The Neuroscience of Clinical Psychiatry PDF

The Neuroscience of Clinical Psychiatry The Pathophysiology of Behavior and Mental Illness THIRD EDITION Edmund S. Higgins, MD Clinical Associate Professor of Psychiatry and Family Medicine, Medical University of South Carolina, Charleston, South Carolina Mark S. George, MD Distinguished Profes...

The Neuroscience of Clinical Psychiatry The Pathophysiology of Behavior and Mental Illness THIRD EDITION Edmund S. Higgins, MD Clinical Associate Professor of Psychiatry and Family Medicine, Medical University of South Carolina, Charleston, South Carolina Mark S. George, MD Distinguished Professor of Psychiatry, Radiology, and Neurosciences, Layton McCurdy Endowed Chair, Director, Brain Stimulation Laboratory (BSL) Editor-in-Chief Brain Stimulation Medical University of South Carolina, Charleston, South Carolina Table of Contents Cover image Title page Copyright Dedication Preface Acknowledgments About the Authors Section I The Neuroscience Model Chapter 1 Introduction Chapter 2 Neuroanatomy Chapter 3 Cells and Circuits Chapter 4 Neurotransmitters Chapter 5 Receptors and Signaling the Nucleus Chapter 6 Genetics and Epigenetics Section II Modulators Chapter 7 Hormones and the Brain Chapter 8 Plasticity and Adult Development Chapter 9 Immunity and Inflammation Chapter 10 The Electrical Brain Section III Behaviors Chapter 11 Pain Chapter 12 Pleasure Chapter 13 Appetite Chapter 14 Anger and Aggression Chapter 15 Sleep Chapter 16 Sex and the Brain Chapter 17 Social Attachment Chapter 18 Memory Chapter 19 Intelligence Chapter 20 Attention Section IV Disorders Chapter 21 Depression Chapter 22 Anxiety Chapter 23 Schizophrenia Chapter 24 Alzheimer’s Disease Bibliography Answers to End-of-Chapter Questions Index Copyright Acquisitions Editor: Chris Teja Editorial Coordinator: Emily Buccieri Strategic Marketing Manager: Rachel Mante Leung Production Project Manager: Linda Van Pelt Design Coordinator: Elaine Kasmer Manufacturing Coordinator: Beth Welsh Prepress Vendor: TNQ Books and Journals Third edition Copyright © 2019 Wolters Kluwer. © 2013, 2007 by LIPPINCOTT WILLIAMS & WILKINS, a WOLTERS KLUWER business All rights reserved. This book is protected by copyright. No part of this book may be reproduced or transmitted in any form or by any means, including as photocopies or scanned-in or other electronic copies, or utilized by any information storage and retrieval system without written permission from the copyright owner, except for brief quotations embodied in critical articles and reviews. Materials appearing in this book prepared by individuals as part of their official duties as U.S. government employees are not covered by the above- mentioned copyright. To request permission, please contact Wolters Kluwer at Two Commerce Square, 2001 Market Street, Philadelphia, PA 19103, via email at [email protected], or via our website at lww.com (products and services). 9 8 7 6 5 4 3 2 1 Printed in China Library of Congress Cataloging-in-Publication Data Names: Higgins, Edmund S., author. | George, Mark S. (Mark Stork), 1958- author. Title: The neuroscience of clinical psychiatry : the pathophysiology of behavior and mental illness / Edmund S. Higgins, Mark S. George. Description: Third edition. | Philadelphia : Wolters Kluwer, | Includes bibliographical references and index. Identifiers: LCCN 2017058724 | ISBN 9781496372000 (alk. paper) Subjects: | MESH: Mental Disorders–physiopathology | Nervous System– physiopathology | Neuropsychology–methods Classification: LCC RC483 | NLM WM 140 | DDC 616.89–dc23 LC record available at https://lccn.loc.gov/2017058724 This work is provided “as is,” and the publisher disclaims any and all warranties, express or implied, including any warranties as to accuracy, comprehensiveness, or currency of the content of this work. This work is no substitute for individual patient assessment based upon healthcare professionals’ examination of each patient and consideration of, among other things, age, weight, gender, current or prior medical conditions, medication history, laboratory data and other factors unique to the patient. The publisher does not provide medical advice or guidance and this work is merely a reference tool. Healthcare professionals, and not the publisher, are solely responsible for the use of this work including all medical judgments and for any resulting diagnosis and treatments. Given continuous, rapid advances in medical science and health information, independent professional verification of medical diagnoses, indications, appropriate pharmaceutical selections and dosages, and treatment options should be made and healthcare professionals should consult a variety of sources. When prescribing medication, healthcare professionals are advised to consult the product information sheet (the manufacturer’s package insert) accompanying each drug to verify, among other things, conditions of use, warnings and side effects and identify any changes in dosage schedule or contraindications, particularly if the medication to be administered is new, infrequently used or has a narrow therapeutic range. To the maximum extent permitted under applicable law, no responsibility is assumed by the publisher for any injury and/or damage to persons or property, as a matter of products liability, negligence law or otherwise, or from any reference to or use by any person of this work. LWW.com. Dedication To my two sons, who assisted with the artwork on Tuesday mornings at local coffee shops while waiting for school to start. —ESH To my many mentors—four formally designated in research fellowships, numerous others who’ve just helped and taught along the way—and the students and patients who have taught me so much as well. May we all be lifelong students!! —MSG Preface Neuroscience is the basic science of psychiatry. Neuroscience describes the brain mechanisms that gather information from the external and internal world, analyze the information, and execute the best response. Psychiatric disorders are the result of problems with these mechanisms. The increased accessibility to the workings of the brain in the past 30 years has resulted in an explosion of information about neuroscience. Different lines of research such as brain imaging and animal studies along with more traditional postmortem analysis, study of medication effects, and genetic studies have transformed the way we conceptualize normal and abnormal behavior. Bits and pieces of the neuroscience literature have filtered up to the practicing clinician, but a comprehensive understanding of the field is almost inaccessible to all but the most dedicated self-educators. The jargon is foreign and difficult to navigate. The standard textbooks are thick with contributions from multiple authors and almost impossible to read cover to cover. The relevance to the practice of psychiatry can sometimes be hard to appreciate. We hope this book will provide a way for residents and practicing clinicians to gain a thorough appreciation for the mechanisms within the brain that are stimulating (or failing to stimulate) their patients. We also hope that the reader will have more accurate answers for the patient who asks, “What’s causing my problem?” Likewise, we hope the reader will be better prepared for the increasingly difficult neuroscience questions that appear on board certification tests. If we’ve learned anything from our studies on the brain, it is that LEARNING IS WORK! The brain increases its metabolism when conducting academic assignments. The process of focusing one’s attention, understanding the concepts, and storing the new information requires energy. There is no passive learning. Consequently, when learning is interesting and relevant it requires less energy. We have made every effort to make this material appealing and easy to consume. Pictures, drawings, and graphs have been liberally incorporated to allow the reader to learn the concepts quickly and efficiently. Every effort has been made to keep the material short and concise, but not too simple. Finally, we think information that is relevant to the reader is easier to retain, so we have tried to keep bringing the focus back to the practice of psychiatry. We intend our book to be for three populations. First, it is for those in training: psychiatrists, psychologists, counselors, and allied physicians. Second, it is for psychiatric residents seeking to review the topics in preparation for their board examinations. And last, it is for the practicing clinician who was trained before the revolution in neuroscience and who would like to become more up-to-date and familiar with the field. We hope that the reader will have a thorough—soup to nuts—understanding of the important topics in neuroscience and will henceforth be able to read and comprehend the future research in this field. Edmund S. Higgins, MD Mark S. George, MD Edmund S. Higgins, MD Mark S. George, MD Acknowledgments The authors wish to thank the following people for their assistance with this manuscript: Sherri A. Brown for her assistance with the artwork; Pamela J. Wright-Etter, MD, and Robert J. Malcolm Jr, MD, who reviewed individual chapters; and Laura G. Hancock, DO, and L. William Mulbry, MD, residents who reviewed the entire book. We also wish to thank all those readers who pointed out the typos in the first edition. Figures 3.5–3.7 and 22.2 and the dolphin in Chapter 15, Sleep, were drawn by Fess Higgins. For the third edition we would like to thank Eric Brueckner, DO, and Edward M. Kantor, MD, for facilitating a review of the book by the MUSC fourth year residents—and all the helpful feedback they offered. About the Authors Edmund S. Higgins, MD Edmund S. Higgins, MD, is a Clinical Associate Professor of Psychiatry and Family Medicine at the Medical University of South Carolina (MUSC). He received his medical degree from Case Western Reserve University School of Medicine. He completed residencies in family practice and psychiatry at MUSC. He is currently providing psychiatric care for South Carolina Department of Corrections and has a tiny private psychiatric practice. He lives on Sullivan’s Island, SC.  Mark S. George, MD Mark S. George, MD, is a Distinguished Professor of Psychiatry, Radiology, and Neuroscience as well as Director of the Brain Stimulation Division, Psychiatry at the Medical University of South Carolina (MUSC), Charleston. He also holds the Layton McCurdy Endowed Chair in Psychiatry and was the original director of the Center for Advanced Imaging Research at MUSC. He received his medical degree and completed dual residencies at MUSC in both neurology and psychiatry and is board certified in both areas. After a fellowship in London and 4 years at the National Institute of Mental Health, he returned to Charleston where he has conducted pioneering work with functional imaging of the brain, transcranial magnetic stimulation and vagus nerve stimulation, and other forms of brain stimulation. He is on several editorial review boards, has published over 500 scientific articles or book chapters, and has written or edited 6 books. He has been the editor-in-chief of Brain Stimulation for the past decade since it began, a journal published by Elsevier. He also resides on Sullivan’s Island, SC. SECTION I The Neuroscience Model CHAPTER 1 Introduction Overview The brain has not always been of great interest to humankind. Most ancient cultures did not consider the brain to be an important organ. Both the Bible and Talmud fail to mention diseases related to the central nervous system (CNS). Egyptians carefully embalmed the liver and the heart but had no use for the brain; they actually scooped it out and threw it away. (If there really is an Egyptian afterlife—those poor pharaohs are spending eternity without a brain.) Now we are in the Neurocentric Age and view the brain as the most complex organ in the universe. George H. W. Bush, the former President of the United States dedicated an entire decade to the study of the brain. You don’t see the gastrointestinal tract get that kind of attention. We’ve come a long way. This book is intended to bring you an up-to-date review of how the brain does all the amazing things we now recognize it is capable of doing. The best way to read this book is from cover to cover, which should give you a thorough, but easily digestible, understanding of the mechanisms of normal behavior and mental illness. Before we get started, we want to review a few basic principles or themes that run through this book. Heredity It has long been recognized that mental illness travels in families. In 1651 in The Anatomy of Melancholy, Robert Burton succinctly summarized this concept at least for alcoholism when he wrote: “One drunkard begets another.” Fast forward to the 20th century and in-depth family studies provide similar, although less colorful, findings. For example, with schizophrenia, if one family member has the illness, the likelihood that a relative will also develop the disease increases the more closely they are related. The determining variable appears to be the percentage of shared DNA (Figure 1.1).  