Contemporary Clinical Neuroscience – serie

The field ofneurodegenerative diseases is undergoing an unprecedented revolution. The past decade has seen the identification of new mutation mecha- nisms, such as triplet repeat expansions, and new genes causing familial forms of common neurodegenerative diseases, such as Parkinson's and Alzheimer's diseases. Cellular and animal models based on this genetic information are now available and, importantly, common mechanisms are rapidly emerging among diseases that were once considered unrelated. The field is poised for the development of new therapies based on high throughput screenings and a bet- ter understanding of the molecular and cellular mechanisms leading to neurodegeneration. Molecular Mechanisms of Neurodegenerative Diseases reviews recent progress in this exploding field. By nature, such a book cannot be all inclu- sive. It focuses on Alzheimer's, Parkinson's, and CAG triplet repeat diseases. In the first chapter, Bill Klein reviews the role of A~ toxicity in the patho- physiology of Alzheimer's disease. This controversial issue is further exam- ined in the context of transgenic models of Alzheimer's disease by LaFerla and colleagues.Sue Griffin and Robert Mrak, and Caleb Finch and collabora- tors, then examine the role of glial cells and inflammation in Alzheimer's disease; a review of the role of proteolysis in the generation of abnormal pro- tein fragments by Hook and Mende-Mueller follows. Therapeutic opportuni- ties offered by a better understanding of Alzheimer's disease pathophysiology are examined by Perry Molinoff and his colleagues at Bristol-Myers Squibb.

Physicians, nurses, and safety experts comprehensively review sedation and analgesia to provide a completely new reference guide to safe sedation practices consistent with existing guidelines. Starting with an integrated review of the basic physiology and neurobiology of the sedated state, the authors proceed through clinical guidelines and practices, and conclude with an examination of quality-outcome measures and processes. They also review current mandates for safe sedation practices and address the key clinical issues of pharmacology, monitoring, and recovery. Special tables and figures throughout the book summarize protocols, regulatory requirements, recommended dosages, monitoring requirements, and quality assurance tools.

In Glutamate and Addiction, world-renowned scientific experts critically review all of the evidence for the role of glutamatergic systems in opiate, stimulant, and alcohol addiction. Using a variety of pharmacological, biochemical, genetic, and brain imaging techniques, these investigators show precisely how glutamate affects such addictions and how modifying certain elements of the glutamatergic system appear to alleviate particular components of addiction. Their survey takes in both clinical approaches using medications that influence glutamate and cutting-edge preclinical approaches that manipulate specific subtypes of glutamate receptors or specific substrates of the glutamate cascade to determine their roles in various addictive states.

Leading investigators critically evaluate the latest information on how anesthetics work at the molecular, cellular, organ, and whole animal level. These distinguished experts review anesthetic effects on memory, consciousness, and movement and spell out in detail both the anatomic structures and physiological processes that are their likely targets, as well as the cellular and molecular mechanisms by which they operate. Comprehensive and authoritative, Neural Mechanisms of Anesthesia draws together and critically reviews all the recent research on anesthetic mechanisms, highlighting the precise routes along which these substances operate, and how this deeper understanding will lead to the design of effective drugs free ofundesirable side effects.

Kernicterus (bilirubin encephalopathy) is a highly interesting example of metabolic encephalopathy. It fills all the characteristics of a metabolic encephalopathy in that it can develop rapidly, produces signature signs and symptoms, and is amenable to successful treatment. In the absence of treatment kernicterus can produce devastating sequelae and death.The present volume will examine the biochemistry and physiology of bilirubin as well as its hepatic metabolism and renal excretion. Chapters will elaborate bodily disposition of bilirubin and its neuropathology. Both early treatments and current therapy will be discussed in detail. Phototherapy will be presented, and its efficacy and influence on incidence thoroughly examined.

Using rodent models, this volume explores the basic neurobiology of the relationship among chronic pain, opioid pharmacology, and addiction.

This book is a comprehensive overview of the clinical and scientific aspects of Autism from the leading experts in the field. The clinical section covers everything from epidemiological features to epigenetic regulation to behavioral therapies and much in between. The basic science section presents the latest knowledge on the underlying causes of the disorder including the role of various neurotransmitters, neurexins and neuroligins, reelin, and other proteins. Chapters also explore the cognition and motor control in autism and the connection between oxidative stress and mitochondrial dysfunction and autism. The thorough description of these underlying causes may help researchers and clinicians find more effective treatments and therapies for the 1 in 68 American children who have been diagnosed with Autism.

