Clinical research with transcranial direct current
stimulation (tDCS): Challenges and future directions
Andre Russowsky Brunoni,aMichael A. Nitsche,bNadia Bolognini,c,dMarom Bikson,e
Tim Wagner,fLotfi Merabet,gDylan J. Edwards,hAntoni Valero-Cabre,i
Alexander Rotenberg,jAlvaro Pascual-Leone,kRoberta Ferrucci,lAlberto Priori,l
Paulo Sergio Boggio,mFelipe Fregnin
aDepartment of Neurosciences and Behavior, Institute of Psychology, University of S~ ao Paulo, S~ ao Paulo, Brazil
bDepartment of Clinical Neurophysiology, Georg-August University, Goettingen, Germany
cDepartment of Psychology, University of Milano-Bicocca, Milan, Italy
dNeuropsychological Laboratory, IRCCS Instituto Auxologico Italiano, Milan, Italy
eThe City College of City University of New York, New York, New York
fMassachusetts Institute of Technology, Boston, Massachusetts
gMassachusets Eye and Ear Infirmary, Harvard University, Boston, Massachusetts
hBurke Medical Research Institute, White Plains, New York
iBoston University School of Medicine, Boston, Massachusetts
jDepartment of Neurology, Children’s Hospital, Harvard Medical School, Boston, Massachusetts
kBerenson-Allen Center for Non-invasive Brain Stimulation, Beth Israel Deaconess Medical Center, Harvard Medical
School, Boston, Massachusetts
lCentro Clinico per la Neurostimolazione, le Neurotecnologie ed i Disordini del Movimento, Fondazione IRCCS Ca’
Granda Ospedale Maggiore Policlinico, Universit? a degli Studi di Milano Dipartimento di Scienze Neurologiche, Milan,
mSocial and Cognitive Neuroscience Laboratory and Developmental Disorders Program, Center for Health and Biological
Sciences, Mackenzie Prebyterian University, Sao Paulo, Brazil
nLaboratory of Neuromodulation, Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital
and Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
Transcranial direct current stimulation (tDCS) is a neuromodulatory technique that delivers low-
intensity, direct current to cortical areas facilitating or inhibiting spontaneous neuronal activity. In the
past 10 years, tDCS physiologic mechanisms of action have been intensively investigated giving
support for the investigation of its applications in clinical neuropsychiatry and rehabilitation. However,
new methodologic, ethical, and regulatory issues emerge when translating the findings of preclinical
Drs. A. Priori and R. Ferrucci have some stock options in the neurostimulation company Newronika srl (Milan, Italy).
Correspondence: Felipe Fregni, Laboratory of Neuromodulation, Spaulding Rehabilitation Hospital, 125 Nashua Street #727, Boston, MA 02114.
E-mail address: email@example.com
Submitted November 7, 2010; revised January 25, 2011. Accepted for publication March 3, 2011.
1935-861X/$ - see front matter ? 2012 Elsevier Inc. All rights reserved.
Brain Stimulation (2012) 5, 175–95
and phase I studies into phase II and III clinical studies. The aim of this comprehensive review is to
discuss the key challenges of this process and possible methods to address them.
We convened a workgroup of researchers in the field to review, discuss, and provide updates and key
challenges of tDCS use in clinical research.
We reviewed several basic and clinical studies in the field and identified potential limitations, taking
into account the particularities of the technique. We review and discuss the findings into four topics: (1)
mechanisms of action of tDCS, parameters of use and computer-based human brain modeling
investigating electric current fields and magnitude induced by tDCS; (2) methodologic aspects related
to the clinical research of tDCS as divided according to study phase (ie, preclinical, phase I, phase II,
and phase III studies); (3) ethical and regulatory concerns; and (4) future directions regarding novel
approaches, novel devices, and future studies involving tDCS. Finally, we propose some alternative
methods to facilitate clinical research on tDCS.
? 2012 Elsevier Inc. All rights reserved.
medicine; neuropsychiatry; medical devices
transcranial direct current stimulation; brain stimulation; clinical research; physical
The effects of uncontrolled electrical stimulation on the
brain have been reported since the distant past. Scribonius
Largus (the physician of the Roman Emperor Claudius),
described how placing a live torpedo fish over the scalp to
deliver a strong electric current could relieve a headache.1
Galen of Pergamum, the great medical researcher of the
using a live electric catfish for the treatment of epilepsy.2
With the introduction of the electric battery in the 18th
century, it became possible to evaluate the effect of direct
transcranial stimulation systematically. Individuals such as
Walsh (1773), Galvani (1791, 1797), and Volta (1792) all
recognized that electrical stimulation of varying duration
could evoke different physiological effects.3In fact, one of
the first systematic reports of clinical applications of
galvanic currents date back to this period, when Giovanni
Aldini (Galvani’s nephew) and others used transcranial elec-
trical stimulation to treat melancholia.4,5Over the past two
centuries, many other researchers (see Zago et al.3for
further references) used galvanic current for the treatment
of mental disorders with varying results. In more recent
history, the use of electroconvulsive therapy and psycho-
pharmacologic drugs and lack of reliable neurophysiologic
markers have obscured direct current stimulation of the
central nervous system (CNS) as a therapeutic and research
tool particularly in the field of psychiatry. Nonetheless,
galvanic current has been used without interruption for the
treatment of musculoskeletal disorders and peripheral pain.
In fact, a reappraisal of transcranial direct current
stimulation (tDCS) as a form of noninvasive brain stimula-
of Priori and colleagues,6followed by Nitsche and Paulus7
demonstrated that weak, direct electric currents could be
polarity-dependent changes in cortical. Specifically, anodal
direct current stimulation was shown to increase cortical
excitability, whereas cathodal stimulation decreased it. In
addition, animal and human studies have provided insight
plasticity8-11and current distribution according to the brain
area being stimulated.12-15In addition, several studies
of targeted brain areas.16-19Moreover, certain appealing
and has mostly well-tolerated, transient, and mild adverse
effects) have sparked an increase in clinical studies particu-
larly for neuropsychiatricdisorders suchas major depressive
disorder, chronic and acute pain, stroke rehabilitation, drug
addiction, and other neurologic and psychiatric condi-
tions.20-22Although reported effects have been heteroge-
neous and warrant further clinical studies, studies have
been generally promising.
As the field of noninvasive brain stimulation moves
towards more clinical applications, there are new issues that
emerge. One is methodologic; how to study tDCS in
neuropsychiatry that historically has been heavily pharma-
Specifically, what are the optimal
approaches regarding study design (eg, two-arm, three-arm
versus factorial), study methodology (blinding, use of
placebo, concomitant use of drugs), sample requirements
(ie, sample size, eligibility criteria, sample recruitment),
interventions (eg, electrode positioning, dosage, duration,
and also comparison against pharmacotherapy), outcomes
(eg, clinical versus surrogate outcomes), and safety. Another
issue is ethical; who should apply tDCS in clinical settings
(eg, physicians, neuropsychologists, specialized staff); the
tolerable amount of risk for inducing maladaptive, long-
term neuroplasticity, and whether tDCS could be used for
176Brunoni et al
subjects; finally, regulatory issues also need to be discussed.
is delivered through a sophisticated device, tDCS can be
administered with devices already manufactured and used
in pain and cosmetic medicine. These devices deliver direct
current to the joints and/or the skin. Also, contrary to TMS,
these devices are affordable and readily accessible and can
be purchased by nontrained individuals, including patients.
The last question is why conducting clinical research on
tDCS. Among others, we can identify three main reasons:
(1) there is a theoretical clinical basis for tDCS as
a substitutive treatment for pharmacotherapy, such as
patients with poor drug tolerability or those with adverse
pharmacologic interactions (eg, elderly people who use
several drugs). For instance, one group that would poten-
tially benefit from further investigation of tDCS safety is
pregnant women with unipolar depression, as there is
a lack of acceptable pharmacologic alternatives for this
condition24; (2) using tDCS as an augmentative treat-
mentdfor example, tDCS and restraint therapy for stroke25;
or tDCS and pharmacotherapy for chronic pain or major
depression. Again, side effects and noninvasiveness make
tDCS an appealing strategy to boost the effects of other
treatments in addition to its neurophysiologic effects on
membrane resting threshold that likely underlie its syner-
gistic effects. And, (3) tDCS is inexpensive; being therefore
attractive to areas lacking in resources. If proven effective,
tDCS will be an interesting option for developing countries.
The purpose of this reviewis to assess the current stage of
tDCS development and identify its potential limitations in
current clinical studies as to provide a comprehensive
framework for designing future clinical trials. This review
of action of tDCS, parameters of use and computer-based
human brain modeling investigating electric current fields
and magnitude induced by tDCS. Given the conciseness of
this section, the reader is invited to consult more recent
reviews focusing exclusively on the mechanisms of action
and technical development.26,27The second section covers
(ie, preclinical, phase I, phase II, and phase III studies). The
thirdsectionfocuseson ethicaland regulatory concerns. The
last section concludes with a presentation of what are ex-
pected in the near future regarding novel approaches, novel
devices, and future studies involving tDCS.
The electrophysiology of tDCS
Mechanisms of action
TDCS differs from other noninvasive brain stimulation
techniques such as transcranial electrical stimulation (TES)
and TMS. TDCS does not induce neuronal firing by supra-
threshold neuronal membrane depolarization but rather
modulates spontaneous neuronal network activity.27,28At
the neuronal level, the primary mechanism of action is
a tDCS polarity-dependent shift (polarization) of resting
membrane potential. Although anodal DCS generally
enhances cortical activity and excitability, cathodal DCS
has opposite effects.7,29,30Animal studies have shown that
changes in excitability are reflected in both spontaneous
firing rates31,32; and responsiveness to afferent synaptic
inputs.33,34It is this primary polarization mechanism that
underlies the acute effects of low-intensity DC currents on
cortical excitability in humans.6
However, tDCS elicits after-effects lasting for up to 1
hour.9,35Therefore, its mechanisms of action cannot be
solely attributed to changes of the electrical neuronal
membrane potential. In fact, further research showed that
tDCS also modifies the synaptic microenvironment, for
instance, by modifying synaptic strength NMDA receptor-
dependently or altering GABAergic activity.36-38TDCS
also interferes with brain excitability through modulation
of intracortical and corticospinal neurons.10,39The effects
of tDCS might be similar to those observed in long-term
potentiation (LTP), as shown by one recent animal study
that applied anodal motor cortex stimulation and showed
a lasting increase in postsynaptic excitatory potentials.8
Experiments with peripheral nerve39and spinal cord40
stimulation showed that DC effects are also nonsynaptic,
possibly involving transient changes in the density of
protein channels localized below the stimulating electrode.
Given that a constant electric field displaces all polar
molecules and most of the neurotransmitters and receptors
in the brain have electrical properties, tDCS might also
influence neuronal function by inducing prolonged neuro-
chemical changes.38,40For instance, magnetic resonance
spectroscopy showed that after anodal tDCS brain myoino-
sitol significantly increased, whereas n-acetyl-aspartate
failed to change.41
In addition to the ‘‘direct’’ tDCS effects described previ-
ously, ‘‘indirect’’ effects are also observed. This is seen in
neuron activity and evoked neuronal activity, but also spon-
taneous neuronal oscillations. Ardolino et al.39found that
below the cathodal electrode, the slow EEG activity in the
theta and delta band increases. Animal and modeling studies
suggest that a network of tightly coupled active neurons (eg,
than neurons in isolation.44-46
Although most early tDCS studies have been performed
in the motor cortex, it should be noticed that tDCS does not
only induce long-lasting alterations of motor-evoked poten-
tials, but also affects somatosensory and visual-evoked
potentials. This activity is dependent on the area stimu-
lated.47-49Ferrucci et al.50and Galea et al.51provided
evidence that tDCS can influence the human cerebellum.
Clinical research with tDCS177
Cogiamanian et al.40and Winkler et al.52demonstrated that
transcutaneous DC stimulation modulates conduction along
the spinal cord and the segmental reflex pathways.
An important aspect when discussing the mechanisms of
tDCS is the magnitude and location of the current induced
in cortical tissues. Several modeling studies have been
conducted to address this issue and will be discussed in
a later section.
tissues (vessels, connective tissue) and pathophysiologic
in addition, their effects are observed on multiple cellular
CNS. Support for this theory is observed below anodal tDCS
electrode as it can induce prolonged brain vasodilatation.53
In conclusion, the mechanisms of action of DCS remain
to be completely elucidated, an issue that can have
important repercussions for future clinical applications.
These mechanisms likely involve different synaptic and
nonsynaptic effects on neurons and effects on nonneuronal
cells and tissues within the CNS.
Pharmacologic investigation of tDCS
excitability is modified. Therefore, such studies aim to
enhance our knowledge about the mechanisms of action of
tDCS with regard to neuromodulation and neuroplasticity.
