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

描述（由申请人提供）：研究领域标准（RDoC）项目的中心假设是，分类精神障碍与神经回路功能的变化并不“一一对应”。相反，神经回路与更窄的神经行为构念一致，这些构念本身与精神病理学交叉相关：每个构念中的功能障碍与多种形式的精神病理学相关，而大多数形式的精神病理学与不止一种构念中的功能障碍相关。如果不能重新调整研究的焦点，精神病理学的神经生物学将继续变得模糊。我们赞同这些假设，并建议对它们进行检验。我们的第一个目的是测试关于特定神经回路与RDoC正负价和认知系统域的五种神经行为结构之间关联的假设。使用fMRI，我们将分析涉及接近动机和获得奖励（愉悦）的中皮质纹状体系统的功能，涉及对厌恶威胁刺激的预期和反应的边缘/副边缘系统，以及涉及努力反应抑制的控制系统。这解决了RDoC倡议的第一个目标，即将构造映射到大脑回路。RDoC的第二个目标是将构念与精神病理学联系起来，以实现神经生物学对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检验RDoC结构以复杂但可处理的交叉方式与精神病理学相关的假设。我们将基于强有力的证据，将RDoC结构映射到经验定义的精神病理学维度概念，这些证据表明，流行的精神障碍是根据它们的相关性（共病）组织成痛苦、恐惧和外化的

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.