Effects of Vagus Nerve Stimulation on Upper-Limb Motor Function After Stroke: A Systematic Review and Meta-Analysis of RCTs

Mao Hsien Chang 1 2, Wei-Hsi Chang 3 4 5 * , Mao Chang Chang 6 *
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1 Department of Neurology, National Cheng Kung University Hospital, Tainan, Taiwan
2 Department of Sports Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
3 Institute of Medical Science and Technology, National Sun Yat-Sen University, Kaohsiung, Taiwan
4 Department of Emergency Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan
5 Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
6 Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
* Corresponding Author
J CLIN MED KAZ, Volume 23, Issue 3, pp. 73-84. https://doi.org/10.23950/jcmk/18498
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Author Contributions: Conceptualization, M.H.C.; methodology, M.H.C. and W.H.C.; formal analysis, M.H.C.; investigation, M.H.C.; data curation, M.H.C.; writing – original draft preparation, M.H.C.; writing – review and editing, W.H.C. and M.C.C.; visualization, M.H.C.; supervision, W.H.C. and M.C.C.; project administration, M.C.C.; funding acquisition – not applicable. All authors have read and agreed to the published version of the manuscript.

Data availability statement: All data analyzed in this meta-analysis were derived from previously published studies accessible through academic databases. No new datasets were generated.

Artificial Intelligence (AI) Disclosure Statement: The authors declare no AI Tools used for preparation of this work.

ABSTRACT

Background. Stroke results in persistent upper-limb motor impairment, and survivors experience incomplete recovery despite standard rehabilitation. Vagus nerve stimulation (VNS) has emerged as a potential neuromodulatory adjunct capable of enhancing training-dependent plasticity. This meta-analysis evaluated the effectiveness of VNS combined with upper-limb rehabilitation in improving motor outcomes after stroke.
Methods. A systematic search of PubMed, the Cochrane Library, and CNKI from 2010 to November 2025 identified randomized controlled trials evaluating rehabilitation paired with implanted or transcutaneous VNS. The primary outcome was upper-limb motor recovery measured by Fugl-Meyer Assessment–Upper Extremity (FMA-UE) at the longest follow-up. Standardized mean differences (SMDs) were pooled using a random-effects model, and certainty of evidence was appraised with the GRADE approach.
Results. Eight RCTs involving 262 participants met inclusion criteria. Across all VNS modalities, rehabilitation paired with VNS significantly improved upper-limb motor function (SMD = 0.886, 95% CI: 0.098–1.674, p = 0.028). Subgroup analysis demonstrated that transcutaneous VNS showed a significant pooled effect (SMD = 1.332, 95% CI: 0.034–2.629, p = 0.044), whereas implanted VNS yielded a smaller, nonsignificant effect (SMD = 0.161, 95% CI: −0.166–0.487, p = 0.335). Improvements were directionally consistent across trials, though heterogeneity and small sample sizes limited certainty of evidence.
Conclusions. Vagus nerve stimulation paired with structured upper-limb rehabilitation enhance motor recovery after stroke. While the overall evidence remains constrained by heterogeneity and modest trial sizes, this review synthesizes emerging data supporting VNS as a promising adjunct to post-stroke neurorehabilitation and highlights the need for larger, standardized RCTs.
Keywords: Stroke, Vagus nerve stimulation, Upper-limb rehabilitation, Fugl-Meyer Assessment, Meta-analysis

CITATION

Chang MH, Chang WH, Chang MC. Effects of Vagus Nerve Stimulation on Upper-Limb Motor Function After Stroke: A Systematic Review and Meta-Analysis of RCTs. J CLIN MED KAZ. 2026;23(3):73-84. https://doi.org/10.23950/jcmk/18498

