Anatomy of Neuropsychiatry: The New Anatomy of the Basal Forebrain and Its Implications for Neuropsychiatric Illness

By Daniel S. Zahm

Anatomy of Neuropsychiatry: The New Anatomy of the Basal Forebrain and Its Implications for Neuropsychiatric Illness, Second Edition presents the anatomical systems that take part in the scientific and clinical study of emotional functions and neuropsychiatric disorders. The book discusses the limbic system—the cortical and subcortical structures in the human brain involved in emotion, motivation, and emotional association with memory—at length and how this is no longer a useful guide to the study of psychiatric disorders. Newly revised, this book now includes chapters focusing on the anatomy of Basal Forebrain and Cerebellum Macrosystems and the role these macrosystems paly in motion, emotion, and neuropsychiatric illnesses. This book will help reader develop an understanding of the gross anatomical organization of the human forebrain.

• Presents discredited concept of the limbic system
• Reviews the neuroanatomy of the basal forebrain, greater limbic lobe, and reticular core
• Includes Clinical and Basic Science Boxes highlighting specific concepts, structures, and neuronal circuits from functional and clinical perspectives
• Features 10 videos of dissections of human brain done by the late Lennart Heimer

• Language: English
• Publisher: Academic Press
• Release date: Dec 2, 2023
• ISBN: 9780443155970

Daniel S. Zahm

Daniel S. Zahm works at Saint Louis University, St. Louis, MO, USA.

Book preview

Anatomy of Neuropsychiatry

The New Anatomy of the Basal Forebrain and Its Implications for Neuropsychiatric Illness

Second Edition

Daniel S. Zahm

Saint Louis University, St. Louis, MO, United States

Table of Contents

Cover image

Title page

Copyright

Preface to the second edition

Preface to the first edition

Acknowledgments

Introduction

The enigma of brain function

The enigma of brain structure

Chapter One. The limbic system—an eroding concept in perpetual search for a definition—and some key experimental neuroanatomical discoveries that have undermined it

1.1. The birth of the limbic system

1.2. The continuing evolution of the limbic system

1.3. Why then not cerebellum as an integral part of the limbic system?

1.4. The evolution of the limbic system: no end in sight

1.5. The triune brain concept and the controversy surrounding it

1.6. The limbic system: a concept in perpetual search for a definition

1.7. New anatomical discoveries provide an alternative to the limbic system

1.8. Conclusion

Chapter two. The anatomy of the basal forebrain

2.1. Introduction

2.2. The ventral striatopallidal system

2.3. Parallel cortico-subcortical reentrant circuits (basal ganglia loops)

2.4. The extended amygdala

2.5. Septal–preoptic complex

2.6. Substantia innominata and the magnocellular basal forebrain system (basal nucleus of meynert)

2.7. Summary

Chapter Three. The greater limbic lobe

3.1. Limits, topography, and related concepts

3.2. The greater limbic lobe

3.3. The nonisocortical character of the limbic lobe

3.4. The olfactory system of the limbic lobe

3.5. Other sensory input to the limbic lobe

3.6. Limbic lobe output

3.7. Concluding remarks

Chapter four. Focus on basal forebrain macrosystems

4.1. What, precisely, is a macrosystem

4.2. Basal ganglia

4.3. Ventral striatopallidum—ventral parts of the basal ganglia

4.4. Extended amygdala

4.5. Lateral septum–preoptic complex

4.6. Forebrain macrosystems considered collectively

Chapter Five. Interfaces of macrosystems with the brainstem reticular formation, thalamus, and each other

5.1. Reticular formation and behavior

5.2. The miscible interface between macrosystems and the reticular formation

5.3. Selected macrosystem–reticular formation interfaces

5.4. Thalamus and epithalamus

5.5. Interfaces between macrosystems

5.6. The problems of subdivisions and boundaries

Chapter six. Macrosystems in motion, representation, value, emotion, and neuropsychiatric illness

6.1. Motion

6.2. Representation

6.3. Value

Chapter seven. Cerebellum as a macrosystem

7.1. Cerebellum in brief

7.2. Is cerebellum a macrosystem?

Chapter Eight. Basal forebrain macrosystems as a fundamental organizing principle of vertebrate brain

Epilogue

Literature cited

Index

Copyright

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Preface to the second edition

More than 15 years ago, the first edition of Anatomy of Neuropsychiatry (2008) introduced ventral striatopallidum, extended amygdala, and the septal–preoptic complex in a book format suitable for general readership. By then, the concepts underlying basal forebrain functional–anatomical macrosystems already had been under development for decades, ever since Lennart Heimer discovered in 1972 that output from the primary olfactory cortex in the rat is not focused first and foremost on the hypothalamus, which up to then was dogma. Instead, olfaction engages a pattern of circuitry identical to that of the basal ganglia.¹ Starting from there, Heimer et al. went on to establish the concept of ventral striatopallidum as a ventral counterpart of the classical basal ganglia, i.e., dorsal striatopallidum,² and then found striatopallidum everywhere they looked, ultimately concluding that the entire cerebral cortex is served by basal ganglia-like mechanisms. That means not only olfactory, cingulate, and orbitomedial (prefrontal) areas, but also structures in the temporal lobe, including the amygdala and hippocampus, both keystones of the limbic system.³ The story of how these discoveries served to further decimate an already conceptually deficient limbic system, and at the same time fill out districts in the substantia innominata which prior had been inexplicable, is retold in Chapters 1–3 of this second edition of Anatomy of Neuropsychiatry.

Much new has been learned about basal forebrain since 2008. First, as regards macrosystems themselves, new methods using transgenic subjects and molecular biological methods have grown the story of direct and indirect opponent pathways through basal ganglia, which, in view of the basal ganglia-like disposition of the macrosystems, brings into play the existence of direct and indirect opponent pathways within the macrosystems. This further relegates to the macrosystems a long-anticipated role in the modulation of neural signal valence, which is key to neuropsychiatric function. Current views on opponent pathways through the ventral striatopallidum, extended amygdala, and septal–preoptic system features copiously in the second edition.

