Methodological Considerations for Transcranial Direct Current Stimulation in Clinical Trials

  • Roy H. HamiltonEmail author
  • Sudha K. Kessler
  • Laura Castillo-Saavedra
  • Felipe Fregni
  • Donel Martin
  • Colleen Loo
  • Helena Knotkova
  • Adam J. Woods


While recent years have witnessed a steady rise in the number of studies exploring transcranial direct current stimulation (tDCS) as a potential therapy for disorders of the central nervous system, there are to date no FDA approved clinical indications for this form of noninvasive neuromodulation. Successful development of tDCS as an approved therapy in the US and elsewhere will require the implementation of well designed, appropriately powered clinical trials, which, in turn, requires careful consideration of a variety of methodological factors. The choice of study design (e.g. between-subjects, within-subjects) is one the most fundamental decisions in designing a clinical trial. This choice is often influenced by the specific symptoms and natural histories of the disorders being investigated. Disease-related symptoms and disability may influence the design and execution of tDCS trials in other ways, for instance interfering with the ability of patients to participate in studies that involve frequent stimulation sessions in a research setting, or complicating the ability of patients to provide informed consent. Common medical co-morbidities may also influence the efficacy of tDCS as a therapy, either negatively by interfering with the effectiveness of brain stimulation, or positively by providing new treatment targets. The parameters being used to deliver tDCS including stimulation intensity, frequency, and duration, as well as electrode size, number, and location, also play a critical but only partially understood role in tDCS studies. Finally, the use of robust control conditions is an important concern in all clinical trials, including those involving tDCS. This chapter will review these issues as they pertain to the design of tDCS clinical trials, and will conclude with recommendations for the standardization of methods for tDCS clinical trial reporting.


Clinical trials Neurology Neuromodulation Neurorehabilitation Noninvasive brain stimulation Pain management Placebo Psychiatry tES Transcranial electrical stimulation 


  1. Angelakis, E., Liouta, E., Andreadis, N., Korfias, S., Ktonas, P., Stranjalis, G., & Sakas, D. E. (2014). Transcranial direct current stimulation effects in disorders of consciousness. Archives of Physical Medicine and Rehabiliattion, 95(2), 283–289. PubMedCrossRefGoogle Scholar
  2. Antal, A., Kincses, T. Z., Nitsche, M. A., Bartfai, O., & Paulus, W. (2004). Excitability changes induced in the human primary visual cortex by transcranial direct current stimulation: Direct electrophysiological evidence. Investigative Opthalmology & Visual Science, 45, 702–707.CrossRefGoogle Scholar
  3. Antal, A., Polania, R., Schmidt-Samoa, C., Dechent, P., & Paulus, W. (2011). Transcranial direct current stimulation over the primary motor cortex during fMRI. NeuroImage, 55(2), 590–596. PubMedPubMedCentralCrossRefGoogle Scholar
  4. Antal, A., Terney, D., Poreisz, C., & Paulus, W. (2007). Towards unravelling task-related modulations of neuroplastic changes induced in the human motor cortex. European Journal of Neuroscience, 26(9), 2687–2691. PubMedPubMedCentralCrossRefGoogle Scholar
  5. Bang, D., & Bong, S. (2015). Effect of combination of transcranial direct current stimulation and feedback training on visuospatial neglect in patients with subacute stroke: A pilot randomized controlled trial. Journal of Physical Therapy Science, 27(9), 2759–2761. PubMedPubMedCentralCrossRefGoogle Scholar
  6. 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. Journal of Physiology, 591, 1987–2000. PubMedPubMedCentralCrossRefGoogle Scholar
  7. Bikson, M., Datta, A., Rahman, A., & Scaturro, J. (2010). Electrode montages for tDCS and weak transcranial electrical stimulation: Role of “ return” electrode’s position and size. Clinical Neurophysiology, 121, 1976–1978. PubMedPubMedCentralCrossRefGoogle Scholar
