Challenges, Open Questions and Future Direction in Transcranial Direct Current Stimulation Research and Applications

  • Michael A. NitscheEmail author
  • Helena Knotkova
  • Adam J. Woods
  • Marom Bikson


The broad overview of theoretical and practical aspects pertaining to tDCS applications in this book demonstrates that tDCS applications are rapidly expanding with enormous potential in brain research and therapy. Building on the foundation of existing evidence, tDCS can benefit from further technological development and methodological refinement. This chapter discusses the state of the art as well as open questions and gaps in existing knowledge and provides insight into possible future technology developments and research initiatives intended to substantiate the potential that tDCS holds for research and clinical applications. In specifics, the need includes: further research supported by advanced neurophysiological and neuroimaging methods in order to bridge gaps in understanding the neurophysiological mechanisms of tDCS and relations to specific functional outcomes; optimization and standardization of stimulation protocols; building a pool of long-term safety data and an environment for data sharing; development toward user-friendly solutions; progress toward implementation of tDCS to clinical practice; initiatives supporting education and professional competence in tDCS use in research and clinical settings.


Transcranial direct current stimulation (tDCS) Non-invasive neuromodulation Technology development Good practice 


  1. Batsikadze, G., Moliadze, V., Paulus, W., Kuo, M. F., & Nitsche, M. A. (2013). Partially non-linear stimulation intensity-dependent effects of direct current stimulation on motor cortex excitability in humans. The Journal of Physiology, 591(7), 1987–2000.PubMedPubMedCentralGoogle Scholar
  2. Bestmann, S. (2015). Computational neurostimulation in basic and translational research. Progress in Brain Research, 222, xv–xx.PubMedGoogle Scholar
  3. Bikson, M., Dmochowski, J., & Rahman, A. (2013a). The “quasi-uniform” assumption in animal and computational models of non-invasive electrical stimulation. Brain Stimulation, 6(4), 704–705.Google Scholar
  4. Bikson, M., Grossman, P., Thomas, C., Zannou, A. L., Jiang, J., Adnan, T., … Woods, A. J. (2016). Safety of transcranial direct current stimulation: Evidence based update 2016. Brain Stimulation, 9(5), 641–661.PubMedPubMedCentralGoogle Scholar
  5. Bikson, M., Rahman, A., & Datta, A. (2012). Computational models of transcranial direct current stimulation. Clinical EEG and Neuroscience, 43(3), 176–183.PubMedGoogle Scholar
  6. Bikson, M., Inoue, M., Akiyama, H., Deans, J. K., Fox, J. E., Miyakawa, H., & Jefferys, J. G. (2004). Effects of uniform extracellular DC electric fields on excitability in rat hippocampal slices in vitro. The Journal of Physiology, 15(557), 175–190.Google Scholar
  7. Bikson, M., Name, A., & Rahman, A. (2013b). Origins of specificity during tDCS: Anatomical, activity-selective, and input-bias mechanisms. Frontiers in Human Neuroscience, 21(7), 688.Google Scholar
  8. Bindman, L. J., Lippold, O. C., & Redfearn, J. W. (1964). 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. The Journal of Physiology, 172, 369–382.PubMedPubMedCentralGoogle Scholar
  9. Brunoni, A. R., Nitsche, M. A., Bolognini, N., Bikson, M., Wagner, T., Merabet, L., … Fregni, F. (2012). Clinical research with transcranial direct current stimulation (tDCS): Challenges and future directions. Brain Stimulation, 5(3), 175–195.Google Scholar
