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）

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：癫痫猝死 (SUDEP) 是难治性癫痫患者死亡的主要原因，估计占该人群所有死亡的 50%，占所有死亡的 17%。令人惊讶的是，患者和医生普遍缺乏对癫痫患者猝死风险增加的认识，在最近的一项调查中，只有 56% 的加拿大儿科医生治疗癫痫患者。癫痫患者知道他们的患者猝死的风险增加，而这些医生中只有 33% 知道 SUDEP 这个术语，关于心力衰竭或呼吸骤停作为主要死因是否更重要存在争议，但心脏和呼吸系统的数据很少。例如，在患者接受 EMU 监测时发生的 20 多例 SUDEP 病例中，没有一个患者进行了通气甚至血氧测量。在高危癫痫患者将依赖于确定导致癫痫发作至死亡的机制。我们的初步数据表明，呼吸抑制是某些 SUDEP 病例的主要原因，并且 Dravet 综合征患者在围周期曾出现过不典型的呼吸异常。此外，我们的数据表明存在一条抑制通气的解剖通路，该通路从杏仁核和前颞叶延伸到控制呼吸的髓质核。在目标 1 中，我们将描述 Dravet 综合征患者的发作期心肺控制以及这种病理学的小鼠模型。在目标 2 中，我们将定义从杏仁核到杏仁核的解剖通路。最后，在目标 3 中，我们将确定在癫痫发作期间接收来自杏仁核的输入并抑制呼吸和意识的脑干神经元的身份。这项工作将确定皮层癫痫发作侵入中脑和脑干并导致心肺功能下降和觉醒的解剖学途径，我们的研究结果有可能描述该回路的关键组成部分，并可能确定可用于开发有效的生物标志物。更好地了解 SUDEP 背后的机制将有助于未来开发可能降低 SUDEP 风险的预防性治疗。