Neuromodulation has been used in the treatment of various pelvic organ dysfunctions for almost 40 years and several placebo-controlled studies have confirmed its clinical effect. Many neuromodulation methods using different devices and stimulation parameters, targeting different neural structures have been introduced, but only a limited number have been adopted into routine clinical use. A substantial volume of basic research and clinical studies addressing specific effects of neuromodulation in the treatment of overactive bladder (OAB) have been published to date; however, their mechanistic implications have not been comprehensively summarized. Thus, our understanding of the mechanism of action of neuromodulation in OAB treatment is mainly based on postulated theories. Results from animal experiments suggest that different neuromodulation methods used to treat OAB share the same basic principles. The most likely explanation for the effect of neuromodulation in OAB therapy is the suppression of bladder afferent signalling, promotion of spinal guarding reflexes and modulation of non-specific supraspinal regulatory circuits.

Department of Clinical Medicine University of Copenhagen Copenhagen Denmark

Department of Regional Health Research University of Southern Denmark Odense Denmark

Department of Surgical Studies Ostrava University Ostrava Czech Republic

Department of Urology Copenhagen University Hospital Herlev and Gentofte Hospital Copenhagen Denmark

Department of Urology Esbjerg and Grindsted Hospital University Hospital of Southern Denmark Odense Denmark

Department of Urology Odense University Hospital Odense Denmark

Department of Urology University Hospital Ostrava Czech Republic

Research Unit of Urology Department of Clinical Research University of Southern Denmark Odense Denmark

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Haylen, B. T. et al. An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction. Int. Urogynecol. J. 21, 5–26 (2010). PubMed DOI

D’Ancona, C. et al. The International Continence Society (ICS) report on the terminology for adult male lower urinary tract and pelvic floor symptoms and dysfunction. Neurourol. Urodyn. 38, 433–477 (2019). PubMed DOI

Eapen, R. S. & Radomski, S. B. Review of the epidemiology of overactive bladder. Res. Rep. Urol. 8, 71–76, (2016). PubMed PMC

Leron, E., Weintraub, A. Y., Mastrolia, S. A. & Schwarzman, P. Overactive bladder syndrome: evaluation and management. Curr. Urol. 11, 117–125 (2018). PubMed DOI PMC

Bartoli, S., Aguzzi, G. & Tarricone, R. Impact on quality of life of urinary incontinence and overactive bladder: a systematic literature review. Urology 75, 491–500 (2010). PubMed DOI

Peyronnet, B. et al. A comprehensive review of overactive bladder pathophysiology: on the way to tailored treatment. Eur. Urol. 75, 988–1000 (2019). PubMed DOI

Tanagho, E. A. Neuromodulation and neurostimulation: overview and future potential. Transl. Androl. Urol. 1, 44–49, (2012). PubMed PMC

Fowler, C. J., Griffiths, D. & de Groat, W. C. The neural control of micturition. Nat. Rev. Neurosci. 9, 453–466 (2008). PubMed DOI PMC

Blok, B. F. Central pathways controlling micturition and urinary continence. Urology 59, 13–17 (2002). PubMed DOI

Lovick, T. A. Central control of visceral pain and urinary tract function. Auton. Neurosci. 200, 35–42 (2016). PubMed DOI

Yoshimura, N. & Chancellor, M. B. Neurophysiology of lower urinary tract function and dysfunction. Rev. Urol. 5, S3–S10 (2003). PubMed PMC

Yoham, A. L. & Bordoni, B. in StatPearls. (StatPearls, 2024).

Goidescu, O. C. et al. The distribution of the inferior hypogastric plexus in female pelvis. J. Med. Life 15, 784–791 (2022). PubMed DOI PMC

Hegde, S. S. Muscarinic receptors in the bladder: from basic research to therapeutics. Br. J. Pharmacol. 147, S80–S87 (2006). PubMed DOI PMC

Ye, F. et al. Applied anatomy of female pelvic plexus for nerve-sparing radical hysterectomy (NSRH). BMC Womens Health 23, 533 (2023). PubMed DOI PMC

de Groat, W. C., Griffiths, D. & Yoshimura, N. Neural control of the lower urinary tract. Compr. Physiol. 5, 327–396 (2015). PubMed DOI PMC

Chai, T. C. Continence and micturition: physiological mechanisms under behavioral control. Am. J. Physiol. Renal Physiol. 309, F33–F34 (2015). PubMed DOI

Alkatout, I., Wedel, T., Pape, J., Possover, M. & Dhanawat, J. Review: pelvic nerves — from anatomy and physiology to clinical applications. Transl. Neurosci. 12, 362–378 (2021). PubMed DOI PMC

Rojas-Gómez, M. F. et al. Regional anesthesia guided by ultrasound in the pudendal nerve territory. Colomb. J. Anesthesiol. 45, 200–209 (2017).

