Safety of transcranial magnetic stimulation: review of international guidelines and new findings

Transcranial magnetic stimulation (TMS) is a rapidly developing method of neuromodulation. The use of TMS has increased significantly in both research and clinical practice. This allows not only to better understand this method, but also assess possible risks and consequences for both healthy individuals and patients. In 1998 and 2009 safety, ethical considerations, and application guidelines for the use of TMS in clinical practice and research were published. These recommendations are now the basis for safe application of the method in clinical practice and research. Safety of brain stimulation includes several aspects: the prevention and treatment of adverse effects, the strategy of patient and stimulation protocols selection, as well as safety and monitoring procedures. The most common adverse effects of TMS include headache and neck pain, syncope, transient hearing impairment. The risk of epileptic seizureis extremely low and can be minimized by careful selection of patients and the use of safe stimulation protocols. Careful selection of patients is important, taking into account a large number of factors that influence the risk of adverse effects. These factors are considered in the questionnaires to identify limitations and absolute or relative contraindications to TMS. Another important part of TMS safety is the choice of the stimulation protocol and parameters such as intensity, frequency, duration of one train of stimuli, and the interstimulus interval. Currently, the recommended limits of stimulation parameters are covered in the safety guidelines. It is also necessary to follow the procedure, including the monitoring the patient's condition during TMS and the providing qualified assistance in case of adverse effects.

1. Wassermann E.M. 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. Electroencephalogr Clin Neurophysiol 1998;108(1):1–16. PMID: 9474057.

2. Hallett M., Wassermann E.M., Pascual-Leone A. Repetitive transcranial magnetic stimulation. Recommendations for the practice of clinical neurophysiology: guidelines of the international federation of clinical neurophysiology. In: Electroencephalography and clinical neurophysiology, 2nd edn. (Suppl 52). 1999; p.105–13.

3. Rossi S., Hallett M., Rossini P.M. et al. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol 2009;120(12):2008–39. DOI: 10.1016/j.clinph.2009.08.016. PMID: 19833552.

4. Najib U., Horvath J.C. Transcranial Magnetic Stimulation (TMS) Safety Considerations and Recommendations. In: Transcranial magnetic stimulation. Eds. A. Ro - tenberg, J.C. Horvath, A. Pascual-Leone. New York: Humana Press, 2014. Pp.15–31.

5. Ruohonen J., lmoniemi R. Physical principles for transcranial magnetic stimulation. In: Handbook of transcranial magnetic stimulation. Eds.: A. Pascual-Leone, N.J. Davey, J. Rothwell et al. New York: CRC Press, 2002.

6. Roth B.J., Pascual-Leone A., Cohen L.G. et al. The heating of metal electrodes during rapid-rate magnetic stimulation: a possible safety hazard. Electroencephalogr Clin Neurophysiol 1992;85(2):116–23. PMID: 1373364.

7. Rotenberg A., Harrington M.G., Birnbaum D.S. et al. Minimal heating of titanium skull plates during 1 Hz repetitive transcranial magnetic stimulation. Clin Neurophysiol 2007;118:2536–8. DOI: 10.1016/j.clinph.2007.08.003. PMID: 17890148.

8. Matsumi N., Matsumoto K., Mishima N. et al. Thermal damage threshold of brain tissue--histological study of heated normal monkey brains. Neurol Med Chir (Tokyo) 1994;34(4):209–15. PMID: 7520542.

9. Barker A.T. An introduction to the basic principles of magnetic nerve stimulation. J Clin Neurophysiol 1991;8(1):26–37. PMID: 2019648.

10. Kumar R., Chen R., Ashby P. Safety of transcranial magnetic stimulation in patients with implanted deep brain stimulators. Mov Disord 1999;14(1): 157–8. PMID: 9918361.

11. Kuhn A.A., Trottenberg T., Kupsch A. et al. Pseudo-bilateral hand motor responses evoked by transcranial magnetic stimulation in patients with deep brain stimulators. Clin Neurophysiol 2002;113(3):341–5. PMID: 11897534.

12. Schrader L.M., Stern J.M., Fields T.A.

13. et al. A lack of effect from transcranial magnetic stimulation (TMS) on the vagus nerve stimulator (VNS). Clin Neurophysiol 2005;116(10):2501–4. DOI: 10.1016/j.clinph.2005.06.025. PMID: 16122980.