Figure 1.1 As the shared genetic profile with someone having schizophrenia increases, the risk of developing schizophrenia also increases. (Data from Gottesman II. Schizophrenia Genesis. New York: W.H. Freeman; 1991.) The domestication of animals provides another example of the genetic control of behavior. Charles Darwin, without any knowledge of genes, believed the temperament of domestic animals was inherited. Dmitry Belyaev, a Russian geneticist, validated this with his famous farm-fox experiment in Siberia. Belyaev domesticated wild foxes simply by selecting and breeding the tamest animals. He started with 130 wild foxes and used a simple test of tameness. Humans approached the caged foxes, and those that were most tolerant were mated. The process was repeated with the offspring, each time mating the tamest animals from the litter. Within 20 years the foxes were domesticated. Within 40 years, the offspring of wild foxes were literally house pets. Of interest, the brains of the domesticated foxes produced less corticosteroids (the stress hormones) and higher levels of serotonin than did the wild foxes.  It is a bit unsettling to accept that our personalities, seemingly molded by the events of our lives, are actually hardwired from our genes. Eccentric, stingy, gregarious, thin-skinned, etc., are more a product of our genes than our environment. But what role does the environment play in the development of our personalities? Bouchard and others have tried to tease out nature and nurture by looking at personality characteristics in monozygotic (identical) and dizygotic (fraternal) twins—reared together and reared apart. Using personality tests to assess the five major personality traits, they found more correlations for monozygotic twins compared with dizygotic twins regardless of whether they were raised together or apart (Table 1.1). In other words, the monozygotic twins reared apart shared more personality characteristics than did the dizygotic twins reared in the same household. Bouchard concluded that personality traits are strongly influenced by inheritance and only modestly affected by environment. (The lay press unfortunately summarized this research as “Parents Don’t Matter.”) Table 1.1 The Correlations for Five Personality Traits in Monozygotic Twins and Dizygotic Twins Reared Apart and Together a Monozygotic Monozygotic Raised Apart Raised Personality Trait Together 0.41 0.54 Extraversion  0.49 0.48 Neuroticism 0.54 0.54 Conscientiousness 0.24 0.39 Agreeableness 0.57 0.43 Openness 0.45 0.48 Mean aThe mean correlations are surprisingly similar to the lifetime risk of developing schizophrenia for identical (monozygotic) and fraternal (dizygotic) twins shown in Figure 1.1. Figure 1.2 shows a remarkable example of identical twins separated at birth (5 days old) and raised in different households—one in Brooklyn, the other in New Jersey. They did not meet again until they were 31 years old. Both are firefighters, bachelors, with mustaches and metal frame glasses. Not only do they have the same mannerisms, but they also laugh at the same jokes and enjoy the same hobbies. Yet, they were exposed to entirely different environmental influences throughout their lives. Our individuality—who we are, how we socialize, what we like, even our religious beliefs—are likely influenced more by the brain we are born with than by the experiences we have along the way. Figure 1.2 Gerald Levy (left) and Mark Newman (right) are identical twins who were separated at birth, yet have made many of the same choices in life. (With permission from The Image Works, Woodstock, New York.) A word of caution: even though there is about a 50% concurrence between monozygotic twins for personality traits and schizophrenia, the other 50% are out of sync—yet they share the same DNA. This is also true for bipolar disorder, alcoholism, and panic disorder. About half the monozygotic twins have the same illnesses, whereas the other half do not. Clearly, our brains are more programmed by our genes than we previously believed, but that does not explain everything. Experiences during our lives impact our personality, particularly trauma, and especially when the trauma occurs early in life. The challenge for us is to unravel the brain mechanisms that are predetermined by genetics and understand how they can change in response to the environment. The Brain Is Dynamic In 1894, Santiago Ramón y Cajal, maybe the first neuroscientist, stated in a lecture to the Royal Society of London, “the ability of neurons to grow in an adult and their power to create new connections can explain learning.” This is often cited as the origin of the synaptic theory of memory. Hebb, a Canadian psychologist, wrote in 1949 a phrase that is loosely paraphrased as neurons that fire together, wire together. These men surmised that the brain must change in some way for details to be remembered, but their tools were not sophisticated enough to identify the mechanisms. Proving that the adult brain can change in response to experience (plasticity) has been the most exciting discovery in neuroscience. Although many individuals have been involved in this research, no single individual has done more than Eric Kandel. Kandel was able to prove what Ramón y Cajal could only speculate about—that learning changes the cells of the brain and even the chemical composition of those cells. Kandel worked with the simple sea snail Aplysia because it can remember and has only about 20,000 neurons in its entire CNS (compared with 100 billion in humans). Kandel taught the snail a few simple tasks—habituation (gradually ignoring an innocuous stimulus) and sensitization (remembering an aversive stimulus) (Figure 1.3).  Figure 1.3 Aplysia’s gill-withdrawal reflex. A: Aplasia slugging along. B: Resting state with gill exposed. C: Gill withdrawal to mild stimulus to the siphon. Habituation to this stimulus will develop with repeated exposure. D: A strong gill-withdrawal reflex persists when a strong stimulus is applied to the tail. (Adapted from Kandel ER. In Search of Memory: The Emergence of a New Science of the Mind. New York: W. W. Norton & Company; 2006.) For Aplysia, the gill with its siphon is a sensitive and important organ—one that quickly withdraws with any sign of danger. Habituation is induced by sequentially touching the siphon with a soft brush. With repetition, the snail learns to ignore the gentle stimuli. Sensitization, on the other hand, is elicited with an electrical shock to the tail coupled with the soft brush of the siphon. This is something not to forget. Indeed, after many sessions the gill is still retracted with great vigor. After training Aplysia to habituate or react (forget or remember), Kandel and his colleagues dissected and analyzed the changes in the sensory neurons. With habituation the neurons regressed (don’t need them), whereas with sensitization the number and size of the synaptic terminals grew (Figure 1.4). Kandel wrote, “we could see for the first time that the number of synapses in the brain is not fixed – it changes with learning!” And there may be nothing more important in a brain than learning and memory.  Figure 1.4 A: The number of synapses from the average sensory neuron to the motor neuron changes with learning. B: A schematic representation of morphologic changes in the connections between sensory and motor neurons. (Adapted from Kandel ER. In Search of Memory: The Emergence of a New Science of the Mind. New York: W.W. Norton & Company; 2006.) Making the Diagnosis Another theme in this book is the difficulty making an accurate diagnosis. We are not big fans of the Diagnostic and Statistical Manual now in its fifth edition (DSM-5) or the International Classification of Diseases now in its tenth revision (ICD-10). Both of these classification systems are based on symptoms, not actual neurophysiology. It is all self-reported. Therefore patients who are stoic are likely to underreport symptoms, and hysterical patients are... well, all over the place. The former may not receive a diagnosis, and the latter receives too many. Neither gets a diagnosis that accurately reflects what occurs in the brain. Further complicating the symptom-based categorization is that the brain only has a few ways to show distress: psychosis, depression, anxiety, autistic behavior, etc. However, there are probably hundreds of different causes for any of these symptoms. Figure 1.5 shows a metaphor for this concept. Just as all the aquifers and streams in the Midwest ultimately coalesce into the mighty Mississippi River, all enduring psychosis (for example) will be called schizophrenia, even though many different genes and negative experiences are responsible. With symptom-based categorization, we cannot differentiate one form of schizophrenia from another. The biology may be different, but the symptoms are the same. The main point is this: there are no laboratory tests, X- rays, brain scans, or genetic profiles that can assist in separating the different forms of mental illness—with the possible exception of Alzheimer’s disease. Figure 1.5 All the water that flows past New Orleans is called the Mississippi River, even though it comes from many different locations. Psychiatric disorders develop from heterogeneous pathophysiology, but, within a diagnostic class, all presentations are given the same name. We believe psychiatric diagnosis is about where pneumonia was in the mid- 19th century. At that time, pneumonia was described by several symptoms: cough, sputum production, fever, etc. It was not until the recognition of the germ theory that the different causes of pneumonia were accurately identified. Andrew Solomon, in his book Far From the Tree, provides a similar change in nomenclature that has occurred for some forms of autism. Autism is a catchall category for an unexplained constellation of symptoms. Whenever a subtype of autism with a specific mechanism is discovered, it ceases to be called autism and is assigned its own diagnostic name. Rett syndrome produces autistic symptoms; so, often, do phenylketonuria (PKU), tuberous sclerosis, neurofibromatosis, cortical dysplasia-focal epilepsy, Timothy syndrome, fragile X syndrome, and Joubert syndrome. People with these diagnoses are usually described as having “autistic-type behaviors,” but not autism per se. This is an excellent description of how our diagnostic terms (such as autism, schizophrenia, depression, etc.) are typically reserved for that which we cannot explain. Once we find the mechanism, we give it a medical name. Ostensibly, all psychiatric disorders will have a medical name in the future. We simply haven’t discovered them yet. Tom