Over the past decade, theta-burst stimulation (TBS) has become a focus of interest in neurostimulatory research. Compared to conventional repetitive transcranial magnetic stimulation (rTMS), TBS produces more robust changes in cortical excitability (CE). There is also some evidence of an analgesic effect of the method. Previously published studies have suggested that different TBS parameters elicit opposite effects of TBS on CE. While intermittent TBS (iTBS) facilitates CE, continuous TBS (cTBS) attenuates it. However, prolonged TBS (pTBS) with twice the number of stimuli produces the opposite effect. In a double-blind, placebo-controlled, cross-over study with healthy subjects (n = 24), we investigated the effects of various pTBS (cTBS, iTBS, and placebo TBS) over the right motor cortex on CE and pain perception. Changes in resting motor thresholds (RMTs) and absolute motor-evoked potential (MEP) amplitudes were assessed before and at two time-points (0-5 min; 40-45 min) after pTBS. Tactile and thermal pain thresholds were measured before and 5 min after application. Compared to the placebo, prolonged cTBS (pcTBS) transiently increased MEP amplitudes, while no significant changes were found after prolonged iTBS. However, the facilitation of CE after pcTBS did not induce a parallel analgesic effect. We confirmed that pcTBS with twice the duration converts the conventional inhibitory effect into a facilitatory one. Despite the short-term boost of CE following pcTBS, a corresponding analgesic effect was not demonstrated. Therefore, the results indicate a more complex regulation of pain, which cannot be explained entirely by the modulation of excitability.

Clinical Centre National Institute of Mental Health Klecany Czechia

Department of Normal Pathological and Clinical Physiology 3rd Faculty of Medicine Charles University Prague Czechia

Department of Psychiatry 3rd Faculty of Medicine Charles University Prague Czechia

See more in PubMed

Andre-Obadia N., Magnin M., Simon E., Garcia-Larrea L. (2018). Somatotopic effects of rTMS in neuropathic pain? A comparison between stimulation over hand face motor areas. Eur. J. Pain 22, 707–715. 10.1002/ejp.1156 PubMed DOI

André-Obadia N., Mertens P., Gueguen A., Peyron R., Garcia-Larrea L. (2008). Pain relief by rTMS. Differential effect of current flow but no specific action on pain subtypes. Neurology 71, 833–840. 10.1212/01.wnl.0000325481.61471.f0 PubMed DOI

Antal A., Paulus W. (2010). Effects of transcranial theta-burst stimulation on acute pain perception. Restor. Neurol. Neurosci. 28, 477–484. 10.3233/rnn-2010-0555 PubMed DOI

Borckardt J. J., Reeves S. T., Beam W., Jensen M. P., Gracely R. H., Katz S., et al. . (2011). A randomized, controlled investigation of motor cortex transcranial magnetic stimulation (TMS) effects on quantitative sensory measures in healthy adults: evaluation of TMS device parameters. Clin. J. Pain 27, 486–494. 10.1097/ajp.0b013e31820d2733 PubMed DOI PMC

Cárdenas-Morales L., Nowak D. A., Kammer T., Wolf R. C., Schönfeldt-Lecuona C. (2010). Mechanisms and applications of theta-burst rTMS on the human motor cortex. Brain Topogr. 22, 294–306. 10.1007/s10548-009-0084-7 PubMed DOI

Chung S. W., Hill A. T., Rogasch N. C., Hoy K. E., Fitzgerald P. B. (2016). Use of theta-burst stimulation in changing excitability of motor cortex: a systematic review and meta-analysis. Neurosci. Biobehav. Rev. 63, 43–64. 10.1016/j.neubiorev.2016.01.008 PubMed DOI

Csifcsak G., Nitsche M. A., Baumgärtner U., Paulus W., Treede R.-D., Antal A. (2009). Electrophysiological correlates of reduced pain perception after theta-burst stimulation. Neuroreport 20, 1051–1055. 10.1097/wnr.0b013e32832e0c74 PubMed DOI

de Andrade D. C., Mhalla A., Adam F., Texeira M. J., Bouhassira D. (2011). Neuropharmacological basis of rTMS-induced analgesia: the role of endogenous opioids. Pain 152, 320–326. 10.1016/j.pain.2010.10.032 PubMed DOI

