To evaluate whether repetitive transcranial magnetic stimulation (rTMS) applied using excitatory and inhibitory sequences could cause structural neuronal changes in drug resistant major depressive disorder (MDD) patients.Two homogeneous groups of drug resistant MDD patients received either active or sham bifrontal rTMS therapy (active group: 19 patients, mean age = 37 years, 10 females; sham group: 18 patients, mean age = 37 years, 10 females). On average, patients received therapy for 27 days (range 24-28 days). The rTMS therapy was administered with neuronavigated rTMS by applying excitatory 10Hz stimulation (1150 pulses/day) on the left and inhibitory 1Hz (560 pulses/day) on the right dorsolateral prefrontal cortex (DLPFC) on consecutive days, excluding the weekends. The active rTMS was given with a stimulation intensity of 110% of the hand resting motor threshold, whereas the sham stimulation was administered with 50% of the maximum stimulator output using a special sham coil. Before and after the therapy period the T1-weighted structural images (voxel size 1mm³) were acquired with a 1.5T MR scanner. The absence of morphological abnormalities in the MR images were verified by a neuroradiologist. The grey matter (GM) changes were evaluated with whole-brain voxel based morphometry (VBM). The MR images were first segmented to identify grey and white matter. Thereafter, the VBM was conducted using the DARTEL toolbox¹ in SPM12. The structural differences caused by the active rTMS versus sham therapy (MRI after–MRI before) were evaluated with a general linear model by using a two-sample t-test.Patients treated with active rTMS showed a significant increase in GM when compared to sham group in the right post- and precentral gyri (p<0.001, uncorrected, Figure 1A). After multiple comparison correction the increase in postcentral gyrus survived (p<0.05, FWE corrected, Figure 1B). Furthermore, there was a decrease in GM in a small area in the superior part of the right precentral gyrus due to active TMS (p<0.001, uncorrected), but it did not survive the multiple comparison correction. No differences in GM were observed in the left hemisphere.GM was found to increase in the right post- and precentral gyri after DLPFC stimulation, in the hemisphere of inhibitory stimulation. Furthermore, a decrease in GM was observed in the superior part of the right precentral gyrus. GM changes following inhibitory rTMS have also been seen in previous studies in healthy subjects² and tinnitus patients³. Yet, not all of them are sham-controlled similarly to the present study. The direct effects of rTMS are mainly limited to the stimulation target, however, stimulation also causes indirect effects in functionally connected areas⁴. Previous studies have shown a functional connection between DLPFC and post- and precentral gyri ^4,5.The structural changes detected in MDD patients demonstrate the potential of rTMS to be used as a comprehensive tool to modulate both functional and structural neuroplasticity.