Thalamic stimulation to prevent impaired consciousness in epilepsy

丘脑刺激可预防癫痫意识障碍

• 批准号: 9811685
• 负责人: HAL BLUMENFELD
• 金额: $ 95.72万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9811685
• 关键词: Adverse effects; Algorithms; Anterior Nuclear Group; Area; Arousal; Awareness; Behavioral; Bilateral; Brain region; Breathing; Caring; Central Lateral Nucleus; Chronic Disease; Clinical Trials; Communication; Conscious; Consciousness Disorders; Custom; Data; Data Storage and Retrieval; Databases; Deep Brain Stimulation; Depressed mood; Detection; Devices; Drowning; Electroencephalography; Electrophysiology (science); Enrollment; Epilepsy; Feasibility Studies; Functional disorder; Goals; Hand; Hippocampus (Brain); Impairment; Implant; Inpatients; Institutional Review Boards; Investigation; Monitor; National Institute of Neurological Disorders and Stroke; Operative Surgical Procedures; Outpatients; Patients; Performance; Pharmaceutical Preparations; Phase; Physiological; Polysomnography; Preclinical Testing; Quality of life; Randomized; Refractory; Research; Risk; Running; Schools; Seizures; Sensitivity and Specificity; Site; Stigmatization; Stimulus; Stream; Temporal Lobe; Temporal Lobe Epilepsy; Testing; Thalamic structure; Therapeutic; Work; behavior test; cloud based; conventional therapy; detector; diaries; improved; improved outcome; innovation; neuroimaging; open label; pre-clinical; prevent; primary outcome; safety and feasibility; safety testing; secondary outcome; social; sudden unexpected death in epilepsy; translational study; vehicular accident

PROJECT SUMMARY / ABSTRACT Impaired consciousness during seizures has a major negative impact on quality of life for people with epilepsy. Consequences include risk of motor vehicle accidents, drowning, poor work and school performance, and social stigmatization. Impaired ictal/postictal arousal may also compromise breathing leading to sudden unexpected death in epilepsy. Although the primary goal of epilepsy care is to stop seizures, restoring conscious awareness in patients whose seizures cannot be stopped (by medications, surgery or deep brain stimulation) could significantly improve outcome. Disorders of consciousness other than epilepsy have long been known to arise from dysfunction of subcortical-cortical arousal circuits. Deep brain stimulation (DBS) of the thalamic intralaminar central lateral nuclei (CL) is a promising approach to restore conscious arousal currently being trialed for chronic disorders of consciousness (N. Schiff, NINDS UH3 NS095554). Recent neuroimaging and EEG studies have shown that transient impaired consciousness in temporal lobe epilepsy (TLE) seizures also depends on subcortical-cortical arousal including thalamic CL. Translational studies from our research group further demonstrate depressed CL function in limbic seizures, and most importantly that thalamic CL stimulation has the potential to restore physiological and behavioral arousal in the ictal and postictal periods. DBS treatment of epilepsy has advanced rapidly with FDA approval of responsive neurostimulation (RNS, NeuroPace) and thalamic anterior nucleus stimulation (Medtronic). Investigational devices such as the RC+S (Medtronic) provide a unique opportunity for responsive stimulation of up to 4 separate brain regions, enabling conventional sites such as hippocampus (HC) to be combined with innovative targets such as thalamic CL. Meanwhile, Dr. Worrell’s group at Mayo has developed the Epilepsy Personal Assistant Device (EPAD), a custom application running on a hand-held device with bi-directional communication with the RC+S. The EPAD will enable cloud-based data storage, seizure diaries, and automatic behavioral tests similar to those we have validated previously. Therefore, our goal is to develop and pilot test the feasibility and safety of bilateral thalamic CL stimulation using RC+S to restore conscious arousal in TLE seizures which are not stopped by conventional responsive neurostimulation, offering hope to greatly improve quality of life in these patients. Our aims are to first conduct final benchtop preclinical verification of RC+S and EPAD algorithms for CL stimulation leading to FDA IDE approval. Second, we will initiate a small clinical trial implanting RC+S in patients with refractory TLE and beginning with open-label HC stimulation and baseline EPAD behavioral testing. Third, we will adjust responsive thalamic CL stimulation parameters for arousal. Finally, we will test safety and initial feasibility of responsive CL stimulation to restore arousal during seizures.

项目概要/摘要 癫痫发作期间意识受损对癫痫患者的生活质量产生重大负面影响。 后果包括机动车事故、溺水、工作和学习表现不佳的风险，以及 社会污名化。发作/发作后觉醒受损也可能会影响呼吸，导致突发性呼吸困难。 癫痫意外死亡。尽管癫痫治疗的主要目标是停止癫痫发作，但 无法停止癫痫发作（通过药物、手术或深部脑部治疗）的患者的意识意识 刺激）可以显着改善结果。长期以来，除癫痫以外的意识障碍 已知是由皮层下-皮层唤醒回路功能障碍引起的。深部脑刺激（DBS） 丘脑板内中央外侧核（CL）是恢复意识唤醒的一种有前途的方法 目前正在针对慢性意识障碍进行试验（N. Schiff，NINDS UH3 NS095554）。最近的 神经影像学和脑电图研究表明，颞叶癫痫患者存在短暂性意识障碍 (TLE) 癫痫发作还取决于皮质下-皮质唤醒，包括丘脑 CL。转化研究来自 我们的研究小组进一步证明了边缘叶癫痫发作时 CL 功能下降，最重要的是 丘脑 CL 刺激有可能恢复发作期和发作期的生理和行为唤醒 后期。随着 FDA 批准有效的 DBS 治疗癫痫，进展迅速 神经刺激（RNS、NeuroPace）和丘脑前核刺激（美敦力）。研究性的 RC+S（Medtronic）等设备提供了独特的机会，可进行最多 4 次的响应刺激 分离的大脑区域，使海马体 (HC) 等传统部位能够与创新部位相结合 丘脑 CL 等目标。与此同时，梅奥大学沃勒尔博士的团队开发了癫痫个人 助理设备 (EPAD)，一种在手持设备上运行的自定义应用程序，具有双向功能 与 RC+S 通信。 EPAD 将实现基于云的数据存储、癫痫日记和自动 行为测试与我们之前验证的类似。因此，我们的目标是开发和试点 使用 RC+S 双侧丘脑 CL 刺激恢复 TLE 意识觉醒的可行性和安全性 常规反应性神经刺激无法阻止的癫痫发作，有望大大改善 这些患者的生活质量。我们的目标是首先对 RC+S 进行最终的台式临床前验证 用于 CL 刺激的 EPAD 算法获得 FDA IDE 批准。其次，我们将启动一个小型临床试验 在难治性 TLE 患者中植入 RC+S，并从开放标签 HC 刺激和基线开始 EPAD 行为测试。第三，我们将调整丘脑 CL 刺激参数以实现唤醒。 最后，我们将测试反应性 CL 刺激在癫痫发作期间恢复觉醒的安全性和初步可行性。