# Fear Reversal Learning in Combat-Related PTSD: A Multi-Model fMRI-PET Approach

> **NIH VA I01** · VA CONNECTICUT HEALTHCARE SYSTEM · 2022 · —

## Abstract

Project Summary/Abstract
Posttraumatic stress disorder (PTSD) is one of the most prevalent, chronic, and disabling
psychiatric disorders in combat veterans. Despite some advances in characterizing biological
factors associated with PTSD, the neurobiology of this disorder remains incompletely
understood. Elucidation of the neurobiology of PTSD is important, as it has the potential to
improve understanding of the etiology and inform the development of more targeted,
mechanism-based, and personalized treatments for this disorder. To this end, we propose a
state-of-the-art, multi-modal functional magnetic resonance imaging-positron emission
tomography (fMRI-PET) study that will determine, for the first time, functional neural and
molecular (i.e., cannabinoid type 1 [CB1] receptor) underpinnings of fear reversal learning, a
core feature of PTSD characterized by the ability to flexibly control and maneuver acquired fear
responses in combat veterans presenting with the full dimensional spectrum of combat-related
PTSD symptoms. Given that fear reversal learning is impaired in PTSD and contributes to the
chronicity of this disorder, characterization of neurobiological factors that underlie its component
processes can inform both the etiology and personalization of treatments for this disorder.
Upon returning from the battlefield, why is it that some combat veterans develop PTSD but
others do not? A predominant theory is that individuals with PTSD are markedly impaired in
their ability to extinguish and reverse fear learning. During fear reversal learning, an individual
first acquires a conditioned response to a fear predictive cue while ignoring another cue that
predicts nothing (acquisition phase). Then, the individual flexibly switches the fear response
between cues, when the conditioned one does not predict the fearful outcome anymore, but the
previously safe one does (reversal phase). As in combat and other stressful situations, fear
reversal learning engages two processes simultaneously—learning what to fear and learning
what is safe—which in turn helps to promotes flexible adaptation to fear.. While behavioral
models of fear reversal learning in PTSD are well established, scarce research has examined
the neurobiology of this core component of this disorder. This information is essential to
understanding the neurobiology of how combat veterans process fear-related information in
complex and dynamic situations, particularly as they adapt to civilian life after deployment.
To address this gap in the literature, we propose a multi-modal fMRI-PET study of the neural
correlates of fear reversal learning in combat veterans presenting with the full dimensional
spectrum of combat-related PTSD symptoms. The proposed study, which directly addresses the
CSR&D high priority area of PTSD research, will generate novel insights into the neural,
molecular, and behavioral underpinnings of fear reversal learning in combat-related PTSD. By
employing PET molecular imagi...

## Key facts

- **NIH application ID:** 10409697
- **Project number:** 5I01CX001538-04
- **Recipient organization:** VA CONNECTICUT HEALTHCARE SYSTEM
- **Principal Investigator:** ILAN HARPAZ-ROTEM
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10409697

## Citation

> US National Institutes of Health, RePORTER application 10409697, Fear Reversal Learning in Combat-Related PTSD: A Multi-Model fMRI-PET Approach (5I01CX001538-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10409697. Licensed CC0.

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