Predicting treatment response to transcutaneous auricular vagus nerve stimulation in patients with insomnia: resting-state functional connectivity based multivoxel pattern analysis

The salience network, with the insula as its central hub, plays a pivotal role in the pathophysiology of primary insomnia (PI). Transcutaneous auricular vagus nerve stimulation (taVNS) shows therapeutic potential, its neural mechanisms and predictive biomarkers remain uncharacterized. In a double-blind trial, 67 PI patients (taVNS = 34, sham = 33) underwent clinical assessments and resting-state fMRI at baseline and after 4-week treatment. We analyzed:1)Treatment-induced changes in bilateral insula-cortical functional connectivity (FC); 2)Predictive value of baseline FC using support vector regression. TaVNS group showed significantly improved clinical assessment compared with staVNS. Decreased rs-FCs were found between the left insula and areas involved in DMN(superior parietal gyrus, SPG), Visual/Auditory (superior occipital gyrus, SOG; middle occipital gyrus, MOG; calcarine and middle temporal gyrus, MTG) and cingulo-opercular network(middle frontal gyrus, MFG and cerebellum).In addition, decreased FC between left insula and left cerebellum correlated negatively with sleep disturbances score improvement (r = -0.502, p = 0.006, Bonferroni correction), while decreased FC between left insula and right SOG positively with sleep latency score (r = 0.391, p = 0.040,uncorrection). Baseline left insula-visual/auditory circuit FC can predicte taVNS treatment response in PI (r = 0.534, p = 0.002, 5000 permutation test). TaVNS may alleviate PI symptoms by reducing FCs between the salience and task-positive networks and within the cingulo-opercular network to reduce visual-related overactivity and hypervigilance.The baseline functional connectivity in the left insula-visual/auditory circuit could act as a candidate biomarker for predicting taVNS treatment response, which enable the screen of therapy-responsive insomnia patients before treatment. Chinese Clinical Trial Registry (ChiCTR 1900022535, 2019-04-16).