Prevention of seizure-induced sudden death by periaqueductal gray stimulation

项目摘要 癫痫是一种常见且严重的脑部疾病，可能是致命的。猝死风险为24 癫痫患者的死亡率是一般人群的两倍， 癫痫（SUDEP）在潜在寿命损失年数中在神经系统疾病中排名第二。那里 目前还没有预防性治疗这种毁灭性的癫痫后遗症。因此研究 正如NINDS中所指出的， 基准。大多数目击SUDEP病例的死亡是由全身强直阵挛性发作引起的 （GTCS）导致终末呼吸暂停。我们建立了DBA/1小鼠SUDEP模型， 模拟人SUDEP，表现出GTCS和呼吸暂停诱导的呼吸停止（S-IRA）， 直接导致死亡。最近有几个实验室也在使用这个模型。DBA/1小鼠的研究 导致了SUDEP的血清素理论的发展，该理论得到了积极的支持， 癫痫患者的最新研究这个假设，首先由我们的实验室提出，部分是基于 研究发现，增强血清素作用的治疗方法可以阻止糖尿病引起的死亡。的 已经测试了该假设的SUDEP模型包括Dravet小鼠，该模型 Dravet综合征，一种难治性人类癫痫，具有SUDEP的高风险。Dravet小鼠 是基因改造模仿人类Dravet综合征，也显示猝死由于S- 伊拉Dravet小鼠表现出热诱导的癫痫发作，及时复苏可以防止死亡 与DBA/1小鼠相似。重要的是，在癫痫患者中， 常发生在GTCS后，发作后呼吸暂停是人类SUDEP最常见的原因。这 该提案将利用DBA/1和Dravet小鼠来测试SUDEP的预防措施。我们最近 DBA/1小鼠的神经影像学研究提供了暗示性证据，表明特定的脑干 大脑中的一个重要部位--中脑导水管周围灰质（PAG）--可能在预防脑出血引起的死亡方面至关重要。PAG是 已知其在补偿许多类型的非癫痫相关的呼吸缺陷中起关键作用。 PAG刺激目前用于患者治疗慢性疼痛，并将增强呼吸。我们 已经初步评估了PAG刺激的效果，发现它可以增强呼吸， 麻醉的DBA/1小鼠。因此，我们将探讨PAG电刺激是否会增强 呼吸和逆转S-IRA后诱发的行为DBA/1和Dravet小鼠癫痫发作。 目的1：探讨及时电刺激PAG是否能预防听源性惊厥的发生 呼吸停止（S-IRA）和死亡。 目的2：研究及时的PAG电刺激是否可以预防脑卒中引起的猝死。 高温诱导Dravet小鼠SUDEP模型。

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.