Aoun, F. et al. Pudendal nerve release for lower urinary tract symptoms in young males. Low. Urin. Tract. Symptoms 13, 286–290 (2021). PubMed DOI

Birder, L. et al. Neural control of the lower urinary tract: peripheral and spinal mechanisms. Neurourol. Urodyn. 29, 128–139 (2010). PubMed DOI PMC

Häbler, H. J., Jänig, W. & Koltzenburg, M. Activation of unmyelinated afferent fibres by mechanical stimuli and inflammation of the urinary bladder in the cat. J. Physiol. 425, 545–562 (1990). PubMed DOI PMC

Michel, M. C. & Chapple, C. R. Basic mechanisms of urgency: roles and benefits of pharmacotherapy. World J. Urol. 27, 705–709, (2009). PubMed DOI PMC

Merrill, L., Gonzalez, E. J., Girard, B. M. & Vizzard, M. A. Receptors, channels, and signalling in the urothelial sensory system in the bladder. Nat. Rev. Urol. 13, 193–204 (2016). PubMed DOI PMC

Deruyver, Y., Voets, T., De Ridder, D. & Everaerts, W. Transient receptor potential channel modulators as pharmacological treatments for lower urinary tract symptoms (LUTS): myth or reality? BJU Int. 115, 686–697 (2015). PubMed DOI

Applebaum, A. E., Vance, W. H. & Coggeshall, R. E. Segmental localization of sensory cells that innervate the bladder. J. Comp. Neurol. 192, 203–209 (1980). PubMed DOI

Danziger, Z. C. & Grill, W. M. Sensory and circuit mechanisms mediating lower urinary tract reflexes. Auton. Neurosci. 200, 21–28 (2016). PubMed DOI

Lee, C. L. et al. Sophisticated regulation of micturition: review of basic neurourology. J. Exerc. Rehabil. 17, 295–307 (2021). PubMed DOI PMC

Reitz, A., Schmid, D. M., Curt, A., Knapp, P. A. & Schurch, B. Afferent fibers of the pudendal nerve modulate sympathetic neurons controlling the bladder neck. Neurourol. Urodyn. 22, 597–601 (2003). PubMed DOI

Kim, J. W., Kim, S. J., Park, J. M., Na, Y. G. & Kim, K. H. Past, present, and future in the study of neural control of the lower urinary tract. Int. Neurourol. J. 24, 191–199 (2020). PubMed DOI PMC

Blok, B. F. Sacral neuromodulation for the treatment of urinary bladder dysfunction: mechanism of action and future directions. Bioelectron. Med. 1, 85–94 (2018). DOI

Holstege, G. How the emotional motor system controls the pelvic organs. Sex. Med. Rev. 4, 303–328 (2016). PubMed DOI

Michels, L. et al. Supraspinal control of urine storage and micturition in men-an fMRI study. Cereb. Cortex 25, 3369–3380 (2015). PubMed DOI

Zare, A., Jahanshahi, A., Rahnama’i, M. S., Schipper, S. & van Koeveringe, G. A. The role of the periaqueductal gray matter in lower urinary tract function. Mol. Neurobiol. 56, 920–934 (2019). PubMed DOI

Ding, Y. Q. et al. Direct projections from the periaqueductal gray to pontine micturition center neurons projecting to the lumbosacral cord segments: an electron microscopic study in the rat. Neurosci. Lett. 242, 97–100 (1998). PubMed DOI

Kitta, T. et al. Brain-bladder control network: the unsolved 21st century urological mystery. Int. J. Urol. 22, 342–348 (2015). PubMed DOI

Griffiths, D. Neural control of micturition in humans: a working model. Nat. Rev. Urol. 12, 695–705 (2015). PubMed DOI

Roy, H. A. & Green, A. L. The central autonomic network and regulation of bladder function. Front. Neurosci. 13, 535 (2019). PubMed DOI PMC

Pang, D., Gao, Y. & Liao, L. Functional brain imaging and central control of the bladder in health and disease. Front. Physiol. 13, 914963 (2022). PubMed DOI PMC

Yamaguchi, O. et al. Defining overactive bladder as hypersensitivity. Neurourol. Urodyn. 26, 904–907 (2007). PubMed DOI

Cardozo, L., Rovner, E., Wagg, A., Wein, A. & Abrams, P. Incontinence 7th edn. (ICI-ICS, 2023).

