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Efficacy and safety of transcutaneous auricular vagus nerve stimulation for patients with treatment-resistant schizophrenia with predominantly negative symptoms: a randomized clinical trial and efficacy sensitivity biomarkers

Molecular Psychiatry volume 30, pages 5437–5447 (2025)Cite this article

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Abstract

Negative symptoms in treatment-resistant schizophrenia (TRS) are notably persistent and minimally affected by antipsychotics, the transcutaneous auricular vagus nerve stimulation (taVNS) is a promising treatment approach. However, clinical trials are scarce, and further efficacy data are needed. We conducted a double-blind, sham-controlled, randomized clinical trial to determine the efficacy and safety of taVNS as an add-on treatment for patients with TRS with predominantly negative symptoms and to investigate potential biomarkers of efficacy. A total of 50 patients underwent a two-week intervention of active taVNS (n = 25) or sham taVNS (n = 25), followed by a two-week follow-up. Primary outcome was the change in the PANSS-factor score for negative symptoms (PANSS-FSNS) assessed after the intervention. In the intention-to-treat analysis, patients receiving active taVNS showed a significantly greater improvement in negative symptoms compared with those receiving the sham procedure (PANSS-FSNS difference, −1.36; effect size, −0.62; 95% CI, −1.20 to −0.04; p = 0.033), with effects sustained at follow-up and good tolerability. Inflammatory cytokines and EEG coherence showed that in the active group, the change in PANSS-FSNS scores after treatment was significantly correlated with changes in tumour necrosis factor (TNF)-α (r = 0.56, corrected p = 0.017) and beta-band coherence between the left frontal and parietal regions (r = −0.56, p = 0.004), but not in the sham group. This study suggests that taVNS may effectively and safely ameliorate negative symptoms in TRS, with TNF-α and beta-band coherence between the left frontal and parietal regions as potential sensitivity efficacy biomarkers. Chinese Clinical Trial Registry (http://www.chictr.org.cn.), ChiCTR2400085198.

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Fig. 1: CONSORT Participant Flow Diagram.
Fig. 2: Change in PANSS-FSNS.
Fig. 3: Correlation Outcomes.

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Data availability

Study-related data are available from the corresponding author upon reasonable request and with approval from the hospital administration.

Code availability

The statistical analyses were conducted using R (version 4.2.3), and EEG feature extraction was performed using custom scripts written in MATLAB (version 2024a). The code is available from the corresponding author upon reasonable request.

References

  1. Saha S, Chant D, Welham J, McGrath J, Farooq S, Choudry A, et al. A Systematic Review of the Prevalence of Schizophrenia. PLoS Med. 2005;2:e141.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Howes OD, McCutcheon R, Agid O, de Bartolomeis A, van Beveren NJM, Birnbaum ML, et al. Treatment-resistant schizophrenia: treatment response and resistance in psychosis (TRRIP) working group consensus guidelines on diagnosis and terminology. AJP. 2017;174:216–29.

    Article  Google Scholar 

  3. Owen MJ, Sawa A, Mortensen PB. Schizophrenia. The Lancet. 2016;388:86–97.

    Article  Google Scholar 

  4. Sicras-Mainar A, Maurino J, Ruiz-Beato E, Navarro-Artieda R. Impact of negative symptoms on healthcare resource utilization and associated costs in adult outpatients with schizophrenia: a population-based study. BMC Psychiatry. 2014;14:225.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Galderisi S, Mucci A, Buchanan RW, Arango C. Negative symptoms of schizophrenia: new developments and unanswered research questions. Lancet Psychiatry. 2018;5:664–77.

    Article  PubMed  Google Scholar 

  6. McCutcheon RA, Reis Marques T, Howes OD. Schizophrenia—An Overview. JAMA Psychiatry. 2020;77:201.

    Article  PubMed  Google Scholar 

  7. Fusar-Poli P, Papanastasiou E, Stahl D, Rocchetti M, Carpenter W, Shergill S, et al. Treatments of negative symptoms in schizophrenia: meta-analysis of 168 randomized placebo-controlled trials. Schizophr Bull. 2015;41:892–9.

