Repetitive transcranial magnetic stimulation (rTMS) is thought to be a method of inducing increases or decreases in excitatory in inhibitory post-synaptic potentials following the application of a large number of TMS pulses to one cortical area, which can be followed by a period of time where a change in cortical excitability in the site of stimulation (or the broader network containing the site stimulation) (Fitzgerald et al., 2006). This change in cortical excitability can be an excitatory one or an inhibitory one but this change tends to outlast the period of rTMS. As a result, rTMS has been investigated as a potential therapeutic intervention and is currently and US Food and Drug Administration (FDA) approved treatment for depression and migraine. In addition to its therapeutic use, the ‘offline’ effects of rTMS has also been extensively used as means of transiently interfering with cortical area of interest and then observing the effects on task performance to provide causal evidence for brain area in cognitive process (e.g. Verbruggen et al., 2010). rTMS does not require a behavioural task to be used as physiological probe; it is also possible to rely on neuroimaging measures such as electroencephalography (e.g. Rocchi et al., 2018), magnetoencephalography (e.g. Allen et al., 2014), magnetic resonance spectroscopy (e.g. Allen et al., 2014), functional magnetic resonance imaging (e.g. Tupak et al., 2011) or positron emission tomography (e.g. Siebner et al., 2001).
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 was 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 produce 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 active motor threshold (Suppa et al., 2016). Initially, TBS was found to produce excitatory or inhibitory effects depending on 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 long present when an NMDA antagonist was administered to subjects, suggesting that a NMDA-dependent mechanism linked to long-term potentiation (LTP) or long-term depression (LTD) underlies the offline effects of TBS on 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 showed an effect in the expected direction whereas other participants showed an effect in the opposite direction (Hamada et al., 2013). This outcome prompted 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 shown 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 the 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 importance of the IBI of 5 seconds. The difference between monophasic and biphasic pulse shapes also highlights that the pulse shaped 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 altered the pulse width of a monophasic pulse and also manipulated the extent to which a pulse shape in biphasic (Halawa et al., 2019). The effect of 900 TMS pulses at 1 Hz on MEP amplitudes changed depended 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, causing 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 emphasis that there are still many parameters that can be altered that have not yet been fully explored, which could be come a future basis for optimising rTMS protocols or invented new rTMS protocols altogether.
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