Transcranial Direct Current Stimulation: Protocols and Physiological Mechanisms of Action

  • Michael A. NitscheEmail author
  • Min-Fang Kuo
  • Walter Paulus
  • Andrea Antal


Tonic stimulation with direct currents (transcranial direct current stimulation [tDCS]) was reintroduced about a decade ago as a method to modulate cortical excitability, activity, and to elicit neuroplasticity in the human brain. tDCS alters cortical excitability for up to hours after the end of stimulation, depending on its duration and intensity. While anodal stimulation increases excitability, cathodal stimulation reduces it. Beyond these local effects under the electrodes, an impact of tDCS on cortical networks was revealed recently. During the last 12 years, tDCS has been demonstrated to modify perceptual, motor, and cognitive functions reversibly in healthy subjects. Moreover, the results of clinical pilot studies suggest its suitability as a treatment in neurological and psychiatric diseases. This review will give an overview of the principles of tDCS. It will be discussed how specific stimulation parameters, like stimulation intensity, duration, electrode size, and configuration, including recently developed new stimulation protocols, determine the direction, magnitude, and duration of effects. Moreover, an overview of the main putative regional and network physiological mechanisms will be given.


Motor Cortex Functional Connectivity Stimulation Protocol Cortical Excitability Anodal tDCS 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



M.A.N. receives funding by the German Research Society (DFG) via grants Ni 683/4-2, and Ni 683/6-1.


  1. 1.
    Ziemann U, Paulus W, Nitsche MA, Pascual-Leone A, Byblow WD, Berardelli A, et al. Consensus: motor cortex plasticity protocols. Brain Stimul. 2008;1:164–82.PubMedCrossRefGoogle Scholar
  2. 2.
    Bindman L, Lippold O, Redfearn JWT. The action of brief polarizing currents on the cerebral cortex of the rat (1) during current flow and (2) in the production of long-lasting after-effects. J Physiol Lond. 1964;172:369–82.PubMedCentralPubMedGoogle Scholar
  3. 3.
    Rush S, Driscoll DA. Current distribution in the brain from surface electrodes. Anesth Analg. 1968;47:717–23.PubMedCrossRefGoogle Scholar
  4. 4.
    Dymond AM, Coger RW, Serafetinides EA. Intracerebral current levels in man during electrosleep therapy. Biol Psychiatry. 1975;10:101–4.PubMedGoogle Scholar
  5. 5.
    Pfurtscheller G. Spectrum analysis of EEG: before, during and after extracranial stimulation in man. Elektromed Biomed Tech. 1970;15:225–30. Article in German.PubMedCrossRefGoogle Scholar
  6. 6.
    Costain R, Redfearn JWT, Lippold OCJ. A controlled trial of the therapeutic effects of polarization of the brain in depressive illness. Br J Psychiatry. 1964;110:786–99.PubMedCrossRefGoogle Scholar
  7. 7.
    Lippold OCJ, Redfearn JWT. Mental changes resulting from the passage of small direct currents through the human brain. Br J Psychiatry. 1964;1964:768–72.CrossRefGoogle Scholar
  8. 8.
    Redfearn JWT, Lippold OCJ, Costain R. A preliminary account of the clinnical effects of polarizing the brain in certain psychiatric disorders. Br J Psychiatry. 1964;110:773–85.PubMedCrossRefGoogle Scholar
  9. 9.
    Lolas F. Brain polarization: behavioral and therapeutic effects. Biol Psychiatry. 1977;12:37–47.PubMedGoogle Scholar
  10. 10.
    Elbert T, Lutzenberger W, Rockstroh B, Birbaumer N. The influence of low-level transcortical DC-currents on response speed in humans. Int J Neurosci. 1981;14:101–14.PubMedCrossRefGoogle Scholar
  11. 11.
    Jaeger D, Elbert T, Lutzenberger W, Birbaumer N. The effects of externally applied transcephalic weak direct currents on lateralization in choice reaction tasks. J Psychophysiol. 1987;1:127–33.Google Scholar
  12. 12.
    Nitsche M, Paulus W. Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. J Physiol. 2000;527(Pt 3):633–9.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Nitsche M, Paulus W. Sustained excitability elevations induced by transcranial DC motor cortex stimulation in humans. Neurology. 2001;57:1899–901.PubMedCrossRefGoogle Scholar
  14. 14.
    Nitsche MA, Cohen LG, Wassermann EM, Priori A, Lang N, Antal A, et al. Transcranial direct current stimulation: state of the art 2008. Brain Stimul. 2008;1:206–23.PubMedCrossRefGoogle Scholar
  15. 15.
