Network dynamics of sleep-wake states in epilepsy

癫痫睡眠-觉醒状态的网络动力学

• 批准号: 10591896
• 负责人: Joline Fan
• 金额: $ 21.7万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-15 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591896
• 关键词: Address; Anatomy; Antiepileptic Agents; Area; Award; Biometry; Biophysics; Brain; Brain region; Chronic; Clinical; Clinical Trials; Coupling; Data; Development Plans; Diffusion Magnetic Resonance Imaging; Drug resistance; Electrophysiology (science); Epilepsy; Frequencies; Goals; Human; Image; Intractable Epilepsy; Investigation; Knowledge; Light; Location; Machine Learning; Magnetoencephalography; Measures; Medical; Mentorship; Methods; Modeling; Outcome; Partial Epilepsies; Pathologic; Pathway Analysis; Patients; Persons; Pharmaceutical Preparations; Physicians; Physiological; Play; Property; Quality of life; Research; Research Project Grants; Scientist; Seizures; Sleep; Structure; Therapeutic; Time; Training; Translational Research; Variant; Wakefulness; Work; biophysical model; career; career development; connectome; epileptiform; frontal lobe; improved; innovation; insight; multidisciplinary; multimodality; neural; neural patterning; neuroregulation; non rapid eye movement; predictive modeling; programs; rational design; signal processing; skills; therapy design; tool; tractography; treatment effect

PROJECT SUMMARY/ABSTRACT Of 46 million people worldwide with active epilepsy, one third are drug-resistant. Emerging neuromodulation- based therapies have demonstrated great potential to reduce seizure frequency and improve the quality of life in patients with drug-resistant epilepsy over time. The mechanisms underlying such therapies are thought to relate to the progressive restructuring of the epileptogenic network toward dynamics that reduce epileptic activity. Yet, the network properties underlying low and high epileptic potential are poorly understood, and the management of neuromodulatory therapies thus remains largely empiric with variable outcomes. To move toward rational approaches rooted in mechanistic understanding, there is a critical need to first fundamentally understand how network dynamics influence epileptogenic activity. In this proposal, we turn to the rich relationship between sleep and epilepsy, as sleep-wake states offer a robust and systematic way to cycle through a wide range of network dynamics that are strongly associated with different epileptic potentials. By leveraging sleep-wake states as a portal to probing dynamic brain networks, the overall objective of this proposal is to identify salient network features that represent states of variable epileptogenic potential and to determine associated network mechanisms that indicate reconfiguration into epileptogenic states. Using a combination of magnetoencephalography (MEG) imaging and diffusion tensor imaging (DTI)/tractography, I will first identify physiologic network dynamics of sleep-wake states in patients with focal epilepsy (Aim 1). I will then identify state-dependent network predictors and develop biophysical models of pathologic states predictive of interictal epileptiform activity (Aim 2). The expected outcome of this work is to gain a deeper understanding of key network features that augment epileptic potential and insight into their underlying mechanisms. This proposal combines an innovative research project with translational implications and a rigorous training and career development plan, which are highly complementary and together will facilitate my transition into an independent physician-scientist. I have assembled a leading, multidisciplinary mentorship team that has a constellation of expertise aligned with my research and training goals, including in epilepsy, sleep, MEG imaging, structural-function network analysis, neural computation, and biostatistics. In addition, through formal training, coursework, and directed mentorship, I will advance my skills in the areas of signal processing, machine learning, dynamical models, sleep electrophysiology, and clinical trials, which I will continue to use throughout my scientific career. The knowledge and training obtained during this award period will enable me to establish a robust independent research program that leverages multimodal electrophysiology and imaging in humans and insights from the rich relationship between sleep and epilepsy to improve therapeutic tools for patients with medically refractory epilepsy.

项目概要/摘要 全球 4600 万活动性癫痫患者中，三分之一具有耐药性。新兴的神经调节- 基于疗法已显示出降低癫痫发作频率和改善生活质量的巨大潜力 随着时间的推移，患有耐药性癫痫的患者。这种疗法的潜在机制被认为是 与致癫痫网络的逐步重组有关，以减少癫痫的发生 活动。然而，人们对低癫痫电位和高癫痫电位背后的网络特性知之甚少，并且 因此，神经调节疗法的管理在很大程度上仍然是经验性的，结果可变。移动 对于植根于机械理解的理性方法，迫切需要首先从根本上 了解网络动态如何影响癫痫活动。在这个提案中，我们转向富人 睡眠与癫痫之间的关系，因为睡眠-觉醒状态提供了一种稳健且系统的循环方式 通过与不同癫痫电位密切相关的广泛网络动态。经过 利用睡眠-觉醒状态作为探测动态大脑网络的门户，该项目的总体目标 提议是确定代表可变致癫痫潜力状态的显着网络特征，并 确定指示重新配置为致癫痫状态的相关网络机制。使用 结合脑磁图（MEG）成像和扩散张量成像（DTI）/纤维束成像，我将 首先确定局灶性癫痫患者睡眠-觉醒状态的生理网络动态（目标 1）。我会 然后确定状态依赖的网络预测因子并开发病理状态的生物物理模型 预测发作间期癫痫样活动（目标 2）。这项工作的预期成果是获得更深入的了解 了解增强癫痫潜力的关键网络特征并深入了解其潜在因素 机制。该提案结合了具有转化意义的创新研究项目和 严格的培训和职业发展计划，两者是高度互补的，共同促进我的发展 转变为一名独立的医师科学家。我组建了领先的多学科指导团队 团队拥有一系列与我的研究和培训目标相一致的专业知识，包括癫痫领域的专业知识， 睡眠、脑磁图成像、结构功能网络分析、神经计算和生物统计学。此外， 通过正式培训、课程作业和指导指导，我将提高我在信号领域的技能 处理、机器学习、动力学模型、睡眠电生理学和临床试验，我将 在我的整个科学生涯中继续使用。在此奖励期间获得的知识和培训 将使我能够建立一个强大的独立研究计划，利用多模式 人类的电生理学和成像以及睡眠与癫痫之间丰富关系的见解 改进医学难治性癫痫患者的治疗工具。