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：
8700052
负责人：
HAL BLUMENFELD
金额：
$ 24.98万
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 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8700052
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 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 Therapy Clinical 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 public health relevance 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带来严重的后果，包括危险驾驶，工作/学校表现降低和社会污名化。患有医学和外科手术癫痫的患者经常患有意识障碍，没有可行的治疗选择。最近的神经影像学和电生理学发现表明，部分癫痫发作的意识受损与远离癫痫发作焦点的广泛区域的皮质功能有关。我们开发了一种大鼠模型，该模型复制了人类发现，包括电脑造影术（EEG）的慢波，脑血流减少（CBF）降低，在新皮层中的功能性MRI（fMRI）信号降低，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步表明，局灶性癫痫发作降低了皮层唤醒结构的活性，包括上脑干和丘脑内丘脑。反过来，这导致了缔合皮质的睡眠或昏迷变化，并在癫痫发作期间和之后的意识丧失。在其他意识障碍（例如最低意识状态）中，最近的工作表明，丘脑刺激会增加行为的唤醒。这些发现为一种新的治疗方法铺平了道路，以部分癫痫发作直接治疗意识受损：通过深脑刺激对皮层唤醒系统的重新激活。当前建议的目的是在大鼠模型中测试这种方法，从而为可能的人类治疗试验提供原则上的功效。我们的初步研究表明，刺激丘脑丘脑内层内侧核（CL）将皮质中的慢波活性转化为清醒的脑电图模式，并且还基于fMRI增加了皮质功能。因此，我们的目的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状况。我们将获得合适的治疗刺激参数，旨在基于电生理学和术中fMRI实现皮质激活。其次，我们将测试CL刺激的治疗功效，以提高清醒癫痫发作期间的皮质功能和行为反应能力。我们将在两种诱发的癫痫发作过程中测试刺激的效果，并响应自发性癫痫发作 - 使用类似于在人体设备中使用的闭环刺激在自发性癫痫发作中检测到。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，防止意识受损会大大改善生活质量。如果深脑刺激可以改善动物模型部分癫痫发作期间的皮质功能和意识，则可能会迅速导致这种新方法的人类治疗试验方法。