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来源，也是退伍军人康复的一个特殊挑战。尽管手术修复的技术已经取得了进步，但结果仍然不可预测。过去，外周与大脑的连接被认为是成年人固定的，但现在越来越多的人认识到，与移除外周感觉输入有关的大脑功能的可塑性。例如，已知的是，与失神经身体区域相关的感觉皮质被重新分配，在外科损伤修复后，紊乱的皮质功能持续存在。然而，肢体的成功使用不仅需要大脑与外周目标的连接，还需要大脑内众多活动的协调参与，包括与其他感觉部位以及运动、视觉和认知区域的互动。因此，我们假设，神经损伤修复后，大脑互动活动的中断是康复挑战的基础。现在有了新的非侵入性技术来评估大脑的综合表现。具体地说，功能磁共振成像(FMRI)可以显示大脑各个部位的协同激活，而静息状态功能连接磁共振(rs-fMRI)则可以显示在没有刺激的情况下大脑各部位之间的通信模式。我们的初步数据显示，在实验性神经损伤和修复后，协调大脑功能严重中断。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记物奠定基础，该标记物可以指导针对适当特定功能的个性化康复。我们的另一个目标是测试在修复后的康复阶段人工维持大脑传入感觉神经元的活动是否可以减轻或防止大脑的混乱。在此SPIRE应用程序中提出的工作中，我们将使用我们的新技术，在有限数量的动物中以纵向方式定义大脑对神经损伤/修复的反应，包括提供和不提供替代传入活动，从而获得初步观察结果，以证实我们的假设。此外，我们将开发利用可植入的光遗传光源来实现神经元刺激的方法，这些光源在病毒基因传递后激活感觉神经元中表达的光敏通道。我们认为，将康复的视角从神经修复扩展到包括脑功能，可能会打开一扇门，使康复评估、规划和成功达到一个新的水平。

 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.