De Martino E., Fernandes A. M., Galhardoni R., Souza C. D. O., De Andrade D. C., Graven-Nielsen T. (2019). Sessions of prolonged continuous theta burst stimulation or high-frequency 10 Hz stimulation to left dorsolateral prefrontal cortex for 3 days decreased pain sensitivity by modulation of the efficacy of conditioned pain modulation. J. Pain 20, 1459–1469. 10.1016/j.jpain.2019.05.010 PubMed DOI

Di Lazzaro V., Pilato F., Dileone M., Profice P., Oliviero A., Mazzone P., et al. . (2008). The physiological basis of the effects of intermittent theta burst stimulation of the human motor cortex. J. Physiol. 586, 3871–3879. 10.1113/jphysiol.2008.152736 PubMed DOI PMC

Di Lazzaro V., Pilato F., Saturno E., Oliviero A., Dileone M., Mazzone P., et al. . (2005). Theta-burst repetitive transcranial magnetic stimulation suppresses specific excitatory circuits in the human motor cortex. J. Physiol. 565, 945–950. 10.1113/jphysiol.2005.087288 PubMed DOI PMC

Dowdle L., Imperatore J., Hamilton S., George M., Borckardt J., Hanlon C. (2019). Attenuating pain with theta burst stimulation (TBS): a sham-controlled neuroimaging study evaluating the relative efficacy of medial versus dorsolateral stimulation. Brain Stimul. 12, 531–532. 10.1016/j.brs.2018.12.751 DOI

Gaertner M., Kong J. T., Scherrer K. H., Foote A., Mackey S., Johnson K. A. (2018). Advancing transcranial magnetic stimulation methods for complex regional pain syndrome: an open-label study of paired theta burst and high-frequency stimulation. Neuromodulation 21, 409–416. 10.1111/ner.12760 PubMed DOI PMC

Galhardoni R., Correia G. S., Araujo H., Yeng L. T., Fernandes D. T., Kaziyama H. H., et al. . (2015). Repetitive transcranial magnetic stimulation in chronic pain: a review of the literature. Arch. Phys. Med. Rehabil. 96, S156–S172. 10.1016/j.apmr.2014.11.010 PubMed DOI

Gamboa O. L., Antal A., Moliadze V., Paulus W. (2010). Simply longer is not better: reversal of theta burst after-effect with prolonged stimulation. Exp. Brain Res. 204, 181–187. 10.1007/s00221-010-2293-4 PubMed DOI PMC

Garcia-Larrea L., Peyron R. (2007). Motor cortex stimulation for neuropathic pain: from phenomenology to mechanisms. NeuroImage 37, S71–S79. 10.1016/j.neuroimage.2007.05.062 PubMed DOI

Goldsworthy M. R., Pitcher J. B., Ridding M. C. (2012). A comparison of two different continuous theta burst stimulation paradigms applied to the human primary motor cortex. Clin. Neurophysiol. 123, 2256–2263. 10.1016/j.clinph.2012.05.001 PubMed DOI

Goldsworthy M. R., Pitcher J. B., Ridding M. C. (2013). Neuroplastic modulation of inhibitory motor cortical networks by spaced theta burst stimulation protocols. Brain Stimul. 6, 340–345. 10.1016/j.brs.2012.06.005 PubMed DOI

Goldsworthy M. R., Vallence A.-M., Hodyl N. A., Semmler J. G., Pitcher J. B., Ridding M. C. (2016). Probing changes in corticospinal excitability following theta burst stimulation of the human primary motor cortex. Clin. Neurophysiol. 127, 740–747. 10.1016/j.clinph.2015.06.014 PubMed DOI

