Quadripulse stimulation – a promising patterned repetitive transcranial magnetic stimulation protocol

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Abstract

Quadripulse stimulation (QPS) is a relatively new and highly promising repetitive transcranial magnetic stimulation protocol. QPS is based on the application of bursts, consisting of 4 monophasic stimuli with a very short interstimulus interval (5 or 50 ms, QPS 5 and QPS50, respectively), which are repeated every 5 seconds. Long-term neuromodulating effects of QPS protocols are bi-directional depending on interstimulus interval: QPS5 increases the excitability of motor cortex while QPS50 decreases it. The main advantage of QPS protocols is a high reproducibility of their effects, which exceeds that of other repetitive transcranial magnetic stimulation protocols. This review discusses the physiological effects and possible mechanisms for inducing neuroplasticity by QPS protocols. Special attention is paid to QPS application in clinical practice both for therapeutic neuromodulation and development of new biomarkers of functional brain state. Available QPS safety data are provided and previous works limitations as well as directions for further studies are analyzed.

About the authors

Ilya S. Bakulin

Russian Center of Neurology and Neurosciences

Author for correspondence.
Email: bakulin@neurology.ru
ORCID iD: 0000-0003-0716-3737
Russian Federation, 80 Volokolamskoe Shosse, Моscow, 125367

A. R. Relina

Russian Center of Neurology and Neurosciences

Email: bakulin@neurology.ru
ORCID iD: 0009-0000-3653-2736
Russian Federation, 80 Volokolamskoe Shosse, Моscow, 125367

A. G. Poydasheva

Russian Center of Neurology and Neurosciences

Email: bakulin@neurology.ru
ORCID iD: 0000-0003-1841-1177
Russian Federation, 80 Volokolamskoe Shosse, Моscow, 125367

A. Kh. Zabirova

Russian Center of Neurology and Neurosciences

Email: bakulin@neurology.ru
ORCID iD: 0000-0001-8544-3107
Russian Federation, 80 Volokolamskoe Shosse, Моscow, 125367

D. Yu. Lagoda

Russian Center of Neurology and Neurosciences

Email: bakulin@neurology.ru
ORCID iD: 0000-0002-9267-8315
Russian Federation, 80 Volokolamskoe Shosse, Моscow, 125367

N. A. Suponeva

Russian Center of Neurology and Neurosciences

Email: bakulin@neurology.ru
ORCID iD: 0000-0003-3956-6362
Russian Federation, 80 Volokolamskoe Shosse, Моscow, 125367

M. A. Piradov

Russian Center of Neurology and Neurosciences

Email: bakulin@neurology.ru
ORCID iD: 0000-0002-6338-0392
Russian Federation, 80 Volokolamskoe Shosse, Моscow, 125367

