Advertisement
Research Article| Volume 9, ISSUE 5, P740-754, September 2016

Tolerability of Repeated Application of Transcranial Electrical Stimulation with Limited Outputs to Healthy Subjects

      Highlights

      • Tolerability and compliance were tested for tDCS and MHF-tPCS, which were used repeatedly for an extended period of time.
      • One hundred healthy subjects completed more than 1900 sessions and did not report any serious adverse effects.
      • The compliance (elected sessions completed) for MHF-tPCS was significantly greater when compared to sham-tDCS.

      Abstract

      Background

      The safety and tolerability of limited output transcranial electrical stimulation (tES) in clinical populations support a non-significant risk designation. The tolerability of long-term use in a healthy population had remained untested.

      Objective

      We tested the tolerability and compliance of two tES waveforms, transcranial direct current stimulation (tDCS) and modulated high frequency transcranial pulsed current stimulation (MHF-tPCS) compared to sham-tDCS, applied to healthy subjects for three to five days (17–20 minutes per day) per week for up to six weeks in a communal setting. MHF-tPCS consisted of asymmetric high-frequency pulses (7–11 kHz) having a peak amplitude of 10–20 mA peak, adjusted by subject, resulting in an average current of 5–7 mA.

      Method

      A total of 100 treatment blind healthy subjects were randomly assigned to one of three treatment groups: tDCS (n = 33), MHF-tPCS (n = 30), or sham-tDCS (n = 37). In order to test the role of waveform, electrode type and montage were fixed across tES and sham-tDCS arms: high-capacity self-adhering electrodes on the right lateral forehead and back of the neck. We conducted 1905 sessions (636 sham-tDCS, 623 tDCS, and 646 MHF-tPCS sessions) on study volunteers over a period of six weeks.

      Results

      Common adverse events were primarily restricted to influences upon the skin and included skin tingling, itching, and mild burning sensations. The incidence of these events in the active tES treatment arms (MHF-tPCS, tDCS) was equivalent or significantly lower than their incidence in the sham-tDCS treatment arm. Other adverse events had a rarity (<5% incidence) that could not be significantly distinguished across the treatment groups. Some subjects were withdrawn from the study due to atypical headache (sham-tDCS n = 2, tDCS n = 2, and MHF-tPCS n = 3), atypical discomfort (sham-tDCS n = 0, tDCS n = 1, and MHF-tPCS n = 1), or atypical skin irritation (sham-tDCS n = 2, tDCS n = 8, and MHF-tPCS n = 1). The rate of compliance, elected sessions completed, for the MHF-tPCS group was significantly greater than the sham-tDCS group's compliance (p = 0.007). There were no serious adverse events in any treatment condition.

      Conclusion

      We conclude that repeated application of limited output tES across extended periods, limited to the hardware, electrodes, and protocols tested here, is well tolerated in healthy subjects, as previously observed in clinical populations.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      References

