There is some limited evidence suggesting that the spaced application of repetitive transcranial magnetic stimulation (rTMS) protocols may extend the duration of induced neuroplastic changes. However, this has yet to be demonstrated in the human primary motor cortex (M1). We evaluated whether the paired application of an inhibitory rTMS protocol [continuous theta burst stimulation (cTBS)] at 10‐min intervals prolonged the duration of induced M1 plasticity. Motor evoked potentials (MEPs) were recorded from the right first dorsal interosseous muscle before and following single and paired cTBS protocols applied with two intensities: 80% of active motor threshold (AMT₈₀) and 70% of resting motor threshold (RMT₇₀). Single cTBS protocols did not significantly influence MEP amplitudes. Whereas paired trains applied at AMT₈₀ had no effect on MEP amplitudes, paired cTBS trains at RMT₇₀ significantly reduced them. MEP amplitudes remained suppressed for at least 2 h following the second train. Control experiments suggested that the contraction used to establish active motor threshold prior to cTBS application may be responsible for blocking the effect of paired cTBS trains at AMT₈₀. The results suggest that the spaced application of cTBS protocols may be an effective approach for establishing long‐lasting M1 neuroplasticity only in the absence of prior voluntary motor activation. These findings may have important implications for the therapeutic application of rTMS.

The potential of non-invasive brain stimulation (NIBS) for both probing human neuroplasticity and the induction of functionally relevant neuroplastic change has received significant interest. However, at present the utility of NIBS is limited due to high response variability. One reason for this response variability is that NIBS targets a diffuse cortical population and the net outcome to stimulation depends on the relative levels of excitability in each population. There is evidence that the relative excitability of complex oligosynaptic circuits (late I-wave circuits) as assessed by transcranial magnetic stimulation (TMS) is useful in predicting NIBS response. Here we examined whether an additional marker of cortical excitability, MEP amplitude variability, could provide additional insights into response variability following application of the continuous theta burst stimulation (cTBS) NIBS protocol. Additionally we investigated whether I-wave recruitment was associated with MEP variability. Thirty-four healthy subjects (15 male, aged 18-35 years) participated in two experiments. Experiment 1 investigated baseline MEP variability and cTBS response. Experiment 2 determined if I-wave recruitment was associated with MEP variability. Data show that both baseline MEP variability and late I-wave recruitment are associated with cTBS response, but were independent of each other; together, these variables predict 31% of the variability in cTBS response. This study provides insight into the physiological mechanisms underpinning NIBS plasticity responses and may facilitate development of more reliable NIBS protocols.