Santiago Ramön y Cajal

Texture of the Nervous System of Man and the Vertebrates

Volume I

An annotated and edited translation of the original Spanish text with the additions of the French version by Pedro Pasik and Tauba Pasik

Springer-Verlag Wien GmbH Prof. em. Dr. Pedro Pasik Prof. em. Dr. Tauba Pasik Department of Neurology Mount Sinai School of Medicine New York, NY, USA

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© 1999 Springer-Verlag Wien Originally published by Springer-Verlag Wien New York in 1999 Softcover reprint of the hardcover 1st edition 1999

Typesetting: Thomson Press (India) Ltd., New Dehli

Cover design: B. Kollmann Printed on acid-free and chlorine-free bleached paper

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With 270 (partly coloured) Figures

ISBN 978-3-7091-7323-7 ISBN 978-3-7091-6435-8 (eBook) DOI 10.1007/978-3-7091-6435-8 TO THE MEMORY OF

JANOS (JOHN) SZENTAGOTHAI 1912-1994 FOREWORD

Most scientists agree that the 21st century will be the "Century of Biology". The revolution that started a few decades ago with the extraordinary develop­ ment of molecular biology, has provided the basis for the understanding of the mechanisms that govern life through the regulation of cell function and cell-to­ cell interactions. Neuroscience will surely be one of the biological disciplines that will profit the most from this revolution. Neuroscience comprises the study of the brain, and the more difficult relationship of brain and behavior. It is indeed a very broad field of investigation that, from molecular biology and genetics, passing through systems physiology, functional mapping of the brain, and even human behavior, has as the ultimate goal the understanding of how the brain works. The importance of this aim is immense, since it is the only scientific approach to understanding ourselves. Today, owing to the great progress made in neuroscientific research, there is a real hope that highly complex processes such as sensory perception, ICTlg­ term memory, learning and others will soon be comprehended in their entirety. This progress is timely to help in finding solutions to social and health problems emerging in our society from the growth of urban population density and its cohorts of stress and tensions, the increase in drug-addiction, the prolongation of longevity, etc. It is obvious that a better understanding of brain function, and therefore of ourselves, will improve the quality6f our life. In a sense, neuroscience can be viewed as ushering in a new humanism, ready to challenge the nature of human beings and their responsibilities. From Neuro­ science shall emerge a new vision of the world and of mankind within the world. The present revolution in Neuroscience has its roots in the work of Santiago Ramon y Cajal, who during almost half a century (1887-1934) of patient work was able to show that the nervous system is made up of billions of indepen­ dent, richly and precisely interconnected nerve cells. His studies on the architectural organization of the brain, and his prophetical predictions of its functions became the basis of neuroanatomy, neurophysiology, neuropathol­ ogy, and what he named as "rational psychology". This monumental work justifies his well deserved title of founder of modem Neuroscience. Of course, despite the outstanding accomplishments of Cajal, and his genius in unraveling the complexity of brain structure, the postulation and subsequent demonstration of the neuron doctrine, was not solely the result of his own viii Foreword investigation. As it always happens in Science, the contemporary knowledge in the field and the introduction of novel analytical and experimental methods greatly contributed to Cajal's achievements. During the second half of the 19th century, most investigators considered the nervous system as a huge syncitium, within which protoplasmic processes emerging from cell bodies, after breaking up into thinner branches, dissolved into a tight network that terminated by reconstituting the nerve fibers of the white matter. Investigators such as Wilhelm His in Germany and August Forel in Switzerland were the first to fight successfully the network, or reticularist, theory. W. His (1886), analyzing the early stage of nervous system development, was able to determine that embryonicaxons are a continuation of the first process emerging from postmitotic nerve cells, and that they grow from the free distal end of this process. Forel (1887) based his conclusions of Gudden's type of experiments by showing that, after axonal avulsion of motor cranial nerve roots, only those cells at the origin of the avulsed axons become atrophic. These observations gave indirect proof of the reciprocal trophic dependency between axons and their cell bodies. There is no doubt, however, and despite some recent unfounded attacks, that Cajal was crucial in solving the controversy about the way nerve cells communicate, and their processes terminate. Cajal's technical skills in modifying Camillo Golgi's silver stain (reazione nera), and in developing new metallic impregnation methods, as well as the successful use of the embryonic and degeneration approaches of his predecessors, provided the necessary tools for his discoveries. It is interest to recall that neuromorphologists are currently passing through a somewhat similar innovative period to that experienced by Cajal after Golgi's technical breakthrough in 1873. Thus, the longed-for wish to correlate the chemical constituents of the neuron with their structural counterparts, as a valuable approach to better appraise neuronal function and organization, is now a reality. In the last quarter of this century, great technological advances emerging from physics, chemistry and molecular biology, have revolutionized the field and breathed new life into the morphological approach. The main advances in histochemistry, which have made neuromorphology one of the most rapidly expanding fields in Neuroscience, can be summarized as follows: Histofiuorescent methods for studying monoaminergic systems, which opened up the new field of analysis of neuronal systems with identified neurotransmitters. Autoradiography and the diversity of its application, from tracing connections (axoplasmic transport), identifying neurotransmitters in neu­ rons (specific reuptake mechanisms), quantitative analysis of receptor­ binding and metabolic activity of neuronal networks, to in situ hybridization for the detection of messenger RNAs in order to study gene expression and regulation. Foreword ix

- Immunocytochemistry with its many uses, such as antibodies to study the morphological distribution of small (i.e. amino acid haptens) and large molecules. Among many important discoveries, it is noteworthy that this method was the basis for the concept of the co-localization of multiple neurotransmitters in the same neuron and axon terminal. Finally, advances in physical science and informatics have been extremely useful in generating new tools to study the organization, chemical composition and dynamics of the neuron. Hence, the development of computer-assisted image-analysis has greatly promoted quantitative studies that were impossible only a few years ago. For instance, the quantification of receptors distribution, and of metabolic activity of neurons in autoradiograms; three-dimensional morphometry of neuronal bodies and their dendrites in Golgi-stained or, better yet, in intracellularly injected neurons; analysis of somatodendritic gradients of neurotransmitter receptor-protein distribution, or synaptic density in immunofluorescent preparations analyzed with confocal microscopy, etc. In addition, new tools (video-enhanced contrast microscopy, and optical recording of neuronal activity, positron emission tomography (PET), and the newly generated functional magnetic resonance imaging (MRI) techniques have added a new temporal dimension to the morphological approach. Indeed, these non-invasive imaging techniques allow the investigator to examined the same neuronal populations over extended periods of time, and even to repeat the observations weeks, months or years later. In my view, although research and technical advances contemporary with Cajal were instrumental in carrying out his work, it was his analytical power and brilliant interpretations the sole responsible for his discoveries. We are in his debt for opening up this new era in the history of Neuroscience. The best evidence for my enthusiastic assertion is the validity of Cajal's opus magnum, the "Textura del Sistema Nervioso del Hombre y de los Vertebrados". This book, published in Madrid between 1899 and 1904, and its French translation by L. Azoulay in 1909 and 1911, has kept the attention of most neuroscientists for almost a century. It is still widely cited today, not much because of its historical value but for the accuracy of its descriptions of brain organization, and the present interest in the interpretations advanced therein. Just as an example, in 1892 Cajal published his first ideas on the "chemotactic hypothesis" in the article "La retine des vertebres" (La Cellule 9: 121-152; 1892). His main concern was to explain how developing or regenerating axons find their way toward their specific targets. This concept, renamed in the book "neurotropic hypothesis", was further elaborated for over 20 years of continuous work. Cajal assumed that the targets produced diffusible chemoattractant factors, to guide the arriving axons at a distance. However, since no evidence was found for the occurrence of such attracting substances, the hypothesis was abandoned in favor of Paul Weiss' "contact guidance" x Foreword theory (J Exp Zool 68: 393-448, 1934). Studies carried out during the last 10 years, however, have provided not only direct evidence for a chemotropic guidance of developing axons, but also of chemorepulse influences. Furthermore, a family of chemoattractant molecules, the netrins, was identified, and their genes have been cloned already. In this respect, the work of Marc Tessier-Lavigne and Thomas Jessell was essential for the molecular understanding of how developing commissural spinal axons are attracted to and cross the anterior commissure of the embryonic spinal cord. Modem cellular and molecular studies have revived the neurotropism of Cajal, and his figure 7 of the development of commissural spinal neurons (Anatomischer Anzeiger 5: 85-95, 1890) has been reproduced profusely. One major problem with Cajal's opus magnum is that it was published in Spanish. Although beautifully written, it was poorly understood by most scientists. Cajal himself was aware that Spanish was not the most favorable vehicle for scientific communication. His work, although universal, was addressed to the few scientists who could understand and discuss his inno­ vative ideas. For historical (the Spanish-American war) and cultural reasons, Cajal chose French as his scientific language. Since 1905, three years after starting his journal (Trabajos del Laboratorio de Investigaciones Biologicas de la Universidad de Madrid), most of his articles appeared in French. Moreover, Cajal had the good fortune that L. Azoulay, professor of Histology at the University of Paris and an excellent writer, volunteered to translate the Texutra. The only serious disadvantage was that Azoulay, probably due to a lack of familiarity with some of the subtleties of the Spanish language, introduced a number of errors, despite the fact that Cajal reviewed and updated this French translation. As stated above, the rapid and important current advances in Neuroscience producing great expectations for the forthcoming millennium, and the un­ relenting interest in Cajal's work mark the urgent need for the first English version of the "Textura del Sistema Nervioso del Hombre y de los Verte­ brados". This necessity is now fulfilled through the efforts of Pedro and Tauba Pasik, and their excellent version of Cajal's book. This remiition, avoiding the errors present in the French translation, reveals for the first time the entirety of Cajal's original ideas in the present universal language of Science. Pedro and Tauba Pasik meet all the requirements for this mammoth job. They are brilliant neuroscientists, and their work on the primate thalamus and basal ganglia, particularly that with the Golgi silver impregnation and derivatives, deserves to be considered as a continuation of Cajal's own "spirit". Moreover, Spanish is their mother tongue, they studied Anatomy from French textbooks, and English is their scientific language. This trilingual training offers the best guarantees for the optimal translation of Cajal's book. Moreover, their extensive knowledge of Neuroanatomy vouches for the scholarly treatment of some obscured points in their annotations. Finally, their strenuous efforts in Foreword xi providing an accurate list of references will be greatly appreciated by serious researchers interested in tracking original sources. We are indebted to Pedro and Tauba Pasik for making the original Textura, a treasure only accessible to a few of us, available to all neuroscientists. What an excellent homage to celebrate the first centennial of this book!

