Brain Renaissance: from Vesalius to Modern Neuroscience

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CATANI ————— & ————— SANDRONE

BRAIN RENAISSANCE From VESALIUS TO MODERN NEUROSCIENCE

CATANI ————— & ————— SANDRONE

BRAIN RENAISSANCE From VESALIUS TO MODERN NEUROSCIENCE

Introduced, translated and commented upon by

Marco Catani

NatBrainLab, Institute of Psychiatry Psychology & Neuroscience King’s College London London, UK

Stefano Sandrone

NatBrainLab, Institute of Psychiatry Psychology & Neuroscience King’s College London London, UK 1 1

Oxford University Press is a department of the University of Oxford. It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide. Oxford New York Auckland Cape Town Dar es Salaam Hong Kong Karachi Kuala Lumpur Madrid Melbourne Mexico City Nairobi New Delhi Shanghai Taipei Toronto With offices in Argentina Austria Brazil Chile Czech Republic France Greece Guatemala Hungary Italy Japan Poland Portugal Singapore South Korea Switzerland Thailand Turkey Ukraine Vietnam Oxford is a registered trademark of Oxford University Press in the UK and certain other countries. Published in the United States of America by Oxford University Press 198 Madison Avenue, New York, NY 10016 © Oxford University Press 2015 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Oxford University Press, or as expressly permitted by law, by license, or under terms agreed with the appropriate reproduction rights organization. Inquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above. You must not circulate this work in any other form and you must impose this same condition on any acquirer. Library of Congress Cataloging-in-Publication Data Catani, Marco, author, commentator, translator. Brain renaissance from Vesalius to Modern Neuroscience / translated, with commentary, by Marco Catani, Stefano Sandrone. p. ; cm. Translation and commentary of those chapters of De humani corporis fabrica dedicated to the brain. Includes index. ISBN 978–0–19–938383–2 (alk. paper) I. Sandrone, Stefano, author, commentator, translator. II. Vesalius, Andreas, 1514–1564. De humani corporis fabrica. Selections. English. Analysis of (work): III. Title. [DNLM: 1. Vesalius, Andreas, 1514–1564. 2. Brain—anatomy & histology. 3. Anatomy—history. 4. Physicians—history. WL 300] QP376 612.8′2—dc23 2014032888 The science of medicine is a rapidly changing field. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy occur. The author and publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is accurate, complete, and in accordance with the standards accepted at the time of publication. However, in light of the possibility of human error or changes in the practice of medicine, neither the author, the publisher, nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete. Readers are encouraged to confirm the information contained herein with other reliable sources and are strongly advised to check the product information sheet provided by the pharmaceutical company for each drug they plan to administer.

9 8 7 6 5 4 3 2 1 Printed in the United States of America on acid-free paper

To Raffaela, Giulia, Matteo and Chiara Maria with whom I share a wonderful journey (Marco Catani)

To my beloved grandfather Renato (Stefano Sandrone)

Contents

Preface xi

Acknowledgments xiii

PART ONE: VESALIUS’S LIFE: THE ANATOMY OF AN ANATOMIST

1. Vesalius, a Man of His Time 3

2. A Flemish Formation in Brussels and Leuven 7

3. Vesalius Meets Galen in Paris 10

4. The Paduan School of Anatomy 13

5. A Slow Departure From Galen 16

6. The Making of the Fabrica 19

7. Dissecting the Fabrica 23

8. Vesalius and Venice 28

9. A Life Among Eminent Men, with Many Honors and Gifts 31

10. From Anatomy to Surgery 34

11. Desolation in Spain 37

12. The Last Journey 40

PART TWO: THE FABRICA OF THE HUMAN BRAIN

13. The Brain Is Fabricated for the Sake of the Supreme Spirit, the Senses, and Also the Movement That Depends upon Our Will 45

14. On the Hard Membrane That Surrounds the Brain and the Small Membrane Covering the Skull Under the Skin 50

15. On the Thin Membrane of the Brain 58

16. On the Number, Position, Shape, Convolutions, and Substance of the Brain and Cerebellum 60

Commentary: Scratching the Surface of Complexity 68

vii viii Contents

17. On the Corpus Callosum of the Brain and the Septum of the Right and Left Ventricles 79

Commentary: The Corpus Callosum: A Tale of Anarchic Hands and Split Brains 82

18. On the Cerebral Ventricles 93

Commentary: The Liquor of our Souls 99

19. On the Brain Structure That Expert Dissectors Have Compared to a Tortoise-Like Vault 104

Commentary: The Fornix: A Memory Thread in the Brain 106

20. On the Cerebral Gland Resembling a Pine Nut 116

Commentary: The Pineal Gland: From the Seat of the Soul to the “SAD” Lamps 118

21. On the Testes and Buttocks of the Brain 124

Commentary: Sex on the Hills 126

22. On the Cerebellar Processes Resembling Worms and the Tendons That Contain Them 131

Commentary: The Cerebellum: More Than a Little Brain 133

23. On the Infundibulum, the Glandule That Receives the Cerebral Phlegm, and the Other Ducts That Cleanse It 141

Commentary: The Axis of Survival 146

24. On the Networks of the Brain Believed to Be Similar to the Reticular Plexus and the Placenta 152

Commentary: The Net of Wonder 154

25. On the Organ of Smell 158

26. On the Eye, the Instrument of Vision 159

27. On the Organ of Hearing 168

28. On the Organ of Taste 169

29. On the Organ of Touch 170

30. How to Dissect the Brain and all the Other Organs Discussed in This Book 171

PART THREE: A BRIEF HISTORY OF NEUROSCIENCE FROM VESALIUS TO THE CONNECTOME

31. Introduction to Network Neuroscience 185

32. Protoconnectome Maps 189 ix Contents

33. Seeing Things in Gray and White 191

34. Phrenology and Animal Electricity 194

35. Microscopic Discoveries 197

36. Early Cartography 202

37. From Electrophysiology to Neuroimaging 205

38. Metaphors and Myths 210

Appendix: Figures from the Seventh Book of the Fabrica 215

Notes 253

References 259

Index 273

Preface

Brain Renaissance, from Vesalius to Modern Neuroscience has been written to mark the birth of the remarkable anatomist Andreas Vesalius five centuries ago, and the 450th anniversary of his lonely death on the coast of Greece. Born in Brussels in 1514, Vesalius studied in Paris and Leuven. As professor of anatomy in Padua, he began writing the De Humani Corporis Fabrica at the age of 24. It took him four years to complete what is still considered a true landmark in the history of medicine. He supervised all aspects of the making of the book and his final publication in 1543 represented the final act of the realization of a true masterpiece of science and art. How can a book published almost 500 years ago still be relevant to contemporary neuroscience? Andreas Vesalius was a Renaissance man who dared question the received wisdom of his day, which came from ancient teachings about the human body and mind. Inspired by the finest cartographers and artists of his time, Vesalius laid down a modern paradigm in science: the power of direct observation. The result was a new anatomy of the human body. Five hundred years later, technological development permits the scientific and medical community to study the anatomy of the human body with a greater spatial and temporal resolution. Concerning the brain, the so called neuroimaging techniques, such as positron emission tomography (PET), functional magnetic resonance imaging (fMRI), and Diffusion Tensor Imaging (DTI) tractography are essential tools for the analysis of organized neural systems in working and resting states, both in normal and pathological conditions. These methods, when complemented with microscopy techniques could open the possibility of mapping the entire wiring of the human brain. As neuroscientists we exploit the advantages offered by modern neuroimaging techniques. But we are also deeply aware that our approach to neuroscience, although modern in the tools employed, intellectually owns much to Vesalius’s philosophy. Our book grew from a wish to understand the roots of our own discipline, which has involved tracing the origins of neuroscience back to that extraordinary period of artistic, intellectual, and scientific awakening, the Renaissance, and back to Vesalius. The book is divided into three parts and readers can start at any of these parts, depending upon their personal interests. Part 1 provides an account of what is known of the life of Andreas Vesalius. The story of the man behind the Fabrica is almost as fascinating as the Fabrica itself.

xi xii Preface

Part 2 of the book gives in English the eighteen chapters of Vesalius’s Fabrica dedicated to the brain, originally in Latin, the international language in his time. Each of the translated chapters on the brain has brief explanatory notes. For those with direct relevance to modern neuroscience, we also provide a glance at the progress made since Vesalius wrote his book. Part 3 offers a brief overview of the major discoveries in neuroscience to have emerged since the publication of the Fabrica. Here we track the evolution of ideas and approaches to understanding the brain within their historical context, and pay tribute to the work of many pioneers. As our account moves toward modern times, the brain is perceived in terms of the major technical achievements of each era: the brain as an electrical device or in the 21st century, as a connectome, which identifies the brain as an intricate wiring system, a sort of ‘social network’ for random but controlled interactions. Working on this book has taken us on an unforgettable journey, inspired by the work of Vesalius. We wrote Brain Renaissance to share our understanding of Vesalius and his legacy, and the history of neuroscience. We also wrote it for the next generation of neuroscientists: we especially hope younger readers will be inspired by it to spend a life in science. Marco Catani and Stefano Sandrone, Zakynthos 7th September 2014

Acknowledgments

First in our list is Craig Panner, Associate Editorial Director of Medicine Books at OUP, New York, who went well beyond his editorial duties to publish the book exactly the way we wanted it. Grazie Craig! We own Matt Dawson a huge debt of gratitude for all his work on the different ver- sions of the entire manuscript. Also Ruth Richardson read some of the chapters in bits and pieces and gave precious advice on the final structure of the book. Antonio Damasio provided very helpful suggestions to fill some gaps in moder history of neuroscience. Dr Giuseppe Zappala’ (Pippo) proofread the entire book and gave fruitful comments. In the initial preparatory stages of the book, Professor Rik Vandenberghe organized for us a timely and rather wonderful tour of the places associated with the life of Vesalius in Leuven. Herman Verbruggen was our enthusiastic guide through the streets of the town. During the tour we met Eddy Put, Senior Researcher at the Belgian State Archives in Leuven, who allowed us to take a close photograph of the name of Vesalius enlisted in the 1530 register of the Collegium Castrense. In Padua Giuseppe Ongaro and Maurizio Rippa Bonati gave us precious information on the life of Vesalius and his relationship with other academics living in the Italian town at the time. By talking to Franco Guida, neurosurgeon of the Venetian USLL number 12, we realized that a chapter on Vesalius and Venice was necessary and this resulted in the addition of chapter 8. Doctor Luigi Scorolli double-checked the translation of chapter 26 on the eye and the legends for figures A19 and A20 in the appendix. We are very thankful to a number of people that provided some of the figures reproduced in our book: Antonio Di leva for figure 17.3, Alberto Bizzi for figure 17.5 (left), Gabriele Polonara for figure 17.5 (right), and Andres Lozano for figure 19.9. Pascale Pollier, Theo Dirix, and Mark Gardiner organized a very stimulating con- ference in Zakynthos where the search for the grave-place of Andreas Vesalius continues to these days. We are also very honored for the words of praise written by Alistair Compston, Stanislas Dehaene, Sergio Della Sala, Pim Levelt, and Marsel Mesulam. Their appre- ciation means a lot to us. Finally we would like to thank the other members of the Catani family for alle- viating our sufferance with music, food, football playing, turning bubbling into first words, and infinite patience.

xiii

Part One Vesalius’s Life: The Anatomy of an Anatomist

1 Vesalius, a Man of His Time

Andreas Vesalius was born in Brussels on the last day of 1514. In the same year, Leonardo da Vinci abandoned all hope of completing what would have become, if published, the most beautiful treatise on human anatomy of all time. Much of it was based on human dissection, a practice that artists often performed to better appreciate the proportions of the body. But by the time Vesalius was born Leonardo had moved to Rome, to the court of Pope Leone X, who promptly forbade him from conducting such dissections. It was a moment that changed the course of history. Leonardo did as he was told, ended his anatomical observations, and returned to drawing and civil engineer occupations. Within thirty years Leonardo was long dead—his illustrations of the human body still remaining unpublished—and Vesalius had shown that dissection was as much a method of scientific enquiry as an aid to the pursuit of art. Vesalius succeeded where Leonardo had failed: he published in 1543 the first map of the new human anatomy, De Humani Corporis Fabrica (On the Fabric of the Human Body). In many respects Vesalius was perfectly placed to see the power of an atlas and to raise awareness of its benefits to the medical field. The fifty years of life granted to him span a period of great intellectual awakening. Europe widened its horizons toward the New World, which inspired a remapping of the geographical borders of human knowledge. Scholars and thinkers ventured to explore new areas of mathematics, philosophy, art, astronomy, science, and religion. This sudden and rapid accumulation of information required a systematic approach. Cartography grew out of necessity. Maps and globes became popular forms of visual representation of new lands, continents, and skies. Atlases gave the coordinates for further exploration. In a climate fueled by an exploratory spirit, maps became not only artistic displays but also visual accounts of the known and unknown. At a glance, they provided a portrait of the achieved and the achievable. Vesalius was a contemporary of many outstanding cartographers. Among them was Gemma Frisius, so well known for his astral maps that, as in the case of Vesalius, a lunar crater was dedicated to him. Then there was Gerardus Mercator, Gemma’s student, maker of the finest terrestrial globes of the time. In addition to their deep knowledge of geography and astronomy they offered unique technical skills. Mercator was an exceptional engraver of brass plates, a mastery that he put to good use in mapmaking. This ability to translate conceptual knowledge into visually appealing yet informative maps made his works stand out as representative of a new intellectual

3 4 BRAIN RENAISSANCE figure: one person comprising the scholar, the artist, and the craftsman. In Vesalius’s early academic formation, observing these masters at work was a thrill to him. He was in awe of their skills, so it is no surprise that the young physician became to anatomy what Mercator and Frisius were for geography and astronomy. The fact that Vesalius was so open to new thinking and new visual representations may explain why he was so quick to break boundaries—in particular those between the three roles traditionally involved in the teaching of anatomy during dissections: the professor who read from Galen’s texts of reference while seated on an elevated chair (lector, the reader), the barber-surgeon who actually performed the dissection at the anatomical table (sector, the dissector), and the assistant (ostensor, the demonstrator), who indicated the anatomical structures as they were named by the reader and dissected by the barber-surgeon (Figure 1.1). Vesalius liked to do things differently. To him dissection was a one-man show where he could perform hands on, indicating the anatomical parts as he exposed them and even providing his own commentary. When Vesalius began his education, the anatomical observations of the Greek- Roman physician Galen were regarded as unquestionable truths. This is a remarkable fact given that they had been made over a thousand years earlier. But the direct experiential knowledge that Vesalius acquired through his dissections is the main reason behind his departure from traditional anatomical teachings and his refusal to accept classical anatomical knowledge as the only source of truth. Vesalius had stressed on many occasions that Galen’s accounts derived from animal observations did not match the real anatomy of the human body. Vesalius laid down a new paradigm in medical knowledge: a revolutionary induc- tive approach that seeks direct evidence to explain the wonders of the human form. Vesalius was not prepared to take for granted what had not been clearly demonstrated for the human body at the dissection table. His anatomy was based only on knowledge derived from direct observation, which led him to identify significant differences between animals and humans. If he had not dissected it, or had not seen it, he chose not to mention it rather than report the words of others. His work constitutes the expression of a firm belief, one that now underpins modern science in the power of observation as a direct source of knowledge. Such approach to anatomy left him open to harsh criticism. The most severe came from eminent Galenists, medieval anatomists, and humanists, many of whom were close acquaintances. They felt that Vesalius was not able to understand anything beyond the visible, an ability with which only those of great intellect were endowed. After all, they argued, one can surely see that human dissections are not even strictly necessary: anatomical problems could and should be solved by disputation alone. Indeed, it is not Vesalius’s words that do most of the talking but his illustrations. He could see so much more than he could say. In his book there is a clear discrep- ancy between the highly informative, esthetically mesmerizing quality of the illustrations, and the repetitive but didactic style of the written text. His images were the real breakthrough, revealing a new human anatomy—one that was immediately accessible to everyone, even those who had no medical education or could not read. A 5 Vesalius, a Man of His Time

Fig 1.1 Johannes de Ketham’s Fasciculus Medicinae (1493). A group of students attend the anatomy lecture around the dissection table. The lecturer sits on the high chair and reads from the classic texts. The dissector has a knife in his hand and isolates the internal organs, muscles and nerves. The demonstrator indicates with a stick in his hand the anatomical parts under examination.

cogent parallel is with some of the masterpieces on European cathedral walls created by Renaissance painters to illustrate scenes of the Bible. Vesalius’s illustrations are still, five hundred years later, a treasure trove of anatomical knowledge. Considering that most of the illustrations were made by his artist fellows and that some of the new anatomical observations are in the figures rather than in the text, one may wonder if the artists more than Vesalius should be credited with the discoveries. Yet given the revolutionary way in which Vesalius approached anatomy, it is surprising to find no reference to his achievements in the thousands of eponyms used to describe all the many parts of our bodies (Singer, 1952). Falloppia has his tubes, Willis his arterial polygon, Rolando his scissure, Broca and Wernicke their own regions of 6 BRAIN RENAISSANCE the brain, Golgi his cells. But the truth is that Vesalius made few original contributions to existing anatomical knowledge. His writings on the brain, for example, are often limited to short summaries of what Galen had previously said. Vesalius so rigorously identified, labeled, and systematized the individual parts of the body that when his great book De Humani Corporis Fabrica was published, it quickly became one of the most celebrated works of its time. That same year, 1543, Copernicus published his De Revolutionibus Orbium Coelestium (On the Revolution of the Heavenly Spheres), a direct attack to the ancient Ptolemaic doctrine of the solar system. This is a significant and beautiful coincidence because both books are revolutionary in a shared sense. They mark a break with conventional theories: one explores the macrocosm of space, the other the microcosm of the human body. Together, they brought an end to dogmatic tradition and signaled the beginning of a new inquisitive search for the mysterious working of Nature and Science—a search that continues to this day.

2 A Flemish Formation in Brussels and Leuven

Andreas Vesalius was born and spent most of his childhood in a house on Rue de Minimes, a street located in the neighbourhood of Sablon, just south of the ram- parts of Brussels. The house, situated within the second city walls, no longer exists. It was dismantled to make way for a convent, which later became a modern church. Instead, a single marble tablet with a brief Latin inscription marks Vesalius’s birthplace: “In this area, in the XVI century, was the home of the outstanding author Andreas Vesalius of Brussels . . . who in 1542 sent to print his illustrious book De Humani Corporis Fabrica for the happiness of posterity.” The birthplace of the father of modern human anatomy is, then, a little underwhelming. You have to go two kilometers south for a more appropriate tribute. Place de Barricades in Brussels is the square where the French writer Victor Hugo lived throughout 1851 while in exile. He was frequently visited by his friend Charles Baudelaire, a man whose poems reveal a fascination with death. The view from Hugo’s window would have thrilled Baudelaire because, dominating the square, standing erect and tall, was a newly built bronze statue of the great anatomist. Beautifully poised, it depicts Vesalius with a flowing robe, a pen in hand, and an anatomy book tucked under his left arm. A plaque at his feet indicates his date of birth as December 31, 1514, a year that contrasts with the incorrect 1515 inscribed on the tablet found at Vesalius’s birthplace. Andreas was one of four children—three brothers and one sister—born to Andries Vesalius and Isabella Crabble. Little is known about Vesalius’s mother other than that she was the daughter of Jacob Crabble. Vesalius’s father came from a very influential family of physicians and pharmacists, many of who personally attended royalty. Vesalius’s great-great grandfather Peter had been physician to the Emperor Frederick III; his great grandfather Johannes physician to Maria Borgogna, wife of the Emperor Maximilian I, and professor at the University of Leuven (Belloni, 1964). Vesalius’s grandfather Everard diagnosed the ailments of Charles V of Spain. Finally there was his father, whose duties, as royal apothecary to Charles V of Spain and later to Philip II, King of Spain, meant that he was often away from the family. It was left to Isabella to tend to the early education of the children (O’Malley, 1964). It is an illustrious lineage that gave Vesalius a lot to live up to. And he was proudly aware of it. In a letter dated 1546 he tells of the derivation of his surname. His

7 8 BRAIN RENAISSANCE family was formerly called Wijtinck and came originally from the town of Wesl, in the Rhenian region of western Germany (Belloni, 1964; O’Malley 1964). Emperor Frederick III granted his great-grand-father Johannes the privilege of using the surname Wesalia, which evolved quickly into Vesalius (Belloni, 1964). Both his medical heritage and his birthplace meant that young Vesalius became exposed to the decaying flesh of the dead from a very early age. His family home, on the outskirts of Brussels, overlooked Gallows Hill. Here criminals were executed and their bodies left to be picked at by foraging birds (Nuland, 1995). As a child, running across the fields near the hill, Vesalius frequently stumbled upon and tentatively approached the corpses (Vesalius, 1546). Their visceral constituents would have been as memorable to him as the repulsive smell. As he grew, so did his curiosity. By vivi- secting animals found in the neighbourhood, he learned more about the joys of anatomical discovery (Zilboorg, 1943). And perhaps sneaking into his father’s library to read the abundance of formal anatomical books, he was given a taste of what these discoveries could mean. By the age of 14 he had clear idea of what he wanted to do with his life: to study medicine. At age 15, Vesalius chose to move to Leuven and, on February 25, 1530, enrolled in the Faculty of Arts at the Pedagogium Castrense (Castle College) (Figure 2.1), the very same college where his father studied before him and his younger brother Franciscus after him. Most of the teaching was done in a building (now known as Universiteitshal) that had formerly housed the local wool market. The college taught wealthy young men of the distinct subjects, including grammar, rhetoric, algebra, astrology, and music. By the time Vesalius arrived, the university was at the forefront of the humanist movement, which preferred individual thought and evidence over an established doctrine or faith. The new spirit was celebrated with the founding of a new language college. The Trilingual College was originally established in 1517 using the funds of the wealthy patron of learning Jeroen van Busleyden and under the cultural guidance of

Fig 2.1 At age 15, Vesalius enrolled in the Faculty of Arts at the Pedagogium Castrense (Castle College). The name of Andreas Vesalius (Andreas da Wezl de Bruxella) appears on the faculty’s register (1530). 9 A Flemish Formation in Brussels and Leuven

Erasmus of Rotterdam, leading humanists of the time. It taught not only Latin, the standard language for any educated individual, but also Greek and Hebrew. It was here that Vesalius benefited from a new approach to languages, which would later allow him to access and compare original anatomical texts. Vesalius completed his studies in three years and in the summer of 1533, at the age of 18, made his way across the border to Paris, where he would spend the next four years studying what he loved the most: anatomy and medicine.

3 Vesalius Meets Galen in Paris

The University of Paris was an outpost of humanist spirit and of Galenic tradition. Here, scholars sidestepped the cultural domain of medieval thinking and Arabic medicine by re-examining the original Greek texts and re-translating them into Latin. At the medical school, most of these texts were the works of Galen of Pergamon (129–216 AD), who had been the undisputed authority in anatomical teaching for over a thousand years (Nutton, 2002; Rocca, 2003). This Greek-speaking Roman physician was a prolific author, having written some six hundred treatises covering anatomy, physiology, hygiene, therapeutics, semiotics, and pathology. Only about a third of his works survive today (Boudon-Millot, 2007). The Roman law lex( de sepulcris) had prohibited dissection of the human body, forcing Galen to make most of his anatomical observations from oxen, pigs, and monkeys (Manzoni, 2001). He expected his followers to make further speculations as when they could. The problem was that few of them ever speculated further. In the Middle Ages, Galen’s work was translated into Arabic and Latin and became the only and irrefutable source of anatomical knowledge to both Muslims and Catholics. By the time Vesalius arrived in Paris, Galen’s anatomical works had been completely retranslated from Greek into Latin as many earlier translations contained mistakes (Castiglioni, 1943; Lowry, 1979). Two of these academics involved in the retranslation of Galen’s work would become Vesalius’s anatomy teachers: the Latin scholar Jacobus Sylvius and Johann Guenther von Andernach, who had taught Vesalius Greek in Leuven (Cushing, 1943) (Figure 3.1). They took a shine to the enthusiastic young Vesalius and asked him to replace the barber-surgeon during anatomical demonstrations (Simeone, 1984). This was a great privilege for the 18-year-old medical student. The barber-surgeon was responsible for the actual cutting process, the dissection of the body (Foster, 1901), leaving Sylvius or Guenther to read anatomical texts aloud to the students from the reader’s chair (Singer, 1943; Benini and Bonar, 1996). Vesalius gained practice in the art of dissection and learned more from direct experience than from his teachers. As Vesalius writes in the Fabrica:

“When I first studied the bones with Matthaeus Terminus, distinguished physician in all branches of medicine and lifelong friend and companion of my studies,

10 11 Vesalius Meets Galen in Paris

Fig 3.1 Portraits of Jacobus Sylvius (1478–1555) and Johann Guenther von Andernach (1505–1574).

our supply was very abundant. After we had studied them long and tirelessly we dared at times to wager with our companions that even blindfolded we could, for the space of a half-hour, identify by touch any bone offered to us. Those of us who wished to learn had to study all the more zealously since there was virtually no help to be had from our teachers in this part of medicine”.

Nevertheless, his teachers were respected anatomists of the time. Sylvius improved the nomenclature, which before his time was in disarray, including the introduction of the term corpus callosum. His teaching was eloquent and his anatomical dissections very popular among the students (Singer, 1957). Guenther, on the other hand, contributed to anatomy more through his translation of Greek texts into Latin than with practical dissections. He translated Galen’s book De Anatomicis Administrationibus (On Anatomical Procedures) in 1531 and, five years later, assisted by Vesalius, produced his own textbook for medical students—Institutionum Anatomicarum, Secundum Galeni Sententiam (Anatomical Institutions According to the Opinion of Galen). While respectful for the teaching he received from these men, Vesalius’s frus- tration grew. Owing to the anatomical differences between humans and animals, mismatches between the Galenic descriptions and what actually Vesalius saw as he dissected became increasingly clear to him. Sylvius would try to minimize these issues by saying that anatomy could have changed since Galen described it, and “not always for the better” (O’Malley, 1964). Galen’s word, Sylvius said, was the absolute truth, and anatomical evidence should adapt around it. But to Vesalius, the need for clarity became more and more urgent. 12 BRAIN RENAISSANCE

In July 1536, war broke out between Henry II, king of France, and Charles V, the Holy Roman emperor. Vesalius, as son of the apothecary to Charles V, was forced to flee Paris before graduating, and before making his feelings about dissection truly known. He returned to Brussels and then to Leuven, where in 1537 he completed his dissertation entitled Paraphrasis In Nonum Librum Rhazae Medici Arabis, namely a commentary to the ninth book of Rhazes. In Leuven, Vesalius found himself well-connected to men of power and wealth. After lamenting to the burgomaster about the lack of opportunity to explore human anatomy in Paris, Vesalius was granted permission to perform public dissections in Leuven. He began roaming execution sites to collect body parts until he had assembled an entire skeleton. Through the dead flesh of executed men, Vesalius learned more and more about the realities of the true human body. The more learned, the more he began to dream about Italy, the cradle of medical knowledge.

4 The Paduan School of Anatomy

Vesalius never confirmed his reasons for leaving Leuven, although an overt dispute with Thriverius Brachelius, the professor of medicine, on the method of bloodletting may have been the push he needed (Saunders and O’Malley, 1950). The allure of Italy to him, and especially the University at Padua, had been too strong. Padua is 50 kilometers west of Venice. There are no as many canals or islands as those of its more illustrious counterpart. Instead, Padua stands on the banks of the Bacchiglione river, looking out toward the tranquil Euganean Hills. Officially founded in 1222, the University of Padua is one of the oldest universities in Italy. From the outset its medical school had played an important role in teaching anatomy and medicine (Del Negro, 2001; Porzionato et al., 2012). Its history already included many eminent scholars, and its tradition encouraged intellectual freedom and independence from papal control—an attractive combination for a man of Vesalius’s characters. So, soon after obtaining his degree, Vesalius packed up his possessions, and climbed aboard a horse-drawn coach to begin the long, tiring journey to Italy. On the way, he passed through Basel, a city in the process of building a great printing tradition. During his short stay there he became acquainted with Robert Winter and Johannes Oporinus, printers who would later offer him precious advice and experience. Like Vesalius, these men did not shy from controversy. Five years after this meeting, Oporinus published the first-ever Latin translation of the Koran in the world. The outcry this caused had only just subsided when he agreed to publish, in 1543, Vesalius’s Fabrica. Vesalius reached Padua in the summer of 1537, where, on December 5, he graduated with the highest distinction as a doctor of medicine (Simeone, 1984). Within a day he was appointed professor of surgery. It was a role that carried a heavy teaching load, but one that delighted the enthusiastic graduate. Public dissections were suddenly his responsibility, and he would soon be performing them for other institutions as well, as far afield as Bologna and Pisa (Benini and Bonar, 1996). Andreas Vesalius found himself at the beating heart of an anatomical renaissance. And with it came a feeling of belonging. A long list of celebrated anatomists had already graced Padua, many of whom helped place the university at the forefront of medical knowledge (Andrioli and Trincia, 2004). The methodical exploration of the dead had been popular at Padua’s medical school as early as the thirteenth century

13 Fig 4.1 The frontispiece image of the Fabrica hints at the extreme popularity of Vesalius’s public dissections. Vesalius is the only figure looking directly at the reader. His hands are well in evidence, one touching the cadaver and the other pointing up, perhaps to indicate the link between the mortal body and the eternal soul, the earth and the heavenly spheres. 15 The Paduan School of Anatomy

(Ongaro, 2001). Indeed, arguably the first dissection in Padua had been performed by Pietro d’Abano (1250–1315), who used an autopsy to confirm lead intoxication as the cause of a local pharmacist’s death. Among other Italian anatomists was Mondino de Liuzzi whose major work, Anathomia Corporis Humani, was written in 1316 and went through several editions for two hundred and fifty years. His work together with writings of other authors had been collected into a single publication first released in 1491 and titled the Fasciculus Medicinae. It was one of many anatomical publications available by the time Vesalius arrived: such books, annotations, collections, and observations circulated widely among the medical students. Padua responded to the growing demand for medical training by erecting a new building dedicated to the teaching of medical theory, practice, and surgery. Padua was to become Vesalius’s home. Vesalius’s public dissections rapidly became popular (Figure 4.1)—in part because of his clear talent for teaching and also because of his engaging style. Gone was the traditional three-man approach to dissections—they were now replaced by a one-man show. Vesalius would display an entire human skeleton or hold up single parts to reveal the anatomy of the bones. He drew figures of the peripheral distribution of arteries, veins, and nerves to assist students’ understanding of the vascular and nervous systems. Students flocked to his lectures, copying his drawings with gusto.

5 A Slow Departure From Galen

For Vesalius, this success in teaching engendered a wish to publish, both to make his work available and to consolidate his academic career. But it was ultimately the fear of plagiarism that prompted the printing of the Tabulae anatomicae sex (Six anatomical tables) in April 1538: “since many in vain have sought to copy what I have done, I have sent these drawings to the press” (Vesalius, 1538). These consist of a collection of large prints, which show the internal organs, including the male and female reproductive systems, the arteries, and the veins, as well as the skeleton in lateral (side), anterior (front), and posterior (back) views (Figure 5.1). These figures, together with a few lines of text and captions, were published to provide students with silhouettes of the human body that they could use, annotate, cutout and hang on their walls (Lindeboom, 1975). Yet they offer few hints of what was to come five years later in theFabrica . There is no clear departure from traditional teaching, and in many respects Vesalius replicated Galen’s anatomical errors, including the existence of the rete mirabile (a complex set of veins and arteries found in some mammals) at the base of the brain (see Chapter 24), as well as the incorrect division of the liver into fives lobes and of the sternum (breast bone) into seven bones. The one possible sign that he was preparing to diverge from established tradition was subtle, to say the least. His dedication to the royal physician of Charles V, Doctor Narcissus Parthenopeus Vertunus, contained Vesalius’s statement of intent: “If I shall find this work acceptable to you and to students, someday I hope to add something greater.” It is likely Vesalius was well aware of how his Tabulae would be received. Many physicians were opposed to illustrations, because they thought that images would degrade scholarship and trivialize that great learning found in classical works containing only text. So while they were popular with students, the Tabulae were not considered of great value by academics. Vesalius, though, was undeterred. He saw a great opportunity and decided to embark on a new editorial project, one that would complement his illustrations with an authoritative text. Later that year, Vesalius edited a new edition of Guenther von Andernach’s medical text, under the title Institutiones Anatomicae, Secundum Galeni Sententiam. Popular among medical students, the book provided a synopsis of the anatomical writings of Galen. A few years earlier, when he had been a young student of

16 17 A Slow Departure From Galen

Fig 5.1 In 1538, Vesalius published six anatomical tables (Tabulae Anatomicae Sex), which he used to teach his students.

Guenther’s, Vesalius had helped him with the dissections, a fact noted in the first edition of the Institutiones:

“with the assistance of Andreas Vesalius, son of the apothecary of the Emperor, a young man for which I have high expectations, for Hercules, talented and dexter- ous in both language and dissection of the body, after a long disquisition on the parts [of the body], we came to this conclusion.”

Vesalius corrected many errors that had appeared in the first edition of Guenther’s book. Out of respect to his old teacher, Vesalius attributed the errors to misprints (Castiglioni, 1943). His work on the book provided Vesalius with ample opportunities to revisit Galen’s opinions, and to identify factual errors in Galen’s work by comparison to the actual human anatomy he observed during his dissections. The more he questioned Galen’s findings, the more Vesalius became fully conscious of a new approach to knowledge—one based on direct anatomical observation “to corroborate speculation” (Vesalius, 1539). 18 BRAIN RENAISSANCE

TheVenesection Letter that he published in 1539 can be considered the first mani- festo of his new philosophy: in it, Vesalius set out his views on whether the correct method for bloodletting should be based on the teaching of classic authorities or on newly gathered empirical evidence. Unsurprisingly, he introduced new anatomical evidence in support of a modern approach. The true value of his contribution, though, is less in the content of his letter and more in his argument that evidence should be gathered from direct observation, not from mere theoretical disquisition. In publishing his letter, Vesalius had laid out the foundation of the scientific vision that would become the leitmotif of his masterpiece.

6 The Making of The Fabrica

With the enthusiasm of youth, his deep knowledge of the shortcomings of classical anatomy, and armed with a unique talent for performing accurate dissections, Vesalius came to a bold decision. He dared to challenge conventional medical beliefs and shake the academic establishment by producing an unprecedented informative atlas of the human body. He knew it would require the dissection of numerous bodies and a team of talented artists and engravers; an endeavor that eventually took him almost five years to complete. In 1543,De Humani Corporis Fabrica (On the Fabric of the Human Body) was published: it was immediately recognised as a triumph of the Renaissance spirit in medical science. The Fabrica is composed of seven books, almost seven hundred pages, and more than two hundred illustrations. It is a monumental work. Vesalius coordinated the entire project from start to finish. He worked tirelessly, almost obsessively, writing and creating, dissecting and drawing, and overseeing the illustrations and their woodcutting, often taking body parts home with him so that he could fit more work into his day. Vesalius contributed a significant number of figures himself, but it is clear that the Fabrica is the work of more than one man. There was a heavy reliance on artistic collaboration, especially with Stephen Calcar, a young Flemish artist, who had been working in the Venice workshop of the great Renaissance artist Titian (Figure 6.1). The volume of work was so great, however, that there is good reason to believe that the team illustrating the Fabrica extended beyond Vesalius and Calcar. Considering every illustration at the same difficulty of realization, each would take at least 10 days to complete (Ivins, 1943; McLeod, 1996). It would have been difficult or impossible for only two men to keep up such a fast pace, especially over less than five years—even more so if one considers evidence suggesting that the Fabrica was completed more quickly than this. In fact, Vesalius himself indicates that there may have been additional help. Three years after publication, he wrote that all was not happy during the illustrative process, alluding to a poor attitude among the wider team, mentioning “bad temper of artists and sculptors [wood- block cutters] who made me more miserable than did the bodies I was dissecting” (Vesalius, 1546). Vesalius submitted the first two books of the Fabrica to the publisher in 1541. This left him and his team just one year to complete the writing and illustration of

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Fig 6.1 A young Andreas Vesalius (left) in a portrait by Stephen Calcar. Calcar studied with Titian, who made a portrait of Vesalius later in life (right).

the remaining five books. A challenge they met. The rest of the book was submitted to the publisher at the beginning of August 1542 (Saunders and O’Malley, 1950). Even though the content of the Fabrica was mostly created in Padua, it was printed over the Alps, in Basel. Why Vesalius decided to ship the whole work some 500 kilometers north when he could have used a more convenient local publisher is not officially known (Cushing, 1943; Lambert et al., 1952). Basel was an expensive option, making the choice unusual for a man known to be careful with his money. But then again, Vesalius trusted his friend Oporinus as a reliable and talented printer. Robert Winter, Oporinus’s former partner in Basel, had, after all, already produced Vesalius’s Paraphrasis and the Venesection Letter. Vesalius’s reasons may also go deeper than mere friendship. By publishing his masterpiece with a Venetian printer, he could have placed himself in a difficult position. Between 1538 and 1541, while Vesalius was working on the Fabrica, many academics agreed to contribute to another text, the entire translation into Latin of the work of Galen (Opera Galeni). Edited by his friend and mentor Joannes Battista Montanus, the book was a major project of the influential Venetian publisher Giunta. Vesalius might have suspected, whether rightly or wrongly, that submitting his Fabrica with such a strong anti-Galenic stance to the Giunta firm, would have given the publisher reasons to delay the release of Vesalius’s book. There was little chance of this with Oporinus. On September 5, 1542, Vesalius wrote to Oporinus giving him precise instructions on how to print the Fabrica. He urged him to preserve the plates “faultlessly and elegantly” and keep firm control over them not to allow their distribution without 21 The Making of the Fabrica his approval. Such was Vesalius’s fear of intellectual theft that he went as far as to obtain special permission from the Venetian Senate “warning everyone not to print the plates without his consent’’ (Saunders and O’Malley, 1950). A few weeks later, Vesalius left Italy for Basel, where he intended to remain for the whole period of printing. While in Basel, Vesalius made another lasting contribution to medicine in producing what is still considered the world’s oldest anatomical preparation. Jakob Karrer von Gebweiler was a notorious murderer who was publicly beheaded in Basel for his crimes. Together with the surgeon Franz Jeckelmann, Vesalius boiled the felon’s body, removed his flesh, and reassembled his bones into a complete skeleton (Figure 6.2). The specimen was presented to the University of Basel for public exhi- bition and is still on display today. The Fabrica was finally published in June 1543. Its remarkable detail was impres- sive to many but its immense length less so to others. Having foreseen this problem, Vesalius produced a second smaller book, one intended to accompany the publication of the Fabrica. TheEpitome , designed with students in mind, was released two months later, in good time for the start of the medical school year. Despite a reduced

Fig 6.2 The skeleton of Jakob Karrer von Gebweiler prepared by Andreas Vesalius and Franz Jeckelmann in 1543 and still on display at the Anatomisches Museum of the University of Basel. 22 BRAIN RENAISSANCE number of illustrations and much less text, it had the great advantage of containing large figures that could be cut out to compose a manikin of different layers—from the nude skin right down to the bones. Within months of publication, the Fabrica and the Epitome had become the standard texts for many students, anatomists, and physicians alike. In short, Vesalius’s work had become a sensation.

7 Dissecting the Fabrica

The seven books of theFabrica are dedicated to separate aspects of the human body: (1) bones, (2) muscles, (3) arteries and veins, (4) nerves, (5) internal organs of the abdomen, (6) internal organs of the chest, and (7) brain. Compared with other anatomy books of the time, this order is itself a point of departure from tradition. While Guenther von Andernach’s Institutiones, for example, follows an order that goes from the abdomen to the chest and then to the head and limbs, Vesalius devised his own approach. His new arrangement was probably motivated more by practicality than by a desire to distance himself from the work of other anatomists. The availability of whole bodies and soft-tissue specimens was unreliable and the ability to preserve body parts limited. Bones could be obtained much more easily, and, once boiled, could be used indefinitely. The best that could be hoped for with muscles, arteries, and veins was to preserve them at lower temperatures, restricting decomposition to a matter of weeks. Preserving the visceral content was even more problematic. The abdomen and chest would putrefy in a matter of days, while the brain, without fixa- tion, liquifies within hours. Vesalius probably started working on his Fabrica using what was most easily available to him and to the artists. He needed just one skeleton for the bones but, as we shall explain later, at least six heads for the seventh book on the brain. This order is also the most logical one if the goal is to comprehend the structure of the human body in its entirety. Start with the skeleton and cover it with the muscles, which are perfused by blood vessels and controlled by nerves; then add the abdominal and thoracic cavities filled with their contents, all of which serve the supreme organ of the brain. It is a logic that we still follow today and which was utilised in many later anatomical works, including the celebrated Gray’s Anatomy when it was first published in 1858. The first book of theFabrica concentrates on osteology. It includes 60 chapters spread over 168 pages, within which Vesalius rejects Galen’s descriptions of those bones that were dissected in animals but lacked correspondence in humans. A prime example is Galen’s division of the sternum (breast bone) into seven bones, which is typical of apes but not humans, an erroneous observation Vesalius himself repeated just five years earlier in his Tabulae. His use of illustrations is also peculiar. Small figures are placed between individual chapters, sometimes inter- spersed within them. Some of these figures are not of outstanding quality and

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Fig 7.1 The three skeletons at the end of the Fabrica’s first book on the anatomy of bones. perhaps were made by Vesalius himself. But three much larger figures of complete human skeletons are positioned at the end of the first book (Figure 7.1). They convey a message that goes beyond mere anatomical description. All of them seem alive and engaging with their own mortality, with the finite quality of the human condition. The first skeleton leans on a spade with his head toward the sky, seemingly resting after the hard work of digging his own grave. With one arm open, he could be reciting the Lord’s Prayer. The second skeleton is more contempla- tive, with legs crossed, head propped up on his left arm resting on a tomb, the spare hand grasping a skull. It is an image that might have inspired Shakespeare’s description of Hamlet talking to a skull. It is certainly the image that was copied by Hans Holbein the Younger the year of his death in 1543. The third skeleton clasps his hands together in a position of prayer, sorrow, and despair. As a series, these three skeletons leave the reader thinking beyond anatomy and wondering more about philosophical aspects of life. They are skeletons with a soul speaking to the human condition. The originality of these drawings is the use of artistic poses for skeletons. Their poses were certainly borrowed from the classic Greek statues and Renaissance’s paintings and frescos. The first skeleton, for example, stands in the pose that is typical of Greek stautes of the ‘leaning satyr’. The third skeleton is reminiscent of Adam covering his face with both hands depicted in the ‘Expulsion from the Garden of Eden’ painted by Masaccio in 1425. Hence, the skeletons testify the influence that Art had on Vesalius’s anatomy and Vesalius’s anatomy on Art. This is a theme that applies also to the figures of the second book of the Fabrica. The second book of the Fabrica, on muscles, is the most voluminous, with 288 pages and 62 chapters. The position of the figures is contrary to that of the first book. Fourteen large drawings dominate the opening pages, followed by a series Fig 7.2 When 13 of the 14 images of the second book are put together, an Italian landscape emerges in the background. It has been speculated that the landscape is reminiscent of what must have been a town in the vicinity of the Euganean hills, perhaps Padua itself. 26 BRAIN RENAISSANCE of smaller figures at the beginning of each chapter. These large figures are flayed bodies, seven seen from the front, six from the back and one from the left side. The complex arrangement of their muscles and tendons is on display, the anatomical details are astonishing. The figures could be easily used nowadays to teach medical students. The bodies are not dead but standing and posing to reveal the intimate details of their inner constituents. When the figures are linked together, their backgrounds reveal an urban townscape (Figure 7.2) (Jackschath, 1903; Lambert et al., 1952); the river, churches, arcaded buildings, and bridges are highly suggestive of Padua itself. The third book, on the blood supply of the vascular system, has 59 pages and a smaller number of figures compared with the first two books. Throughout its 15 chapters, there are only two one-page illustrations: one before the fifth chapter and another before the twelfth. A large image appears as a double-page spread at the end of the book, the largest of all the illustrations in the Fabrica. This is a comprehensive map of the body’s arteries and veins, a useful tool for the Renaissance doctors whose principal therapeutic intervention was blood letting from the extremities. Here the use of the images is also intended to inform the reader of the marvelous complexity of the human body. The fourth book is dedicated to the peripheral nervous system. Its 40 pages and 17 chapters make it the shortest of the seven books, perhaps owing to the limited practical value that a detailed knowledge of the peripheral nerves had for the barber-surgeons of the time, or the difficulty of discerning their paths, and their functions at that date. While the illustrations are informative, they lack the artistic quality of the first three books, which suggests that they may have been the work of a different artist or Vesalius himself. The fifth book, on the internal abdominal organs (splanchnology), consists of 104 pages, but, unlike the books before it, it includes very few figures, all of which are placed at the beginning of the book. Except for the figure in the frontispiece, this is the only place in the Fabrica featuring images of the female body. The need to show the reproductive organs makes the use of the female form in the fifth book crucial, but the motivation for not using it in others is less clear. The most likely explanation is one of both practicality and preference. Female corpses were rarely available to anatomists, as there were fewer women executed for crimes. This fact would not have worried most anatomists, as they generally preferred the strong, muscular composition of the male form. But medical students in Padua have been reported complaining of the lack of female bodies for dissections. Death from birth was indeed one of the leading causes of mortality at the time: anatomical knowledge of the female anatomy was paramount to save the lives of their pregnant clients. The Fabrica’s sixth book focuses on the organs of the chest, including lungs and heart. It is 46-page long and contains 16 chapters. All 13 of its figures are placed at the opening of the first chapter. The lower quality of these images, many of which fail to clearly illustrate anatomical details, suggests that they may have been made by Vesalius himself. Of particular interest is the second figure, where the chest is open to show the organs contained in it (Figure 8.1). The trousers left on the cadaver and 27 Dissecting the Fabrica the rope still around the neck indicate that little time has lapsed since his execution. Perhaps this is the dissection of the body in which Vesalius observed the heart still beating, a confession that he had prudently removed from the second edition of the Fabrica to avoid being accused of human vivisection. The seventh and final book is dedicated to the brain and sense organs. It consists of 60 pages with 19 chapters, the first 13 of which are devoted to different structures of the brain, 14 to 17 to the organs of sense, and the final 2 to the methods of brain dissection and vivisection. There are 11 large figures of open skulls, all from male bodies (see Appendix). Vesalius used at least six heads for these illustrations. As was usual at the time, the dissections were performed in situ, leaving the brain inside the skull, while progressively cutting away slices, generally in horizontal sections. The images of the brain are remarkably realistic, and they show a number of distinct features, which go unexplained in Vesalius’s text. A good example is that of the gyri, the convolutions that make up the characteristic ridges of the brain. Vesalius’s second figure illustrates the exact orientation of the three longitudinal most anterior gyri of the frontal lobe as well as the vertical direction of the precentral and postcentral gyri in the frontal and parietal lobes (Figure A2 in the Appendix). It would be another two hundred years before this division was officially defined. Also in many figures Vesalius separates the white and gray matter (Piccolomini, 1586). In Figure A7, the head of the caudate nucleus and the putamen, the two nuclei of the striatum, are drawn in great detail. These nuclei would be formally named by Thomas Willis only in 1664 (Willis, 1664). The cortex of the insula, a structure “discovered” by Felix Vicq d’Azyr and Johann Christian Reil 350 years later, is also clearly visible (Vicq d’Azyr, 1786; Reil, 1809). The Fabrica ends with a detailed index of words and names in which Galen is mentioned more than two hundred times. Compare this to Aristotle, with 28 citations, Hippocrates with 8, Plato with 3, and Avicenna with 2. Many of Vesalius’s contemporary anatomists are cited just once; we are thus provided with a candid insight into Vesalius’s aims. While many of these citations are included in order to flatter and credit those who produced original anatomical descriptions, Galen’s citations do not constitute an endorsement. To Vesalius, most of the mention of the Greek physician only served to highlight his mistakes. It is therefore very clear what Vesalius had in mind when he published his Fabrica: to demonstrate that his anatomy was superior to that of Galen and, by doing this, to impose himself as the new Galen of his time.

8 Vesalius and Venice

Vesalius left no clues on where the Fabrica was actually prepared. It is often reported that the Fabrica was realized in Padua, where Vesalius was living and working. Padua is only 40 km from Venice and at the time was part of the Serenissima republic of Venice. All administrative and political matters, including academic appointments at Padua’s university, were decided in Venice. Between 1538 and 1540-years in which Vesalius was intensively working on the Fabrica-Marcantonio Contarini, a member of one of the most influential Venetian families, was podesta’ (chief magistrate) of Padua. According to Vesalius, who mentions him in the eighteenth chapter of the seventh book of the Fabrica, Contarini facilitated his access to the ‘fresh’ bodies of executed criminals (see Chapter 30). Vesalius also seems to have been well-connected among those Venetian Senators and Governors who were deputed to decide the timetable for executions, which provided the corpses for public dissection in Padua. Vesalius seems to have been able to request that certain executions be delayed until he was ready to use the bodies, and had assembled the artists with whom he intended to work. It is also likely that Vesalius performed some dissections in the city of Venice. Here, executions occurred more frequently than in Padua, where students notoriously complained about the scarcity of corpses for their studies. Venice was also a convenient location for the artists of the Fabrica. Titian’s studio, traditionally associated with the Fabrica, was located in the area of Fondamente Nove, not far from where the civil hospital of Saints Giovanni and Paolo stands. The hospital hosts St Mark’s School of Medicine, an old confraternity that was responsible for the anatomical dissections carried out by decree in Venice since 1368. Vesalius would have performed his anatomical dissections at this medical school with his team of artists only a couple of streets away. Throughout the years Titian’s studio had developed an expertise in the technique of printing drawings by xylography (wood cutting). This technique required close collaboration between the artists and the woodcutters: the image was trans- ferred in reverse onto the surface of a wood-block, and the white areas were then carved away, leaving the design standing proud to take the printing ink. The technique had the advantage of allowing the printing of images and text on the same page. Vesalius chose this technique to print his Fabrica. While Titian was certainly not the artist that worked directly on the images, there is little doubt that his assistants

28 29 Vesalius and Venice and craftsmen were able to offer the know-how to guide Vesalius as he created his masterpiece. There is also another important element that points toward Titian’s studio as a vital cog in the production of the Fabrica. Titian and his collaborators had benefitted from the commissions and friendship of some of the most influential Venetians and their families. Among them was Domenico Grimani, the son of the 70th Doge (head of state for the republic of Venice), an art lover whose outstanding private collection included some of finest Greek and Roman statues in Italy. Grimani generously made his collection available to Titian and other Venetian artists to study. The statues of the Galatians (gladiators) were in the Grimani’s collection and Titian is well known to have used these as models. His painting, the Martirio di San Lorenzo (The Martyrdom of Saint Lawrence), features the Dying Galatian, while the Dead Galatian is similar to one of the figures in the 6th book of the Fabrica (Figure 8.1). The Grimani’s collection, which is now part of the National Archeological Museum at the Correr museum in Venice, opened in 1523. It immediately attracted young Venetian artists who hoped the many sculptures would be a constant source of inspiration. The influence of this classical iconography went beyond the large drawings of the Fabrica. Putti are chubby male infant motifs often portrayed in Greek and Roman

Fig 8.1 The statue of the Dead Galatian (left) from the Correr Museum (Grimani’s collection) and the second figure of the sixth book of theFabrica (right) bear a close resemblance. 30 BRAIN RENAISSANCE

Fig 8.2 The putti in a relief from the ‘Throne of Saturn’ st(1 century AD) holding the sickle and the scepter of the god (from Archeological Museum of Venice) (left) and the putti from the first decorated initial of the Fabrica (right). reliefs. Their revival during Renaissance brought about their first known use in medical illustration when Vesalius chose to incorporate them into his Fabrica. The decorated opening letters of the Fabrica use putti to tell the unique story of how to procure, prepare and dissect the bodies of animals and humans (Figure 8.2). Owing to the artistic influence Vesalius received from his Venetian collaborators, the Fabrica became a book of two tales. The text moves along a serial path, a sequential description of parts and actions that helps the student to assimilate a vast amount of factual knowledge and to be able to repeat the same procedures at the dissection table. The figures, especially those with a large format, linked to one another by a flowing landscape, give a comprehensive view of human anatomy, and show how individual parts are harmoniously arranged together to form a single body. Vesalius was thus able to explain the finest details of human anatomy with his words, while constantly reminding us with his illustrations of the unity of man. Here he differs from Leonardo, whose drawings deal more with single parts, a zoomed-in look into the structure and working of individual organs, muscles and bones. Vesalius, instead, dissects the body down to its single parts, but always recomposes them into a unitary entity: the fabrica of the human body. Vesalius had therefore a mission that went beyond anatomy. Understanding the unity of the body from its single parts meant understanding the human condition. This could explain why he suddently decided to leave anatomical teaching and return to Brussels. Armed with his deep anatomical knowledge he was now ready to apply it to the living, this time as physician at the court of Charles V.

9 A Life Among Eminent Men, with Many Honors and Gifts

Vesalius was well aware that in the Fabrica he had produced a masterpiece. He implicitly stated as much in an inscription borrowed from Virgil on the plinth of one of the large illustrated skeletons shown in the first book of the Fabrica: “Vivitur ingenio, caetera mortis erunt” (the genius lives on, all else is mortal). Not everyone agreed, though. Criticism of the Fabrica was fierce, especially from those who opposed Vesalius’s anti-Galenic spirit. It was painful for Vesalius to acknowledge that Jacob Sylvius and Guenther von Andernach, his old mentors back in Paris, were among his harshest critics. Sylvius did not hold back when he described Vesalius as a “very ignorant and arrogant man who, through his ignorance, ingratitude, impudence, and impiety denies everything his deranged and feeble vision cannot locate” (Simeone, 1984). Insultingly addressing him as Vaesanus, the common Latin word for a madman, Sylvius wrote to Charles V, asking that his former pupil receive a heavy punishment for poisoning the air of Europe (Castiglioni, 1943; Dunn, 2003). He furiously denounced Vesalius’s work as being of such limited value that it could have been reduced to “a single sheet of paper provided the illustrations were omitted, which are not worth anything anyway” (Simeone, 1984). Or perhaps this reaction had not surprised Vesalius at all, since he intended to indirectly attack the teaching of his mentors while criticizing Galen’s anatomy. Indeed, Vesalius’s approach to anatomy was much closer to Galen’s philosophy than his Parisian teachers. Galen had used his anatomy and vivisections as the only basis for his philosophical ideas. He refused to speculate beyond experimental evidence (Manzoni, 2001). Vesalius did not shy away from this conflict. Two years after publication of the Fabrica, he wrote a letter ostensibly appraising a fashionable herbal remedy, the china root, but which in reality concentrates on vigorously defending his own anatomical work. Confident in his beliefs and knowing that they were derived from direct evidence gained at the dissection table, he attacked the Galenists by taking aim at their Achilles’ heel—their ignorance of human anatomy. Of his Parisian mentor, Guenther von Andernach, Vesalius wrote, “I reverence him on many counts and in my published writings I have honored him as my teacher. He is largely indebted to me for whatever he knows of anatomy apart from what is in the books of Galen. My mentor never used a knife except at the dinner table” (Vesalius, 1546).

31 32 BRAIN RENAISSANCE

It has often been said that Vesalius was so discouraged by the outcry against his Fabrica that he decided to burn his manuscripts, leave the University of Padua, and end his academic career (Nutton, 2012). There is evidence, though, that for a while at least, Vesalius enjoyed a period of celebrity. While some in Europe denounced his ideas, many Italian anatomists embraced them. Admirers of his work soon began inviting him to perform public dissections and contribute to anatomical debates. Vesalius traveled to Bologna, Pisa, and Florence, where he was provided with corpses and facilities to perform his dissections in public. In Italy, the medical world wanted to hear him speak, and to see him in action. Documented evidence of the warm reception Vesalius received in Pisa in January 1544 shows that Cosimo I de’ Medici, duke of Florence and renowned patron of the arts, ordered his private secretaries to obtain two fresh bodies for Vesalius to dissect before an audience (Corsini, 1915; Cushing, 1943). At Cosimo’s instruction Marzio Marzi, the bishop of Pisa, requested “two human bodies be taken from the Hospital of Santa Maria in Florence, put in a coffin and sent to Pisa by boat on the Arno river.” This request was highly confidential because the law held that only the bodies of convicted felons could be dissected, as part of their punishment. Instead of two men, however, they received the body of a nun. Vesalius stayed in Pisa for three weeks, long enough to dissect also the bodies of other two people, one of a 17-year-old hunchback girl who had died of pneu- monia, the other of a male jurist, Marcantonio Bellarmati, who had befriended Vesalius while still alive. People flocked to see the great anatomist in action. So much so that January 30 1544 was declared a public holiday to allow more locals to attend. On each occasion the packed anatomical theater thronged with excite- ment. Students jostled one another in order to obtain a closer glimpse of the organs. Spectators engaged in lively discussion. Supporters of Galen shouted their detractions while Vesalius championed his own views, often simply by pointing to the body before him. High above the dissection table, many leaned dangerously forward to obtain a better view. At one point Carlo Cortese, a local surgeon, fell from one of the upper benches, the impact leaving him with life-threatening injuries (Ciranni, 2010). The people of Pisa were enthralled by the skill and knowledge on show. One of the duke’s secretaries wrote in a letter that “Vesalio is praised for his abilities and in all his lectures he continuously challenges Galen and Aristotle, and they cannot stand the comparison with him on the matter of anatomy.” (Ciranni, 2010). Cosimo de’ Medici even offered Vesalius a position in Pisa, stating money to be no object. Vesalius politely declined. The truth is that Vesalius had already decided on where his future lay. He wanted to return home. With Charles V soon to be at war with the French again, the king needed more military surgeons and so offered Vesalius a position. It was an opportunity too good to turn down. The move back to Brussels coincided with a period of great upheaval in the anatomist’s life. Within months he was married to Anne van Hamme, the daughter of a rich councilor and master of the Chamber of Accounts of Brussels (Saunders and O’Malley, 1950). And then, in the winter of 1544, his father 33 A Life Among Eminent Men, with Many Honors and Gifts died. Vesalius thus acquired a substantial inheritance, one that included the family residence—the perfect place in which to start his own family. In July 1545, Vesalius’s daughter, Anne, was born. At the age of 31, he found himself an accomplished man in both his professional and private life. But his ambitions were higher still. He aspired to attain what Doctor Narcissus Parthenopeus Vertunus had accomplished before him, as Vesalius clearly alludes in the dedication of the Fabrica:

“I have ventured to ascribe it to the fame of your name, partly because, in addition to an incomparable command of various tongues, you have gained an extraordinary and singular knowledge of anatomy as well as of medicine and philosophy, so that you are deservedly regarded by the most erudite of all nations as a distinguished leader and ornament of the most skilled physicians and lit- erary men. Partly because among the most famous you prevail by prudence of mind, integrity and extraordinary gentleness and sweetness of nature toward all, so that Charles the Fifth, the invincible and ever august emperor of the Romans, a most penetrating judge of ability, especially established a position for you, not only to guard his health or to regain it if lost, but also appointed you in the very prime of life as the most trusted censor over all physicians and pharmacists of the kingdoms of Spain and Naples and has singled you out most splendidly, even among so many eminent men, with many honors and gifts.”

When Vesalius sat down to write this dedication to Doctor Narcissus in 1538, his family history may very well have been at the forefront of his mind, leading Vesalius to imagine an illustrious path for himself through the imperial medical rankings. A dream that in part he never fulfilled.

10 From Anatomy to Surgery

Vesalius, with his own “command of various tongues” and having already “gained an extraordinary knowledge of anatomy,” reckoned that an ascension to a position with “many honors and gifts” could be accomplished only by becoming the most trusted of all the physicians in the kingdoms of Charles V. Becoming a surgeon was not just the most convenient step in his career but also a fine opportunity to put his knowledge of the human body to the test. After all, anatomy was not an end to itself but an obligatory step in the pursuit of medical excellence. By resigning his academic position in Padua, Vesalius made the conscious decision to prove that what he had learned from the dead could serve the living. In the two decades that followed the publication of the Fabrica, Vesalius the anatomist became Vesalius the surgeon. It was a humbling time for him. Going from the comfort of the academic arena, where he had risen quickly to the status of a “great anatomist,” to the apprenticeship of a young military surgeon, was difficult professionally. Moreover, the extreme injuries suffered by the soldiers took their toll emotionally. Things did not start well, many commenting on their surprise that the anatomist did not excel in surgical procedures. Disarticulating limbs on the living provided very different challenges compared with those of the dead. Wound dressing required an altogether whole new set of skills. Vesalius worked hard, just as he had in anatomy. His confidence grew; his surgical approach began to show originality of thought. No more so than in 1545, when a knight called Busquen was brought to his attention. The soldier had a fever and complained of extensive pain in his leg. Inspecting the swollen and infected limb, Vesalius knew he should amputate but instead chose to try something new— the draining of the purulent material. To the surprise of many, the young knight recovered and the incident became one of the earliest documented operations for the conservative relief of a bone infection (osteomyelitis) (O’Malley, 1964). A similar procedure was then pioneered for abscesses in the chest. By cutting open the pleural cavity, the pus that had accumulated around the lungs (empyema) could be drained. With time, Vesalius’s interests also began to diversify. His interest for herbal remedies intensified, while in his spare time he began writing letters to patients advising them on medical conditions such as epilepsy, even though they had no particular surgical relevance.