        • McIntire L.K.
        • McKinley R.A.
        • Goodyear C.
        • Nelson J.
        A comparison of the effects of transcranial direct current stimulation and caffeine on vigilance and cognitive performance during extended wakefulness.
        Brain Stimul. 2014; 7: 499-507https://doi.org/10.1016/j.brs.2014.04.008
        • Wade S.
        • Hammond G.
        Anodal transcranial direct current stimulation over premotor cortex facilitates observational learning of a motor sequence.
        Eur J Neurosci. 2015; 41: 1597-1602https://doi.org/10.1111/ejn.12916
        • Del Felice A.
        • Magalini A.
        • Masiero S.
        Slow-oscillatory transcranial direct current stimulation modulates memory in temporal lobe epilepsy by altering sleep spindle generators: a possible rehabilitation tool.
        Brain Stimul. 2015; 8: 567-573https://doi.org/10.1016/j.brs.2015.01.410
        • Zhu F.F.
        • Yeung A.Y.
        • Poolton J.M.
        • Lee T.M.C.
        • Leung G.K.K.
        • Masters R.S.W.
        Cathodal transcranial direct current stimulation over left dorsolateral prefrontal cortex area promotes implicit motor learning in a golf putting task.
        Brain Stimul. 2015; 8: 784-786https://doi.org/10.1016/j.brs.2015.02.005
        • Pisoni A.
        • Turi Z.
        • Raithel A.
        • Ambrus G.G.
        • Alekseichuk I.
        • Schacht A.
        • et al.
        Separating recognition processes of declarative memory via anodal tDCS: boosting old item recognition by temporal and new item detection by parietal stimulation.
        PLoS ONE. 2015; 10 (e0123085)https://doi.org/10.1371/journal.pone.0123085
        • McKinley R.A.
        • McIntire L.
        • Bridges N.
        • Goodyear C.
        • Bangera N.B.
        • Weisend M.P.
        Acceleration of image analyst training with transcranial direct current stimulation.
        Behav Neurosci. 2013; 127: 936-946https://doi.org/10.1037/a0034975
        • Elmasry J.
        • Loo C.
        • Martin D.
        A systematic review of transcranial electrical stimulation combined with cognitive training.
        Restor Neurol Neurosci. 2015; 33: 263-278https://doi.org/10.3233/RNN-140473
        • Miniussi C.
        • Ruzzoli M.
        Transcranial stimulation and cognition.
        Handb Clin Neurol. 2013; 116: 739-750https://doi.org/10.1016/B978-0-444-53497-2.00056-5
        • Levasseur-Moreau J.
        • Brunelin J.
        • Fecteau S.
        Non-invasive brain stimulation can induce paradoxical facilitation. Are these neuroenhancements transferable and meaningful to security services?.
        Front Hum Neurosci. 2013; 7: 449https://doi.org/10.3389/fnhum.2013.00449
        • Krause B.
        • Cohen Kadosh R.
        Can transcranial electrical stimulation improve learning difficulties in atypical brain development? A future possibility for cognitive training.
        Dev Cogn Neurosci. 2013; 6: 176-194https://doi.org/10.1016/j.dcn.2013.04.001
        • Martin D.M.
        • Liu R.
        • Alonzo A.
        • Green M.
        • Player M.J.
        • Sachdev P.
        • et al.
        Can transcranial direct current stimulation enhance outcomes from cognitive training? A randomized controlled trial in healthy participants.
        Int J Neuropsychopharmacol. 2013; 16: 1927-1936https://doi.org/10.1017/S1461145713000539
        • Borckardt J.J.
        • Bikson M.
        • Frohman H.
        • Reeves S.T.
        • 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: 112-120https://doi.org/10.1016/j.jpain.2011.07.001
        • Fertonani A.
        • Ferrari C.
        • Miniussi C.
        What do you feel if I apply transcranial electric stimulation? Safety, sensations and secondary induced effects.
        Clin Neurophysiol. 2015; 126: 2181-2188https://doi.org/10.1016/j.clinph.2015.03.015