Paris, Spring 1997 Constantino Sotelo PRESENT A nON

On behalf of the Instituto Cajal and myself I have the pleasure to present this, I hope definitive, English version of Santiago Ramon y Cajal's opus magnum "Textura del Sistema N ervioso del Hombre y de los Vertebrados" . The "Textura" was originally published in two volumes by Nicolas Moya of Madrid in 1899 (Ist volume) and 1904 (2nd volume, in two parts) collating a number of monographs in which Cajal had published his results obtained in just fifteen years of intense and passionate work using the, at that time novel, Golgi method and silver impregnation techniques. The "Textura" became widely appreciated owing to Cajal's international reputation amongst leading authori­ ties of the day. Just a few years later, a French translation under the title "Histol­ ogie du Systeme Nerveux de I'Homme et des Vertebres" was prepared by Leon Azoulay, a brilliant man and a good friend in Cajal's own words. This trans­ lation was reviewed and updated by Cajal himself with new additions of text and drawings pertaining to his most recent findings. It was published by A. Maloine of Paris in 1909 (1st volume) and 1911 (second volume). Today, there is general acceptance that this was the starting point of modem neuroscience. The French "Histologie" of 1909-1911, which is considered the standard reference edition, was reprinted by the Instituto Cajal on the occasion of the centennial of its founder in 1952-1955. This edition appeared most timely as electron microscopy was able to show, for the first time, the existence of the synaptic gap; the most brilliant confirmation of the theory of the independence of neurons postulated many years back by Cajal. This edition was soon out of print, and a second reprinting was published in 1972. A facsimile of the "Textura" appeared recently, beautifully reproduced by colleagues at the University of Alicante. There is also an English translation by Neely and Larry Swanson from the French "Histologie" published by Oxford University Press in 1995. The present edition by Professors Tauba and Pedro Pasik is a translation from Spanish into English of "Textura" with additions from "Histologie", preserving Cajal's most direct literary style, which had been lost in the French edition. The present version also corrects a number of errors in the French edition that have persisted in subsequent re-impressions, most of which were apparently due to the lack of familiarity of the French translator with the subtleties of the Spanish language. The task of translating is certainly critical, and must be performed adhering to the spirit of the original. I remember a fellow, back in the early sixties, when I was at Harvard, trying to read a passage in Spanish of one of Cajal's descriptive techniques. He was trying to xiv Presentation grasp the meaning of " ... los resultados de esta reaccion saltan a la vista", translating this to " ... the results of this reaction jump to your eyes". As he asked me for help I could only translate this as " ... the results of this reaction are most evident"; the meaning was the same but flavor was lost. The job can only be undertaken by a Spanish speaking person who has a thorough command of English and a broad basis in Neuroscience. Not only have Professors Tauba and Pedro Pasik meet these special requirements at large, but both also have a dedicated reverence for Cajal's work and style. In his many literary and scientific writings, Cajal used a direct and exuberant language which even appears aggressive when dealing with specific points of interest or debate. In his own recollections, this particular writing style had a deliberate objective: to stir up the minds and convey to the readers the overwhelming excitement of discovery. It will suffice to mention the high praise offered by Cajal himself in the description of the Golgi technique which had such a profound impact at the beginning of my own career. I must confess that at present, when scientific papers run so telegraphically, and writing a contribution becomes a race against time and space, reading the scientific writings of Cajal in his own (and my own too) mother language is a relaxing pleasure. Since I am not native of an English speaking country, I will make an act of faith and believe that reading this new English version of the "Textura", carefully revised and annotated, will give my colleagues abroad the same rewarding bliss. There is another relevant point concerning the present edition which is no less important for being mentioned second. This is that in his faithful and precise delineation of structures of the nervous system Cajal was second to none. To make sense of the structures observed, he prepared many drawings to accompany his descriptions, sometimes schematic, sometimes complex, but always speaking for themselves. These drawings, which even today are accepted by some as executed with an excusable artistic license, are indeed faithful transcriptions of the reality and I can attest to this assertion. Examining preparations made by Cajal from the Cajal Museum, I had the feeling on several occasions that a page of "Textura" had been inadvertently slipped under the objective. Undoubtedly, the best tribute we can pay to our Master is to search for the most faithful reproduction of his many drawings and lament the quality of poor reproductions that I am sure have made Cajal tum over in his grave. As it will be seen, Tauba and Pedro Pasik accomplish this responsibility with great dedication since the majority of the figures are reproduced from the originals in order to obtain the highest quality. Those who love classics will agree with me that the same masterpiece sounds different depending on the performance. We now have found the best conductors and welcome having Cajal's text, in his own style, accessible to the scientific community in the universal language of Science.