References

  1. Burke M.J., Fried P.J., Pascual-Leone A. Transcranial magnetic stimulation: Neurophysiological and clinical applications. Handb Clin Neurol 2019;163:73–92. doi: 10.1016/B978-0-12-804281-6.00005-7
  2. Vucic S., Stanley Chen K.H., Kiernan M.C. et al. Clinical diagnostic utility of transcranial magnetic stimulation in neurological disorders. Updated report of an IFCN committee. Clin Neurophysiol 2023;150:131–75. doi: 10.1016/j.clinph.2023.03.010
  3. Rektorová I., Pupíková M., Fleury L. et al. Non-invasive brain stimulation: current and future applications in neurology. Nat Rev Neurol 2025. doi: 10.1038/s41582-025-01137-z
  4. Piradov M.A., Bakulin I.S., Zabirova A.Kh. et al. Transcranial magnetic stimulation in clinical and research practice. Moscow: Goryachaya Liniya – Telekom, 2024. 584 p. (In Russ.).
  5. Kricheldorff J., Göke K., Kiebs M. et al. Evidence of neuroplastic changes after transcranial magnetic, electric, and deep brain stimulation. Brain Sci 2022;12(7):929. doi: 10.3390/brainsci12070929
  6. Bhattacharya A., Darmani G., Udupa K. et al. Induction of plasticity and metaplasticity using noninvasive brain stimulation. Trends Neurosci 2025;48(10):792–807. doi: 10.1016/j.tins.2025.07.009
  7. Lefaucheur J.P., Aleman A., Baeken C. et al. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): an update (2014–2018). Clin Neurophysiol 2020;131(2):474–528. doi: 10.1016/j.clinph.2019.11.002. Erratum in: Clin Neurophysiol 2020;131(5):1168, 1169.
  8. Nicolo P., Ptak R., Guggisberg A.G. Variability of behavioural responses to transcranial magnetic stimulation: origins and predictors. Neuropsychologia 2015;74:137–44. doi: 10.1016/j.neuropsychologia.2015.01.033
  9. Miniussi C., Bortoletto M. Harnessing neural variability: implications for brain research and non-invasive brain stimulation. Neurosci Biobehav Rev 2025;176:106312. doi: 10.1016/j.neubiorev.2025.106312
  10. Homan S., Muscat W., Joanlanne A. et al. Treatment effect variability in brain stimulation across psychiatric disorders: a meta-analysis of variance. Neurosci Biobehav Rev 2021;124:54–62. doi: 10.1016/j.neubiorev.2020.11.033
  11. Boucher P.O., Ozdemir R.A., Momi D. et al. Sham-derived effects and the minimal reliability of theta burst stimulation. Sci Rep 2021;11(1):21170. doi: 10.1038/s41598-021-98751-w
  12. Prei K., Kanig C., Osnabruegge M. et al. Limited evidence for reliability of low and high frequency rTMS over the motor cortex. Brain Res 2023;1820:148534. doi: 10.1016/j.brainres.2023.148534
  13. Kanig C., Osnabruegge M., Schwitzgebel F. et al. Retest reliability of repetitive transcranial magnetic stimulation over the healthy human motor cortex: a systematic review and meta-analysis. Front Hum Neurosci 2023;17:1237713. doi: 10.3389/fnhum.2023.1237713
  14. Bakulin I.S., Poidasheva A.G., Lagoda D.Yu. et al. Prospects for the development of therapeutic transcranial magnetic stimulation. Nervnye bolezni = Nervous Diseases 2021;(4):3–10. (In Russ.). doi: 10.24412/2226-0757-2021-12371.
  15. Soleimani G., Nitsche M.A., Hanlon C.A. et al. Four dimensions of individualization in brain stimulation for psychiatric disorders: context, target, dose, and timing. Neuropsychopharmacology 2025;50(6):857–70. doi: 10.1038/s41386-025-02094-3. Erratum in: Neuropsychopharmacology 2025;50(10):1615. doi: 10.1038/s41386-025-02134-y
  16. Klooster D.C.W., Ferguson M.A., Boon P.A.J.M., Baeken C. Personalizing repetitive transcranial magnetic stimulation parameters for depression treatment using multimodal neuroimaging. Biol Psychiatry Cogn Neurosci Neuroimaging 2022;7(6):536–45. doi: 10.1016/j.bpsc.2021.11.004