Thyroid hormone plays an important role in development and functional maintenance in the central nervous system.  Deficiency of thyroid hormone during fetal and early postnatal life induces abnormal development known as cretinism in humans.  However, the molecular mechanism of thyroid hormone action has not yet been fully understood.  Thyroid hormone action in the brain may be disrupted under various pathological conditions.  In addition, environmental factors including endocrine-disrupting chemicals and bacterial endotoxins may disrupt thyroid hormone action in brain, causing abnormal brain development and functional disruption.   This is a first book to comprehensively describe the effect of thyroid hormone disruption in the central nervous system.  The first section deals with the disruption of thyroid hormone action at the molecular level.  First the authors provide a summary of the possible molecular mechanisms of thyroid hormone action in the brain, then they discuss several factors that may disrupt thyroid hormone action. In the second section, animal models to study thyroid hormone action will be introduced.  An interesting character of thyroid hormone deficiency is that, without thyroid hormone, the thyroid hormone receptor may act as a “repressor” of gene expression, causing more severe consequence than those of thyroid hormone receptor knockout animals.  Thus, several different kind of animal models may be used to clarify the role of thyroid hormone and its receptor in the brain. In the third section, human studies on thyroid disease and neurodevelopment will be introduced.  Although endemic cretinism induced by iodine deficiency and sporadic cretinism by various thyroid mutation are well known, the pathophysiological mechanisms that create each abnormal phenotype are not fully understood.  ​

This book is a comprehensive overview of the clinical and scientific aspects of Autism from the leading experts in the field. The clinical section covers everything from epidemiological features to epigenetic regulation to behavioral therapies and much in between. The basic science section presents the latest knowledge on the underlying causes of the disorder including the role of various neurotransmitters, neurexins and neuroligins, reelin, and other proteins. Chapters also explore the cognition and motor control in autism and the connection between oxidative stress and mitochondrial dysfunction and autism. The thorough description of these underlying causes may help researchers and clinicians find more effective treatments and therapies for the 1 in 68 American children who have been diagnosed with Autism.

Thyroid hormone plays an important role in development and functional maintenance in the central nervous system.  Deficiency of thyroid hormone during fetal and early postnatal life induces abnormal development known as cretinism in humans.  However, the molecular mechanism of thyroid hormone action has not yet been fully understood.  Thyroid hormone action in the brain may be disrupted under various pathological conditions.  In addition, environmental factors including endocrine-disrupting chemicals and bacterial endotoxins may disrupt thyroid hormone action in brain, causing abnormal brain development and functional disruption.   This is a first book to comprehensively describe the effect of thyroid hormone disruption in the central nervous system.  The first section deals with the disruption of thyroid hormone action at the molecular level.  First the authors provide a summary of the possible molecular mechanisms of thyroid hormone action in the brain, then they discuss several factors that may disrupt thyroid hormone action. In the second section, animal models to study thyroid hormone action will be introduced.  An interesting character of thyroid hormone deficiency is that, without thyroid hormone, the thyroid hormone receptor may act as a “repressor” of gene expression, causing more severe consequence than those of thyroid hormone receptor knockout animals.  Thus, several different kind of animal models may be used to clarify the role of thyroid hormone and its receptor in the brain. In the third section, human studies on thyroid disease and neurodevelopment will be introduced.  Although endemic cretinism induced by iodine deficiency and sporadic cretinism by various thyroid mutation are well known, the pathophysiological mechanisms that create each abnormal phenotype are not fully understood.  ​

A clear and comprehensive account of how genetic abnormalities, neurobiology, and neuropsychology work together to manifest cognitive-behavioral dysfunction. The authors review the current status of research in autosomal disorders that produce cognitive-behavioral dysfunction and syndromal and nonsyndromal disorders that produce mental retardation. Comprehensive and up-to-date, Genetics and Genomics of Neurobehavioral Disorders integrates the molecular, genomic, neuropsychological, and neurobehavioral factors that produce learning disabilities and mental retardation into a coherent framework for the understanding and assessment of neurobehavioral disorders.

Attention deficit hyperactivity disorder (ADHD) is a common neurobehavioral disorder affecting 5-10 per cent of children and adolescents and 3 per cent of adults. This book offers a comprehensive overview of critical aspects of this disorder and will enable practitioners to better understand, diagnose and treat ADHD,

The G Protein-Coupled Receptors handbook provides a comprehensive overview of recent advances in the G protein-coupled receptor (GPCR) field. This volume reviews the recent advances and current knowledge regarding GPCR's from the basics of GPCR structure to dimerization and drug discovery.