Insel, the former director of the NIMH, would like to see our field move toward diagnostic criteria that incorporate biomarkers: genetics, neuroimaging, and metabolic findings, along with signs and symptoms. The NIMH has launched the Research Domain Criteria (RDoC) to classify mental disorders with more biomedical precision. Insel would like to see mental health evaluations identifying and intervening before the problems develop into a full disorder, similar to the way we treat hyperlipidemia and hypertension to prevent heart disease. Unfortunately, with our current knowledge, the neurobiologic markers are not precise enough... yet. The Spectrums of Brain Functions We believe psychiatric disorders occur along spectrums rather than in discrete categories. Recent findings with prosopagnosia provide a good example of a spectrum. Prosopagnosia, “face blindness,” is a neurologic disorder in which patients, who are otherwise intellectually intact, are unable to recognize human faces—even their own face. It can be quite problematic, for example, when a mother picks up the wrong child at school. We all have this to some degree, but patients with the disorder are significantly further along the impairment scale. Prosopagnosia was described in the 19th century. What is new is the other end of the spectrum, what Russell and his colleagues call “super-recognizers: people with extraordinary face recognition ability” in their 2009 paper. Apparently, Scotland Yard employs super-recognizers to review video footage of crimes and identify the culprit. Russell et al. stated, “these ‘super-recognizers’ are about as good at face recognition and perception as developmental prosopagnosics are bad.” Facial recognition is a good example of a brain function that occurs along a spectrum from “severely impaired” to “exceptional,” with most of us residing in the middle. We believe psychiatric disorders reside along similar spectrums, which are best understood as thoughts/feelings/behaviors controlled by the brain, with most of us having average capacity and some individuals functioning at either extreme. Localizing of Function Before the 1860s the brain was seen as a single multipurpose organ, much the way we currently view the liver or pancreas. The French physician Paul Broca with his famous case in 1861 confirmed for the first time that certain functions were localized to specific regions of the brain (Figure 1.6). Broca’s patient developed a sudden loss of articulate speech. All he could say was one syllable: “tan.” His utterances could convey great emotional tone (he retained oral dexterity, and he could hear and comprehend), but one syllable was all he could express. After his death, an autopsy revealed a lesion of his left frontal lobe— what is now called Broca’s aphasia. The fact that almost all similar cases were on the left hemisphere and that similar right hemispheric lesions did not affect speech also led Broca to identify left/right dominance for some functions.  Figure 1.6 The preserved brain of the patient who helped Broca convince physicians that some functions—in this case the ability to speak—were localized in the cerebrum. (Adapted from Bear MF, Connors BW, Paradiso MA, eds. Neuroscience: Exploring the Brain. 4th ed. Baltimore: Lippincott Williams & Wilkins; 2015.) The belief that one function or emotion resides in a specific area in the brain appeals to our desire for uncomplicated organization. Figure 1.7 shows the sort of characterization of the male brain that we would like to believe is possible. It is rarely this simple, particularly with behavior. When we do find discrete regions of the brain, which appear to control one function, it is usually what we would consider in the realm of neurology: motor, sensory, sleep, speech, etc. Typically, behaviors (and consequently mental illness) are a confluence of networks communicating back and forth between different regions of the brain. It can be confusing and convoluted. This is why it has been so difficult to determine where behaviors arise in the brain and to identify what goes wrong in mental illness. Consequently, we need to be cautious when reading new studies that purport to have localized a specific behavior to a discrete region of the brain.  Figure 1.7 Localization of function in the male brain. Intuitively correct, but not supported by research. Modern Research: How We Study the Brain Dissection We do not biopsy psychiatric brains. Probably the only time live brains are touched in psychiatric patients occurs in those rare occasions when a patient undergoes neurosurgery for a separate disorder. In all other instances, as with Broca, we have to wait for the patient to die to examine the brain tissue..., and Broca had it easy. Examining one brain from a psychiatric patient has been of little value in understanding the pathology of psychiatric disorders. Because psychiatric symptoms likely reside in diffuse networks, finding and identifying the pathology has been difficult, so researchers need to compare many diseased and “normal” brains. This approach has spawned the creation of brain banks. Brain banks (not FDIC insured) are laboratories that collect and store brains from patients with known disorders. The largest consortium in the United States is the NIH NeuroBioBank, which includes six centers (Harvard, Mt Sinai, the Universities of Maryland, Pittsburgh, and Miami, and UCLA) and has about 12,000 brains in storage. They collect brains from patients who had bipolar disorder, schizophrenia, borderline personality disorder, and autism (to name a few). Studies typically involve only a small amount of tissue so that one brain can be used in many different studies. Dr Michelle Freund of NIH recently stated that 10,000 samples of tissue were analyzed in various studies in the past 2 years. The new trend in brain banks is to gather clinical information premortem to compare and contrast with postmortem findings. This particularly applies to studies of Alzheimer’s disease. Of interest, the brain banks are always in need of normal brains. Give them a call if you think you have one. The brain has the consistency of gelatin. To see nerve cells, it is necessary to fix the brain before cutting thin slices. One of the advantages of central administration of the NIH brain banks is the ability to establish uniform criteria for preparing and storing the brains. This enables analysis of brains from different centers in the same study. Brain cells are not easily identified in an unstained brain. In 1873 an Italian physician, Camillo Golgi, discovered a selective silver stain that allowed researchers to visualize the individual nerve cells in what would otherwise be a uniform blob of color. Termed the Golgi stain, and still used today, researchers can see sharp black images of individual nerve cells and identify specific parts such as the cell body and the dendritic branches (Figure 1.8). The morphology of the neuron (meaning the shape and structure) is a topic that comes up time and again in this book. We discuss alterations in neuron morphology as an indication that something is different in the brains of those with certain disorders: mental retardation, substance abuse, schizophrenia, etc.  Figure 1.8 Pyramidal nerve cells after incubation with Golgi’s silver stain. Only about 1% of the neurons absorb the stain, which allows for the identification of individual cells in what would otherwise be a very crowded slice. (Adapted from Bear MF, Connors BW, Paradiso MA, eds. Neuroscience: Exploring the Brain. 4th ed. Baltimore: Lippincott Williams & Wilkins; 2015.) Imaging Noninvasive analysis of the CNS has transformed the way we study behavior and mental disorders. Early attempts to image the brain were unhelpful, painful, and even dangerous. An ordinary X-ray provides little information because the brain is soft and is not radiopaque. Back in the day, searching for displacement of calcified structures (indirect evidence of a mass) was about the best they could hope for. Pneumoencephalography, in which cerebrospinal fluid is removed and replaced with air to enhance visualization of the CNS, is an example of the painful and dangerous extremes that were foisted on patients in earlier times. The development of noninvasive imaging techniques (Table 1.2) has led to a small revolution in neuroscience. Although the functional studies (positron emission tomography [PET], single photon emission computed tomography [SPECT], and functional magnetic resonance imaging [fMRI]) remain largely limited to research, the noninvasive structural analyses (computed tomography [CT] and magnetic resonance imaging [MRI]) have transformed the practice of neurology. Diffusion tensor imaging (DTI), a technique using MRI scans to measure the movement of water in tissue, creates images of white matter tracts. Table 1.2 A Brief History of Imaging Methods Used to Analyze the Central Nervous System A word of caution regarding brain imaging studies and psychiatric disorders: throughout this book, we mention numerous studies examining brain volume or brain function for various psychiatric disorders. However, Ioannidis reviewed brain volume studies and found that the reported number of positive studies far exceeded what would be expected based on the power estimates of the studies. He believes the studies that do not find a significant difference between control subjects and patients are seldom published. More recently, Daniel Weinberger, one of the original leaders in psychiatric brain imaging, wrote an editorial urging caution before uncritically accepting reports purporting to find “the elusive psychiatric ‘lesion.’” Weinberger noted that common variables more likely found in patients than controls (smoking, substance abuse, excessive weight, stress, medication use, and head motion, to name a few) can confound the results and give the illusion of a neurobiologic finding. Ioannidis and Weinberger remind us that, in spite of the significant statistics and impressive images provided in journals, the studies may be more artifact than actual differences.  Point of Interest The figure shows a method of using imaging studies frequently found in the literature. That is, one functional study is subtracted from another and the result is superimposed on a structural image. In this case the subject is performing a finger opposition task with his right fingers while in a SPECT scanner (A). The white arrow shows the activation of the left motor cortex. (B) A SPECT scan in the controlled state (not moving) is also produced. (C) The control image is subtracted from the task image. (D) The results are superimposed on an MRI of the same location, and drawings of the human homunculus along the motor cortex are added for further understanding. Nonhuman Animal Studies Nonhuman animal studies provide another approach to understanding the marvels of the brain. The nonhuman animal brain is accessible in ways that are beyond the ethics of human research. Although they might have paws and whiskers, nonhuman brains have much in common with those of humans. The protein-coding regions of the mouse and human genomes are 85% identical. Nature is conservative, and many of the molecular and cellular mechanisms that underlie behavior are preserved from one species to the next. However, animals do not possess a similarly developed human cerebral cortex, nor can we ever be sure they actually have the psychiatric symptoms being studied. In spite of these limitations, tweaking animal brains has been invaluable in enhancing our understanding of the functions of the brain. Ablation studies—removing part of the brain and observing how the animal behaves—are the crudest animal studies. Electrical stimulation provides more precision and has been the bedrock of neuroscience research. However, the more modern approaches have focused on the genes. Markers of Gene Activation Two words