Advertisement

Safety and tolerability of transcranial direct current stimulation to stroke patients – A phase I current escalation study

Published:February 27, 2017DOI:https://doi.org/10.1016/j.brs.2017.02.007

      Highlights

      • tDCS current > 2 mA have not been investigated in stroke patients.
      • This phase I dose escalation study establishes safety and tolerability of up to 4 mA in stroke patients.
      • No predefined major response was noted at any current level.
      • Skin temperature did not rise, and skin barrier function remained intact.
      • Transient skin redness without injury was a common finding irrespective of dose level.

      Abstract

      Background and objective

      A prior meta-analysis revealed that higher doses of transcranial direct current stimulation (tDCS) have a better post-stroke upper-extremity motor recovery. While this finding suggests that currents greater than the typically used 2 mA may be more efficacious, the safety and tolerability of higher currents have not been assessed in stroke patients. We aim to assess the safety and tolerability of single session of up to 4 mA in stroke patients.

      Methods

      We adapted a traditional 3 + 3 study design with a current escalation schedule of 1»2»2.5»3»3.5»4 mA for this tDCS safety study. We administered one 30-min session of bihemispheric montage tDCS and simultaneous customary occupational therapy to patients with first-ever ischemic stroke. We assessed safety with pre-defined stopping rules and investigated tolerability through a questionnaire. Additionally, we monitored body resistance and skin temperature in real-time at the electrode contact site.

      Results

      Eighteen patients completed the study. The current was escalated to 4 mA without meeting the pre-defined stopping rules or causing any major safety concern. 50% of patients experienced transient skin redness without injury. No rise in temperature (range 26°C–35 °C) was noted and skin barrier function remained intact (i.e. body resistance >1 kΩ).

      Conclusion

      Our phase I safety study supports that single session of bihemispheric tDCS with current up to 4 mA is safe and tolerable in stroke patients. A phase II study to further test the safety and preliminary efficacy with multi-session tDCS at 4 mA (as compared with lower current and sham stimulation) is a logical next step.
      ClinicalTrials.gov Identifier: NCT02763826.

