Clinical efficacy and neurophysiological changes associated with combined transcutaneous auricular vagus nerve stimulation and repetitive transcranial magnetic stimulation in chronic insomnia disorder: protocol for a randomised controlled trial

Abstract

Abstract Introduction Chronic insomnia disorder (CID) is a prevalent condition associated with substantial impairment in quality of life and increased risk of comorbidities. Emerging evidence suggests that CID is associated with autonomic dysregulation and cortical hyperarousal, consistent with the hyperarousal model. Neuromodulation techniques, including transcutaneous auricular vagus nerve stimulation (taVNS) and repetitive transcranial magnetic stimulation (rTMS), have shown therapeutic potential. However, most previous studies have focused on single-modality interventions and whether a combined approach provides incremental clinical or neurophysiological benefits remains unclear. This study aims to evaluate the incremental clinical benefit of combined taVNS and rTMS relative to either active component alone and to explore associated neurophysiological changes. Methods and analysis This study is a randomised, double-blind, three-arm parallel-group controlled trial. A total of 90 eligible participants will be randomly assigned to one of three groups: Group A (taVNS+rTMS), Group B (sham taVNS+rTMS) or Group C (taVNS+sham rTMS). The intervention will be administered over 2 weeks (10 sessions) followed by a 12-week follow-up period. The primary outcome is the Pittsburgh Sleep Quality Index (PSQI) assessed post-intervention (T1) and at the 4-week (T2) and 12-week (T3) follow-ups. Secondary outcomes include electroencephalography, functional near-infrared spectroscopy, resting motor threshold, heart rate variability and sleep/daytime function-related scales. A baseline-adjusted mixed model for repeated measures will be used for the longitudinal analysis of PSQI. At the primary efficacy time point (T1), the two prespecified primary treatment contrasts will compare Group A with Group B and Group A with Group C. Ethics and dissemination This study has been approved by the Ethics Committee of Guangdong Provincial Hospital of Chinese Medicine (approval number: ZF2025-268-02). Written informed consent will be obtained from all participants prior to enrolment. The results of this study will be disseminated through peer-reviewed publications and academic conferences. Trial registration ChiCTR2600120955; registered on 23 March 2026.