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: 10041687
• 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/10041687
• 关键词: Address; Affective; Anxiety; Award; Biological; 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; Structure; 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; interest; memory retrieval; 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）是一种普遍且令人衰弱的神经精神伴侣 军事战斗，压迫许多退伍军人的巨大负担。 疾病，症状从患者到患者的临床决策不同 症状表现的多样性导致人们越来越兴趣开发生物学上的地面 神经精神疾病的框架是重点是症状，而不是诊断类别，并且 症状是功能失调的神经回路的共同点。 指南精密医学方法通过识别潜在症状特异性神经回路的方法 对特定治疗的最敏感。 PTSD来自使用单个神经影像措施在单个机制上比较诊断组。 这些独立成像的方法排除了更复杂关系的识别 在神经机制和PTSD症状之间。 以及探测特定PTSD症状基础的多料神经回路机制的多元方法。 当前的建议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）“自上而下”对工作记忆（WM）存储的认知控制和2） “自下而上”抑制恐惧灭绝期间的恐惧反应。 对任务 - 无关威胁的资源可能有助于部分解释与创伤有关的侵入性记忆，并 无法消除具有PTSD的个体的特征的恐惧反应。 经历了标准的退伍军人（n = 85） - A创伤且具有轻度至重度PTSD 症状将完成措施，包括情感WM任务和恐惧灭绝召回 范式在fmri时 PTSD症状升高的退伍军人不必要地维持WM的威胁 - 分布者 WM的能力下降。 控制和恐惧灭绝的召回。 WM和Feand恐惧灭绝之间的整合使功能障碍预测PTSD症状群 调查最后一个目标，我们将使用创新的多元神经影像学分析策略 多模式的神经成像融合。 多种神经措施和PTSD症状之间的尺寸神经模式 方法会错过。 该项目的资深PTSD人口的分析将为建立和 验证多模式的方法来开发认知中PTSD症状异质性的生物标志物 以及基于灭绝的机制，这是当前PTSD处理显然不可或缺的两种机制。 基于申请人先前对WM功能障碍的神经测量的经验 支撑培训计划为恐惧学习方法中的新动手培训提供了机会， 多模式神经影像学和高级多元神经影像学分析，以实现直接目标 在这些领域中发展技能。 在整合多种神经影像学方式方面发展了专业知识，以增强 神经影像学用于PTSD诊断评估和治疗预测的临床实用性。 项目将提供关键和直接的试点数据，以成功地准备VA优异奖。 与申请人一起研究和培训计划，以过渡到独立的临床 VA系统中的研究人员。