{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T13:51:10Z","timestamp":1790603470232,"version":"4.1.0"},"reference-count":51,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T00:00:00Z","timestamp":1766966400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["1R01AT009491\u201301A1"],"award-info":[{"award-number":["1R01AT009491\u201301A1"]}]},{"name":"NIH","award":["R03 AG085084-01"],"award-info":[{"award-number":["R03 AG085084-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JFMK"],"abstract":"<jats:p>Background: Chronic pain conditions such as fibromyalgia syndrome (FMS) reflect maladaptive network physiology across perceptual\u2013autonomic\u2013immune axes, yet most treatments remain symptomatic and incompletely effective. Methods: We conducted a comprehensive systematic review to evaluate vagus nerve stimulation (VNS) and FMS within a network physiology framework. PubMed, Embase, and Cochrane CENTRAL were searched on October 24, 2025. Risk of bias was assessed using the ROB-2 tool. An iterative thematic synthesis was performed to develop an integrative conceptual framework and to identify knowledge gaps and future research directions. Results: We first summarize physiological evidence showing autonomic imbalance (e.g., decreased heart rate variability), neuroinflammatory activation, and aberrant cortical network connectivity in FMS, supporting a network-dysregulation model. We then included 6 studies (4 clinical studies and 2 protocols) on VNS effects, highlighting improvements in pain, fatigue, sleep disturbance and autonomic regulation, along with emerging mechanistic insights. Key methodological heterogeneity\u2014such as stimulation parameters, outcome metrics, type of control arm, sham definition, and small samples\u2014limits current interpretability. Finally, we outline a research agenda centered on network-based biomarkers, immunophenotyping, adaptive trial designs and stratification of responders, with the aim of validating taVNS as a scalable neuromodulatory intervention for FMS. Conclusions: By reframing FMS from a symptom-centric pharmacologic model to a network-centric neuromodulation approach, taVNS is a promising tool for mechanism-based therapeutics in central sensitization syndromes and chronic pain.<\/jats:p>","DOI":"10.3390\/jfmk11010015","type":"journal-article","created":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T14:08:11Z","timestamp":1767190091000},"page":"15","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Potential of Vagus Nerve Stimulation to Modulate Fibromyalgia\u2019s Network Physiology: A Systematic Review"],"prefix":"10.3390","volume":"11","author":[{"given":"Joao Pedro","family":"Perin","sequence":"first","affiliation":[{"name":"Neuromodulation Center and Center for Clinical Research Learning, Harvard Medical School, Spaulding Rehabilitation Hospital, Boston, MA 02138, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3624-5185","authenticated-orcid":false,"given":"Carla","family":"Pastora-Ses\u00edn","sequence":"additional","affiliation":[{"name":"Neuromodulation Center and Center for Clinical Research Learning, Harvard Medical School, Spaulding Rehabilitation Hospital, Boston, MA 02138, USA"},{"name":"Trybe Health, Torre Lexus, Avenida Escaz\u00fa, San Rafael de Escaz\u00fa 10203, Costa Rica"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sungjoon","family":"Kang","sequence":"additional","affiliation":[{"name":"Admission AG, Irvine, CA 92618, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alba","family":"Navarro-Flores","sequence":"additional","affiliation":[{"name":"Institute of Psychiatric Phenomics and Genomics (IPPG), LMU University Hospital, LMU Munich, 80336 Munich, Germany"},{"name":"International Max Planck Research School for Translational Psychiatry (IMPRS-TP), 80804 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felipe","family":"Fregni","sequence":"additional","affiliation":[{"name":"Neuromodulation Center and Center for Clinical Research Learning, Harvard Medical School, Spaulding Rehabilitation Hospital, Boston, MA 02138, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Pacheco-Barrios","sequence":"additional","affiliation":[{"name":"Neuromodulation Center and Center for Clinical Research Learning, Harvard Medical School, Spaulding Rehabilitation Hospital, Boston, MA 02138, USA"},{"name":"Unidad de Investigaci\u00f3n para la Generaci\u00f3n y S\u00edntesis de Evidencias en Salud, Vicerrectorado de Investigaci\u00f3n, Universidad San Ignacio de Loyola, Lima 15023, Peru"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,29]]},"reference":[{"key":"ref_1","unstructured":"Bhargava, J., and Goldin, J. (2025). Fibromyalgia. StatPearls, StatPearls Publishing."