Transcranial direct current stimulation for depression: 3-Week, randomised, sham-controlled trial

Article (PDF Available)inThe British journal of psychiatry: the journal of mental science 200(1):52-9 · January 2012with224 Reads
DOI: 10.1192/bjp.bp.111.097634 · Source: PubMed
Abstract
Preliminary evidence suggests transcranial direct current stimulation (tDCS) has antidepressant efficacy. To further investigate the efficacy of tDCS in a double-blind, sham-controlled trial (registered at www.clinicaltrials.gov: NCT00763230). Sixty-four participants with current depression received active or sham anodal tDCS to the left prefrontal cortex (2 mA, 15 sessions over 3 weeks), followed by a 3-week open-label active treatment phase. Mood and neuropsychological effects were assessed. There was significantly greater improvement in mood after active than after sham treatment (P<0.05), although no difference in responder rates (13% in both groups). Attention and working memory improved after a single session of active but not sham tDCS (P<0.05). There was no decline in neuropsychological functioning after 3-6 weeks of active stimulation. One participant with bipolar disorder became hypomanic after active tDCS. Findings confirm earlier reports of the antidepressant efficacy and safety of tDCS. Vigilance for mood switching is advised when administering tDCS to individuals with bipolar disorder.
Although the use of weak electrical currents to stimulate the brain
has been described for centuries in the histor y of medicine, it has
been reintroduced with higher intensity currents since 2000 as
‘transcranial direct current stimulation (tDCS).
1
It involves
passing a weak, depolarising current through the brain. This shifts
the resting membrane potential, with anodal stimulation
depolarising the soma of pyramidal cells, whereas cathodal
stimulation results in hyperpolarisation.
2
The effects of tDCS on
neuronal excitability have now been demonstrated in numerous
neuroimaging and physiological studies, providing a sound
neurobiological basis for its use for neuromodulation in patient
populations.
1,3
Increased understanding of the effects of tDCS has been
accompanied by application in clinical trials exploring its
therapeutic potential in neurology and, more recently, psychiatry.
1
Its potential role in depression has generated particular interest.
Prior to 2000, early stimulation trials used relatively low current
intensities (0.02–0.5 mA) with considerable variability in
stimulation technique. As a result, outcomes were highly
variable.
3,4
Since then, the development of commercial equipment
enabling the reliable delivery of currents in the 1–2 mA range has
led to renewed interest in tDCS in clinical research. Since 2000,
three sham-controlled trials investigating the efficacy of tDCS
for treating depression have reported encouraging results. Fregni
et al
5
(n = 10, tDCS given at 1 mA, 20 min per session, 5 sessions
on alternate days) and Boggio et al
6
(n = 40, 2 mA, 20 min, 10
sessions on consecutive weekdays) both found tDCS more
effective than a sham control. In Loo et al
7
(n = 40, 1 mA,
20 min, 5 sessions on alternate days followed by 5 further active
treatments) clinically meaningful improvement was seen with
active tDCS over 10 sessions of treatment, but differences
failed to reach statistical significance over the initial 5-session
sham-controlled comparison period.
This present study further tested the efficacy of tDCS in
individuals with current depression, administering stimulation
at 2 mA, for 20 min in 15 daily sessions, with a further 15 sessions
on an open-label basis (registered at www.clinicaltrials.gov:
NCT00763230). Acute and cumulative neuropsychological effects
were also assessed with a detailed battery of tests chosen to
specifically assess verbal memory and executive function.
Method
Participants
The study was approved by the human research ethics committee
of the University of New South Wales and was conducted at the
Black Dog Research Institute in Sydney. Recruitment began in
September 2008 and the final 1-month follow-up was conducted
in February 2011. The trial was closed after the intended sample
size was reached (including an additional two participants who
had already been screened as suitable and consented at the time
of the decision to close the study). The sample size was estimated
from the results of Fregni et al,
5
the only published study of tDCS
given in the 1–2 mA range in February 2007, and our pilot data in
nine participants. From changes in responses to the Hamilton
Rating Scale for Depression reported in Fregni et al
5
(60% mean
reduction in the active group, 10% mean reduction in the sham
group), assuming a baseline depression score of 20 (with a
standard deviation of 7.5), a sample size of 10 participants per
group (a total of 20 for the study) would have been required to
detect an effect of the same magnitude with 80% power and
a = 0.05. Our pilot data from the first nine participants of the
study described in Loo et al
7
showed a 4.5-point difference in
52
Transcranial direct current stimulation
for depression: 3-week, randomised,
sham-controlled trial
{
Colleen K. Loo, Angelo Alonzo, Donel Martin, Philip B. Mitchell, Veronica Galvez
and Perminder Sac hdev
Background
Preliminary evidence suggests transcranial direct current
stimulation (tDCS) has antidepressant efficacy.
Aims
To further investigate the efficacy of tDCS in a double-blind,
sham-controlled trial (registered at www.clinicaltrials.gov:
NCT00763230).
Method
Sixty-four participants with current depression received
active or sham anodal tDCS to the left prefrontal cortex
(2 mA, 15 sessions over 3 weeks), followed by a 3-week
open-label active treatment phase. Mood and
neuropsychological effects were assessed.
Results
There was significantly greater improvement in mood after
active than after sham treatment (P50.05), although no
difference in responder rates (13% in both groups). Attention
and working memory improved after a single session of
active but not sham tDCS (P50.05). There was no decline in
neuropsychological functioning after 3–6 weeks of active
stimulation. One participant with bipolar disorder became
hypomanic after active tDCS.
