Experimental Brain Research

, Volume 161, Issue 1, pp 114–124 | Cite as

Distinct changes in cortical and spinal excitability following high-frequency repetitive TMS to the human motor cortex

  • Angelo QuartaroneEmail author
  • Sergio Bagnato
  • Vincenzo Rizzo
  • Francesca Morgante
  • Antonio Sant’Angelo
  • Fortunato Battaglia
  • Corrado Messina
  • Hartwig Roman Siebner
  • Paolo Girlanda
Research Article


It has been shown that high-frequency repetitive transcranial magnetic stimulation (rTMS) to the human primary motor hand area (M1-HAND) can induce a lasting increase in corticospinal excitability. Here we recorded motor evoked potentials (MEPs) from the right first dorsal interosseus muscle to investigate how sub-threshold high-frequency rTMS to the M1-HAND modulates cortical and spinal excitability. In a first experiment, we gave 1500 stimuli of 5 Hz rTMS. At an intensity of 90% of active motor threshold, rTMS produced no effect on MEP amplitude at rest. Increasing the intensity to 90% of resting motor threshold (RMT), rTMS produced an increase in MEP amplitude. This facilitatory effect gradually built up during the course of rTMS, reaching significance after the administration of 900 stimuli. In a second experiment, MEPs were elicited during tonic contraction using weak anodal electrical or magnetic test stimuli. 1500 (but not 600) conditioning stimuli at 90% of RMT induced a facilitation of MEPs in the contracting FDI muscle. In a third experiment, 600 conditioning stimuli were given at 90% of RMT to the M1-HAND. Using two well-established conditioning-test paradigms, we found a decrease in short-latency intracortical inhibition (SICI), and a facilitation of the first peak of facilitatory I-waves interaction (SICF). There was no correlation between the relative changes in SICI and SICF. These results demonstrate that subthreshold 5 Hz rTMS can induce lasting changes in specific neuronal subpopulations in the human corticospinal motor system, depending on the intensity and duration of rTMS. Short 5 Hz rTMS (600 stimuli) at 90% of RMT can selectively shape the excitability of distinct intracortical circuits, whereas prolonged 5 Hz rTMS (≥900 stimuli) provokes an overall increase in excitability of the corticospinal output system, including spinal motoneurones.


Corticospinal excitability Human motor cortex Paired pulse TMS Repetitive transcranial magnetic stimulation Transcranial electrical stimulation 



H.R. Siebner was supported by the Bundesministerium für Bildung und Forschung (grant 01GO0206) and the Volkswagen Foundation (grant I/79 932).


