Abstract
INTRODUCTION: Transcranial magnetic stimulation (TMS) over the left dorsolateral prefrontal cortex (L-DLPFC) is an established intervention for treatment-resistant depression (TRD), yet the underlying therapeutic mechanisms remain not fully understood. METHODS: This study employs an integrative approach that combines TMS with concurrent functional magnetic resonance imaging (fMRI) and electroencephalography (EEG), aimed at assessing the acute/immediate effects of TMS on brain network dynamics and their correlation with clinical outcomes. Furthermore, this study explored the brain-state dependent effects of TMS, as the brain-state indexed by the phase of EEG prefrontal alpha oscillation. RESULTS: Our study demonstrates that TMS acutely modulates connectivity within vital brain circuits, particularly the cognitive control and default mode networks. We found that the baseline TMS-evoked responses in the cognitive control and limbic networks significantly predicted clinical improvement in patients receiving a novel EEG-synchronized repetitive TMS treatment. Clinical outcomes in this novel treatment were linked to state-specific TMS-modulated functional connectivity within a pivotal brain circuit of the L-DLPFC and the posterior subgenual anterior cingulate cortex within the limbic system. CONCLUSIONS: These findings contribute to our understanding of the therapeutic effects underlying TMS treatment in depression and support the potential of assessing state-dependent TMS effects. This study emphasizes the importance of personalized timing of TMS for optimizing target engagement of specific clinically relevant brain circuits. Our results are crucial for future research into the development of personalized neuromodulation therapies for TRD patients.