Cellular and network mechanisms of epilepsy and neuromodulation summary epilepsy is the world's most common, serious brain disorder, affecting nearly 50 million people worldwide, and accounting for 1%…

Cellular and network mechanisms of epilepsy and neuromodulation summary epilepsy is the world's most common, serious brain disorder, affecting nearly 50 million people worldwide, and accounting for 1% of the global burden of disease. Seizures occur sporadically and paroxysmally in epilepsy and several interictal biomarkers that are present between seizures have been identified to aid in management. Three major interictal biomarkers for seizure risk have been identified, including epileptiform discharges (SPIKES), high- frequency oscillations (RIPPLES) and their CO-occurrence known as spike RIPPLES. We and others have demonstrated that spike RIPPLES in human scalp EEG and stereotactically placed intracranial EEG recordings are the most specific biomarkers to isolate epileptogenic cortex and predict seizure risk. While clinically significant, the neural mechanisms of this epilepsy biomarker remains unknown, and its relationship to seizure generation is unclear. Further, neuromodulation through electrical stimulation is a rapidly expanding and promising treatment option for patients with drug-resistant refractory epilepsy, but the lack of understanding of the neuronal mechanisms has prevented a principled approach in identifying optimal stimulation parameters for consistent clinical response. To address these challenges, we formed an interdisciplinary team with expertise in epilepsy, human neurophysiology, neurostimulation, animal experiments, modeling, and statistics. We will use cutting- edge cellular membrane voltage imaging that we recently pioneered, in conjunction with traditional optogenetics and local field potential recordings, to probe the cellular and network mechanisms of spike RIPPLES and seizures in cortical epilepsy mouse models. Further, we will examine the real-time neuronal impact of clinical electrical stimulation parameters across frequencies and durations on this epilepsy biomarker and seizure, using cellular voltage imaging, free of electrical stimulation artifacts, and compare the impact of stimulation delivered locally at the cortical epileptogenic zone versus at a thalamic "hub" within the epileptic network. At the completion of the study, we hope to elucidate the neuronal mechanisms underlying epileptic activity, reveal insights on how spike RIPPLES relate to seizure, and gain progress towards a principled approach to neurostimulation with an ultimate goal of improving care for patients with epilepsy.