1.1 The Neuroscience of Psychiatry
This section of the Textbook contains a remarkable collection of 30 chapters that provide an overview of the landscape of the current understanding of the neuroscience foundations of psychiatry. The brain is the principal organ of psychiatry, so understanding brain science is the starting point for a comprehensive knowledge of the field. These chapters bear careful reading as they reflect the first indications of the emergence of explanatory science within psychiatry. This progress arises from the application of technologies that have transformed our understanding of the brain and brain-behavior relationships, such as optogenetics, DREADDs, and CRISPR. It also arises from the maturation of fields, such as cognitive neuroimaging and psychiatric genetics, transforming them from intellectual curiosities to strategies to answer important questions about human behavior and mental illness.
What are the signs of this progress? The last issue of The Comprehensive Textbook in Psychiatry appeared in 2009. Thus a quote attributed to Bill Gates, known as “Gates Law” applies, “most people overestimate what they can achieve in a year, but underestimate what they can achieve in ten years.” There are many inspiring stories. With respect to etiology, advances in genome sequencing have enabled the discovery of growing numbers of rare gene variants that contribute significantly to the genetic risk for autism and schizophrenia. We are now beginning to understand in what regions of the brain and in which cell types these genes are preferentially expressed, as well as when in development, these genes are critically engaged. This knowledge establishes a foundation for understanding when, where, and how the development of the brain goes awry to give rise to the pathophysiology of psychiatric disorders. With the emergence of spatial transcriptomics, we will soon resolve our molecular understanding of pathophysiology to cells embedded in specific microcircuits within particular brain regions. As we have seen for Mendelian disorders, such as spinal muscular atrophy, identification of the molecular etiology may set the stage for diseasemodifying interventions, such as gene therapy. With respect to pathophysiology, optogenetic studies
in animals, neuroimaging studies in humans, and a new generation of intracortical physiology and stimulation studies have provided deep new insights into how depression and other psychiatric disorders might be expressed at the level of neural circuits. These “raw data” provide the basis for computational neuroscience studies that rigorously describe for the first time the relationships between the activity of neurons and networks or networks and behavior. In turn, these insights are providing a basis for a growing array of neurostimulation treatments for mood disorders. At the same time, some transformative advances in treatments, such as the discovery of the rapid antidepressant effects of ketamine and the psychedelics, have stimulated basic science advances that shed new light on the neurobiology of stress. In fact, since the last edition of this textbook, the FDA has approved the first two mechanistically novel antidepressants in over 50 years, Esketamine (treatment-resistant depression and depression in the context of increased suicide risk) and brexanolone (postpartum depression). Why do psychiatrists need to understand neuroscience to practice their art?
Psychiatry is moving away from viewing individual psychiatric patients solely as representative of static diagnostic categories, as might be reflected in the
Diagnostic and Statistical Manual. One might predict that as psychiatrists become increasingly comfortable incorporating an understanding of the neurobiology of psychiatric disorders into their clinical formulations of individual patients, it will enrich their understanding of their patients and suggest new opportunities to enhance treatment. CASE STUDY The author will illustrate this point by referring to a case conference in which he participated, which he first presented in a blog to the American College of Neuropsychopharmacology in January 2012. The Yale Psychiatry Residents invited the author to interview a patient and then present his formulation to their group. The patient was a young man who suffered from long-standing psychotic symptoms. He met diagnostic criteria for schizophrenia, exhibiting many domains of preserved intellectual capacity but noted problems with sustained attention and memory. He also exhibited low levels of affective blunting but impairments in many social and functional domains. Upon interview, he also vividly described a childhood pattern of accentuated attention to nonsocial environmental details, and he both described and displayed perseverative tendencies and mild irritability when challenged. He also mentioned that both the diagnoses of schizophrenia and bipolar
