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: 8366546
• 负责人: Benjamin B Lahey
• 金额: $ 125.31万
• 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/8366546
• 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; Genetic Variation; 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; Resources; Rewards; Sampling; Stimulus; Substance abuse problem; Symptoms; System; Testing; Twin Multiple Birth; Variant; base; cognitive system; cohort; disability; fundamental research; 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. PUBLIC HEALTH RELEVANCE: Because mental disorders and substance abuse create enormous personal distress, disability, and economic burden, there is an urgent need to understand the nature of these disorders to improve prevention and treatment. The present study, proposes to test key hypotheses of the Research Domains Criteria (RDoC) initiative, which posits that research on the neurobiological bases of psychopathology has been misled because dysfunctional brain circuits do not align one-to-one with disorders, but align with a number of functional constructs that should be the focus of study. We propose to use a subsample from a large and representative cohort oversampled on psychopathology to elucidate neural circuits associated with five key RDoC constructs, and to test the central RDoC hypothesis that these constructs are associated with psychopathology in a complex but predictable cross-cutting fashion.

描述（由申请人提供）：研究领域标准 (RDoC) 项目的中心假设是，分类精神障碍并不与神经回路功能的变化一对一地“排列”。相反，神经回路与更狭窄的神经行为结构相一致，这些神经行为结构本身以横切的方式与精神病理学相关：每种结构的功能障碍都与多种形式的精神病理学有关，而大多数形式的精神病理学与不止一种结构的功能障碍有关。如果不能重新聚焦这种精神研究，将继续模糊精神病理学的神经生物学。我们认可这些假设，并建议对其进行检验。我们的首要目标是测试有关 RDoC 正价、负价和认知系统领域中特定神经回路与五种神经行为结构之间关联的假设。使用功能磁共振成像，我们将分析涉及接近动机和奖励获得（愉悦）的中皮质纹状体系统、涉及对厌恶威胁刺激的预期和反应的边缘/旁边缘系统以及涉及努力反应抑制的控制系统的功能。这解决了 RDoC 计划的第一个目标，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，以实现基于神经生物学的精神病理学新分类。为了推进这一目标，我们的第二个目标是检验 RDoC 结构以复杂但易于处理的交叉方式与精神病理学相关的假设。我们将根据强有力的证据，将 RDoC 构造映射到经验定义的精神病理学维度概念，即流行的精神障碍按其相关性（共病）组织为痛苦、恐惧和外化 方面。使用结构方程模型，我们将检验以下假设：选定的五个 RDoC 结构与精神病理学的这三个维度以横切方式相关。这反映了我们的假设，即每个广泛维度上的精神障碍都聚集在一起，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化模式。我们还将测试 RDoC 构建体表达的相对差异是否会导致精神病理学三个维度内症状表达的异质性。我们的第三个目标是检验一个重要的假设，即神经回路功能的变化以相同的横切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。我们提出的研究基于从大型代表性队列中战略性挑选的 400 名年轻成年双胞胎的信息丰富的样本。在青春期表现出精神病理学的参与者将被大幅过度采样，以极大地丰富精神病理学样本。至关重要的是，这对双胞胎将使我们能够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。 公共卫生相关性：由于精神障碍和药物滥用会造成巨大的个人痛苦、残疾和经济负担，因此迫切需要了解这些疾病的性质，以改善预防和治疗。本研究提议测试研究领域标准（RDoC）计划的关键假设，该假设假设对精神病理学的神经生物学基础的研究被误导了，因为功能失调的大脑回路并不与疾病一对一地对齐，而是与疾病对齐。许多功能结构应该成为研究的重点。我们建议使用来自对精神病理学进行过采样的大型代表性队列的子样本来阐明与五个关键 RDoC 结构相关的神经回路，并测试 RDoC 的中心假设，即这些结构以复杂但可预测的横切方式与精神病理学相关。