In patients with spinal cord injury, regaining bladder and bowel function is of great importance, in paraplegics it is considered even more important than regaining walking function. Patents with lower motor neuron lesions resulting in flaccid bladder paralysis cannot use functional electrical stimulation (FES) to induce bladder emptying because the neural connection between the spinal cord and the bladder has been disrupted. These patients require new neural pathways to regain control of bladder function. The goal of these studies is to provide the final burden of proof for human trials of somatic nerve transfer to reinnervate the urinary bladder. This proposal is designed to achieve the following specific aims:
Specific aim 1 : Determine whether transfer of the genitofemoral (GF) nerve to the anterior vesicle branch of the pelvic nerve reinnervates the internal sphincter smooth muscle as well as the detrusor muscle. Determine whether both autonomic intramural ganglia and smooth muscle cells become functionally reinnervated. These investigations will test the hypothesis that the new nerves growing from the transferred GF nerve into the bladder through the vesical branch of the pelvic nerve may reach all the way down to the urethra to reinnervate the internal smooth muscle sphincter and external skeletal muscle sphincter.
Specific aim 2 : Determine whether unilateral GF to vesicle nerve transfer provides as much functional reinnervation for bladder emptying as the bilateral nerve transfer provides. Clinical application of this nerve transfer would be performed unilaterally and this aim will test the hypothesis that unilateral nerve transfer provides sufficient reinnervation for bladder emptying function.
Specific aim 3 : Determine whether spontaneous bladder emptying without FES occurs with GF nerve transfer to the vesical branch of the pelvic nerve following bladder denervation in the sacral spine. If spontaneous bladder emptying function does return after nerve transfer then implantation of the FES system would not be required.
This aim tests the hypothesis that following GF nerve reinnervation of the bladder, the central nervous system develops alternate pathways that induce bladder emptying.
Specific aim 4 : Determine whether the urinary and anal sphincter muscles can also be reinnervated by anterior femoral to pudendal nerve transfer procedures. Control of urinary and fecal continence may require new neural pathways to the urinary and anal sphincters.
This aim will test the hypothesis that reinnervation of the pudendal nerve with the anterior femoral nerve will allow both urethral and anal sphincter reinnervation and restore urinary and fecal continence.

Public Health Relevance

The goal of the studies described in this proposal is to develop a surgical approach to reinnervate the lower motor neuron lesioned urinary bladder so the patient can regain control of bladder emptying. These studies are intended to provide the final burden of proof for human trials of somatic nerve transfer to reinnervate the urinary bladder.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
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Jakeman, Lyn B
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Temple University
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Barbe, Mary F; Gomez-Amaya, Sandra; Braverman, Alan S et al. (2017) Evidence of vagus nerve sprouting to innervate the urinary bladder and clitoris in a canine model of lower motoneuron lesioned bladder. Neurourol Urodyn 36:91-97
Gomez-Amaya, Sandra M; Barbe, Mary F; Lamarre, Neil S et al. (2015) Neuromuscular nicotinic receptors mediate bladder contractions following bladder reinnervation with somatic to autonomic nerve transfer after decentralization by spinal root transection. J Urol 193:2138-45
Gomez-Amaya, Sandra M; Barbe, Mary F; de Groat, William C et al. (2015) Neural reconstruction methods of restoring bladder function. Nat Rev Urol 12:100-18
Gomez-Amaya, S M; Ruggieri Sr, M R; Arias Serrato, S A et al. (2015) Gross anatomical study of the nerve supply of genitourinary structures in female mongrel hound dogs. Anat Histol Embryol 44:118-27
Gomez-Amaya, Sandra M; Barbe, Mary F; Brown, Justin M et al. (2015) Bladder reinnervation using a primarily motor donor nerve (femoral nerve branches) is functionally superior to using a primarily sensory donor nerve (genitofemoral nerve). J Urol 193:1042-51
van Koeveringe, Gommert A; Rademakers, Kevin L J; Birder, Lori A et al. (2014) Detrusor underactivity: Pathophysiological considerations, models and proposals for future research. ICI-RS 2013. Neurourol Urodyn 33:591-6
Ruskin, David N; Svedova, Julia; Cote, Jessica L et al. (2013) Ketogenic diet improves core symptoms of autism in BTBR mice. PLoS One 8:e65021
Brown, Justin M; Barbe, Mary F; Albo, Michael E et al. (2013) Anatomical feasibility of performing a nerve transfer from the femoral branch to bilateral pelvic nerves in a cadaver: a potential method to restore bladder function following proximal spinal cord injury. J Neurosurg Spine 18:598-605
Brown, Justin M; Barbe, Mary F; Albo, Michael E et al. (2012) Anatomical feasibility of performing intercostal and ilioinguinal nerve to pelvic nerve transfer: a possible technique to restore lower urinary tract innervation. J Neurosurg Spine 17:357-62
Barbe, Mary F; Brown, Justin M; Pontari, Michel A et al. (2011) Feasibility of a femoral nerve motor branch for transfer to the pudendal nerve for restoring continence: a cadaveric study. J Neurosurg Spine 15:526-31

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