    Nitsche MA, Paulus W. Transcranial direct current stimulation: update 2011. Restor Neurol Neurosci. 2011;29:463–92.PubMedGoogle Scholar
  16. 16.
    Dundas JE, Thickbroom GW, Mastaglia FL. Perception of comfort during transcranial DC stimulation: effect of NaCl solution concentration applied to sponge electrodes. Clin Neurophysiol. 2007;118:1166–70.PubMedCrossRefGoogle Scholar
  17. 17.
    Nitsche M, Nitsche M, Klein C, Tergau F, Rothwell J, Paulus W. Level of action of cathodal DC polarisation induced inhibition of the human motor cortex. Clin Neurophysiol. 2003;114:600–4.PubMedCrossRefGoogle Scholar
  18. 18.
    Nitsche M, Niehaus L, Hoffmann K, Hengst S, Liebetanz D, Paulus W, et al. MRI study of human brain exposed to weak direct current stimulation of the frontal cortex. Clin Neurophysiol. 2004;115:2419–23.PubMedCrossRefGoogle Scholar
  19. 19.
    Iyer M, Mattu U, Grafman J, Lomarev M, Sato S, Wassermann E. Safety and cognitive effect of frontal DC brain polarization in healthy individuals. Neurology. 2005;64:872–5.PubMedCrossRefGoogle Scholar
  20. 20.
    Liebetanz D, Koch R, Mayenfels S, Konig F, Paulus W, Nitsche MA. Safety limits of cathodal transcranial direct current stimulation in rats. Clin Neurophysiol. 2009;120:1161–7.PubMedCrossRefGoogle Scholar
  21. 21.
    Ambrus GG, Antal A, Paulus W. Comparing cutaneous perception induced by electrical stimulation using rectangular and round shaped electrodes. Clin Neurophysiol. 2011;122:803–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Ambrus GG, Al-Moyed H, Chaieb L, Sarp L, Antal A, Paulus W. The fade-in—short stimulation—fade out approach to sham tDCS—reliable at 1 mA for naive and experienced subjects, but not investigators. Brain Stimul. 2012;5:499–504.PubMedCrossRefGoogle Scholar
  23. 23.
    Paulus W. On the difficulties of separating retinal from cortical origins of phosphenes when using transcranial alternating current stimulation (tACS). Clin Neurophysiol. 2010;121:987–91.PubMedCrossRefGoogle Scholar
  24. 24.
    Gandiga PC, Hummel FC, Cohen LG. Transcranial DC stimulation (tDCS): a tool for double-blind sham-controlled clinical studies in brain stimulation. Clin Neurophysiol. 2006;117:845–50.PubMedCrossRefGoogle Scholar
  25. 25.
    Miranda PC, Faria P, Hallett M. What does the ratio of injected current to electrode area tell us about current density in the brain during tDCS? Clin Neurophysiol. 2009;120:1183–7.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Faria P, Hallett M, Miranda PC. A finite element analysis of the effect of electrode area and inter-electrode distance on the spatial distribution of the current density in tDCS. J Neural Eng. 2011;8:066017.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Purpura DP, McMurtry JG. Intracellular activities and evoked potential changes during polarization of motor cortex. J Neurophysiol. 1965;28:166–85.PubMedGoogle Scholar
  28. 28.
    Creutzfeldt OD, Fromm GH, Kapp H. Influence of transcortical d-c currents on cortical neuronal activity. Exp Neurol. 1962;5:436–52.PubMedCrossRefGoogle Scholar
  29. 29.
    Kabakov AY, Muller PA, Pascual-Leone A, Jensen FE, Rotenberg A. Contribution of axonal orientation to pathway-dependent modulation of excitatory transmission by direct current stimulation in isolated rat hippocampus. J Neurophysiol. 2012;107:1881–9.PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Monte-Silva K, Kuo MF, Hessenthaler S, Fresnoza S, Liebetanz D, Paulus W, et al. Induction of late LTP-like plasticity in the human motor cortex by repeated non-invasive brain stimulation. Brain Stimul. 2012;6:424–32.PubMedCrossRefGoogle Scholar
  31. 31.
    Accornero N, Li Voti P, La Riccia M, Gregori B. Visual evoked potentials modulation during direct current cortical polarization. Exp Brain Res. 2007;178:261–6.PubMedCrossRefGoogle Scholar
  32. 32.
    Antal A, Terney D, Poreisz C, Paulus W. Towards unravelling task-related modulations of neuroplastic changes induced in the human motor cortex. Eur J Neurosci. 2007;26:2687–91.PubMedCrossRefGoogle Scholar
  33. 33.
