Repetitive Transcranial Magnetic Stimulation

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive method of brain stimulation that involves applying TMS pulses at a rhythmic frequency for an extended duration.

By delivering multiple TMS pulses to a specific cortical area, rTMS can induce changes in excitatory or inhibitory post-synaptic potentials, leading to alterations in cortical excitability within the stimulated site or its broader network (Fitzgerald et al., 2006). These changes in cortical excitability, which can be either excitatory or inhibitory, tend to persist beyond the duration of rTMS.  

Due to its potential therapeutic effects, rTMS has gained attention as an FDA-approved treatment for depression, anxiety, and migraine. The current FDA protocol prescribes 90,000 pulses over 4-6 weeks with a frequency of 10Hz and 120% motor threshold intensity (Tan et al., 2023).

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 (Verbruggen et al., 2010). 

rTMS does not require a behavioural task, it can also serve as a physiological probe using neuroimaging techniques such as electroencephalography (EEG), magnetoencephalography (MEG), magnetic resonance spectroscopy (MRS), functional magnetic resonance imaging (fMRI), or positron emission tomography (PET) (Rocchi et al., 2018; Allen et al., 2014; Tupak et al., 2011; Siebner et al., 2001). 

rTMS Applications

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.

  1. Enhanced awareness followed reversible inhibition of human visual cortex: a combined TMS, MRS and MEG study. Allen, C.P.G., et al. PLoS One 9(6). (2014)
  2. Theta burst stimulation is optimal for induction of LTP at both apical and basal dendritic synapses on hippocampal CA1 neurons. Capocchi, G., Zampolini, M. and Larson, J. Brain Research 591(2): 332-336. (1992)
  3. A comprehensive review of the effects of rTMS on motor cortical excitability and inhibition. Fitzgerald, P.B., Fountain, S. and Daskalakis, Z.J. Clinical Neurophysiology 117(12): 2584-2596. (2006)
  4. Neuronal tuning: selective targeting of neuronal populations via manipulation of pulse width and directionality. Halawa, I., Shirota, Y. and Neef, A., et al. Brain Stimulation 12(5): 1244-1252. (2019)
  5. Bidirectional long-term motor cortical plasticity and metaplasticity induced by quadripulse transcranial magnetic stimulation. Hamada, M. et al. J Physiol 586(16): 3927-3947. (2008)
  6. The role of interneuron networks in driving human motor cortical plasticity. Hamada, M., Murase, N. and Hasan, A., et al. Cereb Cortex 23(7): 1593-1605. (2013)
  7. Inter- and Intra-individual variability following intermittent theta burst stimulation: implications for rehabilitation and recovery. Hinder, M.R., Goss, E.J. and Fujiyama, H., et al. Brain Stimulation 7(3): 365-371. (2014)
  8. Consensus: new methodologies for brain stimulation. Huang, Y. et al. Brain Stimul. 2(1): 2-13. (2009)
  9. The after-effect of human theta burst stimulation is NMDA receptor dependent. Huang, Y., Chen, R. and Rothwell, J.C., et al. Clin Neurophysiol. 118(5): 1028-1032. (2007)
  10. Theta burst stimulation of the human motor cortex. Huang, Y., Edwards, M.J. and Rounis, E., et al. Neuron 45(2): 201-206. (2005)
  11. Induction of synaptic potentiation in hippocampus by patterned stimulation involves two events. Larson, J. and Lynch, G. (1986). Science 232(4753): 985-989. (1986)
  12. Theta pattern stimulation and the induction of LTP: the sequence in which synapses are stimulate determines the degree to which they potentiate. Larson, J. and Lynch, G. Brain Res. 489(1): 49-58. (1989)
  13. Variability in response to quadripulse stimulation of the motor cortex. Nakamura, K. et al. Brain Stimul. 9(6): 859-866. (2016)
  14. Variability and predictors of response to continuous theta burst stimulation: A TMS-EEG study. Rocchi, L., Ibáñez, J. and Benussi, A., et al. Frontiers in Neuroscience 12. (2018)
  15. Activation of frontal premotor areas during suprathreshold transcranial magnetic stimulation of the left primary sensorimotor cortex: A glucose metabolic PET study. Siebner, H.R., Peller, M. and Bartenstein, P., et al. Human Brain Mapping 12(3): 157-167. (2001)
  16. Ten years of theta burst stimulation in humans: established knowledge, unknowns and prospects. Suppa, A., et al. Brain Stimul. 9(3): 323-335. (2016)
  17. Tolerability and effectiveness of rTMS for geriatric patients with treatment-resistant depression in a naturalistic clinic setting. Tan, A.C., et al. The American Journal of Geriatric Psychiatry 31(3): S118-S119. (2023)
  18. Inhibitory transcranial magnetic theta burst stimulation attenuates prefrontal cortex oxygenation. Tupak, S.V., et al. Human Brain Mapping 34(1): 150-157. (2011)
  19. Theta burst stimulation dissociates attention and action updating in human inferior frontal cortex. Verbruggen, F., Aron, A.R., Stevens, M.A. and Chambers, C.D. Proc Natl Acad Sci USA 107(31): 13966-13971. (2010)

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