[Transcranial direct current stimulation: a promising alternative for the treatment of major depression?].
ABSTRACT In recent years, a number of new somatic (non-pharmacological treatments) have been developed for the treatment of major depression and other neuropsychiatric disorders. Among these, one of the most promising is transcranial direct current stimulation.
For the present literature review we searched the PubMed between January 1985 and February 2009. To be included, articles should have been published in English and should address general principles of transcranial direct current stimulation and its use in major depression.
Current protocols for the treatment of major depression with transcranial direct current stimulation usually involve the application of two sponge-electrodes in the scalp. In general, the positive electrode is applied in the region above the left dorsolateral prefrontal cortex (i.e., F3 region of the 10/20 International System for EEG) and the negative electrode is applied in the region above the right supra-orbital area. A direct electrical current of 1-2 mA is then applied between the electrodes for about 20 minutes, with sessions being daily performed for one to two weeks. Initial studies (including a randomized, double-blind, placebo-controlled clinical trial) showed that transcranial direct current stimulation is effective for the treatment of non-complicated major depression and that this technique, when used in depressed patients, is associated with improvement in cognitive performance (including working memory). Finally, transcranial direct current stimulation is safe and well tolerated.
Recent studies show that transcranial direct current stimulation is an important neuromodulatory method that may be useful for the treatment of depressed patients. However, further studies are needed to better clarify its precise role in the management of depressive disorders.
- [show abstract] [hide abstract]
ABSTRACT: Vagus nerve stimulation (VNS) therapy is the first US Food and Drug Administration-approved somatic clinical intervention for treatment-resistant depression (TRD). Long-term open data suggest a sustainable antidepressant response over time. Here we review the clinical data that exist so far and their limitations. We also discuss guidelines that may inform the clinical utilization of this procedure. Further clinical studies, in addition to prospective cost utilization and health economic investigations, are needed to better understand VNS therapy and the impact it holds on TRD care.Current Psychiatry Reports 01/2007; 8(6):445-51. · 3.23 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Transcranial direct current stimulation (tDCS) is a noninvasive method of brain stimulation that has been increasingly tested for the treatment of neuropsychiatric disorders. It has useful characteristics, such as low cost, ease of use, reliable sham methodology, and relatively powerful effects on cortical excitability. Because of its potential to modulate cortical excitability noninvasively, tDCS has been tested for the treatment of depression for several decades. Therefore, we reviewed evidence on the use of tDCS for major depression examining evidence from past and recent tDCS studies. We also briefly compared tDCS with other techniques of neuromodulation, namely deep brain stimulation, vagal nerve stimulation, and transcranial magnetic stimulation; and suggest future directions for the use of tDCS in major depression. Results from past clinical trials testing direct current stimulation as a therapeutic tool had mixed methodology and showed heterogeneous results. Recent studies on tDCS and depression using novel approaches, such as different parameters of stimulation, have improved its neuromodulatory effect thus resulting in larger clinical effects. In fact, two recent small trials have shown that tDCS is associated with significant clinical gains. On the basis of these findings there is still not enough evidence to support tDCS as a therapeutic modality for depression. However, findings to date encourage further studies in this area that should explore novel parameters of stimulation. In fact, it appears that current methods of tDCS might not be fully optimized and, in fact, (1) individualized parameters of stimulation, (2) longer stimulation sessions, and (3) methods to focalize tDCS might be useful strategies to provide greater clinical benefits.Current opinion in psychiatry 04/2009; 22(3):306-11. · 3.57 Impact Factor
- The Journal of Physiology 09/1964; 172:369-82. · 4.38 Impact Factor
Estimulação transcraniana por corrente direta:
uma alternativa promissora para o tratamento da
Transcranial direct current stimulation: a promising
alternative for the treatment of major depression?
Marcelo T. Berlim
6875 LaSalle Blvd., FBC-3 Pavilion
Rm. F-3116-2, Montréal, Québec, Canada, H4H 1R3
Marcelo T. Berlim,1 Vitor Dias Neto,1 Gustavo Turecki1
1 Depressive Disorders Program, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada
Objective: In recent years, a number of new somatic (non-pharmacological treatments) have been developed for the treatment of major
depression and other neuropsychiatric disorders. Among these, one of the most promising is transcranial direct current stimulation.
