Brain Circuitry and Psychological Predictors of PTSD

描述(申请人提供)：创伤后应激障碍(PTSD)是一种非常普遍和衰弱的疾病，广泛分布在美国人口中。它的定义是对创伤性事件的恐惧反应，包括重新体验、唤醒和避免提醒创伤性暴露。尽管人们努力描述创伤后应激障碍的病理生理学特征，但目前还没有生物标记物来促进诊断、治疗发展或预测治疗反应。然而，有几条证据表明，创伤后应激障碍症状是由涉及大脑恐惧回路网络的功能失调过程调节的。然而，目前尚不清楚创伤后应激障碍的康复失败是否与该回路的功能缺陷有关。拟议的五年跨学科项目将阐明创伤后应激障碍精神病理学的基础电路，并首次探索创伤后应激障碍长期暴露(PE)治疗后症状改善的神经电路。我们的目标与NIMH战略计划战略1.3一致，即“识别和整合与精神障碍相关的生物标记和行为指标”。该项目直接建立在我们评估灭绝学习和记忆缺陷的初步工作基础上，通过将基本的科学恐惧消失范式应用于暴露于创伤的健康对照组和创伤后应激障碍患者。这项拟议的研究将采用功能磁共振成像(FMRI)和皮肤电导反应(SCR)评估的既定消光范式，对PTSD患者和创伤暴露健康对照(TE-HC)受试者进行大量且具有良好特征的样本。100名受试者，包括60名创伤后应激障碍患者和40名暴露于创伤中的健康对照组，将通过fMRI和SCR进行评估，以表征恐惧消退任务中神经回路的激活。在这个为期两天的情绪学习任务中，将同时获得fMRI和SCR数据。所有60名PTSD患者和20名随机分配的TE-HC参与者将在PTSD患者完成10周的强化PE治疗后重复这些程序。创伤后应激障碍严重程度的临床评级将在治疗完成三个月后进行，以允许分析较长期治疗耐受性的神经预测因素。该项目将产生关于神经回路的新见解和信息，这些神经回路是PTSD特征的已识别的灭绝缺陷的基础。它还将提供关于PE治疗的神经效应的至关重要的新信息，PE治疗是创伤后应激障碍的一线治疗。综合起来，这些研究不仅将促进创伤后应激障碍生物标志物的识别，而且还将促进对这种经验性支持的治疗的临床反应生物标志物的识别，这可能会指导未来的治疗发展，如PE的药理辅助药物以及增强创伤后应激障碍患者消退过程的新方法。 与公共健康相关：拟议研究的目标是使用功能磁共振成像(FMRI)、消退学习和回忆范式以及皮肤电导反应(SCR)评估，以检查创伤后应激障碍患者与创伤后未患上创伤后应激障碍患者之间神经回路激活的差异，并探讨长期暴露(PE)治疗期间症状改善的神经机制。综合起来，这些研究将有助于确定创伤后应激障碍的基于大脑的生物标记物，并有助于临床对经验性支持的疾病治疗的反应。

DESCRIPTION (provided by applicant): Posttraumatic stress disorder (PTSD) is a highly prevalent and debilitating disorder that is broadly distributed in the US population. It is defined by a fearful response to traumatic events, and involves reexperiencing, arousal, and avoidance of reminders of the traumatic exposure. Despite efforts to characterize the pathophysiology of PTSD, no biomarkers currently exist to facilitate diagnosis, treatment development, or prediction of treatment response. Yet several lines of evidence suggest that PTSD symptoms are mediated by dysfunctional processes involving the brain's fear-circuitry network. It is not known, however, whether failure to recover from PTSD is governed by functional deficits in this circuitry. The proposed five year interdisciplinary project will clarify circuits underlying PTSD psychopathology and probe, for the first time, neural circuitry of symptomatic improvement in response to prolonged exposure (PE) treatment of PTSD. Our goals are congruent with NIMH strategic plan strategy 1.3 to "identify and integrate biological markers and behavioral indicators associated with mental disorders". The project builds directly on our preliminary work in assessing deficits in extinction learning and recall by applying a basic science fear extinction paradigm to trauma-exposed healthy controls and patients with PTSD. The proposed study will employ an established extinction paradigm with functional magnetic resonance imaging (fMRI) and skin conductance response (SCR) assessments in a large and well characterized sample of patients with PTSD and trauma exposed healthy control (TE-HC) subjects. One hundred subjects including 60 individuals with PTSD and 40 trauma exposed healthy controls will be assessed by fMRI and SCR to characterize neural circuitry activation to the fear extinction task. fMRI and SCR data will be acquired simultaneously during this two-day emotional learning task. All 60 PTSD and 20 randomly assigned TE-HC participants will repeat these procedures after PTSD patients have completed 10 weeks of intensive PE treatment. Clinical ratings of PTSD severity will be conducted three months after treatment completion to permit analysis of neural predictors of longer-term treatment durability. The project will yield new insights and information concerning the neural circuitry that underlies identified extinction deficiencies that characterize PTSD. It will also provide vitally important new information concerning the neural effects of PE treatment, a first line treatment for PTSD. Together these lines of research will not only advance the identification of biomarkers for PTSD, but also facilitate identification of biomarkers of clinical response to this empirically-supported treatment that may guide future treatment development of pharmacological adjuncts to PE and novel methods for enhancing extinction processes among patients with PTSD. PUBLIC HEALTH RELEVANCE: The goal of the proposed study is to use a functional magnetic resonance imaging (fMRI), and extinction learning and recall paradigm with skin conductance response (SCR) assessment, in order to examine differences in neural circuitry activation between subjects with PTSD and those exposed to trauma and didn't develop PTSD, and to probe neural mechanisms of symptomatic improvement during a treatment of Prolonged Exposure (PE) treatment. Together these lines of research will facilitate identification of brain based biomarkers for PTSD and for clinical response to an empirically supported treatment of the disorder.