  8. Boggio, P. S., Ferrucci, R., Rigonatti, S. P., Covre, P., Nitsche, M., Pascual-Leone, A., & Fregni, F. (2006). Effects of transcranial direct current stimulation on working memory in patients with Parkinson's disease. Journal of the Neurological Sciences, 249(1), 31–38. PubMedCrossRefGoogle Scholar
  9. Borckardt, J. J., Bikson, M., Frohman, H., Reeves, S. T., Datta, A., Bansal, V., … George, M. S. (2012). A pilot study of the tolerability and effects of high-definition transcranial direct current stimulation (HD-tDCS) on pain perception. Journal of Pain, 13, 112–120. CrossRefGoogle Scholar
  10. Borckardt, J. J., Reeves, S. T., Robinson, S. M., May, J. T., Epperson, T. I., Gunselman, R. J., … George, M. S. (2013). Transcranial direct current stimulation (tDCS) reduces postsurgical opioid consumption in total knee arthroplasty (TKA). The Clinical Journal of Pain, 29(11), 925–928. PubMedPubMedCentralCrossRefGoogle Scholar
  11. Bortoletto, M., Pellicciari, M. C., Rodella, C., & Miniussi, C. (2015). The interaction with task-induced activity is more important than polarization: A tDCS study. Brain Stimulation, 8(2), 269–276. PubMedCrossRefGoogle Scholar
  12. Brunoni, A. R., Ferrucci, R., Bortolomasi, M., Scelzo, E., Boggio, P. S., Fregni, F., … Priori, A. (2012). Interactions between transcranial direct current stimulation (tDCS) and pharmacological interventions in the major depressive episode: Findings from a naturalistic study. European Psychiatry, 28(6), 356–361. PubMedCrossRefGoogle Scholar
  13. Brunoni, A. R., Ferrucci, R., Bortolomasi, M., Vergari, M., Tadini, L., Boggio, P. S., … Priori, A. (2011). Transcranial direct current stimulation (tDCS) in unipolar vs. bipolar depressive disorder. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 35, 96–101. PubMedCrossRefGoogle Scholar
  14. Brunoni, A. R., & Fregni, F. (2011). Clinical trial design in non-invasive brain stimulation psychiatric research. International Journal of Methods in Psychiatric Research, 20(2), E19–E30. PubMedCrossRefGoogle Scholar
  15. Brunoni, A. R., Valiengo, L., Baccaro, A., Zanão, T. A., 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. PubMedPubMedCentralCrossRefGoogle Scholar
  16. Celnik, P., Paik, N., Vandermeeren, Y., Dimyan, M., & Cohen, L. G. (2009). Effects of combined peripheral nerve stimulation and brain polarization on performance of a motor sequence task after chronic stroke. Stroke, 40(5), 1764–1771. PubMedPubMedCentralCrossRefGoogle Scholar
  17. Cha, Y., Urbano, D., & Pariseau, N. (2016). Randomized single blind sham controlled trial of adjunctive home-based tDCS after rTMS for Mal De Debarquement syndrome: Safety, efficacy, and participant satisfaction assessment. Brain Stimulation, 9(4), 537–544. PubMedPubMedCentralCrossRefGoogle Scholar
  18. Chang, M. C., Kim, D. Y., & Park, D. H. (2015). Enhancement of cortical excitability and lower limb motor function in patients with stroke by transcranial direct current stimulation. Brain Stimulation, 8(3), 561–566. PubMedCrossRefGoogle Scholar
  19. 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, 9. Google Scholar
  20. Chow, S.-C., & Chang, M. (2008). Adaptive design methods in clinical trials – A review. Orphanet Journal of Rare Diseases, 3, 11. Google Scholar
  21. Clark, V. P., Coffman, B. A., Mayer, A. R., Weisend, M. P., Lane, T. D., Calhoun, V. D., … Wassermann, E. M. (2010). TDCS guided using fMRI significantly accelerates learning to identify concealed objects. NeuroImage, 59(1), 117–128. PubMedCrossRefGoogle Scholar
  22. (2016). Retrieved July 14, 2016, from
  23. Cramer, S. C. (2008). Repairing the human brain after stroke: I. Mechanisms of spontaneous recovery. Annals of Neurology, 63(3), 272–287. PubMedCrossRefGoogle Scholar
  24. Cruciani, R. A., Esteban, S., Sibirceva, U., & Knotkova, H. (2009). Non-invasive brain stimulation therapy for the management of complex regional pain syndrome (CRPS). Journal of Pain Management, Special issue on “Brain stimulation for treatment of pain”, 2(3), 277–285.Google Scholar
  25. D’Urso, G., Mantovani, A., Micillo, M., Priori, A., & Muscettola, G. (2013). Transcranial direct current stimulation and cognitive-behavioral therapy: Evidence of a synergistic effect in treatment-resistant depression. Brain Stimulation, 6(3), 465–467. PubMedPubMedCentralCrossRefGoogle Scholar