The Orexin/Hypocretin System: Physiology and Pathophysiology provides an overview of all the recent exciting discoveries in the field as well as new findings such as ligand replacement and gene therapies in the animal models of narcolepsy. Several contributions cover sleep and the multiple systems involved in its regulation. Also covered are clinical applications of orexin/hypocretin agonists and antagonists for various diseases, several experimental methods for orexin/hypoccretin research and their limitations, and careful observations in the appropriate animal models of the disease.

In this up-to-date survey and critical assessment of transgenic and knockout models in neuropsychiatry and behavior, a panel of leading researchers comprehensively assesses how and whether the genetic abnormalities produced from these models manifest the neuropsychiatric disorders to which they correspond. The authors focus on transgenic and knockout models of neurocognitive dysfunction and neuropsychiatric dysfunction. The discussion of neurobiological problems covers mental retardation, polyglutamate, and speech disorders, as well as disorders that involve cognitive, social, speech, and language dysfunction. The neuropsychiatric dysfunctions examined include psychosis and schizophrenia, anxiety, depression, and bipolar disorder.

Twenty-five years ago, Earl R. Stadtman, PhD discovered that specific enzymes regulating metabolism can be inactivated by oxidation [1]. He later showed that age-related oxidative modification contributes, at least in part, to age-related loss of function of the enzymes [2, 3]. Dr. Stadtman broke the ground for a new field of study to discover how oxidative stress contributes in significant ways to age-related cellular dysfunction and protein accumulation and that oxidation in the aging brain influences Alzheimer’s disease, ischemia-reperfusion injury, amyotrophic lateral sclerosis, and lifespan [4–6]. Today, his research and mentorship have positively influenced the work of hundreds of scientists in this field. We dedicate this book to Dr. Earl R. Stadtman (1912–2008), in celebration of his passion for science and his superior collaborative and mentorship skills. This book is comprised of three sections. The first describes the valuable roles reactive oxygen species (ROS) and reactive nitrogen species (RNS) play in cellular biology. The second section provides an overview of redox imbalance injury with effects on mitochondria, signaling, endoplasmic reticular function, and on aging in general. The third section takes these mechanisms to neurodegenerative disorders and provides a state-of-the-art look at the roles redox imbalances play in age-related susceptibility to disease and in the disease processes. In the first section we attempt to answer a question posed by Dr. Stadtman, ‘‘Why have cells selected reactive oxygen species to regulate cell signaling events’’ [7].

Brain Hypoxia and Ischemia explores the various aspects of cell death and survival that are crucial for understanding the basic mechanisms underlying brain hypoxia and ischemia. Chapters focus on a panorama of issues including the role of ion channels/transporters, mitochondria and apoptotic mechanisms, the roles of glutamate/NMDA, mechanisms in penumbral cells and the importance of intermittent hypoxia and gene regulation under these stressful conditions. The volume explores findings from both mammalian and invertebrate model systems and their applicability to human systems and diseases. Careful consideration is also given to differences in hypoxia and ischemia across development. This volume aims to increase the understanding of these mechanisms and to stimulate research on better diagnosis and treatment of diseases that afflict the brain and potentially other organs when O2 levels are dysregulated. Brain Hypoxia and Ischemia is designed for neuroscientists, clinicians and medical/graduate students for use in both basic research and clinical practice.

Thiamine deficiency and related clinical disorders represent an intriguing area of both basic and clinical investigation. Modern imaging strategies have facilitated the rapid treatment, and potential reversal of these clinical disorders. The fusion of laboratory and clinical knowledge serve as an example of how research can translate to successful treatment. The goal of Thiamine Deficiency and Related Clinical Disorders is to bring together cogent results from basic and clinical investigation and to stimulate further investigations in these areas. This data will be useful to neurologists, internists, nutritionists, biochemists, neurochemists, neuroscientists, and others with interest in thiamine deficiency.

