The physiological effects of non-invasive brain stimulation fundamentally differ across the human cortex

Abstract Non-invasive brain stimulation reliably modulates brain activity and symptoms of neuropsychiatric disorders. However, stimulation effects substantially vary across individuals and brain regions. We combined transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) to investigate the neuronal basis of inter-individual and inter-areal differences after TMS. We found that stimulating sensory and cognitive areas yielded fundamentally heterogeneous effects. Stimulation of occipital cortex enhanced brain-wide functional connectivity and biophysical modeling identified increased local inhibition and enhanced forward-signaling after TMS. Conversely, frontal stimulation decreased functional connectivity, associated with local disinhibition and disruptions of both feedforward and feedback connections. Finally, we identified brain-wide functional integration as a predictive marker for these heterogeneous stimulation effects in individual subjects. Together, our study suggests that modeling of local and global signaling parameters of a target area will improve the specificity of non-invasive brain stimulation for research and clinical applications.