  17. Zrenner C., Ziemann U. Closed-loop brain stimulation. Biol Psychiatry 2024;95(6):545–52. doi: 10.1016/j.biopsych.2023.09.014
  18. Csukly G., Orbán-Szigeti B., Réthelyi J.M. Response prediction for repetitive transcranial magnetic stimulation treatment. Curr Opin Psychiatry 2025;38(5):334–40. doi: 10.1097/YCO.0000000000001026
  19. Lin Y.L., Potter-Baker K.A., Sankarasubramanian V. et al. Stratification algorithm for repetitive TMS in stroke (START): results from an exploratory crossover study. J Neurol Sci 2025;473:123478. doi: 10.1016/j.jns.2025.123478
  20. Matsumoto H., Ugawa Y. Quadripulse stimulation (QPS). Exp Brain Res 2020;238(7–8):1619–25. doi: 10.1007/s00221-020-05788-w
  21. Hamada M., Ugawa Y. Quadripulse stimulation – a new patterned rTMS. Restor Neurol Neurosci 2010;28(4):419–24. doi: 10.3233/RNN-2010-0564
  22. Hamada M., Hanajima R., Terao Y. et al. Quadro-pulse stimulation is more effective than paired-pulse stimulation for plasticity induction of the human motor cortex. Clin Neurophysiol 2007;118(12):2672–82. doi: 10.1016/j.clinph.2007.09.062.
  23. Hamada M., Terao Y., Hanajima R. et al. Bidirectional long-term motor cortical plasticity and metaplasticity induced by quadripulse transcranial magnetic stimulation. J Physiol 2008;586(16):3927–47. doi: 10.1113/jphysiol.2008.152793
  24. Nakamura K., Groiss S.J., Hamada M. et al. Variability in response to quadripulse stimulation of the motor cortex. Brain Stimul 2016;9(6):859–66. doi: 10.1016/j.brs.2016.01.008.
  25. Kimura I., Ugawa Y., Hayashi M.J., Amano K. Quadripulse stimulation: A replication study with a newly developed stimulator. Brain Stimul 2022;15(3):579–81. doi: 10.1016/j.brs.2022.03.006
  26. Malenka R.C., Bear M.F. LTP and LTD: an embarrassment of riches. Neuron 2004;44(1):5–21. doi: 10.1016/j.neuron.2004.09.012
  27. Fitzgerald P.B., Fountain S., Daskalakis Z.J. A comprehensive review of the effects of rTMS on motor cortical excitability and inhibition. Clin Neurophysiol 2006;117(12):2584–96. doi: 10.1016/j.clinph.2006.06.712
  28. Rounis E., Huang Y.Z. Theta burst stimulation in humans: a need for better understanding effects of brain stimulation in health and disease. Exp Brain Res 2020;238(7–8):1707–14. doi: 10.1007/s00221-020-05880-1
  29. Wischnewski M., Schutter D.J. Efficacy and time course of theta burst stimulation in healthy humans. Brain Stimul 2015;8(4):685–92. doi: 10.1016/j.brs.2015.03.004
  30. Suppa A., Huang Y-Z., Funke K. et al. Ten years of theta burst stimulation in humans: established knowledge, unknowns and prospects. Brain Stimul 2016;9(3):323–35. doi: 10.1016/j.brs.2016.01.006
  31. Speranza B.E., Hill A.T., Do M. et al. The neurophysiological effects of theta burst stimulation as measured by electroencephalography: a systematic review. Biol Psychiatry Cogn Neurosci Neuroimaging 2024:S2451-9022(24)00206-4. doi: 10.1016/j.bpsc.2024.07.018
  32. Kirkovski M., Donaldson P.H., Do M. et al. A systematic review of the neurobiological effects of theta-burst stimulation (TBS) as measured using functional magnetic resonance imaging (fMRI). Brain Struct Funct 2023;228(3–4):717–49. doi: 10.1007/s00429-023-02634-x
  33. Di Lorenzo C., Tavernese E., Lepre C. et al. Influence of rTMS over the left primary motor cortex on initiation and performance of a simple movement executed with the contralateral arm in healthy volunteers. Exp Brain Res 2013;224(3):383–92. doi: 10.1007/s00221-012-3318-y
  34. Sohn M.N., Brown J.C., Sharma P. et al. Pharmacological adjuncts and transcranial magnetic stimulation-induced synaptic plasticity: a systematic review. J Psychiatry Neurosci 2024;49(1):E59–76. doi: 10.1503/jpn.230090