of advice we would give to any student interested in neuroscience: gene expression. The DNA that gets turned on (or alternatively turned off) is referred to as “gene expression,” and this process controls the growth and activity of the brain. Understanding which genes are responsible is the key to understanding the brain and behavior. Researchers can now measure mRNA or proteins that result from gene expression. Cyclic adenosine monophosphate responsive element–binding protein (CREB) and proteins in the Fos family are two transcription factors that are frequently used as markers of gene expression. Identifying CREB or c-Fos in a postmortem brain slice helps pinpoint the areas in the brain that were active in the animal during the experimental manipulation. Knockout Mice Animals (typically mice) can be engineered so that specific genes are turned off—rendered mute. Animals with silenced genes are called knockout mice. They are raised (if possible) and observed for changes in behavior compared with control mice—often called “wild” mice. Knockout mice have been used to understand obesity, substance abuse, and anxiety. Although these studies represent a valuable research tool, one has to be cautious about generalizing from the results. The downstream effects of silencing the gene during development can never be fully appreciated. Transgenic Mice Transgenic mice are genetically engineered creatures. DNA from one organism is introduced into the DNA of a mouse egg, which is then fertilized. The adult mouse incorporates the foreign DNA into its genome. For example, DNA from jellyfish encoding for fluorescent proteins has been inserted into the mouse genome. Brain slices from these mice “light up” when viewed under fluorescent microscopes. Likewise, the ability to insert disease-causing DNA into mice and then observe the damage it causes to the brain has revolutionized neurology. Viral-Mediated Gene Transfer Viruses can be used as a vehicle to insert a section of DNA into the brain of living animals at specific locations. When the DNA is incorporated into the host DNA, new genes are expressed with possible alterations in behavior. For example, a virus was used to implant the DNA for the vasopressin receptor in the ventral pallidum of promiscuous voles. Responding voles were transformed into monogamous, family-oriented, card-carrying social conservatives (specifics in Chapter 17, Attachment). Lighting Up the Brain Despite all these wonderful techniques to investigate the brain, we still do not have a good grasp of what is actually going on. That is, how activity in cells and networks gives rise to memories, thoughts, and feelings. Furthermore, we only vaguely grasp the failures that produce psychiatric disorders. Optogenetics is a new technique that gives more precision in understanding the effects of distinct neural circuits and behavior in animals. Optogenetics describes the combination of optics and genetics to make neurons respond to light. Figure 1.9 provides the basics of this method. It starts with green algae, which possess receptors that, when exposed to light, open and allow ions to pass. When the DNA for these receptors is inserted into DNA in neurons in rodents, light will open the receptor allowing ions to pass and “fire” the neuron. Then, conveniently, shining a light on the neurons can activate the specific network and allow researchers to observe changes in behavior when those neurons are turned “on” and “off.” This technique has been used to elucidate neural circuits in animal models of anxiety, depression, schizophrenia, addiction, and social dysfunction.  Figure 1.9 The DNA from light-sensitive algae, when inserted into the DNA of a rodent, enables the neuron to fire in the presence of a laser light—a process that is called optogenetics. Following the DNA The rapid growth of genetic knowledge requires its own chapter, but there are two techniques for analyzing the brain that are worth mentioning now. Microarrays DNA microarrays (also called gene chips) enable researchers to compare the mRNA (and therefore gene activity) found in tissue samples with DNA of known identity. The microarray is a chip no bigger than a postage stamp with thousands of different DNA molecules, multiplied, segregated, and attached in separate tiny locations (Figure 1.10).  Figure 1.10 The microarray chip contains multiple copies of many different genes so that a broad spectrum of gene activity can be analyzed quickly in a scanner. (Adapted from Friend SH, Stoughton RB. The magic of microarrays. Sci Am. 2002;286:44–53.) The mRNA from the tissue being studied is transcribed to DNA, labeled with fluorescent markers, and dropped onto the microarray chip. The single-stranded DNA from the tissue sample will bind with similar single-stranded DNA on the microarray. The chip is then read in a scanner that calculates the amount of binding between the tissue DNA and the chip DNA in each discrete spot, giving an estimate of that specific gene activity in the tissue. As an example, this procedure was done with small samples from the prefrontal cortex of schizophrenic and control postmortem brain. The schizophrenic brains showed reduced expression of myelination-related genes, suggesting a disruption in the myelin as part of the pathogenesis of schizophrenia (see Chapter 23, Schizophrenia). Growing Brain Cells: Induced Pluripotent Stem Cells In 2006, Shinya Yamanaka found a way to turn fully differentiated adult cells back into pluripotent stem cells. This means, cells already formed into tissuelike skin or fibroblasts, after some manipulation, act like embryonic stem cells and can develop into any type of cell in the body—without all the ethical questions provoked by using human embryos. Called induced pluripotent stem cells, the trick is to fool the cell into removing the “breaks” that constrain cellular differentiation. With considerable trial and error, Yamanaka, who went on to win a Nobel Prize in 2012, discovered that, by introducing into the cell four genes for transcription factors, he could turn back the cellular “clock” (Figure 1.11).  Figure 1.11 The creation of pluripotent stem cells from fibroblasts enables researchers to grow “minibrains” and may enable the development of better models of neuropsychiatric disorders. Fred Gage’s laboratory (the Salk Institute for Biological Studies) unitized this procedure to study neurons from bipolar patients—without having to biopsy the brains. They reprogrammed fibroblasts and grew hippocampal dentate gyrus– like neurons from bipolar patients who were “lithium responders” and compared them with bipolar patients who were nonresponders to lithium and normal controls. They found hyperexcitability in the neurons from bipolar patients, which was reversed by lithium, but only in those patients who responded to lithium. It is unclear if this specific finding will have enduring significance, but what it represents (disease in a dish, as some have called it) is an extraordinary way to study the physiology of neurons from patients with mental illness. The Controlled Trial It is discouraging that the brain is so resistant to change. It is more discouraging to read about eccentric clinicians, parents, teachers, and other meddlers expounding the effectiveness of unproven interventions to reduce symptoms or improve behavior. Sugar and hyperactivity were “known” to have a cause-and-effect relationship that has failed to materialize in controlled trials. It is important to prove that our efforts to heal are actually helping. Unfortunately, there are many instances of treatments that proved to be ineffective and too many that are even harmful. Perhaps the greatest research tool in health care has been the randomized controlled clinical trial. With controlled studies we can determine with some confidence how effective interventions might be, which then gives us some insight into the workings of the brain. But replication of studies is the hallmark of effective treatment. Sexy, innovative studies are like catnip to journal editors and NPR news. However, a recent study in Science suggests that we need to do more to “verify whether we know what we think we know.” The authors of the Open Science Collaboration attempted to replicate 100 psychological studies from three prominent journals. The results the second time around were embarrassingly disappointing. Although 97% of the original studies were statistically significant, only 36% were so in the replication. Ouch! We (ESH & MSG) are guilty of hearing the siren call of new, innovative studies and falling in love with the results. In this third edition we have made considerable efforts to substantiate previous findings and throw overboard the ones that have not stood the test of time. CHAPTER 2 Neuroanatomy Cerebral Cortex There are many large textbooks with extensive writings and illustrations providing all the known specifics about the anatomy of the nervous system. If you are looking for that sort of detail, then you are reading the wrong book. We —on the other hand—have tried to limit our discussion of neuroanatomy to those structures frequently identified in the scientific articles that are relevant to the clinician treating mental illness. First, we feel compelled to review a bit about the developing brain. You can best understand how brain anatomy is organized by remembering how it formed itself in the first place. Development The fertilized egg quickly divides and differentiates into an embryo with three cell lines: the ectoderm, mesoderm, and endoderm (see Figure 1.11 as example). A portion of the ectoderm folds and forms the neural tube, which becomes the rudimentary nervous system. The most anterior cells of the nervous system spend the ensuing weeks proliferating, migrating, and developing into the different regions of the brain. The process of differentiating is almost unbelievable. How one undeveloped cell decides it should be a neuron while a similar one becomes an astrocyte is simply amazing. The evidence suggests that chemical signals between cells turn the DNA on and off, which then controls the destiny, but orchestrating all this is almost beyond comprehension. The migration of cells to their appropriate location in the brain is another remarkable aspect of the developing brain. Neuroblasts (undeveloped neural cells) multiply in an area called the ventricular zone. Then they shinny up radial cells (specialized glial cells), which form a kind of scaffolding to build the cerebral cortex (Figure 2.1). As the neuroblasts reach the surface of the brain, they differentiate into the various mature neurons and astrocytes that make up the gray matter.  Figure 2.1 A: Cross section of the brain of a 50-day-old fetus. B: Neuroblasts climb up the radial glial cells to the developing gray matter. C: Inhibitory neurons develop from neuroblasts that migrate tangentially from lower regions of the brain. Other neuroblasts migrate tangentially from the bottom of the ventricles. These neuroblasts typically develop into the inhibitory interneurons. They start in a different location and must come up and around before they intermingle with the other neuroblasts climbing the radial cells. It boggles the mind that all these cells find their correct location and make the right connections while we can barely find what we are looking for in Walmart. A residual portion of the ventricular zone remains in the adult brain and allows limited neurogenesis to continue beyond the fetal stage—more on this topic in Chapter 8, Plasticity and Adult Development.  