{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T18:45:59Z","timestamp":1792089959377,"version":"4.4.0"},"reference-count":47,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,5,25]],"date-time":"2023-05-25T00:00:00Z","timestamp":1684972800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Tinnitus is the perception of sound in the absence of actual external stimuli. Other associated symptoms include frustration, annoyance, anxiety, depression, stress, cognitive dysfunction, insomnia, or emotional exhaustion. Objective: In this study, we aimed to conduct a systematic review and meta-analysis on the effectiveness of the non-invasive neuromodulation of the vagus nerve in patients with tinnitus. Methods: Six databases were searched from their date of inception to 15 June 2022 to identify clinical trials in which at least one group received any form of non-invasive neuromodulation of the vagus nerve for tinnitus management, with outcomes based on annoyance and related disability. Data on participants, interventions, blinding strategies, assessment outcomes, and results were extracted by two reviewers. Results: The search identified 183 articles with five clinical trials eligible for inclusion in the review and four for the meta-analysis. The methodological quality scores ranged from 6 to 8 (mean: 7.3, SD: 0.8) points. The meta-analysis identified a significant positive effect on THI post-treatment for unilateral auricular stimulation (hg = 0.69, 95% CI 0.06, 1.32) or transcutaneous nerve stimulation (hg = 0.51, 95% CI 0.1, 0.9) compared with a comparative group. No effect on loudness intensity was observed. Conclusion: The results of the meta-analysis suggest that the application of the non-invasive neuromodulation of the vagus nerve has a positive effect post-treatment in terms of related disability in patients with tinnitus, although its clinical relevance is low. No firm conclusions about the effect of the non-invasive neuromodulation of the vagus nerve on tinnitus are available based on the current literature.<\/jats:p>","DOI":"10.3390\/jcm12113673","type":"journal-article","created":{"date-parts":[[2023,5,26]],"date-time":"2023-05-26T02:00:19Z","timestamp":1685066419000},"page":"3673","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Effects of Non-Invasive Neuromodulation of the Vagus Nerve for Management of Tinnitus: A Systematic Review with Meta-Analysis"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4387-9046","authenticated-orcid":false,"given":"David","family":"Fern\u00e1ndez-Hernando","sequence":"first","affiliation":[{"name":"Universidad San Pablo-CEU, CEU Universities, Urbanizaci\u00f3n Montepr\u00edncipe, 28660 Boadilla del Monte, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3772-9690","authenticated-orcid":false,"given":"Cesar","family":"Fern\u00e1ndez-de-las-Pe\u00f1as","sequence":"additional","affiliation":[{"name":"Department of Physical Therapy, Occupational Therapy, Physical Medicine and Rehabilitation, Universidad Rey Juan Carlos, 28922 Alcorc\u00f3n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Machado-Mart\u00edn","sequence":"additional","affiliation":[{"name":"Servicio de Otorrino-Laringolog\u00eda, Hospital Universitario Quiron Salud Pozuelo, Universidad Europea de Madrid, 28670 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7868-7442","authenticated-orcid":false,"given":"Santiago","family":"Angulo-D\u00edaz-Parre\u00f1o","sequence":"additional","affiliation":[{"name":"Facultad de Medicina, Universidad San Pablo CEU, 28660 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9072-4904","authenticated-orcid":false,"given":"Francisco J.","family":"Garc\u00eda-Esteo","sequence":"additional","affiliation":[{"name":"Universidad San Pablo-CEU, CEU Universities, Urbanizaci\u00f3n Montepr\u00edncipe, 28660 Boadilla del Monte, Spain"},{"name":"Facultad de Medicina, Universidad San Pablo CEU, 28660 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7285-1870","authenticated-orcid":false,"given":"Juan A.","family":"Mesa-Jim\u00e9nez","sequence":"additional","affiliation":[{"name":"Universidad San Pablo-CEU, CEU Universities, Urbanizaci\u00f3n Montepr\u00edncipe, 28660 Boadilla del Monte, Spain"},{"name":"Facultad de Medicina, Universidad San Pablo CEU, 28660 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13063-015-0630-4","article-title":"Transcutaneous