Project Summary Epilepsy is the third most common chronic neurological disorder, affecting about 3 million persons in the USA. Approximately 30% of patients remain refractory to medical treatment. Sudden unexpected death in epilepsy (SUDEP) occurs in at least 1:1000 people with epilepsy annually. This risk increases to ~1:150 per year for individuals with poorly controlled and severe seizures, and these risk statistics are thought to be underestimated. In terms of person years lost, SUDEP is second only to stroke. Although some risk factors have been elucidated, the unpredictability of SUDEP has contributed to major challenges in human studies. Thus, it is unknow whether systems necessary to promote survival deteriorate and permit SUDEP. The goal of this proposal addresses this critical need. We propose the innovative idea that susceptibility to SUDEP is progressive. We aim to identify whether systems necessary for survival become unstable prior to death, and thus permit death. Understanding how survival systems fail will identify targets for treatment strategies to postpone or prevent SUDEP. We capitalize on our published and novel findings regarding the molecular and physiological changes that precede SUDEP and contribute to susceptibility. Here, using a preclinical mouse model of SUDEP, combined whole body plethysmography and EEG-EMG-ECG recording techniques and ex vivo slice electrophysiology, we will employ innovative approaches and analytical methods to determine whether progressive impairment of survival responses precede SUDEP. In this application, we continue the journey to highly novel and translatable solutions to a major human health problem.