Skip to main content
Log in

Transcranial magnetic stimulation and synaptic plasticity: experimental framework and human models

  • Review
  • Published:
Experimental Brain Research Aims and scope Submit manuscript

Abstract

Interest in the therapeutic potential of non-invasive human brain stimulation has been boosted by an improved understanding of the mechanisms of synaptic plasticity and the stimulus protocols that can induce plasticity in experimental preparations. A range of transcranial magnetic stimulation (TMS) protocols are available that have the potential to mimic these experimental protocols in the human. Repetitive TMS emulates aspects of activity-dependent plasticity, and theta-burst refinements may be able to take into account excitatory and inhibitory networks, paired associative stimulation can extend network considerations to incorporate sensorimotor integration, inhibitory networks may be targeted with short-interval paired stimulation and finally even the precision of spike-timing dependent plasticity may be accessible through I-(indirect)wave dynamics. This review will provide a synthesis of current concepts of activity- and time-dependent plasticity and their homeostatic regulation based on experimental studies, and relate these concepts to the promising range of TMS interventions that are available to target human brain plasticity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Abraham WC, Bear MF (1996) Metaplasticity: the plasticity of synaptic plasticity. Trends Neurosci 19:126–130

    Article  PubMed  CAS  Google Scholar 

  • Baker SN, Curio G, Lemon RN (2003) EEG oscillations at 600 Hz are macroscopic markers for cortical spike bursts. J Physiol 550:529–534

    Article  PubMed  CAS  Google Scholar 

  • Barrionuevo G, Schottler F, Lynch G (1980) The effects of repetitive low frequency stimulation on control and “potentiated” synaptic responses in the hippocampus. Life Sci 27:2385–2391

    Article  PubMed  CAS  Google Scholar 

  • Bear MF (2003) Bidirectional synaptic plasticity: from theory to reality. Philos Trans R Soc Lond B Biol Sci 358:649–655

    Article  PubMed  Google Scholar 

  • Bear MF, Abraham WC (1996) Long-term depression in hippocampus. Annu Rev Neurosci 19:437–462

    Article  PubMed  CAS  Google Scholar 

  • Behrens CJ, van den Boom LP, de Hoz L, Friedman A, Heinemann U (2005) Induction of sharp wave-ripple complexes in vitro and reorganization of hippocampal networks. Nat Neurosci 8:1560–1567

    Article  PubMed  CAS  Google Scholar 

  • Benwell NM, Mastaglia FL, Thickbroom GW (2006) Paired-pulse rTMS at trans-synaptic intervals increases corticomotor excitability and reduces the rate of force loss during a fatiguing exercise of the hand. Exp Brain Res 175:626–632

    Article  PubMed  Google Scholar 

  • Bi GQ, Poo MM (1998) Synaptic modifications in cultured hippocampal neurons: dependence on spike timing, synaptic strength, and postsynaptic cell type. J Neurosci 18:10464–10472

    PubMed  CAS  Google Scholar 

  • Bi GQ, Rubin J (2005) Timing in synaptic plasticity: from detection to integration. Trends Neurosci 28:222–228

    Article  PubMed  CAS  Google Scholar 

  • Bienenstock EL, Cooper LN, Munro PW (1982) Theory for the development of neuron selectivity: orientation specificity and binocular interaction in visual cortex. J Neurosci 2:32–48

    PubMed  CAS  Google Scholar 

  • Bliss TV, Lomo T (1973) Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol 232:331–356

    PubMed  CAS  Google Scholar 

  • Bliss TVP, Collingridge GL, Morris RGM (2003) Long-term potentiation: enhancing neuroscience for 30 years. Philos Trans R Soc Lond B Biol Sci 358:607–611

    Article  PubMed  Google Scholar 

  • Brown RE, Milner PM (2002) Foreward. In: Hebb DO, The organization of behavior. Lawrence Erlbaum Associates, Mahwah, p F.6

  • Buzsaki G, Chrobak JJ (1995) Temporal structure in spatially organized neuronal ensembles: a role for interneuronal networks. Curr Opin Neurobiol 5:504–510

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • Collingridge GL (2003) The induction of N-methyl-D-aspartate receptor-dependent long-term potentiation. Philos Trans R Soc Lond B Biol Sci 358:635–641

    Article  PubMed  CAS  Google Scholar 

  • Connors BW, Long MA (2004) Electrical synapses in the mammalian brain. Annu Rev Neurosci 27:393–418

    Article  PubMed  CAS  Google Scholar 

  • Cooke SF, Bliss TV (2006) Plasticity in the human central nervous system. Brain 129:1659–1673