  26. Dasilva, A. F., Volz, M. S., Bikson, M., & Fregni, F. (2011). Electrode positioning and montage in transcranial direct current stimulation. Journal of Visualized Experiments, 54. Google Scholar
  27. 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.e1. CrossRefGoogle Scholar
  28. Di Lazzaro, V., Dileone, M., Capone, F., Pellegrino, G., Ranieri, F., Musumeci, G., … Fregni, F. (2014). Immediate and late modulation of interhemipheric imbalance with bilateral transcranial direct current stimulation in acute stroke. Brain Stimulation, 7(6), 841–848. PubMedCrossRefGoogle Scholar
  29. Duncan, P., Studenski, S., Richards, L., Gollub, S., Lai, S. M., Reker, D., … Johnson, D. (2003). Randomized clinical trial of therapeutic exercise in subacute stroke. Stroke, 34(9), 2173–2180. PubMedCrossRefGoogle Scholar
  30. Edwards, D., Cortes, M., Datta, A., Minhas, P., Wassermann, E. M., & Bikson, M. (2013). Physiological and modeling evidence for focal transcranial electrical brain stimulation in humans: A basis for high-definition tDCS. NeuroImage, 74, 266–275. PubMedPubMedCentralCrossRefGoogle Scholar
  31. Electronic Code of Federal Regulations. (2016). Retrieved July 15, 2016, from
  32. Elsner, B., Kugler, J., Pohl, M., & Mehrholz, J. (2013). Transcranial direct current stimulation (tDCS) for improving function and activities of daily living in patients after stroke. Cochrane Database of Systematic Reviews, 11. Google Scholar
  33. Faber, M., Vanneste, S., Fregni, F., & Ridder, D. D. (2012). Top down prefrontal affective modulation of tinnitus with multiple sessions of tDCS of dorsolateral prefrontal cortex. Brain Stimulation, 5(4), 492–498. PubMedCrossRefGoogle Scholar
  34. Fagerlund, A. J., Hansen, O. A., & Aslaksen, P. M. (2015). Transcranial direct current stimulation as a treatment for patients with fibromyalgia. Pain, 156(1), 62–71. PubMedCrossRefGoogle Scholar
  35. Ferrucci, R., Vergari, M., Cogiamanian, F., Bocci, T., Ciocca, M., Tomasini, E., … Priori, A. (2014). Transcranial direct current stimulation (tDCS) for fatigue in multiple sclerosis. NeuroRehabilitation, 34, 121–127. Google Scholar
  36. Flöel, A. (2014). TDCS-enhanced motor and cognitive function in neurological diseases. NeuroImage, 85(3), 934–947. PubMedCrossRefGoogle Scholar
  37. Fregni, F., Boggio, P. S., Nitsche, M. A., Rigonatti, S. P., & Pascual-Leone, A. (2006). Cognitive effects of repeated sessions of transcranial direct current stimulation in patients with depression. Depression and Anxiety, 23(8), 482–484. PubMedCrossRefGoogle Scholar
  38. Friedman, L. M., Furberg, C. D., & DeMets, D. L. (2014). Fundamentals of clinical trials (3rd ed.). Cham, Switzerland: Springer.Google Scholar
  39. Fusco, A., Assenza, F., Iosa, M., Izzo, S., Altavilla, R., Paolucci, S., & Vernieri, F. (2014). The ineffective role of cathodal tDCS in enhancing the functional motor outcomes in early phase of stroke rehabilitation: An experimental trial. BioMed Research International, 2014, 1–9. CrossRefGoogle Scholar
  40. Galeotti, F., Vanacore, N., Gainotti, S., Izzicupo, F., Menniti-Ippolito, F., Petrini, C., … Raschetti, R. (2012). How legislation on decisional capacity can negatively affect the feasibility of clinical trials in patients with dementia. Drugs Aging Drugs & Aging, 29(8), 607–614. Google Scholar
  41. Gartlehner, G., Hansen, R. A., & Nissman, D. (2006). Criteria for distinguishing effectiveness from efficacy trials in systematic reviews. Agency for Healthcare Research and Quality, 12, 1–17.Google Scholar
  42. Giampieri, M. (2012). Communication and informed consent in elderly people. Minerva Anestesiologica, 78(2), 236–242.Google Scholar
  43. Gill, J., Shah-Basak, P. P., & Hamilton, R. (2014). It’s the thought that counts: Examining the task-dependent effects of transcranial direct current stimulation on executive function. Brain Stimulation, 8, 253–259. Google Scholar
  44. Glaser, J., Reeves, S. T., Stoll, W. D., Epperson, T. I., Hilbert, M., Madan, A., … Borckardt, J. J. (2016). Motor/prefrontal transcranial direct current stimulation (tDCS) following lumbar surgery reduces postoperative analgesia use. Spine, 41(10), 835–839. PubMedCrossRefGoogle Scholar