Conclusions
Findings confirm earlier reports of the antidepressant efficacy
and safety of tDCS. Vigilance for mood switching is advised
when administering tDCS to individuals with bipolar
disorder.
Declaration of interest
None.
The British Journal of Psychiatry (2012)
200, 52–59. doi: 10.1192/bjp.bp.111.097634
{
See pp. 10–11, this issue.
depression scores between active (n = 4) and sham (n = 5) tDCS
treatment over a 1.5-week sham-controlled study period, with
tDCS given at 1 mA for 20 min. As the present study involved
tDCS at 2 mA on consecutive weekdays, with sham and active
treatment compared over a 15-session, 3-week study period, we
estimated there would be at least a six-point difference between
active and sham groups in depression scores at the end of the
sham-controlled treatment phase. Using end of treatment mean
scores of 17.3 (active group) and 23.3 (sham group), and a
s.d. = 8.2, based on our pilot data, the power analysis indicated
that 31 participants per group (total sample 62) would be required
to detect this effect with 80% power and a = 0.05.
Sixty-four participants with a DSM-IV
8
major depressive
episode and with a score of 520 on the Montgomery–A
˚
sberg
Depression Rating Scale (MADRS)
9
gave informed written
consent and were enrolled as out-patients. Diagnosis was based
on a structured assessment using the Mini-International Neuro-
psychiatric Interv iew (MINI)
10
and confirmed in a clinical
interview by a study psychiatrist (C.K.L.). Exclusion criteria were
other Axis I disorders, alcohol misuse, drug dependence or
misuse, neurological disorders, electronic or metal implants,
history of heart disease, neurological disorders, failure to respond
to electroconvulsive therapy in the current depressive episode,
pregnancy and concurrent treatment with medications that have
been shown to alter effects of tDCS (benzodiazepines, anti-
convulsants, dextromethorphan and pseudoephedrine).
11,12
Treat-
ment resistance was assessed for the current episode of depression
as the number of failed adequate courses of antidepressant
medications, and also according to the Maudsley Staging system.
13
During the study, participants were either medication free or
remained on antidepressant medications (to which they had failed
to respond after an adequate treatment trial). For clinical and
ethical reasons, participants were not required to withdraw from
these medications if they or their treating clinicians had concerns
about possible deterioration as a consequence of medication
withdrawal. Any concurrent antidepressant medications were
continued at stable doses, which had not been altered for at least
4 weeks prior to study entry.
Study design
Participants were stratified by gender and age and randomly
assigned by a computer-generated random sequence to active
(n = 33) or sham (n = 31) treatment over a 3-week masked
treatment phase. After being screened and signing consent,
participants were enrolled and allocated to treatment groups by
research staff who were not involved in mood ratings. The
treatment assignment was indicated by a code on study treatment
sheets, which were concealed from raters. Active or sham tDCS
was administered every weekday (15 treatments in total), with
participants and raters masked to group allocation. All
participants were then offered an additional 3 weeks of open-label
active tDCS, also administered every weekday. Participants who
met the criterion for response (50% improvement in MADRS
score from baseline) were eligible to receive further sessions of
tDCS on a weekly basis, over the 1-month follow-up period. After
both the sham-controlled and open-label phases, participants were
asked to guess their group allocation in the sham-controlled phase
to assess integrity of the masking. Participants and raters were
unmasked after the 6-week trial duration or at trial exit for
participants who withdrew before trial completion.
Treatment with tDCS
The tDCS was administered by an Eldith DC-stimulator
(NeuroConn GmbH, Germany) with the anode over the left
dorsolateral prefrontal cortex, identified as pF3 on the inter-
national 10/20 EEG (electroencephalogram) system, and the
cathode placed over the lateral aspect of the contralateral orbit,
at the F8 position (10/20 system). Conductive rubber electrodes
(765 = 35 cm
2
) covered by sponges soaked in saline were used
and held in place by a band. Stimulation was given at 2 mA for
20 min, with a gradual ramp up and ramp down of the current
over 30 s. For sham stimulation, a 1 mA current was applied for
30 s giving an initial sensation of tDCS while minimising
stimulatory effects. Ramp up and ramp down was over 10 s. The
safety procedure utilised during stimulation was as previously
described in Loo et al.
14
Assessment of mood and cognition
The primary outcome measure for mood evaluation was the
MADRS. Participants were evaluated at baseline, after sessions 8,
15, 23 and 30, and at 1 week and 1 month after trial completion.
Each participant was rated by the same psychiatrist or
psychologist throughout the study using the MADRS, Inventory
of Depressive Symptomatology (IDS)
15
and Clinical Global
Impression Severity of Illness (CGI-S)
16
scale. The clinician-rated
Quick Inventory of Depressive Symptomatology (QIDS-C)
17
score
was also calculated as a subset of scores derived from the IDS.
At the same time points, participants rated their mood using
the self-rated version of the QIDS (QIDS-SR).
17
At baseline,
participants were also rated using the CORE Measure of Psycho-
motor Disturbance (CORE)
18
as a possible predictor of response.
Neuropsychological functioning was assessed at baseline, and
after the sham-controlled (post-session 15) and open-label
(post-session 30) phases using the following tests: Rey Auditory
Verbal Learning Test (RAVLT),
19
Digit Span Forwards and
Backwards,
20
Stroop Test,
21
Controlled Oral Word Association
Test (COWAT)
22
and Letter–Number Sequencing.
