Effects of activity dependent plasticity on recovery of bladder and sexual function after human spinal cord injury

描述(申请人提供)：脊髓损伤(SCI)导致运动、感觉和自主神经功能受损，严重影响整体健康和生活质量。最近关于人类活动依赖可塑性的发现导致了一种广泛实施的康复干预，即运动训练，其中包括在跑步机上使用手动促进的体重支持进行步进。有证据表明，这种特殊的类型 任务专业性训练可以优化腰椎脊椎回路。我们有来自四名不能站立或行走的SCI患者的耐人寻味的证据，他们在接受运动训练后，膀胱和性功能得到了改善。这些泌尿生殖功能的改变可能是由于调节排尿和勃起功能的腰骶部回路的活动依赖性可塑性所致。脊髓损伤后适当的膀胱管理对于降低上尿路疾病的风险是必要的，上尿路疾病是发病率的主要来源。脊髓损伤需要终生的泌尿外科护理 然而，大多数努力都是治疗症状，但并不能改善内在功能。此外，截瘫患者将性功能列为损伤后应优先考虑的功能，以提高生活质量。本研究的重点在于脊髓损伤后，在硬膜外刺激和硬膜外刺激的情况下，通过阶梯训练诱导的活动依赖性可塑性反应中，膀胱和性功能的脊髓环路重组的机制。站立训练和/或手臂曲柄练习作为对照。潜在的重要机制是神经营养因子参与了膀胱功能的调节。因此推测，脊髓损伤后的负重运动任务特异性训练可诱导神经网络的可塑性，神经网络不仅调节行走，还调节膀胱和性功能，并可能通过减少脊髓损伤后升高的特定神经营养因子来实现对膀胱功能的调节。我们的独特方法将利用每个研究人员的专业知识来1)确定负重任务专项运动训练对人类创伤性不完全性上运动神经元脊髓损伤后排尿频率和尿动力学参数的影响是否由于运动和膀胱回路之间的相互作用(相对于站立或一般运动)；2)评估LT对严重不完全性脊髓损伤后尿(生物标志物)和膀胱(活检组织)NGF和BDNF水平的影响；3)确定负重任务专项运动训练对人类创伤性不完全性上运动神经元脊髓损伤后勃起功能和性满意度的影响；4)观察硬膜外刺激联合LT对人上运动神经元完全性损伤和感觉不全损伤后排尿频率、尿流动力学参数、勃起功能和膀胱/尿NGF、BDNF水平的影响。我们创新的多学科研究可能会将负重台阶训练、硬膜外刺激、 和神经营养因子操作，以促进脊髓损伤后多个系统的功能恢复。

DESCRIPTION (provided by applicant): Spinal cord injury (SCI) results in impairments of locomotor, sensory and autonomic functions, severely affecting overall health and quality of life. Recent discoveries related to activity-dependent plasticity in humans have led to a widely implemented rehabilitation intervention, Locomotor Training, which includes stepping using body weight support on a treadmill with manual facilitation. Evidence suggests that this particular type of task specific training optimizes the lumbosacral spinal circuitry. We have intriguing evidence from four SCI individuals who are unable to stand or walk showing improved bladder and sexual function after undergoing Locomotor Training. These changes in urogenital function may be due to activity-dependent plasticity of lumbosacral circuitry that mediates micturition and erectile functions. Proper bladder management post-SCI is necessary to decrease the risk of upper urinary tract disease, a major source of morbidity. The life-long urologic care is required for SCI individuals, yet most efforts treat symptoms but do not improve intrinsic function. In addition, paraplegics rank sexual function as the function post-injury that should be given the highest priority in order to enhance quality of life. This proposal focuses on the mechanisms involved in the reorganization of spinal cord circuits for bladder and sexual function in response to activity-dependent plasticity induced by step training after SCI, with and without epidural stimulation. Stand training and/or arm crank exercise serve as controls. Of potential mechanistic importance is that neurotrophins have been implicated in modulating bladder function. It is therefore hypothesized that weight bearing task specific training for locomotion post-SCI induces plasticity of neural networks that mediate not just walking but bladder and sexual function as well and may do so for bladder function by reducing specific neurotrophins that are elevated post-SCI. Our unique approach will utilize the expertise of each investigator to 1) To determine whether the effect of weight-bearing task-specific training for locomotion on voiding frequency and urodynamic parameters is due to an interaction between locomotor and urinary bladder circuitry after traumatic incomplete upper motor neuron SCI in humans (versus standing or general exercise); 2) To assess the effect of LT on urine (biomarkers) and bladder (biopsy tissue) NGF and BDNF levels after severe incomplete SCI; 3) To determine the effect of weight-bearing task-specific training for locomotion on erectile function and sexual satisfaction after traumatic incomplete upper motor neuron SCI in humans; and 4) To assess the effect of epidural stimulation in combination with LT on voiding frequency, urodynamic parameters, erectile function, and bladder/urine NGF and BDNF levels after complete and motor complete/sensory incomplete upper motor neuron SCI in humans. Our innovative multi-disciplinary study may lead to the translation of a combination approach of weight bearing step training, epidural stimulation, and neurotrophic factor manipulation to promote functional recovery for multiple systems following SCI.