Method: For the present literature review we searched the PubMed between January 1985 and February 2009. To be included, articles
should have been published in English and should address general principles of transcranial direct current stimulation and its use in
major depression. Discussion: Current protocols for the treatment of major depression with transcranial direct current stimulation usually
involve the application of two sponge-electrodes in the scalp. In general, the positive electrode is applied in the region above the left
dorsolateral prefrontal cortex (i.e., F3 region of the 10/20 International System for EEG) and the negative electrode is applied in the region
above the right supra-orbital area. A direct electrical current of 1-2 mA is then applied between the electrodes for about 20 minutes,
with sessions being daily performed for one to two weeks. Initial studies (including a randomized, double-blind, placebo-controlled
clinical trial) showed that transcranial direct current stimulation is effective for the treatment of non-complicated major depression and
that this technique, when used in depressed patients, is associated with improvement in cognitive performance (including working
memory). Finally, transcranial direct current stimulation is safe and well tolerated. Conclusion: Recent studies show that transcranial
direct current stimulation is an important neuromodulatory method that may be useful for the treatment of depressed patients. However,
further studies are needed to better clarify its precise role in the management of depressive disorders.
Descriptors: Depression; Transcranial direct current stimulation; Brain; Mental disorders; Review literature as topic
Objetivo: Nos últimos anos, uma série de novos tratamentos somáticos não-farmacológicos vem sendo desenvolvida para o tratamento
da depressão maior e de outros transtornos neuropsiquiátricos. Dentre esses, um dos mais promissores é a estimulação transcraniana
por corrente direta. Método: Para a presente revisão da literatura consultou-se no PubMed a literatura publicada entre janeiro de
1985 e fevereiro de 2009. Os artigos deveriam ser publicados em língua inglesa e deveriam abordar princípios gerais da estimulação
transcraniana por corrente direta e sua utilização na depressão maior. Discussão: Os protocolos atuais de estimulação transcraniana
por corrente direta para o tratamento da depressão maior envolvem a aplicação de dois eletrodos-esponja no escalpo. Em geral, o
eletrodo positivo é aplicado na região sobrejacente ao córtex pré-frontal dorsolateral esquerdo (região F3 do Sistema Internacional 10/20
para eletroencefalograma) e o eletrodo negativo é aplicado na região sobrejacente à área supra-orbital direita. Uma corrente elétrica
direta de 1-2 mA é então aplicada entre os dois eletrodos por cerca de 20 minutos, sendo as sessões de estimulação transcraniana
por corrente direta realizadas diariamente durante uma a duas semanas. Estudos iniciais (incluindo um ensaio clínico randomizado,
duplo-cego e controlado por placebo) demonstraram que a estimulação transcraniana por corrente direta é efetiva no tratamento da
depressão maior não-complicada e que essa técnica, quando utilizada em pacientes deprimidos, está associada com melhoras no
desempenho cognitivo (incluindo a memória de trabalho). Por fim, a estimulação transcraniana por corrente direta é segura e bem
tolerada. Conclusão: Investigações recentes demonstram que a estimulação transcraniana por corrente direta é um importante método
neuromodulatório que pode ser útil no tratamento de pacientes deprimidos. Contudo, novos estudos são necessários para esclarecer
seu real papel no manejo dos transtornos depressivos.
Descritores: Depressão; Estimulação transcraniana por corrente direta; Encéfalo; Transtornos mentais; Literatura de revisão como
Rev Bras Psiquiatr. 2009;31(Suppl I):S34-8
Berlim MT et al.
Rev Bras Psiquiatr. 2009;31(Suppl I):S34-8
Neurostimulation: is it relevant in the treatment of neuropsychiatric
The therapeutics with neurostimulation techniques has been often
used as an adjunct tool in the treatment of several neurological
and psychiatric illnesses, especially when medications are not
efficient.1,2 Neurostimulation uses specific techniques according
to the structure to be stimulated (e.g., spinal medulla, deep brain
nuclei or cortical regions).3
Cortical stimulation is especially interesting, as it can be reached
by both invasive (e.g., surgical implantation of electrodes and pulse
generator) and non-invasive (e.g., magnetic or electric transcranial
stimulation)4 procedures. Non-invasive cortical stimulation was
initially developed for the management of chronic pain5 and only
after had its use expanded to other diseases.