    Article  PubMed  CAS  Google Scholar 

  • Curio G (2000) Linking 600-Hz “spikelike” EEG/MEG wavelets (“sigma-bursts”) to cellular substrates: concepts and caveats. J Clin Neurophysiol 17:377–396

    Article  PubMed  CAS  Google Scholar 

  • Dan Y, Poo MM (2004) Spike timing-dependent plasticity of neural circuits. Neuron 44:23–30

    Article  PubMed  CAS  Google Scholar 

  • Davies CH, Starkey SJ, Pozza MF, Collingridge GL (1991) GABA autoreceptors regulate the induction of LTP. Nature 349:609–611

    Article  PubMed  CAS  Google Scholar 

  • 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 412:449–473

    PubMed  CAS  Google Scholar 

  • Desai NS, Rutherford LC, Turrigiano GG (1999) Plasticity in the intrinsic excitability of cortical pyramidal neurons. Nat Neurosci 2:515–520

    Article  PubMed  CAS  Google Scholar 

  • Destexhe A, Marder E (2004) Plasticity in single neuron and circuit computations. Nature 431:789–795

    Article  PubMed  CAS  Google Scholar 

  • Di Lazzaro V, Thickbroom GW, Pilato F, Profice P, Dileone M, Mazzone P, Insola A, Ranieri F, Tonali PA, Rothwell JC (2007) Direct demonstration of the effects of repetitive paired-pulse transcranial magnetic stimulation at I-wave periodicity. Clin Neurophysiol 118(6):1193–1197

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Eccles JC (1990) Developing concepts of the synapses. J Neurosci 10:3769–3781

    PubMed  CAS  Google Scholar 

  • Esser SK, Hill SL, Tononi G (2005) Modeling the effects of transcranial magnetic stimulation on cortical circuits. J Neurophysiol 94:622–639

    Article  PubMed  CAS  Google Scholar 

  • Fitzgerald PB, Fountain S, Daskalakis ZJ (2006) A comprehensive review of the effects of rTMS on motor cortical excitability and inhibition. Clin Neurophysiol 117:2584–2596

    Article  PubMed  Google Scholar 

  • Fregnac Y (1998) Homeostasis or synaptic plasticity? Nature 391:845–846

    Article  PubMed  CAS  Google Scholar 

  • Gulledge AT, Kampa BM, Stuart GJ (2005) Synaptic integration in dendritic trees. J Neurobiol 64:75–90

    Article  PubMed  CAS  Google Scholar 

  • Hamada M, Hanajima R, Terao Y, Arai N, Furubayashi T, Inomata-Terada S, Yugeta A, Matsumoto H, Shirota Y, Ugawa Y (2007) Origin of facilitation in repetitive, 1.5 ms interval, paired pulse transcranial magnetic stimulation (rPPS) of the human motor cortex. Clin Neurophysiol. doi:10.1016/j.clinph.2007.03.009

  • Hanajima R, Ugawa Y, Terao Y, Enomoto H, Shiio Y, Mochizuki H, Furubayashi T, Uesugi H, Iwata NK, Kanazawa I (2002) Mechanisms of intracortical I-wave facilitation elicited with paired-pulse magnetic stimulation in humans. J Physiol 538:253–261

    Article  PubMed  CAS  Google Scholar 

  • Harris KM, Fiala JC, Ostroff L (2003) Structural changes at dendritic spine synapses during long-term potentiation. Philos Trans R Soc Lond B Biol Sci 358:745–748

    Article  PubMed  Google Scholar 

  • Hausser M, Spruston N, Stuart GJ (2000) Diversity and dynamics of dendritic signaling. Science 290:739–744

    Article  PubMed  CAS  Google Scholar 

  • Hebb DO (1949) The organization of behavior. Lawrence Erlbaum Associates, Mahwah

    Google Scholar 

  • Heide G, Witte OW, Ziemann U (2006) Physiology of modulation of motor cortex excitability by low-frequency suprathreshold repetitive transcranial magnetic stimulation. Exp Brain Res 171:26–34

    Article  PubMed  CAS  Google Scholar 

  • Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC (2005) Theta burst stimulation of the human motor cortex. Neuron 45:201–206

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Inghilleri M, Berardelli A, Cruccu G, Manfredi M (1993) Silent period evoked by transcranial stimulation of the human cortex and cervicomedullary junction. J Physiol 466:521–534

    PubMed  CAS  Google Scholar 

  • Johnston D, Christie BR, Frick A, Gray R, Hoffman DA, Schexnayder LK, Watanabe S, Yuan LL (2003) Active dendrites, potassium channels and synaptic plasticity. Philos Trans R Soc Lond B Biol Sci 358:667–674

