书目名称 | Neurophenotypes | 副标题 | Advancing Psychiatry | 编辑 | Vinoth Jagaroo,Susan L. Santangelo | 视频video | http://file.papertrans.cn/665/664345/664345.mp4 | 概述 | Critically appraises clinical neuroscience research at the intersection of genomics, phenomics, and other ‘omics’ disciplines..Explores neurophenotypes as operational constructs of brain-behavioral do | 丛书名称 | Innovations in Cognitive Neuroscience | 图书封面 |  | 描述 | .The interest in ‘biomarkers’ seen across a spectrum of biomedical disciplines reflects the rise of molecular biology and genetics. A host of ‘omics’ disciplines in addition to genomics, marked by multidimensional data and complex analyses, and enabled by bioinformatics, have pushed the trajectory of biomarker development even further. They have also made more tractable the complex mappings of genotypes to phenotypes – genome-to-phenome mapping – to which the concept of a biomarker is central..Genomic investigations of the brain are beginning to reveal spectacular associations between genes and neural systems. Neural and cognitive phenomics are considered a necessary complement to genomics of the brain. Other major omics developments such as connectomics, the comprehensive mapping of neurons and neural networks, are heralding brain maps of unprecedented detail. Such developments are defining a new era of brain science. And in this new research environment, neural systems and cognitive operations are pressed for new kinds of definitions – that facilitate brain-behavioral alignment in an omics operating environment. .This volume explores the topic of markers framed around the | 出版日期 | Book 2016 | 关键词 | Behavioral genetics; Behavioral phenotype; Cognition; Cognitive dysfunction; Cognitive phenotype; Conting | 版次 | 1 | doi | https://doi.org/10.1007/978-1-4614-3846-5 | isbn_softcover | 978-1-4939-7932-5 | isbn_ebook | 978-1-4614-3846-5Series ISSN 2509-730X Series E-ISSN 2509-7318 | issn_series | 2509-730X | copyright | Springer Science+Business Media LLC 2016 |
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Introduction and Structure of the Volume |
Vinoth Jagaroo,Susan L. Santangelo |
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This introductory chapter provides a summary description of key developments in the neurosciences and biomedical sciences that have compelled the topic of the volume—neural and cognitive markers. The emergence of “omics” disciplines is described—where large or complex data sets are deciphered with bioinformatics methods in a systems biology framework. The developments of phenomics in the context of genome-to-phenome mapping, connectomics in neuroscience, and Research Domain Criteria in psychiatry are then staged, as is the current research-scientific environment, characterized by data repositories and knowledge discovery systems. The central point converged upon is that the impact of systems biology necessitates that the clinical and behavioral neurosciences delineate cognitive and neural systems in a manner that can be integrated with broader scientific frameworks. This chapter also explains the volume’s adoption of the umbrella term “neurophenotype” and provides an operating definition of the term. The two-part structure of the volume is then laid out with the topic of each chapter summarized.
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Brain and Cognition in the “Omics” Era |
Susan L. Santangelo,Vinoth Jagaroo |
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The developments of phenomics, connectomics, and Research Domain Criteria (RDoC) set forth in the introductory chapter are given expanded review in this chapter. The strategy of phenomics is laid out with particular reference to the influences of genetic studies—both candidate gene and genome-wide association studies. How current developments in genomics are serving the alignment of gene networks with phenotypic elements is also described. Connectomics is laid out through its two main prongs—cellular-level or microscale connectomics carried out through automated electron microscopy, and macroscale connectomics or white matter tractography, via functional imaging. Circuit neurophenotypes, from the perspective of connectomics, are also delineated. The RDoC initiative and related developments are described in terms of their rationale and approach, and attention is given to RDoC’s emphasis on the neural circuit as the central level around which a brain-based nosology of mental disorders may be constructed. This chapter elaborates on each of these developments while also bringing forth some perspectives of neural circuitry, a topic that is the focus in the following chapters.
