Quadripulse stimulation: A replication study with a newly developed stimulator

Quadripulse stimulation (QPS) is a patterned repetitive transcranial magnetic stimulation (rTMS) protocol that induces long term potentiation (LTP) and depression (LTD) like after-effect [[1]Hamada M. Terao Y. Hanajima R. Shirota Y. Nakatani-Enomoto S. Furubayashi T. et al.Bidirectional long-term motor cortical plasticity and metaplasticity induced by quadripulse transcranial magnetic stimulation.J Physiol. 2008; 586: 3927-3947Crossref PubMed Scopus (192) Google Scholar]. The after-effect of QPS, compared to another patterned rTMS protocol – theta burst stimulation, was reported to be stronger and less variable across participants [[2]Tiksnadi A. Murakami T. Wiratman W. Matsumoto H. Ugawa Y. Direct comparison of efficacy of the motor cortical plasticity induction and the interindividual variability between TBS and QPS.Brain Stimul. 2020; 13: 1824-1833Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar]. Moreover, the after-effect of QPS is not affected by gene-polymorphisms of BDNF [[3]Nakamura K. Enomoto H. Hanajima R. Hamada M. Shimizu E. Kawamura Y. et al.Quadri-pulse stimulation (QPS) induced LTP/LTD was not affected by Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene.Neurosci Lett. 2011; 487: 264-267Crossref PubMed Scopus (42) Google Scholar], often influencing the rTMS after-effect [[4]Ridding M.C. Ziemann U. Determinants of the induction of cortical plasticity by non-invasive brain stimulation in healthy subjects: induction of cortical plasticity by non-invasive brain stimulation.J Physiol. 2010; 588: 2291-2304Crossref PubMed Scopus (522) Google Scholar]. Therefore, QPS emerges as a promising rTMS protocol for neuro-modulational research and treatment. Recently, Deymed Diagnostic has developed a new stimulator specifically designed for QPS (DuoMAG MP-Quad, https://deymed.com/duomag-qps), which appears as a promising QPS-stimulator [[5]Matsumoto H. Ugawa Y. Quadripulse stimulation (QPS).Exp Brain Res. 2020; 238: 1619-1625Crossref PubMed Scopus (10) Google Scholar]. However, the after-effect induced by the DuoMAG MP-Quad has not yet been systematically investigated. The degree of after-effect may differ between QPS-stimulators considering that the waveform of stimulation pulses slightly differs between manufacturers [[6]Wessel M.J. Draaisma L.R. Morishita T. Hummel F.C. The effects of stimulator, waveform, and current direction on intracortical inhibition and facilitation: a TMS comparison study.Front Neurosci. 2019; 13: 703Crossref PubMed Scopus (11) Google Scholar]. We thus studied the QPS after-effects induced by the DuoMAG MP-Quad stimulator. The participants were thirteen healthy adult volunteers comprising five females, 20–24 years of age (mean ± standard deviation: 21.5 ± 1.3). They were right-handed without a history of neurological or psychiatric disorders. Our study comprised two sessions with a within-subject design, applying two different types of QPS: QPS with an interpulse-interval of 5 ms (QPS5) and 50 ms (QPS50). These two protocols are expected to potentiate and depress the stimulated region most effectively [[1]Hamada M. Terao Y. Hanajima R. Shirota Y. Nakatani-Enomoto S. Furubayashi T. et al.Bidirectional long-term motor cortical plasticity and metaplasticity induced by quadripulse transcranial magnetic stimulation.J Physiol. 2008; 586: 3927-3947Crossref PubMed Scopus (192) Google Scholar]. The two sessions were separated by over a week, while their order was randomly assigned and counterbalanced across the participants. QPS was delivered over the left primary motor cortex (M1) using DuoMAG MP-Quad (Deymed Diagnostic s.r.o., Hronov, Czech Republic) with a butterfly-shaped 70-mm air-cooling coil (DuoMAG 70BF Air Cooled Coil; Deymed Diagnostic s.r.o., Hronov, Czech Republic). Throughout the session, motor evoked potentials (MEPs) were recorded from the right first dorsal interosseous (FDI) muscle using a Brainsight surface-electromyogram (Rogue Research Inc., Montreal, Canada). In each session, we first localized the hotspot, defined as the location evoking the largest MEPs, for the right FDI, and measured active motor threshold (AMT), defined as the intensity evoking MEPs larger than 100 μV in 5 out of 10 trials, with a slight contraction of the right FDI (∼10% of maximum voluntary contraction). We then measured 30 MEPs at the intensity evoking ∼500 μV of MEPs in the relaxed FDI as a baseline (pre-QPS). We further assessed alertness of the participants with a Stanford Sleepiness Scale (SSS; one participant presenting SSS >4 was excluded) [[7]Hoddes E. Dement W.C. Zarcone V. The development and use of the Stanford sleepiness scale (SSS).Psychophysiology. 