State-Dependent Pudendal Nerve Stimulation to Increase Bladder Capacity and Voiding Efficiency in Cats

Hokanson J1, Langdale C1, Milliken P2, Sridhar A2, Grill W1

Research Type

Basic Science / Translational

Abstract Category

Overactive Bladder

Abstract 628
Basic Science: Novel Bladder Insights
Scientific Podium Short Oral Session 31
Friday 31st August 2018
13:52 - 14:00
Hall D
Animal Study Neuromodulation Overactive Bladder
1. Duke University, 2. Galvani Bioelectronics
Presenter
J

James Hokanson

Links

Abstract

Hypothesis / aims of study
Despite the increased use of botulinum toxin A and sacral neuromodulation to treat the symptoms of overactive bladder, many patients fail to find adequate symptom relief using these therapies. Pudendal nerve stimulation is a promising alternative approach to these third-line therapies for treating overactive bladder symptoms that is not yet in clinical use.

Recent work demonstrated that electrical stimulation of the sensory pudendal nerve in rats increases bladder capacity [1]. However, the stimulation parameters that most strongly inhibited the bladder during filling also caused substantial reductions in voiding efficiency.

Those results motivated the present study in cats combining continuous stimulation of the dorsal genital nerve, as well as state-dependent stimulation of the dorsal genital and motor pudendal nerves. State-dependent stimulation used one stimulus pattern to promote bladder storage during the filling phase and another stimulus pattern to promote bladder voiding during the emptying phase.

The aims of the study were to determine whether we also saw a decrease in voiding efficiency from continuous stimulation, as has been reported in rats, and to determine whether state-dependent stimulation increased both bladder capacity and voiding efficiency relative to a no-stimulation condition.
Study design, materials and methods
Electrical stimulation of branches of the pudendal nerve was conducted in male cats anesthetized with chloralose (n=6). Bipolar nerve cuffs were placed on the dorsal genital (DGN) and motor branches of the pudendal nerve. Wires were placed percutaneously to measure evoked anal sphincter EMG in response to stimulation. A bladder catheter was placed through the dome of the bladder for filling and pressure measurement. Bladder capacity and voiding efficiency were measured from single-fill cystometrograms using saline with a non-occluded urethra.

Bladder inhibition was achieved by stimulating the DGN at 10 Hz and 3T (3x the amplitude required to evoke reflexive EAS EMG activity). In some trials this stimulation persisted throughout voiding (continuous stimulation), mimicking traditional stimulation paradigms. In other trials at the onset of voiding the stimulation was terminated (fill-only stimulation), or a different stimulus was employed to promote voiding (state-dependent stimulation). Stimuli used to promote voiding were either 33 Hz, 3T stimulation of the DGN or a bursting pattern applied to the pudendal motor branch. Bursting occurred at the minimum stimulus amplitude which generated the maximal EAS EMG response.

Stimulus patterns were randomized within block and values were normalized to preceding control levels for plotting and summary statistics. Voiding efficiency was compared between no-stimulation controls, continuous stimulation, and the state-dependent stimulation conditions using the Friedman ANOVA test, followed by the Benjamini, Krieger and Yekutieli two-stage step-up method for post-hoc comparison of conditions to continuous stimulation in GraphPad (Version 7.04) with p<0.05 considered to be significant.
Results
Example data are shown in Figure 1. Continuous 10 Hz stimulation of the DGN increased bladder capacity by a median of 26%, and, as reported for the rat, decreased voiding efficiency in 5 of the 6 experiments (median 33% decrease) relative to controls although this trend was not statistically significant (p = 0.072, n=5).

Relative to no-stimulation controls, both termination of continence-promoting 10 Hz DGN stimulation at the onset of voiding and 33 Hz stimulation during voiding increased voiding efficiency (median increases of 14% and 19%, respectively), although neither was statistically significant (p>0.05, n=5). The largest and most consistent increase in VE came from switching from 10 Hz DGN stimulation to motor nerve burst stimulation, which produced a 379% median increase in VE (p=0.028, n=5). 

Relative to continuous stimulation, state-dependent stimulation led to significant increases in voiding efficiency (p=0.003 for ANOVA test, p=0.028 for fill only, p=0.048 for 33 Hz, p<0.001 for motor bursting, n=5).
Interpretation of results
Similar to results in rats, continuous stimulation of the DGN to inhibit the bladder and increase capacity during filling also inhibited voiding in 5 of 6 animals, with a median decrease of 33%. This result however was not statistically significant (p = 0.072, n=5), likely due to the small number of animals tested.

All state-dependent stimulation approaches, including terminating the stimulus during voiding, increased voiding efficiency relative to continuous stimulation. However only one state-dependent stimulation paradigm, motor-bursting during voiding, reliably increased voiding efficiency relative to control values. Traditional stimulation of the pudendal nerve or its subcomponents (e.g., dorsal genital nerve) do not target individually the motor and sensory components. Future work remains to determine how best to translate this approach to the clinic.

Stimulation of the dorsal genital nerve at 33 Hz increased voiding efficiency relative to controls by 19% but this result was not statistically significant due to high variability and the small number of experiments. This approach remains attractive for further testing as implementing this approach clinically would be relatively straightforward [2].
Concluding message
Electrical stimulation of the pudendal nerve is a promising approach for treating overactive bladder symptoms. Continuous pudendal nerve stimulation increases bladder capacity but may so strongly inhibit the bladder so as to reduce the efficiency of subsequent voiding. State-dependent stimulation, using different stimulation paradigms to promote both bladder filling and voiding, increased bladder capacity relative to controls and voiding efficiency relative to continuous stimulation in male cats. Motor stimulation during voiding also reliably increased voiding efficiency beyond control levels. State-dependent stimulation of the pudendal nerve may be a useful approach for treatment of overactive bladder symptoms.
Figure 1
References
  1. Hokanson JA, Langdale CL, Sridhar A, Grill WM. Stimulation of the Sensory Pudendal Nerve Increases Bladder Capacity in the Rat. Am. J. Physiol. Renal Physiol. ( November 15, 2017). doi: 10.1152/ajprenal.00373.2017.
  2. Goldman HB, Amundsen CL, Mangel J, Grill JH, Bennett M, Gustafson KJ, Grill WM. Dorsal genital nerve stimulation for the treatment of overactive bladder symptoms. Neurourol Urodyn 27: 499–503, 2008.
Disclosures
<span class="text-strong">Funding</span> Galvani Bioelectronics and NIDDK K12 DK100024 <span class="text-strong">Clinical Trial</span> No <span class="text-strong">Subjects</span> Animal <span class="text-strong">Species</span> Cat <span class="text-strong">Ethics Committee</span> IACUC