        • Monte-Silva K.
        • Kuo M.-F.
        • 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. 2013; 6: 424-432https://doi.org/10.1016/j.brs.2012.04.011
        • Fricke K.
        • Seeber A.A.
        • Thirugnanasambandam N.
        • Paulus W.
        • Nitsche M.A.
        • Rothwell J.C.
        Time course of the induction of homeostatic plasticity generated by repeated transcranial direct current stimulation of the human motor cortex.
        J Neurophysiol. 2011; 105: 1141-1149https://doi.org/10.1152/jn.00608.2009
        • Boggio P.S.
        • Liguori P.
        • Sultani N.
        • Rezende L.
        • Fecteau S.
        • Fregni F.
        Cumulative priming effects of cortical stimulation on smoking cue-induced craving.
        Neurosci Lett. 2009; 463: 82-86https://doi.org/10.1016/j.neulet.2009.07.041
        • Loo C.K.
        • Alonzo A.
        • Martin D.
        • Mitchell P.B.
        • Galvez V.
        • Sachdev P.
        Transcranial direct current stimulation for depression: 3-week, randomised, sham-controlled trial.
        Br J Psychiatry. 2012; 200: 52-59https://doi.org/10.1192/bjp.bp.111.097634
        • Brunoni A.R.
        • Valiengo L.
        • Baccaro A.
        • Zanão T.A.
        • de Oliveira J.F.
        • Goulart A.
        • et al.
        The sertraline vs. electrical current therapy for treating depression clinical study: results from a factorial, randomized, controlled trial.
        JAMA Psychiatry. 2013; 70: 383-391https://doi.org/10.1001/2013.jamapsychiatry.32
        • Widdows K.C.
        • Davis N.J.
        Ethical considerations in using brain stimulation to treat eating disorders.
        Front Behav Neurosci. 2014; 8: 351https://doi.org/10.3389/fnbeh.2014.00351
        • Maslen H.
        • Douglas T.
        • Cohen Kadosh R.
        • Levy N.
        • Savulescu J.
        The regulation of cognitive enhancement devices: extending the medical model.
        J Law Biosci. 2014; 1: 68-93https://doi.org/10.1093/jlb/lst003
        • Fitz N.S.
        • Reiner P.B.
        The challenge of crafting policy for do-it-yourself brain stimulation.
        J Med Ethics. 2013; https://doi.org/10.1136/medethics-2013-101458
        • Wexler A.
        The practices of do-it-yourself brain stimulation: implications for ethical considerations and regulatory proposals.
        J Med Ethics. 2015; https://doi.org/10.1136/medethics-2015-102704
        • Hamilton R.
        • Messing S.
        • Chatterjee A.
        Rethinking the thinking cap: ethics of neural enhancement using noninvasive brain stimulation.
        Neurology. 2011; 76: 187-193https://doi.org/10.1212/WNL.0b013e318205d50d
        • Forum on Neuroscience and Nervous System Disorders, Board on Health Sciences Policy, Institute of Medicine, The National Academies of Sciences, Engineering, and Medicine
        Non-invasive neuromodulation of the central nervous system: opportunities and challenges: workshop summary.
        National Academies Press (US), Washington, DC2015
        • Terney D.
        • Chaieb L.
        • Moliadze V.
        • Antal A.
        • Paulus W.
        Increasing human brain excitability by transcranial high-frequency random noise stimulation.
        J Neurosci. 2008; 28: 14147-14155https://doi.org/10.1523/JNEUROSCI.4248-08.2008
        • Chaieb L.
        • Kovacs G.
        • Cziraki C.
        • Greenlee M.
        • Paulus W.
        • Antal A.
        Short-duration transcranial random noise stimulation induces blood oxygenation level dependent response attenuation in the human motor cortex.
        Exp Brain Res. 2009; 198: 439-444https://doi.org/10.1007/s00221-009-1938-7
        • Paulus W.
        Transcranial electrical stimulation (tES – tDCS; tRNS, tACS) methods.
        Neuropsychol Rehabil. 2011; 21: 602-617https://doi.org/10.1080/09602011.2011.557292