    Article  PubMed  Google Scholar 

  8. Mishra BR, Agrawal K, Biswas T, Mohapatra D, Nath S, Maiti R. Comparison of acute followed by maintenance ECT vs clozapine on psychopathology and regional cerebral blood flow in treatment-resistant schizophrenia: a randomized controlled trial. Schizophr Bull. 2022;48:814–25.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Melzer-Ribeiro DL, Ribeiro Grilli-Tissot MC, Elkis H. ECT versus Sham for clozapine-resistant schizophrenia: A secondary analysis of a pilot study based on PANSS-30 individual items. Brain Stimul. 2020;13:1517–8.

    Article  PubMed  Google Scholar 

  10. Aleman A, Enriquez-Geppert S, Knegtering H, Dlabac-de Lange JJ. Moderate effects of noninvasive brain stimulation of the frontal cortex for improving negative symptoms in schizophrenia: Meta-analysis of controlled trials. Neurosci Biobehav Rev. 2018;89:111–8.

    Article  PubMed  Google Scholar 

  11. Tseng P-T, Zeng B-S, Hung C-M, Liang C-S, Stubbs B, Carvalho AF, et al. Assessment of noninvasive brain stimulation interventions for negative symptoms of schizophrenia: a systematic review and network meta-analysis. JAMA Psychiatry. 2022;79:770–9.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Lindenmayer JP, Kulsa MKC, Sultana T, Kaur A, Yang R, Ljuri I, et al. Transcranial direct-current stimulation in ultra-treatment-resistant schizophrenia. Brain Stimul. 2019;12:54–61.

    Article  CAS  PubMed  Google Scholar 

  13. Tuppurainen H, Määttä S, Könönen M, Julkunen P, Kautiainen H, Hyvärinen S, et al. Navigated and individual α-peak-frequency–guided transcranial magnetic stimulation in male patients with treatment-refractory schizophrenia. JPN. 2024;49:E87–E95.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Loo CK, Katalinic N, Smith DJ, Ingram A, Dowling N, Martin D, et al. A Randomized controlled trial of brief and ultrabrief pulse right unilateral electroconvulsive therapy. Int J Neuropsychopharmacol. 2014;18:pyu045.

    PubMed  PubMed Central  Google Scholar 

  15. Nettekoven C, Volz LJ, Leimbach M, Pool E-M, Rehme AK, Eickhoff SB, et al. Inter-individual variability in cortical excitability and motor network connectivity following multiple blocks of rTMS. Neuroimage. 2015;118:209.

    Article  PubMed  Google Scholar 

  16. Gianlorenco ACL, De Melo PS, Marduy A, Kim AY, Kim CK, Choi H, et al. Electroencephalographic Patterns in taVNS: A Systematic Review. Biomedicines. 2022;10:2208.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Gerez M, Tello A. Selected quantitative EEG (QEEG) and event-related potential (ERP) variables as discriminators for positive and negative schizophrenia. Biol Psychiatry. 1995;38:34–49.

    Article  CAS  PubMed  Google Scholar 

  18. Hudgens-Haney ME, Clementz BA, Ivleva EI, Keshavan MS, Pearlson GD, Gershon ES, et al. Cognitive impairment and diminished neural responses constitute a biomarker signature of negative symptoms in psychosis. Schizophr Bull. 2020;46:1269–81.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Sharaev MG, Malashenkova IK, Maslennikova AV, Zakharova NV, Bernstein AV, Burnaev EV, et al. Diagnosis of schizophrenia based on the data of various modalities: biomarkers and machine learning techniques (Review). Sovrem Tekhnologii Med. 2022;14:53–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Koopman FA, Chavan SS, Miljko S, Grazio S, Sokolovic S, Schuurman PR, et al. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc Natl Acad Sci USA. 2016;113:8284–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405:458–62.

    Article  CAS  PubMed  Google Scholar 

  22. Fox D. The shock tactics set to shake up immunology. Nature. 2017;545:20–22.

    Article  CAS  PubMed  Google Scholar 

  23. Lin A, Kenis G, Bignotti S, Tura G-J-B, De Jong R, Bosmans E, et al. The inflammatory response system in treatment-resistant schizophrenia: increased serum interleukin-6. Schizophr Res. 1998;32:9–15.

    Article  CAS  PubMed  Google Scholar 

  24. Goldsmith DR, Haroon E, Miller AH, Strauss GP, Buckley PF, Miller BJ. TNF-α and IL-6 are associated with the deficit syndrome and negative symptoms in patients with chronic schizophrenia. Schizophr Res. 2018;199:281.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Halstead S, Siskind D, Amft M, Wagner E, Yakimov V, Shih-Jung Liu Z, et al. Alteration patterns of peripheral concentrations of cytokines and associated inflammatory proteins in acute and chronic stages of schizophrenia: a systematic review and network meta-analysis. The Lancet Psychiatry. 2023;10:260–71.

