Microstructural changes in prefrontal-cingulate networks following bilateral dorsomedial prefrontal cortex-targeted...

Intermittent theta-burst stimulation (iTBS) is a transcranial magnetic stimulation protocol used in treatment-resistant depression (TRD), yet its effects on brain structural connectivity remain incompletely understood. The dorsomedial prefrontal cortex (dmPFC), a key node within emotion regulation networks, has emerged as a promising therapeutic target. This study investigated white matter microstructural changes associated with bilateral dmPFC-targeted iTBS and their relationship with treatment response. A total of 21 patients with TRD and 32 healthy controls were included. Diffusion tensor imaging was acquired in all participants and repeated in patients after a full course of dmPFC-targeted iTBS. Analyses focused on longitudinal changes in white matter microstructure within prefrontal-cingulate-limbic pathways, group differences, and their associations with changes in depressive symptom severity. Correction for multiple comparisons was applied throughout. iTBS treatment was associated with a significant reduction in depressive symptoms. At the microstructural level, a post-treatment increase in fractional anisotropy was observed in a left prefrontal-cingulate pathway. Notably, changes in several pathways showed associations with clinical improvement. The tract-level findings were significant under tract-wise FDR correction but did not survive correction across all tract-metric comparisons, and are therefore interpreted as exploratory. Baseline microstructural properties within orbitofrontal-subgenual cingulate connections were also related to treatment response. These findings indicate tract-specific changes in diffusion metrics within prefrontal-cingulate-limbic pathways over the course of dmPFC-targeted iTBS. Given the modest sample size and the absence of a sham-controlled comparison, the results should be regarded as exploratory and hypothesis-generating, and require confirmation in larger, sham-controlled studies.