J Physiol 595.
11 (2017) pp 3265–3266
JOURNAL CLUB
Dose dependency of transcranial
direct current stimulation:
implications for neuroplasticity
induction in health and disease
Mitchell R. Goldsworthy1,2
and Brenton Hordacre1,3
1
Robinson Research Institute, School of
Medicine, University of Adelaide, Australia
2
Discipline of Psychiatry, School of
Medicine, University of Adelaide, Australia
3
Department of Physiotherapy,
Repatriation General Hospital, SA
Health, Daw Park, Australia
Email: mitchell.goldsworthy@adelaide.edu.
au
The Journal of Physiology
There has been a rapid growth in the
use of non-invasive brain stimulation
to induce neuroplasticity and modulate
human brain function over the past decade.
An example of this is transcranial direct
current stimulation (tDCS), which involves
the application of weak electrical currents
between at least two electrodes placed over
the scalp. When applied to the primary
motor cortex (M1), tDCS can induce
lasting polarity-dependent changes in
excitability, with facilitation following
anodal stimulation and suppression
following cathodal stimulation. These
changes share similarities with the
long-term potentiation (LTP) and
long-term depression (LTD) observed
in animal models, and importantly, there is
some evidence that tDCS can have positive
therapeutic effects for patients with various
neurological and psychiatric conditions.
Of the various techniques developed for
non-invasively inducing neuroplasticity in
the human brain, the advance of tDCS in
particular has been met with significant
enthusiasm, due in no small part to its
relative low cost, compact design and ease
of use. However, as is becoming increasingly
evident for many neuroplasticity-inducing
non-invasive brain stimulation protocols,
its after-effects can be extremely variable
between individuals, not just in magnitude
and duration, but in direction also.
This inter-individual variability of tDCS
after-effects is problematic for its translation
to clinical practice, and thus, determining
the causes of this variability is of critical
importance.

C 2017 The Authors. The Journal of Physiology 
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Many factors have been identified
that could contribute to tDCS response
variability (Ridding & Ziemann, 2010);
however, surprisingly little attention has
been paid to the optimal dose of stimulation.
While increasing the duration and/or
intensity of stimulation might be assumed
to maximise the therapeutic effects of
tDCS, there is now growing evidence in
healthy human populations suggesting a
dose–response relationship for tDCS that
is not linear, but instead is more complex
than initially thought (Batsikadze et al. 2013;
Kidgell et al. 2013; Monte-Silva et al. 2013).
In a recent article published in The
Journal of Physiology, Jamil et al. (2017)
sought to further examine the dose
dependency of tDCS by systematically
measuring the neuroplastic response to
stimulation across the full DC intensity
range. Healthy participants received either
anodal or cathodal tDCS applied for
15 min to left M1 at five different
intensities: sham, 0.5, 1.0, 1.5 and
2.0 mA. Single-pulse transcranial magnetic
stimulation (TMS)-elicited motor-evoked
potentials (MEPs) were recorded before
and at multiple time points up to 2 h
following stimulation to quantify M1
plasticity. The results showed no evidence
for a linear relationship between increasing
stimulation intensity and the induced
neuroplastic response for either anodal
or cathodal tDCS. Across the early time
points (0–30 min) post-stimulation, anodal
tDCS induced MEP facilitation for all
active intensities relative to sham, with no
difference between stimulation intensities.
While a difference between stimulation
intensities was observed for cathodal tDCS,
this was due to a reduced MEP suppression
at higher intensities (1.5 and 2.0 mA), with
active stimulation at 1.0 mA producing the
optimal response.
The non-linear relationship between tDCS
intensity and the induced plasticity response
has been shown in previous studies. For
instance, Kidgell et al. (2013) compared
the effects of anodal tDCS applied for
10 min at 0.8, 1.0 and 1.2 mA, and
found no difference in MEP facilitation
between stimulation intensities. In another
study, Batsikadze et al. (2013) compared
the M1 plasticity response to cathodal tDCS
applied for 20 min at either 1.0 or 2.0 mA.
While 1.0 mA stimulation induced the
expected suppression in MEP amplitudes,
cathodal stimulation at 2.0 mA reversed the
polarity of after-effects from suppression to
facilitation.
Further evidence for the non-linear
dose–response relationship for tDCS has
been shown in studies comparing different
stimulation durations. As well as examining
different spacing intervals for repeated
applications of tDCS, Monte-Silva et al.
