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.

癫痫由同步大脑活动引起的复发性癫痫发作，并影响超过1％的人群。大约三分之一的患者对抗癫痫药不反应，可能需要进行手术干预，例如组织切除或电刺激。与切除术不同，大约一半的癫痫患者无癫痫发作，很少有患者通过刺激治疗获得癫痫发作自由。癫痫背景下的刺激机制尚不清楚。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发现这些机制。我将使用颞叶癫痫病的金天谷处理的啮齿动物模型制备，我将应用相锁，低频，高频，超高频和高频刺激，以识别最佳方法来识别可阻止癫痫发作的最佳方法。此外，我将通过两光子显微镜和钙成像发现癫痫停滞的机制。我将使用人类电生理学，计算建模和连通性分析来探索人类患者网络中的癫痫停滞机制。我将与植入神经液反应性神经刺激的患者的功能和结构连通性指标的癫痫患者的癫痫发作减少相关，并测量对立体情感脑摄影期间单位刺激的网络响应。我将接受有关来自两个学科癫痫病的导师的培训：在功能性神经外科医生下的人类电生理学John John Rolston博士，立体诊断和功能性神经外科手术的主任，以及在药理学和毒理学系主任Karen Wilcox博士领导下的Slice电生理学。威尔科克斯博士在癫痫发生和抗癫痫药物的机理方面拥有悠久的历史，他将在SLICE电生理学和钙成像领域的基础科学技术中训练我，从而发现使用刺激疗法的癫痫发作机制。在Rolston博士下的培训将使我能够进行人类受试者研究，收集颅内神经数据以及分离癫痫脑回路的刺激与阳性临床结果相关，以指导在诊所使用的新型刺激策略。 Wilcox博士和Rolston博士的培训将在诊所中使用神经调节来实现癫痫停滞的机理发现，并将其转化为诊所癫痫患者。此外，每个赞助商的跨学科影响将有助于塑造对癫痫发作停滞机制的多方面理解，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使循证刺激策略转化为临床结果，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