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

摘要 这项研究的总体目标是开发和转化有效的神经刺激疗法， 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。 长期残疾在美国，有一个新的方法，以促进恢复和持续的需要， 幸存者的康复。我们的研究小组以前已经表明，侧脑室的脑深部电刺激（DBS） 小脑核（LCN）是齿状丘脑皮质（DTC）上行通路的起源， 对额叶和顶叶皮质区域以及基底神经节的影响（通过丘脑）增强 大脑中动脉缺血慢性啮齿动物模型的运动康复。治疗收益是 与病灶周围大脑皮层兴奋性的变化，增强的大脑皮层重组， 以及病灶周围皮质中突触发生增加的证据。在这里，我们将评估是否治疗 对于TBI后的持续性运动和认知缺陷，使用受控的 皮质撞击（CCI）模型。此外，我们将进一步表征LCN DBS诱导的生理学特性， 以及发生在病灶周围皮质区域的细胞变化。除了证据之外 由我们先前在啮齿动物大脑中动脉缺血模型中的工作和我们在人类大脑中动脉缺血模型中的早期结果提供。 翻译这项工作，我们提供了初步的证据，行为功效和潜在的生理 两种治疗模型的机制：液压冲击损伤（FPI）TBI后诱导运动缺陷的大鼠 以及在双额叶CCI靶向后表现出认知缺陷的动物 内侧前额叶皮质区在目前的提案中，我们的具体目标是：1）确认和扩大我们的 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介导的病灶周围病变的性质， CCI损伤后DTC通路重组;以及4）检查CCI损伤后DTC通路的细胞和分子变化。 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 对于这种新型治疗方法的未来转化努力，以增强慢性TBI后的缺陷。

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.