Breathing Rescue for SUDEP Prevention (BreatheS)

项目总结 癫痫突发意外死亡(SUDEP)是癫痫的一种破坏性并发症，也是癫痫的主要原因 慢性失控癫痫患者过早死亡的风险。尽管对预期寿命有重大影响 在这些人中，目前没有有针对性的SUDEP预防战略。大多数SUDEP发生在 全身抽搐发作，受害者通常以俯卧姿势躺在床上。直到最近，SUDEP 被认为是由于心血管衰竭，但对在接受监测时死亡的患者进行的研究 医院癫痫病房显示，大多数SUDEP是由于惊厥后中枢性呼吸暂停所致。最重要的是，三分钟 惊厥后的机会窗口被确定，超过这个窗口，呼吸和呼吸的末梢级联 心力衰竭似乎是不可挽回的。通过提高我们对前脑呼吸网络的理解，我们可以 制定促进呼吸和抢救呼吸暂停的神经调节策略，可预防SUDEP 这一关键的时间窗口。这个项目的目标是了解前脑通过使用 解剖精确的颅内立体定向脑电(SEEG)数据，可以确定最佳 促进呼吸的刺激范例。研究人群是药物难治性患者 接受1)用于癫痫手术的植入深度电极的颅内SEEG评估的癫痫，以及 2)同步多导心肺监测胸腹偏移，鼻腔和口腔 空气流量、血氧饱和度、二氧化碳、体积描记和心电图。为了实现这一目标，在目标1中，我们将 识别电活动与呼吸活动相耦合的前脑区域 与任务相关的呼吸数据和监测同步的脑信号动力学。我们将进一步分析功能 作为呼吸任务的功能连接到图表网络，以便将网络中心作为候选 刺激靶点的区域，以便揭示全面的皮质连接体。在目标2中，我们将 对这些区域施加电刺激，以评估对呼吸的神经调节效应。有效刺激 在本研究的后半部分，范例/部位将在惊厥后立即状态下进行测试，以证明 在这种状态下神经调节的可行性，这些发作将与非刺激性发作进行比较 从NINDS SUDEP研究中心获得，采用1：5匹配(年龄、性别、SUDEP风险匹配 因素-癫痫持续时间和GCS频率)。我们的项目将确定有效的刺激地点和 呼吸抢救的范例，并将建立后刺激方法的可行性 抽搐状态。我们的结果将为神经调节抢救呼吸暂停的疗效的临床试验奠定基础 作为潜在的抗SUDEP疗法，适用于SUDEP高危人群。这项工作还将提供对 与其他神经系统疾病、心力衰竭和中风相关的中枢性呼吸暂停的潜在治疗。 。

PROJECT SUMMARY Sudden unexpected death in epilepsy (SUDEP) is a devastating complication of epilepsy and a leading cause of premature death in persons with chronic uncontrolled epilepsy. Despite the major impact on life expectancy in these individuals, no targeted SUDEP preventive strategies currently exist. Most SUDEPs occur after a generalized convulsive seizure, and victims are typically found in bed in the prone position. Until recently, SUDEP was thought to be due to cardiovascular failure, but research on patients who died while being monitored in hospital epilepsy units reveal that most SUDEP is due to post-convulsive central apnea. Crucially, a three-minute post convulsive window of opportunity was identified, beyond which the terminal cascade of respiratory and cardiac failure appears irrevocable. By advancing our understanding of forebrain breathing networks, we can develop neuromodulatory strategies for respiratory facilitation and apnea rescue that may prevent SUDEP during this critical time window. The objective of this project is to understand forebrain modulation of breathing by using anatomically precise intracranial stereotactic electroencephalography (SEEG) data that can determine optimal stimulation paradigms for breathing enhancement. The study population are patients with medically refractory epilepsy undergoing 1) intracranial SEEG evaluation with implanted depth electrodes for epilepsy surgery, and 2) simultaneous polygraphic cardiorespiratory monitoring of thoracoabdominal excursions, nasal and oral airflow, oxygen saturation, carbon dioxide, plethysmography and EKG. To achieve this goal, in Aim 1, we will identify forebrain regions in which electrical activity is coupled with respiratory activity by using spontaneous and task-related breathing data and monitoring simultaneous brain signal dynamics. We will further analyze functional connectivity to graph networks as a function of breathing tasks, in order to establish network hubs as candidate regions for stimulation targets and in order to reveal a comprehensive cortical connectome. In Aim 2, we will apply electrical stimulus to these regions to assess neuromodulatory effects on respiration. Effective stimulation paradigms/sites will be tested in the immediate post-convulsive state in the latter part of this study, to prove feasibility of neuromodulation in this state, and these seizures will be compared with non-stimulated seizures obtained from the NINDS Center for SUDEP Research, using 1:5 matching (matched for age, sex, SUDEP risk factors-duration of epilepsy and GCS frequency). Our project will identify effective stimulation sites and paradigms for breathing rescue as well as will establish feasibility of stimulation approaches in the post- convulsive state. Our results will set the stage for a clinical trial of efficacy of neuromodulation for apnea rescue as potential anti-SUDEP therapy, in individuals who at high SUDEP risk. This work will also provide insights into potential treatment of central apnea associated with other neurological diseases, heart failure, and stroke. .