RDoC Constructs: Neural Substrates, Heritability, and Relation to Psychopathology

RDoC 结构：神经基质、遗传性以及与精神病理学的关系

• 批准号: 8664935
• 负责人: Benjamin B Lahey
• 金额: $ 115.29万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-12 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8664935
• 关键词: Address; Adolescence; Biological Assay; Brain; Classification; Comorbidity; Complex; Conceptions; Cues; DNA; Data Set; Diagnosis; Diagnostic; Dimensions; Disease; Distress; Economic Burden; Environment; Environmental Risk Factor; Equation; Etiology; Exhibits; Failure; Fright; Functional Magnetic Resonance Imaging; Functional disorder; Future; Genes; Genetic; Goals; Heritability; Heterogeneity; Individual Differences; Interview; Learning; Link; Maps; Mediating; Mental Health; Mental disorders; Mind; Modeling; Molecular Genetics; Motivation; National Institute of Mental Health; Nature; Neurobiology; Neurosciences; Nomenclature; Participant; Pathology; Pattern; Prevention; Psyche structure; Psychopathology; Qualifying; Research; Research Domain Criteria; Resources; Rewards; Sampling; Stimulus; Substance abuse problem; Symptoms; System; Testing; Twin Multiple Birth; Variant; base; cognitive system; cohort; disability; genetic variant; improved; motivational processes; neural circuit; neurobehavioral; pleasure; relating to nervous system; response; young adult

DESCRIPTION (provided by applicant): The central hypothesis of the Research Domain Criteria (RDoC) project is that categorical mental disorders do not "line up" one-to-one with variations in the functioning of neural circuits. Rather, neural circuits align with narrower neurobehavioral constructs that are themselves related to psychopathology in cross-cutting fashion: Dysfunction in each construct is related to multiple forms of psychopathology and most forms of psycho- pathology are related to dysfunction in more than one construct. Failure to refocus research with this is mind will continue to obscure the neurobiology of psychopathology. We endorse these hypotheses, and propose to test them. Our first aim is to test hypotheses regarding the association between specific neural circuits and five neurobehavioral constructs in the RDoC positive and negative valence and cognitive systems domains. Using fMRI, we will assay the functioning of a mesocorticostriatal system involved in approach motivation and reward attainment (pleasure), a limbic/paralimbic system involved in anticipation and response to aversive-threatening stimuli, and control systems involved in effortful response inhibition. Thi addresses the first goal of the RDoC initiative of mapping constructs to brain circuits. RDoC's second goal is to relate constructs to psychopathology to enable a new classification of psychopathology informed by neurobiology. To advance this goal, our second aim is to test the hypothesis that RDoC constructs are associated with psychopathology in a complex but tractable cross-cutting manner. We will map RDoC constructs to empirically-defined dimensional conceptions of psychopathology based on strong evidence that prevalent mental disorders are organized by their correlations (comorbidity) into distress, fears, and externalizing dimensions. Using structural equation modeling, we will test the hypothesis that the five selected RDoC constructs are related in cross-cutting fashion to these three dimensions of psychopathology. This reflects our hypothesis that the mental disorders that load on each broad dimension cluster together precisely because they share the same pattern of variations of these neurobiological constructs and etiologic influences. We will also test the possibility that relativ differences in the expression of RDoC constructs produces heterogeneity in the expression of symptoms within the three dimensions of psychopathology. Our third aim is to test the crucial hypothesis that variations in functioning of the neural circuits are associated with psychopathology in the same cross-cutting manner and their associations with psychopathology are mediated by the RDoC constructs. Our proposed study is based on a highly informative sample of 400 young adult twins strategically selected from a large representative cohort. Participants who exhibited psychopathology in adolescence will be steeply oversampled to greatly enrich the sample on psychopathology. Critically, the twins will allow us to determine the extent to which genetic influences are shared in common by the neural circuits, constructs, and dimensions of psychopathology.

描述（由申请人提供）：研究领域标准（RDOC）项目的中心假设是，分类精神障碍并不是“对”一对一，而神经回路功能的变化。相反，神经回路与较狭窄的神经行为结构保持一致，这些结构本身与精神病理学有关：每种结构中的功能障碍与多种形式的心理病理学有关，并且大多数形式的心理病理学与功能障碍有关，而不是一种构造中的功能障碍。未能将其重新研究的心态将继续掩盖心理病理学的神经生物学。我们认可这些假设，并建议对其进行测试。我们的第一个目的是检验有关RDOC正值和负面价和认知系统域中特定神经回路与五个神经行为构建体之间关联的假设。使用fMRI，我们将测定参与进能动机和奖励成就（愉悦）涉及的中皮质纹状体系统的功能，这是一种涉及预期和对厌恶威胁性威胁性刺激的响应的边缘/旁白系统，以及涉及努力抑制的控制系统。这是针对RDOC计划将构造构造为脑电路的第一个目标。 RDOC的第二个目标是将构造与心理病理学联系起来，以使神经生物学告知的新精神病理学分类。为了促进这一目标，我们的第二个目标是检验以复杂但可拖延的跨切割方式与心理病理学相关的假设。我们将基于有力的证据表明，通过其相关性（合并症）组织的苦难，恐惧和外在化，我们将RDOC构造将精神病理学的维度概念映射到经验定义的维度概念。 方面。使用结构方程建模，我们将检验以下假设：五个选定的RDOC构建体以交叉切割方式与精神病理学的这三个维度有关。这反映了我们的假设，即在每个广泛维度聚类上负载的精神障碍恰恰是因为它们具有这些神经生物学结构和病因学影响的相同变化模式。我们还将测试RDOC构建体表达的相对差异在心理病理学三个维度内的症状表达中产生异质性的可能性。我们的第三个目的是检验至关重要的假设，即神经回路功能的变化以相同的跨切割方式与心理病理学相关，并且它们与精神病理学的关联是由RDOC构建体介导的。我们提出的研究是基于从策略性地从大型代表队列中选出的400个年轻成人双胞胎的信息丰富的样本。在青春期表现出心理病理学的参与者将被大量地采样，以极大地丰富心理病理学的样本。至关重要的是，双胞胎将使我们能够确定由神经回路，构造和精神病理学的遗传影响共享的遗传影响的程度。