Our long-term goals are to develop surgical approaches to reinnervate the lower motor neuron-lesioned urinary bladder, urethra and anal sphincter. We have been highly successful in using a canine model to prove that somatic nerves can be rerouted to the anterior vesical branch of the pelvic nerve (between the pelvic plexus and the bladder dome) to reinnervate the bladder muscle. We found that electrical stimulation of these transferred nerves can increase detrusor pressure and induce bladder emptying, and confirmed regrowth of these rerouted nerves using retrograde tracing methods.4, 25, 44-46 Nevertheless, a number of clinically relevant questions remain that we need to answer in this animal model before these surgical procedures are widely accepted and applied to human patients with lower motor neuron lesioned bladder dysfunction. The most clinically relevant overall question is does this reinnervation actually improve storage and emptying function in the awake animal? This will be addressed in the aims below by performing urodynamic studies, using implanted radiofrequency (RF) micro-stimulators and functional electrical stimulation (FES) of the rerouted nerves,25, 45, 46 on non-anesthetized animals at regular intervals as their bladders and urethral sphincters become reinnervated during a 6-month post-operative observation period. At euthanasia, the effects on reinnervation will be explored using electrophysiological, pharmacological, neuroanatomical, and neurobiological methods.
Aim 1 - To determine whether reinnervation of the bladder by obturator nerve transfer and reinnervation of the urethral and anal sphincters by transfer of femoral nerve branches provides return of both continence and emptying function. We found that transfer of a primarily motor donor nerve (femoral nerve branches) provides superior bladder reinnervation than a mixed sensory and motor nerve (GFN).25 We also found that the pudendal nerve could be reinnervated by transfer of motor branches of the femoral nerve.15, 47 We have not yet reinnervated the bladder, urethra and anal sphincters in the same animal that would be important to human patients to restore voiding function, fecal and urinary continence. The obturator nerve, like the femoral nerve, is a primarily motor nerve, and its natural path runs very close to the pelvic plexus. Animals will be decentralized by bilateral transections of L7 and all roots caudal to L7 in the spinal column. The obturator nerve will be transferred bilaterally to the anterior vesical branch of the pelvic nerve (OBNT-to-PN) and branches of the femoral nerve will be transferred bilaterally to the pudendal nerve (FNT-to-PudN) as it emerges from the pudendal (Alcock's) canal. Un-anesthetized urodynamics will be performed monthly for 6 months; half receiving implanted radiofrequency (RF) micro-stimulators for FES of transferred obturator and femoral nerve branches to monitor return of nerve stimulation evoked detrusor, urethra and anal sphincter pressures, before the terminal assays at 6 months.
Aim 2 - To determine whether the bladder, urethra and anal sphincters remain capable of being reinnervated after prolonged decentralization for up to one year. We found in a group of 5 dogs that 4.50.9 months after decentralization, stimulation of sacral roots or spinal cord segments does not increase detrusor pressure, proving decentralization. However, stimulating anterior vesical branches of the pelvic nerve (between the pelvic plexus and bladder dome) increases detrusor pressure in 5 of 5 decentralized animals.25 We also proved that the bladder can be reinnervated by genitofemoral nerve transfer (GFNT) at 1 and 3 months after decentralization.46 The longer after decentralization that the bladder remains capable of being reinnervated, the more feasible this approach would be for human patients with long standing flaccid bladder paralysis. Bladders will be decentralized, as described for aim 1. Cuff electrodes interfaced with RF microstimulators will be placed on anterior vesical branches of the pelvic nerve and on pudendal nerve branches as they emerge from the pudendal canal in a subset of these animals. The effects of nerve stimulation on detrusor, urethral and anal sphincter pressure will be determined at monthly intervals starting 3-4 weeks after decentralization and continuing to 6 or 12 months. OBNT-to-PN and FNT-to-PudN will be performed in separate groups of animals at 6 and 12 months after decentralization. These groups will be compared to sham-decentralized animals with identically implanted RF micro-stimulators. This model will determine whether the distal pelvic plexus/ganglia-bladder, urethra and anal sphincter circuitry remain viable and capable of being reinnervated for periods of up to 1 year after decentralization to provide guidance for surgeons who would consider similar nerve transfer in the human following cauda equina injury. These proposed studies are designed to answer questions that will allow these surgical procedures to be widely accepted and applied to human patients with lower motor neuron lesioned bladder dysfunction; a group that includes patients with lower spinal cord injuries, spina bifida, pelvic or sacral fractures, and other neurological injuries to lower lumbar and sacral nerves.

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, urethral and anal sphincter 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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Special Emphasis Panel (ZRG1)
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Jakeman, Lyn B
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Temple University
Anatomy/Cell Biology
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Salvadeo, Danielle M; Tiwari, Ekta; Frara, Nagat et al. (2018) Determining integrity of bladder innervation and smooth muscle function 1 year after lower spinal root transection in canines. Neurourol Urodyn 37:2495-2501
Lam Van Ba, Ornella; Barbe, Mary F; Caremel, Romain et al. (2018) Lumbar to sacral root rerouting to restore bladder function in a feline spinal cord injury model: Urodynamic and retrograde nerve tracing results from a pilot study. Neurourol Urodyn 37:153-162
Barbe, Mary F; Gomez-Amaya, Sandra M; Salvadeo, Danielle M et al. (2018) Clarification of the Innervation of the Bladder, External Urethral Sphincter and Clitoris: A Neuronal Tracing Study in Female Mongrel Hound Dogs. Anat Rec (Hoboken) :
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

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