    Roth BJ. Mechanisms for electrical stimulation of excitable tissue. Crit Rev Biomed Eng. 1994;22:253–305.PubMedGoogle Scholar
  34. 34.
    Priori A, Berardelli A, Rona S, Accornero N, Manfredi M. Polarization of the human motor cortex through the scalp. Neuroreport. 1998;9:2257–60.PubMedCrossRefGoogle Scholar
  35. 35.
    Antal A, Kincses TZ, Nitsche MA, Bartfai O, Paulus W. Excitability changes induced in the human primary visual cortex by transcranial direct current stimulation: direct electrophysiological evidence. Invest Ophthalmol Vis Sci. 2004;45:702–7.PubMedCrossRefGoogle Scholar
  36. 36.
    Moliadze V, Antal A, Paulus W. Electrode-distance dependent after-effects of transcranial direct and random noise stimulation with extracephalic reference electrodes. Clin Neurophysiol. 2010;121:2165–71.PubMedCrossRefGoogle Scholar
  37. 37.
    Monte-Silva K, Kuo M-F, Liebetanz D, Paulus W, Nitsche MA. Shaping the optimal repetition interval for cathodal transcranial direct current stimulation (tDCS). J Neurophysiol. 2010;103:1735–40.PubMedCrossRefGoogle Scholar
  38. 38.
    Fregni F, Gimenes R, Valle AC, Ferreira MJ, Rocha RR, Natalle L, et al. A randomized, sham-controlled, proof of principle study of transcranial direct current stimulation for the treatment of pain in fibromyalgia. Arthritis Rheum. 2006;54:3988–98.PubMedCrossRefGoogle Scholar
  39. 39.
    Loo CK, Alonzo A, Martin D, Mitchell PB, Galvez V, Sachdev P. Transcranial direct current stimulation for depression: 3-week, randomised, sham-controlled trial. Br J Psychiatry. 2012;200:52–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Reis J, Schambra HM, Cohen LG, Buch ER, Fritsch B, Zarahn E, et al. Noninvasive cortical stimulation enhances motor skill acquisition over multiple days through an effect on consolidation. Proc Natl Acad Sci U S A. 2009;106:1590–5.PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Lang N, Siebner H, Ward N, Lee L, Nitsche M, Paulus W, et al. How does transcranial DC stimulation of the primary motor cortex alter regional neuronal activity in the human brain? Eur J Neurosci. 2005;22:495–504.PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Nitsche MA, Doemkes S, Karakose T, Antal A, Liebetanz D, Lang N, et al. Shaping the effects of transcranial direct current stimulation of the human motor cortex. J Neurophysiol. 2007;97:3109–17.PubMedCrossRefGoogle Scholar
  43. 43.
    Datta A, Bansal V, Diaz J, Patel J, Reato D, Bikson M. Gyri-precise head model of transcranial direct current stimulation: improved spatial focality using a ring electrode versus conventional rectangular pad. Brain Stimul. 2009;2:201–7. 207.e201.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Cogiamanian F, Marceglia S, Ardolino G, Barbieri S, Priori A. Improved isometric force endurance after transcranial direct current stimulation over the human motor cortical areas. Eur J Neurosci. 2007;26:242–9.PubMedCrossRefGoogle Scholar
  45. 45.
    Borckardt JJ, Bikson M, Frohman H, Reeves ST, Datta A, Bansal V, et al. A pilot study of the tolerability and effects of high-definition transcranial direct current stimulation (HD-tDCS) on pain perception. J Pain. 2012;13:112–20.PubMedCrossRefGoogle Scholar
  46. 46.
    Dmochowski JP, Datta A, Bikson M, Su Y, Parra LC. Optimized multi-electrode stimulation increases focality and intensity at target. J Neural Eng. 2011;8:046011.PubMedCrossRefGoogle Scholar
  47. 47.
    Hallett M. Transcranial magnetic stimulation: a primer. Neuron. 2007;55:187–99.PubMedCrossRefGoogle Scholar
  48. 48.
    Nitsche M, Seeber A, Frommann K, Klein C, Rochford C, Nitsche M, et al. Modulating parameters of excitability during and after transcranial direct current stimulation of the human motor cortex. J Physiol. 2005;568(Pt 1):291–303.PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Nitsche M, Liebetanz D, Schlitterlau A, Henschke U, Fricke K, Frommann K, et al. GABAergic modulation of DC stimulation-induced motor cortex excitability shifts in humans. Eur J Neurosci. 2004;19:2720–6.PubMedCrossRefGoogle Scholar
  50. 50.