REFERENCES

  • Feigin VL, Brainin M, Norrving B, Martins SO, Pandian J, Lindsay P, et al. World Stroke Organization: Global Stroke Fact Sheet 2025. Int J Stroke. 2025; 20 (2): 132-44. https://doi.org/10.1177/17474930241308142
  • Hilkens NA, Casolla B, Leung TW, de Leeuw F-E. Stroke. The Lancet. 2024; 403 (10446): 2820-36. https://doi.org/10.1016/S0140-6736(24)00642-1
  • Paul T, Cieslak M, Hensel L, Wiemer VM, Grefkes C, Grafton ST, et al. The role of corticospinal and extrapyramidal pathways in motor impairment after stroke. Brain Commun. 2023; 5 (1): fcac301. https://doi.org/10.1093/braincomms/fcac301
  • Aderinto N, Abraham IC, Olatunji G, Kokori E, Hasan A, Uwishema O. Mapping the role of vagus nerve stimulation in post-stroke arm motor recovery. J Neuroeng Rehabil. 2025; 22 (1): 215. https://doi.org/10.1186/s12984-025-01759-w
  • Cabral DF, Fried P, Koch S, Rice J, Rundek T, Pascual-Leone A, et al. Efficacy of mechanisms of neuroplasticity after a stroke. Restor Neurol Neurosci. 2022; 40 (2): 73-84. https://doi.org/10.3233/rnn-211227
  • Sikuka HM, Lupenga J, Nkhata L. Predictors of upper limb motor recovery in stroke survivors: a pre-post test study design. BMJ Open. 2024; 14 (11): e081936. https://doi.org/10.1136/bmjopen-2023-081936
  • Gil-Salcedo A, Dugravot A, Fayosse A, Jacob L, Bloomberg M, Sabia S, et al. Long-Term Evolution of Functional Limitations in Stroke Survivors Compared With Stroke-Free Controls: Findings From 15 Years of Follow-Up Across 3 International Surveys of Aging. Stroke. 2022; 53 (1): 228-37. https://doi.org/10.1161/strokeaha.121.034534
  • Wurzinger HE, Abzhandadze T, Rafsten L, Sunnerhagen KS. Dependency in Activities of Daily Living During the First Year After Stroke. Front Neurol. 2021; 12 736684. https://doi.org/10.3389/fneur.2021.736684
  • Semprini M. Editorial: Innovative approaches to promote stroke recovery. Front Neurosci. 2025; 19 1657124. https://doi.org/10.3389/fnins.2025.1657124
  • Das UC, Le NT, Vitoonpong T, Prapinpairoj C, Anannub K, Akarathanawat W, et al. An innovative model based on machine learning and fuzzy logic for tracking lower limb exercises in stroke patients. Sci Rep. 2025; 15 (1): 11220. https://doi.org/10.1038/s41598-025-90031-1
  • Huang J, Ji JR, Liang C, Zhang YZ, Sun HC, Yan YH, et al. Effects of physical therapy-based rehabilitation on recovery of upper limb motor function after stroke in adults: a systematic review and meta-analysis of randomized controlled trials. Ann Palliat Med. 2022; 11 (2): 521-31. https://doi.org/10.21037/apm-21-3710
  • Ren L, Ng S, Chi Keung CR, Woo J, Wong T. Efficacy of combined vagus nerve stimulation and exercise training for upper limb recovery in people with stroke: a systematic review and meta-analysis. Topics in Stroke Rehabilitation. 2026; 1-15. https://doi.org/10.1080/10749357.2026.2648211
  • Khan I, Shakir M, Vijayanarasimhan V, Lodhi BA, Parker JJ, Miller KJ, et al. Implantable Vagus Nerve Stimulator-Paired Neurorehabilitation for Upper Limb Function After Ischemic Stroke: Evidence From a Systematic Review and Meta-Analysis With Best Practice Recommendations. Neurosurgery. 2025; https://doi.org/10.1227/neu.0000000000003545
  • Roy JM, Musmar B, Ritz C, Sizdahkhani S, Karadimas S, Papadopoulos E, et al. Vagus nerve stimulation paired with rehabilitation for post-stroke recovery: A single center experience of patient satisfaction and outcomes. Clin Neurol Neurosurg. 2025; 257 109043. https://doi.org/10.1016/j.clineuro.2025.109043