Anesthetics produce a reversible state of unconsciousness accompanied by ante- grade amnesia. This remarkable phenomenon brings great relief to surgical patients and wonder to clinicians and scientists. To date, we do not fully understand the mechanisms by which anesthetics ablate conscious sensation and memory. We are, however, making progress. This book presents original results as well as overviews of the current state of knowledge of the problem. It is authored by investigators who know the ?eld well; their research at a number of levels has contributed substantially to our c- rent understanding of anesthetic modulation of memory and consciousness. Most of the contributors were presenters at two workshops organized by Dr. Pearce and Dr. Hudetz at the 40th Annual Winter Conference on Brain Research, held at Snowmass Village, Colorado, from January 27 through February 2, 2007. One workshop focused on anesthetic modulation of consciousness and another on an- thetic modulation of memory. Seven of the chapters are based on material presented at these symposia – appropriately updated with new relevant ?ndings. This infor- tion is supplemented by chapters on anesthesia and sleep, computational analysis of the state of anesthesia, and the clinical phenomenon of “anesthesia awareness,” a topic that has recently received much public attention. With these three additional contributions, the book thus includes 10 chapters.

The field ofneurodegenerative diseases is undergoing an unprecedented revolution. The past decade has seen the identification of new mutation mecha- nisms, such as triplet repeat expansions, and new genes causing familial forms of common neurodegenerative diseases, such as Parkinson's and Alzheimer's diseases. Cellular and animal models based on this genetic information are now available and, importantly, common mechanisms are rapidly emerging among diseases that were once considered unrelated. The field is poised for the development of new therapies based on high throughput screenings and a bet- ter understanding of the molecular and cellular mechanisms leading to neurodegeneration. Molecular Mechanisms of Neurodegenerative Diseases reviews recent progress in this exploding field. By nature, such a book cannot be all inclu- sive. It focuses on Alzheimer's, Parkinson's, and CAG triplet repeat diseases. In the first chapter, Bill Klein reviews the role of A~ toxicity in the patho- physiology of Alzheimer's disease. This controversial issue is further exam- ined in the context of transgenic models of Alzheimer's disease by LaFerla and colleagues.Sue Griffin and Robert Mrak, and Caleb Finch and collabora- tors, then examine the role of glial cells and inflammation in Alzheimer's disease; a review of the role of proteolysis in the generation of abnormal pro- tein fragments by Hook and Mende-Mueller follows. Therapeutic opportuni- ties offered by a better understanding of Alzheimer's disease pathophysiology are examined by Perry Molinoff and his colleagues at Bristol-Myers Squibb.

Physicians, nurses, and safety experts comprehensively review sedation and analgesia to provide a completely new reference guide to safe sedation practices consistent with existing guidelines. Starting with an integrated review of the basic physiology and neurobiology of the sedated state, the authors proceed through clinical guidelines and practices, and conclude with an examination of quality-outcome measures and processes. They also review current mandates for safe sedation practices and address the key clinical issues of pharmacology, monitoring, and recovery. Special tables and figures throughout the book summarize protocols, regulatory requirements, recommended dosages, monitoring requirements, and quality assurance tools.

In Glutamate and Addiction, world-renowned scientific experts critically review all of the evidence for the role of glutamatergic systems in opiate, stimulant, and alcohol addiction. Using a variety of pharmacological, biochemical, genetic, and brain imaging techniques, these investigators show precisely how glutamate affects such addictions and how modifying certain elements of the glutamatergic system appear to alleviate particular components of addiction. Their survey takes in both clinical approaches using medications that influence glutamate and cutting-edge preclinical approaches that manipulate specific subtypes of glutamate receptors or specific substrates of the "glutamate cascade" to determine their roles in various addictive states.

Leading investigators critically evaluate the latest information on how anesthetics work at the molecular, cellular, organ, and whole animal level. These distinguished experts review anesthetic effects on memory, consciousness, and movement and spell out in detail both the anatomic structures and physiological processes that are their likely targets, as well as the cellular and molecular mechanisms by which they operate. Comprehensive and authoritative, Neural Mechanisms of Anesthesia draws together and critically reviews all the recent research on anesthetic mechanisms, highlighting the precise routes along which these substances operate, and how this deeper understanding will lead to the design of effective drugs free ofundesirable side effects.

A clear and comprehensive account of how genetic abnormalities, neurobiology, and neuropsychology work together to manifest cognitive-behavioral dysfunction. The authors review the current status of research in autosomal disorders that produce cognitive-behavioral dysfunction and syndromal and nonsyndromal disorders that produce mental retardation. Comprehensive and up-to-date, Genetics and Genomics of Neurobehavioral Disorders integrates the molecular, genomic, neuropsychological, and neurobehavioral factors that produce learning disabilities and mental retardation into a coherent framework for the understanding and assessment of neurobehavioral disorders.

