SUDEP Research Alliance: Respiratory and Arousal Mechanisms, Application 5 of 7

SUDEP 研究联盟：呼吸和唤醒机制，应用 5（共 7）

• 批准号: 9132848
• 负责人: GEORGE B RICHERSON
• 金额: $ 63.8万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9132848
• 关键词: Accounting; Acetylcholine; Agonist; Amygdaloid structure; Anterior; Apnea; Arousal; Arrhythmia; Awareness; Biological Markers; Blood; Brain; Brain Stem; Breathing; Cardiac; Cardiovascular system; Cause of Death; Cell Nucleus; Cessation of life; Chronic; Coma; Conscious; Data; Defect; Depressed mood; Development; Diagnosis; Electrocardiogram; Electroencephalography; Environmental air flow; Epilepsy; Forensic Medicine; Frequencies; Functional disorder; Future; Goals; Heart failure; Human; Hypercapnic respiratory failure; Incidence; Invaded; Knowledge; Lead; Link; Measurement; Measures; Mental Depression; Midbrain structure; Monitor; Mus; Myocardial dysfunction; Neurobiology; Neurons; Neurotransmitters; Oxygen; Partial Epilepsies; Pathology; Pathway interactions; Patients; Pharmacology; Physicians; Play; Population; Prevention strategy; Preventive Intervention; Preventive treatment; Prosencephalon; Refractory; Research; Respiration; Risk; Role; Seizures; Serotonin; Slice; Sudden Death; Sudden infant death syndrome; Surveys; Synapses; Syndrome; System; Temporal Lobe; Transgenic Mice; Ventilatory Depression; Work; base; cholinergic neuron; high risk; monoamine; mortality; mouse model; novel; optogenetics; pediatrician; prevent; public health relevance; receptor; respiratory; response; screening; sudden unexpected death in epilepsy

 DESCRIPTION (provided by applicant): Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy, estimated to account for up to 50% of all deaths in this population and up to 17% of deaths in all patients with epilepsy. There is a surprisingly common lack of awareness among patients and physicians of this increased risk of sudden death. In a recent survey, only 56% of Canadian pediatricians who treat patients with epilepsy knew their patients were at increased risk for sudden death and only 33% of these physicians knew the term SUDEP. There is controversy regarding whether cardiac failure or respiratory arrest is more important as the primary cause of death, but cardiac and respiratory data is rarely collected simultaneously from human cases of SUDEP or from mouse models. For example, in the more than 20 documented cases of SUDEP that occurred while the patient was undergoing EMU monitoring, none of these patients had measurements of ventilation or even blood oxygenation. Effective preventive strategies in high-risk epileptic patients will rely on defining the mechanisms that lead from seizures to death. Our preliminary data suggest that respiratory depression is the primary cause of death in some cases of SUDEP and that patients with Dravet syndrome have previously uncharacterized breathing abnormalities in the peri-ictal period. Furthermore, our data has indicated there is an anatomical pathway that inhibits ventilation, which extends from the amygdala and anterior temporal lobe to medullary nuclei that control breathing. However, it is unclear how this circuit is connected and the identities of the neurons involved. In Aim 1, we will characterize peri-ictal cardiorespiratory control in human patients with Dravet syndrome as well as mouse models of this pathology. In Aim 2, we will define the anatomical pathway from the amygdala to the brainstem that inhibits the cardiovascular and respiratory control networks during seizures. Finally, in Aim 3 we will determine the identity of brainstem neurons that receive inputs from the amygdala and inhibit breathing and consciousness during seizures. This work will identify an anatomical pathway by which cortical seizures can invade the midbrain and brainstem and cause depressed cardiorespiratory function and arousal. Our findings have the potential to characterize key components of this circuit and may identify biomarkers that can be used to develop effective screening strategies. Better understanding mechanisms that underlie SUDEP will allow future development of preventative treatments that may decrease SUDEP risk.

 描述（由适用提供）：癫痫突然出现意外死亡（SUDEP）是难治性癫痫患者的主要死亡原因，估计占该人群中所有死亡的50％，在所有患有癫痫患者的患者中，死亡人数最多可占17％。令人惊讶的是，患者和医生之间普遍缺乏意识，因为这种猝死风险增加了。在最近的一项调查中，只有56％的加拿大儿科医生对患有癫痫患者的患者知道他们的患者猝死风险增加，并且只有33％的医生知道SUDEP一词。关于心脏衰竭或呼吸停滞是否更重要，这是死亡的主要原因，但心脏和呼吸数据很少从人类的SUDEP或小鼠模型中收集，这是有争议的。例如，在患者正在进行EMU监测时发生的20多个记录的SUDEP病例中，这些患者均未进行通风甚至血液氧合的测量。高危癫痫患者的有效预防策略将依赖于定义从癫痫发作到死亡的机制。我们的初步数据表明，在某些情况下，呼吸道抑郁症是死亡的主要原因，而Dravet综合征患者以前在杂物期间呼吸异常。此外，我们的数据表明，有一种解剖途径可以抑制通风，从杏仁核和前临时叶到控制呼吸的髓质核。但是，目前尚不清楚该电路如何连接以及涉及的神经元的身份。在AIM 1中，我们将表征人类Dravet综合征患者以及该病理学的小鼠模型的心脏呼吸性控制。在AIM 2中，我们将定义从杏仁核到脑干的解剖途径，该途径在癫痫发作期间抑制心血管和呼吸控制网络。最后，在目标3中，我们将确定从杏仁核接收输入的脑干神经元的身份，并抑制癫痫发作期间的呼吸和意识。这项工作将确定一条解剖途径，皮质性癫痫发作可以侵入中脑和脑干，并引起心肺功能下降和唤醒。我们的发现有可能表征该电路的关键组成部分，并可能识别可用于制定有效筛选策略的生物标志物。更好地理解SUDEP基础的机制将允许未来开发可能降低SUDEP风险的预防治疗。