Central thalamic stimulation for traumatic brain injury

 描述（由申请人提供）：严重至中度创伤性脑损伤（smTBI）每年折磨数十万美国人，造成缺乏有效治疗的慢性认知障碍。本提案将开发一项关键的首次早期临床可行性研究，以支持提供中央丘脑脑深部电刺激（CT-DBS）的下一代器械。CT-DBS被提议作为smTBI幸存者的一种治疗方法，这些幸存者恢复到独立的功能水平，但B慢性认知障碍（持续注意力、工作记忆、处理速度和疲劳方面的困难），其活动仍然明显受限。利益相关者（包括患者）确认其认知困难与CT-DBS支持的功能相匹配，并表示支持这种方法，并愿意在向他们介绍这种方法的概念和风险后考虑参与。本研究的工作假设是，smTBI后观察到的认知缺陷模式起源于由smTBI产生的神经元连接的广泛减少和细胞损失，这将平均产生额纹状体系统的不成比例的下调和中央丘脑的传入阻滞（其共同支持通常在smTBI中受损的执行认知功能的范围），并且CT-DBS可以充分激活这些系统以提供有效的功能改善。初步研究，包括CT-DBS促进不同的，更严重的脑损伤人群的创伤性脑损伤患者的认知功能的证据，以及在完整的非人类灵长类动物（NHP）的临床前行为，电生理和计算建模研究支持的假设和方法。本研究将使用双侧放置的研究单电极系统的传感和记录能力，以帮助中央丘脑的电生理标测。我们的支持数据表明，行为促进可以实现与一个单一的电极系统在人类和NHP。在NHP研究中，我们发现，通过使用多电极系统可以实现更可靠和稳健的治疗反应，该系统能够在丘脑中央的特定纤维束上靶向输送电场。在这里，我们将获得和分析来自人类受试者的神经成像、计算建模、行为和电生理数据，以推进下一代系统的开发，该系统可以使CT-DBS在患者中的应用更具灵活性和可靠性。 脑外伤的病人这些研究将由一个调查团队进行，该团队与多个长期合作，旨在开发CT-DBS技术和TBI后认知障碍的治疗;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，放射学和计算建模方面的专业知识。建议的早期可行性研究已通过了美国食品药品监督管理局的试验用器械豁免的提交前审查。

 DESCRIPTION (provided by applicant): 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-an 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 b 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 thalams. 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.