Chronic stress increases the probability of autoresuscitation failure in preclinical sudep

The National Institute of Neurological Disorders and Stroke awarded Creighton University $497,267 on September 1, 2026, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853) to investigate mechanisms of autoresuscitation failure in sudden unexpected death in epilepsy (SUDEP).

The research project, titled "Chronic Stress Increases the Probability of Autoresuscitation Failure in Preclinical SUDEP," addresses a gap in understanding why approximately 30 percent of individuals with refractory epilepsy fail to spontaneously recover breathing after seizure-induced hypoxic and hypercapnic blood gas fluctuations. The central hypothesis tests whether chronic stress increases the probability of autoresuscitation failure by promoting maladaptive modulatory control of brain regions and circuitries critical for successful recovery. The project will use two clinically relevant animal models of SUDEP to delineate mechanisms driving autoresuscitation failure, with findings intended to inform risk assessment and identify therapeutic opportunities.

The period of performance runs from September 1, 2026, through August 30, 2031. Work is performed in Omaha, Nebraska.

Abstract

Approximately 30% of people with epilepsy are refractory to current anti-seizure medications and sudden unexpected death in epilepsy (sudep) occurs in ~1:150 per year for individuals with severe refractory generalized convulsive seizures (GCS). The long-term goals of our research program are to identify modifiable factors that increase sudep risk. Evidence from the multi-center mortemus study on sudep indicates that patients experienced a series of events promoting hypoxic and hypercapnic (HH) fluctuations in blood gases, from which they were unable to autoresuscitate and succumbed to terminal apnea. However, factors that increase the likelihood that someone may fail to autoresuscitate are not well understood. The objective of the proposed project is to elucidate factors that increase the probability of autoresuscitation failure. The central hypothesis is that the addition of chronic stress will increase the probability of autoresuscitation failure and sudep risk. Our specific aims will test the hypotheses that stress promotes maladaptive modulatory control of key regions and circuitries that are crucial for successful autoresuscitation that will ultimately lead to a failed response. Upon conclusion, we will have delineated mechanisms that drive autoresuscitation failure in the context of epilepsy in two clinically relevant animal models of sudep. This information will offer new research avenues for understanding sudep, assessing risk and identifying therapeutic opportunities.