Chai, T. C., Russo, A., Yu, S. & Lu, M. Mucosal signaling in the bladder. Auton. Neurosci. 200, 49–56 (2016). PubMed DOI

Andersson, K. E. & McCloskey, K. D. Lamina propria: the functional center of the bladder? Neurourol. Urodyn. 33, 9–16 (2014). PubMed DOI

Banakhar, M. A., Al-Shaiji, T. F. & Hassouna, M. M. Pathophysiology of overactive bladder. Int. Urogynecol. J. 23, 975–982 (2012). PubMed DOI

Speich, J. E. et al. Are oxidative stress and ischemia significant causes of bladder damage leading to lower urinary tract dysfunction? Report from the ICI-RS 2019. Neurourol. Urodyn. 39, S16–S22 (2020). PubMed DOI PMC

Chen, L. C. & Kuo, H. C. Pathophysiology of refractory overactive bladder. Low. Urin. Tract. Symptoms 11, 177–181 (2019). PubMed DOI

Yang, J. H., Choi, H. P., Niu, W. & Azadzoi, K. M. Cellular stress and molecular responses in bladder ischemia. Int. J. Mol. Sci. 22, 11862 (2021). PubMed DOI PMC

Fusco, F. et al. Progressive bladder remodeling due to bladder outlet obstruction: a systematic review of morphological and molecular evidences in humans. BMC Urol. 18, 15 (2018). PubMed DOI PMC

Khan, Z. E. A. Chronic urinary infection in overactive bladder syndrome: a prospective, blinded case control study. Front. Cell Infect. Microbiol. 11, 752275 (2021). PubMed DOI PMC

Tyagi, P. et al. Urine cytokines suggest an inflammatory response in the overactive bladder: a pilot study. Int. Urol. Nephrol. 42, 629–635 (2010). PubMed DOI

Walter, M. et al. Considering non-bladder aetiologies of overactive bladder: a functional neuroimaging study. BJU Int. 128, 586–597 (2021). PubMed DOI

Sakakibara, R. et al. Is overactive bladder a brain disease? The pathophysiological role of cerebral white matter in the elderly. Int. J. Urol. 21, 33–38 (2014). PubMed DOI

He, Y., Hara, H. & Núñez, G. Mechanism and regulation of NLRP3 inflammasome activation. Trends Biochem. Sci. 41, 1012–1021 (2016). PubMed DOI PMC

Sheyn, D. et al. Baseline brain segmental volumes in responders and nonresponders to anticholinergic therapy for overactive bladder syndrome. Female Pelvic Med. Reconstr. Surg. 27, e399–e407 (2021). PubMed DOI

Apostolidis, A. et al. Is there “brain OAB” and how can we recognize it? International Consultation on Incontinence-Research Society (ICI-RS) 2017. Neurourol. Urodyn. 37, S38–S45 (2018). PubMed DOI

Suskind, A. M. The aging overactive bladder: a review of aging-related changes from the brain to the bladder. Curr. Bladder Dysfunct. Rep. 12, 42–47 (2017). PubMed DOI PMC

Hsu, L. N., Hu, J. C., Chen, P. Y., Lee, W. C. & Chuang, Y. C. Metabolic syndrome and overactive bladder syndrome may share common pathophysiologies. Biomedicines 10, 1957 (2022).

Kullmann, F. A. et al. Serotonergic paraneurones in the female mouse urethral epithelium and their potential role in peripheral sensory information processing. Acta Physiol. 222, e12919 (2018).

Saxtorph, M. Stricture Urethrae–Fistula Perinee–Retentio Urinae 265–280 (Clinsk Chirurgi, Gyldendalske Fortag, 1878).

Brindley, G. S., Polkey, C. E., Rushton, D. N. & Cardozo, L. Sacral anterior root stimulators for bladder control in paraplegia: the first 50 cases. J. Neurol. Neurosurg. Psychiatry 49, 1104–1114 (1986). PubMed DOI PMC

Schmidt, R. A. & Tanagho, E. A. Feasibility of controlled micturition through electric stimulation. Urol. Int. 34, 199–230 (1979). PubMed DOI

Heine, J. P., Schmidt, R. A. & Tanagho, E. A. Intraspinal sacral root stimulation for controlled micturition. Invest. Urol. 15, 78–82 (1977). PubMed

Gaunt, R. A. & Prochazka, A. Control of urinary bladder function with devices: successes and failures. Prog. Brain Res. 152, 163–194 (2006). PubMed DOI

McGuire, E. J., Zhang, S. C., Horwinski, E. R. & Lytton, B. Treatment of motor and sensory detrusor instability by electrical stimulation. J. Urol. 129, 78–79 (1983). PubMed DOI

Stoller, M. L. Afferent nerve stimulation for pelvic floor dysfunction. Int. Urogynecol. J. 10, 99 (1999).