disorder ran in his family. With regard to treatment, he felt that clozapine was the most effective medication prescribed for him. In addition, he was treated with anticonvulsants, lamotrigine, and valproate. How could psychiatrists understand the appearance of features of autism spectrum disorder (ASD) and his family history of both schizophrenia and bipolar disorder? This patient presented opportunities to reflect on challenges in our diagnostic schema. Bleuler suggested that autistic thinking was a core feature of schizophrenia, but this feature is no longer included in the diagnosis of schizophrenia. Yet, a growing number of rare gene variants with relatively large effects on the risk for schizophrenia also contribute to the risk for ASD. Overlap of schizophrenia and ASD symptoms might be an illustration of pleiotropy. Similarly, recent largescale GWAS studies report regions of the genome that appear to convey relatively modest increases in the risk for both schizophrenia and bipolar disorder. Thus, genetics provides some clues that may help to guide thinking about the features of the presentation of individual patients that conflict with the diagnostic categories of DSMIV. Why would someone add the antipsychotics lamotrigine and valproate to enhance clozapine treatment of schizophrenia? Currently,
there is a small evidence base to guide the pharmacotherapy of clozapine-resistant schizophrenia symptoms. The author was reminded of the evidence in animals and humans that lamotrigine, by itself or in combination with clozapine, attenuates some of the effects of psychotogenic NMDA receptor antagonists. Subsequently, lamotrigine was not found generally effective as an antipsychotic augmentation strategy unless patients had symptoms that had been highly resistant to treatments, including clozapine. Further, anticonvulsants like lamotrigine might protect against the seizure risk associated with pharmacotherapy with higher clozapine doses. Thus, there was a rationale for adding lamotrigine to clozapine in this case. However, the same could not be said for valproate. Psychiatrists discussed the pharmacoepidemiologic data describing common coprescription of valproate and antipsychotic medications for schizophrenia despite the lack of compelling efficacy data for valproate in this adjunctive role. The invitation from the residents to interview a patient in front of them and to present a “biopsychosocial” formulation was embedded in an unspoken question. What do we mean by the “bio” component of the biopsychosocial formulation? Historically, the biologic domain was represented by
general knowledge of psychopharmacology, medicine, and clinical neurology. Basic neuroscience was not included. In fact, historically, neuroscience education was not required in the psychiatry residency. To put this question another way, does it make a difference to a practicing psychiatrist to be a student of genetics and translational neuroscience? In the case that I discussed, the answer turned out to be absolutely! In fact, it seemed that the author’s background in neuroscience informed nearly every aspect of the interview, including the questions that the author asked, the hypotheses that he generated about the patient, and his thoughts about the treatment plan. While it was not yet clear to the author how his knowledge of the genetics of schizophrenia would guide the treatment of this patient, it was not hard to see how keeping abreast of developments in neuroscience might someday make this possible. There is also a growing appreciation that neurobiologic data, along with other types of data, will inform the development of more systematized personalized medicine approaches in psychiatry to improve the matching of individual patients to specific treatments.
