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Neurodevelopment and Schizophrenia
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Book description

This book was originally published in 2004 and concerns developmental neurobiology. In the decade preceding publication, developmental neurobiology made important strides towards elucidating the pathophysiology of psychiatric disorders. Nowhere has this link between basic science and clinical insights become clearer than in the field of schizophrenia research. Each contributor to this volume provides a fresh overview of the relevant research, including directions for further investigation. The book begins with a section on advances in developmental neurobiology. This is followed by sections on etiological and pathophysiological developments, and models that integrate this knowledge. The final section addresses the clinical insights that emerge from the developmental models. This book will be valuable to researchers in psychiatry and neurobiology, students in psychology, and all mental health practitioners.

Reviews

Review of the hardback:'… an excellent book that delivers a scientific map of recent neurodevelopmental concepts.'

Source: British Journal of Neuroscience Nursing

Review of the hardback:'… a well-balanced and comprehensive overview that merits to be read by all students of this fascinating and devastating disorder.'

Source: Genes, Brain and Behaviour

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Contents


Page 1 of 2


  • Preface
    pp xvii-xviii
    • By Matcheri S. Keshavan, University of Pittsburgh School of Medicine, Department of Psychiatry and Western Psychiatric Institute and Clinic, Pittsburgh and the Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, 4201 St Antoine Boulevard, Detroit, MI 48201, USA, James L. Kennedy, Centre for Addiction and Mental Health, University of Toronto, 250 College St, Toronto, ON M5T1R8, Canada, Robin M. Murray, University of Pittsburgh School of Medicine, Department of Psychiatry and Western Psychiatric Institute and Clinic, Pittsburgh and the Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, 4201 St Antoine Boulevard, Detroit, MI 48201, USA
  • 1 - Genes and brain development
    pp 3-34
    • By Timothy A. Klempan, Centre for Addiction and Mental Health, University of Toronto, Toronto, Canada, Pierandrea Muglia, Centre for Addiction and Mental Health, University of Toronto, Toronto, Canada, James L. Kennedy, Centre for Addiction and Mental Health, University of Toronto, Toronto, Canada
  • View abstract

    Summary

    The processes of neurulation, patterning, neuronal specification, and synaptogenesis, as well as the functional dynamics of neurotransmission, are governed by the coordinated actions of products from a wide array of genes. Neurodevelopmental etiology of schizophrenia is suggested by neuroimaging and postmortem studies revealing significant and replicated lateral ventricular enlargement, hippocampal and gray matter deficits, and cellular disarray, independent of duration of the illness and antipsychotic treatment. This chapter provides an overview of the major mechanisms involved in the development of the mammalian central nervous system (CNS), with specific reference to the identity and patterning of genes that are known to regulate the developmental phases. This pattern of gene expression is related to the etiology of schizophrenia through evidence provided by genetic, postmortem, imaging, electrophysiological, and behavioral investigations of the disorder.
  • 2 - Brain development in healthy children and adolescents: magnetic resonance imaging studies
    pp 35-44
    • By Jay N. Giedd, Child Psychiatry Branch, National Institute of Mental Health, Bethesda, USA, Michael A. Rosenthal, Child Psychiatry Branch, National Institute of Mental Health, Bethesda, USA, A. Blythe Rose, Child Psychiatry Branch, National Institute of Mental Health, Bethesda, USA, Jonathan D. Blumenthal, Child Psychiatry Branch, National Institute of Mental Health, Bethesda, USA, Elizabeth Molloy, Child Psychiatry Branch, National Institute of Mental Health, Bethesda, USA, Richard R. Dopp, Child Psychiatry Branch, National Institute of Mental Health, Bethesda, USA, Liv S. Clasen, Child Psychiatry Branch, National Institute of Mental Health, Bethesda, USA, Daniel J. Fridberg, Child Psychiatry Branch, National Institute of Mental Health, Bethesda, USA, Nitin Gogtay, Child Psychiatry Branch, National Institute of Mental Health, Bethesda, USA
  • View abstract