Visca, A., Lay, R., Sessions, A. E., Rabinowitz, R. & Ajay, D. History of peripheral tibial nerve stimulation in urology. Urology 174, 3–6 (2023). PubMed DOI

Schmidt, R. A. et al. Sacral nerve stimulation for treatment of refractory urinary urge incontinence. Sacral Nerve Stimulation Study Group. J. Urol. 162, 352–357 (1999). PubMed DOI

Govier, F. E., Litwiller, S., Nitti, V., Kreder, K. J. Jr. & Rosenblatt, P. Percutaneous afferent neuromodulation for the refractory overactive bladder: results of a multicenter study. J. Urol. 165, 1193–1198 (2001). PubMed DOI

Janssen, D. A., Martens, F. M., de Wall, L. L., van Breda, H. M. & Heesakkers, J. P. Clinical utility of neurostimulation devices in the treatment of overactive bladder: current perspectives. Med. Devices 10, 109–122 (2017). DOI

Siegel, S. et al. Five-year followup results of a prospective, multicenter study of patients with overactive bladder treated with sacral neuromodulation. J. Urol. 199, 229–236 (2018). PubMed DOI

Pezzella, A. et al. Two-year outcomes of the ARTISAN-SNM study for the treatment of urinary urgency incontinence using the Axonics rechargeable sacral neuromodulation system. Neurourol. Urodyn. 40, 714–721 (2021). PubMed DOI PMC

Meng, L. et al. Sacral neuromodulation for overactive bladder using the InterStim and BetterStim systems. Sci. Rep. 12, 22299 (2022). PubMed DOI PMC

Liao, L. et al. Sacral neuromodulation using a novel device with a six-contact-point electrode for the treatment of patients with refractory overactive bladder: a multicenter, randomized, single-blind, parallel-control clinical trial. Eur. Urol. Focus. 8, 1823–1830 (2022). PubMed DOI

van Kerrebroeck, P. et al. First-in-human implantation of a mid-field powered neurostimulator at the sacral nerve: results from an acute study. Neurourol. Urodyn. 38, 1669–1675 (2019). PubMed DOI

Peters, K. M. et al. Randomized trial of percutaneous tibial nerve stimulation versus Sham efficacy in the treatment of overactive bladder syndrome: results from the SUmiT trial. J. Urol. 183, 1438–1443 (2010). PubMed DOI

Finazzi-Agrò, E. et al. Percutaneous tibial nerve stimulation effects on detrusor overactivity incontinence are not due to a placebo effect: a randomized, double-blind, placebo controlled trial. J. Urol. 184, 2001–2006 (2010). PubMed DOI

Moossdorff-Steinhauser, H. F. & Berghmans, B. Effects of percutaneous tibial nerve stimulation on adult patients with overactive bladder syndrome: a systematic review. Neurourol. Urodyn. 32, 206–214 (2013). PubMed DOI

Booth, J., Connelly, L., Dickson, S., Duncan, F. & Lawrence, M. The effectiveness of transcutaneous tibial nerve stimulation (TTNS) for adults with overactive bladder syndrome: a systematic review. Neurourol. Urodyn. 37, 528–541 (2018). PubMed DOI

van Breda, H. M. K., Martens, F. M. J., Tromp, J. & Heesakkers, J. A new implanted posterior tibial nerve stimulator for the treatment of overactive bladder syndrome: 3-month results of a novel therapy at a single center. J. Urol. 198, 205–210 (2017). PubMed DOI

Vollstedt, A. & Gilleran, J. Update on implantable PTNS devices. Curr. Urol. Rep. 21, 28 (2020). PubMed DOI

Dorsthorst, M. J. T. et al. 3-year followup of a new implantable tibial nerve stimulator for the treatment of overactive bladder syndrome. J. Urol. 204, 545–550 (2020). PubMed DOI

Gilling, P. et al. Twelve-month durability of a fully-implanted, nickel-sized and shaped tibial nerve stimulator for the treatment of overactive bladder syndrome with urgency urinary incontinence: a single-arm, prospective study. Urology 157, 71–78 (2021). PubMed DOI

Krhut, J. et al. Prospective, randomized, multicenter trial of peroneal electrical transcutaneous neuromodulation vs solifenacin in treatment-naive patients with overactive bladder. J. Urol. 209, 734–741 (2023). PubMed DOI

Krhut, J. et al. Peroneal electric transcutaneous neuromodulation (eTNM PubMed DOI PMC

Groen, J., Amiel, C. & Bosch, J. L. Chronic pudendal nerve neuromodulation in women with idiopathic refractory detrusor overactivity incontinence: results of a pilot study with a novel minimally invasive implantable mini-stimulator. Neurourol. Urodyn. 24, 226–230 (2005). PubMed DOI

Possover, M. A new technique of laparoscopic implantation of stimulation electrode to the pudendal nerve for treatment of refractory fecal incontinence and/or overactive bladder with urinary incontinence. J. Minim. Invasive Gynecol. 21, 729 (2014). PubMed DOI

Spinelli, M. et al. A new minimally invasive procedure for pudendal nerve stimulation to treat neurogenic bladder: description of the method and preliminary data. Neurourol. Urodyn. 24, 305–309 (2005). PubMed DOI

Peters, K. M., Feber, K. M. & Bennett, R. C. Sacral versus pudendal nerve stimulation for voiding dysfunction: a prospective, single-blinded, randomized, crossover trial. Neurourol. Urodyn. 24, 643–647 (2005). PubMed DOI