Disorder Mental Retardation The migration of neurons to their specific location is a critical and venerable period of brain development. Fetal alcohol syndrome may in part be a result of aberrant migration due to the toxic effects of ethanol. Radiation is another insult that deters the traveling neuron. Studies of pregnant Japanese women, who were in proximity to the epicenter when the atomic bombs were dropped, found that 80% of the children who developed severe mental retardation were exposed to the radiation between 8 and 16 weeks after conception—the time of peak migration. The migrating and differentiating neuroblasts slowly form into the six layers of the cerebral cortex. Figure 2.2 shows how the process proceeds. The inner layers are formed first: layer IV, then layer V, and so on. This means that cells destined for the outer layers must climb past the other neurons before locating their place in the brain.  Figure 2.2 The six layers of the cerebral cortex develop in reverse order as the neuroblasts migrate up from the ventricular zone. (Adapted from Bear MF, Connors BW, Paradiso MA, eds. Neuroscience: Exploring the Brain. 4th ed. Baltimore: Lippincott Williams & Wilkins; 2015.) The cerebral cortex is made up of white matter and gray matter (Figure 2.3). The gray matter is where the nerve cells and synapses reside. This is where the action occurs psychologically—where we think and feel—where depression, schizophrenia, and dementia likely develop. The white matter is primarily myelinated axons transporting impulses between the gray matter and lower brain structures. The white matter makes up the circuits that connect the regions of the brain.  Figure 2.3 The six layers of the neocortex, from the pial surface above layer I to the white matter below layer VI. (From Snell RS. Clinical Neuroanatomy: An Illustrated Review with Questions and Explanations. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2001.) When we say a “neuron,” we are usually thinking of the large pyramidal neurons with their triangular-shaped cell bodies. They make up approximately 75% of the cortical neurons. They have a single apical dendrite pointed toward the pial surface and a number of basilar dendrite branches projecting horizontally. The axons project (and send impulses) to other cortical regions or the deeper structures of the subcortex. The pyramidal neurons receive signals from the other brain regions as well as from the local interneurons. The afferent signals from other regions are typically excitatory signals that encourage the neuron to generate its own impulse. The interneurons are typically γ-aminobutyric acid neurons, which inhibit the pyramidal neuron and reduce the likelihood that it will fire. Brodmann’s Areas In the early part of the 20th century, many neuroanatomists were struggling to divide the neocortex into structurally distinct regions. Korbinian Brodmann, a German neurologist, was working in a psychiatric clinic where he was influenced by Alois Alzheimer to pursue a career in neuroscience basic research. After extensive analysis of the human and monkey neocortex, he published in 1909 his classic work Comparative Localization Studies in the Brain Cortex, Its Fundamentals Represented on the Basis of Its Cellular Architecture. He had divided the neocortex into 52 regions based on the size, number, and density of the cells, as well as the local connections and long tract projections to and from the subcortical regions (Figure 2.4). Brodmann’s scheme is still widely used and often mentioned in the scientific literature to locate the area in question. Figure 2.4 The human cerebral cortex as delineated by Brodmann in his 1909 publication. The different regions are defined by the composition of the gray matter. Four examples are shown. Prefrontal Cortex Who doesn’t love the prefrontal cortex (PFC)? It is one of the anatomic structures that distinguishes humans from other mammals. Technically, the PFC is the part of the cortex in front of the motor cortex. Brodmann calculated that the PFC as a percentage of the total cortex is 3.5% in the cat, 7% in the dog, 8.5% in the lemur, 11.5% in the macaque, 17% in the chimpanzee, and 29% in humans. Dysfunction in the PFC is implicated as a possible source of pathology in many psychiatric disorders—depression, schizophrenia, anxiety, and attention deficit hyperactivity disorder (ADHD), as well as disorders of anger and violence. There are four regions of the PFC that are frequently mentioned in the scientific literature (Figure 2.5): lateral, orbital, and medial PFC as well as the cingulate gyrus. Modifying terms are often added to more precisely define the area of interest; for example, dorsolateral, ventromedial, and anterior cingulate are particularly popular. The ever-expanding jargon of the scientific writers is one of the great challenges of understanding neuroscience. Figure 2.5 The important regions of the prefrontal cortex frequently mentioned in studies of normal behavior and mental illness. The numbers are Brodmann’s areas. (Adapted from Fuster JM. The Prefrontal Cortex. 5th ed. Philadelphia: Elsevier; 2015.) Neurologists, assessing and following patients with injuries (e.g., Phineas Gage—Figure 14.4), have identified three syndromes associated with frontal lobe damage. Disinhibited—poor impulse control and inappropriate behavior Disorganized—memory deficits and poor planning Apathetic—unmotivated and paucity of spontaneous behavior Next time you are sitting in front of a patient with old scars across his or her forehead or a history of traumatic brain injury, ask about these syndromes. Typically, patients are> more aware of the disinhibition and disorganization but less cognizant of the apathy. A lot goes on in the frontal lobes, including language and motor functions. But it is the executive functions (attention, working memory, planning, and inhibitory control) along with the emotional and social functions that are of most interest to us. As we discussed in the previous chapter, it is difficult to resist the urge to match functions with regions of the PFC. Joaquin Fuster, who recently finished the fifth edition of his book The Prefrontal Cortex, has written that the functions of the PFC are “interrelated and widely distributed.” Here is his best attempt to assign functions to regions: “At most…the lateral prefrontal cortex is predominantly, but not exclusively, involved in time integration and organizing functions, such as working memory. On the other hand, the medical and ventral prefrontal cortices are predominantly involved in such emotional and social functions as control of impulse, mood and empathy. However, any attempt to localize any such function, exclusively and specifically, in one prefrontal area or another is implausible.” So we must not give in to the desire to put functions in boxes in the brain. Insula Cortex The insula is a part of the PFC that is hidden within folds of the lateral cortex and temporal lobes, which is not readily visible if you hold a brain in your hand like a neuropathologist Hamlet. We mention the insula in this edition because of a fascinating recent study out of Stanford University. The researchers collected over 15,000 MRI brain scans—roughly half of them patients and half of them controls. The scans were all from studies that had compared cases with matched controls. The difference in this study was that the patient group lumped together subjects with schizophrenia, bipolar disorder, major depression, substance abuse disorder, obsessive–compulsive disorder (OCD), and several anxiety disorders. Remarkably, the authors found that the mentally ill patients had more common deficits than differences. Specifically, they found gray matter loss in the insula and anterior cingulate (see Figure 2.6). What this means is that patients with an array of different symptoms and different diagnoses have a similar gray matter loss not found in the healthy controls. The authors called this a “shared neural substrate” and proposed that it is a common pathway that appears to involve executive function—a frequent finding of major mental illness. Figure 2.6 Lateral (A) and coronal (B) view of insula. Shared patterns of decreased gray matter (in brown) in the anterior insula and dorsal anterior cingulate (C). (C: Data from Goodkind M, Eickhoff SB, Oathes DJ. Identification of a common neurobiological substrate for mental illness. JAMA Psych. 2015;72:305–315.) Hippocampus The hippocampus and the amygdala are the essential structures of what is commonly called the limbic lobe—although there is no specific lobe. The hippocampus is a folded structure incorporated within the temporal lobe—dorsal to other important cortical structures of the rhinal sulcus (or primitive smell brain). The hippocampus is made up of two thin sets of neurons that look like facing “C”s—the dentate gyrus and the Ammon’s horn. Ammon’s horn has four regions, of which only CA3 and CA1 are shown in Figure 2.7. Figure 2.7 Different views of the hippocampus. (Adapted from Bear MF, Connors BW, Paradiso MA, eds. Neuroscience: Exploring the Brain. 4th ed. Baltimore: Lippincott Williams & Wilkins; 2015; and Kandel ER, Schwartz JH, Jessell TM, eds. Principles of Neural Science. 4th ed. New York: McGraw-Hill; 2000.) The hippocampus plays an essential role in the development of memories (see Chapter 18, Memory) and is one of the few locations in the brain where neurogenesis persists in adults (see Chapter 8, Plasticity and Adult Development). Additionally, the volume of the hippocampus is decreased in various psychiatric disorders (e.g., posttraumatic stress disorder, Alzheimer’s disease, and major depression), suggesting that this region may play a role in the pathogenesis of these disorders. Amygdala  The amygdala lies within the temporal lobe just anterior to the hippocampus (Figure 2.8). Using the anatomy and connections, the amygdala can be divided into three regions: the medial group, the central group, and the basolateral group. The basolateral group, which is particularly large in humans, receives input from all the major sensory systems. The central nucleus sends output to the hypothalamus and brain stem regions. Therefore, the amygdala links sensory input from cortical regions with hypothalamic and brain stem effectors. The amygdala is active when people are anxious and/or angry, which will be discussed further in subsequent chapters. Likewise, when the organ is removed, these emotions are impaired. Figure 2.8 The location and groups (often called nuclei) of the amygdala. (Adapted from Bear MF, Connors BW, Paradiso MA, eds. Neuroscience: Exploring the Brain. 4th ed. Baltimore: Lippincott Williams & Wilkins; 2015.) Treatment Prefrontal Lobotomy The infamous prefrontal lobotomy was developed in Portugal in 1935 by the neurologist Egas Moniz. He coined the term psychosurgery and later even won the Nobel Prize for Medicine for his work. Oops! The procedure was intended to sever the afferent and efferent fibers of the prefrontal lobe and produce a calming effect in patients with severe psychiatric disease (apathy?). Walter Freeman popularized and simplified the procedure in the United States. He developed a minimally invasive technique, shown in the figure, called the transorbital lobotomy. An instrument resembling an ice pick was inserted under the eyelid through the orbital roof and blindly swept left and right. It is hard to believe what Freeman reported in 1950—that of 711 lobotomies, 45% yielded good results, 33% produced fair results, and 19% left the patient unimproved or worse. Although initially received with enthusiasm, in part because of the unavailability of other effective treatments, the development of unacceptable personality changes (such as unresponsiveness, decreased attention span, disinhibition, etc.) led to a decline in the procedure. Ultimately, the development of effective pharmacologic treatments brought an end to the biggest mistake in the history of psychiatry. Transorbital frontal lobotomy. (Adapted from Bear MF, Connors BW, Paradiso MA, eds. Neuroscience: Exploring the Brain. 4th ed. Baltimore: Lippincott Williams & Wilkins; 2015.)  