Genetic, Imaging, and Cognition study of Positive Valence Systems in Psychotic Syndromes

项目摘要 研究领域标准(RDoC)倡议是由NIMH制定的，以解决日益增长的担忧 关于《精神障碍诊断和统计手册》(DSM)的有效性及其限制潜力 关于精神疾病的研究。RDoC的首要目标是确定大脑结构和功能的维度 这将具有更大的生物学有效性，而不是我们目前的分类学为理性诊断带来的巨大希望 以及精神疾病的治疗。这项拟议的研究旨在研究RDoC的核心组成部分之一 这是集中在奖励电路和行为，即正价系统域(PVS)。这个 PVS与多种精神疾病有关，包括精神分裂症、双相情感障碍和严重的 抑郁障碍。人们一致认为精神分裂症和双相情感障碍具有相同的基因 皮质纹状体脑回路、认知水平的风险和多个重叠表型变异 功能和行为。然而，确切地说，哪些维度是共享的，哪些维度可能会出现分歧，目前还不清楚 症状之间的关系，以及相关的表型如何与共同和非共同的遗传风险相关。这个 拟议的研究将在两个具有遗传信息的大型队列中检查RDoC PVS结构域 由荷兰已经确认的5000多人组成。参与者包括1,000人 精神分裂症患者，1750名双相情感障碍患者，1000多名一级亲属和几乎 1500名健康对照受试者。大量的临床和神经认知数据已经可用，这将 对我们理解控制健康和疾病行为的基本大脑回路有很大帮助。 可用的全基因组基因型和全基因组测序数据提供了一个独特的机会 检查PVS测量的遗传度及其与精神障碍病因学的关系。 我们将收集与确定的四个主要PVS组件进程相关的多层次数据 RDoC研讨会的重点是通过以下方式寻求奖励和消费行为(接近动机) 对这些认知结构的在线评估。这些将通过实验室内的测量得到进一步验证 在一组参与者(n=500)中使用功能磁共振成像。分析将集中在腹侧纹状体(VS)和 腹内侧前额叶皮质(VmPFC)对预期和接受奖励的反应。我们将派生出 来自四个PVS认知测试的反应简档，这些测试相对于以下方面具有最大的同时有效性 神经回路功能的个体差异。 这项研究的结果将为PVS组分过程之间的关系提供重要的新数据 在RDoC中提出的对初级神经回路的研究，并在我们的遗传信息样本中实现结果 将在对广泛的精神障碍和健康个人进行研究的背景下进行评估。

Project Summary The Research Domains Criteria (RDoC) initiative was developed by the NIMH to address growing concern about the validity of the Diagnostic and Statistical Manual of Mental Disorders (DSM) and its potential to limit research on mental illness. The overarching aim of RDoC to identify dimensions of brain structure and function that will possess greater biological validity than our current taxonomy holds great promise for rational diagnosis and treatment of mental illness. The proposed study aims to examine one of the core components of RDoC that is focused on reward circuits and behavior, namely the Positive Valence Systems domain (PVS). The PVS has been linked to diverse psychiatric disorders including schizophrenia, bipolar disorder and major depressive disorder. There is consensus that schizophrenia and bipolar disorder share substantial genetic risk and multiple overlapping phenotypic variations at the levels of corticostriatal brain circuits, cognitive functions, and behavior. Yet it remains unknown precisely which dimensions are shared, which may diverge between syndromes, and how the associated phenotypes relate to shared and non-shared genetic risk. The proposed research will examine the RDoC PVS domains in two large genetically informative cohorts comprising more than 5,000 individuals already ascertained in the Netherlands. Participants include 1,000 schizophrenia patients, 1,750 subjects with bipolar disorder, more than 1,000 first-degree relatives and almost 1,500 healthy comparison subjects. Extensive clinical and neurocognitive data is already available, which will contribute significantly to our understanding of basic brain circuitry that controls behavior in health and disease. Available genome-wide genotype and whole genome sequencing data provide a unique opportunity to examine the heritability of the PVS measures and its relationship with the etiology of psychiatric disorder. We will collect multi-level data pertaining to each of the four primary PVS component processes identified by the RDoC Workshop focused on Reward Seeking and Consummatory Behavior (Approach Motivation) through online assessments of these cognitive constructs. These will be further validated by in-laboratory measures using functional MRI in a subset of participants (n=500). Analyses will focus on the ventral striatal (VS) and ventromedial prefrontal cortex (vmPFC) responses to anticipation and receipt of reward. We will derive response profiles from the four PVS cognitive tests that possess greatest concurrent validity with respect to individual differences in neural circuit function. Results of this study will provide important new data about the relations of the PVS component processes proposed in RDoC to the primary neural circuits, and enable the results in our genetically informative samples to be evaluated in the context of research on a broad range of mental disorders and healthy individuals.