    Article  PubMed  Google Scholar 

  26. Mondelli V, Ciufolini S, Belvederi Murri M, Bonaccorso S, Di Forti M, Giordano A, et al. Cortisol and inflammatory biomarkers predict poor treatment response in first episode psychosis. SCHBUL. 2015;41:1162–70.

    Article  Google Scholar 

  27. Goldsmith DR, Rapaport MH. Inflammation and negative symptoms of Schizophrenia: implications for reward processing and motivational deficits. Front Psychiatry. 2020;11:46.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Goldsmith DR, Massa N, Pearce BD, Wommack EC, Alrohaibani A, Goel N, et al. Inflammatory markers are associated with psychomotor slowing in patients with schizophrenia compared to healthy controls. NPJ Schizophr. 2020;6:8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Tan C, Qiao M, Ma Y, Luo Y, Fang J, Yang Y. The efficacy and safety of transcutaneous auricular vagus nerve stimulation in the treatment of depressive disorder: a systematic review and meta-analysis of randomized controlled trials. J Affect Disord. 2023;337:37–49.

    Article  PubMed  Google Scholar 

  30. Colle R, Ait Tayeb AEK, Delhay L, Boniface B, Gasnier M, Martin S, et al. Efficacy and safety of adjunctive vagus nerve stimulation in the treatment of resistant depression with psychotic features: a case report. Brain Stimul. 2021;14:498–9.

    Article  PubMed  Google Scholar 

  31. Wagner E, Kane JM, Correll CU, Howes O, Siskind D, Honer WG, et al. Clozapine combination and augmentation strategies in patients with schizophrenia —recommendations from an international expert survey among the treatment response and resistance in psychosis (TRRIP) working group. Schizophr Bull. 2020;46:1459–70.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Association WM. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310:2191–4.

    Article  Google Scholar 

  33. Leucht S, Barabássy Á, Laszlovszky I, Szatmári B, Acsai K, Szalai E, et al. Linking PANSS negative symptom scores with the Clinical Global Impressions Scale: understanding negative symptom scores in schizophrenia. Neuropsychopharmacol. 2019;44:1589–96.

    Article  Google Scholar 

  34. Addington D, Addington J, Maticka-tyndale E. Assessing depression in schizophrenia: the calgary depression scale. Br J Psychiatry. 1993;163:39–44.

    Article  Google Scholar 

  35. Parente J, Carolyna Gianlorenco A, Rebello-Sanchez I, Kim M, Mario Prati J, Kyung Kim C, et al. Neural, anti-inflammatory, and clinical effects of transauricular vagus nerve stimulation in major depressive disorder: a systematic review. Int J Neuropsychopharmacol. 2023;27:pyad058.

    Article  PubMed Central  Google Scholar 

  36. Tian Q-Q, Cheng C, Yin Z-X, Yuan Y-Y, Wang C, Zeng X, et al. Combined transcutaneous auricular vagus stimulation (taVNS) with 0.1Hz slow breathing enhances insomnia treatment efficacy: A pilot study. Brain Stimul. 2024;17:4–6.

    Article  PubMed  Google Scholar 

  37. Sun J-B, Tian Q-Q, Yang X-J, Deng H, Li N, Meng L-X, et al. Synergistic effects of simultaneous transcranial direct current stimulation (tDCS) and transcutaneous auricular vagus nerve stimulation (taVNS) on the brain responses. Brain Stimul. 2021;14:417–9.

    Article  PubMed  Google Scholar 

  38. Shi X, Zhao L, Luo H, Deng H, Wang X, Ren G, et al. Transcutaneous auricular vagal nerve stimulation is effective for the treatment of functional dyspepsia: a multicenter, randomized controlled study. Am J Gastroenterol. 2024;119:521–31.

    Article  CAS  PubMed  Google Scholar 

  39. Sun J-B, Cheng C, Tian Q-Q, Yuan H, Yang X-J, Deng H, et al. Transcutaneous auricular vagus nerve stimulation improves spatial working memory in healthy young adults. Front Neurosci. 2021;15:790793.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Shen L-L, Sun J-B, Yang X-J, Deng H, Qin W, Du M-Y, et al. Reassessment of the effect of transcutaneous auricular vagus nerve stimulation using a novel burst paradigm on cardiac autonomic function in healthy young adults. Neuromodulation. 2022;25:433–42.