Instituto CajaZ, Madrid, Spring 1997 Facundo Valverde PRESENTA nON

On occasion of Santiago Ramon y Cajal's death in 1934, Hugo Spatz, the neuropathologist from Munich, wrote: "Only very exceptionally, scientists meet such a fate as Cajal has been granted: he was one of the popular representatives of his nation; his name was and is known to all his countrymen. Cajal has become a national hero in his country ... How is it possible that Cajal attained so much celebrity? The reasons should be looked for in his personality." If Cajal's scientific achievements were of fundamental importance, it is no less interesting to approach his unique personality: He was not only the greatest explorer of the complex structure of the nervous system, but he also excelled in the art of drawing and painting, was a profound investigator of photographic technique, as well as a good writer. His autobiography and excellent literary pieces have made him known to the public outside Neurology. Presently, and for already many years, scientists of numerous countries have come to Petilla de Aragon, the small village where Cajal was born in 1852, eager to visit those places where he spent the first years of his life. This reflects the interest for knowing his life, in addition to his work. The 82 years of Ramon y Cajal's life coincided with the second half of the 19th century and the first third of the present century. During that time, scientists already worked in teams, laboratories were amply supplied with human resources and enough equipment. Cajal, however, realized his most important research working on his own, with no assistants, in a modest laboratory built in his own home, and defraying himself the expenses of his work. Only in 1900, after he was awarded the Moscow Prize in Paris, was it made available to him an official laboratory, the Laboratorio de Investigaciones Biologicas. This heroic work can only be understood if we take into account Cajal's extraordinary personality, which is so difficult to compare to that of any other scientist. Toward the end of the 19th century, when the various branches of human knowledge were being fostered, Spanish Science was very much behind. For centuries, only the arts and letters had been cultivated in Spain, and our contribution to the universal scientific knowledge had been minimal. It was in the dawning of the 19th century that Cajal's studies on the microscopic anatomy of the nervous system placed for the first time Spanish Science in the forefront. But Cajal did not locked himself in the solitude of his laboratory. He used his influence to orient the politicians of his country toward the necessary XVI Presentation reforms to overcome Spain's scientific and technical backwardness. His advice was heard, and led to the creation of the Junta de Ampliacion de Estudios (1907), which became the basis for the important Spanish cultural revival during the twenties and thirties. The "Textura del Sistema Nervioso del Hombre y de los Vertebrados" conti­ nues to be the most extensive and complete work on neurohistology published until today. It is, no doubt, the most important scientific book written in Spanish. For Cajal, this work published in 1904 after 10 years of preparation, "represented his trophy laid at the feet of the decayed national science, and the offer of fervent love given by a Spaniard to his underrated country." Today, almost 100 years after this first edition, the "Textura del Sistema Nervioso", having reached the category of a classic work, continues to evoke interest. The effort of the present translators, their zeal for preserving Cajal's original thoughts, and the usefulness of their annotations, will be rewarded with their contribution to make Cajal's work widely available, in a time when the English language allows the universal knowledge of all scientific endeavor. In this fashion, it will be possible to dissipate the concern that was always with Cajal, namely the fear that a large part of his research, and that of his disciples, would remain insufficiently known in the scientific world because of their publication in Spanish.

Saragossa, March 1997 Santiago Ramon y Cajal Junquera PREFACE

People throw stones only at the tree laden with fruit (Old Spanish proverb)

The aim of the present collection is to make available to the scientific community for the first time, the works and thoughts of Santiago Ramon y Cajal in a faithful rendition of the original Spanish version of the Texture of the Nervous System of Man and the Vertebrates. Cajal's opera magna, which we shall refer to hereinafter as the "Textura", was published in three books in 1897-1899 (Volume I) and 1904 (Volume II, Parts 1 and 2). The printing of separate fascicles was collected by the author over 10-15 years on subjects covering the entire field of Neuroscience as it was known then and, with few exceptions, as it is still known today. It was produced by his friend, Nicolas Moya, a bookseller in Madrid, and, as the story goes, was financed by Cajal himself at a net loss of 3,000 pesetas (about 530 dollars at the time). Conscious of the limited distribution of a book written in the Spanish language, little used by European researchers, Cajal induced his Parisian friend and colleague Leon Azoulay, to prepare a French translation. To this version, Cajal added certain subjects that became known after. the Spanish publication. In fact, Azoulay's translation, entitled Histology of the Nervous System (referred hereinafter as the "Histologie"), appeared in 1909 and 1911, and in the 7-10 years between the two versions, important advances took place in the field, justifying the updating of the French version by the author. Thus, the French edition, reprinted three times, became the "classic Cajal", quoted almost 200 times yeady in the scientific literature (Scientific Citation Index, 1990-1995). It was through a consultation by Louis Poirier, the Canadian neuroanato­ mist, on a point of reference in the Chapter on the Pons, and our own work on the Striatum, that we first became aware of a number of inconsistencies in the Histologie. This were due in part to misinterpretations of subtleties in the Spanish language, i.e. direct mistranslations, and in part to perpetuating errors that had appeared in the Textura, which had already been anticipated by Cajal in his original Preface. Thus, the idea of producing a translation directly from the original Textura came to mind, and received invaluable encouragement from one of the most distinguished Cajalians of our times, the late Janos Szentagothai. Such a translation would also contain annotations interpreting xviii Preface certain structures described by Cajal that are not known by his designations in present day Neuroanatomy. There have been numerous attempts to write about Cajal's life and accom­ plishments both by friend and foe. Most of them, however, have been authored by people who never knew him personally, and drew from his extensive auto­ biography, and were therefore tainted by what he wrote about himself, representing feelings about his research over a quarter of a century after the fact (Cajal, 1923). Biographies by writers living in Cajal's milieu, who had frequent personal contacts are the best sources, but unfortunately they are only available in Spanish (Cortezo, 1922; Gimeno, 1934; Juarros, 1935; Lafora, 1935). It is outside the purview of this preface to recount at length the romantic story of a boy painting from Nature and museum art works, turned successively from youth gang leader, apprentice barber and cobbler, medical student, army surgeon in Cuba, faculty member of the Universities of Saragossa, Valencia (where he was more of a chess master than a scientist), and finally professor of histology and pathological anatomy at the Universities of Barcelona and Madrid. It was during his Barcelona years (1887-1892) that Cajal produced the bulk of the work reported in the Textura, which took his first dozen years in Madrid to write and illustrate, a formidable task indeed! The following Table gives the chronology of events in Cajal's life between 1887 and 1911, i.e. the period from the start of the work reported in Textura to the publication of the last volume of the Histologie.

Chronological Table

(Period when Cajal worked on, and/or wrote the Textura, and the additions III the Histologie) 1887 Moved to Barcelona Visited Simarro, temporarily in Madrid, where he first observed Golgi stains 1888 Gave up chess, his almost obsessive undertaking in Valencia Applied the Golgi method to embryos of birds and small mammals Studied the cerebellar cortex and discovered basket cells and mossy fibers axons of granule cells becoming parallel fibers climbing fibers (basis of the law of transmission by contact) Published seven articles with own lithographs in his own Revista Trimestral de Histologfa Normal y Patol6gica 1889 Realized that his articles were ignored because they were published in Spanish. Then: Translated papers into French and published them in German journals Travelled to the Berlin Congress of German anatomists Stopped at Frankfurt where he met Weigert, Edinger and Ehrlich Kolliker discovered Cajal at the meeting, and eventually learned Spanish to translate Cajal Preface xix

Met Retzius, His, Waldeyer, Van Gehuchten In Gottingen, met Krause In Pavia, failed to see Golgi who was in Rome Published a "Textbook of Histology and Micrographic Technique" Studied the cerebellum, retina and spinal cord 1890 Continued these studies More neuroembryology: the growth cone Published a "Textbook of General Pathology" 1891 First formal presentation of the neuron doctrine published in Revista de Ciencias Medicas de Barcelona Law of dynamic polarization Considered to have enough material for a book 1892 New article in Rev Cienc Med Barcelona. This and the previous one translated into several languages (German by Held; French by Azoulay) Widespread acceptance of the neuron doctrine Decided to put all in one volume:

the future Textura which took 12 more years to complete

Moved to Madrid in April Neurotropic theory Major work on the retina translated into French 1893 Major work on the hippocampus and the inferior occipital cortex translated into German by Kolliker 1894 Trip to the UK to deliver the Croonian lecture on the Fine Strucutre of the Nervous System Theoretical presentation on the law of economy of space, time and matter at the International Medical Congress in Rome 1895 More studies on the medulla, pons and cerebellum Plasticity: formation of new processes and connections through training and adaptation Avalanche of conduction 1896 Proof of contact and not fusion of processes in the retina Repeated all work on the spinal cord, cerebrum, cerebellum and hippocampus with the Ehrlich methylene blue method, confirming his results with the Golgi method Started the Revista Trimestral Micrognifica 1897 Became Academician Rational bases and technical conditions for biologic research. (Later published as Rules and Advices for Biologic Research) Numerous prizes and honorary memberships Discovered short axon neurons in the cerebral cortex

