de France, also opened the first cinema in Boulogne Billancourt. He further developed stroboscopy in 1882, using a high-speed camera and a projector that could handle 100 images per minute.

4. After the publication of Rademaker’s “Das Stehen” (The physiology of Standing) in 1931,154 the German physiologist Prof. Abderhalden from the University of Halle had predicted “Nach das Stehen kommt das Gehen” [after Standing comes Walking]. And indeed, Rademaker and Ter Braak started their investigation on the fall reflex from a supine position, on the premise that “walking is a fall reflex”. The first step was to study the labyrinthine neck and body righting reflexes and the balance reflexes in the free-falling cat model. Rademaker had already established that these reflexes were well preserved in the decerebrated cat and could conveniently be studied by rotating the labyrinths about the fronto-occipital axis while the animal was held in a hanging position with the head upwards. It appeared that stimulation of the semicircular canals could play a role in the ability of the cat to turn over during free fall, without any point of support. This striking phenomenon had already been investigated by the renowned group of experimental physiologists at the Collège de France in Paris, and others, from the end of the nineteenth century. The researchers Marey, Guyon and Lecornu had used a chrono-

154 Originally published as Monograph in General Neurology and Psychiatry No. 59 by Julius Springer Verlag, Berlin, 1931 (in German).

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photographic technique with high-speed cameras (which formed the basis for the first moving films) in 1897155 to elucidate the underlying mechanism (see accompanying illustration). Magnus had used a similar technique in the period 1922–1924. According to him, the animal’s ability to turn over was based on the labyrinthine righting reflexes followed by the associated neck righting reflex: the labyrinthine righting reflex brought the head into the normal position after which the neck righting reflex came into operation, turning the body (first the thorax and then the pelvis) into the normal position. Rademaker and Ter Braak, however, doubted whether the labyrinthine righting reflexes were indeed responsible for this effect. They pointed out how these reflexes are normally elicited by changes in the position of the head and hence of the labyrinths. Under these conditions, the force of gravity gives rise to changes in the labyrinths that trigger the labyrinthine righting reflexes, which cause the head to be turned back to its normal position. It could thus be said to be the force of gravity that gives rise to the labyrinthine righting reflexes. The unusual feature of the free-fall investigations, however, is that the falling animals are subject to zero gravity (or more correctly microgravity). The implications of this will be worked out below. 5. Rademaker and Ter Braak started the first part of their new investigation in 1931. They summarized the relevant observational evidence in the introduction to their 1935 article152: when a cat is held in the

155 R. Magnus, “Wie sich die fallende Kätze in der Luft umdreht”, Arch. Néerl. De Physiologie de l’homme et des animaux 7, 218–222, 1922. R. Magnus in “Körperstellung”, Julius Springer Verlag, 228, 1924. Marey E.J.M., “Des mouvements que certains animaux exécutent pour retomber sur leurs pieds, lorsqu’ils sont précipités d’un lieu élevé”, Comptes rendus de l’Academie des Sciences T119, 714–718, 1894. Guyon, “Note relative à la communication de m. Marey”, Comptes rendus de l’Academie des Sciences T119, 719, 1894. Maurice Levy, “Observations sur le principe des aires”, Comptes rendus de l’Academie des Sciences T129, 718–721, 1894. Marcel Deprex, “Sur un appareil servant, à metre en evidence certaines conséquences du theorème des aires”, Ebenda t.129, 767–769, 1894. P. Appell, “Sur le theorème des aires”, Ebenda t.129, 770–771, 1894. L. Lecornu, “Sur une application du principe des aires”, Ebenda t.129, 899–900, 1894. D.A. McDonald, “The righting movements of the freely falling cat (filmed at 1500 f.p.s.)”, J. Physiol. (Lond.) 46, 34P–35P, 1955.

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supine position and is then let go, it will—as is well known156—turn over in the air and land with its feet on the ground. A decerebrated cat will turn over in exactly the same way. This indicates that the change of position must be due to a subcortical reflex mechanism. If on the other hand the cat’s labyrinths are removed and it is blindfolded, it will not turn over and will land on the floor (or rather on a strategically placed pile of cushions; see below) on its back. The presence of intact labyrinths is thus a necessary condition for the animal to turn over in the air. As pointed out above, under normal conditions the labyrinthine righting reflexes could be said to be caused by the force of gravity. If the animal falls freely in space, however, this influence of gravity is immediately eliminated. When now an animal (not just a cat, but also a dog or a rabbit) is held in the air in a prone position and slowly turned over backwards, one will initially observe that the head moves in a ventral direction under the influence of the labyrinthine righting reflexes so that it remains in the normal position. As the rotation continues, the labyrinthine righting reflexes will continue to give rise to ventral flexion of the head; however, it will no longer be possible to keep the head in the normal position and it will be directed upwards to an increasing degree. When the plane of the mouth makes an angle of about 43º–60º with the horizontal, the labyrinthine righting reflexes will gradually fail until eventually the animal is lying in a prone position with its head hanging limply backwards. The labyrinthine righting reflexes would thus appear to be inoperative in this position. If, however, the animal is dropped from this position (supine with the head hanging backwards) it will still turn over in the air to land on its feet, despite the fact that the labyrinthine righting reflexes are initially inactive. Conclusion 1: the falling motion elicits the rotation. Even if the animal is supine and its head is held in the normal position, it can still turn over. In other words, rotation still occurs even though the animal’s head is initially in the normal position or is brought into this position by ventral or dorsal flexion, so that there is no reason to activate the labyrinthine righting reflexes. Nevertheless, the labyrinths clearly

156 J.G. Dusser de Barenne, Arch. Néérl. D. Physiologie 4, 31, 1920 and Pflüger’s Archiv. 180, 75, 1921, which cites Rademaker’s initial observations on the cat, the dog, the rabbit and the monkey.

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play some part in helping the animal to turn over, since animals in which the labyrinths have been removed cannot turn over. Conclusion 2: “dass das Umdrehen beim freien Fall nicht auf den, durch die Schwerkraft ausgelösten, Labyrinthstellreflex beruhen kann. . . .” [turning over in free fall cannot be due to the labyrinthine righting reflex elicited by gravity] . . . but it does depend on the labyrinths in some way. Conclusion 3: There must thus be a second type of labyrinthine righting reflexes triggered not by gravity but by the falling motion. These reflexes cause the animal to turn around while falling, so that the head is brought back to the normal position (with the bitemporal axis horizontal and the plane of the mouth inclined about 45º downwards) when the animal is supine or lying on its side before it falls. This is the same result as that obtained in the absence of free fall, when gravity-triggered labyrinthine righting reflexes are operative. As mentioned above, the trunk still turns when the trunk is supine and the head is held in the normal position before the fall. In short, we get the surprising situation that the trunk turns during free fall no matter whether the head is also supine or is in the normal position before the fall. Summarizing, Rademaker and Ter Braak proposed the separation of the labyrinthine righting reflexes and free fall (till that moment, various researchers—not all cited here—had only considered the cases of animals that were either labyrinthless and thus had no labyrinthine reflexes at all or had intact labyrinths and displayed all labyrinthine reactions). In a later series of investigations (1939), Rademaker and Kraan studied animals with apparently intact labyrinths but no labyrinthine reactions, and found that all these animals failed to turn over in free fall and thus landed on their backs. This finding led them to ask whether fully intact labyrinthine righting reflexes were necessary to enable an animal to turn over. Or, to take the question one step further, should we assume that both the reactions postulated above are dependent on the same centre so that if one disappears the other must necessarily do so too? Alternatively, are the two reactions interdependent in some as yet unexplained way? In the second part of their investigations, Rademaker and Ter Braak made use of a series of mirrors ingeniously placed at an angle of

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Fig. 2-32. Drawing of a falling cat by G.G.J. Rademaker and J.W.G. Ter Braak. I: dorsal muscles; II: lateral muscles at the right; III: ventral muscles; IV: lateral muscles at the left.

43º to film the falling of blindfolded cats.157 These films could then be projected in a special set-up giving two-dimensional views of the sequence of events. Due to lack of space, we cannot give full details of these experiments here. The following drawing by the authors summarizing their new observations on the falling reflex must suffice. (See figure) They stated that the fore- and hindlimbs turned together and the essential mechanism was a flexion of the body by the contraction of dorsal, lateral and ventral muscles (see figure). 6. Epilogue As was perhaps to have been expected, succes d’estime et succes de scandale?, this research elicited protests from anti-vivisectionists, who paraded outside the entrance to the Physiology laboratory on the

157 The blindfolded animal turns as well as one with its eyes open, although possibly with an appreciable delay. Vision is also essential for proper landing, as a blindfolded cat falls flat on the floor. To ensure that angular momentum acquired at take-off is not responsible for the effect, some cats were tossed about 2 ft into the air. They turned at the top of the throw in exactly the same way as those dropped from the hand. D.A. McDonald, J. Physiol. (Lond.) 46, 34P-35P, 1955.

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Zonneveldstraat in Leiden, handing out leaflets to passers-by giving details of what they saw as cruelty to the cats, and sometimes rabbits or dogs, who had their labyrinths cut out and were then dropped or even thrown from an appreciable height to investigate the effect of this surgery on their reflexes. One of Rademaker and Ter Braak’s old student assistants remembers these protests well [Personal communicatie Dr. A.G.M. van Vliet]. The kind of activity that aroused the protesters’ concern was described as follows by the researchers on p. 316 of their 1935 article: “Die Katze dreht sich auch in der Luft um, wenn man das Tier schnell herunten wirft, sodass er mit grösseren Anfangsbeschleunigung nach unten bewegt wird als beim freien Fall. Unter diesen Umständen wird beim Anfang der Bewegung, der Einfluss der Schwerkraft auf die Labyrinthe nicht nur afgehoben, sondern sogar durch eine Kraft in entgegen gesetzter Richtung ersatzt.. . .Nicht desto weniger dreht sich auch dann Katze um und auch die Drehrichtung ändert sich nicht. . . .”. (The cat turns around in the air even when the animals is thrown forcibly downwards, so that it moves downwards with a greater acceleration than in free fall. Under these conditions, the influence of gravity on the labyrinth in the initial stages of motion is not only cancelled out but actually replaced by a force acting in the opposite direction . . . Nevertheless, the cat still turns over, and the direction in which it turns remains unchanged . . .)

Despite the meticulous care with which the researchers recorded every detail of their experiments, they forgot to mention that care was taken to ensure a soft landing for the delabyrinthized animals by stipulating that a pile of cushions should be provided for them to fall on (these cushions are not clearly visible in the photographic illustrations accompanying the article either). These protests did not, however, detract from the scientific merits of this brilliant investigation. 1. What did Rademaker and Ter Braak achieve? They were the first to point out the key importance of the microgravity environment encountered in free fall, and to demonstrate that the labyrinthine righting reflexes exhibited by animals under these conditions are distinct from the gravity-induced righting reflexes observed when the animal is not falling, but that the two sets of reflexes are related in

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Figs. 2-33 a & b. The Physiology Laboratory on the Zonneveldstraat in the centre of Leiden was the place where Willem Einthoven (1860–1972) carried out the experiments that won him the Nobel Prize for Medicine in 1924, for his discovery of the electrical properties of the heart using the electrocardiograph which he had invented. When Rademaker succeeded Einthoven as professor of Physiology in 1928, it was in this same laboratory that he performed the experimental work that formed the basis of his monumental monograph Das Stehen (1931; not translated into English, under the title The physiology of Standing, till 1980). The laboratory was demolished in 1946–47.

some way, the exact nature of which is still unknown.158 The effect of microgravity is of key importance in modern space research, since it governs the movements of astronauts in the weightless conditions they encounter when in orbit. 158 There was no reason not to continue this experimental work on the ‘réactions labyrinthiques’ (as both investigators did later) but they were at that time hampered by the absence of an experimental set-up for studying the effects of microgravity on humans and equipment for in vivo recording of the otolithic and cupular reactions.

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Fig. 2-34. Mathematical drawing of a falling cat by G.G.J. Rademaker and J.W.G. Ter Braak.

2. Secondly, they produced a dynamic model of the turning movement of animals in free fall based on their own accurate observations. This model consisted of two coupled cylinders, rotating in opposite directions around their longitudinal axes (see figure). Both Rademaker and Ter Braak were keenly aware of the need for mathematical analysis of the fall reflex, and possessed sufficient mathematical skills to put together this simple model. It would however be left to a later generation of physicists and mathematicians with much more powerful theoretical techniques at their disposal to reveal the nature of the mechanism underlying this process. The key problem here is how a cat can possibly turn over in mid-air without holding on to any fixed point of support, while theory teaches us that the total angular momentum of its body must remain zero throughout the manoeuvre. Rademaker and Ter Braak were aware of this problem in theoretical mechanics, and also tried to identify the muscle groups that were responsible for the cats’s movement. This problem is currently the subject of lively discussion among theoreticians, as an Internet search using the search term “falling cat” will show. A full understanding of the mathematics involved would be beyond the powers of most of my readers, but I have attempted to

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give the essence of the argument here in simple terms.159 The first step towards the solution of the falling cat problem was the publication by Kane and Sher of an article entitled “A dynamical explanation of the falling cat phenomenon” in 1969. The argument was taken further in the early ‘nineties by Prof. Richard Montgomery of the University of California at Santa Cruz, on the basis of theory on high-energy physics and the rotation of molecules provided by the French mathematician Alain Guichardet in 1984. They showed that a multi-body system could show rotation while still keeping its total angular momentum zero if parts of the system exhibited appropriate ‘vibration’. Montgomery puts it as follows in his highly mathematical language: Another such problem is that of a falling cat dropped upside down. The cat flips itself right side up, even though its angular momentum is zero. It does this by changing its shape. In terms of gauge theory, the shape space of the cat forms the base space of a principal SO(3)-bundle, and the statement “angular momentum equals zero” defines a connection on this bundle.

A much simpler explanation based on the same theory, also found on the Internet, is this: The cat manages the feat, with zero angular momentum. She isn’t spinning to start with. So, she must maintain that zero momentum: a cute trick while she twists around to a feet-first descent. First, she thrusts her back legs straight out behind her body and at the same time she tucks her front legs in. Extending her back legs resists spinning. This allows her to twist her body, the front part of the body twisting more than the back. Tucking the front legs encourages spinning. The result twists the front legs down to the ground with the back part of the cat following the twist. She touches down all four paws, oriented feet first—only 18 inches from where she started.

The latest refinement of the mathematical theory is provided by Toshihiro Iwai from the department of Applied Mathematics and Physics at Kyoto University in two papers (1998, 1999), the latter of which is entitled “Classical and quantum mechanics of joined rigid bodies with vanishing total angular momentum”. In particular the articles by Kane and Sher, and by Montgomery, are widely cited nowadays, not only by mathematicians and theoretical physicists but also by sports instructors 159 I am indebted to Dr. Rolf Peeters from the department of Mathematics at the University of Maastricht for providing most of the information on which this summary is based.

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who use the insights gained to teach trampoliners and high divers to improve their execution of complicated manoeuvres in the air.160 This theory makes it possible to calculate and simulate the transfer of energy from vibrational to torsional motion on the basis of the two-cylinder model, 50 years after this model was first described (see figure). Such simulations of the falling-cat phenomenon may also be viewed on the Internet. The mathematics has become much more sophisticated in the 50 years since Rademaker and Ter Braak first made their observations and put forward their simple mathematical model to describe them. Nevertheless, their proposed explanation of the falling cat phenomenon was far ahead of their time, and the advanced mathematical and physical arguments published by Iwai (1998, 1999) may be seen as a representation of the sequence of undulatory and torsional motion they had described. Postscript After Rademaker’s retirement and death in 1957 at the age of 70, Ter Braak continued his work as professor of Neurology in Rotterdam. He kept in touch with important research in his field until he died in 1971. His undiminished interest in the falling cat phenomenon is reflected by the press cutting shown above, taken from the NRC (Nieuwe Rotterdamsche Courant) and summarizing an article that appeared in Nature on 14 April (1960 or 1970?), which was one of the few documents found by his wife in the drawers of his desk at the university after his death. The translation of this press cutting is given below. It may be noted in passing that this ability of the cat to survive falls from great heights has even been used as the theme of a detective 160 Kane T.R. and M.P. Scher, “A dynamical explanation of the falling cat phenomenon”, Int. J. Solids Structures 5, 663–670, 1969. Guichardet A., “On rotation and vibration motions of molecules”, Ann. Inst. Henri Poincaré Phys. Theor. 40, 329–342, 1984. Montgomery R., “Fields Institute Communications”, Amer. Math. Soc. Providence, Vol. 1, 193, 1993. Toshihiro Iwai, “The mechanics and control of multi-particle systems”, J. Phys. A. Math. Ges. 31, 3849–3865, 1998. Toshihiro Iwai, “Classical and quantum mechanics of joined rigid bodies with vanishing total angular momentum”, Journal of mathematical physics 40 (5), 2381–2399, 1999.

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Fig. 2-35. Print of a 2-cylinder animation as can be seen on the website of the Kyoto University. (http://yang.amp.i.kyoto-u.ac.jp/research/anime/3dim.html)

Fig. 2-36. Press cutting from the Dutch NRC (Nieuwe Rotterdamsche Courant): a summary of an article that appeared in Nature on 14 April (1960 or 1970?). Courtesy Mrs. Ter Braak-Faber.

short story called ‘A summer, a fall’ by Mark Montgomery, a namesake of the Prof. Richard Montgomery mentioned above. In this story, a police detective on holiday is moved to investigate the death of an old woman who falls from the thirty-second floor of a skyscraper. Both the old woman and her cat are found dead on the ground, but the detective’s wife provides the key to the mystery by pointing out that the cat should not have been dead, for she had read some time before in the American magazine Newsweek that (as stated in Ter Braak’s cut-

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ting) cats can spread out their legs to act as a kind of parachute when falling from great heights. So it cannot have been an accident, and must be murder. [Translation of press cutting] Falling cats land better if fall lasts longer The saying “a cat has nine lives” comes from the high survival rate of cats that fall from a great height. Scientists have never investigated this, but two American vets have now filled this gap. A total of 132 cats that had fallen from a great height in New York, with its skyscrapers and concrete pavements, were seen last year at the veterinary practice of Whitney and Mehlhoff. The animals had all fallen at least two stories (corresponding to a height of about 10 metres). Ninety percent of the cats survived after their fractures or other injuries had been treated. Only eleven cats died. It is noteworthy that the number of injuries, and the death rate, peaked at a height of 7 stories (about 25 metres). The death rate and the severity of the injuries decreased above this height. For example, one cat survived a free fall of 100 metres with only a broken tooth and a crushed ribcage. Adult humans who fall from a height of more than 35 metres on to concrete have practically no chance of survival. As long as a falling cat undergoes acceleration, the animals will try to turn so that its legs hang down, thus spreading the load at the moment of impact. The cat reaches its maximum speed after a fall of about 35 metres. Acceleration is then no longer operative, and the cat’s legs will tend to splay outwards, just like a flying squirrel. The increased air resistance will slow the cat down. According to the vets, this reflex reaction is the result of natural selection. Millions of years ago, most felines lived in trees. As a result of the jumping and falling associated with this lifestyle, the “airworthiest” cats had the best chance of survival. The fact that a cat has nine lives is thus the result of an evolutionary process. (Nature, 14 April)

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[graph] Mortality (%) 100

humans

50 cats 0 0

10 ... Height of fall in metres

100

Death rate of cats and humans after fall from skyscrapers in New York And then there was Einstein’s ‘happiest thought of his life. . . .’161 As Einstein told later it in november 1907: I was sitting on a chair in the patent office at Bern when all of a sudden a thought occurred to me: “If a person falls freely he will not feel his own weight . . .”

Thoughts like this were not what Einstein was getting paid for. He was there to reject perpetual motion machines, analyze ideas for a better mouse trap, debunk contraptions for turning dung into diamonds etc. If a person falls freely he will not feel his own weight . . .

Einstein called it “the happiest thought of my life. . . .” Was he in a depressive mood considering the benefit of a suicidal attempt, precluding the sensation of the lightness of living or dying or idleness? To conceive or propose a mathematical—physical based neurophysiological model or theorema such as Rademaker and Ter Braak had proposed on the fall reflex for the falling cat seemed at that moment unconceivable for Einstein. 2.7. Infant Development as a Mirror of the Evolutionary Process The interest in the new perspectives offered by Rademaker’s experimental investigations led clinicians, pediatricians and neonatologists to subject clinical observations on the development of these motor

161

Cited in Euclid’s window”, pp. 193–194 from his diary.

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reflexes to further analysis. Surprising discoveries were made, some of which proved to be of significance in clinical diagnostics as pointed out by Landau,162 Peiper, Schaltenbrand and Willemse, and came to be universally accepted. In this way, Rademaker’s innovative views were given a firm basis by experimental physiological findings and their further clinical implications were worked out. The main findings are summarized below. The pediatrician Peiper made a detailed comparison of the results of the animal experiments carried out by Magnus, De Kleyn and Rademaker with the motor behaviour of normal children at various ages, while Schaltenbrandt163 (who had worked as a member of Magnus’s group for a time) summarized the stages in the development of an erect posture and the various locomotor activities that preceded this. When an infant stands up from a recumbent position, the characteristic rotary movements involved are led by the eyes and the head in a way which is similar to that observed in animals under the influence of mesodiencephalic stimuli. During the second and third years of life, these coordinated righting movements are changed into a rotary movement of the pelvis, which is further modified in the third and fourth years of life by supporting action from the arms that permit the trunk to be brought into a sitting position. Adversive rotary movements of the eyes, head and foretrunk—instinctive orientation movements induced by various receptors and central regions—are normally integrated into versatile motor behaviour, but manifest themselves as isolated mechanisms in children. Such isolated mechanisms may also ‘be released after diffuse cerebral lesions’ (see discussion of thesis by N. Verwey, 1938) and may further be observed in cases of senile dementia and organic-psychosyndromes with regression. 162 Landau A., “Über einen tonischen Lagereflex beim älteren Säugling”, Klin. Wochenschrift 2 (27), 1253–1255, 1923. Ibidem, Über motorische Besonderheiten des zweiten Lebenshalbjahres”, Mschr. Kinderheilk. 29, 55–558, 1923. Ibidem, “Zur Motorik des älteren Säuglings”, Zbl. f.d. ges. Neur. u. Psychiatr. 40, 372, 1925. Balduzzi O., “Contribution à l’etude des reflexes toniques de posture”, Rev. Neur. 38, 280–292, 1931. Ibidem, “Die Stützreaktionen beim Menschen in physiologischen und pathologischen Zustanden”, Ztschr. f. die ges. Neur. u. Psychiatr. ½, 141, 1–29, 1932. [Rademaker’s exp. data cit. on pp. 1, 2, 4, 9, 16, 19, 20, 22, 29]. Willemse J., “De motoriek van de pasgeborene in de eerste levensuren” (“Motor reactions of the new born infant during the first hours of life”), Acad. Proefschrift Utrecht, 1961, Uitg. Erven J. Bijleveld, Rademaker data cited on pp. 75–91; 110–111. 163 Georg Schaltenbrandt, professor of Neurology, Hamburg, cited in: “Rudolf Magnus, Physiologist and Pharmacologist 1873–1927”, Koninkl. Ac. van Wetenschappen, Amsterdam, Kluwer Academic Publishers, Dordrecht, Boston and New York.

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book ii Scheme I: Postnatal development of primitive reflexes164 Praematuritas Months → ↓

165

1 A

Moro reflex

B166 Neck righting (Landau) C

2

3

°

4

5

6

7

8

9

10 11 12 13 14 15 16 17

° ° ƒ

Embrace reflex (Umklammerungsreflex)

D167 Labyrinthine righting reflex (Rademaker) E

Optical righting reflex (Magnus)

F

Symmetrical neck reflex (Magnus—de Kleyn)

G162 Tonic labyrinthine reflexes in limbs H

Asymmetrical tonic neck reflexes in limbs

I

Rooting reflex

°

J

Grasp reflex hand (Robinson)

°

K

Grasp reflex foot

L

Asymmetrical tonic neck reflexes (Magnus—de Kleyn)

° °

°

164 These data are collected from experiments (by Magnus, de Kleyn and Rademaker) and clinical observations (by Rademaker, Peiper and others). The incidences shown may differ from those given by other literature sources. According to Peiper, such data should be treated with caution, since they may vary under the influence of factors like the cooperation obtained from the infant examined, the infant’s alertness and the effect of feeding. 165 ° absent; present all or most of time; ---- overlapping; incidental; …………….. 166 The tonic neck reflex (Landau) and the tonic labyrinthine reflex are linked both in experimental animals and in neonates. 167 Disappearing after decerebration in experimental animals.

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Scheme I (cont.) Praematuritas Months → ↓ 1 M

2

3

4

5

6

7

8

9

10 11 12 13 14 15 16 17

Visual placing reflexes

N168 Non-visual (tactile) placing reflexes O

Body righting reflex evoked by contact with the surface of the seat (Garter)

P

Tonic skin reflexes in limbs

Q

‘Parachute reaction’ (Sprungbereitschaft) Rademaker

R

Blink reflex evoked by threat movements (= RaGa I reflex)

S

Supported standing → unsupported standing

T

‘Red nucleus walking’169

U

Step Sign170

V

Vestibular ocular reflexes171

° ° ° ° ambulation overlap

Reflex disappears in the 2 month of development. Babies through their first year of life; like crawling until corticospinal tract myelinates; at that point they can learn to stand up and walk with two instead of four limbs. Some babies never crawl, but stand up and walk as their first voluntary locomotion. In: “Brainstem and cerebellum”, Ch. 15, The Red Nucleus level of motor integration, University of Massachusetts Medical School. 170 Step sign c.s. Sherrington “Remarks on the reflex mechanism of the step”, Presidential Address to the Neurological Section of the Royal Society of Medicine, Brain, Part I, 33, 1–25, 1910; Original Articles and Clinical Cases. 171 Vision is also an important sense for perceiving motion; vestibular-ocular reflexes keep a visual image stable on the retina despite body movement. These reflexes are very adaptable (Young, L.R., “Perception of the body in space: Mechanisms”, in: “Handbook of Physiology”, Section 1: The Nervous System, American Physiological Society, Bethesda, MD, pp. 1023–1026, 1984). 168 169

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book ii Scheme II: Comparison of righting and placing reflexes

I

Righting reflexes (n=5) 1. Optical righting (Magnus) 2. Labyrinthine righting (Rademaker-Ter Braak) 3. Neck righting (Landau) 4. Body righting (Garter)

I A Zero condition 1. All righting absent (in labyrinthless deaf-mutes) (Schaltenbrand, Magnus) II

Placing reflexes 1. Vestibular ocular reflexes172 2. Visual placing reflexes 3. Non-visual (tactile) placing reflexes

172 The simplest vestibular ocular reflex (also known as the vestibule-ocular reflex, VOR) involves a three-neuron arc; the signal originates in the vestibule (midbrain) and travels to the extra-ocular muscle through one of the nuclei of cranial nerve III, IV or VI. Vision is also an important sense for perceiving motion. Vestibular ocular reflexes keep a visual image stable on the retina despite body movement. These reflexes are very adaptable. (Young I.R., “Perception of the body in space mechanisms”, in: Handbook of Physiology, section 1: The Nervous System, J.M. Brookhart and V.B. Mountcastle, eds., American Physiological Society, Bethesda, MD, pp. 1023–1086, 1984).

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Fig. 2-37. An example of the step sign, as observed by the author in his 12-month-old grandson Alexander who is walking with his mother over uneven ground by the edge of a lake in New Jersey (USA). This photo was taken at close range to permit analysis of the act of walking into its postural and kinetic components, reflecting this two-fold activity of the developing nervous system (Sherrington). The proprioceptive Stütz reaction (see part 2.5 of this book) is present from the start (in what Magnus called the Stehbereitschaft). The static component (the ability to maintain an upright posture) is accompanied by the kinetic component formed by the rhythmic alternating movement of the limbs (stepping). The picture clearly shows the postural reflex underlying the act of standing, which is in fact a proprioceptive reflex informed by the protective hand of Alexander’s mother. Propriocepsis is a sensory quality whose sensors include the muscles, tendons, joints and skin, that provide information on movement and location. Proprioception is often called the ‘hidden sense’ because it is not under conscious control and is taken for granted in every day activities.

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Endnote i Von Uexküll and the serendipitous chain of events leading to Magnus’ postural research Baron Jakob Johann von Uexküll (1864–1944), descendent of a poor German aristocratic family from the Baltic countryside, studied zoology at the university of Dorpat (now Tartu), Estonia. He later worked at the Institute of Physiology of the University of Heidelberg under Prof. Wilhelm Kühne and at the Stazione zoologica Anton Dohrn in Naples. He long led the life of an independent amateur researcher, until he was appointed professor of comparative physiology of invertebrates and director of the Institut für Umweltforschung at the University of Hamburg in 1926. His original observations were recorded in a number of classics which had a dominant influence on the field of experimental physiology, in particular Umwelt und Innenwelt der Tiere [The environment and inner world of animals, 1st edn. 1909] (see figure) and numerous articles, some of which are given in the reference list below. Magnus’ lifelong friendship with the physiologist Otto Cohnheim and Jacob von Uexküll began in Heidelberg. All who knew him later with any degree of intimacy will remember the respect, spiced with the humour of true affection, with which Magnus spoke of Von Uexküll’s philosophical outlook and its deep influence on his own intellectual development. This is also recorded in the biography of Magnus by his son. They met later on many occasions, e.g. at congresses, some of which (such as the Eleventh International Congress in Edinburgh in July 1923 and the Twelfth International Congress in Stockholm in August 1926) Rademaker also attended. The Naples Zoological Station, founded in 1872, was the Mecca for experimental biology in the late nineteenth century. One of the many distinguished visiting biologists who spent some time researching the marine organisms abundant in the bay of Naples was the American Thomas H. Morgan. He was so impressed by this institution that he became a prime motor in developing the Marine Biological Station at Woods Hole in Massachusetts (founded in 1888), as its ‘American equivalent’. ( Jan A. Witkowski, “The 51 Most-Cited Articles in the Cold Spring Harbor Symposium on Quantitative Biology”, quoted from Current Contents, 1990). In 1902, Magnus spent some time at the Zoological Station, working with Von Uexküll on the pharmacology of the marine worm Sipunculus nudus. The paper they co-authored on this topic is given in the reference list below. Many important physiological and neurological insights have been gained by the study of such primitive organisms. However, Magnus left Naples with an unsolved problem posed by Von Uexküll. The latter’s investigation on starfish (see figure) had led to the formulation of Von Uexküll’s rule of ‘Schaltung’ or reflex reversal—that the stretching of a muscle increases the likelihood that that muscle will contract in cases where a dilemma of reaction is possible. Now Von Uexküll wanted to know whether this rule also applied to mammals. It was in hope of resolving this conundrum that Magnus visited Sherrington in Liverpool in 1908—the year in which he was appointed to the chair of Pharmacology in Utrecht. Sherrington had become well known in the Netherlands, and in Utrecht in particular, after a visit to Magnus’ laboratory following a congress in the Netherlands and an invitation by medical students in Utrecht to talk about the results of his experimental work. Magnus paid him a return visit after a short stay in Langley’s laboratory in Cambridge, arriving in Liverpool during the Easter holiday of 1908. Sherrington, who had published ‘The Integrative Action of the Nervous System’ (which had brought him worldwide fame) in 1906, was the obvious person to turn to in search of a solution to Von Uexküll’s puzzle. In fact, the visit to Liverpool did not bring a solution to this problem, but it did enable Magnus to make another chance finding, that of extensor rigidity in the decerebrate cat (described in greater detail in endnote II) that sparked off the whole series of investigations on posture for which he would gain lasting international recognition.

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Fig. A. Ophidiaster Ophidianus (Lamarck). Known to fishermen as Stella Marina, violet starfish in English, étoile de mer in French and violettroter Seestern in German. (Photo courtesy of Statione Zoologica Anton Dohrn—Naples.) Present-day visitors to the public aquarium of the Stazione Zoologica—including the autor of the present work—cannot help but be fascinated by the brilliant orange-red colour of this starfish, enhanced by the phosphorescent lighting of the display tanks. The descriptive leaflet available to visitors refers to this as “l’astre du jour qui brille dans les cieux et leur regions de pêcheurs” (the day star that shines in the waters frequented by fishermen as brightly as in the skies). This creature is well known to fishermen in the Bay of Naples, who often find it in their nets. Modern deep-sea divers may also catch it in their spotlight as they swim below the surface of the Bay. The starfish is a popular research organism, because of its relatively simple anatomical and neurological structure. Von Uexküll used his observations on it as part of the basis for his classical and colourful description (1929) of the Umwelt (world view) of such simple creatures as a starfish, a paramecium (an amoeba), a fly and a tick. His book on this topic is currently out of print in German and English, but a French translation is still available under the title “Mondes animaux et monde humain”. Von Uexküll was also the first to describe the retraction response of the starfish to mechanical stimuli that caught Magnus’s attention. Von Uexküll’s contributions (1912) to the study of muscular tonus can be summarized as follows: He defined tonus as a continuous state of excitation (i.e. muscular contraction), and concluded: 1. the lower the tonus, the greater the excitation 2. the lower the tonus, the greater the contraction 3. the stronger the muscle, the lower the tonus.

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– W. Preyer (Professor Physiology at Universität Jena) in: Mittheilungen aus der zoologischen Station Napels (Stazione zoologica Neapel), zugleich ein Reportorium für Mittelmeer-kunde, “Uber die Bewegungen der Seesterne” (Thieren die durch eine relativ weniger verwickelte Organisation in physiologischen Hinsicht den Embryonnahestehend), Bd. 7, 27–127, 1879. – J. von Uexküll, “Zur Muskel und Nervenphysiologie des sipunculus; Die biologische Bauplan von Sipunculus nudus”, Zeitschr. f. Biol., Bd. 33, 1–27, (mit Abbildung), 1896. – J. von Uexküll, “Die Bewegungen der Schlangensterne (zeester)”, Zeitschr. f. Biol., N.F., Bd. XXVIII, ….. – A. Bethe, “…………………….”, Archiv f. mikroskopische Anatomie, Bd. XVIII, 864, 1897. – T. Beer, A. Bethe and J. von Uexküll, “Vorschläge zu einer objektivierenden Nomenklatur in der Physiologie des Nervensystems”, Biol. Centralblatt XIX, 517–521, 1899; ‘Schaltung’ is discussed on p. 518. – J. von Uexküll, “Physiologie der Pedicellarien”, (Neuroderm Organen z.B. an den Pedicellarien der Seeigel), Zeitschr. f. Biol., 334–403, 1899; aus dem physiologischen Laboratorium der zoologischen Station zu Neapel (Mit Tafel IV und V und 2 Abbildungen im Text). – J. von Uexküll, “Physiologie des Seeeigelstachels”, Ztschr. F. Biol., 39 Bd, 73 ff, 1900. – J. von Uexküll, “Die Schwimmbewegungen von Rhizostoma pulmo”, Mitteil. Aus Der Zool. Station zu Neapel, 14, 620–626, 1901. – J. von Uexküll, “Im Kampf um die Tierseele”, Bergmann ed. – J. von Uexküll, “Leitfaden”, Bergmann, Wiesbaden. – J. von Uexküll, “Theoretische Biologie”, Gebr. Paetal, Berlin. – Magnus R., “Die Bedeutung des Ganglions bei Cyona intestinalis”, Mitteil. der Zool. Station zu Neapel, 13, 483–486, 1902 (“The significance of the ganglion of ciona intestinalis”). – J. von Uexküll, “Studien über den Tonus. I. Der biologische Bauplan von Sipunculus nudus”, Ztschr. f. Biol., 44, 269, 1903. – R. Magnus und J. von Uexküll, “Pharmakologische Untersuchungen am Sipunculus nudus”, Zeitschr. Exp. Pathol. u. Pharmakol., 50, 86–122, 1903 (“Pharmacological investigations of sipunculus nudus”). – Bohn, “Attractions et oscillations des animaux marins sons influence de la lumière”, Paris, 1905. – Uexküll J. von, und Grosz, “Resultats des recherches sur les extremités des Langoustes et des Crabes”, Bull. Inst. Océanographie, Monaco, 1909. – F.J.J. Buytendijk (Groningen), “In wieweit können wir symmetrisch bilaterale Bewegungen gleichzeitig anfangen lassen?” (Aus dem physiologischen Institut zu Giessen; mit Tafel X und XI: experiments in adult human and children model right and left handed), Ztschr. f. Biol., 58, 237–250, 1912. – J. van Uexküll, “Studien über den Tonus; VI Die Pilgermuschel”, Pecten maximus muschel, Ztschr. für Biol., 58, 305–332, 1912 [The experimental work by Sherrington „On plastic tonus and propioceptive reflexes“, in: Quart. J. of Exp. Physiology, 1909, Vol. 2, is discussed here]. – J. von Uexküll und Tirala, “Der Tonus bei den Langusten”, Ztschr. f. Biol., 1914.

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Figs. B & C. The student A.W. van’t Hoff, Leiden, february 1924, in his comment on the frontpage on Von Uexküll’s monograph ‘Umwelt und Innenwelt der Tiere’ in the time that physics was in the center of attention, Einstein was nominated as professor in Leiden in 1923: “De biologie is volkomen in staat ons ervoor te bewaren dat de wereld op dat armzalig niveau terugzinkt, waarop de blinde overschatting der physica haar wil neerdrukken”. Endnote ii ‘Körperstellung’ The two main groups of reflexes investigated by Magnus and co-workers and reported on in ‘Körperstellung’ are the tonic labyrinthine reflexes and the tonic neck reflexes. They also investigated a related set of reactions controlling the position of the eyes. We shall discuss these three groups in turn below.

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book ii Tonic labyrinthine reflexes

Tonic labyrinthine reactions can be separated from tonic neck reactions by using animals in which the upper four cervical sensory roots have been severed bilaterally. The labyrinth itself comprises two distinct systems, the otoliths and the semicircular canals. The static labyrinthine reactions are probably mediated by the otoliths, whereas the reactions to angular acceleration appear to stem particularly from the semicircular canals; a clear-cut separation between the two had however never been achieved. The static labyrinthine reactions manifest themselves through changes in resting posture brought about by alteration of the animals’ position in space. When the animal is in a horizontal supine position, the extremities are maximally extended. The snout then lies at an angle of approximately 45E above the horizontal plane. The extensor pattern seen in these circumstances is referred to as the maximal labyrinthine position; the minimal labyrinthine position is that seen in the prone position with the snout tilted 45E below the horizontal plane. In intermediate positions, intermediate degrees of extensor tone are encountered. It should be mentioned again that these are purely static reactions, having nothing to do with acceleration of the animal in space. Their origin in the otoliths has been made plausible in guinea pigs by high-speed centrifugation of the animals, which destroys the otoliths without harming the semicircular canals. Under these conditions, the static labyrinthine reactions are found to be impaired. The intensity of the reflex depends on the position of the otoliths with respect to the maculae of the utriculus and the sacculi, which in its turn depends on the animal’s orientation in space. The maximum intensification of extensor tone by the labyrinthine reflex is produced when the otoliths are suspended from the maculae; this effect is minimal when the otoliths rest on the maculae. When we consider the animal as a whole, this means that the influence of the labyrinthine reflex is maximum when the animal is supine and the line drawn through the mouth makes an angle of 45° above the horizontal plane, and minimal when the animal is standing or lying in a prone position and the line drawn through the mouth makes an angle of 45° below the horizontal plane. Intermediate degrees of extensor rigidity are observed in intermediate postures of the animal, with a fairly continuous variation in rigidity between the maximum and minimum positions. The influence of the tonic labyrinthine reflexes on extensor tone in all four limbs is approximately the same in man as in all experimental animals investigated. Tonic neck reflexes In order to differentiate neck reflexes from labyrinthine reflexes in decerebrate animals, both labyrinths must be destroyed in the experiments and sources of stimulation for static reactions removed so that on turning the neck the influence of the neck muscles alone will be observed. Rotation of the jaw to the right in such a preparation causes a prompt increase in the extension of both limbs on the right side, and relaxation of the limbs on the other side. Dorsal flexion of the head of non-hopping animals causes extension of both forelimbs and relaxation of the hindlimbs (as e.g. in a cat looking up at a shelf); ventral flexion of the head causes relaxation of both forelimbs and extension of the hindlimbs (as in a cat looking under a sofa). These reactions are obviously purposeful; thus, if a cat walking forward in a straight line hears a mouse to the right of it, mere turning of the head to the right causes the extremities on that side to became extended and the animal is automatically prepared for a quick takeoff with its left foot—it has only to decide whether to go for the mouse. The neck reflexes take care of the rest. Clear-cut purpose is also seen in extension and flexion of the forelimbs when the gaze is directed upward and downward, respectively. Section of the dorsal nerve roots in the anterior cervical region abolishes these reac-

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tions, indicating that they are mediated through the three uppermost cervical roots. These reactions are prominent in decerebrate cats, and have also been demonstrated in labyrinthectomized monkeys following bilateral removal of the motor and premotor areas. The tonic neck and the labyrinthine reactions operate in the same direction and thus tend to reinforce one another. Both the labyrinthine reflex and the neck reflex are said to be tonic in nature because the reaction is elicited not by movement of the head but by placing the head in a new position, and persists as long as the head remains in that position. The latency time is characteristically long, in some cases as much as a few seconds—unlike the case with reflex movements elicited by cutaneous stimulation. In other words: the extensor tone of the limbs can still be influenced by changes in the position of the head after bilateral destruction of the labyrinths. The source of the reflexes must now however be sought in the neck and the body. The tonic neck reflexes (as they were called by Magnus and de Kleyn), arise in the proprioceptive nerve endings in the musculature of the throat and neck and deep bone structures, and can be eliminated by transection of the uppermost cervical posterior roots. They can be investigated free of complications after bilateral extirpation of the labyrinths. It would seem to be appropriate at this point to repeat the above information about the labyrinthine and neck reflexes in somewhat greater detail, while at the same time introducing some of the key German technical terms introduced by Magnus and de Kleyn. It will have become clear to the reader by this point that one of the great problems in this investigation was the need to provide a clear description of the complex interplay of motions governed by the reflexes investigated; the terminology introduced by these authors made an important contribution to the solution of this problem. The terms introduced will also prove useful at later stages in this work, and for consultation of the original literature if so desired. Both rotation (‘Drehung’) of the head about its long axis (i.e. the line drawn from snout to foramen magnum) in animals and about the dorsoventral axis in man and lateral, dorsal or ventral flexion (‘Wendung’) produce characteristic tonic responses in the musculature of the limbs. For example, rotation of the head to the right (i.e. in the case of a rabbit, vertex to the right, snout to the left), will be followed after an interval of one or more seconds by an increase in the rigidity of the limbs on the left (called the ‘Kieferbeine’—literally ‘jaw legs’—by Magnus and de Kleyn) and a reduction in extensor tone of the limbs on the right (the ‘Schädelbeine’—literally ‘skull legs’). Lateroflexion to the right causes an increase in the tone of the extensors in the limbs on the right and a reduction in the tone on the left. When rotation and lateroflexion are combined their results are opposed, but since rotation is the more potent stimulus it predominates. Dorsal flexion increases the extensor tone in all limbs in the rabbit, but has a reciprocal effect on the fore- and hindlimbs of the cat, i.e. in this case the extensor tone of the forelimbs is reinforced while that of the hindlimbs is inhibited. When the head is rotated backwards around a bitemporal axis, therefore, all four limbs move backwards—the hindlimbs being strongly stretched while the forelimbs are slightly bent (and the head and neck move forwards again). Ventral flexion of the head has exactly the opposite effect. When the head is turned the opposite way, opposite reactions are observed. It is relatively easy to demonstrate these reactions in the normal cat, as follows: when a standing cat is offered a piece of meat which is held somewhat higher than its head, its forelimbs will stiffen in an extended position while its hindlimbs bend downwards and show less tone than normal. If on the other hand a piece of meat is placed on the ground before the animal, its forequarters will be lowered on bent legs while the hindlimbs remain extended, supporting the hindquarters in their original position. It is not always so simple, however. It will be clear that when the tonic labyrinthine reflex and the tonic neck reflex are both active at the same time, they will combine in different ways depending on the

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position of the animal in space. This fact, and the fact that the tonic labyrinthine reflex is more intense in some animals while the tonic neck reflex is more intense in others, can cause difficulties in interpreting these phenomena. Since moreover some labyrinthine reflexes have a more marked effect on the musculature of the neck than on that of the limbs, the change in the position of the neck resulting from this can give rise to secondary neck reflexes which in their turn act on the limbs. When two or more tonic reflexes act simultaneously on a given muscle zone, they tend to add up algebraically (as Sherrington described in the case of double reciprocal innervation). Reflexes controlling the position of the eyes The position of the eyes is also influenced by changes in the position of the head. For each head alignment, there exists a corresponding eye position. Man and primates have eyes that are practically coplanar and situated in the front of the head. The two visual fields largely overlap. Each eye thus has an optical check on the position of the other, and can adjust its direction of gaze to match that of the other. This is not possible in animals with eyes at the side of their head, such as rabbits and guinea pigs. In these animals, the visual fields overlap very little, if at all. These animals thus need some non-optical mechanism for synchronizing the movements of the eyes so that the left-hand and right-hand visual fields remain compatible when the head moves, and hence ensuring that these animals retain the necessary optical orientation. Such a reflex mechanism does exist in these animals. It is independent of optical effects, since it may also be observed in blind animals; and it does not depend on the animals’ ‘will’, since it is fully operative even in decerebrate preparations (which means that it must be subcortical). The compensatory eye positions in the rabbit will serve as an example of this. If a rabbit sitting in the ‘normal position’ is moved to various recumbent or other positions in space, its eyes will move in their sockets so as partially to compensate the movement of the head in space. Similarly, if the head is rotated about a bitemporal axis then the eyes will rotate simultaneously to compensate partially for the movement of the head in space. All other movements of the head will give rise to appropriate compensatory movement of the eyes. These reflex eye movements are generated by the otoliths of the vestibular organs. When the animal moves its head while sitting in the ‘normal position’, the head moves not only in space but also with respect to the rest of the body. This gives rise to rotation, flexion etc. of the neck, which will in their turn cause reflex changes of the position of the eyes—again, in such a way as to partially compensate for the movement of the head. Both groups of reflexes governing eye movements, those derived from the otoliths and the neck muscles, try to compensate for head movements. Each individual group can only do this in part. De Kleyn showed however that when the two groups of reflexes act together they can give complete compensation within certain limits, i.e. when the head moves within certain limits the eyes move in the opposite direction in such a way that the position of the eyes in space—and hence also the position of the images on the retina—remain unchanged. According to Magnus, however, the above is not a complete description of the fine mechanism involved. When an animal sitting in the ‘normal position’ moves its head from position A to position B, it performs a certain motion, which stimulates the receptors of the semicircular canals. This also elicits reflexes leading to short-lived eye movements. Further research by Magnus’s group showed that here again, the direction of the eye movements is such as to oppose the head movements that brought them about, so that the eyes remain more or less at rest. The new eye position is then maintained by the combination of otolith and neck reflexes. According to Magnus, thus, the reflexes

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generated by the semicircular canals initiate control of the eye position and the otolith and neck reflexes maintain the new position. “It is difficult to imagine a more refined mechanism”, Magnus wrote in 1925—unaware that much more trailblazing work on ‘motion vision’ was still to be carried out by Rademaker and Garcin, and later by Zéki et al.ii Differences in animal species thus prove to play an important role in determining which types of reflex are predominant. In animals with laterally placed eyes (such as the rabbit) and without binocular vision, the tonic labyrinthine and neck reflexes are the best developed. In animals with frontally placed eyes and binocular vision (such as dogs or cats), the adaptation of eye position to head position is realized with the aid of retinal stimuli. Standing reflexes and righting reflexes The tonic reactions described above represent the sum total of the postural reflexes that can be elicited in the decerebrate animal. The predominant role of the head in determining body posture has emerged clearly from our discussion of these reflexes. It will be equally clear that in this model, the animal has no power over the reflex control of its head in space or in relation to the rest of its body. Any movements of the head required to generate the above-mentioned reactions can only be brought about passively, through manipulation by the researcher. All that these reactions are able to do is to maintain the animal in the posture in which it has been placed. The animal can stand, but it cannot change its posture without help from others. If it receives a push on the flank, it will fall over and remain motionless on the ground in a posture determined by gravity. This standing posture is one in which the animal has been passively placed. It differs markedly, moreover, from the standing posture that may be observed in an intact animal: as Magnus put it, this posture is “a caricature of standing”. Magnus referred to the group of reflexes discussed above as the ‘Stehreflexe’ (‘standing reflexes’). It will be clear that there must be many more reflexes in the intact animal which make it possible to orient the head in space and thus to adapt the body to a variety of postures. Magnus called these additional reflexes the ‘Stellreflexe’ (‘righting reflexes’); they can be investigated by transection of the brainstem rostral of the above-mentioned upper limit for production of the decerebrate preparation. An animal treated in this way is referred to as a ‘thalamus preparation’ (see figure). If however the transection is performed at a more caudal level so that the cerebral hemispheres including the thalami are also removed, the animal is referred to as a ‘mid-brain preparation’). It will be clear from what has been said above that an essential condition for the integrity of these two models is that the entire mid-brain block should not be separated from the pons, medulla and spinal cord by the section. Although the mid-brain animal lacks the cerebral hemispheres, it makes a strikingly different impression from the decerebrate animal. When it awakes from the anaesthesia used for the operation, it raises its head followed first by the front part of its body and then by the rear part, until it is sitting up. The distribution and intensity of tone over the various muscle groups is by and large normal, and there is no trace of rigidity. Such an animal, however, is a kind of ‘automaton’: it is incapable of performing any purposive act, and all the activities it does manifest are purely reflex in nature. All normal nutritional reflexes, and many pseudo-affective reflexes, are however, present. The animal jumps up in response to a loud sound in its vicinity. When it is placed on its side or its back, it can immediately get up without help. When appropriate stimuli

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are given, it can walk, run or jump—all with perfect coordination. When the stimuli are removed, the animal resumes the sitting position. No matter what posture it is placed in, its head is always raised and it clearly possesses all reflex reactions required to do this. Since the position of the head determines that of the body and limbs, it follows that the animal retains reflex control of all elements of its posture. Rademaker subsequently subjected the following groups of righting reflexes to further analysis: 1. the labyrinthine righting reflexes acting on the head; 2. the reflexes derived from the body musculature and influencing the position of the head; 3. the reflexes arising from the neck and secondary to group 1; 4. the reflexes arising from and acting on the musculature of the body and limbs. There is a fifth group of righting reflexes, derived from the retina, which is present in the intact animal. Magnus and de Kleyn published a number of papers on the results of experimental investigations of these optical righting reflexes in the dog and cat in 1919/1920*. These investigations were based on the finding that when both labyrinths are extirpated and the animal is blindfolded, it is no longer able to right its head in space; but it can if the labyrinths are extirpated but it can still see. Speciesspecific differences (depending on whether the eyes are frontally or laterally placed) are found to be present here too: optical righting reflexes are present in the cat, dog and monkey, but not in the guinea pig or rabbit. Static reactions One final group of reactions investigated by Magnus and his school—which partly overlaps the reflexes dealt with above—remains to be discussed here. These are the static reactions (called ‘statische Reflexe’ or ‘Reflexe der Lage’ by Magnus). Postural reactions, sometimes designated as “attitudinal” reflexes (Magnus, 1924/1926)** fall into three categories: (i) local static reactions, (ii) segmental static reactions and (iii) general static reactions, including the tonic neck and labyrinthine reflexes. All are propioceptive in nature, the local static reactions stemming primarily from gravitational stimuli, the segmental reactions from the effects of movement of one extremity on the opposite extremity and the general static reactions from the position of the head in space. Acceleration-based reactions, e.g. postrotational nystagmus, arise from the semicircular canals and are distinct from the tonic labyrinthine reactions, which are

* Magnus R. and the Kleyn A., “Optische ‘Stellreflexe’ bij den hond en bij de kat”, [Optical righting reflexes in the dog and cat] Verslagen Koninklijke Akademie van Wetenschappen, Amsterdam, Wis- en natuurkundige Afdeling, Bd 28, p. 670, 1920; “On optic ‘Stellreflexe’ in the dog and in the cat”, Koninklijke Akademie of Wetenschappen, Amsterdam, Proceedings Bd 22, 948–953, 1920; A. de Kleyn and R. Magnus, “Beiträge zum Problem der Körperstellung IV. Mitteilung Optische Stellreflexe bei Hund und Katze” [Contributions to the problem of posture, IV. Optical righting reflexes in the dog and cat], Pflüger’s Archiv. f.d.ges. Physiologie des Menschen u.der Tiere, Bd. 180, 291–297, 1920. ** Magnus R., “Körperstellung” Monographien aus dem Gesamtgebied der Physiologie der Pflanzen und der Tiere. Sechster Band, Experimentell-Phsyiologische Untersuchungen über die einzelnen bei der Körperstellung in Tätigkeit tretenden Reflexe, über ihr Zusammenwirken und ihre Störungen. Berlin Verlag von Julius Springer, 1924, 740 pp. Magnus R., “Körperstellung”, p. 7, 1924; Lancet ii, 531–536; 585–588, 1926.