  1. Chen R, Classen J, Gerloff G, Celnik P, Wassermann EM, Hallett M, Cohen LG (1997) Depression of motor cortex excitability by low frequency transcranial magnetic stimulation. Neurology 48:1398–1403PubMedGoogle Scholar
  2. Day BL, Dressler D, Maertens de Noordhout A, Marsden CD, Nakashima K, Rothwell JC, Thompson PD (1989) Electric and magnetic stimulation of human motor cortex: surface EMG and single motor unit responses. J Physiol 412:449–473PubMedGoogle Scholar
  3. Di Lazzaro V, Oliviero A, Profice P, Saturno E, Pilato F, Insola A, Mazzone P, Tonali P, Rothwell JC (1998) Comparison of descending volleys evoked by transcranial magnetic and electric stimulation in conscious humans. Electroen Clin Neuro 109:397–401CrossRefGoogle Scholar
  4. Di Lazzaro V, Oliviero A, Profice P, Insola A, Mazzone P, Tonali P, Rothwell JC (1999) Direct recordings of descending volleys after transcranial magnetic and electric motor cortex stimulation in conscious humans. Electroen Clin Neuro Suppl 51:120–126Google Scholar
  5. Di Lazzaro V, Oliviero A, Mazzone P, Pilato F, Saturno E, Dileone M, Insola A, Tonali PA, Rothwell JC (2002) Short-term reduction of intracortical inhibition in the human motor cortex induced by repetitive transcranial magnetic stimulation. Exp Brain Res 147:108–113CrossRefPubMedGoogle Scholar
  6. Fitzgerald PB, Brown TL, Daskalakis ZJ, Chen R, Kulkarni J (2002) Intensity-dependent effects of 1 Hz rTMS on human corticospinal excitability. Clin Neurophysiol 113:1136–1141CrossRefPubMedGoogle Scholar
  7. Gangitano M, Valero-Cabre A, Tormos JM, Mottaghy FM, Romero JR, Pascual-Leone A (2002) Modulation of input-output curves by low and high frequency repetitive transcranial magnetic stimulation of the motor cortex. Clin Neurophysiol 113:1249–1257CrossRefPubMedGoogle Scholar
  8. Gerschlager W, Siebner HR, Rothwell JC (2001) Decreased corticospinal excitability after subthreshold 1 Hz rTMS over lateral premotor cortex. Neurology 57:379–380PubMedGoogle Scholar
  9. Hallett M (2000) Transcranial magnetic stimulation and the human brain. Nature 6792:147–150CrossRefGoogle Scholar
  10. Kujirai T, Caramia MD, Rothwell JC, Day BL, Thompson PD, Ferbert A, Wroe S, Asselman P, Marsden CD (1993) Corticocortical inhibition in human motor cortex. J Physiol 471:501–519PubMedGoogle Scholar
  11. Maeda F, Keenan JP, Tormos JM, Topka H, Pascual-Leone A (2000a) Modulation of corticospinal excitability by repetitive transcranial magnetic stimulation. Clin Neurophysiol 111:800–805CrossRefPubMedGoogle Scholar
  12. Maeda F, Keenan JP, Tormos JM, Topka H, Pascual-Leone A (2000b) Interindividual variability of the modulatory effects of repetitive transcranial magnetic stimulation on cortical excitability. Exp Brain Res 133:425–430CrossRefPubMedGoogle Scholar
  13. Modugno N, Nakamura Y, MacKinnon CD, Filipovic SR, Bestmann S, Berardelli A, Rothwell JC (2001) Motor cortex excitability following short trains of repetitive magnetic stimuli. Exp Brain Res 140:453–459CrossRefPubMedGoogle Scholar
  14. Muellbacher W, Ziemann U, Boroojerdi B, Hallett M (2000) Effects of low-frequency transcranial magnetic stimulation on motor excitability and basic motor behavior. Clin Neurophysiol 111:1002–1007CrossRefPubMedGoogle Scholar
  15. Oldfield RC (1971) The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 9:97–113CrossRefPubMedGoogle Scholar
  16. Pascual-Leone A, Valls-Sole J, Wassermann EM, Hallett M (1994) Responses to rapid-rate transcranial magnetic stimulation of the human motor cortex. Brain 117:847–858PubMedGoogle Scholar
  17. Pascual-Leone A, Tormos JM, Keenan J, Tarazona F, Canete C, Catala MD (1998) Study and modulation of human cortical excitability with transcranial magnetic stimulation. J Clin Neurophysiol 15:333–343CrossRefPubMedGoogle Scholar
  18. Peinemann A, Lehner C, Mentschel C, Munchau A, Conrad B, Siebner HR (2000) Subthreshold 5-Hz repetitive transcranial magnetic stimulation of the human primary motor cortex reduces intracortical paired-pulse inhibition. Neurosci Lett 296:21–24CrossRefPubMedGoogle Scholar
  19. Peinemann A, Reimer B, Löer C, Quartarone A, Münchau A, Conrad B, Siebner HR (2004) Long-lasting increase in corticospinal excitability after 1800 pulses of subthreshold 5 Hz repetitive TMS to the motor cortex. Clin Neurophysiol 115(7):1519–26CrossRefPubMedGoogle Scholar
  20. Rizzo V, Siebner H, Modugno N, Pesenti A, Munchau A, Gerschlager W, Webb RM, Rothwell JC (2004) Shaping the excitability of human motor cortex with premotor rTMS. J Physiol 554:483–495CrossRefPubMedGoogle Scholar
  21. Romero JR, Anschel D, Sparing R, Gangitano M, Pascual-Leone A (2002) Subthreshold low frequency repetitive transcranial magnetic stimulation selectively decreases facilitation in the motor cortex. Clin Neurophysiol 113:101–107CrossRefPubMedGoogle Scholar