  10. Brunoni, A. R., Valiengo, L., Baccaro, A., Zanão, T. A., de Oliveira, J. F., Goulart, A., … Fregni, F. (2013). The sertraline vs electrical current therapy for treating depression clinical study: Results from a factorial, randomized, controlled trial. JAMA Psychiatry, 70(4), 383–391.PubMedPubMedCentralGoogle Scholar
  11. Charvet, L. E., Kasschau, M., Datta, A., Knotkova, H., Stevens, M. C., Alonzo, A., … Bikson, M. (2015). Remotely-supervised transcranial direct current stimulation(tDCS) for clinical trials: Guidelines for technology and protocols. Frontiers in Systems Neuroscience, 17(9), 26.Google Scholar
  12. Dasilva, A. F., Mendonca, M. E., Zaghi, S., Lopes, M., Dossantos, M. F., Spierings, E. L., … Fregni, F. (2012). tDCS-induced analgesia and electrical fields in pain-related neural networks in chronic migraine. Headache, 52(8), 1283–1295.PubMedPubMedCentralGoogle Scholar
  13. DaSilva, A. F., Volz, M. S., Bikson, M., & Fregni, F. (2011). Electrode positioning and montage in transcranial direct current stimulation. Journal of Visualized Experiments, 23(51), 1–11.Google Scholar
  14. Datta, A., Bansal, V., Diaz, J., Patel, J., Reato, D., & Bikson, M. (2009). Gyri-precise head model of transcranial direct current stimulation: Improved spatial focality using a ring electrode versus conventional rectangular pad. Brain Stimulation, 2(4), 201–207.PubMedPubMedCentralGoogle Scholar
  15. Datta, A., Truong, D., Minhas, P., Parra, L. C., & Bikson, M. (2012). Inter-individual variation during transcranial direct current stimulation and normalization of dose using MRI-derived computational models. Frontiers in Psychiatry, 22(3), 91.Google Scholar
  16. Datta, A., Zhou, X., Su, Y., Parra, L. C., & Bikson, M. (2013). Validation of finite element model of transcranial electrical stimulation using scalp potentials: Implications for clinical dose. Journal of Neural Engineering, 10(3), 036018.PubMedGoogle Scholar
  17. Esmaeilpour, Z., Schestatsky, P., Bikson, M., Brunoni, A. R., Pellegrinelli, A., Piovesan, F. X., … Fregni, F. (2017). Notes on human trials of transcranial direct current stimulation between 1960 and 1998. Frontiers in Human Neuroscience, 23(11), 71.Google Scholar
  18. Fresnoza, S., Paulus, W., Nitsche, M. A., & Kuo, M. F. (2014). Nonlinear dose-dependent impact of D1 receptor activation on motor cortex plasticity in humans. Journal of Neuroscience, 34(7), 2744–2753.PubMedGoogle Scholar
  19. Furuya, S., Klaus, M., Nitsche, M. A., Paulus, W., & Altenmüller, E. (2014). Ceiling effects prevent further improvement of transcranial stimulation in skilled musicians. Journal of Neuroscience, 34(41), 13834–13839.PubMedGoogle Scholar
  20. Gellner, A. K., Reis, J., & Fritsch, B. (2016). Glia: A neglected player in non-invasive direct current brain stimulation. Frontiers in Cellular Neuroscience, 8(10), 188.Google Scholar
  21. Gillick, B., Menk, J., Mueller, B., Meekins, G., Krach, L. E., Feyma, T., & Rudser, K. (2015a). Synergistic effect of combined transcranial direct current stimulation/constraint-induced movement therapy in children and young adults with hemiparesis: Study protocol. BMC Pediatrics, 15, 178.PubMedPubMedCentralGoogle Scholar
  22. Gillick, B. T., Feyma, T., Menk, J., Usset, M., Vaith, A., Wood, T. J., … Krach, L. E. (2015b). Safety and feasibility of transcranial direct current stimulation in pediatric hemiparesis: Randomized controlled preliminary study. Physical Therapy, 95(3), 337–349.PubMedGoogle Scholar
  23. Hahn, C., Rice, J., Macuff, S., Minhas, P., Rahman, A., & Bikson, M. (2013). Methods for extra-low voltage transcranial direct current stimulation: Current and time dependent impedance decreases. Clinical Neurophysiology, 124(3), 551–556.PubMedPubMedCentralGoogle Scholar