    Summary

    Using Magnetic resonance imaging (MRI), the team at the Child Psychiatry Branch of the National Institute of Mental Health has been collecting brain MRI scans on healthy children and adolescents since 1989. As of 2003, over 300 scans from 150 healthy subjects are acquired. The data presented in this chapter is largely drawn from this cohort unless otherwise stated. MRI is adept at discerning gray matter, white matter, and fluid on brain images. These boundaries are used to define the size and shape of brain structures or regions. Characterization of normal brain development is imperative to assess the hypothesis that many of the most severe neuropsychiatric disorders of childhood onset are manifestations of deviations from that normative path. Sexual dimorphism in healthy brain development may lead to differential vulnerability, which would account for some of the clinical differences in childhood neuropsychiatric disorders.
  • 3 - Cognitive development: functional magnetic resonance imaging studies
    pp 45-68
    • By Beatriz Luna, Western Psychiatric Institute and Clinic, Pittsburgh, USA, John A. Sweeney, The Psychiatric Institute, University of Illinois, Chicago, USA
  • View abstract

    Summary

    Pediatric neuroimaging techniques can probe the integrity of brain function and normal brain maturational processes and provide a window into possible abnormalities in neurocognitive development. This chapter describes the initial investigations and discusses what has been found regarding the changes in brain function that support the healthy maturation of cognitive control of behavior. Basic cognitive processes, which are evident in infancy and show dramatic changes throughout childhood, continue to develop throughout adolescence. Two higher-order cognitive abilities crucial to the voluntary control of behavior are working memory and voluntary suppression of context-inappropriate responses. Most pediatric functional magnetic resonance imaging (fMRI) studies are performed to assist in the localization of language areas to guide excision lesions to relieve epileptic seizures. Pediatric fMRI studies have provided insight into the possible factors underlying the etiology of developmental abnormalities such as attention-deficit hyperactivity disorder (ADHD) and dyslexia.
  • 4 - Cognitive development in adolescence: cerebral underpinnings, neural trajectories, and the impact of aberrations
    pp 69-88
  • View abstract

    Summary

    This chapter discusses the gains in function made during adolescence, a time of major upheaval in behavioral and social domains. It reviews the structural brain changes that occur during this time and explores neuropsychological development, with a special focus on executive functions. The chapter discusses links between cognitive and cerebral development, with an emphasis on the impact of developmental lesions. Finally, it presents a hypothesis explaining the neuropsychological deficits in schizophrenia as an interaction between the timing of illness onset and the timing of normal cognitive development. Specifically, the chapter suggests that cognitive functions that mature around the time when the illness first presents, such as working memory, are more impaired than those functions that mature earlier. The study of cognitive development through adolescence is of great importance to the understanding of the neurobiology of disorders that first present at this time.
  • 5 - Brain plasticity and long-term function after early cerebral insult: the example of very preterm birth
    pp 89-108
  • View abstract

    Summary

    This chapter deals with the developmental plasticity and discusses the recovery, or sparing, of functions and the reorganization of brain structure that occurs as a consequence of early brain injury, using the example of preterm birth. From the public health point of view, one of the most important challenges to early brain plasticity comes from preterm birth. In the assessments of the University College Hospital London (UCHL) very preterm (VPT) cohort, assessments were made of neurological, neuropsychological, and behavioral function. Some of these results are summarized in this chapter. The animal studies suggest that a brain lesion may remain relatively 'silent' until later in life, only causing functional compromise when the neural system involved reaches maturity. It is important to continue to follow up preterm individuals as they enter adulthood and to determine which factors are associated with poor outcome.
  • 6 - Do degenerative changes operate across diagnostic boundaries? The case for glucocorticoid involvement in major psychiatric disorders
    pp 111-120
  • View abstract

