Cortical Stimulation to Enhance Motor Recovery Following Traumatic Brain Injury

描述（由申请人提供）：这些研究的主要目的是确定皮层刺激联合运动康复治疗是否会改善创伤性脑损伤（TBI）后的运动功能。运动恢复被认为是一个“再学习”的过程，其中运动功能通过备用脑区域内的功能补偿重新获得。几个实验室已经证明，这种功能补偿是由残余神经回路内的突触可塑性支持的，这些神经回路是由康复驱动的。先前在中风模型中的研究也强烈地表明，在运动康复训练（RT）期间通过给予皮层刺激（CS）来增强行为改善和皮层可塑性。人们通常认为，运动障碍，从而减轻他们的治疗策略，是相同的TBI和中风引起的运动皮层损伤。然而，用于治疗缺血性中风和挫伤后的最佳参数几乎肯定会有所不同，因为它们具有非常不同的细胞反应模式，行为恢复的时间线和对康复训练的反应性。此外，由于TBI似乎对经验依赖性神经可塑性产生了持久的抵抗力，因此克服这种抵抗力的连续性治疗对于释放这种类型损伤后行为干预的潜力尤其重要。我们假设，在康复训练过程中，在挫伤的感觉运动皮层上提供有效的CS将诱导更大的行为改善，并且这些改善将至少部分地得到剩余运动皮层功能相关重组的增强的支持。我们最近的初步数据在大鼠模型中的控制性皮质撞击（CCI）损伤支持的可能性，CS + RT可用于改善运动性能TBI后，这可能是由于其增强运动皮层可塑性。然而，有必要更好地了解CS治疗的参数，最大限度地提高其促进运动功能持久改善的有效性，并了解有效与无效治疗的神经基础。本研究将1）在单侧CCI大鼠模型中建立最佳刺激参数; 2）确定有效CS是否增强运动皮层对康复训练的结构和功能反应以及重组皮层对行为改善的必要性; 3）调查CS诱导的改善效果是否存在敏感期;和4）研究CS效应是否持久以及治疗开始的时间是否影响CS持久性。我们将使用敏感的行为措施，定量光学显微镜分析神经元结构可塑性的标志物的变化，和皮质内微刺激（ICMS）映射，以揭示运动皮层的功能完整性和组织的组合。这些研究有望为创伤性脑损伤幸存者提供一种潜在的强大治疗选择。

DESCRIPTION (provided by applicant): The main objective of these studies is to determine if cortical stimulation combined with motor rehabilitative therapy will improve motor function following traumatic brain injury (TBI). Motor recovery is thought to be a process of "relearning" in which motor functions are reacquired through functional compensation within spared brain regions. Several laboratories have demonstrated that such functional compensation is supported by synaptic plasticity within residual neural circuits that are driven by rehabilitation. Previous studies in stroke models also strongly indicate that behavioral improvements and cortical plasticity are enhanced by administering cortical stimulation (CS) during motor rehabilitative training (RT). It is often assumed that motor impairments, and thus treatment strategies to alleviate them, are the same between TBI- and stroke-induced motor cortex damage. However, the optimal parameters used for treatment following ischemic stroke and contusion injury are almost certain to vary because they have very different patterns of cellular responses, time-line of behavioral recovery and responsiveness to rehabilitative training. Furthermore, because TBI appears to create an enduring resistance to experience-dependent neural plasticity, it may be that adjunctive treatments that overcome this resistance are especially critical to unleash the potential of behavioral interventions after this type of injury. We hypothesize that effective CS delivered over the contused sensorimotor cortex during rehabilitative training will induce greater behavioral improvements and that these improvements will be supported, at least in part, by enhancement of functionally relevant reorganization of remaining motor cortex. Our recent preliminary data in a rat model of controlled cortical impact (CCI) injury supports the likelihood that CS+RT can be used to improve motor performance after TBI and that this may be a result of its enhancement of motor cortical plasticity. However there is a need to better understand the parameters of CS treatment that maximize its effectiveness for promoting enduring improvements in motor function and to understand the neural basis of effective versus ineffective treatment. The proposed studies will 1) establish optimal stimulation parameters in a rat model of unilateral CCI; 2) determine if effective CS enhances the motor cortical structural and functional responses to rehabilitative training and the necessity of the reorganized cortex for the behavioral improvements; 3) investigate if there is a sensitive period for the effectiveness of CS-induced improvements; and 4) investigate if CS effects are enduring and if timing of treatment initiation affects CS endurance. We will use a combination of sensitive behavioral measures, quantitative light microscopy to assay changes in markers of neuronal structural plasticity, and intracortical microstimulation (ICMS) mapping to reveal the functional integrity and organization of motor cortex. These investigations are expected to provide support for a potentially powerful treatment option for survivors of traumatic brain injuries.