Farag, F. F., Martens, F. M., Rijkhoff, N. J. & Heesakkers, J. P. Dorsal genital nerve stimulation in patients with detrusor overactivity: a systematic review. Curr. Urol. Rep. 13, 385–388 (2012). PubMed DOI

Parodi, S., Kendall, H. J., Terrone, C. & Heesakkers, J. P. Evolving types of pudendal neuromodulation for lower urinary tract dysfunction. Cent. European J. Urol. 77, 82–88 (2024). PubMed PMC

Tish, M. M. & Geerling, J. C. The brain and the bladder: forebrain control of urinary (in)continence. Front. Physiol. 11, 658 (2020). PubMed DOI PMC

Fan, Y. H., Lin, C. C., Lin, A. T. & Chen, K. K. Are patients with the symptoms of overactive bladder and urodynamic detrusor overactivity different from those with overactive bladder but not detrusor overactivity? J. Chin. Med. Assoc. 74, 455–459 (2011). PubMed DOI

Shen, J. D. et al. Review of animal models to study urinary bladder function. Biology 10, 1316 (2021).

Wang, Y. & Hassouna, M. M. Neuromodulation reduces c-fos gene expression in spinalized rats: a double-blind randomized study. J. Urol. 163, 1966–1970 (2000). PubMed DOI

Shaker, H. et al. Role of C-afferent fibres in the mechanism of action of sacral nerve root neuromodulation in chronic spinal cord injury. BJU Int. 85, 905–910 (2000). PubMed DOI

Brink, T. S., Zimmerman, P. L., Mattson, M. A., Su, X. & Nelson, D. E. A chronic, conscious large animal platform to quantify therapeutic effects of sacral neuromodulation on bladder function. J. Urol. 194, 252–258 (2015). PubMed DOI

Kovacevic, M. & Yoo, P. B. Reflex neuromodulation of bladder function elicited by posterior tibial nerve stimulation in anesthetized rats. Am. J. Physiol. Renal Physiol. 308, F320–F329 (2015). PubMed DOI

Dieter, A. A., Degoski, D. J., Dolber, P. C. & Fraser, M. O. The effects of bilateral bipolar sacral neurostimulation on urinary bladder activity during filling before and after irritation in a rat model. Neurourol. Urodyn. 34, 387–391 (2015). PubMed DOI

Ren, J., Chew, D. J. & Thiruchelvam, N. Electrical stimulation of the spinal dorsal root inhibits reflex bladder contraction and external urethra sphincter activity: is this how sacral neuromodulation works? Urol. Int. 96, 360–366 (2016). PubMed DOI

Tai, C. et al. Prolonged poststimulation inhibition of bladder activity induced by tibial nerve stimulation in cats. Am. J. Physiol. Renal Physiol. 300, F385–F392 (2011). PubMed DOI PMC

Matsuta, Y., Roppolo, J. R., de Groat, W. C. & Tai, C. Poststimulation inhibition of the micturition reflex induced by tibial nerve stimulation in rats. Physiol. Rep. 2, e00205 (2014). PubMed DOI PMC

Park, E. et al. The long-lasting post-stimulation inhibitory effects of bladder activity induced by posterior tibial nerve stimulation in unanesthetized rats. Sci. Rep. 10, 19897 (2020). PubMed DOI PMC

Boggs, J. W., Wenzel, B. J., Gustafson, K. J. & Grill, W. M. Spinal micturition reflex mediated by afferents in the deep perineal nerve. J. Neurophysiol. 93, 2688–2697 (2005). PubMed DOI

Woock, J. P., Yoo, P. B. & Grill, W. M. Intraurethral stimulation evokes bladder responses via 2 distinct reflex pathways. J. Urol. 182, 366–373 (2009). PubMed DOI PMC

Theisen, K. et al. Frequency dependent tibial neuromodulation of bladder underactivity and overactivity in cats. Neuromodulation 21, 700–706 (2018). PubMed DOI PMC

Tai, C. et al. Plasticity of urinary bladder reflexes evoked by stimulation of pudendal afferent nerves after chronic spinal cord injury in cats. Exp. Neurol. 228, 109–117 (2011). PubMed DOI

Bandari, J. et al. Neurotransmitter mechanisms underlying sacral neuromodulation of bladder overactivity in cats. Neuromodulation 20, 81–87 (2017). PubMed DOI

Kadow, B. T. et al. Sympathetic β-adrenergic mechanism in pudendal inhibition of nociceptive and non-nociceptive reflex bladder activity. Am. J. Physiol. Renal Physiol. 311, F78–F84 (2016). PubMed DOI PMC

Rogers, M. J. et al. Propranolol, but not naloxone, enhances spinal reflex bladder activity and reduces pudendal inhibition in cats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 308, R42–R49 (2015). PubMed DOI

Lyon, T. D. et al. Pudendal but not tibial nerve stimulation inhibits bladder contractions induced by stimulation of pontine micturition center in cats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 310, R366–R374 (2016). PubMed DOI

