Novel Neurostimulation of Autonomic Pelvic Nerves Overcomes Bladder-Sphincter Dyssynergia

Abstract

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.

Neuromodulation of pelvic nerve during early phase of spinal cord injury in rats using implantable prototype devices - a preliminary study

“…As the complete SCI was performed at the thoracic level above L6-S1, 20 Hz pelvic nerve stimulation alone, in the absence of dorsal root rhizotomy or 20 kHz frequency block, could still evoke reflexive EUS EMG activity, causing detrusor-sphincter dyssynergia 9 , and thus resulting in suboptimal voiding efficiency (32.97% and 62.98%) in our experiments. In order to reduce stimulation-evoked detrusor-sphincter dyssynergia , a combination of low frequency stimulation (10 -20 Hz) and 20 kHz high frequency nerve block at the pelvic nerve would be required 9 , but these will require further optimization of our implantable electrode and nerve stimulator prototype.…”

“…Metal screws and dental cement were used for anchoring the head-plug on the rat's skull. The rat was then removed from the stereotaxic frame, and turned to the supine position for an abdominal muscle incision to expose the left pelvic nerve branches as previously described 9 . The electrode was then implanted onto the exposed pelvic nerve, and secured with silicone elastomer (Kwik-Sil, World Precision Instruments).…”

“…For 2 subjects, the animal was first placed in a prone position to perform a complete spinal cord transection at T8, similar to that described in Section 2.1, and then placed in a supine position for further surgery. The surgical procedures to expose the bladder, pelvic nerve, and external urethral sphincter (EUS) were as described previously 9 . Platinum iridium hook electrodes were implanted unilaterally on the pelvic nerve, and secured with Kwik-Sil for extraneural recording of pelvic nerve electroneurogram (ENG).…”

“…For recording using commercial benchtop systems, both ENG and EMG signals were amplified by using the Intan preamplifier 2216, and acquired at either 20 or 30 kHz with the Intan RHD2000 (Intan Technologies) with a 50 Hz notch filter. Intravesical bladder pressure was recorded using a saline-filled catheter (C30PU-RCA1302, Instech Laboratories Inc) connected to a pressure sensor and infusion pump as described previously 9 . Pressure data was also acquired via the Intan RH2000 system, and then low-pass filtered at 30 Hz.…”

“…While early sacral neuromodulation in complete SCI patients prevented the development of urinary incontinence, the patients were not able to void on demand 4 . A possible alternative to restore voiding in the areflexive bladder is to activate the parasympathetic pathway for bladder contraction, either by stimulating the pelvic nerve or efferent nerve endings in the bladder wall [5][6][7][8][9] , or in the case of complete SCI patients, sacral anterior root stimulation (SARS) by the commercially available Finetech-Brindley device 10 . However, SARS is usually available as a treatment only many months after injury, and requires a dorsal rhizotomy 11 .…”