Clinical Neurophysiology 120 (2009) 1033–1034

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Clinical Neurophysiology
journal homepage: www.elsevier.com/locate/clinph

Editorial

Establishing safety limits for transcranial direct current stimulation

The recent resurgence in the use of transcranial Direct Current observed at a minimum cathodal electrode current density
Stimulation (tDCS) for electrotherapy and human cognition studies 142.9 A/m2 for durations greater than 10 min. For current densities
was motivated by studies demonstrating lasting change in cortico- between 142.9 and 285.7 A/m2, lesion size increased linearly with
spinal excitability following tDCS (Priori et al., 1998; Nitsche and charge density (current density  time); with an extrapolated zero
Paulus, 2000, 2001) including at the University of Gottingen. Sub- lesion size intercept of 52400 C/m2. Thus Liebetanz and colleagues
sequent tDCS studies have largely adapted the Gottingen protocols conclude that both the stated cathodal current density and charge
including the use of relatively-large wet sponges with size nomi- density thresholds must be exceeded to induce histopathologically
nally 25–35 cm2 and currents of 1–2 mA applied for durations up visible brain tissue damage. These findings must be interpreted in
to 20 min (resulting in charge densities of 343–960 C/m2). Repro- the context of limited understanding of damage mechanisms, and
duction of these protocols across a wide range of applications translational issues relating to clinical electrode montages and hu-
and subjects (Nitsche et al., 2003a; Fregni et al., 2006; Webster man anatomy.
et al., 2006; Boggio et al., 2007), has resulted in only isolated pub- The authors propose tissue heating (burning) as a probable mech-
lished reports on injury, limited to (acute) skin irritation under the anism for damage. Though temperature measurements were not
sponges (Poreisz et al., 2007; Dundas et al., 2007; Bikson et al., conducted in the present study, the requirement for a current den-
2008; Lagopoulos et al., 2008; Palm et al., 2008) such that current sity threshold, as well as the increased lesion size with time/charge
tDCS procedures are considered ‘‘safe” (Nitsche and Paulus, 2001; density once current density threshold is exceeded, are consistent
Nitsche et al., 2003b,c, 2004a; Iyer et al., 2005). None-the-less, with burning. Electrical current generates heat in tissue through
the need for continued vigilance in examining potential hazards, joule heat, which is linearly dependent on current density. For anal-
combined with the desire by clinicians to explore increasing inten- ogy: Touching a moderately warm plate, even for a long time, will
sity protocols and duration of after effects (Nitsche et al., 2004b; not induce skin burns when passive (heat conduction) and active
Fregni et al., 2006) warrants investigation of the thresholds and (blood flow) mechanisms control peak temperature rise. Similarly,
mechanisms of potential tDCS hazards. the temperature changes generated by low levels of current density
In developing safety guidelines for tDCS, several biophysical in the brain may be regulated to non-harmful levels. Returning to the
qualifications should be made. Firstly, if and what type of injury re- hot plate analogy: Even if the plate is heated to a potentially harmful
sults from electrical stimulation is wholly dependent on the precise temperature, just touching the plate briefly will not cause a burn, be-
stimulation hardware and waveform applied; thus while one can cause: (1) it takes time for tissue to heat; and (2) exposure at that
draw general insights from a broad range of electrical safety studies temperature only for an extended time will lead to tissue damage
(Agnew and McCreery, 1987; Merrill et al., 2005), it is neither accu- (Lee et al., 2000; Kiyatkin, 2004; Elwassif et al., 2006).
rate nor prudent to determine quantitative safety standards for Hence, damage by heating is critically dependent on exposure
tDCS from these reports. Moreover, tDCS itself represents a constel- time (in contrast, for example, to immediate damage by electropor-
lation of technologies and approaches (e.g. sponge salinity, elec- ation), which is consistent with the dependence of tissue lesion size
trode configurations, ramp waveform, intensity; Bikson et al., on time/charge density observed by Liebetanz and colleagues. We
2008) such that the safety standards may be tDCS protocol specific. calculate that a uniform current density of 142.9 A/m2 will increase
Second, the injurious effects of tDCS on skin and brain are not nec- the temperature of brain tissue to 47.75 °C in 10 min (assuming no
essarily linked, and should be considered independently from both blood flow and metabolic heat source; initial temperature = 37 °C;
the risk and mitigation stand-point. Acute pain and tissue damage electrical conductivity = 0.3 S/m; specific heat = 3650 J/(Kg °C);
of skin can further be distinguished, as should brain cognitive density = 1040 kg/m3). If temperature changes result only from
impairment versus brain tissue damage factors. joule heating, without a contribution from electrical alteration in
The report in this edition by Liebetanz and colleagues in Gottin- neuronal metabolic activity, then tissue damage thresholds would
gen is a valuable contribution towards this last factor. Brain tissue be polarity independent. However, in the absence of a verified tissue
damage was accessed in a rat model following epicranial electrode damage mechanism and explicit testing of anodal stimulation,
stimulation (Liebetanz et al., 2009). By fixing the electrode directly safety results from cathodal stimulation do not necessarily apply
on the cranium, and using a large counter electrode on the ventral for anodal stimulation.
thorax, the study design maximized the electrode current that In relating the findings of this report to human safety standards,
crosses directly into the skull; thus in this model the peak current Liebetanz and colleagues acknowledge the (unavoidable) limita-
density in the rat brain may approach the current density at the tions of the animal model but correctly indicate that the epicranial
electrode. Liebetanz and colleagues report that brain lesions were electrode montage may provide a worst case scenario for the fraction

