Repetitive transcranial magnetic stimulation (rTMS) is a method of non-invasive brain stimulation that involves applying TMS pulses at a rhythmic, repetitive frequency to a subject for a prolonged period of time.
rTMS is able to induce increases or decreases in excitatory or 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 delivered.
As a result, rTMS has been investigated as a potential therapeutic intervention and is currently a US Food and Drug Administration (FDA) approved treatment for depression, anxiety, and migraine.
In addition to its therapeutic use, the ‘offline’ effects of rTMS have also been extensively used as means of transiently interfering with cortical areas of interest and subsequently observing the effects on task performance to provide causal evidence for brain area in the cognitive process (e.g. Verbruggen et al., 2010).
Repetitive TMS does not require a behavioural task to be used as a physiological probe; it is also possible to rely on neuroimaging measures such as electroencephalography (EEG) (e.g. Rocchi et al., 2018), magnetoencephalography (MEG) (e.g. Allen et al., 2014), magnetic resonance spectroscopy (e.g. Allen et al., 2014), functional magnetic resonance imaging (fMRI) (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 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.
- Neuronal tuning: Selective targeting of neuronal populations via manipulation of pulse width and directionality. I. Halawa, Y. Shirota, A.Neef, M.Sommer, W.Paulus. Brain Stimulation. October 2019
- Variability in Response to Quadripulse Stimulation of the Motor Cortex. Koichiro Nakamura, Stefan Jun Groiss, Masashi Hamada, Hiroyuki Enomoto, Suguru Kadowaki, Mitsunari Abe, Takenobu Murakami, Winnugroho Wiratman, Fangyu Chang, Shunsuke Kobayashi, Ritsuko Hanajima, Yasuo Terao, Yoshikazu Ugawa. Brain Stimulation. December 2016
- Ten Years of Theta Burst Stimulation in Humans: Established Knowledge, Unknowns and Prospects. A Suppa, Y-Z Huang, K Funke, M C Ridding, B Cheeran, V Di Lazzaro, U Ziemann, J C Rothwell. Brain Stimulation. May 2016
- The role of interneuron networks in driving human motor cortical plasticity. Masashi Hamada, Nagako Murase, Alkomiet Hasan, Michelle Balaratnam, John C Rothwell. Cerebral Cortex. July 2013
- Bidirectional long-term motor cortical plasticity and metaplasticity induced by quadripulse transcranial magnetic stimulation. Masashi Hamada, Yasuo Terao, Ritsuko Hanajima, Yuichiro Shirota, Setsu Nakatani-Enomoto, Toshiaki Furubayashi, Hideyuki Matsumoto, Yoshikazu Ugawa. The Journal of Physiology. August 2008
- The after-effect of human theta burst stimulation is NMDA receptor dependent. Ying-Zu Huang, Rou-Shayn Chen, John C Rothwell, Hsin-Yi Wen. Clinical Neurophysiology. May 2007
- Theta burst stimulation of the human motor cortex. Ying-Zu Huang, Mark J Edwards, Elisabeth Rounis, Kailash P Bhatia, John C Rothwell. Neuron. January 2005
- Theta burst stimulation is optimal for induction of LTP at both apical and basal dendritic synapses on hippocampal CA1 neurons. G.Capocchi, M.Zampolini, J.Larson. Brain Research. September 1992
- Consensus: New methodologies for brain stimulation. Ying-Zu Huang, Martin Sommer, Gary Thickbroom, Masashi Hamada, Alvero Pascual-Leonne, Walter Paulus, Joseph Classen, Angel V Peterchev, Abraham Zangen, Yoshikazu Ugawa. Brain Stimulation. January 2009
- Theta pattern stimulation and the induction of LTP: the sequence in which synapses are stimulated determines the degree to which they potentiate. J Larson, G Lynch. Brain Research. June 1989
- Induction of synaptic potentiation in hippocampus by patterned stimulation involves two events. J Larson, G Lynch. Science. May 1986
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