Building a multi-factor etiological model of the emergence of general psychopathology (the "P factor") in adolescence with multi-modal neuroimaging in ABCD

摘要 有大量证据表明，精神病理学是有层级结构的。除了两个主要具体内容 因素，内化和外化，有一个压倒一切的一般因素，“P因素”，它解释了 在精神症状上有相当大的差异。P因子模型代表了最近在 我们对精神病理学体系结构的理解。然而，我们目前存在着一个严重的差距 知识：我们对导致P的神经发育病因知之甚少 年轻时的因素。 我们有一个理想的机会来解决这个与青少年大脑认知发展(ABCD)的差距 纵向研究(n=11,875；在这项五年赠款过程中进行了4次两年一次的数据波动)。我们有 建立了双重不成熟模型，在该模型中，P因子产生于 两个系统中的青春期：执行控制系统(导致全球更高阶认知的减少和 抑制控制)和脉冲产生系统(导致全局提升的脉冲产生)。我们有 还对ABCD的精神病理学数据进行了全面的分析，以得出和验证 上位的一般精神病理因素(“P因素”)。我们在这个项目中的首要目标是在 这些结果并结合知识描述了ABCD中青年P因子的多因素病因 跨越社会环境、心理、神经和基因层面的分析。 更具体地说，我们寻求实现四个目标。目标1使用潜在增长建模方法来量化联合 发展心理变量(包括执行功能、负面情绪和攻击性 冲动)与青春期P因素的出现有关。在目标2中，我们使用先进的方法 分割的大脑成像映射成一小部分凝聚的成分。然后，我们使用潜在增长 建模以确定与P因子共同发育的大脑成分。对于目标3，我们描述了基因 影响P因子的因素。为此，我们确定了调节这种关系的大脑组件 P因子的多基因风险与青春期晚期P因子的出现之间的关系。对于目的4， 我们将前面的因素(心理、神经和遗传)与额外的社会环境相结合 变量为P因子的出现建立了一个整体的法理网络，我们区分了这一点 网络从类比网络中出现内化和外化的具体因素。 通过将开创性的ABCD数据集和先进的多变量多模式神经成像方法结合在一起， 该项目将给我们提供重要的新的机制洞察多因素神经发育病因学。 P因子。这一知识是下游研究项目的关键输入，例如寻求 确定高危青年或制定干预措施，以减轻或阻止精神病的出现。

Abstract There is substantial evidence that psychopathology is structured hierarchically. In addition to two major specific factors, internalizing and externalizing, there is a single overarching general factor, the “P factor”, that explains a sizable share of variance in psychiatric symptoms. The P factor model represents a major recent advance in our understanding of the architecture of psychopathology. However, there is a critical gap in our current knowledge: We have little understanding of the neurodevelopmental etiological factors that produce the P factor during youth. We have an ideal opportunity to address this gap with the Adolescent Brain Cognitive Development (ABCD) longitudinal study (n=11,875; 4 biennial waves of data over the course of this five-year grant). We have formulated a Dual Dysmaturation Model in which the P factor arises from altered maturation during adolescence in two systems: executive control systems (leading to globally reduced higher-order cognition and inhibitory control) and impulse generation systems (leading to globally elevated impulse generation). We have also undertaken a comprehensive analysis of psychopathology data in ABCD to derive and validate a superordinate general psychopathology factor (“P factor”). Our overarching aim in this project is to build on these results and delineate the multi-factor etiology of the P factor in youth in ABCD, integrating knowledge across socio-environmental, psychological, neural, and genetic levels of analysis. More specifically we seek to achieve four aims. Aim 1 uses a latent growth modeling approach to quantify co- development of psychological variables (including executive functions, negative emotions, and aggressive impulses) with the emergence of the P factor over adolescence. In Aim 2, we use advanced methods to fractionate brain imaging maps into a small number of cohesive components. We then use latent growth modeling to identify brain components that co-develop with the P factor. For Aim 3, we delineate genetic factors that contribute to the P factor. For this aim, we identify brain components that mediate the relationship between polygenic risk for the P factor and the emergence of the P factor in late adolescence. For the Aim 4, we integrate the preceding factors (psychological, neural, and genetic) with additional socio-environmental variables to build an overall nomological network for the emergence of the P factor, and we distinguish this network from analogous networks for the emergence of internalizing and externalizing specific factors. By bringing together the seminal ABCD dataset and advanced multivariate multi-modal neuroimaging methods, this project will give us important new mechanistic insights into the multi-factor neurodevelopmental etiology of the P factor. This knowledge is a key input to downstream research programs, such as programs that seek to identify high-risk youth or to develop interventions that mitigate or block the emergence of psychopathology.