Deep brain stimulation to prevent impaired consciousness in epilepsy

深部脑刺激可预防癫痫意识障碍

基本信息

批准号：
8804292
负责人：
HAL BLUMENFELD
金额：
$ 20.81万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8804292
关键词：
Adverse effects Anesthesia procedures Animal Model Animals Arousal Automobile Driving Behavior Behavioral Brain Stem Cell Nucleus Cerebrovascular Circulation Characteristics Clinical Clinical Trials Collaborations Coma Complex Conscious Consciousness Disorders Deep Brain Stimulation Depressed mood Devices Drowning Electroencephalography Electrophysiology (science)Epilepsy Focal Seizure Functional Imaging Functional Magnetic Resonance Imaging Functional disorder Funding General Anesthesia Goals Health Hippocampus (Brain)Human Image Impairment Laboratories Lateral Lateral Nuclear Group Lead Minimally Conscious States Modeling Monitor National Institute of Neurological Disorders and Stroke Neocortex Neurobiology Operative Surgical Procedures Outcome Patients Pattern Performance Pharmaceutical Preparations Physiological Pilocarpine Quality of life Rattus Refractory Rodent Rodent Model Schools Seizures Signal Transduction Sleep Stigmatization Stimulus Structure System Testing Thalamic structure Therapeutic Therapeutic Trials Translating Translational Research Translations Treatment Efficacy U-Series Cooperative Agreements Unconscious State Work adverse outcome association cortex awake base behavior test design efficacy testing encephalography experience implantation improved neocortical neuroimaging new therapeutic target novel strategies novel therapeutic intervention prevent programs research study response safety testing social therapy development treatment trial vehicular accident

项目摘要

DESCRIPTION (provided by applicant): Impaired consciousness during epileptic seizures has serious consequences, including hazardous driving, decreased work/school performance and social stigmatization. Patients with medically and surgically refractory epilepsy often suffer from partial seizures with impaired consciousness, and no viable treatment options. Recent neuroimaging and electrophysiology findings suggest that impaired consciousness in partial seizures is related to depressed cortical function in widespread regions remote from the seizure focus. We have developed a rat model that replicates the human findings, including slow waves on electro- encephalography (EEG), decreased cerebral blood flow (CBF) and decreased functional MRI (fMRI) signals in the neocortex, as well as behavioral arrest during seizures. Advances based on both human work and the rat model demonstrates that focal seizures decrease activity in subcortical arousal structures including the upper brainstem and intralaminar thalamus. This in turn leads to sleep- or coma-like changes in the association cortex, and to loss of consciousness during and following seizures. In other disorders of consciousness, such as minimally conscious state, recent work has shown that thalamic stimulation can increase behavioral arousal. These finding pave the way for a new therapeutic approach to directly treat impaired consciousness in partial seizures: reactivation of the subcortical arousal systems through deep brain stimulation. The goal of the current proposal is to test this approach in the rat model, providing proof-of-principle efficacy for possible human therapeutic trials. Our preliminary studies suggest that stimulation of the rostral thalamic intralaminar centro-lateral nucleus (CL) converts slow wave activity in the cortex into an awake EEG pattern, and also increases cortical function based on fMRI. Therefore our aims are to first test CL thalamic stimulation under general anesthesia, to emulate the conditions during surgical device implantation. We will obtain suitable therapeutic stimulus parameters aimed to achieve cortical activation based on electrophysiology and intraoperative fMRI. Second, we will test the therapeutic efficacy of CL stimulation to improve cortical function and behavioral responsiveness during seizures in awake, behaving animals. We will test the effects of stimulation during both evoked seizures, and in response to spontaneous seizures-automatically detected using closed-loop stimulation similar to that employed in human devices. Although stopping seizures is ideal, for patients in whom seizures cannot be stopped, preventing impaired consciousness would greatly improve quality of life. If deep brain stimulation can improve cortical function and consciousness during partial seizures in an animal model, this may rapidly lead to translation of this new approach to human treatment trials.

描述（由申请人提供）：癫痫发作期间意识受损会产生严重后果，包括危险驾驶、工作/学校表现下降和社会耻辱。药物和手术难治性癫痫患者经常患有以下疾病：部分性癫痫发作伴有意识障碍，并且没有可行的治疗方案。最近的神经影像学和电生理学研究结果表明，部分性癫痫发作时的意识受损与远离癫痫病灶的广泛区域的皮质功能下降有关。我们开发了一种大鼠模型，可以复制人类的发现，包括脑电图（EEG）慢波、大脑血流量（CBF）减少和新皮质功能性磁共振成像（fMRI）信号减少，以及癫痫发作期间的行为停止。基于人类工作和大鼠模型的进展表明，局灶性癫痫发作会降低皮质下唤醒结构（包括上脑干和层内丘脑）的活动。这反过来会导致关联皮层发生睡眠或昏迷样变化，并导致癫痫发作期间和癫痫发作后意识丧失。在其他意识障碍中，例如最低意识状态，最近的研究表明丘脑刺激可以增加行为唤醒。这些发现为直接治疗部分性癫痫发作中意识受损的新治疗方法铺平了道路：通过深部脑刺激重新激活皮质下唤醒系统。当前提案的目标是在大鼠模型中测试这种方法，为可能的人类治疗试验提供原理验证功效。我们的初步研究表明，刺激丘脑头侧层板内中央外侧核（CL）可将皮质中的慢波活动转化为清醒脑电图模式，并且基于功能磁共振成像（fMRI）也可增强皮质功能。因此，我们的目标是首先在全身麻醉下测试 CL 丘脑刺激，以模拟手术装置植入过程中的条件。我们将根据电生理学和术中功能磁共振成像获得合适的治疗刺激参数，旨在实现皮层激活。其次，我们将测试 CL 刺激的治疗效果，以改善清醒、行为动物癫痫发作期间的皮质功能和行为反应性。我们将测试诱发癫痫发作期间的刺激效果以及对自发癫痫发作的反应 - 使用类似于人体设备中使用的闭环刺激自动检测。尽管停止癫痫发作是理想的选择，但对于无法停止癫痫发作的患者来说，预防意识障碍将大大提高生活质量。如果深部脑刺激可以改善动物模型部分性癫痫发作期间的皮质功能和意识，这可能会迅速导致这种新方法转化为人类治疗试验。