  45. Hankey, G. J., Spiesser, J., Hakimi, Z., Bego, G., Carita, P., & Gabriel, S. (2007). Rate, degree, and predictors of recovery from disability following ischemic stroke. Neurology, 68(19), 1583–1587. PubMedCrossRefGoogle Scholar
  46. Hesse, S., Werner, C., Schonhardt, E. M., Bardeleben, A., Jenrich, W., & Kirker, S. B. (2007). Combined transcranial direct current stimulation and robot-assisted arm training in subacute stroke patients: A pilot study. Restorative Neurology & Neuroscience, 25(1), 9–15.PubMedCrossRefGoogle Scholar
  47. Ho, K., Taylor, J. L., Chew, T., Gálvez, V., Alonzo, A., Bai, S., … Loo, C. K. (2016). The effect of transcranial direct current stimulation (tDCS) electrode size and current intensity on motor cortical excitability: Evidence from single and repeated sessions. Brain Stimulation, 9(1), 1–7. PubMedCrossRefGoogle Scholar
  48. Horn, S. D., Dejong, G., Smout, R. J., Gassaway, J., James, R., & Conroy, B. (2005). Stroke rehabilitation patients, practice, and outcomes: Is earlier and more aggressive therapy better? Archives of Physical Medicine and Rehabilitation, 86(12), 101–114. CrossRefGoogle Scholar
  49. Iacono, T., & Carling-Jenkins, R. (2012). The human rights context for ethical requirements for involving people with intellectual disability in medical research. Journal of Intellectual Disability Research, 56(11), 1122–1132. PubMedCrossRefGoogle Scholar
  50. Iuculano, T., & Kadosh, R. C. (2013). The mental cost of cognitive enhancement. Journal of Neuroscience, 33(10), 4482–4486. PubMedPubMedCentralCrossRefGoogle Scholar
  51. Jones, K. T., Stephens, J. A., Alam, M., Bikson, M., & Berryhill, M. E. (2015). Longitudinal neurostimulation in older adults improves working memory. PLoS One, 10(4), e0121904. PubMedPubMedCentralCrossRefGoogle Scholar
  52. Jørgensen, H. S., Nakayama, H., Raaschou, H. O., & Olsen, T. S. (1999). Stroke: Neurologic and functional recovery. The Copenhagen stroke study. Physical Medicine and Rehabilitation Clinics of North America, 10(4), 887–906.CrossRefGoogle Scholar
  53. Jørgensen, H. S., Nakayama, H., Raaschou, H. O., Vive-Larsen, J., Støier, M., & Olsen, T. S. (1995). Outcome and time course of recovery in stroke. Part II: Time course of recovery. The Copenhagen stroke study. Archives of Physical Medicine and Rehabilitation, 76(5), 406–412. PubMedCrossRefGoogle Scholar
  54. Kang, N., Summers, J. J., & Cauraugh, J. H. (2015). Transcranial direct current stimulation facilitates motor learning post-stroke: A systematic review and meta-analysis. Journal of Neurology, Neurosurgery & Psychiatry, 87(4), 345–355. CrossRefGoogle Scholar
  55. Kasschau, M., Reisner, J., Sherman, K., Bikson, M., Datta, A., & Charvet, L. E. (2016). Transcranial direct current stimulation is feasible for remotely supervised home delivery in multiple sclerosis. Neuromodulation: Technology at the Neural Interface, 19, 824–831. CrossRefGoogle Scholar
  56. Kessler, S. K., Minhas, P., Woods, A. J., Rosen, A., Gorman, C., & Bikson, M. (2013). Dosage considerations for transcranial direct current stimulation in children: A computational modeling study. PLoS One, 8(9), e76112. PubMedPubMedCentralCrossRefGoogle Scholar
  57. Kessler, S. K., Turkeltaub, P. E., Benson, J. G., & Hamilton, R. H. (2012). Differences in the experience of active and sham transcranial direct current stimulation. Brain Stimulation, 5(2), 155–162.CrossRefGoogle Scholar
  58. Khedr, E. M., Shawky, O. A., El-Hammady, D. H., Rothwell, J. C., Darwish, E. S., Mostafa, O. M., & Tohamy, A. M. (2013, September 22). Effect of anodal versus cathodal transcranial direct current stimulation on stroke rehabilitation: A pilot randomized controlled trial. Neurorehabilitation and Neural Repair, 27(7), 592–601.PubMedCrossRefGoogle Scholar
  59. Kim, D., Lim, J., Kang, E. K., You, D. S., Oh, M., Oh, B., & Paik, N. (2010). Effect of transcranial direct current stimulation on motor recovery in patients with subacute stroke. American Journal of Physical Medicine & Rehabilitation, 89(11), 879–886.CrossRefGoogle Scholar