  35. Cirillo G., Di Pino G., Capone F. et al. Neurobiological after-effects of non-invasive brain stimulation. Brain Stimul 2017;10(1):1–18. doi: 10.1016/j.brs.2016.11.009
  36. Krasilnikova A.P., Egorova A.V., Voronkov D.N. et al. Cellular and molecular mechanisms underlying transcranial magnetic stimulation: experimental data for evaluating changes in nervous tissue. Annaly klinicheskoy i eksperimentalnoy nevrologii = Annals of Clinical and Experimental Neurology 2024;18(4):96–109. (In Russ.). doi: 10.17816/ACEN.1152
  37. Thickbroom G.W., Byrnes M.L., Edwards D.J., Mastaglia F.L. Repetitive paired-pulse TMS at I-wave periodicity markedly increases corticospinal excitability: a new technique for modulating synaptic plasticity. Clin Neurophysiol 2006;117(1):61–6. doi: 10.1016/j.clinph.2005.09.010
  38. Tiksnadi A., Murakami T., Wiratman W. et al. Direct comparison of efficacy of the motor cortical plasticity induction and the interindividual variability between TBS and QPS. Brain Stimul 2020;13(6):1824–33. doi: 10.1016/j.brs.2020.10.014
  39. Simeoni S., Hannah R., Sato D. et al. Effects of quadripulse stimulation on human motor cortex excitability: a replication study. Brain Stimul 2016;9(1):148–50. doi: 10.1016/j.brs.2015.10.007
  40. Viganò A., Sasso D’Elia T., Sava S.L. et al. Exploring the therapeutic potential of quadripulse rTMS over the visual cortex: a proof-of-concept study in healthy volunteers and chronic migraine patients with medication overuse headache. Biomedicines 2024;12(2):288. doi: 10.3390/biomedicines12020288
  41. Shimizu T., Hanajima R., Shirota Y. et al. Plasticity induction in the pre-supplementary motor area (pre-SMA) and SMA-proper differentially affects visuomotor sequence learning. Brain Stimul 2020;13(1):229–38. doi: 10.1016/j.brs.2019.08.001
  42. Okawada M., Kaneko F., Shibata E. Effect of primary motor cortex excitability changes after quadripulse transcranial magnetic stimulation on kinesthetic sensitivity: a preliminary study. Neurosci Lett 2021;741:135483. doi: 10.1016/j.neulet.2020.135483
  43. Tian D., Izumi S.I. TMS and neocortical neurons: an integrative review on the micro-macro connection in neuroplasticity. Jpn J Compr Rehabil Sci 2023;14:1–9. doi: 10.11336/jjcrs.14.1
  44. Enomoto H., Terao Y., Kadowaki S. et al. Effects of L-Dopa and pramipexole on plasticity induced by QPS in human motor cortex. J Neural Transm (Vienna) 2015;122(9):1253–61. doi: 10.1007/s00702-015-1374-8
  45. Hanajima R., Tanaka N., Tsutsumi R. et al. Effect of caffeine on long-term potentiation-like effects induced by quadripulse transcranial magnetic stimulation. Exp Brain Res 2019;237(3):647–51. doi: 10.1007/s00221-018-5450-9
  46. Bakulin I.S., Poidasheva A.G., Zabirova A.Kh. et al. Metaplasticity and non-invasive brain stimulation: the search for new biomarkers and directions for therapeutic neuromodulation. Annaly klinicheskoy i eksperimentalnoy nevrologii = Annals of Clinical and Experimental Neurology 2022;16(3):74–82. (In Russ.). doi: 10.54101/ACEN.2022.3.9
  47. Müller-Dahlhaus F., Ziemann U. Metaplasticity in human cortex. Neuroscientist 2015;21(2):185–202. doi: 10.1177/1073858414526645
  48. Abraham W.C. Metaplasticity: tuning synapses and networks for plasticity. Nat Rev Neurosci 2008;9(5):387. doi: 10.1038/nrn2356
  49. Cooper L.N., Bear M.F. The BCM theory of synapse modification at 30: interaction of theory with experiment. Nat Rev Neurosci 2012;13(11):798–810. doi: 10.1038/nrn3353
