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

> **NIH VA IK2** · VA SAN DIEGO HEALTHCARE SYSTEM · 2021 · —

## Abstract

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 es...

## Key facts

- **NIH application ID:** 10041687
- **Project number:** 5IK2CX001861-02
- **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM
- **Principal Investigator:** Daniel Stout
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-10-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10041687

## Citation

> US National Institutes of Health, RePORTER application 10041687, Identifying integrated circuit mechanisms of PTSD: Multimodal neuroimaging fusion of fear inhibition and cognitive control (5IK2CX001861-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10041687. Licensed CC0.

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