Lesion and activity dependent corticospinal tract plasticity

病变和活动依赖性皮质脊髓束可塑性

• 批准号: 8051602
• 负责人: John H Martin
• 金额: $ 36.35万
• 依托单位: CITY COLLEGE OF NEW YORK
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-19 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8051602
• 关键词: Adult; Affect; Axon; Behavioral; Brain; Brain Stem; Cell Nucleus; Cerebral cortex; Chronic; Contralateral; Corticospinal Tracts; Deafferentation procedure; Development; Electric Stimulation; Ensure; Fiber; Forelimb; Goals; Health; Human; Impairment; Injury; Ipsilateral; Left; Lesion; Limb structure; Mediating; Modeling; Motor; Motor Cortex; Motor Neurons; Motor Skills; Neurons; Pathway interactions; Patients; Pattern; Publishing; Pyramidal Tracts; Rattus; Recovery; Recovery of Function; Rehabilitation therapy; Research; Role; Sensory; Severities; Shapes; Side; Spinal; Spinal Cord; Spinal cord damage; Spinal cord injury; Stroke; Synapses; System; Time; Transcranial magnetic stimulation; Translating; base; gray matter; improved; limb movement; motor control; relating to nervous system; repaired; research study; response; visual motor

DESCRIPTION (provided by applicant): The overall goal of our experiments is to use activity to promote corticospinal system function after partial injury to the corticospinal tract (CST), such as occurs after most spinal cord injuries or stroke. Repair of CST connections through reactive sprouting and recovery of function occurs spontaneously after injury, but both are limited. However, our studies show that augmenting the activity of the spared CST can be used to promote repair and motor recovery. This is based on our findings that selective electrical stimulation of the CST in the mature rat, as in development, increases CST axon outgrowth and promotes formation of spinal connections. Importantly, our newly published and preliminary findings show that stimulation of CST axons spared after injury augments reactive sprouting. strengthens CST connections, and can improve motor skills. We use a reproducible partial injury model in the adult rat, a unilateral pyramidal tract (PT) lesion, which destroys the CST from one cortex. The rat CST, like in humans, is largely crossed, but there is a significant contingent of axons that terminate ipsilaterally. After unilateral PT damage, the spinal cord contralateral to the lesion losses its dense contralateral CST projection; only the sparse ipsilateral axons remain. Our studies focus on these ipsilateral CST axons as a model of spared axons after partial spinal cord injury and stroke. In the proposed experiments we will selectively activate the undamaged CS system by electrical stimulation of spared CST axons in the PT, to augment spontaneous recovery after PT lesion. In Aim 1 we will determine whether specific interactions between spared ipsilateral CST terminations on the impaired side of the spinal cord and mechanosensory afferents limit CST outgrowth, and if augmenting CST activity mitigates this. In Aim 2 we will determine if augmenting sprouting after PT lesion leads to a more "contralateral" pattern of connections between spared ipsilateral CST axons and identified spinal neuron classes on the impaired side, a pattern that may ensure stronger motoneuron activation. We will also determine if activity augments outgrowth into brain stem motor centers that comprise relays for indirect cortical paths to the spinal cord. In Aim 3 we will determine if augmenting CST activity after PT lesion promotes recovery of skilled limb movements and the extent to which this recovery is mediated by the damaged or undamaged side. Elucidating systems-level mechanisms of spontaneous CS system repair, and the capacity for selective CS stimulation to augment repair, will help to devise new strategies for promoting recovery of motor skills after injury. Our research has the strong potential to be translated to patients with brain or spinal cord injury. Selective stimulation of the Mi outflow can be achieved non-invasively in humans using transcranial magnetic stimulation (TMS). Our stimulation approach would likely apply to various levels of severity and different times after injury. PUBLIC HEALTH RELEVANCE: The overall goal of our experiments is to promote motor function after spinal cord injury or stroke. We focus on the corticospinal tract, the principal motor control pathway in humans. Using a rat model, we increase neural activity of the corticospinal tract after injury, by electrical stimulation, to restore lost connections to spinal cord motor control centers. We will determine the importance of plasticity in the cerebral cortex, brain stem, and spinal cord in recovery of skilled motor function.

描述（由申请人提供）：我们实验的总体目标是在皮质脊髓束（CST）部分损伤后（例如大多数脊髓损伤或中风后发生的情况）利用活动来促进皮质脊髓系统功能。损伤后，通过反应性萌芽和功能恢复来修复 CST 连接，但两者都是有限的。然而，我们的研究表明，增强幸存的 CST 的活性可用于促进修复和运动恢复。这是基于我们的发现，即在发育过程中对成熟大鼠的 CST 进行选择性电刺激会增加 CST 轴突的生长并促进脊柱连接的形成。重要的是，我们新发表的初步研究结果表明，损伤后幸存的 CST 轴突的刺激会增强反应性萌芽。加强 CST 连接，并可以提高运动技能。我们在成年大鼠中使用了一种可重复的部分损伤模型，即单侧锥体束 (PT) 损伤，它破坏了一侧皮质的 CST。与人类一样，大鼠的 CST 大部分是交叉的，但有大量轴突终止于同侧。单侧 PT 损伤后，病变对侧脊髓失去其密集的对侧 CST 投射；仅保留稀疏的同侧轴突。我们的研究重点是这些同侧 CST 轴突，作为部分脊髓损伤和中风后幸存轴突的模型。在拟议的实验中，我们将通过电刺激 PT 中幸存的 CST 轴突来选择性激活未受损的 CS 系统，以增强 PT 损伤后的自发恢复。在目标 1 中，我们将确定脊髓受损侧的同侧 CST 终止点与机械感觉传入之间的特定相互作用是否会限制 CST 的生长，以及增强 CST 活性是否可以缓解这种情况。在目标 2 中，我们将确定 PT 损伤后增强萌芽是否会导致同侧 CST 轴突与受损侧已识别的脊髓神经元类别之间的连接更加“对侧”模式，这种模式可以确保更强的运动神经元激活。我们还将确定活动是否会增强脑干运动中心的生长，这些中心包括通往脊髓的间接皮质路径的中继。在目标 3 中，我们将确定 PT 损伤后增强 CST 活性是否会促进熟练肢体运动的恢复，以及这种恢复在多大程度上是由受损或未受损一侧介导的。阐明自发 CS 系统修复的系统级机制，以及选择性 CS 刺激增强修复的能力，将有助于制定促进损伤后运动技能恢复的新策略。我们的研究具有应用于脑或脊髓损伤患者的巨大潜力。使用经颅磁刺激 (TMS)，可以对人类进行非侵入性的 Mi 流出道选择性刺激。我们的刺激方法可能适用于不同的严重程度和受伤后的不同时间。公众健康相关性：我们实验的总体目标是促进脊髓损伤或中风后的运动功能。我们关注皮质脊髓束，这是人类主要的运动控制通路。使用大鼠模型，我们通过电刺激增加损伤后皮质脊髓束的神经活动，以恢复与脊髓运动控制中心失去的连接。我们将确定大脑皮层、脑干​​和脊髓的可塑性对于恢复熟练运动功能的重要性。