In theory, any psychiatric or neurological disorder that involves
primary or secondary cortical dysfunction may be a good indication
for cortical stimulation. In a simplified view, the therapeutic effects
of cortical stimulation can be achieved by reactivating hypoactive
neuronal structures or inhibiting hyperactive ones.3 More specifically,
the changes induced by cortical stimulation may affect neuronal
excitability (as demonstrated by cortical excitability studies,
using single and paired magnetic pulses), regional brain activity
(demonstrated by functional neuroimaging methods) or else behavior
and symptoms (as demonstrated by clinical and neurocognitive
In the last years, several neurostimulation techniques have been
developed for the management of non-complicated major depressive
disorder and, especially, of treatment-resistant depression2 (whose
prevalence ranges from 10-15% of the depressed patients7).
Among these new techniques are included transcranial magnetic
stimulation,8 deep brain stimulation,9 vagal nerve stimulation10
and direct current transcranial stimulation.11 The latter is currently
considered one of the most promising neurostimulation techniques
and, owing to this, will be the focus of this review.
Methodology of the literature review
For this literature review we have consulted PubMed for studies
published between January 1985 and February 2009. Articles
should have been published in English and in peer-reviewed
journals. The searching syntaxes used contained combinations of
the following words in the title and/or in the abstract “depress*”,
“antidepress*”, “tDCS”, “direct current”, “stimulation”, “transcranial”
and “cortical”. Besides this, the references of the identified articles
were visually inspected.
Transcranial direct current stimulation (TDCS)
1. General aspects
Up to recently, the TDCS technique was mainly used in animal
experiments. Most studies with humans were performed in the
1960’s12-14 and new studies related to it have started being
published specially since the 1990’s.
TDCS studies on the treatment of major depression and
schizophrenia were carried out in the 1960’s and 1970’s and
showed inconclusive results15,16 (for an in depth review about these
pioneering investigations, please consult Murphy et al.11). The
negative findings of some of these studies could be attributed to the
use of different methodologies. Actually, more recent studies which
used different sizes and positions of electrodes, besides different
stimulation parameters, showed that TDCS is a method capable of
modulating the cortical activity12,17 and, therefore, could be useful
in the treatment of major depression.18,19
TDCS has important advantages when compared to other
neuromodulatory techniques: it is easily administered, its equipment
may be easily transported, it is a relatively cheap, non-invasive,
painless and safe therapeutic alternative, and its simulated form
(sham) can be efficiently used in double-blind studies.1,6,20
Current TDCS protocols for the treatment of major depression
generally involve the application of two surface sponge electrodes
(non-metallic) of 25-35 cm2 (bathed in water or NaCl solution) to
the scalp, one serving as an anode (positive pole) and the other as
a cathode (negative pole or reference electrode). A direct electric
current of 1-2 mA (produced by a constant current stimulator, fed
by an ordinary battery) is applied between these two electrodes,
for approximately 20 minutes6,11,21 (for further information about
TDCS equipment, please consult Wagner et al.22). The current
flow from the cathode towards anode is deviated through the scalp
and moves towards the cerebral cortex, leading to an increase or a
decrease in the cortical excitability that depends on the stimulation
polarity.1,11 More specifically, anodic stimulation increases the
cortical excitability and cathodic stimulation decreases it.17,23
This way, in TDCS, a weak direct electric current is applied on
the scalp’s surface, resulting in a polarity-dependent modulation of
the cerebral activity. The current density produced by present TDCS
protocols ranges between 0.029 and 0.08 mA/cm2.1,4,11
In order to mount the electrodes on the depressed patients’ scalp,
the 10/20 International System for electroencephalogram (EEG)
is generally used, in which F3 corresponds to the left dorsolateral
pre-frontal cortex (LDLP).4 The positive electrode (anode) is placed
above F3, and the negative electrode (cathode) is placed on the
right supra-orbital area11 (for a visual representation of the mounting
of the electrodes, please consult Murphy et al.11). Normally, the
scalp’s skin is “prepared” by using an abrasive solution whose
objective is to reduce the resistance and improve the homogeneity
of the electric field.
During a typical TDCS session the patient remains awaken and
2. General parameters
The efficacy of TDCS to induce acute modifications in the polarity
of the neuronal membrane depends on the density of the current
(that determines the power of the induced electric field) and is
determined by the ratio between the current power and the electrode
size1,14. Besides, it was demonstrated in humans, that higher
densities result in more significant cortical effects.1,24,25
Other important parameter of TDCS is the duration of stimulation.