Beyond this, much progress has been made during the past 15 years to reveal additional neuroanatomical details about brain structures to which macrosystems are already known to be closely related by connections, such as the brainstem and diencephalic reticular formation and structures embedded within it. Key among these is the midbrain dopamine complex, including the substantia nigra compacta, ventral tegmental area, and retrorubral field. Much new about the connectivity, internal structure, physiology, multiplexed neuromediators, and, especially, complex interrelationships of these structures with basal forebrain macrosystems has come to light in parallel with the popularization of experimental methods that combine neuroanatomical and electrophysiological studies in experimental subjects with gene substitutions. The same can be said of other of the cell groups embedded in the reticular formation that give rise to long, ascending neuromodulatory projections and express potent neuromediators, such as acetylcholine, orexin, histamine, serotonin, norepinephrine, GABA, and glutamate.

Since the macrosystems were described, previously unrecognized brain structures have been discovered, with which, not surprisingly, the macrosystems have been found to be extensively interrelated by connections. The rostromedial tegmental nucleus (RMTg) was first reported in 2004,⁴ and, during the ensuing several years, has come to be recognized as one of the preeminent mediators of valence signaling in brain.⁵ Experimental neuroanatomical results indicate that it is likely that the macrosystems, via relays in a continuum of structures that includes the ventral pallidum, lateral preoptic area–lateral hypothalamic continuum, and lateral habenula,⁶ control the firing of the RMTg neurons, which in turn regulates, in an almost digital fashion, the release of dopamine in the forebrain and serotonin in the brainstem, both prominent modulators of valence signaling in the brain. Chapters 4–6 of the second edition provide updates of these neuroanatomical substrates in some detail.

Consistent with the neuroanatomical organization discovered by Heimer et al., the macrosystems are now recognized as central to linking the goings on in the entire cerebral cortex to numerous diencephalic and brainstem structures known to be part of the reticular formation, such as hypothalamus, substantia nigra, and habenula, among others, all with known involvement in neuropsychiatric function. Beyond abundant information that has come to light about the functional–anatomical organization of cortical inputs to the basal forebrain, much new conceptual ground also has been broken in recent years in the field of cortical function per se. In the context of macrosystems, predictive processing,⁷ a.k.a. active inference,⁸ is particularly relevant. This is the idea that experience is not sensed so much as constructed from information already existing in brain from the past, even at least in part in the form of genetically dictated hardwiring.⁹ Release of this information permits rapid prediction and anticipation of the upcoming in rapidly developing circumstances. Basal forebrain macrosystems in concert with reticular formation appear to have a role in the validation of such predictions. Further, Lisa Feldman Barrett¹⁰ has put forward theory extending principles of predictive processing to the construction of emotions, wherein selection of stored replicates of experience and value assessments are combined as instances of emotion. Macrosystems appear to be eminently positioned as the neuroanatomical substrate that instantiates Barrett’s concept by virtue of being intimately privy to cortical representations, via the massive corticostriatal output system, and, in concert with the reticular formation, capable of assigning signal valence. Another concept, that of the efference copy, holds that cortical instructions, especially pertaining to intent, are delivered as copies to multiple structures. Input of such copies may play a crucial role in the ability of macrosystems in concert with the brainstem reticular formation to assess the subjective consequences of actions. These possibilities are considered in detail in the second edition.

The approach taken in the second edition is to first provide an introduction, lacking in the first edition, that sets historical and methodological contexts for the story to come. Then, we revisit the seminal discoveries of Lennart Heimer et al. that led to the appreciation of basal forebrain functional–anatomical macrosystems and follow this up with a detailed consideration of the rich legacy of insights and new discoveries that during the last 15 years have been built on that foundation. In view of the forceful way both Chapters 1 and 2 of the first edition of Anatomy of Neuropsychiatry challenged the validity of the limbic system concept; the two have been combined in sequence in this second edition as a single Chapter 1. The original Chapters 3 and 4 thus are Chapters 2 and 3 in the revision. The text of the original Chapters 1–3 of the second edition otherwise has been minimally altered from how it appeared about 15 years ago in the first edition of the book and the accompanying supplemental Basic Science and Clinical Boxes are also reprised in the revision. Much of the content of the boxes was provided by Michael Trimble. Accordingly, the reader should keep in mind that the substance and referencing in Chapters 1–3 and the Boxes (except in some of the footnotes) are from circa 2007. It was done this way not only to reprise the depth and clarity of the original narrative, but also in part to commemorate the longevity and far-reaching significance of the experimental observations and, finally, to acknowledge and celebrate the fact that, since the first edition was published, few substantive objections to or refutations of the findings have appeared in the literature. Where some areas of disagreement have arisen or, more precisely, persisted, mainly in arguments promulgated by Larry Swanson and his students, these are addressed in Chapters 2, 4, and 5 in which some of the details of the anatomy of the basal forebrain macrosystems are discussed. Chapter 6 poses questions about existing dogma from the cognitive neurosciences in the context of functional implications of neuroanatomical concepts described in this book, even going as far as providing what we think are some novel hypotheses supported by conceptualization of the neuroanatomy that Lennart Heimer pioneered. The possibility voiced in Chapter 1 that the cerebellum functions as a macrosystem is considered in Chapter 7. To conclude the book, a more global perspective on basal forebrain macrosystems is presented in Chapter 8. As in the first edition, digital video recordings of Lennart Heimer’s famous dissections of the human brain are bundled with the book, as video links in this edition, replacing the erstwhile DVD.