23
Immediate
effects of tDCS on processing speed were also assessed at treatment
sessions 1 and 15 (tested immediately before and after
stimulation) using the Symbol Digit Modalities Test (SDMT),
24
and simple and choice reaction-time tests. Alternative test versions
were used on different testing occasions for the RAVLT, COWAT
and SDMT.
Statistical analysis
The two treatment groups were analysed for differences in
demographic and clinical variables at baseline using w
2
-tests for
categorical variables and t- tests for continuous variables (Table
1). Statistical tests were two-tailed. Intention-to-treat last-
observation-carried-forward scores were used for the analyses
below. Only those participants with at least one post-baseline
rating were included in the analyses.
To test the effect of condition on mood over the course of
treatment, for each depression rating, a 2 6 2 mixed between–
within ANCOVA covarying for baseline CORE scores was
conducted with the between-groups factor being condition (active
v. sham tDCS) and the within-participants factor being time
(baseline and post-session 15). Analyses tested for main effects
of condition and time as well as the condition 6 time interaction.
Baseline CORE ratings were correlated (Pearson’s correlation)
with the percentage change in MADRS scores over the 15 active
treatment sessions (i.e. sessions 1–15 for active group, 16–30 for
sham group) to examine whether CORE scores predicted
response.
The number needed to treat (NNT) to obtain one responder
to active treatment was calculated for active v. sham tDCS over
the 3-week sham-controlled period. In a further exploratory
53
Transcranial direct current stimulation in depression
Loo et al
analysis, the NNT to obtain a responder was also calculated for 6
weeks of active tDCS (i.e. tDCS received in the active group over
the sham-controlled and open-label phases) v. 3 weeks of sham
tDCS.
Scores from neuropsychological tests examining changes over
the first 15 sessions (active or sham), and scores from tests
administered immediately before and after sessions 1 and 15
(active or sham) were also analysed with a mixed between–within
ANOVA testing for main effects of condition and time as well as
condition 6 time interactions. In addition, neuropsychological
tests scores were separately analysed for participants who received
30 active treatments (i.e. active group), examining for a main
effect of time across the 30 sessions using a repeated measures
ANCOVA controlling for the percentage change in MADRS scores
over the same period.
To test the integrity of masking, a w
2
-test was used to test for
an association between participants’ group allocation in the sham-
controlled phase and whether they guessed their treatment was
‘active or ‘sham’.
Results
Participants
The only significant difference between the active and sham
groups at baseline was higher CORE scores for the active group
(Table 1). In total, 58 participants completed the 15-session
sham-controlled phase with 52 participants going on to complete
the open-label phase (Fig. 1). In total 13/31 participants (active
group) and 10/29 participants (group initially assigned to sham
treatment) received further sessions of tDCS (given weekly)
during the 1-month follow-up period.
Mood outcomes
There were significant main effects of time over the sham-
controlled phase for all mood outcome measures indicating that
scores were significantly lower at the end of the sham-controlled
phase compared with baseline (Table 2). The only main effect of
group was found in the QIDS-SR with higher scores for the sham
group.
A significant interaction between group and time was found in
MADRS scores (the primary outcome measure), with simple
effects indicating that there was a greater decrease in scores from
baseline to the end of the sham-controlled phase in the active
group (Fig. 2) (effect size: 0.49). However, the same interaction
only trended towards significance in QIDS-C scores and did not
reach significance in the remaining mood outcome measures.
Over the sham-controlled phase, four participants in both the
active and sham groups met the criterion for response. No
participants in either group met the criterion for remission
(MADRS score 510). By the end of the additional open-label
phase, 15 participants in the active group and 12 participants in
the sham group met the criterion for response. At 1-week
follow-up the proportion of responders was 16/26 (active group)
and 6/26 (sham group). At 1-month follow-up there were 13/20
(active group) and 7/23 (sham group) responders. The NNT was
16.7 for the 3-week active–sham comparison. The NNT for 6
weeks’ active tDCS compared w ith 3 weeks’ sham stimulation
was 2.6. There was no significant correlation between CORE
scores and percentage change in MADRS scores over the 3-week
active treatment period.
Neuropsychological functioning
sham
v.
active tDCS
Over the sham-controlled phase, a significant main effect of time
was found for Stroop Interference, indicating that participants
were quicker in performing the task at the end of the sham-
controlled phase compared with baseline. However, there was no
interaction between group and time (Table 3).
