One seminal early study performed PET scanning while rTMS trains of varying lengths were applied to the frontal eye fields (Paus et al., 1997) to demonstrate a significant positive relationship between blood flow and TMS in the region being stimulated (the left frontal FEF), as well as in a number of distant cortical regions, including the left medial parieto-occipital cortex, the bilateral superior parietal cortex, and the right supplementary eye field (Figure 4). Thus, TMS produced changes in cerebral blood flow not only at the site of stimulation, but in a distributed network of functionally connected regions. A subsequent study showed that the pattern of blood flow changes varies as a function of the stimulated region (Chouinard et al., 2003): rTMS to premotor cortex modulated a widespread network, including several regions in the prefrontal and parietal cortices; in contrast, rTMS to motor cortex modulated activity in a smaller number of brain regions, primarily confined to the cortical and subcortical motor systems. More recent studies combining TMS with fMRI have confirmed and extended the above findings, demonstrating that even subthreshold TMS can activate a widespread cortical and subcortical network (Bestmann et al., 2003, 2004, 2005); (Figure 5a).
