Targeting pathologic spike-ripples to isolate and disrupt epileptic dynamics

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Project Summary Epilepsy is the world’s most common, serious brain disorder, affecting nearly 50 million people worldwide. For one-third of patients, seizures remain poorly controlled despite maximal medical management. In these patients, seizures often arise from a localized brain region, and neurosurgical interventions are the most effective treatment option. When successful, surgical interventions provide cure from seizures, and also prevent or reverse the disabling consequences of uncontrolled seizures. Critical to successful intervention is accurate identification of the core tissue responsible for generating seizures (i.e., the epileptogenic zone). Traditionally, this tissue would be surgically resected, but modern approaches aim to focally disrupt this tissue with targeted electrical stimulation (i.e. neuromodulation). Improvements in epilepsy care are now limited by (i) the inability to accurately identify the epileptogenic zone; (ii) a limited understanding of the mechanisms underlying epileptiform activity; (iii) a lack of understanding of how to target these mechanisms with neurostimulation. The most common approach to identify the epileptogenic zone is through continuous recording of a patient’s cortical electrical activity to capture seizures. However, because seizures are infrequent, this approach is expensive, time consuming, and unpleasant for patients. Moreover, this approach often fails to identify the epileptogenic zone, resulting in unsuccessful neurosurgical intervention in 20-70% of cases. To address this, interictal biomarkers of the epileptogenic zone that manifest between seizures are required. Two such biomarkers have been proposed: (a) interictal discharges or spikes, and (b) high frequency oscillations or ripples. While both signals have been extensively studied, neither accurately delimits the epileptogenic zone. Spikes are specific for epilepsy, but too spatially diffuse to identify the epileptogenic zone. Ripples are spatially focal, but represent both pathologic and physiologic processes. We address these limitations by focusing on the simultaneous occurrence of a spike and ripple, “spike-ripple” discharges, as an improved biomarker for the epileptogenic zone. Spike-ripples commonly occur in patients with epilepsy, improve the spatial specificity of spikes for the epileptogenic zone, and disentangle physiologic from pathologic ripples. Our interdisciplinary team will apply expertise in epilepsy, neurophysiology, neurosurgery, animal experiments, modeling, and statistics to: (i) develop a fully automated spike-ripple detector and compare its clinical utility to predict surgical outcome to spikes and ripples alone, (ii) identify the biological mechanisms that generate spike-ripple discharges using novel voltage imaging techniques in animal models combined with computational models; and (iii) develop principled neurostimulation protocols to disrupt the mechanisms that generate spike-ripples. Completion of these Aims will represent significant progress towards resolving fundamental questions in modern epilepsy research, an understanding of mechanisms in the core epileptogenic network that generate spike-ripples, and a principled approach to neurostimulation to focally disrupt these pathologic dynamics.