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: 10622969
• 负责人: Jason Brant Carmel
• 金额: $ 13.98万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10622969
• 关键词: Affect; Behavioral; Brain; Caliber; Cervical spinal cord injury; Cervical spinal cord structure; Chronic; Clinical Trials; Disease; Dorsal; Electric Stimulation; Electrodes; Food; Forelimb; Hand; Joints; Knowledge; Measures; Mediating; Mission; Motor; Motor Cortex; Motor Neurons; Movement; Muscle; Muscle Tension; Nature; Neurostimulation procedures of spinal cord tissue; Paralysed; Pathway interactions; Persons; Positioning Attribute; Public Health; Rattus; Recovery; Recovery of Function; Research; Sensory; Source; Spinal; Spinal Cord; Spinal cord injury; Stroke; Supination; Testing; Therapeutic; Thinness; Time; Translating; Treatment Protocols; United States National Institutes of Health; Viral; Walking; arm; awake; design; disability; epidural space; experience; improved; innovation; neural circuit; novel strategies; optogenetics; relating to nervous system; repaired; response; sensorimotor 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.

总结 经验通过神经回路的相关活动导致行为改变。使用此 原则，配对刺激已被用于选择性地加强电路，针对相对 运动皮层和运动神经元之间的稀疏连接或皮层中的感觉和运动连接。在 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 和大直径的传入神经，其介导关节位置和肌肉张力的感觉。在大鼠中， 阈值脊髓刺激，激活传入，强烈增强运动皮层诱发的肌肉 在脊髓中会聚时的反应。当重复执行配对时， 刺激皮层和脊髓的肌肉反应增强，前肢改善 颈脊髓损伤（SCI）后的功能。我们假设运动皮层和感觉脊髓 脊髓刺激将促进颈脊髓的感觉运动可塑性和术后的功能恢复。 SCI.目标1测试配对的时间和皮层活动的来源，这是正确定位的关键问题。定时 与皮质相反，聚集在脊髓中的信号被预测为最强。我们还将测试， 时间，自主运动前内源性皮层活动触发的脊髓刺激与外源性 皮层刺激预计内源性活性对靶肌肉更特异。目标2测试 特定运动和感觉通路对大鼠配对刺激效应的必要性和充分性 SCI.预测用化学遗传学失活显示出必要性，并且配对的光遗传学或电遗传学失活是必要的。 刺激，以显示充足性。最后，目标3测试是否重复运动皮层和背侧颈脊髓 脊髓损伤大鼠10天以上，将导致皮质和脊髓兴奋性的持续增加， 前肢技术总之，这些研究将填补关键空白的性质，联想可塑性，在 感觉运动系统和测试一种新的策略来修复SCI后的连接。我们的新策略将受到考验 创新的工具。为了长期刺激清醒大鼠的颈脊髓，我们开发了薄的 （<50μm）电极，当放入硬膜外腔时会软化，并已被证明安全有效，超过4 个月皮质和脊髓电极能够实现潜在的治疗性配对刺激和纵向刺激。 询问目标电路前肢技能将与前肢旋后任务， 发明，以及熟练的行走和食物操作的测试。脊髓的输入信号将被操纵 使用特定于电路的病毒工具。因此，我们打算缩小我们对配对刺激如何影响神经元的理解方面的差距。 感觉运动回路应该针对脊髓，以及它是否对恢复有效。这 知识可以改变我们如何靶向电刺激来诱导联想可塑性。运动皮层和 颈椎脊髓刺激是安全的，因此配对刺激可以迅速转化为临床试验。