electrical stimulation at auricular acupoints innervated by auricular branch of vagus nerve pairing tone for tinnitus: Study protocol for a randomized controlled clinical trial","volume":"16","author":"Li","year":"2015","journal-title":"Trials"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1007\/s40211-018-0299-5","article-title":"Migraine headache and depression in adults: A systematic Review and Meta-analysis","volume":"33","author":"Amiri","year":"2019","journal-title":"Neuropsychiatrie"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"284","DOI":"10.3389\/fnins.2020.00284","article-title":"Critical Review of Transcutaneous Vagus Nerve Stimulation: Challenges for Translation to Clinical Practice","volume":"14","author":"Yap","year":"2020","journal-title":"Front. Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1016\/j.brs.2017.12.009","article-title":"Neurophysiologic effects of transcutaneous auricular vagus nerve stimulation (taVNS) via electrical stimulation of the tragus: A concurrent taVNS\/fMRI study and review","volume":"11","author":"Badran","year":"2018","journal-title":"Brain Stimul."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1186\/s10194-020-01135-0","article-title":"Persistent post-traumatic headache: A migrainous loop or not? The preclinical evidence","volume":"21","author":"Benemei","year":"2020","journal-title":"J. Headache Pain"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"267","DOI":"10.5152\/iao.2018.3977","article-title":"Characteristics of Stimulus Intensity in Transcutaneous Vagus Nerve Stimulation for Chronic Tinnitus","volume":"14","author":"Choi","year":"2018","journal-title":"J. Int. Adv. Otol."},{"key":"ref_7","first-page":"1","article-title":"Current Directions in the Auricular Vagus Nerve Stimulation I\u2013A Physiological Perspective","volume":"13","author":"Kaniusas","year":"2019","journal-title":"Front. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"101971","DOI":"10.1016\/j.nicl.2019.101971","article-title":"Transcutaneous auricular vagus nerve stimulation at 1 Hz modulates locus coeruleus activity and resting state functional connectivity in patients with migraine: An fMRI study","volume":"24","author":"Zhang","year":"2019","journal-title":"NeuroImage Clin."},{"key":"ref_9","first-page":"139","article-title":"\u4e73\u9f20\u5fc3\u808c\u63d0\u53d6 HHS Public Access","volume":"176","author":"Richards","year":"2018","journal-title":"Physiol. Behav."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1016\/j.brs.2019.02.003","article-title":"The influence of respiration on brainstem and cardiovagal response to auricular vagus nerve stimulation: A multimodal ultrahigh-field (7T) fMRI study","volume":"12","author":"Sclocco","year":"2019","journal-title":"Brain Stimul."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Kim, H.-J., Lee, H.-J., An, S.-Y., Sim, S., Park, B., Kim, S.W., Lee, J.S., Hong, S.K., and Choi, H.G. (2015). Analysis of the Prevalence and Associated Risk Factors of Tinnitus in Adults. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0127578"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Rhee, J., Lee, D., Suh, M.-W., Lee, J.H., Hong, Y.-C., Oh, S.H., and Park, M.K. (2020). Prevalence, associated factors, and comorbidities of tinnitus in adolescents. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0236723"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.heares.2016.05.009","article-title":"A systematic review of the reporting of tinnitus prevalence and severity","volume":"337","author":"McCormack","year":"2016","journal-title":"Hear. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1001\/jamaneurol.2022.2189","article-title":"Global Prevalence and Incidence of Tinnitus: A Systematic Review and Meta-analysis","volume":"79","author":"Jarach","year":"2022","journal-title":"JAMA Neurol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1002\/lary.26107","article-title":"Relationships between tinnitus and the prevalence of anxiety and depression","volume":"127","author":"Bhatt","year":"2017","journal-title":"Laryngoscope"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"378","DOI":"10.3109\/00016489.2012.750736","article-title":"Transcutaneous vagus nerve stimulation in tinnitus: A pilot study","volume":"133","author":"Ylikoski","year":"2013","journal-title":"Acta Oto-Laryngologica"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Stegeman, I., Velde, H.M., Robe, P.A.J.T., Stokroos, R.J., and Smit, A.L. (2021). Tinnitus treatment by vagus nerve stimulation: A systematic review. