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Physiology of modulation of motor cortex excitability by low-frequency suprathreshold repetitive transcranial magnetic stimulation

Abstract

Many studies show consistently that repetitive transcranial magnetic stimulation (rTMS) with a frequency of 1 Hz and an intensity above the resting motor threshold (RMT) performed for several minutes over the primary motor cortex (M1) leads to a depression of cortical excitability. Furthermore, most studies concur on a facilitation of the non-stimulated contralateral M1. Little is known, however, about the physiological mechanisms underlying these effects. In 11 healthy volunteers, we stimulated the left M1 for 15 min with 1 Hz-rTMS of 115% RMT. Before, immediately after, and 30 min after the rTMS train, we examined short-interval intracortical inhibition (SICI; interstimulus interval (ISI) of 2 and 4 ms), intracortical facilitation (ICF; ISI 10 ms), and short-interval intracortical facilitation (SICF; ISI 1.5 ms) with established paired-pulse protocols. Mean unconditioned motor evoked potential (MEP) amplitudes and RMT were also measured. Two sessions were run at least 1 week apart, in one excitability of the stimulated M1 was tested, in the other one excitability of the non-stimulated M1. rTMS led to the expected reduction of MEP amplitude of the stimulated M1, which was significant only immediately after the rTMS train. rTMS increased MEP amplitude of the non-stimulated M1, which lasted for at least 30 min. RMT, SICI, ICF and SICF did not show any significant change in either M1, except for a long lasting increase of SICF in the non-stimulated M1. In conclusion, the MEP increase in the non-stimulated M1 lasted longer than the MEP decrease in the stimulated M1. Only the long-lasting MEP increase was associated with a specific change in intracortical excitability (increase in SICF). Modulation of motor cortical inhibition did not play a role in explaining the rTMS induced changes in MEP amplitude.

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References

  1. Asanuma H, Okuda O (1962) Effects of transcallosal volleys on pyramidal tract cell activity of cat. J Neurophysiol 25:198–208

    PubMed  CAS  Google Scholar 

  2. Bagnato S, Currà A, Modugno N, Gilio F, Quartarone A, Rizzo V, Girlanda P, Inghillieri M, Berardelli A (2005) One-hertz subthreshold TMS increases the threshold for evoking inhibition in the human motor cortex. Exp Brain Res 160:368–374

    PubMed  Article  CAS  Google Scholar 

  3. Boroojerdi B, Battaglia F, Muellbacher W, Cohen LG (2001) Mechanisms influencing stimulus-response properties of the human corticospinal system. Clin Neurophysiol 112:131–137

    Article  Google Scholar 

  4. Bütefisch CM, Davis BC, Wise SP, Sawaki L, Kopylev L, Classen J, et al (2000) Mechanisms of use-dependent plasticity in the human motor cortex. Proc Natl Acad Sci USA 97:3661–3665

    PubMed  Article  Google Scholar 

  5. Calford MB, Tweedale R (1990) Interhemispheric transfer of plasticity in the cerebral cortex. Science 249:805–807

    PubMed  Article  CAS  Google Scholar 

  6. Chen R, Classen J, Gerloff C, Celnik P, Wassermann EM, Hallett M, Cohen LG (1997) Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation. Neurology 48:1398–1403

    PubMed  CAS  Google Scholar 

  7. Di Lazzaro V, Oliviero A, Profice P, Pennisi MA, Pilato F, Zito G, Dileone M, Nicoletti R, Pasqualetti P, Tonali PA (2003) Ketamine increases motor cortex excitability to transcranial magnetic stimulation. J Physiol 547:485–496

    PubMed  Article  CAS  Google Scholar 

  8. Di Lazzaro V, Oliviero A, Pilato F, Saturno E, Dileone M, Mazzone P, Insola A, Tonali PA, Rothwell JC (2004) The physiological basis of transcranial motor cortex stimulation in conscious humans. Clin Neurophysiol 115:255–266

    PubMed  Article  CAS  Google Scholar 

  9. Ferbert A, Priori A, Rothwell JC, Day BL, Colebatch JG, Marsden CD (1992) Interhemispheric inhibition of the human motor cortex. J Physiol 453:525–546

