Epilepsy is classified by recurrent seizures caused by synchronous brain activity and affects more than 1% of the population. Approximately one-third of patients do not respond to anti-epileptic medications and may require surgical interventions such as tissue resection or electrical stimulation. Unlike with resection, in which about half of epilepsy patients become seizure free, very few patients achieve seizure freedom through stimulation therapy. Stimulation mechanisms in the context of epilepsy remain unclear. In this work, I will use basic science approaches and clinical electrophysiology to uncover these mechanisms at the cellular and network level. Using a slice electrophysiology preparation from a kainic acid-treated rodent model of temporal lobe epilepsy, I will apply phase-locked, low-frequency, high-frequency, ultra-high-frequency, and aperiodic stimulation to identify optimal approaches to arrest seizures. Further, I will uncover mechanisms of seizure arrest through two-photon microscopy and calcium imaging. I will explore seizure arrest mechanisms at the network level in human patients using human electrophysiology, computational modeling, and connectivity analysis. I will correlate seizure reduction in epilepsy patients with functional and structural connectivity metrics for patients implanted with NeuroPace responsive neurostimulation leads and measure network responses to single-site stimulation during stereo-electroencephalography. I will receive training from mentors focused on epilepsy from two disciplines: human electrophysiology under functional neurosurgeon Dr. John Rolston, director of stereotactic and functional neurosurgery, and slice electrophysiology under Dr. Karen Wilcox, chair of the Pharmacology and Toxicology department. Dr. Wilcox, who has a long history in mechanisms of epileptogenesis and anti-epileptic drug discovery, will train me in basic science techniques in slice electrophysiology and calcium imaging to uncover cellular mechanisms of seizure arrest using stimulation therapy. Training under Dr. Rolston will enable me to conduct human subjects research, collect intracranial neural data, and isolate stimulation of epileptic brain circuits correlated with positive clinical outcomes to guide novel stimulation strategies to be used in the clinic. Training under Dr. Wilcox and Dr. Rolston will enable mechanistic discoveries of seizure arrest using neuromodulation and lead to their translation into epilepsy patients in the clinic. Additionally, the interdisciplinary influence from each sponsor will help shape a multi-faceted understanding of seizure arrest mechanisms, from the cellular level using in vitro electrophysiology to the neural circuit using network connectivity approaches. Understanding stimulation mechanisms from cellular and network perspectives will allow the translation of evidence-based stimulation strategies into the clinic and improvements in clinical outcomes.
Understanding of stimulation mechanisms for seizure arrest is lacking, especially since relatively few patients achieve complete seizure freedom with stimulation therapy. An improved understanding on how stimulation can arrest seizures on the cellular and network level will guide stimulation strategies for medication-resistant patients, a patient population with the most challenging cases of epilepsy. This analysis will identify cellular mechanisms and optimal network targets of stimulation that may guide surgical targeting and improve clinical outcomes for epilepsy patients.