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independent of movement or acceleration. The afferent sources of stimulation for these three categories of postural reactions are as follows: (i) static reactions originate in the muscles themselves; (ii) segmental reactions develop as a result of afferent signals from one muscle acting upon other muscles of the same segment on the opposite side; and (iii) neck and labyrinthine reactions stem from receptors in the membranous labyrinth (the otolith) and in the neck muscles. Types of static reactions in the decerebrate animal All three of the above-mentioned types of static reactions are well developed in the decerebrate animal. We shall now discuss them in turn. Local static reactions are most conspicuously developed in the extremities, and they have to do primarily with stance—the fixed standing posture that prevents collapse of the extremity under the force of gravity. Magnus described the essence of the local static reaction as follows (Magnus, 1926)*: A movable limb is at times used as an instrument for very different purposes (such as scraping, scratching, fighting etc.) and moves freely in all joints, whereas at other times it is transformed into a stiff and strong pillar, which gives the impression of being one solid column, able to carry the weight of the body. Experiments have shown that this is accomplished by a series of local static reflexes. In becoming pillar-like, joints must become fixed; this involves simultaneous contraction of opposing muscle groups. The stretch reflex, which is at the basis of the antigravity response, is not in itself sufficient to fix a given joint; opposing muscles must contract simultaneously to ensure the joint fixation, but must relax reciprocally when the position of the extremity is changed even to a slight degree. The basis of this coordinated response involving the entire musculature of an extremity was discovered by Magnus in a decerebrate dog. Here the stretch reflexes as judged by the knee jerk were exaggerated, but an extension response which caused the extremity to follow the stimulus when the pads of the feet were lightly touched was even more exaggerated: the extremity followed the finger touching it as if it were a magnet. This response was therefore called the ‘magnet reaction’ (‘Magnetreaktion’) when it was first described. This name was later replaced by a more neutral designation, the ‘positive supporting reaction’. On close analysis it was found that the reaction is initiated by touching the skin of the toe pad i.e. by use of an exteroceptive stimulus; this, however, is followed by a proprioceptive stimulus, viz the stretch of the interosseus muscles by separation of the toe pads. When the skin of the toe pads is anaesthetized, the exteroceptive phase is abolished, but the proprioceptive stimulus still initiates the response promptly as soon as the toe pads becomes separated. Once the extremities encounter active resistance, other muscles are stretched and they in turn reinforce the reaction initiated from the skin and small muscles of the toe pads. The reaction itself transforms the flexible, toneless extremity into a supporting member having the stiffness of a rigid pillar. It is present in normal animals and in man, but is more readily demonstrated in a decerebrate preparation where all the static reactions are released and exaggerated. Once the stretch stimulus of the small muscles of the foot is removed, the extremity again loses its rigid attitude and the various muscle groups become inactive. This process is sometimes referred to as the ‘negative supporting reaction’.

* Magnus R., “Some results of studies in the physiology of posture”, Cameron Prize Lectures Lancet ii 531–536; 585–588, 1926.

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Segmental static reactions The crossed extensor reflex, one of the classical reactions of the decerebrate animal, is an example of a segmental static reaction. Intersegmental static reactions have also been observed. For example, when a hindlimb is caused to extend by the positive supporting reaction or a crossed extensor reflex, the opposite forelimb also extends, thus demonstrating the influence of the lumbar segments on the cervical segments. The same pattern also occurs in reverse: the extension of one forelimb is automatically accompanied by the extension of the opposite hindlimb—a pattern essential for both quadrupedal standing and locomotion. General static reactions Once an animal succeeds in standing, various modifications of stance can develop in accordance with the needs of the given situation. If, for example, a cat lifts its head to look up at a shelf, both forelimbs become automatically extended. If on the other hand it tries to look under a sofa, both forelimbs become flexed. The general static reactions are due in part to the influence of one muscle group on muscle groups in other segments, but they are also modified by the tonic neck and labyrinthine reflexes. The reflexes of labyrinthine origin are generated in the otolith organs of the utriculus and sacculus, and not by endolymph currents in the semicircular canals: the latter stimuli give rise to reactions of a completely different type. As mentioned above (in the section on tonic labyrinthine reflexes), this has been demonstrated by centrifuging a guinea pig so that the otoliths are forced downwards and inactivated. All tonic labyrinthine reflexes are then found to have been eliminated while those originating in the semicircular canals remain active. This technique allows the two types of labyrinthine reflexes to be studied separately. This finding of the functional dualism of the labyrinth was not the least of the fruits of the work done by Magnus and his school. As regards the CNS mechanisms involved in the tonic reflexes, conclusive proof was provided that the grey matter of the nerve arcs lay entirely within the region defined by the brainstem, mid-brain, pons and medulla, and that the afferent and efferent branches of the reflex pathways never passed the cerebellum—since ablation of the latter organ did not eliminate any of the tonic reactions discussed above. Rademaker’s subsequent spectacular investigations, carried out with the aid of experimental brainstem lesions in an attempt to answer some of the questions left by the work of Magnus and co-workers, the results of which are laid down in his thesis, showed that the centre responsible for the righting reflexes lay in the nucleus ruber (see Book II, Part 2.2.–2.3.). Stato-kinetic reflexes One final group of reflexes investigated by Magnus and his school, which we need to discuss here, comprised what Magnus called the ‘stato-kinetische Reflexe’. Unlike the tonic reflexes, these are generated not by changes in the position of the head, body or extremities, but by movement of certain parts of the body—or more exactly speaking by the initiation, cessation or modification of movement (i.e., by acceleration). The motion involved may be either rotational or linear. The various types of reflex in this group will now be discussed in turn.

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Reactions to rotation When a sitting animial is subjected to rotation by placing it on a turntable with the head on the outside and the rear in the middle, then if the turntable is rotated to the right, the animal’s head will turn to the left (lateroflexion). When the rotation stops, the animal’s head will turn to the right again (‘Kopfdreh Nachreaktion’); this latter reaction is accompanied by head nystagmus and a delayed nystagmus (after nystagmus). Thus, the fast component of the movement of the head is opposed to the direction of rotation while the movement when the turntable stops is in the direction of rotation. The eyes also move in this process, in much the same way and to much the same extent as they do when the stationary animal’s head is turned. The body and extremities are also found to be subject to similar effect, not unlike those investigated in humans in clinical practice by Bárány’s pointing test after rotation. Reactions to upward or downward linear motion (‘Reaktionen auf Progressiv-bewegungen’) These reactions are also easy to demonstrate in the intact animal by placing the animal on a horizontal plate, which can be moved up or down. When the downward movement starts, the animal will stretch its legs and spread its toes, and when the movement ends it will bend its legs. If on the other hand the plate is moved upwards, the animal will initially settle down with bent legs, while the legs will stretch when the movement ceases. These movements are known in the German-speaking literature as ‘Liftreaktion’. A similar effect is observed in a guinea pig, which is held vertically with the head downwards (“Hängelage”). If the animal is now suddenly brought downwards—i.e. almost dropped—the animal will extend its forelimbs forwards as if to take its weight while falling to the ground. (This effect is known as ‘Sprungbereitschaft’ or ‘readiness to jump’). Reactions of an identical nature arise in other parts of the body—with the exception of the labyrinths. This is thus an example of the general fact that movement in one part of the body can generate movement in other parts. The situation of the falling cat represents a special case of this*. The ease with which a cat, dropped or falling from a great height, can still land on its feet depends on a combination of the various reactions considered, both static and stato-kinetic. Labyrinthine righting reflexes bring the head into an upright position and the tonic neck reflexes (which according to Magnus are secondary to these labyrinthine reflexes) then bring the body and extremities in line with one another and with the head. Reactions to gradual motion of the various parts of the animal now ensure that it lands softly and safely on its feet. Unilateral extirpation of one labyrinth Round about 1919, Magnus and de Kleyn had the opportunity to investigate the effect of unilateral extirpation of one labyrinth as part of their overall study of postural reflexes**. Armed with an exact knowledge of the normal functions of the labyrinths— de Kleyn was a practicing ear, nose and throat specialist outside the laboratory—the two researchers experienced little trouble in determining and analysing the functional disturbances arising from such an experimental lesion. The information obtained

* Discussed in detail in Book II, Part 2.6. ** R. Magnus, “Beiträge zum Problem der Körperstellung. II Mitteilung. Stellreflexe beim Kaninchen nach einseitiger Labyrinthextirpation” [Contributions to the problem of posture, II. Righting reflexes in the rabbit after unilateral labyrinth extirpation], Pflüger’s Archiv. f.d.ges. Physiologie der Menschen und der Tiere, Bd.174, 134–151, 1919.

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in this way proved later to be of great significance for clinical neurologists and ear, nose and throat specialists—though it must be surmised that not all of them had the knowledge of the normal functioning of the labyrinths required to make proper use of this knowledge. The immediate consequences of destroying one of a rabbit’s labyrinths may be summarized as follows: a ‘skew deviation’ of the eyes, nystagmus, rotation and lateroflexion of the head towards the side where the lesion is situated. Further, a certain amount of spiral rotation of the neck and body towards the side with the lesion, an increase in the muscle tone of the limbs on the normal side and a reduction of the tone on the side with the lesion. In some cases, rolling movements were also noted. These symptoms may be divided into transitory and permanent losses of function. The transitory signs are nystagmus and rolling movements—the latter comprising rotation of the neck and head, reciprocal changes in the muscle tone of the extremities and abnormal eye positions. ‘Skew deviation’ of the eye is characteristically found in the rabbit and other animals with laterally placed eyes, and is hardly ever found in the cat and dog with their forward-looking eyes. The nystagmus found in these cases has a fast component involving movement towards the mid-line, with a slow return towards the side where the lesion is situated. Rotation of the head tends to increase in severity for a number of weeks after the operation and to remain permanently present after that. The spiral rotation of the neck and body varies in intensity from one species to another and tends to decrease in severity during the first few weeks after the operation. The reciprocal changes in the muscle tone of the extremities, on the other hand, are permanent. Analysis shows that the permanent symptoms may be divided into direct and indirect ones. The former are caused by the ‘unopposed’ or unbalanced action of stimuli from the same side as the intact labyrinth, and comprise rotation of the head and deviation of the eyes; the latter are due to secondary tonic neck reflexes induced by rotation of the head, which in their turn cause reciprocal muscle-tone changes in the extremities and spiral rotation of the body. The direct symptoms coming from the labyrinths have only a transitory influence on the tone of the extremities. The rolling movement is a forced motion, and has been shown to be due to the animal’s running or jumping while its body is subject to spiral rotation, so that when the forelimbs are placed vertically on a horizontal surface the rear part of the body and the hindlimbs are at an angle. The animal thus moves, or drags itself, forward with a corkscrew-like motion, making one complete rotation around the longitudinal axis per pair of steps. The movement occurs in ‘fits’, and is ascribed to stimulation from the fresh operation wound (probably affecting the central stump of the eighth cranial nerve). This rolling movement is thus partly ‘dynamic’ in origin (to use Luciani’s phraseology—see section on ‘The cerebellum and the labyrinths’ and footnote 24 below) and may be partly regarded as a set of ‘release’ symptoms. Magnus concluded that the labyrinth influences the tone of the muscles in the extremities, the eyes and the body on both sides, but predominantly on the contralateral side, while the neck muscles are only influenced on one side; however, this unilaterality would seem to be functional rather than anatomical since the muscles on both sides are involved in all movements. The reactions to movements are reflexes originating in the semicircular canals, and which like the above-mentioned reflexes derived from the otoliths have reflex arcs, which do not pass through the cerebellum. On tonic labyrinthine reflexes in swimming (Rademaker) A dog that has undergone bilateral labyrinthectomy is unable to swim: if it jumps into the water, it will turn either to the left or to the right about its longitudinal axis, making rotary movements with its head, and will sink and drown if no help is available. A dog can swim after unilateral labyrinthectomy—clumsily at first, with irregular and poorly coordinated movements, though it soon learns to move normally; its bodily posture will

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be roughly the same as on land. Rademaker was able to explain these phenomena on the basis of his knowledge of the various reflexes influencing posture and balance. It seems surprising that after bilateral labyrinthectomy a dog can compensate reasonably well for the unevenness of the ground and irregularities in its gait so as to keep its balance even in the first few days after the operation, but is unable to swim. It should be remembered however that when such a dog is in water, the movements of the water constantly expose it to changes in position similar those those produced by sudden, unexpected changes in the angle of the support plane on dry land, leading to rotation of the head around the bitemporal or occipitofrontal axis and hence to disorientation. It will be unable to respond adequately to such abrupt changes even on dry land, and even less so in the water where it cannot make use of the non-labyrinthine righting reflexes that are available to it on dry land: according to Rademaker, these reflexes are evoked under the influence of the counter-pressure of the ground on the dog’s flanks and later the stimuli due to pressure on the paws; in the water, on the other hand, only the labyrinthine righting reflexes will be operative—but not, of course, after labyrinthectomy. A swimming dog keeps its head straight with the face above water in such a way that it can keep on breathing; even the slightest tendency to lateral or anteroposterior displacement allows water to enter the nostrils. Furthermore, the legs are no longer used for support, but to propel the dog through the water. Labyrinthectomy reduces the tone of the neck muscles; on dry land, this is compensated for by the righting reflexes and non-labyrinthine support but as we have seen these are not operative in water. Differences in the level of the body and the head caused by movements of the limbs can no longer be compensated for when the animal is in the water, either by the preliminary reflexes or by optical correction. It should be remembered that on land, the animal has a visual check on its position based on its visual estimate of the distance of its head from the ground; if this visual check on position is suppressed by blindfolding, animals can no longer walk normally but may be seen to roll over. When swimming, the animal also has no visual check on its position. Thus, according to Rademaker, a dog that has undergone bilateral labyrinthectomy has no effective righting mechanisms at its disposition in water, nor does it have an effective visuial check on its position. As a result, any slight displacement of the head will not be corrected but will tend to lead to continuous motion in the same direction. No matter whether the animal is thrown into the water or introduced gently in a symmetrical position, it will tend sooner or later to exhibit rolling movements (André-Thomas*). Similar rolling movements are observed after section of the root of the labyrinthine nerve at the moment when the animal falls into the water. Once rotational movement has been initiated in a particular direction, an animal that has lost its vestibular reactions is thus no longer able to correct it and will continue to roll until it drown or is helped out of the water. Comparable disturbances have been observed in other animals after labyrinthectomy; for example, frogs will perform unccordinated movements up to the point of exhaustion, after which they simply float. Apart from the general interest, which experimental studies must have, Magnus’s book “Körperstellung” (On Posture) contains information derived from clinical observations which shows that the main tonic and stato-kinetic reflexes described in animals may also be identified in man. Clinical applications of Magnus’s work were published as early as 1915; these publications also revealed new links between the physiology of

* André-Thomas and A. Durupt, “Localisations cérébelleuses”, Travail du professeur Déjérine, Paris Vigot Frères Ed. 1914, pp. 154–175.

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lower animal species as investigated by Von Uexküll* (also see endnote) and of man (as studied by Magnus’s own school).** This type of experiment was very attractive to clinical researchers in this period, and they turned to it for inspiration in increasing numbers after Magnus’s first publications appeared; the possibilities of analysing clinical pictures on the basis of pathological and anatomical findings had already been developed some time before this. A number of general principles underlying or governing the activities of the nervous system had already been laid down in Sherrington’s book, “The Integrative Action of the Nervous System”, which appeared in 1906*** (see figure). This book, which has become a classic—and which is a masterpiece of book design as well as of neurological research—will always remain an important milestone on the path towards understanding of the physiology of the nervous system. Magnus’ book, which dated from 1924 and whose contents are summarized above, may be regarded as a sequel to Sherrington’s. It was one of the first fruits of the application of the fundamental concepts introduced there to specific problems relating to the function of the brain, leading to a more profound understanding of the topics involved and—which is of importance for the experimental initiatives Rademaker was to develop once he had settled into the research environment at Magnus’s laboratory—it left room for new additions to this knowledge, the direction and scope of which could not have been envisaged in advance. The cerebellum and the labyrinths At this point, it worth mentioning another of Rademaker’s predecessors, a legendary physiologist whose work he often cited (though often in a critical sense). When the Italian physiologist Luciani (1840–1919) published his first work on cerebellar functions some thirty-five years before Rademaker’s thesis appeared (in 1891, to be precise), experimental physiologists and clinical neurologists were wrestling in vain to define the functions of the cerebellum and to analyse the results observed after experimental ablation of this organ. This was true in particular of the motor activities the cerebellum was supposed to govern. Rademaker and Holmes were the first to make it clear that many of the symptoms thought to be signs of loss of cerebellar function did not in fact originate in the cerebellum but were the result of associated labyrinthine lesions. It was moreover not until work by Magnus, and later by Rademaker and also by Holmes, provided sufficiently clear and well-documented insights into the motor functions of the brainstem and spinal cord that the way was cleared to study the problem of cerebellar physiology free of the old preconceptions. Despite all his valuable contributions, Luciani long remained in Rademaker’s eyes the researcher who had unnecessarily led neurophysiologists up the wrong path concerning the functions of the cerebellum. He

* Von Uexküll J. (1864–1944), “Die eersten Ursache des Rhythmus in der Tierreihe”, Ergebnisse d. Physiol. Bd. 3–(2), 1, 1904; Cited by Magnus R. in “Körperstellung”, Berlin Verlag van Julius Springer, 1924. (See also Book II at the end of Part 2.4). ** Summarized in: R. Magnus and A. de Kleyn, “Weitere Beobachtungen über Hals und Labyrinthreflexe auf die Gliedermuskeln der Menschen” [Further observations on neck and labyrinthine reflexes acting on the extremities in man], Pflüger’s Archiv. f.d.ges. Physiologie des Menschen und der Tiere, Bd. 160, 429–444, 1915. *** Sherrington C., “The integrative action of the nervous system”, London, Archibald Constable & Co Ltd., 1906, p. 411 (see picture Frontispiece).

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Fig. D. Frontispiece of “The integrative action of the nervous system” by Sir Charles Sherrington, as it appeared in London in 1906. First edition. This book became a neurological classic. It was published when Sherrington was Professor of Physiology at Liverpool University and was based on the Stillman lectures he gave at Yale. The concepts of ‘final common path’, ‘synaptic connections’, ‘central inhibition’, ‘central excitation’ and ‘reciprocal innervation’ introduced here are keystones of modern neurophysiology (Brazier, 1960). The work stands as the true foundation of modern neurophysiology; it is considered by Fulton (Yale) to rank in importance with Harvey’s De Motu Cordis while Walshe asserts that it holds a position in neurophysiology similar to Newton’s Principia in physics returned to this theme several times, both in the spoken word and in his writings*, especially with reference to the functional disturbances noted after ablation of the cerebellum** (see e.g. pp. 172 and 186 of the text referred to in the footnote).

* E.g. in the chapter on the cerebellum in the Nederlandsch Leerboek voor de Physiologie [Dutch Textbook of Physiology]; see Ref. 2 and 3 on pp. 187–188. ** Luciani was the first researcher who succeeded in keeping animals (dogs) whose cerebellum had been ablated alive for long periods of time. He also gave an accurate description of the phenomena observed in these animals. This investigation was repeated by many other workers (Munk, André Thomas, Lewandowsky, Dusser de Barenne etc.) without many new findings being added. Opinions were however divided as to the cause of the observed phenomena. According to Luciani, the effects seen in decerebrate animals were the expression of atony (reduced muscle tone), asthenia (general loss of strength) and astasia (inability to maintain constant muscle tone for an appreciable time, and hence inability to stand). Hence, he concluded that the main function of the cerebellum is to intensify and control muscle tone. He believed the astasia to be due to a loss of ability to fuse the elementary muscle contractions to a steady tetanus after ablation of the cerebellum. While the whole phenomenon of decerebrate rigidity discovered by Sherrington already argues against Luciani’s conclusions, Rademaker also showed convincing proofs of the incorrectness of Luciani’s views in experiments on ‘mid-brain animals” (see section on Standing reflexes and righting reflexes above). He

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Rademaker soon settled in as a member of Magnus’s research team. He took care to relate the results of his initial researches as far as possible to those of the other members of the team—especially when there was any overlap. He started by concentrating on the brainstem, the midbrain (mesencephalon) and the neuro-anatomical correlations and checks provided by the anatomist Winkler. He soon became good friends with the latter, and this friendship continued even after Rademaker moved to Leiden. Rademaker also kept an interested eye on the work done by Magnus and de Kleyn, who were actively engaged in study of variants of the tonic neck reflexes. The first investigation Rademaker carried out on his own in Magnus’s laboratory concerned the reflex mechanisms involved in standing, which he studied by bringing about lesions in—or near—the mesencephalon, analysing the changes this brought about in the reflex patterns when the experimental animals were standing, being supported or lying down, and finally performing microscopic anatomical examination of the material. In one of the first lectures he gave to the Royal Dutch Academy of Sciences in 1927, entitled “On the physiology of standing”, he had the following to say about this initial stage of his study of the significance of the cerebellum for standing: When an investigation of the functions of the cerebellum was started a few years ago, one of the first things to be done was of course to consult the existing literature. According to Luciani, animals in which the cerebellum has been ablated show astasia—despite the fact, which seems something of a contradiction in terms, that they can stand. Bechterew also claims that such animals show abnormalities in their ability to stand: “astasia due to a disturbance in static coordination”. The question was now, what was wrong with the ability of these decerebrate animals to stand? This question gave rise in its turn to two others: what is needed in order to be able to stand, and how does the normal act of standing come about? These questions seem to me to be of great importance for clinical practice too. In the days when I was clinically active, I had wondered why it is that when we wish to examine the tone of the leg muscles in a patient who is lying in bed, it is relatively easy to grasp the leg above the ankle and bend it passively, even if the leg muscles are hypertonic; while when a normal person is standing up you can push down on his shoulders as hard as you can without causing him to bend his knees. Another example pointing in the same direction is the fact that the legs of a standing stevedore can carry a load of two hundred kilograms in addition to the man’s own weight. This is not entirely a voluntary act, but something he does largely mechanically, without thinking about it much.

demonstrated that rigidity may often be seen right after the ablation of the cerebellum, indicating that there is certainly no loss of the ability to fuse contractions. Moreover, he went on, “when the [mid-brain] animals which have reached the steady-state disturbance stage are held up in the air by their hindquarters, they raise the front part of their body actively, without any signs of trembling. Animals without cerebellum have certainly not lost the ability to fuse [muscle contractions] to a steady tetanus. Such animals can walk for hours. They can carry a sandbag equal in weight to their own body on their back, can get up from a supine position with such a sandbag on their back and walk around with it. There is thus no evidence either for the marked asthenia (adynamia) [suggested by Luciani]. . . .” (Rademaker, 1944).

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Since so little could be learnt from the scientific journals, the latest textbooks of physiology (e.g. that of Starling) and of neurology were consulted—but next to nothing was found there. The neurology textbooks only had the standard pictures of abnormalities in standing and standing up associated with progressive muscular dystrophy . . . Endnote iii The bicycle began life, in the nineteenth century as a diversion for rich European, physicians, theologians, anti-feminists, and journalists condemned it as a hazardious fad. Man is a locomotion machine of Nature’s own making, not to be improved by the addition of any cranks or wheels of mortal invention wrote an opponent— and cyclists were sometimes set upon by mobs, by the century’s end, however, with a safe, efficient model available to the commuter and the Sunday pleasure seeker. The bicycle created thousands of jobs, spurred road construction, and transformed fashion, while dare devil, brandy-swilling racing cyclists (appeared) acquired heroic status. Heliby (David V. Herliby, “Bicycle”, Yale S35) portraits the men who pioneered this gravity-defyring wonder, they worked in near-obscurity, lit by the industrial Age’s spirit of invention, the capitalist impulse, and the utopian hope that the bicycle would ‘take men away from the gambling rooms and rumshops, out into God’s light and sunshine’. Endnote iv In a general introduction preceding the formulation of the problem of standing and the static reactions associated with it, Rademaker mentions the observations made by Duchenne de Boulogne (1806–1875) in 1867. He had been the first to point out that continuous action of the flexor and extensor muscles is necessary for maintenance of the various positions of standing. Sherrington showed later that muscular reflexes exerted an influence on standing. He observed the rigidity that was produced after section of the mesencephalon and that disappeared after section of the posterior spinal roots pertaining to the limbs. Rademaker further mentioned the researches carried out by Magendie, Longet, Schiff, Vulpian, Christiani, Munk and Goltz in this field. These neurophysiologists, renowned for their experimental work, demonstrated that decerebrate animals could stand, but this ability appeared to be of a reflex nature. Luciani, on the other hand, observed astasia in decerebellate animals. Edinger considered the cerebellum to be the organ of ‘statotonus’, while von Bechterew regarded it as the centre for static coordination. He further believed that this reflex activity of the muscles presupposes a particular static perception, which permits precise determination of the position of the body and head in relation to the vertical plane. This would allow the consequences of movement of the body’s centre of gravity to be corrected. In response to these interesting theories, Rademaker points out that the labyrinthine reactions and the postural reactions are still present after bilateral extirpation of the cerebellum. At the start of the book, Rademaker gives an exhaustive review of what is known about the effect of lesions of the spinal cord on postural reflexes, and about the way these reflexes are influenced by section of the posterior roots. Much of this information had more or less sunk into oblivion before he resurrected it. For example, Rademaker recalls an interesting case studied by Sherrington, which indicated that proprioceptive stimuli can arise in the muscles themselves. He goes on to discuss whether tendon reflexes are of spinal origin or are derived from centres in the midbrain. Rademaker further notes Bastian’s opinion that flaccid paraplegia with anaesthesia and lack of all reflexes must in all cases follow complete section of the spinal cord. However, reports contradicting this view gradually appeared in the literature. For example, Kausch published details of a case involving a patient with complete section of the spinal

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cord in whom a patellar reflex could clearly be elicited. There were also publications describing the work by Head, Riddock and Lhermitte who made a careful study of war casualties with total transversal section of the spinal cord where muscle tone and both spinal and cutaneous reflexes could be observed, and where the Achilles and periosteal reflexes returned after the acute phase together with homolateral flexion and crossed extension. Riddock and Lhermitte stressed the complete correspondence between the observations in man and the results of animal experiments. Endnote v It may be noted, by the way, that not everyone was happy with the use of ablation techniques in investigations of the function of the cerebellum. The eminent Dutch physiologist and anatomist Bolk expressed his doubts on this point in the following passage taken from his monograph on the physiological signifance of the cerebellum (similar comments were made a couple of decades later by the American neurophysiologist Henry Alsop Riley—see the discussion at the end of part 2.1). When one compares the morphological character of the experiments performed so far (i.e. up to 1903) with the given morphology of the mammalian cerebellum, it is as if someone tried to work out the structure and hence the operation of a very complicated clock with a seconds hand and a striking mechanism not by removing the different cogwheels in a systematic manner but rather by slicing off a part of one or other of these components. The effect is then always the same: the entire mechanism jams, or in physiological terms the coordination of the entire muscular system is disturbed. A rational approach would be first to remove the cogwheels actuating the striking mechanism, leaving the rest of the clock to function normally; then to remove the cogwheels actuating the seconds hand, and so on. This explains what I meant when I spoke previously of the need for the experimenter to have a rational basis for his comparative morphological investigation. However, there is also another reason for the discrepancies found between the results of the many experiments that have been performed. In the various experiments, one removed sometimes a larger part and sometimes a smaller part of the white matter. The function of the cerebellum is associated with—the various components of that function are localized in—the cortex of the cerebellum. As soon as one removes part of the cerebellum, penetrating more or less deeply into the interior of this organ—perhaps as far as the pedunculi, then any conclusion drawn from this experiment is completely worthless since one does not know precisely what morphological disturbance has been caused. After all, the white matter of one hemisphere contains in the first place the fibres from the homolateral cortex but also a not inconsiderable proportion of heterolateral fibres. If I remove one hemisphere, or even part of one, I compromise the function of the other hemisphere to an extent, which cannot be estimated. In my opinion, this is a general argument against the utility of excision experiments. He went on to suggest that the use of chemical substances that stimulated the contex might be a more effective research tool in this field.

BOOK III

PHYSIOLOGY LEIDEN AFTER EINTHOVEN In the meantime, Rademaker was nominated as successor of the Nobel laureate Einthoven (ECG) in Leiden, for the chair of Physiology. He remained in this position from 1928 to 1942. To borrow a term from a later successor of Rademaker as professor of physiology, professor Tammeling, who wrote on the history of that event in an understatement in dry Dutch “het was wel even wennen” (de komst van Rademaker)—operating rooms and recovery for animal experimental work, replaced instruments and large arrays for photographic and film documentation. His students liked the way he taught—especially the demonstrations, where he used the postoperative findings to elucidate the underlying neurophysiology. Rademaker expressed himself as an intellectual force to expand with roots laying in the Renaissance or even before. During lectures Rademaker, with his leptosome build, impeccable tailor-made suit, knife-edge creases in his trousers and highly polished shoes, was the very model of the English gentleman or ‘le gentilhomme’ in the sense, which gives the Larousse “homme qui fait preuve de delicatesse dans sa conduite”. He let no opportunity slip to express his admiration for Sherrington and similar eminent scientists, and to cite their works. Illustrations show him either working in the laboratory in a messy lab coat, or adjusting some piece of scientific apparatus in the same laboratory or an animal shed, dressed in a three-piece blue tailor-made suit. During his early years as professor of Physiology in Leiden, he completed his monograph ‘Das Stehen’ [Standing], which summarized the results of his extensive programme of experiments and parts of his clinical work (1931). The earlier work of Magnus and De Kleyn, mainly focussed on peripheral mechanisms and reflex patterns associated with posture, standing and walking, was now supplemented by Rademaker’s findings obtained during experiments focussed on central mechanisms. ‘Das Stehen’ was a monumental work, a neurological classic which was

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translated into English (the latter by Dr. Denny-Brown, as late as 1980!!). This summary of his original findings (including film documentation) was Rademaker’s neurophysiological manifesto. The monograph ‘Réactions labyrinthiques’, written in French, appeared in 1933. It contained the results of a logical sequence of studies of equilibrium reactions in experimental situations and clinical practice. Both aspects attracted a great deal of interest at the time. The tests making use of a tiltable table, which he developed in association with his friend Garcin, professor of Neurology in Paris, became generally known in French neurology. The text was full of new ideas, but never received much attention outside the French-speaking world because an English version was never published. As pointed out in the book itself ‘Réactions labyrinthiques’ was intended as a follow-up to his previous monograph ‘Das Stehen’. Neurology In the second half of the nineteenth century, clinical neurology took the first steps towards full independence as a separate discipline in many centres of university education. In Central Europe and Germany, neurology grew out of psychiatry and not out of internal medicine as it did e.g. in the United Kingdom. The idea that mental illness was to be regarded as disease of the brain prevailed in the Netherlands as it did in the above-mentioned countries. This helps to explain why the first professor of Neurology in the Netherlands, Winkler (1855–1941), was also professor of Psychiatry in Amsterdam. This was an interesting period for many reasons, not least because it was characterised by three successive combined approaches to the discipline of neurology, which may have overlapped to a certain extent. This is borne out by data from archives, which have recently been opened for inspection. These three approaches are: 1. the psychiatry/neurology/neuropsychology complex (in which the leading figures were Prof. Jelgersma, Carp and Dr. Gans); 2. the (neuro)physiology/neurology complex (favoured by Prof. Rademaker); 3. the neurology/comparative neuropathology complex (under Prof. Verhaart).

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Figs. 3-1 a & b. Aerial photos of the University Hospital, Rijnsburgerweg 10, (now LUMC, Albinusdreef 2), Leiden, in course of construction in 1928 and as seen from the east in 1934. Courtesy: KLM Aerocarto, Arnhem. Building work started before the First World War. The pavilion structure of the hospital is clearly visible. The poor state of the Dutch economy at that time delayed the construction of the complex, which has been erroneously stated to be in the ‘cité médicale’ architectural style (as found e.g. in Bordeaux). Rademaker participated in the deliberations of the Board of the medical faculty after he had been appointed professor of Physiology. Decision-making about the allotment of the different departments, clinics and laboratories to the various buildings initially proceeded very slowly, since the approach taken was new to the professors, who were, after all, specialists in various clinical fields and not in architecture. A core group of professors and other key medical staff led by Rademaker, including Gorter, Borge, Van der Hoeven and later supplemented by Mulder and Querido, made a plea for a model involving much stronger research content in every department (which would then have to recruit appreciably more scientific staff ). This idea of a hospital as a ‘workshop’ for scientific research combined with advanced patient care thus replaced the concept of a municipal and university hospital serving the inhabitants of Leiden and providing teaching facilities for the students of the university in the minds of the group. The minutes of the medical faculty meetings during these years, kept by Rademaker (he later chaired these meetings), confirm the length of the discussions. Rademaker made his mark on the new approach by planning the construction of a physiological and pharmacological laboratory right in the middle of the complex. He also suggested that there should be an experimental physiological laboratory. It took a long time for the ‘musical chairs’ (as Mulder called it) to come to an end. In particular, the year-long debate as to whether the department of psychiatry to be built should be intramural or extramural was finally resolved in Mulder’s reign in favour of an intramural department. These aerial photos give a good impression of the complexity of the ideas underlying the planning of the hospital, which were frequently modified in the course of construction. It was not until after the Second World War in 1945 that Rademaker (who had in the meantime been appointed as profeesor of Neurology) was able to perform the official opening of ‘his’ Neurological Institute containing the department of Clinical Neurology, for which he had been able to obtain undertakings from the Senate of the university (and from the government) that sufficient funds would be available for the facilities required e.g. for electroencephalographic (EEG) investigations (a first for the Netherlands at that time), electromyography (EMG) and a laboratory for liquor analysis with immunoelectrophoresis. The vision of the future of the university hospital propagated by the core group of medical staff under the leadership of Rademaker had become reality, as Mulder stated in the eulogy he delivered after Rademaker’s death.

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These combinations seem to have been tried out at the time in an attempt to deal with the rising tide of subspecialisms that were then flooding the medical field. They have all proved more or less viable some developing more strongly in one part of the world than in another. In Leiden, the professor of Psychiatry (G. Jelgersma, 1859–1942) also lectured on neurology when the occasion arose. This was the situation, which Rademaker encountered when he was appointed professor (initially of Physiology) at Leiden. He was made professor of Neurology later, and became involved in the separation of psychiatry and neurology and their development to two separate disciplines. During this development process, he gave expression to his own view that the stress should rather be laid on the relationship between neurophysiology and neurology. Research and other activities stopped entirely in Leiden during the years of the Second World War (1940–1945), after the university was shut down in protest at the sacking of the Jewish professors at the university imposed by the occupying forces. Rademaker adopted an active resistance stance, and partook in underground activities during these years. These activities included the setting up of a resistance cell (with its own printing press, cache of weapons and sick-bay) in his laboratory and the adjoining basement. 3.1. Blink Reflex The blink reflex in response to threat and other threat-induced reflexes Rademaker extended the original Cartesian concept of the reflex, basing himself on Pavlov’s reflex theory, which had in its turn been stimulated by the work of Sechenov. One example of this extension was the experimental work he and his co-workers did on “the blinking of the eyes in response to a threat”, which we shall be discussing in detail below. First of all, there were animal experiments performed under laboratory conditions by Rademaker’s pupil Gelderblom1 and later by Rademaker and Gelderblom, and finally clinical work on neurological

1 Gelderblom J.J., “Het centrale mechanisme van den oogknipreflex op dreigbewegingen bij de kat”, Ned. Tijdschr. v. Gen. 74, 2174–2175, 1930.

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Fig. 3-2. A dinner of the medical debating society “Boerhaave”, with Rademaker seated second from the right. Courtesy: Mrs. Kato Pomer-van Leeuwen, USA.

patients in cooperation with Garcin. All this work was marked by the simplicity, which was so characteristic of this research approach. It is worthwhile pausing for a moment at this point to underline the clinical significance of the blink reflex in response to threat. Generally speaking, a distinction may be made between two main types of conditioned reflexes: I individual-specific conditioned reflexes, which occur in a particular animal or human subject, and which are dependent on the particular conditions under which that individual lives; II species-specific conditioned reflexes, which occur in all animals of a particular species and are dependent on the conditions under which all animals of this species live. The blink reflex in response to threat and the withdrawal of the extremities in response to a tactile stimulus are examples of the second type. When a conditioned reflex occurs in all members of a species, even very young ones, it can sometimes be difficult to determine whether one is dealing with a conditioned or unconditional reflex. Nevertheless,

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it is the second type of conditioned reflexes defined above which lends itself particularly to the purposes of neurological diagnosis, because it is present in all normal humans. The only conditioned reflex which has achieved significance for neurological diagnosis in human adults is the blink reflex in response to threats. There is plenty of evidence that Rademaker had been interested in threat-induced reflexes for a long time. The general interest in the physiological world at the start of this century in the model of the cerebrum-less dog developed by Goltz in Strasbourg may be mentioned in this context.2 In the above-mentioned inaugural lecture delivered by Rademaker in 1928 when he accepted the chair of Physiology at Leiden as successor to the Nobel Prize winner Einthoven, he gave a lively summary of the motor and other (e.g. visual) faculties still present in such an experimental animal. He said e.g. in this connection (p. 13): When a rapid movement of the hand is made before the eyes, a normal animal blinks while an animal without cerebrum does not. Even though this reaction is mediated by the cerebral cortex and shows various features, which are characteristic of cortical reactions, no one would suggest that it is a voluntary reaction. After all, everyone knows that when a hand suddenly makes a movement just in front of his eyes, he will blink involuntarily and often indeed unconsciously.

In connection with his rejection in the same lecture of the division of reflexes into voluntary and involuntary in favour of the conditioned/ unconditional classification proposed by Pavlov (see above), Rademaker continues with a description of the blink reflex in response to threat (p. 18): If someone suddenly moves a hand towards your eye, you will blink. If however this gesture is repeated several times without touching your eye you will no longer respond in the same way. The blinking will however recur if the same gesture is made the next day or if the eye is touched during one of these gestures, i.e. if the conditional stimulus is replaced by the unconditional one . . .

2 Goltz F., “Der Hund ohne Grosshirn”, Pflüger’s Archiv. f.d. ges. Physiologie d. Menschen u. der Tiere 5, 570–614, 1892.

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He later gave a detailed description of the anatomical and physiological aspects of these reflexes in an article in Brain.3 The blinking reflex (sic) excited by touching the cornea or the eyelids, and the blinking reflex, elicited by a bright light are subcortical reactions, whereas the blinking reflex brought about by a menacing movement is a cerebral reaction. The former two still occur, the last is abolished after the removal of both cerebral hemispheres. After the extirpation of the right cerebral hemisphere only the blinking reflex brought about by the sudden approach of an object in the left half of the visual field is abolished. It is however, not necessary to remove the whole hemisphere for the reflex is abolished, • by the removal of the right striate area and • by free extirpation of the eyelid region of the right motor cortex. The eyelid region is that part of the motor cortex which brings about the closing of the eye lids of both eyes when it is electrically stimulated.4 This region with surrounding cortex, that is to say the whole sulcus coronarius, must be removed. • After the transection of the cortex of the parietal lobe between the striate area and the motor cortex. The unilateral disappearance of the reflex after removal of the right striate area can be due to the ensuing left-sided hemianopia, while the absence after destruction of the eyelid region of the motor cortex can be explained by a partial supranuclear facial palsy. The third lesion, the transection of the cortex of the parietal lobe, entails no visual disturbances nor partial facial palsy, but still produces loss of the blinking reflex. It appeared experimentally important that in order to bring about the disappearance of the reflex, it is not even necessary to remove the whole striate area, the removal of only the caudal part has the same effect,

3 Rademaker G.G.J. and Ter Braak J.W.G., “On the central mechanism of some optic reactions”, Brain 71, 48–76, 1948. 4 Rademaker G.G.J., Gelderblom J.J., “Der zentrale Mechanismus der Blinzelreflexes auf Drohbewegungen”, Proc. Section Sciences, Kon. Ac. v. Wetensch. 33, 1210–1216, 1930 (communicated by prof. B. Brouwer, at the meeting of December 20, 1930); Rademaker G.G.J., Gelderblom J.J., “Het centrale mechanisme van den oogknipreflex op dreigbewegingen bij katten”, Verslag Kon. Ac. v. Wetenschappen van de gewone vergadering afdeeling Natuurkunde 39, 172, 1930.

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Fig. 3-3. Schematic representation of the reflex arcs for the blink reflex in response to menacing movements, after Rademaker and Garcin (1933). F, cortical centre of the facial nerve for the orbicular muscles; hatched lines, optical pathways; black line, occipito-rolandic segment of the reflex arcs (OF); broken line, central arc and peripheral neurone of the facial nerve; VII, bulbo-protuberential nucleus of the facial nerve.

whereas the reflex still occurs when the whole rostral and medial part of the striate area has been removed and only the small lateral caudal part is spared.5 Rademaker concluded on the basis of these observations that the reflex arc of the blink reflex elicited by a sudden menacing movement in the left visual field was as follows: right half of the left retina | right optic tract | lateral / caudal part of the right striate area | eyelid region of the right motor cortex | nuclei of the 7th nerves | muscles of the eyelids of both eyes (see figure). While working with Garcin, Rademaker initially examined four patients with asymmetrical blink reflexes.6 In all four cases the blink reflex could be elicited by a menacing movement in one-half of the visual

5 Rademaker G.G.J. and Ter Braak J.W.G., “On the central mechanism of some optic reactions”, Brain 71, 48–76, 1948. 6 Rademaker G.G.J. et Garcin R., “Le réflexe du clignement à la menace. Sa valeur diagnostique dans les lésions corticales et occipito-rolandiques dans des hémisphères cérébraux”, C.R. Société Biologie Paris t. III, 547–550, 1932; Ibid, Rev. Neur. t. I, 186; 384–391, 1933; Rademaker G.G.J. et Garcin R., “Le reflexe du clignement à la menace: étude physiologique et clinique. La valeur sémciologique de son abolition dans les lésions corticales rolandiques et occipito-rolandiques des hémisphères en l’absence de toute hémianopsie”, L’Encephale 29, 1–17, 1934.

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field, but not by the same movement in the other half; there was no hemianopia and no other disturbances of vision, nor the slightest sign of facial palsy. The blink reflexes elicited by touching the cornea, the conjunctiva, the eyelids or the lashes, and the blink reflex excited by bright light, or noise7 occurred on both sides. It is evident from these results that in human subjects the blink reflex elicited by the sudden movement of an object towards the eye can also be abolished without the simultaneous occurrence of hemianopia and without simultaneous partial facial palsy. As verified by operation, one of the above-mentioned patients had a tuberculoma, another had a meningioma and the two remaining ones had cystic gliomata, all located in the parietal lobe behind the Rolandic fissure, i.e. between the striate area and the eyelid region of the motor cortex. The striking accordance between these observations in man and those in animals is evident.8 Borowski (1929)9 studied the blink reflex in 114 cases of hemiplegia. In 43 cases the blink reflex brought about by a menacing movement on the hemiplegic side was abolished; there was no hemianopia and the corneal and conjunctival reflexes occurred on both sides. In the other 71 cases the blink reflexes were all unimpaired. It seems, therefore, that in these cases the eyelid region of the motor cortex and the pathway from this region to the nuclei of the 7th nerves were undamaged. Rademaker had shown through this investigation that the reflex arc has a mainly intracortical course. The animal experiments he carried out in the cat together with Gelderblom revealed that the blink reaction in response to a menacing movement in the contralateral temporal field could no longer be elicited after removal of the part of the motor cortex, which causes blinking after electrical stimulation.10 Anatomical

Galant S., “Reflexus cochleopalpebralis und Ohr-Lidschlagreflex”, Archiv. f.d.ges. Physiologie des Menschen u.d. Tiere 176, 221–222, 1919. 8 This condition was known as ‘the Rademaker-Garcin sign’, and in the French clinical literature as ‘le signe du réflexe du clignement à la menace de RademakerGarcin’ (or sometimes Garcin-Rademaker!). 9 Borowski M.L., “Der Blinzelabwehrreflex. Sein biologisches Wesen und seine Verhinderungen als neues Symptom bei Hemiplegie”, Dtsch. Z. Nervenheilk. 110, 134–150, 1929. 10 Rademaker G.G.J., Gelderblom J.J., “Der zentrale Mechanismus der Blinzelreflexes auf Drohbewegungen”, Proc. Section Sciences, Kon. Ac. v. Wetensch. 33, 1210–1216, 1930 (communicated by prof. B. Brouwer, at the meeting of December 20, 1930); Rademaker G.G.J., Gelderblom J.J., “Het centrale mechanisme van den oogknipreflex 7

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and physiological examination of these cats revealed no evidence of the existence of hemianopia. Rademaker assumed on the basis of these findings that the reflex arc for the blink reaction in response to threat had a transcortical course, from the optical cortex to a region of the motor cortex. In man, this transcortical arc would be expected to pass through the parietal lobe (see figure). Rademaker was later able to confirm this in human material, while working with Garcin in 1932 and 1933.11 The blink reflex in response to threat could not be elicited by a stimulus in the contralateral temporal field in five patients with a process in the parietal region without hemianopia, or in five patients with a process in the central convolutions. This experimental study by Rademaker and co-workers was the first investigation of a simple cortical reaction in which it was shown that it was important within the context of the study to distinguish between: I the afferent arc with the associated projection area (the analyser, as Pavlov called it); II the transcortical arc joining the analyser to III a motor region of the cortex. The precise path followed by the stimuli from the motor region was not known. The noteworthy aspect of this condition for clinicians is that the reflex is still often found in cases of hemiplegia and central facial paresis. Discussion It had long been known that this reflex required the integrity of the optical cortex. If the left optical cortex was destroyed, it was imposop dreigbewegingen bij katten”, Verslag Kon. Ac. v. Wetenschappen van de gewone vergadering afdeeling Natuurkunde 39, 172, 1930 11 Rademaker G.G.J. et Garcin R., “Le réflexe du clignement à la menace. Sa valeur diagnostique dans les lésions corticales et occipito-rolandiques dans des hémisphères cérébraux”, C.R. Société Biologie Paris t. III, 547–550, 1932. Ibid, Rev. Neur. t. I, 186; 384–391, 1933; Rademaker G.G.J. et Garcin R., “Le réflexe du clignement à la menace: étude physiologique et clinique. La valeur sémciologique de son abolition dans les lésions corticales rolandiques et occipito-rolandiques des hémisphères en l’absence de toute hémianopsie”, L’Encephale 29, 1–17, 1934.

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sible to elicit this response by a menacing movement in the right half of the field of vision, and vice versa. This reaction thus had the features of a conditioned reflex. It was initially assumed that the absence of this reaction indicated the existence of hemianopia: the possibility that the reaction could be eliminated by anything other than a complaint in the afferent part of the reflex arc was neglected. Guillain et al. later pointed out that peduncular and ponto-bulbar complaints could sometimes also lead to loss of the ability to elicit this reflex.12 They suggested that this condition might be due to a lesion of the efferent part of the reflex arc. The cortical localization continued to intrigue researchers. Rademaker’s co-worker Ter Braak (1938)13 tried to determine whether it was possible to demonstrate a localization of cortical reactions within the projection fields; his investigations made a real contribution to this field of study. Ter Braak used excision of certain afferent projection areas, the transcortical arc and the motor region of the cortex in his attempts to test the possibility of demonstrating a localization of certain reactions in the optical cortex. He carried out his experiments in dogs. When he had removed just enough of the cortex to prevent the occurrence of any cortical optical reflex in response to the appropriate stimuli, he assumed that the entire optical cortex had been extirpated. The limits of this region corresponded to those of the ‘visual cortex’ defined by Campbell.14 (See figures) Ter Braak now went on to investigate which parts of this optical cortex were of importance for the occurrence of the following two optical cortex reactions: I the blink reflex in response to menacing gestures; II the reflex retraction of the forepaws in response to optical stimuli.

Guillain G., Mathieu P., Bertrand I., “Étude anatomo-clinique sur deux cas d’atrophie olivo-ponto-cérébelleuse avec rigidité”, Ann. de Méd. 20, 417–459, 1926; Guillain G., Garcin R. et Bertrand I., “Sur un syndrome cérébraux précédé d’un état hypertonique de type parkinsonien, sclérose corticale diffuse du cervelet, intégrité des noyaux gris centraux, l’hypertonie d’origine cérébelleux”, Rev. Neur. i., 565–575, 1932. 13 J.W.G. ter Braak, “Enkele corticale optische reacties bij honden in verband met de localisatie in de area striata”, Ned. Tijdschr. v. Gen. 82, 3818–3822, 1938. 14 Campbell, “Histological Studies on the localisation of cerebral function”, Cambridge, 1905. 12

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Fig. 3-4. Forebrain of the dog, after Campbell (1908).

Fig. 3-5. Reflex arc of the blink reflex elicited by a menacing movement in the left half of the field of vision, after Campbell (1908).

The results of his study were remarkable, and may be summarized as follows: If a small frontal part of the area striata remains intact, optical retraction reflexes can still be elicited: the animal jumps over, or avoids, low obstacles, though it does sometimes bump into obstacles at head height. The blink reflex, however, cannot be elicited from any part of the visual field. If only a small lateral caudal part is left intact, the blink reflex in response to menacing movements can still be elicited, but the optical retraction reflex cannot. This is not due to any lesion of a motor centre, since the tactile retraction reflex is preserved.

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Ter Braak concluded from these observations that the principle governing the localization of the reactions in question in the optical cortex differed from that to be expected on the basis of current sensory localization theory. Sensory localization is based on psychological data. Ter Braak determined which part of the cortex corresponds to a given part of the visual field, mainly on the basis of observations on patients with occipital lesions. These observations confirmed that certain parts of the visual field do indeed correspond to certain areas of the cortex. Anatomical data, obtained later, about the distribution of the afferent fibres to the optical cortex supported this supposition. New sensory localization theory predicts that when a certain part of the cortex is removed, no stimuli from the corresponding part of the visual field can be processed by the cortex, so it should be impossible to elicit cortical reactions from that region. The results of Ter Braak’s investigations contradicted this supposition. Optical retraction reflexes are produced by optical stimuli from the lower part of the visual field. If one attempts to explain the retention of this reflex in the animals which had undergone an operation leaving only a frontal residue of the optical cortex by assuming that the signals from the lower part of the visual field are represented here, it is impossible to understand why the blink reflex in response to menacing movements cannot be elicited from this part of the visual field. Dogs with a lateral caudal residue of the optical cortex no longer showed the optical retraction reflex. They did however show the blink reflex in response to menacing movements from all parts of the visual field—including the lower part. In other words, some stimuli from the lower part of the visual field do lead to a reaction while others do not. Ter Braak came to the conclusion that a sensumotor localization in the optical cortex was the most likely explanation of his findings. This work gave rise to an interesting discussion.15 One key question in this context is whether sensory localization is compatible with the sensumotor localization found by Ter Braak. It has

15 Verbiest H., “De iinvloed van het achterstrengsysteem op de tonische corticospinale innervatie der extremiteiten. Het buigingsverschijnsel der vingers”, Thesis, Leiden, 1939, see pages 141–142 from this book.

