Transcranial magnetic stimulation as a tool to induce and explore plasticity in humans.

Activity-dependent synaptic plasticity is the main theoretical framework to explain mechanisms of learning and memory. Synaptic plasticity can be explored experimentally in animals through various standardized protocols for eliciting long-term potentiation and long-term depression in hippocampal and cortical slices. In humans, several non-invasive protocols of repetitive transcranial magnetic stimulation and transcranial direct current stimulation have been designed and applied to probe synaptic plasticity in the primary motor cortex, as reflected by long-term changes in motor evoked potential amplitudes. These protocols mimic those normally used in animal studies for assessing long-term potentiation and long-term depression. In this chapter, we first discuss the physiologic basis of theta-burst stimulation, paired associative stimulation, and transcranial direct current stimulation. We describe the current biophysical and theoretical models underlying the molecular mechanisms of synaptic plasticity and metaplasticity, defined as activity-dependent changes in neural functions that modulate subsequent synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD), in the human motor cortex including calcium-dependent plasticity, spike-timing-dependent plasticity, the role of N-methyl-d-aspartate-related transmission and gamma-aminobutyric-acid interneuronal activity. We also review the putative microcircuits responsible for synaptic plasticity in the human motor cortex. We critically readdress the issue of variability in studies investigating synaptic plasticity and propose available solutions. Finally, we speculate about the utility of future studies with more advanced experimental approaches.