    Summary

    Crucial supportive evidence for the theory was given by studies showing that classical degenerative brain changes were largely absent, by the presence of microscopic brain changes indicative of abnormal brain development, and by the absence of clear evidence for progressive ventricular dilatation among schizophrenia subjects. It is possible that the microscopic neuropathological changes described in schizophrenia may be vulnerable factors for schizophrenia. Alternatively, they could be an intrinsic component or a consequence of illness. Neuropathological studies cannot tell which interpretation is correct. However, there are some important similarities in the neuropathology of schizophrenia, major depressive disorder (MDD) and bipolar disorder (BPD), which suggest that a common process of change is involved in each disorder. There are several lines of investigation that support the view that glucocorticoid-related neurotoxicity may be implicated in depression and schizophrenia. The glial deficit found in these disorders may also relate to glucocorticoid effects.
  • 7 - Velo-cardio-facial syndrome (deletion 22q11.2): a homogeneous neurodevelopmental model for schizophrenia
    pp 121-137
    • By Stephan Eliez, University of Geneva School of Medicine, Geneva, Switerland, Carl Feinstein, Stanford University School of Medicine, Stanford, USA
  • View abstract

    Summary

    There is now a very impressive body of data supporting the neurodevelopmental hypothesis of schizophrenia. This chapter summarizes the available clinical, neuroimaging, and genetic information regarding velo-cardio-facial syndrome (VCFS), so that it may be available for clinical research in schizophrenia. Developmental delays in the preschool period may result in identification of VCFS at that time, but some children with VCFS and adults whose condition was unrecognized in childhood are never identified, because of low clinical index of suspicion. Studies of the relationship between VCFS and schizophrenia have recently stimulated interest in further molecular genetic analysis of 22q11.2 site, utilizing both family- and population-based schizophrenia samples. A review of most of the available neuroimaging studies of children with VCFS suggests that there is an early alteration of parietal lobe and cerebellum, and that the decrease of temporal lobe gray matter and hippocampus can be observed only in adults.
  • 8 - Can structural magnetic resonance imaging provide an alternative phenotype for genetic studies of schizophrenia?
    pp 138-155
    • By Colm McDonald, Institute of Psychiatry, King's College London, De Crespigny Park, London, UK, Robin M. Murray, Institute of Psychiatry, King's College London, De Crespigny Park, London, UK
  • View abstract

    Summary

    This chapter reviews the value of structural brain deviations identified through magnetic resonance imaging (MRI) as potential endophenotypes in genetic studies of schizophrenia and the evidence to date that a number of specific brain deviations are linked to susceptibility genes for schizophrenia from studies of patients and their unaffected relatives. One of the earliest studies of brain structure in normal twins was a computed tomographic (CT) study of subjects from the Maudsley Twin Series. In this study, measurements of ventricular volume in normal MZ twins were much more highly correlated than those of DZ twins, indicating strong genetic control over ventricular size, with estimates of heritability for ventricular size using different methods all over 80%. Despite heterogeneous patient samples and methodologies, neuroimaging studies consistently identify subtle volumetric deviations in a range of brain structures when schizophrenia patients are compared with controls.
  • 9 - Nutritional factors and schizophrenia
    pp 156-173
  • View abstract

    Summary

    This chapter discusses the role of essential nutritional factors such as amino acids, lipids, vitamins, and minerals on the course and outcome of schizophrenia. Both under- and malnutrition have been found to impair the brain and behavioral development, as well as affect the health of the body and mind in the adult. Arachidonic acid (AA) and docosahexaenoic acid (DHA) make 50% of the fatty acids that are attached to brain phospholipids, which comprise almost 60% of brain mass. Many factors influence the dietary intake of essential polyunsaturated fatty acids (EPUFAs) by an individual: the season in which a person is conceived and born, family size, birth order, whether the person was breast-fed as an infant, culture, socioeconomic status, and domicile. At present the primary concerns for nutritional factors in schizophrenia relate to intake of EPUFAs, particularly the omega-3 essential fatty acids (EFAs), and antioxidants, such as vitamins E and C.
  • 10 - Schizophrenia, neurodevelopment, and epigenetics
    pp 174-190
  • View abstract