Evidence suggests that blocking voltage-gated sodium
and calcium channels decreases the excitability enhancing
effect of anodal tDCS. In contrast, cathodal tDCS-generated
excitability reductions are not affected.36,37These findings
are in line with the assumption that tDCS induces shifts in
membrane resting threshold of cortical neurons.
Regarding neurotransmitters, it has been shown that
NMDA-glutamatergic receptors are involved in inhibitory
and facilitatory plasticity induced by tDCS. Blocking
NMDA receptors abolishes the after-effects of stimulation,
whereas enhancement of NMDA receptor efficacy by d-
cycloserine enhances selectively facilitatory plasticity.9,54
In contrast, GABAergic modulation with lorazepam results
in a delayed then enhanced and prolonged anodal tDCS-
induced excitability elevation55(Table 1).
amphetamines (that increase monoaminergic activity)
seem to enhance tDCS-induced facilitatory plasticity.56
For the dopaminergic system, tDCS-generated plasticity
is modulated in a complex dosage- and subreceptor-
dependent manner. Application of the dopamine precursor
l-dopa converts facilitatory plasticity into inhibition, and
prolongs inhibitory plasticity,57whereas blocking D2
receptors seems to abolish tDCS-induced plasticity,58D2
agonists, applied at high or low dosages, decrease plasticity.
Furthermore, plasticity is restituted by medium dosage D2
inhibitor rivastigmine affects tDCS-induced plasticity in
a similar fashion as l-dopa.11For the serotoninergic system,
the 5-HT reuptake-inhibitor citalopram enhances facilita-
tory plasticity and also converts inhibitory plasticity into
From a clinical point of view, these results show that
pharmacotherapy and tDCS interact, which might be an
issue when studying clinical samples receiving both
Pharmacologic agents that interact with tDCS effects on cortical excitability
Citalopram SERT blockerEnhancement of the duration of facilitatory anodal effects;
Facilitation of cathodal tDCS effects59
Enhancment of the duration of facilitatory anodal effects.55
For anodal: excitability turns into inhibition; For cathodal: effects are
Abolishment of tDCS-induced plasticity57
Enhancement of the duration of cathodal tDCS effects57,58
NET/DAT competitive inhibitor
Amino acid metabolism
Dopamine agonist agent
GABA allosteric modulator
Anodal effects are delayed, but then enhanced and prolonged.100
Abolishment of anodal tDCS effects; stabilization of cathodal tDCS
Abolishment of the after-effects of anodal and cathodal tDCS.36,37
Enhancement of the duration of anodal effects; no effects during
NMDA antagonist agent
NMDA agonist agent
Voltage-sensitive channel blockers
Voltage-sensitive sodium channel blocker
Voltage-sensitive calcium channel blocker
Abolishment of the depolarizing effects of anodal tDCS.36,37
Similar effects of Carbamazepine.
tDCS 5 transcranial direct current stimulation; NET 5 norepinephrine transporter; DAT 5 dopamine transporter; GABA 5 gamma-aminobutyric acid;
NMDA 5 n-methyl-d-aspartic acid; SERT 5 serotonin transporter.
178Brunoni et al
interventions. In fact, the complex nonlinear interaction
makes it difficult to foresee the specific effects of
pathophysiologic alterations or drug application on the
amount and direction of tDCS-induced plasticity; thus
demanding further empirical research on this topic.
Parameters of stimulation
TDCS parameters can vary widely and several factors need
to be defined. These factors include electrode size and
positioning, intensity, duration of stimulation, number of
sessions per day, and interval between sessions. By varying
these parameters, different amounts of electric current can
be delivered, thus inducing diverse physiologic and adverse
effects. Another potential concern is that tDCS devices are
not worldwide standardized. These devices can be easily
constructed using standard equipment and technology in
engineering laboratories of colleges and universities. In
fact, more than a dozen different tDCS devices can be
found throughout neuromodulation laboratories worldwide.
Although tDCS electrical fields are relatively nonfocal,
electrode positioning is critical. For instance, a previous
study showed that changing the electrode reference from
DLPFC to M1 eliminated tDCS effects on working
memory.16Other studies have shown that phosphene-
thresholds are modulated only during occipital (visual
cortex) DCS and not other areas.49,61Likewise, a tDCS trial
for major depression showed that only DLPFC stimulation
(and not occipital stimulation) ameliorated symptoms.62
Although current evidence suggests site-dependent effects,
other issues have yet to be exploreddfor instance, one
open question is whether and how brain stimulation in
one area influences adjacent and more distant areas.
TDCS studies usually use one anode and one cathode
electrode placed over the scalp to modulate a particular
area of the CNS. Electrode positioning is usually deter-
mined according to the International EEG 10-20 System.
Given the focality of tDCS, this appears appropriate. For
instance, studies exploring the motor cortex place elec-
trodes over C3 or C4; for the visual system, electrodes are
typically placed over O1 or O2 (for a review of tDCS
studies exploring different brain areas see Utz et al.63).
In this study, some terms used to describe tDCS
montages should be discussed: when one electrode is placed
bellow the neck, the entire montage is usually described as
‘‘unipolar.’’ In contrast, montages with two electrodes on the
head are termed usually ‘‘bipolar.’’ However, this nomen-
clature might be inaccurate as technically the DC stimula-
tion is always generated via two poles (electrodes)
generating an electric dipole between the electrodes.
Therefore, an alternative nomenclature of ‘‘mono-cephalic’’
and ‘‘bi-cephalic’’ is proposed to differentiate between
‘‘unipolar’’ and ‘‘bipolar’’ setups, respectively. Researchers
in the field also use the terms ‘‘reference’’ and ‘‘stimulating’’
electrode to refer to the ‘‘neutral’’ and ‘‘active’’ electrode,
respectively. However, the term ‘‘reference’’ electrode may
also be problematic, especially for bicephalic montages
because the ‘‘reference’’ electrode is not physiologically
inert and can contribute to activity modulation as well. This
could be a potential confounder depending on the main
study question. Nonetheless, researchers use these terms to
highlight that (in their study) they are under the assumption
that in their particular montage one electrode is being
explored as the ‘‘stimulating,’’ whereas the other is the
In contrast, having the possibility to increase and
decrease activity in different brain areas simultaneously
may be advantageous. For instance, this could be useful in
conditions involving animbalanced
activity (ie, in stroke).64In scenarios whether the reference
electrode poses a confounding effect, an extracephalic
reference electrode could theoretically aid in avoiding
this issue. However, this might increase the risk of shunting
the electric current through the skin (which would then not
reach brain tissue) or displacing the current. Ultimately, the
choice of montage will be application specific; for example,
a recent study comparing different tDCS setups showed
that, although bicephalic setups were effective, the monoce-
phalic setup was no different than sham stimulation.65
Finally, in a monocephalic setup, using very high currents
there is the potential risk of influencing brain stem activity,
including respiratory control (note that this risk is theoret-
ical and was only observed in one historical report).66
Nevertheless, in choosing the extracephalic position, the
researcher must be confident that a significant electric field
will be induced on the target brain area.
Moreover, because current flow direction/electrical field
orientation relative to neuronal orientation might determine
the effects of tDCS,7it might be that the effects of an ex-
tracephalic electrode differs relevantly from that of a bipolar
electrode arrangement. Alternatively, enhancing the size of
one electrode, thus reducing current density, might enable
functional monocephalic stimulation also with a bicephalic
Direct current stimulation can also be delivered over
noncortical brain areas. Ferrucci et al.50stimulated the cere-
bellum showing changes in performance in a cognitive task
for working memory. Galea et al.51explored the inhibitory
effects of the cerebellum on motor-evoked potentials
that tDCS could modify MEPs in a polarity-specific manner.
In addition, Cogiamanian et al.40observed that cathodal
transcutaneous DC over the thoracic spinal cord suppressed
modulates the postactivation depression of the H-reflex.
Preliminary data indicates spinal DCS also influences noci-
ception67suggesting that the spinal cord as a target for trans-
cutaneous DCS. Challenges for stimulation in this area must
be considered such as location of induced electrical fields.
Clinical research with tDCS179
During tDCS, current is generated across the brain; different
montages result in distinct current flow through the brain and
thus the ability to adjust montage allows customization and
optimization of tDCS for specific applications (see above).
Though tDCS montage design often follow basic assump-
tions (eg, ‘‘increased/decreased excitability under the anode/
cathode’’), computational models of brain current flow
during tDCS (so called ‘‘forward’’ models) provide more
accurate insight into detailed current flow patterns, and in
some cases show that the basic assumptions are not valid.
When interpreting the results of such simulations, it is
important to recognize that the intensity of current flow in
any specific brain region does not translate in any simple
linear manner to the degree of brain modulation. However, it
seems reasonable to predict that regions with more current
flow are more likely to be affected by stimulation, whereas
regions with little or no current flow will be spared the direct
effects of stimulation.
Computational models of tDCS range in complexity
from concentric sphere models to individualized high-
resolution models based an individual’s structural magnetic
resonance imaging (MRI). The appropriate level of detail
depends on the available computational resources and the
clinical question being asked (see technical note below).
Regardless of complexity, all models share the primary
outcome of correctly predicting brain current flow during
transcranial stimulation to guide clinical practice in a mean-
Most clinical studies use tDCS devices that apply direct
electric currents via a constant current source, but even
within this space there are infinite variations of dosage and
montage that can be leveraged, with the help of models, to
optimize outcomes. The current is sent through patch
electrodes (surface areas typical range from 25 to 35 cm2
but can vary by an order of magnitude) attached to the scalp
surface. Total current injected ranges in magnitude are
typically from 0.5 to 2 mA. Steps taken to improve tDCS
specificity (including the use of larger ‘‘return’’ sponges
and extracephalic electrodes) have been proposed but more
analysis is required to determine the role of electrode-
montage in neuromodulation and targeting. Modeling
approaches are instrumental toward this goal. For example,
modeling studies have recently predicted a profound role
of the ‘‘return’’ electrode position in modulating overall
current flow including under the ‘‘active’’ (or ‘‘stimulating’’)
electrode.68Specifically, for a fixed active electrode position
on the head, changing the position of the return electrode
(including cephalic and extracephalic positions) influences
current flow through the presumed target region directly
under the active electrode. Therefore, in addition to consid-
ering the role of scalp shunting and action on deep brain
structures (see above) when determining electrode distance,
the complete design of electrode montage may subtly modu-
late cortical current flow.69Again, computer modeling can
provide valuable insight into this process.
Recent modeling studies suggest that individual anatom-
ical differences may affect current flow through the cortex.
In comparison to TMS, which uses MEPs to index its
potency, there is no similar rationale for titrating tDCS
dosage. A related issue is the modification of tDCS dose
montages for individuals with skull defects or stroke-
related lesions. Such individuals may be candidates for
tDCS therapy but defects/lesions are expected to distort
current flow. For example, any defect/injury filled with
cerebrospinal fluid (CSF), including those related to stroke
of traumatic brain injury, is expected to preferentially
‘‘shunt’’ current flow.15Ideally, tDCS would be adjusted
in a patient-specific (defect/lesion specific) manner to
take advantage of such distortions in guiding current flow
to targeted regions, while simultaneously avoiding any
safety concerns (such as current hot spots).
Evidence from modeling studies suggests that for typical
tDCS significant amounts of current can reach broad
cortical areas especially between and under the electrode
surface.12,13Modeling studies also show that electrode
montage is critical to the amount of current shunted through
Electrode montage is critically associated to the amount
of current being shunted through the skin, how much is
delivered to the brain, and to what targets. The overall
theme emerging from modeling efforts is that despite
clinical success in applying simplifying rules in dose
design, all the details and aspects of electrode montage
design combine to influence current flow such that these
simplifying rules are applicable but only within a limited
parameter range. For example, average current density
(total current/electrode area) at the ‘‘active’’ electrode may
be a useful metric to normalize specific neurophysiologic
outcomes (eg, TMS evoked MEPs), there is no universal
relationship between current density and brain modulation
when one considers the full spectrum of possible electrode
Recent modeling data taking into consideration gyri and
sulci geometry have shown that electric current can
concentrate on the edge of gyri.71Therefore, the effects
might not be homogeneous throughout the stimulated
area. Increased appreciation of the complexity of current
flow through the head (reflecting the complexity of neuro-
anatomy), reinforces the use of applying computational
models to assist in tDCS dose design72rather than simply
relying on some heuristic rules (eg, ‘‘increased excitability
under the anode’’).
In addition to predicting brain current flow, modeling
studies also provide insight into electrode design by
predicting current flow patterns through the skin. Modeling
studies has reinforced that current is not passed uniformly
through the skin but rather tends to concentrate near
electrode edges or skin inhomogeneities.13
design can be simple saline-soaked cotton or sponge pads
or specifically designed patches with unique shapes and
materials to maximize stimulation magnitude and focality.
