Neural and Genetic Basis of Negative Valance Traits

负价特征的神经和遗传基础

• 批准号: 8573627
• 负责人: RANDY L BUCKNER
• 金额: $ 69.14万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-16 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8573627
• 关键词: Address; Amygdaloid structure; Anatomy; Anxiety; Architecture; Base of the Brain; Behavioral; Behavioral Genetics; Biological; Brain; Categories; Classification; Classification Scheme; Clinical; Clinical assessments; Cognition; Collection; Consensus; DNA; Data; Diagnosis; Diagnostic and Statistical Manual; Diffusion; Dimensions; Disease; Dissection; Emotions; Etiology; Functional Magnetic Resonance Imaging; Functional disorder; Future; Genetic; Genome; Genomics; Goals; Heritability; Image; Imaging Techniques; Imaging technology; Impairment; Individual; Individual Differences; Language; Limbic System; Link; Magnetic Resonance Imaging; Major Depressive Disorder; Measures; Medial; Mediating; Mental disorders; Methods; National Institute of Mental Health; Neurobiology; Neurosciences; Pathogenesis; Pathway Analysis; Pathway interactions; Patient Self-Report; Personality; Phenotype; Population; Prefrontal Cortex; Principal Investigator; Procedures; Psychopathology; Recruitment Activity; Research; Resources; Risk; Sampling; Severities; Signs and Symptoms; Social Functioning; Staging; Symptoms; Syndrome; United States National Institutes of Health; Variant; Work; base; behavior measurement; behavioral genomics; clinically relevant; clinically significant; data acquisition; disease classification; exome; functional disability; genome-wide; insight; neurobehavioral; neuroimaging; novel; programs; psychologic; public health relevance; relating to nervous system; research and development; response; trait; white matter

DESCRIPTION (provided by applicant): The current classification of psychiatric disorders is based on categorical clustering of signs and symptoms, without regard to underlying neurobiologic mechanisms. The reification of these categories has constrained efforts to develop an understanding of the fundamental behavioral, neural and genetic mechanisms that give rise to various forms of psychopathology. To address this disconnect between mechanism and nosology, the NIMH recently launched the RDoC project to facilitate a more "bottom up" approach to psychopathology. Our proposal focuses on the "negative valence" domain of the RDoC matrix and aims to characterize and validate a neural phenotype of the "Anxiety" construct ("response to potential threat"). In a uniquely large neuroimaging resource (the MGH Genomic Superstruct Project, GSP) we have recently identified a neural measure of limbic system integrity (amygdala enlargement and medial prefrontal cortical [mPFC] thinning) that is robustly associated with dimensional measures of trait anxiety. Consistent with the goals of the RDoC framework, we now propose to validate key biological and clinical features of this anxiety dimension in three stages: 1) Clinical Characterization: we will demonstrate the relevance of this neural phenotype to clinical populations presenting with significant anxiety symptoms and its association with symptom severity, chronicity and functional impairment; 2) Neural Dissection: we will use advanced Connectome imaging technology to examine the relationship between the anxiety neural phenotype and white matter connectivity between the mPFC and specific amygdala subnuclei; and 3) Genetic Dissection: using common and rare (exome array) genomewide data (N = 2078), we will conduct single variant, genome partitioning, and biological pathway analyses to identify allelic contributions to the anxiety neural phenotype and characterize the aggregate heritability and biological significance of contributing loci. Successfu completion of these aims will yield novel insights into the neural, behavioral, and genetic basis of the RDoC anxiety dimension and provide a crucial step towards the RDoC's goal of a new framework for psychiatric classification grounded in etiology and pathogenesis.

描述（由申请人提供）：目前精神疾病的分类是基于体征和症状的分类聚类，而没有考虑潜在的神经生物学机制。这些类别的具体化限制了努力发展对产生各种形式精神病理学的基本行为、神经和遗传机制的理解。为了解决机制和分类学之间的这种脱节，NIMH最近启动了RDoC项目，以促进一种更“自下而上”的精神病理学方法。我们的建议侧重于RDoC矩阵的“负价”域，旨在表征和验证“焦虑”结构（“对潜在威胁的反应”）的神经表型。在一个独特的大型神经成像资源（MGH基因组超结构项目，GSP）中，我们最近确定了边缘系统完整性的神经测量（杏仁核增大和内侧前额叶皮层[mPFC]变薄），这与特质焦虑的维度测量密切相关。与RDoC框架的目标一致，我们现在建议分三个阶段验证这种焦虑维度的关键生物学和临床特征：1)临床特征：我们将证明这种神经表型与临床表现出显著焦虑症状的人群的相关性，以及它与症状严重程度、慢性和功能障碍的关联；2)神经解剖：我们将使用先进的连接组成像技术来研究焦虑神经表型与mPFC与特定杏仁核亚核之间白质连接的关系；3)遗传解剖：利用常见和罕见（外显子组阵列）全基因组数据（N = 2078），我们将进行单变异、基因组划分和生物学途径分析，以确定对焦虑神经表型有贡献的等位基因，并表征贡献位点的总遗传力和生物学意义。这些目标的成功完成将对RDoC焦虑维度的神经、行为和遗传基础产生新的见解，并为RDoC建立基于病因和发病机制的精神病学分类新框架的目标迈出关键一步。