  24. Huang, Y., Liu, A. A., Lafon, B., Friedman, D., Dayan, M., Wang, X., … Parra, L. C. (2017). Measurements and models of electric fields in the in vivo human brain during transcranial electric stimulation. eLife, 6, e18834.PubMedPubMedCentralGoogle Scholar
  25. Jackson, M. P., Rahman, A., Lafon, B., Kronberg, G., Ling, D., Parra, L. C., & Bikson, M. (2016). Animal models of transcranial direct current stimulation: Methods and mechanisms. Clinical Neurophysiology, 127(11), 3425–3454.PubMedPubMedCentralGoogle Scholar
  26. Kabakov, A. Y., Muller, P. A., Pascual-Leone, A., Jensen, F. E., & Rotenberg, A. (2012). Contribution of axonal orientation to pathway-dependent modulation of excitatory transmission by direct current stimulation in isolated rat hippocampus. Journal of Neurophysiology, 107(7), 1881–1889.PubMedPubMedCentralGoogle Scholar
  27. Kasschau, M., Sherman, K., Haider, L., Frontario, A., Shaw, M., Datta, A., … Charvet, L. (2015). A protocol for the use of remotely-supervised transcranial direct current stimulation (tDCS) in multiple sclerosis (MS). Journal of Visualized Experiments, 26(106), e53542.Google Scholar
  28. Kim, J. H., Kim, D. W., Chang, W. H., Kim, Y. H., Kim, K., & Im, C. H. (2014). Inconsistent outcomes of transcranial direct current stimulation may originate from anatomical differences among individuals: electric field simulation using individual MRI data. Neuroscience Letters, 564, 6–10.PubMedGoogle Scholar
  29. Knotkova, H., Leuschner, Z., Soto, E., Davoudzadeh, E., Greenberg, A., & Cruciani, R. A. (2014). Evaluating outcomes of transcranial direct current stimulation (tDCS) in patients with chronic neuropathic pain. The Journal of Pain, 15(4), S69.Google Scholar
  30. Knotkova, H., Woods, A., & Bikson, M. (2015). Transcranial direct current stimulation(tDCS): What pain practitioners need to know. Practical Pain Management, 2, 58–65.Google Scholar
  31. Kronberg, G., Bridi, M., Abel, T., Bikson, M., & Parra, L. C. (2017). Direct current stimulation modulates LTP and LTD: Activity dependence and dendritic effects. Brain Stimulation, 10(1), 51–58.PubMedGoogle Scholar
  32. Labruna, L., Jamil, A., Fresnoza, S., Batsikadze, G., Kuo, M. F., Vanderschelden, B., … Nitsche, M. A. (2016). Efficacy of anodal transcranial direct current stimulation is related to sensitivity to transcranial magnetic stimulation. Brain Stimulation, 9(1), 8–15.Google Scholar
  33. Lafon, B., Rahman, A., Bikson, M., & Parra, L. C. (2017). Direct current stimulation alters neuronal input/output function. Brain Stimulation, 10(1), 36–45.Google Scholar
  34. Lee, C., Jung, Y. J., Lee, S. J., & Im, C. H. (2017). COMETS2: An advanced MATLAB toolbox for the numerical analysis of electric fields generated by transcranial direct current stimulation. Journal of Neuroscience Methods, 277, 56–62.PubMedGoogle Scholar
  35. López-Alonso, V., Fernández-del-Olmo, M., Costantini, A., Gonzalez-Henriquez, J. J., & Cheeran, B. (2015). Intra-individual variability in the response to anodal transcranial direct current stimulation. Clinical Neurophysiology, 126(12), 2342–2347.Google Scholar
  36. Macedo, I. C., de Oliveira, C., Vercelino, R., Souza, A., Laste, G., Medeiros, L. F., … Torres, I. L. (2016). Repeated transcranial direct current stimulation reduces food craving in Wistar rats. Appetite, 103, 29–37.PubMedGoogle Scholar