14. Phielipp N.M., Saha U., Sankar T. et al. Safety of repetitive transcranial magnetic stimulation in patients with implanted cortical electrodes. An ex vivo study and report of a case. Clin Neurophysiol 2017;128(6):1109–15. DOI: 10.1016/j.clinph.2017.01.021. PMID: 28259678.

15. Machii K., Cohen D., Ramos-Estebanez C. et al. Safety of rTMS to non-motor cortical areas in healthy participants and patients. Clin Neurophysiol 2006;117(2):455–71. DOI: 10.1016/j.clinph.2005.10.014. PMID: 16387549.

16. Loo C.K., McFarquhar T.F., Mitchell P.B. A review of the safety of repetitive transcranial magnetic stimulation as a clinical treatment for depression. Int J Neuropsychopharmacol 2008;11(1):131–47. DOI: 10.1017/S1461145707007717. PMID: 17880752.

17. Zangen A., Roth Y., Voller B. et al. Transcranial magnetic stimulation of deep brain regions: evidence for efficacy of the H-coil. Clin Neurophysiol 2005;116(4):775–9. DOI: 10.1016/j.clinph.2004.11.008. PMID: 15792886.

18. Perera T., George M.S., Grammer G. et al. The Clinical TMS Society Consensus Review and Treatment Recommendations for TMS Therapy for Major Depressive Disorder. Brain Stimul 2016;9(3):336–46. DOI: 10.1016/j.brs.2016.03.010. PMID: 27090022.

19. Dobek C.E., Blumberger D.M., Downar J. et al. Risk of seizures in transcranial magnetic stimulation: a clinical review to inform consent process focused on bupro-pion. Neuropsychiatr Dis Treat 2015;11:2975–87. DOI: 10.2147/NDT.S91126. PMID: 26664122.

20. Lahteenmaki M., Sormunen E., Koivisto M. et al. TMS-Induced Seizure Following Focal Single-Pulse IPS Stimulation. Brain stimul 2015;8(6):1238. DOI: 10.1016/j.brs.2015.09.003. PMID: 26460198.

21. Agosta S., Galante E., Ferraro F. et al. Report of a delayed seizure after low frequency repetitive Transcranial Magnetic Stimulation in a chronic stroke patient. Clin Neurophysiol 2016;127(2):1736–7. DOI: 10.1016/j.clinph.2014.11.029. PMID: 26299388.

22. Groiss S.J., Trenado C., Sabel M. et al. Focal seizure induced by preoperative navigated transcranial magnetic stimulation in a patient with anaplastic oligoastrocytoma. Brain stimul 2017;10(2):331–2. DOI: 10.1016/j.brs.2016.12.006. PMID: 28017645.

23. Cogne M., Gil-Jardine C., Joseph P.A. et al. Seizure induced by repetitive transcranial magnetic stimulation for central pain: adapted guidelines for post-stroke patients. Brain stimul 2017;10(4):862–4. DOI: 10.1016/j.brs.2017.03.010. PMID: 28359831.

24. Kumar N., Padma Srivastava M.V., Verma R. et al. Can low-frequency repetitive transcranial magnetic stimulation precipitate a late-onset seizure in a stroke patient? Clin Neurophysiol 2016;127:1734–6. DOI: 10.1016/j.clinph.2015.06.033. PMID: 26306660.

25. Sakkas P., Theleritis C.G., Psarros C. et al. Jacksonian seizure in a manic patient treated with rTMS. World J Biol Psychiatry 2008;9(2):159–60. DOI: 10.1080/15622970701624595. PMID: 18428081.

26. Gomez L., Morales L., Trapaga O. et al. Seizure induced by sub-threshold 10-Hz rTMS in a patient with multiple risk factors. Clin Neurophysiol 2011;122:1057–8. DOI: 10.1016/j.clinph.2010.09.007. PMID: 21036102.

27. Hu S.H., Wang S.S., Zhang M.M. et al. Repetitive transcranial magnetic stimulation-induced seizure of a patient with adolescent-onset depression: a case report and literature review. J Int Med Res 2011;39(5):2039–44. DOI: 10.1177/147323001103900552. PMID: 22118010.

28. Chiramberro M., Lindberg N., Isometsa E. et al. Repetitive transcranial magnetic stimulation induced seizures in an adolescent patient with major depression: a case report. Brain stimul 2013;6(5):830–1. DOI: 10.1016/j.brs.2013.02.003. PMID: 23518261.