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been suggested that the afferent fibres carrying the pulses, which lead to perception, might be distributed according to the sensory principle. These could then also carry pulses for those cortical reactions in which perception does not play an important role. Another possible explanation was based on the following considerations: our visual field is ‘constructed’ making use of data not only from optical stimuli but also from other senses. The existence of an ‘up’ and a ‘down’, a ‘left’ and a ‘right’ in the visual field are examples of this. Now when e.g. sickness leads to disturbances of visual perception, which are inconsistent with the judgements we have built up concerning our visual field, suppression mechanisms are called into action to resolve this inconsistency. When double vision is present, the signals from the eyes are quickly suppressed. A patient with cortical hemianopia hardly notices it at all. It is not inconceivable that the fibres, which cannot be distributed according to the sensory localization principle, also carry pulses that can lead to visual percepts, but that these percepts fit so poorly in the visual field that they are suppressed. The conditional nature of these cortical reactions is a disadvantage for neurological investigations. They disappear after having been elicited for some time. Rademaker showed the importance of the blink reflex for neurological examination. He also pointed out that the presence or absence of the optical retraction reflex of the arms is of diagnostic importance—but only in babies. There are practical considerations, which make this reaction more difficult to investigate in adults. Little or nothing is known about other simple acoustic, olfactory or tactile conditioned reflexes of this kind, which are present in all normal humans. Rademaker pointed out that it would be very important from the viewpoint of clinical neurology to possess knowledge of a few more of these cortical reactions and to be able to add them to the diagnostic arsenal: this would enable the neurologist to dispense with sensitivity studies, which have the disadvantage—especially when one wishes to investigate the mechanisms underlying the ability to maintain an upright posture, and passive movements—of requiring above-average intelligence and good practice in performing the test from the patients being tested. Sensitivity studies are moreover time-consuming, and tiring both for the patient and for the investigator. It is not always possible to exclude other than organic functional disturbances as the cause of

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a significant (abnormal) test result, since sensitivity disorders are often due to psychogenic causes. The transcortical arc involved in tactile conditioned reflexes is however very short—no longer in any case than the distance from the gyrus centralis posterior to the gyrus centralis anterior—so that it should in theory be much easier to localize a complaint giving rise to interruption of this reflex arc than e.g. one giving rise to interruption of the reflex arcs for the blink reflex in response to menacing movements. This cortical-subcortical reflex discovered by Rademaker and co-workers must thus be regarded as a new entity alongside the ‘Eigenreflex’, which measures the excitability of the stretchreceptors in the muscle (muscle spindles) or the motor neurones. The H-reflex, initially described by Hoffmann in 192216 is a monosynaptic reflex involving both sensory and motor fibers of the peripheral nerves (Troni, 1981).17 Rademaker’s work together with Garcin on the blink reflex was a mixture of ‘pure’ research and applications to medical treatment. The method known as the Rademaker-Garcin reflex was widely used in the clinic to locate cortical lesions e.g. those due to tumours or injury,18 and proprioceptive reflexes via the skin of the sole of the foot or the abdomen, or as the cremaster reflex.19 According to the data available at the time, these last cortical reflexes involved would need an estimated 6 to 7 synapses, and would thus be expected to have a long latency time, as compared to the blink reflex.

Hoffmann P., “Eigenreflexe”, Berlin J. Springer Verlag, 1922. Troni N., “Analysis of conduction velocity in the H-pathway, part I. Methodology and results in normal subjects”. J. Neurol.Sci. 51, 223–233, 1981. 18 L.A.H. Hogenhuis, “Het teken van Rademaker-Garcin”, in: “Het neurologisch onderzoek in eponymen”, P.J. Koehler, G.W. Bruyn and N.J.M. Arts (eds.), pp. 78–84, 1995, Arts & Boere, Nijmegen, 1995 (in dutch). 19 Paillard J., “Reflexe et régulation d’origine propioceptive chez l’homme”, Paris, 1955, Libraire Arnette. 16 17

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Rademaker and Garcin met for the first time in 1928, during a working visit of French physiologists and neuropsychiatrists to Amsterdam on the occasion of the opening of Prof. Brouwer’s new neurology clinic at the university of Amsterdam.20 The French professor of Neurophysiology Henri Baruk (1897–1999), who had been working in Amsterdam for several months on a Rockefeller Foundation grant, had the following to say about the reasons for his visit: “Les etudes neurologiques, qui n’ont jamais cessé d’être en honneur en Hollande, ont depuis quelques années dans ce pays un developpement de plus en plus grand”. He himself a known specialist on experimental katatonia, worked in Amsterdam on this subject with the biochemist-pathologist H. de Jong He acted now as guide to the French delegation. The following quotation is taken from his account of this visit, published in Revue Neurologie.21 “C’est à Leyde puis à Amsterdam que nous avons eu personellement l’heureuse fortune de rencontrer le professeur Rademaker lors de nôtre séjour d’étude en Hollande en 1928 dans la laboratoire de physiologie du professeur Brouwer. Nous avons vu de nos propres yeux la fondation par pr. Brouwer de son service de neurochirurgie pour lequel il avait appel à Rademaker (en lui offrant une formation aux Etats-Unis chez un des pionniers de la Neurochirurgie, le professeur Harvey Cushing à Boston; Rademaker declina cette offre.) Nous n’oublierons jamais la magistrale demonstration qui nous fut donnée par Rademaker sur la preparation d’un chat décerebré dans la laboratoire de Brouwer. Son habilité était véritablement prestigieuse, grand majesteuse autant que simple et modeste, Rademaker donnait une impression de force, et d’aisance que rien ne peuvait rebutter.” (It was at Leiden and then in Amsterdam that we had the pleasure and the honour of meeting Prof. Rademaker during a working visit to Holland in 1928, in particular to the Physiology laboratory of Prof. Brouwer. We were present when Prof. Brouwer opened his neurosurgery unit, for which he had called in the assistance of Rademaker (offering him the opportunity of training in the Unites States under one of the pioneers of neurosurgery, Professor Harvey Cushing of Boston;

20 H. Baruk, “Chroniques, Variétés informations. La Nouvelle Clinique Neurologique de l’Université d’Amsterdam”, Presse Médicale, nr. 92, 1505, 1929. 21 H. Baruk, Necrologie Revue Neurologique, 134–135, 1957.

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Rademaker declined this offer). We will never forget the masterly demonstration Rademaker gave of the preparation of a decerebrated cat in Brouwer’s laboratory. His skill was truly remarkable, his bearing at the same time majestic yet simple and modest. Rademaker gave an impression of power combined with unconquerable ease.) Rademaker had made a similar impression on the English neurologist Francis Walshe when the latter visited Magnus’s laboratory in Utrecht with a group of British scientists (see Book VI, part 6.1). Rademaker’s demonstration, for which he provided the commentary in French himself, was a sort of epiphany for Garcin. He was literally dumbstruck. (Other members of the French delegation commented that he was struck by a ‘coup de foudre’.) He immediately made an appointment to visit Rademaker in his laboratory in Leiden, forgot completely about the rest of the working visit and went off to Leiden, where he stayed with Rademaker for a few days. Rademaker, who was almost equally impressed by the encyclopaedic knowledge of clinical neurology and paediatrics of the more experienced Garcin, agreed to pay a return visit to the latter at La Salpetrière in Paris. Garcin had just started his own experimental physiological work in a new biomedical laboratory with support from Guillain, the head of the department of Clinical Neurology. Garcin had married Guillain’s daughter, which helped to assure his future as a (not very well paid) clinician with a very strong bent for physiological research. Rademaker, on the basis of his recent experience, was tending to make the reverse transition, from a pure experimentalist to a greater interest in clinical matters. Of course, during his time in the Dutch East Indies Rademaker had been a working physician and general surgeon, but he had left that behind on his return to Holland. When he started working at Magnus’s laboratory in Utrecht, he had concentrated on decerebration in experimental animals using the Sherrington-Magnus model; later, he had gone on to experiment on muscle tone, bodily posture and labyrinthine reflexes. While the clinical significance of these findings may always have been in the back of his mind, he had had little opportunity to test them on real patients. And so it came about that Rademaker travelled to Paris during his summer holidays, six years in a row, to confront the experimental data he had summarized in his monograph Das Stehen with pathology selected by Garcin from the French clinics to which he had access, covering a wide range of conditions and all the different stages of the diseases—though the chronic stages were particularly well represented.

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Garcin remembered these periods of working with Rademaker with particular pleasure, ‘as if he had been playing truant.’ They resulted in several original papers (Rondot, 2000).22 In fact, Rademaker and Garcin produced 8 joint papers and one chapter in Rademaker’s final monograph, ‘Reactions labyrinthiques et équilibre’. There was a joke going the rounds among French neurologists at the time that there were three great French neurologists, Rademaker, Garcin and Rademaker-Garcin. Garcin transmitted most of his knowledge orally, by teaching, and left relatively few publications. Moreover, most of what he did publish was in French, which limited the dissemination of his ideas (Rondot, loc. cit.). Nevertheless, Rademaker and Garcin’s joint investigations on a large number of patients at La Salpêtrière and other Parisian hospitals did not go unremarked in scientific and other circles. They also took the opportunity during Rademaker’s stays in Paris to carry out examinations in rehabilitation centres, nursing homes and old people’s homes in Paris, and would work out their observations in Garcin’s office during the evenings. Rademaker and Blanche were welcome dinner guests at Garcin’s home. The duo Rademaker-Garcin enjoyed careering round Paris during the daytime in Garcin’s tiny 2CV Citroën, on their way from one clinic to another or visiting museums (which were almost empty at that time, when the population of Paris emigrated en masse to the French countryside during the summer holidays). Garcin was a fairly good aquaralist himself. They would regale Garcin’s children with tales of their adventures at the family dinner table. [Personal communication Jean Loup Garcin, 2001] What Garcin recalled years later from these rounds with his friend in the summers along Parisian museums was on the occasion of a visit (on invitation together with his staff, to the ‘L’Institut Néerlandais’ which harbours the famous Frans Lugt collection of Dutch seventeenth century paintings, the particular attention both had paid on these occasions to the aspects of in these paintings of movement and posture such as while skating on ice by adults and children (with and without help of a chair from the start, for support,23 for balance, avoiding falling), or dancing, alone or in groups, and Rademaker’s comments thereby.

Rondot, P. Raymond Garcin (1897–1971). J. Neurol. 247, 315–6, 2000. The earliest known proof as to my knowledge of Sherrington’s concept of propriocepsis infancy (see Book II—part 2.7.). For Garcin Paul Claudel’s word “connaitre c’est naître avec”. 22 23

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What Netherlandisch art historians, dealers and curators, surfacing in conferences or in seminars chatter as an unclassifiable, and what one can find in manuals call ‘houding’—the interlocking juxtaposition of cool and warm, light and warm, light and dark passages of paint to create illusion of three dimensional modelling in space—are universally calibrated.

Cited from a note in an Anglo-Saxon ‘art journal’ which appeared later, made by an (unknown) art critic which is in line with and indicates the difficulty in describing abouve mentioned aspects of posture and tonus. Rademaker had, in my mind-memory, once called tonus and posture concisely “a matter of frozen energy which seemed appropriate to me now more then ever. Through all this wide-ranging knowledge and experience, all these clinical exercises and investigations, Rademaker (still professor of Physiology at Leiden—see illustration of his laboratory there) seems to have been preparing himself consciously or unconsciously for the position of professor of Neurology, to which he would be elected unanimously by the medical faculty at Leiden after the war. Till then, his main formal excursions into the field of neurology had been when he (and Ter Braak) filled in for Dr. Gans, the reader in Neurology at Leiden, during the latter’s prolonged periods of sick leave. In retrospect, these Parisian summers revealed an astonishing synergy between Rademaker, the highly skilled experimental neurophysiologist, and Garcin, the walking encyclopaedia who had ‘gained his stripes’ as a clinical neurologist by years of experience. French clinicians (and later clinicians from other countries) honoured them in their way by ‘the 3 eponyms’ associating their names with three different clinical effects and nominated Rademaker for the Legion d’honneur he was to receive from the French government. After their Parisian odyssey, the words of Euripides (pottery fragment 910) are surely applicable to the pair: “happy is the man whose knowledge comes from practice . . . his own experience” and one might add, “. . . from friendship.” Even more apposite, perhaps, are the words to be found at the beginning of the Analects of Confucius (which they would doubtless not have known): “To learn and regularly practice—is that not a joy? To have friends come from afar [to study with you]—is that not delightful?” 3.2.1. The Results: The Three Eponyms The core of the work Rademaker and Garcin carried out in the period between 1929 and 1935 can be encapsulated in the two effects and the

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Fig. 3-6. Prof. Raymond Garcin with his staff and visiting assistants (assistants étrangers).

clinical tests named after them in the French and Dutch neurological literature: the Rademaker-Garcin blink reflex, the Rademaker-Garcin ‘step sign’ and the Rademaker-Garcin static adaptation test. The results of the studies from which these eponyms were derived have not been published in the Anglo-Saxon literature. They were however reported in the French-language scientific literature24 and by means of presentations to the Société de Neurologie in Paris and neurology associations in Leiden and Amsterdam. The investigations of the blink reflex and their results are also discussed above (see Book III, part 3.1), while details of the static adaptation test and the tilting table (initially devised by Rademaker for his experiments on decerebrated dogs) on which this test was performed are given in Book III, part 3.3.

24 The main peer-reviewed journals in which these publications appeared were Revue Neurologie, Comptes Rendus de la Société de Biologie, and l’Encéphale, 1932:2, 1933:3, 1934:1 and 1935:1. An account may also be found in Chapter 5 of the monograph ‘Réactions labyrinthiques et équilibre’.

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The work Rademaker and Garcin did on the static adaptation test using the tilting table drew their attention to the importance of the support reactions (known as Stützreaktionen in the German literature) that are elicited by counter-pressure via the soles of the feet on the legs while the subject is standing upright. Rademaker and Garcin had often referred in their teaching to the value of such support reactions in infant development (‘step sign’): during their clinical investigations in Paris, they found that exaggeration of these support reactions was also (at least in part) responsible for a group of gait disorders in adult patients loosely categorized under the names of astasia and abasia and at that time thought to be related to cerebellar lesions (Luciani). They showed that patients with lacunar strokes or bulbar signs of arteriosclerotic origin with a high incidence of macroscopic or microscopic lesions could show a gait disorder characterized by hypertonicity and walking with small steps, even though both legs have perfectly intact or satisfactory motility. Rademaker and Garcin identified a group of 7 patients with the above-mentioned signs and followed them up over a three-year period. On the basis of their findings with this patient group, they developed a simple test for support reactions in both legs that could be used while the patients were lying on their back, as most of them were. The procedure involved is as follows: in general, dorsiflexion of the foot permits easy mobilization of the foot, the different segments of the leg remaining supple. However, when the dorsiflexion is brought about by pressure applied over the whole sole and gradually and persistently increased (leading to passive stretching of the posterior muscles of the leg) this manoeuvre gradually (since this is a tonic reaction) evokes tonic contraction of the quadriceps femoris muscle followed by generalized hypertonicity of the leg examined which is in particular opposed to bending of the lower leg towards the thigh. This has come to be known (at least in the French and Dutch medical literature) as the Rademaker-Garcin ‘step sign’.25 Its importance may be illustrated by the fact (reported by Rondot, 2000) that when Garcin presented these findings to the Société

LAH Hogenhuis, “Het teken van Rademaker-Garcin” (Rademaker-Garcin’s sign; in Dutch); in “Het neurologisch onderzoek in eponiemen” (Neurological research in eponyms), P.J. Koehler, GW Bruyn and NJM Arts (eds.), Dutch-language publication by Arts & Boeve, Nijmegen 1995, pp. 78–84. 25

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de Neurologie de Paris,26 in fact it could in my opinion be considered as an analogon from the Babinski reflex. Babinski asked whether he could visit him the next day to examine the patient in question himself. Garcin was both flattered and rather overwhelmed by this attention from the grand old man of French neurology.27 Babinski apparently suspected that the effect discovered by Rademaker and Garcin might be related to that he himself had discovered, which has come to be known as Babinski’s sign. This anecdote still lives on among French neurologists. The work Rademaker and Garcin did on these three eponymous effects between 1929 and 1935 had a number of striking characteristics: • the extreme simplicity of the methods used and the clinical examinations performed; • the patient-friendliness of the examination methods; • the adaptation of results initially obtained from animal experiments to clinical semeiology in man (for example, the static adaptation test 26 Rademaker G.G.J. et Garcin R., “Sur une variété d’astasie-abasie conditionnée par l’exagération de soutien (Stützreaktion). Leur extérisation dans le decubitus”, Rev. Neur. T.1, 186–391, 1933 a. See ref. 35. 27 Joseph F.F. Babinski (1857–1932) was of Polish origin but was brought to Paris by his parents as a young boy and received his medical education there. He became Charcot’s favourite student, but despite his great promise he was passed over for a professorship for various reasons. This left him free to devote more time to making use of his great powers of clinical observation and to discover a whole series of neurological effects which are still named after him. The most famous is Babinski’s sign. Normally, the great toe curls downward when the examiner draws a hard or sharp object up the sole of the foot. In the presence of a corticospinal tract lesion, it curls upward instead, and the other toes may fan out; this is Babinski’s sign. Babinski was one of the founders of the Société de Neurologie de Paris, to which he was profoundly devoted. His co-founders included Édouard Brissaud (1852–1909), Pierre Marie (1853– 1940), Joseph Jules Dejerine (1849–1917) and Alexandre-Achille Souques (1860–1944). Babinski’s obituary in The Lancet ended with the following words: “None (of Charcot’s pupils) is surer to be remembered for his achievements in the field of neurology.” One of those drawn to Babinski was Antonio Caetano de Abreu Freire Egas Moniz (1875–1955), the Portuguese who was later to receive the Nobel Prize for physiology or medicine for his discovery of prefrontal lobotomy as a method of treatment in schizophrenia. Today, however, Egas Moniz is remembered more for his introduction of cerebral contrast angiography in humans. The medical establishment initially received this revolutionary method of neurological diagnosis, first adapted in 1927 after exhaustive studies on cadavers, rather coolly. Babinski, however, was an exception. In the preface he wrote to Egas Moniz’ monograph, published in 1931, Babinski gave a vivid description of how Egas Moniz planned and executed his huge project with an insight, a courage, and a single-mindedness that reminded one of his great fellow-countrymen Bartolomeo Diaz and Vasco da Gama, as they embarked on their voyages to find the sea route to India. The description applies equally well to Babinski’s life achievement.

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provided a useful physio-clinical method for investigating vestibular and labyrinthine function which put less strain on patients than traditional methods such as injecting hot or ice-cold water into the ear); • added insight into human behaviour under unusual or menacing circumstances (e.g. the blink reflex); • contributions to the differential diagnosis of gait abnormalities, which had hitherto generally been regarded as almost exclusively indicative of psychic disorders even when organic complaints were also involved; • better understanding of the condition of elderly, bedridden or incapacitated patients, leading to the possibility of better care for such patients. In particular, use of the above-mentioned test for the presence of the support reaction made it possible to show that motility could be perfect or satisfactory even when premature gait abnormalities were found. As Rademaker and Garcin put it, “il ne saurait guère s’agir dans ces cas de rigidité de désequilibre mais plutôt de désequilibre de rigidité . . .” (these patients do not seem to tensing their muscles because they are in danger of losing their balance so much as being in danger of losing their balance because their muscles are tensing up). I would like to make a plea for wider use of the three eponyms—the Rademaker-Garcin blink reflex, the Rademaker-Garcin support reaction and the Rademaker-Garcin test of static adaptation—in the Anglo-Saxon neurological literature in honour of the almost unique combination of skills in the field of experimental physiology and deep, wide-ranging clinical experience displayed by these two researchers and in view of the continued clinical relevance of the three eponymous signs as reflected in the frequency with which they are still cited in the literature. There can be no doubt that at the time when these eponyms were coined, experienced neurologists regarded it as an honour, a recognition of the clinical and scientific merits of the person concerned to attach his or her name to the effect or clinical picture in question. Indeed, personal eulogies of the discoverers were not uncommon soon after the initial publication. Times have changed, however, and it does not seem to be so popular nowadays to honour researchers and clinicians in this

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way. Yet I would like to echo the remark made in the above-mentioned work “Neurological research in eponyms”:28 “Qu’on ne jette pas à la poubelle ces éponymes si utiles de plusieurs points de vue.” (Let us not throw these eponyms, which are so useful in various ways, into the dustbin.) It might be argued that there are enough eponyms already, and that it is a waste of our increasingly precious time to say or write “the Rademaker-Garcin blink reflex, the Rademaker-Garcin support reaction and the Rademaker-Garcin static adaptation test” when “the blink reflex, the support reaction and the static adaptation test” will do. But we have to remember those who went before us. In this age of computerized medicine and classification by alphanumeric codes, my administrative assistant Mrs. R. Lensen combined these two considerations in a masterly way by devising the abbreviations RaGa 1, 2 and 3 for the three Rademaker-Garcin signs. 3.3. ‘Réactions labyrinthiques et équilibre’—The Study of Labyrinthine Function In his book ‘Man on His Nature’,29 Sherrington (1940) gives a description of the labyrinths and the labyrinthine reflexes that might serve as an introduction to Rademaker’s experimental work on this topic (which had in fact been published a few years earlier): We have, and animals have likewise, a pair of tiny waterfilled bags, one on each side of the head, cased in the bone of the skull. Each bag is lined with cells, and a patch of these curly hairlets. A tiny crystalline stone attached to the hairlets rests amid them. The bag has a nerve. It runs from the patch of hairlet-cells to the brain. Any shift of the stone amid the hairlets stimulates this nerve. Through the brain the nerve connects with chains of nerve-centres putting muscles of the neck and body and limbs in touch with the hairlet-patch. When our head is squarely erect, the stimulation from the two patches right and left is similar and equal, because the two stones lie and act symmetrically. The balanced action of the muscles right and left maintains the balanced pose of the head. If the head then inclines a trifle to one side the slip, microscopic though it be, of the two stones on their nerve-patches brings the two stones into

28 P.J. Koehler, G.W. Bruyn, N.J.M. Arts, “Het neurologisch onderzoek in eponymen”, Arts & Boere Nijmegen, 1995 (in Dutch), 303 pp. 29 Sir Charles Scott Sherrington, “Man on his Nature”, Cambridge University Press, London, 1940. This book contains the published text of the Gifford Lectures for 1937–38, which had been delivered by Sherrington.

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Fig. 3-7. “Réactions labyrinthiques et équilibre. L’ataxie labyrinthique” was published in 1935. The sixth chapter, “Réactions labyrinthiques des extrémités chez l’homme; l’épreuve d’adaptation statique; l’épreuve de la chaise basculée”, was written jointly by Rademaker and Professor R. Garcin on the basis of the examinations of patients at La Salpêtrière and other Parisian clinics they had carried out over a period of several years.

asymmetry. From that slip there results the due corrective action of the muscles of the neck and limbs to bring the head back to symmetrical verticality, and secure the required stability. It is the same kind of act as happens when a moving image which is being looked at slips off the central point of sight, and the eye muscles at once shift the eye so as to slip the central point of sight back under the image once again. The mind knows nothing of this, except the result. If indeed it can be said to know what it accepts as a situation without even attentive observation to detail. It is an ancient system of adjustments, present, variously stereotyped, in great numbers of our stock, forerunners of ourselves. We can see it at work in the sweep and wheel of the gull in flight. Its body inclines with each slope and tilt of the outstretched wings, but the head keeps plumb to the horizontal line owing to compensation by the neck. From that steady pose of vantage the eyes watch sea and ship for food.

The monograph “Réactions labyrinthiques et équilibre. L’ataxie labyrinthique” was published in Paris in 1935. It was no easy reading for those who were not acquainted with Rademaker’s earlier work, but those who persevered were rewarded with a wealth of new data mainly derived from animal experiments. Since the last part of the book is based on the examination of patients at La Salpêtrière and other clinics in Paris, it is hardly surprising that the book was published in French. When

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Rademaker asked Guillain30 to write a foreword to the book, this was however a request the latter had not expected. He regarded it not only as a personal honour but also as a tribute to French neurology. As he put it in his foreword, . . . it is my particular pleasure to convey to Professor G.G.J. Rademaker how highly his kind decision to publish this research, which has not yet seen the light of day, in Paris and in French is appreciated by French neurologists and physiologists . . .

This was Guillain’s way of confirming what had been common knowledge in French neurological circles for many years, that Rademaker had in effect won a place for himself as a leading French neurologist, to the mutual benefit of both parties concerned. Guillain went on to sketch his first impressions of the book: Perusal of these physiological data, derived from experiments carried out by Professor G.G.J. Rademaker in collaboration with Raymond Garcin in their search for a method of examination which they call the “static adaptation test” would seem to suggest that they could have important clinical applications. . . .

and to mention his personal memory of the fact that: They have studied this static adaptation test in the neurology clinic of La Salpêtrière . . . for several years31

Rademaker opened the introduction to this, his last book, with a striking line of argument. By way of justification for this mass of experimental data, he reminded his readers of the classical paradox faced by ENT specialists, physiologists and neurologists when considering the labyrinths: they believe these structures to be organs for the control of 30 G.C. Guillain (1876–1961), French neurologist and discoverer, among other things, of the Guillain-Barré syndrome. At the time Rademaker published the monograph, Guillain was head of the department of Clinical Neurology at La Salpêtrière and Garcin’s father-in-law. 31 These studies, summarized in Chapter VI of the monograph (pp. 101–137), entitled “Réactions labyrinthiques des extremités chez l’homme, l’épreuve d’adaptation statique, l’épreuve de la chaise basculée”, had already been reported in the following publications: Rademaker G.G.J. and Garcin R., “Note sur quelques réactions labyrinthiques des extremités chez l’animal et chez l’homme; Étude physiologique et clinique”, Revue Neurologique 39, 637–653, 1932 with a demonstration to the Société de Neurologie in Paris at a meeting held on 7 April 1932; Rademaker G.G.J. and Garcin R., “Suite à l’étude de quelques réactions des extrmités d’origine labyrinthique”, Revue Neurologique i, 186, 1933; Rademaker G.G.J. and Garcin R., “L’Épreuve d’adaptation statique: suite à l’étude de quelques reactions des extrémités d’origine labyrinthique”, Revue Neurologique t.2, 566–579, 1933.

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posture and the maintenance of the body’s equilibrium, but have not yet determined what reactions these organs use to maintain this equilibrium—or rather, to restore it each time it is disturbed. Rademaker laid down the following definitions in this context: an organ of equilibrium is “an organ that generates equilibrium reactions”, and an equilibrium reaction is “a reaction that ensures that the body’s centre of gravity remains within the vertical boundaries defined by the body’s support base or that returns it to within these boundaries”. The support base of a human standing upright is the area between the outer periphery of the two feet, while that for an animal standing on all fours is the rectangle defined by the outer periphery of the four paws.32 The pronounced originality of the methods of analysis Rademaker used for this study lies in his categorical rejection of what he calls ‘unphysiological’ techniques—techniques that destroy the organ under investigation, render it inoperative or subject it to abnormal or excessive stimuli. He mentions the widely used caloric test of the labyrinths as a specific example of the techniques to be avoided. This leaves truly physiological stimuli such as free fall in space and rotation about various axes in three dimensions as the only tools available in his investigative kit. Rademaker distinguished three groups of labyrinthine reactions for the purposes of these experimental studies: 1) reactions evoked by linear vertical movements; 2) reactions evoked by rotation; and 3) reactions determined by changes in the positions of the labyrinths with respect to the direction of gravity. The first five chapters of this book are devoted to these experimental studies. Chapter 1 deals with the labyrinthine reactions evoked by three types of vertical fall and the lift reaction. If the experimental animal is dropped in a prone position, it reacts by pulling the head and neck back, convexity of the back and hyperextension of the four legs with spreading of the toes. Dropping it head-down leads to forward extension of the forelegs, backward extension of the rear legs, arching of the back and dorsal curling of the tail. Finally, dropping the animal

32 G.G.J. Rademaker, “De labyrinthaire evenwichtsreacties der zoogdieren” (The labyrynthine equilibrium reactions in mammals; in Dutch), a paper read to the Amsterdam Association of Neurologists on 04.02.1932, Ned.Tijdschr.v.Gen. 76 III, 30, 1932, 3678–3690.

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with its rear end down causes it to pull the neck back, straighten the back and extend the rear legs backwards. The postural differences between these three reaction patterns are thus not determined by the directions in which the labyrinths move, or by the deep reflexes of the musculature of the neck and throat. They do on the other hand seem to be related to the different positions of the trunk and the limbs at the start of the fall. The stimuli that bring these reactions about are in all probability due to the reduction of the pressure exerted on the utriculi by the otoliths.33 The ‘lift reaction’ observed by Magnus and de Kleyn can be explained in much the same way. On the other hand, Rademaker interprets the bracing reactions and the reactions involved in jumping and hopping on one leg (called ‘saut à cloche-pied’ in French) in a different manner. These reactions to linear movement in a horizontal plane are not of labyrinthine origin but are ascribed to muscular traction. In Chapter 2, Rademaker deals with the reactions observed on rotation of the labyrinths around the cranio-basal axis, viz. horizontal movement of the eyes, lateral head movement and concavity of the spinal column—all in a sense opposed to the direction of rotation—accompanied by nystagmus of the eyes and head in mutually opposed directions. Detailed analysis of each of these reactions in the normal animal and in the animal from which the labyrinths have been removed reveals the striking fact that when the latter animals (those without labyrinths) are placed on the turntables, they always show reactions that (tend to) maintain equilibrium, while normal animals are sometimes found to display reactions that help them to keep their balance but sometimes reactions that make it more difficult for them to do so. The reactions evoked by movements such as rotation of the head about the bitemporal axis—dealt with in Chapter 3—differ for forward (ventral) and backward (dorsal) rotation. Dorsal rotation causes: a) downward movement of the eyes followed by upward nystagmus or (only in animals with the eyes at the side of the head) forward rotation of the eyes around a vertical axis followed by backward rotary nystagmus, b) ventral movement of the head and neck, sometimes followed by For Rademaker’s observations concerning the functions of the otoliths and a discussion of the four theories of otolith function current at that time, see the review by Rademaker in Ned.Tijdsch.v.Gen. 79 I, 12, 1310–1311, 1935 and the description of the doctoral thesis by C. Ruys in Book IV, Part 4.1 of the present work. 33

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dorsal head nystagmus, c) dorsal movement of the pelvis and d) an increase in support tone associated with backward movement of all four legs. Ventral rotation around the bitemporal axis, on the other hand, causes: a) upward movement of the eyes followed by downward vertical nystagmus (in animals with eyes placed frontally), b) dorsal movement of head and neck, sometimes followed by ventral head nystagmus, c) ventral movement of the pelvis and d) forward movement associated with a reduction in support tone in all four legs. The reactions evoked by rotation of the head, the trunk and the extremities around the bitemporal axis also tend to neutralize the effects of the passive displacement in the sagittal plane, thus helping the animal to keep its balance during these movements. The results of the experiments described in Chapters 2 and 3 later proved to be of key importance in the development of the static adaptation test (tilt test) for use in clinical neurology, which has been found in practice to be of great use in the differential diagnosis of various forms of severe ataxia. The results of the study of this test are summarized separately in Chapter 4, while the results obtained with its aid are dealt with in part III of this book. Chapter 5 deals with the effects observed on rotation round the fronto-occipital axis. Clockwise rotation round this axis causes: a) rotary movement of the eyes, the top of the eyeball moving to the right, followed by rotary nystagmus to the left (in animals with eyes placed frontally in the head), b) rotation of the head so that the top of the head approaches the right shoulder, sometimes followed by rotary head nystagmus in the opposite direction, c) abduction and an increase in support tone of the two legs on the left, which are braced outwards and d) adduction and a reduction in support tone of the two legs on the right, which tend to buckle. Here again, the reactions of the extremities proved to be real equilibrium reactions which tended to neutralize the passive displacements of trunk and stabilize the position of the body in the frontal plane. The results of all these experiments may be briefly summarized as follows: The changes in the position of the extremities observed during the rotations of the labyrinths are due to reinforcement or relaxation of the support tone and are in all probability caused by the vertical semicircular canals, since they only occur during rotation round the bitemporal and fronto-occipital axes and not (or less) during rotation round the craniobasal axis. Analysis of the endolymphatic flows in this connection

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The application of these data obtained from animal experiments to neurological diagnosis is described in Chapter 6, which deals with the above-mentioned, almost classical tilt tests developed by Rademaker and Garcin. This chapter includes the case histories of 21 patients with labyrinthine syndromes where the extremity reactions were lacking as compared with 6 patients with cerebellar syndromes, 5 with tabes, 1 with hemiplegia and 1 who was congenitally deaf and dumb where these reactions were still present. Part II of the monograph summarizes the studies of labyrinthine reactions evoked by changes in the positions of the labyrinths. Compensatory eye movements, labyrinthine righting reflexes and Magnus-de Kleyn tonic labyrinthine reflexes are dealt with in turn. These studies led to the following new insights: 1) tonic labyrinthine reflexes in decerebrate animals lead to an increase in the rigidity of the neck when the neck is rotated approximately 90° from a “normal position”.34 This applies both to rotation about the longitudinal axis and ventral or dorsal rotation about the bitemporal axis. The 90° rotation brings the surfaces of the utricular maculae into a practically vertical position, and converts the pressure exerted by the utricular otoliths when the head is in a “normal position” into traction parallel to the surface of the maculae. 2) The labyrinthine righting reflexes become inoperative when an animal is turned backwards so far that its nose points about 45° upwards. This again brings the head about 90° out of the “normal position” and the pressure exerted by the utricular otoliths is completely converted into backward traction of the otoliths. 3) During free fall, an animal (cat, rabbit, guinea-pig or rat) will turn its body around in mid-air if its head is held in the “normal position” and its trunk is held in a supine position before the fall, even though this posture means that the factors that evoke the labyrinthine righting reflexes are not present (cf. the observations of Rademaker and Ter Braak in their studies of the fall reflex (Book II, part 2.6).

34 The “normal position” in animals is understood to be that in which the crown of the head faces upwards, the bitemporal axis is horizontal and the nose points about 45° downwards.

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Apart from the morphology, explanatory material was included in the form of elegantly presented filmstrips (which often took up entire pages in the book) together with EMG recordings of antagonist musculature. Finally, Rademaker used a procedure he had devised previously to bring these data from animal experiments into relationship with other observations from the literature, such as the three cases published by Magnus and de Kleyn,35 case histories from Walshe,36 Brouwer,37 Böhme and Weiland38 and the three cases described by Pette.39 This revealed the reciprocal roles played by the otoliths of the utriculi and the semicircular canals, and the essential function of the labyrinths—which is to neutralize the effect of passive displacements and to stabilize the positions of the eyes, the head and the trunk in space. It is only by virtue of these three groups of reactions that the labyrinths really deserve the name of equilibrium organs. Rademaker summed all this up in his remark that the labyrinthine reactions are essentially ‘negativistic reactions’. In the third and final part of the book, the experimental data are brought into relationship with clinical problems and the concept of ‘labyrinthine ataxia’ is defined. To this end, Rademaker gives an exhaustive analysis of the various elements of labyrinthine ataxia revealed after unilateral and bilateral labyrinthectomy and compares the clinical findings with the experimental reactions observed in animals after removal of the labyrinths and the cerebellum, and in particular after the removal of both these organs in succession in the same animal. This analysis enables Rademaker to create a synthesis of his own experiences, collected over a period of many years, in relation to a topic of primordial importance.

Magnus R., de Kleyn A., “Weitere Beobachtungen über Hals- und Labyrinthreflexen auf die Gliedermuskeln des Menschen”, Pflüger’s Archiv. f.d. ges. Physiologie des Menschen u. der Tiere LCX, 429–444, 1915. 36 Walshe F.M.R., “On certain tonic postural reflexes in hemiplegia with special reference in the so-called associated movements”, Brain 46, 1–37, 1923. 37 Brouwer B., “Ueber Meningo-Encephalitis und die Magnus-Kleynschen Reflexe”, Zeitschr.f.d.ges. Neurol. u. Psychiatrie 36, 161–180, 1917. 38 Böhme A. and Weiland W., “Einige Beobachtungen über die Magnusschen Hals- und Labyrinthreflexe beim Menschen”, Zeitschr. f.d.ges. Neurol. u. Psychiatrie 64, 94–100, 1918. 39 Pette H., “Klinische und anatomische Studien zum Kapitel der tonischen Halsund Labyrinthreflexe beim Menschen”, Dtsch. Z. Nervenheilk. 86, 193–219, 1925. 35

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After citing the classical views of Flourens, Goltz, Ewald, Breuer, Maxwell, Magnus and de Kleyn, Rademaker gives an entirely new perspective based on his experimental findings, in which the labyrinthine reactions of the extremities are given a dominant place in the equilibrium mechanism. In his opinion, the phenomenon of equilibrium can only be properly understood by further study of the labyrinth—not with the usual caloric tests, which as mentioned above he considered unphysiological, but solely with the aid of physiological stimuli as in the fall reflex and the effects of the various forms of rotation. Rademaker put enormous energy into the documentation of these equilibrium reactions, with the aid among things of striking cinematographic illustrations taken from the comprehensive film archives he had built up. In the various chapters devoted to the reactions of the limbs of the experimental animal which is dropped from a ventral or vertical (‘longitudinal’) position, detailed attention is paid to the movements made during the fall that enable the experimental animal to break its fall and land lightly. The Magnus-de Kleyn ‘lift reaction’, for example, also has the effect of protecting the animal’s head and trunk against collisions when the vertical movement is abruptly stopped. The data collected on the labyrinthine reactions, affecting the muscles of the eyes, neck, trunk and extremities, which are evoked by rotation about the cranio-basal, bitemporal or fronto-occipital axis are equally informative. Detailed analysis of these reactions in intact normal animals, decerebellate animals and animals with unilateral or bilateral labyrinthectomy shows how the response can vary in the different cases. Rademaker had noticed that the essential changes observed in the extremities during the various rotations of the labyrinth in fact all came down to reinforcement or weakening of the support reactions. He further concluded that each labyrinth influences the support tone on both sides of the body. This theory, which was very accurately confirmed by the results of the physiological experiments, explains the short-lived bilaterality of the reactions at the extremities after unilateral labyrinthectomy and also the fact that the animal regains its balance a few weeks after the operation. A clinical test based on these experimental data that was developed by Rademaker and Garcin at La Salpêtrière was called the “épreuve d’adaptation

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Fig. 3-8. Tilt test (Rademaker and Garcin). Normal subjects (1, 2, 3, 4) show bracing reactions in response to rapid rotation. Subjects with labyrinthine disorders (5, 6, 7, 8) show no bracing reactions in response to rapid rotation, but are thrown off the bed like a dead weight.

statique”40 (the static adaptation test or tilt test). In this test, patients lay on a specially constructed bed (see figures) that could be tilted and rotated in such a way as to permit rotation of the patient’s labyrinths round the bitemporal or fronto-occipital axis and hence testing of the patient’s equilibrium reactions in just the same way as Rademaker had done with the experimental animals.

40

See also Book III, Part 3.2.

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The results obtained with this tilt test showed that when a healthy, intact person was subjected to sudden movements, bracing reactions were observed that allowed that person’s balance to be maintained. These reactions were not however observed in patients with labyrinthine disorders. Rademaker and Garcin made the striking discovery that patients with cerebellar disorders or tabes dorsalis showed normal equilibrium reactions when tested in this way if their labyrinthine functions were intact, but not if these functions were damaged or absent. Rademaker pointed out the resemblance between the syndrome noted after hemilabyrinthectomy and that produced after extirpation of half the cerebellum, which is due to the fact that both operations lead to complications that are analogous to different non-labyrinthine reactions. A similar analogy had led Flourens to conclude in his “Recherches experimentales sur les propriétés et les functions du système nerveux dans les animaux vertébrés” (Experimental studies of the properties and functions of the nervous system in vertebrate animals) (1842) that the cerebellum is the centre for labyrinthine reactions, and this view remained unchallenged among physiologists until the middle of the 20th century. Now, however, Rademaker claimed on the basis of his own experimental work that the cerebellum cannot be the centre for labyrinthine reactions, since all labyrinthine reactions without exception are still present after its ablation—which does not necessarily mean that the cerebellum normally plays no part at all in these reactions, or that the labyrinthine reactions proceed perfectly normally after its ablation. Comparison of the behaviour of an animal without cerebellum with that of one without labyrinths shows, according to Rademaker, that the cerebellum and the labyrinth have more or less comparable functions. The labyrinths are sensory organs that can also give rise to certain reactions, while the cerebellum plays a role in the regulation of the motor system by ensuring that the various motor actions are carried out on time, without exaggeration and in an appropriate manner. While it must be admitted that both the labyrinth and the cerebellum reinforce muscle tone, Rademaker’s experiments show that combined ablation of both does not lead to a reduction in support tone; however, bilateral labyrinthectomy in an animal without cerebellum leads to a marked increase in the disturbances associated with cerebellar ataxia. Many critics were of the opinion that the subtlety of this series of investigations deserved the highest praise. The wealth of illustra-

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tions—drawings by Rademaker himself, diagrams and the abundance of filmstrips—was also greatly appreciated. This work, “digne pendant de ceux consacrés au noyau rouge et à la station” (a worthy companion to those on the red nucleus and on the physiology of standing) was thus regarded not only as an integral part of Rademaker’s triptych but also as an indispensable reference handbook for all otological, neurological and physiological clinics (Mollaret, 1936). This, the last book Rademaker wrote, cannot be considered in isolation from the other two parts of the triptych. Once again, it contained a summary of his scientific work, including much that had not been previously published. And once again, great attention was paid to the relation between insights gained from experimental work and their clinical applicability. Apart from the clearly proven relevance of Rademaker’s work with experimental animals for clinical neurology and the importance of the various neurological signs derived from it, it also proved—half a century later—to make a real contribution to space physiology, as this new branch of science developed in the laboratory of the Collège de France under the leadership of Professor A. Berthoz. Berthoz presented some of the advances in this field in his brilliant monograph “Le sens du mouvement” from 1998, where he cites Rademaker’s experimental work on the vestibular reactions.

BOOK IV

WARTIME. THE PHILOSOPHY BEHIND RESISTANCE.1 IN MEMORIAM JAN MULDERS. DEVELOPMENT OF THE IDEA OF CIVITAS ACADEMICA The war years (1940–1945) Rademaker was a monarchist and a patriot. When the Second World War broke out, he realized that the existence and future not only of his country but also of ‘his’ University of Leiden were at stake. “Resistance and revolt were his logical steps”, as Denny-Brown put it later. Awareness of the developments in the academic world in Germany grew gradually in Rademaker and his colleagues in the medical faculty. This was especially clear in the case of friends such as Barge, Gorter, Van der Hoeven, who like Rademaker were members of the Board of the faculty and with whom he shared his concerns about what was going on in Germany. Johan Huizinga, professor of History at Leiden and author of a number of world-famous books on the history of culture, had also written about these dangers without mincing his words. His international reputation guaranteed that these warnings were also heard outside the borders of the Netherlands. Members of the medical faculty at Leiden also had one special source of information in the form of Prof. Siemens, who occupied the chair of Dermatology. A German citizen and member of the Siemens family of industrialists who specialized in medical technology, Prof. Siemens had paid frequent visits to relatives and captains of industry in Germany since 1933. As a member of such an influential family, he had access to secret information about Germany’s invasion plans, the types of occupation the Germans had in mind for civilians in the countries they hoped to occupy and the plans for the nazification of institutes of (higher) education such as Delft and Leiden. He passed much of this information on to Rademaker and other members of the medical staff. The inner circle of the medical faculty

1

See also endnotei.

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thus became gradually imbued with an appreciation of the impending risks, thanks to his repeated warnings. Siemens himself decided to renounce his German citizenship and voting rights before the outbreak of war. The Netherlands was invaded on the 10th of May 1940. Despite all warnings, the blow to the intellectual community could not have been more severe. On the day of the invasion, Menno ter Braak, the brother of Wim ter Braak, the physiologist and neurologist who had collaborated as conservator of the Physiology laboratory in Leiden since 1933 and who was a good friend and colleague of Rademaker, committed suicide (with his brother’s assistance). It was the clearest message this well-known author and journalist (who worked for the daily newspaper “Het Vaderland” in The Hague) could give the younger intellectual Dutch generation for whom he was the figurehead. Rademaker understood this. Menno ter Braak had warned in articles of the disaster that could overcome the country if it were exposed to the pernicious logic of Nazi doctrine. 1942 and later A chronology of the events of the period 1940–1945, including Rademaker’s activities as secretary and spokesman of the Board of the Medical Faculty, has been documented elsewhere.2 These events could not be fully documented at the time, for security reasons. The intellectual leadership of the medical faculty—Gorter, Barge, Van der Hoeven, Siemens, Rademaker and others—had to face up to the ethical implications for physicians of the general strike of university staff announced by the Vice-Chancellor Prof. F.R. Cleveringa, the dean of the faculty of law, on 26th November 1940, when the occupying powers ordered dismissal of Jewish professors and other members of staff in line with Nazi philosophy. The physicians on the university staff had two tricky ethical problems to deal with: on the one hand, could they respond to the call for a general strike in protest at the directives of the occupying forces? And on the other, could they stop treating Jewish patients in the University Hospital, as ordered by the occupy-

2 P.J. Idenburg, “De Leidse Universiteit 1928–1948”, pp. 201–203, 382, 1978, Universitaire Pers Leiden, ’s-Gravenhage, 1978.

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ing forces? In principle, any refusal of medical care to a patient who needs it is anathema to a physician. The following example illustrates the dilemmas faced at this time: When the occupying powers started to transport bedridden Jewish patients from the wards of Zuidwal Hospital, the big teaching hospital in The Hague in 1942, Wim ter Braak (who was responsible for the care of the neurology patients there) refused categorically to cooperate with this move in any way. He was initially held in Scheveningen (in the notorious “Oranje Hotel” prison, where male and female resistance fighters were incarcerated), condemned to six months’ imprisonment in the concentration camp at Vught in the southeast of the country, and released when he had served his sentence there3

Rademaker continued to care for Jewish and other patients at home. In another incident, the University Hospital in Leiden (ironically, now headed by Rademaker’s former assistant Dr. H.H. Maas,4 who had chosen to collaborate with the occupying forces) was visited in 1942 by civil servants from the Ministry of Health in The Hague (who were also collaborating with the German occupiers). These medical administrators classified a group of patients from a ward for children with minimal brain damage suffering from dietary problems (for which they were receiving special attention from Prof. Gorter), spina bifida and hydrocephalus neonatorum, together with a group of ‘doubly handicapped’ spastic children with specific reflex abnormalities, as ‘not in need of care’, thus effectively condemning them to death.5 This decision was based on one of the main tenets of Nazi ideology, formulated by Rudolf Hess, the theoretician of the Nazi party who had become the deputy Führer of the ‘Third Reich’. He had declared that ‘national socialism is nothing but applied biology’. The Nazi laws in Germany had been straightforward logical extensions of this statement, and were based on the assumption that inferior races (‘non-Aryans’) and those with incurable diseases and mental or physical/neurological handicaps (in Naziterminology “Lebensunwertes Leben”, life unworthy of life) had no

Cited in the article by Otto Magnus, “Over Dr. J.W.G. ter Braak”, in “Drie Neurologen” [Three Neurologists], Lambertus J. Endtz, Otto Magnus and J.A. Schipper (eds.), The Hague, 1984, pp. 17–26. This collection was published to mark the 75th anniversary of the founding of the department of Neurology of the municipal hospitals in The Hague. 4 See Maas’s thesis from 1933, Book IV, Part 4.1. 5 See thesis by N. Verwey (1938), a member of Rademaker’s research staff, Book IV, Part 4.1. 3

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ultimate right to life.6 In the face of the above-mentioned decision of the medical administrators from The Hague, Gorter and Rademaker defiantly announced that they would continue to care for these patients, and fiercely refuted the inhuman philosophy that had sentenced them to death. Though Gorter and Rademaker could easily dominate this debate, silencing the visitors with details of sophisticated clinical research reports, they knew that the bureaucrats in The Hague would probably follow the line laid down by the occupying powers in the long run. Nevertheless, they decided to continue treating the patients as if nothing had happened. This event made a deep impression on the nursing staff who witnessed it.7 The Medical Faculty was at war. . . . An ever growing number of students and academics (including some professors) from German universities, Jewish or otherwise, had come to Leiden since 1933. They brought the clearest evidence of the racial and other discriminatory systems installed in Germany. Leiden had a long tradition of harbouring such asylum seekers who were looking for help in continuing their studies when this was made impossible in their country of origin. The task of accommodating such numbers of students, teachers and researchers represented a heavy burden for the administrators of the medical faculty. (Details are preserved in the faculty archives.) The newly nazified University of Strassbourg in occupied Alsace reopened in November 1942 as the “Reichsuniversität Strassbourg”. Rademaker’s wife Blanche, née Stoltz, born in Paris of Alsatian stock, returned from a courageous visit to family and friends in Alsace shortly after, with detailed information on what to expect from such a ‘reconstruction’ of a university in occupied territory. This confirmed the worst scenarios Prof. Siemens had painted. In this same annus horribilis of 1942, J.A.J. Barge (1884–1952), professor of Anatomy and Anthropology in Leiden and one of Rademaker’s best friends, was imprisoned as a hostage in the concentration camp in Vught. 6 See for recently published evaluation of the Hallervorden-Spatz condition: S.J. Hayflick et al., “Genetic, clinical and radiographic delineation of the Hallervorden-Spatz syndrome”, The New Engl. J. of Med. 348, 33–40, 2003; M. Sherell, “Hallervorden and History”, The New Engl. J. of Med. 348, 3–4, 2003; I am indebted to my son Wl. Hogenhuis MD for drawing my attention to these publications. 7 I am indebted to staff nurse Noordergraaf [personal communication] for details of this incident. She later adopted a handicapped child herself.

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Fig. 4-1. Prof. J.A.J. Barge (1884–1952).

