Spinal cord associative plasticity

摘要 经验通过神经回路的联想活动导致行为变化。利用这一原则， 配对刺激已经被用来选择性地加强神经回路。我们建议将脊髓作为治疗的目标 联想塑性，利用下行电机连接和大直径的强交互作用 传入，它调节关节位置和肌肉紧张的感觉。在大鼠和人类中，亚阈值 颈部刺激，激活传入，强烈增强运动皮质诱发的肌肉反应，当 定时汇聚在脊髓中。当大鼠重复配对时，脊髓联合 可塑性(SCAP)是随着兴奋性的大幅和持续增加而诱导的。在颈髓大鼠中 损伤(SCI)后，SCAP治疗10d后前肢功能明显改善。我们假设SCAP将 增强颈椎脊髓损伤患者的脊髓兴奋性，调节反射，增加捏合力。目标1 测试配对的时机和调节配对刺激的回路，这是正确定位的关键问题。计时 与皮质相反，皮质和脊柱在脊髓会聚的刺激被预测为最强的。 我们将同时使用无创和有创脊髓刺激。对于非侵入性刺激，我们将 将颈部的经皮刺激与皮质的经颅磁刺激相结合。为 侵入性刺激，我们将结合脊髓硬膜外刺激和经颅电刺激在 临床上有手术指征。目的2测试SCAP产生持续增加脊髓兴奋性的效果， 用皮质和脊髓诱发电位和捏压测力法测量。控件将隔离 特别是通过配对而引起的变化。最后，目标3测试配对的运动皮质和颈椎 脊髓刺激在患有脊髓损伤的两个最常见原因--颈椎病的患者中产生类似的效果 脊髓病和创伤性脊髓损伤，作为未受伤的参与者。脊椎兴奋性预计会增加，夹紧力 预计会变得更强，而脊椎反射预计会减弱。脊柱通路的完整性 将测量结果与生理和颈椎MRI分析结果进行比较。总之，这些研究将填补关键的空白。 关于感觉运动系统中联想可塑性的本质并测试一种新的强化策略 脊髓损伤后残留连接。这一策略将通过侵入性和非侵入性刺激进行测试， 首次允许对这些方法进行直接比较。因此，我们打算弥合我们在 了解成对刺激感觉运动回路应如何针对脊髓和 哪些残余电路支持可塑性。这些知识可以优化我们如何对准电刺激 诱导SCAP。运动皮质和颈髓刺激的多种方法已被证明是 安全，因此这些机制研究可以迅速转化为疗效试验。

SUMMARY Experience leads to behavioral change through associative activity of neural circuits. Using this principle, paired stimulation has been used to selectively strengthen circuits. We propose to target the spinal cord for associative plasticity, exploiting strong interaction of descending motor connections and large diameter afferents, which mediate the senses of joint position and muscle tension. In rats and humans, sub-threshold cervical stimulation, which activates afferents, strongly augments motor cortex evoked muscle responses when timed to converge in the spinal cord. When pairing is performed repeatedly in rats, spinal cord associative plasticity (SCAP) is induced with a large and sustained increase in excitability. In rats with cervical spinal cord injury (SCI), 10 days of SCAP significantly improved forelimb function. We hypothesize that SCAP will strengthen spinal excitability, modulate reflexes, and increase pinch force in people with cervical SCI. Aim 1 tests the timing of pairing and the circuits mediating paired stimulation, key issues for proper targeting. Timing cortical and spinal stimulation to converge in the spinal cord, as opposed to cortex, is predicted to be strongest. We will use both non-invasive and invasive spinal cord stimulation. For non-invasive stimulation, we will combine transcutaneous stimulation over the neck with transcranial magnetic stimulation over cortex. For invasive stimulation, we will combine spinal epidural stimulation with transcranial electrical stimulation during clinically indicated surgery. Aim 2 tests the effects of SCAP to produce a lasting increase in spinal excitability, as measured by both cortical and spinal evoked potentials and pinch dynamometry. Controls will isolate the changes induced specifically through pairing. Finally, Aim 3 tests whether paired motor cortex and cervical spinal cord stimulation produces similar effects in people with the two most common causes of SCI, cervical myelopathy and traumatic SCI, as uninjured participants. Spinal excitability is predicted to increase, pinch force is expected to become stronger, and spinal reflexes are expected to diminish. The integrity of spinal pathways will be measured with both physiology and analysis of cervical MRI. Together, these studies will fill critical gaps about the nature of associative plasticity in the sensorimotor system and test a new strategy to strengthen residual connections after SCI. This strategy will be tested with both invasive and non-invasive stimulation, allowing direct comparison of these approaches for the first time. Thus, we intend to close gaps in our understanding of how paired stimulation of sensorimotor circuits should be targeted to the spinal cord and which residual circuits support the plasticity. This knowledge can optimize how we target electrical stimulation to induce SCAP. Multiple methods of motor cortex and cervical spinal cord stimulation have been proven to be safe, so these mechanistic studies can be translated quickly to efficacy trials.