Risk and Resilience in Maltreated Children

描述（由申请人提供）：在过去的十年中，越来越多的人认识到精神障碍是受遗传和环境因素影响的脑回路障碍。该申请是为了响应RFA- MH-12-100而提交的，该申请源于NIMH研究领域标准（RDoC）项目，该项目旨在进一步实现开发遗传学，神经科学和心理学告知的精神障碍诊断系统的长期目标。这个应用程序的重点是RDoC域负价系统，或更具体地说，急性威胁，“恐惧”。拟议的调查利用转化神经科学的角度来研究400名10-15岁的儿童：200名社区控制和200名虐待儿童，他们有发展创伤相关精神问题的风险（例如，抑郁、焦虑、物质滥用）。还计划对其他相关RDoC领域和结构进行评估。本研究将在家庭外安置后六个月内招募受虐待儿童（例如，寄养），因为虐待或忽视的严重程度足以证明驱逐的经证实的报告。与RDoC矩阵一致，在拟议的研究中将检查多个分析单元：基因、电路， 和临床症状的自我报告。具体来说，我们将检查：涉及恐惧条件反射、突触可塑性和髓鞘形成/回路形成的基因中的表观遗传修饰;白色物质结构和功能的多个指数;任务激活和静息状态恐惧回路测量;以及创伤相关神经病学的维度评估。还将收集全面的创伤史和社会支持措施。DNA和临床评估将在400名儿童的整个队列中收集;综合成像方案将仅在125名青年中完成。拟议的受虐待儿童研究对RDoC项目有许多好处，包括：研究经常对标准临床干预治疗有抵抗力的一部分患者; 一个相对同质的样本与精神病理学的发病提出与压力相关的机制;和完善的相关动物模型，以促进转化研究。此外，对接近虐待和脱离父母照顾时间的这一队列的研究显著增强了检测与风险和复原力相关的表观遗传变化的能力。希望这项围绕急性威胁组织的研究计划，恐惧回路，受创伤个体影响的主要回路，将加速了解儿童早期创伤如何影响从基因到行为的整个分析范围。该项目的研究团队由具有精神病和其他健康专业知识的基础和临床科学家组成（例如，癌症）领域，促进研究工作的协同和交叉，以进一步实现RDoC项目和本研究的目标 受虐儿童的风险和恢复力。! 公共卫生相关性：这项调查是一项研究中的研究;它将为RDoC项目提供丰富的数据;也将提供有关风险的宝贵数据 和恢复力的能力。该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RDoC矩阵中包含的多个分析单元的数据：基因，电路和临床症状的自我报告。!

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. !