Depressive symptoms reduction following intermittent theta burst stimulation over dorsomedial prefrontal cortex is related to resting-state connectivity modulation: Preliminary findings from a double blinded sham controlled trial

While repetitive transcranial magnetic stimulation (rTMS) is a promising alternative in treatment resistant depression (TRD) its mechanisms of action remain largely unknown. Here, 20 patients with major depressive disorder (MDD) were randomized to two weeks of two daily sessions of double blinded active or sham intermittent theta burst stimulation (iTBS). The iTBS was applied with 90% of resting foot motor threshold, 1200 pulses/session, two seconds stimulation and eight seconds pause. Stimulation was applied over the dorsomedial prefrontal cortex (dmPFC) using neuronavigation and an angled coil for deeper stimulation (1). Resting-state functional magnetic resonance imaging was performed one day before treatment onset and again four weeks later. A spherical seed (10mm radius) was defined around the target coordinate for treatment within dorsal anterior cingulate cortex (dACC) to assess whole brain functional connectivity. Compared to the sham condition, active treatment was followed by altered connectivity in the posterior hippocampus and calcarine sulcus within the left hemisphere. Including change in MADRS-S score as a covariate, altered dACC connectivity was associated with reduced MADRS-S score, in active treatment compared to sham. This included altered connectivity with default mode network nodes, with the strongest effect found in the posterior cingulate gyrus and including posterior middle temporal gyri and temporal poles bilaterally, as well as left angular and parahippocampal gyri. Other regions included supplemental motor area and bilateral precentral gyri extending into middle frontal gyrus in the left hemisphere. No effects in sham compared to active treatment, or common to both groups, were found. The findings suggest that stimulation of the dmPFC and underlying dACC modulates its connectivity, with widespread connectivity changes being associated with symptom reduction following iTBS in MDD.