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）是一种流行的和衰弱的神经精神后果， 这对许多退伍军人来说是一个沉重的负担。PTSD也是一种高度异质性的 疾病，症状因患者而异，使临床决策复杂化。的 症状表现的多样性导致人们对开发基于生物学的 神经精神障碍的框架，重点是症状，而不是诊断类别， 症状是神经回路功能失调的结果症状衍生的生物标志物可以 通过识别潜在的特定神经回路来指导精准医学方法， 对特定治疗最敏感。然而，我们所知道的大部分关于电路病理学与 创伤后应激障碍来自于使用单一神经影像学方法对单一机制的诊断组进行比较。 这些单变量神经影像学方法排除了更复杂的关系的识别 神经机制和创伤后应激障碍症状之间的联系这种复杂性突出表明， 和多变量方法来探测特定PTSD症状下的多神经回路机制。 目前的建议旨在通过衡量两个关键领域的综合贡献来弥补这一差距。 PTSD的机制：1）对工作记忆（WM）存储的“自上而下”的认知控制，以及2） “自下而上”抑制恐惧反应在恐惧消退回忆。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， 无法消除PTSD患者特有的恐惧反应。为了调查这一点， 退伍军人（N=85）经历过标准-A创伤并患有轻度至重度PTSD 症状将完成单独的措施，包括情感WM任务和恐惧消退回忆 进行功能性磁共振成像时的范例。该项目的第一个目标是使用功能磁共振成像来验证我们的假设， 具有升高的PTSD症状的退伍军人在WM中不必要地维持威胁-分心物， 降低WM能力。第二个目标将是确定共同的神经回路潜在的WM 控制和恐惧消退回忆。这项研究的主要目标是检验神经系统 WM和恐惧消退回忆功能障碍之间的整合预测PTSD症状簇。到 为了研究最后一个目标，我们将使用一种创新的多元神经成像分析策略， 多模式神经影像融合多模态融合分析允许识别独特的和高- 多维神经模式之间的多种神经措施和创伤后应激障碍症状，一个单变量 方法会错过。该项目将是应用多模式神经影像融合的首批研究之一 在退伍军人PTSD人群中进行分析。该项目的成果将为建立和 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， 和基于预防的机制，这两种机制显然是目前PTSD治疗的组成部分。 基于申请人先前对焦虑症中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， 多模式神经影像学和先进的多变量神经影像学分析，以满足眼前的目标， 发展这些领域的技能。这与候选人的长期职业目标相吻合， 发展综合多种神经成像模式的专门知识， 神经影像学在PTSD诊断评估和治疗预测中的临床应用数据从该 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。统称 研究和培训计划将使申请人处于有利地位，过渡到一个独立的临床 研究人员在系统内。