Barge had been Vice-chancellor of the university8 in 1937–138. During a lecture he gave to students in 1940, he courageously presented the evidence demolishing Nazi race theories. Nazi ideology was being introduced as part of the general policy of the occupying powers. This ideology included the idea of the superiority of the Aryan race to which the Germans claimed to belong, culminating in the abovementioned statement by Rudolf Hess. The Nazi secret police were well aware of Barge’s standing, and arrested him in 1942. He was imprisoned in Vught together with other prominent Dutch citizens, including Prof. Huizinga. Ten of them were executed by the Germans as a reprisal for Dutch Resistance activities. Rademaker corresponded with Barge while he was in Vught (see further the figure for a copy of one of Rademaker’s letters). Rademaker was deeply touched by the events. Translation of the handwritten letter: Oegstgeest, 24/8/1942 Dear Colleague [literally ‘My friend’, a common form of greeting between Dutch academics], I have often wanted to write to you, but have been unable to because of the difficult situation here. Now I feel that I cannot postpone my letter any longer since I understand how miserable you must have been feeling of recent days and what a difficult time you will be going through during the coming days, when your oldest daughter is getting married

8 Jolanda Hendriksen B.A., W. Hymans MD, “The anatomy lesson of Professor Barge”, J.R. Soc. Med. 89, 649–650, 1996.

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without your being able to be present. As regards the situation at the university, we continue to live in complete uncertainty. My repeated requests to retire from my post have been met with the answer that the matter is still under review. There appear to be successors for Obstetrics, (?) Otology and Neurology [literally: nerve diseases]. Jan van der Hoeve does not look at all well. I suspect that he is suffering a good deal of pain. But since he never mentions his condition, I do not enquire. Apart from Van der Hoeve and Kuenen, I do not see other colleagues much. And so time passes, in expectation of what is still to come. There is practically no work going on in my laboratory, since experimental animals are unobtainable. I fully understand that this is not much of a letter, but I feel as if my brains have turned into mush. I hope, however, that you will accept the sincere good intentions which impelled me to write. With all best wishes, also from Blanche, [illegible] Gijs Your other colleagues and friends also send their best wishes

Fig. 4-2. Photocopy of the letter Rademaker wrote on 24 August 1942 to Barge, his friend and professor of Anatomy and Anthropology, during the latter’s detention as a hostage at the Nazi concentration camp in the village of St. Michielsgestel (see Hendriksen J.H. and Hijmans W., J.R. Soc. Med. 89, 649–650, 1996). Though he remains unbroken in his attitude of active resistance, Rademaker tells his friend Barge that he has not yet received any reaction to his official announcement of resignation as professor of Physiology afther the closure of the university in protest at the action of the occupying powers in barring Jewish professors from exercising their functions. He ends this letter, written in sympathy with his friend’s plight as hostage of the Nazis, with an expression of his feelings of desolation and his inability to muster any creativity or enthusiasm for his scientific work (hardly surprising under the circumstances!). Kindly made available by the Barge archives, Leiden, courtesy of Mrs. H. Nauta-Barge.

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April of the same year saw the death of another good friend of Rademaker’s, Dr. D.G.W. van Voorthuysen,9 a scientist with a training in pathology and neuro-otology who had worked and taught at the ‘Nederlandsch-Indische Artsenschool’ [ Dutch Indonesian School of Medicine] in Surabaya. Rademaker had worked with him at the start of his career as an experimental physiologist. Van Voorthuysen later collaborated with Ter Braak on studies of the reflex regulation of respiration in Rademaker’s physiology laboratory and published in internationally renowned journals such as Plüger’s Archiv. With his death, Rademaker’s Surabaya years came to an end. The closure of the university in 1940 and the general strike of university staff that lasted throughout the German occupation meant an almost complete end to scientific research at Leiden. This is reflected in the theses produced by Rademaker’s students (see Book IV, Part 4.1). During the war years, Rademaker played an active part in the Resistance. To this end, he subjected his laboratory to a thorough reorganization. Scientific equipment was replaced by a printing press, a cache of weapons was bricked into the walls and floor, and a sick bay for members of the underground was set up in his personal laboratory and adjoining basement. And all this took place almost literally under the noses of the police (who were collaborating with the occupying forces). The police station was just across the road, so he had ample opportunity to observe the coming and going of people in their office, though its large first-floor window. Also visible were large wall maps showing the positions of Allied forces and a wireless for listening to Allied broadcasts. In real danger of being arrested himself and giving up the names of his many friends and colleagues in the Resistance under torture, Rademaker (in common with others in the same position) had a capsule of potassium cyanide implanted under his skin, to be broken in the last resort.10 What was his state of mind at the time? The war had shattered his work as a scientist. As head of a laboratory whose staff were at risk of transport to Germany as forced labour, and as secretary of the medical 9 G.G.J. Rademaker, “In memoriam Dr. D.G.W. van Voorthuysen, ENT specialist voor Keel-, Neus- en Oorheelkunde te ‘s-Gravenhage”, Obituitary Ned. Tijdschr. v. Gen. 86, 11(18), 1111–1112, 1942. 10 Personal communication Prof. Emer. Dr. Jhr. De Beaufort. He was an intimate friend of Rademaker and discussed these matters with him. In my discussions with Prof. De Beaufort he stressed the importance of these considerations for Rademaker, though he was hesitant to go into detail.

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Fig. 4-3. Prof. Rademaker entering the physiology laboratory in the morning during the war years. In the background the local police station. From his room Rademaker had a look on all the visitors entering the police station.

faculty whose students saw their studies come to an abrupt end for the duration of the war, Rademaker helped to find secure refuges elsewhere in the country for many who felt obliged to leave Leiden. Following the line we have adopted throughout this book of analysing the dynamics of Rademaker’s cognition in the various periods of his life, we may say that during the war he was fearless, courageous in his adherence to the Resistance but—conditioned as he was by his Calvinistic upbringing with its belief in the sanctity of life and with his responsibility as a physician to preserve life wherever possible—he showed hesitation when called upon to share the responsibility for decisions to execute collaborators even when it could be clearly shown that they posed a threat to the lives of active members of the Resistance. Rademaker maintained contact with students in hiding, helping them to continue their studies, organizing examinations and keeping up their spirits.11 The students set up a national resistance organisation of their own (known

11 I cite here from interviews with the subsequent professors E. Noach (Emeritus professor of Pharmacology, Leiden) and Prof. J. de Blecourt (Emeritus professor of Rheumatology, Groningen). Each of them studied under Rademaker in Leiden.

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in Dutch as De Raad van Negen—the Council of Nine), which met regularly in The Hague in the years 1942–1944. The German secret police imprisoned the president of this organisation—the 24-year-old medical student. Jan Mulders (see picture)—on suspicion of ‘treason’—in the summer of 1944 on the 13th of June. Apart from his activities in the Resistance, Jan Mulders had been active in the planning of the postwar reorganization of the University of Leiden and as President of the Catholic students’ organization R.K.S.V. St. Augustinus in Leiden had played a key role in formulating, together with Prof. Barge and others, the idea of the Civitas Academica12 [Personal communication Mr. H. Wodrada] for the university community to come. Though heartily endorsed by Rademaker, among others, this idea came after a promising springtime after the war in later years, not really to fruition; the times had changed too much. After his capture, Jan Mulders was imprisoned in the notorious “Oranje Hotel” in Scheveningen for a while, and was later kept in isolation for three months in a bunker in the concentration camp in Vught before being executed, with others, without form of trial on the early morning of 5 September 1944. Rademaker and Gorter were deeply moved by the news. Jan Mulders had taught the university community the meaning of courage. His name—and that of the others who were executed with him—is commemorated by a plaque in the Tweede Kamer (the Second Chamber of the Houses of Parliament in The Hague), in the center ‘Het Eigen Huis’ at the Rapenburg, and streets have been named after him in Leiden and in his birthplace Vlaardingen. Civitas Academica Although the University was formally closed and most activities—outside patient care in the University hospital—interrupted, in the laboratories studies continued in some instants behind the curtains. Students in the hide were visited by their professors and even exams were organised. Rademaker also as officially appointed by the medical faculty as

12 Jules Verhagen, in: “Gedenkboek 1940–1945 in de Katholieke Academische Gemeenschap” (A book commemorating the period 1940–1945 in the Catholic academic community in the Netherlands), compiled and published at the request of the Catholic Students’ Associations in the Netherlands and printed by the Leidsche Courant, Papengracht 31, Leiden, 1947, p. 35.

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Fig. 4-4. Student J.H.A. Mulders, Med.Drs. (13 Sept. 1919–5 Sept. 1944). Courtesy Archive Leidsch Studenten Corps (LSC).

secretary was one of those who helped the students to continue their studies.13 Work on theses was an activity, which could continue. Of the eight theses prepared by students working under Rademaker in the period 1932–1946, three were started during the war and received his full attention despite the chaotic circumstances. They were defended shortly after the end of the war (two in late 1945, and the third in the summer of 1946).14 As such, and in their content, they form a bridge with the post-war period in which Rademaker changed from professor of Physiology to professor of Neurology—he was appointed to the latter chair in 1945. The sense of participating in an intellectual community in a close cooperation with professors and students, ‘scientific staff ’, of which this was an example, had been developing in these years, in particular since the closure of the University in 1941 on proposal and official 13 The story and details have been documented by L.A.H. Hogenhuis in: “History of Neurology in the Netherlands”: G.G.J. Rademaker 1887–1957, Chapter 25 (in English), Uitg. Boom Publishers Amsterdam, pp. 353–360, 2002. 14 The theses prepared under Rademaker’s supervision are as follows (see Book II, Part 6 (?) for further details: 1. J. Visser (16-06-1932) 5. P.C. Kraan (11-10-1939) 2. H.H. Maas (11-10-1933) 6. C. Ruys (14-11-1945) 3. N. Verwey (09-06-1938)—patient 7. W. Storm van Leeuwen (27-09-1945) logistics 4. H. Verbiest (24-02-1939)—patient 8. C.P.J. Stotijn (27-09-1945) logistics

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statement by the rector magnificus prof. Cleveringa in view of sacking the Jewish professors, measurements incompatible with the basic principles on which the University was founded. Praesidium libertatis i.e. freedom of speech, freedom of religion contrasting the Leiden University for being ‘the hornet’s nest of ideological subversion’ as stated in official Nazi documents. The need for a new form of expression for the original philosophy and ideals was already felt throughout the University and coincided with these events. A post-war thinking started by a number of professors, members of the scientific staff such as Gorter, Barge, Rademaker, Van der Hoeve and Ter Braak, Storm van Leeuwen in the medical faculty, later the theologist Van Holk, the munk-historian professor H. van Rooyen OSCr. and Van Laer the professor of philosophy of science, students met in groups on the campus, new socialists and others in the resistance such as the medical student and president of the catholic student association in Leiden, R.K.S.V. St. Augustinus, but equally the national president of the Dutch Student Resistance in Leiden, Jan Mulders—who met regularly in secret in The Hague with representatives of student movements from other universities, the Civitas Academica was conceived in Leiden only. It stayed a state of mind, a valid workable fruitful conception of a University community till years after the war. The neuroanatomists Heringa (1891–1972) and Boeke (1874–1956) respected members of the scientific societies from other universities, which Rademaker frequented. Both were men of principles. Boeke resigned from the (then no longer) Royal Dutch Academy of Sciences when all Jewish members were expelled in 1941. Heringa was interned by German occupants as was Ariens Kappers (1877–1946).

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4.1. Theses Prepared under Rademaker’s Supervision at the Neurophysiology Laboratory, Leiden (1932–1946) 1. Visser J., “Optische reacties van duiven zonder groote hersenen” (Optical reactions of decorticated pigeons), Leiden, 193215 The objective of this study was to determine the extent to which the residual reactions in birds after extirpation of the cerebrum could be influenced by optical stimuli. This investigation continued on the foundation laid by the experiments on the basal ganglia and the brainstem in birds by Kalischer (1900,16 1905),17 (Roger, 1923),18 Edinger (1903)19 and von Holst, 1951.20 After a description of the experimental method, the thesis contains chapters on the blink and pupillary reflexes, optokinetic and post15 J. Visser’s doctoral thesis, which he defended in public on 16 June 1932, was written in Dutch and did not contain a French, German or English summary. Its contents were published in four parts in Archives Néerlandaises de Physiologie de l’homme et des animaux in the period 1934–1937: – Visser J. und G.G.J. Rademaker, “Die optischen Reaktionen grosshirnloser Tauben. Mitteilung I”. Archives Néerlandaises de Physiologie de l’homme et des animaux 19, 482–501, 1934. – Visser J. und G.G.J. Rademaker, “Die optischen Reaktionen grosshirnloser Tauben. Mitteilung II. Photokinetische und phototrope Reaktionen”, Archives Néerlandaises de Physiologie de l’homme et des animaux 20, 103–115, 1935. – Visser J. und G.G.J. Rademaker, “Die optischen Reaktionen grosshirnloser Tauben. Mitteilung III. Ausweichreaktionen”, Archives Néerlandaises de Physiologie de l’homme et des animaux 21, 285–295, 1936. – Visser J. und G.G.J. Rademaker, “Die optischen Reaktinonen grosshirnloser Tauben. Mitteilung IV. Beeinflüssung der optischen Reaktionen durch Abstandsverhältnisse”, Archives Néerlandaises de Physiologie de l’homme et des animaux 22, 398–417, 1937. 16 O. Kalischer, “Ueber Grosshirnextirpation bei Papegeien”, Sitzungsberichte d. Preuss. Acad. d. Kgl. Wiss., 5. July 1900. Fortschritte d. Medizin, vol. 18 No. 233, 722–726, 1900. 17 O. Kalischer, “Das Grosshirn der Papageien in anatomischer und physiologischer Beziehung”, Sitzungsberichte d. Kgl. Preuss. Acad. d. Wiss. in Berlin, 12 April, 23, 463–466, 1905. 18 F.T. Roger, “An experimental study of the corpus striatum of the pigeon as related to various instinctive types of behaviour”, J. of Comp. Neur. 35, 21 [–24]; 61–65, 1923. 19 L. Edinger, “Untersuchungen über die vergleichende Anatomie des Gehirnes. Das Vorderhirn der Vögel”, Abhandlungen, herausgegeben von der Senckenbergischen Naturförschenden Gesellschaft, Band 20, 343–426, 1903. 20 E. von Holst, Zentralnervensystem und Peripherie in ihrem gegenseitigen Verhältnis”, Klin. Wschrift 29, 97–105, 1951.

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rotatory nystagmus and the influence of optical stimuli on aural nystagmus and nystagmus following rotation of the head, photokinetic and phototropic reactions, evasion reactions and distance-dependent reactions, together with a separate chapter on whether decorticated birds can actually see or not. Visser concluded that pigeons still possessed primitive powers of sight after removal of the cerebrum. All the remaining optical reactions belonged to the group called ‘Gründreflexe’ by Pavlov.21 These Gründreflexe include not only walking, flying and pecking for food but also, as this study showed, more composite reactions such as leaving one perch and flying to another, avoiding thin and thick white cords strung up as obstacles, walking along the edge of a table without stumbling, etc. According to Pavlov and others, the Gründreflexe also include those animal reactions characterized as instinctive, which they considered to be composite reflexes or reflex chains (sequences of simple reflexes) such as Magnus’s chain reflex. Even though the reactions displayed by decorticated pigeons were still quite complex, their more or less automatic nature was striking. This facilitated the investigation of the factors leading to—or blocking—these reactions in pigeons from which the cerebrum had been removed. The sensitivity of the birds to stimuli proved to be of decisive importance for the occurrence of various motor reactions. The birds were found to be more sensitive if they were starved, and if the illumination level in the room where they were placed was increased. The intensity and the nature of the birds’ reaction to optical stimuli was found to depend on various factors, such as: • • • • •

the the the the the

intensity of the light from the objects or images used as stimuli, contrast between these objects or images and their surroundings, distance, position and size of the objects or images, and duration of exposure to the stimuli.

21 Pavlov understood these to be innate subcortical reactions, which did not have to be acquired, and are sometimes present at birth, such as the pecking of newborn chicks, the swimming of newborn ducklings, etc. However, other reactions, which did not arise until some time after birth, were also regarded as innate if they only arise after the organs or neural pathways required for them have developed. An example is the flying of pigeons, which does not have to be learnt but only manifests itself 4–6 weeks after birth when the wings have developed. Similarly, the reactions required for reproduction in animals are not seen until certain endocrine glands have developed.

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It was further found that other stimuli, e.g. those acting on the bird’s feet from the underlying surface, can inhibit the reaction to optical stimuli. The author stated that one of his objectives in this study was “to provide a basis for the argument that there is no need to assume higherlevel associations, mental processes or e.g. something called ‘instinct’ to explain the occurrence of these reactions.” 2. Maas H.H., “Onvolwaardig voedsel en krop” (Dietary deficiencies and struma), Leiden, 1933 Both as a researcher in his own right, but also as coordinator of research involving animal experiments at the Physiology laboratory in Leiden, Rademaker was keenly aware of the need for proper care and accommodation for the experimental animals. He often expressed these concerns at meetings of the consultative bodies set up within Leiden University Hospital to supervise the care of experimental animals. The present study may be seen as arising from these concerns, and also from Rademaker’s personal interest in the pathogenesis of exophthalmus, a complaint from which his wife Blanche had been suffering for some years. The immediate reason for the study was however the chance observation that the puppies in a litter born at the Physiology laboratory were suffering from enlarged thyroid of unknown origin. This condition was rarely seen among dogs, at least in the Netherlands, at this time. Other young dogs at the Physiology laboratory were also included in the study and were given the same diet as those discovered to have enlarged thyroids. In order to eliminate the possibility that non-dietary factors associated with the laboratory were causing this conditions, young animals born and raised elsewhere in the University Hospital were given the same diet. Bitches due to give birth to litters of experimental animals were also given the diet. To investigate the possible role of dietary deficiencies as a causative factor, a number of dogs in these groups were given dietary supplements. Thyroid enlargement was also studied in young dogs of other breeds, and the influence on thyroid enlargement of vitamin D, of various mineral salts and of iodine added to the diet was investigated. The degree of exophthalmus and the cardiac functions of the animals were monitored during the study.

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The author concluded that the normal standard diet for these experimental animals, consisting of raw horsemeat, brown bread and unboiled water from the dunes, did not meet the dietary requirements of young dogs fully and when given over an extended period led to struma. When a bitch had been given this diet exclusively for about a year, its pups often showed clear signs of struma before they were weaned. This struma could not be ascribed to hereditary factors or to local effects (including uncleanness of the surroundings). The clinical signs found in the animals with struma-included curvature of the bones, thickening of the joints, retarded growth and low weight, myopathy, disturbances in the dentition, thin, dry fur and sometimes exophthalmus.22 There was no clear relationship between the size of the struma on the one hand and the growth retardation and disturbances in the muscular and skeletal system on the other. The addition of the above-mentioned mineral supplement to the incomplete diet did not completely prevent the occurrence of struma parenchymatosa. However, the addition of small amounts of iodine (1/100 milligram per day) did prevent the enlargement and structural changes in the thyroid glands of these dogs. This study, carried out in 1933 by Maas and dedicated to his teacher, the neuroanatomist Prof. C. Winkler, had important implications for the diet of experimental animals at this time when dietary studies were still in their infancy. The diet of the experimental animals kept at the Physiology laboratory and elsewhere was changed on the basis of Maas’s findings. 3. v. Niekerk J., “Constitutie en allergische ziekten” (Constitution and allergic diseases), Rotterdam, 1934 23 The results of this experimental work were published in the following four articles:

These findings were later confirmed by investigations carried out by Kuypers in the Physiology laboratory in Leiden. C. Kuypers, “Untersuchungen über den Mechanismus des Exophthalmus”, Arch. Néerl. De Physiologie de l’homme et des animaux, 25, 323–335, 1941. 23 Prof. Storm van Leeuwen Sr, who had initially been appointed as research supervisor for this thesis, was unable to complete his task because of a terminal disease and asked his friend Rademaker to submit the text of the thesis to critical review and to act as research supervisor during the public defence of the thesis. 22

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• Ter Braak J.W.G., van Niekerk J., “Der Einfluss des Vagus auf die Innervation des Diaphragmas”, Acta Brevia Neerlandica 4, No. 5/6, 92, 1934 • van Niekerk J., Ter Braak J.W.G., “Die Anpassung der Atmung an Stenose der Luftwege”, Acta Brevia Neerlandica 4, No. 5/6, 93, 1934 • Ter Braak J.W.G., van Niekerk J., “Der Einfluss des zentripetalen Lungenvagus auf Lage und Bewegung des Zwerchfelles”, Pflüger’s Archiv. f.d.ges. Physiol. des Menschen u. der Tiere 235, 582–587, 1935 • van Niekerk J., Ter Braak J.W.G., “Die Anpassung des Atmungsvorganges an Widerstandsänderungen in den Atmungswegen”, Pflüger’s Archiv. f.d.ges. Physiol. des Menschen u. der Tiere 236, 44–51, 1935 4. Verwey N., “Over de lichaamshouding en de motoriek regelende reacties bij laagstaande oligophrenen, haar klinische en physiologische beteekenis” (On posture and motor-system control in extreme oligophrenia, and their clinical and physiological significance), Leiden, 1938 This study follows on from previous experimental and clinical work on such aspects of muscle tone such as dystonia, posture and ‘associate movements’ performed for example (to mention the main Anglo-Saxon researchers in this field after Sherrington) by Fulton and Denny-Brown at Yale and Wilson (1920), Riddoch (1921) and Walshe (1923, 1924) in London. Walshe in particular studied cases of decerebration rigidity that could be observed in neurological wards24 and other phenomena that had been mathematically quantified by Sherrington25 but not yet followed up in detail. Verwey’s study population consisted of children diagnosed as having oligophrenia (severe mental and physical retardation), since previous investigations had shown that these children had many of the postural

24 F.M.R. Walshe, “Decerebrate Rigidity in Animals and its Recognition in Man”, Proc. Roy. Soc. of Medicine, 15, 41–47, 1921. 25 Cited in F.M.R. Walshe, “The Decrebrate Rigidity of Sherrington in Man (its Recognition and Differentiation from other forms of tonic muscular contractions)”, Arch. of Neurology and Psychiatry, 10, 1–28, 1923, p. 7.

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reflexes that were also observed in experimental animals and normal infants. Oligophrenic children had the advantage for the purposes of this study that they retained certain postural reflexes that were only present in normal infants during certain relatively short phases of their development. This made it easier to study these reflexes; the results could then possibly be used to explain the reactions found in normal infants.26 Three groups of oligophrenic children were investigated: 1) those who were unable to sit up at all and were thus confined to bed in decubitus dorsalis; 2) those who could sit up unaided and could stand if supported but lost their balance if not supported, though they did sometimes retain static adaptation reactions; 3) those who could stand and walk without support, though they might often prefer to go on all fours. Results Group 1. These children all lacked the labyrinthine righting reflexes. They did however show Landau’s reflex, i.e. they lifted their head dorsally when held in the air or placed on a support face down. It was therefore concluded that Landau’s reflex cannot be a manifestation of the labyrinthine righting reflex but is probably related to the set of reflexes associated with decerebrate rigidity in experimental animals. This group also lacked other righting reflexes such as the exteroceptive righting reflexes of the body and the head, the optical righting reflexes etc. Some children in this group did however retain the neck righting reflexes more or less intact. This did not however lead to the reflex chain, which normally enables the child to sit up, suggesting the presence of defective subcortical mechanisms. However, purposeful cerebral reactions (such as bending forward and pushing up with the arms are also lacking, indicating that the operation of the cerebrum is also defective. These children showed two main bodily positions which compete for primacy, viz.: a) one characterized by stiffness of the neck, dorsal

26

See Book IV, Part 4.1.

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flexion of the head and opisthotonos, resembling decerebrate rigidity and b) a foetal position resembling ‘paraplégie en flexion’. Verwey pointed out that paraplégie en flexion is also due to an incomplete form of a condition resembling decerebrate rigidity. The patients from this group also showed other signs related to decerebrate rigidity, viz. the tonic neck and labyrinthine reflexes (though sometimes only in rudimentary form, as in normal infants), ‘plasticity’, the ‘clasp-knife phenomenon’ and the ‘shortening reaction’. The last three signs, which all relate to a sudden loss of resistance in the legs during passive bending and stretching, were also observed in group 2. Group 1. patients also showed marked magnet reflexes and support reflexes. (The former is tested for by passing a finger lightly over the sole of the foot while the leg is bent. The leg then follows the finger as if drawn by a magnet.) These two reflexes play a role in the normal standing mechanism,27 but are gradually lost by normal infants (in fact, they probably continue to play a role under control of the cerebral reactions, but can no longer be elicited by artificial means). The bending and stretching movements that were clearly marked in some patients from this group resemble the kicking of the legs displayed by normal infants. Like the similar alternating movements of the legs observed in spinal experimental animals, they are based on spinal reflex mechanisms. According to Rademaker, their significance for normal motor development lies in the field of walking movements. Group 2. Labyrinthine righting reflexes were present in children from this group, but were pathologically strong. Verwey ascribed the marked reflex nature of these righting movements to the lack of higher inhibitory cerebral reflexes. Investigation of the labyrinthine righting reflexes in these patients showed a phenomenon, which is also observed in normal experimental animals. When an oligophrenic child was tilted backwards so far that the plane of the mouth made an angle of 30° with the upward vertical, it could no longer hold up its head, neck and trunk which sagged downwards. This indicated that the labyrinthine righting reflexes were no longer operative.

27 Rademaker G.G.J., “The physiology of Standing”, V. The supporting reactions. A. The magnet reaction (exteroceptive supporting reaction) of the hindlimb; B. The magnet reaction of the forelimb, pp. 56–73, 1980 (originally published in 1931).

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Another phenomenon, which also proved to be based on the lack of inhibition of the labyrinthine righting reflexes, was that when most group 2 children sat up, the plane of their mouth was about 30° below horizontal. The mechanism by which these oligophrenic children sit up involves first bending the head ventrally and then lifting the trunk, during which process the abdominal muscles are tensed and the legs are stretched and usually lifted high above the underlying surface. When these patients were laid on their back, they were seen to have a constant tendency to bend the head ‘spontaneously’ in a ventral direction. This observation was so uniform as to suggest the presence of a reflex reaction. The ventral bending of the head and the trunk would seem to be at least partly due to exteroceptive stimuli acting on the child’s back. This indicated that exteroceptive righting reflexes could also be demonstrated in man. Of course, labyrinthine righting reflexes also play a role in helping the child to sit up. The fact that they are not solely responsible for this could be demonstrated by laying these oligophrenic children down on a table with the head hanging over the edge—a position in which the labyrinthine righting reflexes were no longer operative. It was found that they could still sit up from this position. This ‘symmetrical’ way of sitting up which was preferred by these patients was probably due to the presence of these uninhibited labyrinthine and exteroceptive righting reflexes. Some normal infants also sit up in this way right from the start, and the reflex reactions described above probably play a role there too. When group 2 children sit up as described above, their legs react in a way which is also seen in patients with cerebellar complaints and in young children: when the trunk has reached a vertical position, the legs are quickly stretched and lifted from the underlying surface. Rademaker regards this as a manifestation of hypersynergy and as part of the reflex chain initiated by the ventral bending of the head and leading to lifting of the trunk. The lack of inhibition mentioned above probably also plays a role in this reflex chain. Young children who are just learning how to sit up may also show similar reactions. They are also found in the righting reflex (Aufrichtungsreflex) described by Peiper28—though it is probably not true, as Peiper claims, that this is due to ‘the goodwill’ of the child (an explanation

28 Peiper A., in his monograph: “Die Hirntätigkeit des Säuglings”, Berlin, J. Springer, 1928.

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Peiper often gives when the child’s reaction differs from what he had expected). In Peiper’s case, as in the case of the oligophrenic children, the above-mentioned reflex mechanisms probably play a key role. As mentioned in connection with group 1, group 2 children also show plasticity, the clasp-knife phenomenon and lengthening and shortening reactions in the legs. The displacement reactions of group 2 children also showed interesting features. These children could not stand unaided, though they did show an appreciable supporting muscle tone in the legs. Now when the researcher tried to help the child to walk, the child tended to show adaptation reactions e.g. only on the right side, but these reactions occurred too late, were too slow and were not very effective. The limping gait produced in this way was reminiscent of that found in decerebrated animals. The stretching tone of the legs also showed other changes when the standing child was made to lean over sideways. When for example it was made to lean to the left, the contralateral leg was lifted from the ground. This reaction is due to the abduction and adduction of the first leg and the stretching tone of the other, and is typical of the ‘Schunkelreaktionen’ (‘seesaw reactions’) shown by decerebrated dogs. The reflexes Rademaker had discovered in decerebrated dogs and which allowed the animal to stand on its legs and keep its balance were similar to those found in the oligophrenic child in whom, as shown by various effects, cerebral reactions are very weakly developed. This rolling gait allowed the oligophrenic child to walk in much the same way as a normal child who is just learning to walk. It could best be observed by holding the child by both arms and tilting it over alternately to the left and the right. This caused the legs to be alternately lifted and lowered, causing the child to wobble from one leg to the other without going forward very much. Labyrinthine adaptation reactions could also be observed in these children, both when sitting and when standing. However, tactile and optical righting reflexes—which are cerebral reactions—were almost entirely lacking, in line with the effects noted above. Group 3. Observation of these children permitted an elegant demonstration of the mechanism of getting up called ‘primitive’ by Schalten-

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brand,29 viz. rolling over till one is lying on the stomach and then getting up on all fours. This way of getting up represents a normal stage in the motor development of some children. However, when observed in children up to 4 years of age it indicated that their motor development had come to a halt at a low level. As mentioned above, group 3 children often went about on all fours. The way in which they got into this position was very characteristic. After rolling over from lying on their side to lying on their stomach, they got up by pushing off from the ground with their outstretched arms and then placing their legs under their body. This brought them up on all fours. They could then go about on all fours, or rise to a vertical stance from this position. Observation of the way they rolled about the body’s longitudinal axis showed that this was preceded by rotation of the head. A reflex chain then led to rotation of the trunk and the pelvis in the same direction. It was noteworthy, however, that the neck-righting reflex could not be elicited passively when the child was lying down. The mechanism that these group 3 children used to get up was thus different from that used by group 2 oligophrenics to sit up, which as mentioned above was based on bending the head and the trunk in a ventral direction, these movements being generated by labyrinthine and exteroceptive righting reflexes free from cerebral inhibition. Some patients in this group showed inhibition of the labyrinthine righting reflexes under certain conditions, probably under the influence of cerebral reactions. The brain damage in such patients was apparently not so advanced as to remove the inhibition of certain subcortical reactions, though they did manifest certain signs that were still of a very primitive nature. Cerebral reactions such as intentional grasping movements, eye movements and optical righting reflexes could be clearly observed in these children. Children in this group walked in a way that resembled normal children who were just learning to walk, under the control of ‘seesaw reactions’. This is a further sign that the highest cerebral reactions are

29 Schaltenbrand G., “Ueber die Entwicklung des menschlichen Aufstehens und dessen Störungen bei verschiedenen Nervenkrankheiten”, Dtsch. Z. Nervenh.k. 89, 82–90, 1925.

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not yet well developed and are unable to inhibit subcortical reactions sufficiently. These children could get around better on all fours. Close observation of their movements showed that movement of a given leg preceded that of the contralateral arm—a pattern that could to a certain extent be explained by analysing the influence of the position of one extremity on the support tone in the other on the basis of Rademaker’s findings in experimental animals. Verwey concluded finally that it was desirable to carry out extensive examination of the motor system, even in children with extreme mental retardation, to permit proper training and if possible further development of the residual motor functions.30 5. Verbiest H., “De invloed van het achterstrengsysteem op de tonische corticospinale innervatie der extremiteiten. Het buigingsverschijnsel der vingers” (The influence of the posterior columns system of the spinal cord on the tonic corticospinal innervation of the extremities; the finger flexor sign), Leiden, 1939 This study was based on the original visions of Bell,31, 32 Magendie and Bernard. The Scottish anatomist Sir Charles Bell (1774–1842) had discovered the existence of sensory and motor nerves and had shown that the anterior columns of the spinal cord had a motor function while the posterior columns had a sensory function. He had also been the first to describe ‘the muscular sense’33—the ability of humans to perceive the movement of their own muscles—and had discussed its relationship with visual perception.34

30 See Bobath B., “Treatment principles and planning in cerebral palsy”, Physiotherapy April 1963, and the illustrations and accompanying text in Book IV, Part 4.2 of the present work. 31 Bell C. (1774–1842), “The Hand; its mechanism and vital endowments as evincing design”, London, 1832. 32 Spector B., “Sir Charles Bell and the Bridgewater treatises”, Bull. of the History of Medicine XII, 314–322, 1942. 33 Charles Bell, “An exposition of the Natural System of the Nerves of the Human Body with a Republication of the Papers Delivered to the Royal Society, on the Subject of Nerves”, Spottiswoode London, 1824. 34 See Charles Bell: “Essays on the Anatomy of Expression in Painting”, London, 1806. This book went through six editions and gave a rather philosophical exposition of the knowledge of human anatomy required by an artist.

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François Magendie (1783–1855) showed in 1822 that resection of the posterior columns led to severe motor disturbances, while Claude Bernard (1813–1878) observed that a frog without skin could move without major functional impairment. It was thought for many years that Bell’s ‘muscular sense’ was a separate sensory function, and successive researchers claimed to have discovered an increasing number of distinct varieties of this sense. For example, Goldscheider35 distinguished the ability to sense passive and active movements, the position of the limbs, weight and resistance to motion. Verbiest studied patients in whom disease had affected the posterior columns of the spinal cord, the medial lemniscus, the sensory thalamocortical radiation or the gyrus centralis posterior and found disturbances of the superficial and deep sensibilities and of motility. The motility disturbances were similar to what most neurologists would regard as ataxia. He also described ‘athetosoid’ movements of the hand and fingers (which most neurologists might characterize as static ataxia) as one of the signs of disturbance of the senses of passive movements and position in these patients. Verbiest coined the name the flexor sign for this phenomenon. The best way of studying it is to get the patient to keep his hands in a vertical position, the palms turned towards the examiner, and to ask him to close his eyes and to keep his hands in this position with the fingers stretched and pressed together. In cases where the senses of passive movement and position of the fingers are disturbed, the patient is unable to maintain this position and the fingers show a slow flexion at all joints. Verbiest concluded that the flexor sign may be absent because the patient can prevent the flexion of the fingers by a special effort of his stretch muscles (only observed in one patient with a very slight disturbance of deep sensibility); normal stretching of the fingers is accompanied by a slight palmar flexion of the hand at the wrist (this synergy may be exaggerated by some lesions resulting in the ‘choreic hand’,36 a clinical sign in which the fingers are overextended and the

35 Goldscheider A., “Ueber den Muskelsinn und die Theorie der Ataxie”, Ztschr. f. klin. Med. 15, 82–161, 1889; Goldscheider A., Archiv. f. Physiologie XIII u. Suppl. Band; Goldscheider A., Archiv. f. Physiologie XIV. 36 As described by S.A. Kinnier Wilson in “Modern Problems in Neurology”, London, 1928.

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hand is flexed at the wrist in palmar direction. Cases showing a ‘choreic hand’ do not exhibit the flexor sign, despite a disturbance of the deep sensibility of the fingers); and, in some cases with moderate disturbance of deep sensibility, the flexion of the fingers may be slightly inhibited by a passive palmar flexion of the hand. He further observed that in two normal control persons, where the metacarpo-phalangeal joints and surrounding tissues of the second and third finger had been anaesthetized by infiltration of Novocainadrenaline, the sense of passive movements of these two fingers was only slightly diminished, while the direction of passive movements was well estimated. The sense of position was lost, however: the position could only be guessed when the direction of the passive movement, which had led to it, was taken into account. It was concluded from these experiments that the senses of passive movements and of the direction of these movements originate from impulses arising in the muscles and their tendons. This conclusion can explain the clinical observations in cases where the patient’s recognition of passive sideward movement of the fingers is more disturbed than that of flexor or extensor finger movements (Verbiest’s personal observations) or those in which the sense of flexion is more disturbed than the sense of extension (cases described by Bergmark).37 Investigators such as Goldscheider (1889), who had attributed the sense of movement and direction of movements to impulses originating from the articular surfaces, could not explain these observations. In some cases38 of chorea minor, encephalitis or cerebellar tumour another flexor sign was encountered, which consisted of a flexion of the stretched fingers at the metacarpo-phalangeal joints resulting in a posture similar to that observed in cases of Parkinsonism. These patients never show correction movements. The inability to maintain the extremities in a fixed position was described earlier by many authors as a symptom of a pyramidal lesion (e.g. Mingazini’s sign, the inability to keep the arm stretched horizontally

Bergmark G., “Cerebral monoplegia, with special reference to sensation and to spastic phenomena”, Brain 32, 342–477, 1909. 38 This sign was not observed in all cases showing cerebellar symptoms, nor in a case where the greater part of the cerebellum had been removed. 37

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(G. Mingazini, 1859–1929)39 and Barré’s pyramidal sign, the inability to keep the leg bent while lying in a prone position). Verbiest’s investigations showed, however, that the same symptoms may be observed in cases of disturbed conduction of myogenic impulses along the posterior columns of the spinal cord, medial lemnisci or sensory thalamo-cortical radiation. 6. Kraan P.C., “Experimenteel onderzoek omtrent het Centrale Mechanisme van de Ontherseningsstijfheid en van eenige Righting reflexes” (Experimental study concerning the central mechanism of decerebrate rigidity and certain righting reflexes), Leiden, 193940 Kraan used new experimental techniques to test the conclusions Rademaker had reached about the nucleus ruber and its importance for the regulation of muscle tone in the study leading up to his own doctoral thesis in 1924,41 which had been contested by various authors in the intervening years. Sherrington had reported his initial findings on decerebrated animals in 1898. He had observed that making a transverse section through the mesencephalon and removing all cerebral tissue above this led to a characteristic rigidity in particular of the extensors of the extremities, the back, the neck and the tail. This decerebrate rigidity was particularly marked in the cat and the rabbit. Many other researchers followed his example, hoping that this special form of muscle tone regulation would throw light on the ‘normal’ mechanism for regulation of muscle tone. The results obtained were initially inconsistent, however. One of the main problems was the uncertainty about the precise method, and location, used for the decerebration cut. Strangely enough, Sherrington

39 Mingazini G., “Sur quelques ‘petits signes’ des parésies organiques”, Rev. Neurol. 20, 469–473, 1913. 40 Pieter Christiaan Kraan (1912–1989) was born in Leiden. He gained his medical qualifications in 1940, but his doctorate before that, on 14 Oct. 1939. Originally active as a GP in Emmen during the war (1941–1944), he later trained as a general surgeon in Rotterdam and Heerlen and joined the group of surgeons working at the hospital in Vlissingen, where he remained till his retirement (1950–1972). 41 G.G.J. Rademaker, “Die Bedeutung der roten Kerne und des übrigen Mittelhirns für Muskeltonus, Körperstellung und Labyrinthreflexe”, Berlin, Julius Springer, 1926.

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had contributed to this uncertainty by stating that he performed the section “roughly at the level of the mesencephalon”.42 Rademaker clarified the situation in a masterly fashion during his doctoral study in 1924 by determining precisely which sections consistently led to rigidity, and which always allowed the animal to regulate its muscle tone in the usual way. Since then there has been consensus—and this is one of the few things about which there has been consensus in this field—that a section between the corpora quadrigemina anteriora (c.q.a.) and the corpora quadrigemina posteriora (c.q.p.) leads to decerebration rigidity. There was however far from general agreement with Rademaker’s claims that a section anterior to the c.q.a. allows the animal to retain normal muscle-tone regulation, and that the site of muscle-tone regulation (at least in the cat and the rabbit) is the red nucleus (nucleus ruber). Many authors also expressed disagreement with the views put forward by Bard43 and Ranson.44 Bard (1933) was almost exclusively interested in higher cortical effects, and tended to neglect the influence of the mesencephalic centres. Ingram and Ranson (1932, 1934),45 on the other hand, did investigate

42 Magnus also shows the same lack of precision in his Croonian Lecture on Animal Posture (Proc. Roy. Soc. Vol. 98, 1925, p. 341): “By cutting accross the brain-stem somewhere between the posterior half of the medulla oblongata and the foremost part of the midbrain, the ‘decerebrate rigidity’ arises, in which the standing muscles acquire an abnormally high degree of tone . . .” and goes on to state that in order to obtain a normal distribution of muscle tone: “the foremost part of the midbrain is neccessary; by cutting the brain-stem somewhere in front of the midbrain or by extirpation of the forebrain so that a ‘mid-brain animal’ or a ‘thalamus animal’ results. . . .” Rademaker brought the necessary precision into this field by specifying the location of the coronary section in his experiments with the greatest possible accuracy and meticulous reporting of the results obtained with the different locations. 43 Bard P., “Studies on the cerebral cortex I. Localized control of placing and hopping reactions in the cat”, Arch. Neurol Psychiat. Chicago 30, 40–74, 1933; Bard P., “The cortical representation of certain postural reactions and the normal functioning of cortical remnants”, Arch. Neurol. Psychiat. Chicago 28, 745–747, 1933 (Abstract); presented at the meeting of the Boston Society of Psychiatry and Neurology, June 21, 1932. 44 Ranson S.W.; Hinsey J.C., “Extensor-tone after transection of the brainstem at varying levels”, J. of Nerv. and Mental Diseases 70, 584–597, 1929. 45 Ingram W.R., Ranson S.W., “Effects of lesions in the red nuclei in cats”, Arch. Neurol. Psychiat. 28, 483–512, 1932 [technique used was the Horsley-Clarke instrument]. Ingram W.R., Ranson S.W., Hannett F.I., Zeiss F.R., Terwilliger E.H., “Results of stimulation of the tegmentum with the Horsley-Clarke stereotaxic apparatus”, Arch. Neurol. Psychiat 28, 513–541, 1932.

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the mesencephalic centres and in particular the red nuclei in depth (making use among other things of the Horsley-Clarke stereotaxic apparatus, which Kraan also employed; see below), but their studies—unlike those of Rademaker’s—mainly concerned intact animals. The varying views on the subject of decerebration rigidity round about 1939 may be summarized as follows: 1. since Rademaker’s studies, no one contested the idea that the mesencephalon influenced decerebrate rigidity; 2. Rademaker’s claim that the regulation of muscle tone was primarily localized in the red nuclei was however disputed by others; 3. Rademaker recognized that the cortex could also play a role in regulating muscle tone, but did not believe that elimination of this cortical effect was necessary for the occurrence of decerebrate rigidity; 4. other workers regarded the cortex as much more important in this context, and considered that elimination of the cortical effect was essential for the development of decerebrate rigidity; 5. most researchers concluded that the cortical effect was localized in the motor cortex, though a few believed it to be situated in the frontal lobe (the premotor cortex) (Langworthy, 1928); 6. there was no proof that decerebrate rigidity is a release phenomenon (as claimed by Sherrington in 1896 and later by Bard in 1935).46 Moreover, as Kraan put it, Rademaker destroyed the red nuclei in mesencephalon animals by piercing them with a needle, and observed that this led to a state of rigidity. The general criticism of this method was however that it was relatively unselective and must have destroyed other parts of the mesencephalon in addition to the red nuclei so that it was incorrect to conclude that the rigidity observed was entirely due to the destruction of the red nuclei. Another fact that must be taken into account is that the cortex probably has a relatively small effect on muscle tone in the rabbit, his main experimental animal, e.g. because the pyramidal tract can only be followed as far as the cervical spinal cord.

Ingram W.R., Ranson S.W., Barris R.W., “The red nucleus; its relation to postural tonus and righting reflexes”, Arch. Neurol. Psychiat. 31, 768–786, 1934. 46 Sherrington C.S., “Decerebrate Rigidity and reflex coordination of movements”, J. Physiol. 22, 319–332, 1898; Bard P. in MacLeod’s “Physiology in Modern Medicine” 7th edition, 1935.

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Kraan used two techniques in an attempt to clear up the uncertainties indicated above: the Horsley-Clarke stereotaxic apparatus for precise localization of all neurosurgical operations, and local freezing of the mesencephalon as a less invasive means of shutting down the functions of this organ. In general, he studied the body righting reflexes and the labyrinthine righting reflexes of the experimental animals postoperatively. The Horsley-Clarke apparatus Rademaker had a slightly modified Horsley 47-Clarke48 stereotaxic apparatus, designed in his own laboratory workshop, installed in his laboratory in 1939 (see figure). It was used first for neuroanatomical purposes but was later employed in the neurophysiology laboratories and finally for neurosurgery. As Tepperman (1970) put it, “The pre-eminent place of the HorsleyClarke instrument in the furtherance of knowledge of the brain is difficult to match; in fact the invention has been compared in importance to that of Galileo’s telescope and the microscope of Leeuwenhoek”.49 The principle on which the stereotaxic instrument was constructed50 lay in determining a reliable baseline. This was accomplished in the rhesus monkey cadaver by inserting a fine ivory knitting needle from one auditory meatus across the head to the opposite meatus; the same was done for the orbital ridges. When one or two millimetre sagittal

47 Victor Haden Horsley (1857–1916). London general surgeon who made his mark in neurosurgery, recognized the advantage of cerebral localization of bodily movements in determining whether diseased brain should be operated. His most significant contribution to neuroscience was made when he inspired Robert Clarke to design a stereotaxic instrument. 48 Robert Clarke (1850–1926). Physician-physiologist, with whom he worked on the cerebellum. To overcome their difficulty in identifying the localization of their experimental stimulus, Clarke applied geometric principles to the problem of precise and trauma-free electrode penetration into the brain and conceived, designed and supervised the construction of the stereotaxic instrument. 49 Tepperman J., “Horsley and Clarke: a biographical medallion”, Perspect. Biol. Med., 13, 295–308 [304], 1970. 50 Horsley V., Clarke R.H., “The structure and function of the cerebellum examined by a new method”, Brain 31, 45–124, 1908. Details of its construction and use were published with a note that experimental data on the cerebellum would follow. Unfortunately there was no subsequent publication—the close friendship between Horsley and Clarke cooled and the collaborators drifted apart.

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Fig. 4-5. Photograph of the Horsley-Clarke apparatus used by Kraan, taken from his thesis. The apparatus is seen in use on an anaesthetized cat.

sections of the frozen head were cut, the needles served as baseline guides for lining up the superimposed millimetre grid. Since the findings of Ranson et al. (1932)51 concerning the consequences of isolated lesions of the nucleus ruber, which conflicted with Rademaker’s conclusions, were made with the aid of this instrument, it was considered appropriate to use in Kraan’s study in an attempt to throw more light on to the situation. Local freezing of the mesencephalon The method developed by Trendelenburg (1910)52 for “reversible stimulus-free elimination of CNS functions” was used here. The experimental animal was first anaesthetized with ether. After craniotomy, a transverse section was made just anterior to the corpora quadrigemina, and all mesencephalic neural tissue situated anterior to this section was cut out and removed. After a pause for equilibration, a glass tube containing a freezing mixture of ether and carbon-dioxide snow was applied to the cut, leading to freezing of the corpora quadrigemina anteriora and the part of the mesencephalon situated ventral to them, leading to complete 51 Ingram W.R. and Ranson S.W., “Effects of lesions in the red nuclei in cats”, A.M.A. Arch. Neurol. Psychiat. 28, 483–512, 1932. Ingram W.R., Ranson S.W., Hannett F.P., Zeiss F.R., Terwilliger E.H., “Results of stimulation of the tegmentum with the Horsley-Clarke stereotaxic apparatus”, Arch. Neurol. Psychiat. 28, 512–541, 1932. For discussion see also Book II, Part 2.3 of this book. 52 Trendelenburg W., “Untersuchungen über reizlose vorübergehende Ausschaltung am Zentralnervensystem”, Pflüger’s Archiv. f.d. ges. Physiol. des Menschen u. der Tiere 135, 469–505, 1910.

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elimination of the normal function of these tissues. Kraan gave some thought to the question of whether this method really is so “stimulusfree” as Trendelenburg claimed. The complex nature of the freezing process, where the condition of the nerve cells, the conductivity of the nerve cell, the state of the capillaries and of the blood all play a role, makes it impossible to construct a theoretical picture of precisely what happens during freezing, particularly at the interface between frozen and unfrozen tissue. Nevertheless, Kraan concluded that it was reasonable to assume on the basis of the observations by Trendelenburg and others that at temperatures of around 6°C no stimuli are produced but that the conduction of stimuli is eliminated or interrupted. Temperatures higher than 6°C do not give rise to stimuli either, according to these investigators. It would thus appear that the decerebration rigidity observed under these conditions was not due to stimuli arising from the site of the cut. This is powerful evidence in favour of Sherrington’s view that decerebration rigidity is a release phenomenon. The rigidity, the support reflex, the magnet reflex and in particular the body and labyrinthine righting reflexes of the experimental animals were examined in detail after this local freezing of the encephalon. The second part of the study involved selective destruction of the red nuclei and/or the formatio reticularis in the cat. First, a mesencephalon animal was created by transection anterior to the corpora quadrigemina anteriora as indicated above. A needle, located with the aid of the Horsley-Clarke stereotaxic instrument, was then used to destroy the selected structure, the needle being inserted at right angles to the plane of the section rather than laterally to reduce the chance of destroying other neural tissue. The localization of the lesion was verified microscopically in all experiments. This led to the following results: 1. extirpation of the cerebral cortex or part of it gave no rigidity but a slight tendency to increased stretching of the extremities; 2. extirpation of the cerebral cortex combined with ‘stimulus-free’ interruption of the function of the entire mesencephalon by the Trendelenburg freezing method gives pronounced rigidity which is indistinguishable from ‘normal’ decerebration rigidity; 3. the body righting reflexes and labyrinthine righting reflexes disappear as soon as the mesencephalon loses its function as a result of the freezing, and rigidity develops;

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4. a section through the anterior edge of the corpora quadrigemina anteriora to the middle or the anterior edge of the corpora mamillaria need not give rise to any rigidity or even an increased tendency to stretching of the extremities; 5. it is impossible to determine whether this section gives rise to a normal or abnormal (enhanced or diminished) muscular tension; 6. extirpation of the cortex and destruction of the red nuclei give only slight rigidity;53 7. extirpation of the cortex together with destruction of the red nuclei and the surrounding formatio reticularis—especially in the rostral region of the red nuclei—gives pronounced rigidity which is (almost) indistinguishable from ‘normal’ decerebration rigidity; 8. the formatio reticularis in the immediate environment of the red nuclei, especially in the rostral region, appears to play a role in regulation of muscle tension by playing a major role in preventing rigidity; 9. it must be assumed that the efferent pathway from this formatio reticularis is not crossed at this point. These results led Kraan to the following conclusions (see pp. 134–135 of his thesis): 1. Animals (cats) in which the red nuclei have been destroyed or have lost their function bilaterally are unable to maintain their body righting reflexes and labyrinthine righting reflexes. 2. The formatio reticularis surrounding these nuclei has little or no direct significance for the maintenance of these reflexes. 3. The destruction of the rostral or caudal part of the red nuclei does not have enough effect to eliminate the body righting reflexes. 4. The destruction of the caudal part of the red nuclei is also not sufficient to eliminate the labyrinthine righting reflexes. These conclusions thus support the importance Rademaker attached to the red nuclei as the centres for the body and labyrinthine righting

53 This result conflicts with the observartions and views of Bard et al. (Bard P., C.M. Brooks and C.N. Woolsely, “Decorticate and decerebrate rigidities in the cat”, The Amer. Journal of Physiology 109 (1), 5, 1934), who claimed to observe rigidity even after extirpation of part of the cortex (in particular the motor cortex).

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reflexes. As regards the question of whether the regulation of muscle tension was to be regarded as a cortical mechanism, Kraan concluded that Bard et al. were too one-sided in the importance they attached to the cortex—though Rademaker erred in attaching too little importance to it. According to him, the views of Ingram, Ranson et al. were closest to the truth, though what they called “a slight rigidity” could better be referred to as an increased tendency to stretching. As Kraan put it at the end of his thesis, The results of our experiments do not support Rademaker in his view that the regulation of muscle tension is primarily a subcortical matter. Furthermore, according to us the red nuclei are not the only mesencephalic bodies to play a role in the regulation of muscle tension: the formatio reticularis—especially the part surrounding the rostral tips of the red nuclei—is also important in this connection.

