{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:21:26Z","timestamp":1787026886456,"version":"build-2736575974"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2020,12,17]],"date-time":"2020-12-17T00:00:00Z","timestamp":1608163200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004330","name":"GlaxoSmithKline","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004330","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["OT2OD023872"],"award-info":[{"award-number":["OT2OD023872"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:p>Bioelectronic medical devices are well established and widely used in the treatment of urological dysfunction. Approved targets include the sacral S3 spinal root and posterior tibial nerve, but an alternate target is the group of pelvic splanchnic nerves, as these contain sacral visceral sensory and autonomic motor pathways that coordinate storage and voiding functions of the bladder. Here, we developed a device suitable for long-term use in an awake rat model to study electrical neuromodulation of the pelvic nerve (homolog of the human pelvic splanchnic nerves). In male Sprague-Dawley rats, custom planar four-electrode arrays were implanted over the distal end of the pelvic nerve, close to the major pelvic ganglion. Electrically evoked compound action potentials (ECAPs) were reliably detected under anesthesia and in chronically implanted, awake rats up to 8 weeks post-surgery. ECAP waveforms showed three peaks, with latencies that suggested electrical stimulation activated several subpopulations of myelinated A-fiber and unmyelinated C-fiber axons. Chronic implantation of the array did not impact on voiding evoked in awake rats by continuous cystometry, where void parameters were comparable to those published in na\u00efve rats. Electrical stimulation with chronically implanted arrays also induced two classes of bladder pressure responses detected by continuous flow cystometry in awake rats: voiding contractions and non-voiding contractions. No evidence of tissue pathology produced by chronically implanted arrays was detected by immunohistochemical visualization of markers for neuronal injury or noxious spinal cord activation. These results demonstrate a rat pelvic nerve electrode array that can be used for preclinical development of closed loop neuromodulation devices targeting the pelvic nerve as a therapy for neuro-urological dysfunction.<\/jats:p>","DOI":"10.3389\/fnins.2020.619275","type":"journal-article","created":{"date-parts":[[2021,1,7]],"date-time":"2021-01-07T18:57:34Z","timestamp":1610045854000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Recording of Electrically Evoked Neural Activity and Bladder Pressure Responses in Awake Rats Chronically Implanted With a Pelvic Nerve Array"],"prefix":"10.3389","volume":"14","author":[{"given":"Sophie C.","family":"Payne","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole M.","family":"Wiedmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Calvin D.","family":"Eiber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnes W.","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Senn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peregrine B.","family":"Osborne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet R.","family":"Keast","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James B.","family":"Fallon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2020,12,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1065","DOI":"10.1007\/s00192-014-2359-0","article-title":"Transcutaneous posterior tibial nerve stimulation: evaluation of a therapeutic option in the management of anticholinergic refractory overactive bladder.","volume":"25","author":"Ammi","year":"2014","journal-title":"Int. Urogynecol. J."},{"key":"B2","doi-asserted-by":"publisher","first-page":"636","DOI":"10.1002\/nau.21108","article-title":"Rodent models for urodynamic investigation.","volume":"30","author":"Andersson","year":"2011","journal-title":"Neurourol. Urodyn."},{"key":"B3","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1111\/j.1748-1716.1990.tb08864.x","article-title":"Urinary bladder and urethral responses to pelvic and hypogastric nerve stimulation and their relation to vasoactive intestinal polypeptide in the anaesthetized dog.","volume":"138","author":"Andersson","year":"1990","journal-title":"Acta Physiol. Scand."},{"key":"B4","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1111\/joa.13221","article-title":"Functional segregation within the pelvic nerve of male rats: a meso- and microscopic analysis.","volume":"237","author":"Bertrand","year":"2020","journal-title":"J. Anat."