Assessing the efficacy and reproducibility of four common repetitive transcranial magnetic stimulation protocols: a sham controlled study

Repetitive transcranial magnetic stimulation (rTMS) has been widely used in both clinical and research settings to modulate brain activity and assess brain plasticity. The effects of rTMS are generally believed to involve modulation of cortical excitability; protocols such as 10 Hz and iTBS increase cortical excitability, while 1Hz and cTBS are considered inhibitory. However, recent meta-analyses and studies have shown a wide array of interindividual responses to each protocol and poor reliability of the results. Here, we applied two sessions of the four most commonly used rTMS protocols (iTBS, cTBS, 10Hz, 1Hz) and Sham to the primary motor cortex and assessed their neurophysiological and behavioral effects. We hypothesized that relative to Sham, 10Hz and iTBS would increase motor excitability and modulate motor response times, while 1Hz and cTBS would have opposite effects. We recorded single-pulse TMS-EEG-EMG pre-rTMS and five and 25 minutes post-rTMS. Participants performed a sequential finger-tapping task (SFTT) 20 minutes pre-rTMS and 15 minutes post-rTMS. Our main outcome measures were: P30 amplitude, early LMFP (15-75 ms) area under-the-curve, MEP and SFTT completion time. We calculated the Intra-Class Correlation between each session for each measure. For each protocol, we found no consistent protocol-dependent group effect on MEPs, TEPs or behavior, with high intra-individual variability across sessions. An increase in SFTT completion time occurred for all active protocols but also Sham. The test-retest reliability of rTMS effects was low (ICC<0.5) for almost all protocols and metrics. This study is the first comprehensive assessment of the effects and reliability of the most commonly used rTMS protocols on cortical excitability and behavior. Our results suggest that rTMS effects are not reliable, at least at the single-session level, and that the inclusion of Sham rTMS is essential for identifying protocol-specific effects. These results also suggest that a fundamental and unbiased re-evaluation of potential rTMS mechanisms is necessary.