Post Traumatic Nonconvulsive Epileptiform Activity

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DESCRIPTION (provided by applicant): The main aim of this proposal is to study the incidence of epileptiform discharges and seizures that occur during coma after traumatic brain injury, possible mechanisms of generating epileptiform activity and the neurochemical consequences of this activity. The investigator has made exciting preliminary observations that post-traumatic nonconvulsive seizure activity on continuous electroencephalography (EEG) occurs frequently, is associated with adverse neurochernical changes and increases mortality. Previous animal brain injury models have documented neurochernical and ionic perturbation with an energy crisis and compensatory hyperglycolysis. At the same time there is a selective loss of neuronal inhibition (GABA, y-amino-butyric acid, containing cells) and reduced extracellular magnesium that leads to a decrease in seizure threshold. As a consequence of early post traumatic seizures, cellular energy demand may be increased and lead to secondary injury of cells that survived the initial trauma. Preliminary studies demonstrate an increased incidence of EEG-defined seizures. and epileptiforin activity, however the relationship between early post-traumatic epileptiform activity, the disordered neurochernical state, increased glucose metabolism and secondary cellular injury remain unknown. Thus the central hypothesis of this grant is that early post-traumatic nonconvulsive epileptiform activity is common and leads to further hyperglycolytic neurochernical events (increased lactate, glutamate and decreased glucose) and additional neuronal membrane injury. The specific aims of this proposal will be: (1) delineate the incidence rate, type and duration of early EEG-defined post-traumatic epileptiform activity (TEEA); (2) define the mechanistic influence of impaired neuronal inhibition in generating TEEA; (3) determine if TEEA results in a hyperglycolytic response; and (4) determine if TEEA leads to additional brain tissue membrane injury, as determined by time-locked increases in extracellular glycerol. The application is intended to pen-nit the candidate to gain important didactic education in research and statistical methods and experience in conducting a human-based basic research paradigm complemented by future animal models. The hypothesis and unique approach come at a crucial time of failed clinical trials and address an important new therapeutic target.