  • Ananda R, Roslan MHB, Wong LL, Botross NP, Ngim CF, Mariapun J. Efficacy and Safety of Vagus Nerve Stimulation in Stroke Rehabilitation: A Systematic Review and Meta-Analysis. Cerebrovasc Dis. 2023; 52 (3): 239-50. https://doi.org/10.1159/000526470
  • Malley KM, Ruiz AD, Darrow MJ, Danaphongse T, Shiers S, Ahmad FN, et al. Neural Mechanisms Responsible for Vagus Nerve Stimulation-Dependent Enhancement of Somatosensory Recovery. Res Sq. 2024; https://doi.org/10.21203/rs.3.rs-3873435/v1
  • Wang L, Xu Q, Luo M, Xing X, Wang J, Liang Y, et al. Vagus nerve stimulation in various stages of stroke and associated functional impairments: A review. Neuroscience. 2025; 577 80-113. https://doi.org/10.1016/j.neuroscience.2025.04.037
  • Austelle CW, Cox SS, Wills KE, Badran BW. Vagus nerve stimulation (VNS): recent advances and future directions. Clin Auton Res. 2024; 34 (6): 529-47. https://doi.org/10.1007/s10286-024-01065-w
  • Çalι A, Özden AV, Ceylan İ. Effects of a single session of noninvasive auricular vagus nerve stimulation on sports performance in elite athletes: an open-label randomized controlled trial. Expert Rev Med Devices. 2024; 21 (3): 231-7. https://doi.org/10.1080/17434440.2023.2299300
  • Dawson J, Engineer ND, Cramer SC, Wolf SL, Ali R, O'Dell MW, et al. Vagus Nerve Stimulation Paired With Rehabilitation for Upper Limb Motor Impairment and Function After Chronic Ischemic Stroke: Subgroup Analysis of the Randomized, Blinded, Pivotal, VNS-REHAB Device Trial. Neurorehabil Neural Repair. 2023; 37 (6): 367-73. https://doi.org/10.1177/15459683221129274
  • Lin S, Rodriguez CO, Wolf SL. Vagus Nerve Stimulation Paired With Upper Extremity Rehabilitation for Chronic Ischemic Stroke: Contribution of Dosage Parameters. Neurorehabil Neural Repair. 2024; 38 (8): 607-15. https://doi.org/10.1177/15459683241258769
  • Ramos-Castaneda JA, Barreto-Cortes CF, Losada-Floriano D, Sanabria-Barrera SM, Silva-Sieger FA, Garcia RG. Efficacy and Safety of Vagus Nerve Stimulation on Upper Limb Motor Recovery After Stroke. A Systematic Review and Meta-Analysis. Frontiers in Neurology. 2022; Volume 13 - 2022 https://doi.org/10.3389/fneur.2022.889953
  • Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Bmj. 2021; 372 n71. https://doi.org/10.1136/bmj.n71
  • Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019; 366 l4898. https://doi.org/10.1136/bmj.l4898
  • Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011; 64 (4): 383-94. https://doi.org/10.1016/j.jclinepi.2010.04.026
  • Guyatt GH, Oxman AD, Kunz R, Atkins D, Brozek J, Vist G, et al. GRADE guidelines: 2. Framing the question and deciding on important outcomes. J Clin Epidemiol. 2011; 64 (4): 395-400. https://doi.org/10.1016/j.jclinepi.2010.09.012
  • Balshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz R, Brozek J, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol. 2011; 64 (4): 401-6. https://doi.org/10.1016/j.jclinepi.2010.07.015
  • Guyatt GH, Oxman AD, Vist G, Kunz R, Brozek J, Alonso-Coello P, et al. GRADE guidelines: 4. Rating the quality of evidence--study limitations (risk of bias). J Clin Epidemiol. 2011; 64 (4): 407-15. https://doi.org/10.1016/j.jclinepi.2010.07.017