Disorder Limbic Lobe The limbic lobe concept is a term that occasionally appears in psychiatric literature, but not one that we will use. It was originally introduced in 1878 by Broca, who noted that the cingulate gyrus, hippocampus, and their connecting bridges formed a circle on the medial side of the hemispheres. He called the structure le grand lobe limbique. Paul MacLean in the mid-1950s popularized the concept by linking the structure to emotional functions. Historically, this was a big step in associating emotions with neuroanatomy and had a large impact on biologic psychiatry. Exactly what constitutes the limbic system has never been well defined nor is it clear that the structures involved (amygdala, hippocampus, and cingulate gyrus) have unique connections that process emotions. The problem originates from the attempt to impose emotional functions onto a number of closely related structures, rather than trying to find which structures are responsible for particular emotions. We prefer to identify the neuroanatomy involved with a specific emotion instead of using the more ambiguous limbic system concept. Hypothalamus If there is a tiny person that sits inside our head, watching the “control panel” from our body and making decisions about internal settings, he or she is sitting at the hypothalamus. This small cluster of nuclei makes up less than 1% of the brain mass yet has powerful effects on the body’s homeostasis. The hypothalamus controls basic functions such as eating, drinking, sleeping, and temperature regulation, to name a few. A small lesion in the hypothalamus has devastating effects on the body’s basic functions. The suprachiasmatic nucleus is an example of a small cluster of cells within the hypothalamus that has a profound impact on sleep–wake cycles (see Figure 15.8). The hypothalamus sits in a commanding position within the central nervous system (CNS), between the cortex and brain stem (Figure 2.9). It receives input from four sources: the higher cortex, the brain stem, internal chemoreceptors, and hormonal feedback. The cortex relays filtered cognitive and emotional information about the external environment. The sensory neurons in the body send signals about the internal milieu up through the brain stem. The hypothalamus has its own chemoreceptors that measure glucose, osmolarity, temperature, and so on in the blood. Finally, the hypothalamus receives feedback from the steroid hormones and neuropeptides. Figure 2.9 The hypothalamus lies on either side of the third ventricle in close proximity to the pituitary gland. The hypothalamus can be subdivided into multiple nuclei, many of which are not shown. (Adapted from Kandel ER, Schwartz JH, Jessell TM, eds. Principles of Neural Science. 4th ed. New York: McGraw-Hill; 2000.) The hypothalamus lies on either side of the third ventricle and is divided into three zones. The lateral zone controls arousal and motivated behavior. The medial zone is more involved with homeostasis and reproduction. The periventricular zone is of most interest to us. It includes the suprachiasmatic nucleus, the cells that control the autonomic nervous system (ANS) and the neurosecretory neurons that extend into the pituitary (see Chapter 7, Hormones and the Brain). Autonomic Nervous System The two branches of ANS can be thought of as the brain’s conduit to the vital organs of the body (Figure 2.10). One branch is the sympathetic division, which originates in the posterolateral region of the periventricular zone of the hypothalamus. The other branch is the parasympathetic division, which originates in the anterior cells of the same zone in the hypothalamus. The sympathetic and parasympathetic divisions appear to operate in parallel but with opposite effects, using different neurotransmitters.  Figure 2.10 The two divisions of the autonomic nervous system and the end organs they innervate. (Adapted from Bear MF, Connors BW, Paradiso MA, eds. Neuroscience: Exploring the Brain. 4th ed. Baltimore: Lippincott Williams & Wilkins; 2015.) The sympathetic division, in a simplified sense, controls the fight–flight response and plays a prominent role in the physical symptoms of anxiety, for example, racing heart. These neurons send out axons from the thoracic and lumbar regions to preganglionic neurons, which primarily reside in the sympathetic chain on either side of the spinal cord. The postganglionic sympathetic neurons innervate the smooth muscles of the vital organs as well as the walls of blood vessels. The preganglionic neurons are cholinergic, whereas the postganglionic neurons use norepinephrine. The postganglionic norepinephrine receptors likely explain why β-blockers can be used to quell the physical symptoms of anxiety. The parasympathetic neurons mediate functions that the body performs in times of calm, for example, digesting food. These neurons emerge from the brain stem and sacral region of the spinal cord. The axons travel longer distances and innervate ganglia typically located at the end organ. Unlike the sympathetic neurons, the parasympathetic neurons are exclusively cholinergic. For the psychiatrist, the ANS occasionally complicates the treatment of mental disorders—particularly when using the tricyclic antidepressants. Side effects such as dry mouth, tachycardia, and constipation can be seen as an imbalance between the sympathetic and parasympathetic divisions. These symptoms are not so much the result of sympathetic stimulation as they are the result of parasympathetic blockade. The likely culprit is blockade of the muscarinic receptor in the cholinergic neurons of the parasympathetic division. Disorder Cardiac Autonomic Activity A 2016 prospective study of 1 million Swedish recruits found that heart rate at the age of 18 years was associated with psychiatric disorders as they became adults. Men with resting heart rates above 82 beats per minute (compared to 62 bpm) were at increased risk for OCD, schizophrenia, and anxiety disorder. In contrast, men with lower resting heart rates were more likely to exhibit substance use disorders and violent behavior. Similar associations were observed with blood pressure.  Treatment Vagus Nerve Stimulation The ANS actually is a two-way street. That is, signals originating from the internal organs proceed up to the brain. Remarkably 80% of the signals traveling through the vagus nerve are afferent—from the organs toward the CNS. This is why vagus nerve stimulation can reduce seizure activity and improve mood. Some smart people have remarked that we think with our body, not just our brain. Cerebellum The cerebellum sits on the top of the brain stem, at the back of the skull, below the cerebral cortex. Once considered the “lesser brain” and only involved with the coordination of movement, more recent functional imaging studies have shown that the cerebellum “lights up” in a wide variety of behaviors. Not only is it active in sensation, cognition, memory, and impulse control, but it has also been suggested to be playing a role in the pathophysiology of autism, ADHD, and schizophrenia. Fossil records document that the cerebellum has grown throughout human evolution and actually contains more neurons than any other part of the brain. Yet its function is not clearly understood. Of particular interest, if the cerebellum is totally removed, especially in young persons, with time the person can regain almost normal function. It appears that the cerebellum is a supportive structure for the cerebral cortex. Some have speculated that it grew throughout evolution to provide extra computational support for an overburdened cortex. This reasoning proposes that the cerebellum is not responsible for any one particular task but rather functions as an auxiliary structure for the entire cerebral cortex—not just motor coordination. In the future we anticipate increased reports of the important role of the cerebellum in mental illness. Blood–Brain Barrier  The brain needs to be bathed in a pristine extracellular environment. If the brain is exposed to the fluctuations in hormones, amino acids, or ions as occurs in the rest of the body, unexpected neuronal activity could result. The brain uses the blood–brain barrier (BBB) to live in a more muted environment buffered from the hysterical fluctuations of the body. Historically, it was thought that the barrier was produced by the astrocytes that hold the capillaries with their foot processes. Later it became clear that it is the tight junctions between the endothelial cells of the capillaries that prevent many substances from leaking into the CNS (Figure 2.11). There are a few areas of the brain that have gaps in the BBB. The pituitary gland and some parts of the hypothalamus are two examples of these BBB gap regions. This is appropriate because these areas need to receive unfiltered feedback regarding the status of the endocrine system by way of the circulating blood. Figure 2.11 A: The tight junctions formed by the brain endothelial cells  along with the astrocytes make up the blood–brain barrier. B: Transport mechanisms facilitate or impede the movement of substances between the brain and blood stream. (A: Adapted from Goldstein GW, Betz AL. The blood-brain barrier. Sci Am. 1986;255:74–83. Figure adapted from original by Patricia J. Wynne.) The BBB is not an impenetrable wall because the brain needs constant supplies to perform its functions. Lipid-soluble substances can readily diffuse through the lipophilic cell walls. Conversely, water-soluble substances are deflected by the endothelial cell wall. Yet the brain needs some water-soluble substances, such as glucose, and indeed there are active transport mechanisms within the endothelial cell wall to bring these essential substances into the brain.  Treatment Breaching the Blood–Brain Barrier Approximately 98% of small molecules and nearly all the large molecules do not cross the BBB. Overcoming this obstacle is of utmost importance if new therapeutic agents are to reach their target. Several options are being explored—some more reasonable than others. (1) Implants—medications impregnated in biodegradable wafers placed in the brain. (2) Administering high-frequency ultrasound or transcranial magnetic stimulation to disrupt the BBB and increase penetration of the drug into the brain. (3) Intranasal delivery. (4) Trojan horse—attach the medication to a molecule that binds with a transcytosis receptor. The medication then sneaks into the brain by endocytosis. (5) If all else fails, direct injection into the brain—always a favorite. The endothelial cells also actively transport offensive substances out of the brain’s extracellular environment. The P-glycoprotein is such a transporter. Found in the gut as well as the brain, this protein actively removes a wide variety of drugs and deposits them in the capillary lumen. For example, the newer antihistamines are excluded from the CNS by this protein so they can work their magic on allergens in the body but not sedate the brain. Some psychiatrists speculate that a very active P-glycoprotein transporter contributes to treatment resistance by diminishing the cerebral concentration of medications; for example, olanzapine and risperidone are substrates for P-glycoprotein. Questions 1. Brodmann’s areas are differentiated by the a. Cortical morphology. b. Cellular architecture. c. Afferent connections. d. Predominant neurotransmitter. 2. The orbitofrontal aspect of the PFC describes the area a. Above the corpus callosum.  b. Posterior to the amygdala. c. At the base of the PFC. d. Anterior to the cingulate gyrus. 3. Lesions of the medical (also ventromedial) PFC are associated with a. Paucity of spontaneous behavior—apathetic. b. Disorganized cognitive function. c. Concrete thinking. d. Poor impulse control. 4. All of the following are true about the hippocampus except that it a. Is smaller in some psychiatric disorders. b. Is involved with memory. c. Is disrupted by frontal lobotomy. d. Contains undifferentiated stem cells. 