REVIEW OF THE NEUROSCIENCE
CHAPTERS To facilitate this type of interplay between neuroscience and clinical psychiatry, the authors
structured this section of the Textbook to cover the waterfront of progress in neuroscience that was most relevant to psychiatry. Experts in the field were asked to provide chapters that would be rigorous but accessible to clinicians. The section builds from elemental questions, that is, genetics, the properties of neurons, the basics of chemical neurotransmission, cortical networks, and network functions, and the pathophysiology of psychiatric disorders. The topics covered are broad, but some topics were not included. Similarly, the reviews provide depth, but hopefully not at the expense of accessibility. The Neuroscience Section of the Textbook is organized into five thematic subsections that are described briefly below. The first subsection begins with three chapters that describe the organization and development of the brain. The first chapter (Chapter 1.2) in this subsection introduces the reader to core themes related to the overall structural organization of the brain, while the second and third chapters (Chapters 1.3 and 1.4) introduce the reader to molecular and cellular mechanisms governing the development of what is arguably one of the most complex structures in the universe. The next seven chapters provide an overview of the basic signaling mechanisms that underlie communication
and plasticity within the brain. Chapter 1.5 introduces readers to core cellular and synaptic mechanisms underlying neural communication. The next five chapters review the principal classes of chemical neurotransmission in the brain, including amino acid neurotransmitters (Chapter 1.5), monoamine neurotransmitters (Chapter 1.7), neuropeptides (Chapter 1.6), neurotrophic factors (Chapter 1.7), and novel neurotransmitters (Chapter 1.8). Intraneuronal signaling, the mechanisms through which the effects of transmitters and drugs are transduced chemically within neurons, are reviewed in Chapters 1.9 and 1.10. Homeostatic and appetitive mechanisms are covered in the five chapters in the third subsection. These chapters cover topics that are implicated in nearly every psychiatric condition, such as psychoneuroendocrinology (Chapter 1.12), immunebrain interactions (Chapter 1.13), chronobiology (Chapter 1.14), sleep and insomnia (Chapter 1.15), pain (Chapter 1.16), and appetite (Chapter 1.17). The fourth subsection covers a wide range of topics that are sometimes referred to as “the ’omics.” Chapter 1.18 introduces the reader to the relationship between genetics and brain biology, that is, the genome (the sources of genetic variation), the transcriptome (the levels of gene expression), and the proteome (the
levels of various proteins). The following chapters in this subsection address particular aspects of psychiatric risk and resilience, including genomics (Chapter 1.19) and epigenomics (Chapter 1.20).
Epigenomics is a topic of growing interest with regard to psychiatry biomarker development as epigenomic modifications provide a path for various environmental exposures (stress, abused substances, rewarding stimuli) to produce lasting changes in gene expression without altering the DNA sequence.
Chapter 1.21 reviews the challenging area of pharmacogenomics, that is, the effort to find genomic predictors for the safety and effectiveness of psychiatric treatments. Lastly, for this subsection, animal models for psychiatric disorders are reviewed in chapter 1.22. Animal models, also known as animal research platforms, provide unique opportunities to test causal hypotheses related to brain structure, chemistry, and function. As a result, they are a critical component of the translational neuroscience mission in psychiatry. The last 10 chapters in Section 1 cover special topics in systems, cognitive, and behavioral neuroscience. Chapter 1.23 covers basic issues in systems neuroscience. Chapter 1.24 addresses the important area of computational modeling, and it provides a foundation for the emerging focus on
computation in psychiatry, that is, “computational psychiatry.” Chapters 1.25 to 1.28 present the key techniques for studying human cortical circuit function and chemistry, including nuclear magnetic resonance (sMRI, fMRI, dwMRI/DTI, MRS), cortical electrophysiology (EEG, MEG), and radiotracer imaging (PET, SPECT). Neuroscience is also informing our understanding of our sense of self (Chapter 1.29). The last two chapters in this section address learning theory and its application to the study of addiction (Chapters 1.30 and 1.31).
CONCLUSIONS
The information conveyed in the following 30 chapters provides evidence that psychiatric neuroscience is progressing at a dizzying pace. Nonetheless, in the final analysis, psychiatrists must be humble with regard to our current understanding of the biology and treatment of psychiatric disorders. The brain is unimaginably complicated. To quote chapter 1.3, it has “approximately 86 billion neurons connected by hundreds of thousands of kilometers of myelinated axons and several hundred trillion to well over a quadrillion synapses, along with a roughly equal number of glial cells.” Fundamental aspects of the pathophysiology of neuropsychiatric disorders remain beyond our grasp. Although some parts of the psychiatric community are put off by the growing
complexity of neuroscience, others are attracted to the increasing explanatory power of this work. Although cautious in applying neuroscience advances to patients, psychiatry probably overestimates our knowledge and underestimates the challenges faced in trying to understand the etiology, pathophysiology, treatment, and prevention of neuropsychiatric disorders. Nonetheless, psychiatrists have a clinical, scientific, and humanistic imperative to continue to advance our understanding of the neurobiology of psychiatric disorders and to see that this knowledge improves the clinical practice of psychiatry. Before closing, the author wishes to acknowledge the outstanding quality of the chapters in this Section as well as the wonderful collaboration with Mr. Sean Hanrahan and Dr. Robert Boland in shaping this Section. The author had the pleasure of reading these chapters several times and, with each repetition, learned more. He thanks the authors of these chapters for helping to inform you about some of the most exciting advances in all of science and for making this process so enjoyable. FURTHER
READINGS Anand A, Charney DS, Oren DA, et al.
