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 有大量的证据表明，精神病理学是分层结构的。除了两个具体的 因素，内化和外化，有一个单一的总体因素，“P因素”，解释了 在精神症状上有很大的差异P因子模型代表了最近的一个重大进展， 我们对精神病理学架构的理解然而，我们目前的工作中存在着一个关键的差距， 知识：我们对产生P的神经发育病因学因素知之甚少 青年时期的因素。 我们有一个理想的机会来解决这个差距与青少年大脑认知发展（ABCD） 纵向研究（n= 11，875;在五年赠款期间，每两年进行一次数据收集）。我们有 制定了一个双重不成熟模型，其中P因子来自于成熟过程中的改变。 青少年在两个系统：执行控制系统（导致全球减少高阶认知， 抑制控制）和脉冲生成系统（导致全局提升的脉冲生成）。我们有 还对ABCD中的精神病理学数据进行了全面分析，以得出并验证 高级一般精神病理学因素（“P因素”）。我们在这个项目中的首要目标是建立在 这些结果和描绘的多因素病因的P因子在青年ABCD，整合知识 在社会环境、心理、神经和遗传层面的分析。 具体而言，我们力求实现四个目标。目标1使用潜在增长模型方法来量化共同增长， 心理变量的发展（包括执行功能，负面情绪和攻击性） 冲动）随着青春期P因素的出现。在目标2中，我们使用先进的方法， 碎脑成像映射成少量的内聚成分。然后我们利用潜在增长 建模以识别与P因子共同发展的大脑成分。对于目标3，我们描述了遗传学 影响P因子的因素。为此，我们确定了调节这种关系的大脑成分， P因子的多基因风险与青春期后期P因子的出现之间的关系。对于Aim 4， 我们将上述因素（心理、神经和遗传）与其他社会环境因素相结合， 变量来建立一个P因素出现的整体法则网络，我们区分这一点， 网络从类似的网络出现的内部化和外部化的具体因素。 通过将开创性的ABCD数据集和先进的多变量多模态神经成像方法结合在一起， 该项目将为我们提供重要的新机制的见解，多因素的神经发育病因学， P因素。这些知识是下游研究计划的关键投入，例如寻求 确定高危青年或制定干预措施，减轻或阻止精神病理学的出现。

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.