Analyses of participants’ performance in the SDMT
immediately before and after the first (tDCS 1) and final (tDCS
15) sessions in the sham-controlled phase, showed a significant
effect of time only at the first tDCS session. In addition, there
was a significant interaction between time and group with simple
effects revealing that there was no difference between pre- and
54
Table 1 Comparison of demographic and clinical variables at study entry for sham and active g roups
Sham Active Test statistic
n Mean s.d. n Mean s.d. d.f. F w
2
P
Categorical variables
Gender, male/female 15/14
a
17/14
a
1 0.06 0.81
Melancholic/non-melancholic 15/14
a
16/15
a
1 0.00 0.99
Concurrent antidepressant medication, yes/no 21/8
a
22/9
a
1 0.02 0.90
Bipolar diagnosis, yes/no 4/25
a
4/27
a
1 0.01 0.92
Edinburgh Handedness Inventory, right/left 25/4
a
28/2
a
1 0.82 0.37
Continuous variables
Age, years 48.6 12.6 47.8 12.5 1,58 0.23 0.82
Age at onset, year 28.2 12.5 28.3 12.6 1,58 0.25 0.98
Duration of current episode, months 55.6 65 33.8 56.2 1,58 1.39 0.17
Duration of all previous episodes, months 82.3 93.2 54.9 65.5 1,58 1.33 0.19
Antidepressants failed current episode, n: mean 1.79 2.14 1.71 1.62 1,58 0.17 0.87
Total lifetime failed antidepressants, n: mean 2.79 3.36 3.13 2.63 1,58 0.43 0.67
Maudsley Staging parameters 6.93 2.51 6.65 2.11 1,58 0.48 0.63
Baseline MADRS score 29.5 4.96 30.4 6.02 1,58 0.63 0.53
Baseline IDS score 35.7 7.37 36.6 9.63 1,57 0.41 0.69
Baseline QIDS-C score 14.9 2.48 15.3 3.50 1,58 0.59 0.56
Baseline CGI score 4.28 0.53 4.45 0.62 1,58 1.17 0.25
Baseline CORE score 3.71 2.61 6.40 5.51 1,42 2.40 0.02
Baseline QIDS-SR score 16.0 3.26 14.6 4.69 1,57 1.36 0.18
MADRS, Montgomery–A
˚
sberg Depression Rating Scale; IDS, Inventory of Depressive Symptomatology; QIDS-C, Quick Inventory of Depressive Symptomatology (Clinician-rated);
CGI, Clinician Global Impression; CORE, CORE Measure of Psychomotor Disturbance; QIDS-SR, Quick Inventory of Depressive Symptomatology (Self-Report).
a. Actual tally recorded.
Transcranial direct current stimulation in depression
55
Table 2 Moo d ratings over sham-controlled period ( first 15 treatmen t sessions): sham
v.
active
a
Baseline Post-session 15 Test statistics
Sham (n = 31) Active (n = 33) Sham (n = 29) Active (n = 31) Sham v. active Time effects Time6group interaction
Scale Mean SEM Mean SEM Mean SEM Mean SEM d.f. FPFPFP
MADRS 29.7 1.03 29.9 1.00 24.9 1.41 20.6 1.36 55 2.09 0.15 25.00 50.01 4.68 0.04
IDS 36.4 1.61 35.6 1.58 29.8 1.68 25.2 1.65 54 1.83 0.18 18.60 50.01 2.23 0.14
QIDS-C 15.1 0.58 15.0 0.57 12.7 0.73 10.7 0.71 55 2.56 0.12 13.00 50.01 2.77 0.10
CGI 4.34 0.10 4.35 0.10 3.93 0.14 3.70 0.14 55 0.52 0.48 8.77 0.01 1.27 0.27
QIDS-SR 16.2 0.79 14.0 0.79 12.5 0.89 10.3 0.89 53 4.23 50.05 16.00 50.01 50.01 0.98
SEM, standard error of the mean; MADRS, Montgomery–A
˚
sberg Depression Rating Scale; IDS, Inventory of Depressive Symptomatology; QIDS-C, Quick Inventory of Depressive Symptomatology (Clinician-rated); CGI, Clinician Global Impression; QIDS-SR, Quick
Inventory of Depressive Symptomatology (Self-Report).
a. All analyses control for baseline CORE Measure of Psychomotor Disturbance score.
Allocated to sham (
n
=31)
Received intervention
as assigned (
n
=31)
Lost to follow-up (
n
=5)
Discontinued in masked phase
(
n
=3)
Too busy
Headache after first session
Personal reasons
Discontinued in open phase
(
n
=2)
Surgery
Became hypomanic
Analysed at end masked phase
(
n
= 29)
Excluded from analysis (
n
=2)
Did not have a rating
after baseline
Allocated to active (
n
=33)
Received intervention
as assigned (
n
=33)
Lost to follow-up (
n
=7)
Discontinued in masked phase
(
n
=3)
Too unwell
No improvement
Difficulty travelling
Discontinued in open phase
(
n
=4)
Too busy
Switched to a different trial
Difficulty travelling
Side-effects from mood
stabiliser and direct
current stimulation
Analysed at end masked phase
(
n
= 31)
Excluded from analysis (
n
=2)
Did not have a rating
after baseline
Excluded (
n
= 279)
Did not meet inclusion
criteria (
n
= 269)
Changed mind (
n
=10)
Assessed for eligibility
(
n
= 343)
Randomised
(
n
=64)
Fig. 1 Consort diagram showing progress of participants
through the trial.
.........
......
.......
....
0
<
<
0
<
0
<
0
<
0
<
0
<
0
35
30
25
20
15
10
5–
0–
Baseline 8 15 23 30
1-month
follow-up
1-week
follow-up
Number of treatment sessions completed
Montgomery A
˚
sberg Depression Rating Scale
Fig. 2 Mean Montgomery–A
˚
sberg Depression Rating Scale
scores for active and sham treatment groups over the masked
(first 15 sessions) and open-label (sessions 16–30) study phases,
and at follow-up, with standard error bars.
