Persisting functional CNS changes following peripheral nerve repair

 描述（由申请人提供）： 周围神经损伤是残疾的常见原因，也是退伍军人群体康复的一个特殊挑战。虽然外科修复技术已经取得了进展，但结果仍然不可预测。过去，人们认为成年人的外周与大脑的连接是固定的，但越来越多的人认识到，大脑功能的可塑性与外周感觉输入的去除有关。例如，已知与失神经支配的身体区域相关联的感觉皮层被重新分配，并且在手术损伤修复后，紊乱的皮层功能持续存在。然而，肢体的成功使用不仅需要大脑与周边目标的连接，还需要协调参与大脑内的许多活动，包括与其他感觉部位以及运动，视觉和认知区域的相互作用。因此，我们假设，干扰互动的大脑活动的神经损伤修复后的康复挑战的基础。新的非侵入性技术现在存在，以评估大脑的综合性能。具体来说，功能性磁共振成像（fMRI）可以指示各种大脑位点的协调激活，而静息状态功能性连接MRI（rs-fMRI）揭示了在没有刺激的情况下大脑位点之间的通信模式。我们的初步数据显示，在实验性神经损伤和修复后，协调的脑功能会受到实质性的破坏。我们的长期目标是在时间和解剖细节上定义这种现象，这将为开发一种成像生物标志物奠定基础，这种生物标志物可以指导针对适当特定功能的个性化康复。我们还有一个额外的目标，即测试在修复后的愈合阶段人工维持传入感觉神经元对大脑的活动是否可以减轻或防止大脑的混乱。在这项SPiRE应用程序中提出的工作中，我们将获得初步观察结果，以证实我们的假设，通过定义大脑对神经损伤/修复的反应，并在有限数量的动物中以纵向方式提供替代传入活动，使用我们的新技术。此外，我们将开发实现神经元刺激的方法，用于使用植入式光遗传学光源治疗未拴系动物，该光源在病毒基因递送后激活感觉神经元中表达的光敏通道。我们相信，将康复的视角扩展到神经修复之外，包括大脑功能，可能会为精细的康复评估，规划和成功打开一扇新的大门。

 DESCRIPTION (provided by applicant): Peripheral nerve injury is a frequent source of disability and a particular challenge for rehabilitation in the Veteran population. Although techniques for surgical repair have progressed, outcomes remain unpredictable. In the past, connections of the periphery to the brain had been thought to be fixed in adults, but there is a growing recognition of plasticity in brain function associated with removal of peripheral sensory input. For instance, it is known that sensory cortex associated with denervated body regions become reassigned, and disordered cortical function persists after repair of a surgical lesion. However, successful use of the limbs requires not just brain connections to peripheral targets, but also the coordinated participation o numerous activities within the brain, including interaction with other sensory sites as well as motor, visual, and cognitive areas. We therefore hypothesize that disruption of interactive brain activity underlies rehabilitation challenges after nerve injury repair. New noninvasive technology now exists to assess the integrated performance of the brain. Specifically, functional magnetic resonance imaging (fMRI) can indicate coordinated activation of various brain loci, while resting state functional connectivity MRI (rs-fMRI) reveals patterns of communication between brain sites in the absence of stimuli. Our preliminary data show substantial disruption of coordinated brain function following experimental nerve injury and repair. We have the long-term goals of defining this phenomenon in temporal and anatomic detail, which would lay the groundwork for developing an imaging biomarker that could guide personalized rehabilitation that targets appropriate specific functions. We have the additional goal of testing whether artificially maintaining afferent sensory neuron activity to the brain during the healing phase after repair may lessen or prevent brain disorganization. In the work proposed in this SPiRE application, we will obtain initial observations to substantiate our hypotheses by defining brain responses to nerve injury/repair with and without supplying replacement afferent activity, in a limited number of animals in a longitudinal fashion, using our novel techniques. Further, we will develop the means to achieve neuronal stimulation for treatment of untethered animals using implantable optogenetic light sources that activate photosensitive channels expressed in sensory neurons after viral gene delivery. We believe that extending the rehabilitation perspective beyond the nerve repair to include brain function may open the door to a new level of refined rehabilitation assessment, planning, and success.