  37. Márquez-Ruiz, J., Leal-Campanario, R., Sánchez-Campusano, R., Molaee-Ardekani, B., Wendling, F., Miranda, P. C., … Delgado-García, J. M. (2012). Transcranial direct-current stimulation modulates synaptic mechanisms involved in associative learning in behaving rabbits. Proceedings of the National Academy of Sciences of the United States of America, 109(17), 6710–6715.PubMedPubMedCentralGoogle Scholar
  38. Minhas, P., Bansal, V., Patel, J., Ho, J. S., Diaz, J., Datta, A., & Bikson, M. (2010). Electrodes for high-definition transcutaneous DC stimulation for applications in drug delivery and electrotherapy, including tDCS. Journal of Neuroscience Methods, 190(2), 188–197.PubMedPubMedCentralGoogle Scholar
  39. Nitsche, M. A., Müller-Dahlhaus, F., Paulus, W., & Ziemann, U. (2012). The pharmacology of neuroplasticity induced by non-invasive brain stimulation: Building models for the clinical use of CNS active drugs. The Journal of Physiology, 590(19), 4641–4662.PubMedPubMedCentralGoogle Scholar
  40. Nitsche, M. A., Kuo, M. F., Karrasch, R., Wächter, B., Liebetanz, D., & Paulus, W. (2009). Serotonin affects transcranial direct current–induced neuroplasticity in humans. Biological Psychiatry, 66(5), 503–508.PubMedPubMedCentralGoogle Scholar
  41. Nitsche, M. A., Liebetanz, D., Antal, A., Lang, N., Tergau, F., & Paulus, W. (2003). Modulation of cortical excitability by weak direct current stimulation–technical, safety and functional aspects. Supplements to Clinical Neurophysiology, 56, 255–276.PubMedGoogle Scholar
  42. Nitsche, M. A., & Paulus, W. (2000). Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. The Journal of Physiology, 527(Pt 3), 633–639.PubMedPubMedCentralGoogle Scholar
  43. Opitz, A., Falchier, A., Yan, C. G., Yeagle, E. M., Linn, G. S., Megevand, P., … Schroeder, C. E. (2016). Spatiotemporal structure of intracranial electric fields induced by transcranial electric stimulation in humans and nonhuman primates. Scientific Reports, 6, 31236.PubMedPubMedCentralGoogle Scholar
  44. Opitz, A., Paulus, W., Will, S., Antunes, A., & Thielscher, A. (2015). Determinants of the electric field during transcranial direct current stimulation. NeuroImage, 109, 140–150.Google Scholar
  45. Paneri, B., Adair, D., Thomas, C., Khadka, N., Patel, V., Tyler, W. J., … Bikson, M. (2016). Tolerability of repeated application of transcranial electrical stimulation with limited outputs to healthy subjects. Brain Stimulation, 9(5), 740–754.PubMedPubMedCentralGoogle Scholar
  46. Pikhovych, A., Stolberg, N. P., Jessica Flitsch, L., Walter, H. L., Graf, R., Fink, G. R., … Rueger, M. A. (2016). Transcranial direct current stimulation modulates neurogenesis and microglia activation in the mouse brain. Stem Cells, 2016, 1–9.Google Scholar
  47. Polanía, R., Nitsche, M. A., & Paulus, W. (2011a). Modulating functional connectivity patterns and topological functional organization of the human brain with transcranial direct current stimulation. Human Brain Mapping, 32(8), 1236–1249.PubMedPubMedCentralGoogle Scholar
  48. Polanía, R., Paulus, W., Antal, A., & Nitsche, M. A. (2011b). Introducing graph theory to track for neuroplastic alterations in the resting human brain: A transcranial direct current stimulation study. NeuroImage, 54(3), 2287–2296.PubMedPubMedCentralGoogle Scholar
  49. Polanía, R., Paulus, W., & Nitsche, M. A. (2012). Modulating cortico-striatal and thalamo-cortical functional connectivity with transcranial direct current stimulation. Human Brain Mapping, 33(10), 2499–2508.PubMedPubMedCentralGoogle Scholar
  50. Rahman, A., Lafon, B., & Bikson, M. (2015). Multilevel computational models for predicting the cellular effects of noninvasive brain stimulation. Progress in Brain Research, 222, 25–40.PubMedGoogle Scholar
