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

 描述(申请人提供)：癫痫突发意外死亡(SUDEP)是难治性癫痫患者的主要死亡原因，估计占该人群所有死亡人数的50%，占所有癫痫患者死亡人数的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，治疗癫痫患者的加拿大儿科医生中只有56%知道他们的患者猝死的风险增加，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是更重要的主要死亡原因存在争议，但心脏和呼吸数据很少同时从人类SUDEP病例或从小鼠模型收集。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人进行了通气量测量，甚至没有测量血氧含量。高危癫痫患者的有效预防策略将取决于确定导致癫痫发作至死亡的机制。我们的初步数据表明，呼吸抑制是一些SUDEP患者的主要死亡原因，Dravet综合征患者在发作期以前有无特征的呼吸异常。此外，我们的数据表明，存在一条抑制呼吸的解剖路径，从杏仁核和前颞叶延伸到控制呼吸的髓核。然而，目前还不清楚这个电路是如何连接的，也不清楚涉及的神经元的身份。在目标1中，我们将描述人类Drave氏综合征患者以及这种病理的小鼠模型的发作期心肺控制的特征。在目标2中，我们将定义从杏仁核到脑干的解剖路径，该路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。这项工作将确定一种解剖学途径，通过这种途径，皮质癫痫可以侵犯中脑和脑干，并导致心肺功能抑制和觉醒。我们的发现有可能描述这一回路的关键组成部分，并可能识别可用于开发有效筛查策略的生物标志物。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。

 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.