Large-scale brain network modulation by auricular vagus neuromodulation in major depressive disorder: a systematic review of neuroimaging evidence.

Background: Auricular vagus neuromodulation, encompassing transcutaneous auricular vagus nerve stimulation (taVNS) and transcutaneous electrical cranial-auricular acupoint stimulation (TECAS), is an emerging noninvasive intervention for major depressive disorder (MDD). Neuroimaging studies of its central effects have expanded rapidly, yet findings remain dispersed across heterogeneous designs and have not been integrated at the cohort level. Methods: We followed PRISMA 2020 guidelines and searched five databases (PubMed/MEDLINE, Embase, Cochrane CENTRAL, Web of Science Core Collection, and PsycINFO) from inception to June 30, 2026; only English-language reports were included. Two reviewers independently screened records, extracted effect-level data, and appraised methodological quality using the 2024 JBI tool for quasi-experimental studies. Reports from the same cohort were identified via trial registrations, and denominators were counted once per cohort. Findings were stratified by five imaging paradigms and synthesized via cohort-level vote-counting, with null effects reported alongside positive findings. Results: Seventeen neuroimaging reports arose from nine independent cohorts (321 enrolled patients with MDD, 293 in imaging analyses, 144 healthy controls). The most reproducible finding was bidirectional normalization in striatal-cortical reward-circuit regions across four cohorts, qualified by null nucleus accumbens and putamen seed findings in one cohort. Default-mode-network regions were implicated in seven of nine cohorts, with heterogeneous directions. The only anterior insula effect surviving between-group correction was confined to an acute stimulation-state paradigm, and stimulation-state connectivity changes were frequency-band-specific. Twenty-seven of the coded effects were explicitly null. The sole machine-learning model (AUC = 0.856) was evaluated only by internal cross-validation. Quality appraisal rated two reports high, fourteen moderate, and one low. Conclusion: The evidence remains strictly hypothesis-generating: auricular vagus neuromodulation is accompanied by distributed treatment-associated brain changes, but establishes neither causal pathways nor clinically actionable imaging markers. Confirmatory multi-center, sham-controlled trials with preregistered imaging endpoints, harmonized stimulation parameters, explicit null-result reporting, and independent external validation are needed. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD420261421762, identifier CRD420261421762.