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

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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 epileptogenesis and development of partial and generalized epilepsy using a combination of expert assessment and seizure detection algorithms using established procedures in the laboratory. We will collect blood serum, sleep data, imaging, and electrophysiology for these animals during this time course. In addition, pigs will be assessed for neurological and behavioral deficits using a hole-board task that we have developed in our laboratory. These are established procedures in the laboratory, and the CCI injury has led to PTE in a number. Pigs will be monitored up to a year post injury and will be assessed for progression of epileptogenesis and development of partial and generalized epilepsy using a combination of expert assessment and seizure detection algorithms. Post-mortem neuropathology will be performed in order to compare the chronic neurodegeneration and hippocampal neuropathology with the outcomes of the electrophysiology, as well as the blood biomarkers. This proposal will therefore compare PTE outcomes in two large animal TBI models (focal and repetitive mTBI), leading to a translational platform for mechanistic investigation and therapeutic development in order to benefit those Veterans suffering from PTE, and to develop prognostic markers for those with TBI yet to develop PTE.