180Brunoni et al
Modeling confirms that decreasing the salinity of the pads
reduces peak current concentration at the edges (even as
the total current applied and average current density is
In summary, modeling studies are expected to play
a critical role in the development of next-generation tDCS
technologies and approaches. Notably, tDCS devices have
not drastically changed since the time when the battery was
first discovered. Thus, conventional technology has certain
limitations. These include focality (area stimulated), depth
of penetration, and targeting-location control. To overcome
these and other limitations, technologies using arrays of
electrodes74such as ‘‘High Definition’’ tDCS (HD-tDCS)71
and others (eg, simultaneous EEG monitoring during tDCS
as to adjust dosage and parameters) have been recently
proposed. Ultimately, as we begin integrating modern tech-
nology with transcranial stimulation techniques, clinical
control and efficacy will undoubtedly improve.
On a final technical note: Though there has been a recent
emphasize to develop increasingly accurate and complex
models,71,72,75certain universal technical issues should be
considered for high-precision models, beginning with: (1)
high-resolution (eg, 1 mm) anatomic scans so that the entire
model work flow should preserve precision. Any finite-
element human head model is limited by the precision
and accuracy of tissue dimensions (masks) and conductivity
values incorporated (inhomogeneity and anisotropy). One
hallmark of precision is the cortical surface used in the
final finite-element mask solver should represent realistic
sulci and gyri; (2) Simultaneously, a priori knowledge of
tissue anatomy and factors known to shape current flow
are applied to further refine segmentation. Particularly crit-
ical are discontinuities not present in nature that result from
limited scan resolution; notably both unnatural perforations
in planar tissues (eg, holes in cerebrospinal fluid where
brain contacts skull) and microstructures (eg, incomplete
or voxelized vessels) can produce significant aberrations
in predicted current flow. Addition of complexity without
proper parameterization can evidently decrease prediction
accuracy. An improper balance between these factors can
lead to distortions in brain current flow of an order of
magnitude or moreduncontrolled additional complexity
can in fact induce distortion. We thus emphasize that the
most appropriate methodology (ranging from concentric
spheres to individualized models) ultimately depends on
the clinical question being addressed.
The clinical research of tDCS
Studies in nonhumans (Preclinical)
Previous animal studies have assessed safety limits of tDCS
current intensity. In one study, 58 rats received tDCS with
varying current densities for up to 270 minutes and
histologic evaluation was conducted to assess neuronal
lesion. Results suggest that brain lesions occurred when
current density was at least two orders of magnitude higher
than typically used in humans88and may reflect increase in
brain temperature never observed using conventional tDCS
protocols.14Another interesting insight from this study is
that duration of tDCS only becomes a safety issue when
the intensity of stimulation is near the threshold associated
with neuronal lesion. Other animals studies conducted with
different goals have also shown that tDCS used with
charges similar to human studies do not induce histological
Finally, animal studies are useful for test dosing and
exploring physiologic aspects of tDCS mechanisms. In
contrast, such studies are rare, and positioning of the
electrodes as well as different cortical architecture, might
be critical. Still, animal models might be important for
answering specific questions not possible to be done in
Studies on healthy volunteers (Phase I)
In drug-based trials, phase I studies are nonrandomized,
noncontrolled clinical (human) trials designed to address
safety and optimal dosage of drugs. This is performed by
assessing the adverse effects/safety and dosage or the drugs.
In this section, previous tDCS studies that address these
questions and present issues that remain unsolved (dose
parameters was above discussed) are reviewed (Table 2).
Although tDCS differs in many aspects from other
noninvasive neuromodulatory therapies in that it does not
induce neuronal action potential and uses weak electric
currents, there are safety concerns that must be addressed.
If the electrochemical products generated by these currents
contact the skin, skin irritation may occur; in addition,
tissue heating associated with nonintact skin (therefore this
is especially important in people with skin diseases and/or
in protocols using daily tDCS applications and/or high
electric currents) may induce skin burning92dalthough
mild redness is more likely related to local, vasodilatation
skin changes rather than skin damage.93In fact, considering
there is no direct contact between the brain and the elec-
trode and also the distance, electrochemical or heating
lesions to the neuronal tissue is less likely. Moreover,
experimental and modeling studies suggest no significant
temperature increases for typical tDCS protocols.7,71,73
TDCS has been tested in thousands of subjects world-
wide with no evidence of toxic effects to date. In addition to
the hundreds of studies exploring tDCS effects in diverse
contexts, some studies have focused specifically on safety.
For instance, in a large retrospective study, Poreisz et al.94
reviewed adverse effects in 77 healthy subjects and 25
patients who underwent a total of 567 1 mA stimulation
sessions. Results show the most common effects were
Clinical research with tDCS181
Main issues in the clinical research of tDCS and possible solutions to effectively handle them
Current evidenceKey issues Possible solutions
Phase I studies
Safety/adverse effects TDCS is not likely associated to long-term,
deleterious effects. AEs are mild and transient
at usual doses.
Higher doses, higher current densities and higher
periods of stimulation seem to be associated
with effects of larger magnitude and duration.
Safety has not been sufficiently investigated in
people with skull defects and/or patients with
Great between-subjects variability of effects;
using higher doses is limited due to AEs;
pharmacotherapy alters dose-effect curve;
optimal parameters not yet defined.
Further research should actively investigate
adverse effects; long-term follow-up; modeling
Further research addressing pharmacological
modification of tDCS effects; increasing
duration span of tDCS to avoid skin damage;
bayesian approaches and modeling studies to
define optimal dose.
Phase II/III studies
Recruitment TDCS is still on its infancy, and few patients and
physicians are aware of this novel technique.
Non-referral due to lack of knowledge/
suspiciousness of tDCS and time constraints in
ambulatory settings; ethical issue of receiving
Sources of heterogeneity are: concomitant use of
medications, incorrect diagnosis of
neuropsychiatric condition, wide spectrum of
severity and refractoriness.
Daily visits to the research center and skin
damage are specific issues related to dropout in
Using multiple referral sources; specific
neuromodulation ambulatories; building trust
with volunteers and physicians (lectures, web
sites, explanatory videos).
Stratification during randomization; post-hoc
analysis controlling for severity, refractoriness
and medications; drug washout.
Eligibility Sample should be homogeneous, especially in
phase II studies.
Attrition High attrition rates might lead to negative
findings; especially if intention-to-treat
analyses are performed.
Careful explanation of study objectives and
possible side effects; covering of
transportation costs; flexible schedules; using
run-in period to identify noncommitters.
Blinding Blinding is the strongest approach to minimize
bias. Sham TDCS involves applying an electrical
current for less than 30 seconds, as to mimic
intial side effects.
Several studies suggested that the sham method
is reliable, at least in healthy volunteers, with
intermediate-high doses and in one-session
studies. TDCS device can be turned off
manually (single-blinded, requiring another
person to evaluate subjects) or automatically
Number of sessions and time period between
stimulations are still undefined as well as the
extent of such effects after the initial sessions.
Further studies should explore whether this sham
method is reliable in other contexts, e.g. daily
stimulations for 5-10 days, higher doses and
nonna€ ıve subjects. Staff blinding should also
be more carefully evaluated.
Approach To induce long-lasting (days to weeks) effects,
tDCS must be delivered continuously
(usually daily for 5 to 10 days).
Long follow-up of subjects (months to years);
performing specific studies designed to
evaluate cumulative changing in cortical
excitability according to the number of
stimulations (and time between them).
Studies exploring mechanisms of tDCS could have
three groups; studies using tDCS as treatment
should prefer using a sham group.
Control group In tDCS research, the control group might be
either a sham-group or an active group in
which polarities are inverted.
The latter approach is an even more reliable
blinding method than sham; although it can as
well induce effects.
TDCS 5 transcranial direct current stimulation; AE 5 adverse effects.
Brunoni et al
mild tingling sensations (75%), light itching sensation
(30%), moderate fatigue (35%), and headache (11.8%);
and most of these effects did not differ from those of
placebo stimulation. In another study, 164 sessions of stim-
ulation were analyzed. Authors found only mild adverse
effects with a low prevalence (0.11% in active and 0.08%
in sham stimulation group).95Other initial studies90,91,96-99
also reported only mild, benign, and transient side effects.
In fact, the most severe adverse event reported is skin
lesions on the site of electrode placement.92
Historically, the most severe adverse effect was observed
in the first study of tDCS. During the 1960s Lippold and
Redfearn66related a brief respiratory and motor paralysis in
a bifrontal electrode montage with the current reference
placed on the leg. No loss of consciousness was reported
and respiration returned to normal when the current was
stopped. This was attributed to the fact that the subject
received 10 times the intended intensity, probably 3 mA.27
General exclusion criteria for noninvasive brain stimu-
lation also apply for tDCS. Subjects must be free of unstable
medical conditions, or conditions that may increase the risk
of stimulation such as uncontrolled epilepsy; although
epileptic seizures have not been observed in a pilot study
with patients with active epilepsy.100Also, subjects must
have no metallic implants near the electrodes.
Finally, it should be underscored that most of these
observations were extracted from single stimulation studies
in healthy subjects without medications. Less is known
about the adverse effects of daily (or even twice daily) tDCS
in patients with neuropsychiatric disorders who use phar-
macotherapy. In such conditions, the adverse effects can
be magnified and therefore they should be actively inquired
during trials. For instance, some single-patient studies
report that tDCS can induce mania/hypomania in patients
with major depression.101-103Therefore, we suggest that
a medical monitor should supervise tDCS treatment in
such contexts of increased risk of significant adverse effects.
TDCS dosage is defined by the following parameters: (1)
current dosage (measured in amperes); (2) duration of
stimulation; and (3) electrode montage (size and position of
all electrodes). Current density (current dose divided by
electrode size) is also an important parameter in considering
dosage; especially for defining safety58; see the following
trode sizes are of 25-35 cm2with currents of 1-2 mA (gener-
ating densities ranging from 0.28-0.80 A/m2) for up to 20-40
minutes. However, the current that effectively reaches
neuronal tissue depends on other less controllable factors.
These include skin resistance, skull resistance, resistance of
intracranial structures(eg, bloodvessels, cerebrospinal fluid,
neurons, white matter, and so on). Moreover, patients with
and others106) and/or presenting neuropsychiatric disorders
(eg, major depression,107schizophrenia,108fibromyalgia,109
migraine,110and others); an issue that is likely to interfere
with the chosen dosage. Finally, other variables influence
baseline cortical excitability such as gender,111age,112and
smoking.113Hence, the same amount of current is likely to
For instance, one study showed that low (25 mg) and high
(200 mg) doses of l-dopa abolished tDCS-induced effects
on cortical excitability, whereas an intermediate (100 mg)
dosage increased inhibitory effects.114Notwithstanding,
cated in other contexts and samples, especially in clinical
Therefore, in the context of clinical research, such
enough, may result in negative findings. To avoid this, one
alternativeistostandardize the source of error inthe sample.
For instance, using saline-soaked sponges to minimize skin
resistance (which can also be measured by an ohmmeter
adapted in the tDCS devicedsome devices do give the
resistance), excluding patients under pharmacotherapy, or
controlling when it is not feasible (eg, benzodiazepines),
avoiding sample heterogeneity using specific diagnostic
criteria, particularly when working with a small, neuropsy-
chiatric subject pool. Future studies addressing the interac-
to explore and identify which drugs do not interfere
with tDCS effects and which ones could block or enhance
Initial studies measuring brain excitability demonstrate
that currents as low as 0.28 A/m2present depolarizing and
hyperpolarizing effects.6,7In addition, phase I/II studies ad-
dressed the effects of varying dose and/or time of stimula-
tion on cortical excitability and/or neuropsychologic tasks.
Ohn et al.115tested the effects on working memory during
30 minutes of stimulation, showing that performance
increased in a time-dependent fashion. Other studies
showed the cognitive effects induced by tDCS are depen-
dent on the current intensity; demonstrating effects such
as enhanced verbal fluency improvement at 2 mA (versus
lower improvement at 1 mA)18; and working memory
improvement at 2 mA (versus no improvement at 1 mA)
(See Box 1 for other tDCS studies on cognition).116Never-
theless, it remains unclear whether there is a linear (dose
versus effect) curve associated with direct current stimula-
tion and the influence of each parameter (dose, current
density, stimulation duration) on these effects. It is known
that increasing current densities will increase the depth of
the electrical field, thus affecting different populations of
neurons. However, at greater intensity tDCS might be pain-
ful to the subjects. For these reasons, a more effective
approach designed to prolong tDCS effects is to increase
Clinical research with tDCS183
the stimulation duration as opposed to the current
Short applications (ie, seconds to a few minutes) of
anodal/cathodal tDCS result in excitability shifts during
stimulation but no after-effects. However, no long-term
effects are seen. In contrast, 10 minutes or more of
stimulation can elicit prolonged after-effects, which can
be sustained for over an hour.7,27,39The exact duration of
effects depends on the targeted cortical area and on the
type of variable assessed.