34 35 From Anatomy to Surgery

None of this went unnoticed. Slowly and progressively Vesalius’s reputation as physician rose high. The attention of prominent surgeons and powerful individuals was engaged. Charles V began entrusting him with the most difficult or notable cases often on nobel figures whose lives where deemed of special value. Among the most notorious Francesco d’Este (1544), son of the Duke of Ferrara Alfonso I d’Este; the Venetian ambassador Bernardino Navagero (1546); Lucrezia Borgia, the daughter of Pope Alexander Sixth (1546); and Maximilian of Egmont, Count of Buren and a commander of the Holy Roman Emperor (1548), to name a few. By now Vesalius was settled in Brussels. He had established a lucrative private practice, alternating his role as a physician with that of a post-mortem dissector. Wealth began to accumulate, as did further anatomical observations. During the endless surgery and post-mortem examination, Vesalius’s passion for anatomy never dried up. He continued to take detailed notes, record novel observations, and attend to those things that had been missed or printed as errors in the Fabrica. It soon became clear that a revision of the first edition was required. A second edition of the Fabrica was eventually published in 1555. Vesalius added details in many of his descriptions and numerous new observations. In Book III, for example, Vesalius reports the presence of valves in the veins, as observed by his friend Giovanni Battista Canano a few years earlier. To Vesalius, the valves were fibrous rings that acted as supports for the soft venous walls when in fact their function is to facilitate the return of blood toward the heart (O’Malley, 1964). It would be another eighty years before William Harvey, another medical student graduated in Padua, would announce his discovery of the circulation of the blood based on several anatomical observations, including those made by Canano on the orientation of the valves. In Book V, Vesalius greatly improves his description of the fetal membranes using observations made while dissecting embryological specimens. The changes made to the second edition also reveal a more prudent attitude toward vivisections. In one paragraph, where he had previously discussed the beating heart of “two men that had just been killed,” the account is corrected—he explained that one died in an accident and the other by execution (Book VI). Perhaps unsurprisingly, his earlier mentions of grave-tabbing was also removed. But the most significant changes were reserved for the section dedicated to the acknowledgments. Over a decade might have passed since the first edition, but all was not forgotten. Some anatomists cited in the first edition found themselves removed either because they were deceased, like Narcissus Parthenopeus Vertunus and Johannes Centurius of Genoa, or because they had openly criticized Vesalius’s work, such as Johannes Dryander and Realdo Colombo. Not surprisingly, the name of his mentor Jacobus Sylvius was struck out and replaced by an allusion to him, one that complains of the “calumnies and utterly false disparagement of certain mali- cious old men consumed by ill will.” By 1556, at the age of 42, Vesalius had it all. With the second edition of the Fabrica published, an elevation to the high rank of Count Palatine confirmed, and a lifetime pension to complement his comfortable income, he stood at the pinnacle of his career. But driven by the hostility and jealousy of others, this success soon turned 36 BRAIN RENAISSANCE to misfortune. Within a year, Charles V, who held Vesalius in such high esteem, had abdicated, and his son Philip II took his place. This new heir kept Vesalius on in his role of imperial physician, but the anatomist’s political power began to wane. Philip II, having been raised in Spain, preferred to trust the word of Spanish physicians— those still dedicated to the classical medical texts. It became increasingly clear to Vesalius that under Philip II he would never reach the rank of protomedicus (the highest position in the royal medical hierarchy), the one title he longed for. To make matters worse, a series of incidents meant that Vesalius’s medical abilities were soon called into question. In 1558, there was a misdiagnosis of Anna Van Egmont, wife of William I “the silent,” with melancholia. Within a few days she was dead. Then, in the summer of 1559, Vesalius was asked to examine Henry II, king of France, who had sustained a serious injury caused by a wooden lance, which pierced his skull during a jousting tournament (O’Malley and Saunders, 1946). Upon arrival at Henry’s bedside, Vesalius asked the royal patient to bite a white clean cloth, which he then pulled with force from the king’s mouth. Such was his cry of pain that Vesalius announced that the brain injury would be fatal. It was a subdural haem- orrhage and there was nothing anyone could do. France, Vesalius declared, should prepare itself for the imminent death of its king. The loss of such high status lives left many harbouring ill feeling toward the Flemish physician. The cardinal Anthony Perrenot de Granvelle summed up the sentiment when he wrote in 1559: “he always declares them mortally ill so that if they die, he is excused and if they live, he has performed a miracle”.

11 Desolation in Spain

Toward the end of 1559, Philip II decided to move his court from Brussels to Madrid. Vesalius followed but struggled to adapt to life in a new country. He is not listed among the royal physicians of the time and his medical services were mainly limited to members of the embassies. The bigoted religious atmosphere began to feel stifling. As a devoted Catholic and supporter of the Spanish inquisition, the king laid down laws aimed at restricting individual freedom of thought. Because the king forbade Spaniards from studying at foreign universities, the country was rapidly plunged into an intellectual isolation. Vesalius found his opportunity for dissections limited, complaining that it was impossible to even obtain a skull for his studies. Now in his mid-forties, and acutely conscious of being an outcast, Vesalius looked back at his time in Padua with growing nostalgia. Such feelings were not helped, when, in 1561, Vesalius received a copy of the Observationes Anatomicae by Gabriele Falloppia, the man who had succeeded him as professor of anatomy in Padua. Within this book, Falloppia provides an unillustrated commentary of the Fabrica, the main text he used for his teaching and one he truly admired. But this did not prevent the younger professor from comparing the details of the book with his own direct observations. The Vesalian method was being used to interrogate Vesalius himself. By seeking the truth through direct observation of the human body rather than taking for granted what the great anatomists before him had written, Falloppia began to highlight some incorrect observations made by the “divine Vesalius”—a wording that complements those used by Vesalius toward Galen. However, unlike Galen, Vesalius had the opportunity to reply. In December 1561, he wrote a personal letter to Falloppia—the Anatomicarum Observationum Gabrielis Fallopii Examen. This is a 260 pages long document that Vesalius asked Paolo Tiepolo, the Venetian ambassador to Spain, to present to the Paduan anatomist on his return to Venice. It offers a remarkable insight into Vesalius’s mood at the time.

“Three days ago, my dear Falloppia, I received yourObservationes anatomicae through the kindness of Gilles de Hertogh, physician of Brussels. I was greatly pleased, not only because it was produced by you, who are considered highly skilled in the dissection of the bodies as well as in the other parts of medicine, but also because it is the product of the Paduan school, the most worthy in the

37 38 BRAIN RENAISSANCE

whole world, where for almost six years I held the same chair you now occupy. . . . I sincerely hope that you may long pursue your studies in that delightful leisure of letters and among those learned men who are so intent upon their studies, and with whom you can constantly compare your thoughts. I feel that the elaboration of our art has come from that arena, from which as a young man I was diverted to the mechanical practice of medicine, to numerous wars, and constant travel. . . . therefore may our common school, whose memory has always remained so dear to me, be further honored by the results of your talent and industry.”

Gone are the combative and sarcastic tones that peppered the correspondence of his youth. In their place is a wistful view of the Paduan school of anatomy. Vesalius may have recognized himself in the young Falloppia, which may explain his benevo- lent acceptance of the criticism. On many points he plainly agrees with Falloppia, openly admitting that mistakes had been made. In other passages he defends his position, particularly in response to Falloppia’s praise for Valverde—a man claimed to have copied the work of others, and to have posed off their discoveries as his own. But most importantly he expresses his regret for being unable to provide answer to some of the points raised by Falloppia due to the impossibility of studying anatomy in the conservative Spanish atmosphere (O’Malley, 1964). TheExamen is a wonderful example of Vesalius’s intellectual honesty. The reading of Falloppia’s Observationes signified the beginning of the end for Vesalius at the Royal Court. It confirmed feelings that had been brewing for some time—that it was time to head back to Padua and return to academia. But things moved much more slowly within the Spanish royal household: to swiftly resign from his court position and leave Madrid was impossible. It would be another two years before he set off, and Vesalius probably did not imagine that this journey would be his last. Having gained the king’s permission to leave Spain, Vesalius found that departure was not simple. His medical knowledge was still sought after throughout the court, even if his peers did not officially recognize it. This disparity often placed him in difficult situations, no more so than when he came to treat Don Carlos, the son of Philip II. Born in 1545, Don Carlos was the eldest son and heir to the throne. At the age of 17 he fell down a flight of stairs, sustaining serious head injuries. The Spanish royal physicians were immediately sent for, but within a matter of days Don Carlos’s wound had become infected and his condition deteriorated (O’Malley and Saunders, 1943). His chances of survival were now considered slim. Philip II decided to consult Vesalius. On one side of the bed now stood the Spanish physicians still promoting Galenic tradition while on the other was the great anatomist. The Spaniards engaged in lengthy consultations, debating all possible complications and outcomes as predicted by the teachings of classical medicine. At one point, the king became so exhausted by the confusion that he asked them to speak without “quoting so many texts.” The physicians scoffed when Vesalius, having based his diagnosis on anatomical knowledge and his experience as a surgeon, announced that the only chance of 39 Desolation in Spain saving the boy would be trepanation—the drilling of a hole into his skull. This was the only way to release the internal pressure caused by the infected wound. At first no one listened. As the patient’s condition worsened, desperation set in. Ointment from a Moorish quack named Pinterete from Valencia was applied to the wound, only to cause burning of the skin. Then the mummified remains of Friar Diego of Alcalá, who had died a century earlier and was reputed to have performed numerous miracles during his lifetime, were left beside Don Carlos’ bed (Simeone, 1984). In an uncontrollable rise of religious delirium, a parade of thousands of fla- gellants—flagellation being the mortification of one’s own flesh by whipping—was organized. Tensions escalated. A mob gathered, directing its anger at the inept physicians. Like everyone else, Vesalius was close to the end of his tether by the time it was finally decided to perform the surgical procedure he had suggested. Following an incision into the orbit and the extensive extraction of purulence from the wound, Don Carlos began to recover. Praise for Vesalius, though, was not forthcoming. Instead, Friar Diego was presumed to have conducted yet another miracle, this time from beyond the grave.

12 The Last Journey

Records of Vesalius’s last three years of life now become progressively murky. One of the most mysterious aspects concerns how he finally managed to convince the king to let him leave and why he then ended up on a pilgrimage to Jerusalem rather than Padua. The many theories could not be more wildly different (O’Malley, 1964). One report states that Vesalius was charged with human vivisection. After he was condemned to death by the Inquisition, the king took pity and commuted the sentence down to a pilgrimage to the Holy Land. There is, though, little direct evidence for this claim. Others suggest that Vesalius may have suffered an illness so grave that he was granted permission to leave Spain. But this account fails to explain why Vesalius chose to head for Jerusalem. On the contrary, evidence clearly shows that throughout his final year at the Royal Court there was no lessening of his medical duties. The motivation may not have rested in Spain at all but in the arid soil of the Middle East. Herbal remedies had become an increasing and enduring fascination for Vesalius. A trip to Jerusalem would allow him to dedicate time to the study of the indigenous medical plants, especially those known to grow throughout Palestine (Fraenkel and Franco, 1962). In fact, Bonifacio Stefano of Ragusa (now named Dubrovnik), a Franciscan friar who accompanied Vesalius during part of his journey, reveals that the anatomist spent many hours collecting herbal material while visiting Jericho and the Jordan River. Vesalius came to receive a special pass from the king and he finally left the increasingly insalubrious climate of Madrid in the spring of 1664. At the Spanish-French border, Vesalius had an argument with his family, which resulted in his wife and daughter continuing northward to Brussels rather than following him toward the east. Whether he realized or not, this was the fulfilment of a prophecy Vesalius had made upon leaving Padua as a successful young man: “He who espouses science must not marry a wife: he cannot be true to both.” Vesalius traveled from Marseilles to Genoa by ship and then on to Venice by land. Here he stayed for some time, perhaps meeting with influential members of the Republic in the hope that they would help him regain his position at the University of Padua. There is documental evidence of a meeting between Vesalius and some ‘distinguished physicians’ in the bookshop of Francesco de Franceschi who reported:

40 41 The Last Journey

“When not long ago Andreas Vesalius was about to set forth from here for Jerusalem he was greeted in my bookshop by Agostino Gadaldino, Andrea Marino, and some other distinguished physicians who had met together by chance, and they asked him what had happened to his Examen of the Observationes Anatomicae of Gabriele Falloppia, which Marino declared he had learned from Alessandro Baranzono had been given to a Venetian ambassador to carry to Padua. Vesalius replied that his Examen had indeed been given to Paolo Tiepolo, distinguished representative of the Venetian Senate, when he was departing from the court of King Philip. However, because of the civil war in France and lack of a trireme, he had been compelled to remain for many months in Catalonia and had returned to Venice very tardily. Falloppia, as they knew, had died and for that reason Tiepolo had kept the Examen, which could be readily obtained from him. Whereupon some of those who were present desired a copy of it, but finally everyone agreed that when it had been obtained from Tiepolo it be given to me and that I make it available to all in print. . . .”

According to Pietro Bizzarri, a sixteenth-century Italian writer and spy, Vesalius’s tactics worked, and “the illustrious Senate called Vesalius to the famous university of Padua, with a very honorable stipend, in place of the learned Falloppia, who a little earlier had passed to a better life” (Bizzarri, 1568). By this time, though, Vesalius had already set sail for the Holy Land. For the first par of his journey he was accompanied by Giacomo Malatesta of Rimini, a captain of the Venetian fleet. He toured Palestine for four months, showing far more interest in the local plants than the places of prayer. Beyond this we know very little of his activities. By the summer of 1664, Vesalius was ready to head home to Venice and Padua. Instead of waiting for one of the Venetian fleet, he boarded a pilgrims’ ship, perhaps with the aim of being back in time for the opening of the academic year. But he would never make it. Struck down by illness, he deteriorated rapidly and died during a stopover on the Greek island of Zakynthos (Zante). Accounts of his death are somewhat contradictory. Pietro Bizzarri tells us that:

“while he was traveling to Italy, driven by fortune and contrary winds, he went ashore on the island of Zante, where he was assailed by a sudden and grave illness, and within a short time he miserably closed and terminated the course of his life in a vile and impoverished inn in a solitary place, without any human assistance.”

In contrast, a direct account from Georg Boucher, a merchant from Nuremberg, suggests that Vesalius’s ship:

“driven for full forty days by storms, was unable to reach land. Many became sick, partly through lack of biscuit and partly through lack of water, and Vesalius’s mind was so disturbed by [the] casting of the dead into the sea that he fell ill, first through anxiety and then through fear, and asked that if he should die he might 42 BRAIN RENAISSANCE

not, like the others, become food for the fish. Finally, after being tumbled about in the sea, the ship reached Zante, and as soon as possible Vesalius lept down from it and made his way to the gate of the city, where he fell to the earth dead.”

Many other speculations about Vesalius’s death have come forward in the recent years, from starvation to scurvy (vitamin C deficiency) and plague (De Caro et al., 2014). Vesalius was buried in Santa Maria delle Grazie, a small church on the north side of the town of Zakynthos. This was the church where important foreigners were buried and claims have emerged that in the same church the tomb of Cicero was found (Sarton, 1954). The church has been destroyed by several earthquakes and in its place a private house adorned with a perennial hibiscus tree has been built. Vesalius never returned to Padua, but his spirit continued to live on through a new generation of Renaissance anatomists. The chair that was originally offered to him went to Girolamo Fabrici d’Acquapendente, who would teach Vesalian anatomy to his students for fifty years. Fabrici d’Acquapendente used Vesalius’s achievements as a motivation for his own. He designed the university’s first permanent theater for public anatomical dissections, from which he made his own important discoveries. His contribution to our knowledge of embryology and the functional anatomy of the sense organs made him known as “the father of embryology.” In addition, his description of how the venous valves were oriented toward the heart allowed William Harvey, his student in Padua, to discover the circulation of the blood. But of course Vesalius’s approach goes well beyond anatomy and medicine. Just as Leonardo da Vinci had abandoned his anatomical map in the year that another outstanding anatomist was born, Vesalius died in the year that another great Italian scientist came into the world. As professor of mathematics in Padua, Galileo Galilei introduced a new experimental scientific method, one based on direct observation and quantification of natural phenomena. Applied to medicine, this method com- bines the observation of anatomy with the language of mathematics. Put another way, the combination of the Vesalian approach to anatomy and the Galilean quantitative method represents the very foundation on which contemporary medicine is based. In 1564, the historical relay between the lives of these two great minds set the move of medicine into the modern era of experimental science.

Part Two The Fabrica of the Human Brain

13 The Brain Is Fabricated for the Sake of the Supreme Spirit, the Senses, and Also the Movement That Depends upon Our Will

THE TOPICS EXAMINED IN THE FIFTH AND SIXTH BOOKS1

In the previous two books, I dealt with the organs of nutrition. The former [Book V] described the organs that serve food and drink (whose principal bowels lodge the natural spirit) and the members dedicated to procreation, which have a contiguous position and connection with these organs. The latter [Book VI] reviewed the organs that are in charge of restoring the aerial substance and augmenting and recreating the innate heat: we mentioned that the energy of the vital spirit is situated primarily among these organs. There, we did not agree with the belief of the Stoics and Peripatetics,2 who stated that the supreme spirit is located in the heart or that the nerves take origin from this organ.

THE CONTENT OF THE SEVENTH BOOK

The origin of sensation, voluntary movement, and supreme spirit (by means of which we imagine, reason, and remember) remains to be mentioned. The present book will be dedicated specifically to this and will examine the brain, all its parts, and the organs of sense.

BRIEF ENUMERATION OF THE FUNCTIONS AND PARTS OF THE BRAIN

While the energy of the vital spirit instills the substance of the heart, the faculty of the natural spirit instills the liver’s own flesh. The liver produces the thicker blood and natural spirit,3 which is extremely murky, while the heart in turn produces the blood with the vital spirit that impetuously flows through the body. And these organs distribute the substances they produce to all parts of the body through dedicated tributary channels. In the same way, the dedicated districts of the brain take up the material necessary for its function, and by means of the organs specialized

45 46 BRAIN RENAISSANCE for this purpose, prepare the animal spirit, which is very clear and fine. Part of this is used for the divine operations of the supreme spirit and part is constantly distributed to the organs of sense and voluntary movement through the nerves and cords. This spirit, which is continuously supplied, is considered the principal promoter of the function of those organs. In fact, just like the liver and the heart, the brain leaves no part of the body without the materials they require (as long as the person is healthy), even though they do not always distribute them in the same quality and abundance. The nerves (whose origin is in the brain, as we indicated in Book IV) perform for the brain the same task that the great artery does for the heart and the vena cava for the liver.4 Like diligent assistants and messengers, they deliver the spirit prepared by the brain to those organs that need it. The vital spirit provides the material for the animal spirit as well, which is abundant in the series of arteries that reach the two cerebral membranes. The brain is also supplied with the air that, as we said earlier, is breathed in and conveyed to it through small cerebral openings.5 These are carved in the eighth bone of the skull, where the organ of smell is, and in particular where the skull faces the palate. When we breathe in, the air is sucked through extremely narrow, winding, and tortuous ducts between the hard and the thin cerebral membrane. In this way, the air is rarified by the hindered flow and then shaped by the brain. Wherever it finds its way through, the air insinuates into the right, left, and middle ventricle. Even if the vital spirit is present in copious quantity in all the vessels or ducts of the thin and the hard membrane, much of it is transported to the right and left cerebral ventricles by the principal branches of the arteries that, we explained, in opposition to Galen’s opinion,6 perforate the skull. These arteries have a curved and extended course along the sides of the gland7 that receives the phlegm of the brain. In fact, from these arteries, which Galen explained form the reticular plexus, there are no irrelevant offshoots that, supported by the processes of the thin membrane, enter through the lowest regions of the right and left ventricles before finally coursing through the entire length of these ventricles. Indeed, in addition to these arteries, another vessel passes under the body that resembles a tortoise shell or an arch-like room8, which has been called vaulted by us. This goes from what I named the fourth sinus of the hard membrane to the anterior part of the brain, through the common cavity of the right and left ventricles, or rather the third brain ventricle. This vessel finally divides into two branches that distribute to both right and left ventricles. It merges with the local arteries, and forms a network that takes its name from its resemblance to the outermost wrapping of the fetus. The brain has the faculty of refining the animal spirit in the right and left ventricles and in their shared cavity or third ventricle. The animal spirit is composed of the air that has entered the brain, as well as the vital spirit that is progressively transformed for the proper working of the brain by frequent winding meanders.9 We believe that this transformation is sensitive to the opportune mixture of those elements that are of benefit to the brain substance. 47 How the Brain Is Fabricated

Then, a portion of this animal spirit is conveyed from the third ventricle through the elongated passage10 that extends between the cerebral bodies, which are assimilated to the brain’s buttocks and testes.11 Here, it is finally transported into the cerebellar ventricle12 that is formed in part by the cavity of the cerebellum and in part by the cavity of the dorsal marrow.13 From this ventricle a significant portion of the animal spirit is distributed into the spinal cord and so also into the nerves that propagate from this. We think that the spirit is also dispensed from the other brain ventricles into nerves that take origin from their immediate vicinity14 and from here into the organs of the senses and voluntary movement. We are not really eager to debate whether this extremely thin spirit is directed through passages in the nerves (like the vital spirit through the arteries) or along the sides of the nerve fibers like the light shining against a column; or whether the energy of the brain reaches the organs only through the continuity of the nerves. And so far I can only reasonably grasp the functioning of the brain with a certain approximation and accuracy from the vivisections of animals. But I cannot possibly imagine from these how the brain performs its tasks with regard to imagination, reasoning, thinking, or memory15 (or whatever subdivision or enumeration is used for the powers of the supreme spirit in accordance to who- ever’s teachings). And if I can finally have some insight that could reveal that such speculations are correct by means of accurate and tireless observation of the brain’s parts and by examination of the other parts of the body whose function is already accessible and known to one trained in dissection, I couldn’t possibly do this without confiding in the most solid faith.16

THE OPINIONS OF THOMAS, SCOTUS, ALBERTUS, AND THE WRITERS OF THAT GROUP ABOUT THE CEREBRAL VENTRICLES

Who, immortal God, would not, therefore, be astonished by the crowd of philosophers of our time and, I might add, of theologians, who ridiculously denigrate the divine and supremely admirable mechanism of the human brain through their highly blasphemous dreams against the Creator of the human fabric, as if they believed they were Prometheuses? And I do not know how many lies they said about the structure of the brain that the infinite Maker of things forged with incredible forethought and such mastery, so that it can attend the functions necessary to the body. By keeping the brain far away from their eyes, those teachers proposed to students their own version filled with monstrous falsehood, uncon- cerned and careless (shame on them) of what they teach to the tender minds of their students. But with the course of time, the students, no longer assigned to dissections under their teachers, but passionate about learning and knowing the works of nature, will become familiar with examining more carefully with their own hands those things about humans and other animals that had been passed down to them.17 In fact, I still remember, while studying at the Pedagogium of the Gymnasium in the Castrum College of Louvain, certainly the leading and most prestigious of the 48 BRAIN RENAISSANCE colleges, the commentaries on Aristotle’s De Anima, read out by our teacher, a theo- logian by profession, and for that reason one of the most knowledgeable academics among those inclined to confuse religious opinions with those of philosophers. It was written that the brain had been provided with three ventricles, and that the first of them was the anterior, the second the middle, and the third the posterior, and that they obtained their name after their position and their function. Therefore the first, or anterior, which was said to face the forehead, was named the ventricle of “common sense” because these men thought that the five sensory nerves depart to their organs from here, and that odors, colors, flavors, sounds, and tactile qualities are conducted by these nerves to this ventricle. Hence, the main function of the first ventricle, that we usually call common sense, was considered to be the transmission of the percepts of the five senses to the second ventricle, which is connected to the first by a passage, allowing the second ventricle to imagine, reason, and think about the object of perception. Thought or reason was certainly attributed to this ventricle. The third ventricle, which was consecrated to memory, received from the second one everything it needed consigned to memory after the objects of perception had been reasoned. The third ventricle, which is moister, according to whether it is wetter or dryer, or faster or slower, it engraves these things in itself as if in wax or hard stone. Therefore those commentaries teach that, according to the ease or difficulty of inscribing, this ventricle retains the things assigned to it for either a short or long interval of time.18 And certainly, this third ventricle does not retain or engrave these things for itself or to serve its own purposes, but for the sake of the second ventricle, so that when the latter begins to reason about something previously entrusted to the cavity of memory, the former delegates and passes whatever this is to the second ventricle, the craftshop of reason.19 Also, to make sure that we understood every single thing that we were taught, a drawing of the already mentioned ventricles, from I do not know which Margarita of philosophy,20 was displayed and placed in front of our eyes. The more passionate about scholastic diagrams we were, the more precisely we would draw it in our notes. And we were persuaded that, not only were the three ventricles shown to us in this picture, nor only the brain, but also all the other structures of the head. These are the falsehoods of people who never look at the ingenuity of our Creator in the making of the human body: they are incorrect in their explanation of the anatomy of the brain, as I will show in the reasoning that follows. By means of the same method I have used in the two previous books, after a brief description, each part of the brain along with the organs of sense will be separately explained. How pitiless, to the inexperienced minds of those who are not yet firmly devoted to our holiest faith, is the possibility of reconciling our description of the functions of the cerebral ventricles, which concerns the power of the supreme spirit with the opinion of those (although we could be quiet about this) who have learned that the brains of quadrupeds are, in every aspect, the closest thing you can find to the human 49 How the Brain Is Fabricated brains. But according to the opinions of those theologians, animals have been denied any power of reason and principally the rational soul.

THE STRUCTURE OF THE ANIMAL BRAIN DOES NOT DIFFER FROM THAT OF THE HUMAN BRAIN

Indeed there is no difference at all in the structure of the brain in the parts that I have dissected in the sheep, goat, cow, cat, monkey, dog, and birds when compared with the human brain. This is particularly true for the ventricles, except that we know for sure that brains vary in size proportionally to the intelligence they appear to have been given.21 In fact, the brain is largest in man, then in the ape, the dog, and so on, depending on whatever evidence we collect on the power of intelligence of certain animals. Not only is the human brain larger proportionally to his body, but also larger than the brains of all the animals. The human brain appears even larger than the brains of two horses, two cattle, or two asses. But all this, along with the anatomy of the ventricles, will become very clear in what follows.

14 On the Hard Membrane That Surrounds the Brain and the Small Membrane Covering the Skull Under the Skin

The hard membrane of the brain is illustrated in several figures. In the first figure [A1] the whole external surface is shown at the level of the cut we usually perform to divide the skull and gain access to the brain. The second figure [A2], as well as the ninth [A9], twelfth [A12], and thirteenth [A13], shows the internal surface of the membrane covering the skull at level of the aforementioned cut. The letters D, D in the third figure [A3] indicate the other process between the right and left parts of the brain. The letters O, O, O in the seventh figure [A7] indicate the process that lies on the cerebellum. The cavity of the hard membrane is also visible in those figures and in the fourteenth figure of the third book. Furthermore, we have nowhere represented the membrane that covers outermost part of the skull; it is thin and its roundness can be appreciated from the shape of the skull bones.

A single membrane covers the entire cavity of the skull, which has adapted to contain the brain. This is similar to the peritoneum that embraces, like a sack, everything enclosed in the cavity where the organs of nutrition are lodged, and the membrane that encloses the ribs and wraps everything inside the chest, as we have previously described.22 It is thicker not only compared to the other membranes of the brain but also to those of the whole body, and for this reason we call it thick, or hard, or skin for its remarkable strength.23

POSITION, NUMBER, SIZE, AND SHAPE OF THE HARD MEMBRANE

This membrane, similar to the peritoneum and the membrane enclosing the ribs, is single and continuous, except where it is pierced by certain openings and by sinuses that are constructed like veins. Even though I am not going to say more about it, the knowledge of the bones instantly teaches us about the position of the present membrane, its shape on the outer surface, and size. This membrane is not pressed inward or opened by any protruding bone of the skull that may project into the skull cavity for whatever reason.

50 51 On the Hard Membrane

In addition, there is no sinus in the skull cavity that is not filled with the hard membrane. You will hear shortly (once and for all), that this membrane is continuously attached to the bones, more loosely or more tightly at different points. For this reason, the outer surface of the hard membrane, adapting to the recesses of the bone, is unevenly extended and, therefore, does not appear perfectly smooth, neither it is slippery due to the presence of the fibers by which it attaches to the bones. The larger bony projections, which can be seen very well at the base of the head, prevent the membrane from being spherical and rounded like a sphere.24 Among the largest of these projections we can list the bony septum, which separates the olfactory organs; then the protuberance of the skull that projects into the space of the head at the front of its base and at the sides of the nasal septum where a suitable seat sculpted in the skull lodges the eyes. In addition, we can include in the list the irregularity next to the thick cuneiform bone that is characterised by its own cells.25 This thick projection is located approximately in the middle of the skull cavity and, shaped like a convenient seat, contains the glandule that receives the brain’s phlegm.26 Two other remarkable protrusions project into this space so that Nature could carve a proper seat for the organ of hearing. Lastly, we should add to those already mentioned the protuberance of the occipital bone. This projects from the back of the passage that is continuous with the spinal cord to the mid-part of the interval between that passage and the most prominent aspect of the suture shaped like the Greek letter lambda. And these bony projections of the skull are considered the main reason why, at the base of the skull, the hard membrane does not resemble an elongated sphere, but it is slightly pressed at the front on both sides. Similarly, other tubercles that follow the swelling veins do not really interfere with the spherical form of the hard membrane nor prevent it from appearing roundly shaped. These tubercles generally contain veins and arteries that are attached to the outer surface of the hard membrane. Also, there are no sinuses in the skull cavity (except those protrusions that essentially form the cavities at the base of the skull, which have been mentioned above) that Nature did not sculpt for the benefit of the vessels of the hard membrane. It is clear that the function of these sinuses is to support the vessels and leave space for them without compression, and therefore not to place the vessels of the hard membrane at risk of being damaged by the membrane itself while also preventing these from being too close to the bones. Among these sinuses are those cavities that protrude onto the side of the first, second, and third sinus of the hard membrane, and also those sinuses that are carved onto the sides of the skull to hold the complex veins of the middle cavity, and any other vein of this type that can be seen in the anterior region of the seat of the olfactory organs. Indeed, we faithfully described in the third book what these vessels of the hard membrane are, and from where they take their origin. With this aim, we diligently and completely summarise in this account our knowledge of the outer surface of this membrane that, by Hercules!, is of absolute importance when there are wounds to the head. I will now review the fibers themselves and their connection to the skull. 52 BRAIN RENAISSANCE

CONNECTION OF THE HARD MEMBRANE TO THE SKULL

First, this membrane is always adjacent to the skull bone with no body between the two except for a small region above the middle of the sphenoid bone, where the hard membrane is separated from the bone. Here the hard membrane lies above both the glandule that receives the brain’s phlegm and the largest offshoots of the sleep arteries,27 which other professors of dissection wrongly believe to form the reticular plexus. This membrane is adjacent and attached to all parts of the skull in the same way, with two muscles always mutually adherent and connected lying one on top of the other. But with this kind of connection, the membrane is more firmly held at the base of the skull than at the sides, the vertex, the forehead, or the occiput. Also, it is firmly attached to every sharp bony process as if it took origin from them. Indeed, these kinds of processes include the bony septum that divides the seat of the olfactory organs, those at the sides of the foramina traversed by the optic nerves, those lateral to the sinus that hold the gland receiving the phlegm, and those processes next to the opening that hold the thicker root of the fifth pair of cerebral nerves, and, in general, all of the processes and openings facing the skull cavity. In the same manner this membrane is also attached to the skull sutures, but the connection is not as strong as the one with the bony processes. This is because the attachment to the sutures is just a simple line, not as large as the attachment of the bony processes. The hard membrane is attached not just to the sutures but also to the external surface of the skull through thin and membranous fibers. This is why these fibers protrude like simple lines into the hard membrane when the vertex of the skull is pulled up during dissection. They are also responsible for the rough aspect of the membrane’s surface while reproducing at the same time the position of the sutures and their impression on the membrane itself. Then, besides these fibers, the outer surface of the hard membrane is made less even by some tubercles that are prominent in the summit where the sagittal suture frequently joins the coronal suture. When these are present, they are not uniformly prominent, and have sinuses similar to those to which they are persistently attached to within the skull. Therefore projections of this type must also be examined with attention, especially when we cauterize or pierce the skull to treat wounds of the head.28 And, in fact, if these projections are overlooked (because in some areas and along some sutures the membrane is difficult to separate from the bone), we might perforate them together with the bone and cause great damage. Small veins strengthen the connection between the membrane and the skull and contribute to the roughness of the outer surface of the membrane through pores in the skull. Some of these veins originate from the hard membrane and reach the wrappings of the skull, while others extend from these wrappings to the hard membrane. In this way the hard membrane surrounds the skull cavity and covers all the organs contained in it. 53 On the Hard Membrane

PROCESSES OF THE HARD MEMBRANE

And besides these, the hard membrane inserts a large portion of itself between the brain and the cerebellum, covering the whole superior seat of the cerebellum and separating it from the cerebral region that lies upon it.29 Indeed, from the middle aspect of this portion of the hard membrane, where the right cerebral half faces the left one, and along the whole length of the third sinus of the hard membrane, another portion or process of the hard membrane also takes origin. This portion separates the right part of the brain from the left along the length of the head.30 To some extent, this process resembles the scythe used by reapers: in fact, the part of the membrane that is continuous with the portion of the hard membrane covering the cerebellum corresponds to the base of the scythe. Indeed, that part attached to the septum between the sinuses of the organs of smell can be compared to the tip of the scythe. The protruberance of the hard membrane that projects forward from the back of the head progressively arches and narrows just like the blade of a scythe. Then, the part of this process that is continuous with the third sinus of the hard membrane appears to dissectors not dissimilar to the back of a scythe, curving outward and appearing thicker because of the third sinus of the hard membrane, whereas the part facing the corpus callosum of the brain is curved inward; consequently its form is like the sharp edge of the scythe. In general, these portions, or processes, of the membrane show little variation throughout the surface of the membrane except for the only place where they differ in thickness and hardness. In fact, dissectors can see that the membrane is thicker only where it covers the cerebellum. This is exactly where the membrane is nearest to the brain buttocks31 and is about three times thicker and harder than in any other region. And, evidently, it is for this reason that dogs have a bone here covering the superior region of the cerebellum and sustaining the brain so that this does not press upon the cerebellum. But neither of these processes or structures is duplicated (as taught by Galen, who did not examine it enough): it is certainly single, like the membrane itself, in the portion where it extends toward the sides of the brain or the skull. Indeed, when you cut the third sinus of the hard membrane with a knife along its length, a twin process of the membrane that is between the two parts of the brain can be observed first, and this consists of a doubled membrane that has this feature because of the sinus. In fact, no matter how hard you try to separate the lower angle of the third sinus, the membrane outside the sinus cavity can never be separated into two. And the same reason applies to the part of the hard membrane covering the upper aspect of the cerebellum. There, if the lowest angle of the sinuses of the hard membrane is considered proof of its duplication, the same would certainly apply for the other two angles of the sinuses, and you could correctly conclude that the hard membrane of the brain is double wherever it makes contact with the skull. 54 BRAIN RENAISSANCE

NATURE OF THE INNER SURFACE OF THE HARD MEMBRANE

In addition, the surfaces of these two processes32 are similar in nature to the inner surface of the hard membrane; among all the surfaces of the body, you will not find another one that is more shiny or smooth, and free of any fat (this cannot be discussed here), similar to everything that constitutes the skull cavity. Indeed, this inner surface is far more soaked in aqueous humor than the outer one, and also appears much brighter. Furthermore, this appears more slippery and polished than the outer surface due to the paucity of the fibers that are attached to the outer surface. Also, just as the outer surface of the hard membrane faces the skull bone throughout, so the inner one faces the thin membrane of the brain. The two membranes adhere, or attach, to each other by means of nothing else but the ducts that resemble veins, which take origin from the hard membrane and project into the thin membrane. If the hard membrane were attached to the thin membrane, and thus to the brain itself, in the same manner as it is to the skull, it would have been an obstacle for the vessels of the thin membrane, and thus the expansion and contraction of the brain itself. With the aim of preventing this, Nature created the cavity of the hard membrane larger than the size of the brain itself, just like the wrapping of the heart appears larger than the heart itself. Nevertheless Nature has not freed the hard membrane from the thin—as she did for the wrapping of the heart from the heart—which are certainly not attached to each other by means of a single fiber.

THE CONNECTION OF THE HARD MEMBRANE TO THE THIN MEMBRANE

The hard membrane, with marvelous ingenuity, extends to the thin membrane with innumerable ducts that resemble veins. Those ducts perform the functions of the vein and artery and at the same time that of a bond so that the brain is held up properly and not damaged, while the movements of the vessels of the thin membrane and of the brain itself are not hindered. And if you have not forgotten the series of cerebral blood vessels that I taught in the third book, you shall have little trouble understanding this unique mystery of Nature. I am referring here to the numerous offshoots of branches that, from the third sinus of the hard membrane on each side along the whole length of the brain, project into the thin membrane of the right and the left part of the brain. These strongly link the superior part of the brain to the hard membrane and hold up the brain so it does not collapse upon itself. The hard membrane performs this function by virtue of its attachment to the skull and by not allowing the fibers that distribute through the sutures to protrude from the skull. And since the hard membrane is not attached to the thin membrane anywhere else (except maybe here and there by very loose and scattered ducts), it does not interfere with the free movement of the brain and vessels that belong to the thin membrane. 55 On the Hard Membrane

VESSELS OF THE HARD MEMBRANE OF THE BRAIN

Moreover, the present account now reasonably requires that I explain the number, position, and nature of the sinuses and vessels of the hard membrane. But since this was touched upon to the best of my ability in the third book, here I will save pages for that.

OPENINGS

For the same reason, I do not think the openings of the hard membrane deserve a dedicated explanation. This would be lengthy and would include nothing more than a catalogue of the skull openings that reach the skull cavity where the brain is contained, and that I have already mentioned in the first book. In fact, wherever there are openings in the aforementioned skull cavity, the hard membrane is generally pierced, always extending its projections to the nerves that take their origin in the brain, and wrapping around the dorsal cord. And, therefore, the hard membrane of the brain has as many openings as there are pairs of nerves taking origin in the brain. The only exceptions are for the opening common to both the fourth pair and the thicker root of the third pair. Yet the thinner root of the third pair pierces individually through the hard membrane before it makes contact with the nerve of the second pair. To these seven pairs of openings, another one should be added on each side, which lodges a tiny nerve that I observed arising not far from the root of the fifth pair. Finally, the hard membrane is also pierced by a single, unpaired, round and true opening that guarantees the passage of the funnel33 and receives the cerebral phlegm. Beside this opening, another one is observed on each side, which allows the passage of the largest branch of the arteries directed toward the brain. Lastly, the hard brain membrane is full of many small openings at the location of the olfactory organs. Also, we do not count as openings the sinuses of the present membrane that form the passage of the veins and arteries entering the skull, nor the ducts that propagate like veins out of these sinuses into the thin membrane.

FUNCTION OF THE HARD MEMBRANE AND RATIONALE OF ITS STRUCTURE

Among the primary functions of the hard membrane is the gathering of all the veins and arteries (except for two branches) directed toward the skull into specifically dedicated spaces and the collecting of their material into its own sinuses. In this way, it transfers into the thin membrane what is conducted along the offshoots, which are similar to veins originating from the sinuses. The hard membrane also acts like a flask of wine for the thin membrane and the brain, from which they can draw material that has been transmitted to the head through the veins and arteries for their specific functions. 56 BRAIN RENAISSANCE

In addition, the offshoots of both sides of the third sinus of the hard membrane, deriving in a great number from the branches that are closest to the thin membrane, sustain the brain, as we pointed out above. The hard membrane is, therefore, both a wrapping and a support for the brain, which is thus suspended so that it does not damage itself on its lower side or compresses its own ventricles. Again, the fibers sprouting from the hard membrane through the sutures are useful for holding the hard membrane of the brain (that could not be attached to very hard bone in any other way) to the skull. And this is the reason why the hard membrane is not tugged down by the weight of the brain and does not slip downward.

CREATION AND FUNCTION OF THE MEMBRANE COVERING THE EXTERNAL ASPECT OF THE SKULL

These fibers could not have really performed this function if Nature had not fabricated a peculiar trick outside the skull, which craftsmen imitate every day whenever they bend over the sharp ends of the nails joining two boards together, so that when one board is pulled the nail is not taken out of the other.34 Indeed Nature used its most superior art to make these fibers, like the bonds that Vulcan used to tie Mars and Venus together, since they both bind and sustain.35 Nature made these fibers course through curved ducts, which hold the fibers because of their obliquity, and increased their length after they have passed through the ducts. They merge all into one, so that they become the thin membrane that, since it covers the skull, is named perikranios36 by the Greeks. Professors of dissection believe that this membrane is attached to the skull without any other intervening structure: however, underneath this membrane there is another tenuous membrane. This is quite common to almost all bones, and the termperiosteon is used to indicate its main feature, that of embracing and surrounding the bones. The inner skull cavity, which is adapted to contain the brain, is among the bones that do not have this membrane;37 this is true for the region of the skull where the bone makes contact directly with the hard membrane. Conversely, in those regions where the skull cavity is not attached to the hard membrane, the bone is also surrounded by this tenuous membrane, just like the other bones. This is particularly visible in the region where we find the glandule of the hard membrane, which receives the brain’s phlegm and the largest branches of the arteries that project to the brain. Also, from the shape of the hard membrane one can appreciate how Nature, the creator of all things, provided for the particular benefit of these fibers two transverse sutures. One of these is along the length of the head so that the membrane is appropriately sustained on its upper side along this line. While dissecting we learn that, after lifting up the third sinus of the hard membrane with its liquid, Nature,38 whose ingenuity we passionately admire, created a portion or process of the hard membrane between the cerebellum and the brain, so that, when it is in its upward 57 On the Hard Membrane position, it sustains the brain and does not constitute with its weight an obstacle for the cerebellum. The part of the hard membrane dividing the right side of the brain from the left, and everything continuous with the base of the aforementioned process is of great help. If something concerning the shrewd harmony of the hard membrane has not been explained so far, I will add it to the chapter of the thin membrane.

15 On the Thin Membrane of the Brain

DIVISIONS OF THE THIN MEMBRANE

The thin membrane,39 like the hard membrane, is single and continuous. You will not find any of its portion, whether at the cerebellum, or at each half side of the brain, or in the ventricles and convolutions of the brain, or in one word in the whole area bounded by the hard membrane, that is not considered as part of this single thin membrane. This is like when the skin of an animal is removed from the body, and one can appreciate that the parts of the skin covering the ears, the feet, and the tail are a continuous whole.

POSITION

Also, its position may be deduced from the knowledge of the brain and cerebellum: in fact, nothing that the hard membrane embraces is not wrapped also by the thin membrane. And indeed there is not the smallest portion of the outer surface of the brain, cerebellum, dorsal cord, and nerves that is not covered by the thin membrane. This membrane lies close to the brain without the intervention of another body, except the upper surface of the corpus callosum, the only one not contained by this membrane because of its hard consistency. Furthermore, all the sulci of the brain and cerebellum, into which the thin membrane inserts its parts and processes everywhere, indicate the position, shape, and size of the membrane.

OUTER SURFACE

The outer surface of the thin membrane is covered by a sort of aqueous liquid40 and swells out to follow the external protruberances of the skull. And its thickness, which presents slight variations throughout, has the appearance of a very thin membrane covered with the ducts of innumerable vessels.

EXPLANATION OF ITS STRUCTURE AND FUNCTION

The Creator of all things crafted the membrane primarily for the benefit of the vessels, so that, like the mesentery, the lower membrane of the omentum and the outermost

58 59 On the Thin Membrane wrapping of the fetus (from which the Greek name of the thin membrane, choroeides, derives), could protect and support those vessels.41 Moreover, it represents more than just a wrapping of the brain and the cerebellum, like the hard membrane that is more than a cover, because it provides a defensive wall for the brain against collisions with the skull. This wrapping contains and stabilizes its substance, as the cheese molds that both sustain and give shape to the recently coagulated milk. And it was for these purposes that Nature produced this extremely apt membrane: indeed so soft and thin and pliable as to perfectly insert into all the sulci and sinuses to the fullest depth, and sustain the vessels that the brain needs. Also, it is so light that it causes no damage to the brain, but it is so strong and hard that it is not torn at all when the hard membrane is lifted up. Having been prepared so perspicaciously by Nature with the dense, innumerable, and continuous series of vessels, the thin membrane supports the force of the suspension and has enough strength to elegantly wrap and sustain the brain substance, similar to a mold (as we mentioned earlier). We can admire the wisdom of Nature even more when we discover that she used no less skill here as in assigning to each of the four elements its own position. This becomes immediately obvious if you compare the skull to the earth, the hard membrane to the water, the thin membrane to the air, and the substance of the brain to the fire. Then, consider the intelligence of the Creator, who placed water and air between earth and fire, because of their nature they are the farthest from each other. Similarly, the Creator set the two membranes between the skull and the brain (the two most discrepant substances), not satisfied with having nothing but the bond of their friendship between them.42 It is necessary that what intervenes should not only be for its position but also for its consistency; in fact, only something lying halfway between two extremes can be truly considered as an intermediate. However, the two membranes are not so different as the skull and the brain: the thin membrane is a long way from being as hard as the skull but not so far from being as soft as the brain; on the other hand, the hard membrane is much harder than the brain but only slightly softer than the bone. Indeed if Nature had created only the thin membrane, the brain would not collide with the skull without damage, and if Nature had created only the hard membrane, the brain would have been damaged by erosion. Therefore, to protect the brain itself or its closest wrapping from damage, the thin membrane has been placed first before the hard membrane. Moreover, the hard membrane is much softer than the bone and much harder than the thin membrane, whereas the thin membrane is much softer than the hard membrane and the brain is softer than the thin membrane. The softness of the thin membrane is so useful that it can easily insert anywhere into the sulci of the brain and extend its processes along with the vessels into the ventricles, as previously reported. I shall indeed explain the nature of these processes while attempting to describe the cerebral plexuses and ventricles and properly discuss the brain.

16 On the Number, Position, Shape, Convolutions, and Substance of the Brain and Cerebellum

DIVISION OF THE BRAIN

Professors of dissection usually divide the anterior brain, which they call the cerebrum, from the posterior brain, which they call the cerebellum: in turn, the anterior is normally divided into right and left. Not that the great masters of anatomy think that the brain is entirely divided, nor that it is not always continuous from every part (although some of their writings repeatedly indicate such a thing), but as a single hand is divided into fingers, so the brain is separated into different parts. In fact, in the same way we distinguished different parts of the thin cerebral membrane, here we can see different parts of the brain as being continuous with each other and composed of the same substance, which shows only minimal variations in consistency and color. These are the right and left parts of the brain, and with them the cerebellum, the dorsal cord, and every single nerve, as well as the buttocks and testes of the brain, and indeed the corpus callosum and the part shaped like a tortoise shell; in addition to these, the septum between the right and left ventricles, the vermiform process of the cerebellum, and other processes of this kind. Moreover, all the parts I have just listed differ from each other by their position, function, composition, magnitude, and other similar aspects that we have examined as individual components, but they have misled many people into thinking they are different and divided structures. As such, how many among the anatomists will you find who do not insist that the brain is linked to the cerebellum without any continuity of substance? Add others who teach that the brain is split into two parts like the lungs, and their continuous itch for writing is what gives them faith in their dreams but alters our reality. Certainly, even if the brain is divided into two parts in the region where it lies upon the cerebellum and where it faces the forehead, and the same division is visible on the upper part along the whole brain length, it is not for that reason that we can also divide its middle portion located next to its base and between the occiput and the forehead.43

60 61 On The Brain And Cerebellum

THE REGION WHERE THE RIGHT AND LEFT PARTS OF THE BRAIN ARE CONTINUOUS

The right and left parts of the brain are continuous in the region where the corpus callosum extends for its entire length. In addition to the corpus callosum, the two parts of the brain are linked by means of the structure that is like a tortoise shell, as well as the septum between the right and the left ventricle above the cavity that is common to them. Moreover, these are also continuous at the base, where they are linked by a region that is wide and deep and includes the brain testes, buttocks and all that arises from the middle of the cerebral base, including the beginning of the dorsal cord, which is single, large, thick, and continuous with the two halves of the brain.

HOW THE CEREBELLUM IS LINKED TO THE BRAIN

In terms of continuity of the brain, even if the right and left cerebral halves are linked in the region where they cover the cerebellum and are no less continuous with the cerebellum itself, the lower part of the cerebellum is linked in two places with the upper part of the dorsal cord mentioned above, with which it makes a unique body. Also, I will explain separately in the right place the principal regions of continuity, and all those parts that I have listed briefly above. What I have included in the discussion so far has been motivated by the necessity to avoid someone already trained and about to approach the dissection thinking that I am at this point falsely dazzled by the complexity of the brain, like the other anatomists. It is therefore now appropriate to address the position of the brain, which will be learned mainly from the description of the membranes of the brain itself and the inner space of the skull. Except for the space occupied by the two cerebral membranes, the gland receiving the cerebral phlegm and certain branches of the largest arteries directed to the brain, the rest of the skull is completely filled by the brain and cerebellum.

POSITION AND SIZE OF THE CEREBELLUM

The cerebellum is ten or eleven times smaller than the brain. Together with the upper part of the dorsal cord, the cerebellum claims for itself an area of the skull cavity that is delimited by the posterior projection of the bone that lodges the auditory organs and protrudes into the skull cavity and by the two cavities of the occipital bone. The latters are sculpted in the skull in such a way that the bone can accommodate the first two sinuses of the hard membrane, which we refer to as the left and right. In fact, there are no cerebellar parts extending beyond this circular boundary, which indicates the exact site of the cerebellum. Not in humans, but perhaps in oxen (the only species that Galen seems to have used to investigate the brain)44 the cerebellum extends until the occiput, so that the 62 BRAIN RENAISSANCE most extreme part of the brain does not reach as far as the most posterior part of the cerebellum, which fills what we call the occiput. There is no doubt that the most posterior and superior parts of the human cerebellum barely rise to a point we could touch with our fingers, which indicates the lowest part of the occiput. Furthermore, in humans there is no place where the occipital bone is free of muscular insertions and is in contact with the cerebellum at the same time. The cerebellum fills the entire region that slightly protrudes into the occiput, even if sometimes this is considered by anatomists the site from which to measure people’s power of memory and intellect according to its bulge.45 The upper portion of the cerebellum extends, at most, up to the midpoint between the posterior part of the opening that offers a path for the dorsal cord, and the part of the suture that resembles the lambda letter and connects to the sagittal suture. Others, deceived by their oxen and asses, or by their dreams, have written that the cerebellum ascends up to that connection. In addition, in humans the superior part of the cerebellum does not protrude like a globe, or sharply, as it definitely does in dogs, oxen, and sheep; but it appears flat, low and slightly bulging in the center. And the region of the skull dedicated to contain the cerebellum determines in this way its location, boundary, shape, and size.

SHAPE OF THE CEREBELLUM

When the cerebellum is observed in its position, its width is greater than its length or depth. In its lower region, especially in the posterior part, it resembles a rather large globe, in the middle of which it has a sharp but not very broad impression caused by a marked protrusion of the occipital bone that is similar to a very thick line. This protrusion, to which the hard membrane of the brain is securely attached, increases the strength of the bone significantly. At the front, the cerebellum extends up to the brain buttocks, and converges toward a point, where it adapts to its seat.

SIZE AND SHAPE OF THE BRAIN

The rest of the brain, which you could refer to as the anterior brain, shows similar characteristics but occupies the rest of the skull cavity that is not filled by the cerebellum. Given that the brain is also depressed along its base and does not show any rounded prominence, it appears uneven and not of a uniform shape. Where it rests above the position of the eyes and the cavities of the olfactory organs, it is varied: in fact, it extends forward to the cavities of the olfactory organs and leaves an impression on either side of those cavities due to the prominent projection of the bone into the skull. In the same place, the bone juts out irregular protuberances to appropriately form the sites of the eyes and the nasal openings. Further back, the brain fills two large spaces in the skull cavity, which are at either side of the bone that resembles a wedge46 and sustains the gland that receives the phlegm of the brain. The brain, thus, occupies the shape of the bone inside of which it is contained like a lump of clay, and from its own base swells out on both sides like a protuberance 63 On The Brain And Cerebellum resembling a semisphere. Between these protuberances, the brain appears flattened, due to the processes of the cuneiform bone,46 which extend alongside the sinus and support the aforementioned gland. Very similarly, the base of the brain models its shape within the remainder of this area so it fits inside the bony protuberances that house the organs of hearing and the superior region of the cerebellum, and inserts itself into all the cavities and delicately leans against these protuberances. Thus, at the sides, the front, the back, and the top, the brain is shaped like the cavity of the skull. In fact, in these regions the brain appears like an elongated sphere, flattened toward the front on both sides, owing to the temporal cavity, but rounded and much broader toward the rear. As if the brain itself and the cerebellum did not need a proper shape, and it is sufficient for them to place their own substance in a large mass, which, at the same time, occupies the head and has sinuses within it that are dedicated to the cerebral and cerebellar functions. This is also evident from the sinuses, the prominent projections at the base of the skull, and the hollow left by the temporal muscles.

THE CLEFT SEPARATING WHAT WE CALL THE RIGHT PART OF THE BRAIN FROM THE LEFT, AND OTHER CEREBRAL FISSURES

The skull cavity clearly reproduces its image on the outer surface of the brain, together with the cleft that splits the brain and the innumerable gyri and convolutions. Indeed the entire region of the brain is divided by this cleft, like the cloven hoofs of animals with split toenails, and it corresponds to a large area of the outermost brain surface. Nevertheless, this cleft does not interfere much with the described shape of the brain, given that the right part of the brain lies alongside the left one. In addition, the parts of the brain divided by that straight line are separated only by a layered structure composed of the hard cerebral membrane in the centre lying between the thin membrane doubled on either side. In humans but not in sheep, a portion, or a process, of the hard membrane separates the whole cleft, like a septum, between the two parts of the brain. The thin membrane wraps separately and envelops each of the two parts of the brain. The gyri and convolutions of the brain, which were very elegantly likened by Erasistratus to the turns of the small intestines, present with a similar pattern over the entire brain surface. There are, indeed, many spaces deeply penetrating into the brain substance that very closely resemble the turnings of the small intestines. And I think that this comparison could not be more apt, unless perhaps they might be compared to the clouds that untrained art students or children in schools usually draw; although it is not so difficult to search for a resemblance, since the human brain is not unique in this regard: the convolutions in the brain substance are common to man, asses, horses, oxen, and other animals that I have not yet examined closely. Perhaps someone could make a distinction here, since Nature gave man deeper gyri for the greater abilities of his brain. 64 BRAIN RENAISSANCE

FUNCTION OF THE CEREBRAL FISSURES

You can learn the layout of these turnings by examining the brain of any animal served at lunch or dinner. Then, when considering their function, not only physicians but also philosophers, are anguished by discussions of whether or not humans are intelligent because of them; for example Galen was against the opinion of Erasistratus, and he argued the following: asses also have a very complex brain appearance that, when considering the crudeness of their habits, should be utterly simple with the least possible variation. Instead, it would be better for intelligence to result from a good mixture of the substance in the intelligent body (whatever this body might be), and not from the variety of its composition. Nor, I reckon, should the perfection of intellect be linked to the amount of animal spirit more than to its quality.47 Here Galen, as often happens in his work when we look into it in closer detail, refrains from elaborating and shifts to a new topic when instead he should have explained the function of the convolutions. He simply stated that these convolutions are not responsible for intelligence. This is sound and we do not reject it,48 but nevertheless it would have been opportune for Galen to add more about how these convolutions show the great ingenuity of the Creator, for no other reason than they were created to provide nutrition to the cerebral substance. In fact, the cerebral substance is continuous, without any complex membranous fiber and also firm enough so that arteries and veins can be distributed throughout it, just as in other parts of the body; and it is so solid that if veins and arteries extended only on its surface, they would be insufficient to nourish it and feed its innate heat, given that the deeper parts of the brain would lack aliment if the vessels were extended that way. Foreseeing this, Nature impressed those sinuous folds everywhere in the brain substance so that the thin membrane, filled with numerous vessels, would insert itself into them to supply nourishment to the brain substance in the most efficient manner.

RATIONALE FOR THE DIVISION OF THE BRAIN

It is for the sake of this nourishment that the brain was divided into two parts, so that the thin membrane can really fold itself into its center: here the membrane, inserted into the folds, can nourish the entire cerebral substance. In fact, that aspect of the brain, where the right part faces the left, could not have been nourished in any other way without such division of the brain and its very deep convolutions.

RATIONALE AND TYPES OF THE CEREBELLAR FOLDING

The same concept applies to the convolutions of the cerebellum, which, however, do not penetrate anywhere near as deeply as the cerebral ones but instead are just below the surface where they can be seen inserted in large quantity and in a serial and continuous pattern. They evidently run more superficially because only a smaller pro- portion needs to be nourished and also because the cerebellum is pierced by deeper 65 On The Brain And Cerebellum convolutions extending into its ventricle. In fact, they are in a greater number to compensate for their rather superficial penetration. Furthermore, their serial pattern is threefold, which is nothing like that of the cerebral convolutions.49 From observation of its convolutions, and the impression left by the protuberance of the occipital bone on its posterior surface, the cerebellum appears to be composed of three parts: one on the right, another on the left, and a third in the middle. And the right and left parts of the cerebellum definitely resemble two spheres beside each other. The third part of the cerebellum occupies the space between them, where the spheres do not touch. The convolutions of the third part run transversely to the length of the cerebellum at an equal distance from one another, and for this reason it resembles a worm in wood or fresh cheese. The extremities of this third part bend toward the inferior aspect of the cerebellum, and form the vermiform processes of the cerebellum. You will be taught this in the appropriate place. On the superior aspect, four parallel convolutions extend downward along the entire width of the right and left parts of the cerebellum. These gather together in the middle, as they direct toward that cerebellar region, which we could say is attached to the upper part of the dorsal cord. It goes without saying that the convolutions of the right part extend to, and are continuous with, the upper region of the dorsal cord on the same side, and those on the left to the other side. But these parts of the cerebellum are not separated from each other, or discontinuous, as they constitute rather a unitary and single body, which is the cerebellum.

GALEN ASSIGNED AN INCORRECT RATIONALE TO THE UNITY OF THE CEREBELLUM

Galen states that the cerebellum was fabricated by Nature as a single body, and not divided like the brain because it was not appropriate for man to have two spines and two dorsal cords. That is to say, as if the brain is necessarily divided in two parts and not continuous in substance, from which a single dorsal cord could not be produced, and consequently the cerebellum has been created as a single body to suit the upper part of the single dorsal cord.

THE UPPER PART OF THE DORSAL CORD

Oh Galen, you have been so often deluded without good reason by things of little importance and sometimes also by your apes. You used to mock Herophilus, Lycus, Andreas, and other professors of dissection of Alexandria who actually examined human bodies.50 Although divided above, the human brain is single along the center of its base. It produces a single dorsal cord, where Nature carved in its upper part a passage from which the middle space of the fourth cerebral ventricle originates. In fact, the remaining space of this ventricle is filled by the cerebellum, which is attached only at both sides of the cavity of the dorsal cord, as if by two circular 66 BRAIN RENAISSANCE appendices that make a continuous body with the dorsal cord. Certainly, neither the middle part of the rear region of the cerebellum, nor the front part is continuous with, or attached to, the dorsal cord, whereas the rear part is united to the dorsal cord only by the thin membrane. Nature could not have done any better, believe me, to construct the cerebellum in this most appropriate way for the function of transmitting the spirit from the cerebral cavities to the dorsal cord. No matter how careful you are in trying to identify differences in consistency between the cerebellum and the brain, and pondering the reason why the cerebellum is separated from the brain, you will not find any offshoot of the smallest nerves taking origin from the cerebellum.

CONSISTENCY OF THE BRAIN AND CEREBELLUM, AND ORIGIN OF THE NERVES

There is no difference in consistency between the cerebral part facing the forehead and the part that, in man, extends farther back than the cerebellum into the occiput.51 Nor is there any notable contrast in consistency between the brain and the cerebellum where the latter is not enclosed within the thin membrane. However, the base of the brain, from which the dorsal cord takes its origin, is harder than all the other parts of the brain and the cerebellum itself. Hence, the dorsal cord is also progressively harder from its outset, and does not resemble, in color or consistency, the cerebellum attached above it.