Contributions by Lennart Heimer and his colleagues to our understanding of basal forebrain circuitry have such broad implications for concepts of how the brain works, that by now basal forebrain macrosystems should have replaced the standard dogma on limbic forebrain neuroanatomy still presented in textbooks. This has not happened, possibly due not so much to any scientific objections as to natural inertia, the tendency to stick with the familiar, which is an ever-present impediment to change in just about every area of human endeavor. However, there may also be some actual resistance to such change. To practitioners in the inherently conservative health sciences professions, any change in how the organization of brain is viewed carries with it the objectionable implication that institutionalized approaches to diagnoses and treatments might also benefit from revision. Especially, prescription of neuropsychiatric drugs is not always done in an entirely evidence-based manner, but perhaps sometimes proceeds more by trial and error or at the behest of sales professionals representing a powerful, acquisitive drug industry. Although this is a problem not apt to go away soon, patients may benefit if their physicians enjoy a more empirical understanding of the brain substrates that such drugs influence. But medical professionals in training are not taught about these substrates. On the contrary, medical school coursework, syllabi, and textbooks, especially in medical neuroscience, neurology, and psychiatry, tend to emphasize more what is covered by the examinations than strive to instill a deep understanding of the respective disciplines. And it is the conservative medical professions, after all, that write the examinations that students must pass to gain entry to and then to continue to practice in the sundry medical disciplines.

Sadly, Lennart Heimer passed away on March 12, 2007, shortly after the writing of the first edition of Anatomy of Neuropsychiatry began in 2006, as did Gary Van Hoesen on August 13, 2012, a few years after its publication. By presenting their original chapters and Lennart's human brain dissections minimally altered in this second edition of this book, we quietly endorse the strength and durability of concepts they championed. Quite simply, they provided a clearer picture of the neuroanatomical substrates in parts of the brain with known involvement in neuropsychiatric function. Numerous discoveries made in the 15 years since the publication of the first edition of this book are fully consistent with the template Lennart and Gary set out, which has turned out to be foundational for further advancement of our understanding of brain substrates presumably disturbed in neuropsychiatric conditions. It follows that a better understanding of neuropsychiatric function should come with such knowledge, and I continue to look forward to a time when seminal concepts developed by Lennart, Gary et al.¹¹ to which this progress owes, will have entirely displaced the petrified limbic system dogma still lingering in popular general neuroscience and medical textbooks.

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¹ Heimer (1972).

² e.g., Heimer and Wilson (1975), Heimer and Van Hoesen (1978), Heimer et al. (1982).

³ Alheid and Heimer (1988).

⁴ Chou et al. (2004), Jhou et al. (2009b), Kaufling et al. (2009).

⁵ Bourdy and Barrot (2012).

⁶ Jhou et al. (2009a), Yetnikoff et al. (2015).

⁷ Friston and Kiebel (2009).

⁸ Parr et al. (2022).

⁹ Edelman (1987, 1989, 1992).

¹⁰ Barrett (2017a,b).

¹¹ George Alheid and Jose de Olmos must be mentioned here.

Preface to the first edition

This book emerged in part from a series of workshops on the functional anatomy of the human brain organized by Lennart Heimer. The first A New Anatomical Framework for Neuropsychiatric Disorders: Systems Analysis and Hands-on Dissection of the Human Brain took place in 2003 and was repeated during the three succeeding years as one of the workshops offered by Practical Anatomy and Surgical Education, a continuing medical education and community out-reach provider attached to the Department of Surgery of the Saint Louis University School of Medicine. The objective of the New Framework workshops certainly would seem unique, namely the teaching of functional neuroanatomy to health care professionals in physical and occupational therapy, psychology, psychiatry, neurology, and neurosurgery, all fields where perhaps a fairly detailed knowledge of the functional–anatomical organization of the brain would seem to be a fundamental element. Nevertheless, the workshops invariably booked to capacity, attracting diverse collections of practitioners from all of these disciplines. The special attraction of the workshop seemed to be the promise of hands-on dissection of the human brain. Some workshop participants complained that their training had lacked such an opportunity, but more lamented that, at the time they had been provided with the opportunity, they were intellectually or emotionally unprepared to appreciate its rich rewards.

It was little anticipated by workshop registrants that Lennart Heimer actually meant "New Anatomical Framework literally, or that, during the course of the workshop, many of them would come to appreciate a way of conceptualizing the interrelationships of the cortical mantle, deep telencephalic nuclei, and descending and ascending systems of the brainstem that differs in significant respects from what they likely were taught during their professional studies. The new functional–anatomical concepts have emerged during the past 35 years, gradually, but steadily, gaining currency among the basic neuroscience cognoscenti. In contrast, the more conservatively minded clinical disciplines of the workshop participants have been slower to embrace the new ideas, which is somewhat unfortunate, insofar as the concepts in question reflect a functional–anatomical basis for comprehending the inextricable linkage of mechanisms (if not the mechanisms themselves) subserving cognitive, emotional, and motor components of behavior. Indeed, despite the pervasive resistance of the clinical neurosciences to these contemporary concepts of brain organization, certain clinico-anatomical constructs that have grown out of them, e.g., parallel, segregated cortico-basal ganglia-thalamocortical circuits, have achieved prominence in contemporary neurological, neurosurgical, and neuropsychiatric thought. It is a telling fact that such diverse and, in the thinking of some, mutually exclusive (or nearly so) clinical disciplines find common ground in such neuroanatomical substrates. Not surprisingly, breaking down the barriers between neurology, neurosurgery, and psychiatry was a consistent theme in Lennart Heimer's writings, voiced perhaps most strongly in Perestroika in the Basal Forebrain: Opening the Border between Neurology and Psychiatry" (1991). Indeed, it was in the spirit of strenuously contesting the unnatural schisms between these disciplines that Lennart was joined by Michael Trimble, a behavioral neurologist keenly aware of the behavioral side of neurological disorder, and Gary Van Hoesen, a student of the cerebral cortex and its disorders, particularly Alzheimer's disease, to assist him in presenting the workshops. The core faculty was supplemented during the course of the 4 years that the workshops were done by contributions from Nancy Andreasen, Wayne Drevets, Stefanie Geisler, Stephan Heckers, Andres Lozano, Joel Price, Paul A. Young, and Scott Zahm.

