Physical and Pharmacological Effects on Movement in SCI

描述(申请人提供)：有大量的实验历史表明，脊髓损伤(SCI)后运动行为的改变可能部分是下行神经调节(特别是5-羟色胺能和去甲肾上腺素能)传入脊髓回路受损的结果。这些单胺的激动剂作用于特定的脊髓通路，调节运动行为(包括运动)及其对感觉信息的反应，并已被证明在增强运动回路中的神经可塑性方面发挥关键作用。虽然自愈和特定的物理干预(即体重支持的跑步机训练)可以促进人类运动不完全脊髓损伤后运动控制的恢复，但物理和药物的组合改变运动恢复仍有待详细研究。因此，我们建议研究选择性5-羟色胺再摄取抑制剂(即SSRIs、氟西汀)在慢性(&gt；)1年后的意志和痉挛运动行为中的作用。后)人类运动不完全性脊髓损伤及其与特定物理干预(即BWSTT)相结合的影响。目的1将对等长意志性运动输出(最大扭矩输出、激动剂/拮抗剂共激活)、不自主痉挛行为(与过度兴奋的屈肌和伸展反射相关的参数)以及运动和肌电活动进行定量评估，并与使用氟西汀前后的肌肉力量、痉挛和地面行走质量(辅助水平、使用的设备、速度和步态模式)的临床测量进行比较。目的2将使用机器人辅助和药物操作相结合的方法，研究BWSTT 12周后这些运动行为的可塑性。行为的改变将与没有接受药物干预的运动性不完全脊髓损伤受试者的对照组进行比较。我们希望单胺类药物能降低选定传入通路的兴奋性，但增强负责意志运动输出和运动的电路，从而加速BWSTT运动能力的恢复。作为这些发现的结果，运动性不完全性脊髓损伤的药理学治疗将发生根本性的变化。

DESCRIPTION (provided by applicant): There is extensive experimental history demonstrating that alteration in motor behaviors following spinal cord injury (SCI) may be partly a result of damage to descending neuromodulatory (in particular serotonergic and noradrenergic) inputs to spinal circuits. Agonists to these monoamines act on specific spinal pathways to modulate motor behaviors (including locomotion) and their responses to sensory information, and have been shown to play a critical role in enhancement of neural plasticity in locomotor circuits. While spontaneous healing and specific physical interventions (i.e., body-weight supported treadmill training, BWSTT) can facilitate return of motor control following motor incomplete SCI in humans, the combination of physical and pharmacological agents to alter motor recovery has yet to be studied in detail. Accordingly, we propose to study the role of selective serotonin reuptake inhibitors (i.e., SSRIs, fluoxetine) on volitional and spastic motor behaviors following chronic (> 1 yr. post) motor incomplete SCI in humans and their effects in combination with specific physical interventions (i.e., BWSTT). Aim 1 will provide quantitative assessment of isometric volitional motor output (maximal torque output, agonist/antagonist co-activation), involuntary spastic behaviors (parameters associated with hyperexcitable flexor and stretch reflexes), and kinematics and EMG activity during locomotion to be compared with clinical measurements of muscle strength, spasticity and quality of overground ambulation (level of assistance, devices used, speed and gait pattern) before and following administration of fluoxetine. Aim 2 will investigate the plasticity of these motor behaviors following 12 weeks of BWSTT using robotic assistance in combination with pharmacological manipulations. Changes in behaviors will be compared to a control group of subjects with motor incomplete SCI that do not receive pharmacological interventions. We expect the monoaminergic agents to depress excitability of selected afferent pathways, but enhance circuitry responsible for volitional motor output and locomotion, thereby expediting the recovery of locomotor capability with BWSTT. As a consequence of these findings, a radical change in pharmacological management of motor incomplete SCI will be indicated.