  50. Sorkhabi M.M., Wendt K., Wilson M.T., Denison T. Numerical modelling of plasticity induced by quadri-pulse stimulation. IEEE Access 2021;9:26484–90. doi: 10.1109/ACCESS.2021.3057829
  51. Nakatani-Enomoto S., Hanajima R., Hamada M. Bidirectional modulation of sensory cortical excitability by quadripulse transcranial magnetic stimulation (QPS) in humans. Clin Neurophysiol 2012;123(7):1415–21. doi: 10.1016/j.clinph.2011.11.037
  52. Watanabe T., Hanajima R., Shirota Y et al. Bidirectional effects on interhemispheric resting-state functional connectivity induced by excitatory and inhibitory repetitive transcranial magnetic stimulation. Hum Brain Mapp 2014;35(5):1896–905. doi: 10.1002/hbm.22300
  53. Tsutsumi R., Hanajima R., Terao Y. et al. Effects of the motor cortical quadripulse transcranial magnetic stimulation (QPS) on the contralateral motor cortex and interhemispheric interactions. J Neurophysiol 2014;111(1):26–35. doi: 10.1152/jn.00515.2013
  54. Shindo K., Kaneko F., Okawada M. et al. Efficacy and safety of multiple sessions of quadripulse stimulation in patients with stroke: a report of two cases. Brain Stimul 2019;12(3):821–23. doi: 10.1016/j.brs.2019.02.017
  55. Nakatani-Enomoto S., Hanajima R., Hamada M. et al. Quadripulse transcranial magnetic stimulation inducing long-term depression in healthy subjects may increase seizure risk in some patients with intractable epilepsy. Clin Neurophysiol Pract 2023;8:137–42. doi: 10.1016/j.cnp.2023.07.001
  56. Chou Y.H., Sundman M., Ton That V. et al. Cortical excitability and plasticity in Alzheimer’s disease and mild cognitive impairment: a systematic review and meta-analysis of transcranial magnetic stimulation studies. Ageing Res Rev 2022;79:101660. doi: 10.1016/j.arr.2022.101660
  57. Shah M., Suresh S., Paddick J. et al. Age-related changes in responsiveness to non-invasive brain stimulation neuroplasticity paradigms: a systematic review with meta-analysis. Clin Neurophysiol 2024;162:53–67. doi: 10.1016/j.clinph.2024.03.002
  58. Murakami T., Abe M., Tiksnadi A. et al. Abnormal motor cortical plasticity as a useful neurophysiological biomarker for Alzheimer’s disease pathology. Clin Neurophysiol 2024;158:170–9. doi: 10.1016/j.clinph.2023.12.131
  59. Balloff C., Janßen L.K., Hartmann C.J. et al. Predictive value of synaptic plasticity for functional decline in patients with multiple sclerosis. Front Neurol 2024;15:1410673. doi: 10.3389/fneur.2024.1410673
  60. Balloff C., Penner I.K., Ma M. The degree of cortical plasticity correlates with cognitive performance in patients with Multiple Sclerosis. Brain Stimul 2022;15(2):403–13. doi: 10.1016/j.brs.2022.02.007
  61. Hanajima R., Tanaka N., Tsutsumi R. et al. The effect of age on the homotopic motor cortical long-term potentiation-like effect induced by quadripulse stimulation. Exp Brain Res 2017;235(7):2103–8. doi: 10.1007/s00221-017-4953-0
  62. Nakatani-Enomoto S., Hanajima R., Hamada M. et al. Some evidence supporting the safety of quadripulse stimulation (QPS). Brain Stimul 2011;4(4):303–5. doi: 10.1016/j.brs.2010.10.004
  63. Rossi S., Antal A., Bestmann S. et al. Safety and recommendations for TMS use in healthy subjects and patient populations, with updates on training, ethical and regulatory issues: Expert Guidelines. Clin Neurophysiol 2021;132(1):269–306. doi: 10.1016/j.clinph.2020.10.003
  64. Jung N.H., Gleich B., Gattinger N. et al. Quadri-pulse theta burst stimulation using ultra-high frequency bursts – a new protocol to induce changes in cortico-spinal excitability in human motor cortex. PLoS One 2016;11(12):e0168410. doi: 10.1371/journal.pone.0168410

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