COLOR AND SUBSTANCE OF THE BRAIN, CEREBELLUM AND DORSAL CORD

The cerebellum appears more yellow or ashy gray in color, besmeared with a very few bright lines, and shining only at the surface of its cavity. The entire seat of origin of the dorsal cord is very white at the region that, under the cerebellum, attaches to the brain. Because it takes origin from the base of the brain, it lacks all of the convolutions and fissures that are plentiful in the cerebellum. Indeed, these aspects of the substance and all these parts can also be learned at the dinner table from the brains of calves, rabbits or from certain birds. However, the cerebral substance is peculiar and characteristic, and you will find nothing like it in the entire body: and this is no less appropriate for brain function than the substance of the heart or the flesh of the lungs, liver, kidneys, and testicles are for their functions.

DIFFERENCE BETWEEN THE SUBSTANCE OF THE BRAIN AND THE MARROW OF THE BONES

The cerebral substance,52 which others have called the marrow of the skull, differs from the marrow of the bones because of many accidental aspects and because it 67 On The Brain And Cerebellum cannot be liquefied or consumed in times of starvation or other circumstances, as with other fat of the body. When compared with the convolutions, the cerebral substance is not completely white but slightly yellow or ashy gray and is so always at an equal distance from the surface of the convolution. In fact, whatever the depth of the convolution, the substance of the brain, where the color we mentioned is observed, has the same distance from the innermost part of the convolution, as if this color duplicates the shape of the convolutions in its inner substance. Not all the cerebral parts are very shiny and bright white. But given that there are so many cerebellar convolutions, it appears, as I mentioned briefly before, almost totally yellow to dissectors. So, as you uncover the substance of the brain or cerebellum from the thin membrane that closely surrounds it, this will always appear slightly yellow and covered with a sort of aqueous humor but never enveloped by veins, even if sometimes you might observe occasional reddish bloody dots, mainly in the cerebral substance of those who have suffered from phrenitis53 before their death, although these points never resemble a vein.

HOW THE CEREBRAL SUBSTANCE RECEIVES NUTRITION

The brain takes nourishment from no vessel apart from those that surround it and are supported by the thin membrane. The necessity of covering the brain everywhere with many vessels explains its several divisions, as we discussed. These divisions, like the convolutions, play a minor role in sustaining the soft cerebral substance or in protecting it from damage and in supporting it. In fact, I grant little weight to Galen’s rationale as to why the brain is divided or, as he said, doubled. Galen says that the brain is doubled so that we can preserve one half, similar to when one eye is damaged or a testicle is cut off: in the same way, when the right brain ventricle is damaged, the left one would still perform its own task. This explanation of Galen could perhaps have some place if we consider the number of ventricles, but not for the description of the division of the brain, which is doubled or divided only at the level of the ventricles.54 The body that we shall call the corpus callosum is continuous with both parts of the brain and is positioned near the upper region of the right and left ventricles. It is now time to address the brain ventricles, and thus to examine the inner brain surface and the other parts of it that still remain to be explained.

Commentary

SCRATCHING THE SURFACE OF COMPLEXITY

When we think of a human brain, two things dominate the image created in our mind. There is the distinctive shape, like a boxer’s glove when seen from the side, a coffee bean when seen from above. Then there is the complex and crammed pattern of convolutions. We see the ridges, or gyri, and the grooves, or sulci. It is difficult not to compare the surface of the brain to that of a walnut or even a fingerprint in the sense that each of us is defined by our own unique pattern. These convolutions are so distinctive that their history goes back further than any other structure in neuroscience. The Edwin Smith surgical papyrus is an ancient book on trauma surgery written around the seventeenth century B.C. It is named after an American Egyptologist who purchased the scroll in 1862, the same year Egyptian hieroglyphics were decoded. Translation of this papyrus has changed our understanding of medical history, because it demonstrated that ancient Egyptian medicine, far from being rooted in superstition, was much more sophisticated than we had thought. The scroll reports anatomical observations of injuries, fractures, and dislocations from different patients, providing notes on their treatment and prognosis according to the teachings of one man, the highest priest Imhotep (Breasted, 1930). For neuroscience, this Egyptian scroll represents a series of firsts: it is the earliest known writing system to document the concept of a “brain”, and there is also a hieroglyphic for “corrugations of the brain” (Figure 16.1). Patient number twenty mentioned in the scroll is of particular interest. He had suffered a penetrating wound of the skull and had become “speechless” when his exposed brain was poked by the examiner. This case provides the first known docu- mentation of a correlation between speech arrest and a specific region of the brain. In 1861, Paul Broca recognized it as the cortical region that controls speech production, later named Broca area after him (Broca, 1861a). But because Egyptians looked upon the heart, not the brain, as the seat of “spirit, intellect, passion, motor control, and sensation,” Imhotep, for all his remarkable clinical observations, never took the important step of correlating speech with the brain. The shift from the heart to the brain as the central organ of human cognition and behavior took another millennium. Philosophers before Socrates made mention of the relationship in their writings from around the sixth century B.C. Among them, Alcmaeon of Croton in Italy, arguably the first to have performed body dissections, recognized that the organs of sense are connected to the

68 69 On The Brain And Cerebellum

“brain” “corrugations of the brain”

Rabbit

Monkey Human

Fig 16.1 The origin of neuroscience and the development of surface neuroanatomy in Egyptian and Greek antiquity. Top row: Hieroglyphics for “brain” and “corrugations of the brain” (gyri) appeared for the first time in human history in the Edwin Smith Surgical Papyrus, an ancient Egyptian document dated around the seventeenth century B.C. Bottom row: Erasistratus of Alexandria suggested that the superior intellect of humans compared with other animals was related to the complexity of the cerebral convolutions.

brain through the nerves. He then argued that the brain must be the organ that receives sensation and produces cognition and behavior. Alcmaeon’s cephalo- centric ideas influenced later philosophers such as Pythagoras, Plato, Herophilus, Erasistratus, and even Galen. But not everyone was convinced. Others—such as Empedocles, Democritus, Aristotle, Diocles, the Stoics, and the Epicureans— continued to favor the heart (Clarke and O’Malley, 1996). Among the philosophers that believed in the brain, Erasistratus of Alexandria was the first to draw attention to the cerebral convolutions (Figure 16.1) and even speculated on possible functional correlations by observing that the brain is “like the small bowel and very much folded. . . . Since man greatly surpasses other beings in intelligence, his brain is greatly convoluted”. As an idea this is remarkably insightful, and represents the first attempt to correlate some general features of brain morphology with the complexity of animal behavior and intelligence. As Vesalius knew, Galen had different opinions: he rejected Erasistratus’s idea, favoring the ventricular theory, which soon became a dogma. The Christian church believed it; and anatomists accepted it. For many centuries, few felt the need to prove its validity experimentally (Manzoni, 1998). It was not until the Renaissance that some people began to perform detailed human dissection again, and observe the real anatomy of the human brain. Vesalius was one of them, and in the fourth chapter of the seventh book of his Fabrica he suggested 70 BRAIN RENAISSANCE

Fig 16.2 Drawing of the ventral convolutions of the human brain by Christopher Wren for Thomas Willis’s Cerebri Anatome (1664). a mechanistic role for the convolutions. To him they anchored the blood vessels to the surface of the brain, allowing nourishment to penetrate deeper into the central regions. Yet, while Vesalius expressed his doubts about the old ventricular theory, his explanation of the convolutions does not depart very much from Galen’s ideas. The most significant dissenter from Galen’s teachings was Thomas Willis (Figure 16.2). This seventeenth-century English anatomist combined Vesalius’s mechanistic view with Erasistratus’s comparative reasoning. The result was a far more complex understanding of cerebral function (Willis, 1664):

“Since for the various act of imagination and memory the animal spirits must be moved back and forth repeatedly within certain distinct limits and through the same tracts or pathways, therefore numerous folds and convolutions of the brain are required for these various arrangements of the animal spirits; that is, the appearance of perceptible things are stored in them, just as in various storerooms and warehouses, and at given times can be called forth from them. Hence these folds or convolutions are far more numerous and larger in man than in any other animal because of the variety and number of acts of the higher faculties.” 71 On The Brain And Cerebellum

With the “foldings” acting as “storerooms” or “warehouses” for memories, Willis put forward a forerunner of the localizationist theory, in which the brain is a mosaic of centers, each having a specific cognitive function. But Willis, like his predecessors, fails to identify, or at least record, any distinctive features within the convolutions of the brain. Instead, the first separation of the cerebral gyri into a superior and inferior group was made by a contemporary of Willis, Franciscus Sylvius (François Deleboe). He noticed that every brain had a deep groove running along both lateral aspects of the hemispheres (Figure 16.3, left) (Bartholin, 1641). The description of this groove, today known as the Sylvian fissure, heralded a new era for brain classification and mapping. French physician Vicq d’Azyr, for example, concerned himself with the size of the convolutions and their asymmetry between hemispheres. He was also the first to divide the convolutions into frontal, parietal, and occipital lobes (Figure 16.3, right) (Vicq d’Azyr, 1786). The more these distinct anatomical features were revealed, the more anatomists tried to explain them. The result was one of the most influential theories in neuroscience: phrenology. In the late eighteenth century, German anatomist Franz Joseph Gall started to take measurements of his classmates. In particular, he was interested in the variation in the size of their skulls and facial features. He became convinced that the brain is the organ of the mind, which he believed was composed in turn of multiple smaller “organs” that could be identified by their characteristic convolutions. Gall argued that mental faculties or “propensities” are located within the organs and that a total of 27 exist, including tenderness for offspring, poetic talent, sense of cunning, and even the murder instinct (Figure 16.4). A particularly well-developed faculty requires a well-developed cortical organ. Gall argued that the uneven bumps that marked a human skull were impressions caused by pressure exerted from the large convolutions beneath. Based on the size of these bumps, he believed it was possible to make assumptions about someone’s character.

Fig 16.3 After the Renaissance, anatomists recognized distinct sulci and convolutions of the human brain. Left: Figure fromInstitutiones Anatomicae (1641) by Thomas Bartholin; he named the lateral fissure after Sylvius, who was teaching his students about this deep groove but decided to write on it only in 1663, after being credited for the discovery. Right: drawing from Felix Vicq d’Azyr’s Traité d’anatomie et de physiologie (1786) showing the labeling of different gyri on the lateral surface. 1. Instinct of Generation. 2. Love of O spring. 3. Friendship, Attachment. 4. Courage, Self-Defence. 5. Murder, Wish to Destroy. 6. Cunning. 7. Sentiment of Property. 8. Pride, Self-Esteem, Haughtiness. 9. Vanity, Ambition. 10. Cautiousness, Foresight, Prudence. 11. Memory of ings, Educability. 12. Local Memory. 13. Memory of Persons. 14. Verbal Memory. 15. Memory for Languages. 16. Colors. 17. Music. 18. Number. 19. Aptitude for Mechanical Arts. 20. Comparative Aptitude for Drawing Comparisons. 21. Metaphysical Depth of ought, Aptitude for Drawing 22. Wit. 23. Poetry. 24. Good Nature. 25. Mimicry. 26. eosophy, Religion. 27. Firmness of Character.

Fig 16.4 Division of the human skull into 27 ‘faculties’ according to the phrenological doctrine (Gall and Spurzheim, 1810). 73 On The Brain And Cerebellum

Phrenology opened a new path to what was believed at that time to be a viable treatment for disorders of the mind. For instance, Gall reported the case of a young woman with sex addiction. Born to a well-respected family, she showed a voracious sexual appetite. Her disgraceful habit forced her to leave the social temptations of Paris to live in isolation with her mother in the countryside. But phrenology came to her help. According to Gall’s phrenological map, the region covering the cerebellum on the back of the brain was considered as the center of sexual propensity. Hence, bloodletting from this region was thought to reduce the activity of the cerebellum and consequently her deviant sexual habit. Reportedly, she was able to return to a socially acceptable conduct only after regular applications of leeches to the skin overlying the cerebellum at the back of the head. Of course Gall’s map and use of skull features as an indirect measure of character was flawed, and the phrenological system eventually fell into disrepute; but his ideas on cerebral convolutions had a far-reaching influence. Gall’s most significant insight was that there appeared to be a correlation between the convolutions of the frontal lobes and the faculty of language (Gall and Spurzheim, 1810). It was an observation that had a deep influence on two people in particular, Jean-Baptiste Bouillaud and his son-in-law Simon Alexandre Ernest Auburtin. These physicians were among the most fervent supporters of the idea that the ability to speak is localized to a particular region of the brain (Bouillaud, 1825). They became obsessed with collecting the brains of patients with aphasia—a distur- bance in the ability to comprehend or articulate speech. In April 1861, their fascination led them to present extraordinary evidence of speech localization in an actual living human brain. At a meeting of the Société d’Anthropologie in Paris, Auburtin stood nervously before his peers to describe the case of a patient, Monsieur Cullerier. Rather unfortunately, Cullerier had shot himself in circumstances that are not fully known. To make matters worse, he had shot himself in the head. Cullerier was still conscious upon admission to the hospital and even chatted away as doctors, including Auburtin, peered into the open wound on the left side of his forehead. The frontal lobe of his brain was fully exposed. For Aubertin, this was an opportunity too good to miss. And so, as Cullerier answered his questions, the physician had the audacity to apply light pressure to the wounded man’s brain:

“the frontal bone was completely removed. The anterior lobes of the brain were exposed but they were not damaged. Intelligence was intact as well as speech. This unfortunate survived several hours, and we could carry out the following observation. While he was interviewed the blade of a large spatula was placed on the anterior lobes; a light pressure was applied and speech suddenly terminated; a word that had been commenced was cut in two. The faculty of speech reappeared as soon as the compression ceased.” (Auburtin, 1861)

Among the audience of the Société d’Anthropologie that day was Paul Broca, whom we have mentioned earlier. Broca felt that this idea of speech localization was correct 74 BRAIN RENAISSANCE in principle but needed further experimental evidence. As an anthropologist, anatomist, and surgeon with access to an endless supply of patients, Broca provided new evidence. Just a few days after Auburtin’s presentation, Broca admitted Monsieur Leborgne, a 51-year-old man with a long history of epilepsy and speech difficulties. He had severe gangrene in his right leg and by now had almost completely lost the ability to talk coherently. Despite Broca’s efforts, Leborgne died within a week. At post-mortem examination, the surgeon took the opportunity to test the hypothesis that speech is localized in the frontal region of the brain. If the theory was correct, Broca expected to find a lesion near the part of the left frontal lobe that Auburtin had touched in his patient. Broca was not disappointed. In the posterior third of the left inferior frontal gyrus, was the damage Broca had hoped to see (Figure 16.5).

Fig 16.5 The brain of Monsieur Leborgne, the first patient of Paul Broca, who had long- standing speech difficulties. The brain is preserved at the Dupuytren Museum in Paris. 75 On The Brain And Cerebellum

Broca presented his work to a second meeting of the Société d’Anthropologie the same year. As time went by he continued to observe cases of patients with deficits in their verbal fluency, all associated with lesions to a similar region of the brain. Today we refer to this region as Broca’s area (Broca, 1861a). The late nineteenth century saw an explosion in the identification of other centers for language. Carl Wernicke described the center for understanding words (Wernicke, 1874), which is now known as Wernicke’s area. Joseph Jules Déjérine proposed the “reading center” (Déjérine, 1892), and Sigmund Exner pointed to the center for writing (Exner, 1881). Others did not stop at language. After all, why should language be localized but not other cognitive abilities? In England, John Hughlings Jackson drew attention to the functions of the right hemisphere (Jackson, 1876), where some argued for the existence of an “emotion center” (Luys, 1881) or a “geography center” (Dunn, 1895). Although localizationism received further support from other disciplines, in particular from cortical electrophysiology, the majority of scientists remained less prone to embrace it. Instead, the study of the relationship between intelligence and the general features—such as the weight or complexity of gyral patterns—had remained as popular as ever. One notable champion of the anti-localization idea was Marie-Jean Pierre Flourens, a French physician, who is best known for his belief that any part of the cerebral cortex could participate in or perform any function, a concept later known as equipotentiality of brain function (Lashley, 1950). He also believed that there were important differences in brain size not just across species but between different human beings as well (Flourens, 1824). To test this theory, neuroanatomists began to compare brains among individuals from different races, genders, social backgrounds, and cultures. In Germany, the anatomist Rudolph Wagner examined the brain of the great astronomer and mathematician Carl Friedrich Gauss. Despite its average weight, Wagner described Gauss’s brain as truly exceptional in terms of its intricate pattern of sulci and convolutions (Figure 16.6) (Wagner, 1860). To his great disappointment, however, Wagner could find none of the same features in the brains of other professors at Göttingen. This did not surprise Paul Broca, who stated, in reply to Wagner’s conclusions that “a professorial robe is not necessarily a certificate of genius; there may be, even at Göttingen, some chairs occupied by not very remarkable men” (Broca, 1861b). And it appeared that Broca was right. Neither brain weight nor the complexity of the convolutions seemed to play a role in intellectual ability. At the other end of the spectrum, criminals’ brains were considered by investigators to be smaller and closer to the simian brains of apes. The Italian criminologist Cesare Lombroso believed in the existence of two groups of criminals: those born wicked and those who became wicked. He thought that for some, committing a crime meant acting against their good hereditary traits. For others, their adverse hereditary traits meant that they had been destined to become criminals. Only the latter group would show distinct anatomical features, the chief of which was a small brain (Lombroso, 1911). Lombroso promulgated the idea that people should be judged not 76 BRAIN RENAISSANCE

Carl Friedrich GaussLeon Czolgosz

Fig 16.6 The German mathematician Friedrich Gauss donated his brain for anatomical investigation. His brain was exceptionally convoluted. The autopsy of the American anarchist Leon Czolgosz showed little anatomical differences in his brain compared to the average population. just on the basis of their crimes but also their inherited traits. Some criminals simply could not help it. These debates fascinated the general public, no more so than when an entire nation was shaken by a heinous crime. Often neuroanatomists (mostly psychiatrists) were called in such cases to judge the mental state of the accused and then to examine the brain in search of evident abnormalities after the execution. In 1882, psychiatrist Edward Charles Spitzka testified as expert witness at the trial of Charles Guiteau, the assassin of US President James Garfield. Spitzka was asked to examine the prisoner and formulate a judgment on his mental state. The psychiatrist gave a vigorous and passionate testimony, explaining that “Guiteau is not only now insane, but that he was never anything else” (Rosenberg, 1995). During his trial, Guiteau became a media sensation. He cursed constantly. Almost no one was untouched by his profanity, from the judge and witnesses to his own defense team. His testimony was provided through a series of epic poems. Nevertheless the assassin was still deemed sane, convicted, and hanged. At the autopsy, Spitzka found pathological signs indicative of syphilis; however, the opinion of the public and the experts converged toward a diagnosis of hereditary insanity. Suddenly, in the view of the nation, a sentence of death was deemed unjust. Spitzka’s son, Edward Anthony Spitzka, chose to follow in his father’s footsteps by also conducting autopsies on famous criminals (Spitzka, 1901). In 1901, another US president, William McKinley, was assassinated by Leon Czolgosz, an anarchist. The assassin was condemned to death and electrocuted. Spitzka’s son was asked to conduct the autopsy, where he found no structural abnormalities. Insanity was ruled out 77 On The Brain And Cerebellum

(Haines, 1995) and the young Spitzka concluded that it was dangerous to make broad generalizations from these kinds of observations (see Figure 16.6). As the twentieth century progressed, fascination with this anatomical approach to the human mind continued unabated. Technological advances saw anecdotal reports replaced by objective quantitative measurements. First came refinements to the post- mortem examination, then new ways of measuring living brains using x-ray, computed tomography, and magnetic resonance imaging (MRI). Brain morphometry—the measurement of changes in brain shape, weight, and volume—became particularly popular, especially in the world of American behavioral neurologist Norman Geschwind, a pioneer of this approach. His report on the asymmetry of the planum temporale—a triangular region that forms the heart of Wernicke’s area dedicated to language comprehension—revitalized the field (Geschwind and Levitsky, 1968). Geschiwnd showed that this region is more developed in the left hemisphere than the right and went on to link it with the development of human language (LeMay, 1976). He also suggested that neurodevelopmental conditions like autism and dyslexia are characterized by loss of the normal asymmetry of the planum temporale (Galaburda et al., 1978). In the

le right

curvature sulci gyri

Fig 16.7 Examples of some of the possible applications of MRI to the study of the in vivo surface anatomy of the human brain. Top row: 3D reconstruction of the living human brain for quantitative morphometric studies of sulci and gyri. In this figure the course of the posterior branch of the lateral fissure is reconstructed and measured to assess interhemispheric differences. The asymmetry of the lateral fissure has been associated with language lateralization (LeMay, 1976). Bottom image: Flat map of the gyral and sulcal patterns of the living human brain. 78 BRAIN RENAISSANCE

1970-80s computerized tomography (CT) substituted postmortem examination in the legal assessment of the mental insanity of the living. But most importantly CT and later MRI, became widely used for clinical and research purposes, allowing for a greater precision in the anatomical localization of lesions. Atlases of the human brain based on imaging (Damasio, 1995) became important tools to continue the investigation of the anatomical underpinnings of neurological syndromes; coupled with refined neuropsychological testing, neuroimaging gave clinicians the confidence to explore also new areas of behavioural neurology linked, for example, to disorders of attention (Watson and Heilman, 1979; Mesulam, 1999), emotions (Gainotti, 1972; Bechara et al., 1999; Dolan, 2003), and decision making (Bechara et al., 1995). In contemporary neuroscience MRI methods have become increasingly sophisticated (Figure 16.7), allowing data to be acquired rapidly from living human brains and from large numbers of people. This has made possible to challenge some of the long- lasting ideas on brain anatomy. For example, recent results have raised doubts about an assumption that has dominated for centuries: that “more” or “bigger” is better. Certainly, people with schizophrenia (Kulynich et al., 1997) or bipolar disorder (Penttilä et al., 2009) have been shown to have reduced “gyrification indexes”, namely indexes reflecting the complexity of the gyral pattern. But then children with autistic symptoms have increased gyrification in the parietal lobe (Kates et al., 2009). The more we measure and scan people of different ages, backgrounds, and disease, the less clear the picture seems to be. We are five hundred years on from Vesalius and his account of the brain’s convolutions, but we are now more aware than ever that the relationship of the mind and the convolutions of the brain is very complex. Our knowledge of the sulci and gyri is still only touching the surface.

17 On the Corpus Callosum of the Brain and the Septum of the Right and Left Ventricles

The third figure [A3] elegantly shows the upper part of the corpus callosum in its entirety as indicated by the letters L, L. In the fourth figure [A4] the letters I, I, I indicate the upper aspect of the corpus callosum from above, but freed from the lateral cerebral substance. The fifth figure [A5] offers a view of the lower part of the corpus callosum indicated by R, R, R, whereas the septum is indicated by X, X and Y, Y.

POSITION AND NOMENCLATURE OF THE CORPUS CALLOSUM

Earlier I reported that the brain and cerebellum are externally surrounded by the thin membrane and where facing the membrane they are slightly yellow and ashy gray in color. However, a region of the brain not covered by the thin membrane can be noticed on the outer surface. Indeed, similar to the internal substance of the brain, this region is shiny white on its external surface and harder than the rest of the cerebral substance that form the surface.55 This is the reason why the earliest Greeks named this part tylloeides,56 and following them I always called this part the corpus callosum in all my writings. It is also called psalloeides57 by other Greeks, for its shape, which is curved like an arch on its inferior aspect, and for its supporting function. I will explain later in more detail the anatomy of the brain structure to which most people rightly have referred to by this name. The corpus callosum appears located in the middle of the brain from a right and left view, in the middle of the cerebral basis from an inferior view, and in the uppermost part of the brain from a superior view. Nevertheless, if you compare the front and the back of the brain, the corpus callosum is only approximately in the middle. In fact, its most posterior part is slightly closer to the front of the brain than its front is to the posterior cerebral region.58 The corpus callosum can be clearly appreciated by the dissectors once they have gently separated with their hands the right side of the brain from the left. Whenever you separate the brain, the corpus callosum, which unifies the cerebral hemispheres, will appear white and rather long but narrow. When the brain is separated and its

79 80 BRAIN RENAISSANCE surface becomes more visible, the corpus callosum appears curved. It is similar to the vertex of the head that surmounts the forehead, the back, and the sides of the head; however, the curvature of the corpus callosum is not as prominent as that of the vertex of the head.

THE ORIGIN OF THE CORPUS CALLOSUM, NAMELY ITS CONTINUITY WITH THE RESIDUAL SUBSTANCE OF THE BRAIN

When the brain is actually opened in two, as I said, the upper surface of the corpus callosum appears extremely smooth, which indicates that the corpus callosum is part of the brain; and its origin is not from the softer and slightly yellow surface of the brain substance, but from the harder, white internal substance.

THE GROOVES VISIBLE ON THE SIDES OF THE CORPUS CALLOSUM

On each side of the brain substance, along the corpus callosum, the grooves are deep linear incisions that widen on the upper surface of the corpus callosum when the brain is firmly pulled sideways and upward.59 The inner or inferior surface of the corpus callosum first becomes visible to the dissectors only when the left and right brain ventricles are opened. This surface, which curves inward along the length of the corpus callosum while the upper surface curves outward, is not a single surface. In fact, along the entire callosal length two hollow surfaces, like a quarter circle, join to form a tubercle that resembles an extended longitudinal line in the middle of the corpus callosum. Take also into account that if on the medial side the two quarter circles join in the centre of the corpus callosum, on the other side they extend upward and laterally. Inferiorly, this tubercle becomes more prominent and gradually thinner, eventually turning into the septum between the right and left cerebral ventricles: and the total inner surface of the corpus callosum is as large as the combined surface of the right and left ventricles. The right and left portions of the callosal area face the right and left ventricles, respectively.

DESCRIPTION OF THE SEPTUM BETWEEN THE RIGHT AND LEFT VENTRICLES

The septum between the right and left ventricles is of the same substance as the brain; but in its midpart, where it extends from the top to the bottom, it is so thin that when we dissect it by daylight or place a candle on one side, the luminosity shines through it, as it does through the transparent stones that the Italian architects slice very thinly in circular or quadrangular shapes and glue into the stones of doors and windows.60 But even better than this hard stone, you can compare this part of the septum to 81 On the Corpus Callosum the moist sacramental bread that priests use when they celebrate Mass; although the appearance of this structure is closer to a translucent stone. In the upper part, where the septum is continuous with the entire length of the corpus callosum, and in the lower area where it joins the superior part of the brain structure that we say it to be similar to a vaulted room, the septum is thicker than in its midpart. The superior part of the fornix continues into the lower aspect of the septum, whereas the upper part of the septum originates from the lower region of the corpus callosum. The corpus callosum and the septum have no intersecting veins and are not covered anywhere by the thin membrane; they obtain their nutriment from the nearby regions. In fact, this cerebral portion is not large or thick enough to necessitate direct supply from its own vessels, even if it performs an important vital function.

THE FUNCTION OF THE CORPUS CALLOSUM AND SEPTUM

The corpus callosum connects the right and left parts of the brain and gives origin to the septum between the right and left cerebral ventricles. It also lifts the fornix by means of the septum, thus preventing its fall and the compression of the cavity common to the two cerebral ventricles, which could seriously alter all brain functions. Furthermore, the two grooves that are deeply cut into the cerebral substance just above the superior aspect of the corpus callosum are located there because this part of the brain61 is not capable of producing the corpus callosum, which needs to grow out from the deeper substance.62 These grooves are believed to facilitate the flow of the phlegm63 from the upper regions of the brain toward the anterior part. The phlegm is also thought to be produced from the upper regions of the brain and to flow anteriorly on the curved surface of the corpus callosum. Indeed, we will deal with the channels purging the phlegm in the chapter dedicated to them; now, instead, we will conveniently examine the ventricles.

Commentary

THE CORPUS CALLOSUM: A TALE OF ANARCHIC HANDS AND SPLIT BRAINS

To the causal observer the human brain appears to consist of two identical but mirror- imaged sets of structures—the right and left hemispheres. Yet appearances can be mis- leading. We now know there are important differences between them, both in terms of their makeup and their function. The story of how we discovered their diverging roles, and maybe even why they diverged at all, owes much to the vast white matter commissure described by Vesalius in this chapter, the corpus callosum. As the largest fiber bundle in the human brain, the corpus callosum contains anywhere from 200 to 300 million axons of varying size and density (Tomasch, 1954; Aboitiz et al., 1992). Although other commissural fibers exist, the axons of the corpus callosum are the principal link between the left and right hemispheres, allowing cross-talk or, as it is more formally known, interhemispheric communication (Figure 17.1) (Catani and Thiebaut de Schotten, 2012). Cross-talk allows information from motor, perceptual, and cognitive functions to be shared and combined (Gazzaniga, 2000; Zaidel and Iacoboni, 2003). Such integration of information is especially useful because what the left side of the body detects and how it then responds is mainly processed and controlled by the right hemisphere. In contrast, information to and from the right side of the body involves the left hemisphere. However, for most of our actions we rely on the integrated activities of the two hemispheres. Every time we attempt to do anything involving coordination of our hands, from fastening a buckle and typing on a keyboard to cutting a steak or driving a car, our corpus callosum is called into use. Unsurprisingly, given its immense size, this tract was described long before Vesalius made his observations. The Greeks, and especially Galen, were the first to place their interpretations into history, yet we have Jakob Sylvius, anatomy teacher of the young Vesalius while in Paris, to thank for the term corpus callosum. As a direct translation of the Greek tyloeides, which means “callous,” it refers to the structure’s harder consistency compared with the rest of the brain (although it is still softer than most of other tissues of the human body). With the exception of this new name, the description Vesalius gives in his Fabrica is like that provided by Galen. Indeed, both men believed the corpus callosum to be no more than a kind of bolster, one that supported the two hemispheres and stopped them from sagging in the middle. In addition, by suspending the septum and fornix, it prevented the roof of the ventricles from collapsing.

82 83 On the Corpus Callosum

BODY OF THE CORPUS CALLOSUM

SPLENIUM

GENU

TAPETUM ROSTRUM

Fig 17.1 Reconstruction of the corpus callosum in the living human brain with diffusion tractography. The callosal connections link the left and right hemispheres. Subdivisions of the corpus callosum include the rostrum (emotion and reward), genu (behavior and cognition), body (motor and somatosensory), splenium (vision) and tapetum (hearing). (Catani and Thiebaut de Schotten, 2012)

The corpus callosum’s position and extensive bulk makes their conclusion on its function an understandable one. But in the brain, just as with the two hemispheres, appearances can easily mislead. Galen and Vesalius would have been unaware of the structure’s true form—a mass of neuronal fibres. To them it appeared a single substance, one that rapidly blended into the rest of the white matter as it spread into the cerebral hemispheres. The first to move the corpus callosum away from a purely mechanical function was Thomas Willis. Willis grew up during a period somewhat obsessed with locating the anatomical source of the human spirit. The idea most popular with his predecessors, including Vesalius and Galen, was that the components of the spirit—sensory perception, fantasy and memory—circulated within the brain using the ventricles. Willis was not convinced by this explanation, but nor was he swayed by alternative suggestions of others either. One of the most popular among these alternatives was formulated by René Descartes, the French philosopher, who argued that the pineal gland was the perfect candidate to be the “seat of the soul”, mainly due to its central location and unusual unpaired existence (see Chapter 20). In 1664, Willis rejected all previous ideas. Instead, he proposed that the individual aspects of the human spirit resulted from their passage through three separate regions of the brain: the corpus striatum for perception, the corpus callosum for fantasy and the cerebral cortex for 84 BRAIN RENAISSANCE

Fig 17.2 Left: Drawing from Thomas Willis’sCerebri Anatome (1664). The brain is seen from the back after the posterior part of the brain has been removed. Willis believed that the spirit flows from the sense organs to the corpus striatum (black arrows), where perception occurs. If the spirit continues through the corpus callosum (white arrows), perception stimulates fantasy. Finally, if the spirit arrives at the cortex (black arrowheads), perception is stored within memory. Right: Drawing from Raymond Vieussens’s Neurographia Universalis (1684). The central portion of the corpus callosum (black arrows) is removed. The remaining fibers are projection tracts connecting the cortex to the sense organs and the spinal cord for the movement of muscles. Vieussens united the projection tracts underneath the cortex by the term centrum ovale, which is still used in contemporary radiology. memory (Figure 17.2, left). Such is the convenient location of the corpus callosum between the deeply seated corpus striatum and the more superficial cortex, Willis mused, that it is well placed for lodging the more creative processes of fantasy— where perceptions meet memories. While Willis was championing the corpus callosum, three hundred miles away across the North Sea, Nicolaus Steno, a Danish bishop and anatomist, was using more advanced anatomical techniques to take a closer look. Steno used midsagittal sections, where the brain is split into left and right halves, to describe different divisions within the structure. What he saw forced him to downplay speculation on the commissure’s possible function, responding rather bluntly that “we know so little of the true structure of the corpus callosum, that a man of tolerable genius may say about it whatever he pleases” (Steno, 1669). But Steno may have been closer to revealing the true nature of the corpus callosum than history or even he acknowledged. Numerous sources record that he used a novel method to split out white matter fibers. The trouble is that neither the specific information about his approach nor any image of the fibre of the corpus callosum survive to the present day. The story is different for another anatomist. A decade after Steno had expressed caution about the true nature of the corpus callosum, a Frenchman called Raymond Vieussens made an observation that changed our view of the brain’s structure forever. He found that boiling the brain in oil before dissecting it (Vieussens, 1684) renders the white matter fibers harder and thus easier to separate out by manual dissection. Using his new method, Vieussens realized that the corpus callosum was not 85 On the Corpus Callosum a single substance, as Vesalius had presumed, but an intricate bundle of fibers. And not just this, but it was a separate bundle from the other white matter located in each individual hemisphere. He called the latter the centrum ovale and believed that these connections were composed of projection fibres that ran from under the cortical gray matter to the spinal cord. To Vieussens this made the centrum ovale a prime candidate to be the “seat of the soul” (Figure 17.2, right). At the dawn of the 18th century, it was left to Giovanni Maria Lancisi to rein- state to corpus callosum to its previous glory. Best known as an epidemiologist who first described the link between malaria and mosquitoes, the Italian also took a keen interest in anatomy. He opposed both the centrum ovale and the pineal gland as the locations of the human spirit, favoring instead the corpus callosum. In his Dissertatio Physiognomica (1713), Lancisi provides a complex explanation as to why. It was impossible not to notice that parallel streaks ran along the fiber bundle’s upper aspect, perpendicular to the main direction of the callosal fibers (Figure 17.3). To Lancisi, these streaks, later named striae of Lancisi, acted as conductors between the anterior part of the corpus callosum, which he believed linked to the soul, and the

Fig 17.3 The corpus callosum and longitudinal striae identified by Giovanni Maria Lancisi in 1713. Along the midline the longitudinal striae run perpendicular to the callosal fibers and connect the anterior and posterior portions of the corpus callosum. Lancisi believed that the anterior part of the corpus callosum is linked to the soul and the posterior part to the sensory organs. (Image courtesy of Antono Di leva) 86 BRAIN RENAISSANCE posterior part, which he said links to the other organs in the body. These striae, he thought, guarantee continuity between the two (Di leva et al., 2007). It was not until 1749, when the German anatomist and botanist Johann Gottfried Zinn conducted a series of experiments which involved sectioning a dog’s corpus callosum down the midline, that this theory was at least partially disproved. To Zinn’s surprise, the dogs showed no immediately obvious changes in behavior, certainly none that might imply a disconnection between the body and its spirit. By the late eighteenth century anatomists had begun to abandon the idea that a precise location of the soul could be found in the brain. Connections quickly became central to a new concept of brain function, one based on distributed networks and parallel processing. New and growing anatomical knowledge of fibers, together with evidence for the existence of animal electricity—the idea that the body is powered by electrical impulses (Galvani, 1791)—set the basis for a modern understanding of how the brain works (McComas, 2011; Piccolino and Bresadola, 2013). The great French anatomist Felix Vicq d’Azyr was one of the first to put forward such an advanced understanding of the brain:

“It seems to me that the commissures are intended to establish sympathetic com- munications between the different parts of the brain . . . everything is arranged in the system to multiply the connections of different parts of the brain so that inconveniences which would result from difficulty occasioned in any part of the brain, are prevented.” (Vicq d’Azyr, 1786)

Anatomical research in the nineteenth century saw a refinement of methods for studying connections. New tracts were discovered and existing ones were subdivided. In 1810, Joseph Gall and Johann Spurzheim, known as the founders of the phrenological theory, made a series of original observations about the corpus callosum, many of which still hold true today. They proposed a topological arrangement for the fibers. The corpus callosum together with other cerebral commissures contributed to “producing action and reciprocal reaction and unity of action between the same parts of the two hemispheres” (Gall and Spurzheim, 1810). They sparked controversy by challenging the firmly held but erroneous belief that callosal fibers were actually projection fibers; in other words they rejected the idea that callosal fibers cross the midline before turning down sharply into the brain stem. Connections actually originate in the cortex, they said, and different cortical “organs” presided over specific functions. Gall and Spurzheim proposed that “all parts have their connections” and that we should aim “to discover to which part each connection belongs.” Their findings were later corroborated and extended by the degeneration studies of the great Austrian-German neuroanatomist Theodor Meynert (Meynert, 1872). But for some, this evidence was still not enough. A small group stoically stayed unconvinced, citing a growing number of experiments that continued to proclaim the corpus callosum as a bundle of projection fibers. In the end, it was left to electrophysiological studies to provide a conclusive answer: nerve impulses could be 87 On the Corpus Callosum conducted through the callosal fibers from one hemisphere to the other, not down the brain stem (Bykov and Speranski, 1925). By the time we knew where the callosal fibers originated, a new controversy was rag- ing. Damage to the corpus callosum in humans seemed to provide highly inconsistent clinical manifestations if any at all. This raised the important question of whether we actually need a corpus callosum to function normally. Such uncertainty had already intrigued the German psychiatrist Johann Christian Reil, who in 1812 performed the first autopsy of a patient born without the corpus callosum (agenesis of the corpus callosum):

“This is a case report of a woman of some 30 years. She was otherwise healthy but idiotic, nevertheless she could be sent from the village where she lived to the city to deliver messages. She suddenly collapsed in front of a bakery and died immediately. Upon autopsy it was found that, apart from reduced water accumulation within the ventricles, the corpus callosum was split in the middle along its length. It is more likely, however, that the middle and the free part of the callosum were entirely missing.” (Reil, 1812)

Armed with a growing number of similar reports, Reil concluded that the corpus callosum was vital for the development of normal intelligence. Others agreed. By 1887, a Polish neurologist by the name of Bronislaw Onufrowicz had compiled a long list of patients born without a corpus callosum (Forkel et al., 2014). Many of them were described as “idiots” of low intelligence, but not all. Confusingly, some appeared completely normal. It was not until the 1960s that a link between agenesis of the corpus callosum and developmental disorders became established, many of which we now know are linked to genetic abnormalities (Paul et al., 2007). Some of these patients display difficulties with social interaction. Most showed some form of language delay, where as children they failed to develop language abilities along the usual timetable (Figure 17.4). About ten percent are diagnosed with a frank autistic condition (Paul et al., 2014). But for others the differences manifest subtly if at all. Absence of a corpus callosum is often an incidental finding on magnetic resonance imaging (MRI) (Figure 17.5, left). Where the normally light-gray and arched corpus callosum should be seen on a midsagittal section, there is either just an empty darkness or an encroaching cortex. Incredibly, the majority of these people demonstrate normal intelligence. But the puzzlement does not end here. Some individuals with an acallosal brain even display exceptional but isolated, abilities. These “idiot savants” show peaks of outstanding intellectual skills in the context of a learning disability. Without doubt one of the best-known among them is a fictional one—Raymond Babbitt in the movie Rain Man. The inspiration for Babbit, however, came from Kim Peek, the recently deceased American “megasavant” who could read two pages simultaneously—the left page with his left eye and the right page with his right eye. Not only this, but he did it at a speed of two pages every 20 seconds. His memory was formidable, encyclopedic in scale. It 88 BRAIN RENAISSANCE

Fig 17.4 Left: Comparison between the writing of a nine-year-old boy with an intact corpus callosum (arrow) and that of a child with no corpus callosum (being acallosal) (asterisk). Both are of the same chronological and mental age. Right: The sophisticated testing of subjects with acallosal brains performed in the 1960s (Jeeves, 1965).

Fig 17.5 Left: MRI scan of the brain in a 68-year-old woman born without the corpus callosum, indicated by the asterisks (image courtesy of Alberto Bizzi). Right: Image of a 35-year-old woman with a partial callosotomy (removal of the anterior part of the corpus callosum, as indicated by the asterisk). (Image courtesy of Gabriele Polonara) is reported that he could remember ninety-eight percent of what he read, including the content of more than 12,000 books. But Peek also needed constant help with more trivial everyday tasks, especially those that required manual dexterity. It was not until Peek was studied with MRI that the absence of a corpus callsoum was revealed. 89 On the Corpus Callosum

Complete agenesis of the corpus callosum is relatively rare. Partial damage to the fibers, however, is far more frequently described in relation to tumours or stroke in adulthood. And this can often lead to a disconnection syndrome. The first to describe a disconnection mechanism in the corpus callosum was the French neurologist Jules Déjérine. In 1892, he met a patient who was unable to read despite maintaining an ability to write; a condition we now know as pure alexia. Déjérine predicted that this condition would be found to stem from a lesion in the most posterior part of the corpus callosum, an area known as the splenium (Déjérine, 1892). A disconnection here means a breakdown in communication between visual areas in both occipital lobes and the center specialized for reading in the left parietal lobe; the connections to regions specialized for writing remaining intact. Within a few years, another neurologist, Hugo Liepmann (1900), posited a similar explanation for left-hand apraxia. Here the patient fails to perform actions with any fine dexterity despite having previously learned how to do them. This total lack of coordination results from disconnection of the fibers in the anterior body of the corpus callosum between the left- and right-hand regions. As strange as these symptoms may seem, others can be downright bizarre. Individuals with the “anarchic hand” syndrome describe situations in which one of their hands “moves at its own will.” For many it is almost as if the hand were “under the control of an alien intelligence” (Della Sala et al., 2007). It is this common description that gives the condition its alternative name—“alien hand syndrome.” Those affected report being attacked by this lawless hand as they attempt to climb into bed, often being repeatedly slapped, punched, or even strangled. Others, perus- ing the wares of a shop, may find the anarchic hand moving toward or grasping an object that is unwanted. In some cases the hand attempts to take another person’s belongings (an “involuntary” kleptomaniac hand). The anarchic hand may even sab- otage the action of its opposite, a “diagonistic hand” (Akelaitis, 1941). One patient recalls sitting at a dinner table witnessing his diagonistic hand attempting to grasp a spoon despite the fact that it was being used by the other hand. A few find that the hand does not always feel as if it belonged to them. In a case of main étrangère (foreign hand), a patient was asked to hold both hands behind his back. The moment he did, he calmly denied that the hand belonged to him (Brion and Jedynak, 1972). Despite the presence of these syndromes, many physicians and researchers were reluctant to accept callosal disconnection as sufficient to cause these deficits. It was a belief fueled by initial reports from a different kind of corpus callosal disconnection, one caused by surgical incision. This particular fate befell patients with refrac- tory epilepsy in the first half of the twentieth century. Neurosurgery became a viable approach for the treatment of epilepsy after the American surgeon Walter Dandy (1936) made a cut to the posterior half of a patient’s corpus callosum in order to remove a tumor of the pineal gland. The apparent absence of symptoms following surgery gave other neurosurgeons an idea. They began using callosotomy—the severing of the corpus callosum—as a way of limiting the spread of epilepsy from one hemisphere to the other (Figure 17.5, right) (Wagenen and Herren, 1940). Cutting the connections, they thought, would limit the electrical storm of the seizure to one side of the brain. 90 BRAIN RENAISSANCE

By the early 1940s, the American psychologist Andrew Akelaitis was studying the effects that complete disconnection was having on these initial “split-brain” patients. He found very few negative effects on cognitive functions. Thirty years later, it became clear that this was far from the truth. It was not that there were no negative effects, just that psychological methods used were not sophisticated enough to detect them. In 1963, two neurosurgeons in the United States, Joseph Bogen and Philip Vogel, reported a new set of split-brain cases. They worked alongside Michael Gazzaniga, a psychologist and graduate student in Roger Sperry’s lab, to reveal that, despite previous reports, these callosotomy patients did suffer significant effects on their cognition (Glickstein and Berlucchi, 2008). Some were obvious like those already discussed. But many effects were subtle and detected only because the researchers employed sophisticated psychological testing. Little did they know, when they set out, that their studies would become among the best known and most fascinating in all neuroscience (Gazzaniga, 2000). The testing methods devised by Gazzaniga and Sperry were ingenious. They understood that the brain was particularly good at adapting, especially when it came to sharing information from one hemisphere to the other. So to spot potential cognitive defects they needed a way to present sensory input to just one hemisphere. They began running experiments that included tachiscopic visual presentation, where images are presented rapidly to just one eye, or dichotic listening, where sound is played to only one ear (Figure 17.6). The results stunned them. Many patients, for example, could no longer verbally describe stimuli when they were presented only to the right hemisphere via the left visual field. It seemed that the left hemisphere was dominant for language but the right was not mute or deaf. Indeed, some language

KEY KEY ? ? KEY

language language le hand language le hand le hand area area area area area area

Fig 17.6 Split-brain patients are unable to perform tasks that require the transfer of information from one hemisphere to the other. Left: A split-brain patient is unable to name an object that he holds in his left hand with his eyes closed. This occurs owing to the loss of callosal connections between the left hand tactile area on the right hemisphere and the language areas in the left hemisphere. Middle: A split-brain patient is unable, with the left hand, to pick up an object whose name is presented in the right visual field. This occurs owing to the lack of connections between the area of the left hemisphere that recognizes the word with the area that controls movement of the left hand in the right hemisphere. Right: Split-brain patients progressively acquire a variety of strategies for circumventing their interhemispheric transfer deficits. For example, reading out loud the name of the object that is seen in the right visual field allows the right hemisphere to comprehend the word so that the patient can pick up the object with the left hand. 91 On the Corpus Callosum functions were carried out by the right hemisphere and, for some functions, like spatial representation, the right was dominant over the left. Thus, severance of the commissural fibers provided Gazzaniga and Sperry with an opportunity to understand not just the functions of the corpus callosum, but also to demonstrate that the hemispheres were not as similar as many thought. In some cases brain function was lateralized. It was this work that led Roger Sperry to the Nobel Prize in 1981 for his “discoveries concerning the functional specialization of the cerebral hemispheres.” Today callosotomy is rarely performed, as most of the epileptic patients can be treated with medication or other less invasive methods. And given that many of the original patients have now passed away, opportunities for studying new split-brain cases are slim. This fact has spurred a growth in new ways to learn about the function of the corpus callosum and the hemispheres. In animals, electrophysiological approaches in combination with anatomical tracing methods have helped to precisely elucidate functional correlates of callosal fibers. In humans, the introduction of new imaging methods over the last three decades has begun to reveal more and more about the role of the corpus callosum in everyday life and in disease.

Callosal projections density 8 4 High 9 5 7 6 3-1-2 46 10 40 39 44 Low 45 43 41 19 18 47 42 11 22 17 38 21 37

Anterior 20 temporal Wernicke’s Broca’s lobe region region Geschwind’s region Visual word form area

Fig 17.7 The density of callosal projections to cortical areas calculated with diffusion tractography. Lighter areas indicate lower density of connections passing through the corpus callosum (transcallosal connections). Note the reduced interhemispheric connectivity for most of the language regions dedicated to reading (37), words (22), metaphor and irony comprehension (39), and speech production (44, 45). The anterior temporal lobe is a region that processes word meaning and is connected only by the anterior commissure (Amunts and Catani, 2014). 92 BRAIN RENAISSANCE

In particular, the structure of the corpus callosum may reflect variation in the function of brain systems, both in healthy and psychiatric patients. Structural MRI has provided us with a remarkable insight into the ways in which the integrity of the corpus callosum may be reduced in a wide a range of conditions, including attention deficit and hyperactivity disorder (ADHD), Gilles de la Tourette syndrome (Yazgan and Kinsbourne, 2003), autism (Alexander et al., 2007), schizophrenia (Cowell et al., 2003), and depression (Ballmaier et al., 2008). Furthermore, with diffusion tractography, it is possible to track connections in the living human brain and directly correlate this anatomy with behavioral performance. Heidi Johansen-Berg and colleagues did just this when they showed that in healthy people the ability to coordinate both hands at the same time (bimanual coordination) is correlated with the organization of the callosal fibers connecting the two hand regions of the left and right hemispheres (Johansen-Berg et al., 2007). That is, these investigators showed that the phrenologists Gall and Spurzheim were, after all, correct in their prescient speculations on the callosal functions. It remains to be clarified how callosal fibers contribute to lateralization of cognitive functions. Diffusion tractography in humans shows that in the left hemisphere, regions specialized for language receive fewer callosal connections than do nonlanguage regions (Figure 17.7) (Amunts and Catani, 2014). Could it be that lateralized regions in the brain reduce “unnecessary cross-talk” with areas in the opposite hemisphere? This lack of cross-talk may result in strengthening of connections between specializing regions in the same hemisphere, such as those for language in the left and those for visuospatial functions in the right (Doron and Gazzaniga, 2008). These questions and many others can now be addressed with contemporary neuroimaging methods. Despite these advancements, the very fact that most subjects born without a corpus callosum still lead a normal life remains a remarkable and endearing ambiguity. It is almost five hundred years since Vesalius made his observations about the corpus callosum, yet the only thing we are truly sure of is that he was wrong about its function. The sole purpose of the corpus callosum is not to sustain the weight of the brain; it is an information highway. Beyond this, the more we discover about this commissure, the more questions we are forced to ask. It remains to be established what callosal fibers do during development and why cognitive functions can develop normally despite the absence of the largest single groups of connections in the human brain. We do have some much smaller commissures, posterior and anterior ones, for example, so it may be that these can compensate for the absence of the corpus callosum. But if this is the case, why has nature not disposed of the corpus callosum during human evolution? It is an enduring mystery and one that may well go on to fascinate scientists for another five hundred years.

18 On the Cerebral Ventricles

L, L in the fourth [A4] and fifth [A5] figure and D, D in the sixth figure [A6] indicate the right ventricle of the brain. M, M in the fourth and fifth figure, N, N in the fourth figure, and E, E in the sixth figure indicate the left ventricle. H in the seventh [A7] and eight figure [A8] shows the common cavity or third ventricle, whose passage directed toward the fourth ventricle is indicated with the letter K. The letter E in the eleventh figure [A11], in part by the letter I in the ninth figure [A9], and L, M, N, O in the tenth figure [A10] indicate the fourth ventricle.

DIVISION OF THE VENTRICLES

The list of the cerebral ventricles includes the one common to both the brain and dorsal cord64; this is called the fourth ventricle. Following Herophilus, we also recognize three other ventricles in the brain: one in the right part of the brain, one in the left part, and one in the middle between the first two ventricles.65

DESCRIPTION OF THE RIGHT AND LEFT VENTRICLES

The right and left ventricles are exactly the same for what concern their position, shape, size, and other features that are usually considered in examining the anatomy of body parts. Hence, each single thing that I write about the right ventricle equally applies to the left one. It is located in the right part of the brain, extending for its entire length. The distance between its front and the forehead is equal to the distance between its rear and the back of the brain. And this distance is the same as that between the outer surface of the brain that faces the sides of the skull and the right external wall of the ventricle. Along the length of the corpus callosum, the inner side of the right ventricle is next to the inner side of the left ventricle; no intervening space separates the two except for a small, thin, membranous portion of the brain, which we have called the septum. This originates from the corpus callosum and, as we said, is attached lengthwise and is continuous to the whole upper area of the body that is constructed like a chamber, the fornix. Thus the medial sides of the right and left ventricles are separated by the smallest gap over a distance that entirely corresponds to the extension of the

93 94 BRAIN RENAISSANCE septum and for a length that is equal to the length of the corpus callosum. However, in the regions where they stand apart, they are at a significant distance, as, for example, in the region above the cerebellum and next to the forehead, where the sides of the ventricles show the greatest separation. In addition to the interposing membranes of the brain, a lot of cerebral substance also divides the ventricles. Hence, the right or outer side of the right ventricle, which has a hunched shape, lies farther to the right in its anterior and posterior part than in its middle, while its left side extends more to the left in its middle than at its extremities.66 The anterior part of the ventricle is blunt and rounded, and to me it does not seem to have a sharp termination at the olfactory organs or the optic nerves, as all the others have written. Also, there are no ducts that originate from its surface except the one on its inner side, which reaches down to the third ventricle,67 as I will amply explain soon. Moreover, the posterior region of the ventricle facing toward the back of the brain is indeed blunt and rounded, but it gradually becomes narrower as it directs downward and forward into the cerebral substance.68 It ends at the origin of the organs of smell and the optic nerves, where the largest branches of the sleep arter- ies69 enter the brain. And if you observe its entire length, this duct is more than half the length of the ventricle that extends, as we said, from the back to the front. And also, about halfway along its length, the duct passes through the brain substance and terminates like a horn in a point at equal distance from the origins of the optic nerves and the olfactory organs and without any continuation or perforation of those nerves and the organs of smell. Indeed, it terminates at the base of the brain in one of the cerebral convolutions70 and receives the largest artery that reaches the brain together with the process of the thin membrane that holds it.

MANY OF THE TEACHINGS BY GALEN THAT WERE THOUGHT TO BE TRUE ARE NOT DESCRIBED HERE

In saying this, I have no doubts that the innumerable teachings by Galen cannot prove me wrong. For example, in his teaching he affirms that the anterior brain ventricles are the organs of smell, and that these ventricles become gradually thinner and terminate with a sharp tip at the optic nerves, and, strangest of all, that these anterior brain ventricles expel phlegm into the nostrils. These and other similar false teachings should be discussed and learned from dissection rather than from a lengthy disputation. These things are so clear that one warning is enough, for you should not put your faith only in books but dissect the brain with your hands or stand close to someone with proper experience in dissections. Moreover, the whole surface of the ventricle is smooth and covered with an aqueous liquid, which often fills them during the dissection. The upper part of the ventricle is free of any unevenness and similar in each of the two sides, except the slightly curving duct of the ventricle that seems to induce a sort of protuberance. The inferior part of the ventricle is made uneven by a furrow71 that, originating from the outer side of the posterior part of the ventricle, courses obliquely and anteriorly toward the common cavity, so that it facilitates the down-flow of the phlegm. The 95 On the Cerebral Ventricle part of the ventricle that courses downward in a posterior-to-anterior direction also contributes to the unevenness of the ventricle. In fact, the bend in the ventricle, along with the furrow, is the reason why there is a sort of small swelling in the anterior and posterior regions of the lower part of the ventricle,72 and this facilitates the flow from the right to the left ventricle, and then downward toward the common space of the ventricles. The lower parts of the right and left ventricles, which are continuous along the total length of the corpus callosum, incline downward toward the common cavity between them. They are not rounded, like the upper parts or sides, and are separated from each other by a septum.

ACCOUNT OF THE CAVITY COMMON TO THE RIGHT AND LEFT VENTRICLES OR THE THIRD VENTRICLE

The cavity shared by the ventricles is nothing other than the inclining and convergent part of the lower right and left ventricles, just under the body likened in appearance to a tortoise shell73 by the professors of dissection. Along its lower part it resembles a long valley between two neighboring mountains, forming an acute angle along its length. Indeed, in its upper seat, the cavity is seen as curved or rounded along the void, similar to a body imitating the appearance of a tortoise shell. Later more will be explained about the structure of this body.

PASSAGES THAT ORIGINATE FROM THE THIRD VENTRICLE

My discussion on the ventricles has just started, and we have described two of them, the right and the left one, and now we will describe the third one, namely the cavity common to both of them, which gives origin to the two following passages. One of these starts from the lower part of the third ventricle,74 where it forms an acute angle like a groove along its entire length and goes downward straight toward the gland receiving the cerebral phlegm.75 The other76 is more posterior and this is certainly not an irrelevant part of the third ventricle: it passes down between the testes and buttocks77 of the brain and over the upper part of the dorsal cord to reach the fourth ventricle from a posterior direction. The origin of these passages is not exactly circular but somewhat triangular. In fact, the passage that originates from its lower region has the same acute angle as the cavity from which it derives, whereas in the upper region close to the pineal gland, which controls the division of the vessels directed to the third brain ventricle, a transverse line connects the sides of the angle of the cavity. In this way it forms two more angles that create the opening of the passage that faces the fourth ventricle under the brain buttocks. From the lower angle of this passage, just where it begins its course between the cerebral testes, another passage78 can sometimes be seen: this runs downward and forward through the brain substance, eventually reaching the funnel which, as we will properly explain, receives the cerebral phlegm. 96 BRAIN RENAISSANCE

DESCRIPTION OF THE FOURTH VENTRICLE

The fourth ventricle, to which the posterior passage of the third ventricle extends, is made by cavities of the dorsal cord and the cerebellum. The whole ventricle is not carved in the body of the cerebellum but is a single cavity that resembles the space between two hands joint together. The dorsal cord originates from the region of the brain where the third ventricle first connects to the fourth ventricle through a passage. The brain’s testes and buttocks are continuous with the upper part of the dorsal cord and, together with this initial part of the dorsal cord, give origin to the third ventricle, so that the superior part of the passage is carved in them, whereas the inferior part arises from the dorsal cord. After the buttocks, the portion of the passage that is sculpted in the dorsal cord begins to broaden out, forming a cavity that extends almost to the point where the dorsal cord is about to leave the skull. Herophilus correctly compared the cavity of the fourth ventricle to the concavity inside a reed pen that we use to write. Indeed, if you compare this cavity to the part of the pen we dip into the ink, you will certainly recognize that the orifice in the pen, still rounded and close to the incision, corresponds to the end of the passage of the third ventricle that protrudes below the brain buttocks. You will also observe that the tip of the reed pen that we use to write letters resembles the bottom of the sinus, where a sort of pore or narrow passage extends into the dorsal cord when this is about to leave the skull. You will notice that the two angles of the reed pen, which are at the sides of the cavity of the reed, between the tip and the beginning of the upper section of the quill, remarkably resemble the sides of the ventricular cavity. At the sides of this cavity, in correspondence of those angles, there is, on each side, a circular process79 of the dorsal cord, to which only the cerebellum is attached, and that forms a continuous body with the dorsal cord. And this is the anatomy of the cavity of the dorsal cord, which contributes to form the cavity of the fourth ventricle. I am now about to tell you more on the cavity that can be observed in the cerebellum. Between the two round parts of the cerebellum by which this attaches to the dorsal cord, and between the ends of that cerebellar part that we considered as its third portion, a shallow cavity, whose width is greater than its length, is impressed. This constitutes the part of the fourth ventricle that opens anteriorly and posteriorly, where as neither the anterior nor the posterior part of the cerebellum is attached to the dorsal cord. However, this cavity is sealed at the front and at the back by the thin membrane of the brain: in fact, anteriorly the thin membrane covers the space where the cerebellum is linked to the brain and the brain buttocks, whereas posteriorly it is covered by a portion of the thin membrane that binds the cerebellum to the dorsal cord.

THE CONTENT OF EACH VENTRICLE

At the dissection table the fourth ventricle appears to contain nothing but aqueous humor, which is shared with the other ventricles as well as the passage from the third 97 On the Cerebral Ventricle cerebral ventricle to the fourth. The right and left ventricles contain, in addition to this humor, a certain plexus that those skilled in dissection compare to the outermost wrapping of the fetus. The common cavity, or third ventricle, allows the passage of the venous vessel that, as we taught in Book III, originates from the fourth cavity of the hard membrane and contributes to the formation of the plexus. Occasionally the anterior part of these ventricles receives from this vessel certain small and thin venules that are very similar to the ones we can observe arrayed across the adherent tunic of the eye. And these venules are more prone to be attached to the surface of the ventricles because the cerebral substance is harder and almost more callous at the surface of the ventricles than elsewhere.

