Thalamic stimulation to prevent impaired consciousness in epilepsy

丘脑刺激可预防癫痫意识障碍

• 批准号: 10477293
• 负责人: HAL BLUMENFELD
• 金额: $ 180.19万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10477293
• 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; Persons; Pharmaceutical Preparations; Phase; Physiological; Polysomnography; Preclinical Testing; Quality of life; Randomized; Refractory; Research; Risk; Running; Schools; Seizures; Sensitivity and Specificity; Site; Stigmatization; Stimulus; Temporal Lobe; Temporal Lobe Epilepsy; Testing; Thalamic structure; Therapeutic; Work; behavior test; cloud based; conventional therapy; data streams; detector; diaries; improved; improved outcome; innovation; neuroimaging; open label; pilot test; 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.

项目总结/摘要 癫痫发作期间意识受损对癫痫患者的生活质量有重大负面影响。 后果包括机动车事故、溺水、工作和学习成绩差的风险，以及 社会污名化发作/发作后觉醒受损也可能影响呼吸，导致突发性 癫痫意外死亡虽然癫痫护理的主要目标是阻止癫痫发作， 癫痫发作无法停止（通过药物、手术或脑深部）的患者的意识觉醒 刺激）可以显著改善结果。除了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。脑深部电刺激（DBS） 丘脑板内中央外侧核（CL）是恢复意识觉醒的一个有前途的途径 目前正在接受慢性意识障碍（N。Schiff，NINDS UH3 NS 095554）。最近 神经影像学和脑电图研究表明，颞叶癫痫的短暂意识障碍 (TLE)癫痫发作还依赖于包括丘脑CL的皮质下-皮质唤醒。翻译研究从 我们的研究小组进一步证明了边缘癫痫发作中CL功能的抑制，最重要的是， 丘脑CL刺激具有恢复发作期生理和行为唤醒的潜力， 发作后时期DBS治疗癫痫的进展迅速，FDA批准了反应性 神经刺激（RNS，NeuroPace）和丘脑前核刺激（Medtronic）。试验用 诸如RC+S（Medtronic）的装置提供了用于高达4 分离的大脑区域，使海马体（HC）等传统部位能够与创新的 靶点如丘脑CL。与此同时，沃勒尔博士在马约的研究小组开发了一种名为“癫痫个人”的 助理设备（EPAD），在手持设备上运行的自定义应用程序，具有双向 与RC+S通信。EPAD将实现基于云的数据存储，扣押日记和自动 行为测试类似于我们以前验证过的那些。因此，我们的目标是开发和试点测试 双侧丘脑CL电刺激RC+S恢复TLE清醒的可行性和安全性 癫痫发作不能通过传统的反应性神经刺激停止，这为极大地改善 这些患者的生活质量。我们的目标是首先进行RC+S的最终实验室临床前验证， CL刺激的EPAD算法获得FDA IDE批准。其次，我们将启动一项小型临床试验 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，我们将调整反应性丘脑CL刺激参数唤醒。 最后，我们将测试响应CL刺激在癫痫发作期间恢复唤醒的安全性和初步可行性。