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.

项目摘要癫痫（SUDEP）突然意外死亡是癫痫的致命并发症，可杀死每年4,000名美国人。 SUDEP很难研究，因为虽然常见，但通常不会发生这种情况。存在有限的临床数据表明SUDEP是直接发生的心肺崩溃癫痫发作后。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系统途径通常在相对中起作用，因此激活很少。在保存反射的氧气家族（OCR）中，两种途径都共同激活以诱导呼吸（呼吸暂停），心率降低（心动过缓）和外周血血管的变窄（血管收缩）。呼吸暂停可防止攻击。心动过缓保存氧气。血管收缩优先将氧气携带到必需器官（即心脏和大脑）。癫痫发作引起的自主神经功能，再加上外部触发的OCR，可能导致癫痫突然意外死亡的死亡（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，麻醉的各种氧气的生理基线 AIM 1中的动物。这将为心脏，呼吸道和 OCR之前，期间和之后健康动物的神经生理信号。它也将提供重要的随后探索健康和健康信号之间因果关系的数据集自主妥协的受试者。含义超出了SUDEP。在AIM 2中将确定更改从各种氧气中的生理基线来保存夺取动物的反射。这将提供数据各种癫痫模型的具体作用，在损害自主系统的背景下触发了OCR，并将显示导致动物突然死亡的独特事件序列。在目标3我们从急性转移到慢性动物模型。我们将自由地确定清醒的重要性 - 对猝死涉及的生理链事件的慢性癫痫行为。我们会这样做使用美国植入式设备先前开发的，监测完整的生理范围慢性，自由行为的男性和雌性大鼠的参数。分离抓取和非参与，OCR与No- OCR，随着时间的推移，在同一自由移动的动物中的回应将为角色提供一个全新的窗口正常和自主性副业受试者中的交感神经和副交感神经共激活。