},{"key":"B5","doi-asserted-by":"publisher","first-page":"4878","DOI":"10.1523\/JNEUROSCI.12-12-04878.1992","article-title":"Increased c-fos expression in spinal neurons after irritation of the lower urinary tract in the rat.","volume":"12","author":"Birder","year":"1992","journal-title":"J. Neurosci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"R326","DOI":"10.1152\/ajpregu.1993.265.2.R326","article-title":"Induction of c-fos expression in spinal neurons by nociceptive and nonnociceptive stimulation of LUT.","author":"Birder","year":"1993","journal-title":"Am. J. Physiol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1037\/a0012850","article-title":"Comparisons of methods for multiple hypothesis testing in neuropsychological research.","volume":"23","author":"Blakesley","year":"2009","journal-title":"Neuropsychology"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1541","DOI":"10.1016\/b978-0-12-805353-9.00131-5","article-title":"Chapter 131 \u2013 Sensing and decoding neural signals for closed-loop neuromodulation and advanced diagnostics in chronic disease and injury","author":"Bouton","year":"2018","journal-title":"Neuromodulation"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.1016\/j.juro.2013.10.024","article-title":"Electrical stimulation of somatic afferent nerves in the foot increases bladder capacity in healthy human subjects.","volume":"191","author":"Chen","year":"2014","journal-title":"J. Urol."},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1088\/1741-2552\/aaa569","article-title":"Chronic implantation of cuff electrodes on the pelvic nerve in rats is well tolerated and does not compromise afferent or efferent fibre functionality.","volume":"15","author":"Crook","year":"2018","journal-title":"J. Neural. Eng."},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2017.00623","article-title":"High frequency stimulation of the pelvic nerve inhibits urinary voiding in anesthetized rats.","volume":"8","author":"Crook","year":"2017","journal-title":"Front. Physiol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1080\/003655902320765944","article-title":"Bladder and urethral responses to pelvic nerve stimulation in the pig.","volume":"36","author":"Dalmose","year":"2002","journal-title":"Scand. J. Urol. Nephrol. Suppl."},{"key":"B13","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1016\/b978-0-12-805353-9.00019-x","article-title":"Chapter 19 \u2013 Mechanisms of action of sacral nerve and peripheral nerve stimulation for disorders of the bladder and bowel","author":"de Groat","year":"2018","journal-title":"Neuromodulation"},{"key":"B14","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1007\/978-3-540-79090-7_4","article-title":"Afferent nerve regulation of bladder function in health and disease.","volume":"194","author":"de Groat","year":"2009","journal-title":"Handb. Exp. Pharmacol."},{"key":"B15","article-title":"Principles of recording from and electrical stimulation of neural tissue","author":"Fallon","year":"2016","journal-title":"Neurobionics: The Biomedical Engineering of Neural Protheses"},{"key":"B16","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1002\/cne.21886","article-title":"Cochlear implant use following neonatal deafness influences the cochleotopic organization of the primary auditory cortex in cats.","volume":"512","author":"Fallon","year":"2009","journal-title":"J. Comp. Neurol."},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.17504\/protocols.io.bfwyjpfw","author":"Fallon","year":"2020","journal-title":"Electrophysiological Recording of Electrically-Evoked Compound Action Potentials."},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.17504\/protocols.io.bjvxkn7n","author":"Fallon","year":"2020","journal-title":"Implantation of A Pelvic Nerve Array in Rats."},{"key":"B19","article-title":"A highly configurable neurostimulator for chronic pre-clinical stimulation studies","author":"Fallon","year":"2018","journal-title":"Proceedings of the Neural Interfaces Conferences"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fnana.2015.00043","article-title":"Peripheral injury of pelvic visceral sensory nerves alters GFRalpha (GDNF family receptor alpha) localization in sensory and autonomic pathways of the sacral spinal cord.","volume":"9","author":"Forrest","year":"2015","journal-title":"Front. Neuroanat."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1868","DOI":"10.1002\/nau.24415","article-title":"Best practices for cystometric evaluation of lower urinary tract function in muriform rodents.","volume":"39","author":"Fraser","year":"2020","journal-title":"Neurourol. Urodyn."},{"key":"B22","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1002\/nau.20544","article-title":"Dorsal genital nerve stimulation for the treatment of overactive bladder symptoms.","volume":"27","author":"Goldman","year":"2008","journal-title":"Neurourol. Urodyn."},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-34566-6","article-title":"Thin film multi-electrode softening cuffs for selective neuromodulation.","volume":"8","author":"Gonzalez-Gonzalez","year":"2018","journal-title":"Sci. Rep."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1146\/annurev-bioeng-061008-124927","article-title":"Implanted neural interfaces: biochallenges and engineered solutions.","volume":"11","author":"Grill","year":"2009","journal-title":"Annu. Rev. Biomed. Eng."