The human vagal complex: from gross anatomy to single neurons, from brainstem to abdomen

The human vagal complex: from gross anatomy to single neurons, from brainstem to abdomen | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article The human vagal complex: from gross anatomy to single neurons, from brainstem to abdomen Nicole Pelot, Ian Baumgart, Ari Blitz, Brandon Brunsman, Eleana Cintron, and 30 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7707775/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract The vagus nerve (VN) connects the brainstem to the viscera to regulate many physiological functions. Mapping the VN with state-of-the-art high-resolution imaging modalities has tremendous potential to improve the safety and efficacy of existing autonomic neuromodulation therapies and to inform design of new therapies. We developed the most comprehensive mapping pipeline of the VN to date, from the perspectives of sample size, lengths of nerve, and range of imaging modalities. Our pipeline maps cadaveric human vagal anatomy with complementary imaging modalities applied serially to the same tissue: pre-dissection MRI, pre-dissection CT, 3D tracing of the dissected nerve in situ, CT of the excised nerve, microCT, histology, and a novel serial block-face imaging technique, “3D-MUSE”. The resulting co-registered data enable quantification of gross anatomy, fascicular morphology, and fiber organization in three dimensions. We demonstrated the utility of the data by implementing anatomically realistic computational models of vagus nerve stimulation. These approaches and resulting anatomical data will seed and accelerate the development of novel neuromodulation therapies to treat diseases. Biological sciences/Neuroscience/Peripheral nervous system Health sciences/Medical research/Translational research Biological sciences/Neuroscience/Computational neuroscience Full Text Additional Declarations There is NO Competing Interest. Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7707775","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":520637221,"identity":"ebc61105-0dc7-42cb-ad6b-421d39af94b2","order_by":0,"name":"Nicole Pelot","email":"","orcid":"https://orcid.org/0000-0003-2844-0190","institution":"Duke University","correspondingAuthor":false,"prefix":"","firstName":"Nicole","middleName":"","lastName":"Pelot","suffix":""},{"id":520637222,"identity":"158cce27-629e-4864-ba6b-fcb7e62fcef8","order_by":1,"name":"Ian Baumgart","email":"","orcid":"","institution":"Duke University","correspondingAuthor":false,"prefix":"","firstName":"Ian","middleName":"","lastName":"Baumgart","suffix":""},{"id":520637223,"identity":"c9966e9a-4c88-4fdd-8e00-e9bc0ee4a9fc","order_by":2,"name":"Ari Blitz","email":"","orcid":"","institution":"Case Western Reserve University and University Hospitals Cleveland Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Ari","middleName":"","lastName":"Blitz","suffix":""},{"id":520637224,"identity":"6fa141ff-e493-4f52-8bc5-1500c21463cc","order_by":3,"name":"Brandon Brunsman","email":"","orcid":"","institution":"Case Western Reserve University","correspondingAuthor":false,"prefix":"","firstName":"Brandon","middleName":"","lastName":"Brunsman","suffix":""},{"id":520637225,"identity":"3bbbd5fa-4377-4e3a-b883-f61d5461d1b4","order_by":4,"name":"Eleana Cintron","email":"","orcid":"","institution":"Case Western Reserve University","correspondingAuthor":false,"prefix":"","firstName":"Eleana","middleName":"","lastName":"Cintron","suffix":""},{"id":520637226,"identity":"6205c53b-896e-4a12-92ed-794dff3dd0e6","order_by":5,"name":"Jennifer Coleman","email":"","orcid":"","institution":"Case Western Reserve University","correspondingAuthor":false,"prefix":"","firstName":"Jennifer","middleName":"","lastName":"Coleman","suffix":""},{"id":520637227,"identity":"81239b34-5c27-4b13-a851-9da4b2ecd6ea","order_by":6,"name":"Andrew Crofton","email":"","orcid":"","institution":"Case Western