1388-2457/$36.00 Ó 2009 International Federation of Clinical Neurophysiology. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.clinph.2009.03.018
1034 Editorial / Clinical Neurophysiology 120 (2009) 1033–1034

of electrode current entering the brain. In clinical studies, it is conve- quantifying transcranial electrotherapy dosage. Curr Treat Options Neurol
2008;10:377–85.
nient to report stimulation intensity as average current density: cal-
Boggio PS, Bermpohl F, Vergara AO, Muniz AL, Nahas FH, Leme PB, et al. Go-no-go task
culated by dividing the current delivered to the electrode by the total performance improvement after anodal transcranial DC stimulation of the left
sponge contact area. Using sponge electrodes, the current density at dorsolateral prefrontal cortex in major depression. J Affect Disord 2007;101:91–8.
the scalp is concentrated near the sponge edges and thus exceeds the Datta A, Elwassif M, Battaglia F, Bikson M. Transcranial current stimulation focality
using disc and ring electrode configurations:FEM analysis. J Neural Eng
average current density (Miranda et al., 2006; Wagner et al., 2007). 2008;5:163–74.
The scalp-skull interface, however, acts to diffuse current flow such Datta A, Bansal V, Diaz J, Patel J, Reato D, Bikson M. Gyri-precise head model of
that these concentrations are not reflected on the brain surface transcranial DC stimulation: improved spatial focality using a ring electrode
versus conventional rectangular pad. Brain Stimulation in press.
(Miranda et al., 2006; Datta et al., 2008; Datta et al., in press). More- Dundas JE, Thickbroom GW, Mastaglia FL. Perception of comfort during
over, depending on the clinical electrode montage used, a significant transcranial direct current stimulation: effect of NaCl solution concentration
portion of the applied current may be ‘shunted’ by the scalp and not applied to sponge electrodes. Clin Neurophysiol 2007;118:1166–70.
Elwassif MM, Kong Q, Vasquez M, Bikson M. Bio-heat transfer model of deep brain
enter the brain. Simplistically, if one speculates that average current stimulation-induced temperature changes. J Neural Eng 2006;3:306–15.
density at the tDCS electrodes reflects an upper-limit on current den- Fregni F, Boggio PS, Lima MC, Ferreira MJ, Wagner T, Rigonatti SP, et al. A sham-
sity in the brain, then the average electrode current density may be controlled, phase II trial of transcranial direct current stimulation for the treat-
ment of central pain in traumatic spinal cord injury. Pain 2006;122:197–209.
rationally limited to 142.9 A/m2 in order to prevent the tissue dam- Iyer MB, Mattu U, Grafman J, Lomarev M, Sato S, Wassermann EM. Safety and
age observed by Liebetanz and colleagues. It would be premature to cognitive effect of frontal DC brain polarization in healthy individuals.
arbitrarily apply this average electrode current density standard in Neurology 2005;64:872–5.
Kiyatkin EA. Brain hyperthermia during physiological and pathological conditions:
clinical testing because: (1) as emphasized by the authors, these re-
causes, mechanisms, and functional implications. Curr Neurovasc Res 2004;1:
sults ‘‘are solely based on morphological [animal data] and do not in- 77–90.
clude studies on long-term morphological changes or behavioral Kuo MF, Unger M, Liebetanz D, Lang N, Tergau F, Paulus W, et al. Limited impact of
changes”; and (2) details of human anatomy, including cortical fold- homeostatic plasticity on motor learning in humans. Neuropsychologia
2008;46:2122–8.
ing, will affect current flow and can result in regional cerebral blood Lagopoulos J, Degabriele R. Feeling the heat: the electrode-skin interface during
flow/current density ‘‘clustering” (Lang et al., 2005; Datta et al., in DCS. Acta Neuropsychiatrica 2008;20:98–100.
press). Conversely, this standard does not imply that any tDCS proto- Lang N, Siebner HR, Ward NS, Lee L, Nitsche MA, Paulus W, et al. How does
transcranial DC stimulation of the primary motor cortex alter regional neuronal
col where average electrode current density exceeds this value is activity in the human brain? Eur J Neurosci 2005;22:495–504.
necessarily hazardous: Firstly, Liebetanz and colleagues demon- Liebetanz D, Koch R, Mayenfels S, Konig F, Paulus W, Nitsche MA. Safety limits of
