Repetitive transcranial magnetic stimulation (rTMS) was initially applied to the motor cortex (M1) at either a fixed frequency or in patterned bursts and the consequences of these rTMS protocols were then revealed by measuring whether the amplitude of motor evoked potentials (MEPs) evoked by single pulses of TMS to M1 were changed after the application of rTMS. One of the most popular rTMS protocols that were developed using this method was theta burst stimulation (TBS) (Huang et al., 2005). TBS was inspired by the idea that the application of four pulses at 100Hz separated by a 5 Hz interval produces plasticity like changes in hippocampal brain slices (Capocchi et al., 1992; Larson & Lynch, 1986, 1989). In rTMS, however, 3 (biphasic) pulses were applied at a lower frequency of 50 Hz due to hardware constraints but a 5Hz interval was still applied to the interval between bursts at 80% of the active motor threshold (Suppa et al., 2016). Initially, TBS was found to produce excitatory or inhibitory effects depending on whether the 3 pulse bursts were delivered for a 2-second period followed by an interval (iTBS) or whether the 3 pulse bursts were delivered continuously (cTBS) (Huang et al., 2005). The application of cTBS was initially found to decrease MEP amplitude for up to an hour whereas iTBS was found to increase MEP amplitude for ~15 minutes (Huang et al., 2005). Such an effect was no longer present when an NMDA antagonist was administered to subjects, suggesting that an NMDA-dependent mechanism linked to long-term potentiation (LTP) or long-term depression (LTD) underlies the offline effects of TBS on the excitability of the motor cortex (Huang et al., 2007). 

Despite the early promise of TBS, however, later studies revealed variability in the response to TBS with some participants showing an effect in the expected direction whereas other participants showed an effect in the opposite direction (Hamada et al., 2013). This outcome prompted an investigation into why such intra- and inter-individual reasons for why such variability exists (Suppa et al., 2016; Hinder et al., 2014) and whether additional TMS protocols can be revealed that also show robust offline effects (Huang et al., 2009). One new protocol that is showing promising effects is Quadro-pulse stimulation (QPS), which monophasic pulse shapes, not biphasic pulse shapes. QPS involves administering bursts containing 4 pulses with a 5-second interval between one burst and a subsequent burst. Inhibitory or excitatory effects of QPS have been found to depend on the interval separating each pulse within a burst (Hamada et al., 2008). A 5ms (QPS-5) interval between each pulse was found to increase MEP amplitude whereas a 50ms interval was found to decrease MEP amplitude relative to baseline (Hamada et al., 2008). When a 5-second interval was used, 80% of participants showed the expected increase in MEP amplitude when QPS-5 was used (Nakamura et al., 2016).

rTMS Pulse Shapes

The impact of the pulse shape has also been highlighted by QPS protocols. One study kept the QPS parameters exactly the same, but delivered the pulses through monophasic or biphasic stimulators, and also varied the inter-burst interval (Nakamura et al., 2016). This study revealed that monophasic QPS led to longer-lasting offline effects than biphasic QPS, highlighting the potential impact of the monophasic pulse shape in rTMS protocols in addition to the importance of the IBI of 5 seconds. The difference between monophasic and biphasic pulse shapes also highlights that the pulse used to produce offline effects of an rTMS protocol may be a critical determinant of its efficacy. Recent work with controllable pulse parameter (cTMS) devices has shown that the direction of the magnetic pulse shape - biphasic or monophasic - can have an impact on the efficacy of an rTMS protocol. Moreover, the majority of the rTMS protocols recruited biphasic pulse shapes rather than monophasic pulse shapes. A recent experiment has altered the pulse width of a monophasic pulse and also manipulated the extent to which a pulse shape is biphasic (Halawa et al., 2019). The effect of 900 TMS pulses at 1 Hz on MEP amplitudes changed depending on the pulse shape that was administered by the stimulator. Quasi-unidirectional, shorter pulses widths (40 μs, 80 μs) increased MEP amplitude whereas a longer pulse width (120 μs) increased MEP amplitude. However, changing the overall directionality of a TMS pulse, caused it to resemble a biphasic pulse shape, on the other hand, increased MEP amplitude once the rTMS protocol was completed (Halawa et al., 2019). This experiment emphasises that there are still many parameters that can be altered that have not yet been fully explored, which could become a future basis for optimising rTMS protocols or inventing new rTMS protocols altogether.