Cellular and Network Mechanisms of Seizure Control Through Stimulation

通过刺激控制癫痫发作的细胞和网络机制

• 批准号: 10321257
• 负责人: DARIA NESTEROVICH ANDERSON
• 金额: $ 6.76万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321257
• 关键词: Affect; Antiepileptic Agents; Area; Basic Science; Brain; Calcium; Cells; Clinic; Clinical; Computer Models; Data; Department chair; Discipline; Disease; Distant; Electric Stimulation; Electrodes; Electroencephalography; Electrophysiology (science); Epilepsy; Epileptogenesis; Evoked Potentials; Excision; Failure; Freedom; Frequencies; Hippocampus (Brain); Human; Human Subject Research; Image; Implant; In Vitro; Intractable Epilepsy; Kainic Acid; Lead; Measures; Mentors; Mentorship; Modeling; Monitor; Movement Disorders; Network-based; Neurons; Neurosurgeon; Operative Surgical Procedures; Outcome; Parahippocampal Gyrus; Patients; Pharmaceutical Preparations; Pharmacology and Toxicology; Phase; Physiologic pulse; Population; Preparation; Rattus; Recording of previous events; Recurrence; Research; Resected; Resistance; Rodent Model; Seizures; Shapes; Site; Slice; Structure; Syndrome; Techniques; Temporal Lobe Epilepsy; Tissues; Training; Translations; Work; dentate gyrus; drug discovery; evidence base; experimental study; implantation; improved; neural circuit; neuroimaging; neuroregulation; neurosurgery; novel; patient population; prospective; relating to nervous system; response; success; symptom management; two photon microscopy

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.

癫痫的分类是由同步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，例如组织切除或电刺激。与切除术不同的是，大约一半的癫痫患者可以摆脱癫痫发作，而很少有患者通过刺激疗法实现癫痫发作。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来揭示细胞和网络层面的这些机制。使用红藻氨酸处理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、超高频和非周期性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揭示癫痫发作停止的机制。我将利用人体电生理学、计算模型和连接分析来探索人类患者网络层面的癫痫发作停止机制。我将把癫痫患者的癫痫发作减少与植入 NeuroPace 响应性神经刺激引线的患者的功能和结构连接指标相关联，并在立体脑电图期间测量网络对单点刺激的反应。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，由立体定向和功能神经外科主任、功能神经外科医生 John Rolston 博士指导，以及切片电生理学，由药理学和毒理学系主任 Karen Wilcox 博士指导。 Wilcox 博士在癫痫发生机制和抗癫痫药物发现方面拥有悠久的历史，他将培训我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抑制癫痫发作的细胞机制。在 Rolston 博士的指导下进行的培训将使我能够进行人体研究，收集颅内神经数据，并隔离与积极临床结果相关的癫痫脑回路刺激，以指导临床中使用的新型刺激策略。在 Wilcox 博士和 Rolston 博士的指导下进行的培训将能够利用神经调节发现癫痫发作的机制，并将其转化为临床上的癫痫患者。此外，每个赞助商的跨学科影响将有助于形成对癫痫发作抑制机制的多方面理解，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。从细胞和网络角度理解刺激机制将使基于证据的刺激策略转化为临床并改善临床结果。

项目成果

Probabilistic comparison of gray and white matter coverage between depth and surface intracranial electrodes in epilepsy.

• DOI: 10.1038/s41598-021-03414-5
• 发表时间: 2021-12-17
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Anderson DN;Charlebois CM;Smith EH;Arain AM;Davis TS;Rolston JD
• 通讯作者: Rolston JD

Chronic intracranial recordings after resection for epilepsy reveal a "running down" of epileptiform activity.

癫痫切除后的慢性颅内记录显示癫痫样活动“减弱”。

• DOI: 10.1111/epi.17645
• 发表时间: 2023
• 期刊: Epilepsia
• 影响因子: 5.6
• 作者: Kundu,Bornali;Charlebois,ChantelM;Anderson,DariaNesterovich;Peters,Angela;Rolston,JohnD
• 通讯作者: Rolston,JohnD