Loo et al
56
Table 3 Cognitiv e test result s over 15-s ession masked period: sh am
v
.active
a
Baseline Post-session 15 Test statistics
Sham Active Sham Active Sham v. active Time effects Time6group interaction
Measure Mean SEM Mean SEM Mean SEM Mean SEM d.f. FPFP F P
RAVLT
Total 52.4 2.15 56.5 2.33 52.4 2.33 56.0 2.25 54 1.53 0.22 0.00 0.96 0.08 0.78
Delay 10.6 0.66 11.8 0.64 10.1 0.63 11.9 0.61 54 2.82 0.10 0.58 0.45 0.88 0.35
Digit Span
Forwards 10.6 0.54 10.3 0.52 11.1 0.48 10.4 0.46 54 0.52 0.48 1.16 0.29 0.67 0.42
Backwards 6.89 0.51 7.43 0.49 7.20 0.58 7.35 0.55 54 0.22 0.64 0.01 0.92 0.47 0.50
Letter–Number Sequencing 11.8 0.58 10.6 0.55 12.3 0.63 11.4 0.60 54 1.78 0.19 0.00 0.93 0.23 0.63
COWAT, letter: total 42.1 2.42 40.2 2.28 45.6 2.53 40.0 2.39 51 1.25 0.27 3.00 0.09 2.49 0.12
Stroop, interference: s 26.6 2.56 30.6 2.51 22.7 1.89 24.4 1.85 49 0.87 0.36 5.24 0.03 0.80 0.73
SEM, standard error of the mean; RAVLT, Rey Auditory Verbal Learning Task; COWAT, Controlled Oral Word Association Test.
a. All analyses control for baseline CORE Measure of Psychomotor Disturbance score and percentage change in Montgomery–A
˚
sberg Depression Rating Scale score over the sham-controlled period.
Table 4 Cognitive tests results immediately before and after direct current stimulation sessions 1 and 15: sham
vs.
active
a
Pre-direct current stimulation Post-direct current stimulation Test statistics
Sham Active Sham Active Sham v. active Time effects Time6group interaction
Mean SEM Mean SEM Mean SEM Mean SEM d.f. FPFP F P
Session 1
Symbol Digit Modalities Test 50.4 2.03 46.5 1.99 50.1 1.80 50.7 1.77 54 0.37 0.54 10.1 50.01 10.0 50.01
Simple reaction time, ms 289 22.0 307 21.0 294 21.0 327 20.0 53 0.88 0.35 3.31 0.08 0.39 0.53
Choice reaction time, ms 670 26.0 643 25.0 644 23.0 641 22.0 51 0.22 0.64 0.32 0.58 0.62 0.43
Session 15
Symbol Digit Modalities Test 52.3 2.53 51.4 2.39 53.7 2.23 53.3 2.11 54 0.04 0.84 2.90 0.09 0.08 0.79
Simple reaction time, ms 288 11.0 281 10.0 305 16.0 302 15.0 54 0.11 0.75 0.08 0.79 0.04 0.84
Choice reaction time, ms 659 27.0 648 26.0 648 24.0 633 24.0 51 0.14 0.71 0.47 0.50 0.06 0.81
SEM, standard error of the mean.
a. All analyses control for baseline CORE Measure of Psychomotor Disturbance score.
Transcranial direct current stimulation in depression
post-tDCS scores for the sham group, whereas scores in the active
group significantly improved following tDCS (Table 4).
Effects of 6 weeks of active tDCS on
neuropsychological test performance
In the active group (the only group to receive 6 weeks of
active tDCS), there was a trend for main effect of time on the
Letter–Number Sequencing Task, suggesting higher scores at 6
weeks compared with baseline (F = 3.46, d.f. = 28, P = 0.07). No
significant differences over time were found within the other
measures: RAVLT total (F = 0.12, d.f. = 28, P = 0.73), RAVLT delay
(F = 0.41, d.f. = 28, P = 0.53), Digit Span Forwards (F = 1.02,
d.f. = 28, P = 0.32), Digit Span Backwards (F = 0.01, d.f. = 28,
P = 0.93), Stroop Interference (F = 0.24, d.f. = 26, P = 0.63) and
COWAT (F = 1.72, d.f. = 27, P = 0.2).
Adverse outcomes and side-effects
During the sham-controlled phase, side-effects occurring during
active treatment were skin redness (objectively observed) at the
anode and/or cathode site (n = 30), tingling at anode and/or
cathode site (n = 26), itching at anode and/or cathode site
(n = 23), burning/heating sensation at anode and/or cathode site
(n = 14), headache (n = 12), dizziness/light-headedness (n = 10),
fatigue (n = 7), nausea (n = 3), blurred vision (n = 3), pain at
anode and/or cathode site (n = 2), pulsing sensation at anode
and/or cathode site (n = 2), neck soreness (n = 1), visual effects
when eyes closed (n = 1), seeing dots in the periphery (n = 1),
giddiness (n = 1), flaky skin (n = 1), watery eyes (n = 1), a feeling
of being ‘spaced out’ (n = 1) and shakiness (n = 1). In addition,
one participant experienced transient hypomania in the open
phase and was subsequently withdrawn from the trial. Side-effects
occurring during sham treatment were skin redness at anode and/
or cathode site (n = 29), tingling at anode and/or cathode site
(n = 27), itchiness at anode and/or cathode site (n = 22), headache
(n = 10), burning/heating sensation at anode and/or cathode site
(n = 7), dizziness/light-headedness (n = 6), fatigue (n = 4), pulsing
sensation at anode and/or cathode site (n = 2), right ear ache
(n = 1), ringing in ears (n = 1), nausea (n = 1), twitching of right
arm (n = 1), stiffness in neck and shoulders (n = 1), tingling on
neck (n = 1), tingling on tongue (n = 1), a ‘funny feeling’ in head
(n = 1), facial numbness (n = 1) and reflux (n = 1). All side-effects
were transient and mostly ranged from mild to moderate in
intensity.
Integrity of masking
When asked to guess their treatment assignment, correct
responses were made by 14/24 participants in the active group
and 16/25 participants in the sham group. The w
2
-test indicated
no significant difference between groups in the likelihood of
active/sham guesses (w
2
= 2.45, d.f. = 1, P = 0.12).
