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造成严重后果，包括危险驾驶、工作/学习成绩下降和社会污名化。内科和外科治疗难治性癫痫的患者通常患有