Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy and is two to four times as common as sudden infant death syndrome (SIDS). Because the mechanisms responsible for SUDEP have not been clearly defined, there are no specific treatments to prevent it. Observations from human and animal studies indicate that seizure-induced respiratory arrest typically precedes asystole, and that many patients experience varying degrees of respiratory depression, autonomic dysfunction, and impaired arousal following seizures. There is a fundamental gap in understanding how seizures do this, and why only a small fraction of seizures lead to death. Serotonin (5-HT) neurons are central CO2 chemoreceptors (CCR) that regulate breathing, autonomic function, and arousal. Patients with low interictal CCR are more hypercapnic following a generalized tonic-clonic seizure (GTCS), and seizures may depress CCR, an effect that can be measured with the hypercapnic ventilatory response (HCVR) test. Impairment of CCR by seizures may contribute to autonomic dysfunction and impaired arousal after GTCS, increasing the risk of SUDEP. The long-term goal is to develop new treatments to prevent SUDEP by elucidating the mechanisms responsible for seizure-induced respiratory depression, autonomic dysfunction, and impaired arousal. This knowledge will also lead to novel biomarkers to identify patients at highest risk. The objective here is to characterize the relationship between seizure-induced blunting of CCR and postictal respiratory depression, autonomic dysfunction, and impaired arousal. The central hypothesis is that seizures inhibit 5-HT neurons in a subset of patients, and this leads to impairment of the ability to detect hypercapnia and to initiate respiratory, autonomic and arousal responses to restore blood gas homeostasis. This hypothesis has been formulated based on human and animal data from the applicants’ own laboratories and will be tested with the following Specific Aims. (1) Characterize the role of CCR in postictal respiratory control and the acute effect of seizures on CCR. (2) Determine how CO2 affects interictal autonomic function and how this is altered by seizures. (3) Determine whether seizures impair the ability of CO2 to hasten recovery of consciousness in the postictal state. Patients admitted to the epilepsy monitoring unit for video EEG study will undergo HCVR testing during the interictal period and several times after seizures to determine the time course of impaired CCR and its effect on cardiorespiratory and autonomic function. We will also measure the effect of CO2 on arousal from sleep and on recovery of consciousness after GTCS, and relate these measures to CCR. This approach is innovative because it is the first to directly examine how inhibition of serotonin neuron function by seizures affects the respiratory, autonomic, and arousal response to CO2. The proposed research is significant because ...