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Principal Investigator: MARTIN J GALLAGHER
Organization: VETERANS HEALTH ADMINISTRATION
Fiscal Year: 2024
Funding agency: Veterans Affairs
During the recent conflicts in Iraq and Afghanistan, thousands of service personnel suffered mild traumatic
brain injuries (mTBIs), those that do not cause gross anatomical damage or hemorrhage and produce only
brief periods of altered awareness. Although these brain injuries are classified as “mild,” many veterans with
mTBI experience short- and long-term neurological dysfunction including epilepsy and somatosensory (SS)
dysregulation that may underlie pain/headache. We urgently need new mTBI therapies.
Most previous investigations of mTBI pathophysiology focused on injury effects on the histology, physiology
and cellular biology of neurons in small brain regions near a point of focal injury. However, explosive blasts
impacting widespread brain regions comprise most modern combat mTBIs and thus there is often no single
point of focal injury. Moreover, new data suggest that dysfunction of large-scale brain networks (spatially
separate, but functionally connected brain regions) lead to epilepsy and SS processing disorders. Therefore, it
is critical to determine the effects of mTBI on large scale brain networks and if therapeutically modulating
network physiology (e.g. brain stimulation) reduces seizures and their comorbidities. Previous studies in
nontraumatic patients and animal models demonstrated that abnormal physiology within SS thalamocortical
(ssTC) and somatosensory corticocortical (ssCC) networks are strongly associated with focal and generalized
seizures and SS processing disorders. Therefore, it is likely that mTBI will also alter ssCC and ssTC
physiology to produce epilepsy and SS dysregulation.
Genetic risk factors likely play an important role in the development of post-mTBI seizures. A family history
of epilepsy increases the risk of post-mTBI epilepsy from 1.5-2.2-fold to 5.8-fold risk and epidemiology studies
suggest that 9.3% mTBI patients have a first degree relative with epilepsy. To develop network-specific
therapies (e.g. neurostimulation), it is necessary to know whether mTBI causes different epileptogenic changes
in ssTC and ssCC networks in genetically susceptible individuals.
This application will test the overarching hypothesis that mTBI alters the activity and
connectivity of ssCC and ssTC networks to produce post-mTBI seizures and SS dysfunction and that these
changes are greater in subjects with genetic vulnerabilities. This hypothesis will be tested using a top-down
clinically translatable approach to determine the effects of mTBI on 1) seizures/SS function (Aim 1), 2) long-
range ssCC connectivity using high density EEG (HdEEG, Aim2 A/B) and 3) ssTC connectivity by
HdEEG/stereotactic EEG (SEEG, Aim 2C). Importantly, (Aim 3) primary somatosensory cortex (S1) activity will
then be causally manipulated to determine the effects on ssCC/ssTC network connectivity and seizures and to
extend the observations beyond mere correlation and provide a foundation for future studies of network-
specific modulation therapies (e.g. neurostimulation). The hypothesis will be tested using wild type (WT) mice
as well as the PI’s novel mouse model with heterozygous (Het) expression of a human epilepsy risk gene
(Gabra1A322D). Aim 1 will determine the effects of mTBI on seizures and somatosensory function in WT and
Het mice. Early and long-term effects of mTBI on (A) seizures quantified on continuous EEG monitoring and
(B) SS function measured by neurobehavioral testing. Aim 2 will elucidate the effect of mTBI on ssTC and
ssCC networks in WT and Het mice. The PI’s established HdEEG method will be compared with an innovative
minimally invasive MXene HdEEG arrays for determining ssCC network activity and connectivity in mTBI
subjects. Next, the effects of mTBI on ssCC (B) and ssTC (C) network physiology with HdEEG (B) and
HdEEG/SEEG (C) recordings will be determined. Finally, aim 3 will determine the effects of S1
neurostimulation on post mTBI ssCC/ssTC network connectivity and seizures using A) open loop and B)
closed loop stimulation.
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