  22. Rossini PM, Barker AT, Berardelli A, Caramia MD, Caruso G, Cracco RQ, Dimitrijevic MR, Hallett M, Katayama Y, Lucking CH (1994) Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application. Report of an IFCN committee. Electroen Clin Neuro 91:79–92CrossRefGoogle Scholar
  23. Rothwell JC (1997) Techniques and mechanisms of action of transcranial stimulation of the human motor cortex. J Neurosci Meth 74:113–122CrossRefPubMedGoogle Scholar
  24. Rothwell JC (1999) Paired-pulse investigations of short-latency intracortical facilitation using TMS in humans. Electroen Clin Neuro Suppl 51:113–119Google Scholar
  25. Rounis E, Siebner HR, et al (2003) The effect of 5 Hz repetitive transcranial magnetic stimulation over the left primary motor hand area on regional blood flow and motor cortex excitability. NeuroImage 19:17822 (available on CD-Rom in Issue 2, Suppl 1)Google Scholar
  26. Siebner HR, Rothwell J (2003) Transcranial magnetic stimulation: new insights into representational cortical plasticity. Exp Brain Res 148:1–16Google Scholar
  27. Siebner HR, Peller M, Willoch F, Minoshima S, Boecker H, Auer C, Drzezga A, Conrad B, Bartenstein P (2000) Lasting cortical activation after repetitive TMS of the motor cortex: a glucose metabolic study. Neurology 54:956–963PubMedGoogle Scholar
  28. Siebner HR, Takano B, Peinemann A, Schwaiger M, Conrad B, Drzezga A (2001) Continuous transcranial magnetic stimulation during positron emission tomography: a suitable tool for imaging regional excitability of the human cortex. NeuroImage 14:883–890CrossRefPubMedGoogle Scholar
  29. Sommer M, Wu T, Tergau F, Paulus W (2002) Intra- and interindividual variability of motor responses to repetitive transcranial magnetic stimulation. Clin Neurophysiol 113:265–269CrossRefPubMedGoogle Scholar
  30. Tokimura H, Ridding MC, Tokimura Y, Amassian VE, Rothwell JC (1996) Short latency facilitation between pairs of threshold magnetic stimuli applied to human motor cortex. Electroen Clin Neuro 101:263–272CrossRefGoogle Scholar
  31. Touge T, Gerschlager W, Brown P, Rothwell JC (2001) Are the after effects of low-frequency rTMS on motor cortex excitability due to changes in the efficacy of cortical synapses? Clin Neurophysiol 112:2138–2145CrossRefPubMedGoogle Scholar
  32. Ugawa Y, Rothwell JC, Day BL, Thompson PD, Marsden CD (1991) Percutaneous electrical stimulation of corticospinal pathways at the level of the pyramidal decussation in humans. Ann Neurol 29:418–27PubMedGoogle Scholar
  33. Valero-Cabre A, Oliveri M, Gangitano M, Pascual-Leone A (2001) Modulation of spinal cord excitability by subthreshold repetitive transcranial magnetic stimulation of the primary motor cortex in humans. Neuroreport 12:3845–3848CrossRefPubMedGoogle Scholar
  34. Wassermann EM (1998) Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5–7, 1996. Electroen Clin Neuro 108:1–16Google Scholar
  35. Wu T, Sommer M, Tergau F, Paulus W (2000) Lasting influence of repetitive transcranial magnetic stimulation on intracortical excitability in human subjects. Neurosci Lett 287:37–40CrossRefPubMedGoogle Scholar
  36. Ziemann U (1999) Intracortical inhibition and facilitation in the conventional paired TMS paradigm. Electroen Clin Neuro Suppl 51:127–136Google Scholar
  37. Ziemann U, Lonnecker S, Steinhoff BJ, Paulus W (1996) Effects of antiepileptic drugs on motor cortex excitability in humans: a transcranial magnetic stimulation study. Ann Neurol 40:367–378PubMedGoogle Scholar
  38. Ziemann U, Tergau F, Wassermann EM, Wischer S, Hildebrandt J, Paulus W (1998a) Demonstration of facilitatory I waves interaction in the human motor cortex by paired transcranial magnetic stimulation. J Physiol 511:181–190CrossRefPubMedGoogle Scholar
  39. Ziemann U, Tergau F, Wischer S, Hildebrandt J, Paulus W (1998b) Pharmacological control of facilitatory I-wave interaction in the human motor cortex. A paired transcranial magnetic stimulation study. Electroen Clin Neuro 109:321–330CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Angelo Quartarone
    • 1
    • 5
    Email author
  • Sergio Bagnato
    • 1
    • 2
  • Vincenzo Rizzo
    • 1
  • Francesca Morgante
    • 1
  • Antonio Sant’Angelo
    • 1
  • Fortunato Battaglia
    • 3
  • Corrado Messina
    • 1
  • Hartwig Roman Siebner
    • 4
  • Paolo Girlanda
    • 1
  1. 1.Department of Neuroscience, Psychiatric and Anaesthesiological SciencesUniversity of MessinaMessinaItaly
  2. 2.Dipartimento di Scienze Neurologiche and Istituto Neurologico Mediterraneo Neuromed IRCCSUniversita degli Studi di Roma “La Sapienza”RomaItalia
  3. 3.Department of Physiology and PharmacologyCity University of New York Medical SchoolUSA
  4. 4.Department of NeurologyChristian-Albrechts-UniversityKielGermany
  5. 5.Clinica Neurologica 2Policlinico UniversitarioMessinaItaly

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