  • Guyatt GH, Oxman AD, Montori V, Vist G, Kunz R, Brozek J, et al. GRADE guidelines: 5. Rating the quality of evidence--publication bias. J Clin Epidemiol. 2011; 64 (12): 1277-82. https://doi.org/10.1016/j.jclinepi.2011.01.011
  • Guyatt GH, Oxman AD, Kunz R, Brozek J, Alonso-Coello P, Rind D, et al. GRADE guidelines 6. Rating the quality of evidence--imprecision. J Clin Epidemiol. 2011; 64 (12): 1283-93. https://doi.org/10.1016/j.jclinepi.2011.01.012
  • Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M, et al. GRADE guidelines: 7. Rating the quality of evidence--inconsistency. J Clin Epidemiol. 2011; 64 (12): 1294-302. https://doi.org/10.1016/j.jclinepi.2011.03.017
  • Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M, et al. GRADE guidelines: 8. Rating the quality of evidence--indirectness. J Clin Epidemiol. 2011; 64 (12): 1303-10. https://doi.org/10.1016/j.jclinepi.2011.04.014
  • Kimberley TJ, Pierce D, Prudente CN, Francisco GE, Yozbatiran N, Smith P, et al. Vagus Nerve Stimulation Paired With Upper Limb Rehabilitation After Chronic Stroke. Stroke. 2018; 49 (11): 2789-92. https://doi.org/10.1161/strokeaha.118.022279
  • Dawson J, Liu CY, Francisco GE, Cramer SC, Wolf SL, Dixit A, et al. Vagus nerve stimulation paired with rehabilitation for upper limb motor function after ischaemic stroke (VNS-REHAB): a randomised, blinded, pivotal, device trial. Lancet. 2021; 397 (10284): 1545-53. https://doi.org/10.1016/s0140-6736(21)00475-x
  • Dawson J, Pierce D, Dixit A, Kimberley TJ, Robertson M, Tarver B, et al. Safety, Feasibility, and Efficacy of Vagus Nerve Stimulation Paired With Upper-Limb Rehabilitation After Ischemic Stroke. Stroke. 2016; 47 (1): 143-50. https://doi.org/10.1161/strokeaha.115.010477
  • Badran BW, Peng X, Baker-Vogel B, Hutchison S, Finetto P, Rishe K, et al. Motor Activated Auricular Vagus Nerve Stimulation as a Potential Neuromodulation Approach for Post-Stroke Motor Rehabilitation: A Pilot Study. Neurorehabil Neural Repair. 2023; 37 (6): 374-83. https://doi.org/10.1177/15459683231173357
  • Capone F, Miccinilli S, Pellegrino G, Zollo L, Simonetti D, Bressi F, et al. Transcutaneous Vagus Nerve Stimulation Combined with Robotic Rehabilitation Improves Upper Limb Function after Stroke. Neural Plast. 2017; 2017 7876507. https://doi.org/10.1155/2017/7876507
  • Wei X. Effect of TaVNS combined with upper limb training on upper limb motor function and brain plasticity of ischemic stroke subjects. Tianjin University of Sport. 2020.
  • Zhang LP, Yu ML, Wang SR, et al. Effect of transcutaneous vagus nerve stimulation on the recovery of upper limbmotorfunctioninpatients with ischemic stroke. Chinese J Rehabil Med. 2020; 35 1316–20.
  • Wu D, Ma J, Zhang L, Wang S, Tan B, Jia G. Effect and Safety of Transcutaneous Auricular Vagus Nerve Stimulation on Recovery of Upper Limb Motor Function in Subacute Ischemic Stroke Patients: A Randomized Pilot Study. Neural Plast. 2020; 2020 8841752. https://doi.org/10.1155/2020/8841752
  • Ierardi E, van Wijck F, Ali M, Best C, Coupar F. Defining Severity Levels for Post-Stroke Upper Limb Motor Impairment and Activity Limitation: A Systematic Review. NeuroRehabilitation. 2026; 58 (1): 3-16. https://doi.org/10.1177/10538135251393516
