Behavioral and molecular responses to high-intensity exercise in humans with iSCI

描述（由申请人提供）：脊髓损伤（SCI）导致力量和感觉严重受损，可导致独立活动能力丧失和日常活动参与减少。在不完全SCI后，许多患者的主要目标是恢复独立行走能力。任务特异性和练习量都是 已知在神经损伤后基于运动恢复的干预的功效中具有关键作用。这是一个重要的干预参数， 对患有神经损伤的人的影响是基于运动的干预的强度或功率输出。在SCI动物模型中的研究表明，高强度的运动练习导致神经营养因子的表达增加，神经元连接改善，并恢复步行。此外，神经营养因子的产生也被认为受到神经调节剂5-羟色胺的影响。这些研究结果表明，运动强度和5-羟色胺信号在脊髓回路可能被操纵，以加强神经可塑性和改善恢复功能运动后SCI，虽然强度相关的影响尚未在人类中进行严格的检查。 以前对神经系统人群进行高强度运动方案的限制是这样的概念，即这些活动将导致痉挛性运动行为增加并导致异常运动模式。然而，急性和慢性影响的强度对运动性能尚未得到很好的表征。因此，拟议的目标将填补这一知识空白，并评估运动强度对行为和分子参数的影响，以及血清素对后者的影响。这将通过测量分级强度运动范式期间的关节运动学、协调性、肌肉活动、代谢活动和神经营养因子的血清水平来实现。这些测量将在基线条件下、慢性高强度训练后以及运动与血清素水平的急性药理学操作配对时收集。这些信息将提高我们对不完全SCI患者干预强度影响的理解。特别是，它将阐明干预强度的急性和长期影响，并阐明这些影响的潜在潜在细胞机制。最后，它将进一步描绘最大限度地恢复功能的干预参数，并促进神经损伤后最有效的康复干预措施的发展。

DESCRIPTION (provided by applicant): Spinal cord injury (SCI) results in profound impairments in strength and sensation which can lead to the loss of independent mobility and decreased participation in daily activities. Following incomplete SCI, a primary goal of many patients is to regain independent walking ability. Both task specificity and amount of practice are known to have critical roles in the efficacy of locomotor recovery-based interventions after neurological injury. A significant intervention parameter that has yet to be thoroughly explored in humans with neurological injury is the intensity, or power output, of locomotor-based interventions. Studies in animal models of SCI have demonstrated that high-intensity locomotor practice results in an increased expression of neurotrophic factors, improved neuronal connectivity, and the recovery of stepping. Furthermore, the production of neurotrophic factors has also been suggested to be influenced by the neuromodulator serotonin. These findings suggest that locomotor intensity and serotonin signaling in spinal circuitry may be manipulated to potentiate neural plasticity and improve recovery of functional movement following SCI, although rigorous examination of intensity-related effects has not yet been conducted in humans. A previous limitation to the performance of high-intensity exercise regimens in neurological populations is the notion that such activities will lead to increased spastic motor behaviors and result in abnormal movement patterns. However, the acute and chronic effects of intensity on locomotor performance have yet to be well characterized. Therefore, the proposed aims will fill this gap in knowledge and evaluate the effects of locomotor exercise intensity on behavioral and molecular parameters, in addition to the effect of serotonin on the latter. This wil be achieved through the measurement of joint kinematics, coordination, muscle activity, metabolic activity, and serum levels of neurotrophic factors during a graded-intensity locomotor paradigm. The measurements will be collected under baseline conditions, following chronic high-intensity training, and again while exercise is paired with acute pharmacological manipulation of serotonin levels. This information will improve our understanding of the effect of intervention intensity in humans with incomplete SCI. In particular, it will clarify the acute and long-term effects of intervention intensity and elucidate a potential underlying cellular mechanism for these effects. Finally, it will further delineate the intervention parameters that maximize functional recovery, and promote the development of the most effective rehabilitation interventions following neurological injury.