Prevention of seizure-induced sudden death by periaqueductal gray stimulation

导水管周围灰质刺激预防癫痫发作引起的猝死

• 批准号: 10426656
• 负责人: CARL L FAINGOLD
• 金额: $ 22.13万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10426656
• 关键词: Affect; Animals; Apnea; Benchmarking; Brain; Brain Diseases; Brain Stem; Cause of Death; Cell Nucleus; Cessation of life; Chronic; Clinical; Clinical Trials; DBA/1 Mouse; Deep Brain Stimulation; Development; Electric Stimulation; Epilepsy; Exhibits; General Population; Goals; Human; Hypoxia; Implanted Electrodes; Inbred DBA Mice; International; Intractable Epilepsy; Intractable Pain; Lead; Magnetic Resonance Imaging; Mediating; Methods; Modeling; Mus; National Institute of Neurological Disorders and Stroke; Patients; Persons; Pharmacology; Play; Prevention; Preventive measure; Preventive treatment; Research; Respiration; Resuscitation; Risk; Role; Seizures; Serotonin; Site; Stroke; Structure; Sudden Death; Suggestion; Temperature; Testing; Time; Tonic - clonic seizures; Ventilatory Depression; audiogenic seizure; base; chronic pain management; dravet syndrome; experimental study; high risk; loss of function mutation; midbrain central gray substance; mouse model; nervous system disorder; neuroimaging; novel; novel strategies; premature; prevent; preventable epilepsy; respiratory; response; sudden unexpected death in epilepsy; theories; years of life lost

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.

项目摘要 癫痫是一种常见而严重的脑部疾病，可能是致命的。突然死亡的风险是24 癫痫患者的时代高于一般人群，突然无法解释的死亡 癫痫（SUDEP）在潜在生命的潜在几年中的神经系统疾病中排名第二。那里 目前尚未针对这种毁灭性癫痫后遗症进行预防治疗。因此，研究 如Nind所示，进入预防SUDEP的机制至关重要 基准。在大多数见证的SUDEP案件中，死亡是由普遍的强直性持续性癫痫发作引起的 （GTC）导致末端呼吸暂停。我们已经开发了SUDEP的DBA/1鼠标模型， 模仿人类Sudep，因为它表现出GTC和癫痫发作诱导的呼吸停滞（S-IRA） 直接导致死亡。其他几个实验室最近使用了该模型。 DBA/1小鼠的研究 导致SUDEP的5-羟色胺理论的发展，该理论在 最近对癫痫患者的研究。我们实验室首先提出的这个假设部分基于 研究结果可以增强5-羟色胺阻滞诱发死亡的作用。这 已检验假设的SUDEP模型包括Dravet小鼠，哪个模型 Dravet综合征，一种顽固的人类癫痫病，对SUDEP的风险很高。 Dravet小鼠 在遗传上修改为模仿人Dravet综合征，并且由于S-而显示出猝死 艾拉。 Dravet小鼠表现出热诱导的癫痫发作，可以通过及时复苏来预防死亡 类似于DBA/1小鼠。重要的是，癫痫患者非致命但明显的呼吸缺陷 经常在GTC之后发生，而帖子呼吸暂停是人类SUDEP的最常见原因。这 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小鼠中的神经影像学研究提供了暗示性的证据表明特定的脑干 位点 - 邻齿灰色（PAG） - 可能对防止癫痫发作诱发的死亡至关重要。 PAG是 众所周知，可以弥补许多类型的非癫痫相关呼吸缺陷的关键作用。 目前在患者中使用PAG刺激来治疗慢性疼痛，并会增强呼吸。我们 已经初步评估了PAG刺激的作用，并发现它增强了呼吸 麻醉的DBA/1小鼠。因此，我们将探讨PAG电刺激是否会增强 在行为DBA/1和Dravet小鼠中引起的癫痫发作后的呼吸和反向S-IRA。 目的1：探索是否及时对PAG进行电刺激可以防止听力癫痫发作诱导 SUDEP的DBA/1小鼠模型中的呼吸停滞（S-IRA）和死亡。 目的2：检查是否及时PAG电刺激可以防止癫痫发作诱发的猝死 由温度升高引起的SUDEP的Dravet小鼠模型。