PROJECT SUMMARY Epilepsy is a neurological disorder that is characterized by spontaneous, recurrent seizures. However, a significant population (~1/3rd) of focal epilepsy patients does not respond to anti-epileptic drugs. Furthermore, alternative treatment strategies (such as electrical stimulation or resective surgery) depend on accurate localization of the seizure onset zone, which can be difficult with current technology. This may be due to poor spatial resolution of clinical recording modalities, such as electroencephalography. To this end, this project seeks to identify unique markers that arise from activity within the seizure onset zone and thus, elucidate the mechanisms responsible for seizure recruitment in drug-resistant focal epilepsy. In the long term, the results generated by this research will not only increase our overall understanding of epilepsy pathology, but also refine individualized therapies for drug-resistant focal epilepsy patients. The overall hypothesis is that the spiking activity from the seizure onset zone interacts with the local field potential of the macroscopic penumbra and that this relationship is unique in human focal epilepsy. To fulfill this objective and test the overall hypothesis, the following aims will be pursued: (1A) Determine the spatiotemporal spike-triggered average between spiking activity and the LFP by accounting for both spike timing and location. (1B) A mathematical model of seizure activity within and outside of the seizure onset zone will be developed to corroborate the results. (2A) Sort spikes from the ictal epoch into excitatory and inhibitory populations using template- matching and modeling of convex hull changes. (2B) Investigate the spatiotemporal dynamics of excitatory- inhibitory populations during a seizure. The results from this analysis will yield a powerful multi-scale characterization of network states during and around seizure events. The computational approaches that will be utilized will probe specific mechanisms that underlie seizure onset, propagation, and termination. The outcomes of this proposal may have translational implications that facilitate identification of the seizure onset zone or the development of novel therapeutic strategies, such as intracortical stimulation approaches. This proposed research will be conducted in a collaborative and interdisciplinary environment with significant training potential as it includes growth in opportunities for mentorship, collaborations, publications, grantsmanship, and communication. Specifically, this research will be conducted under the mentorship of experts at the University of Chicago in computational epilepsy work. This training experience will also provide opportunities to build expertise in scientific inquiry, epilepsy pathology, computational modeling, theoretical neuroscience, nonlinear dynamics, and data analysis.