Childhood trauma, hippocampal function, and anhedonia among those at heightened risk for psychosis

项目摘要/摘要 患有精神分裂症谱系障碍的人会经历一系列的症状，这些症状会导致 功能障碍，因此对个人和公共卫生造成很大负担。同样，个人在 精神病发展的临床高危(CHR)经历一般工作和学习障碍 社会损害和生活质量下降，甚至在全阈值开始之前就已经明显 精神错乱。因此，评估CHR群体的研究有助于揭示精神分裂症的症状 首先提出并指出更有效的早期干预途径。特别重要的是考试 阴性症状，如快感缺乏，往往在阳性症状出现之前出现，是 对治疗的抵抗力更强，对功能结果的预测性更强。此外，尽管 快感缺乏症通常发生在精神病患者中，它也是抑郁症的一个特征，是一种与 慢性阻塞性肺病患者的共病发生率较高。越来越多的证据表明，童年创伤不仅增加了患病风险 发展为精神病，但与快感缺乏有关，特别是在各种诊断中，包括 抑郁症患者，以及非精神控制组。此外，童年创伤有有害的影响。 关于中脑边缘系统，特别是海马体，这是动物模型最近发现的一个区域 在快感缺乏背后的奖赏不足的发展过程中。尽管有这些趋同的研究路线，但没有人， 到目前为止，已经研究了中脑边缘功能在儿童创伤之间的关系中的中介作用 快感缺乏症。因此，这项拟议的研究将考察童年创伤和 在新奇事物加工过程中，通过间接影响海马体功能而导致快感缺乏，这已被证明 启动多巴胺能奖赏系统。在我的赞助者NIMH资助的R01的背景下，拟议的研究， 将招募不寻求帮助的16-30岁的年轻人，他们代表着全部的精神病风险，以完成自我 报告问卷和临床访谈，其中一个子集同时完成静息状态和基于任务的 功能磁共振成像(FMRI)扫描。拟议中的研究结果有能力 提供对先前建立的与快感缺失相关的奖励相关改变的更多洞察，例如 为理解童年创伤和快感缺乏之间的关系提供了一个新的框架。此外， 我们将探索儿童创伤、中边缘接触和儿童心理创伤之间的潜在差异 慢性再生障碍性贫血和非慢性再生障碍性贫血患者之间的快感缺乏以评估特异性。为了完成这项研究，一项培训计划 已经开发了由正式课程、研讨会、体验式学习和指导组成的课程。这 奖学金将使我获得更多的培训机会，否则我不会有这样的机会， 为了发展奖赏功能障碍的病理生理学、神经成像和数据分析方面的专业知识 成为一名独立的临床科学家所必需的。

PROJECT SUMMARY/ABSTRACT Individuals with schizophrenia spectrum disorders experience a range of symptoms which cause high levels of functional impairment, thus representing a large personal and public health burden. Similarly, individuals at clinical high risk (CHR) for the development of psychosis experience general work and academic impairments, social impairment, and reductions in quality of life that are evident even prior to the onset of full-threshold psychosis. Therefore, studies evaluating CHR populations can help to uncover how symptoms of schizophrenia first arise and indicate more effective avenues for early intervention. Of particular importance is the examination of negative symptoms, such as anhedonia, as they tend to present prior to the onset of positive symptoms, are more resistant to treatment, and are more strongly predictive of functional outcomes. Further, although anhedonia commonly occurs in those with psychosis, it also is a hallmark feature of depression, a disorder with high comorbidity in CHR individuals. Mounting evidence suggests that childhood trauma not only increases risk of developing psychosis, but is associated with anhedonia, specifically, across diagnoses, including for individuals with depression, as well as non-psychiatric controls. Further, childhood trauma has deleterious effects on the mesolimbic system, particularly the hippocampus, a region which animal models have recently implicated in the development of reward deficits underlying anhedonia. Despite these converging lines of research, no one, to date, has examine the mediating role of mesolimbic functioning in the relationship between childhood trauma and anhedonia. Therefore, the proposed study will examine the association between childhood trauma and anhedonia via the indirect effect of hippocampal function during novelty processing, which has been shown to engage dopaminergic reward systems. The proposed study, in the context of my sponsor's NIMH-funded R01, will recruit non-help-seeking 16-30 year olds who represent the full spectrum of psychosis-risk to complete self- report questionnaire and clinical interviews, with a subset completing both resting-state and task-based functional magnetic resonance imaging (fMRI) scans. Findings from the proposed study have the capacity to provide additional insight into previously established reward-related alterations associated with anhedonia, thus providing a novel framework to understand the relationship between childhood trauma and anhedonia. Further, we will explore potential differences in the association between childhood trauma, mesolimbic engagement, and anhedonia across CHR and non-CHR individuals to assess specificity. To complete this study, a training plan has been developed that consists of formal coursework, workshops, experiential learning, and mentorship. This fellowship would allow me to obtain additional training opportunities that would not otherwise be available to me, in order to develop the expertise in the pathophysiology of reward dysfunction, neuroimaging, and data analysis necessary to become an independent clinical scientist.