But it is only partially correct to assert that the book owes its existence to the workshops. To the contrary, Lennart Heimer had long worked to integrate functional–anatomical concepts emerging from the research laboratory, which were based on data generated in rodents and monkeys, with human brain organization. Efforts to do this took the form of extensive analyses of histochemically processed postmortem human brain material¹ and innumerable gross dissections of human brains, leading to the two editions of his textbook for medical students, The Human Brain and Spinal Cord-Functional Neuroanatomy and Dissection Guide, regarded as among the most lucid available accounts of this difficult subject. As regards the brain dissections, the antecedents of this book harken back to now locally legendary sessions beginning in the late 1970s and continuing through 2006 in which Lennart demonstrated the prosected human brain to neurology and neurosurgery medical residents at the University of Virginia. These teaching sessions led in the 1990s to the production of an acclaimed series of videotaped human brain dissections and ignited a seemingly perpetual process of refinement and rerecording of the dissections, culminating in those recorded on the DVD bundled with this book, which reflect the work of a consummate neuroanatomist recorded with state-of-the-art technology. Thus, it was the idea to combine the teaching of the new functional–anatomical concepts in juxtaposition with classical demonstrations of human brain organization, as revealed by gross dissection, and liberal recourse to clinical correlations that became the glue, or magic, if you will, that for 4 years held together a program that consistently merited rave reviews from collections of diverse and, we might add, intimidatingly discerning clinicians.

All of us involved in the writing of this book, some with neuroanatomical training, others with clinical insights, came to realize that knowledge of the significant advances in neuroanatomy of especial relevance for understanding behavior had only reached a proportion of those for whom it is relevant for their daily research or practice. This in part reflects on the somewhat esoteric nature of the subject and neuroanatomy abounding in connectional and histochemical complexities far exceeding those found in other anatomical systems, say, e.g., the liver or heart. But it also relates to the relative entrenchment in current clinical textbooks and discussions of the concept of the limbic system, typically still viewed as it was envisaged some 50 years ago. Neuroanatomy, like all disciplines has progressed in many directions, but of relevance here has been the opening up of our understanding of the anatomy of the basal forebrain and the expansion of the concept of the limbic lobe. Further, modularity has given way to circuitry, as systemic relationships, i.e., macrosystems, have been identified within the anatomical complexity. Such advances have arisen not only from new methods of exploring the brain, including new neuroanatomical staining techniques and brain imaging methods in humans, but also from a need to unite our knowledge of brain function and structure with clinical observations. The task is to enable an integration of brain–behavior relationships which not only makes sense, but which also has practical application in treating a spectrum of neurological and psychiatric disorders.

The text however originates from a neuroanatomical perspective. This is not a book on neuropsychiatry or biological psychiatry, and we have not elaborated on clinical presentations of various disease states. There are many other books which do that. Instead, it is hoped that the clinical relevance of the new neuroanatomy will emerge naturally from the individual chapters, and that the interested reader will be stimulated to enhance his or her clinical knowledge with the underlying neuroanatomical principles. However, some interesting pointers are provided by way of Clinical Boxes, as are some of the laboratory methods and basic science issues enlivened by Basic Science Boxes.

Lennart Heimer is the principal author of Chapters 1–3. Chapters 1 and 2 provide a brief description of the origin and evolution of the concept of the limbic system and some deficiencies attributed to it as a basis for understanding behavior and human neuropsychiatric disorders. Chapter 3 describes the new anatomy—an alternative way to conceptualize brain systems subsumed in the more conventional thinking by the limbic system. First, Lennart reveals how the discovery of the striatopallidal relations of the olfactory system leads logically to [1] discrediting the idea of a limbic system–exptrapyramidal system dichotomy and [2] significantly expanding the role of basal ganglia–thalamocortical functions in behavioral synthesis. He then shows that, in functional–anatomical terms, much of the amygdala emulates cortex and that this is quite consistent with the manner in which the great classical neuroanatomists conceived it. He goes on to show that the definitive, highly characteristic histostructural features attributed to the central nucleus of the amygdala are in actuality much more broadly represented in basal forebrain than credited in most contemporary neuroanatomical accounts, although this, too, was recognized by the classical neuroanatomists. Two new major constructs to emerge from these considerations, ventral striatopallidum and extended amygdala, together with the cholinergic basal nucleus of Meynert and the septum, are then considered as subcortical output channels for Broca's great limbic lobe, a magnificent concept that, as Gary Van Hoesen reveals in Chapter 4, nevertheless does not escape the keen logic of the new anatomy unaltered. In Chapter 5, Lennart's erstwhile student and long-time collaborator, Scott Zahm, explores the systems and behavioral implications of the new anatomy. Throughout this book and, particularly, in numerous Clinical Boxes, neurological, behavioral, and neuropsychiatric implications of the new anatomy are illuminated by Michael Trimble, who writes in a style that all readers of the book, from beginning students, to seasoned neuroscientists, to jaded clinicians from all of the brain-concerned disciplines, should find to be accessible and rewardingly informative.

Lennart Heimer's new anatomy may seem for some to be not so new. Indeed, as Lennart himself liked to point out, the structure of the brain is no different after 1972 than it was before. What occurred instead is that a realization that Lennart had about how the brain is organized led to a series of further discoveries and revisitations to the classical neuroanatomical literature, culminating in a different way of looking at vertebrate brain organization with significant implications for human brain–behavior relationships and neuropsychiatry. No longer can the psychiatric (limbic system) and neurological (extrapyramidal system) be conveniently compartmentalized and relegated to segregated clinical disciplines. To the contrary, the inextricable interwovenness of the cognitive, emotional, visceral, and somatic realms of human experience is clearly reflected in the new anatomy and continues to gain acceptance in clinical medicine. The experimental neuroanatomical basis for this new way of thinking about brain as described herein is presented in elegant counterpoint to the beauty and elegance of the human brain itself, as revealed in the video recorded dissections included with the book, executed and demonstrated by a master of functional neuroanatomy.

