Persisting functional CNS changes following peripheral nerve repair

周围神经修复后中枢神经系统功能持续变化

• 批准号: 9031926
• 负责人: Quinn H Hogan
• 金额: --
• 依托单位: CLEMENT J. ZABLOCKI VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9031926
• 关键词: Adult; Afferent Neurons; Anatomy; Anesthetics; Animals; Area; Attention; Behavioral; Body Regions; Brain; Central Nervous System Diseases; Clinical; Cognitive; Communication; Communication impairment; Data; Deafferentation procedure; Disease; Electric Stimulation; Electrophysiology (science); Elements; Esthesia; Event; Excision; Face; Functional Magnetic Resonance Imaging; Funding; Future; Goals; Healed; Imaging Techniques; Implanted Electrodes; Injury; Learning; Lesion; Light; Limb structure; Magnetic Resonance Imaging; Maps; Measures; Modality; Monitor; Nerve; Nerve Crush; Neurons; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Pattern; Performance; Peripheral; Peripheral Nerves; Peripheral nerve injury; Phase; Population; Process; Rattus; Recovery; Rehabilitation Outcome; Rehabilitation therapy; Research; Rest; Sensory; Severities; Signal Transduction; Site; Source; Stimulus; Techniques; Technology; Testing; Therapeutic; Time; Veterans; Work; design; dexterity; disability; healing; high risk; imaging biomarker; imaging modality; improved; injured; injury and repair; longitudinal design; nerve injury; nerve transection; novel; novel therapeutic intervention; operation; optogenetics; peripheral nerve transection; prevent; public health relevance; repaired; research study; response; sensory cortex; sensory input; sensory system; success; trafficking; viral gene delivery; visual motor

 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.

 描述（由申请人提供）： 周围神经损伤是导致残疾的常见原因，也是退伍军人康复的一个特殊挑战。尽管手术修复技术已经取得进步，但结果仍然难以预测。过去，人们认为成年人的外周与大脑的连接是固定的，但人们越来越认识到与去除外周感觉输入相关的大脑功能的可塑性。例如，众所周知，与失去神经的身体区域相关的感觉皮层会被重新分配，并且在手术损伤修复后，紊乱的皮层功能仍然存在。然而，成功使用四肢不仅需要大脑与周围目标的连接，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、视觉和认知区域的相互作用。因此，我们假设大脑交互活动的破坏是神经损伤修复后康复挑战的基础。现在存在新的非侵入性技术来评估大脑的综合性能。具体来说，功能磁共振成像 (fMRI) 可以指示各个大脑位点的协调激活，而静息态功能连接 MRI (rs-fMRI) 则可以揭示在没有刺激的情况下大脑部位之间的通信模式。我们的初步数据显示，实验性神经损伤和修复后，大脑协调功能受到严重破坏。我们的长期目标是在时间和解剖细节上定义这种现象，这将为开发成像生物标志物奠定基础，该标志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愈合阶段人为维持大脑传入感觉神经元活动是否可以减轻或防止大脑紊乱。在此 SPiRE 应用中提出的工作中，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，以纵向方式定义大脑对神经损伤/修复的反应，从而获得初步观察结果来证实我们的假设。此外，我们将开发一种方法来实现神经元刺激，使用可植入的光遗传学光源来治疗不受束缚的动物，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。我们相信，将康复视角从神经修复扩展到包括脑功能可能会为精细康复评估、规划和成功的新水平打开大门。