Identifying integrated circuit mechanisms of PTSD: Multimodal neuroimaging fusion of fear inhibition and cognitive control

创伤后应激障碍(PTSD)是一种普遍存在的、使人衰弱的 军事战斗，对许多退伍军人来说是一个沉重的负担。创伤后应激障碍也是一种高度异质性 障碍，症状因人而异--使临床决策复杂化。这个 症状表现的多样性导致了人们对开发以生物学为基础的 神经精神障碍框架，其中重点是症状，而不是诊断类别，以及 症状是神经回路功能障碍的结果。症状衍生的生物标记物随后可以 通过识别潜在的症状特定的神经回路来指导精准医学方法 对特定治疗最敏感。然而，我们所知道的许多关于电路病理学的知识与 创伤后应激障碍来自使用单一神经成像测量在单一机制上比较诊断组。 这些单变量神经成像方法排除了对更复杂关系的识别 神经机制和创伤后应激障碍症状之间。这种复杂性突显了对集成的 以及探索特定PTSD症状背后的多种神经回路机制的多变量方法。 目前的提案旨在通过衡量两个关键因素的共同贡献来解决这一差距 创伤后应激障碍的机制：1)对工作记忆的“自上而下”的认知控制；2) 在恐惧消退回忆过程中“自下而上”抑制恐惧反应。首先，我们假设错误分配WM 任务无关威胁的资源可能有助于部分解释创伤相关的侵入性记忆，以及 无法消除创伤后应激障碍患者特有的恐惧反应。为了调查此事， 退伍军人(N=85)，经历过标准A级创伤并有轻度到重度的创伤后应激障碍 症状将完成单独的测量，包括情感工作记忆任务和恐惧消退回忆 在接受功能磁共振成像的同时进行范式检查。该项目的第一个目标将是使用功能磁共振成像来测试我们的假设 创伤后应激障碍症状升高的退伍军人不必要地在西医中保持威胁-分心因素，因此 不断减少的WM容量。第二个目标将是确定WM背后的共同神经回路 控制和恐惧消亡的回忆。这项研究的主要目标将是检验这样一种假设，即 工作记忆与恐惧消退、回忆功能障碍之间的整合可以预测创伤后应激障碍症状群。至 为了实现这最后一个目标，我们将使用一种创新的多变量神经成像分析策略 多模式神经影像融合。多模式融合分析允许识别独特的和高度的 多个神经测量和PTSD症状之间的维度神经模式是单变量 接近将会失手。该项目将是应用多模式神经影像融合的首批研究之一。 对老兵创伤后应激障碍人群的分析。该项目的成果将为建立和 用多模式方法开发认知领域中创伤后应激障碍症状异质性的生物标记物 以及基于消退的机制，这两种机制显然是目前创伤后应激障碍治疗不可或缺的一部分。 根据申请者先前在焦虑的WM功能障碍的神经测量方面的经验， 拟议的培训计划为恐惧学习方法方面的新实践培训提供了机会， 多模式神经成像和先进的多变量神经成像分析，以实现以下直接目标 发展这些领域的技能。这与候选人的长期职业目标相吻合 发展多种神经成像模式综合方面的专门知识，以加强 神经影像在创伤后应激障碍诊断评估和治疗预测中的临床应用。来自于此的数据 该项目将为成功筹备退伍军人事务部优秀奖提供关键和直接的试点数据。团结在一起， 研究和培训计划将使申请者处于有利地位，过渡到独立的临床 退伍军人制度内的研究人员。

Posttraumatic stress disorder (PTSD) is a prevalent and debilitating neuropsychiatric consequence of military combat, representing a significant burden for many Veterans. PTSD is also a highly heterogeneous disorder, with symptoms varying from patient to patient—complicating clinical decision-making. The diversity in symptom presentation has led to a growing interest in developing a biologically-grounded framework for neuropsychiatric disorders, where the focus is on symptoms, not diagnostic categories, and where symptoms are a consequence of dysfunctional neural circuits. Symptom-derived biomarkers can then guide precision medicine approaches by identifying the underlying symptom-specific neural circuits that are most sensitive to specific treatments. Yet, much of what we know about the circuit pathology associated with PTSD comes from comparing diagnostic groups on a single mechanism using a single neuroimaging measure. These univariate neuroimaging approaches precludes identification of the more complex relationship between neural mechanisms and PTSD symptoms. This complexity underscores the need for an integrated and multivariate approach to probe multiple neural circuit mechanisms underlying specific PTSD symptoms. The current proposal aims to address this gap by measuring the combined contribution of two critical mechanisms of PTSD: 1) the ‘top-down’ cognitive control over working memory (WM) storage, and 2) ‘bottom-up’ inhibition of fear responses during fear extinction recall. First, we posit that misallocating WM resources to task-irrelevant threat may help partially explain the trauma-related intrusive memories, and inability to extinguish fear responses that are characteristic of individuals with PTSD. To investigate this, Veterans (N=85) that have experienced a criterion-A trauma and have mild to severe levels of PTSD symptoms will complete separate measures including an affective WM task and a fear extinction recall paradigm while undergoing fMRI. The first goal of the project will be to use fMRI to test our hypothesis that Veterans with elevated PTSD symptoms unnecessarily maintain threat-distracters in WM and consequently diminishing WM capacity. The second goal will be to identify the common neural circuit underlying WM control and fear extinction recall. The primary goal of the study will be to test the hypothesis that the neural integration between WM and fear extinction recall dysfunction predicts PTSD symptom clusters. To investigate this last goal, we will use an innovative multivariate neuroimaging analytic strategy called multimodal neuroimaging fusion. Multimodal fusion analysis allows for the identification of unique and high- dimensional neural patterns among multiple neural measures and PTSD symptoms that a univariate approach would miss. This project will be one of the first studies to apply a multimodal neuroimaging fusion analysis in a Veteran PTSD population. Results from this project will lay the groundwork for establishing and validating the multimodal approach to develop biomarkers of PTSD symptom heterogeneity within cognitive and extinction-based mechanisms, two mechanisms that are clearly integral to current PTSD treatments. Building upon the applicant’s prior experience with neural measures of WM dysfunction in anxiety, the proposed training plan provides an opportunity for new hands-on training in fear learning methodology, multimodal neuroimaging, and advanced multivariate neuroimaging analysis to meet the immediate goal of developing skills in these domains. This dovetails with the long term career goal for the candidate of developing of expertise in the integration of multiple neuroimaging modalities for the purpose of enhancing clinical utility of neuroimaging for PTSD diagnostic assessment and treatment prediction. Data from this project will provide critical and direct pilot data for successful preparation of a VA Merit Award. Together, the research and training plan will make the applicant well-positioned to transition to an independent clinical researcher within the VA system.