5. The “command center” of the brain is the a. Hippocampus. b. Amygdala. c. Autonomic nervous system. d. Hypothalamus. 6. All of the following are true about the sympathetic nervous system except that it a. Stimulates digestion. b. Is associated with anxiety. c. Stimulates secretions from the adrenal medulla. d. Relaxes the airways. 7. The cerebellum a. Solely functions to support movement. b. Has been implicated with autism. c. Is similar to the motor cortex. d. Is relatively small in humans. 8. The BBB can be crossed by all of the following except a. Lipid-soluble molecules. b. Active transport across the cell wall. c. Breaches in the tight junctions. d. Most medications. See Answers section at the end of this book. CHAPTER 3 Cells and Circuits The Neuronal Cell The human brain is the most complex organ known to exist in the universe. Its weight is just 3% of the body, but it consumes 17% of the body’s energy. The workhorse of the brain is the neuron. It is estimated that we have 100 billion neurons with 100 trillion connections. When we think of a neuron, we are typically thinking of a pyramidal neuron in the cerebral cortex. These neurons have a diamond-shaped cell body and usually reside in layers III or V of the gray matter (Figure 3.1).  Figure 3.1 A: Cross section of the right prefrontal cortex (PFC). B: The six layers of neurons in the gray matter of the PFC. C: A stereotypical pyramidal neuron found in layer III of the cerebral cortex. ER, endoplasmic reticulum. (Adapted from Bear MF, Connors BW, Paradiso MA, eds. Neuroscience: Exploring the Brain. 4th ed. Baltimore: Lippincott Williams & Wilkins; 2015.) Let’s start with a brief review of cell biology. The cell body of the neuron is full of the usual assortment of organelles, although not in the same proportions as seen in nonneural cells. Structures such as the endoplasmic reticulum (ER) and mitochondria are found more frequently in neurons than in other brain cells, presumably because of the increased need for protein synthesis and energy production. The instructions for the functioning of the cell are contained in the DNA, which resides in the nucleus. The instructions are read when the DNA is transcribed into messenger ribonucleic acid (mRNA), which is translated into proteins in the cytoplasm (Figure 3.2). As mentioned in Chapter 1, Introduction, this process is often called gene expression—two of our favorite words. Figure 3.2 Messenger ribonucleic acid (mRNA) carries the genetic instructions from the nucleus to the cytoplasm where translation into proteins occurs. (Adapted from Bear MF, Connors BW, Paradiso MA, eds. Neuroscience: Exploring the Brain. 4th ed. Baltimore: Lippincott Williams & Wilkins; 2015.) The ribosome is the organelle in which mRNA is translated into proteins (Figure 3.3). The ribosomes are usually attached to the rough ER but can also be floating freely in the cytoplasm. The proteins, once they are refined, are used by the cell for structural (e.g., receptors), functional (e.g., enzymes), or communication (e.g., neuropeptides) purposes, to name a few.  Figure 3.3 Messenger ribonucleic acid (mRNA) binds to a ribosome, initiating protein synthesis. Proteins synthesized on the rough endoplasmic reticulum (ER) as shown are eventually inserted into the membrane. Proteins synthesized on free ribosomes (not shown) are utilized in the cytosol. (Adapted from Bear MF, Connors BW, Paradiso MA, eds. Neuroscience: Exploring the Brain. 4th ed. Baltimore: Lippincott Williams & Wilkins; 2015.) The Golgi apparatus, which looks like ER without the ribosomes, is where much of the “posttranslation” refinement, sorting, and storage of proteins occurs. This structure enables proteins to be appropriately transported to distant sites within the cell. The mitochondria are the remarkably abundant energy generators of the neuron. The brain requires considerable energy, even at rest, just to maintain an electrical gradient poised to respond at a moment’s notice. The mitochondria convert adenosine diphosphate (ADP) into adenosine triphosphate (ATP), and it is ATP that the cell uses to perform its functions.  Point of Interest One of our former patients, a very bright man with bipolar disorder and diabetes, could lower his blood glucose level (when it was high) by solving calculus equations—a good example of the propensity of the brain to be an energy hog (and the effort needed to master calculus). The dendrites are the part of the neuron that sprout off the cell body and look like tree branches. They are often called the ears of the neuron for they receive input from other neurons and relay the signal to the cell body. Most dendrites have “little knobs” along their stalks that are called dendritic spines. Each spine is the postsynaptic receptor for an incoming signal from another neuron (Figure 3.4). Figure 3.4 Spines are the “little knobs” on the dendrites. They are on the receiving side of the electrochemical signal from other neurons—also called the postsynaptic membrane. The morphology (structure and density) of the dendritic spines has been a source of considerable interest since Ramón y Cajal first identified them over one hundred years ago. Spines can change in shape, volume, and number with remarkable speed and frequency. This plasticity is one of the great discoveries of modern neuroscience. We mention spines throughout this book as their morphology changes in a number of conditions, including substance abuse, mental retardation, schizophrenia, and learning (see Point of Interest).  Point of Interest Enhanced branching and spine formation have been found consistently in rats raised in enriched environments when compared with rats raised in standard wire cages. The neurons in the following figure are from rats raised in different environments. Note the increased branching (also called arborization) of the neuron from the rat raised in the enriched environment. Abundant dendritic branching with multiple connections seems to be a microscopic sign of a healthy active brain. (Reprinted from Kolb B, Forgie M, Gibb R, et al. Age, experience and the changing brain. Neurosci Biobehav Rev. 1998;22:143–159. Copyright 1998 with permission from Elsevier.) The axon is perhaps the most unique structure of the neuron. Starting at the axon hillock and running anywhere from a few micrometers to the entire length of the spinal cord, the axon can transmit a signal quickly without degradation to other neurons or end organs. For this reason the axon is often conceptualized as the telephone wire of the brain. Because the axon is devoid of ribosomes and incapable of protein synthesis, a process called axoplasmic transport enables the neuron to send material down the microtubules to the distal ends of the cell. The terminal end of the axon forms the synapse (Figure 3.5). This is where one neuron talks to another—if the dendrites are the ears, the synapse is the voice. Here the electrical signal streaming down the axon is converted into a chemical signal, so the impulse can pass from one cell to another. The neurotransmitters that form the basis of the chemical signal are stored in vesicles. When released, they diffuse across the synaptic cleft to receptors on the postsynaptic dendrite (more on this later in the chapter). Figure 3.5 A synapse seen with an electron microscope (A) and in a schematic drawing (B). Note the high concentration of vesicles filled with neurotransmitter and mitochondria to power the rapid processing. (Adapted from Bear MF, Connors BW, Paradiso MA, eds. Neuroscience: Exploring the Brain. 4th ed. Baltimore: Lippincott Williams & Wilkins; 2015.) Electrical Signaling All living cells maintain a negative internal electronic charge relative to the fluid outside the cell—roughly—60mV in a neuron. Nerve cells use the depolarization (rapid change in the electrical charge) to communicate with other nerves or end organs. There are two basic steps in this process. The neuron first receives signals through the dendrites—what are called postsynaptic potentials. Second, the cell sums the incoming impulses, and if they are high enough, then it sends an impulse down the axon—an action potential. Postsynaptic Potentials A single pyramidal cell will receive input from 1 to 100,000 neurons through the postsynaptic synapses (spines) on the dendrites and cell body. When the neurotransmitters bind with the receptor at the postsynaptic synapse, ions flow into the neuron and change the electrical potential, making it more positive or more negative—or what is called depolarization and hyperpolarization. This proceeds in two ways: Depolarize (excitatory) with an influx of positive ions such as Na+. Hyperpolarize (inhibitory) with an influx of negative ions such as Cl−. These are appropriately called excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) (Figures 3.6 and 3.7). The EPSP and IPSP are, respectively, the accelerator and brake for the brain. An EPSP is more likely to generate an action potential; an IPSP inhibits the generation of an action potential. The goal for a healthy brain is to maintain the correct balance—if there is too much excitation, one can have a seizure; if there is too much inhibition, the brain is sluggish, even comatose. Actually, most of us want our brains to be excited during the day and inhibited at night—something our residual paleolithic brains are not always wired to accommodate. Figure 3.6 Neurotransmission from an excitatory neuron (A) promotes the entry of positively charged sodium ions into the dendrite (B). The resulting depolarization generates an EPSP (C). (Adapted from Bear MF, Connors BW, Paradiso MA, eds. Neuroscience: Exploring the Brain. 4th ed. Baltimore: Lippincott Williams & Wilkins; 2015.) Figure 3.7 Neurotransmission from an inhibitory neuron (A) promotes the entry of negatively charged chloride ions into the dendrite (B). The resulting  hyperpolarization generates an IPSP (C). (Adapted from Bear MF, Connors BW, Paradiso MA, eds. Neuroscience: Exploring the Brain. 4th ed. Baltimore: Lippincott Williams & Wilkins; 2015.) The Action Potential The decision to fire an action potential is made at the axon hillock. Moment to moment, the sum of all the incoming EPSPs and IPSPs at the axon hillock determines whether the neuron sends an impulse down the axon. If the potential has depolarized to the threshold, then an action potential is generated. Figure 3.8 shows how the neuron requires enough depolarization (excitation) but not too much hyperpolarization (inhibition) to generate an action potential. Figure 3.8 A signal from one excitatory neuron (A) increases the excitatory postsynaptic potential (EPSP) but is not sufficient to reach the threshold. Two excitatory impulses reaching the neuron at the same time (B) generate an EPSP that reaches the threshold at the axon hillock, and an action potential is fired. However, with inhibitory input from a third neuron (C), the membrane potential again fails to reach the threshold.  Treatment Calm Down We often treat patients who have too much cerebral activity. Anxiety, attention deficit hyperactivity disorder, insomnia, and mania are four conditions in which the brain is going too fast. Such patients have too much excitation and not enough inhibition. It is encouraging that more research is being directed toward treatments that increase inhibitory potentials (e.g., γ- aminobutyric acid). The challenge is to selectively inhibit the annoying trait without slowing down the whole brain: calmer but not dumber. Once the threshold (−40mV) has been reached at the axon hillock, the neuron “pulls the trigger” and shoots an action potential down the axon. Because of the unique design of the voltage-gated sodium channels, the action potential maintains its integrity as it proceeds along the axon—there is no diminution in the signal. This occurs because the voltage-gated sodium channels facilitate a rapid influx of positive ions. Like other ion channels, the voltage-gated sodium channel is a protein embedded in the lipid member of the cell. The “gated” nature of the channel allows a large and rapid influx of the ions once the threshold has been crossed. The voltage-gated channel is like a trap waiting to be sprung. When the switch is tripped, the ions pour into the axon. Electrochemical Signaling Otto Loewi demonstrated in 1921 that the communication within the nervous system is both electrical and chemical. Figure 3.9 shows a representation of the arrival of the action potential at the synaptic terminal, the release of the neurotransmitters, and the generation of an EPSP or IPSP in the dendrite of the neighboring neuron. This example happens to be a dopamine neuron, which is an excitatory neuron, but the same principles apply to all the neurons and neurotransmitters.  