    Summary

    The neurodevelopmental theory of schizophrenia is based on the hypothesis that early brain insults affect brain development and eventually cause dysfunction of the mature brain, predisposing to schizophrenia. A large group of putative etiological factors has been suggested, investigated, and categorized into environmental and genetic groups. The first group includes various obstetric complications such as birth trauma, maternal viral infection during pregnancy, pre-eclampsia, and deficiencies in nutrition. The second group provokes emphasis on DNA sequence variation in the genes that may play a role in neurodevelopment. This chapter suggests the idea that developmental changes in schizophrenia can be caused and/or mediated by epigenetic factors. It argues that shifting the emphasis from the traditional gene-environment dichotomy to epigenetics may provide a cohesive theoretical framework for a myriad of fragmented phenomenological and molecular findings in schizophrenia and lead to a series of new molecular strategies, designs, and approaches.
  • 11 - Early environmental risk factors for schizophrenia
    pp 191-209
    • By Mary Cannon, Institute of Psychiatry, King's College, London, UK; Royal College of Surgeons in Ireland, Dublin, Ireland, Kimberlie Dean, Institute of Psychiatry, King's College, London, UK, Peter B. Jones, University of Cambridge, UK
  • View abstract

    Summary

    The existence of early environmental risk factors for schizophrenia is central to the notion of schizophrenia as a neurodevelopmental disorder and these risk factors represent some of the most challenging and interesting targets of schizophrenia epidemiology. This chapter discusses prenatal and perinatal risk factors for schizophrenia. The risk of developing schizophrenia has consistently been found to be increased (1.5 to 2-fold) among those born in cities compared with those born in rural Areas. Rhesus (Rh) incompatibility, characterized by an Rh-negative mother pregnant with an Rh-positive fetus, has been associated with an elevated risk for schizophrenia. Prenatal stress is associated with smaller head circumference, neonatal neurological impairment and behavior problems in childhood. The best evidence to date is for prenatal exposure to influenza and other respiratory infections, prenatal rubella, hypoxia-related obstetric complications and low birth weight or intrauterine growth retardation.
  • 12 - Transcriptomes in schizophrenia: assessing altered gene expression with microarrays
    pp 210-223
  • View abstract

    Summary

    This chapter reviews the current status of the technology to assess transcriptomes, its associated strengths and limitations, and initial findings resulting from the use of the approaches to study schizophrenia. Two types of microarray platform have been used in studies of schizophrenia: complementary DNA (cDNA) microarrays and synthetic oligonucleotide probe arrays. The study of gene expression in human brain tissue, the area of interest in schizophrenia, requires the use of postmortem human brain specimens. In postmortem brain specimens from subjects with schizophrenia, a difference in the expression level of one or a cluster of genes may have several different meanings. The application of transcriptome-based methods to studies of the molecular neuropathology of schizophrenia is clearly in their infancy, and like newborns they offer great promise for the future. However, careful rearing is essential to fulfill this promise.
  • 13 - Is there a role for social factors in a comprehensive development model for schizophrenia?
    pp 224-247
    • By Jane Boydell, Institute of Psychiatry King's College London, UK, Jim van Os, Maastricht University, Maastricht, the Netherlands, Robin M. Murray, Institute of Psychiatry King's College London, UK
  • View abstract

    Summary

    In the 1950s and 1960s, there was much extravagant discussion of the role of social factors in the etiology of schizophrenia. A decade later, the neurodevelopmental model of schizophrenia was proposed, and it became the dominant etiological and pathogenetic model. This chapter reviews the social factors that are postulated to operate early in life and those which may act more proximal to the onset of the disorder. It considers how animal research has informed on psychiatric conditions. Studies using intensive field methods to examine subjective experience of stress in the flow of daily life have found that individuals with schizophrenia, and individuals with genetic susceptibility to schizophrenia, display greater levels of emotional reactivity to small daily life stressors than do control subjects. The chapter also presents the evidence that early social adversity can affect brain development.
  • 14 - How does drug abuse interact with familial and developmental factors in the etiology of schizophrenia?
    pp 248-270
  • View abstract