THE FIRST THREE CEREBRAL VENTRICLES ARE NOT ENCLOSED BY THE THIN MEMBRANE

I am astonished by Galen and all his followers that confided excessively and wrongly in him (as if they could learn something good), who have passed on matters concerning anatomy and have been publishing incorrect facts without performing any dissection of their own. They were not ashamed of writing that the surface of the first three but not the fourth cerebral ventricle is, like the brain itself, surrounded and covered by the thin membrane: in fact, no surface of any ventricle or passage is covered by the thin membrane at all. Who, I wonder, while diligently examining the parts of the human fabric, without being dependent upon the writings or pictures of others (as, reasonably, nobody should be), will not see how Galen used his imagination for many things, and especially in the books of De usu partium? And in fact, he thought the brain substance was so soft that the ventricles carved in it would have collapsed if they were not enclosed by the thin membrane. Then, by attributing a harder substance to the cerebellum, he persuaded himself that its ventricle could work without the benefit of a membrane to support it. I do think that, when Galen was writing those books, he had read, in the work of Herophilus, or Andreas, or Marinus, or Lycus, or certainly other outstanding professors of dissection at Alexandria, the description of the cerebral thin membrane and its processes extending into the three brain ventricles, but not into the fourth ventricle. By doing this they were not indicating that the thin membrane, like the peritoneum or the tunic undergirding the ribs, coats the ventricles. They were aware that those parts of the thin membrane deliver vessels into the ventricles, and that these vessels originate the plexuses formed like the placenta. But no part of the thin membrane extends to the fourth ventricle. Indeed, in addition to the fact that there is no reason that could justify the presence of the membranes in the ventricles, such membranes could represent a possible obstacle in between, and would prevent the brain substance from transforming the material delivered to its ventricle into the animal spirit. Besides the processes of the thin membrane already mentioned, the right cerebral ventricle and the left contain in their posterior region the uppermost part of the body shaped like a chamber or tortoise shell, at the point where this begins to bend 98 BRAIN RENAISSANCE downward. Incidentally, I wanted to mention this body here (so it will not seem that something has been passed over in the description of the ventricles). After the following paragraph in which I will review the function of the ventricles, certainly there will be a chapter dedicated to this particular body. Here I must end this chapter by making reference to the function of the ventricles.

FUNCTION OF THE VENTRICLES

At the beginning of this book, when I started to give an account of the brain functions in passing, I included everything I dared to mention and commit to set down in writing. For the moment, I have told that the ventricles are nothing more than cavities or passages in which air is attracted by inspiration, and the vital spirit, conveyed to them from the heart, is mutated into animal spirit by the power of the substance of the brain itself. Then, the animal spirit is distributed through the nerves to the organs of sense and movement. By means of this spirit and their structure, which is adapted to their tasks, these organs perform their function, whereby the muscles move, the eye sees, the olfactory organs smell, the organs of hearing perceive sounds, the tongue distinguishes flavors, and every innervated part discerns tactile qualities. I do not hesitate to ascribe to the ventricles the function of generating animal spirit, and I believe that nothing should be told about the locations in the brain of the faculties of the supreme spirit (although those who nowadays are proud to be called theologians think they can do anything with impunity, even dare to localize them). All those theologians, with whom we have to cohabit, strongly deny the special powers of the supreme spirit to apes, dogs, horses, sheep, cattle, and similar animals, and not to mention other powers; for what I can understand from them, they attribute only to man a faculty of reasoning, and the same to all humans. But, at the dissection table, we observe that humans do not surpass these animals for what concern the cerebral cavity: not only is the number the same, but everything else is extremely similar from one to another (with the only exception of the size and the integrity of the sense of justice). Hence, even when concerning humans, I abstain from another inquiry into the function of the ventricles, and from mentioning the opinion of Galen, who taught in the third book of De Placitis Hippocratis et Platonis that the middle ventricle was the most important one, whereas in De usu partium it was the posterior ventricle. And let us sing hymns to God, the Creator of all things, and give thanks to him for providing us with a rational spirit. This is something we have in common with the angels (as Plato, mindful of the much-criticised philosophers, also referred to) and whose benefit, if faith is present, we shall enjoy in eternal happiness, when the place and substance of the soul shall be investigated without the need for body dissection or a reason limited by corporal impediment.80 He, who is true wisdom, will teach us when we no longer exist in a body subjected to degeneration and putrefaction, but rather in a spiritual body very similar to His own. But until then we are still what our feeble reason keeps saying we are, so let us chase in the remaining parts of the brain, to the best of our abilities, the ingenuity of the Creator of all things.

Commentary

THE LIQUOR OF OUR SOULS

Just as inspecting the surface of limestone bedrock will tell you little about the depths of the caverns below, the brain surface reveals nothing of its own intricate system of cavities. Hidden deep, straddling the center of the brain, are a set of chambers and passages that in antiquity were considered the ultimate “seat of the mind,” the ventricles (Figure 18.1). To gain access to these well-concealed cerebral regions, ancient Greeks developed what at the time was a revolutionary method to study the brain, one we now term sectional anatomy. Back then the Greeks achieved this by removing the upper part of the skull and slicing the brain without removing it from the head. Sectional anatomy originated around the end of the fourth century B.C., probably owing to the work of Herophilus of Alexandria, a Greek physician who paid particular attention to the ventricles. Herophilus noticed that these cavities are filled with a fluid, or “liquor,” which we now call the cerebrospinal fluid. He considered this liquor to be the origin of the “animal spirit” or “soul,” which would flow through the nerves and move the muscles. What Herophilus was promoting is one the most enduring, but ultimately incorrect, theories in neuroscience—the ventricular theory of brain function.

Anterior (frontal) horn Lateral ventricle (body) Posterior (occipital) horm

Pineal recess

ird ventricle

Interventricular foramen of Monro Acqueduct of Sylvius

Inferior (temporal) horn Fourth ventricle Fastigium Lateral recess and foramen of Luschka

Median aperture (or foramen of Magendie)

Fig 18.1 The ventricular system reconstructed with MRI (Catani and Thiebaut de Schotten, 2012).

99 100 BRAIN RENAISSANCE

The work of Herophilis is almost entirely lost. But some of his insights are reported five hundred years later in the writings of Galen, who studied in Alexandria:

“Since all the nerves below the head spring either from the hind-brain [cerebellum] or the spinal cord, the [fourth] ventricle must be of considerable size, and receives the animal spirits previously compounded in the anterior ventricles; so that there must necessarily be a passage from them to it.” (Translated in Dobson, 1925)

Galen grew up surrounded by scholarly tradition. His father was an architect with interests in mathematics, philosophy and astronomy, and he urged his son to study medicine. Within a decade of graduation, Galen had earned a reputation as one of the most accomplished medical practitioners, anatomists, and philosophers of his time. He traveled widely, immersing himself in different medical theories, and became the personal physician to several emperors in Rome. This meant that his personal belief in the ventricular theory made it popular, and it rapidly became the central dogma in the philosophy of mind. Unlike those before him, Galen went a step further in his exploration of these brain cavities. He wanted proof that his belief about the ventricles and their central role in producing mental activities was a correct one. He performed vivisection on animals to compare the effects of different ventricular lesions, reporting that while incising the posterior ventricles harms the animal the most, incision of the anterior ventricles causes a less serious injury (Figure 18.2). He accurately reports that compression of the ventricles can cause changes in mental states as well as to stupor

Fig 18.2 Two of Leonardo da Vinci’s drawings of the lateral ventricles. Left: Uncritical reproduction of the anterior, middle, and posterior ventricles of the human brain according to Galen’s doctrine (ca. 1490). Right: A more realistic representation of the anatomy of the ventricles from post-mortem dissections (ca. 1504). 101 On the Cerebral Ventricle and even coma. These effects were more pronounced in older animals than young ones (Rocca, 1997, 2003). In humans, he became skilful in performing the popular procedure of trepanation, the process of making a hole in the skull to release intracranial pressure. Galen applied this to hydrocephalus, the accumulation of water in the brain, to drain the fluid. To Galen, his experiments with vivisection and the clinical results of the trepanation were the direct evidence he needed that the central role of the ventricles was to produce mental activity. The more he performed these procedures, the more he became convinced that the ventricular theory was correct. Such was his conviction that, combined with the support of the church and a ban on human dissection, this dogma endured for thirteen hundred years after his death at the start of the third century. Vesalius was among the firsts to openly criticize Galen and the ventricular theory. What troubled Vesalius the most was purely a comparative issue. As humans, our ventricles are nothing spectacular compared with those of other animals. There are no special or extra cavities; they are not even the biggest. In this chapter, Vesalius argues that not only are the number of ventricles the same “but all other things are very much alike in man and animal except in respect to the mass of the brain and a temperamental urge toward upright conduct.” Vesalius’s open criticism initiated a slow decline in the ventricular theory. It progressively lost credit among anatomists, even though the idea of fluids or spirits flowing through the brain continued to endure. In the eighteenth century in particular, anatomists and philosophers enjoyed putting forward a variety of different structures and theories for brain function. To Thomas Willis, for example, mental activities were the product of the spirit flowing from inside the brain to the outside through the striatum and the corpus callosum (see Chapter 16). To the French philosopher René Descartes the oscillations of the pineal gland moved by animal spirit transformed sensation into cognition (see Chapter 20). When it comes to structure, except for the identification of tiny passages between different ventricular cavities by Monro (1783), Magendie (1842), and Lushka (1855), the anatomy of the ventricular system has remained largely unchanged for the last three centuries. There are two lateral ventricles, a right and a left, which then link to the third and fourth. This is not to say, however, that ventricles have no importance in contemporary medicine. Since the advent of neuroimaging, an enlargement of the lateral ventricles (ventriculomegaly) represents the single most replicated finding in patients with schizophrenia (Johnstone et al., 1976). What makes this finding so remarkable is that until this point mental disorders were thought to have no anatomical basis. This enlargement of the lateral ventricles is asymmetrical, more so on the left than the right, and increases progressively throughout life (Kempton et al., 2010). It would be easy to identify this as possible evidence that Galen was correct all along. In fact, ventriculomegaly is a byproduct of the surrounding brain structures slowly wasting away, causing the ventricles to expand and fill the space. This wasting is not specific to schizophrenia and is found in other disorders of the brain, including bipolar affective disorder, Alzheimer’s disease, Parkinson’s disease, and even simple 102 BRAIN RENAISSANCE blockage of the ventricles. These are not the only disorders that can cause enlargement of the ventricles. Blockage of ventricular flow can lead to an often fatal brain abnormality associated with hydrocephalus. In the normal brain, a drop of liquor is secreted into the ventricles every minute. Most of this liquor is produced from inside the lateral ventricles, from whence it passes to the third and fourth ventricles. Through the foramina of Luschka and Magendie, the liquor flows into the space surrounding the cerebellum and the brain before being reabsorbed by a special membrane called the arachnoid. The flow of this liquor plays a few important roles. First, the brain floats in it, which prevents the lowest part of the brain from being squashed under the magnitude of its own weight. Second, in the event of trauma, the liquor limits brain movement and diffuses its impact on the surrounding skull. Third, the liquor collects dangerous toxins and flushes them away. But when the flow is restricted, as with hydrocephalus, a backlog of liquor can occur. The pressure then rises quickly. Within days the stress and force of the buildup can start to damage the nervous tissue and, in young children, even the tender bones of the skull expand (Figure 18.3, left). The results can be devastating. When hydrocephalus occurs early in life, the damage is often deadly. High pres- sures distort the weaker, developing bones of the skull, causing an alien-like deformation of the head. Some children do survive but go on to have significant neurological problems. In old age the story is slightly different. There is no deformity. The stronger skull of an adult can cope with the increase of pressure, but at the expenses of the softer brain substance that is progressively damaged. Cognitive impairment, loss of balance and incontinence are the typical consequences of this condition. The aim of modern treatment for hydrocephalus does not differ from that of Galen’s era nearly two millennia ago. Modern medicine’s only real improvement is

Fig 18.3 Hydrocephalus in a child (left) and in a 68-year-old man (right). Note that while hydrocephalus in children often leads to enlargement of the head, in adults an increase in intracranial pressure causes dilatation of the lateral ventricles and brain damage without bone deformation. 103 On the Cerebral Ventricle that we now try to make sure that the body reabsorbs the fluid. Cerebral shunts are placed into a ventricle to bypass the blockage, drain liquor, and reduce intracranial pressure. The surgeon then directs the excess of liquor into a different body cavity, such as that of the abdomen, from whence it can be reused. Despite this progress, mortality and the neurological consequences of hydrocephalus remain high. Hydrocephalus is a true medical emergency. So as much as Vesalius was right to criticize the ventricular theory along with Galen’s and his peers’ blind faith in his anatomical teachings, even Vesalius would be forced to humbly admit that Galen’s clinical acumen deserves our highest respect.

19 On the Brain Structure That Expert Dissectors Have Compared to a Tortoise-like Vault

S, T, V in the fifth figure [A5] show from above the position of the structure that is called Zach or Zachd in the books of Arabic commentators. Similarly, L, M in the fourth figure [A4] display part of the same structure as well as B, C in the sixth figure [A6], where its inferior part is indicated with A, A, A.

This structure, shaped like an arch or a tortoise, is one of those parts of the brain that extends continuously from right to left. It is therefore a single structure in the middle of the brain, common to both sides. It has the same substance, length, and function as the corpus callosum, but a shape and origin of its own. This structure originates from the rear of the right and left ventricles, precisely where they bend anteriorly and ventrally, and its substance is similar to that of the walls of the cerebral ventricles, although somewhat harder and whiter. The portion of this structure that originates from the right ventricle is continuous with the one from the left ventricle.81 These two parts form the body of the fornix, and as they leave the substance from which they originate, they always abruptly end at the level of the cavity shared by the right and left ventricles.82 Here, this structure forms an acute angle with the cerebral substance and merges with it, but for the rest of its inferior surface it is not attached to the three ventricles or connected to them by any other element.83 This structure has a triangular shape with sides of different length. The first side, which is the shortest, extends between the posterior regions of the right and left ventricles. The second side lies in the right ventricle and projects medially from the back to the front end of the third ventricle. The third side lies in the left ventricle and equals the second side in length. Along these two sides are the plexuses that professors of dissection explain to be similar to the placenta.84 Given that all three sides are equally distanced, this structure connects to the brain only by its three corners. In its upper region, the structure and the cerebral substance are in contact and form a single forward-facing acute angle. In its lower area, the structure has a single triangular surface resembling a tortoise or arch-like vault. This analogy and its function led the ancient Greeks to use the term psalidoeides to describe it. This surface forms the roof of the third ventricle and the common part

104 105 On the Structure Compared to a Tortoise-Like Vault of the right and left ventricles. The upper surface of this structure is curved, whereas the lower surface is concave and not always linear and continuous like the upper one. In fact, the upper surface continues along the entire length of the body and forms an acute angle in the midline where it merges with the septum of the right and left ventricles, creating a single surface that is visible on each side. This surface originates from the posterior region of the ventricles and is rounded in shape, similar to an elongated sphere85, which has been mistaken for the buttocks of the brain by previous anatomists. In Italian universities, others have arrogantly considered them to be the vermis of the brain,86 thus claiming to have made a remarkable discovery. But here I must refrain from giving further space to such inept anatomists: they are not only totally ignorant but they ostensibly claim to have made great discoveries, which are facts of little significance and rather useless to medicine. Moreover, they try hard to prove, wrongfully and trivially, what Galen had already elegantly and precisely demonstrated.87 All the surfaces of this tortoise-like vault are entirely even and perfused with an aqueous liquid. They face the three ventricles: as already mentioned, the whole lower surface forms the top of the third ventricle; the right side of the upper surface is directed toward the right ventricle, and the left surface turns to the left ventricle. As a matter of fact, these ventricles are not covered by the thin membrane, and the vaulted body is entirely free of this membrane; indeed, nothing but the brain substance contributes to its composition. Nature created this tortoise-like vaulted structure to sustain the third ventricle and to prevent it from collapsing; at the same time its upper part offers resistance, thus acting to maintain the same width. This structure is appropriate for this function, being erected on the three corners on which it rests. Moreover, it raises the septum between the ventricles, which is also held up by the corpus callosum. This structure, which extends along most of the cavity of the third ventricle, allows the vessel from the fourth dural cavity to pass underneath itself and protect it from compression.88 This vessel pursues a linear course in the third ventricle, then splits into two parts that follow the right and left ventricles.

Commentary

THE FORNIX: A MEMORY THREAD IN THE BRAIN

The arched fiber bundle described by Vesalius as the tortoise-like body is known in modern neuroanatomy as the fornix. We now recognize that it connects brain regions dedicated primarily to memory—from the hippocampus to the hypothalamus and mammillary bodies. Through direct observation of fresh specimens, Vesalius produces a description that is accurate in many respects but also one that is unoriginal. Galen made similar observations and speculation that the fornix may play a mechanical supportive function was common among earlier anatomists. What makes Vesalius’s contribution so unique is the quality of the illustrations. Such accurate detail was truly pioneering. Together with the corresponding text, this chapter became a powerful resource for medical students and dissectors performing autopsies. Experimental tracing methods in animals (Gudden, 1870) and more recent neuroimaging techniques in humans (Concha et al., 2010; Scheltens and van de Pol, 2012; Catani et al., 2013a) now provide us with far more detailed visualizations of the fornix (Figure 19.1). Thanks to these methods we now understand how damage to its fibers impairs memory (Vann and Aggleton, 2004). The story of the fornix, from its origins to the present day, is a remarkable one that says as much about how science was performed through the ages as it does about the function of the structure itself. Among the anatomists of the Greek school of Alexandria, the term psalidoeides (arch-like) was commonly used to indicate the structure’s bending shape. But the term was also used to indicate the corpus callosum, and the two structures were assimilated into one single entity. The word fornix did not come into common usage for another couple of centuries. The influential Roman physician Galen agreed with the Greeks in many respects, but he correctly criticized those who either claimed the fornix to be nonexistent or used the term wrongly to indicate the whole corpus callosum (Galen, Book IX) (see Chapter 17). He borrowed the figurative concept of arch-like during his descriptions and started the interchangeable use of the two Latin terms fornix and testudo. Why he chose these words is of some debate. Fornix derives from the Latin root far meaning “to sustain,” and this would make it an obvious choice if there had not been a wealth of suitable alternatives. The Roman architect Marcus Vitruvius uses the terms arcus, camera, fornix, and testudo without distinction in referring to vaulted ceilings. Given that Galen was a son of a famous architect, he may have chosen fornix after hearing it from his father (Rocca, 1998). Yet as attractive as this theory is, it appears unlikely. Galen himself acknowledged that the term was already adopted in

106 107 On the Structure Compared to a Tortoise-Like Vault

Body of fornix

Fimbria of fornix Posterior commissure

Column

Termination in the mammillary bodies

Hippocampal projections

Fig 19.1 Tractographic reconstruction of the fornix. Fibers arise from the hippocampus of each side, run through the fimbriae (i.e., the two legs of the fornix), and join beneath the splenium of the corpus callosum to form the body of the fornix. Other fimbrial fibers continue medially, cross the midline through the hippocampal commissure, and project to the contralateral hippocampus. Most of the fibers within the body of the fornix run anteriorly beneath the body of the corpus callosum toward the mammillary bodies and the hypothalamus (Catani et al., 2013a). other areas of anatomy before his time, so it seems more reasonable to suggest that he simply picked it up from there. Others have speculated that there may be a more seedy reason for the choice. In ancient Rome, fornix found its way into popular usage as slang for a poky and uncomfortable room usually inhabited by prostitutes, slaves, or poor Roman citizens. Prostitutes were restricted to soliciting their clients under the archways of outer city gates. The architectural termfornix thus became interchangeable with brothel and, by association, the verb fornicare (to fornicate) identified the sinful act of sex performed in these rooms (Pianigiani, 1993). According to this explanation, the term fornix alludes to its fallic shape. Finally, Singer suggested that the term testudo refers to the siege device in which a number of heavily armed soldiers hold curved rectangular shields over their heads in combined defensive formation. This explanation also contrasts with the opening caption written by Vesalius, where he refers to the Arabic term Zach or Zachd, which means “long-roofed chamber,” for fornix (Singer, 1952). Vesalius’s description of the fornix, like that of Galen, is incomplete. His view of the structure was constrained by the dissection method he used. Vesalius used in situ dissection, where the brain is sliced without being removed from the skull. This was a popular method at the time. Cutting the brain along a back-to-front plane (axial) allowed him to expose and illustrate the full longitudinal extension of the central part of the fornix (the body). Observing the serial sections of the fornix meant that the close relationship of the fornix to other structures could be appreciated. So while 108 BRAIN RENAISSANCE there were benefits to his method, it also meant that Vesalius never explored deeply enough to reveal the full extent of the fibers. Vesalius failed to identify the ventral projections, which left his description of what we now refer to as the fimbriae of the fornix incomplete. Instead, Vesalius erroneously attributes the origin of the fornix to the lateral ventricles. Vesalius’s oversight was soon corrected. As a pupil of Vesalius, the Italian anatomist Giulio Cesare Aranzio began to produce his own highly original and figurative observations, some of which are still in use today (Aranzio, 1587). The fornix, he correctly reported, actually originates at the hippocampus, which he likened to the “image of a little seahorse” or “a white silkworm” (Lewis, 1923). But how was the student capable of making observations that his master had missed? The answer rests on his choice of the dissection technique. Aranzio adopted a revolutionary method introduced by Costanzo Varoli ten years after the death of Vesalius. Whereas Vesalius kept the brain in the skull, Varoli removed it. He would then slice the brain from the base upward. In this way, Varoli discovered the pons, later named after him aspons Varolii, and many other structures (Varoli, 1573). Removal of the brain from the skull not only gives dissectors better access to deep structures located in the brain stem but also means that they can perform dissections along different planes. This methodological shift is evident on directly comparing Vesalius’s drawings with the figures in Thomas Willis’s Cerebri Anatome (1664). In the latter, the brain can be seen from different views and the overall anatomical features appreciated in more detail. There is little doubt that this technique allowed Willis to make a lasting contribution to neuroanatomy. Willis was the first to use the term limbus (from the Latin word for “border”) to indicate a set of cortical gyri (i.e., cingulate and parahippocampal gyri) encircling the brain stem and terminating at the hippocampus (Figure 19.2) (Willis, 1664). As we will see, Willis’s “limbus” and the fornix became integrated in a unitary model of memory and emotion called the limbic system (Catani et al., 2013a). Identification of the ventral origin of the fornix took only a decade, but the search for its anterior termination lasted two hundred years. As a pair of rounded tubercles, the mammillary bodies are tiny, the size of small peas, and are located in the region where the ventral surface of the anterior brain joins the brain stem. While missed by Vesalius, they were described by one of his contemporaries. Bartolomeo Eustachi made the first anatomical reproduction of the mammillary bodies in his Tabulae Anatomicae but never proceeded to trace their connection (Meyer, 1971; Jones, 2011). It was Felix Vicq d’Azyr (1786), more than two centuries later, who identified the link between the fornix and the mammillary bodies. At the same time, Vicq d’Azyr also detected a small bundle in the proximity of the anterior part of the fornix connecting the mammillary body to the thalamus—a connection we now call the mammillothalamic tract or tract of Vicq d’Azyr (Figure 19.3). The method of fiber dissections employed by Vicq d’Azyr was advanced in many respects but crude in delineating the exact course and origins of these small tracts. 109 On the Structure Compared to a Tortoise-Like Vault

Fig 19.2 Thomas Willis described the limbic system for the first time in 1664 to indicate cortical regions located around the brain stem (Willis, 1664).

It was left up to the German psychiatrist Bernhard von Gudden to provide definitive evidence for the separation of the mammillothalamic tract from the anterior columns of the fornix—an achievement he managed through a technique we still refer to as the Gudden method. Gudden ingeniously chose to sever neuronal tracts or damage their origin. This induced secondary degeneration and atrophy, but only in the affected fiber connections (Gudden, 1870). Gudden found that he could now trace the origins not by following what was there but by observing what was missing. It was nearly the end of the nineteenth century and knowledge of the fornix had reached an impasse. Anatomists knew where it started, where it ended, and how it arched beautifully in between. But few people if anyone had considered its importance to brain function. The Greeks, Romans, and Vesalius, after all, dismissed it as a purely supportive structure. The next one hundred and fifty years saw a dramatic shift in opinion. The first suggestion of a possible link between fornix and memory was made by the German brothers Gottfried and Ludolph Treviranus (1816). They noted that the hippocampus, in virtue of its many connections and especially those of the olfactory system, “is probably involved with a higher mental function, perhaps that of memory” (Meyer, 1971). Subsequent studies in animal models by later anatomists reinforced its role in olfactory memory. But then things stalled. Half a decade drifted by, and it was not until 1878 that someone again took notice of this strange arch-like structure. That someone was Paul Broca, most famous for his research into a region of the brain that would later take his name—Broca’s area, the brain’s speech center (see Chapter 16). Along with the 110 BRAIN RENAISSANCE

Fig 19.3 The fornix (arrows) and the mammillo-thalamic tract (arrowheads) described by Vicq d’Azyr (1786). The mammillary body is indicated by the asterisk. center for language, Broca enjoyed proposing models for other brain regions. His grand lobe limbique is a system composed of the fornix, the “limbus”, the cingulate cortex described by Willis, and the olfactory nuclei (Figure 19.4). Broca compared specimens from different species to argue that this system was mainly, but probably not exclusively, an olfactory structure common to all mammalian brains. After Broca’s report, functional evidence started to accumulate. In animals, ablation studies (where brain tissue is surgically removed) broadened the role of the

Fig 19.4 Thegrand lobe limbique described by Paul Broca (1878) consisted of the hippocampal gyrus (H, H’) and cingulate gyrus (C, C’, C’’), both connected to the olfactory bulb (O). 111 On the Structure Compared to a Tortoise-Like Vault limbic structures beyond olfaction to include social behavior (Brown and Schäfer, 1888) and physiological response to harmful events (fight-or-flight response) (Cannon, 1927). In humans, clinical accounts of patients with memory deficits reinforced the link between the fornix and memory, confirming that olfaction may be only part of the story. People with Korsakoff syndrome suffer from an inability to form or retrieve memories. This amnesia is the result of peripheral nerve degeneration and mammillary body hemorrhaging due to chronic alcoholism. It was first described by the Russian Sergei Korsakoff (1897), who noted an intriguing aspect to the disease—amnesic patients attempted to fill their memory voids with confabulatory accounts based on dreams, real events, and fantasies (Gamper, 1928). Three years later, Wladimir Bechterew reported the case of a man with similar memory deficits following a bilateral hippocampal stroke (Bechterew, 1900b). Thus, lesions to either end of the fornix appeared to cause similar problems in memory consolidation. Using the growing wealth of evidence in animal and human studies, Bechterew went on to propose a more advanced version of Broca’s “limbique” model. As detailed as Bechterew’s model is, he missed one fundamental element: direct connections between the orbitofrontal cortex and the thalamic nuclei that receive projections from the mammillothalamic tract. This model of the limbic network, the one we know today, became popular due to the influence of James Papez (Figure 19.5). In the period between the two world wars, he proposed that the limbic network was composed of subcortical projection fibers centered around the fornix and hippocampus. The fornix, he mused, probably plays a central role in emotion (Papez, 1937). While largely incorrect about the function of the fornix, he became famous for his limbic network. Throughout North America it became known as the “Papez circuit.” Yet Papez made no reference to where his influences lay; Broca and his “limbique” system received no mention. And neither, intriguingly, did another neuroanatomist, Christfried Jakob who thirty years earlier made a strikingly similar observation (Figure 19.5) (Jakob, 1906). In fact, the Papez circuit is an exact duplicate of the Jakob circuit. But unlike Jakob, whose work was largely ignored, Papez’s influence during the second half of

Fig 19.5 The limbic system as an integrated system of cortical and subcortical structures linked by projection and association tracts was described for the first time by Christfried Jakob in 1906. James Papez reproposed the diagram in 1937 and linked it to emotion processing. 112 BRAIN RENAISSANCE the twentieth century, when surgery took center stage in the treatment of psychiatric disorders, was lasting. Neurosurgeons liked the Papez model. It provided the anatomical rational for possible treatments of mental disorders. Carlyle Jacobsen and John Fulton tested this by performing lobotomies—cutting away a portion of the frontal lobe—in chimpan- zees. After the operation, the chimps displayed a reduction in aggressive behavior without any apparent loss of other mental functions. Jacobsen and Fulton were also unable to provoke a form of experimental neurosis in these animals, supporting the idea that projecting connections from the thalamus to the frontal lobe mediate aggressive behavior (Jacobsen et al., 1935; Fulton, 1952). Jacobsen and Fulton presented these results in 1935 at the Second International Neurological Congress in London, attended by the most prestigious clinical neuroscientists of the time. Among them was Antonio Egas Moniz, a neuropsychia- trist from the University of Lisbon, who was greatly influenced by what he heard. Upon returning to his clinic, he had the idea of applying this frontothalamic disconnection approach to humans with severe psychoses. Together with the neurosurgeon Almeida Lima, he performed the first leucotomy, or white matter cutting, by injecting pure alcohol into the frontal lobe (Moniz and Lima, 1936). The results pleased them. Symptoms generally improved in severely agitated depressive patients, with a more modest effect in patients diagnosed with chronic schizophrenia (Moniz, 1937). Shortly after his first report on leucotomy, Moniz was visited by Walter Freeman, an ambitious American neurologist. Despite a high rate of side effects, Freeman pop- ularized the method in North America by simplifying the procedure. Armed with an adapted ice pick, he began doing transorbital leucotomies by introducing the device into the brain through the internal corner of the eye cavity (Figure 19.6). This “ice pick” leucotomy was easy to perform and became a common treatment for chronic

Fig 19.6 Walter Freeman performing an “ice pick leucotomy” in a psychiatric patient. 113 On the Structure Compared to a Tortoise-Like Vault psychiatric patients living in asylums. In a span of two decades, Walter Freeman operated on more than 3,000 patients (Freeman, 1957). Moniz’s report paved the way to other experimental neurosurgical treatments. One of these was proposed by William Scoville. As a young neurosurgeon practic- ing at Hartford Hospital in Connecticut, he pioneered the unilateral resection of the hippocampus for the treatment of psychosis. He made the remarkable observation that the operation not only diminished psychosis but also reduced seizures in two psychotic women suffering with epilepsy (Scoville et al., 1953). Within months he was operating on Henry Gustav Molaison, a 27-year-old who had had partial seizures since the age of 10 (Figure 19.7). Henry’s epileptic fits had become more and more severe throughout his teenage years. When pharmacological treatments failed to fully control the seizures, the family doctor advised his parents to consult Dr. Scoville for possible neurosurgery. The electroencephalographic results on Henry showed diffuse bilateral activity, making it difficult to determine the exact site of the epileptic focus. Dr. Scoville chose to perform his experimental procedure on Henry, but this time on both sides of the brain. The treatment was a success inasmuch as it ameliorated the seizures. But unfortunately Henry plunged into severe anterograde amnesia (Scoville and Milner, 1957). He was unable to remember any of the events that occurred in his life after the operation. Henry could still maintain information in his mind for a few seconds, but his ability to convert short-term memories into long-term ones was completely lost (Corkin, 2013). This surgical reign terror continued into the 1960s, when new data began to emerge—like the story of Henry Molaison—concerning severe side effects from such procedures. Coupled with the introduction of chlorpromazine, an antipsychotic agent for rapid tranquilization, this era of radical surgery for severe psychiatric and neurological disorders finally came to an end (Finger, 1994). The case of Henry

Fig 19.7 Henry Molaison, know as patient H.M., suffered with severe amnesia throughout his life following bilateral hippocampal removal (white arrow) as surgical treatment for epilepsy (Corkin et al., 1997). 114 BRAIN RENAISSANCE

Time 0 18 months 36 months

Fig 19.8 Progressive atrophy of the hippocampus in a patient with Alzheimer’s disease (Scheltens and van de Pol, 2012).

Fig 19.9 Electrodes implanted anteriorly to the columns of the fornix in a patient with Alzheimer’s disease. (Figure courtesy of Andres Lozano)

Molaison was heralded as an important lesson in neuroscience, a tragic experiment never to be repeated in the years to come. In modern times, memory deficits like those suffered by Henry Molaison are more likely to occur in patients with bilateral damage to the fornix, often after stroke, encephalitis, or brain tumor (Markowitsch, 2000). These patients present with global amnesia, making it impossible for them to encode, associate, or retrieve new information. Other patients with damage confined to the fibers of the fornix but without involvement of the hippocampus or mammillary bodies do present with anterograde amnesia, although seemingly not as severe as that resulting from bilateral hippocampal damage (Aggleton, 2008). 115 On the Structure Compared to a Tortoise-Like Vault

Amnesia associated with injury is relatively rare compared with the most common forms of memory impairment, those associated with age-related disorders. Among these, Alzheimer’s disease is characterized by the accumulation of protein “plaques” (amyloid) and “tangles” (tau) in the brain, leading to progressive atrophy in areas such as the hippocampus (Figure 19.8). Alzheimer’s disease remains one of the biggest challenges in modern neuroscience, not just in terms of understanding the disease but also, with an aging population, in reducing its social impact. Many experimental treatments are currently being tested, but the results have been less than satisfactory. A vaccine for Alzheimer’s disease failed (Lemere, 2009; Lambracht-Washington and Rosenberg, 2013). Moreover, novel drugs that were thought to be capable of arresting the accumulation of toxic proteins in the brain have proved to be disappointing. The hopes of millions of suf- ferers are currently in the hands of neurosurgeons trying to stimulate the recovery of memory by planting electrodes deep in the anterior columns of the fornix (Figure 19.9) (Lozano and Lipsman, 2013). The struggle to find a cure for Alzheimer’s disease is a reminder that despite the increasing knowledge of the anatomy and functions of the fornix accumulated over five hundred years, treatments for memory disorders are still in their infancy.

20 On the Cerebral Gland Resembling a Pine Nut

This gland is indicated by the letter L in the seventh figure [A7], the letter M in the eighth figure [A8], and the letter D in the tenth figure [A10].

LOCATION OF THE PINEAL GLAND

In the proximity of the posterior part of the fornix, where the venous vessel88 begins to travel from the fourth sinus of the hard membrane to the third cerebral ventricle, Nature created a small gland similar to a pine nut, or a cone, and for this it was named konarion or konoeides89 by the ancients. It is located under the origin of the venous vessel, with its tip facing upward and its base lying on the brain substance that is just posterior to the beginning of the passage90 that courses from the third to the fourth ventricle of the brain. Its position can be truly understood only if I add that it rests on the most superior and anterior part of the brain testes.91 Therefore, in man, it rests upon a region of the brain, but it cannot be considered as continuous with the cerebral substance nor a small part of the brain. In fact, in humans it does not adhere to the brain: very frequently, if one does not pay careful attention to what one is doing, it is pulled away with the venous vessel during dissection. However, in the lamb or in a sheep of advanced age, not only does it attach to the brain but it is also to some extent continuous with its substance. In addition, this gland is even smaller in man than in the lamb: it is thus more convenient to approach the brain of the lamb first, as it is easier to see this gland and other organs that will be described in the following chapters. In fact, in the lamb’s brain, these glands are very prominent and more fully formed, so that they can be conveniently compared to something else.

THE FUNCTION OF THE PINEAL GLAND

Galen denied that this gland, which is harder than the substance of the brain and whose nature is therefore closer to that of a hormonal gland than that of the brain, controls the closing of the passage from the third to the fourth cerebral ventricle, as it seemed to other professors of dissection. He, therefore, did not attribute to this

116 117 On the Cerebral Gland Resembling a Pine Nut gland the same function as to the glandulous body that is attached to the duodenum, and is under the right opening of the stomach and that Galen thought to be in charge of opening and closing the passage of the stomach. We showed in the appropriate place92 that it was not created for that task; so here too we agree with Galen that the present cerebral gland does not close the passage, especially because it is not suffi- ciently close to the passage to seal its opening. I think that this gland, like many other little glands in the body, was created to raise the vessel that enters the third cerebral ventricle. This vessel, immediately after its origin, divides into several branches weaving into the thin membrane and supporting it. The gland prevents the vessel, which lies upon the entrance of the passage, from blocking the animal spirit as it passes from the third cerebral ventricle to the fourth.93

Commentary

THE PINEAL GLAND: FROM THE SEAT OF THE SOUL TO “SAD” LAMPS

The structure Vesalius describes may be small, just five to nine millimeters in length, but it has a large philosophical and historical importance. Known today as the pineal gland, or epiphysis by some, it takes its name from a distinctive appearance that was first noted by Galen. It is shaped like a pine cone and lies along the midline of the brain (Figure 20.1), near the very center—a location that gives a tantalizing hint as to why many throughout history have glorified its importance and why, even today, despite its function being well defined, a few still shroud it in mystery. Vesalius, however, gave this tiny structure very little prominence. His description is short and unoriginal. On function, he merely repeats Galen’s assumption, and like the Roman physician, Vesalius rejects the idea, popular at the time, that the pineal gland regulates the flow of the spirit between the third and fourth ventricles. Instead, he held that it plays a purely structural role by sustaining the so- called great vein of Galen, one of the largest blood vessels in the human brain. But just a hundred years after Vesalius’s observations, the gland was transformed from being an afterthought to the potential location of all thought. As one of the few bodies in the brain without a double, its uniqueness did not go unnoticed by

Fig 20.1 Left: The MRI scan of a healthy subject showing the location of the pineal gland (arrow) in relation to the acqueduct of Sylvius (arrowheads) between the third (3) and fourth (4) ventricle. Right: The pineal gland is sometimes filled with liquid (pineal cyst), often a benign finding.

118 119 On the Cerebral Gland Resembling a Pine Nut

Fig 20.2 A representation of Descartes’s mechanism for the conversion of sensory inputs into perception and cognition. The letters A, B, C represent three objects that belong to the material world (res extensa). An image of these objects is projected onto the retina and then conveyed by the nerve “filaments” to the most internal part of the brain. This is indicated with NB and B, the space between which Descartes considered the seat of memory. The filaments release animal spirit into this space and generate a flow (indicated by the dots) that then reaches the pineal gland (H). Note that the points on the retina indicated by numbers 2, 4, 6 are symmetrically reversed on the surface of the pineal gland. The flow causes the pineal gland to move and with it the flap attached to it. Through the flow of the spirit and movement of the pineal gland and its attached flap, sensory inputs are transformed into ethereal perception and thoughts (Descartes, 1664a). philosophers, and it rapidly became one of their most debated topics. For one man in particular, it was as central to his theory of who we are as its location in the brain. René Descartes considered the pineal gland the best candidate for lodging the “seat of soul.” In his De Homine Figuris, Descartes described an ingenious mechanism that transforms sensory stimuli belonging to the material world (res extensa)—such as a face or a color—into cognition (res cogitans) (Figure 20.2) (Descartes, 1664a). According to Descartes, little filaments within the nerves convey the animal spirit from the more peripheral organs of sense to the central pineal gland. Here, the spirit generates small movements within the gland and its outer flap. These motions are then perceived by the mind and transform sensations into ideas, thoughts and memories. Descartes’s ideas on this subject received a less than warm reception. Opinions among his peers were hostile. The Dutch philosopher Baruch Spinoza replied to Descartes that his idea provoked reactions of either “laughter or disgust,” as it proposed that the human brain works like a mechanical device (Spinoza, 1677). But it was sound anatomical knowledge that was able to reject his theory altogether. Some of his basic anatomical assumptions were shown to be either incorrect or not 120 BRAIN RENAISSANCE able to back up his theory. A core requirement is the ability of the pineal gland to shift its position, for which no evidence exists. Thomas Willis used his deep knowledge of both human and animal brains to point out a further problem. He wrote that “it is hard to believe . . . that this is the seat of the soul, or that highest faculties originate from it; because animals, which seem to lack imagination, memory, and other superior powers of the Soul, have a large and remarkable pineal gland” (Willis, 1664). As Willis rightly suggests, the pineal gland is not unique to humans. In fact, it is present in different shapes and sizes in nearly all vertebrates, the exception being animals of early evolutionary origins such as the hag- fish, an eel-shaped, slime-producing marine vertebrate that has barely evolved for over three hundred million years. But if not the soul, then what is the pineal the seat of? Unfortunately and maybe not surprisingly, the pineal gland fell into obscurity for a further hundred years. Then Giovanni Battista Morgagni noticed something peculiar about the gland during his autopsies—it appeared to vary drastically not only between species but also within them (Morgagni, 1761). Morgagni described several cases of patients with abnormalities in the pineal gland’s texture, color, and size. These abnormal glands included a soft pineal gland from a “man who was insane and one night evaded his keepers and threw himself from the window.” Another pineal gland, that of a “twenty-one-year-old delirious wool-comber,” was of a rosy hue. The one found in an “intelligent thirteen-year-boy with convul- sions,” was unusually enlarged, as was that of “a middle-aged woman with mental derangement.” Other anatomists began to report that the gland appeared to change with age, showing signs of calcification in many older individuals. These were important hints for the possible functional roles of the gland that remained unnoticed until the 1898, when the German physician Otto Heubner reported the case of a young boy with precocious puberty. This is a rare condition where the child starts to develop secondary sexual characteristics, such as body hair and deep voice, at an unusually early age. What made this case interesting to Heubner was the existence of a tumor in the boy’s pineal gland (Heubner, 1898). Soon after he announced his finding, similar reports flooded in. Confusingly, though, the relationship was not straightforward. In a few patients the tumor appeared to have exactly the opposite effect on sexual development, leaving these children stuck in adolescence for a longer time. Reviewing the cases, scientists concluded that tumors near the pineal gland but not in it could hamper its function, causing early puberty. Tumors that were actually in the pineal tissue could cause an increase in its activity and seemingly delay the onset of adolescence (Kitay and Altschule, 1954). Interest in the gland was now on the rise, and with it came some surprising experiments with equally astonishing results. Carey McCord and Floyd Allen began working on the pineal at the John Hopkins University in the United States. Crushing one down from a cow brain, they placed it into a water tank along with a group of tadpoles. To their amazement the tadpoles’s skin began to bleach. Taken together, the cases of children with tumors and the experiments with tadpoles seemed to suggest that the pineal gland was releasing something, a substance that would become identified only in 1958. 121 On the Cerebral Gland Resembling a Pine Nut

Almost exactly 50 years after Heubner’s first observation, Aaron Lerner, an American dermatologist and expert on skin pigmentation, led a team of researchers who set out to isolate the pineal secretion. They identified it as melatonin, a hormone now known to play a role not only in the sexual development of children but also in the suppression of libido (Lerner et al., 1958). Melatonin is produced by a special type of pineal cell called the pinealocyte (Figure 20.3) (del Río-Hortega, 1922). These cells are unlike anything else in the brain, meaning that their origin is still highly debated. It has been suggested that they may belong to the same class as the retinal cells of the eye—the photoreceptors—a comparison that has led some to describe the gland as the “third eye.” Although this label may possibly be appropriate for a few cold-blooded vertebrates, where the pinealocytes

Fig 20.3 The histology of the pineal cells as described by Pío Del Río-Hortega (1922), a student of Santiago Ramón y Cajal. A, C, E indicate giant pinealocytes containing melatonin. F, H indicate cells that are degenerated owing to the presence of a calcified body (I). D and B indicate other smaller cells. 122 BRAIN RENAISSANCE have limited photoreceptor functions, it has little scientific grounding in humans (Holmgren, 1918). Our pineal gland has no photoreceptor properties, although this does not mean that it is entirely unaffected by visual stimuli. Indeed, the activity of the pineal gland is highly dependent on the circadian rhythm in our physiological processes, a roughly 24-hour cycle. Visual stimuli collected by the photoreceptors of the retina are first sent to the suprachiasmatic nucleus in the hypothalamus. Here a small group of neurons send axonal projections to the pinealocytes. In daylight, the circuit acts as a break, limiting the production of melatonin; during the night or in darkness, release of the hormone increases. This link between the circadian rhythm and the reproductive system is well exploited in modern farming. Given that melatonin has a suppressive effect on libido, chickens may be exposed to longer hours of light so as to limit release of the hormone and thus increase egg production (Wurtman, 1968). In humans the effects of melatonin and the circadian rhythm go much deeper. When taken in large doses, the hormone induces sleep and depresses mood, a potential explanation for why the incidence of depression is higher in winter. Those short days really could be affecting some people’s temperament. Such a theory has given rise to a controversial but remarkably simple treatment for the prevention of low mood in the so-called seasonal affective disorder (SAD). People affected by SAD are more likely to suffer relapses during the dark, cold winter months. Some of them are prescribed light therapy, which is often administered using special “SAD” lamps. Although initial trials proved inconclusive, later reports suggest that light therapy might be as effective as one of the most popular antidepressant drug (fluoxetine) (Lam et al., 2006), but with far less risk of side effects. Light therapy may not be suitable for everyone, however. Assuming that the effects of light on mood are mediated by a reduction in the levels of melatonin, one may wonder what effect this treatment would have in people whose levels of the hormone are already low. With age, for example, the progressive calcification and loss of pinealocytes in the pineal gland means that the production of melatonin at night is often reduced. This suggests that light therapy may have limited usefulness in older people; it also explains why children tend to sleep longer hours than adults, who often suffer insomnia in later life. In fact, in modern pharmacology, melatonin is used to modulate sleep patterns in a variety of people, from children with sleep problems and adults with jet leg to elderly individuals with insomnia (Borjigin et al., 2012). The role of the pineal gland and melatonin has recently expanded to other fields of neuroscience and medicine. Melatonin has proven to be an antioxidant and anti-inflammatory molecule able to reduce cell damage associated with oxidative stress and inflammation. This effect could be exploited in the near future to treat neurodegeneration, damage associated with stroke and myocardial infarction, and cancer (Pandi-Perumal et al., 2006). Vesalius could have not predicted the rises 123 On the Cerebral Gland Resembling a Pine Nut and falls of this little gland throughout the history. He, who denied this gland a regulatory role, would have been certainly surprised to hear the broad range of effects that melatonin has and its significant influence over many of the body's physiological functions. Although the pineal gland will never return to its splen- dors of Descartes’s philosophy, its central position in the field of chronobiology will continue to thrive.

21 On the Testes and Buttocks of the Brain

These structures are indicated first by M, N in seventh figure [A7], then by N, O and P, Q in the eighth figure [A8], and finally by E, G and F, H in the tenth figure [A10].

DIVISION OF THE TESTES AND BUTTOCKS OF THE BRAIN

These regions of the brain94 are also considered to be part of a category of structures that have a right portion continuous with the left one. In fact, these testes and buttocks are nothing other than a small portion of the brain created so that the passage going from the third to the fourth cerebral ventricle is protected, without any pressure from the upper parts of the brain. Even if this small portion of the brain is given a plural name, it is not divided into several distinct parts. Indeed, it can be considered as a single body, with their names elegantly alluding only to their visual resemblance.

POSITION

This cerebral region is located between the front of the cerebellum and the back of the third ventricle. On its lower side, it faces the beginning of the dorsal cord, and on its upper side the area where the brain sits on the forepart of the cerebellum. It is continuous with the brain or (to say it more correctly) it grows entirely out of the brain from its anterior and inferior aspect. At the sides, the top, and the back, it is not continuous with anything but is merely covered by the thin membrane, like the remaining surface of the brain.

CONSISTENCY

Since it is wrapped by the thin membrane, its consistency is yellowish and similar to the cerebral substance that is found next to the thin membrane everywhere. Superiorly and close to the front, the small gland,95 which we showed just before as being in charge of the passage of the vessels, lies upon it.

124 125 On the Testes and Buttocks of the Brain

FORM

This region is very similar to two buttocks attached to each other. But since its upper part is more similar to testes and because of the presence of the gland resembling a penis,95 the ancients who, by hereditary right, trained their sons in dissection at home, called it didymoi. After them, we call it the testes or the twins. Moreover, since the opening of the passage running from the third to the fourth ventricle is prominent in the posterior and inferior part of this region, and given that this orifice looks like an anus and a linear groove extends transversely at the rear of this part of the brain, thus dividing its upper parts from its lower, I believe the ancients gave the name gloutia to this posterior and inferior part, and we still call them buttocks or glutes. However, with the passage of time, the Greeks seem to have confused these names and to have called the area that, shaped by the supreme intelligence of the Creator, contains and conveys the channel going from the third ventricle to the fourth, sometimes didymoi, sometimes gloutia.

Commentary

SEX ON THE HILLS

In this chapter, Vesalius displays his most inventive use of figurative similitudes. He is describing the small rounded protuberances at the posterior surface of the brain stem. Vesalius thought of these structures as having a merely supportive function, just like the corpus callosum (see Chapter 17) that prevented the collapse of the acqueduct of Sylvius, a passage between the third and fourth cerebral ventricle. It was an incredibly important job, because for the Flemish anatomist this was the most vital passage in the human brain, the point where the animal spirit could flow to the peripheral nerves and control movement. Despite this importance, Vesalius simply could not ignore the fact that they stood out far more because of their resemblance to a particular part of the male body: the testes and buttocks. Today, we refer to these using far less emotive expressions. They are the superior and inferior colliculi, a Latin term for “little hills.” Every so often the term corpora quadrigemina, or “quadruplet bodies,” is also used. In a departure from the other chapters, Vesalius also digresses into an explanation about the origins of what he considers to be an “elegant” visual analogy. The Greeks likened this region of the brain to the perineum, an area of skin rich in nerve endings located close to the genitals. The orifice of the aqueduct of Sylvius reminded them of the anus, which is surrounded from above by the testes (superior colliculi) and from below by the buttocks (inferior colliculi) (Figure 21.1). The testes and buttocks are located on the other side of the mammillary bodies, thus transforming the whole region into one of the “sexiest” places in the brain. The use of these similitudes and terms remained unchanged for more than three hundred years. But not without confusion. In the first edition of the Gray’s anatomy the same language is used but in an upside down orientation. The term “nates” (buttocks) indicates the upper pair and the testes the lower ones. When Henry Gray came to explain the change there was no denying he had a point. The term nates should be used to indicate the upper pair, he said, because it is formed of the larger, more rounded eminences (Gray, 1858). In the late nineteenth and early twentieth centuries this unfortunate terminology was reinforced by a series of experiments that actually linked them to genital function. Inhibition of the colliculi was reported to interrupt sexual intercourse in frogs (Luciani, 1919), a link that has since been discredited. Efforts to discover the true role of the colliculi were well underway long before Henry Gray. In 1750, a French doctor and writer, Pierre Tarin, had described

126 127 On the Testes and Buttocks of the Brain

Fig 21.1 Left: A posterior view of the brain stem showing the gland resembling a penis (the pineal gland) (D), the left (E) and right (G) testes, and the left (F) and right (H) buttocks (from the ninth chapter of the seventh book of the Fabrica). Right: The terms used by Vesalius are derived from the similarity between this region of the brain and the perineum as seen in a surgical position from the same period (Paré, 1564).

an anatomical connection that linked the superior colliculi with the thalamus (Tarin, 1750). Sixty years later Gall and Spurzheim (1810), of phrenology fame, traced the same direct connection. They speculated that this might play a role in vision. It was a suggestion backed up by several observations made during the dissection of brains from different animals (Leuret and Gratiolet, 1857). In lower species, the superior colliculi represent the optic lobe and are larger than the entire brain itself. During evolution, the colliculi gradually reduce in size as most aspects of vision begin to be overseen by other regions in the brain (Figure 21.2). In our species, the occipital cortex. Despite this relative reduction in volume, the superior colliculi continue to play a central role in vision, particularly in the control of fast and brief movements of the eye—a process of small micro-adjustments we call saccades. Saccades was introduced as a term by the French ophthalmologist Émile Javal, who likened it to the rapid, jerking movements of a horse during dressage (Javal, 1876). Ever since, saccades have been extensively studied both in animals and man. Probably the most seminal contribution to the field came from a Russian psychologist, a man well known to every student of experimental psychology, Alfred Lukyanovich Yarbus. In the 1960s, Yarbus asked how humans observe pictures, faces or scenes. He wanted to know exactly what we look at first, for how long and if there was any pattern to our behaviour. To answer this, he built an ingenious device that recorded the saccades of a person watching an image (Figure 21.3) (Yarbus, 1967). Admittedly, it looks like something out of a horror movie. The eye is taped open to stop blinking, a plexiglass mask fitted to the face, and suction cup attached to the eye. As the person’s 128 BRAIN RENAISSANCE

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Fig 21.2 The optic lobe is larger in fish and progressively smaller in size as the species evolve a larger brain. head rests on a stand, they are asked to explore an image. The light reflected from the eye is then recorded on photogenic paper. If the eye stays still, the light is focused and recorded on just one tiny point of the paper. Yarbus demonstrated that our eyes are rarely stationary. Unlike fish and birds, humans look at a scene by constantly moving their eyes and fixating only for a brief moment on specific points. These are used to create a mental three-dimensional reconstruction of the scene that relies on a few salient visual details. As such, this mental reconstruction is not a faithful duplication of the real scene but rather a “visual grasp” of the dynamics within it.

Fig 21.3 Yarbus’s experiment on the recording of saccadic movements (Yarbus, 1967). Left: During the experiment the subject wears a plexiglass mask to which accessories are attached. Adhesive strips are used to keep the eyelids open and avoid eyeblinking interference during recording. Middle: One of the experiments consisted in recording eye saccades while the subject observed An Unexpected Visitor, a painting by Ilya Repin (1884). Right: Three recordings of the saccades after the subject was instructed to freely observe the painting (top), give the ages of the people (middle), or estimate how long the unexpected visitor had been away from the family (bottom). In the first condition, the eyes focus primarily on the faces, although other elements are scanned, including the clothes and the window. In the second condition, attention is directed to the faces of the people only. In the third condition, the saccades move between the main protagonists of the scene to capture their visual interaction (Yarbus, 1967). 129 On the Testes and Buttocks of the Brain

Yarbus found that humans concentrate their attention primarily on people and their faces. To be more specific, the eyes and the mouth topped the list of focal points. Why should this be so? The selection of the visual targets is driven by the need to collect information. In other words, the eyes sample those details that allow the person to understand what is going on in the scene. As humans, we are interested in things that help us build a narrative. Every time we look at something we are essentially asking: “what is the meaning?” To achieve this, we pick out the most important elements. For us, this means the people. We look at their expression and the way they interact. We take in their position in space and their body posture. Their eyes and the mouth, tell us about their mental state, whether they are happy, sad, angry or upset. One of the most astonishing aspects of this phenomenon is that the saccadic movements occur before we are aware of what we are observing. There is a mechanism in the brain that allows the eyes to move and scan the scene so that we can become conscious of what we are seeing in the most efficient way. The saccadic movements are necessary to align visual stimuli, such as objects or people, with the central part of the retina (the fovea). This point has the highest density of retinal cells, making it more capable of detailed vision. Moving the eye allows small but important parts of a scene to be sensed with greater resolution. Central to this mechanism are our cerebral testes, the superior colliculi. These contain cells that respond to visual stimuli. Each cell receives input from the eye’s retinal neurons and are distributed to form a map of the visual field. One cell will always respond to stimulus from a specific part of the visual field. This visual, or retinotopic, map is in constant communication with the motor map that generates saccades. Thus, when a visual stimulus activates neurons in the associated region of the superior colliculus, these in turn activate the neurons that control the muscles responsible for the horizontal or vertical movements of the eye. The generated saccade moves the eye enough to align the centre of the retina with the region of visual space that provided the initial stimulation (Purves et al., 2001). The endless amount of information stored in any one scene, means our eyes are forever flicking about as we try to take in as much as possible. Since Yarbus first published his results, scientists have recognised that a visual stimulus is not the only way to orientate our eyes via a saccade. We also do so in response to an intriguing sound or sudden pain. Indeed, spatial maps of auditory and somatosensory stimuli also exist in the superior colliculi, but it is in our bottocks, the inferior colliculi, that we find cells highly specialized in processing sound. Here, the neurons respond to different tones and are also organized into an orderly map, this time a tonotopic one. Each inferior colliculus receives auditory information from both ears, allowing us to integrate a sound, figure out where it is coming from, and then orientate ourselves. Just as the superior colliculi have shown anatomical differences between species, so too have the inferior colliculi. Nocturnal birds of prey, such as owls, hunt at night, predominantly relying on non-visual senses. Their inferior colliculi are extremely sensitive to fine sounds such as those made by a mouse scurrying through the grass. As such, an owl receives all the information needed to locate its prey simply from the 130 BRAIN RENAISSANCE distinctive rustling in the field below (Payne, 1971). As humans, our auditory inputs have a much more important role in language. For this reason, the major connections from the inferior colliculi reach the medial geniculate of the metathalamus, and from here the primary auditory cortex in the brain. It is at this point that any spoken sound is transformed into a word and the meaning decoded. You understand whether it is a noun or an adjective, and if it is meant as a metaphor or simile. So if Vesalius were to stand before you now and invite you to have a look at the buttocks, you will know he was probably referring to a dissection of the inferior colliculi.

22 On the Cerebellar Processes Resembling Worms and the Tendons That Contain Them

The structure of these processes can be found first in the eleventh figure [A11] indicated by the letters C, D, and c, d; and then by H, I. Also the eighth figure [A8] shows these processes indicated by the letter R and L in the midline, and by C, E in the ninth figure [A9].

In an earlier explanation of the structure of the cerebellum, we have mentioned its worm-like cerebellar processes. In fact, we said that a portion of the cerebellum is circular in shape from front to back, and so curled that it shows a remarkable resemblance to a worm coming out from wood. The two tips of this portion, one pointing toward the front of the ventricle in common with the cerebellum and the dorsal cord and the other toward the back, have been named skolekoeides96 by the ancient Greeks. Without doubt this is due to the aforementioned similarity. They are indeed nothing more than a prominent piece of cerebellar substance resembling (as I said) a worm.97 I don’t know what exactly Galen had in mind when he imagined that a worm-like process controls the lower opening of the passage between the third and the fourth ventricle98 and explained its function as if it were just a single process or tip. Also, it is difficult for me to be certain which of them, whether the anterior or the posterior one, he was referring to. In fact, if he meant the anterior one, its tip could not possibly have reached the opening of the passage, since it extends from front to back. If it did reach further, it would have been directed more toward the back and would have occupied the common ventricle of the cerebellum and the dorsal cord instead. As for the posterior process, which is directed from the back to the front, its tip clearly blends into the substance of the cerebellar cavity more than the anterior one and, being not as prominent as the other, does not extend to the opening of the common ventricle. But why should I mention these things, given that I think that no one is in doubt that the passage extending from the third cerebral ventricle to the one shared by the cerebellum and the dorsal cord should never be closed? Whatever reason you may think of, we cannot see any functional aim related to this obstruction: this passage needs to be always open for the spirit to flow continuously into the dorsal cord. Nor do I think that anyone, except perhaps those that have been taught by Albertus, Thomas, Scotus, and theologians of that group, has been persuaded to believe that the tips of the vermis are in charge of controlling this passage (in fact, it is not possible 131 132 BRAIN RENAISSANCE for both to close a single opening). By doing so they control the entering of the visual representations into the seat of memory, which those theologians imagine being in the cerebellum, and then transmit them, like thieves fettered in the prison of memory, into the middle ventricle, which is considered the seat of reason. In that case, God, the Creator of the world, would not have bestowed in vain the dog, sheep, and other animals with worm-like processes, since the authors I have mentioned ascribe no power of reasoning to these animals. But I beg to ask how did this movement, which depends on will, happens to be assigned to this process? Even if some particular movement had been attributed to it because it is made of some substance or particular temperament, it still could not lengthen and shorten itself like a worm. The rings that make these processes look like worms do not go around them in full circle like the coils of worms, and there is nothing on which these processes could cling to in order to roll themselves up except where they are continuous with the cerebellar substance along their length. Whatever the structure is, it is sufficient here for me to teach you the location and structure of these processes, and to attribute to them the same movement or function that I attribute to the rest of the cerebellar substance. And if one is free to imagine how things are, I might even invent several absurd functions, not only for one process, which seems to be all that Galen is able to acknowledge sometimes, but for the two processes of who he only reports the number. And I might also boldly assert that the anterior process elongates by curling itself backward and becomes thinner; and by doing this it forms the upper side of the beginning of the fourth ventricle, which is broader and more open. I could likewise imagine that the posterior process is sometimes extended forward, and by becoming thinner it opens a channel-like passage from the back of the fourth ventricle into the dorsal cord as soon as the dorsal cord leaves the skull. I could also affirm that when the processes become thinner, they form an opening, and I could similarly claim that when they are gathered together and therefore are thicker, they narrow the passages they control. But I do not wish to review in detail some false impression of the Creator’s ingenuity and at the same time neglect all the rest of the working of the brain. Hence, I am also even more astonished by Galen who uses the terms tendons and vincula for the parts of the thin membrane that bind the cerebellum to the cerebral testes that surround the worm-like process on both sides and prevent it from bending to the side when it moves. Those tendons orvincula of Galen are indeed nothing other than portions of the aforementioned thin membrane. Moreover, I am astonished that Galen did not count among the tendons that part of the thin membrane that binds the back of the cerebellum to the dorsal cord. Here, the worm-like body turns inward and forward into the fourth ventricle, since this portion of the membrane directs the posterior process more precisely than the anterior one.99

Commentary

THE CEREBELLUM: MORE THAN A LITTLE BRAIN

At the back of the head, nestling under the occipital lobes is the cerebellum, the “wise old man” of the nervous system. It provides guidance and help to others, listens patiently, and chooses its moment to speak with care. Its appearance is even suggestive of a lifetime spent frowning at all that has come before, with wrinkles carved into its surface like a shriveled, shrunken second brain. To Aristotle this is exactly what the cerebellum appeared to be, a “little brain.” In his writings, he uses this term to distinguish it from the larger cerebral hemispheres. But this appellation is very much relative. The cerebellum’s size varies wildly in different species. Taking into account the volume of the brain, sharks have a relatively larger cerebellum compared with humans, while among the mammals the elephant is king, both in absolute and relative terms (Maseko et al., 2012). But then again, using volume as the point of reference could be deemed unfair. The cerebellum may occupy only ten percent of the skull, but so densely packed are its neurons that it has more than the rest of the brain put together. Yet while the cerebellum may appear old on the outside, cut along its vertical plane and new life rests quietly, ready to flourish; its internal ramifications are reminiscent of the blossoming foliage of a small tree (Figure 22.1). For this reason the ancients also referred to it as the arbor vitae—the tree of life. Galen was rather taken by the cerebellum. His dissections of animals led him to believe that it was the origin of the motor nerves and dorsal cord. And after beginning experiments that compressed the ventricles, he gave particular importance to

Fig 22.1 The internal anatomy of the cerebellum visualized with high-resolution magnetic resonance imaging (MRI). The several ramifications of its internal structure are called folia, or leaves (Dell’Acqua et al., 2013).

