Abstract
Repetitive transcranial stimulation (rTMS) paradigms have been used to induce lasting changes in brain activity and excitability. Previous methods of stimulation were long, often ineffective and produced short-lived and variable results. A new non-invasive brain stimulation technique was developed in John Rothwell’s laboratory in the early 2000s, which was named ‘theta burst stimulation’ (TBS). This used rTMS applied in burst patterns of newly acquired 50 Hz rTMS machines, which emulated long-term potentiation/depression-like effects in brain slices. This stimulation paradigm created long-lasting changes in brain excitability, using efficient, very rapid stimulation, which would affect behaviour, with the aim to influence neurological diseases in humans. We describe the development of this technique, including findings and limitations identified since then. We discuss how pitfalls facing TBS reflect those involving both older and newer, non-invasive stimulation techniques, with suggestions of how to overcome these, using personalised, ‘closed loop’ stimulation methods. The challenge in most non-invasive stimulation techniques remains in identifying their exact mechanisms of action in the context of neurological disease models. The development of TBS provides the backdrop for describing John’s contribution to the field, inspiring our own scientific endeavour thanks to his unconditional support, and unfailing kindness.
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References
Akkad H, Dupont-Hadwen J, Frese A, Tetkovic I, Barrett L, Bestmann S, Stagg CJ (2019) Increasing motor skill acquisition by driving theta-gamma coupling. BioRxiv. https://doi.org/10.1101/2019.12.20.883926
Allman C, Amadi U, Winkler AM, Wilkins L, Filippini N, Kischka U, Stagg CJ, Johansen-Berg H (2016) Ipsilesional anodal tDCS enhances the functional benefits of rehabilitation in patients after stroke. Sci Transl Med 8:330. https://doi.org/10.1126/scitranslmed.aad5651
Asamoah B, Khatoun A, McLaughlin M (2019) tACS motor system effects can be caused by transcutaneous stimulation of peripheral nerves. Nat Commun 10(1):266. https://doi.org/10.1038/s41467-018-08183-w
Barker AT, Jalinous R, Freeston IL (1985) Non-invasive magnetic stimulation of human motor cortex. Lancet 1(8437):1106–1107
Berardelli A, Inghilleri M, Rothwell JC, Romeo S, Curra A, Gilio F, Modugno N, Manfredi M (1998) Facilitation of muscle evoked responses after repetitive cortical stimulation in man. Exp Brain Res 122(1):79–84
Brittain JS, Probert-Smith P, Aziz TZ, Brown P (2013) Tremor suppression by rhythmic transcranial current stimulation. Curr Biol 23(5):403–407
Capocchi G, Zampolini M, Larson J (1992) Theta burst stimulation is optimal for induction of LTP at both apical and basal dendritic synapses on hippocampal CA1 neurons. Brain Res 591:332–336
Cheeran B, Talelli P, Mori F, Koch G, Suppa A, Edwards M, Houlden H, Bhatia K, Greenwood R, Rothwell JC (2008) A common polymorphism in the brain-derived neurotrophic factor gene (BDNF) modulates human cortical plasticity and the response to rTMS. J Phyisol 586(23):5717–5725
Chen R, Gerloff C, Classen J, Wassemann EM, Hallett M, Cohen LG (1997) Safety of different inter-train intervals for repetitive transcranial magnetic stimulation and recommendations for safe ranges of stimulation parameters. Electroencephalogr Clin Neurophysiol 105(6):415–421
Daskalakis ZJ, Christensen BK, Fitzgerald PB, Chen R (2002) Transcranial magnetic stimulation: a new investigational and treatment tool in psychiatry. J Neuropsychiatry Clin Neurosci 14(4):406–415