  60. Knotkova, H., Homel, P., & Cruciani, R. A. (2009). Cathodal tDCS over the somatosensory cortex relieved chronic neuropathic pain in a patient with complex regional pain syndrome (CRPS/RSD). Journal of Pain Management, Special issue on “Brain stimulation for treatment of pain”, 2(3), 365–368.Google Scholar
  61. Knotkova, H., Malamud, S. C., & Cruciani, R. A. (2014). Transcranial direct current stimulation (TDCS) improved cognitive outcomes in a cancer survivor with chemotherapy-induced cognitive difficulties. Brain Stimulation, 7(5), 767–768.PubMedCrossRefGoogle Scholar
  62. Knotkova, H., Riggs, A., Patel, V., Troung, D., Arce, D., Datta, A., & Bikson, M. (2016). Adjustment of headgear for easy use by chronically ill patients performing non-invasive neurostimulation at home. Poster. New York, NY: Metropolitan Jewish Health System Research Day.Google Scholar
  63. Knotkova, H., Rosedale, M., Strauss, S. M., Horne, J., Soto, E., Cruciani, R. A., … Malamud, D. (2012). Using transcranial direct current stimulation to treat depression in HIV-infected persons: The outcomes of a feasibility study. Frontiers in Psychiatry, 3.Google Scholar
  64. Kuo, H., Bikson, M., Datta, A., Minhas, P., Paulus, W., Kuo, M., & Nitsche, M. A. (2013). Comparing cortical plasticity induced by conventional and high-definition 4 × 1 ring tDCS: A neurophysiological study. Brain Stimulation, 6(4), 644–648.CrossRefGoogle Scholar
  65. Kutner, J. S., Blatchford, P. J., Taylor, D. H., Ritchie, C. S., Bull, J. H., Fairclough, D. L., … Abernethy, A. P. (2015). Safety and benefit of discontinuing statin therapy in the setting of advanced, life-limiting illness. JAMA Internal Medicine, 175(5), 691–700.PubMedCrossRefGoogle Scholar
  66. Kwon, Y. H., & Jang, S. H. (2011). The enhanced cortical activation induced by transcranial direct current stimulation during hand movements. Neuroscience Letters, 492(2), 105–108.PubMedPubMedCentralCrossRefGoogle Scholar
  67. Lee, S., Walker, J. R., Jakul, L., & Sexton, K. (2004). Does elimination of placebo responders in a placebo run-in increase the treatment effect in randomized clinical trials? A meta-analytic evaluation. Depression and Anxiety, 19(1), 10–19.PubMedCrossRefGoogle Scholar
  68. Lefebvre, S., Dricot, L., Laloux, P., Gradkowski, W., Desfontaines, P., Evrard, F., … Vandermeeren, Y. (2014). Neural substrates underlying stimulation-enhanced motor skill learning after stroke. Brain, 138(1), 149–163.PubMedPubMedCentralCrossRefGoogle Scholar
  69. Lefebvre, S., Laloux, P., Peeters, A., Desfontaines, P., Jamart, J., & Vandermeeren, Y. (2013). Dual-tDCS enhances online motor skill learning and long-term retention in chronic stroke patients. Frontiers in Human Neuroscience, 6.Google Scholar
  70. López-Alonso, V., Cheeran, B., Río-Rodríguez, D., & Fernández-Del-Olmo, M. (2014). Inter-individual variability in response to non-invasive brain stimulation paradigms. Brain Stimulation, 7(3), 372–380.PubMedCrossRefGoogle Scholar
  71. Martin, D. M., Liu, R., Alonzo, A., Green, M., & Loo, C. K. (2014). Use of transcranial direct current stimulation (tDCS) to enhance cognitive training: Effect of timing of stimulation. Experimental Brain Research, 232(10), 3345–3351.PubMedPubMedCentralCrossRefGoogle Scholar
  72. Martin, D. M., Liu, R., Alonzo, A., Green, M., Player, M. J., Sachdev, P., & Loo, C. K. (2013). Can transcranial direct current stimulation enhance outcomes from cognitive training? A randomized controlled trial in healthy participants. The International Journal of Neuropsychopharmacology, 16(9), 1927–1936.PubMedCrossRefGoogle Scholar
  73. Mattioli, F., Bellomi, F., Stampatori, C., Capra, R., & Miniussi, C. (2015, May 26). Neuroenhancement through cognitive training and anodal tDCS in multiple sclerosis. Multiple Sclerosis Journal, 22(2), 222–230.PubMedCrossRefGoogle Scholar
  74. Meinzer, M., Darkow, R., Lindenberg, R., & Floel, A. (2016). Electrical stimulation of the motor cortex enhances treatment outcome in post-stroke aphasia. Brain, 139(4), 1152–1163.PubMedCrossRefGoogle Scholar
  75. Meinzer, M., Lindenberg, R., Phan, M. T., Ulm, L., Volk, C., & Floel, A. (2015). Transcranial direct current stimulation in mild cognitive impairment: Behavioral effects and neural mechanisms. Alzheimer’s & Dementia, 11(9), 1032–1040.CrossRefGoogle Scholar
