Brain Circuitry and Psychological Predictors of PTSD

描述（由申请人提供）：创伤后应激障碍（PTSD）是一种广泛分布于美国人群中的高度流行和衰弱性疾病。它被定义为对创伤事件的恐惧反应，包括重新体验，唤醒和避免创伤暴露的提醒。尽管努力表征PTSD的病理生理学，但目前还没有生物标志物来促进诊断、治疗开发或治疗反应的预测。然而，一些证据表明，PTSD症状是由涉及大脑恐惧回路网络的功能失调过程介导的。然而，目前尚不清楚PTSD的恢复失败是否是由该回路的功能缺陷所控制的。 拟议的五年跨学科项目将澄清电路潜在的PTSD精神病理学和探针，第一次，神经电路的症状改善，以应对长期暴露（PE）治疗PTSD。我们的目标与NIMH战略计划策略1.3一致，即“识别和整合与精神障碍相关的生物标志物和行为指标”。该项目直接建立在我们的初步工作，通过将基础科学恐惧灭绝范式应用于创伤暴露的健康对照和PTSD患者，评估灭绝学习和回忆的缺陷。 拟议的研究将采用功能性磁共振成像（fMRI）和皮肤电导反应（SCR）评估在一个大的和充分表征的样本与创伤后应激障碍患者和创伤暴露的健康对照（TE-HC）受试者建立灭绝范式。将通过fMRI和SCR评估100名受试者，包括60名患有PTSD的个体和40名创伤暴露的健康对照，以表征恐惧消退任务的神经回路激活。在这两天的情绪学习任务中，将同时采集fMRI和SCR数据。所有60名PTSD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。治疗完成后3个月将进行PTSD严重程度的临床评级，以分析长期治疗持久性的神经预测因子。 该项目将产生新的见解和信息的神经回路的基础确定灭绝缺陷的特点创伤后应激障碍。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PTSD的一线治疗。这些研究不仅将促进PTSD生物标志物的鉴定，而且还将促进对这种药物支持的治疗的临床反应的生物标志物的鉴定，这可能指导未来对PE的药理学抑制剂的治疗开发和用于增强PTSD患者的消退过程的新方法。 公共卫生相关性：该研究的目的是使用功能性磁共振成像（fMRI）和消退学习和回忆范式与皮肤电导反应（SCR）评估，以检查受试者与创伤和未发生创伤后应激障碍的受试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。这些研究将有助于识别基于大脑的PTSD生物标志物，并对经验支持的疾病治疗做出临床反应。

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.