Davarre M, Rothwell JC, Lemon RN (2010) Causal connectivity between the human anterior intraparietal area and premotor cortex during grasp. Curr Biol 20(2):176–181
Di Lazzaro V, Pilato F, Dileone M, Profice P, Oliviero A, Mazzone P, Insola A, Ranieri F, Meglio M, Tonali PA, Rothwell JC (2008a) The physiological basis of the effects of intermittent theta burst stimulation of the human motor cortex. J Physiol 586(16):3871–3879
Di Lazzaro V, Pilato F, Dileone M, Profice P, Capone F, Ranieri F, Musumeci G, Cianfoni A, Pasqualetti P, Tonali PA (2008b) Modulating cortical excitability in acute stroke a repetitive TMS study. Clin Neurophysiol 119(3):715–723
Diamond DM, Dunwiddie TV, Rose GM (1988) Characteristics of hippocampal primed burst potentiation in vitro and in the awake rat. J Neurosci 8:4079–4088
Edwards MJ, Huang YZ, Mir P, Rothwell JC, Bhatia KP (2006) Abnormalities in motor cortical plasticity differentiate manifesting and nonmanifesting DYT1 carriers. Mov Disord 21:2181–2186. https://doi.org/10.1002/mds.21160
Fierro B, Piazza A, Brighina F, La Bua V, Buffa D, Oliveri M (2001) Modulation of intracortical inhibition induced by low- and high-frequency repetitive transcranial magnetic stimulation. Exp Brain Res 138(4):452–457
Fitzgerald PB, Brown TL, Daskalakis ZJ, Chen R, Kulkarni J (2002) Intensity-dependent effects of 1Hz rTMS on human corticospinal excitability. Clin Neurophysiol 113(7):1136–1141
Froc DJ, Chapman CA, Trepel C, Racine RJ (2000) Long-term depression and depotentiation in the sensorimotor cortex of the freely moving rat. J Neurosci 20:438–445
Gentner R, Wankerl K, Reinsberger C, Zeller D, Classen J (2008) Depression of human corticospinal excitability induced by magnetic theta burst stimulation: evidence of rapid polarity-reversing metaplasticity. Cereb Cortex 18(9):2046–2053
Goldsworthy MR, Pitcher JB, Ridding MC (2012) The application of spaced theta burst protocols induces long-lasting neuroplastic changes in the human motor cortex. Eur J Neurosci 35:125–134. https://doi.org/10.1111/j.1460-9568.2011.07924.x
Guo Q, Li C, Wang J (2017) Updated review on the clinical use of repetitive transcranial magnetic stimulation in psychiatric disorders. Neurosci Bull 33(6):747–756
Hamada M, Terao Y, Hanajima R, Shirota Y, Nakatani-Enomoto S, Furubayashi T et al (2008) Bidirectional long-term motor cortical plasticity and metaplasticity induced by quadripulse transcranial magnetic stimulation. J Physiol 586:3927–3947
Hamada M, Murase N, Hasan A, Balaratnam M, Rothwell JC (2013) The role of interneuron networks in driving human motor cortical plasticity. Cer Cortex 23:1593–1605
Hermann CS, Rach S, Neuling T, Struber D (2013) Transcranial alternating current stimulation: a review of the underlying mechanisms and modulation of cognitive processes. Front Hum Neurosci 7:279
Hsu YF, Liao KK, Lee PL et al (2011) Intermittent theta burst stimulation over primary motor cortex enhances movement-related beta synchronisation. Clin Neurophysiol 122:2260–2267. https://doi.org/10.1016/j.clinph.2011.03.02710.1016/j.clinph.2007.01.021
Huang YZ (2005) Theta burst stimulation of human cortex. Doctoral thesis. University of London, London
Huang YZ, Rothwell JC (2004) The effect of short-duration bursts of high-frequency, low-intensity transcranial magnetic stimulation on the human motor cortex. Clin Neurophysiol 115:1069–1075