29. Червяков А.В., Пойдашева А.Г., Наза-рова М.А. и др. Навигационная ритмическая транскраниальная магнитная стимуляция в постинсультной реабилитации: рандомизированное слепое плацебоконтролируемое исследование. Анналы клинической и экспериментальной неврологии 2015;9(4):32–8. [Chervyakov A.V., Poydasheva A.G., Nazarova M.A. et al. Navigated repetitive transcranial magnetic stimulation in post-stroke rehabilitation: a randomized, double-blind, sham-controlled study. Annaly klinicheskoy i eksperimental’noy nevrologii = Annals of Clinical and Experimantal Neurology 2015;9(4):32–8. (In Russ.)].

30. Nowak D.A., Hoffmann U., Conne mann B.J. et al. Epileptic seizure following 1 Hz repetitive transcranial magnetic stimulation. Clin Neurophysiol 2006;117(7):1631–3. DOI: 10.1016/j.clinph.2006.03.017. PMID: 16679059.

31. Nitsche M.A. Co-incidence or causality? Seizures after slow rTMS in stroke patients. Clin Neurophysiol 2016;127:1020–1. DOI: 10.1016/j.clinph.2015.07.019. PMID: 26265566.

32. Homberg V., Netz J. Generalised seizures induced by transcranial magnetic stimulation of motor cortex. Lancet 1989;2(8673):1223. PMID: 2572937.

33. Fauth C., Meyer B.U., Prosiegel M. et al. Seizure induction and magnetic brain stimulation after stroke. Lancet 1992;139:362. PMID: 1346431.

34. Haupts M.R., Daum S., Ahle G. et al. Transcranial magnetic stimulation as a provocation for epileptic seizures in multiple sclerosis. Mult Scler 2004;10(4):475–6. DOI: 10.1191/1352458504ms1062cr. PMID: 15327050.

35. Tharayil B.S., Gangadhar B.N., Thirthalli J. et al. Seizure with single-pulse transcranial magnetic stimulation in a 35-year-old otherwise-healthy patient with bipolar disorder. J ECT 2005;21(3):188–9. PMID: 16127313.

36. Bernabeu M., Orient F., Tormos J.M. et al. Seizure induced by fast repetitive transcranial magnetic stimulation. Clin Neurophysiol 2004;115(7):1714–5. DOI: 10.1016/j.clinph.2004.02.021. PMID: 15203073.

37. Oberman L.M., Pascual-Leone A. Report of seizure induced by continuous theta burst stimulation. Brain Stimul 2009;2(4):246–7. DOI: 10.1016/j.brs.2009.03.003. PMID: 20160904.

38. Miniussi C., Ruzzoli M. Transcranial stimulation and cognition. Handb Clin Neurol 2013;116:739–50. DOI: 10.1016/B978-0-444-53497-2.00056-5. PMID: 24112935.

39. Lage C., Wiles K., Shergill S.S. et al. A systematic review of the effects of low-frequency repetitive transcranial magnetic stimulation on cognition. J Neural Transm 2016;123(12):1479–90. DOI: 10.1007/s00702-016-1592-8. PMID: 27503083.

40. Ella R., Zwanzger P., Stampfer R. et al. Switch to mania after slow rTMS of the right prefrontal cortex. J Clin Psychiatry 2002;63(3):249. PMID: 11926727.

41. Sakkas P., Mihalopoulou P., Mourtzou hou P. et al. Induction of mania by rTMS: report of two cases. Eur Psychiatry 2003;18(4):196–8. PMID: 12814856.

42. Krstic J., Ilic T.V. Switch to hypomania induced by repetitive transcranial magnetic stimulation and partial sleep deprivation added to antidepressant: a case report. Vojnosanit Pregl 2014;71(2):207–10. PMID: 24665581.

43. Xia G., Gajwani P., Muzina D.J. et al. Treatment-emergent mania in unipolar and bipolar depression: focus on repetitive transcranial magnetic stimulation. Int J Neuropsychopharmacol 2008;11(1):119–30. DOI: 10.1017/S1461145707007699. PMID: 17335643.

44. Janicak P.G., O’Reardon J.P., Sampson S.M. et al. Transcranial magnetic stimulation in the treatment of major depressive disorder: a comprehensive summary of safety experience from acute exposure, extended exposure, and during reintroduction treatment. J Clin Psychiatry 2008;69(2):222–32. PMID: 18232722.

