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Disrupted communication along the brain-gut axis contributes to impaired visceral function and debilitating symptoms. Colonic dysmotility in particular remains poorly managed by conventional pharmaceuticals. The objectives of our study were to restore colonic motility by electrical stimulation of the sacral nerves optimize the stimulation pattern to relieve constipation and elucidate the mechanisms of motor patterns evoked by stimulation. Through a combination of computational ex vivo and in vivo preclinical models we engineered temporal patterns of sacral nerve stimulation to evoke maximally propulsive prokinetic motility. We validated the optimized pattern of stimulation by measuring defecatory behavior in a loperamide model of constipation in rats. Compared with sham stimulation and the continuous pattern of stimulation conventionally used in the clinic burst-patterned sacral nerve stimulation significantly increased fecal output to baseline and relieved constipation in awake behaving rats. Further we systematically varied stimulation frequency stimulation duration and interburst interval and determined the minimum effective parameters to maximize anorectal contractions. We demonstrated that a precise temporal pattern of sacral nerve stimulation relieves constipation in rats establishing pre-clinical evidence and the foundational principles for translation to future pilot clinical trials.
Disrupted communication along the brain-gut axis contributes to impaired visceral function and debilitating symptoms. Colonic dysmotility in particular remains poorly managed by conventional pharmaceuticals. The objectives of our study were to restore colonic motility by electrical stimulation of the sacral nerves optimize the stimulation pattern to relieve constipation and elucidate the mechanisms of motor patterns evoked by stimulation. Through a combination of computational ex vivo and in vivo preclinical models we engineered temporal patterns of sacral nerve stimulation to evoke maximally propulsive prokinetic motility. We validated the optimized pattern of stimulation by measuring defecatory behavior in a loperamide model of constipation in rats. Compared with sham stimulation and the continuous pattern of stimulation conventionally used in the clinic burst-patterned sacral nerve stimulation significantly increased fecal output to baseline and relieved constipation in awake behaving rats. Further we systematically varied stimulation frequency stimulation duration and interburst interval and determined the minimum effective parameters to maximize anorectal contractions. We demonstrated that a precise temporal pattern of sacral nerve stimulation relieves constipation in rats establishing pre-clinical evidence and the foundational principles for translation to future pilot clinical trials.