Huang YZ, Edwards MJ, Rounis E, Bhatia K (2005) Theta burst human of the human motor cortex. Neuron 45(2):201–206
Huang YZ, Chen RS, Rothwell JC, Wen HY (2007) The after-effect of human theta burst stimulation is NMDA receptor dependent. Clin Neurophysiol 118:1028–1032
Huang YZ, Rothwell JC, Edwards MJ, Chen RS (2008) Effect of physiological activity on an NMDA-dependent form of cortical plasticity in human. Cereb Cortex 18:563–570. https://doi.org/10.1093/cercor/bhm087
Huang YZ, Rothwell JC, Lu CS, Wang J, Chen RS (2010) Restoration of motor inhibition through an abnormal premotor-motor connection in dystonia. Mov Disord 25:696–703. https://doi.org/10.1002/mds.22814
Huang YZ, Rothwell JC, Chen RS, Lu CS, Chuang WL (2011a) The theoretical model of theta burst form of repetitive transcranial magnetic stimulation. Clin Neurophysiol 122:1011–1018. https://doi.org/10.1016/j.clinph.2010.08.016
Huang YZ, Rothwell JC, Lu CS, Chuang WL, Chen RS (2011b) Abnormal bidirectional plasticity-like effects in Parkinson's disease. Brain 134:2312–2320. https://doi.org/10.1093/brain/awr158
Huang YZ, Lu CS, Rothwell JC, Lo CC, Chuang WL, Weng YH, Lai SC, Chen RS (2012) Modulation of the disturbed motor network in dystonia by multisession suppression of premotor cortex. PLoS ONE 7(10):e47574. https://doi.org/10.1371/journal.pone.0047574
Huang YZ, Lu MK, Antal A et al (2017) Plasticity induced by non-invasive transcranial brain stimulation: a position paper. Clin Neurophysiol 128:2318–2329. https://doi.org/10.1016/j.clinph.2017.09.007
Huang YZ, Chen RS, Fong PY et al (2018) Inter-cortical modulation from premotor to motor plasticity. J Physiol 596:4207–4217. https://doi.org/10.1113/JP276276
Iezzi E, Conte A, Suppa A, Agostino R, Dinapoli L, Scontrini A, Berardelli A (2008) Phasic voluntary movements reverse the aftereffects of subsequent theta burst stimulation in humans. J Neurophysiol 100(4):2070–2076
Jackson SE, Chester JD (2015) Personalised cancer medicine. Int J of cancer 137:262–266
Koch PJ, Hummel FC (2017) Towards precision medicine: tailoring interventional strategies based on noninvasive brain stimulation for motor recovery after stroke. Curr Opinion in Neurol 30(4):388–397
Koch G, Mori F, Marconi B, Codeca C, Pecchioli C, Salerno S, Torriero S, Lo Gerfo E, Mir P, Oliveri M, Caltagirone C (2008) Changes in intracortical circuits of the human motor cortex following theta burst stimulation of the lateral cerebellum. Clin Neurphysiol 119(11):2559–2569
Larson J, Lynch G (1989) Theta pattern stimulation and the induction of LTP: the sequence in which synapses are stimulated determines the degree to which they potentiate. Brain Res 489:49–58
Lefaucheur JP, Andre-Obadia N, Antal A et al (2014) Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation. Clin Neurophys 125(11):2150–2206
Lioumis P, Kicic D, Savolainen P, Makela JP, Kahkonen S (2009) Reproducibility of TMS-Evoked EEG responses. Hum Brain Mapp 30:1387–1396. https://doi.org/10.1002/hbm.20608
Maeda F, Keenan JP, Tormos JM, Topka H, Pascual-Leone A (2000) Interindividual variability of the modulatory effects of repetitive transcranial magnetic stimulation on cortical excitability. Exp Brain Res 133(4):425–430
Modugno N, Curra A, Conte A, Inghilleri M, Fofi L, Agostino R, Manfredi M, Berardelli A (2003) Depressed intracortical inhibition after long trains of subthreshold repetitive magnetic stimuli at low frequency. Clin Neurophysiol 114(12):2416–2422
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
