Risk and Resilience in Maltreated Children

描述(由申请人提供)：在过去的十年里，人们越来越多地认识到精神障碍是受遗传和环境因素影响的大脑回路障碍。本申请是对RFA-MH-12-100的响应，RFA-MH-12-100源于NIMH研究领域标准(RDoC)项目，该项目旨在进一步实现长期目标，即开发一个由遗传学、神经科学和心理学提供信息的精神障碍诊断系统。这个应用专注于RDoC领域的负价系统，或者更具体地说，严重的威胁，“恐惧”。拟议的调查利用翻译神经科学的观点研究了400名10-15岁的儿童：200名社区控制儿童和200名虐待儿童，他们有可能出现与创伤有关的精神问题(例如，抑郁、焦虑、药物滥用)。还计划对其他相关的RDoC域和结构进行评估。受虐待儿童将在离家安置(例如寄养)后六个月内被招募参加本研究，原因是有确凿的虐待或疏忽报告，其严重程度足以被遣送离开。与RDoC矩阵一致，在拟议的调查中将检查多个分析单位：基因、电路、 以及临床症状的自我报告。具体地说，我们将检查：参与恐惧条件反射、突触可塑性和髓鞘形成/回路形成的基因的表观遗传修饰；白质结构和功能的多个指数；任务激活和静止状态的恐惧回路测量；以及创伤相关症状的维度评估。还将收集全面的创伤病史和社会支持措施。将收集400名儿童的全部队列的DNA和临床评估；全面的成像方案将仅在125名青年中完成。拟议的对虐待儿童的研究对RDoC项目有许多好处，包括：研究经常对标准临床干预措施产生抗药性的患者子集；检查 一个相对同质的样本，与精神病理学的开始被认为与压力相关的机制有关；以及完善的相关动物模型，以促进翻译研究。此外，对接近虐待和脱离父母照料时间的这一队列的研究显著增强了检测与风险和韧性相关的表观遗传变化的能力。希望这项围绕急性威胁、恐惧回路组织的研究计划，将促进人们对儿童早期创伤如何影响从基因到行为的整个分析范围的了解。这个项目的研究团队由在精神病学和其他健康(如癌症)领域具有专业知识的基础和临床科学家组成，促进研究努力的协同和交叉，以促进RDoC项目和这项研究的目标 受虐待儿童的风险和复原力。好了！ 公共卫生相关性：这项调查是一项研究中的一项研究；一项将为RDoC项目提供丰富数据的研究；一项还将提供关于风险的宝贵数据的研究 以及受虐待儿童的恢复能力。这个应用程序描述了检查RDoC域负价系统的计划，或者更具体地说，急性威胁-“恐惧”；并建议收集关于RDoC矩阵中包括的多个分析单元的数据：基因、电路和临床症状的自我报告。好了！

DESCRIPTION (provided by applicant): Over the past decade there has been growing appreciation of mental disorders as brain circuit disorders that are influenced by genetic and environmental factors. This application is being submitted in response to RFA- MH-12-100, which stems from the NIMH Research Domain Criteria (RDoC) project that aims to further the long-range goal of developing a diagnostic system for mental disorders informed by genetics, neuroscience, and psychology. This application focuses on the RDoC domain Negative Valence Systems, or more specifically, acute threat, "fear". The proposed investigation utilizes a translational neuroscience perspective to study 400 10-15 year old children: 200 community-control and 200 maltreated children who are at-risk of developing trauma-related psychiatric problems (e.g., depression, anxiety, substance misuse). Assessments of other relevant RDoC domains and constructs are also planned. Maltreated children will be recruited for the present study within six months of out-of-home placement (e.g., foster care) due to a substantiated report of abuse or neglect of sufficient severity to warrant removal. Consistent with the RDoC matrix, multiple units of analyses will be examined in the proposed investigation: genes, circuits, and self-reports of clinical symptoms. Specifically, we will examine: epigenetic modifications in genes involved in fear conditioning, synaptic plasticity, and myelination/circuitry formation; multiple indices of white matter structure and function; task-activated and resting-state fear circuitry measures; and dimensional assessments of trauma-related symptomatology. Comprehensive trauma history and social supports measures will also be collected. DNA and clinical assessments will be collected on the full cohort of 400 children; the comprehensive imaging protocol will only be completed on 125 youth. The proposed study of maltreated children has a number of advantages for the RDoC project, including: the study of a subset of patients that are frequently treatment resistant to standard clinical interventions; examination of a relatively homogenous sample with the onset of psychopathology proposed to be associated with stress-related mechanisms; and well-established relevant animal models to facilitate translational research. In addition, the study of this cohort close to the time of abuse and removal from parental care significantly enhances power to detect epigenetic changes associated with risk and resilience. It is hoped that this research program organized around the acute threat, fear circuit, a primary circuit affected in traumatized individuals, will accelerate knowledge regarding how early childhood trauma influences the entire range of analysis from genes to behavior. The research team for this project is comprised of basic and clinical scientists with expertise in psychiatric and other health (e.g., cancer) areas, facilitating synerg and cross-fertilization of research efforts to further the goals of the RDoC project and this study of risk and resilience in maltreated children. ! PUBLIC HEALTH RELEVANCE: This investigation represents a study within a study; one that will provide rich data for the RDoC project; and one that will also provide invaluable data on risk and resilience in maltreated children. This application delineates plans to examine the RDoC domain Negative Valence Systems, or more specifically, acute threat - "fear;" and proposes to collect data on multiple units of analysis included in the RDoC matrix: genes, circuits, and self-reports of clinical symptoms. !