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质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，在这个过程中，运动功能通过备用脑区的功能补偿而重新获得。几个实验室已经证明，这种功能补偿是由康复驱动的残余神经回路中的突触可塑性支持的。先前对脑卒中模型的研究也强烈表明，在运动康复训练（RT）期间给予皮质刺激（CS）可以增强行为改善和皮质可塑性。人们通常认为，在脑外伤和中风引起的运动皮层损伤之间，运动损伤以及减轻运动损伤的治疗策略是相同的。然而，缺血性中风和挫伤后治疗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似乎对经验依赖的神经可塑性产生了持久的抵抗，因此克服这种抵抗的辅助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，在康复训练期间，有效的CS传递给挫伤的感觉运动皮层，会引起更大的行为改善，而这些改善将得到支持，至少部分地，通过增强剩余运动皮层的功能相关重组。我们最近在控制性皮质撞击（CCI）损伤大鼠模型中的初步数据支持CS+RT可用于改善TBI后运动表现的可能性，这可能是其增强运动皮质可塑性的结果。然而，有必要更好地了解CS治疗的参数，以最大限度地提高其促进运动功能持久改善的有效性，并了解有效治疗与无效治疗的神经基础。拟进行的研究将：(1)建立大鼠单侧CCI模型的最佳刺激参数；2)确定有效的神经刺激是否能增强运动皮质对康复训练的结构和功能反应，以及重组皮质对行为改善的必要性；3)调查cs诱导改善的有效性是否存在一个敏感期；4)研究CS效应是否持久，以及开始治疗的时机是否影响CS的持续时间。我们将结合使用敏感的行为测量，定量光学显微镜来分析神经元结构可塑性标记物的变化，以及皮质内微刺激（ICMS）映射来揭示运动皮层的功能完整性和组织。这些研究有望为创伤性脑损伤幸存者提供潜在的强有力的治疗选择。

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.