    Article  PubMed  Google Scholar 

  41. Zhao R, He Z-Y, Cheng C, Tian Q-Q, Cui Y-P, Chang M-Y, et al. Assessing the effect of simultaneous combining of transcranial direct current stimulation and transcutaneous auricular vagus nerve stimulation on the improvement of working memory performance in healthy individuals. Front Neurosci. 2022;16:947236.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Zhao R, Chang M-Y, Cheng C, Tian Q-Q, Yang X-J, Du M-Y, et al. Transcutaneous auricular vagus stimulation (taVNS) improves human working memory performance under sleep deprivation stress. Behav Brain Res. 2023;439:114247.

    Article  PubMed  Google Scholar 

  43. Tian Q-Q, Cheng C, Liu P-H, Yin Z-X, Zhang M-K, Cui Y-P, et al. Combined effect of transcutaneous auricular vagus nerve stimulation and 0.1 Hz slow-paced breathing on working memory. Front Neurosci. 2023;17:1133964.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Evensen K, Jørgensen MB, Sabers A, Martiny K. Transcutaneous vagal nerve stimulation in treatment-resistant depression: a feasibility study. Neuromodulation. 2022;25:443–9.

    Article  PubMed  Google Scholar 

  45. Kaczmarczyk M, Antosik-Wójcińska A, Dominiak M, Święcicki. Use of transcutaneous auricular vagus nerve stimulation (taVNS) in the treatment of drug-resistant depression - a pilot study, presentation of five clinical cases. Psychiatr Pol. 2021;55:555–64.

    Article  PubMed  Google Scholar 

  46. Frangos E, Ellrich J, Komisaruk BR. Non-invasive access to the vagus nerve central projections via electrical stimulation of the external ear: fMRI evidence in humans. Brain Stimul. 2015;8:624–36.

    Article  PubMed  Google Scholar 

  47. Andreasen NC. The Scale for the Assessment of Negative Symptoms (SANS): conceptual and theoretical foundations. Br J Psychiatry Suppl. 1989;4:49–58.

  48. Pinna F, Deriu L, Diana E, Perra V, Randaccio RP, Sanna L, et al. Clinical Global Impression-severity score as a reliable measure for routine evaluation of remission in schizophrenia and schizoaffective disorders. Ann Gen Psychiatry. 2015;14:6.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Addington D, Addington J, Matickatyndale E. Specificity of the calgary depression scale for schizophrenics. Schizophr Res. 1994;11:239–44.

    Article  CAS  PubMed  Google Scholar 

  50. Wobrock T, Guse B, Cordes J, Wölwer W, Winterer G, Gaebel W, et al. Left Prefrontal high-frequency repetitive transcranial magnetic stimulation for the treatment of schizophrenia with predominant negative symptoms: a sham-controlled, randomized multicenter trial. Biol Psychiatry. 2015;77:979–88.

    Article  PubMed  Google Scholar 

  51. Delorme A, Makeig S. EEGLAB: an open source toolbox for analysis of single-trial EEG dynamics including independent component analysis. J Neurosci Methods. 2004;134:9–21.

    Article  PubMed  Google Scholar 

  52. Faul F, Erdfelder E, Lang A-G, Buchner A. G*Power 3: A flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 2007;39:175–91.

    Article  PubMed  Google Scholar 

  53. Niknian M. Permutation tests: a practical guide to resampling methods for testing hypotheses. Technometrics. 1995;37:341–2.

    Article  Google Scholar 

  54. Ludbrook J, Dudley H. Why permutation tests are superior to t and F tests in biomedical research. Am Stat. 1998;52:127–32.

    Google Scholar 

  55. Buuren SV, Groothuis-Oudshoorn K. mice: Multivariate Imputation by Chained Equations in R. J Stat Soft. 2011;45:1–67.

  56. Pesarin F, Salmaso L. Permutation Tests for Complex Data: Theory, Applications and Software. John Wiley & Sons; 2010.