(2013) compared a single application of
1.0 mA anodal tDCS, applied for either
13 or 26 min. Rather than increasing
the facilitatory response, doubling the
duration of stimulation reversed the
polarity of effects from MEP facilitation
to suppression. The MEP suppression
induced by 26 min of anodal tDCS was
abolished by flunarizine, suggesting that
the polarity reversal following prolonged
stimulation was probably calcium channel
dependent. Given the known role of
calcium in determining LTP/LTD induction,
it is possible that similar calcium
channel-dependent mechanisms may be
responsible for the differential response
to cathodal tDCS at different intensities,
although this remains to be tested.
In addition to investigating the influence
of different stimulation intensities on tDCS
response, Jamil et al. (2017) also examined
different sources of inter-individual
variability in their data. Consistent with
previous research (Labruna et al. 2016),
they found that the facilitatory response
to 1.0 mA anodal tDCS was greatest in
those participants with higher sensitivity to
TMS (i.e. requiring a lower TMS intensity
to elicit an MEP with 1 mV peak-to-peak
amplitude). This relationship is probably
the result of inter-individual differences in
anatomical (e.g. skull thickness, cortical
morphology, etc.) and physiological (e.g.
neurotransmitter availability and receptor
distribution) factors that similarly affect the
efficacy of both TMS and tDCS (Labruna
et al. 2016). Interestingly, Jamil et al.
(2017) found there was a tendency for
participants with lower sensitivity to TMS
(that is, requiring higher TMS intensities
to elicit a 1 mV MEP response) to respond
with a greater facilitatory response to
anodal tDCS at higher intensities of 1.5
and 2.0 mA, although this did not reach
statistical significance. Nevertheless, this
may lead to intriguing possibilities for
DOI: 10.1113/JP274089
3266
using the stimulus–response characteristics
of TMS as a way of identifying the optimal
stimulation intensity and individualising
tDCS dose.
While the work of Jamil et al.
(2017) has provided some useful new
information regarding tDCS dose–response
relationships, there remains much to
be investigated. For instance, while the
effects of varying stimulation intensity
and duration have each been studied,
it is still unclear how these variables
might interact to affect tDCS response.
Further complicating matters is the possible
influence of electrode size and montage,
as well as different repetition intervals for
multiple stimulation sessions (Monte-Silva
et al. 2013). Although the results of Jamil
et al. (2017) and others suggest that
intensities of 0.5–2.0 mA for anodal and
1.0 mA for cathodal may be sufficient to
produce the desired MEP response to tDCS
at the group level, it is clear that such
generalised approaches will not work for
every participant. On this basis, further
studies aimed at individualising tDCS
parameters based on individual anatomy or
physiology are required.
Finally, while the current research has
been largely focused on tDCS effects on
M1 in healthy young adults, whether
the dose–response relationship differs for
non-motor cortical targets and in patient
populations remains an open question.
While investigating the neurophysiological
effects of tDCS outside M1 presents its
own challenges, continual progress is being
made in the combination of TMS and
Journal Club
tDCS with neuroimaging modalities such
as functional magnetic resonance imaging,
positron emission tomography, and electro-
encephalography, providing several new
and exciting insights. The application of
these novel techniques to examine the dose
dependency of tDCS will be essential for
advancing treatment options for a variety
of neurological and psychiatric disorders,
in particular those characterised by
pathophysiological changes in non-motor
regions, such as depression, schizophrenia
and dementia.
The findings of Jamil et al. (2017)
highlight the complexity of the tDCS
dose–response relationship, and may lead
to novel solutions for individualising
stimulation and reducing inter-individual
response variability. While the obstacles
associated with characterising the optimal
dose for all possible stimulation parameters
and cortical targets are not trivial, this line
of research remains necessary for tDCS to
reach its full therapeutic potential.
References
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Nitsche MA (2013). Partially non-linear
stimulation intensity-dependent effects of
direct current stimulation on motor cortex
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1987–2000.
Jamil A, Batsikadze G, Kuo H-I, Labruna L,
Hasan A, Paulus W & Nitsche MA (2017).
Systematic evaluation of the impact of
stimulation intensity on neuroplastic
after-effects induced by transcranial direct
current stimulation. J Physiol 595, 1273–1288.

C 2017 The Authors. The Journal of Physiology 
J Physiol 595.11
Kidgell DJ, Daly RM, Young K, Lum J, Tooley G,
Jaberzadeh S, Zoghi M & Pearce AJ (2013).
Different current intensities of anodal
transcranial direct current stimulation do not
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Labruna L, Jamil A, Fresnoza S, Batsikadze G,
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Additional information
Competing interests
None declared.
Funding
M.R.G. is supported by an NHMRC-ARC
Dementia Research Development Fellowship
(National Health and Medical Research Council
of Australia (NHMRC) and Australian Research
Council (ARC); 1102272). B.H. is supported
by a research fellowship from the NHMRC
(1125054)
C 2017 The Physiological Society