Alignment of cortical development trajectories with emergent dimensional psychopathology and related risk factors among early adolescents in the ABCD Study

破译精神疾病生物学特征的努力现在越来越多地集中在青春期， 在许多疾病的发病高峰期之前，大脑迅速发育。成熟 这段时间的大脑皮层一直被认为是早期症状出现的媒介。 然而，虽然特定的皮质变化与少数特定的综合征有关， 在大多数情况下，作为精神病理学分化基础的皮层发育模式仍然存在， 不确定正在进行的青少年大脑认知发展（ABCD）研究提供了一个前所未有的 有机会将精神病理学的特定模式的出现与皮层的特定变化联系起来， 成熟在未来5年内，ABCD将获得年度标准化措施， 精神病理学和两年一次的MRI扫描，对美国21个地点的11，875名青少年进行了研究，覆盖9至16岁。 拟议的研究将利用这种纵向设计来发现区域和时间特异性 与维度精神病理学的出现相关的皮质发育特征，然后 将这些模式与潜在的基因组和环境风险的具体情况联系起来。分析基线 包括在本申请中的9-10岁的数据表明，精神病理学处于早期阶段， 分化，虽然已经与儿童发病疾病的多基因风险密切相关， 产前和产后的环境伤害。拟议研究的目的1将临床和 从基线到三个随访时间点的成像数据，主要关注是否偏离 神经典型年龄相关皮质变薄轨迹（通过截距、斜率和二次指数评估） 与特定疾病的出现有关。精确的临床和 皮层变薄轨迹将朝着推断因果关系迈出第一步，这将进一步 通过与基因组（目标2）和环境（目标3）风险概况的三角关系得到证实。多基因 由精神病学基因组学联盟开发的评分方法将用于确定是否 在Aim 1中开发的皮质成熟轨迹介导基因组风险和紧急事件之间的关系 维度精神病理学然后，利用数百项环境措施的数据， 参与者的日常活动，营养，生活压力源，社会经济地位，家庭动态，邻居 安全和许多其他因素，我们将使用新的机器学习方法来开发配置文件， 预测紧急维度精神病理学的危险因素，并决定皮质 成熟模式介导环境风险概况和临床过程之间的关系。由 我们希望建立特定的皮层信号，以桥接因果因素 在青春期出现精神病理学，这可以用来开发新的预防性药物， 干预措施。

Efforts to decipher biological signatures for mental illness now focus increasingly on adolescence, a period of rapid brain development that immediately precedes the peak age of onset for many disorders. Maturation of the cerebral cortex during this time has long been thought to mediate emergence of early symptoms. However, while specific cortical changes have been implicated in a small number of specific syndromes, for the most part, patterns in cortical development that underlie the differentiation of psychopathology remain uncertain. The ongoing Adolescent Brain Cognitive Development (ABCD) study provides an unprecedented opportunity to align emergence of specific patterns of psychopathology with specific changes in cortical maturation. Over the next 5 years, ABCD will obtain annual, standardized measures dimensional psychopathology, and biennial MRI scans, of 11,875 youths across 21 US-based sites, covering age 9 to 16. The proposed studies will leverage this longitudinal design to discover regionally- and temporally-specific features of cortical development that associate with emergence of dimensional psychopathology, and then to relate these patterns to specific profiles of underlying genomic and environmental risk. Analysis of baseline data from age 9-10, included in this application, indicates that psychopathology is in early stages of differentiation, although already strongly related to polygenic risk for child-onset disorders, and to well- established pre- and post-natal environmental insults. Aim 1 of the proposed studies will juxtapose clinical and imaging data from baseline through three follow-up time points, focusing primarily on whether departures from neurotypical age-related cortical thinning trajectories (assessed via intercept, slope, and quadratic indices) associate with emergence of specific dimensions of illness. The precise temporal alignment of clinical and cortical thinning trajectories will take an initial step towards inferring causal relationships, which will be further substantiated through triangulation with genomic (Aim 2) and environmental (Aim 3) risk profiles. Polygenic scoring methods developed by the Psychiatric Genomics Consortium will be used to determine whether cortical maturation trajectories developed in Aim 1 mediate relationships between genomic risk and emergent dimensional psychopathology. Then, using data from hundreds of environmental measures that canvass participants’ daily activities, nutrition, life stressors, socioeconomic status, family dynamics, neighborhood safety, and numerous other factors, we will use novel machine learning methods to develop profiles of exposomic risk factors that predict emergent dimensional psychopathology, and determine whether cortical maturation patterns mediate the relationship between environmental risk profiles and clinical course. By the conclusion of the proposed studies we hope to establish specific cortical signatures that bridge causal factors with emergent psychopathology in adolescence, and that can be leveraged to develop new preventative interventions.