    Book  Google Scholar 

  57. Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing - Benjamini - 1995 - Journal of the Royal Statistical Society: Series B (Methodological) - Wiley Online Library. https://rss.onlinelibrary.wiley.com/doi/abs/10.1111/j.2517-6161.1995.tb02031.x. Accessed 10 November 2024.

  58. Leucht S, Priller J, Davis JM. Antipsychotic drugs: a concise review of history, classification, indications, mechanism, efficacy, side effects, dosing, and clinical application. Am J Psychiatry. 2024;181:865–78.

    Article  PubMed  Google Scholar 

  59. Hasan A, Wolff-Menzler C, Pfeiffer S, Falkai P, Weidinger E, Jobst A, et al. Transcutaneous noninvasive vagus nerve stimulation (tVNS) in the treatment of schizophrenia: a bicentric randomized controlled pilot study. Eur Arch Psychiatry Clin Neurosci. 2015;265:589–600.

    Article  PubMed  Google Scholar 

  60. Kirkpatrick B, Fenton WS, Carpenter WT, Marder SR. The NIMH-MATRICS consensus statement on negative symptoms. Schizophr Bull. 2006;32:214–9.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Furukawa TA, Levine SZ, Tanaka S, Goldberg Y, Samara M, Davis JM, et al. Initial severity of schizophrenia and efficacy of antipsychotics: participant-level meta-analysis of 6 placebo-controlled studies. JAMA Psychiatry. 2015;72:14.

    Article  PubMed  Google Scholar 

  62. Lieslehto J, Tiihonen J, Lähteenvuo M, Tanskanen A, Taipale H. Primary nonadherence to antipsychotic treatment among persons with schizophrenia. Schizophr Bull. 2022;48:655–63.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Perez SM, Carreno FR, Frazer A, Lodge DJ. Vagal nerve stimulation reverses aberrant dopamine system function in the methylazoxymethanol acetate rodent model of schizophrenia. J Neurosci. 2014;34:9261–7.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Kane JM. Tools to assess negative symptoms in schizophrenia. J Clin Psychiatry. 2013;74:e12.

    Article  PubMed  Google Scholar 

  65. Rabany L, Weiser M, Werbeloff N, Levkovitz Y. Assessment of negative symptoms and depression in schizophrenia: revision of the SANS and how it relates to the PANSS and CDSS. Schizophr Res. 2011;126:226–30.

    Article  PubMed  Google Scholar 

  66. Marder SR, Kirkpatrick B. Defining and measuring negative symptoms of schizophrenia in clinical trials. Eur Neuropsychopharmacol. 2014;24:737–43.

    Article  CAS  PubMed  Google Scholar 

  67. Chang C-C, Kao Y-C, Chao C-Y, Tzeng N-S, Chang H-A, Corripio I, et al. Deep brain stimulation in treatment resistant schizophrenia: a pilot randomized cross-over clinical trial. EBioMedicine. 2020;51:102568.

    Article  Google Scholar 

  68. Kayo M, Scemes S, Savoia MG, Bichuette A, Abreu AC, Da Silva EP, et al. A randomized controlled trial of social skills training for patients with treatment-resistant schizophrenia with predominantly negative symptoms. Psychiatry Res. 2020;287:112914.

    Article  PubMed  Google Scholar 

  69. Valiengo LDCL, Goerigk S, Gordon PC, Padberg F, Serpa MH, Koebe S, et al. Efficacy and safety of transcranial direct current stimulation for treating negative symptoms in schizophrenia. JAMA Psychiatry. 2020;77:121–9.

    Article  PubMed  Google Scholar 

  70. Howes O, Fusar-Poli P, Osugo M. Treating negative symptoms of schizophrenia: current approaches and future perspectives. Br J Psychiatry. 2023;223:332–5.

    Article  PubMed  Google Scholar 

  71. Salazar de Pablo G, Besana F, Arienti V, Catalan A, Vaquerizo-Serrano J, Cabras A, et al. Longitudinal outcome of attenuated positive symptoms, negative symptoms, functioning and remission in people at clinical high risk for psychosis: a meta-analysis. EClinicalMedicine. 2021;36:100909.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Huston JM, Ochani M, Rosas-Ballina M, Liao H, Ochani K, Pavlov VA, et al. Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis. J Exp Med. 2006;203:1623–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Rosas-Ballina M, Ochani M, Parrish WR, Ochani K, Harris YT, Huston JM, et al. Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia. Proc Natl Acad Sci USA. 2008;105:11008–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Olofsson PS, Levine YA, Caravaca A, Chavan SS, Pavlov VA, Faltys M, et al. Single-pulse and unidirectional electrical activation of the cervical vagus nerve reduces tumor necrosis factor in endotoxemia. Bioelectron Med. 2015;2:37–42.