        • Fertonani A.
        • Pirulli C.
        • Miniussi C.
        Random noise stimulation improves neuroplasticity in perceptual learning.
        J Neurosci. 2011; 31: 15416-15423https://doi.org/10.1523/JNEUROSCI.2002-11.2011
        • Magis D.
        • Sava S.
        • d'Elia T.S.
        • Baschi R.
        • Schoenen J.
        Safety and patients' satisfaction of transcutaneous supraorbital neurostimulation (tSNS) with the Cefaly® device in headache treatment: a survey of 2,313 headache sufferers in the general population.
        J Headache Pain. 2013; 14: 95https://doi.org/10.1186/1129-2377-14-95
        • Kessler S.K.
        • Turkeltaub P.E.
        • Benson J.G.
        • Hamilton R.H.
        Differences in the experience of active and sham transcranial direct current stimulation.
        Brain Stimul. 2012; 5: 155-162https://doi.org/10.1016/j.brs.2011.02.007
        • Morales-Quezada L.
        • Cosmo C.
        • Carvalho S.
        • Leite J.
        • Castillo-Saavedra L.
        • Rozisky J.R.
        • et al.
        Cognitive effects and autonomic responses to transcranial pulsed current stimulation.
        Exp Brain Res. 2015; 233: 701-709https://doi.org/10.1007/s00221-014-4147-y
        • Poreisz C.
        • Boros K.
        • Antal A.
        • Paulus W.
        Safety aspects of transcranial direct current stimulation concerning healthy subjects and patients.
        Brain Res Bull. 2007; 72: 208-214https://doi.org/10.1016/j.brainresbull.2007.01.004
        • Raimundo R.J.S.
        • Uribe C.E.
        • Brasil-Neto J.P.
        Lack of clinically detectable acute changes on autonomic or thermoregulatory functions in healthy subjects after transcranial direct current stimulation (tDCS).
        Brain Stimul. 2012; 5: 196-200https://doi.org/10.1016/j.brs.2011.03.009
        • Nitsche M.A.
        • Liebetanz D.
        • Lang N.
        • Antal A.
        • Tergau F.
        • Paulus W.
        Safety criteria for transcranial direct current stimulation (tDCS) in humans.
        Clin Neurophysiol. 2003; 114 (author reply 2222–3): 2220-2222
        • Russo R.
        • Wallace D.
        • Fitzgerald P.B.
        • Cooper N.R.
        Perception of comfort during active and sham transcranial direct current stimulation: a double blind study.
        Brain Stimul. 2013; 6: 946-951https://doi.org/10.1016/j.brs.2013.05.009
        • Tadini L.
        • El-Nazer R.
        • Brunoni A.R.
        • Williams J.
        • Carvas M.
        • Boggio P.
        • et al.
        Cognitive, mood, and electroencephalographic effects of noninvasive cortical stimulation with weak electrical currents.
        J ECT. 2011; 27: 134-140https://doi.org/10.1097/YCT.0b013e3181e631a8
        • Brunoni A.R.
        • Amadera J.
        • Berbel B.
        • Volz M.S.
        • Rizzerio B.G.
        • Fregni F.
        A systematic review on reporting and assessment of adverse effects associated with transcranial direct current stimulation.
        Int J Neuropsychopharmacol. 2011; 14: 1133-1145https://doi.org/10.1017/S1461145710001690
        • Bikson M.
        • Datta A.
        • Elwassif M.
        Establishing safety limits for transcranial direct current stimulation.
        Clin Neurophysiol. 2009; 120: 1033-1034https://doi.org/10.1016/j.clinph.2009.03.018
        • Brunoni A.R.
        • Nitsche M.A.
        • Bolognini N.
        • Bikson M.
        • Wagner T.
        • Merabet L.
        • et al.
        Clinical research with transcranial direct current stimulation (tDCS): challenges and future directions.
        Brain Stimul. 2012; 5: 175-195https://doi.org/10.1016/j.brs.2011.03.002
        • Sellers K.K.
        • Mellin J.M.
        • Lustenberger C.M.
        • Boyle M.R.
        • Lee W.H.
        • Peterchev A.V.
        • et al.
