Paired brain and spinal cord stimulation to strengthen spinal sensorimotor circuits

配对大脑和脊髓刺激以增强脊髓感觉运动回路

• 批准号: 10156241
• 负责人: Jason Brant Carmel
• 金额: $ 53.91万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-15 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10156241
• 关键词: Address; Affect; Axon; Behavioral; Brain; Brain Stem; Caliber; Cervical spinal cord injury; Cervical spinal cord structure; Chronic; Clinical; Clinical Research; Clinical Trials; Cortical Cord; Data; Disease; Dorsal; Electric Stimulation; Electrodes; Food; Forelimb; Goals; H-Reflex; Hand; Hand functions; Hour; Hyperreflexia; Individual; Joints; Knowledge; Location; Measures; Mediating; Mission; Motor; Motor Cortex; Motor Neurons; Motor Pathways; Movement; Muscle; Muscle Tension; Nature; Neurostimulation procedures of spinal cord tissue; Pain; Paralysed; Pathway interactions; Pattern; Physiology; Positioning Attribute; Proprioceptor; Public Health; Rattus; Recovery; Recovery of Function; Research; Reticular Formation; Sensory; Site; Source; Specificity; Spinal; Spinal Cord; Spinal cord injury; Stimulus; Stroke; Supination; System; Techniques; Testing; Therapeutic; Thinness; Time; Translating; Treatment Protocols; United States National Institutes of Health; Viral; Walking; arm; arm function; awake; base; design; dexterity; disability; epidural space; experience; improved; injury and repair; innovation; neural circuit; novel strategies; optogenetics; predicting response; relating to nervous system; repaired; response; sensorimotor system; sensory system; skills; tool

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.

概括 经验通过神经回路的相关活动导致行为改变。使用此 原理，配对模拟已用于选择性强的电路，以相对为目标 运动皮层与运动神经元之间的稀疏连接，或者在皮质中的感觉和电动机连接。 对比，我们建议通过下降电动机连接的牢固相互作用靶向脊髓 和大直径传入，介导关节位置和肌肉张力的感觉。在大鼠中，子 - 阈值脊髓刺激，激活传入，强烈增强运动皮层诱发的肌肉 定时收敛时的响应。反复进行配对时，有强大的 刺激皮质和脊髓刺激并改善前肢而增加了肌肉反应 宫颈脊髓损伤（SCI）后的功能。我们假设配对运动皮层和感觉脊柱 绳索刺激将促进颈脊髓中的感觉运动可塑性，并在 科学。 AIM 1测试配对的时机和皮质活动的来源，即适当靶向的关键问题。定时 在脊髓中融合而不是皮层，预计将是强的。我们还将测试第一个 时间，在自愿运动与外源性之前，由内源性皮质活性触发的脊柱刺激 皮质刺激。预测内源性活性对靶向肌肉更为特异。 AIM 2测试 特定电动机的必要性和充分性以及对大鼠配对模拟效果的特定电动机和感觉途径 科学。预计用化学遗传学灭活将表明必要，并配对光学遗传学或电气 刺激以显示安全性。最后，AIM 3测试重复运动皮层和背颈脊柱是否 SCI大鼠的绳索超过10天，会导致皮质和脊柱持久增加和改善 前肢技能。总之，这些研究将填补有关关联可塑性本质的关键空白 感觉运动系统并测试科学后修复连接的新策略。我们的新颖策略将进行测试 使用创新工具。为了长期刺激清醒大鼠的颈脊髓，我们发育很薄 （<50μm）将放置在硬膜外空间中时软化的电子，并证明是安全有效的4个 月份。皮质和脊柱电极既实现了可能的治疗配对模拟，又可以纵向 询问目标电路。前肢技能将通过前肢旋转任务来测量我们 发明了，以及熟练的步行和食物操纵的测试。将操纵脊髓的输入 使用特定电路的病毒工具。这，我们打算弥合对配对刺激的理解 感觉运动电路应针对脊髓，以及它是否有效恢复。这 知识可以改变我们靶向电刺激以诱导关联可塑性的方式。运动皮层和 颈脊髓刺激是安全的，因此可以将配对刺激迅速转化为临床试验。