For clinical purposes, longer-lasting effects are crucial.
Single-dose tDCS interventions have relatively short-lived
after-effects. Multiple stimulation sessions are required to
induce a significant manipulation in synaptic efficacy.117,118
In fact, repeated sessions of tDCS may have cumulative
effects associated with greater magnitude and duration of
behavioral effects. For example, cathodal tDCS applied
over 5 consecutive days is associated with cumulative
motor function improvement lasting up to 2 weeks after
the end of stimulation. This is an effect which is not
observed when sessions are applied weekly (as opposed
to daily).98Whether this approach is appropriate to maxi-
mize and stabilize the electrophysiologic effects of tDCS
remains under investigation. The optimal repetition rate
and duration to promote tDCS-induced plasticity also
remains to be determined. In animal experiments, repetition
of tDCS during the after-effects of a first stimulation
session has been shown to enhance efficacy.32However,
repeated plasticity induction may result in homeostatically
driven antagonistic effects.119Recently, Monte-Silva and
coworkers118directly compared the effects induced by
single sessions of cathodal tDCS over the motor cortex to
the effects of repetitive stimulation during or after the
after-effects of the first stimulation. The results showed
that increasing cathodal tDCS duration (1 mA, with no
interstimulation interval) resulted in longer-lasting after-
effects, typically over 1 hour (tDCS duration from 9 to
18 min prolonged the after-effects from 60 to 90 minutes).
Interestingly, when the second stimulation was performed
during the after-effects of the first, a prolongation and
enhancement of tDCS-induced effects for up to 120
minutes after stimulation was observed. In contrast, when
the second session was performed 3 or 24 hours after the
first, tDCS effects on cortical excitability were mixed.
This was shown with a primary reduction or abolishment
of the initial effects of cathodal tDCS, followed by a later
reoccurrence of tDCS-induced cortical inhibition. Such
neurophysiologic evidence is indicative of a stimulation
timing-dependent plasticity regulation in the human motor
cortex. Understanding the interaction of the consecutive
stimulation protocols appears crucial to effectively target
spontaneous changes of cortical activity and excitability
(See Box 2 for a discussion on ‘‘offline’’ vs. ‘‘online’’ stim-
ulation). Hence, implementing more effective procedures
of plasticity induction procedures in clinical settings is
crucialdin fact these results need to be replicated in
Studies on patients with neuropsychiatric
conditions (Phase II/III)
Phases II and III studies relate to using an intervention in
clinical samples. Phase II studies are typically small and use
targeted samples to obtain additional information regarding
optimal parameters of stimulation. Phase III are pivotal
Insight from tDCS studies on cognition
TDCS has been increasingly used to transiently modify cognitive functions in the healthy human brain. This field
presents an exciting opportunity to extend the application of tDCS from a neuroscience research tool to the potential
treatment of cognitive impairments. Indeed, the understanding of how to successfully manipulate cortical excitability
for the formation of new memories or the acquisition of new skills could fill an important gap between phase I and II
clinical studies. TDCS studies have shown that anodal tDCS delivered over the dorsolateral prefrontal cortex facilitate
visual working memory.16Conversely, cathodal stimulation had a detrimental effect on short-term auditory memory
performance.76Regardless of polarity, tDCS over the cerebellum disrupts practice-dependent improvement during
a modified Sternberg verbal working-memory task,50whereas intermittent bifrontal tDCS impairs response selection
and preparation in the same task.77Moreover, anodal tDCS to the anterior temporal lobes delivered before the
encoding and retrieval phase was effective in reducing false memories, whereas maintaining veridical memories.78
Finally, the application of anodal tDCS during slow-wave sleep improved declarative memory consolidation.79Further
effects of tDCS on cognitive functions in healthy individuals have been shown for decision-making,80,81probabilistic
classification learning,82attention,83-85and language.86,87Overall, these studies focused on the short-term improve-
ments in performance induced by a single session of stimulation, typically delivered online during the task or imme-
diately before it. The main limitations are the lack of control conditions over different cortical areas and the lack of
a systematic monitoring of the duration of the effects. The effects of repeated applications of tDCS, their interaction
with specific learning stages and tasks and the extent to which these performance improvements are retained in the
long-term remain to be addressed. Hypothesis-driven behavioral paradigms or stimulation strategies are also necessary
to further explore the functional role of different cortical areas in human learning.
184 Brunoni et al
studies, involving larger samples. In the United States, two
positive phase III trials are required for approving a drug or
device by the Food and Drug Agency (FDA) (See Box 3 for
phase II/III studies in major depression).
As mentioned previously, several studies have explored
the therapeutic application of tDCS in several neuropsy-
chiatric disorders. The results of these studies reveal long-
lasting tDCS effects and have promoted its use in clinical
settings. Because clinical development of tDCS is being
conducted mainly in academia, studies are not widely
standardized regarding variables and population samples,
therefore limiting conclusions. These findings are also
limited by small sample sizes and experimental design. In
fact, a similar scenario has been observed for TMS 5 to 10
years ago.120This section aims to comprehensively review
the main issues of the later phases of clinical trial develop-
ment for tDCS.
Issues related to recruitment and eligibility
Recruiting subjects for tDCS clinical trials presents a chal-
lenge. Proposing an intervention alternative to the main-
stream pharmacotherapy might be seen by prospective
patients and referring physicians in nonacademic settings
as suspicious. This issue can be particularly important when
a large sample size is required and/or if the eligibility criteria
exclude refractory patients who are more prone to enroll in
research protocols. Likewise, referral physicians, due to time
constraints in the ambulatory setting, usually prefer to treat
drug-na€ ıve patients themselves. Indeed, daily visits for 1-to-
2 weeks to research centers might sound unappealing and/or
unaffordable even to refractory patients. In such contexts, it
is advisable to have multiple referral sources and to use
broad recruitment strategies. Building trust with potential
volunteers is imperative. One cost-effectiveness approach
could be using explanatory videos in lay language.26
Another issue is sample heterogeneity. In pivotal clinical
trials comparing tDCS against pharmacotherapy, large
samples are typically required and patient heterogeneity
might be larger than for drug trials for the same condition.
This is due to the fact that the severity of the condition
ranges from drug-na€ ıve to refractory subjects. Targeting
only the former would create difficult enrollment (for the
reasons mentioned previously), although targeting only the
latter decreases overall generalizability. Possible solutions
include stratification during randomization (refractory
versus nonrefractory), post hoc analysis controlling for
refractoriness, or increasing sample size to address some of
the issues associated with heterogeneity.
It appears easier to conduct sham-controlled trials using
tDCS compared with TMS. TMS induces itching and pain
sensations over the stimulation site, whereas tDCS induces
a mild tingling sensation that usually rapidly fades.
Therefore, sham protocols begin with active tDCS, which
is switched off within a minute. In addition, the tingling
sensation relates to the velocity in which the current is
either increased or decreased. In fact, an increase of current
delivery from 0.1 to 0.2 mA/s generates no discomfort for
most subjects.121Interestingly, some subjects in the sham
group continue feeling some tingling even after the current
These sensations are related to the total amount of
charge delivered. Although this has yet to be systematically
evaluated, this relationship can be a potential issue when
delivering relatively high charges (.1.5-2 mA/s) and/or
higher current densities. There is evidence that electrolyte
solutions with lower NaCl concentrations (15 mM) are
perceived as more comfortable during tDCS than those
solutions with higher NaCl concentrations (220 mM).
Two types of study design in tDCS: ‘‘Online’’ versus ‘‘Offline’’
Clinical researchers usually apply tDCS in two main modalities regarding the time point in which the primary outcome
variable is collected. When tDCS and the main outcome are coincident in time (ie, when the variable is collected during
tDCS application) the experiment is said to test the ‘‘online’’ effects of tDCS. The concept is also used when another
intervention (usually having a similar time span than tDCS such as physical therapy) and tDCS are applied
simultaneously. The rationale for an ‘‘online’’ approach is to take advantage of the putative property of tDCS to
induce excitability modifications of the brain (which is analogous to TMS) to test neuromodulatory effects on the study
hypothesis, such as alterations of brain functions during tDCS. For instance, an area of investigation that uses this
approach is transient modulation of moral judgment and decision making during tDCS (see Discussion on ethics in this
On the other hand, when tDCS and the variable being measured can be distinguished in time, it is said that the
experiment is applying tDCS in an ‘‘offline’’ protocol. An ‘‘offline’’ tDCS protocol applies, for instance, when one
surrogate outcome (or clinical parameter) is used before and after stimulation to index tDCS effects (see Discussion on
surrogate outcomes). An ‘‘offline’’ approach is also used in phase II/III tDCS studies. In such cases, tDCS is an
experimental intervention and its long-term, neuroplastic effects are indexed with one or more surrogate and/or
Clinical research with tDCS185
Because the ionic strength of deionized water is much less
than that of all NaCl solutions, there is a significantly larger
voltage required to carry current through the skin compared
with NaCl solutions. Thus, it is recommended the use of
solutions with relatively low NaCl concentration, in the
range 15 mM to 140 mM, as tDCS at these concentrations
is more likely to be perceived as comfortable, requires low
voltage and still allows good conduction of current.122It
has also been proposed to apply topical anesthetics to alle-
viate this issue.27
An additional blinding issue is the local vasodilatation
after tDCS. This causes the skin to turn red that might not
be acknowledged by the subject but might be seen by the
staff and other patients. In clinical protocols, such redness
can be evident after several days of stimulation. This can
become a logistical issue, demanding stimulated patients to
leave the setting immediately, avoiding contact with other
people (patients and researchers) as to avoid blinding
breaking. Another approach would be to interview patients
before (and not after) being stimulated. If a rater notices
evidence of redness on the scalp of a patient, another
blinded rater should substitute him/her, although this matter
is more important in sham-controlled studies as in studies
using active groups differing only regarding polarity (and
not scalp site of stimulation) cathodal and anodal stimula-
tion cannot be distinguished between each other. Also, 30
seconds of active stimulation in the sham protocols might
also lead to local redness.
Clinical protocols should assess post hoc the effective-
ness of blinding; though investigators need to be aware that
potential differences might occur because active tDCS is
more effective than sham tDCS. It is not easy to detangle
unblinding versus response because effectiveness. Other
alternatives are (1) to avoid crossover trials, especially
when the crossover happens in the same section, as to avoid
subjects noticing the differences; (2) to apply active
protocols but switching polarity so that adverse effects do
not threaten blinding even if noticed, although the issue
would be whether changing polarity would be an appro-
priate control condition, when the reference electrode is not
Four approaches in tDCS clinical trials for neuropsychiatric
disorders are possible: (1) to compare active versus tDCS
sham in a superiority trial; (2) to compare tDCS versus
another therapy (eg, acupuncture, pharmacotherapy) as
a superiority or noninferiority trial; (3) to combine tDCS
with another therapy (eg, physical therapy, pharmaco-
therapy) versus sham tDCS and another therapy as
a superiority trial; and (4) combination of these approaches.
Two-arm designs are suitable when comparing active
versus tDCS sham, an approach commonly used in pilot,
‘‘proof-of-concept’’ studies. This approach is effective in
studies exploring the mechanisms of action of tDCS, for
example, with neuroimaging or serum measurements.
In the past 10 years, several trials applied tDCS to subjects with major depressive disorder (MDD). Fregni et al.124
performed a pilot randomized, sham-controlled, double-blind trial in which 10 patients were randomly assigned to
receive either 5 days of active or sham stimulation. Boggio et al.62also enrolled 40 MDD subjects with different
degrees of refractoriness (but medication-free) and randomized them to 10 sessions of active dorsolateral prefrontal
cortex (DLPFC) tDCS, active occipital tDCS or sham tDCS. The findings suggested that the active DLPFC tDCS group pre-
sented a superior, significant improvement in HDRS scores compared with the other groups. Rigonatti et al.90
demonstrated in an open-label study that Fluoxetine 20 mg/d and active tDCS (from patients of Boggio’s study) pre-
sented similar scores after 6 weeks of treatment. Ferrucci et al.91stimulated 14 patients with severe MDD using 2 mA for
20 minutes for 5 days twice a day, showing a significant improvement in mood. Such effects seem to be more robust in
more severe patients.125Loo et al.99enrolled 40 patients with severe MDD, in a double-blinded, sham-controlled study
but failed to demonstrate significant difference between groups in this phase; tDCS was only more effective during the
open-label phase in which patients received additional five sessions. However, this study has some limitations: the
dose applied was relatively low (1 mA), and only five stimulations sessions were held, which were alternated (other
studies used consecutive sessions). Moreover, patients with axis II disorders were not excluded. Finally, Brunoni
et al.126compared patients with unipolar versus bipolar depression and found that tDCS might be a potential
treatment for both conditions. However, as with phase II trials, these studies share common characteristics:
relatively small sample sizes, heterogeneous sample (eg, refractoriness, medication use), blinding vulnerability
(some studies were open-label), absence of primary hypothesis (most of them used several depression rating scales),
and presence of ‘‘carryover’’ effects (in crossover studies). These initial trials likely incurred in some false-positive and
false-negative results; nevertheless, they revealed the potential effectiveness of tDCS for major depressive disorder.