    Summary

    The environmental risk factors for schizophrenia can be summarized as operating either early in life or later nearer the onset of frank psychosis. This chapter focuses on the role of drug abuse as one of the later factors, and on how it interacts with familial and developmental factors. All the molecular genetic study results discussed are preliminary; both the positive and the negative findings need replication in larger samples. It is likely that certain drugs change the expressions of genes related to neurotransmitter systems such as dopamine or glutamic acid and also for transcription factors, cell proliferation, apoptosis, cell adhesion, and the synapse. Recent research suggests that dopamine sensitization may underlie both craving and the onset of drug-associated psychosis. A drug abuser with low liability to psychosis may use psychostimulant drugs regularly for longer periods without developing psychosis or, at worst may have just brief psychotic symptoms.
  • 15 - Developmental dysregulation of the dopamine system and the pathophysiology of schizophrenia
    pp 273-294
  • View abstract

    Summary

    Evidence suggests that the dopamine (DA) system plays a key role in the pathophysiology and treatment of schizophrenia. Therefore, drugs that increase DA transmission are known to exacerbate this disorder and mimic paranoid psychosis in normal individuals, and drugs that are effective antipsychotic agents all have DA receptor-blocking properties in common. Substantial evidence exists to suggest that the pathological processes contributing to schizophrenia occur early in life, supporting the contention that schizophrenia is a developmental disorder. This chapter presents a model whereby stress is proposed to interact with an existing pathology within the limbic system to cause the delayed emergence of the positive symptoms of schizophrenia. The involvement of stress is demonstrated by the finding that, of the children at risk for developing schizophrenia, those that do go on to show the pathology exhibit higher levels of anxiety and stress premorbidly.
  • 16 - The development of “mis-wired” limbic lobe circuitry in schizophrenia and bipolar disorder
    pp 295-309
  • View abstract

    Summary

    In patients with schizophrenia, a variety of anomalies have been detected in the limbic lobe, a phylogenetically old portion of the cerebral cortex that includes the anterior cingulate region and hippocampal formation. In addition, the basolateral subdivision of the amygdala, another component of the limbic lobe, has been implicated in the pathophysiology of psychotic disorders, in part because it sends important inputs to the cingulate cortex and hippocampus. The three major components of the limbic lobe play a central role in generating disturbances in motivation, attention, emotion, and social interactions in schizophrenia and bipolar disorder. This chapter describes studies in both human and rodent brains that have contributed to our understanding of how this complex circuitry may be altered during development, leading to the appearance of psychotic disorders during late adolescence and early adulthood. It discusses two particular neurotransmitters: gamma-aminobutyric acid (GABA) and dopamine.
  • 17 - Development of thalamocortical circuitry and the pathophysiology of schizophrenia
    pp 310-329
  • View abstract

    Summary

    Schizophrenia is a multithetic disorder in which the diverse signs and illness symptoms arise as a result of dysfunction in a number of brain regions. Individuals with schizophrenia perform poorly on cognitive tasks that require the use of working memory: the ability to maintain information "on line" in order to guide behavior. Both imaging and postmortem studies have revealed abnormalities in the thalamus of subjects with schizophrenia. Evidence for abnormalities in mediodorsal nucleus (MDN) to dorsolateral prefrontal cortex (DLPFC) projections includes reductions of both pre- and postsynaptic markers for the axons. The discussed findings suggest that alterations in MDN-DLPFC circuitry play a critical role in the pathophysiology of cognitive dysfunction in schizophrenia. Relatively few studies have examined details of the organization of MDN-DLPFC circuitry in primates, and much of our understanding of the functional attributes of this circuitry represents reasonable but speculative extrapolation from studies of sensory thalamic systems.
  • 18 - X chromosome, estrogen, and brain development: implications for schizophrenia
    pp 330-346
  • View abstract

