Towards understanding rTMS mechanism of action: Stimulation of the DLPFC causes network-specific increase in functional connectivity

Transcranial magnetic stimulation (TMS) is a powerful non-invasive technique for the modulation of brain activity. While the precise mechanism of action is still unknown, TMS is applied in cognitive neuroscience to establish causal relationships between stimulation and subsequent changes in cerebral function and behavioral outcome. In addition, TMS is an FDA-approved therapeutic agent in psychiatric disorders, especially major depression. Successful repetitive TMS in such disorders is usually applied over the left dorso-lateral prefrontal cortex (DLPFC) and treatment response mechanism was therefore supposed to be based on modulations in functional networks, particularly the meso-cortico-limbic reward circuit. However, mechanistic evidence for the direct effects of rTMS over DLPFC is sparse. Here we show the specificity and temporal evolution of rTMS effects by comparing connectivity changes within 20 common independent components in a sham-controlled study. Using an unbiased whole-brain resting-state network (RSN) approach, we successfully demonstrate that stimulation of left DLPFC modulates anterior cingulate cortex (ACC) connectivity in one specific meso-cortico-limbic network, while all other networks are neither influenced by rTMS nor by sham treatment. The results of this study show that the neural correlates of TMS treatment response are also traceable in DLPFC stimulation of healthy brains and therefore represent direct effects of the stimulation procedure.