Daniel S. Zahm, PhD

Michael R. Trimble, MD

Gary W. Van Hoesen, PhD

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¹ See, e.g., Alheid et al., 1990; Heimer et al., 1999; Sakamoto et al., 1999.

Acknowledgments

The author is indebted to several individuals and organizations without whose support this update of Anatomy of Neuropsychiatry could not have been produced. He gratefully acknowledges support from the Saint Louis University School of Medicine and is especially indebted to the Chairpersons of the Department of Pharmacology and Physiology, Dr. Daniela Salvemini, whose support during the writing phase was unconditional, and Dr. Tom Westfall, who lifted up the author and his family in tough times. The author’s research program was supported over the years by USPHS NIH grants NS-23805, DA-15207, and MH-70624 and grants from the United Parkinson Foundation and American Parkinson Disease Foundation. Heartfelt thanks go Elsevier Senior Acquisitions Editor, Joslyn Chaiprasert-Paguio, for her confidence and kind encouragement from the start, Editorial Project Manager, Pat Gonzalez, whose energetic entry into the project interjected new vigor, and Sajana Devasi P.K., for razor sharp production. Most of all, I am deeply grateful to my family. Jacob and Claire, my adult children, provided bonhomie and generous portions of encouragement, and I have accrued a deep debt of gratitude that I wonder if I can ever properly repay to my wife, Stefanie Geisler, and our daughter, Frida, for abiding tolerance of serial absence while present during the past year and a half. They have both borne and sustained this project with grace, humor, and the occasional reprimand.

Introduction

The baseline anxiety of human beings so often turns on questions of how transformable we creatures are – on how it is that these meat-and-blood bodies we live within can somehow become the sites of spirit and speculation and grace, by which we include free will.

– Adam Gopnik

The enigma of brain function

After 150,000 or more years, beginning with hominid and then human curiosity about the matter, the jury is still out and reportedly rather hostile on whether we will ever understand how the brain works. Although there has been no lack of interest in this problem going back to the furthest reaches of antiquity,¹ the likelihood of solving it can seem as slim now as perhaps ever. René Descartes famously so despaired of reconciling the workings of mind and brain as to philosophically snatch mind away from the brain, in essence dismissing the brain as a mere device for interacting with the environment, irrelevant to thought. But Descartes really was just evading a different question, the so-called hard problem, posed again much later by David Chalmers,² which demands resolution of the relationship between the capacity to experience and physical processes in the brain. Chalmers’s and Descartes’s query may well be a permanently intractable impediment to full understanding of brain, although their question is the object of all matter of opinion.³ But it perhaps matters less now because, by now, the evidence is so abundant as to be unassailable that brain mechanisms, irrespective of mind, underlie behavior, including that of human beings. That is to say, while we cannot at present, perhaps ever, solve the hard problem framed by Descartes and Chalmers, the less hard problem—how physical processes of the brain synthesize behavior (David Chalmers called it the easy problem)—unlike the hard problem, seems not impossible, at least theoretically. People speculate⁴ that, as solutions are discovered that gradually whittle away at the less hard problem, the significance of the hard one may fade in proportion.

It would seem that we already know quite a lot about the brain. Any number of massive textbooks on neuroscience exists, as do thousands of books that focus on more specific aspects of the brain sciences and hundreds of thousands of peer-reviewed papers published in hundreds of scientific journals devoted to neuroscience. Because of the sheer immensity of this body of knowledge, contemporary books about brain tend toward the areas of interest or expertise of its respective correspondents, and, in that regard, this one is not different. Much of this knowledge concerns the structure of brain, that is to say, its parts and supporting structures, the cells that comprise it, of which many are neurons, and the multitudinous interconnections of those cells. But most people who like to think about the brain rank their fascination with its function far above any interest they may have in its structure, and, indeed, what most would consider the ultimate function of brain—thinking—seems to bear little known relation to its structure. Consequently, why one would come at it from the anatomical point of view merits some explanations, which we attempt to provide here.

To get started, we take up some historical underpinnings that establish that the investigation of the functional and, particularly, structural, composition of the brain has never been a straightforward, purely objective undertaking. Quite the contrary, the quest for knowledge about the brain has been undermined every step of the way by superstition, the tyranny of conflicting belief systems, religious and authoritarian interference, and the clashing egos of competing investigators, not to mention the absent to primitive state of the technologies available to early investigators. The purported ability of mind and consciousness to render the physical brain seemingly superfluous, or at least nearly so, has also hindered the progress of brain science, and this is taken up next. Indeed, after Descartes, interest in the brain has been invariably associated with a choice to either address, circumvent or ignore mind and consciousness. But brain and mind coexist, so the imperative is to go forward, if the thing is ever to be solved. Indeed, the means available in modernity to study the brain have improved and numbers of people doing so increased, both to such an incredible extent that one might presume that we are on a fast track to doing just that, that the historical impediments to the acquisition of accurate concepts about brain structure and function are gone. To the contrary, modern versions of such deterrents to the smooth, linear, and precise expansion of knowledge about brain (and mind) remain as tenacious as ever, as seemingly permanent sources of interference and bias against which contemporary neuroscientists must be constantly vigilant. This concern hangs in the background as we go on in this chapter and, then, throughout the rest of this book, to contend that there is more than one way to look at the structure of brain and that how one looks at structure may influence one’s viewpoints regarding how the various parts of the brain may have come to be able to work together to accomplish what the brain does, up to, almost—thinking. So, returning to the beginning.

