Effects of transcutaneous auricular vagus nerve stimulation on patients with post-stroke insomnia: a randomized controlled trial protocol.

BACKGROUND: Post-stroke insomnia (PSI) is one of the most common and difficult-to-treat complications following stroke, with a prevalence exceeding 50%, and is an independent risk factor for stroke recurrence and secondary anxiety and depressive disorders. Current first-line strategies, namely sedative-hypnotics and cognitive behavioral therapy for insomnia, are constrained by the risks of tolerance, dependence, and cognitive side effects, as well as by limited medical resources and poor patient adherence. Transcutaneous auricular vagus nerve stimulation (taVNS), a non-invasive neuromodulation technique, has demonstrated therapeutic potential in primary insomnia and post-stroke depression. However, evidence for taVNS in PSI remains limited to a few isolated case reports; high-quality randomized controlled trials are lacking, and its underlying central nervous system mechanisms have not been characterized. This protocol is designed to address these gaps.

METHODS/DESIGN: This single-blind randomized controlled trial will enroll 48 patients with PSI, randomly assigned in a 1:1 ratio to a taVNS group or a sham-taVNS group. Both groups will receive the assigned intervention once daily, five days per week, for four weeks, in addition to standard post-stroke basic treatment. The primary outcomes are multimodal magnetic resonance imaging (MRI) indicators acquired before and after the 4-week intervention, including resting-state functional MRI (amplitude of low-frequency fluctuation, fractional amplitude of low-frequency fluctuation, regional homogeneity, and functional connectivity), three-dimensional T1-weighted structural metrics (gray matter volume, cortical thickness, and cortical surface area), and arterial-spin-labeling cerebral blood flow. The secondary outcomes are clinical efficacy scales, namely the Pittsburgh Sleep Quality Index, the National Institutes of Health Stroke Scale, the Activities of Daily Living scale, the 17-item Hamilton Depression Rating Scale, and the 14-item Hamilton Anxiety Rating Scale, assessed at baseline, week 2, and week 4. Between- and within-group differences will be examined using two-sample and paired t-tests with Gaussian random field correction for imaging data and repeated-measures analysis of variance for clinical data, and Pearson or Spearman correlation analyses will relate neuroimaging changes to clinical improvement.

DISCUSSION: By integrating brain function, brain structure, and cerebral perfusion through multimodal MRI, this study aims to evaluate the clinical efficacy of taVNS in patients with PSI and to elucidate its underlying central nervous system mechanisms. The main limitations are a relatively small sample size and a single-blind design, which may limit the generalizability of the findings and introduce a degree of implementation bias. Nevertheless, the findings will provide evidence-based support for the clinical application of taVNS in PSI and lay the foundation for the development of individualized neuromodulation strategies for post-stroke sleep disorders.

CLINICAL TRIAL REGISTRATION: http://itmctr.ccebtcm.org.cn/, identifier ITMCTR2025002545.