# Neuromodulation as a Therapy for PTSD following Chronic TBI

> **NIH VA I01** · PHILADELPHIA VA MEDICAL CENTER · 2024 · —

## Abstract

Although PTSD and cognitive dysfunction are frequent comorbidities of chronic traumatic brain injury (TBI) in
Veterans, the neurophysiological basis of how TBI affects these processes remains unknown. In addition, there
are currently no effective treatments available for these prevalent, severely disabling comorbidities. The limbic
system, including the hippocampus, amygdala, and regions of the prefrontal cortex, underlies fear acquisition
and extinction, as well as many aspects of learning and memory. An exaggerated fear response is thought to
be essential to the pathophysiology of PTSD, as well as an associated lack of extinction of fear responses.
Extinction, rather than a “forgetting” of the trigger and response, has been demonstrated to be a different form
of learning, with new circuits over-riding existing fear responses. A number of studies in humans and rodents
have demonstrated that TBI can exacerbate fear responses, while also diminishing the ability to extinguish fearful
associations. Tremendous advances have recently been made in understanding how the memory of fear and
associated aspects such as contextual information is encoded in the amygdala and its associated neural
networks, how neuronal activity in this network interacts with oscillations to encode information, and how fear
related memories are recalled and extinguished. Surprisingly, however, there have been few reports to date of
how the neurophysiological mechanisms of fear encoding, recall, and extinction are affected by chronic TBI.
Elucidating the mechanisms by which TBI affects the circuitry encoding fear learning and extinction in the
amygdala and associated brain regions will lead to better targeted treatments, including neuromodulation, for
PTSD comorbid with TBI and other learning-associated cognitive dysfunction. Treating PTSD with Deep Brain
Stimulation (DBS, a form of neuromodulation) is being tested in Veterans, and it is essential to develop animal
models of this clinical intervention, including the potential influence of TBI on behavioral outcomes. Therefore,
the overall objective of the current application is to determine how the encoding of fear in extended amygdalar
circuitry is exacerbated following TBI, and to utilize electrical stimulation to restore normal balance to this system,
enhancing extinction and potentially restoring cognition. As the limbic system underlies many forms of cognition,
learning and memory, this may have broader implications in chronic TBI as well. Our central hypothesis is that
TBI disrupts normal communication between the amygdala and the hippocampus underlying fear associated
memory which leads to overexpression of fear responses, an inability to extinguish learned fear in chronic TBI,
and that this network imbalance can be rectified with neuromodulation. We will test the above hypotheses first
by determining the effects of chronic TBI-induced disruption on the circuitry underlying fear responses and
cognitive tasks in rats using...

## Key facts

- **NIH application ID:** 10853792
- **Project number:** 2I01RX002705-06A1
- **Recipient organization:** PHILADELPHIA VA MEDICAL CENTER
- **Principal Investigator:** John Allen Wolf
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2018-04-01 → 2028-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10853792

## Citation

> US National Institutes of Health, RePORTER application 10853792, Neuromodulation as a Therapy for PTSD following Chronic TBI (2I01RX002705-06A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10853792. Licensed CC0.

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