, 2005). While the direct D-wave recorded in the pyramidal tract is the result of direct activation of corticospinal axons, later I-waves reflect synchronous activity originated from trans-synaptic activation of cortical neurons. However, the fact that I-waves are modified by TBS does not prove that changes in synaptic plasticity are solely involved. Several studies have pointed toward the role of NMDA or GABA modulation; others have suggested a change in the Rapamycin manufacturer expression of immediate early gene proteins (for a review, see Cardenas-Morales et al., 2010). The hypothetical LTP and LTD

effects of TBS are based on studies describing the induction of LTP in the rodent motor cortex or hippocampus; however, direct evidence in humans is still lacking. In this context, the combination of TMS with EEG offers new insights. Our results suggest that the effects of cTBS protocols, i.e. gamma rhythm triplets repeated at a theta rhythm, are not uniform across different populations of neurons. Moreover, the timing of response to cTBS might be specific to each system. Similar to Noh et al. (2012), we found that the effects on oscillations can be detected later than the effects on MEPs. Future studies

will need to explore why modulation of oscillations is delayed compared with modulation of MEPs. To summarize, systems-level effects involving cortical oscillators need to be considered when evaluating the TBS effects. Using real-time integration of TMS and EEG, we provide novel insights on the neural substrate of the effects

of cTBS. R428 clinical trial We found that cTBS modulates TEPs, but also resting oscillations and TMS-induced oscillations, with opposite effects between cortical theta and beta oscillators. This suggests that the effects of TBS involve a complex, systems-level impact of TMS on brain function. Furthermore, it should be noted that the time courses for of all these TMS-induced modulations (MEPs, EEG after single-pulse TMS, EEG at rest) are different, which suggests that cTBS effects last longer than one can expect from MEP recordings. Future studies are needed to examine these observations at the individual level (for TEPs) and with populations from a different age range. If confirmed, TMS-induced potentials and oscillations might be useful tools to explore plasticity of areas outside the motor cortex where no MEPs can be recorded. This work was supported in part by grants from CIMIT (A.P.-L.), the National Center for Research Resources – Harvard Clinical and Translational Science Center (UL1 RR025758). A.P.-L. serves on the scientific advisory boards for Nexstim, Neuronix, Starlab Neuroscience, Neosync and Novavision, and is a listed inventor on issued and pending patents on the real-time integration of transcranial magnetic stimulation (TMS) with electroencephalography (EEG) and magnetic resonance imaging (MRI). M.V. was supported by the Fyssen Foundation (France). W.-K.Y.