  76. Mendonca, M. E., Simis, M., Grecco, L. C., Battistella, L. R., Baptista, A. F., & Fregni, F. (2016). Transcranial direct current stimulation combined with aerobic exercise to optimize analgesic responses in fibromyalgia: A randomized placebo-controlled clinical trial. Frontiers in Human Neuroscience, 10.Google Scholar
  77. Minhas, P., Bikson, M., Woods, A. J., Rosen, A. R., & Kessler, S. K. (2012). Transcranial direct current stimulation in pediatric brain: A computational modeling study. 2012 Annual International Conference of the IEEE Engineering in Medicine and Biology Society.Google Scholar
  78. Mori, F., Codecà, C., Kusayanagi, H., Monteleone, F., Buttari, F., Fiore, S., … Centonze, D. (2010). Effects of anodal transcranial direct current stimulation on chronic neuropathic pain in patients with multiple sclerosis. The Journal of Pain, 11(5), 436–442.PubMedPubMedCentralCrossRefGoogle Scholar
  79. New England Institutional Review Board. (2016). Retrieved August 15, 2016, from
  80. Ng, M. F., Tong, R. K., & Li, L. S. (2008). A pilot study of randomized clinical controlled trial of gait training in subacute stroke patients with partial body-weight support electromechanical gait trainer and functional electrical stimulation: Six-month follow-up. Stroke, 39(1), 154–160.PubMedCrossRefGoogle Scholar
  81. Nikolin, S., Loo, C. K., Bai, S., Dokos, S., & Martin, D. M. (2015). Focalised stimulation using high definition transcranial direct current stimulation (HD-tDCS) to investigate declarative verbal learning and memory functioning. NeuroImage, 117, 11–19.PubMedCrossRefGoogle Scholar
  82. Nikulina, V., Guarino, H., Acosta, M. C., Marsch, L. A., Syckes, C., Moore, S. K., … Rosenblum, A. (2016). Patient vs provider reports of aberrant medication-taking behavior among opioid-treated patients with chronic pain who report misusing opioid medication. Pain, 157(8), 1791–1798.PubMedPubMedCentralCrossRefGoogle Scholar
  83. Nitsche, M. A., Cohen, L. G., Wassermann, E. M., Priori, A., Lang, N., Antal, A., … Pascual-Leone, A. (2008). Transcranial direct current stimulation: State of the art 2008. Brain Stimulation, 1(3), 206–223.PubMedPubMedCentralCrossRefGoogle Scholar
  84. Nitsche, M. A., Fricke, K., Henschke, U., Schlitterlau, A., Liebetanz, D., Lang, N., … Paulus, W. (2003a). Pharmacological modulation of cortical excitability shifts induced by transcranial direct current stimulation in humans. Journal of Physiology, 553(1), 293–301.PubMedPubMedCentralCrossRefGoogle Scholar
  85. Nitsche, M. A., Kuo, M. F., Karrasch, R., Wachter, B., Liebetanz, D., & Paulus, W. (2009). Serotonin affects transcranial direct current-induced neuroplasticity in humans. Biological Psychiatry, 66(5), 503–508.PubMedPubMedCentralCrossRefGoogle Scholar
  86. Nitsche, M. A., Liebetanz, D., Schlitterlau, A., Henschke, U., Fricke, K., Frommann, K., … Tergau, F. (2004). GABAergic modulation of DC stimulation-induced motor cortex excitability shifts in humans. European Journal of Neuroscience, 19(10), 2720–2726.PubMedPubMedCentralCrossRefGoogle Scholar
  87. Nitsche, M. A., Nitsche, M. S., Klein, C. C., Tergau, F., Rothwell, J. C., & Paulus, W. (2003). Level of action of cathodal DC polarisation induced inhibition of the human motor cortex. Clinical Neurophysiology, 114(4), 600–604.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 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(3), 633–639.PubMedPubMedCentralCrossRefGoogle Scholar
  89. Nitsche, M. A., & Paulus, W. (2001). Sustained excitability elevations induced by transcranial DC motor cortex stimulation in humans. Neurology, 57(10), 1899–1901.PubMedPubMedCentralCrossRefGoogle Scholar
  90. Oliveira, L. B., Lopes, T. S., Soares, C., Maluf, R., Goes, B. T., Sá, K. N., & Baptista, A. F. (2015, April 20). Transcranial direct current stimulation and exercises for treatment of chronic temporomandibular disorders: A blind randomised-controlled trial. Journal of Oral Rehabilitation, 42(10), 723–732.PubMedCrossRefGoogle Scholar
  91. Palm, U., Schiller, C., Fintescu, Z., Obermeier, M., Keeser, D., Reisinger, E., … Padberg, F. (2012). Transcranial direct current stimulation in treatment resistant depression: A randomized double-blind, placebo-controlled study. Brain Stimulation, 5(3), 242–251.PubMedCrossRefGoogle Scholar
