Interactions of traumatic brain injury with pre-existing mild epilepsy on thalamocortical dysfunction, sensory processing, and seizures

Veterans Health Administration, Decatur PA

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Abstract

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.