Cortical Stimulation to Enhance Motor Recovery Following Traumatic Brain Injury

描述(申请人提供)：这些研究的主要目的是确定皮质刺激结合运动康复治疗是否能改善创伤性脑损伤(TBI)后的运动功能。运动恢复被认为是一个重新学习的过程，在这个过程中，运动功能通过大脑备用区域的功能补偿重新获得。几个实验室已经证明，这种功能补偿是由康复驱动的残留神经回路中的突触可塑性支持的。先前对中风模型的研究也有力地表明，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质损伤中，运动损伤和减轻运动损伤的治疗策略是相同的。然而，用于治疗缺血性中风和挫伤后的最佳参数几乎肯定是不同的，因为它们的细胞反应模式、行为恢复的时间线和对康复训练的反应性非常不同。此外，由于脑外伤似乎对经验依赖的神经可塑性产生了持久的抵抗力，因此克服这种抵抗力的辅助治疗对于释放此类损伤后行为干预的潜力尤为关键。我们假设，在康复训练期间，有效的CS传递到挫伤的感觉运动皮质将导致更大的行为改善，这些改善将至少部分地通过增强剩余运动皮质的功能相关重组来支持。我们最近在受控皮质撞击(CCI)损伤大鼠模型中的初步数据支持CS RT可用于改善脑外伤后运动能力的可能性，这可能是由于其增强了运动皮质的可塑性。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续改善的有效性，并了解有效治疗与无效治疗的神经基础。拟议的研究将1)建立单侧CCI大鼠模型的最佳刺激参数；2)确定有效的CS是否增强了康复训练的运动皮质结构和功能反应，以及重新组织的皮质对于行为改善的必要性；3)研究CS诱导的改善是否存在敏感期；以及4)研究CS的效应是否持久以及治疗开始的时机是否影响CS的耐力。我们将结合敏感的行为测量、定量光学显微镜来分析神经元结构可塑性标志物的变化，以及皮质内微刺激(ICMS)映射来揭示运动皮质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一种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.