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

 描述（由申请人提供）：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，如走路，坐着和洗澡，并可能使康复工作复杂化。肌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，如本提案中所述，具有非常高的潜在意义。本申请旨在研究一种新方法的效果，该方法利用跨脊髓阈下直流电刺激（tsDCS）来减弱脊髓损伤（SCI）小鼠的异常肌张力。我们的实验室正在测试阈下直流电可以调节脊髓兴奋性的一般假设。我们正在进行参数研究，包括与其他刺激策略的组合，以优化tsDCS的效果。 我们的初步数据是第一个表明，应用脊髓-坐骨神经直流电刺激（DCS）可以减少或增加紧张性或阶段性拉伸反应（取决于电流的方向）在麻醉SCI小鼠。该建议旨在进一步研究麻醉和清醒动物的脊髓-坐骨神经DCS。具体目的是测试：1）持续时间较长的脊髓-坐骨DCS对麻醉SCI动物的肌张力和皮质输出的长期影响，2）脊髓-坐骨DCS对挫伤性SCI后痉挛状态的清醒动物的短期影响，以及3）重复脊髓-坐骨DCS对SCI动物的痉挛状态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，可以可靠地测量痉挛，定义为速度依赖性增加肌肉张力，在麻醉小鼠，我们将使用这个建议，以适应系统来测量清醒动物的痉挛。将使用植入式系统在清醒动物中输送重复性脊髓-坐骨神经DCS。这种方法有望永久缓解痉挛状态，并改善SCI后熟练运动的恢复。此外，根据我们的初步结果，所提出的方法也可以用于在刺激期间管理痉挛，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）。总体目标是证明概念验证，这将为将所提出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.