Goudra B., Shah D., Balu G., Gouda G., Balu A., Borle A., et al. . (2017). Repetitive transcranial magnetic stimulation in chronic pain: a meta-analysis. Anesth. Essays Res. 11, 751–757. 10.4103/aer.AER_10_17 PubMed DOI PMC

Guo Q., Li C., Wang J. (2017). Updated review on the clinical use of repetitive transcranial magnetic stimulation in psychiatric disorders. Neurosci. Bull. 33, 747–756. 10.1007/s12264-017-0185-3 PubMed DOI PMC

Hamada M., Murase N., Hasan A., Balaratnam M., Rothwell J. C. (2013). The role of interneuron networks in driving human motor cortical plasticity. Cereb. Cortex 23, 1593–1605. 10.1093/cercor/bhs147 PubMed DOI

Herwig U., Kölbel K., Wunderlich A. P., Thielscher A., Von Tiesenhausen C., Spitzer M., et al. . (2002). Spatial congruence of neuronavigated transcranial magnetic stimulation and functional neuroimaging. Clin. Neurophysiol. 113, 462–468. 10.1016/s1388-2457(02)00026-3 PubMed DOI

Hirayama A., Saitoh Y., Kishima H., Shimokawa T., Oshino S., Hirata M., et al. . (2006). Reduction of intractable deafferentation pain by navigation-guided repetitive transcranial magnetic stimulation of the primary motor cortex. Pain 122, 22–27. 10.1016/j.pain.2005.12.001 PubMed DOI

Houzé B., Bradley C., Magnin M., Garcia-Larrea L. (2013). Changes in sensory hand representation and pain thresholds induced by motor cortex stimulation in humans. Cereb. Cortex 23, 2667–2676. 10.1093/cercor/bhs255 PubMed DOI

Huang Y.-Z., Edwards M. J., Rounis E., Bhatia K. P., Rothwell J. C. (2005). Theta burst stimulation of the human motor cortex. Neuron 45, 201–206. 10.1016/j.neuron.2004.12.033 PubMed DOI

Jacobs M. F., Tsang P., Lee K. G., Asmussen M. J., Zapallow C. M., Nelson A. J. (2014). 30 Hz theta-burst stimulation over primary somatosensory cortex modulates corticospinal output to the hand. Brain Stimul. 7, 269–274. 10.1016/j.brs.2013.12.009 PubMed DOI

Jannati A., Block G., Oberman L. M., Rotenberg A., Pascual-Leone A. (2017). Interindividual variability in response to continuous theta-burst stimulation in healthy adults. Clin. Neurophysiol. 128, 2268–2278. 10.1016/j.clinph.2017.08.023 PubMed DOI PMC

Johansson R., Vallbo A., Westling G. (1980). Thresholds of mechanosensitive afferents in the human hand as measured with von Frey hairs. Brain Res. 184, 343–351. 10.1016/0006-8993(80)90803-3 PubMed DOI

Khedr E. M., Kotb H., Kamel N., Ahmed M., Sadek R., Rothwell J. (2005). Longlasting antalgic effects of daily sessions of repetitive transcranial magnetic stimulation in central and peripheral neuropathic pain. J. Neurol. Neurosurg. Psychiatry 76, 833–838. 10.1136/jnnp.2004.055806 PubMed DOI PMC

Kim J. K., Park H. S., Bae J. S., Jeong Y. S., Jung K. J., Lim J. Y. (2020). Effects of multi-session intermittent theta burst stimulation on central neuropathic pain: a randomized controlled trial. NeuroRehabilitation 46, 127–134. 10.3233/nre-192958 PubMed DOI

Kohútová B., Fricová J., Klírová M., Novák T., Rokyta R. (2017). Theta burst stimulation in the treatment of chronic orofacial pain: a randomized controlled trial. Physiol. Res. 66, 1041–1047. 10.33549/physiolres.933474 PubMed DOI