      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

        • 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: 208-214
        • Schlaug G.
        • Renga V.
        Transcranial direct current stimulation: a noninvasive tool to facilitate stroke recovery.
        Expert Rev Med Devices. 2008; 5: 759-768
        • 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 2–3): 2220-2222
        • Nitsche M.A.
        • Liebetanz D.
        • Antal A.
        • Lang N.
        • Tergau F.
        • Paulus W.
        Modulation of cortical excitability by weak direct current stimulation–technical, safety and functional aspects.
        Suppl Clin Neurophysiol. 2003; 56: 255-276
        • Nitsche M.A.
        • Paulus W.
        Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation.
        J Physiol. 2000; 527: 633-639
        • Zheng X.
        • Alsop D.C.
        • Schlaug G.
        Effects of transcranial direct current stimulation (tDCS) on human regional cerebral blood flow.
        Neuroimage. 2011; 58: 26-33
        • Lindenberg R.
        • Renga V.
        • Zhu L.L.
        • Nair D.
        • Schlaug G.
        Bihemispheric brain stimulation facilitates motor recovery in chronic stroke patients.
        Neurology. 2010; 75: 2176-2184
        • Fregni F.
        • Boggio P.S.
        • Mansur C.G.
        • Wagner T.
        • Ferreira M.J.
        • Lima M.C.
        • et al.
        Transcranial direct current stimulation of the unaffected hemisphere in stroke patients.
        Neuroreport. 2005; 16: 1551-1555
        • Kim D.Y.
        • Lim J.Y.
        • Kang E.K.
        • You D.S.
        • Oh M.K.
        • Oh B.M.
        • et al.
        Effect of transcranial direct current stimulation on motor recovery in patients with subacute stroke.
        Am J Phys Med Rehabil. 2010; 89: 879-886
        • Hummel F.
        • Celnik P.
        • Giraux P.
        • Floel A.
        • Wu W.H.
        • Gerloff C.
        • et al.
        Effects of non-invasive cortical stimulation on skilled motor function in chronic stroke.
        Brain. 2005; 128: 490-499
        • Hesse S.
        • Werner C.
        • Schonhardt E.M.
        • Bardeleben A.
        • Jenrich W.
        • Kirker S.G.
        Combined transcranial direct current stimulation and robot-assisted arm training in subacute stroke patients: a pilot study.
        Restor Neurol Neurosci. 2007; 25: 9-15
        • Hesse S.
        • Waldner A.
        • Mehrholz J.
        • Tomelleri C.
        • Pohl M.
        • Werner C.
        Combined transcranial direct current stimulation and robot-assisted arm training in subacute stroke patients: an exploratory, randomized multicenter trial.
        Neurorehabil Neural Repair. 2011; 25: 838-846
        • Boggio P.S.
        • Nunes A.
        • Rigonatti S.P.
        • Nitsche M.A.
        • Pascual-Leone A.
        • Fregni F.
        Repeated sessions of noninvasive brain DC stimulation is associated with motor function improvement in stroke patients.
        Restor Neurol Neurosci. 2007; 25: 123-129
        • Chhatbar P.Y.
        • Ramakrishnan V.
        • Kautz S.
        • George M.S.
        • Adams R.J.
        • Feng W.
        Transcranial direct current stimulation post-stroke upper extremity motor recovery studies exhibit a dose-response relationship.
        Brain Stimul. 2016; 9: 16-26
        • Lippold O.C.
        • Redfearn J.W.
        Mental changes resulting from the passage of small direct currents through the human brain.
        Br J Psychiatry. 1964; 110: 768-772
        • 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: 206-223
        • Bikson M.
        • Grossman P.
        • Thomas C.
        • Zannou A.L.
        • Jiang J.
        • Adnan T.
        • et al.
        Safety of transcranial direct current stimulation: evidence based update 2016.
        Brain Stimul. 2016; 9: 641-661
        • Bikson M.
        • Datta A.
        • Elwassif M.
        Establishing safety limits for transcranial direct current stimulation.
        Clin Neurophysiol. 2009; 120: 1033-1034
        • Liebetanz D.
        • Koch R.
        • Mayenfels S.
        • Konig F.
        • Paulus W.
        • Nitsche M.A.
        Safety limits of cathodal transcranial direct current stimulation in rats.
        Clin Neurophysiol. 2009; 120: 1161-1167
        • Storer B.E.
        Design and analysis of phase I clinical trials.
        Biometrics. 1989; 45: 925-937
        • Penel N.
        • Isambert N.
        • Leblond P.
        • Ferte C.
        • Duhamel A.
        • Bonneterre J.
        “Classical 3 + 3 design” versus “accelerated titration designs”: analysis of 270 phase 1 trials investigating anti-cancer agents.
        Invest New Drugs. 2009; 27: 552-556
        • Ratain M.J.
        • Mick R.
        • Schilsky R.L.
        • Siegler M.
        Statistical and ethical issues in the design and conduct of phase I and II clinical trials of new anticancer agents.
        J Natl Cancer Inst. 1993; 85: 1637-1643
        • Hansen A.R.
        • Graham D.M.
        • Pond G.R.
        • Siu L.L.
        Phase 1 trial design: is 3 + 3 the best?.
        Cancer Control. 2014; 21: 200-208
        • Rorden C.
        • Bonilha L.
        • Fridriksson J.
        • Bender B.
        • Karnath H.O.
        Age-specific CT and MRI templates for spatial normalization.
        Neuroimage. 2012; 61: 957-965
        • Tabesh A.
        • Jensen J.H.
        • Ardekani B.A.
        • Helpern J.A.
        Estimation of tensors and tensor-derived measures in diffusional kurtosis imaging.
        Magn Reson Med. 2011; 65: 823-836
        • Nitsche M.A.
        • Niehaus L.
        • Hoffmann K.T.
        • 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: 2419-2423
        • Fish R.M.
        • Geddes L.A.
        Conduction of electrical current to and through the human body: a review.
        Eplasty. 2009; 9: e44
        • Vernieri F.
        • Assenza G.
        • Maggio P.
        • Tibuzzi F.
        • Zappasodi F.
        • Altamura C.
        • et al.
        Cortical neuromodulation modifies cerebral vasomotor reactivity.
        Stroke. 2010; 41: 2087-2090
        • Grimnes S.
        Dielectric breakdown of human skin in vivo.
        Med Biol Eng Comput. 1983; 21: 379-381
        • Smoot A.
        • Bentel C.
        Electric shock hazard of underwater swimming pool lighting fixtures.
        IEEE Trans Power Appar Syst. 1964; 83: 945-964
        • Reiner E.
        • Paoletti X.
        • O'Quigley J.
        Operating characteristics of the standard phase I clinical trial design.
        Comput Stat Data Anal. 1999; 30: 303-315
        • Truong D.Q.
        • Huber M.
        • Xie X.
        • Datta A.
        • Rahman A.
        • Parra L.C.
        • et al.
        Clinician accessible tools for GUI computational models of transcranial electrical stimulation: BONSAI and SPHERES.
        Brain Stimul. 2014; 7: 521-524