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。 原则上，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。 相比之下，我们建议通过下行运动连接的强烈相互作用来瞄准脊髓 和大直径传入神经，介导大鼠的关节位置和肌肉张力的感觉。 阈值脊髓刺激可激活传入神经，强烈增强运动皮层诱发的肌肉 当重复进行配对时，脊髓中的反应会很强烈。 刺激皮质和脊髓增强肌肉反应并改善前肢 颈脊髓损伤（SCI）后的功能。 脊髓刺激将促进颈脊髓的感觉运动可塑性和术后功能恢复 SCI。目标 1 测试配对的时间和皮质活动的来源，这是正确定位的关键问题。 与皮质相比，脊髓的聚合预计最强，我们也将首先进行测试。 时间，随意运动前由内源性皮质活动触发的脊髓刺激与外源性刺激 预计内源性活动​​对目标肌肉更具特异性。 特定运动和感觉通路对大鼠配对刺激作用的必要性和充分性 SCI。预计化学遗传学灭活是必要的，并且配对光遗传学或电学。 最后，目标 3 测试是否重复运动皮层和背侧颈椎。 SCI 大鼠脊髓超过 10 天将导致皮质和脊髓兴奋性持续增加，并改善 总之，这些研究将填补关于联想可塑性本质的关键空白。 感觉运动系统并测试 SCI 后修复连接的新策略 我们的新策略将得到测试。 为了长期刺激清醒大鼠的颈脊髓，我们开发了薄层。 (<50μm) 电极在放入硬膜外腔时会软化，并且已被证明安全有效超过 4 年 皮质和脊柱电极可实现潜在的治疗性配对刺激和纵向刺激。 我们将通过前肢旋后任务来测量目标回路的询问。 发明，以及对熟练步行和食物操作的测试将被操纵。 因此，我们打算弥合我们对配对刺激如何理解的差距。 感觉运动回路应针对脊髓以及它是否对恢复有效。 知识可以改变我们如何针对电刺激来诱导联想运动皮层和运动皮层。 颈脊髓刺激是安全的，因此配对刺激可以快速转化为临床试验。