Breathing Rescue for SUDEP Prevention (BreatheS)

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PROJECT SUMMARY Sudden unexpected death in epilepsy (SUDEP) is a devastating complication of epilepsy and a leading cause of premature death in persons with chronic uncontrolled epilepsy. Despite the major impact on life expectancy in these individuals, no targeted SUDEP preventive strategies currently exist. Most SUDEPs occur after a generalized convulsive seizure, and victims are typically found in bed in the prone position. Until recently, SUDEP was thought to be due to cardiovascular failure, but research on patients who died while being monitored in hospital epilepsy units reveal that most SUDEP is due to post-convulsive central apnea. Crucially, a three-minute post convulsive window of opportunity was identified, beyond which the terminal cascade of respiratory and cardiac failure appears irrevocable. By advancing our understanding of forebrain breathing networks, we can develop neuromodulatory strategies for respiratory facilitation and apnea rescue that may prevent SUDEP during this critical time window. The objective of this project is to understand forebrain modulation of breathing by using anatomically precise intracranial stereotactic electroencephalography (SEEG) data that can determine optimal stimulation paradigms for breathing enhancement. The study population are patients with medically refractory epilepsy undergoing 1) intracranial SEEG evaluation with implanted depth electrodes for epilepsy surgery, and 2) simultaneous polygraphic cardiorespiratory monitoring of thoracoabdominal excursions, nasal and oral airflow, oxygen saturation, carbon dioxide, plethysmography and EKG. To achieve this goal, in Aim 1, we will identify forebrain regions in which electrical activity is coupled with respiratory activity by using spontaneous and task-related breathing data and monitoring simultaneous brain signal dynamics. We will further analyze functional connectivity to graph networks as a function of breathing tasks, in order to establish network hubs as candidate regions for stimulation targets and in order to reveal a comprehensive cortical connectome. In Aim 2, we will apply electrical stimulus to these regions to assess neuromodulatory effects on respiration. Effective stimulation paradigms/sites will be tested in the immediate post-convulsive state in the latter part of this study, to prove feasibility of neuromodulation in this state, and these seizures will be compared with non-stimulated seizures obtained from the NINDS Center for SUDEP Research, using 1:5 matching (matched for age, sex, SUDEP risk factors-duration of epilepsy and GCS frequency). Our project will identify effective stimulation sites and paradigms for breathing rescue as well as will establish feasibility of stimulation approaches in the post- convulsive state. Our results will set the stage for a clinical trial of efficacy of neuromodulation for apnea rescue as potential anti-SUDEP therapy, in individuals who at high SUDEP risk. This work will also provide insights into potential treatment of central apnea associated with other neurological diseases, heart failure, and stroke. .