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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的这项研究的总体目标是开发和转化有效的基于神经刺激的疗法促进继发于获得性脑损伤的慢性、持续性缺陷患者的神经功能恢复。尽管急性干预策略取得了进展，但创伤性脑损伤 (TBI) 仍然是长期脑损伤的主要原因。在美国，长期残疾一直需要新的方法来促进康复和治疗幸存者的康复。我们的小组之前已经证明，侧脑深部刺激（DBS）小脑核 (LCN) 是上行齿丘丘脑皮质 (DTC) 通路的起源，具有广泛的应用（通过丘脑）跨越额叶和顶叶皮质区域以及基底神经节的影响，增强大脑中动脉缺血慢性啮齿动物模型的运动康复。治疗收益为与病灶周围大脑皮质兴奋性的变化、增强的大脑皮质重组相关，以及病灶周围皮层突触发生增加的证据。在这里，我们将评估是否有治疗作用对于 TBI 后持续的运动和认知缺陷，使用受控的方法也可以类似地实现益处啮齿类动物的皮质影响（CCI）模型。此外，我们将进一步表征 LCN DBS 诱导的生理学特征以及病变周围皮质区域发生的细胞变化。除了支持证据之外我们之前对大脑中动脉缺血的啮齿动物模型的研究以及我们对人类的早期结果提供了通过翻译这项工作，我们提供了行为功效和潜在生理学的初步证据两种治疗模型的机制：液体冲击损伤（FPI）TBI后诱发运动缺陷的大鼠感觉运动皮层以及双额 CCI 靶向后表现出认知缺陷的动物内侧前额皮质区域。在当前的提案中，我们的具体目标是 1) 确认并扩展我们的关于 LCN DBS 对 TBI 后运动恢复影响的初步结果，2) 评估潜在的 LCN DBS 改善 TBI 后认知功能，3) 表征 LCN DBS 介导的病灶周围和 CCI损伤后DTC通路重组； 4）检查细胞和分子的变化与 LCN DBS 相关的病灶周围皮质区域。这项研究将提供临床前证据和支持表彰这种新的治疗方法未来的转化努力，以增强慢性、创伤后脑损伤后的缺陷。