Finally, a search made on clinicaltrials.gov in September 2010 revealed that there are at least seven trials exploring
the antidepressive effects of tDCS worldwide; and the design and methods of one of them127has been recently
Insights from tDCS studies for major depression
186 Brunoni et al
Three-arm and ‘‘double-dummy’’ (ie, placebo pill 1
activetDCSversuspharmacotherapy 1sham tDCS)designs
are adequate for comparing tDCS against another therapy.
The placebo arm is interesting for increasing assay sensi-
groups when there are reasons to believe that treatment
efficacy among study arms is imbalanced (principle of
useful to test tDCS with and/or against another therapy of
interest.Forinstance,inatrialtestingtDCS forchronic pain,
pharmacotherapy, tDCS, and pharmacotherapy and sham
plus placebo. In fact, such a design is the most robust as it
tests two interventions simultaneously and also one inter-
vention against another, making them optimal for pivotal
studies. Although comprehensive, this approach is more
demanding regarding resources, sample size, and logistics.
The n-of-one (n 5 1) trial is a possible approach when
the researcher is confident that tDCS effects are short-
lasting (which is not usually the case for studies using
multiple sessions of tDCS). In this design, one subject is
randomized to receive repeated randomized allocations of
the tDCS treatment. This is helpful especially to address
different parameters of stimulation for single session
Attrition (or ‘‘dropout’’) is the premature discontinuation of
participation in a trial occurring either immediately after
the baseline visit or at any time before endpoint. The
specific reasons for attrition in tDCS trials should still be
investigated. Although some might be the same for
pharmacotherapy, one reason more specific for tDCS trials
is the difficulty to comply with required daily visits to the
research center (that usually occur during the first 2 weeks
of the study). In intention-to-treat trials, this issue can be
particularly perturbing as such subjects will maintain the
same baseline scores at endpoint and thus diminish the
effect size between groups. To avoid attrition in tDCS trials,
some measures can be taken such as: (1) concede one or
two nonconsecutive missing visits, which are replaced at
the end of the daily stimulation phase and (2) using a ‘‘run-
in’’ period, that is, a phase before trial onset in which
subjects receive either active or placebo/sham treatment
(usually for 1 week) as a method to preemptively screen
and discard nonadherent subjects. Although the usefulness
of run-in phases is controversial in pharmacotherapy given
the potential for selection bias, the rationale for using tDCS
is to select subjects that can commit to the stimulation
Finally, although uncommon, another issue is skin burn.
This would prevent further stimulations, breaking blinding,
and also forcing the investigators to withdraw treatment,
leading to a study dropout. Skin burning can be avoided by
diminishing electric density (ie, increasing electrode size
and/or diminish electric current) and electric resistance (by
using rubber electrodes involved with saline-soaked
sponges) over the stimulation site.
Being that most tDCS trials are exploratory and using small
samples, they are particularly vulnerable to type I and type
Type I (false-positive) errors occur in exploratory studies
performing several statistical tests, being the case of many
phase II tDCS trials. In this scenario, investigators need to
decide whether to claim findings as exploratory or to
determine a priori the statistical method for the primary
outcome, differentiating other statistical analyses as
Type II (false-negative) errors occur in small studies and
are related to underpowered trials. Again, most phase II
tDCS trials recruit small samples and are prone to this error.
To avoid this, researchers must perform sample size
calculations when designing the trial. Another approach is
to use adaptive designs, which allow sample increasing
during the study, although this method may be challenging
for researchers and readers to interpret the data. In this
context, given that most of tDCS trials are conducted with
limited resources, the best choice of primary study outcome
statistical power (and consider other analyses as secondary).
Although baseline differences are usually not significant in
tDCS trials probably because trials have a relatively homo-
geneous population, one option is to calculate normalized
differences from baseline. In this case a simple approach to
calculate sample size is to use independent two-sample t test
provided in most statistical software packages.
Pilot versus pivotal studies for tDCS
Most phase II studies are also referred as ‘‘proof-of-
concept’’ or ‘‘pilot’’ studies. These studies typically use
small, high-targeted samples that represent the more severe
spectrum of a disease to address the efficacy of a given
treatment in optimal conditions. They also use several
surrogate endpoints and perform many exploratory anal-
yses. Exploratory phase II studies are necessary as they
provide data to be used in subsequent trials. Furthermore,
data of small studies can be pooled together in metaanal-
yses. However, the validity of these analyses can be
contested when approving clinical interventions.128,129
An additional challenge for pilot studies is the explor-
atory nature and thus an important degree of risk regarding
outcomes that is normally not seen in animal models in
neuromodulation research. This hinders the ability to test
the clinical efficacy of tDCS for a particular condition for
the first time. In such context, a negative finding might be
due to tDCS parameters or a poor neurobiologic model (eg,
a negative finding in a pain trial with anodal stimulation
over the DLPFC area might represent, besides being a true-
negative, either the use of incorrect tDCS parameters,
Clinical research with tDCS187
a misconception in the neurologic model; thus the DLPFC
area being unrelated to pain pathophysiology). This issue
poses an additional challenge in tDCS research.
Therefore, pivotal (phase III) studies are necessary to
validate tDCS as an effective treatment when proof-of-
concept trials showed encouraging results. Future phase III
studies should include: (1) sample size estimation based on
prior, pilot trials or metaanalyses; (2) robust blinding
method (eg: using tDCS devices that can be automatically
turned off as to keep both patients and appliers unaware of
the intervention delivered) and (3) assessment of sample
heterogeneity, either targeting particular samples (eg,
medication-free patients) or identifying potential sources
of heterogeneity (eg, degree of refractoriness, number of
depressive episodes, depression severity, and others) and
controlling for them during study design (stratified random-
ization approaches) or statistical analysis.
Although several definitions for surrogate (or substitutive)
outcomes exist, they are typically understood as laboratory
outcomes for being in a prior step in the pathophysiologic
pathway of the disease.130In neuromodulation research,
this also includes neuropsychologic tests and neuroimaging
scans. The advantage of using surrogate outcomes is avoid-
ing long-term, expensive research. This is achieved by
substituting ‘‘hard’’ outcomes (death or serious events) for
‘‘soft’’ measurements that take place earlier. Furthermore,
surrogate outcomes must have high accuracy and low vari-
ability; otherwise their utility is limited (Table 3).
One surrogate outcome that is often used is TMS-
indexed cortical excitability, a neurophysiologic measure-
ment. According to the protocol used, it indexes and detects
changes in brain activity.131For instance, measurement of
motor thresholddthe lowest intensity to elicit motor-
evoked potentials of more than 50 uV in at least 50% of
trialsdis used for studying whether different tDCS proto-
cols change motor cortical excitability. Also, measurement
of the silent perioddthe period of electromyographic
suppression (or voluntary muscle activity) after one single
suprathreshold TMS pulsedcan be also used for addressing
whether and how tDCS affects the inhibitory cortical inter-
neurons that are recruited during this task. Moreover,
paired-pulse TMS is also used for studying inhibitory or
excitatory cortical mechanisms elicited after one supra-
threshold pulse and is another method that can be coupled
with tDCS for indexing cortical excitability. Nonetheless,
all these methods are limited to the motor cortex and thus
might not necessarily reflect net brain cortical excitability
and/or cortical excitability of specific brain areas.
Neuropsychologic tests are able to measure brain
activity in some areas, especially those that cannot be
indexed through TMS. Moreover, cognitive deficits are
a common consequence of brain injury, stroke, epilepsy,
neurodegenerative, and other neurologic disorders. Hence,
the rehabilitation of cognitive function, such as language,
spatial perception, attention, memory, calculation, and
praxisrepresents an expanding
rehabilitation and has recently attracted growing attention
within the scientific community. For instance, changes in
the activity of the prefrontal cortex can be measured
using tests of working memory and attention, whereas
working memory tests. A drawback of several neuro-
psychologic tests is the need of a control group to adjust
for learning effects biases. Performance is also influenced
by educational level and, therefore, the results of one
study might not be valid for similar samples in different
Neurophysiologic measurements are another possible
approach to surrogate outcomes. Besides TMS, brain
activity can be measured using electrodes, which can be
interpreted using several methods. These include the qual-
itative EEG, which measures spontaneous neuronal firing;
the event-related potentials (ERPs), which modifies accord-
ing to the brain area provoked; the quantitative EEG
(qEEG), which maps brain activity; and, finally, new
approaches that provide a three dimensional brain imaging
based on electromagnetic reconstruction of the brain (which
in fact are not widely accepted due to the ‘‘inverse problem
solution.’’ For a review on this topic, see Pascual-Marqui
et al.132). Such measurements lack specificitydsimple
psychological, cognitive, or motor task recruits several brain
networks and thus the measured ERP can be an epiphenom-
enon of another brain region rather than a relevant finding
(ie, a ‘‘noise’’ and not a ‘‘signal’’). Another issue is that
the devices measuring brain activity must be adapted to
decrease the electrical noise generated by the tDCS device;
or, alternatively, the measurement must be collected either
before or after (but not throughout) tDCS delivery.
Neuroimaging methods are divided into two branches:
the first uses radiotracers and is represented by the positron-
emission tomography (PET) and the single-photon emis-
sion computed tomography (SPECT), which assess brain
metabolism through the emission of gamma rays. The
advantage of PET/SPECT in tDCS research is that the
radiotracer can be injected during brain stimulation, thus
providing ‘‘real-time’’ brain imaging. However, the spatial
resolution of such methods is poor. Because they obligatory
require using radiotracers, the radiation dose needs to be
carefully controlled and monitored. The second branch of
neuroimaging is the MRI. This technique presents high
approaches for MRI, which allows evaluation of different
aspects of brain activity. For example, functional MRI
(fMRI) explores the paramagnetic properties of hemoglobin
to infer brain metabolism (based on blood oxygen satura-
tion), whereas magnetic resonance spectroscopy (MRS)
analyzes the magnetic fields of relevant molecules (eg,
glutamate, GABA) and provides a noninvasive ‘‘chemical
biopsy’’ of the brain. Some of these techniques such as
188Brunoni et al
Substitutive outcomes used in tDCS research
Outcome DefinitionPros Cons
Neuropsychologic tests Paper or computerized tests that explore
Nonexpensive, relatively easy to apply,
specific tests can be used according to
the brain area under study.
Low signal-to-noise ratio, as performance
depends on the rater, the subject’s
characteristics (age, educational level);
learning effects, thus requiring a control
group. Relatively nonspecific.
Relatively nonspecific (measurement of
several brain networks) and medium to
low spatial relationship. Devices should
be adapted to minimize electrical noise
Measures obtained with TMS have
considerable intra and inter-subject
variability; usually applied over the
motor cortex only.
Poor spatial resolution, invasive, PET is
expensive and not always available
(requires a cyclotron).
Analyses are difficult and can yield false-
positive results, expensive, not always
available, tDCS devices and MRI cannot
be used simultaneously.
Minimal spatial resolution (brain
metabolites are usually not specific of
a particular area), low temporal
resolution (metabolites must cross the
BBB), lack of important biologic blood
markers in neuropsychiatry.
Neurophysiologic measurements Techniques that record electrical brain
activity (EEG, qEEG,ERP) as to examine
changes in brain activity.
Strong temporal relationship (ie, very
sensible to change), able to index
Transcranial magnetic stimulation (TMS)TMS used as a tool to index cortical
Relatively affordable and easy to apply,
provide several measures of cortical
Neuroimaging methods-radiotracers Methods such as PET and SPECT that use
radioactivity to assess brain
MRI-based analyses (e.g. functional,
structural, spectroscopy, DTI) that
provide static and dynamic
Blood measurement of substances
expressed by the CNS that cross BBB.
Good temporal relationship, able to index
subclinical changes, can be used during
Not-invasive, excellent spatial and
temporal resolution (according to the
MRI-based neuroimaging methods
Blood chemistry Minimally invasive, easy to perform,
samples can be frozen and analyzed
later, gives a quantitative measurement,
sensible to change.
tDCS 5 transcranial direct current stimulation; EEG 5 electroencephalography; qEEG 5 quantitative EEG; ERP 5 evoked-related potentials; PET 5 positron-emission tomography; SPECT 5 single photon
emission computed tomography; MRI 5 magnetic resonance imaging; DTI 5 diffusion tensor imaging; CNS 5 central nervous system; BBB 5 blood-brain barrier.