        Transcranial direct current stimulation (tDCS) of frontal cortex decreases performance on the WAIS-IV intelligence test.
        Behav Brain Res. 2015; 290: 32-44https://doi.org/10.1016/j.bbr.2015.04.031
        • Tremblay S.
        • Lepage J.-F.
        • Latulipe-Loiselle A.
        • Fregni F.
        • Pascual-Leone A.
        • Théoret H.
        The uncertain outcome of prefrontal tDCS.
        Brain Stimul. 2014; 7: 773-783https://doi.org/10.1016/j.brs.2014.10.003
        • Sarkar A.
        • Dowker A.
        • Cohen Kadosh R.
        Cognitive enhancement or cognitive cost: trait-specific outcomes of brain stimulation in the case of mathematics anxiety.
        J Neurosci. 2014; 34: 16605-16610https://doi.org/10.1523/JNEUROSCI.3129-14.2014
        • Peterchev A.V.
        • Wagner T.A.
        • Miranda P.C.
        • Nitsche M.A.
        • Paulus W.
        • Lisanby S.H.
        • et al.
        Fundamentals of transcranial electric and magnetic stimulation dose: definition, selection, and reporting practices.
        Brain Stimul. 2012; 5: 435-453https://doi.org/10.1016/j.brs.2011.10.001
        • Minhas P.
        • Bansal V.
        • Patel J.
        • Ho J.S.
        • Diaz J.
        • Datta A.
        • et al.
        Electrodes for high-definition transcutaneous DC stimulation for applications in drug delivery and electrotherapy, including tDCS.
        J Neurosci Methods. 2010; 190: 188-197https://doi.org/10.1016/j.jneumeth.2010.05.007
        • Shiozawa P.
        • da Silva M.E.
        • Raza R.
        • Uchida R.R.
        • Cordeiro Q.
        • Fregni F.
        • et al.
        Safety of repeated transcranial direct current stimulation in impaired skin: a case report.
        J ECT. 2013; 29: 147-148https://doi.org/10.1097/YCT.0b013e318279c1a1
        • Harty S.
        • Robertson I.H.
        • Miniussi C.
        • Sheehy O.C.
        • Devine C.A.
        • McCreery S.
        • et al.
        Transcranial direct current stimulation over right dorsolateral prefrontal cortex enhances error awareness in older age.
        J Neurosci. 2014; 34: 3646-3652https://doi.org/10.1523/JNEUROSCI.5308-13.2014
        • Joseph L.
        • Butera R.J.
        High frequency stimulation selectively blocks different types of fibers in frog sciatic nerve.
        IEEE Trans Neural Syst Rehabil Eng. 2011; 19: 550-557https://doi.org/10.1109/TNSRE.2011.2163082
        • Tai C.
        • de Groat W.C.
        • Roppolo J.R.
        Simulation of nerve block by high-frequency sinusoidal electrical current based on the Hodgkin–Huxley model.
        IEEE Trans Neural Syst Rehabil Eng. 2005; 13: 415-422https://doi.org/10.1109/TNSRE.2005.847356
        • Tai C.
        • de Groat W.C.
        • Roppolo J.R.
        Simulation analysis of conduction block in unmyelinated axons induced by high frequency biphasic electrical currents.
        IEEE Trans Biomed Eng. 2005; 52: 1323
        • Kilgore D.K.L.
        • Bhadra N.
        Nerve conduction block utilising high-frequency alternating current.
        Med Biol Eng Comput. 2004; 42: 394-406https://doi.org/10.1007/BF02344716
        • Koga K.
        • Furue H.
        • Rashid M.H.
        • Takaki A.
        • Katafuchi T.
        • Yoshimura M.
        Selective activation of primary afferent fibers evaluated by sine-wave electrical stimulation.
        Mol Pain. 2005; 1: 13https://doi.org/10.1186/1744-8069-1-13
        • Freeman D.K.
        • Eddington D.K.
        • Rizzo J.F.
        • Fried S.I.
        Selective activation of neuronal targets with sinusoidal electric stimulation.
        J Neurophysiol. 2010; 104: 2778-2791https://doi.org/10.1152/jn.00551.2010
        • Bernhard C.G.
        • Skoglund C.R.
        Selective activation of a transient reflex by restricting stimulation to certain frequencies.
        Acta Physiol Scand. 1942; 4: 125-135https://doi.org/10.1111/j.1748-1716.1942.tb01448.x
