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VNS is used in treatment-resistant epilepsy, and is increasingly being explored for other disorders, such as depression, and as a cognitive enhancer. However, the promise of VNS is only partially fulfilled due to a lack of mechanistic understanding of the transfer function between stimulation parameters and neuromodulatory response, together with a lack of biosensors for assaying stimulation efficacy in real time. We here develop an approach to VNS in head-fixed mice on a treadmill and show that pupil dilation is a reliable and convenient biosensor for VNS-evoked cortical neuromodulation. In an \u2018optimal\u2019 zone of stimulation parameters, current leakage and off-target effects are minimized and the extent of pupil dilation tracks VNS-evoked basal-forebrain cholinergic axon activity in neocortex. Thus, pupil dilation is a sensitive readout of the moment-by-moment, titratable effects of VNS on brain state.<\/jats:p>","DOI":"10.1038\/s41467-021-21730-2","type":"journal-article","created":{"date-parts":[[2021,3,9]],"date-time":"2021-03-09T06:03:14Z","timestamp":1615269794000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":114,"title":["Graded recruitment of pupil-linked neuromodulation by parametric stimulation of the vagus nerve"],"prefix":"10.1038","volume":"12","author":[{"given":"Zakir","family":"Mridha","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5875-8282","authenticated-orcid":false,"given":"Jan Willem","family":"de Gee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6363-4137","authenticated-orcid":false,"given":"Yanchen","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rayan","family":"Alkashgari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8710-7497","authenticated-orcid":false,"given":"Justin","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Suminski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew P.","family":"Ward","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6516-9670","authenticated-orcid":false,"given":"Matthew James","family":"McGinley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,9]]},"reference":[{"key":"21730_CR1","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1152\/jn.1938.1.5.405","volume":"1","author":"P Bailey","year":"1938","unstructured":"Bailey, P. & Bremer, F. 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