  92. Palmer, B. W., Savla, G. N., Roesch, S. C., & Jeste, D. V. (2013, June 09). Changes in capacity to consent over time in patients involved in psychiatric research. The British Journal of Psychiatry, 202(6), 454–458.PubMedCrossRefGoogle Scholar
  93. Parazzini, M., Fiocchi, S., Liorni, I., & Ravazzani, P. (2015). Effect of the interindividual variability on computational modeling of transcranial direct current stimulation. Computational Intelligence and Neuroscience, 2015, 1–9.CrossRefGoogle Scholar
  94. Park, J., Hong, S. B., Kim, D., Suh, M., & Im, C. (2011). A novel array-type transcranial direct current stimulation (tDCS) system for accurate focusing on targeted brain areas. IEEE Transactions on Magnetics, 47(5), 882–885.CrossRefGoogle Scholar
  95. Park, S., Seo, J., Kim, Y., & Ko, M. (2014). Long-term effects of transcranial direct current stimulation combined with computer-assisted cognitive training in healthy older adults. Neuroreport, 25(2), 122–126.PubMedCrossRefGoogle Scholar
  96. Reis, J., Fischer, J. T., Prichard, G., Weiller, C., Cohen, L. G., & Fritsch, B. (2015). Time- but not sleep-dependent consolidation of tDCS-enhanced visuomotor skills. Cerebral Cortex, 25(1), 109–117.PubMedCrossRefGoogle Scholar
  97. Reis, J., Schambra, H. M., Cohen, L. G., Buch, E. R., Fritsch, B., Zarahn, E., … Krakauer, J. W. (2009). Noninvasive cortical stimulation enhances motor skill acquisition over multiple days through an effect on consolidation. Proceedings of the National Academy of Sciences of the United States, 106(5), 1590–1595.CrossRefGoogle Scholar
  98. Richmond, L. L., Wolk, D., Chein, J., & Olson, I. R. (2014). Transcranial direct current stimulation enhances verbal working memory training performance over time and near transfer outcomes. Journal of Cognitive Neuroscience, 26(11), 2443–2454.PubMedCrossRefGoogle Scholar
  99. Rosedale, M., Malaspina, D., Malamud, D., Strauss, S. M., Horne, J. D., Abouzied, S., … Knotkova, H. (2012). Developing patient-centered treatment protocols in brain stimulation: A rationale for combining quantitative and qualitative approaches in persons with HIV. Journal of the American Psychiatric Nurses Association, 18(3), 166–174.PubMedPubMedCentralCrossRefGoogle Scholar
  100. Rosenkranz, G. K. (2016). Remarks on designs enriching for placebo non-responders. Clinical Trials, 13(3), 338–343.PubMedCrossRefGoogle Scholar
  101. Rushmore, R. J., Desimone, C., & Valero-Cabré, A. (2013). Multiple sessions of transcranial direct current stimulation to the intact hemisphere improves visual function after unilateral ablation of visual cortex. European Journal of Neuroscience, 12, 3799–3807.PubMedCrossRefGoogle Scholar
  102. Sandrini, M., Brambilla, M., Manenti, R., Rosini, S., Cohen, L. G., & Cotelli, M. (2014). Noninvasive stimulation of prefrontal cortex strengthens existing episodic memories and reduces forgetting in the elderly. Frontiers in Aging Neuroscience, 6.Google Scholar
  103. Sattler, V., Acket, B., Raposo, N., Albucher, J., Thalamas, C., Loubinoux, I., … Simonetta-Moreau, M. (2015). Anodal tDCS combined with radial nerve stimulation promotes hand motor recovery in the acute phase after ischemic stroke. Neurorehabilitation and Neural Repair, 29(8), 743–754.PubMedCrossRefGoogle Scholar
  104. Segrave, R. A., Arnold, S., Hoy, K., & Fitzgerald, P. B. (2014). Concurrent cognitive control training augments the antidepressant efficacy of tDCS: A pilot study. Brain Stimulation, 7(2), 325–331.PubMedCrossRefGoogle Scholar
  105. Stagg, C. J., Lin, R. L., Mezue, M., Segerdahl, A., Kong, Y., Xie, J., & Tracey, I. (2013). Widespread modulation of cerebral perfusion induced during and after transcranial direct current stimulation applied to the left dorsolateral prefrontal cortex. Journal of Neuroscience, 33(28), 11425–11431.PubMedCrossRefGoogle Scholar
  106. Stagg, C. J., & Nitsche, M. A. (2011). Physiological basis of transcranial direct current stimulation. The Neuroscientist, 17(1), 37–53.PubMedPubMedCentralCrossRefGoogle Scholar
  107. The CONSORT Statement. (2016). Retrieved July 7, 2016, from
