In this renewal grant application, a novel approach to restore both micturition and continence functions after spinal cord injury (SCI) was proposed based on the new findings from our previous grant support. Normal functions of the lower urinary tract are storage and timely elimination of urine. These functions become abnormal after SCI. Detrusor and urethral sphincter contract simultaneously during voiding (detrusor sphincter dyssynergia, DSD) and the detrusor also contracts frequently during storage (detrusor hyperreflexia, DH). DSD prevents complete elimination of urine, generates high bladder pressure and requires daily urethral catheterization. High bladder pressure causes vesicoureteral reflux and renal failure in the long-term. Residual urine in the bladder and urethral catheterization cause cystitis and infection. In addition, DH causes a low bladder storage capacity and transient high intravesical pressures resulting in incontinence, risk for kidney damage and bladder hypertrophy. The problems of the lower urinary tract result in large medical cost and tremendous social and psychological impacts on people with SCI and their families. The goal of this project is to find new methods to treat both DSD and DH. Although electrical stimulation of sacral anterior roots has been successful to restore bladder control after SCI, it requires transection of sacral posterior roots (dorsal rhizotomy) to prevent DSD and DH. Dorsal rhizotomy is destructive and irreversible, and results in the loss of reflex sexual function and reflex defecation. Our new approach will utilize the remaining and newly emerged spinal reflexes after SCI to restore the lost functions, rather than further damaging the neural pathways by dorsal rhizotomy. During urine storage, we will electrically activate an inhibitory pudendal-to-bladder spinal reflex to abolish the hyperreflexic bladder contractions and treat DH. When voiding is attempted, we will activate an excitatory pudendal-to-bladder spinal reflex to induce bladder contraction while electrically blocking pudendal nerve conduction to relax the external urethral sphincter and thereby treat DSD. With this approach, a large bladder capacity and low pressure voiding with a minimal residual volume of urine will be expected. Our approach preserves the spinal reflex functions for bowel and sexual organ, and more importantly provides people with SCI the opportunity to benefit from advances in neural regeneration and repair techniques in the future.

Public Health Relevance

The urological dysfunctions after spinal cord injury (SCI) result in large medical cost and tremendous social and psychological impacts on people with SCI and their families. Our studies proposed in this grant renewal will find new methods to restore both continence and micturition functions after SCI. Our new approach also preserves the spinal reflex functions for bowel and sexual organ, and more importantly provides people with SCI the opportunity to benefit from advances in neural regeneration and repair techniques in the future.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK068566-07
Application #
8321908
Study Section
Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
Program Officer
Mullins, Christopher V
Project Start
2004-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
7
Fiscal Year
2012
Total Cost
$258,364
Indirect Cost
$87,827
Name
University of Pittsburgh
Department
Urology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Yang, Guangning; Xiao, Zhiying; Wang, Jicheng et al. (2016) Post-stimulation block of frog sciatic nerve by high-frequency (kHz) biphasic stimulation. Med Biol Eng Comput :
Schwen, Zeyad; Matsuta, Yosuke; Shen, Bing et al. (2014) Combination of foot stimulation and tolterodine treatment eliminates bladder overactivity in cats. Neurourol Urodyn 33:1266-71
Yang, Guangning; Wang, Jicheng; Shen, Bing et al. (2014) Pudendal nerve stimulation and block by a wireless-controlled implantable stimulator in cats. Neuromodulation 17:490-6; discussion 496
Xiao, Zhiying; Reese, Jeremy; Schwen, Zeyad et al. (2014) Role of spinal GABAA receptors in pudendal inhibition of nociceptive and nonnociceptive bladder reflexes in cats. Am J Physiol Renal Physiol 306:F781-9
Reese, Jeremy; Xiao, Zhiying; Schwen, Zeyad et al. (2014) Effects of duloxetine and WAY100635 on pudendal inhibition of bladder overactivity in cats. J Pharmacol Exp Ther 349:402-7
Zhao, Shouguo; Yang, Guangning; Wang, Jicheng et al. (2014) Effect of non-symmetric waveform on conduction block induced by high-frequency (kHz) biphasic stimulation in unmyelinated axon. J Comput Neurosci 37:377-86
Schwen, Zeyad; Matsuta, Yosuke; Shen, Bing et al. (2013) Inhibition of bladder overactivity by duloxetine in combination with foot stimulation or WAY-100635 treatment in cats. Am J Physiol Renal Physiol 305:F1663-8
Matsuta, Yosuke; Schwen, Zeyad; Mally, Abhijith D et al. (2013) Effect of methysergide on pudendal inhibition of micturition reflex in cats. Exp Neurol 247:250-8
Mally, Abhijith D; Matsuta, Yosuke; Zhang, Fan et al. (2013) Role of opioid and metabotropic glutamate 5 receptors in pudendal inhibition of bladder overactivity in cats. J Urol 189:1574-9
Schwen, Zeyad; Matsuta, Yosuke; Shen, Bing et al. (2013) Involvement of 5-HT3 receptors in pudendal inhibition of bladder overactivity in cats. Am J Physiol Renal Physiol 305:F663-71

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