Microstructural Changes and Treatment Response Predictors for Two‐Day Accelerated iTBS in Adolescents With Major Depressive Disorder: A DTI Study

Background Adolescents with major depressive disorder (aMDD) face unique treatment challenges, as conventional multiweek repetitive transcranial magnetic stimulation protocols may conflict with academic and developmental demands. Accelerated intermittent theta burst stimulation (aiTBS) offers a time‐efficient alternative with potential for rapid symptom relief. This exploratory study investigated the clinical and microstructural effects of a 2‐day aiTBS protocol in aMDD and explored potential neuroimaging predictors of treatment response. Methods Thirty‐two aMDD patients underwent diffusion tensor imaging before and after aiTBS, while 34 healthy controls (HCs) were scanned at baseline. Clinical effects were assessed using the Montgomery–Åsberg Depression Rating Scale (MADRS). Diffusion metrics were derived using a combined method approach integrating tract‐based spatial statistics and atlas‐based region‐of‐interest extraction. Group differences and longitudinal changes in diffusion metrics were analyzed, and partial correlations were performed to explore associations with clinical improvement. Ridge regression with cross‐validation was employed to predict treatment response. Results Following aiTBS, MADRS scores decreased in the aMDD group, accompanied by an increase in fractional anisotropy in the left tapetum. Compared with HCs, the pre‐aiTBS aMDD group showed decreased mean diffusivity and axial diffusivity in the right external capsule, as well as decreased radial diffusivity in the right superior fronto‐occipital fasciculus. These alterations were partially restored to levels comparable with HCs following aiTBS. Moreover, changes in diffusion metrics within motor‐related, prefrontal‐limbic, and prefrontal‐occipital tracts were associated with clinical improvement. Baseline diffusion metrics in sensorimotor integration, prefrontal‐limbic, and prefrontal‐occipital tracts tentatively predicted treatment response. Conclusions These findings provide preliminary evidence that a 2‐day aiTBS protocol may be a feasible and time‐efficient intervention, with associated symptom improvement in aMDD. Our results support a tentative neurobiological model in which aiTBS may enhance top‐down regulation through prefrontal‐limbic and prefrontal‐occipital circuits to exert clinical effects.