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Appraising Circuit-Centered Neurophenotypes |
Vinoth Jagaroo,William Bosl,Susan L. Santangelo |
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This chapter provides a critical appraisal of the concept of a circuit-centered neurophenotype that is conceptualized within a genome-to-phenome framework. Representing many of the kinds of variables that complicate this model are a few select ones that are sampled in this chapter. They include the following: (a) The problem of minimal circuit definition—the many scales of neural circuitry and the difficulty of demarcating circuits within some forms of neural architecture; (b) the modulation of neural circuits and the alterations of circuit architecture through non-gene-regulated factors such as synaptic plasticity, extra-synaptic neuromodulation, and bioelectric dynamics; and (c) technical and methodological considerations in circuit delineation—as is coming to light in the field of microscale connectomics. Adding these complex variables from neuroscience into the fray make for great attenuation of the notion of a circuit neurophenotype in the behavioral neurosciences, and this is given some depth of coverage in this chapter. However, the chapter does not dismiss the utility of the concept of circuit neurophenotypes. It concludes with a discussion of the kinds of additional inform
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Cognitive Phenotypes and Endophenotypes: Concepts and Criteria |
Carrie E. Bearden,Anderson Winkler,Katherine H. Karlsgodt,Robert Bilder |
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Despite major advances in neuroscience, existing treatments for neuropsychiatric syndromes have only limited effectiveness. Because existing diagnoses rely on heterogeneous clusters of symptoms that are not closely associated with direct drug targets, discovery of new treatments almost always occurs by chance. Conventional diagnostic phenotypes are marked by significant heterogeneity and overlap, calling into question the biological validity of these diagnostic categories. In this chapter, the authors review the value of quantitative traits for unraveling complex disease and discuss phenotypes, endophenotypes, biomarkers, and cognitive phenotypes in particular. They then explore the necessary and sufficient criteria for viable cognitive phenotypes, including reproducibility and heritability. Next, they explore the utility of endophenotypes for genetic mapping studies, before moving on to discuss the specificity of cognitive phenotypes and their association with categorical disease phenotypes, their relevance to biological mechanisms, cognitive and neuroanatomic phenotypes in population samples, successful utilization of endophenotypes in the study of non-psychiatric complex traits,
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The Strategy and Utility of the Endophenotype Approach to Neurobehavioral Function |
Ellen Quillen,David Glahn,Laura Almasy |
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Like many complex traits, the genetic architecture of mental illness is expected to be extremely complex with a number of biological pathways involved, multiple genetic variants contributing to variation in each pathway, and interaction among genes and with the environment. After defining the concept of endophenotype and introducing its potential utility in the field of psychiatry, this chapter reviews the shortcomings of other types of research methodologies that have been employed in psychiatry, due in part to their near-exclusive focus on dichotomous diagnoses, and discuss how the heterogeneity of symptomatology, subclinical symptoms in unaffected individuals, and similarities of disease domains across diagnoses have contributed to the failure to identify novel therapeutic targets. The chapter then reviews the advantages of an endophenotype-based approach in detail, positing that endophenotypes are considered more closely related to the root of the disorder, that case–control studies lack statistical power, and that quantitative traits enhance statistical power. Most psychiatric disorders appear to be continuous in nature with a liability-threshold model overlaid for the purpose
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Limitations of the EP Concept in an Idealized Gene–Phene Framework |
Amy Vashlishan-Murray |
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Flexible definitions of cognitive phenotypes (CPs) or neurophenotypes acknowledge them as being not necessarily heritable but still biologically informative (see Chaps. . and . in this volume). Until such flexible perspectives are more widely adopted, the assumptions inherent in the gene-centered endophenotype (EP) concept remain a theoretical basis for tempering the CP construct. Numerous critiques of the EP construct have been written (e.g., Flint and Munafo in Psychol Med 37(2):163–180, .; Green et al. in Nat Rev Neurosci 9:710–720, .; Kendler and Neale in Mol Psychiatry 15(8):789–797, .), but few or none have focused on a fine dissection of some of the assumptions and underpinnings of the EP concept. This chapter does not seek to render another critique of EPs. In the context of the discussion of CPs, it tackles three key issues tied to EPs: (a) heritability, (b) complexity in the association of neural systems to genes, and (c) reliability and validity of EP measurements and standards. This chapter maintains that the heritability estimates that underlie the promise of the EP concept are questionable in terms of their meaningfulness. It also argues that it may be unreasonable to
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Response Inhibition |
Kei Mochizuki,Shintaro Funahashi |
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In our everyday lives, we continuously select actions from plenty of possible options. To perform the chosen action correctly, the remaining unchosen actions must be inhibited. The importance of response inhibition is especially appreciated when one considers the outcomes when it does not work correctly. Malfunction of the inhibition process can lead to an impairment in decision-making (resulting, for example, in the inability to appropriately select steering direction when driving) or deficient motor control (resulting, for example, in an accident). Studies have proposed that the impaired ability of response inhibition may contribute to the symptoms in several psychiatric and developmental disorders, such as ADHD (Barkley in Psychol Bull 121(1):65–94 .). In this review, we first explain the experimental definition of response inhibition and how it can be assessed by cognitive tasks. Next, we briefly summarize the neural mechanism of response inhibition and our current knowledge about its relationship to psychiatric disorders. Finally, we discuss the validity of response inhibition as a behavioral phenotype, and suggest future directions for clinical and experimental studies.