Epicrise Each attack on the Rademaker-Winkler interpretation of the experimental cross-coronal section data of the brainstem has strengthened their position. However, when thinkers of the calibre of Fulton in Yale, try to find flaws with a theory, but the defenders of the nucleus ruber theory were able to refute all or many of the attackers (Ranson, Hinsey, Hare, Bard filled a whole issue of the Archives of Neurology and Psychiatry)54 at that time. Some had to be admitted by Rademaker (with the though incomplete arguments—also—by his own pupil Kraan). There is no point in going over all of the ground work of the above mentioned arguments that resulted in the refutation of all the counter proposals to the Rademaker interpretation, a job that has been well done by PHD student Kraan in his thesis. The most important one’s to notice is those made by Kraan and Bard. Some are an improvement of the Rademaker interpretation such as the pyramidal tract i.c. possible cortical involvement and the rostrally located formatio reticularis, that still includes the nucleus ruber (nota refutation or counterproposal by Kraan) or as Denny-Brown stated ultimately, “the red nucleus is but one

Archives of Neurology and Psychiatry, Vol. 28, number 3 September 1932, pp. 483–756. 54

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of a series of levels of elaboration of the righting reflexes. Rademaker’s monograph (of his thesis) greatly clarified the issues”.55 The combination of theory and experimental data that had let us to the three complementary things in one model, as a unitary concept of movement, as a thought experiment in which it would theoretically be possible to measure (mathematically?) complementary things at once, tonus, posture and movements—or its precise energy at a precise moment and so on. Electromyographic evedence pointed in this direction as Rondot showed later. Or could it not be carried out in that way? A historical note is relevant here: during the 1940–1945 period Rademaker’s life was in turmoil. Experimental work became impossible. Laboratory facilities, animal provision were lacking because of economic reasons. Various twists and turns of Rademaker’s mind on this subject after Kraan’s experiments at that time, are only indirectly known and have not been documented as to my knowledge. There has been no paper with a follow-up of Rademaker’s thoughts after Kraan submitted his thesis (in Dutch language). It had been a remarkable fact that Rademaker had accepted that Kraan could repeat his experiments—although with a slightly modified Horsley-Clarke instrument in his hands—in Rademaker’s laboratory, performing this experimental work in a difficult period as the war years were. Rademaker was a truly honest man, always and under these circumstances ready to accept sound experimental evidence even if it would mean to refute his earlier conclusions and by his own pupil. This experimental verification of Rademaker’s earlier work, his premises and axiomata, is so important that it is presented a chapter in itself (see further). Could electromyography, a relative simple device, solve the problems raised? Could it demonstrate the movement of energy from bottom to top, from A → B → C, or from top to bottom, and motion in space, to squeeze three space dimensions into one? A technical difficulty, a serial writing up, diverse ‘remainements’? (see further)

In: “The Physiology of Standing” by G.G.J. Rademaker. Translated by D. DennyBrown, Published by University of Minnesota Press, 1980, Foreword, p. V. 55

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In retrospect and by studying in detail the protocols of experimental animal operations, where controversies had arisen, the following remarks can be made: • Species specificity was underscored in a number of studies. Pathologicalanatomical controles clarified this sometimes and the sizes of the ruber nucleus in patients could differ (see figures in Brain article).56 • The methods used to arrive at the decerebration state as required by Sherrington and Magnus differed in a number of cases. Instead of ablation by coronal section at the proper level, the ‘anaemic method’ was used. • Postoperative care, avoiding infections, malnutrition etc. In the literature there were great differences in this respect. • Operative methods for analysing. A remarkably difference made the introduction of the Victor Horsley-Clarke apparatus. • Methods to examine the postoperative status such as tonus in different muscle groups was not uniform (as was observed by Denny-Brown and Rademaker). • As was known Rademaker was only interested in chronic cases i.e. long standing after the operation before conclusions could be drawn from their neurological status. The interpretation of Rademaker’s experiments was criticized when Magoun and Rhines57 found that the pontine and medullary formation were (also) involved in the regulation of posture. Rademaker’s experiments did not distinguish between the contribution of the red nuclei and the reticular formation till 1938 when Rademaker’s pupil and collaborator did his experiments for his thesis just before the war broke out and experimental work had to be stopped. At present, in Kraan’s thesis (in Dutch language) using the HorsleyClarke’s, the contribution of the reticular formation around the ruber nucleus was clearly established. Communications were bad in the war and sure enough Magoun and Rhines could not have been aware of See figures in Brain 81, 284–289; p. 163 of the present book. Magoun H.W. and Rhines R., “An inhibitory mechanism in the bulbar reticular formation”, Neurophysiol., 9, 165–171, 1946 at Ranson’s Institute of Neurology of North Western University Medical School. 56 57

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these results in Rademaker’s laboratory since the thesis was published only in the Dutch language (in 1941!). Rademaker’s thesis “The significance of the red nuclei and other parts of the mesencephalon for nuscle tone, body posture and labyrinth reflexes”, Utrecht, 1924, assigned for the first time on the ground of exact experimental research a function to a deliminated nuclear area in the brainstem whose anatomical connections in themselves gave no direct indication of this function (Ter Braak et al., 1953).

And that if the forebrain is intact, righting reflexes (except optic righting; my underlining LH) may still be elicited when the red nucleus have been destroyed. The essentials of Rademaker’s observations are still undisputed and find a place in any textbook of physiology (ibidem)

Rademaker arrived at these results after redesigning the experimental set-up from Sherrington and independently from him conceived design from Magnus, to obtain the decerebration model in rabbit (n = 35), and cats (n = 6), in order to exact localisation of the ruber nucleus by ablation studies with pathological anatomical control (Winkler) and a comparative pathological anatomical study of the world literature on this subject as appeared in the periode 1871–1906, on human pathology, using the French clinicopathological correlations method (Clarke and Jacyna, 1987). Where clinicopathological findings mirroring the clinical data in humans. As Rademaker has shown without any doubt the nucleus ruber is indeed the centre for the labyrinth reflexes acting on the body but not for the righting reflexes acting on the head. The efferent path of the two first named reflexes is the rubrospinal bundle, the afferent tracts had still to be found. But the beginning was made towards translating the physiological facts into anatomical language, ultimately leading to the red nucleus level of motor integration which it has become (reflecting motor activities, tonus and posture that the intact midbrain, pons, medulla and spinal cord can organize when disease or trauma disconnects the corticospinal-rubrospinal tracts in the creberal hemispheres and reticular substance in the brainstem. Looking back over the space of 65 years on the controversy between Rademaker and other authors about the function of the red nucleus and the attempts of Kraan to resolve this, we may conclude that the

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researchers on both sides of this controversy made a big contribution to our understanding of the mechanisms of neural control of posture and movement. As Denny-Brown put it in 1980, “Rademaker . . . concluded that the essential structure [in determining the course of righting reflexes] was the red nucleus. Subsequent investigators, reviewed by Fulton (1943), showed that the question is more complex; the red nucleus is but one of a series of levels of elaboration of the righting reflexes. Rademaker’s monograph [i.e. his 1926 thesis] nevertheless greatly clarified the issues”.58 No one on either side doubted that the red nuclei played an important part in this matter, but there was considerable doubt in particular as to the relative contributions of cortical and subcortical systems. Today we have a much clearer picture. It may be mentioned that one of those who contributed to development of the theory in this field was Pierre Rondot, a pupil of Rademaker’s friend and colleague Raymond Garcin. He used advanced electromyographic measurements, not available in Rademaker’s time, in an attempt to understand postural mechanisms from another point of view.59 The development of our understanding of the red nucleus may be illustrated from a neuroanatomical perspective by comparing what Gray’s Anatomy had to say about the red nucleus in 1901 and in 1995. The 1901 edition contained the following very brief statement: “The red nucleus or nucleus of the tegmentum, is a tract of gray matter situated on either side of the middle line, and is composed of numerous large cells, which are deeply pigmented. It is pierced by the fibres of the third [motor oculi] nerve, and prolonged above into the posterior part of the subthalamic region.” The 1995 edition, on the other hand, devotes two pages to the topic. It gives a diagram of the principal afferent and efferent connections of the red nucleus in man, discusses the structural relationships between the corticorubral, rubrospinal and corticospinal tracts and mentions some of the differences between these systems in man and in various experimental animals. As regards the functional aspects, the University of Massachusetts Medical School gives an excellent review of current understanding

58 In “The Physiology of Standing” by G.G.J. Rademaker. [Translation of Das Stehen] Edited with a foreword by D. Denny-Brown, University of Minnesota Press, Minneapolis 1980, Foreword, p. V. 59 He reviewed his own results in “The shadow of movement”, the Presidential Address to the Second European Neurological Society Meeting at Brighton in 1990. This is discussed at somewhat greater length in Book IX, Part 9.

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of the red nucleus level of motor integration as part of its course on the brainstem and cerebellum. This explains that many four-footed mammals have no corticospinal tract or only a rudimentary one, so all voluntary locomotion behaviour is necessarily organized by the red nucleus. A horse walking, trotting or galloping is a pure example of what this course calls ‘red nucleus walking’. In humans, this form of locomotion may be found in babies in the first year of life, if the rubrospinal tract myelinates before the cerebrospinal tract; it also governs the way humans swing their arms when they walk (a kind of reflection of the way quadrupeds move their limbs); and it may be found when the function of the cerebrospinal tract is disrupted in strokes. These various insights help to resolve many of the disagreements between Rademaker and his contemporaries about the primacy of the motor cortex and the red nuclei in the control of movement. Kraan completed his thesis in 1939. Research at Leiden was impossible during World War II, since as mentioned elsewhere the university was closed down in protest at the treatment of Jewish students and teaching staff by the occupying powers. There is no written record of the development of Rademaker’s ideas on the red nucleus in response to Kraan’s research. Rademaker’s life—like that of everyone else in the Netherlands—was in turmoil in the period from 1940 to 1945. After the war, it took another turn. One interesting anecdote showing the relationship between Rademaker and Kraan in a completely different light is given in the endnoteii. 7. Ruys C., “Over rotatoire oogdeviaties opgewekt door centrifugaalkracht” (On ocular rotation due to centrifugal force), Leiden, 1945 This study was carried out in an attempt to resolve the long-standing disagreement between Quix60 on the one hand and Magnus, de Kleyn F.H. Quix (1874–1946) was one of the leading Dutch otorhinolaryngologists of his day and an authority on many aspects of this field. He was appointed to a chair in Utrecht. His contributions included advances in ENT surgery. Together with H. Zwaardemaker (1857–1930), who succeeded Donders to the Chair of Physiology at Utrecht, he proposed a system of Dutch speech sounds to be used in the diagnosis of hearing loss. He also devised the Quix test for vestibular dysfunction, in which the patient stands, eyes closed, with the arms straight ahead. Lateral drift is reegarded as a positive (abnormal) result. 60

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and Rademaker on the other about the mechanism of the compensatory movements of the eyes, which played an important role in maintaining equilibrium and in righting reactions. It was generally assumed that the function of these movements was to neutralize (at least in part) the movement of the images on the retina due to movement of the head or body. A great deal of research had preceded Ruys’s study. Van der Hoeven and de Kleyn (1917)61 had measured these movements in rabbits in Magnus’s laboratory, and had found that the neutralization of the movement of the retinal images was far from complete. According to de Kleyn (1920),62 this incomplete neutralization was partly due to the experimental method used by van der Hoeven and himself, which eliminated the effect of the tonic neck reflexes. When a rabbit moves its head, the position of the head changes not only with respect to the force of gravity but also with respect to its body. As Bárány (1907)63 had been the first to show, this movement of the head with respect to the body triggered eye movements by what came to be known as ‘tonic neck reflexes of the eyes’. De Kleyn therefore carried out further studies on rabbits both with and without labyrinths, and found that if the head is fixed and the body is moved with respect to the head, or if the head is moved passively by the researcher, complete neutralization is obtained if the head movements are within the range from 55° ventral to 45° dorsal with respect to the normal position (with the plane of the mouth about 35° below the horizontal).64 Fleisch (1922)65 studied vertical compensatory eye movements—also in rabbits—shortly after, using ingenious techniques to record the eye movements. He confirmed the previous conclusion that there is a tendency to neutralize the movement of the retinal images, but showed experimentally that blind rabbits show different movements from

v.d. Hoeven J. and de Kleyn A., “Tonische Labyrinthreflexe auf die Augen”, Pflüger’s Archiv. f.d. ges. Physiologie des Menschen u. der Tiere 169, 241–262, 1917. 62 de Kleyn A., “Tonische Labyrinth- und Halsreflexe auf die Augen”, Pflüger’s Archiv. f.d. ges. Physiologie des Menschen u. der Tiere 186, 82–97, 1920. 63 Bárány R., “Augenbewegungen durch Thoraxbewegungen ausgelöst”, Zentralblatt für Physiologie 20, 298–302, 1907. Bárány won the Nobel Prize for Physiology in 1914 for his work on the physiology and pathology of the vestibular system. 64 According to Ruys, de Kleyn had neglected to verify whether the eye movements found in this way were the same as those produced when the head is moved with respect to the body but not with respect to gravity. 65 Fleisch A., “Tonische Labyrinthreflexe auf die Augenstellung”, Pflüger’s Archiv. f.d.ges. Physiologie des Menschen u. der Tiere 194, 554–573, 1922. 61

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sighted ones, and that the results can be influenced by various optical effects. He also found that the head had to be moved very slowly to achieve complete neutralization: according to him, even a rotation of 2° in 3 seconds could have a noticeable influence on the position of the retinal images.66 There was fairly general agreement between all researchers that the labyrinthine reactions were elicited by the position of the labyrinths with respect to the force of gravity, via impulses brought about by the otoliths. Ter Braak (1936) pointed out that a possible difference in density between the cupula and the endolymph of the semicircular canals could influence the results. There was further fairly general agreement that rotary compensatory eye movements were generated by the otoliths of the utriculus, but there was a difference of opinion about the origin of the impulses that caused vertical compensatory eye movements. Quix (1918)67 and Fleisch (1922)68 claimed that they came from the otoliths of the sacculus, but Parker (1909),69 Laudenbach (1899),70 Maxwell (1923)71 and Versteegh (1927)72 had shown that these reactions could still observed in animals in which the otoliths of the sacculus had been removed or destroyed. This led to vigorous debate at meetings and congresses and in the scientific literature between Quix and his camp on the one hand and Magnus, de Kleyn en Rademaker on the other throughout the period 1915–1930. There were in fact five different theories about the mechanism involved: 66 According to Ter Braak, an angular acceleration of 0.23°/sec2 always gave an ocular deviation in rabbits, while even an angular acceleration of 0.09°/sec2 sometimes did. See Ter Braak J.W.G., “Ueber die Empfindlichkeit des Bogengangsapparates für Winkelbeschleunigungen”, Pflüger’s Archiv. f.d. Physiologie des Menschen u. der Tiere 238, 327–332, 1936. 67 Quix F.H., “Metingen en beschouwingen over de otolithenfunctie”, Ned. Tijdschr. v. Gen., 902–913, 1918. 68 Fleisch A., “Tonische Labyrinthreflexe auf die Augenstellung”, Pflüger’s Arch. f.d. ges. Physiologie des Menschen u. der Tiere 194, 554–573, 1922. 69 Parker G.H., “Influence of the eyes, ears and other allied sense organs on the movements of the dogfish”, Bull United States Bureau of Fisheries, Dpt. of Commerce, 45–57, 1909. 70 Laudenbach J.P., “Zur Otolithenfrage”, Pflüger’s Arch. f.d. ges. Physiologie des Menschen u. der Tiere 77, 311–321, 1899. 71 Maxwell S.S., “Labyrinth and equilibrium”, J.B. Lippincott Company, Philadelphia and London, 1923. 72 Versteegh C., “Ergebnisse partieller Labyrinth-extirpation bei Kaninchen”, Acta Oto-Laryngologica XI, 393–408, 1927.

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I The ‘push’ theory This theory, energetically proposed in the Netherlands by Quix (1918, 1921, 1923),73 assumed that the nerve endings in the maculae were only stimulated if the otoliths exerted pressure on the maculae. The greater the pressure the greater would be the stimulus, and the greater the reaction.74 A zero or negative pressure on the other hand would not produce a stimulus. This theory was disputed by Rademaker75 among others. II The ‘push-pull’ theory This theory, proposed in the Netherlands by Magnus and de Kleyn (1921a, 1921b, 1922),76 assumed that the nerve endings were stimulated not only when the otoliths exerted pressure on the maculae but also when they exerted a tensile force. Maximum pressure would produce an effect in one direction and maximum tensile force an effect in the opposed direction. III The ‘slide’ theory Breuer (1891)77 suggested that movements of the head cause tension in the hairs of the neuroepithelium in the labyrinths because the otoliths move parallel to the surface of the maculae, and that this lateral movement generates the labyrinthine reactions. 73 Quix F.H., “Metingen en beschouwingen over de otolithenfunctie”, Ned. Tijdschr. v. Gen., 902–913, 1918; Quix F.H., “La fonction des Otolithes”, Arch. Néerl. de Physiol., Deel VI, 1–19, 1921; Quix F.H., “La fonction des Otolithes”, Arch. Néerl. de Physiol., Deel VIII, 427–468, 1923. 74 Quix F.H., “The function of the vestibular organ and the clinical examination of the otolithic apparatus”, J. Laryngol. and Otology 40, 425–443; 493–511, 1934; Quix F.H., “De klinische onderzoeksmethoden van het gehoorszintuig en het vestibulair orgaan”, in: “Leerboek der zenuwziekten”, Bouman and Brouwer (eds.), vol. II B, p. 734, De Erven F. Bohn, Haarlem, 1930. 75 See summary of discussion after lecture by G.G.J. Rademaker on “Labyrinth en evenwicht” (Labyrinth and equilibrium) in Ned. Tijdschr. v. Gen. 78, 5793–5797, 1934. 76 de Kleyn A., Magnus R., “Über die Funktion der Otolithen. I Mitteilung. Otolithenstand bei den tonische Labyrinthreflexen”, Pflüger’s Arch. f.d. ges. Physiol. des Menschen u. der Tiere 186, 6–48, 1921; de Kleyn A., Magnus R., “Über die Funktion der Otolithen. II Mitteilung. Isolierte Otolithenausschattung bei Meerschweinchen”, Pflüger’s Arch. f.d. ges. Physiol. des Menschen u. der Tiere 186, 61–81, 1921; de Kleyn A., Magnus R., “Über die Funktion der Otolithen. III Mitteilung. Kritische Bemerkungen zur Otolithentheorie van Herrn F.H. Quix”, Pflüger’s Arch. f.d. ges. Physiol. des Menschen u. der Tiere 194, 407–434, 1922. 77 Breuer J., “Über die Funktion der Otolithen-apparate”, Pflüger’s Arch. f.d. ges. Physiologie des Menschen u. der Tiere 48, 195–306, 1891.

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IV Maxwell’s ‘bowl’ theory (1923)78 Maxwell assumed that the surface of the macula is concave, so that the otoliths move like balls in a bowl when the head moves. The labyrinthine reactions would then be produced as a result of this displacement, the direction in which the hairs of the neuroepithelial cells are pulled determining the direction of the reaction. V The ‘endolymph’ theory Finally, Werner concluded on the basis of the observation that rotary eye movements occur even when the otoliths are completely removed from their place by centrifugation “dass der adequate Reiz in lokalen Wirkungen des Flüssigkeitsdruckes beruht” (that the adequate stimulus consisted of the local effect of the pressure in the endolymph). Ruys hoped that looking at labyrinthine reactions from a new perspective, obtained by submitting the experimental animals to a centrifugal force, might provide new data that would enable him to resolve the conflict of views indicated above. In fact, Nelissen (1934),79 working in Quix’s laboratory in Utrecht, had already investigated the influence of centrifugal forces on the labyrinthine reactions (in particular the vertical compensatory eye movements). In his opinion, his results confirmed Quix’s pressure theory (even though several of his observations conflicted with this theory). Ruys recorded the eye movements of his experimental animals with the aid of an ingenious set-up he had constructed himself.80 He chose the 78 Maxwell S.S., “Labyrinth and equilibrium”, J.B. Lippincott Company, Philadelphia and London., 1923. 79 Nelissen A.A.M., “Labyrinthreacties op oogen en ledematen, opgewekt door rechtlijnig werkende krachten en door constante centrifugaalkrachten” (Labyrinthine reactions on eyes and limbs generated by linear forces and by centrifugal forces), Thesis, Utrecht, 1934. 80 This consisted of a copper tube with a light source (the light from which passed through a horizontal slit) at one end and a lens at the other. The narrow beam of light emitted by this lens was refracted by a prism and then reflected by a mirror mounted on a shaft at right angles to the line of the tube, finally landing on the cornea of the experimental animal (a rabbit) which was lying in a prone position with its head fixed at a certain angle. A marker was previously mounted on the cornea under cocaine anaesthesia. The light reflected by this marker travelled back along roughly the same path. This whole set-up, mounted on a turntable, allowed the light signals to be picked up and hence the position of the rabbit’s eye to be accurately recorded even when the turntable was rotating. Rotation of the turntable at an adjustable angular velocity allowed the experimental animal to be subjected to a centrifugal force. Each animal was centrifuged in this

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centrifugal forces to which the animals were exposed so that the resultant of the force of gravity and the centrifugal force remained within physiological limits—unlike Nelissen, who had used much larger centrifugal forces. Ruys did however express certain reservations about the unphysiological nature of his experiments (see p. 17 of his thesis): Seen from a mechanistic perspective, the unphysiological nature of our experiments resides not in the magnitude of the forces used but in the fact that the labyrinth is exposed for a certain length of time to two mutually perpendicular forces—a situation which does not occur under physiological conditions.

This comment seems to echo the views of Ruys’s teacher Rademaker, who was always critical of tests of labyrinthine reactions (such as the caloric test) that were characterized as unphysiological, and rejected their use for clinical purposes.81 By comparing the magnitude and direction of the rotary eye movements caused by centrifugal forces with the eye movements elicited by the force of gravity as the position of the experimental animal’s head was varied and assuming, as was generally held to be the case, that the rotary compensatory eye movements were caused by the otoliths of the utriculus, Ruys came to the following conclusions: 1) the compensatory eye movements cannot be due to an increase or decrease in the pressure exerted by the otoliths of the utriculus at right angles to the macula; 2) nor can they be caused by an increase or decrease in a tensile force exerted by these otoliths at right angles to the mucula; 3) in other words, neither Quix’s theory nor that of Magnus and de Kleyn can explain these eye movements; 4) on the basis of the experimental results, the eye movements observed could be due to traction by the otoliths of the utriculus parallel to the plane of the macula, but no absolute proof of this claim can be given. Furthermore,

way at 12 angular settings, differing in steps of 30°, obtained by turning the animal slowly and uniformly backwards or forwards around its bitemporal axis at an angular velocity of 1° per second. 81 See G.G.J. Rademaker, “Reactions labyrinthiques et équilibre”, Introduction pp. 1–6, Masson et Cie, 1935.

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5) prolonged stimulation (for more than about 5 minutes) of the labyrinths by a centrifugal force less than or equal to ½ P (where P is the weight of the otolith) can give rise to an after-effect lasting more than 20 minutes. 8. Storm van Leeuwen W., “Arhythmia cordis door experimentele beschadiging van het centrale zenuwstelsel” (Arrhythmia cordis caused by experimental damage to the CNS), Leiden, 194582 Rademaker had originally asked Storm van Leeuwen Jr to record the electrical activity of the cerebral cortex and the red nuclei in the rabbit. [Personal communication] However, the Einthoven string galvanometer available for this purpose was not suitable for recording at the high frequencies required in this application. It was therefore decided to change the topic under investigation to the influence of damage to the CNS on heart arrhythmias in cats. There were very few publications on this topic in the pre-1930 literature. Heidenhahn83 reported in 1872 that Faradic stimulation of the medulla oblongata in cats subsequent to transection of the vagus nerves led to a rise in blood pressure and irregularities in heart rate (though, as Storm van Leeuwen mentioned in the introduction to his thesis, Heidenhahn has not cut off all neural pathways leading to the heart as he thought, since he had left the thoracic nerves to the heart intact). Various publications on reflex cardiac arrest in man and animals indicated that the CNS had some role to play in connection with cardiac irregularities. Friedenthal (1901)84 caused sudden anaemia of the brains and spinal cord by simultaneous clamping off of both carotids and the subclavian arteries,85 which led to terminal cardiac arrest if the clamps were not

82 This was the first doctoral thesis to be defended in Leiden after World War II. Shortly before this, Storm van Leeuwen had been the first medical student to take his final exams in Leiden after the war. The university had been closed during the war years as a protest against the treatment of Jewish professors by the occupying powers. 83 Heidenhahn, “Ueber arhytmische Herztätigkeit”, PAV 143, cited by Storm van Leeuwen, 1872. 84 Friedenthal H., “Ueber reflectorische Herztod bei Menschen und Thieren”, Arch. f. Anat. u. Phys. 25, 1901. 85 Kussmaul and Tenner’s method, cited by W. Storm van Leeuwen.

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removed within 15 seconds. The cardiac arrest did not occur, however, if the vagus nerves had previously been transected. On the basis of his experimental results, Friedenthal concluded that sudden cardiac arrest in man and animals as a result of psychological causes was due to a combination of four factors: stimulation of the vagus and accelerator nerves, lack of oxygen due to cessation of breathing and a rise in blood pressure. The literature contained references to animal experiments in which extrasystoles (arising e.g. after chloroform narcosis) disappeared after decerebration (Brow et al., 1930).86 On the other hand, there were also reports of extrasystoles due to inhalation of benzene vapour, which still occurred after transection through the cerebral hemispheres and the metencephalon (Allen, 1931).87 Allen (1931) commented in this connection: that the hypothalamus is not the only area of the brainstem in rabbits from which this arrhythmia can be induced, is shown by the previous experiment where the arrhythmia from insufflations was readily obtained after the metencephalon had been transsected. Indirectly this experiment contributes further data to substantiate the importance of the entire formatio reticularis of the brain stem and various nuclei derived from it for altering circulation, respiration and for the production of convulsions.

Storm van Leeuwen used a thick needle to cause lesions in various parts of the brainstem of cats under ether narcosis, and recorded the animals’ electrocardiograms with the aid of two string galvanometers. Preliminary investigation showed that ether narcosis alone rarely led to cardiac arrhythmias. It was further found that ablation of the entire cerebrum, even when combined with removal of the corpora striata and thalami optici, did not give rise to extrasystoles—nor did transection of the midbrain using Rademaker’s decerebration cut. The experiments were carried out on a total of 40 cats and were divided into three groups involving a) lesions of the metencephalon in thalamus and decerebrated cats, produced by puncturing one of

86 Brow G.R., Long C.L.H. and Beattie J., “Irregularities of the heart under chloroform. Their dependence on the sympathetic nervous system”, JAMA 95, 715–717, 1930. 87 Allen W.F., “An experimental produced premature systolic arrhythmia (pulsus bigeminus) in rabbits”, IV. Effective Areas in the Brain, Am.J. Phys. 98, 344–351, 1931.

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the corpora quadrigemina posteriora; b) lesions of the metencephalon in decerebrated cats produced by puncturing the cerebellum or the medulla behind the cerebellum; c) chemical or electrical inactivation or stimulation of parts of the metencephalon. It was found that lesions of the metencephalon often led to irregular heart rhythms. Since Faradic stimulation, the insertion of strychnine crystals and injection of a strychnine solution did not lead to arrhythmia while pricking with a pin, injection of cocaine or passage of a galvanic current did, it was concluded that this effect was not due to stimulation but to inhibition of or damage to a metencephalic mechanism. Despite the routine taking of histological samples, the precise location of this mechanism could not be determined. It appeared to be near the centres that regulate blood pressure and respiration, however. The action on the heart appears to be via both the parasympathetic and the sympathetic nerves, as shown from observations made after transection of these nerves. The mechanism may have a regulatory influence on the heart, so that when it is inhibited or damaged arrhythmias arise. These irregularities disappear after some time, however, when the system has adapted to deal with the situation. The lesions of the metencephalon led to arrhythmias both in thalamus or decerebrated cats and in cats that had not been subjected to these operations. Intravenous injection of a 5% solution of barium chloride into the jugular vein also led to arrhythmias, even if the heart was entirely cut off from the nervous system. This finding confirmed previous observations by Blumenthal and Oppenheimer (1939).88 Storm van Leeuwen’s investigations revealed the remarkable fact that destruction of certain parts of the CNS (e.g. the cerebrum) actually inhibits the production of arrhythmias, while the destruction of other parts (in particular a specific part of the metencephalon) causes arrhythmia. On the other hand, removal of the cerebrum with the brainstem (including the entire metencephalon) hinders the production of arrhythmias again.

88 Blumenthal R., Oppenheimer E.T., “Method for study of ventricular fibrillation”, Amer. Heart J. 18, 363–367, 1939.

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It is known that CNS dysfunction due e.g. to a brain tumour can lead to other ECG changes apart from arrhythmias, in particular to changes in the T peak.89 Storm van Leeuwen found that in the course of his experiments an iso-electric or positive T peak could become negative after: a) extirpation of the cerebrum, b) puncture of the right corp. quadr. post. after decerebration, or c) injection of cocaine into the right-hand or left-hand half of the metencephalon in the cat. An iso-electric or negative T peak could on the other hand become positive after: a) decerebration or b) puncture of the right or left corp. quadr. post. 9. Stotijn C.P.J., “Experimentele onderzoekingen over het cardiazol insult” (Experimental study of cardiazol-induced seizures), Leiden, 1946 Before undertaking his doctoral research in Leiden, Stotijn had pursued his neurological training under Pötzl in Vienna and Kinnier Wilson in London. The latter had a particular interest in epilepsy, and had introduced a new classification of the various forms of this condition.90 In an attempt to throw more light on the nature of the epileptic seizure, Stotijn used cardiazol to induce seizures in animals (mainly cats, but also rabbits) after removal of certain parts of the CNS. Experiments involving the induction of seizures in animals after ablation of parts of the CNS had already been carried out towards the end of the 19th century (Binswanger, 1890;91 Ziehen, 1890).92 Ziehen observed among other things that transection of the corpora quadrigemina posteriora gave rise to a general extensor spasm. His description of this condition resembled that of ‘decerebrate rigidity’ given some years later by

89 Asschenbrenner R., Bodechtel G., “Ueber E.KG. Veränderungen bei Hirntumor Kranken”, Klin. Wschr. 17(9), 298–302, 1938. 90 Cited by C.P.J. Stotijn (1946): S.A. Kinnier Wilson, “Modern Problems in Neurology”, London, 1928; S.A. Kinnier Wilson, “The Epilepsies”, in: “Neurology”, London, 1940, pp. 1469–1545. 91 O. Binswanger, “Experimentelle Untersuchungen zur Pathogenese des Epileptischen Anfalles”, Allg.Zeitschr.Psychiatr. Bd 46, 519–522, 1890. 92 T. Ziehen, “Zur Physiologie der infracorticalen Ganglien und über ihre Beziehungen zum epileptischen Anfall”, Arch.Psych.Nervenkr.h. 21, 863–897, 1890.

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Sherrington.93 Ziehen considered it likely that this rigidity was due to a reflex reaction, and suggested that it was identical with the tonic phase of the seizure induced by Faradic stimulation of the cerebral cortex. In his view, the clonic phase of this seizure was of cortical origin while the tonic phase was of infracortical origin. The neurophysiologist Muskens from Amsterdam had induced seizures in cats by chemical means in his study of epilepsy. He wrote a monograph on epilepsy in 1924,94 in which he suggested that the seizures and myoclonic shocks observed in these cases were a physiological mechanism aimed at neutralizing various toxins. Various researchers round about this time had postulated that epileptic seizures were due to abnormal secretions from various glands, and many other similar theories were put forward. Stotijn dismissed all such hypotheses in his literature survey, stating that “none of them has stood the test of criticism”. Cardiazol (chemical name pentamethylene tetrazol) was discovered in 1924. It stimulates certain parts of the brainstem, strengthens respiration and raises the blood pressure. Given in high doses, it causes spasms, and when injected intravenously it gives rise to convulsions. It was used for various clinical applications since 1925, initially as an analgesic and for the treatment of collapse. After the introduction of convulsion therapy in psychiatry, cardiazol was widely used for this purpose for a number of years. However, Hoogerwerf and Jelgersma, using the recently developed ECG equipment in the Physiology laboratory in Utrecht, under the leadership first of Einthoven and later of Rademaker, were able to show that cardiazol convulsion therapy gave rise to abnormal changes in the electrocardiogram which persisted for some considerable time after the cessation of the therapy.95 The main question Stotijn wanted to answer in his study was what form the seizures took when different parts of the CNS were made

Sherrington C.S., “Decerebrate rigidity and reflex coordination of movements” J. of Physiol. 22, 319–322, 1897/1898. 94 L.J.J. Muskens, “Epilepsie, vergelijkende pathogenese, verschijnselen, behandeling”, Amsterdam, 1924, with a foreword by Sherrington. 95 S. Hoogerwerf en H.C. Jelgersma, “Das Electrocardiogramm während der Cardiazoltherapie der Schizophrenie”, Psychiatr.Neur.Bl., 1–3, 1938. 93

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inoperative. His own summary of his results (with slight editorial changes) follows. Convulsions were produced with metrazol (= cardiazol) in normal cats, thalamic cats (decorticated cats), decerebrate cats, decapitated cats and in cats in which the spinal cord had been cut. The symptoms observed after administration of Metrazol subcutaneously (2 cc), intravenously (0.5 cc), intra-arterially (0.5 cc in carotid artery) to the cat and intracysternally (0.5 cc in the cisterna magna) to the rabbit are described. The integrity of the central nervous system is a conditio sine qua non for occurrence of the complete convulsive seizure. Partial convulsive seizures, which were considered to be the substructure of the complete seizure, can originate from the mutilated brain as well as from the spinal cord. These partial seizures were most complicated; they varied individually and could not be expressed by a short formula. The convulsions in animals in which the nervous system was intact took a regular and harmonious course, in contrast to the convulsions of the operated animals, which proceeded in a quite disorderly manner. Removal of certain parts of the nervous system did not result in the disappearance of any distinct phase of the Metrazol seizure but caused the Metrazol to give rise to quite different syndromes of convulsive signs, which, to a certain extent, were characteristic of the action of the remaining amount of the nervous tissue. These syndromes included clonic spasms in some cases. They differed however from those occurring in the convulsions of the intact animal. Very schematically the results obtained could be formulated as follows: In the intact animal the tonic phase consisted of a general flexor spasm, which started in the hind legs and gradually changed into a general extensor spasm. The clonic phase developed gradually from the tonic phase. In the thalamic animal the tonic phase usually consisted of an extensor spasm only, while the clonic phase was most often absent, being replaced by running movements or various other movements. In the decerebrate animal in some cases the only change consisted in a strengthening of the extensor rigidity; in other cases an incomplete tonic flexor spasm resulted or a combination of a partial flexor and extensor spasm was observed. In addition a great number of complicated movements occurred, torsional movements being prominent in some cases. In the decapitated animal a short tonic extensor spasm occurred, the forelegs being stretched downwards, the hind legs forming a right angle with the body and the back slightly bent. In some cases, the legs were

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moved to and fro or were kicked backwards in this condition. Regular clonic movements, scratching and running movements sometimes appeared. After section of the spinal cord at the Th 9 level, the convulsions of the front part of the animal were independent of those of the hind part. Moreover, the convulsion of the front part differed from those in the front part of the intact animal: the flexor spasm no longer changed into an extensor spasm, and the clonic spasms were of a different nature. The spasms and movements of the hind part of the body were comparable with those in the corresponding parts of the decapitated animal, involving the appearance of tonic extensor spasm of the hind legs and various movements. The overall conclusion is that the phenomena observed during a cardiazol-induced seizure resemble those found in decerebrate rigidity, coupled with cessation of the inhibition of subcortical reflex mechanisms.96 4.2. Professor of Neurology (1944–1957) Neurology is one step further (Rademaker)

One innovation Rademaker introduced was the parallel connection between the clinical wards and the laboratories, aimed at creating a better climate for research. It reminded me of the plan for the first and second floors of the new building for pharmacotherapeutic research in Utrecht in which Rademaker had been involved in drawing the plans together with Magnus.97 Rademaker referred in his inaugural address98 as professor of physiology in 1928 to his collaboration with Magnus:

Verwey included this conclusion as proposition No. 6 appended to his 1938 doctoral thesis (see thesis No. 4 above). 97 For discussion of the history of this project for which the Rockefeller Foundation contributed a large grant on the interesting condition ‘that the new institute would be close to the University hospital and that it would not stand alone but form part of the group of medical faculty laboratories’, see O. Magnus in: “Rudolf Magnus, physiologist and pharmacologist”, Chapter 8 “Life in Utrecht”, pp. 204–205, with reproduction of the plans, Koninklijke Nederlandse Akademie van Wetenschappen, Amsterdam, Kluwer Academic Publishers, Dordrecht, Boston and New York. 98 G.G.J. Rademaker, “Willekeurige en onwillekeurige handelingen”, Inaugural addres 10–10–1928, p. 23, N.V. Boek- en Steendrukkerij Eduard Ydo, Leiden. 96

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Figs. 4-6 a & b. The newly built Magnus-Rademaker Physiology Laboratory in Utrecht. Partly financed by the Rockefeller Foundation. Design and working drawings prepared by Magnus and Rademaker.

Magnus left me a special personal legacy. During the construction of the new laboratory in Utrecht, plans were continually being made for the physiological investigations to be carried out there and timetables were drawn up for joint studies of the function of various parts of the central nervous system. I regard it as a sacred duty to accept this legacy, to execute these plans and to continue Magnus’s work in the field of neurophysiology. . . . .

This approach was later copied elsewhere (e.g. at a number of American universities and the National Institutes of Health in Bethesda, Maryland). Laboratories for advanced liquor analysis99 served all departments of the University Hospital in Leiden, and other clinical institutions further afield. Neuroradiology and Neurophysiology (EEG) were both made separate departments located on an upper floor but easily accessible from all wards. One feature that struck visitors was the installation 99

Personal communication, Ms H.A. Boersma, 1996, 1998†.

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of aquaria in the corridor on the ground floor. These were used for the culture of seaweeds and unicellular organisms for colorimetric serum cocarboxylase determinations on behalf of patients with peripheral neuropathy of both toxic and diabetic origin,100 and added an unusual touch of colour to the laboratory environment. The separate department for motor-skills rehabilitation101 was also new. This department, which was the apple of Rademaker’s eye, attracted many visitors—especially those with an interest in neuropediatrics. Live-in interns worked not only in the Neurology department but also in the Neurosurgery annex. The rapid changes in the condition of neurotraumatology patients often made it esstential to be able to call on assistance without delay. Rademaker had given this arrangement high priority in the reorganization of the department; he was with Verbiest and Luyendijk a leader in this field in the Netherlands at the time. Day-to-day management of the department Rademaker’s place in this clinical setting can be characterized quite simply: he demonstrated the paradoxical combination of deep personal humility and ‘intense professional will. In my personal experience over many years, he counted on a spirit of collegiality in his staff in the first place. His calm but determined use of inspired standards, developed in the course of his long clinical experience, allowed him to resolve many ethical dilemmas. His staff was well aware of this. It would take me too far to go into further detail on this point. He had never written his golden rules of medical ethics down on paper, but always based his attitude on the Hippocratic principle that the physician should at all times avoid harming his patient. Active euthanasia was never an 100 Personal communication, Dr. L.J. Endtz (1926–1989): – “Het pyrodruivenzuur gehalte van het bloed bij neurologische aandoeningen”. Proefschrift Utrecht (1963). – “Pathogenie de la neuropathie diabétique”. In: Journées Annuelles de Diabetologie de L’Hôtel Dieu. Méd. Flammacion (Paris), 1968; 51–3. – L.-J. Endtz (Leiden) et E. Schuller (Paris), “Epreuves fonctionelles Biochemiques en Neurologie”, “L’épreuve du pyruvicémie après surcharge glucosée”, La Presse Médicale 69 (51), 1933–1936; (53), 2037–2039, 1960. 101 The Bobath rehabilitation method, based on learned suppression of primitive reflexes, was further developed by Mrs. Nel de Vries and her Danish collegue, Miss Inge Holgerson.

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Fig. 4-7. Patient demonstration by Professor Rademaker (1945: during lecture for students in Department of Neurology Academic Hospital).

option for him; he tended to characterize this as “a question of lack of knowledge” or “an over-hasty decision”—to cite his own words. Pain control was a “science” to be developed using all available means (even including alternative and esoteric techniques, if they proved effective). (See endnoteii) 4.3. ‘The Lengthening and Shortening Reactions’ After the introduction of the experimental decerebrate rigidity model, in which the standing and support reactions may be observed in uninhibited form, Sherrington pointed out a number of other effects that could be manifested by the decerebrate animals (and sometimes also by the chronic spinal animal, i.e. an animal in which the spinal cord had been cut through a few weeks before), namely the ‘claspknife phenomenon’ and ‘the lengthening and shortening reactions’.102 What did these reactions involved? If one tries to bend the rigid forelegs of the decerebrate animal by exerting pressure against the paws, one will initially encounter an 102 Rademaker took up the subject on the lengthening and shortening reactions and their occurrence in man in 1947 that had originally been initiated by Liddell and Sherrington in experiments in the decerebrate cat in 1924. E.G.T. Liddell and C.S. Sherrington, “Reflexes in response to stretch”, Proc. Roy. Soc., 96, 267–283, 1924.

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increasing resistance to this movement. However, if one continues to exert this pressure one will find at a given moment that the legs give way like the blade of a claspknife. This phenomenon is probably due to the fact that a muscle that is stretched initially emits activating impulses but later, in response to very powerful stretching, emits largely inhibitory impulses. Further, the muscles of a decerebrate animal often show a remarkable plasticity, i.e. they assume any length given to them by passive movement. If one bends the leg of a decerebrate animal, the leg will often be found to remain bent when it is released, while if it is straightened passively it will remain extended when released. Sherrington found that this phenomenon can also be observed in a leg where all muscles apart from the quadriceps have been removed or denervated. He called the persistence of bending after the leg is passively bent (thus lengthening the quadriceps) ‘the lengthening reaction’, and the persistence of extension after the leg has been passively straightened (thus shortening the quadriceps) ‘the shortening reaction’). Sherrington did not manage to give a full explanation of these effects, though it was clear that they were due to reflex reactions, i.e. mediated by the central nervous system, under the influence of impulses emitted by the muscle itself. Since the reactions occur with different loads on the muscle, and since the muscular tension is always in equilibrium with the load on the muscle, after both passive shortening and passive lengthening, it was clear that the load was responsible for the tension produced after shortening and lengthening. Shortly after his appointment as professor of Neurology and the inauguration of his new laboratory, Rademaker published the results of his study “On the lengthening and shortening reactions and their occurrence in man” in Brain (Vol. 70, 109–126, 1947). It aroused great interest in clinical neurophysiologists, as this was the first time anyone had succeeded in testing Sherrington’s ideas about this type of reaction, dating from 1909, by a non-invasive method in man. Rademaker’s test subjects were two idiot children (‘idiot’ being the term used at the time to designate mental retardation). As Rademaker put it, “In order to be obtained it is necessary that the reactions are released from cerebral control”, which may be assumed to be the case in these children. Such subjects will not show cerebral inhibition of their reactions and moreover, it is only under this condition that one can be sure that the reactions occurring are brought about by a reflex reaction, and not voluntarily.

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Rademaker started his article somewhat enigmatically by stating: Muscles with intact innervation have the capacity to bear:— I Different weights at the same length II The same weight at different lengths.

As was usual with Rademaker, this article was comprehensively illustrated by filmstrips covering eight half pages. Rademaker confirmed that the reactions initially observed by Sherrington in the experimental animal could also be seen in man. Sherrington had given the following definitions of the two above-mentioned reactions: The lengthening reaction is as follows: when the tonic muscle is stretched it assumes, by virtue of its propioceptive arc, a new tonic length which is approximately that to which it has been stretched. Conversely, when in the tonic preparation of the knee-extensor the muscle is shortened, either passively or by active contraction of the muscle itself, the muscle retains approximately the shortened length thus given it. This is the shortening reaction.

Rademaker decided to use these reactions as a research tool for estimation of the tonic arc latencies of reactions in a number of conditions such as Parkinson’s disease, athetosis and dystonia. Since etiological heterogenicity (due e.g. to postencephalitic or arteriosclerotic Parkinsonism) had to be eliminated before collection of the pathology,103 he organised an outpatient setting where potential test subjects were collected and examined by three independent researchers: Rademaker himself, chief senior neurologist J.A. Taselaar, Dr. Luyendijk and the present author (unpublished results). The project had previously discussed with Prof. R. Garcin of the Salpêtrière hospital in Paris, who drew our attention to the publication by Foix C., Thévènard A., “Les reflexes de posture”, Rev. Neurol. 30, 44–468, 1923.104 103 Parkinson’s disease PD as a distinct primary form of Parkinsonism that is characterized had to be differentiated clinically or on outpatient basis from secondary Parkinsonism and related syndromes which share featrures of PD, and which are associated with encephalitis (n = 4), early Wilson’s disaese (n = 1), ‘multiple system atrophy’ (n = 2) (later diagnosed as Shy-Dreger’s disease), dementia with Lewy bodies (later the Den Hartog Jagers observations (n = 2)), frontotemporal dementia with Parkinson’s and Huntington disease (n = 4). These conditions though extremely rare (see numbers) were subject of discussion on the criteria for admittance as Luyendrijk and I remembered later. 104 A similar study was performed much later by A. Berardelli and M. Hallett. Their results were published in “Shortening reaction of human tibialis anterior”, Neurology (Cleveland) 34, 242–246, 1984.

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Fig. 4-8. ‘Decerebrate rigidity’ and postural reflexes. Diagram illustrating differences in man between decorticate rigidity and true ‘decerebrate rigidity’: A. lying prone with the head unturned; note that both forelimbs are flexed; B. and C.: note change of position with head turning; D. true ‘decerebrate rigidity’ in man with arms rigidly extended en pronated. Magnus’ and De Kleyn’s tonic reflex, which is similar to responses observed in decerebrate cats, received worldwide recognition as a possible sign of brainstem pathology in clinical neurology (it was mentioned as a ‘classsic’ sign for use in neurological investigations in Howell’s Textbook of Physiology, as edited by the leading authority in the field of neurophysiology Prof. J.F. Fulton). However, in the long run this reflex proved to be of limited use for diagnostic purposes, since it is only produced by highly localized defects of the brainstem. While these defects are found in the experimental situation, according to F.M.R. Walshe et al. they are seldom observed in clinical practice—mainly in the initital stages of restricted vascular lesions. The reflex is of no assistance in localizing the seat of the complaint in more extensive vascular lesions or invasive tumours.

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Endnote i One of the first to oppose the rising tide of Fascism and National Socialism whole-heartedly from the very beginning was the writer Menno ter Braak ( Jan Willem’s brother, 1991). He announced the setting up of an Anti-Fascist Student Committee in Leiden in an article entitled ‘Student en Fascisme’ (The student and Fascism) that he published in the first number of ‘De Sleutel’ (The Key), the official organ of the committee: The Anti-Fascist Student Committee regards it as its task to unite all students who wish to serve the cause of freedom of culture, peace and progress, irrespective of their political or religious convictions. The committee, founded in 1934, soon became very active in the Leiden student community. The name of its journal was derived from the keys of St. Peter, the patron saint of Leiden, that appear in the arms both of the city and of the university (this has also led Leiden to be referred to colloquially as the sleutelstad or ‘city of the keys’). The manifesto of the new organization was also published in De Sleutel (see de Gids, April 1991, 150 (4) 270). The first issue appeared in stencilled form in October 1935. From that time, De Sleutel proudly announced itself to be ‘The Organ of the Anti-Fascist Student Committee in Leiden’. Endnote ii In a rare turn of events, Rademaker was called out late one night in 1941 in response to a serious traffic accident in Emmen in the Northeast of the country, about 150 km from Leiden. A motorcyclist—who turned out to be none other than Kraan—had suffered multiple traumata including abdominal concussion. He was admitted to a local hospital in a serious condition and the doctors in charge of his case were in considerable doubt as to the differential diagnosis. Rademaker was called in as a consultant at Kraan’s request. When Rademaker was informed of the case, his instinctive response as a physician was to find a taxi to drive him from Leiden to the hospital where Kraan lay, with headlights blazing in defiance of the stringent blackout regulations imposed by the occupying powers and without the requisite travel documents. On his arrival, he helped to decide on the diagnosis and the necessity for immediate intervention and assisted in the emergency laparatomy, which probably saved Kraan’s life. Rademaker’s diagnosis (ruptured intestine with ileus) was ultimately confirmed. [Personal communication from Dr. W.A. Bax, surgeon in Vlissingen, 13–09– 1999.] Such a flamboyant disregard for the rules and regulations imposed by the occupier was typical of him and many other Dutch doctors during the war years (as tales I heard from my father and his colleagues confirm); looking back on it, we can only admire him, and them, for this. “Never had the career of a professor of Physiology been able to give Rademaker full satisfaction”, wrote Ter Braak et al., his friends and former colleagues, in a Festschrift to mark his silver jubilee as professor at Leiden in Folia Psychiat. Neurol. Neurochir. Neerland. 56 (1953). “The urge to be a practising physician, to be in direct contact with patients, was too strong for him.” He maintained a neurology practice alongside his chair in Physiology, and continued to see patients—Jewish and others—on appointment at his home in Oegstgeest during the war. He acted as ‘GP’ for a number of other medical professors. Storm van Leeuwen remembered that he volunteered to assist Prof. Suermondt in the first neurosurgical operations performed in Leiden, and took charge of the patients’ postoperative care.

BOOK V

RADEMAKER THE MAN In Leiden, Rademaker manifested himself as the introverted, modest scientist with high ethical standards, the ‘éminence grise’ of later years. The American neurophysiology world (e.g. the well known Fulton and Denny-Brown) knew him as the ‘king of the red nucleus’, French neurologists as the ‘prestidigateur’ (the magician), Italian neurophysiologists as ‘Rademaker innovante’, English neurophysiologists as the microsurgeon with the golden hand, his students as the inspired ‘artist’, and his colleagues apart from the above epithets as the film-maker who loved to record all details of his experiments—including himself—for subsequent showing on the silver screen. His fellow professors and university staff knew him as the well balanced administrator with high ethical standards, always prepared to listen when differences of opinion arose between colleagues, and finally after the war years as the man with the authority to carry out the most difficult tasks such as completing ‘Plan Cité Médicale’ type of architecture (see figure) for the Academic Hospital at Leiden in 1945 and the newly built neurology department and subdivisions. He was always marked by great objectivity, sense of humour and the courage to tackle any problem. Rademaker had a number of friends from which can be cited Winkler, Storm van Leeuwen Sr. and Jr., Barge, Mulder, Gorter, Ter Braak, Verbiest and from abroad Fulton, Denny-Brown and Garcin from Paris with who he worked so fruitfully. According to visitors such as Verbiest and Luyendijk (both of whom had studied under Rademaker and later became professors of Neurosurgery), Blanche had decorated the house in a characteristic French style—quite different from that of the other Leiden professors. To quote Luyendijk again, She made a great impression on all of us. One special feature of her appearance was the massive exophthalmos she had. She had been irradiated,

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Figs. 5-1 a & b. These photos show the houses where Rademaker and his wife Blanche lived during the early years of their marriage, while he was engaged in scientific research under Magnus at the Institute of Pharmacology in Utrecht, as they were at the time in question. Both these houses, Maliesingel 29 (where he lived from 1922 to 1924) and Maliesingel 35 (1924–1928), faced the Institute, the building which Rademaker helped to supervise after the the untimely death of Magnus in 1927. The Rademakers used their basement for the postoperative care of the animals Rademaker was working on. Courtesy: Municipal Photo Archives, Utrecht. For details on the plans for the first and second floor of the new building as designed by Magnus and Rademaker, see ‘Rudolf Magnus—Physiologist and Pharmacologist’ by Otto Magnus, p. 204, Koninklijke Academie van Wetenschappen, Amsterdam / Kluwer Academic Publishers, Dordrecht, Boston, New York.

but not operated on, for goitre, and was left with this exophthalmos. It was very striking.1 I could tell you lots of stories about the Rademakers: they were very unusual people . . . Blanche Rademaker had plenty of amusing stories about her husband, the absent-minded professor. Rademaker had the habit of going to bed very late and getting up very late: we never saw him in the clinic before 10 o’clock in the morning . . . but he did stay up very late at night, working. One of the stories Blanche Rademaker told was that she woke up round about half past two in the morning one day, to find her husband sitting on the edge of the bed in his pyjamas, fumbling with them and saying, “Blanche, help me please, am I getting up or going to bed?”