Reserve University","correspondingAuthor":false,"prefix":"","firstName":"Andrew","middleName":"","lastName":"Crofton","suffix":""},{"id":520637228,"identity":"a7bcd0bf-8011-44e2-a92a-ef06424fdcd2","order_by":7,"name":"Jennifer D'Silva","email":"","orcid":"","institution":"Case Western Reserve University","correspondingAuthor":false,"prefix":"","firstName":"Jennifer","middleName":"","lastName":"D'Silva","suffix":""},{"id":520637229,"identity":"98909bb1-c457-42a9-83bc-9d2902ce9a96","order_by":8,"name":"Chris Flask","email":"","orcid":"","institution":"Case Western Reserve University and University Hospitals Cleveland Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Chris","middleName":"","lastName":"Flask","suffix":""},{"id":520637230,"identity":"082a29c7-128b-484c-9143-5b7331d1c896","order_by":9,"name":"Aniya Hartzler","email":"","orcid":"","institution":"Case Western Reserve University","correspondingAuthor":false,"prefix":"","firstName":"Aniya","middleName":"","lastName":"Hartzler","suffix":""},{"id":520637231,"identity":"a03ce2b0-76fc-4a38-b5ac-85962d8276db","order_by":10,"name":"Daniel Herzka","email":"","orcid":"","institution":"Case Western Reserve University and University Hospitals Cleveland Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Daniel","middleName":"","lastName":"Herzka","suffix":""},{"id":520637232,"identity":"3a7e3a4a-8a23-43cc-8834-759f4a85ebff","order_by":11,"name":"Proapa Islam","email":"","orcid":"","institution":"Case Western Reserve University","correspondingAuthor":false,"prefix":"","firstName":"Proapa","middleName":"","lastName":"Islam","suffix":""},{"id":520637233,"identity":"2ab47eaa-6bae-45b6-b998-52d9c263d5a4","order_by":12,"name":"Michael Jenkins","email":"","orcid":"","institution":"Case Western Reserve University","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Jenkins","suffix":""},{"id":520637234,"identity":"54d4f132-b568-4ab1-997e-a98bc65dc853","order_by":13,"name":"Talya Jeter","email":"","orcid":"","institution":"Case Western Reserve University","correspondingAuthor":false,"prefix":"","firstName":"Talya","middleName":"","lastName":"Jeter","suffix":""},{"id":520637235,"identity":"75973ea0-1fe0-48e3-a09b-e40f58d25e79","order_by":14,"name":"Naomi Joseph","email":"","orcid":"","institution":"Case Western Reserve University","correspondingAuthor":false,"prefix":"","firstName":"Naomi","middleName":"","lastName":"Joseph","suffix":""},{"id":520637236,"identity":"20b27d1a-8c7f-457d-96f8-5282a9e9c860","order_by":15,"name":"Beverly Koepf","email":"","orcid":"","institution":"Case Western Reserve University","correspondingAuthor":false,"prefix":"","firstName":"Beverly","middleName":"","lastName":"Koepf","suffix":""},{"id":520637237,"identity":"2a9eafa6-628b-48a1-9477-05208153c76a","order_by":16,"name":"Chaitanya Kolluru","email":"","orcid":"","institution":"Case Western Reserve University","correspondingAuthor":false,"prefix":"","firstName":"Chaitanya","middleName":"","lastName":"Kolluru","suffix":""},{"id":520637238,"identity":"14084ec7-0a5f-4aa9-9086-580e81b1a23f","order_by":17,"name":"Shruti Kumari","email":"","orcid":"","institution":"Case Western Reserve University","correspondingAuthor":false,"prefix":"","firstName":"Shruti","middleName":"","lastName":"Kumari","suffix":""},{"id":520637239,"identity":"95d8699e-27b0-4a25-9694-66161e92f29f","order_by":18,"name":"Valerie Lam","email":"","orcid":"","institution":"Case Western Reserve University","correspondingAuthor":false,"prefix":"","firstName":"Valerie","middleName":"","lastName":"Lam","suffix":""},{"id":520637240,"identity":"69ff0c3f-87a8-41df-9249-73969af9c28d","order_by":19,"name":"Leina Lunasco","email":"","orcid":"https://orcid.org/0000-0003-3403-7429","institution":"Case Western Reserve University","correspondingAuthor":false,"prefix":"","firstName":"Leina","middleName":"","lastName":"Lunasco","suffix":""},{"id":520637241,"identity":"a992b60f-6d1c-414b-8756-396f037fc195","order_by":20,"name":"Michael