Kostek M., Polaski A., Kolber B., Ramsey A., Kranjec A., Szucs K. (2016). A protocol of manual tests to measure sensation and pain in humans. J. Vis. Exp. 118:e54130 10.3791/54130 PubMed DOI PMC

Lefaucheur J.-P., Aleman A., Baeken C., Benninger D. H., Brunelin J., Di Lazzaro V., et al. . (2020). Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): an update(2014–2018). Clin. Neurophysiol. 131, 474–528. 10.1016/j.clinph.2019.11.002 PubMed DOI

Lefaucheur J. P., Ayache S., Sorel M., Farhat W., Zouari H., De Andrade D. C., et al. . (2012). Analgesic effects of repetitive transcranial magnetic stimulation of the motor cortex in neuropathic pain: influence of theta burst stimulation priming. Eur. J. Pain 16, 1403–1413. 10.1002/j.1532-2149.2012.00150.x PubMed DOI

Lefaucheur J.-P., Drouot X., Keravel Y., Nguyen J.-P. (2001). Pain relief induced by repetitive transcranial magnetic stimulation of precentral cortex. Neuroreport 12, 2963–2965. 10.1097/00001756-200109170-00041 PubMed DOI

Lefaucheur J., Drouot X., Menard-Lefaucheur I., Keravel Y., Nguyen J. (2006). Motor cortex rTMS restores defective intracortical inhibition in chronic neuropathic pain. Neurology 67, 1568–1574. 10.1212/01.wnl.0000242731.10074.3c PubMed DOI

Lefaucheur J.-P., Jarry G., Drouot X., Ménard-Lefaucheur I., Keravel Y., Nguyen J.-P. (2010). Motor cortex rTMS reduces acute pain provoked by laser stimulation in patients with chronic neuropathic pain. Clin. Neurophysiol. 121, 895–901. 10.1016/j.clinph.2009.12.028 PubMed DOI

Leo R. J., Latif T. (2007). Repetitive transcranial magnetic stimulation (rTMS) in experimentally induced and chronic neuropathic pain: a review. J. Pain 8, 453–459. 10.1016/j.jpain.2007.01.009 PubMed DOI

Leung A., Donohue M., Xu R., Lee R., Lefaucheur J.-P., Khedr E. M., et al. . (2009). rTMS for suppressing neuropathic pain: a meta-analysis. J. Pain 10, 1205–1216. 10.1016/j.jpain.2009.03.010 PubMed DOI

Maeda F., Keenan J. P., Tormos J. M., Topka H., Pascual-Leone A. (2000). Interindividual variability of the modulatory effects of repetitive transcranial magnetic stimulation on cortical excitability. Exp. Brain Res. 133, 425–430. 10.1007/s002210000432 PubMed DOI

Mars R. B., Bestmann S., Rothwell J. C., Haggard P. (2007). Effects of motor preparation and spatial attention on corticospinal excitability in a delayed-response paradigm. Exp. Brain Res. 182, 125–129. 10.1007/s00221-007-1055-4 PubMed DOI

Mhalla A., Baudic S., De Andrade D. C., Gautron M., Perrot S., Teixeira M. J., et al. . (2011). Long-term maintenance of the analgesic effects of transcranial magnetic stimulation in fibromyalgia. Pain 152, 1478–1485. 10.1016/j.pain.2011.01.034 PubMed DOI

Moisset X., De Andrade D. C., Bouhassira D. (2016). From pulses to pain relief: an update on the mechanisms of rTMS-induced analgesic effects. Eur. J. Pain 20, 689–700. 10.1002/ejp.811 PubMed DOI

Moisset X., Goudeau S., Poindessous-Jazat F., Baudic S., Clavelou P., Bouhassira D. (2015). Prolonged continuous theta-burst stimulation is more analgesic than ‘classical’ high frequency repetitive transcranial magnetic stimulation. Brain Stimul. 8, 135–141. 10.1016/j.brs.2014.10.006 PubMed DOI