The couple had an infectious sense of humour, which they shared with those who knew them well.

1 See figure 5-2 in the present book: photo of Mrs. Rademaker, where the residual exophthalmos is clearly visible.

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There is one very nice story which I heard from an acquaintance of theirs, a banker from Amsterdam . . . they sometimes went out with him in the evening, returning in the small hours. The incident I want to tell you about occurred in the winter of 1928/1929—a very cold winter. Well, there was a night watchman who went round the houses whose owners had subscribed to a night security service. He made one call about 11 o’clock at night, and left a blue chit in the letter-box as proof that he had been round. His second call was about 3 in the morning, when he left a red chit. The watchman had very little to do between these two calls, and had got into the habit of sitting in the little hut intended for the inspector of the blue tram that used to run along Endegeester Lane in the neighbourhood in those days. One night the cold was too much for him, and he was taken to the University Hospital to recover. Anyway, the whole neighbourhood heard about the poor man. Some time later, when he had thawed out, he was discharged from the hospital and he came to tell various subscribers that he was back on duty again. Warm-hearted Blanche Rademaker said to him, “You don’t need to go through that again in this terribly cold weather. Here is the key to our house. You can come and sit in the yellow salon (a tiny room at the front of the house, with very comfortable easy chairs in it) in between your calls”. Well, you can be sure he didn’t need asking twice. But you know, the spirit is willing but the flesh is weak, and the result was that he began taking a longer and longer break between his 11 o’clock and 3 a.m. visits—and in the end he just dropped both the blue and the red chit in the people’s letter-boxes at the start of the night and then settled down for a good sleep in the Rademakers’ lovely warm room. One night, the Rademakers came home late from a night out, and found the night watchman snoring in one of their chairs when he was supposed to be out on his late round. They couldn’t resist the temptation to tie him up in the chair with a rope, just to teach him a lesson. Imagine his surprise when he woke up . . .2

The arguments—comparative neuroanatomy Like neuroscientists such as Magnus and Sherrington, and others with a philosophical bent, Rademaker took arguments from other branches of science (e.g. physics and biology) as an aid to elucidation and analysis of his claims—which themselves often crossed the boundaries of

2 From a transcript of a conversation between Prof. W. Luyendijk and Prof. Kamphuisen on 14 January 1988, pp. 12–13, kept in the archives of the department of ‘Metamedica’ at the university of Leiden (Prof. Dr. H. Beukers).

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Fig. 5-2. Mrs. M.J.W. Rademaker-Stoltz (‘Blanche’), born 28-09-1894, whom Rademaker married on 27-05-1922 in Auteuil, then a suburb of Paris. She died on 15-01-1962 in Oegstgeest, near Leiden in the Netherlands.

existing disciplines. Various examples of such arguments can be given. An example is of an anatomical argument. The results of the experimental work by Rademaker on the red nucleus were the basis for his thesis ‘De beteekenis der roode kernen en van het overige mesencephalon voor spiertonus, lichaamshouding en labyrinthaire reflexen’ (1924). These results could only be applied to human physiology if a homologue of the nucleus ruber magnocellularis and a rubrospinal tract existed in man. This, however, had been doubted by a number of investigators (see figure). It was well known that in man the red nucleus is in its cyto-architecture and in its fibre-tract connections a complicated centre and very different even from that of anthropoid apes. Von Monakow (1910) had concluded from certain morphological features that a small residuum of the nucleus magnocellularis existed in man. Its position is the level of the ‘nucleus albus’ of Stilling (the brachium conjunctivum oral to its decussation), the caudal tip of the main red nucleus and the transition between the nuclei of the 3rd and 4th nerves. Small clusters of giant cells of a ‘motor’ type may be found in two different places in cross sections. One group is ventral and lateral to the 3rd nucleus, between the latter and the centre of the brachium conjunctivum, the other group is dorsal to the substantia nigra between the latter and the brachium conjunctivum. This distribution, however, and the size of the group vary greatly with different individuals and animals (see figure). In a caudo-oral direction they occupy only a short distance and on the

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Fig. 5-3. Brain 81, 284–289, 1938. This investigator, a neuro-anatomist who assisted Rademaker in this complex matter related to his experimental work on the red nucleus helped to elucidate the rudimentary ‘palaeo-rubrum’ and the existence of the rubrospinal tract in man, a question which was still the subject of discussion in the literature at that time (Karl Stern from Greenfield’s neuropathology laboratory in the National Hospital, Queen Square, London clarified the matter in ‘A note on the nucleus ruber magnocellularis and its efferent pathway in man, in: Brain 81, 284–289, 1938. The schematic drawings by Stern are modified after Winkler (1929).). I am indebted to prof. W. Blackwood, neuropathologist who during my stay in his laboratory kindly demonstrated to me the microscopic slides of the two relevant human cases; one case of a spinal cord transverse lesion at a high thoracic level due to invasion of the spine by bronchial carcinoma (F.C.P.M. No. 32, 1936) and a case (H.B. 1936) of the posterior inferior cerebellar artery where the nucleus ruber magnocellularis (Von Monakow) was investigated for retrograde chromatolytic changes, from the archives of Greenfield’s collection present in the Pathological Laboratory of the National Hospital, Queen Square, London.

average one finds not more than about three cells in one section according to Winkler (1929). The results reviewed His working method proved to be innovative. He drew a significant distinction between acute and chronic experiments, which allowed the confusion associated with the ‘decerebrate rigidity’ model widely used at that time (e.g. in the laboratory headed by Sherrington) to be cleared up. This new working method made it finally possible to elucidate the function of the ‘red nucleus’ (nucleus ruber) cells in the mesencephalon. The thesis he wrote on this topic (5), passed cum laude at the University

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of Utrecht, was translated into many languages. The findings reported there had important consequences in the field of clinical neurophysiological and neuro-anatomical views. They could also be related to known findings in the field of clinical pathology. These aspects were all dealt with in the monograph, which grew out of the thesis, with illustrations from the contemporary literature. In the tradition of the reflexological approach dating back to Descartes and further developed on the basis of the experimental work which started with Sechenov and extended up to Pavlov, Rademaker set up a new programme of experimental work to explain the blink reflex in response to perceived threats on the basis of new data obtained from study of the ‘big brainless dog’ e.g. by Goltz in Strasbourg and other workers in various German laboratories. Rademaker was able 1) to reveal the mechanism of this reflex, using ingenious techniques for ablation of parts of the cerebrum (in co-operation with Gelderblom and later with Ter Braak), and 2) to show the clinical relevance of this study later, in co-operation with Garcin at the Salpêtrière in Paris. This was the first neurophysiological and clinical demonstration of a cortical reflex—a matter attracting a great deal of interest in the neurological world. His followers; theses prepared under his supervison (1932–1946) and contributions of his laboratory Rademaker’s first disciples come from his period as professor of Physiology at Leiden. The seeds he sowed bore rich fruit in many, such as the brilliant Ter Braak, later professor of clinical neurology at Rotterdam, his ‘favourite son’ Storm van Leeuwen, later professor of neurophysiology at Leiden, Verbiest, one of the first professors of neurosurgery in the Netherlands and finally Luyendijk, the first professor of neurosurgery at Leiden. Among Rademaker’s followers from abroad may be counted DennyBrown from Harvard Boston and Fulton from Yale University in the United States, and Guillain and Garcin from the Salpêtrière Paris. They have borne witness in both the spoken and the written word to his importance for their well-known contributions to neurophysiology and/or neurology. In this connection, we may also mention nine significant doctoral theses prepared under his supervision. These are described and discussed

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in Book IV—part 4.1. in the present book. Since most of them were published in Dutch and were not followed by publications elsewhere (partly because most of them appeared during the war), this description of them in English fills an important gap. Cybernetic interpretations of neurophysiology Rademaker was fascinated by the widely applicable concept of cybernetics sketched in Wiener’s book, and looked for possible applications in his own field. He gave a number of talks (often at a fairly popular level) about the relationship between cybernetics and nerve physiology. He suggested at a conference as an example for a combined research with the cardiologist and neurologist: the relation between on the one hand, the tonic, clonic, and phasic contractions in epilepsy, and on the other hand, the tonic spasm, beat and fibrillation of the heart. To give an example: in fact, Rademaker’s own approach to neurophysiology lent itself well to a cybernetic interpretation.3 This topic aroused a great deal of interest in Dutch scientific circles.4 It was in this new discipline that Rademaker developed cybernetic interpretations of neurophysiology through the work of Dusser de Barenne in Yale and Bok the neurohistologist in Leiden. The Latter had published a book on cybernetics. Dusser de Barenne had developed the method of chemical (strychnine) neuronography and had shown experimentally the non-existence of sharp boundaries around cerebral functional areas warning (in 1934) about the parochialism of designating localisation for a function that so patently takes place in many parts and levels of the brain. Dusser de Barenne preferred ‘corticalisation’ as the more accurate term. Rademaker endorsed his views and presented Dusser’s experimental data in his lectures.

3 His last publication: Rademaker G.G.J., “La régulation du nystagmus optocinétique par un mécanisme du type feedback” [“The regulation of the optokinetic nystagmus by a mechanism of the feed-back type”], Revue Neurologique, 93, 301–302, 1955. 4 S.T. Bok (1892–1964 wrote a monograph on the subject “Cybernetica (‘stuurkunde’ in Dutch), hoe sturen wij ons leven, ons werk en onze machines?”, Utrecht, Uitgeverij Het Spectrum, 1958, 252 pp. (in Dutch). He started as neuropathologist (Amsterdam), was elected professor of Histology and Microscopic Anatomy in Leiden in 1929 and became later Director of the Central Institute of Brain Research in Amsterdam; he wrote an ‘introduction to cybernetics’ for students (Prismaseries) and specialized in quantitative histology, ontogenesis and areal distribution of the cerebral cortex.

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In his mechanistic conception of the function of the central nervous system in which he followed Sherrington, Pavlov and Magnus, 1) he assigned for the first time on the ground of experimental research a function to a delimited nuclear area in the brainstem whose anatomical connections in themselves gave no direct indication of this function; 2) he defined that the cerebellum had not the importance for equilibrium, tone etc. which the elder theories had attached to it; 3) finally he made a stand against the (at that time) still deep-rooted conception of the labyrinth as an organ of equilibrium; he argued that labyrinthine reactions sometimes may also be detrimental to the maintenance of equilibrium. The educator with an ‘héritage sans testament’ (as he once described himself ), he was always rather formal in his contacts with others, certainly not a fluent speaker, somewhat hesitant and always avoiding apodictic statements. His ‘French connection’ was often mentioned. This referred in the first place to his wife, who came from French Alsace, and in the second place to his many friends in the French neurological world—in particular Garcin, with whom he worked so fruitfully. In the last analysis, however, he always remained the physician with his hand on the patiënt’s pulse, constantly looking for ways to alleviate his pain or other form of suffering. During his period as professor of physiology, and even throughout the war years, he continued to see patients at home and to follow up their cases for many years after the initial treatment, often by correspondence. He also sought contact with colleagues who shared his interest in the patients, often with incurable complaints, who came to him for treatment. The repercussions of his work His scientific studies had many and varied repercussions. In particular in the United States, UK and France. As far as possible, these were mentioned either by means of footnotes to the discussion of his work or via quotations from the work of well known researchers in this period.

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The ultimate consequence of Rademaker’s work was its clinical applicability, both at the bedside and in the laboratory. Particularly in neurophysiology, to which he contributed so much, and on neuropathology (for which he set up a separate laboratory). He was the first scientist in the Netherlands who installed EEG equipment for clinical purposes. In view of all these contributions, his fame is hardly surprising. He received many decorations, and was an honoured representative of the Dutch scientific world at congresses abroad. The brains and motion The sudden death of Magnus, who had achieved world fame with his concept of ‘Körperstellung’ (posture), left an enormous gap in this field. Instead of replacing Magnus at Utrecht, a position for which he had been more or less groomed, Rademaker chose to become professor of Physiology at Leiden. It has often been asked why the school of Magnus at Utrecht died such a sudden death. No really adequate answer to this question is possible. Attempts were made, however, to map with success the sequence of motor development in the child (Balduzzi, Peiper, Schaltenbrand and others). To develop a notation for short sequences of dance movements (by analogy with the neurophysiological problems encountered in the world of ballet by Marey in “Physiologie artistique”) has not been completed. Most recently renewed interest has been expressed by Berthoz (1998) in the results of the experimental work by Rademaker and the concept he used on studying ‘labyrinthine reactions and equilibrium’, now applicable in space neurology. 5.1. Rademaker the Physician, the Surgeon, the Neurologist Storm van Leeuwen and colleagues wrote in their Festschrift for Rademaker in 1953, The career of a professor of Physiology was never enough to give Rademaker full satisfaction

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and He had already set up as a practising neurologist at the time he assumed his chair in Physiology.

These are clear indications of his constant wish to be in contact with patients—which had in fact led him to with clinical science in the first place. Rademaker continued to see patients—Jewish or non-Jewish—on appointment throughout the war at his home in Oegstgeest. He was also consulted as neurologist in Leiden University Hospital and was asked to fill in for the lecturer Dr. Gans (1885–1971) during the latter’s fairly frequent periods of sick leave. During one such extended period lasting from 1936 to 1938, Rademaker actually ran the neurology clinic together with Ter Braak. The entire university of Leiden was closed during the war, in protest against the anti-Semitic measures imposed by the German occupiers. Rademaker had become the counsellor and general physician of many of his co-professors and had regular contact with them. During the war, when some of them had been taken hostage in a concentration camp, Rademaker paid them bedside visits at their request according to Prof. Huizinga. Rademaker also took particular interest in assisting one of his former pupils, Prof. W. Suermondt (professor of General Surgery and ad hoc acting as neurosurgeon, in which position he was replaced by Luyendijk in 1945), in the first neurosurgical operations undertaken in the University Hospital. In a paper presented to the Royal Dutch Academy of Sciences,5 another of Rademaker’s pupils and subsequently professor of Neurophysiology, W. Storm van Leeuwen, recalls instances when Rademaker stood up to help in localising brain tumours or other anomalies at Suermondt’s side, discussing the patient’s condition during the operation and participating actively in postoperative follow-up while patients were recovering in hospital and even later. In more general terms, Storm van Leeuwen commented: “Rademaker always continued his role as a physician alongside his function as a scientist. He had an intense interest in the patient as a person. He dedicatedly paid repeated visits to ‘difficult’ and ‘unrewarding’ cases—the patients, in fact, who needed help most, who were seriously, chronically

5 W. Storm van Leeuwen, “Levensbericht van Gijsbertus Godefriedus Johannes Rademaker (19-03-1987–19-04-1957).”

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and often seemingly incurably ill. He never gave up on ‘hopeless’ cases either, and would keep on looking for remedies that would bring cure or at least alleviation of the patient’s suffering. He was of the opinion that greater insight could be gained into various neurological complaints where both the aetiology and the therapy was still unknown with the aid of further biochemical research.” [During this period, he urged the curators of the department of Physiology to expand the Biochemistry laboratories there.]

Fig. 5-4. The house at Prins Hendriklaan 2 in Oegstgeest, where the Rademakers lived from 1928 till his death in 1957. It was designed by the architect Jesse, who was responsible for well known houses and other buildings in and around Leiden. Rademaker may be credited with a good taste for architecture: witness also the new physiology building at the Vondellaan in Utrecht (see earlier pictures), designed by the architects of the Amsterdam school of architecture. Courtesy Mrs. FerwerdaVogelsang, Wageningen.

BOOK VI

THE END OF POSTURAL RESEARCH. A SHORT SUMMARY WITH CHRONOLOGY Why did the line of research so successfully pursued by Rademaker in the 1920s and 30s on the basis provided by his teacher Rudolf Magnus Sr. peter out? This question has often been asked but never satisfactorily answered. The purpose of the present note is to argue that, in terms of the theoretical framework laid down by Thomas Kuhn in his influential book The structure of scientific revolutons,1 it was the victim of the revolution in neurology that took place in the course of the twentieth century. Kuhn put forward the idea that the activities of each scientific discipline is guided by a paradigm, a set of problem-solving rules that lay down what problems can fruitfully be tackled and what methods can be used to solve them. Each paradigm has only a limited life. As evidence of its shortcomings accumulates, the more revolutionary members of the scientific community are impelled to develop a new paradigm, which will more effectively meet their needs. In general, any proposed new paradigm will meet with massive resistance from the more conservative members of the scientific community. If however it eventually wins the struggle for acceptance, this constitutes a successful revolution within the discipline in question. The history of the discipline as laid down in the standard textbooks will now be rewritten so that the concerns raised by the old paradigm and the struggle to replace it are largely forgotten and the course of the discipline is portrayed as a smooth advance in knowledge. Do the known facts about the rise and fall of postural research fit into this framework? One major facet of the paradigm within which Rademaker operated was the idea that important neurological insights could be generated by studying the residual reflex reactions in experimental animals in which major neurological lesions had been brought about. Rademaker’s

1 T. Kuhn, ‘The structure of scientific revolutions’, 3rd ed., University of Chicago Press.

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teacher, Magnus, was made aware of this possibility during his period of work with Charles Sherrington in Liverpool in 1908, and devoted a great deal of his time and energy to this ‘hobby’, as he described it, during his time as professor of Pharmacology at Utrecht. Taking decerebrate or decerebellate animals as his experimental model, he laid down all the major concepts in this field and drew up a research programme listing the major problems to be solved. He published Körperstellung (Bodily posture), in which he laid down his brilliant neurophysiological analysis of the activities and standing, in 1924. By that time, he had built up a research team in Utrecht working on the problems he had defined. Magnus’ personal contribution to this field, and his chance of personal distinction (including a Nobel Prize nomination together with his collaborator) were cut short by his tragically early death in 1927, but this did nothing to slow down the impetus of the research. He had laid down his views of future advances in the Cameron Prize Lecture which he gave in Edinburgh on 20th May 1926. Rademaker had joined Magnus’ team in 1922, helped to give substance to his unique contribution to this field of research. After Magnus’ death, Rademaker was appointed professor of Physiology in Leiden, as successor of the Nobel laureate Einthoven (discover of the electrocardiogram). He remained in this position from 1928 to 1942. Research and other activities in Leiden came to a complete halt during the Second World War, after the university was shut down in protest at the sacking of Jewish professors at the orders of the occupying forces. In 1945, Rademaker was appointed professor of Neurology in Leiden and remained in this position till his retirement at the age of 70 in 1957. He died later in the same year. During his time with Magnus and in his early years in Leiden, Rademaker produced three major monographs: The significance of the red nuclei . . . for muscle tone, body posture and labyrinthine reflexes (doctoral thesis, Utrecht, 1924); Das Stehen (The physiology of standing) (1931); Réactions labyrinthiques et equilibre (in collaboration with Raymond Garcin from the Salpêtrière in Paris) (1933); in which he laid down the results of his detailed experimental studies. His ability (with the aid of his French wife, Blanche) to keep his decerebrate and decerebellate animals alive much longer than anyone else thanks to devoted personal care and his hands-on approach allowed

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him to study the reflex reactions of these animals in unprecedented detail and over unprecedentedly long periods. His long-lasting interest in movement, combined with a sense of showmanship which contrasted with his gentlemanly image, led him to keep voluminous records of his investigations in the form of photos and film fragments, in which he ‘performs’ with his animals (all of which he gave individual names rather than serial numbers) to show what residual abilities they possessed after ablations, the surgical lesions to which they had been subjected. He also tried, without complete success, to develop a symbolic notation for dance and other movements. Rademaker’s assessment that this field of research was by no means exhausted appears clearly from the detailed discussion of muscle tone and the long list of working hypotheses he gave in the final chapter of Das Stehen and from the fact that he followed this with yet another monograph on a related topic: Les réactions labyrinthiques et equilibre. Nevertheless, his flow of publications largely ceased, and from the late 1930s he devoted himself more to clinical applications of his experimental findings, teaching and organisational advances within his department. Maybe his research drive was exhausted—in other words, maybe he felt that despite the problems remaining, he had done his bit; maybe he was too modest or too self-critical to produce other publications until he was certain that they were free of flaws. As a teacher, Rademaker had a major influence on the next generation of Dutch neurologists. His pupils included: J.W.G. ter Braak, professor of Clinical Neurology in Rotterdam; W. Storm van Leeuwen, professor of Neurophysiology at Leiden and Utrecht; H. Verbiest, first professor of Neurosurgery at Utrecht; W. Luyendijk, first professor of Neurosurgery at Leiden; L.J. Endtz, head of the Neurology department, Leyenburg teaching hospital, The Hague. Nevertheless, he failed to produce a school of researchers to carry on the line of investigation he had laid down in the above-mentioned monographs. In 1980, his old friend and colleague D. Denny-Brown, emeritus professor of Neurology at Harvard, acted as editor for the English translation of Das Stehen, published nearly fifty years after the original under the title The physiology of Standing, Postural Reactions and

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Equilibrium with special references to the behaviour of Decerebellate Animals (Univ. of Minnesota Press). Denny-Brown wrote at the end of the introduction to this book that its translation ‘is a tremendous service to the many investigators in neurology, neurophysiology and in the special senses whose interests lies in motor co-ordination, cerebellar and labyrinthine function’. We may assume that he hoped that the publication of this translation would revive interest in this field of research, though the correspondence between himself and the publishers does not in fact give any concrete evidence of such expectations. But this was not to be. I believe that the reason for this was that by the time research in Leiden picked up after the Second World War, and certainly by the time of Rademaker’s death in 1957, the old neurological paradigm had been replaced by one depending on a variety of largely non-invasive investigative techniques. These included electroencephalography (EEG), invented by Hans Berger in the 1920s, electromyography (EMG), the development of computerized axial tomography (CAT scans) in the early 1970s and nuclear magnetic resonance (NMR) imaging in the 1980s, together with cerebral angiography and a variety of chemically based techniques using e.g. analysis of cerebrospinal fluid obtained from spinal taps which led to the identification of chemical agents in the central nervous system and the elucidation of the roles these substances played in the transmission and blocking of nerve impulses. All these advances permitted the development of specific drug therapies for neurological conditions. Within this new regime, there was no room for the old paradigm. Its concerns had been forgotten, and efforts by the ‘old guard’ such as Denny-Brown to revive interest in them were fruitless. Besides, Rademaker’s combination of surgical skill, analytical rigour, close bonding with his experimental animals and romantic love of motion was so unique as to make him almost irreplaceable. It may perhaps be surmised that these characteristics, in particular the whiff of romance and showmanship that surrounded his experimental work, was not entirely acceptable to the academic establishment in Leiden, This might possibly explain the complete destruction of his ‘laboratoire des images’ (his extensive collection of photos and film fragments, together with his laboratory logbooks) by his successors in Leiden which his former pupil and associate H. Verbiest (and through him Denny-Brown) suspected [Personal communication H. Verbiest], was not a terrible mistake but rather an intentional iconoclastic act.

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6.1. Walshe’s2 Account of a Visit to Magnus’s Laboratory By way of an epilogue to the above considerations and an introduction to a final chapter on ‘The origin of movement’, we give here a brief report by the English researcher Walshe of one of Rademaker’s experiments, together with one of Rademaker’s drawings of this or a similar experiment. When a group of British neurologists and other scientists, including Walshe, visited Magnus’s laboratory in Utrecht, they were particularly struck by an experiment they saw Rademaker performing (see figure) in which a silk thread was passed through the brainstem of a rabbit in vivo to permit ligation of Forel’s decussation. Traction on the loop led to selective interruption of the rubrospinal tracts, which elicited an acute change in the rabbit’s state of consciousness alongside total loss of muscle tone and paraplegia, and (in Walshe’s words) “Rademaker was catapulted to fame and his name and appearance became symbols for the genius of the experimental physiologists from the grand school of Dutch physiology in the midst of the 20th century”. Rademaker was a man who changed our conception of tonus and movement. A man who had earlier been a successful general physician and surgeon, a man with a adventurous life in the tropics, six years working under primitive circumstances, who liked horse racing but retained his simplicity and openness and disliked pomposity. To say that Rademaker taught us to see the universe of posture, development, tonus and movement as a whole and anew, is no understatement. Magnus had assumed that ‘Körperstellung’ [posture] was based on a fixed framework of reflexes modelled through the variety of circumstances and peripheral stimuli, and could be measured and experimentally altered. A framework against which all other motion could in theory be measured. Rademaker examined the central origins [of posture]—as an alternative fixed frame, as a law of nature. He came up with new conclusions such as on tonus and posture, interrelated as they were as a matter of frozen energy—when at rest.

2

Francis Martin Rouse Walshe, British neurologist (1885–1973).

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Fig. 6-1. One of Rademaker’s experiments: a silk thread was passed through the brainstem of a rabbit in vivo to permit ligation of Forel’s decussation.

Another consequence is that we can no longer think of muscle tone, posture and movement as separate. This complex had to be seen as a continuum.3 His theory of tone was based on an idealized model—after his first experiments on the red nucleus—in which hyper- and hypotonia were identical expressions allowing or inhibiting movement, explaining both gravity and inertia (complete inhibition) in his laws of motion, exemplified in the falling reflex (in cats). Another touch of genius of Rademaker was in the experimental situation to treat gravity and acceleration as the same phenomenon (as Einstein had done). Though still incomplete [through lack of electromyographic data at that time, L.H.], he found mathematical tools together with Ter Braak. Finally, a word on the red nucleus. Rademaker’s concepts were not uncontroversial. They had competitors (Ranson)4 and appeared initially inconsistent with other great achievements (such as those of W.R. Hess in Zurich).5 But right or wrong on this point of view [see

My italics LH. Dr. Stephen Ranson (1880–1942), professor and director of the Institute of Neurology at Northwestern University School of Medicine, Chicago, which is now named after him. Author of the classic textbook The anatomy of the nervous system (1920). He studied, among other things, the respiratory and pupillary reactions induced by electrical stimulation of the hypothalamus. 5 Walter Rudolf Hess won the Nobel Prize for Medicine in 1949, for “his discovery of the functional organization of the interbrain as a coordinator of the activities of the internal organization”. He showed that electrical stimulation of regions of the cat’s hypothalamus via very thin stainless steel electrodes evoked a ‘defence reaction’: 3 4

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Denny-Brown’s opinion, L.H.], it is in the very fruitfulness and novelty of Rademaker’s work on the red nucleus and the developmental reflexes that the marks of his genius lie, as a magnificent and beautiful achievement of human intellect . . .”

the cat became angry, snarling and wagging its tail furiously with its claws out and its hair standing on end, just as if it was being attacked by a dog.

BOOK VII

THE INTELLECTUAL CLIMATE IN THE NETHERLANDS A whole series of Dutch scientists won the Nobel Prize during this period, year after year: van ’t Hoff,1 Zeeman and Lorentz jointly,2 van der Waals,3 Kamerlingh-Ones4 and Einthoven.5 Magnus Sr. had been officially nominated for the Nobel Prize for Physiology, but his early death prevented him from receiving it. As we shall see below, Rademaker received his introduction to neurological research from Magnus, and he succeeded Einthoven as professor of Physiology at Leiden.

Fig. 7-1. Prof. W. Einthoven (second from the right) and staff members Ir. W.F. Einthoven, F. Hugenholtz, Dr. Waar, Dr. Flohil, Dr. F.L. Bergansius, Dr. J. Bijtel. Courtesy: Boerhaave Museum, Leiden.

J.H. van ’t Hoff (1852–1911) received the Nobel Prize for Chemistry in 1901. P. Zeeman (1865–1943) received the Nobel Prize for Physics together with his compatriot A.H. Lorentz (1853–1928) in 1902. 3 J.D. van der Waals (1837–1923) received the Nobel Prize for Physics in 1910. 4 H. Kamerlingh-Ones (1853–1926) received the Nobel Prize for Physics in 1913. 5 W. Einthoven (1860–1927) received the Nobel Prize for Physiology in 1924. 1 2

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The total dedication with which Rademaker carried out his research must have owed a lot to the high-powered intellectual climate of the Netherlands at that time. Seen from abroad, the Netherlands were going through ‘une époque épique’ as French colleagues have put it. Apart from this close association with Magnus as his mentor over many years, Rademaker’s friends included Winkler and Stenvers Sr., Ariens Kapperso, Brouwer and Ter Braak—all men of renown in the Netherlands. This period, around the turn of the century and the first few decades after that, became recognized in the Netherlands and abroad as the start of the golden age of Dutch neurology. Researchers flocked to the Netherlands to visit laboratories such as that occupied by the school of Magnus, where the visitors were struck by the dedication and efficient organization of the laboratory work which helped to form the firm basis on which the most complicated operations could be performed on experimental animals. Magnus was recognized as the brilliant leader of a group of carefully chosen researchers,6 good for more than three hundred publications between them. Their field of activity was the reflex mechanisms, which control posture. This was fundamental research, characterized later by the physiologist Henry Dale (1875–1968)7 as dealing with ‘essential neurological problems’. It had all started so casually with the observation, in March 1908, that the front paws of a decerebrated cat whose myelum had been thoracically transacted showed marked extension when the animal was moved from a lateral decubitus position. Those who know Rademaker’s later work will recognize this as one of the sparks of inspiration, which he must have received when he started to interest himself in Magnus’ work. Such a key observation is what French clinicians would call “une observation priviligée”—or, as Magnus put it in his guide to scientific research, “Man muss sich am richtigen Augenblick wundern” [It is important to exercise one’s sense of wonder at the right moment]

6 F.M.R. Walsh, “The work of Magnus and his collaborators on the nervous regulation of posture, and its bearing on some modern neurological problems”, Med. Science 7, 109–118, 1922. 7 H.H. Dale (1875–1968), won the Nobel Prize for Physiology and Medicine together with O. Loewi (1873–1961) for their discoveries relating to the chemical transmission of the nerve impulses.

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It was in this circle, in 1922, that Rademaker—after getting to know Magnus under circumstances about which we know little or nothing—took his first steps along the path of pure science which had been unknown territory to him up to this time. Scientists round about 1900 were fascinated by the functioning of the human or animal brain regarded as a single organ with its own laws, or of a part of this organ. The debate about the localization of the various functions of the brain was in full swing, but there was a need for greater precision. Descartes’ original reflex theory was given a necessary new dimension by the views of Pavlov, as Rademaker pointed out later in his inaugural lecture as professor of Physiology at Leiden.8 Magnus added his own new theme to the concert of the localization debate. Sherrington had taught, on the basis of further development of the ideas of Hughlings Jackson, that the higher function (that of the integral summation of various reflexes) was already localized in the spinal cord. Magnus opened up a new horizon in his book “Körperstellung” [Posture] by showing that different adjustment reflexes have a relative localization at different levels. On this basis, he developed the concept of postural reflexes, which were built up in a ‘bottom up’ process. In contrast to this, Rademaker later developed a (complementary) ‘top down’ view, to which we shall be returning at length below. There were high hopes that these new insights could lead to new methods of treatment. Allied with the techniques of neurosurgery such as stereotaxis with the Horsley-Clarke instrument—still in their infancy—they gave promise of a therapeutic breakthrough in the treatment of complaints, such as tumors, for which no therapy existed as yet. Innovative, original techniques of neuroradiological diagnosis, such as the subtraction technique developed in the Netherlands by Ziedses des Plantes (1932),9 were devised to permit the localization of lesions.

8 Cited in part 3.1 of Book III: “On reflexes and the first experimentally based description of a cortical/subcortical conditional reflex (the blink reflex) by Rademaker, p. 480, 1930. 9 Ziedses des Plantes B.G., anatomist, neuroradiologist (1902–1993) “Een nieuwe differentiatietechniek in de röntgenologie”, Ned Tijdschr. V. Gen. 76, 3691–3696, 1932 (in Dutch).

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New institutes were created, such as the Herseninstituut (Brain Institute) founded in 1909 by Ariens Kappers (1877–1946) and the Institute for Aviation Medicine Research founded by Van Wulfften Palthe. Great collections of comparative neuro-anatomy saw the light of day, such as that which formed the basis for the ‘Atlas anatomicum cerebri humani’ (Scheltema & Holkema, Amsterdam, 1931) published by Jelgersma (1859–1942) after his retirement as professor of Neurology and Psychiatry at Leiden, which yielded him international fame. So much for the scientific background against which Rademaker lived and worked. We know surprisingly little about the details of his life. Remarkably few documents have been preserved from which this information can be distilled. The basic structure is known, but there are not many incidental details to give it colour. We have a few letters and photos. A large part of his film archives—in wich, as we shall see below, vital background information about his research over a period of many years had been preserved—has been lost. There are, however, many anecdotes about his life told by his contemporaries, old colleagues and even old patients which I have been able to collect—hardly surprisingly, really, for he was a well known man in his time and in his field. For this reason, and because ‘une vie se deroule dans l’espace et non dans le temps’, as Chateaubriand put it, this memorial is largely devoted to a systematic analysis of Rademaker’s publications to permit an indepth assessment of his scientific oeuvre. Rademaker is above all himself in his work, and his writings about his work were his way of expressing his personality. These biographical notes may thus be seen as a synthesis of a single spirit. Finally, I have attempted to assess the repercussions of Rademaker’s work on present-day neurological science. The full bibliography given at the end of the book helps to give an impression of the fields in which Rademaker was interested; much of this information was not hitherto available in the Anglo-Saxon literature. 7.1. Bibliography: The Publications of Rademaker and his Students (73); Monographs (3); Theses (10); Collaborators—Co-Workers (18) Publications by and about Rademaker and publications by his coworkers are listed below. Every attempt has been made to make this

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bibliography as complete as possible. It is divided into the following categories: (A) articles in medical journals where Rademaker was the sole author or co-author (73 publications); to the best of the present author’s knowledge, this is the first complete list of such papers to be published; (B) contributions Rademaker made to medical textbooks; (C) his own doctoral thesis on the significance of the red nuclei (1924) and the translations made of this thesis; (D) his monographs; (E) theses prepared under his supervision; (F) publications by his research associates; (G) publications giving details of his life; (H) the Festschrift prepared in 1953 to mark the 25th anniversary of his appointment as professor of Physiology at Leiden; and, in an Addendum, two medical articles dedicated to him by his nephew. The articles in category (A) cover a wide range of physiological topics, the main themes being the role of the mesencephalon and in particular the red nuclei in posture and the support and righting reflexes, the peripheral labyrinthine reflexes and the cerebellum. Most of them were written by Rademaker himself, starting in 1923. Many of his coauthors later achieved international renown in their own right, such as Snellen (who became professor of cardiology in Leiden) and Ter Braak (later appointed to the chair of Neurology in Rotterdam). These articles included four abstracts written for congresses (e.g. Stockholm 1926 and Bern 1931) that were subsequently elaborated into full papers for leading journals like Brain. This category also includes papers read to learned societies and printed in the proceedings of these societies (sometimes together with the discussion following the reading of the paper, which gave an interesting insight into the views prevailing at that time). Rademaker published in the first instance in Dutch journals such as Extraits des Archives Néerlandaises de Physiologie and Verhandelingen (Proceedings) van de Koninklijke Academie van Wetenschappen te Amsterdam, where papers could be in German, French and English as well as in Dutch.10 Reprints were used to send to colleagues abroad. Outside the Netherlands, he initially published exclusively in German and French journals. In later years, however, he also had some publications in English and American journals (Brain and Arch. Neur. Psych.) respectively. Most of Rademaker’s publications from his Utrecht period (1922–28) may be found in Part 1 of the third series of Onderzoekingen Physiologisch Laboratorium Leiden. Unlike the first two series, the articles were not

10 These publications were reviewed by G.J. Tammeling in Publikaties van de Leidse fysiologie 1866–1972; Periode Rademaker (1928–1945), Pub.Hist. Fy 2, Leiden, March 1992.

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reprinted for inclusion in the collection. Instead, existing reprints were bound together with (typed) contents lists. Nearly half of Rademaker’s publications were in Dutch. Up till 1937, he also wrote frequently in German and (especially from 1930 to 1934, the period of his collaboration with Garcin, see Book III, Part 3.2) even more frequently in French. Only four of his publications were in English. As mentioned in section C below, his thesis was translated into German, and a French summary was also published. Perhaps the most significant translation of his works is however the English translation of his monograph Das Stehen (1931) which appeared in 1980 under the title The physiology of Standing. This monograph is discussed at length in Book II, Part 2.5. A previous survey of Rademaker’s publications by Tammeling (1999) suffered from a number of defects, and made no mention of Rademaker’s monographs and contributions to textbooks, among other things.11 A. Articles In Medical Journals Publications marked with an * could be consulted personally. * 1. Magnus R. and Rademaker G.G.J., “Die Bedeutung des roten Kernes für die Körperstellung”. (Vorläufige Mitteilung) Schweiz. Arch.f.Neurol. u. Psychiatr. 13, 408–411, 1923; Festschrift f. Constantin von Monakow * 2. Rademaker G.G.J., “Der rote Kern, die normale Tonusverteilung und die Stell-funktion”. Klin.Wochenschr.Jg. 2, 404–405, 1923. Contribution Eleventh International Congress, Edinburgh 23–27 July 1923 * 3. Rademaker G.G.J., “La signification des noyaux rouges et du reste du mésencéphale pour le tonus musculaire, les attitudes normales et les reflexes labyrinthiques”. Rev.d’Oto-Neuro-Oculistique 3, 1–9, 1925 * 4. Rademaker G.G.J., “Demonstratie van 2 katten zonder cerebellum, 2 honden zonder cerebellum en van een hond, waarbij behalve het cerebellum tevens de rechter grote hersenen geëxtirpeerd zijn”.

11 Tammeling G.J., “130 jaar Leidse Physiologie”. Published 13 February 1999, pp. 3, 11–12. A list of Rademaker’s publications from the ‘third period’ (1928–1945) appeared earlier, in March 1992 (DOC:PUB-3–3–FY2).

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* *

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Verg.versl.Ned.Tijdschr. v.Geneesk. (subsectie voor Psychologie) 2166–2177, 1926a 5. Rademaker G.G.J., “Démonstration de 2 chats décérébellés, de 2 chiens décérébellés et d’un chien ayant subi l’ablation, outre du cervelet, de la moitié droite du cerveau”. Onzième Réunion annuelle de physiologistes néerlandais, 12 Decembre 1925, Arch. Néerl.physiol.de l’homme et des anim. 11, 445–450, 1926b 6. Rademaker G.G.J., “Statik und Motilitätsstörungen kleinhirnloser Tiere”. (Mit kinematographischer Vorführung); Verhandlungen der Gesellschaft deutscher Nervenärzte;16. Jahresversammlung in Düsseldorf vom 24–26 September 1926; Ztschr. Nervenheilk. 94, 144–148, 1926c; *(Summary in: Zentrbl.f.d.ges. Neurol. u.Psychiatrie 44, 1926) 7. Rademaker G.G.J., “Körperstellung und Statik kleinhirnloser Tiere sechs oder mehr Monate nach der Operation (mit kinematographischer Vorführung)”. In: Abstracts of communications to the XIIth International Congres of Physiology, Stockholm 3–6 August, Skand.Arch. 49, p. 138, 1926d 8. Rademaker G.G.J., “Motilitätsstörungen kleinhirnloser Tiere”. Abstracts of communications to the XIIth International Congres of Physiology, Stockholm, Skand.Arch. 49, p. 138, 1926e 9. Rademaker G.G.J., “Over de physiologie van het staan” Verslag van de gewone vergadering afdeeling Natuurkunde (aangeboden door de heeren R. Magnus en C. Winkler). Verhandelingen en bijdragen Nederlandse Akademie van Wetenschappen Afd. Natuurkunde 36, 635–649, 1927a 10. Rademaker G.G.J., “On the physiology of reflex-standing”; Verhandelingen en bijdragen Nederlandse Akademie van Wetenschappen Afd. Natuurkunde 30, 796–810, 1927b (communicated by R. Magnus) 11. Rademaker G.G.J., “Iets over de physiologie en pathologie van het staan”. Nederlandsche Algemeene Ziektekundige Vereeniging 14—de algemeene vergadering op 19 juni 1926, Verg.versl.Ned. Tijdschr.v.Geneesk. 71, 1641–1645, 1927c 12. de Kleyn A. en Rademaker G.G.J., “Experimenteel onderzoek van den optischen nystagmus”. Verslag van de Nederlandsche Keel-neus- en oorheelkundige Vereniging 46ste vergadering op 9 en 10 juni 1928 te Rotterdam. Ned. Tijdschr. v.Geneesk., 72, 5529–5530, 1928

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* 13. Rademaker G.G.J., “Willekeurige en onwillekeurige handelingen”. (Inaugural lecture) Leiden. N.V. Boek- en Steendrukkerij Edward Ydo, Leiden, 26 p. 1928 * 14. Rademaker G.G.J. and Winkler C., “Annotations on the physiology and the anatomy of a dog, living 38 days, without both hemispheres of the cerebrum and without cerebellum”. Communicated at the meeting of April 28, 1928; Proc.Sect.of Sci. Kon.Akad.v. Wetensch. te Amsterdam 31, 332–338, Figs. 9, 1928 * 15. Rademaker G.G.J. and Winkler C., “Eenige physiologische en anatomische opmerkingen omtrent een hond, die 38 dagen zonder hersen-hemisphaeren en zonder cerebellum heeft geleefd”. Verslag van de gewoone vergadering afdeeling Natuurkunde Kon. Ac. v. Wetensch. 37, 356–362, 1928a * 16. Rademaker G.G.J., “De verschijnselen na extirpatie der kleine hersenen”. Ned.Tijdschr.v.Geneesk. 73, 5924, 1929 * 17. Rademaker G.G.J. and Hoogerwerf S., “L’allure des muscles fléchisseurs et extenseurs du coude lors de la rigidité décérébrée”. Arch.Néerl.de physiol.de l’homme et des anim. 14, 445–469, 1929 * 18. Rademaker G.G.J., “Labyrinthaire reacties der extremiteiten bij zoogdieren”. Ned.Tijdschr.v.Geneesk. 74, 2180, 1930a * 19. Rademaker G.G.J., “Expériences sur la physiologie de cervelet”. Rev.Neurol. 37, 337–367, 1930b * 20. Rademaker G.G.J. and Gelderblom J.J., “Der zentrale Mechanismus der Blinzelreflexes auf Drohbewegungen”. Proc. Section Sciences, Kon. Ac. v. Wetensch. 33, 1210–1216, 1930a (communicated by prof. B. Brouwer, at the meeting of December 20, 1930) * 21. Rademaker G.G.J. and Gelderblom J.J., “Het centrale mechanisme van den oogknipreflex op dreigbewegingen bij katten”. Verslag Kon.Ac.v.Wetensch. van de gewone vergadering afdeeling Natuurkunde, 39, 172, 1930b * 22. Rademaker G.G.J. and Hoogerwerf S., “Réactions provoquées pour l’allongement passif du muscle sémi-tendineux”. Arch. Néerland.de Physiol. de l’homme et des anim. 15, 338–357, 1930 * 23. Rademaker G.G.J. and Hoogerwerf S., “Observations sur les réflexes labyrinthiques toniques”. Arch.Néerland.de Physiol. de l’homme et des anim. 16, 305–336, 1931

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* 24. Gelderblom J.J. and Rademaker G.G.J., “L’allure des muscles fléchisseurs et extenseurs du coude lors de la rigidité décérébrée; communication II”. Arch.néerl.de Physiol.de l’homme et des anim. 17, 257–267, 1932 * 25. Rademaker G.G.J., “De labyrinthaire evenwichtsreacties der zoogdieren en haar beteekenis voor de neurologische diagnostiek”. Ned.Tijdschr.v.Geneesk. 76, 3678–3690, 1932a * 26. G.G.J. Rademaker, “Les facteurs régularisant le tonus musculaire”. Abstracts of communication to the International Neurological Congress, Bern, 1931; reprinted in Arch. Neurol. Psychiat. 28, 664, 1932b * 27. Rademaker G.G.J. and Garcin R., “Note sur quelques réactions labyrinthiques des extremités chez l’animal et chez l’homme”; étude physiologique et clinique”. Rev.Neur. 39, 637–653, 1932c (séance du 7 Avril 1932) * 28. Rademaker G.G.J. and Bergansius F.L., “Experiences sur la physiologie de l’ouïe”. Arch.Néerl.de Physiol. de l’homme et des anim. 16, 346–349, 1931; resumé in: Rev.Neur. tii, 310, 1932 * 29. Rademaker G.G.J. and Garcin R., “Le réflexe du clignement à la menace. Sa valeur diagnostique dans les lésions corticales et occipito-rolandiques des hémisphères cérébraux”. C.R. Société Biologie Paris t.III, 547–550, 1932 * 30. Rademaker G.G.J. and Hoogerwerf S., “Observations sur les réflexes toniques labyrinthiques”. Rev.Neur. t.1, 322–323, 1932 (analysis of article No. 25 above) * 31. Garcin R. and Rademaker G.G.J., “Sur une variété d’astasieabasie conditionnée par l’exagération des réactions de soutien (Stützreaktion). Leur extériorisation dans le décubitus”. Rev.Neur. t.1, 1–7, 1933a * 32. Garcin R. and Rademaker G.G.J., “Suite à l’étude de quelques réactions des extrémités d’origine labyrinthique”. Rev.Neur. t.1, 186, 1933b * 33. Rademaker G.G.J., “De booggangreacties der ledematen” (with film demonstration; discussion with Burger en P. de Haan). Ned. Tijdschr.v. Geneesk. 77, 2570–2571, 1933a 34. Rademaker G.G.J., “De booggangreacties der ledematen”. Ned. Tijdschr.v. Geneesk. .., 3678–3690, 1933b * 35. Rademaker G.G.J. and Garcin R., “Sur une variété d’astasieabasie conditionnée par ‘exagération des réactions de soutien (Stützreaktion). Leur extériorisation dans le decubitus”. Rev. Neur. t.1,186; 384–391, 1933a

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* 36. Rademaker G.G.J. and Garcin R., “Le réflexe de clignement à la menace. Sa valeur diagnostique dans les lésions corticales et occipito-rolandiques de hémisphères cérébraux”. Rev.Neur. t.1, 611–612, 1933b * 37. Rademaker G.G.J. and Garcin R., “l’Épreuve d’adaptation statique suite à l’étude de quelques réactions des extrémités d’origine labyrinthique”. Rev.Neur. t.2, 566–579, 1933c * 38. Rademaker G.G.J., “Merkwaardige stoornissen der labyrinthaire en optische reacties in een geval van hydrocephalus internus”. Ned.Tijdschr.v.Geneesk. 78, 4815–4819, 1934a * 39. Rademaker G.G.J., “Labyrinth en evenwicht”. Verslag van de vergadering Genootschap ter bevordering van natuur-, genees- en heelkunde te Amsterdam 28 februari 1934 (afd. voor geneeskunde en biologie), Ned. Tijdschr.v. Geneesk. 78, 5793–5797, 1934b * 40. Rademaker G.G.J., “De beteekenis van het ontbreken van den oogknipreflex op dreigbeweging voor de neurologische diagnostiek”. Ned.Tijdschr.v.Geneesk. 78, 2477–2483, 1934c * 41. Rademaker G.G.J., “Über die Verrichtungen des Kleinhirns”. Psych.u.Neurol.Bl. 5, 814–827, 1934d * 42. Rademaker G.G.J. and Garcin R., “Le réflexe du clignement à la menace: étude physiologique et clinique. La valeur sémeiologique de son abolition dans les lésions corticales rolandiques et occipito-rolandiques des hémisphères en l’absence de toute hémianopsie”. L’Encephale 29, 1–17, 1934 * 43. Visser J. and G.G.J. Rademaker, “Die optischen Reaktionen grosshirnloser Tauben. Mitteilung I”. Archives Néerlandaises de Physiologie de l’homme et des animaux, 19, 482–501, 1934 * 44. Rademaker G.G.J., “Schildklier en jodium”. Handelingen van het XXVe Ned.Natuur- en Geneesk.Congres, Delft, 205–222, 1935a * 45. Rademaker G.G.J., “Enkele waarnemingen omtrent de functie der otolithen”. Ned.Tijdschr.v.Geneesk. 79, 1310–1318, 1935b (discussion De Kleyn) * 46. Rademaker G.G.J., “Over het mechanisme van enkele cerebrale optische reacties”. Psychiatr.Neurol.Bladen, 3, 43–51, 1935c * 47. Rademaker G.G.J. and Ter Braak J.W.G., “Das Umdrehen der fallenden Katze in der Luft”. Acta Oto-Laryngologica 23, 313–343, 1935 * 48. Visser J. and G.G.J. Rademaker, “Die optischen Reaktionen grosshirnloser Tauben. Mitteilung II. Photokinetische und phototrope Reaktionen”. Archives Néerlandaises de Physiologie d l’homme et des animaux, 20, 103–115, 1935

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* 49. Visser J. and G.G.J. Rademaker, “Die optischen Reaktionen grosshirnloser Tauben. Mitteilung III. Ausweichreaktionen”. Archives Néerlandaises de Physiologie de l’homme et des animaux, 21, 285–295, 1936 * 50. Rademaker G.G.J., “Physiologie expérimentale du tronc cérébral (à l’exception des fonctions végétatives)”. Originally appeared in German in Bumke and Foerster’s Handbuch der Neurologie (see also section B, No. 1 below) * 51. Visser J. and G.G.J. Rademaker, “Die optischen Reaktionen grosshirnloser Tauben. Mitteilung IV. Beeinflüssung der optischen Reaktionen durch Abstandsverhältnisse”. Archives Néerlandaises de Physiologie de l’homme et des animaux, 22, 398–417, 1937 * 52. Rademaker G.G.J., “Traumatische arachnoiditis”. Ned.Tijdschr. v. Geneesk. 82, 264–271, 1938a * 53. Rademaker G.G.J., “Optokinetische nystagmus”. Ned.Tijdschr. v. Geneesk. 82, 910–911, 1938b * 54. Rademaker G.G.J., “De ziekte van Morgagni (hyperostosis frontalis interna)”. Ned.Tijdschr.v.Geneesk. 82,2245–2256, 1938c * 55. Rademaker G.G.J., “Over het centrale mechanisme van enkele cerebrale optische reacties”. Verslagen der Koninklijke Nederlands Akademie van Wetenschappen Afd. Natuurkunde, tweede sectie (voortzetting van verhandelingen der Kon. Ned. Akad. v. Wetenschappen) 48, 26–30, 1939a * 56. Rademaker G.G.J., also on behalf of Hinnen A.B. en Kraan P.C., “Over de electrische verschijnselen van het gehoor apparaat”. Verslag Kon.Ac.v.Wetenschappen van de gewone vergadering afdeeling Natuurkunde 49, 24, 1940a * 57. Rademaker G.G.J., “Enkele waarnemingen omtrent de physiologie en pathologie der kleine hersenen bij mensch en dier (with film)”. Ned.Tijdschr.v.Geneesk. 84, 472–479, 1940b * 58. Rademaker G.G.J., “Ataxie. Over ataxie in het algemeen en over de cerebellaire ataxie in het bijzonder”. Ned.Tijdschr.v. Geneesk. 84, 3651–3657, 1940c * 59. Rademaker G.G.J., “Cerebellaire ataxie”. Ned.Tijdschr.v. Geneesk. 84, 3763–3766, 1940c * 60. Rademaker G.G.J., “Ataxie III. De zoogenaamde ‘achterstrengataxie’”. Ned.Tijdschr.v.Geneesk. 85, 3517–3521, 1941a * 61. Rademaker G.G.J., “In Memorian Dr. D.G.W. van Voorthuysen”. Ned.Tijdschr. v.Geneesk. 86, 1111–1112, 1942a

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* 62. Rademaker G.G.J., “Labyrinthaire en frontale ataxie”. Ned. Tijdschr.v. Geneesk. 86, 1526–1530, 1942b * 63. Rademaker G.G.J., “On the lengthening and shortening reactions and their occurrence in man”. Brain 70, 109–127, 1947 * 64. Rademaker G.G.J. and Ter Braak J.W.G., “On the central mechanism of some optic reactions”. Brain 71, 48–76, 1948 * 65. Rademaker G.G.J., “A. Multiple Sclerose. B. Myasthenia Gravis”. Vorderingen der Geneeskunst 1945–1948, hoofdstuk V, Neurologie, Leiden. Universitaire Pers Leiden, Leiden, 343–353, 1949 * 66. Rademaker G.G.J., “Sur le mécanisme central et la signification des phénomènes se manifestant après la labyrinthectomie unilatérale”. Acta Oto-Rhino-Laryng.Belg. 4, 310–319, 1950a * 67. Rademaker G.G.J., “On the toxic effects of penicillin on the nervous system”. Folia Psychiatrica Neurologica et Neurochirurgica Neerlandica 53, 292–293, 1950b * 68. Rademaker G.G.J., “Narcose-encephalopathie”.—klinische les - Ned.Tijdschr.v.Geneesk. 96, 1682–1685; 1952, discussie waaraan deelnamen S.A. Klein, H.C. Voorhoeve, Mw. D.M.E. Vermeulen-Cransch, H.R. Bax * 69. Rademaker G.G.J., “A. Poliomyelitis anterior acuta. B. Niet-bacteriële lymphocytaire chorio-meningitis. C. Myasthenia gravis. D. De betekenis van adrenocorticotroop hormoon (A.C.T.H.) en cortison voor de neurologie”. Vorderingen der Geneeskunst 1949–1952, Leiden Universitaire Pers, pp. A: 433–443; B: 444–447; C: 445–457; D: 458–461; 1953 * 70. Rademaker G.G.J., “Levensbericht van Sir Charles Scott Sherrington (28 nov. 1858–1 maart 1952)”. Jaarboek der Koninklijke Nederlandse Akademie van Wetenschappen, 1–8, 1953–1954 * 71. Rademaker G.G.J., “De werkwijze van het zenuwstelsel”. Ned. Tijdschr.v. Geneesk. 98, 2320–2328, 1954a * 72. Rademaker G.G.J., “Pijn en haar bestrijding”. Ned.Tijdschr. v.Gen. 98, 3122–3126, 1954b * 73. Rademaker G.G.J., “La regulation du nystagmus optocinétique par un mécanisme du type ‘feedback’”. Revue Neurologique 93, 301–302, 1955 Contributions to textbooks * 1. Rademaker G.G.J., “Experimentelle Physiologie des Hirnstammes”, Handbuch der Neurologie, herausgegeben von O. Bumke und O. Foerster; Julius Springer Verlag, Berlin: Band 2, 187–234, 1937

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* 2. “Nederlandsch Leerboek der Physiologie”. Compiled by professors from various Dutch universities under the leadership of G. van Rijnberk. Part 5: Centraal zenuwstelsel by J. ten Cate, C.U. Ariens Kappers, G.G.J. Rademaker andG. van Rijnberk. Physiologie der kleine hersenen” (pp. 163–204); “Physiologie van den Hersenstam” (pp. 234–274) and “De Groote Hersenen” (pp. 277–295). First edition 1941; Second revised and expanded edition, with an index, 1944/1946, C.V. Swets & Zeitlinger, Boekhandel en Uitg. Maatschappij Amsterdam, Keizersgracht 471. * 3. Rademaker G.G.J., “Physiologie van de kleine hersenen, van den Hersenstam en Groote hersenen”. In: Nederlandsch Leerboek der Physiologie, vijfde deel: Centraal Zenuwstelsel. J. ten Cate, C.U. Ariens Kappers, G.G.J. Rademaker, G. van Rijnberg (eds.), 163–213; 234–275; 277–334. Second revised and expanded edition, with an index, 1946, C.V. Swets & Zeilinger, Boekh. en Uitg. Maatschappij, Amsterdam. 4. Rademaker G.G.J., “Practicum Experimenteele Physiologie”, Leiden, Oktober 1937, p. 81; published privately by the department of Physiology at the University of Leiden. C. Rademaker’s doctoral thesis and translations * 1. Rademaker G.G.J., “De beteekenis der roode kernen en van het overige mesencephalon voor spiertonus, lichaamshouding en labyrinthaire reflexen”. Diss.Univ.Utrecht. E. Ydo., 381 pp. 1924. Defended in public on 20–05–1924, doctorate awarded cum laude * 2. Rademaker G.G.J., “Die Bedeutung der roten Kerne und des übrigen Mittelhirnes für Muskeltonus, Körperstellung und Labyrinthreflexe”. German translation by E. le Blanc. Monographien a.d. Gesamtgebiete der Neurol.u.Psych. (Herausgegeben von O. Foerster und K. Williams) Heft 44, S.1–340, Berlin, Julius Springer, 192612

A few additions have been made in this translation especially to the chapters on the physiology and pathology of the midbrain, and the number of illustrations has been increased. 12

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* 3. Rademaker G.G.J., “La signification des noyaux rouges et du reste du mésencephale pour le tonus musculaire, les attitudes normales et les reflexes labyrinthiques”, Rev. Oto-neuro-ocul. 3 (1), 1–9, 1925. French translation, summary D. Monographs * 1. Rademaker G.G.J., “Das Stehen, Statische Reaktionen, Gleichgewichtsreaktionen und Muskeltonus unter besonderer Berücksichtigung ihres Verhaltens bei kleinhirnlosen Tieren”. Heft 59. Monografieën a.d. Gesamtgeb.v.Neurol.u.Psych. Herausgeg. v. O. Foerster u. K. Williams. Verlag von Julius Springer, Heidelberg, 1931 * 2. Rademaker G.G.J., “Réactions labyrinthiques et équilibre: l’ataxie labyrinthique”. Masson et Cie, Paris, pp. 1–262, 1935 * 3. Rademaker G.G.J., “The Physiology of Standing” (Das Stehen). Postural Reactions and Equilibrium with Special Reference to the Behavior of Decerebellate Animals” by G.G.J. Rademaker. Edited with a Foreword by D. Denny-Brown. Translated for the Public Health Service, National Library of Medicine, US Department of Health, Education, and Welfare and the National Science Foundation, Washington DC by Franklin Book Programs, Inc. Cairo, 1975. Published by the University of Minnesota, pp. 668, 1980 E. Doctoral theses prepared under Rademaker’s supervision With the exception of thesis No. 4 (by O. Sager)—where Rademaker was not the main supervisor—these theses are summarized in Book IV, part 4.1. * 1. Visser J., “Optische reacties van duiven zonder groote hersenen”. Leiden, 1932; Uitg. N.V. Boek en Steendrukkerij Eduard IJDO—Leiden; published in Dutch, p. 178. Defended in public on 16–06–1932. * 2. Maas H.H., “Onvolwaardig voedsel en krop”. Leiden, 1933; Uitg. N.V. Boek en Steendrukkerijk Eduard IJDO—Leiden; published in Dutch, p. 150. Defended in public on 11–10–1933. * 3. v. Niekerk J., “Constitutie en allergische ziekten”. Uitg. De Voorpost, Rotterdam, 1934;

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* 4.