Even during times shrouded in the earliest mists of prehistory, hominid predecessors of Homo erectus knew that well aimed blows to the head, if not killing outright, could render prey or an enemy immobile, insensate, and vulnerable to capture or finishing off. Attesting so are hundreds of skulls recovered by forensic anthropologists over the years, having once belonged to various animals and prehuman hominids, including Australopithecines, Neandertals, and Denisovans, and also to Homo erectus and members of the several prehuman variants of that genus—all crushed, depressed, or penetrated in such characteristic ways as to leave little doubt as to the cause—wielded and thrown weapons.⁵ The connection between head, brain, and behavior thus must have been made at a very early stage of mankind’s descent and we can reasonably presume that the very earliest primates we recognize as people, and even their forebears, had already begun to ponder, as have their descendants ever since, on thought, actions and the brain and how they are related to each other.

However, despite the wealth of seemingly obvious clues about brain function lurking in the behavior nulling effects of head injury, appreciation by humans of the central role of the brain in perceiving and responding has evolved by excruciatingly gradual fits, starts and reversals over the course of many centuries. To start with, the waxings and wanings of bodily injuries and ailments mostly were viewed by commoners in the ancient civilizations not objectively, as conditions and circumstances with causes that could be determined, but rather as unavoidable catastrophes veiled in superstition or as punishments and rewards meted in relation to vicissitudes in the moods of the Gods. Frequent, dreadfully unpredictable, seemingly inevitable visitations of violence ending up in death and injuries, often involving the head, and the utter pervasiveness of disease, which often disrupted or diminished mind and movements, compelled ancient peoples to seek out wiley sorcerers and the divine wisdom of clerics, who often claimed an ability to intervene with the Gods on their behalf. Gods were also greatly valued by the shamans and, medicine men themselves, and, occasionally, physicians, that treated sick and injured common people. They could put the blame on deities for unhappy outcomes of injuries and disease that they were unable to treat or cure. Clergy and sovereigns colluded to co-manipulate the pervasive dread and spiritual solace-seeking of commoners as sources of power and control over their respective constituencies. It was to the mutual benefit of all members of the pastoral and ruling classes that head bashing and brain disease should be due to the whims of the Gods, rather than something that something could be done about because then people could expect that something should be done about it.

Consequently, the clergy and ruling classes were content to abide the idea that it is the Gods that dictate events and, accordingly, alternative explanations, as a rule, aroused little official interest, except of course as pertained to maladies affecting people belonging to the clergy and ruling classes, and their wealthy supporters. Their injuries and illnesses were diligently attended by early physicians, who sometimes wrote down detailed notes on their observations and experiences, thus providing early learned accounts of pathophysiology and theory about brain and mind. Much evidence indicates that even very ancient physician-philosophers within these affluent social circles well apprehended apparent brain-behavior correlations. Translations of medical notes recorded in ancient Egyptian hieroglyphs dating to the Old Kingdom (2800–2200 BCE) describe, e.g., the association of head injury with disrupted eye–hand coordination and that motor deficits on one side of the body accompany brain damage on the opposite side. One surviving document called the Atharvaveda, from ancient India (2500 BCE), provides vivid descriptions of epilepsy, insanity, neuralgia, headache, and blindness.

Despite the quite early interest and contributions of learned physicians during prehistory and in ancient cultures, recognition of the role of brain in guiding behavior developed gradually. Even though a broad variety of symptoms, such as vertigo, confusion, disordered thoughts, visual and perceptual deficits, loss of consciousness, malaise, and paralysis, were readily observable consequences of witnessed brain injuries, the involvements of the intact and impaired brain in normal and deranged behavior seem to have persistently eluded the ancients. Surviving written evidence from ancient Egypt, India, Mesopotamia, and China indicates that, to the contrary, it was the heart, not brain, regarded by the cognoscenti and authorities as the organ of mentation, emotion, and seat of the soul. It should not be surprising that the ancients concluded in this manner. For one thing, for as long as hominids had apprehended the debilitating effects of head whacking, they must also have observed that it is when the heart stops beating that an organism is dead, that all chance of regaining sentience is forever gone. It is not unreasonable then to look to the heart as the ultimate seat of mind and soul. In a similar vein, the racing of the heart in the lead up to fighting or fleeing fits with some presumptive role of the heart in the mysteries of courage and cowardice, just as intense visceral awareness that accompanies joy, pride, attachment, dread, fear, shock, grief, and the like fits with a thoraco-abdominal localization of strong emotions.

But, at the same time, not everybody was on the same page as regards such matters, because anthropologists also have found among the artifacts of ancient civilizations many human skulls exhibiting clear evidence of having been surgically drilled or trephined during life, presumably to permit the escape of bad spirits. Clearly, someone in those old cultures dared to conjecture that the basis for bizarre behavior and disordered thoughts and movements resides in the head, not the heart.

The relative roles of head and heart in the mediation of thinking and feeling may have clarified sooner if the ancients had had more opportunity to examine the respective physical structures. But, in most ancient cultures, mutilation of the bodies of the dead, which includes removal of the brain, was strictly proscribed, again, with the stern support of the clergy and ruling classes. So it wasn't until the 5th century BCE, in the more open, uncommonly intellectual atmosphere of classical Greece, that the first recorded human brain dissections were done by Alcmaeon⁶, who, in an early recognition of an apparent structure–function relationship, is said to have declared that brain is the central organ of sensation based upon its connections with the eyes via the optic nerves. Anaxagoras (500–428 BCE), having also dissected brains, proposed similarly that brain is the organ of mind, as also did Hippocrates (460–370 BCE), who sagely opined that "Man ought to know that from nothing else, but the brain come joys, delights, laughter and sports, and sorrows, griefs, despondency and lamentations," and forthwith rejected the idea that brain disease is the work of the Gods.