Attenuation
of
the neuropsychiatric effects of ketamine with lamotrigine: support for hyperglutamatergic effects of N-methyl-Daspartate
receptor antagonists. Arch Gen Psychiatry. 2000;57:270–276. Association AP. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. American Psychiatric Press; 2013. Brody SA, Geyer MA, Large CH. Lamotrigine prevents ketamine but not amphetamineinduced deficits in prepulse inhibition in mice. Psychopharmacology (Berl). 2003;169:240–246. Chen H, Deshpande AD, Jiang R, Martin BC. An epidemiological investigation of off-label anticonvulsant drug use in the Georgia Medicaid population. Pharmacoepidemiol Drug Saf. 2005;14:629–638. Duman RS, Aghajanian GK, Sanacora G, Krystal JH. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med. 2016;22:238–249. Farber NB, Jiang XP, Heinkel C, Nemmers B. Antiepileptic drugs and agents that inhibit voltage-gated sodium channels prevent NMDA antagonist neurotoxicity. Mol Psychiatry. 2002;7:726–733. Goff DC, Keefe R, Citrome L, et al. Lamotrigine as add-on therapy in schizophrenia: results of 2 placebo-controlled trials. J Clin Psychopharmacol. 2007;27:582–589. Gulsuner S, Walsh T, Watts AC, et al. Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network. Cell. 2013;154:518–529. Insel T, Cuthbert B, Garvey M, et al. Research
domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am J Psychiatry. 2010;167:748–751. Krystal JH, State MW. Psychiatric disorders: diagnosis to therapy. Cell. 2014;157:201– 214. Mendell JR, Al-Zaidy S, Shell R, et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med. 2017;377(18):1713–1722. Moskowitz A, Heim G. Eugen Bleuler’s Dementia praecox or the group of schizophrenias (1911): a centenary appreciation and reconsideration. Schizophr Bull. 2011;37:471– 479. Ripke S, Sanders AR, Kendler KS, et al. Genome-wide association study identifies five new schizophrenia loci. Nat Genet. 2011;43:969–976. Schwarz C, Volz A, Li C, Leucht S.
Valproate for schizophrenia. Cochrane Database Syst Rev. 2008;(3):CD004028. State MW, Levitt P. The conundrums of understanding genetic risks for autism spectrum disorders. Nat Neurosci. 2011;14(12):1499–1506. Tiihonen J, Wahlbeck K, Kiviniemi V. The efficacy of lamotrigine in clozapine-resistant schizophrenia: a systematic review and meta-analysis. Schizophr Res. 2009;109:10– 14. Treadway MT, Pizzagalli DA. Imaging the pathophysiology of major depressive disorder — from localist models to circuit-based analysis. Biol Mood Anxiety Disord. 2014;4:5. Tye KM, Mirzabekov JJ, Warden MR, et al. Dopamine neurons modulate
neural encoding and expression of depression-related behaviour. Nature. 2013;493:537–541. Wang XJ, Krystal JH. Computational psychiatry. Neuron. 2014;84:638–654. Williams HJ, Zamzow CR, Robertson H, Dursun SM. Effects of clozapine plus lamotrigine on phencyclidine-induced hyperactivity. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30(2):239–243. Willsey AJ, Sanders SJ, Li M, et al. Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism. Cell. 155:997–1007. 1.2 Functional Neuroanatomy DARLENE S. MELCHITZKY, M.S., AND DAVID A. LEWIS, M.D. The broad range of affective, cognitive, and behavioral characteristics of humans arise as a consequence of specific patterns of activation in networks of neurons that are distributed across the central nervous system (CNS). These patterns of activation are mediated by the connections among specific brain structures. Consequently, understanding the neurobiologic bases for the disturbances in affective, cognitive, and behavioral processes present in psychiatric disorders requires an appreciation of the major principles governing the functional organization of these structures and their connections in the human brain. This chapter reviews some of these anatomic
principles and illustrates them in the functional circuitry of neural systems that are of particular relevance to psychiatric disorders. PRINCIPLES OF BRAIN ORGANIZATION