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e15428","DOI":"10.1111\/1756-185X.15428","article-title":"Epidemiology of Fibromyalgia: East Versus West","volume":"27","author":"Soroosh","year":"2024","journal-title":"Int. J. Rheum. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e1229","DOI":"10.1097\/PR9.0000000000001229","article-title":"Gender Differences in Clinical Presentations and Sensory Profiles in Patients with Fibromyalgia: Implications of Peripheral and Central Mechanisms","volume":"10","author":"Liu","year":"2025","journal-title":"Pain Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1001\/jama.2014.3266","article-title":"Fibromyalgia: A Clinical Review","volume":"311","author":"Clauw","year":"2014","journal-title":"JAMA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1007\/s11916-013-0356-5","article-title":"Worldwide Epidemiology of Fibromyalgia","volume":"17","author":"Queiroz","year":"2013","journal-title":"Curr. Pain Headache Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"152060","DOI":"10.1016\/j.semarthrit.2022.152060","article-title":"The Economic Burden of Fibromyalgia: A Systematic Literature Review","volume":"56","author":"Ciaffi","year":"2022","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e003904","DOI":"10.1136\/rmdopen-2023-003904","article-title":"Health Inequities and Societal Costs for Patients with Fibromyalgia and Their Spouses: A Danish Cohort Study","volume":"10","author":"Amris","year":"2024","journal-title":"RMD Open"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s13561-024-00527-1","article-title":"Social Costs Associated with Fibromyalgia in Spain","volume":"14","year":"2024","journal-title":"Health Econ. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1136\/annrheumdis-2016-209724","article-title":"EULAR Revised Recommendations for the Management of Fibromyalgia","volume":"76","author":"Macfarlane","year":"2017","journal-title":"Ann. Rheum. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1186\/ar3306","article-title":"The Role of the Central Nervous System in the Generation and Maintenance of Chronic Pain in Rheumatoid Arthritis, Osteoarthritis and Fibromyalgia","volume":"13","author":"Lee","year":"2011","journal-title":"Arthritis Res. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1002\/ejp.1607","article-title":"Peripheral and Central Nervous System Correlates in Fibromyalgia","volume":"24","author":"Vecchio","year":"2020","journal-title":"Eur. J. Pain"},{"key":"ref_12","first-page":"14651858","article-title":"Cochrane Handbook for Systematic Reviews of Interventions","volume":"4","author":"Chandler","year":"2019","journal-title":"Hoboken Wiley"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 Statement: An Updated Guideline for Reporting Systematic Reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"l4898","DOI":"10.1136\/bmj.l4898","article-title":"RoB 2: A Revised Tool for Assessing Risk of Bias in Randomised Trials","volume":"366","author":"Sterne","year":"2019","journal-title":"BMJ"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"l6890","DOI":"10.1136\/bmj.l6890","article-title":"Synthesis without Meta-Analysis (SWiM) in Systematic Reviews: Reporting Guideline","volume":"368","author":"Campbell","year":"2020","journal-title":"BMJ"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Ivanov, P.C. (2021). The New Field of Network Physiology: Building the Human Physiolome. Front. Netw. Physiol., 1.","DOI":"10.3389\/fnetp.2021.711778"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"100201","DOI":"10.1088\/1367-2630\/18\/10\/100201","article-title":"Focus on the Emerging New Fields of Network Physiology and Network Medicine","volume":"18","author":"Ivanov","year":"2016","journal-title":"New J. Phys."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1038\/nature01321","article-title":"The Inflammatory Reflex","volume":"420","author":"Tracey","year":"2002","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1038\/nri2566","article-title":"Reflex Control of Immunity","volume":"9","author":"Tracey","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"ref_20","first-page":"S39","article-title":"Groupo ICAF Resource Utilisation and Health Care Costs in Patients Diagnosed with Fibromyalgia in Spain","volume":"27","author":"Rivera","year":"2009","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_21","first-page":"203","article-title":"The Gut-Brain Axis: Interactions between Enteric Microbiota, Central and Enteric Nervous Systems","volume":"28","author":"Carabotti","year":"2015","journal-title":"Ann. Gastroenterol. Q. Publ. Hell. Soc. Gastroenterol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Ho, T., Elma, \u00d6., Kocanda, L., Brain, K., Lam, T., Kanhere, T., and Dong, H.