Abstracts

Rationale: Sudden Unexpected Death in Epilepsy (SUDEP) affects ~18% of people with epilepsy and ~50% of those with drug-resistant epilepsy. The cause is unknown although it is believed that respiratory depression may play a significant role. Spreading Depolarization (SD) is a neurophysiological phenomenon of long-lasting neuronal inactivity that follows a large-scale depolarization of brain cells, propagating through the brain at approximately 3-5 mm per minute. We hypothesize that during fatal seizures SD invades respiratory control centres in the brainstem, propagating from neighboring brain regions that normally act as gates to SD propagation. Methods: SD causes swelling in the brain tissue invaded, which alters the diffusion properties of cerebral spinal fluid at the cellular level. We have visualized the spatiotemporal propagation of SD across the entire brain with Diffusion-Weighted Magnetic Resonance Imaging (DW-MRI). Combining DW-MRI with EEG monitoring and both electrical and targeted optogenetic brain stimulation we examined the propagation of SD during seizures in a mouse model of Sudden Unexpected Death in Epilepsy (SUDEP). Results: This has identified brain regions susceptible to SD during fatal and non-fatal seizures in vivo, which we correlated with intrinsic excitability and synaptic activity in those brain regions in vitro. Further, utilizing advanced MRI tractography we determined whether the integrity of white matter tracts in the brain are altered  in the SUDEP model allowing for diffusional spread of SD to the brainstem. Conclusions: Specific regions in the brain of a mouse model of SUDEP demonstrate functional abnormalities making them susceptible to SD during seizures. Funding: S.M.C. is funded by the CURE - Taking Flight Award and was previously funded by the BC Epilepsy Society.T.P.S. is funded by the Canadian Institutes of Health Research and is a Tier 1 Canada Research Chair.