Markley","email":"","orcid":"","institution":"University Hospitals Cleveland Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Markley","suffix":""},{"id":520637242,"identity":"5cda828b-fa8c-4a21-bdec-1f1d4be1d5f7","order_by":21,"name":"Noa Nuzov","email":"","orcid":"","institution":"Case Western Reserve University","correspondingAuthor":false,"prefix":"","firstName":"Noa","middleName":"","lastName":"Nuzov","suffix":""},{"id":520637243,"identity":"7fb3f948-8ff1-4833-b013-8e2c21117761","order_by":22,"name":"Ashley Onabiyi","email":"","orcid":"","institution":"Case Western Reserve University","correspondingAuthor":false,"prefix":"","firstName":"Ashley","middleName":"","lastName":"Onabiyi","suffix":""},{"id":520637244,"identity":"0a4a5a3c-91f4-4306-813b-b304ed2d9987","order_by":23,"name":"Tatiana Pascol","email":"","orcid":"","institution":"Case Western Reserve University","correspondingAuthor":false,"prefix":"","firstName":"Tatiana","middleName":"","lastName":"Pascol","suffix":""},{"id":520637245,"identity":"a36ee2a4-07b2-440e-9dce-2a640001e659","order_by":24,"name":"Rebecca Prince","email":"","orcid":"","institution":"Case Western Reserve University","correspondingAuthor":false,"prefix":"","firstName":"Rebecca","middleName":"","lastName":"Prince","suffix":""},{"id":520637246,"identity":"b2560f18-f65c-4c9f-b666-19cb096b80a7","order_by":25,"name":"Zeyna Samba","email":"","orcid":"","institution":"Case Western Reserve University","correspondingAuthor":false,"prefix":"","firstName":"Zeyna","middleName":"","lastName":"Samba","suffix":""},{"id":520637247,"identity":"9e8fc2de-13d2-426a-a1e3-5113fa006b1c","order_by":26,"name":"James Seckler","email":"","orcid":"","institution":"Case Western Reserve University","correspondingAuthor":false,"prefix":"","firstName":"James","middleName":"","lastName":"Seckler","suffix":""},{"id":520637248,"identity":"86421cc1-ee15-457d-8371-7ddcb59f0481","order_by":27,"name":"Anandakumar Shunmugavel","email":"","orcid":"","institution":"Case Western Reserve University","correspondingAuthor":false,"prefix":"","firstName":"Anandakumar","middleName":"","lastName":"Shunmugavel","suffix":""},{"id":520637249,"identity":"afe2783d-d3b0-48f9-85b3-ef785a5528ea","order_by":28,"name":"Mallika Singh","email":"","orcid":"","institution":"Case Western Reserve University","correspondingAuthor":false,"prefix":"","firstName":"Mallika","middleName":"","lastName":"Singh","suffix":""},{"id":520637250,"identity":"b0aa8f41-be0c-4e7f-b430-fc3be91f09c7","order_by":29,"name":"Sunah Song","email":"","orcid":"https://orcid.org/0000-0002-3139-0035","institution":"Case Western Reserve University","correspondingAuthor":false,"prefix":"","firstName":"Sunah","middleName":"","lastName":"Song","suffix":""},{"id":520637251,"identity":"1c992703-d255-41cb-9d46-9d18754df16d","order_by":30,"name":"Aniruddha Upadhye","email":"","orcid":"","institution":"Case Western Reserve University","correspondingAuthor":false,"prefix":"","firstName":"Aniruddha","middleName":"","lastName":"Upadhye","suffix":""},{"id":520637252,"identity":"3bb2eef0-6b4d-4f8a-9d91-1f168e453467","order_by":31,"name":"David Wilson","email":"","orcid":"","institution":"Case Western Reserve University","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"","lastName":"Wilson","suffix":""},{"id":520637253,"identity":"25a50c02-1693-444a-9ede-5368a0b42169","order_by":32,"name":"Katharine Workman","email":"","orcid":"","institution":"Case Western Reserve University","correspondingAuthor":false,"prefix":"","firstName":"Katharine","middleName":"","lastName":"Workman","suffix":""},{"id":520637254,"identity":"2deccd7f-4d27-4af7-97a5-f9f680f2ec8f","order_by":33,"name":"Jichu Zhang","email":"","orcid":"","institution":"Case Western Reserve University","correspondingAuthor":false,"prefix":"","firstName":"Jichu","middleName":"","lastName":"Zhang","suffix":""},{"id":520637220,"identity":"a8b234ac-ab09-4e41-ad03-3a0d7e867eab","order_by":34,"name":"Andrew