},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1088\/1741-2560\/13\/4\/041002","article-title":"Vagus nerve stimulation: state of the art of stimulation and recording strategies to address autonomic function neuromodulation.","volume":"13","author":"Guiraud","year":"2016","journal-title":"J. Neural. Eng."},{"key":"B26","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1152\/physiol.00030.2018","article-title":"Electroceutical targeting of the autonomic nervous system.","volume":"34","author":"Horn","year":"2019","journal-title":"Physiology (Bethesda)"},{"key":"B27","doi-asserted-by":"publisher","first-page":"R990","DOI":"10.1152\/ajpregu.1996.270.5.R990","article-title":"Role of NMDA and AMPA glutamatergic transmission in spinal c-fos expression after urinary tract irritation.","author":"Kakizaki","year":"1996","journal-title":"Am. J. Physiol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/S0074-7696(06)48003-7","article-title":"Plasticity of pelvic autonomic ganglia and urogenital innervation.","volume":"248","author":"Keast","year":"2006","journal-title":"Int. Rev. Cytol."},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.17504\/protocols.io.w3ffgjn","author":"Keast","year":"2019","journal-title":"Intracardiac Perfusion with Fixative for Anatomical Studies."},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.17504\/protocols.io.bakjicun","author":"Keast","year":"","journal-title":"Cystometry in Awake Rats."},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.17504\/protocols.io.bakkicuw","author":"Keast","year":"","journal-title":"Immunohistochemical Labelling of Spinal Cord Neurons Involved in Bladder Activity."},{"key":"B32","doi-asserted-by":"publisher","first-page":"F1357","DOI":"10.1152\/ajprenal.00068.2020","article-title":"Stimulation of the pelvic nerve increases bladder capacity in the PGE2 cat model of overactive bladder.","volume":"318","author":"Langdale","year":"2020","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"F657","DOI":"10.1152\/ajprenal.00116.2017","article-title":"Stimulation of the pelvic nerve increases bladder capacity in the prostaglandin E2 rat model of overactive bladder.","volume":"313","author":"Langdale","year":"2017","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1007\/bf00240958","article-title":"Cyclophosphamide cystitis as a model of visceral pain in rats: model elaboration and spinal structures involved as revealed by the expression of c-Fos and Krox-24 proteins.","volume":"105","author":"Lanteri-Minet","year":"1995","journal-title":"Exp. Brain Res."},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2019.108523","article-title":"A review for the peripheral nerve interface designer.","volume":"332","author":"Larson","year":"2020","journal-title":"J. Neurosci. Methods"},{"key":"B36","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1016\/j.nanoen.2019.03.082","article-title":"Mechano-neuromodulation of autonomic pelvic nerve for underactive bladder: a triboelectric neurostimulator integrated with flexible neural clip interface.","volume":"60","author":"Lee","year":"2019","journal-title":"Nano Energy"},{"key":"B37","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/0165-0270(95)00123-9","article-title":"Cuff electrodes for chronic stimulation and recording of peripheral nerve activity.","volume":"64","author":"Loeb","year":"1996","journal-title":"J. Neurosci. Methods"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-10639-w","article-title":"Chronic interfacing with the autonomic nervous system using carbon nanotube (CNT) yarn electrodes.","volume":"7","author":"McCallum","year":"2017","journal-title":"Sci. Rep."},{"key":"B39","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1002\/cne.902260207","article-title":"The location and morphology of preganglionic neurons and the distribution of visceral afferents from the rat pelvic nerve: a horseradish peroxidase study.","volume":"226","author":"Nadelhaft","year":"1984","journal-title":"J. Comp. Neurol."},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2019.108539","article-title":"DARPA investment in peripheral nerve interfaces for prosthetics, prescriptions, and plasticity.","volume":"332","author":"Naufel","year":"2020","journal-title":"J. Neurosci. Methods"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1004","DOI":"10.1002\/nau.22359","article-title":"Subject-controlled stimulation of dorsal genital nerve to treat neurogenic detrusor overactivity at home.","volume":"32","author":"Opisso","year":"2013","journal-title":"Neurourol. Urodyn."},{"key":"B42","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1016\/b978-0-12-805353-9.00032-2","article-title":"Chapter 32 \u2013 Implanted sensors in neuromodulation via electrical stimulation","author":"Parker","year":"2018","journal-title":"Neuromodulation"},{"key":"B43","doi-asserted-by":"publisher","first-page":"71","DOI":"10.2217\/bem-2017-0005","article-title":"Electrically evoked compound action potential recording in peripheral nerves.","volume":"1","author":"Parker","year":"2018","journal-title":"Bioelectron. Med."