133 134 BRAIN RENAISSANCE the vermis, a little stripe of neurons that runs along its midline. Galen incorporated the vermis into the ventricular theory, speculating that it acted as a valve to regulate the flow of the animal spirit from the brain down the spinal cord (see Chapter 18) (Rocca 1998, 2003). Vesalius uses direct anatomical observations to voice his dissent with Galen’s idea. In fact, of all the chapters in the Fabrica, this is the one where Vesalius releases his sharpest invective against Galen’s teachings on anatomy and function. Three points in particular incense the Flemish anatomist. First, the vermis is anatomically unfit to close the passage between the fourth ventricle and the dorsal cord. Second, even if this were the case, Vesalius sees no reason why the spirit should be obstructed because “the passage needs to be always open for the spirit to flow continuously into the dorsal cord.” Third, he objects to the idea of memories being stored in the cerebellum because the very same structure exists in other animals, the same animals that Galen considered to lack any power of reasoning. For all his criticism, however, Vesalius is not forthcoming with his own suggestions on possible functions for the vermis or the cerebellum as a whole. Part of the reason for this may have been his refusal to remove the brain from the skull during dissection. In 1573, ten years after Vesalius’s death, the Italian anatomist Costanzo Varoli began to dissect the brain after removing it from the skull. Almost immediately a new structure thus became visible to him: the pons in the brain stem, which he correctly argued constitutes a mass of fibers connecting the cerebellum with the rest of the brain. This simple change allowed Varoli to connect all the evidence. The cerebellum, he said, must play some role in movement as Galen had already suggested. Using the same method, Thomas Willis (1664) extended this work (Figure 22.2). The English doctor described the three main connections of the cerebellum, the

Fig 22.2 The anatomy of the cerebellum according to Thomas Willis (1664). The three cerebellar peduncles are visible as distinct anatomical structures in the right figure: inferior cerebellar peduncle (R), middle cerebellar peduncle (O), superior cerebellar peduncle (P). 135 On the Cerebellar Processes superior, middle, and inferior peduncles. He also reiterated Vesalius’s comparative observation, remarking that there was little variation in the structure across vertebrates (Willis, 1664). In Willis’s view, the cerebellum was not the seat of memory but the highest control of involuntary movement. It was crucial for keeping our hearts beating and our lungs breathing. By the eighteenth century anatomists had turned their attention back to other animals. They began removing the cerebellum of live pigeons (Preston, 1697), dogs (Kaau-Boerhaave, 1745) and kittens (Morgagni, 1761) and then watched what would happen. Cerebellectomy, as it is known, impaired the equilibrium and movements of the animals. They behaved as though they were drunk. Interestingly and slightly confusingly, they did not drop dead. If Willis was right, their vital functions should also have been impaired. But this was not the case. Despite the wobbling and the falling, hearts kept beating and lungs breathing. The scientists were perplexed. If not the cerebellum, then what? The answer came from Albrecht von Haller, a Swiss physician who is often referred to as “the father of modern physiology.” Haller proposed that cardiac and respiratory functions were, in fact, activities that relied entirely on the brain stem nuclei—the brain stem being a structure lying just anterior to the cerebellum that Vesalius refered to as the dorsal cord (Haller, 1762). While Haller had been able to say what the cerebellum was not, it was left to the Italians to say more about what it was. Perhaps the most important contribution was the first monograph on the structure written in 1776 by Michele Vincenzo Giacinto Malacarne. This anatomist pulled everything we had so far learned about our little brain into one definitive account of its function and structure, even attempting to correlate the number of the cerebellar foldings with intellectual abilities (Malacarne, 1776). His descriptions are so accurate that many of the terms he introduced are still in use today. More insights into the cerebellum’s anatomy and function came from the work of Luigi Rolando. Like his predecessors, he found that the best way to garner evidence on its function was to remove it. Using reptiles, birds, sheep and pigs, he noticed that if he extracted half the cerebellum, the animals acted as if paralyzed, but only on the same side as the lesion. Inspired by this and the work of Alessandro Volta, who had recently developed electrochemical batteries as a new method of generating electricity (Piccolino and Bresadola, 2013), Rolando asked what would happen if he applied electricity to different areas of the nervous system. Using a voltaic pile and crude electrodes, he moved around the brain and body and fired jolts of electricity. Limbs began to move. But more importantly, the movements became stronger in the vicinity of the cerebellum. Rolando therefore speculated that the cerebellum’s thin and regular foldings, or laminations, could act just like his voltaic pile. That is, he became convinced that the cerebellum was in essence an electric motor that controlled the movement of their limbs (Rolando, 1809). A few years later, the French physiologist Pierre Flourens was able to refine Rolando’s conclusions. He observed that lesions had the same effect no matter where they occurred—an idea we now refer to as the “unitary concept of cerebellar action.” And for the animals, all appeared not lost either. In a few cases they recovered some 136 BRAIN RENAISSANCE of their motor abilities—an important observation helping to clarify the plasticity of the brain:

“All movements persist after ablation of the cerebellum; all that is missing is that they are not regular and coordinated. From this, I am led to conclude that production and coordination of movements consist of two essentially distinct orders of phenomena as well; namely coordination in the cerebellum, production in the spinal cord and medulla oblongata.” (Flourens, 1824)

Through the power of experimental evidence, the little brain’s role in coordination and precision was becoming firmly established. However, this did not stop others from proposing their own bizarre conjectures on its function. One of the most fervid imaginations belonged to Joseph Franz Gall, the father of phrenology. The cerebellum, he proposed, was responsible for locating the faculty of amativeness. In other words, without a fully functioning cerebellum, it was impossible to become sexually excited. To back up his claims, he provided several accounts in support of his ideas (see Chapter 16), but perhaps the most controversial comes from Baron Larrey, a surgeon in Napoleon Bonaparte’s army. Larrey reported the study of a soldier who took a musket shot to the back of the head close to the cerebellum. During his recovery the patient lost his libido, and subsequent examination of the man’s genitals proved particularly important to Gall: “The testicles diminished in size, and fell into a state of atrophy or wasting. The penis was also reduced in size and remained without action” (Gall et al., 1838). For Gall this was direct evidence of the link between cerebellum and sexual functions. Despite these sporadic and unreliable case reports, clinical-anatomical observation in human became the chief method of investigation of cerebellar function in the second half of the nineteenth century. More and more people with cerebellar lesions were presenting to physicians while still alive. Their brains, upon their deaths, were subsequently analyzed at the dissection table. There were a remarkable variety of symptoms. For some, cerebellar impairment affected motor function similarly to what was observed in animals (Figure 22.3). They were unable to stand or walk without help. Smaller lesions led to unbalanced walking with a characteristic side-to-side sway, while speech was tremulous and slurred. In others the lesion manifested with symptoms reminiscent of a vestibular syndrome, such as vertigo and nausea, coupled with a rapid “dancing” movement of the eyes (nystagmus). A few people became distracted, inattentive, and impulsive. This all led to the conclusion that the cerebellum must have specialized regions for different functions—an idea that contrasted sharply with Flourens’s “unitary concept of cerebellar action.” Early attempts to divide the cerebellum included an old “paleocerebellum” in the anterior regions and an evolutionary “younger” posterior “neocerebellum”. Key to this division were stimulation studies based on novel methods, such as the targeted positioning of stereotactic probes or axonal tracing, which helped decode the pattern 137 On the Cerebellar Processes

Fig 22.3 Left: A frog loses the ability to coordinate movement after damage to the left cerebellum (Onimus, 1872). Right: This soldier suffered a severe injury to his right cerebellum. Ten weeks later his right thigh can be fully flexed onto the chest, his heel placed on his buttock, and his foot flexed upwards with minimal effort (Holmes, 1917). of connections between the cerebellum and the rest of the brain. By 1888, parcellation of the cerebellum was also dividing scientific opinion, nowhere more so than in London. When neurologist John Hughlings Jackson speculated that these new patterns of connection suggested that the cerebellum had an opposite representation of the body compared with the cortical one, where the head is represented on the upper part and the feet on the lower regions, his colleague William Gowers scoffed at the localizationist idea. Instead, in the first edition of his Manual of diseases of the nervous system, it was Flourens’s original unitary concept that Gowers favored. Moreover, taking a forerunning stance, he was convinced that the cerebellum contributes to higher cognitive functions:

“[The cerebellar hemispheres] are connected chiefly with those parts of the cortex of the cerebrum which chiefly subserve psychical processes. . . . Hence it seems possible that the old theory may be correct which assumes that the cerebellar hemispheres are in some way connected with psychical processes.” (Gowers, 1888)

The debate between these two giants of neurology reached an impasse. But by the time Gowers and Jackson had begun their squabble, many had already turned their attention to a new and different way of viewing biological phenomena, including the brain. The advent of powerful microscopes was providing anatomists with a wealth of new insights into the makeup of tissue, no more so than when Theodor Schwann stepped forward with his theory that the basic unit of life was the humble cell (see Chapter 35). It was hoped that by exploring the microscopic features of the cerebellum it might be possible to determine whether it really was specialized. Thus the search for neurons that were unique to the cerebellum begun. In 1838, Jan Purkinje indentified previously undescribed “flasked-shaped ganglion bodies” in cerebellar tissue. These large, elaborately branched neuronal cells would go on to take his name Fig 22.4 Viewing the cerebellum through a microscope revealed its microscopic features, but started one of the longest running disagreements in neuroscience. Left: Camillo Golgi’s representation of the cerebellar cells organized in a syncytium (Golgi, 1903–1929). Right: Santiago Ramón Cajal’s version, with neurons displayed as single units (Cajal, 1911). 139 On the Cerebellar Processes

Superior cerebellar pedunculus

Intracerebellar Middle cerebellar bres pedunculus

Inferior cerebellar pedunculus

Fig 22.5 Tractography permits to visualize cerebellar connections in the living human brain (Catani et al., 2008).

(Purkinje cells). Then, in 1874, Camillo Golgi announced a second population of cerebellar cells, which he identified using his newly discovered black staining method. These too would end up bearing his name (Golgi’s cells) (Golgi, 1874). There certainly seemed to be some cell specialization in the cerebellum, but it was difficult to tell how this related to the pattern of connections because Golgi’s staining method revealed only a limited number of structures and did so at random. Spanish neuroanatomist Santiago Ramón y Cajal (1911) refined Golgi’s method to show that neuronal cells connected like “a forest of outstretched trees”—no more so than in the microcircuitry of the cerebellum (Figure 22.4). But instead of providing the answers to questions regarding cerebral connectivity, as Cajal had hoped, this finding set off another argument. Golgi and Cajal struggled to agree on whether the gigantic cells that were so well delineated by the black reaction staining method were connected in a continuous net (Golgi’s syncytium) or whether they were separated by gaps that later became known as synapses (Cajal’s theory of the neuron). This dispute became so vehement that when the two men were awarded the Nobel Prize in 1906, they did not even bother to speak to one another (see Chapter 35) (Golgi, 1906; Cajal, 1906). Despite the advancements made in the last century in anatomy, physiology, and neuroimaging (Figure 22.5), the cerebellum continues to split the opinion in 140 BRAIN RENAISSANCE contemporary neuroscience. The question of whether it really does hold some regional specialisation is still unresolved. All scientists are firmly convinced that the cerebellum plays a role in motor learning and motor coordination, but not all believe it to have a role in cognitive functions and behavior (Glickstein, 1993; Schmahmann and Shermann, 1998; Ramnani, 2006). The wise old man of the nervous system continues to wait patiently for us to reveal his secrets. Thus, two thousand years on from Aristotle, this tree of life continues to sow seeds of discord.

23 On the Infundibulum, the Glandule That Receives the Cerebral Phlegm, and the Other Ducts That Cleanse It

These cavities can be seen first in the third figure [A3], where they are indicated by the -let ter M, M at the sides of the corpus callosum. The passage that drains the phlegm from the cavity shared by the right and left ventricle is indicated by the letter I in the seventh [A7] and eighth figure [A8]. Then the basin that collects the phlegm is indicated by the letter S in the thirteenth figure [A13], C, C in the fourtheenth [A14], and E in the fifteenth [A15], and B in the sixteenth [A16] and eighteenth [A18]. Finally, the gland in which the phlegm is escreted is labeled by the letter A in the sixteenth figure [A16], E in the seventeenth [A17], and also A in the eighteenth [A18], where incidentally C, D, E, F indicate the passages that drain the phlegm into the gland.

BRIEF ENUMERATION OF THE STRUCTURES THAT DRAIN THE PHLEGM

In the first book, where the function of the sutures of the skull was surveyed, I explained that they assist the careful removal of the cerebral sooty residues. This point now requires that we enumerate each of the individual structures that contribute to the excretion of the phlegm. They are as follows: two passages carved in the cerebral substance, a portion of the thin membrane that is shaped like a funnel, a glandule that receives the pit of this funnel, and passages that lead the phlegm from this glandule to the palate and nasal openings.100

THE PASSAGES THAT ORIGINATE FROM THE THIRD BRAIN VENTRICLE

While discussing the third brain ventricle, or common cavity of the right and left ventricles, I previously reviewed these two brain passages. And I said that the one that is of quite remarkable size and hollowed out of the cerebral substance expands straight down in the middle of the common cavity.101 This passage terminates exactly in the region of the skull that forms the cavity that lodges the glandule receiving the cerebral phlegm. The other passage,102 which I have very rarely observed and appears

141 142 BRAIN RENAISSANCE to dissectors much narrower than the aforementioned one, emerges from the chan- nel103 that extends from the third to the fourth brain ventricle through the brain’s testes and buttocks. In fact, as soon as this channel arrives at the brain’s testes, another cerebral passage that also purges the phlegm originates from the anterior and lower region. This second passage runs progressively downward and forward until it terminates at the end of the first one, and a shared opening originates from both of them.

THE BASIN104 WHERE THE CEREBRAL PHLEGM DRAINS INTO

At the sides of this opening, the thin membrane surrounds the base of the cerebellum with a circular extension. This is similar to the substance of the rest of the thin membrane except that it is interwoven with thin veins that are sometimes quite numerous. The first portion of this process vividly resembles the upper part of the funnel used to pour wine into flagons with narrow necks. It is wide and circular. Like funnels, this structure gradually narrows until eventually ending in a long and tight pipe-like shape that extends downward. Through a particular opening carved in the hard cerebral membrane, it terminates with its tip in the gland that receives the cerebral phlegm. This entirely membranous body should, therefore, be considered very similar to a funnel in both appearance and function, and this is why it is called choana105 by the Greeks. Also, because of its cup- or shell-like shape (which the superior part of this body mimics) that is similar to what we use to wash in at the baths, it is also called pyelos.106 Nevertheless, elsewhere others have called choana only the lower part of this body, which resembles the pipe of a funnel. They have used the term pyelos only for the remaining superior part, which gradually narrows and lies to a great extent beneath the part where the optic nerves come together. Again, I often see that some use the term pyelos for the entire membranous body while others use it only for the gland that receives the phlegm, for its shape is similar to a structure into which something is poured. And if the ancients, who taught their sons anatomy from generation to generation, would have not given this name to the gland, they would have appeared to have left only this gland lacking its own name among all the parts situated in the skull cavity.

ACCOUNT OF THE GLAND THAT COLLECTS THE PHLEGM

This gland, which is located under the hard cerebral membrane, has its own sinus carved in the wedge-shaped bone. For this reason it takes the shape of the cavity, which is depressed in form, quite gibbous and round in the inferior part, but concave and hollow on its superior aspect. It does not appear as perfectly round as a sphere or completely cubic. Its substance is glandulous, but much harder and more compact than the consistency of other glands. It is surrounded everywhere by the thin membrane, which arises either from the end of the infundibulum attached to the cavity of the glandule 143 On the Infundibulum or from the membrane that covers the skull throughout that area, where the hard cerebral membrane departs from the skull bone and stands apart from it. At this point the gland is firmly held by this membrane covering the skull, and it also adheres to the two larger offshoots of the sleep arteries, which pass along its sides and are ludicrously believed by some professors of dissection to form the reticular plexus in humans. This gland was created to serve these offshoots and for them has the same functions as the other glandules, which is to provide support, and sustain the distribution and branching of other vessels.

PASSAGES COMING OUT FROM THE GLAND

At each side of this gland two ducts course downward: one anteriorly into the opening that lodges the second pair of cerebral nerves, which we mentioned, contrary to Galen’s opinion, is much larger than the opening of the optic nerve. The other descends more posteriorly, and is led throughout the uneven and rough opening, or crack, at the front and sides of the opening that allows the passage into the skull cavity of the largest branch of the sleep artery.

ACCOUNT OF THE FUNCTION AND STRUCTURE OF THE PARTS THAT SO FAR WE CONSIDERED SERVING THE PURGATION OF THE PHLEGM

All the parts that serve the removal of the brain’s phlegm are: the two passages, which we said are carved into the cerebral substance and lead this fluid out of the cerebral ventricles into the infundibulum, and the infundibulum itself. The latter is broad and wide in its upper part, and fed not only by these passages that ultimately end in a single opening, but also by the terminal passages of the right and left brain ventricles, which we mentioned arise from the posterior seat of the ventricles, curve anteriorly among the convolutions of the brain and end here. These passages also drain the phlegm from their own area into the infundibulum. In addition, owing to its size, the infundibulum accumulates the phlegm from above the corpus callosum and the cavities that we observed at its sides.107 From here it falls into the infundibulum by means of the thin membrane. In fact, whether this fluid descends from the anterior region of the corpus callosum, which is prominent and shaped like a vault, or from its posterior part, it can then flow into the thin membrane that covers the base of the brain and hence slip gradually into the cavity of the infundibulum. Indeed, the infundibulum receives the phlegm from all these passages and then narrows so it can finally convey the phlegm through its own unique opening in the hard membrane, and allow the phlegm to harmlessly drain into the center of the gland. Because of a certain similarity of their substances, the gland can sustain the force of the drainage. And I suspect it protects the bone from injury by receiving this phlegm and gradually allowing it to run down, without dripping from its sides, through all the openings sculpted at the base of the skull for the benefit of the veins, arteries, and nerves. 144 BRAIN RENAISSANCE

In fact, no opening in the bone is specialized for conducting the phlegm except maybe the crack surrounding the anterior parts, as well as the opening at its sides that provides an entrance to the largest branch of the sleep artery. And what Galen continuously reported about these openings, that the perforations are like sponges or sieves, is certainly ridiculous, since there is no small opening of this kind under the gland. I would rather prefer you carefully consider this issue by taking into account the structure of the bone that imitates a wedge, and the viscosity and substance of the dripping fluid, rather than investigating with indolent laziness and making asser- tions only on the basis of what the authors who charge me with impiety agree on. It seems that I am challenging the dogmas of Galen and all the professors of dissection whom I read. They think that they are able to attract to themselves the admi- ration of the Creator without carefully pondering how thoughtless God would have been if he had created the bone in the manner they had imagined. God created a continuous bone here, so that the phlegm could cause no damage to it. This is far from having a bone skillfully made of pervious openings (as they imagine), particularly given that this part of the skull is sculpted with so many passages for nerves, veins, and arteries; and the cuneiform bone itself, in this seat where the glandule lies upon it, shows the presence of two cavities rather recognizable and prominent, which extend into the nasal cavity by means of two openings, as we taught in the first book. And if these small cavities do not appear, as we have seen sometimes during dissections, then the bone itself is as solid as the heel bone or talus, and this clearly indicates that the phlegm does not flow down through its openings or small cavities. The phlegm thus drifts down and is conveyed into the palate through openings facing the palate, as well as a substantial portion through the opening of the second pair of nerves into the origin of the orbital cavity of the eyes; then it travels through the large opening unknown to other professors of dissection, and through a very large number of other openings, into the nasal cavity. Also, I have no doubt that someone will wonder why I have not yet explained any passage delivering the phlegm into the cavities of the organs of smell. This, of course, is due to no other reason than my belief that there is no phlegm that is purged through these cavities. I am more surprised at the audacity with which others have not blushed when they write that the phlegm is conveyed to the nostrils from the anterior brain ventricles through the slender nerve similar to cerebral processes, which we associate with the organ of smell. But there is no evidence of such a passage anywhere in them, neither the space, in humans, necessary to lodge a passage for conveying the phlegm. And in addition, there is absolutely no possibility of imagining a passage for the phlegm that directs toward the cavities of the olfactory organs, unless perhaps the anterior region of the corpus callosum draining the phlegm flowing into it toward the space of the olfactory organs: this maybe happens when the brain is disturbed by an excess of phlegm. As a consequence of this, an unnatural discharge of phlegm occurs through the nostrils when itching, heat, pain, impaired sense of smell, and symptoms of this kind arise, which we experience as a dripping to the ends of the nostrils and we call a cold. 145 On the Infundibulum

As we ponder each thing very carefully, it will be necessary to declare that, when a man is governed following the law of Nature,108 no phlegm drains out through the cavities or the small openings of the organs of smell, or through the sieve- or sponge-like holes. And, if, by chance, it does flow out, we should consider this flux to be as abnormal as when the opening sculpted at the sides of the gland does not drain all of the phlegm. This causes the phlegm to run down toward the opening that is dedicated to the transmission of the dorsal cord, and, while slipping dorsally, it would go into the back, and then along the course of the nerves to the arms, legs, lumbar muscles, or elsewhere. Now, I would be better to stop talking about how Nature should have been severly criticized for making such passages in the skull cavity so wide and large when the phlegm is in fact so thin and watery, and also for extending such twisted, narrowed, and winding passages in the eighth bone of the head.

Commentary

THE AXIS OF SURVIVAL

Just below the center of the brain, level with the back of the eyes, is one of life’s great double acts. It consists of two small cerebral structures: one the master, which receives the information, the other the servant, which responds to it. Together they work, day after day, night after night, attempting to guarantee the individual’s survival whatever threats the environment may pose. The master is the hypothalamus, so named because its location is hypo, or below, the thalamus (Figure 23.1). Like the region above it, the hypothalamus is made up of distinct and compact sections of neurons known as nuclei. There are at least ten of them, packed into an area no bigger than an almond. This small region is a control center that processes information from many areas of the brain and body.

Other brain regions Hypothalamus Releasing hormones and inhibiting factors

Anterior k Infundibulum alamus pituitary

Posterior

ve feedbac pituitary ti ega N Pituitary gland ADH Hypothalamus Oxytocin Target glands Infundibulum peripheral Hormones

Fig 23.1 Left: Location of the hypothalamus, pituitary gland, and infundibulum on the MRI scan of a healthy subject. Right: The diagram shows the hypothalamic nuclei as well as the anterior and posterior parts of the pituitary gland. The hypothalamic nuclei receive stimuli from the brain and the body. In turn they respond by releasing substances directly into the bloodstream. The axons reaching the posterior pituitary gland release oxytocin and vasopressin. These two hormones act directly on their target organs. The oxytocin induces uterine contractions during delivery and promotes lactation in the mammillary glands. The vasopressin (or antidiuretic hormone, ADH) regulates renal excretion and therefore blood pressure. The other hypothalamic nuclei release substances that stimulate the secretion of hormones stored in the anterior pituitary gland. From here several hormones are released into the bloodstream and control the activity of several glands including the thyroid (thyroid-stimulating hormone, TSH), the adrenal gland (adrenocorticotropic hormone, ACTH), and the gonads (follicle- stimulating hormone, FSH and luteinizing hormone, LH). The growth hormone (GH) acts directly on the cells of many tissues and promotes an accelerated metabolism. The prolactin (PRL) acts on the mammillary galnds where promotes the secretion of milk.

146 147 On the Infundibulum

Most of the hypothalamic nuclei orchestrate responses to specific stimuli. The vast majority of these are sent straight to the servant, the pituitary gland. This tiny, bag- like structure hangs below the hypothalamus, linked to it via a thin stalk of neurons. The pituitary gland is crammed full of hormones which, when the signal comes, are released directly into the bloodstream (Figure 23.1). These regulate the activity of other glands around the body, which in turn produce further hormones. It is a process of positive feedback, where the hypothalamic nuclei continually monitor and finely tune their responses. Together, the two structures play a vital role in helping the body adjust to external and internal conditions; they prepare the body to take appropriate action. The hypothalamus knows when the individual is too terrified to move or too much in love to speak; it then tells the pituitary to respond appropriately. The heart races, blood pressure rises, breathing deepens and the body begins to sweat. This hypothalamic-pituitary axis is a partnership that is intimately linked to almost every bodily function: from body temperature, hunger, and thirst to sexual activity, endocrine function, and emotional behavior. But as history shows, much of what has been learned about this axis since the Fabrica was published is a result of the partnership breaking down. Sometimes the pituitary servant fails to obey its hypothalamic master. In the Fabrica, Vesalius does not use the term hypothalamus, but he does give a clear description of that part of the third ventricle, the “infundibulum,” which is surrounded by hypothalamic nuclei. According to Vesalius, the infundibulum is a funnel-like passage that conveys phlegm—a waste fluid released into the nasal cavity. He believed that the infundibulum and pituitary gland work together as a team. If phlegm started to accumulate in the third ventricle, the infundibulum would pass it to the pituitary gland, which then set about cleansing and excreting it in the nose. A hundred years after Vesalius’s death, Conrad Victor Schneider, a German physician, challenged the idea that the pituitary gland acts as an excretion device. Unlike most, Schneider was particularly interested in mucus—so much so that he wrote a book on the topic: Liber Primus De Catharris (First book on the mucus) (Schneider, 1660). Here he suggested that it is the soft tissue of the nasal cavity, not the third ventricle, that actually produces mucus. Similar observations were also being made further north in England. The physician Richard Lower was well known for his work on fluids. He was the first to realize that blood changed when it was exposed to air in the lungs and that it could be transfused from one person to another. Lower took one look at the nasal bone and immediately questioned Vesalius’s idea. There is simply no way that a liquid could pass from the brain into the nose, he said, since the bone is entirely impermeable (Lower, 1672). The search for the gland’s function stagnated in the seventeenth and eighteenth centuries despite the fact that anatomists were becoming increasingly aware of the effects that a large pituitary tumor could have on surrounding structures. In 1664, Thomas Willis, a good friend of Lower, performed an autopsy on a scholar who had complained of sudden lethargy a week before he died. When Willis dissected the man’s brain, he found some of the ventricles full of water and a large tumor seated within the pituitary gland. He concluded that the tumor was obstructing the passage of fluid through the third ventricle and out of the brain (Williams et al., 2003; 148 BRAIN RENAISSANCE

Zimmer, 2004). For Willis, it was not a disruption of the pituitary that was causing the lethargy; it was the pressure building within the ventricles. Further cases involving the pituitary gland were soon reported. It rapidly became clear that there was a link between these tumors and endocrine disorders. In 1761, the Italian pathologist Giovanni Battista Morgagni reported autopsies of patients with pineal tumors who, along with mental changes, displayed a range of physical symptoms. Some showed signs of hyperostosis frontalis interna, a thickening of the inner side of the frontal bone of the skull. Females often presented with virilism, the sudden appearance of masculine features such as a deep voice or excessive facial hair. Many were simply obese. The diversity of the changes was remarkable, but—unknown to Morgani—the impact of a pituitary tumor was sometimes even greater (Morgagni, 1761). A fine example is the case of Aama Bataillard. In the 1890s, Aama, an adoles- cent living in France, drew instant attention wherever she went. Being nearly 6 feet 8 inches (2.03 meters) tall, she was hard to miss (Figure 23.2). Her towering height, caused by a condition known as gigantism, gave her instant fame. She started touring around the world as “Eve’s tallest daughter” or “Lady Aama.” By autumn 1892 she had arrived in the United States and begun performing to packed auditoriums. The Boston Sunday Globe described her as a “ponderous specimen of womanhood,” “a colossal maiden” with a marvelous appetite:

Fig 23.2 Aama Bataillard stood over two meters tall and suffered from gigantism caused by a pituitary tumor. She traveled the world performing before large audiences as Lady Aama. In this flyer she is shown with her midget sister, called Princess Josepha, and the daughter of their manager. 149 On the Infundibulum

“She is said to eat six times as much as the ordinary mortal and never to drink less than 20 to 25 quarts of water daily. Not withstanding her enormous size, her proportions are very symmetrical; there is nothing gawky or awkward in her movements. . . . She is sure to make a sensation here.”

Unfortunately the fame did not last. Lady Aama died two months after visiting Boston. Her body was sold to Iowa State University, where it was dissected by Woods Hutchinson, an Englishman. As professor of anatomy, Hutchinson was excited by what he might find in such an unusual patient, and he was not disappointed, reporting a “hyperthrophy of the pituitary body and enormous size of the pituitary fossa” (Hutchinson, 1895). For Hutchinson, the initial conclusion was clear: gigantism was the result of a tumor in the pituitary. It was an important finding because the prevail- ing view of this disease was very different across the Atlantic. Nearly a decade before Hutchison reported his findings, the French neurologist Pierre Marie had also described people with pituitary tumors, but his patients exhib- ited slightly different symptoms. While there was deformation of the patients’ bones and skin, their overall height remained largely unchanged. In 1886 Pierre Marie provides vivid descriptions of these cases, including a 37-year-old woman who:

“at the age of twenty-four, at the time the menstruation suddenly ceased, noticed the sudden increase in her hands. Her face at this time also underwent changes . . . so that when the patient returned home none of her relatives could recognize her . . . . The whole feet are large, including the toes. Though the latter are increased in size, they have preserved their form, there is no true deformity, their appearance is simply that of a very big person . . . . The tongue is enlarged. The patient is a little deaf, and the sight is also slightly defective. . . . The cranial vertex is of nearly the same size as the end of the chin. The lower jaw is well developed.”

Marie proposed the term acromegaly to identify patients with enlarged body features, but he believed the disease to differ from gigantism, which to him was merely an exaggeration of normal development (Marie, 1886). Hutchison’s description was part of growing evidence that Marie was wrong. The two diseases shared the same pathological mechanism, but a different age of onset. If the tumor manifested in adulthood, the patient presented with acromegaly (Figure 23.3). Should it grow during childhood or in adolescence, when the individual was still growing, the result was gigantism. By the time this distinction was made, an Italian anatomist had provided a reason as to why. Two years after Lady Aama’s death, Roberto Massalongo decided to take a look, under the microscope, at pituitary tumor cells taken from a person with acromegaly. What he saw was a specific type of granulated cell. It allowed him to propose that the overgrowth that characterized these patients was the result of overactivity (hyperfunctioning) of the tumor cells he observed (Massalongo, 1895). Definitive experimental evidence of this did not come until the 1930s, when scientist Philip Smith started to extract pituitary glands from rats. Removal of this structure slowed body growth and delayed sexual development. However, if the same animals 150 BRAIN RENAISSANCE

Fig 23.3 Left: Rondo Hatton, age 19, when he was playing for the Hillsborough High School football team (Hillsborough High School yearbook photo, 1913). Right: During the 1930s he became a famous Hollywood actor but suffered from acromegaly. His head, face, and hands became progressively enlarged, transforming his appearance and making his face an icon and Hatton a popular actor in many horror movies. Today his name is linked with the Rondo award, which recognizes the best contributions to horror film production. were then treated daily with an extract of pituitary gland from a cow’s brain, normal development returned. Almost four hundred years after Vesalius proposed that the pituitary was excreting phlegm, Smith unequivocally proved that he was partly right. The pituitary was excreting something, even if it was not mucus. A lack of this substance was causing a diverse range of effects: reduced bone growth and gonad size, with limited functioning of the thyroid and adrenal glands (Figure 23.4) (Smith, 1930). Within a few decades, the major substances produced by the pituitary gland were identified as hormones. Among them is a group that controls the menstrual cycle, spermatogenesis, and milk secretion. There is also a growth hormone that acts on the ossification processes, partially explaining the exaggerated bone growth seen in people like Lady Aama. Other hormones stimulate either the thyroid or the suprare- nal gland. The pituitary quickly became known as the master of all other hormonal glands, even though researchers had begun to notice that it was not even the master of itself. The pituitary does not function alone. The hypothalamus also released substances straight into the bloodstream. Some of these act independently, exerting their effects directly around the body. Among these is vasopressin, which regulates blood pressure, and oxytocin, which induces uterine contractions during childbirth. Most of these substances, however, do not have to travel far to instigate their effect, because they directly target cells in the pituitary gland, controlling its release of hormones. The hypothalamus tells the pituitary when to release a given substance and by how much. Hence, in the second half of the twentieth century, neuroscientists began to 151 On the Infundibulum

Fig 23.4 One of the images published in Philip Smith’s seminal 1930 paper, in which he shows the effects of removing the pituitary gland. Left: A normal control rat (left) and a littermate (right) that underwent removal of the pituitary gland 36 days after birth. At 125 days of age the operated rat shows less growth, and its testicle is smaller compared with the control. Right: The same pair, this time at the age of 199 days, after a daily transplant of pituitary tissue from a cow into the previously operated rat. The transplant restored body growth to almost normal and the testiclesof the two rats reached similar size. appreciate that the hypothalamus acts as regulatory center: it balances out feedback from peripheral glands in a self-regulating loop while performing direct cross-talk with regions of the brain that process emotions and behavior. For the pituitary gland, the last five hundred years have witnessed a remarkable turnaround. A structure that was once believed to clean the brain’s liquid sewage is now seen as an integral part of a hypothalamic-pituitary axis that could conceivably take the place of the pineal gland in Descartes’s mind-body dualism. Indeed, this is a system that allows the mind to interact with the body and the body to influence the mind. Unlike many other anatomical structures that Vesalius described in his seventh book, this axis is really indispensible for the individual’s survival. Today’s understanding of this hypothalamic master and its pituitary servant represents one of the most important triumphs of contemporary medicine.

24 On the Networks of the Brain Believed to Be Similar to the Reticular Plexus and the Placenta

These networks are clearly shown in the figure of the fourteenth chapter of Book III, and the fourth [A4] and fifth figure [A5] of this book where they are indicated by the letters O, O; they are also indicated by M, N in the sixth figure [A6] and approximately in the whole sixteenth [A16] and seventeenth figure [A17].

The blessed plexus mirabile109 that Galen, the most notable among the professors of dissection, constantly mentions in his books, is credited to him by physicians and anatomists who often follow his teachings without good reason. These physicians have spoken of it more often than anything else, and they describe it on the basis of Galen’s opinion, even if they have never seen it (at least, not in a human body). But I shall say nothing more about these others; instead I shall marvel more at my own stupidity and blind faith in the writings of Galen and other anatomists. I had labored so hard in my devotion to Galen that I never attempted to explain in my public dissections the human head without a lamb or ox head. This helped me to show in the lamb head what I could not find in the human head, thus fooling the audience and avoiding the need to say that I could not find the net whose name is familiar to everybody. Nothing is, in fact, less true than considering that the sleep arteries110 contribute to the formation of the reticular plexus, which Galen first recognized. And the arteries that he claimed to enter the opening contribute even less because they do not form that plexus at all. First, the whole right sleep artery (and, indeed, the same holds true for both sides) as it approaches the skull does not enter undivided through a single opening as Galen mentioned; rather, in proximity to the base of the skull, it sends a large offshoot to the passage of the sixth cerebral nerve. First, this offshoot, paired with the great vein, flows into the right cavity of the hard cerebral membrane. Second, the sleep artery does not share a canal with the third pair of nerves: in fact, the Creator has been much more ingenious than Galen thought and devised for the larger branch of the sleep artery an oblique opening that extends with significant depth into the bone. It is the passage through this opening that produces the effect that Galen ascribed to the plexus, namely that the vital spirit is processed in the several twists and turns of the artery and turned into suitable material for generating the animal spirit. 152 153 On the Networks of the Brain

Galen said that as soon as the artery enters the cavity of the head, it is dispersed into innumerable branches that lie upon each other and commingle in such a way that they form a plexus like the one we can see in a piled fishing net, or when several nets lie one upon the other, resulting in a complex pattern. And he claims that this net is between the bone and the hard cerebral membrane, in a pocket formed by a small portion of this hard membrane covering the bone. Then, he believes that the net is woven out of one or two vessels when he refers to the right vessel joining the left one. He then states that the twigs of this complex bunch up together gradually and eventually end in two vessels, resembling the vessels from which the network originates. This could not be more distant from the truth and would assume the indifference of Nature. Those who have learned the actual course of the sleep artery know that, as we said, it passes into the skull through a diagonal opening in the bone. And without mentioning many other things, it is clearly impossible for those vessels, which are as large as the ones that first reach the skull, to enter directly into the brain. Being so large, they have to branch out through the openings of the second pair of nerves and reach both the optic and nasal cavities before they arrive at the thin cerebral membrane. In the third book, while trying to describe the vessels of the brain as well as the other veins and the arteries of the body, I endeavored to depict the distribution of these vessels so accurately and precisely that there is no need to repeat it here. But if the memory of the things I included there has vanished, I refer the reader to that, and urge him to carefully read that chapter and transpose all its content here again. There I described the offshoot of this branch of the sleep artery and reviewed the nature of the plexus, which we liken to the external wrapping of the fetus.111 Therefore what remains for me to do here is to warmly urge students, who have not attended my dissections in the last two years, to attend an autopsy. They are now warned that after reading Galen’s and my descriptions, they should carefully examine the actual fabric of the human body and in the future have less faith in anatomy books. The reason for mentioning here these cerebral plexuses again was so as not to leave out of this book anything concerning the structure of the brain. And to avoid this, I shall now approach each organ of sense in order.

Commentary

THE NET OF WONDER

This chapter represents a direct attack on the idea at the heart of Galen’s doctrine. Galen believed that the pituitary gland (Chapter 23) was embedded in a net of arteries and veins called the rete mirabile. Here the vital spirit conveyed through the “sleep” (carotid) arteries is transformed into the animal spirit before then flowing through the ventricles and nerves to peripheral organs. Vesalius’s decision to depart from this speculation is potentially driven by an observation made at the dissection table: humans do not have a rete mirabile. Galen’s limited opportunities to do direct human dissections meant that he took his observation from another mammal, probably a pig, an ox, or a sheep. He then applied what he saw directly to humans. In Book III of the Fabrica, Vesalius refutes the existence of a rete mirabile in man, despite its presence in other animals. He then blames himself for his “own stupidity and blind faith” in the Galenic writings and openly admits that he had deceived his students at the dissection table when it came to demonstrate the anatomy of the rete mirabile. Instead of showing it in the human brain, he had to pull out from under the table the brain of an animal, either an ox or a lamb, to persuade them about its existence. Vesalius was not the first to challenge the existence of the rete mirabile in humans. Jacopo Berengario Da Carpi already wrote in 1521:

“Note reader that I have worked hard to discover this rete and its location; I have dissected more than a hundred heads almost solely for the sake of this rete and even now I don’t understand it. . . . I doubt that Galen did otherwise than imagine that a rete mirabile is located there. I have careful eyes, hands, and instruments suited to separating the dura mater from the cranium. I have dissected many heads as I said above, and did not find such a rete except in that place mentioned by me. It is my opinion that if there is a rete there in the latter location, it must be concluded that Galen erred. . . . Thus I believe that Galen imagined the rete mirabile but never saw it; and I believe that all others after Galen that spoke of the rete mirabile did so on the strength of his opinion rather than their own perception of it.”

But the voices of Berengario da Carpi and Vesalius were the only dissenting ones outside the chorus. The rete mirabile tricked also Leonardo da Vinci’s eye (Figure 24.1). This tells us a lot about the power of dogmatic ideas and their endurance despite the lack of

154 Fig 24.1 Transition from the rete mirabile to the circle of Willis. Left: Leonardo da Vinci’s drawing of the rete mirabile according to the teaching of Galen. Centre: Giulio Casseri’s representation is a graphical compromise between Galenic tradition and the true anatomy. Right: The circle of arteries described by Thomas Willis in his 1664 Cerebri anatome. Note that while the images in the left and right show the front of the brain in the upper position, image in the centre is oriented in the opposite direction. 156 BRAIN RENAISSANCE supporting evidence. Even in Vesalius’s Fabrica we find discordance between what he writes and what he shows in the picture (see Figure A17). Paradoxically, here the text is right and the image wrong. The rete mirabile was pivotal to the ventricular system of Galen; denying its existence meant a direct blow to the heart of the most established doctrine of the time. Although Vesalius was bold enough to challenge it (at least in his words), others tried to find a compromise between Galen and his opponents. This is clearly evident in the work of Giulio Casseri, who graduated in Padua, where he continued to work as anatomist and later professor of clinical medicine between 1680 and the year of his death in1616 (Riva et al., 2001). His image of the vessels at the base of the brain clearly shows the existence of larger vessels surrounding the brain stem, from which smaller arteries depart in great number (Figure 24.1) (Casseri, 1627).

Fig 24.2 Some examples of the eighty-three types of circle of Willis found in the Japanese population (Adachi, 1928). 157 On the Networks of the Brain

But the final attack on the dogma came from Thomas Willis, who in 1664 had the audacity to replace the rete mirabile with a “circle” (which today takes his name) (Figure 24.1). The circle of Willis is one of the most important discoveries of the seventeenth century for two reasons. First, Willis was very accurate in his anatomical description of the circle, where he clearly demonstrates that anterior (carotid) and posterior (vertebral) arteries, which enter separately into the skull, are linked through a series of intermediate branches. He also understood the purpose of this arterial link: the maintenance of a constant blood flow in the event of an occlusion of one of the arteries. This is crucial for the survival of patients presenting with occlusion in that region, as many of the vessels branching off the circle of Willis supply blood to vital centers located at the base of the brain (Willis, 1664). Second, Willis’s discovery remains a milestone in the history of vascular medicine. It stimulated later research aimed at explaining why people with similar arterial occlusions may have different clinical symptoms. This may be explained by the incredible variability of links that may form the circle of Willis, which someone had calculated could amount, for example, to 83 types in the Japanese population (Figure 24.2) (Adachi, 1928). Paradoxically, the discovery of the true anatomy and function of the circle of Willis led neuroscientists to lose interest in it. This group of arteries at the base of the brain, while providing a blood supply to vital brain structures, has no direct involvement in generating cognitive activities.

25 On the Organ of Smell

While writing the third chapter of Book IV where all the structures of the olfactory organ were described according to the order of the nerves, I thought I would give a more detailed account of this organ here, considering that in the previous chapter its description was limited to its anatomy. But even if I dedicate more time to the closer examination of the nature of this olfactory organ, I would not discover anything new.112 Hence I would like this chapter to be combined with that one. In addition to the two brain processes113 that are not different in function from the nerves and reach the sinuses in the eighth bone of the skull, here I can mention also the sinuses in the frontal bone, the substance they contain, and the openings of the hard membrane and those of the bones. However, I will not explain here in detail anything about the nature of odors, the medium of this sense, or anything concerning their composition: if I did that, my book, which is already longer than what I originally planned, would become infi- nitely long.

158

26 On the Eye, the Instrument of Vision

POSITION OF THE EYE

In the first book, while examining the rationale for the formation of the head, we114 described the position of the eyes, which is obvious to everybody. Then, in the second book, we dealt with the division of the eyes, the muscles moving them, and the important role of the eyelids.

HOW TO DESCRIBE THE STRUCTURE OF THE EYE

In the present chapter, we will explain the exact round spherical structure of the eye, starting either from the center or from its outermost circumference, in the same way as if one would approach the structure of an egg proceeding from its yolk to its white, then to the thin membrane surrounding the white, and then to the shell or the crust. Alternatively, the description could proceed from the shell to the thin membrane, then to the white and the yolk. Exactly in the same way one could consider the parts of the universe, either from the earth to the water, air, fire, moon’s heaven, and so on to the outermost heaven, or from that heaven to the center of the universe, which is obviously Earth. Hence, where structure is concerned, the organization of the eye can be compared to the universe and the egg. So to explain it with greater accuracy, and to retain it more firmly in memory, we shall carefully investigate it from the center to its outermost surface first and then on the reverse order.115

THE CRYSTALLINE HUMOR

At the center of the eye there is therefore a humor that the Greeks name krystalloeides, and in the same way we defined it glacial, certainly not for its consistency or hardness, but rather for its similarity in color, or light and transparency with the clearest ice and the most perfect crystal. In fact, this humor is absolutely transparent like the finest crystal, and once removed, it magnifies with great power everything on which it is placed, like a magnifying glass or certain small lenses. Also its consistency is such that, when removed from the eye, it does not disperse, but preserves its rounded shape like a soft wax.116

159 160 BRAIN RENAISSANCE

And this does not represent an exactly rounded globe, being slightly more compressed at its anterior and posterior parts, as if you had removed from a wooden globe a thick slab from the middle with a saw, and then attached again the two parts of the globe together. Similarly, this humor protrudes less in its anterior and posterior parts then along its great circle, somehow resembling a lentil. I think this is also why this humor was called phakoeides117 by the Greeks, even if I don’t know which tunic of the eye they referred to. Its surface is smooth and very slippery.

THE SMALL ONION-LIKE TRANSPARENT TUNIC ATTACHED TO THE ANTERIOR ASPECT OF THE CRYSTALLINE HUMOR

A small tunic resembling an extremely thin onion skin is attached to the entire anterior aspect of the crystalline humor. It is as thin and perfectly transparent as the skin we might find between the thicker layers of the onion. But this tunic, which is harder than the onion’s skin, covers (as I said) the whole anterior surface of the crystalline humor, nowhere touching its posterior aspect, and terminates where the crystalline humor shows its broadest extension.118 And the circumferences of the tunic could be even more ample if we imagine the crystalline humor being at the center of many equidistant circles or lines. This small tunic does not seem to have been given any specific name except for the term arachnoeides, which the Greeks used for its resemblance to the continuous spin of spiders’ webs. It is certainly similar to those spiders’ webs in thinness but not at all in strength or hardness. In my dissections, as I have already said, I compare it to the thinnest and most transparent onion skins, or also to the horn, if the horn could be split into layers as thin, transparent, and smooth as this tunic. In fact, the substance of this tunic is not different from that of the horn. Thus, let the present tunic be the second structure of the anatomy of the eye that we describe, which covers only part of the front and the center of the crystalline humor, and appears to be of hemispherical shape when we consider the composition of the eye.

THE VITREOUS HUMOR

The posterior part of the crystalline humor, which is not coated by the above-mentioned small tunic, is in contact with another fluid, a copious humor similar to a hemisphere located in the rear part of the eye, and matching in color and transparency an ordinary white glass after it cooled down.119 It is certainly not as clear as the crystalline humor, or as perfectly translucent. Instead, it is much softer in consistency than the crystalline humor, and when removed from the eye, it does not maintain its edge or shape at all. Nevertheless, it does not diffuse like water, but it has the consistency of glass fused in furnaces, which can be seen covering the iron canes that artisans use to remove the glass from the furnace. And once the glass is fired in this 161 On the Eye, the Instrument of Vision way, that humor equals its consistency but not its color or transparency, given that the humor, as I said earlier, matches the glass in transparency after it cooled down, whereas the fused glass is extremely similar in color to the incandescent iron. Therefore, as this humor matches the consistency of the fused glass but the translucency of the cooled and already formed glass, it is called hyaloeides120 by the Greeks, and accordingly vitreous by us. This humor exceeds the abundance of the crystalline humor many times; when still placed in the eye, it is similar to a hemisphere whose flat surface faces the front of the eye, with its round or convex part extending to the posterior. In the middle of its anterior part or flat surface, a groove as long as the posterior part of the crystalline humor is impressed on it. In fact, the crystalline is inserted in the vitreous humor like a globe floating in water with exactly half of it being submerged and the other one visible above the water’s surface. And as nothing comes between the globe and water, so nothing at all is interposed between the crystalline and the vitreous humor121: these humors are not joined together any more than a globe would be surrounded by a rather firm porridge. Later, at the right place, I will tell how a small tunic covers the rest of the anterior vitreous humor, which is not in touch with the crystalline, and that we will compare to the lashes of the eyelids or hairs that, as I will explain, appear above the great circle of the crystalline humor.

THE LAYER OF THE EYE THAT DERIVES FROM THE SUBSTANCE OF THE OPTIC NERVE AND RESEMBLES A NET

Now comes the need for me to explain the layer in which the posterior part of the vitreous humor is enclosed, which in the fourth book was said to be of the same substance of the optic nerve.122 In fact, the optic nerve, accompanied by the thin and hard cerebral membranes as well as some veins and arteries, reaches the posterior aspect of the eye and inserts itself into the outer side of the eye, where its substance blends into the layer that is about to be described. In reality, the thin membrane covering the substance of the nerve transforms into another tunic of the eye, which will be named the uvea, and also the hard membrane ends into another one, which will be called the hard tunic; in a similar way the nerve and veins enter and form part of the eye (as I will explain in an orderly manner). So, as soon as the substance of the optic nerve merges into the eye, it becomes softer and spreads out, becoming a wide layer that covers the rear of the vitreous humor; it does not spread further than halfway toward the anterior part of the eye and is interwoven with extremely thin but nevertheless visible small veins and arteries. These minute veins extend forward from the root of the tunic and cover it as soon as the nerve spreads out. In the tenth book of the De usu partium,123 Galen mentioned that this layer is not deemed worthy of the name of tunic by most, perhaps because it is not as membranous as other tunics but soft and rather similar to some discharge from the nostrils. 162 BRAIN RENAISSANCE

In fact, when this layer is torn away by dissectors and suspended from its root, it resembles the mucus or brain substance diluted with water. It is not seen as solid and thick as the brain matter. Whatever its composition, it needs to be called tunic, because this is the term that Galen uses for this layer in De placitis Hippocratis et Platonis124 and in the eight book of De usu partium. And I do not know what name could be more suitable than layer or tunic, as, we said, it tightly surrounds and covers the whole posterior part of the vitreous humor. And we can say that this is similar to the way a thin egg membrane still covers the white of the egg when we hold in our hands with the eggshell broken into pieces. In fact this layer can be really compared to the shape of half an egg, or to a smaller fishermen’s net that is fitted into a single pole and assumes the shape of a hemisphere, going from a broad base to a blunt tip. I believe that because of its resemblance to this net, the Greeks called this layer amphiblestroeides.125 Certainly it resembles the shape of a net but not its weave, being continuous everywhere, unless perhaps where the tiny veins and arteries interweav- ing through it give the appearance of a net. So far I have reviewed four parts of the eye: two humors and two tunics. Therefore, I may now proceed to that tunic generated by the thin membrane that accompanies the optic nerve.

THE TUNIC THAT ORIGINATES FROM THE THIN MEMBRANE OF THE BRAIN AND IS CALLED THE UVEA

Indeed as soon as this thin membrane enters the eye along with the nerve, it continues as a tunic that extends to all parts of the eye like, so to speak, a globe. In fact, not only does it occupy the posterior part of the eye, as the tunic mentioned above that originates from the substance of the nerve, but it also surrounds the anterior part. In addition to the whole posterior aspect of the eye, this tunic wraps the closest tunic derived from the substance of the nerve,122 and nothing is interposed between them at the point of their junction, and they are not joined together by anything else but just their contact. Furthermore, starting from the point of contact with the thin membrane, the present tunic reaches everywhere, and covers the anterior part of the eye, and internally the humor that, you will hear shortly after, is described as aqueous and whitish in color. Indeed, the outer surface of this tunic is most closely covered here and there by the tunic that, I shall say, arises from the hard membrane that covers the optic nerve. Nothing intervenes between these two as the nerve progresses into the eye, but indeed they are joined together in the same way as the hard membrane surrounds the thin one. However, this happens to that tunic arising from the thin membrane especially, because it is not exactly round like a globe. In fact, in the anterior region it is somewhat compressed inward, displaying in a certain area a flat surface instead of a convex and spherical one. This tunic extends to the region at the front of the eye that contains what we call the iris, the great circle of the eye that separates the white of the eye (so to speak) from the black. In this region the part of the layer originating from the hard cerebral membrane,126 and which we will liken to a horn for its translucency and consistency, grows 163 On the Eye, the Instrument of Vision out and separates from the hard membrane. The tunic is compressed posteriorly at the point where it is beneath the hornlike layer, whereas, in the rest of the eye, it lies under the tunic formed by the hard membrane. The tunic generated by the thin cerebral membrane not only shows an indentation, but also, in the middle of this groove, there is a hole that forms the smallest circle in the eye, which we call the pupil. This tunic is very similar to that part of a grape berry from which you have removed the stem that holds it, especially if you imagine that the grape berry is slightly damaged and is emptied of some of its content in that part where you have extracted the stem. In fact, the whole skin of the grape berry would correspond to this tunic, whereas the damaged part would correspond to the anterior compressed part of the tunic. Then, the hole through which the stem is held can be compared to the pupil itself. Because of this similarity to the grape berry the Greeks called the present tunic rhagoeides127 and roga,128 whereas we call it the uvea. Since this tunic is made up of the subtle cerebral membrane named choroeides,129 the Greeks called it also choroid. Although they did not give it that name just because it is produced by the subtle membrane of the brain, but perhaps because it sustains the veins and arteries of the eye in the same way the subtle membrane supports the brain vessels. Over the entire area covered by this tunic, which, as I shall soon say, the hard cerebral membrane generates, twigs of veins and arteries extend from here into the uvea, and roughen the uvea so that also this part resembles the inner surface of the skin of a grape berry containing the fibers by which the flesh of the grape berry and its seeds are sustained. Since, therefore, so many twigs of vessels are spread into the uvea from the tunic that the hard cerebral membrane generates, it is by means of these twigs that the uvea is attached to the choroid tunic.

COLORS OF THE UVEAL TUNIC

Where the uveal tunic separates from the choroid tunic and is pressed inward along the circle of the iris, the uvea it tightly attaches to the choroid all around the entire circumference of the circle, and varies its color. For example, over the surface where the uvea is surrounded by the hard tunic, it is always colored black, and is moderately moist. In the anterior part of its indentation, it is instead variously tinged, and always displays the same color as the iris or the greater circle of the eye, or the black of the eye. This is the reason why we talk about black, grayish blue, or glaucus130 eyes.

THE COLOR OF THE EYE IS NOT AFFECTED BY THE NUMBER OF HUMORS OR SPIRITS

There is certainly no reason for the colors of the eyes to depend on the humors. Even if this is a great paradox, nevertheless, I would like to demonstrate that this is the case whether the eye is intact, or the humor drained out, or the uvea itself has been detached and torn away from the hard tunic. 164 BRAIN RENAISSANCE

Not only can this be noticed in the human eye, but also in the eye of any animal. Moreover, the inner surface of the uvea is stained here and there with a variety of colors. At the back of the eye, where this tunic first takes origin, it is whitish, then green, and then blue like the iris. And its inner surface still has those colors in the posterior region of the eye, whereas in the anterior part it is generally all dark. And it appears smooth here as at the back: this happens especially because of the processes that branch out from here to constitute the tunic covering the anterior part of the vitreous humor. The tunic interposes itself between the vitreous and that part that we shall call the aqueous humor.

THE TUNIC THAT WE COMPARED WITH THE HAIRS AND LASHES OF THE EYELIDS

The present tunic131 has only flat surfaces, not concave or convex surfaces. You would form this tunic if you cut out of the finest spider’s web a circle the size of the front part of the vitreous humor and then within this circle, cut out another tiny circle by making an opening as large as the great circle of the crystalline humor. Similarly, you may compare the present tunic with such a circle if you imagine that in a circular shape it originates from the uveal tunic and is attached at its opening to the great circle of the crystalline humor. This tunic is indeed generally thinner than the spider’s web and consists of tiny processes originating from the uvea. It is remarkably similar to the black hairs or lashes of the eyelids, but I am not going to spend time here to say whether it should be called a tunic or something else. I will not add more to what I already said about where it is located, what parts it attaches to, and its appearance and consistency. To me, there is no more apt name for it than tunic or interstice between the vitreous humor and the one that we shall call the albugineous132 or aqueous.

THE HARD TUNIC OF THE EYE THAT ORIGINATES FROM THE HARD MEMBRANE OF THE BRAIN

But now it is time to include the hard tunic into our description, which we believe originates from the hard membrane of the brain that covers the optic nerve. In fact, as soon as this membrane inserts in the posterior part of the eye, it broadens out and becomes thicker and harder than the hard cerebral membrane itself, and it covers the eye everywhere in a circular fashion, reaching the front and the back. Even if it is the same everywhere, it is not given a single name. Where it forms the rear of the eye and reaches the front to the greater circle of the eye or iris, it is thick and hard (and for this reason it is called sklerotes133). Like the hard cerebral membrane, it is opaque and not at all transparent. Here, where the dark of the eye or the iris is, this tunic assumes the appearance of a horn that is divided into layers and is perfectly smooth, shaped as the glass of a lantern, and is transparent.134 165 On the Eye, the Instrument of Vision

This part of the present tunic alone matches and even surpasses the lucidity and consistency of the horn: indeed, this part of the tunic is hard like the horn. And just like the horn, it can be divided into layers and shaved, so this part of the tunic can be similarly shaved and separated by dissectors as if it constituted a number of layers or scales compacted together. And this explains the treatment given by ocular physicians who scrape away this part of the tunic in elderly people. For its great resemblance to the horn the Greeks call it keratoeides135, and we indeed call it cornea. However, many among the Greeks seem to have used this term not only for this part of the present hard tunic, but for the entire tunic (since it is remarkably hard). Certainly, for the present tunic I will not distinguish the translucent part from the rest of it that is not transparent, as if it were another tunic; I think nobody will be surprised, given that these parts do not differ from each other in any way except for what we said. The inner surface of this tunic, over the whole area where it is not transparent like the horn, surrounds the uveal tunic with no interposed substance and is attached to it by means of veins and arteries, as we said earlier. In the same way it is firmly attached to it in a circle around the great circle or iris of the eye. Then, over the whole area where this tunic is transparent like the horn, it does not touch the uvea, and so long as the eye is healthy, it stands noticeably apart from the uvea in the anterior region where the uvea is compressed. This interval and the entire space between the front of the crystalline humor and the pupil is filled up by the humor that remains to be described, and that is thought to be a true fluid.

THE VITREOUS HUMOR

To dissectors and those treating cataracts this humor appears as being more or less like water, and is quite remarkably transparent like water: for this reason it is called hydatoeides136 by the Greeks, and aqueous by us. Even if many people compare it to the humor of an egg, they call it albugineous: but I think that the Greeks did not compare this humor to the egg white placed next to the fire, since it is by no means as thick as, but rather closer to the humor that we notice coming out of a fresh and intact egg. And this humor supports, in fact, the part of the uveal tunic that, in a healthy eye, is not contiguous to the cornea and (as I said) is contained in its anterior and posterior parts. When it is located in the eye and, as I might say, confined by a limit not of its own, it forms a hemisphere as the vitreous humor, whose posterior part, namely the flat surface, has a groove as long as the part of the crystalline humor that protrudes forward. The front of the aqueous humor is arched, round like a hemisphere, and follows the shape of the eye. Over the whole area that appears transparent like the horn, the outer surface of the hard tunic is very smooth and slippery: whereas elsewhere it appears rough and uneven to permit the mutual intersection of the attached membranes. 166 BRAIN RENAISSANCE

THE ADHERENT OR WHITE TUNIC OF THE EYE

In the posterior aspect of the hard membrane, for example, besides the tortuous veins and arteries, a muscle that we counted as the seventh among the muscles moving the eye is inserted there. Furthermore, into the sides and the upper and lower seats of this outer surface of the eye are inserted thin, sinewy ends of muscles that we ascertained to belong to the first six muscles that move the eye. In the front of the white tunic, as far as the iris or greater circle of the eye, a tunic, that so far remains to be mentioned, is attached. Since it wraps the eye and gathers it together with the nearby parts, it is called the adherent tunic, or the white tunic because of its color. This membrane,137 which covers only the anterior part of the eye, is thin and continuous with the membrane that covers the inside of the eyelids. It is listed as one of the parts of the eye together with the eyelids themselves, if one wants them to also be part of the eye structure. Finally, this is the order of the parts of the eye: the crystalline humor; the small tunic that is transparent like the thinnest onion skin and attached to the anterior part of the crystalline humor; the vitreous humor, that is located only in the posterior part of the eye; the tunic that is continuous with the substance of the optic nerve, and that surrounds only the back of the vitreous humor; the uveal tunic, originating from the thin cerebral membrane; the black tunic or circle that is thin as a spider’s web, and interposed between the vitreous and the aqueous humor; the hard tunic that becomes transparent like the horn in the anterior part of the eye; the aqueous humor; the seven muscles moving the eye138; the adherent or white tunic, attached only to the front of the eye; the eyelids, and finally the veins and arteries. Furthermore, if someone wants to approach the structure of the eye from the outside to the most internal part, it is now readily possible to explore these parts in reverse order: or if one wants to refer to the humors separately and then the tunics, nothing prohibits this. So far, I have explained the eye according to the order I am used to following in schools, first explaining the structure of the eye, and then sketching in parallel a rather large picture on a sheet of paper, similar to the one I have tried to reproduce in the first figure placed at the beginning of this chapter. Then, after the explanation, I perform the actual dissection, as I will discuss at the most appropriate place in the final chapter of this book.

