Temporal interference stimulation (TIS) for major depressive disorder: right lingual gyrus as a predictor

Temporal interference stimulation (TIS) enables selective modulation of deep-brain targets without cortical activation, yet its therapeutic utility in major depressive disorder (MDD) remains unknown. Therefore, this multicenter, randomized controlled trial evaluated right-amygdala targeted TIS for MDD and identified predictors of treatment response.

This study was a secondary analysis of a multicenter, randomized, double-blind, sham-controlled trial. Seventy-six MDD patients were enrolled across Tianjin Anding Hospital and Shanghai Ruijin Hospital and randomly assigned in a 1:1 ratio to active or sham groups. Resting-state functional MRI (rs-fMRI) and 17-item Hamilton Depression Rating Scale (HDRS-17) assessments were obtained at baseline, and clinical outcomes were evaluated at weeks 3 and 8. Within the active group, patients were categorized as responders or nonresponders based on week-8 HDRS-17 outcomes. Baseline amplitude of low-frequency fluctuations (ALFF) was compared between groups using two-sample t-tests. Associations between the identified regions and symptom improvement were examined using partial correlations. Logistic regression and ROC analyses were used to evaluate the predictive value of baseline ALFF measures for treatment response. The study was registered with ClinicalTrials.gov, NCT06477276.

14 patients (44%) responded to active TIS. Responders showed significantly lower baseline ALFF in the right lingual gyrus (GRF voxel p < 0.001, cluster p < 0.05, one-tailed). Right lingual gyrus ALFF was negatively correlated with HDRS-17 improvement (r = -0.696, p < 0.001). Logistic regression confirmed its predictive value (Model 1: OR = 0.016, 95% CI = 0.000 to 0.915, p = 0.045; Model 2 adjusted for age: OR = 0.000, 95% CI = 0.000 to 0.125, p = 0.011). ROC analysis yielded an AUC of 0.714 (p = 0.040, 95% CI = 0.550 to 0.893).

Right-amygdala TIS improves depressive symptoms, and lower baseline right lingual gyrus ALFF emerged as a promising biomarker for predicting response.