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Fear Conditioning and Extinction |
Bronwyn M. Graham,Mohammed R. Milad |
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Fear conditioning is useful in modeling the symptoms of anxiety in both humans and animal models. It is also often used as a task for examining the cognitive, behavioral, and neurobiological mechanisms underlying memory formation. After providing an overview and definitions of fear conditioning and extinction, this chapter discusses the cognitive and neural mechanisms of fear conditioning and extinction, including cognitive, behavioral, and developmental theories. First, cognitive and behavioral theories of conditioning and extinction are discussed, followed by a description of neurobiological models of conditioning and extinction. This is followed by a discussion of whether and how conditioning and extinction might constitute behavioral phenotypes or endophenotypes, including how well they meet the criteria described by Gottesman and Gould (.) for defining useful endophenotypes, e.g., how well do they represent the putative genetic basis for anxiety. The evidence for reliability, heritability, and association with anxiety disorders is reviewed along with a discussion of the issues of co-segregation and state-independency.
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Neural Markers of Errors as Endophenotypes in Neuropsychiatric Disorders |
Dara S. Manoach,Yigal Agam |
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Learning from errors is fundamental to adaptive human behavior. It requires detecting errors, evaluating what went wrong, and adjusting behavior accordingly. These dynamic adjustments are at the heart of behavioral flexibility and accumulating evidence suggests that deficient error processing contributes to maladaptively rigid and repetitive behavior in a range of neuropsychiatric disorders. Neuroimaging and electrophysiological studies reveal highly reliable neural markers of error processing. In this review, we evaluate the evidence that abnormalities in these neural markers can serve as sensitive endophenotypes of neuropsychiatric disorders. We describe the behavioral and neural hallmarks of error processing, their mediation by common genetic polymorphisms, and impairments in schizophrenia, obsessive–compulsive disorder, and autism spectrum disorders. We conclude that neural markers of errors meet several important criteria as endophenotypes including heritability, established neuroanatomical and neurochemical substrates, association with neuropsychiatric disorders, presence in syndromally unaffected family members, and evidence of genetic mediation. Understanding the mechanisms
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Reward Dependence and Reward Deficiency |
Marlene Oscar-Berman,Kenneth Blum |
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. are biologically predisposed to drink, eat, reproduce, and desire pleasurable experiences. Underlying the reward value and affective properties of these behaviors and the stimuli that elicit them is an extended cortical–subcortical network in which dopamine (DA) acts as the major neurotransmitter for reward and reinforcement. Genes that control dopamine-related synthesis, vesicular storage, metabolism, receptor formation, and catabolism have variations that can lead to an impairment of the neurochemical events involved in the neuronal release of DA.
