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，分类精神障碍不会与神经回路功能的变化一对一地“排队”。相反，神经回路与本身以横切方式与精神病理学相关的较窄的神经行为结构对齐：每个结构中的功能障碍与多种形式的精神病理学相关，并且大多数形式的精神病理学与不止一种结构中的功能障碍相关。如果不能以这种心态重新关注研究，将继续模糊精神病理学的神经生物学。我们赞同这些假设，并建议测试它们。我们的第一个目标是测试的假设之间的关联特定的神经回路和五个神经行为结构的RDoC积极和消极的效价和认知系统域。使用功能性磁共振成像，我们将分析的功能的mesocorticostriatal系统参与的方法的动机和奖励的实现（快乐），边缘系统/边缘系统参与的预期和反应，厌恶的威胁性刺激，和控制系统参与努力的反应抑制。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告知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测试的假设，RDoC结构与精神病理学在一个复杂的，但易于处理的横切方式。我们将映射RDoC结构到精神病理学的维度概念，其基础是强有力的证据，即普遍的精神障碍是由它们的相关性（共病性）组织成痛苦、恐惧和外化的 尺寸.使用结构方程模型，我们将测试的假设，即五个选定的RDoC结构相关的横切方式，这三个方面的精神病理学。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学影响的相同变化模式。我们还将测试RDoC结构表达的相对差异在精神病理学的三个维度内产生症状表达异质性的可能性。我们的第三个目的是测试的关键假设，即神经回路的功能变化与精神病理学在相同的横切方式和他们的协会与精神病理学介导的RDoC结构。我们提出的研究是基于一个高度信息化的样本400年轻的成年双胞胎战略选择从一个大的代表性队列。在青春期表现出精神病理学的参与者将被急剧过采样，以极大地丰富精神病理学的样本。至关重要的是，这对双胞胎将使我们能够确定遗传影响在多大程度上被精神病理学的神经回路、结构和维度所共有。

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.