  • Darrow MJ, Torres M, Sosa MJ, Danaphongse TT, Haider Z, Rennaker RL, et al. Vagus Nerve Stimulation Paired With Rehabilitative Training Enhances Motor Recovery After Bilateral Spinal Cord Injury to Cervical Forelimb Motor Pools. Neurorehabil Neural Repair. 2020; 34 (3): 200-9. https://doi.org/10.1177/1545968319895480
  • Yu M, Wang S. The Effect of Vagus Nerve Stimulation on the Rehabilitation of Stroke: A Systematic Review and Meta-analysis. Arch Phys Med Rehabil. 2026; https://doi.org/10.1016/j.apmr.2026.01.009
  • Ganzer PD, Darrow MJ, Meyers EC, Solorzano BR, Ruiz AD, Robertson NM, et al. Closed-loop neuromodulation restores network connectivity and motor control after spinal cord injury. Elife. 2018; 7 https://doi.org/10.7554/eLife.32058
  • Kilgard MP, Epperson JD, Adehunoluwa EA, Swank C, Porter AL, Pruitt DT, et al. Closed-loop vagus nerve stimulation aids recovery from spinal cord injury. Nature. 2025; 643 (8073): 1030-6. https://doi.org/10.1038/s41586-025-09028-5
  • Sargusingh MJ, Addo JJA, Damaser MS, Zimmern P, Hays SA, Hernandez-Reynoso AG. Enhancing Neuroplasticity via vagus nerve stimulation to improve urinary dysfunction after spinal cord injury: a perspective. Bioelectron Med. 2025; 11 (1): 15. https://doi.org/10.1186/s42234-025-00178-5
  • Gargus M, Ben-Azu B, Landwehr A, Dunn J, Errico JP, Tremblay M. Mechanisms of vagus nerve stimulation for the treatment of neurodevelopmental disorders: a focus on microglia and neuroinflammation. Front Neurosci. 2024; 18 1527842. https://doi.org/10.3389/fnins.2024.1527842
  • Zhao K, Yang J, Huang J, Zhao Z, Qu Y. Effect of vagus nerve stimulation paired with rehabilitation for upper limb function improvement after stroke: a systematic review and meta-analysis of randomized controlled trials. Int J Rehabil Res. 2022; 45 (2): 99-108. https://doi.org/10.1097/mrr.0000000000000509
  • Liu CY, Russin J, Adelson DP, Jenkins A, Hilmi O, Brown B, et al. Vagus nerve stimulation paired with rehabilitation for stroke: Implantation experience from the VNS-REHAB trial. J Clin Neurosci. 2022; 105 122-8. https://doi.org/10.1016/j.jocn.2022.09.013
  • Kimberley TJ, Cramer SC, Wolf SL, Liu C, Gochyyev P, Dawson J, et al. Long-Term Outcomes of Vagus Nerve Stimulation Paired With Upper Extremity Rehabilitation After Stroke. Stroke. 2025; 56 (8): 2255-65. https://doi.org/doi:10.1161/STROKEAHA.124.050479
  • Korupolu R, Miller A, Park A, Yozbatiran N. Neurorehabilitation with vagus nerve stimulation: a systematic review. Front Neurol. 2024; 15 1390217. https://doi.org/10.3389/fneur.2024.1390217
  • Saylor A, Patrick L, Reddy CG, Gandhi R. Vagus Nerve Stimulation Paired With Upper Extremity Rehabilitation for Chronic Stroke: Real-World Implementation and Outcomes. Arch Rehabil Res Clin Transl. 2026; 8 (1): 100580. https://doi.org/10.1016/j.arrct.2025.100580
  • Gao L, Fan Y, Zhang N, Chen L. Transcutaneous Auricular Vagus nerve stimulation paired with exercise training for upper-limb motor function and activities of daily living after stroke: A systematic review and meta-analysis. Archives of Physical Medicine and Rehabilitation. 2026; https://doi.org/https://doi.org/10.1016/j.apmr.2026.03.008
  • Yan L, Qian Y, Li H. Transcutaneous Vagus Nerve Stimulation Combined with Rehabilitation Training in the Intervention of Upper Limb Movement Disorders After Stroke: A Systematic Review. Neuropsychiatr Dis Treat. 2022; 18 2095-106. https://doi.org/10.2147/ndt.S376399