    Article  PubMed  CAS  Google Scholar 

  • Kandel ER (2001) The molecular biology of memory storage: a dialogue between genes and synapses. Science 294:1030–1038

    Article  PubMed  CAS  Google Scholar 

  • Kelso SR, Ganong AH, Brown TH (1986) Hebbian synapses in hippocampus. Proc Natl Acad Sci USA 83:5326–5330

    Article  PubMed  CAS  Google Scholar 

  • Khedr EM, Gilio F, Rothwell J (2004) Effects of low frequency and low intensity repetitive paired pulse stimulation of the primary motor cortex. Clin Neurophysiol 115:1259–1263

    Article  PubMed  Google Scholar 

  • 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 471:501–519

    PubMed  CAS  Google Scholar 

  • Larson J, Lynch G (1986) Induction of synaptic potentiation in hippocampus by patterned stimulation involves two events. Science 232:985–988

    Article  PubMed  CAS  Google Scholar 

  • Linden DJ (1999) The return of the spike: postsynaptic action potentials and the induction of LTP and LTD. Neuron 22:661–666

    Article  PubMed  CAS  Google Scholar 

  • Lisman J (2003) Long-term potentiation: outstanding questions and attempted synthesis. Philos Trans R Soc Lond B Biol Sci 358:829–842

    Article  PubMed  CAS  Google Scholar 

  • Lomo T (1966) Frequency potentiation of excitatory synaptic activity in the dentate area of the hippocampal formation. Acta Physiol Scand 68:128

    Google Scholar 

  • Lomo T (2003) The discovery of long-term potentiation. Philos Trans R Soc Lond B Biol Sci 358:617–620

    Article  PubMed  Google Scholar 

  • Maeda F, Keenan JP, Tormos JM, Topka H, Pascual-Leone A (2000a) Interindividual variability of the modulatory effects of repetitive transcranial magnetic stimulation on cortical excitability. Exp Brain Res 133:425–430

    Article  PubMed  CAS  Google Scholar 

  • Maeda F, Keenan JP, Tormos JM, Topka H, Pascual-Leone A (2000b) Modulation of corticospinal excitability by repetitive transcranial magnetic stimulation. Clin Neurophysiol 111:800–805

    Article  PubMed  CAS  Google Scholar 

  • Magee JC, Johnston D (1997) A synaptically controlled, associative signal for Hebbian plasticity in hippocampal neurons. Science 275:209–213

    Article  PubMed  CAS  Google Scholar 

  • Malenka RC (2003) The long-term potential of LTP. Nat Rev Neurosci 4:923–926

    Article  PubMed  CAS  Google Scholar 

  • Malenka RC, Bear MF (2004) LTP and LTD: an embarrassment of riches. Neuron 44:5–21

    Article  PubMed  CAS  Google Scholar 

  • Malenka RC, Nicoll RA (1999) Long-term potentiation—a decade of progress? Science 285:1870–1874

    Article  PubMed  CAS  Google Scholar 

  • Marder E, Goaillard JM (2006) Variability, compensation and homeostasis in neuron and network function. Nat Rev Neurosci 7:563–574

    Article  PubMed  CAS  Google Scholar 

  • Matsuzaki M, Honkura N, Ellis-Davies GC, Kasai H (2004) Structural basis of long-term potentiation in single dendritic spines. Nature 429:761–766

    Article  PubMed  CAS  Google Scholar 

  • McDonnell MN, Orekhov Y, Ziemann U (2006) The role of GABA(B) receptors in intracortical inhibition in the human motor cortex. Exp Brain Res 173:86–93

    Article  PubMed  CAS  Google Scholar 

  • Montgomery JM, Madison DV (2004) Discrete synaptic states define a major mechanism of synapse plasticity. Trends Neurosci 27:744–750

    Article  PubMed  CAS  Google Scholar 

  • 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(Pt 4):847–858

    Article  PubMed  Google Scholar 

  • Quartarone A, Siebner HR, Rothwell JC (2006) Task-specific hand dystonia: can too much plasticity be bad for you? Trends Neurosci 29:192–199

    Article  PubMed  CAS  Google Scholar 

  • Rich MM, Wenner P (2007) Sensing and expressing homeostatic synaptic plasticity. Trends Neurosci 30:119–125

    Article  PubMed  CAS  Google Scholar 

  • Ridding MC, Taylor JL (2001) Mechanisms of motor-evoked potential facilitation following prolonged dual peripheral and central stimulation in humans. J Physiol 537:623–631

