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 non-reversible nerve transection and sub-optimal intermittent stimulation methods to reduce dyssynergia.
Highlights
Recent developments in the field of bioelectronic medicine call for new innovations in stimulating the nervous system for treating diseases (Kristoffer Famm, 2013; Birmingham et al, 2014; Reardon, 2014), including the targeting of peripheral nerves that modulate the function of visceral organs, such as the urinary bladder and spleen (Pavlov and Tracey, 2012)
The current amplitudes used in our experiments fell within normal ranges of nerve stimulation associated with lower urinary tracts, and were able to elicit graded bladder contractions, as well as voiding at higher, suprathreshold amplitudes (Figure 1C)
Our findings could be useful for advancing pelvic nerves as a more suitable neuromodulation target for restoring voluntary control of bladder voiding in the future
Summary
Recent developments in the field of bioelectronic medicine call for new innovations in stimulating the nervous system for treating diseases (Kristoffer Famm, 2013; Birmingham et al, 2014; Reardon, 2014), including the targeting of peripheral nerves that modulate the function of visceral organs, such as the urinary bladder (de Groat and Tai, 2015; Lee et al, 2015; McGee et al, 2015) and spleen (Pavlov and Tracey, 2012). Dysfunction of the urinary bladder can stem from neurological impairment (Yoshimura and Chancellor, 2003), such as spinal cord injuries (Taweel and Seyam, 2015), and can affect the process of micturition, which is comprised of a coordinated sequence of contraction of bladder detrusor muscles, and relaxation of sphincter muscles to expel urine stored in the bladder through the urethra. This process requires descending inputs from the pontine micturition center to excite sacral parasympathetic neurons, which synapse onto postganglionic neurons in the pelvic plexus in humans and the major pelvic ganglion (MPG) in rodents, to contract the smooth detrusor muscles. This approach has been shown to elicit voiding, but its success is dependent on intact spinal reflexes (Boggs et al, 2005; Woock et al, 2008; Yoo et al, 2008), and has limited voiding efficacy (Langdale and Grill, 2016)
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