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

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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.