THE FUNCTION OF THE STRUCTURES OF THE EYE

Because I am used to displaying the anatomy of the eye with such care that no one among the audience will need to know more about it, so here I say completely nothing to explain the function of its parts. This is because I am not satisfied myself with what is known about the primary instrument of vision, and I am persuaded that in this section I cannot report what is soundly established. Of course, I could mention that the crystalline humor is the principal instrument of vision, and that the vitreous is produced for the nourishment of the crystalline, and that the other parts of the 167 On the Eye, the Instrument of Vision eye are formed for the benefit of the vitreous humor. This was explained at length by Galen in the tenth book of De usu partium, and it is not necessary that I write again about this in detail. The reason for refraining is that I am myself not certain as to what vision is or what the other structures linked to it are. I should perhaps consider writing separately about such scientific and medical controversies to keep my present work at the proper length.

27 On the Organ of Hearing

Earlier, in Book I, I explained everything that needs to be said about the anatomy of the organ of hearing, and I would have reported it here if nothing had been already mentioned there. In Chapter 8 of Book I, I reviewed the cavity in the skull139 that contains the organ of hearing, along with the openings, membranes, and ossicles140 of this cavity. In Chapter 16 of the same book I have already accurately described the structure of the auricular cartilages and the other structures that I was able to observe to the best of my abilities. I cannot add anything more in detail here than what I reported there concerning the sense of hearing and the perception of sounds except that I find this topic even more ambiguous now than when I was writing that chapter, and I am really far less satisfied. And I never cease to be astonished by all those authors who write pages and pages about hearing and its related aspects without having even the most superficial knowledge of this organ; indeed, any further discussion of this should be based on demonstrations.

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28 On the Organ of Taste

All physicians and scientists have agreed that the tongue, which fits perfectly in the mouth cavity, is the instrument of taste. In Chapter 19 of Book II, I reviewed the nine muscles of the tongue, the different patterns of their fibers, and the part of the tongue visible in the open mouth before dissection, together with its wrappings. In Book III, I similarly described the series of veins and arteries going to the tongue, and in Book IV I did not neglect at all its nerves. One of these was counted as the principal portion of the major root of the third pair of nerves,141 linked to the tongue primarily for the purpose of taste, while the other comprises offshoots of the seventh pair of cerebral nerves and weaves into the tongue for the muscles.142 I think that no one will ask me to start writing a long and detailed account on the anatomy of the tongue (and, honestly, I am less familiar with this topic than I am with other parts of the body), or about the different kinds of taste and taste qualities.

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29 On the Organ of Touch

I think that the instrument of touch was properly dealt with at the beginning of Book IV, where I stated that there is no nerve in the whole body that lacks the sense of touch. There I also reported the aims of Nature concerning the distribution of nerves as far as necessary at that point: I was smiling at the opinion of those thinking that one very small portion of the nerve is in charge of sensation whereas another part of the same nerve is in charge of movement without sensation. And therefore I have now completed, to the best of my ability, my account of the anatomy of the entire human body; it remains for me to explain in detail the method of dissection of all the parts that we have described in the present book. And I will add at the end the method of dissection of those parts mentioned in other books but not yet reported. Finally, I will suggest some remarks about vivisection.

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30 How to Dissect the Brain and All the Other Organs Discussed in This Book

HOW TO PREPARE A HEAD FOR THE EXAMINATION OF THE BRAIN

Assuming that you have previously investigated the muscles in the neck and the nerves of the cervical spinal cord on the same cadaver used to examine the organs of nutrition and the vital faculty, I recommend that you now remove the head from the rest of the body, as advised at the end of the previous book. Once removed, the head is easy to handle. For this reason, the heads of beheaded people are very suitable for our aim: furthermore, thanks to the help of broadminded judges, they can be obtained immediately after the execution, when still fresh. Among these benefactors, I would undoubtedly mention a patron and the finest figure of the most illustrious Venetian senate, Marcantonio Contarini, a formidable man with wide knowledge of science and languages and a worldwide reputation for the many diplomatic missions he accomplished. He is now the most thoughtful governor of the city of Padua, providing us with plenty of material for our anatomical procedures.143 Moreover, he is an ardent student of the working of the human body, comparable to Boethus or Sergius among the Romans.144

HOW TO OPEN THE SKULL TO DISSECT THE BRAIN

Whatever head you succeed in procuring, it is always necessary to saw the skull first, then take a knife, or a razor, and make an incision right around the head, cutting through the skin down to the bone. This incision should be one thumb above the eyebrows; then continue cutting through the temporal region to the back of the head, exactly where the occiput145 protrudes out farthest, and from here through the other temporal region back to the forehead. After completing this skin incision, use a sharp saw, similar to the one for the amputation of gangrenous limbs or the type used by the manufacturers of ivory combs, and cut along the skull around the skin incision, paying attention to avoid sawing what is under the bone. Before doing this, try not to shave off the hair or remove the ears as they can be of help in this task. In fact, by holding them in your other hand or, alternatively, asking your assistant to grasp them with his hands, you will be able to prevent the head from being pushed away by the

171 172 BRAIN RENAISSANCE saw. Saw through the skull around the circular incision; then, to ascertain whether the bone needs to be further cut at certain points, pass the sharp edge of a knife through the incision. If you are not confident in doing this by yourself (though it is really the easiest way of proceeding), and to further prevent the extremity of your saw-cut from ending higher or lower than the beginning of the incision, you can adopt the method used to cut timbers into planks. Take a dye-soaked cord and pass it closely around the bare skull; this way while sawing you will be guided by the colored line left around the skull. After completing the circular incision through the skin, the dye-soaked cord should be tied again around the bone. This is because the skin incision cannot be used as a guide per se for the bone incision: in fact, by holding the head you will pull away the skin from the skull and tear out the edges of the incision on the skin. Once the skull has been divided, detach and remove the lower jaw from the neck, so that the head can rest on the table on its base: you can also place a stone, or something similar, on each side to further stabilize the head and prevent it from falling sideways. If at this point in the dissection procedure the head is still attached to the rest of the body, place some square stones or blocks under the neck and occiput to raise the head and bend it forward, so that it rests on its base. Then, you can place the back of a big knife transversely across the forehead, against the saw-cut, and carefully open the incision by moving it gently up and down. Do the same at the occiput and at the tem- ple regions to make sure that the skull is detached from the hard cerebral membrane; then use your hand to grasp the hair on the top of the head and pull the bone away.

EXAMINATION OF THE SKIN, FAT, AND FLESHLY MEMBRANE, FOLLOWED BY THE WRAPPING OF THE SKULL AND THE UNDERLYING MEMBRANE

After you have removed the bone, the skin can be easily pulled away with the hand, although occasionally you may need to use a knife to detach it.146 Then you can pull away the fat and the fleshly membrane and, using the tip of a small knife, observe what the Greeks call the perikranion or periosteon.147 You will also notice the tiny veins within the skull, going from the skin at the top to the hard cerebral membrane and backward.

HOW TO EXAMINE THE ENTIRE HARD CEREBRAL MEMBRANE

Pierce with a knife the hard cerebral membrane and insert into the hole a quill pen, a small pipe, or the siphon used for evacuating urine and firmly hold the edges of the hole around it with your fingers, then blow into it. This procedure will show you how much larger the hard membrane is compared with the overall size of the brain. The air blown into it distends the hard cerebral membrane entirely, so only one side is to be pierced. If you accidentally cut through the hard membrane somewhere while 173 How to Dissect the Brain sawing the skull, you will have to hold the hole shut while inflating the membrane, otherwise the air will leak. Then cut through the membrane and insert the tip of a sharp knife into the third sinus148: this sinus lies longitudinally and protrudes from the membrane along the entire length of the head. Make an incision as far as you can along its length, from the occiput to the forehead or from the front to the back. If your subject died by hanging or in any different way from beheading, you will see this sinus full of blood, which should be removed. Then, stretch the sinus and observe its form, and also examine the opening of the branches sprouting out from its bottom on both sides.

UNCOVERING THE THIN MEMBRANE

To strip bare the brain of its hard membrane, pierce the membrane close to the frontal bone at the side of the third sinus; then insert a stylus into the hole and make an incision with a knife along the stylus, all the way to the occiput on each side of the sinus. After cutting both sides, use the tip of the knife to pierce the hard membrane again, near the bone that is close to each ear; from here, make an incision straight up toward the incision that was made longitudinally along the length of the head. Then, use your fingernails to lift up the four angles of these adjacent incisions at the top of the head and pull them down away from the brain. In addition, take note of the branches stretching into the thin cerebral membrane from the third sinus of the hard membrane and from the vessels interwoven at the sides of it. Using your hands, gently divide the right side of the brain from the left; raise as far as possible the septum attached to the hard membrane between the two hemispheres and also all the projections149 on the sides of the third sinus from the hard to the thin membrane; now you can observe how the brain is held up by them. Remove these projections from the sinus using a sharp knife and free the portion of the hard membrane from the septum between the olfactory organs. Lift this portion of the hard membrane away from the brain and fold it backward, not forgetting to inspect its sinus elongating like a vein along its base. We will later discuss the origin of this and other veins; for now, let us examine the projections between the thin and the hard membrane. When you have turned back the aforementioned portion of the hard membrane and divided the two sides of the brain, you will notice the long projections in the thin membrane extending along the entire length of the head, from the end of the fourth sinus of the hard membrane to the thin membrane. Here, do not focus on the origins of these but spread apart the two brain hemispheres softly to avoid accidental damage. Moreover, I advise you to separate as far as you can the two hemispheres at the back and, with the tip of a sharp knife, cut the hard membrane between the two sides of the brain and between the cerebellum and the brain. This procedure will reveal the fourth sinus and its projections. Then, if you lift the brain slightly, away from the hard membrane between the brain and the cerebellum, you will be able to see the tiny branches that extend from the hard into the thin membrane. Indeed, these can be better observed after this portion of the brain has been removed. 174 BRAIN RENAISSANCE

SEPARATION OF THE THIN MEMBRANE FROM THE CEREBRAL CONVOLUTIONS

When you have finished examining the projections of the thin membrane that lie lengthwise in the head above the corpus callosum, at some point you will have to divide the thin membrane with a knife or with your fingernails and then, using only your fingers, pull it away gently from the brain and its convolutions. When this membrane is removed, the grooves become visible and one can understand the continuity between the brain and the thin membrane by observing how the brain expands when the membrane is removed.

EXAMINATION OF THE SUPERIOR SURFACE OF THE CORPUS CALLOSUM

The height and depth of these grooves can now be investigated using fingers or a stylus. Moreover, with your fingers alone, you can study the top of the corpus callosum and the cavities150 on its sides.

OPENING THE RIGHT AND LEFT VENTRICLES

Once the cavities have been located, you must detach a large portion of the brain on each side. Take a big sharp razor and make an incision through the cavity on the right, alongside the corpus callosum, so you can remove, in one piece, the right brain portion above the cavity that extends from the front to the rear. If you need to make more than one incision, that procedure is incorrect. Leave the portion of the brain you removed on the table, with the top of the right ventricle visible. If the incision has been made correctly along the cavity on the right side of the corpus callosum, as described before, it should cut through the right ventricle. After having removed the right portion of the brain in this way, repeat the same procedure on the left side, open the left ventricle, and make your incision along the left cavity beside the corpus callosum so that this remains in situ but free to move as much as possible.

EXAMINATION OF THE SEPTUM BETWEEN THE RIGHT AND LEFT VENTRICLES

After examining the cerebral ventricles, the translucent septum between them can be observed if, delicately using the fingertips of both hands, you gently and carefully lift the portion of the corpus callosum that has been separated on each side from the brain. If you lift the corpus callosum in this way and place a candle at the side opposite to the one you are looking at (assuming that is not a bright day with the sunlight shining on it), you will recognize the septum. Then, with a knife, detach the anterior part of the corpus callosum from the region of the brain between the olfactory organs, pull it up with your fingers, and fold it back. At the top, the 175 How to Dissect the Brain transparent septum is attached to the corpus callosum, whereas its inferior part is continuous with the structure of the brain that we compare to a tortoise shell or a vaulted room.151

EXAMINATION OF THE BODY THAT RESEMBLES A TORTOISE SHELL

The vaulted body, whose top is now clearly visible, can be properly examined with the help of a blunt stylus. Take a siphon-shaped stylus and insert it into the vaulted body, from the right to the left ventricle: observe its sides, then take a knife and cut through its anterior part, which is attached to the cerebral substance close to the septum of the olfactory organs. Lift it up with your fingers and bend it back to expose its lower surface, which is hollow like a tortoise shell. After having bent the vaulted body back, you can use more than one stylus to examine its posterior origin from both the right and left cerebral ventricles. Then place it back to its original position and make an incision throughout its length, or alternatively cut its base off with a knife. But before you do this, it is better to insert a stylus under it, through the area where the vessels or passages from the fourth cavity of the hard membrane travel under the vaulted body toward the anterior cerebral ventricles; thus you can carefully investigate its function and the very elegant design of its structure.

EXAMINATION OF THE RIGHT AND LEFT VENTRICLES AND THE VESSELS THEY CONTAIN

Once the vaulted body has been removed or alternatively divided by a longitudinal incision and pulled apart to each side, attention should be paid to the plexus named by the Greeks choroeides152 because of its resemblance to the placenta; also take a look at the passage growing out from the base of the fourth cavity into the hard membrane. Then, use a stylus to examine the posterior part of the ventricle and observe how it curves down from the back to the front. Meanwhile the long artery, as it runs forward, rises to join the portion of the passage that originates from the fourth sinus of the hard membrane and extends under the vaulted body to reach the anterior brain. In fact, you can see that this passage travels some distance in a straight line over the cavity common to the right and left ventricles before splitting into two branches that depart to the right and left ventricles; you will also notice that the plexus is formed by the passage and the aforementioned artery. When you look at the passages from the fourth sinus of the hard membrane, you should also examine the passages from the fourth sinus to the thin membrane, and the base of the hard membrane that divides the right from the left hemisphere. When you have examined these, take a knife and cut through the passages that from the fourth sinus under the vaulted body reach the cerebral ventricles, where they form the aforementioned plexuses. Lift them up and bend them gently backward, making sure that you do not remove with them the gland named konarion153 by the Greeks. 176 BRAIN RENAISSANCE

THE GLAND ABOVE THE TESTES OF THE BRAIN

The pineal gland becomes visible after the passages have been removed. In doing so, you should have a sheep’s brain at hand where the gland, the cerebral testes and buttocks are easier to observe than in the human brain. Reposition the gland in its seat and, with your fingers, enlarge the cavity common to the right and left cerebral ventricles: this looks like a crack. Then, examine the passages that connect to the cavity leading to the pituitary gland formed by the thin membrane, as well as the beginning of the passage154 that stretches from the third ventricle, or shared cavity, to the fourth ventricle.

THE THIRD VENTRICLE AND ITS PASSAGES

After examining all these structures, make a transverse incision in the brain and remove all the structures resting upon the cerebellum. While you do this, you must be careful not to sever the ducts or arteries ascending into the posterior right and left ventricles as well. You will now see the area of the hard membrane that divides the cerebellum from the portion of the brain that is immediately above it155 and also the right from the left side of the brain.156

THE SINUSES OF THE HARD MEMBRANE

Now it is time to focus on all four sinuses of the hard membrane at once. Insert a lead stylus into the third sinus, which is the same one on to which you have already made a longitudinal incision, and slip it into the other three sinuses of the membrane. First of all, push the stylus against each side, where the top of the cerebellum is closest to the bone, because this is the best way to find the right and left (or first and second) sinuses. You will then find the fourth sinus by moving the stylus under the base of the hard membrane between the right and left hemisphere. If you are willing to carefully examine them, make several longitudinal incisions of their passages and open them with the tip of a sharp knife.

DISPLAYING THE CEREBELLUM

After removing the hard membrane that covers the top of the cerebellum with a knife, make a circular incision along the bone; alternatively, you can cut it longitudinally and separate the membrane by folding it back. Take a quick look at the cerebellum before returning to the brain. Now spread apart the cavity that is common to the right and left ventricles and examine more closely the passages of the pituitary gland by inserting a stylus. Inspect also the passages of the shared cavity or third cerebel- lar157 ventricle by inserting a curved stylus into the cavity and slowly moving it into the cerebellum. A heavier curved siphon-like stylus will slip along this cavity into the cerebellum without any pushing. With the stylus still in the passage, carefully ease 177 How to Dissect the Brain the cerebellum away from the cerebral testes with your fingers until you see the stylus between these and the cerebellum. You will then be able to identify, particularly in a sheep’s brain, the part of the brain that is similar to the testes and buttocks.

EXAMINING THE TESTES AND BUTTOCKS OF THE BRAIN

Now take a knife and cut through the cerebral testes and buttocks along the stylus: this will reveal the passage running from the cavity shared by the right and left ventricles to the cerebellum and, even more clearly, the one in the brain that carries phlegm to the infundibulum. You will be able to use a hook to separate the thin membrane of the cerebellum and to examine the vein running from its passages into the lower back of the anterior ventricles. This can be easily found when you look for it beside the connection that links the front of the cerebellum to the brain, which is represented by the vein itself.

WHERE THE DORSAL CORD JOINS UP WITH THE CEREBELLUM

To study the link between the cerebellum and the dorsal cord, you must tilt the head forward on to its face, put your hand between the cerebellum and the hard cerebral membrane that is connected to the occipital bone, and pull the cerebellum forward and downward until the whole of it detaches from the spinal cord. You should now clearly see the tiny veins or ducts that extend into the cerebellum from the beginnings of the first and second sinuses of the hard membrane or from the veins and arteries running through the transverse processes of the cervical vertebrae. Moreover, you will notice not only the cerebral origin of the dorsal cord but also its shape, as well as the cavity that, together with the cavity of the cerebellum, forms the fourth ventricle.

EXAMINING THE FOURTH VENTRICLE AND THE WORM-LIKE PROCESSES

Place the head in its former position with the cerebellum lying on its front. Observe its cavity and the parts through which it was connected to the dorsal cord, focusing on the remarkable aspect of its convolutions: they will direct you to the two worm-like processes of the convolutions, which are the ends of the convolutions going lengthwise through the middle cerebral part. You will see them very clearly once you separate them from the rest of the substance of the cerebellum by making a long incision lengthwise on either side of the convolutions, and then laying them out on the table after their excision. They will appear to you like a worm, similar to those that fall from willow trees in spring or silkworms before they wrap themselves up in their cocoon (and even more when they have been in their cocoon for some time but have not yet gnawed their way out of it). If you do not cut away all the middle convolutions 178 BRAIN RENAISSANCE but only the extremities, you can display the worm-like processes of the cerebellum, one at the front and one at the back. Cutting them away like this will allow you to appreciate even better their likeness to a worm as explained above; moreover, when the cerebellum is pulled away from the beginning of the spinal cord, you can focus on investigating their function.

EXAMINING THE PAIRS OF NERVES

Now that you have inspected the different parts of the cerebellum, you should examine the pairs of nerves. It will be easier if you put your hand between the brain and the frontal bone and gently lift the brain; by doing so you will make visible the structure known as cerebral mammillary process158 first and then the olfactory organ. The latter should be separated from their cavities using a stylus, or one finger, and then bent backward and upward along with the brain. When doing this, tilt the head back on its occiput since this position (that is, bent back) shows very well the origin of these processes. At the same time, you can observe the origins of the optic nerves and their joining together159 as well as the basin160 receiving the excretion of the cerebral phlegm under them. Then you will see the region where arteries enter into the cavity of the hard membrane: some continue into the thin membrane, whereas others run into the right and left cerebral ventricles. To examine in detail the order of these arteries, you must detach the thin membrane from the brain. Note that the ventricles end in the convolutions, not in the olfactory organs or in the optic nerves, and therefore the phlegm is neither excreted from the ventricle into these organs nor conveyed by them to the eighth bone of the head. Now separate the optic nerves from the brain and carefully cut away the portion that you can see in the skull cavity, taking care to avoid the removal of the aforementioned basin with them. By doing so, the passage from the third ventricle is fully visible, and can be studied clearly. You can also see how the basin ends in the gland under the hard membrane, which reveals itself when dilating its special opening in the hard membrane. Until you have examined the other cerebral nerves, the membrane should not be damaged. Then tilt the head so that it lies on its left side, replace in its seat the remaining part of the brain, and bend the brain down and left in order to study the origin of the second pair before the small root of the third pair. Pull this away and bend the brain still further to the left and investigate the origin of the third and fourth pairs followed by the origin of the fifth pair. Cut through this to see the tiny nerve that takes origin beside the root of the fifth pair and goes toward the temporal muscle as well as the one hidden in the mouth that raises the jaw. The sixth and seventh pairs can be seen if you follow the numerous offshoots they originate from. When examining these pairs, you should also notice the channels that run like veins from the sinuses of the hard membrane into the thin membrane. In the same way, you can find the nerve origins on the left side. Then, pull away any remaining of the dorsal cord, and the part of the brain that remains in the head, revealing the section of the hard membrane that underlies the still undamaged base of the brain. 179 How to Dissect the Brain

Notice that the cavities belonging to the olfactory organs are pierced with tiny openings and that nerves travel out from them on all sides. After examining this, focus on the origin of the first and second sinuses of the hard membrane and the vessels that enter into them, which you should be able to open with the tip of a sharp knife.

EXAMINING THE STRUCTURES AT THE BASE OF THE HARD MEMBRANE

Then, without any further cuts, you can see the ducts along the sides of the hard membrane at its base, close to the front. To observe the gland, and the net-like plexus that the outstanding professors of dissection claimed to have seen, you have to study the opening in the hard membrane receiving the middle part of the basin, or funnel, with part of the basin still attached.

THE GLAND RECEIVING THE PHLEGM AND THE ARTERIES LYING BESIDE IT

Do not forget the artery that enters into the hard membrane on each side of this opening. Have a quick look at that and then, using the tip of a sharp knife, make an incision on each side from this opening to the region through which the artery passes. By stretching the edges of these incisions you will reveal the pituitary gland with the arteries lying beside it. It may be easier to see these arteries if you separate or open the hard membrane as much as you can at this point, using hooks and the tip of a sharp knife, and push a lead stylus from the artery entering into the hard membrane to the sleep artery161 here in the neck. If you want to lose your faith and trust in Galen’s name you can easily perform this procedure in man by using your own eyes. In fact, now it should be really clear to you what astonishing comments all the authors have made about the net-like plexus162 in humans so far, particularly if you have the brain of a sheep or ox at your disposal for dissection. Then remove the small gland from the position in which it lies, and compress it to test its hardness. Think about what Galen could have had in mind when he believed that phlegm strains down to the palate through the thickest part of the sphenoid bone, which he considered to be porous like a sponge, and failed to investigate that there are specific openings for the phlegm and the air that is inhaled, not to mention that some are rather large.

DISSECTION OF THE EYE

We shall now leave the interior of the skull and investigate the eye. You can dissect a human eye if the cadaver you have is fresh; otherwise, you should get a very fresh ox eye and work on that. First of all, examine the muscles of the eyelids and then those of the eye itself, as mentioned in Book II. In doing this, consider also the passages of nerves, veins, and arteries through the orbit of the eyes: I mean the second pair of nerves and the small root of the third pair. You will easily find their very small branches if you look for them in the fat that covers the muscle of the 180 BRAIN RENAISSANCE eye. Unless you do not want to damage the bones, especially if you use a saw to cut the triangular piece of the frontal bone, namely the upper aspect of the orbit of the eye, you can study these nerves after you have removed the eye and carefully investigated its muscles. Alternatively, you can remove the eye and its muscles without damaging the bone. You can use a sharp knife to make the incisions next to the bone all around the eye and to the exit of the optic nerve that leaves the skull cavity containing the brain. Whatever procedure you follow to remove the eye, you will always have to remove the adherent membranes as closely as possible to the bone. You should at the same time keep attached to the eye the part of the membrane that constitutes the inside of the eyelids. This way you can separate the membrane from the eye up to the iris, as if you were peeling the skin away from a body with a sharp knife, and also keep the eye muscles still intact and localize their point of insertion. Sometimes it can happen that you study it only after the removal of the eye muscles, keeping always in mind that it fully encloses the anterior aspect of the eye except the cornea, which is the transparent portion of the hard tunic. The muscles embrace the whole rear of the eye except the area occupied by the entering optic nerve. With the eye free from the muscles and the adherent membrane, you can now examine the optic nerve. First, make a longitudinal incision cutting the veins and arteries following the nerve from the brain into the hard tunic and then through part of the optic nerve. Use the tip of your knife to study the portions of the hard and thin membrane that embrace the nerve before studying the substance of the nerve, and observing the beginnings of the three principal tunics of the eye. After that, cut the optic nerve so to have only a perfectly spherical hard tunic. Hold this sphere with the fingertips of your left hand, with your thumb on the pupil and the other fingers on the region where the optic nerve inserts. Take a sharp razor in your right hand and make an incision as long as you can, transversely in the hard tunic of the eye; all the humors will spill out of the eye without squeezing it. After having made the incision, you take the eye in your right hand and allow the humors to drain into the hollow of your left palm so that the crystalline humor lies above the vitreous. If you allow the vitreous humor to be turned above the crystalline, you are not doing it right. But you can avoid this if you keep the back of the eye, where the optic nerve inserts, facing the palm of your right hand when you hold the eye to help the humors flow out. Once you have collected the humors that have been drained out from the part of the eye in which they were stored, gently and gradually turn your hand so that the aqueous humor flows out from the hollow of your left hand and only the vitreous and the crystalline humors remain in your hand. Then consider the tunic that is similar to eyelashes, which is attached in a circle around the crystalline humor and covers anteriorly the vitreous humor. Detach this tunic from the crystalline humor with the tip of a knife, lift it away from the vitreous humor, and place it on a sheet of paper. With your fingers, remove the crystalline humor from the vitreous, but pay attention to exert only a minimal pressure with your finger. Place the vitreous humor on the paper and the undamaged crystalline humor on another piece of paper that has some writing on it. By gently poking with the tip of the knife into its side, lift it up and down over the writing to see how it magnifies everything like a lens. 181 How to Dissect the Brain

Its tunic, as we said, is harder, but also thin and transparent like a rather tenuous onion skin. It needs now to be peeled away first from its sides with the tip of a knife, and subsequently, with your fingernails, from the crystalline humor itself before you place it on the sheet of paper. Alternatively, you can compress it between your fingers until it breaks so to appreciate how hard the crystalline humor is, and then place it on the paper. To investigate the three remaining tunics, turn over upon your left thumb the portion of the eye from which the humor leaked out. This is the tunic formed of the same substance of the optic nerve; it can spread out or, generally, it appears of the same consistency of the mucus. If this is the case, you have to distend it once again using a stylus to investigate its size, color, and consistency. Then unify it again, cut it away from its origin, namely the only link by means of which it is firmly held, and place it on the paper. You can now observe the inner surface of the uveal tunic, you can have a look at its colors, peel it away from the hard tunic using a hook, and examine the course of veins that from the hard tunic enter into it as well as its dark color. In dissecting the iris, admire its very strong connection to the cornea and the pupil. Observe the color of the uvea where it leaves the cornea and stands opposite to it. Once the uvea is peeled away, cut it at its origin, where it is anchored to the cornea or hard tunic, and place it on the paper. Examine the hard tunic along with the transparent, or horn-like, part of it named cornea, and observe its thickness and its transparent aspect. When you have finished, place this on the paper, and learn this procedure yourself by heart, by going through the list of parts from the center of the eye to the outer surface and then back again to the center. And if this is not too difficult, you can investigate the left eye by removing the adherent membrane and the muscles as done before.

ANOTHER METHOD OF DISSECTING THE EYE

Make an incision through both the hard tunic and the uvea, but compress the eye as little as possible and, with the help of the tip of a knife, gently make an incision only in the hard tunic. Importantly, do not try to cut through it in one attempt only, but make several cuts until the incision reaches down to the uveal tunic. Then insert a thin stylus with a blunt tip into the incision and gradually separate the uveal tunic from the hard tunic, and by means of small scissors make the incision in the hard tunic all around the eye without damaging the uvea. This way you can better appreciate the passage of veins from the hard tunic to the uvea and, after the dissection of the uveal tunic, the place containing the humors.

EXAMINATION OF THE ORGAN OF HEARING

After having completed the dissection of the eye, you should now dissect the organ of hearing, unless you want to keep the bone intact. The nature of the ear can be appreciated by separating on each side the skin from the cartilaginous substance that constitutes the ear. The process of the auditory nerve is more difficult to find. But the membrane into which the nerve dissolves and also the very small bones belonging to this organ can be seen after you cut the portion of the bone that lies 182 BRAIN RENAISSANCE above the meatus with a very large saw, and you then remove with a strong knife the rest of the bone until you reach the meatus. However, if the saw touches the meatus, the entire dissection will go wrong and you will not get anything even with the knife, because in this narrow and winding channel the thin and soft nerve can be easily snatched or damaged with the bones. To me everything is satisfactorily working when I use the saw to separate the piece of bone containing the organ of hearing from the rest of the skull, and then strongly use a knife to cut transversely right through the bone. You should separate the area of bone that first receives the nerve leaving the brain from the bone where the ear is attached. Once again, if you do not want to preserve the bones intact, I would advise you to break the frontal bone in several places where this faces the eyebrows so that you can properly investigate the cavity within the frontal bone. The same procedure can be applied to the cuneiform bone to study the numerous cavities within it, and their content. Thus nothing described in the seventh book is missing.163

Part Three A Brief History of Neuroscience from Vesalius to the Connectome

31 Introduction to Network Neuroscience

If you were to compare the workings of your brain with one of humanity’s inventions, what would you choose? At the start of the new millennium most of us would have opted for a computer. Maybe you still would now. Back then the brain was a piece of hardware, the mind its software. All the while we “processed” information and “downloaded” our memories. Nowadays, though, many may decide upon something slightly different, choosing to compare it not with a single processing center but a network, perhaps a social network. This shift in description is another manifestation of our acceptance of metaphors to portray the brain. It is an enduring fascination that tracks the history of neuroscience and means that the pattern of scientific investigation through time cannot be understood in isolation—that pattern must be set against the background of wider trends in the sciences, methodological advancements, and the general culture of the time (Clarke and Jacyna, 1987). As obvious as it is, when Vesalius sat at his desk to begin writing his Fabrica, there was no computer, not even a typewriter, that he could look to for inspiration, let alone to record his thoughts. His explanations for the brain relied on borrowing terms from the most advanced disciplines of the time— hydraulic and mechanical models. In many respects the case was similar for Galen, who extracted ideas from the plumbing systems that sanitized the Roman era. It meant that the inner cavities of our ventricles were the perfect places for animal spirits to “flow” through. Nowadays social, biological, and technological network models dominate approaches to complexity (Egerstedt, 2011). Telecommunications, social networks, transportation logistics, molecular interactions, and metabolic pathways are just some examples wherein complex dynamics can be described using network analysis (Sporns, 2011; Strogatz, 2001). And neuroscientists are no different. We too have adopted a network-based approach to describe the complexity of the nervous system. The interactions between our 80 billion neurons are defined using terms borrowed from networking. There are nodes, hubs, and connections. Their properties are quantified in terms of efficiency and centrality as well as global and local integration (Bullmore and Sporns, 2009). The general perception has been that network analysis could bring us closer to a true understanding of the real working of the human brain and thus the causes of its disorders. The ultimate goal is a complete map of the human brain’s connections—a

185 Table 31.1 Major developments in the history of neuroscience from Vesalius to the 19th century

MICROSCOPY ELECTROPHYSIOLOGY/COMPUTATIONAL NEUROANATOMY/NEUROIMAGING

Hans and Zacharias Janssen invent the Arcangelo Piccolomini describes the medulla 1590 Rene Descartes describes the re ex action as a sensory- 1586 microscope 1649 (white matter) and the cerebrum (grey matter) motor mechanism for involuntary muscle contraction Jan Swammerdam discovers that the mechanical stimulation omas Willis speculates on the sensory and motor Marcello Malpighi observes the cortex and describes 1660 1664 nature of ascending and descending projection 1666 of nerves produces muscle contraction its “globules” and “bres” pathways Antonius van Leeuwenhoek provides the rst Raymond Vieussens separates commissural bres of the 1674 1684 detailed description of nerve bres Isaac Newton suggests the electrical nature of corpus callosum from projection bres of the 1713 nerve signal propagation centrum ovale Leonhard Euler gives a mathematical formulation of the 1736 Königsberg Bridge and start the modem graph theory 1786 Felix Vicq d’A zyr describes commissural and 1791 Luigi Galvani publishes his work on Animal Electricity and associative pathways describes nerves as “pathways that conduct electricity” 1803 Giovanni Aldini, applies electrical currents to mammalian Joseph Gall identies di§erent cerebral gyri and brains to trigger motor responses 1810 localizes cerebral functions in the cerebral cortex Johann Christian Reil describes several association 1809–12 tracts, including the uncinate, arcuate, inferior longitudinal fasciculus and cingulum 1819–26 Karl Friedrich Burdach extends Reil’s work and gives latin names to association tracts Jean-Baptiste Bouillaud demonstrates that speech Christian Ehrenberg, Gabriel Valentin Carlo Matteucci measures an electrical voltage across 1825 1830s is localized in anterior regions of the brain 1833–8 and Jan Purkinje describe individual the cell membrane populations of cerebral cells 1839 eodor Schwann describes the cells that form the myeline sheet Jules Baillarger describes the cortical layers Wilhelm Griesinger and omas Laycock develop the concept 1840 1843–45 and compare them to a Galvanic pile of psychic re ex for higher cognitive functions 1848 Emile du Bois-Reymond discovers the action potential (negative Schwankung) Augustus Waller describes the “Wallerian” 1850 1850 Herman von Helmholtz measures the propagation degeneration of axons speed of the nerve impulse Rudolph Kölliker distinguishes cyto- 1850 Bartolomeo Panizza discovers the visual centre in the and myeloarchitecture 1855 occipital lobe 1860 Otto Friedrich Karl Deiters describes axonal 1857 François Lauret and Louis Pierre Gratiolet propose and dendritic processes. criteria for a lobar division of the brain 1862 Carl Weigert develops the rst myelin stain 1861 Paul Broca identies an area for speech production eodor Meynert describes variations in the 1867 Julius Bernstein obtains direct recording of the action cortical layering between lobes 1868 potential and its kinetics 1870–85 eodor Meynert formulates the associationist 1870 Gustav Fritsch and Julius Hitzig use electricity to theory of brain function localize motor regions Carl Wernicke puts forward the rst network model 1873 Camillo Golgi discovers the Black Reaction 1874 1875 Richard Caton records electrical activity from exposed of higher cognitive functions rabbit and mouse brains James Sylvester introduces for the rst 1878 Vittorio Marchi develops a technique to trace Santiago Ramón y Cajal proposes the neuron time the mathematical term “graph” 1886 1887 degenerating axons over long distances theory 1891 Heinrich Waldeyer-Hartz uses the term “neuron” to indicate the functional unit of the nervous system Paul Flechsig obtains myelogenetic maps of the 1897 human brain and distinguishes primary and 1897 Charles Sherrington coins the term “synapse” association areas Table 31.2 Major developments in the history of neuroscience in the 20th century.

MICROSCOPY ELECTROPHYSIOLOGY/COMPUTATIONAL NEUROANATOMY/NEUROIMAGING

Joseph Déjérine describes the topographic Julius Bernstein advances the hypothesis that the action 1901 1902 potential results from a change in the permeability of the distribution of bres within the internal capsule axonal membrane to ions Ivan Pavlov discovers the conditioned reex as an 1903 automatic form of learning 1905 Alfred Campbell publishes the rst map of the brain divided into 17 cortical elds Luis Lapicque publishes a model of integrate-and-re Korbinian Brodmann produces cyto- 1907 1909 neurons suggesting a threshold for ring architectonic maps of the brain Oskar and Cecile Vogt produce myelo- 1910 architectonic maps of the human frontal lobe 1918 Walter Dandy introduces ventriculography Constantin Economo and Georg Koskinas 1925 publish an atlas of the human brain 1927 Hans Berger records the rst human EEG 1927 Egas Moniz invents cerebral angiography divided into 107 cortical elds Jacob Moreno presents the rst sociogram as a tool to study 1933 and visualize patterns of interpersonal relationships 1935 Joseph Klinger develops a new procedure to perform post-mortem white matter dissections Wilder Peneld and Edwin Boldrev demonstrate the motor 1938 Ernst Ruska develops the electron microscope 1937 and sensory homunuculus in man 1942 Albert Coons describes a new method based on immunouorescence staining 1943 Warren McCulloch and Walter Pitts propose the rst mathematical model of a neural network. Felix Block and Edward Purcell independently 1946 Donald Hebb develops his theory for synaptic plasticity and 1946 describe the NMR phenomenon for liquid and solid Walle Nauta and Paul Gygax develop a new learning 1951 e rst Positron Emission Tomography staining method for degenerating axons 1950s 1952 Alan Hodgkin and Andrew Huxley describe the mathematical scanners are produced model for nerve excitation

1959 David Hubel and Torsten Wiesel discover oriented receptive elds in the cat’s primary visual cortex Intra-axonal tract tracing compounds 1960s David Cohen invents MEG 1960–70 developed using horseradish peroxidase and radiolabeled amino acids 1969–71 David Marr and James Albus develop a computational theory of cerebellar function 1970s Godfrey Hounseld develops Computerised Tomography

1973 Paul Lauterbur publishes the rst NMR image 1977 Hans Kuypers employs uorescent tracers Eduardo Macagno uses a serial electron 1979 microscopy to map an isolated neuron in the water ea 1980 First Clinical MRI scanner

Electron microscopy is used to describe the rst Jay McClelland and David Rumelhart apply parallel 1985 Denis Le Bihan applies diusion MRI to the 1986 complete connectomme of the C. elegans (~300 1986 distributed processing theories to cognitive psychology living human brain neurons) and cognitive neuroscience 1988 Jean Talairach and Pierre Tournoux publish the rst atlas in a common space of reference Gabriella Ugolini exploits viruses as transneuronal 1987 Tim Berners-Lee develops a new hypertext system that tracers 1990 Seiji Ogawa describes the BOLD eect 1989 runs across the internet, the world wide web Peter Basser develops Diusion Tensor Imaging Rabies virus introduced to study polysynaptic Duncan Watts and Steven Strogatz present a 1994 1995 1998 neural networks. mathematical model to describe small world networks 1999 First in vivo human diusion tractography reconstructions 188 BRAIN RENAISSANCE hope encapsulated in the term connectome (Sporns et al., 2005; Hagmann, 2005). Two recent multicenter research projects testify to the interest and commitment the international scientific community extends to this endeavor. The Human Connectome Project, a five-year program, was launched in 2009. It is funded to the tune of $40 million by the National Institute of Health (NIH), the medical research agency of the United States. NIH has set out a large-scale plan to employ functional and structural magnetic resonance imaging (MRI) to map human brain connections in 1,200 healthy individuals. Across the Atlantic, along similar lines, the European Commission has plans for something even grander. The Human Brain Project is one of its flagship programs. Launched in 2013, it is expected to receive funding in the region of €1 billion toward “a simulation of all the connectivity of the entire human brain at a neuronal level and emulation of its computational capabilities”. Yet enthusiasm does not end here. Months before the Human Brain Project officially began, the US government announced the possibility of $300 million a year for at least 10 years dedicated to the BRAIN (Brain Research through Advancing Innovative Neurotechologies) Initiative. The goal is truly remarkable—“to produce a revolutionary new dynamic picture of the brain that, for the first time, shows how individual cells and complex neural circuits interacts in both time and space” (Insel et al., 2013). It is a field of research that is constantly expanding—an interest fueled in a large part by the development of new methods with which to image networks in the living human brain, not to mention the computational capability of processing and storing the huge amounts of data produced. But these are just a few of many advances that signpost the history of neuroscience. The connectome approach, although new in its overarching concept, represents the culmination of converging lines of research that have developed over the course of many centuries. It is a fascinating series of physiological and methodological developments that have helped define and then redefine anatomy and function on both a micro- and macroscopic scale. As the predominant theoretical construct changed over time, brain maps, with their nodes and connections, have evolved too. In this regard, since Vesalius completed his Fabrica, there have been many pivotal discoveries in the various fields that feed neuroscience: from microscopy, electrophysiology, and computational sciences to anatomy and neuroimaging. Tables 31.1 and 31.2 provide brief highlights of these key developments, which are just some of the threads entwined in the question of how a brain is connected (Catani et al., 2013b). And as we unravel them, retrace past achievements, and consider earlier attempts to map the brain, we encounter a network of pioneers who, together, have edged us just a bit closer to understanding what it is that makes us who we are.

32 Protoconnectome Maps

In the Renaissance, while Vesalius was exploring the human form, the most popular representations of the brain and its functions consisted of diagrams depicting a variable number of intercommunicating ventricular chambers (Figure 32.1). This ventricular theory, as it is now known, was the direct result of brain dissections originally undertaken by classical physicians: first Herophilus of Alexandria in the fourth century B.C. and then, six centuries later, Galen (Clarke and O’Malley, 1996). The metaphorical influence of these men came from the great advancements made by the Greeks and Romans in hydraulics. Aqueducts were constructed and maintained to supply water and remove sewage from ancient towns and cities. This meant that in these maps, nodes corresponded to ventricular reservoirs or cells, each of which had a specialized function. Such reservoirs communicated with each other through a system of interventricular foramina, or holes, and led to peripheral organs by means of hollow nerves. Our cognitive processes—what we think, what we imagine, what we feel—resulted from the passage of “spirits” or fluid from one cell to the next. While knowledge of white matter connections was still centuries away, these protoconnectome maps do contain some of the essential elements of contemporary connectome descriptions (Catani et al., 2013b). Implicit in the ventricular theory is a functional specialization—one based on anatomically different reservoirs that constitute a chain of command within a combined network. Brain functions emerged from the dynamic and regulated exchange between these reservoirs, which differ in size and hierarchy as defined by the number of passages between them. This ventricular model had a long-lasting influence despite evidence of its fallacy, which emerged during the Renaissance. At the start of sixteenth century, Leonardo da Vinci had turned his insatiable curiosity to an examination of the brain. As part of his exploration, he chose to use a new sculpting technique to reveal the shape of the ventricles. By making two holes in the reservoirs, a syringe could be inserted and melted wax injected. When the wax hardened, the rest of the brain was cut away to reveal a cast of the ventricles. What da Vinci saw clearly departed from the classical representation of the ventricular system (Pevsner, 2002). It was a moment that should have signified an enormous scientific advancement. Instead, somewhat mystifyingly, da Vinci’s notes and observations remained largely uncritical of Galen’s overarching ventricular theory.

189 190 BRAIN RENAISSANCE

Fig 32.1 The ventricular system represented in a drawing dating from about 1310. The five cells are named according to their specialization of function: the most anterior cells are the sensus communis (common sense) and the ymaginatio (visual sense) connected to the eyes through the optic nerves. Behind are the cell estimativa and the cell cogitativa, the latter connected to a fifth cell, the vis memorativa, located below the vermis of the cerebellum (Clarke and Dewhurst, 1972). Cognitive processes result from the passage of “spirit” from one cell to the other. Also note the hierarchical arrangement of the cells, with the visual sense acting as a major hub connected to three other cells and the eye, while the other cells are connected only to either one or two cells (Catani et al., 2013b).

Da Vinci was not alone, however. Vesalius also produced descriptions that question the classical ventricular doctrine (see Figures A4–A6 in the Appendix) (Vesalius, 1543). While dissecting, he noticed that ‘humans do not surpass other animals for what concerns the anatomy of the cerebral cavities: everything is the same except for the size, which is bigger in man.’ If these ventricles allowed the spirit to drift around the brain, why did animals lack many of the cognitive abilities of humans? Vesalius found it hard to reconcile his anatomical observations with Galen’s ventricular theory, but preferred to ‘abstained from another inquiry into the function of the ventricles’ (see Chapters 13 and 18). Thus, throughout the 16th century the ventricular theory and its diagrammatic representations continued to dominate almost unchallenged.

33 Seeing Things in Gray and White

From the seventeenth century onward, the ventricular theory coexisted with a new principle in science. Gone was reliance on the word of the classical scholars; in its place came the experimental method (Galilei, 1638) and a renewed belief in an intimate relationship between anatomy and function (Catani, 2007; Catani and Thiebaut de Schotten, 2012). Post-mortem dissection became the primary method of investigating the nervous system, and with it came important anatomical discoveries. Potentially none were more defining than one by Arcangelo Piccolomini in 1586, some 20 years after Vesalius’s death. This former teacher of medicine from Rome observed a clear distinction between the “cerebrum” (gray matter or cortex) and the “medulla” (white matter):

“I call the cerebrum that whole ashen-colored body, darkening from white, which very closely encompasses the medulla. The medulla is the whole of the white and more solid body, which is concealed within the ashen-colored one. Thus the cerebrum differs and is distinguished from the medulla in color, because the cerebrum is ashen-colored but the medulla white; in consistency, because the cerebrum is softer and the medulla a little harder and more compact; in location, because the medulla is in the middle of the cerebrum, which wholly covers it over; also the ashen-colored body is distinguished from the white by certain lines.”

Although Vesalius himself was able to observe such difference (see Figure A7 in the Appendix), Piccolomini provides the first description of a clear separation between gray and white matter. Of course we now recognize that the white matter Piccolomini described contains millions of neuronal fibers, many of which follow a common pathway. Some connect gray matter to gray matter and some connect gray matter to deeper subcortical structures, also made of gray matter. After Piccolomini many started to notice that fiber trajectories could be followed and described if specimens were carefully prepared. Nicolas Steno, a Danish Catholic bishop with a passing interest in anatomy, went so far as to say that the origin of the marvels of the human mind is to be found in the complex arrangement of the brain fibers (Steno, 1669):

191 192 BRAIN RENAISSANCE

“Fibers must be disposed in the most artful manner, since all the diversity of our sensations and movements depends upon them. We admire the contrivance of the fibers in each muscle, and ought still more to admire their disposition in the brain, where confined in a very small space, each executes its particular offices without confusion or disorder.”

From these anatomical studies a new view of the white matter began to emerge; now it was no longer seen as a homogenous support structure around the ventricles but rather as a complex medium composed of tubular filaments that allowed the passage of fluid from the central cells to the peripheral nerves. These connecting filaments originated in the gray matter (Malpighi, 1666) and specialized in both motor and sensory functions (Willis, 1664). Filaments coordinated a wide range of behaviors, from simple reflex responses to higher cognitive functions (Descartes, 1664a). By now the concept of connectivity was implicit in the idea of fibers and nerves. But yet the vast majority of the mapmakers of this period incorporated little if any anatomical accuracy. One figure in René Descartes’s De Homine illustrates the complexity of white matter connections, but it is more pictorial in its representation of a philosophical concept than a faithful portrait of the real anatomy (Figure 33.1) (Descartes, 1664b). Some did try to be more accurate, however. Raymond Vieussens, a French pioneer of neuroanatomy, performed his post-mortem dissections with the explicit aim of producing true anatomical depictions (Figure 33.1) (Vieussens, 1684). Yet even though the connections were visible, the ventricular theory continued to hold power. The hydraulic metaphor was difficult to shake. The physiology of the brain and white matter was still simplified into an inner set of channels. But a new

Fig 33.1 The beginning of the modern study of white matter connections based on methods for fiber dissection. Left: Descartes’s (1664b) representation of the intricate system of white matter passages in the human brain had little anatomical correspondence. Right: Vieussens (1684) used post-mortem dissections to identify white matter tracts and was the first to separate the centrum ovale, composed of projection fibers (indicated by D), from the commissural fibers of the corpus callosum (here cut in the middle). 193 Seeing Things in Gray and White belief emerged: if our deepest thoughts are generated from the flow of fluid through hollow fibers, an exact description of these pathways could reveal the mechanisms of brain function. Nothing could stop the sheer volume of anatomical findings that continued to appear. There were soon so many that it became impossible to ignore the pressure they placed on the ventricular theory. Some attempted to evolve it and fit the theory around either anatomical findings or developments under way in society. Descartes reformulated the theory and expressed it in terms of new technological advancements, comparing the flow of spirits to the movement of a clock powered by a hydraulic system. Descartes saw a unitary, central structure called the pineal gland as the “seat of the soul,” not the ventricles. A core component of his theory was the ability of the gland to shift its position mechanically. As the pineal gland was tilted backward and forward, it would open and close valves, allowing sensation to be transformed into cognition (see Chapter 20). In contrast, the British physician Thomas Willis suggested shifting from a central ventricular specialization of function to a compartmentalized one in the gyri, the ridges of the brain (Willis, 1664). For Willis these ridges form little pockets, like reservoirs acting as stores for the animal spirit. Within them, the animal spirit would be held until required by the brain to instigate memory, imagination, or emotion. Important to Willis was an observation about the relative sizes of the folds in humans versus those seen in animals. The fact that these folds are far more numerous and larger in humans than in any other animal supported the validity of his theory and explained our superior mental faculties (see Chapter 16). Although still deeply routed in a hydraulic model, Willis’s idea of brain function represented the first attempt to localize single cognitive abilities in discrete regions of the brain, a line of thinking that would culminate in the nineteenth century phrenological model of Gall and Spurzheim.

34 Phrenology and Animal Electricity

At the turn of the nineteenth century brain maps of white matter connections were starting to become more refined. Tracts were differentiated into those running in the three dominant dimensions of the brain: from hemisphere to hemisphere (commissural pathways), anterior to posterior in the same hemisphere (association pathways), and vertically to and from the spinal cord (projection pathways). Individual association pathways, in particular, were being delineated, their anatomy often described in detail (Reil, 1809, 1812; Burdach, 1822). The German physician Johann Christian Reil noticed that one group of fibers seemed to arch through the temporal, parietal, and frontal lobes. This bundle, located deep within the white matter, navigated around the Sylvian fissure, the most prominent sulcus, or deep crevasse, in both hemispheres of the human brain. Reil thought little of it, not even bothering to give it a name; he preferred instead to describe the fibres as Ungenannte Marksubstanz (unnamed white matter). It would be another 20 years before anyone again gave more than a passing mention to this tract. When they did, it was as part of an attempt to produce a new atlas of neuroanatomy. Like Reil, Karl Friedrich Burdach was also a German neuroanatomist. He gave great importance to both the anatomical and historical aspects of the human brain, a belief he strongly expressed in his own neuroanatomical masterpiece: a three-volume treatise entitled Vom Baue und Leben des Gehirns (Of the structure and life of the brain). Within this book he confirmed Reil’s findings and described in detail the system of white matter tracts around the Sylvian fissure, which he named the Fasciculus arcuatus (Arcuate fasciculus). Around the same time, the idea of corticalization was tentatively coming to the fore. Scientists had begun to realize that the gray matter described by Piccolomini over two hundred years before might play a role in the brain’s function. As anatomical advancements converged with this progressive “corticalization of brain faculties,” it did not take long for anatomists to create a theory combining the two. Those anatomists were Franz Joseph Gall and Johann Gaspar Spurzheim. Gall and Spurzheim believed that the brain was the organ of the mind, which in turn was made up by a series multiple “organs,” each with specific functions (Figure 34.1). These organs, they proposed, could be identified through the convolutions of the brain. Gall and Spurzheim named this their “organology theory” (Gall and Spurzheim, 1810):

194 195 Phrenology and Animal Electricity

Fig 34.1 Organology and phrenology according to Gall and Spurzheim (1810). Left: lateral view of a human brain where different groups of gyri are indicated with progressive numbering according to their functional specialisation (organology). Right: protuberances on the skull that, according to the phrenological theory, result from the progressive expansion of the underlying gyri. Note the correspondence of the numbers between the two figures.

“The convolutions, as far as they constitute an organ, receive their fibers from different regions. . . . These fibers or fiber bundles have a constant and uniform direction, different, however, in each region; they form their own expansions and their own convolutions; they develop at different stages of life; their number varies greatly in different kinds of animal . . . each organ is independent and acts by itself by virtue of its own powers, and it contains directly within itself the proxi- mate cause of the phenomena it offers.”

But their view, although very modern in some respects, fell into disrepute for two main reasons. Gall and Spurzheim were also the first proponents of phrenology, the study of the structure of human skull to determine a person’s character and mental capacity (see commentary to Chapter 16). Well-developed faculties, they said, are localized in equally well-developed cortical organs. Therefore, the larger the organs, the larger the impressions they would leave on the skull. With this new phrenological theory they hoped to “ascertain the several intellectual and moral disposi- tions of man and animal, by the configuration of their heads” (Gall and Spurzheim, 1810). But while the theory was popular with many, it also meant that, once their theory was discovered to be flawed, these scholars lost practically all of their scientific credibility. Added to this was Gall and Spurzheim’s inability to embrace new ideas. In particular, they ignored important findings on the physiology of the nervous system. They made no attempt to incorporate a new paradigm that was emerging in the first half of the nineteenth century: animal electricity (Galvani, 1791). Luigi Galvani was an Italian physician who enjoyed a fairly strange pastime: he liked to skin frogs and conduct experiments on them. Galvani discovered that the muscles of a dead frog’s leg could be made to twitch if struck by a small charge of electricity. This finding sparked debates in Italy and across Europe, and propelled science toward a new series 196 BRAIN RENAISSANCE of experiments that would lead to the origin of modern electrophysiology (McComas, 2011; Piccolino and Bresadola, 2013). The thought of electricity coursing through our bodies meant that anatomy was no longer fascinating only to physicians and artists, but also to illustrious figures from the world of physics. There was a rapid growth in both theories and measurement techniques (Piccolino and Bresadola, 2013). After a current applied to the cortex was found to elicit movement in the muscles (Aldini, 1803), gray matter became to be considered as an “electrical generator” wrapped around the brain (Baillarger, 1840). This new discipline, electrophysiology, required novel recording methods to study the characteristics of the action potential in the muscles (Matteucci, 1830; Bois-Reymond, 1848) and peripheral nerves (Bernstein, 1868). Insights gained from experiments conducted on muscles and peripheral nerves were soon applied to functions of the spinal cord and the brain. By the mid-nineteenth century, the concept of a spinal reflex was well established and a similar mechanism envisaged for the brain (Griesinger, 1843). This line of research found definitive experimental evidence in the work of Ivan Pavlov (1903) for which he was awarded the Nobel prize in 1904. Thank to his work, the conditioned reflex became a basic component of physiological psychology. Then, suddenly, neuroscience underwent an entire shift in scale.

35 Microscopic Discoveries

The middle of the nineteenth century saw an explosion in advanced methods of microscopy, which led to one of the most important dinner party conversations in the history of science. In 1837, legend has it that Theodor Schwann, a German physiologist, was drinking coffee with his friend Matthias Jakob Schleiden, a botanist. The conversation shifted to their work and they began to describe the cells they could see through their microscopes. One man mentioned that his cells appeared to form from the nuclei of old ones, and the other simply sat in stunned silence. Although Schleiden was working on plants and Schwann on animals, both were seeing exactly the same thing. The conclusion was undeniable. Within two years, Schwann had proposed his “cell theory”—the idea that the basic functional unit of all living organisms was the cell (Schwann, 1839). Initially, however, there was an exception to the theory: the nervous system. A widely held belief said that the brain was not composed of individual cells, like the rest of the body. Instead, cells fused to create a continuous meshwok of interconnected fibers. One of the most famous champions of this “reticular theory” was Camillo Golgi, an Italian scientist from the University of Pavia (Mazzarello, 2010). Among Golgi’s many achievements was the development of a new histological method capable of staining an entire nerve cell by impregnating the tissue with potassium dichromate and silver nitrate; it was called the reazione nera (black reaction) (Golgi, 1873). The most important feature of this staining method was that it hardly ever worked. Only a few cells were stained through black deposits left in the cell body, axon, and dendrite, which made them stand out clearly from their neigh- bors (Figure 35.1). To many scientists this was a revelation, because it allowed them to view the paths of the axons of single cells in the brain for the very first time. Yet paradoxically, to Golgi it was proof that the nervous system was one continuous network. Despite the dominance of the reticular theory, Schwann’s theory catalyzed the description of new cells in the brain. Albert von Kölliker divided histological features of the cortex into myelo- (the pattern of cortical fiber distribution) and cytoarchitectonics (the pattern of cellular distribution in the cortex) (Kölliker, 1850). A decade later, Theodor Meynert realized that there were consistent variations in how the cortex was layered from one region to the next—both in terms of cell type and the number of layers (Meynert, 1868).

197 198 BRAIN RENAISSANCE

Fig 35.1 Microscopy applied to the study of microcircuits of the hippocampus. Left: Hippocampal histology according to Camillo Golgi, inventor of the reazione nera (black reaction) method in 1873. Right: Hippocampal histology according to Santiago Ramón y Cajal (1911). Cajal also used the black reaction, but he was in support of the neuron theory and introduced new concepts derived from his anatomical observations, including the directionality of impulse propagation (here indicated by arrows).

Methods for staining white matter fibers advanced at an even faster pace. The introduction of techniques by Carl Weigert and Vittorio Marchi to stain only myelin around the axons and the development of the precision microtome—a tool that can cut the brain into extremely thin slices for the study of serial sections—permitted scientists to go from seeing only the whole tract to viewing the tiny individual fibers (Bentivoglio and Mazzarello, 2010). Others devised techniques that concentrated not on what was there but what had disappeared. In 1870, German psychiatrist Bernhard von Gudden perfected an experimental method in animals that allowed him to produce secondary degeneration and atrophy of the nerve nuclei and their connections. On removing peripheral sense organs such as the eyes, ears, and various cranial nerves, he found that the axons would die away, leaving him free to follow their tra- jectory via the space they left behind (Gudden, 1870). It is a technique some still refer to as the Gudden method. Both the myelin staining and Gudden methods allowed a new generation of German scientists to trace more and more connections within the brain. Costantin von Monakow, an assistant of Gudden, continued the work of his mentor but concentrated on the thalamic and motor projection fibers (Monakow, 1897). By removing 199 Microscopic Discoveries areas of the cortex, he was able to trace the degenerating fibers from the gray matter to the thalamic nuclei and other subcortical nuclei. Paul Emile Flechsig, meanwhile, was more interested in the developing brain connections of newborns. His myelogenetic method consisted of staining myelin and then mapping different stages of brain development in prematures and babies born at term. Considering that the projection tracts, which connect the brain to the rest of the body via the spinal cord, are among the first to myelinate, he was able to trace the origin and course of the corticospinal tract (Flechsig, 1876) (Figure 35.2). The nineteenth century saw a rapid enhancement in our knowledge of cells, the brain, and its white matter, the vast majority of these advances being due to the work of German and Italian scientists. The trouble was that this left those who spoke neither German nor Italian isolated from the rest of the community of anatomists. Some scientists were finding their research going unnoticed, while others were not exposed to recent findings and theories. This meant that those scientists began working in the field of neuroscience with few preconceptions. Nowhere was this truer than in the country that had been home to Vesalius for the latter half of his life—Spain. In 1887 Santiago Ramón y Cajal, a young Spanish physician, moved to Barcelona to start a new job at the university as professor of histology and pathological anatomy. Within days he was introduced to Golgi’s silver method for staining nervous tissue. He began using it and then adapting it. His modifications allowed cells to be stained more deeply and enabled further detail to be brought out. Cajal became acutely aware that there were gaps, later called synapses, between the cells. From his research, he concluded that there were several fundamental laws governing the organization of neural tissue (Cajal, 1893, 1911). The shapes of axons and dendrites, he proposed, are

Fig 35.2 Cortical myelogenetic maps and white matter projections according to Flechsig (1896). Left: Flechsig identified different areas according to their degree of myelination at birth. Primordial areas are already myelinated at birth and have some correspondence with primary sensory and motor areas (densely dotted areas). Association areas myelinate after birth and correspond to large regions of the frontal, parietal, temporal, and occipital lobes. Sparsely red- dotted areas show intermediate degrees of myelination at birth. Right: Flechsig was able to reconstruct the trajectories of the main projections fibers from his myelogenetic maps. 200 BRAIN RENAISSANCE constrained by biophysical parameters such as the volume of cytoplasm, the space in which they are confined, and the time they take to conduct a signal. He also introduced the law of dynamic polarization, which identifies dendrites and their cell bodies as the main receiving structures of an action potential and axonal terminations as the main areas of transmission. For Cajal these laws meant two things. As hard as he looked, he found no evidence for the reticular theory. The very fact that he had identified “axonal terminations” meant that the nervous system was not a mesh of unremitting fibers but a series of discrete units of neurons. And because of dynamic polarization, it was possible to infer the direction of an impulse from one neuron to the next (Figure 35.1) (Cajal, 1911). This neuron doctrine, as it would come to be known, and the staining method used to provide evidence in support of it would eventually win Cajal and Golgi the Nobel Prize (DeFelipe, 2010). Inspired by these microscopic discoveries, the French neurologist Joseph Déjérine and the Russian neurologist Wladimir Bechterew both proposed that a true understanding of the nervous system was possible only through a precise depiction of neurons, their connections and associated clinical symptoms (Bechterew, 1900a; Déjérine and Déjérine-Klumpke, 1895, 1901). Clinicians had indeed an advantage over their histologist colleagues: the possibility to apply their neuroanatomical insights to their patients. The clinical-anatomical correlation method, where brain function is inferred by studying the relationship between clinical manifestations and the location of cortical or subcortical lesions, replaced phrenology as the popular method for finding correlations between function and anatomy (Bouillaud, 1825; Broca, 1861a). Disorders of the nervous system were clarified by a whole new set of maps, which explained a disorder in

Fig 35.3 Centers and connections in the late nineteenth century defined by the use of clinicoanatomical correlation and post-mortem dissections. Left: Cerebral centers in the human brain dedicated to higher cognitive functions, as displayed in one of the most prominent neuroanatomy textbooks of the time (Testut, 1897): (I) writing center of Exner; (II) Broca’s center for speech; (III) motor center, lower limb; (IV) motor center, upper limb; (V) motor center, face and tongue; (VI–VII) center for reading; (VIII) Wernicke’s acoustic center for verbal comprehension. The surrounding areas are zones of the association centers according to Flechsig (1896). Right: Déjérine’s representation of the white matter tracts of the human brain responsible for language and reading (Déjérine and Déjérine-Klumpke, 1895). 201 Microscopic Discoveries terms of either damage to the cortex or its connections (see Figure 35.3) (Déjérine and Déjérine-Klumpke, 1895, 1901; Monakow, 1897). Behind these maps was a common idea: that the brain should be understood as a a system of integrated and interconnected areas, not a set of localized regions. It was an approach fraught with complexity, requiring a good degree of approximation. And it often resulted in a trivialized transposition of complex anatomical details into highly simplified diagrams that had little anatomical support (Head, 1926). Thus, the nineteenth century terminated with anatomists and clinicians facing a critical dilemma. Microscopists on one side who could try at their best to work out the functions of neurons and their connections but were limited in their ability to understand cognition and its disorders. Clinicians on the other hand were able to study the mind and its disorders with limited understanding their underlying anatomical correlates. The solution of this impasse required a new approach to anatomy, an opportunity that arised with the advent of the first World War (Catani and ffytche, 2005).

