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Lack of explicit consideration for producing equivalent nerve responses could contribute to clinical outcomes not replicating promising results from preclinical animal studies.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>We used models of VNS built with ASCENT (Musselman, PLoS Comput Biol 17:e1009285, 2021) to quantify nerve responses across species and simulate translation of VNS therapies via either recycling or linear scaling of stimulation parameters. For humans (<jats:italic>n<\/jats:italic>\u2009=\u20099) and pigs (<jats:italic>n<\/jats:italic>\u2009=\u200912), we used previously validated computational models with the standard clinical helical cuff electrode on individual-specific nerve morphologies (Musselman, J Neural Eng 20:acda64, 2023b). We also modeled rat VNS (<jats:italic>n<\/jats:italic>\u2009=\u20099) with the Micro-Leads Neuro bipolar cuff. We calculated thresholds for fiber activation (A-, B-, and C-fibers) with biphasic rectangular pulses (0.13, 0.25, 0.5\u00a0ms). We defined \u201cK\u201d as the ratio of activation thresholds between a pair of individuals. We used a mixed model ANOVA on the natural logarithm of K to test for differences in inter-species Ks across fiber types and pulse widths. Lastly, using the same nerve morphologies and application-specific device design (cuff and waveform), we developed models to predict nerve responses in chronic human and rat VNS studies for treatment of stroke, inflammation, and heart failure.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Depending on the individual and species, the activation amplitude required to produce a given nerve response varied widely. Thus, applying the same VNS parameters across individuals within a species produced a large range of nerve responses. Further, applying the same or linearly scaled stimulation amplitudes across species also produced highly variable responses. Ks were greater for B fibers than A fibers (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001) and decreased with longer pulse widths (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001 between consecutive pairs).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>The results highlight the need for systematic approaches to select stimulation parameters that account for individual- and species-specific differences in nerve responses to stimulation. Such parameter tuning may lead to higher response rates and greater therapeutic benefits from VNS therapies.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s42234-025-00174-9","type":"journal-article","created":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T23:01:46Z","timestamp":1747350106000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Scaling of vagus nerve stimulation parameters does not achieve equivalent nerve responses across species"],"prefix":"10.1186","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5295-7267","authenticated-orcid":false,"given":"Eric D.","family":"Musselman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2180-5268","authenticated-orcid":false,"given":"Ishani","family":"Raha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2844-0190","authenticated-orcid":false,"given":"Nicole A.","family":"Pelot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5240-6588","authenticated-orcid":false,"given":"Warren M.","family":"Grill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,16]]},"reference":[{"issue":"1","key":"174_CR1","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1113\/jphysiol.1957.sp005703","volume":"135","author":"E Agostinu","year":"1957","unstructured":"Agostinu E, Chinnock JE, De Daly MB, Murray JG. 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