Sleep state-dependent mechanisms of seizure-induced death

摘要 癫痫猝死(SUDEP)是导致癫痫患者死亡的主要原因 难治性癫痫。大多数SUDEP病例发生在夜间，在睡眠期间，但为什么这是 案件情况不明。有人提出，这些案件中的一部分可能是由于缺乏足够的 在夜间进行监督，并在癫痫发作后转播复苏努力。近期 有证据表明，这并不是故事的全部。有许多生理变化， 发生在睡眠中，这可能使睡眠相对无法忍受额外的生理侮辱 癫痫发作。癫痫引起的呼吸、心脏和觉醒机制的损害都是 与SuDEP有牵连。所有这些都受到睡眠状态依赖的调节。一大堆 有证据表明，神经递质5-羟色胺信号的异常在 苏德普。5-羟色胺也以依赖于睡眠状态的方式进行调节，并参与 调节呼吸、心脏活动、睡眠和觉醒，并可调节癫痫发作。 这项建议的主要目标是了解在睡眠中发生的癫痫发作是如何 致命的。在追求这一目标的过程中，我们将检验有关5-羟色胺参与 调控癫痫致死的状态依赖性。在目标1中，我们将确定癫痫发作如何 发生在睡眠时，呼吸功能失调。在目标2中，我们将确定癫痫发作是如何 发生在睡眠过程中的唤醒机制失调。最后，在目标3中，我们将确定如何 快速眼动睡眠对癫痫有保护作用。完成这些目标将提供一种理解 睡眠中癫痫发作是如何致命的，其中一些发现可能是直接的 可翻译到诊所，以帮助识别SUDEP的高危人群并实施 新的预防策略。这项工作还将为未来的项目奠定基础 更深入地研究这些机制。

ABSTRACT Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy. The majority of SUDEP cases occur at night, during sleep, but why this is the case in unclear. It has been proposed that a portion of these cases may be due to lack of adequate supervision during the nighttime and relayed resuscitation efforts following a seizure. Recent evidence suggests this is not the whole story. There are a number of physiologic changes that occur during sleep, that may make sleep relatively intolerant to the additonal physiologic insult of a seizure. Seizure-induced impairment of respiratory, cardiac, and arousal mechanisms have all been implicated in SUDEP. All of these are subject to sleep state-dependent regulation. A large body of evidence suggests that abnormalities in signaling of the neurotransmitter serotonin are important in SUDEP. Serotonin is also regulated in a sleep state-dependent manner, and is involved in the regulation of breathing, cardiac activity, and sleep and wakefulness, and can modulate seizures. The primary goal of this proposal is to understand how seizures that occur during sleep become fatal. In pursuing this goal we will test the overarching hypothesis that serotonin is involved in regulating the state-dependence of seizure-induced death. In Aim 1 we will determine how seizures that occur during sleep dysregulate respiratory function. In Aim 2 we will determine how seizures that occur during sleep dysregulate arousal mechanisms. Finally, in Aim 3 we will determine how REM sleep is protective against seizures. Completion of these aims will provide an understanding of how seizures that occur during sleep could be fatal, and some of the findings could be directly translatable to the clinic to aid in identification of persons at risk for SUDEP and in implemention of novel prophylactic strategies. This work will additionally lay the groundwork for future projects delving deeper into these mechanisms.