Paired brain and spinal cord stimulation to strengthen spinal sensorimotor circuits

摘要 经验通过神经回路的相关活动导致行为变化。使用这个 原则上，配对刺激被用来选择性地加强电路，目标是相对 运动皮质和运动神经元之间的稀疏连接，或皮质中感觉和运动的连接。在……里面 相反，我们建议通过下行运动连接的强烈相互作用来靶向脊髓 大直径传入神经，调节关节位置感觉和肌肉张力。在大鼠身上，亚种 阈值脊髓刺激，激活传入，强烈增强运动皮质诱发的肌肉 当反应被定时汇聚在脊髓中时。当重复执行配对时，存在健壮性 皮质和脊髓刺激的肌肉反应增强和改良的前肢 颈髓损伤(SCI)后的功能我们假设运动皮质和感觉脊椎的配对 脊髓刺激可促进颈髓感觉运动可塑性及术后功能恢复 SCI。AIM 1测试配对的时机和皮质活动的来源，这是正确靶向的关键问题。计时 据预测，汇聚在脊髓而不是皮质的强度最大。我们还将进行第一次测试 自主运动前内源性皮质活动触发的脊髓刺激与外源性刺激相比 大脑皮层刺激。内源性活动被预测为对目标肌肉更具特异性。AIM 2测试 特定的运动和感觉通路对大鼠双相刺激效应的必要性和充分性 SCI。化学遗传的失活被预测为必要的，并且与光遗传或电学配对。 刺激以显示充分性。最后，目标3测试重复运动皮质和背侧颈椎 脊髓损伤大鼠脊髓损伤超过10天后，皮质和脊髓兴奋性持续增加，改善 前肢技巧。总之，这些研究将填补关于联合可塑性本质的关键空白 感觉运动系统，并测试修复脊髓损伤后连接的新策略。我们的新战略将受到考验 用创新的工具。为了长期刺激清醒大鼠的颈髓，我们开发了一种 (&lt；50μm)电极放入硬膜外间隙时会软化，并已被证明是安全有效的 月份。皮质和脊髓电极使潜在的治疗性成对刺激和纵向 审问目标电路。前肢技能将通过我们的前肢后仰任务来衡量 发明的，以及对熟练行走和食物操纵的测试。对脊髓的输入将被操纵 使用特定于电路的病毒工具。因此，我们打算弥合我们对如何配对刺激的理解的空白 感觉运动回路应以脊髓为靶点，以及它对恢复是否有效。这 知识可以改变我们如何瞄准电刺激来诱导联想可塑性。运动皮质和 颈髓刺激是安全的，因此配对刺激可以迅速转化为临床试验。

SUMMARY Experience leads to behavioral change through the associated activity of neural circuits. Using this principle, paired stimulation has been used to selectively strengthen circuits, targeting either the relatively sparse connections between motor cortex and motoneurons or sensory and motor connections in cortex. In contrast, we propose to target the spinal cord through the strong interaction of descending motor connections and large diameter afferents, which mediate the senses of joint position and muscle tension. In rats, sub- threshold spinal cord stimulation, which activates afferents, strongly augments motor cortex evoked muscle responses when timed to converge in the spinal cord. When pairing is performed repeatedly, there is robust augmentation of muscle responses from stimulation of both cortex and spinal cord and improved forelimb function after cervical spinal cord injury (SCI). We hypothesize that pairing motor cortex and sensory spinal cord stimulation will promote sensorimotor plasticity in the cervical spinal cord and functional recovery after SCI. Aim 1 tests the timing of pairing and the source of cortical activity, key issues for proper targeting. Timing to converge in the spinal cord, as opposed to cortex, is predicted to be strongest. We will also test, for the first time, spinal stimulation triggered by endogenous cortical activity before voluntary movement versus exogenous cortical stimulation. Endogenous activity is predicted to be more specific for a targeted muscle. Aim 2 tests the necessity and sufficiency of specific motor and sensory pathways for the paired stimulation effect in rats with SCI. Inactivation with chemogenetic is predicted to show necessity, and paired optogenetic or electrical stimulation to show sufficiency. Finally, Aim 3 tests whether repetitive motor cortex and dorsal cervical spinal cord over 10 days in rats with SCI will lead to lasting increases in cortical and spinal excitability and improved forelimb skill. Together, these studies will fill critical gaps about the nature of associative plasticity in the sensorimotor system and test a new strategy to repair connections after SCI. Our novel strategy will be tested with innovative tools. To chronically stimulate the cervical spinal cord in awake rats, we have developed thin (<50μm) electrodes that soften when placed into the epidural space and have proved safe and effective over 4 months. Cortical and spinal electrodes enable both potentially therapeutic paired stimulation and longitudinal interrogation of the targeted circuits. Forelimb skill will be measured with a forelimb supination task we invented, as well as tests of skilled walking and food manipulation. Inputs to the spinal cord will be manipulated with circuit-specific viral tools. Thus, we intend to close gaps in our understanding of how paired stimulation of sensorimotor circuits should be targeted to the spinal cord and whether it is effective for recovery. This knowledge can change how we target electrical stimulation to induce associative plasticity. Motor cortex and cervical spinal cord stimulation are safe, so paired stimulation could be translated quickly to clinical trials.