The disruption of coordination between smooth muscle contraction in the bladder and the relaxation of the external urethral sphincter (EUS) striated muscle is a common issue in dysfunctional bladders. It is a significant challenge to overcome for neuromodulation approaches to restore bladder control. Bladder-sphincter dyssynergia leads to undesirably high bladder pressures, and poor voiding outcomes, which can pose life-threatening secondary complications. Mixed pelvic nerves are potential peripheral targets for stimulation to treat dysfunctional bladders, but typical electrical stimulation of pelvic nerves activates both the parasympathetic efferent pathway to excite the bladder, as well as the sensory afferent pathway that causes unwanted sphincter contractions. Thus, a novel pelvic nerve stimulation paradigm is required. In anesthetized female rats, we combined a low frequency (10 Hz) stimulation to evoke bladder contraction, and a more proximal 20 kHz stimulation of the pelvic nerve to block afferent activation, in order to produce micturition with reduced bladder-sphincter dyssynergia. Increasing the phase width of low frequency stimulation from 150 to 300 µs alone was able to improve voiding outcome significantly. However, low frequency stimulation of pelvic nerves alone evoked short latency (19.9-20.5 ms) dyssynergic EUS responses, which were abolished with a non-reversible proximal central pelvic nerve cut. We demonstrated that a proximal 20 kHz stimulation of pelvic nerves generated brief onset effects at lower current amplitudes, and was able to either partially or fully block the short latency EUS responses depending on the ratio of the blocking to stimulation current. Our results indicate that ratios >10 increased the efficacy of blocking EUS contractions. Importantly, we also demonstrated for the first time that this combined low and high frequency stimulation approach produced graded control of the bladder, while reversibly blocking afferent signals that elicited dyssynergic EUS contractions, thus improving voiding by 40.5 ± 12.3%. Our findings support advancing pelvic nerves as a suitable neuromodulation target for treating bladder dysfunction, and demonstrate the feasibility of an alternative method to nonreversible nerve transection and sub-optimal intermittent stimulation methods to reduce dyssynergia.

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ObjectivesThe bladder becomes retentive during the early phase of spinal cord injury, and requires proper bladder management to prevent damage to the lower urinary tract and kidney. We investigated the effects of on-demand pelvic nerve stimulation on the areflexive bladder during the earliest phase of complete spinal cord injury in rats and the use of pelvic nerve signals as a proxy to estimate intravesical pressure for closed-loop applications. Materials and MethodsIn order to stimulate the pelvic nerves in female Sprague-Dawley rats with complete spinal cord transection (T7 level), a flexible electrode was implanted unilaterally on pelvic nerve, and electrical stimulation was provided by a custom-built nerve stimulator. Stimulationevoked voiding was monitored in the awake state while size, capacity and spontaneous contractions of the bladder were analysed under anaesthesia. Separately, recordings of the pelvic nerve signals, external urethral sphincter activity and intravesical pressure were performed in animals with intact and transected spinal cord under anaesthesia. ResultsSuccessful pelvic nerve stimulation enabled more frequent voiding, reduced overdistension of bladder, and preserved non-voiding spontaneous bladder contractions.Typical bladder management protocol for SCI rats (manual expression every 8 -12 hours) resulted in more severe bladder overdistention. Signal processing of the recorded extraneural pelvic nerve signals successfully reconstructed changes in intravesical pressure, demonstrating their use in estimating the fullness and contractions of the bladder. ConclusionsThe preliminary results suggest that pelvic nerve stimulators can serve as an alternative method for frequent emptying of the areflexive bladder. Simultaneous recording of the same pelvic nerve will be useful for development of a closed-loop neuroprosthesis.

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