Subthreshold high-frequency TMS of human primary motor cortex modulates interconnected frontal motor areas as detected by interleaved fMRI-TMS.

To elucidate changes in human brain activity evoked by repetitive transcranial magnetic stimulation (rTMS), sub- and suprathreshold rTMS (4 Hz, 10 s) over the left primary sensorimotor cortex (M1/S1) was interleaved with blood-oxygenation-level-dependent (BOLD) echo-planar imaging of primary and secondary motor areas. Suprathreshold rTMS over left M1/S1 caused marked increases in BOLD signal in the stimulated area and SMA-proper in seven of eight subjects. By contrast, we found no change in BOLD signal in the stimulated M1/S1, when rTMS was given at intensities that were subthreshold for inducing motor responses in the contralateral hand. However, five of eight subjects showed consistent increases in BOLD MRI signal in the SMA-proper and, to a lesser extent, in bilateral lateral premotor cortex (LPMC) during subthreshold rTMS. A decrease in BOLD MRI signal was found in contralateral (right) M1/S1 in 6/8 subjects across all conditions. No significant changes were observed in the pre-SMA. The results support the notion that BOLD MRI responses to suprathreshold rTMS over M1/S1 are dominated by neuronal activity related to reafferent processing of TMS-induced hand movements. At subthreshold intensity, a short train of high-frequency rTMS seems to predominantly modulate activity of corticocortical connections which link the stimulated area with remote frontal premotor areas.