Dray, A. & Metsch, R. Inhibition of urinary bladder contractions by a spinal action of morphine and other opioids. J. Pharmacol. Exp. Ther. 231, 254–260 (1984). PubMed DOI

Hisamitsu, T. & de Groat, W. C. The inhibitory effect of opioid peptides and morphine applied intrathecally and intracerebroventricularly on the micturition reflex in the cat. Brain Res. 298, 51–65 (1984). PubMed DOI

Noto, H. et al. Opioid modulation of the micturition reflex at the level of the pontine micturition center. Urol. Int. 47, 19–22 (1991). PubMed DOI

Roppolo, J. R., Booth, A. M. & De Groat, W. C. The effects of naloxone on the neural control of the urinary bladder of the cat. Brain Res. 264, 355–358 (1983). PubMed DOI

Willette, R. N., Morrison, S., Sapru, H. N. & Reis, D. J. Stimulation of opiate receptors in the dorsal pontine tegmentum inhibits reflex contraction of the urinary bladder. J. Pharmacol. Exp. Ther. 244, 403–409 (1988). PubMed DOI

Su, X., Nickles, A. & Nelson, D. E. Role of the endogenous opioid system in modulation of urinary bladder activity by spinal nerve stimulation. Am. J. Physiol. Renal Physiol. 305, F52–F60 (2013). PubMed DOI PMC

Pintauro, M. et al. Role of opioid and β-adrenergic receptors in bladder underactivity induced by prolonged pudendal nerve stimulation in cats. Neurourol. Urodyn. 42, 1344–1351 (2023). PubMed DOI PMC

Tai, C. et al. Differential role of opioid receptors in tibial nerve inhibition of nociceptive and nonnociceptive bladder reflexes in cats. Am. J. Physiol. Renal Physiol. 302, F1090–F1097 (2012). PubMed DOI PMC

Befort, K. Interactions of the opioid and cannabinoid systems in reward: insights from knockout studies. Front. Pharmacol. 6, 6 (2015). PubMed PMC

Jiang, X. et al. Role of cannabinoid receptor type 1 in tibial and pudendal neuromodulation of bladder overactivity in cats. Am. J. Physiol. Renal Physiol. 312, F482–F488 (2017). PubMed DOI

Malcangio, M. & Bowery, N. G. GABA and its receptors in the spinal cord. Trends Pharmacol. Sci. 17, 457–462 (1996). PubMed DOI

DeGroat, W. C. The effects of glycine, GABA and strychnine on sacral parasympathetic preganglionic neurones. Brain Res. 18, 542–544 (1970). PubMed DOI

Igawa, Y., Mattiasson, A. & Andersson, K. E. Effects of GABA-receptor stimulation and blockade on micturition in normal rats and rats with bladder outflow obstruction. J. Urol. 150, 537–542 (1993). PubMed DOI

McGee, M. J., Danziger, Z. C., Bamford, J. A. & Grill, W. M. A spinal GABAergic mechanism is necessary for bladder inhibition by pudendal afferent stimulation. Am. J. Physiol. Renal Physiol. 307, F921–F930 (2014). PubMed DOI PMC

Fuller, T. W. et al. Sex difference in the contribution of GABA PubMed DOI

Jiang, X. et al. Contribution of GABAA, glycine, and opioid receptors to sacral neuromodulation of bladder overactivity in cats. J. Pharmacol. Exp. Ther. 359, 436–441 (2016). PubMed DOI PMC

Wein, A. J. Re: spinal GABAergic mechanism is necessary for bladder inhibition by pudendal afferent stimulation. J. Urol. 196, 1215–1216 (2016). PubMed DOI

Miller, K. E., Hoffman, E. M., Sutharshan, M. & Schechter, R. Glutamate pharmacology and metabolism in peripheral primary afferents: physiological and pathophysiological mechanisms. Pharmacol. Ther. 130, 283–309 (2011). PubMed DOI PMC

Uy, J. et al. Glutamatergic mechanisms involved in bladder overactivity and pudendal neuromodulation in cats. J. Pharmacol. Exp. Ther. 362, 53–58 (2017). PubMed DOI PMC

Ramage, A. G. The role of central 5-hydroxytryptamine (5-HT, serotonin) receptors in the control of micturition. Br. J. Pharmacol. 147, S120–S131 (2006). PubMed DOI PMC

Danuser, H. & Thor, K. B. Spinal 5-HT2 receptor-mediated facilitation of pudendal nerve reflexes in the anaesthetized cat. Br. J. Pharmacol. 118, 150–154 (1996). PubMed DOI PMC

Matsuta, Y. et al. Effect of methysergide on pudendal inhibition of micturition reflex in cats. Exp. Neurol. 247, 250–258 (2013). PubMed DOI PMC

Kakizaki, H. & de Groat, W. C. Role of spinal nitric oxide in the facilitation of the micturition reflex by bladder irritation. J. Urol. 155, 355–360 (1996). PubMed DOI