strate a second concurrent charge-density threshold which indicates cathodal transcranial direct current stimulation in rats. Clin Neurophysiol
2009;120:1161–7.
a pivotal role for exposure time. Second, the reduction in current Lee RC, Zhang D, Hannig J. Biophysical injury mechanisms in electrical shock
density from the electrode to brain surface (due to scalp-skull diffu- trauma. Annu Rev Biomed Eng 2000;2:477–509.
sion, scalp/CSF shunting) adds an additional safety factor that can be Miranda PC, Lomarev M, Hallett M. Modeling the current distribution during
transcranial direct current stimulation. Clin Neurophysiol 2006;117:1623–9.
determined for each montage (Wagner et al., 2007; Datta et al., 2008; Merrill DR, Bikson M, Jefferys JG. Electrical stimulation of excitable tissue: design of
Datta et al., in press). efficacious and safe protocols. J Neurosci Methods 2005;141:171–98.
Finally, regarding other safety factors: Prevention of brain dam- Nitsche MA, Paulus W. Excitability changes induced in the human motor cortex by
weak transcranial direct current stimulation. J Physiol 2000;527:633–9.
age for tDCS electrode montages does not preclude undesirable cog-
Nitsche MA, Paulus W. Sustained excitability elevations induced by transcranial DC
nitive side-effects; though to-date, reports of tDCS modulation of motor cortex stimulation in humans. Neurology 2001;57:1899–901.
cognitive function have generally indicated only transient improve- Nitsche MA, Schauenburg A, Lang N, Liebetanz D, Exner C, Paulus W, et al.
ments or impairment in performance, if any change at all (Nitsche Facilitation of implicit motor learning by weak transcranial direct current
stimulation of the primary motor cortex in the human. J Cogn Neurosci
et al., 2003a; Antal et al., 2004a,b; Iyer et al., 2005; Kuo et al., 2003a;15:619–26.
2008). Skin irritation and damage can be readily accessed in human Nitsche MA, Liebetanz D, Lang N, Antal A, Tergau F, Paulus W. Safety criteria for
subjects. Especially given the limitation of animal models and the re- transcranial direct current stimulation (tDCS) in humans. Clin Neurophysiol
2003b;114:2220–2.
lated importance of exactly reproducing electrode montages (e.g. Nitsche MA, Nitsche MS, Klein CC, Tergau F, Rothwell JC, Paulus W. Level of action of
size); a rational approach to skin safety is controlled and incremental cathodal DC polarisation induced inhibition of the human motor cortex. Clin
evaluation in human subjects. For example, results by our group Neurophysiol 2003c;114:600–4.
Nitsche MA, Niehaus L, Hoffmann KT, Hengst S, Liebetanz D, Paulus W, et al. MRI
indicate that with appropriate hardware (electrodes, adapters, and study of human brain exposed to weak direct current stimulation of the frontal
gels), current densities of 25.46 A/m2 can be applied for 20 min with cortex. Clin Neurophysiol 2004a;115:2419–23.
minimal sensation and no skin damage (unpublished observations). Nitsche MA, Grundey J, Liebetanz D, Lang N, Tergau F, Paulus W. Catecholaminergic
consolidation of motor cortical neuroplasticity in humans. Cereb Cortex
In these studies, subjects scored pain perception during forearm 2004b;14:1240–5.
stimulation under anode and cathode electrodes; in addition pH Palm U, Keeser D, Schiller C, Fintescu Z, Reisinger E, Padberg F, et al. Skin lesions
and temperature changes in the customized stimulation gel were after treatment with transcranial direct current stimulation (tDCS). Brain
Stimulation 2008;1:386–7.
not detected.
Poreisz C, Boros K, Antal A, Paulus W. Safety aspects of transcranial direct current
In summary, the contribution by Liebetanz and colleagues is cor- stimulation concerning healthy subjects and patients. Brain Res Bull
rectly, a ‘‘first estimate of a safety threshold for deleterious DC” 2007;72:208–14.
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motor cortex through the scalp. Neuroreport 1998;9:2257–60.
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and animals as well as the continued development of tDCS direct current stimulation: a computer-based human model study. Neuroimage
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