Mutanen T, Nieminen JO, Ilmoniemi RJ (2013) TMS-evoked changes in brain-state dynamics quantified by using EEG data. Front Hum Neurosci 7:155. https://doi.org/10.3389/fnhum.2013.00155
Obeso I, Wilkinson L, Teo JT, Talelli P, Rothwell JC, Jahanshahi M (2017) Theta burst magnetic stimulation over the pre-supplementary motor area improves motor inhibition. Brain Stim 10(5):944–951
Pascual-Leone A, Grafman J, Hallett M (1994) Modulation of cortical motor output maps during development of implicit and explicit learning. Science 263(5151):1287–1289
Peinemann A, Reimer B, Loer C, Quartarone A, Munchau A, Conrad B, Siebner HR (2004) Long-lasting increase in corticospinal excitability after 1800 pulses of subthreshold 5Hz repetitive TMS to the primary motor cortex. Clin Neurophysiol 115(7):1519–1526
Peterchev AV, Murphy DL, Lisanby SH (2010) Repetitive transcranial magnetic stimulator with controllable pulse parameters (cTMS). Conf Proc IEEE Eng Med Biol Soc 8:2922–2926. https://doi.org/10.1109/IEMBS.2010.5626287
Ridding MC, Ziemann U (2010) Determinants of the induction of cortical plasticity by non-invasive brain stimulation in healthy subjects. J Physiol 588(Pt 13):2291–2304
Romei V, Driver J, Schynz PG, Thut G (2011) Rhythmic TMS over parietal cortex links distinct brain frequencies to global versus local visual processing. Curr Biol 21:334–337
Rothwell JC (2011) Using transcranial magnetic stimulation methods to probe connectivity between areas of the brain. Hum Mov Sci 30:906–915
Rounis E, Lee L, Siebner HR, Rowe JB, Friston KJ, Rothwell JC, Frackowiak RS (2005) Frequency specific changes in regional cerebral blood flow and motor system connectivity following rTMS to the primary motor cortex. Neuroimage 26(1):164–176
Rounis E, Stephan KE, Lee L, Siebner HR, Pesenti A, Friston KJ, Rothwell JC, Frackowiak RS (2006) Acute changes in frontoparietal activity after repetitive transcranial magnetic stimulation over the dorsolateral prefrontal cortex in a cued reaction time task. J Neurosci 26(38):9629–9638
Rounis E, Maniscalo B, Rothwell JC, Passingham RE, Lau H (2010) Theta-burst transcranial magnetic stimulation to the prefrontal cortex impairs metacognitive visual awareness. Cogn Neurosci 1:165–175
Schaworonkow N, Triesch J, Ziemann U, Zrenner C (2019) EEG-triggered TMS reveals stronger brain state-dependent modulation of motor evoked potentials at weaker stimulation intensities. Brain Stimul 12:110–118. https://doi.org/10.1016/j.brs.2018.09.009
Siebner HR, Tormos JM, Ceballos-Baumann AO, Auer C, Catala MD, Conrad B, Pascual-Leone A (1999a) Low-frequency repetitive transcranial magnetic stimulation of the motor cortex in writer's cramp. Neurology 52:529–537
Siebner HR, Mentschel C, Auer C, Conrad B (1999b) Repetitive transcranial magnetic stimulation has a beneficial effect on bradykinesia in Parkinson's disease. NeuroReport 10:589–594
Stagg CJ, Wylezinska M, Matthew PM, Johansen-Berg H, Jezzard P, Rothwell JC, Bestmann S (2009) Neurochemical effects of theta burst stimulation as assessed by magnetic resonance spectroscopy. J Neurophysiol 101:2872–2877
Stubbeman WF, Zarrabi B, Bastea S, Ragland V, Khairkhah R (2018) Bilateral neuronavigated 20Hz theta burst TMS for treatment refractory depression: an open label study. Brain Stimul 11:953–955. https://doi.org/10.1016/j.brs.2018.04.012
Suppa A, Huang YZ, Funke K, Ridding MC, Cheeran B, Di Lazzaro V, Ziemman U, Rothwell JC (2016) Ten years of theta burst stimulation in humans: established knowledge, unknowns and prospects. Brain Stim 9:323–335
