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.

Public Health Relevance

Spinal cord injury (SCI) results in devastating effects on overall health and quality of life. The Christopher and Dana Reeve Foundation has recently estimated that 1,275,000 people are living with paralysis from SCI in the United States alone. This country could save an estimated $400 billion on direct and indirect lifetime costs if we can find ways to treat and prevent SCI. Bladder and sexual dysfunction affects daily life, reduces quality of life and results in numerous life-long health complications. Improvements in bladder and sexual function have been reported in some people with incomplete SCI while they are undergoing a new rehabilitation intervention, Locomotor Training. In addition, four individuals with motor complete SCI who have received epidural stimulation in combination with Locomotor Training have also reported significant improvements in bladder and sexual function. We propose unique experimental human studies to understand whether spinal cord circuits responsible for walking are also important for bladder and sexual functions and reorganize in response to Locomotor Training and/or epidural stimulation after SCI to improve these functions and alter important chemicals in the body. The knowledge gained from our innovative multi-disciplinary study may lead to the translation of non-invasive approaches that will improve bladder and sexual function in people with SCI. Because we study humans with SCI directly, what we learn will be immediately applicable to patients and provide immense improvements in quality of life.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Special Emphasis Panel (UGPP)
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Nitkin, Ralph M
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University of Louisville
Anatomy/Cell Biology
Schools of Medicine
United States
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Hubscher, Charles H; Herrity, April N; Williams, Carolyn S et al. (2018) Improvements in bladder, bowel and sexual outcomes following task-specific locomotor training in human spinal cord injury. PLoS One 13:e0190998