Mechanisms of Transcranial Magnetic Brain Stimulation

Transcranial magnetic stimulation (TMS) non-invasively activates the human cortex through the intact skull and is now employed worldwide to interrogate physiological and pathological functions of the human brain, and to treat a variety of neurological and psychiatric brain disorders. Yet, the precise routes from the induced electric field to neuronal excitation including network effects remain not fully resolved, limiting the mechanistic basis of all TMS applications. This review deeply surveys how TMS activates the human cortex. We integrate evidence from physics, biophysics, computational modeling, neurophysiological studies in humans using electromyography, electroencephalography, and epidural spinal recordings, and converging non-human primate, rodent, and cortical-slice studies. Collectively, the data suggest that TMS preferentially depolarizes superficial large-diameter myelinated axons, likely at bends, thereby triggering near-instantaneous synaptic activation of local cortical circuits and the emergence of long-range corticocortical and cortico-subcortical network activity. Through this cascade––axonal excitation, cell and circuit recruitment, and network propagation––TMS provides a versatile probe of excitability, function, and dysfunction across spatial scales, from single axons to distributed human brain networks.