Thalamocortical Responsive Neurostimulation for the Treatment of Lennox-Gastaut Syndrome

项目摘要/摘要 Lennox-Gastaut综合征(LGS)是一种具有认知功能的儿童期癫痫 功能障碍和非常频繁的全身性癫痫发作(GOS)往往会导致损伤。由于缺乏 脑反应性刺激的有效治疗方法及其安全性和有效性 难治性局灶性发作(FOS)，这项研究将测试大脑反应性神经刺激是否 丘脑皮质网络(RNS-TCN)是治疗LGS的一种可行策略。具体地说，该项目旨在： (1)获得RNS-TCN治疗LGS的安全性和有效性的初步证据；(2)建立 基于患者特定计算网络模型的交互式治疗决策支持系统 机器学习，以确定最佳的引线位置和刺激参数。 使用FDA批准用于FOS的RNS®系统，将进行早期可行性集成开发环境研究 在20名患有LGS和药物难治性GOS的患者的6个癫痫中心。这些患者将参加 两个10人的队列，第一个队列的安全性和有效性里程碑管理第二个队列的招募 一群人。患者将在双侧丘脑中央正中核内放置两个深度导联 两个硬膜下带状导联放置在两侧的内侧前额叶皮质上。之所以选择这些目标，是因为 它们与LGS中GOS的发生和扩散有关。线索将位于每个目标内，以便 在有限元生物物理模型的指导下，刺激最大限度地参与丘脑皮质网络 由结构磁共振成像和扩散加权成像创建。有限元 生物物理模型也将被用来确定RNS-TCN的初始刺激途径和电流幅度。 在盲性评估期内，患者将随机接受高频短脉冲治疗 (HFSB)或低频长突发(LFLB)RNS-TCN，然后进入冲洗期，然后切换到 接受其他治疗条件。在开放标签期间，可在以下位置修改刺激参数 医生的判断力。参数调整将通过使用贝叶斯优化来通知 专门为每个患者开发的模型。所有的临床和电生理数据都是在 这项研究将用于确定临床反应的生物标记物；如果发现，这些将有助于未来的癫痫研究 和临床实践。如果安全性是有利的，并且有初步的疗效证据，那么这个早期 经验将为未来更大规模的可行性研究的设计提供参考。 除了治疗有需要的人群外，该项目还致力于在 推广网络癫痫，并开发新的自动治疗选择策略，具有 有可能改善LGS和其他癫痫障碍患者的生活。

Project Summary / Abstract Lennox-Gastaut Syndrome (LGS) is a devastating form of childhood onset epilepsy with cognitive dysfunction and very frequent generalized onset seizures (GOS) often leading to injury. Driven by the lack of effective therapies and the demonstrated safety and efficacy of brain-responsive stimulation for medically intractable focal onset seizures (FOS), this study will test whether brain-responsive neurostimulation of thalamocortical networks (RNS-TCN) is a feasible strategy to treat LGS. Specifically, the project aims to: (1) acquire preliminary evidence for safety and efficacy in treating GOS of LGS with RNS-TCN; (2) create an interactive therapy-decision support system based on patient-specific computational network models and machine learning to identify optimal lead placement and stimulation parameters. Using the RNS® System, which is FDA approved for FOS, an early feasibility IDE study will be conducted at 6 epilepsy centers in 20 patients with LGS and medically intractable GOS. The patients will be enrolled in two cohorts of 10, with safety and efficacy milestones in the first cohort governing the enrollment of the second cohort. Patients will have two depth leads placed bilaterally in the centromedian nucleus of the thalamus and two subdural strip leads placed bilaterally on the medial prefrontal cortex. These targets are selected because they are implicated in the onset and spread of GOS in LGS. Leads will be located within each target such that stimulation maximally engages the thalamocortical network, guided by finite-element biophysical models created from structural magnetic resonance imaging and diffusion weighted imaging. The finite-element biophysical models will also be used to identify the initial RNS-TCN stimulation pathway and current amplitude. During the blinded evaluation period patients will be randomized to receive either high-frequency short burst (HFSB) or low-frequency long burst (LFLB) RNS-TCN, then enter a washout period before crossing over to receive the other treatment condition. During the open label period stimulation parameters can be modified at the discretion of the physician. Parameter adjustments will be informed by using a Bayesian optimization model developed for specifically for each patient. All clinical and electrophysiological data collected during the study will be used to identify a biomarker of clinical response; if found, these will aid future epilepsy research and clinical practice. If safety is favorable and there is preliminary evidence for efficacy, then this early experience will inform the design of a future larger feasibility study. In addition to treating a population in need, this project engages in fundamental discovery of biomarkers in generalized network epilepsies, and develops novel automated therapy selection policies that have the potential to improve the lives of patients with LGS and other seizure disorders.