Cells The human brain contains approximately 1011 nerve cells or neurons. In general, neurons are composed of four morphologically identified regions (Fig. 1.2–1): (1) the cell body, or soma, which contains the nucleus and can be considered the metabolic center of the neuron; (2) the dendrites, processes that arise from the cell body, branch extensively, and serve as the major recipient zones of input from other neurons; (3) the axon, a single process that arises from a specialized portion of the cell body (the axon hillock) and conveys information to other neurons; and (4) the axon terminals, fine branches near the end of the axon that form contacts (synapses) generally with the dendrites or the cell bodies of other neurons, release neurotransmitters, and provide a mechanism for interneuronal communication.
Distinctiveness of the Human Brain Compared with the brains of other primate species, the human brain is substantially greater in size, with certain areas expanded disproportionately. The prefrontal cortex has been estimated to occupy only 3.5 percent of the
total cortical volume in cats and 11.5 percent in monkeys but close to 30 percent of the much larger cortical volume of the human brain. Conversely, the relative representation of other regions is decreased in the human brain; for example, the primary visual cortex accounts for only 1.5 percent of the total area of the cerebral cortex in humans, but in monkeys, a much greater proportion (17 percent) of the cerebral cortex is devoted to this region. Thus, the distinctiveness of the human brain is attributable to its size and to the differential expansion of certain regions, particularly the areas of the cerebral cortex devoted to higher cognitive functions. In addition, the expansion and differentiation of the human brain are associated with substantial differences in the organization of certain elements of neural circuitry. For example, compared with rodents, the dopaminergic innervation of the human cerebral cortex is much more widespread and regionally specific. The primary motor cortex and certain posterior parietal regions receive a dense dopamine innervation in monkeys and humans, but these areas receive little dopamine input in rats. The human brain is also distinctive at the cellular level, with greater relative percentages of certain neuronal and glial cells in the cerebral cortex. For example, the relative
proportion of GABAergic interneurons is ∼15 percent in rodent cerebral cortex, but in humans, 20 to 25 percent of all neurons in most cortical areas are GABAergic. In addition, molecular characterization has revealed subtypes of neurons in the human cerebral cortex that are not found in rodent cerebral cortex. Intralaminar and polarized astrocytes are found exclusively in humans, and human protoplasmic astrocytes are larger and have more processes than their rodent counterparts. Furthermore, the astrocyte to neuron ratio is fivefold greater in humans compared to rodents, leading to greater astrocytic coverage of neurons and synapses and thus possibly enhanced regulation of neurotransmission in human cerebral cortex. These findings of a greater contribution of astrocytes in human brain function suggest that astrocytes are critical for higher brain functions and may be vulnerable in human psychiatric disorders. Thus, the human brain exhibits differences in gross anatomy, cellular constituents, and molecular composition, features that distinguish it from phylogenetically lower species. FIGURE 1.2–5. Photographs of the lateral (top) and medial (bottom) aspects of the left hemisphere of a human brain indicating the location of major surface landmarks. F, frontal lobe; O,
occipital lobe; P, parietal lobe; T, temporal lobe; Th, thalamus; ccG, genu of the corpus callosum; ccS, splenium of the corpus callosum. These types of species differences indicate that there are limits to the accuracy of generalizations made concerning human brain function when using studies in rodents or even nonhuman primates as the basis for the inference. Direct investigation of the organization of the human brain, however, is obviously limited and complicated by numerous factors. As indicated earlier, the expansion of the human brain is associated with the appearance of additional regions of the cerebral cortex. For example, the entorhinal cortex of the medial temporal lobe in humans is sometimes considered to be a single cortical region, but the cytoarchitecture and chemoarchitecture of this cortex differ substantially along its rostral–caudal extent (see Fig. 1.2–3). It is tempting to identify these regions by their location relative to other structures, but sufficient interindividual variability exists in the human brain to make such a topologic definition unreliable. In the case of the entorhinal cortex, the location of its different subdivisions relative to adjacent structures, such as the amygdala and the hippocampus, varies across human brains. Therefore, in all studies, particularly studies using the human