-J. (2025). The Brain-Gut Axis and Chronic Pain: Mechanisms and Therapeutic Opportunities. Front. Neurosci., 19.","DOI":"10.3389\/fnins.2025.1545997"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Liu, F.-J., Wu, J., Gong, L.-J., Yang, H.-S., and Chen, H. (2024). Non-Invasive Vagus Nerve Stimulation in Anti-Inflammatory Therapy: Mechanistic Insights and Future Perspectives. Front. Neurosci., 18.","DOI":"10.3389\/fnins.2024.1490300"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1038\/nrendo.2012.189","article-title":"The vagus nerve and the inflammatory reflex\u2014Linking immunity and metabolism","volume":"8","author":"Pavlov","year":"2012","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e25656","DOI":"10.1002\/cne.25656","article-title":"What Is the Vagal\u2013Adrenal Axis?","volume":"532","author":"McAllen","year":"2024","journal-title":"J. Comp. Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1003206","DOI":"10.37349\/ei.2025.1003206","article-title":"Fibromyalgia Syndrome and the Immune System: A Review with Comparative Perspectives on Chronic Immune-Related Syndromes Including CFS\/ME and IBS","volume":"5","author":"Nizzero","year":"2025","journal-title":"Explor. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1186\/ar4441","article-title":"Review of Pharmacological Therapies in Fibromyalgia Syndrome","volume":"16","author":"Walitt","year":"2014","journal-title":"Arthritis Res. Ther."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Yap, J.Y.Y., Keatch, C., Lambert, E., Woods, W., Stoddart, P.R., and Kameneva, T. (2020). Critical Review of Transcutaneous Vagus Nerve Stimulation: Challenges for Translation to Clinical Practice. Front. Neurosci., 14.","DOI":"10.3389\/fnins.2020.00284"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1111\/j.1526-4637.2011.01203.x","article-title":"Safety and Efficacy of Vagus Nerve Stimulation in Fibromyalgia: A Phase I\/II Proof of Concept Trial","volume":"12","author":"Lange","year":"2011","journal-title":"Pain Med."},{"key":"ref_30","first-page":"1095","article-title":"Vagal Nerve Stimulation and Fibromyalgia: An Additional Therapeutic Option","volume":"43","author":"Dolcini","year":"2025","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"8656218","DOI":"10.1155\/2020\/8656218","article-title":"The Impact of Auricular Vagus Nerve Stimulation on Pain and Life Quality in Patients with Fibromyalgia Syndrome","volume":"2020","author":"Kutlu","year":"2020","journal-title":"BioMed Res. Int."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Paccione, C.E., Stubhaug, A., Diep, L.M., Rosseland, L.A., and Jacobsen, H.B. (2022). Meditative-Based Diaphragmatic Breathing vs. Vagus Nerve Stimulation in the Treatment of Fibromyalgia\u2014A Randomized Controlled Trial: Body vs. Machine. Front. Neurol., 13.","DOI":"10.3389\/fneur.2022.1030927"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Cai, Y., Zhang, Y., Fang, Y., Hu, H., Li, X., and Fang, L. (2024). Evaluating the Efficacy and Acceptability of Vagus Nerve Stimulation for Fibromyalgia: A PRISMA-Compliant Protocol for a Systematic Review and Meta-Analysis. Front. Neurol., 15.","DOI":"10.3389\/fneur.2024.1367295"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Molero-Chamizo, A., Nitsche, M.A., Bolz, A., And\u00fajar Barroso, R.T., Alameda Bail\u00e9n, J.R., Garc\u00eda Palomeque, J.C., and Rivera-Urbina, G.N. (2022). Non-Invasive Transcutaneous Vagus Nerve Stimulation for the Treatment of Fibromyalgia Symptoms: A Study Protocol. Brain Sci., 12.","DOI":"10.3390\/brainsci12010095"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e39","DOI":"10.2196\/resprot.8692","article-title":"Functional Magnetic Resonance Imaging Evaluation of Auricular Percutaneous Electrical Neural Field Stimulation for Fibromyalgia: Protocol for a Feasibility Study","volume":"7","author":"Gebre","year":"2018","journal-title":"JMIR Res. Protoc."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5730","DOI":"10.1080\/09638288.2024.2313123","article-title":"Clinical Application of Transcutaneous Auricular Vagus Nerve Stimulation: A Scoping Review","volume":"46","author":"Gerges","year":"2024","journal-title":"Disabil. Rehabil."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1002\/art.24000","article-title":"A Systematic Review on the Effectiveness of Treatment with Antidepressants in Fibromyalgia Syndrome","volume":"59","author":"Sommer","year":"2008","journal-title":"Arthritis Care Res."