Attention deficit hyperactivity disorder (ADHD) is a common neurobehavioral disorder affecting 5–10% of children and adolescents and 3% of adults. Attention Deficit Hyperactivity Disorder: From Genes to Patients aims to provide a comp- hensive, state-of-the-art overview of the critical aspects of ADHD, and hopefully will serve as a quick and up-to-date reference source for professionals with an int- est in ADHD. The book is divided into three major areas that follow an historical survey. The first group of chapters deals with current theories on the pathophysiology of ADHD, and focuses on neurotransmitters and the contributions and validity of animal m- els. The second section emphasizes the evaluation and treatment of patients with ADHD, from the day-to-day approach by the clinical psychologist to the more sophisticated anatomical and functional imaging strategies that have emerged in the last decade. In addition, chapters dealing with specific impairments, such as those pertaining to reading, social interaction, and working memory, are also included for more detailed analysis of these important aspects and their respective contributions to global functioning. The third and final section provides an expanded review on the pharmacotherapy of ADHD and the appropriate methods for selection of specific drugs for individual patients based on drug kinetics and gene expression. David Gozal, MD Dennis L. Molfese, PhD vii CONTENTS Dedication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v Preface. . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi 1 Historical Aspects of Attention Deficit Hyperactivity Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Roscoe A. Dykman 2 Scanning the Genome for Attention Deficit Hyperactivity Disorder . . . . . . . . . . . . . . . . . . . . . . . . .

A comprehensive survey of the many recent advances in the field of G protein-coupled receptors (GPCR). The authors describe the current knowledge of GPCR receptor structure and function, the different mechanisms involved in the regulation of GPCR function, and the role of pharmacological chaperones in GPCR folding and maturation. They also present new findings about how GPCR dimerization/oligomerization modifies the properties of individual receptors and show how recent developments are leading to significant advances in drug discovery, such as the detection of ligands for orphan GPCRs. Also discussed are the most recent developments that could lead to new drug discoveries: the role of GPCRs in mediating pain, the development of receptor-type selective drugs based on the structural plasticity of receptor activation, and the identification of natural ligands of orphan GPCRs (deorphanization) as possible drug targets.

The Orexin/Hypocretin System provides an overview of all the recent exciting discoveries in the field as well as new findings such as ligand replacement and gene therapies in the animal models of narcolepsy. Several contributions cover sleep and the multiple systems involved in its regulation.

In this up-to-date survey and critical assessment of transgenic and knockout models in neuropsychiatry and behavior, a panel of leading researchers comprehensively assesses how and whether the genetic abnormalities produced from these models manifest the neuropsychiatric disorders to which they correspond. The authors focus on transgenic and knockout models of neurocognitive dysfunction and neuropsychiatric dysfunction. The discussion of neurobiological problems covers mental retardation, polyglutamate, and speech disorders, as well as disorders that involve cognitive, social, speech, and language dysfunction. The neuropsychiatric dysfunctions examined include psychosis and schizophrenia, anxiety, depression, and bipolar disorder.

Twenty-five years ago, Earl R. Stadtman, PhD discovered that specific enzymes regulating metabolism can be inactivated by oxidation [1]. He later showed that age-related oxidative modification contributes, at least in part, to age-related loss of function of the enzymes [2, 3]. Dr. Stadtman broke the ground for a new field of study to discover how oxidative stress contributes in significant ways to age-related cellular dysfunction and protein accumulation and that oxidation in the aging brain influences Alzheimer’s disease, ischemia-reperfusion injury, amyotrophic lateral sclerosis, and lifespan [4–6]. Today, his research and mentorship have positively influenced the work of hundreds of scientists in this field. We dedicate this book to Dr. Earl R. Stadtman (1912–2008), in celebration of his passion for science and his superior collaborative and mentorship skills. This book is comprised of three sections. The first describes the valuable roles reactive oxygen species (ROS) and reactive nitrogen species (RNS) play in cellular biology. The second section provides an overview of redox imbalance injury with effects on mitochondria, signaling, endoplasmic reticular function, and on aging in general. The third section takes these mechanisms to neurodegenerative disorders and provides a state-of-the-art look at the roles redox imbalances play in age-related susceptibility to disease and in the disease processes. In the first section we attempt to answer a question posed by Dr. Stadtman, ‘‘Why have cells selected reactive oxygen species to regulate cell signaling events’’ [7].