    Article  Google Scholar 

  75. Goldsmith DR, Bekhbat M, Mehta ND, Felger JC. Inflammation-related functional and structural dysconnectivity as a pathway to psychopathology. Biol Psychiatry. 2023;93:405–18.

    Article  CAS  PubMed  Google Scholar 

  76. Krynicki CR, Dazzan P, Pariante CM, Barnes NM, Vincent RC, Roberts A, et al. Deconstructing depression and negative symptoms of schizophrenia; differential and longitudinal immune correlates, and response to minocycline treatment. Brain Behav Immun. 2021;91:498–504.

    Article  CAS  PubMed  Google Scholar 

  77. Miller AH, Haroon E, Felger JC. Therapeutic implications of brain-immune interactions: treatment in translation. Neuropsychopharmacology. 2017;42:334–59.

    Article  CAS  PubMed  Google Scholar 

  78. Ogyu K, Matsushita K, Honda S, Wada M, Tamura S, Takenouchi K, et al. Decrease in gamma-band auditory steady-state response in patients with treatment-resistant schizophrenia. Schizophr Res. 2023;252:129–37.

    Article  CAS  PubMed  Google Scholar 

  79. Nucifora FC, Woznica E, Lee BJ, Cascella N, Sawa A. Treatment resistant schizophrenia: Clinical, biological, and therapeutic perspectives. Neurobiol Dis. 2019;131:104257.

    Article  PubMed  Google Scholar 

  80. Molent C, Olivo D, Wolf RC, Balestrieri M, Sambataro F. Functional neuroimaging in treatment resistant schizophrenia: a systematic review. Neurosci Biobehav Rev. 2019;104:178–90.

    Article  PubMed  Google Scholar 

  81. Takahashi T, Goto T, Nobukawa S, Tanaka Y, Kikuchi M, Higashima M, et al. Abnormal functional connectivity of high-frequency rhythms in drug-naïve schizophrenia. Clin Neurophysiol. 2018;129:222–31.

    Article  PubMed  Google Scholar 

  82. MacKay M-AB, Paylor JW, Wong JTF, Winship IR, Baker GB, Dursun SM. Multidimensional connectomics and treatment-resistant schizophrenia: linking phenotypic circuits to targeted therapeutics. Front Psychiatry. 2018;9:537.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Higashima M, Takeda T, Kikuchi M, Nagasawa T, Koshino Y. Functional connectivity between hemispheres and schizophrenic symptoms: a longitudinal study of interhemispheric EEG coherence in patients with acute exacerbations of schizophrenia. Clin EEG Neurosci. 2006;37:10–15.

    Article  PubMed  Google Scholar 

  84. Keatch C, Lambert E, Kameneva T, Woods W. Functional connectivity analysis of transcutaneous vagus nerve stimulation (tVNS) using magnetoencephalography (MEG). IEEE Trans Neural Syst Rehabil Eng. 2023;31:3630–40.

    Article  PubMed  Google Scholar 

  85. Zhang Y, Lin P, Wang R, Zhou J, Xu X, Jiang W, et al. Insula-medial prefrontal cortex functional connectivity modulated by transcutaneous auricular vagus nerve stimulation: an fMRI study. IEEE J Biomed Health Inform. 2024;28:5962–70.

    Article  PubMed  Google Scholar 

  86. Poppa T, Benschop L, Horczak P, Vanderhasselt M-A, Carrette E, Bechara A, et al. Auricular transcutaneous vagus nerve stimulation modulates the heart-evoked potential. Brain Stimul. 2022;15:260–9.

    Article  PubMed  Google Scholar 

  87. Engelen T, Solcà M, Tallon-Baudry C. Interoceptive rhythms in the brain. Nat Neurosci. 2023;26:1670–84.

    Article  CAS  PubMed  Google Scholar 

  88. Ferstl M, Teckentrup V, Lin WM, Kräutlein F, Kühnel A, Klaus J, et al. Non-invasive vagus nerve stimulation boosts mood recovery after effort exertion. Psychol Med. 2022;52:3029–39.