},{"key":"B44","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/j.expneurol.2015.02.026","article-title":"Regeneration of sensory but not motor axons following visceral nerve injury.","volume":"266","author":"Payne","year":"2015","journal-title":"Exp. Neurol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"235","DOI":"10.2217\/bem-2018-0011","article-title":"Vagus nerve stimulation to treat inflammatory bowel disease: a chronic, preclinical safety study in sheep.","volume":"1","author":"Payne","year":"2018","journal-title":"Bioelectron. Med."},{"key":"B46","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1038\/s41575-018-0078-6","article-title":"Bioelectric neuromodulation for gastrointestinal disorders: effectiveness and mechanisms.","volume":"16","author":"Payne","year":"2019","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2018.00186","article-title":"Novel neurostimulation of autonomic pelvic nerves overcomes bladder-sphincter dyssynergia.","volume":"12","author":"Peh","year":"2018","journal-title":"Front. Neurosci."},{"key":"B48","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1002\/nau.20823","article-title":"Chronic pudendal neuromodulation: expanding available treatment options for refractory urologic symptoms.","volume":"29","author":"Peters","year":"2010","journal-title":"Neurourol. Urodyn."},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1186\/1743-0003-11-73","article-title":"Biomechanical and functional variation in rat sciatic nerve following cuff electrode implantation.","volume":"11","author":"Restaino","year":"2014","journal-title":"J. Neuroeng. Rehabil."},{"key":"B50","doi-asserted-by":"publisher","first-page":"1924","DOI":"10.1152\/jn.2000.84.4.1924","article-title":"Sensory fibers of the pelvic nerve innervating the rat\u2019s urinary bladder.","volume":"84","author":"Shea","year":"2000","journal-title":"J. Neurophysiol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1006\/mcne.1999.0814","article-title":"Activating transcription factor 3 (ATF3) induction by axotomy in sensory and motoneurons: a novel neuronal marker of nerve injury.","volume":"15","author":"Tsujino","year":"2000","journal-title":"Mol. Cell. Neurosci."},{"key":"B52","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.jneuroim.2005.04.019","article-title":"Anti-TNF-alpha reduces the inflammatory reaction associated with cuff electrode implantation around the sciatic nerve.","volume":"165","author":"Vince","year":"2005","journal-title":"J. Neuroimmunol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"R1027","DOI":"10.1152\/ajpregu.2000.278.4.R1027","article-title":"Alterations in spinal cord Fos protein expression induced by bladder stimulation following cystitis.","volume":"278","author":"Vizzard","year":"2000","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"904","DOI":"10.1038\/nbt.3667","article-title":"A spark at the periphery.","volume":"34","author":"Waltz","year":"2016","journal-title":"Nat. Biotechnol."},{"key":"B55","author":"Watson","year":"2009","journal-title":"The Spinal Cord: A Christopher and Dana Reeve Foundation Text and Atlas."},{"key":"B56","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/cne.24949","article-title":"Sex differences in c-Fos and EGR-1\/Zif268 activity maps of rat sacral spinal cord following cystometry-induced micturition.","author":"Wiedmann","year":"2020","journal-title":"J. Comp. Neurol."},{"key":"B57","doi-asserted-by":"crossref","first-page":"4653","DOI":"10.1109\/IEMBS.2011.6091152","article-title":"Recovery of neural activity from nerve cuff electrodes","author":"Wodlinger","year":"2011","journal-title":"Proceedings of the 2011 Annual International Conference of the IEEE Engineering in Medicine and Biology Society, Boston, MA"},{"key":"B58","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1016\/j.neuron.2018.10.013","article-title":"Activity-regulated transcription: bridging the gap between neural activity and behavior.","volume":"100","author":"Yap","year":"2018","journal-title":"Neuron"},{"key":"B59","doi-asserted-by":"publisher","first-page":"6781","DOI":"10.1109\/IEMBS.2009.5333982","article-title":"Intraurethral activation of excitatory bladder reflexes in persons with spinal cord injury.","volume":"2009","author":"Yoo","year":"2009","journal-title":"Conf. Proc. IEEE Eng. Med. Biol. Soc."},{"key":"B60","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1016\/j.juro.2010.03.004","article-title":"Impaired bladder function in aging male rats.","volume":"184","author":"Zhao","year":"2010","journal-title":"J. Urol."}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2020.619275\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,1,10]],"date-time":"2021-01-10T03:34:40Z","timestamp":1610249680000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2020.619275\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,17]]},"references-count":60,"alternative-id":["10.3389\/fnins.2020.619275"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2020.619275","relation":{},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,17]]},"article-number":"619275"}}