Physical and Pharmacological Effects on Movement in SCI

描述（由申请人提供）：有大量的实验历史证明，脊髓损伤（SCI）后运动行为的改变可能部分是脊髓回路下行神经调节（特别是肾上腺素能和去甲肾上腺素能）输入受损的结果。这些单胺的激动剂作用于特定的脊髓通路以调节运动行为（包括运动）及其对感觉信息的反应，并且已被证明在运动回路中的神经可塑性增强中起关键作用。虽然自发愈合和特定的物理干预（即，体重支持的跑步机训练（body-weightsupportedtreadmill training，BWSTT）可以促进人类运动不完全性SCI后运动控制的恢复，但是物理和药理学试剂的组合改变运动恢复还有待于详细研究。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）对慢性（> 1年）后）运动不完全性脊髓损伤及其与特定物理干预（即，BWSTT）。目标1将提供等长意志运动输出的定量评估（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牵拉反射相关的参数），以及运动过程中的运动学和EMG活动，与肌肉力量，痉挛和地上肌肉质量的临床测量进行比较（辅助水平、使用的器械、速度和步态模式）。目的2将研究这些运动行为的可塑性后，12周的BWSTT使用机器人辅助结合药理学操作。行为变化将与未接受药物干预的运动不完全性SCI受试者对照组进行比较。我们期望单胺能药物抑制所选传入通路的兴奋性，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。由于这些发现，一个根本的变化，在药物管理的运动不完全性脊髓损伤将表明。

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.