Spinal sciatic direct current stimulation normalizes muscle tone in spinal cord injured animals with spasticity

 描述(申请人提供)：痉挛对生活质量有负面影响。它会导致疼痛和疲劳，干扰睡眠，限制日常活动，如行走、坐着和洗澡，并可能使康复努力复杂化。肌肉张力异常的管理是一个严重的挑战，有时是无法克服的。因此，旨在开发新的治疗干预措施的研究，如本提案中描述的那些，具有非常高的潜在意义。本应用旨在研究一种新的方法，即利用跨脊髓阈值下直流电刺激(TsDCS)来减轻脊髓损伤(SCI)小鼠异常肌张力的效果。我们的实验室正在测试亚阈值直流电可以调节脊髓兴奋性这一普遍假设。我们正在进行参数研究，包括与其他刺激策略相结合，以优化tsDCS的效果。 我们的初步数据首次表明，施加脊髓-坐骨神经直流电刺激(DC)可以降低或增强麻醉SCI小鼠的紧张性或相性牵张反应(取决于电流的方向)。这项建议旨在进一步研究麻醉和清醒动物的脊髓-坐骨神经DCs。其具体目的是测试：1)较长时间的脊髓-坐骨神经DCS对麻醉脊髓损伤动物肌肉张力和皮质输出的长期影响，2)脊髓-坐骨神经DCS对清醒的挫伤后痉挛动物的短期影响，以及3)重复的脊髓-坐骨神经DCS对脊髓损伤动物痉挛和熟练运动恢复的长期影响。我们已经开发了一种测试系统，可以可靠地测量麻醉小鼠的痉挛，定义为肌肉张力的速度依赖性增加，我们将使用这一建议来调整该系统来测量清醒动物的痉挛。一种植入式系统将被用来在清醒的动物身上传递重复的脊髓-坐骨神经DCs。这种方法有望永久性地减弱脊髓损伤后的痉挛状态，提高熟练运动能力的恢复。此外，根据我们的初步结果，所提出的方法还可以用于治疗刺激期间的痉挛，因为它不会阻止从脊髓或大脑到肌肉目标的正常信号(例如在行走期间)。首要目标是证明概念的证据，这将为将拟议的方法转化为人类管理痉挛或恢复正常肌肉张力提供基础。

 DESCRIPTION (provided by applicant): Spasticity negatively influences quality of life. It causes pain and fatigue, disturbs sleep, restricts daily activities like walking, sitting, and bathng, and can complicate rehabilitation efforts. Management of muscle tone abnormalities is a serious challenge that is sometimes insurmountable. Thus, investigations designed to develop novel therapeutic interventions, such as those described in this proposal, have very high potential significance. This application aims to investigate effects of a new method that utilizes trans-spinal subthreshold direct current stimulation (tsDCS) to attenuate abnormal muscle tone in mice with spinal cord injury (SCI). Our laboratory is testing the general hypothesis that subthreshold direct current can modulate spinal excitability. We are performing parametric studies, including combination with other stimulation strategies, to optimize the effects of tsDCS. Our preliminary data are the first to show that applying spinal-sciatic direct current stimulation (DCS) can decrease or increase tonic or phasic stretch responses (depending on the direction of the current) in anesthetized SCI mice. This proposal aims to further investigate spinal-sciatic DCS in anesthetized and awake animals. The specific aims are to test: 1) long-term effects of longer duration spinal-sciatic DCS on muscle tone and cortical outputs in anesthetized SCI animals, 2) short-term effects of spino-sciatic DCS in awake animals with spasticity following contusive SCI, and 3) long-term effects of repetitive spinal-sciatic DCS on spasticity and recovery of skilled locomotion in animals with SCI. We have developed a testing system that can reliably measure spasticity, defined as velocity-dependent increase in muscle tone, in anesthetized mice, and we will use this proposal to adapt the system to measure spasticity in awake animals. An implantable system will be used to deliver repetitive spinal-sciatic DCS in awake animals. This approach is expected to permanently attenuate spasticity and improve recovery of skilled locomotion after SCI. Moreover, according to our preliminary results, the proposed approach can also be used to manage spasticity during the stimulation period because it does not block normal signals from the spinal cord or brain to muscle targets (e.g. during walking). The overarching goal is to demonstrate proof of concept, which will provide the basis to translate the proposed approach to humans to manage spasticity or restore normal muscle tone.