Central thalamic stimulation for traumatic brain injury

项目摘要/摘要 严重到中度的创伤性脑损伤(SmTBI)每年折磨着成千上万的美国人。 造成缺乏有效治疗的慢性认知障碍。本提案将发展一个关键的 首例人类早期临床可行性研究，以支持下一代设备提供中央丘脑深部 脑刺激(CT-DBS)。CT-DBS被建议作为一种治疗SMTBI幸存者的方法，这些幸存者康复到 独立的功能水平，但他们的活动仍然受到慢性认知障碍的严重限制 (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， 包括患者认为他们的认知困难与建议支持的功能相匹配 CT-DBS表示支持这一方法，并愿意在获得 向他们介绍了这种方法的概念和风险。本研究的工作假设是， SMTBI后认知障碍的模式起源于神经元连接和细胞的广泛减少 SMTBI造成的损失，平均将导致额纹状体系统不成比例的下调 和中央丘脑的去传入(共同支持执行认知功能的范围 通常在SMTBI中受损)，CT-DBS可以充分激活这些系统，以提供有效的 功能上的改进。初步研究包括CT-DBS易化认知功能的证据 创伤性脑损伤患者和临床前患者的不同、更严重的脑损伤人群 非人灵长类动物(NHP)的行为、电生理和计算模型研究 支持这一假设和方法。本研究将使用双边放置的研究单一- 具有传感和记录能力的电极系统，以辅助中央的电生理标测 丘脑。我们的支持数据表明，行为促进可以通过单一电极来实现 在人类和自然资源保护系统中。在NHP的研究中，我们发现一种更可靠和更有力的治疗方法 可通过使用能够定向输送电能的多电极系统来实现响应 中央丘脑中特定纤维束上的视野。在这里，我们将获得并分析神经成像， 来自人类受试者的计算建模、行为和电生理数据，以促进 开发下一代系统，以实现更大的灵活性和可靠性 CT-DBS在颅脑损伤患者中的应用这些研究将由一个调查小组进行， 多项长期合作，旨在开发CT-DBS技术和治疗 颅脑损伤后的认知障碍；该团队拥有临床试验、神经学、神经外科、 神经生理学、神经康复、神经心理学、放射学和计算建模。最早的 建议的可行性研究已经通过了对调查设备豁免的提交前审查 与食品和药物管理局合作。

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.