Figure 3.9 This is an example of the electrochemical signaling from a dopamine neuron. If this were an inhibitory neuron, γ-aminobutyric acid or glycine for example, the postsynaptic potential would be an inhibitory postsynaptic potential and not an excitatory postsynaptic potential. (Adapted from Rosenzweig MR, Watson NV. Biological Psychology. 7th ed. Sunderland, MA: Sinauer; 2013, by permission of Oxford University Press, USA.) The arrival of the action potential at the terminal depolarizes the membrane, which opens the voltage-gated calcium channels. The voltage-gated calcium channels are similar to the voltage-gated sodium channels except they are permeable to Ca2+. Consequently, there is a large and rapid influx of Ca2+, which is required for exocytosis and the release of the neurotransmitter. Nonneuronal Cells The glial cells that make up the rest of the cells in the central nervous system (CNS) actually outnumber the neurons by 9:1. Traditionally seen as supportive cells with no role in communication, recent research has shown that glial cells modulate the synaptic activity. There are three kinds of glial cells: astrocyte, oligodendrocyte, and microglia. The microglia are similar to macrophages found in the peripheral tissue. They respond to injury with a dramatic increase in their numbers and remove cellular debris from the damaged area. (For more information on the microglia, refer Chapter 9, Immunity and Inflammation.) The oligodendrocyte is considered the CNS equivalent of the Schwann cell in the peripheral nervous system (Figures 3.10 and 23.10). They are the cells that wrap myelin around the axons of the neurons, and by acting as an electrical insulator, they greatly increase the speed of the transmission of the action potential. This process of myelinization is not complete at birth and proceeds rapidly in the first years of life, which has a dramatic effect on behavior. In children, this process results in improved motor skills as they mature. Complete myelinization of the prefrontal cortex (PFC) is delayed until the second and even third decade of life. Hence why we worry about our teens—the bodies of adults without the brakes of matured frontal lobes.  Figure 3.10 Oligodendroglial cells wrap a myelin sheath around the axon, providing electrical insulation. This can improve the speed of the transmission of an action potential up to 15 times. (Adapted from Bear MF, Connors BW, Paradiso MA, eds. Neuroscience: Exploring the Brain. 4th ed. Baltimore: Lippincott Williams & Wilkins; 2015.) Demyelinating disorders such as multiple sclerosis and Guillain–Barré have devastating effects on patients. Clearly, a neuron without its myelin is not as effective. Regarding mental illness, recent research suggests that some failure in myelination may play a role in schizophrenia. The astrocyte is the star-shaped cell that fills the spaces between the neurons (Figure 3.11). We have already seen that the astrocyte plays a role in maintaining the blood–brain barrier, but other functions include regulating the chemistry of the extracellular fluid, providing structural support, and bringing nutrients to the neurons. Even more interesting is the role the astrocyte plays in modulating the electrical activity at the synapse. Research has shown that astrocytes encircle the synapse and have receptors that respond to the neurotransmitters released by the neuron. The astrocyte may in turn release its own neurotransmitter, which enhances the transmission of the signal. This may facilitate learning and memory. Additionally, there is evidence that the presence of astrocytes or their proteins increases the number of synapses a neuron will form. The lowly glial cells are more involved in the communication within the brain than previously thought. Figure 3.11 The astrocyte not only supports the neurons and blood vessels but also has some role in modulating the transmission of information.  Disorder Epilepsy Increasing evidence is pointing to the astrocyte as playing an instigating role in epilepsy—a problem historically assigned to dysfunctional neurons. Analysis of specimens after surgical resection for epilepsy often shows prominent gliosis. Glutamate released from astrocytes can trigger experimental models of seizures. Finally, several effective antiepileptic drugs (such as valproate, gabapentin, and phenytoin) potently reduce astrocytic Ca2+ signaling—an event believed to precede seizure activity. If aberrant astrocytes are the nidus for seizures, then new treatments might be developed that can calm the astrocytes without dulling the neurons. Circuits The capacity to communicate quickly over long distances (relative to the size of a cell) is the most unique feature of the nerve cell. Sending a signal, receiving feedback, and adjusting further responses are the essence of communication— cellular or social. The white matter tracts—bundles of axons just underneath the gray matter—connect the nerve cells with other regions of the cortex, subcortical nuclei, and end organs such as muscles and glands (Figure 3.12).  Figure 3.12 Beneath the gray matter are white matter tracts that allow communication between widely separated regions of the brain or between the brain and end organs. (Adapted from Rosenzweig MR, Watson NV. Biological Psychology. 7th ed. Sunderland, MA: Sinauer; 2013, by permission of Oxford University Press, USA.) A new imaging technique, called diffusion tensor imaging (DTI), has been developed to assess the quality of the white matter tracts. Using an magnetic resonance imaging scanner, the technique involves following the movement of water (diffusion) in the brain. In most tissue the water molecules move in every direction. In the white matter tracts, the water molecules tend to move along the length of the axons. Thus, with some Herculean number crunching by the MRI computer, images can be produced showing remarkable detail of the white matter tracts (Figure 3.13). Although still a research tool, DTI is being used to identify white matter abnormalities in patients with psychiatric disorders.  Figure 3.13 Visualization of white matter tracts in the brain using diffusion tensor imaging technology. (Courtesy of G. Russel Glenn, Medical University of South Carolina, 2016.) The networks that coordinate a behavior are called circuits. A simple example of a circuit is evident in substance abuse. The addict is reminded of getting high and feels a compulsion to use but does not have enough control to abstain and does extraordinary things to get the drug. The interplay of regions involving memories, urges, and control (or absence of control) fails in the substance abuser. It is the coordination of the circuit—not one particular location in the brain—that goes awry in the substance abuser. The elusive nature of the biologic causes of mental disorders has been the bane of psychiatry. Although Broca could pinpoint the damaged region to explain his aphasic patients, conspicuous lesions corresponding to psychiatric conditions have not been possible to locate. Increasing evidence suggests that problems in brain circuits may explain variants in behavior. Perhaps this is because it is not one specific region that is at fault but rather the dysfunction of the communication. However, this is difficult to measure. Figure 3.14 shows a schematic representation of a hypothetical circuit between the PFC, temporal cortex, and subcortical regions. Imaging studies suggest that dysfunction of emotional circuits may explain some psychiatric disorders—particularly depression, anxiety, and substance abuse. One common example involves the PFC. Insufficient activity from the PFC allows the expression of impulses from lower regions of the brain—a problem we will address when we discuss anger, attention, and anxiety. Figure 3.14 Dysfunctional circuits may explain behavioral and cognitive symptoms in psychiatric disorders. Questions 1. The pyramidal cells in the gray matter reside predominantly in which layers? a. I and III. b. II and IV. c. III and V. d. IV and VI. 2. Protein synthesis requires all of the following except a. Rough ER. b. Gene expression. c. Transcription and translation. d. Messenger RNA. 3. Enhanced arborization of the dendrites is found with a. Mental retardation. b. Stimulating environments. c. Usual laboratory environments. d. Schizophrenia. 4. An IPSP a. Results from the influx of sodium ions. b. Depolarizes the cell. c. Can induce seizures. d. Hyperpolarizes the cell. 5. The neuron generates an action potential based on the postsynaptic potential at the a. Axon hillock. b. Synapse. c. Nucleus. d. Node of Ranvier. 6. Exocytosis of the neurotransmitters at the synapse requires opening of the a. Voltage-gated sodium channels. b. Voltage-gated calcium channels. c. Excitatory postsynaptic channels. d. Inhibitory postsynaptic channels. 7. The cell responsible for myelin in the CNS is a. Astrocyte. b. Microglia. c. Schwann cell. d. Oligodendrocyte. 8. Modulates electrochemical activity at the synapse: a. Astrocyte. b. Microglia. c. Schwann cell. d. Oligodendrocyte. See Answers section at the end of this book. CHAPTER 4 Neurotransmitters  Point of Interest It is not uncommon in our practices for patients to announce at the initial evaluation, “Doc, I have a chemical imbalance,” as though it is some sort of Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnosis. It is not likely that a “chemical imbalance” is the source of mental illness, but most assuredly the manipulation of these chemicals remains the bread and butter of psychiatry. They are the chemical part of the “electrochemical” communication and the focus of this chapter. A “neurotransmitter” is technically defined by meeting three criteria: 1. The substance must be stored in the presynaptic neuron. 2. It must be released with depolarization of the presynaptic neuron induced by the influx of Ca2+. 3. The substance must bind with a specific receptor on the postsynaptic neuron. Neurotransmitters differ from hormones by their close physical proximity of the release to the receptor—although this turns out to be less straightforward than one might imagine. The classic neurotransmitters—the ones we frequently discuss—are small molecules designed for economy of use. For neurotransmitters, the body needs a substrate that can be produced quickly, with ease, and be recycled—much like the daily newspaper. Figure 4.1 shows some representative neurotransmitters compared with a neuropeptide substance P. The common neurotransmitters such as γ-aminobutyric acid (GABA) and norepinephrine (NE) are small and constructed with elements that are easy for the body to find. This facilitates the rapid creation and release of the signals that are the essential features of neural communication. Figure 4.1 A sample of neurotransmitters showing the relative size of the amino acids (A), two of the amines (B), and a neuropeptide (C). GABA, γ- aminobutyric acid. (Adapted from Bear MF, Connors BW, Paradiso MA, eds. Neuroscience: Exploring the Brain. 4th ed. Baltimore