First installment of Textura

1898 April to August: Spanish-American war Entered the political forum of the Regeneration movement Confirmed the hernidecussation of optic nerve fibers in the chiasm, and offered hypothesis on its significance Started studies on the cerebral cortex, circumventing regulations to obtain brains of infants and fetuses in the almost immediate postmortem period xx Preface

1899 Described cortical interneurons and their increase on ascending the phylogenetic scale, attaining the highest number in humans Visit to the US for the Clark University Decennial Celebration

Volume I of Textura is published

1900 Moscow Prize at the 13th International Medical Congress in Paris Many honors (Grand Crosses, etc.) Became Director of the National Hygiene Institute Continued studies on the cerebral cortex 1901 Became director of the newly created Laboratory of Biologic Research, for the first time well equipped and funded Rev Trim Microgr becomes the Trabajos del Laboratorio de Investigaciones Biologicas de la Universidad de Madrid More on the cerebral cortex and significance of short axon cells Published "Memories of my Life. My infancy and Youth" 1902 Works on septal nuclei, inferior colliculus, medial geniculate body, thalamus and sensory pathways 1903 Vacationing in Italy during which trip he came up with the idea of the reduced silver nitrate method Many publications, particularly on the thalamus, visual pathways, and application of the new method Critique of Bethe's theory regarding the structure and connections of nerve cells 1904 Peak year of scientific productivity: fifteen articles mostly on neurofibrils architecture

Culmination with the final Volume II, Part 1 and 2 of the Textura

1905 Works on adult sensory and sympathetic ganglia and the effect of aging Helmholtz medal and more honors Published "Holidays Stories (Pseudoscientific Narratives)" 1906 Bethe's revival of the reticular theory Final rebuttal by Cajal on the basis of nerve regeneration after lesions Nobel Prize in Physiology and Medicine Refused twice the offer to become Minister of Education 1907 Credited His and Forel specifically for the neuron theory Rebuttal of the Hensen-Held neurogenetic hypothesis with new observations 1908 Studies on nerve regeneration Rebuttal of Apathy's continuity hypothesis Described the interstitial nucleus of the posterior (medial) longitudinal fasciculus (nucleus of Cajal) Chemotaxis in the genesis and evolution of the nervous system 1909 Volume I of the Histologie is published More on the medulla and midbrain 1910 Observations supporting the neurotropic hypothesis Technical improvements of the reduced silver nitrate method More on regeneration 1911 Volume II of the Histologie is published Studies on neuronal degeneration This period of Cajal's life coincided with troublesome times in Spain, a country of about 17-18 million people, because they were marked by dramatic Preface xxi

events. The king Alfonso XII died in 1885. His wife, Maria Cristina acted as Queen-Regent until 1902, when their son became king, Alfonso XIII. The first part of this period belongs to what is known as the Restoration, which extended from the end ofthe short-lived First Republic in 1873 to the Spanish-American war in 1898. It was dominated by a conservative politician, Antonio Canovas del Castillo, whose governing principles were to exclude the Army from political power, and a deep distrust for free elections which would have returned a Radical, mostly Republican, majority to Parliament. An agreement was cast for alternating conservative and liberal governments with the only significant difference between the two being that the latter were anti -clerical and more interested in education. Thus, in 1885, Pnixedes Sagasta, a liberal, formed a "new" government at the death of Alfonso XII. Most of Cajal's work on the Textura was made during the Regency. His stay in Barcelona coincided with a resurgence of Catalan nationalism induced by this city becoming the center of Spanish industrialism. At the same time, the anarchist movement became entrenched, turned increasingly toward terrorism, which exploded in Barcelona just as Cajal left for Madrid, with attempts of political assassinations as well as bombing of public places. It culminated with the killing of Premier Canovas in 1897. The period ended with the Spanish-American war. The words of Henry Cab,ot Lodge Sr. point to a significant antecedent. "The sinister influence of slavery led the United States to hold Cuba under the yoke of Spain, because free Negroes were not to be permitted to exist upon an island so near their Atlantic coast" (Cabot Lodge Sr., 1899). The US therefore helped suppress all attempts at Cuban independence until the Civil War, and began supporting revolutionary movements thereafter. Cajal, as a drafted military physician participated in defending the Spanish claims in Cuba, and barely escaped death from malaria and tuberculosis in 1878. A final Cuban insurrection started in 1895, under the leadership of Jose Marti, and swept almost the entire island. From then on, it was progressively downhill for Spanish power. Ferocious repression finally rouse American public opinion through the Hearst's press­ engendered furor. Under President McKinley, and the expansionist (imperi­ alist) influence of Captain Mahan, who considered Cuba vital to the strategic defense of the future Panama canal, the US recognized the belligerency of Cuba. The situation deteriorated further under Prime Minister Sagasta, when the US sent a battleship to Havana to protect Americans there. It blew up under mysterious circumstances, and two months later it was war. It ended after eight months with the defeat of Spain and the loss of colonial Spanish power (in Cuba, Puerto Rico and The Philippines), except for the Mediterranean strip of Morocco which, forced upon Spain by the combined European powers, remained a constant drain of resources both human and financial. The defeat gave rise to a general pessimism in Spain, leading to apathy in every intellectual endeavor. This attitude slowly but surely was replaced by a XXll Preface so-called "active pessimism" that attempted to overcome the morass. The resulting so-called Regeneration movement included outstanding writers, artists and, of course, was joined by Cajal. Their action was centered at El Ateneo de Madrid, which, even in the most reactionary periods, represented a place where everyone was allowed to exercise maximum freedom of expression. Scientific studies were poorly developed in Spain during this period since the emphasis was placed by government and people alike on the humanities. Yet, there were individual cases of exceptionally endowed selfmade scientists, but of no particular school, motivation or government support. Cajal was indeed the greatest but he remained largely unknown. It is surprising that even in the 1940s he was still ignored by such distinguished historians as Altamira (1945), who cites Oloriz and Simarro, contemporaries and even friends of Cajal, but not Cajal. Another revealing aspect of the Spanish milieu at the time was the widely rampant fanaticism and irrational beliefs present in the last decades of the century, with renewed trials by clerics and exorcists to combat the "evils's eye". A notable reaction against this backwardness was a most famous zarzuela, "La Bruja" (The Witch), premiered at the end of 1897 with music by Ruperto Chapi, who was a major contributor to elevating the autoctonous Spanish zarzuela to a recognized musical form. The lyrics by Ramos Carrion, an exponent of the so-called Theater of Protest, featured a biting satire about witchcraft, finally declaring the end of intolerance and superstition in Spain. The magnificent Parque del Retiro in Madrid hosts statues by the same sculptor, Victorio Macho, of both Cajal and Chapi, dedicated by students and faculty colleagues for the former, and the Authors Guild for the latter. The preceding paragraphs are intended to give a glimpse of the environment where Cajal developed his Opera magna, and suggest possible reasons for the apparently major motivation of his efforts, namely his love of country and his unrelenting striving to pull it out of its omnipresent quagmire. It is remarkable that this sense of patriotic endeavor is still present in our times in spite of the generalized "brain drain" characteristic of developing nations from where scientists are almost magnetically drawn to developed countries offering both the environment and resources to fulfill their goals. Two clear examples were the Argentinean Eduardo De Robertis and the Hungarian Janos Szentagothai, both deceased, who refused extremely attractive offers to leave their respective countries even at times of dangerous political turmoil. References to Cajal's scientific contributions are plentiful and occasionally debatable as befitting scientific discourse (see below). His personality, however, was often discussed against the background of the opinion of himself as expressed in his autobiography, which has misled some of the "new prophets" of Science, to use rather nasty epithets on addressing this issue. Our previously mentioned preference for considering the thoughts of people that Preface xxiii

