Prevention of seizure-induced sudden death by periaqueductal gray stimulation

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PROJECT ABSTRACT Epilepsy is a common and serious brain disorder that can be fatal. The risk of sudden death is 24 times greater in epilepsy patients than the general population, and sudden unexplained death in epilepsy (SUDEP) ranks 2nd highest among neurologic diseases in potential years of life lost. There are currently no preventative treatments for this devastating epilepsy sequelae. Therefore, research into mechanisms for prevention of SUDEP is critically important, as indicated in the NINDS benchmarks. Death in most witnessed SUDEP cases results from generalized tonic-clonic seizures (GTCS) leading to terminal apnea. We have developed the DBA/1 mouse model of SUDEP, which mimics human SUDEP in that it exhibits GTCS and seizure-induced respiratory arrest (S-IRA) that leads directly to death. Several other labs have recently utilized this model. Research in DBA/1 mice led to the development of the serotonin theory of SUDEP, which has received positive support in recent studies in epilepsy patients. This hypothesis, first proposed by our lab is based, in part, on the findings that treatments which enhance the action of serotonin block seizure-induced death. The SUDEP models in which the hypothesis has been tested include the Dravet mice, which model Dravet syndrome, an intractable form of human epilepsy that has a high risk for SUDEP. Dravet mice are genetically modified to mimic human Dravet syndrome and also show sudden death due to S- IRA. Dravet mice exhibit heat-induced seizures, and death can be prevented by timely resuscitation similar to DBA/1 mice. Importantly, in epilepsy patients non-fatal but significant respiratory deficits frequently occur after GTCS, and postictal apnea is the most common cause of human SUDEP. This proposal will utilize DBA/1 and Dravet mice to test preventative measures for SUDEP. Our recent neuroimaging studies in DBA/1 mice have provided suggestive evidence that a specific brainstem site- the periaqueductal gray (PAG)-may be critical in preventing seizure-induced death. The PAG is known to play a critical role to compensate for many types of non-epilepsy-related respiratory deficits. PAG stimulation is currently used in patients to treat chronic pain and will enhance respiration. We have preliminarily evaluated the effects of PAG stimulation and found that it enhances respiration in anesthetized DBA/1 mice. Therefore, we will explore if PAG electrical stimulation will enhance respiration and reverse S-IRA following seizures induced in behaving DBA/1 and Dravet mice. Aim 1: To explore if timely electrical stimulation of the PAG can prevent audiogenic seizure-induced respiratory arrest (S-IRA) and death in the DBA/1 mouse model of SUDEP. Aim 2: To examine if timely PAG electrical stimulation can prevent seizure-induced sudden death in the Dravet mouse model of SUDEP induced by elevated temperature.