Minardi, D. et al. Activity and expression of nitric oxide synthase in rat bladder after sacral neuromodulation. Int. J. Immunopathol. Pharmacol. 21, 129–135 (2008). PubMed DOI

Douven, P. et al. Sacral neuromodulation for lower urinary tract and bowel dysfunction in animal models: a systematic review with focus on stimulation parameter selection. Neuromodulation 23, 1094–1107 (2020). PubMed DOI PMC

Wan, X., Liang, Y., Li, X. & Liao, L. Inhibitory effects of a minimally invasive implanted tibial nerve stimulation device on non-nociceptive bladder reflexes in cats. Int. Urol. Nephrol. 53, 431–438 (2021). PubMed DOI

Shapiro, K. et al. Additive inhibition of reflex bladder activity induced by bilateral pudendal neuromodulation in cats. Front. Neurosci. 14, 80 (2020). PubMed DOI PMC

Zhang, F. et al. Neural pathways involved in sacral neuromodulation of reflex bladder activity in cats. Am. J. Physiol. Renal Physiol. 304, F710–F717 (2013). PubMed DOI

Li, X. et al. Frequency-dependent effects on bladder reflex by saphenous nerve stimulation and a possible action mechanism of tibial nerve stimulation in cats. Int. Neurourol. J. 25, 128–136 (2021). PubMed DOI PMC

Noblett, K. et al. Results of a prospective, multicenter study evaluating quality of life, safety, and efficacy of sacral neuromodulation at twelve months in subjects with symptoms of overactive bladder. Neurourol. Urodyn. 35, 246–251 (2016). PubMed DOI

de Wall, L. L. & Heesakkers, J. P. Effectiveness of percutaneous tibial nerve stimulation in the treatment of overactive bladder syndrome. Res. Rep. Urol. 9, 145–157 (2017). PubMed PMC

Groenendijk, P. M. et al. Urodynamic evaluation of sacral neuromodulation for urge urinary incontinence. BJU Int. 101, 325–329 (2008). PubMed DOI

Amarenco, G. et al. Urodynamic effect of acute transcutaneous posterior tibial nerve stimulation in overactive bladder. J. Urol. 169, 2210–2215 (2003). PubMed DOI

Doherty, S., Vanhoestenberghe, A., Duffell, L., Hamid, R. & Knight, S. A urodynamic comparison of neural targets for transcutaneous electrical stimulation to acutely suppress detrusor contractions following spinal cord injury. Front. Neurosci. 13, 1360 (2019). PubMed DOI PMC

Girtner, F. et al. Randomized crossover-controlled evaluation of simultaneous bilateral transcutaneous electrostimulation of the posterior tibial nerve during urodynamic studies in patients with lower urinary tract symptoms. Int. Neurourol. J. 25, 337–346 (2021). PubMed DOI PMC

Bosch, J. L. & Groen, J. Neuromodulation: urodynamic effects of sacral (S3) spinal nerve stimulation in patients with detrusor instability or detrusor hyperflexia. Behav. Brain Res. 92, 141–150 (1998). PubMed DOI

Groen, J., Ruud Bosch, J. L. & van Mastrigt, R. Sacral neuromodulation in women with idiopathic detrusor overactivity incontinence: decreased overactivity but unchanged bladder contraction strength and urethral resistance during voiding. J. Urol. 175, 1005–1009 (2006). discussion 1009. PubMed DOI

Van Meel, T. D. & Wyndaele, J. J. Reproducibility of urodynamic filling sensation at weekly interval in healthy volunteers and in women with detrusor overactivity. Neurourol. Urodyn. 30, 1586–1590 (2011). PubMed DOI

Flisser, A. J., Walmsley, K. & Blaivas, J. G. Urodynamic classification of patients with symptoms of overactive bladder. J. Urol. 169, 529–533 (2003). discussion 533–524. PubMed DOI

Lee, S. R., Kim, H. J., Kim, A. & Kim, J. H. Overactive bladder is not only overactive but also hypersensitive. Urology 75, 1053–1059 (2010). PubMed DOI

Erol, B., Danacioglu, Y. O. & Peters, K. M. Current advances in neuromodulation techniques in urology practices: a review of literature. Turk. J. Urol. 47, 375–385 (2021). PubMed DOI

Wenzler, D. L., Burks, F. N., Cooney, M. & Peters, K. M. Proof of concept trial on changes in current perception threshold after sacral neuromodulation. Neuromodulation 18, 228–231 (2015). discussion 232. PubMed DOI

Chermansky, C. J. & Moalli, P. A. Role of pelvic floor in lower urinary tract function. Auton. Neurosci. 200, 43–48 (2016). PubMed DOI

Schmidt, R. A., Bruschini, H. & Tanagho, E. A. Sacral root stimulation in controlled micturition. Peripheral somatic neurotomy and stimulated voiding. Invest. Urol. 17, 130–134 (1979). PubMed

