Neural Response to Theta‐Burst Stimulation Predicts Long‐Term Relapse in Patients With Alcohol Use Disorder: A Pilot fMRI Study

Alcohol use disorder (AUD) is characterized by high relapse rates, and relapse is often driven by cue-induced cravings linked to prefrontal-subcortical network dysregulation. This study investigated the neurobiological effects of inhibitory continuous theta-burst stimulation (cTBS) targeting the right dorsolateral prefrontal cortex (rDLPFC) in patients with AUD. In a randomized, double-blind, sham-controlled trial, 28 patients (16 in the active cTBS group and 12 patients in the sham group) underwent 10 sessions of rDLPFC-cTBS. fMRI was performed before and after intervention to assess neural responses to alcohol cues, and relapse was monitored for 1 year. The active cTBS group exhibited a significantly lower relapse risk over the 12-month follow-up compared to the sham group (HR = 0.210, 95% CI [0.070, 0.633]). A significant group-by-intervention interaction was found in the right superior frontal gyrus (p = 0.047); active cTBS prevented the cue-induced hyperactivity that was observed in the sham group, suggesting a network stabilization effect. Furthermore, a machine learning model that was trained on intervention-induced changes in brain-wide neural activity accurately predicted long-term relapse (accuracy: 78.7%; AUC: 0.903). Increased postintervention reactivity to cues in the left medial prefrontal cortex was the strongest predictor of relapse. These findings demonstrate that rDLPFC-cTBS modulates craving-related circuits and that the dynamic neural response to treatment is a powerful biomarker for predicting relapse; the findings pave the way for the development of personalized addiction medicine.