Cellular and Network Mechanisms of Seizure Control Through Stimulation

癫痫的分类是由同步的大脑活动引起的反复发作，影响超过1%的人口。大约三分之一的患者对抗癫痫药物没有反应，可能需要手术干预，如组织切除或电刺激。与手术不同的是，在手术中，大约一半的癫痫患者癫痫发作消失，而很少有患者通过刺激治疗实现癫痫发作缓解。癫痫背景下的刺激机制仍不清楚。在这项工作中，我将使用基础科学方法和临床电生理学在细胞和网络水平上揭示这些机制。使用红藻氨酸治疗的颞叶癫痫啮齿动物模型的切片电生理学制剂，我将应用锁相、低频、高频、超高频和非周期刺激来确定阻止癫痫发作的最佳方法。此外，我将通过双光子显微镜和钙成像来揭示癫痫发作停止的机制。我将使用人类电生理学、计算模型和连通性分析，在人类患者的网络水平上探索癫痫发作停止的机制。我将把癫痫患者的癫痫发作减少与植入NeuroPace响应性神经刺激导联的患者的功能和结构连通性指标相关联，并在立体脑电图期间测量网络对单部位刺激的反应。我将接受来自两个学科的专注于癫痫的导师的培训：人体电生理学在功能神经外科医生约翰·罗尔斯顿博士的指导下，他是立体定向和功能神经外科主任，切片电生理学在Karen Wilcox博士的指导下，他是药理学和毒理学部门的主席。威尔科克斯博士在癫痫发生机制和抗癫痫药物研发方面有着悠久的历史，他将向我培训切片电生理学和钙成像方面的基础科学技术，以揭示使用刺激疗法阻止癫痫发作的细胞机制。罗尔斯顿博士的培训将使我能够进行人类受试者研究，收集颅内神经数据，并分离与阳性临床结果相关的癫痫脑回路刺激，以指导临床使用新的刺激策略。在威尔科克斯博士和罗尔斯顿博士的指导下进行的培训将使人们能够利用神经调节来机械地发现癫痫发作的停止，并将他们转化为临床上的癫痫患者。此外，来自每个赞助者的跨学科影响将有助于形成对癫痫阻止机制的多方面理解，从使用体外电生理学的细胞水平到使用网络连接方法的神经回路。从细胞和网络的角度了解刺激机制将有助于将循证刺激策略转化为临床应用，并改善临床结果。

Epilepsy is classified by recurrent seizures caused by synchronous brain activity and affects more than 1% of the population. Approximately one-third of patients do not respond to anti-epileptic medications and may require surgical interventions such as tissue resection or electrical stimulation. Unlike with resection, in which about half of epilepsy patients become seizure free, very few patients achieve seizure freedom through stimulation therapy. Stimulation mechanisms in the context of epilepsy remain unclear. In this work, I will use basic science approaches and clinical electrophysiology to uncover these mechanisms at the cellular and network level. Using a slice electrophysiology preparation from a kainic acid-treated rodent model of temporal lobe epilepsy, I will apply phase-locked, low-frequency, high-frequency, ultra-high-frequency, and aperiodic stimulation to identify optimal approaches to arrest seizures. Further, I will uncover mechanisms of seizure arrest through two-photon microscopy and calcium imaging. I will explore seizure arrest mechanisms at the network level in human patients using human electrophysiology, computational modeling, and connectivity analysis. I will correlate seizure reduction in epilepsy patients with functional and structural connectivity metrics for patients implanted with NeuroPace responsive neurostimulation leads and measure network responses to single-site stimulation during stereo-electroencephalography. I will receive training from mentors focused on epilepsy from two disciplines: human electrophysiology under functional neurosurgeon Dr. John Rolston, director of stereotactic and functional neurosurgery, and slice electrophysiology under Dr. Karen Wilcox, chair of the Pharmacology and Toxicology department. Dr. Wilcox, who has a long history in mechanisms of epileptogenesis and anti-epileptic drug discovery, will train me in basic science techniques in slice electrophysiology and calcium imaging to uncover cellular mechanisms of seizure arrest using stimulation therapy. Training under Dr. Rolston will enable me to conduct human subjects research, collect intracranial neural data, and isolate stimulation of epileptic brain circuits correlated with positive clinical outcomes to guide novel stimulation strategies to be used in the clinic. Training under Dr. Wilcox and Dr. Rolston will enable mechanistic discoveries of seizure arrest using neuromodulation and lead to their translation into epilepsy patients in the clinic. Additionally, the interdisciplinary influence from each sponsor will help shape a multi-faceted understanding of seizure arrest mechanisms, from the cellular level using in vitro electrophysiology to the neural circuit using network connectivity approaches. Understanding stimulation mechanisms from cellular and network perspectives will allow the translation of evidence-based stimulation strategies into the clinic and improvements in clinical outcomes.