# Chronic Focal and Diffuse Traumatic Brain Injury: Mechanisms Underlying Epileptogenesis and Progressive Dysfunction

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

## Abstract

Military traumatic brain injury (TBI) is complex, often involving both diffuse and multi-focal components, and/or
repetitive TBI. While the high incidence of epilepsy following TBI in Veterans is well known, PTE is often resistant
to standard anti-epileptic therapeutics. In addition, the mechanisms underlying the transition from trauma to
injury are unclear, making new treatment development challenging. However, the long gestation period between
injury and seizure development (epileptogenesis) make this process an attractive target for intervention. Due to
the key role of network localization of hyperexcitability in epileptogenesis, we propose that a large animal model
(pig) with a gyrencephalic brain and complex white matter pathways may be the only way to model these injury
phenotypes and epileptogenesis accurately. We will therefore utilize our large animal pre-clinical model of brain
injury induced epileptogenesis in order to investigate the underlying mechanisms contributing to the transition to
PTE, and investigate whether repetitive TBI can also induce these network states. Early epileptiform activity,
blood biomarkers of axonal and glial pathology, and white matter imaging will be utilized to assess their predictive
value for prognosis and risk stratification. This unique combination of large animal TBI models,
electrophysiology, neuropathology and biomarkers will allow us to address the fundamental mechanisms of
epileptogenesis following trauma as well as develop predictive models of PTE development. Our analyses will
allow for greater understanding of the pathological and neurophysiological mechanisms whereby trauma leads
to epilepsy. In addition, an understanding of the effects of this progression on waking behavior and mechanisms
underlying sleep disruption are important questions for treating Veterans with PTE related chronic dysfunction.
We will therefore characterize and validate a PTE model of controlled cortical impact injury and compare with
diffuse, repetitive injury. We will also examine the progression of sleep and behavioral dysfunction associated
with TBI induced epileptogenesis, and compare biomarkers for PTE (blood, sleep, neuroimaging, early
electrophysiology) with electrophysiological outcomes to develop predictors of PTE development in the VA
population. We will also correlate chronic post-mortem neuropathology with electrographic characterization and
behavioral outcomes in order to develop mechanistic understanding of progression for future treatment
development. In order to carry out these goals, we will compare a focal injury model (CCI) with the repetitive,
sagittal injury in order to assess the long-term development of PTE and hyperexcitability. We will chronically
implant pigs following injury with cortical and hippocampal electrodes, and characterize epileptogenesis and
seizure progression over 9 months to 1 year. Pigs will be monitored chronically using video-EEG and will be
assessed for progression of epilepto...

## Key facts

- **NIH application ID:** 11091408
- **Project number:** 5I01RX003498-05
- **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:** 5
- **Project period:** 2020-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11091408

## Citation

> US National Institutes of Health, RePORTER application 11091408, Chronic Focal and Diffuse Traumatic Brain Injury: Mechanisms Underlying Epileptogenesis and Progressive Dysfunction (5I01RX003498-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11091408. Licensed CC0.

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