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0247221"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"849291","DOI":"10.3389\/fnins.2022.849291","article-title":"Common Cholinergic, Noradrenergic, and Serotonergic Drugs Do Not Block VNS-Mediated Plasticity","volume":"16","author":"Morrison","year":"2022","journal-title":"Front. Neurosci."},{"key":"ref_19","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_20","doi-asserted-by":"crossref","first-page":"d5928","DOI":"10.1136\/bmj.d5928","article-title":"The Cochrane Collaboration\u2019s tool for assessing risk of bias in randomised trials","volume":"343","author":"Higgins","year":"2011","journal-title":"BMJ"},{"key":"ref_21","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_22","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1093\/ptj\/83.8.713","article-title":"Reliability of the PEDro Scale for Rating Quality of Randomized Controlled Trials","volume":"83","author":"Maher","year":"2003","journal-title":"Phys. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1136\/ebm.13.6.162-a","article-title":"GRADE: Assessing the quality of evidence for diagnostic recommendations","volume":"13","author":"Oxman","year":"2008","journal-title":"BMJ Evidence-Based Med."},{"key":"ref_24","unstructured":"Higgins, J.P.T., Churchill, R., Chandler, J., and Cumpston, M.S. (2017). Cochrane Handbook for Systematic Reviews of Interventions, Cochrane. Available online: www.training.cochrane.org\/handbook."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/0197-2456(86)90046-2","article-title":"Meta-analysis in clinical trials","volume":"7","author":"DerSimonian","year":"1986","journal-title":"Control. Clin. Trials"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1177\/0272989X05282643","article-title":"The Interpretation of Random-Effects Meta-Analysis in Decision Models","volume":"25","author":"Ades","year":"2005","journal-title":"Med. Decis. Mak."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1136\/bmj.327.7414.557","article-title":"Measuring inconsistency in meta-analyses","volume":"327","author":"Higgins","year":"2003","journal-title":"BMJ"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1111\/ner.12452","article-title":"An Investigation of Feasibility and Safety of Bi-Modal Stimulation for the Treatment of Tinnitus: An Open-Label Pilot Study","volume":"19","author":"Hamilton","year":"2016","journal-title":"Neuromodulation"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"102326","DOI":"10.1016\/j.amjoto.2019.102326","article-title":"The effect of transcutaneous electrical nerve stimulation (TENS) on chronic subjective tinnitus","volume":"41","author":"Tutar","year":"2019","journal-title":"Am. J. Otolaryngol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"100409","DOI":"10.1016\/j.imr.2020.100409","article-title":"Comparing the effects of manual acupuncture, electroacupuncture, and transcutaneous electrical nerve stimulation on chronic tinnitus: A randomized controlled trial","volume":"9","author":"Kim","year":"2020","journal-title":"Integr. Med. Res."},{"key":"ref_31","first-page":"1","article-title":"A comparative study on the effects of systemic manual acupuncture, periauricular electroacupuncture, and digital electroacupuncture to treat tinnitus: A randomized, paralleled, open-labeled exploratory trial","volume":"17","author":"Kim","year":"2017","journal-title":"BMC Complement. Altern. Med."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Yakunina, N., Kim, S.S., and Nam, E.-C. (2018). BOLD fMRI effects of transcutaneous vagus nerve stimulation in patients with chronic tinnitus. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0207281"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e76","DOI":"10.1097\/AUD.0000000000000123","article-title":"Transcutaneous Vagus Nerve Stimulation Modulates Tinnitus-Related Beta- and Gamma-Band Activity","volume":"36","author":"Yrttiaho","year":"2015","journal-title":"Ear Hear."