Effects of Amygdala–Targeted Transcranial Temporal Interference Stimulation on Brain Functional Networks in Major Depressive Disorder

Major depressive disorder (MDD) is a prevalent psychiatric condition with limited treatment efficacy for many patients, underscoring the need for novel neuromodulation strategies. Transcranial temporal interference stimulation (tTIS) offers non-invasive deep-brain targeting, but the underlying brain network mechanisms driving its therapeutic effects in MDD remain unclear. In this unblinded single-arm trial involving 31 MDD patients, we assessed the impact of five daily sessions of right amygdala-targeted tTIS on clinical symptoms and functional brain dynamics. Participants exhibited marked symptom reductions, with 61.3% achieving response post-treatment, largely sustained at 4-week follow-up. Resting-state fMRI disclosed tTIS-induced functional connectivity (FC) reconfiguration, featuring decreased within-default mode network (DMN) connectivity and enhanced DMN integration with visual and attention networks. Critically, therapeutic heterogeneity emerged between responders and non-responders: responders showed persistent DMN decoupling and cross-network enhancements at follow-up, whereas non-responders displayed opposing patterns. High-amplitude co-fluctuation analysis further revealed that acute dynamic shifts in whole-brain activity predicted sustained clinical gains. These results position amygdala-targeted tTIS as a promising MDD intervention and highlight DMN-centric static and dynamic biomarkers for stratifying treatment response.