Clinical research with tDCS
fMRI lack temporal resolution as it does not measure
electrical activity changes directly (it does indirectly via
changes in cerebral flow). Diffusion tensor imaging (DTI)
focuses on the white matter fibers, revealing the neural
connectivity between brain areas. Finally, voxel-based
morphometry (VBM) is a computational analysis of
morphologic images that makes inferences about brain
activity based on the differences of brain tissue concentra-
tion among areas. For tDCS, these methods present the
advantage of high spatial resolution; allowing to assess
subtle changes in the stimulated area. For instance, one
study used VBM to assess neuroplastic changes after 5 days
of TMS over the superior temporal cortex; showing
macroscopic gray matter changes in the region.133Even
though, the reliability of some methods of MRI are
currently under dispute.134Moreover, tDCS is not used
concomitantly with MRI yet due to serious risks of over-
heating and thus an ‘‘online’’ visualization of the stimulated
area is not possible although this technical difficulty might
be resolved in the near future.
Finally, there is a wide range of blood measurements
used in neuropsychiatry research for surrogate outcomes.135
One biomarker under intensive investigation is the brain-
derived neurotrophic factor (BDNF). This marker plays an
important role in synaptogenesis and neuroplasticity and
ders, for instance, BDNF serum levels are low in depressed
patients and increase after antidepressant treatment.136A
recent study showed BDNF expression also increases
after tDCS.8Additional biomarkers used in neuropsychiatry
include inflammatory proteins such as interleucin-1, interleu-
cin-6, and TNF-alpha137; hypothalamic-pituitary-adrenal
activity, which is measured by serum and salivary cortisol138;
and oxidative stress proteins such as nitric oxide and other
neuroinflammatory protein markers.139,140These biomarkers
present two important drawbacks: first, because of the
blood-brain barrier, serum levels might not reflect ‘‘real-
time’’ brain activity (or even brain activity at all); second,
serum levels can only express the net brain activity, and do
not represent a specific area. Therefore, perhaps the most
in phase II/III studies (Also see Box 4 for a discussion on
TDCS in children
As the brain is under intensive development during child-
hood and adolescencedparticularly
cortex,141intensive research is currently being made to
explore how cognition, emotion, behavior, and other
Challenges for outcome measures in tDCS clinical research
As neither the full spectrum of clinical efficacy nor the mechanism of action of tDCS are completely described, outcome
measures for tDCS trials ideally will inform both about tDCS clinical potency and about the biology of tDCS. With respect
to clinical data, the common accepted behavioral outcomes might be insensitive to subtle changes in neurologic
function. This is particularly relevant for tDCS as it has a modest (perhaps subclinical) neuromodulatory and behavioral
effect, particularly for single exposures. Thus in the present early stages of investigation, the field of study may benefit
from clinical trial designs that incorporate secondary outcomes in addition to measures of the patient’s chief symptom.
Among these are changes in normal function that may be affected by tDCS. For example, an investigator testing tDCS
effects on chronic pain might add a battery of motor tasks to see whether there is any subtle loss of normal function
with treatment. Similarly, an investigator applying tDCS for treatment of epilepsy may add a questionnaire to assess
Further, prospects for improving tDCS clinical efficacy improve if the tDCS mechanism of action is better understood. To
date, the common feature in tDCS trials appears to be its capacity to produce a lasting change in regional cortical
excitability. Given these data, outcome measures aimed to capture the extent to which tDCS induces synaptic plasticity
may also be useful additions to ongoing trials. That is, one could ask whether tDCS improved the symptom in question,
and in parallel ask whether an LTP-type or LTD-type change in regional cortical excitability has occurred. If so, then
perhaps in future trials, the tDCS effect may be augmented by the addition of appropriate pharmacologic agents or
behavioral tasks that facilitate synaptic plasticity. As an example, in future trials in which cathodal tDCS may be applied
over an epileptic seizure focus, whether LTD-type suppression has occurred over the stimulated area can be determined
within hours of tDCS. However to find out whether seizures are reduced in frequency may take days to weeks. Thus
subjects can be stratified into groups that have or have not undergone regional LTD, and clinical outcomes can be
evaluated separately for subjects that did and did not experience regional depotentiation. This subclassification of
subjects in an epilepsy trial would potentially reduce confounding results from subjects where tDCS was not biologically
effective at the time it was administered. In addition, investigators would be wise to bear in mind the potential pitfall
of choosing outcome scales that are not sufficiently sensitive to capture a relatively modest clinical tDCS effect. Thus, if
tDCS strongly changes a component of a larger clinical scale, further research can be stimulated, even if negative results
were found initially.
190 Brunoni et al
functions evolve. Having neuromodulatory properties,
tDCS would be an interesting tool to explore which brain
areas are particularly important in each stage of develop-
ment both in healthy and pathologic conditions, such as
epilepsy, cerebral palsy, autism, and mental deficiency.
However, because of its potential to induce neuroplastic
changes, tDCS should be used carefully especially during
important phases of brain development associated with
intensive plasticity and also other processes such as
A further step would be using tDCS for treating
neuropsychiatric disorders in children, but this has not
been tested yet. In a review of TMS studies in children, no
adverse effects were reported, but its use is still limited for
some reasons, including lack of established safety guide-
lines.142Notwithstanding, tDCS is a promising tool for
children neurology and psychiatry.
The ethics of tDCS
TDCS is a putative candidate for adjuvant therapy for
a range of neuropsychiatric conditions. tDCS is a valuable
tool in neuroscience research, as its focality can be used
to explore several brain aspects. Studies regarding tDCS
ethics reveals its ability to induce changes in behavior
such as in moral judgment,143deception,144,145and decision-
making.146For instance, one recent study showed tDCS
affected utilitarian behavior. Similarly to other studies in
tDCS, the polarity-dependent effects resulted in a selfish
versus selfless behavior in women.143Although the effects
were short-lasting (volunteers were not exposed to daily
stimulation), the targeted area is similar than used in studies
exploring the long-lasting tDCS effects. Therefore, the
ethical concern is whether tDCS could induce maladaptive
behavior changes, and if so, to what intensity and extent of
Diverse tDCS studies on healthy subjects have shown
positive changes in attention and memory.84,85,147From the
scope of neuroethics, the issue is whether tDCS enhances
cognition in healthy subjects. Can tDCS be used to boost
performance in specific situations (eg, before school tests)?
Another issue is that the cognitive effects described
(increased attention and memory) from tDCS are in some
aspects similar to amphetamines. Despite therapeutic appli-
cations, amphetamines are sold illegally as a recreational
and performance enhancer drug (with the suggestive
name of ‘‘speed’’). As a tDCS device is easily built and
inexpensive (contrary to TMS), it could also be used for
nonresearch and nontherapeutic objectives by lay people.
In fact, there are online videos in popular web sites such
as Youtube explaining how to build and use a tDCS
device.148Although it should be underscored that all the
enhancement effects were present for a short period, it is
possible that prolonged daily stimulation could increase
the time span of such effects, thus inducing maladaptive
changes. In contrast, other legal substances such as caffeine
are also frequently used as cognitive boosters.
In fact, because applications in these fields are currently
in the research stage, fixed protocols and safety guidelines
are yet to be defined. Research and development of any new
devices provides an opportunity for brain science and
clinical care to advance, and also challenges the medical
and wider communities to address potential dangers and
complications, ethical and moral quandaries, and issues of
healthcare economics and distributive justice. For innova-
tive neurotechnologies, these are major potential pitfalls to
look out for. Intervening in the brain is always fraught with
the potential for serious consequences. Despite these
concerns, only by conducting carefully planned clinical
and experimental studies can we provide the impetus to
advance care for people with brain, emotional or psycho-
logic, or neuropsychiatric disorders.
The current paper addresses the main aspects of the clinical
research of tDCS. This technique has a wide range of
potential applications and can be used to explore the basic
aspects of neurosciences as well as for the treatment of
neuropsychiatric disorders. TDCS has unique characteris-
tics such as ability to induce antagonistic effects in cortical
excitability according to the parameters of stimulation;
concomitant (‘‘online’’) use with neuropsychologic and
psychophysiologic tests; noninvasiveness and thus absence
of pharmacokinetics interactions, being a putative substi-
tutive/augmentative agent in neuropsychiatry; and low-cost
and portability, making it suitable for increasing access to
novel therapies. However, such characteristics also bring
challenges regarding clinical design, neuroethics and legal
issues. In this paper, we aimed to provide an overview of
tDCS in clinical research; thereby providing knowledge for
conducting proper clinical trials using this promising
We are thankful to Erin Connors for copyediting this
manuscript. We are also grateful to Scala Institute and
Mackenzie University (Sao Paulo, Brazil) for the additional
support to organize this working group meeting in the II
working group meeting was the 2nd International tDCS
club workshop, which took place in Sao Paulo, Brazil, in
March 2010, at the Social and Cognitive Neuroscience
Laboratory of Mackenzie Presbiterian University. The first
meeting was held in Milan, Italy in 2008. D.E. was
supported by NIH grant R21HD060999 and F.F. was
supported by NIH grant (5R21DK081773-03).
Clinical research with tDCS191
1. Largus S. De compositionibus medicamentorum. Paris1529.
2. Kellaway P. The part played by the electric fish in the early history of
bioelectricity and electrotherapy. Bull Hist Med 1946;20:112-137.
3. Zago S, Ferrucci R, Fregni F, Priori A. Bartholow, Sciamanna,
Alberti: pioneers in the electrical stimulation of the exposed human
cerebral cortex. Neuroscientist 2008;14(5):521-528.
4. Aldini G. Essai theorique et experimental sur le galvanisme.
5. Arndt R. Die electricitat in der psychiatrie. Arch Psychiat Nervenk-
6. Priori A, Berardelli A, Rona S, Accornero N, Manfredi M. Polariza-
tion of the human motor cortex through the scalp. Neuroreport 1998;
7. Nitsche MA, Paulus W. Excitability changes induced in the human
motor cortex by weak transcranial direct current stimulation.
J Physiol 2000;527(Pt 3):633-639.
8. Fritsch B, Reis J, Martinowich K, et al. Direct current stimulation
promotes BDNF-dependent synaptic plasticity: potential implications
for motor learning. Neuron 2010;66(2):198-204.
9. Nitsche MA, 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
10. Nitsche MA, Seeber A, Frommann K, et al. Modulating parameters
of excitability during and after transcranial direct current stimulation
of the human motor cortex. J Physiol 2005;568(Pt 1):291-303.
11. Kuo MF, Paulus W, Nitsche MA. Boosting focally-induced brain
plasticity by dopamine. Cereb Cortex 2008;18(3):648-651.
12. Wagner T, Fregni F, Fecteau S, Grodzinsky A, Zahn M, Pascual-
Leone A. Transcranial direct current stimulation: a computer-based
human model study. Neuroimage 2007;35(3):1113-1124.
13. Miranda PC, Lomarev M, Hallett M. Modeling the current distribu-
tion during transcranial direct current stimulation. Clin Neurophysiol
direct current stimulation. Clin Neurophysiol 2009;120(6):1033-1034.
15. Datta A, Bikson M, Fregni F. Transcranial direct current stimulation
in patients with skull defects and skull plates: high-resolution compu-
tational FEM study of factors altering cortical current flow. Neuro-
16. Fregni F, Boggio PS, Nitsche M, et al. Anodal transcranial direct
current stimulation of prefrontal cortex enhances working memory.
Exp Brain Res 2005;166(1):23-30.
17. Boggio PS, Alonso-Alonso M, Mansur CG, et al. Hand function
improvement with low-frequency repetitive transcranial magnetic
stimulation of the unaffected hemisphere in a severe case of stroke.
Am J Phys Med Rehabil 2006;85(11):927-930.
18. Iyer MB, Mattu U, Grafman J, Lomarev M, Sato S, Wassermann EM.
Safety and cognitive effect of frontal DC brain polarization in healthy
individuals. Neurology 2005;64(5):872-875.
19. Fecteau S, Pascual-Leone A, Zald DH, et al. Activation of prefrontal
cortex by transcranial direct current stimulation reduces appetite for
risk during ambiguous decision making. J Neurosci 2007;27(23):
20. George MS, Aston-Jones G. Noninvasive techniques for probing neu-
rocircuitry and treating illness: vagus nerve stimulation (VNS), trans-
cranial magnetic stimulation (TMS) and transcranial direct current
stimulation (tDCS). Neuropsychopharmacology 2010;35(1):301-316.