    Article  PubMed  Google Scholar 

  89. Ventura-Bort C, Weymar M. Transcutaneous auricular vagus nerve stimulation modulates the processing of interoceptive prediction error signals and their role in allostatic regulation. Hum Brain Mapp. 2024;45:e26613.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Kraus T, Kiess O, Hösl K, Terekhin P, Kornhuber J, Forster C. CNS BOLD fMRI effects of sham-controlled transcutaneous electrical nerve stimulation in the left outer auditory canal – a pilot study. Brain Stimul. 2013;6:798–804.

    Article  PubMed  Google Scholar 

  91. Andreasen NC, O’Leary DS, Flaum M, Nopoulos P, Watkins GL, Ponto LLB, et al. Hypofrontality in schizophrenia: distributed dysfunctional circuits in neuroleptic-naïve patients. The Lancet. 1997;349:1730–4.

    Article  CAS  Google Scholar 

  92. Shukla DK, Chiappelli JJ, Sampath H, Kochunov P, Hare SM, Wisner K, et al. Aberrant frontostriatal connectivity in negative symptoms of schizophrenia. Schizophr Bull. 2019;45:1051–9.

    Article  PubMed  Google Scholar 

  93. Sheffield JM, Huang AS, Rogers BP, Blackford JU, Heckers S, Woodward ND. Insula sub-regions across the psychosis spectrum: morphology and clinical correlates. Transl Psychiatry. 2021;11:346.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Burke MJ, Kaptchuk TJ, Pascual-Leone A. Challenges of differential placebo effects in contemporary medicine: the example of brain stimulation. Ann Neurol. 2019;85:12–20.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The present study was partly funded by the Xidian University Specially Funded Project for Interdisciplinary Exploration (grant number TZJH2024014), which is gratefully acknowledged. We thank all research assistants, physicians, and nursing staffs at Kunming Psychiatric Hospital for their assistance during the study process, as well as the technicians in the EEG room, who performed the EEG collection, without whom this work could have been possible. We are also grateful to Yixuan Wu, Yu Tao and Hao Jing for their valuable support during the early stages of the project.

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Authors and Affiliations

  1. Engineering Research Center of Molecular and Neuro Imaging of the Ministry of Education, School of Life Science and Technology, Xidian University, Xian, 710126, China

    Yapeng Cui, Jinbo Sun, Yangyang Yuan, Fang He & Wei Qin

  2. Wearable BCI and Intelligent Rehabilitation Innovation Lab, Guangzhou Institute of Technology, Xidian University, Xian, 710126, China

    Jinbo Sun, Jianan Wang, Qianqian Tian & Wei Qin

  3. Kunming Mental Hospital, Kunming, 650000, China

    Bingkui Zhang, Taipin Guo, Zhiqin Li, Ying Chen, Mingbing Su, Dongniya Wu, Jingxia Wu, Qian Wang, Lei Wu, Xinghua Li & Yi Gong

  4. School of Second Clinical Medicine/The Second Affiliated Hospital, Yunnan University of Chinese Medicine, Kunming, 650500, China

    Taipin Guo & Shumin Zhang

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Contributions

JB.S, Y.G, and W.Q contributed to conceptualization and methodology; BK.Z, TP.G, SM.Z, ZQ.L, Y.C, MB.S, DNY.W, JX.W, and Q.W contributed to collect the clinical data or implement the interventions; JN.W, L.W, and XH.L contributed to collate the clinical data; YP.C, YY.Y, and F.H contributed to formal analysis and visualization of clinical trial data; QQ.T contributed to write the intervention program; YP.C and F.H contributed to writing the original draft; JB.S contributed to revised drafts. All authors contributed to review and editing of the final manuscript.

Corresponding authors

Correspondence to Jinbo Sun, Yi Gong or Wei Qin.

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Competing interests

The authors declare no competing interests.

Ethics approval

This study was performed in accordance with the Declaration of Helsinki and was approved by the Kunming Psychiatric Hospital in China Review Board. Informed consent was provided by all of the participants.

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Cui, Y., Sun, J., Zhang, B. et al. Efficacy and safety of transcutaneous auricular vagus nerve stimulation for patients with treatment-resistant schizophrenia with predominantly negative symptoms: a randomized clinical trial and efficacy sensitivity biomarkers. Mol Psychiatry 30, 5437–5447 (2025). https://doi.org/10.1038/s41380-025-03132-8

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