Talelli P, Wallace A, Dileone M, Hoad D, Cheeran B, Oliver R, VandenBoz M, Hammerbeck U, Barratt K, Gillini C, Musumeci G, Boudrias MH, Cloud GC, Ball J, Marsden JF, Ward NS, Di Lazzaro V, Greenwood RG, Rothwell JC (2012) Theta burst stimulation in the rehabilitation of the upper limb: a semirandomized, placebo-controlled trial in chronic stroke patients. Neurorehabil Neural Repair 26(8):976–987
Teo JT, Swayne OB, Rothwell JC (2007) Further evidence for NMDA-dependence of the after effects of human theta burst stimulation. Clin Neurophysiol 118:1649–1651
Thut G, Veniero D, Romei V, Miniussi C, Schyns P, Gross J (2011) Rhythmic TMS causes local entrainment of natural oscillatory signatures. Curr Biol 21:1176–1185
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(11):2138–2145
Trepel C, Racine RJ (1998) Long-term potentiation in the neocortex of the adult, freely moving rat. Cereb Cortex 8:719–729
Tse NY, Goldsworthy MR, Ridding MC, Coxon JP, Fitzgerald PB, Fornito A, Rogasch NC (2018) The effect of stimulation interval on plasticity following repeated blocks of intermittent theta burst stimulation. Sci Rep 8:8526. https://doi.org/10.1038/s41598-018-26791-w
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. Electroencephalogr Clin Neurophysiol 108:1–16
Williams NR, Sudheimer KD, Bentzley BS et al (2018) High-dose spaced theta-burst TMS as a rapid-acting antidepressant in highly refractory depression. Brain 141:e18. https://doi.org/10.1093/brain/awx379
Wilson MT, Fulcher BD, Fung PK, Robinson PA, Fornito A, Rogasch NC (2018) Biophysical modelling of neural plasticity induced by transcranial magnetic stimulation. Clin Neurophys 129:1230–1241
Ziemann U, Paulus W, NitescheMA P-L, Byblow WD, Berardelli A, Siebner HR, Classen J, Cohen LG, Rothwell JC (2008) Consensus: Motor cortex plasticity protocols. Brain Stimul 1(3):164–182
Zrenner C, Belardinelli P, Muller-Dahlhaus F, Ziemann U (2016) Closed-Loop Neuroscience and Non-Invasive Brain Stimulation: A Tale of Two Loops. Front Cell Neurosci 10:92. https://doi.org/10.3389/fncel.2016.00092
Zrenner C, Desideri D, Belardinelli P, Ziemann U (2018) Real-time EEG-defined excitability states determine efficacy of TMS-induced plasticity in human motor cortex. Brain Stimul 11:374–389. https://doi.org/10.1016/j.brs.2017.11.016
Acknowledgements
We are grateful to Professor John Rothwell for supervising our respective PhDs and for providing his support in our development as clinician scientists after this was completed. He has guided the development of TBS, and supported its implementation across disciplines, remaining open to criticism and investigating mechanisms of action at neuropharmacological and electrophysiological levels. He has provided new ways of identifying reasons for variability in the results obtained (Rothwell 2011, Hamada et al. 2013). He has been a role model for implementing our scientific endeavours with kindness, humility, and perseverance. He is one of the rare basic scientists to have provided a comprehensive body of clinical work, having collaborated very effectively with clinicians throughout his career.
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Rounis, E., Huang, YZ. Theta burst stimulation in humans: a need for better understanding effects of brain stimulation in health and disease. Exp Brain Res 238, 1707–1714 (2020). https://doi.org/10.1007/s00221-020-05880-1
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DOI: https://doi.org/10.1007/s00221-020-05880-1