But then, with no evidence indicating so, Hippocrates went on to propose that a proper balance of body humors representing earth (phlegm), air (yellow bile), fire (blood), and water (black bile) undergirds bodily, including mental, equilibrium. Seizures, paralysis, and all sorts of other unhappy conditions reflect disrupted humoral balance and will be overcome by reestablishing it. During the same period Democritus (460–370 BCE), regarded by some as the father of science, promoted an atomic theory—that all matter in the universe, including organic (which includes brain), comprises aggregates of eternal, indivisible particles that he called atoms. Liquids, he thought, were composed of round, smooth ones, whereas solids were formed from rough ones. The former contributed to sweet tastes and rough, hooked ones to sharp, acidic tastes. Democritus, together with his revered mentor, Plato (429–348 BCE), imagined a triune mind, reckoning that the head is the seat of the intellect, whereas anger, fear, pride, and courage are enlivened by the heart. The gut (mainly the liver), harbors lust, greed, desire, and the like. Consistent with his beliefs regarding the composition of matter, Democritus believed that the soul is lost with dissolution of the body substance after death. This early, seemingly materialist viewpoint⁷ appears to hold that the intangible and ethereal soul can be embodied, or at least enabled, by mere matter. Plato, on the other hand, conceded only that components of soul linked to the heart and liver might dissipate upon a person's demise, but believed that those in the head are immaterial and eternal.⁸ In contrast, Aristotle (384–322 BCE) flatly denied the brain any role in mentation, instead assigning the intellect, perceptions, and passions to the heart, because of its warmth. He considered the brain, with its dense investment by blood vessels, as but an elaborate cooling device contrived to dissipate heat generated by the heart. While we might in the present marvel at how wrong about this Aristotle was, he was on a very good track in another important sense. That is, his thinking on the matter represented a then novel way of postulating function from an appreciation of anatomical structure regarded in the light of known physical principles, in this case the efficient radiation of heat from the increasingly numerous and finer gauge vessels at each successive branching of the brain vasculature.

Shortly after the founding of the Hellenist-Egyptian cultural center of Alexandria, circa 300 BCE, postmortem human dissections became freely tolerated there under the auspices of the early Ptolemies, who generously supplied cadavers to their favorite physicians and philosophers, going so far as to offer up the still living bodies of (accused) criminals for live vivisection. The early anatomists Hemophilus (325–280 BCE), who has been called the father of anatomy, and Erasistratus (310–250 BCE) were among the more prolific beneficiaries of Ptolemaic largesse and, accordingly, wrote about the cerebrum, cerebellum, and ventricles, which, consistent with Hippocrates's ideas on humoral balance, they associated with the psyche.

But it was Galen (130–200), born in Greece, trained in Alexandria and later a resident mostly of Rome, where he was court physician to numerous Emperors, that more than any other classical physician included extensive examinations of brain among his many dissections mainly of monkeys, and also sheep, oxen, and others. Galen wrote hundreds of papers describing diverse aspects of brain structure involving the cerebral hemispheres, cerebellum, brainstem, cranial nerves, and autonomics, including the ganglia, sympathetic trunks, and communicating rami. He differentiated sensory and motor pathways, regarding the former, which he associated with the cerebrum, as softer and thus more amenable to sensory impressions, whereas the pathways he perceived as firmer were assigned motor function and associated with the cerebellum. He disagreed with Erasistratus that abundant brain convolutions reflect high intelligence, citing the extensively convoluted brain of the stupid donkey as evidence in this regard. He also bluntly rejected Aristotle's notion of brain as heat exchanger, believing instead that vital spirits from the heart are transformed into higher spirits in the rete mirabile, a dense tangle of blood vessels at the base of the brains of some animals, e.g., sheep and cattle, that Galen mistakenly thought is also present in humans. Galen surmised that higher spirits are stored in the ventricles until passed through hollow nerves to force muscles into action. But it is the brain substance that is the seat of the imagination, intellect, and memory in his view, because damage to brain substance affects the mind. Highest animal spirits must therefore flow, via the marvelous net (rete mirabile), from the heart into the brain substance as well as the ventricles and nerves. Unfortunately, contemporaneous ecclesiastical interpreters of Galen's ideas were unwilling to associate the mind with the cerebral substance and, instead, split the mind, putting perception in the lateral ventricles, cognition in the third ventricle and memory in the fourth ventricle. This churchly misapprehension would dominate thought on mind for many centuries, somewhat ironically it would seem, because, as noted, Galen had it wrong, insofar as human brain circulation lacks a rete mirabile, which he saw as essential to getting animal spirits from the heart to the brain. But, like Aristotle, Galen, while wrong, was on a rational track wherein the notion of structure–function relationships was beginning to gain a stable presence.

The foregoing (and parts of the upcoming) account, which for historical detail relies heavily on compendia prepared by Stanley Finger (1994), Clarke and O’Malley (1996), Jones, (1999, 2007), Larry Swanson (2000), Harari (2011/2015) and Cobb (2020),⁹ reveals that early progress in the development of human understanding of the human brain and its functions was characterized by a recurring underlying pattern. First, ample opportunity for the formulation of rational projections about brain function has always been available throughout hominid and human existence in the form of the visible consequences of brain injury and illness. Second, because their world was beset by countless terrifying eventualities—horrendous intertribal warfare replete with wanton head bashings, epileptic children, excruciating toothaches, insanity, blindness, deafness, and on and on—the ancients lived under such a constant pall of fear and anxiety that they entertained sundry superstitions and eagerly grasped at the Gods to explain the various calamities and illnesses that befell them. Third, as noted, the clergy and ruling classes were only too happy to exploit the fears of the people to solidify their own status and power by means of promotion and mandate. They actively contributed to the durability of bad ideas about how the world, including the mind, works—to a much greater extent than did logical force and accuracy of observation to the attractiveness and longevity of good, evidence-based ideas about such things. Furthermore, due possibly to the existential overtones of these difficult issues (and negligible chance that one's proclamations could be persuasively falsified), objective hypothesizing about the role of the brain in behavior was often supplemented by baseless theorizing well beyond logical extension of the observations, frequently culminating in highly speculative, often idiosyncratic, notions that were apt to be accepted as fact.