had direct contact with Cajal gave a more convincing picture, drawn from writings and journalistic sources of the time by, among others, Charles Sherrington, Gregorio Marafion, Galo Leoz, F. Tello Valdivieso (son of Jorge F. Tello, Cajal's successor as chairman of Histology, Pathological Anatomy and Microbiology at the University of Madrid), and Luis Ramon y Cajal, the youngest of Cajal's seven children, who had the longest opportunity to share the daily life of his father. Cajal was consistently described as affectionate and fun-loving, a great conversationalist, with an almost encyclopedic knowledge of many subjects, accompanied by a fine sense of humor, in spite of his always adopting a stem tone of voice. Every Sunday he used to take wife and children to the, presently non-existent, Cafe Suizo for coffee and cakes. During vacations at one or other of their country homes he taught chess to the younger children, while the oldest daughters modeled for him in colorful shawls for color photography on plates that he himself produced. He delighted in the singing of the children which he recorded in "cylinders" brought from the U.S. Examples of his tenderness abound, and just to mention one, he took the five year-old son of a close collaborator for a snack. Cajal's total lack of vanity was recognized by all who knew him. These opinions may be contrasted with some interpretations of claims found in the autobiography. Interpretations of statements can be as varied as the inter­ preters, and some of Cajal's hyperbole must be understood in terms of the feelings of a Spaniard, almost a century ago, in a country being scathingly considered as the North of Africa instead of a part of Europe, his anguished desire to show the World that also in Spain Science could flourish, and at the highest level, and his need to shout it so that people would hear it; and indeed they did. Indications of his modesty were his declining nobility titles including the creation of a duchy for him by the king Alfonso XIII, as well the Ministry of Education under the liberal government of Moret. He did accept, however, the presidency of the Junta de Ampliacion de Estudios with no remuneration, as well as the appointment of life senator, also gratis, following the European tradition of giving such posts to prominent people in the arts and sciences. He voted consistently in support of the liberal Prime Minister Canalejas, although he never identified with any political party. His rigorous ethics and courage extended to social issues. His intervention in favor of Giuseppe Levi, unjustly incarcerated in Italy for an alleged antifascist plot, is now well known. His humility extended after his death, with his request to have a secular, private burial with the expressed wish that his remains never be transferred to the special grounds reserved for illustrious people. Finally, his generosity had no limits, both to his family, as well as to disciples and friends, particularly once his financial situation improved upon obtaining the Chair in Valencia. It is worth noting that he legated the entire proceeds of his Nobel Prize to the Academy of Sciences for fellowships and prizes to medical students. xxiv Preface

The present version

The Text.-In rendering literary works in another language, the translator is always faced with the dilemma of a literal versus a sense-to-sense version. Whereas the latter approach is optimal for forms like poetry, it becomes risky and even dangerous in scientific works where it necessarily implies at least a certain degree of interpretative reasoning. Following our stated goals, therefore, we elected to translate the original Textura adhering as much as possible to the letter of the text. This choice has the additional advantage of preserving Cajal's sometimes exuberant style, including certain carelessness to some details, such as keeping the uniformity of headings, as if his only com­ pulsion was for fundamental details. In other words, great care of the essence, little of the form. Perhaps the only license we took was to split excessively long sentences, which would make reading them in English rather awkward, and to correct obvious errors already predicted by Cajal in his Preface. Additions from the Histologie.-We then proceeded to compare carefully the Textura with the Histologie which, although occasionally easier to read and at times better organized, is clearly not in Cajal's style. It also contains a number of new errors. One can readily understand the commission of some inaccuracies in translating into French some nuances of the Spanish language which may have escaped Cajal's proof-reading, if it ever took place. Moreover, Cajal's French was "sadly imperfect" and "driven to its utmost limit or beyond" (Sherrington, 1949), at least during his visit to England to deliver the Croonian lecture in 1894. We disregarded the new style, in fact Azoulay's, and concentrated on factual additions which amounted to about 15% over the original Volume I of Textura, and are indicated in the text by brackets. They fell into several categories. (1) New findings made after the publication of Textura, which essentially concerned the discovery of neurofibrils, duly credited to Bethe, and the extensive results of Cajal on this subject using his newly developed technique of reduced silver nitrate, the so-called transparent stain, as opposed to the opaque profiles of the Golgi method. (2) All references after 1896-97 on new as well as past subjects. (3) Issues on which Cajal changed his mind in the interim between Textura and Histologie. Special attention to these instances is given in the corres­ ponding annotations (see below). Nomenclature.-We encountered several classes of nomenclature problems. (1) Few present day investigators, particularly younger generations, are familiar with eponym designations such as the fascicles of Goll, Burdach or Flechsig. We replaced them by the contemporary scientific English naming, which in these examples are fasciculus gracilis, fasciculus cuneatus and dorsal spinocerebellar tract. (2) Some structures have been known in the English scientific literature with different descriptive terms, and the equivalence is more commonly known. Preface xxv

Example: superior colliculus for anterior quadrigeminal tubercle. Others are less familiar, such as "nucleo del techo" or "noyaux du toit" (Histologie, Vol I, p. 182) equivalent to fastigial nucleus of the cerebellum, and sometimes misinterpreted as tectal nuclei. To the same category belong certain disease designations such as "zona" (Histologie Vol I, p. 228) which in fact is a synonym of herpes zoster. (3) Finally, there are structures, either with eponyms or not, that do not have a direct equivalent in present day Neuroanatomy. Examples: the fascicle of Gowers, which is actually a composite of at least the ventral spinocerebellar tract and the lateral spinothalamic tract; the dorsal hom bundle that may be just a part of the fasciculi proprii of the lateral funiculus. These issues are discussed in more detail in the corresponding annotations. Annotations.-The annotations, indicated in the text and legends for figures by lower case superscripts and appearing at the end of each chapter, are our personal views on various topics that merit comments. They include, among others, Cajal's changing concepts over time; attempts to elucidate the meaning of certain descriptions that do not have present day equivalents, such as the "nucleus of giant cells" (Textura, Vol. II, p. 786; Histologie, Vol II, p. 512) in the corpus striatum which Cajal properly treated as a separate entity from the globus pallidus. Annotations include also explanations of symbols appearing in illustrations but not mentioned in the corresponding original legends. Illustrations.-The majority of the figures were reproduced from Cajal's original art work, still extant at the Museum of the Instituto Cajal in Madrid. Some of them exhibit the rubber stamp and catalogue number of the Museum, the remainder was obtained from the Textura and! or the Histologie. The final illustrations include all figures appearing in the Textura, some of which are not found in the Histologie. Most of the additions from the Histologie are from results obtained using the reduced silver nitrate method. Several figures appear more than once in the Textura and Histologie. The repeats were deleted from the present version. A list of present figure numbers with their equivalents in the Textura and Histologie is given in Appendix I. References.-The style of quoting references has been adapted to modem standards by author and year in the text, and a complete alphabetical list at the end of the volume. The accuracy of most of them has been verified against original publications which revealed a rather disturbing proportion of errors in the year and/or volume of the periodicals, and even in the referred journals themselves. Completion of the paging in both periodicals and books was also included as well as publishers and city in the latter. In sum, the bibliography is now, for the most part, uniform and according to contemporary standards, and thus may facilitate searches by interested investigators. Unverified references amounted to less than 5% and are indicated in the list by asterisks. Special attention is called to the style in quoting Cajal, whom some purists correctly refer to as Ramon y Cajal. We chose to adhere to the obvious wishes of Don Santiago who quoted himself as Cajal, i.e. the family name of his XXVI Preface mother. There are several stories and/or opinions about such a choice. We should like to offer a partial transcript on this matter by Cajal himself, taken from his Charlas de Caje, which also appears in a small, less known, book entitled La Mujer: "In these times of effervescent and militant feminism, I am amazed that women do not fight for themselves and their children for the right of, not only rejecting the husband's family name, but bearing first the maternal name. Here are some biologic reasons for such a right. 1st. The mother contributes an enormously grater amount of protoplasm than the father at the time of pro­ creation. 2nd. Since the mother is fully responsible for the nutrition of the fetus and nursing of the infant, it is impossible not to accept-even disregarding the material process of growth-that a good part of her chemical and cellular architecture is transmitted to the offspring. 3rd. According to the above, the child, particularly if very talented, is often more like the mother than the father. I am not negating, however, the possibility of the reverse phenomenon, nor the combination in variable proportions of characteristics of both parents. 4th. It is not infrequent in the animal series the occurrence of natural or experimental parthenogenesis, i.e. procreation without a father but never without a mother. 5th. Such an effect has been obtained in amphibians and other vertebrates by inducing the penetration into the ovum of seminal cells rendered without chromosomes (genetic material), either by means of radiation or using mere chemical substances". (Cajal, 1932, pp. 169-173). Apparently this tradition was followed by at least one of his children, Jorge, who published his own neuroanatomical work under Fafiamis, the maternal family name (recall the Fafianas cell of the cerebellum). Taxonomy.-An effort was made to identify the various animals species (and one plant in Vol I) appearing in the text, with present scientific names, as well as their colloquial English counterparts. A glossary of equivalents terms of Cajal's designations is given in Appendix II. Subject Index.-A full index will appear at the end of Volume III, and will include equivalent designations of contemporary terms and Cajal's nomen­ clature.