Shoffstall","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEUlEQVRIiWNgGAWjYHACAyjJ+OADkJbhY2+AShwgqIXZcAZDAgMPGw9MKfFaJBLwa+Gf3bztw8c2Bntz9mbGxp8/7HjYJB8//PijgkGO70YCVi0Sd44Vz5zZxpC4s+cwYzNPQjIPm3SasTTPGQZjSRxaGG7kGDPzbmNIMLiRf/wxQwIzUEsOgzQj0JANOLTIg7T83cZgb3AjmbHxR0I90GFnmH/+/MdQj0uLAUgL4zYGxg1ALQ08CYeB3gci3gaQvdi1GN5IK2bs/SeRuOEMyC9px4GBnGZmzXNMwnDmmQdYtcjdSN7M8OOMjb3BcWCI/bCpluNnP/z45o8aG3m+4zi8Dw04IkRGwSgYBaNgFBAPAMV2XDCOof/6AAAAAElFTkSuQmCC","orcid":"","institution":"Case Western Reserve University","correspondingAuthor":true,"prefix":"","firstName":"Andrew","middleName":"","lastName":"Shoffstall","suffix":""}],"badges":[],"createdAt":"2025-09-25 02:15:25","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7707775/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7707775/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":95527580,"identity":"c90be4b3-a197-4618-8211-67429f276735","added_by":"auto","created_at":"2025-11-10 10:14:15","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1402178,"visible":true,"origin":"","legend":"Article File","description":"","filename":"PelotEtAlVagalAnatomy.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7707775/v1_covered_9f6d4ef6-7fc7-45cf-b591-67d1346732f1.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"The human vagal complex: from gross anatomy to single neurons, from brainstem to abdomen","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7707775/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7707775/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"The vagus nerve (VN) connects the brainstem to the viscera to regulate many physiological functions. Mapping the VN with state-of-the-art high-resolution imaging modalities has tremendous potential to improve the safety and efficacy of existing autonomic neuromodulation therapies and to inform design of new therapies. We developed the most comprehensive mapping pipeline of the VN to date, from the perspectives of sample size, lengths of nerve, and range of imaging modalities. Our pipeline maps cadaveric human vagal anatomy with complementary imaging modalities applied serially to the same tissue: pre-dissection MRI, pre-dissection CT, 3D tracing of the dissected nerve in situ, CT of the excised nerve, microCT, histology, and a novel serial block-face imaging technique, “3D-MUSE”. The resulting co-registered data enable quantification of gross anatomy, fascicular morphology, and fiber organization in three dimensions. We demonstrated the utility of the data by implementing anatomically realistic computational models of vagus nerve stimulation. These approaches and resulting anatomical data will seed and accelerate the development of novel neuromodulation therapies to treat diseases.","manuscriptTitle":"The human vagal complex: from gross anatomy to single neurons, from brainstem to abdomen","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-20 03:15:03","doi":"10.21203/rs.3.rs-7707775/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-methods","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"nmeth","sideBox":"Learn more about [Nature Methods](http://www.nature.com/nmeth)","snPcode":"","submissionUrl":"","title":"Nature Methods","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"60eed712-a7a4-46d0-aa88-43a4452a7e0f","owner":[],"postedDate":"October 20th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":55343245,"name":"Biological sciences/Neuroscience/Peripheral nervous system"},{"id":55343246,"name":"Health sciences/Medical research/Translational research"},{"id":55343247,"name":"Biological sciences/Neuroscience/Computational neuroscience"}],"tags":[],"updatedAt":"2026-04-28T21:11:13+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-20 03:15:03","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7707775","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7707775","identity":"rs-7707775","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}