    Summary

    The neurodevelopmental theory is now regarded by many psychiatrists as a dominant explanatory model of schizophrenia. In order to evaluate this model critically, it is important to understand how the normal brain develops and changes across the lifespan. The important factors, reviewed in this chapter, include the sex chromosomes and sex steroids. The chapter offers evidence that sex chromosomes and sex steroids (in particular estrogen) significantly modulate the structure and function of normal brain, and this is considered when forming developmental theories of schizophrenia, when attempting to explain sex differences in schizophrenia, and when considering the role of sex steroids in the genesis and treatment of schizophrenia. It suggests that estrogen and the chromosome play a modulatory role in brain maturation, and their mechanism of action needs to be understood in order to place the neurodevelopmental theory of schizophrenia in context.
  • 19 - Premorbid structural abnormalities in schizophrenia
    pp 347-372
  • View abstract

    Summary

    Hundreds of structural brain imaging studies have demonstrated that there is a neuroanatomy of schizophrenia. This chapter reviews evidences, for premorbid abnormalities in patients with schizophrenia and related populations. Computed tomography (CT) demonstrated ventricular enlargement and a generalized loss of brain tissue, which may have conflated separate disease processes. Magnetic resonance imaging, which now requires a structural prefix (sMRI), has replicated these findings and convincingly shown additional volume deficits in the prefrontal and temporal lobes, as well as further decrements in the medial and superior temporal lobe. The Edinburgh High Risk Study examines subjects with two close relatives with schizophrenia. Researchers in the Melbourne High Risk Study have adopted a different but complementary approach. Evidence shows that obstetric complications (OCs) are related to small hippocampi in schizophrenia, possibly through gene-environment interaction. Evidence related to the hypothermic treatment of hypoxic brains is proved in reducing adverse neurodevelopmental outcomes.
  • 20 - Neurodegenerative models of schizophrenia
    pp 373-389
  • View abstract

    Summary

    The concept of schizophrenia as a neurodegenerative disorder has a long and somewhat controversial past. The absence of a histopathological phenotype in schizophrenia has been cited as evidence against a neurodegenerative hypothesis. However, studies of schizophrenia increasingly demonstrate subtle yet consistent histopathological deficits in addition to evidence of progressive clinical and neuroimaging findings. It is believed that schizophrenia can be considered as a limited neurodegenerative disorder with neurodevelopmental antecedents. Studies from clinical, neurocognitive, neuroimaging, and neuropathological domains are reviewed in critical analysis of this hypothesis. The conclusion is increasingly supported by neuroimaging studies that find progressive neurostructural changes, especially in gray matter content and ventricle size, and studies that report limited progression of clinical symptoms and neurocognitive function. Future studies utilizing high-resolution neuroimaging and sophisticated neuropsychological testing techniques will undoubtedly provide greater insight on the timing, regionality, and degree of progression in the early stages of schizophrenia.
  • 21 - Does disordered brain development occur across diagnostic boundaries?
    pp 390-412
  • View abstract

    Summary

    This chapter focuses on the neurodevelopmental basis of diagnostic overlap and symptom commonality by addressing similarities and differences in the neuroanatomical and functional neurochemical basis of three common childhood/adolescent-onset neuropsychiatric disorders: attention-deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), and mood disorder, including major depressive disorder (MDD) and bipolar disorder (BPD). These disorders are selected because of the clinical commonalities with schizophrenia and because of the known or presumed developmental origins of these disorders. Schizophrenia, BPD, and OCD have their onset in adolescence or early adulthood, and they may be preceded by symptoms similar to those in developmental disorders such as ADHD. The disorders are discussed in comparison with schizophrenia. The chapter describes the relevant findings in schizophrenia. It limits the pathophysiological discussion to the neuroimaging findings, and considers common genetic and environmental etiologic factors that may cut across these disorders.

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