Anatol Bragin - US grants

DESCRIPTION (provided by applicant): Almost 200,000 new cases of epilepsy are diagnosed every year in the United States. Many of these are caused by an initial precipitating injury (IPI) (e.g status epilepticus, febrile seizures or traumatic brain injury). There is a need to develop interventions that could prevent the occurrence of epilepsy in these patients. The clinical challenge for testing and applying antiepileptogenic therapy is in identifying the subset of those who eventually became epileptic out of approximately 2 million individuals experiencing an IPI each year. The NINDS, in association with the AES, recently published a report identifying the most important research directions that should be undertaken to ultimately find cures for epilepsy. One of the 3 benchmarks considered as a top priority for the near future is the identification of biomarkers for epileptogenesis. At the present time, no biomarkers predictive of the likelihood of developing epilepsy after an IPI are available and this is an important reason why no clinical trials have identified an intervention during the latent period that clearly prevents the occurrence of epilepsy. The main goal of this proposal is to determine whether a new noninvasive electrographic putative biomarker of epileptogenesis in an animal model of chronic epilepsy can be consistently recorded during the latent period, and whether it can be used to reliably identify which animals later develop recurrent spontaneous seizures. The results of the proposed research could be used to facilitate assessment of antiepileptogenic interventions in patients. The putative biomarker we wish to study is an abnormality of the UP-DOWN State (UDS) EEG pattern. The features of the normal UDS pattern consist of an UP-phase and a Down-phase as a slow oscillation with a frequency of less than 1 Hz. The UP-phase is associated with prominent beta-gamma oscillations. The features of the pathological UDS pattern, which are seen only in epileptic animals include: 1- the occurrence of epileptiform events we have termed "UPspikes" during the UP-phase, and 2 - a prolongation of the UP-phase duration. We hypothesize that this pathological UDS pattern could be a valuable predictor of future seizure occurrence. We also propose to evaluate mechanisms of pathological change in the UDS pattern by analyzing the activity of principal cells and interneurons identified by juxtacellular labeling. We will focus our efforts on the analysis of the UDS electrographic pattern prior to pilocarpine induced status epilepticus and compare it to activity recorded during the latent period before spontaneous seizures occur. We anticipate that the identification of pathological features in the UDS EEG pattern will make them a valuable early diagnostic biomarker of epileptogenesis and predictor of later seizure occurrence. An understanding of the neuronal mechanisms underlying the pathological UDS EEG patterns will provide novel targets for future approaches to the treatment of epilepsy in its earlier stages, and help pave new ways to prevent epilepsy. PUBLIC HEALTH RELEVANCE: At the present time, no biomarkers predictive of the likelihood of developing epilepsy after a traumatic brain injury are available and this is an important reason why no clinical trials have identified an intervention during the latent period that clearly prevents the occurrence of epilepsy. Early diagnosis of progressive epileptogenesis with early intervention is important for more effective treatment options and disease management strategies. The goal of this proposal is to identify cellular mechanisms responsible for generation of UPspikes, which is a new biomarker of epileptogenesis.

Project Summary/Abstract Epilepsy is one of the most serious neurological disorders, with a low rate of successful treatment, and pharmacoresistant epilepsy is a major health burden on society. Preventive treatment is one way to make treatment more efficient and is why there is a need for biomarkers capable of predicting the development of epilepsy during its earlier stages. Early in our experiments, we discovered pathological high-frequency oscillations (pHFOs), which are reliable biomarkers of epileptogenesis. They are generated by clusters of pathologically interconnected neurons (PIN clusters) and reflect bursts of population spikes. In this proposal, we plan to analyze the mechanisms of the formation of PIN cluster networks, and anticipate that this study will improve our understanding of the mechanisms of epileptogenesis (Aim 1). However, a significant limitation of pHFOs as biomarkers for clinical use is that they require the implantation of electrodes into the brain. The current proposal also focuses on the search for noninvasive biomarkers, which could potentially be translated to clinical application. In Aim 2, we plan to investigate whether functional magnetic resonance imaging (fMRI) and diffusion tension imaging (DTI) parameters, such as fractional anisotropy (FA), are biomarkers of epileptogenesis. During data analysis, we will investigate whether changes of imaging parameters are better predictors of epileptogenesis than pHFOs. In our earlier publications we showed that pHFOs initially appear in the perilesional area. In Aim 3, we will test the hypothesis that the suppression of neuronal activity within the perilesional area will prevent the development of epileptogenesis. For this purpose, we will apply a new, recently developed DREADD technology that suppresses the discharges of neurons after binding with the adenovirus attached channels. This approach might open a new approach to the prevention of epilepsy development and identify novel targets for interventions to treat, prevent, and cure epilepsy.