* 5.

* 6.

* 7.

* 8.

* 9.

*10.

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Supervisor Prof. W. Storm van Leeuwen (Rademaker took over from Prof. Storm van Leeuwen during the latter’s absence due to sickness) Sager O. (Bucarest), “Etude anatomique du système nerveux d’un chien auquel on a extirpé les deux hémisphères cérébraux et le cervelet. Quelques considérations physiologiques”, Uitg. De Erven F. Bohn NV; published in French, p. 68, 1935. The publication of this thesis was funded by the R.A. Laan Fonds, Amsterdam. Supervisor Prof. B. Brouwer; adjunct supervisor Prof. G.G.J. Rademaker Verwey N., “Over de lichaamshouding en de motoriek regelende reacties bij laagstaande oligophrenen, haar klinische en physiologische beteekenis”. Leiden, 1938; Uitg. N.V. Boek- en Steendrukkerij Eduard IJDO—Leiden; published in Dutch, p. 174. Defended in public on 09–06–1938. Verbiest H., “De invloed van het achterstrengsysteem op de tonische corticospinale innervatie der extremiteiten. Het buigingsverschijnsel der vingers”. Leiden, 1939; Uitg. N.V. Boek en Steendrukkerij Eduard IJDO—Leiden; published in Dutch, pp. 144. Summary in English, pp. 134–140. Defended in public on 24–02–1939. Kraan P.C., “Experimenteel onderzoek omtrent het Centrale Mechanisme van de Ontherseningsstijfheid en van enige Oprichtreflexen”. Leiden, 1939; Uitg. N.V. Boek- en Steendrukkerij Eduard IJDO—Leiden; published in Dutch, p. 202. Defended in public on 11–10–1939. Ruys C., “Over rotatoire oogdeviaties opgewekt door centrifugaalkracht”. Leiden, 1945; Uitg. Eduard IJDO—Leiden; published in Dutch, p. 65. Defended in public on 14–11–1945. Storm van Leeuwen W., “Arhythmia cordis door experimenteele beschadiging van het centrale zenuwstelsel”. Leiden, 1945; Uitg. N.V. Boek- en Steendrukkerij Eduard IJDO—Leiden; published in Dutch, p. 111. Defended in public on 27–09–1945. Stotijn C.P.J., “Experimentele onderzoekingen over het cardiazolinsult”. Leiden, 1946; Uitg. Drukkerij “Luctor et Emergo”—Leiden; published in Dutch, pp. 264. Summary and Conclusions in English, pp. 242–246. Defended in public on 27–09–1945.

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F. Publications by staff at the department of Physiology, Leiden, during Rademaker’s time as professor. Some studies were performed in cooperation with the Institute of Pharmacotherapy; these are indicated by a „ *„ 1. Hoogerwerf S., “Elektrokardiographische Untersuchungen der Amsterdamer Olympiadekämpfer”, Zschr. f. Physiologie des Menschen bei Arbeit und Sport 2, 61–75, 1929 * 2. Raymond Morrison L., “Anatomical studies of the central nervous systems of dogs without forebrain or cerebellum”; De Erven F. Bohn Haarlem, 1929. Dissertation Utrecht? This study was funded by the R.A. Laan Fonds. * 3. Gelderblom J.J., “Het centrale mechanisme van den oogknipreflex op dreigbewegingen bij de kat”, Ned. Tijdschr. v. Gen. 74, 17, 2174–2175, 1930 *„ 4. Hoogerwerf S., “Considérations au sujet de la technique de l’enregistrement phonographique en usage dans l’étude dialectique”, Arch. Néerl. Pnonétique Expérimentale 5, 147–159, 1930 „ 5. Ter Braak J.W.G., van Niekerk J., “Der Einfluss des Vagus auf die Innervation des Diaphragmas”, Acta Brevia Neerlandica 4, No. 5/6, 92, 1934 * „ 6. van Niekerk J., Ter Braak J.W.G., “Die Anpassung der Atmung an Stenose der Luftwege”, Acta Brevia Neerlandica 4, No. 5/6, 93, 1934 * * 7. Snellen H.A., “Einige Untersuchungen über das Wever- und Bray-Phenomen”, Acta Oto-Laryngologica 23, No. 3/4, 470– 480, 1935 * 8. Ter Braak J.W.G., “Optokinetische nystagmus”, Ned. T. Geneesk. 79, No. 16, 1853–1858, 1935 * 9. Ter Braak J.W.G., “Untersuchungen über optokinetischen Nystagmus”, Arch. Néerl. Physiol. 21, 309–376, 1935 *„10. Ter Braak J.W.G., van Niekerk J, “Der Einflusz des zentripetalen Lungenvagus auf Lage und Bewegung des Zwerchfelles”, Pflüger’s Arch. ges. Physiol. des Menschen u.d. Tiere 235, 582–587, 1935 * *„11. van Niekerk J., Ter Braak J.W.G., “Die Anpassung des Atmungsvorganges an Widerstandsänderungen in den Atmungswegen”, Pflüger’s Arch. ges. Physiol. des Menschen u.d. Tiere 236, 44–51, 1935 *

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* 12. Ter Braak J.W.G., “Über die Empfindlichkeit des Bogenapparates für Winkelbeschleunigungen”, Pflüger’s Arch. ges. Physiol. des Menschen u.d. Tiere 238, 319–326, 1936 * 13. Ter Braak J.W.G., “Kann der Bogengangsapparat durch geradelinige Beschleunigung gereizt werden?”, Pflüger’s Arch. ges. Physiol. des Menschen u.d. Tiere 238, 327–332, 1936 * 14. van Voorthuysen D.G.W., Ter Braak J.W.G., “Die Rolle des Vagus in der Selbststeuerung der Atmung”, Pflüger’s Arch. ges. Physiol. des Menschen u.d. Tiere 238, 307–318, 1936 * 15. Ter Braak J.W.G., “Enkele corticale optische reacties bij honden, in verband met de localisatie in de area striata”, Ned. T. Geneesk. 82, No. 31, 3818–3822, 1938 * 16. Verbiest H., “Ervaringen over therapie van myasthenia gravis”, Ned. Tijdschr. v. Gen. 82, 621–633, 1938 * 17. Ter Braak J.W.G., van Voorthuysen D.G.W., “Weitere Beobachtungen über den tonische Vaguseinfluss bei verschiedenem konstantem Lungenvolum”, Pflüger’s Arch. ges. Physiol. 243, 724–732, 1940 * 18. Kuypers C., “Untersuchungen über den Mechanismus des Exophthalmus”, Arch.Néerl. Physiol. 25, 323–335, 1941 G. Biographical publications * 1. Ter Braak J.W.G., Storm van Leeuwen W., Verbiest H., “Prof. Rademaker; the man and his work”. Folia Psychiatrica, neurologica et Neurochirurgica, 56, 393–406, 1953 * 2. “Prof. dr. G.G.J. Rademaker binnenkort zeventig jaar” [Prof. Rademaker approaching his seventieth birthday]. Leidsch Dagblad, Part 2, No. 29086, 14 March 1957 * 3. “Prof. dr. G.G.J. Rademaker op de drempel van emeritaat overleden” [Prof. Rademaker died on threshold of retirement]. Leidsch Dagblad 96, 20 April 1957 * 4. “G.G.J. Rademaker”. Revue Neurologique, 2, 134–135, 1957 (seance du 4 Juillet 1957, Dr. Baruk) * 5. “In Memoriam Prof. Dr. G.G.J. Rademaker”. Ned.Tijdschr.v.Gen., 101, 849–851, 1957 (Dr. H. Verbiest) * 6. “Levensbericht van Gijsbertus Godefriedus Johannes Rademaker (19 maart 1887–19 april 1957”. Jaarboek der Kon.Ned. Akademie van Wetenschappen 1956–1957; pp. 238–243 (Dr. W. Storm van Leeuwen)

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* 7. “Levensschets Gijsbertus Godefriedus Johannes Rademaker”, verslag van de gewoone vergadering der Afdeling Natuurkunde van de Kon. Ned. Akademie van Wetenschappen, zaterdag 27 april 1957, deel LXVI No. 4, pp. 58–59 * H. ‘Festschrift’—Liber amicorum “Miscellenea medica in honorem viri clarissimi Gysberti Godefridi Ionassis Rademaker, collecta a collegis amicis discipulis” Folia Neurolog., Neurochirurg. Neerlandica 56, 393–565, 1953 With contributions from (in alphabetical order): Nils Antoni, A. Biemond and L. van Bogaert, Bok S.T., Ter Braak J.W.G., Bremer F. and Bonnet V., ten Cate J. and Horsten G.P.M., Drooglever Fortuyn J., Fulton John F., Garcin R. and Godlewski, van Gehuchten P., Hoelen E., Magnus O., Smit Sillevis W.G. and van der Most van Spijk D., Snellen H.A., Stenvers H.W., Storm van Leeuwen W. and Miss L. Kok, Stotijn C.P.J., André-Thomas, Verbiest H., Verhaart W.J.C., van Wulffen Palthe P.M. Addendum Publications dedicated to Rademaker by his nephew G.A. Rademaker, paediatrician in Surabaya. – G.A. Rademaker, “Poliomyelitis acuta anterior” (Demonstratie van drie patiëntjes), Gen. Tijdschrift van Nederlands-Indië 79, 2423– 2425, 1939b – G.A. Rademaker, “Seizoenskoorts bij kinderen in Surabaia” en de behandeling ervan in luchtgekoelde kamer (naar een voordracht gehouden voor de Geneeskundige Kring te Soerabaja), Geneeskundig Tijdschrift van Nederlands-Indië 81, 2021–2038, 1941b 7.2. The Triptych The final book of the ‘triptych’ formed by Rademaker’s thesis on the red nucleus and his two monographs, described clinical applications of previous experimental work on static adaptation, based on examination of patients in various Parisian clinics by Rademaker and Garcin

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during the former’s visits to the Salpêtrière in five successive summers (1930–1935). Taken together, the trilogy can also be regarded as an unfinished portrait of experimental physiology in the first half of the twentieth century. Apart from the fact that these three books are written in three different languages, they may be said to be composed in an international language based on the concepts Magnus and de Kleyn developed to describe the work that formed the basis for Magnus’s Die Körperstellung. The three parts of the triptych reinforce one another to give a wellbalanced cumulative impression of heady yet delicate intelligence. While each book taken separately is no easy reading matter, together they give a powerful picture of Rademaker’s modus operandi. Lengthy reviews of Rademaker’s books appeared in the major journals of physiology and neurology (such as those by Mussen and Walshe in Brain and Molleret et al. in Revue neurologique); Denny-Brown’s foreword to the English translation of Das Stehen (The physiology of Standing) that he edited may also be regarded as a review of this monograph. While his work was keenly discussed in neurological circles in the UK, USA, France and Germany, it made surprisingly little impact in his own country. The tests he devised saw limited clinical application in the Netherlands: Biemond dismissed the test for the blink reflex as giving ‘unattributable’ results; Drooglever Fortuyn spoke of it as being ‘unattributable but interesting’; on the other hand, Ter Braak, Verbiest, Luyendijk, Querido and others from Rademaker’s own circle recognized its value. In retrospect, Rademaker was ironic about his aims: “I did not want to produce an audience-friendly narrative of well-made plots and lovable characters.” It is perhaps understandable, then, that his major works were never much read by physiologists, neurologists, general practitioners, medical students and the like, though his ideas were known and appreciated by neurophysiological researchers all over the world just as his clinical and physiological lectures were appreciated by students. Looking back on his scientific career, we are confronted by two questions that are often confused: was he right, and did his work advance the cause of science in general? It is not necessarily so, as is generally assumed, that both these questions have to be answered in the same way. Anyone who was acquainted with Rademaker’s experimental work was struck by the air of authority emanating from it, and he certainly made major contributions to our understanding of locomotor functions. Even Ingram and Ranson,

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who criticized many of his conclusions, referred to Das Stehen as “his fine study of postural reflexes”.13 On the other hand, it may be argued that he was one of the last great animal experimenters. This line of research, that had a long history going back well before Sherrington (such as Magendie),14 has lost much of its popularity today: even Rademaker was much less active in this field after the War. In any case, he was never very outspoken in drawing conclusions from his animal experiments e.g. on cerebellar functions (Ter Braak mentions this in the Festschrift produced to mark the silver jubilee of his professorship) or on the functions of the red nucleus. Indeed, some of the criticisms levelled at him by such researchers as Ranson may refer to conclusions which he never draw explicitly, preferring to point out the existence of new vistas in our understanding. To sum up, we may end with a saying of Rademaker’s that Ter Braak once quoted to me verbatim: if anyone asked him for a fully worked-out concept in a given field, he would answer, The power of longing for a definitive concept is more durable than the thrill of possessing one.

7.3. Honours In view of all his contributions, his fame is hardly surprising. He received many decorations: Member of the Royal Academy of Sciences in the Netherlands, he was an honoured representative of the Dutch scientific world at congresses abroad; he was promoted to the rank of ‘Officier of the Légion d’Honneur’ in France and elected member of the prestigious Leopoldino order in Halle, Germany. He was selected as vice-president of the World Neurology Congress in Brussels (1957). He was promoted to the rank He was honoured by being portrayed together with Cornelis Winkler (1855–1941), ‘the father of Dutch neurology’, on the medal struck for the 11th World Congress of Neurology in September 1977 (see figures)

13 Ingram WR, Ranson SW and Barris RW, The red nucleus, its relation to postural tonic and righting reactions, Arch. Neurol. Psychiat. 31, 769 (1934). 14 See Book II—Part 2.4.

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Figs. 7-2 a & b. Rademaker’s bound handwritten lecture notes with drawings. These notes, which Rademaker used for his lectures and ‘theoretical neurology’ demonstrations, were for his personal use only and have never been published. Rademaker put a great deal of work into the preparation of his lectures, making use of the most recent data from the literature (Noach, 2005) together with relevant data from the investigations he was currently pursuing in the neurology clinic; sometimes he even gave demonstrations of patients he was treating. The lectures, which he generally delivered in an undertone, were thus very up to date and were listened to with great attention by the students— sometimes even by reporters, when he demonstrated cases of narcosis epilepsy in a numeber of young children, caused by narcosis techniques that were under discussion at the time and that were found to be the cause of the CNS pathology observed. [Personal communication drs. Max van der Kruk, surgeon] The students were particularly interested in the very skilful drawings he produced on the blackboard, some of which were used in publications (For example in the “Nederlands Leerboek der Physiologie” (Dutch Handbook of Physiology); see: ‘Contributions to textbooks’ on pp. 187–188 of the present book. According to Jan Taselaar, former head of the Neurology clinic in Leiden [personal communication], “The printer thought that these illustrations, with their minutely executed details, were the work of a professional draughtsman. He was astonished to learn that they were produced by Rademaker himself (and Rademaker was flattered to hear this).”). These bound lecture notes were donated by Dr. L.J. Endtz to the Rademaker archives in the Library of the neurological teaching hospital Leyenburg in The Hague.

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Fig. 7-3. G.G.J. Rademaker, 1935. Courtesy: Deutsche Akademie der Naturforscher LEOPOLDINA, Halle (Germany).

Figs. 7-4 a & b. The medal for the 11th World Congress of Neurology in September 1977 in Amsterdam, on which Rademaker and Winkler are portrayed. Design: Ger Zijlstra, Amsterdam.

BOOK VIII

‘ON THE ORIGIN OF MOVEMENT’. HISTORY Introduction; historical aspects The purpose of science is to understand reality through explanations. The characteristic (though not the only) method of criticism used in science, is experimental testing. An experimental test is an experiment whose outcome, may falsify one or more of a set of rival theories. (David Deutsch, 2000)

Rademaker’s experimental work concentrated largely on posture, muscle tone and movement. He cited Aristotle’s statement that “to be ignorant of motion is to be ignorant of nature”. Gaining knowledge of nature—and in particular on the origin of movement—was the goal he set himself in this experiments. His conclusions could be distilled to yield his philosophy of science. The triangle of movement The movement of a living organism is more than the mechanical displacement of an object. Rademaker’s experimental work led him to a number of new insights into the origin of movement and motor development that can be encapsulated in what we may call the “triangle of movement” (see figure), which represents the relationship between the three basic criteria (in the literal sense of the Greek word κρίτεριον = cornerstone): movement, posture and muscle tone. The basic idea of creating the concept of movement and separating its into its component constituents was developed by Rademaker in his monography Das Stehen (1931).1 The idea of representing the

1 Translated into English and edited by the American physiologist D. Denny-Brown almost fifty years later (1980) under the title The physiology of Standing.

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Fig. 8-1. The triangle of movement, showing the connections between movement, posture and muscle tone. A. rest point of zero acceleration B. neutral posture C. atonia, leading to a balance between hypotonia (to the left) and hypertonie (to the right) which represents normal muscle tone A → C movement due to changes in muscle tone (as e.g. in the case of ‘avoiding’ movement)

relation between these constituents in graphical form comes from the present author. This diagram is based on a number of considerations, which we will develop further in the historical review given separately in the first part of this chapter. In the second part, we will sketch the development of Rademaker’s experimental work and the insights he derived from it. Finally, we will discuss Rademaker’s ideas about “cybernetic physiology”. Recent electromyographic data promise to provide the basis for a mathematical analysis of posture, movement and muscle tone that has not yet been fully realized. It is the objective of a proposed research project. 8.1. Rademaker’s Axioms and Postulates I. The inseparability of movement and posture. Movement can be seen as the sum of a series of postures. Of course, such movement in a living organism is necessarily subject to sensory guidance, a multivariate condition in which different types of sensory stimuli elicit their own particular type of motor response. In a normal

‘on

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Figs. 8-2 a & b. These two paintings by the avant-garde Russian artist Varvara Stepanova (1894–1958) give a lively impression of the disjointed movements she saw as symbolic of the times she lived in. They also bear an uncanny resemblance to the “mouvements décomposées” observed by physicians in patients with neurological disorders (dyskinesias) known under the general name of chorea, which is derived from the Greek χορεία (a kind of dance). Stepanova adds anatomical exactitude by using different colours for muscle groups that are in extension and contraction.

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nervous system, these reflex motor responses to varied sensory stimuli are in equilibrium, i.e. certain types of sensory stimuli produce specific reflex changes in posture and movement. This reflex organisation based on specific types of sensory stimuli can be manipulated by the organism fot its own purpose. After injury to the nervous system, there is a loss of equilibrium causing a defect of motor activity. (M.,P.) II. The mechanisms of posture and movement. Posture and movement are not the same thing but they are the same sort of thing, they are created in the same way and they are inseparably linked. Increasing impairment of the types of movement involved in maintaining posture leads to increasingly obvious postural disorders. So movement disorders such as chorea, athetosis and the like are primary disorders of posture. Each motor reaction has an adequate stimulus, and the nervous system as a whole contributes to each motor set. (P.,M.) III. There are no separate mechanisms for posture and movement. Postural reactions are based on fundamental features of neural organisation, and movement in its most elementary form may be seen as modification of posture (in terms of figure 8-1, A → B). (P.,M.) IV. The original decerebration model of Sherrington was the starting point for the experiments of Magnus, de Kleyn and Rademaker in this field. It was used for studying, not only the rigidity in the anti gravitational extensor muscles of the lower extremities, initially demonstrated by Sherrington, and in the flexor muscles of the upper extremities (subsequently demonstrated by Rademaker and Hoogerwerf 2 and Rademaker en Gelderblom),3 but also for studying disequilibrium of postural mechanisms due to disturbances at lower levels in the nervous system, leading to impairment in posture (called ‘caricatural posture’ by Magnus) and gait. (P.T.)

2 Rademaker G.G.J. and Hoogerwerf S., “L’allure des muscles fléchisseurs et extenseurs du coude lors de la rigidité décérébrée”, Arch. Néerl. de Physiol. de l’homme et des animaux, 14, 445–469, 1929. 3 Rademaker G.G.J. et Gelderblom J., “L’allure des muscles fléchisseurs et extenseurs du coude lors de la rigidité décérébrée II”, Arch. Néerl. de Physiol. de l’homme et des animaux, 17, 257–267, 1932.

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V. Another basic conclusion of Rademaker’s experimental work was that in every sense, the syndrome of complete cerebellar ablation proved to be the reverse of decerebrate rigidity (inasmuch as the extremities are flexed). All the reactions that make up the classical decerebrate posture are depressed. Only fleeting traces of the labyrinthine and neck reflexes can be elicited. In the monkey without cerebellum, posture is influenced by contact sensation from broad areas of the body causing flexion. This can be abolished by decerebration. If the decerebellated monkey is decerebrated, a typical release of decerebrate rigidity is observed. The defect in displacement reactions is severe after cerebellar ablation, owing to failure of the positive supporting mechanisms. VI. The transition from hypo- to hypertonia does not take place by way of normal tonus, though normal tonus, due to the cessation of central mechanisms, is sometimes transformed into hypotonia and sometimes to hypertonia. The succession of the different stages of tonus is atonia → hypotonia or hypertonia → normal muscle tonus. Hypo- and hypertonia are originally very closely related phenomena and sometimes even merge into one another. Hypertonus is not an augmentation of tonus but the continuation of muscular contraction under circumstances in which it would normally be abolished.4 (T.) VII. Muscle tone and movement. Muscle tone has had a long reputation in physiology as a deeply mysterious entity. Fulton5 and Sherrington6 have both written accounts of historical development of our ideas about muscle tone. A summary of this history—largely based on Sherrington’s article—would seem to be in place here. Aristotle gave the first description of the phenomenon of muscle tone in his “De motu animalium”. 4 Rademaker G.G.J., “Physiology: Les facteurs régularisant le tonus musculaire”, Archiv. Of Neur. Psych. 28, 664, 1932. Sherrington C.S. Concluding remarks to the discussion on tonus of skeletal muscles. Ibidem 676–678, 1932. 5 Fulton J.F., “Notes on the history of postural reflexes”, in: “Miscellenea medica in honorem viri clarissimi Gysberti Godefridi Ionassis Rademaker collecta a collegis amicis discipulis”, Folia Neurolog. Neurochirurg. Neerlandica, 56(4), 455–459, 1953. 6 Cited in Sherrington C.S., “Note on the history of the word ‘tonus’ as a physiological term” (pp. 261–266) in Vol. I: Contributions to medical and biological research dedicated to Sir William Osler, Barth., M.D., F.R.S., in honour of his seventieth birthday July 12, 1919 by his pupils and co-workers, New York, Paul B. Hoeber, 1919, 2 Vols.

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VIII. (cont. axioma’s and postulates) Thus movement in terms of postural organization and temporo-spatial sequence (P.) IX. ‘The walk reflex is a fall reflex’ [Personal communication by Berthoz, 2002] Sherrington cites Galen’s tract: Περί μνών κινήσεως, “De moto musculorum”7 where it is pointed out that the resting posture of a frog’s muscle is dependent upon the integrity of the innervation of the muscle in question—thus recognising the fact that muscle tone depends on the integrity of the connections with the central nervous system. Various seventeenth-century authors (such as Fabricius ab Aquapendente and Borelli) made similar observations. For example, Fabricius ab Aquapendente8 gave observational evidence and wrote as follows in his “De motu locali animalium”: Let us see how the legs behave in standing. When both legs stand although there is in them no visible motion of the muscles, all the muscles are of a truth in motion and in action. And this motion, unapparent though it is, is rightly, designated by the term tonic, τεινω in Greek, which would say tense. For the motion is tonic by which the arm or leg or other member is maintained tense in virtue of all the muscles whether flexors or extensors operating in it have been drawn in the above sense tight.

Borelli expressed a similar opinion in his “De motu animalium”9,10 (see figure). He did not refer to tone as motus tonicus, but as actio tonica. With the like meaning, however, and chiefly instanced by the same example, standing. For Borelli, the term ‘tonic’ still meant ‘postural’. His account shows an advance in the analysis of posture: Therefore the falling forward is prevented solely by the extensor muscles, and not in fact by the tonic action of extensors and flexors operating concurrently.

7 Galen (129 BC–210 BC), “De motu musculorum” in C.G. Kühn’s edition of Galen’s Operat omnia, Medic. Graecor. opera, Quae existant, 1822, Vol. 4, pp. 367–484. Useful is also J. Canappe’s French translation: “Du mouvements des muscles; livres deux”, Lyons, Etienne Dolet, 1541, 83 pp., 2B. 8 Fabricius ab Acquapendente (Girolamo FABRIZIO) J. (1533–1619), an anatomist from Padua, wrote “De motu locali animalium; secundum totum” (1618). This has been reprinted by Padua University Press, De Martinis (ed.), 123 + 34 pp. 9 Borelli, Giovanni Alfonso B., 1608–1679, Italian mathematician and physicist, wrote “De motu animalium—pars altera”, Roma, 1680, 2 Vols., Bernabo. 10 Giovanni Alfonso Borelli, “On the movement of animals”, translated by Paul Macquet, Berlin, Heidelberg, Springer Verlag, 1989.

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Therefore men do not maintain station by the tonic action of all the antagonistic muscles, but by the operation of all the extensor muscles and some of the flexors, while some of the flexors remain inoperatively at rest (Liber I, proposition CXXXVI). (see next page)

This is an approximation to the modern view. In short, the word tonus existed unchanged for nearly sixteen centuries, and even a century of the Renaissance had not surcharged it with more, or at least with altered meaning, comments Sherrington. But biology was the latest of all chapters of Renaissance science to develop, because analytic—as distinct form merely descriptive—biology had to wait for the rebirth of physics and chemistry before it could find itself. Propositus CXXXVI Lib. I 11 “Man is not maintained erect by the tone of the antagonistic muscles of all the limbs.” “We must find with which muscles men control their oscillations when standing erect. First of all we must reject the error of those who think that the erect position of man is maintained by the simultaneous action of all the extensor and flexor muscles. Oscillation and fall can occur forwards, backwards or to the sides. Falling forwards results from anterior flexion of the lower legs about the feet and anterior flexion of the spine towards the knees. The femur, however, cannot flex anteriorly about the knee without dislocation. Anterior flexion of the leg can be prevented only by the extensor muscles of the leg, the soleus and the glutei. The flexor muscles of the leg are not involved. They would rather enhance the fall. Therefore, they remain inactive. Consequently, flexion and fall forwards are impeded by the extensor muscles alone and not by the simultaneous tone of both extensor and flexor muscles acting together. Fall backwards results from too much plantar flexion of the ankle, flexion of the femur about the knee and backwards flexion of the spine. Flexion of the knee can be controlled by the extensor muscles of the knee alone and not the flexor muscles. Exaggerated plantar flexion of

11 Translated by Paul Macquet: Giovanni Alfonso Borelli, “On the movement of animals”, Springer-Verlag, 1989, Berlin Heidelberg New York London Paris Tokyo, p. 131.

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Fig. 8-3. Giovanni Alfonso Borelli (1608–1679). Frontispiece drawing.

Fig. 8-4. Frontispiece of “De motu animalium” by Giovanni Alfonso Borelli, Editio Novissima, Auctior et Emendatior. Hagae Comitum. Excudit Petrum Gosse. Bibliop. MDCCXXXXIII.

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Fig. 8-5. Frontispiece of thesis on muscular contraction written in 1694 by Johann Bernoulli (1705–1748). He modelled his views of muscular action on those of Borelli and made use of the mathematical theories developed by Leibniz. There was a whole dynasty of mathematical Bernoulli’s; Johann followed his brother Jakob (1655–1705) into the chair of mathematics at the University of Basel, and Johann’s son (also called Johann) followed Johann as professor of mathematics after his death. According to the Dictionary of Scientific Biography, the latter “personified the mathematical genius of his native city in the second half of the eighteenth century”.

Fig. 8-6. Table V of “De motu animalium”, showing elements of animal movements. The resemblance of this figure to the paintings of Varvara Stepanova, reproduced earlier in this part 8.1., is striking.

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the ankle and extension of the hip backwards are prevented by the dorsiflexor muscles of the ankle and the flexor muscles of the hip. Similarly, sidewards oscillation can be checked by the muscles on the opposite side. Consequently, standing erect does not involve the tonic pull of all the antagonistic muscles but only extensor and some flexor muscles whereas some flexor muscles of the knees remain inactive. Muscular tone may be present at ankle and hip level but not at knee level. Nowhere have the above views been more picturesquely described than by the eminent seventeenth-century physician Sir Thomas Browne who in his book “On vulgar and common errors”12 mentions the case of the elephant whose stance was steady and rigid, and he adds: For station is properly no rest, but one kinde of motion, relating unto that which Physicians (from Galen) doe name extensive or tonical; that is an extension of the muscles and organs of motion, maintaining the body at length or in its proper figure; wherein although it seem to be unmoved, it is nevertheless not without all motion; for in this position the muscles are sensibly extended and labour to support the body; which permitted unto its proper gravity, would suddenly subside and fall unto the earth as it happened in sleep, diseases and death. From which occult action and invisible motion of the muscles in station (as Galen declareth) proceed more offensive lassitudes then from ambulation.

The problems of muscle tone were discussed at length in the eighteenth century by Stahl, Hales and others,13 but there were few disclosures of note concerning the postural reflexes. “Tonus” became regarded—and this continued into the nineteenth century—as that “state of slight contraction found in all healthy muscles” whose nerves were still in anatomical connection with the spinal cord (as Sherrington put it). A mathematical, biochemical, ‘iatromecanical’ analysis was proposed by the Swiss mathematician J. Bernouilli (1667–1748) in his thesis “De

12 Browne Sir Thomas, “Pseudodoxia epidemica: or enquiries into very many received tenents, and commonly presumed truths”, London, Edward Dool, 1646, 10 fl., 386 pp. [p. 105]. 13 Georg Ernst Stahl (1660–1734); Stephen Hales (1677–1761). Cited in Sherrington C.S., “Note on the history of the word ‘tonus’ as a physiological term” (pp. 261–266) in Vol. 1: Contributions to medical and biological research dedicated to Sir William Osler, Barth., M.D., F.R.S., in honour of his seventieth birthday July 12, 1919 by his pupils and co-workers, New York, Paul B. Hoeber, 1919, 2 Vols.

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motu musculorum” (1721)14 using Leibniz (1646–1716) differential calculus and insights in kinetics and mechanics. The physiologist Marshall Hall (1790–1857) suggested that ‘tonus’ was a reflex.15 Experimental data or observations on which this claim could be based were however lacking according to Sherrington. The existence of skeletal muscle tone seems to have been doubted by many physiologists in the 1850s, but it was reaffirmed by the observations of Brondgeest. A relatively unknown Dutch investigator at that time, he devoted his thesis (presented in 1860 at Utrecht in the Netherlands)16 to a study of muscle tone, describing crucial experiments “that brought him fame as the able Dutch investigator” (Fulton, 1953).17 Brondgeest showed in frogs that had had the skin removed from their hindlimbs that if the afferent spinal roots of one hindlimb be severed, this limb is less flexed than the sound fellow limb when the frog is held vertical. He argued that the greater flexion of the sound limb is due to reflex-induced tone of its muscles. The observation—the first evidence for the neurogenic basis of muscle tone—was soon recognized as trustworthy and came to be regarded as a hallmark of experimental excellence.18 Rademaker preferred to cite the French investigator Duchenne de Boulogne (1806–1875) as a source of observational evidence in this field, and wrote as follows in the chapter on “General information The physiology of Standing and postural reactions” of his monograph “The physiology of Standing”:

14 Bernouilli Johannis, “De motor musculorum; De effervescentia and fermentatione. Dissertationes physio-mechanicae”, Typ. Pinellorum Fratrum 1721, 123 pp. (in Latin); see the frontispiece of Borelli’s book, figures 8-3 and 8-4 in the present book. 15 Hall M., “On the reflex function of the medulla oblongata and medulla spinalis”, Philos. Trans., 123, 635–665, 1833. 16 Brondgeest P.Q., “De tono musculorum voluntati subdidorum”. Thesis. Utrecht, 1860, X, 91 pp. (In Dutch with second title: “Onderzoekingen over den tonus der willekeurige spieren”. German summary in: Arch. Physiol., 1860, 703–704. Also in: Holländische Beiträge z. Physiol. Wissensch., 1860 (cited by Sherrington C.S., in Brain, part III, Vol. 38, 1915). 17 Fulton J.F., “Notes on the history of postural reflexes”, in: “Miscellenea medica in honorem viri clarissimi Gysberti Godefridi Ionassis Rademaker collecta a collegis amicis discipulis”, Folia Neurolog. Neurochirurg. Neerlandica, 56(4), 455–459, 1953. 18 Brondgeest’s experimental work was discussed and commented upon in Rademaker’s monograph “The Physiology of Standing (Das Stehen); Postural Reactions and Equilibrium with Special Reference to the Behavior of Decerebellate Animals” by G.G.J. Rademaker, translated and with an introduction by D. Denny-Brown, University of Minnesota Press, 1980, p. 66.

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book viii How obvious it may seem now, but Duchenne19 was to perceive in 1867 that the ligaments alone could not possibly suffice for the fixation of the bones in the various positions of standing, but that rather a continuous muscular contraction was necessary for standing. He drew attention to the fact that muscles in the standing position feel hard and strained and extensors as well as flexors of the legs participate in the process of fixation. He further pointed out the fact that standing may be considerably impaired by muscular atrophy.

Development of Rademaker’s ideas about posture, movement and muscle tone Muscle tone In his Cameron Prize Lectures on “Some results of studies in the physiology of posture”,20 Magnus had the following to say about local static reactions of the limbs of mammals and other vertebrates, with particular reference to investigation of the muscle tone of these animals. This quotation gives an impression of the state of the art at the time (1922) when Rademaker started to work in his laboratory. We were confronted in the laboratory with this problem [of muscle tone] during the investigation of decerebellated animals which had been operated upon by Dr. G.G.J. Rademaker and of which the condition of muscle-tone had to be followed during the course of many months. It soon became evident that this was not a simple task, and that the state of tone of a limb at any given moment depended greatly upon the way in which the tone is investigated. If, for instance, a dog is lying down in the lateral position and the resistance of one forelimb against passive flexion is measured with the hand and fingers flexed, often no resistance can be felt. But if the later are extended and pressure exerted against the pads of the foot, then the fore-limbs become strongly extended and can hardly be flexed at all. The same difference can also be demonstrated in intact animals. We therefore decided to make a more detailed investigation of these reaction. . . . .

It was about this time that Rademaker started to tackle the problem of the effect of muscle tone on movement and vice versa. To understand the Duchenne (de Boulogne) G.B., “Physiologie des mouvements”, Paris: J.B. Baillière, 1867; cited in “The physiology of Standing”, p. 7. 20 Delivered by Magnus in 1926 in Edinburgh, at the invitation of British physiologists, these lectures represented a final summing up of his experimental work on “Körperstellung” (posture) before his sudden death in 1927. 19

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philosophical and scientific situation, we need to consider the historical observations and the conclusions Rademaker had drawn from his experimental work and presented in his monograph Das Stehen, published in 1931, which was primarily an analysis of cerebellar defect but with much wider significance in relation to the neurological mechanisms of righting, standing, equilibrium and tonus. Rademaker devised ingenious clinical tests to investigate the exact nature of the complex abnormalities of posture and movement that had hitherto been loosely categorized as “incoordination”, “asthenia”, “dyssynergia” and “atonia”,

commented Denny-Brown many years later in his introduction to the English translation of Das Stehen, published under the title The physiology of Standing (1980). What were those final conclusions? What about the ‘origin of motor development’? At the time Rademaker started his experiments, it was quite customary in the fields of physiology and neurology to definite muscle tone as ‘the state of tension of a muscle at rest’. (This was e.g. the definition adopted by the Dutch physiologists Wertheim Salomonson (1864–1922) and Dusser de Barenne (1885–1940), and by the German physiologist Spiegel).21 Rademaker remarked in this connection: However, when is a muscle at rest and how can the state of tension be investigated without rousing it from its position of rest?

and further:22 When a muscle causes the movement of a body part, it is certainly not at rest. Is it indeed in a state of rest in passive movement, which, as is well known, produce reflex tensions? When the tension of the biceps is increased voluntary without flexing the elbow, is in this case the muscle at rest? Do isometric tensions, caused by reflexes abolish rest? In ventral and dorsal posture, the muscle tension of the extremities is differently influenced by reflexes from the labyrinths and the body surface; in which position of the trunk and in which posture of the head are the muscles at rest, and in which are they not? Are the muscles at rest while sleeping, although in this case they still respond to some stimulations? What

21 E.A. Spiegel, “Der Tonus der Skeletmuskulatur”, Monographien aus dem Gesamtgebiete der Neurologie und Psychiatrie. Herausgegeben von G. Foerster und K. Williams, Heft 51, pp. 1–203 [80–97]; [120–126]; [132–138]. 22 G.G.J. Rademaker in “The physiology of Standing” (1980), pp. 489–490.

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book viii is the state of rest in muscles of horses and other animals which sleep in a standing posture? Alterations in temperature, acoustic and optical impulses, stimulations of the labyrinths, from the body surface, from the deeper parts of the neck, from other muscles, from the interior organs can produce alterations in tension. Which of these stimulations must be absent to produce the muscular state of rest? Even in deeper narcosis it is never possible to eliminate all reflex influences; dogs still make alternating flexing and extending movements with their legs in deep narcosis (Graham Brown). It seems, therefore, more than doubtful whether it is at all possible for a muscle to be at rest as long as it is alive. Fibrillar tremors and undulating contractions can be observed even some time after death; mechanical electrical, thermal and chemical stimulations as well as alternations in humidity of the environment cause movements of the muscle fibers even on excised muscles. Practically, the muscle tonus is determined by measuring of muscular resistance in passive alteration in position of parts of the body to each other. The ‘hardness’ of the muscle can be determined separately.”

Rademaker initially defined muscle tone as follows: the tension with which a muscle resists to the passive alteration in position of a part of the body.23 By muscular force I understand the maximum force with which the muscles can perform a movement; it is measured by determining the force which is able to present this movement.

He went on to comment: Other authors, too, give a similar definition for muscle tonus, however, with the difference that with muscle tonus they only mean the involuntary resistance or involuntary tension. In my opinion, this limitation is incorrect since there is no objectively discernible difference between voluntary and involuntary contraction. Apart from the fact that is very doubtful whether one can really speak of a volition and voluntary action and muscular contraction in animals (for example conditioned reflexes). In human beings, certain muscular contractions are termed voluntary without reason and sometimes quite erroneously. The muscles of the abdominal wall, for instance, can become so strongly reflexly contracted on palpation in highly excitable persons that an examination of the organs of the abdomen is made impossible. On strong persuasion the tension often relaxes. The clinician says in this case that, at the beginning, examination was rendered difficult by voluntary contraction, although the patient had desired this examination and had no intention at all to prevent it by

23 The tonus (resistance) is, in this case, the total muscular elasticity and a tension which is dependent on the central nervous system.

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straining the abdominal muscles and probably on the contrary, had tried to achieve a relaxation of the tension24

On hypertonia Hypertonia is an increased resistance and hypotonia a reduced resistance of muscular tension against passive alterations in position of parts of the body to each other. Thus, hypertonia and hypotonia are opposite conditions. Hypertonia is a positive manifestation i.e. its appearance proves that a central reflex mechanism must be present, while hypotonia can be caused by a total absence of these mechanisms. The point they have in common is that they represent deficiency phenomena. Hypertonia is at the same time a deficiency symptom and a positive manifestation. The transition from hypo- to hypertonia does not take place by way of normal muscle tonus, though normal muscle tonus, due to the cessation of central mechanisms, is sometimes transformed into hypotonia and sometimes into hypertonia. The succession of the different stages of tonus is atonia / hypotonia or hypertonia / normal muscle tone. Hypo- en hypertonia thus are originally very closely related phenomena and sometimes even merge into one another, a hypotonia into a hypertonia or vice versa, for instance after a cerebrovascular accident, a cerebral haemorrhage. In this case, there is no intertonus; the latter will appear only after complete cure. Hypertonia is an increased resistance of muscular tension to passive alteration of position, but this increased resistance is only relative. The force of resistance against passive flexion of the rigid foreleg of a decerebrate animal is not stronger than the strength of supporting tonus of this leg before decerebration or of the foreleg of a decorticate dog of the same size. This resistance against passive flexion of the hypertonic, noncontracted leg of a hemiplegic patient is not stronger than the resistance of the healthy opposite leg in a standing posture.

Rademaker defines hypertonia here as the continuance of a strong muscular tension in circumstances, among others the influence of reflexes, which would normally cancel it. Inactivation of all central mechanisms, e.g. section of the motor nerves, leads to true hypotonia of muscles. In man, the exclusive preservation of spinal mechanisms, as after the transverse lesion of the spinal cord, can account for the appearance of a hypertonia, in addition to hypotonia, particularly in the adductors, the quadriceps and the calf muscles or, in other words, an increased tonic resistance to passive extension (cf. earlier authors such as Riddoch and Lhermitte). Similar manifestations can be observed in spinal animals. 24 Decorticated dogs, too, show a strong tension of the abdominal muscles on palpation in a dorsal position.

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book viii Since hypotonia as well as hypertonia can be present after elimination of all stimulations from centers situated oral from the spinal cord, one has—according to Rademaker—to allow the conclusion that a total destruction of the cerebrum, cerebellum or of the red nuclei or of other centers of the brainstem excludes neither hypertonia nor hypotonia

He continues with reference to his previous work on the red nucleus (which was the basis for his thesis and was published in his first monograph); the conclusions of which did not remain unchallenged. He argued: In a previous work I concluded that the occurrence of decerebrate rigidity is based in the first place on a functional loss of the red nuclei. This however, does not mean that a destruction of these nuclei excludes a hypotonia due to a simultaneous inefficiency of centers situated more caudally. Whether the cerebellum has a tonus promoting or a tonus reducing influence excludes neither the occurrence of a hypotonia nor of a hypertonia, as shown by numerous cases of cerebellar diseases, described in the literature, which partly show hypotonia and partly hypertonia of the muscles

On the possibilities of further experimental testing of the muscle tone: Experimental investigations into the question of participation of various parts of the central nervous system in the maintenance of normal distribution of muscle tone are extremely difficult and should be utilized only with great care, since it can often be hardly decided whether the distribution of tonus is normal or whether there are transitions to hypoor hypertonia. Moreover, a hypo- or hypertonia appearing after a partial extirpation of the central nervous system is no proof at all that the centers of a normal distribution of muscle tone are situated in the extirpated part, since both hypertonia and hypotonia are deficiency symptoms which can also be caused by shock or diaschisis of the remaining centers. Besides, an abnormal distribution of muscle tone does not necessarily have to be produced centrally, as shown by Sherrington’s observations on a dog with a severed spinal cord. The dog constantly kept one limb in a flexed and the other in an extended position due to a decubitus injury in the paw of the flexed limb. Other similar observations of peripheral triggers have been made in so-called thalamic dogs.

Finally, Rademaker states: The investigation on a central mechanism of distribution of muscle tonus is rendered more difficult by the fact that, for the establishment of an eventual hyper- or hypotonia, intact animals have to be used for comparison, whose distribution of muscle tone always varies strongly due to cerebral influences. When investigating the muscle tonus of the extremi-

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ties in a number of intact dogs, one will see that a number of animals, as soon as they are touched, lie down “shamming dead”, start back and draw their paws in a flexed position (in cats this happens almost always). In this case, the legs only show a strong flexor tonus, while the extensor tonus is absent. Others submit quietly to a turning into a dorsal position and offer only a very slight resistance against passive flexion and extension. Others again are obstinate, make defensive movements and show at times an excessively strong extensor tonus and at times a particularly strong flexor tonus. It is also striking how much the distribution of tonus can be altered by blindfolding the eyes. Human beings can voluntarily either reduce muscular tension to such a degree that passive movement hardly encounters any resistance, or increase it to such an extent that a passive movement has to overcome a resistance which is not less strong than the maximum resistance of a hypertonic patient. Cerebral influences, of course, are absent in spinal, decerebrate and decorticate animals. On cerebral influences on tonus and contractions of muscles of the extremities after section of the posterior roots a number of investigators had already drawn attention (between them Mott and Sherrington, Munk in experiments on monkeys and particularly Foerster). In most of the diseases in man which are accompanied by hyper- and hypotonia, their effect is also strongly reduced. Conversely, all preceding statements, including those concerning cerebral influences, equally apply to the distribution of muscle tonus in totally and partially decerebellate animals.

