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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS050514-09
Application #
8502764
Study Section
Special Emphasis Panel (ZRG1-ETTN-F (02))
Program Officer
Ludwig, Kip A
Project Start
2005-01-01
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
9
Fiscal Year
2013
Total Cost
$352,493
Indirect Cost
$123,238
Name
Duke University
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Gonzalez, Eric J; Grill, Warren M (2017) The effects of neuromodulation in a novel obese-prone rat model of detrusor underactivity. Am J Physiol Renal Physiol 313:F815-F825
Danziger, Zachary C; Grill, Warren M (2017) Sensory feedback from the urethra evokes state-dependent lower urinary tract reflexes in rat. J Physiol 595:5687-5698
McGee, Meredith J; Swan, Brandon D; Danziger, Zachary C et al. (2017) Multiple Reflex Pathways Contribute to Bladder Activation by Intraurethral Stimulation in Persons With Spinal Cord Injury. Urology 109:210-215
Medina, Leonel E; Grill, Warren M (2016) Nerve excitation using an amplitude-modulated signal with kilohertz-frequency carrier and non-zero offset. J Neuroeng Rehabil 13:63
McGee, Meredith J; Grill, Warren M (2016) Temporal pattern of stimulation modulates reflex bladder activation by pudendal nerve stimulation. Neurourol Urodyn 35:882-887
Langdale, Christopher L; Grill, Warren M (2016) Phasic activation of the external urethral sphincter increases voiding efficiency in the rat and the cat. Exp Neurol 285:173-181
Danziger, Zachary C; Grill, Warren M (2016) Estimating postvoid residual volume without measuring residual bladder volume during serial cystometrograms. Am J Physiol Renal Physiol 311:F459-68
McGee, Meredith J; Grill, Warren M (2016) Modeling the spinal pudendo-vesical reflex for bladder control by pudendal afferent stimulation. J Comput Neurosci 40:283-96
Danziger, Zachary C; Grill, Warren M (2016) Sensory and circuit mechanisms mediating lower urinary tract reflexes. Auton Neurosci 200:21-28
Danziger, Zachary C; Grill, Warren M (2015) Dynamics of the sensory response to urethral flow over multiple time scales in rat. J Physiol 593:3351-71

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