1972; 1972: 150Google Scholar]. Subsequently, we applied QPS over the hotspot with one burst of four monophasic pulses delivered every 5 s for 30 min with a intensity of 90% AMT [[1]Hamada M. Terao Y. Hanajima R. Shirota Y. Nakatani-Enomoto S. Furubayashi T. et al.Bidirectional long-term motor cortical plasticity and metaplasticity induced by quadripulse transcranial magnetic stimulation.J Physiol. 2008; 586: 3927-3947Crossref PubMed Scopus (192) Google Scholar]. After applying QPS, we measured 20 MEPs every 10 min until 90 min after QPS (post-10 to post-90) using the same intensity as for the pre-QPS. The coil position was monitored with a Brainsight (Rogue Research Inc.) to confirm stable coil position. To evaluate the overall after-effect in QPS5 and QPS50, we first compared the MEPs between pre- and post-QPS (post-10 to post-90) for each QPS protocol. The grand mean MEP amplitudes of post-QPS normalized to pre-QPS (normalized MEP) was 1.71 ± 0.41 (from below mean ± standard deviation) in QPS5 and 0.82 ± 0.23 in QPS50 (Fig. 1A). Two-tailed paired Student's t-tests of the absolute MEP amplitude between pre- and post-QPS revealed significant enlargement after QPS5 (P < 0.001, d’ = 1.40) and significant reduction after QPS50 (P = 0.019, d’ = −0.80). To evaluate the time-course of MEPs, we separated the time-course into three time-blocks (post-10–30, post-40–60, and post-70–90), then averaged MEPs among each time-block [[2]Tiksnadi A. Murakami T. Wiratman W. Matsumoto H. Ugawa Y. Direct comparison of efficacy of the motor cortical plasticity induction and the interindividual variability between TBS and QPS.Brain Stimul. 2020; 13: 1824-1833Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar]. The mean of normalized MEP in post-10–30, post-40–60, and post-70–90 was 1.51 ± 0.36, 1.79 ± 0.48, 1.79 ± 0.48, respectively, for QPS5 (Figs. 1B), and 0.84 ± 0.32, 0.80 ± 0.26, and 0.83 ± 0.17, respectively, for QPS50 (Fig. 1C) (see Supplementary Fig. 1 for the individual time courses of MEPs). Repeated-measures one-way ANOVA revealed significant effect of time-block in QPS5 (P < 0.001, η2 = 0.60) and moderate effect of time-block in QPS50 (P = 0.051, η2 = 0.24). Post-hoc paired t-tests of the absolute MEP amplitude with correction for multiple comparisons using the Holm's method also showed significant enlargement in all time-blocks by QPS5 (post-10–30, P = 0.002, d’ = 1.14; post-40–60, P = 0.001, d’ = 1.35; post-70–90, P = 0.001, d’ = 1.42), together with a moderate reduction in post-10–30 and significant reduction in post-40–60 and post-70–90 by QPS50 (post-10–30, P = 0.093, d’ = −0.53; post-40–60, P = 0.030, d’ = −0.90; post-70–90, P = 0.047, d’ = −0.76). In terms of baseline physiological parameters, no significant differences were found in AMT (P = 0.73), stimulus intensity (SI) for recording MEPs (P = 0.49), SI for applying QPS (P = 0.68) or mean baseline MEP amplitude (P = 0.29) (Fig. 1D) between the QPS5 and QPS50 sessions. These findings confirm steady experimental conditions across the sessions. As expected from previous studies using the Magstim stimulator (The Magstim Co. Ltd., Whitland, UK) [[1]Hamada M. Terao Y. Hanajima R. Shirota Y. Nakatani-Enomoto S. Furubayashi T. et al.Bidirectional long-term motor cortical plasticity and metaplasticity induced by quadripulse transcranial magnetic stimulation.J Physiol. 2008; 586: 3927-3947Crossref PubMed Scopus (192) Google Scholar,[2]Tiksnadi A. Murakami T. Wiratman W. Matsumoto H. Ugawa Y. Direct comparison of efficacy of the motor cortical plasticity induction and the interindividual variability between TBS and QPS.Brain Stimul. 2020; 13: 1824-1833Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar,[8]Nakamura K. Groiss S.J. Hamada M. Enomoto H. Kadowaki S. Abe M. et al.Variability in response to quadripulse stimulation of the motor cortex.Brain Stimul. 