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

识别 PTSD 的集成电路机制：恐惧抑制和认知控制的多模式神经影像融合

• 批准号: 10295168
• 负责人: Daniel Stout
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10295168
• 关键词: Address; Affective; Anxiety; Award; Biological Markers; Caring; Categories; Characteristics; Clinical; Cognition; Cognitive; Complex; Control Groups; Cues; Data; Diagnostic; Disease; Emotional; Emotions; Etiology; Extinction (Psychology); Fright; Functional Magnetic Resonance Imaging; Functional disorder; Future; Goals; Heterogeneity; Hippocampus (Brain); Impairment; Individual; Joints; Learning; Link; Maintenance; Measures; Memory; Memory impairment; Mental Health; Mentors; Methodology; Military Personnel; Mission; Modality; Modeling; Multivariate Analysis; Neurobiology; Neurocognitive; Parietal Lobe; Pathology; Patients; Pattern; Performance; Population; Positioning Attribute; Post-Traumatic Stress Disorders; Prediction of Response to Therapy; Prefrontal Cortex; Preparation; Psyche structure; Reporting; Research; Research Personnel; Research Support; Research Training; Resources; Sampling; Severities; Short-Term Memory; Signal Transduction; Symptoms; System; Techniques; Testing; Training; Trauma; Veterans; Weight; affective neuroscience; associated symptom; base; career; clinical decision-making; cognitive control; cognitive neuroscience; combat; emotion regulation; experience; fear memory; fusiform face area; high dimensionality; innovation; integrated circuit; interest; memory retrieval; multimodal neuroimaging; multimodality; multitask; neural circuit; neural patterning; neurobiological mechanism; neuroimaging; neuromechanism; neuropsychiatric disorder; neuropsychiatry; novel; post-traumatic symptoms; precision medicine; relating to nervous system; response; skills; stress related disorder; symptom cluster; symptomatology; tool

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.

创伤后应激障碍 (PTSD) 是一种普遍存在且使人衰弱的神经精神后果 军事战斗对许多退伍军人来说是一个沉重的负担，但创伤后应激障碍也是一种高度异质性的疾病。 疾病，每个患者的症状各不相同，这使临床决策变得复杂。 症状表现的多样性导致人们对开发基于生物学的方法越来越感兴趣 神经精神疾病的框架，重点是症状，而不是诊断类别，以及 症状是神经回路功能失调的结果。 通过识别潜在的症状特异性神经回路来指导精准医学方法 然而，我们所了解的大部分与回路病理相关的知识对特定治疗最为敏感。 创伤后应激障碍（PTSD）来自使用单一神经影像学测量在单一机制上比较诊断组。 这些单变量神经影像学方法无法识别更复杂的关系 神经机制和 PTSD 症状之间的复杂性强调了整合的必要性。 以及多变量方法来探究特定 PTSD 症状背后的多种神经回路机制。 当前的提案旨在通过衡量两个关键的综合贡献来解决这一差距 PTSD 的机制：1）对工作记忆（WM）存储的“自上而下”认知控制，以及 2） 首先，我们假设恐惧消退回忆过程中恐惧反应的“自下而上”抑制。 与任务无关的威胁的资源可能有助于部分解释与创伤相关的侵入性记忆，以及 无法消除 PTSD 患者特有的恐惧反应。 经历过 A 标准创伤并患有轻度至重度 PTSD 的退伍军人 (N=85) 症状将完成单独的措施，包括情感 WM 任务和恐惧消退回忆 该项目的第一个目标是使用功能磁共振成像来检验我们的假设： 具有严重 PTSD 症状的退伍军人不必要地在 WM 中保留威胁分散因素，因此 第二个目标是确定 WM 的共同神经回路。 该研究的主要目标是检验神经控制和恐惧消退回忆的假设。 WM 和恐惧消退回忆功能障碍之间的整合可以预测 PTSD 症状群。 为了研究最后一个目标，我们将使用一种创新的多变量神经影像分析策略，称为 多模态神经影像融合。多模态融合分析可以识别独特且高水平的神经影像。 多种神经测量和 PTSD 症状之间的维度神经模式，单变量 该项目将是应用多模态神经影像融合的首批研究之一。 该项目的结果将为建立和建立基础奠定基础。 验证多模式方法以开发认知内 PTSD 症状异质性的生物标志物 和基于消退的机制，这两种机制显然是当前 PTSD 治疗不可或缺的一部分。 基于申请人之前对焦虑中 WM 功能障碍的神经测量的经验， 拟议的培训计划为恐惧学习方法的新实践培训提供了机会， 多模式神经影像和先进的多变量神经影像分析，以满足近期目标 这与候选人的长期职业目标相吻合。 开发整合多种神经影像模式的专业知识，以增强 神经影像学在 PTSD 诊断评估和治疗预测中的临床应用。 该项目将为成功准备 VA 优异奖提供关键和直接的试点数据。 研究和培训计划将使申请人做好向独立临床过渡的准备 VA 系统内的研究员。