Challenges to Cajal and his contributions

In the last few years there have been some attempts to the so-called demys­ tification of Cajal, first crediting others with his discoveries, and then challenging two of his basic tenets, namely the neuron doctrine and the law of dynamic polarization. Nothing could be more unjust than to question Cajal's fundamental enunciation of the neuron as the unit of the nervous system from the multiple viewpoint of its embryologic, morphologic, functional and metabolic nature. It is true that His and Forel, and perhaps Nansen, preceded Cajal in bringing forward the idea of the neuron as a unit, and this was indeed painstakingly Preface xxvii

acknowledged by Cajal in the Textura. But where were these scientists when the neuron doctrine was attacked, not just by the reticularists of the Gerlach­ Golgi type, but by the neoreticularists of the Bethe-Held-Apathy sort? It is quite clear that to come up with and idea, even though based on a solid finding, is not enough for its recognition and adoption by the scientific community. It not only needs verification with accumulation of new supporting facts, but the courage and fighting spirit of Cajal to make it accepted, thus becoming the guiding principle for the entire field of Neuroscience during at least the ensuing three quarters of a century. The battle was long-lasting indeed, and the last skirmish possibly took place at the time around Cajal's death on the grounds of autonomic nerve terminals, the neurofibrils of which were claimed to invade other cells, mainly Schwann elements (Boeke, 1933). In fact, this issue became the subject of Cajal's last publication (Cajal, 1934). It was in the same Boeke's preparation, namely the rodent iris, that Szentagothai (then Schimert) (1936) demonstrated with silver impregnation of degenerated fibers, that the so-called neurofibrils were in fact axons present within invaginations of the Schwann cell membrane. Challenges to the neuron doctrine and the law of dynamic polarization, are based on the discovery of gap junctions between some neurons, and particularly glial cells, and the dye-coupling phenomenon; the occurrence of dendrodendritic, and for that matter somatodendritic synapses; the existence of at least two types of physiologic activity, namely the all-or-none brief action potentials and the more prolonged graded potentials; and even the possibility that some dendrites may conduct the nerve impulse away from the cell body and the axon. Although these facts appear to deviate from Cajal's tenets, the discrepancies may be more apparent than real since they reflect different organizational strata, as brilliantly expressed by Shepherd (1991, p. 291) when stating that the neuron "contains several levels of local subunits, and is itself a part of larger multineuronal unit". On these terms, the demanded revisions of Cajal's tenets do not detract from the basic ideas, just as Einstein's theories do not invalidate Newtonian mathematics, and the recent findings of Dicke, and of Preskill and Thorne do not disprove Einstein's. Indeed, there is no danger to the progress of Science in revering Newton, Einstein and Cajal. We are offering here accessible means for the reader to form his or her own opinions about Cajal's discoveries and his provocative thoughts, as well as to appreciate the incredible wealth of factual information on practically every structure of the central nervous system.

Acknowledgments

We are indebted to several individuals and institutions for the advice, help and support of various phases of this work, and are especially pleased to identify some by name. First and foremost, our dear friend Janos Szentagothai for providing inspiration, encouragement and fruitful discussions in the planning xxviii Preface stages. It is most unfortunate that his untimely death robbed us of the pleasure of seeing his twinkling eyes expressing his excitement for the work accomplished. Jose Valciukas, our first graduate student and a veteran in book writing, for sharing with us his expertise in preparing the book proposal and his interest in the work in progress. Josefina Cano and Alberto Machado for their help in locating and reproducing the original Textura before the facsimile published by the University of Alicante became available. Maria Angeles and Santiago Ramon y Cajal Junquera, who as Cajal's heirs, gave their approval and generous authorization for the present version, as well as for providing a wealth of information about Cajal, and current controversial issues regarding the great man. The Instituto Cajal of the Consejo Superior de Investigaciones Cientificas, and particularly its Director at the time, Alberto Fernis, who enthusiastically supported our intention and placed at our disposal the facilities and materials of the Institute. The long hours spent at the Museum and Library allowed us to identify and find the majority of Cajal's original art work, as well as the few drawings by Tello which appear in the Textura and Histologie. The skillful assistance of Maria Angustias Perez de Tudela in this enterprise, and in locating obscure references, was invaluable. We could not have succeeded without her profound knowledge of Cajal's work and her loving care in preserving and cataloguing the material. The rich collections of the Library of the New York Academy of Medicine, the Research Library of the American Museum of Natural History, and the Gustave L. Levy Library of the Mount Sinai School of Medicine were the main sources of our bibliographic research. We are indeed grateful for the time dedicated by their respective personnel in facilitating our work. Our editors and publishers, Rudolf Siegle and Raimund Petri-Wieder of Springer-Verlag Wien New York grasped from the very beginning the impor­ tance of the work, and committed themselves to producing the highest quality product available. We rest confident of their assurance. Special thanks are due to Constantino Sotelo, Facundo Valverde and Santiago Ramon y Cajal Junquera for their unselfish contributions, and the kind words appearing in the Foreword and Presentations. Our recognition also extends to the various divisions of the National Institutes of Health (NIMH, NEI and NINCDS) for having supported our research uninterruptedly during almost 35 years. Finally, we are grateful to our children and grandchildren for their loving understanding of our taking time, that belonged to them, for this work, and singularly to Alexander Pasik, for guiding us in the intricate field of computer­ assisted desk publishing. Without his help we could not have completed the work in the required time.

New York, Spring 1997 Pedro Pasik and Tauba Pasik Preface XXIX

References

Altamira R (1988) Historia de la civilizacion espanola. Critic a, Barcelona, pp 326 (from unpublished version of 1945) Boeke J (1933) Innervationsstudien. III. Die Nervenversorgung des M. Ciliaris und des M. sphincter iridis bei Saugem und Vogeln. Ein Beispiel plexiformer Innervation der Muskelfasem. Z mikrosk anat Forsch 33: 233-275 Cabot Lodge Sr H (1899) The war with Spain. Harper, New York London, pp 276 Cajal SRy (1923) II. Historia de mi labor scientifica. In: Recuerdos de mi vida. Pueyo, Madrid, pp 444 Cajal SRy (1932) La mujer. Aguilar, Madrid, pp 175 Cajal SRy (1934) Die Neuronenlehre und die periterminalen Netze. Boeke's Arch Psychiat Nervenkrankh 102: 322-332 Cortezo CM (1922) Cajal; su personalidad, su obra, su escuela. Trodoxo, Madrid, pp 250 Gimeno A (1934) Santiago Ramon y Cajal. Bo) Acad Espafi: 7-18 Juarros C (1935) Ramon y Cajal-vida y milagros de un sabio. Nuestra Raza, Madrid, pp 187 Lafora GR (1935) La inftuencia de la personalidad y del canicter de Cajal sobre su obra. Tierra Firme, Madrid, pp 31-54 Schimert (Szentagothai) J (1936) Untersuchungen tiber den Ursprung und die Endausbrei­ tung der Nerven der Iris. Z Zellforsch mikrosk Anat 25: 247-258 Scientific Citation Index (1990-1995) Institute for Scientific Information, Philadelphia Shepherd G (1991) Foundations of the neuron doctrine. Oxford University Press, New York Oxford, pp 338 Sherrington C (1949) A memoir of Dr. Cajal. In: Cannon OF (ed) Explorer of the human mind. Schuman, New York, pp ix-xv TEXTURA DEL S[STEMA NERVIOSO

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ESTU DIOS SOBRE EL PLAN ESTRUCTURAL Y COMPOSIC16N HISTOL6GlCA DE LOS CENTROS NERVIOSOS ADICIONADOS DE CONSIDERACIONES I~ISIOL6GICAS }j'UNDA DAS EN LOS NUEVOS DESCUBRIMIENTOS

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Catedratico de Histoiogi8o en 180 Universid80d de Madrid.