        • Carlson M.D.
        • Geha A.S.
        • Hsu J.
        • Martin P.J.
        • Levy M.N.
        • Jacobs G.
        • et al.
        Selective stimulation of parasympathetic nerve fibers to the human sinoatrial node.
        Circulation. 1992; 85: 1311-1317
        • Plachta D.T.T.
        • Gierthmuehlen M.
        • Cota O.
        • Espinosa N.
        • Boeser F.
        • Herrera T.C.
        • et al.
        Blood pressure control with selective vagal nerve stimulation and minimal side effects.
        J Neural Eng. 2014; 11: 036011https://doi.org/10.1088/1741-2560/11/3/036011
        • Antal A.
        • Kincses T.Z.
        • Nitsche M.A.
        • Paulus W.
        Modulation of moving phosphene thresholds by transcranial direct current stimulation of V1 in human.
        Neuropsychologia. 2003; 41: 1802-1807
        • Kanai R.
        • Chaieb L.
        • Antal A.
        • Walsh V.
        • Paulus W.
        Frequency-dependent electrical stimulation of the visual cortex.
        Curr Biol. 2008; 18: 1839-1843https://doi.org/10.1016/j.cub.2008.10.027
        • Kanai R.
        • Paulus W.
        • Walsh V.
        Transcranial alternating current stimulation (tACS) modulates cortical excitability as assessed by TMS-induced phosphene thresholds.
        Clin Neurophysiol. 2010; 121: 1551-1554https://doi.org/10.1016/j.clinph.2010.03.022
        • Turi Z.
        • Ambrus G.G.
        • Janacsek K.
        • Emmert K.
        • Hahn L.
        • Paulus W.
        • et al.
        Both the cutaneous sensation and phosphene perception are modulated in a frequency-specific manner during transcranial alternating current stimulation.
        Restor Neurol Neurosci. 2013; 31: 275-285https://doi.org/10.3233/RNN-120297
        • Kar K.
        • Krekelberg B.
        Transcranial electrical stimulation over visual cortex evokes phosphenes with a retinal origin.
        J Neurophysiol. 2012; 108: 2173-2178https://doi.org/10.1152/jn.00505.2012
        • Johnson M.I.
        Transcutaneous electrical nerve stimulation (TENS): research to support clinical practice.
        OUP Oxford, Oxford2014
        • Almay B.G.
        • Johansson F.
        • von Knorring L.
        • Sakurada T.
        • Terenius L.
        Long-term high frequency transcutaneous electrical nerve stimulation (hi-TNS) in chronic pain. Clinical response and effects on CSF-endorphins, monoamine metabolites, substance P-like immunoreactivity (SPLI) and pain measures.
        J Psychosom Res. 1985; 29: 247-257
        • Darras B.T.
        • Jones Jr, H.R.
        • Ryan M.M.
        • Vivo D.C.D.
        Neuromuscular disorders of infancy, childhood, and adolescence: a clinician's approach.
        Elsevier, Amsterdam2014
        • Van Buyten J.-P.
        • Al-Kaisy A.
        • Smet I.
        • Palmisani S.
        • Smith T.
        High-frequency spinal cord stimulation for the treatment of chronic back pain patients: results of a prospective multicenter European clinical study.
        Neuromodulation. 2013; 16: 59-66https://doi.org/10.1111/ner.12006
        • Kapural L.
        • Yu C.
        • Doust M.W.
        • Gliner B.E.
        • Vallejo R.
        • Sitzman B.T.
        • et al.
        Novel 10-kHz high-frequency therapy (HF10 therapy) is superior to traditional low-frequency spinal cord stimulation for the treatment of chronic back and leg pain: the SENZA-RCT randomized controlled trial.
        Anesthesiology. 2015; 123: 851-860https://doi.org/10.1097/ALN.0000000000000774
      1. EEG – Electroencephalography, Neuromonitoring blog Dr Richard Vogel.
        (n.d.; accessed 20.06.16)
        • Highsmith J.M.
        MD. Cervical and thoracic spine. Spine Universe.
        (n.d.; accessed 19.04.15)
      2. Siever D. Transcranial DC stimulation. NeuroConnections n.d.:33–40.

