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: 8934221
• 负责人: GEORGE B RICHERSON
• 金额: $ 62.73万
• 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/8934221
• 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; 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

 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（由申请方提供）：癫痫猝死（SUDEP）是难治性癫痫患者的主要死因，估计占该人群所有死亡的50%，占所有癫痫患者死亡的17%。令人惊讶的是，患者和医生普遍缺乏对猝死风险增加的认识。在最近的一项调查中，只有56%治疗癫痫患者的加拿大儿科医生知道他们的患者猝死的风险增加，只有33%的医生知道SUDEP一词。关于心力衰竭或呼吸骤停作为主要死亡原因是否更重要存在争议，但很少从SUDEP的人类病例或小鼠模型中同时收集心脏和呼吸数据。例如，在20多个记录在案的SUDEP病例中，患者在接受EMU监测时发生，这些患者中没有一个测量通气甚至血氧。有效的预防策略，在高风险的癫痫患者将依赖于定义的机制，导致从癫痫发作到死亡。我们的初步数据表明，呼吸抑制是某些SUDEP病例死亡的主要原因，Dravet综合征患者在发作期有先前未表征的呼吸异常。此外，我们的数据表明，存在一种抑制通气的解剖学途径，该途径从杏仁核和前颞叶延伸到控制呼吸的髓核。然而，目前还不清楚这个回路是如何连接的，以及所涉及的神经元的身份。在目标1中，我们将表征Dravet综合征患者以及这种病理学的小鼠模型的发作期心肺控制。在目标2中，我们将定义从杏仁核到脑干的解剖学通路，该通路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，我们将确定脑干神经元的身份，这些神经元接受来自杏仁核的输入，并在癫痫发作期间抑制呼吸和意识。这项工作将确定一个解剖学途径，通过该途径皮质癫痫发作可以侵入中脑和脑干，并导致心肺功能和唤醒抑制。我们的研究结果有可能表征该电路的关键组成部分，并可能确定可用于开发有效筛选策略的生物标志物。更好地理解SUDEP的机制将有助于未来开发可能降低SUDEP风险的预防性治疗。