45. Foerster A., Schmitz J.M., Nouri S. et al. Safety of rapid-rate transcranial magnetic stimulation: heart rate and blood pressure changes. Electroencephalogr Clin Neurophysiol 1997;104(3):207–12. PMID: 9186235.

46. Jenkins J., Shajahan P.M., Lappin J.M. et al. Right and left prefrontal transcranial magnetic stimulation at 1 Hz does not affect mood in healthy volunteers. BMC Psychiatry 2002;2:1. PMID: 11825340.

47. Yozbatiran N., Alonso-Alonso M., See J. et al. Safety and behavioral effects of high-frequency repetitive transcranial magnetic stimulation in stroke. Stroke 2009;40(1):309–12. DOI: 10.1161/STROKEAHA.108.522144. PMID: 18845801.

48. Gulli G., Tarperi C., Cevese A. et al. Effects of prefrontal repetitive transcranial magnetic stimulation on the autonomic regulation of cardiovascular function. Exp Brain Res 2013;226(2):265–71. DOI: 10.1007/s00221-013-3431-6. PMID: 23455721.

49. Van den Eynde F., Claudino A.M., Camp-bell I. et al. Cardiac safety of repetitive transcranial magnetic stimulation in bulimic eating disorders. Brain Stimul 2011;4(2):112–4. DOI: 10.1016/j.brs.2010.06.003. PMID: 21511212.

50. Vernieri F., Maggio P., Tibuzzi F. et al. High frequency repetitive transcranial magnetic stimulation decreases cerebral vasomotor reactivity. Clin Neurophysiol 2009;120(6):1188–94. DOI: 10.1016/j.clinph.2009.03.021. PMID: 19423387.

51. Vernieri F., Altamura C., Palazzo P. et al. 1-Hz repetitive transcranial magnetic stimulation increases cerebral vasomotor reactivity: a possible autonomic nervous system modulation. Brain Stimul 2014;7(2):281–6. DOI: 10.1016/j.brs.2013.12.014. PMID: 24485467.

52. Makovac E., Thayer J.F., Ottaviani C. A meta-analysis of non-invasive brain stimulation and autonomic functioning: Implications for brain-heart pathways to cardiovascular disease. Neurosci Biobehav Rev 2017;74(Pt B):330–41. DOI: 10.1016/j.neubiorev.2016.05.001. PMID: 27185286.

53. Szuba M.P., O’Reardon J.P., Rai A.S. et al. Acute mood and thyroid stimulating hormone effects of transcranial magnetic stimulation in major depression. Biol Psychiatry 2001;50(1):22–7. PMID: 11457420.

54. George M.S., Wassermann E.M., Williams W.A. et al. Changes in mood and hormone levels after rapid-rate transcranial magnetic stimulation (rTMS) of the prefrontal cortex. J Neuropsychiatry Clin Neurosci 1996;8(2):172–80. DOI: 10.1176/jnp.8.2.172. PMID: 9081553.

55. Kito S., Hasegawa T., Fujita K. et al. Changes in hypothalamic-pituitary-thyroid axis following successful treatment with low-frequency right prefrontal transcranial magnetic stimulation in treatment-resistant depression. Psychiatry Res 2010;175(1–2):74–7. DOI: 10.1016/j.psychres.2008.10.002. PMID: 20004482.

56. Evers S., Hengst K., Pecuch P.W. The impact of repetitive transcranial magnetic stimulation on pituitary hormone levels and cortisol in healthy subjects. J Affect Disord 2001;66(1):83–8. PMID: 11532537

57. Bridgers S.L., Delaney R.C. Transcranial magnetic stimulation: an assessment of cognitive and other cerebral effects. Neurology 1989;39(3):417–9. PMID: 2927652.

58. Wassermann E.M., Grafman J., Berry C. et al. Use and safety of a new repetitive transcranial magnetic stimulator. Electro-encephalogr Clin Neurophysiol 1996;101(5):412–7. PMID: 8913194.

59. Claudino A.M., Van den Eynde F., Stahl D. et al. Repetitive transcranial magnetic stimulation reduces cortisol concentrations in bulimic disorders. Psychol Med 2011;41(6):1329–36.