    Article  PubMed  CAS  Google Scholar 

  • Sjostrom PJ, Nelson SB (2002) Spike timing, calcium signals and synaptic plasticity. Curr Opin Neurobiol 12:305–314

    Article  PubMed  CAS  Google Scholar 

  • Sjostrom PJ, Turrigiano GG, Nelson SB (2001) Rate, timing, and cooperativity jointly determine cortical synaptic plasticity. Neuron 32:1149–1164

    Article  PubMed  CAS  Google Scholar 

  • 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(Pt 3):572–584

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Stuart G, Spruston N, Sakmann B, Hausser M (1997) Action potential initiation and backpropagation in neurons of the mammalian CNS. Trends Neurosci 20:125–131

    Article  PubMed  CAS  Google Scholar 

  • Stuart G, Spruston N, Hausser M (eds) (1999) Dendrites. Oxford University Press, New York

  • Stuart GJ, Hausser M (2001) Dendritic coincidence detection of EPSPs and action potentials. Nat Neurosci 4:63–71

    Article  PubMed  CAS  Google Scholar 

  • Thickbroom GW, Byrnes ML, Mastaglia FL (1999) Methodology and application of TMS mapping. Electroencephalogr Clin Neurophysiol Suppl 51:48–54

    PubMed  CAS  Google Scholar 

  • Thickbroom GW, Byrnes ML, Edwards DJ, Mastaglia FL (2006) Repetitive paired-pulse TMS at I-wave periodicity markedly increases corticospinal excitability: a new technique for modulating synaptic plasticity. Clin Neurophysiol 117:61–66

    Article  PubMed  Google Scholar 

  • 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. Electroencephalogr Clin Neurophysiol 101:263–272

    Article  PubMed  CAS  Google Scholar 

  • Turrigiano GG (1999) Homeostatic plasticity in neuronal networks: the more things change, the more they stay the same. Trends Neurosci 22:221–227

    Article  PubMed  CAS  Google Scholar 

  • Turrigiano GG, Nelson SB (2000) Hebb and homeostasis in neuronal plasticity. Curr Opin Neurobiol 10:358–364

    Article  PubMed  CAS  Google Scholar 

  • Turrigiano GG, Nelson SB (2004) Homeostatic plasticity in the developing nervous system. Nat Rev Neurosci 5:97–107

    Article  PubMed  CAS  Google Scholar 

  • Vargas-Caballero M, Robinson HP (2003) A slow fraction of Mg2+ unblock of NMDA receptors limits their contribution to spike generation in cortical pyramidal neurons. J Neurophysiol 89:2778–2783

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Wilson SA, Lockwood RJ, Thickbroom GW, Mastaglia FL (1993) The muscle silent period following transcranial magnetic cortical stimulation. J Neurol Sci 114:216–222

    Article  PubMed  CAS  Google Scholar 

  • Witcher MR, Kirov SA, Harris KM (2007) Plasticity of perisynaptic astroglia during synaptogenesis in the mature rat hippocampus. Glia 55:13–23

    Article  PubMed  Google Scholar 

  • Wolters A, Sandbrink F, Schlottmann A, Kunesch E, Stefan K, Cohen LG, Benecke R, Classen J (2003) A temporally asymmetric Hebbian rule governing plasticity in the human motor cortex. J Neurophysiol 89:2339–2345

    Article  PubMed  Google Scholar 

  • Woodin MA, Ganguly K, Poo MM (2003) Coincident pre- and postsynaptic activity modifies GABAergic synapses by postsynaptic changes in Cl- transporter activity. Neuron 39:807–820

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  Google Scholar 

  • Ziemann U, Tergau F, Wassermann EM, Wischer S, Hildebrandt J, Paulus W (1998) Demonstration of facilitatory I wave interaction in the human motor cortex by paired transcranial magnetic stimulation. J Physiol 511(Pt 1):181–190

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

I am indebted to Frank Mastaglia for suggesting this review, and for encouragement, comment, and welcome suggestions. I thank my colleagues and students who have contributed at a number of levels, and in particular Julian Rodrigues for the interesting discussions of plasticity mechanisms. In preparing this review I have benefited from several excellent and considerably more thorough reviews of the topics covered, and these I have referred to in the body of the text.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Gary W. Thickbroom.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Thickbroom, G.W. Transcranial magnetic stimulation and synaptic plasticity: experimental framework and human models. Exp Brain Res 180, 583–593 (2007). https://doi.org/10.1007/s00221-007-0991-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00221-007-0991-3

Keywords

Navigation