21. Fregni F, Pascual-Leone A. Technology insight: noninvasive brain
stimulation in neurology-perspectives on the therapeutic potential
of rTMS and tDCS. Nat Clin Pract Neurol 2007 Jul;3(7):383-393.
22. Nitsche MA, Boggio PS, Fregni F, Pascual-Leone A. Treatment of
depression with transcranial direct current stimulation (tDCS):
a review. Exp Neurol 2009;219(1):14-19.
23. Brunoni AR, Tadini L, Fregni F. Changes in clinical trials method-
ology over time: a systematic review of six decades of research in
psychopharmacology. PLoS One 2010;5(3):e9479.
24. Zhang X, Liu K, Sun J, Zheng Z. Safety and feasibility of repetitive
transcranial magnetic stimulation (rTMS) as a treatment for major
depression during pregnancy. Arch Womens Ment Health 2010;
25. Bolognini N, Pascual-Leone A, Fregni F. Using non-invasive brain
J Neuroeng Rehabil 2009;6:8.
26. Zaghi S, Acar M, Hultgren B, Boggio PS, Fregni F. Noninvasive
brain stimulation with low-intensity electrical currents: putative
mechanisms of action for direct and alternating current stimulation.
27. Nitsche MA, Cohen LG, Wassermann EM, et al. Transcranial direct
current stimulation: state of the art 2008. Brain Stimul 2008;1(3):
28. Priori A, Hallett M, Rothwell JC. Repetitive transcranial magnetic
stimulation or transcranial direct current stimulation? Brain Stimul
29. Bindman LJ, Lippold OC, Redfearn JW. Relation between the size
and form of potentials evoked by sensory stimulation and the back-
ground electrical activity in the cerebral cortex of the rat. J Physiol
30. Purpura DP, McMurtry JG. Intracellular activities and evoked poten-
tial changes during polarization of motor cortex. J Neurophysiol
31. Creutzfeldt OD, Fromm GH, Kapp H. Influence of transcortical d-c
currents on cortical neuronal activity. Exp Neurol 1962;5:436-452.
32. Bindman LJ, Lippold OC, Redfearn JW. The action of brief polar-
izing currents on the cerebral cortex of the rat (1) during current
flow and (2) in the production of long-lasting after-effects.
J Physiol 1964;172:369-382.
33. Jefferys JG. Influence of electric fields on the excitability of
granule cells in guinea-pig hippocampal slices. J Physiol 1981;
34. Bikson M, Inoue M, Akiyama H, et al. Effects of uniform extracel-
lular DC electric fields on excitability in rat hippocampal slices in
vitro. J Physiol 2004;557(Pt 1):175-190.
35. Nitsche MA, Paulus W. Sustained excitability elevations induced by
transcranial DC motor cortex stimulation in humans. Neurology
36. Liebetanz D, Nitsche MA, Tergau F, Paulus W. Pharmacological
approach to the mechanisms of transcranial DC-stimulation-
induced after-effects of human motor cortex excitability. Brain
37. Nitsche MA, Fricke K, Henschke U, et al. Pharmacological modula-
tion of cortical excitability shifts induced by transcranial direct
current stimulation in humans. J Physiol 2003;553(Pt 1):293-301.
38. Stagg CJ, Best JG, Stephenson MC, et al. Polarity-sensitive modula-
tion of cortical neurotransmitters by transcranial stimulation.
J Neurosci 2009;29(16):5202-5206.
39. Ardolino G, Bossi B, Barbieri S, Priori A. Non-synaptic mecha-
nisms underlie the after-effects of cathodal transcutaneous direct
40. Cogiamanian F, Vergari M, Pulecchi F, Marceglia S, Priori A. Effect
of spinal transcutaneous direct current stimulation on somatosensory
evoked potentials in humans. Clin Neurophysiol 2008;119(11):
41. Rango M, Cogiamanian F, Marceglia S, et al. Myoinositol content in
the human brain is modified by transcranial direct current stimulation
in a matter of minutes: a 1H-MRS study. Magn Reson Med 2008;
42. Boros K, Poreisz C, Munchau A, Paulus W, Nitsche MA. Premotor
transcranial direct current stimulation (tDCS) affects primary motor
excitability in humans. Eur J Neurosci 2008;27(5):1292-1300.
human brain.J Physiol2005;
192 Brunoni et al
43. Lang N, Siebner HR, Ward NS, et al. How does transcranial DC stim-
ulation of the primary motor cortex alter regional neuronal activity in
the human brain? Eur J Neurosci 2005;22(2):495-504.
44. Parra LC, Bikson M. Model of the effect of extracellular fields on
spike time coherence. Conf Proc IEEE Eng Med Biol Soc 2004;6:
45. Deans JK, Powell AD, Jefferys JG. Sensitivity of coherent oscilla-
tions in rat hippocampus to AC electric fields. J Physiol 2007;
46. Frohlich F, McCormick DA. Endogenous electric fields may guide
neocortical network activity. Neuron 2010;67(1):129-143.
47. Accornero N, Li Voti P, La Riccia M, Gregori B. Visual evoked
potentials modulation during direct current cortical polarization.
Exp Brain Res 2007;178(2):261-266.
48. Matsunaga K, Nitsche MA, Tsuji S, Rothwell JC. Effect of transcra-
nial DC sensorimotor cortex stimulation on somatosensory evoked
potentials in humans. Clin Neurophysiol 2004;115(2):456-460.
49. Antal A, Kincses TZ, Nitsche MA, Bartfai O, Paulus W. Excitability
changes induced in the human primary visual cortex by transcranial
direct current stimulation: direct electrophysiological evidence.
Invest Ophthalmol Vis Sci 2004;45(2):702-707.
50. Ferrucci R, Marceglia S, Vergari M, et al. Cerebellar transcranial
direct current stimulation impairs the practice-dependent proficiency
increase in working memory. J Cogn Neurosci 2008;20(9):
51. Galea JM, Jayaram G, Ajagbe L, Celnik P. Modulation of cerebellar
excitability by polarity-specific noninvasive direct current stimula-
tion. J Neurosci 2009;29(28):9115-9122.
52. Winkler T, Hering P, Straube A. Spinal DC stimulation in humans
modulates post-activation depression of the H-reflex depending on
current polarity. Clin Neurophysiol 2010;121(6):957-961.
53. Merzagora AC, Foffani G, Panyavin I, et al. Prefrontal hemodynamic
changes produced by anodal direct current stimulation. Neuroimage
54. Nitsche MA, Jaussi W, Liebetanz D, Lang N, Tergau F, Paulus W.
D-cycloserine. Neuropsychopharmacology 2004;29(8):1573-1578.
55. Nitsche MA, Liebetanz D, Schlitterlau A, et al. GABAergic modula-
tion of DC stimulation-induced motor cortex excitability shifts in hu-
mans. Eur J Neurosci 2004;19(10):2720-2726.
56. Nitsche MA, Grundey J, Liebetanz D, Lang N, Tergau F, Paulus W.
Catecholaminergic consolidation of motor cortical neuroplasticity in
humans. Cereb Cortex 2004;14(11):1240-1245.
57. Kuo MF, Unger M, Liebetanz D, et al. Limited impact of homeostatic
plasticity on motor learning in humans. Neuropsychologia 2008;
58. Nitsche MA, Doemkes S, Karakose T, et al. Shaping the effects of
transcranial direct current stimulation of the human motor cortex.
J Neurophysiol 2007;97(4):3109-3117.
59. Monte-Silva K, Kuo MF, Thirugnanasambandam N, Liebetanz D,
Paulus W, Nitsche MA. Dose-dependent inverted U-shaped effect
of dopamine (D2-like) receptor activation on focal and nonfocal plas-
ticity in humans. J Neurosci 2009;29(19):6124-6131.
60. Nitsche MA, Kuo MF, Karrasch R, Wachter B, Liebetanz D,
Paulus W. Serotonin affects transcranial direct current-induced neu-
roplasticity in humans. Biol Psychiatry 2009;66(5):503-508.
61. Antal A, Kincses TZ, Nitsche MA, Paulus W. Manipulation of phos-
phene thresholds by transcranial direct current stimulation in man.
Exp Brain Res 2003;150(3):375-378.
62. Boggio PS, Rigonatti SP, Ribeiro RB, et al. A randomized, double-
blind clinical trial on the efficacy of cortical direct current stimulation
for the treatment of major depression. Int J Neuropsychopharmacol
63. Utz KS, Dimova V, Oppenlander K, Kerkhoff G. Electrified minds:
transcranial direct current stimulation (tDCS) and galvanic vestibular
stimulation (GVS) as methods of non-invasive brain stimulation in
neuropsychology: a review of current data and future implications.
64. Williams JA, Pascual-Leone A, Fregni F. Interhemispheric modula-
tion induced by cortical stimulation and motor training. Phys Ther
65. Mahmoudi H, Haghighi AB, Petramfar P, Jahanshahi S, Salehi Z,
Fregni F. Transcranial direct current stimulation: electrode montage
in stroke. Disabil Rehabil 2010 November 26 (Epub ahead of print).
66. Redfearn JW, Lippold OC, Costain R. A preliminary account of the
clinical effects of polarizing the brain in certain psychiatric disorders.
Br J Psychiatry 1964;110:773-785.
67. Cogiamanian F, Vergari M, Ardolino G, et al. Effects of transcuta-
neous spinal cord direct current stimulation (tsDCS) on the lower
limb nociceptive flexion reflex in humans. Proceedings of the XLI
Congress of the Italian Neurological Society; 2010: Neurological
68. Datta A, Rahman A, Scaturro J, Bikson M. Electrode montages for
tDCS and weak transcranial electrical stimulation role of "return"
electrode’sposition and size.
69. Moliadze V, Antal A, Paulus W. Electrode-distance dependent after-
effects of transcranial direct and random noise stimulation with ex-
tracephalic reference electrodes. Clin Neurophysiol 2010;121(12):
70. Datta A, Elwassif M, Battaglia F, Bikson M. Transcranial current
stimulation focality using disc and ring electrode configurations:
FEM analysis. J Neural Eng 2008;5(2):163-174.
71. Datta A, Bansal V, Diaz J, Patel J, Reato D, Bikson M. Gyri-precise
head model of transcranial direct current stimulation: Improved
spatial focality using a ring electrode versus conventional rectangular
pad. Brain Stimul 2009;2(4):201-207.
72. Sadleir RJ, Vannorsdall TD, Schretlen DJ, Gordon B. Transcranial
direct current stimulation (tDCS) in a realistic head model. Neuro-
73. Minhas P, Bansal V, Patel J, et al. Electrodes for high-definition trans-
cutaneous DC stimulation for applications in drug delivery and elec-
trotherapy, including tDCS. J Neurosci Methods 2010;190(2):
74. Faria P, Leal A, Miranda PC. Comparing different electrode config-
urations using the 10-10 international system in tDCS: a finite
element model analysis. Conf Proc IEEE Eng Med Biol Soc 2009;
75. Suh HS, Kim SH, Lee WH, Kim TS. Realistic simulation of transcra-
nial direct current stimulation via 3-d high-resolution finite element
analysis: effect of tissue anisotropy. Conf Proc IEEE Eng Med
Biol Soc 2009;638-641.
76. Elmer S, Burkard M, Renz B, Meyer M, Jancke L. Direct current
induced short-term modulation of the left dorsolateral prefrontal
cortex while learning auditory presented nouns. Behav Brain Funct
77. Marshall L, Molle M, Siebner HR, Born J. Bifrontal transcranial
direct current stimulation slows reaction time in a working memory
task. BMC Neurosci 2005;6(1):23.
78. Boggio PS, Fregni F, Valasek C, et al. Temporal lobe cortical electri-
cal stimulation during the encoding and retrieval phase reduces false
memories. PLoS One 2009;4(3):e4959.
79. Marshall L, Molle M, Hallschmid M, Born J. Transcranial direct
current stimulation during sleep improves declarative memory.
J Neurosci 2004;24(44):9985-9992.
80. Fecteau S, Knoch D, Fregni F, Sultani N, Boggio P, Pascual-Leone A.
Diminishing risk-taking behavior by modulating activity in the
prefrontal cortex: a direct current stimulation study. J Neurosci
81. Hecht D, Walsh V, Lavidor M. Transcranial direct current stimulation
facilitates decision making in a probabilistic guessing task. J Neurosci
Clinical research with tDCS193
82. Kincses TZ, Antal A, Nitsche MA, Bartfai O, Paulus W. Facilitation
of probabilistic classification learning by transcranial direct current
stimulation of the prefrontal cortex in the human. Neuropsychologia
83. Stone DB, Tesche CD. Transcranial direct current stimulation modu-
lates shifts in global/local attention. Neuroreport 2009;20(12):
84. Sparing R, Thimm M, Hesse MD, Kust J, Karbe H, Fink GR. Bidi-
rectional alterations of interhemispheric parietal balance by non-
invasive cortical stimulation. Brain 2009;132(Pt 11):3011-3020.
