Cortico-cortical connectivity: the road from basic neurophysiological interactions to therapeutic applications.

Transcranial magnetic stimulation (TMS) based methods are emerging as a unique approach to evaluate in real-time brain electrical activity in healthy and pathological conditions. By applying TMS pulses in two different bran areas within a short temporal frame of few milliseconds, it is possible to investigate their physiological interactions. These paradigms, collectively termed dual-site TMS, have been inspired by Professor John Rothwell's work, based on the idea that applying a conditioning stimulus over a cortical area may activate putative pathways projecting onto a second target area, thus providing a unique opportunity to test the causal effects between interconnected brain areas. This review highlights the most important features of dual-coil TMS protocols, mainly pioneered in Professor John Rothwell's lab. In the first part, I reviewed development of dual-site TMS protocols leading to the discovery of a distributed system of short-latency interactions within the human parieto-frontal network, likely mediated by direct anatomical pathways. In the second part, the physiological role of these dual-site TMS evoked pathways is considered, describing how these functional interactions are not fixed but vary depending on the brain activation, the condition and on the precise time window in which they are explored. Then, I reviewed recent advances showing that the repeated coupling of interconnected neuronal populations, by means of dual-coil TMS, is able to induce spike-time-dependent plasticity and to determine selective potentiation of physiological connectivity between two human brain regions. Finally, the therapeutic implications of these novel discoveries are discussed, pointing to multi-site TMS as a novel tool to identify early features of synaptic dysfunctions, to monitor disease progression and potentially to provide novel therapeutic approaches by reshaping plasticity in different neurological and psychiatric conditions.