Considering a constant current density, the increase in the duration
of the stimulation determines the occurrence and the maintenance of
the post-stimulatory effects.22 Besides, a crucial factor to determine
the stimulated neuronal population is the orientation of the electric
field, which is generally defined by the position of the electrodes
on the scalp and by their polarity.22
The increase in the focalization of TDCS can be achieved, for
example, by reducing the size of the electrode responsible for the
cortical stimulation (keeping the current density constant), by
reducing the current density in the reference electrode or else by
using an extra-encephalic reference electrode.1
As the increase in the density of the electric current provokes
an increase in the cutaneous feeling of pain and affects different
neuronal populations (due to a higher penetration of the effective
electric field), it is recommended, in general, the increase in the
duration of stimulation and not in the current density to prolong
the effects of TDCS.22
Transcranial direct current stimulation in depression
Rev Bras Psiquiatr. 2009;31(Suppl I):S34-8
For repeated applications of TDCS, it is suggested a sufficiently
large interval between the sessions in order to avoid undesired
cumulative effects. The duration of this interval depends on the
stimulation procedure. If the objective is to induce stable changes
in the cortical function, daily TDCS sessions may be adequate.11,22
However, new studies are needed to establish more precisely the
ideal interval between TDCS sessions.
Lastly, for studies involving simulated (sham) TDCS, the best
results are obtained by gradually increasing and decreasing the
electric current in the beginning and in the end of the stimulation
session, respectively.20 Nevertheless, some patients succeed in
discerning real from sham stimulation and, therefore, the utilization
of post-stimulation questionnaires is important in order to verify the
efficacy of blind studies.1
3. Mechanism of action
During the stimulation of the motor and visual cortex, anodic
TDCS is associated with an increase in the cortical excitability,
being the effect the opposite of that observed during the application
of cathodic TDCS.26 The effects of cortical inhibition suggest that
TDCS modulates the excitability of both the inhibitory inter-neurons
and excitatory neurons.6
Pharmacological studies offer some clues about the
neurophysiological mechanism of TDCS.6 Especially, it was
demonstrated that calcium and sodium channel blockers have
eliminated the short- and long-term effects of anodic stimulation,
whereas glutamate channels blockers have eliminated only the
The effects produced by TDCS may induce synaptic neuroplastic
processes (by means, for example, of long-term potentiation), being
the duration of these effects dependent on the stimulation intensity.
Besides, it was hypothesized that post-TDCS effects could be
explained by the modulation of the activity of N-methyl-D-aspartic
acid (NMDA) receptors.27
In summary, despite not being yet totally clear, the specific
mechanism of action of TDCS seems to involve a combination of
hyper- and depolarizing effects in the neuronal axons, as well as
alterations in the synaptic function.1,6 However, there is no direct
evidence to date that TDCS influences neurotransmitters.11
4. Is it efficient in the treatment of major depression?
The first post-1970 research about the efficacy of TDCS in major
depression was published in 2006 by Fregni et al.18 This pilot
study has investigated the efficacy of anodic stimulation of the left
dorsolateral prefrontal (DLPF) cortex in depressed patients who
were alternately randomized for active treatment and simulated
stimulation (sham). The approach used included 20-minute TDCS
administrated every other day during five days with a 1-mA current.
The results demonstrated that four out of five patients submitted
to active stimulation showed a significant reduction of depressive
symptoms [i.e., nearly 60% of reduction according to the Hamilton
Depression Scale (HAM-D) and more than 70% according to the
Beck Depression Inventory (BDI)], whereas the control group did
not show clinical improvement.
Another study compared TDCS to pharmacological treatment with
fluoxetine (20mg/day) in 42 depressed patients.28 The parameters
used were similar to those described by Boggio et al.21 (see below).
Even though patients had not been simultaneously assessed, the
results showed a significant reduction in the depressive symptoms
(according to the BDI)] two weeks after TDCS versus sham TDCS
(p = 0.0002), and a similar reduction to that observed after six
weeks of fluoxetine treatment (p = 0.54). More specifically, after
two weeks of active TDCS it was observed a reduction of 43.1%
(± 30.9) in the BDI scores versus 15% (± 35.2) after two weeks
under fluoxetine. However, the improvement in the depressive
symptoms was similar between both groups after six weeks with
fluoxetine [i.e., 36.2% (± 38.9) and 38.1% (± 36.9), respectively].
The HAM-D scores demonstrated similar results. Thus, the
antidepressant action of active TDCS was observed faster than that
associated with fluoxetine.