  108. Triccas, L. T., Burridge, J., Hughes, A., Pickering, R., Desikan, M., Rothwell, J., & Verheyden, G. (2016). Multiple sessions of transcranial direct current stimulation and upper extremity rehabilitation in stroke: A review and meta-analysis. Clinical Neurophysiology, 127(1), 946–955.PubMedCrossRefGoogle Scholar
  109. Valle, A., Roizenblatt, S., Botte, S., Zaghi, S., Riberto, M., Tufik, S., … Fregni, F. (2009). Efficacy of anodal transcranial direct current stimulation (tDCS) for the treatment of fibromyalgia: Results of a randomized, sham-controlled longitudinal clinical trial. Journal of Pain Management, 2(3), 353–362.Google Scholar
  110. Villamar, M. F., Wivatvongvana, P., Patumanond, J., Bikson, M., Truong, D. Q., Datta, A., & Fregni, F. (2013). Focal modulation of the primary motor cortex in fibromyalgia using 4×1-ring high-definition transcranial direct current stimulation (HD-tDCS): Immediate and delayed analgesic effects of cathodal and anodal stimulation. The Journal of Pain, 14(4), 371–383.PubMedPubMedCentralCrossRefGoogle Scholar
  111. Werner, C., Frankenberg, S. V., Treig, T., Konrad, M., & Hesse, S. (2002). Treadmill training with partial body weight support and an electromechanical gait trainer for restoration of gait in subacute stroke patients: A randomized crossover study. Stroke, 33(12), 2895–2901.PubMedCrossRefGoogle Scholar
  112. Wirth, M., Rahman, R. A., Kuenecke, J., Koenig, T., Horn, H., Sommer, W., & Dierks, T. (2011). Effects of transcranial direct current stimulation (tDCS) on behaviour and electrophysiology of language production. Neuropsychologia, 49(14), 3989–3998.PubMedCrossRefGoogle Scholar
  113. Woods, A., Antal, A., Bikson, M., Boggio, P., Brunoni, A., Celnik, P., … Nitsche, M. (2016). A technical guide to tDCS, and related non-invasive brain stimulation tools. Clinical Neurophysiology, 127(2), 1031–1048.PubMedPubMedCentralCrossRefGoogle Scholar
  114. Woods, A. J., Bryant, V., Sacchetti, D., Gervits, F., & Hamilton, R. (2015). Effects of electrode drift in transcranial direct current stimulation. Brain Stimulation, 8(2), 320–321.CrossRefGoogle Scholar
  115. Woods, A. J., Hamilton, R. H., Kranjec, A., Minhaus, P., Bikson, M., Yu, J., & Chatterjee, A. (2014). Space, time, and causality in the human brain. NeuroImage, 92, 285–297.PubMedPubMedCentralCrossRefGoogle Scholar
  116. You, D. S., Kim, D., Chun, M. H., Jung, S. E., & Park, S. J. (2011). Cathodal transcranial direct current stimulation of the right Wernicke’s area improves comprehension in subacute stroke patients. Brain and Language, 119(1), 1–5.PubMedCrossRefGoogle Scholar
  117. Zimerman, M., Heise, K. F., Hoppe, J., Cohen, L. G., Gerloff, C., & Hummel, F. C. (2012). Modulation of training by single-session transcranial direct current stimulation to the intact motor cortex enhances motor skill acquisition of the paretic hand. Stroke, 43(8), 2185–2191.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2019

Authors and Affiliations

  • Roy H. Hamilton
    • 1
    • 2
    • 3
    Email author
  • Sudha K. Kessler
    • 4
    • 5
  • Laura Castillo-Saavedra
    • 6
  • Felipe Fregni
    • 6
  • Donel Martin
    • 7
  • Colleen Loo
    • 8
  • Helena Knotkova
    • 9
    • 10
  • Adam J. Woods
    • 11
  1. 1.Department of NeurologyUniversity of PennsylvaniaPhiladelphiaUSA
  2. 2.Department of Physical Medicine and RehabilitationUniversity of PennsylvaniaPhiladelphiaUSA
  3. 3.Goddard Laboratories, Room 518, University of PennsylvaniaPhiladelphiaUSA
  4. 4.Departments of Neurology and PediatricsPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaUSA
  5. 5.Children’s Hospital of PhiladelphiaPhiladelphiaUSA
  6. 6.Spaulding Neuromodulation Center, Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Harvard Medical SchoolBostonUSA
  7. 7.Black Dog Institute, The University of New South WalesSydneyAustralia
  8. 8.School of Psychiatry, Black Dog Institute, The University of New South WalesSydneyAustralia
  9. 9.MJHS Institute for Innovation in Palliative CareNew YorkUSA
  10. 10.Department of Family and Social MedicineAlbert Einstein College of MedicineBronxUSA
  11. 11.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

Personalised recommendations