2016; 9: 859-866Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar], MEPs were bidirectionally modulated for over 60 min by QPS with the newly developed stimulator. In previous studies, the grand mean normalized MEP was ∼2.0 [[1]Hamada M. Terao Y. Hanajima R. Shirota Y. Nakatani-Enomoto S. Furubayashi T. et al.Bidirectional long-term motor cortical plasticity and metaplasticity induced by quadripulse transcranial magnetic stimulation.J Physiol. 2008; 586: 3927-3947Crossref PubMed Scopus (192) Google Scholar], 1.60 [[8]Nakamura K. Groiss S.J. Hamada M. Enomoto H. Kadowaki S. Abe M. et al.Variability in response to quadripulse stimulation of the motor cortex.Brain Stimul. 2016; 9: 859-866Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar], and ∼1.2 [[2]Tiksnadi A. Murakami T. Wiratman W. Matsumoto H. Ugawa Y. Direct comparison of efficacy of the motor cortical plasticity induction and the interindividual variability between TBS and QPS.Brain Stimul. 2020; 13: 1824-1833Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar] in QPS5, versus ∼0.5 [[1]Hamada M. Terao Y. Hanajima R. Shirota Y. Nakatani-Enomoto S. Furubayashi T. et al.Bidirectional long-term motor cortical plasticity and metaplasticity induced by quadripulse transcranial magnetic stimulation.J Physiol. 2008; 586: 3927-3947Crossref PubMed Scopus (192) Google Scholar], 0.67 [[8]Nakamura K. Groiss S.J. Hamada M. Enomoto H. Kadowaki S. Abe M. et al.Variability in response to quadripulse stimulation of the motor cortex.Brain Stimul. 2016; 9: 859-866Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar], and ∼0.8 [[2]Tiksnadi A. Murakami T. Wiratman W. Matsumoto H. Ugawa Y. Direct comparison of efficacy of the motor cortical plasticity induction and the interindividual variability between TBS and QPS.Brain Stimul. 2020; 13: 1824-1833Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar] in QPS50. The grand means of normalized MEP measured in the present study (1.71 ± 0.41 in QPS5 and 0.82 ± 0.23 in QPS50) were comparable to those induced by the Magstim stimulator. These effects induced by the newly developed stimulator are supported by previous observations showing that short-interval intracortical inhibition is not sensitive to slight differences in TMS pulse waveform [[6]Wessel M.J. Draaisma L.R. Morishita T. Hummel F.C. The effects of stimulator, waveform, and current direction on intracortical inhibition and facilitation: a TMS comparison study.Front Neurosci. 2019; 13: 703Crossref PubMed Scopus (11) Google Scholar]. In the present study, the effect sizes of MEP-changes after QPS50 were found to be smaller than those measured after QPS5. A similar trend was reported in previous studies [[1]Hamada M. Terao Y. Hanajima R. Shirota Y. Nakatani-Enomoto S. Furubayashi T. et al.Bidirectional long-term motor cortical plasticity and metaplasticity induced by quadripulse transcranial magnetic stimulation.J Physiol. 2008; 586: 3927-3947Crossref PubMed Scopus (192) Google Scholar,[8]Nakamura K. Groiss S.J. Hamada M. Enomoto H. Kadowaki S. Abe M. et al.Variability in response to quadripulse stimulation of the motor cortex.Brain Stimul. 2016; 9: 859-866Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar,[9]Simeoni S. Hannah R. Sato D. Kawakami M. Rothwell J. Simeoni S. et al.Effects of quadripulse stimulation on human motor cortex excitability: a replication study.Brain Stimul. 2016; 9: 148-150Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar]. Together, these findings reveal that the newly developed QPS stimulator is as effective as the original QPS stimulator [[1]Hamada M. Terao Y. Hanajima R. Shirota Y. Nakatani-Enomoto S. Furubayashi T. et al.Bidirectional long-term motor cortical plasticity and metaplasticity induced by quadripulse transcranial magnetic stimulation.J Physiol. 2008; 586: 3927-3947Crossref PubMed Scopus (192) Google Scholar]. A promising approach to boost the after-effect of QPS50 would be to combine QPS with afferent electric stimulation of the peripheral nerves using paired-associative QPS [[10]Wiratman W. Murakmi T. Tiksnadi A. Kobayashi S. Hanajima R. Ugawa Y. Enhancement of LTD-like aftereffects by combining quadripulse stimulation for LTD with paired-associative peripheral nerve stimulation (paired-associative QPS).Clin Neurophysiol. 2022; 138: 9-17Crossref PubMed Scopus (1) Google Scholar]. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The following is the Supplementary data to this article: Download .docx (.36 MB) Help with docx files Multimedia component 1

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