60. DOI: 10.1017/S0033291710001881. PMID: 20925970.

61. Baeken C., De Raedt R., Leyman L. et al. The impact of one session of HF-rTMS on salivary cortisol in healthy female subjects. World J Biol Psychiatry 2009;10(4 Pt 2):586–90. DOI: 10.1080/15622970701560351. PMID: 17886168.

62. Nahas Z., Bohning D.E., Molloy M.A. et al. Safety and feasibility of repetitive transcranial magnetic stimulation in the treatment of anxious depression in pregnancy: a case report. J Clin Psychiatry 1999;60(1):50–2. PMID: 10074879.

63. Klirova M., Novak T., Kopecek M. et al. Repetitive transcranial magnetic stimulation (rTMS) in major depressive episode during pregnancy. Neuro Endocrinol Lett 2008;29(1):69–70. PMID: 18283246.

64. Zhang X., Liu K., Sun J. et al. Safety and feasibility of repetitive transcranial magnetic stimulation (rTMS) as a treatment for major depression during pregnancy. Arch Womens Ment Health 2010;13(4):369–70. DOI: 10.1007/s00737-010-0163-5. PMID: 20386939.

65. Kim D.R., Epperson N., Pare E. et al. An open label pilot study of transcranial magnetic stimulation for pregnant women with major depressive disorder. J Womens Health (Larchmt) 2011;20(2):255–61. DOI: 10.1089/jwh.2010.2353. PMID: 21314450.

66. Hizli Sayar G., Ozten E., Tufan E. et al. Transcranial magnetic stimulation during pregnancy. Arch Womens Ment Health 2014;17(4):311–5. DOI: 10.1007/s00737-013-0397-0. PMID: 24248413.

67. Eryilmaz G., Sayar G.H., Ozten E. et al. Follow-up study of children whose mothers were treated with transcranial magnetic stimulation during pregnancy: preliminary results. Neuromodulation 2015;18(4):255–60. DOI: 10.1111/ner.12231. PMID: 25257229.

68. Kim D.R., Wang E. Prevention of supine hypotensive syndrome in pregnant women treated with transcranial magnetic stimulation. Psychiatry Res 2014; 218(1–2):247–8. DOI: 10.1016/j.psychres.2014.04.001. PMID: 24768354.

69. Krishnan C., Santos L., Peterson M.D. et al. Safety of noninvasive brain stimulation in children and adolescents. Brain Stimul 2015;8(1):76–87. DOI: 10.1016/j.brs.2014.10.012. PMID: 25499471.

70. Allen C.H., Kluger B.M., Buard I. Safety of transcranial magnetic stimulation in children: a systematic review of the literature. Pediatr Neurol 2017;68:3–17. DOI: 10.1016/j.pediatrneurol.2016.12.009. PMID: 28216033.

71. Bergmann T.O., Karabanov A., Hartwig-sen G. et al. Combining non-invasive transcranial brain stimulation with neuro-imaging and electrophysiology: Current approaches and future perspectives. Neuroimage 2016;140:4–19. DOI: 10.1016/j.neuroimage.2016.02.012. PMID: 26883069.

72. Westin G.G., Bassi B.D., Lisanby S.H. et al. Determination of motor threshold using visual observation overestimates transcranial magnetic stimulation dosage: safety implications. Clin Neurophysiol 2014;125(1):142–7. DOI: 10.1016/j.clinph.2013.06.187. PMID: 23993680.

73. Zarkowski P., Navarro R., Pavlicova M. et al. The effect of daily prefrontal repetitive transcranial magnetic stimulation over several weeks on resting motor threshold. Brain Stimul 2009;2(3):163–7. DOI: 10.1016/j.brs.2009.02.001. PMID: 20161065.

74. 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. PMID: 26947241.

75. Huang Y.Z., Edwards M.J., Rounis E. et al. Theta burst stimulation of the human motor cortex. Neuron 2005;45:201–6. PMID: 15664172.

76. Silvanto J., Muggleton N.G., Cowey A. et al. Neural activation state determines behavioral susceptibility to modified theta burst transcranial magnetic stimulation. Eur J Neurosci 2007;26:523–8. DOI: 10.1111/j.1460-9568.2007.05682.x. PMID: 17650122.

77. Nyffeler T., Wurtz P., Lüscher H.R. et al. Extending lifetime of plastic changes in the human brain. Eur J Neurosci 2006;24:2961–6. PMID: 17156218.