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We then established a semi-analytic model that also uses hybrid electromagnetic-electrophysiological simulations to model evoked compound action potential (eCAP) signals from multi-fascicular nerves populated with heterogeneous fiber populations. For validation, model predictions were compared with cuff electrode recordings of activity induced by vagus nerve stimulation in\n                    <jats:italic>in vivo<\/jats:italic>\n                    porcine experiments. The semi-analytic model produces signals that approximate the shape and amplitude of\n                    <jats:italic>in vivo<\/jats:italic>\n                    measurements. It can account for the important variation in the recorded eCAP due to changes in the shape and placement of the stimulus and recording electrodes. We find that partially activated fascicles contribute particularly to the signal, as eCAP contributions from smoothly varying fiber calibers in fully activated ones partially cancel. As a result, eCAP magnitude does not depend monotonically on the stimulation current and recruitment level. Our method can be used to rapidly assess new stimulation and recording setups involving complex nerves and neurovascular bundles, e.g., to maximize signal information content, for closed-loop control in bioelectronic medicine applications, and potentially to non-destructively reconstruct structural and functional nerve topologies through inverse problem solving. In a proof-of-concept study, we demonstrate that parameter optimization can recover the ground-truth distribution of fiber diameters in a simplifed variant of our model.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1013452","type":"journal-article","created":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T17:52:19Z","timestamp":1757699539000},"page":"e1013452","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Simulation insights on the compound action potential in multifascicular nerves"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2390-4104","authenticated-orcid":true,"given":"Joseph James","family":"Tharayil","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ciro","family":"Zinno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Filippo","family":"Agnesi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bryn","family":"Lloyd","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Farcito","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonino","family":"Cassara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Niels","family":"Kuster","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Reimann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4396-8217","authenticated-orcid":true,"given":"Silvestro","family":"Micera","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Esra","family":"Neufeld","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,9,12]]},"reference":[{"issue":"1","key":"pcbi.1013452.ref001","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/BF02368460","article-title":"A model for compound action potentials and currents in a nerve bundle. 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Bioelectricity: a quantitative approach. 3rd ed. New York: Springer; 2007."},{"issue":"13","key":"pcbi.1013452.ref039","doi-asserted-by":"crossref","first-page":"14051","DOI":"10.1109\/JSEN.2021.3056530","article-title":"Implantable fiber bragg grating sensor for continuous heart activity monitoring: ex-vivo and in-vivo validation","volume":"21","author":"D Ferraro","year":"2021","journal-title":"IEEE Sensors J."},{"issue":"11","key":"pcbi.1013452.ref040","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0080591","article-title":"Impact of acute changes of left ventricular contractility on the transvalvular impedance: validation study by pressure-volume loop analysis in healthy pigs","volume":"8","author":"V Lionetti","year":"2013","journal-title":"PLoS One."},{"issue":"1","key":"pcbi.1013452.ref041","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1088\/1741-2560\/5\/1\/005","article-title":"Analysis of the quasi-static approximation for calculating potentials generated by neural stimulation","volume":"5","author":"CA Bossetti","year":"2008","journal-title":"J Neural Eng."},{"issue":"6","key":"pcbi.1013452.ref042","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1109\/TNSRE.2008.2010348","article-title":"Fascicular perineurium thickness, size, and position affect model predictions of neural excitation","volume":"16","author":"Y Grinberg","year":"2008","journal-title":"IEEE Trans Neural Syst Rehabil Eng."},{"key":"pcbi.1013452.ref043","unstructured":"Hasgall P, Di Gennaro F, Baumgartner C, Neufeld E, Lloyd B, Gosselin M, et al. IT\u2019IS database for thermal and electromagnetic parameters of biological tissues.."},{"issue":"6","key":"pcbi.1013452.ref044","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1007\/BF00584655","article-title":"Na currents and action potentials in rat myelinated nerve fibres at 20 and 37 degrees C","volume":"409","author":"JR Schwarz","year":"1987","journal-title":"Pflugers Arch."},{"issue":"2","key":"pcbi.1013452.ref045","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1177\/107385840100700207","article-title":"NEURON: a tool for neuroscientists","volume":"7","author":"ML Hines","year":"2001","journal-title":"Neuroscientist."},{"issue":"1","key":"pcbi.1013452.ref046","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0006-3495(77)85532-X","article-title":"A study of conduction velocity in nonmyelinated nerve fibers","volume":"20","author":"G Matsumoto","year":"1977","journal-title":"Biophys J."},{"issue":"85","key":"pcbi.1013452.ref047","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/newbio238217a0","article-title":"Relative conduction velocities of small myelinated and non-myelinated fibres in the central nervous system","volume":"238","author":"SG Waxman","year":"1972","journal-title":"Nat New Biol."}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1013902","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T00:00:00Z","timestamp":1768867200000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1013452","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T14:09:31Z","timestamp":1766498971000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1013452"}},"subtitle":[],"editor":[{"given":"Helmut","family":"Schmidt","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2025,9,12]]},"references-count":47,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9,12]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1013452","relation":{},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,12]]}}}