    PubMed  CAS  Google Scholar 

  10. Fitzgerald PB, Brown TL, Daskalakis ZJ, Chen R, Kulkarni J (2002) Intensity-dependent effects of 1 Hz rTMS on human corticospinal excitability. Clin Neurophysiol 113:1136–1141

    PubMed  Article  Google Scholar 

  11. Gilio F, Rizzo V, Siebner HR, Rothwell JC (2003) Effects on the right motor hand-area excitability produced by low-frequency rTMS over human contralateral homologous cortex. J Physiol 551:563–573

    PubMed  Article  CAS  Google Scholar 

  12. Hanajima R, Ugawa Y, Terao Y, Sakai K, Furubayashi T, Machii K, Kanazawa I (1998) Paired-pulse magnetic stimulation of the human motor cortex: differences among I waves. J Physiol 509:607–618

    PubMed  Article  CAS  Google Scholar 

  13. Ilic TV, Meintzschel F, Cleff U, Ruge D, Kessler KR, Ziemann U (2002) Short-interval paired-pulse inhibition and facilitation of human motor cortex: the dimension of stimulus intensity. J Physiol 545:153–167

    PubMed  Article  CAS  Google Scholar 

  14. Kammer T, Beck S, Thielscher A, Laubis-Herrmann U, Topka H (2001) Motor thresholds in humans: a transcranial magnetic stimulation study comparing different pulse waveforms, current directions and stimulator types. Clin Neurophysiol 112:250–258

    PubMed  Article  CAS  Google Scholar 

  15. Kujirai T, Caramia MD, Rothwell JC, Day BL, Thompson FD, Ferbert A, Wroe S, Asselman P, Marsden CD (1993) Corticocortical inhibition in human motor cortex. J Physiol 471:501–519

    PubMed  CAS  Google Scholar 

  16. Liepert J, Hamzei F, Weiller C (2000) Motor cortex disinhibition of the unaffected hemisphere after acute stroke. Muscle Nerve 23:1761–1763

    PubMed  Article  CAS  Google Scholar 

  17. Matsunami K, Hamada I (1984) Effects of stimulation of corpus callosum on precentral neuron activity in the awake monkey. J Neurophysiol 52:676–691

    PubMed  CAS  Google Scholar 

  18. 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 140:453–459

    PubMed  Article  CAS  Google Scholar 

  19. 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 111:1002–1007

    PubMed  Article  CAS  Google Scholar 

  20. Nitsche MA, Fricke K, Henschke U, Schlitterlau A, Liebetanz D, Lang N, Henning S, Tergau F, Paulus W (2003) Pharmacological modulation of cortical excitability shifts induced by transcranial direct current stimulation in humans. J Physiol 553:293–301

    PubMed  Article  CAS  Google Scholar 

  21. Orth M, Snijders AH, Rothwell J (2003) The variability of intracortical inhibition and facilitation. Clin Neurophysiol 114:2362–2369

    PubMed  Article  CAS  Google Scholar 

  22. Pascual-Leone A, Valls-Sole J, Wassermann EM, Hallett M (1994) Responses to rapid-rate transcranial magnetic stimulation of the human motor cortex. Brain 117:847–858

    PubMed  Article  Google Scholar 

  23. Plewnia C, Lotze M, Gerloff C (2003) Disinhibition of the contralateral motor cortex by low-frequency rTMS. Neuroreport 14:609–612

    PubMed  Article  Google Scholar 

  24. Rossini PM, Barker AT, Berardelli A, Caramia MD, Caruso G, Cracco RQ, Dimitrijevic MR, Hallett M, Katayama Y, Licking 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. Electroencephalogr Clin Neurophysiol 91:79–92

    PubMed  Article  CAS  Google Scholar 

  25. Schambra HM, Sawaki L, Cohen LG. (2003) Modulation of excitability of human motor cortex (M1) by 1 Hz transcranial magnetic stimulation of the contralateral M1. Clin Neurophysiol 114:130–133

    PubMed  Article  CAS  Google Scholar 

  26. Schwenkreis P, Witscher K, Janssen F, Addo A, Dertwinkel R, Zenz M, Malin J-P, Tegenthoff M (1999) Influence of the N-methyl-d-aspartate antagonist memantine on human motor cortex excitability. Neurosci Lett 270:137–140