36 Early Cartography

Whole-brain maps had become a sudden possibility owing to the development of new staining methods coupled with the efforts of those prepared to make painstaking observations of thousands of brain slices. It was time-consuming work, and not all cartographers agreed that it was actually possible to understand brain function from such maps. Among the pioneers of this approach was Alfred Campbell, an Australian neurologist of Scottish descent. Unlike others, he gave great emphasis to the relationship between brain function and anatomy (Campbell, 1905). For him it was possible to go beyond cytoarchitectonic cartography and combine it with myeloarchitectonic observations, which in turn could be integrated with clinical and physiological evidence to provide a role for each cortical region (ffytche and Catani, 2005). He even went so far as to label some of the 17 regions he described not by a number but by function. There is a “visuo- sensory” and a “visuo-psychic” field, as well as others labeled “audito-sensory”, “audito-psychic”, and “olfactory” (Figure 36.1). His work began in a lonely laboratory attached to an asylum near Liverpool, where he was the resident medical officer. It culminated in a manuscript sent to the Royal Society for publication in 1903. Campbell’s work was so extensive, however, that the Royal Society refused to publish it in a journal. By the time it was finally released in 1905 as a monograph, Campbell had moved back to Australia and few scientists were made aware of his contribution (ffytche and Catani, 2005). For others, these were primarily anatomical maps that offered no or limited information about the function of a brain region. Among the supporters of this view was Korbinian Brodmann, a German neurologist working at the University of Berlin. Brodmann spent hours making razor-thin slices of different regions of human and primate brains. The work cumulated in a map made of 52 distinct areas in the primate cortex and 44 that could be found in humans, each of which was labeled with its own number (Figure 36.1). Brodmann’s work was published in 1909 as Vergleichende Lokalisationslehre der Großhirnrinde in ihren Prinzipien dargestellt auf Grund des Zellenbaues (Comparative localization studies in the brain cortex, its fundamentals represented on the basis of its cellular architecture). It was a monumental, groundbreaking work but, to Brodmann, little more than a show of cellular anatomy. In his publication he demonstrates clear disdain toward the idea that function could be localized to his cortical areas (Brodmann, 1909):

202 203 Early Cartography

Fig 36.1 Early cytoarchitectonic maps of the human brain. Left: Campbell’s division of the cortex into 17 fields according to interregional anatomical differences, and functional specialization (1905). Right: Brodmann’s map according to purely cytoarchitectonic criteria (1909).

“In reality there is only one psychic center: the brain as a whole with all its organs activated for every complex psychic event, either all together or most at the same time, and so widespread over the different parts of the cortical surface that one can never justify any separate specially differentiated “psychic” centers within this whole.”

What makes these comments so remarkable and even ironic is that Brodmann’s maps have become the lingua franca of cortical localization in modern neuroimaging— their numbers are used universally as shorthand for a precise cortical locus in the brain and, in some cases, a precise functional role (see Figure 36.1). This era of cortical mapping ended with two final attempts to refine the cortical boundaries and create an even greater division than that achieved by Brodmann. Oskar and Cecile Vogt were a husband-and-wife team who ran the laboratory in Berlin from which Brodmann had produced his maps. By studying the variation

Fig 36.2 Cortical divisions of the human brain and corresponding clinical syndromes according to Economo and Koskinas (1925). Left: Distribution of the five principal types of neocortex in the lateral surface of the human brain: (1) agranular, (2) frontal, (3) parietal, (4) granular, (5) polar. Right: Corresponding clinical syndromes (in German). Note the attempt to localize not only neurological syndromes but also psychiatric conditions (e.g., “depressive” versus “expansive” mental disorders in the frontal lobe). 204 BRAIN RENAISSANCE of cortical myeloarchitecture, these neurologists identified more than 200 areas, many of which represented subdivisions of Brodmann’s original 52 (Vogt and Vogt, 1926). They strongly believed that the specific structural organization of each cortical area revealed a unique contribution to specific cognitive functions (Nieuwenhuys, 2013). Although the Vogts never published a complete cortical map, another team of neurologists did find the time to do so. However, this did not find favor within the scientific community. In 1912, Romanian-born Italian physician Constantin von Economo, working in western Europe, became frustrated with the cytoarchitectonic maps of others and decided to create his own. He set about to overcome many of the obstacles that he believed stood in the way of producing a complete map. Seven years later Georg Koskinas, a Greek colleague, joined Economo in his quest. The pair finally published in 1925 “The cytoarchitectonics of the cortex of adult man”. There were 107 cortical areas, each with quantitative measurements of cortical thickness, volume, size, cell number, density, and grouping of stripes and layers (Figure 36.2). Instead of numbers, like Brodmann, they used a lettering system. In addition they provided a complementary map of neurological and psychiatric syndromes associated with lesions of each of the 107 areas. It was a colossal effort. Yet although many considered this to be the definitive text on cortical cartography, its use never really took off. Its small print run, encyclopedic proportions, complexity, and general lack of clear boundaries between some of the smallest cortical areas led researchers to prefer the relative simplicity of Brodmann’s divisions (Le Gros Clark, 1952).

37 FROM ELECTROPHYSIOLOGY TO NEUROIMAGING

Cortical and white matter mapping brought with it a series of landmark discoveries. The brain’s gray matter was split into primary cortex, those areas that dealt directly with our senses and movement, and associative cortex, composed of areas that gave meaning to these sensations (see Figure 3.5) (Flechsig, 1896). Long white matter projection tracts that for so long had been difficult to distinguish were delineated (Flechsig, 1896). Moreover, the years of hard work on the part of cartographers like Campbell, Economo, and Koskinas meant improved localization of functions and associated symptoms (Campbell, 1905; Economo and Koskinas, 1925). However, while the cartographers were able to say roughly what each region of the cortex was involved in, they struggled to provide a more precise functional meaning. Instead, accuracy was provided by group of scientists who had moved away from their microscopes and adopted a different approach to describing neuronal interaction. The mid- twentieth century had seen the emergence of a new set of techniques. It meant that while cartographers were busy using the brains of the dead, others were concentrat- ing their efforts on the brains of the living. By now scientists were well aware that the fundamental means of communication between neurons was an electrical impulse. In 1932, physiologist Edgar Adrian had been awarded the Nobel Prize for his work on neuronal function. An important aspect of this was providing a definitive way to register and amplify a neuron’s electrical impulse. He found that by inserting a very fine wire (an electrode) into the optic nerve of a toad, a neuron’s electrical response to a stimulus could be recorded (Adrian, 1932). As Adrian himself would admit, it was an almost accidental discovery:

“I had arranged electrodes on the optic nerve of a toad in connection with some experiments on the retina. The room was nearly dark and I was puzzled to hear repeated noises in the loudspeaker attached to the amplifier, noises indicating that a great deal of impulse activity was going on. It was not until I compared the noises with my own movements around the room that I realized I was in the field of vision of the toad’s eye and that it was signaling what I was doing.”

205 206 BRAIN RENAISSANCE

The use of an electrode to measure these action potentials—an approach termed single- or multi-unit recording—paved the way for a new method to map the brain. It was an approach exemplified by the work of physiologists such as Vernon Mountcastle and Thomas Powell (1959) as well as Nobel Laureates David Hubel and Torsten Wiesel (1962), who used multi-unit recording to analyze sensory processing. Mountacastle and Powell concentrated on the somatosensory cortex of monkeys. They started inserting electrodes into the monkeys’ brains to measure an individual neuron’s response to a stimulus. What they found amazed them. Single nerve cells responded to specific types of touch—some to superficial touch, some to deep pressure, but almost never both. When the investigators combined this with axonal tracing and cytoarchitectural description of sections later cut from the same brain, key principles of cellular organization and neuronal physiology were revealed. Mountacastle and Powell saw that cells responding to the same stimulus were seg- regated into vertical columns comprising thousands of neurons. They termed this “columnar organization”, the basic unit of cortical organization. A few years later Hubel and Wiesel (1962) applied a similar method to the visual cortex of cats. When streaks of light and dark were projected onto a screen in front of an anesthetized animal, a region of neurons fired when the lines were at one angle, while others responded only after the line rotated. These “oriented receptor fields” offered a tantalizing insight into how the visual system constructs complex representations from a simple stimulus. Experiments on animals were becoming popular (Figure 37.1). Monkeys were subjected to procedures that disconnected certain parts of their brains so that researchers could observe their behavioral response and extend their speculations to connections (Mishkin, 1966). The end of the 1960s also saw the development of powerful methods for axonal tracing. These took advantage of expanding knowledge concerning how proteins are actively transported along the axonal fibers. When the tracer is injected into a pre- determined cortical or subcortical region while the animal is still alive, it can enter the neuron and be transported along the axon, either in the anterograde direction, from the cell body to its terminations, or in the opposite, retrograde, direction (Morecraft et al., 2009). Once the animal has been euthanized, the route of the tracer can be observed by dissection. This meant that for the first time it had been possible to identify not only the existence of an axon but also the exact location of its source and termination (Nauta and Gygax, 1951; Fink and Heimer, 1967; Mesulam, 1982; Petrides and Pandya, 1984). The hubs of the networks were being revealed and the solid foundations for computational approaches to brain function being laid down. The reliance on animals, however, was a problem. The general assumption that findings from mammals could be directly translated to humans held true in some areas of neuroscience, but their legitimacy was questioned when it came to higher cognition, such as language, unique to humans. By the early eighties, despite all the advances seen in neuroscience, the best way to explore the major connections in the human brain was, in essence, still the same as when Déjérine and Flechsig were alive. There was a heavy reliance on post-mortems, and these were limited in both their accuracy and benefit, especially in trying to 207 From Electrophysiology to Neuroimaging

Fig 37.1 Connectivity maps based on animal studies. One of the advantages of animal models is the ability to use data obtained by different methods and directly test network-based models of brain functions using experimental approaches (e.g., disconnection lesions). Lower left: Ungerleider and Mishkin used animal electrophysiology, axonal tracing, and lesion studies to formulate a dual-streams model of visual processing (Mishkin et al., 1983). Right: Felleman and Van Essen’s (1991) projectome of the visual system showing the hierarchical connectivity of the visual areas. One of the limitations of these approaches is the inability to quantify the strength of connectivity between different areas. This means that the arrows and lines in the diagrams could be representative of single axons or large bundles. Also, these maps have been transposed to humans without a direct anatomical verification. Bailey and Bonin (1951), for example (upper left), applied their findings from the monkey directly to the human brain. relate anatomy to function. Change was in the air, however. Researchers were starting to believe that technological advances might lead to improvements to their anatomical techniques techniques. But beyond this, there was growing belief that further exploration of the brain should be possible without having cut or inject at all. The last three decades have shown both of these beliefs to have been right. Post- mortem techniques have advanced considerably. We no longer just map the connections but the nodes as well. In Germany, Karl Zilles and collaborators have developed a number of methods for mapping cytoarchitectonic, receptor type, and density in post-mortem human brains (Zilles and Amunts, 2009). Distribution patterns vary considerably, not just between motor, sensory, and association areas of the cortex but also within these functional groups. The added advantage of these maps is that they provide a standard template of reference and can be used to guide, complement, and integrate one the greatest advances in neuroscience of the last five hundred years: neuroimaging (Caspers et al., 2013). In addition to post-mortem advancements, contemporary neuroimaging methods have inaugurated a new era in the study of functional and anatomical connectivity. For 208 BRAIN RENAISSANCE the first time we can map the living human brain. And although the methods are still in development and their use is limited in clinical settings, the results are proving to be fascinating. Magnetic resonance imaging (MRI), which measures changes in the magnetic resonance of a proton, provides structural information of the brain while a person lies down, sometimes falling asleep, inside the scanner. MRI makes it possible not only to see a black-and-white snapshot of a living brain almost instantly but also offers new ways to take measurements. A prime example is the ability to assess the variation in cortical thickness in both healthy individuals and those with neurological and psychiatric disorders. Before structural MRI, our knowledge of language networks, for example, relied primarily on the post-mortem examination of patients who had suffered a stroke. Suddenly, we no longer had to wait for a person to pass away before we could explore the effects of a disease (Damasio, 1995). In people with primary progressive aphasia—a progressive loss of language due to the neurodegeneration of specific brain regions—we can map the loss of cortex through time (Rogalski et al., 2014). This process has significantly expanded our knowledge of language networks and what happens when regions are disconnected (Catani et al., 2013c). Other forms of neuroimaging, which draw together data from large populations, have revealed the existence of brain functions that would have otherwise remained invisible. Positron emission topography (PET) is a technique that detects gamma rays emitted from a tracer injected into the body, making it possible to construct a three- dimensional image of the metabolic and functional processes of the brain. Together with functional MRI (fMRI), which detects brain activity by measuring associated changes in blood flow, the existence of remarkable new brain networks has been revealed. The default mode network (DMN), for example, was discovered almost by accident. When researchers first started using PET and fMRI to measure brain activity, they found that something interesting was happening. Normally the person in the scanner would be given something to do, such as looking at pictures, listening to music, or saying words. The way in which these activities influenced brain function could then be measured. But in between, when the scanner was still running and the person was simply lying in a dark chamber with limited direct stimulation—what is known as the “resting state”—a specific network of medial and lateral brain regions became active. In most people this DMN is engaged during periods of introspective, self-directed streams of thought. In others words, the DMN becomes active when we daydream (Raichle et al., 2001; Raichle and Snyder, 2007). As soon as we have to execute a goal-directed task, a synchronous deactivation of the DMN is observed. So, for example, when we focus on sensory activities—such as attempting to understand other people’s intentions (mentalizing or theory of mind), engaging in prospective thinking (envisioning the future), or accessing memories of personal events (autobio- graphical memory)—we have to suppress our resting state to focus our attention to externally driven activities (Catani and Thiebaut de Schotten, 2012). When researchers switched their attention to the DMN in patients with neuropsychiatric disorders, such as autism and schizophrenia, they found that it was altered, as if these patients were unable to fully suppress their resting state (Broyd et al., 2009; Sandrone, 2013). 209 From Electrophysiology to Neuroimaging

Similarly, diffusion tensor imaging (DTI) and spherical deconvolution (SD) are leading the way in improving our understanding of anatomical connections in the human brain. Using an MRI scanner, it is possible to map the natural displacement of water molecules by diffusion in the white matter (Basser et al., 1994; LeBihan, 2003). This molecular diffusion is not free; instead, many obstacles found in the brain impede it. There are cell membranes, glial cells, axonal fibers, and a myelin sheath all blocking the water’s path. The result is that the direction of water molecule diffusion is greater along axons than across them (Pierpaoli et al., 1996). Both DTI and SD take advantage of this to indirectly map major neuronal tracts and reveal the existence of novel ones underlying, for example, frontal lobe functions (Catani et al., 2012a) , visuo-spatial attention (Thiebaut de Schotten et al., 2011) and language (Catani et al., 2005, 2013c). The fundamental strength of this technique is that it allows researchers to describe differences in brain connectivity between individuals while providing quantifiable but indirect measurements of the functional and “anatomical strength of the connections” between regions (Catani, 2007; Thiebaut de Schotten et al., 2011; López-Barroso et al., 2013). Where once the white matter was an indiscernible mass of tissue, modern imaging has revealed it to be a discernible mass of information about how our brains are connected. These examples are indicative of the far-reaching potential of neuroimaging; they show how we are rapidly answering questions that could not be addressed before. But it is important to realize that neuroimaging is only one of the methods mapping the connectome. There is an important distinction between those approaches that adopt neuroimaging to map whole-brain networks and those that characterize the detailed features of microconnections using advanced techniques in microscopy. For both approaches the suffix -ome refers to different concepts. The first is related to the totality of the brain—the “connectome” as a map of the entire brain’s connectivity (Sporns, 2011). It is macroscopic, providing a global, whole-brain overview of the main brain networks from large-scale connections or bundles. The second is related to the totality of all the brain’s constituents—the “connectome” as the most detailed description of the elements that form neuronal connections. It is microscopic, aspir- ing to provide a comprehensive account of the local circuits comprising single axons and dendrites (Seung, 2012). While the first approach can be achieved only through data reduction and oversimplification, the second is so grandiose that it may never be realized for the entire brain. In essence, to the first approach the connectome is a metaphor (the maps produced by neuroimaging are not the real thing); to the second it could well be a scientific myth (Catani et al., 2013b).

38 Metaphors and Myths

So what of the future? Five hundred years of history have led to the belief that the brain consists of billions of cells that connect to form intricate local circuits, which then combine to create complex networks. Neuroimaging makes it possible to examine the structure and function of the whole brain but reveals very little about the action of individual cells (Logothetis, 2008). Microscopy and the use of electrodes make it possible to observe and probe tiny collections of cells but do not give away much of the bigger picture. Up to now these two approaches to mapping the brain have, for the most part, acted separately. But the future of the connectome may well lie between the two. The next century could see their convergence at the mesoscale level, that intermediate point where local circuits come together to form large-scale networks (Della’Acqua et al., 2013). Knowledge in neuroscience is advancing at an unprecedented rate. It took Vesalius almost five years to have hisFabrica written and printed. Yet just since the start of the present decade, approaches to brain mapping have evolved hugely. Fast-paced advances in computing, quantitative and statistical neuropsychological testing, and MRI capability are beginning to coalesce. In computing, data processing is becoming quicker and quicker, storage options are rising exponentially, new software developments appear almost yearly, and computational theory is a blossoming field. Whereas MRI was once hindered by poor detail, it now offers higher resolution capabilities and a plethora of sequences for both structural and functional imaging (Lichtman and Denk, 2011; Seung, 2012; Sporns, 2011). There is no sign of a decline in these advances. The use of automated histological analysis to process high volumes of information combined with transmitter receptor distribution and microarray profiling is beginning to delineate a new landscape of human brain cartography. Where scientists were once lucky to know one thing about a region of the brain, each area is now awash with multiple pieces of information, from cytoarchitectonics to receptor and gene expression (Zilles and Amunts, 2009; Amunts et al., 2013; Hawrylycz et al., 2012). This could lead for the first time to multimodal brain maps that define inter- individual variability among the general population. The more that is understood about the neural mechanisms of normal cognition, the more it will be possible to identify vulnerable connectivity patterns in those at risk for mental illness, to foresee their treatment responses, and to predict recovery after injury (Bullmore and Sporns, 2009; Forkel et al., 2014).

210 211 Metaphors and Myths

It is a great hope. Yet the more the two types of connectome converge (the macro- and micro-), the more we should be aware of the limitations. There is a real risk in modern connectomics that we may ignore some of the lessons that our journey through neuroscience’s history has taught us. In 1943, McCulloch and Pitts proposed the first mathematical model for a neural network. But it quickly evolved into statistical and pattern-recognition tools far removed from the action of complex neurophys- iological and biological mechanisms (Rosenblatt, 1958). These first mathematical network models disregarded real brain anatomy and instead followed a path of their own. They ignored the lessons handed down to us by Vesalius, who exploited the power of direct observation, and Galileo, who taught us about quantifiable analysis. Without these we risk being diverted from the real functional anatomy of the brain. Therefore, just a Vesalius pointed out problems with Galen’s doctrine of the human body, we conclude with the limitations that could blight our search for a contemporary connectome at the mesoscale. These are just some of the difficulties we need to overcome in the future if we are to have a complete map of the human brain. Some limitations have been with us since the start of neuroimaging. Mapping methods often come with restrictions that can make the real structural and functional anatomy difficult to distinguish. Resolutions are sometimes as low as only a few millimeters and distortions can be common owing to high background noise. Signals derived from MRI scans reflect average information that derives from a combination of the complex features of the underlying biological tissue, thus making any interpretation of the results unspecific and often speculative (Logothetis, 2008; Catani et al., 2012b). Such are the number of ways to perform data processing that there is no homogeneity, which can lead to anatomical artifacts. The second limitation stems from the language used in contemporary techniques of mapping and analysis. Sometimes it can be ambiguous, leading to confusion or misinterpretation. At times terminology alludes to anatomical properties when in fact it reflects only features of the derived maps or graphs. A prime example is in graph theory. A distance between two nodes in a network described using graph theory is the minimum number of steps required to connect the two nodes, not the physical axonal length between the neurons (Bullmore and Sporns, 2009; Fornito et al., 2013). Similarly, DTI uses a method known as tractography to visualize tracts as color-coded streamlines while also providing quantifiable measurements (Figure 38.1). However, the average length of the streamlines is not equivalent to the average physical length of the connecting axonal fibres. Moreover, many apparently functional properties of the neuroimaging networks, such as connectivity and synchrony, are mathematical and statistical concepts rather than physiological ones. Therefore it could be incorrect to conclude that the brains of certain groups of patients have reduced connectivity because of reduced fMRI coactivation or a shorter length of their tractography streamlines. The third limitation involves the potential for information overload. The more neuroimaging advances, the more data we collect and the more we try to integrate the findings. However, this creates an inevitable tension in contemporary mapmaking. How much information can be crammed in before things stop being clear? Current 212 BRAIN RENAISSANCE

Fig 38.1 Tractographic reconstruction of the human brain connections based on diffusion tensor imaging. One of the advantages of this method is the ability to reconstruct cerebral pathways in the living human brain. connectomes too often reflect a distorted image of the real architecture of the brain, and we tend to see patterns of neuronal organization that may only represent a biased view of the real anatomy. Therefore validation by post-mortem and animal models is paramount (Lee et al., 2012; Mesulam, 2012). The final problem also explains why many have chosen to study neuroscience at all—the unimaginable complexity of the brain. At the microscopic level, advanced imaging methods based on fluorescent protein staining, electron microscopy, and superresolution light microscopy are providing more confidence in the interpretation of their connectome results than in neuroimaging (Lichtman and Sanes, 2008) but not confidence in whether the entire brain can be mapped. The realization of a complete connectome, including 302 neurons and 5,000 synapses, from the nervous system of Caenorhabditis elegans (White et al., 1986) was a remarkable achievement and led to the hope of mapping much larger brains. But this was almost 30 years ago (Figure 38.2). Since then we have found the human brain to contain a network of 86 billion neurons and 100 trillion synapses. This already feels overwhelming. So how are we to cope when this anatomy is ever-changing? Indeed, whenever we engage in an action or thought, we form new synapses and prune our neuronal dendritic trees. In other words, we reshape our connections. Even the reading of this book could have changed them in the brain of the reader. We wake up with one connectome and go to bed with another. Ultimately, only a connectome map of “the brain in action” will capture the anatomical, electrophysiological, and computational elements of those networks that characterize human cognition and behavior. It is this dynamic nature that holds the key to the real working of the brain. 213 Metaphors and Myths

Fig 38.2 The three-dimensional reconstructions of the connectome of theC. elegans (left) (from openworm.org) and the human brain (right).

Just discussing these limitations can make the idea of combining the macroscopic connectome with the microscopic one seem like an overly ambitious goal. There is hope, however. There is one final map that offers a real reason for optimism. In 2013, researchers from Ashburn, Virginia, announced a startling piece of research. Misha Ahrens and collaborators recorded activity across a whole larval fish brain, detecting 80 percent of its 100,000 neurons (Ahrens et al., 2013). Their imaging system com- prised a microscope and detector aimed at a zebrafish. Researchers favor this tropical freshwater fish because it is cheap, it breeds quickly, and its larvae (with the exception of the nervous system) are almost entirely transparent. Therefore the researchers genetically engineered its neurons to produce a protein that fluoresces in response to fluctuations in calcium ion concentration. In other words, there is a noticeable change in color every time the nerve cells fire. The activity of the zebrafish brain can be recorded over milliseconds and regions that fire simultaneously can be seen. It is a system that may reveal the dynamic, ever-changing nature of a brain as the animal lives its life. Certainly the journey from here to the point at which we will be able to use similar methods in the human brain will be a long one. But the concept of a “map of neural connections” has been a constant inspiration to those who believed the brain to be the organ of intellect. Thus the connectome is a term with a short history but long past. And unless another brain metaphor comes along to take its place, it will be part of the exciting future of modern neuroscience.

Appendix Figures from the Seventh Book of the Fabrica 216 Appendix

Figure A1.

The first figure of the seventh book shows the human head after being removed from the neck and the inferior jawbone dislodged, so that the brain could be properly displayed to the dissectors. Furthermore, a circular saw was used to remove as much of the skull as possible so as to gain a better view of the content inside the skull cavity. Indeed, how much of the skull removed can be clearly estimated if you examine the seventh figure of the sixth chapter of Book I, which shows the inner surface of the part of the skull removed here. The present figure precedes the others that follow according to the order dictated by the dissection procedure. We designated this as the first figure of Book VII, since it shows the hard membrane of the brain still undamaged and in no part perforated or torn. We also removed, to the extent possible, the attachments of the same membrane. These extend throughout the sutures of the head to form the membrane that is named periosteon because it encloses the skull. At the same time small vessels passing through the tiny openings of the skull and the sutures were also removed along with these attachments. These vessels are shared by the hard membrane itself and the membrane enclosing the skull. Moreover, the two circles that can be seen in the figure represent the skin and the membranes that are under the rim of the skull. Indeed, everything enclosed in the skull circle concerns the hard membrane of the brain, which is marked by all the letters that can be observed displayed in the figure. These letters are specified in order as follows: 217 Appendix

A, A Right side of the hard cerebral membrane, namely the part of the membrane enclosing the right region of the brain. B, B Left side of the hard cerebral membrane. C, C, C Third sinus of the hard membrane, extending along the entire length of the head; this shows no openings and in its dorsal aspect is by its own nature continuous, protruding like a quadrant. D, D, D Two veins placed next to each other, running along the entire side of the hard cerebral membrane. E Passage of the cerebral hard membrane that lodges the sixth vein entering the skull. F, F, F The small veins are indicated by these letters. From the hard membrane of the brain and through small openings of skull they reach the skin of the head and the membranes surrounding the skull. The most numerous and thicker of these membranes are observed by most people near the letter F, which is almost hidden in the back. G, G, G Small portions of the projections that from the hard membrane protrude through the coronal suture toward the membrane that encloses the skull. H, H Small portions of the projections to which the sagittal suture offers a passage. I, I These letters are also hidden in the shadow of the occipital region, marking the seat from which the projections extend through a suture like the Greek lamba, constituting the wrapping of the skull. K One of the protuberances often attached to the uneven sinus in the skull, in the region near to the junction between the sagittal and the coronal suture. The head used to draw this first figure had three protuberances of this kind; we marked one of these with the letter K, and one that can be seen on both sides of the letter H. L The cavity of the frontal bone near the eyebrows. It is often opened during dissection, particularly when the frontal bone, which is not far from the eyebrows, is cut by the saw. 218 Appendix

Figure A2.

In the present figure, which follows the first in this series of dissections, the third sinus of the hard membrane (indicated in the first figure by the letter C) is fully opened by a longitudinal incision along the head. In addition, following the length of the head, I have performed two lateral incisions along the third sinus, one on each side. The incisions (marked with D, D, D in the figure) penetrate only the hard membrane and separate the sides of the hard membrane from the membrane dividing the right and left parts of the brain. Besides the three incisions mentioned above, I made another one on each side, extending from the ear to the top. This incision divides only the hard membrane, so that later it can be properly separated from the thin membrane of the brain and bent downward (as shown in the figure). Consequently here we find that the thin membrane of the brain is completely intact and wraps the brain. A series of the same vessels is elegantly visible in the uncovered region. A, A, A Upper part of the hard membrane interposed between the right and left side of the brain. The sides of the third sinus that reach the brain are dissected through the middle and indicated with the letters A and A. B, B The opened cavity of the third sinus of the hard membrane. C, C The opening of the vessels that originate from the third sinus of the hard membrane and extend to the thin membrane. Here the openings of the vessels can be seen extending 219 Appendix from the left side of the sinus into the part of the thin membrane that surrounds the left brain. D, D Instead the openings that take origin from the right side are not visible here, whereas the origin of the vessels projecting into the thin membrane surrounding the right brain are indicated by D, D and D. E, E etc. The thin membrane surrounding the brain. F, F, F Ducts or vessels that course through the thin membrane following the pattern of the cerebral convolutions. G, G, G Branches of the ducts running on the side of the hard membrane. Some of them join the thin membrane as indicated by the letter D in the first figure. H, H, H Portions of the hard membrane removed from the thin membrane and bent downward. 220 Appendix

Figure A3.

In the present figure, we have removed both cerebral membranes, the thin and the hard, from the entire part of the brain above the circular cut of the skull we made with the saw. We also removed from the bony septum between the sinuses of the olfactory organs the portion of the hard membrane that divides the right from the left brain, still in its position in figure 2. To fully appreciate the membrane, we left it lying over the left part of the brain, and similarly we stretched by hand the other membranes on the right and left parts of the brain so that the superior aspect of the corpus callosum comes elegantly to view. A, A, A Right side of the brain. B, B, B Left side of the brain. C, C, etc. Here the cerebral convolutions, gyri, and sulci are abundantly indicated. D, D, D A portion of the hard cerebral membrane separating the right and left brain, here removed from its original position and folded over the left brain. E, E, E When we try to divide the right and left parts of the brain, the vessels coursing from the hard to the thin membrane throughout both sides of the third sinus are often broken 221 Appendix during manual dissection. This occurred also for the preparation of this figure, and therefore the broken beginnings of these vessels can be seen here. F Duct running like a vein into the lower part of the hard membrane that divides the right from the left brain; this duct takes origin from the anterior part of the fourth sinus of the hard membrane. G, G, G Branches of the duct already marked with F that run upward into the same region of the hard membrane. H, H, H Propagations that originate from the lower angle of the third sinus of the hard membrane and continue into the portion of the hard membrane that divides the right from the left side of the brain. I, I First portion of the ducts that, like the veins, project from the fourth sinus of the hard membrane into the thin membrane of the brain. These course along the superior part of the corpus callosum, and at this level they are ripped together with the thin membrane. K Beginning of the vessel arising from the end of the forth sinus of the hard membrane. This vessel runs into the third ventricle of the brain under the cerebral structure that we compare to a tortoise shell or a vaulted room, and forms the plexus that we liken to the placenta or the outer wrapping of the fetus. L, L Corpus callosum of the brain. M, M Sinuses at the side of the corpus callosum, which we cannot show in any other way because they are narrow, similar to very deep cracks. N Portion of the part of the hard membrane between the right and left side of the brain, indicated above with D, that is attached to the septum that separates the olfactory organs and to a process of the eight bone of the head. O, O Portion of the thin membrane detached from the brain. P, P Portion of the hard membrane of the brain. 222 Appendix

Figure A4.

In the fourth figure, we have resected all the parts of the hard and the thin membrane that we encountered in the previous figures. In the dissection that follows, we removed a portion of the right and left side of the brain so that the cerebral ventricles can be fully appreciated. In fact, we first made a long cut longitudinally along the right side of the corpus callosum, at the level of the sinus indicated with one of the M’s in the third figure. This incision along the right cerebral ventricle removed a portion of the right side of the brain above the circular cut we performed with the saw. When we realized the same procedure on the left side, we placed the left part of the brain next to the head so as to show the superior seat of the left ventricle on one side, with the corpus callosum still preserved in its position inside the head. A, A, A Right part of the brain still inside the head. B, B, B Left part. C, C, C Left cerebral portion removed from the rest of the brain during the serial dissection, here lying on its back. D, D, D Lines showing, in part, the depth of the brain and, in part, the varied colors of the cerebral substance. All that is external to these lines is almost yellow and rather grayish, whereas everything that is internal is just white. E, F E and F indicate the same yellowish substance in the right and left part of the brain. G, H G and indeed H are really white, with scattered red spots. 223 Appendix

I, I, I Corpus callosum, free on both sides of the cerebral substance with which it is otherwise continuous. K, K A small portion of the corpus callosum still attached to the left part of the brain that has been removed. L, L Right cerebral ventricle. M, M Left cerebral ventricle. N, N Portion of the superior aspect of the left ventricle. O, O The cerebral plexus called choroides owing to its similarity to the outermost wrapping of the fetus. P, P Thin veins, like cobwebs, attached in this region to the substance of the left and right ventricles. They branch off the vessels that form the plexus that we said to be similar to the placenta. Q Small veins that from the aforementioned vessels run into the thin membrane under the anterior aspect of the corpus callosum and showing an irregular pattern during dissection, like the ones indicated with P. 224 Appendix

Figure A5.

With respect to the portion of the brain that is left in the skull, the present figure is not different from the previous one. At the same time it differs because here we have first separated the anterior part of the corpus callosum from the brain, and then lifted it and bent it back, pulling away the septum between the right and left ventricles, and thus revealing the superior surface of the body that resembles a tortoise shell. From A to Q: A, A, A and B, B, B, then D, D, D, and E and F, and G and H indicate here the same structures as in figure four. Similarly, also L, L, M, M, O, P and Q refer to the same parts. R, R, R Mark the inferior surface of the corpus callosum, which here has been removed from its seat and bent back. S, T, V Show the superior surface of the body that is constructed like an arch or a tortoise shell. We delineated its almost triangular outline with letters, from S to T, T to V, and V to T. 225 Appendix

X, X Indicate the inferior part of the septum interposed between the right and left ventricle, continuous with the body resembling a tortoise shell. Y, Y Superior part of the aforementioned septum, continuous with the corpus callosum. It does, indeed, depict this septum as if it had just been pulled away. In another figure that was prepared, two hands (as I am accustomed to using while performing dissection) hold up the corpus callosum just before the anterior part that was detached to expose the septum or root still intact. But this, indeed, is not very clear in the figure as well as in the dissection itself, so I preferred not to waste space on the page. 226 Appendix

Figure A6.

For what concerns the portion of the brain that is left in the skull, this figure corresponds once again to the fourth figure. It is different from the fifth by the fact that we have freed the body that is fabricated like a tortoise shell from the brain at its anterior part, and folded it upward and backward, so that its inferior surface is visible. This also permits to visualize the vessel that takes origin from the fourth sinus of the hard membrane, and courses under the body constructed like a tortoise shell. Finally, this vessel constitutes a rather substantial portion of the plexum that the ancients likened to the placenta. The letters of this figure are the following: A, A, A The organ constructed like a tortoise shell, here seen from its inferior surface, which forms the superior aspect of the third ventricle. B, B Portion of the organ formed like a tortoise shell that originates from the cerebral substance in the right ventricle. 227 Appendix

C Portion of the organ resembling in form and function a tortoise shell, which arises from the left cerebral ventricle. D, D Right cerebral ventricle. E, E Left cerebral ventricle. F The artery that, from the branch of the right sleep artery and from the right ventricle, pierces the hard cerebral membrane and ascends in the right ventricle. G Artery ascending into the left cerebral ventricle. H Vessel that originates from the fourth sinus of the hard membrane of the brain, and rapidly reaches the common cavity of the right and left ventricles, or third ventricle, under the structure that is shaped like a tortoise shell. I Place where the vessel marked with H separates into two branches. K The branch of the vessel marked with H, heading toward the right cerebral ventricle. L Portion of the aforementioned vessel accessing the left ventricle of the brain. M The plexus of the right ventricle that resembles the placenta is formed by the artery marked with F and a portion of the vessel H that we marked with K. N Plexus that fills the left cerebral ventricle, insinuated between the vessels marked with G and L. O, O Similarly, those small veins that are attached to the substance of the brain and originate from the vessels that we marked with K and L. P Small branches originating from the veins that are here attached to the cerebral substance, reach the thin cerebral membrane outside the space of the ventricles. Q The duct that from the common cavity of the right and left ventricles, namely the third cerebral ventricle, heads directly toward the basin that collects the cerebral phlegm, and through the funnel carries it to the gland positioned under the terminal part of the funnel. R, S Very small channels or sinuses that, sculpted in the substance of the ventricles, conduct the phlegm to the opening of the duct indicated with Q. 228 Appendix

Figure A7.

The present figure varies significantly from the three that immediately preceed. In fact, the part of the cerebral substance left intact in those figures and forming most of the right and left ventricles, is removed in this one. Then here, all that still rests on the cerebellum, is resected too, so that the portion of the hard membrane that intercedes between the cerebellum and the brain can be observed. Moreover, here we opened the sinus of the hard membrane, by means of cuts performed with the tip of the anterior part of a knife. We then folded back the vessel that extends from the fourth sinus of the hard membrane to the ventricles of the brain, here lifted from the third cerebral ventricle and detached from the plexuses that resemble the placenta. This permits to better appreciate the position of the third cerebral ventricle, or cavity shared by the right and left ventricles, along with the duct of this cavity. A, A Right part of the cerebral substance still left in the skull. B, B Left part of the cerebral substance still remaining in the skull. C, C, C The lines seen here correspond to the ones showed in the three immediately preceding figures. Indeed, given that lines of this kind, which indicate a greater diversity of the cerebral substance, are present only where the brain is closer to the thin membrane, the preceding figures showed only the outer ones. Conversely, when a larger portion of the brain 229 Appendix is removed, and the surface of the lower brain appears closer to the thin membrane, the lines can also be seen at the base. D, D What is therefore here delimited by these lines is the yellow or slightly pale cerebral substance: like, for example, the regions indicated by D, D, D. E, E, E indicate what is outside these lines, a white and rather transparent cerebral substance. F, This is a portion of the sleep artery that courses along the lower and narrower aspect of the right ventricle up toward the plexus that is similar to the structure of the placenta. Moreover, if you carefully consider where F is actually placed, and where it is in the sixth figure, you can immediately recognize that the right cerebral ventricle, as the left, is compressed and curved like a horn, arching from its back, through the cerebral substance downward and toward the anterior part. Here, in fact, where a larger portion of the cerebral substance is removed than in the sixth figure, the present portion of the artery marked with F curves anteriorly more than the part indicated with F in the sixth figure, where the letter identifies also the same portion of the artery that has already ascended from the posterior part of the ventricle. F and G in the subsequent figure, where I removed more cerebral substance than in this seventh figure and the letters refer to the same artery of the ventricle, show this more clearly. G Portion of the sleep artery that ascends upward along the lower and more posterior aspect of the left ventricle, similar to, for example, the artery marked with F. H The lowest aspect of the third ventricle that we have represented larger than its real size to be properly appreciated. I The passage that originates from the third ventricle of the brain and transfers the cerebral phlegm to the basin apt to receive it. K The passage that from the third cerebral ventricle courses between the testes and buttocks of the brain, and projects to the cavity common to the cerebellum and the dorsal cord. L The small gland that is similar to a pine nut, and acts as a support for the vessels going from the fourth sinus of the hard membrane to the brain. M, N We also call this part the testes and buttocks of the brain, here still surrounded by the thin membrane. O, O, etc. Process or portion of the hard cerebral membrane placed between the cerebellum and the brain. The ducts are similar to veins that here take their origin partly from the first and the second sinus of the hard membrane, and partly from the fourth ventricle. P, P Right or first sinus of the hard cerebral membrane. Q, Q Left or second sinus of the hard cerebral membrane. R Junction of the first and second sinuses of the hard membrane that some Greeks called linom, meaning winepress. S Beginning of the third sinus of the hard membrane. T Fourth sinus of the hard membrane, which opens here like the others. V The vessel that extends from the fourth sinus of the hard membrane to the brain ventricles, here folded backward from its position. X, X The cerebellum shown in this position is not surrounded by the hard cerebral membrane. Y The ducts that course like veins from the fourth sinus of the hard cerebral membrane into the thin membrane, and surround the testes of the brain. Z, Z Position of the hard membrane attached to the entire body of the hardest bone that contains the auditory organ. We removed this portion of the skull from the brain. 230 Appendix

Figure A8.

The present figure differs from the seventh by the fact that here we have further removed more of the brain, and divided the testes with a lengthwise cut to show the passage between the third and the fourth ventricle. Moreover, the portion of the hard membrane that covers the cerebellum has been cut here and can be seen folded back. Certainly, the present figure has many aspects in common with the seventh one. Letters from A to H A, A, and B, B, and C, C, and D, D, and E, E, and F and G and H, indicate the same structures as in the seventh figure. However, the arteries indicated by the letters F and G are farther forward here, because more of the brain at the base was removed compared to the seventh figure, and the same amount was also removed from the seventh figure compared to the sixth one. I This duct, which is marked with I in the sixth figure, directs straight down and carries the phlegm to the basin. K The duct that is set to carry the phlegm, which sometimes is seen coming from the passage that goes from the third ventricle between the testes to the fourth ventricle. 231 Appendix

L To avoid leaving the L completely in the shadow or making it more visible by carving it out of the shadow in its proper position but thus altering the sketch here, I moved the letter L to the anterior part of the cerebellum. Here it indicates the opening and the passage from the third to the fourth ventricle. If the letter L had been placed in the opening, it would not have been possible to represent it at all. M The gland similar to a pine nut was left in its position; this serves as a support for the vessels passing from the fourth sinus of the hard membrane to the ventricles of the brain. N, O, P, Q These four letters indicate the body that was sectioned and labeled with M and N in the seventh figure but here we left intact. Here, indeed, it is divided in two by the serial dissection. N and O indicate the position of this body to which the name testes has been given. Moreover, P and Q indicate those structures that we usually call buttocks. R, R, R The cerebellum still covered by the thin membrane. S, S, etc. Vein-like vessels that entangle the thin membrane of the cerebellum. T, T Branches of the vessels entangling the thin membrane of the cerebellum, extending to the arteries that ascend along the back parts of the right and left cerebral ventricles to form the networks that expert dissectors compared to the outer wrapping of the fetus. V, V Portion of the hard membrane that originally separated the superior part of the cerebellum from the brain. X, X These mark the branches from which the vessels that entangle the aforementioned portion of the hard membrane, penetrate into the thin membrane that envelops the cerebellum. Z, Z Here Z and Z indicate the same structures as in the seventh figure, where the hard membrane of the brain is attached to the bone lodging the organ of hearing. 232 Appendix

Figure A9.

In this figure, the portion of the brain shown is the same as in figure eight. Indeed, the present figure rests completely on its face, so that the part of the hard membrane that divides the brain from the cerebellum and the region that is normally in contact with the skull can be seen. The cerebellum, which has been manually removed from its seat in the skull, hangs slightly down. At the same time one can appreciate the cavity of the dorsal cord forming part of the fourth ventricle. Moreover, the course of certain veins and nerves, and the first and second cavity of the hard membrane are left open and accurately represented. A, A Portion of the brain still left in the skull cavity and here kept in its own position. B, C, D These three letters indicate the cerebellum shown folded downward from its seat, and still surrounded by the thin membrane and connected to the dorsal cord. In fact, B indicates the right part of the cerebellum, corresponding to the skull cavity indicated with P. Instead, D indicates the left part, which is usually lodged in the region of the skull marked with R. C indicates the middle part of the cerebellum that resembles a worm, and whose ends constitute the processes that the ancients compared also to worms. E Posterior end of the middle part of the cerebellum, to which I will refer to as the posterior part of the vermiform process. F, G, H Part of the dorsal cord still kept in the skull; F and G indicate the parts of the dorsal cord to which the cerebellum is attached. H marks the position of the dorsal cord that protrudes into the skull cavity. 233 Appendix

I The cavity of the dorsal cord that is similar to the tip of a reed pen that we use to write, and that constitutes the middle cavity of the ventricle between the dorsal cord and the cerebellum. The expert dissectors have called this the fourth cerebral ventricle. K Vessels or ducts that are very similar to veins. These extend into the cerebellum from the vessels draining into the first and second cavity of the hard membrane. And since these ducts are very frequent, they do not always course following the same pattern. L A vein-like duct that spreads on this side from the vessels that, in this region, weave into the hard membrane of the brain. M Fifth pair of the cerebral nerves. N Sixth pair of the cerebral nerves. O Seventh pair of the cerebral nerves. Here can also be seen all the protuberances that from the dorsal cord and not the cerebellum, give origin to the last two pairs of the cerebral nerves. P, Q, R Cavities of the occipital bone that have the same shape of the cerebellum. For example, P on the cerebellum corresponds to B; whereas Q to C, and R to D. S, S, S Right or first cavity of the hard membrane, here fully opened with the tip of a knife. T, T, T Left or second cavity of the hard membrane. In no other sketches of the brain can the duct of these sinuses be seen as clearly as in the present figure. 234 Appendix

Figure A10.

In this figure, we have represented that portion of the brain that arises from the beginning of the dorsal cord. The cerebellum has been removed from the part of the dorsal cord that is visible here, so that the testes and buttocks of the brain, the gland similar to a pine nut, and finally the cavity of the dorsal cord that together with the cavity of the cerebellum forms the fourth ventricle of the brain are all shown here. A, A Part of the brain that originates the dorsal cord. B The passage that under the buttocks of the brain, heads from the third cerebral ventricle to the fourth. C I have used this letter to mark the termination of the passage that extends into the fourth ventricle. D The cerebral gland that is compared to a pine nut by the professors of dissection. E, F, G, H The testes and buttocks of the brain are indicated by these letters. The experts in dissections have distinguished the superior protuberances indicated by E and G from the inferior ones, marked with F and H, along the line visible between E and F and between G and H. They have called the superior ones testes because the gland that lies upon them resembles a penis. The inferior ones, instead, were called buttocks for the resemblance of the end of the passage between the third and the fourth ventricle, here marked with C, to an anus. I, K Two regions where the beginning of the dorsal cord is attached to the cerebellum. 235 Appendix

L, M, N, O Cavity at the beginning of the dorsal cord that constitutes part of the fourth ventricle and was compared by Herophilus to the cavity of a reed pen that we dip into the ink while writing. In fact, the region indicated with L corresponds to that part of the pen cavity that is near the index finger of the writer. M and N can be, instead, compared to the angles at the sides of the pen cavity. O is similar to the tip of the reed pen that we use to draw letters. P The dorsal cord has been cut at the level of its departure from the skull into the vertebrae. 236 Appendix

Figure A11.

In this figure, the cerebellum has been removed from the skull and the dorsal cord, and it lies on its back, thus showing more of its inferior aspect where it faces the dorsal cord. The regions continuous with the dorsal cord itself, and above it the cavity that forms part of the fourth ventricle common to the cerebellum and the dorsal cord, are also visible. Then, we represent the ends of the middle part of the cerebellum at the bottom of this figure, so that the nature of the processes that are similar to a worm can be observed. A Right part of the cerebellum removed from the thin membrane that normally covers it; the whole cerebellum is here shown without this membrane. B Left part of the cerebellum. C, c Middle region of the cerebellum. C indicates the anterior region of this area, whereas c indicates its posterior area. D, d Terminations of the middle part of the cerebellum, where D indicates the anterior process and d the posterior one. E Cavity of the cerebellum that, together with the cavity of the dorsal cord, constitutes what we call the fourth cerebral ventricle. G, G The portion where the cerebellum is attached to the dorsal cord. H Anterior end of the middle part of the cerebellum represented here as if it has been resected from the rest of the cerebellum. I Posterior end of the middle part of the cerebellum severed from the cerebellum. 237 Appendix

Figure A12. In this figure, the head is viewed from the left side, with the right side somewhat lifted. Here we have also removed the cerebellum from the skull cavity, and left only the part of the brain that was kept in the eighth and ninth figures. Indeed this portion of the brain is not in its original position, but lifted and slightly bent back from the base of the skull toward the posterior part, so that those cerebral processes that are similar to the nerves and support the olfactory organ, can be easily seen. The left part of the olfactory organ has been lifted from its original position together with the brain itself, while the right part is still attached to the hard membrane of the brain where it surrounds the eighth bone of the head. A, A Right side of the brain. B, B Left side of the brain, still enveloped by the thin membrane like the right side. C Right olfactory organ still left in its original position. D Left olfactory organ, folded backward with the brain. E Cavity that lodges the left olfactory organ. Here it is indicated the region of the hard membrane that, for the benefit of the sense of smell, is perforated by many small holes. F The sixth vein that is directed toward the skull. Here it extends into the hard cerebral membrane with a certain number of protuberances. G The septum that separates the cavities shaped for the organs of smell. H The portion of the hard membrane of the brain that divides the right part of the brain from the left. I, I The region of the brain that occupies the largest cavity of the skull, here fitting the space hollowed out the region of the frontal bone. The small bumps that have been called by others the mamillary processes of the brain protrude here. 238 Appendix

K The fifth vein that enters the skull and whose path is determined by the opening engraved for the second pair of nerves. L L Like the following letters, they remain hidden in the shadow of the occipital cavity, and their significance is limited. M, N, O, P, Q Since L indicates the cavity of the skull, to which the right part of the cerebellum conforms, M faces the middle part of the cerebellum. N the cavity in which the left part of the cerebellum is placed. O, indicates the right or first cavity of the hard membrane. P, instead, the third, Q the second, or the left. 239 Appendix

Figure A13.

This figure consists entirely of the occipital region and all the cerebral substance left in it has been bent downward and toward the back to better appreciate the olfactory organ, the chiasm of the optic nerves, and the largest branch of the sleep artery. A, A Right part of the brain, still covered by the thin membrane of the brain. B, B Left part of the brain. C, C The proturbances of the brain that are called mammillary processes of the brain by most people due to their resemblance with the nipples. D, D The cavities lodging the olfactory organs. E The septum that separates the cavities lodging the olfactory organs. F, F Cavities of the skull to which the mammillary processes of the brain marked with C and C conform. G, G These mark on either side the sixth vein entering the skull. H The fifth vein entering the skull. I Indicates the vein-like vessel that courses through the thin cerebral membrane from the vessels that are located in the hard membrane. 240 Appendix

K The beginning of the vessels that run through the side of the hard membrane similarly to a vein joining an artery. These vessels are indicated in the first figure by many D’s. LL The olfactory organs here detached together with the brain from the hard membrane and placed downward. M Chiasm of the optic nerves. N Optic nerve directed toward the right eye. O Optic nerve directed toward the left eye. Like the right nerve, it is accompanied by a small vein that branches off from the vessels that in the same area interweave with the thin membrane of the brain. P The branch of the sleep artery that perforates the hard membrane of the brain at the side of the gland receiving the cerebral phlegm. Q The branch of the artery indicated with P, entering the right ventricle of the brain. R The branch of the artery indicated with P, here spreading like a protruberance into the thin cerebral membrane. S Here one can see the portion of the basin receiving the cerebral phlegm. 241 Appendix

Figure A14.

Here the head lies reclined on the left ear, and shows the base of the inner cavity of the skull, coated by the hard membrane of the brain. A small quantity of the brain and the dorsal cord has been kept, enough to show the pairs of cerebral nerves. I have resected the origin and the chiasm of the optic nerves in order to show the basin receiving the cerebral phlegm. A, A Small portion of the brain and beginning of the dorsal cord. B, B The optic nerves, here visible in their portion that enters the skull cavity. C, C Basin receiving the cerebral phlegm. D Here the duct that drains the cerebral phlegm from the third ventricle extends into the basin, and is indicated with I in the seventh and eighth figures. E Branch of the right sleep artery perforating the hard membrane at the right side of the gland that receives the cerebral phlegm. F Branch of the left sleep artery perforating the hard membrane at the left side of the aforementioned gland. G Second pair of cerebral nerves. H Thinner root of the third pair of cerebral nerves. I Thicker root of the third pair of cerebral nerves. K Fourth pair of cerebral nerves, adjacent to the thicker root of the third pair. L The small root of the fifth pair of cerebral nerves, unknown to all the professors of anatomy. M Fifth pair of cerebral nerves, or greater root of the fifth pair. 242 Appendix

N Beginnings and branches of the sixth pair of cerebral nerves. O Beginnings and branches of the seventh pair of cerebral nerves. If anything remains to be seen in this figure, it can be immediately understood without the help of the letters, or with the indications of the preceding figure. 243 Appendix

Figure A15.

In the present figure, we have represented the portion of the skull cavity that is surrounded by the cerebral hard membrane that stands above the middle of the cuneiform bone, together with the organs that are about to be enlisted. It would have been of no help to describe the entire head just for the sake of these small details. A, B Portions of the optic nerves. C Artery of the left side that in this point perforates the hard membrane and is distributed partly into the thin membrane of the brain and partly into the right cerebral ventricle. D Artery of the right side. E The cerebral phlegm flowing down from the third ventricle is collected and accumulated in the receiving basin. F The opening through which the end of this basin that is constructed like a funnel reaches the gland receiving the cerebral phlegm. G, G Portions of the second pair of cerebral nerves. 244 Appendix

Figure A16.

In this figure we have depicted the bare gland where the cerebral phlegm is collected, with the basin or funnel that drains it, and here flabbily inclined. At the sides, we have represented portions of the sleep arteries, which are said to form the reticular plexus, as we came across them during the dissection. And given that these portions of the arteries can present in different ways to dissectors, we have also variedly represented them here. A Gland receiving the cerebral phlegm. B The basin or funnel that is located above the aforementioned gland and drains the cerebral phlegm. C, C Portion of the arteries that course obliquely after they leave the openings in the bone of the skull. D Branch of the left artery running into the left side of the hard membrane. E Portion of the left artery extending to the nasal cavity through its own opening. F, F In this region we have delineated an alternative pattern of the artery. The right F indicates an artery that follows an undivided pattern here; the left F indicates an artery that splits into two branches that are soon about to join in one. G Portions of the arteries that penetrate into the hard membrane of the brain, and disperse partly into the cerebral ventricles and partly into the thin membrane that surrounds the cerebral base. H Branch of the artery coming out from the skull through the opening of the second pair of cerebral nerves and directed toward the optic nerve and then the eye. 245 Appendix

Figure A17.

In the upper figure we have sketched the plexus in a way that conforms with the description that Galen gives of it in De usu partium. A, B Let A and B thus indicate the arteries that enter the skull and immediately insert into the rete mirabile. C, D C and D indicate the branches gathering the offshoots of that rete and corresponding in size to the arteries that we indicated with A and B. E indicates the gland receiving the cerebral phlegm.

In the lower figure we have represented the series of the arteries that are under the hard membrane of the brain, and pass along the sides of the gland receiving the cerebral phlegm; the same series that we observe in the heads of sheep and cattle. And it was a good idea to display it here so nobody would think that we are not aware of the difference between these animals and man. In this figure, instead, A indicates the aforementioned gland, B and C the position of the arteries where they first enter the skull. 246 Appendix

Figure A18.

In this small figure, we have represented the basin, or cup, that distills the cerebral phlegm into the gland that is placed under it. Then here we also represented the four ducts draining the phlegm from the gland through the openings near the gland. Therefore, let A indicate the gland into which the phlegm is drained. B the basin through which it is conducted. C, D, E, F the passages that facilitate an easier flow of the phlegm remaining stagnant. Then, besides these figures of Book VII, which aim to indicate what is contained in the skull cavity, the two figures added immediately after the end of the first chapter of the fourth book also have the same function, and represent the sketch of the seven pairs of the cerebral nerves. Because we have already abundantly discussed them in that section, it would be a waste of space to reproduce the same figures and the list of their features here again. Moreover, even if the figures representing the structure of the eye refer to the seventh book, I will include them only at the beginning of the fourteenth chapter because that is dedicated to the anatomy of the eyes. And I shall do this for those figures because they serve no other chapter apart from the aforesaid one. 247 Appendix

Figure A19.

This figure is the first among those that are inserted at the beginning of the present chapter, and it represents half of an eye, with a cut from the anterior to the posterior aspect, thus dividing it through the optic nerve. This is like when someone cuts longitudinally an onion in half so as to have a surface that is continuous and matching with the other half. This is also the method that we commonly use to pictorially represent the celestial spheres and the four elements in a two-dimensional space. A Crystalline humor. B Tunic coating the anterior surface of the crystalline humor, and transparent like the thinnest onion skin. C Vitreous humor. D Substance of the optic nerve. E Tunic that we compare to a net, made of the same soft substance of the optic nerve. F Portion of the thin cerebral membrane covered by the optic nerve. G Uveal tunic into which the thin membrane that coats the optic nerve continues. 248 Appendix

H Here the uveal tunic is compressed and does not touch the cornea tunic that coates the external part. I Opening through which the uvea is perforated, or pupil. K Tunic that takes its origin from the uvea and corresponds in appearance to the eyelids or hairs, thus to form an interstice between the vitreous and aqueous humor. L Portion of the hard membrane of the brain that envelops the optic nerve. M The hard tunica of the eye that is constituted of the hard cerebral membrane. N Part of the hard tunica of the eye that is translucent like a horn. O, O The aqueous humor and the region where the majority of the cataracts appear indicated by the inferior O. P, P The muscles that move the eye. Q The adherent or white tunic of the eye.

The other subsequent figures represent in a serial order the parts of the eye, beginning with the humors, and then the tunics. And you should always compare all these figures to the first one that we represented here: because these figures follow each other according to the order of organization of the eye, and are represented following the same criteria adopted for this first figure. 249 Appendix

Figure A20.

The second figure represents only the anterior aspect of the crystalline humor, and therefore, it will appear free from all the parts that cover it to someone directly staring at it. The third figure shows the completely bare crystalline humor in a position that displays its side.

R Marks the roughness of the region where the tunic of the eye that resembles the eyelids and the hairs, which is also represented in the eleventh and twelfth figures, attaches to the crystalline humor. 250 Appendix

The fourth figure shows the anterior aspect of the vitreous humor after removing the crystalline humor. Here, it is represented in its original form, which it assumes when inside the eye. S This letter, in fact, indicates the cavity in which half of the crystalline humor is lodged. T The fifth figure represents the vitreous humor from the same view as in the fourth figure, but the crystalline humor, indicated by T, still floats in it. V The sixth figure represents the vitreous humor from the side, along with the crystalline that, marked with V, still floats in it.

The seventh figure shows the lateral view of the aqueous humor as if still positioned in the eye. X This letter covers the anterior aspect of the crystalline humor. Y While in the present figure X marks the crystalline humor, Y indicates in the same figure the region of the aqueous humor where part of the enclosed uveal tunic is divided from the cornea by a gap (given the eye is still intact). a, b The eighth figure shows the vitreous humor indicated by a, and at the same time the aqueous humor, marked by b, which are both opened and divided by the tunic that we correctly compared to the eyelids and hairs. c Indicates the position of this small tunic between those two humors.

The ninth figure represents, from the side, the remarkably transparent tunic attached to the anterior aspect of the crystalline humor, here separated from the crystalline humor itself. The tenth figure shows the crystalline humor from the side, still coated by the small tunic shown in the ninth figure. d, e. Here d and e indicate the small tunic and the posterior part of the crystalline humor that is not covered by the small tunic, but which floats in the vitreo humor when the eye is intact.