Discussion
Efficacy
This study reports the largest sample of individuals with current
depression treated hitherto in a randomised controlled trial of
tDCS. It used treatment parameters that exceeded those of
previous trials, in an attempt to optimise efficacy. Overall, this
study confirmed previous reports of significant antidepressant
effects with tDCS, with the active treatment group showing
significantly greater improvement compared with the sham group
over the 3-week study period on the primary outcome measure
(change in MADRS). However, results over the 3 weeks were
clinically modest, with only a 28% decline in MADRS scores after
active stimulation, a small proportion of responders (which did
not differ between active and sham treatment groups) and
active–sham differences failing to reach significance on the other
mood rating scales. The antidepressant effects measured in this
study did not appear as robust as those previously reported in
the sham-controlled trials of Fregni et al
5
(60% improvement after
5 sessions/1.5 weeks) and Boggio et al
6
(43% improvement after
10 sessions, 2 weeks), despite the use of tDCS at higher stimulus
intensities, over a longer treatment period and with more
stimulation sessions. These results in the active treatment group
are comparable though, to those reported in our earlier trial of
tDCS (37% improvement after 10 sessions/3.5 weeks)
7
and a
recent open-label trial of tDCS (18% improvement in unipolar
depression after 10 sessions/1 week).
25
The studies above did not differ obviously in sample
characteristics but did differ in permitting concurrent anti-
depressant medication during tDCS. In the two trials with greater
response, participants were free of medications prior to and
during the trial (clarified in a personal communication from
F. Fregni, March 2011),
5,6
whereas in others
7,25
and in this study,
participants continued on antidepressant medication. Although
participants in these latter trials were still significantly depressed
at the time of commencing tDCS, the potential for further
improvement with a physical treatment may have been limited
compared w ith individuals not already receiving some treatment.
A meta-analysis of trials of transcranial magnetic stimulation
(TMS), another non-convulsive stimulatory treatment for
depression, found greater efficacy when TMS was given as a
monotherapy than when it was added to pre-existing
pharmacotherapy.
26
The trials above also differed in stimulus intensity and session
frequency. Recent trials (Boggio et al,
6
this trial, Brunoni et al
25
)
increased both stimulus intensity (2 mA) and session frequency
(daily or twice daily) in an attempt to optimise outcomes,
however, results are not clearly superior to trials that used 1 mA
and second daily treatments.
5,7
Although the duration of
stimulation has been shown to affect the duration of after effects,
27
the influence of stimulus intensity and session frequency on
efficacy are as yet unknown. In a recent study of tDCS to the
motor cortex, we found that daily stimulation sessions led to
greater cumulative changes in cortical excitability than second
daily stimulation, over a given stimulation period (1 week), when
all other parameters were kept constant.
28
In a similar experiment,
we did not find any difference in outcomes (cortical excitability)
between gradual increase of stimulus intensity from 1 mA to
2 mA over five sessions conducted on consecutive weekdays, and
maintaining stimulation intensity at 2 mA for all five session
(details available from the authors on request). The effects of these
variations in stimulus parameters on cortical effects warrant
further systematic study.
Although results after 3 weeks of daily tDCS were modest, the
number of responders after 6 weeks of treatment was much more
encouraging, and comparable w ith outcomes from a recent large
study of 6 weeks of TMS given on an open-label basis to
participants with pharmacotherapy-resistant depression (42.4%
responders).
29
The response rate was superior to that reported
for antidepressant medication in individuals who had failed a first
course of medication in the large Sequenced Treatment
Alternatives to Relieve Depression (STAR*D) study (28.5%).
30
This suggests that tDCS has meaningful antidepressant efficacy,
including in those individuals resistant to pharmacotherapy.
Comparison of MADRS outcomes and response rates between
participants who received 3 and 6 weeks of active treatment
57
Loo et al
suggest that further and more lasting benefit may be derived from
extension of the treatment period to 6 weeks. Whether this is
related to the number of treatments received (i.e. 30 v. 15) or
the overall duration of the treatment course (6 weeks rather than
3 weeks) cannot be determined from this study. Interpretation of
these outcomes is limited by the fact that treatment in the second
3 weeks of the study was administered under open-label
conditions.
Cognitive effects
Tests for acute cognitive effects following the first tDCS session
showed improvement on the SDMT in the active tDCS group
relative to the sham group. This finding suggests that tDCS may
enhance acute attention and working memory in people w ith
depression, in line with the acute attention-enhancing effects found
following equivalent stimulation in individuals post-stroke.
31
Consistent with our previous study,
7
neuropsychological tests
after 3 weeks (15 sessions) of active tDCS did not show any
changes in performance across multiple cognitive domains. These
results demonstrate that multiple tDCS sessions are safe and not
associated with any adverse cognitive outcomes. Previously, Fregni
et al
32
showed that five daily tDCS sessions enhanced performance
on the Digit Span Forwards and Backwards test, a finding we
failed to replicate in a larger sample.
7
Similarly, in the current
study no improvement was found on these same measures after
either 15 or 30 active tDCS sessions. This suggests that multiple
tDCS sessions do not have cumulative cognitive enhancing effects
independent of mood effects. Nonetheless, the use of more
sensitive neurocognitive measures may help elucidate potential
cognitive-enhancing effects of multiple tDCS treatments in future
studies.
