Bilateral repetitive transcranial magnetic stimulation modulates the hemispheric imbalance in major depressive disorder

ABSTRACT Background Major depressive disorder (MDD) is characterised by interhemispheric functional imbalance, yet the neuromodulatory mechanisms underlying its correction remain poorly understood. Repetitive transcranial magnetic stimulation (rTMS) has shown promise in restoring hemispheric balance, but evidence regarding its effects on alpha‐band functional connectivity (FC) is limited. Aims This randomised, two‐arm controlled trial aims to elucidate the neural mechanisms by which bilateral rTMS ameliorates interhemispheric functional imbalance in patients with MDD by reducing alpha‐band functional hyperconnectivity in the left hemisphere. Methods Fifty‐two patients with MDD were randomised to active ( n = 31) or sham ( n = 21) bilateral rTMS targeting the dorsolateral prefrontal cortex (dlPFC). Active stimulation involved 20 Hz over the left dlPFC and 1 Hz over the right dlPFC. Participants underwent emotional attention network task testing with simultaneous electroencephalography recording before and after 10 sessions of rTMS. Phase slope index (PSI) was used to quantify directional FC in the alpha band (8–13 Hz). Clinical symptoms and behavioural performance were also assessed. Results Active rTMS significantly improved sleep quality (PSQI, F = 5.52, p = 0.023) and reduced reaction times under both congruent and incongruent emotional conditions (−in−: t = −2.23, p = 0.031, +in−: t = −2.01, p = 0.05). Alpha‐band FC analysis revealed decreased left hemispheric hyperconnectivity in the active group, particularly in the occipital, left temporoparietal and left frontocentral regions ( t ranging from 2.42 to 3.65, all p = 0.038). The sham group showed placebo‐driven improvements in subjective mood but no significant FC changes. Conclusions Bilateral rTMS modulates interhemispheric imbalance in patients with MDD by reducing pathological alpha‐band FC in left hemispheric regions, which is correlated with improved emotional processing and attentional performance. These findings support the use of alpha‐band FC as a biomarker for rTMS efficacy and highlight the potential of network‐targeted stimulation protocols for the individualised treatment of MDD.