Deep brain stimulation to prevent impaired consciousness in epilepsy

深部脑刺激可预防癫痫意识障碍

• 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
• 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

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/学习成绩下降和社会耻辱。药物和手术难治性癫痫患者通常患有 部分性癫痫伴意识受损，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，部分性癫痫发作中的意识受损与远离癫痫发作病灶的广泛区域的皮质功能低下有关。我们已经开发了一种复制人类发现的大鼠模型，包括脑电图（EEG）上的慢波、脑血流量（CBF）减少和新皮层中功能性MRI（fMRI）信号减少，以及癫痫发作期间的行为停滞。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的活动，包括上脑干和板内丘脑。这反过来又导致联合皮层的睡眠或昏迷样变化，以及癫痫发作期间和之后的意识丧失。在其他意识障碍中，如最低意识状态，最近的工作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的意识障碍的新治疗方法铺平了道路：通过深部脑刺激重新激活皮层下唤醒系统。目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性功效证明。我们的初步研究表明，丘脑喙部板内中央外侧核（CL）的刺激转换成清醒的脑电图模式在皮层中的慢波活动，也增加了基于功能磁共振成像的皮层功能。因此，我们的目标是首先在全身麻醉下测试CL丘脑刺激，以模拟手术器械植入期间的条件。我们将获得合适的治疗刺激参数，旨在实现基于电生理学和术中功能磁共振激活皮层。第二，我们将测试CL刺激在清醒的行为动物癫痫发作期间改善皮质功能和行为反应性的治疗效果。我们将测试在诱发癫痫发作期间刺激的效果，以及对自发性癫痫的响应-使用类似于人体设备中采用的闭环刺激自动检测。虽然停止癫痫发作是理想的，但对于癫痫发作无法停止的患者，预防意识受损将大大提高生活质量。如果脑深部电刺激可以在动物模型中改善部分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。