Limitations and strengths
A limitation of this study is that most participants were on
antidepressant medications concurrently with tDCS. This was
allowed in the study design for several reasons: ethical and
scientific concerns that withdrawal of medications may have
caused clinical deterioration prior to study entry; no evidence
for safety issues with concurrent use of antidepressants and tDCS;
and also because the continuation of medication while tDCS is
introduced is likely to be the approach used if tDCS is eventually
undertaken in clinical practice. Nevertheless, it means that the
effects of tDCS could not be assessed independently of the
presence of medications, which would be scientifically preferable.
It is unlikely that the continuation of medications would have
enhanced antidepressant effects, as these were medications to
which participants had already failed to respond, and doses were
stable for at least 4 weeks prior to study entry and during the
study. On the contrary, this factor may have limited the scope
of further antidepressant effects with tDCS, as discussed above.
Strengths of the study include the relatively large sample size,
extension of tDCS stimulation to 30 sessions over 6 weeks, careful
methodology with good participant adherence to the study
protocol and detailed neuropsychological testing.
Implications
In conclusion, this trial studied tDCS at stimulation parameters
beyond those previously used in depression and confirmed earlier
reports of the antidepressant efficacy and safety of tDCS. The
evidence to date suggests that tDCS is a potentially useful treatment
for depression, and that treatment should be given for longer than
3 weeks for an adequate response.
Funding
This study was supported by an Australian National Health and Medical Research (NHMRC)
council research grant number 510142.
Acknowledgements
The authors thank Dusan Hadzi-Pavlovic for advice on statistical analysis, Michael Player,
Jessica Cheung, Dr Aparna Menon, Vincent Chan, Joshua Garfield and Manasi Kogekar
for assistance with data collection and processing, Professsor Walter Paulus and Dr
Michael Nitsche for advice on tDCS, and Natalie Katalinic for assistance with manuscript
preparation.
Colleen K. Loo, MB BS, MD, FRANZCP, School of Psychiatry, University of New South
Wales, Sydney, St George Hospital, South Eastern Sydney Illawarra Health and Black
Dog Institute, Sydney, Australia; Angelo Alonzo, BA, BSc (Hons), PhD, Donel
Martin, MClinNeuroPsych, PhD, Philip B. Mitchell, AM, MB BS, MD, FRCPsych,
FRANZCP, School of Psychiatry, University of New South Wales and Black Dog
Institute, Sydney, Australia; Veronica Galvez, MD, School of Psychiatry, University of
New South Wales, Sydney, Black Dog Institute, Sydney, and Mood Disorders Clinical
and Research Unit, Psychiatry Department, Bellvitge University Hospital &
Neuroscience Group, IDIBELL (Bellvitge Biomedical Research Institute) L’Hospitalet de
Llobregat, Barcelona, Spain; Perminder Sachdev, MB BS, MD, PhD, FRANZCP,
School of Psychiatry, University of New South Wales and Neuropsychiatric Institute,
Prince of Wales Hospital, Randwick, Sydney, Australia
Correspondence: Col leen Loo, Lev el 2, James Law s House, St George Hospital ,
Kogarah, NSW 2217, Australia. Email: colleen.loo@unsw.ed u.au
First received 6 Jun 2011, final revision 9 Oct 2011, accepted 26 Oct 2011
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59
The butterfly
Shabbir Amanullah
As adults, we consider ourselves capable of interpreting, at least to some extent, the behaviour of children. Many a text has
been written about childhood behaviour and its interpretation. We use strategies to reinforce or root out certain behaviours.
However, we often fail to grasp the immense strength of a child’s imagination. On Canada Day we were at a park, waiting
for the fireworks display to begin at sundown. It was a warm day and children were running around the place. There was
the usual popcorn, fizzy drinks, ice cream, lobster (exclusive to Prince Edward Island), balloons and, of course , face
painting. While sitting beside a fence with a few friends, we saw a child coming towards us. She was beaming and seemed
extremely content. She had a butterfly painted on her face. It was in three different colours and covered her face entirely.
Thinking that she had come to show us all that she ‘acquired’ at the fair so far, we commented on the different things she
had with her. In a typically childish way, she explained how she got them. Then, as she was about to leave, I said, ‘You have
a pretty butterfly painted on your face’. She looked at me in stunned silence and then replied in a huff ‘I
am
the butterfly!’
We fail to comprehend the extent, depth and importance of the child’s imagination by assuming we ‘know’.