The eleventh figure indicates the anterior or posterior part of the tunic that the uvea produces, and g, g the tunic that is compared to the eyelids and hairs. g, g, f, f The rest that takes origin either from the circle attached to the uvea or the circle in the crystalline humor is marked with g and g, and with f and f respectively. h, h, i The twelfth figure contains the tunic that the eleventh figure shows still in the vitreous humor and attached to the crystalline. In fact, h and h mark the tunic and i the crystalline humor. k The thirteenth figure shows the tunic that experts in dissections compare to a net, and this is represented from the side along with the substance of the optic nerve marked with k, after removing the hard and the thin membrane of the brain.

The fourteenth figure shows the internal surface of the uveal tunic. Here, in fact, we have delineated this surface while dissecting. 251 Appendix l, m Therefore, l indicates a small portion of the tunic that is continuous with the substance of the optic nerve. The anterior region of the uvea is compressed inward, toward the posterior seat, indicated by m.

The fifteenth figure shows the external surface of the uveal tunic seen from the side, along with the substance of the optic nerve surrounded by the thin membrane of the brain. n Indeed, n indicates the substance of the optic nerve, here free from the thin membrane that coats it. o The thin membrane is marked by o and covers the substance of the optic nerve; here the thin membrane has been freed from the hard membrane that also surrounds it in the intact eye. p, p These are tiny portions of the veins and the arteries that from the hard tunic of the eye extend toward the uvea, which is shown here as already broken. q, q. These indicate the position where the anterior part of the uveal tunica is compressed and separated from the cornea. r The opening that corresponds to the pupil of the uvea.

The sixteenth figure shows the hard tunic of the eye from the side, here divided by a transversal section made to allow a view of the series of vessels passing from the same tunic into the uvea. s Therefore, s points to the truncated optic nerve, along with the two membranes, veins, and arteries that surround it. t, t Indeed, t and t show the veins and arteries running through the hard tunic of the eye. u, u Instead, u and u indicate here the uveal tunic, which can be seen following the severing of the hard tunic that receives small branches of the vessels from the hard tunic. x Moreover, x indicates the place where the hard tunic of the eye thins out like a horn, and appears very translucent. y Instead, the opening of the pupil corresponds to the area marked with y.

The seventeenth figure reveals the intact and uncoated external surface of the hard tunic of the eye, seen from the side, along with a great portion of the optic nerve. α, β, γ, δ The letter α marks the substance of the hard tunic, β the thin membrane that surrounds it, γ the hard membrane of the brain, δ the veins and the arteries along the optic nerve. x, y Moreover, x and y indicate here the same as in the sixteenth figure. ε, ζ, ζ The eighteenth figure describes, from the side, the eye without the eyelids, and avulsed from its position in the skull, along with its own muscles not yet detached. ε indicates the optic nerve, ζ and ζ the muscles that move the eye. η, η These indicate the adherent tunic of the eye. θ This marks the greater circle of the eye or iris, where the termination of the adherent membrane is firmly attached to the tunic of the cornea. 252 Appendix

κ This marks the area that emerges from the region of the pupil, or the minor circle.

The nineteenth figure represents the anterior part of the intact eye, which is free from the eyelids. λ Here λ indicates the lacrimal caruncle, placed in the major nasal angle of the eye’s cavity. θ, θ, μ Here θ, θ, and μ indicate the same structures as in the preceding figure.

Moreover, if someone wants to follow a description of the eye from its external parts, he will only have to consider the same order the other way around, swapping the position of the nineteenth figure of the eye with the the second, the eighteenth with the third, and the same for those that follow.

Notes

1. Vesalius begins the seventh book with a brief summary of the previous two books dedicated to the abdominal organs (Book V) and the chest’s organs (Book VI). For Vesalius this is a necessary introduction, as he believes that the supreme spirit, upon which depends the functioning of the brain, is originated from the vital spirit that governs the heart, and the natural spirit that governs the liver. For Vesalius the brain has the important role of generating the animal spirit by mixing the vital spirit with air. Then the animal spirit is further transformed into the supreme spirit. 2. Here Vesalius takes the stances of Galen who disagreed with the Stoics and Peripatetics that believed the heart as the organ of intellect and the nerves taking origin from it. Galen demonstrated that this view was incorrect with an experiment showing the sudden interruption of the animal’s screaming after the ligature of the laryngeal nerves originating from the brain. 3. This is the bile. 4. Vesalius’s anatomy of the main vein and artery originating from the liver and heart, respectively, and the description of the ‘circulation’ are surprisingly correct considering that he had no understanding of the human circulation. 5. These openings, which Vesalius believed to be located at the back of the nose, do not exist. 6. Galen talks about this in his book ‘De Usu Partium’ (On the Use of the Parts). 7. The pituitary gland (Chapter 23). 8. The fornix (Chapter 19). 9. The Latin term for meanders is anfractus, which is also used to indicate the sulci of the brain. Hence, Vesalius may here refers to the passage of the vital spirit through the sulci of the brain. 10. The aqueduct of Sylvius between the third and the fourth ventricle. 11. Testes and buttocks are terms used to indicate the superior and inferior colliculi in the brain stem (Chapter 21). 12. The fourth ventricle. 13. The dorsal cord is the brain stem. 14. The cranial nerves. 15. Vesalius acknowledges the limits of using animal vivisections to understand higher cognitive functions that are unique to humans. 16. Here Vesalius recognizes that anatomy as a mean of investigation of the human mind has its own limitations. 17. One of the most direct critiques that Vesalius moves against previous theologians, such as Thomas Aquinas, John Duns Scotus, and Albertus Magnus; the whole paragraph is a clear example of the Vesalian philosophy based on empirical evidence. 18. A mechanical analogy that was used to explain why memories are retained for short or long periods.

253 254 Notes

19. In modern neuropsychology this corresponds to the process known as recall of memories. 20. The Margarita philosophica was written by Gregor Reisch in 1503 and widely printed in several later editions. It contained diagrams, including a figure of the human head with the ventricles. 21. The idea of the complexity of the brain surface to be correlated with the intellectual functions of the individual species was proposed by Erasistratus of Alexandria (c. 310-250 BC) and rejected later by Galen (Chapter 16). Here Vesalius extends this concept to other structures of the brain, including the ventricles. 22. The membrane in the chest that Vesalius is referring to is called pleura. 23. The current anatomical term for this membrane is dura mater or simply dura. 24. Vesalius’s prose often contains many hendiadys, a figure of speech consisting in the use of two words to express the same concept. 25. The ethmoid bone. 26. The pituitary gland. 27. The charotid arteries. 28. Cauterization of the wound was a treatment still used at the time of Vesalius. A contemporary of Vesalius, the French surgeon Amboise Paré, demonstrated that the application of an ointment for dressing the wounds was far superior in terms of speed of recovery than cauterization with hot oil. 29. This is known in modern time as the cerebellar tentorium (the tent of the cerebellum). 30. The cerebral falx, so named for its sickle-like form. 31. The brain buttocks are the inferior culliculi in the brain stem (see Chapter 21). 32. The cerebellar tentorium and the cerebral falx. 33. The infundibulum (see Chapter 23). 34. This is a very effective visual analogy taken from a common craftsmen scene. It contrasts with the analogy in the paragraph that follows, that is taken from classical mythology. 35. Vulcano used a very thin but strong net of invisible fibres to catch his wife Venus and her lover Mars while committing adultery. 36. Literally meaning ‘around the skull’. 37. The periosteon. 38. Nature as the creator of all things is mentioned ten times in this chapter. It reveals Vesalius’s profound pantheistic belief. 39. The current anatomical term for this membrane ispia mater or simply pia. 40. The liquor, or cerebrospinal fluid. 41. Vesalius sees a common principle of functioning for different membranes of the body. 42. The use of this astronomical analogy is very effective. The air is the atmosphere, which with the water is between the sun (fire) and the planet Earth. 43. In this case Vesalius argues against the generalization of the principle of symmetry of the human body. In particular he considers the symmetry of the organs (e.g. kidney, lungs, etc.) a characteristic that cannot be extended to the entire brain due to the presence of a common base, the midbrain, between the two hemispheres. 44. This is incorrect as Galen had dissected many other animals, including pigs, goats, and monkeys. 45. Here Vesalius anticipates a phrenological concept that Gall and Spurzheim will theo- rize at the turn of the 18th and 19th century (see Chapter 34). 46. The sphenoid bone. 255 Notes

47. Galen links the intellectual functions to the ‘quality’ of the substances that govern the brain, not to their ‘quantity’. 48. This comment on Galen is unusual for Vesalius, an anatomist who claimed that he believed only to his eyes and not on speculations that are not supported by anatomical evidence. 49. The small cerebellar circonvolutions are called lamellae. They are organized in parallel and are greater in number compared to the cerebral ones. 50. Vesalius addresses Galen directly and accuses him of having been deceived by the dissections he performed on apes; Vesalius defends other anatomists of the school of Alexandria that Galen had ridiculed when in fact they had actually dissected the human body. Vesalius argues that the brain is not split as it may seems but unified at its base. 51. The cerebral part facing the forehead is the frontal lobe whereas the part that, in man, extends farther back is the occipital lobe. 52. Here Vesalius refers to the white matter of the brain (see Chapter 33). 53. Encephalitis, an inflammation of the brain most frequently caused by infective agents or autoimmune diseases. 54. Galen’s idea was largely correct. It has been recently demonstrated that in patients with left hemisphere stroke and subsequent aphasia, the right hemisphere can compensate in part for the loss of language. 55. Vesalius correctly indicates that most of the cerebral surface covered by the soft membrane constists of gray matter, which is the cortex. The upper surface of the corpus callosum, being made of white matter substance, is an exception to this rule. 56. Tylloeides means ‘like a callus’ in Greek and indicates the hard consistency of the corpus callosum. 57. Psalloeides means ‘like an arch’ in Greek, and refers to the shape of the corpus callosum seen from the side after cutting the brain in half. 58. This is a very clumsy way to say that the corpus callosum is slightly shifted toward the front of the brain. 59. These incisions are called callosal sulci in modern nomenclature. 60. An architectonic metaphor intended to give a sense of the thin translucent aspect of the septum. The stones Vesalius is referring to were used as transparent panels for doors and windows. 61. This part of the brain is the gray matter. 62. This is the white matter. 63. According to Vesalius the phlegm is a waste fluid that is sluiced down the corpus callosum and through the infundibulum into the nose (see Chapter 23). 64. The dorsal cord corresponds to the brain stem. 65. This is an unusual way of presenting the ventricles. Vesalius begins from the last, the fourth ventricle, then he introduces the other three. 66. The lateral ventricles have a boomerang-like shape and this rather complicated description intends to explain that the extremities of the ventricles are closer to the lateral aspect of the brain, while the middle portion bends toward the center of the brain. 67. The interventricular foramen of Monroe. 68. This is the temporal portion of the lateral ventricles. 69. The sleep arteries are the carotid arteries. 70. The cerebral convolution Vesalius is referring to is probably the uncus. 256 Notes

71. This is the groove between the thalamus and the internal capsule. 72. The anterior swelling is the bulging head of the caudate nucleus, the posterior swelling is the protruding thalamus. 73. The fornix. 74. The supraoptic recess of the third ventricle. 75. The pituitary gland. 76. The acqueduct of Sylvius. 77. The superior and inferior colliculi, respectively. 78. Infundibular recess. 79. The middle cerebellar peduncles. 80. This paragraph reveals Vesalius’s belief in the continuation of the soul in the afterlife. 81. These are the fimbriae of fornix that Vesalius thought to originate from the posterior part of the lateral ventricles. 82. Third ventricle. 83. The columns of fornix project into the mammillary body and hypothalamic nuclei. 84. Choroid plexuses. 85. Vesalius is referring to the dorsal aspect of the thalamus, which is rounded and elongated. 86. The vermis of the cerebellum. 87. One of the rare occasions where Vesalius praises Galen. 88. The great vein of Galen. 89. This term means ‘shaped like a cone’. 90. The acqueduct of Sylvius. 91. The superior colliculi. 92. In Book V. 93. Vesalius agrees with Galen on the mechanical function of the pineal gland. 94. Testes and buttocks are the superior and inferior colliculi, respectively. 95. The pineal gland. 96. Worm-like. 97. Vesalius is describing the vermis of the cerebellum and the two processes he is referring to are the superior and inferior ends of the vermis that has a ring-like shape. 98. The acqueduct of Sylvius. 99. Vesalius erroneously believes that the cerebellum is attached to the brain stem through processes of the meninges. There is no mention here of the cerebellar peduncles which connect the cerebellum to the brain stem and spinal cord. 100. In this chapter Vesalius describes a system that he believes to be dedicated to the excretion of the phlegm, a waste fluid produced in the brain and eliminated as secretion through the nose. 101. The supraoptic recess of the third ventricle. 102. The infundibular recess. 103. The acqueduct of Sylvius. 104. The basin, indicated also with the term funnel, corresponds to the infundibulum. 105. ‘Choana’ in Greek means funnel. 106. ‘Pyelos’ in Greek means basin (see Figure A18). 107. The callosal sulci (see Chapter 16). 108. In good health. 109. This literally means the wonderful net. 110. The carotid arteries. 257 Notes

111. Choroid plexus. 112. Suprisingly, Vesalius decides that anatomical investigations of the olfactory organs would not lead to new insights. We suspect that this was motivated by the lack of time to perform such lengthy and meticulous dissections. The Fabrica was close to its final printing and he may have had little time for further dissections. 113. These are the olfactory tract and bulb. 114. In this chapter Vesalius uses the pluralis majestatis, namely the use of the first-person plural instead of the first-person singular. 115. This is one of the most effective metaphors used in the Fabrica to explain the rather complex anatomical structure of the eye. 116. This observation is very important to understand the process of accommodation that the eye uses to maintain a clear image at different distances. This process depends on the elastic properties of the crystalline, which reduces with age with subsequent limited ability to accommodate from a short distance. 117. This Greek term means ‘tunic-shaped’. 118. Vesalius erroneously thinks that the capsule of the crystalline, which he refers to as the ‘onion-like transparent tunic’ is present only in the anterior part of the surface, when actually this capsule wraps the whole surface of the crystalline. 119. Here Vesalius refers to the process of glass making that is traditionally a Venetian activity in the island of Murano. The hot glass is soft but opaque and it becomes hard and very transparent when cooled down. 120. This Greek term means ‘glass-like’. 121. This is incorrect. See note 118. 122. The retina. 123. On the function of the parts. 124. On the doctrines of Hippocrates and Plato. 125. This Greek term means ‘net-like’. 126. The cornea. 127. This Greek term means ‘grape-like’. 128. This Greek term means ‘nipple’. 129. This Greek term means ‘placenta-like’. 130. Bluish-gray or green. 131. Ciliar body. 132. Whitish. 133. This Greek term means ‘rigid’. 134. Cornea. 135. This Greek term means ‘horn-like’. 136. This Greek term means ‘water-like’. 137. Conjunctiva. 138. This is a mistake. There are only six external muscles of the eye. 139. The petrous part of the temporal bone. 140. Vesalius describes for the first time two of the three ossicles of the middle ear, namely the malleus (hammer) and the incus. The stapes will be described three years after by the Sicilian anatomist Giovanni Filippo Ingrassia. 141. Vesalius’s nomenclature of the cranial nerves does not correspond to the contemporary one. His third pair of nerves is likely to correspond to the trigeminal nerve, which is not dedicated to taste perception. This function is carried out by the seventh and ninth cranial nerves. 258 Notes

142. Innervation of the tongue muscles is primarily from the tenth and twelfth pairs of cranial nerves. 143. Marcantonio Contarini belonged to one of the most influential families of Venice and became governor of Padua between 1538 and 1540 (see also Chapter 8). 144. Boethus and Sergius were two of Galen’s patrons. Indirectly Vesalius elevates himself to the status of Galen by saying that his patron, Contarini, is of the same value of Galen’s patrons. 145. The occiput is an anatomical term that indicates the most posterior part of the skull. 146. Nowadays autopsies are performed in a similar way but the skin of the head is left attached and only the upper skull is removed. 147. These Greek terms mean ‘around the skull’ and ‘around the bone’, respectively. 148. Superior sagittal sinus. 149. The septum is the falx cerebri, while the projections are the trabeculae of the arachnoid membrane. 150. The callosal sulci. 151. The fornix. 152. This Greek term means ‘placenta-like’. 153. This Greek term means ‘little cone’ and indicates the pineal gland. 154. The acqueduct of Sylvius. 155. The tentorium cerebelli. 156. The falx cerebri. 157. Vesalius may have meant cerebral here. 158. Except for figure 13, this is the only mention of the mammillary bodies in the whole Fabrica. However, here and in figure 13 Vesalius refers to the frontal poles. 159. The optic chiasm. 160. Infundibulum. 161. The carotid artery. 162. Rete mirabile. 163. This chapter continues with instructions on how to perform dissection of the muscles, veins, arteries and nerves of the arm. We have not included these three paragraphs as they are not directly related to the brain.

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Index

bold denotes photo; f denotes figure; n denotes notes; t denotes table acallosal brain, 87, 88f animals, experiments on, 206, 207f. See also acoustic center, 200f specific animals acqueduct of Sylvius, 99f, 118f, 126, anfractus, 253n9 256n76, 256n90, 256n98, 256n103, antidepressants, 122 258n154 antipsychotic agents, 113–114 acromegaly, 150f, 149 apraxia, 89 action potential (negative aqueous humor, 248, 250 Schwankung), 186t arachnoeides, 160 ADHD (attention deficit and hyperactivity Aranzio, Giulio Cesare, 108 disorder), 92 arbor vitae (tree of life), 133, 140 Adrian, Edgar, 205 arch-like (psalidoeides), 104, 106 Ahrens, Misha, 213 arcuate fasciculus (fasciculus arcuatus), Akelaitis, Andrew, 90 186t, 194 Albertus, 131 Aristotle, 27, 32, 48, 69, 133, 140 Albus, James S., 187t arterial polygon. See circle of Willis Alcmaeon of Croton, 68, 69 arteries, in appendix figures, 226, 227, 229, Aldini, Giovanni, 186t 230, 231, 239, 240, 244, 244, 245, alien hand syndrome, 89 245, 251 Allen, Floyd, 120 asses, experiments on, 49, 63 Alzheimer’s disease, 101, 114f, 115 associationist theory, 186t amativeness, faculty of, 136 association pathways, 194 amnesia, 111, 113, 113f, 115 associative cortex, 205 anarchic hand syndrome, 89 associative pathways, 186t Anathomia Corporis Humani (de Auburtin, Alexandre Ernest, 73, 74 Liuzzi), 15 autism, 77, 87, 92 anatomical evidence, 255n48 automated histological analysis, 210 anatomical renaissance, 13 Avicenna, 27 Anatomicarum Institutionum, Secundum axonal processes, 186t Galeni Sententiam (Anatomical axonal termination, 200 Institutions according to the axonal tracing, 136, 206, 207f Opinion of Galen) (Gueinther), 11 Anatomicarum Observationum Gabrielis Babbitt, Raymond (fictional Fallopii Examen (Vesalius), character), 87 37, 38, 41 Bailey, Percival, 207f animal brain, according to Vesalius, 49 Baillarger, Jules, 186t animal electricity, 186t, 195–196 Baranzono, Alessandro, 41 animal electrophysiology, 207f Bartholin, Thomas, 71f

273 274 Index

Basel as compared to social network, 185 printing of Fabrica in, 20 consistency of, according to Vesalius, 66 Vesalius in, 13, 21 of criminals, 76–77 basin, 227, 229, 230, 241, 243, 244, 246, dissection of, according to Vesalius, 256n104 171–184 Basser, Peter J., 187t division of, according to phrenological Bataillard, Aama (Lady Aama), doctrine, 73 148–149, 148 division of, according to Baudelaire, Charles, 7 Vesalius, 60, 64 Bechterew, Wladimir, 111, 200 functions and parts of, according to Bellarmati, Marcantonio, 32 Vesalius, 45–47, 253n1 Berengario Da Carpi, Jacopo, 154 hard membrane of, according to Berger, Hans, 187t Vesalius, 50–57 Berners-Lee, Tim, 187t hydraulic models of/hydraulic metaphor, Bernstein, Julius, 186t, 187t 185, 189, 192 bimanual coordination, 92 mechanical models of, 70, 83, 119, bipolar affective disorder (BPAD), 78, 101 185, 211 birds, experiments on, 49, 66, 128, 129, 135 number, position, shape, convolutions Bizzarri, Pietro, 41 and substance of, according to black reaction (reazione nera). See Golgi’s Vesalius, 60–67 silver method plasticity of, 136 Block, Felix, 187t size and shape of, according to bloodletting, 13, 18, 73 Vesalius, 62–63 body (subdivision of corpus structure of, according to Vesalius, callosum), 83f 104–105 Boethus, 258n144 as subject of seventh book of Fabrica, 27 Bogen, Joseph, 90 testes and buttocks of, according to BOLD effect, 187t Vesalius, 47, 53, 60, 61, 62, 95, 96, Boldrev, Edwin, 187t 105, 116, 124–125, 126–130, 127f, Bologna, Vesalius in, 32 132, 142, 176, 177, 256n94, 256n77, bone marrow, difference between substance 256n91, 256n94 of brain and, according to testes of brain, according to Vesalius, Vesalius, 66–67 229, 230, 234, 235 Bonifacio Stefano of Ragusa, 40 thin membrane of, according to Vesalius, Bonin, Gustav von, 207f 54, 58–59. See also thin membrane Borgia, Lucrezia, 35 tortoise-like vault structure, according to Borgogna, Maria, 7 Vesalius, 104–105, 221, 224, 226 Boucher, Georg, 41 vermis of, 105 Bouillaud, Jean-Baptiste, 73, 186t BRAIN (Brain Research through Brachelius, Thriverius, 13 Advancing Innovative brain Neurotechnologies) Initiative, 188 animal brain, according to Vesalius, 49 brain fibers, 192, 198 animal spirit transformation, according brain maps, 188, 189, 192, 194, 199f, to Vesalius, 253n1 200–201, 202, 207, 210 cerebral ventricles, according to Vesalius brain morphometry, 77–78 and others, 47–49 brain slices, 202 color and substance of, according to brainstem, 255n64, 256n99 Vesalius, 66 brain tumor, 114 275 Index

Broca, Paul, 5, 68, 74, 75, 1109, 110, color and substance of, according to 110f, 186t Vesalius, 66, 67 Broca’s area, 68, 74, 110, 200f commentary on, 133–140 Brodmann, Korbinian, 187t, 202–203, 203f consistency of, according to Vesalius, 66 Brussels, Vesalius in, 3, 7–8, 12, 32, 35 fourth ventricle, according to Burdach, Karl Friedrich, 186t, 194 Vesalius, 96 Busleyden, Jeroen van, 8 Galen as assigning incorrect rationale for Busquen, 34 unity of, according to Vesalius, 65 buttocks of brain, according to Vesalius, 47, internal anatomy of, 133f 53, 60, 61, 62, 95, 124–125, 126, 127f, as linked to brain, according to Vesalius, 61 130, 142, 176, 177 number, position, shape, convolutions and substance of, 60–67 Caenorhabditis elegans, 212, 213f peduncles of, 134f, 135, 139f Cajal, Santiago Ramón y, 121f, 138f, 139, position and size, according to 186t, 198f, 199, 200, 201, 202 Vesalius, 61–62 Calcar, Stephen, 19, 20f shape of, according to Vesalius, 62 callosal fibers, 85, 85f, 86, 87, 91, 92 Vesalius on dissection of, 176–177 callosal projections, 91f cerebral angiography, 187t callosal sulci, 255n59, 256n107, 258n150 cerebral convolutions, 219, 220 callosotomy, 88f, 89, 90, 91 cerebral cortex, 75, 84 Campbell, Alfred, 187t, 202, 203f, 205 cerebral falx, 254n30, 254n32 Canano, Giovanni Battista, 35 cerebral fissures, according to cancer, 122–123 Vesalius, 63–64 carotid arteries, 254n27, 255n69, 256n110 cerebral gland, according to Vesalius, Casseri, Giulio, 155f, 156 116–117 Caton, Richard, 186t cerebral mammillary process, 178 cattle, experiments on, 49, 98 cerebral nerves, 233, 244 caudate nucleus, 256n72 cerebral phlegm, according to Vesalius. See cauterization, 254n28 phlegm (cerebral) C. elegans, connectomme of, 187t cerebral plexuses, 223 cell bodies, 200 cerebral plexuses, according to Vesalius, 59, cell theory, 197 152–153. See also plexum/plexus/ centrum ovale, 84f, 85, 192f plexuses Centurius, Johannes, 35 cerebral shunts, 103 cerebellar cells, 137, 138f cerebral substance, 222, 228, 229, 239 cerebellar circonvolutions, 255n49 cerebral ventricles cerebellar folding, 64–65, 135 according to Vesalius and others, 47–49 cerebellar lesions, 136 in appendix figures, 222, 223, 227, 228, cerebellar peduncles, 134f, 135, 231, 234 139f, 256n79 contents of, according to Vesalius, 96–98 cerebellar processes, according to Vesalius, description of, according to 131–132 Vesalius, 93–94 cerebellar tentorium, 254n28, 254n32 division of, according to Vesalius, 93 cerebellectomy, 135 function of, according to Vesalius, 98 cerebellum Galen’s teachings on as not in anatomy of, 134f Fabrica, 94–95 in appendix figures, 228, 229, 230, 231, as “seat of the mind,” 99 232, 233, 234, 235, 236, 237, 238 third ventricle, according to Vesalius, 95 276 Index

Cerebri Anatome (Willis), 70f, 84f, 108, 155f connectivity, 139, 188, 192, 207, 209, cerebrospinal fluid (CSF), 99, 254n40 210, 211 cerebrum, 60, 128f, 137, 191 connectivity maps, 207f Charles V, 7, 12, 31, 32, 34, 35, 36 connectome approach, 188, 189, 191, 201, chest, organs of, as subject of sixth book of 209, 210, 212 Fabrica, 26, 29f connectomics, 191, 211 chlorpromazine, 113–114 Contarini, Marcantonio, 28, 171, 258n143 choana, 142 convolutions, 68, 69–71, 69f, 70f, 71f, 73, choroeides, 163 76f, 78 choroid, 163 Coons, Albert, 187t choroides, 223 Copernicus, 6 choroid plexuses, 256n84, 257n111 cornea, 250, 257n126, 257n134 Christianity, as believing ventricular corpora quadrigemina (quadruplet bodies). theory, 69 See brain, testes and buttocks of cingulate cortex, 110 corpus callosum cingulate gyrus, 110f absence of, 87–88, 88f, 92 cingulum, 186t in appendix figures, 221, 222, 223, circadian rhythm, 122 224, 225 circle of Willis, 5, 155f, 156f, 157 commentary on, 82–92 cleft separating right brain from left brain, function of, according to Vesalius, 81 according to Vesalius, 63 grooves on sides of, according to clinical-anatomical correlation Vesalius, 80 method, 200 introduction of term, 11, 82 cogitativa, 190f origin of, according to Vesalius, 80 cognition (res cogitans), 119 position and nomenclature of, according Cohen, David, 187t to Vesalius, 79–80 colliculi. See brain, testes and buttocks of reconstruction of, 83f Colombo, Realdo, 35 septum between right and left ventricles, columnar organization, 206 according to Vesalius, 80–81 commentaries corpus striatum, 83, 84, 101 axis of survival (hypothalamic-pituitary Cortese, Carlo, 32 axis), 146–151 cortex, 84f, 86, 87, 137, 191, 192, 196, cerebellum, 133–140 197, 199, 200, 202, 203f, 205, 206, corpus callosum, 82–92 207, 208 fornix, 106–115 cortex of the insula, 27 liquor of our souls (cerebrospinal cortical electrophysiology, 75 fluid), 99–103 corticalization, 194 net of wonder (rete mirabile), 154–157 cortical localization, 203 pineal gland, 118–123 cortical mapping, 203–204, 203f, 205 scratching surface of complexity, 68–78 cortical myeloarchitecture, 203–204 sex on the hills (superior and inferior cortical myelogenetic maps, 199f colliculi), 126–130 cortical organization, 206 commissural pathways, 186t, 194 corticospinal tract, 199 common sense, 48, 190f Cosimo I de’ Medici, 32 computed tomography, 77, 187t Crabble, Isabella, 7 conditioned reflex, 196 Crabble, Jacob, 7 conjunctiva, 257n137 cranial nerves, 253n14, 257n141 277 Index cross-talk, 82, 92, 151 Democritus, 69 crystalline humor, 159–160, 161, 164, 165, dendrites, 200, 209 166, 180, 181, 247, 249, 250, 257n116, dendritic processes, 186t 257n118 De Placitis Hippocratis et Platonis (Galen), CSF. See cerebrospinal fluid (CSF) 98, 162 Cullerier, Monsieur, 73 depression, 92, 112, 122 cuneiform bone, 243 De Revolutionibus Orbium Coelestium (On cytoarchitectonic maps, 203f, 204 the Revolution of the Heavenly cytoarchitectonics, 197, 210 Spheres) (Copernicus), 6 Czolgosz, Leon, 76f, 75 Descartes, René, 83, 101, 119f, 120, 123, 151, 186t, 192, 192f, 193 d’Abano, Pietro, 15 d’Este, Francesco, 35 Dandy, Walter, 89, 187t De Usu Partium (Galen), 97, 98, 161, 162, data processing, challenges/limitations of, 167, 245, 253n6 210, 211 developmental disorders, 87 d’Azyr, Félix Vicq, 71, 71f, 86, 108, diagonistic hand, 89 110f, 186t dichotic listening, 90 ‘Dead Galatian’ (statue), 29f didymoi, 125 De Anatomicis Administrationibus (On Diego, Friar (of Alcalá), 39 Anatomical Procedures) (Galen), 11 diffusion MRI, 187t De Anima (Aristotle), 48 diffusion tensor imaging (DTI), 187t, 209, default mode network (DMN), 208 211, 212f de Franceschi, Francesco, 40 diffusion tractography, 83f, 91f, 92 De Homine Figuris (Descartes), 119, 192 Diocles, 69 De Humani Corporis Fabrica (On the disconnection syndrome, 89 Fabric of the Human Body) dissection (Vesalius) Alcmaeon of Croton as first to as celebrated work, 6 perform, 68 content of all books of, 23–27 how to, according to Vesalius, 171–182 content of seventh book of, 45 permission for Vesalius to perform, 12 description of, 23–27 post-mortem, 191, 207 drawings of, 14f, 24, 30, 215–252 as prohibited, 10 Falloppia’s commentary of, 37 in situ, 107 figures from seventh book of, 215–252 Vesalius finding opportunity for as as first map of new human anatomy, 3 limited, 37 frontispiece image of, 14f Vesalius’s practice of, 10 making of, 19–22 Vesalius’s responsibility for public printing of, 20 dissections, 13–15 publication of, 13, 19, 20, 21, 22 Dissertatio Physiognomica (Lancisi), 85 second edition of, 35 DMN. See default mode network (DMN) Vesalius as discouraged by outcry dogs, experiments on, 49, 53, 62, 86, 135 against, 32 Don Carlos, 38–39 as Vesalius’s masterpiece, 31 dorsal cord, 253n13 Deiters, Otto Friedrich Karl, 186t according to Vesalius, 65–66, 96 Déjérine, Joseph Jules, 75, 89, 187t, in appendix figures, 232, 234, 235, 236, 200, 200f 241, 255n64 Deleboe, François, 71 Vesalius on dissection of, 177 278 Index

Dryander, Johannes, 35 Falloppia, Gabriele, 5, 37, 38, 41 DTI. See diffusion tensor imaging (DTI) falx cerebri, 258n156 Du Bois-Reymond, Emil, 186t fasciculus arcuatus (arcuate fasciculus). dura mater/dura, 254n23 See arcuate fasciculus (fasciculus ‘Dying Galatian’ (statue), 29 arcuatus) dynamic polarization, law of, 200 Fasciculus medicinae (de Ketham), 5f, 15 dyslexia, 77 Felleman, Daniel J., 207f fiber dissection, 108, 192f Economo, Constantin von, 187t, 204, fiber trajectories, 191 203f, 205 fight-or-flight response, 111 Edwin Smith Surgical Papyrus, 69, 69f fimbriae, 107f, 108 Egmont, Anna Van, 36 fimbriae of fornix, 256n81 Ehrenberg, Christian G., 186t first sinus, 177, 179, 229 electrical impulses, body as powered by, 86 Flechsig, Paul Emile, 186t, 199, 199f, 200f electroencephalography (EEG), 187t Florenas, Nicolas, 9 electron microscopy, 187t, 212 Florence, Vesalius in, 32 electrophysiology, 75, 86, 91, 186t–187t, 188, Flourens, Marie-Jean Pierre, 75, 135, 137 191, 196, 207f fluorescent protein staining, 212 emotion center, 75 fluoxetine, 122 Empedocles, 69 fMRI. See functional MRI (fMRI) encephalitis, 114, 255n53 foldings, 64–65, 71, 135 endocrine disorders, 148 folia (leaves), 133f Epicureans, 69 foramen, 99f epilepsy, 89, 91, 113, 113f foreign hand (main étrangère), 89 epiphysis, 118–123 fornix, 82, 104, 106–115, 107f, 110f, 253n8, Epitome (Vesalius), 22 256n73, 256n83, 258n151 Erasistratus of Alexandria, 64, 69, 69f fourth sinus, 220, 221, 226, 227, 228, 229 Erasmus of Rotterdam, 9 Frederick III (emperor), 7, 8 estimativa, cell, 190f Freeman, Walter, 112, 112 ethmoid bone, 254n25 Frisius, Gemma, 3 Euler, Leonhard, 186t Fritsch, Gustav T., 186t European Commission, 188 frogs, experiments on, 126, 128f, 137f Eustachi, Bartolomeo, 108 frontal lobe, 255n51 Examen. See Anatomicarum Fulton, John, 112 Observationum Gabrielis Fallopii functional MRI (fMRI), 208, 211 Examen (Vesalius) funnel, 227, 243, 244, 256n104, 256n105 Exner, Sigmund, 75 experimental method, 191, 198 Gadaldino, Agostino, 41 eye Galenists, 4, 31 according to Vesalius, 159–167 Galen of Pergamon in appendix figures, 247–252 anatomical observations of, 4 Vesalius on dissection of, 179–181 as author of most medical texts, 10 on cerebellum, 133, 134 Fabrica. See De Humani Corporis Fabrica on corpus callosum, 82 (On the Fabric of the Human Body) on fornix, 106–107 (Vesalius) great vein of, 118 Fabrici d’Acquapendente, Girolamo, 42 in index of Fabrica, 27 279 Index

as influence on Alcmaeon, 69 Gray’s Anatomy, 23, 126 synopsis of anatomical teachings of, 16 great vein of Galen, 118, 256n88 on ventricular theory, 100–101, 156, 189 Griesinger, Wilhelm, 186t Vesalius’s challenge of, 32. See also Vesalius, Grimani, Antonio, 29 Andreas, on Galen’s teachings Grimani, Domenico, 29 Vesalius’s summaries of, 6 Gudden, Bernhard von, 109, 198 works of Gudden method, 109, 198 De Anatomicis Administrationibus Guenther von Andernach, Johann, 10, 11, (On Anatomical Procedures), 11 11f, 16, 23, 31 De Placitis Hippocratis et Platonis, Guiteau, Charles, 76 98, 162 Gygax, Paul, 187t De Usu Partium, 97, 98, 161, 162, 167 gyri, 27, 63, 68, 69f, 71, 71f, 77f, 78, 108, 193, Galilei, Galileo, 42, 211 195f, 220 Gall, Franz Joseph, 71, 73, 75, 86, 92, 127, gyrification indexes, 78 136, 186t, 194–195, 195f, 254n45 Galvani, Luigi, 186t, 195 Haller, Albrecht von, 135 Garfield, James, 76 hard cerebral membrane/hard membrane Gauss, Carl Friedrich, 76f, 75, 76 according to Vesalius, 50–57 Gazzaniga, Michael, 90–91 in appendix figures, 217, 218, 219, 220, Gebweiler, Jakob Karrer von, 21, 21f 221, 222, 226, 228, 229, 230, 231, gene expression, 210 232, 233, 237, 238, 239, 243, 245, 247 genu (subdivision of corpus Harvey, William, 35 callosum), 83f Hatton, Rondo, 150 geography center, 75 hearing, organ of Geschwind, Norman, 77 according to Vesalius, 168 gigantism, 148f, 149 in appendix figures, 231 Gilles de la Tourette syndrome, 92 Vesalius on dissection of, 181–182 Giunta, publisher, 20 Hebb, Donald, 187t gloutia, 125 Helmholtz, Hermann von, 186t goats, experiments on, 49 hendiadys, 254n25 God/Creator, Vesalius’s acknowledgment Henry II, 12, 36 of, 47, 48, 58, 59, 64, 98, 125, 132, herbal remedies, as fascination for 144, 152 Vesalius, 34, 40 Golgi, Camillo, 6, 139, 138f, 139, 186t, 197, Herophilus of Alexandria, 65, 69, 93, 96, 97, 198f, 200 99, 100, 189, 235 Golgi’s cells, 6, 139 Heubner, Otto, 120 Golgi’s silver method, 186t, 197, 198f, 199 hippocampal gyrus, 110f Golgi’s syncytium, 139 hippocampal histology, 198f Gowers, William, 137 hippocampus, 106, 107f, 108, 109, 111, 113, grand lobe limbique, 110, 110f 114f, 115, 198f Granvelle, Antoine Perrenot de, 36 Hippocrates, 27, 257n124 graph, use of term, 186t Hitzig, Julius E., 186t graph theory, 186t, 211 Hodgkin, Alan Lloyd, 187t Gratiolet, Louis Pierre, 186t homunuculus, 187t Gray, Henry, 126 hormones, 121, 122, 146, 146f, 147, 150 gray matter, 85, 186t, 191, 194, 196, 199, horses, experiments on, 49, 63, 98 205, 255n55, 255n61 Hounsfield, Godfrey, 187t 280 Index

Hubel, David, 187t, 206 Jackson, John Hughlings, 75, 137 Hugo, Victor, 7 Jacobsen, Carlyle, 112 Human Brain Project, 188 Jakob, Christfried, 111, 111f Human Connectome Project, 188 Janssen, Hans, 186t human head, removed from neck with Janssen, Zacharias, 186t jawbone dislodged, 216f Javal, Émile, 127 humanists, 4, 9, 10 Jeckelmann, Franz, 21 human language, 75, 78, 87, 90, 92, 110, Jerusalem, Versalius in, 40 130, 194, 200f, 208 Josepha, Princess, 148 Hutchinson, Woods, 149 Huxley, Andrew Fielding, 187t Keller, Philipp, 213 hyaloeides, 161 keratoeides, 165 hydatoeides, 165 Ketham, Johannes de, 5f hydrocephalus, 101, 102–103, 102f kittens, experiments on, 135 hyperostosis frontalis interna, 148 Klinger, Joseph, 187t hypothalamic nuclei, 146f, 147 Kölliker, Albert von, 186t, 197 hypothalamic-pituitary axis, 147, 151 konarion, 116, 175 hypothalamus, 106, 107f, 122, 146–151, Königsberg Bridge, 186t 146f, 151 konoeides, 116 Korsakoff, Sergei, 111 ice pick leucotomy, 112, 112 Korsakoff syndrome, 111 idiot savants, 87 Koskinas, Georg, 187t, 204, Imhotep, 68 203f, 205 immunofluorescence staining, 187t krystalloeides, 159 incus, 257n140 Kuypers, Hans, 187t inferior cerebellar peduncle, 134f, 135, 139f inferior colliculi, 126, 130 Lady Aama, 148–149, 148, 150 inferior longitudinal fasciculus, 186t lamb, experiments on. See sheep, information overload, as limitation of experiments on neuroimaging, 211–212 Lancisi, Giovanni Maria, 85 infundibular recess, 256n78, 256n102 Lapicque, Luis, 187t infundibulum, 141–145, 146f, 177, 254n33, Larrey, Baron, 136 256n104, 258n160 lateral ventricles, 100f, 101, 102, 102f, 108, Ingrassia, Giovanni Filippo, 257n140 255n66, 254n68 Institutiones Anatomicae (Bartholin), 71f Lauterbur, Paul, 187t Institutiones Anatomicae (Fundamentals Laycock, Thomas, 186t of Anatomy) (Guenther von leaves (folia), 133f Andernach), 16, 17, 23 Le Bihan, Denis, 187t interhemispheric connectivity, 91f Leborgne, Monsieur, 74, 76f internal abdominal organs Leeuwenhoek, Antonius van, 186t (splanchnology), as subject of fifth left hemisphere, 78, 81, 82, 90, 90f, 92, book of Fabrica, 26 175, 176 interventricular foramen of Leonardo da Vinci, 3, 30, 42, 100f, 154, Monroe, 255n67 155f, 189 intra-axonal tracing compounds, 187t Lerner, Aaron B., 121 in-vivo human diffusion tractography lesions (cerebellar lesions), 136 reconstructions, 187t lesion studies, 207f in vivo surface anatomy, 77f leucotomy, 112 281 Index

Leuret, François, 186t Marzi, Marzio, 32 Leuven, Vesalius in, 8, 12 Massalongo, Roberto, 149 Liber Primus de Catharris (First book on material world (res extensa), 119, 119f the mucus) (Schneider), 147 Matteucci, Carlo, 186t Liepmann, Hugo, 89 Maximilian I (emperor), 7 light therapy, 122 Maximilian of Egmont, 35 Lima, Almeida, 112 McClelland, Jay, 187t limbic system or network, 108, 109f, McCord, Carey, 120 111, 111f McCulloch, Warren Sturgis, 187t, 211 limbus, according to Willis, 108, 110 medial frontal cortex, 208 linom (winepress), 229 medulla, 47, 55, 65, 128f, 136, 191 “little brain,” 133 melatonin, 121–122, 121f Liuzzi, Mondino de, 15 memory lobotomies, 112 cerebral cortex for, 84 localizationism, 75, 137 as component of the spirit, 83 localizationist theory, 71 deficits/disorders, 111, 114 Lombroso, Cesare, 75 fornix as memory thread, 106, 109, 110 Lower, Richard, 147 olfactory system and, 109 Luschka, Hubert, 101, 102 recovery of, 115 Lycus, 97 role of gyri in, 193 seat of, 119f, 132, 135 Macagno, Eduardo, 187t unitary model of, 108 macroscopic connectome, 188, 209, 213 Vesalius on, 47, 48, 62, 70 Madrid, Vesalius in, 37 mental disorders, 101, 112, 203f Magendie, François, 101, 102 Mercator, Gerardus, 3 magnetic resonance imaging (MRI), 77, 77f, metaphors, 185, 189, 193, 210–214, 255n60, 78, 87, 92, 187t, 188, 208, 210, 211 257n115 magnetoencephalography (MEG), 187t metathalamus, 130 main étrangère (foreign hand), 89 Meynert, Theodor, 86, 186t, 197 Malacarne, Michele Vincenzo Giacinto, 135 microarray profiling, 210 Malatesta, Giacomo, 41 microscopic connectome, 188, 209, 213 malleus, 257n140 microscopy, 186t–187t, 188, 197, 198f, 202, Malpighi, Marcello, 186t 209, 210, 212 mammillary bodies, 106, 107f, 108, 110f, middle cerebellar peduncle, 134f, 114, 126, 258n158 135, 139f mammillary processes, 239 mind-body dualism, 151 mammillothalamic tract, 109, 110f, 111 Mishkin, Mortimer, 207f Manual of diseases of the nervous system Molaison, Henry Gustav, 113–114, 113 (Gowers), 137 Monakow, Constantin von, 198 Marchi, Vittorio, 186t, 198 Moniz, Antonio Egas, 112, 187t Margarita philosophica, 254n20 monkeys, experiments on, 10, 49, 69f, 206 Marie, Pierre, 149 Monro, Alexander, 101 Marino, Andre, 41 Monro, foramen of, 99 Marinus, 97 Montanus, Joannes Battista, 20 Marr, David, 187t Moreno, Jacob, 187t Mars (god), 254n35 Morgagni, Giovanni Battista, 120, 148 Martirio di San Lorenzo (The Martyrdom motor center, 200f of Saint Lawrence) (Titian), 29 Mountcastle, Vernon, 206 282 Index

MRI. See magnetic resonance imaging Observationes Anatomicae (Falloppia), multi-unit recording, 206 37, 38, 41 Murano, 257n119 occipital bone, 233 muscles, as subject of second book of occipital cavity, 238 Fabrica, 24–26, 25f occipital cortex, 127 myelination, 199f occipital lobe, 255n51 myeline sheet, 186t occipital region, 239 myelogenetic method, of Flechsig, 199 occiput, 258n145 myocardial infarction, 122 Ogawa, Seiji, 187t olfactory bulb, 110f, 128f, 257n113 National Archeological Museum (Correr olfactory organs, 51, 52, 55, 62, 94, 98, 144, Museum), 29 158, 173, 174, 175, 178, 179, 221, 237, National Institute of Health (NIH), 188 239, 257n112 nausea, 136 olfactory system, 109 Nauta, Walle, 187t olfactory tract, 257n113 Navagero, Bernardino, 35 Onufrowicz, Bronislaw, 87 neocerebellum, 136 Opera Galeni (Montanus, ed.), 20 neocortex, 203f Oporinus, Johannes, 13, 20, 21 nerve fibres, 186t optic chiasm, 239, 241, 258n159 nerves, origin of, according to optic lobe, 127, 128f Vesalius, 66 optic nerve, 52, 94, 142, 143, 161, 162, 164, network analysis, 185 166, 178, 180, 181, 190f, 205, 239, network model, 186t 240, 243, 244, 247, 251 neuroanatomy, 69f, 76, 108, 186t–187t, 188, orbitofrontal cortex, 111 192, 194 organology, 71, 194, 195f neurodegeneration, 122, 208 oriented receptor fields, 206 Neurographia Universalis osteology, as subject of first book of (Vieussens), 84f Fabrica, 23–24, 24f neuroimaging, 101, 106, 139f, 186t–187t, oxen, experiments on, 10, 61, 62, 63, 152, 188, 191, 207, 208, 209, 210, 154, 179 211, 212 oxytocin, 146f, 150 neuronal function, 205 neuron doctrine, 200, 201 Padua, Italy, 13 neurons, 137, 139, 186t paleocerebellum, 136 neuron theory, 186t Palestine, Versalius in, 41 neuroscience Panizza, Bartolomeo, 186t history of, 185–214 pantheistic belief, 254n38 introduction to, 185–188 Papez, James, 111, 111f metaphors and myths, 210–214 Papez circuit, 111 microscopic discoveries, 197–201 Paraphrasis In Nonum Librum Rhazae modern cartography, 202–209 Medici Arabis, namely a neurosurgery, 89, 113 commentary to the ninth book of Newton, Isaac, 186t Rhazes (Vesalius), 12, 20 NIH (National Institute of Health), 188 Paré, Amboise, 254n28 NMR images, 187t Paris, Vesalius in, 9–12 NMR phenomenon, 187t Parkinson’s disease, 101 Nobel Prizes, 91, 139, 200, 205 partial callostomy, 88f 283 Index

Pavlov, Ivan, 187t, 195 plexum/plexus/plexuses, 226, 227, 228, Pedagogium Castrense (Castle 229, 245 College), 8, 8f plexus mirabile. See rete mirabile Peek, Kim, 87–88 pluralis majestatis, 257n114 Penfield, Wilder, 187t pons. See pons Varolii perikranion/perikranios, 56, 172 pons Varolii, 108, 134 periosteon, 56, 172, 216, 254n37 positron emission topography (PET), Peripatetics, 45 187t, 208 peripheral nervous system, as subject of Powell, T. P., 206 fourth book of Fabrica, 26 precision microtome, 198 perisylvian fibers, 194 primary auditory cortex, 130 PET. See positron emission projection pathways, 194 topography (PET) protoconnectome maps, 189–190 petrous part (of temporal bone), 257n139 psalidoeides (arch-like), 104, 106 phakoeides, 160 psalloeides, 79, 255n57 Philip II, 7, 36, 37, 41 psychiatrists, 76 phlegm (cerebral), 141–145, 150, 227, psychic reflex, 186t 230, 241, 243, 244, 246, 255n63, psychosis, 113 256n100 pupilla, 248 photoreceptors, 122 Purcell, Edward, 187t phrenology, 73, 86, 127, 136, 195, 195f, 200 Purkinje, Jan, 137, 186t pia mater/pia, 254n39 Purkinje cells, 137 Piccolomini, Arcangelo, 186t, 191, 194 pyelos, 142 pigeons, experiments on, 135 Pythagoras, 69 pigs, experiments on, 10, 135, 154 pineal cells, 121f quadruplet bodies (corpora pineal cyst, 118f quadrigemina), 126 pineal gland quantifiable analysis, 211 in appendix figures, 229, 230, 234 to Descartes, 101 rabies virus, 187t function of, according to Vesalius, Rain Man (movie), 87 116–117 rats, experiments on, 151f, 151 location of, 116, 118f, 256n95 reading center, 75, 200f as resembling penis, 127f reazione nera (black reaction). See Golgi’s role of, 256n93 silver method as “seat of the soul,” 83, 119, 193 receptor expression, 210 Vesalius on dissection of, 176 regulatory center, 151 pinealocytes, 121, 122 Reil, Johann Christian, 87, 186t, 194 pineal tumor, 148f reptiles, experiments on, 135 Pinterete from Valencia, 39 res cogitans (cognition), 119 Pisa, Vesalius in, 32 res extensa (material world), 119, 119f Pitts, Walter, 187t, 211 resting state, 208 pituitary gland, 147, 146f, 147–148, 253n7, rete mirabile, 152, 154–157, 155f, 245, 245, 254n26, 256n75 258n161 pituitary tumor, 148, 149 reticular plexus, 46, 52, 143, 152, 244 Plato, 27, 69, 98, 257n124 reticular theory, 197, 200 pleura membrane, 254n22 retina, 257n122 284 Index rhagoeides, 163 Singer, Charles, 107 right hemisphere, 75, 82, 83f, 90, 90f, 92 single-unit recording, 206 Río Hortega, Pio del, 121f sinus roga, 163 first, 177, 179, 229 Rolando, Luigi, 5, 135 fourth, 220, 221, 226, 227, 228, 229 Rondo award, 150f second, 177, 179, 229 rostrum (subdivision of corpus third, 218, 220, 221, 229 callosum), 83f sinuses (number not specified), 50, 51, 52, Rumelhart, David E., 187t 53, 55, 59, 61, 62, 63, 66, 144, 158, Ruska, Ernst, 187t 176, 220, 221, 227, 228, 233, 236 sklerotes, 164 saccades, 127, 129 skolekoeides, 131 saccadic movements, 129, 128f skull cavity, 216, 237, 238, 243 SAD. See seasonal affective disorder (SAD) sleep arteries, 52, 94, 143, 144, 152, SAD lamp, 122 153, 154, 179, 226, 229, 239, 241, schizophrenia, 78, 92, 101, 112 244, 255n69 Schleiden, Matthias Jakob, 197 smell, organ of, according to Vesalius, 158 Schneider, Conrad Victor, 147 Smith, Edwin, 68 Schwann, Theodor, 137, 186t, 197 Smith, Philip E., 150, 151f Scotus, 131 social network, brain as compared to, 185 Scoville, William, 113 Société d’Anthropologie, 73, 75 SD (spherical deconvolution), 209 sociogram, 187t seasonal affective disorder (SAD), 122 somatosensory cortex, 206 “seat of the mind,” ventricles as, 99 spatial representation, 91 “seat of the soul” speech center, 109 centrum ovale as, 85 speech localization, 73, 74 perhaps not in the brain at all, 86 Sperry, Roger, 90–91 pineal gland as, 83, 119, 193 sphenoid bone, 254n46 Second International Neurological spherical deconvolution (SD), 209 Congress (1935), 112 spinal reflex, 195 second sinus, 177, 179, 229 Spinoza, Baruch, 119 sectional anatomy, 99 “spirits,” belief in flow/passage of, 83, 99, seizures, 89, 113 101, 126, 134, 152–153, 154, 185, 189, sense organs, as subject of seventh book of 190f, 193 Fabrica, 27 Spitzka, Edward Anthony, 77f sensory inputs, 119f Spitzka, Edward Charles, 76, 77f sensus communis (common sense), cell, splenium (subdivision of corpus 48, 190f callosum), 83f septum, 51, 52, 53, 60, 61, 63, 80, 81, 82, 93, split-brain, 90, 90f, 91 95, 105, 173, 174–175, 220, 221, 224, Spurzheim, Johann Kaspar, 86, 92, 127, 225, 237, 239, 255n60 194–195, 195f, 254n45 Sergius, 258n144 staining methods, 139, 186t, 187t, 197, 198, sheep, experiments on, 49, 62, 63, 98, 116, 199, 202, 212 132, 135, 153, 154, 176, 177, 179 Steno, Nicolaus, 84, 191 Sherrington, Charles S., 186t stereotactic probes, 136 silver method (for staining nervous St Mark’s School of Medicine, 28 tissue), 199 Stoics, 45, 69 285 Index striae of Lancisi, 85–86, 85f Thomas, 131 Strogatz, Steven, 187t 3D reconstruction of brain, 77f stroke, 114, 122 ‘Throne of Saturn,’ 29f sulci, 58, 59, 68, 71f, 75, 77f, 78, 220 Tiepolo, Paolo, 37, 41 superficial cortex, 84 Titian, 19, 28, 29 superior cerebellar peduncle, 134f, 135, 139f touch, organ of, according to Vesalius, 170 superior colliculi, 126, 127, 129 Tourette syndrome. See Gilles de la superior sagittal sinus, 258n148 Tourette syndrome superresolution light microscopy, 212 Tournoux, Pierre, 187t supraoptic recess (of third ventricle), trabeculae of the arachnoid membrane, 256n74, 256n101 258n149 Swammerdam, Jan, 186t tracing methods, 91, 106, 187t Sylvester, James J., 186t tract of Vicq d’Azyr Sylvian fissure, 71, 71f, 194 (mammillothalamic), 108 Sylvius, Franciscus, 71 tractography, 83f, 91f, 92, 107f, 139f, 207f, Sylvius, Jacobus, 10, 11, 11f, 31, 35, 82 211, 212f symmetry, 254n43 transmitter receptor distribution, 210 synapses, 139, 186t, 199, 212 tree of life (arbor vitae), 133, 140 Treviranus, Gottfriend, 109 Tabulae Anatomicae Sex (Six anatomical Treviranus, Ludolph, 109 tables) (Vesalius), 16, 17f, 23, 108 Trilingual college, 8 tachiscopic visual presentation, 90 tumors Talairach, Jean, 187t brain tumor, 114 tapetum (subdivision of corpus pineal tumor, 148f callosum), 83f pituitary tumor, 148, 149 Tarin, Pierre, 126 tylloeides, 79, 255n56 taste, organ of, according to Vesalius, 169 tentorium cerebelli, 258n155 Ugolini, Gabriella, 187t terminology, challenges/limitations of, 211 uncinate, 186t Terminus, Matthaeus, 10 uncus, 255n70 testes of brain, according to Vesalius, Ungenannte Marksubstanz (unnamed white 47, 53, 60, 61, 62, 95, 96, 105, 116, matter) (Reil), 194 124–125, 126–130, 127f, 132, 142, Ungerleider, Leslie, 207f 176, 177, 254n31, 256n77, 256n91, unitary concept of cerebellar action, 135, 256n94 136, 137 testing methods, of Gazzaniga and University of Padua, 13 Sperry, 90 University of Paris, 10 testudo, 106, 107 uvea, 161, 162–164, 165, 181, 248, 250, 251 thalamus, 108, 112, 127, 146, 256n71 uveal tunic, 248, 250, 251 thin membrane, 54, 58–59, 219, 220, 221, 222, 223, 228, 229, 231, 232, 240, 247, 251 Valentin, Gabriel G., 186t third eye, 121 Valverde, 38 third sinus, 218, 220, 221, 229 Van Essen, David, 207f third ventricle, 46, 47, 48, 93, 94, 95, 96, van Hamme, Anne, 32 97, 104–105, 124, 125, 147, 176, 178, Varolio, Costanzo, 108, 134 221, 226, 227, 229, 230, 243, 256n74, vascular system, as subject of third book of 256n101 Fabrica, 26 286 Index vasopressin, 146f, 150 and Galen, 10–12, 16–18 Venesection Letter, 18, 20 on Galen’s teachings, 46, 53, 61, 64, Venice, Vesalius in, 28, 40 65, 67, 94–95, 97, 98, 101, 103, ventricle, third. See third ventricle 105, 116, 117, 131, 132, 134, 143, ventricles, in appendix figures, 222, 223, 144, 152–153, 161, 162, 167, 224, 226, 227, 228, 229, 230, 232, 179, 211 234, 235, 236 honors/gifts, 31–33 ventricular system, 99f, 101, 156, 189, 190f images/illustrations of, 4–5 ventricular theory, 69, 70, 99, 100, 101, 103, last three years of life, 40–44 134, 189, 191, 192–193 as man of his time, 3–6 ventriculography, 187t marriage of, 32 ventriculomegaly, 101 misfortunes of, 35–36 Venus (goddess), 254n35 mother of, 7 Vergleichende Lokalisationslehre in Padua, 13–15 der Großhirnrinde in ihren Paduan School of Anatomy, 13–15 Prinzipien dargestellt auf Grund in Paris, 10–12 des Zellenbaues (Comparative portraits of, 20f localization studies in the brain as professor of surgery, 13 cortex, its fundamentals represented as revisiting Galen’s opinions/identifying on the basis of its cellular factual errors, 17 architecture) (Brodmann), 202 scientific vision of, 18 vermis, 105, 131–132, 134, 190f, siblings of, 7 256n86, 256n97 in Spain, 37–39 vertigo, 136 as surgeon, 34–36 Vertunus, Narcissus Parthenopeus, in Venice, 28–30 16, 33, 35 works of Vesalius, Andreas Anatomicarum Observationum academic formation of, 4, 8–9, 10, 13 Gabrielis Fallopii Examen, 37, 38, 41 from anatomy to surgery, 34–36 De Humani Corporis Fabrica (On the anti-Galenic spirit of, 31 Fabric of the Human Body). See in Basel, 13 De Humani Corporis Fabrica (On belief in observation as direct source of the Fabric of the Human Body) knowledge, 4 (Vesalius) birth of, 3 Epitome, 22 in Brussels and Leuven, 7–9, 12 Paraphrasis In Nonum Librum celebrity status of, 32 Rhazae Medici Arabis, namely a childhood of, 7 commentary to the ninth book of criticism of, 4, 31 Rhazes, 12, 20 daughter of, 33 Tabulae Anatomicae sex (Six death of, 41–42 anatomical tables), 16, 17f, 23, 108 desire of to publish, 16 Vesalius, Andries (father), 7, 33 desolation of, 37–39 Vesalius, Anne (daughter), 33 as doctor of medicine, 13 Vesalius, Everard (grandfather), 7 as exploiting power of direct Vesalius, Franciscus (brother), 8 observation, 211 Vesalius, Isabella (mother), 7 family home, 8 Vesalius, Johannes (great grandfather), 7, 8 father of, 7, 33 Vesalius, Peter (great-great grandfather), 7 287 Index vestibular syndrome, 136 white matter, 82, 83, 84, 85, 112, 186t, 189, Vieussens, Raymond, 84–85, 186t, 192, 192f 191–192, 192f, 192, 194, 198, 199, virilism (in females), 148 199f, 200f, 202, 205, 209, 255n52, vision, 127. See also eye 255n55, 255n62 vis memorativa, cell, 190f white matter cutting, 112 visual processing, 129, 207f whole-brain maps, 202 vitreous humor, 160–161, 162, 164, 165, 166, Wiesel, Torsten, 187t, 206 167, 180, 247, 250 Wijtinck, former family name of Vesalius, 8 Vitruvius, Marcus, 106 Willis, Thomas, 5, 70, 71, 83–84, 101, 108, Vogel, Philip, 90 109f, 120, 134–135, 134f, 148, 155f, Vogt, Cecile, 187t, 203 157, 186t, 193 Vogt, Oskar, 187t, 203 Willis’s limbus, 108 Volta, Alessandro, 135 Winter, Robert, 13, 20 Vom Baue und Leben des Gehirns (Of the worm-like processes (cerebellar processes), structure and life of the brain) according to Vesalius, 131–132 (Burdach), 194 Wren, Christopher, 70f Vulcano (god), 254n35 writing center of Exner, 75, 200f

Wagner, Rudolph, 75 x-rays, 77 Waldeyer-Hartz, H., 186t xylography (wood cutting), 28 Waller, Augustus, 186t Wallerian degeneration of axons, 186t Yarbus, Alfred Lukyaovich, 127, 128, Watts, Duncan J., 187t 128f, 129 Weigert, Carl, 186t, 198 ymaginatio (visual sense), cell, 190f Wernicke, Carl, 5, 74, 75, 186t, 200f Wernicke’s area, 74, 77 zebrafish, experiments on, 213 Wesalia, former family name of Vesalius, 8 Zilles, Karl, 207 Wesl, Andreas de, 8f Zinn, Johann Gottfried, 86