Deep Brain Stimulation of the Cerebellar Dentate Nucleus to Enhance Chronic, Post-Traumatic Brain Injury Rehabilitation

小脑齿状核的深部脑刺激可增强慢性、创伤后脑损伤的康复

• 批准号: 10204143
• 负责人: KENNETH B BAKER
• 金额: $ 50.85万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10204143
• 关键词: Acute; Animals; Anxiety; Area; BRAIN initiative; Basal Ganglia; Behavioral; Brain Injuries; Cerebellar Nuclei; Cerebrum; Chronic; Cognitive; Cognitive deficits; Contralateral; Data; Deep Brain Stimulation; Dentate nucleus; Electric Stimulation; Experimental Designs; Family; Frequencies; Future; Glutamates; Goals; Homologous Gene; Human; Individual; Infarction; Injury; Intervention; Ischemia; Ischemic Stroke; Lateral; Learning; Lesion; Link; Long-Term Potentiation; Magnetic Resonance Imaging; Manganese; Maps; Medial; Mediating; Memory; Mission; Modeling; Molecular; Motor; Motor Activity; National Institute of Neurological Disorders and Stroke; Nature; Occupational Therapy; Outcome; Parietal; Pathway interactions; Patients; Pattern; Phase I Clinical Trials; Physical therapy; Physiological; Physiological Processes; Prefrontal Cortex; Process; Public Health; Quality of life; Rattus; Recovery; Rehabilitation therapy; Research; Rodent; Rodent Model; Role; Secondary to; Severities; Societies; Speech Therapy; Stroke; Structure; Survivors; System; Thalamic structure; Therapeutic; Therapeutic Intervention; Time; Tissue Sample; Tissues; Translating; Translations; Traumatic Brain Injury; United States; United States National Institutes of Health; Work; base; cognitive disability; cognitive enhancement; cognitive function; cognitive recovery; controlled cortical impact; daily functioning; design; disability; fluid percussion injury; functional improvement; improved; injury recovery; insight; memory retention; microstimulation; middle cerebral artery; motor deficit; motor recovery; motor rehabilitation; neurological recovery; novel strategies; novel therapeutic intervention; post stroke; pre-clinical; primary outcome; response; spatial memory; stroke patient; synaptogenesis; therapeutically effective

ABSTRACT The overall goal of this research is to develop and translate effective neurostimulation-based therapies to facilitate neurologic recovery for patients with chronic, persistent deficits secondary to acquired brain injury. Despite progress in acute intervention strategies, traumatic brain injury (TBI) remains a leading cause of long- term disability in the United States and there is an on-going need for novel approaches to facilitate recovery and rehabilitation for survivors. Our group has shown previously that deep brain stimulation (DBS) of the lateral cerebellar nucleus (LCN), the origin of the ascending dentatothalamocortical (DTC) pathway with widespread influence (via thalamus) across frontal and parietal cortical regions as well as to the basal ganglia, enhances motor rehabilitation in a chronic rodent model of middle cerebral artery ischemia. Therapeutic gains were associated with changes in perilesional cerebral cortical excitability, enhanced cerebral cortical reorganization, and evidence of increased synaptogenesis in perilesional cortex. Here, we will evaluate whether therapeutic benefit can be similarly realized for persistent motor and cognitive deficits following TBI, using a controlled cortical impact (CCI) model in rodents. Moreover, we will further characterize the LCN DBS-induced physiological and cellular changes that occur across perilesional cortical regions. In addition to the supporting evidence afforded by our prior work in rodent models of middle cerebral artery ischemia and our early results from human translation of that work, we provide preliminary evidence of behavioral efficacy and underlying physiological mechanisms in two treatment models: rats with induced motor deficits following fluid percussion injury (FPI) TBI over sensorimotor cortex as well as animals that showed cognitive deficits following bi-frontal CCI targeting medial prefrontal cortical regions. In the current proposal, our specific aims are 1) to confirm and extend our preliminary findings regarding LCN DBS' effects on post-TBI motor recovery, 2) to evaluate the potential LCN DBS to improve post-TBI cognitive function, 3) to characterize the nature of LCN DBS-mediated perilesional and DTC pathway reorganization post-CCI injury; and 4) to examine the cellular and molecular changes in perilesional cortical regions associated with LCN DBS. This study will provide preclinical evidence and support for future translational efforts of this novel therapeutic approach to enhancing chronic, post-TBI deficits.

摘要 这项研究的总体目标是开发有效的神经刺激疗法并将其转化为 促进继发于获得性脑损伤的慢性持续性缺陷患者的神经康复。 尽管在急性干预策略方面取得了进展，但创伤性脑损伤(TBI)仍然是长期脑损伤的主要原因。 在美国有长期残疾，持续需要新的方法来促进康复和 幸存者的康复。我们的小组以前已经证明，外侧脑深部刺激(DBS) 小脑核(LCN)，齿状皮质(DTC)上行通路的起源，具有广泛的 通过丘脑对额叶和顶叶皮质区域以及对基底节的影响，增强 慢性大脑中动脉缺血啮齿动物模型的运动康复。治疗上的收获是 与皮损周围大脑皮层兴奋性的变化，增强的大脑皮层重组， 而且有证据表明，皮损周围皮质中的突触发生增加。在这里，我们将评估是否具有治疗作用 对于脑外伤后的持续性运动和认知障碍，使用受控的 啮齿动物皮质撞击(CCI)模型。此外，我们还将进一步表征LCN DBS诱导的生理 以及发生在皮损周围皮质区域的细胞变化。除了支持证据之外 由我们先前在啮齿动物大脑中动脉缺血模型上的工作和我们在人类身上的早期结果所提供的 这项工作的翻译，我们提供了行为有效性和潜在的生理效应的初步证据 两种治疗模型：大鼠液压冲击伤后诱发运动功能障碍的机制 感觉运动皮质以及双额叶CCI靶向后表现出认知缺陷的动物 内侧前额叶皮质区域。在目前的提案中，我们的具体目标是：1)确认和延长我们的 LCN DBS对颅脑损伤后运动恢复影响的初步研究：2)评估潜在的LCN DBS改善脑损伤后认知功能，3)表征LCN DBS介导的周围和 DTC途径在CCI损伤后的重组；4)检测脑损伤后的细胞和分子变化。 与LCN DBS相关的皮质区。这项研究将为临床前研究提供证据和支持 为这一新的治疗方法的未来翻译努力，以增强慢性，脑外伤后的缺陷。