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: 8918233
• 负责人: Benjamin B Lahey
• 金额: $ 3.43万
• 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/8918233
• 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，绝对性精神障碍与神经回路功能的变化不是一对一的。相反，神经回路与较窄的神经行为结构相一致，这些结构本身以横切的方式与精神病理学相关：每个结构中的功能障碍与多种形式的精神病理学有关，而大多数形式的精神病理与多个结构中的功能障碍有关。未能重新聚焦于这一思想的研究将继续模糊精神病理学的神经生物学。我们支持这些假设，并建议对它们进行检验。我们的第一个目标是测试关于RDoC正负配价和认知系统领域中特定神经回路与五个神经行为结构之间的关联的假设。使用功能磁共振成像，我们将分析参与接近动机和奖励获得(愉悦)的中皮质纹状体系统的功能，参与对厌恶威胁刺激的预期和反应的边缘/边缘旁系统，以及参与努力反应抑制的控制系统的功能。这解决了RDoC倡议的第一个目标，即将结构映射到大脑回路。RDoC的第二个目标是将结构与精神病理学联系起来，以实现由神经生物学提供信息的精神病理学的新分类。为了推进这一目标，我们的第二个目标是以一种复杂但容易处理的横切方式测试RDoC结构与精神病理学相关的假设。我们将基于强有力的证据将RDoC结构映射到精神病理学的经验性定义的维度概念，该证据表明，普遍存在的精神障碍是通过它们与痛苦、恐惧和外化的相关性(共病)来组织的 尺寸。使用结构方程模型，我们将检验所选的五个RDoC结构与精神病理学的这三个维度之间存在交叉关系的假设。这反映了我们的假设，即加载在每个广泛维度上的精神障碍聚集在一起，正是因为它们共享这些神经生物学结构和病因影响的相同变异模式。我们还将测试RDoC结构表达的相对差异是否可能在精神病理学的三个维度内产生症状表达的异质性。我们的第三个目标是检验这一关键假设，即神经回路功能的变化以相同的交叉方式与精神病理学相关，并且它们与精神病理学的关联是由RDoC结构介导的。我们提出的研究是基于从一个具有代表性的大队列中战略性地选择了400对年轻的成年双胞胎的高度信息量的样本。在青春期表现出精神病理学的参与者将被大幅过度抽样，以极大地丰富精神病理学的样本。重要的是，这对双胞胎将允许我们确定精神病理学的神经回路、结构和维度在多大程度上共享遗传影响。