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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要癫痫猝死 (SUDEP) 是癫痫的致命并发症，可导致约每年有 4,000 名美国人。 SUDEP 很难研究，因为虽然它很常见，但通常是在未被观察到的情况下发生的。现有的有限临床数据表明，SUDEP 是一种直接发生的心肺衰竭癫痫发作后。心肺功能很大程度上受自主神经系统（ANS）调节。交感神经和副交感神经自主神经系统通路通常相反运作，因此激活的情况很少见。在守氧反射家族 (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）和外周血管变窄（血管收缩）。呼吸暂停可防止误吸。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）。癫痫发作引起的自主神经功能障碍，加上外部触发的 OCR 可能会导致癫痫猝死（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、麻醉状态下各种氧保存反射的生理基线目标 1 中的动物。这将为心脏、呼吸和呼吸之间的时间关系建立基线。 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用于随后探索健康和健康中这些信号之间的因果关系的数据集自主神经受损的受试者。其影响超出了 SUDEP 范围。然后在目标 2 中将识别变化与捕捉动物的各种氧保存反射的生理基线相比。这将提供数据各种癫痫模型的具体作用，在损害自主神经系统的背景下触发 OCR，并将显示导致捕获动物猝死的独特事件序列。在目标 3 我们从急性动物模型转向慢性动物模型。我们将确定清醒、自由的重要性—— 行为，慢性癫痫对与猝死有关的生理事件链的影响。我们会这样做使用我们之前开发的植入式设备来监测全方位的生理情况慢性、自由行为的雄性和雌性大鼠的参数。区分卡住和非卡住，OCR 与无卡住 OCR，随着时间的推移，同一个自由移动的动物的反应将为了解该角色提供一个全新的窗口正常和自主神经受损受试者中交感神经和副交感神经的共同激活。