Indeed, this sort of thing is precisely what kept beliefs about ventricular localization of intellectual faculties alive for centuries. As the dark ages descended upon Europe (circa 400–450 CE), Middle Eastern philosophers, having access to European texts, including those of Galen, kept the ecclesiastically altered gist of Galen's thinking alive for the next about one thousand years, well beyond the dawning of the Renaissance. Even the illuminati of the Renaissance contributed to its perpetuation. Leonardo da Vinci (1472–1519) performed many surreptitious human dissections (they were banned by papal edict), producing the finest anatomical drawings of brain structure up till then achieved. Leonardo was especially interested in the ventricles and produced anatomically precise casts of the human ventricular system, diagrams of which differed so decisively from the cartoonish drawings depicting Galen's ventricular localizations as to call the whole idea into question. Nonetheless, Leonardo held to the doctrine that mental faculties reside in the ventricles and activate body functions by acting via hollow nerves. Shortly after, Andreas Vesalius (1514–64), another very prolific documentarian of human dissections, bluntly criticized much of what had come down from Galen, showing, e.g., that humans have no rete mirabile. But he, too, now about 1450 years after Galen, was disinclined to reject ventricular localization of intellectual faculties. Perhaps it is attractive and fits with our intuitive predispositions that thought, being fluid (in the sense of without sharp boundaries), would reside in the fluid of the ventricles.

Well into the 17th century, fealty to ventricular localization of function was reasserted in the thinking of the aforementioned René Descartes (1596–1660), who proposed that vital spirits infused nerves and, in turn, the body, via (with no discernible anatomical basis) the pineal body, which somehow received them from the ventricles. Given the long history of ventricular localization, Descartes's derivative ruminations in this area made few ripples. It was his conviction regarding the absolute independence of mind from structure, however, that would have a stultifying effect on the progress of thought about brain and behavior for yet more centuries to come.

There are good reasons why the idea of thought (for that matter, the idea of an idea) can seem unrelated to the structure of the brain. Any attempt to think about the brain holistically, especially from the point of view of its structure, is hamstrung from the start by mind. Comprising something deep within, in part inaccessible, but with an accessible component—conscious awareness—mind encompasses the interrelated knowledge of our bodies and the external world, and our thoughts, feelings, and plans. Despite the fervent attentions of intelligent men and women over many thousands of generations of human existence, we have no objective explanation of what mind or consciousness is, and little beyond correlational evidence that either is generated by the substance of the brain. As has been said of great art (and pornography¹⁰)—that we can't very well define it but know it when we see it—so it goes with consciousness and feelings—we don't know what they are, but we sure recognize them when we think or feel them!

That one possesses this thing that seems so much to reflect the very essence of self, of being, but also can seem a disembodied inhabitation, has always been a spooky puzzlement to mankind. Early modern thinkers like, e.g., the great American philosopher, C.S. Peirce (1839–1914), and the Austrian originator of psychoanalysis, Sigmund Freud (1856–1939), among many others,¹¹ have revealed that philosophical inquiry into mind and consciousness is a virtual minefield of logical fallacy and intuitive blind alleys.¹² Thinkers going back beyond written history have agonized regarding where the brain should stand in relation to the mind. Among modern materialists, a presumption, almost faith, has emerged that the mind somehow inhabits the brain. This relatively new dogma actually echoes Galen’s ideas from the classical Greco-Roman period, which, almost unimaginably, were lost for more than 1600 years during which the mind was presumed lodged in the cerebral ventricles due, amazingly, to ecclesiastical misrepresentation. And then came Descartes, who removed the mind to … well, we do not know where.

That wise man's solution to the conundrum, which was foreshadowed, if not outrightly shared by Socrates, Plato, Augustine, and Kant¹³, was to beg off. Recognizing the immense chasm between thought and action, Descartes formalized the doctrine that mind and body (including the brain) are by nature separate and distinct entities.¹⁴ He awarded thought to the mind and action to the brain, and thus for (possibly) all posterity set apart the human mind and, by extension, mankind, from the rest of the biological world. Right or wrong, Descartes's influence so cemented behavior within the boundaries of philosophy, that during the next more than 200 years the brain had no role in psychology. For many people, Cartesian dualism stands rock solid up to this very day. Indeed, dualist conviction is institutionalized in Thomistic theses numbers 14–21 approved as part of a core philosophical belief system acceptable to the Catholic church¹⁵. Given the still unyielding persistence, even today, of the question of what to do with mind and conscious awareness, it yet remains as possible as not that dualism is correct. To be sure, Descartes gave sensorimotor reflexes to the brain and unpersuasively suggested (after Galen) that mind could influence body via valves associated with the pineal body. More recently, Nobel laureate Sir John Eccles¹⁶ and his associate, the philosopher Karl Popper, have stridently defended a position they call interactive dualism in which the mind and body are separate, but interact,¹⁷ although probably not via the pineal.¹⁸ Either way, dualist philosophy, in its essence, effectively sequesters off thoughts and feelings in such a way as to render interest in the brain rather pointless.

Not surprisingly, however, a never fully suppressed, quiet conviction that the brain must have something to do with thinking periodically reemerged, as expressed in the writings of, e.g., Thomas Willis (1621–75) and Emmanuel Swedenborg (1688–1772). Whereas Swedenborg's extensive ruminations on the cerebral localization of thought were recorded only in his private writings and have remained relatively obscure,¹⁹ the sophisticated dissections illustrated in Willis's Cerebri anatome (1664) by his famous friend, the architect Christopher Wren, revealed so much previously unappreciated details of brain structure as to lead not only Willis but many other people as well to speculate that different physiological functions might be attached to such diverse structures as the cerebral cortex, basal ganglia, cerebellum, pons, colliculi, and much else of brain.²⁰ The prescient insights of these and numerous 18th and 19th century investigators to follow nourished persistent skepticism regarding detachment of mind from brain and, by the mid-19th century, critical observation and