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Oarrclas, 8, 11 Gurcilusu J 6.

1899 TEXTURE OF THE NERVOUS SYSTEM

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STUDIES ON THE STRUCTURAL PLAN AND HISTOLOGIC COMPOSITION OF THE NEURAL CENTERS WITH PHYSIOLOGIC CONSIDERATIONS BASED ON NEW DISCOVERIES

BY

s. RAMON CAJAL

Professor of Histology of the University of Madrid

With numerous black and white and color illustrations

Volume I

MADRID PRINT SHOP AND BOOKSTORE OF NICOLAS MOYA Carrelas, 8, and Garcilaso, 6

1899 PREFACE

The book we present today to the medical public is the result of personal investigations. We give in summary form, but with the necessary detail, the entire substantial content of our numerous articles (over 80) on the fine struc­ ture of the nervous system. We have included the results of our students Pedro Ramon, Cl. Sala, C. Calleja, R. Terrazas, I. La Villa, F. Oloriz Aguilera and others. These studies are little known because they appeared almost exclusively in Spanish journals scarcely distributed abroad. Needless to say, we have tried to reflect also the present state of neurological science, expounding with the required detail the important conquests realized outside Spain during the last decade. The title of the book relates to its content. Our purpose has not been to produce a new treatise of Neurology, mostly macroscopic, along the lines of the excellent ones by Schwalbe, Obersteiner, Edinger and Van Gehuchten. Instead, the goal was to write a book from the point of view of the texture, essentially cytological and histological, including the infinite details of cellular form and structure that can be found today only in special monographs. The book by Kolliker (1896), and the well thought and written monograph on the spinal cord by Lenhossek (1895b) follow the same criterion. These works, however, although of great merit, do not fulfill our program, because the former is rather meager in detail and succinct in many of its chapters, and the latter includes only the neuron theory and the structure of the spinal cord. As a consequence of this plan, that excludes to a great extent the macros­ copic anatomy, the reader must approach our book with sufficient preparation in descriptive neurology, and most of all, with de visu knowledge of the internal and external configuration of the neuraxis. Nevertheless, avoiding rigid criteria that could be detrimental to clarity, we give also a summary of the external configuration and gross structure as derived from the examination of macroscopic sections, on subjects where these features are needed for the understanding of the microscopy, for example the medulla, pons, colliculi, etc. The microscopic anatomy of the nervous system is presently in a state of renewal from the double standpoint of facts and doctrine. Precise, positive, easy to confirm observations have followed imperfect descriptions based on fallacious methods. And quite daring conjectures, developed less on the basis of facts than by imposition of foreign disciplines such as physiology and pathology, have been superseded by more satisfactory theories, evolved from direct examination of Nature under the bright light of research procedures of great differentiating power. These methods reduce to a minimum the subjective xxxiv Preface factor which, being an inseparable companion of all observations, is the origin of infinite number of errors. Books that appeared in this period, so pregnant with criticism and renovation, are usually fortunate, although they may not be of extraordinary merit. This has happened with our modest work of 1894, New ideas on the structure of the nervous system, which went rapidly out of print in its Spanish and German editions as well as two successive printings of Dr. Azoulay's excellent French version. The present work represents a considerable expansion of this first outline. In addition to the mentioned reasons, we were encouraged by the success of that first attempt at systematization, the truly undeserved favor with which distinguished investigators received our other works on Neurology, and the wish, expressed by many, of seeing together a compilation of Spanish monographs difficult to find and consult abroad. This kind of publication cannot be written rapidly. It would be excellent if the author, as a photographer who catches instantaneously a running train, were reflecting in one shot, and without oversights or delays, the present state of science. Unfortunately, the labor of the analyst and narrator does not allow snapshots. Even the most modest work of popularization demands belabored preparation, if it is going to be more than a production of style, during which the train of science advances and, what is worse, increases incessantly its length by the addition of new wagons. Under these conditions, the convoy will never give exact copies but vague silhouettes, in spite of how luminous the objective of the writer may be. And this without even taking into account the risk assumed by the compiler who, hallucinated by the deafening noise of present times, may confuse the important with the accessory and, similarly forget positive progress by often paying credence to criticism tainted by conflict of interest, or to even more biased silences, and finally alter completely the straight moral perspective of each discovery and each theory. It happens frequently that scientific advances published during the writing of a book are so important, or contradict openly the ideas supported by the author, that the latter cannot do less than to postpone the work, and go back to the laboratory to appraise the value and extent of recent acquisitions. The reader should blame to these unavoidable switches from the pen to the microscope, not only the slowness in completing the book, but also the lack of unity of the text, and even certain degree of disproportion in the space dedicated to each subject. These defects could be corrected only in a second edition, if we were so lucky to come to it. Those having the patience to read us, will realize that the present book is far from being only a storage of micrographic observations and small facts collected and recorded without considering their respective physiologic value. On the contrary, we have tried to the extent of our possibilities, to develop also theoretical science. Thus, the text abounds in theories, hypotheses or mere conjectures destined to interpret the structural arrangements of nerve cells and nuclei from the standpoint of their functional significance. That was the Preface xxxv

criterion of classic anatomy, that knew quite will that its goal was physiology, and that the dynamic interpretation of the organ represented one of the most valued outcomes of the dissector's arid labor. Most of all, it is impossible to separate static from dynamic aspects in histology. The microscopic anatomy of the nervous system has not arrived as yet to a degree of development that requires a separation of domains (static and dynamic neurocytology) according to the demands of the division of labor. Such a separation will be always more or less artificial in the theoretical terrain, because the shape is an unstable property subjected to movement and constant evolution, so that anatomy comes to represent something like the visible face of a hidden activity that escapes the scrutiny of our senses. Actually, the appearance of an adult neuron represents the end of a series of processes, of internal and external forces that act during embryonic and juvenile periods. In time, the precise definition of these mechanisms shall provide the true explanation of cellular organization. Thus, the reason for the shape resides entirely in the present or past function. In the future, when Science will attain fully its means of inquiry, and chemistry and physics will be just two aspects of molecular mechanics, the anatomist will consider the significance of a structural fact sufficiently clarified only after answering the following three questions. Which function does it subserve for the organism? Which is the mechanism of that function? On the basis of which chemo-mechanic processes has it developed historically through the ontogenetic and phylogenetic series? Only the Science of the future will be able to accomplish such an ambitious and fulfilling program. For the time being, we can only babble some interpretative, timid, conjectural explanations, almost always premature, which certain discontented readers, very influenced by rigorous demonstrations, will find entirely fruitless. Certainly, we shall not negate how weak and ill-founded are many of our speculations, and how much they are in need of modification, rectification or even substitution. But hypotheses in Science, even erroneous ones, have an important goal. This aim is not always to formulate a truth, but to indicate the path to an investigation. They are, above all, great awakeners of souls, because they agitate the moral environment (that dead sea of the routine which is fatal to all progress), stimulate the spirit of doubt and contradiction, so much developed in laboratory men, and are the starting point of new and fruitful observations and experiments. I know quite well that regarding such a difficult subject as the functional mechanism of the brain, and facing so arduous problems that can be estimated as the most risky that modem Science has formulated, our solutions are gross, simplistic, almost infantile. To a certain extent they are comparable to those that could be proposed by a savage in the presence of a phonograph or an electrical appliance. But primitive and all, they are necessary for progress, and are the only possible bridge toward the truth. It is well known that our theoretical scheme on the functioning of the gray matter varies, from lustrum to lustrum, to the rhythm of new methodological xxxvi Preface advances. But note that in every transformation the theory depurates itself of errors, sharpens its contours, explains a greater number of facts, agrees better with truths belonging to related domains, and without representing yet the entire truth, it contains each time a larger number of elements of the truth. Thus, we must consider as plausible and temporary acceptable any hypothesis that, without explaining fully a phenomenon, represents a necessary phase of this ideal process toward the truth, and gives research results. We shall reject as unacceptable and useless only the hypothesis that, because of insufficiency, cannot be included in that process, nor will it have enough virtue to provoke flows of thought and action in the scientific field. We must always avoid to take such theories (transient constructions destined to artificially synthesize the facts and make feasible a panoramic view) as firm truths, as definitive edifices where to rest from the harsh analysis. We could cite many and highly placed examples of such a pernicious blindness. As the reader shall see, we have illustrated the text with a great number of figures, reproduced some in black and white and others in color, and almost all copied as exactly as possible from our microscopic preparations. As far as. clarity is concerned - and because they are destined to facilitate the com­ prehension of the text - it is better to offer more than necessary than less. Particularly in an anatomy book, the illustrations are almost more essential than the text. They represent the objective factor, that is Nature, whereas the text is the subjective, that is the author, whose intelligence, because of the fatalisms of cerebral organization, tends constantly to deform and simplify the external reality. Good drawings as well as good microscopic preparations are pieces of reality, scientific documents that preserve their value indefinitely, and the reexamination of which will always be profitable no matter the inter­ pretations they may have elicited. This first volume has appeared as fascicles separated by considerable intervals. Each one contained some unpublished ideas and observations, so that it should be convenient to record here the dates when they were printed. The first one, comprising the general section, that is the Elements of the nervous tissue, appeared in December 1897; the second, that deals with the Spinal cord, spinal ganglia, neural endings and physiological considerations on the direction of pathways in the cord, arrived in 1898; and the third which gives the comparative histology of the spinal cord and the development of nervous tissue, was published in July 1899. And with this, we finish this long series of warnings and considerations. It remains now to beg the benevolent reader, on formulating the definitive verdict, to consider not the smallness of the results, but the effort and time required to have obtained them and, above all, the healthy and patriotic intention that has guided the author.