The main study about TDCS in the treatment of major depression
was a randomized double-blind placebo-controlled clinical trial
published in 2008 by Boggio et al.21 Its main objective was to
determine the short-term efficacy of anodic active stimulation of
the left DLPF cortex, when compared to both a sham controlled
stimulation and an active controlled stimulation of the occipital
cortex. This active control was employed to exclude the possibility
that the cathodic stimulation of the right supra-orbital region could
have any relevant clinical effect (as during TDCS both anodic and
cathodic stimulation occur). In this trial, 40 patients with a diagnosis
of major depressive disorder without pharmacological treatment for
at least two months were included. The TDCS protocol involved daily
sessions (for 20 minutes) for a period of two weeks with a 2-mA
current. The results were encouraging: the active anodic stimulation
of the DLPF cortex was associated with a significant reduction in the
depressive symptoms assessed both by the HAM-D (p = 0.0018
versus sham ETCD and p = 0.009 versus occipital TDCS) and by
the BDI (p = 0.0045 versus sham TDCS). Besides, active TDCS
was associated with higher rates of response to treatment (defined
as a ≥ 50% reduction in the HAM-D score; p = 0.019) and clinical
remission (defined as a score of ≤ 7 in the HAM-D; p = 0.02). The
clinical improvement remained significant for at least 30 days after
the end of treatment.
However, a recent pilot study (double-blind, randomized, and
placebo-controlled) involving 10 patients with treatment-resistant
depression (i.e., absence of response to at least two antidepressants
in the current episode) was not able to demonstrate a significant
difference between active and simulated (sham) TDCS.29
Nevertheless, despite using a disposition of electrodes similar to
that described by Boggio et al.,21 the current employed was of only
1 mA and this fact (added to the small number of participants)
might explain the negative results found.
5. Adverse effects
The accumulated experience in the last four decades has
demonstrated that TDCS is associated with only mild and transient
side-effects (both in normal volunteers and in individuals with varied
neuropsychiatric disorders).30,31 However, the safe limits of current
duration and intensity are not yet fully clear.1
The adverse effects most commonly associated with the treatment
of major depression by TDCS include mild transient headache (with
a duration of less than one hour) and mild transient pruritus and
erythema in the stimulation site (the latter with a duration of less
than 40 minutes).18,21,28 Other less prevalent side-effects include
nausea, difficulty of concentration, visual fosphenes and vertigo.11
Lastly, the secondary side-effects of TDCS can be usually
minimized by means of a gradual increase and decrease of the
electric current during the beginning and the end of the session,
6. Cognitive effects in major depression
A recent study has assessed the neurocognitive impact of TDCS
Berlim MT et al.
Rev Bras Psiquiatr. 2009;31(Suppl I):S34-8
in major depression.32 For that, 26 depressed patients were
randomized to receive alternatively anodic TDCS in the left DLPF
cortex, anodic TDCS in the occipital cortex and simulated (sham)
TDCS (with mounting and parameters similar to those used by
Boggio et al.21). For the assessment of their cognitive function,
patients were submitted to an affective “go-no-go” task just before
and after TDCS (for more information about this task, please consult
Murphy et al.33). Post-hoc analyses have demonstrated that a single
post-hoc active TDCS session was associated with a significant
improvement in the performance of depressed patients (in terms
of the number of correct answers; p = 0.005). Besides, this effect
was specific to figures with positive emotional valence. However,
this performance change occurred only regarding the accuracy
(and not the performance speed) and was not correlated to mood
alterations observed after 10 days of TDCS.
In a previous randomized study, Fregni et al. assessed the cognitive
performance of 18 depressed patients before and after five sessions
of active TDCS (administered on the DLPF cortex) or simulated
TDCS.34 For that, they used a series of neuropsychological tests
associated with the pre-frontal cortex function. Statistical analyses
demonstrated a significant improvement in working memory
(according to two specific tests) only after active TDCS (p = 0.009
and p = 0.048, respectively).
TDCS is currently one of the most promising neuromodulation
techniques. Recent studies have shown that it can be useful in the
treatment of major depression and several other neuropsychiatric
disorders. Nevertheless, new studies (with larger samples and in
distinct populations) are needed to confirm the usefulness of TDCS
in depression and determine, among other things, which are the
optimal stimulation parameters and the most efficient and well
tolerated mounting of the electrodes. Besides, the combination of
TDCS with different forms of psychotherapy, medication and somatic
interventions might significantly expand the available arsenal for the
treatment of the depressive disorders. The use of specific research
tools (e.g., neuroimaging), in turn, might help explain the mechanisms
of action underlying this neuromodulatory technique.
Lastly, TDCS can be considered a potentially useful therapeutic
alternative for developing nations like Brazil,35 as the equipment
needed is simple, relatively cheap (it may cost less than U$ 200,00)
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