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Face Perception |
Jennifer Richler,Isabel Gauthier |
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Face perception is a critical and complex cognitive operation, and it poses unique the cognitive demands. This chapter addresses the question of whether face perception can be viewed as a cognitive phenotype. Evidence from neurophysiological and neuropsychological studies are summarized that reflect specialization of parts of the visual system for face processing, for example, face-tuned neurons in the superior temporal sulcus of non-human primates, and cortical regions associated with prosopagnosia in humans. Data from cognitive neuroscience (especially functional imaging studies) are presented, illustrating that many distinct brain regions show that activity in response to faces though the lateral fusiform gyrus or “fusiform face area” (FFA) shows a particularly robust response. Current interpretations of FFA activity and how it may be functionally parsed out from the activity of the occipital fusiform area and anterior temporal lobe are then laid out, and this raises the tricky question of what differs between the perception faces and non-face objects as may be expressed along these neural centers. Our discussion on face perception as a potential cognitive phenotype suggests tha
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Language Phenotypes |
Mabel Rice,Helen Tager-Flusberg |
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This chapter introduces language as a complex, uniquely human capacity. From birth, infants are prepared to acquire language, which then develops over time with most of the essential elements in place by the time a child enters school. The rapid acquisition of this hierarchically organized communication system is an excellent example of a biologically based cognitive system that develops over the course of time as the child interacts with rich social and nonsocial environments. But for a minority of children, despite the available and appropriate environmental contexts, speech and language development do not proceed as expected, especially in the early years. This chapter provides an overview of language phenotyping for genetics inquiry and notes that even for specific language impairment (SLI), autism spectrum disorder (ASD), and speech sound disorder (SSD), which are all highly heritable, relatively few of the estimated thousand or more risk genes have been identified. Finding the genes requires the use of valid phenotypes, which leads to a description of the PhenX project. This chapter focuses on language phenotypes that have shown significant promise in current research on deve
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Phenotypic Markers in Event-Related Potentials |
Mei Hua-Hall |
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Event-related brain potentials (ERPs) are a noninvasive method of measuring brain activity during cognitive processing. ERPs provide an insight into very early stages of information processing. Because of their high temporal resolution, noninvasiveness, relatively low cost, and ability to provide a continuous measure of the brain’s information processing, ERPs have been widely adopted by scientists to study normal cognitive processing and functions at different developmental stages, as well as to illuminate how and why these cognitive processes are altered in neurological and psychiatric disorders. A number of ERPs have been identified as intermediate markers or endophenotypes for psychiatric illnesses. This chapter selectively describes six ERP measures that are commonly studied in neuropsychiatric disorders. Each measure may be useful in diagnosis prediction, identifying genetic susceptibility, understanding cognitive behavior and brain function, and as biomarkers for drug discovery.
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EEG-Derived Neurophenotypes |
William Bosl |
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In this chapter, scalp electrophysiological measurements using electroencephalographs or EEGs are examined in light of new developments in complex systems theory. At the most fundamental level, brain function is electrical. The neural network that comprises the brain and peripheral nervous system, along with all the specialized cellular structures for propagating electrical impulses, is designed to support exquisitely fine control over the electrical patterns that determine all thought and behavior. It is not an exaggeration to say that the most fundamental medium of the mind is an electric field. Measurements of brain electrical activity may thus in principle contain information about cognitive phenotypes, if recurring patterns can be found that reliably correlate with them. The brain meets the mathematical definition of a complex dynamical system and EEG measurements are time series or signals produced by local clusters of neurons in this system. This chapter presents a methodology for discovering patterns in the complex systems parameters that can be derived from EEG measurements that is based on machine learning or pattern recognition algorithms. Without attempting to describe
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Conclusion: Implications for Psychiatry and Neuropsychology |
Susan L. Santangelo,Vinoth Jagaroo |
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The theme of this volume that psychiatry and neuropsychology be systematically aligned with the neurophenotype approach in order to facilitate a systems-level understanding of brain–behavior relationships is reiterated across chapters. This chapter outlines a few conceptual and programmatic adjustments that these disciplines must undertake in order to promote that goal. Firstly, this chapter argues that the historically influential endophenotype concept must be constrained that it has been applied by default to cognitive and neural markers without adequate consideration of the host of variables that modulate neural systems tied to cognition. In this regard, it is also argued that the broader neurophenotype concept has greater utility. Secondly, the need for refinement of cognitive and behavioral constructs is stressed; how ontologies for cognitive and neural processes serve this end is discussed. Thirdly, the imperative that psychiatry and neuropsychology adopt data formats that facilitate data integration in genome–phenome mapping systems is emphasized. And to illustrate the point, a few pioneering examples of knowledge discovery and neuroinformatics platforms that relate to these
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,Erratum to: Neurophenotypes, |
Vinoth Jagaroo,Susan L. Santangelo |
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