The British Journal of Psychiatry (2012)
200, 59. doi: 10.1192/bjp.bp.111.099622
extra
    • "prefrontal dysfunctions are associated with a variety of neurological and psychiatric diseases, prefrontal tDCS holds promise as a means of improving impaired brain function in neurological (for review see Flöel, 2014) and psychiatric diseases (Fregni and Pascual-Leone, 2007; Iyer et al., 2005; Kuo et al., 2014). Clinical applications of prefrontal tDCS have been investigated in patients with disorders of consciousness (Thibaut et al., 2014), chronic pain (Arul-Anandam et al., 2009; Valle et al., 2009), Parkinson's disease ( Fregni et al., 2006d), major depression (MD) (Boggio et al., 2008; Brunoni et al., 2013; Dell'Osso et al., 2012; Ferrucci et al., 2009; Kalu et al., 2012; Loo et al., 2012; Loo et al., 2010; Martin et al., 2013 Martin et al., , 2011 Palm et al., 2012; Rigonatti et al., 2008 ), schizophrenia (Barr et al., 2012; Bose et al., 2014; Brunelin et al., 2012; Fitzgerald et al., 2014; Nawani et al., 2014; Vercammen et al., 2011), craving (Boggio et al., 2009Boggio et al., , 2008 Conti and Nakamura-Palacios, 2014; da Silva et al., 2013; Nakamura-Palacios et al., 2012 ), attention deficit hyperactivity disorder (ADHD) (Prehn-Kristensen et al., 2014) and tinnitus (Frank et al., 2012;). Anatomically targeted analyses of NIBS methods, including tDCS, in neuropsychiatric diseases have generated promising results (Fox et al., 2014; Fox et al., 2012). "
    [Show abstract] [Hide abstract] ABSTRACT: Transcranial current stimulation approaches include neurophysiologically distinct non-invasive brain stimulation techniques widely applied in basic, translational and clinical research: transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS) and transcranial random noise stimulation (tRNS). Prefrontal tDCS seems to be an especially promising tool for clinical practice. In order to effectively modulate relevant neural circuits, systematic research on prefrontal tDCS is needed that uses neuroimaging and neurophysiology measures to specifically target and adjust this method to physiological requirements. This review therefore analyses the various neuroimaging methods used in combination with prefrontal tDCS in healthy and psychiatric populations. First, we provide a systematic overview on applications, computational models and studies combining neuroimaging or neurophysiological measures with tDCS. Second, we categorise these studies in terms of their experimental designs and show that many studies do not vary the experimental conditions to the extent required to demonstrate specific relations between tDCS and its behavioural or neurophysiological effects. Finally, to support best-practice tDCS research we provide a methodological framework for orientation among experimental designs.
    Full-text · Article · Aug 2016
    • "In addition to evidence that non-invasive neuromodulation alters immediate cognitive function (Wassermann and Grafman, 2005; Jacobson et al., 2012) some findings have suggested that LTD and LTP may be extended over several weeks (Reis et al., 2009). With the ability to induce long term changes in neural function, researchers have explored clinical applications, such as treatment of epilepsy (Fregni et al., 2006), stroke rehabilitation (Boggio et al., 2007), treatment of depression (Loo et al., 2012), and the specific topic of this special issue, pain management (Castillo-Saavedra et al., 2016). Despite these advances, TES as a technology can still be regarded as being in its early stages, with many issues to still be resolved (Horvath et al., 2014). "
    [Show abstract] [Hide abstract] ABSTRACT: In pain management as well as other clinical applications of neuromodulation, it is important to consider the timing parameters influencing activity-dependent plasticity, including pulsed versus sustained currents, as well as the spatial action of electrical currents as they polarize the complex convolutions of the cortical mantle. These factors are of course related; studying temporal factors is not possible when the spatial resolution of current delivery to the cortex is so uncertain to make it unclear whether excitability is increased or decreased with anodal versus cathodal current flow. In the present study we attempted to improve the targeting of specific cortical locations by applying current through flexible source-sink configurations of 256 electrodes in a geodesic array. We constructed a precision electric head model for 12 healthy individuals. Extraction of the individual’s cortical surface allowed computation of the component of the induced current that is normal to the target cortical surface. In an effort to replicate the long-term depression (LTD) induced with pulsed protocols in invasive animal research and transcranial magnetic stimulation studies, we applied 100 ms pulses at 1.9 sec intervals either in cortical-surface-anodal or cortical-surface-cathodal directions, with a placebo (sham) control. The results showed significant LTD of the motor evoked potential as a result of the cortical-surface-cathodal pulses in contrast to the placebo control, with a smaller but similar LTD effect for anodal pulses. The cathodal LTD after-effect was sustained over 90 minutes following treatment. These results support the feasibility of pulsed protocols with low total charge density in noninvasive neuromodulation when the precision of targeting is improved with a dense electrode array and accurate head modeling.
    Full-text · Article · Jul 2016
    • "A variety of factors influence the likelihood of developing TEM, including the potency of the agent being used and the individual characteristics of the patient. There are four stand-alone case reports in literature [161][162][163][164]and some reports in randomized clinical trials (1 case in Ref. [165] and 6 cases in Ref. [166] , of which 5 patients were given tDCS combined with sertraline) of mania or hypomania induction after tDCS treatment. It is important to note that some of these patients were not known to have bipolar disorder. "
    [Show abstract] [Hide abstract] ABSTRACT: This review updates and consolidates evidence on the safety of transcranial Direct Current Stimulation (tDCS). Safety is here operationally defined by, and limited to, the absence of evidence for a Serious Adverse Effect, the criteria for which are rigorously defined. This review adopts an evidence-based approach, based on an aggregation of experience from human trials, taking care not to confuse speculation on potential hazards or lack of data to refute such speculation with evidence for risk. Safety data from animal tests for tissue damage are reviewed with systematic consideration of translation to humans. Arbitrary safety considerations are avoided. Computational models are used to relate dose to brain exposure in humans and animals. We review relevant dose-response curves and dose metrics (e.g. current, duration, current density, charge, charge density) for meaningful safety standards. Special consideration is given to theoretically vulnerable populations including children and the elderly, subjects with mood disorders, epilepsy, stroke, implants, and home users. Evidence from relevant animal models indicates that brain injury by Direct Current Stimulation (DCS) occurs at predicted brain current densities (6.3-13 A/m(2)) that are over an order of magnitude above those produced by conventional tDCS. To date, the use of conventional tDCS protocols in human trials (≤40 min, ≤4 milliamperes, ≤7.2 Coulombs) has not produced any reports of a Serious Adverse Effect or irreversible injury across over 33,200 sessions and 1000 subjects with repeated sessions. This includes a wide variety of subjects, including persons from potentially vulnerable populations.
    Full-text · Article · Jun 2016
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