Nahmias F., Debes C., De Andrade D. C., Mhalla A., Bouhassira D. (2009). Diffuse analgesic effects of unilateral repetitive transcranial magnetic stimulation (rTMS) in healthy volunteers. Pain 147, 224–232. 10.1016/j.pain.2009.09.016 PubMed DOI

Passard A., Attal N., Benadhira R., Brasseur L., Saba G., Sichere P., et al. . (2007). Effects of unilateral repetitive transcranial magnetic stimulation of the motor cortex on chronic widespread pain in fibromyalgia. Brain 130, 2661–2670. 10.1093/brain/awm189 PubMed DOI

Pell G. S., Roth Y., Zangen A. (2011). Modulation of cortical excitability induced by repetitive transcranial magnetic stimulation: influence of timing and geometrical parameters and underlying mechanisms. Prog. Neurobiol. 93, 59–98. 10.1016/j.pneurobio.2010.10.003 PubMed DOI

Poreisz C., Csifcsák G., Antal A., Levold M., Hillers F., Paulus W. (2008). Theta burst stimulation of the motor cortex reduces laser-evoked pain perception. Neuroreport 19, 193–196. 10.1097/wnr.0b013e3282f45498 PubMed DOI

Rolke R., Magerl W., Campbell K. A., Schalber C., Caspari S., Birklein F., et al. . (2006). Quantitative sensory testing: a comprehensive protocol for clinical trials. Eur. J. Pain 10, 77–77. 10.1016/j.ejpain.2005.02.003 PubMed DOI

Rossini P. M., Barker A., Berardelli A., Caramia M., Caruso G., Cracco R., et al. . (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. 10.1016/0013-4694(94)90029-9 PubMed DOI

Summers J., Johnson S., Pridmore S., Oberoi G. (2004). Changes to cold detection and pain thresholds following low and high frequency transcranial magnetic stimulation of the motor cortex. Neurosci. Lett. 368, 197–200. 10.1016/j.neulet.2004.07.008 PubMed DOI

Suppa A., Huang Y.-Z., Funke K., Ridding M., Cheeran B., Di Lazzaro V., et al. . (2016). Ten years of theta burst stimulation in humans: established knowledge, unknowns and prospects. Brain Stimul. 9, 323–335. 10.1016/j.brs.2016.01.006 PubMed DOI

Suppa A., Ortu E., Zafar N., Deriu F., Paulus W., Berardelli A., et al. . (2008). Theta burst stimulation induces after-effects on contralateral primary motor cortex excitability in humans. J. Physiol. 586, 4489–4500. 10.1113/jphysiol.2008.156596 PubMed DOI PMC

StatSoft, Inc. (2008). STATISTICA (data analysis software system), version 12. Available online at: www.statsoft.com.

Torta D. M., Legrain V., Algoet M., Olivier E., Duque J., Mouraux A. (2013). Theta burst stimulation applied over primary motor and somatosensory cortices produces analgesia unrelated to the changes in nociceptive event-related potentials. PLoS One 8:e73263. 10.1371/journal.pone.0073263 PubMed DOI PMC

Turrigiano G. G. (2008). The self-tuning neuron: synaptic scaling of excitatory synapses. Cell 135, 422–435. 10.1016/j.cell.2008.10.008 PubMed DOI PMC

Wischnewski M., Schutter D. J. (2015). Efficacy and time course of theta burst stimulation in healthy humans. Brain Stimul. 8, 685–692. 10.1016/j.brs.2015.03.004 PubMed DOI

Yamamotová A., Hrabak P., Hříbek P., Rokyta R. (2017). Do multiple body modifications alter pain threshold? Physiol. Res. 66, S493–S500. 10.33549/physiolres.933804 PubMed DOI

Yoo W.-K., Kim Y.-H., Doh W.-S., Lee J.-H., Jung K.-I., Park D.-S., et al. . (2006). Dissociable modulating effect of repetitive transcranial magnetic stimulation on sensory and pain perception. Neuroreport 17, 141–144. 10.1097/01.wnr.0000198438.37012.d6 PubMed DOI