    PubMed  Article  CAS  Google Scholar 

  27. Siebner HR, Auer C, Conrad B (1999) Abnormal increase in the corticomotor output to the affected hand during repetitive transcranial magnetic stimulation of the primary motor cortex in patients with writer’s cramp. Neurosci Lett 262:133–136

    PubMed  Article  CAS  Google Scholar 

  28. Stefan K, Kunesch E, Cohen LG, Benecke R, Classen J (2000) Induction of plasticity in the human motor cortex by paired associative stimulation. Brain 123:572–584

    PubMed  Article  Google Scholar 

  29. Stefan K, Kunesch E, Benecke R, Cohen LG, Classen J (2002) Mechanisms of enhancement of human motor cortex excitability induced by interventional paired associative stimulation. J Physiol 543:699–708

    PubMed  Article  CAS  Google Scholar 

  30. Tokimura H, Ridding MC, Tokimura Y, Amassian VE, Rothwell JC (1996) Short latency facilitation between pairs of threshold magnetic stimuli apllied to human motor cortex. Electroencephalogr Clin Neurophysiol 101:263–272

    PubMed  Article  CAS  Google 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 112:2138–2145

    PubMed  Article  CAS  Google Scholar 

  32. Ugawa Y, Hanajima R, Kanazawa I (1993) Interhemispheric facilitation of the hand area of the human motor cortex. Neurosci Lett 160:153–155

    PubMed  Article  CAS  Google Scholar 

  33. Wassermann EM, Wedegaertner FR, Ziemann U, George MS, Chen R (1998) Crossed reduction of human motor cortex excitability by 1-Hz transcranial magnetic stimulation. Neurosci Lett 250:141–144

    PubMed  Article  CAS  Google Scholar 

  34. Werhahn KJ, Mortensen J, Kaelin-Lang A, Boroojerdi B, Cohen LG (2002) Cortical excitability changes induced by deafferentiation of the contralateral hemisphere. Brain 125:1402–1413

    PubMed  Article  Google Scholar 

  35. Ziemann U, Lonnecker S, Steinhoff BJ, Paulus W (1996a) Differential effects of various antiepileptic drugs on motor cortex excitability in man. A transcranial magnetic stimulation study. Ann Neurol 40:367–378

    Article  CAS  Google Scholar 

  36. Ziemann U, Rothwell JC, Ridding MC (1996b) Interaction between intracortical inhibition and facilitation in human motor cortex. J Physiol 496:873–881

    CAS  Google Scholar 

  37. Ziemann U, Chen R, Cohen LG, Hallett M (1998a) Dextromethorphan decreases the excitability of the human motor cortex. Neurology 51:1320–1324

    CAS  Google Scholar 

  38. Ziemann U, Tergau F, Wassermann EM, Wischer S, Hildebrandt J, Paulus W (1998b) Demonstration of facilitatory I-wave interaction in the human motor cortex by paired transcranial magnetic stimulation. J Physiol 511:181–190

    Article  CAS  Google Scholar 

  39. Ziemann U, Tergau F, Wischer S, Hildebrandt J, Paulus W (1998c) Pharmacological control of facilitatory I-wave interaction in the human motor cortex. A paired transcranial magnetic stimulation study. Electroencephalogr Clin Neurophysiol 109:321–330

    Article  CAS  Google Scholar 

  40. Ziemann U, Muellbacher W, Hallett M, Cohen LG (2001) Modulation of practice-dependent plasticity in human motor cortex. Brain 124:1171–1181

    PubMed  Article  CAS  Google Scholar 

  41. Ziemann U (2004a) TMS induced plasticity in human cortex. Rev Neurosci 15:253–266

    Google Scholar 

  42. Ziemann U (2004b) TMS and drugs. Clin Neurophysiol 115:1717–1729

    Article  CAS  Google Scholar 

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Correspondence to G. Heide.

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Heide, G., Witte, O. & Ziemann, U. Physiology of modulation of motor cortex excitability by low-frequency suprathreshold repetitive transcranial magnetic stimulation. Exp Brain Res 171, 26–34 (2006). https://doi.org/10.1007/s00221-005-0262-0

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Keywords

  • Repetitive transcranial magnetic stimulation
  • Motor cortex
  • Cortical excitability
  • Intracortical inhibition
  • Human