In view of the above, it is not surprising that opinions concerning the influence of the cerebellum on muscle tone differed widely at that time.25 After comparing the experimental data from the literature and his own, Rademaker disagreed with the conclusions drawn by Luciani, Munk and André-Thomas (to mention only a few). He formulated his own definition of muscle tone as: “the resistance caused by muscular tension against passive alteration in position of the body parts to each other.” This resistance is in his opinion normally brought about by three factors: 1. the specific elasticity of the muscle substance, i.e. by the tension which is still detectable in the denervated muscle; 2. reflex tensions, i.e. contraction produced by subcortical stimulations; 3. the tension produced by cerebral influences (conditioned and unconditioned cortical reflexes)

25 Rademaker cited a number of authors such as Luciani (1840–1919) and Flourens (1794–1847).

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To cite him further: Flexor tonus is the muscular resistance against passive extension movements and extensor tonus a muscular resistance against a passive flexion movement. In a passive extension movement, the flexors are stretched, in a passive flexor movement the extensors, and according to the reaction of the muscle to the stretch, the tonus i.e. the muscular resistance against this passive movement, will be very different. Thus, an investigation of the resistance against passive movement is, in the first place, an investigation into the behavior of the various stretch reflexes.26

The contribution that study of muscle tone could make to understanding of the motor system was clearly apparent to Rademaker right from the start of his experimental work (on the red nuclei). Moreover, his experiments showed that a relationship existed between movement (i.e. changes in position and posture, movement as a state, the gait, etc.),27 the central organization of the progress of motion, mobility and range of movement on the one hand and consciousness on the other. They thus offered a possibility of experimental investigation of the neurophysiology of that mysterious phenomenon we call consciousness. The physiologist Einthoven, Rademaker’s predecessor at Leiden, had already speculated about this possibility. Moreover, the (at that time) recent discovery of thalamocortical connections by Dusser de Barenne28 had also raised

26 Rademaker could distinguish eight types (‘orders’) of stretch reflexes: 1. stretch reflexes first order; these are the reflex contractions of the stretched muscles themselves (the myotatic reflexes according to Liddell and Sherrington—see above—and the specific reflexes according to Hoffmann), 2. stretch reflexes of the second order are reflex contractions of synergic muscles caused by stretch of a certain muscle, 3. stretch reflexes of the third order are reflex muscular contractions produced by extension of antagonists, and 4. stretch reflexes of the fourth order are reflex contractions of muscles which have neither a similarly directed nor an opposite effect caused by the stretch of a certain muscle. 5. Stretch reflexes of the fifth order are contralateral reflexes caused by an increase in extension, 6. Stretch reflexes of the sixth order are relaxation produced by stretch and 7. Stretch reflexes of the seventh order are alternating contraction and relaxation due to stretch of muscles. In particular the stretch reflexes of the fourth order are of importance since they involve the contraction of muscles of different activities – as is the case with propioceptive supporting reactions. These are of primary importance for standing as has been shown later by Willemse (1961) in his observations of the motor reactions of the newborn infant during the first few hours of life. – Willemse J., “Motor reactions of the newborn infant during the first few hours of life”, Thesis Utrecht, 1961, p. 78, Summary in English and French, Uitg. Erven J. Bijleveld, Utrecht, 1961. 27 Rademaker obtained experimental evidence for these conclusions in his clinical investigations performed in cooperation with Raymond Garcin. 28 Dusser de Barenne J.G. and Mc Culloch W.S., “The direct functional interrelation of sensory cortex and optic thalamus”, J. Neurophysiol. 1, 176–186, 1938.

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hopes of being able to study the phenomenon of consciousness via another experimental pathway. The conception of a thalamo cortical circulation of neural impulse as was elucidated by Dusser de Barenne and Mc Culloch in 1938, will in the future come to be found as fundamental for the neurology of what was colloquially called “thought”, as the conception of a circulation of the blood is for modern physiology,

wrote Campion (1934).29 He went on to say, The circulation of the thalamic and cortical currents maintains this constant state of readiness and is a vital and essential part of consciousness and mind” (ibid., p. 24).

And further, They were writing about the neural basis of thought, but the state of readiness referred to, was muscle tone, again an illustration of the historical fact that entrée to the physiology of the nervous system was by way of the experimental study of muscular action.30

Mathematical analysis of the results of experiments on muscle tone and movement: cybernetic physiology Apart from being a brilliant experimenter, Rademaker was keenly interested in making use of the latest insights in physics and mathematics to analyse the known neurophysiological facts. One discipline which seemed particularly promising for this purpose was that of cybernetics. This term, derived from the Greek kybernetes (meaning ‘steersman’ or ‘governor’) was first applied to the theory of control mechanisms by the American mathematician Norbert Wiener in 1948.31 In fact, neurophysiological thinking had contributed largely to the initial development of this science. One key paper in this context was that by the neurophysiologist Mc Culloch and the mathematician Pitts

Campion G.G., in: Campion G.G. and G.E. Smith (eds.), “The Neural Basis of Thought”, 1934, p. 97, Harcourt Brace New York Int. Library of Psychology, Philosophy and Science; Campion’s co-author G. Eliott Smith subscribed to the same idea. 30 Cited in Marshall L.H. and H.W. Magoun *(eds.), “Discoveries in the Human Brain”, Humana Press, Totowa New Jersey, 1998, p 259. 31 Norbert Wiener, “The Human Use of Human Beings. Cybernetics and Society”, The Doubleday Anchor Books. Doubleday & Company Garden City, New York— Second Ed., 1947, Preface [7–12], [15–27], [28–47], 58–69], [187–193]. 29

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(see section on “A logical calculus of the ideas immanent in nervous activity” below). Cybernetics has had a marked influence on theories of communication and control, not only in mathematics, engineering and electronics, where it began, but in such areas as psychiatry and psychotherapy, neurology and physics. Biomathematical modelling was in the wind and the cyberniticians were already taking the nerve impulse into the more complex territory of nerve nets around 1952, which Dusser de Barenne had shown to exist experimentally with his chemical (strychnine) neuronography. In 1953, Rademaker gave a lecture on ‘cybernetic physiology’32 for a congress of Dutch neurologists and generalists, in which he suggested how this new science could be used as a powerful tool for the analysis and explanation of physiological data. As part of the lecture, Rademaker summarized the basic facts of theoretical neurophysiology and the cardinal assumptions on which they rest. The nervous system can be seen as a nest of neurons, each one having a soma and an axon; the junctions, or synapses, between neurons are always between the axon of one neuron and the soma of another. Various stimuli can generate electrical impulses in the soma of a neuron, which pass along the axon to the synapse with the next neuron in the network. At any given instant, this next neuron will have a threshold, which the excitation arriving at the synapse must exceed to initiate a new impulse in it. While the presence and timing of excitation are of course independent of the neuron at which it arrives, the level of the threshold is determined by the neuron, not by the excitation. The new impulse is propagated to all parts of the neuron from the point of excitation. These phenomena, and other aspects of impulse transmission in nerves such as the velocity of propagation of the impulses along the axon (which varies directly with its diameter) have been experimentally verified during the past few decades. The movement of living organisms affords many points of attack for research because it involves changes in the condition of the body or its parts, which attract the attention of the observer—the clinician—and can be recorded and measured. This is not the case in the same way when posture is studied as we have

32 G.G.J. Rademaker, “De werkwijze van het zenuwstelsel”, Ned. Tijdschr. v. Gen. 98, 2320–2328, 1954 with discussions with Stenvers and Ter Braak on current models i.e. ‘reverberating circuits.’

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Fig. 8-7. The triangle movement at a given moment in time and stage of development. It should be noted that: a. Time and development must be considered in biological terms here b. There are explanatory gaps in this presentation of facts c. Penumbra (shadow): such as ‘preliminary postural adjustment’ and ‘Bereitschaftspotential’, ‘in the shadow of movement’ (Rondot) d. To understand our best theories, we must take them seriously as explanations of reality and not regard them as mere summaries or summations of existing observations

seen above. Here we had to deal with a constant condition without apparent changes, so that our desire to search for causal factors is not stimulated, and we did not immediately suppose that active processes were at work. A logical calculus of the ideas immanent in nervous activity Mc Culloch and Pitts published their seminal paper33 in 1943. They stated that because of the “all-or-nothing” character of nervous activity, neural events and the relations among them can be treated by means of propositional logic. They found that the behaviour of every neural net could be described in these terms, with the addition of more complicated logical means to deal with nets including closed circuits, and Warren S. Mc Culloch and Walter Pitts, “A logical calculus of the ideas immanent in nervous activity”, Bull. of Mathematical Biophysics”, 5, 115–133, 1943. Warren S. Mc Culloch (1898–1969) started working on this matter while collaborating with *Rademaker’s friend Dusser de Barenne J.G. (1885–1940) at Yale. “That 1943 article, still dicussed and cited at the end of the century, reflected the interchange of ideas among the Chicago group and the Rosenbureth/Wiener nucleus at MIT, plus John von Neumann at the Institute for Advanced Study at Princeton. It generated a great deal of excitement among some biomathematicians and neuroscientists about the possibilities of understanding brain function by pairing logical analysis of the romanticized machine-organism with detailed experimental neurophysiology” (Marshall L.M. and Horace W. Magoun, “Discoveries in the Human Brain”, p. 262, Humana Press Totowa, New Jersey, 1998). 33

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that for any logical expression satisfying certain conditions one could find a net behaving in the fashion it describes. They further showed that many particular choices among possible neurophysiological assumptions were equivalent, in the sense that for every net behaving under one assumption, there existed another net which behaved under the other and gave the same results, although perhaps not in the same time frame. They discussed various applications of their calculus. This paper had a considerable influence on the development of cybernetics. In the Netherlands, Rademaker and Storm van Leeuwen Jr. applied McCulloch and Pitt’s conclusions as a basis for the study of movement and much later Drooglever Fortuyn, a personal acquaintance of Mc Culloch since 1946, used them to ‘to support considerations’ on learning and behaviour (1994).34 In conclusion, therefore, we would like to propose that the triangle of movement presented above should be completed by addition of the Mc Culloch and Pitt theorem, based on the following premise. If—and only if—the next excitation of a neuron during the brief period of latent addition exceeds the neuron’s threshold voltage will transmission take place across the synapse and a pulse be generated and travel from the neuron along its axon toward other neurons. . . . .,

to generate or facilitate movement or some other physiological response.

Drooglever Fortuyn J., “Het individu en zijn hersenen; een neuro-wetenschappelijke studie over de biologie van het geestesleven” (The individual and his brains; a neuroscientific study of the biology of Mind; in Dutch), Van Gorcum, 1994, 71 pp., [ch. VII]. 34

BOOK IX

GEOMETRICAL—TRIGONOMETRICAL CLUE Introduction Pierre Rondot, one of Garcin’s pupils, brought a new approach to the study of the relationship between posture, movement and muscle tone. He summarized his researches and compared his results with a wide range of data taken from the literature in his presidential address to the second European Neurological Society meeting, held in Brighton in 1990,1 under the eloquent title ‘The shadow of movement’. It would take us too far to go into the content of this interesting paper in detail. It may be mentioned, however, that one of the main themes is the finding that any movement of the human body is normally preceded by a complex series of reflex reactions that ensure that the body is in the right posture to allow the movement in question to be performed effectively. These reactions generally disappear when the movement ceases, though in certain pathological conditions such as dystonia, athetosis and Parkinson’s disease they may persist for longer and in other cases they may not occur at all. Rondot used electromyographic measurements to determine the timing of the various reactions involved. Many of Rondot’s findings appear to be in line with the axioms Rademaker distilled from his experimental work, such as the statements that (A) the transition from hypotonia to hypertonia does not occur via normal muscle tone, though the cessation of central mechanisms can sometimes cause normal tonus to be transformed into hypotonia or hypertonia, and (B) hypotonia and hypertonia are originally very closely related phenomena and sometimes even merge into one another (see above). Experimental physiological data can be systematized with the aid of mathematics, as Rademaker and Ter Braak showed in the case of the fall reflex (see Book II, Part 2.6). It is then in principle possible to simulate the movement in question, as Berthoz and co-workers (2001,

1

Rondot P., The shadow of movement, J. Neurol. 238, 411–419, 1991.

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2002) did for the movements made by animals and man when rising to a standing position. Preliminary note on hypotonia in clinical neurology Thesis V appended to the doctoral dissertation by Rademaker’s student P.C. Kraan (1939) (see Book IV, part 4.1 of the present work) stated: Oppenheim’s myatonia congenita2 and infantile spinal muscular atrophy (Werdnig-Hoffmann disease) are probably identical.

This group of neuromuscular complaints, mainly characterized by muscular weakness and hypotonia and also known as ‘floppy infant syndrome’, was studied by Milton Shy, W. King Engel and Gerard Fenichel at the National Institutes of Health, Bethesda (MD) in the USA and by the present author and later Victor Dubowitz at Hammersmith Hospital, London, with the aid of newly developed techniques for the histo- and cytochemical investigation of freshly frozen muscle biopsies obtained from patients with clinical signs of hypotonia and muscle atrophy. Previous investigations of experimentally denervated gastrocnemius muscle tissue in animals (guinea-pigs) using the same techniques had provided evidence of selective inactivation of the enzyme myophosphorylase3. These techniques, which later provided the basis for standard neurodiagnostic tests, did not show any histo-/cytochemical inactivation of substrates or enzymes in the above-mentioned neuromuscular disorders. Hence, the results of these investigations—and of other, light-microscopy studies of striated muscle biopsies taken from patients with hypotonia—do not confirm the supposition stated in Kraan’s thesis cited above (and also supported by Rademaker). Werdnig-Hoffmann disease4 is clearly a neurogenic disorder5, while the 2 Oppenheim H. in “Lehrbuch der Nervenkrankheiten”, 5. Auflage, Berlin, S.-Karger, 1908. 3 Hogenhuis Leon A.H. and King Engel W., “Histochemistry and Cytochemistry of Experimentally Denervated Guinea Pig Muscle”, Acta Anat., 30, 39–65, 1965. 4 Hogenhuis Leon A.H., Spaulding W.A. and King Engel W., “Neuronal RNA Metabolism in Infantile Muscular Atrophy (Werdnig-Hoffmann’s Disease)—studied by Radioautography. A New Technique in the Investigation of Neurological Disease”, J. Neuropath. Exper. Neurol. XXVI, 335–342, 1967. 5 Hogenhuis Leon A.H., Spaulding W.A., “Autoradiography of long-term RNA metabolism in rabbit neurones with the use of tritiated uridine”, Nature 215, 281–283, 1967.

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term ‘Oppenheim’s myotonia’ seems to designate a form of muscular weakness of suspect myogenic origin. (This term is no longer current in clinical neurology.) My contribution to the development of new investigative techniques together and in collaboration with the neuromuscular group at the N.I.H. in Bethesda, USA, guided by dr. W. King Engel and dr. Milton Shy have been summarized in the references at the end of the book. 9.1. The Shadow of Movement ‘Rondot’s shadows’, a new philosophy of nature Rondot’s concepts seem to represent a form of ‘mathematical Platonism’—a term coined by David Ruelle6 in his book “The Mathematical Brain” (2007). In “The Republic”,7 Plato speaks of a world of pure ideas to which the philosopher (scientist) has access while his less fortunate contemporaries are like prisoners chained in a dark cave who only see floating shadows of reality. The structures of mathematics (which may be taken to include the mathematically processed electromyographic recordings) are like Plato’s pure ideas to which mathematicians have access, but which are hidden to those without mathematical insights. Rondot uses the powers of natural philosophy to generate insights, invisible to clinicians and pathologists without mathematical skills, concerning the significance of the lengthening and shortening reactions studied by Sherrington, Rademaker and the Amsterdam neurophysiologist J.K.A. Wertheim Salomonson8 (an early pioneer in this field with his paper on the Verkürzungsreflex published in 1914). One of Rondot’s original contributions in this field was to perform his electromyographic observations after mirroring and in combination with simultaneous recording of the Westphal reaction—a phenomenon first described in 1877 by Carl Friedrich Otto Westphal, widely known

6 Ruelle David, “The mathematical Brain”, Princeton University Press, Princeton and Oxford, p. 144, 2007. 7 Plato, The Republic, English Edition of the Complete Works of Plato, eds. J.M. Cooper and D.S. Hutchinson, Hackett Publishing, Indianapolis (IN), 1957. 8 J.K.A. Wertheim Salomonson, “Verkürzungsreflex”, Neurol. Centralblatt 33, 1180–1188, 1914.

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in German neurology thanks to the favourable attention paid to it by Westphal’s mentor at Heidelberg Prof. Wilhelm Heinrich Erb. The Westphal reaction Westphal was surprised to note that in certain paralyses of the lower limbs, passive dorsiflexion of the foot did not give rise to the usual clonic contraction in the ankle but instead led to contraction of the anterior tibial muscle with prominence of the tendon. He regarded this as a paradoxical contraction, because it was located in an antagonistic muscle. Others, however, had initially considered it to be a natural consequence of the stretching of the soleus muscle produced under these circumstances. Rondot reviewed the many reports of this topic in the literature, including Rademaker’s “On the lengthening and shortening reaction and their recurrence in man” (see Book IV). His attention was drawn to this reaction during clinical rounds at the Salpêtrière Hospital in Paris (also often attended by the present author), where Garcin demonstrated the ‘reflexes de posture de Foix et Thévènard’9 and drew special attention to the prominent tendon of the anterior tibial muscle. It was Rondot’s electromyographic investigation of this effect that led to his above-mentioned conclusions concerning ‘the shadow of movement’. A model of this kind, based on measurements performed on a millisecond scale, not only increases our understanding of the phenomena in question but also provided a basis for more effective treatment planning with ‘the right drug at the right moment’. It may be mentioned by way of example that observations by Rondot and others yielded valuable insights into Parkinson’s disease that are summarized below.

9 Foix C., E. Thévènard, “Les réflexes de posture”, Revue Neurologique 30, 449–468, 1923, his poetic concept to compare with Keppler’s ‘music from heaven’ measuring movement and the celestrial mechanics of heavenly bodies.

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Key electromyographic features of Parkinson’s disease • the silent period: the length of this silent period before movement is longer in the bradykinetic parkinsonian patient than in controls (Kaneoke et al., 1989).10 • Another mechanism that plays a role in the premotor period and is directly related to the preparation of movement is the Bereitschaftpotential or ‘readiness potential’ (Kornhuber and Decke, 1965)11 • Rondot detected the pre-movement postural mechanisms involved in preparation for tonic activity and quantified them electromyographically in all their complexity, in terms both of postural organisation and temporo-spatial sequence. [Conrad et al. (1983)12 addressed the question arising from this, of whether movement can be considered as a continuum, with the preparatory period representing the projected shadow of the tonic activity it mirrors.] • Compensatory postural activity plays an active role in preventing an undue shift in the centre of gravity when the movement to be performed might make it difficult for the subject to maintain his or her balance. Electromyographic measurements yield an identifiable sign here. • Modified postural activity. The forward directed loss of balance, or the imbalance provoked by bending the arm(s), is partially corrected by a backward pull exerted by the patient (Rondot). • Preparatory activity for movement can be detected in the corpus striatum and globus pallidus of the basal ganglia . This activity has been related to the intended direction of movement of the limbs. • Finally, motivation provoked by compensation can also lead to pre-movement neuronal stimuli. This plays a role in self-paced movements or those involving or reaction times.

Kaneoke Y. Koike, Sakurai N., Takahshi A., “Reacton times of movement in patients with Parkinson’s disease”, Neurology 39, 1989. 11 Kornhuber H.H., Decke L., “Hirnpotentialänderungen bei Willkurbewegungen und positiven Bewegungen des Menschen, Bereitschaftpotential und reafferente Potentiale”, Pflüger’s Archive 284, 10–17, 1965. 12 Conrad B., Benecke R., Goehmann M., “Premovement silent period in fast movement initiation”, Exp. Brain Res. 51, 310–313, 1983. 10

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Final appraisal of Rondot’s ‘shadow of movement’ concept Movement is preceded, accompanied and followed by a series of reactions that are like the shadow of the movement projected into the future (Rondot) Rondot’ electromyographic measurements allowed him to conclude that there are mechanisms, invisible to the eye of the observer, which act to ensure the precision of any movement before, during and after the movement in question. Using this technique to examine a number of clinical conditions such as Parkinson’s disease, dystonia, athetosis and experimental decerebrate rigidity as described by Sherrington (1910, 1915),13 he made a number of new observations. The conclusions he drew from these observations—that the intensity of tonic activity continuing after the movement is in direct relation to that of the contraction preceding it, and that the pre-movement link between postural adjustment and compensatory activity is indispensable for correct execution of the movement—were not new, however: clinicians such as Babinsky had been well aware of them in the past. In the case of experimental decebrate rigidity, Sherrington had stressed the importance of posture in determining movement and had distinguished between protagonist and fixator muscles, the latter giving the former the support they need to perform the movement in question; this is just another way of saying that postural adjustment comes before movement. He added that the period before the movement during which postural adjustment is established is too short to be detected by clinical observation: electromyographic recordings were needed to evaluate the reaction time and to specify the nature of the phenomena taking place during this period.

13 Sherrington C.S., “Flexion reflex of the limb, crossed extension reflex and reflex stepping and standing”, J. Physiol. (London) 40, 28–121, 1910 Sherrington C.S., “Postural activity of muscle and nerve”, Brain 38, 191–232, 1915.

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9.2. Mathematics Research with Rondot’s Summary, Geometrical and Trigonometrical Model by the Author M M0

T S

AM in sec. v in rad. sec–1

a(1) ϕ

A1

M0 for t = 0:

A

O

(OA,OM0) = φ + ωτ.

preliminary postural adjustment u1

u PST

m

K

BP P

– orthogonal projection on to u1u axis; (OA), A, O and M project into P, K and m Km = OM.cos (OA, OM0) and xm = r.ws (φ + ωt)

– BP ‘Bereitsschaftspotential’ = premotion silent period (EMG) 1,6 ms T At the end of movement: tonic = Tonic perseveration S Shortening reaction (in decerebration model) and pathological states P Preliminary postural adjustment The initial mechanisms represent highly sophisticated processes thoroughly adapted to living in an upright state. A description of the event initiating motion is needed. Fig. 9-1. Trigonometric model of some locomotor functions with relevant EMG data (devised by the present author, LAHH). NB: The equations underlying this diagram have not been included here for reasons of space.

DEATH On 2 April 1957, during a meeting of the Faculty of Medicine at Leiden, the Dean (Prof. J. Mulder) conveyed to Rademaker “who has recently turned 70, and was not at home on that day”1 the “best wishes and hearty congratulations of the whole Faculty”, and went on to say: Reaching one’s 70th birthday is not always an unmixed pleasure for a professor, since it marks the end of his active academic career. However, the Faculty does not wish to let this day pass without mention, and without offering him our hearty congratulations.

The Faculty marked their approval of these sentiments by applause.

Fig. E. Prof. J. Mulder.

1 Minutes of a meeting of the Faculty of Medicine at the University of Leiden held on 2 April 1957. As was his custom, Rademaker had not attended his own birthday party. He was, however, present at the faculty meeting as an ordinary member.

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No one could have imagined that in the very next faculty meeting,2 the very same Dean, the specialist in internal medicine Mulder who had so often stood side by side with Rademaker and others in their attempts to achieve complete modernization of the faculty, attacking so many sacred cows and colliding with so many established interests in the process—each in his own way—would be pronouncing a solemn eulogy in his memory. Rademaker had died of an asymptomatic ruptured aneurysm of the thoracic aorta early in the morning of 19 April 1957. The Dean had the following words to say on this occasion: It is never easy to accept the passing of faculty members as the years go by. Rademaker was still so active that his death domes as a particular shock. He began his career as a surgeon, later becoming a physiologist with a special interest in neurophysiology. It was the important work he did in this field which earned him his nomination as member of the Royal Dutch Academy of Sciences. When Einthoven died, he took on the leadership of the department of Physiology and finally he became a clinical neurologist. When he was appointed professor of Neurology, he found a department which was only partly developed. He set his shoulder to the wheel with all the energy he possessed, and managed to build up a flourishing department, and he was say without exaggeration that he created this department, and he was fortunate enough to live to see his work completed and an example of organization for many others. Above all, however, Rademaker was a man with a great concern for the well-being of the faculty. How often have we not seen him giving up his time to advise both young and old. He was a good man, seldom aggressive, though he did have his criticisms of the way some things were done in the faculty. The way in which he responded to questions on faculty issues and his dedication to the tasks assigned to him, such as the emergency credit fund for faculty members facing unexpected serious problems and so many other matters, are outstanding characteristics which were highly appreciated. In him we lose a great scholar, a good organizer, a man with a warm heart and above all a good human being. . . . .

The faculty stood for a few moments of silence to mark his passing. Rademaker died on the threshold of his retirement. Having reached the compulsory retirement age just a month before, he was due to leave his active university life at the end of the current academic year; but fate decreed otherwise. This unexpected end to his life meant that he was spared the painful moment of leaving the working atmosphere which 2 Minutes of a meeting of the Faculty of Medicine at the University of Leiden held on 7 May 1957.

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he loved, knowing that though he was still in possession of his faculties he would no longer be able to put them to active use. A “peaceful end to his days” was not a prospect that appealed to him. In any case, he had not planned to spend it in Leiden, but to move with his wife to Monaco or to Australia. I well remember the deep feeling of shock that struck both physicians and other staff at the clinic when they heard the news of his death. The loss was much worse for his wife, of course: “the first and last great sadness of my life”, as she put it later to close friends, as they walked back in the cemetery. He was buried, as he had wished, without any pomp and ceremony in a family grave in the ‘Oud Eik & Duinen’ (Old Oak and Dunes) cemetery in The Hague—perhaps the most beautiful in the country. There were no speeches, and the coffin was accompanied to the grave only by a few old students and those nearest and dearest to him. Five years later, on 15 January 1962, he was rejoined by his wife who had been seven years younger than him in life. She had been very ill for some time, and died in Leiden from the consequences of lung cancer and Graves’ disease with exophthalmos.

Fig. F. The Rademaker family (the parents and an earlier died brother of Rademaker) grave in the “Oud Eik en Duinen” cemetery in The Hague, where Rademaker was buried on 21 April 1957; Grave 1-1083; Laan van Eik en Duinen 38.

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For the student of his life, for the reader, had he been a happy man? Happiness is not a subjectieve state of mind but a characterisation of an entire life that be reckoned only at death—as Herodotus puts it.

RADEMAKER’S LEGACY . . . What characterized Rademaker as an experimental physiologist in the first half of the 20th century? First of all his originality, which made a great contribution to the international reputation of Dutch experimental physiology in his days. Prominent English, French, American and German workers in this field all agreed about this in words and writing. For example, Berthoz spoke of ‘la grande école de physiologie Hollandaise dans cette periode’ while Walshe stated that “his name and appearance became symbols for the genius of the experimental physiologists from the grand school of Dutch physiology in the midst of the 20th century”. A second characteristic was his modernity, the contribution his findings and ideas has made to fields of study that were embryonic or even non-existent at the time and even today are regarded as innovative, such as the neural development of infants (Willemse), space physiology (Berthoz) and biological mathematics (Toshihiro Iwai). His intellectual approach to the problems he tackled was analytical and lent itself well to discussion and refinement, embodied e.g. in the geometrical model of muscle tone, posture and movement developed by the author on the basis of Rademaker’s data (see Book IX) and the treatment of the falling cat phenomenon initiated by Rademaker and Ter Braak in the early 1930s and continued with increasing mathematical refinement e.g. by Guichardet, Montgomery and Iwai right up to the end of the 20th century (see Book II, part 2.6). The imperative of finding clinical application for his experimental work ran like a red line through his entire professional life and has been remarked on frequently in this biography. His initial training as a doctor, a healer, never left him throughout his scientific career as a physiologist and neurologist. His high ethical standards did not cause him to refrain from animal experiments in a search for cures for human ills, but did lead to great empathy with his experimental animals and feelings of friendship and

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even almost collegiality with them that were almost unique in this field. The three eponymous clinical signs that he has left behind, the Rademaker-Garcin blink reflex, the Rademaker-Garcin step sign and the Rademaker-Garcin static adaptation test, continue to bear witness to the clinical applicability of his experimental work. Perhaps his most important legacy is the mechanistic approach to tonic and other reflexes initiated by Sherrington and Magnus with reference to peripheral mechanisms and worked out in detail by him with respect to the control of the CNS over such peripheral reactions. This approach has left a permanent mark on present-day neurological research and education. What this comes down to in a few words is the primacy of the motor aspect in any study of the nervous system, which is elegantly encapsulated in the triangular model of the relationship between movement, posture and muscle tone presented in this work.

EPILOGUE: FOUR EPIPHANIES It is not good to analyse an epiphany too closely. Three well-documented epiphanies occurred during Rademaker’s life. I give them here in chronological order. A fourth, less well-documented incident is recalled to round off this epilogue. First of all, a group of English neurologists from the National Hospital in Queen Square, London, together with other scientists, visited Magnus’s laboratory in Utrecht in 1924. They were particularly struck by an experiment they saw Rademaker performing there. This event made a particularly deep impression on Francis Walshe, one of the neurologists, who was a member of Sherrington’s school, and he reported on it in extenso later. As he put it, “Rademaker was catapulted to fame and his name and appearance became symbols for the genius of the experimental physiologists from the grand school of Dutch physiology in the midst of the 20th century”. Walshe was well acquainted with experimental physiology in general and the decerebration model in particular, and in his own research he tried to find the significance of the results obtained with this model for neurology patients who might be thought to be in comparable clinical situations. (See Book VI, part 6.1 of this biography.) Four years later, Raymond Garcin experienced a similar epiphany during a working visit of French physiologists and neuropsychiatrists to Amsterdam to view Prof. Brouwer’s newly opened neurology clinic at the University of Amsterdam. The French professor of Neurophysiology Henri Baruk, who had been working in Amsterdam for several months on a Rockefeller Foundation grant, acted as guide to the French delegation. During the visit, Rademaker gave a demonstration, which he accompanied by his own commentary in fluent French. The following quotation is taken from Baruk’s account of this visit, published in Revue Neurologique: Nous n’oublierons jamais la magistrale demonstration qui nous fut donnée par Rademaker sur la preparation d’un chat décerebré dans la laboratoire de Brouwer. Son habilité était véritablement prestigieuse, grand majesteuse

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epilogue: four epiphanies autant que simple et modeste, Rademaker donnait une impression de force, et d’aisance que rien ne peuvait rebutter. (We will never forget the masterly demonstration Rademaker gave of the preparation of a decerebrate cat in Brouwer’s laboratory. His skill was truly remarkable, his bearing at the same time majestic yet simple and modest. Rademaker gave an impression of power combined with unconquerable ease.)

Garcin in particular was literally dumbstruck by the demonstration. (Other members of the French delegation commented that he seemed to have received a ‘coup de foudre’.) He immediately changed his return ticket to Paris to allow him to continue his discussion with Rademaker about the latter’s other animal experiments and their significance for clinical practice. He forgot completely about the rest of the working visit and went off to Leiden where he stayed with Rademaker for a few days, leaving the rest of the French group to return to Paris without him, somewhat dumbfounded by his sudden departure. (See Book III, part 3.2.) The third epiphany again involved Garcin. Rademaker only appears here indirectly. It has been reported in the Journal of Neurology by Garcin’s old pupil Prof. P. Rondot. Garcin had read a paper to the Société Neurologique in Paris in 1932 describing the animal experiments he had been carrying out with Rademaker since 1929 and his introduction of a new clinical sign, the step sign, derived from these experiments. During the discussion that followed, the grand old man of French neurology Babinski jumped up excitedly as if stung by a bee and asked Garcin’s permission to visit the latter’s ward to examine the patients in question himself since he suspected that the Rademaker-Garcin step sign might be related to his own Babinski’s sign. Garcin was so taken aback by Babinski’s totally unexpected request that he was seen to sweat profusely. This event was long discussed by French neurophysiologists: is not every day that one can present a new neurological reflex test . . . and even less frequent that such a discovery elicits such an enthusiastic reaction from so eminent a source! (See Book III, Part 3.2.1.) The above incidents remind the author of the fact, also documented, that Rademaker’s old friend and former pupil Henk Verbiest, one of the first professors of Neurosurgery in the Netherlands, often asked him to give talks to small groups of colleagues and research assistants about the experiments that had been carried out in Utrecht and Leiden

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in the ‘twenties and ‘thirties, to recapture some of the magic that had existed round the old master and to pass his enthusiasm for research on to a new generation. Another incident in which we may speak of the passing on of Rademaker’s legacy to succeeding generations was recounted to the author many years later. Shortly after the birth of her firstborn son, Mrs. Toni Luyendijk (now emeritus professor of the History of Medicine at Leiden University) received a visit in hospital from her husband Willem, one of Rademaker’s pupils who was still completing his specialist training in neurosurgery and who would later become one of the first professors of Neurosurgery in the Netherlands. Willem was accompanied on this occasion by Rademaker, who was a good friend of the family as well as being Willem’s teacher. After the baby had been proudly presented to Rademaker, it was at the latter’s request carefully placed in his arms. Rademaker now began, with the innate sensitivity that was so characteristic of him, to demonstrate the whole sequence of neonatal motor reflexes that he had helped to establish (see Book II, Part 2.7), such as the step sign, the neck righting reflex and the placing reflex, on the young infant as the mother and the small circle of medical staff standing round the bed looked on. This emotionally charged, impressive demonstration made the mother hold her breath; she—and the others who were present at that time, retained a vivid memory of this epiphany for many years. The mother named her son Gijs—the familiar form of Rademaker’s own name. This was a very concrete, moving illustration of the conviction that accompanied Rademaker all his working life: in the words of Goethe’s Faust, ‘In the beginning there was movement.’

L’ANECDOTE EST LE PRETEXTE . . . ET L’HISTOIRE DE L’INTIMITÉ There are interesting parallels between the lives and working styles of Rademaker and Sir William Herschel (1738–1822), the Germanborn English astronomer (see reproduction of the frontispiece of the French translation of his Treatise on Astronomy from the author’s collection).1

Fig. G. Frontispiece of Herschel’s Traité d’Astronomie.

Both Rademaker and Herschel showed unusual commitment to their work, both tried to study every aspect of their field, and both received indispensable assistance from a woman (in Herschel’s case, his sister Caroline). One major difference is that Caroline built up a reputation as an astronomer in her own right, especially after Herschel’s death.

1 I am indebted to Dr. Ronald Bathgate PhD for drawing my attention to this topic.

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Herschel was born Friedrich Wilhelm Herschel in Hanover, Germany. He is reputed to have been a musician in a military band in Hanover, but to have fled to England at the age of 19 to avoid compulsory military service. He initially worked as a music teacher and organist but devoted all his spare time to astronomy and mathematics. Unable to afford adequate instruments, he built his own telescopes and constantly improved them. In 1774, with the aid of his sister Caroline, he began a comprehensive and systematic survey of the heavens. He was 26 at the time—one year older than Rademaker was when he started his research career. For years, he spent every night in his observatory; Caroline brought him cups of tea and noted down his findings. In 1781 he discovered a new planet, which he named Georgium Sidus in honour of king George III but which is now universally called Uranus. A year later he was appointed private astronomer to the king, a position that enabled him to devote all his time to his astronomic pursuits. He erected a telescope at Slough with a 48–in (1.22–m) mirror and a focal length of 40 ft (12.2 m). Using this, he discovered two satellites of Uranus and the sixth and seventh satellites of Saturn. He studied the rotation period of many planets and the motion of double stars, and also catalogued more than 800 double stars. He studied nebulae, contributing new information on their constitution and increasing the number of observed nebulae from about 100 to 2500. Herschel was the first to propose that these nebulae were composed of stars. He was elected to the Royal Society in 1781 and knighted in 1816. He is considered the founder of sidereal astronomy. The BBC made an interesting TV programme about Herschel some years ago, in which his interest in the stars was linked with his love of music (‘the harmony of the spheres’). This is comparable with Rademaker’s love of movement and dance. The programme also mentioned Herschel’s close friendship with Haydn (1732–1908). Haydn was very popular in England at the time and visited London twice, in February 1791 and May 1794, on the occasion of the performance of two series of his concerts. While Rademaker was doing his research in Leiden, his wife developed into a well-known concert pianist. Her speciality was the accompaniment of soprano and alto singers. She was especially interested in the works of Schubert and Mahler [Personal communication Mrs. Ferwerda-Vogelsang, Wageningen]. The latter was very popular in the Netherlands at the time, mainly due to the performances of his Lied von der Erde —still relatively unknown in that period—by the Concertgebouw orchestra in Amsterdam and to his friendship with W. Mengelberg, the conductor of that orchestra.

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Fig. H. Jeltje, the daughter of Rademaker’s butler, with her dog. This photo was in the possession of the daughter of Rademaker’s butler, who lived with his family in Rademaker’s house. As a result, Jeltje grew up in close contact with Rademaker and his wife. The Rademakers never had any children of their own. The butler’s family were employed in the household, and also looked after the garden behind the house. Jeltje had the run of the house and often played with her dog in the professor’s study and even browsed through his manuscripts that were lying there or inspected the large number of associated photos. Rademaker often worked till late at night preparing his manuscripts for publication. This frequently involved cutting the photos that were to go with the manuscripts to size. He would throw the remaining fragments of the photos into the wastebasket and the young girl would sift through them later, thus developing her own form of ‘wastebasket archaeology’. The highly descriptive term ‘wastebasket archaeology’ is the translation of the Dutch ‘papiermand archeologie’, which may be found in the article “Wat zegt ons de papyrus?” (What does papyrus tell us?) by Job Cohen (Secretary of State for Justice in the Dutch government at the time, and Mayor of Amsterdam since 2001). The article appeared in the publication Kopstukken over Topstukken (‘Top people talking about national treasures’), which contained the text of a series of lectures delivered in the period from October 2000 to early 2001 by various prominent members of Dutch society about important items taken from the collection of the University of Leiden, to mark the 425th anniversary of the foundation of the university. The book was published by Leiden University Press in 2004. During the daytime, Jeltje would try to piece together the fragments of photos she took from Rademaker’s waste-paper basket to form meaningful patterns, with some guidance from Rademaker. This activity closely resembled the meticulous work done by papyrologists in making sense of the fragments of texts on papyrus discovered in ancient Egyptian excavation sites. It might also be called a ‘jeu cognitif ’ (cognitive game)—a term coined by Jean-Pierre Changeux in his book “L’homme neuronal” (Neuronal Man: The Biology of The Mind, originally published in 1985). Rademaker used the principle of this cognitive game, originally worked out in his study, during lectures later, for example by displaying his experimental animals to demonstrate their remarkable post-operative recovery [Personal communication, Dr. L. Kuenen], by projecting illustrations he had drawn himself for his monograph “On the Physiology of Standing” or for the Nederlandsch Leerboek der Physiologie (Dutch Handbook of Physiology) or by playing self-made films of his animal experiments. Courtesy Mrs. J. Ferwerda-Vogelsang, wife of Prof. Ferwerda of Wageningen University.

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While Rademaker was writing till deep in the night on his voluminous monograph ‘On Standing’ his wife was often playing or exercising on the piano in the salon of their house. In fact it was a demonstration of “creative writing” bij Rademaker. He allowed company while he was in his library working. The young daughter [Personal communication Mrs. Ferwerda-Vogelsang, Wageningen] of the butler in the house could play with the paper cuttings of the pictures and filmstrips he used for his publications and which she found in the wastebasket in the room. He used to help her in her jeu cognitief to reassemble the pieces. Children of the neighbours and others back from school, seeing him sitting for the window writing, could come in without hesitancy to ask him questions and help for their homework. He enjoyed these secondary school rehearsals of mathematics chemistry and physics.

ACKNOWLEDGMENTS This list may also serve as a second ‘liber amicorum’. Dr. Coen Arkema—Kapelle (Belgium) Dr. N. Arts—Nijmegen Miss Attema—Municipal Archives, Den Haag Prof. Alain Berthoz—Paris Prof. Dr. H. Beukers—Leiden Bibliotheek en Rademaker archief—Ziekenhuis Leyenburg, Den Haag (Drs. Theo C.A.M. van Woerkom) Mme. Karin Blanc—Paris Prof. Dr. Em. De Blécourt (1998) †—Groningen Drs. W.A. Blokhuis—Maastricht Miss H.P. Boersma †—Leiden Prof. Dr. Michel Bonduelle—Paris Mrs. H.J. Ter Braak-Faber—Wassenaar Prof. Dr. Em. G.W. Bruyn † Mrs. P.H.R. Burgerdorf Mulder Prof. Dr. O.J.S. Buruma—Leiden Prof. Dr. Arnold Carmicheal †—London / Bethesda USA Prof. Dr. Em. F. Cleton—Oegstgeest Mr. J. Drijber Prof. Dr. Em. J. Drooglever Fortuyn †—Groningen Mrs. Claude Endtz-Hageneau—Den Haag Prof. Dr. Ir. Em. J.D. Ferwerda †—Wageningen Mrs. J. Ferwerda-Vogelsang—Wageningen Mr. Claude Garcin—Paris Mr. Jean Loup Garcin—Paris Prof. Em. Raymond Garcin † Mr. Thierry Garcin—Paris Dhr. G. van de Giessen—medical photography LUMC, Leiden Prof. Dr. Godlewski †—Paris Mme. Godlewski—Paris Miss Nicole Grimaud—Paris Drs. J. Hartman—Wassenaar Prof. Dr. Em. W. Hijmans

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acknowledgments

Drs. Cor Hoekstein †—Dordrecht Prof. Dr. Em. M.W. van Hoff—Rotterdam Mrs. A. Hogenhuis-Seliverstoff—Boulogne Mr. P. Hogenhuis Sr. †—Stadskanaal Mr. F.W. ’t Hooft—Noordwijk Drs. K. Hoogerheide † Miss Irene van Houten—afdeling Voorlichting en Documentatie Koninklijke Nederlandse Academie van Wetenschappen, Amsterdam Drs. J. Hugenholtz—Oegstgeest Mrs. Y. Janelli Prof. Dr. Em. Kamphuizen Dr. P.J.J. Koehler—Heerlen Drs. L. Kuenen—Leiden Prof. Dr. Em. W. Kramer Mr. C.J.M. Kramers—Den Haag Drs. M. van de Kruk † Prof. Jean Lapresle PHD †—Paris Dhr. H.J.F.M. Leechburch Auwers—Boerhaave Museum, Leiden Prof. Dr. M.J. van Lieburg—Rotterdam Prof. Dr. Em. W. Luyendijk †, Prof. Dr. Em. Luyendijk-Elshout— Oegstgeest Drs. A. Maas M.D.—Wassenaar Dr. O. Magnus Jr. Dr. Purdon Martin †—Queensquare-London Prof. Dr. Em. H. Meinardi—Leiden Mr. P.C. Meuffels—Department Medical Photography, Sittard Dr. Em. P. Mouton—Zeist Prof. Dr. Em. J. Mulder † Prof. Dr. Em. J. Nauta and Mrs. Dra. Nauta-Barge—Leiden Prof. Dr. Em. E.L. Noach—Leiden Mrs. Maja Nysingh-Munk—Zwolle Miss Elisabeth van der Poel †—Leiden Dra. Kato Pomer-van Leeuwen—U.S.A. Drs. P.H. Postma—Gapinge Drs. H.J. del Prado—Dordrecht Prof. Dr. A. Querido †—Leiden Mr. Ir. R.D. Rademaker Prof. Dr. Pierre Rondot—Paris Prof. Dr. H.C. Rümke † Prof. Dr. Em. H. Schneider †—Bilthoven

acknowledgments

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Drs. J. Schoen † Prof. Drs. Em. A.Th. Schweitzer—Leiden Prof. Dr. Em. B. Smalhout Dr. F.L.M. Steenwinkel (1996) Prof. Dr. Em. W. Storm van Leeuwen Jr. Prof. Dr. Em. A. Struyvenberg Prof. Dr. Em. Tammeling †—Leiden Drs. J. Taselaar—Emst Prof. Dr. Em. Vanhof—Rotterdam Prof. Dr. Em. H. Verbiest † Prof. Dr. W.J.C. Verhaart † Mrs. E. Vlaar-van Gulik—Rotterdam Dr. A.G.M. van Vliet—Rotterdam Miss N. de Vries Mrs. P.B. de Vries-Postema Prof. Dr. Em. J. Willemse—Utrecht Mr. H. Wodrada, Kamperland Drs. Theo C.A.M. van Woerkom—Den Haag Tropenmuseum—Linnaeusstraat 2, Amsterdam Dr. R.H. Bathgate PHD translated, edited and critically reviewed the manuscript and made a number of contributions based on his knowledge on the subject from my own earlier publications of the subject. Mrs. R. Lensen-Hausmans cheerfully undertook the task of creating order from chaos in her typing numerous versions of the manuscript.

CONCLUSION ON THE MODEL OF COGNITION PRESENTED At the onset of the book biography had been defined as a model of the dynamics of cognition leading to a dual account of the life and scientific endeavours of Gysbertus Godefriedus Johannes Rademaker (1887– 1957). Attention has been paid to how his scientific ideas developed over time, over which research has been done in this study. Pivotal themes as they have to become known during this research have been recorded in this sense. Chronology has been recorded insofar as his publications went over years. A complete list of his publications has been added. The intuitive and experimental evidence of Rademaker’s scientific work has been researched in documents and were conformed by his peers national and international. The dynamics of cognition came so to life. ‘In the beginning there was movement’ as Dr. Faustus stated in Goethe’s writing. Rademaker did not deviate from this thought and philosophy. His main line of research was followed from the origin of movement, to which the title of this book indicates. It was fruitful to follow his lines of basic research and spread from the biomedical discipline as physiology developed over years, to metamedics, metamathematics and the arts such as ballet. The patient stayed at the centre of the universe. . . .

INDEX

Animal experiments: ablation techniques 49–50 anaesthesia and postoperative care 34, 42 chronic animal model in neurophysiology 43 decapitation 68 Anatomy nucleus ruber—see thesis cum laude Rademaker (1924) 57–67

Haldane, J.B.S. (1892–1964) 127 Herschel, Sir William (1738–1823) 341–342 Horsley-Clarke apparatus 62–67, 229–232, 235–236, 281

Barge, Prof. J.A.J. (1884–1952) 203–213 Bereitschaftspotential 321, 327 Berthoz, Prof. A. 201, 306, 323–335 Biographic approach 10–14

Magendie, F. (1783–1855) 67–69, 91, 224–225 Magnus, Prof. R. (1873–1957) 21–42, 50–60, 76, 128–131, 143–150, 153–165, 194–198, 236–244, 251–252, 260–261, 266–267, 271–272, 275, 279–281, 336–337 Körperstellung (Posture, 1924) 21–34, 267, 272, 275, 281, 297 Marey, Etienne-Jules (1830–1904) 130, 267 Mulder, Prof. J. (1903–1965) 56, 169, 331–332 Mulders, Jan (1919–1944), student and resistance hero 203, 211–213 Muscle tone 25–30, 37–38, 57, 65, 88, 90, 113–115, 159–160, 227–229, 272–276, 301–306, 310–319, 335–336 Muscle tone: Rademaker’s views on m. 37–38, 312–319

Cognitive model 1, 349 Cybernetic physiology (see Wiener, Norbert) 265, 302, 319–321 Decerebrate rigidity and postural reflexes 257 Development: infant 142–146 Diaschisis 43–47 DuBois-Reymond, E. (1818–1896) 72–74 Einstein, A. (1879–1955); anecdote on a thought he had 126, 142 Epiphanies 337–339 Experimental model: choice of 38 Extirpation: combined e. of cerebrum and cerebellum 123–125 unilateral e. of one labyrinth 123, 159 Fulton, John Farquhar (1899–1960) 50–53 Garcin, Raymond (1897–1971) 41–42, 168, 171, 174–192, 196–200, 238, 337–338 and blink reflex 145, 170–179, 186, 190, 336 and step sign 186–187, 336–339

Jelgersma, Prof. G. (1859–1942) 120 ‘Jeu cognitif ’ 343

Neurology in wartime 203–213 Nucleus ruber and stereotaxis 59–63 Nystagmus: optokinetic 128–129 Odour of the animal room 55–57 ‘On the origin of movement’, history 301–322 Parkinson’s disease 226–228 Pavlov, Ivan (1849–1936) 76–80, 170–172 “Physiology of Standing” (translation of Das Stehen) 85–142

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Physiology: French, Russian and Anglo-Saxon approaches compared 67–84 Rademaker, Gysbertus Godefriedus Johannes (1887–1957): axioms and postulates 301–301 death 331–334 friendship and professional cooperation with Garcin 182–190 Rademaker, Geurt Arend (father) (1834–1908) 11–13 Rademaker, Geurt Arend (brother) (1881–1971) 13, 16 Rademaker, M.J.W. (Blanche) (wife) (1894–1962) 34–35, 259–262 RaGa (Rademaker/Garcin) story in Paris 182–185 Réactions labyrinthiques 190–201 Reactions: Lengthening and shortening r. 254–257, 325–326 Static r. 156–165 Support r. (Stützreaktionen) 187–190 Westphal r. 325–326 Reflexes: Blink r. 70–71, 170–181, 189–190 Cochleopalpebral r. 175 Fall r. 125–141 Labyrinthine righting r. 48–50, 131, 135, 144–145, 219–223, 232–233 Oculomotor r.; reflexes controlling the position of the eyes 154–155 Righting r., as baseline 39 Standing r. 88–91, 155–170 Stato-kinetic r. 158–159 Switch r. 83 Tonic labyrinthine r. 152–154 Tonic labyrinthine r. in swimming 160 Tonic neck r. 152–160 Rondot, Prof. P. 238, 321–329

Sechenov, Prof. Ivan Michailovich (1829–1905) in St. Petersburg 72–77 Serendipities 148 Sherrington, Sir Charles Scott (1857–1952) 21–33, 44–48, 76–92, 116–117, 163–165, 255–256, 304–307, 316–318 Sign: finger flexor (see thesis H. Verbiest) 224–227 Stehbereitschaft 115–119, 123–124 Stepanova, Varvara (1894–1958) 303, 309 Stützreaktionen (support reactions) 187–190 Surabaya (1916–1922, G.P. and surgeon) 3–4, 16–18 Ter Braak, J.W.G. (1903–1971) 126–141, 176–179, 297–298 Theses (prepared under Rademaker’s supervision) 214–251 Tilt test 195–196, 199–200 Triangle of movement 301–302, 322 Trigonometric model of some locomotor functions 329 Tsion, Ilya Fadeyevich (alias Élie de Cyon (1842–1912)) 84 Von Monakow, C. (1853–1930) 44–46, 261–262 Von Uexküll, Jakob Johann (1864–1944) 22–23, 83–84, 148–151 Westphal, Carl Friedrich Otto (1833–1890) 325–326 Wiener, Norbert (1894–1964) 265, 319 Zero condition 39–40, 145 Zero option (in experimental neurophysiology) 40

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1. Fruton, J.S. Fermentation. Vital or Chemical Process? 2006. ISBN 978 90 04 15268 7 2. Pietikainen, P. Neurosis and Modernity. The Age of Nervousness in Sweden, 2007. ISBN 978 90 04 16075 0 3. Roos, A. The Salt of the Earth. Natural Philosophy, Medicine, and Chymistry in England, 1650-1750. 2007. ISBN 978 90 04 16176 4 4. Eastwood, B.S. Ordering the Heavens. Roman Astronomy and Cosmology in the Carolingian Renaissance. 2007. ISBN 978 90 04 16186 3 (Published as Vol. 8 in the subseries Medieval and Early Modern Science) 5. Leu, U.B., R. Keller & S. Weidmann. Conrad Gessner’s Private Library. 2008. ISBN 978 90 04 16723 0 6. Hogenhuis, L.A.H. Cognition and Recognition: On the Origin of Movement. Rademaker (1887-1957): A Biography. 2009. ISBN 978 90 04 16836 7 7. Davids, C.A. The Rise and Decline of Dutch Technological Leadership. Technology, Economy and Culture in the Netherlands, 1350-1800 (2 vols.). 2008. ISBN 978 90 04 16865 7 (Published as Vol. 1 in the subseries Knowledge Infrastructure and Knowledge Economy) 8. Grellard, C. & A. Robert (Eds.). Atomism in Late Medieval Philosophy and Theology. 2009. ISBN 978 90 04 17217 3 (Published as Vol. 9 in the subseries Medieval and Early Modern Science) 9. Furdell, E.L. Fatal Thirst. Diabetes in Britain until Insulin. 2009. ISBN 978 90 04 17250 0