  51. Rahman, A., Lafon, B., Parra, L. C., & Bikson, M. (2017). Direct current stimulation boosts synaptic gain and cooperativity in vitro. The Journal of Physiology, 595(11), 3535–3547.PubMedPubMedCentralGoogle Scholar
  52. Rahman, A., Reato, D., Arlotti, M., Gasca, F., Datta, A., Parra, L. C., & Bikson, M. (2013). Cellular effects of acute direct current stimulation: somatic and synaptic terminal effects. The Journal of Physiology, 591(10), 2563–2578.PubMedPubMedCentralGoogle Scholar
  53. Reato, D., Gasca, F., Datta, A., Bikson, M., Marshall, L., & Parra, L. C. (2013). Transcranial electrical stimulation accelerates human sleep homeostasis. PLoS Computational Biology, 9(2), e1002898.PubMedPubMedCentralGoogle Scholar
  54. Reato, D., Rahman, A., Bikson, M., & Parra, L. C. (2010). Low-intensity electrical stimulation affects network dynamics by modulating population rate and spike timing. The Journal of Neuroscience, 30(45), 15067–15079.PubMedPubMedCentralGoogle Scholar
  55. Ridding, M. C., & Ziemann, U. (2010). Determinants of the induction of cortical plasticity by non-invasive brain stimulation in healthy subjects. The Journal of Physiology, 588(Pt 13), 2291–2304.PubMedPubMedCentralGoogle Scholar
  56. Saturnino, G. B., Antunes, A., & Thielscher, A. (2015). On the importance of electrode parameters for shaping electric field patterns generated by tDCS. NeuroImage, 120, 25–35.Google Scholar
  57. Seibt, O., Brunoni, A. R., Huang, Y., & Bikson, M. (2015). The pursuit of DLPFC: Non-neuronavigated methods to target the left dorsolateral pre-frontal cortex with symmetric bicephalic transcranial direct current stimulation (tDCS). Brain Stimulation, 8(3), 590–602.Google Scholar
  58. Stagg, C. J., Best, J. G., Stephenson, M. C., O’Shea, J., Wylezinska, M., Kincses, Z. T., … Johansen-Berg, H. (2009). Polarity-sensitive modulation of cortical neurotransmitters by transcranial stimulation. The Journal of Neuroscience, 29(16), 5202–5206.PubMedGoogle Scholar
  59. Strube, W., Bunse, T., Nitsche, M. A., Palm, U., Falkai, P., & Hasan, A. (2016). Differential response to anodal tDCS and PAS is indicative of impaired focal LTP-like plasticity in schizophrenia. Behavioural Brain Research, 311, 46–53.PubMedGoogle Scholar
  60. Woods, A. J., Antal, A., Bikson, M., Boggio, P. S., Brunoni, A. R., Celnik, P., … Nitsche, M. A. (2016). A technical guide to tDCS, and related non-invasive brain stimulation tools. Clinical Neurophysiology, 127(2), 1031–1048.PubMedPubMedCentralGoogle Scholar
  61. Woods, A. J., Bryant, V., Sacchetti, D., Gervits, F., & Hamilton, R. (2015). Effects of electrode drift in transcranial direct current stimulation. Brain Stimulation, 8(3), 515–519.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2019

Authors and Affiliations

  • Michael A. Nitsche
    • 1
    • 2
    Email author
  • Helena Knotkova
    • 3
    • 4
  • Adam J. Woods
    • 5
  • Marom Bikson
    • 6
  1. 1.Department of Psychology and NeurosciencesLeibniz Research Centre for Working Environment and Human FactorsDortmundGermany
  2. 2.University Medical Hospital BergmannsheilBochumGermany
  3. 3.MJHS Institute for Innovation in Palliative CareNew YorkUSA
  4. 4.Department of Family and Social MedicineAlbert Einstein College of MedicineBronxUSA
  5. 5.Center for Cognitive Aging and Memory (CAM), McKnight Brain Institute, Department of Clinical and Health Psychology, College of Public Health and Health ProfessionsUniversity of FloridaGainesvilleUSA
  6. 6.Department of Biomedical EngineeringThe City College of New YorkNew YorkUSA

Personalised recommendations