brain, areas of interest must be defined in a manner (e.g., using cyto-, chemo-, or myeloarchitectural features) that allows investigators to accurately identify the same region in all cases. An additional limitation to the study of the human brain concerns the changes in morphology and biochemistry that can occur during the interval between the time of death and the freezing or fixation of brain specimens. In addition to the influence of the known postmortem interval, such changes may begin to occur during the agonal state preceding death. When comparing aspects of the organization of the human brain with that of other species, the researcher must try to account for changes that may have occurred in the human brain as a result of postmortem delay or agonal state. In the study of disease states, appropriate controls must be used because differences in neurotransmitter content or other characteristics among cases could be a result of factors other than the disease state, such as methods of tissue preparation. Studies of the human brain in vivo—using such imaging techniques as positron emission tomography (PET), magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and diffusion tensor imaging (DTI)— circumvent many of these problems but are limited by
insufficient resolution for the study of many aspects of human brain organization. STRUCTURAL COMPONENTS Major Brain Structures In the early stages of human brain development, three primary vesicles can be identified in the neural tube: the prosencephalon, the mesencephalon, and the rhombencephalon (Fig. 1.2–6). Subsequently, the prosencephalon divides to become the telencephalon and the diencephalon. The telencephalon gives rise to the cerebral cortex, the hippocampal formation, the amygdala, and some components of the basal ganglia. The diencephalon becomes the thalamus, the hypothalamus, and several other related structures. The mesencephalon gives rise to the midbrain structures of the adult brain. The rhombencephalon divides into the metencephalon and the myelencephalon. The metencephalon gives rise to the pons and the cerebellum; the medulla is the derivative of the myelencephalon. The cerebral cortex of each hemisphere is divided into four major regions: the frontal, parietal, temporal, and occipital lobes (see Fig. 1.2– 5). The frontal lobe is located anterior to the central sulcus and consists of the primary motor, premotor, and prefrontal regions (Fig. 1.2–7). The prefrontal cortex can be divided into dorsolateral and ventrolateral regions, with each of these regions
having different functional properties. For example, the dorsolateral prefrontal cortex (DLPFC) seems to be more involved in the manipulation of data during working memory tasks than does the ventrolateral prefrontal cortex, which seems to be more involved with pure maintenance of information during working memory. The primary somatosensory cortex is located in the anterior parietal lobe; in addition, other cortical regions related to complex visual and somatosensory functions are located in the posterior parietal lobe. The superior portion of the temporal lobe contains the primary auditory cortex and other auditory regions; the inferior portion contains regions devoted to complex visual functions. In addition, some regions within the superior temporal sulcus receive a convergence of input from the visual, somatosensory, and auditory sensory areas. The occipital lobe consists of the primary visual cortex and other visual association areas. The brains of humans and other anthropoid primates also contain a major area called the insula which is a cortical region located within the depths of the lateral sulcus (Figs. 1.2–8 and 1.2–9), covered dorsally by the frontal and parietal opercula and ventrally by the temporal operculum.