    Antal A, Paulus W. Investigating neuroplastic changes in the human brain induced by transcranial direct (tDCS) and alternating current (tACS) stimulation methods. Clin EEG Neurosci. 2012;43:175.PubMedCrossRefGoogle Scholar
  51. 51.
    Boros K, Poreisz C, Münchau A, Paulus W, Nitsche MA. Premotor transcranial direct current stimulation (tDCS) affects primary motor excitability in humans. Eur J Neurosci. 2008;27:1292–300.PubMedCrossRefGoogle Scholar
  52. 52.
    Nitsche M, Fricke K, Henschke U, Schlitterlau A, Liebetanz D, Lang N, et al. Pharmacological modulation of cortical excitability shifts induced by transcranial direct current stimulation in humans. J Physiol. 2003;553:293–301.PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Nitsche M, Jaussi W, Liebetanz D, Lang N, Tergau F, Paulus W. Consolidation of human motor cortical neuroplasticity by D-cycloserine. Neuropsychopharmacology. 2004;29:1573–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Islam N, Aftabuddin M, Moriwaki A, Hattori Y, Hori Y. Increase in the calcium level following anodal polarization in the rat brain. Brain Res. 1995;684:206–8.PubMedCrossRefGoogle Scholar
  55. 55.
    Stagg CJ, Best JG, Stephenson MC, O’Shea J, Wylezinska M, Kincses ZT, et al. Polarity-sensitive modulation of cortical neurotransmitters by transcranial stimulation. J Neurosci. 2009;29:5202–6.PubMedCrossRefGoogle Scholar
  56. 56.
    Reymann KG, Frey JU. The late maintenance of hippocampal LTP: requirements, phases, ‘synaptic tagging’, ‘late-associativity’ and implications. Neuropharmacology. 2007;52:24–40.PubMedCrossRefGoogle Scholar
  57. 57.
    Nitsche MA, Müller-Dahlhaus F, Paulus W, Ziemann U. The pharmacology of neuroplasticity induced by non-invasive brain stimulation: building models for the clinical use of CNS active drugs. J Physiol. 2012;590:4641–62.PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Nitsche M, Grundey J, Liebetanz D, Lang N, Tergau F, Paulus W. Catecholaminergic consolidation of motor cortical neuroplasticity in humans. Cereb Cortex. 2004;14:1240–5.PubMedCrossRefGoogle Scholar
  59. 59.
    Nitsche M, Lampe C, Antal A, Liebetanz D, Lang N, Tergau F, et al. Dopaminergic modulation of long-lasting direct current-induced cortical excitability changes in the human motor cortex. Eur J Neurosci. 2006;23:1651–7.PubMedCrossRefGoogle Scholar
  60. 60.
    Kuo M-F, Paulus W, Nitsche MA. Boosting focally-induced brain plasticity by dopamine. Cereb Cortex. 2008;18:648–51.PubMedCrossRefGoogle Scholar
  61. 61.
    Monte-Silva K, Liebetanz D, Grundey J, Paulus W, Nitsche MA. Dosage-dependent non-linear effect of L-dopa on human motor cortex plasticity. J Physiol Lond. 2010;588:3415–24.PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.
    Monte-Silva K, Kuo M-F, Thirugnanasambandam N, Liebetanz D, Paulus W, Nitsche MA. Dose-dependent inverted U-shaped effect of dopamine (D2-like) receptor activation on focal and nonfocal plasticity in humans. J Neurosci. 2009;29:6124–31.PubMedCrossRefGoogle Scholar
  63. 63.
    Nitsche MA, Kuo M-F, Grosch J, Bergner C, Monte-Silva K, Paulus W. D1-receptor impact on neuroplasticity in humans. J Neurosci. 2009;29:2648–53.PubMedCrossRefGoogle Scholar
  64. 64.
    Nitsche MA, Kuo M-F, Karrasch R, Wächter B, Liebetanz D, Paulus W. Serotonin affects transcranial direct current-induced neuroplasticity in humans. Biol Psychiatry. 2009;66:503–8.PubMedCrossRefGoogle Scholar
  65. 65.
    Kuo M-F, Grosch J, Fregni F, Paulus W, Nitsche MA. Focusing effect of acetylcholine on neuroplasticity in the human motor cortex. J Neurosci. 2007;27:14442–7.PubMedCrossRefGoogle Scholar
  66. 66.
    Thirugnanasambandam N, Grundey J, Adam K, Drees A, Skwirba AC, Lang N, et al. Nicotinergic impact on focal and non-focal neuroplasticity induced by non-invasive brain stimulation in non-smoking humans. Neuropsychopharmacology. 2011;36:879–86.PubMedCentralPubMedCrossRefGoogle Scholar
  67. 67.