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"570196","DOI":"10.3389\/fpsyg.2020.570196","article-title":"Stress and Tinnitus; Transcutaneous Auricular Vagal Nerve Stimulation Attenuates Tinnitus-Triggered Stress Reaction","volume":"11","author":"Ylikoski","year":"2020","journal-title":"Front. Psychol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.heares.2017.12.003","article-title":"Transauricular vagus nerve stimulation at auricular acupoints Kindey (CO10), Yidan (CO11), Liver (CO12) and Shenmen (TF4) can induce auditory and limbic cortices activation measured by fMRI","volume":"359","author":"Peng","year":"2018","journal-title":"Hear. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1631\/jzus.B1700117","article-title":"Neuromodulation for tinnitus treatment: An overview of invasive and non-invasive techniques","volume":"20","author":"Peter","year":"2018","journal-title":"J. Zhejiang Univ. Sci. B"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2088","DOI":"10.1016\/j.cub.2021.02.049","article-title":"Vagus nerve stimulation induces widespread cortical and behavioral activation","volume":"31","author":"Collins","year":"2021","journal-title":"Curr. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"113718","DOI":"10.1016\/j.expneurol.2021.113718","article-title":"Vagus nerve stimulation enhances fear extinction as an inverted-U function of stimulation intensity","volume":"341","author":"Souza","year":"2021","journal-title":"Exp. Neurol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.jneumeth.2019.02.010","article-title":"ReStore: A wireless peripheral nerve stimulation system","volume":"320","author":"Sivaji","year":"2019","journal-title":"J. Neurosci. Methods"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e32058","DOI":"10.7554\/eLife.32058","article-title":"Closed-loop neuromodulation restores network connectivity and motor control after spinal cord injury","volume":"7","author":"Ganzer","year":"2018","journal-title":"Elife"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"159","DOI":"10.3233\/NRE-172273","article-title":"Vagus nerve stimulation paired with tactile training improved sensory function in a chronic stroke patient","volume":"42","author":"Kilgard","year":"2018","journal-title":"Neurorehabilitation"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"11960","DOI":"10.1038\/s41598-017-12178-w","article-title":"Vagus Nerve Stimulation Paired with Tones for the Treatment of Tinnitus: A Prospective Randomized Double-blind Controlled Pilot Study in Humans","volume":"7","author":"Tyler","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1111\/jep.13397","article-title":"Time as a barrier to evidence uptake\u2014A qualitative exploration of the concept of time for clinical practice guideline uptake by physiotherapists","volume":"27","author":"Stander","year":"2020","journal-title":"J. Eval. Clin. Pract."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1136\/bmjebm-2020-111385","article-title":"Building capacity: Getting evidence-based practice into healthcare professional curricula","volume":"26","author":"Lehane","year":"2021","journal-title":"BMJ Evidence-Based Med."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Worum, H., Lillekroken, D., Roaldsen, K.S., Ahlsen, B., and Bergland, A. (2020). Physiotherapists\u2019 perceptions of challenges facing evidence-based practice and the importance of environmental empowerment in fall prevention in the municipality-a qualitative study. BMC Geriatr., 20.","DOI":"10.1186\/s12877-020-01846-8"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1177\/0964528420938380","article-title":"Acupuncture for tinnitus: A systematic review and meta-analysis of randomized controlled trials","volume":"39","author":"Huang","year":"2021","journal-title":"Acupunct. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2331216518821449","DOI":"10.1177\/2331216518821449","article-title":"Tinnitus Treatment Using Noninvasive and Minimally Invasive Electric Stimulation: Experimental Design and Feasibility","volume":"23","author":"Zeng","year":"2019","journal-title":"Trends Hear."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/12\/11\/3673\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:42:10Z","timestamp":1760125330000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/12\/11\/3673"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,25]]},"references-count":47,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["jcm12113673"],"URL":"https:\/\/doi.org\/10.3390\/jcm12113673","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,25]]}}}