A Study of Childhood Irritability: Neural Mechanisms and Developmental Pathways to Internalizing and Externalizing Psychopathology

摘要 易怒是儿童被推荐接受心理健康服务的最常见原因。然而，易怒- 缺乏特定的治疗方法，部分原因是对其病理生理学知之甚少。这也是一个可遗传的陷阱1，2， 即使在相对较低的水平3，4，也会增加许多常见精神疾病的风险。一项新兴的文学作品表明 认知灵活性受损可能是导致易怒的核心机制13，14。 调节易怒青年认知僵化的机制尚未确定。此外，人们对此知之甚少 关于易怒导致不同形式的精神病理的机制。而认知缺陷 灵活性可能是一种共同的机制，在许多形式的易怒、执行的其他领域的损害 功能可能会影响易怒的发展和临床表现，导致一些年轻人发展 内化，外化，精神病态21。这项研究提案的目的是阐明 调节易怒的神经认知机制，并确定塑造易怒的方式的调节因素 在儿童和青少年早期发育过程中表现为临床上的表现。这方面的知识对发展 共同针对共同和具体责任和机制的干预/预防努力 精神变态学。建议的研究有三个具体目标：(1)发展适应和心理测量学验证 与时间敏感事件相关电位(ERPs)结合使用的新型威斯康星卡片分类任务 分离和理清集合转换、工作记忆和反馈加工在认知灵活性中的作用；(2) 7-10岁儿童易怒与集合转换、工作记忆和强化学习神经指标的关系 (n=95)；以及(3)利用NIMH资助的对12岁儿童进行的大型纵向研究(N=609)，使用 交叉滞后路径模型检验6岁和9岁儿童的错误相关负波(ERN)是否缓和了异型性 从3岁到12岁对内化和外化症状易怒的连续性。目前的培训方案将 请允许我整合来自联合赞助商和顾问的培训，他们在运行大规模研究方面具有专业知识 青少年易怒(Klein博士和Leibenluft博士)，儿科人群任务发展(Hajcak博士和Leibenluft博士) 进行纵向数据分析的高级统计技术(Kotov博士)和发展神经科学(Dr。 托特纳姆)。

Abstract Irritability is the most common reason that children are referred for mental health services9. However, irritability- specific treatments are lacking, in part because little is known about its pathophysiology. It is also a heritable trait1,2 that, even at relatively low levels3,4, increases risk for many common psychiatric disorders. An emerging literature suggests that impairments in cognitive flexibility may be a core mechanism underlying irritability13,14. However, the precise mechanisms that mediate the cognitive rigidity in irritable youth have yet to be identified. In addition, little is known about the mechanisms by which irritability leads to disparate forms of psychopathology. While deficits in cognitive flexibility may be a shared mechanism underlying many forms of irritability, impairments in other domains of executive functioning may influence the development and clinical expression of irritability, leading some youth to develop internalizing, and others externalizing, psychopathology21. The goal of this research proposal is to elucidate the neurocognitive mechanisms mediating irritability, and identify moderators that shape the way in which irritability is expressed clinically over the course of child and early adolescent development. This knowledge is crucial to developing intervention/prevention efforts that jointly target both common and specific liabilities and mechanisms of psychopathology. The proposed study has three specific aims: (1) Developmentally adapt and psychometrically validate a novel Wisconsin Card Sorting Task for use in conjunction with temporally sensitive event-related potentials (ERPs) to isolate and disentangle the role of set-switching, working memory and feedback processing in cognitive flexibility; (2) Relate neural indices of set-switching, working memory and reinforcement learning to irritability in 7-10 year old children (N = 95); and (3) Capitalizing on a large ongoing NIMH-funded longitudinal study (N=609) of 12 year-old children, use cross-lagged path modeling to examine whether the error-related negativity (ERN) at ages 6 and 9 moderates heterotypic continuity of irritability to internalizing and externalizing symptoms from ages 3 to 12. The current training proposal will allow me to integrate training from co-sponsors and consultants who have expertise in running large-scale studies on youth irritability (Drs. Klein and Leibenluft), task development for pediatric populations (Drs. Hajcak and Leibenluft) advanced statistical techniques to conduct longitudinal data analysis (Dr. Kotov), and developmental neuroscience (Dr. Tottenham).