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

节氧反射激活期间导致癫痫猝死的生理事件序列

• 批准号: 10097583
• 负责人: Pedro Irazoqui
• 金额: $ 5.83万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10097583
• 关键词: Acute; Age; Air Movements; American; Anesthesia procedures; Animal Model; Animals; Apnea; Autonomic nervous system; Blood; Blood Pressure; Bone Screws; Bradycardia; Brain; Brain Stem; Cardiac; Catheters; Central Sleep Apnea; Cessation of life; Chronic; Clinical Data; Complication; Coupled; Data; Data Set; Development; Disease; Diving; Drops; Electrocardiogram; Electrocorticogram; Electrodes; Epilepsy; Event; Family; Female; Heart; Heart Arrest; Heart Rate; Hippocampus (Brain); Human; Individual; Intraperitoneal Injections; Kainic Acid; Larynx; Lead; Link; Long-Evans Rats; Measures; Modeling; Monitor; Neurons; Nose; Organ; Oxygen; Pathology; Pathway interactions; Physiologic Monitoring; Physiologic pulse; Physiological; Prevention; Rattus; Recovery; Reflex action; Respiratory Diaphragm; Rest; Role; Seizures; Signal Transduction; Sudden Death; Sudden infant death syndrome; System; Tetanus; Time; United States; Work; awake; diving reflex; fighting; implantable device; insight; intraperitoneal; male; novel; peripheral blood vessel; prevent; public health relevance; relating to nervous system; respiratory; response; subcutaneous; sudden unexpected death in epilepsy; vasoconstriction

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.

项目摘要 癫痫猝死（SUDEP）是癫痫的致命并发症， 每年4,000个美国人。SUDEP很难研究，因为它虽然常见，但通常发生时未被观察到。 现有的有限临床数据表明，SUDEP是一种直接发生的心肺衰竭， 在癫痫发作后呼吸功能主要由自主神经系统（ANS）调节。 交感神经和副交感神经自主神经系统的通路通常是相反的，所以合作。 激活是罕见的。在氧保存反射家族（OCR）中，两种途径共同激活以诱导 屏气（呼吸暂停）、心率降低（心动过缓）和外周血管狭窄 （血管收缩）。呼吸暂停可防止吸入。心动过缓可以保存氧气。血管收缩优先 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紊乱 再加上外部触发的OCR可能导致癫痫猝死 （SUDEP）。为了阐明生理参数、OCR和猝死之间的因果关系， 我们建议测量健康的、麻醉的、 目标1中的动物这将建立心脏、呼吸和 在OCR之前、期间和之后，健康动物的神经生理信号。它还将提供一个重要的 数据集，用于随后探索健康和肥胖患者中这些信号之间的因果关系。 有危险的实验对象。影响超出了SUDEP。在目标2中，然后将确定变化 从生理基线的各种氧气保存反射捕捉动物。这将提供数据 癫痫的各种模型的具体作用，在损害自主系统的背景下， 触发OCR，并将显示导致动物突然死亡的事件的独特顺序。在 目的3从急性动物模型转向慢性动物模型。我们将决定清醒，自由的重要性- 行为，慢性癫痫的生理链的事件牵连到猝死。我们会这样做 使用美国先前开发的可植入装置来监测生理的全部范围， 参数在慢性，自由行为的雄性和雌性大鼠。分离卡死和非卡死，OCR与无- OCR，随着时间的推移，同一个自由移动的动物的反应将为角色提供一个全新的窗口 交感神经和副交感神经的共同激活。