},{"key":"ref_38","first-page":"346","article-title":"Transauricular Vagus Nerve Stimulation (taVNS) Enhances Conditioned Pain Modulation (CPM) in Healthy Subjects: A Randomized Controlled Trial","volume":"17","author":"Gianlorenco","year":"2024","journal-title":"Brain Stimul. Basic Transl. Clin. Res. Neuromodulation"},{"key":"ref_39","first-page":"e66309","article-title":"Understanding the Effects of Non-Invasive Transauricular Vagus Nerve Stimulation on EEG and HRV","volume":"203","author":"Gianlorenco","year":"2024","journal-title":"J. Vis. Exp. JoVE"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Farmer, A.D., Strzelczyk, A., Finisguerra, A., Gourine, A.V., Gharabaghi, A., Hasan, A., Burger, A.M., Jaramillo, A.M., Mertens, A., and Majid, A. (2021). International Consensus Based Review and Recommendations for Minimum Reporting Standards in Research on Transcutaneous Vagus Nerve Stimulation (Version 2020). Front. Hum. Neurosci., 14.","DOI":"10.3389\/fnhum.2020.568051"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.seizure.2020.09.027","article-title":"Learnings from 30 Years of Reported Efficacy and Safety of Vagus Nerve Stimulation (VNS) for Epilepsy Treatment: A Critical Review","volume":"83","author":"Toffa","year":"2020","journal-title":"Seizure"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1186\/ar2146","article-title":"Biology and Therapy of Fibromyalgia. Stress, the Stress Response System, and Fibromyalgia","volume":"9","year":"2007","journal-title":"Arthritis Res. Ther."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.semarthrit.2013.03.004","article-title":"Heart Rate Variability in Patients with Fibromyalgia and Patients with Chronic Fatigue Syndrome: A Systematic Review","volume":"43","author":"Meeus","year":"2013","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1007\/s12264-020-00619-y","article-title":"Transcutaneous Auricular Vagus Nerve Stimulation: From Concept to Application","volume":"37","author":"Wang","year":"2020","journal-title":"Neurosci. Bull."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"34531","DOI":"10.1038\/s41598-025-17821-5","article-title":"The Effects of Non-Invasive Transcutaneous Auricular Vagus Nerve Stimulation on Resting-State Delta Oscillation: A Randomized, Double-Blinded, Sham-Control Trial","volume":"15","author":"Camargo","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e13571","DOI":"10.1111\/psyp.13571","article-title":"Moving beyond Belief: A Narrative Review of Potential Biomarkers for Transcutaneous Vagus Nerve Stimulation","volume":"57","author":"Burger","year":"2020","journal-title":"Psychophysiology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.ynpai.2017.03.002","article-title":"Do the Psychological Effects of Vagus Nerve Stimulation Partially Mediate Vagal Pain Modulation?","volume":"1","author":"Frangos","year":"2017","journal-title":"Neurobiol. Pain"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4993","DOI":"10.1097\/JS9.0000000000001592","article-title":"Transcutaneous Auricular Vagus Nerve Stimulation as a Novel Therapy Connecting the Central and Peripheral Systems: A Review","volume":"110","author":"Zou","year":"2024","journal-title":"Int. J. Surg. Lond. Engl."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/496159a","article-title":"A Jump-Start for Electroceuticals","volume":"496","author":"Famm","year":"2013","journal-title":"Nature"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1016\/j.neubiorev.2021.10.021","article-title":"The Role of the Vagus Nerve in Fibromyalgia Syndrome","volume":"131","author":"Martins","year":"2021","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1159\/000531626","article-title":"Role of Vagus Nerve Stimulation in the Treatment of Chronic Pain","volume":"30","author":"Shao","year":"2023","journal-title":"Neuroimmunomodulation"}],"container-title":["Journal of Functional Morphology and Kinesiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2411-5142\/11\/1\/15\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T05:10:54Z","timestamp":1767676254000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2411-5142\/11\/1\/15"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,29]]},"references-count":51,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["jfmk11010015"],"URL":"https:\/\/doi.org\/10.3390\/jfmk11010015","relation":{},"ISSN":["2411-5142"],"issn-type":[{"value":"2411-5142","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,29]]}}}