Loss of bladder control as a result of neurological disease or injury such as spinal cord injury (SCI) has devastating effects. SCI results in loss of voluntary control of bladder evacuation, bladder hyper-reflexia, and bladder sphincter dysynergia. These factors often lead to ureteric reflux and obstruction, infection of the kidneys, long-term renal damage, episodes of autonomic dysreflexia with dangerous rises in blood pressure, incontinence which contributes to skin breakdown, as well as frequent urinary tract infections. Loss of bladder control also has profound social impact and leads to decreased quality of life, as well as large direct medical costs from procedures, supplies, and medication. The long-term goal of this research is to develop a neural prosthesis to restore bladder function (continence and micturition) in persons with neurological disorders, particularly spinal cord injury. We are pursuing an innovative approach using electrical stimulation of afferent (sensory) fibers in the pudendal nerve (and its branches) that engage spinal reflexes that either inhibit the bladder to maintain continence or activate the bladder to produce micturition. This novel approach differs substantially from prior approaches using electrical stimulation of the spinal roots in that it does not require a spinal laminectomy, does not require irreversible surgical transection of the sacral sensory nerve roots, and stimulates the afferent rather than the efferent side of the system. During the first funding period we developed and evaluated a closed-loop control system to improve continence in both animals and in persons with spinal cord injury, we discovered and quantified the properties of reflexes that activated the bladder in response to pudendal afferent stimulation, we determined the surgical access to the pudendal n. and that the nerve is amenable to cuff implantation, and we designed a flat interface nerve electrode for selective stimulation of the human pudendal nerve. The overall objective of the present proposal is to increase the efficiency of bladder emptying achieved by electrical stimulation of pudendal afferents. In the previous period we discovered and characterized two reflexes that when activated by electrical stimulation of pudendal afferents excite the bladder, inhibit the sphincter, and produce micturition. However, the voiding that was achieved was limited, and in persons with chronic SCI, activation of pudendal afferents produced small amplitude or transient contractions of the bladder. Therefore, we will develop and evaluate several novel approaches to enhance bladder emptying induced by pudendal afferent stimulation through complementary experiments in an animal model and in persons with spinal cord injury. Successful completion of this project will advance the development of an effective neural prosthetic system for restoration of bladder function.

Public Health Relevance

Loss of bladder control as a result of neurological disease or injury such as spinal cord injury (SCI) has substantial negative health effects (incontinence, urinary tract infections, etc.), negatively impacts quality of life, and leads to substantial medical expense. Electrical stimulation of the nervous system is a promising approach to restore control of bladder function - including urinary continence and bladder emptying - and the objective of this work is to continue development of an implanted medical device to restore bladder function to persons with spinal cord injury.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-ETTN-F (02))
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Ludwig, Kip A
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Duke University
Biomedical Engineering
Schools of Engineering
United States
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Danziger, Zachary; Grill, Warren M (2015) A neuron model of stochastic resonance using rectangular pulse trains. J Comput Neurosci 38:53-66
Medina, Leonel E; Grill, Warren M (2014) Volume conductor model of transcutaneous electrical stimulation with kilohertz signals. J Neural Eng 11:066012
McGee, Meredith J; Danziger, Zachary C; Bamford, Jeremy A et al. (2014) A spinal GABAergic mechanism is necessary for bladder inhibition by pudendal afferent stimulation. Am J Physiol Renal Physiol 307:F921-30
Kent, Alexander R; Grill, Warren M (2013) Model-based analysis and design of nerve cuff electrodes for restoring bladder function by selective stimulation of the pudendal nerve. J Neural Eng 10:036010
Chen, Shih-Ching; Grill, Warren M; Fan, Wen-Jia et al. (2012) Bilateral pudendal afferent stimulation improves bladder emptying in rats with urinary retention. BJU Int 109:1051-8
Snellings, Andre' E; Yoo, Paul B; Grill, Warren M (2012) Urethral flow-responsive afferents in the cat sacral dorsal root ganglia. Neurosci Lett 516:34-8
Woock, John P; Yoo, Paul B; Grill, Warren M (2011) Mechanisms of reflex bladder activation by pudendal afferents. Am J Physiol Regul Integr Comp Physiol 300:R398-407
Yoo, Paul B; Horvath, Eric E; Amundsen, Cindy L et al. (2011) Multiple pudendal sensory pathways reflexly modulate bladder and urethral activity in patients with spinal cord injury. J Urol 185:737-43
Wongsarnpigoon, Amorn; Woock, John P; Grill, Warren M (2010) Efficiency analysis of waveform shape for electrical excitation of nerve fibers. IEEE Trans Neural Syst Rehabil Eng 18:319-28
Woock, John P; Yoo, Paul B; Grill, Warren M (2010) Finite element modeling and in vivo analysis of electrode configurations for selective stimulation of pudendal afferent fibers. BMC Urol 10:11

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