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，可能致命。猝死的风险是24 癫痫患者的发病率是普通人群的几倍，并且不明原因的突然死亡 癫痫（SUDEP）在神经系统疾病中的潜在寿命损失排名第二。那里 目前还没有针对这种毁灭性癫痫后遗症的预防性治疗方法。因此，研究 正如 NINDS 所示，研究 SUDEP 的预防机制至关重要 基准。大多数目击 SUDEP 病例的死亡都是由全身性强直阵挛性癫痫发作引起的 (GTCS) 导致终末呼吸暂停。我们开发了SUDEP的DBA/1小鼠模型， 模仿人类 SUDEP，因为它表现出 GTCS 和癫痫引起的呼吸骤停 (S-IRA)， 直接导致死亡。其他几个实验室最近也使用了这种模型。 DBA/1 小鼠研究 导致了SUDEP血清素理论的发展，该理论得到了积极的支持 最近对癫痫患者的研究。我们实验室首先提出的这一假设部分基于 研究结果表明，增强血清素作用的治疗可以阻止癫痫发作引起的死亡。的 检验该假设的 SUDEP 模型包括 Dravet 小鼠，该模型 Dravet 综合征是人类癫痫的一种难治性形式，具有较高的 SUDEP 风险。德拉维特小鼠 经过基因改造以模仿人类 Dravet 综合症，并且还表现出因 S- 导致的猝死 爱尔兰共和军。 Dravet 小鼠表现出热诱发癫痫发作，及时复苏可以防止死亡 与DBA/1小鼠相似。重要的是，癫痫患者存在非致命性但显着的呼吸缺陷 经常发生在 GTCS 后，发作后呼吸暂停是人类 SUDEP 的最常见原因。这个 该提案将利用 DBA/1 和 Dravet 小鼠来测试 SUDEP 的预防措施。我们最近的 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 导水管周围灰质（PAG）部位对于预防癫痫引起的死亡可能至关重要。 PAG 是 已知在补偿多种非癫痫相关的呼吸缺陷方面发挥着关键作用。 PAG 刺激目前用于患者治疗慢性疼痛并增强呼吸。我们 初步评估了 PAG 刺激的效果，发现它增强了呼吸 麻醉 DBA/1 小鼠。因此，我们将探讨 PAG 电刺激是否会增强 在行为 DBA/1 和 Dravet 小鼠中诱导癫痫发作后的呼吸和逆转 S-IRA。 目标 1：探讨及时电刺激 PAG 是否可以预防听源性癫痫发作 SUDEP DBA/1 小鼠模型中的呼吸停止 (S-IRA) 和死亡。 目标 2：检查及时的 PAG 电刺激是否可以预防癫痫引起的猝死 高温诱导的 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.