Madrid, July 1899 T ABLE OF CONTENTS, VOLUME I

CHAPTER I

General concept of the nervous system.-Structural plan of the neural centers in the animal series......

CHAPTER II

Review of research methods and resulting discoveries...... 17

CHAPTER III

Components of the nervous tissue.-The nerve cell-its size and general morphology ...... 37

CHAPTER IV

Morphology of nerve cells (Continuation}.-Mode of termination of dendritic and axonal processes.-Intercellular connections ...... 53

CHAPTER V

Physiologic inferences from the morphology and connectivity of neurons.­ Conductive role of all parts of the neuron.-Refutation to Golgi's theory on the nutritional role of dendritic processes.-Theory of dynamic polarization.-Theory ofaxipetal polarization.-[Avalanche of conduction.-] The laws of economy of space, time and matter that rule. cell morphology, and the course and origin ofaxons ...... 85

CHAPTER VI

Structure of the nerve cell.-Cell membrane.-Protoplasm.-Structure of the axon and dendrites.-Nucleus Physiologic inferences based on the cell structure.-Significance of the spongioplasm and Nissl bodies.-Transverse and longitudinal conduction in cell processes.-Considerations about the unit of sensation.-Schematics on the dynamics of the nerve cell ...... 123 xxxviii Table of Contents

CHAPTER VII

Continuation of the physiologic interpretation of neuronal structure.-Structural variations correlated with various functional states.-Morphologic variations of neurons.-Changes by pathologic inftuences.-Significance of chromatolysis. -[Changes in the neurofibrillar reticule according to temperature variations and other conditions] ...... 185

CHAPTER VIII

Neuroglia.-Morphology of the neuroglial cell (Deiters cell).-Neuroglial type of the white matter.-Neuroglial type of the gray matter.-Epithelial neuroglial cell.-Structure of neuroglia.-General considerations regarding the functional significance of neuroglial cells...... 205

CHAPTER IX

Nerve fibers.-Peripheral myelinated nerve fiber (shape, volume, structure, etc.).­ Central myelinated nerve fiber.-Fibers of Remak.-Grouping of nerve fibers to form nerves, etc...... 225

CHAPTER X

Neural centers.-White and gray matter Spinal cord.-Its external and internal configuration.-Territories or systems of the white matter (pyramidal tract, fascicle of Flechsig or dorsal spinocerebellar tract, dorsal horn bundle, intermediate bundle, system of the intermediate nucleus, commissural bundle, fascicles of the dorsal funiculus, etc.) ...... 249

CHAPTER XI

Structure of the white matter of the spinal cord.-Nerve fibers, [unmyelinated fibers,] neuroglial cells and axon collaterals. -Varieties of collaterals according to the gray zones where they terminate.-Synthesis of the distribution of collaterals.-Terminal nerve fibers.-Displaced fascicles of the white matter. .. 263

CHAPTER XII

Structure of the gray matter.-General characteristics and classification of spinal neurons.-Motoneurons.-Motor cells or neurons of the ventral roots.-Motor cells of dorsal roots.-Ventral roots.-Axon terminals in striated muscles. . . .. 307

CHAPTER XIII

Commissural and funicular cells.-Ventral and dorsal commissural cells.­ Homolateral funicular cells.-Bifunicular cells.-Bilateral or hecateromeric funicular cells...... 333 Table of Contents XXXIX

CHAPTER XIV

Distribution of funicular cells in various regions of the gray matter.-Ventral hom (motor nucleus, commissural nucleus, nucleus of the lateral funiculus, intermediate and central gray matter).-Dorsal hom (column of Clarke, medial basal nucleus, head and lateral basal portion of the dorsal hom, substantia gelatinosa, intermediate nucleus).-Short axon neurons...... 343

CHAPTER XV

Sensory neurons, i.e. neurons with somata outside the spinal cord sending axons to the cord.-Spinal ganglia.-Structure and morphology of their cells in higher vertebrates.-Ordinary type, cell varieties, pericellular arborizations. Spinal ganglion cells in lower vertebrates...... 367

CHAPTER XVI

Endings of peripheral processes of spinal ganglion cells.-Intraepidermic free terminations (cornea, skin, mucous membranes and hairs).-Specialized endings: spindles of Kuhne, Golgi tendon organs, Ruffini corpuscles, Golgi- Mazzoni corpuscles, corpuscles of Merkel, Meissner, Krause, Pacini and Timofejew.-Sensory endings in the heart and arteries ...... 405

CHAPTER XVII

Central processes of sensory neurons.-Historical notes.-Bifurcation of dorsal roots.-Long and short radicular fibers.-Arrangement of ascending and descending branches.-Intrinsic fibers of the dorsal funiculus...... 435

CHAPTER XVIII

Neuroglia of the gray matter of the spinal cord.-Ependymal cells, and cells of short and long processes.-Distribution of these elements in different territories of the gray matter.-Blood vessels and neuroglial covering of the cord...... 445

CHAPTER XIX

Physiologic inferences based on a new structural concept of the spinal cord. -Reception of stimuli by sensory axon terminals.-Conjectures about the functioning of each termination type.-Hypothesis on the functions of the ganglion cell body.-Arrival of the imulse to the dorsal root and spinal cord. -Interpretation of the march of the excitation in tenninal and collateral branches of radicular fibers.-[Direct propagation of impulses to motor cells.] 455 Reflex movements.-Simple reflexes, unilateral and bilateral, circumscribed and diffuse.-Coordinated and cerebral reflexes.-Central sensory pathways.- Voluntary movements xl Table of Contents

CHAPTER XX

Comparative histology of the spinal cord.-Amphioxus.-Myxine and Petromyzon.-Amphibians.-Reptiles.-Birds.-Overview of the spinal cord in vertebrates ...... 487

CHAPTER XXI

Histogenesis of the spinal cord and spinal ganglia.-Germinal cells.­ Neuroblasts and spongioblasts.-Growth and development of nerve cells (growth cone, primitive neural arborization, formation of dendrites, development of collaterals, etc.).-Ganglioblasts.-Developmental laws governing neurons.-Growth and development of the ependyma and neuroglia. -[Development of spinal ganglia.-Formation of nerves; theories and hypotheses.-] Hypotheses regarding the causes of growth and transformation of neurons and neuroglial cells ...... 517

Appendix I: Table of equivalent figure numbers ...... 585

Appendix II: Taxonomy glossary...... 589

References...... 591