# Neuromodulation as a Therapy for PTSD following Chronic TBI

> **NIH VA I01** · PHILADELPHIA VA MEDICAL CENTER · 2020 · —

## Abstract

Although PTSD is a frequent co-morbidity of traumatic brain injury in Veterans, the neurophysiological basis
underlying the contribution of TBI to PTSD remains unknown, and there are currently few effective treatments
available for this prevalent co-morbidity. A number of human and rodent studies have demonstrated that TBI
can exacerbate fear responses, and affect the ability to extinguish a conditioned fear response. Others have
demonstrated in PTSD models that there is a shift in the balance between limbic structures (prefrontal cortex,
the hippocampus and amygdala) after fear conditioning. Surprisingly, there have been few reports to date of
how the network neurophysiology underlying these behavioral changes are affected by TBI. A potential
treatment for PTSD using neuromodulation is in trials in Veterans, but we don’t have a clear understanding of
how TBI would affect this neuromodulation. There is no accepted theory or supporting data demonstrating how
the encoding/recall of fear learning and memory are disrupted by TBI, or how TBI affects the ability to extinguish
fear. Therefore, a critical need exists to determine the underlying mechanism of how TBI leads to alteration of
fear learning and extinction after traumatic brain injury. Without a deeper understanding of how TBI affects this
circuitry, rational design of neuromodulatory and other therapies targeting fear processing remains improbable.
The overall objective of the current application is to determine how the coding of fear in extended amygdalar
circuitry is affected following TBI, and whether neuromodulation can enable faster fear extinction. Our central
hypothesis is that TBI disrupts normal communication between the amygdala and other regions
underlying fear memory, which leads to overexpression of fear learning, generalization to other
situations, and an inability to extinguish learned fear. This hypothesis is based in part on predictions from
our preliminary data demonstrating that injured animals have increased time to extinguish fear, that neurons in
the limbic system have different firing properties and entrain to oscillations in a different manner following injury,
and others data demonstrating that neuromodulation in the amygdala can eliminate PTSD-like symptoms. In
order to test the above hypothesis, we will first determine the mechanism of TBI induced fear responses in rats
using simultaneous multi-site recordings and neuropathology. We believe axonal injury affects top down input
from the prefrontal cortex, as well as organizing input from the hippocampus (theta oscillations), leading to
heightened amygdalar fear responses and poor consolidation of extinction memory. For the first time, we will
also test neuromodulation as a treatment to restore normal balance in the extended amygdalar circuitry and
restore extinction of fear. We hypothesize that extinction of fear responses in the amygdala can be restored by
modulating the remaining prefrontal and/or hippocampal connec...

## Key facts

- **NIH application ID:** 9942274
- **Project number:** 5I01RX002705-03
- **Recipient organization:** PHILADELPHIA VA MEDICAL CENTER
- **Principal Investigator:** John Allen Wolf
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9942274

## Citation

> US National Institutes of Health, RePORTER application 9942274, Neuromodulation as a Therapy for PTSD following Chronic TBI (5I01RX002705-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9942274. Licensed CC0.

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