Sequence of physiological events during oxygen conserving reflex activation leading to sudden death in epilepsy

项目摘要 癫痫猝死(SUDEP)是癫痫的一种致命并发症，可导致约 每年有4000名美国人。SUDEP很难研究，因为虽然很常见，但它通常发生在人们看不到的情况下。 现有的有限临床数据表明，SUDEP是一种直接发生的心肺衰竭。 在癫痫发作后。心肺功能在很大程度上受自主神经系统(ANS)的调节。 交感神经和副交感神经的自主神经系统通路通常以相反的方式运作，所以共同 激活的情况很少。在保氧反射家族(OCR)中，两条通路共同激活以诱导 屏气(呼吸暂停)、心率减慢(心动过缓)和周围血管变窄 (血管收缩)。呼吸暂停阻碍了吸入。心动过缓可以保存氧气。血管收缩优先考虑 血液将氧气输送到重要器官(即心脏和大脑)。癫痫引起的自主神经功能障碍， 再加上外部触发的OCR可能导致癫痫患者猝死 (SUDEP)。为了阐明生理参数、OCR和猝死之间的因果关系， 我们建议在健康的麻醉状态下测量各种保氧反射的生理基线。 目标1中的动物。这将为以下各项之间的时间关系建立基线：心脏、呼吸和 健康动物OCR前、中、后的神经生理信号。它还将提供一个重要的 用于随后探索这些信号之间的因果关系的数据集 自主妥协的受试者。其影响超出了SUDEP的范围。然后，在Aim 2中将确定更改 从生理基线的各种保氧反射中抓取动物。这将提供数据 各种癫痫模型在损害自主神经系统方面的具体作用 触发了OCR，并将显示在抓住动物时导致猝死的独特事件序列。在……里面 目的3我们从急性动物模型转向慢性动物模型。我们将自由地确定觉醒的重要性- 行为，慢性癫痫在生理事件链上与猝死有关。我们会这么做的 使用之前由美国开发的植入性设备来监测完整的生理范围 慢性、行为自由的雄性和雌性大鼠的参数。分离抓取和非抓取，OCR VS NO- OCR，随着时间的推移，同一只自由移动的动物的反应将为了解这一角色提供一个全新的窗口 在正常和自主神经受损的受试者中交感神经和副交感神经共同激活。

Project Summary Sudden unexpected death in epilepsy (SUDEP) is a fatal complication of epilepsy that kills approximately 4,000 Americans every year. SUDEP is difficult to study because, while common, it usually occurs unobserved. The limited clinical data that exists suggests that SUDEP is a cardiorespiratory collapse that occurs directly after a seizure. Cardiorespiratory function is largely modulated by the autonomic nervous system (ANS). Sympathetic and parasympathetic autonomic nervous system pathways typically operate in opposition, so co- activation is rare. In the Oxygen Conserving family of Reflexes (OCRs), both pathways co-activate to induce breath-holding (apnea), lowered heart rate (bradycardia), and narrowing of peripheral blood vessels (vasoconstriction). Apnea prevents aspiration. Bradycardia conserves oxygen. Vasoconstriction prioritizes blood-carrying oxygen to essential organs (i.e. heart and brain). Seizure-induced autonomic disfunction, coupled with an externally triggered OCR may lead to death in Sudden Unexpected Death in Epilepsy (SUDEP). To elucidate the causal relationship between physiological parameters, OCRs, and sudden death, we propose to measure a physiological baseline of various oxygen conserving reflexes in healthy, anesthetized animals in Aim 1. This will establish a baseline for the temporal relationship between: cardiac, respiratory, and neural physiological signals in healthy animals before, during, and after OCR. It will also provide an important data set for subsequent exploration of causal relationships between those signals in both healthy and autonomically compromised subjects. Implications extend beyond SUDEP. In Aim 2 will then identify changes from the physiological baseline in various oxygen conserving reflexes for seizing animals. This will provide data of the specific role of various models of epilepsy, on compromising the autonomic system in the context of triggered OCR, and will show the unique sequence of events leading to sudden death in seizing animals. In Aim 3 we shift from acute to chronic animal models. We will determine the importance of awake, freely- behaving, chronic epilepsy on the physiological chain-of-events implicated in sudden death. We will do this using previously developed by us implantable devices to monitor the complete range of physiological parameters in chronic, freely-behaving male and female rats. Separating seizing and non-seizing, OCR vs no- OCR, responses in the same freely-moving animal over time will provide an entirely new window into the role of sympathetic and parasympathetic co-activation in normal and autonomic-compromised subjects.