85. Bolognini N, Fregni F, Casati C, Olgiati E, Vallar G. Brain polariza-
tion of parietal cortex augments training-induced improvement of
visual exploratory and attentional skills. Brain Res 2010;1349:76-89.
86. Fertonani A, Rosini S, Cotelli M, Rossini PM, Miniussi C. Naming
facilitation induced by transcranial direct current stimulation. Behav
Brain Res 2010;208(2):311-318.
87. Sparing R, Dafotakis M, Meister IG, Thirugnanasambandam N,
Fink GR. Enhancing language performance with non-invasive brain
stimulationda transcranial direct current stimulation study in
healthy humans. Neuropsychologia 2008;46(1):261-268.
88. Liebetanz D, Koch R, Mayenfels S, Konig F, Paulus W, Nitsche MA.
Safety limits of cathodal transcranial direct current stimulation in
rats. Clin Neurophysiol 2009;120(6):1161-1167.
89. Fregni F, Liebetanz D, Monte-Silva KK, et al. Effects of transcranial
direct current stimulation coupled with repetitive electrical stimula-
tion on cortical spreading depression. Exp Neurol 2007;204(1):
90. Rigonatti SP, Boggio PS, Myczkowski ML, et al. Transcranial direct
stimulation and fluoxetine for the treatment of depression. Eur
91. Ferrucci R, Bortolomasi M, Vergari M, et al. Transcranial direct
current stimulation in severe, drug-resistant major depression.
J Affect Disord 2009;118(1-3):215-219.
92. Palm U, Keeser D, Schiller C, et al. Skin lesions after treatment
with transcranial direct current stimulation (tDCS). Brain Stimul
93. Durand S, Fromy B, Bouye P, Saumet JL, Abraham P. Vasodilatation
in response to repeated anodal current application in the human skin
relies on aspirin-sensitive mechanisms. J Physiol 2002;540(Pt 1):
94. 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(4-6):208-214.
95. Tadini L, El-Nazer R, Brunoni AR, et al. Cognitive, mood and EEG
effects of noninvasive cortical stimulation with weak electrical
currents. J ECT 2010 October 5. (Epub ahead of print).
96. Nitsche MA, Liebetanz D, Lang N, Antal A, Tergau F, Paulus W.
Safety criteria for transcranial direct current stimulation (tDCS) in
humans. Clin Neurophysiol 2003;114(11):2220-2222. author reply
97. Fregni F, Boggio PS, Nitsche MA, Rigonatti SP, Pascual-Leone A.
Cognitive effects of repeated sessions of transcranial direct current
stimulation in patients with depression. Depress Anxiety 2006;
98. Boggio PS, Nunes A, Rigonatti SP, Nitsche MA, 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(2):123-129.
99. Loo C, Martin D, Pigot M, Arul-Anandam P, Mitchell P, Sachdev P.
Transcranial direct current stimulation priming of therapeutic repet-
itive transcranial magnetic stimulation: a pilot study. J ECT 2009;
100. Fregni F, Thome-Souza S, Nitsche MA, Freedman SD, Valente KD,
Pascual-Leone A. A controlled clinical trial of cathodal DC polariza-
tion in patients with refractory epilepsy. Epilepsia 2006;47(2):
101. Arul-Anandam AP, Loo C, Mitchell P. Induction of hypomanic
episode with transcranial direct current stimulation. J ECT 2010;
102. Baccaro A, Brunoni AR, Bensenor IM, Fregni F. Hypomanic episode
in unipolar depression during transcranial direct current stimulation.
Acta Neuropsychiatrica 2010;22(6):316-318.
103. Brunoni AR, Valiengo L, Zanao T, Oliveira J, Bensenor IM, Fregni F.
Manic psychosis following transcranial direct current stimulation and
sertraline. J Neuropsychiatry Clin Neurosci (in press).
104. Miranda PC, Faria P, Hallett M. What does the ratio of injected
current to electrode area tell us about current density in the brain
during tDCS? Clin Neurophysiol 2009;120(6):1183-1187.
105. Fregni F, Boggio PS, Valle AC, et al. Homeostatic effects of plasma
valproate levels on corticospinal excitability changes induced by 1Hz
rTMS in patients with juvenile myoclonic epilepsy. Clin Neurophy-
106. Ziemann U. Pharmacology of TMS. Suppl Clin Neurophysiol 2003;
107. Bajwa S, Bermpohl F, Rigonatti SP, Pascual-Leone A, Boggio PS,
Fregni F. Impaired interhemispheric interactions in patients with
major depression. J Nerv Ment Dis 2008;196(9):671-677.
108. Soubasi E,Chroni E,Gourzis
Papathanasopoulos P. Cortical motor neurophysiology of patients
with schizophrenia: a study using transcranial magnetic stimulation.
Psychiatry Res 2010;176(2-3):132-136.
109. Mhalla A, de Andrade DC, Baudic S, Perrot S, Bouhassira D. Alter-
ation of cortical excitability in patients with fibromyalgia. Pain 2010;
110. Brighina F, Palermo A, Fierro B. Cortical inhibition and habituation
to evoked potentials: relevance for pathophysiology of migraine.
J Headache Pain 2009;10(2):77-84.
111. Chaieb L, Antal A, Paulus W. Gender-specific modulation of short-
term neuroplasticity in the visual cortex induced by transcranial
direct current stimulation. Vis Neurosci 2008;25(1):77-81.
112. Ferri R, Del Gracco S, Elia M, Musumeci SA. Age-related changes
of cortical excitability in subjects with sleep-enhanced centrotempo-
ral spikes: a somatosensory evoked potential study. Clin Neurophy-
113. Lang N, Hasan A, Sueske E, Paulus W, Nitsche MA. Cortical hypo-
excitability in chronic smokers? A transcranial magnetic stimulation
study. Neuropsychopharmacol 2008;33(10):2517-2523.
114. Monte-Silva K, Liebetanz D, Grundey J, Paulus W, Nitsche MA.
Dosage-dependent non-linear effect of L-dopa on human motor
cortex plasticity. J Physiol 2010;588(Pt 18):3415-3424.
115. Ohn SH, Park CI, Yoo WK, et al. Time-dependent effect of transcra-
nial direct current stimulation on the enhancement of working
memory. Neuroreport 2008;19(1):43-47.
116. Boggio PS, Ferrucci R, Rigonatti SP, et al. Effects of transcranial
direct current stimulation on working memory in patients with
Parkinson’s disease. J Neurol Sci 2006;249(1):31-38.
117. Froc DJ, Chapman CA, Trepel C, Racine RJ. Long-term depression
and depotentiation in the sensorimotor cortex of the freely moving
rat. J Neurosci 2000;20(1):438-445.
118. Monte-Silva KK, Kuo MF, Liebetanz D, Paulus W, Nitsche MA.
Shaping the optimal repetition interval for cathodal transcranial
direct current stimulation (tDCS). J Neurophysiol 2010;103(4):
119. Siebner HR, Lang N, Rizzo V, et al. Preconditioning of low-
frequency repetitive transcranial magnetic stimulation with transcra-
nial direct current stimulation: evidence for homeostatic plasticity in
the human motor cortex. J Neurosci 2004;24(13):3379-3385.
120. Brunoni AR, Fregni F. Clinical trial design in noninvasive brain stim-
ulation psychiatric research. Int J Methods Psychiatry Res (in press).
121. Gandiga PC, Hummel FC, Cohen LG. Transcranial DC stimulation
(tDCS): a tool for double-blind sham-controlled clinical studies in
brain stimulation. Clin Neurophysiol 2006;117(4):845-850.
P, ZisisA, Beratis S,
194 Brunoni et al
122. Dundas JE, Thickbroom GW, Mastaglia FL. Perception of comfort Download full-text
during transcranial DC stimulation: effect of NaCl solution concen-
tration applied to sponge electrodes. Clin Neurophysiol 2007;
123. Freedman B. Equipoise and the ethics of clinical research. N Engl
J Med 1987;317(3):141-145.
124. Fregni F, Boggio PS, Nitsche MA, Marcolin MA, Rigonatti SP,
Pascual-Leone A. Treatment of major depression with transcranial
direct current stimulation. Bipolar Disord 2006;8(2):203-204.
125. Ferrucci R, Bortolomasi M, Brunoni AR, et al. Comparative benefits
of Transcranial Direct Current Stimulation (tDCS) treatment in
patients with mild/moderate vs. severe depression. Clin Neuropsychi-
126. Brunoni AR, Ferrucci R, Bortolomasi M, et al. Transcranial direct
current stimulation (tDCS) in unipolar vs. bipolar depressive disorder.
Prog Neuropsychopharmacol Biol Psychiatry 2011;35(1):96-101.
127. Brunoni AR, Valiengo L, Baccaro A, et al. Sertraline vs. electrical
current therapy for treating depression clinical studyddesign, ratio-
nale and objectives. Contemp Clin Trials 2011;32:90-98.
128. Schutter DJ. Nosce te ipsum: on the efficacy of transcranial magnetic
stimulation in major depressive disorder. Biol Psychiatry 2010;67(5):
e27; reply e9.
129. Yu E, Lurie P. Transcranial magnetic stimulation not proven effec-
tive. Biol Psychiatry 2010;67(2):e13; reply e5-7.
130. D’Agostino RB Jr. Debate: the slippery slope of surrogate outcomes.
Curr Control Trials Cardiovasc Med 2000;1(2):76-78.
131. Kobayashi M, Pascual-Leone A. Transcranial magnetic stimulation
in neurology. Lancet Neurology 2003;2(3):145-156.
132. Pascual-Marqui RD, Esslen M, Kochi K, Lehmann D. Functional
imaging with low-resolution brain electromagnetic tomography
(LORETA): a review. Methods Find Exp Clin Pharmacol 2002;
133. May A, Hajak G, Ganssbauer S, et al. Structural brain alterations
following 5 days of intervention: dynamic aspects of neuroplasticity.
Cereb Cortex 2007;17(1):205-210.
134. Kriegeskorte N, Lindquist MA, Nichols TE, Poldrack RA, Vul E.
Everything you never wanted to know about circular analysis, but
were afraid to ask. J Cereb Blood Flow Metab 2010;30(9):
135. Gelenberg AJ, Thase ME, Meyer RE, et al. The history and current
state of antidepressant clinical trial design: a call to action for
proof-of-concept studies. J Clin Psychiatry 2008;69(10):1513-1528.
136. Brunoni AR, Lopes M, Fregni F. A systematic review and meta-
analysis of clinical studies on major depression and BDNF levels:
implications for the role of neuroplasticity in depression. Int J Neuro-
137. Dowlati Y, Herrmann N, Swardfager W, et al. A meta-analysis of
cytokines in major depression. Biol Psychiatry 2010;67(5):446-457.
138. Quinones MP, Kaddurah-Daouk R. Metabolomics tools for identi-
fying biomarkers for neuropsychiatric diseases. Neurobiol Dis
139. Marques AH, Cizza G, Sternberg E. [Brain-immune interactions
and implications in psychiatric disorders]. Rev Bras Psiquiatr 2007;
140. Maes M, Yirmyia R, Noraberg J, et al. The inflammatory & neurode-
generative (I&ND) hypothesis of depression: leads for future
research and new drug developments in depression. Metab Brain
141. Spencer-Smith M, Anderson V. Healthy and abnormal development
of the prefrontal cortex. Dev Neurorehabil 2009;12(5):279-297.
142. Frye RE, Rotenberg A, Ousley M, Pascual-Leone A. Transcranial
magnetic stimulation in child neurology: current and future direc-
tions. J Child Neurol 2008;23(1):79-96.
143. Fumagalli M, Vergari M, Pasqualetti P, et al. Brain switches utili-
tarian behavior: does gender make the difference? PLoS One 2010;
144. Luber B, Fisher C, Appelbaum PS, Ploesser M, Lisanby SH. Non-
invasive brain stimulation in the detection of deception: scientific
challenges and ethical consequences. Behav Sci Law 2009;27(2):
145. Mameli F, Mrakic-Sposta S, Vergari M, et al. Dorsolateral prefrontal
cortex specifically processes generaldbut not personaldknowledge
deception: multiple brain networks for lying. Behav Brain Res 2010;
146. Boggio PS, Campanha C, Valasek CA, Fecteau S, Pascual-Leone A,
Fregni F. Modulation of decision-making in a gambling task in older
adults with transcranial direct current stimulation. Eur J Neurosci
147. Reis J, Robertson E, Krakauer JW, et al. Consensus: ‘‘Can tDCS and
TMS enhance motor learning and memory formation?’’. Brain Stimul
148. Anonymous. 2010 [cited 2010 September 25th]; Available at: http://
Clinical research with tDCS195