    Matsunaga K, Nitsche MA, Tsuji S, Rothwell JC. Effect of transcranial DC sensorimotor cortex stimulation on somatosensory evoked potentials in humans. Clin Neurophysiol. 2004;115:456–60.PubMedCrossRefGoogle Scholar
  68. 68.
    Dieckhofer A, Waberski TD, Nitsche M, Paulus W, Buchner H, Gobbele R. Transcranial direct current stimulation applied over the somatosensory cortex: differential effect on low and high frequency SEPs. Clin Neurophysiol. 2006;117:2221–7.PubMedCrossRefGoogle Scholar
  69. 69.
    Zaehle T, Beretta M, Jancke L, Herrmann CS, Sandmann P. Excitability changes induced in the human auditory cortex by transcranial direct current stimulation: direct electrophysiological evidence. Exp Brain Res. 2011;215:135–40.PubMedCrossRefGoogle Scholar
  70. 70.
    Kirimoto H, Ogata K, Onishi H, Oyama M, Goto Y, Tobimatsu S. Transcranial direct current stimulation over the motor association cortex induces plastic changes in ipsilateral primary motor and somatosensory cortices. Clin Neurophysiol. 2011;122:777–83.PubMedCrossRefGoogle Scholar
  71. 71.
    Feurra M, Bianco G, Polizzotto NR, Innocenti I, Rossi A, Rossi S. Cortico-cortical connectivity between right parietal and bilateral primary motor cortices during imagined and observed actions: a combined TMS/tDCS study. Front Neural Circuits. 2011;5:10.PubMedCentralPubMedCrossRefGoogle Scholar
  72. 72.
    Polania R, Paulus W, Antal A, Nitsche MA. Introducing graph theory to track for neuroplastic alterations in the resting human brain: a transcranial direct current stimulation study. Neuroimage. 2011;54:2287–96.PubMedCrossRefGoogle Scholar
  73. 73.
    Stagg CJ, O’Shea J, Kincses ZT, Woolrich M, Matthews PM, Johansen-Berg H. Modulation of movement-associated cortical activation by transcranial direct current stimulation. Eur J Neurosci. 2009;30:1412–23.PubMedCrossRefGoogle Scholar
  74. 74.
    Polania R, Nitsche MA, Paulus W. Modulating functional connectivity patterns and topological functional organization of the human brain with transcranial direct current stimulation. Hum Brain Mapp. 2011;32:1236–49.PubMedCrossRefGoogle Scholar
  75. 75.
    Polania R, Paulus W, Nitsche MA. Modulating cortico-striatal and thalamo-cortical functional connectivity with transcranial direct current stimulation. Hum Brain Mapp. 2011;32(8):1236–49.PubMedCrossRefGoogle Scholar
  76. 76.
    Polania R, Paulus W, Nitsche MA. Reorganizing the intrinsic functional architecture of the human primary motor cortex during rest with non-invasive cortical stimulation. PLoS ONE. 2012;7:e30971.PubMedCentralPubMedCrossRefGoogle Scholar
  77. 77.
    Keeser D, Meindl T, Bor J, Palm U, Pogarell O, Mulert C, et al. Prefrontal transcranial direct current stimulation changes connectivity of resting-state networks during fMRI. J Neurosci. 2011;31:15284–93.PubMedCrossRefGoogle Scholar
  78. 78.
    Pena-Gomez C, Sala-Lonch R, Junque C, Clemente IC, Vidal D, Bargallo N, et al. Modulation of large-scale brain networks by transcranial direct current stimulation evidenced by resting-state functional MRI. Brain Stimul. 2012;5:252–63.PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.
    Liebetanz D, Nitsche MA, Tergau F, Paulus W. Pharmacological approach to the mechanisms of transcranial DC-stimulation-induced after-effects of human motor cortex excitability. Brain. 2002;125:2238–47.PubMedCrossRefGoogle Scholar
  80. 80.
    Kuo HI, Bikson M, Datta A, Minhas P, Paulus W, Kuo MF, et al. Comparing cortical plasticity induced by conventional and high-definition 4x1 ring tDCS: a neurophysiological study. Brain Stimul. 2012;6:644–8.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2015

Authors and Affiliations

  • Michael A. Nitsche
    • 1
    Email author
  • Min-Fang Kuo
    • 1
  • Walter Paulus
    • 1
  • Andrea Antal
    • 1
  1. 1.Department of Clinical Neurophysiology, University Medical CenterGeorg-August-UniversityGoettingenGermany

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