        • Mendonca M.E.
        • Santana M.B.
        • Baptista A.F.
        • Datta A.
        • Bikson M.
        • Fregni F.
        • et al.
        Transcranial DC stimulation in fibromyalgia: optimized cortical target supported by high-resolution computational models.
        J Pain. 2011; 12: 610-617https://doi.org/10.1016/j.jpain.2010.12.015
        • Reato D.
        • Gasca F.
        • Datta A.
        • Bikson M.
        • Marshall L.
        • Parra L.C.
        Transcranial electrical stimulation accelerates human sleep homeostasis.
        PLoS Comput Biol. 2013; 9: e1002898https://doi.org/10.1371/journal.pcbi.1002898
        • Parasuraman R.
        • McKinley R.A.
        Using noninvasive brain stimulation to accelerate learning and enhance human performance.
        Hum Factors. 2014; 56: 816-824https://doi.org/10.1177/0018720814538815
        • Gladwin T.E.
        • den Uyl T.E.
        • Fregni F.F.
        • Wiers R.W.
        Enhancement of selective attention by tDCS: interaction with interference in a Sternberg task.
        Neurosci Lett. 2012; 512: 33-37https://doi.org/10.1016/j.neulet.2012.01.056
        • Guleyupoglu B.
        • Schestatsky P.
        • Edwards D.
        • Fregni F.
        • Bikson M.
        Classification of methods in transcranial electrical stimulation (tES) and evolving strategy from historical approaches to contemporary innovations.
        J Neurosci Methods. 2013; 219: 297-311https://doi.org/10.1016/j.jneumeth.2013.07.016
        • Merrill D.R.
        • Bikson M.
        • Jefferys J.G.R.
        Electrical stimulation of excitable tissue: design of efficacious and safe protocols.
        J Neurosci Methods. 2005; 141: 171-198https://doi.org/10.1016/j.jneumeth.2004.10.020
        • Camel E.
        • O'Connell M.
        • Sage B.
        • Gross M.
        • Maibach H.
        The effect of saline iontophoresis on skin integrity in human volunteers. I. Methodology and reproducibility.
        Fundam Appl Toxicol. 1996; 32: 168-178
        • Draize J.
        • Woodard G.
        • Calvery H.
        Methods for the study of irritation and toxicity of substances applied topically to the skin and mucous membranes.
        J Pharmacol Exp Ther. 1944; 8: 377-390
        • Guarienti F.
        • Caumo W.
        • Shiozawa P.
        • Cordeiro Q.
        • Boggio P.S.
        • Benseñor I.M.
        • et al.
        Reducing transcranial direct current stimulation-induced erythema with skin pretreatment: considerations for sham-controlled clinical trials.
        Neuromodulation. 2015; 18: 261-265https://doi.org/10.1111/ner.12230
        • Marteau T.M.
        • Bekker H.
        The development of a six-item short-form of the state scale of the Spielberger State–Trait Anxiety Inventory (STAI).
        Br J Clin Psychol. 1992; 31: 301-306https://doi.org/10.1111/j.2044-8260.1992.tb00997.x
        • Glantz S.A.
        Primer of biostatistics.
        7th ed. McGraw-Hill Medical, New York2011
        • Ware J.E.
        • Sherbourne C.D.
        The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection.
        Med Care. 1992; 30: 473-483
        • Monica 1776 Main Street Santa, 90401-3208 C
        36-item short form survey scoring instructions | RAND.
        (n.d.; accessed 25.04.16)
        • Nitsche M.A.
        • Cohen L.G.
        • Wassermann E.M.
        • Priori A.
        • Lang N.
        • Antal A.
        • et al.
        Transcranial direct current stimulation: state of the art 2008.
        Brain Stimul. 2008; 1: 206-223https://doi.org/10.1016/j.brs.2008.06.004
        • Jaberzadeh S.
        • Bastani A.
        • Zoghi M.
        • Morgan P.
        • Fitzgerald P.B.
        Anodal transcranial pulsed current stimulation: the effects of pulse duration on corticospinal excitability.
        PLoS ONE. 2015; 10 (e0131779)https://doi.org/10.1371/journal.pone.0131779
        • Richardson J.D.
        • Fillmore P.
        • Datta A.
        • Truong D.
        • Bikson M.
        • Fridriksson J.
        Toward development of sham protocols for high-definition transcranial direct current stimulation (HD-tDCS).
        Neuro Regul. 2014; 1: 62https://doi.org/10.15540/nr.1.1.62
        • Xu K.
        • Wang L.
        • Mai J.
        • He L.
        Efficacy of constraint-induced movement therapy and electrical stimulation on hand function of children with hemiplegic cerebral palsy: a controlled clinical trial.
        Disabil Rehabil. 2012; 34: 337-346https://doi.org/10.3109/09638288.2011.607213
        • Merring C.A.
        • Gobert D.V.
        Recovery 9 years post stroke with standardized electrical stimulation.
        Occup Ther Health Care. 2011; 25: 108-118https://doi.org/10.3109/07380577.2011.556696
        • Quandt F.
        • Hummel F.C.
        The influence of functional electrical stimulation on hand motor recovery in stroke patients: a review.
        Exp Transl Stroke Med. 2014; 6: 9https://doi.org/10.1186/2040-7378-6-9
        • Dundas J.E.
        • Thickbroom G.W.
        • Mastaglia F.L.
        Perception of comfort during transcranial DC stimulation: effect of NaCl solution concentration applied to sponge electrodes.
        Clin Neurophysiol. 2007; 118: 1166-1170https://doi.org/10.1016/j.clinph.2007.01.010
        • Kronberg G.
        • Bikson M.
        Electrode assembly design for transcranial direct current stimulation: a FEM modeling study.
        Conf Proc IEEE Eng Med Biol Soc. 2012; 2012: 891-895https://doi.org/10.1109/EMBC.2012.6346075