Fowler, C. J., Swinn, M. J., Goodwin, R. J., Oliver, S. & Craggs, M. Studies of the latency of pelvic floor contraction during peripheral nerve evaluation show that the muscle response is reflexly mediated. J. Urol. 163, 881–883 (2000). PubMed DOI

Vaganee, D. et al. Neural pathway of bellows response during SNM treatment revisited: conclusive evidence for direct efferent motor response. Neurourol. Urodyn. 39, 1576–1583 (2020). PubMed DOI

Voorham, J. et al. Sacral neuromodulation changes pelvic floor activity in overactive bladder patients — possible new insights in mechanism of action: a pilot study. Neuromodulation 25, 1180–1186 (2022). PubMed DOI

Knowles, C. H. et al. The science behind programming algorithms for sacral neuromodulation. Colorectal Dis. 23, 592–602 (2021). PubMed DOI

Blok, B. F., Groen, J., Bosch, J. L., Veltman, D. J. & Lammertsma, A. A. Different brain effects during chronic and acute sacral neuromodulation in urge incontinent patients with implanted neurostimulators. BJU Int. 98, 1238–1243 (2006). PubMed DOI

Gill, B. C. et al. Real-time changes in brain activity during sacral neuromodulation for overactive bladder. J. Urol. 198, 1379–1385 (2017). PubMed DOI

Weissbart, S. J. et al. Specific changes in brain activity during urgency in women with overactive bladder after successful sacral neuromodulation: a functional magnetic resonance imaging study. J. Urol. 200, 382–388 (2018). PubMed DOI

Pang, D., Liao, L., Chen, G. & Wang, Y. Sacral neuromodulation improves abnormal prefrontal brain activity in patients with overactive bladder: a possible central mechanism. J. Urol. 207, 1256–1267 (2022). PubMed DOI

Mehnert, U. et al. Brain activation in response to bladder filling and simultaneous stimulation of the dorsal clitoral nerve — an fMRI study in healthy women. Neuroimage 41, 682–689 (2008). PubMed DOI

Li, X., Fang, R., Liao, L. & Li, X. Real-time changes in brain activity during tibial nerve stimulation for overactive bladder: evidence from functional near-infrared spectroscopy hype scanning. Front. Neurosci. 17, 1115433 (2023). PubMed DOI PMC

Krhut, J. et al. Differences between brain responses to peroneal electrical transcutaneous neuromodulation and transcutaneous tibial nerve stimulation, two treatments for overactive bladder. Neurourol. Urodyn. 42, 1352–1361 (2023). PubMed DOI

Moazzam, Z. & Yoo, P. B. Prolonged inhibition of bladder function is evoked by low-amplitude electrical stimulation of the saphenous nerve in urethane-anesthetized rats. Physiol. Rep. 10, e15517 (2022). PubMed DOI PMC

Ness, T. J., Randich, A., Nelson, D. E. & Su, X. Screening and optimization of nerve targets and parameters reveals inhibitory effect of pudendal stimulation on rat bladder hypersensitivity. Reg. Anesth. Pain. Med. 41, 737–743 (2016). PubMed DOI

de Groat, W. C. & Theobald, R. J. Reflex activation of sympathetic pathways to vesical smooth muscle and parasympathetic ganglia by electrical stimulation of vesical afferents. J. Physiol. 259, 223–237 (1976). PubMed DOI PMC

Duchalais, E. et al. Long-term results of sacral neuromodulation for the treatment of anorectal diseases. J. Visc. Surg. 159, 463–470 (2022). PubMed DOI

Huang, J. et al. The current status and trend of the functional magnetic resonance combined with stimulation in animals. Front. Neurosci. 16, 963175 (2022). PubMed DOI PMC

Jairam, R. et al. Predictive factors in sacral neuromodulation: a systematic review. Urol. Int. 106, 323–343 (2022). PubMed DOI

Choudhary, M., van Mastrigt, R. & van Asselt, E. The frequency spectrum of bladder non-voiding activity as a trigger-event for conditional stimulation: closed-loop inhibition of bladder contractions in rats. Neurourol. Urodyn. 37, 1567–1573 (2018). PubMed DOI

Majerus, S. J. A. et al. Feasibility of real-time conditional sacral neuromodulation using wireless bladder pressure sensor. IEEE Trans. Neural Syst. Rehabil. Eng. 29, 2067–2075 (2021). PubMed DOI PMC

Ouyang, Z. et al. Closed-loop sacral neuromodulation for bladder function using dorsal root ganglia sensory feedback in an anesthetized feline model. Med. Biol. Eng. Comput. 60, 1527–1540 (2022). PubMed DOI PMC

Chen, S. C., Chu, P. Y., Hsieh, T. H., Li, Y. T. & Peng, C. W. Feasibility of deep brain stimulation for controlling the lower urinary tract functions: an animal study. Clin. Neurophysiol. 128, 2438–2449 (2017). PubMed DOI