Central thalamic stimulation for traumatic brain injury

中枢丘脑刺激治疗创伤性脑损伤

• 批准号: 9929883
• 负责人: CHRISTOPHER R BUTSON
• 金额: $ 4.78万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9929883
• 关键词: Acute; Advanced Development; Adverse effects; American; Anatomy; Anterior; Arousal; Attention; Behavior; Behavior Control; Behavioral; Behavioral Model; Bilateral; Brain; Brain Injuries; Cells; Chronic; Clinical; Clinical Research; Clinical Trials; Cognitive; Cognitive deficits; Collaborations; Computer Simulation; Data; Databases; Deafferentation procedure; Deep Brain Stimulation; Deterioration; Development; Device Designs; Devices; Diffusion Magnetic Resonance Imaging; Dorsal; Down-Regulation; Electrodes; Electrophysiology (science); Elements; Family; Fatigue; Feasibility Studies; Fiber; Funding; Glasgow Outcome Scale; Goals; Human; Impaired cognition; Impairment; Implant; Individual; Investigation; Lead; Link; Measurement; Measures; Medial; Mediating; Mental Health; Microelectrodes; Mission; Modeling; Mus; National Institute of Neurological Disorders and Stroke; Neurology; Neurons; Neuropsychology; Neurorehabilitation; Outcome; Outcome Measure; Pathology; Patients; Pattern; Performance; Physiological; Population; Positioning Attribute; Primates; Prosencephalon; Psychometrics; Public Health; Quality of life; Radiology Specialty; Recovery; Regulation; Research; Resolution; Resources; Risk; Safety; Severities; Short-Term Memory; Sleep; Societies; Standardization; Statistical Models; Study models; Survivors; System; TBI Patients; Technology; Testing; Thalamic structure; Therapeutic Intervention; Translating; Traumatic Brain Injury; Treatment Efficacy; United States Food and Drug Administration; Variant; base; biophysical model; clinical development; cognitive capacity; cognitive disability; cognitive function; daily functioning; effective therapy; electric field; executive function; first-in-human; flexibility; functional disability; functional improvement; human data; human imaging; human subject; imaging study; implantation; improved; in situ imaging; neuroimaging; neurophysiology; neurosurgery; next generation; nonhuman primate; patient population; pre-clinical; preclinical study; processing speed; response; safety testing; social engagement; sustained attention; targeted delivery; technology development; treatment response; willingness

PROJECT SUMMARY/ABSTRACT Severe to moderate traumatic brain injury (smTBI) annually afflicts many hundreds of thousands of Americans producing chronic cognitive disabilities that lack effective treatments. The present proposal will develop a critical first-in-man early clinical feasibility study to support a next generation device to provide central thalamic deep brain stimulation (CT-DBS). CT-DBS is proposed as a therapy for the survivors of smTBI who recover to independent functional levels but remain significantly limited in their activities by chronic cognitive impairment (difficulties with sustained attentional effort, working memory, processing speed and fatigue). Stakeholders, including patients identifying their cognitive difficulties as matched to the functions proposed to be supported by CT-DBS, have shown support for this approach and willingness to consider participation after having the concepts and risks of this approach presented to them. The working hypothesis for the present study is that the pattern of cognitive deficits seen after smTBI takes origin in a broad reduction of neuronal connections and cell loss produced by smTBI that will on average produce disproportionate down-regulation of frontostriatal systems and deafferentation of the central thalamus (which collectively support the range of executive cognitive functions typically impaired in smTBI), and that CT-DBS can activate these systems sufficiently to provide effective functional improvements. Preliminary studies including evidence of CT-DBS facilitation of cognitive function in a different, more severely brain-injured population of patients with traumatic brain injuries as well as pre-clinical behavioral, electrophysiological, and computational modeling studies in intact non-human primates (NHP) support the hypothesis and the approach. The present study will use bilateral placement of a research single- electrode system with sensing and recording capabilities to aid the electrophysiological mapping of the central thalamus. Our supporting data demonstrate that behavioral facilitation can be achieved with a single electrode system in both the human and NHP. In NHP studies we have found that a more reliable and robust therapeutic response can be achieved through the use of a multiple electrode system capable of targeted delivery of electric fields across a specific fiber tract in the central thalamus. Here we will obtain and analyze neuroimaging, computational modeling, behavioral, and electrophysiological data from human subjects to advance the development of a next-generation system that may allow more flexibility and reliability of for the application of CT-DBS in patients with traumatic brain injuries. These studies will be carried out by an investigative team with multiple, long-standing collaborations aimed at the development of CT-DBS technologies and treatment of cognitive impairment following TBI; the team spans expertise in clinical trials, neurology, neurosurgery, neurophysiology, neurorehabilitation, neuropsychology, radiology, and computational modeling. The early feasibility study proposed has been through a presubmission review for an Investigational Device Exemption with the Food and Drug Administration.

项目概要/摘要 每年有数十万美国人遭受重度至中度创伤性脑损伤 (smTBI) 的折磨 产生缺乏有效治疗的慢性认知障碍。本提案将制定一个关键的 首次人体早期临床可行性研究，支持下一代设备提供中央丘脑深部 脑刺激（CT-DBS）。 CT-DBS 被提议作为 smTBI 幸存者的一种治疗方法，这些幸存者可以康复 独立的功能水平，但由于慢性认知障碍，其活动仍然受到显着限制 （持续注意力、工作记忆、处理速度和疲劳方面的困难）。利益相关者， 包括患者确定他们的认知困难与建议支持的功能相匹配 CT-DBS 表示支持这种方法，并愿意在获得批准后考虑参与 向他们介绍这种方法的概念和风险。本研究的工作假设是 smTBI 后出现的认知缺陷模式源于神经元连接和细胞的广泛减少 smTBI 产生的损失平均会导致额纹状体系统不成比例的下调 和中央丘脑的传入神经阻滞（共同支持一系列执行认知功能） 通常在 smTBI 中受损），并且 CT-DBS 可以充分激活这些系统以提供有效的 功能改进。初步研究包括 CT-DBS 促进认知功能的证据 不同的、更严重的脑损伤人群，包括创伤性脑损伤患者以及临床前的患者 完整非人类灵长类动物 (NHP) 的行为、电生理学和计算模型研究 支持假设和方法。本研究将使用研究单侧的双边放置 具有传感和记录功能的电极系统，可帮助绘制中枢的电生理图 丘脑。我们的支持数据表明，使用单个电极即可实现行为促进 人类和 NHP 中的系统。在 NHP 研究中，我们发现一种更可靠、更稳健的治疗方法 可以通过使用能够有针对性地输送电力的多电极系统来实现响应 穿过中央丘脑特定纤维束的场。在这里我们将获得并分析神经影像， 来自人类受试者的计算模型、行为和电生理学数据，以推进 开发下一代系统，可以为应用程序提供更大的灵活性和可靠性 CT-DBS 在脑外伤患者中的应用。这些研究将由一个调查小组进行 旨在开发 CT-DBS 技术和治疗 TBI 后认知障碍；该团队涵盖临床试验、神经病学、神经外科、 神经生理学、神经康复、神经心理学、放射学和计算模型。早期的 拟议的可行性研究已通过研究设备豁免的提交前审查 与食品和药物管理局。