The application of repetitive transcranial magnetic stimulation (rTMS) to the motor cortex (M1) involved fixed frequency or patterned bursts. The effects of these rTMS protocols were assessed by measuring changes in motor evoked potentials (MEPs) following single pulses of TMS to M1. One of the most widely used protocols in rTMS is theta burst stimulation (TBS), which was developed based on the concept of inducing plasticity-like changes seen in hippocampal brain slices through the application of four pulses at 100Hz with a 5Hz interval (Capocchi et al., 1992; Larson and Lynch, 1986, 1989). In rTMS, however, due to hardware limitations, three biphasic pulses were applied at a lower frequency of 50Hz, maintaining a 5Hz interval between bursts at 80% of the active motor threshold (Suppa et al., 2016). Initially, TBS demonstrated either excitatory or inhibitory effects depending on whether the three-pulse bursts were delivered for a 2-second period with an interval (iTBS) or continuously (cTBS) (Huang et al., 2005). cTBS was found to decrease MEP amplitude for up to an hour, while iTBS increased MEP amplitude for approximately 15 minutes (Huang et al., 2005). The presence of these effects was diminished when NMDA antagonists were administered, suggesting that NMDA-dependent mechanisms associated with long-term potentiation (LTP) or long-term depression (LTD) contribute to the offline effects of TBS on motor cortex excitability (Huang et al., 2007).

Despite the initial promise of TBS, subsequent studies have revealed variability in individual responses, with some participants exhibiting the expected effects while others showing effects in the opposite direction (Hamada et al., 2013). This finding prompted investigations into the intra- and inter-individual factors contributing to this variability (Suppa et al., 2016; Hinder et al., 2014), as well as the exploration of additional TMS protocols that exhibit robust offline effects (Huang et al., 2009). One such promising protocol is Quadripulse stimulation (QPS), which utilises monophasic pulse shapes instead of biphasic pulses. QPS involves delivering bursts of four pulses with a 5-second interval between each burst. The inhibitory or excitatory effects of QPS are dependent on the interval between pulses within each burst (Hamada et al., 2008). Specifically, a 5ms interval (QPS-5) has been found to increase MEP amplitude, while a 50ms interval leads to a decrease in MEP amplitude compared to baseline (Hamada et al., 2008). When a 5-second interval is used, approximately 80% of participants demonstrate the expected increase in MEP amplitude with QPS-5 (Nakamura et al., 2016).  

rTMS pulse shapes

The influence of pulse shape in repetitive transcranial magnetic stimulation (rTMS) protocols has gained attention, particularly in the context of Quadripulse stimulation (QPS). A study by Nakamura et al., (2016) examined the impact of pulse shape by delivering QPS with either monophasic or biphasic stimulators while varying the inter-burst interval (IBI). The findings revealed that monophasic QPS produced longer-lasting offline effects compared to biphasic QPS, highlighting the potential significance of pulse shape in rTMS protocols, along with the importance of a 5-second IBI. This distinction between monophasic and biphasic pulse shapes underscores the critical role of the pulse utilised in generating offline effects in rTMS protocols.

Recent investigations utilising controllable pulse parameter (cTMS) devices have further demonstrated that the directionality of the magnetic pulse shape, whether biphasic or monophasic, can impact the efficacy of rTMS protocols. Interestingly, most rTMS protocols have predominantly employed biphasic pulse shapes. In an experiment by Halawa et al., (2019), altering the pulse width of a monophasic pulse and manipulating the pulse shape's degree of biphasic nature yielded varying effects on motor evoked potential (MEP) amplitudes following 900 TMS pulses at 1Hz. Shorter pulse widths (40μs, 80μs) with quasi-unidirectional characteristics increased MEP amplitude, while a longer pulse width (120μs) also increased MEP amplitude. On the other hand, modifying the overall directionality of a TMS pulse to resemble a biphasic shape resulted in increased MEP amplitude following completion of the rTMS protocol. This experiment underscores the existence of numerous unexplored parameters that hold potential for optimising existing rTMS protocols or devising novel ones in the future.